Mild Divergent Semireductive Transformations of Secondary and Tertiary Amides via Zirconocene Hydride Catalysis

Abstract

The mild catalytic partial reduction of amides to imines has proven to be a challenging synthetic transformation, with many transition metals directly reducing these substrates to amines. Herein, we report a mild, catalytic method for the semireduction of both secondary and tertiary amides via zirconocene hydride catalysis. Utilizing just 5 mol % of Cp₂ZrCl₂, the reductive deoxygenation of secondary amides is demonstrated to furnish a diverse array of imines in up to 94% yield with excellent chemoselectivity and without the need for glovebox handling. Moreover, a novel reductive transamination of tertiary amides is also achievable when the catalytic protocol is carried out in the presence of a primary amine at room temperature, providing access to an expanded assortment of imines in up to 98% yield. Through slight procedural tuning, the single-flask conversion of amides to imines, aldehydes, amines or enamines is feasible, including multicomponent syntheses.

Nitrogen-containing compounds are pervasive among natural products, agrochemicals, materials and biomolecules. Moreover, greater than 90% of the 100 top-selling small molecule pharmaceuticals in 2021 contained one or more nitrogen atoms.¹ Due to their ubiquity in nature, amide-containing molecules represent abundant precursors for the preparation of other classes of nitrogen-containing compounds, including amines, imines, N-heterocycles, or enamines.² Thus, the development of catalytic strategies for the divergent and redox economical transformation of amides embodies an efficient and potentially powerful tool for organic synthesis (Figure 1, top).³

Figure 1.

Synthetic potential of amides through semireduction.

Due to the attenuated electrophilicity of the amide carbonyl, strong reducing conditions are typically required for amide activation, and continuous reduction to the corresponding amine often prevails.⁴ Despite numerous reports detailing the reduction of amides using metal catalysts (e.g., Fe, Co, Ni, Cu, Zn, Ru, Rh, Pt) in combination with hydrosilanes as exceptionally mild reductants, the vast majority of these protocols directly furnish amines (Figure 1, bottom).⁵⁻⁸ Chemoselective strategies for the catalytic semireduction of amides to imines or hemiaminals without first necessitating preactivation remain exceedingly rare and predominantly rely on the use of iridium, a rare precious metal.^9,10

The hydrozirconation of amides utilizing Schwartz’s reagent (Cp₂ZrHCl) has proven to be a useful synthetic strategy for the direct conversion of amides to the corresponding imines or aldehydes via amidato zirconocene or zirconocene hemiaminal complexes (Figure 2a).^11,12 Despite the redox efficiency of this chemistry, its application on scale is economically and environmentally untenable due to the stoichiometric use of an air- and moisture-sensitive metal hydride. Herein, we report a mild approach for the divergent partial reduction of both secondary and tertiary amides using 5 mol % of zirconocene dichloride (1) for the express preparation of structurally diverse imines and derivatives thereof.

Figure 2.

Initial inspiration and proposed catalytic manifold.

We have recently disclosed a new method for the in situ generation and hydrosilane-mediated turnover of zirconocene hydride (ZrH) catalysts from a more stable and considerably less expensive zirconocene precatalyst, 1.¹³ We envisioned that a similar strategy could be applied to the semireduction of amides, rendering this process catalytic (Figure 2b). During the course of our studies, Cantat and co-workers disclosed a similar procedure on the zirconocene-catalyzed semireduction of secondary amides, leveraging a similar silane-mediated strategy for catalyst turnover.^10d However, this protocol requires the use of 10 mol % of Schwartz’s reagent directly and prolonged heating at refluxing temperatures. Furthermore, this procedure implements (EtO)₃SiH, a potentially dangerous hydrosilane that is known to disproportionately form pyrophoric and noxious byproducts (SiH₄).¹⁴

Instead, we surmised that dichloride 1 could serve as a precatalyst for the ZrH-catalyzed divergent transformation of both secondary and tertiary amides. Upon generation of I, hydrozirconation of secondary amide II would result in amidato zirconocene complex III.^15,16 Consonant with prior reports,^10d,11a,11bIII would undergo deoxygenative reduction furnishing imine IV and the previously reported oxo-bridged dimer V, which mechanistically converges on our prior published work.¹³

Analogously, we wondered whether our platform for ZrH catalysis might likewise enable a novel ZrH-catalyzed reductive transamination of tertiary amides as well. In this context, hydrozirconation of tertiary amide II′ would instead furnish hemiaminal III′. In the presence of a primary amine, III′ would consequently undergo transamination, culminating in the generation of imine IV′.¹⁰⁰ The resulting zirconocene(IV) complex (putatively V′) would then turnover back to hydride I through reaction with the hydrosilane.¹⁷

In accordance with our prior established conditions for ketone reduction, we examined the catalytic reduction of N-benzylbenzamide (2a) at 30 °C using dimethoxymethylsilane (DMMS) in the presence of 5 mol % each of precatalyst 1 and diethylamine (Table 1a). These conditions proved optimal for the semireduction, furnishing imine 3a in 91% yield. Additionally, N-aryl and N-alkylbenzamides were each successfully reduced to the corresponding imines (3b, 3c). Ortho-, meta- and para-substituted aryl amides of varying electronic character were reduced in moderate to high yields (3d–3g). Various heterocycle-containing amides were also efficiently reduced in up to 92% yield under these reaction conditions (3h–3j). Interestingly, these catalytic conditions proved to be selective for the semireduction of amides over that of other functional groups that are known to react with zirconium hydrides. For example, imine 3k was obtained in 91% yield without loss of the terminal alkene functionality. Further, this catalytic protocol exhibits a switch in conventional metal hydride chemoselectivity for the preferential reduction of the amide moiety over that of the ester present in 2l, resulting in the formation of imine 3l in 79% yield. Due to the inherent lack of electronic activation, we found the reduction of dialkyl amides to be particularly challenging. For example, imine 3m was furnished in only 41% yield under the standard conditions. Increasing catalyst loading and temperature did not improve conversion, affording 3m in only 35% yield.

Table 1. Substrate Scope of the ZrH-Catalyzed Semireduction of Secondary Amides and Indolinones.

^aReactions were carried out under an atmosphere of N₂ at 30 °C using 0.5–1.0 mmol of substrate in anhydrous toluene (0.5 M). Yields were determined by ¹H NMR spectroscopy of the crude reaction mixture, using mesitylene as an internal standard. For isolated yields, see Supporting Information.

^bReaction was carried out in anhydrous THF (0.5 M) instead.

^cReaction was carried out at 23 °C.

^dReaction was carried out using 10 mol % Cp₂ZrCl₂ and 10 mol % HNEt₂ instead.

^eReaction was carried out at 60 °C.

^fReactions were carried out under an atmosphere of N₂ at 23 °C using 0.2 mmol of substrate in anhydrous CH₂Cl₂ (0.1 M). Yields reflect isolated yield.

We also explored the application of this protocol to the deoxygenative semireduction of 2-indolinones (Table 1b).^10d Wu and co-workers have previously demonstrated the ZrH-catalyzed reduction of indoles using ammonia borane as a reductant, affording indolines.¹⁸ Under our catalytic manifold employing DMMS, reduction of indolinones 4a–4d was achieved at room temperature, selectively furnishing indoles 5a–5d instead. Notably, high yields were obtained even in the absence of a protecting group on the nitrogen.

Next, we examined the mild reductive transamination of tertiary amides to synthesize differentiated imines (Table 2). Our preliminary studies utilized diethyltoluamide (DEET), a pesticide commonly found as the active ingredient in commercial insect repellent (entries 1–6). Using just 5 mol % Cp₂ZrCl₂ as the precatalyst in the presence of p-anisidine, imine 7a was provided in 76% yield (entry 1), even when carried out at room temperature (for optimization studies, see Supporting Information). Aniline, allyl amine and various alkyl amines were also suitable primary amine reactants, yielding a variety of imines from a single amide precursor in up to 91% yield (entries 2–6). Notably, although these transformations were carried out with the exogenous amine added at the onset of the reaction, competitive reduction of the alkene moiety of allyl amine was not observed.

Table 2. Scope of the Single Step ZrH-Catalyzed Reductive Transamination of Tertiary Amides^a.

^aReactions were carried out under an atmosphere of N₂ at 23 °C using 0.5 mmol of amide in anhydrous THF (2.5 mL) for a duration of 18–24 h. PMB = para-methoxybenzyl.

^bYields were determined by ¹H NMR spectroscopy of the crude reaction mixture, using mesitylene as an internal standard. ND = not detected. For isolated yields, see Supporting Information.

^cReaction was carried out at 35 °C.

^dReaction was carried out in PhMe (0.2 M) instead.

A Weinreb amide also underwent semireductive transamination in the presence of various amines (entries 7–11), including furan- and thiophene-containing amines (entries 10–11) with good to excellent yields. Further, amides bearing N-methylpiperazine, pyrrolidine, piperidine, furan and pyridine moieties were all tolerated (entries 12–16). While aryl amides bearing electron-withdrawing groups worked equally well for these transformations, electron rich amides generally disfavored carbonyl reduction, providing their corresponding imines in lower yields.¹⁹ Finally, the catalytic transaminative semireduction of tertiary amides proved exceptionally chemoselective for internal alkyne-bearing substrates (entries 17–18). However, substrates bearing terminal alkynes exhibited poor conversion and selectivity.^19,20

To better understand the mechanism of this novel ZrH-catalyzed reductive transamination, we carried out a series of stepwise in situ NMR experiments using amide 6i (eqs 1 and 2).¹⁹ Our observations support the formation of a zirconocene hemiaminal intermediate (8) that does not favor silylation in the presence of DMMS (eq 1). Instead, in a separate experiment carried out in the absence of DMMS, we observed the rapid conversion of 8 to imine 7s upon addition of excess allylamine (eq 2).^11d After conversion to imine was complete, the addition of DMMS and another equivalent of

1

6i resulted in the reappearance of hemiaminal 8 and continued conversion to the desired product. These findings suggest the catalytic pathway for the reductive transamination of tertiary amides does not proceed via a silyl hemiaminal intermediate, as observed with analogous iridium-catalyzed transformations.⁹ⁱ Instead, the silane simply enables catalyst turnover. This mechanistic divergence is vital for transamination to occur.

The reductive functionalization of amides has proven to be a useful tool for redox economical syntheses, abridging synthetic strategies to a variety of nitrogen-containing products.^9h,21 To exemplify the utility of this protocol for the efficient diversification of amides, we carried out a series of transformations employing ZrH catalysis with various procedural modifications (Scheme 1). For example, while secondary amide 2g can be reduced to the corresponding imine (3g) in 94% yield, with subsequent hydrolysis to instead afford aldehyde 9, a sequential single-flask semireduction and nucleophilic addition sequence can also be used to yield an α-alkylated amine (10) in 62% yield. Similarly, tertiary amide 6a underwent ZrH-catalyzed three-component combinations when paired with various primary amines and Grignard reagents. Amines 11 and 12 were furnished in synthetically useful yields. The ease of exchanging the primary amine and Grignard reagent components illustrates the power of this methodology for the library preparation of branched benzylic amines from a singular amide starting material.

Scheme 1. Synthetic Utility of the ZrH-Catalyzed Diversification of Amides.

All reactions were carried out under an atmosphere of N₂ using Cp₂ZrCl₂ (5 mol %), HNEt₂ (5 mol %), and DMMS (4.0 equiv). Conditions a:2g (0.5 mmol), PhMe (0.5 M), 30 °C, 24 h. Conditions b:2g (0.5 mmol), PhMe (0.5 M), 30 °C, 24 h, followed by aqueous acidic workup. Conditions c:2g (0.5 mmol), PhMe (0.5 M), 30 °C, 19 h, then THF (2.0 mL), allylmagnesium bromide (4.0 equiv), 0 °C – 23 °C, 6 h. Conditions d:6a (0.5 mmol), allylamine (1.05 equiv), THF (0.2 M), 23 °C, 21 h, then allylmagnesium bromide (4.0 equiv), 0 °C – 23 °C, 5 h. Conditions e:6a (0.5 mmol), p-anisidine (1.05 equiv), THF (0.2 M), 23 °C, 19 h, then benzylmagnesium chloride (4.0 equiv), 0 °C – 23 °C, 6 h. Conditions f:6i (0.5 mmol), diethylamine (2.0 equiv), THF (0.5 M), 60 °C, 18 h. Conditions g:6j (0.3 mmol), piperidine (2.0 equiv), THF (0.5 M), 60 °C, 19 h.

Yield was determined by ¹H NMR spectroscopy of the crude reaction mixture, using mesitylene as an internal standard.

Finally, this catalytic manifold provides direct access to enamines from stable amide precursors. By simply including an excess of diethylamine at the outset of the reaction, the direct reduction of aliphatic tertiary amide 6j to the corresponding enamine 13 was realized in 70% yield. When the exogenous amine is varied, an unprecedented transaminative partial reduction to access diversified enamines is achieved. For example, in the presence of 2 equiv of piperidine, 6j was converted to styrylpiperidine 14 in 78% yield.

In summary, we have developed a mild, general method for the divergent semireduction of amides using a zirconocene hydride catalyst generated in situ. This method can be used to synthesize a variety of imine products with broad functional group tolerance and excellent chemoselectivity, allowing for otherwise stable amides to serve as aldehyde surrogates. No special handling by use of a glovebox is required, and most reactions are carried out at room temperature or with slight warming. An assortment of single-flask catalytic protocols enables the flexible preparation of aldehydes, amines or enamines through hydrolysis, nucleophilic addition or multicomponent syntheses. These examples demonstrate the convenience of amide diversification as a general tool for the preparation of nitrogen-containing compounds.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c11786.

• General procedural information, mechanistic studies, characterization data and spectra (PDF)

The authors declare no competing financial interest.