FeCl3-mediated direct chalcogenation of phenols

Article abstract of DOI:10.1246/cl.2011.1254

Direct sulfenylation and selenylation of phenols using a stoichiometric amount of FeCl3 under an oxygen atmosphere has been developed. The chalcogenated phenols were shown to be suitable for preparing S- and Se-containing compounds using the reaction of the remaining hydroxy group.

Full text of DOI:10.1246/cl.2011.1254

doi:10.1246/cl.2011.1254
1254
Published on the web October 15, 2011
FeCl3-mediated Direct Chalcogenation of Phenols
Kimihiro Komeyama,* Kiyoto Aihara, Tetsuya Kashihara, and Ken Takaki*
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University,
Higashi-Hiroshima, Hiroshima 739-8527
(Received August 18, 2011; CL-110694; E-mail: kkome@hiroshima-u.ac.jp)
Direct sulfenylation and selenylation of phenols using a
Table 1. Screening of reaction conditions for the reaction of
4-cresol and diphenyl disulfidea
stoichiometric amount of FeCl3 under an oxygen atmosphere has
been developed. The chalcogenated phenols were shown to be
suitable for preparing S- and Se-containing compounds using the
reaction of the remaining hydroxy group.
Yield of
Entry Metal (equiv)
Solvent
Aromatic thio- and seleno-ethers are valuable motifs. In
particular, diaryl sulfides and selenides are frequently found in
biological and pharmaceutical active molecules1 and drugs.2 To
synthesize these molecules, numerous procedures have been
explored; for example, classical methods using thermal3 and
basic4 reactions reported. Recently, these have been improved by
using more powerful methods involving transition-metal cata-
lysts.5 However, direct chalcogenation of aromatic C-H bonds is
limited to highly nucleophilic aromatics like indoles,6 that of
other aromatic compounds are rare.7
Phenols are key intermediates and show attractive reactiv-
ities in organic synthesis. For instance, they can be transformed
to diaryl ethers by means of Ullmann-type cross-coupling
reactions.8 Moreover, they can be easily converted to the
pseudohalide-like sulfonates and sulfonamides which enable
various cross-coupling reactions.9 Despite their unique reactivity
and widespread utilization, few practical methods for sulfenyl-
ation and selenylation of phenols have been reported.7a-7e These
methods require a large excess of dichalcogenides (or phenols)
and harsh reaction conditions, resulting in low product yields
and narrow substrate scope. During our study of new synthetic
utilizations with iron complexes, it was discovered that an iron
salt like FeCl3 was a highly effective reagent for the sulfenyl-
ation and selenylation of phenols, making the synthesis of a
wide range of chalcogenated phenols possible under an oxygen
atmosphere.
2-SPh-2ab/%
1
2
3
4
5
6
7
8
9
10c
11d
12
13
14
15
16
17
18
19
20
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (1)
FeCl3 (0.5)
FeCl3 (0.1)
FeCl3 (1)
FeCl3 (1)
FeBr3 (1)
Fe(acac)3 (1)
FeCl2 (1)
CuCl2 (1)
Cu(OAc)2 (1)
DCM
MeNO2
DCE
Toluene
Et2O
96 (88)
82
59
40
8
3
2
35
5
35
40
45
0
0
3
0
0
0
0
3
MeCN
THF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CuCl(OH)(TMEDA) (1) DCM
ZnCl2 (1)
BF3¢OEt2 (1)
AlCl3 (1)
DCM
DCM
DCM
aReaction conditions: 1a (1.0 mmol), (PhS)2 (0.5 mmol), FeCl3
(0.5 mmol), solvent (0.5 mL). bGC yield. Isolated yield is
shown in parentheses. cThe reaction was carried out under
d
argon. The reaction was carried out under air.
When 4-cresol (1a) was treated with diphenyl disulfide
and FeCl3 (1.0 equiv) in DCM at 25 °C for 4 h under O2,
2-phenylsulfanyl-4-cresol (2-SPh-2a) was obtained in 96% yield
(Entry 1, Table 1). The presence of molecular oxygen and a
stoichiometric amount of FeCl3 were crucial for the reaction to
proceed efficiently. Thus, if the reaction was carried out under
argon or by using 10 or 50 mol % of FeCl3 this resulted in a low
yield (Entries 8 and 9). More loading of FeCl3 (2 equiv)
increased the consumption rate of both the substrates (1.5 h),
although an oxidative homocoupling product, 2,2¤-biphenol,
and other unasignable products were obtained. In addition, the
reaction under argon or air atmosphere gave lower yield (Entries
10 and 11). For this direct sulfenylation, nonpolar solvents such
as DCM, MeNO2, DCE, and toluene were suitable (Entries 2-4).
In contrast, Et2O, MeCN, and THF gave sluggish yields of
2-SPh-2a (Entries 5-7). Sulfenylation using FeBr3 also provided
the desired product in a moderate yield (Entry 12), but it
occurred alongside the bromination of 1a. Other iron and
transition-metal complexes like [Fe(acac)3], FeCl2, CuCl2,
Cu(OAc)2, [CuCl(OH)(tmeda)], and ZnCl2 were not effective
at all in the reaction (Entries 13-18). It is known that BF3¢OEt2
and AlCl3 are effective reagents for the activation of disulfides to
¹
provide S-substituted sulfonium ions {RS+(LA )-SR}, which
has good electrophilic character.10 However, these Lewis acids
did not work well in the sulfenylation (Entries 19 and 20).
Once the optimal conditions had been established, the use of
various phenols in the sulfenylation was then explored. These
results are summarized in Table 2. 4-Substituted phenols were
smoothly sulfenylated at the 2-position (Entries 1-7, Table 2).
The reactions of the phenols possessing electron-withdrawing
groups, CO2Me (1e) and CHO (1f), required a high temperature
(80 °C) to generate satisfactory yields of the product (Entries 4
and 5). Interestingly, in the case of 1f, although the conversion
of substrates was very low (each ca. 30%), the sulfenylated
Chem. Lett. 2011, 40, 1254-1256
© 2011 The Chemical Society of Japan
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1255
Table 2. Reaction of various phenols with diphenyl disulfidea
Products 2 and yield/%b
Temp Time
Entry R (1)
/°C
/h
2-SPh 3-SPh 4-SPh
1
2
3
4-F (1b)
4-Cl (1c)
4-Br (1d)
25
25
25
4
5
4
7
8
4
6
6
6
6
6
7
7
5
4
6
5
70
61
51
77
0
0
0
0
0
0
0
0
0
0
0
0
0
20
0
0
®
®
®
®
®
®
®
8
Scheme 1.
Table 3. Reaction of various phenols with diphenyl diselenidea
4c 4-CO2Me (1e) 80
5c 4-CHO (1f)
6c 4-OH (1g)
7c 4-OMe (1h)
80
50
50
25
25
80
80
25
25
25
17
50 (25)d
44 (19)d
8
9
5-F (1i)
5-Br (1j)
86
52
63 (15)e
78
95
23
21
0
38
26
0
10c 5-Me (1k)
Products 3 and yield/%b
2-SePh 3-SePh 4-SePh
11c 5-OMe (1l)
Entry R (1)
Time/h
12
13
14
5-t-Bu (1m)
6-F (1n)
6-I (1o)
0
1
2
3
4
5
6
7
8
9
4-Me (1a)
4-Cl (1c)
4-Br (1d)
4-CO2Me (1e)
5-F (1i)
25
25
25
24
24
24
24
24
24
24
24
54
93
86
69
25
13
33
48
73
14
11
0
0
0
0
0
0
0
4
0
0
0
®
®
®
®
62
30
33
10
0
34
47
78
67
®
15c 6-CO2Me (1p) 80
15c 6-Me (1q)
16f 4-Me (1a)
80
25
32
88
0
5-Br (1j)
aReaction conditions: 1 (1.0 mmol), (PhS)2 (0.5 mmol), FeCl3
(0.5 mmol), DCM (0.5 mL). bIsolated yield. cMeNO2 was used
instead of DCM. dThe yield of 2,5-disulfenylated products.
eThe yield of 6-sulfenylated product. f(MeS)2 was used instead
of (PhS)2.
5-Me (1k)
5-OMe (1l)
5-t-Bu (1m)
6-F (1n)
10
11
82
74
6-Me (1q)
aReaction conditions: 1 (1.0 mmol), (PhSe)2 (0.5 mmol), FeCl3
(0.5 mmol), DCE (1.0 mL). Isolated yield.
product 2-SPh-2f was afforded in 17% yield without the loss of
the formyl group (Entry 5). Phenols having electron-donating
groups such as OH (1g) and OMe (1h) were more reactive,
giving rise to monosulfenylated products 2-SPh-2g (50%) and
2-SPh-2h (44%) with a formation of disulfenylated products
at the 2- and 5-positions (Entries 6 and 7). In the reaction of
5-substituted phenols, the sulfenylation occurred selectively at
the less hindered 2-position (Entries 8-12). In contrast, the
reaction of 6-substituted phenols mainly occurred at the
4-position (Entries 13-15). Additionally, dialkyl disulfides like
(MeS)2 could also take part in this reaction to lead to alkyl aryl
sulfides (Entry 16).
For the present reaction, the role of the iron salt has not been
made clear, yet. Wang and Zeni suggested that FeCl3 would be
reduced with diaryl dichalcogenides like (ArY)2 (Y = S or Se).11
Based on these reports, we tested the possibility of this reduction
in the present sulfenylation (Scheme 1). When FeCl3 was
reacted with (PhS)2 under N2 at 25 °C, an orange solution was
obtained (Scheme 1A).12 After that, the solution was treated
with 4-fluorophenol (1b) under O2, wherein a trace amount of
the sulfenylated phenol 2-Ph-2b was detected. In sharp contrast,
initial exposure of FeCl3 with 1b afforded a brown solution
(Scheme 1B), which was sequentially reacted with (PhS)2 under
O2 to provide 2-Ph-2b in 60% yield.13
b
oxidative coupling of phenol derivatives.15 Moreover, aryl- and
alkyl-radicals could be captured with disulfides and disele-
nides.16 Additionally, an addition of base such as 2,6-di-tert-
butylpyridine or Et3N (2 equivalents based on FeCl3) did not
prevent the sulfenylation.21 In view of these facts, the present
reaction might involve the trapping of the generated aryl radicals
with the disulfide.
Next, the FeCl3-mediated system was applied to the
selenylation of phenols using diphenyl diselenide (Table 3).
This selenylation also required an O2 atmosphere.17 Similar to
the above sulfenylation, various 4-, 5-, and 6-substituted phenols
were converted to the corresponding monoselenylated com-
pounds 3. However, the regioselectivity was slightly different
from the above described sulfenylation. In particular, the
selenylation of 5-substituted phenols 1i, 1j, and 1k selectively
proceeded at the 4-position (Entries 5-7), while that of similar
phenols, but with more electron-donating functions and bulkier
ones, mainly occurred at the 2-position (Entries 8 and 9).
ð1Þ
These results might indicate the generation of the iron-
phenoxide during the reaction. That is, it is known that FeCl3
reacts with the phenol to give the iron-phenoxide,14 which is
shown as an intermediate in the iron-mediated and -catalyzed
Chem. Lett. 2011, 40, 1254-1256
© 2011 The Chemical Society of Japan
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1256
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DCM, 25 °C, 6 h, O2; (b) CuTC (1.0 equiv), DMAc, 100 °C, 2 h;
(c) FeCl3 (0.5 equiv), (4-PhC6H4S)2 (0.5 equiv), MeNO2, 80 °C,
6 h, O2.
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These chalcogenated phenols obtained in the present
reactions could be used to synthesize S- and Se-containing
compounds by means of the transformation of the remaining
hydroxy group. Thus, the sulfenylated and selenylated phenols
were reacted with arylboronic acids in the presence of copper(II)
acetate to provide MeS- and PhSe-substituted diaryl ether
(eq 1).8 Moreover, the protected phenol 7 derived from 2-SMe-
2a could react with the aryl-Grignard reagent in the presence of a
palladium catalyst, giving rise to a biaryl structure possessing an
SMe group (eq 2).18 In addition, the present sulfenylation was
capable of producing halogen-containing diaryl disulfides such
as (2-BrC6H4S)2 and (3-FC6H4S)2, leading to the corresponding
diaryl sulfide 9 and 11 in good yields under identical conditions
(Scheme 2). The hydroxy function and aryl bromide moiety of
the diaryl sulfide 9 reacted intramolecularly using copper(I)-
thiophene-2-carboxylate (CuTC) to give the phenoxathiin
skeleton 10.19 Diaryl sulfide 11 is a key intermediate in the
synthesis of 12, which serves as a Gly-T1 inhibitor.20
In conclusion, the FeCl3-mediated direct synthesis of
sulfenylated or selenylated phenols was shown using the
chalcogenation of various phenols with diaryl disulfides or
diaryl diselenides with chemo- and regioselectivity. In these
reactions, the presence of an oxidant like molecular oxygen and
a stoichiometric amount of FeCl3 were crucial for these reactions
to proceed efficiently. In addition, the transformation of the
chalcogenated phenols into diaryl ethers, diarylphenoxathiin,
and Gly-T1 inhibitor was demonstrated, by means of the
conversion of the remaining hydroxy function.
8
9
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This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology of Japan. We are also grateful for
financial support from the foundation of Sanyo broadcasting.
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References and Notes
21 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
1
a) A. Marcincal-Lefebvre, J. C. Gesquiere, C. Lemer, B. Dupuis,
Chem. Lett. 2011, 40, 1254-1256
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/