A general palladium-catalysed synthesis of aromatic and heteroaromatic thioethers

Article abstract of DOI:10.1016/S0040-4020(01)00157-0

Thioethers can be efficiently prepared via palladium-catalysed cross-coupling of arene- or heteroarene thiols with arene- or heteroarene iodides. A simple, cheap and robust catalytic system is described that couples a broad range of electron-deficient as well as electron-rich substrates in high yield.

Full text of DOI:10.1016/S0040-4020(01)00157-0

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 3069±3073
A general palladium-catalysed synthesis of aromatic
and heteroaromatic thioethers
p
Ulrich Schopfer and Achim Schlapbach
Novartis Pharma AG, Preclinical Research, Lichtstrasse, CH-4002 Basel, Switzerland
Received 8 January 2001; accepted 31 January 2001
AbstractÐThioethers can be ef®ciently prepared via palladium-catalysed cross-coupling of arene- or heteroarene thiols with arene- or
heteroarene iodides. A simple, cheap and robust catalytic system is described that couples a broad range of electron-de®cient as well as
electron-rich substrates in high yield. q 2001 Elsevier Science Ltd. All rights reserved.
Thioethers, especially when they contain heterocyclic rings,
are common featuresin many natural productsand pharma-
cologically important molecules. While the palladium-
catalysed formation of diaryl amines and diaryl ethers
has received considerable interest recently, much less
attention hasbeen focu es d on the formation of diaryl
thioethers. The direct nucleophilic substitution of unacti-
4
1
vated aryl halideswith thiolstypically requirestemperatures
over 1508C or photoinitiation and the use of polar aprotic
solvents. This is still true when the reaction is promoted by
2
3
5
Scheme 1.
Table 1. Effect of Pd source, ligand and base on the coupling reaction of aryl iodides with aromatic thiols
Entry
Catalyst precursor
mol%
Ligand
mol%
Base /1.1 equiv.)
Isolated yield /%)
1
2
3
4
5
6
7
8
9
Pd
Pd
Pd
Pd
Pd
Pd
Pd
2
2
2
2
2
2
2
dba
dba
dba
dba
dba
dba
dba
3
3
3
3
3
3
3
4
1
1
1
1
1
1
1
DPEphos10
DPEphos2
DPEphos1
DPEphos2
DPEphos2
DPEphos2
t-BuOK
t-BuOK
t-BuOK
t-BuONa
94
90
81
82
23
65
,5
13
Cs
phazene P- Ph os
4
2
CO
3
4
PPh
DPEphos2
DPEphos2
3
t-BuOK
t-BuOK
t-BuOK
Pd/OAc)
±
2
,5
Keywords: diaryl thioethers; palladium; cross-coupling; homogeneous catalysis; heterocycles.
Corresponding author. Tel.: 141-61-324-4951; fax: 141-61-324-9794; e-mail: ulrich.schopfer@pharma.novartis.com
p
0040±4020ꢀ01ꢀ$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00157-0

3070
U. Schopfer, A. Schlapbach / Tetrahedron 57 +2001) 3069±3073
Table 2. Pd-catalysed formation of aromatic thioethers
a
2 3
All reactionswere conducted in toluene at 100 8C in the presence of 1 mol% Pd dba , 2 mol% DPEphosand 1.1 equiv. t-BuOK for 2 h.
Reaction time 4 h.
b
4
a,6
copper additives, although it was hs own recently that
the use of Schwesinger's phosphazene bases allows the
formation of a broad range of diaryl sul®des in toluene.
Bidentate ligandshave been sh own to be very ef®cient in a
variety of aryl±heteroatom coupling reactions. Thus,
7
12
recently DPEphoswasintroduced by van Leeuwen
was later used ef®ciently by Buchwald for Pd-catalysed
and
8
9
After early reportsby Muraha sh i and Migita, only a few
examples of nickel- and palladium-catalysed carbon±sulfur
bond-forming reactionshave been reported in the litera-
ture. A general study of the scope and limitations of this
reaction hasbeen lacking to date. Recently, Hartwig has
made considerable inroads into this underdeveloped ®eld
and showed that the stoichiometric reaction of isolated
Pd/II) aryl halide complexeswith thiolatesprovided aryl
sul®des.11
1
3
amination reactions. Herein, the potential of DPEphos,
which isreadily available from commercial os urces/e.g.
Aldrich, $120ꢀ5 g), for the promotion of intermolecular
coupling reactionsof aryl iodidesand aryl thiolswas
evaluated. We wish to report a catalytic system with
cheap and readily available componentsthat couplesa
broad range of activated and deactivated aryl iodideswith
thiolsin high yields/Scheme 1). We anticipate that the
1
0

U. Schopfer, A. Schlapbach / Tetrahedron 57 +2001) 3069±3073
Table 3. Pd-catalysed formation of heteroaromatic thioethers
3071
a
All reactionswere conducted in toluene at 100 8C in the presence of 1 mol% Pd dba
2
Under otherwise identical conditions, reaction without Pd dba gave 7% of 2-thiopyridine.
2 3
3
, 2 mol% DPEphosand 1.1 equiv. t-BuOK for 2 h.
b
extension of the reaction to heterocyclic coupling partners
will be useful for the synthesis of many biologically active
molecules.
electron-donating groupsgave equally good yield.s The
substitution pattern in ortho-, meta- or para-substituted
aryl iodidesdid not greatly in¯uence yields/entries3±5).
1
1b
In concurrence with Hartwig'sob es rvations
ortho-disubstitution /entry 9) led to lower yields, presu-
however,
For the optimisation of reaction parameters, we chose a
model reaction with electron-rich coupling partners/Table
mably due to the prevention of reductive elimination.
1
). Hartwig showed that electron-donating groups on the
1
1
aryl halide decelerate the reaction and we were con®dent
that reaction conditions optimised for these dif®cult cases
would prove generally applicable. We also felt that an
useful reaction should deliver high yields of thioether
from only one equivalent of each aryl halide and thiol.
We found that the reaction of p-tolyl iodide /1) with 4-
methoxythiophenol /2) in the presence of Pd dba , DPEphos
and t-BuOK proceeded in excellent yield /Table 1, entries1
and 2). The catalyst loading could be reduced to 1 mol%
without signi®cant reduction in yield, while 2 mol% of
ligand wasbene®cial. We were intere ts ed in developing
reaction conditionsu is ng `reagent' grade toluene without
drying or degassing in order to make this reaction useful
in parallel synthesis. We therefore did not attempt to mini-
mise catalyst loadings by scrupulous puri®cation of solvent
or reactants.
Finally, we applied these optimised reaction conditions to
heterocyclic substrates /Table 3). Heteroaromatic iodides
/entries1 and 2) aswell asheterocyclic thiols/entries3
and 4) were ef®ciently converted into the corresponding
thioethers. To our knowledge, this has not been achieved
before. Considering the privileged position of hetero-
aromatic compoundsin medicinal chemi st ry, we feel that
the catalytic system reported here will prove useful in the
synthesis of bioactive molecules.
2
3
In summary, we have developed a general method for the
synthesis of thioethers starting from aromatic iodides and
aryl thiols. The reaction uses Pd dba and DPEphosasthe
2
3
catalyst precursors, both cheap and readily available,
t-BuOK asba es and can be performed in `reagent' grade
toluene without any special precautions.
The choice of the base is critical /entries 2, 4±6). Contrary
to our expectations, we found that bases forming more
soluble thiolates like Cs CO or the phosphazene-P base
1. Experimental
2
3
4
led to lower yields. Control experiments /entries 7±9)
showed that DPEphos is a better ligand than triphenyl-
phosphine, Pd dba3 is a better catalyst precursor than
1.1. Representative procedure for mixed aryl sul®des
2
1.1.1. 1-Methyl-2-!p-tolylsulfanyl)-1H-imidazole !14). A
solution of 10.0 mg /10 mmol) Pd dba and 10.8 mg
Pd/OAc) and that palladium-catalysis is needed for the
2
2
3
reaction to proceed.
/20 mmol) DPEphosin 8 ml toluene wa st si rred under
argon atmosphere for 3 min. After addition of 0.22 g
/1.0 mmol) p-tolyl iodide, 0.11 g /1.0 mmol) 1-methyl-2-
mercaptoimidazole and 0.12 g /1.1 mmol) t-BuOK, the
mixture was st irred at 100 8C for 2 h. The reaction mixture
A wide range of substituted aryl iodides were subjected to
the optimised reaction conditions /Table 2). Substituted aryl
iodidescarrying electron-withdrawing groupsaswell as

3072
U. Schopfer, A. Schlapbach / Tetrahedron 57 +2001) 3069±3073
was®ltered over Celite, evaporated, and the re is due was
puri®ed by ¯ash chromatography yielding 180 mg
1.1.9.
125 mg /0.47 mmol, 94%) of slightly brownish crystals
1-[!4-Methoxyphenyl)thio]naphthalene
!10).
1
after ¯ash chromatography. H NMR /400 MHz, CDCl ):
/
0.88 mmol) 1-methyl-2-/p-tolylsulfanyl)-1H-imidazole.
H NMR /400 MHz, CDCl ): 2.29 /s, 3H), 3.62 /s, 3H),
3
1
4.01 /s, 3H), 7.10 /d, 2H), 7.54±7.60 /m, 4H), 7.75 /q,
2H), 7.95 /d, 1H), 8.08 /d, 1H), 8.60 /d, 1H). C NMR
3
1
.04 /d, 1H), 7.06±7.12 /m, 4H), 7.16 /d, 1H). C NMR
3
13
7
/
100 MHz, CDCl ): 21.0, 33.8, 123.6, 128.7, 129.9, 130.0,
3
/100 MHz, CDCl ): 55.3, 115.0, 124.9, 125.1, 125.7,
3
1
30.9, 136.8, 138.7. MS /EI, mꢀz): 204 /100%). HRMS
ESI): C H NaSN [M1Na1CH CN], calcd: 268.0884,
126.3, 126.5, 127.4, 128.5, 132.2, 133.8, 134.0, 134.6,
159.4. Mp 106±1078C. MS /EI, mꢀz): 266 /100%). HRMS
/FAB): C H OS, calcd: 266.0765, found: 266.0761.
/
found: 268.0886.
1
3
15
3
3
1
7
14
1
.1.2. 1-Methoxy-4-[!4-methylphenyl)thio]benzene !3).
03 mg /0.45 mmol, 90%) of a colourless oil after ¯ash
1.1.10. 1-[!4-Methoxyphenyl)thio]-2,4,6-trimethylben-
zene !11). 45 mg /0.17 mmol, 35%) of a colourless oil
1
chromatography. H NMR /400 MHz, CDCl ): 2.29 /s,
1
1
after ¯ash chromatography. H NMR /400 MHz, CDCl
):
2.30 /s, 3H), 2.38 /s, 6H), 3.74 /s, 3H), 6.73 /d, 2H), 6.88
3
3
3
7
H), 3.79 /s, 3H), 6.86 /d, 2H), 7.05 /d, 2H), 7.12 /d, 2H),
.36 /d, 2H). C NMR /100 MHz, CDCl ): 20.9, 55.2,
1
3
13
/d, 2H), 6.96 /s, 2H). C NMR /100 MHz, CDCl
): 21.1,
3
3
1
agreement with lit.
14.8, 125.6, 128.2, 129.3, 129.7, 134.3, 136.0, 159.4. /In
)
21.8, 55.3, 114.6, 127.6, 128.3, 129.0, 129.3, 138.9, 143.4,
157.4. MS /EI, mꢀz): 258 /100%). HRMS /FAB): C16H18OS,
calcd: 258.1078, found: 258.1087.
1
0e
1
.1.3. 1-Methoxy-4-!phenylthio)benzene !4). 81 mg
0.37 mmol, 74%) of a colourless oil after ¯ash chroma-
/
tography. H NMR /400 MHz, CDCl ): 3.77 /s, 3H), 6.88
1.1.11. 3-[!4-Methoxyphenyl)thio]-pyridine !12). 188 mg
/0.87 mmol, 87%) of a pale yellow oil after ¯ash chroma-
): 3.83 /s, 3H), 6.92
1
3
1
d, 2H), 7.05±7.22 /m, 5H), 7.39 /d, 2H). C NMR
3
1
tography. H NMR /400 MHz, CDCl
/
3
/
1
100 MHz, CDCl ): 55.3, 114.9, 124.3, 125.7, 128.5,
3
/d, 2H), 7.14 /dd, 1H), 7.39±7.42 /m, 1H), 7.43 /d, 2H), 8.37
1
28.9, 135.3, 138.6, 159.8. /In agreement with lit. )
4
13
/dd, 1H), 8.43 /d, 1H). C NMR /100 MHz, CDCl
15.2, 122.5, 123.6, 135.3, 135.7, 136.0, 146.7, 148.8,
160.2. MS /EI, mꢀz): 217 /100%). HRMS /ESI):
12NOS [M1H], calcd: 218.0640, found: 218.0640.
): 55.4,
3
1
1
.1.4. 1-Methoxy-2-[!4-methoxyphenyl)thio]benzene !5).
21 mg /0.49 mmol, 99%) of a colourless oil after ¯ash
1
chromatography. H NMR /400 MHz, CDCl ): 3.86 /s,
C H
12
1
3
1
.1.12. 2-[!4-Methoxyphenyl)thio]-pyridine !13). 168 mg
3
H), 3.93 /s, 3H), 6.80±6.95 /m, 5H), 7.15 /m, 1H), 7.49
1
3
/0.77 mmol, 77%) of a white solid after ¯ash chroma-
tography. H NMR /400 MHz, CDCl ): 3.86 /s, 3H), 6.78
/
d, 2H). C NMR /100 MHz, CDCl ): 55.3, 55.8, 110.3,
3
1
1
1
14.7, 121.1, 124.3, 122.7, 126.5, 127.3, 128.0, 128.9,
36.0, 155.6, 159.9. /In agreement with lit. )
3
1
5
/
d, 1H), 6.94±6.98 /m, 1H), 6.98 /d, 2H), 7.40±7.45 /m,
1
H), 7.54 /d, 2H), 8.40 /dd, 1H). C NMR /100 MHz,
3
1
CDCl ): 55.4, 115.3, 119.4, 120.3, 121.0, 136.6, 137.3,
1
.1.5. 1-Methoxy-3-[!4-methoxyphenyl)thio]benzene !6).
8 mg /0.40 mmol, 80%) of a colourless oil after ¯ash
3
1
/
49.4, 160.6, 162.8. MS /EI, mꢀz): 217 /70%), 216
9
chromatography. H NMR /400 MHz, CDCl ): 3.78 /s,
1
100%). Mp 50±518C. /In agreement with lit. )
8
1
3
3
H), 3.86 /s, 3H), 6.68±6.80 /m, 3H), 6.94 /d, 2H), 7.19
1
3
1
.1.13.
2-[!4-Methylphenyl)thio]-benzthiazole
10 mg /0.43 mmol, 43%) of a colourless oil after ¯ash
!15).
/
t, 1H), 7.49 /d, 2H). C NMR /100 MHz, CDCl ): 55.1,
3
1
chromatography. H NMR /400 MHz, CDCl ): 2.44 /s,
5
1
5.3, 111.2, 113.3, 114.9, 120.1, 123.7, 129.6,135.6, 140.0,
59.9. MS /EI, mꢀz): 246 /100%). HRMS /FAB):
1
3
3
/
H), 7.26 /t, 1H), 7.30 /d, 2H), 7.40 /t, 1H), 7.61±7.67
C H O S, calcd: 246.0714, found: 246.0711.
1
4
14
2
1
m, 3H), 7.88 /d, 1H). C NMR /100 MHz, CDCl ): 21.5,
3
3
0
0.49 mmol, 99%) of a colourless oil after ¯ash chroma-
120.7, 121.8, 124.1, 126.1, 126.2, 130.8, 135.4, 135.6,
41.2, 154.0, 170.9. MS /EI, mꢀz): 257 /70%), 256
100%). HRMS /ESI): C H NS [M1H], calcd:
1
.1.6. 1,1 -Thio-bis[4-methoxy]-benzene !7). 122 mg
1
/
/
tography. H NMR /400 MHz, CDCl ): 3.83 /s, 6H), 6.88
1
14 12
2
3
1
3
258.0411, found: 258.0413.
/
d, 4H), 7.44 /d, 4H). C NMR /100 MHz, CDCl ): 55.3,
3
14.6, 127.4, 132.6, 159.0. /In agreement with lit. )
1
5
1
1.1.7. 1-[!4-Methoxyphenyl)thio]-4-!tri¯uoromethyl)ben-
zene !8). 119 mg /0.42 mmol, 84%) of colourless crystals
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