Suzuki-Miyaura reaction in water, conducted by employing an amphiphilic dendritic phosphine-palladium catalyst: a positive dendritic effect on chemical yield

Article abstract of DOI:10.1016/j.tetlet.2007.07.062

A series of amphiphilic dendritic ligands with a phosphine core was synthesized by use of tris(4-hydroxyphenyl)phosphine oxide and poly(benzyl ether) dendron. The corresponding phosphine-palladium core dendrimers were applied as a catalyst to an aqueous-media Suzuki-Miyaura reaction. A positive dendritic effect on chemical yields of cross-coupling products was observed.

Full text of DOI:10.1016/j.tetlet.2007.07.062

Tetrahedron Letters 48 (2007) 6817–6820
Suzuki–Miyaura reaction in water, conducted by employing
an amphiphilic dendritic phosphine–palladium catalyst:
a positive dendritic effect on chemical yield
Hatsuhiko Hattori, Ken-ichi Fujita,* Takahito Muraki and Ai Sakaba
National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 5, 1-1-1,
Higashi, Tsukuba, Ibaraki 305-8565, Japan
Received 5 July 2007; accepted 10 July 2007
Available online 14 July 2007
Abstract—A series of amphiphilic dendritic ligands with a phosphine core was synthesized by use of tris(4-hydroxyphenyl)phosphine
oxide and poly(benzyl ether) dendron. The corresponding phosphine–palladium core dendrimers were applied as a catalyst to an
aqueous-media Suzuki–Miyaura reaction. A positive dendritic effect on chemical yields of cross-coupling products was observed.
Ó 2007 Elsevier Ltd. All rights reserved.
Organic reactions in water without the use of any harm-
ful organic solvents are of great current interest, because
water is an easily available, economical, safe, and envi-
ronmentally friendly solvent.1 To date, various water-
soluble ligands were prepared, and their applications
to aqueous-media organic syntheses were reported.
Above all, water-soluble phosphine–transition metal
catalysts were widely investigated.2
CH2
CO2X
G0[CO2X]:
CO2X
O
OGn[CO2X]
O
O
CO2X
CO2X
CO2X
CO2X
O
P
CH2
G1[CO2X]:
O
O
O
O
O
Gn[CO2X]O
OGn[CO2X]
1(Gn[CO2X])
X = H, K
CO2X
CO2X
CH2
G3[CO2X]:
CO2X
O
O
O
O
O
O
O
O
O
O
CO2X
CO2X
CO2X
CO2X
CH2
G2[CO2X]:
O
O
O
CO2X
CO2X
Figure 1. Structural formulas of dendrimer 1(Gn[CO2X]) and Gn[CO2X] dendrons (n = 0–3).
*
Corresponding author. Fax: +81 29 861 4577; e-mail: k.fujita@aist.go.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.062

6818
H. Hattori et al. / Tetrahedron Letters 48 (2007) 6817–6820
Dendrimers are fascinating molecules due to their
unique physical and chemical properties caused by their
well-defined hyperbranched frameworks.3 Metalloden-
drimers with a functional or catalytic site at their core
have received considerable attention. Their solubility
and physical properties can be altered by peripheral
modification.4 For example, by the introduction of
hydrophilic groups to the peripheral layer of a hydro-
phobic dendron, water-soluble dendritic unimolecular
micelles can be prepared.5 However, there are few exam-
ples of their use as catalysts.5d,f
We examined the utility of dendrimer 1(Gn[CO2H])
as a dendritic ligand by performing Suzuki–Miyaura
coupling reaction using the corresponding amphiphilic
1(Gn[CO2K])–palladium catalyst in water (Table 1).
Table 1. Dendritic effect on chemical yieldsa
H3C
1(Gn[CO2K]) + [PdCl(η3-C3H5)]2
B(OH)2
H3C
[0.5 mol%Pd, P/Pd = 1/1]
K2CO3
+
H2O, 50 ºC, 4 h
Recently, several examples of a positive dendritic effect
on chemical yields, which means that the reactivity is en-
hanced by increasing the generation number of the den-
drimer, have been reported by us6 and by other groups.7
In our previous study, it was found that a hydrophobic
dendron was effective as a reaction field in aqueous-
media organic syntheses.6b,c We wish to report herein
the synthesis of novel amphiphilic dendritic ligands with
a phosphine core,8 utilizing a Suzuki–Miyaura coupling
reaction in water, conducted by employing the corre-
sponding amphiphilic phosphine–palladium catalyst,
and the positive dendritic effect on chemical yields of
the coupling products.
I
5
6
7
Entry
CH3 in 5
Yieldb (%)
G0
G1
G2
G3
1
2
3-CH3
4-CH3
30
37
42
73
57
81
82
90
a Reaction conditions: 1(Gn[CO2K]) (0.0055 equiv), [PdCl(g3-C3H5)]2
(0.0025 equiv, 0.5 mol % Pd), 5 (1 equiv), 6 (1.5 equiv), K2CO3
(4.5 equiv), H2O (0.5 M based on 5), carried out at 50 °C for 4 h.
b Isolated yield.
Novel phosphine core dendrimers 1(Gn[CO2H]), which
are shown in Figure 1, were synthesized as follows
(Scheme 1). An N,N-dimethylformamide (DMF) solu-
tion of tris(4-hydroxyphenyl)phosphine oxide 29 and
poly(benzyl ether) dendritic bromide Gn[CO2CH3]–Br5g
was stirred at 70 °C in the presence of potassium carbon-
ate and a catalytic amount of 18-crown-6 for 6 h under
an argon atmosphere. The obtained dendritic phosphine
oxide 3 was reduced by trichlorosilane in degassed xylene
at 120 °C for 12 h to afford dendritic phosphine 4.
1(Gn[CO2H]) was obtained by hydrolysis of 4 with
potassium hydroxide in degassed aqueous solution
(THF–methanol–H2O) at 50 °C, followed by proton-
ation of the product with hydrochloric acid. All trans-
formations were carried out in fair yields in all
generations.10,11
The coupling reactions were carried out by use of iodo-
toluene 5 and phenylboronic acid 6 with 0.5 mol % of
various generation 1(Gn[CO2K])–palladium catalysts,
which were prepared from 1(Gn[CO2K]) and [PdCl(g3-
C3H5)]2 in situ (P/Pd = 1/1), in water at 50 °C for
4 h.12 Although 1(Gn[CO2K])–palladium catalysts had
micelle-like structures, the reaction mixture was a dis-
persion mixture.13 In both cases of 3-iodotoluene and
4-iodotoluene, the chemical yield of the coupling prod-
uct 7 was enhanced by increasing the generation number
of 1(Gn[CO2K])–palladium catalyst.14 Especially, in the
case of using 4-iodotoluene, the third-generation
1(G3[CO2K])–palladium catalyst afforded 90% yield,
which was higher than that in the case of using commer-
cially available TPPTS15–palladium catalyst (76% yield).
The relationship between the generation number of the
dendritic catalyst and the chemical yields is one of the
positive dendritic effects.6,7,16
In the case of this series of dendritic phosphine ligands
1(Gn[CO2K]), 1(G0[CO2K]) has 3 –CO2K moieties,
1(G1[CO2K]) has 6, 1(G2[CO2K]) has 12, and
1(G3[CO2K]) has 24 –CO2K moieties. To confirm the
effect of the number of –CO2K groups as surfactants
to form dispersions, we have carried out a Suzuki–
Miyaura reaction of 4-iodotoluene and 6 by employing
non-dendritic 1(G0[CO2K])–palladium catalyst having
3 –CO2K moieties and potassium benzoate 8 (x equiv/
1(G0[CO2K])) with the same amount of –CO2K moieties
of 1(Gn[CO2K]) (n = 1–3) (Table 2).
Gn[CO2CH3]-Br
(n = 0−3)
K2CO3
18-Crown-6
HSiCl3
Et3N
O P
OGn[CO2CH3]
O
P
OH
Xylene
120 °C
DMF
70 °C
3
3
3
2
G0 : 99%
G1 : 73%
G2 : 96%
G3 : 88%
1) KOH
THF−MeOH−H2O
50 °C (G0: rt)
12−24 h
P
OGn[CO2H]
P
OGn[CO2CH3]
2) 1M HCl
3
As a result, the yields of the coupling products were
rather low in all cases, thus the addition of 8 was there-
fore not effective in increasing the chemical yield. Based
on these results, it can be concluded that the introduc-
tion of hydrophilic groups to the peripheral layer of
poly(benzyl ether) dendron as a hydrophobic reaction
3
1(Gn[CO2H])
4
G0 : 92%
G1 : 85%
G2 : 93%
G3 : 87%
G0 : 99%
G1 : 94%
G2 : 76%
G3 : 95%
Scheme 1. Synthesis of dendrimer 1(Gn[CO2H]).

H. Hattori et al. / Tetrahedron Letters 48 (2007) 6817–6820
6819
Table 2. Suzuki–Miyaura reaction in water by employing
1(G0[CO2K])–palladium catalyst and 8 with the same amount of
–CO2K moieties of 1(Gn[CO2K]) (n = 1–3)
In summary, by performing an aqueous-media Suzuki–
Miyaura reaction using a novel amphiphilic dendritic
phosphine–palladium catalyst, a positive dendritic effect
on chemical yields was observed. By employing this new
type of water-soluble dendritic catalyst, the range of
more efficient aqueous-media organic syntheses may be
expanded.
CH3
1(G0[CO2K]) + [PdCl(η3-C3H5)]2
[0.5 mol%Pd, P/Pd = 1/1]
PhCO2K 8 (x equiv./1(G0[CO2K]))
K2CO3
CH3
B(OH)2
+
H2O, 50 ºC, 4 h
Acknowledgment
I
6
This work was supported by Industrial Technology
Research Grant Program in ’04 from New Energy
and Industrial Technology Development Organization
(NEDO) of Japan.
Entry
x equiv of 8
Yielda (%)
1
2
3
3
9
21
32
25
18
a Isolated yield.
Supplementary data
field6b,c is essential to an efficient aqueous-media Suzuki–
Miyaura coupling reaction.
Supplementary data (typical procedure for hydrolysis of
4 and characterization data of 1(Gn[CO2H])) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.07.062.
Next, by employing 0.5 mol % of the third-generation
1(G3[CO2K])–palladium catalyst, which afforded the
highest chemical yield in Table 1, we performed various
Suzuki–Miyaura coupling reactions in water, which
were carried out until 9 was consumed (Table 3). In
the case of using iodoarenes, by the introduction of an
acetyl group, which is an electron-withdrawing group,
to substrates 9 or 10, the reactivity was enhanced to
complete the coupling reactions within several hours
(entries 4 and 6). In contrast, although the reactivity
was decreased by the introduction of a methoxy group,
reactions proceeded to afford 11 in excellent yields
(entries 5 and 7, 98% and 99% yield). In the case of using
4-bromotoluene instead of iodoarenes, by carrying out
the coupling reaction at 80 °C, it proceeded to provide
11 in 82% yield (entry 8).
References and notes
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Table 3. Suzuki–Miyaura reaction using 1(G3[CO2K])–palladium
catalyst in water
R1
1(G3[CO2K]) + [PdCl(η3-C3H5)]2
B(OH)2
R1
[0.5 mol% Pd, Pd/P = 1/1]
K2CO3
+
H2O, 50 ºC
X
R2
´
3. (a) Dendrimers and Other Dendritic Polymers; Frechet, J.
9
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R2
11
Entry
R1
X
R2
Time (h)
Yielda (%)
1
2
3
4
5
6
7
2-CH3
3-CH3
4-CH3
4-Ac
4-CH3O
H
I
I
I
I
I
I
I
Br
H
H
H
H
24
10
20
2
20
5
92
88
93
90
98
85
99
82
´
Frechet, J. M. J. J. Polym. Sci.: Part A: Polym. Chem.
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H
Ac
CH3O
H
´
Adv. Catal. 2006, 49, 71–151; (c) Grayson, S. M.; Frechet,
H
20
4
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4-CH3
a Isolated yield.
b Carried out at 80 °C.
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H. Hattori et al. / Tetrahedron Letters 48 (2007) 6817–6820
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11. We have confirmed the formation of 1(G3[CO2H])–palla-
dium complex by the mixing of 1(G3[CO2H]) and
[PdCl(g3-C3H5)]2 (P/Pd = 1/1) in DMSO-d6 according
to 31P NMR; 1(G3[CO2H]): ꢀ10.68 ppm, palladium
complex: 19.35 ppm. This downfield shift is similar to
that reported in the literature: Iwasawa, T.; Komano, T.;
Tajima, A.; Tokunaga, M.; Obora, Y.; Fujihara, T.; Tsuji,
Y. Organometallics 2006, 25, 4665–4669.
Soc. 2003, 125, 14168–14180; (c) Hayakawa, J.; Momo-
take, A.; Arai, T. Chem. Commun. 2003, 94–95; (d) Gong,
L.-Z.; Pu, L. Tetrahedron Lett. 2001, 42, 7337–7340; (e)
´
Liu, M.; Kono, K.; Frechet, J. M. J. J. Control. Release
2000, 65, 121–131; (f) Lee, J.-J.; Ford, W. T. Macromole-
cules 1994, 27, 4632–4634; (g) Hawker, C. J.; Wooley, K.
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L.; Frechet, J. M. J. J. Chem. Soc., Perkin Trans. 1 1993,
1287–1297.
12. General procedure: 1(Gn[CO2K]) was prepared by the
mixing of 1(Gn[CO2H]) (0.0184 mmol) and potassium
hydroxide (1.1 equiv/CO2H) at room temperature in water
(1.5 mL) under an argon atmosphere. By the addition of
[PdCl(g3-C3H5)]2 (0.0084 mmol) to 1(Gn[CO2K]) aqueous
solution, the 1(Gn[CO2K])–palladium catalyst was
prepared with stirring for 15 min. To a mixture of 5
(3.34 mmol), 6 (5.01 mmol), and potassium carbonate
(15.0 mmol) in water (5.2 mL) was added the above-
prepared 1(Gn[CO2K])–palladium aqueous solution at
0 °C. The resulting mixture was stirred for 4 h at 50 °C.
The reaction mixture was subjected to the usual extractive
workup with diethyl ether. The residual oil obtained after
evaporation of diethyl ether, which was dried over
magnesium sulfate, was purified by column chromatogra-
phy on silica gel to give the coupling product 7.
13. The dispersion system was stable within several minutes.
Quick measurement (SEM) of this system indicated that
its particle size was 1 lm. Kobayashi et al. have also
reported that Lewis acid–surfactant-combined catalyst
systems form colloidal dispersions (not micelle): Manabe,
K.; Mori, Y.; Wakabayashi, T.; Nagayama, S.; Koba-
yashi, S. J. Am. Chem. Soc. 2000, 122, 7202–7207.
6. (a) Fujita, K.; Muraki, T.; Hattori, H.; Sakakura, T.
Tetrahedron Lett. 2006, 47, 4831–4834; (b) Muraki, T.;
Fujita, K.; Terakado, D. Synlett 2006, 2646–2648; (c)
Muraki, T.; Fujita, K.; Kujime, M. J. Org. Chem., in press.
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7. (a) Helms, B.; Liang, C. O.; Hawker, C. J.; Frechet, J. M.
J. Macromolecules 2005, 38, 5411–5415; (b) Fujihara, T.;
Obora, Y.; Tokunaga, M.; Sato, H.; Tsuji, Y. Chem.
Commun. 2005, 4526–4528; (c) Zhang, X.; Xu, H.; Dong,
Z.; Wang, Y.; Liu, J.; Shen, J. J. Am. Chem. Soc. 2004,
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X.-M.; Jiang, D.-Z.; Xi, F.; Chan, A. S. C. Chem.
Commun. 2000, 789–790.
8. Previously reported phosphine core dendrimers: (a) Oost-
erom, G. E.; Steffens, S.; Reek, J. N. H.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M. Top. Catal. 2002, 19, 61–73; (b)
Balaji, B. S.; Obora, Y.; Ohara, D.; Koide, S.; Tsuji, Y.
Organometallics 2001, 20, 5342–5350.
9. Senear, A. E.; Valient, W.; Wirth, J. J. Org. Chem. 1960,
25, 2001–2006.
10. Selected data: 1(G3[CO2H]). Light yellow powder; IR
(KBr) 3422, 3068, 2924, 1692, 1595, 1317, 1153,
1288 cmꢀ1 1H NMR (500 MHz; DMF-d7) d = 13.3 (br
;
s, 24H), 8.06 (d, J = 8.2 Hz, 48H), 7.62 (d, J = 8.2 Hz,
48H), 7.25 (dd, J = 8.2, 7.3 Hz, 6H), 7.09 (d, J = 8.2 Hz,
6H), 6.89–6.81 (m, 42H), 6.78–6.70 (m, 21H), 5.24 (s,
48H), 5.18–5.06 (m, 42H); 13C NMR (125 MHz; DMF-
d7) d = 166.5, 159.44, 159.39, 159.3, 141.7, 139.3, 139.2,
139.0, 134.2 (2JC–P = 21 Hz), 129.9, 129.0, 126.8, 114.6
(3JC–P = 3 Hz), 106.2, 106.1, 100.6, 100.5, 68.96, 68.95,
68.86, 68.5; 31P NMR (202 MHz; DMF-d7) d = ꢀ9.74;
14. By employing only [PdCl(g3-C3H5)]2, which was not a
dendritic catalyst, the catalytic reaction did not proceed.
15. TPPTS: triphenylphosphine-3,30,300-trisulfonic acid triso-
dium salt.
16. Previously reported positive dendritic effects on chemical
yields caused by the periphery-catalyzed dendrimers: (a)
Benito, J. M.; de Jesus, E.; de la Mata, F. J.; Flores, J. C.;
Gomez, R. Chem. Commun. 2005, 5217–5219; (b) Delort,
E.; Darbre, T.; Reymond, J.-L. J. Am. Chem. Soc. 2004,
126, 15642–15643; (c) Dahan, A.; Portnoy, M. Org. Lett.
2003, 5, 1197–1200; (d) Drake, M. D.; Bright, F. V.; Detty,
M. R. J. Am. Chem. Soc. 2003, 125, 12558–12566.
MALDI-TOF-MS for
C357H285O93PH m/z: Calcd.:
6094.64 [(M+H)+]. Found: 6094.67; Anal. Calcd for
357H285O93PÆ3H2O: C, 69.74; H, 4.77. Found: C, 69.80;
H, 4.74.
C