Microwave-Assisted Organocatalytic Quadruple Domino Reactions of Acetaldehyde and Nitroalkenes

Abstract

A microwave-assisted, organocatalytic domino Michael/ Henry condensation/Michael/aldol condensation reaction has been developed. Employing acetaldehyde and nitroalkenes as substrates, this quadruple cascade allows an efficient asymmetric synthesis of trisubstituted cyclohexene carbaldehydes in moderate to good yields (25-45%) and high enantioselectivities (ee = 89 to >99%). ESI-MS measurements were carried out to support the proposed complex catalytic cycle.Over the last decade the area of organocatalysis has received much attention, evolving from a narrow field of research with fairly limited examples to one of the main branches in asymmetric catalysis. 1 Within this area, considerable attention has been paid to the development of highly stereoselective asymmetric domino reactions leading to complex molecular structures by convenient onepot protocols via a reaction cascade. 2 A large number of organocatalytic domino reactions have been developed over the last few years. 3,4 Our group, for example, published a diphenylprolinol-TMS-ether catalyzed triple domino reaction 5-9 that forms tri-and tetrasubstituted cyclohexene carbaldehydes. 4c,e-n As carbon-carbon bond forming reactions with acetaldehyde provide access to synthetically useful polyketides, many groups have tried to integrate acetaldehyde into aldol, Michael or Mannich reactions using enzymes, 10a,h trimethyl siloxyethenes as a synthetic equivalent 10e-g or organocatalysis. 10b-d The first synthetically useful organocatalytic reactions with acetaldehyde were reported in 2008 by the groups of List and Hayashi; these approaches involved secondary amine catalysed Michael, (self-)aldol and Mannich reactions. 10i-o Following these protocols, we envisaged a quadruple domino reaction of acetaldehyde with aromatic nitroalkenes, yielding trisubstituted cyclohexene carbaldehydes. To the best of our knowledge, only two amine-catalyzed quadruple domino reactions have been reported so far; these involved an oxa-Michael reaction followed by a Michael addition to a nitroalkene, a consecutive Michael addition of the resulting nitroalkane to an a,b-unsaturated aldehyde followed by an intramolecular aldol reaction. 11

Microwave‐Assisted Organocatalytic Enantioselective Intramolecular aza‐Michael Reaction with α,β‐Unsaturated Ketones

“…[20] This type of activation has been described recently in different types of organocatalyzed asymmetric reactions with the aim of shortening reaction times and catalyst loadings. [21] We found that microwave irradiation had a positive effect on the reaction time and retained very good yields and selectivities. When the reaction was performed in chloroform at 80 8C, a 90 % ee and a 91 % yield were achieved in only 30 min (Table 1, entry 17).…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…A Michael/Henry/condensation/Michael/aldol condensation with nitroolefines and acetaldehyde 30 in the presence of diphenylprolinol derivative 87 was reported by Enders et al [267] Highly substituted chiral cyclohexene carboxaldehydes were isolated under microwave conditions (Scheme 137).…”

Recent Developments in Asymmetric Organocatalytic Domino Reactions

“…[155] Employing amine (S)-3 as the catalyst, three equivalents of acetaldehyde reacted with nitroalkenes according to a quadruple cascade to afford the corresponding trisubstituted cyclohexenecarbaldehydes 341a-e in moderate to good yields (25-45%) and good to high enantioselectivities (89 to > 99% ee) combined with a general diastereoselectivity of > 96% de, as shown in Scheme 90. The authors have proposed the mechanism depicted in Scheme 90 in which the cascade started with the enamine activation of acetaldehyde by the catalyst and Michael addition to the nitroalkene.…”