Boron Recycling in the Metal-Free Transfer C-H Borylation of Terminal Alkynes and Heteroarenes

Article abstract of DOI:10.1021/acscatal.0c02682

Transfer C-H borylation is an isodesmic approach to the borylation reaction using B-C-containing molecules as boron sources. In this work, we report that 2-mercaptothiazole and other analogues are active for the metal-free borylation of heterocycles and t

Full text of DOI:10.1021/acscatal.0c02682

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Article
Boron Recycling in the Metal-Free Transfer C-
H Borylation of Terminal Alkynes and Heteroarenes
Vincent Desrosiers, Cecilia Zavaleta Garcia, and Frédéric-Georges Fontaine
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02682 • Publication Date (Web): 31 Aug 2020
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ACS Catalysis
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Boron Recycling in the Metal-Free Transfer C-H Borylation of Terminal
Alkynes and Heteroarenes
Vincent Desrosiers,a Cecilia Zavaleta Garcia,b Frédéric-Georges Fontainea*
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a Département de Chimie, Université Laval, 1045 Avenue de la Médecine, Quebec City, Quebec, G1V 0A6, Canada.
b Departamento de Química, Cerro de la Venada s/n, C.P. 36040, Guanajuato, Gto, Mexico.
Keywords: Metal-free catalysis • Transfer borylation • C-H activation • Boron recycling • Conjugate addition
Supporting Information Placeholder
sensitive and show low tolerance to many functional
groups. Diboron(4) compounds are also widely
used,10,17,18 but the generation of hydroboranes during
catalytic cycles can be detrimental to catalysis by
reacting with some important functional groups, notably
those that are protic or that can undergo hydroboration
reactions.19 In addition, most of these systems are air
and moisture sensitive and require anhydrous conditions
to operate.
ABSTRACT: Transfer C-H borylation is an isodesmic
approach to the borylation reaction using B-C containing
molecules as boron sources. In this work, we report that
2-mercaptothiazole and other analogues are active for
the metal-free borylation of heterocycles and terminal
alkynes. Alkynes are challenging substrates to C-H
borylate since they undergo side-reactions with most
borylating agents. The ability of these metal-free
catalysts to activate B-C bonds can also be translated to
the activation of B-O bonds in the products of the 1,4-
conjugate addition of alkynylboranes to chalcones. It is
therefore possible to prepare β-alkynylketones from the
corresponding alkynes in a process where the boron
source is used in sub-stoichiometric amounts. The
mechanism and degradation patterns of these catalytic
transformations have been investigated.
Although widely used, boronate functional groups are
mostly considered sacrificial. Therefore, the high cost of
these reagents can be problematic in large-scale
processes where the production costs are high and the
profit margins are low, such as in the agrochemical or
modern materials industries. In an attempt to reduce
synthetic steps, simpler methodologies such as tandem
borylation/functionalization have been reported,20–29
removing one isolation step by having one-pot reactions.
While we have been looking at the design of cheap and
metal-free catalysts for the C-H borylation30–33 using the
concept of FLP chemistry,34–41 a topic of current interest
in metal-free catalysis,42–48 our current efforts are
towards recycling the boronate moiety from the final
products during C-H borylation tandem processes. In
such a process, the borylation reagent could be used in
catalytic amount (Scheme 1). Using a similar concept,
Gellrich and collaborators recently reported a metal-free
pyridonate borane catalyst for the dimerization of
terminal alkynes.49 Still, the development of this type of
reaction is surprisingly stagnant.
INTRODUCTION
The boron-carbon bond is a versatile functional group in
synthetic chemistry. The ability to use alkyl- and
arylboronates to create carbon-carbon bonds via Suzuki-
Miyaura coupling1 or carbon-heteroelement bonds via
Chan-Evans-Lam coupling2,3 makes them attractive
substrates for the synthesis of fine chemicals.4
Consequently, there is a significant interest in the
development of methodologies to create boronate
reagents. While several stoichiometric processes to
borylate organic molecules exist,5–8 usually involving
strong bases, catalysis for the construction of B-C bonds
is an appealing green alternative.9 In these
transformations, C-X10–12 or C-H9,13–16 bonds are
activated to generate the desired molecules. However,
the borane reagents of choice for these catalytic
processes (hydroboranes or haloboranes) are air
We recently demonstrated that 2-mercaptopyridine
could be used as a catalyst for the C-H borylation of
heteroarenes using ArBcat as borylation agent (Ar = 2-
furyl, 4-tolyl, 4-anisyl) by a mechanism illustrated in
Scheme 2.33 This reaction is based on the concept of
isodesmic reactivity,50 aka transfer borylation, which
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allows using arylboronates as boron sources. The system
Page 2 of 14
O
N
O
Bcat
H
1
2
3
4
5
6
7
8
Via
showed good tolerance towards moisture and could
tolerate functional groups that are usually problematic in
C-H borylation methodologies, such as alkynes, alkenes
and nitriles. However, it suffered from low TOF and
TON and required high temperatures to operate. Herein,
we report a new generation of robust catalysts for the
transfer borylation of arenes and terminal alkynes. This
system constitutes the first reported example of a metal-
free catalyst for the C-H borylation of terminal alkynes.
We also demonstrate that this approach can be used to
recycle the boron moiety in tandem C-H
borylation/functionalization reactions by performing 1,4
conjugate addition on chalcone derivatives. To our
knowledge, this report is the first example of a C-H
borylation reaction where the reaction requires only a
sub-stoichiometric amount of borylation agent.
‡
N
S
H
E
[B]
N
S
SH
Bcat
Lewis pair C-H
activation
N
N
Bcat
H
9
Scheme 2. Previously reported transfer C-H borylation
using 2-mercaptopyridine as catalyst33
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RESULTS
Catalyst design. While 2-mercaptopyridine proved to
be a good catalyst for transfer borylation using 2-
furylBcat (2a), it was less efficient when using 4-
anisylBcat (2b), 4-tolylBcat (2c) and phenylBcat (2d),
which are all less expensive and more practical
borylation agents.33,51 In order to cleave the strong B-C
bond in the latter reagents, we sought to find more active
catalysts that have both a Lewis base and Brönsted acid,
such as in 2-mercaptopyridine (1d). Since modifying the
electronic properties of the pyridine backbone did not
yield significant change in reactivity, we investigated the
impact of ring size on the reaction. We screened
commercially available 5-membered rings 2-
mercaptothiazole (1a), N-methyl-2-mercaptoimidazole
(1b) and 2-mercaptooxazole (1c), first using
computational chemistry.
a. Sequential approach
C-H borylation
C-C coupling
C2
Desired product
B
C1
C1
C1
H
C2
Coupling partner
X
B
Y
Stoichiometric
boron source
b. Tandem approach
C-C coupling
C-H borylation
C2
Desired product
C1
C1
H
C2
Coupling partner
X
B
Y
Stoichiometric
boron source
c. Boron recycling approach
C-H borylation
As seen in Scheme 3, we optimized the intermediates
and transition states using DFT (ωB97XD/def2-
TZVP52,53). The important steps in this mechanism are
the B-C bond cleavage of the arylboranate (TS1) and the
C-H activation of the arene (TS2). Both processes are
concerted and typical of FLP chemistry and no impactful
C1
H
Y
H
Sub-stoichiometric
boron source
B
B
Y
C1
This work
C2
X
C2
Desired product
C1
borenium-type intermediates were observed.
The
C-C coupling
energy barrier for the B-C bond cleavage, which is rate
limiting in this catalytic process, is predicted to be lower
with catalysts 1a-c (21.9-23.4 kcal mol-1) than with the
2-mercaptopyridine (28.6 kcal mol-1). Interestingly, the
energy required for the C-H activation from the resting
state (about 20 kcal mol-1) is similar in all systems.
Scheme 1. Approaches to borylation/functionalization
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Scheme 3. Gibbs free energies (ΔG) in kcal mol−1 of the intermediates and transition states for the borylation of N-
methylpyrrole by catalysts 1a-1d calculated at DFT/ωB97XD/def2-TZVP level of theory.
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Table 1. Distortion energies of catalysts 1a-d calculated at
the DFT/ωB97XD/def2-TZVP level of theory.
One hypothesis to explain the lower energy of the
transition state for the B-C bond cleavage is the optimal
geometry of the new catalysts. Indeed, 5-membered
N-C-Sangle ΔE‡
‡
‡
‡
Cat.
ΔEd
ΔEd
ΔEd ΔEi‡
cat
sub
rings lead to a greater N-C-S angle than 6-membered
rings (see Table 1). This change reduces the distortion in
the transition state, making it more readily accessible.
To verify this hypothesis, a strain-distortion/interaction
model was used.54 It allows to separate the electronic
energies of a transition state ΔE‡ in two factors: the
°
kcal mol-1
47.4
1a
1b
1c
1d
124.8
126.3
125.8
118.2
17.7 42.6
16.7 48.2
16.6 43.4
21.9 52.1
90.0 -72.2
97.6 -80.9
88.7 -72.2
106.0 -84.0
49.6
45.3
53.9
‡
distortion energies (ΔEd ) and the interaction energies
‡
(ΔEi‡). ΔEd corresponds to the energies required to bend
With these encouraging computational results in hand,
we tested these candidates for the isodesmic C-H
borylation of N-methylindole (3a). While all catalysts
yielded quantitatively the C3-borylated product (4a)
with 2-furylBcat (2a) in the specific conditions tested
(see Table 2), the 5-membered ring catalysts 1a-c
exhibited significantly higher conversions with 4-
the different components from their ground state to their
geometry in the transition state and the ΔEi‡ corresponds
to the electronic energies that stabilize that given state.
As shown in Table 1, species 1a-c have lower distortion
energies (90.0, 97.6 and 88.7 kcal mol-1, respectively)
than 1d (106.0 kcal mol-1), indicating that the increased
NCS angle is contributing to the decreased energy
barrier.
anisylBcat
(2b)
and
4-tolylBcat
(2c).
2-
mercaptothoazole (1a) seemed to be the most efficient
catalyst as it was able to convert 3a to the 3-Bcat-N-
methylindole (4a) with conversions of 42 % and 19 %
with boron sources 2b and 2c, respectively.
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Table 2. Borylation of N-methylindole with various boron Table 3. Optimization of the borylation of N-methylindole.
sources.
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Entry
Catalyst
2a Temp Time
Conv.a
8
9
(mol %) equiv
°C
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110
110
110
110
80
80
80
50
20
h
18
4
4
4
18
18
18
18
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4
%
> 95
> 95
> 95
93
> 95
> 95
89
82
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26
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1a (10)
1a (10)
1a (5)
1a (2)
1a (2)
1a (10)
1a (5)
1a (2)
1a (10)
1a (10)
1d (5)
2
2
2
2
2
2
2
2
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2
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110
Conversion obtained via 1H NMR. Reactions were
carried out in Teflon sealed NMR tube (J.-Young) with
0.15 mmol of substrate and a hexamethylbenzene internal
standard.
a
a
Reactions carried out for 24 h at with 25 mol % catalyst
loading and 5 equiv of the boron source.
Borylation of arenes. Since 2-mercaptothiazole (1a)
gave the best conversion with N-methylindole, it was
chosen for further optimization (Table 3). By directly
comparing with the catalytic activity of 2-
mercaptopyridine (1d, Entry 12), 1a was more reactive
since we could reduce the catalyst loading from 25 % to
5 %, the excess of borylating agent from 5 equiv to
2 equiv and the reaction time from 24 h to 4 h and still
reach over 95 % conversion (Entry 3). Alternatively, the
reaction can be carried out at 80 °C overnight at the cost
of higher catalyst loading (Entry 6). Interestingly, 26 %
conversion was observed simply by leaving the reaction
at ambient temperature overnight (Entry 11), which is
expected for reactions having predicted energy barriers
ranging from 21.9 to 23.4 kcal mol-1. One hypothesis for
the higher yields using elevated temperatures (80 °C or
110 °C) is that the removal of the volatile furan from the
solution to the gas phase drives the thermodynamically
controlled reaction to completion.
With these optimal conditions, 1a proved more efficient
than 1d for the borylation of a large variety of substrates
(4a-4f, Scheme 4). As expected, the system remains air
and moisture stable and demonstrates a good tolerance
and selectivity towards esters, alkynes and nitriles.
Although the increase in reactivity with 1a is notable
compared to our previous report, the borylation of N,N-
dimethylaniline (4g) remains challenging, with only
12 % conversion after 18 h.
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boranes could be generated in presence of BF3 and bulky
pentamethylpiperidine.43
1
2
Using 2-mercaptothiazole (1a) for the C-H borylation of
phenylacetylene (5a) in the presence of 2-furylBcat (2a)
gave only a 48 % conversion (Table 4, Entry 1).
However, N-methyl-2-mercaptoimidazole (1b) reacted
with phenylacetylene (5a) and 2-furylBcat to give 90 %
of conversion after 18 h at 110 °C (Entry 3). While the
reaction also worked with 1c and 1d, it provided low
conversion of 66 % and 58 %, respectively (Entries 4
and 5). Increasing the catalyst loading, using excess of
the boron source or increasing the reaction time did not
give conversion over 90 % (Entries 6 to 8).
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Table 4. Condition optimization for the borylation of
phenylacetylene (5a).
Entry
Catalyst
Temp
2a
Time Conv.a
(mol %)
1a (5)
1b (5)
1b (5)
1c (5)
1d (25)
1b (5)
1b (10)
1b (5)
°C
equiv
h
18
4
18
18
18
18
18
48
%
48
85
90
66
58
83
90
90
1
2
3
4
5
6
7
8
110
110
110
110
140
110
110
2
2
2
2
5
5
2
2
Scheme 4. Borylation scope for selected arenes. Conversion
obtained via H NMR by the consumption of the starting
material in relationship with the internal standard.
Reactions were carried out in a Teflon sealed NMR tube
1
110
(J.-Young) with 0.15 mmol of substrate and
a
a
1
hexamethylbenzene internal standard.a Mixture of C2-,
Conversion obtained via H NMR by the consumption of
the starting material in relationship with the internal
standard. Reactions were carried out in a Teflon sealed
NMR tube (J.-Young) with 0.15 mmol of substrate and a
hexamethylbenzene internal standard.
C3-borylated and C2,4-bisborylated products in
0.09 mmol scale reaction with 5 equiv of 2a.
a
Borylation of terminal alkynes. While the reactivity
with the N-(CH2C≡CH)-indole (3b) shows that the C-H
activation at the 3-position of the indole is favored over
the activation of the C-H bond of the alkyne (Scheme 4),
we were curious to see if the latter type of activation was
possible. Borylated alkynes are used in synthesis,55 but
the catalytic C-H borylation of alkynes is still
underdeveloped compared to the activation of arenes.
Ozerov and coworkers reported in 2013 an Ir catalyst for
C-H borylation of these substrates.56–58 By carefully
designing a SiNN pincer ligand, they were able to steer
the selectivity of their catalyst away from the usual
aromatic Csp2-H bonds towards Csp-H bonds. This
discovery sparked the rapid development of new
methodologies using various metals like Ag, Zn, Fe, Cu
and Pd.59–64 The first stoichiometric metal-free Csp-H
bond activation using FLPs was reported by Stephan and
collaborators in 200965 and the dehydroboration of
terminal alkynes using borenium species was observed
by Ingleson and collaborators in 2013,73 but to our
knowledge, no catalytic system has been developed for
such a reaction.43,49,65–74 The closest analogy has been
reported by Repo, who demonstrated that alkynyl
With these results in hand, we explored the scope of the
reaction, as demonstrated in Scheme 5. Aromatic
alkynes (6a-l) were smoothly borylated with good
conversion. Under these catalytic conditions, the
selectivity of the Csp-H over the Csp2-H of arenes is
excellent and with electron-rich 3-thienylacetylene (6l)
no borylation on the thiophene ring was observed.
However, since 3b is selectively borylated at the C3
position, it should be noted that this selectivity remains
substrate dependent. Aliphatic alkynes (6m-p) also
underwent borylation with good conversions, although
propargylic esters were more challenging (6q), obtaining
only 23 % conversion. It is also possible to borylate the
TIPS protected alkyne (6r), although the TMS analogue
(5x) did not yield the desired product (vide infra). The
borylation of diynes (6s-u) can also be achieved, giving
a mixture of mono- and bis-borylated products in the
presence 5 equiv of 2-furylBcat (2a). Interestingly,
unprotected alcohols (6v-w) could also be borylated, but
the reaction required 3 equiv of the boron source since 1
equivalent is consumed for the borylation of the O-H
bond, which was shown to occur under 5 min at 20 ℃.
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This is particularly interesting since alcohols have been since protodeborylation still occur during workup,
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8
shown to inhibit the C-H borylation reaction with
aminoborane catalysts.30,75
especially with electron-deficient substrates. It is
important to note that unlike previously reported
methodologies,76 the addition of triethylamine for the
transesterification step lead to complete degradation of
the product. These reactions can be carried out on the
gram scale, as demonstrated with the isolation of 1.028 g
of 6a.
While the isolation of the alkynylBcat products was
challenging, the transesterification to generate
alkynylBpin followed by a short filtration on alumina
and the removal of the remaining volatiles under
vacuum yielded analytically pure samples. However, the
isolated yields are sometime lower than the conversion
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1
Scheme 5. Borylation scope for terminal alkynes. Conversion obtained via H NMR by the consumption of the starting
a
b
material in relationship with the internal standard. Isolated yields in parentheses. 8.00 mmol scale reaction. See ESI.
Isolated as the catechol boronate ester. Presence of impurities in the isolated product. Too volatile for isolation.
Unstable product. 0.09 mmol scale reaction with 5 equiv of 2a. Bis borylated product isolated. Reaction carried out
using 3 equiv of 2a.
c
d
e
f
g
h
We investigated the mechanism of this transformation
using DFT. We found the reaction operating according
to a mechanism analogous to the arene transfer C-H
borylation that we previously disclosed (Scheme 6).33
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Both the transition states of the B-C bond cleavage Similar reactivity was observed with every catalyst.
(21.9 kcal mol-1) and of the C-H activation
(22.1 kcal mol-1) are very close in energy. The overall
process is exergonic by 5.0 kcal mol-1, which is more
important than the borylation of arenes since
alkynylboronates are thermodynamically more stable
than arylboronates.
These products were unstable. Instead, we were able to
isolate the secondary alkenes 7a*, 7b* and 7d* (see
Scheme 7a) resulting from the protodeborylation of the
addition products, confirming the Markovnikov addition
taking place. However, with TMS-acetylene, a substrate
that was found particularly challenging to C-H borylate,
we were able to isolate species 7e’, which is formally
the thioboration of the alkyne with catalyst 1b. Its X-ray
structural characterization supports our hypothesis
(Scheme 7). The N1-B1 bond length of 1.573(2) Å is in
the shorter range of dative N-B bonds,78 supporting a
strong interaction between the Lewis base and the
boronate.
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While several plausible mechanisms were tested using
computational chemistry, the most viable pathway to
obtain 7 is the concerted nucleophilic attack by the
thione and electrophilic boronation of the alkyne from
the resting state. Such process is reminiscent of FLP
addition chemistry.49,68,79–85 While both Markovnikov
and anti-Markovnikov additions are accessible, the
former is favored by approximatively 5.1 kcal mol-1
(1b), explaining the selectivity observed with our
substrates. Other mechanisms, such as the S-H addition
of the alkynylboranate via the carbophilic activation of
the alkyne by 2-furylBcat (2a), analogous to the work of
Blum and co-workers, were not viable processes
according to DFT.86–88
Computational chemistry clearly shows that 2-
mercaptothiazole is more prone than other catalysts to
generate the addition product, as the difference between
the borylation and thioboration energies is only
1.8 kcal mol-1 (Table 5). On the other hand, N-methyl-2-
mercaptoimidazole (1b) is the most selective for the
borylation, by 3.3 kcal mol-1.
Scheme 6. Mechanism of transfer C-H borylation of
terminal alkynes.
To get a better understanding of this reaction, we also
looked for deactivation pathways that could explain the
low yields obtained with some substrates and catalysts.
When reacting p-tolylacetylene (5b) with N-methyl-2-
mercaptotimidazole (1b), no reaction occurred.
However, adding 2-furylBcat (2a) to this reaction
mixture led to the formation of a new product (7b),
which is formally the addition product of the alkyne on
the corresponding S/B Frustrated Lewis pair (Scheme 7),
Table 5. Transition state energies for C-H borylation of
terminal alkyne and thioboration of phenylacetylene (5a)
by 1a-1d calculated at DFT/ωB97XD/def2-TZVP level of
theory.
ΔG‡
Cat.
ΔG‡
ΔΔG‡
borylation
1
thioboration
i.e. thioboration. H NMR shows the disappearance of
kcal mol-1
24.3
the Csp-H proton at δ 3.05 and the appearance of a new
singlet at δ 6.51 corresponding to the olefinic proton
formed during the thioboration. The 11B NMR signal
shifts from a broad singlet at δ 28.3 to a sharper singlet
at δ 8.1, which is a chemical shift similar to previously
reported intramolecular azole boronate adducts.77
1a
1b
1c
1d
22.4
22.1
22.3
25.6
1.8
3.3
2.3
2.6
25.4
24.5
28.2
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a. Degradation of the catalyst via thioboration
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2
3
S
N
4
5
6
7
N
N
O
N
S
+
+
N
SH
B
Bcat
CDCl3, 24 h, 110 °C
[H2O]
O O
N
1.2 eq.
5b
1.2 eq.
7b*
2a
1b
8
9
7b (major)
Markovnikov type
thioboration
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S
N
N
N
N
O
B
O O
Si
+
+
SH
Si
Bcat
CDCl3, 24 h, 110 °C
1.2 eq.
5x
1.2 eq.
2a
1b
7e’ (major)
Anti-Markovnikov
type thioboration
b. Transition states for the thioboration of phenylacetylene (5a) of N-methyl-2-mercaptoimidazole (1b)
TS Markovnikov
25.4 (12.5)
TS anti-Markovnikov
30.5 (17.2)
Scheme 7. Catalyst deactivation via thioboration. Transition states calculated at the DFT/ωB97XD/def2-TZVP level of
theory, energies ΔG (ΔH) in kcal mol−1. Thermal ellipsoid set at 50 % probability.
Catalytic 1,4 conjugate addition. We sought to
develop a transformation where the boronate moiety
could be recycled after the C-H borylation product was
used as a reagent. We got inspired by the work of Chong
and co-workers who reported that alkynyl boronates can
undergo a metal-free conjugate 1,4-conjugate reaction
with α-β unsaturated enones, such as chalconoids.89
Although this reaction is usually assisted by transition
metal catalysts,90–92 we hypothesized that the
catecholboronate would be electrophilic enough to make
this reaction possible without the help of a transition
metal. We also hypothesized that the enolization of the
resulting product could act as a driving force for the
catalyst to recover the boronate at the end of the
reaction.
along with complete consumption of 8a. To prevent this
side-reaction, we used 4-anisylBcat 2b as the boron
source, which does not react with the chalcone by itself,
allowing for 76 % conversion without any undesired
side product (Table 6, Entry 2). Interestingly, we noted
that only 37 % of 2b was consumed during the reaction,
hinting that the boronate moiety of the addition product
could be reused as a borylation agent for the C-H
borylation. It was demonstrated that
stoichiometric amount of the boron source was
a
subs-
required, since 55 % conversion (or 2.2 turnover) was
observed when only 25 mol % of 2b was used (Entry 3).
Although 2c and 2d were initially considered unreactive
boron sources, they also showed the ability to perform
this reaction, albeit in lower yields (Entries 5 and 6).
This suggests that the addition to the chalcone acts as a
thermodynamic driving force for the transfer C-H
borylation. Further optimization of the reaction
conditions allowed to obtain quantitative conversions
after 18 h at 110 °C using 10 mol % catalyst loading,
By using trans-chalcone (8a), we were able to carry out
a one-pot borylation catalyzed by 1b, followed by the
1,4-conjugate addition to yield addition product 9b with
59 % conversion (see Table 6, Entry 1). Surprisingly, the
addition product of 2-furylBcat (2a) was also observed,
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40 mol % of 2b and 2 equiv of the alkyne (Entry 8). This reaction could operate using various arylacetylene
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5
6
7
8
Therefore, it is possible to do the tandem C-H
borylation/Michael addition of alkynes using a sub-
stoichiometric amount of borylation agent.
derivatives with conversions up to 95% (Scheme 8, 9a-
e). Interestingly, it was possible to do the addition of
heteroarenes such as indoles, pyrroles and thiophene to
chalcone 8a to generate products 9f-h. Various
chalconoids were also screened to give products 9i-l. In
several cases the yields are lower, which is mainly
explained by the deactivation of the catalyst by
thioboration of the alkyne, as previously discussed.
Table 6. Condition optimization of the one-pot borylation
and addition of terminal alkynes to α-β unsaturated
ketones.
9
The mechanism was investigated by DFT (Scheme 9).
As expected, the catalyst first cleaves the B-C bond of
the borylation agent 2b to generate the active B/S Lewis
pair, which in turn can do the C-H activation of the
alkyne with a barrier of 22.1 kcal mol-1. The alkynyl
boronate does the 1,4-conjugate addition with the
chalcone to yield the alkoxyboronate intermediate. This
step is rate limiting with an energy barrier of
25.6 kcal mol-1. The boronate is then recovered by the
catalyst with a low barrier of 9.5 kcal mol-1 for the B-O
cleavage step. The enolization of the product makes this
process exergonic by 9.0 kcal mol-1. Although the
inability to isolate alkynylBcat derivatives prevents the
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Entry
5b
Ar-Bcat
Temp Time Conv.a
equiv
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
(mol %)
2a (200)
2b (200)
2b (25)
2b (10)
2c (25)
2d (25)
2b (25)
2b (40)
°C
h
%
59b
75
1
2
3
4
5
6
7
8
110
110
110
110
110
110
110
110
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18
18
18
18
50
22
32
16
systematic
spectroscopic
monitoring
of
this
transformation, we were able to observe each individual
step in this transformation using furylBcat that is
undergoing similar reactivity to alkynyl derivatives (see
ESI pp S115-S120).
64
> 95
Conversions obtained via 1H NMR. Reactions were
carried out in Teflon sealed NMR tube (J.-Young) with
0.15 mmol of substrate and a hexamethylbenzene internal
standard. Mixture of 9b and the addition product with
2a.
a
b
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Scheme 8. Borylation/addition scope for terminal alkynes, arenes and chalconoids. Conversion obtained via 1H NMR by the
consumption of the starting material in relationship with the internal standard. Isolated yields in parentheses.
CONCLUSION
In conclusion, we report a new generation of catalysts
for the transfer C-H borylation of heteroarenes and
alkynes. It was shown that the 2-mercapto-azole rings
have a lower distortion energy in the transition state for
the B-C bond cleavage, affording overall a more active
system. While these catalysts are quite efficient, the
thioboronate intermediates can undergo irreversible
FLP-type addition with alkynes, leading to the
deactivation of the catalyst. We also demonstrated that
this catalytic system can do the tandem C-H
borylation/1,4 conjugate addition of alkynes and
heteroarenes using sub-stoichiometric amounts of boron
precursors. We believe this boron recycling approach
will find broader applications in all systems where
arylboronates are used. We are notably looking at
exploiting this concept in Miyaura-Suzuki coupling
reactions, potentially removing the need for
stoichiometric borylation reactions.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website.
Scheme 9. Proposed catalytic cycle for the C-H
borylation/1,4-conjugate addition.
General procedures and characterization data (PDF)
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Angew. Chem., Int. Ed. 2009, 48, 5350–5354.
Cartesian coordinates of all computed intermediates and
transition states geometry (XYZ)
Crystallographic data of 7e’ (CIF)
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Chow, W. K.; Yuen, O. Y.; Choy, P. Y.; So, C. M.; Lau, C. P.;
Wong, W. T.; Kwong, F. Y. A Decade Advancement of
Transition Metal-Catalyzed Borylation of Aryl Halides and
Sulfonates. RSC Adv. 2013, 3, 12518–12539.
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AUTHOR INFORMATION
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Wang, L.; Cui, X.; Li, J.; Wu, Y.; Zhu, Z.; Wu, Y. Synthesis of
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Broutin, P. E.; Čerňa, I.; Campaniello, M.; Leroux, F.; Colobert,
F. Palladium-Catalyzed Borylation of Phenyl Bromides and
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Bej, A.; Srimani, D.; Sarkar, A. Palladium Nanoparticle
Catalysis: Borylation of Aryl and Benzyl Halides and One-Pot
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Coupling. Green Chem. 2012, 14, 661–667.
Pandarus, V.; Gingras, G.; Béland, F.; Ciriminna, R.; Pagliaro,
M. Clean and Fast Cross-Coupling of Aryl Halides in One-Pot.
Beilstein J. Org. Chem. 2014, 10, 897–901.
Baudoin, O.; Cesario, M.; Guénard, D.; Guéritte, F. Application
of the Palladium-Catalyzed Borylation/Suzuki Coupling (BSC)
Reaction to the Synthesis of Biologically Active Biaryl Lactams.
J. Org. Chem. 2002, 67, 1199–1207.
Corresponding Author
* E-mail : Frederic.Fontaine@chm.ulaval.ca
OCRID
Vincent Desrosiers: 0000-0003-1701-0240
Cecilia Zavaleta Garcia :0000-0002-4843-0056
Frédéric-Georges Fontaine: 0000-0003-3385-0258
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Funding Sources
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Sciences and
Engineering Research Council (NSERC) of Canada and the
Centre de Catalyse et Chimie Verte (Québec). V.D.
acknowledges Fonds de recherche du Québec - Nature et
Technologie (FRQNT) and NSERC for scholarships.
C.Z.G. acknowledge Mexican Council for Research and
Technology (CONACYT) and the Universidad de
Guanajuato 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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