Nickel-catalyzed cross-coupling of photoredox-generated radicals: Uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings

Article abstract of DOI:10.1021/ja513079r

The cross-coupling of sp³-hybridized organoboron reagents via photoredox/nickel dual catalysis represents a new paradigm of reactivity for engaging alkylmetallic reagents in transition-metal-catalyzed processes. Reported here is an investigation into the mechanistic details of this important transformation using density functional theory. Calculations bring to light a new reaction pathway involving an alkylnickel(I) complex generated by addition of an alkyl radical to Ni(0) that is likely to operate simultaneously with the previously proposed mechanism. Analysis of the enantioselective variant of the transformation reveals an unexpected manifold for stereoinduction involving dynamic kinetic resolution (DKR) of a Ni(III) intermediate wherein the stereodetermining step is reductive elimination. Furthermore, calculations suggest that the DKR-based stereoinduction manifold may be responsible for stereoselectivity observed in numerous other stereoconvergent Ni-catalyzed cross-couplings and reductive couplings.

Full text of DOI:10.1021/ja513079r

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals:
Uncovering a General Manifold for Stereoconvergence in Nickel-
Catalyzed Cross-Couplings
Osvaldo Gutierrez, John C. Tellis, David N. Primer, Gary A. Molander,* and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United
States
S
* Supporting Information
ABSTRACT: The cross-coupling of sp3-hybridized
organoboron reagents via photoredox/nickel dual catalysis
represents a new paradigm of reactivity for engaging
alkylmetallic reagents in transition-metal-catalyzed pro-
cesses. Reported here is an investigation into the
mechanistic details of this important transformation
using density functional theory. Calculations bring to
light a new reaction pathway involving an alkylnickel(I)
complex generated by addition of an alkyl radical to Ni(0)
that is likely to operate simultaneously with the previously
proposed mechanism. Analysis of the enantioselective
variant of the transformation reveals an unexpected
manifold for stereoinduction involving dynamic kinetic
resolution (DKR) of a Ni(III) intermediate wherein the
stereodetermining step is reductive elimination. Further-
more, calculations suggest that the DKR-based stereo-
induction manifold may be responsible for stereoselectivity
observed in numerous other stereoconvergent Ni-catalyzed
cross-couplings and reductive couplings.
n the decades following their inception, transition-metal-
catalyzed cross-coupling reactions (CCRs) have assumed a
I
privileged role among methods for the construction of C−C
bonds.1 Although highly reliable for C(sp2)−C(sp2) couplings,
significant limitations are often encountered in the application of
sp3 hybridized reagents, particularly poorly nucleophilic
secondary alkylborons. Here, slower rates of transmetalation
often necessitate forcing conditions and/or harsh reagents (high
temperatures, excess boronic acid, aqueous base), thereby
limiting functional group tolerance while augmenting undesired
side reactions, including protodeboronation, β-hydride elimi-
nation, and subsequent isomerization.2
Figure 1. Initially proposed catalytic cycles (blue) and possible
alternative indicated by computation (red) for photoredox/nickel dual
catalytic CCR of potassium benzyltrifluoroborate and aryl bromides. Ir =
Ir[dFCF3ppy]2(bpy)PF6.
addition to afford arylnickel(II) complex 3 (Figure 1, blue). In
parallel, oxidative fragmentation of an alkyltrifluoroborate 6 by
the excited state of Ir photoredox catalyst 4 yields a C-centered
radical that is rapidly captured by this Ni(II) complex. Reductive
elimination from the resultant Ni(III) species 10 yields the cross-
coupled product and Ni(I) complex 12. Finally, single-electron
reduction of Ni(I) by iridium complex 8 simultaneously
regenerates the Ni(0) catalyst and the ground state photo-
catalyst. MacMillan, Doyle, and co-workers hypothesized a
similar mechanistic scenario for the related cross-coupling of α-
amino acids and N,N-dialkyl-N-arylamines with aryl halides.5
To understand more fully the mechanistic intricacies of this
novel class of CCRs, we undertook a computational analysis of
In an effort to circumvent the challenges of transmetalation
within the conventional catalytic regime, we recently reported a
novel dual catalytic CCR in which the cooperative functions of an
Ir photoredox catalyst and a Ni catalyst effect the cross-coupling
of electronically activated potassium alkyltrifluoroborates with a
variety of aryl bromides under exceptionally mild conditions (eq
1).3 Most notably, the cross-coupling of a secondary benzylic
trifluoroborate occurs stereoconvergently in the presence of a
chiral ligand (eq 2), a stereochemical outcome that is
unprecedented with boron reagents.4
We initially hypothesized a mechanistic scenario in which the
Received: December 23, 2014
Ni(0) catalyst 1 first engages the aryl bromide in oxidative
© XXXX American Chemical Society
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Figure 2. Reaction coordinate for the competing pathways using 2,2′-bipyridine. Relative Gibbs free energy values calculated with SMD-water-
(U)M06/6-311+G(d,p)//UB3LYP/6-31G(d) and SMD-water-(U)M06/6-311+G(d,p)//UB3LYP/LANL2DZ (in parentheses).12
the Ni catalytic cycle. We were particularly interested in
addressing two key questions: (1) To which oxidation state of
Ni does the radical add? (2) Which step in the catalytic cycle is
enantiodetermining? Importantly, although there have been
numerous computational and experimental studies of traditional
transition-metal-catalyzed CCRs,6 there are limited computa-
tional analyses of Ni-catalyzed CCRs in which C-centered
radicals and paramagnetic Ni species are invoked.7 Herein, we
report a detailed density functional theory (DFT) study of the
catalytic cross-coupling of alkyltrifluoroborates and aryl
bromides via single-electron transmetalation. Results reveal
that the final reductive elimination accounts for the origin of
stereoinduction for this important transformation.8 A stereo-
chemical model is proposed and, for the first time, supported by
experiments with a series of substituted aryl bromides. These
mechanistic findings are proposed to have far-reaching
implications related to other stereoconvergent CCRs.
We initiated our studies by calculating the Gibbs free energy
profile with 2,2′-bipyridine as a model ligand for the 4,4′-dtbbpy
ligand used experimentally (Figure 2). Because of the presence of
radicals and low-spin Ni intermediates, all optimizations were
performed using a spin-unrestricted broken-symmetry UB3LYP
functional with both the LANL2DZ and 6-31G(d) basis sets
(with the Guess=mix keyword as implemented in Gaussian09).9
Multiple spin states were considered for all intermediates and
transition states. This method has been used before to rationalize
selectivities accurately,10 model radical Ni systems,7a,b and
account for changes associated with ligands.11 Single-point
energy calculations of optimized structures were carried out in
water (SMD solvation model) at the (U)M06/6-311+G(d,p)
level of theory. For comparison, we computed the energetic
profile by varying the basis set [6-311+G(d,p) for C, N, O, Br, H
and SDD for Ni] and solvent (SMD in acetone), which showed
similar energetics (see Supporting Information). Exhaustive
conformational searches were performed for all intermediates to
map out the lowest energy profile, and intrinsic reaction
coordinate (IRC) calculations were undertaken to ensure
transitions states connected the illustrated ground states.
Beginning from square planar Ni(bpy)(COD) A, dissociation
of 1,5,-cyclooctadiene (COD) and complexation to bromoben-
zene is energetically disfavored by 6−8 kcal/mol (Figure 2).
However, oxidative addition is energetically feasible (15−18
kcal/mol) leading to square planar Ni(II) intermediate A2,
which is ∼26 kcal/mol downhill in energy. The Ni(II)-to-Ni(III)
process, occurring via addition of a benzyl radical (presumably
generated in the concomitant photocatalytic cycle3,5 from Figure
1), is found to proceed via a low barrier (∼4 kcal/mol) transition
state A2-TS and is reversible. Significantly, the reductive
elimination transition state (C-TS) leading to the CCR product
and Ni(bpy)Br intermediate is ∼6 kcal/mol higher in energy than
the radical addition/dissociation.
In an alternative mechanistic pathway, the Ni catalytic cycle
can proceed via an alkylnickel(I) intermediate preceding
oxidative addition (Figure 2 red). Ligand dissociation and radical
η2-complexation to Ni(0) leads to intermediate B1, which
proceeds via a ∼5 kcal/mol energy barrier to form benzylnickel-
(I) intermediate B2, a process that is favorable by ∼10−15 kcal/
mol. This Ni(I) intermediate can undergo facile and irreversible
oxidative addition (via B2-TS) to merge the two energetically
feasible pathways via the pentacoordinated Ni(III) intermediate
C. This result implies that, depending on the concentration of
Ni(0) or Ni(II), both pathways can occur. Irrespective of the
specific pathway, the dual photoredox/cross-coupling cycle
converges onto a Ni(III) intermediate that can dissociate the
stabilized radical to form Ni(II) more rapidly than undergoing
reductive elimination! Subsequent reduction by the photoredox
cycle will generate the Ni(0) intermediate to restart the catalytic
cycle (Figure 1).
In our recent report, we observed modest enantioselectivity
(75:25 er) with the use of chiral 4,4′-dibenzyl-2,2′-bis(2-
oxazoline) ligand, L1 (eq 2). We had previously suggested that
the origin of enantioselectivity in the single-electron trans-
metalation of secondary alkyltrifluoroborates arises from facial
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Figure 4. Predicted and experimental reaction enantioselectivities.17
Moving forward, we became curious whether this DKR-
controlled enantioselectivity operates in other asymmetric Ni-
catalyzed cross-coupling processes. Of particular interest are
reports documenting Ni-catalyzed asymmetric cross-couplings
(Suzuki, Negishi, Hiyama, and Kumada)18 and reductive cross-
couplings.19 Importantly, it can be argued that the “black box”
nature of these transformations have limited their widespread
development and adaptation, as no general model for stereo-
induction has yet been proposed despite the large number of
processes reported to date. Although a number of these
asymmetric cross-couplings employ alkyl groups that would be
precursors to stabilized radicals (i.e., benzylic, allylic, α-carbonyl,
etc.), several examples of asymmetric cross-couplings of
electronically unactivated alkyl subunits have been reported.20
Although the analogy of the former examples to that reported
here is readily apparent, it was less clear whether the proposed
Ni(III) DKR manifold would be viable for systems in which less
stable (e.g., unstabilized secondary alkyl) radicals were generated
via homolysis of the Ni(III) intermediate. In an effort to address
this question, the stereoconvergent cross-coupling of unactivated
secondary alkyl bromides and primary alkylboranes reported by
Fu and co-workers (eq 3)20e was examined computationally.
Figure 3. Competing diastereomeric transition states in the reductive
elimination. Relative free energies (kcal/mol) are computed using
SMD-water-(U)M06/6-311+G(d,p)//UB3LYP/6-31G(d).
selectivity in the addition of the prochiral radical to the ligated
Ni(II) center, followed by stereoretentive reductive elimination.
However, if homolytic equilibration of the Ni(III)/Ni(II) pair is
faster than reductive elimination, as these calculations indicate,
then the origin of stereoselectivity should be found in the
reductive elimination step.7a Thus, we propose that enantio-
selectivity arises from a process best described as a dynamic
kinetic resolution (DKR)13 of Ni(III) complex C′.14 In other
words, addition of the secondary radical to the Ni center operates
under Curtin-Hammett conditions15 furnishing two equilibrat-
ing diastereomeric Ni(III) complexes, one of which reductively
eliminates at a faster rate, leading to the major enantiomer.
Stereoconvergence then results via stereochemical scrambling of
the secondary alkyl subunit through dissociation and recombi-
nation. Indeed, computations of the diastereomeric transition
states C′ corresponding to eq 2 correlate well with experiment;16
specifically, a Boltzmann distribution from calculated free
energies of the eight lowest energy diastereomeric transition
states predicts a 68% ee vs the experimental 50% ee. Examination
of the structures reveals that the α-methylbenzyl group rotates to
avoid gauche-like interactions along the forming C−C bond
(Figure 3). In the lower energy diastereomeric transition state
these interactions are minimized.
Having established reductive elimination as the enantio-
determining step in these systems, other potential substrates
were probed with the aim of establishing a correlation between
the calculated and experimental selectivities. Calculations of the
diastereomeric transition states for several substrates suggested
that substituents at the para-position of the aryl bromide could
enhance the enantioselectivity. In particular, larger para-
substituents encounter steric interactions with the ligand benzyl
group in the transition state leading to the minor enantiomeric
product (see bottom structure in Figure 3). Notably, the
stereochemical influence of these substituents distal from the
bond-forming site would not be evident in the absence of this
computational model. Gratifyingly, these predictions correlated
well with experiment and afforded improved enantioselectivity in
generating 1,1-diarylethane 15 (Figure 4).
Beginning from the putative Ni(III) complex, the transition
states for homolysis of the secondary alkyl substituent and C−C
bond-forming reductive elimination were computed. As shown
in Figure 5, these calculations convincingly support a scenario
analogous to that described above; that is, Ni(III) complex 10a
exists in homolytic equilibrium with Ni(II) complex 3a and the
free alkyl radical in a process that is much faster than the
subsequent reductive elimination leading to Ni(I) complex 12a
and cross-coupled alkane product. As such, we propose that
Figure 5. Energy barriers for the competing unstabilized alkyl radical
dissociation and reductive elimination transition states with chiral
diamine ligand L2. Relative free energies (kcal/mol) are computed using
SMD-water-(U)M06/6-311+G(d,p)//B3LYP/6-31G(d) in SMD
(water) level of theory.
C
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Journal of the American Chemical Society
Communication
stereoconvergence in these processes occurs by the same Ni(III) DKR
process that we have elucidated for photoredox/nickel dual catalytic
organoboron cross-coupling. This newfound knowledge regarding
the fundamental origin of enantioinduction in Ni-catalyzed
stereoconvergent processes can be used to augment stereo-
selectivity in known transformations through rational design and
may be helpful in identifying new substrate classes that can
participate via this manifold. These results are in agreement with
the lack of products with long-lived radical intermediates.
Specifically, radicals that quickly and favorably complex to the Ni
center as proposed in Figure 2 avoid radical pathways such as
cyclization by a pendant alkene. We are currently investigating
the full scope of this proposal for various Ni-catalyzed C−C
bond-forming processes involving alkyl radical intermediates,
including the factors that might change the enantiodetermining
step.
In summary, we have employed DFT calculations to
investigate the reaction pathway of the nickel/photoredox dual
catalytic cross-coupling of aryl bromides with C-centered radicals
derived from alkyltrifluoroborates. These computations suggest a
mechanistic scenario wherein the radical can enter the cross-
coupling cycle by addition to either Ni(0) or Ni(II).21 The two
pathways converge upon a common Ni(III) intermediate that is
able to release the stabilized alkyl radical via Ni−C bond
homolysis, thus establishing an unexpected equilibrium between
this high valent Ni(III) and the Ni(II)/radical pair. The cross-
coupled product is then generated via irreversible reductive
elimination. The reductive elimination barrier was computed to
be significantly higher in energy than the barrier associated with
the reversible homolysis process. Calculations show that the
stereoinduction occurs through DKR of the Ni(III) intermediate
according to the Curtin−Hammett principle. Experimental
results have offered support for the proposed stereochemical
model. Most importantly, the Curtin−Hammett DKR stereo-
induction model appears to be broadly operative in various
related stereoconvergent Ni-catalyzed processes,7,18 offering a
rationalization for the mechanism of stereoselectivity in these
transformations for the first time.
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ASSOCIATED CONTENT
* Supporting Information
■
S
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conformer 2 kcal/mol lower in energy than the lowest energy C-TS′.
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311+G(d,p)//UB3LYP/6-31G(d).
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AUTHOR INFORMATION
■
Corresponding Authors
*gmolandr@sas.upenn.edu
*marisa@sas.upenn.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of Health (GM-087605
to M.C.K. and GM-081376 to G.A.M.) and the National Science
Foundation (CHE1213230 to M.C.K.) for financial support of
this research. Computational support was provided by XSEDE
on SDSC Gordon (TG-CHE120052). Simon Berritt and
members of the UPenn-Merck High Throughput Experimenta-
tion Center at the University of Pennsylvania are acknowledged
for purification of reaction mixtures and for access to chiral
stationary phase supercritical fluid chromatography.
(21) For a recent report on Ni(II) intermediates in the related Negishi
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16588.
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DOI: 10.1021/ja513079r
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