chapter – ii 2,2-bis(ethoxycarbonyl)vinyl (becv) as a versatile amine protecting...

CHAPTER – II

2,2-Bis(ethoxycarbonyl)vinyl (BECV) as a Versatile Amine

Protecting group for Functional Group Transformations

Chapter II Introduction

20

INTRODUCTION

Protecting Groups

Protecting group (PG) is a small molecule, which has the capability to protecting

temporarily the host group from undergoing reaction, allowing the rest of the functional

groups present in the molecule to react without affecting the original reactivity and leave

from the host molecule without affecting the rest of the functional groups.

The protecting group could be called as an ideal protecting group, when it fulfills

the certain criteria. Thus, the protecting group should react with the desired functional

group quickly, should form the protected compound in good yield, the protected

compound should have good stability when stored for a long time. It should have a

minimum functional group to avoid side reaction during the course of the main reaction; it

should not create a new chiral centre at the molecule. At the time of deprotection, it should

cleave under mild reaction condition, should give good yield and the purification must be

simple. There are number of protecting groups available in the literature, for protecting

potentially interfering functional groups such as –OH, –SH, –COOH, –CHO, –C=O, –

NH2, etc.

In general alcoholic and phenolic hydroxyl groups and its sulphur analogues (thiols

and thiophenols) are protected as ethers or esters. Carboxylic acids are protected as esters

or amides. Adehydes and ketones are protected as acetals or ketals. The amino group was

protected as carbamates, amides or imines.

Attempting the synthesize of various complex molecules requires number of

selective functional group transformation involving the use of different reagents and

conditions. The existing protecting groups and available reaction conditions are not

enough to face these problems. Therefore, developing a new protecting groups and a new

conditions for the protection and deprotection of available protecting groups are needed.

Orthogonal Protecting Groups

During the synthesize of complex molecules, the starting material may have the

two or more same functional group (as in the carbohydrate). In this case, it is often

necessary to use same functional group at different times. This can be achieved by


21

choosing a variety of different protecting groups, which can be manipulated using

different reaction conditions. The development of such orthogonal protecting group

strategies makes it possible to remove one set of protecting groups, in any order, using

reagents and conditions that do not affect the other protecting groups in the molecule.

Consider the following molecule, which has three different amine group in a single

molecule protected by the different protecting groups A, B, C and D. The orthogonal

deprotection is the terminology, that the deprotecting condition of A, which will not affect

the other protecting groups B, C and D. Similarly, deprotecting condition of B, will not

affect the protecting groups A, C and D and vice versa (Figure 1).

BHN

COOR

NHDO

H

CHN

RO NHAH

Figure 1. Ideal molecule protected by different protecting group

Boons et al.1 synthesized highly branched disaccharide 2 from β-D-Man-(1→4)-D-

Man disaccharide 1 by the orthogonal protecting group strategy (Scheme 1).

OO O

HO OOHO

PolysaccharideOO HO

ODEIPS = diethylisopropylsilyl,Nap = methylnaphthylAll = allylLev =levulinoylBn = Benzyl

OO O

OBnOLev

ODEIPSO

OPh

NapOBnO

OAll

O OHHO

HOOH

O

H2N

OHOH

HO

O

OHHO

COOH

OLipid A

HO

O

HOHO

OH

HOOrthogonalDeprotection

Glycosylation

1 2

Scheme 1. Orthogonal protection/deprotection in synthesize of highly branched

isaccharide

To cleave the O-allyl group without affecting the levulinoyl, diethylisopropylsilyl,

methylnaphthyl and benzyl group, the allyl deprotecting agent PdCl2, NaOAc, AcOH,

H2O was used. To cleave the O-levulinoyl group without disturbing the allyl,


22

diethylisopropylsilyl, methylnaphthyl and benzyl group, the deprotecting agent hydrazine,

acetic acid in toluene and ethanol mixture was used. Similarly, to deptrotect O-DEIPS

without affecting the allyl, levulinoyl, methylnaphthyl and benzyl group, the deprotecting

reagents TBAF in acetic and THF was used and finally to cleave O-Nap orthogonally, the

reagent DDQ in DCM, water was used (Scheme 2).

OO O

OBnOLev

ODEIPSO

OPh

NapOBnO

OH

PdCl2, NaOAc, AcOH, H2O

OO O

OBnOH

ODEIPSO

OPh

NapOBnO

OAll

NH2NH2.AcOH Tol/EtOH

OO O

OBnOH

OHO

OPh

NapOBnO

OAll

TBAF, AcOH, THF

OO O

OBnOLev

ODEIPSO

OPh

HOBnO

OAll

DDQ, CH2Cl2, H2O

Scheme 2. Regents for orthogonal protection/deprotection

Amine Protecting Groups

Protection of amine group in presence of other functional groups is an important

transformation. This is because, during the synthesize of the natural products, new

chemical entity and the derivatives of existing molecules, the amine groups in the

molecules are more reactive to the most of the common reagents such as nucleophile,

electrophile, strong acid, strong base, Lewis acid, oixidizing agents etc. used.

Protecting groups in peptide synthesize

It is not as straight forward as mixing the amino acids together to form desired

peptides. For example, a mixture of alanine (Ala) and glycine (Gly) would give the

mixture of amides: Ala-Gly, Gly-Ala, Ala-Ala and Gly-Gly and higher polypeptides etc.

To control the coupling reaction, it is necessary to use protecting groups. By protecting the

amine group of one component and the carboxylic acid group of the other, a specific

amide bonds can be formed (Scheme 3).


23

COOH

R

HHN

CO2

R'

HH2N+

CO

R

HHN

HN H

CO2

R,

Protected amine Proected Acid Desired Peptide

Amine Protecting group

Acid Protecting group

Scheme 3. Schematic representation for protecting group in peptide synthesize

Even though, there is a number of amine protecting groups available in the

literature, many of protecting groups do not fulfill the conditions of an ideal amine

protecting groups and orthogonal character. So that, it could not be used in synthesize of

complex organic molecules.

Recently, a large number of amine protecting groups were reported in the

literature. Some of the prominent and novel amine protecting groups are given below.

Wright and Snider2 introduced (1-methyl)cyclopropyloxycarbonylcarbamate

(MPoc) as a amine protecting group. The MPoc group may be introduced to the amine by

reacting the p-nitroderivatives of MPoc 3 with the amine in the presence of triethylamine

in dichloromethane solution. The deprotection was achieved by hydrobromous acid in

presence of palladium catalyst (Scheme 4).

N O

O

R2

R1

NH

R2R1

NO2

O

O

O+

DeprotectionN O

O

R2

R1

NHR2

R1

HOBr, Pd

NEt3

CH2Cl2protection

3 4

4

Scheme 4. MPoc as amine protecting group

Tsunoda et al.3 successfully introduced and demonstrated that the 2-(1,3-dioxan-2-

yl)ethylsulfonyl- (Dios) group could be used for amine protection and activation. To


24

protect the amine with 2-(1,3-dioxan-2-yl)ethylsulfonyl group, 2-(1,3-dioxan-2-

yl)ethylsulfonyl (Dios) chloride (5) was used, which may be synthesized from 2-(2-

chloroethyl)-1,3-dioxane. Initially, 2-(2-chloroethyl)-1,3-dioxane was converted to the

corresponding sodium 2-(1,3-dioxan-2-yl)ethylsulfonate (Na2SO3, DME-H2O, reflux, 72

h) and then the sulfonate was treated with 2 equiv of PPh3 and 2.2 equiv of sulfuryl

chloride (CH2Cl2, 0 °C, 2 h). The deprotection was achieved with the trifluoroacetic acid

in water (Scheme 5).

N

O2SR2

R1

NH

R2R1 +

Protection

Deprotection

CF3COOH/H2ONH

R2

R1

O

O

SO2ClO

O

N

O2SR2

R1 O

O

NEt3

CH2Cl25

6

6

Scheme 5. Dios as amine protecting group

Chandrasekaran4 and Ramesh developed a new amine protecting group called but-

2-ynylbisoxycarbonyl- (Bbc) as a C2-symmetric reagent. The amine group was protected

by treatment with but-2-ynylbisoxycarbonyl chloride (7) in presence of sodium

bicarbonate in DCM. The deprotection was effected with the (PhCH2NEt3)2MoS4 in

acetonitrile solution (Scheme 6).

NH2

+

Protection

Deprotection

H3COOC

OO

Cl O

ClO

OOO

HN

O

NHCOOEtEtOOC

OOO

HN

O

NHCOOEtEtOOC

(PhCH2NEt3)2MoS4

NH2H3COOC

2NaHCO3

CH2Cl2

CH3CN

7 8

8

Scheme 6. Bbc as amine protecting group


25

Romieu et al.5 introduced aryldithioethyloxycarbonyl (Ardec) group for amine

protection. For protection, the 4-(phenyldisulfanyl)ethyl 4-nitrophenyl carbonate (9) was

treated with the corresponding amine in the presence of 5% sodium carbonate in

acetonitrile at 0oC to room temperature. For deprotection of the Ardec group the protected

amine was reduced with thiophenol (Scheme 7).

N O

O

H

RNH

HR

NO2

O

O

O+

5% Na2CO3

Protection

DeprotectionNH

R1

H

SS

Ar SS

Ar

N O

O

R1

H

SS

Ar

SH

CH3CN, 0 oC

9 10

10

Scheme 7. Ardec as amine protecting group

Winssinger and Pothukauri6developed a new protecting group, based on the azide

called azidomethyl carbamate (Azoc). The protection of the amine by Azoc needs,

formation of chloromethyl carbamate using the commercially available chloromethyl

chloroformate 11 followed by the azide displacement. The deprotection of Azoc group

was done with the trimethyl or tributyl phosphine (Scheme 8).

+Protection

Deprotection

Me3P or Bu3P

NH2Cl O

O

Cl NaN3

NH

O

O

N3

NH

O

O

N3NH2

11 12

12

Scheme 8. Azoc as amine protecting group

Enamine based protecting groups

Enamine based protecting groups are unique type of amine protecting groups.

Their preparation, deprotection and applications in organic synthesize are known over a

period of long time. However they are not very popular amine protecting groups as

carbamate based protecting groups. This could be due to some of the limitations in their


26

application in organic synthesize. A detailed literature survey on enamine based protecting

groups was made and salient features are given below.

Cross et al.7 used 5,5-dimethyl-3-oxo-1-cyclohexenyl- (Doc) as a amine protecting

group. It may be obtained from dimedone 13. This is one of the enamine based protecting

group for amine and amino acid. It is cleaved from the protected amines (14) by treatment

with either aqueous bromine or nitrous acid in excellent yield (Scheme 9).

NHR

O

Br2 or HNO2R-NH2

R-NH2

OH

O

O

O

+Protection

NHR

O

Deprotection

13 14

14

Scheme 9. Doc as amine protecting group

Southwick et al.8 developed the 1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl- (Nopy)

(15) as an amine protecting group. For the protection of the amine was stirred with NOPY-

OEt in acetonitrile solution. The deprotection was achieved in ammonia in methanol

solution (Scheme 10).

R-NH2N

OEt

O

O2N

i-Pr

PH 8-9+

N

HN

O

O2N

i-Pr

R

N

HN

O

O2N

i-Pr

R

R-NH2

Protection

Deprotection

NH3

MeOH

1516

16

Scheme 10. Nopy as amine protecting group

Bycroft et al.9 introduced a novel amine protecting group called 1-(4,4-dimethy1-

2,6-dioxocyclohexylidene)ethyl- (Dde) which was obtained from 2-(1-


27

hydroxyethylidene)-5,5-dimethylcyclohexane-1,3-dione (17) which in turn was prepared

by acylation of demedone with acetic anhydride in pyridine medium. Protection of the

amine by the Dde group was done by reacting the amine with the 2-(1-

hydroxyethylidene)-5,5-dimethylcyclohexane-1,3-dione in ethanolic solution. The

deprotecction of Dde needed addition of 2 % hydrazine (v/v) in DMF solution (Scheme

11).

Protection

CH3

O

OOH

R-NH2 +

O

ON

H

O

ON

H

R-NH2

CH3

CH3+

O

NH

N

CH3

Deprotection

EtOHreflux, 60 h

NH2NH2

17 18

1819

R

R

Scheme 11. Dde as amine protecting group

Chan et al. developed some new variants of Dde group in which the methyl group

was replaced by higher alkanes. The starting material, 2-(1-hydroxyalkylidene)-5,5-

dimethylcyclohexane-1,3-dione (21) was prepared by acylation of dimedone with the

DCC/DMAP with corresponding acid. The deprotection condition was little modified thus

1 % trifluoroacetic acid was used instead of hydrazine (Scheme 12).10

2120

Scheme 12. Dde variants as more versatile amine protecting groups

Latter, the hydrazine was replaced by the hydroxylamine hydrochloride in

imidazole. By changing the deprotection conditions, orthogonal deprotection was achieved


28

against some famous amine protection group like Fmoc etc. Various conditions and

reagents used for the deprotection for the Dde group are shown in the Scheme 13.

O

ON

H

CH3

R-NH2

NH2NH2

NH2OH.HCl

TFA

18

R

Scheme 13. Development of new deprotection conditions for Dde

Limitations of Dde as a protecting group

The stability of N-Dde towards 20% piperidine v/v -DMF is acceptable for most

applications, a small loss of Dde does occur during each deprotection cycle in the large

peptides synthesize, which can seriously compromise the purity of large peptides. Dde

undergoes intramolecular N to N' migration from a side chain or α-amino group to the ε-

amino function of lysine, resulting in the scrambling of the group within the peptide chain.

Recently, the N-Dde protecting group under certain conditions has been undergo both intra

and intermolecular N to N' migration, resulting in a number of resin-bound sequences.

During the removal of Dde protecting group (2% hydrazine solution in DMF) on Aloe and

Dde protected peptides, the formation of a side product of two mass units greater than the

expected free peptide was observed presumably arising from partial reduction of the Aloe

double bond. Dde protection group itself lacks emission, which hampers in situ monitoring

of the amine protection / deprotection progress by fluorescence spectroscopy.

Bycroft et. al.11 has successfully exploited 2-acetyl-4-nitroindane-1,3-dione (2-

Nde) or 2-acetyl-5-nitroindane-1,3-dione (4-Nde) as a primary amine protecting group

displaying some advanced versatility (Scheme 13). This Nde protecting group is regarded

as another variant of the Dde protecting group. The preparation of the Nde-OH is very

similar to the Dde. Here, 4-nitro-indan-1,3-dione (22) was acylated with the acetic

anhydride. After preparation of 2-acetyl-4-nitroindane-1,3dione (23), it was introduced in

to amine by refluxing with ethanol. The deprotection of Nde is also similar to the Dde, it

was deprotected by adding the hydrazine solution (Scheme 14).


29

O

O

Ac2O/DMAP

O

OCH3

OH

O

OCH3

OH

+EtOH, Heat

Protection

NH2-CH(R)-COOH

O

OCH3

NH R

COOHH

NO2 NO2

NO2 NO2

O

OCH3

NH R

COOHH

NO2

NH2-CH(R)-COOH

ONO2

NH

N

H3C

+Deprotection

NH2NH2

25

23

24

22

23

24

Scheme 14. Nde as amine protecting group

Lima et al.12 showed the use of 1,3-dimethyl-5-acetyl-barbituric acid (26) (Dab) as

an amine protecting group. For the protection of amines with the Dab, the amine was

refluxed with the 1,3-dimethyl-5-acetyl-barbituric acid (26) in THF solution. For the

deprotection, hydrazine in ethanol solution was used. To achieve improved versatility

ammonia or some primary amines was used (Scheme 15).

N N

O

OO

H3C OH

CH3H3C

R-NH2+N N

O

OO

H3C NH

CH3H3C

R

N N

O

OO

H3C NH

CH3H3C

R

R NH2

Deprotection

Protection

THF

NH2NH2

EtOH, rt

2726

27

Scheme 15. Dab as amine protecting group

Yang and Kuo13 developed coumarin-based triketone as a fluorescent protecting

group for primary amines. According to them, when primary amines or amino acids


30

reacted with 3-acetyl-4-methoxy-7-N,N-dimethylaminocoumarin (30), the resulting

compounds emit blue fluorescence with a quantum yield of 0.25-0.50 in methylenedi

chloride. These protected compounds display satisfactory acid/base stability and this

protecting group can be removed with 5% hydrazine hydrate in DMF within 5 min at

ambient temperature. Similar properties also found in the hydroxyl derivatives (29) which

can also reacted with amino acids and form the diketo compound (31) (Scheme 16).

O O

N O

N

H

O O

OMe O

N

CH3COCl, Et3N

CH2Cl20 oC

KCN, 18 Crown-6, rtO O

OH

N O O

OH O

N CH2N2

EtOAc, 0 oC

R1

R2OOC

MeOH, Et3Nrt

MeOH, Et3Nrt

O O

O N

N

H

R1

COOR2

5% NH2NH2.H2O/DMFrt

NH2

R1

R2OOC

Protection

Deprotection

H2N

R1

COOR2H2N

R1

COOR2

32

28 29 30

31

Scheme 16. Coumarin based triketone as amine protecting group

Tien et. al.14 demonstrated that, the protection of 2,7-dichloro-fluoren-9-

ylidenemethylene can be used as a protecting group for amino acids. For protection, (2,7-

dichloro-fluoren-9-ylidene)-methanol (33) was heated with the amino acid in presence of

sodium hydroxide in methanol. For the deprotection of 2,7-dichloro-9-

fluorenylmethyleneamine group 34, the N-protected compound was hydrogenated with the

Pd/C in ammonium acetate or TFA (Scheme 17).


31

OH

ClClHOOC NH2

R

Protection

+

NH

ClCl

R COOH

NH

ClCl

R COOH

HCOONH4, Pd/Cor TFA

NH2

R COOHDeprotection

NaOH

MeOH, Heat

3433

34

Scheme 17. 2,7-dichloro-fluoren-9-ylidenemethylene as amine protecting group

Gorbunova et al.15a has introduced 4,4,4-trifluoro-3-oxo-1-butenyl- (Tfav) group

for the protection of amine in amino acids. It is formed by reaction of an amine with the

starting material 4-ethoxy-1,1,1-trifiuoro-3-buten-2-one (35) in aqueous sodium

hydroxide. Primary amino acids form the Z-enamines whereas secondary amines such as

proline form the E-enamines. Deprotection is achieved with 1-6 N aqueous HCl in dioxane

at room temperature (Scheme 18).

OF

FFC2H5OR-NH2 +

OF

FFNH

R

1-6 N HClO

F

FFNH

R R-NH2

Protection

Deprotection

3635

36

Scheme 18. Tfav as amine protecting group

2,2- Bis(ethoxycarbonyl)vinyl- (BECV) as an amine protecting group

Apart from the use of 2,2-bis(ethoxycarbonyl)vinyl (37, BECV) group as a novel

building block, It was also used as an amine protecting group. BECV is an important

enamine type amine protecting group. Alaiz et al.15b protected the amino group of the

amino acid with by treatment with BECV in the presence of base at room temperature.

After making the vinylamine derivatives 38, the acid group was converted to its 4-

(phenylazo)phenacyl esters 39 by treatment with corresponding alkyl bromide in


32

triethylamine. The deprotection was done with the bromine in chloroform solutions

(Scheme19).

NH

O

O

OEt OEt

OO

CHCl3, rt75%

O

NN

NH3Br

O

O

O

NN

+ -

O

NN

Br

acetone, NEt3, rt, 30 min, 70%

NH

O

OH

OEt OEt

OO

1. KOH, rt, 5 min2. 1N HCl. rt, 80%

EtO

EtO

O O

OEt+

NH2

OH

O

Protection

Deprotection

Br2

40

3738

39

Scheme 19. BECV as amine protecting group

Mellet et al.16a,b used the BECV group as a protecting group for preparation per-

acetyl aminoaldose derivatives (Scheme 20). The amine group 41 was protected as HN-

BECV group by treatment refluxing with the corresponding amine. After the entire

conversion of the amine into N-protected amine 42 the hydroxyl functional group was

converted in to its acetate, then, the N-protected amine was obtained by treatment with wet

the chlorine in chloroform.


33

CHCl3, Cl20-5 oC, > 3 h O

AcO

AcOOMe

AcO

NH2.HCl

OHO

HOOMe

OH

HN

EtO OEt

O O

OHO

HOOMe

OH

NH2

C2H5O

EtO OEt

O O

12 h, reflux+

(Ac)2O

OAcO

AcOOMe

OAc

HN

EtO OEt

O O

Pyridine

Protection

Deprotection

43

3741

42

42

Scheme 20. Modified deprotection condition for BECV group

Limitations of BECV as amine protecting group

The existing protection and deprotection conditions for using BECV group has

some disadvantages such as longer reaction time and high temperature. Usage of strong

inorganic base and strong mineral acids creates possibility for recemisation, during the

deprotection stage, harmful reagents such as CHCl3 saturated with Cl2 or Br2 was used.

Due to these reagents sensitive and oxidizible groups gave unidentified products.

O-to N- migration of acyl group was observed and amines are obtained as hydrochloride

or bromide salts. The reaction was carried out at 0 oC at first and later at 50 oC for several

hours. This method can’t be used for substrate with aromatic ring and unsaturated bonds.

There was no systematic study on aromatic and aliphatic amines, peptide synthesize and

also no study was made on orthogonality of this protecting group with existing familiar

amine protecting groups.

Chapter II Present Work

34

PRESENT WORK

The carbamate derivatives occupy a prominent position in the ranks of commonly

used amine protecting groups (PGs). The advantage of carbamate PGs, such as Boc, Cbz,

Fmoc and its recent variants Alloc, Troc and Azoc6 over other amine PGs is that the

cleavage condition can be varied considerably, depending on the choice of alkyl

component used. These PGs are useful for the synthesize of peptides, aminoglycosides and

functionalized aromatic amines. However, some of the reagents used for the carbamate

protection such as Fmoc-Cl are expensive and moisture-sensitive.17 Moreover, these

reagents are CO2- and COCl2-based chemicals18 are difficult to prepare as special

precaution is needed for preparation even on the industrial scale. Despite these drawbacks,

the use of carbamate PGs is being continued, due to a lack of alternative PGs that meet the

required standards.17 Hence, there is a clear need to develop alternative amine protecting

groups.

The primary amine protecting group, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)

ethyl (Dde)9 introduced as an alternate to the carbamates has become a valuable tool for

the construction of cyclic side-chain modified peptides and peptide nucleic acid-peptide

conjugates.10 The Dde group is fully orthogonal to the Fmoc protecting group.19 Later,

some of its variants were introduced to overcome its drawbacks such as intramolecular N-

N'-migration10,19 stability towards Fmoc deprotection condition20 and lack of fluorescence

emission.21 The types of reactions carried out using the Dde protected amines are only

limited. These include amide or carbamate bond formation as in peptides and

polyamines,22 reactions involving the use of mild reagents such as tertiary amine,

secondary amine, inorganic base (Cs2CO3)20 and 1% TFA. The reason for this limited

study may be due to the presence of sterically hindered but acidic protons in the 1,3-

cyclohexanedione ring system of Dde group which may lead to side reactions if strong

bases such as NaH, LDA and NaOH are used. Another reason as observed by Bycroft11 is

that the development of Dde was to a large extent influenced by the availability of

dimedone and its conversion to 2-acetyl-5,5-dimethyl-cyclohexane-1,3-dione by acylation

reaction. We found that the 2,2-bis(ethoxycarbonyl)vinyl- (BECV) group, an ester type

variant of Dde, met some of the essential requirements of an amine PG. We herein present

our results (Scheme 21).


35

R-NH2

EtOH / rtEtOH / rtH2NNH2

R = Aromatic or Aliphatic sub units

EtO COOEt

COOEt

OH

NR

EtO

O OEt

Scheme 21. Schematic representation of protection and deprotection of BECV

In the course of our attempt to synthesize novel heterocycles we observed a facile

derpotection of BECV group on 44 in the presence of ethylenediamine in ethanol to give

product 44a in quantitative yield (99%) at room temperature (Scheme 22).

NH

OEtO

OEt

O

NH2

H3CO H3CO

44

44a

H2NNH2

EtOH, rt, 20 min. 99%

Scheme 22. Deprotection of BECV by ethylenediamine

The use of readily available organic reagent ethylenediamine, simple reaction

condition and the high yield of the deprotected product provided the scope for further

development of the techniques used. A complete literature review revealed that the BECV

group was used as an amine PG in the synthesize of amino acid esters15a and

aminoglycosides.16 However, no further reports were made mainly because, the amine

protection needs the use of strong base KOH and the deprotection involves the use of

harmful reagents, such as 4% solutions of Br2 or Cl2 in CHCl3 (wet). The reaction time is

usually long (12 h at 40 °C). Side reactions were observed for compounds containing

unsaturation, acid sensitive functional groups, easily oxidizable groups, which led to the

formation of carbon-to-nitrogen migration and complex mixture of unidentified products.

Further, there was no study on the use of BECV group for selective functional group

transformations on different class of organic compounds.


36

Table 1. Standardization of the reaction conditions for deprotection

NH

OEtO

OEt

OConditions

NH2

H3COH3CO

44 44a

S.No. Solvent Reagent Amount of reagent

Time Yield in %

1 THF H2N-CH2-CH2-NH2 4.0 mol 1.0 h 89

2 Toluene H2N-CH2-CH2-NH2 4.0 mol 3 h 91

3 Diethyl ether H2N-CH2-CH2-NH2 4.0 mol 2.5 h 95

4 Chloroform H2N-CH2-CH2-NH2 4.0 mol 1.5 h 92

5 Water H2N-CH2-CH2-NH2 4.0 mol 24 h 15

6 DMF H2N-CH2-CH2-NH2 4.0 mol 2.5 h 90

7 Acetonitrile H2N-CH2-CH2-NH2 4.0 mol 20 min. 95

8 Ethanol H2N-CH2-CH2-NH2 4.0 mol 20 min. 99

9 Ethanol 1,2-diaminobenzene 4.0 mol > 2 h No reaction

10 Ethanol H2N-NH2 4.0 mol 5 min. 98

11 Ethanol NH3 4.0 mol >24 h 35

12 Ethanol H2N-CH2-CH2-NH2 0.1 mol > 30 h 10

13 Ethanol H2N-CH2-CH2-NH2 0.5 mol 30 h 30

14 Ethanol H2N-CH2-CH2-NH2 1.0 mol >24 h 68

15 Ethanol H2N-CH2-CH2-NH2 2.0 mol 20 h 81

This encouraged us to undertake a complete study on the use of BECV as a protecting

group. In order to standardize the reaction condition, we examined different solvents,

reaction temperature and the use of other amines as deprotecting agents (Table 1).

With the use of less than 4 equiv. of ethylenediamine in ethanol, the deprotection

reaction is very slow (>24 h).23 By comparing the reaction times of various solvents

CHCl3 (1.5 h), CH3CN (20 min.), H2O (>24 h) studied, EtOH (20 min.) was found to be

suitable in terms of quick reaction time and eco-friendliness. With NH3, the reaction was

very slow (>24 h),24 with NH2-NH2 it was very fast (5 min.),25 and with 1,2-

diaminobenzene no reaction was observed (>2 h). However, the use of NH2-NH2, may

create conditions that are too harsh for selective functional group transformations. We


37

therefore decided to use the more moderate reagent, 4 equiv. ethylenediamine in ethanol,

for the remainder of the study.

According to the literature, the BECV group may typically be introduced to amines

by heating a neat mixture of an amine and Diethyl EthoxyMethyleneMalonate (DEMM)

between 100-120 °C,26 or in some cases heating to reflux in ethanol.27,28 However, we

observed that, the coupling reaction of the BECV group with a variety of aromatic,

aliphatic amines takes place with one equiv. of DEMM just by stirring it in ethanol at

room temperature. In the case of amino acids, the use of NEt3 (1 equiv.) was sufficient to

introduce the BECV group to amine at room temperature. The starting material, DEMM,

can be easily synthesized in the laboratory following a simple procedure reported in

literature.29

In order to investigate the electronic influence of the aromatic ring substituents on

protection and deprotection, we used anilines 44a-50a (Table 2). The BECV group was

introduced in presence of ethanol at room temperature to afford an excellent yield of

products 44-50. The higher the electron-withdrawing strength of the substituent in the

aromatic ring, slower the rate of coupling. In general, compounds that undergo the

coupling reaction slowly are also characterized by slow deprotection. Both protection and

deprotection occurred under these conditions in excellent yield. The presence of highly

UV active chromophore in BECV group is an added advantage for monitoring the reaction

by TLC.

The compound 45 crystallised as a single crystal in EtOAc shows an intra

molecular hydrogen bond existing between N-H and the ester carbonyl group. Thus there

exists a close proximity between ester carbonyl and NH group (Figure 2).


38

Figure 2. ORTEP diagram for compound 45

Multifunctional anilines are useful starting materials for the synthesize of

important heterocycles.30 In many instances, functional groups, such as –OH, -SH, –

COOH and also -NH2 must be selectively manipulated over an amine group. We

investigated the compatibility of the BECV group with several potentially competing

functional groups (Table 3). In our study, the starting materials 51a-57a were prepared in

very good yield. Apart from 51a, in which two BECV groups were introduced, the yield is

excellent and the reaction time was short. This shows clearly that by keeping the

competing functional groups –NH2, –OH, –SH, and –COOH unprotected, anilines can be

protected selectively.

The selectively protected anilines were then subjected to functional group

transformations. Acylation and alkylation carried out separately on substrate 51a, yielded

51c, 51e and 51g. On selective deprotection of the BECV group, high yields of 51d, 51f

and 51h were obtained very quickly, after 1.30 h, 15 min. and 15 min. respectively.

Substrate 52a with a sterically encumbered ortho-amino substituent also behaved in a

similar way, demonstrating that one amino group may be selectively functionalized over

another in very high yield. The hydroxyl group in 53a was alkylated, using allyl bromide

and benzyl bromide and esterified using benzoyl chloride and acetyl chloride, each in turn,

thus obtaining compounds 53b, 53d, 53f and 53g respectively. The BECV group was

deprotected under standard conditions to obtain high yields of the corresponding anilines

53c, 53e, and 53h after a short reaction time. This shows that the –OH group can be

selectively functionalized in a substituted aniline.


39

Table 2. Electronic effect of aromatic substituents on Protection / Deprotection

H3CO

NH

OEt

O

OEtO

NH

OEt

O

OEtO

NH

OEt

O

OEtO

Cl

NH

OEt

O

OEtO

O2N

NH

OEt

O

OEtO

H3CO

NH2

NH2

NH2

Cl

NH2

O2N

NH2

N

NH2

H3CO

NH2

NH2

NH2

Cl

NH2

O2N

NH2

N

NH2

Starting MaterialR = Aninlines

Products Products

Protection

Time Yield

20 min

5 h

98%

99%

95%

98%

95%

15 min 99%

6 h

6 h

6 h

Deporotection

Time Yield

30 min

2.15 h

2.30 h

5 h

95%

95%

90%

95%

1.30 h 95%

20 min 99%

S.No.

1

2

3

4

5

6

44a

45a

46a

47a

48a

49a

44

45

46

47

48

49

R-NH2

rt

+

H2NNH2

R-NH2

44-5037

44a-50a OC2H5

OC2H5

O

C2H5O

O

NH

OC2H5

O

C2H5O

O

REtOH

rtEtOH

B

O

O

NH2

O

O

NH2

O

O

NH2

7

50a 50

7 h 6 h92%

N

NH

OEt

O

OEtO

90%

However, in the case of compound 53f, the ethylenediamine deprotected the Ac- group

instead of the BECV group. The same result was observed even with the milder reagent

such as aq.NH3. Similar is the case with 2-aminophenol (54).


40

Following the same strategy, 2-aminothiophenol (55) can be selectively alkylated

on thiol using ethyl bromide to obtain a very good yield of 2-aminothiphenol ethyl ether

(55c). Similarly, the 4-aminobenzoic acid derivative 56a was selectively esterified with

allyl bromide and methyl iodide to obtain excellent yields of 56b and 56d. On

deprotection, compounds 56c and 56e were obtained, in which the allyl and alkyl ester

remained unaffected. A similar observation was also made using 2-aminobenzoic acid

(57). This serves as a method for the selective functionalization of the –SH and –COOH

groups in the presence of –NH2 under very mild conditions.

A number of heterocyclization can be envisaged from many of the bifunctional

molecules discussed. However, these heterocylcization reactions require very high

temperature. For example in the synthesize of, 7-Chloro-6-fluoro-1H-quinolin-4-one, a

crucial intermediate for the drug norfloxacin31 and bipyridine,32 the heterocyclisation was

carried out at <200 °C. We did not observe any of such cyclized products under our

experimental conditions. All the substrates show very good stability at room temperature

and in light.


41

Table 3. Selective Protection / Functional Group Transformation (FGT) / Deprotection of Multifunctional Aromatic Compounds

Entry

1

2

3

15 min (99%)

1.30 h (80%)

Time(Yield)viii

AcHN NHR

HN NHR

NHR

NH2

NHR

HN

15 min (99%)

Product

51c

51e

53b

H2N NH2

51

NH2

NH2

53

Starting Material Product

51a

15 mim (99%)N NHR51g

53a

Time (Yield) Time(Yield)Product

Selective ProductionSelective Functional Group Transformation Selective Deprotection

51b

5 min (17%)

10 min (98%)

(77%) 1.30 h (80%)i

24 h (78%)ii

24 h (20%)ii

24 h (77%)ii

AcHN NH2

HN NH2

NH2

HN

51d

51f

53c

N NH2

51h

FGNH2

OEt

COOEt

COOEt Selective Functional Group Transformation

+

SelectiveProtection

H2NNH2

SFGTNH2H

NCOOEt

COOEt

FG

HN

COOEt

COOEt

SFGTi-vii/rt37

NHRRHN

NHRH2N

NHR4

5

1.30 h (90%)

1.30 h (95%)

HO

NHRBnO

NHRO

52b

53d

NH2HO

52 52a

15 min (99%) 3 h (85%)iii

12 h (92%)iv NH2BnO

NH2O

52c

53e

EtOHrt

EtOHrt

B


42

15 min (99%)

1 h (75%)NHRBzO

NHR

OH

NHR

O

NHR

SH

NHR

S

9 2 h (98%)

53g

57b

54b

NH2

OH

NH2

SH

57

54

7

8

57a

54a

15 min (99%)

20 min (98%)

1 h (99%)v

12 h (99%)ii

24 h (85%)ii

NH2BzO

NH2

O

NH2

S

53h

57c

54c

10 NHRHOOC NHRCO

O

NHRH3COOC

NHR

COOH

NHR

COOCH3

2 h (90%)

2.15 h (95%)

2.30 h (96%)

11

55b

56bNH2HOOC

NH2

COOH

55

56

55a

56d

56a

12

4.30 h (99%)

5.0 h (98%)

36 h (85%)vi

2 h (98%)vii

2 h (98%)vii

NH2CO

O

NH2H3COOC

NH2

COOCH3

55c

56e

56c

Where R = -CH=C(COOCH2CH3)2 = BECV; FGT = Functional Group Transformations; Reaction Conditions for Functional GroupTransformations i) N(C2H5)3, CHCl3, CH3COCl ii) K2CO3 , Acetone, C2H5Br iii) KOH, Acetone, Allyl bromide iv) K2CO3, CHCl3, Benzyl bromide v) N(C2H5)3, CHCl3, Benzoyl chloride vi) K2CO3, Acetone, Allyl bromide vii) K2CO3, Acetone, Methyl iodide viii) Ethanol,Ethylenediamine, rt.

6 5 min (95%)NHRAcO

53f

30 min (99%)i NHRHO

53a


43

The compound 56d was prepared by alkylation of the corresponding acid 56a. The

single crystal structure obtained for the compound 56d further confirms that during

alkylation reaction NH group is not affected (Figure 3).

Figure 3. ORTEP diagram for compound 56a

We then checked the versatility of this PG strategy on aliphatic amines.

Benzylamine reacted instantly and quantitatively to yield the compound 2-(benzylamino-

methylene)-malonic acid diethyl ester (Scheme 23). The deprotection was completed after

45 min. yielding benzylamine (98%). In order to study selective functional group

transformation on aliphatic amines (Scheme 24), we used 2-aminobutanol (58). Following

treatment with DEMM the selective protection of –NH2 group in the presence of free –OH

produced very high yields of 58a. On treatment with benzoyl chloride/NEt3 (Scheme 25),

acetyl chloride/NEt3 (Scheme 26), and ethyl bromide/NaH (Scheme 27) in separate

experiments, compound 58a yielded the corresponding esters 59 and 60 and ether 61.

These compounds on selective deprotection at room temperature gave the –OH

functionalized amines 59a and 61a in excellent yield. In a similar manner to phenyl

acetate 53f, its aliphatic equivalent 60 also underwent acetyl deprotection to yield the

starting material 58a. The hydroxyl group of aliphatic amino alcohols can thus be

selectively functionalized. This result when compared with deprotection aromatic ester

57b, shows that while esters of aromatic acids can survive, but, esters of aliphatic acid are

not stable under the present deprotection condition. All the compounds remained optically

active.


44

NH

OEtO

O

OEt

EtOH, rt

H2N NH2

45 min. 98%

NH2

Scheme 23. Deprotection of BECV from benzylamine

BECV-OEt

rt, 30 min 98%H NH2

OH

58

58a

H NHH3C OH

O OEt

O

OEt

Scheme 24. Selective protection of aliphatic amine in presence of alcohol

A key test of any amine protecting group is its applicability to amino acid-related

functional group transformation.4 With this in mind, we investigated the compatibility of

the BECV group with amino acid esterification.

H NHH3C OH

58a

O OEt

O

OEt

O

Cl+

H NHH3C O

59

O OEt

O

OEt

O

1h, 99%

EtOH, rt

H2N NH2

1h 94%

H NH2

H3C O

59a

O

Et3N

CHCl3, rt

H NHH3C O

59

O OEt

O

OEt

O

Scheme 25. Selective O-benzoylation followed by deprotection

H NHH3C OH

58a

O OEt

O

OEt

H3C

O

Cl+

H NHH3C O

60

O OEt

O

OEt

O

CH3

H2N NH258a

Et3N

EtOH, rt1 h, 70%

CHCl3, rt1 h, 99%

Scheme 26. O-acylation of aliphatic alcohols in presence of BECV


45

H NHH3C OH

58a

O OEt

O

OEt

H3C Br+H NH

H3C O

61

O OEt

O

OEt

CH3H2N NH2

H NH2

H3C O CH3

61a

NaH

DMF, rt24 h, 70 %

EtOH, rt1 h, 90 %

Scheme 27. Selective O-alkylation followed by deprotection

Protection of the amine group in amino acids (62-64) could be carried out at room

temperature in the presence of NEt3 as a base to achieve good yields of 62a-64a (Schemes

28-30). Further treatment with SOCl2/CH3OH provided excellent yields of the

corresponding methyl esters 62b-64b. The BECV group was tolerant to the reagent

SOCl2/CH3OH. The deperotection as usual gave amino acid esters 62c-64c in excellent

yield. Optical rotation values were recorded for all the compounds and compared with the

reported values,15a which confirmed that the deprotection condition does not affect the

chiral centre.

COOH

NH2+

OEt

OEt

O

EtO

O

EtOH, rt, 30 min, 96%

COOH

HN

O

OEt OEt

O

or SOCl2/MeOHrt, 30 min. 95%

COOCH3

HN

O

OEt OEt

O

NH2H2N

EtOH, rt, 2.5 h, 95%

COOCH3

NH2

6262a

62b 62c

CH3I , K2CO3 , Acetone

rt, 24 h, 70%

Et3N

37

Scheme 28. Preperation of phenylalanine methyl ester

CH3

H3C COOH

NH2

+

OEt

OEt

O

EtO

OCH3

H3C COOH

HN

O

OEt OEt

O

CH3

H3C COOCH3

HN

O

OEt OEt

O

NH2H2N

EtOH, rt, 2.15 h, 90%

CH3

H3C COOCH3

NH2

63

63a

63b 63cor SOCl2/MeOHrt, 30 min. 95%


rt, 24 h, 72%

Et3N

EtOH rt, 30 min, 95%

37

Scheme 29. Preperation of leucine methyl ester


46

S COOH

NH2

+

OEt

OEt

O

EtO

O

EtOH, rt, 30 min, 90%

S COOH

HN

O

OEt OEt

O

S COOCH3

HN

O

OEt OEt

O

NH2H2N S COOCH3

NH2

H3C

H3C

H3C

H3C

EtOH, rt, 2.15 h, 90%

6464a

64b64cor SOCl2/MeOH

rt, 30 min. 95%


rt, 24 h, 68%

Et3N

37

Scheme 30. Preparation of methionine methyl ester

The main purpose of the amine PG is to suppress its nucleophilic character,

primarily by delocalization of the lone pair of electrons.18 It is important to note that after

the introduction of the BECV group, the aniline or aliphatic amine still possess a –NH

proton but did not undergo alkylation or acylation even with highly active reagents such as

ethyl bromide/NaH, benzyl bromide/K2CO3 and acetylchloride/NEt3. Thus, we strongly

believe that the BECV group is effective in masking the nucleophilic behaviour of

nitrogen lone pair. In the 1H-NMR spectra of the NH-BECV protected aniline, the peaks

corresponding to BECV group were observed at approximate δ values ≅ 1.33, 4.33, 8.45,

11.00 ppm. These characteristic peaks do not interfere with the spectral interpretation.

We also studied the orthogonal stability of the BECV group using the common

amine protecting groups Boc, Cbz, and Fmoc, as shown in Schemes 31-34.

A mixture of NH-BECV protected phenylalanine (62b) and compound 65 or

compound 66 or compound 67 were treated with ethylenediamine (4 equiv.) in ethanol

separately. While Boc- and Cbz- were stable, Fmoc- was labile. However, when 62b was

treated with 4 equiv. of piperazine in ethanol as the reagent the deprotection of Fmoc took

place exclusively without affecting the BECV group. This clearly establishes that the

BECV group shows orthogonal stability against Fmoc, Cbz and Boc protecting groups.

COOCH3

NHBoc+

NH2NH2

EtOH, rt2.30 h

65 (98%)

COOCH3

HN

O

OEt OEt

O

62b

65

COOCH3

NHBoc

COOCH3

NH2

62c

+

Scheme 31. Orthogonal deprotection of BECV in presence of BOC


47

COOCH3

NHCbz+

NH2NH2

EtOH, rt2.30 h

66 (98%)

COOCH3

HN

O

OEt OEt

O

62b

66

COOCH3

NHCbz

COOCH3

NH2

62c (95 %)

+

Scheme 32. Orthogonal deprotection of BECV in presence of Cbz

COOCH3

NHFmoc+

NH2NH2

EtOH, rt2.30 h

67 (15%)

COOCH3

HN

O

OEt OEt

O

62b

67

COOCH3

NHFmoc

COOCH3

NH2

+

62c

Scheme 33. Deprotection of BECV and Fmoc in ethylenediamine

5% piperazine

EtOH, rt30 min

COOCH3

NHFmoc+

COOCH3

HN

O

OEt OEt

O

62b

67

COOCH3

NH2

+

62c (98%)

COOCH3

HN

O

OEt OEt

O

62b

Scheme 34. Orthogonal deprotection of Fmoc in presence of BECV

In order to check the stability of BECV group towards basic and acidic

conditions10 compounds 62b-64b were treated with 10% TFA in CH2Cl2, 10% aq.HCl and

20% piperazine in DMF separately at room temperature. All the compounds displayed

excellent acid/base stability for more than 24 h. In addition as discussed above the BECV

was also stable towards bases such as NaH, KOH, K2CO3, NEt3. This implies that the NH-

BECV group is adaptable to reactions involving both strong acids as well as base.

Mechanism of Deprotection of the BECV Group

After the deprotection we could isolate mono-BECV (E) as well as di-BECV (F)

protected ethylenediamine in addition to free aniline (G). Based on this we propose the

following mechanism (Scheme 35) for deprotection reaction. We have also observed that,

when mono-BECV protected ethylenediamine (E) was left at room temperature for longer

time it gets converted into di-BECV protected ethylenediamine (F) and free

ethylenediamine (B).


48

H2N NH2

OEt

OEt

O

O

RN OEt

OEt

O

O

RHN

H2NHN

H

H

RNH2 NH

HN

O OEt

OEt

O

EtO

O

EtO O

NH

NH2EtO

O

EtO O

++

EG

B C D

F

Scheme 35. Mechanism for Deprotection of BECV Group

Conclusion

In conclusion, we have developed a simple method for the selective protection of

amino group as NH-BECV and deprotection of the BECV group, at room temperature, on

various substrates such as anilines, aliphatic amines and amino acids. This method is

useful for selective functional group transformations of the OH, NH2, SH and COOH

groups in the presence of the NH2 group. The BECV protecting group is stable towards

both strong acids as well as strong bases except primary amine. The reagents DEMM and

ethylenediamine, used for protection and deprotection respectively, are readily available

at much cheaper price compared with the reagents required for the preparation of

carbamate derivatives or Dde protecting group. This study establishes BECV as a versatile

amine protecting group that makes use of component materials that are readily available,

selectively protect and deprotect under mild conditions and is stable under delicate

functional group transformations of varied applications in organic synthesize. In view of

these advantages the BECV group could be used as an amine protecting group in line with

the well established Dde, Fmoc, Cbz, and Boc protecting groups.

Chapter II Experimental

49

EXPERIMENTAL

Method A: General experimental procedure for protection of amines with 2,2-bis-

(ethoxycarbonyl)cinyl (BECV) group

To asolution of aniline or amine (1 equiv.) in ethanol (5 times w/v), diethyl

ethoxymethylenemalonate (1 equiv.) was added and stirred at room temperature (~28 °C).

After completion of the reaction, during a specific time, ethanol was evaporated under

reduced pressure to get corresponding NH-BECV protected amine or aniline in 77-99%

yield.

Method B: General experimental procedure for deprotection of BECV group from

N- 2,2-Bis(ethoxycarbonyl)vinyl protected aniline or amine

To a solution of NH-BECV protected aniline or amine (1 equiv.) in ethanol (5 times w/v),

ethylenediamine (4 equiv.) was added and stirred at room temperature. After completion

of the reaction, water was added (10 times w/v) and extracted with ethyl acetate (three

portions). Combined organic layer was dried (Na2SO4), evaporated under reduced pressure

and passed through a filter column (Silica gel, Hexane:EtOAc) to get the corresponding

aniline or amine in 75-99% yield.

1) Protection and deprotection of aromatic amines

Preparation of 2-[(4-Methoxy-phenylamino)-methylene]-malonic acid diethyl ester

(44)

OH3C

NH

OOC2H5

OOC2H5

The reaction was carried out according to Method A using 4-methoxyaniline (44a, 500

mg, 4.0 mmol), diethyl ethoxymethylenemalonate (820 μL, 4.0 mmol) and ethanol (2.5

mL). Conditions: room temperature, 15 min. The title compound 44 was obtained as a

colorless solid (1.17 g, 99%). Spectral data of the compound 44 was in agreement with the

values reported in the literature.1

Preparation of 4-methoxyaniline (44a)


50

The reaction was carried out according to Method B using compound 44 (500 mg, 1.7

mmol), ethylenediamine (455 μL, 6.8 mmol) in ethanol (2.5 mL). Conditions: room

temperature, 20 min. The title compound 44a (0.20 g, 99%) was obtained as a colorless

solid after passing through a short silica gel column (Hexane:EtOAc = 9:1). The spectral

data of the compound 44a was in agreement with authentic sample available from

commercial sources.

Preparation of 2-Phenylaminomethylene-malonic acid diethyl ester (45)

NH OCH2CH3

O

OOCH2CH3

The reaction was carried out according to Method A using aniline (45a) (0.500 g, 5.3

mmol) and diethyl ethoxymethylenemalonate (1.08 mL, 5.3 mmol) and ethanol (2.5 mL).

Conditions: room temperature, 20 min. The title compound 45 (1.38 g, 98%) was obtained

as a colorless liquid. The spectral data was in agreement with the values reported in the

literature.33

Preparation of aniline (45a)

The reaction was carried out according to Method B using compound 45 (0.500 g, 1.8


temperature, 30 min. Title compound 45a (0.16 g, 95%) was obtained as a brown liquid

after passing through a short silica gel column (Hexane/EtOAc, 9:1). The spectral data of

the compound 45a was in agreement with authentic sample available from commercial

sources.

Preparation of 2-[(2-Chloro-phenylamino)-methylene]-malonic acid diethyl ester (46)

NH OCH2CH3

O

OOCH2CH3Cl

The reaction was carried out according to Method A using 2-chloroaniline (46a) (0.500 g,

3.9 mmol) diethyl ethoxymethylenemalonate (792 μL, 3.9 mmol) and ethanol (2.5 mL).

Conditions: room temperature, 5 h. The title compound 46 (1.15 g, 99%) was obtained as


51

a pale white solid. Spectral data and melting point of the compound 46 was in agreement

with the values reported in the literature.34

Preparation of 2-chloroaniline (46a)



temperature, 2.15 h. The title compound 46a (0.19 g, 90%) was obtained as a colorless

liquid after passing through a short silica gel column chromatography (Hexane/EtOAc =

9:1). The spectral data of the compound 46a was in agreement with authentic sample

available from commercial sources.

Preparation of 2-[(4-Nitro-phenylamino)-methylene]-malonic acid diethyl ester (47)

NH OCH2CH3

O

OOCH2CH3

O2N

The reaction was carried out according to Method A using 4-nitroaniline (47a, 0.500 g, 3.6

mmol), diethyl ethoxymethylenemalonate (731 μL, 3.6 mmol) and ethanol (2.5 mL).

Conditions: room temperature, 6 h. The title compound 47 (1.00 g, 95%) was obtained as

a pale yellow solid. The spectral data and melting point of the compound 47 was in

agreement with the values reported in the literature.27

Preparation of 4-nitroaniline (47a)



temperature, 2.30 h. The title compound 47a (0.21 g, 95%) was obtained as a yellow solid

after through a short silica gel column (Hexane:EtOAc = 9:1). The spectral data of the

compound 47a was in agreement with authentic sample available from commercial

sources.


52

Preparation of 2-(Naphthalen-1-ylaminomethylene)-malonic acid diethyl ester (48)

NH OCH2CH3

O

OOCH2CH3

The reaction was carried out according to Method A using 1-aminonaphthalene [48a,

0.500 g, 3.4 mmol), diethyl ethoxymethylenemalonate (705 μL, 3.4 mmol) and ethanol

(2.5 mL). Conditions: room temperature, 6 h. The title compound 48 (1.07 g, 98%) was

obtained as a solid. The spectral data and melting point of the compound 48 was in


Preparation of 1-aminonaphthylene (48a)


mmol), ethylenediamine (426 μL, 6.3 mmol) and ethanol (2.5 mL). Conditions: room

temperature, 5.0 h. The title compound 48a (0.21 g, 95%) was obtained as a solid after

passing through a short silica gel column (Hexane: EtOAc = 9:1). The spectral data of the


sources.

Preparation of 2-(Pyridin-2-ylaminomethylene)-malonic acid diethyl ester [49]

NNH OCH2CH3

O

OOCH2CH3

The reaction was carried out according to Method A using 2-aminopyridine (49a, 0.500 g,

5.3 mmol), diethyl ethoxymethylenemalonate (1.07 mL, 5.3 mmol) and ethanol (2.5 mL).

Conditions: room temperature, 6 h. The title compound 49 was obtained as a pale white

solid in (1.33 g, 95%).18

Preparation of 2-aminopyridine (49a)



temperature, 1.30 h. The title compound 49a (0.16 g, 95%) was obtained as a solid after

passing through a short silica gel column (Hexane:EtOAc = 9:1). The spectral data of the


sources.


53

Preparation of 2-[(9,10-Dioxo-9,10-dihydro-anthracen-1-ylamino)-methylene]-

malonic acid diethyl ester (50)

NH OCH2CH3

O

OOCH2CH3O O

The reaction was carried out according to Method A using 1-aminoanthraquinone (50a,

0.500 g, 2.2 mmol), diethyl ethoxymethylenemalonate (452 μL, 2.2 mmol) and ethanol

(2.5 mL). Conditions: room temperature, 7 h. The title compound 50 (0.81 g, 92 %) was

obtained as a red solid. 1H NMR (200 MHz): δ 1.33-1.48 (m, 6H), 4.30 (q, J = 7.0 Hz,

2H), 4.50 (q, J = 7.0 Hz, 2H), 7.76-8.45 (m, 7H), 8.60 (d, J = 12.0 Hz, 1H), 13.46 (d, J =

12.0 Hz, 1H); 13C NMR (75 MHz): δ 14.31, 14.4, 60.4, 60.5, 92.6, 114.8, 116.1, 120.6,

125.2, 127.3, 146.5, 151.0, 166.9, 168.6; IR (KBr): 1282, 1607, 1728, 2924, 3421 cm-1;

Anal. calcd. for C22H19NO6: C, 67.17; H, 4.87; N, 3.56; O, 24.40; Found: C, 67.19; H,

4.53; N, 3.22.

Preparation of 1-aminoanthraquinone (50a)



temperature, 6 h. The title compound 50a (0.25 g, 90%) was obtained as a dark red solid

after passing through a short silica gel column (Hexane/EtOAc = 9:1). The spectral data of

the compound 50a was in agreement with authentic sample available from commercial

sources.

2. Selective protection / Functional Group Interconversion / Derpotection of

multifunctional aromatic amines

Preparation of 2-[(4-Amino-phenylamino)-methylene]-malonic acid diethyl ester

(51a) and Preparation of 3-[4-(2,2-Bis-ethoxycarbonyl-vinylamino)-phenylamino]-2-

ethoxycarbonyl-acrylic acid ethyl ester (51b)

The reaction was carried out according to Method A using 1,4-diaminobenzene (51, 0.500

g, 4.6 mmol) diethyl ethoxymethylenemalonate (934 μL, 4.6 mmol) in ethanol (2.5 mL).

Conditions: room temperature, 5 min. Crude product was purified through column


54

chromatography (silica gel, Hexane: EtOAc = 8:2). First eluted was compound 51b (0.35

g, 17%).

NH OCH2CH3

O

OOCH2CH3

HNO

H3CH2CO

OH3CH2CO

51b: mp: 68 °C; 1H NMR (400 MHz, CDCl3): δ 1.31-1.40 (m, 12H), 4.22-4.34 (m, 8H),

7.15 (s, 4H), 8.46 (d, J = 13.6 Hz, 2H), 10.05 (d, J = 13.6 Hz, 2H); 13C NMR (100 MHz,

CDCl3): δ 14.2, 14.4, 60.1, 60.4, 93.8, 118.5, 136.2, 151.5, 165.5, 169.0; IR (KBr): 463,

531, 756, 800, 920, 1031, 1099, 1232, 1258, 1302, 1348, 1383, 1412, 1453, 1525, 1597,

1640, 1683, 2854, 2926, 2982, 3271, 3443 cm-1; Anal. calcd. for C22H28N2O8: C, 59.92; H,

6.29; N, 6.25; Found: C, 60.01; H, 6.23; N, 6.27.

NH OCH2CH3

O

OOCH2CH3

H2N

Second eluetd was compound 51a (0.99 g, 77% yield) was obtained as a yellow solid. mp:

88 °C; 1H NMR (400 MHz, CDCl3): δ 1.29-1.39 (m, 6H), 3.69 (brs, 2H), 4.20-4.32 (m,

4H), 6.68 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 8.41 (d, J = 14.0 Hz, 1H), 10.94 (d,

J = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 14.4, 59.8, 60.1, 91.7, 115.9,

119.0, 131.0, 144.0, 152.6, 165.9, 169.2; IR (KBr): 407, 596, 699, 736, 804, 968, 1032,

1103, 1225, 1290, 1344, 1372, 1428, 1632, 1683, 2933, 2984, 3031, 3291, 3523 cm-1;

Anal. calcd. for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07; Found: C, 60.47; H, 6.54; N,

10.25.

Preparation of 2-[(4-Acetylamino-phenylamino)-methylene]-malonic acid diethyl

ester (51c)

NH OCH2CH3

O

OOCH2CH3

HNO

To a solution of 51a (0.500 g, 1.7 mmol) and triethylamine (375 μL, 2.6 mmol) in

chloroform (5 mL), acetyl chloride (211 μL, 2.6 mmol) was added slowly under nitrogen

atmosphere. After stirring at room temperature for 1.30 h, water (10 mL) was added and


55

extracted with chloroform (3 X 10 mL). The combined organic layer was dried (Na2SO4),

and evaporated under reduced pressure to get the title compound 51c (0.46 g, 80%) as a

yellow solid. Crude product was purified through column chromatography

(Hexane:EtOAc = 7:3); mp: 165 °C; 1H NMR (400 MHz, CDCl3): δ 1.30-1.38 (m, 6H),

2.17 (s, 3H), 4.21-4.33 (m, 4H), 7.06 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.93 (s,

1H), 8.45 (d, J = 14 Hz, 1H), 10.99 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ

14.1, 14.3, 24.2, 60.0, 60.2, 93.0, 117.6, 121.2, 135.1, 135.2, 151.8, 165.7, 168.5, 168.9;

IR (KBr): 520, 624, 715, 801, 828, 919, 1030,1100,1238, 1225, 1312, 1367, 1411, 1441,

1478, 1520, 1540, 1629, 1672, 1698, 2362, 2909, 2931, 2983, 3070, 3150, 3238, 3325 cm-

1: Anal. calcd. for C16H20N2O5: C, 59.99; H, 6.29; N, 8.74; Found: C, 60.14; H, 6.41; N,

8.72.

Preparation of N-(4-Amino-phenyl)-acetamide (51d)

NHH2N

H3CO

The reaction was carried out according to Method B using compound 51c (0.500 g, 1.5


temperature, 1.30 h. The title compound 51d (0.18 g, 80%) was obtained after passing

through a short silica gel column (Hexane/EtOAc = 7:3). The data of the compound 51d

was in agreement with the values reported in the literature.36

Preparation of 2-[(4-Ethylamino-phenylamino)-methylene]-malonic acid diethyl ester

(51e) and 2-[(4-Diethylamino-phenylamino)-methylene]-malonic acid diethyl ester

(51g)

NH OCH2CH3

O

OOCH2CH3

HN

To a solution of 51a (0.500 g, 17 mmol) in acetone (5 mL), K2CO3 (0.372 g, 2.6 mmol)

was added and stirred for 1 h, followed by which ethyl bromide (201 μL, 2.6 mmol) was

added under nitrogen atmosphere. Stir the reaction mixture at room temperature for 24 h,

the acetone in reaction mixture was evaporated under reduced pressure. Water (10 mL)

was added and extracted with chloroform (3 X 10 mL). The combined organic layer was

dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by


56

column chromatography (silica gel, Hexane:EtOAc = 8:1). First eluted was the 2-[(4-

Ethylamino-phenylamino)-methylene]-malonic acid diethyl ester (51e, 0.42 g, 78%), a

greenish yellow solid and second eluted was 2-[(4-Diethylamino-phenylamino)-

methylene]-malonic acid diethyl ester (51g, 0.12 g, 20%) obtained as a yellow solid.

51e: mp: 52 °C; 1H NMR (400 MHz, CDCl3): δ 1.24-1.39 (m, 9H), 3.11-3.17 (m, 2H),

3.59 (brs, 1H), 4.20-4.32 (m, 4H), 6.59 (d, J = 6.8 Hz, 2H), 6.97 (d, J = 6.8 Hz, 2H), 8.41

(d, J = 13.6 Hz, 1H), 10.95 (d, J = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2,

14.4, 14.7, 38.5, 59.7, 60.0, 91.3, 113.3, 119.0, 129.7, 146.2, 152.6, 165.9, 169.2; IR

(KBr): 520, 562, 750, 809, 921, 995, 1033, 1098, 1180, 1272, 1310, 1377, 1434, 1477,

1526, 1606, 1632, 1678, 2865, 2929, 2981, 3030, 3163, 3260, 3374 cm-1; Anal. calcd. for

C16H22N2O4: C, 62.73; H, 7.24; N, 9.14; Found: C, 63.14; H, 7.21; N, 9.10.

NH OCH2CH3

O

OOCH2CH3

N

51g: mp: 80 °C; 1H NMR (400 MHz, CDCl3): δ 1.12 (t, J = 7.2 Hz, 6H), 1.28 (t, J = 7.2

Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 3.31 (q, J = 7.2 Hz, 4H), 4.17-4.29 (m, 4H), 6.62 (d, J =

7.2 Hz, 2H), 6.99 (d, J = 7.2 Hz, 2H), 8.39 (d, J = 14 Hz, 1H), 10.94 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 12.4, 14.3, 14.4, 44.5, 59.7, 60.0, 91.1, 112.6, 119.1,

128.3, 145.7, 152.6, 166.0, 169.4: IR (KBr): 518, 804, 916, 1030, 1095, 1155, 1255, 1313,

1414, 1446, 1479, 1524, 1570, 1612, 1641, 1686, 2928, 2979, 3183, 3264, 3441 cm-1:

Anal. calcd. for C18H26N2O4: C, 64.65; H, 7.84; N, 8.38; Found: C, 65.02; H, 7.84; N,

8.13.

Preparation of N-Ethyl-benzene-1,4-diamine (51f)

HN NH2

CH3

The reaction was carried out according to Method B using 51e (0.500 g, 1.8 mmol),

ethylenediamine (436 μL, 6.5 mmol) in ethanol (2.5 mL). Conditions: room temperature,

15 min. The title compound 51f (0.22 g, 99%) was obtained after passing through a short

silica gel column (Hexane:EtOAc = 8:2). The data of the compound 51f was in agreement



57

Preparation of N,N-Diethyl-benzene-1,4-diamine (51h)

N

NH2

CH3H3C

The reaction was carried out according to Method B using 51g (0.500 g, 1.4 mmol),

ethylenediamine (399 μL, 5.9 mmol) and ethanol (2.5 mL) Conditions: room temperature,

15 min. The title compound 51h (0.24 g, 99%) was obtained after passing through a short

silica gel column (Hexane:EtOAc = 8:2). The data of the compound 51h was in agreement

with the values reported in the literature. 37

Preparation of 2-[(2-Amino-phenylamino)-methylene]-malonic acid diethyl ester

(52a)

NH OCH2CH3

O

OOCH2CH3NH2

The reaction was carried out according to Method A using 1,2-diaminobenzene (52, 0.500

g, 4.6 mmol), diethyl ethoxymethylenemalonate (934 μL, 4.6 mmol). Conditions: room

temperature, 10 min. The title compound 52a (1.26 g, 98%) was obtained as a yellow

solid. mp: 78 °C; 1H NMR (400 MHz, CDCl3): δ 1.29-1.38 (m, 6H), 3.74 (brs, 2H), 4.19-

4.32 (m, 4H), 6.79-6.85 (m, 2H), 7.00-7.08 (m, 1H), 7.10 (d, J = 1.2 Hz, 1H), 8.40 (d, J =

13.6 Hz, 1H), 10.80 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 14.2, 59.8,

60.1, 93.2, 117.4, 119.0, 119.9, 126.3, 127.6, 137.9, 154.0, 165.5, 169.0; IR (KBr): 544,

592, 654, 733, 833, 867, 909, 1000, 1028, 1071, 1222, 1310, 1383, 1414, 1467, 1504,

2983, 3036, 3140, 3250, 3352, 3408 cm-1; Anal. calcd. for C14H18N2O4: C, 60.42; H, 6.52;

N, 10.07; Found: C, 60.41; H, 6.49; N, 10.09.


58

Preparation of 2-[(2-Ethylamino-phenylamino)-methylene]-malonic acid diethyl ester

(52b)

NH OCH2CH3

O

OOCH2CH3NH

To a solution of 52a (0.500 g, 1.7 mmol) in acetone (5 mL), K2CO3 (0.372 g, 2.6 mmol),

was added, stirred at room temperature for 1 h, followed by which ethyl bromide (201 μL,

2.6 mmol) was added and stirred at room temperature for 24 h. After the reaction

completed acetone in reaction mixture was evaporated under reduced pressure. Water (10

mL) was added and extracted with chloroform (3 X 10 mL). The combined organic layer

was dried (Na2SO4) and evaporated under reduced pressure. The title compound 52b was

obtained as a greenish yellow solid (0.42 g, 77%). The crude product was purified through

column chromatography (silica gel, Hexane:EtOAc = 8:2); mp: 102 °C; 1H NMR (400

MHz, CDCl3): δ 1.19-1.24 (m, 6H), 1.30 (t, J = 7.2 Hz, 3H), 3.11 (q, J = 7.2 Hz, 2H), 3.56

(brs, 1H), 4.12-4.26 (m, 4H), 6.66-6.73 (m, 2H), 7.00-7.08 (m, 2H), 8.28 (d, J = 13.6 Hz,

1H), 10.55 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 14.3, 14.7, 38.5,

59.9, 60.2, 93.4, 112.4, 118.0, 120.3, 127.1, 127.3, 140.5, 155.2, 165.6, 169.1; IR (KBr):

526, 569, 673, 745, 796, 860, 1029, 1084, 1155, 1220, 1257, 1312, 1372, 1418, 1457,

1515,1617, 1660, 1708, 2848, 2887, 2929, 2978, 3074, 3254, 3337, 3446 cm-1; Anal.

calcd. for C16H22N2O4: C, 62.73; H, 7.24; N, 9.14; Found: C, 62.53; H, 6.24; N, 8.91.

Preparation of N-Ethyl-benzene-1,2-diamine (52c)

NH2

NH

H3C

The reaction was carried out according to Method B using compound 52b (0.500 g, 1.6


temperature, 15 min. The crude product was purified by column chromatography

(Hexane:EtOAc = 7:3) to get the title compound 52c (0.22 g, 99%). The data of the

compound 52c was in agreement with the values reported in the literature.38


59

Preparation of 2-[(4-Hydroxy-phenylamino)-methylene]-malonic acid diethyl ester

(53a)

NH OCH2CH3

O

OOCH2CH3

HO

The reaction was carried out according to Method A using 4-aminophenol (53, 0.500 g,

4.5 mmol), diethyl ethoxymethylenemalonate (925 μL, 4.5 mmol) and ethanol (2.5 mL).

Conditions: room temperature, 15 min. The title compound 53a was obtained as a white

solid (1.26 g, 99%). mp: 129 °C; 1H NMR (400 MHz, DMSO-D6): δ 1.22-1.28 (m, 6H),

4.09-4.22 (m, 4H), 6.80 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 8.30 (d, J = 14.0 Hz,

1H), 9.47 (s, 1H), 10.70 (d, J = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 14.3,

60.3, 60.3, 91.7, 116.5, 119.0, 131.9, 153.0, 154.4, 166.6, 169.0; IR (KBr): 710, 767, 803,

834, 869, 1010, 1031, 1092, 1218, 1354, 1379, 1415, 1463, 1517, 1591, 1622, 1657, 2520,

2619, 2744, 2876, 2933, 2982, 3036, 3200 cm-1; LCMS (TOF) [M+1]: 280.2; Anal. calcd.

for C14H17NO5: C, 60.21; H, 6.14; N, 5.02; Found: C, 60.45; H, 5.98; N, 5.12.

Preparation of 2-[(4-Allyloxy-phenylamino)-methylene]-malonic acid diethyl ester

(53b)

NH OCH2CH3

O

OOCH2CH3

O

To a solution of 53a (0.500 g, 1.7 mmol) in acetone (5 mL), KOH (0.150 g, 2.6 mmol)

was added and stirred at room temperature for 30 min. allyl bromide (232 μL, 2.6 mol)

was added and stirring continued till the completion of reaction at room temperature for 3

h. Water (5 mL) was added and extracted with ethyl acetate (3 X 10 mL). The combined

organic layer was dried with (Na2SO4) and evaporated under reduced pressure. Title

compound 53b was obtained a white solid (0.48 g, 85%) after passing the crude product

through column chromatography (silica gel, Hexane:EtOAc = 8:2) . mp: 48 °C; 1H NMR

(400 MHz, CDCl3): δ 1.28-1.37 (m, 6H), 4.19-4.31 (m, 4H), 4.52 (t, J = 4.8 Hz, 2H), 5.27

(d, J = 10.4 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 5.97-6.07 (m,1H), 6.90 (d, J = 8.8 Hz,

2H), 7.05 (d, J = 8.8 Hz, 2H), 8.41 (d, J = 14.0 Hz, 1H), 10.96 (d, J = 14.0 Hz, 1H); 13C

NMR (100 MHz, CDCl3): δ 14.2, 14.3, 59.8, 60.1, 92.4, 115.7, 117.7, 118.6, 132.7, 132.8,

152.4, 156.0, 165.7, 169.0; IR (KBr): 516, 555, 758, 792, 945, 991, 1026, 1091, 1175,


60

1229, 1309, 1386, 1414, 1442, 1473, 1514, 1607, 1680, 2904, 2981, 3252 cm-1; Anal.

calcd. for C17H21NO5: C, 63.94; H, 6.63; N, 4.39; Found: C, 63.82; H, 6.55; N, 4.41.

Preparation of 4-Allyloxy-phenylamine (53c)

H2N O

The reaction was carried out according to Method B using 53b (0.500 g, 1.5 mmol),

ethylenediamine (418 μL, 6.2 mmol) and ethanol (2.5 mL). Conditions: room temperature,

1.30 h. The title compound 53c was obtained (0.21 g, 90%) after passing through a short

silica gel column (Hexane:EtOAc = 8:2). The spectral data of the compound 53c was in


Preparation of 2-[(2-Benzyloxy-phenylamino)-methylene]-malonic acid diethyl ester

(53d)

NH OCH2CH3

O

OOCH2CH3

O

To a solution of 53a (0.500 g, 1.7 mmol) in chloroform (5 mL), K2CO3 (0.371 g, 2.6

mmol) was added, and stirred at room temperature for 1 h, followed by which benzyl

bromide (319 μL, 2.6 mmol) was added under nitrogen atmosphere. The reaction was

complete after 12 h stirring at room temperature; water (5 mL) was added and extracted

with chloroform (3 X 10 mL). The combined organic layer was dried (Na2SO4) and

evaporated under reduced pressure. The title compound 53d was obtained as a white solid

(0.60 g, 92%) after passing though column chromatography (silica gel, Hexane:EtOAc =

7:3) mp: 110 °C; 1H NMR (400 MHz, CDCl3): δ 1.29-1.39 (m, 6H), 4.20-4.32 (m, 4H),

5.04 (s, 2H), 6.96 (d, J = 9.2 Hz, 2H), 7.06 (d, J = 9.2 Hz, 2H), 7.32-7.42 (m, 5H), 8.43

(d, J = 13.6 Hz, 1H), 10.98 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2,

14.3, 59.8, 60.1, 70.2, 92.4, 115.9, 118.6, 127.3, 127.9, 128.5, 132.8, 136.5, 152.4, 156.1,

165.7, 169.1; IR (KBr): 472, 521, 604, 700, 744, 796, 824, 870, 920, 996, 1090, 1121,

1171, 1223, 1309, 1339, 1381, 1413, 1441, 1476, 1511, 1608, 1679, 1979, 2983 cm-1;

Anal. calcd. for C21H23NO5: C, 68.28; H, 6.28; N, 3.79; Found: C, 68.15; H, 6.22; N,

3.79.


61

Preparation of 4-Benzyloxy-phenylamine (53e)

NH2

O

The reaction was carried out according to Method B using 53d (0.500 g, 1.3 mmol),


1.30 h. The title compound 53e (0.25 g, 95%) was obtained, after passing through a short

silica gel column (Hexane:EtOAc = 9:1). The data of the compound 53e was in agreement


Preparation of 2-[(4-Acetoxy-phenylamino)-methylene]-malonic acid diethyl ester

(53f)

NH OCH2CH3

O

OOCH2CH3

OO

To the solution of compound 53a (0.500 g, 1.7 mmol) and triethylamine (374 μL, 2.6

mmol) in chloroform (5 mL), acetyl chloride (190 μL, 2.6 mmol) was added under

nitrogen atmosphere. After stirring at room temperature for 30 min. water (5 mL) was

added and extracted with chloroform (3 X 10 mL). The combined chloroform layer was

dried (Na2SO4) evaporated under reduced pressure. The title compound 53f was obtained

as a white solid (0.56 g, 99%). mp: 64 °C; 1H NMR (400 MHz, CDCl3): δ 1.30-1.39 (m,

6H), 2.30 (s, 3H), 4.21-4.33 (m, 4H), 7.09-7.15 (m, 4H), 8.46 (d, J = 13.6 Hz, 1H), 11.02

(d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 14.3, 20.9, 60.0, 60.3, 93.7,

118.0, 122.9, 136.9, 147.5, 152.0, 165.5, 168.9, 169.3; IR (KBr): 403, 490, 519, 592, 632,

799, 908, 1008, 1084, 1198, 1302, 1370, 1414, 1440, 1512, 1619, 1641, 1685, 1750, 2287,

2932, 2977, 3082 cm-1; ESIMS (TOF) [M+1]: 322.1; Anal. calcd. for C16H19NO6: C,

59.81; H, 5.96; N, 4.36; Found: C, 60.04; H, 6.01; N, 4.24.

Deprotection 2-[(4-Acetoxy-phenylamino)-methylene]-malonic acid diethyl ester (53f)

or Preparation (53a)

The reaction was carried out according to Method B using compound 53f (0.500 g, 1.5



62

temperature, 5 min. Compound 53a (0.41 g, 95%) was obtained after through a short silica

gel column chromatography (Hexane:EtOAc = 9:1).

Preparation of 2-[(4-Benzoyloxy-phenylamino)-methylene]-malonic acid diethyl ester

(53g)

NH OCH2CH3

O

OOCH2CH3

OO

To a solution of compound 53a (0.500 g, 1.7 mmol) and triethylamine (374 μL, 2.6 mmol)

in chloroform (5 mL), benzoyl chloride (311 μL, 2.6 mmol) was added under nitrogen

atmosphere. After stirring at room temperature 1.0 h, water (5 ml) was added and

extracted with chloroform (3 X 10 mL). The combined chloroform layer was dried

(Na2SO4) and evaporated under reduced pressure. The title compound 53g was obtained as

white solid (0.69g, 99%). mp: 79 °C; 1H NMR (400 MHz, CDCl3): δ 1.31-1.40 (m, 6H),

4.22-4.34 (m, 4H), 7.18-7.25 (m, 4H), 7.50-7.54 (m, 2H), 7.62-7.67 (m, 1H), 8.18-8.21

(m, 2H), 8.49 (d, J = 13.6 Hz, 1H), 11.05 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz,

CDCl3): δ 14.2, 14.3, 60.0, 60.3, 93.8, 118.1, 123.0, 128.5, 129.1, 130.1, 133.7, 137.0,

147.8, 152.0, 165.0, 165.5, 169.0 ; IR (KBr): 462, 526, 554, 708, 796, 870, 912, 1022,

1060, 1161, 1208, 1243, 1307, 1347, 1381, 1409, 1441, 1511, 1619, 1686, 1718, 2932,

2977 cm-1; Anal. calcd. for C21H21NO6: C, 65.79; H, 5.52; N, 3.65; Found: C, 65.68; H,

5.45; N, 3.50.

Preparation of Benzoic acid 4-amino-phenyl ester (53h)

NH2

O

O

The reaction was carried out according to Method B using compound 53g (0.500 g, 1.3

mmol), ethylenediamine (348 μL , 5.2 mmol) in ethanol (2.5 mL). Conditions: room

temperature 1 h. The title compound 53h was obtained passing through a short silica gel

column (Hexane:EtOAc = 9:1) (0.20 g, 75%). The data of the compound 53h was in



63

Preparation of 2-[(2-Hydroxy-phenylamino)-methylene]-malonic acid diethyl ester

(54a)

NH OCH2CH3

O

OOCH2CH3OH

The reaction was carried out according to Method A using 2-aminophenol (54, 0.500 g,

4.5 mmol), diethyl ethoxymethylenemalonate (925 μL, 4.5 mmol) in ethanol (2.5 mL).

Conditions: room temperature, 15 min. The title compound 54a was obtained as a white

solid (1.26 g, 99%). mp: 139 °C; 1H NMR (400 MHz, DMSO-D6): δ 1.24-1.29 (m, 6H),

4.11-4.23 (m, 4H), 6.85-7.01 (m, 3H), 7.38-7.40 (d, J = 8 Hz, 1H), 8.52 (d, J = 14 Hz,

1H), 10.35 (s,1H) 11.01 (d, J = 14 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 14.3,

60.3, 60.4, 92.5, 114.7, 116.0, 120.6, 125.0, 127.3, 146.3, 150.9, 166.7, 168.5; IR (KBr):

515, 591, 741, 809, 915, 981, 1038, 1092, 1214, 1313, 1397, 1469, 1524, 1578, 1632,

1661, 2717, 2767, 2979, 3157 cm-1; Anal. calcd. for C14H17NO5: C, 60.21; H, 6.14; N,

5.02; Found: C, 60.11; H, 6.26; N, 5.02.

Preparation of 2-[(2-Ethoxy-phenylamino)-methylene]-malonic acid diethyl ester

(54b)

NH OCH2CH3

O

OOCH2CH3O

To a solution of 54a (0.500 g, 1.7 mmol) in acetone (5 mL), K2CO3 (0.371 g, 2.6 mmol)

was added and stirred at room temperature for 1 h, later, ethyl bromide (200 μL, 2.6

mmol) was added and stirred at room temperature for 12 h. Acetone was evaporated under

reduced pressure, water (5 mL) was added and extracted with chloroform (3 X 10 mL).

The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure.

The title compound 54b (0.54 g, 99%) was obtained as yellow solid. mp: 52 °C; 1H NMR

(400 MHz, CDCl3): δ 1.31-1.39 (m, 6H), 1.50 (t, J = 6.8 Hz, 3H), 4.14 (q, J = 7.2 Hz,

2H), 4.25 (q, J = 7.2 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 6.91-6.98 (m, 2H), 7.04-7.08 (m,

1H), 7.22-7.27 (m, 1H), 8.56 (d, J = 14 Hz, 1H), 11.13 (d, J = 14 Hz, 1H); 13C NMR (100

MHz, CDCl3): δ 14.3, 14.3, 14.6, 59.9, 60.0, 64.4, 93.6, 112.3, 114.3, 121.0, 124.6, 128.9,

148.1, 150.3, 165.9, 168.2; IR (KBr): 562, 735, 813, 924, 987, 1041, 1095, 1116, 1227,

1263, 1338, 1381, 1425, 1506, 1581, 1613, 1644, 1685, 2897, 2932, 2980, 3241, 3413 cm-


64

1; Anal. calcd. for C16H21NO5: C, 62.53; H, 6.89; N, 4.56; Found: C, 62.26; H, 6.76; N,

4.42.

Preparation of 2-Ethoxy-phenylamine (54c)

NH2

O

The reaction was carried out according to Method B using compound 54b (0.500 g, 1.6


temperature, 15 min. The title compound 54c was obtained after passing through a short

silica gel column (Hexane:EtOAc = 8:2) (0.22 g, 99%). The data of the compound 54c

was in agreement with the values reported in the literature.41

Preparation of 2-[(2-Mercapto-phenylamino)-methylene]-malonic acid diethyl ester

(55a)

NH OCH2CH3

O

OOCH2CH3SH

55a

The reaction was carried out according to Method A using 2-aminothiophenol (55, 0.500

g, 3.9 mmol), diethyl ethoxymethylenemalonate (807 μL, 3.9 mmol) and ethanol (2.5 mL).

Conditions: room temperature, 20 min. The title compound 55a was obtained as a syrupy

liquid (1.1 g, 98%). Column chromatography (Hexane:EtOAc = 8:2); 1H NMR (200 MHz,

CDCl3): δ 1.26-1.50 (m, 6H), 4.21-4.36 (m, 4H), 6.94-7.41 (m, 4H), 8.36 (d, J = 14 Hz,

1H), 11.42 (d, J = 14 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 14.4, 29.6, 60.2,

60.4, 95.5, 115.0, 124.3, 131.9, 137.3, 141.4, 149.7, 165.7, 167.7; IR (KBr): 458, 630,

752, 800, 861, 1024, 1094, 1157, 1250, 1306, 1370, 1418, 1447, 1478, 1584, 1611, 1655,

1736, 2904, 2933, 2980, 3064, 3370, 3468 cm-1; Anal. calcd. for C14H17NO4S: C, 56.93;

H, 5.80; N, 4.74; S, 10.86; Found: C, 60.34; H, 5.60; N, 4.11; S, 10.47.


65

Preparation of 2-[(2-Ethylsulfanyl-phenylamino)-methylene]-malonic acid diethyl

ester (55b)

NH OCH2CH3

O

OOCH2CH3S


was added and stirred for 1 h, later ethyl bromide (189 μL, 2.5 mmol) was added and

stirred for 24 at room temperature, for the reaction to complete. Acetone was evaporated

under reduced pressure; water (5 mL) was added and extracted with chloroform (3 X 10

mL). The combined organic layers were dried (Na2SO4) and evaporated under reduced

pressure. The title compound 55b was obtained (0.46 g, 85%). Column chromatography

(Hexane:EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 1.13 (t, J = 7.6 Hz, 3H), 1.23-1.31

(m, 6H), 2.73 (q, J = 7.2 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 6.97-

7.45 (m, 4H), 8.47 (d, J = 13.6 Hz, 1H), 11.46 (d, J = 14 Hz, 1H); 13C NMR (200 MHz,

CDCl3): δ 14.2, 14.3, 14.5, 29.5, 60.0, 60.2, 94.62, 114.4, 124.3, 129.4, 135.5, 140.7,

150.0, 165.8, 167.9; IR (KBr): 1582, 1608, 1656, 1691, 2928, 2978, 3079, 3362, 3463 cm-

1; Anal. calcd. for C16H21NO4S: C, 59.42; H, 6.54; N, 4.33; S, 9.91 Found: 59.42; H, 6.92;

N, 3.97; S, 9.56.

Preparation of 2-Ethylsulfanyl-phenylamine (55c)

NH2

S


ethylenediamine (413 μL, 6.1 mmol) and ethanol (2.5 mL). Conditions: room temperature,

2 h. The title compound 55c (0.22 g, 98%) was obtained after purification through column

chromatography (silica gel, Hexane:EtOAc = 7:3). The data of the compound 55c was in



66

Preparation of 2-[(4-Carboxy-phenylamino)-methylene]-malonic acid diethyl ester

(56a)

NH OCH2CH3

O

OOCH2CH3

HOOC

The reaction was carried out according to Method A using 4-aminobenzoic acid (56, 0.500

g, 3.6 mmol), diethyl ethoxymethylenemalonate (843 μL, 3.6 mmol) and ethanol (2.5 mL).

Conditions: room temperature, 4.30 h. The title compound 56a was obtained as a white

solid (1.10 g, 99%) after purification through column chromatography (silica gel,

Hexane:EtOAc = 9:1). mp: 221 °C; 1H NMR (400 MHz, DMSO-D6): δ 1.26 (q, J = 6.8

Hz, 6H), 4.12-4.25 (m, 4H), 7.46 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 8.44 (d, J =

13.6 Hz, 1H), 10.73 (d, J = 13.6 Hz, 1H), 12.85 (brs, 1H); 13C NMR (100 MHz, DMSO-

D6): δ 14.3, 14.4, 59.8, 60.0, 95.3, 117.1, 126.4, 131.2, 143.2, 150.0, 164.9, 166.9, 167.1;

IR (KBr): 548, 766, 807, 855, 927, 1025, 1098, 1122, 1179, 1239, 1372, 1416, 1447,

1480, 1570, 1594, 1640, 1683, 2545, 2684, 2906, 2985, 3084, 3172, 3265, 3430 cm-1;

Anal. calcd. for C15H17NO6: C, 58.63; H, 5.58; N, 4.56; Found: C, 58.62; H, 5.56; N, 4.46.

Preparation of 2-[(4-Allyloxycarbonyl-phenylamino)-methylene]-malonic acid diethyl

ester (56b)

NH OCH2CH3

O

OOCH2CH3

O

O


was added and stirred at room temperature for 1 h, followed by which allyl bromide (211

μL, 2.4 mmol) was added under nitrogen atmosphere. After 36 h of stirring at room

temperature, acetone was evaporated under reduced pressure; water (5 mL) was added and

extracted with of chloroform (3 X 10 mL). The combined organic layer was dried

(Na2SO4) and evaporated under reduced pressure. The title compound 56b was obtained as

white solid (0.58 g, 85%) after purification through column chromatography

(Hexane:EtOAc = 8:2); mp: 48 °C; 1H NMR (400 MHz, CDCl3): δ 1.32-1.40 (m, 6H),

4.24-4.34 (m, 4H), 4.80-4.83 (m, 2H), 5.28-5.43 (m, 2H), 6.00-6.07 (m, 1H), 7.18 (d, J =

8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 8.54 (d, J = 13.6 Hz, 1H), 11.10 (d, J = 13.6 Hz,

1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 14.3, 60.3, 60.6, 65.5, 95.4, 116.1, 118.3,


67

126.0, 131.6, 132.1, 142.9, 150.5, 165.3, 168.7; IR (KBr): 513, 612, 688, 764, 802, 850,

925, 976, 1025, 1094, 1168, 1240, 1363, 1412, 1443, 1472, 1594, 1636, 1681, 2901, 2938,

2983, 3143 cm-1; LCMS (TOF): Found [M+1]: 348.2; Anal. calcd. for C18H21NO6: C,

62.24; H, 6.09; N, 4.03; Found: 62.61; H, 6.39; N, 4.37.

Preparation of 4-Amino-benzoic acid allyl ester (56c)

NH2

OO


ethylenediamine (384 μL, 5.7 mmol) in ethanol (2.5 mL). Conditions: room temperature, 2

h. The title compound 56c (0.22 g, 90%) was obtained after passing through a short silica

gel column (Hexane:EtOAc = 9:1). The data of the compound 56c was in agreement with

the values reported in the literature.43

Preparation of 2-[(4-Methoxycarbonyl-phenylamino)-methylene]-malonic acid

diethyl ester (56d)

NH OCH2CH3

O

OOCH2CH3

O

O


was added and stirred at room temperature for 1 h, methyl iodide (151 μL, 2.4 mmol) was

added. After stirring at room temperature for 2 h, acetone was evaporated under reduced

pressure; water (5 mL) was added and extracted with chloroform (3 X 10 mL). The

combined organic layers were dried (Na2SO4) evaporated under reduced pressure. The title

compound 56d was obtained as a white solid (0.51 g, 98%). mp: 80 °C; 1H NMR (400

MHz, CDCl3): δ 1.24-1.32 (m, 6H), 3.83 (s, 3H), 4.15-4.26 (m, 4H), 7.08 (d, J = 8.8 Hz,

2H), 7.97 (d, J = 8.8 Hz, 2H), 8.45 (d, J = 13.2 Hz, 1H), 11.01 (d, J = 13.6 Hz, 1H); 13C

NMR (100 MHz, CDCl3): δ 14.1, 14.3, 52.0, 60.2, 60.5, 95.4, 116.1, 126.0, 131.1, 131.4,

131.5, 142.8, 150.4, 165.3, 166.1, 168.6; IR (KBr): 548, 766, 807, 855, 927, 1025, 1098,

1122, 1179, 1239, 1372, 1416, 1447,1480, 1570, 1594, 1640, 1683, 2545, 2684, 2906,


68

2985, 3084, 3172, 3265, 3430 cm-1; Anal. calcd. for C16H19NO6: C, 59.81; H, 5.96; N,

4.36; Found: C, 59.61; H, 5.98; N, 4.34

Preparation of 4-Amino-benzoic acid methyl ester (56e)

NH2

COOCH3

The reaction was carried out according to Method B using 56d (0.500 g, 1.5 mmol),


2.15 h. The title compound 56e (0.22 g, 95%) was obtained after passing through a short

silica gel column (Hexane;EtOAc = 7:3). The data of the compound 56e was in agreement


Preparation of 2-[(2-Carboxy-phenylamino)-methylene]-malonic acid diethyl ester

(57a)

NH OCH2CH3

O

OOCH2CH3COOH

The reaction was carried out according to Method A using 2-aminobenzoic acid (57, 0.500

g, 3.6 mmol), diethyl ethoxymethylenemalonate (843 μL, 3.6 mmol). Conditions: room

temperature, 5.0 h. The title compound 57a was obtained as a white solid (1.10 g, 98%).

mp: 146 °C; 1H NMR (400 MHz, CDCl3): δ 1.33-1.39 (m, 6H), 4.29 (q, J = 7.2 Hz, 2H),

4.38 (q, J = 7.2 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.2

Hz, 1H), 8.16 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 8.60 (d, J = 13.6 Hz, 1H), 10.70 (brs,

1H), 12.57 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 14.3, 60.4, 60.5,

96.8, 115.1, 115.8, 123.1, 132.7, 135.2, 142.2, 149.1, 166.3, 166.7, 170.9; IR (KBr): 482,

578, 648, 672, 755, 792, 866, 917, 997, 1024,1095, 1147, 1246, 1307, 1352, 1382, 1425,

1501, 1567, 1611, 1638, 1680, 1716, 2904, 2935, 2987, 3105, 3221 cm-1; Anal. calcd. for

C15H17NO6: C, 58.63; H, 5.58; N, 4.56; Found: C, 58.54; H, 5.62; N, 4.36.


69

Preparation of 2-[(2-Methoxycarbonyl-phenylamino)-methylene]-malonic acid

diethyl ester (57b)

NH OCH2CH3

O

OOCH2CH3

OO

To the solution of 57a (0.500 g, 1.6 mmol) in acetone (5 mL), K2CO3 (0.337 g, 2.4 mmol)

was added and stirred at room temperature for 1 h, followed by which methyl iodide (151

μL, 2.3 mmol) was added under nitrogen atmosphere. After 2 h stirring at room

temperature acetone in reaction mixture was evaporated under reduced pressure, then

water (5 mL) was added and extracted with chloroform (3 X 10 mL). The combined

organic layers were dried (Na2SO4) and evaporated under reduced pressure. The title

compound 57b was obtained as white solid (0.51 g, 98%). mp.: 40 °C; 1H NMR (400

MHz, CDCl3): δ 1.32-1.40 (m, 6H), 3.99 (s, 3H), 4.27 (q, J1 = 7.2 Hz, 2H), 4.40 (q, J =

7.2 Hz, 2H), 7.12-7.16 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.55-7.59 (m, 1H), 8.07 (dd, J1 =

1.6 Hz, J2 = 7.6 Hz, 1H), 8.60 (d, J = 13.6 Hz, 1H), 12.71 (d, J = 13.2 Hz, 1H); 13C NMR

(100 MHz, CDCl3): δ 00.92, 14.2, 14.3, 52.5, 60.2, 60.3, 96.5, 114.9, 116.7, 123.0, 131.9,

134.4, 141.6, 149.2, 166.0, 167.0, 167.1; IR (KBr): 460, 575, 690, 756, 818, 979, 1026,

1092, 1229, 1279, 1328, 1389, 1423, 1461, 1588, 1652, 1686, 1726, 2854, 2909, 2983,

3218, 3420 cm-1; Anal. calcd. for C16H19NO6: C, 59.81; H, 5.96; N, 4.36; Found: C,

59.80; H, 5.92; N, 4.29.

Preparation of 2-Amino-benzoic acid methyl ester [57c]

NH2

H3COOC

57c


ethylenediamine (416 μL, 6.2 mmol). Conditions: room temperature, 2.30 h. The title

compound 57c (0.22 g, 96%) was obtained after through a short silica gel column

(Hexane:EtOAc = 7:3). The spectral for the title compound 57c was in agreement with the



70

Selective protection, functional group interconversion and deprotecion of aliphatic

amines

Preparation of 2-[(1-Hydroxymethyl-propylamino)-methylene]-malonic acid diethyl

ester (58a)

H3C OHHN H

OH3CH2CO

O

H3CH2CO

The reaction was carried out according to Method A using (S)-(+)-2-amino-1-butanol (58,

0.500 g, 5.6 mmol), diethyl ethoxymethylenemalonate (1.13 mL, 5.6 mmol). Conditions:

room temperature, 30 min. The title compound 58a was obtained as a syrupy liquid (1.42

g, 98%). 1H NMR (400 MHz, CDCl3): δ 0.97 (t, J = 7.2 Hz, 3H), 1.26-1.35 (m, 6H), 1.51-

1.71 (m, 2H), 3.20-3.26 (m, 2H), 3.57-3.74 (m, 2H), 4.13-4.25 (m, 4H), 8.05 (d, J = 14.4

Hz, 1H), 9.14 (dd, J1 = 9.2 Hz, J2 = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 10.2,

14.2, 14.2, 24.5, 59.5, 59.7, 63.7, 64.7, 89.2, 159.7, 166.3, 169.3; IR (KBr): 465, 547, 674,

751, 805, 1030, 1074,1148, 1248, 1316, 1379, 1424, 1463, 1608, 1656, 1693, 2876, 2935,

2974, 3276, 3375, 3451 cm-1; [α]20D = -39.02 (c 1.00, CHCl3); Anal. calcd. for

C12H21NO5: C, 55.58; H, 8.16; N, 5.40. Found: C, 51.01, H, 8.0, N, 5.35.

Preparation of 2-[(1-Benzoyloxymethyl-propylamino)-methylene]-malonic acid

diethyl ester (59)

H3C OHN H

OH3CH2CO

O

H3CH2CO

O

To a solution of 58a (0.500 g, 1.9 mmol) in chloroform (5 mL), triethylamine (403 μL, 2.8

mmol), benzoyl chloride (335 μL, 2.8 mmol) was add under nitrogen atmosphere. After

stirring at room temperature for 1 h, water was added and extracted with chloroform (3 X

10 mL). The combined chloroform layer was dried (Na2SO4) and evaporated under

reduced pressure. The title compound 59 (0.69 g, 99%) was obtained as a syrupy liquid.

The reaction mixture was purified by column chromatography (silica gel, Hexane:EtOAc

= 8:2). 1H NMR (400 MHz, CDCl3): δ 1.05 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H),


71

1.34 (t, J = 6.8 Hz, 3H), 1.67-1.78 (m, 2H), 3.55-3.57 (m, 2H), 4.13-4.27 (m, 5H), 4.44

(dd, J1 = 4.0 Hz, J2 = 11.6 Hz, 1H), 7.38-7.59 (m, 3H), 8.01 (dd, J1 = 1.2 Hz, J2 = 3.2 Hz,

4H), 8.10 (d, J = 14 Hz, 1H), 9.26 (dd, J1 = 9.2 Hz, J2 = 12.8 Hz, 1H); 13C NMR (100

MHz, CDCl3): δ 10.1, 14.2, 14.2, 24.8, 59.5, 59.8, 60.5, 66.5, 90.1, 126.1, 128.3, 129.3,

129.5, 133.2, 159.5, 165.7, 166.0, 169.2; IR (KBr):1606, 1651, 1687, 1720, 2936, 2975,

3267 cm-1; [α]20D = +112.45 (c 1.00, CHCl3); LCMS (TOF): Found: [M+1] 364.1; Anal.

calcd. for C19H25NO6: C, 62.80; H, 6.93; N, 3.85; Found: C, 62.87, H, 6.91, N, 3.79.

Preparation of Benzoic acid 2-amino-butyl ester (59a)

H3C OH2N H

O

The reaction was carried out according to Method B using 59 (0.500 g, 1.3 mmol),

ethylenediamine (367 μL, 5.5 mmol). Conditions: room temperature, 1 h. The title

compound 59a (0.24 g, 94%) was obtained as a solid after purification through column

chromatography (silica gel, Hexane:EtOAc = 3:7). The data of the compound 57c was in


Preparation of 2-[(1-Acetoxymethyl-propylamino)-methylene]-malonic acid diethyl

ester (60)

H3C OHN H

OH3CH2CO

O

H3CH2CO

O

CH3

To the solution of 58a (0.500 g, 1.9 mmol) in chloroform (5 mL), triethylamine (403 μL,

2.8 mmol), acetyl chloride (205 μL, 2.8 mmol) was add under nitrogen atmosphere. After

1 h stirring at room temperature, water (10 mL) was added and extracted with chloroform

(3 X 10 mL). The combined chloroform layer was dried (Na2SO4) and evaporated under

reduced pressure. The title compound 60 was obtained as a syrupy liquid with (0.57 g,

99%) after purification through column chromatography (silica gel, Hexane:EtOAc = 8:2). 1H NMR (400 MHz, CDCl3): δ 1.00 (t, J = 7.6 Hz, 3H), 1.27-1.36 (m, 6H), 1.56-1.73 (m,

2H), 2.08 (s, 3H), 3.40-3.45 (m, 1H), 4.05-4.27 (m, 6H), 8.01 (d, J = 14 Hz, 2H), 9.14 (dd,

J1 = 9.6 Hz, J2 = 12.0 Hz, 1H); IR (KBr): 1608, 1652, 1687, 1744, 2976, 3270 cm-1; 13C


72

NMR (100 MHz, CDCl3): δ 10.0, 14.1, 14.2, 20.5, 24.7, 59.5, 59.7, 60.4, 65.9, 159.3,

166.0, 169.1, 170.5; [α]20D = +47.63 (c 1.00, CHCl3); Anal. calcd. for C14H23NO6: C,

55.80; H, 7.69; N, 4.65; Found: C, 55.82, H, 7.61, N, 4.74.

Deprotection of 2-[(1-Acetoxymethyl-propylamino)-methylene]-malonic acid diethyl

ester (60) or Preparation of compound (58a)


ethylenediamine (443 μL, 6.6 mmol). Conditions: room temperature, 1 h. The reaction

work up gave raise to the starting material 58a (0.30 g, 70%). For spectral data see the

experiment for preparation of 58a.

Preparation 2-[(1-Ethoxymethyl-propylamino)-methylene]-malonic acid diethyl ester

(61)

H3C OHN H

OH3CH2CO

O

H3CH2CO

CH3

To a solution of 58a (0.500 g, 1.9 mmol) in N,N-Dimethylformamide (5 mL), sodium

hydride (0.069 g, 2.8 mmol) was added at 0 ºC and stirred for 30 min. followed by which

ethyl bromide (215 μL, 2.9 mmol) was added under nitrogen atmosphere. After stirring for

24 h at room temperature, water was added and extracted with ethyl acetate (3 X 10 mL).

The combined chloroform layer was dried (Na2SO4) and evaporated under reduced

pressure. The title compound 61 was obtained as a syrupy liquid (0.38 g, 70%) after

purification through column chromatography (Hexane:EtOAc = 8:2). 1H NMR (400 MHz,

CDCl3): δ 0.89 (t, J = 7.6 Hz, 3H), 0.97 (t, J = 7.6 Hz, 3H), 1.25-1.36 (m, 6H), 1.50-1.68

(m, 2H), 3.35-3.50 (m, 6H), 4.15-4.27 (m, 4H), 8.06 (d, J = 14.4 Hz, 1H), 9.17 (dd, J1 =

8.4 Hz, J2 = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 10.3, 13.8, 14.3, 14.4, 19.2,

25.0, 29.6, 31.5, 59.4, 59.6, 61.6, 71.3, 73.0, 89.2, 159.7, 166.2, 169.3; IR (KBr): 1606,

1652, 1068,1151, 1245, 2870 cm-1; [α]20D = +2.83 (c 1.00, CHCl3); Anal. calcd. for

C14H25NO5: C, 58.52; H, 8.77; N, 4.87; Found: C, 58.29; H, 8.82; N, 4.59.


73

Preparation of 1-Ethoxymethyl-propylamine (61a)

H3C OH2N H

CH3


ethylenediamine (465 μL, 6.9 mmol). Conditions: room temperature, 1 h. The title

compound 61a (0.18 g, 90%) was obtained after purification through a short silica gel

column (Hexane:EtOAc = 3:7). The data of the compound 61a was in agreement with the


Preparation of 2-[(1-Carboxy-2-phenyl-ethylamino)-methylene]-malonic acid diethyl

ester (62a)

HN

COOH

O

OEt

O

OEt

To the solution of (L)-Phenylalanine (62, 0.500 g, 3.0 mmol) in ethanol (5 mL),

triethylamine (421 μL, 3.0 mmol), was added and stirred at room temperature for 10 min.

diethyl ethoxymethylenemalonate (611 μL, 3.0 mmol) was added and stirred for 30 min. at

room temperature, the reaction mixture was neutralized with acetic acid, water (5 mL) was

added and extracted with ethyl acetate (3 X 10 mL). The combined ethyl acetate layer was

dried (Na2SO4) and evaporated under reduced pressure. The title compound 62a was

obtained as a syrupy liquid (0.97 g, 96%). 1H NMR (400 MHz, CDCl3): δ 1.13-1-20 (m,

6H), 3.03-3.21 (m, 2H), 3.96-4.11 (m, 4H), 4.63-4.68 (m, 1H), 7.17-7.31 (m, 5H), 7.79 (d,

J = 14 Hz, 1H), 9.18 (dd, J1 = 8.8 Hz, J2 = 14.4 Hz, 1H); 13C NMR (100 MHz, DMSO-

D6): δ 14.2, 14.4, 14.5, 20.9,58.9, 59.1, 59.9, 61.5, 89.5, 127.0, 128.6, 129.6, 136.3, 158.9,

165.1, 167.9, 172.1; IR (KBr): 439, 487, 539, 588, 619, 663, 699, 725, 799, 855, 917,

1030, 1058, 1113, 1180, 1333, 1387, 1404, 1439, 1477, 1497, 1512, 1620, 1650, 1719,

2985, 3082 cm-1; [α]20D = -225.79 (c 1.00, CHCl3); Anal. calcd. for C17H21NO6: C, 60.89;

H, 6.31; N, 4.18; Found: C, 60.37; H, 6.12; N, 4.22.


74

Preparation of 2-[(1-Carboxy-3-methyl-butylamino)-methylene]-malonic acid diethyl

ester (63a)

HN

COOH

O

OEt

O

OEt

To the solution of (L)-Leucine (63, 0.500 g, 3.8 mmol) in ethanol (5 mL), triethylamine

(531 μL, 3.8 mmol) was added and stirred at room temperature for 10 min. diethyl

ethoxymethylenemalonate (770 μL, 3.8 mmol) was added and stirred for 30 min. at room

temperature. The reaction mixture was neutralized with acetic acid, water (5 mL) was

added and extracted with ethyl acetate (3 X 10 mL), the combined ethyl acetate layers was

dried (Na2SO4) and evaporated under reduced pressure. The title compound 63a was

obtained as a syrupy liquid with (1.09 g, 96%). 1H NMR (400 MHz, CDCl3): δ 0.96 (t, J =

7.2 Hz, 6H), 1.26-1.35 (m, 6H), 1.72- 1.79 (m, 2H), 4.0-4.27 (m, 5H), 7.97 (d, J = 14 Hz,

1H), 9.32 (dd, J1 = 8.8 Hz, J2 = 14.0 Hz,1H); 13C NMR (100 MHz, CDCl3): δ 14.2, 14.3,

21.4, 22.7, 24.4, 41.7, 60.4, 91.0, 159.0, 166.7, 168.9, 174.5, 174.5; IR (KBr): 441, 563,

737, 801, 1028, 1069, 1148, 1219, 1373, 1604, 1655, 1721, 2360, 2959 cm-1; [α]20D = -

33.28 (c 1.00, CHCl3); Anal. calcd. for C14H23NO6: C, 55.80; H, 7.69; N, 4.65; O, 31.86;

Found: C, 55.92; H, 7.74; N, 4.34.

Preparation of 2-[(1-Carboxy-3-methylsulfanyl-propylamino)-methylene]-malonic

acid diethyl ester (64a)

HN

COOH

O

OEt

O

OEt

S

64a

To the solution of (L)-Methionine (64, 0.500 g, 3.3 mmol) in ethanol (5 mL),

triethylamine (467 μL, 3.3 mmol), was added and stirred at room temperature for 10 min.

diethyl ethoxymethylenemalonate (677 μL, 3.3 mmol) was added and stirred for 30 min. at

room temperature. The reaction mixture was neutralized with acetic acid, water (5 mL)

was added and extracted with ethyl acetate (3 x 10 mL), the combined ethyl acetate layers

was dried (Na2SO4) and evaporated under reduced pressure. The title compound 64a was

obtained as a syrupy liquid (0.96 g, 96%). 1H NMR (400 MHz, CDCl3): δ 1.17-1.28 (m,


75

6H), 2.03 (s, 3H), 2.16-2.20 (m, 1H), 2.43-2.61 (s, 3H), 4.104.27 (m, 5H), 7.95 (d, J = 14

Hz, 1H) 9.30 (dd, J1 = 8.8 Hz, J2 = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 14.0,

14.1, 15.0, 29.5, 31.7, 59.6, 60.1, 91.2, 159.1, 166.6, 168.8, 173.6; IR (KBr): 1609, 1659,

1736, 2924, 2981, 3274, 3364, 3463 cm-1; [α]20D = -105.03 (c 1.00, CHCl3); Anal. calcd.

for C13H21NO6S: C, 48.89; H, 6.63; N, 4.39; S, 10.04; Found: C, 48.92; H, 6.90; N, 4.18;

S, 10.26.

Preparation of 2-[(1-Methoxycarbonyl-2-phenyl-ethylamino)-methylene]-malonic

acid diethyl ester (62b)

HN

COOCH3

O

OEt

O

OEt

To a solution of 62a (0.500 g, 1.4 mmol) in methanol (5 mL), thionyl chloride (135 μL,

1.8 mmol) was added, stirred for 30 min. at room temperature. Neutralized with 5%

aq.NaHCO3, extracted with ethyl acetate (3 X 10 mL). The combined organic layers were

dried (NaSO4) and evaporated under reduced pressure. The title compound 62b was

obtained (0.51 g, 98%) as a syrupy liquid. 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J = 7.2

Hz, 3H), 1.32 (t, J = 6.8 Hz, 3H), 3.00-3.25 (m, 2H), 3.76 (s, 3H), 4.08-4.26 (m, 5H),

7.12-7.32 (m, 5H), 7.63 (d, J = 13.6 Hz, 1H), 9.38 (dd, J1 = 9.2 Hz, J2 = 13.6 Hz, 1H); 13C

NMR (100 MHz, CDCl3): δ 14.0, 14.1, 14.2, 20.8, 39.9, 52.5, 59.7, 60.1, 63.0, 91.2,

127.3, 128.6, 129.2, 134.8, 158.0, 165.5, 168.4, 170.2, 170.9; IR (KBr): 1607, 1654, 1690,

1745, 2981, 3274 cm-1; [α]20D = -104.3 (c 1.00, CHCl3); Anal. calcd. for C18H23NO6: C,

61.88; H, 6.64; N, 4.01; Found: C, 61.59; H, 6.60; N, 4.12.

Preparation of 2-Amino-3-phenyl-propionic acid methyl ester (62c)

NH2

COOCH3



compound 62c (0.23 g, 90%) was obtained after purification through a short silica gel

column (Hexane:EtOAc = 4:6). The spectral data of the compound 62c is in agreement

with authentic sample available from commercial sources.


76

Preparation of 2-[(1-Methoxycarbonyl-3-methyl-butylamino)-methylene]-malonic

acid diethyl ester (63b)

HN

COOCH3

O

OEt

O

OEt

To a solution of 63a (0.500 g, 1.6 mmol) in methanol (5 mL), thionyl chloride (151 μL,

2.0 mmol) was added and stirred for 30 min. at room temperature. Neutralized with 5%

aq.NaHCO3, extracted with ethyl acetate (3 X 10 mL). The combined organic layer was

dried (Na2SO4) and evaporated under reduced pressure. The title compound 63b was

obtained (0.49 g, 95%) as a syrupy liquid. 1H NMR (400 MHz, CDCl3): δ 1.89 (t, J = 7.2

Hz, 6H), 1.25-1.36 (m, 6H), 1.65-1.75 (m, 3H), 3.77 (s, 3H), 3.99-4.05 (m, 1H), 4.16-4.28

(m, 4H), 7.93 (d, J = 14 Hz, 1H) 9.31 (dd, J1 = 9.6 Hz, J2 = 13.2 Hz, 1H); 13C NMR (100

MHz, CDCl3): δ 14.2, 14.2, 21.4, 22.6, 24.3, 41.9, 52.5, 59.6, 59.8, 60.3, 91.1, 158.4,

165.8, 168.7, 171.4; IR (KBr): 470, 551, 748, 800, 859, 914, 1029, 1067, 1148, 1217,

1318, 1375, 1431, 1604, 1645, 1686, 1743, 2957 cm-1; [α]20D = -23.44 (c 1.00, CHCl3);

Anal. calcd. for C15H25NO6: C, 57.13; H, 7.99; N, 4.44; Found: C, 57.23; H, 7.78; N, 4.52.

Preparation of 2-Amino-4-methyl-pentanoic acid methyl ester (63c)

NH2

COOCH3



compound 63c (0.20 g, 90%) was obtained after passing through a short silica gel column

(Hexane:EtOAc = 4:6). The spectral data of the compound 63c was in agreement with

authentic sample available from commercial sources.


77

Preparation of 2-[(1-Methoxycarbonyl-3-methylsulfanyl-propylamino)-methylene]-

malonic acid diethyl ester [64b]

HN

COOCH3

O

OEt

O

OEt

S

To the solution of 64a (0.500 g, 1.5 mmol) in methanol (5 mL), thionyl chloride (142 μL,

1.9 mmol) was added, stirred for 30 min. at room temperature. Neutralized with 5%

aq.NaHCO3, extracted with ethyl acetate (3 X 10 mL). The combined organic layers were

dried (Na2SO4) and evaporated under reduced pressure. The title compound 64b was

obtained (0.49 g, 95%) as a syrupy liquid. 1H NMR (400 MHz, CDCl3): δ 1.20-1.30 (m,

6H,), 2.03 (s, 3H), 2.10-2.18 (m, 1H), 2.40-2.59 (m, 2H), 3.72 (s, 3H), 4.09-4.22 (m, 4H),

7.90 (d, J = 13.6 Hz, 1H), 9.29 (dd, J1 = 10.0 Hz, J2 = 12.8 Hz, 1H); 13C NMR (100 MHz,

CDCl3): δ 14.2, 14.3, 15.2, 29.5, 32.1, 52.8, 59.8, 60.0, 60.0, 91.7, 158.6, 165.7, 168.8,

170.9; IR (KBr): 1607, 1656, 1689, 1743, 2931, 2981, 3274, 3369, 3463 cm-1; [α]20D = -

23.88 (c 1.00, CHCl3); Anal. calcd. for C14H23NO6S: C, 50.43; H, 6.95; N, 4.20; S, 9.62;

Found: C, 50.72; H, 6.65; N, 4.18; S, 9.46.

Preparation of 2-Amino-4-methylsulfanyl-butyric acid methyl ester (64c)

NH2

COOCH3S



compound 64c (0.22 g, 90%) was obtained after purification through a short silica gel

column (Hexane:EtOAc = 4:6). The spectral data of the compound 64c was in agreement

with authentic sample available from commercial sources.

Chapter II Reference

78

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