The use of coordinating moieties as directing groups for the functionalization of aromatic C-H bonds has become an established tool to enhance reactivity and induce regioselectivity. Nevertheless, with regard to the synthetic applicability of C-H activation, there is a growing interest in transformations in which the directing group can be fully abandoned, thus allowing the direct functionalization of simple benzene derivatives. However, this approach requires the disclosure of new strategies to achieve reactivity and to control selectivity. In this review, recent advances in the emerging field of non-chelate-assisted C-H activation are discussed, highlighting some of the most intriguing and inspiring examples of induction of reactivity and selectivity.

Transition metal catalysis is a powerful means of effecting organic reactions, but it has some inherent drawbacks, such as the cost of the catalyst and the toxicity of the metals. Organocatalysis represents an attractive alternative and, in some cases, offers transformations unparalleled in metal catalysis. Unique transformations are a particular hallmark of N-heterocyclic carbene (NHC) organocatalysis, a versatile method for which a number of modes of action are known. The NHC-catalyzed umpolung (that is, the inversion of polarity) of electrophilic aldehydes, through formation of the nucleophilic Breslow intermediate, is probably the most important mode of action. In this Account, we discuss the reaction of Breslow intermediates with unconventional reaction partners. In two traditional umpolung reactions, the benzoin condensation and the Stetter reaction, some selectivity issues represent significant challenges, especially in intermolecular variants of these reactions. In intermolecular cross-benzoin reactions, high levels of selectivity were recently obtained, even in the hydroxymethylation of aldehydes with formaldehyde. The key to success was careful choice of the NHC catalyst and reaction conditions. Among asymmetric Stetter reactions, intermolecular versions have posed a long-standing challenge. Recently, the groups of Enders and Rovis reported the first selective and efficient systems. We have contributed to this field by developing an efficient intermolecular Stetter reaction for the formation of α-amino acid derivatives, with broad aldehyde scope and high enantiomeric excess. Moreover, tailor-made thiazolylidene catalysts allowed the unprecedented use of nonactivated olefins and alkynes as aldehyde coupling partners. The basis for this reactivity is a unique mode of NHC organocatalysis: dual activation. In a concerted but asynchronous transition state, the positively polarized proton of the Breslow intermediate activates the coupling partner (for example, an olefin), while the nucleophilic enamine moiety starts to attack the activated coupling partner. As a consequence of the concerted nature of this mechanism, excellent values for enantiomeric excess were obtained for many substrates in the intramolecular hydroacylation of alkenes. In addition, thiazolylidene catalysts have enabled the coupling of aldehydes with reactive species, for example, with arynes and with activated alkyl bromides. NHC catalysis should continue to flourish and lead to surprising developments. One remaining challenge is the asymmetric intermolecular hydroacylation of unactivated olefins. In this area, metal-based catalysts have shown promising early results, but they are far from being either general or practical. It will be interesting to see which class of catalyst, whether metal-based or NHC-based, eventually develops into the method of choice.

Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners, and thus, carbohydrate synthesis is not easily predictable. Here, we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of 1,2-trans-, 1,2-cis-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.

rhodium (RhCp*)-catalyzed C À H transformations have emerged as a prosperous field in C À H bond activation. Recent advances in this area have significantly focused on the development of new strategies for C À C and C À heteroatom bond formation that are characterized by the novel reactivity of the RhCp* catalyst to undergo formal S N-type reactions with electrophilic substrates. This review is intended to give an overview on this rather new class of RhCp*-catalyzed C À H transformations, covering recent C À C and C À heteroatom bond-forming reactions. The nature of the reaction partner in these C À H functionalization reactions serves as a guideline throughout this article and, combined with selected descriptions of mechanistic proposals, should emphasize general characteristics of transformations within this novel reaction class.

The family of AZARYPHOS (aza–aryl–phosphane) phosphane ligands, containing a phosphine unit and sterically shielded nitrogen lone pairs in the ligand periphery, is introduced as a tool for developing ambifunctional catalysis by the metal center and nitrogen lone pairs in the ligand sphere. General synthetic strategies have been developed to synthesize over 25 examples of structurally diverse (6‐aryl‐2‐pyridyl)phosphanes (ARPYPHOS), (6‐alkyl‐2‐pyridyl)phosphanes (ALPYPHOS), 4,6‐disubsituted 1,3‐diazin‐2‐ylphosphanes or 1,3,5‐triazin‐2‐ylphosphanes, quinazolinylphosphanes, quinolinylphosphanes, and others. The scalable syntheses proceed in a few steps. The incorporation of AZARYPHOS ligands (L) into complexes [RuCp(L)2(MeCN)][PF6] (Cp=cyclopentadienyl) gives catalysts for the anti‐Markovnikov hydration of terminal alkynes of the highest known activities. Electronic and steric ligand effects modulate the reaction kinetics over a range of two orders of magnitude. These results highlight the importance of using structurally diverse ligand families in the process of developing cooperative ambifunctional catalysis by a metal and its ligand.