Mendeleev Communications Electronic Version, Issue 5, 2001 1 Selectivity of the Lewis acid-induced transformations of polyfunctional compounds containing a 4,6-dialkoxy-7-(arylthio)heptene moiety Dmitrii S. Chekmarev,a Andrei V. Maskaev,a Georgy V. Zatonsky,b Margarita I. Lazareva,b,c Ron Caplec and William A. Smit*b a Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation.Fax: +7 095 200 4204 b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 135 5328 c Department of Chemistry, University of Minnesota-Duluth, Duluth, Minnesota 55812, USA 10.1070/MC2001v011n05ABEH001513 The interaction of the title adducts with Lewis acids may proceed as an attack at either â-alkoxy or ä-alkoxy group to the arylthio substituent leading to the formation of substituted cyclohexane or 1,3-diene derivatives, respectively.As was reported earlier, a set of structurally diverse adducts containing a 7-arylthio-4,6-dialkoxyheptene moiety can be readily assembled from four simple precursors with the help of the one-pot protocol that involves three consecutive intermolecular AdE reactions (Scheme 1).1(a)–(d) These compounds can be used as substrates for further reactions.We report here the Lewis acid-induced reactions of the title adducts. It seems reasonable to assume that an initial attack of a Lewis acid could be directed at either â- or ä-alkoxy group of the adducts (Scheme 2). In both cases, the subsequent elimination of an alkoxy group should be facilitated by the nucleophilic assistance of the properly positioned arylthio substituent.Hence, the formation of either the episulfonium ion (ESI) or the thiophanium ion (TPI) as an intermediate is to be expected as an immediate result of the â- or ä-attack, respectively. As found earlier,2(a)–(e) the ESI salts, once formed as transient intermediates, exhibit a rather high reactivity as electrophiles.In structurally related systems, they react readily with a nucleophilic double bond present in the substrate to give cyclic products. Hence, the â-attack should lead to the formation of cyclohexane derivatives as shown in Scheme 2. At the same time, according to published data,3 the TPI salts are stable and unreactive species; therefore, the final outcome of the ä-attack cannot be predicted certainly.Initial experiments were carried out with 2-methyl-4,6-dimethoxy- 7-(p-methylphenylthio)hept-1-ene 1 prepared via the coupling p-TolSCl + methyl vinyl ether + methyl vinyl ether + trimethylmethallylsilane following the general protocol outlined in Scheme 1.† The interaction of this model compound with a Lewis acid may occur via either ä- or â-attack depending on the nature of the employed reagent.Thus, the treatment of individual diastereomers (1a or 1b) or their mixture (1a,b) with 2 equiv. of trimethylsilyl triflate (TMSOTf) in CH2Cl2 at ambient temperature followed by the quenching of the reaction mixture with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) resulted in the formation of a mixture of conjugated dienes (E)-2-methyl-6- methoxy-7-(p-tolylthio)hepta-2,4-diene 2a and (E)-2-methyl- 6-methoxy-7-(p-tolylthio)hepta-1,3-diene 2b in 50% total yield‡ (2a:2b = 7:1, 1H NMR data).The TLC monitoring of this reaction revealed an almost instantaneous conversion of 1a,b (Rf = = 0.5, hexane–ethyl acetate, 5:1) into a highly polar intermediate (Rf < 0.05, hexane–ethyl acetate, 5:1), which was converted into final product 2a,b (Rf = 0.6, hexane–ethyl acetate, 5:1) upon the treatment with DBU.These data suggested that, under the chosen conditions, the reaction of 1a,b occured as an initial attack of TMSOTf at the ä-methoxy group to give an intermediate which was presumably identified as TPI salt 3.§ The latter underwent further ring opening and proton elimination upon the treatment with a base (Scheme 3).We assume that the predominant formation of 2a is due to the isomerization of initially formed isomer 2b, which is thermodinamically less stable. † General procedure for the preparation of the starting adducts was described earlier.1(a),(b). Below are specified the reaction conditions (Lewis acid, solvent, temperature, time, yields and diastereomer ratio). 1a,b: LiClO4, MeNO2, –25 °C, 3 h, 82%, 1:1.4. 6a,b: LiClO4, MeNO2, –25 °C, 20 °C, 10 h, 94%, 1:1.1. 7a,b: LiClO4, MeNO2, –25 °C to 20 °C, 20 h, 93%, 1:1.1. 12: TiCl4, CH2Cl2, –70 °C to 20 °C, 24 h, 65%, single diastereomer. OR1 ArSCl + OR1 Cl ArS AdE-I OR2 Lewis acid AdE-II S Ar OR2 R1O (– MR3) AdE-III MR3 (M = Si, Sn; R = Alkyl) + ArS OR1 OR2 â ä Scheme 1 ‡ Yields refer to the isolated compounds purufied by flash chromatography on SiO2.The identity of all compounds was established by 1H and 13C NMR data and elemental microanalyses. ArS OR1 OR2 â ä L. a. L. a. â-attack (– OR1) ä-attack (– OR2) OR2 ArS ESI AdE R2O SAr B: ? S R1O Ar TPI B: ? Scheme 2Mendeleev Communications Electronic Version, Issue 5, 2001 2 On the other hand, the treatment of 1a with a TMSOTf– Et2AlCl mixture (1:1, 2 equiv.) followed by quenching with DBU afforded 1-methyl-3-(p-tolylthiomethyl)-5-methoxycyclohex- 1-ene 4a in 65% yield.‡ The TLC monitoring of the reaction revealed the initial formation of a highly polar material (Rf < < 0.05, hexane–ethyl acetate, 5:1).To isolate the latter, the reaction mixture formed upon the complete conversion of 1a was poured into absolute CCl4 at –20 °C.An oily precipitate was separated from the supernatant liquid; it was carefully washed with CCl4 and dissolved in CD2Cl2. The presence of impurities did not allow us to carry out the complete analysis of 1H NMR spectra of this sample. However, these NMR data are consistent with the structure of bicyclic TPI salt 5a, as presented in Scheme 3.¶ This compound is a true intermediate in the above transformation of 1a since the treatment of isolated salt 5a with DBU furnished the same product 4a.These data suggest that cyclohexane derivative 4a was formed as a result of a multistep sequence starting with an initial attack of a Lewis acid (TMSOTf–Et2AlCl) at the â-methoxy group followed by a nearly concerted intramolecular cyclization of the transient ESI-like intermediate to give stabilised bicyclic TPI salt 5a [cf.refs. 2(a),(d),(e)], which can be further converted into the final adduct via sulfonium ring opening and proton elimination. The interaction of the diastereomer 1b with Et2AlCl–TMSOTf followed the pattern established for 1a (TLC monitoring) except that bicyclic intermediate 5b is less stable and more reactive than 5a.The conversion of this intermediate into final product 4b (yield 59%) did not require the presence of DBU and proceeded easily upon the treatment of the reaction mixture with aqueous NaHCO3. Adduct 4b‡ differs from product 4a only in the configuration of the methoxy substituent. Hence, it follows that the conversions 1a ® 4a and 1b ® 4b proceed as highly diastereoselective reactions.Finally, we also found that both the preparation of adducts 1a,b (via four-component coupling, cf. Scheme 1) and the cyclizaton to give product 4a,b (82%, a:b = 1:1.4) can be carried out as a one-pot sequence of three intermolecular and one intramolecular AdE reactions as represented in Scheme 3.†† This unprecedented sequence‡‡ resulted in the assemblage of a cyclohexane ring from simple precursors with the formation of three new C–C bonds.§ The intermediacy of 3 was substantiated by the 1H NMR monitoring of the reaction of 1a with TMSOTf (CD2Cl2, 20 °C). After 2 h, the 1HNMR spectrum indicated a nearly complete formation of a new compound, which was tentatively identified as thiophanium salt 3 by the appearance of downfield-shifted signals of the protons of the MeC6H4 fragment (0.3– 0.5 ppm as compared to the respective signals in 1a,b or 2a,b) (vide infra).S Me OMe OMe p-TolS TMSOTf CH2Cl2 20 °C, 15 min S MeO p-Tol Me DBU Me Me OMe p-TolS : Me OMe p-TolS 1a,b (a:b = 1:1.4) 3 (TPI) 2a 2b ä-attack: Me OMe OMe p-TolS: â-attack: Et2AlCl–TMSOTf CH2Cl2 20 °C, 5 h Me S p-Tol OMe ESI 1a H H Me H H Tol-p OMe 5a (TPI) DBU Me OMe STol- p 4a Me OMe OMe p-TolS Me OMe STol- p 4b 1b A one-pot sequence of 1a,b assemblage followed by cyclization into 4a,b: OMe i, ArSCl –78 °C, CH2Cl2 OMe Cl ArS ii, , Et2AlCl OMe –78 °C, 15 min –78 °C, 3 h Me SiMe 3 iii, 1a,b iv, TMSOTf 20 °C, 10 h 5a,b v, DBU 4a,b Scheme 3 ¶ Analysis of 1H NMR spectra of crude salt 5a revealed the presence of only one MeO singlet, the absence of olefinic proton signals, and a downfield shift of signals of the protons of the MeAr fragment typically observed in related sulfonium salts [cf.data in ref. 1(c),(d)].§§ †† Procedure of the one-pot preparation of 4a,b: To a stirred solution of p-TolSCl (0.159 mg, 1 mmol) in CH2Cl2 (20 ml) at –78 °C a solution of methylvinyl ether (0.174 mg, 3 mmol) in CH2Cl2 (2 ml) was added followed by the addition of Et2AlCl (0.363 g, 3 mmol) in toluene (1.08 ml).The mixture was kept at the same temperature for 15 min and then methallylsilane (0.257 g, 2 mmol) was introduced. TLC monitoring revealed that after two more hours at –78 °C the formation of the adduct 1a,b came to the completion. After that the temperature was raised up to 20 °C, TMSOTf (0.066 g, 3 mmol) was added and the reaction mixture was kept at ambient temperature for 5 h.Thereafter, TLC data indicated the complete disappearance of a spot corresponding to adducts 1a,b (Rf = 0.50, hexane–ethyl acetate, 5:1) substituted by a spot of a highly polar compound (Rf < 0.05). Treatment of the reaction mixture with DBU at 20 °C followed by the usual workup furnished cyclic products 4a,b (yield 82%, a:b = 1:1.4).‡ p-TolS OMe OMe R Me Me 6a,b R = H 7a,b R = Me TMSOTf or TMSOTf–Et2AlCl CH2Cl2, 20 °C, 6 h S MeO p-Tol Me Me R 9 R = H 11 R = Me p-TolS OMe R Me Me 8 R = H, 45% (TMSOTf) 91% (TMSOTf–Et2AlCl) 10 R = Me, 70% DBU OMe i, p-TolSCl –78 °C ii, TMSOTf, Me Me –78 °C –78 to 20 °C, 30 h iii, 6a,b iv, TMSOTf 20 °C, 100 h 8 Scheme 4 OMe SiMe3 65%Mendeleev Communications Electronic Version, Issue 5, 2001 3 The protocol outlined in Scheme 1 was also employed for the preparation of adducts 6a,b and 7a,b.† Treatment of 6a,b with TMSOTf (CH2Cl2, 20 °C) resulted in a fast disappearance of the starting material and appearance of a highly polar compound (TLC monitoring data, cf.data for the similar reaction of 1a,b).The subsequent treatment of the reaction mixture with DBU furnished conjugated diene 8 in 45% isolated yield‡ (Scheme 4). This transformation also proceeds via the intermediate formation of thiophanium salt 9. Much to our surprise, the reaction of 6a,b with TMSOTf–Et2AlCl followed the same ä-attack route to give the same diene 8 (91% yield). The presence of an additional methyl susbstituent at the double bond of adduct 7a,b did not affect the reaction course, and diene 10 was formed as the only isolable product regardless of the nature of the Lewis acid used.Dienes 8 can also be obtained in 65% yield using a one-pot procedure, which involves the in situ assemblage of starting adducts 6a,b from the respective precursors followed by treatment of these adducts with an additional amount of the same Lewis acid (TMSOTf) under a slightly more severe conditions (Scheme 4).As was shown earlier, the sequence outlined in Scheme 1 can also be used for the coupling of cyclic vinyl ethers as the alkene components, which resulted in the highly diastereoselective formation of cyclic adducts.2(d) These adducts react with Lewis acids via a ä-attack. Thus, the reaction of adduct 12† with either TMSOTf or TMSOTf–Et2AlCl with the subsequent treatment of the resulting complex with a base gave diene 13 in 70–80% yield (Scheme 5).‡ The intermediacy of TPI salt 14 in this conversion was established by the results of NMR monitored experiment which indicated an almost instantaneous formation of this intermediate as the only observable product upon the treatment of 12 with TMSOTf.§§ The structure of 14 was unambiguously proved by 1H and 13C NMR spectroscopy with the use of 2D protocols (homo- and heteronuclear correlations, NOESY and ROESY).At present it is hardly possible to advance a fully consistent explanation of the observed sensitivity of the reaction outcome to the nature of the substrates and/or reagents.However, above results clearly demonstrate a possibility to control the selectivity of the Lewis acid-induced transformation of the title multifunctional adducts and thus attest to the promise of further studies in this field. This work was supported by the Russian Foundation for Basic Research (grant no. 00-03-3790), the US CRDF Agency (grant no.RC2-2207) and the Donors of the Petroleum Research Fund administered by the American Chemical Society (ACP-PRF grant no. 35453-B1). References 1 (a) M. I. Lazareva, Yu. K. Kryschenko, A. Hayford, M. Lovdahl, R. Caple and W. A. Smit, Tetrahedron Lett., 1998, 39, 1083; (b) M. I. Lazareva, Yu. K. Kryschenko, A. D. Dilman, A. Hayford, R. Caple and W. A. Smit, Izv. Akad. Nauk, Ser.Khim., 1998, 924 (Russ. Chem. Bull., 1998, 47, 895); (c) M. I. Lazareva, Yu. K. Kryschenko, R. Caple, D. Wakefield, A. Hayford, W. A. Smit and A. S. Shashkov, Tetrahedron Lett., 1998, 39, 8787; (d) M. I. Lazareva, Yu. K. Kryschenko, R. Caple, W. A. Smit, K. A. Lyssenko and A. S. Shashkov, Izv. Akad. Nauk, Ser. Khim., 2000, 82 (Russ. Chem. Bull., 2000, 49, 85). 2 (a) M. T. Mustafaeva, W.A. Smit and V. F. Kucherov, Izv. Akad. Nauk SSSR, Ser. Khim., 1973, 1349 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1973, 22, 1315); (b) C. Liu, K. Kuda, Y. Hashimoto and K. Saigo, J. Org. Chem., 1996, 61, 494; (c) S. R. Harring and T. Livinghouse, J. Org. Chem., 1997, 62, 6388; (d) A. Kamimura, H. Sasatani, T. Hashimoto and N. Ono, J. Org. Chem., 1989, 54, 4998; (e) A. van Oeveran and B.L. Feringa, J. Org. Chem., 1996, 61, 2920. 3 A. C. Knipe, in The Chemistry of Sulfonium Group, eds. C. J. M. Stirling and S. Patai, Wiley, New York, 1981, ch. 14, pp. 313–376. 4 (a) L. F. S. Tietze, Chem. Rev., 1996, 96, 115; (b) T. Hudlicky, Chem. Rev., 1996, 96, 3. ‡‡ It is noteworthy that among more than dozens of various reaction types employed in the one-pot multistep sequences cationic reactions are most typically represented by the intramolecular electrophilic cyclizations.4 OMe STol-p OMe 12 TMSOTf CH2Cl2, 0 °C, 1 h OMe STol-p 13, 73% S OMe Tol-p 1 6 7 8 9 OTf 14 DBU Scheme 5 Received: 8th August 2001; Com. 01/1839 §§Preparation and NMR data of salt 14: To the stirred solution of 12 (0.033 g, 0.3 mmol) in CD2Cl2 (5 ml) at 0 °C TMSOTf (0.041 g, 0.2 mmol) was added. After 30 min, TLC data indicated the complete conversion of 12 into a highly polar compound. The solution was transferred into an NMR tube, and the 1H and 13C NMR spectra were immediately recorded at 20 °C. 1H NMR (500 MHz, CD2Cl2) d: 1.41 (m, Ha at C-3), 1.51 (m, Ha at C-4), 1.63 (m, Ha at C-5), 1.69 (m, He at C-4), 1.91 (m, He at C-2), 1.98 (m, He at C-3), 2.11 (dd, HA at C-7, J1 12.3 Hz, J2 14.0 Hz), 2.19 (m, Ha at C-2), 2.25 and 2.43 (m, 2H at C-9), 2.40 (m, He at C-5), 2.51 (s, 3H, MeAr), 2.92 (dd, HB at C-7, J1 6.0 Hz, J2 14.0 Hz), 3.29 (s, 3H, MeO), 4.06 (dd, Ha at C-1, J1 4.2 Hz, J2 12.5 Hz), 4.23 (m, H at C-8), 4.82 and 5.24 (dd, 2H at C-11, J 10.3 and 17.2 Hz), 5.52 (m, H at C-10), 7.75 and 7.71 (dd, 4HAr). 13C NMR, d: 19.0 (C-4), 21.3 (MeAr), 23.0 (C-2), 24.8 (C-3), 28.3 (C-5), 33.5 (C-9), 40.5 (C-7), 49.0 (MeO), 58.0 (C-8), 70.9 (C-1), 82.0 (C-6), 119.2 (C-11), 131.5 (C-10), 131.8, 133.0, 132.2 and 147.4 (Ar).