Synthesis of aryl sulfides by decarboxylative C-S cross-couplings

Article abstract of DOI:10.1002/chem.200900133

A study was conducted to demonstrate the transition-metal-catalyzed synthesis of aryl sulfides by decarboxylative C-S cross-couplings. Coupling reaction of 2-nitrobenzoic acid with 1-octanethiol were carried in the presence of different combinations of tr

Full text of DOI:10.1002/chem.200900133

DOI: 10.1002/chem.200900133
À
Synthesis of Aryl Sulfides by Decarboxylative C S Cross-Couplings
Zhongyu Duan,[a] Sadananda Ranjit,[a] Pengfei Zhang,[b] and Xiaogang Liu*[a]
[a]
À
Table 1. Decarboxylative C S coupling under different conditions.
Aryl sulfides are used in ad-
vanced materials and industrial
chemicals such as organic sem-
iconductors, herbicides, lubri-
Entry
Pd (mol%)
Cu/Ag (equiv)
Yield[b] [%]
cants, and high boiling point
solvents.[1] They are also key
intermediates for the prepara-
tion of pharmaceuticals.[2] De-
spite the phenomenal growth
in diverse synthetic methodolo-
gies, the primary method for
the synthesis of aryl sulfides is
limited to the condensation re-
action between a metal thio-
late and an alkyl or aryl
halide.[3] Organohalides are a
health and environmental con-
cern, and organohalide waste
requires costly remediation,
particularly on an industrial
scale. In contrast, carboxylic
acids are generally environ-
mentally benign and readily
-NO2
-NH2
1
2
3
4
5
6
Pd
–
G
–
<3
18
10
<3
8
CuCO3·Cu (OH)2 (1.5)
CuCO3·Cu (OH)2 (1.5)
CuCO3·Cu (OH)2 (1.5)
AgBF4 (1.0)
AgBF4 (10.0)
Ag2O (5.0)
<3
<3
<3
<3
46
96(90)
12
48
24
69
10
13
15
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
<3
<3
26
<3
57
41
56
19
66(52)
59
Ag2O (1.0)
7[c]
8
CuCO3·Cu (OH)2 (1.5)
CuCO3·Cu (OH)2 (1.5)
CuCO3·Cu (OH)2 (1.5)
CuCO3·Cu (OH)2 (1.5)
CuCO3·Cu (OH)2 (1.5)
CuCO3·Cu (OH)2 (1.0)
CuCO3·Cu (OH)2 (0.75)
CuCO3·Cu (OH)2 (0.50)
CuCO3·Cu (OH)2 (0.38)
9[d]
10[e]
11
12
13
14
15
22
10
[a] Reaction conditions: aryl acid (0.5 mmol), 1-octanethiol (0.75 mmol), KF (3 equiv), NMP (3 mL), 1608C,
24 h. [b] GC yield. Isolated yield is in parenthesis. [c] Without KF. [d] Under a nitrogen atmosphere. [e] KOH
(3 equiv) was used as the base for KF.
prepared reagents. Decarboxylation of carboxylic acids by
loss of carbon dioxide (CO2) has recently emerged as a
if possible, would provide an alternative access to aryl sul-
fides without the need for halocarbon precursors. Herein,
we describe the integration of these concepts into the transi-
tion-metal-catalyzed synthesis of a broad range of aryl and
diaryl sulfides.
À
promising coupling reaction, but only in the context of C C,
[4]
À
À
C N, and C Se bond-forming transformations. To the best
À
of our knowledge, a process for decarboxylative C S bond
formation has never been proposed or experimentally vali-
dated in the literature. We reasoned that the direct decar-
To test our hypothesis and also to identify an effective
catalyst system, coupling reactions of 2-nitrobenzoic acid
with 1-octanethiol (1.5 equiv) were first carried out in the
presence of different combinations of transition-metal cata-
lysts at elevated temperatures. Selected results from our
screening experiments are summarized in Table 1. Our stud-
ies showed that these reactions formed decarboxylative cou-
pling products containing a mixture of nitrobenzene and
aminobenzene sulfides. Reactions conducted with monome-
tallic PdII, CuII or bimetallic CuII/AgI, PdII/AgI catalysts re-
sulted in low conversions of starting materials (Table 1, en-
tries 1–6). The reactions with bimetallic PdII/CuII catalysts
occurred with moderate to excellent conversions (Table 1,
À
boxylative C S coupling of aryl carboxylic acids and thiols,
[a] Dr. Z. Duan, S. Ranjit, Prof. X. Liu
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6779-1691
E-mail: chmlx@nus.edu.sg
[b] Prof. P. Zhang
College of Material, Chemistry and Chemical Engineering
Hangzhou Normal University, Hangzhou 310036 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900133.
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Chem. Eur. J. 2009, 15, 3666 – 3669

COMMUNICATION
entries 7–15). Importantly, optimal conversion to aminoben-
zene sulfide was achieved with a catalytic amount of Pd-
tries 9, 10), providing an alternative to the use of more reac-
tive and odiferous thiols.
À
(OAc)2 (5 mol%) combined with CuCO3·Cu(OH)2
A hypothetical mechanism for the decarboxylative C S
coupling reaction is depicted in Scheme 1. The organometal-
lic nucleophile formed upon decarboxylation initially reacts
(1.5 equiv) and KF (3 equiv) in N-methyl-2-pyrrolidone
(NMP) at 1608C for 24 h (Table 1, entry 8). In contrast to
KF, a control reaction conducted by using KOH as the base
only gave a relatively low yield of the coupling product
(Table 1, entry 10). This can be attributed to an increase in
PdII catalyst solubility and stability in the presence of the
KF relative to KOH. It should be noted that the reaction
was carried out without the exclusion of oxygen and mois-
ture. Our studies also indicated that equimolar amounts of
2-nitrobenzoic acid and 1-octanethiol under the same condi-
tions afforded a mixture of nitrobenzene and aminobenzene
sulfides (see the Supporting Information, Table S1).
In a further set of experiments, a series of thiols and 2-ni-
trobenzoic acid were evaluated under the optimal condi-
tions, and the results are summarized in Table 2. Primary ali-
phatic thiols such as 1-decanethiol and 1-butanethiol were
successfully transformed to aminobenzene sulfides in high
yields (Table 2, entries 1–3), while cyclohexanethiol and aro-
matic thiols yielded nitrobenzene sulfides as major products
(Table 2, entries 4–8). Notably, disulfide precursors also re-
sulted in high yields of nitrobenzene sulfides (Table 2, en-
Table 2. Decarboxylative coupling of 2-nitrobenzoic acid with thiols or
disulfides.[a]
Scheme 1. Proposed mechanism for the synthesis of aryl sulfides by de-
À
carboxylative C S cross-coupling of 2-nitrobenzoic acid and thiols.
Entry
1
HSR or RSSR
Product
Yield[b] [%]
85
with an electrophilic PdII thiolate (a) intermediate to form
an aryl palladium(II) species (b). Subsequent reductive
elimination generates the aryl sulfide coupling product (c),
followed by CuII-mediated oxidation of the previously re-
duced Pd0 species to regenerate the PdII compound and thus
continue the catalytic cycle for the palladium.[5] The conver-
sion to aminobenzene sulfide (d) through use of alkyl thiols
is possibly ascribed to the more facile auto-oxidation of the
alkyl thiols relative to aryl thiols. In the presence of a palla-
dium catalyst, an excessive amount of alkyl thiols promotes
the reduction of the coupling product c to the aminoben-
zene sulfide d. This hypothesis was further confirmed by
control experiments on the reduction of nitrobenzene with
alkyl thiols (see the Supporting Information, Table S2). In
the absence of the alkyl thiol, a very low yield (5%) of ani-
line product was observed in the control experiment.
2
80
70
75
68
73
81
73
85
77
3
4
5
6
7
To expand the scope of the method, a wide range of aryl
8
À
carboxylic acids were tested as substrates for C S coupling
(Table 3). Benzoic acids with electron-withdrawing substitu-
ents in the ortho-position give the coupling products in mod-
erate to high yield (Table 3, entries 1–3). In contrast, benzoic
acid with an electron-donating substituent in the ortho-posi-
tion did not proceed under the identical conditions (Table 3,
entry 4). In addition, the use of benzoic acids without a sub-
9
10
[a] All the reactions were carried out with aryl acid (0.5 mmol) and thiols
(0.75 mmol) in the presence of Pd(OAc)2 (5.0 mol%), CuCO3·Cu(OH)2
(1.5 equiv), and KF (3.0 equiv). [b] Yields of isolated products are the
average of at least two experiments.
AHCTUNGTRENNUNG
stituent (Table 3, entry 5) or with
a para-substituent
(Table 3, entries 6–11) resulted in a low yield of the coupling
Chem. Eur. J. 2009, 15, 3666 – 3669
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X. Liu et al.
of 2-haloanilides in the presence of Lawessonꢁs reagent.[7]
Table 3. Decarboxylative coupling of carboxylic acid with thiols or disulfi-
des.[a]
À
Alternatively, benzothiazoles can be synthesized by a C H
À
functionalization/intramolecular C S bond-formation pro-
cess.[8] We discovered that a benzothiazole compound can be
alternatively obtained in a moderate yield by a decarboxyla-
tive cross-coupling of 2-nitrobenzoic acid with benzyl thiol
under our standard reaction conditions (Scheme 2). Once
refined, this approach may prove particularly attractive be-
cause it utilizes readily prepared aryl carboxylic acids and
generates CO2 and H2O as by-products rather than hydro-
gen halides, which are formed from the analogous synthesis
with the aryl halide reagent. We attributed this organic
transformation to a process that possibly involves a nitroso
intermediate (f), which is formed via reduction of the decar-
boxylative coupling product (e) by the benzyl thiol
(Scheme 2). The nitroso intermediate subsequently under-
goes intramolecular cyclization by preferential attack on the
benzyl carbon in the presence of a base, followed by acidifi-
cation and dehydration to afford the benzothiazole product
(g).
Entry Product
1
Yield[b] Entry Product
[%]
Yield[b]
[%]
55
10
27
2
76
85
<3
31
25
11
12
13
14
15
28
90
88
85
95
3
4[c]
5
6
7
70
47
14
16
17
18
92
90
80
À
The first identification of direct decarboxylative C S
8[d]
cross-couplings is important because these proof-of-concept
reactions shall provide a valuable and versatile synthetic
method for a broad range of aryl sulfides without the need
for a halocarbon precursor. On the basis of the above find-
ings, further mechanistic investigation and catalyst optimiza-
tion by introducing small organic ligands for enhanced de-
9
[a] All the reactions were carried out with aryl acid (0.5 mmol) and thiols
(0.75 mmol) in the presence of Pd(OAc)2 (5.0 mol%), CuCO3·Cu(OH)2
(1.5 equiv), and KF (3.0 equiv) in NMP (3 mL) at 1608C. [b] Yields of iso-
lated products are the average of at least two experiments. [c] GC Yield.
[d] Ethyl disulfide was used.
AHCTUNGTRENNUNG
À
carboxylative C S bond-forming reactions under relatively
mild conditions are currently in progress.
product, possibly due to the in-
efficiency in the decarboxyla-
tion of these arylcarbroxylic
acids under the current condi-
tions.[4p] Importantly, this C S
À
coupling strategy can be ex-
tended to vinyl and heteroaro-
matic substrates (cinnamic acid
and
pyridine-2-carboxylic
acid). These carboxylic acid
derivatives were converted to
the corresponding sulfides in
excellent yields for most cases
(Table 3, entries 12–18).
Another notable application
of the newly developed direct
À
decarboxylative C S cross-cou-
pling is the synthesis of a ben-
zothiazole compound and pos-
sibly its derivatives that have
found many uses as industrial
dyes and antitumor drug candi-
dates.[6] Conventional methods
typically rely on the cyclization
À
Scheme 2. Proposed mechanism for the synthesis of 2-phenyl-benzothiazole by decarboxylative C S cross-cou-
pling.
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Chem. Eur. J. 2009, 15, 3666 – 3669

Synthesis of Aryl Sulfides
COMMUNICATION
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Experimental Section
Typical procedure: CuCO3·Cu(OH)2 (165 mg, 0.75 mmol), PdACTHNUTRGNEUNG(OAc)2
(5.6 mg, 0.025 mmol), and KF (87 mg, 1.5 mmol) were added to a solu-
tion of N-methyl-2-pyrrolidone (NMP) (3 mL) charged with carboxylic
acid (0.5 mmol) and thiol (0.75 mmol). The resulting mixture was stirred
at 1608C and monitored by TLC. Upon completion of the reaction (ca.
24 h), the mixture was cooled to room temperature, poured into a solu-
tion of HCl in water (1n, 15 mL), and extracted several times with ethyl
acetate (15 mL). The combined organic layers were washed with water
and brine, dried over Na2SO4, and filtered. The solvent was removed in
vacuo and the residue was purified by column chromatography (silica
gel, eluent: hexane/ethyl acetate) to afford the coupling product.
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Acknowledgements
We acknowledge the ARF (R-143–000–342–112) for supporting this
work. X. L. is grateful to the National University of Singapore for a
Start-Up Grant Award (R-143–000–317–101/133) and a Young Investiga-
tor Award (R-143–000–318–123). We thank Professors D. Young, H.
Zeng, and J. Wu for valuable discussions.
Keywords:
carboxylic
acid
·
cross-coupling
·
decarboxylation reaction · thiols · transition metals
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Received: January 18, 2009
Published online: February 26, 2009
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3669