Polyfunctional heteroaromatics: a route to dicyanomethylene thiazoles based on the reaction of α-thiocyanatoketones with malononitrile

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Introduction
][3][4] Recent developments in this area have been reviewed by one of us. 5 The results of earlier efforts have shown that condensation reactions of N-aryl-α-hydrazonoketones 1 with active methylene nitriles can be employed to prepare N-arylsubstituted-pyridazinones and pyridazine-6-imines. [6][7][8] It is assumed that the pathway for this process involves initial condensation of the αhydrazonoketones with the active methylene substances to yield conjugated hydrazone-esters 2 that readily cyclize to produce 3.In contrast, Abdelrazek and Fadda reported that the S-cyanothio unsaturated bis-nitrile 4 undergoes coupling with aromatic diazonium salts to yield the diazo compounds 5, which are reported to be stable substances (Scheme 1). 9 We have already noted that this observation should be reevaluated since, if correct, it would represent the only reported example of an acyclic diazo compound of this type. 5 CN

Scheme 1
Herein, we describe the results of an investigation of this process and, which has led to a reassignment of the structure of 5 to that of the thiazolidine derivatives 7a-c.The recognition of the revised structures led to further work that culminated in the synthesis of a variety of novel condensed thiazolylpyrazolo [1,5-a]pyrimidines that are structurally related to zaleplone.Initially, we explored the report by Abdelrazek et al, 9 which suggested that the S-cyanothio unsaturated bis-nitrile 4 is obtained via condensation reaction of α-thiocyanatoketones 6a with malononitrile in presence of piperidine.Indeed, we observed that this reaction affords a product with the same molecular formula of 5, reported by the authors, 9 However, careful analysis of spectroscopic data indicated that the product of this process has the thiazolidine strucure 7a.For example, the 1 H and 13 C NMR spectra of the product contain no resonances that correspond to protons linked to sp 3 hybridized carbons or sp 3 carbons.The obtained data matched to those expected for the thiazolidine structure 7a.In addition, we observed that reactions of the α-Scyanothioketones 6b,c with malononitrile afforded dicyanomethylene thiazolidines, whose spectroscopic properties matched those of 7b,c (cf.Scheme 2).In further exploratory studies, we observed that 7a-c react with benzenediazonium chloride to generate the diazo compounds 8a-c and that 8a can be transformed to the diaminopyrazoles 10 by reaction with hydrazine hydrate.The pyrazolo-thiazolidines, related to 10, were also produced by direct reactions of 7a-c with hydrazine hydrate and subsequent coupling of the diaminopyrazolyl thiazole products 9a-c with benzenediazonium chloride (cf.Scheme 3).In addition, we found that reaction of 8c with DMF/DMA at reflux for 14 h afforded the thiazolo [5,4-c]pyridazine 12 in 80% yield.This process is assumed to follow a route in which 8c was initially converted to the enamine derivative 11 that then underwent sequential electrocyclization and dimethylamine elimination to form 12 (cf.Scheme 4).Furthermore, diaminopyrazolylthiazoles 9c participate in an efficient condensation reaction with enaminone 13 to yield thiazolylpyrazolo[1,5-a]pyrimidines 14.X-ray crystallographic analysis of this product showed unambiguously that it has the structure 14 (Figure 1) rather than that of the regioisomer 15 (Scheme 5). 11It is important to note that 14 exists in a planar conformation, which suggests that the amino group is hydrogen bonded to thiazole ring nitrogen.

Conclusions
In conclusion, the results of this effort have led to the revised assignment of the thiazolidine structures for 7a-c and a demonstration that these substances serve as versatile precursors to uniquely substituted pyrazolo [1,5-a]pyrimidines and thiazolylpyrazolo[1,5-a]pyrimidines.

Experimental Section
General.Melting points are reported uncorrected and were determined with a Sanyo (Gallaenkamp) instrument.Infrared spectra were recorded using KBr pellets and a Perkin-Elmer 2000 FT-IR instrument. 1 H and 13 C NMR spectra were determined by using a Bruker DPX instrument at 400 MHz for 1 H NMR and 100 MHz for 13 C NMR and either CDCl3 or DMSO-d6 solutions with TMS as internal standards.Chemical shifts are reported in  (ppm).Mass spectra were measured using VG Autospec Q MS 30 and MS 9 (AEI) spectrometer, with the EI (70 EV) mode.Elemental analyses were carried out by using a LEOCHNS-932 Elemental Analyzer.

General procedure for syntheses of 8a-c
A cold solution of benzenediazonium chloride (0.01 mol) was prepared by adding a solution of sodium nitrite (0.7 g in 10 mL H2O) to a cold solution of aniline hydrochloride (0.93 g, 0.01 mol of aniline in 5 mL concentrated HC1) with stirring at room temperature.The resulting solution was then added to cold solutions of 7a-c (0.01 mol) in ethanol (50 mL) containing sodium acetate (2 g).The reaction mixtures was stirred for 1 h and then filtered.The solid products were crystallized from EtOH to give the products as red crystalls.

General procedure for the syntheses of 9a-c
Mixtures of 7a-c (0.01 mol) and hydrazine monohydrate (0.50 g, 0.01 mol) in DMF (10 mL) were stirred at rflux for 20 h (completion assessed by TLC analysis using ethyl acetate-petroleum ether 1:1).The mixtures were cooled and poured into ice-water.The solid products, collected by filtration, were crystallized from DMF to give light yellow crystals.
in DMF (10 mL) was stirred at reflux for 20 h (completion assessed by TLC analysis using ethyl acetate-petroleum ether 1:1 as eluent).The mixture was cooled and poured into ice-water, giving a solid that was collected by filtration and crystallized from EtOH to give the product as yellow ISSN 1551-7012 Page 231  ARKAT USA, Inc.