Synthesis of alkyl 2-(benzoylamino)-3- (4,5-dicyano-1 H -imidazol-1-yl)propenoates

A simple synthetic approach to imidazolyl-substituted unsaturated amino acid esters 2 starting from the diaminomaleonitrile derivative 5 is reported. This synthesis involves the formation of the imidazole ring with triethyl orthoformate followed by an oxazolone ring-opening reaction with alcohols


Introduction
Amino acids containing the imidazole moiety and their derivatives represent a well-known group of organic compounds.Beside L-histidine and its derivatives, several structurally related nonproteinogenic amino acids and their derivatives have been the subject of various investigations.Among them are (1H-imidazol-1-yl)-substituted amino acid derivatives.For example, 2-amino-3-(1H-imidazol-1-yl)propanoic acid and its derivatives have been prepared by the ring-opening reaction of serine β-lactone derivatives with 1-(trimethylsilyl)imidazole 1 or imidazole, 2 or by conjugate addition of imidazole to didehydroalanine derivatives, [3][4][5][6] and has been used in studies concerning the design of orally active renine inhibitors. 2 This amino acid has also been synthesized by the condensation of diethyl α-acetamido-α-(dimethylaminomethyl)malonate methiodide with sodium imidazole in liquid ammonia; and the biological activity concerning the ability to support the growth of a histidine-requiring bacterial mutant has been examined. 7-Amino-3-(4-carboxy-1H-imidazol-1-yl)propanoic acid prepared by the β-lactone route has been examined as an inhibitor of diaminopimelic acid dehydrogenase from Bacillus sphaericus and of diaminopimelic acid epimerase from Escherichia coli. 8(2,4-Dioxoimidazolidin-1yl)alanine derivatives have been formed via the corresponding ureidoalanine intermediate in the course of investigations of the synthesis of quisqualic acid analogues. 92-Amino-3-(1H-imidazol-1-yl)propanoic acid was found to be incorporated into theonellamide F, a bicyclic dodecapeptide isolated from a marine sponge of the genus Theonella, which exhibits antifungal and cytotoxic activities. 10Its derivatives were synthesized by the β-lactone route. 11Additionally, the syntheses of ethylene-bridged analogues of arginine have also been reported. 12n the other hand, relatively little is known about 1H-imidazol-1-yl substituted α,β-didehydroamino acid derivatives.][15] In the course of our investigations of the use of diaminomaleonitrile in heterocyclic synthesis we reported a new approach to 1,2,3-triazol-1-yl-substituted unsaturated amino acid derivatives. 16Attempts to prepare structurally similar imidazolyl amino esters 2 by treatment of propenoates 1 with triethyl orthoformate at reflux temperature failed, giving rise to highly functionalized imidazo[1,5-a]pyrazines 4, probably via intermediates 2 and 3 (Scheme 1). 17

Scheme 1
In order to study the mechanism of the above mentioned formation of 4 and to characterize the imidazole esters 2, we looked for an alternative method of their preparation.Accordingly, we report here an easy approach to imidazole esters 2 based on the oxazolone ring-opening of the bicyclic compound 6 (Scheme 2).

Results and Discussion
The reaction of the N-monosubstituted diaminomaleonitrile derivative 5 16 with hot triethyl orthoformate afforded 1-(4,5-dihydro-5-oxo-2-phenyl-1,3-oxazol-4-ylidenemethyl)-1H-imidazole-4,5dicarbonitrile 6.The subsequent careful treatment of this intermediate 6 with a series of alcohols (methyl, ethyl, propyl, isobutyl, and pentyl alcohol) resulted in the opening of the oxazolone ring affording the corresponding esters 2 in moderate yields.In order to avoid further cyclization of 2 to the imidazo[1,5-a]pyrazine system or other side reactions of the multifunctional products 2 and starting compound 6, all reactions were performed in the absence of acid or base catalyst.The structure of products 2 was established on the basis of NMR spectroscopy ( 1 H, 13 C, HMBC, HMQC), MS, IR data and elemental analysis.It is worth noting that imidazoles 2 are isomers of imidazo[1,5-a]pyrazines 3 and 4 with similar functionalities.The IR spectra of 2 show two absorption bands between 2220-2250 cm -1 clearly indicating the presence of two nitrile groups in contrast to the isomeric imidazopyrazines 3 and 4 with only one nitrile group.Differences are also evident in the 1 H NMR spectra of isomers 2 and 4: While imidazopyrazines 4 exhibit two sets of signals of two tautomeric forms (Scheme 1), 17 imidazoles 2 show only one set.HMBC and HMQC spectra were used for the partial assignment of 13 C signals of 2e.The HMBC spectrum of 2e shows strong correlations between the NH proton and the carbonyl carbon atoms of both the benzoyl and ester groups.The Z configuration of the olefinic bond of.compounds 2 was established by the magnitude of the long-range heteronuclear coupling constant between the carbonyl carbon atom and the 3-H proton of 2a ( 3 J C-H = 4.0 Hz) measured from the antiphase splitting of cross peaks in the HMBC spectra.A similar value was found in the diaminomaleonitrile derivative 1 (R = propyl) ( 3 J C-H = 3.0 Hz). 18][21] In conclusion, we elaborated an easy procedure for the preparation of alkyl 2-(benzoylamino)-3-(4,5-dicyano-1H-imidazol-1-yl)propenoates 2. These products can be transformed into the imidazo[1,5-a]pyrazines 4, 22 and are therefore probable intermediates in the one-pot transformation of 1 into 4.They may be useful starting compounds for the preparation of new histidine analogues.

Experimental Section
General Procedures.Melting points were determined on a Kofler micro hot stage apparatus.IR spectra were recorded with a Perkin-Elmer 1310 or 727 B spectrophotometer.NMR spectra were recorded with a Bruker AVANCE DPX-300 spectrometer (300 MHz for 1 H and 75.5 MHz for

ISSN 1424-6376
Page 99 © ARKAT USA, Inc 13 C) in DMSO-d 6 with TMS as an internal standard; coupling constants (J) are given in Hz.MS spectra were obtained from a VG-Analytical AutoSpec Q instrument (70 eV).Elemental analyses were performed on a Perkin-Elmer CHN Analyzer 2400.Compound 5 was prepared as described in the literature. 16All other compounds were used without purification as obtained from commercial sources.