Cross-electrophile coupling: principles of reactivity and selectivity

Abstract

A critical overview of the catalytic joining of two different electrophiles, cross-electrophile coupling (XEC), is presented with an emphasis on the central challenge of cross-selectivity. Recent synthetic advances and mechanistic studies have shed light on four possible methods for overcoming this challenge: (1) employing an excess of one reagent; (2) electronic differentiation of starting materials; (3) catalyst-substrate steric matching; and (4) radical chain processes. Each method is described using examples from the recent literature.

Figure 1

Comparisons of the selectivity challenges of cross-coupling and XEC.

Figure 2

Transition-metal-catalyzed cross-coupling strategies that alleviate limitations imposed by nucleophilic coupling partners.

Figure 3

XEC strategies that will be discussed in this Synopsis.

Figure 4

High yields can be obtained with electrophiles of nearly equal reactivity by using an excess of one coupling partner at the expense of large amounts of symmetric dimer byproducts. PyBox = pyridyl bis(oxazoline).

Figure 5

Three mechanisms proposed for the XEC of alkyl halides with acid chlorides: (A) sequential oxidative addition, alkyl-first, L = Bpy; (B) disproportionation, L = 4,4′-di-tert-butyl-2,2′-bipyridine; (C) sequential oxidative addition, acyl first, L = chiral bis(oxazoline) for enantioconvergent reactions, bathophenanthroline for achiral reactions.^,

Figure 6

Steric matching as a selectivity model in XEC and key proposed catalytic intermediates for conjugate addition (A and B) and cross-Wurtz coupling (C). L for 23 = 2-(2-pyridyl)imidazoline.

Figure 7

Radical chain cross-coupling of aryl iodides with alkyl iodides. Selectivity derives from the different reactivity of the aryl halides and alkyl halides.

Figure 8

XEC of epoxides with aryl iodides. Iodide (A) or titanium (B) cocatalysis enables selective formation of normal (31) or abnormal (32) addition products.