exist, specifically in the context of secondary
benzylmagnesium reagents, a pyrrolidine-based
organozinc, and a diastereoconvergent cross-coupling of substituted cyclohexylzinc reagents
(33–36). Stereoconvergence in the former is
thought to be enabled by dynamic kinetic resolution of the configurationally unstable Grignard
reagent; the origin of selectivity in the latter is
not fully understood. None of these approaches
constitute a general strategy for stereoconvergent transmetalation beyond the scope of the
directly explored reagents.
In contrast, the stereochemical outcome of
the single-electron transmetalation is dictated
by facial selectivity of the addition of a prochiral
alkyl radical to a ligated Ni center. Thus, application of a chiral ligand framework renders
this process asymmetric and provides a general
reaction manifold in which stereoconvergent
transmetalation can be achieved. Well-known
stereoconvergent cross-couplings of alkyl halides,
which putatively undergo a similar mechanistic
step, provide guidance for selection of appropriate ligand scaffolds to maximize the stereoselectivity of the radical capture (37). Indeed,
when we used commercially available ligand L1
under slightly modified conditions, racemic trifluoroborate 44 was engaged in stereoconvergent
cross-coupling with methyl 3-bromobenzoate,
affording 1,1-diarylethane product 45 in 52%
yield and a promising enantiomeric ratio of 75:25
(Fig. 4). The observed stereoconvergence serves
as an effective mechanistic probe that supports
the role of the organotrifluoroborate as a carbon radical precursor, provides evidence that
the radical is intercepted by the ligated Ni complex, and suggests that C-C bond formation occurs via reductive elimination from Ni.
This preliminary result strongly implies that
high levels of stereoselectivity are possible in
the photoredox cross-coupling of secondary alkyl
nucleophiles with appropriate modification of
reaction conditions and ligand structure. Refinement of this approach to asymmetric cross-coupling
will provide a powerful advancement to the field
by alleviating the need for synthesis of enantioenriched organometallic reagents. Taken together,
our findings effectively validate the single-electron
transmetalation manifold and dual photoredox/
cross-coupling cycle as a viable alternative to
conventional cross-coupling of Csp3-hybridized
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Supported by NIH (grant R01 GM-081376) and Pfizer. We thank
Frontier Scientific for providing all of the organoboron precursors
used in our work.
Materials and Methods
Figs. S1 to S9
19 March 2014; accepted 27 May 2014
Published online 5 June 2014;
436 25 JULY 2014 • VOL 345 ISSUE 6195
Fig. 3. Photoredox cross-coupling of a secondary (a-alkoxy)alkyltrifluoroborate with 4-bromobenzonitrile.
Fig. 4. Probing chemo- and stereoselectivity. (A) Competition experiment between potassium
benzyltrifluoroborate and potassium phenyltrifluoroborate under photoredox cross-coupling conditions.
(B) Stereoconvergent cross-coupling of a racemic trifluoroborate 44 and aryl bromide to afford an
enantioenriched product. Reactions were performed on aryl bromide (0.5 mmol). *Determined by chiral
supercritical fluid chromatography (SFC). †Absolute configuration was assigned as (S) on the basis of
data reported in the literature. er = enantiomeric ratio.