Preparation and Electrooxidative SO-Extrusion of Halogenated 7-Thiabicyclo[2.2.1]heptene 7-Oxides$ Thies Thiemann,*a,b M. Luisa Sa¡� e Melo,a Andre¡� S. Campos Neves,*a Yuanqiang Li,b Shuntaro Mataka,b Masashi Tashiro,b Uwe Gei¡Ælerc and David Waltonc aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, P-3000 Coimbra, Portugal bInstitute of Advanced Material Study, Kyushu University, 6-1, Kasuga-koh-en, Kasuga-shi, Fukuoka 816, Japan cSchool of Natural and Environmental Sciences, Coventry University, Coventry CV1 5FB, UK Halogenated thiophenes have been cycloadded oxidatively to maleimides to give halogenated thiabicyclo[2.2.1]heptene S-oxides which have been subjected to an electrochemical extrusion of SO to give various halogeno-substituted phthalimides.Torssell1 and Fallis and co-workers2 have shown that oxidative cycloaddition occurs on treating alkyl-substituted thiophenes with m-chloroperbenzoic acid (m-CPBA) in the presence of an electron-poor dienophile.We have studied the reaction in greater detail and found it valuable to synthesize novel alkyl-substituted 7-thiabicyclo[2.2.1]heptene 7-oxides in connection with crown ether systems.3 Recently, it was shown that the yield for the oxidative cycloaddition of alkyl-substituted thiophenes, proceeding via intermediate thiophene S-monoxides, could be greatly enhanced by add- ing BF3 Et2O to m-CPBA.4 While the uncatalysed reaction can be run at 0 8C to ambient temperature, the catalysed reaction is run typically at ¢§78 8C.The greater stability of thiophene S-oxides towards further oxidation under catalysed conditions was demonstrated.4,5 The further oxidation of thiophene S-monoxides to the S,S-dioxides is a main side reaction in the oxidative cycloaddition. Oxidation of thiophenes at sulfur proceeds readily when the thiophenes are substituted with electron donors such as alkyl groups. Electron-withdrawing or more ambidentate substituents hinder the oxidation.For this reason the oxidative cycloaddition of halogenated thiophenes does not proceed well at room temperature. Nevertheless, at more elevated temperatures, 7-thiabicyclo[2.2.1]heptene S-oxides from readily in the reaction of 2,5-chlorinated or bromi- nated thiophenes with such idenophiles as maleimides or maleic anhydride (Scheme 1). The products are not very soluble in dichloromethane and partly precipitate during the reaction. Further precipitation can be induced by addition of diethyl ether.Apart from diligent washing with diethyl ether, the products need no additional puri¢çcation for a further transformation, although for analytical purposes column chromatography and recrystallization have been performed. It has been found that the addition of BF3 Et2O has no bene¢çcial e€ect on the reaction, if the thiophene is halo- genated at position 2 and/or 5. In the case of 3,4-dibromo- 2,5-dimethylthiophene 1d, however, an acceptable yield of the cycloadduct was obtained when the reaction was run at ¢§20 8C in presence of BF3 Et2O.In the cycloaddition ¢çve stereocentres are created. Nevertheless, only one isomer is isolated. Although no crystal structural analysis has been performed, it is thought to be the endo-product with the lone-electron pair of the sulfur directed to the newly formed ole¢çnic bond. This is evidenced by comparison to compounds formed in cyclo- additions with donor-substituted compounds.3¡¾5 Thiabicyclo[2.2.1]heptene S-oxides of type 3 are quite stable thermally and extrude SO only in excess of 150 8C.6 On the other hand, 3 may be viewed as precursors for corre- sponding arenes.Photochemical6 and oxidative extrusion3 of SO in 3 has been found to proceed at much lower tem- peratures than the purely thermal extrusion. Nevertheless, the photochemical extrusion has synthetic limitations as to the reaction scale and in some cases gives a number of side products.The oxidative extrusions at ambient temperature, which are run under PTC conditions,7 often require an excess of oxidizing agent (KMnO4) and do not work well in all cases. The extrusion is thought ot proceed via an intermediate oxidation of the bridging sulfoxy group to a sulfone. For these reasons an electrochemical oxidative SO extrusion was tried. A number of electrochemical oxidations both of the thioether and of the sulfoxy moiety are known.Direct8 and indirect9 electrochemical oxidations have been reported. Moreover, oxidations of thioethers and sulfoxides often yield sulfones as by-products.10 First, the cycloadducts 3 were electrolysed in a medium containing NaCl or NaBr in a mixture of acetic acid in water AcOH¡¾H2O 4 :1 (v/v).11 For such systems it is known that the chloride or bromide ions are oxidized to the corre- J. Chem. Research (S), 1998, 346¡¾347$ Scheme 1 Oxidative cycloaddition of halogenated thiophenes. aFor preparation, see ref. 4 $This is a Short Paper as de¢çned in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there- fore no corresponding material in J. Chem. Research (M). *To receive any correspondence. 346 J. CHEM. RESEARCH (S), 1998sponding halogens, which disproportionate in aqueous aceticacid to give hypohalites.12 These are the species responsiblefor the oxidation of the sulfoxides. This could be demon-strated as in a similar case in the literature by replacingsodium halide as electrolyte with sodium sulfate whenno reaction took place.In the electrooxidation using NaClor NaBr as electrolyte [Pt/Pt, 0.1 M NaX, AcOH¡ÓH2O 4:1(v/v)] the desired phthalimides 4 we found as the majorproducts in the early phase of the reaction (up to 15% ofconversion has been achieved) with a small amount ofthe corresponding cyclohexadienes as side products. As thereaction proceeds, however, the reaction mixture becomesmore complex, and a number of products emerge.This canbe attributed to halogenation of the methylidene carbon ato the carbonyl function of the imido moiety. Very slowaddition of bromine to the thiabicyclo[2.2.1]heptene S-oxidesleads to the formation of products identical to those found asside products in the electrooxidation. Thus, a second methodof electrochemical oxidative SO extrusion was studied.It is known that thioethers can be transformed to sulfo-xides directly at platinum electrodes.Moreover, thioacetalsare cleanly oxidatively cleaved to alkanones at suchelectrodes.13 Interestingly, it could be shown that thecycloadducts 3 could be transformed to the correspondingphthalimides 4 under the same conditions [Pt/Pt, CH3CN¡ÓH2O (20 :1 v/v) or dry CH3CN, 0.5 M LiClO4]. In thesereactions the sulfur bridge is oxidized before it is extruded.A sulfone bridge in these molecules is much less stable thanthe corresponding sulfoxy bridge.Although it is believedthat SO2 itself is extruded from the molecules, the gas phaseover the reaction solution has not yet been analysed forSO2. For most systems tried, a satisfactory transformationcould be achieved. Scheme 2 shows a typical example. In allcases a divided cell had to be used. The starting materialsand the products are imides and can be reduced readily atthe cathode. Furthermore, in many cases less material, pro-duct and starting material could be isolated from the anodicchamber with increasing reaction time.Thus, it becamemandatory to shorten reaction times using the same set-up.Moreover, in almost all experiments a gradual blocking ofthe anode was observed. This may be due to oxidized sulfurspecies adsorbing on the electrode.14 To circumvent blockingof the electrode and to shorten the reaction time of theoxidative extrusion, ultrasound was employed. Its use15during electrolysis increases mass transport of the substrateto the electrode and of the product from the electrode inmany cases.16 An increase in current at constant potentialwas noted when using ultrasound.The reaction time of theoxidative SO-extrusion can be shortened without alteringthe product distribution. The electrochemical cell wasimmersed in an ultrasonic bath (Bandelin SonoreperRK 510H). Typically, reaction times could be shortened by30% (e.g. from 6 to 4 h). The yield of 4a was increased to87% upon application of sonication.ExperimentalOxidative Cycloaddition of Halogenated Thiophenes with Phenyl-maleimides.A mixture of 2,5-dibromothiophene 1b (2.42 g,10 mmol), N-phenylmaleimide 2a (1.8 g, 10.4 mmol), and m-chloro-perbenzoic acid (7.3 g, 60 weight %, 25.4 mmol) in dichloro-methane 60 cm3) was reuxed for 48 h.Thereafter the solution wascooled, the precipitate formed ltered o, and the ltrate dilutedwith dry diethyl ether (100 cm3). A second crop of crystallineprecipitate formed and was ltered o.Further concentration ofthe ltrate in vacuo and addition of ether (100 cm3) yielded furtherprecipitate. The combined precipitate was washed with ether(220 cm3) and dried. An analytical sample was recrystallized fromdry ether to give 3b as a pale yellow solid (1.73 g, 42%), mp 254 8C;IR (KBr) ~/cm£¾1=3100, 3062, 2858, 1720, 1494, 1390, 1205, 1130,963, 757, 733, 696, 682, 668. 1H NMR (250 MHz, CDCl3): 4.27(2 H, s), 6.52 (2 H, s), 7.19¡Ó7.22 (2 H m, aromatic H), 7.42¡Ó7.47(3 H, m, aromatic H). 13C NMR (62.9 MHz, CDCl3): 52.78,72.18, 126.25, 129.27, 130.92, 132.79, 135.10, 170.09 (C1O).MS (FAB, 3-nitrobenzyl alcohol): m/z (%) 434 ([81Br2]MH,2.5), 432 ([79Br81Br]MH, 4.1), 430 ([79Br2]MH, 2.1), 394([79Br81Br]MH £¾ SO, 1.5). HRMS (FAB, 3-nitrobenzyl alcohol)(C14H9Br2NO3S H): (81Br2MH) 433.8708 (calc.), 433.8698(found); ([79Br81Br]MH) 431.8728 (calc.), 431.8729 (found);(79Br2MH) 429.8748 (calc.), 429.8746 (found).Electrochemical SO-Extrusion.Typically, a solution of a tetra-bromothiabicyclo[2.2.1]heptene S-oxide (3c, 100 mg, 0.17 mmol)in acetonitrile¡Ó5 volume % water (16 cm3) containing LiClO4(0.5 M, 8 mmol) was electrolysed in a divided cell equipped with aplatinum-sheet anode (21 cm2) at a constant current of 6 mA[cathode compartment: palladium-sheet cathode (21 cm2), CH3CN¡Ó10 volume % water (16 cm3), 0.5 M LiClO4].The electrolysis wascontinued until most of the starting material had been consumed(TLC, until about 4.2 F mol£¾1 were passed). Then the anolyte wasconcentrated in vacuo, ether (15 cm3) was added and the precipitateltered o.The ltrate was dried over MgSO4 and concentrated invacuo. The residue was chromatographed on silica gel (eluent:chloroform) to yield N-phenyltetrabromophthalimide 4a (66 mg,72%) as colorless crystals, mp 278 8C (lit.,17 280 8C); IR (KBr)~/cm£¾1= 1705, 1490, 1385, 1335, 1277, 1122, 753, 735, 688, 663.The groups from Coimbra, Portugal, and from Coventry,UK, are grateful to the European Community for nancialsupport of this work (no.CHRX CT94 0475).Received, 3rd November 1997; Accepted, 2nd March 1998Paper E/7/07882JReferences1 K. Torssell, Acta Chem. Scand., Ser. B, 1976, 30, 353.2 A. M. Naperstkow, J. B. Macaulay, M. J. Newlands and A. G.Gallis, Tetrahedron Lett., 1989, 30, 5077.3 Y. Li, T. Thiemann, T. Sawada and M. Tashiro, J. Chem. Soc.,Perkin Trans. 1, 1994, 2323.4 Y. Li, M. Matsuda, T. Thiemann, T. Sawada, S. Mataka andM. Tashiro, Synlett, 1996, 461; Y.Li, T. Thiemann, T. Sawada,S. Mataka and M. Tashiro, J. Org. Chem., 1997, 62, 7926.5 P. Pouzet, I. Erdelmeier, P. Ginderow, J. P. Mornon, D. M.Dansette and D. Mansuy, J. Chem. Soc., Chem. 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S. Campos Neves, J. Castillo, G. Jung andA. Fontana, J. Chem. Soc., Perkin Trans. 2, 1997, 2055 and refstherein.17 D. S. Pratt and C. O. Young, J. Am. Chem. Soc., 1918, 40, 1415.Scheme 2 Electrochemical SO-extrusionJ. CHEM. RESEARCH (S), 1998 347