syntheses of heterocyclic compounds

G H H T E 3 bl rETEPOUHK]HqEGKHX

GOEHHHEHHR

•

SINTEZY GETEROTSIKLICHESKIKH

SOEDINENII

•

SYNTHESES OF HETEROCYCLIC COMPOUNDS

SYNTHESES OF

HETEROCYCLIC

COMPOUNDS Volumes 1 and 2

Edited by

A. L. MNDZHOIAN

TRANSLATED FROM RUSSIAN

by A. E. Stubbs, Ph.D., F. R.I. C.

SPRINGER SCIENCE+BUSINESS MEDIA, LLC

1959

EDITORIAL BOARD A. A. Aroian, V. G. Afrikian, N. A. Babiian,

o. L. Mndzhoian, G. T. Tatevosian

Originally published (1956/57) by the Armenian Academy of Sciences Press for the Institute {)f Fine Organic Chemistry of the Academy of Sciences of the Armenian SSR.

ISBN 978-1-4757-6660-8 ISBN 978-1-4757-6658-5 (eBook) DOI 10.1007/978-1-4757-6658-5

Library of Congress Catalog Card Number: 59-11346 Copyright 1959 by Springer Scienee+Business Media New York

Origina11y published by Consultants Bureau, Ine. in 1959 Softeover re print of the hardeover 1 st edition 1959

AU rights reserved. No part of this publieation may be reproduced in any form without written

permission from the publisher.

Volume 1

CONTENTS

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 5-Benzyl-2-Furoic Acid . . . . . . . . . . . . . . . . . . . . . . 7 5-(5-Benzyl-2-Furyl)-s-Triazole-3-Thiol . . . . . . . . . . 9 5-Bromo-2-Furoic Acid . . . . . . . . . . . . . . . . . . . . . . 11 2-Furanmethanediol Diacetate . . . . . . . . . . . . . . . . . . 13 5-(Diethylaminomethyl) Furfuryl Alcohol . . . . . . . . . . . 15 Methyl 5-Benzyl-2-Furoate . . . . . . . . . . . . . . . . . . . . 17 Methyl 5-(Bromomethyl)-2-Furoate . . . . . . . . . . . . . . 18 Methyl 5-(Butylthiomethyl)-2-Furoate . . . . . . . . . . . . . 20 Methyl 5-(Diethylaminomethyl)-2-Furoate . . . . . . . . . . 22 Methyl 5-Methyl-2-Furoate . . . . . . . . . . . . . . . . . . . . 23 Methyl 5-(Propoxymethyl)-2-Furoate . . . . . . . . . . . . . 25 Methyl 2-Furoate. . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Methyl 5-(Chloromethyl)-2-Furoate . . . . . . . . . . . . . . 29 2-Methylfuran (Sylvan) . . . . . . . . . . . . . . . . . . . . . . . 31 5-Methyl-2-Furoic Acid . . . . . . . . . . . . . . . . . . . . . . 33 a.- Propylfurfuryl Alcohol . . . . . . . . . . . . . . . . . . . . . 35 5-(Propoxymethyl)-2-Furoic Acid . . . . . . . . . . . . . . . 37 a.-Phenylfurfuryl Alcohol . . . . . . . . . . . . . . . . . . . . . 38 Furan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 2-Furoic Acid and Furfuryl Alcohol . . . . . . . . . . . . . . 43 5-(2-Furyl)-s-Triazole-3-Thiol. . . . . . . . . . . . . . . . . 47 1-(2-Furoyl)-s-Thiosemicarbazide . . . . . . . . . . . . . . . 49 2-Furaldehyde (Furfural) . . . . . . . . . . . . . . . . . . . . . 51 5-Benzyl-2-Furoyl Chloride . . . . . . . . . . . . . . . . . . . 54 5-Methyl-2-Furoyl Chloride . . . . . . . . . . . . . . . . . . . 55 2-Furoyl Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Furfuryl Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . 58 2-Chloroethyl 2-Furoate . . . . . . . . . . . . . . . . . . . . . . 61 2-Chloroethyl 5-(Chloromethyl)-2-Furoate. . . . . . . . . . 62 Ethyl (2-Furoyl) Acetate (Ethyli3-0xofuranpropionate) . . 64

Index to Vol. 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

PREFACE

The chemistry of heterocyclic compounds now forms one of the most extensive and important branches of organic chemistry. The rapid expansion of investigation in this field is due largely to the ever increasing practical importance of heterocyclic compounds. The present stage in the development of organic chemistry and closely allied branches of biology is characterized by extensive investigation of physiologically active substances encountered in the plant and animal world and playing important parts in the life processes of micro- and macro-organisms. This extensive investigation of alkaloids, vitamins, hormones, antibiotics and their synthetic substitutes, and also of substances that control the biochemical processes of the nervous system, has acted as a powerful stimulus to the further development of the chemistry of heterocyclic compounds. Moreover, there are many well known applications of heterocyclic compounds in the manufacture of dyes, synthetic resins, synthetic rubbers, and other important materials.

In response to growing demands, several monographs and treatises on the chemistry of heterocyclic compounds have appeared in recent years, the most comprehensive of these being the series "Heterocyclic Compounds," edited by R. C. Elderfield, which is already appearing in Russian translation. On the other hand, the lack of a practical guide to the laboratory preparation of heterocyclic compounds is being felt more and more.

The periodic publication of methods of synthesizing organic compounds has proved to be extremely valuable: "Organic Syntheses" in Russian translation and the series "Syntheses of Organic

Compounds," which is published by the N. D. Zelinskii Institute of Organic Chemistry of the USSR Academy of Sciences, have been widely acclaimed by chemists and are firmly established in the everyday work of teaching and research laboratories. They greatly facilitate the work of investigators by relieving them of the necessity of searching periodic literature for accessible methods of preparing known substances that are frequently required as starting materials for otganic synthesis. However, the space devoted to heterocyclic compounds in these collections is not very great and is not in keeping with the growing importance of these compounds.

With the object of filling this gap, the Institute of Fine Organic Chemistry of the Academy of Sciences of the Armenian SSR has undertaken the publication of a new series of collections of methods of synthesizing heterocyclic compounds. These will contain not only material based on the work of the Institute, but also methods developed and published by other authors and organizations. For the sake of completeness, methods for the preparation of the parent substances and key compounds in the various heterocyclic series will be included, although these are already to be found in other practical treatises.

Each set of directions will be checked and, if necessary, corrected at the Institute.

In recent years there has been greatly increased interest in furan derivatives, which have become extremely important to the national economy. Compounds· of this series have become accessible as raw material for the preparation of many aliphatic intermediates, the availability of which opens up new prospects in heavy organic synthesis. Also, furan derivatives are used in the preparation of many physiologically active substances employed in medicine and agriculture.

In view of the increasing importance of compounds of this series, we considered that the early volumes of this work should be devoted exclusively to the synthesis of furan derivatives.

4

The preparations given in Volume 1 are arranged in alphabetical order.* The directions are given in the form adopted in other, similar publications. In the compilation of "Other Methods of Preparation," literature published up to the end of 1954 has been reviewed.

The Editorial Board would welcome criticism and suggestions.

A. L. Mndzhoian

* The order of the original has been retained; the translated titles are not, of course, in alphabetical order. - Publisher.

5

CONTENTS

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5-(Aminomethyl)-2-Furoic Acid . . . . . . . . . . . . . . . . . 7 5-Benzylfurfuryl Acetate . . . . . . . . . . . . . . . . . . . . . 10 2-Furyl Methyl Ketone . . . . . . . . . . . . . . . . . . . . . . . 12 2-Benzylfuran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 1-(5-Benzyl-2-Furoyl)-3-Thiosemicarbazide . . . . . . . . 16 5-Benzylfurfuryl Alcohol . . . . . . . . . . . . . . . . . . . . . 18 5,5'-(Thiodimethylene) Di-2-Furoic Acid . . . . . . . . . . . 24 2,3-Dimethylfuran . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4,5-Dimethyl-2-Furoic Acid . . . . . . . . . . . . . . . . . . . 28 1,3-Difurfurylurea . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Diethyl (Tetrahydrofurfuryl) Malonate . . . . . . . . . . . . . 32 Diethyl Furfurylidenemalonate . . . . . . . . . . . . . . . . . . 35 5-Carboxy-2-Furanpropionic Acid . . . . . . . . . . . . . . . 37 Methyl Tetrahydro-5-Methyl-2-Furoate . . . . . . . . . . . 40 Methyl 4-(Chloromethyl)-5-Methyl-2-Furoate . . . . . . . 42 Methyl 5-(Cyanomethyl)-2-Furoate . . . . . . . . . . . . . . . 44 5-Methylfurfuryl Alcohol . . . . . . . . . . . . . . . . . . . . . 46 2-Furanacrylic Acid . . . . . . . . . . . . . . . . . . . . . . . . 48 2-Furanacrolein . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 5-(2-Furyl)-1,3,4-0xadiazole-2-Thiol . . . . . . . . . . . . . 54 2-Furanpropionic Acid . . . . . . . . . . . . . . . . . . . . . . . 57 Furfurylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 N-Benzylfurfurylamine . . . . . . . . . . . . . . . . . . . . . . . 63 N,N-Diethylfurfurylamine . . . . . . . . . . . . . . . . . . . . . 66 5-(Furfurylthiomethyl)-2-Furoic Acid . . . . . . . . . . . . . 68 Furfuryl Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 5-Bromo-2-Furoyl Chloride . . . . . . . . . . . . . . . . . . . 73 5-(Propoxymethyl)-2-Furoyl Chloride . . . . . . . . . . . . . 74 Ethyl 5-(1-Chloroethyl)-2-Furoate . . . . . . . . . . . . . . . 76 5-Ethyl-2-Furoic Acid . . . . . . . . . . . . . . . . . . . . . . . 78

Index to Vol. 2 . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 81

PREFACE

The second volume of "Syntheses of Heterocyclic Compounds," like the first, contains material on the synthesis of furan derivatives; it describes laboratory methods for the preparation of thirty compounds of this series.

In selecting material for publication, the Editorial Board has tried to cover the synthesis of compounds that are frequently used, or could be used, as intermediates in further synthesis. This volume contains directions for the preparation of some furan homologs (2,3-dimethylfuran, 2-benzylfuran), some carbonyl compounds (2-furyl methyl ketone, 2-furanacrolein), primary, secondary, and tertiary amines containing the furfuryl group (furfurylamine, N-benzylfurfurylamine, N,N-diethylfurfurylamine), and various derivatives of furfuryl alcohol, 2-furoic acid, and furylsubstituted aliphatic acids (including their acid chlorides and esters) substituted in the furan or tetrahydrofuran ring by hydrocarbon and functional groups (halogen, amino, cyano, carboxy, alkoxy, alkylthio).

In the compilation of "Other Methods of Preparation," literature published up to the end of 1955 has been reviewed.

A. L. Mndzhoian

5

5-BENZYL-2-FUROIC ACID

QcH,QCOOCH,+NaOH

QcH,QCOONa+CH,OH

QCH,QCOONo+HCI

QcH,QCOOH+NaCI

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by G. T. Tatevosian and N. M. Divanian

PREPARATION

A mixture of 21.6 g (0.1 mole) of methyl 5-benzyl-2-furoate (see p. 17), b.p. 150-155°/1 mm, and 50 ml of 10% sodium hydroxide solution was prepared in a 150-ml round-bottomed flask fitted with stirrer and reflux condenser.

The stirred mixture was heated in a boiling water bath for 3-4 hours; in the course of this time the oily ester layer disappeared completely. The alkaline solution was cooled to room temperature and washed with a little ether; it was then acidified

7

to Congo red with dilute hydrochloric acid. The 5-benzyl-2-furoic acid separated as an oil, which rapidly solidified. The crude product was filtered off at the pump and was purified by dissolving it in saturated sodium carbonate solution, boiling the solution for 20 minutes with 5 g of animal charcoal, filtering, and reprecipitating the product with dilute hydrochloric acid. It was again filtered off at the pump, washed on the filter with a little water, and dried in the air; m.p. 104-105° (see Notes).

The yield was 17-18 g (84.1--89.1%).

5-Benzyl-2-furoic acid (C12H100 3; mol. wt. 202.21) is a colorless crystalline substance, soluble in the usual organic solvents, but insoluble in water.

NOTES

The structure of the 5-benzyl-2-furoic acid prepared as above was confirmed by thermal decarboxylation: the decarboxylation product was identical with the previously described 2-benzylfuran1.

OTHER METHODS OF PREPARATION

5-Benzyl-2-furoic acid has been prepared only by the method described above, i.e. by hydrolysis of its methyl ester, which was synthesized by the condensation of benzene with methyl 5-(chloromethyl)-2-furoate2 (see R.p. 22).

Fenton and Robinson3 described a substance which they regarded as 5-benzyl-2-furoic acid; the substance was obtained in very low yield by the condensation of 5-(chloromethyl)-2-furaldehyde with benzene and oxidation of the aldehyde formed. However, in physical properties (m.p. 167-169j Fenton and Robinson's product differs from the above-described preparation; it was therefore not 5-benzyl-2-furoic acid.

LITERATURE CITED

1 R. Paul, C.r. 200, 1481 (1935). 2 A. L. Mndzhoian and V. G. Afrikian, Doklady Akad. nauk

Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 161 (1953). 3 H. J. H. Fenton and F. Robinson,]. Chern. Soc. 95, 1335 (1909).

8

5-(5-BENZYL-2-FURYL)-s-TRIAZOLE-3-THIOL

Na

ROH

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by N. A. Babiian and A. A. Dokhikian

A mixture of 27.5 g (0.1 mole) of 1-(5-benzyl-2-furoyl)-3-thiosemicarbazide* (m.p. 190j, sodium methoxide solution prepared from 2.6 g (0.11 g-atom) of sodium and 40 ml of methanol, and 100 ml of absolute ethanol (Note 1) was prepared in a 500-ml autoclave.

The reaction mixture was heated at 145-150° for three hours, after which the contents of the autoclave were transferred to a beaker and filtered. Alcohol was distilled from the filtrate under reduced pressure (water pump) until a dry residue was obtained. The residue was dissolved in 100 ml of water, and the solution was stirred while sufficient dilute hydrochloric acid was added to give an acid reaction toCongored. The precipitated 5-(5-benzyl-2-furyl)-s-triazole-3-thiol was filtered off at thepumpandwashed twice on the filter with 25-30 ml of cold water. The air-dried crude product melted at 232°. It was purified by dissolving it in 200 ml of hot saturated sodium carbonate solution, boiling the solution for 5-10 minutes with3gofanimal charcoal, and filtering. When cool, the filtrate was acidified to Congo red with dilute hydrochloric acid. The precipitate formed was filtered off at the pump, washed twice with 25-30 ml of cold water, and dried in the air; m.p. 240° (Note 2).

*The preparation of this compound is described in Volume 2 of this work. - Publisher.

9

Yield 21.5-22.5 g (83.6-87.6%).

5-(5-Benzyl-2-furyl)-s-triazole-3-thiol (C 13H110N3S; mol. wt. 257.32) forms colorless crystals, insoluble in water, benzene, and ether, but soluble in alkalis and to a lesser extent in alcohol and acetone.

NOTES

1. Instead of ethanol the same amount of dry methanol can be used.

2. The crude product can be purified by recrystallization from a mixture of alcohol and acetone, but this method is associated with great loss of material. The treatment described gives a product that is equally pure.


5-(5-Benzyl-2-furyl)-s-triazole-3-thiol has been prepared only by the method described above1•

LITERATURE CITED

1 A. L. Mndzhoian and V. G. Afrikian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 162 (1953).

10

5-BROM0-2-FUROIC ACID

6 Br Ocosr + 2HP03 + IOHBr. 0

Br Ocoor + HsO-+ Br OcooH + HBr 0 0

Proposed by A. L. Mndzhoian and V. G. Afrikian

Checked by M. G. Grigorian and lu. 0. Martirosian

PREPARATION

The reaction was carried out in a two-liter round-bottomed

flask fitted with mercury- sealed stirrer, reflux condenser, and

dropping funnel. In order to absorb hydrogen bromide liberated

in the reaction, the top of the condenser was connected to a

Tishchenko vessel containing a solution of alkali. A mixture of

112 g (1 mole) of 2-furoic acid (see p. 43), m.p. 128--132°, 10 g

of dry red phosphorus, and 800 ml of chloroform was prepared

in the flask.

The mixture was heated at the boil in a water bath and was

stirred while 320 g (2 moles) of bromine was added dropwise

over a period of 5-6 hours. When the addition of bromine was

complete, the mixture was boiled until the evolution of hydrogen

bromide stopped completely. The reflux condenser was replaced

by one set for distillation, and the mixture was stirred while

solvent was distilled off.

Water (500 ml) was added to the residue, and the mixture was

boiled on a sand bath for 3-4 hours. It was cooled to room tem

perature, and 20~ ammonia solution was added until the mixture

was strongly alkaline; 90 g of barium chloride (Note 1) and 10 g

of animal charcoal were then added, and the mixture was again

boiled for 30-40 minutes. The hot solution was filtered, cooled

11

to room temperature, and acidified to Congo red with hydrochloric acid. There was a precipitate of almost colorless scalelike crystals of 5-bromo-2-furoic acid, m.p. 182-183° (Note 2).

Yield 120.5-121.3 g (63.1-63.5%).

5-Bromo-2-furoic acid (C5H30 3Br; mol. wt. 190.99) forms colorless leaves, insoluble in cold water and ligroin. It is readily soluble in alcohol, ether, and hot water, less readily soluble in benzene and chloroform.

NafES

1. Barium chloride is added to remove a by-product-a dibromofuroic acid-which is formed in small amounts and separates in the form of the sparingly soluble barium salt.

2. 5-Bromo-2-furoic acid is obtained in the pure state: further recrystallization does not affect the melting point of the product.

OfHER METHODS OF PREPARATION

5-Bromo-2-furoic acid has been prepared by the bromination of ethyl 2-furoate in acetic acid solution and hydrolysis of the product with alcoholic alkali1; also by the oxidation of 5-bromo-2-furaldehyde, which was prepared by the bromination of2-furanmethanediol diacetate2• A simpler and more convenient method is the direct bromination of 2-furoic acid in absence3 or presence of solvent; solvents that have been used include acetic acid4, diethyl ether5, and also chloroform and carbon tetrachloride6• Bromination proceeds more readily, under milder conditions, and in better yields in presence of red phosphorus 7, i.e. under the conditions of the Zelinskii-Volhard reaction.

The best yields are attained when the procedure described above is followed7•

LITERATURE CITED

1 R. Schiff and G. Tassinari, Ber. 11, 842, 1840 (1878); Gazz. Chim. Ital. 8, 297 (1878); C. 1879, 175; Canzoneri and Oliveri, Gazz. Chim. Ital. 14, 174 (1884); C. 1885, 922.

2 H. Gilman and G. F. Wright, j. Am. Chern. Soc. 52, 1170 (1930).

12

3 H. B. Hill and C. R. Sanger, A. 232, 46 (1886); L. C. Raiford and W. G. Huey, j. Org. Chern. 6, 858 (1941).

' 0. Moldenhauer, G. Trautmann, W. Irion, R. Pfluger, H. Doser, D. Mastaglio, H. Marwitz, and R. Schulte, A. 580, 169 (1953).

5 Y. Obata, Bull. Agr. Chern. Soc. japan 16, 38 (1940); C. A. 34, 5841 (1940).

6 R. M. Whittaker, Rec. trav. chim. 52, 352 (1933). 7 A. L. Mndzhoian, Zh. obshchei khim. (J. Gen. Chern.) 16, 751

(1946).

2-FURANMETHANEDIOL DIACETATE

Checked by V. G. Afrikian and A. A. Dokhikian

PREPARATION

The reaction was carried out in a 300-ml Claisen flask having a 10-cm Vigreux column; 102 g (1 mole) of acetic anhydride was mixed with 0.1 ml (Note 1) of concentrated sulfuric acid with agitation by hand. Shaking was continued while the flask was cooled in an ice bath to 10° and 96 g (1 mole) of freshly distilled 2-furaldehyde, b.p. 157-163°, was added (over a period of ten minutes). The temperature was maintained at 10-20°, When the addition was complete and the contents of the flask had been well mixed, the cooling bath was :removed and the mixture was ailowed to get warm, which it did spontaneously with the heat of reaction; after about five minutes the temperature generally reached about 35°. When the temperature had fallen to that of the room (20-30 minutes), 0.4 g (Note 1) of anhydrous sodium acetate was added and the mixture was vacuum-distilled from an oil bath. The first fraction was collected at 50-140°/20 mm (50-70 g); it consisted mainly of acetic anhydride, 2-furaldehyde, and 2-furanmethanediol diacetate (Note 2). The main product came over at 140-142°/20 mm; it

13

amounted to 129-139 g (65-70%). The distillate solidified completely; m.p. 52-53° (Note 3).

2-Furanmethanediol diacetate (C9H100 5; mol. wt. 198.08) is a colorless crystalline substance, readily soluble in ether and in water.

NOTES

1. It is very important that the amount of catalyst (sulfuric acid, and the sodium acetate added later) should be carefully measured.

2. By redistillation of this fraction it is possible to isolate a further amount of 2-furanmethanediol diacetate and so raise the yield by 5-10%. It is possible to utilize this fraction, so long as it is not kept for more than five days, as starting material in further experiments, in which it can be treated as an equimolecular mixture of acetic anhydride and 2-furaldehyde.

3. It is recommended that collection of the main fraction be started only when cooling of a test sample of the distillate results in its conversion into a crystalline mass. The product collected in this way darkens gradually, but by redistillation a product can be obtained which remains colorless for several months.


2-Furanmethanediol diacetate has been prepared from 2-furaldehyde and acetic anhydride in presence of sulfuric acid1, zinc chloride2, stannous chloride3, acetic acid4, and other catalysts5•

The procedure described above was proposed by R. T. Bertz6•

LITERATURE CITED

1 j. j. Blanksma, Chern. Weekblad6, 717 (1909); C. 1909, II, 1220. 2 H. D. Law, Chern. Zeitung 32, 366 (1908). 3 H. Gilman and G. F. Wright, Rec. trav. chim. 50, 833 (1931). 4 H. Scheibler, F. Sotscheck, and H. Friese, Ber. 57, 1443 (1924). 5 E. Knoevenagel, A. 402, 119 (1913). 6 C. C. Price (Editor-in-Chief), Organic Syntheses, Vol. 33,

p. 39, New York and London (1953).

14

5-(DIETHYLAMINOMETHYL) FURFURYL ALCOHOL

Proposed by A. L. Mndzhoian and M. T. Grigorian Checked by N. A. Babiian and N. M. Ogandzhanian

PREPARATION

A solution of 10.5 g (0.05 mole) of methyl 5-(diethylaminomethyl)-2-furoate (see p. 22), b.p. 102-103°/1.5 mm, in 150 ml of dry ether was added dropwise over a period of 0.5-1 hour to a stirred ethereal solution (200 ml) of lithium aluminum hydride (Note 1) contained in a 500-ml three-necked flask fitted with mercury- sealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube.

The reaction mixture was left overnight, and on the next day the flask was cooled with water and its contents were stirred while 20 ml of water was added dropwise (Note 2). The contents of the flask were filtered, and the residue was washed with three 75-ml portions of ether. The combined filtrate was dried with anhydrous sodium sulfate, solvent was distilled off completely, and the residual material was vacuum-distilled; a product of b. p. 120-12 2°/1 mm was collected.

The yield was 7.3-7.6 g (80.2-83.5%).

5-(Diethylaminomethyl)furfuryl alcohol (C 10H170 2N; mol. wt. 183.25; d204 1.0337; n20D 1.4890) is a colorless viscous liquid, soluble in the usual organic solvents, but insoluble in water.

NOTES

1. The ethereal solution of lithium aluminum hydride was prepared by the method of Finholt et al.l, the "starter" being

15

obtained by Mahe''s method 2*; 200 ml of solution prepared in this way contained about 4.4 g of lithium aluminum hydride.

2. The decomposition of the excess of lithium aluminum hydride must be carried out very cautiously: the addition of water should be controlled in such a way that the ether boils steadily.

aTHER METHODS OF PREPARATION

5-(Diethylaminomethyl)furfuryl alcohol has been prepared only by the method described above3•

LITERATURE CITED

1 A. E. Finholt, A. L. Bond, and H. J, Schlesinger, J. Am. Chern. Soc. 69, 1199 (1947).

2 J. Mahe, J. Rollet, and A. Willemart, Bull. soc. chim. 481 (1949).

3 A. L. Mndzhoian, and M. T. Grigorian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 163 (1953).

* The preparation of lithium aluminum hydride is described in detail in Volume 2 of this series. - Publisher.

16

METHYL 5-BENZYL-2-FUROATE

Proposed by A. L. Mndzhoian, V. G. Afrikian, and A. A. Dokhikian Checked by G. T. Tatevosian and N. M. Divanian

PREPARATION

A solution of 22.7 g (0.13 mole) of methyl 5-(chloromethyl)-2--furoate (see p. 29), b.p. 114-116°/3 mm, in 200 ml of dry benzene was prepared in a 500-ml three-necked round-bottomed flask fitted with mercury-sealed stirrer and reflux condenser protected by a calcium chloride tube, and it was stirred and cooled with ice water for two hours while 40 g (0.3 mole) of anhydrous aluminum chloride was added in small portions. When the vigorous reaction ceased, the mixture was heated in a water bath (temperature of bath 80-85j for 4-5 hours (see Notes).

The reaction mixture was cooled thoroughly with ice and salt and was stirred while small pieces of ice (about 100 g) were added. In order to dissolve the aluminum hydroxide formed, dilute hydrochloric acid (equal volumes of concentrated acid and water) was added until the yellowish tenacious mass disappeared from the bottom and sides of the flask. The benzene layer was separated, and the aqueous layer was extracted with two 50-ml portions of ether, which were combined with the main product; the resulting solution was washed with water and dried with calcined sodium sulfate. Solvent was distilled off, first at atmospheric and then at reduced pressure (water pump), and the residue was vacuumdistilled with collection of the liquid coming over up to 155°/1 mm. In redistillation up to 150°/1 mm, 3-4 ml of an initial fraction was collected, after which 17.5-18 g (62.3-63.81>) of methyl 5-benzyl-2-furoate came over in the range 150-155°/1 mm. When

17

cool, the distillate solidified completely; after being washed with ether, the glistening crystals melted at 43-44°.

Methyl 5-benzyl-2-furoate (C 13H120 3; mol. wt. 216.23) is a colorless crystalline substance, insoluble in water, but soluble in the usual organic solvents.

NOTES

Higher temperatures lead to considerable resinification of the product with reduction in yield.


Methyl 5-benzyl-2-furoate has been prepared onlybythemethod described above1•

LITERATURE CITED

1 A. L. Mndzhoian, V. G. Afrikian, and A. A. Dokhikian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 164 (1953).

METHYL 5-(BROMOMETHYL)-2-FUROATE

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by G. T. Tatevosian and S. G. Agbalian

PREPARATION

A mixture of 126 g (1 mole) of methyl 2-furoate (seep. 27), b.p. 180-18r/760 mm, 250 ml of dry dichloroethane (Note 1), 45 g of paraformaldehyde (1.5 moles calculated as formaldehyde), and 34 g (0.25 mole) of anhydrous zinc chloride was prepared in

18

a one-liter four-necked round-bottomed flask fitted with stirrer, glass tube passing to the bottom of the flask (for the introduction of hydrogen bromide), gas-outlet tube, and thermometer.

The stirrer was set in motion, and a rapid stream of hydrogen bromide was passed in (the hydrogen bromide was first passed through a wash bottle containing sulfuric acid); the temperature of the mixture gradually rose. It was found that the reaction temperature must not be above 24--26°; in order to ensure this the flask must be cooled with water (Note 2).

The reaction lasted for 2-2.5 hours. The end of the reaction was indicated by the complete dissolution of all the paraformaldehyde; at the same time the spontaneous evolution of heat gradually came to a stop. Toward the end of the reaction the mixture became dark red.

The mixture was poured into a flask containing 500 ml of cold water (Note 3); the lower, dichloroethane layer was separated and washed with three 100-ml portions of water. The solution was dried with calcium chloride, solvent was distilled off, and the residue was vacuum-distilled with collection of the liquid coming over at 124-126°/2.5 mm. The substance in the receiver solidified completely; m.p. 32--36°.

The yield was 173-175 g (78.9-79.9%) (Note 4).

Methyl 5-(bromomethyl)-2-furoate (C 7H 70 3Br; mol. wt. 219.03) is a crystalline substance, insoluble in water, but soluble in the usual organic solvents.

NOTES

1. Chloroform, carbon tetrachloride, or tetrachloroethane can be used as solvent without effect on the yield.

2. The optimum temperature is 24-26°; at lower temperatures reaction is too slow, and at higher temperatures resinification occurs with reduction in yield.

3. Methyl 5-(bromomethyl)-2-furoate irritates not only the mucous membrane, but also the skin of the face and hands. The reaction, the treatment of the reaction mixture, and the isolation of the product must therefore be carried out in a fume cupboard with observance of appropriate precautions.

19

4. Ethyl 5-(bromomethyl)-2-furoate can be prepared by the same method.


Methyl 5-benzyl-2-furoate has been prepared onlybythemethod described above1•

LITERATURE CITED

1 A. L. Mndzhoian and V. G. Afrikian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR), 17, 101 (1953).

METHYL 5-(BUTYLTIDOMETHYL)-2-FUROATE

2 CH~CHaCH1CH2SH + 2Na ..... 2CH3CH1CH1CH1SNa + H1

CH3CHaCH1CH1SNa + CICH. QcoocH, -

CH3CH1CH1CH.SCHa QcOOCHa + NaCI

Proposed by A. L. Mndzhoian and N. M. Divanian Checked by 0. L. Mndzhoian and E. R. Bagdasarian

PREPARATION

Sodium freed from encrustation (5. 75 g, i.e. 0.25 g-atom) was added to 100 ml of dry toluene (Note 1) contained in a 250-ml three-necked round-bottomed flask fitted with stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. The mixture was heated until the sodium melted, and the stirrer was then set into motion and the application of heat was stopped; vigorous stirring was continued for 10-15 minutes, during which the temperature of the mixture fell to 40-50°. Gentle stirring of the toluene suspension of finely granulated sodium was continued at this temperature while 30 g (0.33 mole) of freshly distilled

20

1-butanethiol (Note 2) was added dropwise; the mixture was allowed to stand for several hours.

To this suspension of sodium butyl sulfide in toluene, 43.6 g (0.25 mole) of methyl 5-(chloromethyl)-2-furoate (see p. 29), b.p. 114-116°/3 mm, was added dropwise over a period of 2-2.5 hours, after which the dropping funnel was replaced by athermometer immersed in the liquid and the reaction mixture was heated at 90-95° for two hours. When cool, the mixture was transferred to a separating funnel and washed 2-3 times with water. The wash waters were shaken with ether, and the ether extract was combined with the main solution, which was dried over calcined sodium sulfate. Solvent was distilled off, and the residue was vacuum-distilled with collection of the product coming over at 153-155°/4 mm.

Yield 51.8-54 g (89.1-92.9~) (Note 3).

Methyl 5-(butylthiomethyl)-2-furoate (C11H160 3S; mol. wt. 228.18; d204 1.1129; n20D 1.5233) is a colorless liquid of unpleasant odor. It becomes yellow when kept.

NOTES

1. The reaction can be carried out also in dry benzene, the sodium being used in the form of wire.

2. 1-Butanethiol, being a rather volatile substance, is taken in considerable excess in order to ensure complete reaction of the sodium.

3. The methyl and ethyl esters of 5-(alkylthiomethyl)-2-furoic acids in which alkyl may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl can be prepared in 70-95~ yield by the procedure described.


Methyl 5-(butylthiomethyl)-2-furoate has been prepared only by the method described above1•

LITERATURE CITED

1 A. L. Mndzhoian and N. M. Divanian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 164 (1953).

21

METHYL 5-(DIETHYLAMINOMETHYL)-2-FUROATE

CICH, QcOOCH3 + HN(CH.- CH3) 2 ....

(CH -CH2hNCH20COOCH3

HCI O

(CH3-CH2J2NCH. OcOOCH3 + NnOH .... HCI O

Proposed by A. L. Mndzhoian, V. G. Afrikian, and M. T. Grigorian Checked by 0. L. Mndzhoian and 0. E. Gasparian

PREPARATION

A solution of 17.4 g (0.1 mole) of methyl 5-(chloromethyl)-2--furoate (seep. 29), b.p. 114-116°/3 mm, in 50 ml of dry benzene was prepared in a 200-ml round-bottomed flask fitted with reflux condenser and dropping funnel. The solution was cooled with ice water, and a solution of 14.6 g (0.2 mole) of diethylamine in 30 ml of dry benzene was added over a period of ten minutes.

The reaction mixture was boiled in a water bath for 4-5 hours, cooled to room temperature, and acidified to Congo red with 10% hydrochloric acid. The aqueous solution was separated from the benzene layer, which was washed with 20 ml of water. The washings were added to the aqueous solution, which was saturated with sodium carbonate. Ether (50 ml) was added, and this was followed by a few milliliters of concentrated sodium hydroxide solution. The ether layer was separated, and the aqueous layer was extracted with three 30-ml portions of ether. The combined ether extract was dried over calcined sodium sulfate; solvent was distilled off, and the residue was vacuum-distilled with collection ofthe fraction coming over at 102-103°/1.5 mm.

Yield 18-20 g (85.3-94. 7%) (see Notes).

22

Methyl 5-(diethylaminomethyl)-2-furoate (C 11H170 3N; mol. wt. 211.26; d204 1.0520; n20D 1.4857) is a light-yellow liquid, soluble in the usual organic solvents, but insoluble in water.

NaTES

By the procedure described approximately the same yields can be obtained of the ethyl, propyl, isopropyl, butyl, and isobutyl esters of 5-(dialkylaminomethyl)-2-furoic acids in which alkyl may be methyl, ethyl, propyl, or butyl.


Methyl 5-(diethylaminomethyl)-2-furoate has been prepared only by the method described above1•

LITERATURE CITED

1 A. L. Mndzhoian, V. G. Mrikian, andM. T. Grigorian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 165 (1953).

METHYL 5-METHYL-2-FUROATE

Zn

Proposed by A. L. Mndzhoian, V. G. Afrikian, and M. T. Grigorian Checked by G. T. Tatevosian and S. G. Agbalian

PREPARATION

A mixture of 87.2 g (0.5 mole) of methyl 5-(chloromethyl)-2-furoate (see p. 29), b.p. 114-116°/3 mm, and 300 ml of 90% acetic acid was prepared in a one-liter three-necked round-bottomed flask fitted with mercury- sealed stirrer and reflux condenser. The mixture was stirred while 98 g (1.5 g-atoms) of zinc dust was added in small portions over a period of 2-2.5 hours, and with continued stirring the mixture was then boiled for 20 hours (Note 1).

23

The contents of the flask were poured into 600 ml of cold water; the reaction product separated as an oily layer, which was separated from the aqueous layer with the aid of ether; the aqueous layer was extracted several times with ether. The combined ether extract was washed with water, with 5% sodium carbonate solution, and again with water; it was dried over anhydrous sodium sulfate. Solvent was distilled off, and the residue was vacuum-distilled with collection of the liquid coming over at 97-99°/12 mm.

Yield 56.7-58.1 g (81-83%) (Note 2).

Methyl 5-methyl-2-furoate (C 7H80 3; mol. wt. 140.14; d204 1.1352; n20o 1.4930) is a colorless liquid, b.p. 193-196°/680 mm, insoluble in water, but soluble in alcohol and ether.

NOTES

1. When zinc dust containing other metals as impurities is used, a solid residue remains at the bottom of the flask at the end of the reaction.

2. Ethyl 5-methyl-2-furoate can be prepared by the same method in about the same yield.


Methyl 5-methyl-2-furoate has been synthesized by the esterification of the free acid, prepared by the oxidation of 5-methyl-2-furaldehyde with silver oxide1•

In developing this procedure2, the authors took account of the work of R. Andrisano3•

LITERATURE CITED

1 I. j. Rinkes, Rec. trav. chim. 49, 1118 (1930); C. A. 25, 950 (1931).

2 A. L. Mndzhoian, V. G. Afrikian, andM. T. Grigorian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 166 (1953).

3 R. Andrisano, Ann. chim. (Rome) 40, 30 (1950); C. A. 45, 7563a (1951).

24

METHYL 5-(PROPOXYMETHYL)-2-FUROATE

Proposed by V. G. Afrikian and G. L. Papaian Checked by 0. L. Mndzhoian and 0. E. Gasparian

PREPARATION

Freshly cut sodium (6.6 g, i.e. 0.28 g-atom) was added slowly in small pieces to 140 ml (an excess) of dry propyl alcohol contained in a 500-ml three-necked round-bottomed flask fitted with mercury-sealed stirrer and reflux condenser protected by a calcium chloride tube.

When the sodium had dissolved completely, a dropping funnel was inserted in one of the necks of the flask, the stirrer was set into motion, and 50 g (0.28 mole) of freshly distilled methyl 5-(chloromethyl)-2-furoate (see p. 29), b.p. 114-116°/3 rom, was added dropwise over a period of 1-1.5 hours; the addition of the ester was accompanied by the formation of a copious precipitate of sodium chloride. When the addition was complete·, the reaction mixture was boiled for eight hours in an oil bath (bath temperature 120-130°), and the reflux condenser was then replaced by one set for distillation; with continued stirring the greater part of the propyl alcohol was distilled off. The reaction mixture was cooled to room temperature, 150 ml of water was added, and the oily layer was separated. The aqueous layer was extracted with

three 50-ml portions of ether, which were then added to the main product (Note 1). The ether solution was dried over calcined

sodium sulfate, solvent was distilled off, and the residue was vacuum -distilled with collection of the substance boiling at 146-1480/5 rom.

Yield 43.5-44.5 g (76. 7-78.4%) (Note 2).

25

Methyl 5-(propoxymethyl)-2-furoate (C10H14,04; mol. wt. 198.22; d204 1.1482; n2Do 1.4769) is a colorless liquid, soluble in organic solvents, but insoluble in water.

NOTES

1. By treatment of the aqueous alkaline solution with dilute hydrochloric acid, 2-3 g of 5-(propoxymethyl)-2-furoic acid can be isolated.

2. The methyl esters of5-(methoxymethyl)-,5-(ethoxymethyl)-, 5- (isopropoxymethyl)-, 5- (butoxymethyl)-, 5- (isobutoxymethyl)-, 5-(pentyloxymethyl)-, 5-(isopentyloxymethyl)-, 5-(phenoxymethyl)-, 5- (benzyloxymethyl)-, and 5- (phenethyloxymethyl)- 2-furoic acids can be prepared by the above-described method in 67-88% yield.


Only the above-described method 1•2 has been proposed for the preparation of methyl 5-(propoxymethyl)-2-furoate.

LITERATURE CITED

1 A. L. Mndzhoian, V. G. Afrikian, Go L. Papaian, and A. N. Oganesian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 129 (1953).

2 R. Andrisano, Ann. Chim. (Rome) 40, 30 (1950); C. A. 45, 7563a (1951).

26

METHYL 2-FUROATE

0 HCI 0' O COOH + CH 30H ~ O COOCH3 + H20

Proposed by V. G. Afrikian and M. T. Grigorian Checked by G. T. Tatevosian and S. G. Agbalian

PREPARATION

A. A solution of 224 g (2 moles) of 2-furoic acid (seep. 43), m.p. 128-132°, in 500 ml of methanol was placed in a one-liter flask fitted with a reflux condenser and a glass tube, which passed to the bottom of the flask.

The flask was heated in a water bath, and a rapid stream of hydrogen chloride (dried by passage through a wash bottle containing concentrated sulfuric acid) was passed for 2.5-3 hours through the steadily boiling solution. The solution was cooled and poured into a flask containing 1 liter of water; the oily product was separated, and the aqueous layer was extracted with three 100-ml portions of ether. The ether extract was added to the main product, which was then washed, first with 5',(, sodium carbonate solution, and then with water until the reaction was neutral. The solution was dried with calcined sodium sulfate, and ether was distilled off. The residue was distilled with collection of the liquid coming over at 176-177°/680 mm.

Yield 200-206 g (79.3-81.6%) (Note 1).

B. Concentrated sulfuric acid (10 ml) was added to a stirred solution of 112 g (1 mole) of 2-furoic acid in 500 ml of dry methanol contained in a one-liter round-bottomed flask fitted with reflux condenser. The mixture was boiled in a water bath for four hours, and the reflux condenser was then replaced by one set for distillation and the greater part (about 400 ml) of the methanol was distilled off. Water (500 ml) was added to the cooled residue, and the oily layer was separated and treated as indicated above (A)

(Note 1).

27

Yield 95-96 g (75.4-76.2~) (Note 2).

Methyl 2-furoate (C8~0,; mol. wt. 126.11; d21.44 1.1786; n21·4o 1.4871) is a colorless pleasantly smelling liquid, b.p. 18r /760 mm, insoluble iJt water, but soluble in the usual organic solvents. It becomes yellowish when allowed to stand in the air.

NOTES

1. Some unchanged 2-furoic acid may be isolated from the wash waters by treating them with hydrochloric acid.

2. In a similar way, the ethyl, propyl, isopropyl, butyl, and isobutyl esters can be prepared in yields ranging from 75 to 80~.


Methyl 2-furoate has been prepared by the esterification of the free acid 1, including treatment with dimethyl sulfate in an alkaline medium2• The ester has been prepared in moderate yield (36~) by reaction between furoyl chloride and magnesium methoxide in methanol 3 (modification of the Schotten-Baumann reaction). It is formed in yields approaching quantitative by the action of methyl iodide on silver 2-furoate'.

LITERATURE CITED

1 G. Gennari, Gazz. Chim. Ital. 21, 1, 249 (1891); C. 1895 I, 764. 2 C. C. Vernon, E. F. Struss, and H. H. Ruwe, Trans. Kentucky

Acad. Sci. 9, 23 (1941); C. A. 36, 45042 (1942). 3 E. M. Trautner and j. B. Polya, Australian Chern. Inst. Proc.

15, 52 (1948); C. A. 42, 5848d (1948). 4 G. C. Guainazzi, Pitture e vernici, 4, 181 (1948); C. A. 43,

4252 (1949).

28

METHYL 5-(CHLOROMETHYL)-2-FUROATE

CICH2 OcoocH, + H.O 0

Proposed by A. L. Mndzhoian and M. T. Grigorian Checked by G. T. Tatevosian and S. G. Agbalian

PREPARATION

A mixture of 126 g (1 mole) of methyl 2-furoate (seep. 27), b.p. 180-18r/760 mm, 250 ml of dry dichloroethane (Note 1), 45 g of paraformaldehyde (1.5 moles calculated as formaldehyde), and 34 g (0.25 mole) of anhydrous zinc chloride was prepared in a one-liter four-necked round-bottomed flask fitted with stirrer, bent tube reaching to the bottom of the flask, thermometer, and gas-outlet tube. A rapid stream of hydrogen chloride was passed first through a wash bottle containing sulfuric acid and then into the stirred mixture. The temperature of the reaction mixture gradually rose; in order to avoid resinification, the flask was cooled with water so ·as to prevent the temperature from rising above 24-26°. The reaction lasted about two hours; the end of the reaction was indicated by the complete dissolution of the paraformaldehyde: the spontaneous evolution of heat gradually stopped, and the mixture became light yellow in color.

The contents of the flask were poured into 500 ml of cold water (Note 2); the lower, dichloroethane layer was separated and washed with three 100-ml portions of water. It was dried with calcium chloride, solvent was distilled off, and the residue was vacuumdistilled with collection of the substance coming over at 114-116• / /3 mm. On standing, the distillate solidified completely; m.p. 34-36°.

Yield 141-143 g (80. 7-81.9;,) (Note 3).

Methyl 5-(chloromethyl)-2-furoate (C7H10,Cl; mol. wt. 174.59) is a light-yellow crystalline substance, insoluble in water, but

29

soluble in the usual organic solvents; it darkens in color after long standing.

NarES

1. The use of chloroform, carbon tetrachloride, or tetrachloroethane as solvent has no affect on the purity and yield of the product.

2. Methyl 5-(chloromethyl)-2-furoate irritates not only the mucous membrane, but also the skin of the face and hands. The reaction, the treatment of the reaction mixture, and the isolation of the product must therefore be carried out in a fume cupboard with observance of appropriate precautions.

3. The ethyl, propyl, isopropyl, butyl, and isobutyl esters of 5-(chloromethyl)-2-furoic acid can be prepared similarly; the yields obtained range from 80 to 90%.

afHER METHODS OF PREPARATION

Methyl 5-(chloromethyl)-2-furoate has been prepared by the chloromethylation of methyl 2-furoate in methylene chloride solution with paraformaldehyde and hydrogen chloride in presence of zinc chloride1• It has been shown that methylene chloride can be replaced by chloroform2 and that zinc chloride can be replaced by phosphoric acid, aluminum chloride, or a mixture of stannic chloride hexahydrate and anhydrous sodium sulfate3•

The chloromethylation of alkyl 2-furoates proceeds better and in higher yields when carried out as described above4•

LITERATURE CITED

1 British Pat. 588,377 (1947); C. A. 41, 6581f (1947); U. S. Patent 2,450,108 (1948); C. A. 43, 1065b (1949).

2 R. Andrisano, Ann. Chim. (Rome) 40,30 (1950); C. A. 45, 7563a (1951).

3 0. Moldenhauer, G. Trautmann, W. Irion, R. Pfluger, H. Doser, D. Mastaglio, H. Marwitz, and R. Schulte, A. 580, 169 (1951).

'A. L. Mndzhoian and M. T. Grigorian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 101 (1953).

30

2-METHYLFURAN (SYLVAN)

CH, 0' COOH _..... CH3 o~ +COt . 0 0

Proposed by A. L. Mndzhoian and G. T . Tatevosian Checked by V. G. Afrikian and G. L. Papaian

PREPARATION

The 150-ml distillation flask A (Fig. 1) has a side neck carrying a thermometer which reaches almost to the bottom of the flask and a wide side tube branching from a high point on the neck; 63 g (0.5 mole) of 5-methyl-2-furoic acid (see p. 33), m.p. 108-109°, was placed in the flask. The mouth of the flask was closed with a stopper carrying a long glass rod B, which was used for clearing the neck from 5-methyl-2-furoic acid sublimate. The side tube of the flask A was connected to a large U -tube filled with pieces of sodium hydroxide of the size of a pea; the U-tube was surrounded by a boiling water bath so as to prevent the condensation of 2--methylfuran (see Notes) (a tall one-liter beaker is suitable for use as a water bath). The other side of the U -tube was connected to a sloping condenser, which was fitted with a long receiver adapter; the end of the adapter was in the lower part of a longnecked 100-ml flask, which served as a receiver and was cooled with ice water.

B

Fig. 1.

31

When the flask was heated, the 5-methyl-2-furoic acid melted and then began to decompose. The temperature of the liquid was maintained at 170-175°; at this temperature decarboxylation was fairly rapid and distillation of the 2-methylfuran formed proceeded steadily. The 5-methyl-2-furoic acid whichsublimedwithformation of a deposit in the neck of the flask was from time to time pushed back into the flask with the glass rod. Toward the end of the experiment there remained a very small amount of liquid, but there was a layer of sublimed acid on the upper parts of the walls of the flask. In order to decompose this residue, the upper parts and neck of the flask were covered with asbestos paper and the temperature was raised to 200°. The whole process required 2.5-3 hours.

The moist product that collected in the receiver was transferred to a separating funnel, the small amount of water that had distilled over was removed, and the 2-methylfuran was dried with a few pieces of fused potassium carbonate. Redistillation gave 32.9-34.8 g (80.1-84.8%) of pure 2-methylfuran, b.p. 6r /680 mm.

2-Methylfuran (C5lfe0; mol. wt. 82.10) is a colorless liquid of ethereal odor, sparingly soluble in water, but readily soluble in alcohol and ether; b.p. 64-65°/760 mm; d20 4 0.9159; n20D 1.4344. On standing in the air it acquires a pale greenish-yellow color.

NOTES

The U-tube containing sodium hydroxide serves for the absorption of carbon dioxide formed in the decarboxylation. The sodium hydroxide also traps much of the water formed.


2-Methylfuran is a by-product of the wood-chemicals industry; it is formed in the dry distillation of wood and is isolated in large amount from the head fraction of wood-tar distillate1•

Synthetic 2-methylfuran is prepared by the catalytic hydrogenation of 2-furaldehyde in the vapor phase over a copper2 or copper-chromium2 catalyst at temperatures above 200°.

Passage of furfuryl alcohol over alumina at 390° 4 or heating it with a nickel catalyst at 150° 5 results in the formation of a mixture of 2-furaldehyde, furan, and 2-methylfuran.

32

The above-described method for the laboratory preparation of 2-methyliuran is based on the thermal decarboxylation of 5-methyl- 2-furoic acid 6 .

LITERATURE CITED 1 See e.g. A. A. Prianishnikov and I. A. Grigorov, Lesokhim.

prom. (Wood Chemicals Ind.) No. 7, 12 (1939). 2 U.S. Pat. 2,456,187; C. A. 43, 2218h (1949); U.S. Pat. 2,458,001;

C. A. 43, 2805b (1949); British Pat. 634,079; C. A. 44, 6886 (1950). 3 L. E. Schlepp, H. H. Geller, and K. W. Korff, J. Am. Chern.

Soc. 69, 672 (1947); K. Tsuda, Sh. Yoshida, M. Yamada, andY. Maruya, J. Pharm. Soc. Japan 66, 58 (1946); C. A. 45, 6182g (1951).

4 R. Paul, C.r. 200, 1118 (1935); Bull. soc. chim.5 2, 2220 (1935). 5 R. Paul, Bull. soc. chim. 8, 507 (1941). 6 H. Gilman, A. M. Janneym, and C. W. Bradley, Iowa State

Coll. J. Sci. 7, 429 (1933); C. A. 28, 763 (1934); S. Machida, J. Chern. Soc. Japan 64, 1311 (1943); C. A. 41, 4482h (1947).

5-METHYL-2-FUROIC ACID

CH3 0 COOCH3 + NaOH -+ CH3 0 COONa + CH30H 0 0

CH3 0C00Na + HCI-.Cf-1301 COOH + NaCI 0 0


PREPARATION

A mixture of 14 g (0.1 mole) of methyl 5-methyl-2-furoate (see p. 23), b.p. 97-99°/12 mm, and 22 ml of 22% aqueous sodium hydroxide solution was prepared in a 100-ml round-bottomed flask fitted with mercury- sealed stirrer and reflux condenser.

With constant stirring the reaction mixture was heated in a boiling water bath for two hours. It was then allowed to cool, washed with a little ether, and acidified to Congo red with dilute hydrochloric acid. The 5-methyl-2-furoic acid that separated was

33

filtered off at the pump, washed on the filter with 15 ml of cold water, and dried in the air; m.p. 108-109° (see Notes).

Yield 10.5-11 g (83.3-87.3%).

5-Methyl-2-furoic acid (C6lfs03; mol. wt. 126.11) is a colorless crystalline substance, readily soluble in ethanol and in hot water; it is sparingly soluble in cold water.

NarES

The substance is obtained in the pure state: recrystallization from water has no effect on the melting point.


5-Methyl-2-furoic acid is formed in the oxidation of 5-methyl-2-furaldehyde with silver oxide in an alkaline medium1 or with solutions of alkali-metal hypobromites2• The acid can be obtained in low yield by the hypochlorite oxidation of methyl 5-methyl-2--furyl ketone, which is itself obtained by the acetylation of 2-methylfuran in presence of boron trifluoride3• 5-Methyl-2-furoic acid was obtained also as the result of an interesting rearrangement, which occurs in the reaction between potassium cyanide and furfuryl chloride; hydrolysis of the 5-methyl-2-furonitrile formed in the rearrangement gives 5-methyl-2-furoic acid 4•

The best yields of 5-methyl-2-furoic acid are given by the procedure described above5•

LITERATURE CITED

1 H. B. Hill and W. L. Jennings, Am. Chern. J. 15, 167 (1893); I. J. Rinkes, Rec. trav. chim. 49, 1118 (1930); C. A. 9509 (1931).

2 K. Maekawa, J. Fac. Agr. Kyushu Univ. 9, 140 (1949); C. A. 48, 2029g (1954).

3 J. R. Williard and C. S. Hamilton, J. Am. Chern. Soc. 75, 2370 (1953).

4 W. R. Kirner and G. H. Richter, J. Am. Chern. Soc. 51, 3131 (1929); M. M. Runde, E. W. Scott, and J. R. Johnson, J. Am. Chern. Soc. 52, 1284 (1930).

5 A. L. Mndzhoian and M. G. Grigorian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 167 (1953).

34

ct -PROPYLFURFURYL ALCOHOL

Proposed by 0. L. Mndzhoian and N. A. Babiian Checked by G. T. Tatevosian and N. M. Divanian

PREPARATION

Magnesium turnings (5 g, i.e. 0.2 g-atom), which had been washed with absolute alcohol and dry ether, dry ether (100 ml), and a crystal of iodine were introduced into a 500-ml three-necked round-bottomed flask fitted with mercury-sealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. A solution of 32 g (0.26 mole) of freshly distilled propyl bromide in 100 ml of dry ether was added dropwise from the dropping funnel (Note 1). The addition required 2-2.5 hours, and the reaction mixture was then boiled in a water bath until the magnesium had dissolved completely (90 minutes). The contents of the flask were cooled with ice and salt and stirred continuously for one hour while a solution of 18.2 g (0.19 mole) of freshly distilled 2-furaldehyde (Note 2) in 100 ml of dry ether was added. The mixture was then boiled in a water bath for 1-1.5 hours.

The reaction mixture was again cooled with ice and salt; it was stirred while a solution of 34 g of ammonium chloride in 125 ml of waterwasaddeddropwise. The ether layer was separated, and the aqueous layer was extracted with two 100-ml portions of ether. The combined ether solution was washed with a little water and dried over calcined sodium sulfate. Ether was distilled off, and the residue was vacuum-distilled with collection of the fraction coming over at 84-94°/10 mm (92-94° /10 mm in the redistillation).

35

Yield 17-18 g (64.1-67.9%) (Note 3).

a -Propylfurfuryl alcohol (C8H120 2; mol. wt. 140.09) is a colorless liquid, insoluble in water, but soluble in organic solvents; b.p. 66-68°/1.5 mm; d204 1.0268; n20D 1.4680. It gradually darkens in storage, even in a sealed tube.

NaTES

1. Reaction generally begins after a certain amount of the propyl bromide has been added; if necessary, the contents of the flask may be warmed in a water bath, when reaction will start and continue steadily without external heating.

2. Commercial 2-furaldehyde was distilled at 89-90° under the vacuum of a water pump (65 mm residual pressure).

3. a-Methyl-, a-ethyl-, and a-butyl-furfuryl alcohols were prepared by the above-described method in satisfactory yields.


a- Propylfurfuryl alcohol has been prepared only by reaction between propylmagnesium halides and 2-furaldehyde1• The most satisfactory results were obtained with the procedure described above2•

LITERATURE CITED

1 F. N. Peters and R. Fischer, J. Am. Chern. Soc. 52, 2079 (1930); H. Kondo and K. Takeda, j. Pharm. Soc. japan 55, 734 (1935); C. A. 29, 73427 (1953).

2 A. L. Mndzhoian, 0. L. Mndzhoian, and N. A. Babiian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 23, 175 (1956).

36

5-(PROPOXYMETHYL)-2-FUROIC ACID

CHaCH2CH20CH2 OcoOCH3 + NaOH -0

CH3CHzCH20CH2 0COONa + CH30H 0

CH3CH,CH20CH.a OcooNa + HCI -0

Proposed by V. G. Afrikian and G. L. Papaian Checked by 0. L. Mndzhoian and 0. E. Gasparian

PREPARATION

Ground sodium hydroxide (35 g) was added with stirring to 96% alcohol (130 ml) contained in a 500-ml three-necked roundbottomed flask fitted with mercury-sealed stirrer, reflux condenser, and dropping funnel. Withcontinuedstirring, 61g (0.3 mole) of methyl 5-(propoxymethyl)-2-furoate (seep. 25), b.p. 146-148°/ /12 mm, was added gradually.

The mixture was boiled in a water bath for 2-3 hours, and the reflux condenser was then replaced by one set for distillation, and the mixture was stirred while as much alcohol as possible was distilled off (about 100-110 ml). The residue was cooled to room temperature, and 130-150 ml of water was added; the resulting alkaline solution was washed with a little ether and acidified to Congo red with dilute hydrochloric acid. The free acid was liberated as an oil and was separated; the aqueous layer was extracted three times with ether, and the extracts were added to the main product. The solution was dried over calcined sodium sulfate, and solvent was distilled off; the residue was vacuumdistilled and came over at 170-173°/9 mm. The distillate solidified completely; m.p. 43-44°,

The yield was 41-44 g (72.4-76%).

37

5-(Propoxymethyl)-2-furoic acid (C9H120 4; mol. wt. 184.19) is an almost colorless crystalline substance, insoluble in water, but soluble in the usual organic solvents.


5-(Propoxymethyl)-2-furoic acid has been prepared only by the method described above1•

LITERATURE CITED

1 A. L. Mndzhoian, V. G. Afrikian, and G. L. Papaian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 129 (1953).

o. -PHENYLFURFURYL ALCOHOL

0 (CIIaCH,).O 0' Br + Mg Mg13r -

O MgBr + OcHo- OcH 0' ~ 0 0 I -

OMgBr

OcHOHO' + Mg(OH)Br 0 -

Proposed by 0. L. Mndzhoian and E. R. Bagdasarian Checked by G. T. Tatevosian and N. M. Divanian

PREPARATION

Magnesium turnings (7.2 g, i.e. 0.3 g-atom), which had been washed with absolute alcohol and dry ether, dry ether (150 ml), and an iodine crystal were introduced into a one-liter three-necked round-bottomed flask fitted with mercury- sealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. Over a period of 90 minutes a solution of 60 g (0.38 mole) of freshly distilled bromobenzene in 100 ml of dry ether was added from the dropping funnel (Note 1). When the whole of the bromobenzene had

38

been added, the mixture was boiled gently in a water bath for four

hours until dissolution of the magnesium was substantially complete.

The contents of the flask were then cooled with ice and salt and

were stirred continuously for 40-50 minutes while a solution of

27.3 g (0.27 mole) of freshly distilled 2-furaldehyde in 150 ml of

dry ether was added.

When the whole of the 2-furaldehyde had been added, the mix

ture was boiled in a water bath for 2.5-3 hours. It was then cooled

with ice and salt, and with continued stirring the reaction product

was decomposed by gradual addition of a solution of 55 g of ammon

ium chloride in 200 ml of water. The upper, ether layer was sep

arated, and the residue was extracted with three 75-ml portions

of ether (Note 2); these were added to the main solution, which

was dried with calcined sodium sulfate. Ether was distilled off,

and the residue was vacuum-fractionated; a-phenylfurfuryl alcohol

was collected at 137-138°/2 mm (Note 3).

Yield 31.2-32.6 g (59.4-62.1%) (Note 4).

a -Phenylfurfuryl alcohol (C11H100 2; mol. wt. 174.08) is a light

yellow viscous liquid, insoluble in water, but soluble in organic

solvents; b.p. 125-126°/0.5 mm; d204 1.1506; n20D 1.5570. With

keeping, even in a sealed tube, it becomes dark-colored.

NaTES

1. The reaction generally starts after the flask is warmed for a short time in a water bath; it then proceeds steadily to completion.

2. In the extraction of the aqueous solution vigorous shaking of

the separation funnel should be avoided in order to avoid the

formation of a difficultly separable emulsion. 3. It is very important that the residual pressure should not

exceed 2 mm; at higher pressures the substance resinifies during

distillation. 4. a -Cyclohexyl-, a-benzyl-, and a-phenethyl-furfuryl alcohols

were prepared in satisfactory yields by the above procedure.


a- Phenylfurfuryl alcohol has been prepared only by reaction

between phenylmagnesium halides and 2-furaldehyde1• It has been

39

shown that the yield can be increased to 65% by use of excess of Grignard reagent and removal of ether at a residual pressure of 3-4 mm2• The above procedure gives quite satisfactory results3•

LITERATURE CITED

1 F. N. Peters and R. Fischer, J. Am. Chern. Soc. 52, 2079 (1930); A. P. Hewlett, Iowa State Coli. J. Sci. 6, 439 (1932); C. A. 27, 9804 (1933); M. Protiva and M. Borovicka, Chern. Listy, 43, 56 (1949); C. A. 45, 576i (1951); j. H. Biel, j. Am. Chern. Soc. 71, 1306 (1949).

2 R. Paul, C.r. 202, 1444 (1936). 3 A. L. Mndzhoian, 0. L. Mndzhoian, and E. R. Bagdasarian,

Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 23, 175 (1956).

FURAN

OcooH .... 0 +cot 0 0

Checked by G. T. Tatevosian and S. P. Ekmekdzhian

PREPARATION

The apparatus used in the preparation of furan is shown in Fig. 2. The round-bottomed flask A has a side neck which carries a thermometer B reaching almost to the bottom of the flask. The mouth of the flask is closed with a rubber bung through which passes the vertical tube C, 15 em in length and 1.8-2.0 em in diameter. The upper end of the tube C is closed with a rubber stopper, which carries a long glass rod D; this is used for pushing sublimed 2-furoic acid back into the flask. A side tube E, diameter 1.8-2.0 em, is fused to the vertical tube C at 2.5-3 em from its upper end. The narrower (diameter 1 em) vertical part of the tube E ends at the bottom of the column F, which is 3.5-4 em in diameter and 25 em in height. The column F is filled with pieces

40

of sodium hydroxide of the size of a pea, which are separated from the end of the tube E by a layer of cotton wool (Note 1). The column F is immersed in a water bath (a tall beaker) at 45-50°. The exit tube of the column F is connected to a sloping condenser attached to a receiver immersed in ice and salt (Note 2).

F

8

Fig. 2.

Flask A was charged with 80 g (0. 71 mole) of 2-furoic acid (see p. 43), m.p. 128-132°, which was heated to 200-205°; steady decarboxylation of the furoic acid then proceeded in this temperature range. Heating continued for 4-5 hours, after which time a very small amount of liquid remained and the upper parts of the flask walls were covered with a deposit of sublimed 2-furoic acid. In order to decompose the remaining acid the upper parts of the flask were covered with asbestos paper and the temperature was raised to 210-215°. Some of the furoic acid then sublimed into the tube C, and from time to time this was pushed back into the flask with the glass rod D. At the end of the experiment the walls of the flask and the lower part of the vertical tube remained covered with a thin film of 2-furoic acid.

The distillate was poured into a previously cooled (ice water) 100-ml distillation flask, the side tube of which branched from a high point on the neck. It was then redistilled from a water bath, furan being collected at 27-28°/680 mm or 31-34°/745 mm.

Yield 36-39 g (74. 7-80.2c;,).

41

Furan (C4H40; mol. wt. 68.03) is a colorless liquid, insoluble in water, but readilysolubleinalcoholandin ether; b.p. 31-32°/760 mm; d204 0.9087; n20D 1.4220.

NOTES

1. An important cause of low yields lies in the loss of furan by entrainment in the stream of carbon dioxide. The sodium hydroxide column is intended for the absorption of carbon dioxide and water vapor.

2. A small coil condenser forms a satisfactory receiver.


In recent years the decarbonylation of 2-furaldehyde has been widely employed; it is suitable not only for the laboratory preparation of furan, but also for its manufacture. The decarbonylation is carried out by adding 2-furaldehyde toafused mixture of sodium and potassium hydroxides1 or by passage of its vapor over heated soda-lime2• The reaction can be carried out also in presence of the chromites3 and molybdites4 of zinc and copper at 300-400°; in the patent literature nickel, iron, platinum5, and palladium6

catalysts have been recommended.

Convenient laboratory methods for the preparation of furan are based on the decarboxylation of 2-furoic acid. The decarboxylation has been carried out by the dry distillation of the barium salt 7 or by heating this salt with soda lime8• The free acid may be decarboxylated by heating it in quinoline in presence of cupric oxide as catalyst 9•

The procedure given above is, with some modifications in detail, that proposed by W. C. Wilson10 for the thermal decarboxylation of 2-furoic acid.

LITERATURE CUED

1 C. D. Hurd, A. R. Goldsby, and E. N. Osborne, J. Am. Chern. Soc. 54, 2532 (1932).

42

2 V. A. Kozin, Zh. priklad. khim. (J. Appl. Chern.) 26, 442 (1953). 3 0. W. Cass, Ind. Eng. Chern. 40, 216 (1948). 4 U. S. Pat. 2,634,276 (1953); C. A. 48, 2115b (1954).

5 Italian Pat. 421,626 (1947); C. A. 43, 5047g (1949). 8 H. E. Eschinazi, Bull. soc. chim. 967 (1952). 7 P. Freundler, C.r. 124, 1157 (1897); Bull. soc. chim. (3) 17,

613 (1897). R H. Limpricht, A. 165, 281 (1878). 9 E. C. Wagner andj. K. Simons,]. Chern. Educ. 13,270 (1936);

H. Narasaki and N. Ito, Repts. Govt. Chern. Ind. Research Inst. Tokyo 46, 199 (1951); C. A. 46, 4524b (1952).

10 Organic Syntheses (Russian Translation), Vol. 1, p. 449, Foreign Lit. Press, Moscow, 1949 [Organic Syntheses, Collective Vol. 1, 2nd Ed., New York and London, 1941, p. 274.]

2-FUROIC ACID AND FURFURYL ALCOHOL

Checked by V. G. Afrikian and M. T. Grigorian

PREPARATION

A four-liter glass jar fitted with stirrer, dropping funnel, and thermometer was charged with 700 g (600 ml, 7.2 moles) of freshly distilled 2-furaldehyde (see p. 51), b.p. 158-162°, and cooled with ice to 5-8°. Addition was made from the dropping funnel of 500 g of a 30% solution of technical sodium hydroxide at such a rate that the temperature of the reaction mixture did not exceed 15°; when efficient cooling was used, addition of alkali was complete in 25-30 minutes. Stirring was continued for 1.5-2 hours after the addition was complete.

The reaction mixture was allowed to come to room temperature, and 300 ml of water was added to dissolve the sodium 2-furoate that had separated in the form of fine scalelike crystals.

43

The solution was placed in a continuous extractor (Fig. 3), and furfuryl alcohol was extracted with ether (Note 1). When extraction was complete, the ether layer was separated and was distilled until the temperature of the liquid reached 95°; the residue was vacuum -distilled with collection of the fraction coming over at 75-77°/15 mm.

The yield of furfuryl alcohol was 226.8-230.5 g (63.5-64.5i).

Furfuryl alcohol (C5lfa02; mol. wt. 98.05) is a colorless liquid of characteristic odor, readily soluble in water, alcohol, and ether; b.p. 68-69°/10 mm, 170-17r/758 mm; d22 •74 1.1282; n22 •7D1.4851. On standing in the air it becomes light yellow in color.

Fig. 3.

After the extraction, the aqueous solution, which contained sodium 2-furoate, was acidified to Congo red with dilute sulfuric or hydrochloric acid. The furoic acid that separated was filtered off at the pump and dried in the air. For purification it was dissolved in 1500-1600 ml of water and boiled with 70 g of animal charcoal for 50-60 minutes. The hot solution was filtered and cooled to 10-15° with stirring. The precipitated colorless crystals

44

were filtered off at the pump and dried in the air; m.p. 128-132°, weight 277-279 g. By evaporation of the mother liquor to dryness and extraction of the residue with ether a further amount of the acid was isolated; after recrystallization from water it melted at the same temperature and amounted to 48--50 g.

The total yield was 320-327 g (78.4-80.1%).

2-Furoic acid (C5H40 3; mol. wt. 112.08) forms colorless leaves (from water) or needles (when sublimed), m.p. 132-133°; it is sparingly soluble in cold water, dissolves more readily in hot water and in alcohol, and is readily soluble in ether.

NafES

1. The solution was placed in the extractor A, which was then filled to the top with ether. Ether (200-250 ml) was poured into the flask B, which was heated on a sand bath. Ether vapor passed through the tube C into the condenser D, where it condensed and flowed into the extractor. The contents of the extractor were constantly stirred (E represents a mercury-sealed stirrer). From time to time ether was passed into the system from the funnel F.

The extraction of furfuryl alcohol was continued until the ether layer in the extractor was no longer colored (36-40 hours); toward the end of the extraction the ether solution in the flask became light yellow.

2. The furfuryl alcohol obtained is entirely soluble in water and is light yellow in color. If it is to be stored, 0.5-1% by weight of urea should be added as stabilizer.


2-Furoic acid can be prepared by the oxidation of 2-furaldehyde with potassium permanganate1, alkali-metal dichromates2, or atmospheric oxygen in presence of catalysts containing silver oxide3• The oxidation of 2-furaldehyde4, and also of ethyl2-furyl ketone5, to 2-furoic acid has been effected by means of sodium hypochlorite. 2-Furoic acid can be obtained, together with furfuryl alcohol, from 2-furaldehyde by the Cannizzaro reaction, which can be brought about with the aid of sodamide6 or concentrated caustic alkali solutions 7•

45

Furfuryl alcohol can be prepared by the reduction of 2-furaldehyde with sodium amalgam8• The catalytic reduction of 2-furaldehyde is widely used: it is carried out under pressure in the liquid phase at temperatures of the order of 130-160° in presence of copper9 and copper-chromium10 catalysts containing alkaline-earth oxides. Furfuryl alcohol has been obtained in 85% yield by the reduction of 2-furoic acid with lithium aluminum hydride11 • The dismutation of 2-furaldehyde, which may be effected with the aid of sodamide6 or alkali solutions 7, results in the formation of furfuryl alcohol and 2-furoic acid; the yield of furfuryl alcohol can be raised by carrying out a mixed Cannizzaro reaction with 2-furaldehyde and formaldehyde12 *.

The procedure given above was proposed by Wilson13 and ha~ been somewhat modified in detail.

LITERATURE CITED

1 Schwanert, A. 116, 259 (1860); J. Volhard, A. 261, 280 (1891); P. F. Frankland, and F. W. Aston, J. Chern. Soc. 79, 515 (1901); E. C. Wagner and J. K. Simons, J. Chern. Educ. 13, 270 (1936).

2 C. D. Hurd, J. W. Garret, and E. N. Osborne, J. Am. Chern. Soc. 55, 1084 (1933).

3 U. S. Pat. 2,041,184; C. A. 30,45157 (1936); Italian Pat. 439,947; C. A. 44, 5915c (1950); R. Andrisano, Boll. Sci. Faculta chim. Ind. Bologe 7, 66 (1949); C. A. 44, 9404h (1950); Japanese Pat. 1111 (51); C. A. 47, 3883a (1953).

4 Japanese Pat. 1130 (50); C. A. 47, 2214d (1951). 5 M. W. Farrer and R. Levine, J. Am. Chern. Soc. 71-, 1496

(1949). 6 J. Kasiwagi, Bull. Chern. Soc. Japan 1, 66 (1926); C. A. 20,

2491 (1926). 7 H. Limpricht, A. 165,279,300 (1873); K. Bieler and B. Tollens,

A. 258, 119 (1890); E. Erdmann, Ber. 35, 1855 (1902); H. Gilman and C. C. Vernon, J. Am. Chern. Soc. 46, 2576 (1924).

8 Schmelz, F. Beilstein, An. Suppl. 3, 275 (1864-65). 9 U. S. Pat. 2,077,409; C. A. 31, 39444 (1937); J. G. M. Bremner

and R. K. F. Keeys, J. Chern. Soc. 1068 (1947); Australian Pat. 135,530 (1949); C. A. 44, 4932i (1950).

*This method is described in Volume 2 of this work. - Publisher.

46

10 G. Roberti, Ann. chim. applicata 25, 530 (1935); C. A. 30, 41657 (1936); U.S. Pat. 2,094,975; C. A. 31, 85494 (1937); 2,400,959; C. A. 40, 48606 (1946); S. Mizuguchi and M. Iwace, J. Chern. Soc. Ind. Japan 46, 1037 (1943); C. A. 42, 6353i (1948); K. Truda, S. Yoshida, M. Yamada, and Y. Maruya, J, Pharm. Soc. Japan 66, 58 (1946); C. A. 45, 6182e (1951); Italian Pat. 461,821 (1951); C. A. 46, 2842i (1952).

11 R. F. Nystrom and W. G. Brown, J. Am. Chern. Soc. 69, 2548 (1947).

12 A. M. Berkengeim and T. F. Dankova, Zh. obshchei khim. (J. Gen. Chern.) 9, 924 (1939).

13 Organic Syntheses (Russian Translation), Vol. 1, p. 351, Foreign Lit. Press. Moscow, 1949 [Organic Syntheses, Collective Volume 1, 2nd Ed., New York and London, 1941, p. 276.]

5-(2-FURYL)-s-TRIAZOLE-3-THIOL

Na + HaO

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by 0. L. Mndzhoian and N. A. Babiian

PREPARATION

A mixture of sodium methoxide solution prepared from 2.6 g (0.11 g-atom) of sodium and 40 ml of dry methanol, 18.5 g (0.1 mole) of 1-(2-furoyl)-3-thiosemicarbazide (see p. 49), m.p. 2030, and 100 ml of anhydrous ethanol (see Notes) was prepared in an autoclave having a capacity of 0.5-1 liter. The temperature was brought to 145-150° and maintained at this level for three hours.

47

When cool, the product was transferred to a beaker, and the autoclave was washed out with 100-150 ml of 96% alcohol, which was added to the main solution. The solution was filtered, alcohol was distilled off completely under the vacuum of a water pump, and the residue was dissolved in 50 ml of water.

In order to liberate the furyltriazolethiol, 18-20% hydrochloric acid was stirred into the solution until it was acid to Congo red. The precipitate was filtered off at the pump and washed with 30-40 ml of water. The air-dried crude product melted at 263°, For purification it -was dissolved in hot saturated sodium carbonate solution (about 200-250 ml), and the solution was filtered and cooled; 18-20% hydrochloric acid was added to precipitate the product. The precipitate was filtered off at the pump, washed with water until the washings were neutral, and dried in the air; m.p. 272-273°.

Yield 14-15 g (83.8-89.8%).

5-(2-Furyl)-s-triazole-3-thiol (C6lfsON3S; mol. wt. 167.20) is a colorless finely crystalline substance, insoluble in water, ether, and benzene; sparingly soluble cold and moderately soluble hot in methanol, ethanol, and acetone.

NOTES

Instead of ethanol, the same amount of dry methanol can be used.


5-(2-Furyl)-s-triazole-3-thiol has been prepared only by the method described above1•

LITERATURE CITED


48

1-(2-FUROYL)-3-THIOSEMICARBAZIDE

0 01 HH COCI + H1NNHCNH2 .... CON-N-C-NH1 ·HCI

o n o u s s

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by N. A. Babiian and S. S. Manucharian

PREPARATION

A mixture of 28 g (0.22 mole) of thiosemicarbazide hydrochloride and 150 ml of dry pyridine was boiled for 20-25 minutes in a 300-ml four-necked round-bottomed flask fitted with mercurysealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. The contents of the flask were stirred and cooled with ice and salt to a temperature of from -7° to -5°, and 26.1 g (0.2 mole) of 2-furoyl chloride (seep. 56), b.p. 89-90°/ /32 mm, was added dropwise at such a rate that the temperature of the mixture did not rise above -3° (Note 1); 1.5-2 hours was required for the addition of the acid chloride. When the addition was complete, without removal of the bath stirring was continued for four hours (the temperature gradually rose to that of the room); the mixture was then left overnight.

The resulting mixture of furoylthiosemicarbazide and pyridine hydrochloride was filtered off at the pump and carefully pressed on the filter. In order to remove pyridine as completely as possible (Note 2), the filter was transferred to a beaker and carefully treated with fresh portions of dry ether; suction was again applied, and the residue was washed with ether. Ether and pyridine were distilled from the filtrate, first at atmospheric pressure and then under the vacuum of a water pump. Ice water (10 ml) was added to the residue, and the precipitate was filtered off and washed with ether.

The product isolated from the filtrate was added to the main product, which was dried and washed with 30-35 ml of ice water in order to remove pyridine hydrochloride. It was again subjected to suction, pressed off, and dried in the air; this gave a crude product, m.p. 180°. For purification the 1-(2-furoyl)-3-thiosemicarbazide was recrystallized from glacial acetic acid; the product

49

was filtered off, pressed, and washed on the filter with two 25-ml portions of ether; it was dried in the air; m.p. of the pure substance 203°.

Yield 18.5-20.5 g (50-55.4%).

1-(2-Furoyl)-3-thiosemicarbazide (C6H70 2N3S; mol. wt. 185.15) is an almost colorless crystalline substance, soluble in water, alcohol, pyridine, and acetic acid; insoluble in ether and benzene.

NafES

1. Above a temperature of from -3°tO -2°resinification occurs with great reduction in yield.

2. Pyridine must be removed completely; otherwise, in the further treatment of the residue with ice water some of the main product is dissolved in the pyridine-water mixture.


1-(2-Furoyl)-3-thiosemicarbazide has been prepared only by the method described above1•

LITERATURE CITED

1 A. L. Mndzhoian and V. G. Mrikian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 168 (1953).

50

2-FURALDEHYDE (FURFURAL)

C H O -3Ha0 s IO s HaSO.., OcHo

0

Checked by G. T. Tatevosian and N. M. Divanian

PREPARATION

The apparatus used for the preparation of 2-furaldehyde is shown in Fig. 4. The five-liter round-bottomedflaskA is connected by means of a cork to the air condenser B, which consists of a tube of diameter 1.8 em and length 50 em. A bent side tube C is sealed to B at a distance of 15 em from its lower end. The bent upper end of the tube B is connected to a sloping condenser. The end of the condenser is connected to a long receiver adapter having an open side tube. The end of the adapter is at the bottom of a distillation flask, capacity 250-300 ml, which serves as a receiver.

Fig. 4.

51

Before an experiment, 80-100 ml of distilled chloroform is placed in the receiver. The side tube of the distillation flask, which must be a few centimeters higher than the side tube C, is connected to the latter by a rubber tube, and during the distillation of the 2--furaldehyde the aqueous layer flows back to the flask A through this tube. The hydraulic seal formed in the rubber tube below the side tube C prevents the passage of vapor through the rubber tube from the flask A to the receiver.

A mixture of 750 g of corn cob stalks freed from grain and ground to the size of peas, 1 kg of common salt, and 2.5 liters of 1 O% sulfuric acid was prepared in the flask A. The mixture was shaken carefully, the apparatus was assembled as described above, and flask A was placed ina well-heateddeep sand bath (the 2-furaldehyde formed must be distilled off rapidly; see Notes).

The 2-furaldehyde, which came over with steam, collected in the chloroform layer. The distillation was stopped when the chloroform level in the receiver ceased to rise, which required 7-10 hours. The chloroform solution of 2-furaldehyde was separated from the aqueous layer, washed with dilute alkali and with water, and dried over calcined sodium sulfate.

Most of the chloroform was distilled from a flask having a short fractionation column. The rest was distilled off under reduced pressure and was followed by the 2-furaldehyde, which was distilled from an oil bath (the temperature ofthe bath must not exceed 130°). A few milliliters of head fraction were followed by pure colorless 2-furaldehyde, which came over at 70-72°/25 mm.

The yield was 78-80 g.

2-Furaldehyde (C5H40 2; mol. wt. 96.08) is a colorless liquid of characteristic odor, sparingly soluble in water, but readily soluble in alcohol and ether; m.p. -36°; b.p. 161-162°/760 mm; d204 1.1594; n2"o 1.5260. With keeping it becomes dark-colored and gradually resinifies.

NarES

It is recommended that, in order to increase the rate at which the 2-furaldehyde distills, the uncovered parts of the flask A and the air condenser B should be covered with asbestos.

52


2-Furaldehyde can be prepared in high yields by the action of hydrochloric and hydrobromic acids on xylose and other pentoses1•

Vegetable materials containing pentosans form an accessible source of 2-furaldehyde; such materials include corn cob stalks, various woods, husks and straws of oats, rice, and other cerials, hemp fiber, and sugar cane pith. The hydrolysis of the pentosans and distillation of the 2-furaldehyde formed are carried out by heating the vegetable material with dilute hydrochloric or sulfuric acid; more rarely nitric and phosphoric acids are used. The extensive literature on the preparation of 2-furaldehyde has been reviewed in several articles published in recent years2•

The directions given above are those of R. Adams and V. Voorhees3; some modifications in detail have been made.

LITERATURE CITED

1 W. E. Stone and D. Lotz, Ber. 24, 3019 (1891); I. J. Duncan, Ind. Eng. Chern., Anal. Ed. 15, 162 (1943); G. A. Adams and A. E. Castagne, Canadian j. Research 26, B 309 (1948).

2 A. V. Vacek, Angew. Chern. 54, 453 (1941); H. J. Brownlee and C. S. Miner, Ind. Eng. Chern. 40, 201 (1948); E. Lemaire, Industrie chimique 36, 116, 138 (1949); S. Wolf, Faserforsch. Textiltech. 4, 199 (1953).

3 Organic Syntheses (Russian Translation), Vol. 1, p. 454, Foreign Lit. Press, Moscow, 1949 [Organic Syntheses, Collective Vol. 1, 2nd Ed., New York and London, 1941, p. 280.]

53

5-BENZYL-2-FUROYL CHLORIDE

Qcl!, QcooH +SOC I,-· QcH. Qcoct t so.+ HCt

Proposed by V. G. Afrikian and A. A. Dokhikian Checked by G. T. Tatevosian and N. M. Divanian

PREPARATION

The reaction was carried out in a 200-ml round-bottom flask fitted with reflux condenser protected by a calcium chloride tube. In order to trap the gases liberated during the reaction, the end of the calcium chloride tube was connected to a Tishchenko vessel containing a solution of caustic alkali. A solution of 20.2 g (0.1 mole) of 5-benzyl-2-furoic acid (see p. 7), m.p. 104-105°, in 50 ml of dry benzene was introduced into the flask, and a solution of 14.5 g (0.12 mole) of freshly distilled thionyl chloride in 30 ml of benzene was added.

The mixture was boiled in a water bath for four hours, and excess of thionyl chloride and benzene was then distilled off under reduced pressure (water pump). The residue was vacuum-distilled with collection of the substance coming over at 153-155°/2 mm.

The yield was 17.8-19.0 g (80.9-86.3%).

5-Benzyl-2-furoyl chloride (C12H90 2Cl; mol. wt. 220.65) is a light-yellow liquid with a sharp odor; d204 1.2306; n20D 1.5835.


5-Benzyl-2-furoyl chloride has beenpreparedonlybythemethod described above1•

LITERATURE CITED

1 A. L. Mndzhoian, V. G. Afrikian, and A. A. Dokhikian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 169 (1953).

54

5-METHYL-2-FUROYL CHLORIDE

Proposed by A. L. Mndzhoian, V. G. Afrilcian, and M. T. Grigorian Checked by G. T. Tatevosian and S. G. Agbalian

PREPARATION

The reaction was carried out in a 100-ml round-bottomed flask fitted with reflux condenser protected by a calcium chloride tube. In order to trap the hydrogen chloride and sulfur dioxide formed in the reaction the end of the calcium chloride tube was connected to a Tishchenko vessel containing a solution of caustic alkali. A solution of 12.6 g (0.1 mole) of 5-methyl-2-furoic acid (seep. 23), m.p. 108--109°, in 40 ml of dry benzene was introduced into the flask, and a solution of 13.1 g (0.11 mole) of freshly distilled thionyl chloride in 30 ml of dry benzene was added.

The mixture was boiled in a water bath for 4-5 hours, and excess of thionyl chloride and benzene was then distilled off under reduced pressure (water pump). The residue was vacuum-distilled with collection of the substance coming over at 91-92°/35 mm. On standing, the distillate solidified completely; m.p. 30-33° (see Notes).

Yield 12.6-13.3 g (87.5-92.3%).

5-Methyl-2-furoyl chloride (C6H50 2Cl; mol. wt. 144.56) forms yellowish needles which have a sharp odor.

NOTES

5-Methyl-2-furoyl chloride is lacrimatory; appropriate precautions must therefore be taken when working with this substance.


5-Methyl-2-furoyl chloride has been prepared by the action of phosphorus tri- or penta-chloride on the acid1• Higher yields of the acid chloride are obtained when thionyl chloride is used2•

55

LITERATURE CITED

1 H. B. Hill and C. R. Sanger, Am. Chern. J. 20, 171 (1898). 2 A. L. Mndzhoian, V. G. Afrikian, and M. T. Grigorian, Doklady

Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 169 (1953); j. R. Willard and C. S. Hamilton, j. Am. Chern. Soc. 75, 237 (1953).

2-FUROYL CHLORIDE

QcooH + SOCit--. Q COCI +SO, t HCI

Proposed by A. L. Mndzhoian Checked by V. G. Afrikian and M. T. Grigorian

PREPARATION

A mixture of 56 g (0.5 mole) of 2-furoic acid (seep. 43), m.p. 128-132°, and 100 mlofdrybenzenewas prepared in a 300-ml round-bottomed flask fitted with reflux condenser protected by a calcium chloride tube; a solution of 71.5 g (0.6 mole) of freshly distilled thionyl chloride in 50 ml of benzene was then added. The upper end of the calcium chloride tube was connected to a Tishchenko vessel containing a solution of caustic alkali, which served to absorb hydrogen chloride and sulfur dioxide liberated during the reaction.

The mixture was boiled in a water bath for 10-12 hours, and excess of thionyl chloride and benzene was then distilled off under reduced pressure (water pump). The residue was vacuum -distilled at 89-90°/32 mm.

The yield was 59.4-60 g (91.1-92.0%).

2-Furoyl chloride (C5H30 2Cl; mol. wt. 130.53) is a colorless lacrimatory liquid, b. p. 66°/10 mm, 170-173°/760 mm.

56


2-Furoyl chloride has been prepared by heating the acid with phosphorus pentachloride to 160° in absence of solvent 1; higher yields of the acid chloride were obtained by carrying out the reaction in a solvent (chloroform) 2• There is a reference in a patent to the formation of the acid chloride by reaction of 2-furoic acid with an excess of phosgene under pressure at temperatures of up to 100o3. A convenient method for the preparation of 2-furoyl chloride consists in the action of excess of thionyl chloride on the acid in a benzene medium'.

The highest yields of 2-furoyl chloride are obtained by the procedure described above5•

LITERATURE CITED

1 Lies- Bodart, C.r. 43, 393 (1856); A. 100, 327 (1856). 2 P. F. Frankland and F. W.Aston,j.Chem. Soc. 79,516 (1901);

G. Chavanne, C.r. 134, 1439 (1902). 3 Canadian Pat. 373,516 (1938); C. A. 32, 50034 (1938). 4 E. Baum, Ber. 37, 2951 (1904); N. N. Maxim, Bull. Soc. Chim.

Romania 12, 33 (1930); C. A. 25, 5139 (1931); W. W. Hartman and j. B. Dickey, Ind. Eng. Chern. 24, 151 (1932).

5 A. L. Mndzhoian, Zh. obshchei khim. (J. Gen. Chern.) 16, 751 (1946).

57

FURFURYL CHLORIDE

Q CH20H + SOCI 2 - Q CH2CI +SO:~.+ HCI

Proposed by G. T. Tatevosian and S. P. Ekmekdzhian

PREPARATION

A 500-ml four-necked flask fitted with mercury-sealed stirrer, dropping funnel, thermometer, and calcium chloride tube was charged with 46.2 g (0.47 mole) of freshly distilled furfuryl alcohol (see p. 43), b.p. 75-77° /15 mm. With gentle stirring 44.7 g (0.56 mole, 20% excess) of pyridine (driedwithpotassium hydroxide and distilled) was added, and this was followed by 50 ml of dry ether. The flask was cooled with ice and salt and, at a temperature of from -8° to -10°, the mixture was stirred vigorously while a solution of 61.7 g (0.5 mole, 10% excess) of colorless distilled thionyl chloride in 50 ml of dry ether was added dropwise.

The thionyl chloride solution was added at the rate of 10 ml in 25-30 minutes; under these conditions the temperature of the reaction mixture gradually rose. Cooling ofthe flask was controlled so that the temperature of the mixture at the end of the experiment was not above 2-3°. Shortly after the start of the addition of thionyl chloride an oily layer separated and, as a result of the stirring, formed an emulsion. Toward the end of the experiment the layer solidified to a sticky light-brown precipitate; this later became yellowish black in color. The particles of the precipitate stuck together and formed large lumps, which sometimes stopped the stirrer. In such cases the stirrer was switched off, the calcium chloride tube was removed, and the lumps were broken up and ground down with the aid of a thick glass rod; the calcium chloride tube was then replaced, and stirring of the mixture and addition of thionyl chloride were continued. When the whole of the thionyl chloride solution had been added, stirring was continued for about 30 minutes.

In order to extract the reaction product, the calcium chloride tube was removed, part of the flask was cleared of precipitate with

58

the aid of the glass rod, and the flask was firmly stoppered with a cork carrying a siphon tube which reached almost to the bottom of the flask. The long end of the siphon passed into a 500-ml conical flask. With the aid of a rubber bulb attached to the dropping funnel a small pressure was created in the flask, so that the liquid filled the siphon and passed into the conical flask. The siphon was then removed, 50 ml of dry ether was poured into the flask, and the contents were stirred for 5-10 minutes; a space was then cleared for the siphon with the aid of the glass rod, and the liquid was again siphoned into the same receiver. Extraction with ether was performed three times, and in the last extraction the flask was removed from the cooling bath.

The ether solution of the reaction product was placed in an ice bath and was stirred while 50 ml of 50% potassium hydroxide solution (previously cooled with ice water) was added in small portions. As the mixture was stirred, a sticky resin separated and adhered to the walls of the flask. The light-yellow ethereal solution was separated from the water layer and dried with anhydrous sodium carbonate. The total volume of the ethereal solution was 225-230 ml (Note 1).

The ethereal solution was distilled in 75-ml portions (Note 2). The distillation was carried out from a Claisen flask having a capacity of 25--30 ml; it was connected to a small condenser (Note 3). Air which passed through a capillary into the distillation flask was first passed through a tube containing soda-lime. The ethereal solution was poured into the flask in small portions, and ether was distilled off in the cold under reduced pressure. When the whole of the ether had been distilled from 75 ml of solution, a yellowish- brown liquid remained in the flask. When this was heated in a water bath, a colorless liquid boiling at 49-50°/27 mm came over. A little resinous matter remained in the flask.

Yield 7.2--7.5 g (39.4-41%, calculatedonone-thirdofthe amount of furfuryl alcohol taken).

Furfuryl chloride (C5H50Cl; mol. wt. 116.55) is a colorless liquid, soluble in organic solvents, but insoluble in water; b.p. 49.1-49.4°/26 mm, 54-54.4°/33 mm; d204 1.1783; n20D 1.4941. Shortly after distillation the compound develops a turbidity; it then darkens in color and resinifies (Note 4).

59

NaTES

1. When the furfuryl chloride is to be used in further reactions, this ethereal solution is generally used for this purpose without being distilled. The solution obtained by this procedure contains about 13-13.5% by weight of furfuryl chloride.

2. Furfuryl chloride is an unstable substance which rapidly resinifies in absence of solvent. It can be distilled only when special precautions are taken to avoid prolonged heating and to exclude moisture and traces of acid.' The distillation of larger amounts of the ethereal solution, which would necessitate longer heating, leads to considerable reduction in yield due to resinification.

3. The distillation flask, condenser, and receiver (a small distillation flask makes a suitable receiver) must be carefully washed with caustic alkali solution and with distilled water, and then dried thoroughly at 100-130°.

4. Distilled furfuryl chloride cannot be kept, even in sealed tubes; it must be used in syntheses immediately after distillation.


An ethereal solution of furfuryl chloride has been prepared by the action of thionyl chloride on a cooled solution of furfuryl alcohol in ether1; the resulting solution contained about 10% of furfuryl chloride. In this reaction thionyl chloride has been replaced by hydrogen chloride in presence of calcium carbide, which acts as a dehydrating agent1; in this case the furfuryl chloride content of the resulting solution was not more than 5%. It has been proposed that chloroform be used instead of ether as solvent 2•

However, furfuryl chloride cannot be isolated in the pure state from solutions prepared in these ways. It can be isolated from solution only in complete absence of traces of acid, a condition that can be satisfied by carrying out the reaction in presence of pyridine.

The procedure described above was proposed by W. R. Kirner3•

LITERATURE CITED

1 H. Gilman and S. S. Vernon, j. Am. Chern. Soc. 46, 2576 (1924).

60

2 0. Moldenhauer, G. Trautman, R. Pfluger, and H. Doser, A. 580, 180 (1953).

3 W. R. Kirner, J. Am. Chern. Soc. 50, 1955 (1928); T. Reichstein, Ber. 63, 751 (1930).

2-CHLOROETHYL 2-FUROATE

Proposed by A. L. Mndzhoian and M. T. Grigorian Checked by 0. L. Mndzhoian and E. R. Bagdasarian

PREPARATION

A mixture of 22.4 g (0.2 mole) of 2-furoic acid (seep. 43), m.p. 128-132°, and 98 g (1.2 moles) of 2-chloroethanol was prepared in a 250-ml three-necked round-bottomed flask fitted with mercury- sealed stirrer, reflux condenser, and a glass tube which passed to the bottom of the flask.

The mixture was heated to the boil in an oil bath, and a rapid stream of hydrogen chloride (which was first passed through a wash bottle containing concentrated sulfuric acid) was passed into the boiling solution for 5-6 hours. The mixture was then cooled to room temperature and poured into a flask containing 150 ml of water. The oily layer was separated, and the aqueous layer was extracted with two 50-ml portions of ether. The ether extracts were added to the main product, and the whole was washed with 20 ml of 5% sodium carbonate solution and then with water; it was dried over anhydrous sodium sulfate. Solvent was distilled off, and the residue was vacuum -distilled at 126-128°/10 mm.

Yield 25.1-25.4 g (71.9-72. 7%).

2-Chloroethyl 2-furoate (C 7H70 3Cl; mol. wt. 174.59) is a colorless liquid, insoluble in water, but soluble in the usual organic solvents; d20 4 1.2817; n20D 1.5040.

61


2-Chloroethyl 2-furoate has been prepared only by the esterification of the acid with 2-chloroethanol in accordance with the above directions1•

LITERATURE CITED

1 A. L. Mndzhoian and M. T. Grigorian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 170 (1953).

2-CHLOROETHYL 5-(CHLOROMETHYL)-2-FUROATE

QcOOCH2CH2Cl + CH20 + HCI ~ CICH'l Q COOCH2CH 2CI + H20

Proposed by A. L. Mndzhoian, V. G. Afrikian, and M. T. Grigorian Checked by 0. L. Mndzhoian and E. R. Bagdasarian

PREPARATION

A 200-ml round-bottomed four-necked flask fitted with stirrer, glass tube passing to the bottom of the flask, thermometer, and gas-outlet tube was charged with 17.4 g (0.1 mole) of 2-chloroethyl 2-furoate (see p. 61), b.p. 126--128°/10 mm, 4.5 g (0.15 mole, calculated as formaldehyde) of paraformaldehyde, 40 ml of dry chloroform, and 3.4 g (0.025 mole) of anhydrous zinc chloride.

The stirrer was set into motion, and a rapid stream of hydrogen chloride (which was first passed through a wash bottle containing concentrated sulfuric acid) was passed into the reaction mixture; the temperature of the reaction mixture gradually rose. It was found that the temperature must not exceed 24-26° (Note 1), and it was necessary to cool the flask. The end of the reaction was indicated by the complete dissolution of the paraformaldehyde; at

62

this point the reaction mixture turned dark red and spontaneous evolution of heat gradually stopped. The reaction lasted for 2-2.5 hours.

The mixture was poured into a flask containing 150 ml of water. The lower, oily layer was separated, and the aqueous layer was extracted with two 30-ml portions of chloroform, which were added to the main chloroform solution. The solution was washed with two 50-ml portions ofwateranddriedwithcalcium chloride. Solvent was distilled off, and the residue was vacuum-distilled with collection of the product boiling at 145-146°/2 mm.

Yield 17.6--17.8 g (78.9-79.8%).

2-Chloroethyl 5-(chloromethyl)-2-furoate (C8H80 3Cl2; mol. wt. 2?3.06) is a viscous liquid, readily soluble in the usual organic solvents, but insoluble in water (Note 2); d204 1.3571; n20D 1.5310.

NOTES

1. The temperature stated in the text is the optimum temperature: at lower temperatures reaction is very slow, and at higher temperatures resinification occurs and results in greatly reduced yields.

2. If allowed to come into contact with the skin of the face or hands, 2-chloroethyl 5-(chloromethyl)-2-furoate causes irritation and itching; the preparation must therefore be carried out in a fume cupboard.


2-Chloroethyl 5-(chloromethyl)-2-furoate has been prepared only by the method described above1•

LITERATURE CITED

1 A. L. Mndzhoian, V. G. Afrikian, andM. T. Grigorian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 171 (1953).

63

ETHYL(2-FUROYL)ACETATE (ETHYL a -OX0-2-FURANPROPIONATE)

Q COOCH~CH3 + CH3COOCH2CH3 + Na -

0 C = CHCOOCH2CH3 + CH,CHaOH + 1/ 1Ht. Q 1

ON a

OC=CHCOOCH2CH, + HCI ..... I ON a

Checked by A. A. Aroian and G. L. Papaian

PREPARATION

A 300-ml four-necked round-bottomedflaskfittedwithmercurysealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube was charged with 24.8 g (0.177 mole) of freshly distilled ethyl 2-furoate, m.p. 33-34°. The stirrer was set in motion, and the flask was heated in a water bath at a bath temperature of 75-80°. At this temperature 2 g of sodium wire was added (Note 1), and 8.8 g (9.8 ml) of ethyl acetate was added gradually from the dropping funnel (Note 2).

When the sodium had dissolved, the bath temperature was raised to 90-95°, a further 2 g of sodium wire was added, and 8.8 g of ethyl acetate was dropped in slowly. After about 20-30 minutes the contents of the flask turned into a hard red paste, and to dissolve this 50-60 ml of dry benzene was added.

Successive additions of 2 g of sodium wire and 8.8 g of ethyl acetate were made until 12 g (0.52 g-atom) of sodium and 52.8 g (0.6 mole) of ethyl acetate had been added; each new portion was added only after the previously added sodium had dissolved completely. After the addition of the fifth portion it was necessary to add 50-60 ml of dry benzene, and when the whole of these amounts

64

of reactants had been added a further 20-30 ml of dry benzene

was required.

Heating in the water bath (bath temperature 90-95j and stirring

were continued until the sodium was completely dissolved, which

usually required 8-12 hours (Note 3). At the end of the reaction

the contents of the flask were cooled with ice, and the product was

decomposed by the careful addition of 50-60 ml of ice water.

The reaction mixture was poured slowly into a one-liter beaker

containing 250 ml of dilute hydrochloric acid (50 ml of concentrated

acid and 200 ml of water); any lumps that formed were broken up

carefully with the aid of a rod. A further 15 ml of concentrated

hydrochloric acid was added, and the mixture was stirred until

the lumps had completely disappeared. The benzene layer was

separated, and the aqueous layer was extracted three times with

ether. The ether extracts were combined with the main benzene

solution, and the whole was dried over calcined sodium sulfate.

Solvent was distilled off, and the residue was vacuum-distilled.

A mixture of ethyl acetoacetate and unchanged ethyl 2-furoate

(about 5-8 g) was first separated, and a substance was then

collected in the range 119-125° /2 mm. This main, ethyl (2-furoyl)

acetate fraction was redistilled from a Claisen flask having a

Vigreux column (Note 4). The yield of pureproduct, b.p. 123-124°/

/2 mm, was 25-27 g (77.6-83.8~ on the amount of ethyl 2-furoate

taken).

Ethyl (2-furoyl) acetate (C9H100,; mol. wt. 182.18) is a light

yellow liquid, soluble in alcohol and ether, but insoluble in water;

b.p. 142-143°/10 mm, 170°/33 mm; d204 1.1839; n20D 1.5050.

NCYfES

1. Sodium wire can be replaced by fine parings, but the sodium

does not dissolve so readily and the duration of the reaction is

increased considerably. It is very important, especially for the

beginning of the reaction, that the surface of the sodium should

be quite fresh. 2. The ethyl acetate used must be dry and should contain about

2-3~ of alcohol; commercial ethyl acetate should be washed with

twice its volume of water, dried over fused potassium carbonate,

decanted, and used immediately for the synthesis.

65

3. Sometimes, particularly when finely cut pieces of sodium are used, some small pieces of sodium remain unchanged in the reaction mixture and may cause bursts of flame during the decomposition of the product with water.

4. Sometimes a little unchanged ethyl 2-furoate passes over with the main product and crystallizes after a time in the form of long needles. It is therefore recommended that the mixture be carefully fractionated from a flask having a fractionating column.


Ethyl (2-furoyl) acetate can be prepared in 68.2% yield by the condensation of ethyl acetate with methyl 2-furoate in presence of sodium methoxide1• Another method described for its preparation in 70% yield consists in the heating of tert-butyl ethyl (2 -furoyl)malonate with p-toluenesulfonic acid 2•

The above directions are based on the work of Sanderlin3 and of Barger, Robinson, and Smith4•

LITERATURE CITED

1 E. E. Royals, I. C. Hoppe, A. D. Jordan, and A. G. Robinson, ]. Am. Chern. Soc. 73, 5857 (1951).

2 D. S. Breslow, E. Baumgarten, and C. R. Hauser, J. Am. Chern. Soc. 66, 1286 (1944).

3 S. S. Sanderlin, Ber. 33, 492, 1176 (1900). 4 G. Barger, R. Robinson, and L. H. Smith, J. Chern. Soc. 718

(1937).

66

5-(AMINOMETHYL)-2-FUROIC ACID

(CH 2l6N4 • CICH2 0 COOCzH~ 0

(CH2)6N4· CICH2 0 COOCzH5 + 3HCI + I2C2H50H ~

HCI· H2NCHz Oc-DOCzH 5 + 6CH2(0C2H5h + 3NH 4CI ()

HCI· H2NCH2 (JcoOCzHs + NaOH -

H2NCH 2 0COOCzH6+ NaCI + HzO

H2NCH, OcoOCzHs + KOH -

HzNCHz 0 COOK + C2H 50H

H,NCH,oCOOK t CH,COOH-

H,NCH, OCOOH t CH,COOI(

Proposed by A. L. Mndzhoian and V. V. Dovlatian Checked by A. A. Aroian and N. Kh. Khachatrian

7

PREPARATION

Ethyl 5-(Aminomethyl)-2-furoate. A mixture of 56.6 g (0.3 mole) of ethyl 5-(chloromethyl)-2-furoate having b.p. 112-114°/ /2 mm (see Vol. 1 of this work, p. 30), 46.2 g (0.33 mole) of hexamethylenetetramine, and 75 ml of dry chloroform was prepared in a two-liter four-necked round-bottomed flask fitted with a mercury- sealed stirrer and a reflux condenser protected by a calcium chloride tube. The continuously stirred mixture was boiled in a water bath for two hours. To the quaternary salt formed (Note 1) 380 ml of absolute alcohol was added, and heating and stirring were continued while hydrogen chloride (dried by passage through concentrated sulfuric acid) was passed in rapidly. When the mixture was saturated with hydrogen chloride, it was boiled for 1.5-2 hours. It was then allowed to cool to room temperature, the precipitated ammonium chloride was filtered off at the pump, and chloroform, alcohol, and volatile by-products were distilled from the filtrate completely, first at atmospheric and then at reduced pressure. When the residue in the distillation flask cooled, it solidified to a crystalline mass consisting mainly of the hydrochloride of ethyl 5-(aminomethyl)-2-furoate. The salt was treated with 180--200 ml of dry ether and then filtered off (Note 2).

In order to liberate the base, the salt was dissolved in 35 ml of water, 150 ml of benzene was added, and about 30 ml of a 40'/o solution of sodium hydroxide was added in small portions with continual shaking and cooling. The benzene layer was separated, and the aqueous layer was extracted with two 60-ml portions of benzene. The benzene solution was dried with calcined sodium sulfate. Solvent was distilled off, and in the vacuum distillation of the residue a fraction of b.p. 116-118°/3 mm was collected. The product, amounting to 27.4-29.3 g (54.0--57. 7'/o), was ethyl 5-(aminomethyl)-2-furoate, a colorless mobile liquid (Note 3).

Hydrolysis. Freshly distilled ethyl 5-(aminomethyl)-2-furoate (50. 7 g, i.e., 0.3 mole) was added in small portions to a stirred solution of 20.2 g (0.36 mole) of potassium hydroxide in 90 ml of 95'/o ethanol contained in a 500-ml round-bottomed flask fitted with reflux condenser. The mixture was heated in a water bath

8

for four hours, and 225 ml of 95% ethanol and 90 ml of water were added to the crystalline mass formed (Note 4). The solution was filtered, and the filtrate was acidified with 25-30 g of glacial acetic acid. The acid liberated was filtered off at the pump, washed several times with small amounts of alcohol, and dried in the air (Note 5); m.p. 287-288° (with decomposition).

Yield 35.0-36.0 g (82. 7--85.1%).

5-(Aminomethyl)-2-furoic acid (C6H70 3N; mol. wt. 141.13) is a white crystalline substance, moderately soluble in water, but insoluble in alcohol, ether, and benzene; m.p. of oxalate 205° (with decomposition).

NOTES

1. The crystalline quaternary salt can be separated by addition of 100-120 ml of dry chloroform and filtration. The yield of air-dry substance was 95.0--97.3%; m.p. 188-189° (with decomposition).

2. In this way dry analytically pure hydrochloride of ethyl 5-(aminomethyl)-2-furoate is obtained in 73--77% yield; m.p. 127-128° with preliminary softening at 125°.

The substance must be stored as the hydrochloride because the free base undergoes change when kept for a long time.

3. The reaction product must be distilled immediately after the removal of benzene because the undistilled product thickens when allowed to stand and will then resinify when attempts are made to distill it.

4. The alcohol is added to precipitate amino acid dissolved in the water.

5. The product is obtained in an almost pure state: recrystallization from aqueous alcohol has no effect on the melting point of the substance.

9


5-(Aminomethyl)-2-furoic acid has been prepared also by hydrolysis of the ethyl ester of 5-[(2-chloroacetamido)methyl]-2-furoic acid with sulfuric acid 1• The above-described method gives a purer product in better yield.

LITERATURE CITED

10. Moldenhauer, W. Irion, and H. Marwitz, A. 583, 37 (1953).

5-BENZYLFURFURYL ACETATE

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by G. T. Tatevosian and N. M. Divanian

PREPARATION

A mixture of 22.6 g (0.12 mole) of 5-benzylfurfuryl alcohol (see p. 18), 14 g (0.14 mole) of acetic anhydride, 5 g (0.06 mole) of powdered anhydrous sodium acetate, and 80 ml of benzene was prepared in a 500-ml round-bottomed flask having side neck and fitted with mercury- sealed stirrer and reflux condenser protected by a calcium chloride tube. The stirrer was started, and the reaction mixture was boiled in a water bath for six hours. The contents of the flask were cooled and poured into a beaker containing

10

100 ml of cold water. The benzene layer was separated and, in order to remove the excess of acetic anhydride, it was returned to the flask and stirred with 30 ml of 5% sodium acetate solution at room temperature for two hours. The benzene layer was separated from the alkaline solution, washed with two 50-ml portions of water, and dried over anhydrous sodium sulfate. Solvent was distilled off, and the residue was vacuum-distilled: about 1 ml of head fraction was separated, and a substance coming over at 148--149°/2 mm was then collected.

The yield was 23.6-24.0 g (85.5--86.9%).

5-Benzylfurfuryl acetate (C 14H140 3; mol. wt. 230.26) is a lemonyellow mobile liquid, insoluble in water, but soluble in the usual organic solvents; d204 1.1227; n20D 1.5400.


5-Benzylfurfuryl acetate has been prepared only by the method described above1•

LITERATURE CITED

1A. L. Mndzhoian and V. G. Afrikian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 201 (1957).

11

2-FURYL METHYL KETONE

0 + (CH,CO),O H,PO,

Checked by 0, L. Mndzhoian and A. A. Dokhikian

PREPARATION

A mixture of 34 g (0.5 mole) of furan (see Vol. 1 of this work, p. 40), b.p. 31-34°/745 mm, and 51 g(0.5 mole) of freshly distilled acetic anhydride was prepared in a 500-ml four-necked roundbottomed flask fitted with mercury- sealed stirrer, reflux condenser protected by a calcium chloride tube, thermometer, and dropping funnel. The stirrer was started, the mixture was heated to 35°, and a mixture of 5 g of 85% phosphoric acid and 50 g of 95% acetic anhydride (Note 1) was added from the dropping funnel at such a rate that the temperature of the mixture did not rise above 40°.

When the addition was complete, the temperature was maintained at 55--60° (Note 2) while stirring was continued for a further 90 minutes. The mixture was then cooled to below 20°, 200 ml of water was added, and after 30 minutes the mixture was extracted with three 100-ml portions of benzene. The combined benzene extract was washed with 50 ml of water, with 10% potassium carbonate solution, and again with 50 ml of water; it was dried over calcined sodium sulfate. Benzene was distilled off, and the residue was vacuum-distilled from a Claisen flask having a 25-cm Vigreux column; the fraction boiling at 64-66°/13 mm was collected.

The yield of 2-furyl methyl ketone, which was obtained as a colorless oil, was 33.2-35 g (60.4·-63.5%) (Note 3).

2-Furyl methyl ketone (C6Hs~; mol. wt. 110.11) is readily soluble in ether, benzene, alcohol, and acetone, but sparingly soluble in ligroin and water.

12

NOTES

1. The mixture of phosphoric acid and acetic anhydride must be prepared on the previous day and left overnight.

2. At higher temperatures the yield of 2-furyl methyl ketone is lower.

3. When cooled with ice, 2-furyl methyl ketone solidifies; after recrystallization from gasoline it melts at 30-32°. The product described in the text is sufficiently pure for further use in synthesis.


2-Furyl methyl ketone is formed in the dry distillation of coniferous wood 1. It can be prepared by reaction of 2-furonitrile with methylmagnesium iodide2 or of 2-furoyl chloride with dimethylcadmium3. It can be prepared also by the action of diazomethane on 2-furaldehyde4, by passage of the vapors of ethyl 2-furoate and acetic acid over thoria at 460° 5, and by the ketonic scission of (2-furoyl) acetic ester, which is itself prepared by condensation between 2-furoic and acetic esters6.

The usual method of preparing 2-furyl methyl ketone is the catalytic acetylation of furan, which can be brought about by acetyl chloride 7, ketene8 , acetic acid in presence of trifluoroacetic anhydride9, and silicon tetracetate10 . The most satisfactory results are obtained by acetylating furan with acetic anhydride in presence of acid catalysts, namely, iodine and hydriodic acid 11 , zinc chloride12 , boron trifluoride and its complexes13 , phosphoric oxide14 , perchloric acid 15 , and sulfuric, boric, phosphoric, phosphorous, and other acids16 .

The directions given above are based on the work of H. D. Hartough and A. I. Kosak 16 .

13

LITERATURE CITED

1 L. Bouveault, C.r. 125, 1184 (1897); Bull. Soc. Chirn. [3], 25, 435 (1901); A. W. Goos and A. A. Reiter, Ind. Eng. Chern. 38, 132 (1946).

2 Y. Asahina and Y. Muroyarna, Arch. Pharrn. 252, 443 (1914). 3 F. Kipnis and J. Ornfelt, j. Am. Chern. Soc. 70, 3948 (1948). 4T. Yabuta and T. Tamura, j. Agr. Chern. Soc. japan, 19, 546

(1943); [C.A. 46, 965b (1952)]; j. Rarnonczai and L. Vargha, j. Am. Chern. Soc. 72, 2737 (1950).

5 J. L. A. Webb and j. D. Webb, j. Am. Chern. Soc. 71, 2285 (1949).

6 L. Bouveault, C.r. 125, 1186 (1897); Bull. Soc. Chirn [3] 25, 440 (1901); R. Ciusa, Gazz. Chirn. !tal. 52, 43 (1922) [C.A. 17, 14789 (1923)].

7T. Reichstein, Helv. Chirn. Acta 13,356 (1930); Ia. L. Gol'dfarb and L. M. Srnorgonskii, Zh. obshchei khirn. (J. Gen. Chern.) 8, 1523 (1938).

8 U. S. Pat. 2,460,822 and 2,460,825 (1949) [C.A. 43, 3465a (1949)].

9 E. j. Bourne, M. Stacey, j. C. Tatlow, and j. M. Tedder, j. Chern. Soc. 718 (1951).

10 Iu. K. Iur'ev and G. B. Eliakov, Doklady Akad. Nauk SSSR (Proc. Acad. Sci. USSR) 86, 337 (1952).

11 H. D. Hartough and A. I. Kosak, j. Am. Chern. Soc. 68, 2639 (1946).


13 j. V. Heid and R. Levine, j. Org. Chern. 13, 409 (1948); H. D. Hartough and A. I. Kosak, j. Am. Chern. Soc. 70, 867 (1948); U. S. Pat. 2,515,123 (1950) [C.A. 44, 8955d (1950)].


15 U. S. Pat. 1,496,786 (1950) [C.A. 44, 4930b (1950)]. 16 H. D. Hartough and A. I. Kosak, j. Am. Chern. Soc. 69, 3093

(1947).

14

2-BENZYLFURAN

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by G. T. Tatevosian and S. P. Ekmekdzhian

PREPARATION

A 100-ml two-necked round-bottomed flask fitted with reflux condenser and thermometer passing almost to the bottom of the flask was charged with 40.4 g (0.2 mole) of 5-benzyl-2-furoic acid (see Vol. 1 of this work, p. 7). The acid was heated, and decarboxylation set in already at 160-165°; it. proceeded steadily and at an adequate rate at 195-200°, and this temperature was maintained for 3.5-4 hours. Toward the end the temperature was raised to 205-210° and heating was continued for 25--30 minutes. The liquid formed was transferred to a small Claisen flask, and the reaction flask was rinsed out with 25-30 ml of dry ether, which was added to the main product. Solvent was distilled off, and the residue was distilled under reduced pressure and came over at 117-118°/24 mm.

Yield 24.2-25.4 g (76.4-80.2%).

2-Benzylfuran (C 11H100; mol. wt. 158.20) is a colorless mobile liquid, insoluble in water, but soluble in the usual organic solvents; d204 1.0537; n20D 1.5455. It turns yellow with storage.


2-Benzylfuran has been prepared by reaction between furfuryl chloride and phenylmagnesium bromide1 and also by the action of 2-furaldehyde on phenylmagnesium bromide with subsequent dehydration of the secondary alcohol and catalytic hydrogenation of the dehydration product 2•

15

The thermal decarboxylation of 5-benzyl-2-furoic acid 3, which is not accompanied by side reactions, gives a high yield of pure product.

LITERATURE CITED

1 R. Paul, C.r. 200, 1481 (1935). 2 R. Paul, C.r. 202, 1444 (1936). 3 A. L. Mndzhoian and V. G. Mrikian, Doklady Akad. Nauk

Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 201 (1957).

1-(5-BENZYL-2-FUROYL)-3-THIOSEMICARBAZIDE

O CH200 I C-NHNH-C-NHt II II 0 s

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by G. T. Tatevosian and S. G. Agbalian

PREPARATION

A mixture of 10 g (0.11 mole) of thiosemicarbazide and 70 ml of pyridine was prepared in a 250-ml four-necked round-bottomed flask fitted with mercury-sealed stirrer, dropping funnel, calcium chloride tube, and thermometer (which was immersed in the liquid). The mixture was stirred and cooled with ice and salt to a temperature of from -7° to -6°. Dropwise addition was then made of 22.1 g (0.1 mole) of freshly distilled 5-benzyl-2-furoyl chloride (see Vol. 1 of this work, p. 54), b.p. 153-155°/2 mm, at such a rate that a temperature of from -4° to -3° was not exceeded (Note 1). A period of 1.5-2 hours was required for the

16

addition of the whole of the acid chloride. When addition was complete, without removal of the bath stirring was continued until the temperature of the mixture reached that of the room (3-4 hours), and the mixture was then left overnight.

The reaction mixture was stirred into 300 ml of ice water contained in a beaker; the substituted thiosemicarbazide settled to the bottom as an oil, which solidified after it had stood for 2--3 hours. The substance was filtered off at the pump and carefully washed with three portions of ice water, each 50-60 ml. After being dried in the air, the crude product melted at 181-182° and weighed 22-22.9 g (Note 2).

For purification the substance was recrystallized from 100 ml of a 1 : 3 mixture of acetic acid and alcohol, and the crystals were washed carefully with 200 ml of dry ether. The yield of pure product, m.p. 190-19P, was 18.0-18.6 g (65.4-67.6%).

1-(5-Benzyl-2-furoyl)-3-thiosemicarbazide (C 13H13~N3S; mol. wt. 275.33) is a colorless crystalline substance, soluble in pyridine and acetic acid, not very soluble in methanol, ethanol, and acetone, and insoluble in water, ether, and benzene.

NarES

1. Rise in temperature above -3° results in resinification with considerable reduction in yield.

2. Crude 1-(5-benzyl-2-furoyl)-3-thiosemicarbazide, which is formed in 80-83.2% yield, is quite suitable for use in the cyclization reaction with formation of 5-(5-benzyl-2-furyl)-s-triazole-3-thiol (see Vol. 1 of this work, p. 9).


1-(5-Benzyl-2-furoyl)-3-thiosemicarbazide has been prepared only by the method described above1•

17

LITERATURE CITED

1 A. L. Mndzhoian and V. G. Afrikian, Doklady Alcad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 201 (1957).

5-BENZYLFURFURYL ALCOHOL

QcH, QcooH + CH,OH -

QcH, OcoOCH, + H,o

2 0 CH, 0 COOCH, + L!AIH, -

[ QcH, QcH,ol (CH,O),AILI

[ QcH,oCH,01CH,O),AILI+4H,O-

20CH,(JCH,OH + 2CH,OH + AI(OH), + LIOH

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by G. T. Tatevosian and S. P. Ekmekdzhian

PREPARATION

Methyl 5-Benzyl-2-furoate. A solution of 40.4 g (0.2 mole) of 5-benzyl-2-furoic acid (see Vol. 1 of this work, p. 7), m.p. 104-1050, in 200 ml of anhydrous methanol was introduced into a 500-ml three-necked round-bottomed flask fitted with mercury-sealed stirrer, reflux condenser, and glass tube passing to the bottom of

18

the flask. The stirred solution was heated in a water bath to a steady boil, which was maintained for 2.5-3 hours while a rapid stream of hydrogen chloride was passed (the hydrogen chloride was first passed through a wash bottle containing concentrated sulfuric acid). The solution was cooled and poured into a flask containing 500 ml of cold water; the oily product was separated, and the aqueous layer was extracted with three 75-ml portions of ether. The ethereal extract was added to the main product, and the whole was washed with 5% sodium carbonate solution and with water; it was dried over calcined sodium sulfate. Ether was distilled off, and the residue was vacuum-distilled and came over at 160-162°/3 mm. Yield 38.4-39.8 g (88.8-89.3%).

5-Benzylfurfuryl Alcohol. A solution of 4.5 g (0.12 mole) of lithium aluminum hydride in 250 ml of ether (Note 1) was introduced into a one-liter three-necked round-bottomed flask fitted with mercury-sealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. The stirrer was started, and a solution of 21.6 g (0.1 mole) of methyl 5-benzyl-2-furoate in 150 ml of dry ether was added dropwise at such a rate that the ether boiled steadily. When the addition was complete, stirring was continued further for one hour and the reaction mixture was then left overnight. On the next day, with careful stirring 40 ml of water was added dropwise (Note 2). The contents of the flask were filtered, and the filter was washed with four 80-ml portions of dry ether. The combined filtrate was dried over anhydrous sodium sulfate, solvent was distilled off, and the residue was vacuum-distilled with collection of the substance coming ov'er at 143-145°/2 mm.

Yield 16.2-16.4 g (86.0-87.1%).

5-Benzylfurfuryl alcohol (C 12H12~; mol. wt. 183.22) is a colorless viscous liquid, insoluble in water, but soluble in the usual organic solvents; d20~ 1.1231; n21lD 1.5705. The substance yellows with storage.

NOTES

1. The ethereal solution of lithium aluminum hydride was prepared by the method of Finholt and coworkers1 by reaction

19

between lithium hydride and anhydrous aluminum chloride. In order to ensure the necessary rate of reaction the lithium hydride must be finely ground: the commercial hydride was ground in a ball mill and then passed through a No. 100 closed sieve.

Preparation of an Ethereal Solution of Aluminum Chloride. A one-liter three-necked round-bottomed flask fitted with mercurysealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube was charged with 106.8 g (0.8 mole) of sublimed aluminum chloride, and the flask was cooled with water while dry ether was added dropwise. The first drops of ether were added very slowly' for at first complex formation occurred with the evolution of much heat. When the exothermic effect became less marked, the stirrer was started and the ether was added more rapidly; in all, 450 ml of ether was added. The clear dark-brown solution formed in the flask was poured into a bottle having a ground-in stopper.

A somewhat more dilute solution of aluminum chloride, which was required for the preparation of the 11 starter, 11 was then prepared in the same flask: this solution was prepared as described above from 24 g of sublimed aluminum chloride and 150 ml of dry ether. The solution for the preparation of the starter was also kept in a stoppered bottle.

Preparation of an Ethereal Solution of Lithium Aluminum Hydride. The solution of lithium aluminum hydride was prepared in a three-liter four-necked round-bottomed flask A (Fig. 1) fitted with mercury-sealed stirrer B, thermometer C reaching almost to the bottom of the flask, gas- inlet tubeD (for pas sage of nitrogen) reaching to a point just below the base of the neck, dropping funnel E, and reflux condenser F protected by a calcium chloride tube. Before the first portion of the starter was introduced into the flask, air was displaced with nitrogen, a slow stream of which was passed through the flask until the preparation of the solution of lithium aluminum hydride was complete. The nitrogen, which was obtained from a cylinder, was first passed through the vessel G, containing concentrated sulfuric acid, and then through the vessel H, which contained dry ether.

20

Fig. 1.

To ensure smooth reaction it is necessary to have a starter, i.e., a small amount of lithium aluminum hydride in ethereal solution, which must be present right from the beginning of the process. The starter was prepared by Mahe's method 2, as follows. Ground lithium hydride (2.1 g) was placed in a 200-ml flat-bottomed flask, 30 ml of dry ether was added, and then 30 ml of the ethereal solution of aluminum chloride prepared for this purpose. There was a vigorous reaction, lasting 30-60 seconds, and when this subsided the contents of the flask were poured into flask A. Four more portions of starter were prepared in the same way and poured into the reaction flask; in all, 10.5 g of lithium hydride and 24 g of aluminum chloride were used in the preparation of starter. Dry ether (300 ml) was poured into the flask, the stirrer was started, and after ten minutes the mixture was cautiously warmed in a hot water bath so that the temperature of the mixture was gradually brought to 30°. This temperature was maintained for 3-5 minutes; the mixture was then allowed to cool to room temperature, and with continued stirring 35.2 g of lithium hydride was sprinkled into the flask. The mixture was again warmed cautiously in a water bath to 30°. and the mixture was again allowed to cool. Slow dropwise addition of the aluminum chloride solution

21

was then started, and the temperature gradually rose to 27-28°. If no rise in temperature was observed after the addition of the first 15-20 ml of aluminum chloride solution, the addition was stopped and the mixture was cautiously heated in a water bath to 27-28° (the accumulation of an appreciable amount of unchanged aluminum chloride in the mixture generally results in rapid, violent reaction with partial ejection of the reaction mixture from the flask). Cautious addition of aluminum chloride solution was then restarted, and if the temperature of the mixture (heated to 27-28°) did not then fall, this could be taken as a sign that reaction had begun. Further addition was then carried out at such a rate that the temperature was maintained in the range 27-29°; under these conditions addition of the whole of the aluminum chloride solution required about 3.5-4 hours. When the addition was complete, the stirred mixture was allowed to cool to room ternperature. It was then cautiously heated again to 30°, kept at this temperature for 30 minutes, and again allowed to cool. Stirring was stopped, and the mixture was set aside overnight. On the next day the ethereal solution was carefully decanted from precipitate into a narrow graduated bottle having a ground-in stopper. Dry ether (150 ml) was added to the precipitate in the flask (lithium chloride and excess of lithium hydride); the contents of the flask were mixed thoroughly and then allowed to stand, after which the ether was decanted into the same bottle. The precipitate was washed with two more 150-ml portions of ether, and the bottle finally contained 1200-1250 ml of an ethereal solution of 21.5-22.5 g of lithium aluminum hydride (57. 7-60.3%, calculated on the amount of aluminum chloride taken).

The residue in the reaction flask was rendered harmless by adding it a little at the time to a large volume of water.

When the solution was allowed to stand, fine particles transferred in the decantation of the ether settled out; when required for use, the required volume of lithium aluminum hydride solution was poured carefully from the bottle into a measuring cylinder.

In order to reduce the volume of reaction mixture when large amounts of material are to be reduced, the lithium aluminum

22

hydride solution may be concentrated by distilling off most (up to five-sixths of the volume) of the ether.

2. The decomposition of the excess of lithium aluminum hydride must be carried out very cautiously, addition of water being controlled so that the ether boils steadily.


5-BenzyUurfuryl alcohol has been prepared only by the method described above3•

LITERATURE CITED

1 A. E. Finholt, A. L. Bond, and H. j. Schlesinger, j. Am. Chern. Soc. 69, 1199 (1947).

2 J. Mahe', J. Rollet, and A. Willemart, Bull. Soc. Chim. 481 (1949).


23

5,5 I -(THIODIMETHYLENE)DI-2-FUROIC ACID

( CH,OOC 0 CH,), S + 2N•CI

(CH,OOC 0 CH2\ S + 2Na0H -0 Y,

(NaOOC 0 CHt)'l S + 2CH 30H

{Naooc OCH2)2 s + 2HCI -

HOOC OcH,, CH,OCOOH + 2N•C•

Proposed by A. L. Mndzhoian and S. G. Agbalian Checked by V. G. Afrikian and E. A. Markarian

PREPARATION

Dimethyl5,5'-(Thiodimethylene)di-2-furoate. A solutionoflOOg (0.42 mole) of crystalline sodium sulfide (Na2S·9H20) in 150 ml of water was added dropwise over a period of one hour to a stirred solution of 130.8 g (0. 75 mole) ofmethyl5-(chloromethyl)-2-furoate (see Vol. 1 of this work, p. 29), b.p. 114-116°/3 mm, in 300 ml of methanol; in the course of the addition the temperature rose to 50-55°. Mter some time an oily layer formed on the bottom of the flask and gradually solidified. Mter one hour the precipitate was filtered off at the pump, washed with water, and dried; weight of unpurified product 96.0-100.5 g. Recrystallization from 600 ml of ethanol gave 82.5-84.5 g (70.9-72. 7r/o) of pure substance, m.p. 113°.

24

Hydrolysis. A mixture of 62 g (0.2 mole) of dimethyl 5,5'-(thiodimethylene)di-2-furoate and a solution of 20 g (0.5 mole) of sodium hydroxide in 180 ml of water was prepared in a 500-ml round-bottomed flask fitted with mercury-sealed stirrer and reflux condenser. The stirred mixture was heated in a water bath for three hours, and the resulting alkaline solution was then cooled to room temperature, washed with a little ether, and acidified to Congo red with dilute hydrochloric acid. The precipitated acid was filtered off at the pump, washed several times with water, and dried in the air; weight of crude product 52.5-55.5 g.

For purification the acid was dissolved in 1 liter of boiling ethanol and the resulting solution was poured slowly into 3 liters of water. Fine crystals were precipitated: they were filtered off, washed with water, and dried in the air; m.p. 220°.

Yield 45.5-48.0 g (80.6-85.0%).

5,5'-(Thiodimethylene)di-2-furoic acid (C 12H100sS; mol. wt. 282.28) forms almost colorless scalelike crystals, insoluble in water, but soluble in hot methyl and ethyl alcohols.


5,5'-(Thiodimethylene)di-2-furoic acid has been prepared in 42.5% yield together with its dimethyl ester by the action of a solution of an excess of sodium sulfide on methyl 5-(chloromethyl)-2-furoate1.

Higher yields of a purer product are obtained by the procedure described above2•

LITERATURE CITED

1 0. Moldenhauer, G. Trautmann, R. Pfluger, and H. Doser, A. 580, 181 (1953).

2 A. L. Mndzhoian, G. T. Tatevosian, S. G. Agbalian, and N. M. Divanian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 207 (1957).

25

2,3-DIMETHYLFURAN

CHaO CHaO CH31 0 I COOH - CHa 0 I +col

Proposed by A. L. Mndzhoian and M. T. Grigorian Checked by V. G. Afrikian and E. A. Markarian

PREPARATION

The reaction was carried out in a 100-ml distillation flask having a side neck holding a thermometer which reached to the bottom of the flask-; the side tube of the flask was wide and branched from a high point on the neck. The flask was charged with 28 g (0.2 mole) of 4,5-dimethyl-2-furoic acid (see p. 28), m.p. 156-1570, and was then closed with a stopper through which passed a glass rod intended for clearing the neck from sublimate of the acid. The side tube was conected to a condenser, to which was attached a long receiver adapter; this passed down into the lower part of the receiver, which was cooled with ice water.

When heated, the acid melted and then began to decompose. The temperature of the liquid was brought to 180-190°, and in this temperature range rapid decarboxylation occurred with steady distillation of the 2,3-dimethyUuran formed. The acid which sublimed as a deposit in the neck of the flask was from time to time pushed back into the flask with the glass rod. Toward the end of the experiment, in order to decompose the small amount of acid remaining on the upper parts of the flask walls the temperature was raised to 200-220° after covering the upper parts and neck of the flask with asbestos paper. The whole decarboxylation process lasted 40-60 minutes.

The product that collected in the receiver was redistilled; 15.4-16.0 g (80.2-83.3%) of pure substance, b.p. 90-9P, was obtained.

26

2,3-Dimethylfuran (C6H80; mol. wt. 96.13) is a colorless liquid, readily soluble in the usual solvents and insoluble in water; d204 0.9048; n20D 1.4452. The substance is unstable: on standing in the air it becomes discolored and gradually resinifies.


Apart from the above-described method 1, 2,3-dimethylfuran has been prepared by the decarboxylation of 4,5-dimethyl-2-furoic, 4,5-dimethyl-3-furoic, and 4,5-dimethyl- 2,3-furandicarboxylic acids by heating them in quinoline in presence of bronze at 200-28002.

LITERATURE CITED

1 A. L. Mndzhoian, V. G. Afrikian, M. T. Grigorian, and E. A. Markarian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 277 (1957).

2T. Reichstein and A. Grussner, Helv, Chim. Acta 16, 28 (1933).

27

4,5-DIMETHYL-2-FUROIC ACID

CH,0 CH30 CH3 1 O COOCH3 + NaOH _,. CH3 1 O COON a+ CH80H

CH30 CH30 CH3 1 I COON a+ HCI- CH3 1 \ COOH + NaCI

0 0

Proposed by A. L. Mndzhoian and M. T. Grigorian Checked by V. G. Afrikian and V. E. Badalian

PREPARATION

Methyl 4,5-Dimethyl-2-furoate. A mixture of 37.8 g (0.2 mole) of methyl 4-(chloromethyl)-5-methyl-2-furoate (see p. 42), b.p. 120-12P /3 mm, and 120 ml of 9o% acetic acid was prepared in a 250-ml round-bottomed flask having a side neck and fitted with stirrer and reflux condenser. The mixture was stirred while 39.2 g (0.6 g-atom) of zinc dust was added in small portions, and with continued stirring it was heated in a water bath for four hours. It was then cooled and poured into a beaker containing 300 ml of cold water. The oily substance that formed on the bottom was extracted with four 100-ml portions of ether. The combined ether extract was washed with water, with 5% sodium bicarbonate solution until the acetic acid was completely neutralized, and again with water; it was dried with sodium sulfate. Solvent was distilled off, and the residue was vacuum -distilled. The product came over at 78-80°/1 mm; yield 16.4-17.0 g (53.2-55.1%).

Hydrolysis. A mixture of 15.4 g (0.1 mole) of methyl 4,5-dimethyl-2-furoate and 30 ml of 20% sodium hydroxide solution was

28

prepared in a 100-ml round-bottomed flask having a side neck and fitted with stirrer and reflux condenser. The stirred mixture was heated in a water bath for one hour. It was cooled and washed with 30 ml of ether, and dilute hydrochloric acid was stirred in until the mixture was acid to Congo red. The acid liberated was filtered off at the pump and washed on the filter with 15-20 ml of ice water. The air-dried substance melted at 156-157° (see Notes).

Yield 12.6-13.0 g (90.0-92.8%).

4,5-Dimethyl-2-furoic acid (C 7H80 3; mol. wt. 140.14) isacolor

less crystalline substance, readily soluble in alcohol and ether,

but sparingly soluble in cold water.

NOTES

Recrystallization from water had no effect on the melting point.


Apart from the above method 1 of preparing 4,5-dimethyl-2-

furoic acid, the hydrolysis of 4,5-dimethyl-2-furonitrile2 has also

been used. From the point of view of accessibility of starting materials the method described in the text is more convenient.

LITERATURE CITED


2 T. Reichstein and A. Grussner, Helv. Chim. Acta 16, 28 (1933).

29

1 ,3-DIFURFURYLUREA

Proposed by 0. L. Mndzhoian and 0. E. Gasparian Checked by G. T. Tatevosian and S. P. Ekmekdzhian

PREPARATION

A mixture of 19.4 g (0.2 mole) of furfurylamine (seep. 60),

b.p. 83°/85 mm, and 50 ml of 20% aqueous sodium hydroxide

solution was prepared in a 250-ml four-necked round-bottomed

flask fitted with mercury- sealed stirrer, reflux condenser, dropping

funnel, and thermometer (see Notes). The mixture was kept at oo and stirred continuously while a solution of 11-12 g (0.11-

0.12 mole) of phosgene in 100 ml of dry benzene was added from

the dropping funnel over a period of 60-90 minutes. When the addition was complete, the cooling bath was removed and the

mixture was stirred at room temperature for 2.5-3 hours. The

precipitated crystals of 1,3-difurfucylurea were filtered off, washed on the filter with 20 ml of water, and dried in the air.

Recrystallization from 200 ml of boiling benzene gave 20.5-21.0 g (93.2-95.4%) of pure substance, m.p. 126-128°,

1,3-Difurfurylurea (C 11H120 3N2; mol. wt. 220.23) is a pale

cream crystalline substance having a pearly luster; it is readily

soluble in ethanol and hot benzene, but sparingly soluble in cold

benzene, ether, chloroform, and water.

NOTES

The experiment must be performed in an efficient fume

cupboard.

30

CYrHER METHODS OF PREPARATION

1,3-Difurfurylurea has been prepared by reaction between furfurylamine and phosgene in presence of excess of potassium hydroxide1 and also by the condensation of furfurylamine with urea at 100-150° (75% yield) or with nitrobiuret 2• 1,3-Difurfurylurea is formed also in the reductive amination of 2-furaldehyde over a nickel catalyst in presence of urea at high temperature and pressure3•

The condensation of furfurylamine with phosgene, not being accompanied by any side reactions, is the most convenient method for the laboratory preparation of 1,3-difurfurylurea and gives high yields of pure product.

LITERATURE CITED

1 W. Marckwald, Ber. 23, 3207 (1890). 2 U. S. Pat. 2,595,492 (1952) [C.A. 46, 7820a(1952)]; N. Clauson

Kaas, N. Elming, and Z. Tyle, Acta Chern. Scand. 9, 1 (1955). 3 U. S. Pat. 2,673,859 (1954) [C.A. 49, 4015g (1955)].

31

DIETHYL(TETRAHYDROFURFURYL)MALONATE

OcH =C(co,c,H,),-0 cH,CH(co,c,H,l,

Checked by 0. L. Mndzhoian and A. N. Grigorian

PREPARATION

A 150-ml shaking autoclave A (Fig. 2) was charged with 30 g (0.125 mole) of freshly distilled diethyl furfurylidenemalonate (see p. 35), b.p. 147-148°/2 mm, 45 ml of anhydrous ethanol (Note 1), and 2.5-3 g (3-3.6% of the total amount of solution) of Raney nickel catalyst (Note 2), With the autoclave valves B and C closed, the outlet valve D of the cylinder of the hydrogen compressor E was opened and the connecting tube F was filled with hydrogen. The valve D was then closed, the inlet valve B was

Fig. 2.

32

opened slowly, and the autoclave was filled with hydrogen at 10-15 arm; the valve B was then closed, and the pressure in the autoclave was released by opening the valve C carefully (Note 3).

This purging process was carried out three times in all (Note 4), and hydrogen was then passed into the autoclave to the initial pressure of 125 atm; the heat and shaking mechanism were switched on. As the temperature was raised to 130-135° the pressure in the autoclave rose to 160-165 atm; under these conditions rapid absorption of hydrogen occurred with fall in pressure to 40-50 atm (manometer G). Throughout the process fresh portions of hydrogen were passed in with the aid of the compressor E in order to maintain the pressure in the autoclave at 160-165 atm to the end of the experiments; the last portions of hydrogen were absorbed slowly. The temperature (130-135°) was controlled by the thermoregulator H (Note 5).

When hydrogen ceased to be absorbed (Note 6), which occurred after 5-5.5 hours, the autoclave was allowed to cool to room temperature. The outlet valve C was opened carefully, the pressure was released sl~wly (Note 3), and the autoclave was emptied. The solution was filtered from catalyst, which was washed with 10-15 ml of alcohol. Alcohol was distilled from the filtrate, and the residue was vacuum -distilled from a flask fitted with a Vigreux column: at 125-126°/1 mm 25.5-26.0 g (82.2-86.0%) of diethyl (tetrahydrofurfuryl)malonate was collected, after which 2-3 g of a higher-boiling fraction (127-138j, mainly unchanged diethyl furfurylidenemalonate, came over.

Diethyl (tetrahydrofurfuryl)malonate (C12H200 5; mol. wt. 244.27) is a colorless mobile liquid, readily soluble in alcohol and ether, but insoluble in water; d20 4 1.0796; n20D 1.4473.

NarES

1. For this autoclave the total volume of solvent and substance to be hydrogenated must not exceed 75 ml.

2. Covert and Adkins1 give the following directions for the preparation of Raney nickel catalyst.

33

A solution of 300 g of 80% sodium hydroxide in 1200 ml of distilled water contained in a 5-liter jar was cooled with ice water and stirred for 3-3.5 hours while 300 g of finely ground nickel-aluminum alloy was added in small portions; during this process the temperature must not be allowed to rise above 25°. The mixture was stirred at intervals for four hours, and after addition of 400 ml of 19% sodium hydroxide solution it was heated at 112-120° for three hours; after this time hydrogen ceased to be evolved. The mixture was diluted with distilled water to 3 liters, and the dear solution of sodium aluminate was decanted from the nickel. The nickel was washed six times by decantation with distilled water, filtered off, and washed until the filter was neutral to litmus. It was finally washed three times with 95% alcohol.

The catalyst was kept under alcohol in a bottle having a ground-in stopper.

3. Release of pressure during the purging of the autoclave and at the end of the experiment must be carried out very cautiously in order to avoid appreciable losses due to ejection of material.

4. After three purges there remained about 0.5% of air in the autoclave.

5. Control of temperature was effected with the aid of an MRShchPr- 54 regulating pyrometric millivoltmeter.

6. The end of the reaction was indicated by the cessation of fall in pressure in the autoclave. For the hydrogenation of the amount of furfurylidenemalonic ester taken, about 8.4 liters of hydrogen is required under normal conditions.


Diethyl (tetrahydrofurfuryl)malonate has been prepared by the catalytic hydrogenation of diethyl furfurylidenemalonate at high temperatures and pressures2• This ester has been prepared also by the condensation of tetrahydrofurfuryl chloride with malonic ester3•

34

LITERATURE CITED

1 L. Covert and H. Adkins, J. Am. Chern. Soc. 54, 4116 (1932). 2 A. Hinz, G. Meyer, and G. Schucking, Ber. 76, 676 (1943);

G. Barger, R. Robinson, and Y. Urushibara, J. Chern. Soc. 718 (1937).

3 R. Paul and G. Hilly, C.r. 208, 359 (1939).

DIETHYL FURFURYLIDENEMALONATE

OCHO + CH2(COOC2H.), -

OcH = qcooc:H5ls + H,o

Proposed by 0. L. Mndzhoian, E. R. Bagdasarian, and A. N. Grigorian

Checked by G. T. Tatevosian and A. G.· Terzian

PREPARATION

A. A mixture of 96 g (1 mole) of freshly distilled 2-furaldehyde, b.p. 154-155°/680 mm, 160 g (1 mole) of diethyl malonate, and 153 g (1.5 moles) of acetic anhydride was prepared" in a 750-ml round-bottomed flask fitted with a reflux condenser protected by a calcium chloride tube. The mixture was heated in a bath of Wood's metal at a bath temperature of 175-180° for six hours. The reaction mixture was cooled, 200 ml of water was added, and the dark oil that separated was transferred to a oneliter beaker and stirred with a glass rod while saturated sodium carbonate solution was added until the reaction was weakly alkaline. Ether (100 ml) was added to the mixture, the upper layer was separated, and the aqueous layer was extracted with four 100-ml portions of ether. The combined ether extract was washed with water and dried with anhydrous sodium sulfate. Solvent was

35

distilled off, and the residue was vacuum-fractionated from a flask having a small Vigreux column. A head fraction, consisting essentially of unchanged malonic ester (see Notes), was collected up to 147°/2 mm, and diethyl furfurylidenemalonate came over at 147--148°/2 mm as a light-yellow liquid.

Yield 169.0-173.0 g (70.9-72.6%).

B. A mixture of 50 g (0.52 mole) of freshly distilled 2-furaldehyde and 83.5 g (0.52 mole) of diethyl malonate was prepared in a 300-ml round-bottomed flask having a side neck and fitted with reflux condenser and dropping funnel. The mixture was heated in a boiling water bath and stirred while 2.8 g (0.03 mole) of piperidine was added dropwise. Heating was continued for 6-7 hour&, and the mixture was then transferred to a Claisen flask having a Vigreux column and was vacuum-fractionated as described above (A).

Yield 99.5--105.0 g (80.3-84. 7%).

Diethyl furfurylidenemalonate (C 12H140t;; mol. wt. 238.10) is a light-yellow oil, readily soluble in ether, alcohol, and benzene, but insoluble in water. It gradually darkens when allowed to stand in the air and light.

NarES

The head fraction can be used as malonic ester in a subsequent preparation of furfurylidenemalonic ester.


Diethyl furfurylidenemalonate has been prepared by the condensation of 2-furaldehyde with malonic ester in presence of acetic anhydride1 or piperidine2• The use of piperidine as condensing agent simplifies the treatment of the reaction mixture and gives higher yields of product. The methods described above are based on the work of Hinz and co-workers1 and of Knoevenagel 2•

36

LITERATURE CITED

1W. Marckwald, Ber. 21, 1081 (1888); A. Hinz, G. Meyer, and G. Schucking, Ber. 76, 676 (1943).

2 E. Knoevenagel, Ber. 31, 2595 (1898); B. Wojcikand H. Adkins, ]. Am. Chern. Soc. 56, 2424 (1934).

5-CARBOXY -2-FURANPROPIONIC ACID

C02C2Hs

CH,CJH-CH,OCOOCH,+ 3N,OH-II 0 0

NaOOC OCH2CH2COONa 2HC1-

HOOC 0 CH,CH,COOH + 2N•CI

Proposed by A. L. Mndzhoian and G. L. Papaian Checked by G. T. Tatevosian and N. M. Divanian

37

PREPARATION

Ethyl 2- [5- (Ethoxycarbonyl)furfuryl]acetoacetate. Freshly cut sodium (10 g, i.e., 0.43 g-atom) was added in small pieces to 150 ml of dry methanol contained in a 500-ml three-necked roundbottomed flask fitted with mercury- sealed stirrer, dropping funnel, and reflux condenser. When the whole of the sodium had dissolved, the solution was allowed to cool to room temperature, and 80 g (0.6 mole) of freshly distilled acetoacetic ester was stirred in rapidly (see Notes). Stirring was continued further for 25-30 minutes, and then, over a period of about 40 minutes, 30 g (0.17 mole) of methyl 5-(chloromethyl)-2-furoate (see Vol. 1 of this work, p. 29), b.p. 114-116°/3 mm, was added slowly from the dropping funnel. With continued stirring the reaction mixture was boiled in a water bath for 2-2.5 hours, after which time the reflux condenser was replaced by one set for distillation and methanol was distilled off completely. When the residue was cool, 100 ml of cold water was added, the oily layer was separated, and the aqueous layer was extracted several times with small portions of ether. The ether extracts were added to the main product, which was then dried over calcined sodium sulfate. Solvent was distilled off, and the residue was vacuum -distilled with collection of the substance coming over at 152-157°/2 mm. The yield of 2- [5- (ethoxycarbonyl)furfuryl]acetoacetic ester, a light-yellow liquid, was 25.5-27.8 g (55.4-60.5~).

5-Carboxy-2-furanpropionic Acid. A three-necked round-bottomed flask fitted with mercury-sealed stirrer and reflux condenser was charged with 26.8 g (0.1 mole) of ethyl 2-[5-(ethoxycarbonyl)furfuryl]acetoacetate, and a solution of 14 g (0.35 mole) of sodium hydroxide in 30 ml of water was added. The mixture was stirred in a boiling water bath for 3-3.5 hours. The resulting alkaline solution was cooled and washed with 20-25 ml of ether; it was then acidified to Congo red with dilute hydrochloric acid. The 5-carboxy-2-furanpropionic acid liberated was filtered off at the pump and washed with 15-20 ml of cold water. Recrystallization from 50 ml of water gave a colorless substance of m.p. 180°.

Yield 14.5-15.3 g (78.8-83.1~).

38

5-Carboxy-2-furanpropionic acid (CRH80s; mol. wt. 184.15) is a colorless crystalline substance, readily soluble in the usual organic solvents and in hot water, moderately soluble in cold water.

NaTES

The sodium and acetoacetic ester are taken in large excess; the use of smaller amounts results in lower yields and a product of lower purity.


5-Carboxy-2-furanpropionic acid has been prepared in 22. 71o yield by the reduction of 5-carboxy-2-furanacrylic acid with sodium amalgam, the latter compound being itself prepared by the condensation of malonic acid with 5-formyl-2-furoic acid 1•

From the point of view of the availability of the starting materials and the yields of the intermediate and final products, the abovedescribed method is more convenient.

LITERATURE CITED

1 E. Votocek and A. Kroslak, Coll. Czech. Chern. Comm. 11, 47 (1939).

39

METHYL TETRAHYDR0-5-METHYL-2-FUROATE

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by E. A. Markarian

PREPARATION

A 150-ml shaking autoclave was charged with 28 g (0.2 mole) of methyl 5-methyl-2-furoate (see Vol. 1 of this work, p. 23), b.p. 97--99°/12 mm, 30 g of anhydrous methanol (Note 1), and 3 g of catalyst (nickel on a chromic oxide carrier) (Note 2).

After removal of air from the autoclave it was filled with hydrogen at an initial pressure of 100 atm; the shaker motor w,as switched on and heating was commenced (Note 3). When the temperature was raised to 160° the pressure in the autoclave attained 155-160 atm, but it soon began to fall as a result of rapid absorption of hydrogen. By the passage of fresh portions of hydrogen into the autoclave the pressure was maintained in the range 130-150 atm, and the temperature was maintained at 160° with the aid of a thermoregulator. When the absorption of hydrogen stopped (Note 4), which occurred after 3.5-4 hours, the autoclave was cooled to room temperature and the pressure was released cautiously. The autoclave was unloaded, and the solution was filtered from the catalyst, which was washed with 10-15 ml of methanol. Solvent was distilled off under reduced pressure (water pump), and the residue was vacuum-distilled from a flask having a Vigreux column; the substance coming over at 83-86°/12 mm was collected.

The yield was 22.0-23.4 g (76.4-81.2%).

Methyl tetrahydro-5-methyl-2-furoate (C 7H120 3; mol. wt. 144.17) is a colorless liquid, soluble in alcohol, ether, and other organic solvents, but insoluble in water; d20 4 1.0509; n20D 1.4350.

40

NOTES

1. For this autoclave the total volume of solvent and substance to be hydrogenated must not exceed 75 ml.

2. The amount of catalyst is 5% on the total amount of original ester and solvent; the catalyst must be carefully ground before use.

3. For a diagram and description of the experimental arrangement and the filling of the shaking autoclave with hydrogen see p. 32.

4. The end of the reaction was indicated by the cessation of fall in pressure in the autoclave. For the hydrogenation of the amount of 5-methyl-2-furoic ester taken, 8.96 liters of hydrogen is required under normal conditions.


Methyl tetrahydro-5-methyl-2-furoate has been prepared only by the method given above1•

LITERATURE CITED


41

METHYL 4-(CHLOROMETHYL)-5-METHYL-2-FUROATE


PREPARATION

A mixture of 14 g (0.1 mole) of methyl 5-methyl-2-furoate (see Vol. 1 of this work, p. 23), b.p. 97-99°/12 mm, 80 ml of dry chloroform (Note 1), 4.5 g of paraformaldehyde (0.15 mole, calculated as formaldehyde) and 3.4 g (0.025 mole) of anhydrous zinc chloride was prepared ina250-mlfour-neckedround-bottomed flask fitted with stirrer, bent glass tube passing to the bottom of the flask and serving for the introduction of hydrogen chloride, gas-outlet tube, and thermometer.

Hydrogen chloride was passed in a rapid stream through a wash bottle containing sulfuric acid and into the stirred mixture (Note 2); the temperature of the mixture gradually rose. It was found that to avoid resinification the reaction must be carried out at not above 5-7° (Note 3), and it was therefore necessary to place the flask in a cooling mixture. Passage of hydrogen chloride was continued until the whole of the paraformaldehyde dissolved (40-60 minutes); at the same time spontaneous evolution of heat gradually came to a stop and the mixture became light red. The cooling bath was removed, and stirring was continued until the mixture reached room temperature (Note 4).

The reaction mixture was poured into 100 ml of cold water; the lower, chloroform layer was separated, washed with 30 ml

42

of cold w~ter (Note 5), and dried with calcium chloride. Solvent

was distilled off, and the residue was vacuum-distilled with

collection of the liquid coming over at 108-109°/1 mm or 120-

12P/3 mm. Yield 16.5-16.7 g (87.5-88.6%) (Note 6).

On standing the substance solidified; m.p. 42--43°.

Methyl 4-(chloromethyl)-5-methyl-2-furoate (C8H90 3Cl; mol.

wt. 188.60) forms colorless needles, insoluble in water, but

soluble in the usual organic solvents.

NOTES

1. Instead of chloroform, dichloroethane, tetrachloroethane,

and carbon tetrachloride can be used as solvents; the yield of

product is almost the same in all these cases.

Chloroform is preferable to the other solvents because of its

lower boiling point.

2. Hydrogen chloride was prepared by addition of concentrated

hydrochloric acid to concentrated sulfuric acid; the latter was

contained in a one-liter distillation flask, and hydrochloric acid

was added dropwise from a dropping funnel, the end of which was

drawn out into a capillary and reached to the bottom of the flask.

For the preparation of large amounts of hydrogen chloride

it is more convenient to use the following method: concentrat~d

sulfuric acid is added from a dropping funnel to common salt

contained in a distillation flask and covered with concentrated

hydrochloric acid.

3. At higher temperatures resinification occurs withreduction

in yield.

4. Treatment of the reaction mixture immediately after the

passage of hydrogen chloride is stopped lowers the yield to

75-75.5%.

5. Methyl 4-(chloromethyl)-5-methyl-2-furoate irritates the

mucous membrane. All work on the synthesis and isolation of

this substance should therefore be carried out in a fume cupboard.

43

6. The bromomethylation of methyl 5-methyl-2-furoate can be carried out similarly with about the same yield.


Methyl 4-(chloromethyl)-5-methyl-2-furoate has been prepared only by the method described 1•

LITERATURE CITED


METHYL 5-(CYANOMETHYL)-2-FUROATE

CICHa OcoocH3 + KCN-

NC-CH. OCOOCH3 + KCI

Checked by G. T. Tatevosian and 0. E. Gasparian

PREPARATION

A solution of 174 g (about 1 mole) of methyl 5-(chloromethyl)-2-furoate (see Vol. 1 of this work, p. 29), b.p. 114-116°/3 mm, in 400 ml of methanol was prepared in a one-liter three-necked round- bottomed flask fitted with mercury- sealed stirrer, dropping funnel, and thermometer. The solution was stirred while a solution of 100 g (about 1.5 moles) of technical potassium cyanide in 200 ml of water was added rapidly; the temperature of the mixture then rose to 25-30°. The mixture was then heated in a water bath to 30-35°, and the temperature was kept in this range while stirring was continued for six hours.

44

The reaction mixture was cooled to room temperature and poured into a flask containing 1 liter of cold water; the heavy oil liberated was separated with the aid of 200 ml of ether. The aqueous layer was extracted with two 100-ml portions of ether, and the combined ether solution was washed with three 50-ml portions of water; it was dried with anhydrous sodium sulfate.

Solvent was distilled off, and the residue was vacuum-distilled from a Claisen flask having a short Vigreux column. A yellow liquid (62--64 g) came over up to 131--132°/4 mm (see Notes). A second fraction was collected in the range 132--140°/4 mm, and the bulk of this came over at 134-136°/4 mm; the weight of this fraction was 54--55 g. About 25--30 g of resinified substance remained in the flask.

After a short time the second fraction solidified completely. It was crystallized from 50 ml of methanol, and 31-32 g of a colorless substance, m.p. 54-55°, was obtained; after evaporation of the mother liquor to small bulk, a further 9.5-10 g of pure substance was precipitated. The total yield was 40.5--42.0 g (24.5--25.4%).

Methyl 5-(cyanomethyl)-2-furoate (C8H70 3N; mol. wt. 165.15) crystallizes from alcohol in the form of long colorless needles having a feeble nitrile odor; it is readily soluble in the usual organic solvents, but insoluble in water.

NOTES

The first fraction, which consists essentially of unchanged chloromethyl ester, contains also appreciable amounts of reaction product. This fraction can be used without further purification in a subsequent synthesis of methyl 5-(cyanomethyl)-2-furoate; the product is then obtained in somewhat higher yield than that indicated in the text.

45


Methyl 5-(cyanomethyl)-2-furoate has been prepared only by the method described above, which was proposed by 0. Moldenhauer and co-workers1•

LITERATURE CITED

1 0. Moldenhauer, G. Trautmann, W. Irion, R. Pfluger, H. Doser, D. Mastaglio, H. Marwitz, and R. Schulte, A. 580, 169 (1953).

5-METHYLFURFURYL ALCOHOL

2CHa OcooCH3 + LIAtH. -

[ CH, 0 CH,Ol (CH,O),AILI

[ CH, 0 CH,Ol (CH,O),AILI + 4H,O -

2CH 3 OCH20H + 2CH10H + At(OHh + L!OH

Proposed by A. L. Mndzhoian and M. T. Grigorian Checked by N. A. Babiian

PREPARATION

A solution of 8.4 g (about 0.22 mole) of lithium aluminum hydride in 480 ml of ether (Note 1) was introduced into a 750-ml three-necked round-bottomed flask fitted with mercury-sealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. The stirrer was started, and a solution

46

of 28 g (0.2 mole) of methyl 5-methyl-2-furoate (see Vol. 1 of this work, p. 23), b.p. 97-98°/12 mm, in 150 ml of dry ether was added dropwise at such a rate that the ether boiled steadily.

The reaction mixture was left overnight, and on the next day it was stirred while about 40 ml of water was added dropwise (Note 2). The contents of the flask were filtered, and the filter was washed with 3-4 portions of 50-75 ml of dry ether. The combined filtrate was dried with anhydrous sodium sulfate, solvent was distilled off, and the residue was vacuum-distilled; the product boiled at 78-79°/12 mm.

The yield was 18.6--19.2 g (83.0-85. 7%).

5-Methylfurfuryl alcohol (C6H80z; mol. wt. 112.13) is a colorless liquid, soluble in the usual organic solvents; d20 4 1.0838; n20D 1.4890.

NarES

1. For the preparation of the ethereal solution of lithium aluminum hydride see p. 19.

2. The excess of lithium aluminum hydride must be decomposed very cautiously, with control of the addition of water so that the ether boils steadily.

ai'HER METHODS OF PREPARATION

5-Methylfurfuryl alcohol has been prepared by the reduction of 5-(hydroxymethyl)-2-furaldehyde with hydrazine hydrate1 and also by the reduction of 5-methyl-2-furaldehyde over a copperchromium catalyst under pressure at high temperature2•

The above-described procedure for reducing methyl 5-methyl-2-furoate3 is a simple convenient method for the preparation of this substance.

47

LITERATURE CITED

1T. Reichstein and H. Zschokke, Helv. Chim. Acta 15, 249 (1932).

2 0. Dinelli and G. B. Marini-Bettolo, Gazz. Chim. Ital. 71, 117 (1941) [C.A. 36, 19286 (1942)].


2-FURANACRYLIC ACID

OCHO + CH,(COOH), -

OCH=CH-COOH + C02 + H20

Checked by V. G. Afrikian and V. E. Badalian

PREPARATION

A mixture of 192 g (2 moles) of freshly distilled 2-furaldehyde, 208 g (2 moles) of malonic acid, dried at 100°, and 96 ml (1.2 moles) of pyridine, dried over potassium hydroxide, was prepared in a one-liter round-bottomed flask fitted with reflux condenser. The mixture was heated for two hours in a boiling water bath; it was then cooled to room temperature, and 200 ml of water was added. Concentrated aqueous ammonia was then added to the stirred mixture until the acid had almost dissolved; the solution was filtered, and the filter was washed with a little water. The solution was acidified to Congo red with dilute hydrochloric acid and left for 1.5-2 hours in an ice bath. The precipitated 2-furanacrylic acid was filtered off, washed with three 80-ml portions of water, and dried in a desiccator over calcium chloride. The product, which amounted to 252-254 g (91-92%), consisted of colorless needles, m.p. 141 o (see Notes).

48

2-Furanacrylic acid (C 7Ht;03; mol. wt. 138.12) is readily soluble in ether and glacial acetic acid; it is somewhat less soluble in alcohol and in hot water; it is very sparingly soluble in cold water, ligroin, and carbon disulfide.

NOTES

The product is sufficiently pure for further use in synthesis and, in particular, for reduction to 2-furanpropionic acid (see p. 57). If a purer product is required, then the material is dissolved in a slight excess of 50% alcohol (about 1 liter), the solution is boiled with animal charcoal and filtered while hot, the filtrate is diluted with cold water until crystals separate and then heated to the boil, and finally the solution is cooled slowly and placed in a cold cupboard for several hours.


2-Furanacrylic acid is formed in the oxidation of 2-furanacrolein with oxygen in presence of a silver catalyst containing cupric oxide1, and also in the oxidation of 4-(2-furyl)-3-buten-2-one with bleaching powder2• The usual method of preparing 2-furanacrylic acid consists in the Perkin condensation of 2-furaldehyde with sodium acetate3 or potassium acetate4 in presence of acetic anhydride or acetic acid and pyridine5• A convenient method of synthesizing 2-furanacrylic acid consists in the condensation of 2-furaldehyde with malonic acid in presence of ammonia6 or pyridine 7• The procedure given above was proposed by S. Rajagopalan and P. V. A. Raman8•

LITERATURE CITED

1 j. G. Schmidt, Ber. 13, 2344 (1880); Swedish Pat. 118, 461 (1947) [C.A. 42, 223d (1948)]; A. Scipioni, Chim. e ind. (Milan) 34, 78 (1952) [C.A. 46, 7813b (1952)].

2 C. D. Hurd and C. L. Thomas, j. Am. Chern. Soc. 55, 1646 (1933); M. E. Egorova and M. A. Abramova, Zh. priklad. khim. (j. Appl. Chern.) 23, 1311 (1950).

49

3 A. Bayer, Ber. 10, 357 (1877); W. Marckwald, Ber. 20, 2812 (1887); Gibson and Kahnweiler, Am. Chern. j. 12, 314 (1890); M. M. Koton, A. P. Votinova, and F. S. Florinskii, Zh. priklad. khim. (J. Appl. Chern.) 14, 181 (1941); L. Galimberti, Boll. sci. facolta chim. ind. Bologna 351 (1940) [C.A. 37, 34102 (1943)]; A. Mora and j. Infiesta, Combustibles (Zaragoza) 7, No. 37, 27 (1947) [C.A. 42, 8519g (1948)]; Y. Hachihama, M. Imoto, and K. Kawata, j. Soc. Chern. Ind. japan 45, Suppl., 189 (1942) [C.A. 44, 9721e (1950)].

4 A. Scipioni and V. Borsetto, Ann. Chim. (Rome) 42, 185 (1952) [C.A. 47, 3293h (1953)]; A. M. Shur and A. I. Moiseenko, Zh. priklad. khim. (J. Appl. Chern.) 27, 405 (1954).

5 S. Matura, K. Endo, and K. Ota, Bull. Nat. Hyg. Lab. (Japan) 67, 157 (1950).

6 E. Knoevenagel, Ber. 31, 2614 (1898). 1s. Dutt, Quart. ]. Chern. Soc. 1, 297 (1925) [C.A. 19, 24754

(1925)]; P. N. Kurien, K. C. Pandya, and V. R. Surange, j. Indian Chern. Soc. 11, 823 (1934) [C.A. 29, 33255 (1935)].

8 S. Rajagopalan, Proc. Indian Acad. Sci. 16A, 163 (1942) [C.A. :n, 14233 (1943)]; S. Rajagopalan and P. V. A. Raman, Organic Syntheses (Russian Translation), Vol. 3, p. 456, Foreign Lit. Press, Moscow, 1952 [Organic Syntheses, Collective Vol. 3, New York and London, 1955, p. 425).

50

2-FURANACROLEIN

Checked by 0. L. Mndzhoian and N. A. Babiian

PREPARATION

A solution of 7 g (0.175 mole) of sodium hydroxide in 1400 ml of water was cooled to oo in a four-necked round-bottomed flask fitted with mercury- sealed stirrer, reflux condenser, dropping funnel, and thermometer and surrounded by a bath of ice and salt. The solution was stirred (Note 1) while 100 g (1.04 moles) of freshly distilled 2-furaldehyde (Note 2) was added over a period of 30 minutes. Mter the addition of the 2-furaldehyde vigorous stirring was continued, and the temperature was maintained at from -1 o to oo while slow dropwise addition was made of a solution of 66 g (1.5 moles) of acetaldehyde in 330 ml of water (Note 3); addition of the whole of the acetaldehyde solution was completed in 8-10 hours (Notes 4 and 5).

Mter the addition of acetaldehyde, stirring at oo was continued for 30 minutes, and crystalline 2-furanacrolein was then filtered off and washed with five 200-ml portions of ice water. It was carefully pressed, first on the funnel and then twice between filter papers, and was dried in a vacuum desiccator over calcium chloride. Drying for two days gave 98.0-102.0 g (77.0-80.0%) of yellow crystals, m.p. 51-52° (Note 6).

2-Furanacrolein (C 7~0:!; mol. wt. 122.10) forms light-yellow needles, difficultly soluble in cold water, but readily soluble in alcohol, ether, and benzene. On standing in the air and light the substance turns brown.

51

NarES

1. Stirring must be vigorous so as to ensure the formation of a fine emulsion of 2-furaldehyde in water.

2. The yield of 2-furanacrolein depends on the quality of the 2-furaldehyde used; it is necessary to use freshly distilled 2-furaldehyde having a narrow boiling range (156-158° /680 mm).

3. The aqueous solution of acetaldehyde is kept in ice water and is poured into the dropping funnel in small portions.

4. If the addition is over a short period, a noncrystalline or only partially crystalline product is obtained and there is an appreciable reduction in the yield of 2-furanacrolein.

5. The acetaldehyde must be added in such a way that it does not accumulate in the reaction flask. If crystallization of the 2-furanacrolein does not set in, addition of acetaldehyde must be stopped and crystallization must be induced by stirring or by addition of seed crystals of 2-furanacrolein. With good stirring and the maintenance of the necessary temperature (from -1 o to 0°) crystallization sets in within 1.5-2 hours after the addition of about 50 ml of acetaldehyde solution.

6. The product is sufficiently pure for general use in synthesis. If a purer preparation is required, it may be obtained by recrystallization or by vacuum distillation. The product should be recrystallized from dilute alcohol (2 parts of alcohol and 1 part of water) or from a mixture of light gasoline (b.p. 75-80°) and benzene (9 parts of gasoline and 1 part of benzene). The recrystallized 2-furanacrolein is obtained in the form of long lightyellow needles, m.p. 53-54°, but much of the substance remains in the mother liquor. The losses are lower in vacuum distillation (99-103° /6 mm), but the product purified in this way is less stable than the recrystallized product: in storage it becomes dark-colored and resinified in a much shorter time.


2-Furanacrolein is obtained by the condensation of 2-furaldehyde with acetaldehyde in presence of aqueous sodium hydroxide

52

solution1• It has been prepared in 57"/o yield by passing a mixture of 2- fur aldehyde and acetaldehyde vapors through a quartz tube containing magnesium oxide on a kieselguhr carrier at 350° 2•

The above procedure was developed by V. M. Likhosherstov and co-workers3• It has been modified somewhat in detail: the duration of the addition of acetaldehyde has been increased, and the amount of acetaldehyde used is 10"/o greater than that used by these authors.

LITERATURE CITED

1 j. G. Schmidt, Ber. 13, 2342 (1880); H. Rohmer, Ber. 31, 283 (1898); German Pat. 330,358 (1919) [C.A. 15, 21026 (1921); W. Konig, Ber. 58, 2559 (1925); A. Hinz, G. Meyer, and G. Schucking, Ber. 76, 676 (1943); U. S. Pat. 2,527,714 (1950) [C.A. 45, 2715d (1951)]; A. A. Ponomarev, Z. V. Til', and V. V. Zelenkova, Zh. obshchei khim. (J. Gen. Chern.) 20, 1085 (1950); A. Scipioni, Chim. e. ind. (Milan) 34, 78 (1952) [C.A. 46, 7813c (1952)].

2 japanese Pat. 4881 ('52) (1954) [C.A. 48, 9406f (1954) ]. 3 M. V. Likhosherstov, A. A. Arseniuk, E. F. Zeberg, and

I. V. Koritskaia, Zh. obshchei khim. (J. Gen. Chern.) 20, 627 (1950).

53

5-(2-FURYL)-1,3,4-0XADIAZOLE-2-THIOL

QcoocH,tH,N-NH,-

OcoNHNH, t cH,OH

OCONHNH, + cs, + I(QH -·

0 CONH-NH-CS2K+H20

0 -CO 5\-sK ~ 0-c/0 '-C-SK ...!:!9_

0 I I 0 II II NH-NH N-N

Proposed by A. L. Mndzhoian and G. T. Tatevosian Checked by V. G. Afrikian and A. A. Aroian

PREPARATION

2-Furoic Acid Hydrazide. A mixture of 37.8 g (0.3 mole) of methyl 2-furoate (see Vol. 1 of thiswork,p. 27), b.p. 18r/760 mm, and 25 g (about 0.4 mole) of 85% hydrazine hydrate was prepared in a 250-ml round-bottomed flask fitted with an air condenser. The mixture was heated in a boiling water bath for six hours and was poured while still hot into a porcelain dish; it was stirred with a glass rod while being evaporated down on a sand bath (Note 1). Soon after evaporation began white fumes appeared; evaporation was continued until the liquid acquired the consistency of a thick sirup when cooled to room temperature (30-40 minutes), and the mixture was then. set aside to crystallize (Note 2). On the

54

next day the completely solidified product was ground and dried in the air; 34-35 g of crude product was obtained as a colorless crystalline substance. It was purified by vacuum distillation (Note 3). 2-Furoic acid hydrazide came over at 146-148°/3 mm as a colorless liquid which solidified immediately in the receiver; m.p. 74-76°. Yield 27.0-28.0 g (71.4-74.1%) (Note 4).

5-(2-Furyl)-1,3,4-oxadiazole-2-thiol. A solution of 25.2 g (0.2 mole) of distilled 2-furoic acid hydrazide in 150 ml of alcohol was introduced into a 500-ml round-bottomed flask fitted with reflux condenser, and 13.2 g (0.2 mole) of ground potassium hydroxide and 45 ml of carbon disulfide were added. The mixture was boiled in a water bath for 30-32 hours. The precipitate that formed in the flask during the first hours of heating had almost disappeared at the end of this period, and the odor of carbon disulfide became feeble. The reflux condenser was replaced by one set for distillation, and solvent was distilled off completely. The solid residue was dissolved in 200 ml of water, and the solution was filtered and acidified to Congo red with dilute hydrochloric acid. The voluminous precipitate that formed was filtered off and washed on the filter with two 50-ml portions of water.

The air-dried substance was recrystallized from 200 ml of methanol: when the filtered solution was cooled, 17.5-18 g of colorless needles, m.p. 172-173°, was precipitated. After reduction of the bulk of the mother liquor by two-thirds, a further 4.5-6.8 g of pure substance (same melting point) was precipitated (Note 5).

The yield was 22.0-24.8 g (65.4-73.8%).

5-(2-Furyl)-1,3,4-oxadiazole-2-thiol (C6H40:JN2S; mol. wt. 168.18) is soluble in the usual organic solvents and in alkaline solutions, but is insoluble in water.

NOTES

1. The mixture is heated on a sand bath in order to complete hydrazide formation and to remove water.

55

2. Unpurified 2-furoic acid hydrazide often does not crystallize, even after long standing. In such cases it is necessary to rub out a few drops of the oily product with a little water on a watch glass and seed the bulk of the material with the crystals formed.

3. The distillation should be carried out from a Claisen flask having a wide side tube; a small distillation flask can be used as receiver.

4. The above procedure for the preparation of 2-furoic acid hydrazide is based on the work of G. Carrara and co-workers1•

5. After complete removal of solvent from the mother liquor there remains about 3 g of impure substance melting in the range 165-170°.


5-(2-Furyl)-1,3,4-oxadiazole-2-thiol has been prepared only by the method described above2•

LITERATURE CITED

1G. Carrara, F. M. Chiancone, V. D'Amato, E. Ginoulhiac, C. Martinuzzi, U. M. Teotino, and N. Visconti, Gazz. Chim. Ital. 82, 652 (1952) [C.A. 48, 6423d (1954)].

2 A. L. Mndzhoian, G. T. Tatevosian, S. G. Agbalian, and N. M. Divanian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 207 (1957).

56

2-FURANPROPIONIC ACID

OCH=CHCOOH + 2(H) (Na·Hg)

OcH,-CH,cooH

Checked by V. G. Afrikian and V. E. Badalian

PREPARATION

A mixture of 41.4 g (0.3mole) of2-furanacrylic acid (seep. 48),

m.p. 141°, 115 ml of 10% sodium hydroxide solution, and 300 ml of water was shaken in a one-liter glass cylinder having a ground

in stopper until the furanacrylic acid had dissolved completely.

Over a period of 2.5-3 hours, 552 g (0. 72 mole) of 3% sodium amalgam was added in small portions (Note 1). When the addition was complete, the alkaline solution was separated from mercury,

filtered, and acidified to Congo red with concentrated hydrochloric acid (ice-water cooling) (Note 2). The aqueous solution containing

precipitated acid was treated with 3-4 100-ml portions of ether. The combined ether extract was washed with a little water and

dried over anhydrous sodium sulfate. Solvent was distilled off, and the residue was vacuum-distilled with collection of a substance of b.p. 134-136°/12 mm; the furanpropionic acid solidified com

pletely in the receiver; m.p. 58° (Note 3).

The yield was 30.5--31.5 g (72.6-75.0%).

2-Furanpropionic acid (C7H80 3; mol. wt. 140.14) is readily

soluble in the usual organic solvents and is appreciably soluble

in water.

NOTES

1. Each new portion of amalgam is added only when the previous

portion has reacted completely, which requires 2-3 minutes. During

the reduction the contents of the cylinder are shaken constantly.

57

2. The 2-furanpropionic acid forms a precipitate, which may be filtered off, washed with ice water, and dried in a desiccator. However, this procedure does not avoid the necessity of extracting acid dissolved in the water; moreover, the precipitated acid is not pure enough: its melting point does not exceed 52°, and it turns brown in the air.

3. There is no head fraction: the temperature rises immediately to 134° and distillation of 2-furanpropionic acid begins; the end of the distillation is indicated by the appearance of the first drop to be colored brown.


2-Furanpropionic acid has been prepared by the reduction of 2-furanacrylic acid with sodium amalgam in an aqueous medium1•

The reduction has been effected also electrolyticalli and catalytically with Raney nickel 3 or palladium4 as catalyst. Also, 2-furanacrylic ester has been reduced with sodium amalgam in an alcohol medium5•

2-Furanpropionic acid has been prepared by the vacuum distillation of furfurylmalonic6 and furfurylsuccinic 7 acids, and also by the action of carbon dioxide on 2-furylethylmagnesium chloride8• It is formed in fairly high yield by the acidic scission of 2-furfurylacetoacetic ester9 and by the oxidation of 2-furanpropionaldehyde with silver oxide10 •

From the point of view of the accessibility of starting materials, methods based on the reduction of 2-furanacrylic acid must be regarded as the most convenient.

LITERATURE CITED

1 A. Bayer, Ber. 10, 357 (1877); W. Marckwald, Ber. 20, 2812 (1887); J. J. Sudborough and j. M. Gittins, j. Chern. Soc. 95, 320 (1909).

2 A. W. Ingersoll, Organic Syntheses (Russian Translation), Vol. 1, p. 163, Foreign Lit. Press, Moscow, 1949 [Organic Syntheses, Collective Volume 1, 2nd Ed., New York and London, 1941, p. 313].

58

3 P. Lambert and P. Mastaglio, C.r. 235, 626 (1952). 4 R. ]. Railings and j. C. Smith, ]. Chern. Soc. 618 (1953). 5 Y. Asahina and B. Shibata, j. Pharm. Soc. Japan, No. 423,

391 (1917) [C.A. 11, 2457 (1917)]. 6 W. Marckwald, Ber. 21, 1083 (1888). 7 S. S. Sande lin, Ber. 31, 1121 (1898). 8 E. D. Amstutz and j. Plucker, J. Am. Chern. Soc. 63, 206

(1941). 9 W. R. Kirner and G. H. Richter, j. Am. Chern. Soc. 51, 3131

(1929). 10 S. M. Sherlin, A. Ia. Berlin, and T. N. Serebrenikova, Zh.

obshchei khim. (J. Gen. Chern.) 8, 7 (1938).

59

FURFURYLAMINE

[ OcH,NH]2uAI(OHJ,

[ oCH,NHl.LIAI(OHJ. + 2H,O ~

2 OcH,NH, + AI(OHJ, + uoH

Proposed by A. L. Mndzhoian and A. A. Dokhikian Checked by G. T. Tatevosian and S. G. Agbalian

PREPARATION

2-Furaldehyde Oxime. A solution of 34.8 g (0.5 mole) of hydroxylamine hydrochloride and 38.4 g (0.4 mole) of freshly distilled 2-furaldehyde were introduced into a 500-ml three-necked roundbottomed flask fitted with mercury- sealed stirrer, reflux condenser, and dropping funnel.

Over a period of two hours a solution of 26.5 g (0.25 mole) of sodium carbonate in 100 ml of water was added to the stirred mixture. The mixture was then heated in a water bath for five hours, allowed to cool, and extracted with three 100-ml portions of ether. The combined extract was washed with a little water and dried over calcined sodium sulfate. Solvent was distilled off, and

60

the residue was vacuum-distilled with collection of the substance coming over at 96-97°/5 mm (Note 1); the substance solidified in the receiver. The yield was 41.4-42.0 g (93.2--94.5%) (Note 3).

Furfurylamine. A solution of 8.4 g (about 0.22 mole) of lithium aluminum hydride in 480 ml of ether (Note 4) was introduced into a one-liter three-necked round-bottomed flask fitted with mercurysealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube.

The stirrer was started, and a solution of 22.2 g (0.2 mole) of 2-furaldehyde oxime in 100 ml of dry ether was added over a period of 2-2.5 hours, after which the reaction mixture was set aside overnight. On the next day the flask was cooled with cold water while 40 ml of water was added cautiously to the mixture (Note 5). The ethereal solution was filtered, and the residue was washed with three 100-ml portions of ether. The combined filtrate was dried with anhydrous potassium carbonate, solvent was distilled off (Note 6), and the residue was vacuum-distilled with collection of the substance coming over at 83°/85 mm.

The yield was 12.6-13.2 g (64.8-67.9%).

Furfurylamine (C5H 70N; mol. wt. 97.11) is a colorless liquid, soluble in the usual organic solvents and in water; d204 1.0505; n20o 1.4906; b.p. 141-142°/680 mm.

NOTES

1. On distillation the oxime solidifies immediately; an air condenser should therefore be used with a Wurtz flask as receiver.

2. 2-Furaldehyde oxime exists in two stereoisomeric forms, the cis-form (m.p. 91-92°) and the anti-form (m.p. 75-76°). The preparation obtained is a mixture of these two isomers and melts over the range 57-73°.

3. The procedure described above for the preparation of 2-furaldehyde oxime is based on the work of Odernheimer1 and Goldschmidt 2•

61

4. For the preparation of the ethereal solution of lithium aluminum hydride seep. 19.

5. The decomposition of the excess of lithium aluminum hydride must be carried out very cautiously with control of the addition of water so that the ether boils steadily.

6. In the distillation ether vapor entrains appreciable amounts of furfurylamine; the distillation of solvent, therefore, must be carried out through a fractionation column.


Furfurylamine has been prepared by the catalytic reduction of 2-furaldehyde in liquid ammonia in presence of Raney nickel 3•

It has been prepared also by the reduction of 2-furaldehyde oxime with 2.5% sodium amalgam in a medium of alcohol and acetic acid 4, with aluminum amalgam in an aqueous-alcoholic medium5,

with ammonium amalgam6 ; also by catalytic reduction in presence of a palladium 7 or nickel 8 catalyst.

Furfurylamine is formed in the reduction of 2-furaldehyde phenylhydrazone with sodium and alcohol 7 or with 2.5% sodium amalgam in a medium of alcohol and acetic acid 9; it is formed also by reduction of 2-furonitrile with zinc and sulfuric acid 10

and by its catalytic reduction in presence of Raney nickel 11 •

The above-described procedure of reducing 2-furaldehyde oxime with lithium aluminum hydride forms a convenient laboratory method for the preparation of furfurylamine.

LITERATURE CITED

1E. Odernheimer, Ber. 16, 2988 (1883). 2 H. Goldschmidt and F. Zanoli, Ber. 25, 2574(1892). 3 E. j. Schwoegler and H. Adkins, j. Am. Chern. Soc. 61, 3499

(1939); j. C. Robinson and H. R. Snyder, Organic Syntheses (Russian Translation), Vol. 3, p. 449, Foreign Lit. Press, Moscow, 1952 [Organic Syntheses, Collective Vol. 3, New York and London, 1955, p. 717].

62

4 H. Goldschmidt, Ber. 20, 730 (1887). 5 Chao-Lun Tseng and Chi Chang, Science Rep. Nat. Univ.

Peking 1, No. 3, 19 (1936) [C.A. 31, 952 (1937)]. 6 S. Takaki and T. Ueda, j. Pharm. Soc. japan 58, 276 (1938)

[C.A. 32, 53762 (1938) ]. 7N. V. Villiams, Doklady Akad. Nauk SSSR (Proc. Acad. Sci.

USSR) 523 (1930). 8 R. Paul, Bull. Soc. Chim. [5) 4, 1121 (1937). 9 j. Tafel, Ber. 20, 399 (1887).

10 G. I. Ciamician and M. Dennstedt, Ber. 14, 1059, 1475 (1881). 11 W. Huber, j. Am. Chern. Soc. 66, 876 (1944).

N-BENZYLFURFURYLAMINE

[ 0 CH,NHCH 0 ]~IAI(OH),

[ 0 CH,NHCH 0 ]~IAI(OH), + 2H,O -

20CH2NHCH20' + LiOH+ AI(0H)3 0 -

Proposed by A. L. Mndzhoian, V. G. Afrikian, and A. A. Dokhikian Checked by G. T. Tatevosian and S. G. Agbalian

63

PREPARATION

N-Furfurylbenzamide. A solution of 29 g (0.3 mole) of furfurylamine (seep. 60), b.p. 141-142°/680 mm, in460 ml of dry benzene was introduced into a one-liter three-necked round-bottomed flask fitted with mercury- sealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. The solution was stirred while a solution of 28 g (0.2 mole) of freshly distilled benzoyl chloride in 140 ml of dry benzene was added dropwise. When addition was complete (after 1.5-2 hours), the stirred reaction mixture was boiled in a water bath for one hour, cooled to room temperature, and washed, first with 100 ml of water, then with 100 ml of 10% sodium carbonate solution, and finally with 100 ml of water (Note 1). The moist benzene solution, which was yellow in color, was transferred to a one-liter distillation flask, and benzene was distilled off until the volume was reduced to 120-140 ml. The warm benzene solution remaining in the flask was poured slowly with stirring into 300 ml of petroleum ether (b.p. 70--90j contained in a flask. Cream scalelike crystals were precipitated; they were filtered off and washed on the filter with two 50-ml portions of petroleum ether.

The yield was 12.6-13.5 (58.5-62.6%); m.p. 101° (Note 2).

Reduction of the Amide. A solution of 2.85 g (0.075 mole) of lithium aluminum hydride in 160 ml of dry ether (Note 3) was introduced into a 500-ml three-necked round-bottomed flask fitted with mercury- sealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. Ether was distilled off from a water bath until 30-35 ml of solution remained, and 50 ml of dry benzene was added. The stirrer was started, and a solution of 10.05 g (0.05 mole) of N-furfurylbenzamide in 250 ml of dry benzene was added dropwise from the funnel over a period of 10-15 minutes. The mixture was boiled gently on a water bath for four hours, and then, with water cooling and stirring, 30 ml of water was added dropwise (Note 4). Stirring was continued further for one hour. The benzene solution was decanted from the precipitate, and the precipitate was carefully stirred with three successive 75-ml portions of dry ether. The combined ethereal solution was dried over calcined sodium sulfate, solvent

64

was distilled off, and the residue was vacuum-distilled with collection of the substance boiling at 125-127°/4 mm.

The yield was 8.1-8.3 g (86.5--88. 7%).

N-Benzylfurfurylamine (C12H130N; mol. wt. 187.22) is a colorless liquid, soluble in the usual organic solvents, but insoluble in water; d204 1.0710; n20D 1.5490.

NOTES

1. The solution was washed in order to remove furfurylamine hydrochloride and unchanged benzoyl chloride.

2. The amide obtained can be used for reduction toN-benzylfurfurylamine without further purification.

3. For the preparation of the lithium aluminum hydride solution see p. 19.

4. The decomposition of the excess of lithium aluminum hydride must be carried out cautiously in order to avoid a violent reaction.


N-Benzylfurfurylamine has been prepared by the reduction of N-furfurylidenebenzylamine in absolute ethanol in presence of Raney nickel 1. The above procedure, in whichN-furfurylbenzamide is reduced with lithium aluminum hydride, provides a convenient method of preparing N-benzylfurfurylamine.

LITERATURE CITED

1 K. N. Campbell, J. F. Ackerman, and B. K. Campbell, J. Am. Chern. Soc. 71, 2905 (1949); U. S. Pat. 2,640,828 [C.A. 48, 4001c (1954) ).

65

N ,N -DIETHYLFURFURYLAMINE

OCHO + HN(C,H,), + HCOOH -

OcH,N(c,H,l, +co,+ H,o

Checked by 0. L. Mndzhoian and N. A. Babiian

PREPARATION

With stirring and cooling with ice water, 146 g (2 moles) of diethylamine was added over a period of 2.5--3 hours to 108 g (2 moles) of 85% formic acid contained in a 750-ml three-necked round-bottomed flask fitted with mercury-sealed stirrer, dropping funnel, and reflux condenser (Note 1). The reflux condenser was replaced by one set for distillation, and liquid distilling below 135° was removed from the reaction mixture. The contents of the flask were allowed to cool to room temperature, the condenser was replaced by one set for reflux, and 38.4 g (0.4 mole) of freshly distilled 2-furaldehyde, b.p. 159-161°/680 mm, was added from the dropping funnel.

The stirred reaction mixture was heated for 4-6 hours in an oil bath, the temperature of which was kept in the range 165-1700; at this temperature the mixture remained at a steady boil. The mixture was then allowed to cool to room temperature, and 400 ml of water was added. The liquid was poured into a 1500-ml round-bottomed flask and, with water cooling and stirring, 100 g of solid sodium hydroxide was added in small portions (Note 2). The reaction mixture was steam-distilled until 1 liter of liquid had been collected (Note 3); distillation was then stopped, and the distillate was rendered strongly alkaline by adding sodium hydroxide (100-120 g of NaOH) until complete separation into layers occurred. The upper layer of reaction product was separated, and the aqueous layer was extracted with three portions of ether,

66

each amounting to 100--150 ml. The main product and the ether extracts were combined and dried with sodium hydroxide. Ether was distilled off, and the residue was distilled at atmospheric pressure. A liquid which came over in the range 164-172°/680 mm was refractionated with collection of the substance coming over at 166--169°/680 mm.

The yield of N,N-diethyliurfurylamine was 37.5-40.0 g (61.2-65.2% on the amount of 2-furaldehyde taken).

N,N-Diethylfurfurylamine (C9H15NO; mol. wt. 153.22) is a lightyellow liquid, readily soluble in the usual organic solvents; d20 4

0.9308; n20D 1.4630. On standing it darkens in color.

NOTES

1. The addition of diethylamine brings about a vigorous reaction, and it must therefore be slow at first. Later, the rate of addition can be greatly increased.

2. When this amount of sodium hydroxide is added, the reaction mixture separates completely into two layers.

3. N,N-Diethylfurfurylamine comes over completely with this volume of distillate.


N,N-Diethylfurfurylamine has been prepared only by the abovedescribed method, which is based on the work of Weilmuenster and jordan1•

LITERATURE CITED

1E. A. Weilmuenster and C. N. jordan, J. Am. Chern. Soc. 67, 415 (1945).

67

5-(FURFURYLTHIOMETHYL)-2-FUROIC ACID

2 OcH,SH + 2Na - 2 OcH,SNa + H,

OcH,SNa +etcH, QcoocH, -

OcH,SCH,,O coocH, + N.c,

OcH,scH,Q coacH,+ NaOH _

OcH,SCH, QcooNa + CH,OH

OCH.SCH,(JcooNa+HCJ-

(JcH,SCH, QcooH + NaCt

Proposed by A. L. Mndzhoian and N. M. Divanian Checked by G. T. Tatevosian and S. P. Ekmekdzhian

PREPARATION

Methyl 5-(Furfurylthiomethyl)-2-furoate. Dry benzene (150 ml) and 2.3 g (0.1 g-atom) of sodium wire were introduced into a 250-ml three-necked round-bottomed flask fitted with mercurysealed stirrer, dropping funnel, and reflux condenser protected by a calcium chloride tube. From the dropping funnel gradual addition was made of 12.6 g (0.15 mole) of 2-furanmethanethiol (see Notes), b.p. 160°/759 mm. When the addition was complete, the mixture was boiled in a water bath and stirred gently until

68

the sodium disappeared completely, after which the flask was cooled with water and, with continued stirring, dropwise addition was made of a solution of 17.5 g (0.1 mole) of methyl 5-(chloromethyl)-2-furoate (see Vol. 1 of this work, p. 29), b.p. 114-116°/ /3 mm, in 25 ml of dry benzene. The reaction mixture was boiled with stirring for three hours; it was then cooled, and 75 ml of water was added. The benzene layer was separated from the aqueous layer, which was extracted with 50 ml of ether; the ether extract was added to the benzene solution, and the whole was washed with a little water and dried over calcined sodium sulfate. Solvent was distilled off, and the residue was vacuum-distilled; 5--6 ml of head fraction came over below 175°/2 mm, and this was followed at 175-176°/2 mm by methyl 5- (furfurylthiomethyl)-2-furoate as a light-yellow oil.

The yield was 20.5-22.0 g (81.0-86.9% on the amount of methyl 5-(chloromethyl)-2-furoate taken).

Hydrolysis. Methyl 5-(furfurylthiomethyl)-2-furoate (20.2 g, i.e., 0.08 mole) was added to a solution of 5 g (0.125 mole) of sodium hydroxide in 150 ml of 50% alcohol contained in a 250-ml round-bottomed flask fitted with reflux condenser. The mixture was boiled in a water bath for three hours, after which the reflux condenser was replaced by one set for distillation and alcohol was distilled off completely. The alkaline solution remaining in the flask was cooled, washed with ether, and acidified to Congo red with hydrochloric acid. 5-(Furfurylthiomethyl)-2-furoic acid separated as an oil, which rapidly solidified. It was filtered off, washed on the filter with two 20-ml portions of water, and dried in the air. Recrystallization from 1500--1700 ml of light gasoline (b.p. 90-100°) gave 17.0--17.35 g (89.4-90.9%) of colorless crystals, m.p. 89°.

5-(Furfurylthiomethyl)-2-furoic acid (C11H100 4S; mol. wt. 238.26) crystallizes in colorless needles, soluble in alcohol, ether, and benzene, sparingly soluble in petroleum ether, and insoluble in water.

69

NOTES

2-Furanmethanethiol was prepared by H. Kofod's method, i.e., by reaction between furfuryl alcohol and thiourea in presence of hydrochloric acid.


5-(Furfurylthiomethyl)-2-furoic acid has been prepared only by the method described above2•

LITERATURE CITED

1 H. Kofod, Acta Chern. Scand. 7, 1320 (1953). 2 A. L. Mndzhoian, G. T. Tatevosian, S. G. Agbalian, and N. M.

Divanian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 207 (1957).

FURFURYL ALCOHOL

OcHo + CH20 + NaOH -

OcH,OH + HCOONa

Checked by 0. L. Mndzhoian and A. N. Grigorian

PREPARATION

A mixture of 96 g (1 mole) of freshly distilled 2-furaldehyde (Note 1), 250 ml of water, and 250 ml (3.46 moles) of 40% formaldehyde solution (Note 2) was prepared in a one-liter four-necked round-bottomed flask fitted with mercury-sealed stirrer, dropping funnel, thermometer, and reflux condenser.

70

The mixture was cooled to 5°, and gradually, over a period of 25-30 minutes with continuous stirring, 230 g of 50% aqueous sodium hydroxide (2.87 moles) was added from the dropping funnel with maintenance of the temperature of the reaction mixture in the range 15-20° (Note 3), which was attained by external cooling of the flask with ice water and control of the rate of addition of alkali.

When the whole of the sodium hydroxide solution had been added, stirring was continued for five hours while the mixture was maintained at 40-45° (Note 3); it was then left at room temperature for 15-18 hours (Note 4), after which it was extracted with five 150-ml portions of ether. The combined ether extract was dried over anhydrous sodium sulfate, solvent was distilled off, and the residue was vacuum-distilled. About 10 ml of head fraction, mainly unchanged 2-furaldehyde, came over up to 75°/ /15 mm, and this was followed by furfuryl alcohol at 75-76°/15 mm. The yield was 80.0--82.0 g (81.6-83.6%).

Furfuryl alcohol (C5Hs~; mol. wt. 98.05) is a colorless liquid of characteristic odor, readily soluble in water, alcohol, and ether; d22 • 74 1.1282; n22 • 7D 1.4851. On standing in the air it assumes a light-yellow color.

NOTES

1. Technical 2-furaldehyde may be used without appreciable effect on the yield of furfuryl alcohol.

2. The use of equimolecular amounts of reactants lowers the yield of furfuryl alcohol to 53-55%. If the amounts of formaldehyde and sodium hydroxide are reduced to 1.5 and 1.8 moles, respectively, per mole of 2-furaldehyde, furfuryl alcohol is obtained in 71-73% yield. A certain reduction in the yield is compensated, however, by the fact that with stoichiometric proportions of components the total duration of reaction may be only 3-3.5 hours (optimum temperature 15-25°); in this case, leaving the mixture for 15-18 hours has no effect on the yield of furfuryl alcohol.

71

3. At higher temperatures the yield of furfuryl alcohol is reduced because of the formation of polymeric products.

4. When the mixture is treated immediately, without leaving it for 15-18 hours, the yield of furfuryl alcohol is reduced to 70"/c.


Furfuryl alcohol can be prepared by the reduction of 2-furaldehyde with sodium amalgam1• The catalytic reduction of 2-furaldehyde can be carried out in the liquid phase under pressure at temperatures of the order of 130-160° in presence of copper2

and copper-chromium3 catalysts containing alkaline-earth oxides. Furfuryl alcohol has been prepared in 85"/c yield by the reduction of 2-furoic acid with lithium aluminum hydride4• The dismutation of 2-furaldehyde, which can be effected with the aid of sodamide5

or solutions of caustic alkalis6 , results in the formation of furfuryl alcohol and 2-furoic acid. The yield of furfuryl alcohol can be raised by carrying out a mixed Cannizzaro reaction with a mixture of 2-furaldehyde and formaldehyde; the procedure given above was proposed by A.M. Berkengeim and T. F. Dankova7•

LITERATURE CITED

1 Schmeltz and F. Beilstein, A. Suppl. 3, 275 (1864-65). 2 U. S. Pat. 2,077,409 [C.A. 31, 39444 (1937)];J. G. M. Bremmer

and R. K. F. Keeys, J. Chern. Soc. 1068 (1947); Australian Pat. 135,530 (1949) [C.A. 44, 4932i (1950) ].

3 G. Roberti, Ann, Chim. Applicata, 25, 530 (1935) [C.A. 30, 41657 (1936)]; U. S. Pat. 2,094,975 [C.A. 31, 85494 (1937)]; 2,400,950 [C.A. 40, 48606 (1946)]; J. Mizuguchi and M. Iwase, J. Soc. Chern. Ind. Japan 46, 1037 (1943) [C.A. 42, 6353i (1948)]; K. Tsuda, S. Yoshida, M. Yamada, and Y. Maruya, j. Pharm. Soc. Japan 66, 58 (1946) [C.A. 45, 6182e (1951) ]; Italian Pat. 461,821 (1951) [C.A. 46, 2842i (1952)].

4 R. F. Nystrom and W. G. Brown, J, Am. Chern. Soc. 69, 2548 (1947).

5 I. Kasiwagi, Bull. Chern. Soc. Japan 1, 66 (1926) [C.A. 20, 2491 (1926)].

72

6 H. Limpricht, A. 165, 279, 300 (1873); K. Bieler and B. Tollens, A. 258, 119 (1890); E. Erdmann, Ber. 35, 1855 (1902); H. Gilman and C. C. Vernon, j. Am. Chern. Soc. 46, 2576 (1924).

7 A. M. Berkengeim and T. F. Dankova, Zh. obshchei khim. (J. Gen. Chern.) 9, 924 (1939).

5-BROM0-2-FUROYL CHLORIDE

Br 0 COOH +SOC I, - Br 01 COCI + S02 + HCI 0 0

Proposed by A. L. Mndzhoian and V. G. Afrikian Checked by M. T. Grigorian and Iu. 0. Martirosian

PREPARATION

A solution of 57.3 g (0.3 mole) of 5-bromo-2-furoic acid (see Vol. 1 of this work, p. 11), m.p. 182--183°, in 150 ml of dry benzene was prepared in a 300-ml round-bottomed flask fitted with reflux condenser protected by a calcium chloride tube, and 42.8 g (0.36 mole) of freshly distilled thionyl chloride was added.

In order to trap sulfur dioxide and hydrogen chloride liberated during the reaction the end of the calcium chloride tube was connected to a Tishchenko vessel containing a solution of caustic alkali.

The mixture was boiled in a water bath for 13-15 hours, and excess of thionyl chloride and benzene was then distilled off under reduced pressure (water pump). The residue was vacuum-distilled with collection of the substance coming over at 110-111 o /18 mm. On standing, the distillate solidified completely; m.p. 54-55°,

The yield was 54.0-55.0 g (85.9-87.5%).

5-Bromo-2-furoyl chloride (C5H2~BrCl; mol. wt. 209.49) is a light-yellow crystalline substance.

73


5-Bromo-2-furoyl. chloride has been prepared by reaction between the acid and excess of thionyl chloride in an inert solvent 1•

The above - described procedure was proposed by A. L. Mndzhoian2•

LITERATURE CITED

1 L. C. Raiford and W. G. Huey, j. Org. Chern. 6, 858 (1941); I. R. Willard and C. S. Hamilton, J. Am. Chern. Soc. 75, 2370 (1953).

2 A. L. Mndzhoian, Zh. obshchei khim. (J. Gen. Chern.) 16, 751 (1946).

5-(PROPOXYMETHYL)-2-FUROYL CHLORIDE

C3HPCH2 0 COOH + SOCI2 -

CaH?OCH 2 OCOCI + S02 + HCI

Proposed by A. L. Mndzhoian and G. L. Papaian Checked by V. G. Afrikian and Iu. 0. Martirosian

PREPARATION

A solution of 18.4 g (0.1 mole) of 5-(propoxymethyl)-2-furoic acid (see Vol. 1 of this work, p. 37), m.p. 43--44°, in 50 ml of dry benzene was prepared in a 200-ml round-bottomed flask fitted with reflux condenser protected by a calcium chloride tube, and 13.1 g (0.11 mole) of freshly distilled thionyl chloride was added as a solution in 30 ml of dry benzene.

74

The mixture was boiled in a water bath for 5-6 hours; the gases liberated in the reaction were passed into a Tishchenko vessel containing a solution of caustic alkali. The excess of

thionyl chloride and benzene was then distilled off under reduced

pressure (water pump), and the residue vacuum -distilled at

112-115°/8 mm.

The yield was 17.4-18.3 g (86.4-90.9%).

5-(Propoxymethyl)-2-furoyl chloride (C9H110 3Cl; mol. wt.

202.64) is a colorless mobile liquid having a sharp odor; d20 4

1.1710; n20D 1.5000.


5-(Propoxymethyl)-2-furoyl chloride has been prepared only

by the method described above1.

LITERATURE CITED

1 A. L. Mndzhoian, V. G. Afrikian, A. A. Dokhikian, and G. L.

Papaian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 17, 145 (1953).

75

ETHYL 5-(1-CHLOROETHYL)-2-FUROATE

Proposed by A. L. Mndzhoian and A. A. Aroian Checked by 0. L. Mndzhoian and N. A. Babiian

PREPARATION

A mixture of 70 g (0.5 mole) of ethyl 2-furoate, 16 g of anhydrous zinc chloride, and 150 ml of chloroform (Note 1) was prepared in a 500-ml four-necked round-bottomed flask fitted with mercurysealed stirrer, thermometer, dropping funnel, and gas-outlet tube. With continuous stirring the contents of the flask were cooled with a mixture of ice and salt to a temperature of from -1 o to 0°, and 44 g (1 mole) of acetaldehyde (Note 2) was added at such a rate that the temperature of the mixture did not rise above 4-5° (30-40 minutes was required) (Note 3). When the whole of the acetaldehyde had been added, the dropping funnel was replaced by a bent tube which reached to the bottom of the flask, and with continued vigorous stirring a rapid stream of hydrogen chloride (which had passed through a wash bottle containing sulfuric acid) was passed through the mixture; the temperature of the mixture was maintained at not above 4-5° (Note 4). When saturation was reached (1-1.5 hours), a slower stream of hydrogen chloride was passed for one hour further, after which the temperature of the mixture was allowed to rise gradually (over a period of 45--50 minutes) to that of the room; stirring was continued further for 2.5-3 hours. The contents of the flask were then poured into a beaker containing 100 ml of ice water; the chloroform layer was separated, and the aqueous layer was extracted with 25 ml of chloroform, which was then added to the mainproduct. The chloroform solution was washed 2-3 times with 100-ml portions of ice water with careful separation of the aqueous layer (Note 5). Solvent was distilled off under reduced pressure (water pump),

76

and the residue was vacuum-distilled with collection of the liquid coming over at 117-121 o /3 mm. Redistillation gave a substance boiling at 118-120°/3 mm (Note 6).

The yield was 72.6--78.6 g (71.8-77. 7"/o) (Note 7).

Ethyl 5-(1-chloroethyl)-2-furoate (C9H110 3Cl; mol. wt. 202.64) is a light-yellow liqufd, readily soluble in the usual organic solvents, but insoluble in water; d204 1.1840; n20D 1.5040.

NOTES

1. Instead of chloroform, dichloroethane can be used as solvent.

2. Paraldehyde can be used instead of acetaldehyde without appreciable effect on the yield of product.

3. The dissolution of acetaldehyde in chloroform is accompanied by the evolution of an appreciable amount of heat. In order to prevent partial evaporation of acetaldehyde and resinification, the temperature must not be allowed to rise above 4-5°. When paraldehyde is used no sharp rise in temperature is observed.

4. If the chloroethylation is carried out at a higher temperature (12--17}, further transformations of the product occur with formation of a considerable amount of a high-boiling fraction.

5. Drying the chloroform solution with calcium chloride is not recommended, because when the product is left overnight partial resinification sometimes occurs with liberation of hydrogen chloride. It is best to leave the solution in the separating funnel for 10-15 minutes, carefully separate it from water, dry it over sodium sulfate for ten minutes, filter, and distill on the same day.

6. A product containing traces of the original ester and paraldehyde will darken after it has stood for a few days. Pure ethyl 5-(1-chloroethyl)-2-furoate is more stable.

7. Methyl 2-furoate can be chloroethylated similarly in about the same yield 1•

77

ai'HER METHODS OF PREPARATION

Ethyl 5-(1-chloroethyl)-2-furoate has been prepared only by the method described above1•

LITERATURE CITED

1 A. L. Mndzhoian and A. A. Aroian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 267 (1957).

5-ETHYL-2-FUROIC ACID

C2H5 0 COOC2H5 + ZnCla

c.H, Ocooc2Hs + NaOH -

C2H5 OcoONa + CzH50H

C.H, QcooN, + HCI ~ c.H, 0 cooH + N•CI

Proposed by A. L. Mndzhoian and A. A. Aroian Checked by 0. L. Mndzhoian and N. A. Babiian

PREPARATION

Ethyl 5-Ethyl-2-furoate. A mixture of 50.6 g (0.25 mole) of ethyl 5-(1-chloroethyl)-2-furoate (see p. 76), b.p. 108-110°/0.5

78

mm, and 150 ml of glacial acetic acid was prepared in a 500-ml four-necked round-bottomed flask fitted with mercury-sealed stirrer, reflux condenser carrying a gas-outlet tube, thermometer, and glass tube passing to the bottom of the flask and serving for the introduction of hydrogen chloride. Over a period of 20--30 minutes, 49 g (0. 75 g-atom) of zinc dust was added in small portions to the vigorously stirred mixture (Note 1). When all of the zinc had been added, a stream of dry hydrogen chloride was passed into the mixture for 3.5-4 hours at such a rate that the temperature of the mixture did not rise above 55-60° (Note 3). When saturated with hydrogen chloride, the reaction mixture was heated in a water bath for 20-30 minutes (Note 4).

The mixture was cooled and poured into a beaker containing 400 ml of water and ice. The upper layer was separated with the aid of ether from the aqueous layer, which was extracted three times with ether, taken in portions of 75-100 ml. The combined ether extract was washed twice with water, then with sodium bicarbonate solution, and again with water. It was dried over anhydrous sodium sulfate. Solvent was distilled off, and the residue was vacuum-distilled with collection of the substance coming over at 75--76°/0.5 mm (Note 5).

Yield 32.5-33.7 g (77.6-80.1%).

Hydrolysis. A mixture of 33.6 g (0.2 mole) of ethyl 5-ethyl-2-furoate and 120 ml of 10% aqueous sodium hydroxide solution was prepared in a 250-ml round-bottomedflaskfitted with mercurysealed stirrer and reflux condenser. It was heated with constant stirring in a water bath for 60-90 minutes. The contents of the flask were then cooled and washed with a little ether; they were cooled with water and stirred (Note 6) while hydrochloric acid was added until the mixture was acid to Congo red. The 5-ethyl-2-furoic acid liberated was filtered off at the pump, washed with 50 ml of cold water, and dried in the air; m.p. 92-93° (Note 7).

The yield was 23.4-24.3 g (83.5-86.8%) (Note 8).

5-Ethyl-2-furoic acid (C 7H80 3; mol. wt. 140.13) is a colorless crystalline substance, readily soluble in methanol and ethanol, moderately soluble in benzene, and sparingly soluble in water.

79

NarES

1. During the introduction of zinc dust the temperature of the mixture rises sharply, particularly at first. It must therefore be added cautiously, in small portions, with maintenance of the temperature in the flask at not above 60-65°.

2. The reduction can be effected in 55--60% yield without the use of hydrogen chloride. In that case, however, prolonged boiling of the reaction mixture (not less than 25-30 hours) is necessary for the completion of the process. Also, the purity of the zinc used is then of great importance: if the zinc dust is not pure enough, the reaction product is obtained in lower yield and it distills over a wider range of temperature.

3. Reduction is quicker at a higher temperature, but the yield is then somewhat lower.

4. When heated, the contents of the flask assume a lightbrown color, which disappears when the mixture cools.

5. Methyl 5-ethyl-2-furoate can be prepared by the method described in about the same yield 1.

6. Stirring and cooling are essential for the formation of fine uniform crystals; otherwise, the acid separates as an oil, which freezes to a continuous crystalline mass.

7. The substance is obtained in the pure state: recrystallization from 50% methanol or from benzene has no effect on the melting point.

8. 5-Ethyl-2-furoic acid can be prepared by similar hydrolysis of the methyl ester in about the same yield.


5-Ethyl-2-furoic acid has been prepared only by the method given above1•

LITERATURE CITED

1 A. L. Mndzhoian and A. A. Aroian, Doklady Akad. Nauk Arm. SSR (Proc. Acad. Sci. Armenian SSR) 25, 267 (1957).

80

INDEX*

Page numbers referring to recommended methods of preparation are underlined.

Acetic acid, (2-furoyl)-, ethyl ester, 64.

Acylation, 13, 49.

Alcohols, condensation with (chloromethyl) furan derivatives, 25.

Aluminum chloride, condensation in presence of, 17.

Bromination, 11.

Bromomethylation, 18.

1-Butanethiol, condensation with (chloromethyl) furan derivatives, 20.

Cannizzaro reaction, 43.

Chloromethylation, 29, 62.

Condensation, of alcohol with chloro compound, 25; of amine with chloro compound, 22; Claisen, 64; Friedel-Crafts, 17; of thiol

with chloro compound, 20.

Cyclization, 9, 47.

Decarboxylation, of 2-furoic acid, 40; of 5-methyl-2-furoic acid; 31.

Diethylamine, condensation with (chloromethyl) furan derivatives, 22.

Esterification, 27, 74.

Formaldehyde, use in halomethylation, 18, 29, 62.

Friedel-Crafts reaction, 17.

* This index has been compiled by the publishers of the trans

lation. It is based on the system of indexing used in Chemical

Abstracts. The sections entitled "Other Methods of Preparation"

have not been indexed.

67

2-Furaldehyde, 51; acetylation of, 13; Cannizzaro reaction of, 43; Grignard reactions with, 35, 38.

Furan, 40.

Furan, 2-(chloromethyl)-. See Furfuryl chloride.

--, 2-methyl-, 31.

2-Furancarboxylic acid. See 2-Furoic acid.

2-Furanmethanediol, diacetate, 13.

2-Furanpropionic acid, f3 -oxo-, ethyl ester. See Acetic acid, (2-furoyl)-, ethyl ester.

Furfural. See 2-Furaldehyde.

Furfuryl alcohol, 43; treatment with SOC12, 58.

Furfuryl alcohol, a -benzyl-, 39.

--,a -butyl-, 36.

--,a -cyclohexyl-, 39.

--, 5-(diethylaminomethyl)-, 15.

--,a-ethyl-, 36.

--,a-methyl-, 36.

--,a -phenethyl-, 39.

--,a -phenyl-, 38.

--,a -propyl-, 35.

Furfuryl chloride, 58.

2-Furoic acid, 43; bromination of,ll;conversionintoacid chloride, 56; decarboxylation of, 40; esterification of, 27, 74.

butyl, isobutyl, isopropyl, and propyl estera, 28. 2-chloroethyl ester, 61; chloromethylation of, 62. ethyl ester, 28; Claisen condensation with, 64. methyl ester, 27; bromomethylation of, 18; chloromethylation

of, 29.

2-Furoic acid, 5-benzyl-, 7; conversion into acid chloride, 54. methyl ester, 17; hydrolysiS of, 7.

68

--, 5-(benzyloxymethyl)-, methyl ester, 26.

--, 5-bromo-, 11.

--, 5-(bromomethyl)-, ethyl ester, 20. methyl ester, 18.

--, 5-(butoxymethyl)-, methyl ester, 26.

--, 5- (butylthiomethyl)-, ethyl ester, 21. methyl ester, 20.

--, 5-(chloromethyl)-, butyl, ethyl, isobutyl, isopropyl, and

propyl esters, 30. 2-chloroethyl ester, 62. methyl ester, 29; condensation with alcohols, 25; condensation

with amines, 22; condensation with thiols, 20; Friedel-Crafts

reaction with, 17.

5-(dibutylaminomethyl)-, butyl, ethyl, isobutyl, isopropyl,

and propyl esters, 23.

--, 5- (diethylaminomethyl)-, butyl, ethyl, isobutyl, isopropyl,

and propyl esters, 23. methyl ester, 22; reduction of, 15.

--, 5- (dimethylaminomethyl)-, butyl, ethyl, isobutyl, isopropyl,

and propyl esters, 23.

--, 5-(dipropylaminomethyl)-, butyl, ethyl, isobutyl, isopropyl, and propyl esters, 23.

--, 5-(ethoxymethyl)-, methyl ester, 26.

--, 5- (ethylthiomethyl)-, ethyl and methyl esters, 21.

--, 5-(isobutoxymethyl)-, methyl ester, 26.

--, 5-(isobutylthiomethyl)-, ethyl and methyl esters, 21.

--, 5-(isopropoxymethyl)-, methyl ester, 26.

--, 5-(isopropylthiomethyl)-, ethyl and methyl esters, 21.

--, 5-(isopentyloxymethyl)-, methyl ester, 26.

--, 5-(isopentylthiomethyl)-, ethyl and methyl esters, 21.

69

--, 5-methyl-, 33; decarboxylation of, 31; conversion into acid chloride, 55.

ethyl ester, 24. methyl ester, 23; hydrolysis of, 33.

--, 5-(methoxymethyl)-, methyl ester, 26.

--, 5-(methylthiomethyl)-, ethyl and methyl esters, 21.

--, 5-(pentyloxymethyl)-, methyl ester, 26.

--, 5- (pentylthiomethyl)-, ethyl and methyl esters, 21.

--, 5-(phenethyloxymethyl)-, methyl ester, 26.

--, 5-(phenoxymethyl)-, methyl ester, 26.

--, 5-(propoxymethyl)-, 37. methyl ester, 25; hydrolysis of, 37.

--, 5-(propylthiomethyl)-, ethyl and methyl esters, 21.

2-Furoyl chloride, 56.

--, 5-benzyl-, 54.

--, 5-methyl-, 55.

Grignard reaction, 35, 38.

Hydrolysis, of esters, 7, 33, 37.

Lithium aluminum hydride, reduction with, 15.

Propyl alcohol, condensation with (chloromethyl) furanderivatjves, 25.

Pyromucic acid. See 2-Furoic acid.

Reducticn, with LiAIH4, 15; with Zn and acid, 23.

Replacement reactions, OH by Cl, 54, 55, 56, 58. See specific terms (bromination, etc.).

Sylvan. See Furan, 2-methyl.

Thiols, condensation with (chloromethyl) furan derivatives, 20.

Thionyl chloride, use of, 54, 55, 56, 58.

3-Thiosemicarbazide, furoylation of, 49.

70

3-Thiosemicarbazide, 1-(5-benzyl-2-furoyl)-, cyclization of, 9.

--, 1-(2-furoyl)-, 49; cyclization of, 47.

s-Triazole-3-thiol, 5-(5-benzyl-2-furyl)-, ~

--. 5-(2-furyl)-, 47.

Zinc, and acetic acid, reduction with, 23.

71

INDEX*

Page numbers referring to recommended methods of preparation are underlined.

Acetoacetic acid, 2-[5-(ethoxycarbonyl)furfuryl]-, ethyl ester, 38.

Acylation, 10, 12, 16.

Benzamide, N-furfuryl-, 64; reduction of, 64.

1-Chloroethylation, with acetaldehyde and HCl, 76.

Chloromethylation, 42.

Claisen-Schmidt condensation, 51.

Decarboxylation, of 5-benzyl-2-furoic acid, 15; of 4,5-dimethyl-2--furoic acid, 26.

Esterification, 18.

Friedel-Crafts reaction, 12.

2-Furaldehyde, Claisen-Schmidt condensation with, 51; Knoevenagel reaction with, 35, 48; mixed Cannizzaro reaction with formaldehyde, 70; Wallach reaction with, 66.

oxime, 60; reduction of, 61.

Furan, acetylation of, 12.

Furan, 2-benzyl-, 15.

* This index has been compiled by the publishers of the translation. It is based on the system of indexing used in Chemical Abstracts. The sections entitled "Other Methods of Preparation" have not been indexed.

81

--, 2,3-dimethyl, 26.

2-Furanacrolein, 51.

2-Furanacrylic acid, 48; reduction of, 57.

2-Furanpropionic acid, 57.

2-Furanpropionic acid, 5-carboxy-, 37.

Furfural. See 2-Furaldehyde.

Furfuryl alcohol, 70.

Furfuryl alcohol, 5-benzyl-, 18; acetylation of, 10. acetate, 10.

--, 5-methyl-, 46.

Furfurylamine, 60; 30; benzoylation of, 64.

Furfurylamine, N-benzyl-, 63.

--, N, N-diethyl-, 66_.

2-Furoic acid, ethyl ester, 1-chloroethylation of, 77. methyl ester, 1-chloroethylation of, 77; reaction with hydrazine,

54. hydrazide, 54.

2-Furoic acid, 5-(aminomethyl)-, :!._: ethyl ester, 8; hydrolysis of, 8.

hydrochloride, 8.

--, 5-benzyl-, decarboxylation of, 15; methylation of, 18. methyl ester, 18.

--, 5-bromo-, conversion into acid chloride, 73.

--, 4-(bromomethyl)-5-methyl-, methyl ester, 44.

--, 5-(1-chloroethyl)-, ethyl ester, 76. methyl ester, 77. -

--, 5-(chloromethyl)-, 8.

82

methyl ester, 24, 38, 44, 69.

4-(chloromethyl)-5-methyl-, methyl ester, 42; reduction of, 28.

--, 5-(cyanomethyl)-, methyl ester, 44.

--, 4,5-dimethyl-, 28; decarboxylation of, 26. methyl ester, 28; hydrolysis of, 28.

--, 5-ethyl-, 78, 80. ethyl ester, 78. -methyl ester, 80.

--, 5-(furfurylthiomethyl)-, 68. methyl ester, 68; hydrolysis of, 69.

--, 5-methyl-, methyl ester, bromomethylation of, 44; chloro

methylation of, 42; hydrogenation of, 40; reduction of, 46.

--, 5-(propoxymethyl)-, conversion into acid chloride, 74.

--, tetrahydro-5-methyl-, methyl ester, 40.

--, 5,5'-(thiodimethylene)di-, 24. dimethyl ester, 24; hydrolysis of, 25.

2-Furoyl chloride, 5-benzyl-, 16.

--, 5-bromo-, 73.

--, 5-(propoxymethyl)-, 74.

Hydrogenation, 32, 40.

Hydrolysis, of esters, 8, 25, 28, 38, 69, 79.

Ketone, 2-furyl methyl, 12.

Knoevenagel reaction, 35, 48.

Lithium aluminum hydride, 19; reduction with, 19, 46, 61, 64.

Malonic acid, condensation with 2-furaldehyde, 48. diethyl ester, condensation with 2-furaldehyde, 35.

Malonic acid, furfurylidene-, diethyl ester, 35; hydrogenation of, 32.

--, (tetrahydrofurfuryl)-, diethyl ~ster, 32.

1,3,4-0xadiazole-2-thiol, 5-(2-furyl)-, 54.

Raney nickel, 32, 34.

83

Reduction (See also Hydrogenation), with LiAlH4, 19, 46, 61, 64;

with Na/Hg, 57; with Zn and acid, 28, 78.

Replacement reactions, Cl by CN, 44; Cl by N~, 8, 16, 30, 64;

2Cl by S, 28; Cl by SR, 68.

3-Thiosemicarbazide, 16.

3-Thiosemicarbazide, 1-(5-benzyl-2-furoyl)-, 16.

Urea, 1,3-difurfuryl-, 30.

Wallach reaction, 66.

84

syntheses of heterocyclic compounds

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