A carrier-free and recyclable protocol for the cross-coupling of terminal alkynes with arylboronic acids in H2O/TBAB

Article abstract of DOI:10.1016/j.tetlet.2019.06.047

A new and recyclable protocol was developed for Pd(OAc)₂-catalyzed the cross-coupling reaction of terminal alkynes with arylboronic acids using environmentally friendly H₂O/TBAB as reaction medium. A series of cross-coupling products containing internal acetylenic bond can be obtained with good selectivity and yield. The Pd(OAc)₂/H₂O/TBAB system was stable in the Sonogashira-type cross-coupling reaction and could be used at least three cycles without considerable decrease in catalytic performance. The results suggest that the unsupported and recyclable systems can be extended to the other realm of C&C bond formation in synthetic organic chemistry.

Full text of DOI:10.1016/j.tetlet.2019.06.047

Accepted Manuscript
A carrier-free and recyclable protocol for the cross-coupling of terminal alkynes
with arylboronic acids in H2O/TBAB
Bo-Xiao Tang, Ren-Yun Kuang, Ji-Wu Wen, Xiang Huang, Zhen-Xing Zhang,
Yu-Jun Shen, Jia-Ping Chen, Wen-Ying Wu
PII:
S0040-4039(19)30608-2
https://doi.org/10.1016/j.tetlet.2019.06.047
TETL 50888
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 May 2019
20 June 2019
23 June 2019
Please cite this article as: Tang, B-X., Kuang, R-Y., Wen, J-W., Huang, X., Zhang, Z-X., Shen, Y-J., Chen, J-P.,
Wu, W-Y., A carrier-free and recyclable protocol for the cross-coupling of terminal alkynes with arylboronic acids
in H2O/TBAB, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.06.047
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Tetrahedron Letters
A carrier-free and recyclable protocol for the cross-coupling of terminal alkynes with
arylboronic acids in H2O/TBAB
Bo-Xiao Tanga, , Ren-Yun Kuanga, Ji-Wu Wena, Xiang Huanga, Zhen-Xing Zhanga, Yu-Jun Shena, Jia-Ping
Chena and Wen-Ying Wua
a School of Chemistry and Chemical Engineering, The key Laboratory of Coordination Chemistry of Jiangxi Province, and Institute of Applied Chemistry,
Jinggangshan University, Ji’an, 343009, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new and recyclable protocol was developed for Pd(OAc)2-catalyzed the cross-coupling
reaction of terminal alkynes with arylboronic acids using environmentally friendly H2O/TBAB as
reaction medium. A series of cross-coupling products containing internal acetylenic bond can
be obtained with good selectivity and yield. The Pd(OAc)2/H2O/TBAB system was stable in the
Sonogashira-type cross-coupling reaction and could be used at least three cycles without
considerable decrease in catalytic performance. The results suggest that the unsupported and
recyclable systems can be extended to the other realm of C-C bond formation in synthetic
organic chemistry.
Available online
Keywords:
Reusability
Carrier-free
2009 Elsevier Ltd. All rights reserved.
H2O/TBAB
Sonogashira-type coupling
remained: it is difficult to (1) recycle the carrier-free catalysts,
and (2) research in environmentally friendly solvents.
Introduction
Transition-metal-catalyzed the Sonogashira cross-coupling
reaction of terminal alkynes with aryl or vinyl halides has
become one of the most powerful and important synthetic
methods for carbon –carbon bond formation to construct
arylalkyne compounds,1 which are found widely in natural
products, pharmaceuticals, and molecular organic materials.2
Although various modifications have been reported on the
Sonogashira reaction,3 The reaction generally does not work
well for electron-deficient alkynes.1b,3b,4 So, transition-metal-
catalyzed Sonogashira-type couplings of terminal alkynes with
arylboronic acids have been investigated in organic solvents
(Scheme 1, eq 1).5-15 For example, Zou and co-workers firstly
reported a protocol for constructing internal alkynes through
the cross-coupling of terminal alkynes with arylboronic acids
using a Pd(dppf)Cl2 and Ag2O system in CH2Cl2.5 Phan and co-
workers reported the application of the Ni-MOF
Ni2(BDC)2(DABCO) as an efficient and selective heterogeneous
catalyst for the oxidative cross-coupling reaction between
Schem 1. The Sonogashira-type cross-couplings of terminal alkynes
with arylboronic acids
One of the hottest topics in green chemistry is the use of an
environmentally benign reaction medium to replace volatile and
poisonous organic solvents. Because water is non-toxic, non-
inflammable, safe, inexpensive and environment-friendly, it is an
ideal green solvent for use in organic reactions.16 Major
advantages of ionic liquids for application as reaction solvent are
their non-volatility, non-flammability, good solubility
characteristics, and high thermal stability.17 The non-volatility of
ionic liquids is more environmentally friendly than common
phenylboronic
acid
and
phenylacetylene
in
N,N-
Dimethylformamide.9 Li and co-workers reported a palladium-
catalyzed cross-coupling of terminal alkynes with boronic acids
under ligand-free and relatively lower loading Pd conditions in
MeCN.11 In recent years, palladacycle-catalyzed Sonogashira-
type couplings of arylboronic acids were developed and studied
because of structural versatility of palladacycles.12-14 Although
interesting results have been achieved, some limitations still
 Corresponding author. Tel/fax: +86-0796-8100490; e-mail: 520tangboxiao@163.com

2
Tetrahedron
o
organic solvents. Combining the use of water/ionic liquid as
then 1 h at 80 C afforded the cross-coupling product 3a in 82%
yield (Table 1, entry 4), both the temperature decrease and rise
reduce cross-coupling yields greatly (Table 1, entries 10 and 11).
solvent with metal catalysts results in easy separation and
recycling of the catalyst system from the product. Herein, we
report a simple, recyclable, unsupported and ligand-free
Pd(OAc)2-catalyst system for the Sonogashira-type couplings of
terminal alkynes with arylboronic acids in H2O/TBAB
(tetrabutylammonium bromide) media (Scheme 1, eq 2).
o
When the reaction time was 1.5 h at 80 C, the cross-coupling
yield was 68% (Table 1, entry 12). Finally, the ratio of H2O and
TBAB were investigated, the cross-coupling product 3a could be
isolated in 67% and 36% yield with H2O/TBAB ratio of 2:3 and
3:2, respectively (Table 1, entries 13 and 14).
Results and discussion
Table 2. Ligand-free Pd(OAc)2-catalyzed the Sonogashira-
type reaction of arylboronic acids a, b
Table 1. Screening of optimal reaction conditions a
Pd(OAc)2
5 mmol%
OMe
MeO
ArB(OH)2
+
MeO
Ar
H2O/TBAB
MeO
3a
+
NaOH, Ag2O
H2O/TBAB
Pd(OAc)2
1
2
3
MeO
OMe
B(OH)2
2a
1a
4a
B(OH)2
B(OH)2
B(OH)2
Entry
T (oC)
Base
Additive
Yield b (3a)
Yield b (4a)
3c, 48%
3d, <10%
3b, 69%
20→80
20→80
K2CO3
Et3N
Ag2O
Ag2O
40%
14%
52%
60%
1
2
Cl
B(OH)2
Ph
B(OH)2
B(OH)2
B(OH)2
3f, 82%
20→80
20→80
20→80
20→80
20→80
20→80
20→80
20→60
20→100
80
NaHCO3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Ag2O
Ag2O
<10%
82%
12%
56%
19%
74%
81%
35%
54%
68%
67%
36%
85%
<10%
80%
3
3g, 72%
3e, 60%
4
Ph
O
B
B
AgNO3
Ag2CO3
AgOAc
Ag2O
O
O
5
N
B(OH)2
B
Cl
Ph
17%
6
3i, 68%
Pd(OAc)2
3h, 81%
3j (3a),73%
73%
7
8 c
9 d
10
11
12
13 e
14 f
5 mmol%
<10%
<10%
13%
Ar
+
N
B(OH)2
Ar
N
NaOH, Ag2O
H2O/TBAB
Ag2O
1
3
2
Ag2O
Ag2O
27%
Ag2O
<10%
<10%
50%
3k, 66%
3n, 56%
3m, 59%
3l, 84%
20→80
20→80
Ag2O
O
Ag2O
O2N
3p, 29%
3o, 45%
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), Pd(OAc)2 (5 mol%), base
(2.5 equiv), additive (2.5 equiv), H2O (0.5 g):TBAB (0.5 g)=1:1, air, and 0.5 h
at 20 oC and then 1 h at 80 oC. b Isolated yield. c N2 instead of air. d O2 instead
of air. e H2O:TBAB=2:3. f H2O:TBAB=3:2.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (5 mol%), NaOH
(2.5 equiv), Ag2O (2.5 equiv), H2O (0.5 g):TBAB (0.5 g)=1:1, air, and 0.5 h at
20 oC and then 1 h at 80 oC. b Isolated yield.
The Sonogashira-type cross-coupling reaction of 1-ethynyl-4-
methoxybenzene (1a) with phenylboronic acid (2a) was
conducted as a model to screen the optimized reaction
conditions in H2O/TBAB media. The influences of bases, additive
and reaction temperature on the yield were investigated. The
results of cross-coupling and homo-coupling for 1a are
summarized in Table 1. Among the base examined, NaOH
showed the best cross-coupling selectivity and yield in
H2O/TBAB (Table 1, entry 4). Other base, such as K2CO3, Et3N and
NaHCO3, gave good homo-coupling yields (Table 1, entries 1-3).
The influence of additive on the reaction was also investigated
(Table 1, entries 4-7). It can be seen from Table 1 that the Ag2O
condition gave the best result. The cross-coupling selectivity of
other additives including AgNO3, Ag2CO3 and AgOAc were lower
than Ag2O. Using N2 instead of air, the cross-coupling yield
decreased slightly (Table 1, entry 8). However, 81% yield of 3a
can be obtained in O2 (Table 1, entry 9). While 0.5 h at 20 oC and
The scope of the Sonogashira-type reaction was further
explored by employing the conditions of entry 4 in Table 1. As
shown in Table 2, the cross-coupling reaction of a range of
arylboronic acids with 1a can be carried, affording the desired
products in moderate to excellent yields (Table 2, 3b-j). Steric
effect has a great influence on the cross-coupling reaction
activity of arylboronic acids and its performance follows this
order: P-substituent > m-substituent > o-substituent (Table 2,
3b-d). When the B(OH)2 group were in different position of
aromatic ring, the yields of cross-coupling also had a large
difference (Table 2, 3e and 3f, 3g and 3h). To our delight,
arylboronic acids containing heterocyclic atom can obtain
desired product in 68% yield (Table 2, 3i). At the same time, 73%
yield of 2,4,6-triphenyl-1,3,5,2,4,6-trioxatriborinane can also be
got (Table 2, 3j). Next, a variety of terminal alkynes and pyridin-
4-ylboronic acid 2f were subjected to the optimized conditions

using H2O/TBAB system (Table 2, 3k-p). Electron-donating
terminal alkynes all conducted smoothly Cross-coupling
reactions to afford the desired corresponding products in good
yields (Table 2, 3k-n). Unfortunately, electron-withdrawing
group decreased the transformation rate very much (Table 2,
3o-p).
A possible mechanism as outlined in Scheme 2 was proposed
on the basis of the reported mechanism and our experimental
results (Schem 2).6,8,10-11 Firstly, transmetalation with arylboronic
acid affords palladium intermediate A. Subsequently, palladium
intermediate A can react with alkynylsilver B to form palladium
intermediate C. Next, the reductive elimination of the
intermediate C obtains the product 3 and the Pd(0). Finally, the
Pd(0) is oxidized in the presence of the Ag2O to complete the
catalytic cycle.
Table 3. Reusability study of Pd(OAc)2/H2O/TBAB system in
the cross-coupling of terminal alkynes with arylboronic acids
Pd(OAc)2
5 mmol%
Conclusions
ArB(OH)2
+
R
Ar
R
In summary, we have developed a novel Pd(OAc)2-catalyzed
method for the cross-coupling of terminal alkynes with
arylboronic acids using environmentally friendly H2O/TBAB as
reaction medium. This effective protocol has proved to be
practical, economical and environmentally with several
advantages including: (1) carrier-free and recyclable system; (2)
ligand-free and environmentally friendly reaction solvent; (3)
good cross-copling selectivity. Further studies are now ongoing
to investigate the possibility of recycling and reactivation of
Pd/water/ionic liquid systems in industrial production.
3 recycles
terminal alkyne
arylboronic acid
No
Yielda (3)
80% (3a)
76% (3a)
73% (3a)
81% (3l)
78% (3l)
76% (3l)
1b
2c
B(OH)2
MeO
1a
1l
2a
3 c
1 b
2 c
N
B(OH)2
2i
Acknowledgments
3 c
We thank the National Natural Science Foundation of China
(No. 21563015) and the Science and Technology Project of
Jiangxi Provincial Department of Education (No. GJJ170656) for
financial support.
a
b
Isolated yield. Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2
(5 mol%), NaOH (2.5 equiv), Ag2O (2.5 equiv), H2O (0.5 g):TBAB (0.5 g)=1:1,
air, and 0.5 h at 20 oC and then 1 h at 80 oC. Reaction conditions: 1 (0.2
c
mmol), 2 (0.3 mmol), NaOH (1.5 equiv), Ag2O (1.5 equiv), air, and 0.5 h at 20
oC and then 1 h at 80 oC.
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with arylboronic acids (Table 3). As shown in Table 3, 1-ethynyl-
4-methoxybenzene 1a reacted with phenylboronic acid 2a
efficiently to give similar results in three runs using the
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recyclable Pd(OAc)2/H2O/TBAB system (Table 3, 3l).
+
+
Ag2O OAc- + B(OH)2
R
ArB(OH)2
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3
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4
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Highlights：
Ligand-free, recyclable and unsupported Sonogashira-type coupling
systems is demonstrated.
The whole systems can be recovered and used for 3 cycles directly.
Performing the reactions in water/ionic liquid makes this
methodology greener.

2
2
R
3 recycles
reusability
ligand-free
carrier-free
6
Tetrahedron
H2O/TBAB as solvent