B(C6F5)3-Catalyzed Direct C3 Alkylation of Indoles and Oxindoles

The direct C3 alkylation of indoles and oxindoles is a challenging transformation, and only a few direct methods exist. Utilizing the underexplored ability of triaryl boranes to mediate the heterolytic cleavage of α-nitrogen C–H bonds in amines, we have developed a catalytic approach for the direct C3 alkylation of a wide range of indoles and oxindoles using amine-based alkylating agents. We also employed this borane-catalyzed strategy in an alkylation-ring opening cascade.

I ndoles and oxindoles are prevalent motifs in biologically active molecules. 1 Classic indole syntheses involve ring construction. 2 Another approach involves the functionalization of the readily accessible heterocycle core; yet, the direct and selective C3 alkylation of indoles and oxindoles is a surprisingly challenging transformation as the reaction with simple alkyl halides is often not synthetically useful. 2,3 For example, with methyl iodide, 1,2-dimethylindole and 1-methylindole are unreactive, 4 2-methylindole results in mixtures of N-and Cmethylation, 5 and oxindoles undergo dialkylation at C3. 3 The installation of a methyl group is a worthwhile endeavor, considering the interest of medicinal chemists in the "magic methyl effect"; 6 yet only a few methods exist for the direct C3 methylation of indoles and oxindoles (Scheme 1a). Direct C3 methylation is possible with CO 2 /H 2 and a ruthenium catalyst (e.g., for 1,2-dimethylindole and 2-methylindole), 7 and with borrowing hydrogen methods with methanol (e.g., for 2methylindole 8 and 1-phenyl oxindole). 8a, 9 The direct methylation of 1-methylindole is currently unknown. 4 Because of their intrinsic Lewis acidity, borane catalysts have found numerous applications in synthesis and are traditionally used to activate polarized bonds. 10 Triaryl boranes can also activate unpolarized bonds, such as H−H 11 and Si−H bonds. 12 In a similar vein, we considered if boranes could also be used to cleave C(sp 3 )−H bonds heterolytically 13 and unveil new approaches to challenging transformations. Related to this, we were intrigued by a report by Santini that described the heterolytic cleavage of an α-nitrogen C(sp 3 )−H bond during the stoichiometric reaction of dimethyl aniline and B(C 6 F 5 ) 3 to form an iminium borohydride ion pair (Scheme 1b). 14 B(C 6 F 5 ) 3 -mediated α-N C(sp 3 )−H bond cleavage 15 was unrecognized as a synthetic strategy for almost a decade until Stephan and co-workers reported its use in the transfer hydrogenation of imines. 16 Subsequently, Grimme and Paradies, 17a Kanai, 17b and Zhang 17c disclosed methods for the dehydrogenation of N-heterocycles. A major breakthrough came when Erker reported the use of this unusual reactivity in C−C bond-forming reactions where stoichiometric B(C 6 F 5 ) 3 was used to generate iminium ions for Mannich-type processes. 18 Wasa greatly advanced the strategy by reporting the catalytic use of B(C 6 F 5 ) 3 in an asymmetric Mannich process. 19 The iminium ions generated have also been used in electrocyclizations, 20 and in the β-functionalization of amines. 21,22 However, the use of this reactivity in catalytic C−C bond-forming reactions remains rare. 19,20 Inspired by these reports and borrowing hydrogen alkylation reactions, 23 we have applied this underutilized reactivity in challenging alkylation processes.
Here, we have developed a new strategy for the direct C3 methylation of indoles and oxindoles (Scheme 1c). The process utilizes a B(C 6 F 5 ) 3 -mediated α-N C(sp 3 )−H bond cleavage events to activate readily available amine-based alkylating agents. Using this borane-catalyzed method, common undesired reactions, such as the N-methylation of indoles, the formation of 3,3′-bisindolylmethanes, and the dialkylation of oxindoles, are not observed. In addition, the substrate scope is broad and encompasses 1-, 2-, and 1,2substituted indoles, as well as other challenging alkylations, including a novel alkylation-ring opening cascade.
We began by investigating various aniline derivatives as methylating agents in the borane-catalyzed methylation of 1,2dimethyl indole (1a) (Scheme 2). Generally, we discovered that a variety of aryl and diaryl amines were effective in methylating 1a using B(C 6 F 5 ) 3 (10 mol %). 24 Electron-rich diaryl methyl amines, such as 4a and 6a, were determined to be optimal and allowed the formation of 2a in quantitative yields at ambient temperature.
Beyond methylation and alkylation, we also explored the B(C 6 F 5 ) 3 -catalyzed alkylation strategy in a novel alkylationring opening cascade process for the generation of functionalized indoles 15 (Scheme 5). Product 15 contains a 4-(3indolyl)butylamine motif that is found in several serotonergic/ dopaminergic drug molecules, such as vilazodone, roxindole, siramesine, and carmoxirole. 36 Upon reaction of N-aryl

ACS Catalysis
pubs.acs.org/acscatalysis Letter pyrrolidines 14, 37 indoles 1 and B(C 6 F 5 ) 3 catalyst, a variety of 4-(3-indolyl)butylamines 15 were formed in good yields. 38 In order to probe the mechanism and provide direct access to deuterated methyl groups at C3 of indoles, we used deuterated methylating agent 6a-d 3 in the B(C 6 F 5 ) 3 -catalyzed methylation of indoles 1a and 1l under previously optimized conditions (Scheme 6a). Deuterated C3 methylindoles 2a-d 3 and 2l-d 3 were formed in high yield in both cases. 39 Based on these results and literature precedent, we propose the following catalytic cycle for the B(C 6 F 5 ) 3 -catalyzed alkylation of indoles and oxindoles (Scheme 6b). The borane-catalyst mediates heterolytic cleavage, via hydride abstraction, of the α-N C(sp 3 )−H bond in the amine-based alkylating agents (3−7, 13, 14) forming iminium-borohydride ion pairs 16 (Scheme 6b, step (i)). Analogous ion pairs have been observed by Santini and co-workers using NMR spectroscopy (cf. Scheme 1A). 14 The electrophilic iminium 16 is trapped with an indole 1 (or oxindole 8), forging a new C−C bond (step (ii)) in an analogous fashion to the Mannich reaction. Proton transfers enable the ion pair 17 to eliminate the amine 18 (which can be recovered from the reaction) via an E1 CB -type mechanism (step (iii)). 40 The α,β-unsaturated iminium-based ion pair 19 is reduced by the borohydride counterion, producing the alkylated indoles 2 (and oxindoles 9) and regenerating the borane-catalyst (step (iv)). In the boron-catalyzed alkylation/ring opening cascade process (cf. Scheme 5), the cyclic nature of the iminium 20 enables the amino fragment to be retained in product 15 after elimination (Scheme 6c).
In summary, we have developed a new approach to the direct C3 alkylation of indoles and oxindoles. Using a B(C 6 F 5 ) 3 catalyst and amine-derived alkylating agents, we exploit the underexplored ability of boranes to cleave heterolytically α-N C(sp 3 )−H bonds in a catalytic C−C bond-forming reaction. This method provides a metal-free and complementary approach to the few existing methods for the direct C3 alkylation of indoles. Unlike other procedures, this B(C 6 F 5 ) 3catalyzed methodology encompasses several classes of indole, including 1-, 2-, and 1,2-substituted indoles, and allows previously unreported direct methylations. The reaction displays broad scope and exceptional chemoselectivity, avoiding N-methylation and formation of 3,3′-bisindolylmethanes in indole substrates, and dialkylation in oxindoles. Other alkylations are also reported, including a novel alkylation-ring opening cascade process to generate privileged 4-(3-indolyl)butylamines from N-aryl pyrrolidines.