resonance (32). In addition, the protocol developed here is general and will affect experiments
with ion traps and other platforms as system
sizes increase, both in full calibrations of the
coupling matrix and in the ability to observe a
single quantity that serves as a proxy for the
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We thank J. Freericks, B. Yoshimura, E. Edwards, S. Will,
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This work is supported by the U.S. Army Research Office
(ARO) award no. W911NF0710576 with funds from the Defense
Advanced Research Projects Agency Optical Lattice Emulator
Program, ARO award no. W911NF0410234 with funds from the
Intelligence Advanced Research Projects Activity Multi-Qubit
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Materials and Methods
28 January 2014; accepted 3 June 2014
Single-electron transmetalation in
organoboron cross-coupling by
photoredox/nickel dual catalysis
John C. Tellis,* David N. Primer,* Gary A. Molander†
The routine application of Csp3-hybridized nucleophiles in cross-coupling reactions remains
an unsolved challenge in organic chemistry. The sluggish transmetalation rates observed
for the preferred organoboron reagents in such transformations are a consequence of
the two-electron mechanism underlying the standard catalytic approach. We describe a
mechanistically distinct single-electron transfer-based strategy for the activation of
organoboron reagents toward transmetalation that exhibits complementary reactivity
patterns. Application of an iridium photoredox catalyst in tandem with a nickel catalyst
effects the cross-coupling of potassium alkoxyalkyl- and benzyltrifluoroborates with an
array of aryl bromides under exceptionally mild conditions (visible light, ambient temperature,
no strong base). The transformation has been extended to the asymmetric and
stereoconvergent cross-coupling of a secondary benzyltrifluoroborate.
The immense impact of transition metal– catalyzed cross-coupling has been well rec- ognized, with the Suzuki-Miyaura reaction in particular emerging as a preferred meth- od for the construction of C-C bonds in both
industrial and academic settings (1). Traditionally, cross-coupling reactions employ a three-step catalytic cycle (Fig. 1): (i) oxidative addition
of an organic halide at Pd0, (ii) transmetalation
of an organometallic nucleophile to an organo-palladium(II) electrophile, and (iii) reductive elimination from a diorganopalladium(II) species,
releasing the coupled product and regenerating
the Pd0 catalyst (1, 2). Although these methods
are highly effective for Csp2-Csp2 coupling, extension to Csp3 centers has proven challenging because of lower rates of oxidative addition and
transmetalation, as well as the propensity of
the alkylmetallic intermediates to undergo facile
b-hydride elimination (2). Recent advances in
ligand technology and the use of alternative
metals, such as nickel, have greatly expanded
the scope of the electrophilic component, extending even to sterically hindered and unactivated
alkyl substrates, and have largely succeeded in
retarding problematic b-hydride elimination (3).
Despite the progress achieved in advancement
of the other fundamental steps, transmetalation
has remained largely unchanged since the inception of cross-coupling chemistry. As such,
cross-couplings conducted under the traditional
mechanistic manifold typically result in transmetalations that are rate-limiting (4).
To date, strategies aimed at accelerating the
rate of transmetalation of Csp3-hybridized boronic
acid reagents have been largely rudimentary. In
most cases, excess base and high temperature
are used, thereby limiting functional group tol-
erance and augmenting deleterious side reac-
tions (5). Stoichiometric Ag and Cu salts have
been shown to improve transmetalation efficien-
cy in some systems (6–8), although the mech-
anism by which the acceleration is achieved is
unclear (9), thus limiting their widespread ap-
plication. Often, the only viable alternative to
overcome a slow transmetalation is to abandon
the readily available boronic acids and make use
of more reactive organometallic reagents. Thus,
alkylboranes, alkylzincs, or the corresponding
Grignard reagents—all of which lack functional
group tolerance and are unstable to air—are
often used for alkyl cross-coupling (1).
The challenge of alkylboron transmetalation
was recognized to arise directly from mechanistic limitations inherent in the two-electron
nature of the conventional process, wherein reactivity is inversely proportional to heterolytic
C-B bond strength, thus predisposing Csp3
nucleophiles for failure in cross-coupling reactions
(10, 11). Rather than attempting to override the
inherent biases of the conventional transmetalation pathway, we anticipated that development
of an activation mode based on single-electron
transfer (SET) chemistry would constitute a more
efficient strategy for engaging this class of reagents (Fig. 1). Trends in homolytic C-B bond
strength (12) dictate that such a reaction manifold would exhibit reactivity trends complementary to that of a traditional cross-coupling, with
Csp3-hybridized nucleophiles now ideally primed
for successful implementation.
The first challenge associated with the realization of this ideal is the oxidative profile of radical
capture at a transition metal center (R· + Mn →
R-Mn+1), which necessitates a subsequent reduction to maintain the redox neutrality of a traditional transmetalation. Here, application of
visible-light photoredox catalysis (13, 14), was
envisioned to satisfy the requirements of this
unique series of SETs. Encouragement in this
Roy and Diana Vagelos Laboratories, Department of
Chemistry, University of Pennsylvania, Philadelphia, PA
*These authors contributed equally to this work. †Corresponding
author. E-mail: firstname.lastname@example.org