Rapid Ullmann-type synthesis of aryl sulfides using a copper(I) catalyst and ligand under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2009.03.115

A rapid and efficient method for C-S bond formation under microwave irradiation is reported. The reaction of both electron-rich and electron-poor aryl halides with thiols using copper(I) iodide as a catalyst is facilitated by the addition of 2 equiv of trans-cyclohexane-1,2-diol as ligand in the presence of K₂CO₃ as base in 2-propanol. Microwave irradiation at 120 °C for 3 h gives the corresponding aryl sulfide in a procedure amenable to library production.

Full text of DOI:10.1016/j.tetlet.2009.03.115

Tetrahedron Letters 50 (2009) 3661–3664
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid Ullmann-type synthesis of aryl sulfides using a copper(I) catalyst
and ligand under microwave irradiation
*
Mark C. Bagley , Matthew C. Dix, Vincenzo Fusillo
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid and efficient method for C–S bond formation under microwave irradiation is reported. The reac-
tion of both electron-rich and electron-poor aryl halides with thiols using copper(I) iodide as a catalyst is
facilitated by the addition of 2 equiv of trans-cyclohexane-1,2-diol as ligand in the presence of K2CO3 as
base in 2-propanol. Microwave irradiation at 120 °C for 3 h gives the corresponding aryl sulfide in a pro-
cedure amenable to library production.
Received 19 January 2009
Revised 11 March 2009
Accepted 16 March 2009
Available online 21 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The copper-mediated synthesis of aryl sulfides by the reaction
of a thiol and aryl iodide under classical Ullmann conditions has
long been established as a valuable yet challenging transforma-
tion.1 Ullmann reactions require harsh conditions (although often
less so for C–S bond formation than for the corresponding C–O or
C–N bonds), notably in their requirement for very high tempera-
tures and strong bases, and thus often demonstrate poor functional
group tolerance. This, in addition to often suffering from low prod-
uct yields, severely limits the usefulness and application of this
classical condensation reaction, in particular on large scale. Recent
advances in Ullmann chemistry has seen efforts to overcome these
deficiencies with the introduction of new procedures for unactivat-
ed substrates, new nucleophiles and increasing functional group
tolerance2–4 as well as the use of soft non-organometallic nucleo-
philes in Pd-catalysed processes5 as well as a number of alternative
strategies for C–S bond formation.6 Several groups have found that
many of the problems associated with the Ullmann condensation
of thiols under copper catalysis (Scheme 1), such as high tempera-
tures, prolonged reaction times, stoichiometric use of copper, toxic
solvents and low yields, can be overcome through the use of spe-
cific ligands or additives,7 or more recently by the use of a phase
transfer catalyst.8
C–S linkage of sulfide 3a and was most effective under copper-cat-
alysed conditions (10 mol % CuI, Et3N, dioxane, 90 °C, 16 h, 82%).
However, all our efforts to transfer this method to an effective
microwave-mediated procedure for rapid C–S bond formation re-
sulted in extremely low yields of the product (e.g., 10 mol % CuI,
Et3N, dioxane, microwaves, 100 °C, 3 h, 24%) (Scheme 2). Frus-
trated by the poor efficiency of available procedures for Ullmann
C–S bond formation, we set out to address a new method for car-
rying out this condensation under microwave irradiation that
was amenable to automation and library production.
R'
R'
CuI
+
R
SH
X
RS
heat
1
2
3
Scheme 1. Cu-catalysed Ullmann condensation of thiols.
F
F
CN Cl
Cl
CuI (10 mol%)
Et3N, dioxane
+
Recently we undertook the synthesis of the p38a inhibitor VX-
SH
microwaves
N
100 °C, 3 h (24%)
745 in order to study its effect on accelerated ageing in Werner
syndrome cells.9 This inhibitor displays potent p38 activity, clinical
efficacy and an exquisite selectivity profile, effective at 5.0 nM con-
centration with 1000-fold selectivity over closely related kinases,
including ERK1, JNK1-3 and MK2. Our synthesis of the (aryl-
thio)pyrimido[1,6-b]pyridazinone core utilised an Ullmann con-
densation of thiol 1a and chloropyridazine 2a to establish the
F
Cl
N
1a
2a
CN Cl
Cl
Cl
Cl
O
N
S
N
N
N
F
ArS
N
3a
VX-745
* Corresponding author. Tel./fax: +44 29 2087 4030.
E-mail addresses: bagleymc@cf.ac.uk, bagleymc@cardiff.ac.uk (M.C. Bagley).
Scheme 2. C–S bond formation in the synthesis of VX-745.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.115

3662
M. C. Bagley et al. / Tetrahedron Letters 50 (2009) 3661–3664
Microwave dielectric heating has received increasing attention
ence of ethylene glycol,7a the copper-catalysed cross-coupling of
aryl bromides and iodides has been reported using microwave
heating under ligand-free conditions using copper nanoparticles11
or with copper(I) iodide and caesium carbonate in NMP (195 °C,
2–6 h),12 but the latter procedure still required high temperatures
and prolonged reaction times. Such precedent appeared to be a
good starting point for our own investigation.
In preliminary studies, 1-iodo-4-nitrobenzene 2b was irradiated
with thiophenol 1b in the presence of 5 mol % CuI and Cs2CO3
(1 equiv) in NMP, according to the method of Wu and He,12 but dis-
appointingly, only unreacted 1b was recovered (Scheme 3). Fur-
thermore, attempts to reproduce catalyst- and ligand-free sealed
tube experiments7e using thiophenol 1b, bromobenzene 2c and
CsOH with microwave dielectric heating either gave sulfide 3c in
very low yield (15%) under inert anhydrous conditions or gener-
ated disulfide 4 when carried out in the presence of air and mois-
ture, presumably as a consequence of reaction with oxygen.
Clearly an effective general procedure was required and so var-
ious ligands were screened (Table 1) in the copper-catalysed reac-
tion of 1-iodo-4-nitrobenzene 2b and thiophenol 1b. It was
apparent that for this electron-deficient halide, the use of a diol li-
gand, similar to the Kwong–Buchwald conditions,7a with catalytic
quantities of CuI gave improved yields of sulfide 3b. Two diamine
in recent years as a valuable alternative to the use of conductive
heating for accelerating transformations, in both synthetic chemis-
try and the biosciences.10 Considering the benefits in evidence for
many transition metal-mediated processes using microwave irra-
diation, it was surprising to find that little effort had been made
to carry out Ullmann-type condensation reactions under these con-
ditions. Following the ground-breaking work by Buchwald and
Kwong on the copper(I)-catalysed coupling of aryl iodides and
thiols using potassium carbonate as base in 2-propanol in the pres-
I
PhS
PhSH 1b, CuI (5 mol%)
NO2
Cs2CO3, NMP
NO2
microwaves, 195 °C, 2 h
2b
3b
CsOH
CsOH
DMSO
DMSO, N2
PhSH 1b
+
microwaves
microwaves
PhS SPh
PhS Ph
120 °C
10 min
100 °C
10 min
PhBr 2c
4 (75%)
3c (15%)
Scheme 3. Preliminary reactions for C–S bond formation.
Table 1
Screening ligands for the Cu-catalysed synthesis of sulfide 3b under microwave irradiation
I
PhS
microwaves
+
PhSH
NO2
NO2
1b
2b
3b
Entry
Catalyst
Liganda
Conditionsb
Yieldc of 3b (%)
1
2
3
4
5
6
7
CuI (5 mol %)
—
—
—
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 Â 1 h
t-BuONa (1.5 equiv), PhMe, microwaves, 100 °C (150 W), 3 Â 1 h
t-BuONa (1.5 equiv), PhMe, microwaves, 80 °C (150 W), 3 Â 1 h
t-BuONa (1.5 equiv), PhMe, microwaves, 100 °C (150 W), 3 Â 1 h
H2O, microwaves, 120 °C (150 W), 2 Â 1 h
63
58
61
60
46
69
82
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (5 mol %)
Neocuproine (10 mol %)
Neocuproine (10 mol %)
Ethylenediamine (4 equiv)
( )-trans-1,2-Diamino-cyclohexane (4 equiv)
Ethylene glycol (2 equiv)
H2O, microwaves, 120 °C (150 W), 2 Â 1 h
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 Â 1 h
a
Indicates no additional ligand was added.
b
Microwaves refer to microwave irradiation in a single-mode CEM DiscoverÒ microwave synthesiser at the given temperature through moderation of the initial microwave
power (150 W).
c
Isolated yield after purification on silica gel.
Table 2
Optimising the reaction conditions for the Cu-catalysed synthesis of sulfide 3d under microwave irradiation
I
PhS
microwaves
+
PhSH
OMe
OMe
1b
2d
3d
Entry
Catalyst
Liganda
Conditionsb
Yieldc of 3d (%)
1
2
3
4
5
6
7
8
9
CuI (5 mol %)
CuI (5 mol %)
CuI (5 mol %)
CuCl (5 mol %)
CuI (5 mol %)
CuI (5 mol %)
CuI (5 mol %)
—
Ethylene glycol (2 equiv)
Ethylene glycol (2 equiv)
Ethylene glycol (2 equiv)
Ethylene glycol (2 equiv)
( )-trans-1,2-Diamino-cyclohexane (8 equiv)
( )-trans-Cyclohexane-1,2-diol (2 equiv)
—
( )-trans-Cyclohexane-1,2-diol (2 equiv)
( )-trans-Cyclohexane-1,2-diol (2 equiv)
( )-trans-Cyclohexane-1,2-diol (5 mol%)
( )-trans-Cyclohexane-1,2-diol (2 equiv)
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 1 h
K2CO3 (2 equiv), 2-propanol, microwaves, 100 °C (150 W), 2 h
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 h
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 h
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 2 h
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 h
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 h
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 h
K2CO3 (1.05 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 h
K2CO3 (2 equiv), 2-propanol, microwaves, 120 °C (150 W), 3 h
K2CO3 (2 equiv), H2O, microwaves, 120 °C (150 W), 3 h
73
77
89
20
65
95
63
d
—
CuI (5 mol %)
CuI (5 mol %)
CuI (5 mol %)
88
70
31
10
11
a
Indicates no additional ligand was added.
b
Microwaves refer to microwave irradiation in a single-mode CEM DiscoverÒ microwave synthesiser at the given temperature through moderation of the initial microwave
power (150 W).
c
Isolated yield after purification on silica gel.
Indicates no 3d was obtained from the reaction and only unreacted thiophenol 1b was isolated.
d

M. C. Bagley et al. / Tetrahedron Letters 50 (2009) 3661–3664
3663
ligands also proved effective in aqueous media, with ( )-trans-1,2-
diaminocyclohexane (4 equiv) giving the highest yield. The use of
neocuproine as ligand was also successful but, for this substrate,
no appreciable improvements over control reactions were ob-
served. Although the addition of ethylene glycol (entry 7) clearly
gave an increase in yield when compared with the ligand-free con-
trol (entry 1), electron-deficient iodide 2b reacted readily in the
presence of strong base without the addition of either catalyst or
ligand (entry 2) and so a more informative test reaction was sought
for optimisation work.
were carried out on 4-iodoanisole 2d (Table 2) for which it was
anticipated catalyst and ligand combinations would have a more
dramatic effect. It was apparent from the reactions of this elec-
tron-rich iodide 2d with thiophenol 1b, in equimolar ratios, that:
(i) CuI was a much more effective catalyst than CuCl (entry 3 vs en-
try 4); (ii) a high reaction temperature (120 °C) and longer reaction
times gave improved yields (entry 3 vs entry 1); (iii) although eth-
ylene glycol and trans-1,2-diaminocyclohexane were effective as
ligands, ( )-trans-cyclohexane-1,2-diol was superior (entry 6);
(iv) 2-propanol was a better solvent than H2O (entry 6 vs entry
11); (v) using 2 equiv of both base and ligand gave higher yields
of product (entry 3 vs entries 9 and 10). The optimised procedure13
In view of the success of the ligand- and catalyst-free proce-
dures in the reaction of electron-deficient halide 2b, further studies
Table 3
Scope of the microwave-assisted reaction using CuI (5 mol %), ( )-trans-cyclohexane-1,2-diol (2 equiv) and K2CO3 (2 equiv) in 2-propanola
Entry
1
Thiol 1
Halide 2
Sulfide 3
Yieldb (%)
86
1b
1b
1b
1b
1b
1b
1b
1b
2e
2c
2f
3c
3c
3c
3d
3d
3e
3f
SH
SH
SH
SH
SH
SH
SH
SH
I
S
S
S
2
3
4
5
6
7
8
32
Br
Cl
c
—
OMe
OMe
OMe
2d
2g
2h
2i
95
16
91
73
85
I
S
OMe
Br
I
S
S
N
N
I
I
OMe
S
S
OMe
2j
3g
F
F
OMe
OMe
9
10
11
1a
2d
2k
2l
3h
3i
3i
3j
78
94
82
50
SH
S
I
F
F
Br
I
PhS
PhS
1bd
1bd
1c
SH
SH
SH
I
I
PhS
PhS
OMe
OMe
12
2d
I
S
a
Reaction was carried out under microwave irradiation at 120 °C in a sealed tube for 3 h using a CEM DiscoverÒ microwave synthesiser by moderating the initial
microwave power (150 W).
b
Isolated yield after purification on silica gel.
Only unreacted starting materials were recovered from the reaction.
Two equivalents of thiophenol 1b were used.
c
d

3664
M. C. Bagley et al. / Tetrahedron Letters 50 (2009) 3661–3664
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(entry 6) employed CuI (5 mol %), ( )-trans-cyclohexane-1,2-diol
(2 equiv) and K2CO3 (2 equiv) in 2-propanol at 120 °C for 3 h and
gave sulfide 3d in excellent yield (95%), as identified by both spec-
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conditions in the absence of the ligand gave a much lower yield
(entry 7, 63%), and in the absence of the catalyst, did not give
any product at all (entry 8), clearly demonstrating the benefit of
these new conditions.
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aryl halides were reacted in turn with a selection of thiols (Table
3). In general, the reaction gave very good yields and was highly
successful for iodides and specific bromides. An alkyl thiol was
used as an alternative to aryl thiols, with some reduction in effi-
ciency. Furthermore, the simultaneous formation of two C–S bonds
proceeded in excellent yield using dihalobenzene substrates.
In conclusion, microwave irradiation of aryl iodides, or in some
cases the analogous bromide, and a thiol in the presence of cata-
lytic CuI, a cyclohexanediol ligand and base in 2-propanol gives
the corresponding sulfide rapidly and efficiently under microwave
irradiation. This method should be amenable to library synthesis
and applicable for the synthesis of a range of sulfur-containing
targets.
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Acknowledgements
13. In the optimised experimental procedure,
a
solution of 4-iodoanisole 2d
mol),
(117 mg, 0.5 mmol), PhSH 1b (55 mg, 0.05 mL, 0.5 mmol), CuI (5 mg, 25
l
We thank the EPSRC (GR/S25456 and DTA to V.F.), BBSRC (BB/
D524140), and SPARC (award to M.C.B.) for their generous support
of this work, Dr. Rob Jenkins for technical assistance and the EPSRC
Mass Spectrometry Service at the University of Wales, Swansea UK
for mass spectra.
( )-trans-cyclohexane-1,2-diol (116 mg, 1.0 mmol), K2CO3 (138 mg, 1.0 mmol)
in 2-propanol (2 mL) was irradiated at 120 °C for 3 Â 1 h in a pressure-rated
glass tube (10 mL) using
a
CEM DiscoverÒ microwave synthesiser by
moderating the initial power (150 W). After cooling in a flow of compressed
air, the reaction mixture was filtered and evaporated in vacuo. Purification by
column chromatography on silica gel, eluting with hexane–CH2Cl2 (3:1), gave
sulfide 3d (103 mg, 95%) as a yellow oil (found: M+, 216.0607. C13H12OS [M]
requires 216.0609); 1H NMR (400 MHz, DMSO-d6) d 7.42 (2H, m), 7.30 (2H, m),
7.18 (1H, m), 7.13-7.11 (2H, m), 7.01 (2H, m), 3.78 (3H, s); 13C NMR (125 MHz;
DMSO-d6) 159.7 (C), 137.8 (C), 135.3 (CH), 129.2 (CH), 127.7 (CH), 126.0 (C),
123.0 (CH), 115.4 (CH), 55.3 (Me); MS (EI) m/z (rel. intensity) 216 (M+, 100%),
201 (55).
References and notes
1. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384; (b) Ullmann, F. Ber.
Dtsch. Chem. Ges. 1904, 37, 853–857; (c) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906,
39, 1691–1696.