Carbohydrate-based phosphines as supporting ligand for palladium-catalyzed Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2014.01.011

Carbohydrate-based mono-phosphines (1 and 2) derived from glucose have been explored as supporting ligand for palladium-catalyzed Suzuki-Miyaura reaction. The combination of phosphine to palladium in a ratio of 2:1 resulted in a longer-living system than

Full text of DOI:10.1016/j.tetlet.2014.01.011

Tetrahedron Letters 55 (2014) 2904–2907
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Carbohydrate-based phosphines as supporting ligand for
palladium-catalyzed Suzuki–Miyaura cross-coupling reaction
b,c,
b
a
b,
b
Ji-cheng Shi a,b, , Zhonggao Zhou
, Shan Zheng , Qing Zhang , Li Jia , Jinhuo Lin
⇑
⇑
⇑
a College of Chemical Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China
b Key Laboratory of Polymer Materials of Fujian Province, Fujian Normal University, Fuzhou 350007, China
c College of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou 341000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Carbohydrate-based mono-phosphines (1 and 2) derived from glucose have been explored as supporting
ligand for palladium-catalyzed Suzuki–Miyaura reaction. The combination of phosphine to palladium in a
ratio of 2:1 resulted in a longer-living system than that in a ratio of 1:1. Using K2CO3 as base, aryl bro-
mides as well as active aryl chlorides can be coupled nearly quantitatively by 0.1–0.2 mol % of 1/Pd(OAc)2
with 95–99% of isolated yields. The amount of the catalyst could be lowered to 0.01 mol % under the opti-
mized condition with 80% yield at room temperature. The carbohydrate hydroxyl group in 1 was found to
contribute to catalytic activity.
Received 22 October 2013
Revised 26 December 2013
Accepted 3 January 2014
Available online 9 January 2014
Keywords:
Carbohydrate
Phosphine
Ó 2014 Elsevier Ltd. All rights reserved.
Palladium
Cross-coupling
Metal-catalyzed cross-coupling methodology to form new car-
bon–carbon and carbon–heteroatom bonds has advanced organic
synthesis significantly.1 The palladium- and nickel-catalyzed cou-
pling of aryl and alkenyl halides (or pseudo halides) with organo-
boronic acids, known as the Suzuki–Miyaura reaction,2 is one of
the most widely used methods3 in the synthesis of pharmaceutical
compounds,4 natural products,5 and polymers.6 Thanks to the dis-
covery and application of those ligands with electron-rich and ste-
rically demanding characteristics, significant progresses have been
witnessed in the last decade.7–20
to explore the phosphine 1 as supporting ligand in the palla-
dium-catalyzed Suzuki–Miyaura coupling reactions to enrich li-
gand library. The carbohydrate-based phosphine for cross-
coupling reactions has been explored rarely.29,30 Herein we report
a highly efficient carbohydrate-based phosphine/palladium system
for Suzuki–Miyaura coupling of aryl bromides and active aryl
chlorides.
The carbohydrate phosphine 1 is easily accessed through 4
steps from cheap glucose (Scheme 1).21 It had been found that
the 2-hydroxyl group of altropyranoside in 1 coordinated to palla-
dium(II) under basic condition in dichloromethane at room tem-
perature to form phosphino- and alkoxo-palladium(II) chelate-
complex 3 in 86% yield,26 which had been isolated and fully char-
acterized. Since Suzuki–Miyaura reaction is usually conducted un-
der basic condition, the complex 3 can be expected to form
especially as the ratio of phosphine to palladium is 2:1. In order
to clarify the possible participation of species 3 in catalytic cycle,
the 2-hydroxyl group in 1 was masked with methyl to form 2,
The phosphine (1), (methyl 3-deoxy-4,6-O-phenylmethenyl-
a-
D-altropyranosido-3-)-diphenylphosphine, is easily prepared from
glucose21 and has shown interesting coordination mode to transi-
tion metals.22–28 The two phenyl groups on phosphorus atom are
chemically unequivalent shown by both of NMR and X-ray diffrac-
tion data,21 indicating that the steric environment around phos-
phorus atom is crowed. The altropyrano-ring fusing with another
six-member ring creates the highly sterically demanding around
the 3-position phosphorus atom, leading to the chemical
unequivalence of the two phenyl groups. Linking to an altropyr-
ano-ring also makes the phosphorus atom electron-richer com-
pared with triphenylphosphine. With the two features of
electron-richer and sterically demanding, therefore it is attractive
methyl 3-deoxy-2-O-2-methyl-4,6-O-phenylmethenyl-a-D-altro-
pyranosido-3-)-diphenylphosphine.
In the initial experiments, the Suzuki–Miyaura reaction was per-
formed between 4-bromotoluene and phenylboronic acid in differ-
ent solvents with 0.2 mol % of Pd(OAc)2 using K2CO3 as base. It was
found that the reaction proceeded smoothly at room temperature
in both of THF and 95% ethanol at beginning for the ratio of phos-
phine to palladium either 1:1 or 2:1. The catalyst system with a ra-
tio of 1:1 stopped after 12 h with the conversion of 4-bromotoluene
reaching 80% and 90% (Table 1, entries 1 and 3), respectively in THF
⇑
Corresponding authors. Tel./fax: +86 668 2981105 (J.-c.S.); tel./fax: +86 797
8393670 (Z.Z.); tel./fax: +86 591 83465343 (L.J.).
E-mail addresses: jchshi_mmc@126.com (J.c. Shi), zhqzhou@foxmail.com
(Z. Zhou), jiali_elite@126.com (L. Jia).
http://dx.doi.org/10.1016/j.tetlet.2014.01.011
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

J. Shi et al. / Tetrahedron Letters 55 (2014) 2904–2907
2905
O
O
Ph
O
OMe
O
O
O
Ph
O
O
Ph
O
Ph2P
1) Pd(COD)Cl2
2) NaOMe
1) NaH
2) MeI
O
OMe
OMe
Pd
Ph2P
O
O
Ph2P
OMe
Ph2P
OH
2
1
OMe
Ph
O
O
3
Scheme 1. Syntheses of carbohydrate-based phosphines and chelate-alkoxopalladium(II) complex.
Table 1
when the reaction was carried out in refluxing 1,4-dioxane (entry
13).
Effect of solvent and temperature on 1/Pd(OAc)2-catalyzed Suzuki–Miyaura reaction
of 4-bromotoluene with phenylboronic acida
After optimizing solvent and temperature, various bases were
investigated in 95% ethanol. It looked that only K2CO3 matched
with the solvent of 95% ethanol; other bases tried even such as
KOH, Cs2CO3, and NaOH were not of choice (Table 2, entries 3, 6,
and 8). Although the reason for such a big difference between
K2CO3 and Cs2CO3 as base in 95% ethanol was unclear, that strong
base such as NaOH and KOH did not work either might be a clue.
On the other hand using 1,4-dioxane as solvent with 0.1 mol % of
Pd(OAc)2, a variety of bases including K2CO3, K3PO4Á3H2O, KOH,
Cs2CO3, and NaOH proved to be the choice within 1 h (Table 1, en-
try 13; Table 2, entries 1, 3, 5, and 7), but around 1% of diphenyl
could be observed when using KOH or NaOH as base. The perfor-
mance of NaOAc was also good although with a longer time (Ta-
ble 2, entry 9), but the bases Na2CO3 and NaOBu-t resulted in
low yields (entries 11–14).
Since the phosphino- and alkoxo-palladium(II) chelate-complex
3 is easily formed,26 we wondered the complex might participate
in the catalytic reaction. Therefore, the hydroxyl-masked phos-
phine 2 was prepared and tested under the optimized condition
to couple 4-bromotoluene with phenylboronic acid. Using 2 as sup-
porting ligand it took 1 h to afford 96% of isolated yield in 1,4-diox-
ane (Table 3, entry 9), whereas by 1 only 0.2 h of time consumed. In
95% ethanol at room temperature, the difference is slight. These
data suggest that the 2-hydroxyl group functions in the catalytic
cycle and has the effect to increase the reaction rate. Although it
Entry
1
Solvent
THF
Pd/1
Temp (°C)
rtc
Time (h)
Yieldb (%)
1:1
12
24
12
24
12
24
12
24
12
24
12
24
12
24
3
70
80 (75)
65
89 (86)
75
90 (86)
70
97 (95)
40
53
5
5
2
3
4
5
6
7
THF
1:2
1:1
1:2
1:2
1:2
1:2
rt
rt
rt
rt
rt
rt
95% Ethanol
95% Ethanol
Toluene
Acetonitrile
1,4-Dioxane
15
15
8
9
10
11
12
13
THF
95% Ethanol
Toluene
Acetonitrile
1,4-Dioxane
1,4-Dioxane
1:2
1:2
1:2
1:2
1:2
1:2
73
88
123
90
106
106
99 (97)
95 (90)
99 (96)
97 (95)
99 (99)
99 (99)d
12
1
1
0.2
0.2
a
Reaction conditions: 4-bromotoluene (3.0 mmol), phenylboronic acid
(4.5 mmol), Pd(OAc)2 (0.006 mol), K2CO3 (6.0 mmol), solvent (9.0 mL).
GLC yield calibrated via dodecane as an internal standard; isolated yields were
given in parentheses (average of two runs).
b
c
22–32 °C.
0.003 mmol of Pd(OAc)2.
d
and 95% ethanol, however the 2:1 ratio system showed a longer-liv-
ing catalyst and can convert 4-bromotoluene to 97% level with 95%
isolated yield of the desired biaryl (entry 4). Suzuki–Miyaura reac-
tion is often needed in pharmaceutical industry, and the reaction
carrying out in 95% ethanol at room temperature with mild base
such as K2CO3 is highly desired.29 These preliminary data showed
that the carbohydrate-based phosphine 1 is much better than tri-
phenylphosphine for palladium-catalyzed Suzuki–Miyaura reac-
tion, with the latter as supporting ligand 3–5 mol % of palladium
was usually employed.31 Besides, with the carbohydrate-based
phosphine 1 as supporting ligand the desired reaction condition
for pharmaceutical industry upon 0.2 mol % of the palladium load-
ing could be reached. The ratio of 2:1 was chosen and applied for
the following exploration of the carbohydrate-based phosphine as
supporting ligand for palladium-catalyzed Suzuki–Miyaura reac-
tion. Other solvents such as toluene, acetonitrile, and 1,4-dioxane
afforded low conversion of substrate at room temperature (entries
5–7). However, when the reactions were carried out under reflux
conditions in the solvents other than 95% ethanol (entry 9), the
reactions were completed in a much shorter time, and nearly quan-
titative conversion with excellent isolated yields was achieved (en-
tries 8, 10–12). It is worthy of notification that the catalyst could be
reduced to 0.1 mol % without affecting the reaction time and yield
Table 2
Effect of base on 1/Pd(OAc)2-catalyzed Suzuki–Miyaura coupling 4-bromotoluene
with phenylboronic acid
Entry
Base
React. Cond.a
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
K3PO4Á3H2O
K3PO4Á3H2O
KOH
I
II
I
II
I
II
I
II
I
II
I
II
I
II
0.2
24
0.2
24
0.2
24
1
24
6
24
6
99 (99)
10
99 (99)c
<5
KOH
Cs2CO3
Cs2CO3
NaOH
NaOH
NaOAc
98 (97)
13
98 (97)c
<5
94 (90)
10
25
<5
<5
NaOAc
Na2CO3
Na2CO3
NaOBu-t
NaOBu-t
24
6
24
<5
a
Reaction conditions: aryl halide (3.0 mmol), phenylboronic acid (4.5 mmol),
base (6.0 mmol), I or II (I: Pd(OAc)2 (0.003 mmol), ligand (0.006 mmol), 1,4-dioxane
(9 mL), oil bath 106 °C; II: Pd(OAc)2 (0.006 mmol), ligand (0.012 mmol), 95% ethanol
(9 mL), room temperature).
b
GLC yield calibrated via internal standard, isolated yields were given in
parentheses (average of two runs).
c
Around 1% of biphenyl was observed.

2906
J. Shi et al. / Tetrahedron Letters 55 (2014) 2904–2907
Table 3
1/Pd(OAc)2-catalyzed Suzuki–Miyaura reaction of aryl halides with phenylboronic acid
Pd/L = 1:2
K2CO3 (2.0 equiv)
(HO)2B
X
I or II
R
R
X = Br Cl
Entry
Ar-X
Me
Product
Me
Ligand
React. Cond.a
Time (h)
Yieldb (%)
I
II
0.2
24
98
95
Br
Br
1
2
3
4
1
1
1
1
I
II
1
24
80c
Me
Me
78c
I
II
0.2
12
99
97
MeO
MeO
Br
I
II
0.2
12
97
97
Br
Br
I
II
0.2
12
99
98
O
O
Br
5
6
1
1
Me
Me
I
II
0.2
24
98
96
Me
Me
I
II
1
24
98
F3C
Me
Me
Cl
Cl
Br
F3C
7
8
9
1
1
2
25d
I
II
6
24
45d
Me
Me
10d
I
II
1
24
95
94
a
Reaction conditions: aryl halide (3.0 mmol), phenylboronic acid (4.5 mmol), K2CO3 (6.0 mmol), I or II (I: Pd(OAc)2 (0.003 mmol), ligand (0.006 mmol), 1,4-dioxane (9 mL),
oil bath 106 °C; II: Pd(OAc)2 (0.006 mmol), ligand (0.012 mmol), 95% ethanol (9 mL), room temperature).
b
Isolated yield (average of two runs).
0.01 mol % catalyst.
GLC yield.
c
d
is yet unclear how the 2-hydroxyl group participates in the reac-
tion, some clues have been speculated: (a) taking part in producing
Pd(0) species via reductive elimination with phenyl to form a phe-
nyl ether; (b) the coordination of alkoxo anion enriching the elec-
tion density of palladium center, therefore in favor of oxidative
addition of aryl halide; (c) forming an alkoxo anion as intramolec-
ular base to bind to boron atom to participate in transmetallation
step. Further works are needed to clarify the functions of the 2-hy-
droxyl group and the principles found might be utilized in design
of new catalyst system.
Since both of 95% ethanol as solvent and K2CO3 as base are very
suitable for industrial application, the potential of 1 as supporting
ligand was further explored. When 0.01 mol % of Pd(OAc)2 was
loaded with 0.02 mol % of 1, 4-methylbiphenyl was obtained in
respectable yields, 80% within 1 h in 1,4-dioxane at 106 °C of oil
bath and 78% within 24 h in 95% ethanol at room temperature (Ta-
ble 3, entry 2).
1,4-dioxane. With 95% ethanol and K2CO3 combination suitable
for industrial application, the carbohydrate-based phosphine/pal-
ladium catalyst showed room temperature activities and the deac-
tivated aryl bromide was converted nearly quantitatively by
0.1 mol % of palladium. Down to 0.01 mol % of palladium loading
the desired biaryl still can be isolated in 80% yield. The 2-hydroxyl
group in 1 has a positive effect for Suzuki–Miyaura coupling reac-
tion, indicating that the carbohydrate hydroxy participated in the
catalytic cycle in some way. To utilize deactivated chloroarenes
as substrate and water as solvent, synthesis of those phosphines
with two or even three altropyrano-rings is under way.
Acknowledgments
This project was supported by the National Natural Science
Foundation of China (Nos. 20971023, 21272037), the Natural Sci-
ence Foundation of Fujian Province (2007J0306).
As expected the 1/Pd(OAc)2 catalyst system is very effective for
the non-activated and activated aryl bromides (Table 3, entries 4
and 5). For the substrate with one-ortho-substituent 96–98% of
yields were also achieved (entry 6). The catalyst system showed
no influence as the deactivated substrate 4-bromoanisole as sub-
strate (entry 3). These data promoted us to test chloroarenes as
substrates. To our delight, using 1,4-dioxane as solvent 99% of iso-
lated yield could be achieved for activated aryl chloride with
0.1 mol % catalyst loading within 1 h (entry 7), whereas in 95% eth-
anol 25% GLC yield was detected after 24 h. However, only 45% of
the desired product was obtained when the nonactivated substrate
was evaluated even in fluxing 1,4-dioxane (entry 8).
In summary, two carbohydrate-based phosphines have been
found to be highly effective as supporting ligand for palladium-cat-
alyzed Suzuki–Miyaura reaction of aryl bromides and activated
aryl chlorides. The ratio 2:1 of phosphine to palladium afforded a
longer-living catalyst system compared to that with the ratio 1:1.
The base K2CO3 was the best choice for both 95% ethanol and
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014
.01.011.
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