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Chirality and catalysis with aromatic N-fused heterobicyclic carbenes

The benzoannulation of the most common families of aromatic NHCs, imidazol-2-ylidenes and 1,2,4triazol-3-ylidenes, results in heterobicyclic imidazo[1,5-a]pyridin-3-ylidenes (ImPy’s) and [1,2,4]triazolo[4,3-a]pyridin-3-ylidenes (TriPy’s), characterized by a bridged N atom. These are versatile platforms that offer multiple possibilities for the modulation of the steric and electronic properties of the carbene ligand and/or organocatalyst, and offer also diverse opportunities for the introduction of several types of chiralities. In this paper the different families of chiral ImPy and TriPy carbenes and their application in asymmetric catalysis will be discussed.


Introduction
N-heterocyclic carbenes (NHCs) constitute a well-established type of ligand in transition-metal catalysis. 1 Characterized by strong σ-donor and variable π-acceptor properties, 2 these ligands typically provide high thermal and chemical stability to their complexes. Additionally, the steric properties of NHCs are intrinsically distinct from those of phosphines, 3 the alternative family of strongly σ-donating ligands. Together, these are an appealing set of properties for applications in the field of asymmetric catalysis, and, consequently, many laboratories have developed strategies for the introduction of chiral elements, making NHCs the ligand of choice for a number of metal-catalysed asymmetric transformations. 4 Additionally, NHCs have also recently emerged as an useful class of Lewis bases that have found a plethora of applications in asymmetric organocatalysis. 5 Since the isolation of Arduengo's first stable imidazol-2-ylidene, 6 numerous classes of structurally and electronically diverse NHC structures have been reported. 7 One of the strategies used to modify the steric and electronic properties of these ligands has been the inclusion of the diaminocarbene system into a heterobicyclic skeleton. In 2005, we 8 and Glorius 9 independently reported the synthesis and coordination properties of heterobicyclic imidazo[1,5-a] pyridin-3-ylidenes (ImPys). Some years later, the synthesis and coordination behavior 10 of [1,2,4]triazolo[4,3-a]pyridin-3ylidenes (TriPys), along with an evaluation of their properties as organocatalysts 11 were also reported ( Fig. 1). Since then, a number of imidazo/triazolo pyridinium salts and their corresponding NHCs have been developed. In this paper we will focus on the different strategies reported to introduce chirality into carbene ligands, complexes, and catalysts based on the structures of these aromatic N-fused heterobicyclic scaffolds, along with their applications in asymmetric catalysis.

Discussion
Three different strategies have been developed for the synthesis of imidazo[1,5-a]pyridinium salts (ImPy·HX), direct precursors of the free ImPy carbenes and/or ligands: N-alkylation of imidazo[1,5-a]pyridines, 8 cyclisation of 2-formamidomethyl pyridines by phosphoryl chloride 8 or Tf 2 O/Et 3 N, 12 and cyclisation of picolinaldimines using a 1 : 1 mixture of AgOTf and chloromethyl pivalate, although this last method provided the products in moderate yields. 9 Already in the original report, C 2 -symmetric 'chiral at the metal' cationic Rh I bis-carbenes [Rh(COD)(ImPy) 2 ] + X − were selectively formed in the reaction of N-alkyl/aryl imidazo[1,5-a]pyridinium hexafluorophosphates with KO t Bu and [Rh(COD)Cl] 2 , while no trace of the meso isomers was detected (Scheme 1). These complexes, however, were obtained in the racemic form and    interactions. These complexes were successfully used as precatalysts in Pd 0 -catalysed asymmetric allylic alkylations, reaching enantioselectivities up to 95.5 : 4.5 er. The parent silver complexes [(ImPy2)AgX] were also used as catalysts in the 1,3dipolar cycloaddition of iminoglycinates, although, in this case, best results were obtained with C 2 -symmetric S/C/S imidazol-2-ylidene ligands. 15 This was the first example of the use of silver carbenes in asymmetric catalysis.
An elegant example of effective electronic modulation of NHC ligands was described by Fürstner and co-workers by embedding the imidazo[1,5-a]pyridin-3-ylidene system ImPy3 into a planar chiral [2,2]-paracyclophane scaffold. 16 Measurements and calculations of the electronic properties of these ligands revealed that remote electronic variations [achieved by substitution on the cyclophane benzene unit (X = H, F, OMe)] can be transmitted within the cyclophane scaffold to the carbene bonding orbitals. With respect to a simple ImPy4 analogue, this type of ligand possesses similar (but tuneable) σ-donor abilities, but much stronger π-acidity. Interestingly, this characteristic has been used to control the fate of the intramolecular gold(I)-catalysed cycloisomerization of eneallenes (Scheme 3), among the other ligand-driven catalytic reactions. 17 In spite of their high synthetic potential, however, the resolution and application of these planar-chiral ligands in asymmetric catalysis remain unexplored.
A second example of a planar chiral imidazo[1,5-a]pyridinylidene family ImPy5 based on [2.2]paracyclophanes was reported in 2011 by Ma and co-workers. 18 Unlike the precedent case, the ImPy unit is simply attached to a cyclophane structure, not constituting an integral part of the stereogenic unit. These carbenes combine the planar chirality of [2.2]paracyclophane with the central chirality of oxazolines to build heterobidentate C/N ligands. The authors examined their application in enantioselective conjugate β-boration of chalcones (Scheme 4). Best results were obtained with catalysts [(ImPy5) Cu] prepared in situ from the azolium triflate ImPy5·HOTf, Cu 2 O and KI. In a related example, 19 the chiral [(ImPy6)CuCl] complex derived from β pinene was used for the asymmetric β-boration of ethyl cinnamate, although with lower enantioselectivities (er up to 82.5 : 17.5). Similar planar chiral [2.2] paracyclophanyl imidazo[1,5-a]pyridinium salts have been described as precursors of NHCs ImPy7 (Scheme 5) 20 and their rhodium complexes have been tested in the asymmetric 1,2addition of arylboronic acids to aldehydes, although, providing moderate enantioselectivities (er up to 78.5 : 21.5).
Very recently, Scheidt and co-workers have reported on the synthesis and applications of ferrocene-based planar chiral imidazopyridinium salts ImPy8·HX (Scheme 6). 21 In this novel NHC design, the ImPy unit is fused with an iron sandwich complex to provide a strong facial bias. Several challenging applications were explored for these new types of ImPys. The free carbenes, generated in situ from tetrafluoroborates ImPy8·HBF 4 by deprotonation with 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD) as the base were used in homoenolate additions to α-ketoesters. Best results were obtained with the 2,6-dimethoxyphenyl derivative ImPy8a·HBF 4 , which provided the highest level of enantioselectivity (er 85 : 15 for the cis diastereomer), although without any diastereoselectivity (dr = 1 : 1). Their evaluation as ligands for transition-metal complexes was also reported. As a first example, the ImPy8b ligand (Ar = Mes) was used in the nickel-catalysed reductive coupling of 1-phenyl-1-propyne with aldehydes using triethylsilane as the reducing agent. The enantioselectivities observed [er 93 : 7 and 91 : 9] for benzaldehyde and cyclohexanecarboxaldehyde, respectively matched or improved those previously reported for this challenging transformation. Finally, the preformed [(ImPy8b)CuCl] complex was also used as a catalyst in the borylation of olefins, which proceeded with high enantioselectivities for a variety of substrates.
The fixed orientation of the diaminocarbene lone pair (or the C(carbene)-metal bond) in ImPy or TriPy ligands and complexes makes also attractive the integration of these systems into an axially chiral biaryl scaffold, with the stereogenic axis located at C(5). In particular, ligands such as ImPy9 and TriPy1 are well suited to project the asymmetric environment to the antipodes of the carbene carbon in linear Au I complexes (Scheme 7). Preliminary results on the unprecedented asymmetric [2 + 2] cycloaddition between styrenes and alkynes were achieved by using [(ImPy9)Au] + SbF 6 − complexes, leading to the expected cyclobutenes in good yields but modest enantioselectivities. 22 On the other hand, the combination of an enhanced π-acidity in TriPy1 ligands ( provided by the additional N atom in the heterocycle) and a high level of facial discrimination attributed to steric factors allowed us to perform [(TriPy1)Au] + -catalysed intermolecular [4 + 2] cycloadditions of allenamides and dienes, leading to the desired Scheme 5 (ImPy7)Rh I -catalysed asymmetric addition of arylboronic acids to aldehydes.
carbocycles with up to three newly created stereogenic centers in excellent yields and enantioselectivities (er's up to >99 : 1). 23

Conclusions
In conclusion, N-fused heterobicyclic imidazo-and triazolo pyridin-3-ylidene architectures have emerged as versatile platforms that enable multiple strategies for the introduction of chirality 24 and the tuning of steric and electronic effects, in both cases facilitated by their modular structures. While some challenging applications have been already successfully discovered, the potential of these ligands and complexes in asymmetric catalysis is clearly underdeveloped. Some of the structures shown are particularly promising in fields such as Au(NHC)-catalysed reactions or organocatalysis, among others.