Iron-catalyzed thioetherification of thiols with aryl iodides

Article abstract of DOI:10.1039/b907362k

FeCl₃ in combination with bisphosphine ligands represents an efficient catalyst system for the cross-coupling of aryl- and alkyl thiols with aryl iodides, a broad spectrum of functional groups can be tolerated during the catalysis. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b907362k

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Iron-catalyzed thioetherification of thiols with aryl iodidesw
Jhih-Ru Wu, Che-Hung Lin and Chin-Fa Lee*
Received (in Cambridge, UK) 15th April 2009, Accepted 26th May 2009
First published as an Advance Article on the web 12th June 2009
DOI: 10.1039/b907362k
3
FeCl in combination with bisphosphine ligands represents an
efficient catalyst system for the cross-coupling of aryl- and alkyl
thiols with aryl iodides, a broad spectrum of functional groups
can be tolerated during the catalysis.
The transition-metal-catalyzed cross-coupling reaction is
arguably one of the most powerful strategies for constructing
1
carbon–carbon and carbon–heteroatom bonds.
approach has been widely utilized in organic synthesis and
This
2
materials science.
Aryl thioethers are important skeletons for many biologically
3
active compounds. Palladium,
4–8
9
10
nickel, cobalt, copper,
11
12
13
indium and iron are known to serve as the metal sources in
combination with appropriate ligands for the synthesis of aryl
thioethers. Phosphines are a principal class of ligand for
Fig. 1 Structures of the ligands L1–L5.
14
only works with aryl thiols and is completely ineffective for
alkyl thiols. Thus, it is highly desirable to develop a new
system to overcome this limitation. Herein we report the
combination of FeCl3 with bisphosphines that successfully
catalyzes coupling of aryl- and alkyl thiols with aryl iodides
in good to excellent yields.
transition-metal-catalyzed reactions. Monophosphines were
reported as a ligand for the first palladium-catalyzed S-arylation
4
of thiols with aryl halides by Migita et al. in 1980. Recent studies
suggested that bisphophines are more reactive than mono-
5
phosphines for these reactions. Josiphos ligand (1-dicyclohexyl-
5
phosphino-2-di-tert-butylphosphinoethylferrocene, L1), BINAP
0
0
Initially, iodobenzene and thiophenol were selected as
substrates to screen the optimized conditions. The results are
summarized in Table 1. Various bisphosphines were examined.
L1 shows good activity with a 91% isolated yield (entry 1).
(
2,2 -bis(diphenylphosphino)-1,1 -binaphthyl, L2), (R)-Tol-BINAP
6
0
0
[
Xantphos (9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene,
(R)-(+)-2,2 -bis(di-p-tolylphosphino)-1,1 -binaphthyl, L3],
7
8
L4) and DPEphos [bis(2-diphenylphosphinophenyl)ether, L5]
have been investigated in palladium-catalyzed S-arylation of
thiols with aryl halides (Fig. 1). Bisphospines were also utilized
in nickel- and cobalt-catalyzed carbon–sulfur bond
Table 1 Oaptimization of iron-catalyzed coupling of iodobenzene with
thiophenol
9
,10
formation.
Although many metals catalysts have been
explored, it is still desirable to develop an alternative strategy
which uses cheaper and environmentally friendly metals.
Cleaner and cheaper alternatives are especially valuable to
the pharmaceutical industry.
Recently iron has been considered as an ideal choice not
only because of its lower toxicity and cost compared to other
metals but also because it possesses some unusual properties
Entry
[Fe]
Ligand
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
10
FeCl
FeCl
FeCl3
FeCl
FeCl
FeCl
FeCl
FeCl
3
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
L2
L2
L2
—
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Dioxane
DME
Toluene
Toluene
Toluene
91
99
99
97
29
98
—
—
—
33
76
38
63
3
1
5,16
which have been utilized in many transformations.
1
Iron-
7
18
19
catalyzed C–C, C–N and C–O bond forming reactions
have recently been developed. Despite the fact that iron was
3
3
3
3
3
2
known to promote the formation of disulfides, Bolm et al.
0
K
K
2
CO
PO
3
reported that the first iron-catalyzed S-arylation of aryl thiols
0
3
4
FeCl3
2 3
Cs CO
with aryl iodides uses FeCl
3
–N,N -dimethylethylenediamine as
1
the catalyst. However, this approach is limited as this system
3
FeCl
FeCl
FeCl
3
3
3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
11
12
13
14
15
FeF
Fe
FeCl
3
b
2
O
3
79
—
Department of Chemistry, National Chung Hsing University,
Taichung, Taiwan 402, ROC. E-mail: cfalee@dragon.nchu.edu.tw;
Fax: +886 4 2286-2547; Tel: +886 4 2284-0411 ext. 810
w Electronic supplementary information (ESI) available: Experi-
mental procedures and NMR spectra for all compounds. See
DOI: 10.1039/b907362k
3
a
Reaction conditions: iron source (0.05 mmol, 10 mol%), ligand
0.05 mmol, 10 mol%), iodobenzene (0.75 mmol), thiophenol
(
(
b
2 3
0.5 mmol), base (1.0 mmol) in 0.5 mL solvent. Fe O (0.025 mmol).
4
450 | Chem. Commun., 2009, 4450–4452
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This ligand has demonstrated the greatest efficacy in palladium-
catalyzed cross-coupling reactions of aryl halides and pseudo-
coupling with aryl thiols with good to excellent yields. It is
important to note that functional groups such as chloro-
(entries 1 and 9), free alcohol (entry 2), nitro- (entry 3),
enolizable ketone (entry 8), bromo- (entry 10), unprotected
amine (entry 11) and ester (entry 12) are all tolerated during
the catalysis. Interestingly, when iodobenzene was coupled
with 4-methoxythiophenol, 3e resulted in an 83% yield
(entry 4). The same compound was obtained in trace amounts
by reacting electronically deactivated 4-iodoanisole with
thiophenol under the same conditions. However, this can be
dramatically improved by employing L4 as ligand (entry 5). It
implies that L4 is more active than L2 for this process.
5
halides with thiols. However, we felt that the high cost of L1
might limit its practical application. This positive result
encouraged us to screen other cheaper and structurally simpler
bisphosphines L2–L5. Surprisingly, L2, L3 and L4 also
showed excellent activity, even better than L1 (entries 2, 3
and 4). L5 was previously used to couple aryl thiols with aryl
8
iodides in the presence of palladium. However, it could not
provide a satisfactory result (entry 5). After screening bases
and solvents (DMF = N,N-dimethylformamide; dioxane =
1
,4-dioxacyclohexane; DME = dimethoxyethane), weak bases
such as K CO , K PO and Cs CO did not show good results
entries 7–9); NaOtBu and KOtBu were equally active for this
2
3
3
4
2
3
Next we turned our attention to developing the coupling
protocol for alkyl thiols. Unfortunately, when 1-dodecanethiol
and iodobenzene were employed under the optimized
conditions for aryl thiols (using ligands L1 and L2) poor
yields were observed (Table 3, entries 1 and 2, respectively).
L3 is more electron rich than L2 and this modification resulted
in a slightly higher yield. L4 shows better results than L2 but is
still not sufficient (entry 4). After screening other parameters,
including bases (entries 5–8) and solvents (entries 9–11),
KOtBu and dioxane were found to be the best base and
(
5
transformation. Toluene was found to be superior to other
solvents (entries 10–12). The moisture stable Fe O was also
2
3
active with a 79% yield (entry 14). When the reaction was
carried out in the absence of a ligand, disulfide was detected as
the sole product (entry 15).
Using the previous optimizations, Table 2 summarizes the
results of the iron-catalyzed S-arylation. A broad range of
aryl iodides were tested. Electron-donating and electron-
withdrawing aryl iodides all served as suitable partners for
3
solvent; in combination with FeCl –L4 the product was
obtained with a 98% yield (entry 11). A lower yield was
observed when the reaction was carried out at 110 1C; in this
trial disulfide was determined as the major product by GC-MS
analysis (entry 12). Fe O shows lower activity than FeCl3
a
Table 2 Iron-catalyzed S-arylation of aryl iodides with aryl thiols
2
3
with a product yield of 24% (entry 13). Unsatisfactory results
were also observed when the reaction was performed in the
absence of a ligand (entry 14).
Yield
(%)
Yield
(%)
Entry Product
1
Entry Product
7
In order to test the scope of S-arylation using alkyl thiols,
we utilized a wide array of aryl iodides, and the results are
summarized in Table 4. Both long chain alkyl thiols, and
sterically hindered thiols can be employed. For example, both
b
91
91
85
77
83
b
95
Table 3 Evaluation of iron-catalyzed coupling reaction of iodo-
benzene with 1-dodecanethiol
2
3
4
5
8
a
b
77
9
Entry
[Fe]
Ligand
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
3
3
3
3
3
3
3
3
3
3
3
3
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
—
NaOtBu
NaOtBu
NaOtBu
NaOtBu
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
21
33
41
50
62
14
64
70
71
34
98
b
87
10
11
12
K
K
Cs
2
CO
PO
CO
3
b
93
b
92
3
4
2
3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
10
11
12
13
14
DME
Dioxane
Dioxane
Dioxane
Dioxane
b
94
bc
72
6
b
7
24
16
c
Fe
FeCl
2
O
3
3
a
a
Reaction conditions unless otherwise stated: FeCl
0 mol%), L2 (0.1 mmol, 10 mol%), aryl iodide (1.5 mmol), aryl thiol
3
(0.1 mmol,
Reaction conditions: iron source (0.05 mmol, 10 mol%), ligand
(0.05 mmol, 10 mol%), iodobenzene (0.75 mmol), 1-dodecanethiol
1
b
1.0 mmol), NaOtBu (2.0 mmol) in toluene (1.0 mL). L4 was used.
KOtBu was used.
b
c
(
c
(0.5 mmol), base (1.0 mmol) in 0.5 mL solvent. 110 1C. Fe O
(0.025 mmol).
2
3
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a
Table 4 Iron-catalyzed S-arylation of aryl iodides with alkyl thiols
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97
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a
Reaction conditions unless otherwise stated: FeCl
0 mol%), L4 (0.1 mmol, 10 mol%), aryl iodide (1.5 mmol), alkyl
3
(0.1 mmol,
4
1
1
4 J. Tsuji, Palladium Reagents and Catalysis: Innovation in Organic
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1
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3
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In conclusion, we have demonstrated that the combination
3
of FeCl with bisphosphines L2 or L4 proves to be an efficient
catalytic system for S-arylation of aryl- and alkyl thiols with
aryl iodides. To the best of our knowledge, this is the first
example of iron-catalyzed S-arylation of alkyl thiols with aryl
halides. Understanding the origins of this novel system and
applications to other cross-coupling reactions are in progress
in our laboratory.
1
7 T. Hatakeyama and M. Nakamura, J. Am. Chem. Soc., 2007, 129,
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9
Financial support by the National Science Council, Taiwan
NSC 97-2113-M-005-006-MY2) and the National Chung
(
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Hsing University are gratefully acknowledged. We thank
Prof. Fung-E Hong for generously sharing his GC-MS
instruments.
1
9 O. Bistri, A. Correa and C. Bolm, Angew. Chem., Int. Ed., 2008, 47,
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5
4
452 | Chem. Commun., 2009, 4450–4452
This journal is ꢀc The Royal Society of Chemistry 2009