Borylation of Unactivated C(sp3)-H Bonds with Bromide as a Traceless Directing Group

Article abstract of DOI:10.1021/acs.orglett.1c00617

A palladium-catalyzed alkyl C-H borylation with bromide as a traceless directing group is described, providing a convenient approach to access alkyl boronates bearing a β-all-carbon quaternary stereocenter. The protocol features a broad substrate scope, excellent site selectivity, and good functional group tolerance.

Full text of DOI:10.1021/acs.orglett.1c00617

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Letter
Borylation of Unactivated C(sp3)−H Bonds with Bromide as a
Traceless Directing Group
Ge Zhang,§ Meng-Yao Li,§ Wen-Bo Ye, Zhi-Tao He, Chen-Guo Feng,* and Guo-Qiang Lin*
Cite This: Org. Lett. 2021, 23, 2948−2953
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ABSTRACT: A palladium-catalyzed alkyl C−H borylation with
bromide as a traceless directing group is described, providing a
convenient approach to access alkyl boronates bearing a β-all-
carbon quaternary stereocenter. The protocol features a broad
substrate scope, excellent site selectivity, and good functional group
tolerance.
Scheme 1. Pd-Catalyzed Borylation of C(sp3)−H Bonds
lkylboron compounds are versatile intermediates in
organic synthesis,1 and considerable efforts have been
with Directing Groups
A
devoted to their efficient synthesis. Traditional approaches
include transmetalation of organolithium/magnesium with
boronic reagents,2 hydroboration of olefins,3 and direct
borylation of alkyl halides.4 Over the past two decades,
transition-metal-catalyzed C−H activation has become a
powerful tool to transform otherwise unreactive C−H bonds
into carbon−carbon or carbon−heteroatom bonds,5 and the
emergence of the transition-metal-catalyzed borylation of alkyl
C−H bonds offered a more straightforward method.6 In this
respect, impressive advancements have been achieved with
various transition metals like Re,7 Ru,8 Ir,9 and Rh.10 In
contrast, the Pd-catalyzed borylation of alkyl C−H bonds has
been relatively less explored.11 Although Ishiyama, Miyaura,
and coworkers realized the Pd/C-catalyzed borylation of
relatively active benzylic C−H bonds in 2002,12 it was not until
2014 that Shi and coworkers disclosed a Pd(II)-catalyzed
borylation of unactivated C(sp3)−H bonds with an apicolinyl
directing group.13 Soon after, Yu and coworkers demonstrated
a Pd(II)-catalyzed oxidative borylation of primary and cyclic
secondary C−H bonds with amides as directing groups.14a The
same group also described the subsequent enantioselective
version of this reaction by using chiral acetyl-protected
aminomethyl oxazoline ligands (Scheme 1a).14b
difficulty to remove it after the reaction. To overcome these
problems, the application of traceless directing groups
(TDGs),16 which can be automatically removed during the
reaction process, is an alternative and effective approach.
Among the used TDGs,17 halide is an important member and
has been successfully applied in several transformations.18 Very
Owing to the inert nature and the ubiquitous presence of
C−H bonds, the activation of a specific C−H bond would be
practically difficult. Although it is possible to utilize the innate
reactivity of the organic molecule, the directing group (DG)
strategy relying on intramolecular chelation assistance
represents a more popular solution.15 However, the obvious
limitations inherent in this strategy restricted its application,
such as the preinstallation of DG before the reaction and the
Received: February 21, 2021
Published: March 25, 2021
https://doi.org/10.1021/acs.orglett.1c00617
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2948−2953
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a
Table 1. Studies on Reaction Development
b
b
entry
ligand
temperature (°C)
solvent
base
yield (%)
site selectivity (2a/2a′)
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
L1
L2
L3
L4
L5
L6
L7
L8
L8
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
160
140
dioxane
DMF
toluene
m-xylene
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOPiv
K3PO4
Na2CO3
KOtBu
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
22
15
30
45
55
43
18
18
nd
75
65
70
5
75
33
67
75
75
72
1:1
2:1
2:1
2.5:1
3.5:1
3:1
1:2.5
1:1
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
9
10
11
12
13
14
15
16
17
18
19
3:1
2:1
2.5:1
1:1
4:1
3:1
10:1
10:1
10:1
5:1
L8
a
Reaction conditions: 1a (0.20 mmol), (Bpin)2 (0.30 mmol, 1.5 equiv), Pd(OAc)2 (0.02 mmol, 0.1 equiv), ligand (0.06 mmol for monophosphines
b
and 0.03 mmol for bisphosphines), base (0.30 mmol, 1.5 equiv), solvent (2.0 mL) under a N2 atmosphere. Determined by 1H NMR spectroscopy.
nd, not detected.
recently, Zhao and coworkers demonstrated an alkyl C−H
borylation reaction directed by naphthyl bromide (Scheme
1b).19 In their work, the C−H bond is supposed to be
activated by the α-effect of the silicon atom, and no borylation
product was observed with the more inert C−H bond of the
carbon analogue. Therefore, the borylation of the alkyl C−H
bond with more general substrates is still in demand. Herein
we describe our success in the borylation of the inert alkyl C−
H bond directed by aryl bromide (Scheme 1c).
We started our study by investigating the reaction of aryl
bromide 1a with B2pin2 as a model system, and selected results
are shown in Table 1. With Pd(OAc)2 as the precatalyst, PPh3
as the ligand, dioxane as the solvent, and CsOAc as the base,
the desired borylation product 2a was produced in 22%
reaction yield, which was accompanied by an equal amount of
the direct coupling byproduct 2a′ (2a/2a′ = 1:1) (entry 1).
Exploration of the solvent effect found that both the reaction
yield and the site selectivity were significantly affected.
Although a better site selectivity was observed with a polar
aprotic DMF as the solvent, it gave a reduced reaction yield
(entry 2). When the nonpolar and noncoordinating toluene
was used, both the reaction yield and the site-selectivity were
improved (entry 3). An examination of other aromatic solvents
revealed that mesitylene was the optimal choice, improving the
reaction yield to 55% and the site selectivity to 3.5:1 (entries 4
and 5). Next, several bases were also tested, and inferior
reaction yields and site selectivities were observed with K3PO4
and Na2CO3 as the base (entries 7 and 8). The stronger base
KOtBu failed to give any product (entry 9). CsOPiv was a
competent base to promote this reaction, but it was less
effective than CsOAc in this case (entry 6). The importance of
carboxylate salts for this reaction may be ascribed to their
excellent capability to act as inner bases in palladium catalysis,
which is often critical for the C−H activation step through the
well-known concerted metalation deprotonation (CMD)
mechanism.20 The introduction of an electron-donating methyl
group or a mildly electron-withdrawing F to the para or meta
position of the ligand’s phenyl rings can significantly improve
the reaction yield; however, the site selectivity was not
simultaneously improved (entries 10 and 11). We then turned
our attention to bisphosphine ligands with different carbon
linkages (entries 14−17). A big leap in site selectivity was
observed when bisphosphine ligands bearing a linkage of more
than five carbon atoms were used (entries 16 and 17). In
particular, 1,6-bis(diphenylphosphanyl)hexane L8 enhanced
both the reaction activity and the site selectivity, affording 2a
in 75% yield with 10:1 site selectivity (entry 17). Attempts to
further improve the reaction through temperature variation
were unsuccessful (entries 18 and 19).
With the optimized conditions in hand, the scope of the
catalytic alkyl C−H borylation process was investigated
(Scheme 2). The ester types were first examined. Compared
with methyl ester, the reaction yield was increased with ethyl
substitution (2b) but reduced with a more sterically
demanding tert-butyl group (2c). Thus, using ethyl esters,
the substitution effect on the phenyl ring was then examined.
Whereas an electron-withdrawing CF3 group (2d) para to the
quaternary benzylic carbon gave an equally high reaction yield,
mildly electron-withdrawing and electron-donating substitu-
ents like F (2e), Cl (2f), and MeO (2g) resulted in reduced
yields. This dependence of the reaction efficiency on the
electronic properties of the involved carbon sites was
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a b
,
transformations of the produced alkyl boronic ester 2b to a
range of functional groups (Scheme 3). By treating with KHF2
Scheme 2. Substrate Scope Studies
a
Scheme 3. Transformations of Borylation Product 2b
a
Reaction conditions: (a) KHF2, MeOH, rt, 2 h; (b) vinyl magnesium
bromide, THF, −78 °C, then I2, NaOMe, 5 h; (c) lithium thiophene,
THF, −78 °C, then NBS, 5 h; (d) H2O2, NaOH, THF, 0 °C, 1 h; (e)
H2O2, NaOH, THF, 0 °C, 1 h, then Dess-Martin oxidant, CH2Cl2, 0
°C, 3 h; (f) AgNO3, Selectfluor, TFA, CH2Cl2, 50 °C, 10 h.
in MeOH, the borylation product 2b can be converted to
potassium trifluoroborate 3 in 87% yield, which may serve as
an air-stable nucleophilic partner for the Suzuki−Miyaura
coupling. The cross-coupling with alkenyl Grignard reagent or
aryllithium reagent via the 1,2-boron migration process
furnished alkenylation product 4 and heteroarylation product
5 in 90 and 55% yield, respectively.22 The oxidation of boronic
ester 2n offered alcohol 6 in 95% yield, and further oxidation
with the Dess-Martin reagent via a one-pot procedure
delivered aldehyde 7 in 85% yield. Finally, the AgNO3-
catalyzed radical deboronofluorination of alkyl boronic ester
2b generated fluoride 8 in 65% yield.23
a
Reaction conditions: 1 (0.20 mmol), B2pin2 (0.30 mmol), Pd(OAc)2
(0.02 mmol), L6 (0.03 mmol), CsOAc (0.30 mmol), mesitylene (2.0
b
mL) under a N2 atmosphere. Isolated yield.
previously reported,21 and the same trend was observed for
substituents para to the bromine atom (2i and 2j). Although
the obvious steric encumbrance was brought by substituents
ortho to the bromine atom, which might inhibit the initial
oxidative addition and the formation of the following
palladacycle, the desired products were still produced in useful
reaction yields (2k and 2l). The replacement of the phenyl ring
by a naphthyl group (2n) was compatible, affording the desired
product in moderate yield. Furthermore, the pyridyl group
(2o) was also well accommodated (90%), and this catalytic
process was not hampered by the possible coordination of the
pyridine moiety with a palladium catalyst.
A preliminary intramolecular competition experiment
between aryl ester 1a and its deuterated analogue d6-1a was
conducted (Scheme 4). The moderate kinetic isotope effect
(kH/kD = 1.42) suggested that the C−H bond cleavage might
be involved in the rate-determining step.24
On the basis of both our results and previous studies,25
a
tentative catalytic cycle is proposed, as shown in Scheme 5.
The initial oxidative addition of aryl bromide 1a to
palladium(0) catalyst generates the aryl palladium(II) species
A. After the anion exchange from Br− to AcO−, the
palladium(II) complex B subsequently accomplishes intra-
Replacing one of the gem-dimethyl groups with another alkyl
chain showed diminished reactivity (2p−r), perhaps as result
of increasing difficulty in the C−H activation step. Notably,
terminal olefin (2r), a highly reactive functional group in
palladium chemistry, was well tolerated. No product was
detected when an ester group was introduced (2s). When the
ester group was converted to a protected alcohol (2t) or amine
(2u), the reaction proceeded but with reduced efficiency. A
good reaction yield was obtained when it was replaced by a
methyl group (2v). A cyan group was also tolerated, albeit in
reduced reaction yield (2w).
Scheme 4. Intermolecular Competition Experiment
To demonstrate the synthetic applications of this C(sp3)−H
bond borylation reaction, we illustrated some chemical
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Letter
Guo-Qiang Lin − Key Laboratory of Synthetic Chemistry of
Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Shanghai 200032,
China; The Research Center of Chiral Drugs, Innovation
Research Institute of Traditional Chinese Medicine, Shanghai
University of Traditional Chinese Medicine, Shanghai
201203, China; Email: lingq@sioc.ac.cn
Scheme 5. Proposed Mechanism
Authors
Ge Zhang − Key Laboratory of Synthetic Chemistry of Natural
Substances, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Shanghai 200032, China
Meng-Yao Li − Key Laboratory of Synthetic Chemistry of
Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Shanghai 200032,
China
Wen-Bo Ye − The Research Center of Chiral Drugs,
Innovation Research Institute of Traditional Chinese
Medicine, Shanghai University of Traditional Chinese
Medicine, Shanghai 201203, China
Zhi-Tao He − Key Laboratory of Synthetic Chemistry of
Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Shanghai 200032,
China; orcid.org/0000-0003-2375-9557
molecular C(sp3)−H activation via the CMD mechanism
instead of a second oxidative addition with the alkyl C−H
bond. The generated five-membered palladacycle intermediate
C undergoes sequential proton transfer and transmetalation
with B2pin2 and then provides the desired product 2a through
reductive elimination and regenerates the Pd(0) catalyst.
In conclusion, this work established a novel protocol for
palladium-catalyzed unactivated C(sp3)−H bond borylation
with bromide as a traceless directing group, which is
mechanistically distinct from, and thus complementary to, a
borylation reaction with normal directing group strategies.
This methodology features a broad substrate scope, excellent
functional group tolerance, as well as excellent site selectivity,
giving the borylated products in up to 90% yield. The power of
this method was also highlighted by the wide range of
transformations and the potential utility of the present method
in the late-stage modifications of challenging bulky alkyl C−H
bonds.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00617
Author Contributions
§G.Z. and M.-Y.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by financial support from the
National Natural Science Foundation of China (21772216,
21871284, 91956113), the Chinese Academy of Sciences
(XDB 20020100 and QYZDY-SSWSLH026), the Science and
Technology Commission of Shanghai Municipality
(18401933500 and 20XD1423400), and the Shanghai
Municipal Education Commission (2019-01-07-00-10-
E00072).
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AUTHOR INFORMATION
Corresponding Authors
■
Chen-Guo Feng − Key Laboratory of Synthetic Chemistry of
Natural Substances, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Shanghai 200032,
China; The Research Center of Chiral Drugs, Innovation
Research Institute of Traditional Chinese Medicine, Shanghai
University of Traditional Chinese Medicine, Shanghai
201203, China; orcid.org/0000-0001-9899-9489;
Email: fengcg@shutcm.edu.cn
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