Insights into a Chemoselective Cobalt Catalyst for the Hydroboration of Alkenes and Nitriles

Article abstract of DOI:10.1021/acscatal.7b00362

A chemoselective hydroboration protocol with terminal alkene substrates is reported using an electron-rich, low-valent cobalt pincer compound. The process is catalytic and leads to exclusive formation of anti-Markovnikov products, tolerating amino groups, esters, epoxides, ketones, and other functionalities. The protocol was successfully extended toward the hydroboration of nitriles, generating the corresponding amines in moderate to good yields. Labeling studies with deuterated pinacolborane gave insights into the mechanism, establishing the intermediacy of a cobalt hydride, as well as an insertion, β-hydride elimination, and alkene isomerization pathway. These insights provide a rationale for the observed regioselectivity and allow us to propose a catalytic mechanism.

Full text of DOI:10.1021/acscatal.7b00362

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Insights into a Chemoselective Cobalt Catalyst for the Hydroboration
of Alkenes and Nitriles
Abdulrahman D. Ibrahim, Steven W. Entsminger, and Alison R. Fout*
School of Chemical Sciences, University of Illinois at UrbanaChampaign, 600 South Mathews Avenue, Urbana, Illinois 61801,
United States
S
* Supporting Information
ABSTRACT: A chemoselective hydroboration protocol with
terminal alkene substrates is reported using an electron-rich,
low-valent cobalt pincer compound. The process is catalytic
and leads to exclusive formation of anti-Markovnikov products,
tolerating amino groups, esters, epoxides, ketones, and other
functionalities. The protocol was successfully extended toward
the hydroboration of nitriles, generating the corresponding
amines in moderate to good yields. Labeling studies with
deuterated pinacolborane gave insights into the mechanism,
establishing the intermediacy of a cobalt hydride, as well as an
insertion, β-hydride elimination, and alkene isomerization pathway. These insights provide a rationale for the observed
regioselectivity and allow us to propose a catalytic mechanism.
KEYWORDS: hydroboration, alkene, nitrile, cobalt, chemoselective, catalysis
atalytic hydroboration is a powerful synthetic tool for the
enantioselectivity where applicable, as in the case of the chiral
Creduction and functionalization of unsaturated bonds, iminopyridine oxazoline iron complexes reported by Lu.22
Although there has been significant research in this area, we
sought to remove the activators, such as Grignard reagents and
NaBHEt3, from the system and extend the functional group
tolerance to ketone-bearing alkene substrates which has not
been widely reported with earth-abundant metal catalysts.
Similar functional group constraints have also been noted in
the copper-catalyzed systems, several of which feature the use
of activated or simple alkene and alkyne substrates. Recent
reports from the Ito group12,23 and Takaki group24 have
obviated some of these limitations, providing copper-based
systems that can be modulated to provide interesting
Markovnikov regioselectivity or that otherwise confer an
improved functional group tolerance.
We recently reported the hydrosilylation of terminal alkene
substrates with a CoI catalyst bearing an electron-rich CCC
pincer ligand.25 Mechanistic studies suggested that the catalyst
engages in oxidative addition of the Si−H bond to generate a
catalytically active CoIII hydrido silyl complex and then
proceeds along a Chalk−Harrod reaction profile reminiscent
of noble-metal catalysts to afford the targeted alkylsilane
product. This reactivity, as well as the impressive chemo-
selectivity of the (DIPPCCC)CoN2 (1; DIPPCCC = bis(2,6-
diisopropylphenylbenzimidazol-2-ylidene)phenyl) catalyst,
prompted us to explore the hydroboration of alkenes bearing
ketones and other traditionally challenging oxygen-containing
providing products that can serve as valuable synthons in a
variety of chemical transformations. The widely employed
Suzuki−Miyaura coupling, for example, effectively uses organo-
boronates as nucleophiles for the construction of C−C bonds,
cementing its status as one of the most versatile and employed
reactions in the pharmaceutical industry.1,2 Accordingly, several
catalysts have been reported for the preparation of organo-
boron reagents, traditionally via the hydroboration of alkenes or
the borylation of olefinic or alkane substrates.3−5 Catalysts have
typically featured noble-metal centers, primarily Rh and Ir.5
However, the high cost, low abundance, and environmental
impacts associated with the use of such metals has motivated
the development of first-row transition-metal congeners.6,7
Recent reports from the laboratories of Ritter, Chirik, Huang,
and others have provided new Fe, Co, and Cu catalysts for the
hydroboration of alkynes and terminal alkenes.8−18 Such
systems boast operational simplicity and provide powerful
platforms for the reduction of unsaturated bonds. Huang and
co-workers reported a potent Co(PNN) (PNN = 6-
[(dialkylphosphino)methyl]-2,2′-bipyridine) hydroboration
catalyst that tolerates a variety of functional groups, including
ketones, allyl ethers, tertiary amines, and substituted amides.19
Similarly, Chirik reported a complement of simple cobalt
catalyst precursors for the hydroboration of simple alkenes,
including a (PPh3)3CoH(N2) system that is competent toward
the catalytic isomerization−hydroboration of alkenes.20 Recent
reports from Thomas,21 Lu,22 and Huang17 have paralleled such
developments with Fe-based hydroboration catalysts, confer-
ring a notable degree of functional group tolerance or
Received: February 3, 2017
Revised: April 12, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acscatal.7b00362
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functional groups, particularly given the need for earth-
abundant complexes tolerant of such functionalities. Pursuant
to this end, we investigated the hydroboration of 5-hexen-2-one
as a model substrate. Gratifyingly, hydroboration with
pinacolborane proceeded with anti-Markovnikov selectivity at
the alkene at room temperature, with no evidence of ketone
hydroboration. The use of an air-stable CoIII analogue,
Table 1. Substrate Scope for the Hydroboration of Alkenes
and Nitriles
(
DIPPCCC)CoCl2py,26 was also successful with the addition of
NaHBEt3 or TMSCH2Li activators, albeit in reduced yield. A
recent report by Thomas and co-workers,27 published during
the preparation of this paper, led us to also investigate the use
of sodium tert-butoxide as an activator. Although the target
product was obtained, the presence of a significant impurity
precluded the use of this method with our catalytic system.
Finally, optimization of catalytic loading led us to select 2.5 mol
% of CoI catalyst for catalytic reactivity (Table S1 in the
Supporting Information).
Following the determination of catalytic conditions, we
sought to investigate the substrate scope of the cobalt catalyst
(Table 1). The hydroboration of 1-octene and styrene
proceeded in excellent yield, furnishing the anti-Markovnikov
product in both cases with no evidence of dehydrogenative
borylation. The hydroboration of 4-vinylcylohexene, a substrate
bearing both an internal alkene and a terminal alkene,
proceeded selectively at the terminal alkene position, with
complete retention of the internal olefin (2d). More sterically
hindered substrates were not amenable to the hydroboration
protocol. The hydroboration of limonene, a gem-disubstituted
alkene, did not result in any detectable conversion, while the
hydroboration of cyclohexene resulted in only trace product
formation after 17 h, highlighting the steric influence on the
selectivity observed. This sensitivity to steric effects was
previously observed in the hydrosilylation protocol established
with this CoI system and has been observed with the PNN
pincer Co system used by Huang.11
Informed by the steric constraints of the catalytic system and
given the difficulties associated with 1,2-selective additions to
conjugated dienes,28 we turned to the hydroboration of
isoprene (2e), a conjugated diene bearing both a gem-
disubstituted alkene and a monosubstituted alkene. Addition
was 1,2-selective across the less-substituted olefinic bond, as
previously observed in our hydrosilylation studies. Such
examples of 1,2-hydroboration with cobalt or iron catalysts
are uncommon.29 Although Ritter reported the 1,4-hydro-
boration of conjugated dienes with an iron iminopyridine
catalyst,8 the analogous 1,2-addition has rarely been realized
with iron or cobalt catalysts, given the thermodynamic
favorability of π-allyl intermediates.28 Indeed, with few
exceptions, general reports of 1,2-addition with conjugated
dienes are infrequent.
Extension of the catalytic protocol to alkenes bearing oxygen-
containing functional groups proved to be similarly successful.
Allyl ethers, esters, and epoxides were found to be compatible
with the catalyst, with no evidence of competing dehydrogen-
ative borylation pathways. Addition across carbonyl moieties,
with substrates such as 5-hexen-2-one (2a) and 2-allylcyclohex-
enone (2f), was not detected under these conditions.
with no concomitant formation of the N-borylated amine. To
the best of our knowledge, the catalytic compatibility of
unprotected amines has only been reported for a single iron
hydroboration catalyst,21 while the use of such substrates has
not been previously realized with a cobalt system. Interestingly,
the corresponding reaction with 4-aminostyrene, a primary
amine, did not result in the formation of the target
organoboronate ester, suggesting that the observed chemo-
selectivity may be sterically modulated.
Seeking to further probe the chemoselectivity of the
(
DIPPCCC)CoN2 system, the hydroboration of 4-pentenenitrile
was attempted. In contrast to the exclusive alkene selectivity
observed in the hydrosilylation protocol for this catalyst,25 two
organoboronate products corresponding to single and double
additions of borane to the substrate, respectively, were detected
by GC-MS. Intrigued by this reactivity, we sought to investigate
the viability of nitrile reduction. Although such reductions can
be accomplished stoichiometrically, established protocols
typically require the use of LiAlH4 and NaBH4 reagents,
which generate large quantities of inorganic side products.30,31
Encouraged by the tolerance of oxygen-containing functional
groups, we turned our attention to the hydroboration of
amines. The hydroboration of 9-vinylcarbazole with pinacol-
borane proceeded in 80% yield, as assayed by 1H NMR
spectroscopy, after 1 h. Interestingly, N-allylaniline, a secondary
amine, was also tolerated under the hydroboration protocol
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DOI: 10.1021/acscatal.7b00362
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The development of catalytic reduction strategies with
hydrogen is also restricted, often requiring the use of poorly
selective heterogeneous catalysts or the use of highly energetic
conditions.32 Current strategies, developed by Beller,33,34
Milstein,35,36 Sabo-Etienne,37 and others promise to mitigate
some of these challenges but reports are otherwise limited.32
Alternate strategies featuring the use of silanes or boranes for
the reduction of nitriles have gained traction, however. Recent
reports by Szymcak38 and Hill39 have demonstrated homoge-
neous reductions of nitriles using boranes. However, such
hydroborations with first-row transition metals remain rare. As
such, a cobalt catalyst is an attractive option for the reduction of
nitriles, particularly since current strategies are mostly limited
to the use of noble-metal catalysts.32
Initial investigations into the reduction of nitriles (Table 1)
made use of simple aliphatic nitriles (3a,b). Heating a mixture
of 1, pinacolborane, and butyronitrile at 70 °C in benzene
afforded the desired bis(borylated) amine, as detected by GC-
MS. Subsequent workup of the reaction mixture led to the
isolation of the corresponding ammonium salt in good yields
(3a). The reduction of acetonitrile was similarly successful,
furnishing ethylammonium chloride in excellent yield following
workup. To our delight, extension of the protocol to aromatic
nitriles (3c−e) also furnished the corresponding ammonium
salts upon isolation, demonstrating a tolerance for thiophene
moieties (3d), as well as a fluorinated arene (3e).
observed; deuterium is incorporated at both the α and β
carbons of the alkylboronate ester product. Additionally, the
exclusive generation of the linear alkylboronate ester product,
rather than a combination of the branched and linear products,
suggests liberation of product immediately follows 1,2-
insertion: i.e., β-hydride elimination from this insertion mode
is not competitive with elimination of the target organo-
boronate ester while 2,1-insertion is not a productive pathway
to the formation of alkylboronate ester product.
The susceptibility of 2,1-insertion products to β-hydride
elimination and the general lack of turnover observed for this
insertion mode may be a result of the substantial steric
shielding of the generated secondary alkyl cobalt intermediates,
which may preclude elimination with a boryl ligand to give the
target compound. The inactivity of this cobalt system toward
more substituted terminal alkenes is also consistent with this
possibility, as greater substitution at the substrate would
provide significant steric limitations even in the event of a 1,2-
insertion. To test this hypothesis, the addition of deuterated
pinacolborane to cyclohexene, a substrate that generates only
trace amounts of product after 24 h of stirring, was investigated.
Although incorporation into the olefinic bond was not observed
after 6.5 h of stirring, minor deuterium incorporation at the
adjacent aliphatic carbons suggests an alkene-isomerization-
type event, where insertion into the olefin is followed by β-
hydride elimination from a proximal carbon to generate a
deuterium-enriched cyclohexene. Importantly, the absence of
the observed organoboronate product suggests that the
generated secondary alkyl intermediate is unreactive toward
turnover, in stark contrast to primary alkyl cobalt intermediates
which can proceed along the reaction sequence. Interestingly,
stirring the reaction mixture over a longer period (7 days) does
eventually result in deuterium incorporation at all sites of the
cyclohexene substrate, including the olefinic carbons.
Interested in obtaining further insights into hydroboration
with the (DIPPCCC)CoI platform, we turned to labeling
experiments with deuterated pinacolborane. Upon reacting
styrene with 1 equiv of deuterated pinacolborane, we observed
deuterium incorporation into the targeted linear alkylboronate
ester product at both the terminal and benzylic positions in
approximately equal proportion (Figure 1). Moreover,
Intrigued by this result, we sought to study these putative
alkene isomerization events in greater detail. Accordingly, the
hydroboration of the internal alkene trans-4-octene, a substrate
with sterically differentiable primary and secondary alkyl sites,
with deuterated pinacolborane was investigated. Deuterium
incorporation was observed along the length of the substrate,
consistent with alkene isomerization. In contrast to cyclo-
hexene, however, minor resonances corresponding to the linear
alkylboronate ester product were also observed in the 2H NMR
spectrum, indicating that, upon isomerization to the more
sterically accessible termini of the octyl chain, i.e. upon
formation of a primary alkyl cobalt intermediate, liberation of
the alkylboronate ester is viable. Given the profile of the
cyclohexene substrate, i.e. any insertion or hydrocobaltation
step necessarily generates a sterically hindered cobalt−-
secondary alkyl intermediate, the opportunity to generate the
analogous alkylboronate is rendered far less likely and the
catalysis is effectively arrested at the insertion step.
In addition to providing a rationale for the observed
regioselectivity, these data may also explain some of the
chemoselectivity observed for this catalyst platform. The
reduction of a ketone functionality, for example, may be
disfavored given the steric profile of the insertion product. By
extension, reducible functionalities such as esters and
substituted amines should also be, and are, tolerated,
particularly in the presence of a more sterically accessible
terminal alkene that is amenable to reduction with borane. The
competing reductions of the formyl group in 2,2-dimethyl-4-
pentenal (2n) and the nitrile moiety in 4-pentenenitrile (2m)
2
Figure 1. H NMR spectrum of the hydroboration of styrene.
deuterium resonances corresponding to incorporation at vinylic
positions of the styrene starting material were also detected.
These observations are consistent with the intermediacy of a
cobalt hydride over the course of catalysis, as well as β-hydride
elimination processes to regenerate alkene substrate. The
absence of a deuterium resonance at 6.57 ppm, corresponding
to the vinylic proton at the benzylic position of the styrene
substrate, suggests that 1,2-insertion is immediately followed by
liberation of the targeted boronate ester while 2,1-insertion is
reversible and not productive toward the formation of product,
as only the linear alkylboronate ester is formed. This process is
generalizable to non-vinylarene substrates. Upon reaction of 1-
octene with deuterated pinacolborane in the presence of the
cobalt catalyst, evidence of both 2,1- and 1,2-insertions is
3732
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are also expected, as these reducible functionalities are sterically
accessible and would generate insertion products with a steric
profile comparable to that of monosubstituted terminal alkenes.
Informed by these insights and given the similarities to a
processes underpin the regioselectivity, and perhaps the
chemoselectivity, of the system, as the generation of primary
alkyl intermediates over the course of catalysis is required to
liberate the alkylboronate esters.
hydrosilylation protocol previously reported for this system,25
a
ASSOCIATED CONTENT
mechanism was proposed for the observed reactivity (Figure 2).
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.7b00362.
Spectral data and synthesis details for complexes 2a−k
and 3a−e (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.R.F.: fout@illinois.edu.
■
ORCID
Alison R. Fout: 0000-0002-4669-5835
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support for this work was provided by the NSF
(13151961), and A.R.F. is an Alfred P. Sloan Research Fellow.
■
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