CuI-catalyzed coupling reactions of aryl iodides and bromides with thiols promoted by amino acid ligands

Article abstract of DOI:10.1055/s-2004-825584

Novel mild conditions for the CuI-catalyzed coupling reactions of aryl iodides and bromides with aliphatic and aromatic thiols using amino acids as the ligand are reported.

Full text of DOI:10.1055/s-2004-825584

1254
LETTER
CuI-Catalyzed Coupling Reactions of Aryl Iodides and Bromides with Thiols
Promoted by Amino Acid Ligands
C
uI-Catalyzed Coupling
e
Reactions
i
of
A
ryl Iodid
D
es and Bromides eng, Yan Zou, Ye-Feng Wang, Lei Liu,* Qing-Xiang Guo*
Deparment of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China
E-mail: leiliu@chem.columbia.edu; E-mail: qxguo@ustc.edu.cn
Received 1 March 2004
As to Cu(I)-catalyzed coupling reactions, Ma et al. report-
Abstract: Novel mild conditions for the CuI-catalyzed coupling
reactions of aryl iodides and bromides with aliphatic and aromatic
thiols using amino acids as the ligand are reported.
ed that amino acids could accelerate the Cu-catalyzed
coupling reactions between aryl halides and themselves.10
They found very recently that amino acids could also
serve as ligands for the coupling reactions of other nucleo-
philes including amines and phenols.11 At the same time
we reported that amino acids could promote the CuI-cata-
lyzed amidation reactions.12 Herein, we report novel, mild
conditions for the CuI-catalyzed coupling reactions of
aryl iodides and bromides with thiols using amino acids as
the ligand.
Key words: copper iodide, aryl sulfide, cross-coupling, amino acid
ligand
Transition-metal mediated C(aryl)-sulfur bond formation
is an important reaction in synthetic organic chemistry be-
cause aryl sulfides and their sulfone derivatives are of
great significance to the pharmaceutical industry.1 How-
ever, only a few studies have been reported so far for the
formation of aryl-sulfur bonds using either Pd or Ni cata-
lysts.2,3 Alternatively, one can use Cu catalysts to mediate
the C–S bond formation. This approach is attractive from
an industrial perspective because Cu is much less expen-
sive and toxic than Pd and Ni.4
In the first stage of the study we focused on the coupling
between thiophenol and iodobenzene. A variety of experi-
mental conditions were examined (see Table 1). The
Table 1 CuI-Catalyzed Coupling Reaction of Thiophenol and Iodo-
benzene under Various Conditionsa
The traditional Cu-mediated couplings between thiols and
aryl halides require the use of copper salts in greater than
stoichiometric amounts, polar solvents such as HMPA,
and high temperatures around 200 °C.5 Recently, Venkat-
araman et al. reported an improved protocol for the cou-
pling between aryl iodides and thiols using 10 mol% CuI
and 10 mol% neocuproine, with NaOt-Bu as the base, in
toluene at 110 °C.6 Buchwald et al. also reported an effi-
cient Cu-catalyzed C–S coupling reaction between aryl
iodides and thiols using 5 mol% CuI and 2 equivalents of
HOCH2CH2OH as ligand.7 Wu and He then reported that
microwave heating could enhance the CuI-catalyzed C-S
couplings.8 Naus et al. successfully utilized the CuI cata-
lyst for the arylation of 1-thiosugars.9
S
Conditions
HS
I
+
Entry
1
Base
K3PO4
Ligand
Solventb
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
Yield (%)c
N-methyl glycine
79
76
<5
96
19
87
95
67
90
66
90
75
77
2
K2CO3 N-methyl glycine
3
NaH
N-methyl glycine
N-methyl glycine
N-methyl glycine
N-methyl glycine
N-methyl glycine
N-methyl glycine
N-methyl glycine
Glycine
4
KOH
CaO
5
6
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
We were interested in finding more and better catalyst-
ligand systems for the Cu-catalyzed C-S coupling reac-
tions. We were also interested in using aryl bromides,
which are less expensive but also less reactive than aryl
iodides, as the reactant for the coupling reactions. Thus
we paid attention to a special group of ligand, i.e. amino
acids. Any coupling reactions that can use amino acids as
ligand would be very interesting because of the following
reasons: (1) the amino acid ligand is inexpensive, conve-
niently available, and environmentally benign; and (2)
there are a large number of different amino acids that can
be tried.
7
8
THF
9
Toluene
Dioxane
10
11
12
13
N,N-dimethyl glycine Dioxane
a-alanine
b-alanine
Dioxane
Dioxane
a General conditions: 5 mol% CuI, 20 mol% ligand, 10 mL solvent,
5 mmol Ph-I, 6 mmol PhSH, 12.5 mmol KOH, reaction time = 24 h.
b Reaction temperature: 100 °C for dioxane, 120 °C for DMF, and
70 °C for THF.
SYNLETT 2004, No. 7, pp 1254–1258
0
3.
0
6.
2
0
0
4
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-825584; Art ID: S02004ST
© Georg Thieme Verlag Stuttgart · New York
c Isolated yield.

LETTER
CuI-Catalyzed Coupling Reactions of Aryl Iodides and Bromides
1255
highest yield (96%) was obtained when we used 5 mol% pling. The reaction also proceeds well with aryl iodides
CuI as the catalyst, 20 mol% N-methyl glycine as the carrying either electron-donating (e.g. OCH3) or electron-
ligand, KOH as the base, and dioxane as the solvent. withdrawing groups (e.g. COCH3). The yields are mostly
Other bases, including K3PO4, K2CO3, NaH, CaO, and 90–98%, except for 2-nitrophenol iodide. For this partic-
NaOH, provided lower yields. Dioxane was found to be ular case, reduction of the NO2 group was observed.
the best solvent, as DMF, THF, and toluene caused lower
The above procedure is clearly successful for the coupling
yields. Furthermore, using glycine as the ligand gave a
reaction between aryl iodides and thiols. However, using
yield of 66%. Using a- and b-alanine gave yields around
the same procedure for aryl bromide we obtained less than
5% yield (see Table 3). Thus different reaction conditions
should be optimized for aryl bromide. For this purpose we
increased the amount of CuI to 20 mol% but the yield was
75%. Using N,N-dimethyl glycine gave a yield of 90%.
Thus, N-methyl glycine was concluded to be the optimum
amino acid type ligand for aryl thiolation.
Using the CuI/N-methyl glycine/KOH/dioxane procedure only 9%. We also increased the reaction time to 48 hours
we studied the C-S coupling reactions between a number but the yield was only 12%.
of thiols and aryl iodides (see Table 2). It is found that
both aliphatic and aromatic thiols can be used in the cou-
Table 2 CuI-Catalyzed Coupling Reactions of Thiols and Aryl Iodidesa
Entry
1
Thiols
Aryl Iodide
Product
Yield (%)b
96
S
SH
SH
I
2
3
4
5
91
95
90
70
S
S
S
I
CH3
H3C
I
SH
SH
SH
OCH3
COCH3
H3CO
I
H3COC
I
NO2
S
S
NO2
6
7
92
97
I
SH
Br
Br
SH
SH
SH
SH
SH
I
S
S
H3C
H3C
H3C
H3C
H3C
H3C
H3C
8
9
90
93
86
68
I
CH3
H3C
I
S
S
H3C
H3C
OCH3
H3CO
10
11
I
COCH3
H3COC
I
NO2
S
S
NO2
H3C
H3C
12
90
SH
I
Br
H3C
Br
Synlett 2004, No. 7, 1254–1258 © Thieme Stuttgart · New York

1256
W. Deng et al.
LETTER
Table 2 CuI-Catalyzed Coupling Reactions of Thiols and Aryl Iodidesa (continued)
Entry
13
Thiols
Aryl Iodide
Product
Yield (%)b
SH
SH
SH
SH
SH
S
S
98
I
Cl
Cl
Cl
Cl
Cl
Cl
Cl
14
15
16
17
88
I
CH3m
OCH3
H3C
96
83
33
I
S
S
Cl
Cl
H3CO
I
COCH3
H3COC
I
NO2
S
S
NO2
Cl
Cl
18
98
I
SH
Br
Br
Cl
19
20
89
93
I
C8H17
S
S
C8H17SHm
I
C8H17
C8H17SHm
C8H17SHm
C8H17SHm
C8H17SHm
C8H17SHm
CH3
H3C
21
22
23
24
90
90
<5
92
I
C8H17S
OCH3
H3CO
I
C8H17
S
COCH3m
H3COC
I
C8H17
S
O2N
C8H17
NO2m
I
S
Br
Br
a General conditions: 5 mol% CuI, 20 mol% N-methyl glycine, 10 mL dioxane, 5 mmol aryl iodide, 6 mmol thiol, 12.5 mmol KOH, reaction
time = 24 h, reaction temperature = 100 °C.
b Isolated yield.
A dramatic increase of the yield to 51% was observed zene can participate in the C-S coupling reaction in a one-
when DMF was used as the solvent instead of dioxane. It pot fashion. Moreover, the chloro group in 4-chloro-ben-
was also discovered that change of N-methyl glycine to zenethiol does not show any significant coupling. There-
N,N-dimethyl glycine could increase the yield from 59% fore, the present condition is not sufficient for the C-S
to 75%. As it was observed that some DMF decomposed coupling reactions using aryl chlorides as reactants.
in the presence KOH at 120 °C, we changed the base to
At present the mechanism of the Cu-catalyzed coupling
K3PO4. The yield under this condition is 85%, which is
reaction is not completely clear.13 Nonetheless, the results
sufficiently good for synthetic applications.
from the present study are consistent with the mechanism
Using the CuI/N,N-dimethyl glycine/K3PO4/DMF proce- in which a four-coordinated Cu(III) intermediate is in-
dure we studied the C-S coupling reactions between a volved (See Scheme 1).13 According to the mechanism,
number of thiols and aryl bromides (see Table 4). The the role of the amino acid ligand in the reaction is either to
yields are around 72–85%, which are good enough for promote the oxidative addition of ArX to the Cu(I) species
many synthetic applications. It is interesting to note that or to stabilize the Cu(III) intermediate.
both the bromo and iodo groups in 1-bromo-4-iodo-ben-
Synlett 2004, No. 7, 1254–1258 © Thieme Stuttgart · New York

LETTER
CuI-Catalyzed Coupling Reactions of Aryl Iodides and Bromides
1257
Table 3 CuI-Catalyzed Coupling Reaction of Thiophenol and Bromobenzene under Various Conditionsa
S
Conditions
HS
Br
+
Entry
CuI (%)
Base
Ligand
Solventb
Dioxane
Dioxane
Dioxane
DMF
Time (h)
24
Yield (%)c
1
2
3
4
5
6
7
8
5
5
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K3PO4
N-methyl glycine
N-methyl glycine
N-methyl glycine
N-methyl glycine
N-methyl glycine
N,N-dimethyl glycine
N,N-dimethyl glycine
N,N-dimethyl glycine
<5
12
9
48
20
5
24
24
51
59
69
75
85
20
5
DMF
48
DMF
48
20
20
DMF
48
DMF
48
a General conditions: 20 mol% ligand, 10 mL solvent, 5 mmol Ph-Br, 6 mmol PhSH, 12.5 mmol base.
b Reaction temperature is 100 °C for dioxane and 120 °C for DMF.
c Isolated yield.
X–
Acknowledgment
H-SR Base
+
We thank CAS, MOST and NSFC (No. 20332020) for financial
support.
R2
O
R2
O
O
R1 NH
(III)Cu
Ar
O
References
R1 NH
Ar
SR
(III)Cu
(1) (a) Arguello, J. E.; Schmidt, L. C.; Penenory, A. B. Org.
Lett. 2003, 5, 4133. (b) Zhang, X.-M.; Ma, M.; Wang, J.-B.
Chin. J. Chem. 2003, 21, 878. (c) Yao, H.; Richardson, D.
E. J. Am. Chem. Soc. 2003, 125, 6211. (d) Savarin, C.;
Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309.
(e) Nose, M.; Suzuki, H. Synthesis 2002, 1065.
(2) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205.
(3) (a) Moreau, X.; Campagne, J.-M. J. Organomet. Chem.
2003, 687, 322. (b) Wolf, C.; Lerebours, R. J. Org. Chem.
2003, 68, 7077. (c) Baskin, J. M.; Wang, Z. Org. Lett. 2002,
4, 4423. (d) Li, G. Y. J. Org. Chem. 2002, 67, 3643.
(e) Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57,
3069.
(4) Very recent reviews: (a) Kunz, K.; Scholz, U.; Ganzer, D.
Synlett 2003, 2438. (b) Ley, S. V.; Thomas, A. W. Angew.
Chem. Int. Ed. 2003, 42, 5400. (c) Deng, W.; Liu, L.; Guo,
Q.-X. Chin. J. Org. Chem. 2004, 24, 150.
(5) Lindley, J. Tetrahedron 1984, 40, 1433.
(6) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett.
2002, 4, 2803.
X
R2
O
O
R1 NH
Ar-X
Ar-SR
(I)Cu
Scheme 1
To summarize, novel mild conditions have been found for
the CuI-catalyzed coupling reactions of aryl iodides and
bromides with aliphatic and aromatic thiols with amino
acids as the ligand. The coupling yields are 90–98% for
aryl iodides and 72–85% for aryl bromides. We are work-
ing now on the Cu-catalyzed coupling reactions using aryl
chlorides as reactants. Another challenge is how to use
less expensive copper salts such as Cu2O in the reaction.
(7) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(8) Wu, Y.-J.; He, H. Synlett 2003, 1789.
(9) Naus, P.; Leseticky, L.; Smrcek, S.; Tislerova, I.; Sticha, M.
Synlett 2003, 2117.
(10) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459. (b) Ma, D.; Xia, C. Org. Lett. 2001,
3, 2583.
(11) (a) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
(b) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799. (c) Ma, D.;
Cai, Q. Synlett 2004, 128. (d) Zhu, W.; Ma, D. Chem.
Commun. 2004, 888.
(12) Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2004, 45, 2311.
Representative Procedure
An oven-dried three-neck flask was charged with CuI (0.25 mmol,
5.0 mol%), benzenethiol (6.0 mmol), N-methyl glycine (1.0 mmol,
20 mol%) and KOH (12.5 mmol), evacuated and backfilled with ni-
trogen. Aryl iodide (5.0 mmol) and dioxane (10.0 mL) were added
under nitrogen. The reaction mixture was refluxed for 24 h. The re-
sulting suspension was cooled to r.t. and filtered through a 2–3 cm
pad of silica gel eluting with 100 mL of EtOAc. The filtrate was
concentrated and the residue was purified by chromatography to af-
ford pure product.14,15
Synlett 2004, No. 7, 1254–1258 © Thieme Stuttgart · New York

1258
W. Deng et al.
LETTER
Table 4 CuI-Catalyzed Coupling Reactions of Thiols and Aryl Bromidesa
Entry
1
Thiols
Aryl Bromide
Product
Yield (%)b
85
S
SH
SH
Br
2
80
S
Br
I
3
4
85
76
S
SH
S
Br
Br
SH
SH
S
H3C
H3C
H3C
5
6
78
72
CH3
Br
I
S
SH
CH3
S
H3C
Br
H3
Cl
C
S
7
8
80
75
SH
Br
S
Cl
Cl
SH
SH
Cl
Br
I
S
9
80
Cl
S
Br
Cl
Cl
S
10
11
82
76
C8H17SH
Br
C8H17S
C8H17SH
SC8H17
Br
12
84
C8H17SH
C8H17
S
I
SC8H17
Br
a General conditions: 20 mol% CuI, 20 mol% N,N-dimethyl glycine, 10 mL DMF, 5 mmol aryl bromide, 6 mmol thiol (or 12 mmol for 1-bromo-
4-iodobenzene), 12.5 mmol K3PO4 (or 25 mmol for 1-bromo-4-iodobenzene), reaction time = 48 h, 120 °C.
b Isolated yield.
(13) (a) Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748.
(b) See ref. 1d.
(14) All the products are known compounds except for 1,4-
bis(octylthio)benzene.
(15) 1,4-Bis(octylthio)benzene: White solid. IR: 2954, 2921,
1465, 1113, 803 cm–1. 1H NMR (CDCl3, 300 MHz): d = 7.23
(s, 4 H), 2.88 (t, J = 7.3 Hz, 4 H), 1.63 (m, J = 6.8 Hz, 4 H),
1.40–1.26 (br m, 20 H), 0.88 (t, J = 6.4 Hz, 6 H). 13C NMR
(300 MHz, CDCl3): d = 134.6, 129.8, 34.2, 32.0, 29.32,
29.29, 29.0, 22.8, 14.2. MS (EI): m/z (relative intensity): 366
(100), 254 (25), 142 (35). Anal. Calcd for C22H38S2: C,
72.06; H, 10.46. Found: C, 72.20; H, 10.58.
Synlett 2004, No. 7, 1254–1258 © Thieme Stuttgart · New York