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]

Highly diastereo- and enantioselective reactions of enecarbamates with an aldehyde

“…30% yield, entry 2 in Table 1). A similar phenomenon was observed when other Lewis acids such as CuClO 4 $4CH 3 CN, Sc(OTf) 3 , and Yb(OTf) 3 were employed as catalysts (entries 2-5 in Table 1). It is noted that a complex derived from Cu(OTf) 2 and diamine ligand 3a did not accelerate the formation of 8 from 2a at all, and that 7a was isolated in high yield with modest enantioselectivity (93% yield, 55% ee, entry 6 in Table 1).…”

“…2 Recently, we have reported the first catalytic enantioselective addition of enamides and enecarbamates to imines, which afforded imine 4 in high yield with high selectivity (Scheme 1). 3 A C 2 -symmetric copper catalyst prepared from Cu(OTf) 2 and diamine ligand 3a, derived from 1,2-diphenyl ethylenediamine, catalyzed the reaction efficiently. 4 Imine 4 is a versatile compound, which can be converted into 1,3-diamides, 5-membered lactams, 3-keto 1-amides, etc.…”

Highly Diastereo‐ and Enantioselective Reactions of Enecarbamates with Ethyl Glyoxylate To Give Optically Active syn and anti α‐Alkyl‐β‐Hydroxy Imines and Ketones

“…For determining the ee values of the products, 4 was converted into the corresponding ketones 5. [9] Although some copper salts worked well in this reaction, Cu II -diamine complexes, [10] which gave excellent results in Mannich-type reactions of N-acylimino esters with enamides and enecarbamates, [5] afforded the product with moderate enantioselectivity (Table 1, entry 1). On the other hand, it was revealed that much higher enantioselectivities were obtained when Cu Idiimine complexes [11] were used (Table 1, entries 4 and 5).…”

“…[5] In spite of their importance in organic chemistry, examples of nucleophilic additions of enamides or enecarbamates are few, [6] whereas there are many reports on the use of enamines as nucleophiles. [7] Herein we report the first highly diastereo-and enantioselective addition reaction of enecarbamates with ethyl glyoxylate.…”

Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective, Catalytic, Formal Aza [3+3] Cycloaddition Reaction for the Formation of Enantioenriched Piperidines

“…[14] We have applied diphenylprolinol silyl ether to the reaction of a,b-unsaturated aldehydes with enecarbamates and found that a formal aza [3+3] cycloaddition reaction proceeds in a highly enantioselective manner as reported herein (Figure 1). Enecarbamates and enamides have been successfully utilized as reactive nucleophiles by the group of Kobayashi, [15] and Terada et al recently used them in an aza-ene-type reaction.[16] Having reported the asymmetric ene reaction of cyclopentadiene, [9] we employed an enamide and an a,bunsaturated aldehyde with the expectation that an ene reaction would occur. Notably, the asymmetric, catalytic intermolecular ene reaction of a,b-enals as enophiles is rare.…”