An overview of N-heterocyclic carbenes.

The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.

Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands.

Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.

Enantioselective intramolecular hydroacylation of unactivated alkenes: an NHC-catalyzed robust and versatile formation of cyclic chiral ketones.

A highly enantioselective intramolecular N-heterocyclic carbene (NHC)-catalyzed hydroacylation reaction gives access to a range of cyclic ketones from unactivated olefin-substituted aldehydes (up to 99 % ee). Remarkably, aliphatic aldehydes were also transformed efficiently in an NHC-catalyzed hydroacylation reaction for the first time.

N-heterocyclic carbene catalyzed formal [3+2] annulation reaction of enals: an efficient enantioselective access to spiro-heterocycles.

A highly enantioselective N-heterocyclic carbene (NHC) catalyzed formal [3+2] annulation of α,ß-unsaturated aldehydes with azaaurones or aurone generating spiro-heterocycles has been developed. The protocol represents a unique NHC-activation-based approach to access spiro-heterocyclic derivatives bearing a quaternary stereogenic center with high optical purity (up to 95% ee).

NHC-catalyzed hydroacylation of styrenes.

New hydroacylation catalysts: Highly electron-rich N-heterocyclic carbenes (NHCs) facilitate the intermolecular hydroacylation of unstrained olefins. This unprecedented organocatalytic coupling joins simple and abundant aldehydes and styrenes to yield valuable ketone products. EWG=electron-withdrawing group, EDG=electron-donating group.

Synthesis and reactivity of o-benzylphosphino- and o-α-methylbenzyl(N,N-dimethyl)amine-boranes.

The series of o-benzylphosphino-boranes, o-(R(2)B)C(6)H(4)CH(2)PtBu(2) (R = Cl 3, Ph 4, Cy 6, C(6)F(5) 7, Mes 8) and o-(BBN)C(6)H(4)CH(2)PtBu(2) (5), were synthesized from reactions of the respective chloroboranes with the lithiated benzyl-phosphine. In an analogous fashion, the α-methylbenzyl(N,N-dimethyl)amine-boranes o-(R(2)B)C(6)H(4)CH(Me)NMe(2) (R = Cl 10, Ph 11, Cy 12, C(6)F(5) 13, Mes 14) were prepared. While these species were inactive in the catalytic hydrogenation of tBuN═CHPh, compounds 7, 8, and 14 did react with H(2) at elevated temperatures (100 °C), resulting in the elimination of HC(6)F(5) and mesitylene, respectively. In the latter case, the species o-((Mes)HB)C(6)H(4)CH(Me)NMe(2) 15 was isolated. 14 was also shown to react with H(2)O to give the species o-((Mes)(HO)B)C(6)H(4)CH(Me)NMe(2) 16 with the loss of mesitylene. The structure of these compounds and the nature of these reactions were also probed spectroscopically, crystallographically, and computationally. The energies for the products of hydrogenation, the phosphonium and ammonium hydridoborates, were computed. In all cases, these products were endothermic with respect to the precursor phosphine-boranes and amine-boranes and H(2). The barriers to H(2) activation were found to be in the range of 24-38 kcal/mol. These theoretical studies also demonstrate that the steric bulk around the boron center dramatically affects the activation barrier for H(2) activation, while the Lewis acidity of the borane has the largest effect on the stabilization of the resulting onium-borohydride. In the case of the elimination reactions, the driving forces appear to be the loss of arene byproduct and formation of a strong donor-acceptor bond.

Designing N-heterocyclic carbenes: simultaneous enhancement of reactivity and enantioselectivity in the asymmetric hydroacylation of cyclopropenes.

Faster, higher, stronger! The N-heterocyclic carbene (NHC) catalyzed diastereo- and enantioselective hydroacylation of cyclopropenes affords structurally valuable acylcyclopropanes. A new family of electron-rich, 2,6-dimethoxyphenyl-substituted NHCs induces excellent reactivity and enantioselectivity. Preliminary kinetic studies unambiguously demonstrated the superiority of this family of catalysts over known NHCs in this challenging transformation.

Enhanced copper-mediated (18)F-fluorination of aryl boronic esters provides eight radiotracers for PET applications.

[(18)F]FMTEB, [(18)F]FPEB, [(18)F]flumazenil, [(18)F]DAA1106, [(18)F]MFBG, [(18)F]FDOPA, [(18)F]FMT and [(18)F]FDA are prepared from the corresponding arylboronic esters and [(18)F]KF/K222 in the presence of Cu(OTf)2py4. The method was successfully applied using three radiosynthetic platforms, and up to 26 GBq of non-carrier added starting activity of (18)F-fluoride.

N-heterocyclic carbene catalyzed umpolung of styrenes: mechanistic elucidation and selective tail-to-tail dimerization.

The reaction between N-heterocyclic carbenes (NHCs) and styrenes yields alkyl-substituted azolium salts, which are able to form nucleophilic deoxy Breslow intermediates by simple deprotonation. This hitherto unknown reaction of NHCs represents a new way to generate deoxy Breslow intermediates and paves the way for the selective NHC-catalyzed tail-to-tail homodimerization of styrenes. This reaction significantly broadens the scope of the Michael umpolung and provides a new method to generate 1,4-diaryl compounds.