Catalytic Conjugate Addition of Cyanide to Enones: Cooperative Catalysis of Ni(0) and Gd(OTf)₃

Abstract

An efficient, synthetically useful catalytic cunjugate addition of cyanide to enones was developed using cooperative catalysis of Ni(0) and Gd(OTf)₃. The co-catalyst, Gd(OTf)₃, dramatically accelerated the reaction. The substrate scope is broad, including cyclic, linear, branched, and aromatic enones. Synthetic efficiency of the key conversion in our Tamiflu synthesis, conjugate cyanation of an enone, was significantly improved by using this new method. Gadolinium triflate is supposed to facilitate the oxidative addition of Ni(0) to enones, which constitutes a key step in the catalytic cycle.

cooperative catalysis - conjugate addition - cyanide - nickel - gadolinium

References and Notes

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3 We recently developed the first synthetically useful enantioselective conjugate addition of cyanide to enones using a polymetallic Gd catalyst. See: Tanaka Y. Kanai M. Shibasaki M. J. Am. Chem. Soc.  2008,  130:  6072 

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Yields of 2e using other Lewis acid co-catalysts: 13% (TiCl₄), 71% (ZnI₂), 51% [Cu(OTf)₂], 89% (BF₃˙OEt₂).

7

When using TMSCN as a nucleophile, the 1,4-addition products, enol TMS ethers, overreacted with the starting enones under the reaction conditions in the presence of Gd(OTf)₃ in some cases, leading to diminished yields of the 1,4-products. For example, when 2-cyclohepten-1-one (1c) was used as a substrate, the reaction using TMSCN produced a complex mixture, yielding only 40% of the 1,4-addition product. On the other hand, the reaction using TBSCN was clean, yielding 92% of 3c.

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9

In the absence of Gd(OTf)₃, TBSCN was not an effective nucleophile; the yield of 3b decreased to as low as 6% using TBSCN in the absence of Gd(OTf)₃, whereas the yield was 77% using TMSCN in the absence of Gd(OTf)₃ (Table  [³] , entry 3).

10

General Procedure for Ni/Gd(OTf) ₃ -Catalyzed Conjugate Addition of Cyanide to Enones (Table 2, entry 4)
The reaction was performed using degassed solvents under Ar atmosphere. To a solution of Ni(cod)₂ (1.7 mg, 0.006 mmol) in THF (0.2 mL), norbornadiene (1.83 µL, 0.018 mmol) was added. Gadolinium triflate (3.6 mg, 0.006 mmol) was added to the mixture, followed by the addition of 2-cyclohexene-1-one (1b: 29.0 µL, 0.30 mmol). Then, TBSCN (63.6 mg, 0.45 mmol) in THF (0.1 mL) was added to start the reaction. After stirring for 1 h, the reaction mixture was directly loaded on SiO₂ column (Caution! Highly toxic HCN is generated in this step. This operation should be conducted in a well-ventilated hood), and purified by flash column chromatography (SiO₂, Et₂O-hexane, 1:20) to afford 3b (62.6 mg, 0.264 mol) in 89% yield.

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