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. 2015 Jul 3:6:7616.
doi: 10.1038/ncomms8616.

Asymmetric synthesis of N-allylic indoles via regio- and enantioselective allylation of aryl hydrazines

Kun Xu  1 , Thomas Gilles  1 , Bernhard Breit  1
Affiliations

Asymmetric synthesis of N-allylic indoles via regio- and enantioselective allylation of aryl hydrazines

Kun Xu et al. Nat Commun. .

Abstract

The asymmetric synthesis of N-allylic indoles is important for natural product synthesis and pharmaceutical research. The regio- and enantioselective N-allylation of indoles is a true challenge due to the favourable C3-allylation. We develop here a new strategy to the asymmetric synthesis of N-allylic indoles via rhodium-catalysed N-selective coupling of aryl hydrazines with allenes followed by Fischer indolization. The exclusive N-selectivities and good to excellent enantioselectivities are achieved applying a rhodium(I)/DTBM-Segphos or rhodium(I)/DTBM-Binap catalyst. This method permits the practical synthesis of valuable chiral N-allylated indoles, and avoids the N- or C-selectivity issue.

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Figures

Figure 1
Figure 1. Challenges for asymmetric synthesis of N-allylic indoles.
(a) Selected examples of biologically active N α-chiral indoles. (b) Selectivity issue for allylation of indoles. (c) Strategies for transition metal-catalysed asymmetric synthesis of N-allylic indoles. LG, leaving group; EWG, electron-withdrawing group; FI, Fischer indolization.
Figure 2
Figure 2. Scope of Rh-catalysed coupling of aryl hydrazines with allene.
[a]Isolated yield. [b]Determined by chiral HPLC. [c]ee after recrystallization from tosylic acid salt. [d]Reaction in 1.0 mmol scale. [e][Rh(cod)Cl]2 (2 mol%), L1 or L2 (8.0 mol%). [f]Reaction at 100 °C. [g]The NMR spectrum of 1j is not fully pure due to contamination of acetone (formation of hydrazone) during the purification. This problem can be avoided in the process of one-pot asymmetric synthesis of N-allylic indoles. Chp, cycloheptyl; HPLC, high-performance liquid chromatography; Phth, phaloyl; TBS, tert-butylsilyl.
Figure 3
Figure 3. Scope of one-pot asymmetric synthesis of N-allylic indoles.
[a]Scope conditions of Fig. 2. [b]Reaction carried out at 100 °C.
Figure 4
Figure 4. One-pot late-stage indolization of (+)-testosterone acetate.
[a][Rh(cod)Cl]2 (1.0 mol%), L2 (4.0 mol%), 1,2-dichloroethane (0.4 M), 80 °C, 19 h.
Figure 5
Figure 5. Mechanistic investigations.
(a) Control experiment with 1-methyl-1-phenylhydrazine. (b) Isotopic-labelling experiment with [D3]phenylhydrazine. (c) Stoichiometric reaction of phenylhydrazine with catalysts. (d) Proposed mechanism.
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