An efficient sulfenylation of aromatics using highly active quinone mono O,S-acetal bearing a pentafluorophenylthio group

Article abstract of DOI:10.1016/S0040-4039(00)02186-9

A facile sulfenylation of various aromatic nuclei was achieved by use of the novel sulfenylation reagent, the quinone mono O,S-acetal bearing a pentafluorophenylthio group. It functioned below 0°C in the presence of a catalytic amount of TMSOTf.

Full text of DOI:10.1016/S0040-4039(00)02186-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1077–1080
An efficient sulfenylation of aromatics using highly active
quinone mono O,S-acetal bearing a pentafluorophenylthio group
Masato Matsugi, Kenji Murata, Hisanori Nambu and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
Received 10 October 2000; revised 9 November 2000; accepted 24 November 2000
Abstract—A facile sulfenylation of various aromatic nuclei was achieved by use of the novel sulfenylation reagent, the quinone
mono O,S-acetal bearing a pentafluorophenylthio group. This reagent functions below 0°C in the presence of a catalytic amount
of TMSOTf. © 2001 Elsevier Science Ltd. All rights reserved.
nium intermediates, and (iv) coupling reaction via radi-
cal cation. These approaches, however, often require
basic, acidic or heating conditions during the sulfenyla-
tion process.3g We have recently reported a novel and
efficient sulfenylation reagent (1a) having quinone
mono O,S-acetal moiety under mild conditions.4 The
reagent aromatizes below room temperature during the
reaction with various nucleophiles (2) leading to the
corresponding sulfenylated products (3) in high yields.
Although 1a is useful for the sulfenylation of standard
Sulfur functionalities have great versatility as footholds
for the construction of various target molecules,1 mak-
ing the direct sulfenylation of organic compounds an
important subject in synthetic organic chemistry.2
Many methods for sulfenylation have been studied to
date3 that include (i) direct electrophilic substitution
with sulfur-containing electrophiles such as sulfenyl
chloride, sulfenamides, thiosulfonates, and disulfides,
(ii) nucleophilic substitution of aryl halides with metal
mercaptides, (iii) nucleophilic replacement via diazo-
TMS
+
O
route a
Nu-SPh
3
Sulfenylation
PhS OCOCH2Cl
b
O
Nu
TMSOTf (cat.)
MeCN, 0 ˚C
Ready aromatization
+
Nu-H
2
PhS OCOCH2Cl
O
O
Nu
1a
Nu
a
+
route b
PhS OCOCH2Cl
OCOCH2Cl
TMS
4
Addition to -position
of acetal carbon
Nu-H: (route a) silyl enol ethers, electron-rich aromatic compounds
(route b) some di- or trimethoxybenzenes
Scheme 1. Sulfenylation or nucleophilic addition to b-position of acetal carbon.
* Corresponding author. E-mail: kita@phs.osaka-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02186-9

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M. Matsugi et al. / Tetrahedron Letters 42 (2001) 1077–1080
organic compounds involving silyl enol ethers and elec-
tron-rich aromatic compounds (Scheme 1, route a),4b
unexpected desulfenylation products (4) were observed
in some electron-rich aromatic compounds such as di-
and trimethoxybenzenes (2a–c) in fair yields without
the formation of the expected sulfenylation products.
These products (4) may be formed by the addition of 2
to the b-position of the acetal carbon in 1a followed by
elimination of the phenylthio group (Scheme 1, route
b).
tafluorophenyl group in 1g makes the sulfur atom more
electrophilic, allowing chemoselective sulfenylation
reaction to become predominant.
From these findings, we produced the corresponding
pentafluorophenylthio compounds (3f–i) in high yields
by effective sulfenylation reaction using 1g on various
mono- or dimethoxybenzenes (2b–e) (Table 2, entries
1–4). When mesitylene (2f) was used as the substrate,
sulfenylation produced the thioether product (3j) in
96% yield (Table 2, entry 5). The highly reactive reagent
1g was quite effective in the sulfenylation of indole (2g),
indole derivatives (2h–l), 2-methoxynaphthalene (2m),
and various heteroaromatics (2n–q) (Table 2, entries
6–16). In contrast, the previously reported 1a did not
react at all with 2f and some heteroaromatics (2o–q).
Furthermore, 1a did not react with N-tosylated indole
(2h) while its reaction with N-unsubstituted indole (2g)
afforded the corresponding thioether in 69% yield.
We therefore looked into the development of a novel
method of selective sulfenylation, because sulfur func-
tionalities on aromatic ring as well as in aliphatic
compounds are very useful for synthetic transforma-
tions. For example, a sulfur functional group on aro-
matics could be easily converted to an oxygen-
functional group by aromatic Pummerer type
rearrangement5a,b and also ipso-substitution of the sul-
fur functional group by carbon substituents through a
ligand exchange reaction.5c At first, newly synthesized
quinone mono O,S-acetals (1b–g) bearing the electron-
withdrawing group on an aryl thio moiety,6 which were
obtained in 60–85% yields from the corresponding sul-
foxides,5a were examined toward the reaction with 2a.
The results of the investigation of the reaction of this
quinone with 2a are summarized in Table 1. Similar
Finally, we could control the reactivity of quinone
mono O,S-acetals by tuning the structure. The advan-
tages of the new methodology using 1g bearing a strong
electron-withdrawing pentafluorophenyl group on the
sulfur atom are as follows: (i) the sulfenylation reac-
tions are complete within 10 minutes below 0°C under
mild conditions, (ii) the dihydroquinone side product is
easily removed by treatment with weak aqueous alkali,
and (iii) relatively high yields are obtained even in the
case of indole derivatives deactivated by electron-with-
drawing groups. These reagents may prove useful in the
synthesis of biologically active substances having labile
functionalities which are sensitive to basic, acidic or
heating conditions. Besides, we confirmed that the pen-
tafluorophenylthio group works similarly to the
phenylthio group for oxidation and the pen-
tafluorophenyl sulfinyl group also behaves similarly to
results were observed when 1b bearing
a para-
chlorophenyl group on the sulfur atom was used in
place of 1a. Both the thioether product 3 and com-
pound 4a were obtained in the reaction of 2a with
quinone mono O,S-acetals (1c–f) bearing a moderately
strong electron-withdrawing group on the aromatic
ring. The reaction of 2a with 1g bearing a pen-
tafluorophenyl group on the sulfur atom exclusively
afforded the sulfenylation product (3e) in 81% yield.
Replacement of a trifluorophenyl group by a pen-
Table 1. Reaction of quinone mono O,S-acetals 1 with 1,2,3-trimethoxybenzene 2a
O
OMe
OMe
1
O
OMe
OMe
RS OCOCH2Cl
TMSOTf (cat.)
MeO
OMe
MeO
OMe
SR
+
OMe
MeCN
OCOCH2Cl
0 °C, 10 min.
2a
3
4a
Yield (%)a
Entry
R
3
4a
1
2
3
4
5
6
7
1a Ph
N.D.
N.D.
3a 16
3b 23
3c 76
3d 79
3e 81
45
46
25
28
20
13
N.D.
1b p-Cl-Ph
1c p-F-Ph
1d p-CF3-Ph
1e p-NO2-Ph
1f C6H2F3
1g C6F5
a Isolated yield.

M. Matsugi et al. / Tetrahedron Letters 42 (2001) 1077–1080
1079
Table 2. Sulfenylation of various aromatic compounds using quinone mono O,S-acetal 1g
O
C6F5S OCOCH2Cl
Nu-SC6F5
1g
Nu-H
(Substrate)
(Thioether)
TMSOTf (cat.), MeCN
-30 ~ 0˚C, 10 min.
R1 R2 R3 R4 R5
Entry
Yield (%)a
Substrate (2)
Thioether (3)
R2
1
2
3
4
5
R2
2b
2c
3f 94
OMe OMe
H
H
OMe
H
H
H
R3
R4
R1
R3
R4
R1
3g
60
OMe
H
H
83
70
96
3h
3i
2d
2e
2f
OMe
C6F5S
OMe H
H
R5
R5
H
H
H
OMe H
H
3j
Me
Me
H
Me
2g
2h
2i
R3
R3
SC6F5
R2
6
7
3k 83
H
Ts
H
H
H
H
88
3l
N
R1
R2
N
R1
8
Ac
3m
75
H
H
H
2j
CO Et
9
3n 80
H
H
H
2
3o
3p
2k
2l
84
78
10
11
H
H
CN
NO2
SC6F5
OMe
OMe
3q
3r
99
82
2m
12
2n X =NH
13
14
15
SC6F5
X = S
3s 78
2o
X
2p
X = O
78
3t
X
SC6F5
2q
16
3u
88
O
O
aIsolated yield.
the phenyl sulfinyl group in Pummerer type rearrange-
ment on aromatics and syn-elimination in aliphatics.7
The application of sulfenylation reagents as synthons is
currently under investigation.
Org. Chem. 1981, 46, 2793–2795. (e) Oae, S.; Shinhana,
K.; Kim, Y. H. Chem. Lett. 1979, 939–942. (f) Bates, D.
K.; Tafel, K. A. J. Org. Chem. 1994, 59, 8076–8080. (g)
Kita, Y.; Takada, T.; Mihara, S.; Whelen, B. A.; Tohma,
H. J. Org. Chem. 1995, 60, 7144–7148: this method is
effective for the sulfenylation of aromatic compounds; but
is not suitable for heteroaromatic compounds.
References
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K.; Murata, K.; Akai, S. Angew. Chem., Int. Ed. Engl.
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M. Matsugi et al. / Tetrahedron Letters 42 (2001) 1077–1080
7. Both cyclic and acyclic a-pentafluorophenylthioalkanones
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standard conditions.
.