Palladium-catalyzed Suzuki cross-coupling of aryl halides with aryl boronic acids in the presence of glucosamine-based phosphines

Article abstract of DOI:10.1016/S0022-328X(03)00636-3

Carbohydrate-substituted phosphines are easily obtained in quite good yields by coupling of protected or non-protected d-glucosamine with the corresponding diphenylphosphino acid. These neutral ligands, in association with palladium acetate, are very active catalysts in the Suzuki cross-coupling reaction. The polyhydroxy phosphines are more active than the peracetylated phosphines. The process tolerates electron-rich as well as electron-poor substituents. Excellent turnovers, up to 97 000 are observed.

Full text of DOI:10.1016/S0022-328X(03)00636-3

Journal of Organometallic Chemistry 687 (2003) 384ꢀ391
/
www.elsevier.com/locate/jorganchem
Palladium-catalyzed Suzuki cross-coupling of aryl halides with aryl
boronic acids in the presence of glucosamine-based phosphines
Robert Kolodziuk a, Alexandra Penciu a, Mustapha Tollabi a, Eric Framery a,
Catherine Goux-Henry a, Alexander Iourtchenko b, Denis Sinou a,*
a Laboratoire de Synthe`se Asyme´trique, associe´ au CNRS, CPE Lyon, Universite´ Claude Bernard Lyon 1, 43, boulevard du 11 novembre 1918, 69622
Villeurbanne Cedex, France
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskya Street 5, 02094 Kiev 94, Ukraine
Received 28 May 2003; received in revised form 30 June 2003; accepted 8 July 2003
Dedicated to Professor J.-P. Geneˆt on the occasion of his 60th birthday
Abstract
Carbohydrate-substituted phosphines are easily obtained in quite good yields by coupling of protected or non-protected
D-
glucosamine with the corresponding diphenylphosphino acid. These neutral ligands, in association with palladium acetate, are very
active catalysts in the Suzuki cross-coupling reaction. The polyhydroxy phosphines are more active than the peracetylated
phosphines. The process tolerates electron-rich as well as electron-poor substituents. Excellent turnovers, up to 97 000 are observed.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Suzuki coupling; Phosphine; Carbohydrate; Water-soluble
1. Introduction
is the use of a water-soluble organometallic catalyst,
allowing the reaction to occur in water or better in a
Palladium-catalyzed cross-coupling reaction of aryl
two-phase system organic solventꢀwater [2]. This ap-
/
halides with aryl boronic acids, the so-called Suzukiꢀ
Miyaura reaction, is one of the most versatile and
powerful methods for carbonꢀcarbon bond formation
[1]. The versatility of this reaction is its wide applic-
ability, the use of available reagents, the mild reaction
conditions, the tolerance of a broad range of functional
groups, as well as the use of aqueous organic solvent
/
proach would decrease the use of volatile and toxic
organic solvents, and also simplify the catalyst recovery.
With this aim in view, water-soluble phosphines, such as
the sodium salt of monosulfonated triphenylphosphine
(or TPPMS) or the trisodium salt of trisulfonated
triphenylphosphine (or TPPTS), have been applied in
this reaction; however the activity of these systems
remains generally low [3]. So there is a need to find
aqueous-phase catalyst systems exhibiting increased
activities.
Carbohydrate based phosphines appeared recently in
the literature and seemed to have a great potential in this
coupling-reaction. Glycosides of triphenylphosphines [4]
and gluconamide derivatives of triphenylphosphine [5]
were prepared by the groups of Beller and Miyaura,
respectively. The catalyst obtained by association of
these ligands with Pd(OAc)2 achieved higher turnover
numbers (TON) than that obtained from TPPMS or
TPPTS in Suzuki cross-coupling reaction of haloarenes
with aryl boronic acids in water or even in a two-phase
/
such as tolueneꢀH2O. It is also to be noticed that the
/
inorganic by-products of this coupling reaction are non-
toxic and easily removed from the reaction mixture.
However, in most cases, phosphine ligands and high
temperatures are usually required.
From both scientific and environmental points of
view, development of very active and easily separable
organometallic catalysts from the organic products has
attracted much attention. One way to solve this problem
* Corresponding author. Tel.: ꢁ
8914.
E-mail address: sinou@univ-lyon1.fr (D. Sinou).
/
33-47-244-8183; fax: ꢁ33-47-889-
/
0022-328X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00636-3

R. Kolodziuk et al. / Journal of Organometallic Chemistry 687 (2003) 384ꢀ
/391
385
system. However, since glycosides of triphenylphosphine
probably suffered from their easy hydrolytic cleavage in
the presence of water, the recycling of the catalyst would
be less efficient. For the gluconamide derivative, the
screening of other carbohydrate moieties, in order to
improve the catalyst activity and recycling, also seems
difficult. Recently we presented preliminary results
concerning the synthesis of a new class of more stable
carbohydrate-based phosphines 1aꢀ
/
b and 2aꢀb [6],
/
whose modification was very easy both on the phos-
phine as well as on the carbohydrate moieties. These
ligands were very efficient in the palladium-catalyzed
cross-coupling Suzuki reaction. We report herein a more
detailed study concerning the synthesis of these ligands
1ꢀ3 (Fig. 1) having a carbohydrate side-chain and their
/
catalytic efficiency in this coupling reaction between aryl
halides and aryl boronic acids.
Scheme 1. Synthesis of glucosamine-based phosphines 1ꢀ
/
3. (i) 4-
Ph2PC6H4CO2H for 1a or 2-Ph2PC6H4CO2H for 2a, EDC, HOBT,
CH2Cl2/THF, room temperature; (ii) CH3ONa, CH3OH, room
temperature; (iii) 4-Ph2PC6H4CO2H for 1b, 2-Ph2PC6H4CO2H for
2b, 9a for 3a, 9b for 3b, EDC, HOBT, NaHCO3, DMF, H2O, room
temperature.
2. Results and discussion
The synthesis of the glucosamine-based phosphines is
shown in Scheme 1. The reaction of 4-diphenylpho-
sphinobenzoic acid with 2-amino-1,3,4,6-tetra-O-acetyl-
mixture of DMFꢀwater as the solvent in 85% yield. The
/
2-deoxy-b-
D
-glucopyranose (4a) [7] in a CH2Cl2ꢀTHF
/
ligands 2a and 2b were obtained using the same
procedure, 2a as the anomer b only in 68% yield, 2b as
mixture in the presence of EDC (or 1-[3-dimethylami-
nopropyl]-3-ethylcarbodiimide) and HOBT (or 1-hydro-
xybenzotriazole) afforded the peracetylated phosphine
1a in 50% yield. Deacetylation of 1a with a catalytic
amount of sodium methoxide in methanol gave the
polyhydroxy phosphine 1b in 80% yield, as a 87:13
mixture of the a- and b-anomers. This ligand could also
an aꢀb mixture (85/15) in 74% yield [8]. Heterocyclic
/
ligands 3a and 3b were obtained by coupling of the
corresponding heterocyclic acid 9a and 9b and D-
glucosamine (4b) in a mixture of DMFꢀwater in 90
/
and 94% yield, respectively. The heterocyclic acids 9a
and 9b were obtained according to Scheme 2. 2-
be obtained directly by a simple condensation of
D-
Dialkylaminothiazoles 7aꢀb were obtained by conden-
/
glucosamine (4b) with 4-diphenylphosphinobenzoic acid
in the presence of EDC, HOBT, and NaHCO3 in a
sation of an equimolecular amount of the corresponding
N,N-dialkylthioureas with ethyl 4-chloro-3-oxobutano-
ate in alcohol. Phosphorylation of these esters with
Ph2PBr at 20 8C afforded the corresponding phosphines
8aꢀ
compounds 8aꢀ
phines 9aꢀb in 70 and 73% yield.
/b in 64 and 63% yield, respectively. Saponification of
/b gave the heterocyclic carboxylic phos-
/
The cross-coupling reaction of 4-nitroiodobenzene
with phenylboronic acid was carried out in a 3/2/2
mixture tolueneꢀ
/
EtOHꢀH2O in the presence of the
/
complex synthesized in situ from Pd(OAc)2 and the
different ligands (Table 1). All the catalysts were active.
However, we noticed that the acetylated ligands 1a and
2a gave less active catalysts than the corresponding
polyhydroxy ligands 1b and 2b (Table 1, compare entries
1 and 3, 2 and 4, 6 and 7). It is noteworthy that the use
of ligand 1b at 60 8C gave quantitatively the coupling-
product after 5 min; comparison of the ortho- and the
para-substituted polyhydroxyphosphine 1b and 2b
showed that the para-substituted is more active than
the ortho (Table 1, entries 4 and 7). The polyhydroxy
heterocyclic ligands 3a and particularly 3b also gave
Fig. 1.

386
R. Kolodziuk et al. / Journal of Organometallic Chemistry 687 (2003) 384ꢀ391
/
Scheme 2. Synthesis of heterocyclic carboxylic phosphines 9a and 9b. (i) PPh2Br, C5H5N, Et3N, 20 8C, 12 h; (ii) NaOH, CH3CH2OH, room
temperature.
Table 2
Effect of the solvent on the cross-coupling reaction
very active catalysts in this coupling reaction (Table 1,
entries 10ꢀ14). It is to be noticed that no product
/
resulting from the homo-coupling of phenylboronic acid
(biphenyl) was observed under our conditions.
4-NO2C6H4ꢀBrꢁC6H5ꢀB(OH)20 4-NO2C6H4ꢀC6H5
Entry Solvent
Convn (%) (yield%) a
We then studied the influence of the solvent on the
coupling reaction between 4-bromonitrobenzene and
phenylboronic acid using 0.1% Pd(OAc)2 and 1b as the
catalyst, and Na2CO3 as the base, at 60 8C (Table 2). We
noticed that the highest conversions were obtained using
toluene/EtOH/H2O (Table 2, entry 1) or THF/H2O
(Table 2, entry 3) as the solvent. The use of water alone
resulted in lower conversion (56%, Table 2, entry 4),
while very low conversion was observed using toluene/
H2O or Et2O as the solvent (Table 2, entries 2 and 5).
The efficiencies of some bases were also studied in the
coupling reaction between 4-bromonitrobenzene and
phenylboronic acid, using Pd(OAc)2 (0.1 mol.%) asso-
1
2
3
4
5
C6H5CH3/EtOH/H2O (3/2/2)
99 (99)
C6H5CH3/H2O (5/2)
THF/H2O (5/2)
H2O
11
98
56
5
Et2O
All reactions were carried out in 14 ml of solvent in the presence of
4-nitrobromobenzene (0.7 mmol), phenylboronic acid (0.8 mmol),
Pd(OAc)2 0.1 mol.%, ligand 1b 0.3 mol.%, and Na2CO3 (2.1 mmol), at
60 8C for 1 h.
a
Conversion determined by GC; isolated chemical yield after
column chromatography.
the expected coupling-product, while triethylamine is
less efficient.
ciated with ligand 1b in a THFꢀH2O mixture (Table 3).
/
Finally the influence of the nature of the catalyst
precursor was also studied, using 1b as the ligand (Table
Sodium or potassium carbonate, potassium phosphate
and even potassium hydroxide afforded quantitatively
Table 1
Effect of ligands on the coupling reaction
4-NO2C6H4ꢀIꢁC6H5ꢀB(OH)20 4-NO2C6H4ꢀC6H5
Entry
Ligand
T (8C)
Cat. (mol.%)
Time (h)
Convn (%) (yield%) a
1
1a
1a
1b
1b
1b
2a
2b
2b
2b
3a
3a
3b
3b
3b
25
60
25
60
60
60
70
60
60
25
60
25
60
60
1
2
2
(89)
(98)
(90)
(98)
(97)
32
2
1
3
1
24
0.08
1
4
1
5
0.1
1
6
3
7
1
2
93
8
0.1
0.1
1
3
(54)
(99)
(43)
(98)
(90)
(99)
(100)
9
24
18
2
10
11
12
13
14
1
1
1
1
0.1
1
1
All reactions were carried out in 14 ml of toluene/EtOH/H2O (3/2/2) in the presence of 4-nitroiodobenzene (0.7 mmol), phenylboronic acid (0.8
mmol), a palladium catalyst, and Na2CO3 (2.1 mmol). The palladium catalyst was prepared in situ from Pd(OAc)2 (one equivalent) and the ligand
(three equivalents).
a
Conversion determined by GC; isolated chemical yield after column chromatography.

R. Kolodziuk et al. / Journal of Organometallic Chemistry 687 (2003) 384ꢀ
/391
387
Table 3
Effect of the base on the cross-coupling reaction
served after 5 min using 1 mol.% catalyst (Table 5, entry
2). The efficiency of this ligand 1b was demonstrated by
the TON of the catalyst; ligand 1b exhibited effectively
86 000 and 97 000 TON, with a 0.001 mol.% catalyst
loading, in the presence of Na2CO3 and K3PO4 as the
base, respectively (Table 5, entries 6 and 7). Various aryl
boronic acids such as 4-tolylboronic (Table 5, entry 12),
4-NO2C6H4ꢀBrꢁC6H5ꢀB(OH)20 4-NO2C6H4ꢀC6H5
Entry
Base
Convn (%) (yield%) a
1
2
3
4
5
Na2CO3
K2CO3
K3PO4
KOH
99 (99)
99
99
4-formylphenylboronic acid (Table 5, entries 16ꢀ
/18),
and 4-methoxyphenylboronic acid (Table 5, entries 19ꢀ
/
97
35
20) gave the coupling products in quite good yields, even
using 0.1 mol.% catalyst. The sterically hindered 2,6-
dimethylphenylboronic acid reacted also (Table 5, en-
NEt3
All reactions were carried out in 14 ml of THF/H2O (5/2) in the
presence of 4-nitrobromobenzene (0.7 mmol), phenylboronic acid (0.8
mmol), Pd(OAc)2 0.1 mol.%, ligand 1b 0.3 mol.%, and the base (2.1
mmol), at 60 8C for 1 h.
tries 13ꢀ15) affording the coupling product in 79% yield
/
in the presence of 0.1 mol.% catalyst; this yield was
increased to 96% using an increasing amount of aryl
boronic acid.
a
Conversion determined by GC; isolated chemical yield after
column chromatography.
Biaryl coupling of some bromoarenes with various
arylboronic acids is also summarized in Table 6. 4- or 3-
Nitrobromobenzene reacted efficiently with phenylboro-
nic- or 4-tolylboronic acid to give quantitatively the
Table 4
Effect of the catalyst precursor on the cross-coupling reaction
4-NO2C6H4ꢀBrꢁC6H5ꢀB(OH)20 4-NO2C6H4ꢀC6H5
corresponding biaryl compounds (Table 6, entries 1ꢀ
/
5
and 24ꢀ26). Although peracetylated ligand 1a gave
/
Entry
Catalyst/ligand 1b (equivalent)
Convn (%) a
quantitatively the coupling product after 2 h, the
polyhydroxyphosphines 1b and 2b exhibited the highest
1
2
3
4
5
6
Pd(OAc)2/1b (1/2)
Pd(OAc)2/1b (1/3)
Pd(OAc)2/1b (1/4)
PdCl2/1b (1/2)
99
99
99
60
99
56
activities; however the use of a mixture THFꢀH2O as
/
the solvent seemed detrimential for the conversion. It is
to be noted that 2-nitrobromobenzene reacted with 4-
tolylboronic acid using 0.1 mol.% Pd(OAc)2 and ligand
1b as the catalyst at 60 8C to give the coupling product
in 78% conversion (Table 6, entry 27). 4-Formylbromo-
benzene reacted with benzeneboronic acid in high
chemical yields in the presence of 1b as the ligand,
even using a 0.01 mol.% catalyst loading (Table 6,
PdCl2/1b (1/3)
PdCl2/1b (1/4)
All reactions were carried out in 14 ml of THF/H2O (5/2) in the
presence of 4-nitrobromobenzene (0.7 mmol), phenylboronic acid (0.8
mmol), palladium catalyst 0.1 mol.%, and Na2CO3 (2.1 mmol), at
60 8C for 1 h.
Conversion determined by GC; isolated chemical yield after
column chromatography.
a
entries 6ꢀ
/
9); we noticed again the detrimential effect of
9%).
THF/H2O as the solvent in this case (conversion B
/
When the catalyst obtained from Pd(OAc)2 and poly-
hydroxy ligand 2b gave 92% conversion in this coupling
reaction, no reaction occurred when the peracetylated
ligand 2a was used (Table 6, entries 10 and 11). 3-
Acylbromobenzene, bearing a withdrawing group, re-
acted smoothly with benzeneboronic acid at 60 8C, even
4). The coupling reaction between 4-bromonitrobenzene
and phenylboronic acid in THF/H2O in the presence of
Na2CO3 occurred quantitatively starting from Pd(OAc)2
as the palladium precursor, whatever the ratio Pd/ligand
used (Table 4, entries 1ꢀ
palladium precursor gave a less active catalyst, although
the conversion was quantitative using a ratio Pd/1bꢂ1/
3 (Table 4, entries 4ꢀ6).
/3). The use of PdCl2 as the
using 1 mol.% catalyst (Table 6, entries 12ꢀ14).
/
2-Bromochlorobenzene reacted quantitatively with
benzeneboronic acid in the presence of Pd(OAc)2 (1
mol.%) and ligand 1a or 1b (Table 6, entries 15 and 16),
when 4-hydroxybromobenzene reacted smoothly using
0.1 mol.% catalyst (Table 6, entry 17). In the case of
coupling of 4-methoxybromobenzene with benzene-
boronic acid, the more active catalyst was the combina-
/
/
Biaryl coupling of 4-nitroiodobenzene with various
representative arylboronic acids in the presence of
Pd(OAc)2 as the palladium precursor, toluene/EtOH/
H2O as the solvent, and Na2CO3 as the base is
summarized in Table 5. As previously noticed, the
peracetylated ligands 1a and 2a associated with
Pd(OAc)2 gave less active catalysts than the analogues
tion of Pd(OAc)2 and ligand 2b (Table 6, entries 18ꢀ21).
/
Finally when 2-bromonaphthalene and 4-vinylbromo-
benzene gave very low yields of coupling product with
benzeneboronic acid (Table 6, entries 22 and 23), the
condensation of the heterocyclic 2-bromopyridine with
4-tolylboronic acid occurred in quite good yields (Table
obtained using the polyhydroxyligands 1b, 2b and 3aꢀ
/
b
(Table 5, entries 1 and 8 vs entries 2 and 9ꢀ11). It is to
/
be noticed that ligand 1b showed the highest activity,
total conversion of the 4-nitroiodobenzene being ob-
6, entries 29ꢀ30). We noticed again in the last example
/

388
R. Kolodziuk et al. / Journal of Organometallic Chemistry 687 (2003) 384ꢀ391
/
Table 5
Synthesis of biaryls from 4-nitroiodobenzene and Arꢀ
/B(OH)2
4-NO2C6H4ꢀIꢁArꢀB(OH)20 4-NO2C6H4ꢀAr
Entry
Arꢀ
/
B(OH)2 Arꢁ
/
Ligand
Pd(OAc)2 (mol.%)
Time (h)
Convn (%) (yield%) a
1
C6H5
C6H5
1a
1b
1b
1b
1b
1b
1b
2a
2b
3a
3b
1b
1b
1b
2b
1b
1b
3b
1b
1b
1
2
0.08
1
(98)
(98)
(97)
(97)
(100)
(86)
(97)b
32
2
1
3
C6H5
C6H5
0.1
0.1
0.01
0.001
0.001
1
4
1
5
C6H5
C6H5
1
6
18
18
3
7
C6H5
C6H5
8
9
C6H5
C6H5
C6H5
0.1
1
24
2
(99)
(98)
(99)
(98)
(79)
(96) b
(86)
(99)
(88)
(98)
(99)
(90)
10
11
12
13
14
15
16
17
18
19
20
1
1
4-MeC6H4
2,6-Me2C6H3
2,6-Me2C6H3
2,6-Me2C6H3
4-CHOC6H4
4-CHOC6H4
4-CHOC6H4
4-MeOC6H4
4-MeOC6H4
1
1
0.1
0.1
0.1
0.1
0.01
1
18
18
24
1
24
1
1
0.1
18
18
All reactions were carried out in 14 ml of toluene/EtOH/H2O (3/2/2) in the presence of 4-nitroiodobenzene (0.7 mmol), ArꢀB(OH)2 (0.8 mmol), a
/
palladium catalyst, and Na2CO3 (2.1 mmol) at 60 8C; the palladium catalyst was prepared in situ from Pd(OAc)2 (one equivalent) and the ligand
(three equivalents).
a
Conversion determined by GC; isolated chemical yield after column chromatography.
K3PO4 was used as the base.
b
the beneficial effect of K3PO4 on the coupling reaction;
when the corresponding biaryl derivative was obtained
in 81% yield using 0.01 mol.% catalyst after 18 h
reaction in the presence of Na2CO3 as the base, this
yield was increased to 95% after 10 h only in the
presence of K3PO4.
We tried also some coupling reaction between various
chloroarenes and benzeneboronic acid; however, what-
ever the conditions used, the formation of coupling
products was never observed.
4. Experimental
4.1. General
Solvents were purified by standard methods and dried
if necessary. All commercial available reagents were
used as received. All reactions were monitored by TLC
(TLC plates GF254 Merck); detection was effected by
UV absorbance. All manipulations involving palladium
catalyst were performed under usual inert atmosphere
techniques in Schlenk tube. Conversion was determined
by GC using a Quadrex OV1 column (30 mꢃ
Column chromatography was performed on silica gel 60
(230ꢀ240 mesh, Merck). Optical rotations were re-
corded using a PerkinꢀElmer 241 polarimeter. NMR
spectra were recorded with Bruker AC 300 spectrometer
and referenced as following: 1H (300 MHz), internal
SiMe4 at d 0.00 ppm, 13C (75 MHz), internal CDCl3 at
d 77.23 ppm, and 31P (121 MHz), external 85% H3PO4
at d 0.00 ppm.
/
0.25 mm).
3. Conclusion
/
Palladium acetate associated with a carbohydrate-
based phosphine has been shown to be efficient catalysts
for the Suzuki cross-coupling reaction of a wide range or
aryl iodides and bromides and boronic acids, very low
catalyst loading being used. The polyhydroxylated
ligands gave more active catalysts than the peracetylated
ligands. Work is actually in progress in order to extend
this methodology to hydroxylated polysaccharides
based phosphines, in order to recycle efficiently the
catalysts.
/
2-(Diphenylphosphino)benzoic acid and 4-(diphenyl-
phosphino)benzoic acid are commercially available from
Aldrich. 1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-b-
glucopyranose (4a) was prepared according to the
D-

R. Kolodziuk et al. / Journal of Organometallic Chemistry 687 (2003) 384ꢀ
/391
389
Table 6
Synthesis of biaryls from bromoarenes Arꢀ
/
Br and arylboronic acids Ar?ꢀB(OH)2
/
ArꢀBrꢁAr?ꢀB(OH)20 ArꢀAr?
Entry ArꢀBr Arꢂ
4-NO2C6H4
/
/
Ar?B(OH)2 Ar?ꢂ
/
Ligand % Pd Solvent
T (8C) Time (h) Convn (%) (yield%) a
1
C6H5
C6H5
1a
1b
1b
2a
2b
1b
1b
1b
1b
2a
2b
1b
1b
1b
1a
1b
1b
1b
1b
2a
2b
1b
1b
1b
1b
3b
1b
1b
1b
1b
1
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
THF/H2O (5/2)
25
60
60
70
70
60
60
60
60
70
70
60
60
60
70
60
60
60
60
70
70
60
60
60
60
60
60
60
60
60
2
1
100
(95)
99 (99)
0
2
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
3-NO2C6H4
4-CHOC6H4
4-CHOC6H4
4-CHOC6H4
4-CHOC6H4
4-CHOC6H4
4-CHOC6H4
3-MeCOC6H4
3-MeCOC6H4
3-MeCOC6H4
2-ClC6H4
1
3
C6H5
C6H5
0.1
1
1
4
3
5
C6H5
C6H5
1
2
99
6
1
18
1
98 (95)
99 (99)
(88)
9
7
C6H5
C6H5
0.1
0.01
0.1
1
8
1
9
C6H5
C6H5
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
THF/H2O (5/2)
3
0
92
C6H5
C6H5
1
2
1
1
44
44
C6H5
C6H5
0.1
0.1
1
1
1
B3
/
C6H5
C6H5
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
THF/H2O (5/2)
3
97
97
30
32
32
0
2-ClC6H4
4-HOC6H4
1
1
C6H5
C6H5
0.1
1
1
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-Bromonaphtalene
4-VinylC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-Bromopyridine
2-Bromopyridine
1
C6H5
C6H5
0.1
1
1
3
C6H5
C6H5
1
2
99
20
1
1
C6H5
1
1
B5
/
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
0.01
0.1
1
18
1
(81)
46
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
C6H5CH3/EtOH/H2O (3/2/2)
18
18
18
18
10
(77)
78
0.1
1
ꢀ/
99 b
0.01
0.01
(81)
(95) b
All reactions were carried out in 14 ml of solvent in the presence of bromoarene (0.7 mmol), Ar?ꢀB(OH)2 (0.8 mmol), a palladium catalyst, and
/
Na2CO3 (2.1 mmol); the palladium catalyst was prepared in situ from Pd(OAc)2 (one equivalent) and the ligand (three equivalents).
a
Conversion determined by GC; isolated chemical yield after column chromatography.
K3PO4 was used as the base.
b
literature [7]. The preparation of 1,3,4,6-tetra-O-acetyl-
2-deoxy-2-{[4-(diphenylphosphino)benzoyl]amino}-b-
D-glucopyranose (1a) and 2-deoxy-2-{[4-(diphenylpho-
of the solvent gave a residue that was purified by
distillation.
sphino) benzoyl]amino}-D-glucopyranose (1b) was de-
scribed in another paper [8].
4.2.1. Ethyl [2-(dimethylamino)-1,3-thiazol-4-yl]acetate
(7a)
Yield 64%; Eb0.8
1.19 (t, Jꢂ7.0 Hz, 3H, CH3), 2.99 (s, 6H, NMe), 3.52 (s,
2H, CH2CO2), 4.06 (q, 2H, Jꢂ7.0 Hz, CH2), 6.49 (s,
ꢂ
/
105ꢀ
/
107 8C; 1H-NMR (CDCl3): d
/
4.2. Synthesis of ethyl (2-dialkylamino-1,3-thiazol-4-
yl)acetate (7)
/
1H, H-5). Anal. Calc. for C9H14N2O2S (214.28): N,
13.07; Found: N, 12.89%.
A mixture of N,N-dialkylthiourea (0.3 mol) and ethyl
4-chloro-3-oxobutanoate (49.4 g, 0.3 mol) was refluxed
in alcohol (150 ml) for 4 h. The solvent was removed
under reduced pressure, and the residue was dissolved in
the minimal amount of water. The pH of the solution
was brought to 9 by addition of an aqueous solution of
Na2CO3, and then extracted with CHCl3. Evaporation
4.2.2. Ethyl (2-morpholin-4-yl-1,3-thiazol-4-yl)acetate
(7b)
1
Yield 76%; Eb5ꢂ
1.27 (t, Jꢂ
(s, 2H, CH2CO2), 3.80 (m, 4H, OCH2), 4.18 (q, 2H, Jꢂ
/
155ꢀ
/
162 8C; H-NMR (CDCl3): d
/7.2 Hz, 3H, CH3), 3.43 (m, 4H, NCH2), 3.60
/

390
R. Kolodziuk et al. / Journal of Organometallic Chemistry 687 (2003) 384ꢀ391
/
7.2 Hz, CH2), 6.43 (s, 1H, H-5). Anal. Calc. for
C11H16N2O3S (256.32): N, 10.93; Found: N, 10.87%.
OCH2), 3.96 (s, 2H, CH2CO2), 7.34 (m, 10H, C6H5);
31P-NMR (DMSO-d6): d
28.8. Anal. Calc. for
C21H21N2O3PS (412.44): N, 6.79; P, 7.51; Found: N,
ꢄ
/
4.3. Synthesis of ethyl [2-dialkylamino-5-
(diphenylphosphino)-1,3-thiazol-4-yl]acetate (8)
6.72; P, 7.44%.
4.5. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-{[4-
(diphenylphosphino)benzoyl]amino}-b-
(1a)
To a solution of the corresponding dialkylaminothia-
zole 7 (50 mmol) and Et3N (50 mmol) in pyridine (50 ml)
was added at 0 8C Ph2PBr (13.2 mg, 50 mmol). After
being stirred for 20 h at room temperature (r.t.), the
solution was diluted with C6H6 (70 ml), filtered, and the
solvent was evaporated under reduced pressure. The
residue was recrystallized from methanol.
D-glucopyranose
1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-b-
D-gluco-
pyranose (4a) (688 mg, 1.98 mmol), 4-diphenylpho-
sphinobenzoic acid (1.8 mmol), EDC (0.4 g, 2.16 mmol),
and HOBT (0.29 g, 2.16 mmol) were dissolved in a
mixture of CH2Cl2 (10 ml) and THF (20 ml) in a
Schlenk tube under argon. After being stirred for 5 h at
r.t., the solvents were evaporated. The residue was
washed with NaOH 5% (10 ml), and HCl 0.5 M (5
ml), then dried under vacuum to give phosphine 1a.
4.3.1. Ethyl [2-(dimethylamino)-5-(diphenylphosphino)-
1,3-thiazol-4-yl]acetate (8a)
1
Yield 64%; m.p.ꢂ
(DMSO-d6): d 1.08 (t, Jꢂ
NMe), 3.84 (s, 2H, CH2CO2), 4.01 (q, 2H, Jꢂ
CH2), 7.36 (m, 10H, C6H5); 31P-NMR (DMSO-d6): d
28.8. Anal. Calc. for C21H23N2O2PS (398.46): N,
/
101ꢀ
/
103 8C (methanol); H-NMR
/7.2 Hz, 3H, CH3), 2.98 (s, 6H,
/7.2 Hz,
Yield 458 mg, (40%); m.p. 164ꢀ
1, CHCl3); 1H-NMR (CDCl3): d 1.98 (s, 3H, CH3), 2.05
(s, 6H, 2ꢃCH3), 2.10 (s, 3H, CH3), 3.86 (dm, Jꢂ9.6
Hz, 1H, H-5), 4.15 (dd, Jꢂ12.4, 2.1 Hz, 1H, H-6), 4.27
(dd, Jꢂ12.4, 4.6 Hz, 1H, H-6), 4.57 (ddd, Jꢂ9.6, 9.5,
8.7 Hz, 1H, H-2), 5.23 (dd, Jꢂ10.4, 9.6 Hz, 1H, H-4),
5.35 (dd, Jꢂ10.4, 9.5 Hz, 1H, H-3), 5.85 (d, Jꢂ8.7 Hz,
1H, H-1), 6.75 (d, Jꢂ9.5 Hz, 1H, NH), 7.25-8.00 (m,
/
166 8C; [a]2D0ꢂ
/
ꢁ
/
28.0 (c
ꢄ
/
/
/
7.03; P, 7.77; Found: N, 6.95; P, 7.82%.
/
/
/
4.3.2. Ethyl [5-(diphenylphosphino)-2-(morpholin-4-yl-
/
1,3-thiazol-4-yl]acetate (8b)
/
/
Yield 63%; m.p.ꢂ
(DMSO-d6): d 1.07 (t, Jꢂ
4H, NCH2), 3.65 (m, 4H, OCH2), 3.86 (s, 2H, CH2CO2),
4.02 (q, 2H, Jꢂ
7.0 Hz, CH2), 7.36 (m, 10H, C6H5); 31P-
NMR (DMSO-d6): 28.7. Anal. Calc. for
/
91ꢀ
/
92 8C (methanol); 1H-NMR
7.0 Hz, 3H, CH3), 3.32 (m,
/
/
14H, Harom); 13C-NMR (CDCl3): d 20.6, 20.7, 20.8,
20.9, 53.4, 61.1, 67.9, 72.8, 73.0, 92.9, 126.8, 126.9,
128.7, 128.8, 129.2, 129.3, 129.4, 130.4, 133.0, 133.4,
133.7, 133.8, 134.2, 134.3, 136.3, 136.4, 143.1, 142.8,
167.3, 169.4, 169.6, 170.8, 171.4; 31P-NMR (CDCl3): d
/
d
ꢄ
/
C23H25N2O3PS (440.50): N, 6.36; P, 6.89; Found: N,
6.19; P, 7.03%.
ꢄ
/
5.0. HRMS of C33H35O10NP Calc. [Mꢁ
/
H]ꢁ
636.1998, Found: 636.1984.
4.4. Synthesis of [2-(dialkylamino)-5-
(diphenylphosphino)-1,3-thiazol-4-yl]acetic acid (9)
4.6. Synthesis of polyhydroxylated phosphines 1b, 2b,
and 3
A solution of the ester 9 (10 mmol) and NaOH (800
mg, 20 mmol) in EtOH (25 ml) was refluxed for 2ꢀ
until full consumption of the starting material (TLC
control). After cooling to r.t., a 1 N HCl solution was
/
3 h,
A solution of diphenylphosphino acid (0.5 mmol),
EDC (112 mg, 0.6 mmol), and HOBT (81 mg, 0.6 mmol)
in DMF (4 ml) was stirred in a Schlenk tube under
added until pH 5ꢀ/6. The solid was collected by filtration
argon at 0 8C for 1 h. A solution of
D-glucosamine
and recrystallized from MeOH.
hydrochloride (215 mg, 1.0 mmol) in DMF (2 ml) was
added, followed by the addition of a solution of
NaHCO3 (200 mg, 2.4 mmol) in H2O (2 ml). After
being stirred for 24 h at r.t., the solvents were
evaporated under reduced pressure to give a solid that
was purified by flash-chromatography on silica gel using
CHCl3/EtOH 3:1 as the eluent.
4.4.1. [2-(Dimethylamino)-5-(diphenylphosphino)-1,3-
thiazol-4-yl]acetic acid (9a)
1
Yield 70%; m.p.ꢂ
/
107ꢀ
/
108 8C (methanol); H-NMR
(DMSO-d6): d 3.07 (s, 6H, NMe), 3.83 (s, 2H,
CH2CO2), 7.35 (m, 10H, C6H5), 9.25 (1H, s, OH); 31P-
NMR (DMSO-d6):
d
ꢄ28.6. Anal. Calc. for
/
C19H19N2O2PS (370.41): N, 7.56; P, 8.36; Found: N,
7.43; P, 8.23%.
4.6.1. 2-Deoxy-2-{[4-
(diphenylphosphino)benzoyl]amino}-D-glucopyranose
(1b)
4.4.2. [5-(Diphenylphosphino)-2-(morpholin-4-yl)-1,3-
thiazol-4-yl]acetic acid (9b)
Yield 74%; m.p. 120ꢀ
C2H5OH 3:1); [a]D20ꢂ 43.5 (c 1, THF); 1H-NMR
(C5D5N): d 4.01 (ddd, Jꢂ9.2, 5.7, 2.1 Hz, 0.13H, H-
5b), 4.23 (dd, Jꢂ9.2, 9.0 Hz, 0.13H, H-4b), 4.32 (dd,
/
124 8C; Rfꢂ0.59 (CHCl3/
/
/
ꢁ
/
1
Yield 73%; m.p.ꢂ
/
176ꢀ
/
177 8C (methanol); H-NMR
(DMSO-d6): d 3.43 (m, 4H, NCH2), 3.65 (m, 4H,
/
/

R. Kolodziuk et al. / Journal of Organometallic Chemistry 687 (2003) 384ꢀ
/391
391
Jꢂ
0.87H, H-6a), 4.55 (dd, Jꢂ
4.75ꢀ4.86 (m, 1.74H, H-3a, H-5a), 5.11 (ddd, Jꢂ
8.5, 3.2 Hz, 0.87H, H-2a), 5.50 (bs, 4H, OH), 5.59 (d,
Jꢂ8.3 Hz, 0.13H, H-1b), 6.08 (d, Jꢂ3.2 Hz, 0.87H, H-
1a), 7.33ꢀ7.45 (m, 12H, Harom), 8.15ꢀ8.22 (m, 2H,
arom), 8.99 (d, Jꢂ8.5, 0.87H, NH), 9.43 (d, Jꢂ8.7,
0.13H, NH); 31P-NMR (C5D5N): d ꢄ
4.4. HRMS of
C25H27O6NP Calc. [Mꢁ
H]ꢁ 468.1576, Found:
468.1572.
/
9.4, 9.0 Hz, 0.87H, H-4a), 4.41 (dd, Jꢂ
11.7, 2.3 Hz, 0.87H, H-6a),
10.4,
/
11.7, 5.7 Hz,
CH3CO2Et 90:10 as the eluent to give 193 mg of
phosphine 1b (yieldꢂ88%).
/
/
/
/
4.8. Typical cross-coupling procedure
/
/
/
/
Pd(OAc)2 (1.5 mg, 7 mmol) and the ligand (21 mmol)
were placed in a flask under argon. Degassed water (1
ml) and ethanol (2 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, 2.0 mmol) dissolved in
water (3 ml). The resulting mixture was stirred at the
desired temperature. After the indicated time, the
mixture was cooled at r.t., 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-chromatography on silica gel
gave the coupling product.
H
/
/
/
/
4.6.2. 2-Deoxy-2-({[2-(dimethylamino)-5-
(diphenylphosphino)-1,3-thiazol-4-yl]acetyl}amino)-
glucopyranose (3a)
D-
Yield 90%; m.p. 120ꢀ
C2H5OH 4:1); [a]D20ꢂ 16.6 (c 1, CHCl3); 1H-NMR
(C5D5N): d 2.78 (s, 6H, NMe2), 3.95 (dm, Jꢂ9.5 Hz,
0.2H, H-5b), 4.15 (dd, Jꢂ9.5, 8.5 Hz, 0.2H, H-4b), 4.24
(dd, Jꢂ9.2, 9.2 Hz, 0.8H, H-4a), 4.30ꢀ4.40 (m, 3H, H-
6, COCH2), 4.51 (dd, Jꢂ11.5, 2.1 Hz, 0.8H, H-6a), 4.66
(dd, Jꢂ10.5, 9.2 Hz, 0.8H, H-3a), 4.74 (ddd, Jꢂ9.2,
5.3, 2.1 Hz, 0.8H, H-5a), 4.85 (ddd, Jꢂ10.5, 8.5, 3.0 Hz,
0.8H, H-2a), 4.97 (bs, 4H, OH), 5.36 (d, Jꢂ8.3 Hz,
0.2H, H-1b), 5.86 (d, Jꢂ3.0 Hz, 0.8H, H-1a), 7.26ꢀ7.39
(m, 6H, Harom), 7.58ꢀ7.68 (m, 4H, Harom), 9.04 (d, Jꢂ
8.5, 0.8H, NH), 9.24 (d, Jꢂ
7.5, 0.2H, NH); 31P-NMR
(C5D5N): d ꢄ27.6. HRMS of C25H31O6N3PS Calc.
[Mꢁ
H]ꢁ 532.1671, Found: 532.1675.
/
124 8C; Rfꢂ0.53 (CHCl3/
/
/
ꢁ
/
/
/
/
/
/
/
/
/
/
Acknowledgements
/
/
/
/
A.I., R.K., M.T. and A.P. thank the CNRS, Re´gion
Rhoˆne-Alpes, and the MENSR, respectively, for a
fellowship.
/
/
/
4.6.3. 2-Deoxy-2-({[2-(morpholin-4-yl)-5-
(diphenylphosphino)-1,3-thiazol-4-yl]acetyl}amino)-
glucopyranose (3a)
References
D-
[1] (a) N. Miyaura, A. Suzuki, Chem. Rev. 95 (1995) 2457;
(b) A. Suzuki, J. Organomet. Chem. 576 (1999) 147;
(c) A. Suzuki, in: F. Diederich, P.J. Stang (Eds.), Metal-Catalyzed
Cross-Coupling Reactions, VCH, Weinheim, 1998, p. 49;
(d) S.P. Stanforth, Tetrahedron 54 (1998) 263.
Yield 94%; m.p. 102ꢀ
C2H5OH 3:1); [a]D20ꢂ 14.2 (c 1, CHCl3); 1H-NMR
(C5D5N): d 3.23ꢀ3.35 (m, 4H, NCH2), 3.44ꢀ3.57 (m,
4H, OCH2), 3.94 (dm, Jꢂ9.2 Hz, 0.15H, H-5b), 4.15
(dd, Jꢂ9.2, 8.7 Hz, 0.15H, H-4b), 4.24 (dd, Jꢂ9.2, 9.2
Hz, 0.85H, H-4a), 4.30ꢀ4.40 (m, 3H, H-6, COCH2),
4.50 (dd, Jꢂ11.7, 2.0 Hz, 0.85H, H-6a), 4.65 (dd, Jꢂ
10.7, 9.2 Hz, 0.85H, H-3a), 4.71 (ddd, Jꢂ9.2, 5.5, 2.0
Hz, 0.85H, H-5a), 4.85 (ddd, Jꢂ10.7, 8.5, 3.4 Hz,
0.85H, H-2a), 5.36 (d, Jꢂ8.1 Hz, 0.15H, H-1b), 5.86 (d,
Jꢂ3.4 Hz, 0.85H, H-1a), 6.10 (bs, 4H, OH), 7.29ꢀ7.41
(m, 6H, Harom), 7.59ꢀ7.71 (m, 4H, Harom), 9.01 (d, Jꢂ
8.5, 0.85H, NH), 9.25 (d, Jꢂ
7.6, 0.15H, NH); 31P-
NMR (C5D5N): d ꢄ27.8. HRMS of C27H33O7N3PS
Calc. [Mꢁ
H]ꢁ 574.1777, Found: 574.1774.
/
105 8C; Rfꢂ
/
0.48 (CHCl3/
/
ꢁ
/
/
/
/
[2] (a) B. Cornils, W.A. Herrmann (Eds.), Aqueous-Phase Organo-
metallic Catalysis. Concepts and Applications, VCH, Weinheim,
1998;
/
/
/
/
/
(b) B.E. Hanson, Coord. Chem. Rev. 185ꢀ186 (1999) 795;
/
/
(c) D. Sinou, Top Curr. Chem. 206 (1999) 41.
[3] (a) A.L. Casalnuovo, J.C. Calabrese, J. Am. Chem. Soc. 112 (1990)
4324;
/
/
(b) J.-C. Galland, M. Savignac, J.-P. Geneˆt, Tetrahedron Lett. 40
(1999) 2323;
/
/
/
/
(c) C. Dupuis, K. Adley, L. Charruault, V. Michelet, M. Savignac,
J.-P. Geneˆt, Tetrahedron Lett. 42 (2001) 6523.
[4] (a) M. Beller, J.G.E. Krauter, A. Zapf, Angew. Chem. Int. Ed.
Engl. 36 (1997) 772;
/
/
/
(b) M. Beller, J.G.E. Krauter, A. Zapf, S. Bogdanovic, Catal.
Today 48 (1999) 279.
4.7. Saponification of peracetylated phosphine 1a
[5] (a) M. Ueda, M. Nishimura, N. Miyaura, Synlett (2000) 856;
(b) M. Nishimura, M. Ueda, N. Miyaura, Tetrahedron 58 (2002)
5779.
To the acetylated phosphine 1a (300 mg, 0.47 mmol)
dissolved in THF (10 ml) under argon was slowly added
a solution of Na (20 mg, 0.87 mmol) in CH3OH (5 ml).
After being stirred for 1 h at r.t., the solvent was
evaporated to give a yellow solid that was purified by
flash-chromatography on silica gel using CH2Cl2/
[6] S. Parisot, R. Kolodziuk, C. Goux-Henry, A. Iourtchenko, D.
Sinou, Tetrahedron Lett. 43 (2002) 7397.
[7] P. Boullanger, M. Jouineau, B. Bouammali, D. Lafont, G.
Descotes, Carbohydr. Res. 202 (1990) 151.
[8] M. Tollabi, E. Framery, C. Goux-Henry, D. Sinou, Tetrahedron:
Asymm., in press.