1565
Organometallics 1995, 14, 1565-1566
Protonation of Acyllithium Reagents by Dichloromethane and Dichloroarylmethane: A New Method for the Synthesis of a,a-DichloroAlcohols George W. Kabalka," Nan-Sheng Li, and Su Yu Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600 Received February 7,1995@ Summary: The first example of the protonation of acyllithium reagents by dichloromethane and dichloroarylmethane is described. The reaction affords the corresponding a,a-dichloro alcohols in excellent yields.
Introduction. The transformation of organometallic reagents into useful synthetic intermediates has played an important role in organic chemistry for many years. Recently, studies involving acyl anion reagents generated via the carbonylation of organometallic reagents with carbon monoxide have proven to be an especially productive area of Much attention has been focused on the nucleophilic acylation of electrophiles utilizing acyllithium reagents. For example, Seyferth reported that acyllithium reagents, generated in situ from an alkyllithium and carbon monoxide, react with aldehydes,l ketones,l est e q 8 lactone^,^ isocyanates,1°isothiocyanates,1°carbodiimides," carbon disulfide,12carbonyl sulfide,12organic to give acydisulfides,13 and trimethyl~hlorosilanes~~ lated products. Nudelman found that the acyllithium generated from phenyllithium and carbon monoxide, in the presence of alkyl bromides at -78 "C, gave diphenylalkylcarbinols.l 5 , I 6 Although Seyferth predicted that nucleophilic acylation might also be applied in protonation and alkylation reactions to give aldehydes and ketone^,^ no report on the protonation and alkylation of acyl anion reagents has appeared in the literature. Recently, we found that trialkylboranes reacted with acyllithium reagent to afford ketones in modest yields.17 During our investigation of this reaction, the acyllithium reagent was preformed from n-butyllithium and carbon @Abstractpublished in Advance ACS Abstracts, April 1, 1995. (1)Seyferth, D.; Weinstein, R. M.; Hui, R. C.; Wang, W.-L.; Archer, C. M. J . Org. Chem. 1992,57, 5620 and references cited therein. (2)Orita, A.; Fukudome, M.; Ohe, K.; Murai, S. J. Org. Chem. 1994, 59,477 and references cited therein. (3)Seyferth, D.; Weinstein, R. M.; Wang, W.-L.; Hui, R. C.; Archer, C. M. Isr. J . Chem. 1984,24,167. (4)Seyferth, 9.; Hui, R. C.; Weinstein, R. M.; Wang, W.-L. Nova Acta Leopold. 1985,59,335;Chem. Abstr. 1988,108,6056t. (5)Narayana, C.; Periasamy, M. Synthesis 1985,253. (6)Wakefield, B. J. Organolithium Methods; Academic Press: London, 1988;pp 95-97. (7)Hui, R. C.; Seyferth, D. Org. Synth. 1990,69,114. (8) Sevferth. D.: Weinstein. R. M.: Hui.' R. C.: Wana. W.-L.: Archer. C. M. J.-Org. &e&. 1991,56,5768: (9)Weinstein, R. M.;Wang, W.-L.; Seyferth, D. J . Org. Chem. 1983, 48,3367. (10)Seyferth, D.; Hui, R. C. Tetrahedron Lett. 1984,25,5251. ( l l ) S e y f e r t h , D.;Hui, R. C. J. Org. Chem. 1985,50,1985. (12)Seyferth, D.; Hui, R. C. Tetrahedron Lett. 1984,25,2623. (13)Seyferth, D.; Hui, R. C. Organometallics 1984,3,327. (14)Seyferth, D.; Weinstein, R. M. J . Am. Chem. SOC.1982,104, 5534. (15)Nudelman, N. S.;Vitale, A. A. J . Org. Chem. 1981,46, 4625. (16)Vitale, A. A,; Doctorovich, F.; Nudelman, N. S. J . Organomet. Chem. 1987,332,9. (17)Kabalka, G. W.; Gotsick, J. T.; Pace, R. D.; Li, N . 3 . Organometallics 1994,13,5163. 1
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0276-7333/95/2314-1565$09.Q0l0
Scheme 1 RlLi
+
CO + CHC12R2
1. -llO°C, l h W
PH
R'C HCC 12R2
2 . O'C, NH4CI 1
2
3
R1 = M u , s-Bu, t-Bu. R2 = H, Ar
monoxide according to Seyferth's methodl and then equimolar quantities of a butylborane reagent in methylene chloride were added. After the reaction mixture was worked up oxidatively, we found that the reaction produced the desired ketone along with a significant quantity of l,l-dichloro-2-hexanol. These results encouraged us to investigate the reaction of acyl anions with dichloromethane, and its derivates, since a,a-dichloroalcoholsare important synthetic intermediates, which can be transformed into substituted chloroethylene oxides or a-chlorocarbonyl The synthesis of a,a-dichloro alcohols is usually achieved via reduction of a,a-dichloro or by the addition of the dichloromethyl anion to aldehydes or ketones.21s22However, no general method exists for the synthesis of a,a-dichloro a-aryl alcohols.23 We wish to report the preliminary results of a study involving the reaction of acyllithium reagents with dichloromethane (or dichloroarylmethane) to afford a,a-dichloro alcohols (Scheme 1). Results and Discussion. The reactions are straightforward. Commercially available alkyllithium reagents (n-butyl-, s-butyl-, and tert-butyllithium) were utilized in this initial study. However, as demonstrated by Seyferth for the nucleophilic acylation of chl~rosilane,'~ other alkyllithium reagents may be used. The reaction is initiated by the slow addition of the alkyllithium reagent to a solution of dichloromethane (or a dichloroarylmethane) in a 4:4:1 (by volume) solvent system of THF-EtzO-pentane saturated with carbon monoxide at -110 "C. After the alkyllithium is added, the reaction mixture is stirred at -110 "C for 1h, and then the reaction mixture is hydrolyzed using saturated aqueous NHdCl at 0 "C. After separation of the organic layer, and silica gel column chromatography, pure products are obtained in excellent yields (Table 1). (18)Kimpe, N. D.; Corte, B. D. Tetrahedron 1992,48,7345. (19)Gralak, J.; Valnot, J.-Y. Org. Prep. and Proced. Int. 1979,11, 107. ~. (20)Duhamet, P.; Duhamel, L.; Gralak, J. Bull. SOC.Chim. Fr. 1970, 3641. (21)Villieras, J.; Bacquet. C.; Normant, J. F. J . Organomet. Chem. 1975,97,325. (22)Normant, H. J . Organomet. Chem. 1975,100,189. (23)l,l-Dichloro-l-phenyl-2-hexanol was prepared by cathodic addition of trichloromethylbenzene to pentanal in only 25% yield: Jpn. 1988,61, 125. Steiniger, M.;Schaefer, H. J. Bull. Chem. SOC.
0 1995 American Chemical Society
1566 Organometallics, Vol. 14, No. 4, 1995 Table 1. Synthesis of a,a-DichloroAlcohols entry 2:l no.0 productb R1 RZ (molar equivy yield (%)d 15:l 1 3a n-Bu H 81 15:l 2' 3a 58 n-Bu H 6:1 n-Bu H 84 3 3a 4:1 81 4 3a n-Bu H 4:1 5' 3a n-Bu H 59 2:1 74 6 3a n-Bu H 1:l 62 n-Bu H 7 3a 6:1 23 S-BU H 8 3b 4:1 34 S-BU H 9 3b 15:l 10 3c t-Bu H 32 6:l 40 11 3c t-BU H 4:1 36 12 3c t-BU H 2:1 n-Bu Ph 97 13 3d 1:l n-Bu Ph 89 14 3d 2:1 n-Bu a-naphthyl 90 15 3e 1:l n-Bu a-naphthyl 87 16 3e 2:1 74 17 3f n-Bu p-CH&& 1:l 62 18 3f n-Bu p-CH&& n-Bu p-ClCsH4 2:l 90 19 3g 1:l 80 20 3g n-Bu p-ClC& 2:1 21 3h n-Bu p-BrC& 90 1:l 22 3h n-Bu p-BrC6Hd 86 a Acyllithium reagents were generated in the presence of the dichloro compounds at -110 "C in all experiments except where noted. All new products were characterized by appropriate spectral and elemental analyses. All known compounds were characterized by comparing their spectral and physical properties with those in the literature. Ratio of dichloro compound 2 to alkyllithium 1. Isolated yields based on alkyllithium reagent. e Acyllithium reagent was generated prior to the addition of dirhloromethane. f Experiment was carried out at -78 "C.
Scheme 2
0%
NHdCI
*
?H R1CHCC12R2
The reaction presumably occurs via the intermediate formation of an aldehyde generated by proton abstraction from the dichloro reagent by the initially formed acyl anion. The aldehyde then reacts with the chlorinestabilized anion as outlined in Scheme 2. As shown in Table 1,generation of the acyllithium in the presence of dichloromethane (Table 1, entry 1)was more efficient than generating the acyllithium prior to the addition of dichloromethane (Table 1, entry 2). In addition, product yields decreased when higher temperatures (-78 "C) were used (Table 1,entry 5). In most
Communications cases, excess dichloro reagent (2) resulted in an increased product yield; however, a large excess was not required. The reaction of a stoichiometric quantity of the dichloro compound (2) and the acyllithium also gave a,a-dichloro alcohols in good yields (Table 1, entries 7, 14,16,18,20, and 22). The reaction is most efficient when R is a primary alkyl group. Acyl anion reagents generated from secondary or tertiary alkyllithium reagents react with dichloromethane to give a,a-dichloro alcohols in modest yields (Table 1, entries 8-12). The lower yields observed with secondary and tertiary alkyllithium reagents may be due to the steric interactions between the bulkier aldehyde intermediates and the chlorinated anion. The preparation of l,l-dichloro-l-phenyl-2-hexanol (3d) is representative: in a three-necked, 250 mL, round-bottomed flask equipped with magnetic stirrer, glass-enclosed thermocouple probe, and a fritted-glass gas dispersion tube were added a,a-dichlorotoluene (1.61g, 10.0 mmol) and 150 mL of a 4:4:1(by volume) mixture of THF, diethyl ether, and pentane. The solution was cooled to -110 "C by means of a lowtemperature bath. Carbon monoxide was then continuously bubbled into the solution. After 30 min of carbon monoxide addition, n-butyllithium (5.0 mmol, 3.1 mL of a 1.6 M solution, in hexane) was added slowly via syringe over a period of approximately 45 min, forming a pale yellow solution. After the addition was complete, the reaction mixture was stirred at -110 "C for 1 h and warmed t o 0 "C. Hydrolysis was achieved by adding saturated aqueous ammonium chloride (40 mL). The two phases were separated, and the aqueous phase was extracted with diethyl ether (3 x 20 mL). The organic phases were combined, washed with a saturated NaCl solution (20mL), and then dried over anhydrous MgS04. The solvent was removed under reduced pressure, and the residue was isolated by silica gel chromatography (9:lhexane-ethyl acetate (v/v) as eluent) to give 3d23 (1.195g, 97% (Table 1, entry 13)). The reaction described in this communication provides a useful, one-pot synthesis of primary alkyl(dichloroalky1)carbinols and is the first example of acyllithium reagents being protonated to form aldehydes which further react with anions to afford alcohols. Further examination of the scope of this reaction is in progress.
Acknowledgment. We wish to thank the Department of Energy and the Robert H. Cole Foundation for support of this research. OM950099W
