Oxidative Dearomative Cross-Dehydrogenative Coupling of Indoles with Diverse C-H Nucleophiles: Efficient Approach to 2,2-Disubstituted Indolin-3-ones

Abstract

The oxidative, dearomative cross-dehydrogenative coupling of indoles with various C-H nucleophiles is developed. This process features a broad substrate scope with respect to both indoles and nucleophiles, affording structurally diverse 2,2-disubstituted indolin-3-ones in high yields (up to 99%). The oxidative dimerization and trimerization of indoles has also been demonstrated under the same conditions.

A general approach to 2,2-disubstituted indoxyls: total synthesis of brevianamide A and trigonoliimine C

“…Additionally, we found that carbonyl nucleophiles in the form of silyl enol ethers could couple effectively, while a relatively acidic β-diketone was also a viable substrate; the products from these couplings provide versatile ketone ( 38 , 40 ) or enal ( 39 ) functionalities for further elaboration. Finally, although the nucleophile scope is greater than that observed for related indoxyl syntheses, 11,12 we did note that less nucleophilic coupling partners such as anisole ( N = −1.18) 13 b and 2-methylanisole gave either no observed product or only a moderate yield (31%, 33 ), respectively. Based on our experience, nucleophiles with N > 1 tended to react effectively unless steric factors became dominant (see ESI † for unsuccessful partners).…”

“…Aside from being complementary to the prior rearrangement approach, this strategy offers the advantage of being convergent, provided sufficient generality is available for the nucleophilic and electrophilic components. While this approach has been explored, 11 a key issue in such reactions is avoiding simple dimerization of the indole fragment via attack of the nucleophilic indole starting material onto 13 during oxidation to yield an adduct like 15 . In fact, many methods explicitly target such dimers (or trimers) because of this problem.…”

“… 12 Additionally, where cross-couplings are possible, the overwhelming majority of such methods are only suitable for 2-aryl substituted systems and/or require N -substitution, likely due to the instability of the corresponding 2-alkylimine/iminium intermediates ( vide infra ). 11 Though a handful of exceptions exist, 11 a , h , j , m these approaches also typically employ highly nucleophilic coupling partners like indoles or pyrroles (Mayr nucleophilicity parameter, N = 5.5–7) 13 presumably to ensure efficient iminium trapping. Among these methods, You and coworkers reported a notable asymmetric coupling of indoles with spiroindoxyls that relies on a hydroxyalkyl chain as reversible iminium trap (see 16 , Scheme 1B , bottom), building off of racemic work by Kobayashi, 11 a which necessarily limits the scope to specific 2-(hydroxyalkyl) substrates ( 18 ).…”

Recent Studies of Bifunctionalization of Simple Indoles

“…Similar oxidative bifunctionalization of indoles at the C2−C3 double bond could also be achieved by indole themselves [31c,32a–c] . These reactions began with the oxidation of indoles by radical initiators and completed by a Mannich‐type reaction with other indoles [31c,32a] .…”

Advances in Cross-Coupling Reactions

“…In a related procedure, and as alternative to the traditional cross-coupling protocols, Zhang et al present the coupling of indoles with diverse C–H nucleophiles under oxidative dearomative cross-dehydrogenative conditions. As a result, 2,2-disubstituted indolin-3-ones are obtained [ 28 ].…”