Cu-catalyzed one-pot synthesis of unsymmetrical diaryl thioethers by coupling of aryl halides using a thiol precursor

Article abstract of DOI:10.1021/ol103041s

An efficient Cu-catalyzed one-pot approach for the synthesis of unsymmetrical diaryl thioethers using potassium ethyl xanthogenate as a thiol surrogate is developed. This new protocol avoids usage of intricate thiols and makes use of its easily available xanthate as a precursor, and thiol will be generated in situ to prepare the diaryl thioethers through a Cu-catalyzed double arylation. This strategy was further successfully utilized for the synthesis of symmetrical diaryl thioethers, aryl alkyl thioethers, and benzothiazoles. (Figure Presented)

Full text of DOI:10.1021/ol103041s

ORGANIC
LETTERS
2
011
Vol. 13, No. 5
008–1011
Cu-Catalyzed One-Pot Synthesis of
Unsymmetrical Diaryl Thioethers by
Coupling of Aryl Halides Using a Thiol
1
†
Precursor
D. J. C. Prasad and Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai,
Tamil Nadu-600 036, India
gsekar@iitm.ac.in
Received December 15, 2010
ABSTRACT
An efficient Cu-catalyzed one-pot approach for the synthesis of unsymmetrical diaryl thioethers using potassium ethyl xanthogenate as a thiol
surrogate is developed. This new protocol avoids usage of intricate thiols and makes use of its easily available xanthate as a precursor, and thiol
will be generated in situ to prepare the diaryl thioethers through a Cu-catalyzed double arylation. This strategy was further successfully utilized for
the synthesis of symmetrical diaryl thioethers, aryl alkyl thioethers, and benzothiazoles.
6
Sulfur-containing organic molecules are a very impor-
tant motif; particularly, aryl sulfides and their derivatives
are imperative molecules having biological, pharmaceuti-
for molecules containing sensitive functional groups. The
development of transition-metal-catalyzed coupling of
thiols with aryl halides has overcome these difficulties to a great
extent. A number of methods have been developed for the
1
,2
cal, and material interest (Figure 1). The traditional
methods for the synthesis of aryl sulfides involve conden-
7
8
9
synthesis of aryl sulfides using Pd, Cu, Fe, and other metal
3
sation of arenethiols with aryl halides, base-mediated
nucleophilic substitution of activated aryl halides with
(
2) (a) Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.;
Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze,
N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.;
Kosa, M. B.; Lubbenhusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich,
S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979. (b) Liu, G.;
Huth, J. R.; Olejniczak, E. T.; Mendoza, R.; DeVries, P.; Leitza, S.;
Reilly, E. B.; Okasinski, G. F.; Fesik, S. W.; von Geldern, T. W. J. Med.
Chem. 2001, 44, 1202. (c) Martino, G. D.; Edler, M. C.; Regina, G. L.;
Coluccia, A.; Barbera, M. C.; Barrow, D.; Nicholson, R. I.; Chiosis, G.;
Brancale, A.; Hamel, E.; Artico, M.; Silvestri, R. J. Med. Chem. 2006, 49,
4
thiols, and treatment of aryl lithium or Grignard reagents
5
with sulfurated electrophiles. However, these methods often
require harsh reaction conditions which are not suitable
†
This paper is dedicated to Prof. M. Periasamy.
(
1) (a) Jones, D. N. In Comprehensive Organic Chemistry; Barton,
9
47.
(
D. H.; Ollis, D. W., Eds.; Pergamon: New York, 1979; Vol. 3. (b) Rayner,
C. M. Contemp. Org. Synth. 1996, 3, 499. (c) Kondo, T.; Mitsudo, T.
Chem. Rev. 2000, 100, 3205. (d) Ley, S. V.; Thomas, A. W. Angew. Chem.,
Int. Ed. 2003, 42, 5400. (e) Marcincal-Lefebvre, A.; Gesquiere, J. C.;
Lemer, C. J. Med. Chem. 1981, 24, 889. (f) Liu, G.; Link, J. T.; Pei, Z.;
Reilly, E. B.; Leitza, S.; Nguyen, B.; Marsh, K. C.; Okasinski, G. F.; Von
Geldern, T. W.; Ormes, M.; Fowler, K.; Gallatin, M. J. Med. Chem. 2000,
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(7) For selected Pd-catalyzed S-arylation of thiols, see: (a) Migita, T.;
Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi, M. Bull. Chem.
Soc. Jpn. 1980, 53, 1385. (b) Murata, M.; Buchwald, S. L. Tetrahedron
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D. R.; Stevens, M. F. G.; Matthews, C. S.; Bradshaw, T. D.; Westwell,
A. D. J. Med. Chem. 2008, 51, 5135. (h) Dumas, J.; Brittelli, D.; Chen, J.;
Dixon, B.; Hatoum-Mokdad, H.; Konig, G.; Sibley, R.; Witowsky, J.;
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1
0.1021/ol103041s r 2011 American Chemical Society
Published on Web 01/27/2011

Scheme 1. One-Pot Synthesis of Unsymmetrical Aryl Thioethers
from Two Aryl Halides and Xanthate
thioethers from two different aryl halides and potassium ethyl
1
5
xanthogenate as a thiol precursor. In this one-pot synthesis,
initially a copper-catalyzed C(aryl)-S bond forming coupling
reaction takes place between an aryl halide and potassium
ethyl xanthogenate. Next, aryl xanthate hydrolysis takes
place yielding an arene thiolate, which in turn undergoes a
second C(aryl)-S coupling reaction with another aryl halide
to produce diaryl thioethers (Scheme 1).
Figure 1. Some of the sulfur-containing biologically important
molecules.
1
0
catalysts. But, these metal-catalyzed reactions require readily
oxidizable, foul-smelling, expensive, and less available aren-
ethiols. In addition, there are only a very few methods available
We started our studies by reacting p-iodoanisole 1 with
potassium ethyl xanthogenate 2 in the presence of 20 mol %
CuI and 20 mol % ethylene glycol L1 as a ligand at 105 °C.
After 28 h, KOH and PhI were added to the reaction mix-
ture and the resulting mixture was further heated for 20 h
which afforded 46% of an unsymmetric diaryl thioether,
(4-methoxyphenyl)(phenyl)sulfane 5. In this reaction, first,
there is a copper-catalyzed Ullmann type C(aryl)-S bond
formation between p-iodoanisole 1 and potassium ethyl
xanthogenate 2 (xanthate coupling) to give O-ethyl S-4-
1
1
in the literature for preparation of aromatic thiols.
Recently, Hartwig reported the Pd(OAc) -CyPF- Bu
t
2
complex as a catalyst for the synthesis of diaryl thioethers
from TIPS-SH and two different aryl halides, which is a
1
2
striking improvement over the current methods. Firouz-
badi et al. used thiourea as a thiol precursor for the one-pot
13
synthesis of aryl alkyl thioethers using copper as a catalyst.
However, this protocol works only for alkyl aryl thioether
synthesis, as this method generates only alkyl thiolates.
As part of our continuous effort toward copper-catalyzed
C(aryl)-heteroatom bond formation and its application in
1
6
methoxyphenyl carbonodithioate 3. Then, this carbono-
dithioate 3 was hydrolyzed by KOH to give corresponding
thiolate 4, and this in situ generated thiolate reacted with
iodobenzene in the presence of the same copper catalyst to
form a second C(aryl)-S bond (thiolate coupling) to give
the product unsymmetrical diaryl thioether 5 (Scheme 2).
It is very important to mention that this new one-pot
protocol avoids usage of the above-mentioned intricate thiols
and makes use of easily available xanthate 2 as a precursor
which is doubly arylated through Cu-catalyzed C(aryl)-Sbond
forming coupling reactions to give the diaryl thioether.
1
4
important heterocycle synthesis, herein, for the first time,
we report a new one-pot synthesis of unsymmetrical diaryl
(
8) For selected copper-catalyzed S-arylation of thiols, see:
a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (b) Bates,
C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803.
c) Chen, Y.-J.; Chen, H. H. Org. Lett. 2006, 8, 5609. (d) Rout, L.; Sen,
(
(
T, K.; Punniyamurthy, T. Angew. Chem., Int. Ed. 2007, 46, 5583. (e) Lv,
X .; Bao, W. J. Org. Chem. 2007, 72, 3863. (f) Carril, M.; SanMartin, R.;
Domı
A. K.; Singh, J.; Chaudhary, R. Tetrahedron Lett. 2007, 48, 7199.
h) Sperotto, E.; Klink, G. P. M. V.; de Vries, J. G.; Koten, G. V. J.
Org. Chem. 2008, 73, 5625.
9) (a) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008,
´
nguez, E.; Tellitu, I. Chem.;Eur. J. 2007, 13, 5100. (g) Verma,
To increase the efficiency of the one-pot synthesis of
diaryl thioethers, several ligands (L2-L11) were screened
with CuI, and the results are summarized in Figure 2.
A maximum yield of 72% thioether 5 was obtained in a
shorter reaction time when we replaced the ligand L1
with BINAM L6. Then the reaction was carried out with
different copper salts to find out the efficient copper
catalyst for this one-pot synthesis where the BINAM-
(
(
4
7, 2880. (b) Wu, J. R.; Lin, C. H.; Lee, C. F. Chem. Commun. 2009,
4450.
(10) (a) Wong, Y. C.; Jayanth, T. T.; Cheng, C. H. Org. Lett. 2006, 8,
613. (b) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett.
009, 11, 1697.
5
2
(
11) (a) Sawada, N.; Itoh, T.; Yasuda, N. Tetrahedron Lett. 2006, 47,
6
6
2
595. (b) Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J. S. Synthesis 2008,
61. (c) Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org. Lett.
009, 11, 5250.
Cu(OAc) complex as a catalyst provided a maximum of
2
9
4% isolated yield for the diaryl thioether 5 (Table 1,
entry 6). In this reaction, 82% of the ligand BINAM was
recovered after the reaction which can be reused. Solvent
study shows that nonpolar solvents such as toluene and
xylene failed to provide any product, which may be due
to the poor solubility of xanthate in nonpolar solvents
(
12) Fernandez-Rodroeguez, M. A.; Hartwig, J. F. Chem.;Eur. J.
010, 16, 2355.
13) Firouzabadi, H.; Iranpoor, N.; Gholinejad, M. Adv. Synth.
Catal. 2010, 352, 119.
14) (a) Naidu, A. B.; Jaseer, E. A.; Sekar, G. J. Org. Chem. 2009, 74,
675. (b) Rao, R. K.; Naidu, A. B.; Sekar, G. Org. Lett. 2009, 11, 1923.
2
(
(
3
(
(
c) Prasad, D. J. C.; Sekar, G. Org. Biomol. Chem. 2009, 7, 5091.
d) Prasad, D. J. C.; Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2009,
(
entries 12 and 13). DMF as a solvent gave the best
5
0, 1411. (e) Prasad, D. J. C.; Sekar, G. Synthesis 2010, 79. (f) Thakur,
K. G.; Jaseer, E. A.; Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2009, 50,
865. (g) Jaseer, E. A.; Prasad, D. J. C.; Dandapat, A.; Sekar, G.
Tetrahedron Lett. 2010, 51, 5009.
15) To the best of our knowledge, this is the first report for the use of
result. Though a wide range of bases promoted the one-
pot reaction, KOH turned out to be the most efficient
2
(
potassium ethyl xanthogenate as a thiol surrogate in metal-catalyzed
arylations, which is a cheaper and comercially available reagent.
(16) O-Ethyl S-4-methoxyphenyl carbonodithioate 3 was isolated
with good yield.
Org. Lett., Vol. 13, No. 5, 2011
1009

Scheme 2. Double Arylation of Sulfur Using Cu Catalyst
Table 1. Effect of Cu Salts, Solvents, and Bases on One-Pot
Synthesis of Diaryl Thioether
copper
salt
yield
a
entry
solvent
DMF
base
(%)
1
2
3
4
5
6
7
8
9
Cul
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaOH
72
56
57
78
51
CuBr
DMF
CuCl
DMF
Cu(OTf)
2
DMF
CuCl
Cu(OAc)
Cu
CuSO
2
DMF
b
2
DMF
94
2
O
DMF
42
74
41
4
DMF
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
DMSO
dioxane
acetonitrile
toluene
xylene
DMF
c
10
12
c
11
32
12
13
14
15
00
00
78
56
68
84
t
DMF
NaO Bu
Figure 2. Ligands screened for the Cu-catalyzed one-pot synth-
esis of a diaryl thioether.
16
17
Cu(OAc)2
Cu(OAc)2
DMF
K CO
2
3
DMF
2 3
Cs CO
a
b
Isolated yield. 82% Of the ligand BINAM was recovered after the
c
base. The reaction provided only 35% diaryl thioether 5
when onlyCu(OAc) was used as a catalyst without a ligand.
reaction which can be reused. Reaction was carried out at boiling point
of the solvent.
2
Importantly, not even a trace amount of thioether formed
when the reaction was carried out without L6-Cu(OAc)2.
Using this protocol, symmetrical diaryl thioether 6 could be
obtained in excellent yield (Scheme 3). Since, the syntheses of
unsymmetrical thioethers are more advantageous than sym-
metrical thioethers, we focused our interest on the synthesis
of unsymmetrical thioethers.
Scheme 3. Synthesis of Cu-Catalyzed Symmetrical Diaryl
Thioether
To probe the scope of copper-catalyzed in situ genera-
tion of thiolates and its application in a one-pot synthesis
of diaryl thioethers, the methodology was examined with
several types of aryl iodides, and the results are summar-
ized in Table 2. For this diaryl thioether synthesis, all types
of aryl iodides, particularly, electron-releasing, electron-
withdrawing, and stericallyhinderedortho-substitutedaryl
iodides are well tolerated. The xanthate coupling is favored
when substitution in an aryl iodide is more electron-with-
drawing in nature (entries 10 vs 15, 17), but the thiolate
coupling involves a slightly longer reaction time when the
thiolate has an electron-withdrawing substituent (entries
amino group are well tolerated. Less reactive aryl bromides
can be utilized for this diaryl thioether synthesis particularly
when they have electron-withdrawing substituent’s (entries
18-21). A heteroatom-containing aryl bromide also provided
a 62% isolated yield for the corresponding diaryl sulfide.
This new synthetic procedure was successfully utilized
for the synthesis of an aryl alkyl thioether by coupling the
appropriate aryl iodides and alkyl halides using xanthate 2
as a thiol precursor (Table 3). In this protocol, the overall
reaction takes a much shorter time for the final product
formation with10mol % catalyst, asthe second C-S bond
formation is a simple nucleophilic substitution.
1
0 vs 17). The thiolate coupling is faster when the second
aryl iodide contains an electron-withdrawing group (entr-
ies 8 and 9). Sterically hindered ortho-substituted aryl
iodides also gave good yields for this diaryl thioether synth-
esis. Importantly, 60% of the isolated yield was obtained
even both of the aryl iodides are ortho-substituted (entry 12).
Heteroatom-containing aryl iodides also provided very good
results for the diaryl thioether synthesis (entries 5 and 13). In
this one-pot process, the coupling reaction selectively takes
place with the iodo group of o-bromoiodobenzene (entries 4
and 14). A wide range of functional groups including an
After completion of the synthesis of various diaryl and
aryl alkyl thioethers in a one-pot process through in situ
generation of an aryl thiolate using xanthate 2 as a thiol
precursor, this new methodology was successfully utilized
1
7
in the synthesis of biologically important benzothiazoles
(
17) (a) Itoh, T.; Mase, T. Org. Lett. 2007, 9, 3687. (b) Ma, D.; Xie, S.;
Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem., Int. Ed. 2009, 48,
4222.
1
010
Org. Lett., Vol. 13, No. 5, 2011

Table 2. One-Pot Synthesis of Unsymmetrical Diaryl Sulfides
from Two Aryl Halides and Xanthate As Thiol Precursor
Table 3. Cu-Catalyzed One-Pot Synthesis of Aryl Alkyl
Thioether Using Thiol Precursor
a
Scheme 4. Cu-Catalyzed One-Pot Synthesis of Benzothiazoles
Using Thiol Precursor
In conclusion, we have developed a new Cu-catalyzed
one-pot approach for the synthesis of diaryl thioethers
using potassium ethyl xanthogenate as a thiol surrogate. In
this methodology, limitedly available, foul-smelling, and
unstable arene thiols are in situ generated from easily
available aryl iodides and potassium ethyl xanthogenate
through a C(aryl)-S bond forming coupling reaction. The
readily formed aryl thiolate easily reacted with a second aryl
halide to provide unsymmetrical diaryl thioethers through
a second C(aryl)-S bond forming coupling reaction. This
strategy was successfully utilized for the synthesis of sym-
metrical diaryl thioethers, aryl alkyl thioethers, and benzo-
thiazoles. We are currently pursuing further application
of this one-pot procedure for the synthesis of several classes
of sulfur-containing biologically important molecules.
a
Reaction conditions: 0.75 mmol of aryl iodide, 0.75 mmol of
2
potassium ethyl xanthogenate, 0.10 mmol of Cu(OAc) , 0.10 mmol of
L6, 2.0 mmol of KOH, and 0.50 mmol of Ar-X at 105 °C in 3 mL of
DMF. Isolated yield.
b
Acknowledgment. We thank DST (Project No.: SR/S1/
OC-06/2008), New Delhi, India for financial support. D.J.
C.P. thanks UGC, New Delhi, India for a senior research
fellowship.
from 2-iodoanilides and xanthate (Scheme 4). 2-(4-
Methoxyphenyl)benzothiazole 7 was obtained from the
copper-catalyzed one-pot reaction of N-(2-iodophenyl)-4-
methoxybenzamide and potassium ethyl xanthogenate in
the presence of 10 mol % of Cu(OAc) at 80 °C in DMF in
Supporting Information Available. Experimental pro-
2
1
13
1
5 h. It is very important to mention that benzothiazole 9
cedures, characterization data, H NMR and C NMR
spectra for all the compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
containing an aliphatic tertiary butyl group at the 2-posi-
tion was also obtained in good yield.
Org. Lett., Vol. 13, No. 5, 2011
1011