Cobalt(I)-Catalyzed Borylation of Unactivated Alkyl Bromides and Chlorides

Article abstract of DOI:10.1021/acs.orglett.0c00038

A cobalt-complex-catalyzed borylation of a wide range of alkyl halides with a diboron reagent (B₂pin₂ or B₂neop₂) has been developed under mild reaction conditions, demonstrating the first cobalt-mediated cross-coupling with alkyl electrophiles. This protocol allows alkyl boronic esters to be accessed from alkyl halides, including alkyl chlorides, which were used rarely as coupling partners. Mechanistic studies reveal the possible involvement of an alkyl radical intermediate in this cobalt-mediated catalytic cycle.

Full text of DOI:10.1021/acs.orglett.0c00038

pubs.acs.org/OrgLett
Letter
Cobalt(I)-Catalyzed Borylation of Unactivated Alkyl Bromides and
Chlorides
Piyush Kumar Verma, K. Sujit Prasad, Dominic Varghese, and K. Geetharani*
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ABSTRACT: A cobalt-complex-catalyzed borylation of a wide range of alkyl
halides with a diboron reagent (B2pin2 or B2neop2) has been developed under mild
reaction conditions, demonstrating the first cobalt-mediated cross-coupling with
alkyl electrophiles. This protocol allows alkyl boronic esters to be accessed from
alkyl halides, including alkyl chlorides, which were used rarely as coupling partners.
Mechanistic studies reveal the possible involvement of an alkyl radical intermediate
in this cobalt-mediated catalytic cycle.
ver the past few decades, the synthetically useful
organoboron-containing compounds have become a
some of them remain limited in electrophile scope, with
expensive catalysts and ligands, providing ample incentive to
develop a more general strategy.
O
workhorse for the construction of carbon−carbon bonds via
the Suzuki−Miyaura cross-coupling reaction.1 Of relevance,
alkylboronic esters have a broad range of applications in
medicinal chemistry2 and in the field of organic synthesis.3 A
classical approach for the synthesis of alkyl boronic ester
derivatives includes transmetalation with organolithium/
magnesium reagents with compatible boron reagents,4 hydro-
boration of olefins,5 β-borylation of α,β-unsaturated carbon-
yls,6 or via the C−H activation of alkanes.7 Transition-metal-
catalyzed direct borylation of the C−X bond of alkyl halides
represents one of the efficient and most straightforward
strategies to access alkylboronic esters. In recent years, several
reports on transition-metal-catalyzed borylation with Pd,8 Ni,9
Cu,10 Zn,11 Fe,12 and Mn13 for alkyl halides borylation
(Scheme 1a) have been documented. Very recently,
Melchiorre’s and Mo’s groups reported the transition-metal-
free borylation of alkyl halides under photochemical and base-
assisted conditions, respectively.14 Although such approaches
are well-established for the synthesis of alkylboronic esters,
In view of the high abundance of cobalt in the Earth’s crust,
its low cost, and low toxicity, the potential benefits of its
complexes as practical catalysts in various homogeneous
catalytic reactions are significantly explored. In particular,
there are several reports detailing the application of cobalt
complexes in the borylation reactions by the groups of Chirik,
Marder, Ge, Huang and others.15 However, despite these
advances, cobalt-catalyzed borylation of alkyl halides has not
been explored yet. Based on our recent findings on the Co-
based system, which provides a platform for the synthesis of
aryl boronic esters using less reactive aryl chlorides, we sought
to explore the possibility of a cobalt-catalyzed alkyl halide
borylation reaction.16 Herein, we describe a mild Co-catalyzed
method for the selective borylation of unactivated primary,
secondary, and few tertiary alkyl halides (Scheme 1b). This
process can be extended to the unactivated alkyl chlorides and
shows a broad substrate scope and functional group
compatibility.
On the basis of our previous studies on the cobalt-catalyzed
aryl halide borylation, we first attempted the borylation of 1-
bromo-3-phenyl propane, 1a, using [Co(IMes)2Cl2] (I; IMes
= 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) as a cata-
lyst. The GC-MS analysis of the reaction mixture shows the
borylated product 3a in 43% yield, along with the formation of
hydrodehalogenated (propyl benzene) and homo coupled
(1,6-diphenylhexane) byproducts (see the Supporting In-
formation (SI), experiment S1 for more details). Then we
Scheme 1. Transition-Metal-Catalyzed Borylation of
Unactivated Alkyl Halides
Received: January 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00038
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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examined the catalytic performance of the cobalt(I) complex
[Co(IMes)2Cl] which exhibited comparable activity to that of
I. Deng and co-workers reported that [Co(IMes)2Cl] can be
prepared by the addition of 2 equiv of IMes to [Co(PPh3)3Cl]
(A).17
Scheme 2. Substrate Scope of Co-Catalyzed Borylation of
Unactivated Alkyl Bromides
a
Hence, for operational simplicity and practicality, we
decided to use 5 mol % of [Co(PPh3)3Cl] A as the precatalyst.
Notably, when A was examined as a catalyst, it produced 3a in
29% yield (Table 1, entry 1), whereas the cobalt catalyst A in
Table 1. Optimization of Reaction Conditions for the
Borylation of 1-Bromo-3-phenyl Propane (1a) Catalyzed by
a
Cobalt Complex
b
entry
ligand
base
solvent
yield
29
49
96
76
42
12
36
1
2
3
4
5
6
7
8
−
KOMe
KOMe
KOMe
KOtBu
NaOtBu
LiOtBu
LiOMe
NaOEt
−
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
THF
CPME
Hexane
Toluene
Benzene
MTBE
IMes
ICy
ICy
ICy
ICy
ICy
ICy
ICy
ICy
ICy
ICy
ICy
ICy
ICy
c
>99 (92)
trace
68
9
10
11
12
13
14
35
91
48
>99
>99
d
15
a
Reactions were performed with 0.2 mmol of alkyl halide, 0.26 mmol
of B2pin2 and base, 5 mol % Co(PPh3)3Cl, and 10 mol % of ligand at
b
50 °C in 2 mL of solvent unless otherwise mentioned. Yields were
a
determined by NMR spectroscopy using nitromethane as an internal
Reactions were performed with 1.0 mmol of alkyl halide, 1.3 mmol
c
d
standard. Yield of the isolated product. 2 mol % Co(PPh3)3Cl and 4
mol % of ICy ligand were used. MTBE = methyl tert-butyl ether;
CPME = cyclopentyl methyl ether.
of B2pin2 and NaOEt, 2 mol % of Co(PPh3)3Cl, and 4 mol % of ICy
in MTBE as a solvent at 50 °C unless otherwise mentioned. Yields
determined by NMR spectroscopy using nitromethane as an internal
b
standard were given in parentheses. Using 1.1 equiv of B2pin2 and
c
d
NaOEt. Reaction was performed for 24 h. Reaction was performed
using 1.3 equiv of B2cat2 as the boron reagent, followed by
transesterification with pinacol.
the presence of 10 mol % of IMes as a ligand, KOMe as a base,
and B2pin2 (2, bis(pinacolato)diboron) as the boron source
gave the desired alkylboronic ester 3a in 49% yield (entry 2).
However, when 10 mol % of ICy (1,3-bis(cyclohexyl)imidazol-
2-ylidene) was used as a ligand, a significant increase in the
yield of 3a (96%) was observed (entry 3). Other bases, such as
KOtBu, NaOtBu, LiOtBu, and LiOMe, resulted in a decrease in
the desired product yields (entries 4−7). An excellent yield
was obtained when NaOEt was used as a base (3a = >99%
yield; entry 8). A controlled experiment established that the
base is essential for the reaction to proceed (entry 9). The use
of other solvents, such as THF, CPME (cyclopentyl methyl
ether), hexane, and toluene, were less effective (entries 10−
13). However, reaction in benzene gave a comparable yield of
3a (>99%, entry 14). By using 2 mol % of [Co(PPh3)3Cl] and
4 mol % of ICy, the borylated product 3a was obtained in
>99% yield (entry 15).
(1a−1c) were able to produce the alkylboronate products in
good yields. Borylation of substrates having ether substituents,
such as (2-bromoethoxy)benzene (1d), 1-(3-bromopropyl)-4-
methoxybenzene (1e), 2-(2-bromoethyl)-1,3-dioxane (1f),
silylether (1g), and 1-bromo-2-methoxyethane (1i), afforded
excellent yields of the corresponding alkylboronic esters (3d−
3g and 3i).
Many other synthetically important functional groups, such
as CF3 (1h), esters (1j), and hydroxyl (1k) were well tolerated
and gave the desired products in moderate to good yields. The
alkyl halide having a heterocycle is also amenable to the
borylation reaction, furnishing boronate product 3l in 66%
yield. It is noteworthy that the catalyst showed excellent
selectivity for the bromo- group over the chloro- group (1m)
to produce (3m) exclusively, using 1.1 equiv of B2pin2 and
NaOEt. Similar to primary alkyl halides, secondary alkyl
bromides were also borylated in excellent yields, albeit with a
Having the optimized conditions in hand, we evaluated a
series of alkyl bromides to determine the substrate scope. As
illustrated in Scheme 2, several acyclic primary alkyl bromides
B
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slightly longer reaction time (24 h). The borylation of
bromocyclopentane (1n) and bromocyclohexane (1o) pro-
ceeded smoothly, affording the alkylboronates in good-to-
excellent yields. In addition, sterically demanding exo-2-
bromonorborane (1p) reacted to give the borylation product
(3p) in excellent yield (86%). The reaction proceeded well in
the case of an alkyl halide with a protected amine group (1q).
Interestingly, the reaction of cyclohexenyl bromide (1r)
exclusively produced the alkyl halide borylation product (3r),
leaving the olefin moiety intact.
Scheme 3. Substrate Scope of Co-Catalyzed Borylation of
Unactivated Alkyl Chlorides
a
To date, very few examples exist for the borylation of tertiary
halides. For instance, Fu and co-workers developed a nickel-
based method9a and Cook and co-workers developed iron-12a
and manganese-based methods,13 which offer the only
examples beyond 1-bromoadamantane.10g,11 Our method
enables the borylation of 1-bromoadamantane (1s) using
B2cat2 as a diboron reagent, giving an excellent yield of 3s.
However, the reaction of (3-bromo-3-methylbutyl)benzene
(1t) gave a lower yield of 3t (24%). Even a higher temperature,
longer reaction time, and change in the optimized NHC to less
sterically hindered IMe (1,3-dimethylimidazol-2-ylidene) did
not improve the reaction outcome.
Next, we investigated the compatibility of alkyl chloride
using this cobalt system, since the examples of borylation of
unactivated alkyl chlorides remain rare. To date, only two
systems exist for the direct borylation of alkyl chlorides,
allowing access to a range of alkyl boronic esters. The Mn-
based system was developed by Cook et al. for the borylation
of alkyl chlorides, using 1.3 equiv of the Grignard reagent,
EtMgBr.13 Subsequently, Marder et al. reported a Cu(II)−
NHC catalytic system for the borylation of alkyl chlorides.10g
Further, Ito et al. has also reported the copper-catalyzed
borylation of alkyl halides, but only with two examples of alkyl
chlorides.10b When the reaction of 4a was performed using
B2pin2 as a boron source, the alkylboronate 3a was obtained in
only 21% yield, together with a trace amount of hydro-
dehalogenation byproduct. A brief optimization revealed
B2neop2 (5, bis(neopentylglycolato)diboron) as the boron
reagent successfully affording alkyl boronates in good yields
(Scheme 3). The alkyl chlorides bearing acyclic substituents
(4a−4c) reacted well to afford the desired products 6a−6c in
good yields. The reaction proceeded well in the presence of
heterocycles (4d−4f) and produced the corresponding
borylated products in moderate to good yields. Silylether
(4g) as a functional group furnished the desired boronate ester
in good yield (63%). Reaction with secondary alkyl chlorides,
such as cyclohexyl chloride (4h) and acyclic chloride (4i),
proceeded smoothly to furnish the borylation products 6h in
83% yield and 6i in 76% yield. The tertiary alkyl chloride, 1-
chloroadamentane (4j), also readily participated in the reaction
and provided the desired product 3s in good yield (76%).
However, similar to the tertiary bromide 1t, tertiary chloride
4k produced inferior results. It should be also noted that gram
scale reactions of 1a proceeded smoothly to produce 89% of
the isolated borylated product 3a, under the optimized
reaction conditions.
a
Reactions were performed with 1.0 mmol of alkyl chloride, 1.3 mmol
of B2neop2 and NaOEt, 2 mol % Co(PPh3)3Cl, and 4 mol % of ICy in
MTBE as a solvent at 50 °C unless otherwise stated. Yields
determined by NMR spectroscopy using nitromethane as internal
standard were given in parentheses. Reaction was performed using
1.3 equiv of B2cat2 as the boron reagent, followed by trans-
b
esterification with pinacol.
product of toluene; Scheme 4). However, when the reaction
was performed in the absence of 1a, using toluene as a solvent,
Scheme 4. Borylation of 1-Bromo-3-Phenyl Propane (1a) in
Toluene as a Solvent
formation of PhCH2Bpin was not observed, which eliminates
the possibility of the benzylic C−H bond activation of toluene
(see SI, experiment S2-b).18 These results suggest that the
alkyl halide might be the source for the benzyl radical in this
cobalt-mediated catalytic reaction.9,19
Further, to explore the possibility of a radical-mediated
process, the borylation reaction was performed using 6-
bromohex-1-ene that exclusively afforded the cyclized product
cyclopentylmethylboronate (Scheme 5, entry 1). Similar
results were reported for Mn-,13 Zn-,11 and Cu-catalyzed
systems.10a,g Similarly, the reaction of (bromomethyl)-
cyclopropane produced an acyclic isomeric mixture of
borylated products under standard reaction conditions
(Scheme 5, entry 2). The intermediacy of alkyl radicals was
further tested using TEMPO (2,2,6,6-tetramethylpiperidine 1-
oxyl) and 1,10-dihydroanthracene as radical trapping reagents.
When the substrate 1a was subjected to standard reaction
conditions in the presence of TEMPO (1 equiv), the adduct,
3-phenyl-1-(2′,2′,6′,6′-tetramethyl-1′-piperidinyloxy)-propane
was obtained and no 3a was observed (entry 3). Similarly,
At the outset of the mechanistic investigation, we speculated
the possibility of a radical based mechanism, since we observed
a significant drop in the yield of 3a, when the reaction was
performed in toluene as a solvent (Table 1, entry 13). The
GC-MS analysis of the crude reaction mixture revealed the
formation of 3a, propyl benzene (hydrodehalogenation
byproduct), and PhCH2Bpin (benzylic C−H borylation
C
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Scheme 5. Mechanistic Investigations of Co-Catalyzed
Borylation of Unactivated Alkyl Halides on a Radical
Mediated Process
AUTHOR INFORMATION
Corresponding Author
■
K. Geetharani − Department of Inorganic and Physical
Chemistry, Indian Institute of Science, Bangalore 560012,
India; orcid.org/0000-0003-2064-1297;
Email: geetharani@iisc.ac.in
Authors
Piyush Kumar Verma − Department of Inorganic and Physical
Chemistry, Indian Institute of Science, Bangalore 560012, India
K. Sujit Prasad − Department of Inorganic and Physical
Chemistry, Indian Institute of Science, Bangalore 560012, India
Dominic Varghese − Department of Inorganic and Physical
Chemistry, Indian Institute of Science, Bangalore 560012, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00038
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.G. is thankful for funding from the SERB (EMR/2016/
000367), DST inspire faculty award (DST/INSPIRE/04/
2015/000785), and Indian Institute of Science (IISc) start-up
research grant. P.K.V. thanks IISc Bangalore for a research
fellowship. D.V. thanks Kishore Vaigyanik Protsahan Yojana
(KVPY) for a fellowship. We also thank Prof. S. Ramakrishnan,
IISc Bangalore for the GC-MS analysis and the AllyChem Co.
Ltd., China for a gift of B2pin2 and B2neop2.
when 1,10-dihydroanthracene was used under standard
borylation conditions, the yield of 3a reduced to 28%, and
14% of anthracene formation was observed (entry 4). All these
observations are consistent with the hypothesis that a radical
intermediate is involved in the oxidative-addition step.9,12a
Furthermore, several additional experiments were performed
in order to elucidate the composition of the active catalyst.
Since ICy was used as a ligand for this transformation, to
examine the possibility of the in situ formation of the
[Co(ICy)3Cl]20 complex, and it serving as an active catalyst
for this transformation, we explored the catalytic reaction using
1a as a substrate, which produced only a 28% yield of 3a.
Attempts to synthesize the pure form of the active catalyst
through the reaction of [Co(PPh3)3Cl] with 2 equiv of the ICy
ligand was unsuccessful. Therefore, further studies are needed
for a full explanation of the reaction mechanism.
In summary, we have developed a novel and efficient
borylation reaction of alkyl halides, including the effective
couplings of unactivated alkyl chlorides, catalyzed by a
cobalt(I) complex to produce alkyl boronic esters. To the
best of our knowledge, this is the first reported catalytic
procedure to synthesize alkylboronates using cobalt as a
catalyst. The reaction is mild and efficient, thereby making this
an attractive methodology for the preparation of alkylboronic
esters with diverse functional groups. In view of the remarkable
diversity of alkylboronates, we anticipate that our strategy and
discovery could expand the development of versatile catalysts
for a wide range of cross-coupling processes.
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