Note pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 1000−1010
Tropylium-Promoted Oxidative Functionalization of Tetrahydroisoquinolines Giulia Oss, Sander D. de Vos, Kevin N. H. Luc, Jason B. Harper, and Thanh V. Nguyen* School of Chemistry, University of New South Wales, Sydney, Australia S Supporting Information *
ABSTRACT: Structural modification of the tetrahydroisoquinoline (THIQ) framework is of significant interest to organic chemists due to its central role in heterocyclic and medicinal chemistry. Here we demonstrate an efficient metal-free method for the oxidative functionalization of THIQs at the C1 position, which is amenable to a diverse range of C−C coupling reactions. These reactions proceed through a hydride abstraction involving the tropylium ion followed by quenching the generated iminium intermediates with nucleophiles to afford THIQ derivatives with excellent efficiencies and interesting selectivities.
T
(Scheme 1). These reactions involve a simple and mild hydride abstraction with tropylium salt22 followed by quenching the
etrahydroisoquinolines possess a structural motif commonly found in naturally occurring alkaloids1 as well as biologically valuable synthetic substances.2 Since the success of trabectedin,3 an antitumor drug containing three THIQ rings in its structure,4 there has been an increasing interest in drug development based on THIQ derivatives, as many of them have been known for neurotoxicity in Parkinson’s diseases,5 anticancer, and antibiotic activities.6 Functionalization of THIQs therefore has been an ongoing challenge in synthetic organic chemistry.7 Most efforts have been directed toward C−C coupling reactions at the C1 position,8 which generally lead to building blocks and synthetic intermediates for further construction of potentially bioactive scaffolds.9 Prior to this study, there have been numerous synthetic approaches to C1 functionalization of THIQs, including the highly utilized transition-metal-catalyzed,10 metal-free oxidative,11 electrochemical,12 and photocatalytic7,13 cross dehydrogenative coupling (CDC) reactions.14 Herein, we demonstrate a mild, efficient, and environmentally benign method to use tropylium salts for the selective oxidative functionalization of THIQs, which is amenable to a diverse range of alkylation and arylation reactions at the C1 position. The non-benzenoid aromatic tropylium ion possesses a planar conjugated seven-membered carbocycle with six electrons and a positive charge delocalized over the system.15 It has a unique combination of stablility and reactivity that normal benzenoid and other charged polyene structures do not have.16 On the basis of our previous reports on tropylium ion as electrophiles and Lewis acid,17 we envision that tropylium salts might also serve as effective and universal oxidizing agents in organic synthesis.18 The tropylium ion is also known to be a hydride acceptor with a similar electrophilicity parameter to the commonly used oxidant DDQ.19 This role of tropylium was recently examined by Lambert and co-workers in an elegant study on the cyanation of tertiary amine.20,21 We report here our development of a new versatile method to use tropylium salts for the C1 functionalization of N-substituted THIQs © 2017 American Chemical Society
Scheme 1. Oxidative α-Functionalization of THIQs
generated iminium intermediates with different types of nucleophiles to afford a broad library of alkylated and arylated THIQ products with excellent efficiencies and notable selectivities. Our initial investigation used the readily available tropylium tetrafluoroborate23 to oxidize N-substituted THIQs (1) and examined their conversion to the corresponding iminium salts (3) using NMR spectroscopy (Table 1). Interestingly, N-aryl, N-Cbz, as well as N-alkyl THIQs, where the alkyl group is acyclic with three carbons or longer, showed (at best) very poor conversion to the corresponding iminium salts (3) (entries 1−6, Table 1).25 N-Benzyl and other N-phenylalkyl THIQs (entries 8−12, Table 1) were more prone to oxidation by the tropylium oxidant. This trend in reactivity is remarkably dif ferent from DDQ,11h a typical oxidant for this type of reaction,26 for which the mechanism of action was recently demonstrated and Received: October 11, 2017 Published: December 12, 2017 1000
DOI: 10.1021/acs.joc.7b02584 J. Org. Chem. 2018, 83, 1000−1010
Note
The Journal of Organic Chemistry Table 1. Optimization of the Iminium Formation Reaction with Tropylium Salta
entrya
R
X
conversionb (%)
1 2 3 4 5 6 7 8c 9 10 11 12 13 14 15d 16d 17e 18f
Ph H Cbz Me i Pr n C9H19 −CH2Cy −CH2Ph (Bn) −CH2CH2Ph −CH2CH2CH2Ph −CH2Naphthyl −CHPh2 Bn Bn Bn Bn Bn isochroman
BF4 BF4 BF4 BF4 BF4 BF4 BF4 BF4 BF4 BF4 BF4 BF4 Br BPh4 Ph3C+BF4− NO+BF4− BF4 BF4
