A novel class of amide-derived air-stable P,O-ligands for Suzuki cross-coupling at low catalyst loading

Article abstract of DOI:10.1016/j.tetlet.2003.12.142

The benzamide-derived P,O-ligands efficiently promoted the Pd-catalyzed Suzuki cross-coupling reactions of aryl bromides with phenylboronic acid at 0.01mol% of Pd loading at 60-80°C to form biaryls in excellent yields. A sterically hindered arylboronic acid gave a quantitative yield of the coupling product at 110°C with 1mol% Pd.

Full text of DOI:10.1016/j.tetlet.2003.12.142

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1999–2001
A novel class of amide-derived air-stable P,O-ligands for Suzuki
cross-coupling at low catalyst loading
a
b
b
a
Wei-Min Dai,a,b, Yannain Li, Ye Zhang, Kwong Wah Lai and Jinlong Wu
*
aLaboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
bDepartment of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong SAR, China
Received 23 October 2003; revised 15 December 2003; accepted 16 December 2003
Abstract—The benzamide-derived P,O-ligands efficiently promoted the Pd-catalyzed Suzuki cross-coupling reactions of aryl bro-
mides with phenylboronic acid at 0.01 mol % of Pd loading at 60–80 °C to form biaryls in excellent yields. A sterically hindered
arylboronic acid gave a quantitative yield of the coupling product at 110 °C with 1 mol % Pd.
Ó 2004 Elsevier Ltd. All rights reserved.
The palladium-catalyzed Suzuki cross-coupling reaction
of aryl halides with arylboronic acids is a powerful
method for accessing structurally diversified biaryls.1;2
With recent successful development of bulky and elec-
tron-rich phosphines, the Suzuki cross-coupling reac-
tion has significantly advanced to include aryl
chlorides,3 fluorides,4 and tosylates5 and alkyl tosylates6
as the substrates. For example, o-(dicyclohexylphosph-
ino)biphenyl 1 was reported to promote the Suzuki
cross-coupling of hindered substrates. It also effected
the formation of biaryls from aryl bromides at very low
catalyst loading (0.001–0.005 mol % of Pd) at 100 °C.7
The ether-type P,O-ligand 2 was reported to form
monophosphine–Pd intermediates featuring both P and
O coordinations. Its combination with Pd(dba)2 pro-
vides an efficient catalyst system for the Suzuki cross-
coupling of a variety of aryl chlorides at 100–110 °C.8
Moreover, the Suzuki cross-coupling reaction of aryl
bromides in the absence of transition metal was
reported to take place in hot water (150 °C) under
microwave irradiation.9 Recently, we disclosed a novel
class of 1-naphthamide-derived atropisomeric P,O-
ligands for the Pd-catalyzed asymmetric allylic alkyl-
ation in up to 94.7% ee.10 We report here on the Suzuki
cross-coupling reaction of aryl bromides using the
benzamide-derived air-stable P,O-ligands 3 and 4 at low
catalyst loading (0.01 mol % of Pd) at 60–80 °C.
The P,O-ligands 3 and 4 were readily prepared from the
benzamides in one operation via the amide-directed
ortho lithiation11 followed by quenching with (Cy)2PCl.
The tertiary amide moiety in 3 and 4 is considered to
deliver two functions: (a) it provides the necessary
bulkiness to prevent formation of bisphosphine–Pd
complexes as it was noted for the methyl group in 2;8b
and (b) the amide carbonyl oxygen acts as a coordi-
nating atom to Pd.12 Our initial experiments with 3
showed that a 1:2 Pd:ligand ratio13 gave the best yields
of the biaryl products. Therefore, the reactions shown in
Scheme 1 were carried out with 0.005 mol % of Pd2
(dba)3 (0.01 mol % of Pd), 0.02 mol % of the P,O-ligand
3, and 3 equiv of KFÆ2H2O or K3PO4 as the base
in toluene at 60–80 °C. The results are summarized in
Table 1.
i-Pr
N
O
i-Pr
O
O
PCy2
Me
PCy2
PCy2
R
1
2
3: R = H
4: R = Ph
We first attempted the Suzuki reaction of 3-bromotol-
uene 7 with phenylboronic acid at room temperature
using 0.5 mol % of Pd2(dba)3 (1 mol % of Pd). The
Keywords: Amides; Phosphines; Coupling reactions; Aryl bromides.
* Corresponding author. Tel./fax: +86-571-87953128; e-mail addresses:
chdai@ust.hk; chdai@zju.edu.cn
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.142

2000
W.-M. Dai et al. / Tetrahedron Letters 45 (2004) 1999–2001
An electronic effect on the reactivity of 4-substituted
phenyl bromides 8–11 was observed. For the phenyl
bromides 10 and 11 possessing a C4 electron-with-
drawing group, the Suzuki reactions with phenylboronic
acid took place at 60 °C with 0.01 mol % of Pd, affording
the biaryl products in 95% and 99% yields, respectively
(entries 11 and 12). For the electron-rich phenyl bro-
mides 8 and 9, a higher reaction temperature at 80 °C
was required for the coupling reactions with 0.01 mol %
of Pd, giving excellent yields of 93–99% (entries 9 and
10).
0.005 mol% Pd2(dba)3
0.02 mol% 3
PhB(OH)2
Ar Br
+
Ar Ph
KF•2H2O or K3PO4
PhMe, 60-80 °C
5-14
Br
Br
R
Br
6
7: R = 3-Me
5
8: R = 4-Me
9: R = 4-MeO
10: R = 4-CHO
11: R = 4-MeC(O)
The steric effect also plays an important role on the
efficiency of the Suzuki cross-coupling reaction. The
reaction of 9-bromoanthracene with PhB(OH)2 at 60 °C
for 40 h in the presence of 0.01 mol % Pd gave the
product in 84% yield, which could be improved to 97%
using a slightly increased Pd loading of 0.015 mol %
(60 °C, 26 h) (entries 4 and 5). More significantly, two
naphthalene substrates 12 and 13 gave very different
results. With 0.01 mol % of Pd loading at 80 °C for 40 h,
1-bromo-2-methoxynaphthalene 12 gave the product in
only 57% yield compared to 2-bromo-6-methoxynaph-
thalene 13, which afforded the biaryl in 98% yield under
the identical reaction conditions (entries 13 and 15). The
yield of the reaction of 12 was improved to 86% when
0.1 mol % of Pd was employed (entry 14). Finally, the
heterocyclic aryl bromide 14 underwent the Suzuki
reaction with phenylboronic acid at 80 °C for 30 h
to furnish the product in 90% yield (entry 16). The
P,O-ligand 4 acts in a similar manner as 3 and gave
slightly better results in some cases (data not shown).
Br
Br
OMe
MeO
OHC
Br
O
13
12
14
Scheme 1. The Suzuki cross-coupling reaction of aryl bromides.
reaction proceeded initially but almost stopped after
24 h to give the product in 24% yield (entry 6). In con-
trast, the same reaction carried out at 60 °C completed
within 1 h to give the product in 99% yield in the
presence of 1 mol % of Pd or the product was obtained
in 95% yield after 18 h with 0.01 mol % of Pd (entries 7
and 8). In another set of experiments of 9-bromophen-
anthrene 5, the effect of Pd loading on the reaction was
examined. At 60 °C, the coupling of 5 with phenyl-
boronic acid afforded a 99% yield of the biaryl after 4 h
using 1 mol % of Pd whilst a 96% yield was obtained at
80 °C for 26 h using 0.01 mol % of Pd (entries 1 and 2).
Further reduction of Pd to 0.0005 mol %, however, sig-
nificantly diminished the yield of the product to 32%
(entry 3). We found that either KFÆ2H2O or K3PO4
could be used as the base without remarkable differences.
Cross-coupling of sterically hindered substrates via the
Suzuki reaction is an attractive method for accessing
biaryl atropisomers.7b;14 It forms the basis for develop-
ment of the asymmetric version of this catalytic pro-
cess.15 We performed the coupling reaction of 5 with
2,6-dimethylphenylboronic acid using the P,O-ligand 4
Table 1. Suzuki cross-coupling of aryl bromides with phenylboronic acid using amide-derived P,O-ligand 3a
Entry
ArBr
Pd loading (%)
Base
Temperature (°C) Time (h)
Yield (%)b
1
5: 9-bromophenathrene
5: 9-bromophenanthrene
5: 9-bromophenanthrene
6: 9-bromoanthracene
1
KFÆ2H2O
KFÆ2H2O
K3PO4
60
80
80
60
60
rt
4
26
24
40
26
24
1
99
96
32
84
97
24
99
95
99
93
95
99
57c
86c
98
90
2
0.01
0.0005
0.01
0.015
1
3
4
KFÆ2H2O
KFÆ2H2O
K3PO4
5
6: 9-bromoanthracene
7: 3-bromotoluene
6
7
7: 3-bromotoluene
7: 3-bromotoluene
1
K3PO4
60
60
80
80
60
60
80
80
80
80
8
0.01
0.01
0.01
0.01
0.01
0.01
0.1
KFÆ2H2O
KFÆ2H2O
KFÆ2H2O
KFÆ2H2O
KFÆ2H2O
KFÆ2H2O
KFÆ2H2O
KFÆ2H2O
KFÆ2H2O
18
20
24
40
12
40
24
40
30
9
8: 4-bromotoluene
9: 4-bromoanisole
10
11
12
13
14
15
16
10: 4-bromobenzaldehyde
11: 4-bromoacetophenone
12: 1-bromo-2-methoxynaphthalene
12: 1-bromo-2-methoxynaphthalene
13: 2-bromo-6-methoxynaphthalene
14: 5-bromo-2-furaldehyde
0.01
0.01
a Reactions were carried out with 1.0 equiv of aryl bromide, 1.5 equiv of phenylboronic acid, and 3.0 equiv of base in toluene. Pd2(dba)3 was used as
the catalyst precursor with a Pd:ligand ratio of 1:2.
b Isolated yield.
c Debromonation by-product was noted on TLC analysis of the reaction mixture.

W.-M. Dai et al. / Tetrahedron Letters 45 (2004) 1999–2001
2001
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Me
B(OH)2
Br
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2 mol% 4
K3PO4, PhMe
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(99.9%)
5
15
Scheme 2. The Suzuki cross-coupling of hindered arylboronic acid.
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at 110 °C for 9 h to produce the product 15 in 99.9%
yield (Scheme 2).
In summary, we have developed a novel class of amide-
derived P,O-ligands 3 and 4, which are air-stable and
readily available, for the Suzuki cross-coupling of
structurally versatile aryl bromides with phenylboronic
acid at low Pd loading of 0.01 mol % at 60–80 °C. The
P,O-ligands are also effective for cross-coupling of ste-
rically hindered substrates. In our previous work on
asymmetric allylic alkylation, enantiomerically pure
version of the P,O-ligands has been prepared.10 Our
results presented here form the basis for designing
an asymmetric Suzuki cross-coupling employing the
1-naphthamide-derived atropisomeric P,O-ligands.
Study on the asymmetric Suzuki cross-coupling is in
progress in our laboratories.
9. Leadbeater, N. E.; Macro, M. Angew. Chem., Int. Ed.
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12. For examples of X-ray crystal strucutres of amide-type
P,O-coordination with Pd, see: (a) Butts, C. P.; Crosby, J.;
Lloyd-Jones, G. C.; Stephen, S. C. Chem. Commun. 1999,
1707–1708; (b) Kim, Y. K.; Lee, S. J.; Ahn, K. H. J. Org.
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13. The Pd:ligand ratios of 1:2 and 1:3 were used for 1 (Ref.
7b) and 2 (Ref. 8b), respectively.
Acknowledgements
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15. Examples of asymmetric Suzuki reaction, see: (a) Nico-
laou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.;
This work is supported in part by a research grant
provided by Zhejiang University. W.-M.D. is the reci-
pent of Cheung Kong Scholars Award of The Ministry
of Education of China (2003–2007).
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