Glucosamine-based phosphines. Efficient ligands in the Suzuki cross-coupling reaction in water

Article abstract of DOI:10.1016/S0040-4039(02)01749-5

Coupling of protected or non-protected D-glucosamine with o- or p-(diphenylphosphino)benzoic acid generates carbohydrate-substituted phosphines in quite good yields. The catalytic performance of these new neutral ligands is demonstrated in the Suzuki cross-coupling reaction. The polyhydroxy phosphines are more active than the peracetylated phosphines, and the process tolerates electron-rich as well as electron-poor substituents. Excellent turnovers are observed, and the catalyst can be recycled.

Full text of DOI:10.1016/S0040-4039(02)01749-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7397–7400
Glucosamine-based phosphines. Efficient ligands in the Suzuki
cross-coupling reaction in water
Sophie Parisot,a Robert Kolodziuk,a Catherine Goux-Henry,a Alexander Iourtchenkoa,b and
Denis Sinoua,*
aLaboratoire de Synthe`se Asyme´trique, associe´ au CNRS, Universite´ Claude Bernard Lyon 1, CPE Lyon, 43, boulevard du 11
novembre 1918, 69622 Villeurbanne cedex, France
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskya Str. 5, 02094 Kiev 94, Ukraine
Received 22 July 2002; accepted 14 August 2002
Abstract—Coupling of protected or non-protected
D-glucosamine with o- or p-(diphenylphosphino)benzoic acid generates
carbohydrate-substituted phosphines in quite good yields. The catalytic performance of these new neutral ligands is demonstrated
in the Suzuki cross-coupling reaction. The polyhydroxy phosphines are more active than the peracetylated phosphines, and the
process tolerates electron-rich as well as electron-poor substituents. Excellent turnovers are observed, and the catalyst can be
recycled. © 2002 Elsevier Science Ltd. All rights reserved.
From both scientific and environmental points of view,
development of easily separable organometallic cata-
lysts from the organic products has attracted much
attention. One way to solve this problem is the use of a
two-phase catalysis water–organic solvent.1 This implies
the use of hydrophilic ligands such as phosphines in
order to immobilize the catalyst in the aqueous phase.
Most of the hydrosoluble phosphines used in recent
years, such as the sodium salt of monosulfonated
triphenylphosphine (TPPMS) or the trisodium salt of
trisulfonated triphenyl phosphine (TPPTS), possessed
ionic groups. Carbohydrate based phosphines, having
neutral polar groups, appeared recently in the literature
and seem to have a great potential; these ligands belong
to an interesting class of neutral hydrophilic ligands
derived from renewable materials.
Recently, glycosides of triphenylphosphines and glu-
conamide derivatives of triphenylphosphine were pre-
pared by the groups of Beller2 and Miyaura,3
respectively. These ligands associated with Pd(OAc)2
achieved higher efficiencies than that of TPPMS4 and
TPPTS5 for Suzuki cross-coupling reaction of halo-
arenes with aryl boronic acids6–9 in water or in a
two-phase
system.
However,
glycosides
of
triphenylphosphine probably suffered from their easy
Scheme 1. Synthesis of glucosamine-based phosphines 3a–d.
Keywords: Suzuki coupling; carbohydrate; water-soluble; recycling.
* Corresponding author. Tel.: 33 (0)4 72448183; fax: 33 (0)4 78898914; e-mail: sinou@univ-lyon1.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01749-5

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S. Parisot et al. / Tetrahedron Letters 43 (2002) 7397–7400
hydrolysis in the presence of water, precluding the
possibility of an efficient recycling of the catalyst. In the
case of the gluconamide derivative, although the mod-
ification of the phosphine is easy, the screening of other
carbohydrate moieties, in order to improve the catalyst
efficiency, seems more difficult. We present in this
paper some results concerning the synthesis of a new
class of more stable carbohydrate-based phosphines,
whose modification is very easy both on the phosphine
as well as on the carbohydrate moieties, and their
application in Suzuki cross-coupling reactions.
The cross-coupling reaction was performed in a mixture
of ethanol/water/toluene, using Pd(OAc)2 in association
with the ortho-substituted peracetylated ligand 3a, or
the polyhydroxy ligand 3b, using a 1.1/1 ratio of aryl
boronic acid/aryl halide. The results summarized in
Table 1 show that the peracetylated ligand 3a was
surprisingly completely inefficient at 60°C in this cou-
pling reaction, even using aryl iodides. On the other
hand, the polyhydroxy phosphine ligand 3b was found
to catalyze efficiently the coupling of haloaryls and aryl
boronic acids, the cross-coupling being efficient over a
broad spectrum of ortho and para-substituted aryl
iodides and bromides. A large number of functions are
tolerated, and the reaction time for a total conversion is
short (2 h), using 1% mol catalyst. Decreasing the
amount of catalyst to 0.1% also allowed a total conver-
sion by increasing the reaction time (compared entries 2
and 3).
We expected that the carbohydrate side-chain could be
introduced via the usual coupling between an
aminosugar and a triphenylphosphine bearing a car-
boxylic function. In the first approach, we choose glu-
cosamine as the aminosugar. The synthesis of the
glucosamine derivatives of triphenylphosphine 3a–d is
shown in Scheme 1. Condensation of 2-amino-1,3,4,6-
The reaction is chemospecific for aryl bromide in the
presence of aryl chloride (Table 1, entry 15). Even
sterically hindered boronic acid such as 2,6-
dimethylphenyl boronic acid reacted under these condi-
tions with 4-iodonitrobenzene to give the coupling
product in 86% yield after 24 h, using 0.1% mol catalyst
(Table 1, entry 5). It is to be noticed that no formation
of homo-coupling products was observed.
tetra-O-acetyl-2-deoxy-b- -glucopyranose (1a) with o-
D
or p-(diphenylphosphino)benzoic acid (2a) or (2b) in a
mixture of CH2Cl2/THF in the presence of EDC (or
1-[3-dimethylaminopropyl]-3-ethylcarbodiimide)
and
HOBT (or 1-hydroxybenzotriazole) afforded the corre-
sponding carbohydrate based phosphines 3a and 3c in
50% and 68% yields, respectively. Deacetylation of
these peracetylated phosphines with a catalytic amount
of sodium methoxide in methanol gave the polyhydroxy
phosphines 3b and 3d in 80% and 88% yields, respec-
tively. These compounds could also be obtained directly
by condensation of N-glucosamine (1b) with o- or
p-(diphenylphosphino)benzoic acid (2a) and (2b) in the
presence of EDC, HOBT, and NaHCO3 in a mixture of
DMF/water as the solvent in 85% and 74% yields,
respectively.
We then used Pd(OAc)2 in association with para-substi-
tuted ligands 3c or 3d as the catalyst (Table 2). It is
noteworthy that the coupling reaction occurred
efficiently using the peracetylated ligand 3c as well as
the polyhydroxy ligand 3d, and that the reaction could
be performed even at room temperature (Table 2,
entries 1, 3, and 17). However, the polyhydroxy ligand
was more efficient than the peracetylated ligand. Again
Table 1. Suzuki cross-coupling of aryl halides and boronic acids with Pd(OAc)2/3a–ba
Ar-X+Ar%-B(OH)2“Ar-Ar%
Entry
Aryl halide Ar-X
Aryl boronic acid
Ar%B(OH)2
Ligand
Mol Pd (%)
T (°C)/t (h)
Yield Ar-Ar% (%)b
(Conversion)c
1
2
3
4
5
6
7
8
4-Iodonitrobenzene
C6H5B(OH)2
3a
3b
3b
3b
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
1
1
0.1
0.1
0.1
1
1
1
1
1
60/3
70/2
60/24
60/18
60/24
70/4
70/2
70/3
70/2
70/3
70/2
70/3
70/2
70/3
70/2
(32)
(93)
\99
\98
86
(8)
(99)
(0)
(92)
(0)
(99)
(0)
(99)
(0)
(84)
4-Iodonitrobenzene
4-Iodonitrobenzene
4-Bromonitrobenzene
4-MeC6H4B(OH)2
2,6-diMeC6H3B(OH)2
C6H5B(OH)2
4-Bromobenzaldehyde
4-Bromoanisole
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
C6H5B(OH)2
9
10
11
12
13
14
15
1
1
1
1
3-Bromonitrobenzene
4-Bromochlorobenzene
1
a Reaction conditions: [aryl halide]=0.05 M; [aryl halide]/[boronic acid]/[Na2CO3]=1/1.1/3; [Pd]/[ligand]=1/3; toluene/EtOH/H2O=3/2/2.
b Isolated chemical yield after column chromatography.
c Conversion determined by GC.

S. Parisot et al. / Tetrahedron Letters 43 (2002) 7397–7400
7399
boronic acid; when the corresponding biaryl derivative
was obtained in 81% yield using 0.01% catalyst after 18
h reaction in the presence of Na2CO3, this yield was
increased to 95% after only 10 h using K3PO4 as the
base (Table 2, entries 28 and 29). The hindered 2-
bromonitrobenzene reacted with 4-methylphenyl
boronic acid in the presence of K3PO4 to give the
coupling product in 99% yield using 1% catalyst (Table
2, entry 21). It is to be noted again that in all these
experiments, the formation of homo-coupling products
was never observed.
a large spectrum of aryl boronic acids, bearing sub-
stituents such as methyl (Table 2, entry 9), carbonyl
(Table 2, entry 10), and methoxy (Table 2, entry 12),
reacted with 4-iodonitrobenzene to give the correspond-
ing biaryl derivative in excellent yields, even using 0.1%
of catalyst (Table 2, entries 5, 10, 13, 19, and 26).
Moreover, in the case of iodonitrobenzene and boronic
acid, the coupling was quantitative at 60°C using
0.001% of catalyst in the presence of K3PO4 as the base
(Table 2, entries 7 and 8).
The sterically hindered 2,6-dimethylphenyl boronic acid
reacted also and gave the coupled product in 79% yield
using 0.1% of catalyst. This yield was increased to 96%
using an increasing amount of aryl boronic acid (Table
2, entries 14 and 15).
Finally it was possible to recycle the catalyst.10 For
example, the product resulting from the coupling of
4-iodonitrobenzene and phenyl boronic acid in the
presence of 0.1% mol Pd(OAc)2 and 0.3% mol ligand 3d
was obtained in 98% yield after 1 h reaction for the first
cycle, 97% yield after 1 h for the second cycle, and 95%
yield after 3 h for the third cycle. However using a low
palladium loading (0.1% Pd), the degree of conversion
decreases only for the second recycling; this decrease
could be due to some accumulation of salts in the
mixture.
Condensation of 4-bromonitrobenzene and phenyl
boronic acid occurred quantitatively in a short time
using 0.1% catalyst (Table 2, entries 18 and 19). The
beneficial effect of K3PO4 on the coupling was observed
in the reaction of 2-bromopyridine with 4-methylphenyl
Table 2. Suzuki cross-coupling of aryl halides and boronic acids with Pd(OAc)2/3c–da
Ar-X+Ar%-B(OH)2“Ar-Ar%
Entry
Aryl halide Ar-X
Aryl boronic acid
Ar%B(OH)2
Ligand
Mol Pd (%)
T (°C)/t (h)
Yield Ar-Ar% (%)b
(Conversion)c
1
2
3
4
5
6
7
8
4-Iodonitrobenzene
C6H5B(OH)2
3c
3c
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3c
3d
3d
3d
3d
3d
3c
3d
3d
3d
3d
3d
3d
1
1
1
1
25/2
70/2
25/24
60/0.08
60/1
89
98
90
98
97
100
86
97
98
\99
88
\99
90
79
96
0.1
0.01
0.001
0.001d
1
0.1
0.01
1
0.1
0.1
0.1e
0.01
1
60/1
60/18
60/18
60/1
9
4-Iodonitrobenzene
4-Iodonitrobenzene
4-MeC6H4B(OH)2
4-CHOC6H%B(OH)2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
60/1
60/24
60/18
60/18
60/18
60/18
60/18
25/2
60/1
60/2
60/18
60/18
60/18
70/3
60/1
60/18
60/1
60/1
60/18
60/10
4-Iodonitrobenzene
4-Iodonitrobenzene
4-MeOC6H4B(OH)2
2,6-diMeC6H3B(OH)2
m
4-Bromonitrobenzene
C6H5B(OH)2
(100)
95
97
81
\99
78
(97)
(97)
95
\99
88
1
0.1
0.01d
1d
0.1
1
4-Bromonitrobenzene
2-Bromonitrobenzene
4-MeC6H4B(OH)2
4-MeC6H4B(OH)2
2-Bromochlorobenzene
4-Bromobenzaldehyde
C6H5B(OH)2
C6H5B(OH)2
1
1
0.1
0.01
0.01
0.01d
2-Bromopyridine
4-MeC6H4B(OH)2
81
95
a Reaction conditions: [aryl halide]=0.05 M; [aryl halide]/[boronic acid]/[Na2CO3]=1/1.1/3; [Pd]/[ligand]=1/3; toluene/EtOH/H2O=3/2/2.
b Isolated chemical yield after column chromatography.
c Conversion determined by GC.
d K3PO4 was used as the base.
e [aryl halide]/[boronic acid]=1/2.3.

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S. Parisot et al. / Tetrahedron Letters 43 (2002) 7397–7400
In conclusion, palladium associated with a carbohy-
drate-based phosphine has been shown to have very
high efficiency for the Suzuki cross-coupling reaction of
a wide range of aryl halides and boronic acids. The
catalyst can be also recycled. Work is in progress to
extend this methodology to other water-soluble carbo-
hydrate-based phosphines, other aryl halides, as well as
other palladium-catalyzed reactions.
4. Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc.
1990, 112, 4324–4330.
5. (a) Galland, J.-C.; Savignac, M.; Geneˆt, J.-P. Tetrahedron
Lett. 1999, 40, 2323–2326; (b) Dupuis, C.; Adley, K.;
Charruault, L.; Michelet, V.; Savignac, M.; Geneˆt, J.-P.
Tetrahedron Lett. 2001, 42, 6523–6526.
6. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
7. Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim,
1998; pp. 49–97.
Acknowledgements
8. Stanforth, S. P. Tetrahedron 1998, 54, 263–303.
9. Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168.
10. Typical procedure: Pd(OAc)2 (1.5 mg, 7×10−3 mmol) and
the ligand 3 (21×10−3 mmol) were placed in a flask under
argon. Degassed water (1 mL) and ethanol (1 mL) were
added and the solution was stirred for 30 min. A mixture
of aryl halide (0.7 mmol) and boronic acid (0.8 mmol) in
a mixture of toluene (6 mL) and ethanol (2 mL) was then
added in the flask, followed by Na2CO3 (212 mg, 2
mmol) dissolved in water (3 mL). The resulting mixture
was stirred at the desired temperature. After the indicated
time, the mixture was cooled at room temperature, the
two phases were separated, the ethanol/H2O layer was
washed twice with toluene. The combined organic phases
were dried over Na2SO4 and concentrated in vacuo.
Purification of the crude product by flash-chromatogra-
phy on silica gel gave the coupling product. In the case of
the recycling experiments, the water/ethanol layer was
transferred under argon into a second flask containing
the aryl halide, the boronic acid and the base, in a
mixture water/toluene.
A.I. and R.K. thank, respectively, the CNRS and
Re´gion Rhoˆne-Alpes for a fellowship.
References
1. (a) Aqueous-Phase Organometallic Catalysis. Concepts
and Applications; Cornils, B.; Herrmann, W. A., Eds;
VCH: Weinheim, 1998; (b) Hanson, B. E. Coord. Chem.
Rev. 1999, 185–186, 795–807; (c) Sinou, D. In Modern
Solvents in Organic Synthesis, Topics in Current Chem-
istry; Knochel, P., Ed.; 1999; Vol. 206, pp. 41–59.
2. (a) Beller, M.; Krauter, J. G. E.; Zapf, A. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 772–774; (b) Beller, M.; Krauter,
J. G. E.; Zapf, A.; Bogdanovic, S. Catal. Today 1999, 48,
279–290.
3. (a) Ueda, M.; Nishimura, M.; Miyaura, N. Synlett 2000,
856–858; (b) Nishimura, M.; Ueda, M.; Miyaura, N.
Tetrahedron 2002, 58, 5779–5787.