Nitrile Sulfides Part 16 . 1 , 2 Synthesis of 1 , 2-benzisothiazoles via nitrile sulfide cycloaddition reactions

The cycloaddition reactions of nitrile sulfides have been used to prepare benzisothiazole quinones and 1,2-benzisothiazole-5,6-dicarboxylates. The nitrile sulfides, generated by thermal decarboxylation of 1,3,4-oxathiazol-2-ones, reacted with 1,4-naphthoquinone to afford 3-substituted naphtho[2,3-d]isothiazole-4,9-diones (17), together with nitriles as by-products. The corresponding reactions with 1,4-benzoquinone yielded regioisomeric mixtures of 2:1 adducts. The 1,2-benzisothiazole-5,6-dicarboxylates were synthesised by a sequence involving both nitrile sulfide and Diels-Alder cycloaddition reactions. Dimethyl 3-phenylisothiazole-4,5dicarboxylate (34), prepared from benzonitrile sulfide and dimethyl acetylenedicarboxylate (DMAD), was converted into the 4,5-bis(dibromomethyl) analogue 37 via the bis(dihydroxymethyl) compound 35. Treatment of 37 with sodium iodide in the presence of DMAD afforded dimethyl 3-phenyl-1,2-benzisothiazole-5,6-dicarboxylate (30) via the isothiazole o-quinodimethane 32.


Scheme 2
The first successful attempt to prepare naphtho [2,3-d]isothiazole-4,9-diones was reported by Sanders and Grunwell 17 who isolated the trifluoromethyl derivative 5 from NQ and trifluoroacetonitrile sulfide, generated from (trifluoroethylimino)sulfur difluoride; 5-hydroxy-1,4-naphthquinone (juglone) reacted similarly to afford 6.Both products were isolated in low yield, 11 and 14%, respectively.It has also been reported 30 that acenaphthoquinone reacts with benzonitrile sulfide at one of the ketone groups to yield the 1,3,4-oxathiazole 9, thus demonstrating the activating effect of an adjacent carbonyl group.In the same paper the reaction of benzonitrile sulfide with o-pleiadienequinone (10), an β-unsaturated 1,2-dione, was reported to yield the bi(pleiadienylidene)dione 12.The proposed mechanism involved initial cycloaddition to the enone carbonyl and fragmentation of the resulting oxathiazole 13 to generate the unstable thione 11; subsequent dimerisation to a 1,3-dithietane and desulfurization forms the observed pleiadienequinone. 30

Results and Discussion
Cycloaddition of a nitrile sulfide 15 to 1,4-naphthoquinone (NQ) could yield an isothiazoline 16 (and hence an isothiazole 17) by reaction at C(2)=C(3) and/or a spiro-oxathiazole 19 by reaction at one of the carbonyl groups (Scheme 3).To test the site selectivity of this process we examined the reactions of typical nitrile sulfides (15; R = Ph, 4-MeOC6H4, Me) with NQ and also with BQ (Table ).
As nitrile sulfides are short-lived they are usually generated in situ in the presence of the dipolarophile.The most convenient sources are 1,3,4-oxathiazol-2-ones 14, which are readily prepared from the corresponding carboxamide and chlorocarbonylsulfenyl chloride; 31 the nitrile sulfide can then be generated from the oxathiazolone by thermal decarboxylation at 120-160 °C. 31In an early study of nitrile sulfide chemistry Franz and Black 16 had examined the reaction of NQ with an equimolar amount of the phenyloxathiazolone 14a as the source of benzonitrile sulfide (15a), but no cycloadducts were isolated and the main products were benzonitrile and the dibenzothianthrenetetrone 18.We adopted the same approach, except that an excess of NQ (3:1) was used.In a typical experiment a mixture of oxathiazolone 14a (56 mmol) and NQ (168 mmol) in xylene was heated at reflux (~138 °C) until HPLC analysis showed complete consumption of 14a (after 12 h).Filtration afforded an almost insoluble dark blue solid, which was recrystallised from nitrobenzene and identified as compound 18 (6%) by comparison with an authentic sample prepared from 2,3-dichloronaphthoquinone. 32Concentration of the filtrate, removal of the excess NQ by distillation/sublimation, and chromatography of the residue yielded 3-phenylnaphtho [2,3-d]isothiazole-4,9-dione (17a) as a yellow solid.The yields of 17a (36%) and benzonitrile (63%) were determined by HPLC and GC analysis, respectively.There was no evidence for the formation of the spiro-oxathiazole 19a.4][35][36][37] Of particular note are two C=O peaks in the 13 C NMR spectrum at 178.1 and 176.7 ppm, and characteristic signals for the isothiazole ring carbons at 169.7, 167.0 and 134.4 ppm (Table ).The corresponding reaction of p-methoxybenzonitrile sulfide (15b), generated from the oxathiazolone 14b, was complete in 5 h and yielded the naphtho [2,3-d]isothiazole-4,9-dione 17b (42%) together with p-methoxybenzonitrile (52%).The 3-methyl analogue 17c (32%) was prepared similarly (in 4 h) from oxathiazolone 14c.The shorter reaction times in these cases were not unexpected; it has previously been noted that electron-donating substituents increase the rate of reaction, an effect attributed to a partial positive charge developing at the 5-position of the oxathiazolone ring in the transition state for decarboxylation. 31,37The electronic spectra of the products (Table ) show features expected of 2,3-disubstituted 1,4-naphthoquinones, 38 including intense benzenoid and quinoid bands in the 240-290 nm region, a benzenoid band at 330-340 nm, and a quinoid band in the 330-450 nm region.In the mass spectra of products 17a-c there is a peak at m/z 104, which is typical of 1,4-naphthoquinones and can be attributed to C6H4CO + formed by cleavage adjacent to the carbonyl groups at C(3a)-C(4)/C(8a)-C(9) and/or C(4)-C(4a)/C(9)-C(9a); 39,40 for the 3-methyl compound 17c there is also an M + -28 peak corresponding to loss of CO and at M + -41 peak due to loss of MeCN.The formation of the isothiazole-fused quinones 17 is believed to involve initial cycloaddition of the nitrile sulfide to the C(2)=C(3) double bond of NQ to form the isothiazoline 16 and hence its tautomer 20, as illustrated in Scheme 3, followed by in situ dehydrogenation under the reaction conditions, either by atmospheric oxygen or involving a second equivalent of NQ as oxidising agent.A similar mechanism has been established for the corresponding reactions of nitrile oxides.In the latter cases it is often possible to identify the initial isoxazoline cycloadducts 1, which then readily dehydrogenate to the isoxazoles 2. For example, it is reported 12 that benzonitrile oxide reacts with NQs to afford isoxazolines that can be isolated, whereas the adducts from bromoformonitrile oxide dehydrogenate under the reaction conditions.In the present case attempts to identify the isothiazolines 16 were not successful.The reaction of oxathiazolone 14c with NQ was followed by 1 H NMR spectroscopy; there were, however, no signals detectable in the region expected for an isothiazoline [H 4.5-4.8ppm (H-4), 4.8-5.2ppm (H-5)], 24,26 and the only signals observed were those of the starting materials and the isolated product 17c.][21] Sanders and Grunwell 17 investigated the reaction of with 5-hydroxy-1,4-naphthoquinone with trifluoroacetonitrile sulfide (15, R = CF3), generated from (trifluoroethylimino)sulfur difluoride, and reported the isolation of a single cycloadduct in low yield.This was tentatively assigned the structure 6 on the basis of its mass spectrum.Such regioselectivity is remarkable and we therefore investigated the regioselectivity for nitrile sulfide cycloaddition to another asymmetrically substituted naphthoquinone, 5-acetamido-1,4-naphthoquinone (21).The naphthoquinone 21 was heated with two equivalents of the methyloxathiazolone 14c under reflux for 4.5 h.Work up afforded a three-component mixture comprising the two cycloadducts 22 and 23, together with unreacted 21.From this mixture a small amount (1.5%) of one of the cycloadducts was isolated pure as deep red crystals, but it did not prove possible to purify the other isomer (Scheme 4).

Scheme 4
The spectroscopic data for the purified product were consistent with both structures.In the 1 H NMR spectrum there was a broad signal at 11.9 ppm for the amide NH and an ABC pattern in the range 9.1 to 7.8 ppm (JAB 8.3, JAC 1.5, JBC 7.5 Hz) for the benzo ring protons.The IR spectrum showed the characteristic absorptions for the amide group at 3270 and 1710 cm -1 , while in the electronic spectrum the extinction coefficient at wavelengths above 400 nm (max 437 nm,  7922) was increased compared with unsubstituted analogues 17a-c, as expected for the introduction of the 5-NHAc group.HPLC analysis showed that the isomer ratio was ca 55: 45, thus demonstrating that, as anticipated, cycloadditions to 5-substituted naphthoquinones show little regioselectivity.Similar low levels of regioselectivity have been reported for cycloaddition of nitrile oxides to 5-substituted-1,4-naphthquinones. 11aving established that naphtho [2,3-d]isothiazole-4,9-diones could be prepared from nitrile sulfides and 1,4-naphthoquinone, the corresponding reactions with 1,4-benzoquinone (BQ) were examined.BQ has two equivalent alkenic dipolarophiles [C(2)=C(3) and C(5)=C( 6)], both of which are activated by adjacent electron-withdrawing carbonyl groups, and the carbonyl groups themselves are also potential dipolarophiles.Although BQ has proved to be an effective dipolarophile for cycloadditions to a variety of 1,3-dipoles, [9][10][11]41,42 there had been no reports of nitrile sulfides reacting with BQ prior to the present work.
The methyloxathiazolone 14c was heated with four equivalents of BQ at 138 °C in refluxing xylene for 4.5 h and after work up the novel benzodiisothiazole-4,8-dione 24c (19%) was isolated as the major product (Scheme 5) (Table ).It showed one singlet at H 2.82 ppm in the 1 H NMR spectrum and a peak for M + at m/z 250 by mass spectrometry.These observations are consistent with both the trans and cis isomers 24c and 25c.The product was identified as the 2:1 trans-adduct 24c from its 13 5) of the isothiazole rings, whereas for compound 24c the two carbonyl carbons are equivalent.p-Methoxybenzonitrile sulfide 15b reacted similarly with BQ, but in this case both the possible 2:1 benzodiisothiazole-4,8-diones 24b and 25b were isolated.The trans 2:1 product 24b (33%) was the major product, formed together with traces (1%) of the cis 2:1 product 25b and p-methoxybenzonitrile (50%); the last is the expected by-product resulting the competing desulfurisation of the nitrile sulfide.A similar preference for trans 2:1 adducts has been reported for the corresponding reactions of nitrile oxides with BQ. 10,43 [a, R = Ph; b, R = 4-MeOC6H4; c, R = Me] Scheme 5 A characteristic feature of the mass spectra of the 2:1 adducts is a peak for fragment 28, corresponding to cleavage at C(1)-C(2) and C(4)-C(5) of the 1,4-quinone.For methyl-substituted compound 23c there are also peaks at m/z 222, 209 and 181, corresponding to loss of CO, MeCN and CO + MeCN, respectively; there is also a significant peak at 84 consistent with SC2CO + , formed by loss of MeCN from fragment 28c.
The reaction pathway is believed to involve initial formation of the 1:1 isothiazoline adduct 26, its oxidation to the isothiazole 27, followed by a second addition of the nitrile sulfide to form the 2:1 adducts, as illustrated in Scheme 5.It is noteworthy that in neither case was the 1:1 product 27 isolated even though excess of BQ was used.This indicates that the remaining enedione unit in 27, like that in NQ, is a reactive dipolarophile towards nitrile sulfides.
In all the cases investigated the nitrile sulfide reacted exclusively at C(2)=C(3) of the 1,4quinone to yield isothiazole-fused quinones and there was no evidence for competing formation of spiro-oxathiazoles, e.g.19.For example, heating the phenyloxathiazolone 14a with NQ yielded 36% of adduct 17a and 63% of benzonitrile (Scheme 3), thus accounting for 99% of the oxathiazolone and hence of the benzonitrile sulfide.It is known that 1,3,4-oxathiazoles, e.g. 8, can undergo cycloreversion to regenerate the nitrile sulfide and carbonyl compound. 37The possibility that such a cycloreversion was occurring in the present case, as illustrated in Scheme 6, was therefore considered.While such a reaction pathway cannot be ruled out, it is regarded as unlikely since oxathiazoles such as 6 are stable under the reaction conditions (~138 °C) and the cycloreversion requires temperatures >160 °C. 37hese results are in contrast to those reported for o-pleiadienequinone 10, which reacts with benzonitrile sulfide at the -unsaturated carbonyl group to form oxathiazole 13, and not at the activated alkene moiety. 30Of the other nitrilium betaines, nitrile oxides can react at both the alkene and carbonyl group. 9,10,44With NQ the first reaction usually takes place at the alkene unit, followed by addition to the carbonyl; with BQ both reactions can occur depending on the substitution pattern and the reaction conditions.Likewise, for nitrile ylides cycloaddition can take place at both alkene and carbonyl groups. 9,45heme 6 The route used to synthesise the 3-phenyl-1,2-benzisothiazole-5,6-dicarboxylate 30 was prompted by a report by Mitkidou and Stephanidou-Stephanatou, 46 who had prepared the corresponding benzisoxazole 29 from dimethyl 3-phenylisoxazole-4,5-dicarboxylate (33) using the Diels-Alder cycloaddition reaction of the isoxazole-based o-quinodimethane 31 with DMAD (Scheme 7).Heterocyclic o-quinodimethanes have been widely used in synthesis, [46][47][48][49][50] and we hoped that a similar approach should be possible for the benzisothiazole analogue 30 via the isothiazole o-quinodimethane 32, and using the readily accessible isothiazoledicarboxylate 34 as the starting material.

Scheme 8
Compound 30 was identified from its spectroscopic properties.In the NMR spectra there are Under similar conditions the isothiazole quinodimethane 32 reacted with diethyl fumarate to afford the adduct 38 as a mixture of 5R,6R and 5S,6S isomers.In contrast, attempts to prepare the anhydride 39, the imide 40, and the dihydropyridazine 41, by reaction with maleic anhydride, Nphenylmaleimide and diethyl azodicarboxylate, respectively, were not successful.

Conclusions
In conclusion, these results show that isothiazole-fused 1,4-quinones, a class of compounds to which there is currently no alternative synthetic approach, can be synthesised from readily accessible oxathiazolones using nitrile sulfide cycloaddition chemistry.It is also concluded that nitrile sulfides, like nitrile oxides, react preferentially at C(2)=C(3) of 1,4-quinones, rather than at the carbonyl groups.3-Substituted-1,2-benzisothiazoles can be prepared by a short route involving both nitrile sulfide and Diels-Alder cycloaddition reactions.

Table .
Benzisothiazole quinones C NMR spectrum where only five individual carbon signals were detected [172.8 (C=O); 168.4,167.7, 133.4 (isothiazole ring C); 19.4 (Me)].The cis isomer 25c, which was not isolated, would be expected to show six distinct carbon signals: i.e. for two carbonyl carbons in addition to the Me substituents and carbons C(3), C(4) and C(