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.
A general method is presented for the synthesis of alkylated
arenes by the chemoselective combination of two electrophilic carbons.
Under the optimized conditions, a variety of aryl and vinyl bromides
are reductively coupled with alkyl bromides in high yields. Under
similar conditions, activated aryl chlorides can also be coupled with
bromoalkanes. The protocols are highly functional-group tolerant (−OH,
−NHTs, −OAc, −OTs, −OTf, −COMe,
−NHBoc, −NHCbz, −CN, −SO2Me),
and the reactions are assembled on the benchtop with no special precautions
to exclude air or moisture. The reaction displays different chemoselectivity
than conventional cross-coupling reactions, such as the Suzuki–Miyaura,
Stille, and Hiyama–Denmark reactions. Substrates bearing both
an electrophilic and nucleophilic carbon result in selective coupling
at the electrophilic carbon (R–X) and no reaction at the nucleophilic
carbon (R–[M]) for organoboron (−Bpin), organotin (−SnMe3), and organosilicon (−SiMe2OH) containing
organic halides (X–R–[M]). A Hammett study showed a
linear correlation of σ and σ(−) parameters with
the relative rate of reaction of substituted aryl bromides with bromoalkanes.
The small ρ values for these correlations (1.2–1.7) indicate
that oxidative addition of the bromoarene is not the turnover-frequency
determining step. The rate of reaction has a positive dependence on
the concentration of alkyl bromide and catalyst, no dependence upon
the amount of zinc (reducing agent), and an inverse dependence upon
aryl halide concentration. These results and studies with an organic
reductant (TDAE) argue against the intermediacy of organozinc reagents.
The direct reductive cross-coupling of alkyl halides with aryl halides is described. The transformation is efficient (equimolar amounts of the starting materials are used), generally high-yielding (all but one between 55 and 88% yield), highly functional-group-tolerant [OH, NHBoc, NHCbz, Bpin, C(O)Me, CO(2)Et, and CN are all tolerated], and easy to perform (uses only benchtop-stable reagents, tolerates small amounts of water and oxygen, changes color when complete, and uses filtration workup). The reaction appears to avoid the formation of intermediate organomanganese species, and a synergistic effect was found when a mixture of two ligands was employed.
The first general method for the reductive dimerization of alkyl halides, alkyl mesylates, alkyl trifluoroacetates, and allylic acetates is reported which proceeds with low catalyst loading (0.5 to 5 mol%), generally high yields (80% ave yield), and good functional-group tolerance.
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