CuH-Catalyzed Enantioselective Alkylation of Indole Derivatives with Ligand-Controlled Regiodivergence

Abstract

<b>Enantioenriched molecules bearing indole-substituted stereocenters form a class of privileged compounds in biological, medicinal, and organic chemistry. Thus, the development of methods for asymmetric indole alkylation is highly valuable in organic synthesis. Traditionally, achieving N-selectivity in indole alkylation reactions is a significant challenge, since there is an intrinsic preference for alkylation at C3, the most nucleophilic position. Furthermore, selective and predictable access to either N- and C3-alkylated chiral indoles using catalyst control has been a long-standing goal in indole functionalization. Herein, we report a ligand-controlled regiodivergent synthesis of N- and C3-alkylated chiral indoles that relies on a polarity reversal strategy. In contrast to conventional alkylation reactions in which indoles are employed as nucleophiles, this transformation employs electrophilic indole derivatives, N-(benzoyloxy)indoles, as coupling partners. N- or C3-alkylated indoles are prepared with high levels of regio- and enantioselectivity using a copper hydride catalyst. The regioselectivity is governed by the use of either DTBM-SEGPHOS or Ph-BPE as the supporting ligand. Density functional theory (DFT) calculations are conducted to elucidate the origin of the ligand-controlled regiodivergence.</b>

Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis

“…These results are consistent with the previously studied ligand effects, where Ph-BPE ligand promoted the formation of C3-alkylated product. 7 In the reaction with the indazole electrophile (1a), we found that the SN2′ oxidative addition (TS3) requires a higher activation barrier of 28.0 kcal/mol with respect to 10, when compared to the reaction with indole (TS3′), and the product is thermodynamically destabilized by 3.6 kcal/mol (12 versus 12′). Since the C3 oxidative additions are endergonic, the transition states are more product-like and exhibit significant N−O bond elongations (Figure 3B).…”

“…Initially, we attempted the coupling of a variety of readily accessible alkenes with indazole 1a under the conditions previously developed for indole alkylation. 7 Less than 5% yield of the alkylated indazole products were formed in the cases of styrene (Figure 2a). However, when cyclohexylallene was employed, 11 it reacted efficiently with the indazole electrophile 1a, providing the corresponding allyl indazole product (3s) in good yield with a high level of enantioselectivity.…”

“…6 Recently, we developed a method to prepare chiral alkylated indoles through a CuH-catalyzed nucleophilic alkylation reaction. 7 By employing N-(benzoyloxy)indoles as electrophiles and with the appropriate choice of ligand, selective Nalkylation or C3-alkylation was achieved (Figure 1c). Compared to conventional alkylation reactions, wherein indoles are used as nucleophiles, 8 the regioselectivity of this alkylation protocol was dictated by the catalyst, rather than the intrinsic nucleophilicities of the indole.…”

Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis

“…These unfavorable interactions lead to elongation of the forming C-C bond, which results in a later transition state, when compared to the reactions with the intermediate 7 as it can be observed both from the forming C-C bond, as well as the breaking C-Cu bonds. As oxidative addition mechanisms have been proposed to be operative in the indole alkylation reaction reported earlier, 22 we investigated this pathway from the most stable intermediate 7, leading to the cationic Cu III complex with copper bound to the either C (9) or N (10) of the indazole. Both oxidative addition transition states TS3, TS4 were found to be disfavored relative to TS2c (ΔΔG ‡ = 7.0, 12.9 kcal/mol respectively).…”

Recent Advances in the Catalytic Functionalization of “Electrophilic” Indoles

“…In particular, Buchwald and coworkers have recently documented on the copper catalyzed activation of N‐ benzoyloxy‐ indoles 63 and subsequent trapping with in‐situ generated chiral alkyl‐copper reagents (L‐Cu(OAc) 2 /Silane/alkene) . Regiodivergence towards N(1)‐ or C(3)‐functionalization was effectively recorded via selection of chiral organo ligands.…”