Solvent- and metal-free hydroboration of alkynes under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2020.151596

Boronic esters are versatile building blocks extensively used in organic chemistry and essential to a variety of coupling reactions. In this work, the hydroboration reactions of alkynes were performed without metal catalysts using concomitant microwave ir

Full text of DOI:10.1016/j.tetlet.2020.151596

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Solvent- and metal-free hydroboration of alkynes under microwave irradiation
Bruna Gioia, Alexandre Arnaud, Sylvie Radix, Nadia Walchshofer, Anne
Doléans-Jordheim, Luc Rocheblave
PII:
S0040-4039(20)30005-8
DOI:
https://doi.org/10.1016/j.tetlet.2020.151596
TETL 151596
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
6 November 2019
19 December 2019
6 January 2020
Please cite this article as: Gioia, B., Arnaud, A., Radix, S., Walchshofer, N., Doléans-Jordheim, A., Rocheblave,
L., Solvent- and metal-free hydroboration of alkynes under microwave irradiation, Tetrahedron Letters (2020), doi:
https://doi.org/10.1016/j.tetlet.2020.151596
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Solvent- and metal-free hydroboration of alkynes under microwave irradiation
Bruna Gioia,a Alexandre Arnauda, Sylvie Radixa, Nadia Walchshofera, Anne Doléans-Jordheimb, Luc
Rocheblavea*
aUniv Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, B2MC, F-69373, Lyon Cedex 08, France
bUniv Lyon, Université Claude Bernard Lyon 1, VetAgro Sup, UMR CNRS 5557, Ecologie Microbienne, F-69622, Villeurbanne, France; Laboratoire de
Bactériologie, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon (HCL), F-69000, Bron, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Hydroboration
Alkynes
Microwave
Solvent-free conditions
has been described in 1,4-dioxane.11 More recently, it has been
shown that microwave irradiation can be used for the
hydroboration of alkynes in chloroform in the presence of
different boron catalysts.18
In this work, we have focused our attention on the synthesis
of alkenyl boronates as building blocks under microwave
irradiation, using both metal- and solvent-free conditions, an
approach that was not described before.
1. Introduction
Boronic ester derivatives are important to create carbon-
carbon and carbon-heteroatom bonds1 as exemplified by the
Suzuki-Miyaura cross-coupling reaction,2 or oxidative boron
Heck reaction.3 The scope of boron-mediated reactions has
been expanded in organic chemistry to the design and
synthesis of various lead compounds in both the
pharmaceutical and agricultural industries.4, Considering
5
the widespread use of organoboron derivatives, it would be
of interest to develop a simple and eco-friendlier method to
quickly synthesize boronic esters. Alkenylboronic esters
have been traditionally obtained by the reactions of Grignard
reagents with trialkylboronates but the hydroboration of
2. Results and Discussion
7
alkynes has also found to be very efficient.6,
The hydroboration of phenylacetylene 1a, was used as a
model reaction (Scheme 1). A calibration curve was
established using a LC/UV method (see ESI) to determine
the yields of boronic ester 2a in the reaction mixture during
the development of the model reaction (Tables 1-5). Isolated
yields of all boronic acid pinacol esters 2a-t were also
determined after purification by column chromatography on
silica gel.
The most often described hydroborations of alkynes
were conducted under thermal conditions with prolonged
reaction times.8 Moreover, numerous alkyne borylations
have been described including transition metal-catalyzed
reactions.9–12
In recent years, metal-free approaches have also been
investigated:
considered as a good catalyst for the direct hydroboration of
terminal Another example involved
alkynes.13
tris(2,4,6-trifluorophenyl)borane
could
be
O
(diacetoxyiodo)benzene (PIDA) catalysis and t-BuONa for the
O
4-(dimethylamino)
benzoic acid (5 mol%)
B
HB
+
highly selective hydroboration of terminal alkynes under air
O
octane (100 °C)
O
conditions.14 Recently, Jin and co-workers proposed
a
1a
2a
classical thermal conditions, 7 h 2%
microwave irradiation, 15 min 16%
hydroboration of alkynes in solution using carboxylic acid-based
catalysis.15 However, the main drawback to these approaches was
a prolonged reaction time. Thereby, the microwave-assisted
borations of alkynes or alkenes have also been developed, as
described by Kappe and co-workers in a one-pot platinum(0)-
catalyzed diboration/Suzuki-Miyaura cross-coupling sequence in
1,4-dioxane.16 Microwave irradiation has also been applied for
the dehydrogenative borylations of alkenes in the presence of
bis(pinacolato)boron (B2(Pin)2).17 Moreover, the microwave-
assisted hydroboration of ,-unsaturated carbonyl compounds
Scheme 1. Initial conditions for the model hydroboration
reaction.
First, the hydroboration reaction of phenylacetylene 1a
was carried out under similar conditions to those described
by Jin and co-workers15 (octane as the solvent at 100 °C) but
boronic ester 2a was only obtained in trace amounts (2%)
after 7 hours (Scheme 1). At the same time, 2a was obtained

in 16% yield after 15-minute microwave irradiation under
otherwise identical reaction conditions. This promising
result encouraged us to conduct a methodological study to
optimize the reaction conditions. We considered the nature
of the solvent, whether or not a solvent was required, the
reaction temperature and the reaction time, the nature of the
catalyst and its amount.
Octane (Yield 2a, %)a,b
No solvent (Yield 2a, %)a,b
120 °C 150 °C 170 °C
120 °C
14
150 °C
63
170 °C
62
15 min
30 min
77
48
50
20
30
2
15
70
52
aReagents and conditions: phenylacetylene 1a (1 eq, 2.36 mmol), pinacol
borane (4 eq, 9.44 mmol), octane (2.4 mL), 4-(dimethylamino)benzoic acid (5
b
mol%), microwave irradiation. Yields of 2a were determined using a
Considering that octane was not an ideal solvent for
microwave irradiation (= 1.93 at 30 °C, 1 bar), the reaction
was performed in the presence of more polar solvents in
which microwave-assisted reactions are reported to proceed
more efficiently.19 Using the converting rules (according to
Arrhenius law),20 the reaction was conducted at 150 °C for
30 minutes in four different solvents as shown in Table 1.
Surprisingly, the highest yield of 2a was still obtained in
octane (Table 1, entry 4).
calibration curve after a complete conversion of the substrate 1a, under
microwave conditions at different temperatures and reaction time, in the
presence or absence of octane.
Table 3. Microwave-assisted reaction time optimization
under solvent-free conditions.
Entry
Time (min)
Yield 2a (%) a,b
1
2
3
4
5
6
5
38
57
77
64
54
48
10
15
20
25
30
Table 1. Effect of the nature of the solvent.
Entry
Solvent
1,4-Dioxane
Acetonitrile
Yield 2a (%) a,b
1
2
3
4
48
62
3
Dimethylformamide
Octane
aReagents and conditions: phenylacetylene 1a (1 eq, 2.36 mmol), pinacol
70
borane (4 eq, 9.44 mmol), 4-(dimethylamino)benzoic acid (5 mol%),
microwave irradiation, 120 °C. Yields were determined using a calibration
curve.
aReagents and conditions: phenylacetylene 1a (1 eq, 2.36 mmol),
pinacol borane (4 eq, 9.44 mmol), solvent (2.4 mL), 4-
(dimethylamino)benzoic acid (5 mol%), microwave irradiation, 150 °C,
30 min. bYields were determined using a calibration curve.
b
Table 4. Influence of various carboxylic acids as catalysts
on the hydroboration of phenylacetylene 1a with HB(Pin).
Yield 2a (%)
This result prompted us to evaluate the importance of the
solvent for this hydroboration reaction of alkynes, under
metal-free conditions using concomitant microwave
irradiation. First, the reaction was carried out at three
different temperatures (120 °C, 150 °C and 170 °C) for 15
or 30 minutes, with or without octane for comparison. As
shown in Tables 2 and 3, the best result was obtained at 120
°C after 15 minutes irradiation, under neat conditions (77%
yield, Table 2 and Table 3, entry 3). However, increasing the
reaction time did not improve the yield (Table 3, entries 4-
6).
Entry
Catalyst (pKa)
a,b
63
66
77
4
1
2
3
4
5
6
7
4-nitrobenzoic acid (3.44)
benzoic acid (4.20)
4-(dimethylamino)benzoic acid (5.03)
2-(dimethylamino)benzoic acid (8.42)
trifluoroacetic acid (0.52)
formic acid (3.75)
44
41
acetic acid (4.76)
62
aReagents and conditions: phenylacetylene 1a (1 eq, 2.36 mmol), pinacol
borane (4 eq, 9.44 mmol), carboxylic acid catalyst (5 mol%), microwave
We further investigated the nature of the catalyst for this
reaction (Table 4). As Jin and co-workers have shown that
the carboxylic group was crucial for the catalytic
hydroboration of alkynes with HB(Pin) in octane,15 different
carboxylic acids were evaluated. These results showed that
the catalytic activity depends on the acidity of carboxylic
acids. The use of stronger acids resulted in lower yields
b
irradiation, 120 °C, 15 minutes.
calibration curve.
Yields were determined using a
Finally, we observed that the maximum yield of boronic
ester 2a was observed with mol% of 4-
5
(dimethylamino)benzoic acid (Table 5, entry 3). It is worth
noting that an increase of the catalyst amount did not
(Table 4, entries
5
and 6). The weaker 4-
increase the reaction yields (Table 4).
Table 5. Effect of the amount of 4-(dimethylamino)benzoic
acid as a catalyst.
(dimethylamino)benzoic acid proved to be the best catalyst.
It is worth noting that 2-(dimethylamino)benzoic acid was
much less efficient under our solvent-free conditions and
gave boronic ester 2a with a very low 4% yield (Table 4,
entry 4). This different catalytic activity has previously been
reported15 and could be explained by the formation of an
inactive four-coordinate boron species bound to the N and O
atoms of 2-(dimethylamino)benzoic acid.
4-(dimethylamino)
Entry
Yield 2a (%) a,b
benzoic acid (mol%)
1
2
3
4
5
1
31
64
77
71
70
4
5
6
10
aReagents and conditions: phenylacetylene 1a (1 eq, 2.36 mmol),
pinacol borane (4 eq, 9.44 mmol), 4-(dimethylamino)benzoic acid (from
Table 2. Reaction condition optimization in octane or solvent-
free medium under microwave irradiation.

b
1 to 10 mol%), microwave irradiation, 120 °C, 15 min. Yields were
determined using a calibration curve.
lower yields (35-43%) when the hydroboration was carried
out in octane under otherwise identical reaction conditions.
All of the final boronic esters prepared from terminal
alkynes (R’ = H), were stereoselectively obtained with a
trans double bond whose stereochemistry was checked by
At this stage, these new combined solvent- and metal-
free hydroboration conditions were applied to a wide scope
of aromatic or aliphatic alkynes to obtain the corresponding
boronic esters 2a-t in moderate to excellent yields (Table 6).
This reaction proceeded through an anti-Markovnikov and
syn-addition of HB(Pin) to the alkynes.
3
1H NMR (the coupling constant JHH, measured from the
displacements of alkenyl protons, was approximately equal
to 18 Hz).
Table 6. Solvent- and metal-free hydroboration of various
3. Conclusion
aryl- or alkyl-alkynes under microwave irradiation.
In this paper, we have developed a solvent- and metal-
free approach to synthesize boronic esters under microwave
irradiation, which significantly reduced the reaction time
from hours to minutes. This simple and eco-friendlier
procedure has been applied on a wide scope of aromatic and
aliphatic alkynes to lead to the corresponding boronate
esters.
O
O
4-(dimethylamino)
benzoic acid (5 mol%)
B
HB
+
R
R'
R
O
O
no solvent, MW
(120 °C, time)
R'
1a-t
2a-t
Boronic
esters
Time
(min.)
R
R’
Yield 2 (%) a,b
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
15
15
15
15
15
15
15
-
Ph
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
62 (77) c
60
58
79
28
65
48
0
3-(MeO)C6H4
4-(MeO)C6H4
PhCH2
Acknowledgements
Ph
The authors would like to thank the Vaincre la
Mucoviscidose (VLM) and Gregory Lemarchal associations
for the financial support over these past two years. They
thank Pr T. Lomberget for his helpful discussions for this
work. They thank the Ministère de l’Education Nationale de
la Recherche et de Technologie (MENRT) and Ecole
Doctorale Interdisciplinaire Sciences-Santé (EDISS) for the
PhD fellowship of B. Gioia. The authors acknowledge the
helpful suggestions made by Drs L.P. Jordheim, D. Goldie,
J.P. Salvi.
3-(MeO2C)C6H4
4-(MeO2C)C6H4
CH2NH2
CH2NHCH3
CH2OCH3
3-Cl-C6H4
4-Cl-C6H4
(CH2)nCH3 n=2
n=3
-
0
15
15
15
30
30
30
30
30
30
30
30
34
55
92
35
54
64
58
50
62
61
88
n=4
n=5
n=6
n=7
n=8
n=9
References and notes
2t
aReagents and conditions: alkyne (1 eq, 2.36 mmol), pinacol borane (4
eq, 9.44 mmol), 4-(dimethylamino)benzoic acid (5 mol%), microwave
irradiation, 120 °C. b Isolated yields. c Yield shown in parentheses was
determined using a calibration curve. Estimated and isolated yields
could differ because boronate 2a is volatile.
(1)
(2)
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(4)
(5)
As shown in Table 6, this procedure was compatible with
many functional groups such as ethers, esters or chlorine
atoms. In the case of the hydroboration of methyl propargyl
ether or pent-1-yne, the corresponding boronic esters 2j and
2m were obtained with poor isolated yields. In both cases,
purification by column chromatography was challenging
because the Rf values of the alkyne and the corresponding
boronic ester were very close. Moreover, it is worth noting
that the hydroboration did not proceed when propargyl
amines 2h and 2i were used as starting materials. In this
case, the reaction resulted in gas release, which was
presumably hydrogen, produced after a dehydrocoupling
reaction between pinacol borane and amine functionalities.21
This method also allowed us to obtain the more sterically
hindered (Z)-stilbeneboronic acid pinacol ester 2e from
diphenylacetylene and HB(Pin) in a moderate 28% yield.
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The H NMR spectral characteristics of 2e were identical to
that previously published,22 attesting to the syn addition of
HB(Pin) onto the triple bond.
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a minor adjustment concerning the reaction time. It was
observed that the best yields were obtained at 120 °C for 30
min for alkynes having various chain lengths (i.e. C5-C12):
the corresponding aliphatic boronic esters 2m-t were
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Graphical Abstract
Leave this area blank for abstract info.
Solvent- and metal-free hydroboration of
alkynes under microwave irradiation
Bruna Gioia,a Alexandre Arnauda, Sylvie Radixa, Nadia Walchshofera, Anne Doléans-Jordheimb, Luc
Rocheblavea*
a Univ Lyon, Université Claude Bernard Lyon 1, ISPB-Faculté de Pharmacie, EA 4446, B2MC, F-69373, Lyon Cedex 08, France
b Univ Lyon, Université Claude Bernard Lyon 1, VetAgro Sup, UMR CNRS 5557, Ecologie Microbienne, F-69622, Villeurbanne, France; Laboratoire de
Bactériologie, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon (HCL), F-69, Bron, France
O
O
4-(dimethylamino)
benzoic acid (5 mol %)
B
HB
+
H
R
R
O
O
no solvent, MW
(120 °C, time)
H