Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed by Readily Available Chiral Amino Alcohol-Based Ligands

Abstract

The asymmetric alkynylation reaction catalyzed by amino alcohol derived ligands (1R,2S)-3 or (1S,2R)-4 with dimethylzinc provides a simple and practical method to make chiral propargylic alcohols, and it is complementary to the asymmetric reduction methods. In the presence of 10 mol% (1R,2S)-3 or (1S,2R)-4, a variety of aromatic aldehydes were converted to the corresponding chiral propargylic alcohols with very good enantioselectivities and yields. This one-pot asymmetric reaction is carried out under mild reaction conditions. Neither strong base nor transmetallation is required. It is an efficient reaction, greatly accelerated by the added chiral ligand. Preliminary mechanistic and NMR studies have also been carried out. Chiral propargylic alcohols are useful building blocks for the enantioselective synthesis of complex molecules. 1 A powerful approach to these compounds involves the asymmetric reduction of a,b-ynones (approach A, Scheme 1) via either the catalytic asymmetric hydroboration 2 or transition metal catalyzed transfer hydrogenation. 3 While excellent yields and enantioselectivities are obtained for the alkyl substituted propargylic alcohols (R 1 = alkyl), there has been no report of reduction of the corresponding aromatic a,b-ynones (R 1 = Ar) by these methods. A complementary approach to these compounds involves the asymmetric addition of alkynes to aromatic aldehydes (approach B, Scheme 1). Scheme 1However, unlike the catalytic enantioselective addition of dialkyl-4 and alkenylzinc 5 compounds to aldehydes where considerable progress has been made, the current methods for enantioselective alkynylation reactions are far from ideal. 6-8 Some suffer from the use of substoichiometric to stoichiometric amounts of ligands or catalysts, others from either moderate enantioselectivities or the formation of considerable amounts of byproducts (alkylated products).Our research led us to the discovery of a practical and efficient enantioselective method for the alkynylation of aromatic aldehydes with both aromatic and aliphatic acetylene substrates catalyzed by readily available chiral ligands derived from commercially available amino alcohols. We have also devised the method to suppress the alkyl addition to the aldehydes. Scheme 2A typical procedure (Scheme 2) involves the addition of dimethylzinc (1.1-1.2 equiv) in toluene to a solution of the alkyne (1.2 equiv) in THF at -20 °C. The chiral ligand (0.1 equiv) is added as a solid under nitrogen atmosphere after 15 minutes, and after another 15 minutes, the arylaldehyde (1 equiv) is added. The reactions are generally complete in 18-25 hours at -20 °C to -30 °C. An array of aromatic aldehydes has been studied under these conditions, and the representative results are summarized in Table 1. As illustrated in Table 1, the corresponding chiral propargylic alcohols 2 were formed in very good yields and good enantioselectivities. Most of the substituted arylaldehydes underwent the addition reaction with higher levels of enantioselectivity compared with the parent be...

Development of Zn–ProPhenol‐Catalyzed Asymmetric Alkyne Addition: Synthesis of Chiral Propargylic Alcohols

“…Interestingly, similar results were generally observed for dimethyl-and diethylzinc; however, others have noted that alkyl transfer from dimethylzinc is significantly slower than from diethylzinc, and therefore, dimethylzinc was chosen to avoid the formation of potential alkyl addition side products. [24] Utilizing the optimized conditions outlined in Table 1, entries 10 and 12, we set out to investigate the scope of this reaction.…”

Asymmetric Alkynylation Reactions of Aldehydes Using a Zn(OTf)2-Chiral Ligand-Base System

“…An improvement in the ee values (85%) was reported in a later study by Li et al who used dimethylzinc, in conjunction with a terminal alkyne, and a modified amino alcohol ligand [5]. Modification of the amino alcohol, by incorporation of rigid binaphthyl backbone, produced a highly efficient range of catalysts for asymmetric alkynylation reactions [6].…”

“…Asymmetric alkynylation reactions conducted using either standard "Carreira" conditions, zinc triflate, TEA and Nmethylephedrine [9], or dialkyl zinc [5,6,21] add to hindered and unhindered aliphatic aldehydes in good to excellent yields and with excellent levels of enantioselectivity [20]. In contrast to this analogous alkynylations to benzaldehyde derivatives require longer reaction times.…”

“…Enantioselective addition reactions between aldehydes and either dialkylzinc or dialkenylzinc reagents have been well represented in the chemical literarture with a plethora of examples and catalyst types [3]. In contrast asymmetric alkynylation reactions, using dialkynylzinc reagents, have been less well developed [4] with a limited range of catalysts and organometallic reagents coupled with variable yields and enantioselectivities [5].…”

Highly enantioselective alkynylation of aldehydes using a new BINOL/Ti(OiPr)4/chiral sulfonamide catalyst system

“…5 In 1999, Li and coworkers reported the use of chiral amino alcohols to catalyze the alkynylation of aromatic aldehydes with up to 85% ee and 94% yield. 6 We also synthesized a series of binaphthylderived amino alcohols and used them in asymmetric alkynylation of a variety of aromatic aldehydes to the corresponding chiral propargylic alcohols with good and high conversions enantioselectivities. 7 The results compared favorably with other known amino alcohol ligands in similar reactions.…”