Nickel-Catalyzed Alkylation of Amide Derivatives

Abstract

We report the catalytic alkylation of amide derivatives, which relies on the use of nonprecious metal catalysis. Amide derivatives are treated with organozinc reagents, utilizing nickel catalysis, to yield ketone products. The methodology is performed at ambient temperature and is tolerant of variation in both coupling partners. A precursor to a nanomolar glucagon receptor modulator was synthesized using the methodology, underscoring the mild nature of this chemistry and its potential utility in pharmaceutical synthesis. These studies are expected to further promote the use of amides as synthetic building blocks.

Graphical Abstract

The ability to activate traditionally unreactive functional groups as synthons continues to be a vital area of research. One particularly stable functionality is the amide.¹ The resonance stabilization of amides has been well understood for decades;^1,2 consequently, the use of amides in C–N bond cleavage reactions has remained limited. Recently, however, there has been much interest in breaking amide C–N bonds to forge new C–heteroatom and C–C bonds.^3–7 Such methodologies provide new tactics to prepare acyl derivatives, but with the key benefit of amide stability. The use of amides in multistep synthesis, followed by selective C–N bond activation and coupling, should ultimately prove advantageous in the synthesis of complex molecules.

The present study focuses on activating and coupling amides to build acyl C–C bonds in an intermolecular fashion (Figure 1). Such catalytic methodology would complement Weinreb amide chemistry, but without the use of highly basic and pyrophoric organometallic reagents.⁸ Prior contributions in this area include Suzuki–Miyaura couplings (1 → 2) reported by Zou (Pd),⁴ Szostak (Pd),⁵ and our laboratory (Ni).^3b In each of these cases, the nucleophilic coupling partner was restricted to aryl boronate species, thus limiting the application of this methodology. The corresponding alkylative coupling (1 → 3) would be highly desirable, given the prevalence of alkyl ketones in molecules of biological importance and the versatility of alkyl ketones as synthetic building blocks. Herein, we report the first alkylative cross-coupling of amide derivatives.

Figure 1.

Nickel-catalyzed C–C bond forming reactions from amides.

Following unsuccessful attempts to couple amide derivatives with aliphatic boronic acids and esters, we opted to pursue the use of organozinc reagents as cross-coupling partners.⁹ Our earlier studies have relied on the use of nickel catalysis for amide C–N bond activation,³ which is notable, given that nickel is less expensive, more abundant, and displays a smaller CO₂ footprint, compared to its precious metal counterpart, palladium.¹⁰ Catalytic acyl couplings¹¹ with organozinc reagents are well-precedented using acid halides (Pd or Ni),¹² anhydrides (Pd, Ni, or Rh),^12a,13 and thioesters (Pd or Ni),^12a,b,14 but the corresponding coupling of amides has not been reported.

To initiate our study, we examined the coupling of naphthamides 4 with benzylzinc bromide (5) in the presence of catalytic Ni(cod)₂ and the NHC ligand SIPr in THF (Scheme 1). Although several amide derivatives failed to undergo the coupling (entries 1–3), we were delighted to find that N-alkyl,Boc and N-alkyl,Ts derivatives could be utilized (entries 4 and 5, respectively).¹⁵ N-Alkyl,Ts amides (e.g., 4e) are well-suited for use in multistep synthesis.¹⁶ Notably, the successful reactions of 4d and 4e proceeded at room temperature, which compares favorably to the few existing examples of catalytic amide C–N bond activation (ca. 50–160 °C),^3–7 and highlights the mild nature of this coupling.

Scheme 1. Survey of Amide N-Substituents in the Coupling of Substrates 4 with 5^a.

^aConditions: Ni(cod)₂, 10 mol %; SIPr, 10 mol %; substrate, 4, 1.0 equiv; benzylzinc bromide (5), 1.5 equiv; and THF, 1.0 M at 23 °C for 24 h. ^bYields determined by ¹H NMR analysis using hexamethylbenzene as an internal standard.

Having found that the alkylative coupling of amide derivatives was indeed possible,¹⁷ we evaluated the scope of the amide substrate (Figure 2). The use of the parent naphthyl substrate gave 6 in 80% isolated yield. In addition, it was found that the methodology was not restricted to extended aromatics. For example, the substrate derived from benzoic acid coupled smoothly to furnish 7 in 74% yield. Substrates bearing electron-donating groups could also be employed, as demonstrated by the formation of 8–10. From the latter two cases, it should be emphasized that the presence of tertiary amines does not hinder catalysis. As shown by the formation of 11 and 12, the electron-withdrawing −F and −CF₃ substituents were also tolerated.¹⁸

Figure 2.

Scope of the amide substrate. (Conditions, unless otherwise stated: Ni(cod)₂, 10 mol %; SIPr, 10 mol %; substrate, 1.0 equiv; benzylzinc bromide (5), 1.5 equiv; and THF, 1.0 M at 23 °C for 24 h. Yields shown reflect the average of two isolation experiments. The superscripted symbol “a” in the figure denotes that the corresponding N-Bn,Boc benzamide derivative was used.)

Additionally, we examined the scope of the organozinc reagent in this methodology (Figure 3).^19,20 n-Propylzinc bromide was successfully employed to furnish 13 in 80% yield. To assess the tolerance of the methodology toward β-branching, neopentylzinc iodide, a very hindered nucleophile was tested and found to undergo the desired coupling to furnish 14. α-Branched nucleophiles could also be employed, as judged by the formation of 15 and 16. Notably, couplings utilizing secondary organozinc reagents are known to be challenging.²¹ Finally, cyclopentyl and cyclohexyl organozinc reagents underwent the desired coupling in good yield to deliver products 17 and 18, respectively.

Figure 3.

Scope of the organozinc coupling partner. (Conditions, unless otherwise stated: Ni(cod)₂, 10 mol %; SIPr, 10 mol %; substrate, 1.0 equiv; organozinc reagent, 1.5 equiv; and THF, 1.0 M at 23 °C for 24 h. Yields shown reflect the average of two isolation experiments.)

The alkylative cross-coupling methodology was further probed in a synthetic application (Scheme 2). On a gram-scale, amide derivative 19 was coupled with cyclohexylzinc iodide (20) using our optimal nickel-catalyzed reaction conditions. This transformation provided ketone 21 in 71% yield without disturbing the ester.²² Ketone 21 is an intermediate in Pfizer’s synthesis of the glucagon receptor modulator 22.²³ The cross-coupling route to 21 provides a favorable alternative to the known Weinreb amide displacement chemistry described in the literature, which proceeds in 34% yield.²³

Scheme 2.

Gram-Scale Coupling To Form Ketone 21

In summary, we have developed the first catalytic alkylation of amide derivatives. The transformation involves the coupling of N-alkyl,Ts or N-alkyl,Boc amides with organozinc reagents using nickel catalysis. The methodology proceeds at room temperature and is tolerant of variation in both the substrate and nucleophilic coupling partner. The synthesis of 21 underscores the mildness and scalability of this methodology, along with the applicability of this technology to pharmaceutical synthesis. As such, we expect that these studies will further promote the use of amides as synthetic building blocks for use in the synthesis of drugs and natural products.