Organocatalytic visible light mediated synthesis of aryl sulfides

Article abstract of DOI:10.1039/c3cc41867g

Photo-sensitized synthesis of arylsulfides from arenediazonium salts in the presence of eosin Y has been developed. This protocol exhibits high functional group tolerance and a wide substrate scope and is an attractive alternative to the thermal reaction that involves explosive intermediates.

Full text of DOI:10.1039/c3cc41867g

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Organocatalytic visible light mediated synthesis of aryl
sulfides†
Cite this: Chem. Commun., 2013,
49, 5507
Michal Majekz and Axel Jacobi von Wangelin*
Received 13th March 2013,
Accepted 23rd April 2013
DOI: 10.1039/c3cc41867g
www.rsc.org/chemcomm
Photo-sensitized synthesis of arylsulfides from arenediazonium
salts in the presence of eosin Y has been developed. This protocol
exhibits high functional group tolerance and a wide substrate
scope and is an attractive alternative to the thermal reaction that
involves explosive intermediates.
The development of mild and sustainable protocols for
aromatic substitutions is of utmost importance to the synthesis
of fine chemicals, agrochemicals, pharmaceuticals, materials,
and natural products.1 Numerous thermal, Lewis acid-mediated,
and metal-catalyzed protocols are currently available to the
organic chemist in order to access a large variety of substitution
patterns. The re-discovery of visible light as an abundant energy
source for the activation of chemical reactants has prompted
Scheme 1 Formal nucleophilic substitutions at arenediazonium salts via visible
light mediated SET reductions.
renewed interest in light-mediated aromatic substitutions as a iridium photo-catalysts is still a severe limitation of many
powerful alternative to metal-catalyzed ‘‘dark’’ reactions.2 Such photo-redox protocols in terms of sustainability and scalability.
catalytic reactions in the presence of suitable photo-sensitizers The persistent quest to introduce cheaper metal-free dyes has
mostly involve single electron transfer (SET) processes that bear been addressed with the successful use of eosin dyes.7 While
a close conceptual relationship with Sandmeyer-type reactions.3 these reports clearly demonstrate the viability of aryl radical
The merit of the photo-catalytic synthesis is the mild generation trapping by p-donors (i.e. alkenes, arenes), examples utilizing
of aryl radicals by photo-sensitized electron transfer which s-donors have remained scarce. To the best of our knowledge,
avoids the direct photolysis of bonds requiring UV light4 and there is only one report where diboranes have been oxidatively
the employment of stoichiometric copper(I) salts.
cleaved to give arylboronates (Scheme 1).8 In an effort to extend
Early studies of photoredox catalysis utilized arene-diazonium this general concept to the synthesis of thioethers, we have
salts as precursors for aryl radicals, whose choice is not developed visible light-mediated thiolation of diazonium salts
deliberate: diazonium salts are easily prepared and undergo in the presence of eosin Y. Arylsulfides are key structural motifs
facile and irreversible oxidation due to the release of dinitrogen. in synthetic and natural molecules.9 Their synthesis is usually
Ru(bpy)3Cl2-sensitized intramolecular Pschorr-type arylations performed by treatment of readily available arenediazonium
were first reported by Deronzier in 1984.5 Modern developments salts with thiols under neutral or basic conditions.10 However,
include intermolecular arylations of electron-rich p-donors for the intermediate diazosulfide species is a potent explosive even
the synthesis of biaryls, stilbenes, a-arylketones, and thiophenes under wet conditions and has already caused violent detona-
(Scheme 1).6 However, the prevalent use of ruthenium and tions in many instances.11
We envisioned the oxidative cleavage of disulfides by aryl
Institute of Organic Chemistry, University of Regensburg, Universitaetsstr. 31,
93040 Regensburg, Germany. E-mail: axel.jacobi@ur.de; Fax: +49 (0)941 943 4617;
Tel: +49 (0)941 943 4802
radicals to be a promising catalytic strategy for the synthesis of
aryl sulfides.11,12 The high nucleophilicity of sulfur should
entail rapid trapping of the radical and avoid the accumulation
of potentially hazardous intermediates, while the neighboring
sulphur atom can stabilize partial unsaturation or charges. In
combination with the mild visible light-mediated generation of
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc41867g
‡ M.M. is a research fellow of the Graduate School of Chemical Photocatalysis of
the German Research Foundation (DFG).
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5507--5509 5507

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Table 2 Substrate scope
Entry
R
Aryl methyl sulfide
Yield [%]
1
2
3
4
2-Me
2-CO2Me
2-CF3
80
77
68
48
2-NO2
Scheme 2 Azo coupling vs. a disulfide route to aromatic sulfides.
Table 1 Selected optimization experimentsa
5
6
3-Cl
3-NO2
89
60
7
8
9
10
11
12
13
14
15
4-OH
4-OMe
4-Me
4-Cl
4-Br
4-I
4-F
4-CF3
4-NO2
57
87
77
85
73
51a
69
67
39
Entry
Solvent
Dye (mol%)
Equiv. DMDS
2/3 [%]
1b
2
DMSO
DMSO
DMSO
NMP
MeCN
DMF
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Eosin Y (5)
Fluorescein (5)
Neutral red (5)
Ru(bpy)3Cl2 (5)
Eosin Y (2)
Eosin Y (1)
Eosin Y (2)
Eosin Y (2)
—
5
5
5
5
5
5
—
5
5
5
5
5
1.5
1
1.5
0.5
0.5
49/—
73/—
71/—
29/—
65/—
25/27
—/81
25/—
29/—
69/—
72/—
63/—
73/—
42/—
—/—
3/—
3c
4
5d
6
16
–C4H4–
31b
7e
8
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
a
b
10
11
12
13
14
15g
16
17g
Polymer formation observed. 12% 1,4-di(methylsulfanyl)naphthalene.
—
Eosin Y (2)
3/—
a
Standard conditions: 0.5 mmol 4-bromobenzenediazonium tetrafluoro-
borate, 0.025 mmol eosin Y, 2.5 mmol dimethyldisulfide (DMDS), 2 mL
b
solvent, 18 1C, 6 h irradiation with green LED (l = 525 nm, 3.8 W). 2 h.
c
d
e
f
g
20 h. 7 mL MeCN. No DMDS. Without eosin Y. In the dark.
aryl radicals from arenediazonium salts, this would provide an
attractive alternative to thermal reactions involving explosive
intermediates (Scheme 2). The presence of free aryl radicals in
the related ‘‘dark’’ process with stoichiometric copper salts was
proven using EPR spectroscopy.13
Scheme 3 Synthesis of cysteine and selenide derivatives.
Initial experiments with 4-bromobenzenediazonium tetra- substitution of iodide and resultant polymer formation were
fluoroborate (1) and dimethyldisulfide (dmds), a commercial observed (entry 12). Iodoarene moieties are subject to iodine
food additive and a sulfiding agent, supported our assumption transfer to aryl radicals.16 Consistently, addition of iodobenzene
(Table 1). The optimized set of conditions includes irradiation to the reaction of 4-iodobenzenediazonium tetrafluoroborate
(green LED, lmax = 525 nm, 3.8 W) of a solution of 1, 1.5 equiv. also afforded 1,4-diiodobenzene. Conversion of 1-naphthalene-
dmds, and eosin Y (2 mol%) in dimethylsulfoxide (DMSO) at diazonium salt was unselective giving a mixture of mono- and
18 1C for 6 h. N-Methyl pyrrolidinone (NMP) showed low disubstituted products (entry 16). Similar selectivity was
solubilization of 1, while N,N-dimethylformamide also effected observed in the presence of diphenyldiselenide to give an
reductive dediazotation.14 Fluorescein, Neutral Red, and Ru(bpy)3Cl2 unsymmetrical diarylselenide (Scheme 3).17 The synthesis of
gave lower yields.
an arylsulfide bioconjugate bearing an amino acid residue was
A catalyst-free dark reaction gave no product. When irradiating realized by reaction with dimethyl L-cystinate.18
this mixture, very low yields were observed possibly due to a
On the basis of previous reports,5,6 we propose a mechanism
charge transfer complex between 1 and DMSO which exhibits for the photocatalytic thiolation (Scheme 4). The arene-diazonium
absorbance in the visible region.15 The scope of the protocol salt (I) is susceptible to SET reduction by the excited photo-
was evaluated by employment of various arenediazonium salts catalyst. The resulting aryl radical II is attacked by the nucleo-
(Table 2). The reaction conditions tolerated the presence of philic disulfide to give a trivalent sulfur radical, III, which is
esters, nitro groups, and halides (F, Cl, Br), while concomitant stabilized by the neighboring aryl and sulfur substituents.19
c
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furnishes an electrophilic species which undergoes substitution
in the presence of a large excess of DMSO (solvent).20 A long
radical chain mechanism is unlikely, as 1H NMR monitoring
showed that product formation stopped when the light source
was removed.21 We have investigated the nature of by-products.
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elevated temperatures (>40 1C) to give an aryl cation which is
rapidly trapped by the nucleophilic solvent DMSO.22 The resultant
[ArOSMe2]+ was detected using ESI-MS.21
In summary, we have developed a new photocatalytic thiolation
protocol in the presence of only 2 mol% eosin Y, which allows
the facile synthesis of arylsulfides in good yields. The mild
reaction conditions (green light, r.t.) tolerate various functional
groups and can be applied to the conjugation with thiol-
containing amino acids.
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5507--5509 5509