Studies with enamines: Functionally substituted enamines as aldehyde equivalents in Gewald reactions

Several aryl and functionally substituted enamines reacted with ethyl cyanoacetate and elemental sulfur to form 2-aminothiophene-3-carboxylic acid derivatives that proved to be excellent precursors for a variety of thiophenes.


Introduction
][10][11] In the context of our interest in aminothiophenes as precursors to arylazo dyes 12,13 we became interested in 2-amino-4unsubstituted thiophenes with a functional substituent at C-5.

Results and Discussion
The logical starting materials for such thiophenes would be β-functional aldehydes 1, active methylene nitriles 2 and elemental sulfur (cf.equation 1).However as β-functionalized aldehydes are rather unstable compounds therefore, we considered the possible use of functionally substituted enamines as their synthetic equivalents.7][18][19][20] We noted that only a few examples of the use of enamines 3a as precursors to aminothiophenes have been reported. 9,21O elemental Sulphur

Equation 1
We envisioned that the initial step in this sequence would be the addition of an active methylenenitrile to the α,β-unsubstituted moiety in 3 with subsequent elimination of diethylamine to yield 4A or 4B.Alternatively, reaction of adduct 7 with sulfur in the presence of an equivalent amount of piperidine would yield 8 that would cyclise and aromatize to yield 6. This sequence is quite similar to the reported general mechanism of the Gewald reaction. 9In support of this we noted the elimination of H 2 S during the reaction.In either case, the activity of methylene moiety in either 4 or 7 is essential for the success of reaction.Consequently we selected enamines 3b-f with electron attracting substituents to fulfill this prerequisite.We found that, 3b-e reacted smoothly with elemental sulfur and ethyl cyanoacetate in the presence of equivalent amounts of piperidine (cf.Experimental Section) to yield amino thiophenes 6b-e, 6b in 70%, 6c, 73%, 6d, 76% and 6e, 79% yields.Treating 3f similarly with sulfur and ethyl cyanoacetate resulted in the formation of 2-aminothiophene-5-thiocarboxamide 6g in 60% yield.We believe that initially 6f is formed and this reacted further with the hydrogen sulfide produced during the reaction to yield the thioamide 6g (cf.Scheme 1).Attempts to replace ethyl cyanoacetate by malononitrile failed in our hands to yield pure isolable products.An oily mixture of several products was produced with this reactant.Structures 6, taking 6c as a typical example, are supported by spectral and analytical evidence.Thus the MS of the typical example showed an M + peak at 309 (100), two intess peaks at 263 (100) (M + -OC 2 H 5 ), and 139 (100) (Pchlorobenzoyl cation).Its 13 C NMR spectrum showed two signal for sp 3

Scheme 1
The 2-aminothiophene-5-carboxylic acid esters 6b-g proved to be excellent precursors for the synthesis of arylazothiophenes as well as thieno [2,3-d]pyrimidines.Thus diazotizing 6b,e in the presence of hydrochloric acid in acetic acid solution afforded diazonium salts that readily coupled with malononitrile to yield a thienylhydrazonomesoxalonitriles 9b,e.Reacting 9b with hydrazine hydrate gave the 3,5-diaminopyrazoles 10b.Arylazopyrazol-3,5-diamines prepared long ago 22 in our laboratories have recently been shown to have interesting antiprofilerative 23 activity and were also patented for possible utility as oxidative dyes for keratin fiber and for hair. 24Thienylpyrazole-3,5-diamines merit testing in both these areas and this will be carried out.Aminothiophenes 6b also condensed with dimethylformamide dimethylacetal to yield amidines 11b that reacted in turn with acetic acid and ammonium acetate to yield a 1:1 mixture of thienopyrimidine 12b and acetylaminothiophene 13b.The latter could also be obtained via acylation of 6b with acetic anhydride (cf.Scheme 2).

Conclusions
In conclusion we have shown that functionally substituted enamines are excellent precursors for the synthesis of 2-amino-5-functionally-substituted thiophene carboxylic acid esters that can be readily used as precursors to potentially interesting thiophenes.

Experimental Section
General Procedures.All melting points are uncorrected and were determined with a Sanyo (Gallaenkamp) instrument.Infrared spectra were recorded in KBr and were determined on a Perkin-Elmer 2000 FT-IR system.

General procedure to synthesis compounds 6b-e
A mixture of 3b (1.75 g, 0.010 mol), ethyl cyanoacetate (1.13 g, 0.010 mol) and elemental sulfur (0.32 g, 0.010 mol) in dry N,N-dimethylformamide as solvent (10 mL) was treated with an of equivalent amounts of piperidine (2 mL).The reaction mixture was refluxed for 6-8 h, cooled and then poured onto ice-water.The residue, so formed, was extracted by dichloromethane.The organic layer was dried and the solvent was evaporated.The residue was purified through coloumn chromatography on silica gel using a mixture of petroleum ether (60-80) and ethyl acetate (3 : 1) as an eluent.

General procedures for preparation of compounds 9b,e
A solution of 6b or 6e (0.010 mol) in acetic acid (8 mL), was treated with concentrated hydrochloric acid (3 mL) and sodium nitrite (0.69 g, 0.010 mol) at 0 °C, This mixture was added gradually with stirring, to a cooled solution of malononitrile (0.66 g, 0.010 mol) in ethanol (10 mL) and sodium acetate (1.0 g).After complete addition, the reaction mixture was kept at room temperature for one hour.The solid product, so formed, was collected by filtration.

General procedures for preparation of compounds 12b, 13b
A mixture of compound 11b (3.30 g, 0.010 mol), ammonium acetate (2.30 g, 0.03 mol) and acetic acid (7 mL) was refluxed for 4-6 h (monitored by TLC).The reaction mixture was cooled and poured onto ice-water.The solid product, so formed, was collected by filtration and washed with petroleum ether to extract the yellow product 12.The residue was crystallized from ethyl acetate to yield white product 11.
13 NMR and13C NMR spectra were determined on a Bruker DPX at (400 MHz for 1 H NMR and 100 MHz for13C NMR) spectrometer in CDCl 3 or DMSO-d 6 as solvent and TMS as internal standard; chemical shifts are reported in δ (ppm).Mass spectra were measured on VG Autospec Q MS 30 and MS 9 (AEI) spectrometers, with EI 70 EV.Elemental analyses were measured by means of LEOCHNS-932 Elemental Analyzer.