Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis

Article abstract of DOI:10.1126/science.1253647

The routine application of C_sp3-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.

Full text of DOI:10.1126/science.1253647

Reports
which lack functional group tolerance
and are unstable to air, are often em-
ployed for alkyl cross-coupling (1).
The challenge of alkylboron
transmetalation was recognized to arise
directly from mechanistic limitations
inherent to the two-electron nature of
the conventional process, wherein reac-
tivity is inversely proportional to heter-
olytic C-B bond strength, thus
predisposing Csp3 nucleophiles for fail-
ure in cross-coupling reactions (10, 11).
Rather than attempting to override the
inherent biases of the conventional
transmetalation pathway, we anticipat-
ed that development of an activation
mode based on single-electron transfer
(SET) chemistry would comprise a
more efficient strategy for engaging this
class of reagents (Fig. 1). Trends in
homolytic C-B bond strength (12) dic-
tate 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 imple-
mentation.
Single-electron transmetalation in
organoboron cross-coupling by
photoredox/nickel dual catalysis
John C. Tellis,* David N. Primer,* Gary A. Molander†
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia,
PA 19104, USA.
*These authors contributed equally to this work.
†Corresponding author. E-mail: gmolandr@sas.upenn.edu
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. Reported herein is 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 first challenge associated with
realization of this ideal is the oxidative
profile of radical capture at a transition
The immense impact of transition metal-catalyzed cross-coupling has
metal center (R· + Mn → R-Mn+1), which necessitates a subsequent re-
duction to maintain the redox-neutrality of a traditional transmetalation.
Here, application of visible light photoredox catalysis (13, 14), was envi-
sioned to satisfy the requirements of this unique series of SETs. Encour-
agement in this regard was found in the work of Sanford and Glorius,
who had demonstrated that cooperative catalysis between transition met-
als and photoredox catalysts is indeed possible (15–17). Potassium or-
ganotrifluoroborates were identified as promising partners in this new
class of cross-couplings, as previous reports have documented their abil-
ity to function as carbon radical sources upon single-electron oxidation
(18, 19). Furthermore, Akita and co-workers. have employed
Ir[dFCF3ppy]2(bpy)PF6 as a catalyst for the oxidation of activated potas-
sium organotrifluoroborates, demonstrating the feasibility of their im-
plementation in the proposed single-electron transmetalation manifold
(20, 21).
Studies were initiated with nickel as a result of its high reactivity to-
ward organic halides and its favorable single-electron redox potentials.
We anticipated that the combination of a monomeric Ni(0) catalyst 1 and
an aryl halide 2 would result in rapid oxidative addition, generating
Ni(II) species 3. Concomitantly, visible light irradiation of
Ir[dFCF3ppy]2(bpy)PF6 4 would generate excited state complex 5, the
reduction potential of which is sufficiently high [Ered = +1.21 V (22, 23)]
to induce single-electron oxidation of an activated alkyltrifluoroborate 6
[Eox = -1.10 V (20)], affording the desired alkyl radical 7 upon fragmen-
tation. Subsequent capture of the alkyl radical at Ni(II) would then yield
high-valent Ni(III) intermediate 9, which was expected to undergo re-
ductive elimination to generate the desired cross-coupled product 10 and
Ni(I) complex 11. From here, reduction of 11 [Ered > -1.10 V (24, 25)]
by the reduced form of the photocatalyst 8 [Eox = +1.37 V (21)] would
regenerate both the Ni(0) catalyst 1 and the Ir catalyst 4, closing the dual
catalytic cycle.
been well recognized, with the Suzuki-Miyaura reaction in particular
emerging as a preferred method 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 addi-
tion of an organic halide at Pd0, (ii) transmetalation of an organometallic
nucleophile to an organopalladium(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, owing to lower rates of oxidative addition and
transmetalation as well as the propensity of the alkylmetallic intermedi-
ates to undergo facile β-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 β-hydride elimination (3).
Despite the progress achieved in advancement of the other fundamental
steps, transmetalation has remained largely unchanged since the incep-
tion of cross-coupling chemistry. As such, cross-couplings conducted
under the traditional mechanistic manifold typically result in transmeta-
lations 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 employed, thereby
limiting functional group tolerance and augmenting deleterious side
reactions (5). Stoichiometric Ag and Cu salts have been demonstrated to
improve transmetalation efficiency in some systems (6–8), although the
mechanism by which the acceleration is achieved is unclear (9), thus
limiting their widespread application. Often, the only viable alternative
to overcome a slow transmetalation is to abandon the readily available
boronic acids and utilize more reactive organometallic reagents. Thus,
alkylboranes, alkylzincs, or the corresponding Grignard reagents, all of
As a proof of concept, this dual catalytic single-electron transmeta-
lation approach was applied to the cross-coupling of benzylic trifluorob-
/ http://www.sciencemag.org/content/early/recent / 5 June2014 / Page 1 / 10.1126/science.1253647

orates and aryl bromides (Fig. 2). Our efforts were quickly gratified, as a electrophile without competitive radical capture or polymerization, af-
catalytic system consisting of photocatalyst 4, Ni(COD)2 (COD = 1,5- fording diarylmethane 40 in 61% yield. The surprising compatibility of
cyclooctadiene), 4,4-di-tert-butyl-2,2’-bipyridine (dtbbpy) as ligand, and the reaction manifold with this substrate may suggest a mechanistic sce-
2,6-lutidine as an additive effected the cross-coupling of potassium ben- nario more complex than that proposed in Fig. 1. However, the radical
zyltrifluoroborate and bromobenzonitrile in 89% yield upon exposure to nature of the activation mode is strongly supported by the previous stud-
visible light from a 26W compact fluorescent light bulb (CFL) at room ies of Akita (20, 21) and our own experiments utilizing chiral ligand
temperature for 24 hours. Control reactions performed in the absence of scaffolds and racemic secondary alkyl nucleophiles (vide infra).
photocatalyst, Ni catalyst, or light resulted in no detectable product for-
mation, confirming the essential role of each of these components in the gle-electron transmetalation in this dual catalytic cross-coupling, the
dual catalytic process (26).
conditions optimized for use with primary benzylic trifluoroborates were
We next analyzed the scope of the reaction with regard to both the directly applied to the cross-coupling of
secondary (α-
As a demonstration of the broader potential of the application of sin-
a
benzylic trifluoroborate and aryl halide. Expectedly, electronic modifica- alkoxy)alkyltrifluoroborate (Fig. 3). Comparable single-electron oxida-
tion of the trifluoroborate component had a moderate effect on reaction tion potentials (20, 21) serve as the singular commonality between these
yield, with more electron rich, and thus more highly stabilized, radical structurally dissimilar reagents. Thus, C-C bond formation via single-
precursors (16 and 18) performing better than those substituted with electron transmetalation proceeded smoothly under these extremely mild
electron withdrawing groups (15 and 17). Substrates possessing an or- and unoptimized conditions. The differential reactivity between the two-
tho-substituent were well tolerated, evidenced by isolation of product 13 electron and single-electron transmetalation processes is underscored by
in 82% yield. The reaction also exhibited increased efficiency on scale, the stark differences in conditions previously reported for (α-
as diarylmethane 12 was isolated in 97% yield on gram scale with re- alkoxy)alkyltrifluoroborate cross-coupling (5 equiv CsOH, 105°C, 24
duced catalyst loading [1 mol % 4 and 1.5 mol % of Ni(COD)2 and lig- hours) compared to those described herein (31). The observed reactivity
and].
High levels of versatility and functional group tolerance were ob-
also serves to demonstrate tolerance of substrates possessing β-
hydrogens, a characteristic that is requisite of any general method for the
cross-coupling of alkyl substructures.
To highlight further the differences between the activation mode re-
ported here and that of traditional cross-coupling, a competition experi-
ment was performed between potassium benzyltrifluoroborate and
potassium phenyltrifluoroborate. Exposure of these two nucleophiles to
the photoredox cross-coupling conditions resulted in isolation of diaryl-
methane product 12 in 91% isolated yield, with no observable biaryl
served with regard to the aryl halide partner. Substrates bearing electro-
philic functional groups that would be incompatible with more highly
reactive organometallic nucleophiles were well tolerated. Protic func-
tional groups, including amide 27, sulfonamide 39, phenol 26, pyrazole
32, and -NHBoc 28, could also be employed. Substrates possessing sub-
stituents ortho to the halide (25, 37) were tolerated, albeit in diminished
yield. The absence of strong base permitted the coupling of amino acid
derivative 28 with no observable epimerization, demonstrating the po-
-hybridized organometal-
formation (Fig. 4). The ability to engage a Csp3
tential utility of this method for late-stage functionalization of peptides lic reagent selectively in a transition metal-catalyzed C-C bond forming
or for use with molecules containing other base-sensitive functional reaction in the presence of an equivalent Csp2-hybridized organometallic
groups.
represents a dramatic reversal of the reactivity hierarchy of all previous-
A variety of nitrogen-containing heteroaryl bromides, classically ly reported cross-coupling reactions. This effectively demonstrates the
challenging yet highly valued substrates as a result of their prevalence in complementary reactivity patterns observed between the single-electron
biologically active compounds (27), performed well under the optimized and two-electron transmetalation modes.
reaction conditions. Pyridine substrates were coupled in all possible
Another important implication of the single-electron transmetalation
regioisomeric configurations (29, 30, 31, 33). Other important N- manifold is related to the stereochemical outcome of the alkyl transfer.
heterocycles, including pyrimidine 34, indole 35, and quinoline 37 Nearly all cross-coupling reactions of stereo-defined nucleophiles re-
proved to be competent partners. Although five-membered heterocyclic ported heretofore have demonstrated the transmetalation event to be
bromides generally exhibited poor reactivity, electron deficient thienyl stereospecific (32). Thus, enantioenriched products may only be ac-
bromides were coupled in moderate yields, leading to 38 and 39.
cessed from nonracemic and configurationally stable organometallic
Several practical and more sustainable features derive from this ap- reagents, which are often difficult to access. Isolated examples of stere-
proach to cross-coupling. Previous approaches to the cross-coupling of oconvergence in transmetalation exist, specifically in the context of sec-
benzylboron compounds with aryl halides have required excess (3 equiv) ondary benzylmagnesium reagents, a pyrrolidine-based organozinc, and
aqueous base and temperatures no lower than 60°C (28–30). Further- a diastereoconvergent cross-coupling of substituted cyclohexylzinc rea-
more, the present reaction makes use of air stable and inexpensive bipyr- gents (33–36). Stereoconvergence in the former is thought to be enabled
idine ligands with low loading of the Ni catalyst. A derivative of by dynamic kinetic resolution of the configurationally unstable Grignard
photocatalyst 4 has recently been made commercially available and is reagent, while the origin of selectivity in the latter is not fully under-
similarly effective in promoting the desired reactivity.
stood. None of these approaches constitute a general strategy for stere-
The reported cross-coupling reactions generally exhibited levels of oconvergent transmetalation beyond the scope of the directly explored
efficiency and functional group tolerance equal to or surpassing those of reagents.
traditional cross-coupling reactions on similar substrates. Most reactions
In contrast, the stereochemical outcome of the single-electron
cleanly afforded the desired product, with the remaining mass balance transmetalation is dictated by facial selectivity of the addition of a
consisting of only unreacted aryl halide. Competing homocoupling of prochiral alkyl radical to a ligated Ni center. Thus, application of a chiral
the trifluoroborate to afford bibenzyl derivatives was undetectable by ligand framework renders this process asymmetric and provides a gen-
crude HPLC analysis, allowing use of only a slight excess (1.2 equiv) of eral reaction manifold in which stereoconvergent transmetalation can be
this reaction partner, which is typical in traditional Suzuki-Miyaura achieved. Well-known stereoconvergent cross-couplings of alkyl hal-
cross-couplings. Also of note is the compatibility of this reaction mani- ides, which putatively employ a similar mechanistic step, provide guid-
fold with functional groups susceptible to single-electron oxidation or ance for selection of appropriate ligand scaffolds to maximize the
potentially reactive toward the radical intermediates, including phenol, stereoselectivity of the radical capture (37). Indeed, employing commer-
anilide, and thienyl substructures, as well as 5-membered nitrogen heter- cially available ligand L1 under slightly modified conditions, racemic
ocycles. Remarkably, even 4-bromostyrene could be employed as an trifluoroborate 46 was engaged in stereoconvergent cross-coupling with
/ http://www.sciencemag.org/content/early/recent / 5 June2014 / Page 2 / 10.1126/science.1253647

with CF3I. J. Am. Chem. Soc. 134, 9034–9037 (2012). doi:10.1021/ja301553c
Medline
methyl 3-bromobenzoate, affording 1,1-diarylethane product 47 in 52%
yield and a promising 75:25 er (Fig. 4). The observed stereoconvergence
serves as an effective mechanistic probe, supporting the role of the or-
ganotrifluoroborate as a carbon radical precursor, providing evidence
that the radical is intercepted by the ligated Ni complex and suggesting
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 nucleo-
philes 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,
the findings reported herein effectively validate the single-electron
transmetalation manifold and dual photoredox/cross-coupling cycle as a
viable alternative to conventional cross-coupling of Csp3-hybridized nu-
cleophiles.
17. B. Sahoo, M. N. Hopkinson, F. Glorius, Combining gold and photoredox
catalysis: Visible light-mediated oxy- and aminoarylation of alkenes. J. Am.
Chem. Soc. 135, 5505–5508 (2013). doi:10.1021/ja400311h Medline
18. J. W. Lockner, D. D. Dixon, R. Risgaard, P. S. Baran, Practical radical
cyclizations with arylboronic acids and trifluoroborates. Org. Lett. 13, 5628–
5631 (2011). doi:10.1021/ol2023505 Medline
19. G. A. Molander, V. Colombel, V. A. Braz, Direct alkylation of heteroaryls
using potassium alkyl- and alkoxymethyltrifluoroborates. Org. Lett. 13, 1852–
1855 (2011). doi:10.1021/ol2003572 Medline
20. Y. Yasu, T. Koike, M. Akita, Visible light-induced selective generation of
radicals from organotrifluoroborates by photoredox catalysis. Adv. Synth.
Catal. 354, 3414–3420 (2012). doi:10.1002/adsc.201200588
21. K. Miyazawa, Y. Yasu, T. Koike, M. Akita, Visible-light-induced
hydroalkoxymethylation of electron-deficient alkenes by photoredox
catalysis. Chem. Commun. 49, 7249–7251 (2013). doi:10.1039/c3cc42695e
Medline
22. All electrochemical potentials calculated versus the saturated calomel
electrode (SCE).
23. M. Lowry, J. Goldsmith, J. Slinker, R. Rohl, R. A. Pascal, G. G. Malliaras, S.
Bernhard, Single-layer electroluminescent devices and photoinduced
hydrogen production from an ionic iridium(III) complex. Chem. Mater. 17,
5712–5719 (2005). doi:10.1021/cm051312+
24. C. Cannes, E. Labbé, M. Durandetti, M. Devaud, J. Y. Nédélec, Nickel-
catalyzed electrochemical homocoupling of alkenyl halides: Rates and
mechanisms. J. Electroanal. Chem. 412, 85–93 (1996). doi:10.1016/0022-
0728(96)04605-0
25. The reduction of (bpy)NiBr2 is observed as a two-electron wave at -1.1 V,
implying that reduction of (bpy)NiBr to (bpy)Ni0 occurs at a more positive
potential.
References and Notes
1. A. de Meijere, F. Diederich, Eds., Metal-Catalyzed Cross-Coupling Reactions
(Wiley-VCH, Weinheim, Germany, ed. 2, 2004).
2. J. F. Hartwig, Organotransition Metal Chemistry: From Bonding to Catalysis
(University Science, Sausalito, CA, 2010).
3. A. Rudolph, M. Lautens, Secondary alkyl halides in transition-metal-catalyzed
cross-coupling reactions. Angew. Chem. Int. Ed. 48, 2656–2670 (2009).
doi:10.1002/anie.200803611 Medline
4. L. S. Hegedus, B. C. G. Soderberg, Transition Metals in the Synthesis of
Complex Organic Molecules (University Science, Sausalito, CA, ed. 3, 2010).
5. H. Doucet, Suzuki-Miyaura cross-coupling reactions of alkylboronic acid
derivatives or alkyltrifluoroborates with aryl, alkenyl, and alkyl halides and
triflates.
Eur.
J.
Org.
Chem.
2008,
2013–2030
(2008).
26. See supplementary materials on Science Online.
doi:10.1002/ejoc.200700984
27. M. E. Welsch, S. A. Snyder, B. R. Stockwell, Privileged scaffolds for library
design and drug discovery. Curr. Opin. Chem. Biol. 14, 347–361 (2010).
doi:10.1016/j.cbpa.2010.02.018 Medline
6. D. Imao, B. W. Glasspoole, V. S. Laberge, C. M. Crudden, Cross coupling
reactions of chiral secondary organoboronic esters with retention of
configuration. J. Am. Chem. Soc. 131, 5024–5025 (2009).
doi:10.1021/ja8094075 Medline
7. G. Zou, Y. K. Reddy, J. R. Falck, Ag(I) promoted Suzuki-Miyaura cross-
couplings of n-alkylboronic acids. Tetrahedron Lett. 42, 7213–7215 (2001).
doi:10.1016/S0040-4039(01)01536-2
8. J. Z. Deng, D. V. Paone, A. T. Ginnetti, H. Kurihara, S. D. Dreher, S. A.
Weissman, S. R. Stauffer, C. S. Burgey, Copper-facilitated Suzuki reactions:
Application to 2-heterocyclic boronates. Org. Lett. 11, 345–347 (2009).
doi:10.1021/ol802556f Medline
9. M. Aufiero, F. Proutiere, F. Schoenebeck, Redox reactions in palladium
catalysis: On the accelerating and/or inhibiting effects of copper and silver
salt additives in cross-coupling chemistry involving electron-rich phosphine
28. P. Jain, S. Yi, P. T. Flaherty, Suzuki-Miyaura cross-coupling of potassium
organoborates with 6-sulfonate benzimidazoles using microwave irradiation.
J. Heterocycl. Chem. 50, (S1), E166–E173 (2013). doi:10.1002/jhet.1109
29. A. Flaherty, A. Trunkfield, W. Barton, Palladium-catalyzed cross-coupling of
B-benzyl-9-borabicyclo[3.3.1]nonane to furnish methylene-linked biaryls.
Org. Lett. 7, 4975–4978 (2005). doi:10.1021/ol051929x Medline
30. G. A. Molander, T. Ito, Cross-coupling reactions of potassium
alkyltrifluoroborates with aryl and 1-alkenyl trifluoromethanesulfonates. Org.
Lett. 3, 393–396 (2001). doi:10.1021/ol006896u Medline
31. G. A. Molander, S. R. Wisniewski, Stereospecific cross-coupling of secondary
organotrifluoroborates: Potassium 1-(benzyloxy)alkyltrifluoroborates. J. Am.
Chem. Soc. 134, 16856–16868 (2012). doi:10.1021/ja307861n Medline
32. L. Li, C.-Y. Wang, R. Huang, M. R. Biscoe, Stereoretentive Pd-catalysed
Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl
halides. Nat. Chem. 5, 607–612 (2013). doi:10.1038/nchem.1652 Medline
33. T. Hayashi, M. Tajika, K. Tamao, M. Kumada, High stereoselectivity in
asymmetric Grignard cross-coupling catalyzed by nickel complexes of chiral
(aminoalkylferrocenyl)phosphines. J. Am. Chem. Soc. 98, 3718–3719 (1976).
doi:10.1021/ja00428a061
ligands.
Angew.
Chem.
Int.
Ed.
51,
7226–7230
(2012).
doi:10.1002/anie.201202504 Medline
10. Transmetalation rates of organoboron compounds adhere to trends established
for the corresponding organostannanes.
11. J. W. Labadie, J. K. Stille, Mechanisms of palladium-catalyzed couplings of
acid chlorides with organotin reagents. J. Am. Chem. Soc. 105, 6129–6137
(1983). doi:10.1021/ja00357a026
12. A. Finch, P. J. Gardner, E. J. Pearn, G. B. Watts, Thermochemistry of
triphenylboron, tricyclohexylboron and some phenylboron halides. Trans.
Faraday Soc. 63, 1880–1888 (1967). doi:10.1039/tf9676301880
13. C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Visible light photoredox
catalysis with transition metal complexes: Applications in organic synthesis.
Chem. Rev. 113, 5322–5363 (2013). doi:10.1021/cr300503r Medline
14. D. M. Schultz, T. P. Yoon, Solar synthesis: Prospects in visible light
photocatalysis. Science 343, 1239176 (2014). doi:10.1126/science.1239176
Medline
15. D. Kalyani, K. B. McMurtrey, S. R. Neufeldt, M. S. Sanford, Room-
temperature C-H arylation: Merger of Pd-catalyzed C-H functionalization and
visible-light photocatalysis. J. Am. Chem. Soc. 133, 18566–18569 (2011).
doi:10.1021/ja208068w Medline
34. T. Hayashi, M. Konishi, M. Fukushima, T. Mise, M. Kagotani, M. Tajika, M.
Kumada, Asymmetric synthesis catalyzed by chiral ferrocenylphosphine-
transition metal complexes. 2. Nickel- and palladium-catalyzed asymmetric
Grignard cross-coupling. J. Am. Chem. Soc. 104, 180–186 (1982).
doi:10.1021/ja00365a033
35. C. J. Cordier, R. J. Lundgren, G. C. Fu, Enantioconvergent cross-couplings of
racemic alkylmetal reagents with unactivated secondary alkyl electrophiles:
Catalytic asymmetric Negishi α-alkylations of N-Boc-pyrrolidine. J. Am.
Chem. Soc. 135, 10946–10949 (2013). doi:10.1021/ja4054114 Medline
36. K. Moriya, P. Knochel, Diastereoconvergent Negishi cross-coupling using
functionalized cyclohexylzinc reagents. Org. Lett. 16, 924–927 (2014).
doi:10.1021/ol403673e Medline
37. H. Q. Do, E. R. R. Chandrashekar, G. C. Fu, Nickel/bis(oxazoline)-catalyzed
asymmetric Negishi arylations of racemic secondary benzylic electrophiles to
generate enantioenriched 1,1-diarylalkanes. J. Am. Chem. Soc. 135, 16288–
16. Y. Ye, M. S. Sanford, Merging visible-light photocatalysis and transition-
metal catalysis in the copper-catalyzed trifluoromethylation of boronic acids
/ http://www.sciencemag.org/content/early/recent / 5 June2014 / Page 3 / 10.1126/science.1253647

16291 (2013). doi:10.1021/ja408561b Medline
Supplementary Text
Figs. S1 to S9
NMR spectra
38. C. Cazorla, E. Métay, M. Lemaire, Oxidative nucleophilic substitution:
Transformation of alkylboronic derivatives. Tetrahedron 67, 8615–8621
(2011). doi:10.1016/j.tet.2011.09.055
References (38–54)
39. C.-T. Yang, Z. Q. Zhang, H. Tajuddin, C. C. Wu, J. Liang, J. H. Liu, Y. Fu,
M. Czyzewska, P. G. Steel, T. B. Marder, L. Liu, Alkylboronic esters from
copper-catalyzed borylation of primary and secondary alkyl halides and
pseudohalides. Angew. Chem. Int. Ed. 51, 528–532 (2012).
doi:10.1002/anie.201106299 Medline
19 March 2014; accepted 27 May 2014
Published online 5 June 2014
10.1126/science.1253647
40. T. Ishiyama, Ã. Z. Oohashi, T. Ahiko, N. Miyaura, Nucleophilic borylation of
benzyl halides with bis (pinacolato) diboron catalyzed by palladium(0)
complexes. Chem. Lett. 31, 780–781 (2002). doi:10.1246/cl.2002.780
41. D. Hanss, J. C. Freys, G. Bernardinelli, O. S. Wenger, Cyclometalated
iridium(III) complexes as photosensitizers for long-range electron transfer:
Ocurrence of a coulomb barrier. Eur. J. Inorg. Chem. 2009, 4850–4859
(2009). doi:10.1002/ejic.200900673
42. G. A. Molander, B. Biolatto, Palladium-catalyzed Suzuki-Miyaura cross-
coupling reactions of potassium aryl- and heteroaryltrifluoroborates. J. Org.
Chem. 68, 4302–4314 (2003). doi:10.1021/jo0342368 Medline
43. Z. Liu, N. Dong, M. Xu, Z. Sun, T. Tu, Mild Negishi cross-coupling reactions
catalyzed by acenaphthoimidazolylidene palladium complexes at low catalyst
loadings. J. Org. Chem. 78, 7436–7444 (2013). doi:10.1021/jo400803s
Medline
44. G. Schäfer, J. W. Bode, Friedel-Crafts benzylation of activated and
deactivated arenes. Angew. Chem. Int. Ed. 50, 10913–10916 (2011).
doi:10.1002/anie.201105380 Medline
45. M. Giannangeli, L. Baiocchi, Aromatization of aliphatic compounds—V: M-
dialkyl-benzenes and 2-benzyl-naphthalenes. Tetrahedron 36, 1381–1384
(1980). doi:10.1016/0040-4020(80)85052-6
46. C. C. Kofink, P. Knochel, Synthesis of functionalized diarylmethanes via a
copper-catalyzed cross-coupling of arylmagnesium reagents with benzylic
phosphates. Org. Lett. 8, 4121–4124 (2006). doi:10.1021/ol0616790 Medline
47. G. J. Pernı, J. D. Kilburn, J. W. Essex, R. J. Mortishire-Smith, M. Rowley,
Synthesis of functionalized diarylmethanes via a copper-catalyzed cross-
coupling of arylmagnesium reagents with benzylic phosphates. J. Am. Chem.
Soc. 118, 10220–10227 (1996).
48. R. B. Bedford, M. Huwe, M. C. Wilkinson, Iron-catalysed Negishi coupling
of benzyl halides and phosphates. Chem. Commun. 5, 600–602 (2009).
doi:10.1039/b818961g Medline
49. J. R. Schmink, N. E. Leadbeater, Palladium-catalyzed synthesis of
diarylmethanes: Exploitation of carbanionic leaving groups. Org. Lett. 11,
2575–2578 (2009). doi:10.1021/ol900874z Medline
50. L. S. Chupak, J. P. Wolkowski, Y. A. Chantigny, Palladium-catalyzed cross-
coupling reactions of benzyl indium reagents with aryl iodides. J. Org. Chem.
74, 1388–1390 (2009). doi:10.1021/jo802280m Medline
51. C.-R. Chen, S. Zhou, D. B. Biradar, H.-M. Gau, Extremely efficient cross-
coupling of benzylic halides with aryltitanium tris(isopropoxide) catalyzed by
low loadings of a simple palladium(II) acetate/tris(p-tolyl)phosphine system.
Adv. Synth. Catal. 352, 1718–1727 (2010). doi:10.1002/adsc.201000311
52. P. Maity, D. M. Shacklady-McAtee, G. P. A. Yap, E. R. Sirianni, M. P.
Watson, Nickel-catalyzed cross couplings of benzylic ammonium salts and
boronic acids: Stereospecific formation of diarylethanes via C-N bond
activation. J. Am. Chem. Soc. 135, 280–285 (2013). doi:10.1021/ja3089422
Medline
53. M. J. Burns, I. J. S. Fairlamb, A. R. Kapdi, P. Sehnal, R. J. K. Taylor, Simple
palladium(II) precatalyst for Suzuki-Miyaura couplings: Efficient reactions of
benzylic, aryl, heteroaryl, and vinyl coupling partners. Org. Lett. 9, 5397–
5400 (2007). doi:10.1021/ol702291r Medline
54. T. C. Fessard, S. P. Andrews, H. Motoyoshi, E. M. Carreira, Enantioselective
preparation of 1,1-diarylethanes: Aldehydes as removable steering groups for
asymmetric synthesis. Angew. Chem. Int. Ed. 46, 9331–9334 (2007).
doi:10.1002/anie.200702995 Medline
Acknowledgments: The authors thank the NIH (R01 GM-081376) and Pfizer for
their support of this research. We are also grateful to Frontier Scientific for
providing all of the organoboron precursors utilized herein.
Supplementary Materials
www.sciencemag.org/cgi/content/full/science.1253647/DC1
Materials and Methods
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Fig. 1. Comparison of transmetalation in the palladium-catalyzed Suzuki-
Miyaura cross-coupling and the proposed single-electron transmetalation in
photoredox/nickel cross-coupling. Ir = Ir[dFCF3ppy]2(bpy)PF6, R = generic
functional group, Ar = aryl group.
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Fig. 2. Photoredox cross-coupling of benzylic trifluoroborates and aryl bromides. All yields are
percent isolated yield of pure material after chromatography. Reactions were performed on 0.5 mmol
aryl halide. Boc = tert-butoxycarbonyl, Me = methyl, Ph = phenyl, Ac = acetyl.
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Fig. 3. Photoredox cross-coupling of a secondary (α-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 42 and aryl bromide to afford an enantioenriched product.
Reactions performed on 0.5 mmol aryl bromide. *Determined by chiral supercritical
fluid chromatography (SFC). †Absolute configuration was assigned as (S) based on
data reported in the literature. er = enantiomeric ratio.
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