Internationale Ausgabe: DOI: 10.1002/anie.201502822 Cross-Coupling Deutsche Ausgabe: DOI: 10.1002/ange.201502822 Selective Monoarylation of Primary Amines Using the Pd-PEPPSI- IPent Cl Precatalyst** Sepideh Sharif, Richard P. Rucker, Nalin Chandrasoma, David Mitchell, Michael J. Rodriguez, Robert D. J. Froese, and Michael G. Organ* Abstract: A single set of reaction conditions for the palladium- catalyzed amination of a wide variety of (hetero)aryl halides using primary alkyl amines has been developed. By combining the exceptionally high reactivity of the Pd-PEPPSI-IPent Cl catalyst (PEPPSI = pyridine enhanced precatalyst prepara- tion, stabilization, and initiation) with the soluble and non- aggressive sodium salt of BHT (BHT = 2,6-di-tert-butyl- hydroxytoluene), both six- and five-membered (hetero)aryl halides undergo efficient and selective amination. Secondary amines are not only important synthetic inter- mediates, but are also valuable commodities for investigation in the fields of medicine, materials science, and drug discov- ery. [1] Of the various routes available for preparing secondary aromatic amines, the palladium-catalyzed amination of aryl- (pseudo)halides [2, 3] is one of the most robust methods available and serves as a valuable complement to reductive amination and substitution reactions. [4] Whereas the use of secondary amines as nucleophiles in this transformation is straightforward and leads to tertiary aniline products, the use of primary amines can produce either secondary or tertiary anilines resulting from mono- and diarylation, respectively, of the amine. [5] In practice, such mixtures of mono- and diary- lated amines are often observed, and these mixtures can be difficult to separate and also have the disadvantage of lowering the reaction)s efficiency for preparing the desired secondary aniline. Fundamentally, the ratio of secondary to tertiary aniline products observed for any particular amina- tion is a consequence of the catalyst)s ability to discriminate between the starting primary amine and the secondary aniline, which is the product of the initial catalytic cycle. To address this selectivity problem, the steric and electronic properties of ancillary ligands have been varied in an effort to enhance catalyst binding with the primary amine over that of the secondary aniline product. This effort has led to some notable successes, such as the BrettPhos ligand 1 in conjunction with the BrettPhos precatalyst 2, [6] the Josiphos ligand 3, [7, 5a] the DalPhos family (4), [8] as well as limited examples utilizing NHC (N-heterocyclic carbene) ligands (Scheme 1). [9] Despite these efforts, no single univer- sal catalyst, which is capable of promoting the amination of aryl and five- and six-membered heteroaryl halides using either simple or functionalized primary amines, has been developed. We have previously reported that the Pd-PEPPSI- IPent family [10] of palladium precatalysts has shown extremely high reactivity for the coupling of secondary alkyl amines [11] and primary and secondary anilines [12] with six-membered aryl and heteroaryl chlorides and bromides. Herein, we demonstrate the application of these catalysts in the selective amination of six- and five-membered (hetero)aryl chlorides and bromides using simple or functionalized primary aliphatic amines governed under one general protocol. In an initial experiment, we probed the reactivity of Pd- PEPPSI-Pent Cl (5) [13] in the amination of 4-chloroanisole (6) by using octyl amine (7) and cesium carbonate according to the conditions we previously outlined for the analogous amination of aryl chlorides by electron-deficient anilines (Table 1, entry 1). [12a] While complete conversion of the halide was observed at 80 8C, the reaction proceeded with low selectivity for the desired monocoupled product 8. The use of other inorganic bases (e.g., entry 3) did not improve selectiv- ity. However, in a reaction utilizing sodium tert-butoxide, which has been employed extensively by others, [14] the product 8 was formed with moderate selectivity (entry 4). We could improve the selective formation of 8 by lowering the catalyst loading and decreasing the reaction concentration such that 8 could be isolated in 90 % yield with high selectivity (65.6:1 8/9) after 90 min at 80 8C, and using just 0.5 mol % of Scheme 1. Previously reported systems (1–4) for selective amination of primary amines. The palladium precatalyst 5 is the focus of this study. PEPPSI = pyridine enhanced precatalyst preparation, stabilization, and initiation. [*] S. Sharif, [+] Dr. R. P. Rucker, [+] Dr. N. Chandrasoma, Prof. M. G. Organ Department of Chemistry, York University 4700 Keele Street, Toronto, Ontario, M3J1P3 (Canada) E-mail: organ@yorku.ca Dr. D. Mitchell, Dr. M. J. Rodriguez Lilly Research Laboratories, A Division of Eli Lilly and Company Indianapolis, IN 46285 (USA) Dr. R. D. J. Froese The Dow Chemical Company Midland, MI 48674 (USA) [ + ] These authors contributed equally to this work. [**] This work was supported by NSERC Canada in the form of a CRD grant and by the Eli Lilly Research Award Program (LRAP). Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201502822. Angewandte Chemie 9643 Angew. Chem. 2015, 127, 9643 –9647 # 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim