Radical α-C–H Cyclobutylation of Aniline Derivatives

Abstract

A catalytic system has been developed for the direct alkylation of α-C–H bonds of aniline derivatives with strained C–C σ-bonds. This method operates through a photoredox mechanism in which oxidative formation of aminoalkyl radical intermediates enables addition to a bicyclobutane derivative, giving rise to α-cyclobutyl N-alkylaniline products. This mild system proceeds through a redox- and proton-neutral mechanism and is operational for a range of substituted arylamine derivatives.

Graphical Abstract

The high stability of C–C single bonds typically renders them chemically inert; however, conformationally strained-ring systems display unique reactivity profiles. Early work by Wiberg and co-workers and by Gaoni demonstrated that a range of strained polycyclic hydrocarbons (some of which are shown in Figure 1) can be accessed synthetically,^1–3 and that they can serve as effective alkylating agents.^4,5 Indeed, because installation of cyclobutyl groups (cyclobutylation) can be accomplished through direct addition to bicyclo[1.1.0]butane (BCB) derivatives, this represents a potentially valuable method for the synthesis of cyclobutane-containing natural products or drug candidates.

Figure 1.

Strategy for cyclobutylation through addition to strained bicyclic alkanes. The strain energy for each molecule is derived by comparing δH_f with a hypothetical strainless model, as discussed by Wiberg.¹⁹

In addition to anionic nucleophiles,^6–8 organometallics,^9–11 and amines,^12,13 strained BCBs are effective coupling partners for radical species.^7,14 Over the past few years, our laboratory has been interested in developing new methods that permit selective reactions through the use of photoredox catalysis. As part of this program, we recently developed a system for the direct addition of nonactivated amines to peptides through the formation of the corresponding α-amino radicals.¹⁵ This process is highly selective and it functions through a redox- and proton-neutral mechanism, such that stoichiometric additives are not required. We questioned whether these aminoalkyl radical intermediates¹⁶ could be intercepted by strain-activated BCB derivatives in a direct cyclobutylation reaction with amines. Although a number of impressive methods for cyclobutylation of radical intermediates have been described, most recently by the groups of Lin¹⁷ and Aggarwal,¹⁸ this approach (outlined in Figure 1) would be unique, in part, because it would potentially function on a range of nonactivated amine-containing substrates, without the need for programmed radical formation (i.e., halogen installation, etc.).

We considered the catalytic pathway shown in Figure 1, in which photoinduced electron transfer from the amine substrate to a photoredox catalyst would give rise to a radical cation. Deprotonation of the newly acidified C–H bond would afford a key α-amino radical species.^20–23 Attack of this intermediate species on a strain-activated bicyclo[1.1.0]butane would afford a new C–C bond, and single-electron reduction and protonation would deliver the desired α-cyclobutylamine This system would operate in a redox- and proton-neutral manner, without the need for exogenous chemical additives.

To evaluate the feasibility of this proposed transformation, we treated N,N-dimethylaniline with a small series of BCB reagents 1a–c to afford the corresponding cyclobutylated products 2a–c (Table 1). In the presence of 1 mol% of Ir[dF(CF₃)ppy]₂(dtbbpy)·PF₆ [P1; dF = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine] and blue light in N,N-dimethylacetamide (DMA), phenylsulfone 1a gave the desired product 2a in a promising yield (28%, as determined by NMR with an internal standard). Increasing the electron-withdrawing capacity of the sulfonyl activating group resulted in improved reactivity with aminoalkyl radicals. Specifically, the fluorinated phenylsulfone derivatives 1b and 1c gave the corresponding cyclobutane products 2b and 2c in yields of 64 and 69%, respectively. In this system, the aniline substrate was used as the excess reagent (five equivalents with respect to the BCB reagent) to suppress further activation and cyclobutylation of the desired products 2. Importantly, this process was not operational in the absence of a photoredox catalyst or light (Table 1, entries 1 and 2; 0% yield). Other catalysts could also be employed to accomplish this transformation, although less-oxidizing iridium catalysts (such as P2; entry 3: 35% yield) or organic dyes [including penta-9H-carbazol-9-ylbenzonitrile (5CzBn; P3) (entry 4: 64% yield)] were less efficient across an array of substrates. A variety of aprotic organic solvents could be utilized here with acceptable levels of reaction efficiency (entries 5–7; 46–51% yield).

Table 1.

Optimal Conditions for α-Cyclobutylation of N,N-Dimethylaniline

Entry	Deviation from above conditions (with 1c)	Yield (%) of 2c
1	Reaction without catalyst	0
2	Reaction without blue light	0
3	1 mol% Ir[(ppy)2(dtbbpy)]-PF6a (P2) as catalyst	35
4	5 mol% 5CzBnb (P3) as catalyst	64
5	MeCN as solvent	48
6	DCE as solvent	46
7	DMSO as solvent	51

^appy = 2-phenylpyridine.

Having identified an effective protocol for the α-alkylation of anilines with BCB 1c, we evaluated the substrate scope of this process (again utilizing 1c as the limiting reagent with five equivalents of the aniline substrate).²⁴ As shown in Table 2, electron-deficient dimethylaniline derivatives reacted under standard conditions to give the corresponding products 3 and 4 in yields of 65 and 46%, respectively. Cyclic aniline derivatives were also effectively transformed into the corresponding cyclobutylated products. For example, N-phenylpyrrolidine reacted well to afford 5 in 83% isolated yield. These conditions were less effective for the coupling of N-phenylpiperidine (which gave 6 in 33% yield, with 55% remaining starting material), presumably due to increased steric constraints. However, seven- and eight-membered saturated nitrogen heterocycles were excellent substrates, giving rise to the corresponding cyclobutanes 7 and 8 in near-quantitative yield (96% in each case).²⁵ In accord with earlier reports,²¹ aniline derivatives with electron-donating groups in the ortho- or para-positions were not reactive in this system, where coupling attempts uniformly returned the starting materials. However, these conditions were effective for the transformation of electron-deficient aniline derivatives. Alkylation of a variety of N-arylpyrrolidines occurred smoothly; a methoxy substituent was well tolerated in the meta-position (9; 61% yield), as were fluoro and bromo substituents (10–12; 57–79% yield). As expected, the methoxycarbonyl- and nitrile-substituted phenylpyrrolidines were excellent substrates for this transformation, giving rise to products 13 and 14 in yields of 77 and 90%, respectively.

Table 2.

Scope of Anilines. ^a<2:1 dr, ^b2.3:1 dr.

In most cases, the products were isolated as roughly equal (<2:1) mixtures of cis- and trans-cyclobutane stereoisomers. Slightly higher selectivity was observed in a few cases (7, 8, and 11: ~2.3:1 ratio); although chromatographic separation of these diastereomers was often difficult, we were able to purify the major isomer of 7. Crystallization of this isomer permitted its analysis by X-ray crystallography, which demonstrated that the major isomer in this case was the cis-cyclobutane, consistent with protonation occurring from the less sterically hindered face of the cyclobutane ring. The synthetic utility of arylsulfonylcyclobutanes has been extensively demonstrated by the Baran group.¹³ In line with these reports, reductive desulfonylation of product 5 occurred smoothly in the presence of excess magnesium in methanol at room temperature to give 71% yield of the cyclobutyl product 15, as shown in Scheme 1.

Scheme 1.

Reductive desulfonation of arylsulfonylcyclobutane 5

In summary, we have developed a mild system for the direct C–H cyclobutylation of aniline derivates. This process operates through formation of an α-amino radical, followed by direct addition to a strained BCB derivative. The dis-closed protocol readily functionalizes a range of N-aryl amines and heterocyclic compounds of various ring sizes. In accord with previous reports, electron-deficient aniline derivates were shown to be efficient coupling partners. Because the resulting sulfonyl cyclobutane products have been shown to capable of being manipulated in a number of ways, we anticipate this process will be an attractive method for the generation of a range of α-cyclobutyl amine derivatives.