Synthesis of polyfunctionalized thiophenes and enediynesviaring-opening reactions of 3-lithiated thieno2,3-b(and 3,2-b)thiophenes, 3,4-dilithiated thieno2,3-bthiophenes and 3,6-dilithiated thieno3,2-bthiophenes

摘要

S Li R R SLi H 1 2 S SBu Br SiMe2But ButMe2Si 4 R1 = Me, R2 = R4 = SiMe2But, R3 = Bu 5 R1 = R3 = Bu, R2 = R4 = SiMe2But 6 R1 = R3 = Bu, R2 = R4 = H 3 R1S SR3 R2 R4 S S R4 Li R2 Li LiS R4 SLi R2 7 8 MeS SBu Me S S Br Br R R 9 R = SiMe3 10 R = SiMe2But S SBu R Br SiMe2But 11 R = SiMe2But 12 R = H SiMe2But 13 Synthesis of polyfunctionalized thiophenes and enediynes via ring-opening reactions of 3-lithiated thieno2,3-b(and 3,2-b)thiophenes, 3,4-dilithiated thieno2,3-bthiophenes and 3,6-dilithiated thieno3,2-bthiophenes Lance S.Fuller,a Brian Iddon MP*bdagger; and Kevin A. Smithb a Synthetic Chemicals Ltd., Four Ashes, Nr. Wolverhampton, UK WV10 7BP b Chemical Sciences Division, Science Research Institute, University of Salford, Salford, UK M5 4WT Solutions of the title lithiated thienothiophenes were synthesized from 2,5-disubstituted 3,4-dibromothieno2,3-bthiophenes or 3,6-dibromothieno3,2-bthiophenes via Br ? Li exchange with 1.0 or 2.0 equiv. of BuLi (THF, 278 deg;C), respectively, and gave either polyfunctionalized thiophenes or polyfunctionalized enediynes (by a novel tandem ringopening process in these cases) on being allowed to warm up to ambient temperature.Previously we have reported that ethereal (Et2O or THF) solutions of benzobthiophen-3-yllithium1ndash;3 and its derivatives2 ndash;4 (prepared from the corresponding 3-bromobenzob- thiophene via Br ?Li exchange with BuLi at 278 deg;C) undergo a ring-opening process, 1 ? 2 (Scheme 1), as the solutions are warmed up to give the lithium salt of an o-mercaptophenylacetylene, which can react further, e.g.by S-butylation with the bromobutane produced in the initial Br ? Li exchange reaction or through metallation at the terminal alkyne position. Selenophen-3-yllithium5ndash;9 and 3-thienyllithium2,6 ndash;12 behave similarly and yield enynes. We now report novel tandem ring-opening processes of 3,4-dilithiated thieno2,3-bthiophenes and 3,6-dilithiated thieno3,2-bthiophenes which afford novel enediynes.This work was prompted by intense current interest in enediynes as precursors to more complex molecular architectures.13 First we treated 2,3,5,6-tetrabromothieno3,2-bthiophene14,15 successively with 2.0 equiv. of BuLi (THF, ambient temperature) and ButMe2SiCl, then the resulting solution of 3,6-dibromo-2,5-bis(tert-butyldimethylsilyl)thieno3,2-bthiophene14 was cooled to 278 deg;C and a further 1.0 equiv. of BuLi was added. The resulting mixture was allowed to warm up slowly to ambient temperature, then it was quenched by addition of 20 aq.NH4Cl. Following a standard work-up procedure (extraction of the crude product with Et2O and flash chromatography on silica with light petroleum as eluent) we obtained 3-bromo-2-tert-butyldimethylsilyl-5-tert-butyldimethylsilylethynyl- 4-butylsulfanylthiophene 3 (70 yield) as a yellow oil.Dagger; Other 2,5-disubstituted 3,6-dilithiothieno3,2-b- thiophenes14 can be prepared and converted similarly into polyfunctionalized thiophenes analogous to compound 3.When thiophene 3 was treated successively with 1.0 equiv. of BuLi (THF, 0 deg;C) and MeI, it gave the enediyne 4 (89 yield) as a yellow oil, thus demonstrating that each thiolate anion, as it is generated in this two-stage process, can be captured by a different alkylating reagent. Both ring-opening processes can be carried out in tandem. Thus, we converted 2,3,5,6-tetrabromothieno3,2-bthiophene into 3,6-dibromo-2,5-bis(tert-butyldimethylsilyl)thieno3,2-b- thiophene14 in situ, as described before, then added a further 2.0 equiv.of BuLi (THF, 0 deg;C) prior to allowing the reaction mixture to warm up slowly to ambient temperature which, after work-up in the standard way, gave the enediyne 5 (70 yield) as a yellow oil. The extremely unstable enediyne 6 (73.5 yield) was prepared by removal of the ButMe2Si groups from compound 5 via treatment with Bu4NF in THF.Starting from 2,3,5,6-tetrabromothieno3,2-bthiophene we have prepared a number of other enediynes using this strategy. Essentially the thienothiophene ring is a template to which a variety of functional groups can be attached prior to the tandem ringopening process 7 ? 8 (Scheme 2), e.g. via Br ? Li exchange techniques, by Pd0-catalysed coupling reactions or through further modification of initial products such as by Wittig reactions of aldehydes. When 2,3,4,5-tetrabromothieno2,3-bthiophene16 was treated successively with 3.4 equiv.of BuLi (THF, 265 deg;C) and 4.8 equiv. of Me3SiCl, it gave 3,4-dibromo-2,5-bis(trimethylsilyl) thieno2,3-bthiophene 9 (51 yield) as a solid which decomposed when heated to 125 deg;C in a capillary tube. A similar attempt (2.6 equiv. BuLi, THF, but at 0 deg;C instead of Scheme 1 Scheme 2 Chem. Commun., 1997 2355265 deg;C; 2.4 equiv. of ButMe2SiCl) to synthesize 3,6-dibromo- 2,5-bis(tert-butyldimethylsilyl)thieno2,3-bthiophene 10 gave this compound (mp 112ndash;114 deg;C) in only 23 yield together with 3-bromo-2-tert-butyldimethylsilyl-4-tert-butyldimethylsilylethynyl- 5-butylsulfanylthiophene 11 (33), a pale yellow solid with mp 35ndash;37 deg;C, and 4-bromo-3-tert-butyldimethylsilylethynyl- 2-butylsulfanylthiophene 12 (18) as a pale yellow oil (formed by loss of the 2-ButMe2Si group from compound 11).When treated successively with 2.0 equiv. of BuLi (THF, 0 deg;C) and an excess of MeI, the bromothiophene 11 was converted into 2-tert-butyldimethylsilylethynyl-1-butylsulfanyl- 1-methylsulfanylpent-1-en-3-yne 13 (87 yield) as a yellow oil.In this reaction not only does the MeI capture the generated thiolate anion but it also displaces a ButMe2Si group. We thank the EPSRC (CASE award to K. A. S.) and Synthetic Chemicals Ltd. for financial support, Mrs Ruth Howard for recording mass spectra and Dr M. A. Stuckey for recording the 300 MHz 1H NMR spectra. Footnotes and References * E-mail: iddonb@parliament.uk dagger; Present address: House of Commons, Westminster, London, UK SW1A 0AA.Dagger; All new compounds (pure by TLC analysis) were characterised by recording their IR, 1H NMR and low- and high-resolution mass spectra. In most cases they were unstable in air at ambient temperature and we were unable to obtain satisfactory elemental microanalytical results (for C, H and N). 1 R. P. Dickinson and B. Iddon, Tetrahedron Lett., 1970, 975; Int. J. Sulfur Chem.C, 1971, 6, 59; J. Chem. Soc. C, 1971, 3447. 2 B. Iddon, Heterocycles, 1983, 20, 1127. 3 R. M. Scrowston, Adv. Heterocycl. Chem., 1981, 29, 171. 4 R. P. Dickinson and B. Iddon, J. Chem. Soc. C, 1970, 2592; 1971, 182; 1971, 2504. 5 S. Gronowitz and T. Frejd, Acta Chem. Scand., 1969, 23, 2540. 6 S. Gronowitz, Adv. Heterocycl. Chem., 1963, 1, 1 (see p. 75). 7 S. Gronowitz and T. Frejd, Chem. Heterocycl. Compds. (Engl. Transl.), 1978, 14, 353. 8 S. Gronowitz, Chem. Heterocycl. Compds. (Engl. Transl.), 1994, 30, 1252. 9 T. Frejd, Chem. Heterocycl. Compds., 1992, 44, 257; Thiophene and Its Derivatives, ed. S. Gronowitz, Wiley-Interscience, New York, 1992, part 5, ch. II, p. 257 (in particular see p. 721). 10 P. Moses and S. Gronowitz, Arkiv. Kemi, 1962, 18, 119. 11 S. Gronowitz, Phosphorus, Sulfur, Silicon Relat. Elem., 1993, 74, 113. 12 S. Gronowitz, A.-B. H�ornfeldt, E. Lukevics and O. Pudova, Synthesis, 1994, 40. 13 e.g. see Modern Acetylene Chemistry, ed. P. J. Stang and F. Diederich, VCH, Weinheim, 1995. 14 L. S. Fuller, B. Iddon and K. A. Smith, J. Chem. Soc., Perkin Trans. 1, 1997, in the press. 15 K. Yui, H. Ishida, Y. Aso, T. Otsubo, F. Ogura, A. Kawamoto and J. Tanaka, Bull. Chem. Soc. Jpn., 1989, 62, 1547. 16 T. Otsubo, Y. Kono, N. Hozo, H. Miyamoto, Y. Aso, F. Ogura, T. Tanaka and M. Sawada, Bull. Chem. Soc. Jpn., 1993, 66, 2033. Received in Cambridge, UK, 30th Septembert 1997; 7/07033K 2356 Chem. Commun., 19