Pd-catalyzed synthesis of biphenyls with methylthio group

Article abstract of DOI:10.1080/00397910601131049

The synthesis of unsymmetrical biaryls with a methylthio group is achieved using the air-stable palladium-phosphinous acid complexes, [(t-Bu)2P(OH)]2 PdCl2 (POPd), as the catalyst. A great variety of substituted bromobenzenes having electron-withdrawing and electron-donating functional groups in para and meta positions have been successfully coupled with 3-methylthiophenylboronic acid. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601131049

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Pd‐Catalyzed Synthesis of Biphenyls with
Methylthio Group
Zhiqiang Zhang a b , Zhizhi Hu b , Zhixiao Yu b , Haijun Chi b , Peng Lei b ,
Yue Wang b & Ren He a
a Key Laboratory of Fine Chemical Engineering , Dalian University of
Technology , Dalian, China
b School of Chemical Engineering, University of Science and Technology ,
Liaoning, Anshan, China
Published online: 10 Mar 2007.
To cite this article: Zhiqiang Zhang , Zhizhi Hu , Zhixiao Yu , Haijun Chi , Peng Lei , Yue Wang & Ren
He (2007) Pd‐Catalyzed Synthesis of Biphenyls with Methylthio Group, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:5, 683-690, DOI:
10.1080/00397910601131049
To link to this article: http://dx.doi.org/10.1080/00397910601131049
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Synthetic Communicationsw, 37: 683–690, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601131049
Pd-Catalyzed Synthesis of Biphenyls
with Methylthio Group
Zhiqiang Zhang
Key Laboratory of Fine Chemical Engineering, Dalian University
of Technology, Dalian, China and School of Chemical Engineering,
University of Science and Technology, Liaoning, Anshan, China
Zhizhi Hu, Zhixiao Yu, Haijun Chi, Peng Lei, and Yue Wang
School of Chemical Engineering, University of Science and Technology,
Liaoning, Anshan, China
Ren He
Key Laboratory of Fine Chemical Engineering, Dalian University
of Technology, Dalian, China
Abstract: The synthesis of unsymmetrical biaryls with a methylthio group is achieved
using the air-stable palladium–phosphinous acid complexes, [(t-Bu)2P(OH)]2 PdCl2
(POPd), as the catalyst. A great variety of substituted bromobenzenes having
electron-withdrawing and electron-donating functional groups in para and meta
positions have been successfully coupled with 3-methylthiophenylboronic acid.
Keywords: cross-coupling, 3-methylthiophenylboronic acid, POPd, substituted
bromobenzenes
Molecules that possess sulfur atoms are very important in living organisms.[1]
Aryl compounds with a methylthio group are of interest as pesticide and
synthetic intermediates used in the preparation of many pharmaceuticals.
For example, methyl 2-methylthiobenzoate was used to identify the female-
produced sex pheromone of Phyllophaga crinita. Interestingly, methyl
Received in Japan April 7, 2006
Address correspondence to Ren He, Key Laboratory of Fine Chemical Engineering,
Dalian University of Technology, Dalian, China. E-mail: henrry1964@163.com
683

684
Z. Zhang et al.
Scheme 1.
2-methoxybenzoate also captured P. crinita males, but only at a dose 10,000
times higher than the lowest tested dose of methyl 2-methylthiobenzoate
(Scheme 1).[2]
Dithienosilole (DTS) is a very useful intermediate for preparing
electron transporting and emissive materials. Introduction of methylthio
groups on the a,a0-positions of DTS led to a red shift of the absorption
maximum by 25 nm relative to nonsubstituted DTS, indicating that a substi-
tution effect of -SMe groups lowers the HOMO-LUMO band gap of the
molecule (Scheme 2).[3]
The methylthio group can be easily oxidized to form sulfinyl or sulfonyl
groups, which are useful groups in pharmaceuticals. For example, Gans
et al.[4] have reported that the thiophene DuP 697 (ED50 ¼ 0.18 mpk)
shows antiinflammatory activity in the rat adjuvant-induced arthritis model
without the concomitant formation of gastric lesions at 400 mpk, which is
the pharmacological profile expected of a selective COX-2 inhibitor.
Isakson et al.[5] reported that the pyrazole SC-58125 (COX-1 IC50 . 100
pM, COX-2 IC50 ¼ 0.09 pM) is a selective inhibitor of the inducible form
of human recombinant cyclooxyge nase and is orally active (ED50 ¼ 0.4
mpk) in rat adjuvant-induced arthritis (Scheme 3).
The synthesis of biaryl compounds by palladium-catalyzed cross-coupling
reaction between aryl halides with arylboronic acids, which is commonly
called Suzuki–Miyaura coupling, has developed into a powerful synthetic
method in organic synthesis.[6,7] Suzuki–Miyaura cross-coupling reaction
was widely used in the synthesis of many compounds because of its use of
nontoxic and air-stable organoboron reagents.[8–10] The traditional palladium
catalysts are mostly air sensitive and need the addition of a ligand. Li and co-
workers developed a series of novel palladium–phosphinous acid complexes,
Scheme 2.

Biphenyls with Methylthio Group
685
Scheme 3.
which were found to be efficient for variety of cross-coupling reactions.[11–14]
These catalysts have advantages over the traditional catalysts, such as air and
moisture stability, very high activity, and recyclability.
Herein, we investigated the reaction of 3-methylthiophenylboronic acid
with substituted bromobenzenes catalyzed by one kind of Li’s catalysts,
[(t-Bu)2P(OH)]2PdCl2 (dihydrogendichlorobis(di-tert-butylphosphinito-kP)
palladate(2-), CAS no. 391683-95-7), abbreviated as POPd (Scheme 4).
(POPd catalysts are commercially available from Combi-phos Catalysts,
Inc., Princeton, N.J.)
Scheme 4. POPd-catalyzed cross-coupling of 3-methylthiophenylboronic acid and
aryl bromides

686
Z. Zhang et al.
Table 1. POPd-catalyzed cross-coupling results of 3-methylthiophenylboronic acid
and bromobenzene using dioxane as solvent
HPLC (%)
POPd
(mol%)
Time
(h)
Yield (%)a
C
Entry
C
D
E
1
2
3
4
5
2
6
6
35.1
72.1
90.0
92.0
79.7
52.5
67.6
80.1
81.1
74.5
29.5
6.0
3.0
2.3
5.3
12.3
2.8
1.2
1.5
4.9
0.5
0.2
0.1
0.05
3
5
16
aIsolated yields.
Our studies showed that the quantity of POPd used in the system signifi-
cantly affected the reaction results. As shown in Table 1, there are two
by-products: thioanisole (D) and 3,30-dimethylthiobiphenyl (E) in this
reaction. The reaction proceeded well while using 0.1–0.2 mol% POPd, and
the amount of by-products increased when more catalysts were used.
Dioxane was found to be the optimal solvent. The yield of the target
product was also good while using toluene, but the solubility of 3-methylthio-
phenylboronic acid in toluene was poor and more by-products formed
(Table 2, Scheme 4).
It can be seen that the present process, employing the air-stable POPd as
catalyst, affects cross-couplings of 3-methylthiophenylboronic acid with sub-
stituted bromobenzenes (Table 3, Scheme 5). A variety of coupling reactions
were catalyzed to yield the desired products with excellent isolated yields. The
reactions of substituted bromobenzenes with electron-withdrawing groups
give the desired product in excellent yields (Entries 2 and 3, Table 3),
whereas the electron-donating substituted bromobenzenes with electron-rich
groups give lower yields (Entries 6 and 7, Table 3).
In conclusion, we have demonstrated that Suzuki coupling of
3-methylthiophenylboronic acid with a variety of substituted bromobenzenes
proceeds in good to excellent yield using the palladium–phosphinous acid
Table 2. POPd-catalyzed cross-coupling reactions of 3-methylthiophe-
nylboronic acid and bromobenzene in different solvents
HPLC (%)
Time
Entry
Solvent
(h)
C
D
E
1
2
3
Tetrahydrofuran
Toluene
Dioxane
5
4
3
0.4
75.4
80.1
0.4
2.8
3.0
0.3
6.8
1.2

Biphenyls with Methylthio Group
687
Scheme 5.
complex POPd as a catalyst. The further usefulness of this catalyst is currently
under investigation in our laboratories.
EXPERIMENTAL
All reagents were purchased from commercial suppliers and used without
further purification. POPd is available from Combi-phos Catalysts, Inc.
Dioxane, tetrahydrofuran, and toluene were distilled from sodium benzophe-
none ketyl under nitrogen. Melting points were determined with an X-6
melting-point apparatus and are uncorrected. IR, NMR, and MS spectra
were in agreement with the structure and were recorded on a Nicolet FT-IR
20 SX spectrometer, a Bruker AC 500 (TMS as internal standard) and
Agilent 1100, respectively. High-resolution mass spectra were obtained with
a Micromass GCT TOF mass spectrometer.
General Procedure for the Reaction of 3-(Methylthio)
Phenylboronic Acid with Bromo Benzenes (Entry 1, Table 3)
A mixture of 3-methylthiophenylboronic acid (223.0 mg, 1.327 mmol), 4-bro-
mobenzonitrile (161.0 mg, 0.8845 mmol), K2CO3 (366.7 mg, 2.657 mmol) and
Table 3. Experimental results of POPd-catalyzed cross-coupling
Entry
Reactant
R
Product
Time (h)
Yield (%) a
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
H
4-CN
3a
3b
3c
3d
3e
3f
3
3
4
5
5
6
5
90.0
99.7
97.8
96.7
91.2
88.3
85.7
4-NO2
3-OMe
4-COMe
4-OMe
4-Me
1g
3g
aIsolated yields.

688
Z. Zhang et al.
POPd (0.90 mg, 0.00177 mmol, 0.2 mol %) was stirred and refluxed in 2 mL of
dioxane for 3 h. The reaction mixture was allowed to cool to room temperature,
quenched with water, and extracted with EtOAc. The combined organic layers
were washed with brine and dried over MgSO4, and the solvents were removed
under vacuum. The residue was purified by chromatography on silica gel eluting
with hexane/EtOAc (60:1, v:v) to give the products 3a–g.
Data
3-Methylthiobiphenyl (3a). Yield 90.0% as a colorless liquid; IR (KBr):
1
3028, 2932, 1586, 1562, 1466 cm21. H NMR (500 MHz, CDCl3, TMS): d
2.55 (s, 3H), 7.27–7.25 (m, 1H), 7.39–7.36 (m, 3H), 7.49–7.45 (q, 3H,
J ¼ 7.7 Hz), 7.59 (d, 2H, J ¼ 7.5 Hz); 13C NMR (125 MHz, CDCl3,
TMS): d 16.0, 124.1, 125.5, 127.3, 127.6, 128.9, 129.2, 139.1, 140.9, 142.0;
HRMS (EI): Mþ, found 200.0662. C14H11NS requires 200.0660.
4-Cyano-30-methylthiobiphenyl (3b). Yield 99.7% as a white acicular
.
crystal. Mp 64.0–65.58C. IR (KBr): 2230 cm21 1H NMR (500 MHz,
CDCl3, TMS): d 2.54 (s, 3H), 7.31 (d, 1H, J ¼ 7.8 Hz), 7.34 (d, 1H,
J ¼ 7.8 Hz), 7.39–7.42 (t, 1H, J ¼ 7.8 Hz), 7.45 (s, 1H), 7.67 (d, 2H,
J ¼ 8.4 Hz), 7.73 (d, 2H, J ¼ 8.3 Hz); 13C NMR (125 MHz, CDCl3, TMS):
d 15.8, 124., 125.4, 126.7, 127.9, 129.6, 139.5, 139.9, 147.2, 147.3; HRMS
(EI): Mþ, found 225.0616. C14H11NS requires 225.0612.
4-Nitro-30-methylthiobiphenyl (3c). Yield 97.8% as a yellow solid. Mp
.
83.5–84.58C. IR (KBr): 1515, 1349, 847 cm21 1H NMR (500 MHz,
CDCl3, TMS): d 2.56 (s, 3H), 7.33 (d, 1H, J ¼ 7.8 Hz), 7.38 (d, 1H,
J ¼ 7.8 Hz), 7.41–7.43 (t, 1H, J ¼ 7.8 Hz), 7.49 (s, 1H), 7.73 (d, 2H,
J ¼ 8.9 Hz), 8.30 (d, 2H, J ¼ 8.9 Hz); 13C NMR (125 MHz, CDCl3, TMS):
d 15.8, 124.1, 125.4, 126.7, 127.9, 129.6, 139.5, 139.9, 147.2, 147.3;
HRMS (EI): Mþ, found 245.0508. C13H11NO2S requires 245.0510.
4-Acetyl-30-methylthiobiphenyl (3d). Yield 97.8% as a light yellow liquid.
1
IR (KBr): IR (KBr): 1692 cm21; H NMR (500 MHz, CDCl3, TMS): d 2.54
(s, 3H), 2.64 (s, 3H), 7.25 (m, 1H), 7.37–7.39 (m, 2H), 7.49 (s, 1H), 7.66
(d, 2H, J ¼ 8.5 Hz), 8.02 (d, 2H, J ¼ 8.5 Hz); 13C NMR (125 MHz, CDCl3,
TMS): d 15.9, 26.7, 124.1, 125.4, 126.2, 127.3, 128.9, 129.4, 136.1, 139.4,
140.7, 145.3, 197.7; MS (m/z): 243.0 (M þ 1); HRMS (EI): Mþ, found
242.0760. C15H14OS requires 242.0765.
3-Methoxy-30-methylthiobiphenyl (3e). Yield 96.7% as a light yellow liquid.
IR (KBr): 1300 cm21; 1H NMR (500 MHz, CDCl3, TMS): d 2.56 (s, 3H), 3.89
(s, 3H), 6.96, 6.94 (d, 1H, J ¼ 10.7 Hz), 7.146–7.154 (t, 1H, J ¼ 4.2 Hz),
7.19–7.21 (d, 1H, J ¼ 9.9 Hz), 7.27–7.29 (m, 1H), 7.37–7.40 (m, 3H),

Biphenyls with Methylthio Group
689
7.51 (s, 1H); 13C NMR (125 MHz, CDCl3, TMS): d 15.8, 111.2, 118.8, 119.8,
124.0, 125.4, 125.5, 129.3, 129.9, 139.1, 141.9, 142.4, 160.0; HRMS (EI):
Mþ, found 230.0768. C14H14OS requires 230.0765.
4-Methoxy-30-methylthiobiphenyl (3f). Yield 88.3% as a white flakelike
1
crystal. Mp 45.2–46.28C. IR (KBr): 1260, 1040 cm21. H NMR (500 MHz,
CDCl3, TMS): d 2.46 (s, 3H), 3.78 (s, 3H), 6.90 (d, 2H, J ¼ 8.6 Hz), 7.13
(d, 1H, J ¼ 7.1 Hz), 7.25–7.26 (m, 2H), 7.36 (s, 1H), 7.44 (d, 2H,
J ¼ 8.7 Hz); 13C NMR (125 MHz, CDCl3, TMS): d 16.0, 55.4, 114.3,
123.7, 124.9, 125.1, 128.2, 129.2, 133.3, 138.9, 141.6, 159.4; HRMS (EI):
Mþ, found 230.0758. C14H14S requires 230.0765.
4-Methyl-30-methylthiobiphenyl (3g). Yield 85.7% as a colorless liquid. IR
(KBr): 3075, 2960 cm21. 1H NMR (500 MHz, CDCl3, TMS): d 2.43 (s, 3H),
2.56 (s, 3H), 7.266–7.274 (m, 3H), 7.37 (d, 2H, J ¼ 4.9 Hz), 7.51 (d, 3H,
J ¼ 8.3 Hz); 13C NMR (125 MHz, CDCl3, TMS): d 16.0, 21.2, 124.0,
125.2, 125.3, 127.1, 129.2, 129.6, 137.4, 138.0, 139.0, 141.9; HRMS (EI):
Mþ, found 214.0816. C14H14S requires 214.0816.
ACKNOWLEDGMENTS
This project was supported by the Natural Science Foundation of Liaoning
Education Department (Grant No. 202193399). We thank Dr. Li, at Combi-
phos Catalysts, Inc., Princeton, N.J., for helpful discussions regarding the
use of POPd catalyst and Dr. Yan at AstraZeneca Pharmaceuticals, Wilming-
ton, Del., for valuable suggestions.
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