Reduction of a,(?-Unsaturated Ketones by LiAlH4-CUI
J. Org. Chem., Vol. 41, No. 11, 1976 1939
New and Effective Reagents for 1,4 Reduction of a,@-Unsaturated Ketones, LiAlH4-CUI and Its Reactive Species H2AlI E. C. Ashby,* J. J. Lin, and R. Kovar School of Chemistry, Georgia Institute of Technology, Atlanta, Georgia 30332
Received August 26,1975 Conjugate reduction of six enones by the new reagent LiAlH4-CuI has been studied. The optimum conditions for conjugate reduction depend on the ratio of LiAlH4:CuI:enone, temperature, solvent, and reaction time involving contact of LiAlH4 and CUIbefore the enone is added. Enone I can be reduced in quantitative yield and 100%regioselectivity in 1 h or less when the ratio of LiA1Hr:CuI:enone is 1:4:1,the solvent is THF, and the temperature is 0 "C. The enones 11-VI also can be reduced in high yield and 100%regioselectivity. Reduction of enones I and I11 with LiAlH4-Tic13 proceeds with 100% regioselectivity; however, the yields are lower (66 and 34%, respectively) compared to the results obtained with the LiAlH4-CUI reagent. The reagent LiAIH4-FeC13 was found to be ineffective for conjugate reduction. The new reagents (LiAlH4-CUI and LiAlHd-TiC13) show different stereoselectivity than LiAlH4 toward 4-tert-butylcyclohexanone and 3,3,5-trimethylcyclohexanone.Compared with LiAlH4-Cu1, related reagents (LiAlH4-CuCl, LiAlH4-HgI2, and LiAlHh-HgCls) show less regioselectivity in enone reduction; however, the reagent AlH3-CuI is as effective in conjugate reduction as LiAlH4-CuI. H2AlI has been found to be the reactive species of the reagents LiAlH4-CUI and AlH3-CUI. The compounds HzAlX and HAlX2 where X = I, Br, and C1 were synthesized independently and were evaluated as conjugate reducing agents. mostly 1,2 reduction, the 1,4 reduction product is assumed to arise from a species other than LiAlH4. We have studied a wide variety of stoichiometric ratios of LiAlH4:CuI:enone (runs 4-19) and have found that a ratio of 1:4:1 gives the best results under the conditions that LiAlH4 and CUI are allowed to react before the addition of enone. At this stoichiometric ratio enone I was reduced in quantitative yield and 100% regioselectivity to the conjugate reduction product in T H F a t 0 "C when the reaction was allowed to proceed for 1h. Stoichiometry relating the reactive species to ketone is important (runs 14-16) since a significant amount of enone is recovered unreacted when the LiAlH4:CuI:enone ratio is 1:4:4 or 1:4:2. When the LiAlH4-CuI ratio is 1:l or 1:2 a significant amount of 1,2 product or unreacted ketone or both are observed (runs 4-11). When LiAlH4 and CUI are mixed a t 0 "C in T H F a deep black color immediately results with some gas evolution. It was found t h a t -3 min reaction time is required (runs 17-19) for all of the LiAlH4 to be consumed so that no 1,2 reduction product is observed. Reaction of the active reagent with the enone appears to be over in 30-60 min. Temperature studies clarify the stability of the LiAlH4-CUI reagent. No reaction between LiAlH4 and CUIoccurs a t -78 "C (run 26), slow reaction a t -20 "C with some 1,2 reduction and recovered enone (run 27), and partial decomposition of Results and Discussion the active reagent a t room temperature (run 28). When The enone 2,2,6,6-tetramethyl-trans-4-hepten-3-one LiAlH4 and CUI were mixed a t 0 "C and then cooled to -78 (enone I) was chosen as a representative enone for this study "C, no reaction took place as evidenced by complete recovery (eq 1).Reaction products were identified by NMR and comof the enone (run 26). On the other hand, generation of the pared with authentic samples. Yields were determined by active reagent a t 0 "C followed by cooling to -20 "C before GLC using an internal standard. enone addition (run 27) resulted in 84% reaction with 100% regioselective formation of the conjugate reduction product. Since 10% ketone was recovered, it is clear that reduction of the substrate a t -20 "C has no advantage over reduction a t 0 "C. On the other hand, when the reagent was generated a t 0 "C and allowed to warm to room temperature, 67% conjugate reduction product was observed with 29% recovery of the ketone. Apparently enough of the reagent decomposes at room temperature that a substantial amount of the starting material is recovered. I t appears then, that the optimum temperature for generation of the reagent and addition of the substrate is OH 0 "C. (1,4 reduction product) (1,2 reduction product) The optimum conditions (1:4:1 stoichiometry, 0 "C, THF) The effect of LiAlH4-CuI on enone I has been studied in have been applied to other enones (111,IV, V, and VI). The detail and the results are shown in Table I. Since LiAlH4 (runs yields are generally high and the regioselectivity is 100%. 1and 2) and LiAlH4-CuI (catalytic amount of CUI,run 3) give However, the slower reaction rate for cis enone I1 and the
Catalytic hydrogenation1 (Hz-Pd/C) and dissolving metal reduction2 (Na-aqueous "3) are the most common methods for effecting conjugate reduction of enones. The shortcomings of these methods are mainly inconvenience and in many cases low yields. Recently, LiCuRH3 and KB(sec-Bu)3H4 have been reported as effective reagents for conjugate reduction of enones. However, in the former case the reagent is quite difficult t o prepare whereas in the latter case only 1,2 reduction is observed when p substituents are present in the enone. A method of accomplishing conjugate reduction of a,(?-unsaturated carbonyl compounds by the use of an easily prepared reagent would indeed be very useful. I t is well known that LiAlH4 favors 1,2 reduction of en one^.^ On the other hand, the reactivity of LiAlH4 can be substantially modified by the addition of metal salts. In this connection LiAlH4-AlCK36 has found unusual applicability in epoxide reductions, LiA1(OCH3)3H-Cu17 can effect reductive removal of halo and mesyloxy groups, and LiA1H4-TiC1sS has been found t o be an excellent coupling reagent. Since LiAlH4 is commercially available and convenient to handle as a standardized solution in ether or THF, its ability, in admixture with certain metal halides e.g., CUI, CuBr, CuC1, TiC13, HgI2, HgC12, and FeC13, to effect conjugate reduction of enones was studied.
J. Org. Chem., Vol. 41, No. 11, 1976
1940
Ashby, Lin, and Kovar
Table I. Reduction of Enones with LiAlH4-CUI in THF Molar ratio
Products, %a Enone,
Expt
Enone
LiAlH4
CUI
1.0
0
1.0 0.42 1.0 1.0 1.0 1.0
Enoneb
Temp, "C
% recovered
1,4
1,2
0 1
//
H H
t -BuC=C-CBu-
t
4.0
0
12
3
83
0 0.01 1.0
1.0 1.0 2.OC
0 0
0
99 92 50
1.0
1.0
1.0
0.5
4.06
0 7 40 64 49 46 81 58 38 95 82 87
trans (I) 2 3 4 5 6
7
I I
I I
I I I
1,Q
I I I I
1.0
2.0 2.0 2.0 2.0
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 €,0 1.0 1.0 1.0 1,Q 1.0 1.0 1.0 1.0 1.0
2.0 2.0 3.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0
1.0 0.5 1.0 4.0 4.0' 2.0 l,Qe 1.0f 1.8
1.0
30
1.0
4,0
31
1.0
32
8 9 10 11 12 13 14 15 16 17 18 19 20 21
22 23 24 25 26
27 28 29
1,0
I
I I I I
I I I
I I I I I
I I cis (11)
2.QC 2.Qegd
2.0c
0 0 0 0
0 0 RT 0
0 0 0
0
0 0 0 0 54 6 0 62 0 0 0 69 20 21 0 0 0 0 0 47 47 0 0
27 -44 6 9 34
