Palladium on charcoal-catalyzed ligand-free Stille coupling

Article abstract of DOI:10.1016/j.tet.2010.09.027

An efficient ligand-free Stille coupling reaction catalyzed by palladium on charcoal was developed. Tetraphenyltin was reacted with a variety of aryl halides including aryl chlorides using LiCl as an additive. The reactions of tributyl organotin compounds with aryl iodides were effectively expedited by the addition of LiF. These reactions efficiently proceeded without a phosphine or arsenic ligand and no leached palladium was detected in the reaction mixture.

Full text of DOI:10.1016/j.tet.2010.09.027

Tetrahedron 66 (2010) 8654e8660
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium on charcoal-catalyzed ligand-free Stille coupling
,
,
Yuki Yabe a, Tomohiro Maegawa a b, Yasunari Monguchi a, Hironao Sajiki a
*
a Laboratory of Organic Chemistry, Department of Organic and Medicinal Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
b Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2010
Received in revised form 6 September 2010
Accepted 7 September 2010
Available online 21 September 2010
An efficient ligand-free Stille coupling reaction catalyzed by palladium on charcoal was developed.
Tetraphenyltin was reacted with a variety of aryl halides including aryl chlorides using LiCl as an additive.
The reactions of tributyl organotin compounds with aryl iodides were effectively expedited by the ad-
dition of LiF. These reactions efficiently proceeded without a phosphine or arsenic ligand and no leached
palladium was detected in the reaction mixture.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Stille coupling
Heterogeneous catalysis
Ligand-free
Atmospheric condition
Palladium
1. Introduction
report two kinds of efficient protocols for the ligand-free, Pd/
C-catalyzed Stille reaction under atmospheric conditions.
Stille reaction,1 a palladium-catalyzed cross-coupling between
organotin compounds and aryl halides, has been widely used as
a synthetic methods for functional and bioactive materials including
natural products, agrochemicals, pharmaceuticals, and organic
electroluminescent (EL) polymers.2 Organostannanes are air- and
moisture-stable and tolerate a wide variety of functional groups.3
Stille coupling reaction was generally catalyzed by homogenous
palladium catalysts together with expensive phosphine ligands. For
example, Fu and Littke developed a powerful method for the cross-
coupling between aryl chlorides and aryl or alkenyltributyltin
compounds using Pd2(dba)3 and P(n-Bu)3.4 The use of homogeneous
palladium catalysts unfortunately and frequently causes a contami-
nation of the residual metal in the desired product due to the dif-
ficulty of its removal.5 Palladium on charcoal (Pd/C), which has been
employed as a common heterogeneous catalyst for hydrogenations,
is attracting the interests of organic chemists as a practical catalyst
for a variety of bond forming reactions6 due to the air-stability,
andnon-residual properties. We haveinvestigated the applicationof
the Pd/C for the carbonecarbon,7 carbonenitrogen,8 and carbon-
eoxygen9 bond formation reactions. Although the Pd/C-catalyzed
Stille coupling reaction was reported by Farina,10,11 the use of AsPh3
as a ligand and CuI was essential to the reaction progress. We here
2. Results and discussion
The cross-coupling between ethyl 4-bromobenzoate (1) and
2 equiv of tetraphenyltin (2) was effectively catalyzed by 10% Pd/C
(5 mol % as Pd metal)12,13 in NMP at 90 ꢀC without further additives
to give ethyl 4-phenylbenzoate (3) in 87% yield, although a small
amount of unreacted 1 remained (Table 1, entry 1). Since Fu14 and
Nolan15 independently found that a fluoride salt as an additive
played an important role in the activation of organotin com-
pounds16 by generating the corresponding ‘ate’ complex, we also
examined the effect of fluoride as an additive (Table 1). Although
AgF, KF$HF, CaF2, CsF, NaF, and LiF never enhanced the reaction
efficiency (entry 1 vs entries 2e8), tetra-n-butylammonium fluo-
ride (TBAF) and LiCl were found to be effective to afford 3 in
quantitative yields (entries 9 and 10). The addition of LiCl would
lead to an in situ generation of a chloride-ligated zerovalent pal-
ladium species17 facilitating the oxidative addition of aryl halide by
the increased nucleophilicity of palladium atom.18 Furthermore, 1
was successfully reacted with decreased amount of 2 (1 equiv)
under atmospheric conditions in the presence of TBAF or LiCl
without any declination of the yields (entries 11 and 12). Careful
monitoring by TLC analysis revealed that the LiCl-promoted re-
action was completed within 4 h (entry 13).19
The reaction of 4-iodoacetophenone with 2 using LiCl as an
additive also afforded the corresponding 4-acetylbiphenyl in 88%
yield, while the use of TBAF instead of LiCl remarkably reduced the
* Corresponding author. Fax: þ81 58 230 8109; e-mail address: sajiki@gifu-pu.ac.jp
(H. Sajiki).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.027

Y. Yabe et al. / Tetrahedron 66 (2010) 8654e8660
8655
Table 1
of LiCl without the addition of phosphine or arsenic ligands (entries
14e16).
Screening of additives in the cross-coupling between ethyl-4-bromobenzoate (1)
and tetraphenyltin (2)a
The cross-coupling between tributyl organotin compounds and
aryl iodides was next explored (Table 3). 4-Iodoacetophenone (4)
was reacted with 2 equiv of tributylvinyltin (5) in NMP at 90 ꢀC to
give 4-acetylstyrene (6) in only 36% yield (entry 1). The addition of
LiCl or a fluoride salt increased the reaction efficiency (entries 1e8),
and NaF and LiF were particularly effective (83% and 85%, entries 7
and 8). The usage of both 5 and LiF could be decreased to 1.5 equiv
to 4, and the reaction smoothly proceeded even under air condi-
tions (83%, entry 9).
Entry
X
Additive
Yieldb [%]
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
1
1
1
None
AgF
KF$HF
CaF2
CsF
KF
NaF
LiF
TBAF
LiCl
TBAF
LiCl
87
4c
21c
37c
46c
58c
71
Table 3
Screening of additives in the cross-coupling between 4-iodoacetophenone (4) and
tributylvinyltin (5)a
77
99
9
10
11
12
13
99
99d
99d
99e
LiCl
a
All reactions were performed once.
Isolated yield.
Entry
Additive
Yieldb [%]
b
c
1
2
3
4
5
6
7
8
9
None
LiCl
TBAF
KF
36
65
53
52
69
73
83
85
83c
Determined by 1H NMR analysis.
d
e
The reaction was carried out under atmospheric conditions.
The reaction was quenched after 4 h.
CsF
CaF2
NaF
LiF
yield (32%). The scope of the cross-coupling between aryl halides
and 2 (1 equiv) was therefore investigated using LiCl (2 equiv) to-
gether with 10% Pd/C (5 mol %) in NMP after minor tuning of the
reaction temperature (Table 2). Iodobenzenes bearing either an
electron-withdrawing or -donating group smoothly underwent the
cross-coupling regardless of the substitution pattern to give the
desired biphenyl derivatives in good to excellent yields (entries
1e9).20 The cross-coupling reactions using bromobenzene de-
rivatives also proceeded efficiently (entries 10e13). The reaction
scale was increased from 0.25 to 5.0 mmol with only slightly re-
duced yield of the desired biphenyl (entry 10). This protocol was
furthermore applicable to the reaction of electron-withdrawing
nitro or cyano-substituted aryl chlorides by increasing the amount
LiF
a
All reactions were performed once.
Isolated yield.
1.5 equiv of Tributylvinyltin and LiF were used. The reaction was carried out
b
c
under atmospheric conditions.
Diverse aryl iodides possessing either an electron-withdrawing
or -donating functionality on the benzene ring were effectively
reacted with a variety of tributyl organotin compounds (1.5 equiv)
to give the corresponding cross-coupled products in good to ex-
cellent yields (Table 4, entries 1e11) under the optimized condi-
tions using 10% Pd/C (5 mol %) and LiF (1.5 equiv) in heated NMP. It
is noteworthy that heteroaryltributyltin, such as 2-furyl and
Table 2
Cross-coupling of aryl halides with tetraphenyltin (2)a
Table 4
Cross-coupling of aryl iodides with tributyltin derivativesa
Entry
X
R
Temp [ꢀC]
Yieldb [%]
88 (32)c
63
Entry
1
R
R0
Temp
[ꢀC]
Product
Yield
[%]b
1
2
3
4
I
I
I
I
4-COMe
4-NO2
3-NO2
2-NO2
4-CN
50
50
50
50
90
90
60
88
4-COMe Vinyl
90
83
5
I
6
I
3-CN
50
85
7
8
9
10
11
12
13
14
15
16
I
I
I
Br
Br
Br
Br
Cl
Cl
Cl
4-OMe
3-OMe
2-OMe
4-CO2Et
3-NO2
2-CN
4-OMe
2,4-NO2
4-NO2
4-CN
120
110
110
90
70
70
110
120
120
90
79
90
86
2
3
4
4-COMe 1-Phenylethynyl 90
90
90
99 (83)d
86
4-COMe 1-Propynyl
4-COMe 2-Furyl
50
74
68
47e
62e
65d,e
120
89c
a
All reactions (0.25 mmol scale) were performed twice.
Isolated yield.
TBAF (2 equiv) instead of LiCl were used.
Scale of ethyl 4-bromobenzoate (5 mmol) was used.
LiCl (4 equiv) was used.
b
c
5
4-COMe 2-Thienyl
120
75c
d
e
(continued on next page)

8656
Table 4 (continued)
Y. Yabe et al. / Tetrahedron 66 (2010) 8654e8660
the first example of the Stille coupling between heteroaryl halides
and heteroaryltin reagents using heterogeneous palladium catalyst
under ligand-free conditions.
Entry
R
R0
Temp
[ꢀC]
Product
Yield
[%]b
The catalyst activity of Pd/C basically depends on the supplier or
even manufacturing lot numbers of the same product since char-
coal is obtained from natural resources, such as peat or sawdust and
contaminated with a small amount of impurities, such as metals.
During the course of the study on chemoselective hydrogenation,
we previously reported a significant supplier-dependent disparity
in the catalyst activity of commercial Pd/Cs in the hydrogenolysis of
triethylsilyl ether.21 The present Pd/C-catalyzed Stille reaction be-
tween ethyl 4-bromobenzoate and tetraphenyltin was not affected
by either catalyst suppliers (Table 6, entries 1 and 4e7), lot numbers
of the same product (entry 2) or product numbers from the same
supplier (entry 3) to give the corresponding biphenyl in high yield
in each case.
6
2-NO2
Vinyl
90
63
7
2-NO2
3-CN
3-CN
3-CN
2-Furyl
120
70
83c
63
8
1-Propynyl
2-Furyl
9
120
120
74c
67c
Table 6
Evaluation suppliers, lot and product numbers of 10% Pd/C on the Stille Coupling
reactiona
10
2-Thienyl
11
4-OMe 2-Furyl
140
96c
Entry
10% Pd/C
Yieldb
a
1
2
3
4
5
6
7
N.E. Chemcat (K type, Lot21A-050759)
N.E. Chemcat (K type, Lot217-075941)
N.E. Chemcat (NX type, Lot 21A-70169)
Nacalai
Aldrich
Acros
99
92
92
99
89
91
99
All reactions were performed once.
Isolated yield.
LiF (2 equiv) was used.
b
c
2-thienyltributyltins, are also good substrates for the cross-cou-
pling, while heterogeneous palladium-catalyzed cross-coupling
reactions are usually hard to apply to the heterocycles in the
absence of ligands. Then, the cross-coupling reactions between
heteroaryl halides and heteroaryltributyltin derivatives were in-
vestigated. Pyridines bearing an iodine or bromine atom at the 2 or
3 position reacted with 2-tributylstannylfuran and -thiophen to
give the corresponding furyl- and thienylpyridines in moderate
yields (Table 5, entries 1e4). To the best of our knowledge, this is
Kishida
a
All reactions were preformed once.
b
Isolated yield.
The leaching of palladium metal from Pd/C into the reaction
media is an important issue for the practical application. No
leached palladium was detected within the limits of the assay
(<1 ppm) by inductively coupled plasma atomic emission spec-
trometry (ICP-AES) in the filtrate of the Pd/C-catalyzed Stille re-
action of ethyl 4-bromobenzoate with tetraphenyltin using LiCl in
heated NMP (Scheme 1). This result suggests that the Pd/C-cata-
lyzed Stille reaction involves no risk of the elution of Pd species into
the desired product, although the process of ‘release and capture’ of
the Pd metal on the activated carbon might take place during the
reaction.7i,22
Table 5
Cross-coupling of heteroaryl halides with heteroaryltributyltin derivativesa
Entry
Heteroaryl
halide
Heteroaryle
Sn(n-Bu)3
Temp
[ꢀC]
Heteroaryle
heteroaryl
Yieldb
[%]
1
2
3
4
120
140
140
140
62
60
50
55
Scheme 1. Leaching palladium species free Stille cross-coupling reaction.
3. Conclusions
In conclusion, we have developed two kinds of protocols for the
ligand- and copper-free heterogeneous Pd/C-catalyzed Stille cou-
pling reaction under atmospheric conditions. When tetraphenyltin
was used as a coupling partner, the efficient reaction progress was
achieved by the addition of LiCl, and even aryl chlorides could also
be employed as a substrate. The reaction of tributyl organotin
compounds afforded the corresponding coupled products in good
to high yields in the presence of LiF. The distinctive future of these
5
140
50
a
All reactions were performed twice.
Isolated yield.
b

Y. Yabe et al. / Tetrahedron 66 (2010) 8654e8660
8657
methods is that the cross-coupling reactions of a wide range of
substrates efficiently proceed without ligands. No leached palla-
dium was detected in the reaction mixture. The present protocols
will be in practical use for the syntheses of functional and bioactive
materials.
1H NMR
d
8.44 (t, 1H, J¼2.2 Hz), 8.19 (ddd, 1H, J¼8.3, 2.2, 1.2 Hz),
7.91 (dt, 1H, J¼7.8, 1.2 Hz), 7.63e7.57 (m, 3H), 7.49 (t, 2H, J¼7.3,
7.3 Hz), 7.43 (t, 1H, J¼7.3 Hz); 13C NMR
d 148.7, 142.8, 138.6, 133.0,
129.7, 129.1, 128.5, 127.1, 122.0, 121.9; MS (EI) m/z (%) 199
(Mþ, 100), 152 (80), 141 (12), 115 (6), 77 (12), 61 (8), 44 (8); HRMS
(EI) calcd for C12H9NO2 (Mþ) 199.06333. Found 199.06396.
4. Experimental section
4.1. General
4.2.4. 2-Nitrobiphenyl24. For entry 4: 60% (29.9 mg) as a yellow
solid obtained from 2-iodonitorobenzen (62.2 mg, 250
mmol) at
50 ꢀC.
All reagents and solvents were obtained from commercial
sources and used without further purification. The 10% Pd/C was
obtained from N.E. Chemcat Corporation (Japan).
1H NMR (CDCl3)
d
7.84 (dd, 1H, J¼8.0, 1.2 Hz), 7.60 (dd, 1H, J¼7.5,
7.5, 1.2 Hz), 7.49e7.38 (m, 5H), 7.33e7.30 (m, 2H); 13C NMR (CDCl3)
d
149.3, 137.4, 136.3, 132.2, 131.9, 128.6, 128.2, 128.1, 127.9, 124.0; MS
The 1H and 13C NMR spectra were recorded on a JEOL JNM
EX-400 or JEOL JNM AL-400 spectrometer (400 MHz for 1H NMR
(EI) m/z (%) 199 (Mþ, 68), 182 (44), 171 (48), 152 (100), 115 (52), 76
(24); HRMS (EI) calcd for C12H9NO (Mþ) 199.06333. Found
196.06394.
and 100 MHz for 13C NMR). Chemical shifts (
d) are expressed in
parts per million and internally referenced [0.00 ppm for tetra-
methylsilane (TMS)/CDCl3 for 1H NMR and 77.0 ppm for CDCl3 for
13C NMR]. The EI mass spectra were taken on a JEOL JMS-SX102A
instrument. Flash column chromatography was performed using
silica gel 60 N [spherical neutral (63e210 mm)] from Kanto Chem-
ical Co., Inc.
4.2.5. Biphenyl-4-carbonitrile25. For entry 5: 88% (39.4 mg) as
a colorless solid obtained from 4-iodobenzonitrile (57.3 mg,
250
For entry 16: 65% (28.9 mg) as a colorless solid obtained from
4-chlorobenzonitrile (34.3 mg, 250
mol) at 90 ꢀC.
1H NMR
7.74e7.67 (m, 4H), 7.60e7.58 (m, 2H), 7.50e7.42
(m, 3H); 13C NMR
146.1, 139.6, 133.0, 129.5, 129.0, 128.1, 127.6,
m
mol) at 90 ꢀC.
m
d
4.2. Typical procedure for the Stille cross-coupling reaction
using tetraphenyltin (Table 2)
d
119.3,111.3; MS (EI) m/z (%) 179 (100),151 (12), 132 (10), 104 (10), 76
(10); HRMS (EI) calcd for C13H9N (Mþ) 179.07350. Found 179.07264.
A mixture of LiCl (21.2 mg, 500
tetraphenyltin (107 mg, 250
12.5 mol) in NMP (1 mL) in a test tube was stirred at the given
m
mol), the aryl halide (250
mmol),
m
mol), and 10% Pd/C (13.3 mg,
4.2.6. Biphenyl-3-carbonitrile25. For entry 6: 85% (37.9 mg) as
m
a colorless solid obtained from 3-iodobenzonitrile (57.3 mg,
temperature for 24 h. To the mixture at room temperature was
added a saturated aqueous KF solution (10 mL), and the mixture
was stirred overnight, diluted with H2O (20 mL) and EtOAc (20 mL),
and passed through a Celite pad. The filtrate was separated into two
layers and the aqueous layer was extracted with EtOAc (2ꢁ10 mL).
The combined organic layers were washed with another saturated
KF solution (2ꢁ10 mL), dried over MgSO4, and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (n-hexane/EtOAc, 80:1) or preparative TLC on silica gel
(n-hexane/EtOAc, 100:1) to give the corresponding biaryl.
250
m
mol) at 50 ꢀC.
1H NMR (CDCl3)
d
7.85 (t, 1H, J¼3.0 Hz), 7.81 (dd, 1H, J¼7.8, 3.0,
1.8 Hz), 7.62 (dd, 1H, J¼7.6, 1.8 Hz), 7.57e7.51 (m, 3H), 7.47 (t, 2H,
J¼8.0, 7.2 Hz), 7.41 (t, 1H, J¼7.2 Hz); 13C NMR (CDCl3)
d 142.2, 138.6,
132.24, 130.4, 129.4, 128.9, 128.1, 126.8, 118.6, 112.7; MS (EI) m/z (%)
179 (Mþ, 100), 151 (12), 76 (6); HRMS (EI) calcd for C13H9N (Mþ)
179.07350. Found 179.07275.
4.2.7. 4-Methoxybiphenyl23,25. For entry 7: 79% (36.4 mg) as a col-
orless solid obtained from 4-iodoanisole (58.5 mg, 250
mmol) at
120 ꢀC.
4.2.1. 4-Acetylbiphenyl23. For entry 1: 88% (43.1 mg) as a colorless
For entry 13: 68% (31.4 mg) as a colorless solid obtained from
4-bromoanisole (31.3 L, 250
mol) at 110 ꢀC.
solid obtained from 4-iodoacetophenone (61.5 mg, 250
m
mol) at
m
m
50 ꢀC.
1H NMR
d
7.56e7.51 (m, 4H), 7.41 (t, 2H, J¼7.6 Hz), 7.31 (t, 2H,
1H NMR
d
8.02 (d, 2H, J¼8.3 Hz), 7.67 (d, 2H, J¼8.3 Hz), 7.62 (dt,
J¼7.6 Hz), 6.98 (d, 2H, J¼8.8 Hz), 3.84 (s, 3H); 13C NMR
d 159.1, 140.8,
2H, J¼8.1, 2.2 Hz), 7.46 (t, 2H, J¼8.1, 7.1 Hz), 7.40 (tt, 1H, J¼7.1,
133.8, 128.7, 126.7, 126.6, 114.2, 55.3; MS (EI) m/z (%) 184 (Mþ, 100),
169 (36),141 (24),115 (18), 44 (7); HRMS (EI) calcd for C13H12O (Mþ)
184.08882. Found 184.08816.
2.2 Hz), 2.62 (s, 3H); 13C NMR (CDCl3)
d 197.7, 145.8, 139.9, 135.9,
129.0, 128.9, 128.2, 127.7, 127.2, 26.7; MS (EI) m/z (%) 196 (Mþ, 48),
181 (100), 152 (38), 76 (10); HRMS (EI) calcd for C14H12O (Mþ)
196.08882. Found 196.08915.
4.2.8. 3-Methoxybiphenyl23. For entry 8: 90% (42.6 mg) as a color-
less solid obtained from 3-iodoanisole (29.8
mL, 250 m
mol) at 110 ꢀC.
4.2.2. 4-Nitrobiphenyl23,24. For entry 2: 63% (31.4 mg) as a colorless
1H NMR
d
7.58 (d, 2H, J¼8.2 Hz), 7.42 (t, 2H, J¼8.2, 7.8 Hz),
solid obtained from 4-iodonitorobenzen (62.2 mg, 250
mmol) at
7.34 (m, 2H), 7.17 (ddd, 1H, J¼7.6, 1.7, 1.7 Hz), 7.12 (t, 1H, J¼2.4,
50 ꢀC.
1.7 Hz), 6.89 (ddd, 1H, J¼8.3, 2.4,1.7 Hz), 3.84 (s, 3H); 13C NMR
For entry 15: 62% (30.9 mg) as a colorless solid obtained from
4-chloronitorobenzen (39.4 mg, 250
mol) at 120 ꢀC.
d 159.9, 142.7, 141.1, 129.7, 128.7, 127.4, 127.2, 119.6, 112.9, 112.6,
m
55.2; MS (EI) m/z (%) 184 (Mþ, 100), 154 (20), 141 (24), 115 (20),
44 (16); HRMS (EI) calcd for C13H12O (Mþ) 184.08882. Found
184.08798.
1H NMR
d
8.29 (d, 2H, J¼0 8.8 Hz), 7.73 (d, 2H, J¼8.8 Hz), 7.62 (d,
2H, J¼6.8 Hz), 7.52e7.42 (m, 3H); 13C NMR
d 147.6, 147.1, 138.8,
129.2, 128.9, 127.8, 127.4, 124.1; MS (EI) m/z (%) 199 (Mþ, 72), 169
(40), 152 (100), 141 (46), 127 (12), 115 (20), 102 (10), 84 (6), 76 (16),
63 (14), 51 (16); HRMS (EI) calcd for C12H9NO (Mþ) 199.06333.
Found 196.06260.
4.2.9. 2-Methoxybiphenyl23. For entry 9: 86% (39.8 mg) as a color-
less solid obtained from 2-iodoanisole (32.6
1H NMR
7.52 (d, 2H, J¼87.6 Hz), 7.40 (t, 2H, J¼7.6, 7.3 Hz),
7.33e7.29 (m, 3H), 7.02 (t, 1H, J¼7.6 Hz), 6.97 (d, 1H, J¼8.5 Hz), 3.79
mL, 250 m
mol) at 110 ꢀC.
d
4.2.3. 3-Nitrobiphenyl24. For entry 3: 90% (45.0 mg) as a yellow solid
(s, 3H); 13C NMR
d 156.4, 138.5, 130.9, 130.7, 129.5, 128.6, 127.9,
obtained from 3-iodonitrobenzen (62.2 mg, 250
For entry 11: 86% (42.9 mg) as a yellow solid obtained from
3-bromonitrobenzen (56.5 mg, 250
mol) at 70 ꢀC.
m
mol) at 50 ꢀC.
126.9, 120.8, 111.2, 55.5; MS (EI) m/z (%) 184 (Mþ, 100), 169 (46), 141
(36), 115 (32), 91 (8), 44 (6); HRMS (EI) calcd for C13H12O (Mþ)
184.08882. Found 184.08828.
m

8658
Y. Yabe et al. / Tetrahedron 66 (2010) 8654e8660
4.2.10. Ethyl biphenyl-4-carboxylate25,26. Forentry10:99%(56.0mg)
as a colorless solid obtained from ethyl 4-bromobenzoate (40.8 L,
250
mol) at 90 ꢀC.
1H NMR
4.3.3. 1-[4-(1-Propyn-1-yl)phenyl]ethanone29. For entry 3: 90%
m
(35.4 mg) as a colorless solid obtained from 4-iodoacetophenone
m
(61.5 mg, 250
1H NMR
3H), 2.08 (s, 3H); 13C NMR
m
mol) at 50 ꢀC.
d
8.11 (d, 2H, J¼8.3 Hz), 7.64 (d, 2H, J¼8.3 Hz), 7.62 (dd,
d
7.87 (d, 2H, J¼8.5 Hz), 7.45 (d, 2H, J¼8.5 Hz), 2.58 (s,
2H, J¼7.1, 1.2 Hz), 7.46 (dd, 2H, J¼7.1, 7.3 Hz), 7.39 (dd, 1H, J¼7.3,
d
197.4, 135.8, 131.6, 129.1, 128.2, 89.8,
1.2 Hz), 4.40 (q, 2H, J¼7.2 Hz), 1.41 (t, 3H, J¼7.2 Hz); 13C NMR
79.3, 26.6, 4.5; MS (EI) m/z (%) 158 (56), 143 (100), 115 (72), 89 (20),
63 (16), 43(10); HRMS (EI) calcd for C11H10O (Mþ) 158.07317. Found
158.07369.
d
166.2, 145.2, 139.8, 129.8, 129.7, 129.0, 128.6, 127.8, 127.0, 126.7,
60.7, 14.0; MS (EI) m/z (%) 226 (Mþ, 62%), 198 (26), 181 (100), 152
(44), 90 (6), 76 (10); HRMS (EI) calcd for C15H14O2 (Mþ) 226.10022.
Found 226.09938.
4.3.4. 1-[4-(Furan-2-yl)phenyl]ethanone30. Forentry 4:89%(41.3mg)
as a colorless solid obtained from 4-iodoacetophenone (61.5 mg,
4.2.11. Biphenyl-2-carbonitrile23,25. For entry 12: 74% (33.2 mg) as
a yellow solid obtained from 2-bromobenzonitrile (45.5 mg,
250
1H NMR
1H, J¼1.7 Hz), 6.80 (d,1H, J¼3.4 Hz), 6.51 (dd, 1H, J¼1.7, 3.4 Hz), 2.60
(3H, s); 13C NMR
197.3, 152.8, 143.2, 135.5, 134.8, 128.9, 123.5,
m
mol) at 120 ꢀC.
d
7.97 (d, 2H, J¼8.4 Hz), 7.74 (d, 2H, J¼8.4 Hz), 7.53 (d,
250
m
mol) at 70 ꢀC.
1H NMR
d
7.76 (d, 1H, J¼7.8 Hz), 7.63 (t, 1H, J¼7.7 Hz), 7.57e7.41
d
(m, 7H); 13C NMR
d
145.5, 138.1, 133.7, 132.8, 130.0, 128.7, 128.7,
112.0, 107.4, 26.5; MS (EI) m/z (%) 186 (60), 171 (100), 143 (12), 115
(36), 63 (6); HRMS (EI) calcd for C12H10O2 (Mþ) 186.06808. Found
186.06753.
127.5, 118.7, 111.3; MS (EI) m/z (%) 179 (Mþ, 100), 152 (12), 76 (6);
HRMS (EI) calcd for C13H9N (Mþ) 179.07275. Found 179.07350.
4.2.12. 2, 4-Dinitrobiphenyl24. For entry 14: 47% (28.9 mg) as a yel-
4.3.5. 1-(4-Thiophen-2-yl-phenyl)ethanone31. For entry 5: 75%
low solid obtained from 1-chloro 2,4-dinitorobenzene (50.6 mg,
(38.0 mg) as a colorless solid obtained from 4-iodoacetophenone
250
m
mol) at 110 ꢀC.
(61.5 mg, 250
1H NMR
1H, J¼3.6 Hz), 7.37 (d, 1H, J¼4.8 Hz), 7.12 (dd, 1H, J¼4.8, 3.6 Hz), 2.60
(3H, s); 13C NMR
197.2,142.9, 138.7,135.7,129.1,128.3,126.4, 125.6,
m
mol) at 120 ꢀC.
1H NMR
d
8.71 (d, 1H, J¼2.2 Hz), 8.47 (dd, 1H, J¼8.5, 2.2 Hz), 7.68
d
7.96 (d, 2H, J¼8.3 Hz), 7.69 (d, 2H, J¼8.3 Hz), 7.42 (d,
(d, 1H, J¼8.5 Hz), 7.50e7.47 (m, 3H), 7.36e7.33 (m, 2H); 13C NMR
d
149.1, 146.9, 142.3, 135.2, 133.2, 129.6, 129.1, 127.7, 126.4, 119.7; MS
d
(EI) m/z (%) 244 (Mþ, 50), 227 (36), 216 (100), 168 (36), 151 (84), 139
(88), 115 (44), 102 (24), 102 (24), 63 (32), 51 (20); HRMS (EI) calcd
for C12H9N2O4 (Mþ) 244.04908. Found 244.04841.
124.6, 26.51; MS (EI) m/z (%) 202 (64), 187 (100), 159 (20), 115 (52),
89 (8), 79 (6), 63 (6), 43 (6); HRMS (EI) calcd for C12H10O (Mþ)
202.04524. Found 202.04626.
4.3.6. 1-Ethenyl-2-nitrobenzene27. For entry 6: 63% (23.5 mg) as
4.3. Typical procedure for the Stille cross-coupling reaction
using tributyl organotin compounds (Table 4)
a yellow oil obtained from 2-iodonitrobenzen (62.2 mg, 250
mmol)
at 90 ꢀC.
1H NMR
d
7.92 (dd, 1H, J¼8.2, 1.1 Hz), 7.63 (dd, 1H, J¼7.8, 1.6 Hz),
A mixture of LiF (9.8 mg, 375
tributyl organotin compound (375
12.5 mol) in NMP (1 mL) in a test tube was stirred at the given
m
mol), the aryl halide (250
mmol),
7.58 (ddd, 1H, J¼8.0, 7.8, 1.1 Hz), 7.41 (d, 1H J¼8.2, 8.0, 1.6 Hz), 7.17
(dd, 1H, 17.3, 11.0 Hz), 5.75 (dd, 1H, J¼17.3, 1.0 Hz), 5.48 (dd, 1H,
mmol), and 10% Pd/C (13.3 mg,
m
J¼11.0, 1.0 Hz); 13C NMR
d 147.4, 132.9, 132.6, 132.0, 128.0, 127.9,
temperature for 24 h. To the mixture at room temperature was
added saturated aqueous KF solution (10 mL), and the mixture was
stirred overnight, diluted with H2O (20 mL) and EtOAc (20 mL),
and passed through a Celite pad. The filtrate was separated into
two layers and the aqueous layer was extracted with EtOAc
(2ꢁ10 mL). The combined organic layers were washed with an-
other saturated KF solution (2ꢁ10 mL), dried over MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (n-hexane/EtOAc, 80:1) or pre-
parative TLC on silica gel (n-hexane/EtOAc, 100:1) to give the
corresponding biaryl.
123.9, 118.5; MS (EI) m/z (%) 149 (Mþ, 40), 132 (26), 120 (32), 105
(70), 91 (64), 77 (100), 65 (40), 51 (48); HRMS (EI) calcd for
C8H7NO2 (Mþ) 149.04768. Found 149.04822.
4.3.7. 2-(2-Nitrophenyl)furan32. For entry 7: 83% (39.1 mg) as
a brown solid obtained from 2-iodonitorobenzene (62.2 mg,
250
m
mol) at 120 ꢀC.
1H NMR
d
7.71 (dd, 1H, J¼7.8, 1.3 Hz), 7.68 (dd, 1H, J¼8.1, 1.0 Hz),
7.57 (ddd, 1H, J¼7.8, 7.6, 1.0 Hz), 7.51 (d, 1H, J¼1.8 Hz), 7.41 (ddd, 1H,
J¼8.1, 7.6, 1.3 Hz), 6.67 (d, 1H, J¼3.4 Hz), 6.50 (dd, 1H, J¼3.4, 1.3 Hz);
13C NMR
d 148.0, 143.4, 131.5, 128.5, 127.9, 123.8, 123.4, 111.5, 109.3;
MS (EI) m/z (%) 189 (Mþ, 36), 172 (8), 161 (14), 144 (38), 131 (22), 117
(82),103 (24), 89 (84), 77 (100), 63 (56), 50 (24); HRMS (EI) calcd for
C10H7NO3 (Mþ) 189.04260. Found 189.04162.
4.3.1. 1-(4-Ethenylphenyl)ethanone27. For entry 1: 83% (30.2 mg) as
a colorless solid obtained from 4-iodoacetophenone (61.5 mg,
250
m
mol) at 90 ꢀC.
1H NMR
d
7.92 (d, 2H, J¼8.5 Hz), 7.48 (d, 2H, J¼8.5 Hz), 6.76
4.3.8. 3-(1-Propyn-1-yl)benzonitrile. For entry 8: 63% (31.4 mg) as
(dd, 1H, J¼17.6, 10.9 Hz), 5.88 (d, 1H, J¼17.6 Hz), 5.40 (d, 1H,
a
colorless oil obtained from 3-iodobenzonitrile (57.3 mg,
250
mol) at 70 ꢀC.
1H NMR
J¼10.9 Hz), 2.60 (s, 3H); 13C NMR
d
197.6, 142.1, 136.3, 136.0, 128.7,
m
126.3, 116.7, 26.6; MS (EI) m/z (%) 146 (44), 131 (100), 103 (52), 77
(42), 57 (20); HRMS (EI) calcd for C10H10O (Mþ) 146.07317. Found
146.07380.
d
7.65 (s, 1H), 7.58 (dd, 1H, J¼7.8, 1.3 Hz), 7.53 (dd, 1H,
J¼7.8, 1.3 Hz), 7.38 (t, 1H, J¼7.8 Hz), 2.06 (s, 3H); 13C NMR
d 135.7,
134.9, 130.8, 129.1, 125.7, 118.3, 112.7, 88.9; MS (EI) m/z (%) 141 (Mþ,
92), 140 (100), 114 (36), 88 (6), 63 (8), 44 (8); HRMS (EI) calcd for
C10H7N (Mþ) 141.05785. Found 141.05730.
4.3.2. 1-(4-Phenylethynylphenyl)ethanone28. For entry 2: 90%
(49.6 mg) as a colorless solid obtained from 4-iodoacetophenone
(61.5 mg, 250
1H NMR
7.94 (d, 2H, J¼8.8 Hz), 7.61 (d, 2H, J¼8.8 Hz), 7.55 (m,
2H), 7.37 (m, 3H), 2.61 (s, 3H); 13C NMR
197.3, 136.1, 131.7, 131.7,
m
mol) at 90 ꢀC.
4.3.9. 3-(2-Furanyl)benzonitrile33. For entry 9: 74% (31.3 mg) as
d
a yellow oil obtained from 3-iodobenzonitrile (57.3 mg, 250
mmol)
d
at 120 ꢀC.
128.8, 128.4, 128.2, 128.2, 122.6, 92.7, 88.6, 26.6; MS (EI) m/z (%) 220
(72), 205 (100), 176 (36), 151 (16), 102 (6), 88 (8), 43 (6); HRMS (EI)
calcd for C16H12O (Mþ) 220.08882. Found 220.08935.
1H NMR
d
7.93 (s, 1H), 7.86 (dt, 1H, J¼7.6, 1.7 Hz), 7.53e7.45 (m,
3H), 6.74 (d, 1H, J¼3.4 Hz), 6.51 (dd, 1H, J¼3.4, 2.0 Hz); 13C NMR
d
151.5, 143.1, 131.9, 130.3, 129.5, 127.6, 127.1, 118.6, 112.9, 112.0,

Y. Yabe et al. / Tetrahedron 66 (2010) 8654e8660
8659
106.8; MS (EI) m/z (%) 169 (Mþ, 100), 140 (70), 130 (8), 114 (20), 102
(8), 75 (6), 63 (8), 51 (6); HRMS (EI) calcd for C11H7NO (Mþ)
169.05277. Found 169.05213.
4.4.3. 2-(2-Thienyl)pyridine36. For entry 3: 50% (17.3 mg) as a col-
orless solid obtained from 2-bromopyridine (23.9
mL, 250 mmol) at
140 ꢀC.
1H NMR
d
8.58 (dt, 1H, J¼4.5, 1.3 Hz), 7.68e7.62 (m, 2H), 7.58 (dd,
4.3.10. 3-(2-Thienyl)benzonitrile34. For entry 10: 67% (31.0 mg) as
a colorless solid obtained from 3-iodobenzonitrile (57.3 mg,
1H, J¼3.8, 1.2 Hz), 2.08 (s, 3H), 7.39 (dd, 1H, J¼5.0, 1.2 Hz), 7.16e7.10
(m, 2H); 13C NMR
121.9, 118.8.
d 125.6, 149.5, 144.8, 136.6, 128.0, 127.5, 124.5,
250
m
mol) at 120 ꢀC.
1H NMR
d
7.87 (t, 1H, J¼1.5, 1.5 Hz), 7.81 (dt, 1H, J¼7.8, 1.5,
1.2 Hz), 7.55 (dt, 1H, J¼7.8, 1.5, 1.2 Hz), 7.48 (t, 1H, J¼7.8, 7.8 Hz),
7.36 (dd, 1H, J¼4.9, 1.2 Hz), 7.36 (dd, 1H, J¼3.7, 1.2 Hz), 7.12 (dd, 1H,
4.5. Five mmol-scale synthesis of ethyl biphenyl-4-
carboxylate
J¼4.9, 3.7 Hz); 13C NMR
d 141.6, 135.7, 130.6, 130.0, 129.8, 129.2,
129.2, 128.4, 126.4, 124.5, 118.6, 113.2; MS (EI) m/z (%) 185 (Mþ,
100), 140 (12), 58 (4); HRMS (EI) calcd for C10H7N (Mþ) 185.02992.
Found 185.03034.
A mixture of LiCl (424 mg, 10 mmol), ethyl 4-bromobenzoate
(816
mL, 5 mmol), tetraphenyltin (2.14 g, 5 mmol), and 10% Pd/C
(266 mg, 250
mmol) in NMP (20 mL) in a 200 mL-flask was stirred at
90 ꢀC for 24 h. To the mixture at room temperature was added
a saturated aqueous KF solution (10 mL), and the mixture was
stirred overnight, diluted with H2O (20 mL) and EtOAc (20 mL), and
passed through a Celite pad. The filtrate was separated into two
layers, and the aqueous layer was extracted with EtOAc (2ꢁ10 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (n-hexane/EtOAc, 100:1/50:1) to
give ethyl biphenyl-4-carboxylate (939 mg, 83%).
4.3.11. 2-(4-Methoxyphenyl)furan30. For entry 11: 96% (42.0 mg) as
a yellow solid obtained from 4-iodoanisole (58.5 mg, 250
mmol) at
140 ꢀC.
1H NMR
d
7.60 (d, 2H, J¼9.0 Hz), 7.42 (d, 1H, J¼1.8 Hz), 6.92 (d,
2H, J¼9.0 Hz), 6.51 (d,1H, J¼3.2 Hz), 6.44 (dd,1H, J¼3.2,1.8 Hz), 3.83
(s, 3H); 13C NMR
d 159.8, 154.9, 142.2, 126.0, 124.9, 114.9, 112.3,
104.2, 56.1; MS (EI) m/z (%) 174 (Mþ, 100), 159 (68), 131 (30), 115 (8),
102 (16), 77 (20), 57 (8), 43 (8); HRMS (EI) calcd for C10H7NO3 (Mþ)
174.06808. Found 174.06745.
4.6. Procedure for the detection of the leached palladium in
the reaction media (Scheme 1)
4.4. Typical procedure for the cross-coupling reaction using
between heteroaryl halide and heteroaryltributyltin (Table 5)
A mixture of LiCl (424 mg, 10 mmol), ethyl 4-bromobenzoate
A
(250
C (13.3 mg, 12.5
mixture of LiF (13.0 mg, 500
mol), tributyl organotin compound (375
mol) in NMP (1 mL) in a test tube was stirred at
m
mol), the aryl halide
(816
mL, 5 mmol), tetraphenyltin (2.14 g, 5 mmol), and 10% Pd/C
m
mmol), and 10% Pd/
(266 mg, 250
mmol) in NMP (20 mL) in a 200 mL-flask was stirred at
90 ꢀC for 24 h. To the mixture at room temperature was added
a saturated aqueous KF solution (10 mL), and the mixture was
stirred overnight, diluted with H2O (20 mL) and EtOAc (20 mL), and
passed through a Celite pad. The filtrate was separated into two
layers, and the aqueous layer was extracted with EtOAc (2ꢁ10 mL).
The organic layer was filtrated through two membrane filters
m
the given temperature for 24 h. To the mixture at room temper-
ature was added saturated aqueous KF solution (10 mL), and the
mixture was stirred overnight, diluted with H2O (20 mL) and
EtOAc (20 mL), and passed through a Celite pad. The filtrate was
separated into two layers and the aqueous layer was extracted
with EtOAc (2ꢁ10 mL). The combined organic layers were washed
with another saturated KF solution (2ꢁ10 mL), dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica gel (n-hexane/EtOAc, 80:1) or
preparative TLC on silica gel (n-hexane/EtOAc, 100:1) to give the
corresponding heterobiaryl.
(Millipore Corporation, Billerica, MA, USA; Millex-LH, 0.45
mm and
0.25 m). The filtrate was diluted with EtOAc to 50 mL of total
m
volume, and the residual palladium was assayed using a Varian
730-ES (Varian Inc. Corp., Palo Alto, CA, USA) by the inductively
coupled plasma-optical emission spectroscopy.
Acknowledgements
4.4.1. 2-Furan-2-ylpyridine30. For entry 1: 62% (25.2 mg) as a col-
orless oil obtained from 2-iodopyridine (26.6
mL, 250 mmol) at
We thank the N.E. Chemcat Corporation for the gift of the 10%
Pd/C and measurement of the leached palladium. We also appre-
ciate Mr. Keita Sakai’s help for a scale-up reaction.
120 ꢀC.
For entry 3: 50% (18.2 mg) as a colorless oil obtained from
2-bromopyridine (23.9 L, 250
mol) at 140 ꢀC.
m
m
1H NMR
d
8.60 (d, 2H, J¼4.8 Hz), 7.73e7.64 (m, 2H), 7.54 (m, 1H),
Supplementary data
7.15 (m, 1H), 7.06 (d, 1H, J¼3.4 Hz), 6.54 (m, 1H); 13C NMR
d 153.7,
Electronic Supplementary data available: 1H and 13C NMR
spectra of new compounds. Supplementary data associated
with this article can be found in online version at doi:10.1016/
j.tet.2010.09.027. These data include MOL files and InChIKeys of the
most important compounds described in this article.
149.6, 149.5, 143.3, 136.7, 121.9, 118.6, 112.1, 108.6; MS (EI) m/z (%)
145 (100), 117 (48), 89 (32), 78 (20), 63 (30), 51 (24); HRMS (EI)
calcd for C9H7NO (Mþ) 145.05277. Found 145.05347.
4.4.2. 3-Furan-2-ylpryidine35. For entry 2: 60% (21.8 mg) as a col-
orless oil obtained from 3-iodopyridine (51.3 mg, 250
mmol) at
140 ꢀC.
References and notes
For entry 5: 50% (18.2 mg) as a colorless oil obtained from
3-bromopyridine (24.1 L, 250
mol) at 140 ꢀC.
1H NMR
m
m
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(b) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Mighita, T. Chem. Lett. 1977,
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d
8.94 (d, 1H, J¼1.5 Hz), 8.50 (dd, 1H, J¼4.9, 1.5 Hz),
7.95 (ddd, 1H, J¼8.0, 2.2, 1.9 Hz), 7.53 (d, 1H, J¼1.9, 0.7 Hz), 7.31
(ddd, 1H, J¼8.0, 4.9, 0.8 Hz), 6.76 (dd, J¼3.4, 0.7 Hz), 6.52e6.50
(m, 1H); 13C NMR
d 147.9, 145.2, 143.1, 130.9, 127.0, 123.6, 111.8,
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4-cyanoiodobenzene at 50 ꢀC gave the corresponding biphenyl in 80% yield,
indicating almost no difference in the reactivity arisen from the substitution
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1-position that facilitates the oxidation addition to the palladium metal.
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