Highly regioselective synthesis of aryl chalcogenides through C-H functionalization of arenes

Article abstract of DOI:10.1039/c2cc33950a

We report here the regioselective synthesis of aryl chalcogenides through the iridium-catalyzed meta C-H borylation followed by copper-catalyzed C-S coupling reaction with chalcogenide sources in one pot, giving the 3,5-disubstituted aryl chalcogenides wi

Full text of DOI:10.1039/c2cc33950a

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COMMUNICATION
Highly regioselective synthesis of aryl chalcogenides through C–H
functionalization of arenesw
Jun-Hao Cheng, Chih-Lun Yi, Tsung-Jui Liu and Chin-Fa Lee*
Received 1st June 2012, Accepted 3rd July 2012
DOI: 10.1039/c2cc33950a
We report here the regioselective synthesis of aryl chalcogenides
through the iridium-catalyzed meta C–H borylation followed by
copper-catalyzed C–S coupling reaction with chalcogenide
sources in one pot, giving the 3,5-disubstituted aryl chalcogenides
with high regioselectivity and good yields.
in most cases. Third, the mixtures of ortho- and para-arylthiolated
products were found in some cases. Notably, these two systems
prefer the ortho and para rather than meta C–S formation. Very
recently, Frost et al. reported the ruthenium-catalyzed meta
sulfonation of 2-phenylpyridines with sulfonyl chlorides; however,
pyridine is required as a directing group.19 To the best of our
knowledge, the direct meta C–H functionalization of arenes
with sulfur surrogates in the absence of a directing group is not
well-documented.
Aryl chalcogenides are important building blocks in organic
synthesis, materials science and in the pharmaceutical industry.1
Transition-metal-catalyzed cross-coupling reaction of thiols and
disulfides with aryl halides and pseudo halides is one of the most
powerful approaches for preparing aryl thioethers.2–9 Palladium,3
copper,4 cobalt,5 indium,6 gold,7 rhodium8 and iron9 have all been
reported as the catalysts for the coupling reaction of aryl halides
with thiols. Additionally, transition metals such as palladium,
nickel and copper have also been reported as the catalysts for
C–Se and C–Te bond forming reactions.1,10
The combination of iridium-catalyzed C–H and sequential
functionalization of the resulting aryl boronic esters is an
excellent approach for regioselective meta C–H functionalization
of arenes.20 It should be possible to prepare aryl chalcogenides
with high regioselectivity using iridium-catalyzed C–H activation
followed by C–S, C–Se and C–Te cross-coupling reactions. Here,
we report the meta C–H functionalization of arenes with
chalcogenide sources, giving the aryl chalcogenides with high
regioselectivity and good to excellent yields.
Direct C–H functionalization of arenes is an important
consideration from the atom economy standpoint.11 Many
reliable and efficient protocols have been developed for making
C–C,12 C–N,13 and other C-heteroatom bonds14 through metal-
catalyzed activation of arene C–H bonds; C–S bond formation
by this approach is relatively less studied.15–19 Yu et al. reported
the copper-catalyzed ortho-thiolation of 2-phenylpyridine with
thiophenols and methyl disulfide.15 Dong et al. reported the
palladium-catalyzed ortho-sulfonylation of 2-phenylpyridine
with ArSO2Cl.16 These methods enabled the highly regioselective
ortho-C–S bond formation; however, pyridine is required as a
directing group for such systems. Cheng et al. reported the
copper-catalyzed C–H functionalization of arenes, giving the
corresponding aryl thioethers in moderate yields; however, only
very electron-rich arenes such as 1,3,5-trimethoxybenzene and
1,2,4-trimethoxybenzene are suitable as the coupling partners.17
Recently, Beller et al. reported the palladium-catalyzed coupling
of arylsulfonyl cyanides with arenes, giving the diaryl thioethers
in moderate yields.18 However, some limitations remained by this
system. First, the system employs trifluoroacetic acid as a solvent
and acid sensitive functional groups may react under these
conditions. Second, ortho and para C–S formation is observed
The coupling of the resulting arylboronic esters from iridium-
catalyzed C–H activation with sulfur nucleophiles is the key
step for preparing aryl thioethers from arenes. Although the
coupling of arylboronic acids with sulfur sources including aryl
disulfide is known,10d,21 the C–S bond formation between
arylboronic esters and sulfur surrogates is undocumented.
Initially, 3,5-dimethylphenyl boronic ester was selected as a
substrate to screen the optimal reaction conditions with
0.55 equiv. of aryl disulfide as a sulfur surrogate. The results
are summarized in Table 1. The control experiments showed
that no product was obtained when the reaction was carried
out in the absence of the catalyst (Table 1, entry 1), and only a
trace amount of product was observed when the reaction was
performed without a ligand (Table 1, entry 2). The combi-
nation of CuI with bpy (2,20-dipyridyl) in the solvent of
DMSO–H2O showed good reactivity,10d giving the target in
78% isolated yield (Table 1, entry 3). A low yield was observed
when the reaction was carried out in the absence of water
(Table 1, entry 4); this phenomenon has also been recognized
in the copper-catalyzed coupling of nucleophiles with aryl-
boronic esters.20f,g Other solvent systems, including the
comb!ination of EtOH, DMF, or dioxane with water, could
not provide satisfactory results (Table 1, entries 5–7). Inter-
estingly, lower and higher temperatures diminished the yield of
the product (Table 1, entries 8 and 9, respectively). We studied
the effect of ligands (Table 1, entries 10–13), and the results
Department of Chemistry, National Chung Hsing University,
Taichung, 402, Taiwan, R.O.C. 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: Experimental
details, spectral data for new products. See DOI: 10.1039/c2cc33950a
c
8440 Chem. Commun., 2012, 48, 8440–8442
This journal is The Royal Society of Chemistry 2012

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Table 1 Optimized reaction conditionsa
Table 2 Synthesis of diaryl thioethers through tandem C–H boryla-
tion and copper-catalyzed CꢀS coupling reactionsa
Entry
‘‘Cu’’
Ligand
Solvent
Yieldb (%)
1
2
3
4
5
6
7
—
—
—
bpy
bpy
bpy
bpy
bpy
bpy
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO
—
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
CuO
Cu2O
CuCl
Trace
78
29
54
49
21
64
58
Trace
75
74
70
88
EtOH/H2O (2 : 1)
DMF/H2O (2 : 1)
Dioxane/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
DMSO/H2O (2 : 1)
8c
9d
10
11
12
13
14
15
16
17e
18f
bpy
dmphen
dmbpy
dtbpy
phen
bpy
bpy
bpy
bpy
bpy
54
Trace
37
51
a
Reaction conditions: Cu source (0.05 mmol, 5 mol%), ligand
(0.05 mmol, 5 mol%), 3,5-dimethylphenyl boronic ester (1.0 mmol) and
diphenyl disulfide (0.55 mmol) in 0.6 mL solvent. Isolated yield. c 70 1C.
b
d
f
110 1C. e Cu2O: 2.5 mol%. CuCl (3.0 mol%) and bpy (3.0 mol%).
revealed that other ligands such as dmphen (2,9-dimethyl-1,10-
phenanthroline), dmbpy (4,40-dimethyl-2,20-bipyridine), dtbpy
(4,40-di-tert-butyl-2,20-dipyridyl) and phen (1,10-phenanthro-
line) could not provide the product in a good yield. The
screening of copper sources (Table 1, entries 14–17) showed
that CuCl is the best (Table 1, entry 14), giving the product in
88% isolated yield under air at 80 1C. Lower catalyst loading
will reduce the product yield (Table 1, entry 18).
a
Reaction conditions unless otherwise stated: arene (1.0 mmol),
[Ir(cod)OMe]2 (0.0015 mol, 0.15 mol%), dtbpy (0.003 mmol,
0.3 mol%) in 1.5 mL THF for the first step; CuCl (0.05 mmol,
5.0 mol%), bpy (0.05 mmol, 5.0 mol%), disulfide (0.55 mmol) in
Based on the optimized reaction conditions in hand, we then
studied the tandem regioselective meta C–H borylation followed by
C–S bond formation in one pot. As demonstrated in Table 2,
a variety of 1,3-disubstituted arenes and thiophenols bearing
electron-donating and electron-withdrawing substituents were
reacted with B2Pin2 in the presence of iridium catalyst to give the
arylboronates,20f,g,i,j after removing the volatile components, the
reaction mixtures were further conducted with aryldisulfides using
copper catalysis, giving the corresponding diaryl thioethers in
good yields. Meanwhile, free amine (3d, 3o), chloro (3b–3g,
3k–3p and 3u), trifluoromethyl (3h–3j), bromo (3q and 3r) and
nitrogen-containing moieties (3t and 3u) all tolerate the reaction
conditions employed. The halogen-containing products are
particularly amenable to further modification.
b
0.4 mL DMSO and 0.2 mL H2O for the second step. Borylation with
c
0.1 mol% [Ir(cod)OMe]2 and 0.2 mol% dtbpy. Borylation with
3.0 mol% [Ir(cod)OMe]2 and 6.0 mol% dtbpy.
nBu–S–S–nBu, tBu–S–S–tBu, C12H25–S–S–C12H25 and
Me–Se–Se–Me as the coupling partners. Unfortunately, only
trace amounts of the targets were detected by GC-MS analy-
sis. The corresponding arylboronic esters and the starting
dialkyl chalcogenides were both observed as the major materi-
als in such cases.
In conclusion, we have developed a general method for the
regioselective synthesis of diaryl chalcogenides through the
iridium-catalyzed meta C–H borylation followed by copper-
catalyzed C–S coupling reaction with aryl dichalcogenides in
one pot allowing for the direct synthesis of 3,5-disubstituted
diaryl chalcogenides. Preparation of diaryl chalcogenides for
bioactive tests and improvement for the synthesis of aryl–alkyl
chalcogenides are underway in our laboratory.
We next turned our attention to the regioselective meta
C–Se and C–Te bond formations. The results are summarized
in Table 3, the diaryl selenides (4a–4f) and diaryl tellurides
(4g–4k) were obtained when the reactions were conducted with
diselenides and ditellurides, respectively. In general, the diaryl
selenides and tellurides are obtained in moderate to good
yields. Although good results are observed by the reactions
of diaryl chalcogenides, unfortunately, the dialkyl chalcogen-
ides are not suitable as the coupling partners for the synthesis
of aryl–alkyl chalcogenides under the catalysis shown above.
Indeed, we have tried many dialkyl chalcogenides including
Financial support from the National Science Council,
Taiwan (NSC 99-2113-M-005-004-MY2) and the National
Chung Hsing University is gratefully acknowledged. We thank
Prof. Fung-E Hong (NCHU) for generously sharing his
GC-MS instruments. C. F. L. is a Golden-Jade Fellow of
Kenda Foundation, Taiwan.
c
This journal is The Royal Society of Chemistry 2012
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Table 3 Tandem C–H borylation and copper-catalyzed C–Se, C–Te
coupling reactionsa
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a
Reaction conditions unless otherwise stated: arene (1.0 mmol),
[Ir(cod)OMe]2 (0.0015 mol, 0.15 mol%), dtbpy (0.003 mmol,
0.3 mol%) in 1.5 mL THF for the first step; CuCl (0.05 mmol,
5.0 mol%), bpy (0.05 mmol, 5.0 mol%), diaryl selenide or diaryl telluride
(0.55 mmol) in 0.4 mL DMSO and 0.2 mL H2O for the second step.
b
Borylation with 0.1 mol% [Ir(cod)OMe]2 and 0.2 mol% dtbpy.
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8442 Chem. Commun., 2012, 48, 8440–8442
This journal is The Royal Society of Chemistry 2012