Iron-catalyzed S-arylation of thiols with aryl iodides

Article abstract of DOI:10.1002/anie.200705668

(Chemical Equation Presented) Strike while the iron is hot: An efficient iron-catalyzed protocol for the S-arylation of aromatic and heteroaromatic thiol derivatives has been developed, which involves an inexpensive catalyst system formed by combining FeCl₃ and N,N′-dimethylethylenediamine at 135°C. This method avoids the use of expensive and/or air-sensitive ligands and provides in most cases the desired sulfide in high yields.

Full text of DOI:10.1002/anie.200705668

Communications
DOI: 10.1002/anie.200705668
Cross-Coupling Reactions
Iron-Catalyzed S-Arylation of Thiols with Aryl Iodides**
Arkaitz Correa, Mónica Carril, and Carsten Bolm*
Transition-metal-catalyzed cross-coupling reactions of aryl
halides with nitrogen, oxygen, and sulfur nucleophiles are
Table 1: Fe-catalyzed S-arylation of thiophenol (1) with phenyl iodide
(2).[a]
À
À
À
powerful tools for the formation of C N, C O, and C S
bonds, respectively.[1] Although several palladium, nickel, and
copper catalysts have proven to be highly effective in such
coupling processes,[2] the development of new and cheap
alternative catalysts for the aforementioned transformations
is still desirable.
Entry Fe source
Ligand[b] Base
DMEDA K3PO4
Solvent Yield of 3a [%][c]
1
2
3
4
5
6
7
8
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
Fe(ClO4)2
toluene 61
Among the various cross-coupling types, S-arylation is
TMHD
Cs2CO3
DMF
28
comparatively less studied.[3] Two factors make this process
DMEDA Cs2CO3
DMEDA NaOH
DMEDA K2CO3
DMEDA Na2CO3
DMEDA NaOAc
DMEDA KOtBu
DMEDA NaOtBu toluene 91
DMEDA NaOtBu toluene 75[d]
DMEDA NaOtBu toluene trace
toluene trace
toluene trace
toluene 51
toluene trace
toluene trace
toluene trace
À
difficult: First, thiols are prone to undergo oxidative S S
coupling reactions, which result in the undesired formation of
disulfides, and second, organic sulfur compounds can be
effective metal binders, which leads to catalyst modification
(or deactivation).[4] However, given the prevalence of C S
À
9
bonds in a wide range of pharmaceutically active compounds
and polymeric materials,[5] it is desirable to find novel
catalytic procedures that provide efficient access to such
highly useful organic products. In this regard we envisaged the
application of readily available, inexpensive, and environ-
mentally friendly iron salts.[6] A particular challenge was seen
in the required suppression of the known ability of iron to
effect disulfide formation.[7]
10
11
12
13
14
15
[Fe(acac)2] DMEDA NaOtBu toluene trace
Fe
DMEDA NaOtBu toluene trace
FeCl3
FeCl3
DMEDA NaOtBu toluene trace[e]
none
NaOtBu toluene
0
[a] Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), [Fe] (0.1 equiv),
ligand (0.2 equiv), base (2.0 equiv), solvent (1 mLmmolÀ1 of 1), 1358C,
24 h. [b] DMEDA=N,N’-dimethylethylenediamine; TMHD=2,2,6,6-
tetramethyl-3,5-heptadione. [c] Yield of isolated product after flash
chromatography. [d] Use of 5 mol% of FeCl3 and 10 mol% of DMEDA.
[e] Phenyl disulfide was used as the substrate instead of thiophenol (1).
acac=acetylacetonate.
À
Iron-catalyzed C C coupling reactions have recently
emerged as appealing synthetic methods, since easy-to-
handle catalysts can be applied.[8] As part of our ongoing
efforts devoted to the development of novel iron-catalyzed
processes,[9] we introduced ligand-assisted FeCl3-catalyzed
N- and O-arylation reactions.[10,11] To our delight, we have
now found that these iron-based catalysts can also be applied
to arylations of sulfur nucleophiles. Thus, this novel and
Conversely, the conditions for the iron-catalyzed O-aryla-
tion[11] proved rather ineffective, and 3a was obtained in very
low yield (Table 1, entry 2). Moreover, the control experi-
ment of the latter reaction in the absence of catalyst showed
that under those conditions the product could also result from
a classical aromatic nucleophilic substitution reaction.
À
experimentally simple iron-catalyzed C S bond-forming
process provides ready access to valuable aryl sulfides.
Initially, the coupling of thiophenol (1) and phenyl iodide
(2) was selected as a model system to optimize the reaction
conditions. As shown in Table 1, the best conditions for the
iron-catalyzed N-arylation[10a] provided promising results, and
afforded thioether 3a in 61% yield (Table 1, entry 1).
Further experiments revealed a significant dependence of
the S-arylation of 1 with 2 on the nature of the base. Thus,
whereas K3PO4, K2CO3, and NaOtBu provided the arylated
compound in moderate to excellent yield (Table 1, entries 1,
5, and 9), other bases such as Na2CO3, Cs2CO3, NaOH,
NaOAc, and KOtBu only gave trace amounts of 3a (Table 1,
entries 3, 4, and 6–8). It is noteworthy that in all the reactions
the undesired phenyl disulfide, which arises from an iron-
catalyzed oxidation reaction of 1, was detected as a by-
product. Unfortunately, the use of less-oxidizing iron species
(Table 1, entries 11–13), degassed solvents, or other diamine-
type ligands such as N,N,N’,N’-tetramethylethylenediamine or
trans-1,2-diaminocyclohexane did not prevent such compet-
itive oxidation processes. To determine if 3a was obtained by
direct S-arylation of 1 or, alternatively, a two-step procedure
involving oxidation of the thiophenol and subsequent aryla-
[*] Dr. A. Correa, Dr. M. Carril, Prof. Dr. C. Bolm
Institut für Organische Chemie
RWTH Aachen
Landoltweg 1, 52056 Aachen (Germany)
Fax: (+49)241-809-2391
E-mail: carsten.bolm@oc.rwth-aachen.de
[**] We are grateful to the Fonds der Chemischen Industrie for financial
support. A.C. thanks the Basque Government for support by
“Programa de Perfeccionamiento de Doctores en el extranjero del
Departamento de Educación, Universidades e Investigación”, and
M.C. thanks the Spanish Ministry of Education and Sciences (MEC)
for a postdoctoral fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2880
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 2880 –2883

Angewandte
Chemie
Table 2: Fe-catalyzed S-arylation of thiols with aryl halides.[a]
tion of the resulting corresponding
disulfide, thiophenol (1) was
replaced by diphenyl sulfide as the
starting material. The absence of
any arylated product in this reaction
(Table 1, entry 14) ruled out the
latter reaction path.
Entry
1
R-SH
Ar-X
Product
Yield [%][b]
X=I, 91
X=Br, 0
X=Cl, 0
3a
The importance of the ligand
was revealed by a reaction carried
out in its absence: In this case, the
X=I, Br, Cl
2
3
3b
3c
98
À
C S coupling product was not
observed at all, and diphenyl disul-
fide was the only product (Table 1,
entry 15). Thus, the chemoselectiv-
ity of the iron-catalyzed S-arylation
can be entirely controlled by the
addition of a simple diamine ligand
(Table 1, compare entries 9 and 15).
The optimal reaction conditions for
the S-arylation of thiophenol with
phenyl iodide involved the use of
10 mol% of FeCl3, 20 mol% of
DMEDA, and 2 equivalents of
NaOtBu in toluene at 1358C.[12]
The use of 5 mol% of the iron
source furnished 3a, although in
good but lower yield (Table 1,
entry 10).
88[c]
4
5
3d
3e
90[c]
85
6
3 f
84
7
8
9
3g
3h
3i
81
85
91
Next, the scope of this novel
transformation in coupling reac-
tions of other thiols with differently
substituted aryl halides was evalu-
ated (Table 2). In general, all reac-
tions were very clean, and the
thioethers 3 were obtained in high
yields under the previously opti-
mized conditions. In a few cases,
trace amounts of the undesired
disulfide were detected, but those
could be separated during the pu-
rification by column chromatogra-
phy. The current iron-catalyst
system efficiently coupled thiols
with electron-rich, electron-neutral,
and electron-deficient aryl iodides
(32–98% yield, Table 2, entries 1–
10
11
3j
52[d]
71[d]
3k
12
13
3l
61
3m
33[e]
14
15
16
3n
3o
3p
32
91
80
18).
Furthermore,
sterically
demanding ortho substituents did
not hamper the arylation reaction
and the corresponding thioethers 3
were obtained in good yields
(Table 2, entries 4, 11, 13, 16, and
17). Neither aryl bromides nor aryl
chlorides were reactive under the
standard
entry 1).
conditions
Consequently,
(Table 2,
cross-
17
3q
91
coupling reactions with chloro-
substituted aryl iodides proceeded
exclusively at the iodo group
Angew. Chem. Int. Ed. 2008, 47, 2880 –2883
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2881

Communications
Table 2: (Continued)
the known products was confirmed by
1H and 13C NMR spectroscopic analysis,
and the new products were fully charac-
terized. See the Supporting Information
for full details.
Entry
18
R-SH
Ar-X
Product
Yield [%][b]
80
3r
Received: December 11, 2007
Published online: March 3, 2008
19
20
3s
3t
0
0
Keywords: arylation ·cross-coupling·
.
heterogeneous catalysis · iron · thiols
[a] Reaction conditions: R-SH (1.0 equiv), Ar-X (1.5 equiv), FeCl3 (0.1 equiv), DMEDA (0.2 equiv),
NaOtBu (2.0 equiv), toluene (1 mLmmolÀ1 of R-SH), 1358C, 24 h. [b] Yield of isolated product after
flash chromatography. [c] Use of R-SH (1.6 equiv) and Ar-X (1.0 equiv). [d] Use of Cs2CO3 as base.
[e] Use of K3PO4 as base.
[1] a) A. R. Muci, S. L. Buchwald, Top.
Curr. Chem. 2002, 219, 131;
b) Metal-Catalyzed Cross-Coupling
Reactions (Eds.: F. Diederich, A.
de Meijere), Wiley-VCH, Wein-
(Table 2, entries 8 and 16). Importantly, the iron catalyst also
heim, 2004; c) J. F. Hartwig, Synlett 2006, 1283.
proved efficient in coupling reactions of more challenging
thiols bearing heterocycles such as benzisothiazole and
imidazole, thus allowing access to heterocyclic sulfide deriv-
atives which are present in numerous appealing com-
pounds.[13] Unfortunately, all attempts to couple aliphatic
thiols (Table 2, entries 19 and 20) with aryl halides failed. The
tolerance of potentially reactive functional groups such as
carboxylic acids and esters to the described protocol is
remarkable (Table 2, entries 4 and 7, respectively).
In summary, we have developed an efficient iron-
catalyzed S-arylation protocol of aromatic and heteroaro-
matic thiol derivatives, which involves an inexpensive catalyst
system formed by combining FeCl3 and DMEDA. This
method avoids the use of expensive and/or air-sensitive
ligands and provides in most cases the desired sulfide in high
yields. At the present stage, the success of the protocol is
restricted to the use of aryl iodides as the electrophilic
counterpart. This limitation is balanced by the fact that
certain synthetically attractive heterocyclic thiols can be used
as starting materials, which have not been utilized so far in
these kinds of reactions. Overall the novel iron-catalyzed
[2] For general reviews, see a) J. F. Hartwig in Handbook of
Organopalladium Chemistryfor Organic Synthesis, Vol 1 (Ed.:
E.-i. Negishi), Wiley-Interscience, New York, 2002, p. 1051;
b) S. V. Ley, A. W. Thomas, Angew. Chem. 2003, 115, 5558;
Angew. Chem. Int. Ed. 2003, 42, 5400; c) K. Kunz, U. Scholz, D.
Ganzer, Synlett 2003, 2428; d) I. P. Beletskaya, A. V. Cheprakov,
Coord. Chem. Rev. 2004, 248, 2337; e) J.-P. Corbet, G. Mignani,
Chem. Rev. 2006, 106, 2651.
[3] For some S-arylations of thiols, see a) C. Palomo, M. Oiarbide,
R. López, E. Gómez-Bengoa, Tetrahedron Lett. 2000, 41, 1283;
b) F. Y. Kwong, S. L. Buchwald, Org. Lett. 2002, 4, 3517; c) C. G.
Bates, R. K. Gujadhur, D. Venkataraman, Org. Lett. 2002, 4,
2803; d) M. A. Fernµndez-Rodríguez, Q. Shen, J. F. Hartwig, J.
Am. Chem. Soc. 2006, 128, 2180; e) M. A. Fernµndez-Rodríguez,
Q. Shen, J. F. Hartwig, Chem. Eur. J. 2006, 12, 7782; f) A. K.
Verma, J. Singh, R. Chaudhary, Tetrahedron Lett. 2007, 48, 7199;
g) M. Carril, R. SanMartin, E. Domínguez, I. Tellitu, Chem. Eur.
J. 2007, 13, 5100; h) Y. Zhang, K. C. Ngeow, J. Y. Ying, Org. Lett.
2007, 9, 3495; i) L. Rout, T. Sen, T. Punniyamurthy, Angew.
Chem. 2007, 119, 5679; Angew. Chem. Int. Ed. 2007, 46, 5583;
j) B. C. Ranu, A. Saha, R. Jana, Adv. Synth. Catal. 2007, 349,
2690.
[4] For a review dealing with the metal-catalyzed formation of
carbon–sulfur bonds, see T. Kondo, T. Mitsudo, Chem. Rev. 2000,
100, 3205.
À
S-arylation reported here constitutes a promising C S bond-
[5] a) G. Liu, J. R. Huth, E. T. Olejniczak, R. Mendoza, P. DeVries,
S. Leitza, E. B. Reilly, G. F. Okasinski, S. W. Fesik, T. W.
von Geldern, J. Med. Chem. 2001, 44, 1202; b) G. De Martino,
M. C. Edler, G. La Regina, A. Coluccia, M. C. Barbera, D.
Barrow, R. I. Nicholson, G. Chiosis, A. Brancale, E. Hamel, M.
Artico, R. Silvestri, J. Med. Chem. 2006, 49, 947; c) A. Gangjee,
Y. Zeng, T. Talreja, J. J. McGuire, R. L. Kisliuk, S. F. Queener, J.
Med. Chem. 2007, 50, 3046.
forming process of potential industrial significance because of
its operational simplicity and environmental and economic
advantages. Its increased efficiency and enlargement of the
substrate scope are currently under investigation by our
research group.
[6] For general reviews, see a) C. Bolm, J. Legros, J. Le Paih, L.
Zani, Chem. Rev. 2004, 104, 6217; b) A. Fꢀrstner, R. Martin,
Chem. Lett. 2005, 34, 624.
[7] a) T. V. Rao, B. Sain, P. S. Murthy, T. S. R. P. Rao, A. K. Jain,
G. C. Joshi, J. Chem. Res., Synop. 1997, 300; b) H. M. Meshram,
R. Kache, Synth. Commun. 1997, 27, 2403; c) N. Iranpor, B.
Zeynizadeh, Synthesis 1999, 49.
[8] a) A. Fꢀrstner, A. Leitner, Angew. Chem. 2002, 114, 632; Angew.
Chem. Int. Ed. 2002, 41, 609; b) A. Fꢀrstner, A. Leitner, M.
Mꢁndez, H. Krause, J. Am. Chem. Soc. 2002, 124, 13856; c) R.
Martin, A. Fꢀrstner, Angew. Chem. 2004, 116, 4045; Angew.
Chem. Int. Ed. 2004, 43, 3955; d) B. Scheiper, M. Bonnekessel,
H. Krause, A. Fꢀrstner, J. Org. Chem. 2004, 69, 3943; e) I.
Sapountzis, W. Lin, C. C. Kofink, C. Despotopoulou, P. Knochel,
Angew. Chem. 2005, 117, 1682; Angew. Chem. Int. Ed. 2005, 44,
Experimental Section
General procedure for S-arylation of thiols: A sealable tube equipped
with a magnetic stir bar was charged with thiophenol (1, 1.0 equiv),
NaOtBu (2.0 equiv), and FeCl3 (0.10 equiv). The aperture of the tube
was then covered with a rubber septum, and an argon atmosphere was
established. Phenyl iodide (2, 1.5 equiv), N,N’-dimethylethylendi-
amine (0.20 equiv), and toluene (1 mLmmolÀ1 of 1) were added by
syringe. The septum was then replaced by a teflon-coated screw cap,
and the reaction vessel was placed in an oil bath at 1358C. After
stirring the heterogeneous mixture at this temperature for 24 h, it was
cooled to room temperature and diluted with dichloromethane. The
resulting solution was directly filtered through a pad of silica and
concentrated to afford the product, which was purified by chroma-
tography on silica gel to yield thioether 3. The identity and purity of
2882 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 2880 –2883

Angewandte
Chemie
1654; f) I. Iovel, K. Mertins, J. Kischel, A. Zapf, M. Beller,
Angew. Chem. 2005, 117, 3981; Angew. Chem. Int. Ed. 2005, 44,
3913; g) C. C. Kofink, B. Blank, S. Pagano, N. Gꢂtz, P. Knochel,
Chem. Commun. 2007, 1954; h) T. Hatakeyama, M. Nakamura,
J. Am. Chem. Soc. 2007, 129, 9844; i) G. Cahiez, C. Duplais, A.
Moyeux, Org. Lett. 2007, 9, 3253; j) R. Li, S. R. Wang, W. Lu,
Org. Lett. 2007, 9, 2219; k) E. Shirakawa, T. Yamagami, T.
Kimura, S. Yamaguchi, T. Hayashi, J. Am. Chem. Soc. 2005, 127,
17164; l) A. Guꢁrinot, S. Reymond, J. Cossy, Angew. Chem.
2007, 119, 6641; Angew. Chem. Int. Ed. 2007, 46, 6521.
4225; c) V. Lecomte, C. Bolm, Adv. Synth. Catal. 2005, 347, 1666;
d) O. G. Mancheꢃo, C. Bolm, Org. Lett. 2006, 8, 2349; e) M.
Nakanishi, C. Bolm, Adv. Synth. Catal. 2007, 349, 861.
[10] a) A. Correa, C. Bolm, Angew. Chem. 2007, 119, 9018; Angew.
Chem. Int. Ed. 2007, 46, 8862; b) A. Correa, C. Bolm, Adv. Synth.
Catal., 2008, 350, 391.
[11] O. Bistri, A. Correa, C. Bolm, Angew. Chem. 2008, 120, 596;
Angew. Chem. Int. Ed. 2008, 47, 586.
[12] All the experiments were carried out with anhydrous FeCl3
(purity > 98%) obtained from Merck.
[9] For selected iron-catalyzed reactions reported by our research
group, see a) J. Legros, C. Bolm, Angew. Chem. 2003, 115, 5645;
Angew. Chem. Int. Ed. 2003, 42, 5487; b) J. Legros, C. Bolm,
Angew. Chem. 2004, 116, 4321; Angew. Chem. Int. Ed. 2004, 43,
[13] M. Bogenstaetter, N. I. Carruthers, J. A. Jablonowski, T. W.
Lovenberg, K. S. Ly (Ortho McNeil Pharmaceutical, Inc.),
International Patent WO 02/079168, 2002.
Angew. Chem. Int. Ed. 2008, 47, 2880 –2883
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2883