Acetaldehyde: Use in Organocatalysis

Sun Min Kim was born in Uijeongbu, Republic of Korea, in 1983. He received his B.E. degree from Sungkyunkwan University in 2009. He is currently pursuing his M.E./Ph.D. degree in the Department of Energy Science at Sungkyunkwan University under the ­supervision of Professor Jung Woon Yang. His research focuses on the development of enantioselective organocatalytic methods, green oxidation, and stable electrides.

Introduction

Acetaldehyde is a small organic molecule and the simplest enolazable aldehyde. It is an important synthon for the construction of β-amino acid derivatives, α-hydroxy ketones, and so forth, if suitable reagents are employed. ­Despite this versatility, the use of acetaldehyde can be complicated due to its tendency to oligomerize or poly­merize.

Recently, several research groups reported the multifarious utility of acetaldehyde in many diverse asymmetric organocatalytic transformations by controlling the reactivity of acetaldehyde.[1] The reactions furnished the corresponding products in high yields with stereoselectivities. An overview of typical applications of acetaldehyde is shown in Scheme [1].

Scheme 1 Versatile use of acetaldehyde in asymmetric organocatalysis

Abstracts

(A) List and co-worker reported the first proline-catalyzed enantio­selective Mannich reaction of N-Boc imines with acetaldehyde.[2] This method is one of the simplest ways to synthesize enantiopure β3-amino acid derivatives. It is noteworthy that unwanted side reactions were successfully suppressed by using an excess of acetaldehyde (5–10 equiv).
(B) The direct asymmetric crossed-aldol reaction of acetaldehyde was reported by the group of Hayashi.[3] In particular, trifluoromethyl-substituted diarylprolinol 1 was found to be an effective organocatalyst and gave excellent enantioselectivities. Due to its instability, the aldehyde intermediate was transformed into the corresponding alcohol using NaBH4 in methanol.
(C) Hayashi, Uchimaru, and co-workers reported that diarylprolinol silyl ether 2 catalyzed the asymmetric Mannich reaction between N-protected imines and acetaldehyde (5 equiv).[4] A wide range of aromatic N-benzoyl , N-Boc , and N-Ts imines were investigated. The reaction proceeded smoothly to afford β3-aminoaldehydes with high enantioselectivity. The aldehydes were reduced to the corresponding alcohols using LiAlH4.
(D) Maruoka and co-workers designed a new catalyst motif – axially chiral bifunctional amino sulfonamide catalyst 3 – and performed asymmetric Mannich reactions of N-Boc imines with acetaldehyde (36 equiv).[5] As a result, the desired products were obtained in good yields and excellent enantioselectivities (up to 99% ee) in most cases. Undesired side reactions were suppressed with this less nucleophilic chiral amino sulfonamide.
(E) List and co-workers reported the proline-catalyzed double Mannich reaction of N-Boc imines with acetaldehyde.[6] This method provided pseudo-C 2-symmetric β,β′-diaminoaldehydes with extremely high diastereo- and enantioselectivities (dr > 99:1, er > 300:1) by reacting one equivalent of acetaldehyde with three equivalents of both aromatic and aliphatic N-Boc imines via stepwise enamine catalytic activation.
(F) Greck et al. investigated the one-pot, organocatalytic α,α-bifunctionalization of acetaldehyde with two different electrophiles (N-benzoyl imine and di-tert-butylazodicarboxylate) using diaryl­prolinol silyl ether catalyst 2.[7] This reaction consists of a tandem Mannich reaction–electrophilic amination. syn-Selective 2,3-diaminoalcohols were obtained with moderate yields and high diastereo- and enantioselectivities (dr up to 96:4, up to 98% ee).
(G) In N-heterocyclic carbene (NHC) catalysis, the chemoselective intermolecular cross-acyloin condensation reaction of two different aldehydes is one of the biggest challenges. Yang and co-workers ­established an efficient chemoselective catalytic system using acetaldehyde as the acyl anion source.[8] The most striking feature is the switch of chemoselectivity by changing the scaffold of the NHC catalyst.
(H) Yang and co-workers reported the intermolecular Stetter reaction of various Michael acceptors, including trans-chalcone derivatives, with acetaldehyde as a biomimetic acyl anion source.[9] The authors also extended their work to the enantioselective Stetter reaction which resulted in moderate to good enantioselectivities (up to 76% ee) for the corresponding products.

• References

• 1 Alcaide B, Almendros P. Angew. Chem. Int. Ed. 2008; 47: 4632
• 2 Yang JW, Chandler C, Stadler M, Kampen D, List B. Nature 2008; 452: 453
• 3 Hayashi Y, Itoh T, Aratake S, Ishikawa H. Angew. Chem. Int. Ed. 2008; 47: 2082
• 4 Hayashi Y, Okano T, Itoh T, Urushima T, Ishikawa H, Uchimaru T. Angew. Chem. Int. Ed. 2008; 47: 9053
• 5 Kano T, Yamaguchi Y, Maruoka K. Angew. Chem. Int. Ed. 2009; 48: 1838
• 6 Chandler C, Galzerano P, Michrowska A, List B. Angew. Chem. Int. Ed. 2009; 48: 1978
• 7 Coeffard V, Desmarchelier A, Morel B, Moreau X, Greck C. Org. Lett. 2011; 13: 5778
• 8 Jin MY, Kim SM, Han H, Ryu DH, Yang JW. Org. Lett. 2011; 13: 880
• 9 Kim SM, Jin MY, Kim MJ, Cui Y, Kim YS, Zhang L, Song CE, Ryu DH, Yang JW. Org. Biomol. Chem. 2011; 9: 2069