Highly Enantioselective Conjugate Reduction of β,β‐Disubstituted α,β‐Unsaturated Nitriles

Abstract

Optically active nitrile compounds with a b-stereocenter are versatile synthetic intermediates for a number of biologically active compounds.[1] The nitrile group is a very useful synthetic group that can be transformed into other useful functionalities, such as amine, aldehyde, and carboxylic acid groups; furthermore, the isolation of nitrile-containing natural products continues to increase.[2] Despite recent advances in metal-catalyzed conjugate reductions, the development of asymmetric reductions of conjugated nitriles still remains challenging because of their intrinsic low reactivity [3] and the linearity of the CN group. The two asymmetric examples that we are aware of are the Co-catalyzed conjugate reduction of a,b-unsaturated nitriles [4] and the Rh-catalyzed hydrogenation of a,b-unsaturated nitriles.[5] However, the enantioselectivities achieved by these catalyst systems were significantly lower than those for analogous esters and amides, presumably because of the steric and coordinating environment exerted by the linear nitrile group (Scheme 1).Copper hydride ligated by non-racemic ligands has been used for effecting the asymmetric hydrosilylation of aromatic ketones, [6] imines, [7] enones, [8] a,b-unsaturated esters, [9] and nitroalkenes [10] in the presence of excess hydrosilane. However, an enantioselective asymmetric conjugate reduction method of a,b-unsaturated nitriles catalyzed by copper hydride has not been reported yet. Herein, we report a highly enantioselective conjugation reduction of a,b-unsaturated nitriles employing a

Asymmetric bioreduction of α,β-unsaturated nitriles and ketones

“…Some examples of metal catalyzed hydrogenation exist, but the enantioselective carbon-carbon bond reduction of conjugated nitriles remains a challenge due to their inherent low reactivity. 10 For example, the reduction of c-cyano-a,b-unsaturated ketones by a yeast species is known, but only product mixtures of the saturated keto nitrile and the corresponding saturated alcohol were obtained due to the presence of ketone reductases in the whole cells. 11 Smallridge has described the reduction of 2-phenyl-2-propenenitrile to (R)-phenylpropanenitrile in high enantiopurity by employing baker's yeast in petroleum ether.…”

Addition reaction of arylboronic acids to aldehydes and α,β-unsaturated carbonyl compounds catalyzed by conventional palladium complexes in the presence of chloroform

“…Methyl 3-phenylbutanoate (5al) [30] 1 H NMR (CDCl 3 , 300 MHz) d 1.33 (d, J = 6.9 Hz, 3H, -CH 3 ), 2.53-2.70 (m, 2H, -CH 2 CHAr), 3.25-3.37 (m, 1H, -CHAr), 3.64 (s, 3H, -OCH 3 ), 7.19-7.35 (m, 5H, -Ar); 13 C NMR (CDCl 3 , 75 MHz) d 22.1, 36.8, 43.0, 51.9, 126.6, 126.9, 128.7, 145.8, 172.9. 4.33. Methyl 3-phenylpentanoate (5am) [31] 1 H NMR (CDCl 3 , 300 MHz) d 0.78 (t, J = 7.2 Hz, 3H, -CH 3 ), 1.54-1.75 (m, 2H, ÀCH 2 CH 3 ), 2.52-2.67 (m, 2H, ÀCH 2 CO), 2.95-3.05 (m, 1H, ÀCHAr), 3.55 (s, 3H, -OCH 3 ), 7.13-7.29 (m, 5H, -Ar); 13 [32] 1 H NMR (CDCl 3 , 300 MHz) d 0.83 ((t, J = 7.2 Hz, 3H, -CH 3 ), 1.68-1.93 (m, 2H, -CH 2 CH 3 ), 2.57 (t, J = 7.2 Hz, 2H, -CH 2 CN), 2.78-2.85 (m, 1H, -CHAr), 7. 16-7.34 (m, 5H, -Ar); 13 C NMR (CDCl 3 , 75 MHz) d 12.2,25.1,28.3,44.2,118.9,127.4,127.5,129.0,cyclohexanone (5ba) [33] 1 H NMR (CDCl 3 , 300 MHz) d 1.69-1.86 (m, 2H), 2.01-2.15 (m, 2H), 2.29-2.58 (m, 4H), 2.89-2.98 (m, 1H, -CHAr), 3.76 (s, 3H, -OCH 3 ), 6.82-6.87 (m, 2H, -Ar), 7.09-7.14 (m, 2H, -Ar); 13 C NMR (CDCl 3 , 75 MHz) d 25.8,33.3,41.5,44.3,49.5,55.5,114.2,127.7,136.7,158.3,cyclohexanone (5da) [29] 1 H NMR (CDCl 3 , 300 MHz) d 1.69-1.82 (m, 2H), 2.00-2.13 (m, 2H), 2.30 (s, 3H, -CH 3 ), 2.32-2.56 (m, 4H), 2.89-2.96 (m, 1H, -CHAr), 7.06-7.12 (m, 4H, -Ar); 13 C NMR (CDCl 3 , 75 MHz) d 21.4,25.9,33.2,41.5,44.7,49.4,126.6,129.6,136.3,141.6,cyclohexanone (5ea) [34] 1 H NMR (CDCl 3 , 300 MHz) d 1.72-1.88 (m, 2H), 2.04-2.18 (m, 2H), 2.31-2.59 (m, 4H), 2.94-3.03 (m, 1H, -CHAr), 6.99 (m, 2H, -Ar), 7.…”

“…The analytically pure ketone was obtained by chromatography on silica gel. When other enones and arylboronic acid were used, usually the reaction was carried out at 80°C for [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]methanol (3aa) [15] 1 H NMR (CDCl 3 ): d 2.63 (brs, 1H, ÀOH), 5.82 (s, 1H, ÀCHOH), 7.24-7.42 (m, 5H, -Ar), 7.49-7.58 (m, 4H, -Ar), 13 C NMR (CDCl 3 ) d 75. 9,111.3,119.1,126.9,127.2,128.5,129.1,132.5,143.0,methanol (3ab) [16] 1 H NMR (CDCl 3 ): d 2.42 (d, J = 2.7 Hz, 1H, ÀOH), 5.84 (d, J = 2.1 Hz, 1H, -CHOH), 7.…”

Chemoselective reduction of carbonyl groups of aromatic nitro carbonyl compounds to the corresponding nitroalcohols using thiourea dioxide

“…A variety of reagents have been employed to achieve this transformations. [1][2][3][4][5][6][7] Despite the fact that a plethora of reducing agents is available for this operation, new reagents, especially the catalytic versions, are still highly desirable. Thiourea dioxide is much less expensive and does not affect the environment.…”