Heteroatom ChemistryVolume 19, Number 7, 2008

Synthesis and Characterization of Novel(9H-Fluoren-9-ylamino)Carbonylaminomethylphosphonic AcidPetar Todorov,1 Emilia Naydenova,1 Julita Popova,1 and Kolio Troev2

1University of Chemical Technology and Metallurgy, Department of Organic Chemistry,Sofia 1756, Bulgaria

2Institute of Polymers, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria

Received 22 February 2008; revised 7 May 2008

ABSTRACT: The new α-aminophosphonic acidsare synthesized, reacting (9H-fluoren-9-yl)urea withformaldehyde and phosphorus trichloride. (9H-Fluoren-9-yl)urea was prepared from spiro(fluoren-9,4′-imidazolidine)-2′,5′-dione by alkaline hydrolysiswith Ba(OH)2. The structure of the title compoundswas proved by means of IR, 1H, 13C, and 31PNMR spectroscopy. C© 2008 Wiley Periodicals, Inc. Het-eroatom Chem 19:719–722, 2008; Published online inWiley InterScience (www.interscience.wiley.com). DOI10.1002/hc.20500

INTRODUCTION

The discovery of aminophosphonates in living sys-tems stimulated the interest in this group of com-pounds, and the intensive research directed towardsynthesis of α-aminophosphonic acid analogues ofprotein and nonprotein amino acids resulted in anew class of drugs and other bioactive compoundswith a great variety of commercial applications rang-ing from agriculture to medicine. Thus, this class ofcompounds includes promising anticancer agents,strong neuromodulators, plant growth regulatorsand herbicides, antibacterial, metal-sequestering

Correspondence to: Kolio Troev; e-mail: ktroev@polymer.bas.bg.Contract grant sponsor: Ministry of Education and Science,

Bulgaria.Contract grant number: BYX-15.

c© 2008 Wiley Periodicals, Inc.

drugs, radiopharmaceuticals, and NMR imagingagents [1–7]. Several reviews have been devotedto the synthesis of aminoalkanephosphonic acids.However, most of the described methods for the syn-thesis of α-aminophosphonic acids used carbonylcompounds, such as aldehydes, ketones, or car-boxylic acids, as starting compounds [8–12]. Tak-ing into account the fact that the spirohydantoincompounds with a substituted and unsubstanti-ated fluorene ring, which are useful in the treat-ment of complication arising from diabetes mellitussuch as cataracts and neuropathy [13], we synthe-sized a new (9H-fluoren-9-yl-amino)carbonylaminomethylphosphonic acid. Further studies for the bio-logical activity of new α-aminophosphonic acid arein progress.

RESULTS AND DISCUSSION

This article is a continuation of our study onthe synthesis of α-aminophosphonic acids [14–16]. Herein, we describe the synthesis of novel α-aminophosphonic acids (3), reacting phosphorustrichloride with formaldehyde and (9H-fluoren-9-yl)urea (2).

In the present studies we modified the procedureof Engelmann and Pikl [12] by replacing the oxazo-lidinone derivatives with (9H-Fluoren-9-yl)urea. Weoptimized the amount of solvent and reaction timepurposely to increase the yield, and the purity of thecompound 3.

719

720 Todorov et al.

HN

NHO

O

HN C NH

O

CH2 P

O

OH

OHNHCNH

O

CH2P

O

H3CO

H3CO

HCHO + PCl3 + CH3COOH HCHO + CH3OH + (C2H5)3N

+ (CH3O)2P(O)H

Ba(OH)2. 8H2O

1

43

HN C NH2

O2

SCHEME 1 Synthesis of (9H-fluoren-9-yl-amino)carbonylaminomethylphosphonic acid (3).

(9H-Fluoren-9-yl)urea (2) was prepared fol-lowing the procedure, which involves the forma-tion of spiro(fluoren-9,4′-imidazolidine)-2′,5′-dione(1) from fluorenone by the Bucherer–Lieb reaction,followed by alkaline hydrolysis of compound 1. Thesynthetic route is shown in Scheme 1.

It was accepted [17] that the alkaline hydrol-ysis of spiro(fluoren-9,4′-imidazolidine)-2′,5′-dione(1) with Ba(OH)2 at 165◦C furnished 9-amino-9-fluorencarboxylic acid. The NMR data of the reac-tion product revealed that alkaline hydrolysis of 1resulted in the good yield of (9H-fluoren-9-yl)urea(2) (see Scheme 1).

In the 13C{1H} and DEPT-135 NMR spectra ofthe reaction product, the singlet at 55.00 ppm can beassigned to the C-atom from the CH-group becausein the DEPT spectrum this signal is positive. Thesinglet at 158.80 ppm can be assigned to the C-atomfrom NH C(O) NH2-group, not to C-atom from theCOOH-group. These data confirm the formation ofcompound 2.

We tried to synthesize the correspondingaminophosphonic acid (4) using Kabachnik-Fieldsreaction conditions. Our attempts failed.

We decided to use Engelmann and Pikl’s proce-dure to synthesize (9H-fluoren-9-yl-amino)carbon-ylaminomethylphosphonic acid (3) (see Scheme 1).The initial step of the interaction between (9H-fluoren-9-yl)urea (2) and formaldehyde involves theformation of hydroxymethyl-(9H-fluoren-9-yl)urea

(5) that further reacts with phosphorus trichlo-ride to yield phosphite ester (6). The rearrange-ment of 6 to phosphonyl chloride (8) and the sub-sequence hydrolysis resulted in (9H-fluoren-9-yl-amino)carbonyl aminomethylphosphonic acid (3)(see Scheme 2).

In the 1H NMR spectrum of the reaction prod-uct, the doublet at 3.6 ppm with 2 JP−H = 12.0 Hz canbe assigned to the P-CH2 protons. The doublet inthe 13C{H} NMR spectrum at 58.10 ppm with 1 JP,H

= 154.5 Hz has to be assigned to the P-CH2 carbonatom. The signal in the 31P{1H} NMR spectrum at20.45 ppm, which represents a triplet with 2 JP−H =14.0 Hz, is a characteristic for the phosphorus atomin α-aminophosphonic acids. The spectral data in-cluding elemental analysis are reported in the exper-imental section.

Novel (9H-fluoren-9-yl-amino)carbonylamino-methylphosphonic acid has been successfully syn-thesized using Engelmann and Pikl’s procedure.(9H-Fluoren-9-yl)urea was synthesized via alka-line hydrolysis with Ba(OH)2 of spiro(fluoren-9,4′-imidazolidine)-2′,5′-dione.

EXPERIMENTAL

Instruments and Reagents

Fluorenone, phosphorus trichloride, paraformalde-hyde, and solvents were purchased from Fluka andSigma-Aldrich (Taufkirchen, Germany) and Merck

Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Characterization of Novel (9H-Fluoren-9-ylamino) Carbonylaminomethylphosphonic Acid 721

HCl

POCl2

HN C NH

O

CH2 OH

HN C NH

O

CH2

HN C NH

O

CH2 O P

Cl

Cl

HN C NH

O

CH2 PCl

OCl

5 6

8 7

PCl3

SCHEME 2 Mechanism of the reaction.

(Whitehouse Station, NJ) and were used without fur-ther purification.

The infrared (IR) spectra in KBr were recordedon a Perkin–Elmer model 1600 series FTIR instru-ment. The purity of the products was checked byTLC on precoated plates of Silica gel 60 F254 (Merck),using a mobile phase n-BuOH:AcOH:H2O, 3:1:1.Spots on TLS chromatograms were detected by thechlorine/o-tolidine reaction. The microanalyses wereperformed on Perkin–Elmer elemental analyzer. The1H, 13C, and 31P NMR spectra were determined bymeans of a Bruker DRX 400 spectrometer and ref-erenced to the solvent. 13C NMR spectra were fullydecoupled. Chemical shifts are reported in δ values(ppm), and J values are reported in hertz (Hz). Thelow-resolution mass spectra were determined on aHewlett Packard BCD Plus GC-MS system.

Synthesis of Spiro(fluoren-9,4′-imidazolidine)-2′,5′-dione (1) by the Bucherer–Lieb Synthesis

Fluorenone (10.00 g, 0.0554 mol), potassium cyanide(5.40 g, 0.0829 mol), ammonium carbonate (16.00g, 0.1666 mol), ammonium hydroxide (88 mL), andethanol (84 mL) were added in a 1-L stainless steelreaction vessel. The reaction mixture was stirred at125–130◦C for 3.30 h. Then, the reaction mixture wascooled to room temperature and filtered and dilutedwith water 195.00 mL. The cooled mixture was acid-ified with concentrated hydrochloric acid 6 N HCI(pH 2). The crude material was several times recrys-tallized from 96% ethanol.

60.52% (8.40 g) yield; R f = 0.83; mp >300◦C[lit. [18], 324–325◦C]. IR (KBr, cm−1): 3241 (3N H),3049 (1N H), 1776 (2C O), 1704 (4C O), 1475 (NH).1H NMR (400.13 MHz, DMSO), δ (ppm): 7.41–7.97(m, 8H, CH), 8.82 (1H, s) 1NH, 11.31 (1H, s) 3NH.13C{1H} NMR (100.62 MHz, DMSO), δ (ppm): 72.80( C ), 121.00 2,7C, 123.80 1,8C, 128.60 4,5C, 130.203,6C, 141.00 ( C ), 143.20 ( C ), 158.10 (2C O),174.50 (4C O). DEPT-135 (DMSO), δ (ppm): 121.00,124.00, 128.80, 130.30.

Synthesis of (9H-Fluoren-9-yl) Urea (2)

Three grams (0.0119 mol) of Spiro[fluoren-9,4′-imidazolidine]-2′,5′-dione, 5.10-g Ba(OH)2 and 90.00mL H2O were added in a 1-L stainless steel reactionvessel. The reaction mixture was stirred at 165◦Cfor 2 h. Then, the reaction mixture was cooled toroom temperature and filtered and then diluted withhot methanol. Insoluble BaCO3 was removed, andthe products were isolated from the methanol so-lution. The crude material was recrystallized from96% ethanol.

65.00% (1.75 g) yield; R f = 0.36; mp >300◦C.IR (KBr, cm−1): 3481, 3309 (NH), 1650 (C O), 1564(amide II, NH C O). 1H NMR (DMSO), δ (ppm):5.65 (2H, s, NH2), 5.80 (1H, d, NH), 6.52 (1H, d,NH),7.31–7.84 (m, 8H, CH). 13C{1H} NMR (DMSO), δ

(ppm): 54.60 ( 9C ), 119.60 2,7C, 124.40 1,8C, 127.104,5C, 127.80 3,6C, 139.30 ( C ), 145.40 ( C ), 158.80(C O). DEPT-135 (DMSO), δ (ppm): 55.00, 119.70,124.50, 127.10, 127.80.

Heteroatom Chemistry DOI 10.1002/hc

722 Todorov et al.

Synthesis of (9H-Fluoren-9-yl-amino)-Carbonylaminomethylphosphonic Acid (3)

Some amount (0.72 g; 0.0032 mol) of (9H-Fluoren-9-yl)urea and 0.0964 g (0.0032 mol) of paraformalde-hyde were added in a four-necked round-bottomedflask equipped with a magnetic stirrer, reflux con-denser, thermometer, dropping funnel, and argoninert. At vigorous stirring glacial acetic acid of 7 mLwas added dropwise. A white suspension formed.The reaction mixture was refluxed (approximately118◦C) for 2.5 h, after which it became a clear solu-tion. Then the temperature was lowered to 20◦C and0.28 mL (0.0032 mol, 0.44 g) phosphorus trichlo-ride was added dropwise. During and after the addi-tion, hydrogen chloride evolved. The reaction mix-ture was refluxed (approximately 118◦C). After 3.5 hrefluxing, 2.00 mL water (distilled) was added. Af-ter 3 h refluxing, the reaction mixture was concen-trated under reduced pressure. The crude mixturewas purified by the crystallization from the mixtureof methanol/ethyl acetate.

53.70% (0,65 g) yield; R f = 0.25; mp >300◦C. IR(KBr, cm−1): 3441, (NH), 1648 (C O), 1564 (amideII, NH C O), 1193 (P O). 1H NMR (D2O), δ (ppm):3.60 (d, 2H, 2 JP−H = 12.0 Hz, P-CH2), 7.44–7.90 (m,8H, CH). 13C{1H}NMR (D2O), δ (ppm): 55.30 ( 9C ),58.10 (d, 1 JP−C = 154.50 Hz, P-CH2) 118.60 2,7C,122.20 1,8C, 126.20 4,5C, 127.30 3,6C, 140.10 ( C ),144.80 ( C ), 157.90 (C O). 31P{1H}NMR (D2O), δ

(ppm): 20.45 (t, 2 JP−H = 14.0 Hz). Anal. Calcd forC15H15N2O4P (318.26): C, 56.61; H, 4.75; N, 8.80; P,9.73; found: C, 56.80; H, 4.25; N, 8.46; P, 9.22.

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Heteroatom Chemistry DOI 10.1002/hc