Easy and general synthesis of unsymmetrical α-halogeno ketones

摘要

2890 j. CHEM. SOC. PERKIN TRANS. 1 1991 Easy and General Synthesis of Unsymmetrical a-Halogeno Ketones Jose Barluenga,a.* Lujan Llavona,a Miguel Yusb and Jose M. Concellona a Departamento de Quimica Organometalica, Facultad de Quimica, Universidad de Oviedo, 3307 I Oviedo, Spain Departamento de Quimica Organica, Facultad de Ciencias, Universidad de Alicante, 03690 Alicante, Spain The reaction of carboxylic acid esters 1with in situ generated bromohalomethyllithium (1 :2 molar ratio) at -78 "C followed by reaction with lithium dialkylcuprate (1 :1 molar ratio) at 0 "C,leads, after hydrolysis, to the corresponding a-chloro or a-bromo ketones 3. -Halogeno ketones derivatives are an important class of organic compounds, the chemistry of which occupies a key position in modern organic chemistry, and the literature indeed proves the wide synthetic potential of this class of compounds.' However, to our knowledge, the syntheses of unsymmetrical a-halogeno ketones reported are not simple,* or the starting materials are not commercially a~ailable,~ or they can only be used for the preparation of halogenomethyl ketone^.^ Recently we described the synthesis of ,a-dihalogenomethyl ketones,' and a,a,a'-trihalogenomethyl ketones from in situ generated dihalogeno- methyllithium 'and carboxylic or a-halogenocarboxylic acid esters respectively.We now report a simple, general and easy one-pot methodology for preparation of unsymmetrical a-halogeno ketones using dihalogenomethyllithium, carboxylic acid esters and lithium dialkylcuprates.The reaction of several carboxylic acid esters 1 with bromo- chloromethyllithium or dibromomethyllithium (1 :2 molar ratio) at -78 "C and further treatment with lithium dialkyl- cuprate (1: 1 molar ratio) at 0 "C led, after hydrolysis, to the corresponding a-chloro or a-bromo ketones 3, respectively (Scheme 1 and Table l).? 0 i, ii OLi -R+HBrX iii. iv- OEt X 1 2 3 Scheme 1 Reagents and conditions: i, 2 mol equiv. BrClCH,, Br,CH,; ii, 2 mol equiv. LDA, -78 "C; iii, R2,CuLi, 0 "C; iv, aq. HCl, 0 "C Bromochloromethyllithium and dibromomethyllithium were generated in situ by treatment of bromochloromethane or dibromomethane with lithium diisopropylamide. The proposed mechanism proceeds uiu 2 as intermediate, which is stable under the reaction conditions due to the presence of the electronegative halogen ~ubstituents.~ The alkylation of 2 with t Typical procedure: To a stirred solution of bromochloromethane or dibromomethane (10 mmol) and the starting carboxylic acid ethyl ester 1 (5 mmol) in tetrahydrofuran (THF) (10 cm3) was added a solution of lithiumdiisopropylamide in THF (20 cm3) and diethyl ether (10 cm3) during 10 min at -78 "C.The mixture was stirred for 10 min at the same temperature and then was added a solution of lithium dialkyl- cuprate (5 mmol) (prepared from CuI (5 mmol) and the corresponding organolithium compound (10 mmol) in diethyl ether (10 cm3) at 0 "C. After 30 min the mixture was hydrolysed with aq.HCl (6 mol drn-,; 10 cm3), the solid was filtered off, the filtrate was extracted with Et,O, and the ethereal layer was dried (Na,SO,). The solvents were removed (1 5 mmHg) and the resulting residue was distilled to afford the corresponding halogenated ketone 3. Table 1 Preparation of n-chloro or a-bromo ketones 3" Selected 13C NMR data of 3' R' X R2 Yieldb() d,,,, a,, Pr Pr Pr' C1 c1c1 Me Bu Bu 83 87 84 58.0 63.5 61.4 204.7 205.0 208.3 Bu' C1 Bu 78 63.7 204.9 Ph PhCHSH C1c1 Bu Me 50 37 57.5 57.7 193.4 208.4 PhCH=CH CI Bu 85 62.9 193.6 Pr Br Me 68 47.2 203.7 Pr Br Bu 78 53.5 203.9 Pr' Br Me 50 45.8 207.9 " All products 3 were fully characterized by spectroscopic method (IR, 'H and 13C NMR, and mass spectra); purity (>95) was checked by GLC.Isolated yield based on the starting ester. In CDCI,; recorded in a Bruker AC-300 spectrometer. lithium dialkylcuprate affords, after hydrolysis, the a-halogen- ated ketone 3. In summary, we believe that the methodology described in this communication represents a simple, rapid and versatile one-pot procedure for the synthesis of unsymmetrical a-bromo or a-chloro ketones 3 starting from commercially available materials. References See, e.g., N. De Kimpe and R. Verhe, in The Chemistry of a-Haloketones, a-Haloaldehydes and x-Haloimines, ed. s. Patai, J. Wiley, Chichester, 1988. (a)C. J. Kowalksi and M. Hagne, J. Org. Chem., 1985,50, 5140; (b)J. Villieras, B. Kirschleger, R. Tarhouni and M. Rambaud, Bull. Soc. Chim. Fr., 1986,470. (a)B. Hahn, B. Kopke and J. Voss, Liebigs Ann. Chem., 1981,lO;(b)S. Motohashi and M. Satomi, Synthesis, 1982, 1071. (a)G. Friour, G. Cahiez and J. F. Normant, Synthesis, 1984,37; (b)G. Capozzi, G. Romeo, V. Lucchini and G. Modena, J. Chem. Sor., Perkin Trans. 1, 1983, 83 I. J. Barluenga, L. Llavona, J. M. Concellon and M. Yus, J. Chem. SOC., Perkin Trans. 1, 1991, 297. J. Barluenga, L. Llavona, J. M. Concellon and M. Yus, Synthesis, 1990, 1003. J. Barluenga, J. L. Fernandez-Simon, J. M. Concellon and M. Yus, J. Chem. SOC.,Perkin Trans. 1, 1989, 77 and refs. cited therein. Paper 1/04089H Received 6th August 199 1 Accepted 9th September 199 1