Single-Electron Transmetalation: Photoredox/Nickel Dual Catalytic Cross-Coupling of Secondary Alkyl β-Trifluoroboratoketones and -esters with Aryl Bromides

Article abstract of DOI:10.1021/acs.orglett.6b01357

The first cross-coupling of secondary alkyl β-trifluoroboratoketones and -esters has been achieved through application of photoredox/nickel dual catalysis. Although the related β-trifluoroboratoamides have been effectively cross-coupled via Pd-catalysis,

Full text of DOI:10.1021/acs.orglett.6b01357

Letter
pubs.acs.org/OrgLett
Single-Electron Transmetalation: Photoredox/Nickel Dual Catalytic
Cross-Coupling of Secondary Alkyl β‑Trifluoroboratoketones and
-esters with Aryl Bromides
John C. Tellis, Javad Amani, and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: The first cross-coupling of secondary alkyl β-trifluoroborato-
ketones and -esters has been achieved through application of photoredox/
nickel dual catalysis. Although the related β-trifluoroboratoamides have been
effectively cross-coupled via Pd-catalysis, the corresponding ketones and
esters had proven recalcitrant prior to this report. Reactions occur under mild
conditions, and a variety of functional groups and sterically and electronically
diverse reaction partners are tolerated.
he application of secondary alkylboron reagents in cross-
coupling represents a longstanding challenge in organic
cross-coupled product.6 A method for achieving the cross-
coupling of these reagents would not only expand the utility of
an underutilized class of easily prepared compounds but also
complement existing Rh- and Cu-catalyzed methods for the
synthesis of β-arylated ketones by offering an as-yet unrealized
umpolung disconnection.7 This disconnection is especially
valuable upon consideration of the greater availability of aryl
bromide building blocks relative to boronic acids and boronate
esters.
Notably, organoboron reagents represent perhaps the only
viable cross-coupling partners about which a general protocol
for achievement of this particular union could be built.
Secondary ketone homoenolates of zinc, magnesium, and
lithium cannot be prepared because of rapid, intramolecular
nucleophilic attack of the organometallic carbon into the
carbonyl to afford the corresponding cyclopropanolates.8
Although the resultant cyclopropanols can be engaged in
ring-opening cross-coupling to generate β-arylated ketones,
aldehydes, or esters, substituted cyclopropanols typically
participate in C−C bond formation at the less sterically
hindered carbon to generate products of primary alkyl
arylation.9 Furthermore, although secondary alkyltin homo-
enolates have been frequently prepared, only one successful
example of their cross-coupling has been reported.10 Indeed,
the unique properties of organoboron compounds situate these
reagents in a privileged position for realization of this
transformation.
T
synthesis. Chiefly responsible for this methodological gap are
the slow transmetalation rates associated with these sterically
hindered, poorly nucleophilic organometallic reagents, thus
limiting their utility in conventional Suzuki−Miyaura cross-
coupling (Figure 1).1 In an effort to enable the application of
this subclass of reagents in transition-metal-catalyzed cross-
coupling processes, our group has developed an alternative
paradigm for the cross-coupling of alkylboron and alkylsilicon
reagents that relies on the cooperative functions of a nickel
cross-coupling catalyst and an Ir- or Ru-based photoredox
catalyst.2,3 Here, the organometallic reagent is activated by
oxidative fragmentation to the corresponding alkyl radical. This
transient intermediate is then readily intercepted by the nickel
catalyst, which mediates C−C bond formation with an
appropriate aryl halide partner. Exploitation of an odd-electron
activation mode in this process provides reactivity trends
complementary to that of conventional cross-coupling reac-
tions, which typically rely on paradigms rooted in two-electron
processes.
In an effort to expand the capabilities of this photoredox/
nickel dual catalytic approach to cross-coupling, we identified β-
trifluororboratoketones and -esters as a useful class of reagents
for which no effective cross-coupling protocols currently exist.
Although these organoboron compounds are easily accessed via
borylation of the corresponding α,β-unsaturated carbonyl
compounds,4 a single, isolated example of the Suzuki coupling
of a cyclopropyl ketone-derived pinacolboronate represents the
entirety of their utilization in C−C bond-forming reactions.5
Attempts within our own group to apply reaction conditions
developed for use with related β-trifluoroboratoamides to the
corresponding ketones were unsuccessful in affording any
We began our studies with an investigation of the cross-
coupling of secondary alkyltrifluoroborate 2a with 4-bromo-
benzonitrile. Employing a catalytic system of photocatalyst 1
Received: May 10, 2016
© XXXX American Chemical Society
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Presently, we are unable to explain the unique effects of this
unusual combination of additives. We have previously proposed
that the Lewis basic additives (2,6-lutidine, Cs2CO3, K2HPO4,
and/or KF) employed in these cross-coupling reactions serve to
sequester BF3, the highly Lewis acidic byproduct of single-
electron oxidative fragmentation of the alkyltrifluoroborate.2b
Indeed, experiments have confirmed that reaction rates are
reduced in the presence of exogenous BF3·OEt2. Furthermore,
reactions of organobis(catecholato)silicates produce non-Lewis
acidic byproducts and have been observed to proceed efficiently
in the absence of exogenous Lewis base additives.2d
Although it is unclear how or why the combination of
substoichiometric Cs2CO3 and 2,6-lutidine would be more
effective than each additive alone in serving this role, we
speculated that the observed effects may result from either (1)
control of the keto−enol tautomerization rate of the β-
trifluoroboratoketone/ester and/or the corresponding radical
or (2) formation of a more highly active (soluble) salt form of
the alkyltrifluoroborate. Regarding the keto−enol tautomeriza-
tion, it has been documented that radical and radical ion
intermediates can have drastically different acid/base properties
relative to their closed-shell analogues.11 Specifically, in this
case the formation of the enol tautomer from the β-carbonyl
radical would afford a much more highly stabilized enolic
radical. DFT calculations (UB3LYP 6-311+G**) have
indicated a strong thermodynamic preference for the enolic
form of butenal when a radical resides on the β-carbon.11d
However, it is unclear if the kinetics of enolization under the
reported conditions are sufficiently fast as to outcompete the
rate of radical capture at the Ni center. Alternatively, formation
of the enol tautomer from the trifluoroborate precursor would
drastically lower the oxidation potential of the C−B bond. The
transient nature of these species and heterogeneity of the
reaction mixture complicate any attempts to confirm or
disprove the involvement of the enol tautomer during the
cross-coupling, and it is unclear if formation of the species
would be beneficial or detrimental to the process.
Figure 1. (A) Synthesis of β-trifluoroboratocarbonyl compounds from
α,β-unsaturated ketones and esters. (B) β-Trifluoroboratocarbonyl
compounds previously employed in cross-coupling reactions (left) and
those utilized in this report (right). (C) Cross-coupling of β-
trifluoroboratocarbonyl compounds via photoredox/nickel dual
catalysis.
(2.5 mol %), NiCl2·dme (2.5 mol %), and dtbbpy (2.5 mol %)
in 1,4-dioxane led to the formation of product 3a in 36% yield
(Table 1, entry 1). Attempting to apply conditions previously
Table 1. Effect of Additive Stoichiometry on Photoredox/
Nickel Dual Catalytic Cross-Coupling of β-
Trifluoroboratoketone 2
With regard to the hypothesized formation of a more highly
active salt form, we have observed that although dioxane is the
most effective reaction solvent, trifluoroborate 2 is almost
entirely insoluble in this solvent at room temperature.12 It is
possible that combination of the potassium alkyltrifluoroborate
with Cs2CO3 and 2,6-lutidine leads to formation of a
trifluoroborate salt with greater solubility in dioxane and/or
more favorable redox properties. However, notable in this
context is the observation that employing the soluble
tetrabutylammonium salt of 2a nearly shuts down reactivity
under identical conditions, eroding support for the more active
salt argument.
We next examined the substrate scope of this cross-coupling
reaction with regard to both the aryl bromide and
alkyltrifluoroborate partner (Scheme 1). A variety of common
functional groups were well tolerated. Although electron-poor
aryl bromides generally performed best, electron-rich aryl
bromides [4-bromoanisole, ( )-3f, 70%] could also be cross-
coupled with extended reaction times (48 h). Electrophilic
functional groups that may be prone to side reactions in the
presence of more strongly nucleophilic organometallic reagents,
including aldehydes [( )-3d], ketones [( )-3c], esters
[( )-3b], and nitriles [( )-3a], were well tolerated. Heteroaryl
bromides also proved to be able partners, including pyridine
[( )-3j], pyrimidines [( )-3l and ( )-3m], azaindole
[( )-3k], and benzothiophene [( )-3n]. The observed
optimized for structurally analogous unactivated secondary
alkyltrifluoroborates,2b addition of 1.5 equiv of Cs2CO3 resulted
in formation of product in an improved, yet still unsatisfactory,
49% yield (Table 1, entry 2). Exchanging Cs2CO3 for 2,6-
lutidine, which had previously been demonstrated as an
effective additive for these types of dual catalytic processes,
was detrimental to the efficiency of the reactions. Unexpectedly,
the combination of (super)stoichiometric Cs2CO3 and 2,6-
lutidine proved more effective in promoting the desired
reaction than each additive alone. Even more surprisingly, it
was found that reduction of the concentration of these additives
to 0.5 equiv each afforded the highest yield (83%) of β-arylated
product (Table 1, entry 5).
B
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a
Scheme 1. Photoredox/Nickel Dual Catalytic Cross-Coupling of β-Trifluoroboratocarbonyl Compounds: Substrate Scope
a
Reaction time 48 h.
tolerance of nitrogenous substrates bearing Lewis basic
moieties is important for applications in the synthesis of
therapeutically active compounds, where these types of motifs
are prevalent. Also notable is the observed selectivity for
reaction of the aryl bromide exclusively in the presence of
(hetero)aryl chlorides [( )-3j] and triflates [( )-3g], thereby
allowing the possibility of sequential functionalization with a
second organometallic reagent.
ester fragment. A C−H functionalization approach was
reported by MacMillan and co-workers that provides access
to β-(hetero)arylated ketones and aldehydes.14 However, this
method is only effective for electron-poor cyanoarenes and
cannot be applied with sterically and/or electronically non-
biased dialkyl ketones, again highlighting the complementary
characteristics of the protocol reported herein among methods
for the synthesis of this class of compounds.
A variety of β-trifluoroboratocarbonyl compounds were also
found to be competent reaction partners. Importantly, both
alkyl and aryl ketones were well tolerated, as was alkyl and aryl
substitution in the β-position. Cyclic organoboron reagents
were readily tolerated [( )-3q] as well. Notably, methods
previously developed for the cross-coupling of secondary β-
trifluoroboratoamides in our laboratory proved ineffective for
the cross-coupling of cyclic compounds, presumably because of
the need for coordination of the amide carbonyl to the
organopalladium intermediate to suppress undesired β-hydride
elimination pathways and/or acceleration of the sluggish two-
electron transmetalation. Secondary β-trifluoroboratoesters
were also cross-coupled for the first time [( )-3r and
( )-3s] in good yield.
The method reported here for the synthesis of β-arylated
ketones and esters has numerous advantages over existing
methods. Although some of the compounds synthesized in this
report could be accessed via Rh- or Cu-catalyzed conjugate
addition procedures, the photoredox/nickel dual catalytic cross-
coupling displays comparable or greater functional group
tolerance. Furthermore, the instability of many heteroarylme-
tallic reagents13 would greatly reduce access to many of the
compounds reported herein. Access to commercially available
or easily prepared (hetero)aryl bromides makes this method
more attractive for the systematic synthesis of a variety of β-
(hetero)arylated ketones and esters from a common ketone or
Among the limitations of this method are sometimes modest
yields, often resulting from sluggish conversion. We have
previously suggested that long reaction times in these dual
catalytic cross-coupling processes may be a result of poor light
penetration into the reaction mixture, leading to inefficient
excitation of the photocatalyst and effective reduction of the
concentration of “active” photocatalyst.15 This effect is likely to
be exacerbated by the insolubility of the substrate, which both
obscures the path of the light into the solution and introduces a
mass-transfer limitation in oxidation of the trifluoroborate. The
yields of many reactions can be improved by extension of
reaction time, but this benefit comes at the expense of
practicality.
Although a variety of useful functional groups are tolerated,
nitro groups, primary and secondary amides, and primary,
secondary, and tertiary amines have not been coupled
successfully in our hands. Also, aryl bromides bearing ortho
substitution typically coupled in very low yields. Furthermore,
primary and tertiary alkyltrifluoroborates and β-trifluoroborato-
amides are unreactive under the reported conditions. However,
it should be noted that the poor reactivity of primary alkyl
substrates and amides demonstrates the complementary nature
of the reported method to previously reported Pd-catalyzed
methods.6a,16 Taken together, the Pd-catalyzed and newly
reported dual catalytic process allows the cross-coupling of
nearly any primary or secondary β-trifluoroboratoketone, -ester,
C
DOI: 10.1021/acs.orglett.6b01357
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Organic Letters
Letter
J. Am. Chem. Soc. 2015, 137, 11938. (e) Corce,
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̂
́
In summary, we have reported for the first time the cross-
coupling of secondary β-trifluoroboratoketones and -esters with
aryl bromides. Key to the realization of this particular bond
disconnection was the application of photoredox/nickel dual
catalysis wherein previously recalcitrant organoboron reagents
are activated for cross-coupling via single electron oxidation and
fragmentation to a secondary alkyl radical. The reported
method exhibits tolerance of a variety of functional groups and
heteroarenes and can be applied to structurally and electroni-
cally diverse β-trifluoroboratocarbonyl compounds. Reactions
occur under mild conditions and in moderate to very good
yields. The results disclosed herein not only offer an attractive
method for the synthesis of secondary β-(hetero)arylated
ketones and esters but also attest to the power of photoredox/
nickel dual catalysis to realize previously challenging or
impossible bond disconnections.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01357.
Experimental procedures, compound characterization
data, and NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(11) (a) Dinnocenzo, J. P.; Banach, T. E. J. Am. Chem. Soc. 1989, 111,
8646. (b) Zhang, X.; Yeh, S.; Hong, S.; Freccero, M.; Albini, A.; Falvey,
D. E.; Mariano, P. S. J. Am. Chem. Soc. 1994, 116, 4211. (c) Raczyn
*E-mail: gmolandr@sas.upenn.edu.
Notes
́
ska,
E. D.; Stępniewski, T. M.; Kolczynska, K. J. Mol. Model. 2011, 17,
́
The authors declare no competing financial interest.
3229. (d) Huang, Y.; Srinivasadesikan, V.; Chen, W.; Lee, S. Chem.
Phys. Lett. 2013, 565, 18.
ACKNOWLEDGMENTS
(12) No detectable 11B signal could be identified from the 11B NMR
of a suspension of 2a in dioxane.
■
We thank the NIGMS (R01-GM-113878, R01-GM-081376)
for funding this research. Sigma-Aldrich is gratefully acknowl-
edged for generous donation of materials for synthesis of Ir
catalyst 1. Dr. Rakesh Kohli (University of Pennsylvania) is
acknowledged for collection of HRMS data.
(13) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009,
131, 6961.
(14) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W.
C. Science 2013, 339, 1593.
(15) Ryu, D.; Primer, D. N.; Tellis, J. C.; Molander, G. A. Chem. -
Eur. J. 2016, 22, 120.
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D
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