An efficient synthesis of γ-imino-and γ-amino-β-enamino esters

Condensation of ethyl 3-azido-4-oxopentanoate, easily accessible from ethyl 3-chloro-4oxopentanoate, with primary amines was found to produce ethyl 4-imino-3-amino-2-pentenoates. In addition, ethyl 4-imino-3-amino-2-pentenoates were reduced chemoselectively to the corresponding ethyl 4-alkylamino-3-amino-2-pentenoates upon hydrogenation.


Introduction
β-Enamino esters are important building blocks in organic synthesis because they offer easy access to biologically active compounds such as β-amino acids 1 and heterocycles. 2However, βenamino esters with an imino functionality in γ-position (1) are virtually unknown, 3 but may be important synthons for the preparation of biologically active acyclic and heterocyclic compounds, since they contain both the functionalized enamino ester moiety and the 1-aza-1,3butadiene skeleton. 4Furthermore, the corresponding reduced γ-amino-β-enamino esters (2) have already proven to be useful in the synthesis of statine analogues as residues in renin inhibitors, 5 and the Bohlmann-Ratz synthesis of pyridine derivatives, as part of the renin inhibitor cyclothiazomycin, 6 with intracellular calcium ion concentration reducing effect, 7 or for use in library synthesis. 8For these reasons, we wish to report our results on the synthesis of γ-imino-βenamino esters through condensation of primary alkylamines with 3-azido-4-oxopentanoate and the subsequent reduction to the corresponding γ-amino-β-enamino esters.
The required ethyl 3-azido-4-oxopentanoate 5 has already been reported in the literature.A first method involves nucleophilic substitution of ethyl 3-bromo-4-oxopentanoate with azide in acetone in the presence of triethylamine. 9The β-azido ester 5, however, could only be isolated if the time of heating was limited, since prolonged heating resulted in elimination of molecular nitrogen giving ethyl 3-amino-4-oxo-2-pentenoate 3. A more efficient method involves substitution of ethyl 3-[(4-nitrophenyl)sulfonyloxy]-4-oxopentanoate with azide under mild reaction conditions. 10Ethyl 3-azido-4-oxopentanoate 5 was however also easily prepared from reaction of readily available ethyl 3-chloro-4-oxopentanoate 4, 11 with excess sodium azide in acetone under reflux (Scheme 1).The reaction was complete after reflux overnight with four equivalents of sodium azide and the only detectable side-product (<5%) was ethyl 4-oxo-2pentenoate 6 resulting from elimination of hydrogen chloride.

Scheme 1
From earlier research, 12 it is known that condensation of unfunctionalized α-azido ketones with primary amines produces mixtures of α-diimines and α-azido ketimines, depending on the reaction conditions and the steric hindrance in the substrate.However, in contrast to these results, reaction of ethyl 3-azido-4-oxopentanoate 5 with primary amines in the presence of titanium(IV) chloride 13 overnight at reflux temperature afforded the 4-alkylimino-3-amino-2pentenoates 7a-c, as single stereoisomers of undefined E/Z stereochemistry, in 55-84% yield (Scheme 2).These results show the great influence of the additional ester function in β-position of the α-azido ketone 5 in the course of the reaction.From a mechanistic point of view, it is assumed that the intermediate α-azido imine 8, which is in tautomeric equilibrium with the enamine 9, generates the α-diimine 11 with elimination of molecular nitrogen (Scheme 3).Besides the already mentioned report on the synthesis of ethyl 3-amino-4-oxo-2-pentenoate from ethyl 3-azido-4-oxopentanoate 5, 9 some other transformations of α-azido ketones under basic, 14 acidic 15 or thermolytic 16 conditions to α-imino ketones or α-enamino ketones have been described.Finally, the unstable NH-imine 11 is stabilized by tautomerization to the stable 4alkylimino-3-amino-2-pentenoates 7, and no further transimination occurs by condensation with an excess of the primary amine.

Scheme 4
Although unsatisfactorily, the use of the 4-alkylamino-3-amino-2-pentenoates 12 in heterocyclic synthesis was demonstrated by transformation of γ-amino-β-enamino ester 12a into the cyclic urea derivative 13 containing an ethoxycarbonylmethylene chain.The synthesis of related imidazolidin-2-ones with a 4-(alkoxycarbonyl)methylene substitution is only scarcely reported in literature.One report involved palladium-catalyzed oxidative cyclizationalkoxycarbonylation of acetylenic ureas. 17A second example consisted of the cyclization reaction of a cyclic β-enamino ester with an amino function in γ-position to the imidazolidin-2one upon reaction with trifosgene. 18Related to the latter report, cyclization of diamino ester 12a was attempted with different cyclization reagents, such as dimethyl-or diethylcarbonate, ethyl chloroformate, difosgene, urea and thiourea, under different conditions of temperature and solvent.The best result, with disappointingly low reproducibility and low yield, was obtained upon use of urea in toluene under reflux conditions (Scheme 5), while the other conditions gave either no reaction or complex reaction mixtures.

Scheme 5
In conclusion, the present disclosure describes a convenient entry to γ-imino-and γ-aminoβ-enamino esters 7a-c and 12a-c by condensation of ethyl 3-azido-4-oxopentanoate 5 with primary amines and further reduction by heterogeneous hydrogenation.These functionalized β-ARKAT enamino esters 7 and 12 may be important synthons in organic synthesis for the preparation of biologically active compounds such as β-and/or γ-amino acids and heterocycles.

Experimental Section
General Procedures.NMR spectra were recorded on a Jeol JNM-EX 270 NMR spectrometer (270 MHz for 1 H NMR, 68 MHz for 13 C NMR).IR spectra were obtained using a Perkin Elmer Spectrum One FT-spectrophotometer. Mass spectra were recorded on a Varian MAT 112 mass spectrometer (EI 70 eV) or on an Agilent 1100 series VL mass spectrometer (ES 70 eV).Flash chromatography was performed with ACROS silica gel (particle size 0.035-0.070mm, pore diameter ca.6 nm) using a glass column.Diethyl ether was dried and distilled from sodium wire.CAUTION: use safety screens for all reactions with sodium azide or organic azides.