Efficient aqueous-phase Suzuki coupling of activated aryl chlorides with arylboronic acids using D-glucosamine-based dicyclohexylarylphosphine

Article abstract of DOI:10.1016/j.tetlet.2005.03.049

The synthesis of a new D-glucosamine-based dicyclohexylarylphosphine has been developed. The catalytic performance of this neutral ligand is demonstrated in the Suzuki-Miyaura cross-coupling reaction between several arylboronic acids and aryl or heteroaryl chlorides.

Full text of DOI:10.1016/j.tetlet.2005.03.049

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3205–3208
Efficient aqueous-phase Suzuki coupling of activated aryl
chlorides with arylboronic acids using D-glucosamine-based
dicyclohexylarylphosphine
*
Anzhelika Konovets, Alexandra Penciu, Eric Framery, Nathalie Percina,
Catherine Goux-Henry and Denis Sinou*
Laboratoire de Synth e` se Asym e´ trique, UMR UCBL/CNRS 5181, ESCPE Lyon, Universit e´ Claude Bernard Lyon 1,
4
3 boulevard du 11 novembre 1918, F-69622 Villeurbanne Cedex, France
Received 7 January 2005; revised 7 March 2005; accepted 9 March 2005
Available online 24 March 2005
Abstract—The synthesis of a new D-glucosamine-based dicyclohexylarylphosphine has been developed. The catalytic performance
of this neutral ligand is demonstrated in the Suzuki–Miyaura cross-coupling reaction between several arylboronic acids and aryl or
heteroaryl chlorides.
Ó 2005 Elsevier Ltd. All rights reserved.
The palladium-catalyzed cross-coupling reaction of aryl
halides with boronic acids, so-called Suzuki–Miyaura
reaction, is recognized as one of the most attractive syn-
was the use of electron-rich and sterically hindered phos-
phines (such as PCy , PCy Ar, aryl–MOPFs, DmpPR ,
etc.), carbene ligands, or imidazolium salts.
3
2
2
1
thetic routes for the preparation of biaryl compounds.
These biaryls constitute important building blocks for
the synthesis of pharmaceuticals, herbicides, polymers,
materials, liquid crystals, and ligands. Some applica-
Due to the simplicity of catalyst–product separation, the
economy, the safety and the environment impact, the
use of water as a solvent in organic synthesis continues
2
17
tions have been extended on industrial scale. Suzuki–
to attract considerable attention. Only few examples
Miyaura cross-coupling reactions of aryl iodides and
bromides have been extensively studied in the last dec-
ade. Due to their low cost and ready accessibility, aryl
chlorides are more interesting from an industrial point
of view.
have been reported concerning the cross-coupling reac-
tions of chloroarenes with arylboronic acids in water
or biphasic media. The use of water-soluble phosphines
such as the trisodium salt of trisulfonated triphenyl-
phosphine (TPPTS) in combination with NiCl (dppe)
2
in 1,4-dioxane–water has been described by Gen eˆ t and
19
1
8
Some examples of cross-coupling reactions of aryl chlo-
3
co-workers. Oxime-derived palladacycles, di-2-pyr-
20
rides with boronic acids have been described. Indolese
4
idylmethylamine-based palladium complexes, and pal-
21
ladium N-heterocyclic carbene complexes have also
and Miyaura et al. used successfully nickel catalysts,
5
6
7
8
when the groups of Beller, Buchwald, Fu, F u¨ rstner,
12
been reported in the cross-coupling of aryl chlorides
with aryl or alkylboronic acids. However, the observed
turnover numbers (TON) are generally lower for the
coupling of aryl chlorides with phenylboronic acids than
for aryl bromides, where TON up to 734,000 have been
obtained using a more sterically water-soluble alkyl-
9
10
11
Guram, Herrmann,
14
Johannsen,
15
Nolan,
and Ozdemir per-
Rich-
1
3
16
ards,
Xiao,
Protasiewicz,
formed the same reactions in the presence of
palladium catalysts. The key for the successful coupling
2
2
phosphine as ligand.
Keywords: Suzuki coupling; Carbohydrate; Dicyclohexylarylphos-
phine; Water soluble.
The use of carbohydrate-based ligands in this coupling
reaction appeared recently in the literature, and this
approach seems to have a great potential. Glycoside
and gluconamide derivatives of triphenylphosphine have
*
Corresponding authors. Tel.: +33 472 446 264; fax: +33 472 448 160
E.F.); tel.: +33 472 448 183; fax: +33 478 898 914 (D.S.); e-mail
addresses: framery@univ-lyon1.fr; sinou@univ-lyon1.fr
(
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.049

3
206
A. Konovets et al. / Tetrahedron Letters 46 (2005) 3205–3208
24
2
3
been prepared by the groups of Beller and Miyaura,
on D-glucosamine, and its application in the cross-cou-
pling reaction of aryl chlorides with arylboronic acids
in an organic-aqueous medium.
respectively. In the case of glycoside derivative, only the
coupling of aryl bromides has been performed with high
TON (up to 9000). Despite the high TON obtained
using as the catalyst Pd(OAc) associated with the car-
2
The synthesis of glucosamine-based dicyclohexylaryl-
phosphine 3 is shown in Scheme 1. Palladium-catalyzed
coupling of 2-iodobromobenzene with 3-cyanophen-
ylboronic acid, followed by lithiation–phosphorylation
of the C–Br bond according to the procedure described
bohydrate derivatives, the glycoside derivatives of tri-
phenylphosphine suffered from their easy hydrolytic
cleavage in the presence of water, prohibiting the effi-
cient recycling of the catalyst. For the gluconamide
derivatives, the coupling of bromo- and chloroarenes
has although been developed. The screening of others
ligands via the simple modification of the carbohydrate
moiety, in order to improve the catalyst activity and
recycling, seems difficult. Recently, we have presented
some results concerning the synthesis of a new class of
more stable carbohydrate-based triphenylphosphine de-
2
4
0
in the literature from 1,2-dibromobenzene, afforded 2 -
(dicyclohexylphosphino)biphenyl-4-carbonitrile
1
in
0
60% yield. Acidic hydrolysis of compound 1 gave 2 -
(dicyclohexylphosphino)biphenyl-4-carboxylic acid 2 in
45% yield after purification. Coupling of this acid 2 with
D-glucosamine hydrochloride in a DMF–H O solution
2
in the presence of 1-[3-dimethylaminopropyl]-3-ethyl-
carbodiimide (EDC), 1-hydroxybenzotriazole (HOBT),
2
5
rived from D-glucosamine. These ligands have been
successfully used in association with Pd(OAc) in the
0
and NaHCO , afforded 2-deoxy-2-{[[2 -(dicyclohexyl-
3
2
aqueous-phase Suzuki cross-coupling reaction. How-
ever, these systems were limited to the coupling using
aryl iodides and bromides.
phosphino)biphenyl-4-yl]carbonyl]amino}-D-glucopyr-
2
anose 3 in 62% yield.
6
Different cross-coupling reactions of various aryl chlo-
rides with arylboronic acids were investigated, and the
results are summarized in Table 1. The conditions of
Here, we describe the synthesis of a new generation
of sterically hindered dicyclohexylphosphine based
CN
CO H
2
OH
I
O
HO
HO
Br
OH
HN
(
i)
(ii)
PCy2
(iii)
PCy2
(iv)
O
Cy P
2
1
2
3
Scheme 1. Synthesis of the glucosamine-based dicyclohexylphenylphosphine 3. Reagents and conditions: (i) 4-cyanophenylboronic acid, Pd(OAc)
TPPTS, Et N, CH CN/H PCl at rt during 10 h; (iii) HCl, 110 °C; (iv) D-glucosamine
O, 45 °C, 48 h; (ii) n-BuLi at ꢀ100 °C during 1 h, then Cy
hydrochloride, NaHCO , EDC/HOBT, DMF/H O, rt, 24 h.
2
/
3
3
2
2
3
2
a
/3 Ar–X + Ar –B(OH)
0
0
Table 1. Suzuki–Miyaura cross-coupling of aryl halides and boronic acids with Pd(OAc)
2
2
! Ar–Ar
Conversion (%)
0
b
c
Yield (%)
Entry
Aryl halide Ar–X
Arylboronic acid Ar –B(OH)
2
Temp (°C)
d
1
1-Bromo-4-nitrobenzene
1-Chloro-4-nitrobenzene
1-Chloro-4-nitrobenzene
1-Chloro-4-nitrobenzene
1-Chloro-4-nitrobenzene
4-Chlorobenzonitrile
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
Phenylboronic acid
4-Cyanophenylboronic acid
60
60
60
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
98
53
97
50
—
98
99
96
97
94
—
—
93
81
99
95
98
92
99
90
d
2
3
4
76
100
100
96
e
5
6
7
8
9
4-Chlorobenzoic acid
100
94
4-Chlorobenzaldehyde
1-Chloro-4-methylbenzene
2-Chloro-1,3-dimethylbenzene
2-Chloropyridine
23
12
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
100
88
3-Chloropyridine
1-Chloro-4-nitrobenzene
1-Chloro-4-nitrobenzene
1-Chloro-4-nitrobenzene
1-Chloro-4-nitrobenzene
1-Chloro-4-nitrobenzene
1-Chloro-4-nitrobenzene
100
100
100
100
100
100
4-Methoxyphenylboronic acid
4-Acetylphenylboronic acid
4-Formylphenylboronic acid
4-Methylphenylboronic acid
2,6-Dimethylphenylboronic acid
a
b
c
Reaction conditions: [aryl halide] = 0.05 M; [aryl halide]/[boronic acid]/[Na
2 3 2
CO ] = 1/1.1/3; [Pd]/[ligand] = 1/3; toluene/EtOH/H O = 3/2/2.
Conversion determined by GC.
Isolated chemical yield after column chromatography.
Reaction time 1 h.
Catalyst concentration of 0.1% M.
d
e

A. Konovets et al. / Tetrahedron Letters 46 (2005) 3205–3208
3207
the cross-coupling reaction were determined using
In conclusion, the synthesis of a new hydrosoluble glu-
cosamine-based dicyclohexylarylphosphine has been de-
scribed. This phosphine has been used as ligand in the
palladium Suzuki cross-coupling reaction. The efficiency
of this ligand has been demonstrated in a wide range of
coupling between aryl or heteroaryl chlorides and aryl-
boronic acids. The Suzuki reaction was carried out at
4
scribed before,
-nitrobromobenzene and phenylboronic acid. As de-
2
5b
the reaction was carried out in a 3/2/
2
alyst, formed in situ from 1% M of Pd(OAc) and 3% M
toluene/EtOH/H O mixture in the presence of the cat-
2
2
of ligand 3, and in the presence of Na CO (3 equiv) as
2
3
2
7
the base. After 1 h at 60 °C, the conversion and the
yield were 98% and 97%, respectively (Table 1, entry
80 °C in a 3/2/2 mixture of toluene/EtOH/H O in the
2
1
). The same conditions of reactants and temperature
presence of 1.0% or 0.1% M catalyst prepared in situ
from Pd(OAc) and the carbohydrate derivative. With
were applied to the coupling of 4-nitrochlorobenzene
with phenylboronic acid; however the conversion was
only 53% after 1 h (Table 1, entry 2), and 76% after
2
only 1.1 equiv of arylboronic acid in relation to aryl
chloride, the conversions and the chemical yields are
generally high. These results are quite similar to these
2
0 h (Table 1, entry 3). When this cross-coupling reac-
2
4
tion was performed at 80 °C, the conversion and the
yield were 100% and 98%, respectively, after 20 h (Table
published by Miyaura and co-workers using the gluc-
onamide derivative of triphenylphosphine, the same
activities being observed using activated aryl chlorides.
However, the screening of others ligands by the modifi-
cation of the carbohydrate moiety, in order to improve
the catalyst activity and recycling, seems more easy
using our system. Work is in progress actually in order
to prepare new ligands with higher hydrosolubility in
order to perform this reaction in a true biphasic system
water/organic solvent.
1
, entry 4). Decreasing the amount of catalyst to 0.1% M
gave the same results (Table 1, entry 5). Before testing
other aryl chlorides and arylboronic acids, we compared
these first results with those obtained using a ÔligandlessÕ
1
g,28
palladium catalyst.
Under the conditions described
above, but without ligand 3, the conversion was 100%
in the coupling of 4-nitrobromobenzene and phenyl-
boronic acid, when no coupling reaction occurred using
4-nitrochlorobenzene and phenylboronic acid. It is
known that in the case of aryl chloride, temperature
higher than 80 °C or microwave are necessary in order
to perform the coupling reaction.
2
9
Acknowledgements
The biaryl coupling of various chloroarenes with phen-
ylboronic acid was then investigated. Aryl chlorides
bearing electron acceptor groups (Table 1, entries 6–8)
reacted efficiently with phenylboronic acid affording
quantitatively the corresponding biaryl compounds.
Conversely, the aryl chlorides bearing electron donor
groups gave very low conversion: 23% for 4-methylchlo-
robenzene (Table 1, entry 9), and 12% for 2,6-dimethyl-
chlorobenzene (Table 1, entry10). It is known that in the
case of ortho-substituted aryl chlorides, the catalytic effi-
ciency depends on the bulkiness and/or electronic effects
of the substituent. Generally, in order to obtain good
yields starting from phenylboronic acid, a higher tem-
perature (P100 °C) is necessary as shown by Beller
A.K. and A.P. thank the CNRS and the MENSR,
respectively, for a fellowship.
References and notes
1
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2
3
4
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. Szmant, H. H. In Organic Building Blocks of the Chemical
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3
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quite good yields, 93% and 81%, respectively (Table 1,
entry 11 or 12).
8
. (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int.
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Finally, the biaryl coupling of 4-nitrochlorobenzene
with different arylboronic acids was studied in the pres-
ence of our catalyst. The conversion was quantitative
whatever the nature of the substituent of the arylboronic
acids (Table 1, entries 13–18). It is noteworthy that the
coupling of 4-methylphenylboronic acid and 2,6-di-
methylphenylboronic acid with 4-nitrochlorobenzene
occurred, the coupling products being obtained in
6
. (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
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99% and 90% yield, respectively (Table 1, entries 17
and 18).

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2
002, 41, 1363–1365.
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2
D
0
1
1
26. Compound 3: R
(c 0.2, CHCl ); H NMR (C
f
= 0.65 (CHCl
3
/EtOH 2.5/2); ½aꢁ +35.5
1
3
3
5
D
5
N): d 9.43 (d, J = 8.3 Hz,
2. (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P.
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b a
J = 8.3 Hz, 2H, Harom), 7.77–7.67 (m, 1H, Harom), 7.55–
7.30 (m, 5H, Harom), 6.09 (d, J = 2.9 Hz, 0.8H, H1a), 5.61
(d, J = 8.3 Hz, 0.2H, H1b), 5.16 (ddd, J = 3.4, 8.4, 10.8 Hz,
0.8H, H ), 4.87–4.77 (m, 1.8H, H , H , H ), 4.65–4.50
2a 2b 3a 5a
6 6
(m, 1.2H, H3b, H ), 4.47–4.22 (m, 1.8H, H4a, H ), 4.10–
0
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1
1
1
1
1
3
4.00 (m, 0.2H, H4b), 3.67–3.57 (m, 0.2H, H5b), 2.00–1.80
(m, 2H, PCH), 1.97–1.42 (m, 10H, HCy), 1.32–0.90 (m,
3
1
7
10H, HCy); P NMR (C D N): d ꢀ12.6; HRMS of
5
5
+
[M+H]
27. Typical procedure: Pd(OAc)
C
31 6
H
43NO
P calcd 556.2828, found 556.2831.
(2.4 mg, 0.01 mmol) and
2
ligand 3 (16.5 mg, 0.03 mmol) were placed in a flask under
argon. Degassed water (2 mL) and ethanol (2 mL) were
added, and the solution was stirred for 30 min at rt. A
mixture of aryl chloride (1.0 mmol) and phenylboronic
acid (130.0 mg, 1.1 mmol) in a mixture of toluene (8.5 mL)
and ethanol (3.5 mL) was then added in the flask, followed
2 3
by Na CO (318 mg, 3.0 mmol) dissolved in water
(3.5 mL). The resulting mixture was stirred at the desired
temperature. After the indicated time, the mixture was
cooled at rt, the two phases were separated, the ethanol–
water layer was washed twice with toluene. The combined
organic phases were dried over Na SO , and concentrated
1
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179–181; (b) Botella, L.; Najera, C. J. Organomet. Chem.
2
4
2
002, 663, 46–57.
under reduced pressure. Purification of the crude product
by flash-chromatography on silica gel gave the coupling
product.
2
2
0. Najera, C.; Gil-Molto, J.; Karlstr o¨ m, S.; Falvello, L. R.
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