Application of a readily available and air stable monophosphine HBF4 salt for the Suzuki coupling reaction of aryl or 1-alkenyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2009.12.143

In this Letter, a readily available monophosphine HBF₄ salt was applied for the Suzuki coupling reactions of organoboronic acids to afford the cross-coupling products in high to excellent yields. Both aryl or 1-alkenyl boronic acids and chlorides may be used. It is also suitable for sterically hindered cases.

Full text of DOI:10.1016/j.tetlet.2009.12.143

Tetrahedron Letters 51 (2010) 1284–1286
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Application of a readily available and air stable monophosphine HBF4 salt
for the Suzuki coupling reaction of aryl or 1-alkenyl chlorides
*
Bo Lü, Chunling Fu, Shengming Ma
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, a readily available monophosphine HBF4 salt was applied for the Suzuki coupling reactions
of organoboronic acids to afford the cross-coupling products in high to excellent yields. Both aryl or 1-
alkenyl boronic acids and chlorides may be used. It is also suitable for sterically hindered cases.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 22 November 2009
Revised 14 December 2009
Accepted 24 December 2009
Available online 11 January 2010
During the last 10 years much attention has been paid to the
reaction of C–Cl bond1 due to the easily available and cost-effective
nature of organic chlorides and the atom economy caused by the
low atomic weight of chlorine atom as compared to reactions of
the corresponding bromides or iodides.2 Mainly electron-rich and
sterically bulky phosphines have been developed for different
types of coupling reactions involving C–Cl bonds. In this area, some
of the most notable ligands are listed in Figure 1.
After some screening, we have recently designed and prepared a
new ligand, dicyclohexyl 2,4,6-trimethoxyphenyl phosphine, in
which the two cyclohexyl groups and one 2,4,6-trimethoxyphenyl
group may provide the required electron density, steric bulk, and
ease of handling. The methoxy groups may not only play a role
for the coordination to stabilize Pd complex as pointed by Buch-
wald et al.,3e but also facilitate the lithiation to dramatically short-
en the synthetic route of the ligand. In fact, S-trimethoxybenzene
was treated with n-BuLi in THF to generate 2,4,6-trimethoxyphenyl
lithium, which was reacted with Cy2PCl in situ generated from the
reaction of cyclophexyl magnesium chloride with PCl3 to afford
dicyclohexyl 2,4,6-trimethoxyphenyl phosphine 1. This compound
may further be purified by its reaction with HBF4 to afford the air
stable solid salt 2 as Fu and Netherton did5 for further study
(Scheme 1).
tries 6–8). Finally, 3 mol % of Pd(OAc)2 and 6 mol % of 2 as the li-
gand were defined as the standard catalytic system (Table 1,
entry 9).
With the optimized reaction conditions in hand, differently
substituted electron-rich aryl chlorides and aryl boronic acids were
cross-coupled readily to afford the biaryls in 81–97% isolated
yields; even the hindered aryl chlorides and/or the aryl boronic
acids may be used3a,e,h,k,l (Table 2, entries 5 and 7–10). This reac-
tion could also be extended to electron-deficient aryl chlorides to
give the corresponding Suzuki coupling products in good yields
within relatively shorter reaction time as expected (Table 2, entries
11 and 12).
The optimized conditions could also be extended to the Suzuki
coupling reactions with 1-alkenyl boronic acids: 3,5-dimethoxy-
phenyl chloride 3e could react with styryl boronic acid 4f to form
the Suzuki coupling product 5ef with 81% yield (Scheme 2). For a
more complex substrate 3i,6 the Suzuki coupling could also occur
with the C–Cl bond exclusively over the C–O bond to give the cor-
3d
R
P(Cy)2
P(Cy)2
N
P
R
R
We chose the Pd(OAc)2-catalyzed Suzuki coupling of PhB(OH)2
with p-methoxyphenyl chloride to optimize the reaction condi-
tions. The yield of 5aa with K3PO4ꢀ3H2O is higher than that with
K3PO4 (Table 1, entries 1 and 2). Thus, we reasoned that the
amount of water may have something to do with the coupling
reactions: with 3.0 equiv of water using 3.5 equiv of K3PO4 as the
base, 5aa could be afforded in 100% NMR yield (Table 1, entry 4);
less or more amount of water would lead to a lower yield of 5aa
R = Cy 3a
R = t-Bu 3b
R
R = 2,6-(MeO)2 (SPhos) 3e
R = 2,4,6-(i-Pr)3 (XPhos) 3f
R = 2-NMe2 (DavePhos) 3g
R = 2,6-(i-PrO)2 (RuPhos) 3h
3c
R = p-Supported C6H4
3i
P(t-Bu)2
P(Cy)2
3l
Fe
Ph
P(Cy)2
N
Ph
Ph
Ph
Ph
(Table 1, entries
3 and 5); decreasing the amounts of 4a,
N(i-Pr)2
O
R
Pd(OAc)2/2 and K3PO4 would also lead to lower yields (Table 1, en-
R = 2-(2'-methyl-1',3'-dioxolan-2'-yl) 3j
R = 2-(N,N-diethylcarbamoyl) 3k
* Corresponding author.
Figure 1. Typical examples of phosphine ligands for the Suzuki coupling reaction of
E-mail address: masm@mail.sioc.ac.cn (S. Ma).
C–Cl bonds.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.143

B. Lü et al. / Tetrahedron Letters 51 (2010) 1284–1286
MgCl Cy Cy
1285
Cl
H
Cy
Cy
P
P
PCl3
Et2O
OMe
MeO
OMe
HBF4 (aq) MeO
OMe
BF4
+
Cy2PCl
Mg
Et2O
-40 oC~rt
Recrystallization
31% total
Li
OMe
OMe
rt
MeO
MeO
OMe
1
2
n-BuLi
THF
OMe
OMe
Scheme 1. See Ref. 4.
Table 1
Table 2
Suzuki coupling reactions of 3a with 4a under different conditions
Suzuki coupling reactions of various 3 and 4 using 2 as the ligand
Cl
Cl
B(OH)2
3 mol% Pd(OAc)2
6 mol% 2
3 mol% Pd(OAc)2
2
9 mol%
+
+
OCH3
3.5 equiv K3PO4
R
H2O
R'
R
3.0 equiv H2O
dioxane, 110 o
C
3.5 equiv K3PO4
R'
B(OH)2
4a
5
dioxane,110 o
C
3
4
OCH3
2.0 equiv
3a
5aa
2.0 equiv
Entry
R
R0
Time (h) Isolated yield of 5 (%)
1
2
3
4
5
6
7
8
9
4-MeO (3a)
4-Me (3b)
4-MeO (3a)
H (3c)
2,6-(Me)2 (3d)
3,5-(MeO)2 (3e) H (4a)
2,6-(Me)2 (3d) 4-MeO (4b)
H (4a)
11
16
9.5
11.5
13
90 (5aa)
83 (5bb)
97 (5bb)
88 (5aa)
91a (5da)
94 (5ea)
81 (5db)
94 (5ed)
97 (5de)
82 (5fd)
90 (5ga)
91 (5ha)
Entry
H2O (equiv)
Time (h)
NMR yielda (%)
Recovery of 3a (%)
4-MeO (4b)
4-Me (4c)
4-MeO (4b)
H (4a)
1
—
—
11
15.5
12
15.5
15.5
11.5
11.3
21
62
79
92
100
65
77
77
60
100
23
16
3
2b
3
1.0
3.0
5.0
3.0
3.0
3.0
3.0
4
5
—
13
22
35
17
20
40
—
6c
7d
8e
9f
3,5-(MeO)2 (3e) 2,6-(Me)2 (4d) 13
2,6-(Me)2 (3d)
2-MeO (3f)
2-NO2 (3g)
4-CHO (3h)
3-MeO (4e)
2,6-(Me)2 (4d) 22
H (4a)
H (4a)
12.5
10
11
12
11
1
0.6
Determined by 1H NMR analysis using methylene bromide as an internal
a
standard.
a
Biphenyl (5.7%) was formed, which cannot be separated from 5da.
b
K3PO4ꢀ3H2O was used.
c
d
e
f
K3PO4 (3.0 equiv) was used.
PhB(OH)2 (1.5 equiv) was used.
Pd(OAc)2 (1 mol %) and 2 (3 mol %) were used.
Compound 2 (6 mol %) was used.
In conclusion, we have applied the HBF4 salt of a monophos-
phine ligand, that is, dicyclohexyl 2,4,6-trimethoxyphenyl phos-
phine, recently prepared in this group, for the Suzuki coupling
reaction of aryl or 1-alkenyl chlorides with different organoboronic
acids in high to excellent yields. The HBF4 salt of this ligand is easy
responding product 5ie in 88% yield (Scheme 2). This coupling was
also suitable for 1-cyclooctenyl chloride 3j to form the correspond-
ing Suzuki coupling product 5jb with 63% yield (Scheme 2).
Ph
Cl
3 mol% Pd(OAc)2
6 mol% 2
Ph
+
3.5 equiv K3PO4
3.0 equiv H2O
(HO)2B
H3CO
OCH3
H3CO
OMe
OCH3
OTs
Dioxane, 110 o
15 h, 81%
C
3e
4f
5ef
OTs
B(OH)2
3 mol% Pd(OAc)2
Cl
6 mol% 2
+
3.5 equiv K3PO4
3.0 equiv H2O
Dioxane, 110 oC
7 h, 88%
OMe
3i
4e
OMe
5ie
OMe
OMe
3 mol% Pd(OAc)2
6 mol% 2
OMe
Cl
+
3.5 equiv K3PO4
3.0 equiv H2O
B(OH)2
Dioxane, 110 o
22 h, 63%
C
3j
4b
5jb
Scheme 2.

1286
B. Lü et al. / Tetrahedron Letters 51 (2010) 1284–1286
to prepare and air-stable.4 Although the reaction temperature is
still high at this moment, further optimization and new
applications of this type of ligands are being conducted in our
laboratory.
References and notes
1. For recent reviews on coupling reactions of C–Cl bonds, see: (a) Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 4176; (b) Molander, G. A.; Ellis, N. Acc. Chem.
Res. 2007, 40, 275; (c) Weng, Z.; Teo, S.; Hor, T. S. A. Acc. Chem. Res. 2007, 40, 676;
(d) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461; (e) Doucet, H. Eur. J.
Org. Chem. 2008, 2013; (f) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 6338.
Acknowledgments
2. Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
3. (a) Shen, W. Tetrahedron Lett. 1997, 38, 5575; (b) Littke, A. F.; Fu, G. C. Angew.
Chem., Int. Ed. 1998, 37, 3387; (c) Lemo, J.; Heuzé, K.; Astruc, D. Chem. Commun.
2007, 4351; (d) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.;
Monsees, A.; Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983; (e) Walker,
S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43,
1871; (f) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S.
L. J. Am. Chem. Soc. 2003, 125, 6653; (g) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J.
Am. Chem. Soc. 1998, 120, 9722; (h) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc.
2004, 126, 13028; (i) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553; (j) Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S. J.
Org.Chem. 1999, 64, 6797; (k) Kwong, F. Y.; Lam, W. H.; Yeung, C. H.; Chan, K. S.;
Chan, A. S. C. Chem. Commun. 2004, 1922; (l) So, C. M.; Yeung, C. C.; Lau, C. P.;
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Financial support from the National Basic Research Program of
China(No. 2009CB825300) is greatly appreciated. Shengming Ma is
a Qiu Shi Adjunct Professor at Zhejiang University. We thank Mr.
Guangke He for reproducing the results presented in entries 2
and 7 of Table 2.
Supplementary data
Supplementary data (typical experimental procedures and cop-
ies of 1H and 13C NMR spectra of all the products) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.12.143.
4. China Patent Application No. 200910154029.4.
5. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
6. Chai, G.; Lu, Z.; Fu, C.; Ma, S. Chem. Eur. J. 2009, 15, 11083.