Current Organic Synthesis, 2011, 8, 53-78 53 1570-1794/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. Recent Progress in Transition-Metal-Catalyzed C-N Cross-Couplings: Emerging Approaches Towards Sustainability Jaqueline D. Senra a* , Lucia C.S. Aguiar a,b and Alessandro B.C. Simas a a Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, CCS, Bloco H, Ilha do Fundão, Rio de Janeiro, RJ 21941-614, Brazil b Instituto de Química, Universidade Federal do Rio de Janeiro, CT Bloco A 615, Cidade Universitária, Rio de Janeiro RJ 21941-909, Brazil Abstract: Transition-metal-catalyzed coupling of amines with aryl halides (or pseudo-halides) has evolved as the most versatile method available to forge carbon-nitrogen bonds. However, due to economic and environmental concerns, the quest for more attractive protocols in both academic and industrial domains has been pursued. In this review, we have summarized recent developments in the use of alternative methodologies, regarding non-conventional reaction medium, activation source and catalyst system, which can be considered promising for C-N cross-coupling reactions (Buchwald- Hartwig, Ullmann and correlates). Keywords: Buchwald-Hartwig amination, palladium, cross-coupling, green chemistry, Ullmann reaction, homogeneous cataly- sis, heterogeneous catalysis. 1. INTRODUCTION Over the last decades, transition-metal-catalyzed carbon- carbon and carbon-heteroatom bond forming reactions have played a prominent role in enabling the synthesis of complex carbon frameworks with an increasing degree of robustness and versatility [1]. These emerging technologies open up new opportunities for modern process chemistry as applied to fine chemical and pharmaceutical industries [2]. An ever- growing number of applications of metal-catalyzed cou- plings in transformations of functionalized and sensitive sub- strates attest their exceptionally broad scope. Among them, metal-catalyzed carbon-nitrogen bond forming reactions now stands as a very powerful method for the synthesis of nitrogenated compounds, particularly for the preparation of biologically active natural product analogues such as arylamines and imidazole derivatives. Although the uncatalyzed method may be useful and practical, it suffers from narrow scope (e.g., requirement of highly electron- deficient aryl halides and poor functional group tolerance). For this reason, efforts to develop catalytic and general methods have been a flourishing area of research. Neverthe- less, compared to C-C cross-coupling processes, this may still be regarded as a relatively under-explored area. The seeds of discovery were sown by Ullmann and Goldberg more than a century ago, who developed initial works on metal-catalyzed amination on the basis of the or- ganocuprate chemistry [3]. In general, it required relatively harsh conditions with expensive and wasteful product purifi- cation. Since 1995, however, Pd-catalyzed aminations have *Address correspondence to this author at the Núcleo de Pesquisas de Pro- dutos Naturais, Universidade Federal do Rio de Janeiro, CCS, Bloco H, Ilha do Fundão, Rio de Janeiro, RJ 21941-614, Brazil; Tel: +55 21 2562 6792; Fax: +55 21 2562 6512; E-mail: jdsenra@hotmail.com considerably enhanced the ability of synthetic organic chem- ists to assemble nitrogenated molecules due to the pioneering and independent work of Buchwald and Hartwig groups [4]. By such protocols, the coupling of alkenyl/aryl halides or pseudohalides with nucleophilic nitrogenated partners (aro- matic or aliphatic), in the presence of a palladium catalyst and a strong base, yield products formally resulting from the -bond metathesis reaction. The accepted mechanism, even though not general, involves the oxidative addition of Pd(0) species to the carbon-halide or carbon-pseudo-halide bond to form the Pd(II) aryl intermediate. After the amine coordina- tion and its subsequent deprotonation, the Pd(II) complex is then converted into the corresponding arylpalladium amide which can undergo, under adequate conditions [5], reductive elimination to yield the product concomitant with the regen- eration of Pd(0) species (Scheme 1). Typically, the palla- dium precursor is stabilized by an adequate ligand that can also increase the electron density at the metal center to facili- tate oxidative addition as well as accelerating reductive elimination by providing sufficient bulkiness. Therefore, catalysts based on bulky ligands, such as some tertiary phosphines, have the broadest applicability in these reactions. However, they often demand sensitive and/or inert reaction conditions. Recently, the use of well-defined N- heterocyclic carbenes (NHCs)-Pd precatalysts have proved promising due to high catalytic activities and easy handling [6]. Indeed, a range of challeging substrates, including unac- tivated aryl chlorides and, very recently, ammonia, has been encompassed by these protocols [7]. Nevertheless, even with C-N cross-couplings being con- sidered a well stablished research field, new developments are clearly needed with a focus on catalytic protocols with broader scope. In this sense, the search for novel active cata- lyst systems has also addressed the issue of sustainability.