Synthesis of Cyanamides via a One-Pot Oxidation-Cyanation of Primary and Secondary Amines.

An operationally simple oxidation-cyanation method for the synthesis of cyanamides is described. The procedure utilizes inexpensive and commercially available N-chlorosuccinimide and Zn(CN)2 as reagents to avoid direct handling of toxic cyanogen halides. It is demonstrated to be amenable for the cyanation of a variety of primary and secondary amines and aniline derivatives as well as a complex synthetic intermediate en route to verubecestat (MK-8931). Additionally, kinetic measurements and other control experiments are reported to shed light onto the mechanism of this cyanation reaction.

Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions.

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; 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 trans-1,2-, cis-1,2-, and 2-deoxy-ß-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.

Rh(III)-catalyzed halogenation of vinylic C-H Bonds: rapid and general access to Z-halo acrylamides.

Herein, the regio- and stereoselective iodination, along with some examples for the bromination, of readily available acrylamides to access a variety of differently substituted Z-haloacrylic acid derivatives is reported. The reaction proceeds under mild conditions via a Rh(III)-catalyzed C-H-activation/halogenation mechanism and represents a rare example of a direct halogenation of electron-poor acrylic acid derivatives.

Beyond directing groups: transition-metal-catalyzed C-H activation of simple arenes.

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.

Extending NHC-catalysis: coupling aldehydes with unconventional reaction partners.

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.

Diverse strategies toward indenol and fulvene derivatives: Rh-catalyzed C-H activation of aryl ketones followed by coupling with internal alkynes.

The synthesis of indenols and fulvenes was achieved through Rh-catalyzed C-H bond activation of simple and diverse aryl ketone derivatives and subsequent coupling with internal alkynes. The process was found to involve either an α or γ dehydration step, depending on the substrate disposition and representing diverse pathways toward functionalized fulvenes.

Direct and efficient N-heterocyclic carbene-catalyzed hydroxymethylation of aldehydes.

The N-heterocyclic carbene-catalyzed coupling of several aldehydes with paraformaldehyde is reported, directly providing the corresponding valuable hydroxymethyl ketones. Results of first mechanistic experiments for this remarkably selective transformation are also provided.

Remarkable product diversity in the "self-organized" reaction of deprotonated acetonitrile with chlorophosphines.

This study examined the reaction of in situ deprotonated acetonitrile with different chlorophosphines ClPR(2) (5a-d) to find new nitrile functionalized bis(diphenylphosphino)methane (dppm) ligands. Depending on the steric and electronic demand of the phosphines, very different and unexpected products (1b, 6, 9b and 11) were found. In the case of aryl-substituted phosphines (ClPPh(2) (5a) and ClPMes(2) (5b)), bis(diarylphosphino)acetonitrile compounds (1a and 1b) were found. Introduction of alkyl substituents at the ClPR(2) fragment (R = (t)butyl (5c) and cyclohexyl (5d)) changes the overall reaction behavior drastically. A new heteropentafulvene type structure (6), a P/N-disubstituted acetylene (9), and a P-substituted 3-amidocrotononitrile species (11) were found. Considering the experimental simplicity of these three-component reactions, these products are complex and their formations are highly organized. Most compounds were characterized by X-ray diffraction, NMR spectroscopy, and elemental analysis.