A facile one-pot method for preparation of succinic esters containing several functional groups

Hydrazine derivatives undergo reactions with acetylenic esters in the presence of triphenylphosphine yielding multiple functionalized succinic ester derivatives in good to excellent yields.


Introduction
The synthesis and chemistry of hydrazine derivatives have been attracted considerable attention due to their pharmaceutical and biological properties 1 .These compounds are an interesting class of materials that have been used as building blocks in heterocyclic systems containing N-N bonds 2 and azapeptides 3 .Some hydrazines such as phthalazin-1-yl-hydrazine were widely used as a general antihypertensive, and vasodilator agents, some years ago and at the present time as a first-line drug in the management of pregnancy-induced hypertension 4,5 .On the other hand, most of the hydrazines are endothermic systems and they are known to decompose easily in the presence of reactive intermediate such as free radicals which were commonly used as rocket fuels 6,7 .
In resent years, the synthesis of hydrazines connected to phosphorus atom has drawn much more attention.A series of these compounds have been reported in the literature which were obtained from multi-step procedures 8,9 .Since the synthetic application of the compounds has increased enormously in medicinal chemistry we now wish to report a one-step method for the synthesis of succinic esters containing hydrazine group along with other functional groups by reaction of dialkyl acetylenedicarboxylate with hydrazine derivatives in the presence of a desired phosphine such as triphenylphosphine as a good nucleophile.
The results presented here are based on the proposed sequence below (Scheme1).It is known that the reaction of acetylenic esters and Ph 3 P produces the carbene-ylide intermediate 2 which is sufficiently stabilized by resonance 10,11 .Thus, compounds 4a-d are apparently obtained from the initial addition of triphenylphosphine as a good nucleophile [12][13][14][15][16] to acetylenic esters as a Michael acceptor 17 and concomitant protonation of the carbene-ylide intermediate 2 by the NHacid.Then positively charged ion is attacked by the nitrogen of the conjugated base of the NHacid or NH 2 group to form succinic esters containing several functional groups 4. It should be noted that in the final step of the reaction of compound 3b with positive charge, the NH 2 group act as a stronger nucleophile than the conjugated base of the amide group.
The structures of compounds 4a-d were characterized on the basis of their elemental analyses and their IR, mass, high-field 1 H NMR and 13 C NMR spectra.The nature of these compounds as 1:1:1 adducts were apparent from the corresponding mass spectra, which displayed fairly weak molecular ion peaks at m/z 520, 548, 478 and 506 for succinic esters derivatives 4a-d, respectively.The initial fragmentation involves the loss of the PPh 3 and ester moieties.The 1 H NMR and 13 C NMR spectral data of new succinic esters 4a-d exhibited a mixture of two conformational isomers.The ylide moiety of these compounds is strongly conjugated with the adjacent carbonyl group and rotation about the partial double bond in 4-(E), 4-(Z) geometrical isomer is low on the NMR time scale at ambient temperature (Scheme 1).Conformational isomers in phosphoranes have been previously established and reported in the literature [18][19][20] .
The 1 H NMR spectra of 4a showed four sharp signals due to methyl protons of acetyl groups at δ= 1.95, 1.97, 2.00 and 2.04 ppm along with four sharp lines at δ= 3.18, 3.55, 3.72 and 3.78 ppm arising from methoxy protons.Methine protons appeared as two doublet peaks at δ= 5.09 and 5.13 ppm respectively for the Z and E geometrical isomrs and a fairly broad signals at δ= 8.19 ppm, for the NH proton.The aromatic protons appeared as a multiplet at d = 7.47-7.73ppm.The 13 C NMR spectrum of 4a displayed twenty four distinct resonances in agreement with the mixture of two conformational isomers.Although the presence of the 31 P nucleus has complicated both the 1 H and 13 C NMR spectra of 4a, it helps in assignment of signals by longrange spin-spin couplings with 1 H and 13

Scheme 1
The 1 H and 13 C NMR spectra of compound 4b are similar to those of 4a, except for the signals from the ester group, which appear as characteristic resonance lines with the corresponding chemical shifts.The 1 H and 13 C NMR spectroscopic data for compounds 4c-d are also consistent with the proposed structures.The structural assignments made for succinic esters derivatives 4a-d on the basis of the 1 H and 13 C NMR spectra were supported by their IR spectra.In the IR spectra of 4a-b an absorption band at 3354 cm -1 were detected, due to the NH group.The IR spectra of compounds 4c-d are similar to those of compounds 4a-b, except for the new absorption band from the other NH group, which appears at 3304 cm -1 .The carbonyl region of the spectra exhibited absorption bands for each compound.Of special interest is the ester absorption at 1765-1617 cm -1 for these compounds.Conjugation with negative charge accounts for the reduction of the wave numbers of the carbonyl absorption bands.