Copper-Free Sonogashira coupling in water with an amphiphilic resin-supported palladium complex

Article abstract of DOI:10.1016/j.tet.2009.11.011

The palladium-catalyzed coupling reaction of aryl halides with terminal alkynes, the Sonogashira coupling, took place in water under copper-free conditions by use of an amphiphilic polystyrene-poly(ethylene glycol) (PS-PEG) resin-supported palladium-phosphine complex to give the corresponding aryl-substituted alkynes in high yields. The PS-PEG resin-supported palladium catalyst was recovered by simple filtration and reused four times without any loss of catalytic activity.

Full text of DOI:10.1016/j.tet.2009.11.011

Tetrahedron 66 (2010) 1064–1069
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-Free Sonogashira coupling in water with an amphiphilic
resin-supported palladium complex
,
a
a
b,
*
Toshimasa Suzuka a , Yukari Okada , Kazumasa Ooshiro , Yasuhiro Uozumi
*
a University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan
b Institute for Molecular Science(IMS), Higashiyama 5-1, Myodaiji, Okazaki 444-8787, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium-catalyzed coupling reaction of aryl halides with terminal alkynes, the Sonogashira cou-
pling, took place in water under copper-free conditions by use of an amphiphilic polystyrene-poly-
(ethylene glycol) (PS–PEG) resin-supported palladium–phosphine complex to give the corresponding
aryl-substituted alkynes in high yields. The PS–PEG resin-supported palladium catalyst was recovered by
simple filtration and reused four times without any loss of catalytic activity.
Received 26 June 2009
Accepted 16 October 2009
Available online 6 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
We have recently developed amphiphilic polystyrene-poly-
(ethylene glycol) (PS–PEG)9 resin-supported transition metal
The palladium-catalyzed coupling of an aryl halide with a ter-
minal alkyne, the Sonogashira coupling,1 is recognized as the most
successful method for forming an sp-sp2 carbon–carbon bond. Since
its discovery by Sonogashira and co-workers in 1975, considerable
research has been devoted to the synthetic application of the re-
action as well as to improving its efficiency.2 One of the major
problems associated with it lies in the reaction conditions where
the use of both a palladium catalyst and a copper reagent (co-cat-
alyst) is frequently required to promote the reaction, resulting in
contamination of the coupling products with metal residue. In
addition, it has been well-documented that the Sonogashira cou-
pling often suffers from the Glaser-type oxidative dimerization of
the alkyne substrate3 as a side reaction in the presence of a Cu(I) co-
catalyst. Recently, quite a few reports addressing these problems
have appeared, in which the coupling is carried out with an
immobilized palladium catalyst and/or under copper-free
conditions.4,5
catalysts, which promote various catalytic transformations,10
including the palladium-catalyzed
p-allylic substitution, cross-
coupling reaction, and the Heck reaction, smoothly in water under
heterogeneous conditions.11 Our continuing interest in the catalytic
utility of PS–PEG resin-supported palladium complexes led us to
examine the Sonogashira coupling in water with the PS–PEG–Pd
complex under copper-free conditions.12 We report herein our re-
sults demonstrating that the Sonogashira coupling of various aryl
halides with terminal acetylenes proceeds in water in the presence
of a palladium complex of an amphiphilic PS–PEG resin-bound
triarylphosphine ligand under copper-free conditions (Scheme 1).
R
R
Pd
1
(5 mol% Pd)
+
X
R'
R'
Et3N or CsOH
in H2O (without Cu)
2 (X = I, Br, Cl)
3
4
However, given the increasing concern about green and safe
chemical processes, it is not surprising that the development of
water-based organic transformations has become a burgeoning
area of research.6,7 If the Sonogashira coupling were performed in
water with an immobilized catalyst under copper-free conditions,8
the reaction system would represent a clean, green, and safe ap-
plication of the coupling in what may be considered an ideal
chemical process.
O
C
Ph2
P
Pd
Pd
1
PS
O
O
N
H
n
Cl
Scheme 1. Sonogashira coupling in water.
2. Results and discussion
2.1. Coupling conditions
* Corresponding authors. Tel.: þ81 564 59 5571; fax: þ81 564 59 5574.
E-mail addresses: suzuka@sci.u-ryukyu.ac.jp (T. Suzuka), uo@ims.ac.jp
(Y. Uozumi).
Upon screening reaction conditions for the copper-free Sono-
gashira coupling in water with the polymeric palladium 1, we
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.011

T. Suzuka et al. / Tetrahedron 66 (2010) 1064–1069
1065
found that the reaction efficiency was greatly enhanced by the base
employed. Thus, the coupling of iodobenzene (2a) and phenyl-
acetylene (3a) was carried out in water with the polymeric catalyst 1
(5 mol % to Pd) at 40 ꢀC for 6 h in the presence of 3 equiv of base.
The reaction mixture was filtered and the recovered resin beads
were rinsed with a small portion of water and extracted with
EtOAc to give diphenylacetylene (4a). The most effective base
proved to be triethylamine as seen in the representative results
summarized in Table 1. The coupling with sodium bicarbonate,
sodium carbonate, potassium carbonate, and cesium carbonate
gave 4a in <2%, 12%, 12%, and 7% yield, respectively (entries 1–4).
The coupling reaction in aqueous potassium hydroxide afforded 4a
in 26% yield (entry 5). Of inorganic bases examined, cesium hy-
droxide was identified to be an effective base to promote the
Sonogashira coupling, which improved the coupling performance
to afford diphenylacetylene (4a) in 58% yield under otherwise the
identical conditions (entry 6). Organic amines were found to
promote the Sonogashira coupling smoothly in water. Thus, the
reaction with 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave
a 63% yield of 4a under similar conditions (entry 7). When tri-
ethylamine was used, the chemical yield of 4a increased signifi-
cantly, resulting in the quantitative formation of the coupling
product 4a (entry 8).
corresponding biarylacetylenes 4d, 4e, and 4f in 100%,81%, and
85% yield, respectively (Table 2, entries 4, 5, and 6). The coupling
of meta- and ortho-substituted iodobenzenes 2g–j having meta-
methyl, meta-chloro, ortho-methyl, and ortho-chloro groups, took
place with phenylacetylene to give the corresponding products
4g–j in 90%, 91%, 83%, and 87% yield, respectively (entries 7–10).
Coupling of 1-iodonaphthalene (2k) and 3a under the aqueous
copper-free conditions gave naphthylphenylacetylene 4k in 73%
yield (entry 11). The coupling reactions of the bromoarenes 2n–q
with 3a were carried out at a higher reaction temperature
(refluxing water) to give the corresponding biarylacetylenes in
69–87% isolated yield (entries 13–15), although the electron-rich
bromoarene 2m showed lower reactivity under similar condi-
tions. It should be noted that the coupling reactions of the
chloroarenes 2r and 2s also took place in water under similar
copper-free conditions (entries 16 and 17), though the reactivity
was much lower than their iodo and bromo counterparts, 2e, 2f,
and 2p.
Cesium hydroxide was found to promote the Sonogashira
coupling of terminal acetylenes bearing aliphatic carboxylic acid
groups more efficiently than triethylamine, though the optimal
base-substrate combination is not well-rationalized. Thus, the
coupling of iodobenzene (2a) with 6-heptynoic acid (3b) with
the polymeric catalyst 1 in water was complete within 6 h at
60 ꢀC by using CsOH to give an 83% isolated yield of 6-phenyl-6-
heptynoic acid (4m), while the coupling product 4m was
obtained in 35% yield with triethylamine (entry 18 vs entry 19).
The reactivity of alkyne carboxylic acids decreased as their
hydrophobicity decreased. Thus, pentynoic acid (3c) and
propiolic acid (3d) reacted with 2a under similar conditions to
give 4n and 4p in 68% and 58% yield, respectively (entries 20
and 21).
2.2. Substrate tolerance
The heterogeneous aquacatalytic copper-free Sonogashira
coupling was examined with a variety of haloarenes under the
reaction conditions identified above and exhibited wide sub-
strate tolerance. Representative results are summarized in Table
2. The coupling of iodobenzene (2a) with phenylacetylene took
place smoothly in water at 40 ꢀC in the presence of 3 equiv of
Et3N and 5 mol % palladium of the PS–PEG resin-supported
2.3. Recycling experiments
p
-allylpalladium-triaryl-phosphine complex 1 to give a quan-
titative yield of diphenylacetylene (4a) (Table 2, entry 1).
The Sonogashira coupling of p-methoxyiodobenzene (2b) and p-
methyliodobenzene (2c) bearing electron donating groups at
their para-positions gave the corresponding biarylacetylenes 4b
and 4c in 62% and 92% yield, respectively (Table 2, entries 2 and
3). p-(Trifluoromethyl)iodobenzene (2d), p-acetoxyiodobenzene
(2e), and p-(methoxy-carbonyl)iodobenzene (2f) having electron
deficient aromatic rings also underwent the Sonogashira coup-
ling with phenylacetylene under similar conditions to afford the
The recyclability of the PS–PEG resin-supported Pd catalyst 1
was examined for the Sonogashira coupling of iodobenzene (2a)
and phenylacetylene (3a). Thus, after the first reaction, which gave
a quantitative yield of the coupling product 4a (Table 2, entry 1),
the catalyst beads were recovered and successively subjected to
a second through a fifth run of the coupling under the same
conditions to afford 4a in 92%, 81%, 92%, and 87% yield, re-
spectively, (Scheme 2) during which hardly any palladium residue
could be detected by ICP-AES analysis from the aqueous or organic
filtrates.
Table 1
3. Conclusion
Effect of Base on the Sonogashira coupling of Iodobenzene with Phenylacetylene
using Polymeric Catalyst 1 in watera
In conclusion, we have developed a clean, green, and safe pro-
tocol for the Sonogashira coupling of aryl iodides and bromides
with terminal acetylenes using a PS–PEG resin-supported palla-
dium catalyst to give various biarylacetylene derivatives. This cat-
alyst was recovered and reused four times without any loss of
catalytic activity.
Pd
(5 mol% Pd)
1
+
I
Ph
Ph
base
in H2O (without Cu)
2a
3a
4a
Entry
Bases
Yield of 4a
1
2
3
4
Na2CO3
Na2CO3
K2CO3
Cs2CO3
KOH
CsOH
DBU
Et3N
<2%
12%
12%
7%
26%
58%
63%
99%
4. Experimental section
4.1. General methods
5b
6b
7
All manipulations were carried out under a nitrogen atmo-
sphere. Nitrogen gas was dried by passage through P2O5. Water was
deionized with a Millipore system as Milli-Q grade. NMR spectra
were recorded on a JEOL JNM-LA 500 spectrometer (500 MHz for
1H and 125 MHz for 13C). 1H and 13C NMR spectra were recorded in
CDCl3 at 25 ꢀC. Chemical shifts were reported in ppm referenced to
an internal tetramethylsilane standard for 1H NMR. Chemical shifts
8
a
All reactions were carried out with iodobenzene (2a, 0.4 mmol), phenyl-
acetylene (3a, 0.8 mmol), base (1.2 mmol) in the presence of PS–PEG resin-sup-
ported palladium–phosphine complex 1 (5 mol % Pd) in 3.0 mL of H2O at 40 ꢀC for
6 h under nitrogen, unless otherwise noted.
b
Reaction for 12 h.

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T. Suzuka et al. / Tetrahedron 66 (2010) 1064–1069
Table 2
Sonogashira coupling of aryl halides and 1-alkynes with triethylamine and polymeric catalyst 1 in watera
Entry
1
Aryl halide (2)
1-alkyne (3)
Temp (ꢀC)
Time (h)
Product (4)
Yield (%)
99
I
40
6
3a
3a
4a
4b
2a
I
OMe
OMe
CH3
2
3
40
40
6
6
62
99
2b
I
CH3
3a
4c
2c
I
CF3
CF3
4
5
40
40
6
6
99
81
3a
3a
4d
4e
2d
I
COCH3
COCH3
2e
I
COOCH3
2f
COOCH3
6
7
8
40
40
40
6
6
6
85
90
91
3a
3a
3a
4f
CH3
CH3
I
4g
4h
2g
Cl
Cl
I
2h
H3C
I
H3C
9
40
40
6
6
83
87
3a
3a
2i
2j
4i
4j
Cl
I
Cl
10
I
11
12
40
6
73
25
3a
3a
2k
4k
4b
Br
OMe
OMe
100
24
2m
Br
CF3
2n
CF3
13
14
100
100
24
24
87
81
4d
4e
3a
3a
Br
COCH3
2p
COCH3
Br
15
100
24
69
3a
2q
4k

T. Suzuka et al. / Tetrahedron 66 (2010) 1064–1069
1067
Table 2 (continued)
Entry
Aryl halide (2)
1-alkyne (3)
Temp (ꢀC)
100
Time (h)
24
Product (4)
Yield (%)
Cl
COCH3
COCH3
16
22
3a
3a
4e
4f
2r
Cl
COOCH3
COOCH3
17
100
60
24
12
13
83
2s
18b
(CH2)4COOH
(CH2)4COOH
I
I
HOOC(CH2)4
HOOC(CH2)4
3b
3b
2a
2a
4m
4m
19
60
60
12
12
35
68
20b
(CH2)2COOH
I
HOOC(CH2)2
3c
2a
4n
21b
60
12
58
I
HOOC
COOH
3d
2a
4p
a
All reactions were carried out with Ar-X (2; 0.4 mmol), acetylene (3; 0.8 mmol), and triethylamine (1.2 mmol) in the presence of the polystyrene-poly(ethylene glycol)-
supported palladium-phosphine complex 1 in 3.0 mL of H2O at 40–100 ꢀC for 6–24 h under nitrogen.
b
CsOH was used instead of Et3N.
The combined EtOAc extracts were washed with brine (2 mL), dried
Pd
(5 mol% Pd)
over MgSO4, and concentrated in vacuo. The resulting residue was
chromatographed on silica gel (hexane-EtOAc, 100:1) to give
95.0 mg (quantitative yield) of diphenylacetylene 4a.
1
+
I
Ph
Ph
Et3N
in H2O (without Cu)
2a
3a
4a
1st use 99% (Table 2, entry 1)
2nd use 92%; 3rd use 81%;
4th use 92%; 5th use 87%
4.4. Spectral and analytical data for the arylacetylenes 4
4.4.1. Diphenylacetylene (4a). 1H NMR (CDCl3)
d 7.55–7.51 (m, 4H),
7.36–7.29 (m, 6H): 13C NMR (CDCl3)
d 131.5, 128.3, 128.2, 123.2, 89.4.
Scheme 2. Recycling experiments.
MS (EI): m/z (rel%) 178 (bp, Mþ), 152 (24). IR (ATR): (cmꢁ1) v 3062,
1598, 1491. CAS registry number: 64666-02-0.
4.4.2. 1-(p-Methoxylphenyl)-2-phenylacetylene
(CDCl3)
7.55–7.46 (m, 4H), 7.35–7.29 (m, 3H), 6.88 (d, J¼8.1 Hz,
2H), 3.83 (s, 3H): 13C NMR (CDCl3)
(4b). 1H
NMR
of 13C NMR were given relative to CDCl3 as an internal standard (
d
d
77.0 ppm). Mass spectral data were measured on an Agilent 6890
GC/5973 N MS detector (GC–MS); the abbreviation ‘bp’ is used to
denote the base peak. IR analysis was performed on a JASCO FTIR-
460.
d
159.6, 133.0, 131.4, 128.3, 127.9,
123.5, 115.3, 113.9, 89.3, 88.0, 55.3. MS (EI): m/z (rel%) 208 (bp, Mþ),
165 (76), 139 (27). IR (ATR): (cmꢁ1) v 3010, 2214, 1604, 1592, 1508,
1458, 1246. CAS registry number: 7380-78-1.
4.2. Materials
4.4.3. 1-Phenyl-2-(p-tolyl)acetylene (4c). 1H NMR (CDCl3)
d 7.52
(dd, J¼8.1, 1.9 Hz, 2H), 7.43 (d, J¼8.1 Hz, 2H), 7.38–7.30 (m, 3H), 7.15
PS–PEG-supported catalyst 1 was prepared from PS–PEG amino-
resin (Tenta Gel S NH2, average diameter 90 mm, 1% divinylbenzene
cross-linked, average graft length¼68 units, loading value of amino
residue 0.31 mmol/g; purchased from RAPP POLYMERE) according
to the reported procedure.10b
(d, J¼7.8, 2H), 2.36 (s, 3H): 13C NMR (CDCl3)
d 138.3, 134.8, 131.5,
131.4, 129.1, 128.3, 128.0, 127.7, 120.1, 89.5, 21.5. MS (EI): m/z (rel%)
192 (bp, Mþ), 165 (27), 39 (21). IR (ATR): (cmꢁ1) v 3052, 3029, 2215,
1594, 1509, 1441, 1380. CAS registry number: 185817-85-0.
4.4.4. 1-Phenyl-2-(p-trifluoromethylphenyl)acetylene (4d). 1H NMR
4.3. Palladium-catalyzed Sonogashira coupling with
phenylacetylene; typical procedure
(CDCl3)
d
7.62 (dd, J¼14.1, 8.2 Hz, 4H), 7.56–7.54 (m, 2H), 7.37 (m,
3H): 13C NMR (CDCl3)
d
132.5, 131.8, 131.7, 129.8 (q, J¼33.1 Hz, 1C),
128.8, 128.4, 126.4 (q, J¼272 Hz, 1C), 125.2 (q, J¼272 Hz, 1C), 122.5,
91.7, 87.9. MS (EI): m/z (rel%) 246 (73, Mþ), 176 (43), 98 (bp), 75 (49),
51 (46). IR (ATR): (cmꢁ1) v 3080, 2219, 1508. CAS registry number:
370-99-0.
To a mixture of the polymeric catalyst 1 (64 mg, 0.020 mmol)
and iodobenzene (2a; 81.6 mg, 0.40 mmol) in H2O (3.0 mL) was
added phenylacetylene (3a; 81.7 mg, 0.80 mmol) and triethylamine
(121 mg, 1.20 mmol). The reaction mixture was shaken at 40 ꢀC for
6 h and filtered. The recovered resin beads were rinsed with H2O
and extracted three times with EtOAc (6 mL). The EtOAc layer was
separated and the aqueous layer was extracted with EtOAc (5 mL).
4.4.5. 1-(p-Acetoxyphenyl)-2-phenylacetylene (4e). 1H NMR (CDCl3)
d
7.94 (d, J¼8.3 Hz, 2H), 7.61 (d, J¼8.3 Hz, 2H), 7.57–7.52 (m, 2H),
7.45–7.36 (m, 3H), 2.62 (s, 3H): 13C NMR (CDCl3)
d
197.0, 136.1, 131.7,

1068
T. Suzuka et al. / Tetrahedron 66 (2010) 1064–1069
131.6, 128.8, 128.4, 128.2, 128.2, 122.6, 92.7, 88.5, 26.3. MS (EI): m/z
(rel%) 220 (76, Mþ), 205 (92), 176 (bp), 151, (35). IR (ATR): (cmꢁ1) v
2915, 1716, 1603, 1507, 1456. CAS registry number: 1942-31-0.
MS (EI): m/z (rel%) 146 (9, bp), 128 (72), 115 (63), 115 (72). IR (KBr):
(cmꢁ1) v 3288, 3003, 1706. CAS registry number: 637-44-5.
Acknowledgements
4.4.6. 1-(p-Methoxycarbonylphenyl)-2-phenylacetylene (4f). 1H NMR
(CDCl3)
2H), 7.38–7.36 (m, 3H), 3.93 (s, 3H): 13C NMR (CDCl3)
131.4, 129.5, 129.4, 128.7, 128.4, 127.9, 122.6, 92.4, 88.6, 52.9. MS (EI):
m/z (rel%) 236 (80, Mþ), 205 (bp), 176 (91), 151 (34). IR (ATR): (cmꢁ1
v 2949, 2217,1718,1606,1508,1455,1374,1280. CAS registry number:
42497-80-3.
d
8.02 (d, J¼8.5 Hz, 2H), 7.59 (d, J¼8.5 Hz, 2H), 7.57–7.53 (m,
This work was supported by the Young Scientists Program of
University of the Ryukyus and the Joint Study Program of the In-
stitute for Molecular Science. We also thank the MEXT (Scientific
Research on Priority Areas #460) for partial financial support of this
work.
d
166.5, 131.7,
)
References and notes
4.4.7. 1-Phenyl-2-(m-tolyl)acetylene (4g). 1H NMR (CDCl3)
d 7.51 (d,
J¼5.8 Hz, 2H), 7.35–7.28 (m, 5H), 7.21 (t, J¼7.5 Hz, 1H), 7.12 (d,
1. Sonogashira, K.; Tohda, Y. Tetrahedron Lett. 1975, 4467; Sonogashira, K. J.
Organomet. Chem. 2002, 653, 46.
J¼7.5 Hz, 1H), 2.33 (s, 3H): 13C NMR (CDCl3)
d 137.9, 132.1, 131.5,
´
2. For reviews, see: (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874; (b)
129.3, 128.6, 128.2, 128.2, 128.1, 123.3, 122.9, 89.5, 89.0, 21.1. MS (EI):
m/z (rel%) 192 (bp Mþ), 165 (13), 115 (5). IR (ATR): (cmꢁ1) v 3003,
2919, 1492. CAS registry number: 14635-91-7.
Sonogashira, K. In Metal-Catalyzed Reactions; Diederich, F., Stang, P. J., Eds.;
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4.4.8. 1-(m-Chlorophenyl)-2-phenylacetylene (4h). 1H NMR (CDCl3)
d
7.46–7.43 (m, 3H), 7.34–7.32 (m, 1H), 7.29–7.27 (m, 3H), 7.23–7.16
(m, 2H): 13C NMR (CDCl3)
d 134.1, 131.6, 131.4, 129.6, 129.5, 128.5,
128.4, 128.3,124.9,122.7, 90.5, 87.8. MS (EI): m/z (rel%) 212 (bp, Mþ),
176 (46), 151 (13). IR (ATR): (cmꢁ1) v 3055, 1490. CAS registry
number: 51624-34-1.
4.4.9. 1-Phenyl-2-(o-tolyl)acetylene (4i). 1H NMR (CDCl3)
7.39 (m, 3H), 7.25–7.21 (m, 3H), 7.12–7.10 (m, 2H), 7.08–7.04 (m,1H),
d 7.44–
2.41 (s, 3H): 13C NMR (CDCl3)
d 166.5,131.7,131.4,129.5,129.4,128.7,
128.4, 127.9, 122.6, 92.4, 88.6, 52.9. MS (EI): m/z (rel%) 192 (bp, Mþ),
165 (27), 115 (11). IR (ATR): (cmꢁ1) v 3055, 2919, 1600, 1492. CAS
registry number: 14309-60-5.
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Tyrrell, E.; Al-Saardi, A.; Millet, J. Synlett 2005, 487; (h) Djakovitch, L.; Rollet, P.
Adv. Synth. Catal. 2004, 346, 1782 (zeolite); (i) Djakovitch, L.; Rollet, P. Tetra-
hedron Lett. 2004, 45, 1367 (zeolite); (j) Fukuyama, T.; Shinmen, M.; Nishitani,
S.; Sato, M.; Ryu, I. Org. Lett. 2002, 4, 1691 (ionic liquid); (k) Bakherad, M.;
Keivanloo, A.; Bahramian, B.; Mihanparast, S. Tetrahedron Lett. 2009, 50, 6418.
6. For reviews on aqueous-switching, see: (a) Li, C.-J.; Chan, T.-H. Organic
Reactions in Aqueous Media; Wiley-VCH: New York, NY, 1997; (b) Grieco, P. A.
Organic Synthesis in Water; Kluwer Academic: Dordrecht, 1997; (c) Herrmann,
W. A.; Kohlpaintner, C. W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1524; (d)
Lindstro¨m, U. M. Chem. Rev. 2002, 102, 2751; (e) Li, C.-J.; Chan, T.-H. Compre-
hensive Organic Reactions in Aqueous Media; Wiley-Interscience: New Jersey,
2007; (f) Aqueous-Phase Organometallic Catalysis; Cornils, B., Herrmann, W. A.,
Eds.; Wiley-VCH: Weinheim, 2004.
4.4.10. 1-(o-Chlorophenyl)-2-phenylacetylene (4j). 1H NMR (CDCl3)
d
7.57–7.55 (m, 3H), 7.53–7.50 (m, 1H), 7.34–7.32 (m, 3H), 7.22–7.18
(m, 2H): 13C NMR (CDCl3)
d 135.9, 133.2, 131.7, 129.2, 128.6, 128.3,
126.4, 123.1, 122.8, 94.5, 86.2. MS (EI): m/z (rel%) 212 (bp, Mþ), 176
(38), 151 (11). IR (ATR): (cmꢁ1) v 3057, 1491, 1468. CAS registry
number: 10271-57-5.
4.4.11. 1-(1-Naphthyl)-2-phenylacetylene (4k). 1H NMR (CDCl3)
d
8.44 (d, J¼8.3 Hz, 1H), 7.83 (ddd, J¼13.2, 13.2, 4.9 Hz, 2H), 7.75 (d,
J¼7.1 Hz, 1H), 7.64 (d, J¼7.3 Hz, 2H), 7.58 (t, J¼7.3 Hz, 1H), 7.52 (t,
J¼7.3 Hz, 1H), 7.44 (t, J¼7.6 Hz, 1H), 7.39–7.34 (m, 3H): 13C NMR
7. For recent studies on the copper-free Sonogashira coupling under aqueous
conditions, see: (a) Bakherad, M.; Keivanloo, A.; Bahramian, B.; Hashemi, M.
Tetrahedron Lett. 2009, 50, 1557; (b) Gu, S.; Chen, W. Organometallics 2009, 28,
909; (c) Chandra, A.; Singh, B.; Upadhyay, S.; Singh, R. M. Tetrahedron 2008, 64,
11680; (d) Koma´romi, A.; Tolnai, G. L.; Nova´k, Z. Tetrahadron 2008, 49, 7294; (e)
Ines, B.; SanMartin, R.; Churruca, F.; Domingues, E.; Urtiaga, M.; Miren, K.; Ar-
riortua, M. I. Organometallics 2008, 27, 2833; (f) Shi, S.; Zhang, Y. Synlett 2007,
1843; (g) Kawanami, H.; Matsushima, K.; Sato, M.; Ikushima, Y. Angew. Chem.,
Int. Ed. 2007, 46, 5129; (h) Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008,
10, 3793.
(CDCl3)
d 133.1, 131.7, 131.6, 130.3, 128.7, 128.4, 128.3, 128.2, 128.2,
126.7, 126.4, 126.1, 125.2, 125.2, 94.3, 87.5. MS (EI): m/z (rel%) 228
(bp, Mþ), 202 (6), 113 (13). IR (ATR): (cmꢁ1) v 3055, 1488, 1396. CAS
registry number: 4044-57-9.
4.4.12. 7-Phenyl-6-heptynoic acid (4m). 1H NMR (CDCl3)
1H), 7.39–7.38 (m, 2H), 7.28–7.26 (m, 3H), 2.46–2.41 (m, 4H), 1.85–
1.79 (m, 2H), 1.73–1.65 (m, 2H): 13C NMR (CDCl3)
179.8, 131.5,
d 11.1 (br s,
d
8. For copper-free Sonogashira coupling in water with immobilized catalysts, see:
(a) Ye, Z.-W.; Yi, W.-B. J. Fluor. Chem. 2008, 129, 11124; (b) Cai, M.; Xu, Q.; Sha, J.
J. Mol. Cat. A 2007, 272, 293. Also see Ref. 11.
128.2, 127.6, 123.8, 89.4, 81.0, 33.5, 28.0, 23.8, 19.1. MS (EI): m/z
(rel%) 202 (9, Mþ), 142 (6), 129 (77), 115 (bp). IR (KBr s): (cmꢁ1) v
3298, 3041, 1709. CAS registry number: 49769-28-0.
9. (a) Bayer, E.; Rapp, W. In Chemistry of Peptides and Proteins; Voelter, W., Bayer, E.,
Ovchinikov, Y. A., Iwanov, V. T., Eds.; Walter de Gruter: Berlin, 1986; Vol. 3, p 3;
(b) Rapp, W. In Combinatorial Peptide and Nonpeptide Libraries; Jung, G., Ed.;
VCH: Weinheim, 1996; p 425; (c) Du, X.; Armstrong, R. W. J. Org. Chem. 1997, 62,
5678; (d) Gooding, O. W.; Baudert, D.; Deegan, T. L.; Heisler, K.; Labadie, J. W.;
Newcomb, W. S.; Porco, J. A., Jr.; Eikeren, P. J. J. Comb. Chem. 1999, 1, 113.
10. For studies on polymer-supported transition metal complex catalysts from the
author’s group, see: (a) Uozumi, Y.; Danjo, H.; Hayashi, T. Tetrahedron Lett. 1997,
38, 3557 (allylic substitution); (b) Danjo, H.; Tanaka, D.; Hayashi, T.; Uozumi, Y.
Tetrahedron 1999, 55, 14341 (allylic substitution); (c) Uozumi, Y.; Danjo, H.;
Hayashi, T. J. Org. Chem. 1999, 64, 3384 (cross-coupling); (d) Uozumi, Y.; Wa-
tanabe, T. J. Org. Chem. 1999, 64, 6921 (carbonylation reaction); (e) Uozumi, Y.;
Nakai, Y. Org. Lett. 2002, 4, 2997 (Suzuki-Miyaura coupling); (f) Uozumi, Y.;
Kimura, T. Synlett 2002, 2045 (Heck reaction); (g) Uozumi, Y.; Shibatomi, K.
J. Am. Chem. Soc. 2001, 123, 2919 (asymmetric alkylation); (h) Uozumi, Y.;
Tanaka, H.; Shibatomi, K. Org. Lett. 2004, 6, 281 (asymmetric amination);
4.4.13. 5-Phenyl-4-pentynoic acid (4n). 1H NMR (CDCl3)
s, 1H), 7.40–7.38 (m, 2H), 7.28–7.26 (m, 3H), 2.74–2.70 (m, 4H):
d 11.2 (br
13C NMR (CDCl3)
d 178.0, 131.6, 128.2, 127.9, 123.3, 87.5, 81.3, 33.4,
15.0. MS (EI): m/z (rel%) 174 (43, Mþ), 146 (bp), 128 (81), 115 (93).
IR (KBr): (cmꢁ1) v 3278, 3021, 1703. CAS registry number: 3350-
92-3.
4.4.14. 3-Phenyl-2-propiolic acid (4p). 1H NMR (CDCl3)
1H), 7.62 (d, J¼7.0 Hz, 2H), 7.48 (t, J¼7.0 Hz, 1H), 7.40 (t, J¼7.0 Hz,
2H): 13C NMR (CDCl3)
182.8, 133.2, 131.0, 128.6, 119.1, 88.8, 79.9.
d 11.1 (br s,
d

T. Suzuka et al. / Tetrahedron 66 (2010) 1064–1069
1069
(i) Hocke, H.; Uozumi, Y. Synlett 2002, 2049 (asymmetric catalysis); (j) Uozumi,
Y.; Nakazono, M. Adv. Synth. Catal. 2002, 344, 274 (Rh catalysis); (k) Hocke, H.;
Uozumi, Y. Tetrahedron 2003, 59, 619 (asymmetric catalysis); (l) Hocke, H.;
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Y.; Kikuchi, M. Synlett 2005, 1775 (cross-coupling); (o) Uozumi, Y.; Kimura, M.
Tetrahedron: Asymmetry 2006, 17, 161 (asymmetric etherification); (p) Ko-
bayashi, Y.; Tanaka, D.; Danjo, H.; Uozumi, Y. Adv. Synth. Catal. 2006, 348, 1561
(asymmetric alkylation); (q) Uozumi, Y.; Suzuka, T.; Kawade, R.; Takenaka, H.
Synlett 2006, 2109 (allylic azidation); (r) Uozumi, Y.; Suzuka, T. J. Org. Chem.
2006, 71, 8644 (nitromethylation); (s) Uozumi, Y.; Suzuka, T. Synthesis 2008,
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11. PS–PEG beads are known to display relatively uniform swelling in a variety of
solvents from medium to high polarity ranging from toluene to water to
provide a solvent-swollen gel network, which allows relatively rapid diffu-
sional access of reagents to reactive sites (see, Ref. 9 and references cited
therein).
12. Preliminary results on aqueous, heterogeneous, copper-free Sonogashira
coupling have been reported, see: Uozumi, Y.; Kobayashi, Y. Heterocycles 2003,
59, 71.