A facile synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines Min Hu ⇑ , Peter R. Guzzo, Congxiang Zha, Kassoum Nacro, Yuh-Lin Yang, Carla Hassler, Shuang Liu AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA article info Article history: Received 4 November 2011 Revised 2 December 2011 Accepted 5 December 2011 Available online 9 December 2011 Keywords: Tetrahydroisoquinoline THIQ Arylation Dihydroisoquinolinone Palladium abstract A facile and versatile palladium catalyzed a-arylation between dihydroisoquinolinones and various aryl halides is described. Combined with borane reduction, it provides a convenient way to prepare 4-aryl- 1,2,3,4-tetrahydroisoquinolines. Ó 2011 Elsevier Ltd. All rights reserved. Tetrahydroisoquinoline (THIQ) is an interesting structural motif that appears in a number of biologically active compounds. 1 In our efforts to find novel antidepressants, we decided to further explore the THIQ scaffold. During our study of structure–activity relation- ships (SAR) of aryl substitution at the C-4 position of the THIQ core (1, Fig. 1), we developed a facile procedure for making THIQs involving a palladium catalyzed a-arylation reaction between dihydroisoquinolinones and aryl halides followed by a borane reduction. The method is described in this Letter. There are a number of existing methods to build 4-substituted THIQs (2). Several of them, shown in Scheme 1, include: (a) intra- molecular Friedel–Craft cyclization of a benzylic alcohol (3); (b) Bischler–Napieralski cyclization of (4); and (c) a Suzuki coupling [between boronic acid (5) and an aryl halide] followed by a reduc- tion sequence. 2 Even though these methods are robust and gener- ally provide good yields, they have limitations in that they do not provide the flexibility of changing 4-aryl groups at a late synthetic stage, which is preferred for rapidly studying SAR on the C-4 position. Palladium catalyzed arylation of the activated methylene groups of a ketone or ester with aryl or heteroaryl halides has been previously reported. 3 We envisioned that a successful a-arylation reaction between (6) and an aryl bromide would provide 4-aryl- dihydroisoquinolinone (7), which could be reduced to give the corresponding 4-aryl-tetrahydroisoquinoline (2)(Scheme 2). The route offers a quick and convergent approach toward 4-aryl-THIQs and provides the opportunity to change the 4-aryl group at a late stage of synthesis. There was no example of using a lactam, for example, dihydroisoquinolinone (6), in this type of reaction before our patented work. 4 This Letter expands on this work with addi- tional details and examples for this important reaction sequence. Figure 1. 4-Aryl-tetrahydroisoquinolines (2). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.12.022 ⇑ Corresponding author. Tel.: +1 518 512 2817; fax: +1 518 512 2079. E-mail address: min.hu@amriglobal.com (M. Hu). Scheme 1. General routes to synthesize of 4-aryl-tetrahydroisoquinoline (2). Tetrahedron Letters 53 (2012) 846–848 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet