Heimgartner, Heinz

Mlostoń, Grzegorz

ZORA

Zurich Open Repository andArchiveUniversity of ZurichMain LibraryStrickhofstrasse 39CH-8057 Zurichwww.zora.uzh.chYear: 20032,2,4,4-Tetramethylcyclobutane-1,3-dithioneHeimgartner, Heinz; Mloston, GrzegorzAbstract: UnspecifiedPosted at the Zurich Open Repository and Archive, University of ZurichZORA URL: http://doi.org/10.5167/uzh-80024Published VersionOriginally published at:Heimgartner, Heinz; Mloston, Grzegorz (2003). 2,2,4,4-Tetramethylcyclobutane-1,3-dithione. In: Paque-tte, Leo A; Rigby, James H; Crich, David; Wipf, Peter. Electronic Enzyclopedia of Reagents in OrganicSynthesis (e-EROS). Chichester: Wiley-Blackwell, 1-11.ARTICLE – RN00430 12,2,4,4-Tetramethylcyclobutane-1,3-dithioneS S1[10181-56-3] C8H12S2 (MW 172.32)(reagent used as a stable thioketone; useful as a building block tointroduce a cyclobutane moiety as a spacer unit)Alternate Name: 2,2,4,4-tetramethyl-1,3-cyclobutanedithione.Physical Data: mp 123–125 ◦C.Solubility: soluble in hydrocarbons, chlorinated hydrocarbons,ethers, alcohols, pyridine, and other commonly used organicsolvents; insoluble in water.Form Supplied in: orange-red crystals, commercially not avail-able.Analysis of Reagent Purity: single crystal X-ray analysis.1Preparative Methods: the title reagent can be prepared by thion-ation of 2,2,4,4-tetramethylcyclobutane-1,3-dione with P4S10in pyridine at 110 ◦C2–4 or with H2S/HCl in methanol at −5 ◦Cin the presence of ZnCl2.5Purification: column chromatography (silica gel, hexane/dichloromethane); less polar than 2,2,4,4-tetramethyl-3-thioxo-cyclobutanone; sublimation; recrystallization from coldmethanol.Handling, Storage, and Precautions: store in a refrigerator, safein handling, camphoraceous odor.Thermolysis. Pyrolysis of 2,2,4,4-tetramethylcyclobutane-1,3-dithione (1) at 485 ◦C in a quartz tube leads to a mixtureof two new isomeric compounds 2 and 3 (eq 1).1 Formally, bothproducts are dimers of dimethyl thioketene, which is believed tobe an intermediate.S S1 2, 80%(1)485 °CSSSS3, 12%The formation of dimethyl thioketene from 1 is evidenced bythe thermolysis carried out in the gas phase at 940 ◦C using FVPtechnique.6 The reactive dimethyl thioketene can be trapped bydimethyl amine. In boiling toluene, 1 is partially dissociated and a[2 + 3]-cycloaddition of dimethyl thioketene with the azomethineylide generated from aziridine 4 leads to 5 in 26% yield (eq 2).7NPhPh CO2MeCO2MeSNCO2MeCO2MePhPh 12 (2)5toluenereflux42 ARTICLE – RN00430Oxidation Reactions. Reaction of 1 with m-CPBA in diethylether at 0 ◦C affords a colorless solid consisting of anti- and syn-bis(sulfines) (6a and 6b) (eq 3).8 The ratio of the isomers dependson the reaction conditions. In tetrachloromethane at 70–75 ◦C,isomerization to the anti-isomer is achieved.S S1m-CPBAdiethyl ether0 °C86%S S6b(3)OOS S6aOOThe chlorination of 1 with gaseous chlorine in tetrachloro-methane at 0 ◦C leads to a mixture of cis- and trans-bis(α-chloro-sulfanylchlorides) (7a and 7b), respectively (eq 4).9 Treatment ofthe mixture with thioacetic acid yields the corresponding acety-lated disulfanes.9S S1Cl2, CCl40 °C7a(4)SClClSClCl7bSClClClSCl99%Reactions with Organometallics. The reaction of 1 withmethylmagnesium iodide in ether gives 8 as the product of thio-philic addition.10 However, the analogous reaction with methyl-lithium and subsequent alkylation yields 1,3-bis(alkylthio)bicyclo[1.1.0]butanes (9) (eq 5).10S SMe MeS SEt8(5)911. MeLi    diethyl ether2. EtI      79%MeMgBrdiethyl ether 20%Reactions with Carbenes and Carbenoids. Under PTC con-ditions (CHCl3, NaOH, TEBA), 1 is converted into a mixture ofcis- and trans-bis(thiiranes) (10a and 10b) in favor of the cis-isomer.11 After prolonged reaction times, a stepwise desulfur-ARTICLE – RN00430 3ization takes place leading to 1,3-bis(dichloromethylene)cyclo-butane derivative 11 (eq 6).ClClClClSCl ClSClClSCl ClSClCl1(6)1110a 10bPTC conditions 82%CHCl3, NaOHHeating of 1 and 1.1 equiv of (phenyl)(trifluoromethyl)mercuryin benzene in the presence of sodium iodide affords, after 48 h,a mixture of three products, i.e., 12, 13a, and 13b (eq 7).12 Byanalogy to the reaction presented in eq 6, the ratio of 13a/13b wasca. 4:1.1(7)13aSF FSFF13bSF FSFF12SF FSbenzeneNaI, 80 °CPh(CF3)HgDifluorocarbene generated from bis(trifluoromethyl)cadmiumin trichloromethane at −30 ◦C to rt adds to 1 to give, along with12, 13a, and 13b (total yield 50%), an unexpected 2,2-difluoro-1,3-dithiolane (so-called Scho¨nberg product), which is the prod-uct of the interception of an intermediate thiocarbonyl difluo-romethylide by 1.13Dimethoxycarbene, generated by thermolysis of 2,5-dihydro-1,3,4-oxadiazole derivative 14, reacts with 1 to give ring-enlargedproducts 15 and 16 (eq 8).14 No dimethoxythiirane derivative of1 can be detected in the reaction mixture.NON OMeOMeSOMeOMeS SOMeOMeSOMeOMe (8) 15, 30% 14 1 16, 18%110 °Cbenzenesealed tubeThe rhodium-catalyzed decomposition of diazo compound 17in the presence of equimolar amounts of 1 leads to 18, which is4 ARTICLE – RN00430the product of 1,5-dipolar electrocyclization of an intermediateα-keto-functionalized thiocarbonyl ylide (eq 9).15N2OOSOSO 1(9)18Rh2(OAc)4THF, rt38% 17Reaction with 1,3-DipolesDiazo CompoundsDiazomethane adds easily to 1 in diethyl ether at 0 ◦C, and amixture of cis- and trans-configured bis-adducts 19a and 19bis obtained as a colorless solid (eq 10).4 Both cycloadditionsoccur regioselectively to give 1,3,4-thiadiazole derivatives. Thesecompounds are relatively stable at rt but extrude nitrogen inrefluxing chloroform when converted quantitatively into a stereo-isomeric mixture of the corresponding dithiiranes.SNNNNSS SSNNSN NCH2Cl2(10) 19a1 19b3:7diethyl ether      0 °C     quant.In the reaction of 1 with diphenyl diazomethane, the orange-red color of 1 disappears and immediate evolution of nitrogen isobserved.4 The product is a mixture of cis- and trans-dithiiranes(20a and 20b) (eq 11). The reaction of 1 with 1 equiv of diphenyldiazomethane leading to the monothiirane is also described.16Ph2CN2SPh PhSPhPhSPh PhSPhPh1(11)20a 20bdiethyl etherrt, −N2quant.7:3Reactions of different diazo compounds with 1 are carried out inorder to prepare molecules that are used as rigid rod-like ligands,17with cyclobutane as a ferromagnetic coupling unit,18,19 and as re-versible redox systems.20,21 In all procedures, the two-fold extru-sion strategy22 is applied. While the evolution of nitrogen occursspontaneously, removal of sulfur is achieved by using phosphanesor phosphites. A representative example is outlined in eq 12.17ARTICLE – RN00430 5NNN2NNNN1. 1, rt                 diethyl ether2. Bu3P, 140 °C      pyridine, 20% 21 22(12)A limitation of the two-fold extrusion strategy appears whendi(tert-butyl)diazomethane is used; treatment with 0.5 equiv of1 in diethyl ether at −78 ◦C gives the expected 2:1 cycloadductas a single isomer in 68% yield.23 However, the thermal elimi-nation of nitrogen as well as the attempted desulfurization withtriphenylphosphane at variable temperatures do not lead to theexpected sterical, highly congested alkenes.Less reactive diazo compounds such as α-diazo esters, amides,and ketones react slowly with 1 and, therefore, these conver-sions must be catalyzed by the addition of LiClO4. The reactionof 1 with ethyl diazoacetate affords mixtures of stereoisomericbis(thiiranes) which, by desulfurization with tris(dimethylamino)phosphane, are converted into isomeric dicarboxylates (23a and23b) in equal amounts24 (eq 13).N2CHCO2EtEtO2C CO2EtEtO2CCO2Et1. 1, rt    THF2. (Me2N)3P, rt 23b 23a(13)THF     66%On the other hand, the products obtained from the reaction of1 with α-diazo ketones (24) are cis- and trans-bis(1,3-oxathiols)of type 25 (eq 14).15,25 The formation of these products resultsfrom double 1,5-dipolar electrocyclization of the intermediateα-keto functionalized thiocarbonyl ylide. Obviously, the alter-native 1,3-dipolar electrocyclizations leading to thiiranes are notable to compete.6 ARTICLE – RN00430OSR2R1SOR2R1R2ON2R1OSR2R1OSR1R21(14) 25aLiClO4THF60 °C 2425bOrganic AzidesHeating of 1 in excess phenylazide at 40–50 ◦C leads to bis(N-phenylimine) (26) after spontaneous extrusions of nitrogen andsulfur (eq 15).26 Unstable derivatives of 1,2,3,4-thiatriazole andthiaziridine are believed to be intermediates.Ph N3 N NPhPhN2 S1benzene40−50 °C26, 70%(15)NitronesCyclic and non-cyclic nitrones react easily with 1 at rt, but insolution the [2+3]-cycloadducts exist in equilibrium with the start-ing materials. Reactions carried out with 2 equiv of cyclic nitroneslead to 2:1 adducts which are, most likely, mixtures of cis/trans-isomers.3 Reaction of nitrone 27 and 1 in trichloromethane atrt gives the orange-red 1,4,2-oxathiazolidine (28) in 74% yield(eq 16).27 An analogous product was obtained in 84% yield withN-methyl benzophenonimine N-oxide.28O NMeO SONOSMe1CHCl3, rt74%27(16)28Azomethine Ylidestrans-N-(4-Methoxyphenyl)aziridine-2,3-dicarboxylate (29)reacts with 1 in boiling toluene to give a mixture of twodiastereoisomeric 1:1 adducts 30a and 30b (eq 17). Formationof the cis-isomer (30a) results from the expected reaction coursevia conrotatory ring opening of 29 to give the (E,E)-configuredazomethine ylide, which undergoes a stereoselective [2+3]-cyclo-addition with 1.7 Partial isomerization of the azomethine ylide tothe (E,Z)-configured isomer is responsible for the formation of30b as a minor product. No 2:1 adduct is formed.ARTICLE – RN00430 7NCO2MeMeO2CArSNCO2MeArSCO2MeSNCO2MeArSCO2Me 1(17) 30a, 48% 29 30b, 11%Ar = 4-MeOC6H4toluenerefluxThe N-benzyl substituted azomethine ylide 31, generated byusing a desilylation method supported by ultrasound, adds to 1 inacetonitrile to give predominantly the 1:1 adduct 32. Using a two-fold excess of the precursor of 31, the trans-configured 2:1 adduct33 is formed in low yield as the only stereoisomer (eq 18).29NPhSNSPhNS NSPhPh 1(18)32, 65% 3133, 11%acetonitrileCarbonyl YlidesHeating a solution of equimolar amounts of 1 and 3-phenyloxi-rane-2,2-dicarbonitrile (34) in toluene gives 1,3-oxathiolane (36)in 22% yield (eq 19).30 The formation of 36 results from the re-gioselective [2+3]-cycloaddition of the thermally generated car-bonyl ylide with 1.OCNCNPhOCNCNPhSOSCNNCPh 1(19)35343622%130 °Ctoluenesealed tubeThiocarbonyl S-imidesHexafluorothioacetone S-imide (37) reacts with 1 only atelevated temperatures. The product formed is 1,4,2-dithiazolidine(39), which is an isomer of the expected [2+3]-cycloadduct.31Therefore, the reaction pathway is explained by the isomerization8 ARTICLE – RN00430of 37 to the putative thionitrone 38, which undergoes a [2+3]-cycloaddition with 1 to yield 39 (eq 20).(CF3)2C SN AdSNSSCF3CF3Ad(CF3)2C NSAd 37 39 1(20)Ad = Adamantan-1-yl 38100 °CCDCl3Thiocarbonyl S-sulfides (Thiosulfines)The products obtained from three-component reactions of anaromatic thioketone, phenyl azide, and 1 are 1,2,4-trithiolanes (40and 41), formed along with N-phenyl diarylimines (eq 21).32 Thetrithiolanes are interception products of the corresponding thio-carbonyl S-sulfide, which is generated in situ by sulfur-transferfrom an intermediate thiaziridine to 1, with either the aromaticthioketone or another molecule of 1. No products of secondarycycloadditions are formed.Ar2C S PhN3SS SArArSSS SSS(21) 41 80 °C 40 1Ar = 4-MeOC6H4A similar reaction with methyl dithiobenzoate instead of thearomatic thioketone, in which 41 is formed in low yield along witha 1,4,2-dithiazolidine obtained from an intermediate thiocarbonylS-imide and 1, is also reported.33Ring-Enlargement Reactions. A ring enlargement of 1 viainsertion of dimethoxycarbene is presented in eq 8.14 Photolysis of1 in methanolic solution yields five-membered sulfur heterocycles(42–44) (eq 22).34 A similar mixture of products is obtained, inaddition to 1, when dithiolactone 2, which is an isomer of 1, isirradiated with UV-light in methanol or cyclohexane.35,36SSS SSMeO SSMeO 421(22)hν 44 43methanol3-Thioxodithiolactone (42) is formed in 55% yield when a solu-tion of 1 in acetone is treated with elemental sulfur in the presenceof sodium thiophenolate.37ARTICLE – RN00430 9Base-Catalyzed Isomerization. The isomerization of 1 intodithiolactone 2 is easily achieved in boiling benzene with catalyticamounts of sodium methanolate.1,36 Other basic agents can alsobe used.1 The electrochemically induced isomerization of 1 into2 is also reported.38Miscellaneous. The reaction of 1 with cyclohexene oxide (45)in dichloromethane catalyzed by borontrifluoride occurs at rt andleads to a complex mixture of mono- and diastereoisomeric bis-adducts (eq 23).39 Along with the expected 1,3-oxathiolanes (46and 47), secondary products containing a 1,3-dithiolane ring ora C=O group are obtained. Obviously, these products are formedvia sulfur-exchange reactions. 1(23)45 46  47OSOSHHSOHHOSHHBF3  Et2OCH2Cl2rtIn the case of cyclopentene oxide (48), only secondary products49 and 50, which are formed in multistep reactions, are obtainedin low yields (eq 24). 1(24)48 49  50OOSSHHHHSOOBF3  Et2OCH2Cl2rtAn efficient synthesis of imidazole-2-thiones (52) from2-unsubstituted imidazole-3-oxides (51) and 0.5 equiv of 1 isdescribed (eq 25).40 The smooth sulfur-transfer occurs via anintermediate [2+3]-cycloadduct analogous to the products ob-served in reactions with nitrones (eq 16).(25)51  52NNR3R2R1ONNHR3R2R1S1CH2Cl2, rt65−96%The photolysis (λ > 400 nm) of 1 in 2-propanol in the pres-ence of oxygen and in the absence of a sensitizer gives 2,2,4,4-tetramethylcyclobutane-1,3-dione.2 In toluene solution, 1 and 210 ARTICLE – RN00430equiv of (Ph3P)2Pt(η2-C2H4) combine to give the bis-(platinum)complex 53 (eq 26).41S S(Ph3P)2Pt(η2-C2H4)(Ph3P)2PtS SPt(PPh3)2(26) 53 1toluene, rt80%1. Shirrell, C. D.; Williams, D. E., Acta Crystallogr., Sect. B 1973, 29,1648–1653.2. Elam, E. U.; Davis, H. E., J. Org. Chem. 1967, 32, 1562–1564.3. Worman, J. J.; Shen, M.; Nichols, P. C., Can. J. Chem. 1972, 50,3923–3926.4. Black, D. S. C.; Watson, K. G., Aust. J. Chem. 1973, 26, 2491–2504.5. Krapcho, A. P.; Rao, D. R.; Silvon, M. P.; Abegaz, B., J. Org. Chem.1971, 36, 3885–3890.6. Seybold, G., Tetrahedron Lett. 1974, 555–558.7. Mloston, G.; Urbaniak, K.; Linden, A.; Heimgartner, H., Helv. Chim.Acta 2002, 85, 2644–2656.8. Zwanenburg, B.; Wagenaar, A.; Thijs, L.; Strating, J., J. Chem. Soc.,Perkin Trans. 1 1973, 73–75.9. Koch, K. N.; Mloston, G.; Senning, A., Eur. J. Org. Chem. 1999, 83–86.10. Gassman, P. G.; Mullins, M. J., Tetrahedron Lett. 1979, 4457–4460.11. Mloston, G.; Romanski, J.; Swiatek, A.; Heimgartner, H., Helv. Chim.Acta 1999, 82, 946–956.12. Mloston, G.; Romanski, J.; Heimgartner, H., Heterocycles 1999, 50,403–410.13. 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Huisgen, R.; Rapp, J.; Huber, H., Liebigs Ann./Recueil 1997, 1517–1524.38. Kistenbru¨gger, L.; Klages, C. P.; Voss, J., J. Chem. Res. (S) 1979,320–321.39. Blagoev, M.; Linden, A.; Heimgartner, H., Helv. Chim. Acta 1999, 82,2316–2335.40. Mloston, G.; Gendek, T.; Heimgartner, H., Helv. Chim. Acta 1998, 81,1585–1595.41. Weigand, W.; Wu¨nsch, R.; Robl, C.; Mloston, G.; No¨th, H.; Schmidt,M., Z. Naturforsch. 2000, 55b, 453–458.Heinz HeimgartnerOrganisch-chemisches Institut, Universita¨t Zu¨rich,Winterthurerstrasse 190, CH-8057 Zu¨rich, SwitzerlandGrzegorz MlostonSection of Heteroorganic Compounds, University of Lodz,Naturowicza 68, PL-90-136 Lodz, Poland

2,2,4,4-Tetramethylcyclobutane-1,3-dithione

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2,2,4,4-Tetramethylcyclobutane-1,3-dithione

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