Synthetic Methods DOI: 10.1002/ange.201310193 Practical Metal-Free C(sp 3 ) À H Functionalization: Construction of Structurally Diverse a-Substituted N-Benzyl and N-Allyl Carbamates** Zhiyu Xie, Lei Liu,* Wenfang Chen, Hongbo Zheng, Qingqing Xu, Huiqing Yuan, and Hongxiang Lou* Abstract: Described is a practical and universal C ÀH func- tionalization of readily removable N-benzyl and N-allyl carbamates, with a wide range of nucleophiles at ambient temperature promoted by Ph 3 CClO 4 . The metal-free reaction has an excellent functional-group tolerance, and displays a broad scope with respect to both N-carbamates and nucleophile partners (a variety of organoboranes and C ÀH compounds). The synthetic utility in target- as well as diversity- oriented syntheses is demonstrated. a-Substituted nitrogen-containing heterocycles (N-het- erocycles), like tetrahydroisoquinolines (THIQs), tetrahydro- quinolines (THQs), and piperidines, represent ubiquitous structural motifs in numerous alkaloids exhibiting a wide range of pharmacological activities. [1] Among them, 1-benzyl THIQs are the most widely distributed [1a] and serve as key intermediates in the synthesis and biosynthesis [1c] of other types of alkaloids. For instance, tetrahydropalmatine (THP), isolated from Corydalis , has been demonstrated to possess significant analgesic effects and have therapeutic potential for heart disease and liver damage (Figure 1). [2a] Noscapine, mediated by the sigma receptor agonist activity, is well known for its antitussive effects, and reported to have promising effects in the treatment of several cancers and hypoxic ischemia in stroke patients. [2b] Besides the benzyl substruc- ture, aryl and arylethyl substituents are often incorporated at C1. Solifenacin (trade name Vesicare), a competitive antag- onist preventing acetylcholine from binding to the human muscarinic acetylcholine receptor, is used in the treatment for overactive bladder. [2c] Methylphenidate, a piperidine ana- logue, is known to be a psychostimulant drug for the treatment of attention deficit hyperactivity disorder (ADHD). [2d] Inspired by the importance of these compounds in modern pharmacology, significant efforts have been devoted to their construction, and current syntheses mainly rely on three strategies. [3] The two most frequently employed approaches for the synthesis of C1-substituted N-heterocycles are stereoselective cyclizations such as the Pictet–Spengler condensation, and hydrogenation of the C1-substituted imines as in the Bischler–Napieralski cyclization/reduction sequence. Recently, introduction of a carbon unit to the a- position of the N-heterocycles has been investigated as an alternative to the first two traditional methods. In particular, direct C ÀH functionalization of N-heterocycles with a variety of carbon nucleophiles presents an atom-economic protocol without prior installation of activating groups, and is therefore attractive. [4] A number of different approaches have been established for electron-rich amines, especially N-arylated THIQs and dimethylanilines, since the pioneering studies of the groups of Murahashi and Li. [5, 6] However, the difficulty in removing the N-aryl group results in poor functional-group tolerance, and therefore limits the synthetic utility. [7] In sharp contrast, the functionalization of the C(sp 3 ) À H bond adjacent to readily removable amide or carbamate moieties proved to be much more challenging, probably owing to the reduced reactivity, and only a few examples have been disclosed so far. [8] The scope with respect to the nucleophile reported for each method is notably limited, and often focuses on only one Figure 1. Bioactive C1-substituted THIQs, THQs, and piperidines. [*] Z. Xie, Prof. L. Liu, W. Chen, H. Zheng, Prof. H. Lou Key Lab of Chemical Biology of Ministry of Education School of Pharmaceutical Sciences, Shandong University Jinan 250012 (China) E-mail: leiliu@sdu.edu.cn louhongxiang@sdu.edu.cn Homepage: http://www.pharm.sdu.edu.cn/szdw/Liu%20lei/3 /Liu_02/index.htm Q. Xu, Prof. H. Yuan School of Medicine, Shandong University Jinan 250012 (China) [**] We are grateful to Dr. Paul E. Floreancig (University of Pittsburgh) for helpful suggestions on the mechanism. Financial support from the National Science Foundation of China (no. 21202093) and the Young Scientist Foundation Grant of Shandong Province (no. BS2013YY001) is greatly appreciated. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201310193. A ngewandte Chemi e 3985 Angew. Chem. 2014, 126, 3985 –3989  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim