Job/Unit: O42077 /KAP1 Date: 16-04-14 10:53:49 Pages: 5 SHORT COMMUNICATION DOI: 10.1002/ejoc.201402077 Solvent-Free Buchwald–Hartwig Reaction of Aryl and Heteroaryl Halides with Secondary Amines Maxim A. Topchiy, [a] Andrey F. Asachenko, [a] and Mikhail S. Nechaev* [a,b] Dedicated to Academician Alexey R. Khokhlov on the occasion of his 60th birthday Keywords: Palladium / Solvent-free reactions / Cross-coupling / Amination / Palladium A highly efficient solvent-free protocol for the Buchwald– Hartwig amination of (hetero)aryl halides by secondary amines was developed. The reaction is mediated by a Pd(OAc) 2 /RuPhos catalytic system in air. Various (hetero)aryl Introduction The Buchwald–Hartwig amination of aryl halides is a powerful synthetic tool of modern organic chemistry. This reaction has found industrial application in pharmaceutical and materials chemistry. [1] However, solvent-free methods in this field remain rare.To the best of our knowledge, sol- vent-free protocols for Buchwald–Hartwig C–N coupling reactions have been reported only a few times. [2] The first example of the solvent-free amination of aryl bromides catalyzed by Pd(OAc) 2 /DPEPhos [DPEPhos = (oxydi-2,1-phenylene)bis(diphenylphosphine)] was de- scribed in 2003 by Beletskaya et al. [2a] In 2004, Yoshifuji and co-workers reported new palladium π–allyl complex bearing a diphosphinidenecyclobutene ligand, which was used at room temperature under solvent-free conditions for the amination of aryl bromides with a series of amines. [2b] However, only aryl bromides were efficiently coupled in this report. The first example of the solvent-free amination of aryl chlorides catalyzed by Pd 2 (dba) 3 /IAPU (dba= dibenz- ylideneacetone, IAPU = 2,8,9-triisobutyl-2,5,8,9-tetraaza-1- phosphabicyclo[3.3.3]undecane) was described in 2011 by Beccalli et al. [2c] This protocol was limited to the use of indolines at high temperatures with moderate yields of the products. In 2012, Tardiff and Stradiotto reported the cou- [a] A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow, Russian Federation E-mail: m.nechaev@ips.ac.ru http://www.ips.ac.ru [b] M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation E-mail: m.s.nechaev@org.chem.msu.ru http://fhmas.ru Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201402077. Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 halides were coupled with diaryl, alkyl–aryl, and dialk- ylamines in good to excellent yields (51 examples, 50–99 % yield). pling of aryl chlorides in water under solvent-free condi- tions efficiently catalyzed by a [Pd(cinn)Cl] 2 /Mor-DalPhos [cinn = cinnamyl; Mor-DalPhos = di(1-adamantyl)(2- morpholinophenyl)phosphine] system. [2d] The bulky N-heterocyclic carbene palladium complex [Pd(IPr*)(cinn)Cl] {IPr* = 1,3-bis[2,6-bis(diphenylmethyl)- 4-methylphenyl]imidazol-2-ylidene} showed excellent ac- tivity in an efficient solvent-free protocol for the Buchwald– Hartwig amination of unactivated aryl halides, as described by Nolan in 2013. [2e] However, the scope did not exhibit the reactivity of the heteroaryl halides, and only a few examples of the coupling of secondary amines were shown. Notably, despite the fact that the reaction was initiated at room tem- perature, a strong self-generated exotherm was observed during the course of the reaction. In 2013, Becalli reported a solvent-free, ligand-free microwave-assisted protocol for the coupling of indolines and other amines with aryl halides. However, the scope was very limited (22 examples) and moderate conversion and good yields of the products were obtained. [2f] In this contribution, a highly efficient solvent-free proto- col for the Buchwald–Hartwig amination of (het)aryl hal- ides with secondary amines is reported. Results and Discussion Various palladium sources were tested as precatalysts for the Buchwald–Hartwig amination under solvent-free condi- tions: conventional Pd(PPh 3 ) 4 , (PPh 3 ) 2 PdCl 2 , [P(oTol) 3 ] 2 - PdCl 2 ; well-defined phosphine-based catalytic systems such as Pd(OAc) 2 /RuPhos and Pd(OAc) 2 /SPhos; [3] N-heterocy- clic carbene complexes such as SIPrPd(cinn)Cl, IPrPd- (cinn)Cl, [4] and PEPPSI-IPr; [5] and a mixture of Pd(OAc) 2 and iPr*HCl. [6]