CuH-Catalyzed Asymmetric Reductive Amidation of α,β-Unsaturated Carboxylic Acids

Abstract

The direct enantioselective copper hydride (CuH)-catalyzed synthesis of β-chiral amides from α,β-unsaturated carboxylic acids and secondary amines under mild reaction conditions is reported. The method utilizes readily accessible carboxylic acids, and tolerates a variety of functional groups in the β-position including several heteroarenes. A subsequent iridium-catalyzed reduction to γ-chiral amines can be performed in the same flask without purification of the intermediate amides.

Amides are an integral part of the backbone of all biological systems, as well as important elements of many pharmaceutical agents. Consequently, amide bond formation is of great importance in organic chemistry and methods for the direct catalytic amidation of carboxylic acids under mild conditions are highly desirable.¹ In addition, β-chiral amides are found in many natural products and are considered to be important pharmacophores.² Furthermore, this substructure can be regarded as a useful intermediate for the synthesis of additional pharmaceutically-relevant molecules, such as γ-chiral amines.³

The synthesis of amides bearing stereogenic centers at the β-position generally requires multiple steps.⁴ Currently available strategies include copper-catalyzed asymmetric conjugate additions,⁵ asymmetric conjugate reductions,⁶ and transition-metal-catalyzed hydrogenation reactions⁷ of unsaturated carbonyl compounds (Figure 1A). Each of these approaches requires a final amidation reaction, typically involving the use of stoichiometric coupling reagents.⁸

Figure 1.

A: Common multistep strategies to synthesize β-chiral amides from unsaturated carbonyls. B: CuH-catalyzed silyl ester formation and 1,4-reduction allows the reduction and hydroacylation of unsaturated carboxylic acids presumably via ketene intermediates. C: The direct formation of β-chiral amides in one step from unsaturated carboxylic acids (this work).

The enantioselective CuH-catalyzed 1,4-reduction of unsaturated esters,⁹ in which a chiral bisphosphine-ligated CuH-species is generated by a hydrosilane as a stoichiometric reducing agent can be used to asymmetrically reduce a variety of α,β-unsaturated alkenes under mild reaction conditions.¹⁰ The analogous reduction of lactams has been successfully implemented,¹¹ however acyclic amides are not reduced under CuH-catalysis conditions. In general, the alternative access to β-chiral amides via direct enantioselective conjugate transformation of unsaturated amides is more challenging due to their lower reactivity compared to other Michael acceptors.¹²

Despite these advances that have been made in the preparation of β-chiral amides, a general approach that enables the catalytic amidation of carboxylic acids and the formation of a stereogenic center in a single operation under mild conditions would allow the expedited synthesis of substructures found in many biologically active molecules. Our group recently reported the direct asymmetric CuH catalyzed hydroacylation¹³ and 1,4-reduction¹⁴ of α,β-unsaturated carboxylic acids to generate α-chiral ketones (Figure 1B). Mechanistic investigations suggested that these reactions may proceed through a ketene intermediate. Thus, we considered whether this ketene might be intercepted by an exogenous nucleophile, rather than undergoing reaction with LCuH or LCuR. Specifically, whether by performing the 1,4-reduction reaction in the presence of an amine nucleophile might allow for the formation of an amide product with a chiral center at the β-position (Figure 1C).

When we attempted such a reaction using secondary amines as nucleophiles, we indeed observed clean conversion of α,β-unsaturated acid substrates (1) to the desired β-chiral amides (3, Figure 2).¹⁵ Optimization revealed that several β,β-disubstituted unsaturated carboxylic acids were effectively converted using low quantities of the precatalyst mixture (S )-CuCatMix¹⁶ (see Supporting Information for details). The use of dimethoxy(methyl)silane (DMMS) as hydride source permitted efficient amidation at room temperature in THF, while with 1,1,3,3-tetramethyldisiloxane (TMDS)¹⁷ similar conversions were observed at 40 °C.

Figure 2.

Preliminary screen of CuH catalyzed reductive coupling reactions of α,β-unsaturated acids and a secondary amine. (S )-CuCatMix = Cu(OAc)₂, (S )-DTBM-SEGPHOS, PPh₃ (1:1.1:1.1 ratio, precomplexed, air-stable free-flowing powder). Silanes: Dimethoxy(methyl)silane (DMMS) or 1,1,3,3-tetramethyldisiloxane (TMDS).

Next, we examined the substrate scope for the direct CuH-catalyzed amidation reaction at 1.0 mmol scale. Using either of the optimized protocols, DMMS at rt or TMDS at 40 °C, amide 3a was obtained in similar yields and stereoselectivity (Figure 3). Product 3b, which is structurally similar to recently investigated Ubiquitin-specific protease 7 inhibitors,^[2a] could be prepared directly from unprotected 4-hydroxypiperidine. In this case, the procedure employing TMDS at 40 °C was found to be superior.

Figure 3.

Scope of the CuH catalyzed reductive amidation of β,β-disubstituted α,β-unsaturated carboxylic acids with secondary amines.

^a Reaction performed with 1.0 mmol of carboxylic acid and 5.0 mol% (S)-CuCatMix. Reported yields are isolated yields and are the average of two runs. Enantiomeric ratios were determined by SFC ^b Reaction performed with 1.0 mol% (S)-CuCatMix. ^c Reaction performed with TMDS at 40 °C and 1.0 mol% (S)-CuCatMix. ^d Reaction performed with TMDS at 40 °C and at a concentration of 0.06 M, followed by deprotection with TBAF. ^e Reaction performed at a concentration of 0.06 M. ^f Low conversions were observed with ortho-substituted substrates. Conversion determined by ¹H-NMR on 0.10 mmol scale (see SI for more examples).

The reaction of (E)-3-phenylbut-2-enoic acid with α-disubstituted and chiral (S)-(–)-N,α-dimethylbenzyl-amine gave amide 3c in a yield of 61% and with excellent stereoselectivity. Reactions involving tetrazole- or quinoline/diamine-containing acids gave similar yields with high enantiomeric ratio (3d and 3e). A ferrocene substituted acid, as well as α,β-unsaturated carboxylic acids bearing heterocycles including pyrimidine, indole, pyrazole, pyrrole, benzothiazole and dimethylthiazole at the β-position were efficiently coupled with different amines in good to excellent yields and with high enantioselectivity (3g–l). In addition, an alkyl chloride in β-position was well-tolerated under the reaction conditions, although diminished enantioselectivity was observed (3m). Moreover, the β-alkenyl β-alkyl acid derived from β-ionone could be coupled with a furan containing amine (3n). The procedure for the β-(hetero)aryl,β-alkyl-substituted substrates also worked well for β,β-diaryl substituted acids. In particular, acids containing a bromoarene and a thiophene were efficiently converted to the desired products (3o and 3p). However, under these conditions, only low conversions were observed for the reactions of more sterically hindered acids (see 3q and SI for more structures), as well as using sterically hindered amines such as diisopropylamine. We also examined substrates with heteroatoms at the β-position. Silane 3r was obtained in good yield from the corresponding Z-olefin, although with diminished enantiopurity (75:25). In contrast, boronic ester 3s and N-substituted indole 3t were obtained with excellent levels of enantiomeric purity. In the cases of more complex substrates, including nitrogen-rich heterocycles and functional group containing amines, 5 mol% catalyst loading was employed to ensure full conversion of the unsaturated carboxylic acids.

Based on recent work of transition-metal-catalyzed reduction of amides to enamines and amines with hydrosilanes,¹⁸ we also saw an opportunity to develop a one pot synthesis of γ-chiral amines based on our reaction (Figure 4). Amines with stereocenters in γ-position are frequently encountered structural components in bioactive molecules.¹⁹ However, these remote stereocenters are in general challenging to form directly and are usually installed in a stepwise process from a β-chiral aldehyde followed by reductive amination reactions.¹⁴ After a CuH-catalyzed reductive amidation reaction, 0.5 mol% IrCl(CO)(PPh₃)₂ (Vaska’s complex) was added to the crude reaction mixture, upon which the enamine 4a was efficiently formed. Subsequent addition of methanesulfonic acid (MsOH) induced further reduction, presumably via iminium ion formation, delivering γ-chiral amine 5a in excellent yield and enantiomeric ratio.

Figure 4.

One-pot synthesis of γ-chiral amines.

We next investigated some aspects of the mechanism of Cu catalyzed reductive amidation of α,β-unsaturated acids (Figure 5). Based on our previous investigations, we considered path A as a possibility, in which the CuH-catalyzed 1,4-reduction of a silyl ester delivers a copper enolate that could eliminate to a ketene intermediate. Addition of the amine to the ketene would then give the observed β-chiral amide product. An alternative mechanism is illustrated as path B, involving the direct amidation of the intermediate silyl ester,²⁰ followed by conjugate reduction of the resulting unsaturated amide.

Figure 5.

Two reaction pathways are considered after initial silylation of the carboxylic acid.

Several experiments in THF-_d8 were performed and analyzed by ¹H-NMR spectroscopy. To identify and characterize the silyl ester intermediates, (E )-3-phenyl-but-2-enoic acid (1a), 0.5 mol% of (S )-CuCatMix, and one equivalent of DMMS were combined. Full conversion to a mixture of silylated intermediates 6a, 6b and 6c (Figure 6A) in a ratio of 4:1:1 was observed after 60 h. Furthermore, neither 1,4-reduction of the activated silyl esters nor interconversion between the intermediates was observed.

Figure 6.

A: Intermediary silyl ester intermediates identified and characterized by NMR-spectroscopy and high-resolution mass spectrometry. B: The CuH-catalyzed amidation was monitored by ¹H-NMR-spectroscopy. C: The CuH-catalyzed reduction of an unsaturated amide is not efficient under the described conditions.

Next, we monitored reactions using the conditions described in Figure 3 (Figure 6B), using acid 1a and Et₂NH as model substrates. Initially, the same silylated intermediates (6a, 6b, 6c) as observed previously were formed, although their generation was accelerated (36 min vs. 60 h), possibly by the presence of the basic amine.²¹ After complete consumption of the acid, first the more activated²² dimeric intermediate 6b is converted to product 7, followed by the conversion of monomer 6a. No other intermediates resulting from 1,4-reduction, such as Cu-enolates or ketenes were observed. Furthermore, the unsaturated amide 8 was not detected.

When we independently prepared and isolated unsaturated amide 8 and subjected it to the standard reaction conditions, less than 10% of 7 was observed, even with a 7 day reaction time, suggesting that path B plays at most a minor role (Figure 6C) in the CuH-catalyzed asymmetric reductive amidation of unsaturated carboxylic acids.

In conclusion, we have developed a one-step CuH-catalyzed method to access β-chiral amides starting from readily available unsaturated carboxylic acids. The mild reaction conditions tolerate various functional groups and heterocycles. Subsequent one pot reduction with Vaska’s complex allowed the direct reduction to form γ-chiral amines. The formation and consumption of reaction intermediates was monitored and several silyl ester intermediates were identified.