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Rhodium Catalyzed C2-Selective Cyanation of Indoles and Pyrroles Manthena Chaitanya, and Pazhamalai Anbarasan J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Mar 2015 Downloaded from http://pubs.acs.org on March 13, 2015
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The Journal of Organic Chemistry
Rhodium Catalyzed C2-Selective Cyanation of Indoles and Pyrroles Manthena Chaitanya and Pazhamalai Anbarasan* Department of Chemistry, Indian Institute of Technology Madras, Chennai - 600036, India E-mail:
[email protected] FAX: +91-44-22574202
Abstract: An efficient and general rhodium(III) catalyzed C2-selective cyanation of indoles and pyrroles was accomplished employing easily accessible and environmentally friendly cyanating reagent, NCTS. This methodology tolerates various functional groups, uses readily removable directing groups and allows the synthesis of various 2-cyanoindoles and pyrroles in good to excellent yield.
Cyano heteroarenes, particularly 2-cyanoindoles and pyrroles, are important structural motifs present in various therapeutically important natural products.1 Also, they are widely used as building blocks for construction of various pharmaceuticals, agrochemicals (Figure 1) and dyes as well as incorporation of these moiety in polymer provides an unique physical properties to them.2 Thus, efficient and selective synthesis of 2-cyanoindoles and pyrroles are highly desirable in both organic and medicinal chemistry.
Figure 1: Examples of bioactive molecules synthesized from 2-cyanoindole.
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Although traditionally cyano(hetero)arenes were synthesized from corresponding aldehydes and its derivatives or halides,3 over fast few decades, selective and direct cyanation4 of highly abundant C-H bonds of (hetero)arenes has emerged as a powerful tool to achieve atom and step-economy in organic synthesis.5 In this context, the most documented direct cyanation of indoles is the transition metal mediated/catalyzed C3-selective cyanation,6 which is probably due to the inherent property of indoles (Scheme 1). Typically, C3-cyanation of indoles can be achieved using isocyanatophosphoric acid dichloride,7 or triphenylthiocyanogen (TPPT)8 as cyanating reagent. Recently, these strategies were replaced with transition metal catalyzed cyanation of indoles employing tBuNC,9 TMEDA/NH3,10 DMF,11 DMF/NH4I,12 DMSO/NH4HCO3,13 metal cyanides,14 BnCN,15 3,5-(CF3)2C6H3I(OTf)CN16 and N-cyano-N-phenyl-p-toluenesulfonamide (NCTS)17. However, the closely related C2-selective cyanation of indoles and related heteroarenes are rather limited.
Scheme 1: Synthesis of diarylacetic acid derivatives. The known C2-selective cyanation of indoles (pyrroles) includes the directing group assisted palladium-catalyzed cyanation using tert-butyl isocyanide9,18 as “CN” source in combination with 3 equivalent of copper salt and the substoichiometric copper catalyzed cyanation employing acetonitrile19 as “CN” source along with additive such as AgOAc or (Me3Si)2 (Scheme 2). These reactions suffer from the use of high catalyst loading, super stoichiometric amount of expensive additives, harsh reaction conditions and limited substrate scopes. Thus, the efficient catalytic C2-selective cyanation of indoles (pyrroles) is highly warranted. Based on the need of catalytic cyanation and our interest in the C-H functionalization20 and cyanation employing readily accessible and environmentally benign NCTS as a
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cyanating reagent21, we herein reveal the general rhodium catalyzed chelation assisted selective C2cyanation of indoles and pyrroles with NCTS. Initially, we investigated the C2-cyanation of indole derivatives. The C2-cyanation of N-(2pyridyl)indole 1a with NCTS (2 equiv) in the presence of [Cp*RhCl2]2 (1 mol%) as a catalyst and AgSbF6 (10 mol%) as an additive in toluene at 100 ˚C for 36 h.21 To our delight, 2-cyano-N-(2pyridyl)indole 3a was observed in 20% isolated yield (Table 1, entry1). No reaction was observed in the absence of either [Cp*RhCl2]2 or AgSbF6, which shows the cyanation is catalyzed and promoted by rhodium and silver complex, respectively.22 Next, slight improvement in yield was observed while the temperature increasing to 120 ˚C (Table 1, entry 2). Increasing the ratio of rhodium to silver complex by adding 2 mol% of rhodium complex gave the better conversion with 56% isolated yield of 3a, but the opposite effect was observed when the silver complex was reduced to 5 mol% to increase the ratio of Rh(III)/Ag(I) (Table 1, entries 3 and 4). Table 1. Rhodium catalyzed C2-selective cyanation of N-(2-pyridyl)indole 1a: Optimization[a]
Entry X Y Solvent Time (h) Conv. (%)[b] Yield (%)[c] 1[d] 2 1 Toluene 36 20 2 2 1 Toluene 36 60 32 3 2 2 Toluene 36 81 56 [e] 4 2 2 Toluene 36 35
