Isodesmic C-H Borylation: Perspectives and Proof of Concept of Transfer Borylation Catalysis

Article abstract of DOI:10.1021/jacs.9b04305

The potential advantages of using arylboronic esters as boron sources in C-H borylation are discussed. The concept is showcased using commercially available 2-mercaptopyridine as a metal-free catalyst for the transfer borylation of heteroarenes using arylboronates as borylation agents. The catalysis shows a unique functional group tolerance among C-H borylation reactions, tolerating notably terminal alkene and alkyne functional groups. The mechanistic investigation is also described.

Full text of DOI:10.1021/jacs.9b04305

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Article
Isodesmic C-H Borylation: Perspectives and
Proof of Concept of Transfer Borylation Catalysis
Etienne Rochette, Vincent Desrosiers, Yashar Soltani, and Frédéric-Georges Fontaine
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04305 • Publication Date (Web): 08 Jul 2019
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Isodesmic C-H Borylation: Perspectives and Proof of Concept of
Transfer Borylation Catalysis
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Étienne Rochette*, Vincent Desrosiers, Yashar Soltani and Frédéric-Georges Fontaine*
Département de Chimie, Université Laval, 1045 Avenue de la Médecine, Québec City, Québec G1V 0A6, Canada
Supporting Information Placeholder
We reported that ambiphilic aminoborane molecules can catalyze
ABSTRACT: The potential advantages of using arylboronic
esters as boron sources in the C-H borylation are discussed. The
the borylation of heterocycles to generate heteroarylboronates,6
which are important precursors in several transformations such as
the Miyaura-Suzuki7 and Chan-Evans-Lam8 coupling reactions. In
this metal-free process, the Lewis base and the Lewis acid act in a
concerted fashion to cleave the C-H bonds of aromatic molecules
according to the concept of frustrated Lewis pair (FLP) chemistry.9
Since our original findings, several groups have contributed to this
expanding field of metal-free catalysis.10 Although some of these
systems show impressive reactivity and unique selectivity, they
have yet to reach the same broad scope than transition metal
catalysts,11 such as the iridium12 and cobalt systems.13 A common
feature of the stoichiometric14 and catalytic borylation reactions is
the use of high energy and reactive boron precursors, including
hydroboranes, diboranes and haloboranes (Figure 1). These
molecules are present either as starting reagents or are generated
during the catalytic cycle, and some of them, notably hydro- and
haloboranes, can react with water, oxygen, or quench the metal
intermediates generated during catalysis. In addition, metal-free
catalysts are often sensitive to ambient conditions and require
storing under inert atmosphere, which reduces their practicality for
synthesis. Furthermore, some functional groups, such as alkenes
and alkynes, are detrimental to borylation catalysis since they can
react with hydroboranes, metal-boryl, and metal-hydride catalytic
intermediates. In fact, alkenes have been used as scrubbing agents
in some of these catalytic systems when hydrogen or hydroboranes,
generated as side products, inhibit catalysis.15
concept is showcased using commercially available 2-
mercaptopyridine as a metal-free catalyst for the transfer borylation
of heteroarenes using arylboronates as borylation agents. The
catalysis shows a unique functional group tolerance among C-H
borylation reactions, tolerating notably terminal alkene and alkyne
functional groups. The mechanistic investigation is also described.
The search for green and safe alternatives to traditional organic
synthesis is a pressing concern for the pharmaceutical and fine
chemical industries. Out of the several catalytic transformations
that are commonly used, isodesmic reactions have attractive
features. In these chemical transformations, the type of chemical
bond cleaved in the reactant is the same than the bond formed in
the product.1 Notable examples of such a process include transfer
hydrogenation2 and olefin metathesis3 (Scheme 1). Using the same
principle, Morandi and coworkers elegantly demonstrated that
alkyl nitriles could be used as a replacement for highly toxic HCN
to perform the hydrocyanation reaction.4 In addition to enabling the
use of cheaper, safer or more convenient reagents, isodesmic
reactions often exhibit higher functional group tolerance, which is
of importance for late stage functionalization reactions in drug
synthesis.5 Surprisingly, isodesmic C-H functionalization
transformations are extremely scarce.
A) Transfer hydrogenation
H
H
R2
R1
R4
R2
O
R4
R3
Cat.
A) Usual Boron Sources B) Potential Boron Sources C) This Work Boron Source
+
+
+
R3
R1
H
H
O
O
O
R
B
O
O
O
O
O
O
B
B
B
O
B
O
B
R
B(OR')2
O
B) Olefin Metathesis
Fast and Easy Preparation
R
O
R
R2
+
R4
R4
R2
O
Cat.
H
B
O
R1
R3
R1
R3
O
B(OH)2
BX3
R
B(OH)2
C) Transfer hydrocyanation
H
H
R2
R1
R4
R3
R4
R2
Figure 1. Common borylation reagents.
Cat.
+
+
R3
R1
CN
CN
Scheme 1. Examples of isodesmic reactions.
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Figure 2: ΔHo (kcal mol-1) for the dehydrogenation of hydroboranes and the corresponding ΔG‡ (kcal mol-1) of the transition
state (A) using 2-mercaptopyridine as a catalyst. [B] = -BCat (Cat = catechol).
All these limitations made us look for a way to use arylboronates
as cheap and convenient reagents for the C-H borylation reaction.
To fully take advantage of a simpler and convenient methodology,
the catalysts for this transformation should be cheap, stable and not
requiring inert atmosphere storage. Herein, we report the
development of a metal-free isodesmic borylation, aka transfer C-
H borylation, using 2-mercaptopyridine as a catalyst. Not only high
yielding reactions can be obtained, but this transformation shows
unique functional group tolerance, showcasing the advantages of
this unreported borylation methodology.
vinylboronate reagents, which would not be transferable to the
synthesis of arylboronates.17 Although less practical, 1,1-
bis[(pinacolato)boryl]alkanes were recently used for the borylation
of aryl and vinyl halides.18
F
F
A
B
C
N
Bu
[B(C6F5)4]
N
BH2
NH
F
NR2
Fontaine 2015
2
HS
Repo 2016
This work
D: A
Catalysed C-H Borylation Proposed Mechanism
Ar H
A preliminary computational study of the thermodynamic and
kinetic parameters of the isodesmic borylation reaction was carried
out using DFT.16 As depicted in Figure 2, B-Csp3 containing
reagents lead to enthalpically favorable transfer borylation
transformations compared to hydroboranes. However, the
transition state energy for the B-Csp3 bond cleavage using 2-
mercaptopyridine is too high (>35 kcal mol-1) for the reaction to
take place. The thermodynamics of the reaction with B-Csp2
reagents is less favorable but kinetically accessible, with G‡
ranging from 20 to 30 kcal mol-1. Within this subclass of reagents,
2-furylBCat (1) and phenylBCat (2) are higher energy borylation
agents, although the former compound has a lower activation
barrier. Furthermore, these reagents can drive the reaction by
releasing volatile benzene or furan, which have respective boiling
BH2
BH2
C-H Activation
NR2
2
Dimer Cleavage
NR2
H
B
Ar BPin
H
Ar
NR2 H
H2
H
H BPin
 Bond Metathesis
B
H2 Release
Ar
NR2
Figure 3. Metal-free C-H borylation catalysts and general
cycle for the borylation reaction.
points of 80
℃
and 31 ℃. Interestingly, aryl- and
heteroarylboronate reagents are only slightly less favored
thermodynamically than hydroboranes for the borylation reaction,
with enthalpy differences ranging from 2 to 7 kcal mol-1. The most
closely related example of such a transformation consists of a
ruthenium-catalyzed synthesis of functionalized vinylboronates
through an insertion/boryl elimination pathway using pristine
Conceptually, a catalyst for an isodesmic borylation should cleave
or form both a C-B and a C-H bond in a concerted fashion, which
is reminiscent of the aminoborane borylation catalysts we
developed (Figure 3A).6a However, an isodesmic process would not
require  bond metathesis to take place, which proved detrimental
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to the functionalization of some substrates.6c,19 Several design
Table 2. Condition screening for the C-H transfer
borylation reaction using 2-mercaptopyridine.
1
2
3
4
5
6
7
8
parameters were taken into account when looking for a catalyst.
First, one key feature for the efficient activation of C-H bonds using
ambiphilic FLP catalysts is the presence of a 6-membered transition
state, with the Lewis pair preferably linked by an aromatic system
to favor electronic communication. A Lewis base less hindered
than a tertiary aniline is also required to favor the interaction with
an arylboronic ester, which is bulkier than a hydroborane. Whereas
Lewis acids (LA) could be used to cleave C-B bonds, the catalytic
release of the organic moiety once the C-LA bond is formed could
prove difficult. The use of a Brønsted acid that would form a C-H
bond is therefore desirable. Furthermore, it was expected that
oxygen or nitrogen containing Brønsted acids would generate very
strong covalent B-O and B-N bonds, which could be detrimental to
catalysis, as we demonstrated previously with our aminoborane
catalysts.19 Our inspiration came from a report from the Repo group
N
OR
B
OR
N
SH
N
+
Ar
Solvent
Temperature
[B]
Loading
Time
x (equiv.)
9
Boron
Source
Catalyst
Entry Temp. Solvent
°C
Equiv.
Time Yield
Loading
mol%
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
10
10
10
10
10
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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31
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58
59
60
h
24
24
24
24
24
24
24
24
24
24
24
24
1
%
55
72
83
0
CDCl
CDCl
CDCl
C D
1
2
80
1
1
1
2
3
4
4
5
6
6
7
7
1
1
1
1
1
1
1
1
1
1
1
1
1
2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3
3
3
80
3
110
110
110
110
140
110
110
140
110
140
110
110
110
110
110
110
110
110
110
110
180
180
180
where
a
protonated 2-aminopyridine was used as
a
dehydrogenative borylation catalyst (Figure 3B).10a However, in
order to have simpler catalysts that are cheaper and readily
available commercially, to increase their solubility in hydrocarbon
solvents and to avoid the requirement for ionic species, we sought
for a neutral analogue. As such, 2-mercaptopyridines, pyrimidines,
and pyrazines were tested as catalysts for the borylation of 1-
methylindole (Table 1). The B-S bond of the intermediates
generated during catalysis should be labile and therefore
catalytically more active than B-N containing species.
4
6
6
C D
5
0
6
6
6
6
6
6
6
6
6
6
6
6
C D
6
0
6
C D
7
<5
0
6
C D
8
6
C D
9
<5
34
<5
43
57
81
90
>95
35
57
69
87
94
0
6
C D
10
11
12
13
14
15
16
17
18
19
20
21
22
23*
24*
25*
6
C D
6
C D
6
Table 1. Catalyst screening for the borylation of 1-
methylindole.
C D
6
C D
4
6
X = Ar, H
25 mol%
Catalyst
C D
8
N
6
N
X
[B]
+
C6D6
CDCl3
24
1
(2 equiv.)
[B]
80 °C, 24 h
C D
6
6
6
6
6
6
6
Catalyst
C D
4
6
CF3
F3C
CF3
N
N
N
C D
8
6
N
N
SH
N
SH
N
SH
N
SH
SH
C D
24
48
24
2
N
SH
6
Boron Source
C D
O
B
O
6
55%
59%
66%
16%
58%
19%
24%
17%
C D
O
H
6
PhMe
PhMe
PhMe
5
87
91
>95
O
O
90%
76%
16%
76%
20%
B
10
25
2
2
O
11%
4%
0%
4%
0%
H
B
* Reaction carried out in a microwave reactor
O
38%*
52%*
37%*
10%*
21%*
0%*
* After an additional 24 h at 110 °C
The borylation reactions were monitored by 1H NMR spectroscopy
using a 25 mol% catalyst loading with 2 equiv. of the borylation
agent in CDCl3. To our delight, unsubstituted 2-mercaptopyridine
as well as 3- and 5-trifluoromethyl-2-mercaptopyridine derivatives
proved moderately active for both the dehydrogenative and transfer
borylation of 1-methylindole, reaching yields up to 90 %.
Significantly lower activities were observed with the pyrimidine
and pyrazine derivatives. Because of its low cost and simplicity, we
decided to study further the catalytic reactivity of 2-
mercaptopyridine.
1
The optimal catalytic conditions were determined using H NMR
spectroscopy (Table 2). While inactive at 110 °C, the transfer
borylation of 1-methylindole using 25 mol% of 2-mercaptopyridine
is possible at 140 °C for 24 h using phenyl- (4), para-tolyl- (6), or
para-anisolBCat (7) as borylation agents, but with yields ranging
from <5 % to 43 % (entries 6-7, 9-12). Fortunately, the isodesmic
borylation using 2-furylBCat (1) proved easier with over 95% yield
at 110 °C for 24 h (entry 16). This trend can be explained by the
G‡ values of 26.1, 27.6, 28.6, and 29.6 kcal mol-1 for the B-C bond
cleavage of the respective 2-furyl, p-anisol-, p-tolyl, and
phenylBCat derivatives, as determined using DFT. Part of the
higher reactivity of the 2-furylBCat can be explained by the lower
aromaticity of the heteroaryl group and the higher acidity on boron.
While the reaction works in chloroform (entries 1-3), this solvent
induces degradation of some borylated indoles, prompting us to use
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Page 4 of 8
benzene-d6 instead. Monitoring the reaction under the latter
(25 mol%)
1
2
conditions shows that over 50% yield is observed after 1 h (entries
13-15). The reaction still operates with a catalyst loading of 10
mol% (entries 17-21) or with 2 equiv. of 1 (entry 1). No borylation
was observed with boronic acids or boronates originating from
aliphatic alcohols, suggesting that the Lewis acidity and reduced
bulk of BCat is required (entries 4-5, 8). We also demonstrated that
the reaction is possible under microwave conditions (180 °C in
toluene for 2 h) at 5, 10 or 25 mol% catalyst loading, obtaining
almost quantitative yields with a higher loading. As a perk, these
reactions were carried out in air using unpurified solvents and no
significant improvement was observed when running the reactions
under a nitrogen atmosphere, although some of the borylation
products are prone to hydrolysis.
E
E
N
SH
O
+
BCat
conditions a or b
[B]
(5 equiv.)
E= S, O, NR
3
4
5
N
N
N
N
N
6
7
MeO
NC
[B]
[B]
[B]
83%a (39%)b
[B]
93%a (67%)b
[B]
>95%a (70%)b
92%a (72%)b
NC
a
8a
8b
8c
8d
8e
60%
8
Et
9
Ph
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
N
[B]
[B]
[B]
83%a (81%)b
[B]
[B]
88%a (68%)b
77%a (54%)b
8f
8g 89%a (87%)c
8h
8i
8j 74%a (62%)b
The substrate scope for the borylation reaction is illustrated in
Figure 4. The transformation was first examined using H NMR
Ph
1
TBDMS
N
N
N
X
N
spectroscopy, then carried out on a 0.4 mmol scale under
microwave conditions for isolation using respectively the
conditions described in entries 16 and 25 of Table 2. To increase
their stability and facilitate isolation and characterization by NMR
and HRMS, the products were derivatized to generate the
pinacolboranates.10c As seen in Figure 4, the borylation of 1-
methylindole (8a) and various alkylated (8b, 8c) and halogenated
derivatives (8k-n) is possible, obtaining excellent NMR
conversion. It should be noted that the low isolated yield for some
of these products was caused by protodeborylation induced by
silica during flash chromatography. The reaction also works with
electron-donating (8d) and electron-withdrawing (8e) groups on
the arene ring. It is also possible to borylate pyrrole and electron-
rich thiophene derivatives (8o-r). Whereas this reactivity does not
differ from the one observed with aminoborane catalysts, the power
of this catalytic borylation lies in its tolerance towards reactive
functional groups such as alkenes and alkynes. Many transition-
metal catalysts19 and Lewis acids10b,21 C-H borylate terminal
alkynes rather than do the Csp2-H bond activation, or undergo
hydro/carboboration reactions.22 A palladium catalyst was also
shown to borylate alkene-containing indoles, but through C-I rather
than C-H activation.23 This borylation methodology was found to
be compatible with the N-4-CN-C6H4 (8g), N-CH2CH=CH2 (8h),
N-CH2C≡CH (8i) and N-CH2C≡CEt (8j) indole derivatives. It was
also shown to tolerate esters (8u) and borylate the C-H bond of
electron-rich arenes (8y), which aminoborane catalysts cannot do,6
although we cannot say if the low yield is explained by
thermodynamic or kinetic factors. The selectivity of the Csp2-H over
the Csp-H activation can be explained by Figure 2. Although the
borylated alkyne is thermodynamically favored over the borylated
indole by 0.9 kcal mol-1, the nucleophilicity of the C3 carbon of
indole makes the C-H activation kinetically easier by 6.7 kcal mol-
1. As a reminder, the transition state for the C-H activation by the
FLP intermediate (vide infra) is the same than the C-B bond
cleavage by the 2-mercaptopyridine, as seen on Figure 2.
[B]
[B]
[B]
[B]
X:
83%a (82%)b
91%a (66%)b
>95%a (97%)b
84%a (78%)b
>95%a,c (35%)b,d
86%a,c (48%)b,d
88%a,c (62%)b,e
8q
6-I
8k
8l
8o
8p
5-Br
6-Cl
6-F
8m
8n
S
CN
[B]
MeO
N
S
[B]
O
O
[B]
8r 64%a,c
8s >95%a (48%)b
8t 86%a (8%)b
Me
N
Me2N
S
Me
tBu
S
O
[B]
[B]
[B]
MeOOC
Me
[B]
[B]
a
a
a
a
a
8y
9%
8u
8v
8w
8x
47%
23%
40%
27%
1
Figure 4. Substrate Scope (a) H NMR yield ([B] = BCat).
Conditions: C6D6, 24 h, 110 °C, sealed NMR tube. (b)
Isolated yield ([B] = BPin). Conditions: Toluene, 2 h, 180 °C,
mw reactor, followed by addition of pinacol (10 equiv.) and
NEt3 (3.3 equiv.). (c) Mixture of 2-, 3- and 2,4-borylated
product (d) 2,4-(BPin)2 derivative isolated. (e) 2-BPin
derivative isolated.
Figure 5. ORTEP representation of 8i. Thermal ellipsoids
set at 50% probability.
To get more insight on this transformation, we monitored by 1H
NMR spectroscopy the borylation of 1-methylindole and 1-
methylpyrrole at 110 ℃, as respectively shown in Figures 6 and
7. We observed the clean borylation of 1-methylindole at the 3-
position, reaching 95% conversion after 8 hour of reactivity.
This selectivity and the absence of the 2-borylated product is
typical of the borylation of indoles using both electrophilic
boron sources10c,14 and aminoborane catalysts.6 However, the
distribution profile with 1-methylpyrrole is more complex,
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showing the presence of the 2-BCat-, 3-BCat-, and 2,4-(BCat)2
1
2
3
4
5
6
7
8
derivatives. It was determined using DFT that the C-H
activation of the pyrrole at the 2-position is favored over the
activation at the 3-position by approximately 3.4 kcal mol-1 but
both barriers are lower than the C-B bond cleavage of 2-
furylBCat (26.2 kcal mol-1). As such, the concentration of both
products increase rapidly at 110 ℃. We see over time the slow
increase in the concentration of 1-methyl-2,4-(BCat)2-pyrrole
and the concentration of 3-BCat-pyrrole becoming more
important than that of 2-BCat-pyrrole, which is expected
according to the thermodynamics of this transformation
(Scheme 2) and fits with the kinetic simulation data (see ESI).
Considering that the activation of the C-B bond in pyrroles is
low in energy (about 20 kcal mol-1; Fig. 2), it is possible to
imagine that they can be easily activated to generate a
thermodynamic equilibrium, as expected for an isodesmic
reaction.
N
N
24.7 (10.8)
27.5 (12.9)
CatB
-2.8 (-2.1)
0.0 (0.0)
G (H)
G (H )
22.9 (7.8)
26.2 (11.9)
21.3 (6.5)
23.6 (8.9)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
26.5 (14.5)
29.8 (16.2)
BCat
BCat
CatB
-2.3 (-2.4)
-3.3 (-4.1)
Scheme 2. Energy profile for the various borylation
equilibria observed with 1-methylpyrrole.
A proposed mechanism was determined using DFT and is
illustrated in Figure 8. 2-Mercaptopyridine (M3) can be considered
as an ambiphilic molecule having both Lewis basic (pyridine) and
Brønsted acid sites (thiophenol). The Lewis base can interact with
the electrophilic boron atom of the arylboronate (M4) while the
acidic proton can be transferred to the aryl group to generate furan.
The activation energy for this process was found to be rate-limiting
at 26.2 kcal mol-1, which is consistent with a reaction operating at
110 ℃. While the structures of M1 & M1* are expected to be
present in solution, only M1 could be located computationally. In
this calculated structure, a bond is present between the boron and
the sulfur atoms (B-S = 2.100 Å), which is in the higher range of
B-S dative bonds.10b,24 Because of the weak B-S bond, the opened
form M1* can be readily accessed giving a significant nucleophilic
character to the thioamide and a borenium character to BCat. As
such, this intermediate possesses the right characteristics to activate
the C-H bond in a FLP fashion to form M2, as observed in the
aminoborane type catalysts.6,10a The aromatization of the pyridine
upon the C-H activation is expected to be a driving force in this
system. Once the B-C bond is generated, the heteroarylboronate
can be released, generating back the catalyst M3.
Figure 6. 1H NMR monitoring of the borylation of 1-
methylindole using 2-furylBCat as borylation agent.
Figure 7. 1H NMR monitoring of the borylation of 1-pyrrole
using 2-furylBCat as borylation agent.
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Notes
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The authors declare no competing financial interests.
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ACKNOWLEDGMENT
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This work was supported by the National Sciences and Engineering
Research Council (NSERC) of Canada and the Centre de Catalyse
et Chimie Verte (Quebec). E.R. and V.D. acknowledge respectively
Vanier CGS and NSERC for scholarships. We acknowledge
Compute Canada (Calcul Québec) for computation time. F.-G.F.
thanks NSERC for a Canada Research Chair.
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ASSOCIATED CONTENT
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