Single-electron transmetalation: An enabling technology for secondary alkylboron cross-coupling

Article abstract of DOI:10.1021/ja512946e

Single-electron-mediated alkyl transfer affords a novel mechanism for transmetalation, enabling cross-coupling under mild conditions. Here, general conditions are reported for cross-coupling of secondary alkyltrifluoroborates with an array of aryl bromides mediated by an Ir photoredox catalyst and a Ni cross-coupling catalyst.

Full text of DOI:10.1021/ja512946e

Communication
pubs.acs.org/JACS
Single-Electron Transmetalation: An Enabling Technology for
Secondary Alkylboron Cross-Coupling
David N. Primer,† Idris Karakaya,†,‡ John C. Tellis,† and Gary A. Molander*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
‡Department of Chemistry, Faculty of Sciences and Letters, Osmaniye Korkut Ata University, 80000 Osmaniye, Turkey
S
* Supporting Information
ABSTRACT: Sluggish transmetalation rates limit the use
of organoboron nucleophiles in secondary alkyl cross-
coupling. In cases where productive reactivity occurs,
significant isomerization and byproducts in highly
hindered systems are observed. Single-electron-mediated
alkyl transfer affords a novel mechanism for transmetal-
ation, enabling cross-coupling under mild conditions.
Here, general conditions are reported for cross-coupling
of secondary alkyltrifluoroborates with an array of aryl
Figure 1. General catalytic cycle for secondary alkyl cross-coupling,
depicting side reactions and off-cycle intermediates that may occur.
bromides mediated by an Ir photoredox catalyst and a Ni
cross-coupling catalyst.
The most challenging aspect of traditional alkylboron cross-
coupling is the slow rate of transmetalation,6 a problem innate to
the two-electron nature of the process. Because of the inherently
low nucleophilicity of organoborons and the associated high
energy of activation in the transmetalation, general approaches to
secondary alkyl cross-coupling default to the more reactive
alkylboranes,6a alkylzincs,7 alkyl Grignard reagents,8 and alkyl-
lithiums.9 These reagents can normally be cross-coupled in high
yields, but their poor shelf life and lack of functional group
tolerability limit their widespread application, particularly in the
context of parallel synthesis for medicinal chemistry.
Azastannatranes provide a viable solution to this challenge, as
methods developed with these stable reagents are mild, if
untested with highly hindered systems.10 However, their lack of
both atom economy and commercial availability would appear to
inhibit their widespread adoption, particularly given the
perceived toxicity of organostannanes.
ransition-metal-catalyzed cross-coupling reactions are an
Tindispensable mainstay in the repertoire of modern
synthetic chemists. Their tremendous impact is evidenced by
ever-increasing prevalence in laboratories ranging from academic
settings to large-scale industrial manufacture. As an illustrative
example, a recent study revealed that >60% of all C−C bond-
forming reactions performed by medicinal chemists can be
classified as transition-metal-catalyzed cross-couplings.1 Despite
widespread adaptation of cross-coupling methods to construct
2
C−C bonds, these methods remain largely limited to Csp -
hybridized centers owing to the challenges associated with their
3
Csp -hybridized counterparts.
Often, the complications associated with alkyl cross-coupling
3
are inherent to the nature of the Csp organometallic reagents
themselves (Figure 1). The instability of alkylboranes, alkylzincs,
or alkyl Grignard reagents often requires their preparation and
immediate use in superstoichiometric amounts (2−4 equiv) to
achieve high yields.2 Further, for many alkylmetallic reagents,
harsher reaction conditions can lead to proto-demetalation3
instead of the desired cross-coupling. Particularly for the more
attractive organoboron nucleophiles, this decomposition path-
way is difficult to suppress because the conditions that exacerbate
these side reactions (high temperatures and strong basicity4) are
typically required for efficient transmetalation.
In those Pd-catalyzed alkyl cross-couplings where efficient
transmetalation can be achieved, often an ensuing β-hydride
elimination generates alkene byproducts and off-cycle catalyst
intermediates. Successive β-hydride eliminations and reinser-
tions lead to a mixture of difficult-to-remove regioisomeric
products from an isomerically pure alkylmetal.5 Careful ligand
and transition metal selection can overcome these issues to some
extent, but regioselective cross-coupling is often impossible.4b
Among the more preferable organoboron reagents, a number
of substrate-specific secondary alkyl cross-coupling reactions
have been reported, but these always required electronic or
functional group stabilization (β-carbonyl,11 α-boryl,12 α-
alkoxy,13 benzylic,14 or allylic15) to allow effective reaction.16
A
few isolated examples of cross-coupling with unactivated boronic
acid derivatives exist, but these do not comprise a general strategy
for alkyl cross-coupling.4a,17 The most universal transformations
to date involve cross-coupling with alkyltrifluoroborates or
boronic acids under rigorous reaction conditions (3 equiv
K2CO3, 60−100 °C, 24−48 h).4b−d Most importantly, these
methods are uniformly ineffective for more highly substituted systems
such as 2-methylcycloalkylborons.
Received: December 19, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
Recently, a novel concept for transmetalation based on a
single-electron transfer (SET)-mediated pathway was reported.18
In this alternate mechanistic approach, the traditional four-
coordinate transition structure19 was circumvented by a series of
SET processes,20 enabling cross-coupling at room temperature. It
was quickly recognized that this method had profound
implications for Csp −Csp cross-coupling because of the mild
nature of the reaction conditions. Instead of a high activation
energy transmetalation, alkyl transfer was effected through radical
combination with a transition metal-based catalyst complexa
nearly barrierless energetic process.21 In such a transformation,
exciting the photocatalyst provides virtually all of the energy
necessary for the cross-coupling event, alleviating the need to
heat the reactions. These conditions were anticipated to increase
yields by limiting the side reactions that doomed previous alkyl
Suzuki couplings.
the cross-coupled product 10, returning NiI-X species 11.
Reduction of 11, with concurrent oxidation of 5, regenerates
the Ni0 and Ir catalysts.26
As a result of recent computational studies, the catalytic cycle
proposed here differs from that initially hypothesized,18 where
oxidative addition at Ni0 precedes radical combination. It is
interesting, however, that both pathways converge on common
intermediate 9 and, regardless of step order (oxidative addition
before radical combination or vice versa), 9 is predicted to exist in
equilibrium with ligated ArNiIIX species 12 and alkyl radical 4
through rapid and reversible homolytic cleavage of the Ni−C
bond. Both pathways are energetically viable, but the low barrier
for radical addition at Ni0 relative to oxidative addition at Ni0
would appear to favor the mechanism proposed in Figure 2 as
being more representative of the predominant reaction pathway.
Full computational details are forthcoming.27
3
2
Initially, attempts to apply previous conditions for the cross-
coupling of benzylic and secondary α-alkoxyalkyltrifluoroborates
[2.0 mol% 1, 3.0 mol% Ni(COD)2/dtbbpy, acetone/MeOH
(10:1), 3.5 equiv lutidine] proved ineffective (<10% yield). The
low yields achieved using that protocol appeared to be a
consequence of the differing nature of the unstabilized, secondary
alkyl radicals, where radical alkylation of arenes28 and H-atom
abstraction from the solvent29 could outcompete combination
with the Ni catalyst, which was present in low concentration.
Using knowledge of established H-atom abstraction rates,30 these
side reactions could be suppressed by the use of dioxane as
solvent with careful monitoring of the reaction temperature.
Next, various additives were determined to have a profound effect
on the rate of the reaction and the amount of protodehalogen-
ation side product observed. Of those additives screened, Cs2CO3
was the best for maximizing productive cross-coupling while
limiting side reactions. The precise role of the base is not defined,
but rate studies reveal that BF3 appears to inhibit the reaction. Its
removal by added base allows reactions to proceed to completion
in a more timely manner. Applying these conditions to the cross-
coupling of methyl 4-bromobenzoate with potassium
cyclopentyltrifluoroborate furnished product 14 in a satisfactory
92% yield (see Supporting Information for full optimization
studies). Control experiments in the absence of Ni, Ir, and light all
confirmed the dual catalytic nature of this cross-coupling.
With suitable conditions [2.5 mol% 4, 5 mol% NiCl2·dme, 5
mol% dtbbpy, 1.5 equiv Cs2CO3, dioxane, 26 W compact
fluorescent lightbulb (CFL), 24 °C, 24 h] in hand, the scope of
the alkyltrifluoroborate component was explored (Table 1).
Organoborons possessing various ring sizes were coupled in good
to excellent yields. To ensure the scalability and efficiency of this
secondary alkyl coupling, a gram-scale reaction generating 13 was
performed with reduced loadings of Ir and Ni catalysts.
Importantly, only 1.0 mol% of the photoredox catalyst and 2.0
mol% of the Ni catalyst were required, and under these
conditions the cross-coupling of methyl 4-bromobenzoate with
potassium cyclohexyltrifluoroborate was accomplished to afford
13 in 73% yield after 36 h.
Direct application of the previously reported SET strategy to
secondary alkyltrifluoroborates was recognized as challenging
because of their relatively high reduction potentials [+1.50 V vs
SCE22] as compared to their benzylic counterparts [+1.10 V vs
SCE22]. Exceeding the electrochemical potentials of highly
oxidizing photocatalyst Ir(dFCF3ppy)2(bpy)PF6 (1) [+1.32 V vs
SCE23], these substrates appeared to be destined for failure
because of their high electrochemical demands. Nevertheless,
encouragement was found in cases where thermodynamically
unfavorable SETs occur, particularly within the context of an
irreversible oxidation or reduction.22,24 Thus, only asmall portion
of the oxidation wave need overlap with the potential of the
photocatalyst for the reaction to proceed, driven forward by
irreversible C−B bond fragmentation.
Using this rationale, it was reasoned that visible light excitation
of heteroleptic IrIII photocatalyst 1 would generate the long-lived
photoexcited *IrIII complex 2, which could perform the
thermodynamically challenging oxidation of secondary alkyl-
trifluoroborate 3 to the corresponding secondary alkyl radical 4
and the reduced ground-state photocatalyst 5 (Figure 2).
Combining this radical with ligated Ni0 complex 625 would
generate the alkyl-NiI complex 7, which is capable of engaging
aryl halide 8 in oxidative addition to form the high-valent NiIII
intermediate 9. Subsequent reductive elimination would afford
When moving to smaller ring sizes, particularly cyclobutyl and
cyclopropyl systems, where occupying an orbital with greater s-
character destabilizes the resultant radical, yields suffered. In fact,
for the cyclopropyl substrate, no reaction was observed. This
poor reactivity serves to highlight the complementary nature of
2
2
this method compared to established methods for Csp - and Csp -
like cross-coupling, where the two-electron transmetalation
regime has proven quite effective.31 Isopropyl- and sec-butyl-
trifluoroborates were also coupled in good yields. For these
Figure 2. Comparison between traditional transmetalation and single-
electron-mediated activation, and proposed catalytic cycle for photo-
redox cross-coupling.
B
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Table 1. Scope of Secondary Potassium Alkyltrifluoroborates
in Ni/Photoredox Cross-Coupling
Table 2. Aryl Bromide Scope with Both Symmetric and
Nonsymmetric Secondary Potassium Alkyltrifluoroborates
a
Reaction run on gram scale with 1.0 mol% Ir(dFCF3ppy)2bpy·PF6
and 2.0 mol% NiCl2·dme/dtbbpy.
substrates, where isomerization would lead to different products,
only the desired regioisomer was observed.
To probe further the limits of the isomeric fidelity observed in
this transformation, several more bulky secondary alkyltrifluoro-
borates were explored. Gratifyingly, products derived from 2-
methylcyclopentyl and 2-methylcyclohexyl substrates were also
isolated without rearrangement, and the products were
exclusively the trans diastereomer. Remarkably, an even more
sterically demanding pinane derivative, 23, was an able partner.
Aliphatic heterocyclic ring systems containing oxygen (22)
and protected nitrogen (21), which have proven to be recalcitrant
in previous cross-coupling methods,4b did not significantly
reduce yields under the photoredox cross-coupling protocol. In
particular, aryl piperidines structurally analogous to 21, which are
highly desired for incorporation into pharmaceutical libraries,32
could be accessed in excellent yield.
Substituted aryl bromides were screened to explore the scope
of functional group tolerance (Table 2). During this process, a
variety of trifluoroborates were used, particularly those that were
both unsymmetrical and sterically encumbered, in an effort to
showcase the mild nature of these cross-couplings. In previous
work under Pd catalysis, 2-methylcycloalkylborons were
observed to isomerize during the reaction, leading to a complex
mixture where cross-coupling at the less sterically crowded
positions was preferred.4b,d In contrast, the ability to couple even
more crowded trifluoroborates with a range of aryl bromides
under the current paradigm serves to highlight the mechanistic
differences between a traditional transmetalation and the radical-
mediated alkyl transfer described here.
For the aryl bromide component, both electron-poor (24) and
electron-rich systems (25) were coupled in good to excellent
yields. Substitution ortho to the halide in 26 and 28 was tolerated
without significant reduction in yield. Selective cross-coupling
was observed in compounds with multiple electrophilic handles;
both bifunctional aryl chlorides (leading to 26 and 29) and an aryl
triflate, providing 38, coupled exclusively at the bromide. Ketones
and esters (39 and 41), which can be intolerant of Kumada-type
conditions, could be embedded within substrates to afford
products in excellent yields. Further, nitrile-substituted bromides
24 and 36, which were unreactive under the previously developed
Pd chemistry for alkyltrifluoroborates,4b served as competent
reaction partners.
istry,32 readily participated in the cross-coupling. Pyridines (29,
30, 32, 35, 36), pyrimidine (34), and protected heterocycles
(indazole 28, azaindole 33) were all accessed in acceptable yields.
In addition to the more desirable N-heterocycles, a bromo-
benzothiophene was also reactive under the conditions, returning
coupled product 40 in reasonable yield. Overall, the functional
group tolerance for bromides shown here rivals or exceeds that of
any previously developed method for secondary alkyl Suzuki
cross-coupling, particularly within the context of heteroaryl
substrates.
In summary, extremely mild conditions (rt, 1.5 equiv base, 26
W CFL irradiation) for the cross-coupling of secondary
alkyltrifluoroborates with aryl bromides have been developed.
The best previously reported Pd-catalyzed conditions for
secondary alkylboron coupling4b,d required a significant excess
of base and elevated temperatures to achieve less general overall
results. Moreover, extensive Pd source, ligand, and reaction
condition screenings have so far failed to identify satisfactory
results for systems such as 2-methyl-substituted cycloalkyl-
borons. Only slight modification of the initially reported
conditions for benzylic coupling was required to extend both
the nucleophilic and electrophilic scope of secondary alkyl cross-
couplings with the photoredox cross-coupling dual catalytic
system. The ease of this transformation across a broad array of
radical precursors (α-amino,33 α-alkoxy,18,33 benzylic,18 and now
secondary alkyl) speaks to the power of the SET-mediated
approach. Further investigations into Ni precatalysts and ligands
(entities that yielded vast improvements in analogous Pd
chemistry34) can arguably afford similar gains when applied to
this system. With proper screening and catalyst design,
extensions to extremely hindered electrophiles and aryl chlorides
appear feasible.
Protic groups did not diminish reactivity for the acetanilide
substrate leading to 31. A number of N-heterocyclic bromides,
providing privileged substructures of use in medicinal chem-
Finally, it should be noted that several Pd-catalyzed processes
allow the conversion of enantiomerically enriched organoborons
to cross-coupled products with high stereochemical fidel-
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ity.4d,11,13−15 Although such a process is clearly not feasible under
the current paradigm, where radical intermediates are generated
from the organoboron precursors, the prochiral radicals
generated can be engaged in stereoconvergent transformations
byemploying enantioenriched ligands around the Ni catalyst.18,35
The fine-tuning of stereoconvergent protocols by ligand
development and screening has the potential to provide a unique
tactic for asymmetric synthesis by eliminating the need to
synthesize optically active organometallic reagents, approaches to
which are often long, tedious, and intolerant of sensitive
functional groups.36
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The most attractive feature of the reported photoredox cross-
coupling may be its operational simplicity. By eliminating the
need to prepare sensitive organometallics, titrate reagents, or use
glovebox techniques, these methods greatly enhance the
approachability of secondary alkyl cross-couplings. Conse-
quently, the methods described here provide a significant
(15) Glasspoole, B. W.; Ghozati, K.; Moir, J. W.; Crudden, C. M. Chem.
Commun. 2012, 48, 1230.
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3
2
advancement to Csp −Csp cross-coupling.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) Recent reviews on photoredox catalysis: (a) Schultz, D. M.; Yoon,
T. P. Science 2014, 343, 985. (b) Prier, C. K.; Rankic, D. A.; Macmillan, D.
W. C. Chem. Rev. 2013, 113, 5322. (c) Tucker, J. W.; Stephenson, C. R. J.
J. Org. Chem. 2012, 77, 1617. Review on photoredox andtransition metal
catalysis: (d) Hopkinson, M. N.; Sahoo, B.; Li, J.-L.; Glorius, F. Chem.-
Eur. J. 2014, 20, 3874.
■
S
AUTHOR INFORMATION
Corresponding Author
*gmolandr@sas.upenn.edu
Notes
(21) Breitenfeld, J.; Ruiz, J.; Wodrich, M. D.; Hu, X. J. Am. Chem. Soc.
2013, 135, 12004.
■
(22) Yasu, Y.; Koike, T.; Akita, M. Adv. Synth. Catal. 2012, 354, 3414.
(23) Koike, T.; Akita, M. Inorg. Chem. Front. 2014, 1, 562.
(24) Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2010, 132, 13600.
The authors declare no competing financial interest.
(25) In this catalytic cycle, initial reduction of the NiIICl2 is required to
access an active Ni0 catalyst. This is likely mediated by the photocatalyst
through sacrificial oxidation of trifluoroborate and subsequent reduction
of NiIICl2 to generate the active Ni0 species.
ACKNOWLEDGMENTS
■
Alexandra Nilova (University of Pennsylvania) is acknowledged
for some substrate preparation and reaction screening. Dr. Simon
Berritt and Seth Martin (University of Pennsylvania) developed a
photoredox screening platform that greatly facilitated the
research. Frontier Scientific is thanked for the donation of
boron compounds used in this investigation. Johnson-Matthey is
acknowledged for the donation of IrCl3 used for the synthesis of
the photocatalyst. We thank Pfizer, NIGMS (R01 GM081376),
(26) We also recognize the possibility of an alternative quenching cycle,
where reduction of NiI occurs from *IrIII to generate an IrIV species,
which can then oxidize the secondary potassium alkyltrifluoroborate and
generate IrIII in the ground state. However, the high concentration of
RBF3K relative to Ni in the reaction mixture at the outset leads us to favor
the mechanism outlined in the text and Figure 2.
(27) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.;
Kozlowski, M. C., manuscript submitted.
̈
̇
and TUBITAK for financial support of this research.
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Carbon Bonds; Pergamon Press: New York, 1986.
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oxygen was observed alongside the desired alkyl cross-coupling product.
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(32) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem.
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