NH MeO p-TolS CF3 p-Tol S CF3 O NHPMP 1 p-Tol S CF3 O NH2 PMP A CF3CO2 – + TFA TFAA MeO CF3CO2 S NH2 + CF3 p-Tol + CF3CO2 – B S NH MeO CF3 p-Tol •CF3CO2H CF3CO2 – 2 –CF3CO2H CF3CO2 – + S NH MeO CF3 p-Tol •CF3CO2H CF3CO2 – + 2 1 2 S NH MeO CF3 p-Tol CF3CO2 S -p-Tol MeO NH2 3 S -p-Tol MeO N 4 CF3 Me CH2Cl2 reflux NEt3 (2 equiv) HCl 1M 5 S NH MeO CF3 p-Tol •CF3CO2H + CF3CO2 – H 2 1 S H2C NH MeO CF3 p-Tol + 2 CF3CO2H heat or NEt3 C S Me N MeO CF3 p-Tol 4 2 CF3CO2H + + CF3COMe S NH2 MeO p-Tol H2O 3 416 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 416–417† Unusual Trifluoroacetic Anhydride Promoted Fragmentation of a g,g,g-Trifluoro-b-(p-methoxyphenylamino) Sulfoxide† Alberto Arnone,a Pierfrancesco Bravo,*b Luca Bruch�e,b Marcello Crucianelli,b Matteo Zanda*b and Carmela Zappal`aa aC.N.R. - Centro di Studio sulle Sostanze Organiche Naturali, via Mancinelli 7, 20131 Milano, Italy bDipartimento di Chimica, Politecnico, via Mancinelli 7, 20131 Milano, Italy The reaction of a g,g,g-trifluoro-b-(p-methoxyphenylamino) sulfoxide with trifluoroacetic anhydride under Pummerer conditions occurs in an abnormal fashion, providing an excellent yield of the cyclic six-membered sulfonium salt arising from intramolecular interception of the usual trifluoroacetoxy-sulfonium intermediate by the electron rich p-methoxyphenyl group.The Pummerer reaction (PR) of N-monoprotected b-aminosulfoxides has been rarely investigated so far.1 We have recently reported that g-fluoro-b-(N-Z-amino) sulfoxides undergo an unusual ‘non-oxidative’ PR promoted by tri- fluoroacetic anhydride (TFAA) and sym-collidine.2 By this reaction the sulfinyl group can be efficiently and stereoselectively displaced one-pot by a trifluoroacetoxy group in an SN2 fashion.As an extension to our work on the synthesis of chiral fluoro-organic molecules we devised a stereoselective preparation of the 2-trifluoromethyl substituted indoline ring.Based on encouraging results reported in literature, 3 we expected to obtain the target framework via a Pummerer cyclization of the g,g,g-trifluoro-b-(p-methoxyphenylamino) sulfoxide 1. The sulfoxide 1 is readily and stereoselectively available through reduction of the corresponding g-fluoro-b-imino sulfoxide4 or condensation of lithiated methyl p-tolyl sulfoxide with the N-p-methoxyphenyl imine of trifluoroacetaldehyde. 2b Disappointingly, addition of TFAA (1.2 equiv.) to a THF solution of 1 (Scheme 1) resulted in the formation of unidentified by-products (TLC).None of the expected indoline products could be detected by careful examination of the crude reaction mixture. However, a polar compound was isolated which proved to be the cyclic sulfonium trifluoroacetate 2 (50% yield).5 Next, we found that preliminary treatment of 1 with trifluoroacetic acid (TFA), followed by TFAA, produced an almost quantitative yield of the salt 2. The presence of two trifluoroacetoxy groups for each molecule was shown by 19F and 13C NMR analysis.Clearly, the sulfonium trifluoroacetate 2 is produced via trapping of the trifluoroacetoxy-sulfonium cation B by the electron rich p-methoxyphenyl group. The improvement obtained by using TFA suggests that 2 could arise from the ammonium trifluoroacetate A, while the direct reaction of 1 with TFAA should follow other pathways, producing the observed by-products. The chemical behaviour of the sulfonium salt 2 has been investigated (Scheme 2).Surprisingly, upon refluxing the salt 2 in methylene chloride for 4 h the amine 3 was obtained in 46% yield, together with small amounts of the imine 4. The same reaction, though at a much slower rate, was found to occur spontaneously upon storage of neat 2 at 4 °C. Formation of compound 5, expected on the basis of literature reports,5a,b arising from intramolecular nucleophilic attack of the trifluoroacetoxy anion onto the C-1 sp3 carbon and C·S bond breaking, was not observed. On the other hand, treatment of 2 with triethylamine (2 equiv.) resulted in the formation of the trifluoroacetone imine 4 in 90% yield.A reasonable pathway for the formation of 3 and 4 from 2 is shown in Scheme 3. *To receive any correspondence. †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem.Research (M). Scheme 1 (PMP=p-methoxyphenyl) Scheme 2 Scheme 3J. CHEM. RESEARCH (S), 1997 417 The trifluoroacetoxy counterion of compound 2 or triethylamine might promote the b-elimination, triggered by the removal of H-2, unusually acidic for the presence of the strongly electron withdrawing CF3 group. This should lead to the enamine C, which is expected to tautomerize readily to the imine 4. In the absence of a base, the resulting imine 4 can be hydrolysed to the amine 3 and trifluoroacetone (which is highly volatile and could not be isolated) by the 2 equiv.of TFA formed in the process. We checked the relationship existing between 3 and 4 by treating the latter with TFA or with a 1 M aqueous HCl solution overnight: the expected amine 3 was formed in 80% yield, confirming its proposed origin. Experimental The instrumentation and general experimental and analytical procedures have been recently described in detail.6 g,g,g-Trifluoro- b-(p-methoxyphenylamino) sulfoxide 1 was prepared according to literature procedures.2b,4 Sulfonium Trifluoroacetate 2.·A methylene chloride solution (3 ml) of 1 (1 mmol), cooled at 0 °C was treated with 0.22 ml of neat TFA (3 mmol) and then with 0.17 ml of neat TFAA (1.2 mmol) at the same temperature.The reaction mixture immediately turned dark brown. After 5 min the solvent was gently removed under reduced pressure, and the crude mixture submitted to flash chromatography (FC) with CHCl3–methanol (9:1 to 8:2) as eluent.Pure 2 was obtained in nearly quantitative yield as a yellow foam. Compound 2: Rf 0.02 (6:4, hexane:AcOEt); dH (CD3COCD3) 7.84 and 7.54 (4 H, m), 7.59 (1 H, d, J 3.3 Hz), 7.38 (1 H, d, J 9.1 Hz), 7.20 (1 H, dd, J 9.1 and 2.7 Hz), 7.05 (1 H, d, J 2.7 Hz), 5.06 (1 H, dddq, J 6.8, 4.8, 3.3 and 7.7 Hz), 4.86 (1 H, dd, J 13.7 and 4.8 Hz), 4.32 (1 H, dd, J 13.7 and 6.8 Hz), 3.70 (3 H, s), 2.45 (3 H, br s); dF (CD3COCD3) µ71.25 (3 F, d, J 7.7 Hz), µ71.88 (6 F, s); dC (CD3COCD3) 162.16 (q, JCF 34.5 Hz), 154.43, 146.93, 140.20, 132.60, 131.51, 130.10, 124.94 (q, JCF 282 Hz), 124.36, 123.17, 121.60, 117.46 (q, JCF 294 Hz), 113.69, 56.37, 51.46 (q, JCF 32.7 Hz), 39.54, 21.51.Amine 3.·A methylene chloride solution (5 ml) of 2 (0.6 mmol) was refluxed for 4 h. The solvent was removed under reduced pressure and the crude mixture was submitted to FC (hexane– AcOEt, 5:1), affording the amine 3 as main product (46%) together with a minor amount of imine 4 (6%).Amine 3: Rf 0.43 (hexane–AcOEt, 4:1); dH (CDCl3) 7.03 (4 H, s), 7.00 (1 H, d, J 2.8 Hz), 6.83 (1 H, dd, J 8.5 and 2.8 Hz), 6.72 (1 H, d, J 8.5 Hz), 3.72 (3 H, s), 3.50 (2 H, br signal), 2.28 (3 H, br s); dC (CDCl3) 152.33, 142.36, 135.65, 132.64, 129.85, 127.35, 120.62, 117.65, 116.64, 116.42, 55.84, 20.93 (Found: C, 68.48; H, 6.49; N, 5.40%. C14H15NOS requires C, 68.54; H, 6.16; N, 5.71%). The same amine 3 was obtained in 80% yield upon treatment of a solution of the imine 4 (0.2 mmol) in THF (4 ml) with 2 ml of 1 M aqueous HCl or neat trifluoroacetic acid (2 equiv.) at room temperature overnight.Imine 4.·A methylene chloride solution (5 ml) of 2 (0.4 mmol) was treated with 2 equiv. of neat triethylamine and stirred for 2 h at room temperature. The solvent was removed under reduced pressure and the crude mixture was submitted to FC (hexane–AcOEt, 4:1), affording the imine 4 in 90% yield. Rf 0.61 (hexane–AcOEt, 4:1); dH (CDCl3) 7.29 and 7.13 (4 H, m), 6.72 (1 H, dd, J 8.5 and 2.7 Hz), 6.67 (1 H, d, J 2.7 Hz), 6.58 (1 H, d, J 8.5 Hz), 3.69 (3 H, s), 2.33 (3 H, s), 1.92 (3 H, br s).dF (CDCl3) µ75.50 (3 F, br s). dC (CDCl3) 158.21 (q, JCF 33.8 Hz), 157.44, 139.01, 138.23, 133.20, 132.00, 130.16, 119.66 (q, JCF 278 Hz), 119.47, 116.89, 114.90112.18, 55.39, 21.13, 14.68. Received, 2nd June 1997; Accepted, 22nd July 1997 Paper E/7/03814C References 1 (a) S. Wolfe, R. J. Bowers, S.K. Hasan and P. M. Kazmaier, Can. J. Chem., 1981, 59, 406 and references cited therein; (b) K. Yamamoto, S. Yamazaki, I. Murata and Y. Fukuzawa, J. Org. Chem., 1987, 52, 5239; (c) J. E. McCormick and R. S. McElhinney, J. Chem. Soc., Perkin Trans. 1, 1985, 93. 2 (a) P. Bravo, M. Zanda and C. Zappal`a, Tetrahedron Lett., 1996, 37, 6005; (b) P. Bravo, A. Farina, V. P. Kukhar, A. L. Markovsky, S. V. Meille, V. A. Soloshonok, A. E. Sorochinsky, F. Viani, M. Zanda and C. Zappal`a, J. Org. Chem., 1997, 62, 3424. 3 O. De Lucchi, U. Miotti and G. Modena, Organic Reactions, ed. L. A. Paquette, Wiley, New York, 1991, vol. 40. 4 P. Bravo, G. Cavicchio, M. Crucianelli, A. OL. Markovsky, A. Volonterio and M. Zanda, Synlett., 1996, 887. 5 For recent reports on stable sulfonium salts formed under Pummerer conditions see: (a) M. Amat, S. Hadida, G. Pshenichnyi and J. Bosch, J. Org. Chem., 1997, 62, 3158; (b) M. Amat. M.-L. Bennasar, S. Hadida, B. A. Sufi, E. Zulaica and J. Bosch, Tetrahedron Lett., 1996, 37, 5217. We thank Professor J. Bosch for providing us with unpublished experimental data. For unusual Pummerer cyclizations see also: (c) S. G. Pyne and A. R. Hajipour, Tetrahedron, 1994, 50, 13 501. For an overview on the chemistry of sulfonium salts see: (d) The Chemistry of the Sulphonium Group, Parts 1 and 2, ed. C. J. M. Stirling and S. Patai, Wiley, New York, 1981. 6 A. Arnone, P. Bravo, S. Capelli, G. Fronza, S. V. Meille, M. Zanda, G. Cavicchio and M. Crucianelli, J. Org. Chem., 1996, 61, 3375.