Pyrrolidine‐Camphor Derivative as an Organocatalyst for Asymmetic Michael Additions of α,α‐Disubstituted Aldehydes to β‐Nitroalkenes: Construction of Quaternary Carbon‐Bearing Aldehydes under Solvent‐Free Conditions

Abstract

A novel pyrrolidine-camphor organocatalyst 3 was designed, synthesized and proven to be an efficient catalyst for the asymmetric Michael reaction. Treatment of a,a-disubstituted aldehydes with b-nitroalkenes in the presence of 20 mol% organocatalyst 3 and 20 mol% benzoic acid under solvent-free conditions provided the desired Michael product possessing an all-carbon quaternary center with high chemical yields (up to 99% yield) and high levels of enantioselectivities (up to 95% ee).Keywords: asymmetric catalysis; Michael reaction; b-nitroalkenes; quaternary carbon centers; solventfree reaction Remarkable advances have been realized in the use of small privileged organic molecules to catalyze asymmetric reactions. The development of organocatalysts in asymmetric reaction has attracted much attention in recent years as organocatalysts are generally non-toxic, highly efficient and selective, environmentally friendly, and stable under aerobic and aqueous reaction conditions. [1,2] The Michael reaction is one of the most efficient and powerful atom-economic carbon-carbon bond forming reactions in organic chemistry [3] and, therefore, developing enantioselective Michael reactions has been the focus of many organic chemists for decades.[4] Since the pioneering works of organocatalysts, many methods have been developed for the direct asymmetric Michael addition of unmodified aldehydes/ketones with nitroalkenes to produce enantiomerically enriched nitroalkanes. [5] The synthesis of quaternary stereogenic centers is considered a challenging task in organic synthesis [6] and there has been only a few reports on the use of a, a-disubstituted aldehydes.[7] The use of an a,a-disubstituted aldehyde donor should directly produce a Michael product with an all-carbon quaternary center.Most recently, many research groups have independently demonstrated that brine and water are good reaction media for asymmetric Michael reactions of aldehydes and ketones with nitroolefins. [8] Performing organic reactions in aqueous medium is one of the most fundamental and challenging goals and considerable progress has been made in recent years.[9] On the other hand, solvent-free condi-A C H T U N G T R E N N U N G tions, [5k,7a,10] have proved to be very effective in many reaction types due to the intimacy of the reactants. Recently, we have designed and synthesized camphorcontaining thiourea derivatives, as organocatalysts for the asymmetric aldol reaction on water.[11] In continuation of our research interest, we herein, report an eco-friendly process for the direct asymmetric Michael reaction of a,a-disubstituted aldehydes with bnitroalkene acceptors. The novel pyrrolidine-based camphor derivative serves as an efficient bifunctional organocatalyst to catalyze the reaction and provide Michael products possessing an all-carbon quaternary center under solvent-free conditions. High levels of chemical yields and enantioselectivities were generally achieved (up to 99% chemical yield and 95% ee).The design and synthesis of highly stereos...

Asymmetric Michael addition of aldehydes to nitroalkenes using a primary amino acid lithium salt

“…1f,g [α] 26 D = +1.7° (c = 1.0, CHCl3), white solid, Mp. 58-59 °C, δH(CDCl3) 1.00 (3H, s), 1.13 (3H, s), 3.73 (1H, dd, J 4.2, 11.5 Hz), 3.79 (3H,s),4.66 (1H,dd,J 4.2,12.8 Hz),4.81 (1H,dd,J 11.5,12.8 Hz),6.86 (2H,d,J 8.7 Hz),7.11 (2H,d,J 8.7 Hz), 9.53 (1H, s); δC(CDCl3) 18.7, 21.4, 47.7, 48.2, 55.1, 76.4, 113.9, 126.9, 130.0, 159.2, 204.3; ν(KBr)/cm -1 2976,2919,2841,2718,1725,1611,1582,1553,1516,1468,1441,1379,1290,1250,1188,1119,1028,889,839,812,747,635 8, 21.6, 47.8, 48.0, 75.9, 122.1, 130.6, 131.8, 134.3, 203.7; ν(KBr)/cm -1 3030,2973,2934,2874,2818,2718,1728,1559,1487,1468,1441,1410,1381,1350,1306,…”

Asymmetric Organocatalysis

“…Luo and Chan reported that diphenylperhydroindolinol silyl ether 34 [56], which was A novel prolinamide-camphor catalyst 35 has been discovered for the direct asymmetric Michael addition of aldehydes to nitroolefins in high yields and excellent diastereo-and enantioselectivities [57]. For the Michael addition of a, adisubstituted aldehydes to nitroolefins, the pyrrolidine-camphor catalyst 36 exhibited high efficiency under neat conditions [58].…”

Recent Advances in Solvent‐Free Asymmetric Catalysis

“…In 2009, Chen and co‐workers designed a novel pyrrolidine‐camphor organocatalyst 62 for the asymmetric Michael addition reaction . The model reaction of isobutyraldehyde with trans‐β‐nitrostyrene was explored in different solvent and amount of catalyst.…”