Copper(II)‐Catalyzed Highly Enantioselective Addition of Enamides to Imines: The Use of Enamides as Nucleophiles in Asymmetric Catalysis

Abstract

Enamides are potentially useful and atom-economical nucleophiles that contain amide or carbamate moieties after nucleophilic additions. While enamides can be easily prepared, [1] handled, and stored at room temperature, their use in organic synthesis is limited.[2] To the best of our knowledge, there have been no reports of using enamides as nucleophiles in asymmetric catalysis. We describe here the first example of the enantioselective addition of enamides to imines using a chiral copper catalyst.Initially, we examined the reaction of enamide 2 a with imine 1 a [3, 4] in the presence of a chiral copper catalyst (10 mol %) prepared from Cu(OTf) 2 and chiral diamine 3 a (Scheme 1). [4b,c] The addition reaction proceeded smoothly in dichloromethane at 0 8C for 15 min to afford b-aminoimine 4 aa. The yield (83 %) and enantioselectivity (85 %) were determined after conversion of 4 aa to b-amino ketone 5 aa by treatment with acid (HBr in EtOH/H 2 O).[5] Enamides 2 b, 2 c, and 2 d were also investigated in the reaction. The highest ee value (93 %) was obtained with 2 d. Interestingly, enamines 2 e and 2 f reacted with 1 a under the same reaction conditions to afford 5 aa in high yields, but no asymmetric induction was observed.The results obtained employing other imines and enamides are summarized in Table 1. Several imines, including an N-carbamate-protected imine, [6] were treated with 2 d in the presence of the chiral copper catalyst (10 mol %) to afford the corresponding adducts in high yields with high enantiomeric excesses. It was also observed that the reaction proceeded efficiently when 5 mol % of the catalyst was employed. Enamides with aromatic substituents were as successful as substrates as those with alkyl substituents. The use of chiral diamine 3 b instead of 3 a was also effective. All the reactions proceeded smoothly at 0 8C over 15 minutes, and high yields and high levels of enantioselectivity were attained with a wide range of substrates. We also conducted the reaction of (E)-and (Z)-2-methyl-substituted enamides (E)-2 l and (Z)-2 l [7] with imine 1 a in the presence of the chiral copper catalyst (10 mol %) in dichloromethane at 0 8C for 30 min (Scheme 2). Enamide (E)-2 l was treated with 1 a to give the adduct in a high yield with good syn selectivity (syn adduct: 94 % ee). However, the reaction of (Z)-2 l with 1 a also gave the syn adduct as the major product, but the yield and diastereoand enantioselectivities were lower. It is noted that synScheme 1. The copper-catalyzed enantiomeric addition of an enamide 2 with an imine 1 to yield a b-aminoimine 4, which on treatment with acid produces a b-amino ketone 5. Boc = tert-butoxycarbonyl, Bn = benzyl, OTf = trifluoromethanesulfonate. [c] 93(93) [c] 2 [d]

Ru‐Catalyzed Anti‐Markovnikov Addition of Amides to Alkynes: A Regio‐ and Stereoselective Synthesis of Enamides

“…Moreover, they are versatile synthetic intermediates that can serve as substrates for polymerizations, [5] [4+2] cycloadditions, [6,7] cross-coupling reactions, [8] Heck olefinations, [9] halogenations, [8] enantioselective additions, [10] or asymmetric hydrogenations. [11] However, a regioand stereoselective construction of enamide substructures is not at all trivial.…”

Z-Selective hydroamidation of terminal alkynes with secondary amides and imides catalyzed by a Ru/Yb-system

“…Fig. 1 Enamides are versatile synthetic intermediates that can serve as substrates for heterocycle syntheses [10,11], cross-coupling reactions [12], Heck olefinations [13], enantioselective additions [14], or asymmetric hydrogenations [15]. Established enamide syntheses, such as the condensation of carbonyl derivatives with amides [16], require harsh conditions and yield mixtures of E-and Z-enamides.…”

Direct Asymmetric Michael Addition of Cyclic N‐Sulfonylimines to α,β‐Unsaturated Aldehydes

“…Indeed, in 2008, Kobayashi and co-workers proved this synthetic possibility in the direct Mannich reaction of the N-tosylimine of acetophenone with an activated imine by the catalysis of simple NEt 3 ; unfortunately, its applicability is limited due to tautomerization and elimination of the functional groups in the products. [3] As a consequence, the structurally more stable tautomers of imines, enecarbamates and enamides, are generally selected and utilized as the nucleophiles, and have been well explored by Kobayashi and other groups over the past few years, through the catalysis of either metal-based [4] or organic molecules. [5] Cyclic N-sulfonylimines, which can be easily prepared from the abundant, commercially available industrial material saccharin, have long been employed in organic synthesis as electrophiles.…”