Nitrile sulfides. Part 13. 1 Synthesis of 5-acyl-1,2,4-thiadiazoles by cycloaddition of nitrile sulfides to acylcyanides

The periselectivity of the nitrile sulfide cycloaddition to acyl cyanides has been examined. Benzonitrile sulfide, generated by thermal decarboxylation of 5-phenyl-1,3,4-oxathiazol-2-one, reacted exclusively at the cyano group of benzoyl cyanide to afford 5-benzoyl-3-phenyl-1,2,4-thiadiazole. Similar perispecificity was observed with p -toluonitrile sulfide and acetonitrile sulfide, and for cycloaddition of benzonitrile sulfide to 2-furoyl cyanide, acetyl cyanide and 2-oxooctanonitrile. The reactivity of benzoyl cyanide as a dipolarophile was shown to be similar to that of ethyl cyanoformate in a competition experiment which afforded a 51:49 mixture of 5- benzoyl-and 5-ethoxycarbonyl-3-phenyl-1,2,4-thiadiazoles.


Results and Discussion
As nitrile sulfides are short-lived species, for preparative purposes they are usually generated in situ in the presence of the dipolarophile.For the present work the selected sources were 1,3,4oxathiazol-2-ones 7, which are both shelf-stable at ambient temperature and readily accessible from the corresponding carboxamide by treatment with chlorocarbonylsulfenyl chloride. 5The nitrile sulfides were then generated from the oxathiazolone by thermal decarboxylation at 130-160 °C. 5 The procedure is illustrated for the reaction of benzonitrile sulfide 1a with benzoyl cyanide.A solution of phenyloxathiazolone 7a (10 mmol) and benzoyl cyanide (40 mmol) in dry xylene (25 ml) was heated under reflux until HPLC analysis indicated complete consumption of the oxathiazolone (~20 h).The solvent and excess dipolarophile were removed by distillation under reduced pressure to afford an oil from which 5-benzoyl-3-phenyl-1,2,4-thiadiazole 4ad (91%) was obtained by crystallisation from ethanol (Table 1, entry 1).There was no evidence (HPLC) for the formation of the isomeric 1,3,4-oxathiazole 6ad. 7 p-Tolunitrile sulfide 1b and benzoyl cyanide reacted similarly affording thiadiazole 5bd (78%, 88% by HPLC), together with p-toluonitrile and sulfur (12%) (Table , entry 2).The formation of sulfur and nitrile by-products is a common feature of nitrile sulfide reactions 2,5 and is attributed to fragmentation of the nitrile sulfide competing with cycloaddition.A lower yield of adduct 5cd (27%) was obtained for acetonitrile sulfide.The reaction of benzonitrile sulfide with 2-furoyl cyanide, acetyl cyanide and 2-oxooctanonitrile was also examined and, using a 1:1 reactant ratio, thiadiazoles 5ae (77%), 5af (60%) and 5ag (17%) were isolated (Table , entries 4- 6).The yields of cycloadducts (77-91%) obtained from arenenitrile sulfides 1a/1b with aroyl cyanides 4d/4e are much greater than those reported 6 for the corresponding reaction with aryl cyanides, thus demonstrating the activating effect of the acyl substituent on the reactivity of the cyano group towards this class of 1,3-dipoles.Similar yields of adducts have been reported for other activated nitriles including ethyl cyanoformate 3 and trichloroacetonitrile. 7To establish the relative reactivities of benzoyl cyanide and ethyl cyanoformate a competition experiment was performed using a 9:9:1 mixture of PhCOCN, EtO 2 CCN and oxathiazolone 7a (Scheme 3); HPLC analysis of the product mixture showed that the two dipolarophiles had near identical reactivity with the ratio of thiadiazoles 5ad:8 being 51:49.
Table 1.Cycloaddition of nitrile sulfides to acyl cyanides a Yield determined by HPLC.
The products are readily identifiable from their spectroscopic properties, which are broadly similar to those of other 1,2,4-thiadiazoles. 8Their 13 C NMR spectra show characteristic peaks for the heterocyclic ring carbons at 174-175 and 185-187 ppm, which were assigned to C-5 and C-3, respectively, with the aid of fully coupled spectra; the signals for the acyl carbon range from 169 to 194 ppm depending on the substituent.The mass spectra show, in addition to the parent ion, peaks attributable to RCNS, RCN and R'COCN, thus suggesting major fragmentation pathways involving cycloreversion to the  The only previous example of a nitrile sulfide reacting with an acyl cyanide involved generation of dimethylaminoformonitrile sulfide in the presence of α-oxoindole-3-acetonitrile yielding dendrodoine 9. 9 The periselectivity of the acyl cyanide reactions observed in this work and in the literature 9 may be attributed to steric and/or electronic effects.Similar selectivity is observed for the reaction of nitrile sulfides with tetracyanoethylene. 10The major products were 5-alkenyl-1,2,4-thiadiazoles 10 resulting from cycloaddition to one of the nitrile substituents; there was no evidence for reaction at the alkene groups.Likewise the cycloaddition reactions of benzonitrile oxide with acetyl and benzoyl cyanides are also reported to occur exclusively at the nitrile moiety.

CHO
We have previously shown 7 that trichloroacetonitrile, in contrast to simple aliphatic nitriles, is a reactive dipolarophile towards nitrile sulfides, and it was therefore of interest to examine the corresponding reaction with dichloroacetonitrile. Heating a 1:1 mixture of oxathiazolone 7a and Cl 2 CHCN in xylene afforded the expected 5-dichloromethylthiadiazole 11 in 41% yield; and using an excess of Cl 2 CHCN the yield rose to 54%, ie comparable with that observed for trichloroacetonitrile.In contrast, the corresponding reaction with dibromoacetonitrile led only to black tars.
Having established a straightforward and high-yielding route to the 5-dichloromethyl compound 11, the possibility of converting it into the 5-formyl derivative 12 was examined.However, attempted hydrolysis afforded only traces of carbonyl-containing products, and the major component of the crude product was sulfur (m/z 256).
In conclusion, the acyl group activates the C≡N of acyl cyanides for cycloaddition reactions with nitrile sulfides, and 5-acyl-1,2,4-thiadiazoles can therefore be prepared from their readily accessible oxathiazolone precursors.

Experimental Section
General Procedures.The analytical methods for monitoring the reactions and the instruments used for recording IR, 1 H and 13 C NMR, and mass spectra were as previously described. 12The 1,3,4-oxathiazol-2-ones 7a-c were prepared by treatment of the corresponding carboxamide with chlorocarbonylsulfenyl chloride using the established literature procedure. 5neral procedure for preparation of 5-acyl-1,2,4-thiadiazoles (5) A solution of the oxathiazolone 7 and the acyl cyanide in dry xylene was heated under reflux until HPLC analysis showed that all of the oxathiazolone had been consumed (ca 20 h) (for reactant ratio see Table ).After removal of the solvent and unreacted acyl cyanide by distillation under reduced pressure, the products were purified by chromatography (silica; CH 2 Cl 2 /hexane, gradient elution), sublimation and/or recrystallisation from ethanol.