Pd-catalyzed C–P coupling of heteroaryl boronic acid with H-phosphonate diester

Article abstract of DOI:10.1016/j.tetlet.2016.05.038

We report herein a novel protocol to construct C–P bond from heteroaryl boronic acid with H-phosphonate diester under Pd–Ag catalyzed system without addition of base. This method, directly using commercial available heteroaryl boronic acid as the starting

Full text of DOI:10.1016/j.tetlet.2016.05.038

Accepted Manuscript
Pd-catalyzed C-P Coupling of Heteroaryl Boronic Acid with H-Phosphonate
Diester
Zhiyue Geng, Yudan Zhang, Lu Zheng, Jingya Li, Dapeng Zou, Yangjie Wu,
Yusheng Wu
PII:
S0040-4039(16)30550-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.038
TETL 47657
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
16 March 2016
3 May 2016
10 May 2016
Please cite this article as: Geng, Z., Zhang, Y., Zheng, L., Li, J., Zou, D., Wu, Y., Wu, Y., Pd-catalyzed C-P Coupling
of Heteroaryl Boronic Acid with H-Phosphonate Diester, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.05.038
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Pd-catalyzed C-P Coupling of Heteroaryl Boronic
Acid with H-Phosphonate Diester
Leave this area blank for abstract info.
Zhiyue Geng, Yudan Zhang, Lu Zheng, Jingya Li, Dapeng Zou*, Yangjie Wu, Yusheng Wu*

1
Tetrahedron Letters
Pd-catalyzed C-P Coupling of Heteroaryl Boronic Acid with H-Phosphonate Diester
a
a
a
b,c
a,b
a
b,d
Zhiyue Geng , Yudan Zhang , Lu Zheng , Jingya Li , Dapeng Zou , Yangjie Wu , and Yusheng Wu 
a
The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, P. R. China.
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province
Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou, 450052, P. R. China.
Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.
b
c
d
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report herein a novel protocol to construct C-P bond from heteroaryl boronic acid with H-
phosphonate diester under Pd-Ag catalyzed system without addition of base. This method,
directly using commercial available heteroaryl boronic acid as the starting material, provides a
new way to synthesize a variety of useful heteroaryl phosphonates.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Pd Catalyzed
Heteroaryl Boronic Acids
C-P Coupling
1
6
Introduction
work of our research group in boron chemistry, we decided to
tackle this problem and synthesis additional heteroaryl
phosphorus compounds.
The great importance and broad applications of phosphorus
3
compounds in material , organic synthesis , medicinal chemistry
1
2
4
and ligand chemistry have attracted considerable attention. Since
the pioneering work started by the Hirao group on palladium-
catalyzed couplings of aryl and vinyl bromides with dialkyl
Results and Discussion
In preliminary studies, as shown in Table 1, our initial efforts
focused on the reaction of 3-pyridinylboronic acid 1a and
( PrO) P(O)H 2a by using Pd-Ag catalyzed system. The products
5
6
phosphites , many improved method arose. Those relatively
i
7
8
9
10
2
mature methods also covered Pd-, Ni-, Mn-, Cu- and Ag-
11
were detected by LC−MS and HPLC. In the presence of PdCl
catalyst and Ag O as the additive, various ligands (shown in the
Scheme 1) were screened in DMA under N atmosphere, and
dppm gave the best result with yield of 57% (Table 1, entries 1-
). A screening of additive revealed that Ag O was the best
2
as
catalyzed phosphonation from various aryl partners with H-
phosphonate diesters. However, most of these methods have
unsatisfactory yields and poor substrate scopes. In addition
compared with the conventional C-P coupling method from aryl
halide, the stability, low toxicity, commercial availability, and
2
2
3
2
1
2
choice (Table 1, entries 2, 4, 5). After shorten the reaction time
to 4h, the yield did not change too much (Table 1, entry 6). To
our delight, the yield increased drastically to 91% when 3 equiv.
unique functional group tolerance of arylboronic acids make it
possible to work as aryl (hetero-aryl) partners.
In 2009, the first Pd-catalyzed cross-coupling of aryl-boronic
PPh
interesting transformation encouraged us to further examine the
efficiency of this reaction. Decreasing PPh to 2 equiv. and
shortening the time to 2h made the better yield of 96% (Table 1,
entry 10). A screening of Pd source illustrated that PdCl was the
3
was applied to the reaction (Table 1, entry 7). This
1
3
acids with H-phosphonates had been reported , which showed
that aryl-boronic acids are potential reactant for C-P coupling.
This way suffered from the limited scope, as well as the
3
14
requirement of microwave irradiation. Zhao and coworkers
2
reported a C-P coupling reaction using Cu or Pd as catalyst and
Han and coworkers reported copper-catalyzed aerobic oxidative
C-P coupling of arylboronic acids and diethyl phosphite under
best catalyst for this reaction (Table 1, entry 16). Without
catalyst or additive, the coupling did not occur, indicating that the
presence of catalyst and additive are essential for the coupling.
15
air . When we followed the previous reported reaction
conditions in order to get heteroaryl phosphonates by switching
the arylboronic acids to heteroaryl boronic acids as starting
materials, to our disappointment, the reactions did not occur or
gave very low yields. Considering that the use of heteroaryl
boronic acid as starting materials remains totally unexplored in
the construction of heteroaryl phosphonates and the previous
(
Table 1, entries 14-15). We also tested air and argon atmosphere,
and found the yields were less than the result under N
atmosphere (Table 1, entry 17). DMA gave the best yield at
00 °C, whereas using other polar aprotic solvents or changing
2
1
the reaction temperature from 80 to 120 °C resulted in poorer
yields of the desired product (Table 1, entries 18-19).

Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, zdp@zzu.edu.cn

2
Tetrahedron
a
Table 1. Optimization of Reaction Conditions
boronic acids with larger steric hindrance reacted poorly (3t and
u) to get the deboronation byproducts, illustrating that steric
3
hindrance is evident in this coupling reaction. When 5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[2,3-b]pyridine was
used as reactant, yield of 80% was obtained (3w). The reaction
could well tolerate diverse phosphite esters to afford the
corresponding products in moderate to good yields of 56−70%
d
d
b
Entry
Catalyst
Ligand
Additive
Time
Yield (%)
(3m-3o). It worked badly when dimethyl phosphonate was used
1
2
3
4
5
6
7
8
9
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
2
2
2
(15)
(15)
(15)
(15)
(15)
(15)
(15)
(15)
(10)
dppf(20)
dppm (20)
L1-L8
Ag
2
Ag
2
Ag
2
O
O
O
12h
12h
12h
12h
12h
4h
35
57
and the reaction mostly got pyridine. To our delight, this model
reaction was also applied to arylboronic acids. The results
indicated that this protocol is a practical and general method for
giving useful heteroaryl phosphonates..
0-50
40
dppm(20)
dppm(20)
dppm(20)
Ag CO
2 3
Ag source
6~20
56
Table 2. Pd-catalyzed C-P coupling of Heteroaryl Boronic
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
O
O
O
O
O
O
O
O
O
a,b
c
PPh
PPh
PPh
3
3
3
(300)
(200)
(200)
4h
91, (86)
Acid with H-phosphonate Diesters
i
4h
90,48
4h
80
c
1
0
1
2
3
4
5
6
7
8
9
1
PdCl
2
(15)
(15)
(15)
(15)
PPh
PPh
3
(200)
2h
1h
96, (92)
1
1
1
1
1
1
1
1
1
PdCl
PdCl
PdCl
2
3
(200)
87
19
15
0
2
2
dppm(200)
sphos(200)
2h
2h
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
(200)
(200)
(200)
(200)
(200)
(200)
2h
PdCl
2
(15)
2h
0
l
cat1-cat4
Ag
2
Ag
2
Ag
2
Ag
2
O
O
O
O
2h
0-91
e
f
PdCl
PdCl
PdCl
2
2
2
(15)
(15)
(15)
2h
80 , 94
g
h
2h
85 ,25
j
k
2h
81 , 71
d
e, f
a. mol%, 1mol% means 0.01equiv.. Reaction performed respectively
under Ar/Air atmosphere. Reaction performed respectively in the presence
of DMSO, DMF. 100 mol% PPh
material(entries 31-34). Reaction conditions: 0.72 mmol 1a, 0.6 mmol 2a, 15
mol% catalyst, 1.2 mmol additive, 3.0 mL solvent, 100 C, DMA, N
atmosphere. HPLC yield. Isolated yield based on
g, h
i
j
o
k
o
l
3
. 80 C, 120 C. shown in supplementary
a
o
2
b
c
Finally, the optimum reaction condition was achieved through
the combination of 15 mol% PdCl , 2 equiv. PPh , 2.0 equiv.
Ag O and 3 mL DMA at 100 °C under N atmosphere in 2 hours.
2
3
2
2
Scheme 1. Structure of Various Ligands
With the optimized condition, we turned our attention to
survey the cross-coupling of a variety of heteroaryl boronic acids
with different phosphite esters to examine the versatility of the
methodology. As demonstrated in Table 2, the substrates bearing
different functional groups with electron-donating or electron-
withdrawing substituent were all efficiently coupled under these
reaction conditions to provide the corresponding products with
good to excellent isolated yields (3a-3s). As shown in Table 2, a
variety of functional groups, such as N,N-dimethylamino(3b),
trifluoromethyl(3c), methyl(3s), propoxy(3e), phenyl(3f),
fluoro(3d), chloro(3j), phenoxy(3i), benzyloxy(3k) and
pyrrolidine(3l) groups, can be coupled under the optimum
a
2
Reaction conditions: 0.72 mmol 1, 0.6 mmol 2, 15 mol% PdCl , 2 equiv.
b
PPh
yields based on 2.
yl)thieno[2,3-b]pyridine as reactant.
3
, 2 equiv. Ag
2
O, 3 mL of DMA, 100 °C, 2h, N
2
atmosphere. Isolated
c
Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
To gain further insight into the mechanism of the reaction, we
did some confirmatory experiments. When using catalytic
amount, 1 equiv. and 2 equiv. of PPh
homo-coupling product and target product was 90%: 8%: 2%,
0%: 4%: 36% and 1%: 2%: 97% respectively. So we speculate
that excess PPh can control these competing side reactions.
When we put 1 equiv. PPh , 1 equiv. Ag O, 1 equiv.
P(O)H into one tube, silver mirror reaction occurred .
3
, the proportion of pyridine,
6
3
reaction
condition.
The
6-N,N-dimethylamino-3-
3
2
pyridinylboronic acid and 6-propoxy-3-pyridinylboronic acid
afforded 95% and 94%, respectively, illustrating that electron-
donating group can promote the reaction to get excellent isolated
yield. The reactants with electron-withdrawing group resulted in
moderate yields (Table 2, 3c, 3d, 3j), due to the competing side
reaction of homo-coupling of boron partners. Some heteroaryl
i
17
(
PrO)
2
Based on the data presented here, aproposed mechanism was
drawn in Scheme 2. The first step is the reaction of A with
heteroaryl boronic acid , which affords the intermediate B. In
2 3
the presence of Ag O and PPh , C can generate the nucleophilic
15

3
1
8
reagent D . Reductive elimination from E produces F and Pd(0)
5.
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7c,
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regenerate the catalytically active A and finishes the catalytic
2
O
to
6
7
.
.
cycle.
Scheme 2. Possible Mechanism of this Reaction
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1
2
Conclusion
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In conclusion, a more direct, secure and novel route to
heteroaryl phosphonates in one pot was discovered and
developed. By using Pd-Ag catalyzed system, heteroaryl boronic
acid and H-phosphonate diester can readily undergo a C-P
coupling reaction under nitrogen atmosphere for 2 h in 100 °C to
give the hetero-aryl phosphonates.
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We are grateful to the Natural Science Foundation of China
(20772114, 21172200), Research Program of Fundamental and
Advanced Technology of Henan Province (122300413203), and
Technology Research and Development Funds of Zhengzhou
(141PRCYY516) for financial support.
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4
Tetrahedron
C-P bond was constructed under Pd-Ag catalyzed
system without addition of base
The method using commercial available heteroaryl
boronic acid and H-phosphonate
A new way to synthesize a variety of useful
heteroaryl phosphonates