Mechanistic Studies of Cobalt-Catalyzed C(sp2)-H Borylation of Five-Membered Heteroarenes with Pinacolborane

Article abstract of DOI:10.1021/acscatal.7b01151

Studies into the mechanism of cobalt-catalyzed C(sp²)-H borylation of five-membered heteroarenes with pinacolborane (HBPin) as the boron source established the catalyst resting state as the trans-cobalt(III) dihydride boryl, (^iPrPNP)Co(H)₂(BPin) (^iPrPNP = 2,6-(ⁱPr₂PCH₂)₂(C₅H₃N)), at both low and high substrate conversions. The overall first-order rate law and observation of a normal deuterium kinetic isotope effect on the borylation of benzofuran versus benzofuran-2-d₁ support H₂ reductive elimination from the cobalt(III) dihydride boryl as the turnover-limiting step. These findings stand in contrast to that established previously for the borylation of 2,6-lutidine with the same cobalt precatalyst, where borylation of the 4-position of the pincer occurred faster than the substrate turnover and arene C-H activation by a cobalt(I) boryl is turnover-limiting. Evaluation of the catalytic activity of different cobalt precursors in the C-H borylation of benzofuran with HBPin established that the ligand design principles for C-H borylation depend on the identities of both the arene and the boron reagent used: electron-donating groups improve catalytic activity of the borylation of pyridines and arenes with B₂Pin₂, whereas electron-withdrawing groups improve catalytic activity of the borylation of five-membered heteroarenes with HBPin. Catalyst deactivation by P-C bond cleavage from a cobalt(I) hydride was observed in the C-H borylation of arene substrates with C-H bonds that are less acidic than those of five-membered heteroarenes using HBPin and explains the requirement of B₂Pin₂ to achieve synthetically useful yields with these arene substrates.

Full text of DOI:10.1021/acscatal.7b01151

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Article
Mechanistic Studies of Cobalt-Catalyzed C(sp2)-H Borylation
of Five-Membered Heteroarenes with Pinacolborane.
Jennifer V. Obligacion, and Paul J. Chirik
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 17 May 2017
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ACS Catalysis
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Mechanistic Studies of Cobalt-Catalyzed C(sp2)-H Borylation of Five-
Membered Heteroarenes with Pinacolborane.
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Jennifer V. Obligacion and Paul J. Chirik*
Department of Chemistry, Princeton University, New Jersey 08544, United States
ABSTRACT: Studies into the mechanism of cobalt-catalyzed C(sp2)-H borylation of five-membered heteroarenes with
pinacolborane (HBPin) as the boron source established the catalyst resting state as the trans-cobalt(III) dihydride boryl,
(
iPrPNP)Co(H)2(BPin) (iPrPNP = 2,6-(iPr2PCH2)2(C5H3N)), at both low and high substrate conversions. The overall first
order rate law and observation of a normal deuterium kinetic isotope effect on the borylation of benzofuran versus benzo-
furan-2-d1 support H2 reductive elimination from the cobalt(III) dihydride boryl as the turnover-limiting step. These find-
ings stand in contrast to that established previously for the borylation of 2,6-lutidine with the same cobalt pre-catalyst,
where borylation of the 4-position of the pincer occurred faster than the substrate turnover and arene C-H activation by a
cobalt(I) boryl is turnover limiting. Evaluation of the catalytic activity of different cobalt precursors in the C-H borylation
of benzofuran with HBPin established that the ligand design principles for C-H borylation depend on the identities of
both the arene and the boron reagent used: electron-donating groups improve catalytic activity of the borylation of pyri-
dines and arenes with B2Pin2 while electron-withdrawing groups improve catalytic activity of the borylation of five-
membered heteroarenes with HBPin. Catalyst deactivation by P-C bond cleavage from a cobalt(I) hydride was observed in
the C-H borylation of arene substrates with C-H bonds that are less acidic than those of five-membered heteroarenes us-
ing HBPin and explains the requirement of B2Pin2 to achieve synthetically useful yields with these arene substrates.
Keywords: borylation, C-H activation, pinacolborane, mechanism, cobalt
of second-generation catalysts where methyl and pyrroli-
dinyl groups were installed in the 4-position of the pincer
to block unwanted borylation and increase the electron
INTRODUCTION
Transition metal catalyzed arene C(sp2)-H borylation1
has emerged as one of the most widely used C-H func-
density of the cobalt center (Scheme 1).8a The increased
tionalization reactions, both in academia2 and industry3,
activity of these catalysts was applied the borylation of
due to the versatility of the resulting products. While
fluoroarenes where unprecedented levels of selectivity for
highly predictable chemo- and regioselectivities are ob-
sites ortho to fluorine were observed and used in a
streamlined synthesis of the anti-inflammatory drug,
served in these functionalizations using iridium catalysis,
the high cost and low natural abundance of precious met-
Flurbiprofen.9
al catalysts motivate the search for base metal alternatives
that exhibit superior or complementary selectivity in the
Scheme 1. Influence of Arene and Boron Source on
C(sp2)-H borylation of arenes. In ongoing efforts toward
the Mechanism of Cobalt-Catalyzed C(sp2)-H Boryla-
this aim,4 our laboratory5 and others6 have explored earth
tion.
abundant first row transition metal catalysts for the
C(sp2)-H borylation of arenes. Among these, cobalt com-
plexes bearing bis(phosphino)pyridine (iPrPNP) ligands7
are some of the most active and synthetically useful.5a
Our recent mechanistic investigations on the borylation
of
(
pyridines
and
unactivated
arenes
with
iPrPNP)CoCH2SiMe3 (Scheme 1) as the pre-catalyst and
bis(pinacolato) diboron (B2Pin2) as the boron reagent es-
tablished a Co(I)-Co(III) redox couple with turnover-
limiting C-H activation promoted by a cobalt(I) boryl.8a
However, under these conditions, borylation of the 4-
position of the pincer ligand of the cobalt catalyst oc-
curred prior to turnover, rendering the metal relatively
electron poor and slowing the rate of oxidative addition of
the arene C-H bond. These findings inspired the synthesis
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served as the catalyst resting state during the C(sp2)-H
Previous work (ref 8): Using B2Pin2
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borylation of 2-methylfuran with HBPin at 23 C. The data
were collected at 1 hour of reaction time, corresponding
to approximately 12% conversion.5a Monitoring the pro-
gress of the catalytic reaction over the timescale required
for complete conversion has since been carried out using
BPin
N
3 mol% (iPrPNP)CoCH2SiMe3
80 °C, THF
- HBPin
+
B2Pin2
N
C-H activating species:
Slow step
Catalyst design principle
(
iPrPNP)CoCH2SiMe3 as the pre-catalyst. 2-Methylfuran
PiPr2
PiPr2
was selected as the substrate because Co-catalyzed
borylation of this arene with HBPin occurred at a rate
that was conveniently monitored by P NMR spectrosco-
C-H oxidative
addition
N
Co BPin
PiPr2
N
N
Co BPin
PiPr2
PinB
31
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py.
As
shown
in
Figure
1,
only
trans-
electron-donating
blocking group
(
iPrPNP)Co(H)2BPin5a,8 was detected over the course of
the reaction and neither 4-BPin-(iPrPNP)Co(N2)BPin8a
nor 4-BPin-(iPrPNP)Co(H)2BPin8a was observed, demon-
strating that the 4-position of the pincer does not under-
go competitive borylation with the substrate.
This work: Using HBPin
1 mol% (iPrPNP)CoCH2SiMe3
O
O
23 °C, THF
- H2
BPin
+
HBPin
Having identified the catalyst resting state, attention
was devoted to elucidating the identity of the cobalt com-
pound responsible for activation of the C(sp2)-H bond.
The catalyst resting state, trans-(iPrPNP)Co(H)2BPin, is
coordinatively saturated (an 18-electron Co(III) com-
pound) and likely requires either the reductive elimination
of two of its anionic ligands (-H or -BPin) or the dissocia-
tion of one of its neutral ligands (pyridine or phosphine)
to open a coordination site for C-H bond activation. Path-
ways involving reductive elimination of either H2 or HBPin
seem the most plausible as Co(I)- Co(III) redox cycles are
amply precedented in [(PNP)Co] chemistry.8a,22,23 As pre-
sented in Scheme 2, the “hydride pathway” generates
C-H activating species?
Slow step?
Catalyst design principle?
Catalytic arene C-H borylation methods that can em-
ploy HBPin as the stoichiometric boron source are partic-
ularly attractive due to their improved atom economy
over variants that require B2Pin2. However, despite the
mature understanding of the mechanisms of iridium-10-16
and cobalt-catalyzed C(sp2)-H borylation using B2Pin2 as
the boron reagent,8 open questions remain about the op-
erative pathways in cobalt-catalyzed reactions when
HBPin is used as the stoichiometric boron source. With
(iPrPNP) cobalt pre-catalysts, the success of the catalytic
C-H borylation depends on the stoichiometric boron
source. While HBPin is an effective reagent for the boryla-
tion of five-membered heteroarenes, it is far less effective
with pyridines and unactivated arenes. Obtaining insights
into the turnover limiting step and nature of catalyst de-
activation pathways in this class of C-H functionalization
reaction is crucial for the rational design of next genera-
tion catalysts. Information on the speciation of iridium,17,18
ruthenium,19 iron,6a,6d heterobimetallic copper,6c,20 and
frustrated Lewis pair (FLP)21 catalysts in the presence of
HBPin have been reported, however, the turnover-
limiting step and possible catalyst deactivation pathways
have not been identified and principles for future catalyst
development are not evident.
Here we describe a detailed study of the mechanism of
cobalt-catalyzed C-H borylation of five-membered het-
eroarenes using HBPin as the borylating reagent. The cat-
alyst resting state, identity of the C-H activating species,
and the turnover-limiting step have been identified and
these findings demonstrate that the catalyst design prin-
ciples used for optimal performance differ depending on
the identity of the arene and boron reagent used. Catalyst
deactivation pathways for the C-H borylation of pyridines
and unactivated arenes with HBPin were also identified
and provide insight why HBPin is ineffective for these
substrates and why B2Pin2 is necessary for successful C-H
borylation.
(
iPrPNP)CoH following reductive elimination of HBPin
while the alternative “boryl pathway” involves H2 loss to
access (iPrPNP)CoBPin, analogous to the intermediate
responsible for C-H activation during the borylation of
2,6-lutidine with B2Pin2.8 Because of the trans disposition
of the hydride ligands in trans-(iPrPNP)Co(H)2BPin,
isomerization to the cis isomer either by phosphine disso-
ciation24 or HBPin reductive coupling is required to
achieve an appropriate geometry for H2 loss. Mechanistic
experiments were conducted to distinguish the hydride
and the boryl pathways (vide infra).
RESULTS AND DISCUSSION
Determination of the Catalyst Resting State. In our ini-
tial communication, trans-(iPrPNP)Co(H)2BPin was ob-
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1 mol% (iPrPNP)CoCH2SiMe3
O
O
O
O
Resting state:
Not observed:
23 °C, THF
BPin
BPin
+
+
HBPin
HBPin
- H2
PiPr2
H
PiPr2
N2
PiPr2
H
1 mol% (iPrPNP)CoCH2SiMe3
N
H
Co BPin
PinB
N
Co BPin PinB
N
H
Co BPin
23 °C, THF
- HD
D
PiPr2
PiPr2
PiPr2
8
9
Figure 1. 31P NMR spectrum of the reaction mixture of 2-
KIE = 1.9(1) at 23 °C (2 separate vessels)
methylfuran and HBPin in the presence of 10 mol% of
(
iPrPNP)CoCH2SiMe3 in benzene-d6 at 23 C. The peak at 103.2
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ppm in the 31P NMR spectrum corresponds to trans-
iPrPNP)Co(H)2BPin. aNMR yield of borylated product.
The experimental rate law for the C(sp2)-H borylation of
benzofuran with HBPin using (iPrPNP)CoCH2SiMe3 was
determined using the method of initial rates25 (Table 1)
with the goal of distinguishing the pathways in Scheme 2
and providing insight into the turnover limiting step of the
catalytic reaction.
(
Scheme 2. Possible Scenarios for the Generation of
the
(
C-H
Activating
Species
from
trans-
iPrPNP)Co(H)2BPin.
HBPin
Hydride pathway
H
Ar
Ar
H
[Co]
H
BPin
[Co]
H
[Co]
H
H
Table 1. Determination of the Rate Law of the Boryla-
tion of Benzofuran with HBPin.
H2
resting state
x equiv.
y equiv.
PiPr2
Boryl pathway
[Co]
BPin
H
z mol% (iPrPNP)CoCH2SiMe3
Ar
H
O
O
23 °C, THF
N
Co
[Co] =
Ar
[Co]
BPin
BPin
+
HBPin
- H2
PiPr2
[Benzofuran]
[HBPin]
[(iPrPNP)CoCH2SiMe3]
Initial rate (M/s)
0.13 M
0.13 M
0.13 M
0.26 M
0.13 M
0.13 M
0.26 M
0.13 M
6.7 x 10-4
1.3 x 10-3
1.3 x 10-3
1.3 x 10-3
M
M
M
M
7.0 ± 0.3 x 10-6
1.7 ± 0.1 x 10-5
1.7 ± 0.1 x 10-5
1.5 ± 0.2 x 10-5
Kinetic Isotope Effect (KIE) and Rate Law Measurements.
To determine whether C-H bond cleavage is involved in
the turnover-limiting step of the catalytic cycle, the kinetic
isotope effect was measured by comparison of the initial
rates25 (up to 10% conversion) for the C(sp2)-H borylation
of benzofuran and benzofuran-2-d1 measured in two sepa-
rate vessels. Benzofuran was chosen for the KIE and rate
law measurements due to its low volatility compared to 2-
methylfuran in order to avoid loss via evaporation during
the reaction. With 1 mol% of (iPrPNP)CoCH2SiMe3 as the
pre-catalyst with HBPin at 23 C, comparison of the rela-
tive initial rates of the two reactions yielded a normal,
primary deuterium kinetic isotope effect of 1.9(1) (Scheme
3). This value is lower than those measured for the cobalt-
catalyzed borylation of 2,6-lutidine (2.9(1) at 80 ºC)8a and
iridium-catalyzed borylation of 1,2-dichlorobenzene and
1,2-dichlorobenzene-d4 with B2Pin2 (3.3(6) at 25 ºC).10 In
both reported cases, KIEs of this magnitude support oxida-
tive addition of the C-H bond as the turnover-limiting step
during catalysis. The reduced magnitude of the KIE could
arise either from turnover limiting C-H bond activation
with an earlier or later transition state than the previously
reported examples or a from a change in turnover limiting
step.
rate = kobs[(iPrPNP)CoCH2SiMe3]1[benzofuran]0[HBPin]0
2.5E-05
2.0E-05
1.5E-05
1.0E-05
5.0E-06
0.0E+00
0.0E+00
5.0E-04
1.0E-03
1.5E-03
Pre-catalyst Concentration (M)
Figure 2. First order dependence of the initial rate for the for-
mation of 2-BPin-benzofuran on the concentration of the cobalt
pre-catalyst, (iPrPNP)CoCH2SiMe3.
The observed rate law was first order with respect to co-
balt precatalyst (Figure 2) and zero order with respect to
both the heteroarene substrate and HBPin. The zero order
behavior with respect to benzofuran concentration elimi-
nates C-H oxidative addition as the turnover-limiting step
in the catalytic cycle. In addition, the experimentally de-
termined rate law also excludes the hydride pathway as a
mechanistic possibility. If (iPrPNP)CoH were responsible
for C-H activation and C-B bond formation via reductive
elimination to release the product is turnover-limiting, the
reaction would be expected to exhibit a first order depend-
ence on heteroarene substrate (see Figure 3, Hydride
Scheme 3. Determination of the Deuterium Kinetic
Isotope Effect for the Borylation of Benzofuran and
Benzofuran-2-d1 with HBPin as the Boron Source and
(
iPrPNP)CoCH2SiMe3 as the Pre-Catalyst.
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pathway 1). Similarly, a hydride pathway where H-H reduc-
tive elimination is the slow step is also unlikely as this re-
gime would result in a first order dependence on the het-
eroarene and an inverse first order dependence on HBPin
(see Figure 3, Hydride pathway 2).
Page 4 of 8
PiPr2
1
2
3
4
N
Co CH2SiMe3
PiPr2
5
HBPin
6
7
8
9
Hydride pathway 2
Hydride pathway 1
1
H
H
PinBCH2SiMe3
[Co] BPin
H
[Co] BPin
H
PiPr2
Co
resting state
resting state
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H
N
HBPin
HBPin
HBPin
Ar BPin
PiPr2
2
PiPr2
6
[Co]
H
[Co]
H
Ar BPin
Ar
H
H
Ar BPin
Ar
H
H
PiPr2
SLOW
BPin
H
H
[Co] BPin
Ar
H
[Co] BPin
Ar
Co Ar
N
Co
BPin
N
H
[Co]
H
[Co]
H
H
Co(I) - Co(III)
cycle
Ar
Ar
PiPr2
PiPr2
resting state
SLOW
3
5
HBPin
HBPin
H2
H2
[Co] Ar
[Co] Ar
Ar
H
PiPr2
PiPr2
Expected rate law:
Expected rate law:
BPin
H
N
Co BPin
PiPr2
N
Co
turnover
limiting
rate = kobs[Co]total[Ar-H]
rate = kobs[Co]total[Ar-H]
[H2]
H
[HBPin]
PiPr2
4
H2
Figure 3. Hydride pathway 1 with turnover-limiting C-B reduc-
tive elimination (left) and Hydride pathway 2 with turnover-
limiting H-H reductive elimination (right). See Figure S4 and
Figure S5 for the derivation of the rate law.
Effect of the 4-Substituent on Catalytic Activity. To evalu-
ate the effect of the electron-donating ability of the pincer
ligand on the C-H borylation of heteroarenes with HBPin,
the catalytic C-H borylation of benzofuran was monitored
using different cobalt pre-catalysts (Figure 4). The reaction
profiles in Figure 4 show that the rate of benzofuran
borylation with HBPin increases with electron withdraw-
ing groups in the 4-position of the pincer. The origin of
this behavior is likely a result of a decreased barrier for
turnover-limiting H-H reductive elimination with more
electron-poor catalysts. This is opposite of the trend ob-
served for the C(sp2)-H borylation of 2,6-lutidine with
B2Pin2 where electron-donating blocking pyrrolidinyl and
methyl groups enhanced the rate of C-H borylation by
decreasing the barrier for turnover-limiting C-H activation
of the arene substrate.8a These findings demonstrate that
the turnover-limiting step of the C-H borylation catalytic
cycle and hence the catalyst design principles depend on
the identity of the substrates.
Proposed Mechanism. A mechanism that is consistent
with the experimentally measured data is presented in
Scheme 4 and is reminiscent of the boryl pathway present-
ed in Scheme 2. The cobalt precatalyst enters the catalytic
cycle by reaction of HBPin to form an equivalent of
PinBCH2SiMe3 and (iPrPNP)CoH (step 1).5a Oxidative addi-
tion of a second equivalent of HBPin to (iPrPNP)CoH gen-
erates
the
catalyst
resting
state,
trans-
(
iPrPNP)Co(H)2BPin (step 2).5a,26 Turnover-limiting H2
reductive elimination (step 3), either through dissociation
of a phosphine24 or reductive coupling of HBPin, generates
the C-H activating species, (iPrPNP)CoBPin. Heteroarene
C-H oxidative addition (step 4), followed by C-B reductive
elimination to release the heteroarylboronate ester prod-
uct and regenerate (iPrPNP)CoH (step 5) completes the
catalytic cycle. This mechanistic scenario is different from
that of the borylation of pyridines and arenes with B2Pin2,
where catalyst self-borylation is competitive with arene
borylation and arene C-H activation by a cobalt(I) boryl is
turnover-limiting.
Scheme 4. Proposed Mechanism for the Cobalt-
Catalyzed C-H Borylation of Five-Membered Het-
eroarenes with HBPin.
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Fate of cobalt:
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Figure 4. Reaction profiles for the C-H borylation of benzofuran
5a
with HBPin using
(
(
iPrPNP)CoCH2SiMe3
(red), 4-BPin-
PiPr2
H
PiPr2
PiPr2
PHiPr2
8a
iPrPNP)CoCH3 (blue), and 4-pyrr-(iPrPNP)Co(H)2BPin8 (pur-
H
N
H
Co BPin
PinB
N
H
Co BPin
PinB
N
Co
H
ple) as pre-catalysts.
PiPr2
PiPr2
PiPr2
Determination of Catalyst Deactivation Pathway(s). Alt-
hough an effective reagent for the borylation of 5-
membered heteroarenes, HBPin proved less effective with
pyridines and unactivated arenes and led to overall lower
product yields. To probe the origin of this difference, the
borylation of 2,6-lutidine was studied with HBPin in the
presence of 10 mol% of (iPrPNP)CoCH2SiMe3. Monitoring
the catalytic reaction by 31P NMR spectroscopy (Figure 5)
revealed significant borylation of the 4-position of the
pincer ligand. After one hour of reaction time, correspond-
A
B
C
Figure 5. 31P NMR spectrum of the reaction mixture of 2,6-
lutidine and HBPin in the presence of 10 mol% of
a
(
iPrPNP)CoCH2SiMe3 in THF-d8 at 80 C. GC yield of borylated
product.
ing to <5% conversion,
a
and
2:1 ratio of trans-
trans-4-BPin-
(
(
iPrPNP)Co(H)2BPin
iPrPNP)Co(H)2BPin was observed (red spectrum in Fig-
ure 5). Heating the THF-d8 solution of the reaction mix-
ture to 80 ºC for 32 hours produced 19% yield of the
borylated product and a new cobalt compound identified
as 4-BPin-(iPrPNP)Co(H)(PHiPr2). This product, arising
from P-C bond cleavage of the pincer,22 was independently
synthesized from addition of HPiPr2 to 4-BPin-
(
iPrPNP)CoCH38a under an atmosphere of hydrogen gas
(see complete experimental details on page S9) and crys-
tallographically characterized (Figure 6). Performing the
C-H borylation of 2,6-lutidine with HBPin in 0.55 M THF
solution using 10 mol% of 4-BPin-(iPrPNP)Co(H)(PHiPr2)
as the pre-catalyst resulted in no conversion to the
borylated product, establishing that the formation of 4-
BPin-(iPrPNP)Co(H)(PHiPr2) by P-C bond cleavage is a
catalyst deactivation pathway (see S10).
Figure 6. Solid state structure of 4-BPin-(iPrPNP)CoH(PHiPr2)
at 30% probability ellipsoids. Hydrogen atoms, except on the
cobalt-hydride and on the secondary phosphine were omitted
for clarity.
Based on these observations, a pathway accounting for
the origin of the poor catalytic activity with pyridines and
unactivated arenes when HBPin is used as the boron rea-
gent is presented in Scheme 5. Isomerization of trans-4-
BPin-(iPrPNP)Co(H)2BPin to the cis isomer (step 1) fol-
lowed by H2 reductive elimination (step 2) generates the
C-H activating intermediate, 4-BPin-(iPrPNP)CoBPin,
which undergoes oxidative addition of the arene C(sp2)-H
bond (step 3). For pyridines and unactivated arenes where
the C-H bond is less acidic than that of five membered
heteroarenes, reductive elimination of HBPin from trans-
4-BPin-(iPrPNP)Co(H)2BPin
iPrPNP)CoH (step 4) becomes competitive with arene C-
H activation (step 3).27 As shown previously with the un-
to
generate
4-BPin-
(
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modified version of the ligand,22 the Co(I) hydride under-
AUTHOR INFORMATION
goes catalyst deactivation by P-C bond cleavage22 to gener-
ate 4-BPin-(iPrPNP)Co(H)(PHiPr2) (step 5) and unidenti-
fied products. When B2Pin2 is used as the boron reagent,
regeneration of the cobalt boryl occurs via the reaction of
the cobalt hydride with B2Pin2 (step 6), which decreases
the concentration of the cobalt(I) hydride species, or pre-
venting its formation altogether, and thus preventing cata-
lyst deactivation. This explains why the use of B2Pin2 is
necessary to achieve synthetically useful yields in the C-H
borylation of pyridines and unactivated arenes.
1
2
3
4
5
6
7
8
Corresponding Author
*pchirik@princeton.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
9
Financial supported was provided by the National Institutes
of Health (1R01GM121441-01). J.V.O. acknowledges the 2015
Howard Hughes Medical Institute International Student Re-
search Fellowship and the 2016 Harold W. Dodds Honorific
Fellowship (awarded by the Graduate School at Princeton
University). We also thank Máté Bezdek for solving the X-ray
structure of 4-BPin-(iPrPNP)Co(H)(PHiPr2), Dr. Scott P.
Semproni for helpful discussions and Dr. C. Rose Kennedy
for insightful comments and assistance in editing the manu-
script.
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19
20
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22
23
24
25
26
27
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60
Scheme 5. Hypothesis for Why HBPin is an Ineffective
Borylating Reagent for Pyridines and Unactivated
Arenes.
Ar
H
BPin
[Co]
H
BPin
[Co]
H
1
2
3
H
[Co]
BPin
N
slow
H2
HBPin
H
6
B2Pin2
[Co]
H
BPin
PiPr2
Co
PiPr2
REFERENCES
[Co] =
PinB
PHiPr2
H
4
5
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781.
N
[Co]
H
[Co]
catalytically
inactive
HBPin
CONCLUSIONS
Investigations into the mechanism of C-H borylation of
five-membered heteroarenes with HBPin using the cobalt
pre-catalyst, (iPrPNP)CoCH2SiMe3, are consistent with
reductive elimination of H2 from the cobalt(III) resting
state as the turnover limiting step. This kinetic regime is
distinct from the one operative for the borylation of pyri-
dines and arenes with cobalt and iridium catalysts with
B2Pin2, where C-H activation is turnover limiting. Compar-
ison of the catalytic activities of different cobalt pre-
catalysts established that the ligand design principles for
C-H borylation are dictated by the identity of the arene
substrate as well as the boron reagent used as electron-
donating groups improve borylation of pyridines and
arenes with B2Pin2, while electron-withdrawing groups
improve borylation of five-membered heteroarenes with
HBPin. Monitoring the fate of the cobalt catalyst in the
borylation of 2,6-lutidine with HBPin revealed that for
arene substrates containing relatively less acidic C-H
bonds, catalyst deactivation by P-C bond cleavage be-
comes competitive with productive catalysis, thus result-
ing in poor yields. The design of cobalt catalysts that are
less susceptible to deactivation by P-C bond cleavage is
envisioned to enable more atom-economical C-H boryla-
tions of these arene substrates with HBPin.
(7) Khaskin, E.; Diskin-Posner, Y.; Weiner, L.; Leitus, G.;
Milstein, D. Chem. Commun. 2013, 49, 2771-2773.
ASSOCIATED CONTENT
Supporting Information
Complete experimental details, characterization data, NMR
spectroscopic and crystallographic data in CIF format. This
material is available free of charge via the internet at
http://pubs.acs.org.
(8) (a) Obligacion, J. V.; Semproni, S. P.; Pappas, I.; Chirik, P. J. J.
Am. Chem. Soc. 2016, 138, 10645-10653. (b) Obligacion, J. V.; Bez-
dek, M. J.; Chirik, P. J. J. Am. Chem. Soc. 2017, 139, 2825-2832.
(9) There are iridium-catalyzed variants of this reaction where
only ½ equiv. of B2Pin2 is used relative to the arene. In this case,
the use of B2Pin2 as the boron reagent is more atom-economical
because it only generates ½ equiv. of H2 (instead of 1 equiv. of H2
generated from 1 equiv. of HBPin).
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(10) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.;
Miyaura, N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263-
14278.
(11) Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S. J. Am. Chem.
Soc. 2003, 125, 16114-16126.
(12) Vanchura, B. A.; Preshlock, S. M.; Roosen, P. C.; Kallepalli, V.
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(22) Semproni, S. P.; Atienza, C. C. H.; Chirik, P. J. Chem. Sci.
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1
2
3
4
5
6
7
8
(24) Xu, H; Bernskoetter, W. J. Am. Chem. Soc. 2011, 133, 14956-
14959.
(25) The reaction of (iPrPNP)CoCH2SiMe3 with HBPin happens
instantaneously at 23 C and thus pre-catalyst activation is sig-
nificantly faster than the time it takes to reach 10% conversion.
(26) As shown in reference 5a, the C-H borylation of 2-methyl
9
furan with DBPin in the presence of
(
1
mol% of
iPrPNP)CoCH2SiMe3 resulted no deuterium incorporation in
10
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21
22
23
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27
28
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35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
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(15) Green, A. G.; Liu, P.; Merlic, C. A.; Houk, K. N. J. Am. Chem.
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the unreacted arene, but resulted in the formation of HBPin,
consistent with reversible oxidative addition and reductive elim-
ination of B-H(D) bonds.
(27) Performing the reaction depicted in Figure 5 in the absence
of 2,6-lutidine (i.e. addition of 11 equivalents of HBPin to a solu-
tion of (iPrPNP)CoCH2SiMe3 in THF-d8) instantaneously forms
trans-(iPrPNP)Co(H)2BPin (see footnote 25) at 23 C. Heating
this mixture to 80 C for 32 hours resulted in the complete con-
sumption of trans-(iPrPNP)Co(H)2BPin and the formation of
trans-4-BPin-(iPrPNP)Co(H)(PHiPr2) thus supporting the hy-
pothesis that P-C bond cleavage is competitive with arene C-H
activation when the C-H bond is less acidic than that of five
membered heteroarenes.
Keith, J. A. ACS Catal. 2015, 5, 3689-3699.
(21) Légaré, M-A.; Courtemanche, M-A.; Rochette, E.; Fontaine,
F. G. Science 2015, 349, 513-516.
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Insert Table of Contents artwork here
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PinB
O
O
cat. [Co]
BPin
PiPr2
H
H
N
HBPin
-H2
Co
P
PHiPr2
Slow step:
H-H reductive elimination
Catalyst deactivation:
Catalyst design:
P-C bond cleavage
electron-poor cobalt
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Insight into atom-economical C-H borylations with HBPin
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