Copper-catalyzed C-P bond construction via direct coupling of phenylboronic acids with H-phosphonate diesters

Article abstract of DOI:10.1021/ol200465z

A mild and efficient method was developed for the copper-catalyzed additions of H-phosphonate diesters to boronic acids under the copper catalyst system Cu₂O/1,10-phenanthroline. To the best of our knowledge this finding is the first example of a copper-catalyzed synthesis of aryl phosphonates from arylboronic acids and H-phosphonate dialkyl esters.

Full text of DOI:10.1021/ol200465z

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2110–2113
Copper-Catalyzed CÀP Bond
Construction via Direct Coupling
of Phenylboronic Acids with
H-Phosphonate Diesters
Rongqiang Zhuang,† Jian Xu,† Zhenshi Cai,‡ Guo Tang,† Meijuan Fang,*,‡ and
Yufen Zhao*,†,§
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005,
Fujian, China, Department of Pharmaceutical Science, Medical College,
Xiamen University, Xiamen 361005, Fujian, China, and
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University,
Beijing 100084, China
fangmj@xmu.edu.cn; yfzhao@xmu.edu.cn
Received February 28, 2011
ABSTRACT
A mild and efficient method was developed for the copper-catalyzed additions of H-phosphonate diesters to boronic acids under the copper
catalyst system Cu2O/1,10-phenanthroline. To the best of our knowledge this finding is the first example of a copper-catalyzed synthesis of aryl
phosphonates from arylboronic acids and H-phosphonate dialkyl esters.
The importance of phosphorus compounds in organic
synthesis,1 materials,2 and medicinal chemistry3 has been
well documented for years. The creation of new organopho-
sphorus compounds and, naturally, of new phosphination
reactions could thus have a great impact on various fields
of chemical science. The most efficient routes to these
compounds involve palladium-catalyzed cross-coupling
of aryl halides with diaryl and dialkyl phosphites.4 In
general, most efforts in the cross-coupling methods cur-
rently are geared toward a wide variety of phosphorus
nucleophiles, i.e. phosophonates esters, hypophosphite,
dialkyl- or diaryl-phosphine oxides, phosphines, and phos-
phineÀborane complexes.5 While palladium catalysts can
be replaced by copper in many coupling processes,6 this
† Department of Chemistry and Key Laboratory for Chemical Biology of
Fujian Province, College of Chemistry and Chemical Engineering, Xiamen
University.
‡ Department of Pharmaceutical Science, Medical College, Xiamen
University.
§ Tsinghua University.
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r
10.1021/ol200465z
Published on Web 03/18/2011
2011 American Chemical Society

cheaper and more convenient alternative form of catalysis
was not often used in arylÀP bonds formation.7
limited protocols for the direct coupling of arylboronic
acid with secondary phosphonates have been published.12
Here, we report a more convenient and inexpensive
copper-catalyzed method for the synthesis of aryl phos-
phonates. The advantage of this method was that the
coupling reaction could be performed under milder con-
ditions compared to that of the classical Hirao arylation
protocols.4,5
Recent reinvestigation of Chan and Lam8 type chemis-
try showed that many of the carbonÀheteroatom bond
formations may be carried out using boronic acids and
cupric acetate [Cu(OAc)2] as the catalyst. Although the
majority of efforts have been focused on the formation
of carbonÀnitrogen,9 Àoxygen,10 and Àsulfur bonds,11
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Table 1. Optimization of Copper Sourcea
entry
catalyst
yield (%)b
1
2
Cu(OAc)2
Cu(OAc)2
CuO
5c
35
trace
28
7
3
4
CuCl2
CuBr2
Cu(OTf)2
CuCl
5
6
56
40
14
43
75d
7
8
CuBr
9
CuI
10
Cu2O
a Reaction conditions: 1a (1 mmol), 2a (0.5 mmol), copper salt
(0.05 mmol), triethylamine (1.5 mmol), 1,10-phenanthroline (0.05
mmol) in 2 mL of CH2Cl2 at room temperature in air, 24 h. b Isolated
yield based on H-phosphonate diester 2a. c Copper salt (0.5 mmol),
without 1,10-phenanthroline. d Copper salt (0.25 mmol).
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First, the reaction was performed under “classical” ChanÀ
Lam conditions, using 1 equiv of Cu(OAc)2, 2 equiv of
phenylboronic acid 1a, 1 equiv of H-phosphonate diester
2a, and 3 equiv of triethylamine at room temperature in
CH2Cl2. After 24 h, the desired PÀC product was formed
in a 5% yield and 31P NMR spectroscopy showed the
starting material disappeared (Table 1, entry 1). These
results indicated that the cross-coupling was feasible, and
hence a deeper study of the reaction was conducted. It has
been demonstrated that certain additives could be em-
ployed to enhance the efficiency of copper-catalyzed reac-
tions.7,13 Therefore, we decided to test commercially avail-
able 1,10-phenanthroline as a ligand for the copper-cata-
lyzed phosphonation of aryl boronic acid. Various copper
salts were tested for the proposed reaction using 1,10-
phenanthroline as a ligand in air at rt (Table 1, entries
2À10). Cu2O, which is relatively inexpensive and easy to
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Org. Lett., Vol. 13, No. 8, 2011
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handle, showed relatively higher catalytic efficiency com-
pared with other copper salts and thus was chosen as the
catalyst for further optimization.
Table 3. Copper-Catalyzed Cross-Coupling of Arylboronic
Acids with H-Phosphonate Diestersa
Table 2. Ligand and Base Effects on Reactivitya
entry
solvent
base
Et3N
ligand
yield (%)b
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
toluene
THF
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
trace
21
2
Et3N
3
Et3N
75
4
Et3N
66
5
Et3N
19
6
Et3N
91
7
Et3N
54
8
Et3N
81
9
DME
Et3N
82
10
11
12
13
14
15
16
17
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Et3N
23
pyridine
(i-Pr)2NEt
K2CO3
Cs2CO3
(i-Pr)2NEt
(i-Pr)2NEt
(i-Pr)2NEt
54
96
35c
17c
37d
9e
56f
a Reaction conditions: H-phosphonate diester (0.5 mmol), PhB-
(OH)2 (1 mmol), Cu2O (0.025 mmol), base (1.5 mmol), ligand (0.05 mmol)
in 2 mL of solvent at room temperature in air, 24 h. b Isolated yield
based on H-phosphonate diester 2a. c 0.75 mmol of base was used.
d 0.5 mmol of PhB(OH)2 was used. e In ambient nitrogen. f In ambient
oxygen.
Further screening of the catalytic reaction conditions
involved examination of various ligands to promote the
formation of the aryl phosphonates (Table 2, entries 1À5).
The most efficient one was ligand L3, 1,10-phenanthroline,
which gave 3a in 75% yield. The effect of the solvent was
also investigated (Table 2, entries 6À10). Moderate yields
of the desired PÀC product 3a were obtained using aceto-
nitrile as a solvent (91%) (Table 2, entry 6). Other solvents
resulted in lower yields of 3a: i.e. toluene (54%), DME
(82%), and THF (81%) (Table 2, entries 6À10). The effect
of base confirmed that (i-Pr)2NEt was the best choice for
this transformation (Table 2, entries 11À14). In general, 2
equiv of boronic acid are necessary to achieve optimal
yields (Table 2, entry 15). This is due to the competing side
reaction of the formation of PhOH and PhOPh.12c To
evaluate the importance of air, the arylation of H-phos-
phonate diester was performed in pure nitrogen, which
only gave a yield of 9% (Table 2, entry 16). This indicates
thatthe oxygen isessential, probably becauseoxygen could
oxidize the copper complex to Cu(III), facilitating the
a Reaction conditions: H-phosphonate diester (0.5 mmol), PhB(OH)2
(1 mmol), Cu2O (0.025 mmol), (i-Pr)2NEt (1.5 mmol), L3 (0.05 mmol) in
2 mL of CH3CN at room temperature in air, 24 h. b Isolated yield based
on H-phosphonate diester.
reductive elimination of aryl phosphonates.14 However,
when the reaction was performed under pure oxygen
instead of air, the yield also dropped from 96% to 56%
(Table 2, entry 17). This could be due to the accelerating
2112
Org. Lett., Vol. 13, No. 8, 2011

effect of pure oxygen on the competing side reaction of the
formation of tetraethyl hypodiphosphate, which was de-
tected by 31P NMR.15
ketones, and ester groups (Table 3, entries 12À15). The
only studied heteroaromatic boronic acid resulted in a
less satisfying yield of 47% of product 3p (Table 3, entry 16).
Interestingly, aryl halides are also tolerated, without cross-
coupling being observed (Table 3, entry 20). Finally, a
vinylboronic acid was coupled to 2a, proceeding stereoselec-
tively and with retention of the original stereochemistry to
give the desired product 3u in 78% yield (Table 3, entry 21).
In conclusion, we have developed a novel copper-cata-
lyzed carbonÀphosphorus bond formation protocol from
aromatic boronic acids under mild conditions. This reac-
tion further extends the scope of copper-catalyzed aryl and
alkenylboron cross-coupling chemistry, and we anticipate
its use in both complex molecule synthesis and P-chiral
organophosphorus compounds synthesis applications.
Further investigations are in progress.
With these optimized reaction conditions, a variety
of substrates were surveyed to explore the scope and
limitations of the reaction (Table 3). H-phosphonate
diesters bearing different alkyl groups (Table 3, entries
1À3) and boronic acids bearing different aryl groups
with electron-donating or electron-withdrawing sub-
stituents (Table 3, entries 6À9) coupled efficiently
under these reaction conditions. The dibenzyl phos-
phonate resulted in a less satisfying yield of 54% of
product 3d due to partial dealkylation and oxidation,
which was detected by 31P NMR spectroscopy (Table 3,
entry 4). Employing the sterically demanding o-tolyl-
boronic acid (Table 3, entry 5) resulted in a reduced
yield (75%) compared with the p-substituted counter-
part (84%) (Table 3, entry 7). The reaction is tolerant of
a wide range of functional groups, including cyano,
Acknowledgment. We acknowledge financial support
from the Chinese National Natural Science Foundation
(20732004, 20972130), the key project of Tianjin (TJAB-
2009-023), and the Key Scientific Project of Fujian Pro-
vince (2009HZ0004-1).
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Kitagawa, T. J. Am. Chem. Soc. 2000, 122, 2124. (b) Lam, P. Y. S.;
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2003, 44, 1691. (c) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008,
130, 9196. (d) Giri, R.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
15860.
Supporting Information Available. General experimental
procedure and characterization details. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Zhou, Y.; Yin, S.; Gao, Y.; Zhao, Y.; Goto, M.; Han, L.-B.
Angew. Chem., Int. Ed. 2010, 49, 6852.
Org. Lett., Vol. 13, No. 8, 2011
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