HETEROCYCLES

Communication | Special issue | Vol. 86, No. 2, 2012, pp. 979-983
Received, 20th July, 2012, Accepted, 24th August, 2012, Published online, 30th August, 2012.
DOI: 10.3987/COM-12-S(N)101

■ Rapid Trifluoromethylation of Indole Derivatives

Ayako Miyazaki, Ryo Shimizu, Hiromichi Egami, and Mikiko Sodeoka*

Synthetic Organic Chemistry Laboratory, The Institute of Physical and Chemical Research, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Abstract

Rapid trifluoromethylation of indole derivatives was achieved using trimethylsilyltriflate as the catalyst. Good to high yields were observed within only 5 min at room temperature. This reaction system is able to provide not only the mono-trifluoromethylated products, but also the di-trifluoromethylated derivatives, because of its high reaction efficiency.

Indole frameworks have often been found in many natural products and bioactive compounds. Therefore, transformation of indole derivatives is of great interest in organic chemistry and many functionalizations of indoles have been investigated for a long time.1 On the other hand, the trifluoromethyl group has increasingly attracted attention in the pharmaceutical and agrochemical fields. This is because the presence of the trifluoromethyl group often brings about unique properties to molecules, such as improved metabolic stability and hydrophobicity.2 Accordingly, trifluoromethylated indole derivatives would be an intriguing target.3,4 The direct indole trifluoromethylation reaction, in particular the catalytic version, has recently been developed.5 In 2010, we reported the copper-catalyzed direct trifluoromethylation of indole derivatives using Togni reagent 26 (Scheme 1a).7 The C2-trifluoromethylated compounds were selectively obtained, and it was found that the N-protecting group affected the reactivity and selectivity for this reaction. In the course of this study, we encountered curious results (Scheme 1b). The desilylated di-trifluoromethylated product 4b was obtained in 10% yield when N-TMS-3-methylindole 1a was used as a substrate, while the reaction of N-TBDMS-3-methylindole 1c provided only the 2-trifluoromethylated product 3c in 47% yield with the di-trifluoromethylated product 4c not being detected. In the latter case, the TBDMS group remained intact on the nitrogen of the indole ring. Based on these results, we hypothesized that the silyl cation would be a good activator for trifluoromethylation using Togni reagent 2. In this communication, we disclose the rapid trifluoromethylation of indole derivatives using trimethylsilyltriflate (TMSOTf) under mild conditions.

Based on our hypothesis, TMSOTf, which is a representative source of a silyl cation species was used as a catalyst in CH2Cl2 at room temperature. We initially examined the reaction with 3-methylindole 1b. To our surprise, the rate of this reaction was remarkably fast. Compound 3b was obtained in 71% yield within only 5 min, together with the di-trifluoromethylated product 4b in 7% yield (Table 1, entry 1).8 This remarkable result prompted us to examine the trifluoromethylation of other indole derivatives. The electron donating group at the 5-position accelerated the di-trifluoromethylation and the desired products 3d and 4d were obtained in 60% and 19% yields, respectively at 0 °C (entry 2). Various functional groups, such as aryl bromide, methyl ester, ether, carbamate and amide moieties, were tolerated in this reaction (entries 3-7).9 Trifluoromethylated products of the tryptophan derivative 3i and 4i were afforded in 48% and 4% yields, respectively (entry 7). It is noteworthy that the enantiopurity of the derivatives was conserved under this reaction condition. We next examined 1-substituted indole derivatives. N-Methyl-3-methylindole 1j was transformed to produce the desired products in high yield (entry 8). Analogous to the copper-catalyzed system, the N-TBDMS group was intact in this reaction system (entry 9). The reaction with 1k bearing no substituent at the 3-position provided the 2-trifluoromethylated product 3k, albeit in 26% yield (entry 10). In this case, dimer 5 was generated as the main product in 47% yield.10 Unfortunately, we could not isolate 4k and a complex mixture of mono- and di- trifluoromethylated indoles, with yet to be identified structures was obtained.

Inspired by these results, we investigated the reaction using an excess amount of Togni reagent 2 to obtain a higher amount of the di-trifluoromethylated product (Scheme 2). The di-trifluoromethylated compound 4d was produced under the described conditions in 42% yield, together with 3d in 35% yield.

In summary, we achieved the rapid trifluoromethylation of indole derivatives using TMSOTf as a catalyst. This reaction was operated under very mild conditions and the desired trifluoromethylated products were obtained in high yield within 5 minutes. In addition, a reasonable amount of the di-trifluoromethylated product could be obtained when an excess amount of Togni reagent was used. This reaction system provides a quick method for the synthesis of trifluoromethylated indole derivatives.

ACKNOWLEDGEMENTS
This work was supported in part by MEXT (Grant-in-aid for Young Scientists (B) No. 23750116) and by Funding from RIKEN.

References

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