Tandem C/N-Difunctionalization of Nitroarenes: Reductive Amination and Annulation by a Ring Expansion/Contraction Sequence

Abstract

A synthetic method for the reductive transformation of nitroarenes into ortho-aminated and -annulated products is reported. The method operates via the exhaustive deoxygenation of nitroarenes by an organophosphorus catalyst and a mild terminal reductant to access aryl nitrenes, which after ring expansion are trapped by amine nucleophiles to give dearomatized 2-amino-3H-azepines. Treatment of these ring-expanded intermediates with acyl electrophiles triggers 6π electrocyclization to extrude the nitrogen atom and restore aromaticity of the phenyl ring, delivering via C–H activation 2-aminoanilide and benzimidazole products—important scaffolds in industrially relevant and bioactive molecules.

Graphical Abstract

Nitroarenes are readily-accessed and versatile starting materials for synthesis.¹ The nitro moiety itself can be transformed through direct reductive transformation^2–3,4 or ipso substitution⁵ to provide routes to a range of synthetically useful benzenoid intermediates (Figure 1A, a). Alternatively, the nitro moiety can be used to facilitate C–H functionalization reactions⁶ that decorate the aryl periphery with retention of the nitro group.⁷ Such methods include vicarious nucleophilic substitution (S_NAr^H, Mąkosza reaction), oxidative nucleophilic substitution of hydrogen (ONSH) reactions,^8,9 and directed transition metal-catalyzed C–H functionalization (Figure 1A, b).^10,11 A valuable subclass of nitroarene functionalization reactions accomplishes both nitro group reduction and proximal C–H functionalization simultaneously, permitting annulation as exemplified in the Bartoli indole synthesis¹² and catalytic indole-forming methods (Figure 1A, c).¹³ To move beyond indole synthesis, a complementary annulative approach to nitroarene C/N-difunctionalization would ideally provide a synthetically modular method for the synthesis of heterocyclic ring systems, providing the synthetic chemist with control over the functionality incorporated into annulated products (Figure 1A, d).

Figure 1.

(A) Mono- and difunctionalization of nitroarenes. (B) Reductive C/N-difunctionalization of nitroarenes as modular entry to 2-aminoanillides and benzimidazoles.

Towards this goal, a one-pot, three-component coupling protocol utilizing commercially available components was conceived, which relies on the potential of transient nitrogen intermediates—formed under mild conditions from abundant nitroarenes—to participate both as direct sites of bond formation and as indirect activators of proximal sites (Figure 1B). On the basis of prior work,¹⁴ we expected that a redox-active organophosphorus catalyst could drive exhaustive deoxygenation of a nitroarene substrate by P(III)/P(V) cycling¹⁵ to yield a high-energy arylnitrene intermediate (Figure 2). Commonly generated by direct photolytic decomposition of phenylazide,¹⁶

Figure 2.

(A) Mechanistic outline for the reported C/N-difunctionalization of nitroarenes. (B) Conditions for the reductive ring expansion of nitroarenes via arylnitrenes. (C) Synthetic conditions for the one-pot C/N-difunctionalization of nitroarenes.

Phenylnitrene¹⁷ (I) is well-known to isomerize to benzazirine¹⁸ (II) and dehydroazepine¹⁹ (III) valence tautomers, which are susceptible to interception by nucleophilic trapping agents such as amines to give 2-amino-3H-azepines (V) by ring expansion.^20–21,22 Subsequent isomerization of V was envisioned on the conjecture²³ that an azepine-to-azanorcaradiene 6π electrocyclization²⁴ (VI→VII) would be favored by N-acylation, and that decomposition of the fused bicyclic aminal VII could evolve with rearomatization of the arene core.²⁵ The resulting 2-aminoanilide product VIII is then poised to undergo thermal cyclization under established conditions to arrive at the desired benzimidazole product.

Overall, this synthetic approach would result in a reductive amination of the substrate nitroarene, in which both nitro group reduction and C(sp²)–H amination are accomplished through a transient ring expansion of the original aromatic system. The method presents a complement to recent work by Burns,²⁶ which leverages the intermediacy of the azepine ring to perform a nitrogen-for-carbon switch to yield 2-aminopyridines upon ring contraction. Here, we report the development of a one-pot synthetic method for the reductive C/N-difunctionalization of nitroarenes via the intermediacy of high-energy arylnitrenes.²⁷ This ability to generate arylnitrenes from nitroarenes under thermal catalytic conditions enables an expedient entry to 2-aminoanilide and benzimidazole products scaffold useful in pharmaceutical discovery.^28,29

In prior work from our group, we established that reductive functionalization of nitroarenes with primary and secondary amine nucleophiles under conditions of P(III)/P(V)=O redox cycling proceeds by direct N-functionalization, culminating in N–N bond formation to yield unsymmetrical hydrazine products.^4f However, as exemplified by the reaction of 4-trifluoromethylnitrobenzene (2) and diethylamine (3), we find that related conditions (15 mol % of 1,2,2,3,4,4-hexamethylphosphetane P-oxide 1·[O]³⁰ as catalyst, 2.0 equivalents of phenylsilane as terminal reductant) but with omission of an explicit Brønsted acid³¹ lead instead to 2-diethylamino-5-trifluoromethyl-3H-azepine (4) in 78% yield. Presumably, under these conditions, the nitroarene 2 is iteratively deoxygenated by the P(III)/P(V)=O redox catalyst to generate the corresponding arylnitrene,^4b which then evolves along the sequence indicated in Figure 2A to the 2-amino-3H-azepine. These thermal P(III)/P(V)=O catalytic conditions can be applied broadly for formation of 2-substituted-3H-azepines; a synthetic scope for this conversion is included in the SI (Figures S1 and S2).

Importantly, as shown in Figure 2C, the conditions optimized for the formation of azepine 4 could be extended to a two-part synthetic expansion/contraction synthetic sequence, achieved in a single reaction vessel. Specifically, reaction of nitroarene 2 and diethylamine (3) with 15 mol% of 1,2,2,3,4,4-hexamethyl phosphetane P-oxide (1·[O]) and 2.0 equiv of phenylsilane in t-BuOAc for 12 h, followed by a solvent swap to PhMe and addition of 2.0 equiy each of acyl chloride 5 and DABCO lead directly to isolation of ortho-aminoanilide 6 in 78% yield (0.5 mmol scale). As a synthetic transformation, this manipulation brings together readily available nitroarene substrates like 2 with exogenous amines and acyl electrophiles to assemble highly decorated products in a modular fashion by tandem C/N-difunctionalization of the nitroarene substrate.

The scope and potential utility of this method are exemplified in Figures 3–5. 2-Aminoanilide products are reliably accessed by assembly from a range of nitroarenes, secondary amines, and acyl electrophiles (Figure 3). With respect to the amine component, beyond the use of diethylamine (7, 8) as a trapping amine nucleophile, several of the most prevalent secondary amine heterocycles found in pharmaceuticals including piperidine (9, 10, 14), piperazine (11), and morpholine (15–17) derivatives are also readily accessed. Arylalkylamine (13) derivatives are similarly incorporated, but less nucleophilic diarylamines are insufficiently reactive to trap the benazirine/dihydroazepine intermediate. In terms of electrophilic reaction partners, substituted benzoyl (7–9, 11–12, 14–15) and related heteroaryl derivatives (16) are viable partners, as are alkanoyl (10) and fluoroalkanoyl (13) compounds, providing (fluoro)acylated products in good yields.

Figure 3.

Synthesis of 2-aminoanilides by reductive C/N-difunctionalization of nitroarenes. ^a 8:1 regioisomeric ratio. See SI for full experimental details.

Figure 5.

Regiospecific preparation of 1,2,7-benzimidazoles. See SI for full experimental details.

In terms of regiochemistry, nitroarenes bearing a symmetrical substitution patterns only generate one isomer following the ring expansion/contraction reaction sequence (for instance, 7-13, 16). However, for nitroarene substrates with substitution lacking mirror symmetry, two possible regioisomeric products are in principle possible. To a first approximation, the position of apparent C-H amination is dictated by steric considerations. For instance, product 14 is formed in as a single regioisomer, as a result of the insertion of arylnitrene to the sterically less encumbered position distal from the methyl substituent. Nevertheless, in the absence of a large steric bias, electronic effects dominate the regioselectivity, as exemplified by the product 15, in which arylnitrene prefers the insertion at the more electronically rich position. Consistent with electronic arguments, the quinolyl substrate (17) exhibits regioselectivity with apparent C-H amination proximal to the ring fusion. The unobserved regioisomer of the C/N-difunctionalization would need to arise from a benzazirine intermediate that enforces quinoidal structure on the heterocyclic system, whereas as the benzazirine leading to the observed C/N-difunctionalization product does not require disruption of heteroaromatic stabilization of the pyridyl subunit. Taken together, the C/N-difunctionalization method proceeds with predictable regiochemical preference if both steric and electronic factors are adequately considered.

Reactions with primary amines similarly enable the formation of corresponding 2-aminoanilide products, provided that the acyl electrophile employed is sterically encumbered (for instance, 2,6-chlorobenzoyl as in 12). However, when a primary amine nucleophile (e.g. benzylamine) is employed in conjunction with a sterically unencumbered acyl moiety (e.g. trifluoroacyl) then a subsequent cyclodehydration reaction spontaneously ensues under the reaction conditions to furnish a benzimidazole (18, Figure 4). A brief optimization revealed that the azepine contraction and subsequent aromatization/annulation could be achieved in a simple one-pot procedure (Table S2). This strategy could be applied to form benzimidazoles directly from nitroarenes, secondary amines, and acyl electrophiles (Figure 4); benzimidazole derivatives with N-benzyl (18-20, 23-24), N-aryl (21), and N-alkyl (22) substitution could be prepared with the same reductive selectivity for the nitro moiety compared to other reducible (ester 19, amide 24) functionality. With 3-nitroanisole as substrate, the reductive C/N-difunctionalization proceeds with excellent regioselectivity to give 1,2,6-trisubstituted benzimidazoles (25, 26) as the major product. Variation of the acyl electrophile allows control over substitution at the 2-position of the benzimidazole.

Figure 4.

Synthesis of benzimidazoles by reductive C/N-difunctionalization of nitroarenes. See SI for full experimental details.

The modularity and regiochemical predictability of the reductive C/N-difunctionalization allows the benzimidazole to be viewed as a retron accessible by an annulative C/N-difunctionalization transform from simple nitroarenes possessing accessible ortho C-H positions. Practically, this feature may have use for the preparation of benzimidazoles with challenging substitution patterns, for instance where direct N-functionalization of the parent N–H benzimidazole would be unselective or unfavorable due to steric considerations affecting the pseudosymmetry of the N1 and N3 positions.³² In this vein, Figure 5 collects examples of various benzimidazole derivatives synthesized by this protocol with sterically encumbered N-alkyl substituents in the presence of 2-and 7-substitution. Annulated systems with N-substitution next to primary (27, 28, 31, 32) and secondary (29, 30) carbon sites could be synthesized in synthetically useful yields. Collectively, this modular one-pot procedure could be used to access a variety of 2-aminoanilides and benzimidazoles from a range of nitroarenes, primary and secondary amines, and acyl electrophiles.

In summary, the results described above constitute a novel strategy for reductive C–H amination of nitroarenes that leverages tandem C- and N-functionalization to construct valuable 2-aminoanilide and benzimidazole products from readily accessible reaction partners. Integral to the success of this method is the efficient thermal generation of reactive arylnitrenes from nitroarenes, and the ability to achieve ring contraction and aromatization of 3H-azepine intermediates. Taken together, these developments enable new expedient routes to 2-aminoanilides and benzimidazoles via a novel synthetic sequence for C–H functionalization and annulation. In connection with our efforts to explore the biphilic catalytic reactivity of phosphetanes for reductive O-atom transfer processes via the P(III)/P(V)=O redox cycling, this study portends future developments in tandem C/N-difunctionalization of nitroarenes and homologues to access a wide range of elaborated products.