J. CHEM. SOC. PERKIN TRANS. 1 1995 741 A new and convenient one-pot synthesis of a,p-unsaturatedtrifluoromethyl ketones Wei Sheng Huang and Cheng Ye Yuan * Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fengling Lu, Shanghai, 200032, China Alkylphosphonates react with N-phenyltrifluoroacetimidoylchloride in the presence of lithium diisopropyl- amide to afford mixtures which when treated with aldehydes and subjected to acid hydrolysis afford a,P-unsaturated trifluoromethyl ketones. a,P-Unsaturated trifluoromethyl ketones have potential as versatile synthetic precursors in the preparation of trifluoro- methyl-containing compounds, themselves of interest in view of their unique biological properties. However, their synthesis is not simple.Thus, before CH2=CHCH3(CF3)OH can be oxidized with Dess-Martin's reagent,2 CF,CHO and unstable fluorinated organometallic reagents are involved in its preparation. Attempted aldol condensation of trifluoroacetone with aldehydes provides only modest yields of unsaturated trifluoromethyl ketones with aryl or unsaturated aldehyde^,^ and the addition of organocuprate reagents to alkynyl trifluoromethyl ketones affords both 1,2- and 1,4-addition adducts.6 Linderman and co-workers have recently reported a three-step route to p-alkyl-a$-unsaturated trifluoromethyl ketones,' but this has limitations because of its use of Dess- Martin's reagent, inaccessible starting materials and multi- step manipulation. Herein we report a simple and general one-pot synthesis of a,P-unsaturated trifluoromethyl ketones from diethyl alkylphosphonates, N-phenyltrifluoroacetimidoyl chloride and aldehydes. 1 3 4 2 6 7 5 Scheme 1 Reaction conditions and reagents: i, LDA (2 equiv.)-THF, -70 "C; ii, compd.2, -70 "C; iii, R'CHO, -70 "C;iv, 2 mol dm-3 HCI, room temp. Trifluoroacetimidoyl chlorides have been reported to react with Grignard reagents to afford trifluoromethyl ketimines.' When we allowed N-phenyltrifluoroacetimidoyl chloride 2 to react at -70 "C with diethoxyphosphorylmethyllithium,gener-ated in situ from equimolar proportions of diethyl methylphos- phonate and butyllithium, quenching of the reaction mixture and work-up gave a mixture of the imino phosphonate 6 and enamine 7(72 :28 by 'H NMR).When treated with butyllithium 6 and 7 gave rise to the same anion 3 (R' = H), which under- went Horner-Emmons olefination with propionaldehyde to afford the l-aza-1,3-diene 4 (R' = H, R2 = Et). This was assigned an E-configuration on the basis of the vinylic H,H coupling constant (J 17.4 Hz). This reaction constitutes a one-pot synthesis of an a$-unsaturated trifluoromethyl ketone in which (see Scheme 1) the anion 3 is formed by initial treatment of the alkylphosphonate 1 at -70 "C with lithium diisopropyl- amide (2 equiv.) and then with N-phenyltrifluoroacetimidoyl chloride 2. Subsequent reaction of the anion 3 with aldehydes followed by acid hydrolysis provided good yields of the expected products 5. Butyllithium cannot be used as the base since, in excess, it reacts with the imidoyl chloride 2 more rapidly than diethoxyphosphorylmethyllithium.As demonstrated in Table 1, a variety of aldehydes (aliphatic, aromatic and unsaturated) may be converted into a,p-unsaturated trifluoromethyl ketones. All the compounds showed a singlet in their I9FNMR spectra and were identified as E-isomers from vinylic H,H or Me,H coupling constants. The stereochemistry is probably the result of the bulky N-phenyltrifluoroacetimidoylgroup which favours the less hindered threo diastereoisomers of the oxyanion intermediates in the course of the Horner-Emmons reaction, yielding E-olefins upon syn elimination. Although 2-trifluoromethyl-2-(methylimino)ethylphosphon-ate, which is similar to the intermediate 6, has been utilized by Ishihara to prepare a,P-unsaturated trifluoromethyl ketones,' the approach is inconvenient since it requires an earlier four- step preparation of the imino phosphonate from pentafluoro- propionic acid.It is also uneconomical since not easily available sources of fluorine and phosphorus are wasted. Our method- ology, which first described the reaction of alkylphosphonate with imidoyl chloride, is both simpler and more convenient because it is a one-pot operation starting from readily obtain- able materials." Since a variety of substituted methyl phos- phonates (R' = functional group) are available by Arbuzov and Michaelis-Becker reactions," the present method is a general one, providing a,P-disubstituted a,&unsaturated tri- fluoromethyl ketones, not preparable by earlier methods. It is significant that our procedure is stereospecific providing E-isomers exclusively.Experimenta1 Typicalprocedure.To a stirred solution of diisopropylamine (10 mmol, 1.54 cm3) in dry THF (20 cm3) was added dropwise butyllithium (1.6 mol dmP3 in hexane; 10 mmol, 6.25 cm3) at 0 "C. After 10 min, the solution was cooled to -70 "C and diethyl methylphosphonate (5 mmol, 0.75 cm3) was added to it. After the mixture had been stirred for 30 min at the same temperature, N-phenyltrifluoroacetimidoylchloride (5 mmol, 0.80 cm3) was gradually added to it and stirring was continued at -70 "C for 1 h; freshly distilledp-tolualdehyde (5 mmol, 0.59 cm3) was then added dropwise.The resulting mixture was warmed to room temperature over 2 h and then stirred over- night. After addition of 2 mol dm-, aq. HCI (10 cm3) to the mixture it was stirred at room temperature for 4 h and then 742 Table 1 a$-Unsaturated trifluoromethyl ketones R' RZ Yield (%) 5a H Bu 48 5b 5 c H H Pentyl Ph 52 59 5d 5e H H p-MeC& p-FC6H4 63 72 extracted with diethyl ether (3 x 20 cm3). The combined extracts were washed successively with 5% aq. NaHCO, and brine until pH 6 was reached, after which they were dried (Na2S0,) and concentrated under reduced pressure. The crude product was subjected to column chromatography on silica gel using light petroleum as eluent to give compound 5d (0.67 g, 63%) as a pale yellow oil (Found: C, 61.6; H, 4.3.C,,H,F,O requires C, 61.7; H, 4.2%); v,,,(neat)/cm-' 1720 (GO) and 1620 (M);6,(300 MHz; CDCl,; Me,Si) 7.86 (1 H, d, J 15.8, =CHPh), 7.54 (2 H, d, J 8.2, Ph), 7.25 (2 H, d, J 8.0, Ph), 6.88 (1 H,d,J15.8,=CHCOCF3)and 2.41 (3 H,s,Me);6,(60 MHz; CCl,; CFCI,) -76.7 (s); m/z 214 (M', 30%),199 (71), 149 (45), 145 (loo), 117 (53), 115 (86), 91 (55) and 57 (35). Acknowledgements We gratefully acknowledge the financial support of the National Natural Science Foundation of China. References 1 (a) R. Filler and Y. Kobayashi, Biomedicinal Aspects of Fluorine Chemistry, Kodansha, Tokyo, 1982; (b) N. Ishikawa, Biologically Active Organojluorine Compounh, CMC, Tokyo, 1990. J.CHEM. SOC. PERKIN TRANS. 1 1995 R' R2 Yield (%) 5f H P-NOZC~H, 59 5g 5h 5i 5j H Me Me Me PhCH=CH p-MeC,H4 p-FC&, PhCHXH 60 54 58 60 2 R. J. Linderman and D. M. Graves, J. Org. Chem., 1989,54,661. 3 T. Kitazume, J. T. Lin, T. Yamazaki and M. Akeda, J. Fluorine Chem., 1989,43, 177. 4 (a) M. Tordeux, C. Francese and C. Wakselman, J. Chem. Soc., Perkin Trans. I, 1990, 1951; (b) N. J. O'Reilly, M. Maruta and N. Ishikawa, Chem. Lett., 1984, 517; (c) T. Kitazume and N. Ishikawa, J. Am. Chem. Soc., 1985, 107, 5186. 5 D. Mead, R. Loh, A. E. Asato and R. S. H. Liu, Tetrahedron Lett., 1985,26,2873. 6 R. J. Linderman and M. S. Lonikar, Tetrahedron Lett., 1987, 28, 5271. 7 R. J. Linderman, E. A. Jamois and S. D. Tennyson, J. Org. Chem., 1994,59,957. 8 K. Uneyama, 0. Morimoto and F. Yamashita, Tetrahedron Lett., 1989,30,4821. 9 T. Ishihara, T. Maeyawa and T. Ando, Tetrahedron Lett., 1983,24, 4229. 10 K. Tamura, H. Mizukami, K. Maeda, H. Watanabe and K. Uneyama, J. Org. Chem., 1993,58, 32. 11 R. Engel, Synrhesis of Carbon-Phosphorus Bonds, CRC Press, Florida, 1988. Paper 5/00354G Received 20th January 1995 Accepted 26th January 1995
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