Copper-catalyzed protodeboronation of arylboronic acids in aqueous media

Article abstract of DOI:10.1039/c4ra11659c

A general and efficient protocol for the CuSO₄·5H₂O-catalyzed protodeboronation of arylboronic acids in aqueous ethanol is described. This catalytic system exhibits high activity towards a wide range of arylboronic acids. The results

Full text of DOI:10.1039/c4ra11659c

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Copper-catalyzed protodeboronation of
arylboronic acids in aqueous media†
Cite this: RSC Adv., 2014, 4, 54307
*
Chun Liu, Xinmin Li, Yonghua Wu and Jieshan Qiu
Received 11th August 2014
Accepted 14th October 2014
DOI: 10.1039/c4ra11659c
www.rsc.org/advances
A general and efficient protocol for the CuSO4$5H2O-catalyzed pro- rapid and quantitative protodeboronation at pH 12. These
todeboronation of arylboronic acids in aqueous ethanol is described. ndings provide an insight into the stability of ortho-
This catalytic system exhibits high activity towards a wide range of substituted arylboronates for use in the Suzuki–Miyaura cross-
arylboronic acids. The results demonstrate that the proto- couplings. To the best of our knowledge, there are no reports
deboronation reaction is promoted by oxygen.
on the cheap metal-catalyzed efficient protodeboronation of
arylboronic acids.
The protodeboronation is usually considered as no practical
value for organic syntheses. Fortunately, remarkable progress in
applying the protodeboronation to organic syntheses has
recently been made by several groups. Aggarwal's group17–20
reported a series of investigations on applying the proto-
deboronation of boronic esters to stereo-selective synthesis of
natural and non-natural products. For example, using 1.5 equiv.
of CsF, 1.1 equiv. of water in dioxane or using 1.5 equiv.
TBAF$3H2O in pentane at 45 ꢀC, various boronic pinacol esters
afforded the protodeboronation products in excellent yields and
selectivity.17 Furthermore, this method has been successfully
applied to a short synthesis of the sesquiterpene, (S)-turmerone.
Organoboronic acids are valuable reagents for organic
syntheses due to their unique reactivity, high stability and low
toxicity, thus allowing handling without special precautions.1–4
Over the past decades, arylboronic acids and their derivatives
have been widely used in various reactions, in particular, in the
transition-metal-catalyzed Suzuki–Miyaura coupling reaction
which is known as one of most powerful carbon–carbon bond
forming reactions.5–8 The protodeboronation is a common,
sometimes even dominant side reaction in the Suzuki–Miyaura
coupling reaction.9,10 However, little work has been reported in
investigating the mechanism of protodeboronation and in
applying the protodeboronation to organic syntheses. As early
as 1930, Ainley et al.11 reported that the protodeboronation of
arylboronic acids could be performed slowly in boiling aqueous
solution with stoichiometric amounts of metallic salts (CuSO4,
CrBr3, ZnCl2). Subsequently, Kuivila and co-workers12–14 focused
on studying the mechanism of protodeboronation in an acidic,
alkaline or metal-mediated condition. In 2006, Liu et al.15
reported a nano-palladium-catalyzed protodeboronation of
arylboronic acids. In the presence of 1 mol% palladium nano-
particles and 1.1 equiv. K2CO3, the protodeboronation of phe-
nylboronic acid provided the corresponding product in 98%
yield aer 10 h under N2 atmosphere, and a few examples were
employed in this approach. Perrin's group16 studied the proto-
deboronation of electron-decient aryl and heteroarylboronic
acids. Of these, the 2,6-disubstituted-boronic acids underwent
Carreñ
o's group21 reported the reactions of heteroaromatic
compounds with quinonyl boronic acids proceeded by 1,4-
addition and protodeboronation, leading directly to the Frie-
del–Cras alkylation products. The boronic acid group is
essential to trigger the Friedel–Cras process. Very recently,
Cheon's group22,23 reported metal-free thermal proto-
deboronation of electron-rich arylboronic acids. Several reac-
tion parameters were investigated in the paper, and this
protocol was successfully applied to the synthesis of ortho- and
meta-functionalized phenols using the boronic acid moiety as a
blocking group, respectively.
Green chemistry has become a target either in academic
institutions or in industry.24–28 Nowadays, chemists have an
increasing interest in developing green processes, as the
sustainability has become an important issue in every area of
human activity.29–31 Chemists have known protodeboronation of
arylboronic acids for many years. However, the proto-
deboronation reactions mostly either took place under relatively
harsh conditions or suffered from a limited substrate scope.
Therefore, the development of a mild and efficient process of
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Linggong
Road 2, 116024, Dalian, China. E-mail: chunliu70@yahoo.com; Fax: +86 411-
84986182; Tel: +86 411-84986182
† Electronic supplementary information (ESI) available: Experimental detail and
characterization of protodeboronation products. See DOI: 10.1039/c4ra11659c
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Table 2 The effect of base on the protodeboronation reaction of 4-
protodeboronation remains a desirable goal in synthetic
organic chemistry. Herein, we report a green and general
protocol for the copper-catalyzed protodeboronation of aryl-
boronic acids in aqueous ethanol.
(diphenylamino)phenylboronic acida
We initially investigated the effect of different metal catalyts
on the model reaction of protodeboronation of 4-(diphenyla-
mino)phenylboronic acid in air at 80 ꢀC. The results are
summarized in Table 1. In the absence of metal catalyst, only a
54% isolated yield was obtained in 1.5 h (Table 1, entry 1). The
addition of copper catalysts led to a dramatic increase in
activity, and the protodeboronation reactions provided satised
results when using 10 mol% CuI, CuCl, Cu(OAc)2$H2O and
CuSO4$5H2O as catalysts (Table 1, entries 2–5). Interestingly,
the protodeboronation reaction could afford a 96% yield even
the CuSO4$5H2O was reduced to 1 mol% (Table 1, entry 6). The
results demonstrated clearly that copper ions can promote the
protodeboronation reaction, which is consistent with Kuivil's
report.14 On the other hand, HgSO4, ZnCl2 and Co(OAc)2$4H2O
showed rather poor catalytic activity under the same reaction
conditions (Table 1, entries 7–9). FeCl2 provided 57% isolated
yield, nearly the same as that under metal-free conditions
(Table 1, entry 10). Thus, we selected 1 mol% CuSO4$5H2O as
the catalyst for next research.
As reported in the literature,14 base plays an important role
for improving the reactivity of protodeboronation, thus we next
studied the impact of different bases on the same model reac-
tion. As shown in Table 2, only a 14% yield was observed when
the protodeboronation reaction proceeded without any bases
(Table 2, entry 1). However, a 59% yield was obtained in 1.5 h
when 0.1 equiv. K2CO3 was added to the reaction mixture (Table
2, entry 2). Increasing the amounts of K2CO3 could raise the
yield evidently, and a 93% yield was obtained with 1.0 equiv.
K2CO3 (Table 2, entry 4). It is supposed that arylboronic acid
may form arylboronate anion [ArB(OH)3]À under basic
Entry
Base
Equivalent
Yieldb (%)
1
2
3
4
5
6
7
8
9
—
—
14
59
75
93
63
54
54
93
96
93
K2CO3
K2CO3
K2CO3
K3PO4$3H2O
NaOH
NH3$H2O
Et3N
(i-Pr)2NH
DBU
0.1
0.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
10
a
Reaction conditions: 4-(diphenylamino)phenylboronic acid (0.2
mmol), CuSO4$5H2O (1 mol%), base (0.2 mmol), EtOH/H2O (0.5 mL/
0.5 mL), 80 ꢀC, 1.5 h, under air. The reaction was monitored by TLC.
b
Isolated yields.
condition, which can undergo protodeboronation more easily.
A series of bases were subsequently examined, Et3N, (i-Pr)2NH
and DBU delivered the desired products in high yields (Table 2,
entries 8–10), while only moderate yields were observed with
K3PO4$3H2O, NaOH and NH3$H2O (Table 2, entries 5–7).
Hence, (i-Pr)2NH is the best base for this catalytic system.
As literatures reported, the Suzuki reactions4,32 and self-
homocoupling reactions33 which using arylboronic acids as
reagents could be promoted by oxygen. However, the effect of
reaction atmosphere on the protodeboronation has never been
studied. Thus, the next investigation was to study the effect of
atmosphere on the protodeboronation reaction. As shown in
Table 3, the protodeboronation of several arylboronic acids
were performed in different atmospheres. Indeed, the atmo-
sphere had an effect on the protodeboronation which gave
higher yields under oxygen than in nitrogen (Table 3, entries 1c–
4c vs. 1b–4b). For example, the protodeboronation of 4-cyano-
phenylboronic acid provided a 92% yield under air in 1.5 h
(Table 3, entry 2a), while the isolated yield was decreased to a
64% in nitrogen (Table 3, entry 2b). The same proto-
deboronation reaction performed in an oxygen atmosphere
could achieve 94% yield in 1.5 h. Using 4-(diphenylamino)-
phenylboronic acid as substrate, the protodeboronation
provided higher yield in oxygen than in nitrogen (Table 3, entry
4c vs. 4a). The kinetic studies were performed on the proto-
deboronation of 4-(diphenylamino)-phenylboronic acid under
air, nitrogen and oxygen, respectively. The results are illustrated
in Fig. 1. It is clear that the reaction proceeded faster in oxygen.
For example, a 53% yield was obtained in 5 min under oxygen,
higher than a 38% yield in nitrogen in the same reaction time.
Aer 30 min, 85% and 80% yields were reached in oxygen and
air, respectively, while a 71% yield was obtained under nitrogen.
These results reected that molecular oxygen plays a crucial role
in such a copper-catalyzed protodeboronation reaction. More
Table 1 The effect of the metal catalyst on the protodeboronation
reaction of 4-(diphenylamino)phenylboronic acida
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
9
—
CuI
CuCl
Cu(OAc)2$H2O
CuSO4$5H2O
CuSO4$5H2O
HgSO4
ZnCl2
Co(OAc)2$4H2O
FeCl2
54
94
84
86
95
96c
30
34
14
57
10
a
Reaction conditions: 4-(diphenylamino)phenylboronic acid (0.2
mmol), catalyst (10 mol%), (i-Pr)2NH (0.2 mmol), EtOH/H2O (0.5 mL/
0.5 mL), 80 ꢀC, 1.5 h, under air. The reaction was monitored by TLC.
b
Isolated yields. c CuSO4$5H2O (1 mol%).
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Table
reaction of 4-(diphenylamino)phenylboronic acida
3
The effects of atmospheres on the protodeboronation Table 4 Protodeboronation reaction of arylboronic acidsa
Entry
Arylboronic acid
Product
Yieldb (%)
Entry
Ar–B(OH)2
Atmosphere
Yieldb (%)
1
2
88
95
1a
1b
1c
2a
2b
2c
3a
3b
3c
Air
N2
O2
Air
N2
O2
Air
N2
O2
88c
70c
90c
92c
64c
94c
95
3
4
5
92
91
92
71
94
4a
4b
4c
5a
5b
5c
Air
N2
O2
Air
N2
O2
96 (54)
76 (50)
97 (52)
92d
6
7
8
91
89
88
56d
94d
a
Reaction conditions: arylboronic acid (0.2 mmol), CuSO4$5H2O (1
mol%), (i-Pr)2NH (0.2 mmol), EtOH/H2O (0.5 mL/0.5 mL), 80 ꢀC, 1.5 h.
b
Isolated yields yields in parentheses are obtained without using
copper catalyst. c GC yields. d 1 mol% CuI as catalyst.
9
94
10
96c
11
95c
12
13
14
94c
90
Fig. 1 Yield vs. time curves of protodeboronation reaction of 4-
(diphenylamino)phenylboronic acid under air or N2 or O2. Reaction
conditions: 4-(diphenylamino)phenylboronic acid (0.2 mmol),
CuSO4$5H2O (1 mol%), (i-Pr)2NH (0.2 mmol), EtOH/H2O (0.5 mL/0.5
mL), 80 ꢀC, isolated yields.
92c
15
16
64c
88
interestingly, when the reactions were performed without any
copper catalyst, similar yields were afforded under the different
atmospheres (Table 3, entries 4a–4c in parentheses). When
using 1 mol% CuI as catalyst, 92% and 94% yields were reached
in air and oxygen, respectively (Table 3, entries 5a and 5c).
However, only a 56% yield was obtained under nitrogen, which
was similar with the yield without copper catalyst (Table 3,
entries 5b vs. 4a in parentheses). These results suggest that
Cu(II) was actually the active species in this copper-catalyzed
protodeboronation reaction, and the oxygen might play the
17
18
87
86
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Table 4 (Contd.)
Entry
19
Arylboronic acid
Product
Yieldb (%)
92
61d
Fig. 2 Plausible reaction mechanism.
20
a
Reaction conditions: Arylboronic acid (0.2 mmol), CuSO4$5H2O (1
mol%), (i-Pr)2NH (0.2 mmol), EtOH/H2O (0.5 mL/0.5 mL), 80 ꢀC, 1.5 h,
under air. The reaction was monitored by TLC. GC yields. Isolated
yields. d 24 h, isolated yields.
Conclusions
b
c
In conclusion, we have developed a simple and highly active
protocol for the copper-catalyzed protodeboronation of aryl-
boronic acids in aqueous media. A wide range of substrates,
including electron-decient or electron-rich groups, readily
underwent the protodeboronation to give excellent yields. It is
noteworthy that the reaction could be promoted by oxygen.
Further investigations on the precise mechanism and synthetic
application of this protocol are currently underway in our
laboratory.
role of the nal oxidant which lead to regenerate Cu(II) species
for the next catalytic cycle.
With the optimized conditions at hand, we further explored
the scope and limitations of substrates for this protocol and
the results are shown in Table 4. Unlike other protocols,16 the
electronic nature of the substituent group had little effect on
the protodeboronation reactions in this system. Arylboronic
acids bearing electron-decient or electron-rich groups all
exhibited high reactivity and provided the corresponding
products in good to excellent yields (Table 4, entries1–7).
Moreover, ortho-substituted substrates also afforded good
yields (Table 4, entries 8 and 9), while the same substrates
Experimental
General remarks
Arylboronic acids and metal catalysts were purchased from Alfa
Aesar. Other chemicals were obtained commercially and used
1
without any prior purication. H NMR spectra were recorded
on a Bruker Advance II 400 spectrometer using TMS as the
internal standard. The yields were determined by GC using
biphenyl as an internal standard for the liquid products, and
the solid products were isolated by short chromatography on a
silica gel (200–300 mesh) column using petroleumether (60–90
ꢀC), unless otherwise noted. Compounds described in the
could not undergo protodeboronation in
a metal-free
protocol.23 Various polycyclic aromatic boronic acids were
examined in this protocol (Table 4, entries 10–15). For
example, 10-phenylanthracen-9-ylboronic acid afforded the
desired product in 94% yield (Table 4, entry 12). However, 9-
phenyl-9H-carbazol-3-ylboronic acid gave only a 64% yield
(Table 4, entry 15). The present protocol was further extended
to the synthesis of heterocyclic compound. For example, 3-
pyridylboronic acid afforded the product in 88% yield (Table 4,
entry 16) and 3-thioenylboronic acid gave the desired product
in 92% yield (Table 4, entry 19). We also attempted to extend
this protocol to arylboronic esters, however, 4-(diphenyl-
amino)phenylboronic pinacol ester provided a 61% yield
aer 24 h (Table 4, entry 20).
1
literature were characterized by H NMR spectra compared to
reported data.
Typical procedure for protodeboronation of arylboronic acids
A mixture of arylboronic acid (0.2 mmol), CuSO4$5H2O (1
mol%), (i-Pr)2NHꢀ(0.2 mmol) and EtOH/H2O (0.5 mL/0.5 mL)
was stirred at 80 C in air for 1.5 h. The mixture was added to
brine (2 mL) and extracted two times with ethyl acetate (2 mL).
The combined organic layers were dried over sodium sulfate
and the yield was determined by GC analysis with biphenyl as
internal standard or the product was isolated by short chro-
matography on a silica gel (200–300 mesh) column using
Although the detailed mechanism of the copper-catalyzed
protodeboronation reaction of arylboronic acids is unclear, on
the basis of the results described above, a tentative mechanism
is proposed as shown in Fig. 2. Initially, arylboronic acid as mild
organic lewis acids easily reacts with H2O to generate arylbor-
onate anion. Then, Cu(II) ion attacks this tetrahedral adduct to
form the intermediate of arylcopper complex 1. Subsequently,
ꢀ
petroleumether (60–90 C).
Acknowledgements
arylcopper complex undertakes the protodemetallation process
+
with the (i-Pr)2NH2 , delivering the arenes and Cu(I) ion. The The authors thank the nancial support from the National
Cu(I) is oxidized by oxygen to Cu(II) species which enters into the Natural Science Foundation of China (21276043) and the
next catalytic circle.
Ministry of Education (The Program for New Century Excellent
Talents in University, NCET-10-0283).
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