Highly Diastereoselective α-Arylation of Cyclic Nitriles

Abstract

A highly diastereoselective α-arylation of cyclic nitriles has been developed via a Negishi cross-coupling of commercially available aryl, heteroaryl, and alkenyl halides with cyclobutyl nitriles in the presence of tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl•LiCl) and catalytic XPhos-Pd-G2. A variety of electronically diverse electrophiles were well tolerated, and this chemistry was further advanced with application of both cyclopropyl and cyclopentyl nitriles.

Palladium-catalyzed α-arylation for the addition of small rings to aromatic compounds

“…Just one example of the direct α-arylation of cyclobutyl methyl ester was disclosed in a patent and stated to occur in 53% yield 26 . Because of the modest yield and narrow scope of this reaction, the products have been prepared with alternative reactants, such as silyl ketene acetals or nitriles 24,25,31,40 . However, the versatility of esters for further derivatization and the simplicity of using an ester for the coupling reaction make it important to identify conditions and catalyst for the direct α-arylation of cyclobutyl esters.…”

“…1b), whether small carbocyclic or heterocyclic esters, have given no product or have been reported in two examples in patents to give few turnovers and modest yields that we have not been able to reproduce (vide infra) 24–27 . Reactions of Reformatsky reagents generated from alpha-bromo esters requiring multiple steps for preparation have been published 28–30 , and the reactions of small-ring nitriles as surrogates of the esters have been reported 24,25,31 , but the direct reactions of three-membered or four-membered ring carbocyclic or heterocyclic esters with aryl halides in the presence of base and a catalyst have not been published 26,27 . Because esters can be converted easily into a variety of functional groups, the coupling of esters with aryl halides would be the most valuable version of the coupling of a small-ring enolate.…”

A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

“…[4] Recently, deprotometalations of arenes and heteroarenes using metal amide bases have allowed the regioselective introduction of abroad range of functional groups to aplethora of important substrates. [4] Both highly reactive lithium amides,s uch as LDA [5] or TMPLi [6] (TMP = 2,2,6,6-tetramethylpiperidinyl), or more selective reagents such as TMPMgCl•LiCl [7] or TMPZnCl•LiCl [8] have been used successfully.T his gave access to functionalized arenes or heteroarenes,i ncluding pharmaceutically relevant scaffolds such as pyrimidines, pyrazines or pyridazines. [8c,9] However,w hen novel scaffolds were investigated towards directed metalation reactions,t he regioselectivity was difficult to anticipate and had to be determined by experimental methods.…”

“…[8c,9] However,w hen novel scaffolds were investigated towards directed metalation reactions,t he regioselectivity was difficult to anticipate and had to be determined by experimental methods. [7,8] This tedious and inefficient approach hampers ar apid and straightforward systematic functionalization of new heterocycles of the future.…”

A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

“…Considering,t hat the nitrogen-metal bond in the milder, and functional group tolerant base TMPZnCl•LiCl [8] is of more covalent nature in comparison to the magnesium and lithium analogues due to as maller difference in electronegativity (DEN(N À Zn, Pauling) = 1.39, DEN(N À Mg) = 1.73, DEN(NÀLi) = 2.06), [12] TMPZnCl•LiCl is ab ase where thermodynamic effects should predominate and the kinetic aspects should play am inor role.I nf act, the stronger ionic character of the NÀMet bond (Met = metal), the more likely is the kinetic control. Therefore,lithium amides are prone to metalate organic substrates under kinetic control.…”