HETEROCYCLES

Communication | Regular issue | Vol. 91, No. 8, 2015, pp. 1579-1584
Received, 5th June, 2015, Accepted, 21st July, 2015, Published online, 23rd July, 2015.
DOI: 10.3987/COM-15-13261

■ Site-Selective Introduction of an Enamido Group at the C(3)-Position of Indoles

Tomoya Miura,* Qiang Zhao, Yuuta Funakoshi, and Masahiro Murakami*

Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, youdai-katsura, Nishikyo, Kyoto 615-8510, Japan

Abstract

An enamido group is introduced site-selectively at the C(3)-position of indoles by the rhodium(II)-catalyzed reaction with N-sulfonyl-1,2,3-triazoles. Formally, an α-imino rhodium carbene complex is inserted into the C(3)-H bond of an indole.

Indoles are privileged structural motifs found in a myriad of natural products and pharmaceuticals.1 Numerous methods have been developed for the functionalization of indole skeletons.2 Among them, a C-H bond functionalization using metal carbene complexes has received much attention in recent years.3 On the other hand, N-sulfonyl-1,2,3-triazoles have emerged as convenient precursors for the generation of α-imino metal carbene complexes.4 The complexes contain an electrophilic carbene carbon and a nucleophilic imino nitrogen in the molecule. They can trigger a variety of synthetically useful transformations, including not only typical carbene reactions such as cyclopropanation5 and X-H bond insertion (X = carbon,6 oxygen,7 nitrogen8) but also carbene-induced reactions such as [3+2] annulation,9 ring expansion,10 and others.11 Davies and co-workers have demonstrated an excellent method for the functionalization of indole skeletons using α-imino rhodium carbene complexes generated from N-sulfonyl-1,2,3-triazoles; 1,3-disubstituted indoles undergo [3+2] annulation reaction in an enantioselective manner to afford pyrroloindolines (Figure 1(a)).12,13 This fascinating result led us to

examine the rhodium(II)-catalyzed reaction of indole derivatives having C(3)-H bonds. Now, we report a rhodium(II)-catalyzed reaction of 1,2-disubstituted indoles and 1-monosubstituted indoles with N-sulfonyl-1,2,3-triazoles. The presence of the C(3)-H bond shifts the [3+2] annulation pathway to 1,3-insertion of α-imino rhodium carbene complexes into the C(3)-H bond, leading to the formation of α-(3-indolyl)sulfonylenamides with the high (Z)-selectivities (Figure 1(b)).
Initially, 4-phenyl-1-tosyl-1,2,3-triazole (1a) was prepared from phenylacetylene and tosyl azide according to the authentic procedure using a copper(I) catalyst.14 When the triazole 1a (0.2 mmol) was treated with 1,2-dimethyl-1H-indole (2a, 0.3 mmol) in the presence of (tBuCO2)4Rh2 (1 mol%) in chloroform (2 mL) at 80 °C, 1a was completely consumed within 8 hours. Chromatographic purification afforded β-(3-indolyl)sulfonylenamide 3a in 97% isolated yield with the Z/E ratio of >95:5 (Scheme 1). The configuration of the double bond of 3a was confirmed as Z by an NOE study. Unlike the cases with 1,3-disubstituted indoles, no annulation product was formed.15 We propose the following mechanism for the production of 3a. α-Diazo imine 1a’ is generated from the triazole 1a by a ring-chain tautomerization through equilibrium. The transient 1a’ is trapped by a rhodium(II) catalyst to furnish α-imino carbene complex A. Nucleophilic addition of the indole 2a at the C(3)-position to the electrophilic carbene of A gives the zwitterionic intermediate B. The anionic rhodium of B releases an electron pair, which flows onto the imino nitrogen. Since there is a hydrogen atom at the C(3)-position, the imino nitrogen acts as a base to pick up the hydrogen rather than undergoes nucleophilic attack onto the C(2)-carbon atom, furnishing (Z)-isomer of 3a.

1,2-Dimethyl-1H-indole (2a) was reacted with various triazoles 1 (Table 1). Triazoles 1b−e possessing aryl and heteroaryl groups at the C(4)-position all reacted well to afford the corresponding products 3b−e in yields ranging from 90% to 95% with high (Z)-selectivities (entries 1–4). The reaction of the alkyl-substituted triazoles 1f−h gave the products 3f−h, albeit in moderate yields (entries 5–7).7 Aryl group as well as alkyl group were compatible for the R2 substituent on the sulfonyl group to afford the products 3i−m in high yields (entries 8–12).

Next, the use of 1-methyl-1H-indole and its derivatives was examined. The C-H bond functionalization took place site-selectively at the C(3)-position, and the corresponding products 3n−s were obtained in excellent yields (Table 2). In these cases, however, the lower (Z)-selectivities (Z:E = 82:18~88:12) were observed except 3s, which was ascribed to isomerization of the initially formed (Z)-isomer to the (E)-isomer occurring during the course of the reaction. In fact, when the reaction of 1a with 1-methyl-1H-indole was monitored by 1H NMR, the gradual isomerization from (Z)-3n to (E)-3n was observed [96:4 (1 h), 83:17 (4 h), 80:20 (8 h)].

Fused indole 2b with N(1)-to-C(2) was also suitable substrate, giving the product 3t in 95% yield with the Z/E ratio of 87:13 (Eq 1).

An all-in-one-pot procedure was also carried out to demonstrate the practical convenience of the present method (Eq 2). Phenylacetylene (4), tosyl azide, 1,2-dimethyl-1H-indole (2a), copper(I) and rhodium(II) catalysts, and chloroform were put in a reaction vessel, and the mixture was stirred at room temperature. After 3 hours, 4 and tosyl azide were both consumed to generate the triazole 1a. Then, the reaction mixture was stirred at 80 °C for 8 hours, and the following chromatographic purification afforded the product 3a in 79% yield.

The synthetic utility of the products 3 was exemplified by further transformations. The carbon–carbon double bond of 3a, 3n, and 3q was successfully reduced, giving tryptamine derivatives 5, 6, and 7 in good yields when a simple hydrogenation reaction using palladium on charcoal was applied (Eq 3). Furthermore, treatment of 6 with iodine (1.0 equiv) caused electrophilic cyclization to afford fused indole derivative 8 in 77% yield (Eq 4).16

In summary, a regioselective C-H bond functionalization of 1,2-disubstituted- and 1-monosubstituted indoles by α-imino rhodium carbene complexes is reported. The product selectivity is significantly affected by the substitution pattern at the C(3)-position of the indoles. The resulting products are useful intermediates for the synthesis of tryptamine derivatives.

ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research (S) from MEXT and the ACT–C program of the JST. We are grateful to the JSPS for Young Scientists for a Research Fellowship to Y. F. We also thank Dr. Y. Nagata (Kyoto University) for kind help in an X-ray analysis.

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