Benzoic Acid-Promoted C2-H Borylation of Indoles with Pinacolborane

Article abstract of DOI:10.1021/acs.orglett.1c00809

A benzoic acid-promoted C2-H borylation of indoles with pinacolborane to afford C2-borylated indoles is developed. Preliminary mechanistic studies indicate BH3-related borane species formed via the decomposition of pinacolborane to be the probable catalyst. This transformation provides a prompt route toward the synthesis of diverse C2-functionalized indoles.

Full text of DOI:10.1021/acs.orglett.1c00809

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Letter
Benzoic Acid-Promoted C2−H Borylation of Indoles with
Pinacolborane
Youliang Zou, Binfeng Zhang, Li Wang, and Hua Zhang*
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ABSTRACT: A benzoic acid-promoted C2−H borylation of indoles with
pinacolborane to afford C2-borylated indoles is developed. Preliminary
mechanistic studies indicate BH3-related borane species formed via the
decomposition of pinacolborane to be the probable catalyst. This trans-
formation provides a prompt route toward the synthesis of diverse C2-
functionalized indoles.
Scheme 1. Catalytic Electrophilic C−H Borylation of
Indoles
ndole, a “privileged” structural core motif, exists in a wide
Ivariety of biologically active compounds such as pharma-
ceuticals, agrochemicals, and natural products.1 During the
past several decades, transition-metal-catalyzed C−H function-
alization has emerged as a powerful tool for the late-stage
modification of indoles.2 For example, growing efforts have
been devoted to the development of C−H borylation for
indoles, due to the significant opportunity of using organo-
boron compounds in organic synthesis.3 Various transition-
metal catalysts have been developed for C−H borylation of
indoles and exhibit high efficiency.4 Although transition-metal
catalysis dominates aromatic C−H borylation, the metal-free
approach has emerged as a promising alternative strategy.5 In
recent years, metal-free C−H borylation of indoles has been
achieved utilizing borenium cations,6 N-heterocyclic carbene
boranes,7 bis(pinacolato)diborane,8 boron trihalides,9 and aryl
boronic esters10 as boron sources.
As commonly used boron sources in transition-metal-
catalyzed C−H borylation, commercially available and mild
boranes such as pinacolborane (HBpin) and catecholborane
(HBcat) are also good choices in metal-free C−H borylation.
Very recently, various catalytic electrophilic C−H borylations
of indoles with HBpin or HBcat were achieved in the presence
of frustrated Lewis pair (FLP) catalysts,11 boron-based Lewis
acid catalysts,12 and a tethered ruthenium(II) thiolate
complex13 (Scheme 1A). However, despite the great advances
made in this area, several challenges remain to be addressed.
On one hand, the catalysts employed in the previous reports
were either commercially unavailable or very expensive. On the
other hand, due to the intrinsic nature of the indole substrate,
C3−H borylation of indoles was dominantly favored while
C2−H borylation of indoles remains challenging. Therefore, a
C2-selective C−H borylation of indoles enabled by simple,
easy-handling, commercially available, and inexpensive cata-
lysts is highly desired. We report herein a benzoic acid-
promoted C2−H borylation of indoles with pinacolborane
(Scheme 1B).
We began our study by examining various commercially
available and cheap promoters in the reaction of 1-
methylindole (1a) and HBpin. During the investigation, we
are thrilled to find that the addition of benzoic acid (PhCO2H)
provided C2−H borylation product 2a predominately in
considerable yield. After extensive screening, we determined
that the reaction of 1a with HBpin in the presence of PhCO2H
Received: March 8, 2021
Published: March 18, 2021
https://doi.org/10.1021/acs.orglett.1c00809
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2821−2825
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c
(10 mol %) in hexane at 180 °C for 16 h afforded C2-
borylated product 2a, C3-borylated product 3a, and C2,C3-
diborylated product 4a in 62%, 8%, and 15% NMR yields,
respectively.14 As C3 protodeboronation of 4a afforded 2a
quantitatively under acidic conditions, a 74% NMR yield of 2a
was obtained by treating the reaction residue with an aqueous
hydrochloride solution.
Scheme 2. Benzoic Acid-Promoted C2−H Borylation of
a,b
Indoles with Pinacolborane
As shown in Table 1, several examples of variations from the
“standard conditions” are illustrated. In addition to benzoic
a,b
Table 1. Effects of Reaction Parameters on the Benzoic
Acid-Promoted C2−H Borylation of 1a with Pinacolborane
entry variation from “standard conditions”
2a (%)
3a (%) 4a (%)
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
none
62 (74)
55
8
5
4
3
7
1
3
5
0
5
3
4
3
5
15
12
9
6
11
1
4
17
0
10
0
9
CH3CO2H instead of PhCO2H
BnOBpin instead of PhCO2H
no PhCO2H
40
19
37
3
17
57
0
48
22
45
35
51
d
no PhCO2H
HBpin (0.48 mmol)
HBpin (1.2 mmol)
HBpin (2.0 mmol)
B2pin2 instead of HBpin
noctane instead of hexane
c
neat conditions
160 °C instead of 180 °C
140 °C instead of 180 °C
9 h instead of 16 h
6
14
a
Standard reaction conditions: 1a (0.4 mmol), HBpin (2.4 mmol),
b
PhCO2H (0.04 mmol), hexane (1.0 mL), 180 °C, 16 h. 1H NMR
yield. The reaction residue was treated with HCl (1.0 mL, 6.0 M) for
0.5 h. For 48 h.
c
c
d
a
Reaction conditions: 1 (0.4 mmol), HBpin (2.4 mmol), PhCO2H
b
c
c
(0.04 mmol), hexane (1.0 mL), 180 °C, 16 h. Isolated yield. The
acid, acetic acid (CH3CO2H) was also found to be a suitable
promoter (Table 1, entry 2). The use of BnOBpin as a
promoter afforded 2a and 4a in 40% and 9% yields,
respectively (Table 1, entry 3).15 Remarkably, a 19% yield of
2a and a 6% yield of 4a were obtained in the absence of
benzoic acid, which revealed that the borylation could occur
without the addition of exogenous promoters (Table 1, entry
4). Increasing the reaction time led to a 37% yield of 2a and an
11% yield of 4a (Table 1, entry 5). Less HBpin resulted in a
lower conversion of 1a and lower yields of desired products
(Table 1, entries 6−8). When B2pin2 was employed as a boron
source, no products were obtained (Table 1, entry 9). The use
of noctane as a solvent showed an efficiency lower than that of
chexane, while 2a was obtained in 22% yield under neat
conditions (Table 1, entries 10 and 11, respectively).
Decreasing the temperature or the reaction time led to
decreased yields (Table 1, entries 12−14).
d
reaction residue was treated with HCl (1.0 mL, 6.0 M) for 0.5 h.
1
e
f
(1.0 mmol). CH3CO2H (0.04 mmol). 1H NMR yield (C2 and C3
isomers were obtained as a mixture).
C2−H borylation (2c−2g). 1-Methylindoles bearing both
electron-donating and electron-withdrawing substituents such
as methoxy, 1-piperidyl, phenyl, and trifluoromethyl groups
reacted well to produce the corresponding C2-borylated
products in good yields (2h−2k). Halo substituents, such as
F, Cl, and Br, and boron substituent Bpin were all well-
tolerated, providing the possibility for further functionalization
(2l−2o). Remarkably, NH indole (1p) also reacted with
pinacolborane to afford desired C2−H borylation product 2p
in satisfying yield in the presence of acetic acid. In a similar
manner, other heteroarenes like 7-aza indole (1q) and 1-benzyl
pyrrole (1r) were also suitable substrates giving the
corresponding products in 66% and 42% yields, respectively.
Low yields of C2-borylated products 2s and 2t were obtained
employing benzo[b]thiophene (1s) and thiophene (1t) as
substates. N-Methyl carbazole (1u) gave only a trace amount
of the product under the reaction conditions presented here.
With the optimized reaction conditions in hand, the
substrate scope of this benzoic acid-promoted C2−H
borylation was investigated (Scheme 2). Similar to 1a, the
borylation of 1-butyl indole (1b) occurred smoothly to afford
desired product 2b in good yield. A methyl substituent at
different positions of the phenyl ring was well-tolerated in this
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The synthetic versatility of 2-boryl indoles obtained by this
C−H borylation was demonstrated (Scheme 3). Various
employment of these compounds as promoters was also
examined in which significant desired products were obtained
(Scheme 4b). N,N,N′,N′-Tetramethylethylenediamine
(TMEDA) could form mono- and bisadducts with BH3 and
serve as a BH3 indicator.18,19 The addition of TMEDA
significantly inhabited the C−H borylation of 1a (Scheme 4c).
Furthermore, small amounts of borylated products were
observed by the stoichiometric reaction between 1a and
BH3·DMS followed by the addition of HBpin at room
temperature (Scheme 4d). These results indicated BH3-related
borane species are the probable catalyst in this reaction. The
11B NMR analysis of the reaction system was conducted;
however, unfortunately no BH3-related borane species was
observed, which might be due to the very low concentration of
active species (for details, see the Supporting Information).
In contrast to the C3 regioselectivity observed in previous
catalytic electrophilic C−H borylation of indoles, a unique C2
regioselectivity was obtained in this transformation. One
possible reason to explain this phenomenon is that the facile
protodeboronation of the C3 isomers results in the
accumulation of thermodynamically more stable C2 isomers.7
However, the model reaction with the addition of a
stoichiometric amount of 3a afforded a 106% yield of 3a.
The result obtained revealed the stability of 3a under the
conditions presented here, and thus, the speculation presented
above was ruled out (Scheme 4e).
Scheme 3. Transformations of 2-Boryl Indoles
transformations, including oxidation (5), Suzuki coupling (6),
cyanation (7), and C−S bond formation (8), of 2-boryl indoles
were performed, in which different important C2-function-
alized indoles were obtained in moderate to good yields.
To gain brief insights into the mechanism of this C−H
borylation, several control experiments were conducted.
Considering the present reaction conditions and the relevant
literature reports,16−18 we speculate that the active catalyst in
this C−H borylation might be BH3-related borane species
formed by the decomposition of HBpin with the aid of
promoters. Various borane complexes such as BH3·DMS, BH3·
THF, BH3·Py, and BH3·TMA were tested as promoters in this
C−H borylation (Scheme 4a). Moderate to good yields of 2a
and 4a were obtained in the presence of these borane
complexes. Thomas and co-workers reported that simple
nucleophiles such as LiAlH4, LiOtBu, NaOtBu, and KOtBu can
readily mediate the formation of BH3 from HBpin,18 and the
In addition, we monitored the C2−H borylation of 1a by 1H
NMR analysis. As shown in Figure 1, the yield of 2a increased
Scheme 4. Control Experiments
Figure 1. Monitoring of the borylation of 1a with HBpin. The yields
1
were determined by H NMR analysis.
with longer reaction times while the yields of 3a and 4a
increased at a rate much lower than that of 2a during the whole
reaction process. This result confirmed the constant C2
regioselectivity in the whole process.
On the basis of the results presented above and previous
reports,16−18 a mechanism is proposed for this C−H
borylation (Scheme 5). Initially, BH3-related borane species
9 is formed by the decomposition of HBpin mediated by either
promoters or 1a. The reaction of 1a with 9 affords C2-
borylated indole intermediate 10, which subsequently under-
goes transborylation with HBpin to produce 2a, and regenerate
the borane species.
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Scheme 5. Proposed Mechanism
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Natural
Science Foundation of China (21602096).
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In summary, we have demonstrated a benzoic acid-
promoted C2−H borylation of indoles with pinacolborane. A
broad substrate scope and good functional group tolerance are
obtained. The mechanistic insights reveal that the BH3-related
borane species involves the probable catalyst in this C−H
borylation. By employing this protocol, the prompt synthesis of
C2-functionalzied indoles could be achieved.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00809.
Experimental details and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Hua Zhang − Key Laboratory of Catalysis and Energy
Materials Chemistry of Ministry of Education and Hubei Key
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China; College of
Chemistry, Nanchang University, Nanchang 330031, China;
orcid.org/0000-0002-4960-0838; Email: huazhang@
scuec.edu.cn
Authors
Youliang Zou − Key Laboratory of Catalysis and Energy
Materials Chemistry of Ministry of Education and Hubei Key
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China; College of
Chemistry, Nanchang University, Nanchang 330031, China
Binfeng Zhang − Key Laboratory of Catalysis and Energy
Materials Chemistry of Ministry of Education and Hubei Key
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China; College of
Chemistry, Nanchang University, Nanchang 330031, China
Li Wang − Key Laboratory of Catalysis and Energy Materials
Chemistry of Ministry of Education and Hubei Key
Laboratory of Catalysis and Materials Science, School of
Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan 430074, China; College of
Chemistry, Nanchang University, Nanchang 330031, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00809
Notes
The authors declare no competing financial interest.
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