Lewis Acid-Promoted Coupling Reactions of Acid Chlorides with Organoaluminum and Organozinc Reagents Mitsuhiro Arisawa, Yasuhiro Torisawa, Michiaki Kawahara, Masamichi Yamanaka, Atsushi Nishida, and Masako Nakagawa* Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263, Japan Received February 11, 1997 X An efficient synthesis of R,-unsaturated ketones by the reaction of acid chlorides with trialkyl- aluminum (1/3 mole equiv) in the presence of AlCl 3 (1 mol equiv) is described. Dialkylzincs were also useful and are easier to prepare than trialkylaluminum. Reaction of RCOCl with R′AlCl 2 or R′ 2 AlCl gave R′COR, without AlCl 3 , in high yield. The coupling reactions of alkylmetal reagents and acid halides provide a useful method for synthesizing ketones. 1-3 During our study of the Diels-Alder reac- tion, 4 we became interested in reacting acid chlorides with organoaluminum reagents to give ketones in a single operation. Inspired by some earlier reports, 2,3 we devel- oped a practical method for producing (E)-pent-3-en-2- one (1) (Scheme 1), a useful precursor for some silyloxy dienes, by reacting crotonyl chloride and triethylalumi- num. 5 In this report, we describe this reaction in detail and its extension to an organozinc reagent. When a CH 2 Cl 2 solution of trimethylaluminum (0.4 equiv) was added to a solution of crotonyl chloride and aluminum chloride (1.0 equiv) in CH 2 Cl 2 , alkylation proceeded to give (E)-pent-3-en-2-one (1) quantitatively (Table 1). The presence of aluminum chloride was essential; without aluminum chloride, only 9% of 1 was obtained. Although aluminum fluoride and gallium chloride were less effective, methylaluminum chloride and dimethylaluminum chloride were effective for the alkylation of crotonyl chloride. The reaction of phenylpropionyl chloride with tri- methylaluminum was interesting from a mechanistic point of view. When a solution of aluminum chloride was added to a mixture of the acid chloride and trimethyl- aluminum, the desired propiophenone was obtained in 91% yield (Scheme 2). However, the addition of tri- methylaluminum to a mixture of aluminum chloride and the acid chloride under the same conditions gave 1-in- danone quantitatively. These results suggested that the reaction did not proceed via the simple acylinium ion complex (A in Figure 1), but rather proceeded via the acyl chloride-AlR′ 3 complex (B) activated by the AlClXY species (X, Y ) Cl or alkyl) as shown in Figure 1. A bulky aluminum reagent, such as trioctylaluminum, also worked without any problems. The general procedure, which has been reported previ- ously, 5 was generally reproducible for the preparation of a few grams of 1. However, we encountered a serious problem when we tried to prepare a large quantity (>10 g) of 1. Specifically, the product was contaminated by a varying amount of 3-chloropentan-2-one, and it was difficult to separate these compounds because of their close boiling points. The amount of contaminating chloro ketone depended on the workup prodedures (1:chloro ketone ) 1:1-10:1), such as the washing time using aqueous base and the time necessary for removal of CH 2 Cl 2 under atmospheric pressure. Finally, we estab- lished two procedures for the large-scale preparation of 1. One procedure consists of the elimination of hydrogen chloride from the chloro ketone to 1, basically as de- scribed in ref 6. The product obtained using this protocol sometimes contained a trace amount of ,γ-unsaturated ketone. Since the addition of HCl to 1 appeared to occur when CH 2 Cl 2 was removed by distillation under atmospheric pressure, the second procedure included the rapid distil- lation of a mixture of CH 2 Cl 2 and 1 under reduced pressure at less than 50 °C using a cold trap (-78 °C). The solvents were then distilled in the presence of quinoline. Purification of the residue by distillation under vacuum gave on the order of 30 g of pure 1. Regarding the preparation of organometallic reagents, dialkylzinc reagents are much easier to prepare and sometimes more stable than trialkylaluminums. 1,7 Thus, we next focused our attention on the use of dimethylzinc X Abstract published in Advance ACS Abstracts, June 1, 1997. * To whom correspondence should be addressed. Tel.: 81-43-290- 2908. Fax: 81-43-255-1574. E-mail: nakagawa@p.chiba-u.ac.jp. (1) See as general references: (a) Tamao, K. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, pp 463-464. (b) Larock, R. C. Comprehensive Organic Transformations; VCH Publishers: New York, 1989; pp 686- 691. (c) Posner, G. A. Org. React. 1975, 22, 253-400. (d) Shirley, D. A. Org. React. 1954, 8, 28-58. (2) Tolstikov, G. A.; Valitov, F. K.; Kuchin, A. V. J. Gen. Chem. (USSR) 1982, 51, 1359-1361. (3) (a) Wakamatsu, K.; Okuda, Y.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1985, 58, 2425-2426. (b) Takai, K.; Oshima, K.; Nozaki, H. Ibid. 1987, 54, 1281-1282. (4) Nagata, T.; Koide, Y.; Nara, K.; Itoh, E.; Arisawa, M.; Naruto, S.; Torisawa, Y.; Hino T.; Nakagawa, M. Chem. Pharm. Bull. 1996, 44, 451-453. (5) Arisawa, M.; Torisawa, Y.; Nakagawa, M. Synthesis 1995, 1371- 1372. (6) Odom, H. C.; Pinder, A. R. Organic Syntheses; Wiley: New York, 1988; Collect. Vol. VI, pp 883-886. Scheme 1 Scheme 2 4327 J. Org. Chem. 1997, 62, 4327-4329 S0022-3263(97)00244-2 CCC: $14.00 © 1997 American Chemical Society