Nitrile sulfides. Part 12. 1,2 Generation of nitrile sulfides from 1,4,2-dithiazol-5-ones

Thermolysis of 1,4,2-dithiazol-5-ones in the presence of dimethyl acetylenedicarboxylate yielded dimethyl isothiazole-4,5-dicarboxylates, together with sulfur, carbon oxysulfide and nitriles. The proposed mechanism involves initial expulsion of carbon oxysulfide, followed by 1,3-dipolar cycloaddition of the resulting nitrile sulfide to the alkyne. The corresponding reaction of dithiazolone 3b with ethyl propiolate afforded a ca 1:1.2 regioisomeric mixture of ethyl 3- phenylisothiazole-4-and 5-carboxylates, similar to that found for benzonitrile sulfide generated from 1,3,4-oxathiazol-2-one 1b .


Results and Discussion
The dithiazolones 3a-g were prepared by oxidation of the corresponding thiones 2, which are readily available from thiocarboxamides and trichloromethanesulfenyl chloride 8,9 (Scheme 1).Benzonitrile oxide, mercuric acetate, and potassium permanganate are reported 9,10 to be suitable reagents for achieving the thiocarbonyl to carbonyl conversion.We find that treatment with mercuric acetate (3 mol per mol of 2) in acetic acid/chloroform/water at room temperature (5-20 h) provides a convenient and high yielding method.

Scheme 1
The dithiazolethione precursor 2h for the ethoxycarbonyl-dithiazolone 3h was prepared from the readily accessible p-methoxyphenyl analogue 2a by reaction with ethyl cyanoformate.Subsequent treatment with Hg(OAc) 2 afforded 3h (Scheme 2).The formation of 2h is believed to involve cycloaddition of the electron-poor nitrile to the exocyclic sulfur and one of the ring sulfurs, and is accompanied by expulsion of p-methoxybenzonitrile.The mechanism may be concerted (Scheme 3), a process which has been designated 11 [2' + (1,2,3)]-cyclodismutation or cyclosubstitution.Alternatively, it may proceed in two steps, cycloaddition followed by fragmentation, via a bicyclic intermediate (6 or 7) involving a hyper-valent sulphur at one of the bridgeheads.The products are readily identifiable from their spectroscopic properties.In the mass spectra there are prominent peaks for RCNS + , RCS + , RCN + and R + , in addition to the molecular ion, suggesting fragmentation pathways involving initial expulsion of SCO.The 13 C NMR spectra show characteristic absorptions for the heterocyclic ring carbons at 196-199 and 162-165 ppm.Assignment to C-5 and C-3, respectively, was made with the aid of fully coupled spectra.In each case the chemical shifts fall between those of oxathiazolones 1 and dithiazolethiones 2 (Figure 1).A similar trend has been reported 13 for the carbonyl and thiocarbonyl groups in O,S-dialkyl thiocarbonates, S,S-dialkyl dithiocarbonates, and S,S-dialkyl trithiocarbonates.
The dithiazolones 3 prove to be much more stable than the corresponding oxathiazolones 1, with >50 hours under reflux in mesitylene (ca 164 °C) being required for decomposition (5-6 half-lives).Under similar conditions the oxathiazolones are undetectable by HPLC after one hour. 14Analysis of the reaction mixture from the thermolysis of compound 3a indicated the presence of p-methoxybenzonitrile, and carbon oxysulfide was detected in the exit gas (ν max 2080 cm -1 , m/z 60).The fragmentation can proceed by a thermally allowed σ 2 s + σ 2 s + π 2 s process.
To test for the involvement of nitrile sulfides in the decomposition the reaction was repeated in the presence of DMAD, a dipolarophile known to be reactive towards nitrilium betaines including nitrile sulfides. 3,4Phenyl-dithiazolone 3b was heated with DMAD (1:10) in mesitylene under reflux until HPLC analysis indicated its complete consumption (after 100 h).Removal of the solvent and excess dipolarophile by distillation under reduced pressure, followed by chromatography of the residue, afforded the isothiazole 5b in 52% yield.Similarly methyldithiazolone 3c afforded isothiazole 5c (56%).
The effect of substituents on the progress of the reaction was examined for the series of 3arylthiazolones 3a, 3b, 3d-3g.Each was heated with DMAD (1:1) under identical conditions (in mesitylene, 163±1 °C) and the products analysed by HPLC (Table ).The rate of reaction is influenced by the electronic nature of substituents in the aryl ring, with electron-donating groups accelerating the process.This effect is accompanied by a small increase in yield of isothiazole.A similar trend has been reported 4 for the fragmentation of the corresponding oxathiazolones 1.These results are consistent with a pathway (Scheme 5) involving rate-determining cleavage of the dithiazolone at C(3) S(4) and at C(5) S(1), followed by 1,3-dipolar cycloaddition of the resulting nitrile sulfide to the alkyne.The formation of nitriles and sulfur as by-products is a common feature of nitrile sulfide reactions and can be attributed to fragmentation competing with cycloaddition. 3 The dependence of rate on substituent is consistent with a developing positive charge at the 3-position of the 1,4,2-dithiazolone in the transition state for the expulsion of SCO.The 3-ethoxycarbonyl-dithiazolone 3h proved to be more stable.Even after prolonged heating (250 h) with DMAD in refluxing mesitylene the reaction was incomplete, and HPLC and NMR analysis of the reaction mixture revealed a complex mixture containing only traces of the expected isothiazole 5h, together with various DMAD-derived by-products.A similar effect has been reported 16 for ethoxycarbonyl-oxathiazolone 1h; whereas aryl-oxathiazolones, eg 1b, fragment readily in refluxing xylene at 135 °C, the ethoxycarbonyl analogue 1h requires temperatures in the range 160-190 °C.It has also been reported 4 that DMAD forms oligomers on prolonged heating.As nitrile sulfide cycloadditions to electron-poor dipolarophiles are regarded 4 as dipole HOMO-controlled reactions, it is not surprising that EtO 2 C-C≡N +  S -shows lower reactivity than aryl and alkyl nitrile sulfides.
Further evidence for the involvement of nitrile sulfides as discrete intermediates was provided by comparison of the reactions of dithiazolone 3b and oxathiazolone 1b with ethyl propiolate to afford regioisomeric mixtures of 3-phenylisothiazole-4-and 5-carboxylates 8 and 9. Two pathways can be considered: extrusion of SCO or CO 2 generating benzonitrile sulfide, followed by its cycloaddition to the dipolarophile [Scheme 6, path (a)]; or direct reaction between dipolarophile and precursor to form intermediate adducts 10 and 11, which subsequently collapse to form SCO or CO 2 and the observed isothiazoles [path (b)].The regioselectivity is expected to be independent of source for path (a), but not for path (b).In parallel experiments solutions of the precursors 1b or 3b and excess ethyl propiolate were heated in mesitylene at ~163 °C and the reaction mixtures monitored by GC and NMR spectroscopy.Dithiazolone 3b required 100 hours for the reaction to be complete and afforded a multicomponent mixture of products including isothiazoles 8 and 9, together with oligomers of ethyl propiolate; the regioisomer ratio was measured as 8:9 = 1: 1.2 ±   1.The corresponding reaction of oxathiazolone 1b was complete in 1 hour and proved to be much cleaner, affording 8 and 9 in the ratio 1: 1.23 ±    5 A similar ratio (1:1.1) was observed by Howe et al 4 for the latter reaction at 150 °C.The consistent regioselectivity obtained from the two precursors is consistent with path (a) involving benzonitrile sulfide as an intermediate, rather than path (b).

Scheme 6
In conclusion the thermolytic behaviour 1,4,2-dithiazol-5-ones parallels that of 1,3,4oxathiazol-2-ones.Both provide a source nitrile sulfides, although the latter are more accessible and require lower reaction temperatures, and are therefore the more convenient precursors.