Abstract
Ultrasound-promoted N-aminomethylation of indoles can be achieved in basic medium using sodium hydride and dichloromethane (DCM) as C1 donor source. This innovative amino methylation protocol results in good to excellent yields of multifunctional indole derivatives. The procedure is also applicable to other aza-heterocyclic compounds and, interestingly, affords direct access to aminomethyl-substituted aryl alcohols.
Highlights
The indole nucleus is present in a wide range of bioactive natural products and it is considered as privileged structure in the fields of pharmaceutical and material chemistry (Barden, 2010)
When we performed N-methylation reactions of non-substituted indole using CH3I in sodium hydride/DCM/DMF solution assisted by ultrasound irradiation (US), we observed the almost exclusive formation of 1-diindolylmethane (86% of yield), which suggested that DCM is a bridging agent in the formation of this N-aminomethylated compound (Mills et al, 1987, 2009; Matsumoto et al, 1993; Souquet et al, 2006; Rudine et al, 2010; Zhou et al, 2011)
In an attempt to capitalize on DCM behavior, we introduced a secondary amine, piperidine, in SCHEME 1 | Reaction of 1 with piperidine in the presence of CHCl3
Summary
The indole nucleus is present in a wide range of bioactive natural products and it is considered as privileged structure in the fields of pharmaceutical and material chemistry (Barden, 2010). Mannich and Mannich-type Friedel–Crafts reactions, the later using imines, N,O acetals or N,N aminals in the presence of a Lewis acid, constitute the most commonly used chemical approaches for the construction of aminomethylated indoles (Chart 1; Swaminathan and Narasimhan, 1966; Katritzky et al, 1990; Matsumoto et al, 1993; Arend et al, 1998; Saaby et al, 2000; Speckamp and Moolenaar, 2000; Sakai et al, 2003, 2010, 2014; Jiang and Huang, 2005; Lindquist et al, 2006; Wang et al, 2006; Kang et al, 2007; Rowland et al, 2007; Alonso et al, 2008; Zou et al, 2015; Xie et al, 2018) Both approaches are limited by the wellknown regioselectivity toward the C-3 position when 1,3-non-substituted indoles are used (Sakai et al, 2014). Under tBuOK-promoted basic conditions, Love and Nguyen (1998) and Love (2007) described the regioselective formation of the N-1 derivative using the reaction of unprotected indole with 1-(N,N’–dialkylaminomethyl) benzotriazoles as alkylating agents. Sakai et al (2010) showed that, in the reaction of indoles with N,O acetals, the use of Hf(OTf) as Lewis acid regioselectively promoted N-aminomethylation
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