Mechanism of the aromatic hydroxylation of thiophene by acid-catalyzed peracid oxidation

Article abstract of DOI:10.1021/jo0202177

The oxidation of thiophene (1) with peracids in a strongly acidic environment yielded thiophen-2-one (4) as the product of an apparent direct hydroxylation of the thiophene aromatic ring together with the anticipated thiophene-S-oxide dimers, 2a,b, as the main products. Formation of the latter dimers can be rationalized in a straightforward manner by initial oxidation at the sulfur atom of thiophene (1) to yield thiophene-S-oxide followed by subsequent dimerization in a Diels-Alder type reaction. Trapping experiments in the presence of a competing dienophile indicated that thiophen-2-one (4) did not originate from the monomeric thiophene-S-oxide but was the product of an independent reaction pathway. The extent of thiophen-2-one (4) formation correlated with the acidity of the reaction medium and was suppressed in the presence of water, the latter presumably acting as a competing base. As evidenced by the use of 2,5-dideuterated thiophene (1-D), its mechanism of formation involved a 1,2-hydride shift, a feature commonly described in the peracid-mediated epoxidation of aromatic hydrocarbons and indicative for the occurrence of cationic intermediates. In agreement with all these observations we propose a mechanism involving initial protonation of thiophene followed by nucleophilic attack of the peracid in position 2 of the thiophene ring. Intramolecular epoxidation may lead to the formation of thiophene 2,3-epoxide as a highly reactive intermediate that then undergoes heterolytic ring opening and a 1,2-hydride shift to yield thiophen-2-one (4) after a final, acid-catalyzed, isomerization of the double bond.

Full text of DOI:10.1021/jo0202177

Mech a n ism of th e Ar om a tic Hyd r oxyla tion of Th iop h en e by
Acid -Ca ta lyzed P er a cid Oxid a tion
Alexander Treiber*
Actelion Pharmaceuticals Ltd., Department of Preclinical Drug Metabolism and Pharmacokinetics,
Gewerbestrasse 16, 4123 Allschwil, Switzerland
alexander.treiber@actelion.com
Received March 29, 2002
The oxidation of thiophene (1) with peracids in a strongly acidic environment yielded thiophen-2-
one (4) as the product of an apparent direct hydroxylation of the thiophene aromatic ring together
with the anticipated thiophene-S-oxide dimers, 2a ,b, as the main products. Formation of the latter
dimers can be rationalized in a straightforward manner by initial oxidation at the sulfur atom of
thiophene (1) to yield thiophene-S-oxide followed by subsequent dimerization in a Diels-Alder
type reaction. Trapping experiments in the presence of a competing dienophile indicated that
thiophen-2-one (4) did not originate from the monomeric thiophene-S-oxide but was the product of
an independent reaction pathway. The extent of thiophen-2-one (4) formation correlated with the
acidity of the reaction medium and was suppressed in the presence of water, the latter presumably
acting as a competing base. As evidenced by the use of 2,5-dideuterated thiophene (1-D), its
mechanism of formation involved a 1,2-hydride shift, a feature commonly described in the peracid-
mediated epoxidation of aromatic hydrocarbons and indicative for the occurrence of cationic
intermediates. In agreement with all these observations we propose a mechanism involving initial
protonation of thiophene followed by nucleophilic attack of the peracid in position 2 of the thiophene
ring. Intramolecular epoxidation may lead to the formation of thiophene 2,3-epoxide as a highly
reactive intermediate that then undergoes heterolytic ring opening and a 1,2-hydride shift to yield
thiophen-2-one (4) after a final, acid-catalyzed, isomerization of the double bond.
In tr od u ction
The oxidation of organic sulfides to the corresponding
The chemical access to thiophene-S-oxides is complicated
by the intrinsically high reactivity of this class of
compounds. While organic sulfides can be selectively
oxidized to the corresponding sulfoxides by simple kinetic
control, i.e., limitation of the amount of oxidant and/or
low reaction temperatures, this method completely fails
for the oxidation of thiophenes. As a consequence of the
involvement of the sulfur lone pair in the aromatic
1
-3
sulfoxides and sulfones is a well-understood process
for which a large variety of synthetic methods exists.4-9
In contrast, the analogous transformation of thiophenes
in which the sulfur atom is an integral part of the
aromatic system is much less explored, though numerous
attempts toward a selective synthesis of thiophene-S-
oxides have been reported during the past 4 decades.1
2
system, the two oxidation potentials (S-SO and SO-SO )
0-17
are too close to allow control at the stage of the thiophene-
S-oxide. Therefore, thiophene-S,S-dioxides are the usual
products isolated from oxidations of thiophenes with
*
To whom correspondence should be addressed. Phone +41/61/487
5 92. FAX +41/61/487 45 00.
1) Srinivasan, C.; Chellamani, A.; Kuthalingam, P. J . Org. Chem.
982, 47, 428-431.
2) Henbest, H. B.; Khan, S. A. J . Chem. Soc., Chem. Commun. 1968,
036.
4
1
1
peracids,1
0-13
dimethyldioxirane, or oxodiperoxymolyb-
5
15
(
14
denum (MoO
-HPMT). The rare examples of stable
(
thiophene-S-oxides comprise systems with bulky substit-
uents in positions 2 and 5.1
8-19
This steric encumbrance
(
(
(
(
3) Oae, S.; Takata, T. Tetrahedron Lett. 1980, 21, 3213-3216.
4) Modena, G.; Todesco, P. E. J . Chem. Soc. 1962, 4920-4926.
5) Curci, R.; Modena, G. Tetrahedon Lett. 1963, 1749-1752.
6) Beckenbauer, R.; Smart, B. E. J . Org. Chem. 1995, 60, 6186-
is necessary to suppress another common reaction path-
way of thiophene-S-oxides, i.e., their dimerization in a
Diels-Alder-type fashion.1
0,20
However, thiophene-S-
6
6
1
187.
(
7) Colonna, S.; Gaggero, N. Tetrahedron Lett. 1989, 111, 6233-
236.
(8) Riley, D. P.; Smith, M. R.; Correa, P. E. J . Am. Chem. Soc. 1988,
(15) Miyahara, Y.; Inazu, T. Tetrahedron Lett. 1990, 31, 5955-5958.
(16) Thiemann, T.; Li, Y.; Thiemann, C.; Sawada, T.; Ohira, D.;
Tashiro, M.; Mataka, S. Heterocycles 2000, 52, 1215-1230.
10, 177-180.
(
9) Holland, H. L. Chem. Rev. 1988, 88, 473-485.
(10) Davies, W.; Gamble, N.; J ames, F.; Savige, W. Chem. Ind. 1952,
(17) For some recent reviews see: (a) Thiemann, T. Kyushu Daigaku
Chuo Bunseki Senta Hokoku 2001, 18, 1-7 (English). (b) Thiemann,
T.; Arima, K.; Kumazoe, K.; Mataka, S. Kyushu Daigaku Kino
Busshitsu Kagaku Kenkyusho Hokoku 2000, 14, 139-148 (English).
(c) Nakayama, J .; Sugihara, Y. Sulfur Rep. 1997, 19, 349-375.
(18) Mock, W. L. J . Am. Chem. Soc. 1970, 92, 7610-7612.
8
3
04.
(
11) Melles, J . L.; Backer, H. J . Trav. Rec. Chim. 1953, 72, 316-
28.
(
(
(
12) Davis, W.; J ames, F. C. J . Chem. Soc. 1954, 15-18.
13) van Tilborg, W. J . M. Synth. Commun. 1976, 6, 583-589.
14) Chien, C.-S.; Kawasaki, T.; Sakamoto, M. Chem. Pharm. Bull.
(19) Pouzet, P.; Erdelmeier, I.; Ginderow, D.; Mornon J .-P.; Dansette,
P. M.; Mansuy, D. J . Chem. Soc., Chem. Comm. 1995, 473-474.
1
985, 11, 5071-5074.
1
0.1021/jo0202177 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/24/2002
J . Org. Chem. 2002, 67, 7261-7266
7261

Treiber
TABLE 1. In flu en ce of Va r ia tion of Rea ction
Con d ition s on P r od u ct Distr ibu tion in th e Oxid a tion of
Th iop h en ea
timeb 2 + 3
c,d
4e
entry
oxidant
cat. acid
none
CF3CO2H
CF3CO2H
CCl3CO2H
CHCl2CO2H 41
CH2ClCO2H 90
CH3CO2H
none
[h]
[%]
[%] (2 + 3)/4
1
2
3
4
5
6
7
8
9
m-CPBA
m-CPBA
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
30% H2O2
192
15
11
76f
48
58
57
32
22
ndg
14
7
4
1
77:23
89:11
93:7
97:3
99:1
30
F IGURE 1. Product distribution in the TFA-catalyzed peracid
oxidation of thiophene (1).
0.5
nd
f
456
6
oxides, either isolated or generated in situ, have been
used for the synthesis of thiophene-containing cephalo-
sporines and for studies on the effects of the stereoelec-
tronic control of Diels-Alder reactions with substituted
cyclopentadienes.21 More recently, they have been identi-
fied as the primary reactive metabolites in the cyto-
chrome P450-catalyzed oxidation of thiophene-containing
h
192
0.5
2.5
21
17
20
nr
23
54
71
55
83
i
DMD
none
nd
18
18
6
10
100% H2O2 CF3CO2H
75:25
80:20
90:10
98:2
1
1
1
1
2
3
85% H2O2
15% H2O2
8% H2O2
CF3CO2H
CF3CO2H
CF3CO2H
2
a
In methylene chloride at 20 °C, thiophene/acid/oxidant ratio
ca. 1:3:0.2. b Time until complete consumption of the oxidant was
drugs in vitro2
2,23
and in vivo.
24,25
In an earlier com-
c
indicated by using KI/starch. Diels-Alder dimers 2 and sesqui-
munication, we have shown that thiophene itself is
metabolized in vivo in rats and in vitro with rat liver
oxide 3 were quantified by using HPLC-UV (for conditions, see
d
Experimental Section), error ca. 3% of given values. Yields of
sesquioxide 3 were, if not otherwise stated, usually below the
microsomes to the corresponding thiophene-S-oxide, which
detection limit. e Thiophen-2-one (4) was quantified by H NMR
1
underwent subsequent Diels-Alder dimerization.26 The
f
spectroscopy using 1,2-dichloroethane as internal standard. The
H
2
O
2
/trifluoroacetic acid system was introduced as a
g
h
only detected compound was sesquioxide 3. Not detected. No
synthetic tool for the selective mono-oxygen transfer to
thiophene allowing for preparation of sufficient material
to elucidate the exact chemical structure of these dimers.
In this report, we describe another feature of this
particular oxidation system, i.e., the direct hydroxylation
of the thiophene aromatic ring via an independent
reaction pathway presumably bypassing the stage of a
highly unstable thiophene epoxide.
i
reaction. Dimethyldioxirane.
S-oxide dimers 2 and sesquioxide 3 was described in
detail in an earlier communication.26 Product ratios and
yields were calculated after quantification with HPLC-
UV using external calibration with authentic samples of
all three products. In addition to these Diels-Alder
dimers, thiophen-2-one (4) was detected in the organic
phase of the crude extract. Thiophen-2-one (4) was
identified by comparison of its NMR and IR character-
istics with those of an authentic sample prepared by acid-
Resu lts
The oxidation reactions with thiophene (1) were carried
out in methylene chloride at ambient temperature using
2
7
catalyzed pyrolysis of 2-tert-butoxythiophene after ini-
tial purification by silica gel chromatography.
0
.2 equiv of the respective oxidant except for the reaction
with dimethyldioxirane, for which acetone was used. The
various substituted peracetic acids were prepared in situ
by adding 30% H O to a solution of the respective acetic
2 2
The experimental conditions, product ratios, and yields
of the various oxidation reactions of thiophene (1) are
summarized in Table 1. The oxidation of 1 with meta-
chloroperbenzoic acid (m-CPBA) yielded sesquioxide 3 as
the only product in 76% yield (based on the oxidant; entry
1). When the oxidation with m-CPBA was carried out in
the presence of 3 equiv of trifluoroacetic acid under
otherwise identical experimental conditions, formation
of sesquioxide 3 was no longer observed. Instead, the
reaction yielded a mixture of the two thiophene-S-oxide
dimers, 2a and 2b, together with thiophen-2-one (4) in
62% overall yield and a normalized product ratio 2/4 of
77:23 (entry 2).
acid in methylene chloride in a ratio of about 1:3. The
initially biphasic reaction systems homogenized upon
vigorous stirring and oxidation reactions were carried out
after complete homogeneity was attained.
The oxidation of thiophene (1) yielded two different
types of oxidation products, i.e., a mixture of two dia-
stereoisomeric thiophene-S-oxide dimers, 2a and 2b, and
a so-called sesquioxide 3 on one hand and on the other
hand thiophen-2-one (4) (Figure 1). The isolation and
structural characterization of the water-soluble thiophene-
To gain a better understanding of the molecular
mechanisms determining the formation of Diels-Alder
products 2 and 3 or thiophen-2-one (4), the influence of
the strength of the oxidant, pH of the reaction medium,
and the presence of water or a competing Diels-Alder
dienophile on the product distribution was systematically
studied. The effect of the strength of the oxidizing agent
is reflected by the changes in the reaction times (entries
(
20) Thiemann, T.; Ohira, D.; Li, Y.; Sawada, T.; Mataka, S.; Rauch,
K.; Noltemeyer, M.; de Meijere, A. J . Chem. Soc. Perkin Trans. 1 2000,
7, 2968-2976.
21) Naperstkow, A. M.; Macauley, J . B.; Newlands, M. J .; Fallis,
A. G. Tetrahedron Lett. 1989, 30, 5077-5080.
22) Mansuy, D.; Valadon, P.; Erdelmeier, I.; Lopez-Garcia, P.; Amar,
C.; Girault, J .-P.; Dansette, P. M. J . Am. Chem. Soc. 1991, 113, 7825-
826.
23) Ha-Duong, N.-T.; Dijols, S.; Macherey, A.-C.; Goldstein, J . A.;
Dansette, P. M.; Mansuy, D. Biochemistry 2001, 40, 12112-12122.
24) Dansette, P. M.; Thang, D. C.; El Hamri, A.; Mansuy, D.
Biochem. Biophys. Res. Commun. 1992, 186, 1624-1630.
25) Schlenk, D.; Bevers, R. J .; Vertino, A. M.; Cerniglia, C. E.
Xenobiotica 1994, 24, 1077-1083.
26) Treiber, A.; Dansette, P. M.; El Amri, H.; Girault, J .-P.;
Ginderow, D.; Mornon, J .-P.; Mansuy, D. J . Am. Chem. Soc. 1997, 119,
565-1571.
1
(
(
7
(
3
-9, Table 1) with the expected inverse correlation
(
between oxidizing power and reaction time. In contrast,
product distributions in this series of experiments did not
(
(
(27) J akobsen, H. J .; Larson, E. H.; Lawesson, S.-O. Tetrahedron
1963, 19, 1867-1882.
1
7
262 J . Org. Chem., Vol. 67, No. 21, 2002

Thiophene Hydroxylation by Acid-Catalyzed Oxidation
F IGURE 3. Oxidation of 2,5-dideuterated thiophene (1-D)
with trifluoroperactic acid. Percentages indicate the degree of
deuteration in the respective positions. Percentages in paren-
theses indicate the degree of deuteration in a control experi-
ment monitoring the rate of H/D exchange of thiophen-2-one.
F IGURE 2. Product distribution in the TFA-catalyzed peracid
oxidation of thiophene (1) in the presence of N-phenylmale-
imide.
2 2
water-free H O and deuterated trifluoroacetic acid under
correlate with the strength of the oxidant. Though within
the series of substituted peracetic acids there was a
decrease of the relative yields of thiophen-2-one (4)
ranging from 11% with trifluoroperacetic acid to 1% with
chloroperacetic acid, this correlation did not hold with
dimethyldioxirane. Dimethyldioxirane is one of the
strongest known oxidants,28 as suggested by the short
reaction time of 0.5 h (entry 9), but did not yield any
thiophen-2-one (4). These results suggest the presence
of the acid as a prerequisite for thiophen-2-one (4)
formation. The extent of thiophen-2-one (4) formation
clearly correlated with the acidity of the reaction medium
experimental conditions identical to those used for the
oxidation of unlabeled thiophene (1) (Figure 3). The
extent of deuterium incorporation in the different posi-
tions of thiophen-2-one (4) was determined by quantita-
1
tive H NMR spectroscopy directly from the crude reac-
tion mixture to avoid postexperimental H/D exchange
upon workup. In this experiment, 78% and 90% of
deuteration was determined in positions 3 and 5 of
thiophen-2-one (4). In a control experiment, the rate of
H/D exchange in thiophen-2-one (4) was determined by
1
3
H NMR spectroscopy in CDCl in the presence of 50
equiv of deuterated trifluoroacetic acid. After 17 h, i.e.,
the reaction time of the thiophene oxidation experiment,
deuteration was 12% and 72% in positions 3 and 5,
respectively. The yield of deuterated thiophen-2-one (4)
was 15%, i.e., comparable to that obtained in the oxida-
tion of nonlabeled thiophene (1).
in the order trifluoroacetic acid (pK
trichloroacetic acid (pK ) 0.70, 7%) > dichloroacetic
acid (pK ) 1.48, 3%) > chloroacetic acid (pK ) 2.85,
%) > acetic acid (pK ) 4.75, no formation of 4).
a
) 0.23, 11% of 4)29
>
a
a
a
1
a
Accordingly, no thiophen-2-one (4) was found in the
oxidations with m-CPBA and dimethyldioxirane (entries
1
and 9). In control experiments, it was shown that 4
Discu ssion
did not undergo further oxidation with m-CPBA and
dimethyldioxirane under the applied experimental condi-
tions. The importance of acid catalysis for the formation
of 4 was also demonstrated by the addition of water as a
competing base. Whereas the relative yields of 4 were
about 25% in the apparent absence of water in the
oxidations with m-CPBA/trifluoroacetic acid and 100%
In an earlier communication we described for the first
time the formation of thiophene-S-oxide dimers 2a ,b as
the products of thiophene metabolism in vivo in rats and
in vitro using rat liver microsomes.26 The H
O /trifluoro-
2 2
acetic acid system was introduced as a selective tool for
the controlled mono-oxygen transfer to thiophene mim-
icking the enzymatic oxidation process of thiophene.
Protonation of the sulfoxide under the acidic reaction
conditions was proposed as the protective mechanism
against a second electrophilic attack of the oxidant on
the sulfur atom thus preventing the oxidation to the
thiophene sulfone. The exact chemical structures of the
two diastereoisomeric thiophene-S-oxide dimers, 2a and
H
2
O
2
/trifluoroacetic acid (entries 2 and 10) they decreased
steadily with increasing amounts of water present in the
reaction system down to 2% when 8% H was used
entry 13).
Further mechanistic insight was gained by the use of
N-phenylmaleimide as a competing dienophile. Oxidation
of thiophene (1) with 0.2 equiv of water-free H in the
2
O
2
(
2
O
2
2
b, were elucidated by a combination of X-ray crystal-
presence of trifluoroacetic acid yielded the literature-
lography data and a sequence of chemical reactions.
Furthermore, sesquioxide 3 was identified as a secondary
oxidation product rather than the suspected product of
a Diels-Alder reaction between thiophene-S-oxide and
thiophene-S,S-dioxide (Scheme 1). Whereas the formation
of all these products can be rationalized by an initial
oxidation of the sulfur atom of thiophene (1), the mech-
anism behind the formation of thiophen-2-one (4) is less
evident. Aromatic hydroxylations are commonly de-
known Diels-Alder adduct of thiophene-S-oxide and
N-phenylmaleimide 526 and thiophen-2-one (4) as the only
products. The product distribution was determined as
1
7
5:25 in favor of 5 by quantitative H NMR spectroscopy
on the crude reaction mixture (Figure 2). In the chemistry
of arene oxides, a characteristic 1,2-hydride shift, the so-
called NIH-shift,3
0,31
was established as a mechanistic
feature of the spontaneous isomerization of arene ep-
3
2,33
oxides to the corresponding phenols.
The oxidation
of 2,5-dideuterated thiophene (1-D)34 was performed with
scribed in the cytochrome P450-catalyzed biotransfor-
mations of thiophene-containing drugs.2
3,35-39
Their exact
(
28) Adam, W.; Hadjiarapoglou, L.; Curci, R.; Mello, R. In Organic
Peroxides; J . Wiley and Sons: New York, 1992; pp 195-217.
29) pK values of the substituted acetic acids were taken from: CRC
(33) J erina D. M.; Daly, J . W.; Witkop, B.; Zaltzman-Nirenberg, P.;
Udenfriend, S. Biochemistry 1970, 9, 147-155.
(
a
Handbook of Chemistry and Physics, 54th ed.; Weast, R. C.; CRC
Press: Cleveland, 1973.
(34) O¨ stman, B.; Olsen, S. Ark. Kemi 1960, 15, 275-282.
(35) Mansuy, D.; Dansette, P. M.; Foures, C.; J aouen, M.; Moinet,
G.; Bayer, N. Biochem. Pharmacol. 1984, 33, 1429-1435.
(36) Mori, Y.; Sakai, Y.; Kuroda, N.; Yokoja, F.; Toyoshi, K.; Hori,
M.; Baba, S. Drug Metab. Dispos. 1984, 12, 767-771.
(
30) Guroff, G.; Daly, J . W.; J erina D. M.; Renson, J .; Witkop, B.;
Udenfriend, S. Science 1967, 157, 1524-1530.
31) Daly, J . W.; J erina, D. M.; Witkop, B. Experientia 1972, 28,
129-1164.
32) J erina, D. M.; Daly, J . W. Science 1974, 185, 573-582.
(
1
(37) Ishihara, S.; Tsuyuki, Y.; Tomisawa, H.; Fukasawa, H.; Na-
kayama, N.; Tateishi, M.; J oly, R. Xenobiotica 1984, 14, 727-739.
(
J . Org. Chem, Vol. 67, No. 21, 2002 7263

Treiber
SCHEME 1. Mech a n istic P a th w a ys for P r od u ct F or m a tion in th e Acid -Ca ta lyzed P er a cid Oxid a tion of
Th iop h en e (1)
SCHEME 2. Mech a n istic Alter n a tives for th e Oxid a tion of Ar om a tic Hyd r oca r bon s w ith
Tr iflu or op er a cetic Acid
mechanism of formation and particularly the nature of
the primary reactive intermediate are still a matter of
scientific debate. Reports on the direct hydroxylation of
thiophene derivatives by chemical means are rare. The
formation of juglone was reported together with the
expected 1,4-naphthoquinone in the oxidation of thiophene
with perbenzoic acid in the presence of 1,4-benzoquinone
as trapping agent.40 Recently, the formation of thiophen-
same primary intermediate, i.e., thiophene-S-oxide. In
analogy to thiophene, the oxidation of alkyl-substituted
benzene derivatives with trifluoroperacetic acid was also
described to lead to phenolic products.4
2-45
Mechanistic
considerations postulated the initial formation of a
4
6
charge-transfer complex or a direct epoxidation of the
33
aromatic ring (Scheme 2). Common to both mechanisms
is the occurrence of cationic intermediates that undergo
a characteristic 1,2-hydride shift, the so-called NIH-
2
-one was reported as the result of a Pummerer-like
rearrangement of 2,5-bis(trimethylsilyl)-thiophene-S-
oxide in the presence of trifluoroacetic anhydride.41
The product ratios in the oxidations of thiophene (1)
30
shift, on their way to the final phenol products. If either
of these two mechanisms applied for the formation of
thiophene-2-one (4) the extent of its formation should
correlate with the electrophilicity of the oxidant. The
results of the oxidation with dimethyldioxirane, however,
clearly show that such a correlation does not exist since
the strongest oxidant used in these experiments did not
2 2
with m-CPBA and H O in the presence of an excess of
trifluoroacetic acid (entries 2 and 10 in Table 1) were
about 75:25 in favor of the Diels-Alder products and not
affected by the use of N-maleinimide as a competing
trapping agent. It appears therefore unlikely that the
dimers 2a ,b and thiophen-2-one (4) are formed via the
(42) Chambers, R. D.; Goggin, P.; Musgrave, W. K. R. J . Chem. Soc.
1
959, 1804-1807.
(
38) Nishikawa, T.; Nagata, O.; Tanbo, K.; Yamada, T.; Takahara,
Y.; Kato, H.; Yamamoto, Y. Xenobiotica 1985, 15, 1053-1060.
39) Lynch, M. J .; Mosher, F. R.; Levesque, W. R.; Newby, T. J . Drug
(43) Buehler, C. A.; Hart, H. J . Am. Chem. Soc. 1963, 85, 2177-
2178.
(
(44) Waring, A. J .; Hart, H. J . Am. Chem. Soc. 1964, 86, 1454-
1456.
(45) Hart, H.; Buehler, C. A. J . Org. Chem. 1964, 29, 2397-2400.
(46) J erina, D. M.; Daly, J . W.; Witkop, B. Biochemistry 1971, 10,
366-372.
Metab. Rev. 1987, 18, 253-288.
(
(
40) Torsell, K. Acta Chim. Scand. 1976, B30, 353-357.
41) Sato, S.; Zhang, S.-Z.; Furukawa, N. Heteroat. Chem. 2001, 12,
4
44-450.
7
264 J . Org. Chem., Vol. 67, No. 21, 2002

Thiophene Hydroxylation by Acid-Catalyzed Oxidation
SCHEME 3. P r op osed Mech a n ism for F or m a tion of Th iop h en -2-on e (4)
yield any thiophen-2-one (4) at all. Moreover, these
mechanisms do not explain the need for acid catalysis.
In agreement with all experimental observations we
propose the mechanism depicted in Scheme 3.
2a ,b and thiophene-2-one (4). The mechanism of forma-
tion for the dimers 2, as well as for the secondary
oxidation product 3, can be rationalized by an initial
oxidation at the sulfur atom to yield thiophene-S-oxide
followed by a Diels-Alder-type dimerization. Thiophen-
2-one (4) is most likely formed by an independent reaction
pathway involving primary protonation and nucleophilic
attack of the oxidant at the 2-position of the thiophene
ring. Further intramolecular epoxidation, followed by
ring opening of the highly strained thiophene epoxide,
and a 1,2-hydride shift complete the reaction sequence.
The initial step of this sequence constitutes the pro-
tonation of thiophene (1), the protonated species being
represented by the mesomeric structures I-III. The
assumption of a primary protonation is in agreement
with the fact that formation of thiophen-2-one (4) is
favored in the presence of strong acids and with the
observation that increasing concentrations of water,
presumably acting as a competing base, suppressed its
formation. As a result of the involvement of the sulfur
lone pair in the delocalization of the positive charge,
protonation of thiophene might also serve as a protective
mechanism against the predominant oxidation on the
sulfur atom. On the basis of isotope exchange studies,
mesomeric structure II in Scheme 3 has been shown to
be thermodynamically favored by a factor of 1000 com-
pared to structure I34 and thus represents the most likely
target for nucleophilic attack of the peracid leading to a
mixed acyl-allyl-peroxide. This peroxide intermediate
may undergo intramolecular epoxidation, presumably
supported by acid catalysis, yielding the highly unstable
thiophene 2,3-epoxide. Opening of the epoxide, either
spontaneously or acid-catalyzed, results in a cationic
intermediate that might stabilize by a 1,2-hydride shift
leading to the final thiophen-2-one (4) after acid-catalyzed
isomerization of the double bond. Support for this hy-
pothesis is given by the incorporation of deuterium into
position 3 of thiophen-2-one (4) when the experiment is
performed with the deuterated analogue 1-D. Since the
rate of deuterium exchange was much slower in the
control experiment, the 1,2-hydride shift offers a reason-
able explanation for the observed degree of deuteration
in position 3. It is noteworthy that there was no obvious
difference in the yield of thiophen-2-one (4) in the
oxidation experiments of labeled and nonlabeled thiophene
Exp er im en ta l Section
Gen er a l Asp ects. H and 13C NMR spectra were recorded
at 250 and 63 MHz, respectively, the resonance of the solvent
being used as internal standard. Column chromatography was
done using silica gel (70-230 mesh) with an adsorbent/
substrate ratio of about 100:1. Thin-layer chromatography was
performed on silica gel coated aluminum plates. Products were
visualized by using iodine vapor or by means of a 5% ethanolic
solution of molybdophosphoric acid. Melting points are uncor-
rected. All starting materials and solvents were of highest
commercially available quality and used without further
purification. 30% and 85% hydrogen peroxide were of com-
mercial origin; 8%, 15%, and 100% hydrogen peroxide were
prepared either by dilution with water or by treatment of 30%
hydrogen peroxide with trifluoroacetic anhydride. 2,5-Dideu-
terated thiophene (1-D)34 and dimethyldioxirane were pre-
pared following literature procedures.
1
47
Gen er a l P r oced u r e for P er a cetic Acid Oxid a tion of
Th iop h en e (1). To a solution of thiophene (1, 533 mg, 6.63
mmol, 0.50 mL) in 10 mL of methylene chloride was added at
ambient temperature 3 equiv (19.5 mmol) of the acetic acid
derivative and 0.17 equiv (1.13 mmol) of the appropriately
2 2
diluted H O . Upon stirring, the initially biphasic system
became rapidly homogeneous. Stirring at ambient temperature
was continued until no more peroxide could be detected using
KI/starch. The crude reaction mixture was then extracted three
times with 10 mL of water for the separation of the Diels-
Alder products 2 and 3. The aqueous phase was evaporated
to dryness at 25 °C/0.1 Torr, and the residue was taken up in
(
1), indicating that the initial protonation equilibrium
5
mL of water and neutralized to pH 6 with saturated NaHCO
3
does not represent the rate-limiting step in the overall
reaction sequence.
solution. The crude product containing a mixture of the two
thiophene-S-oxide dimers, 2a and 2b, and the sesquioxide 3
was again evaporated to dryness (25 °C/0.1 Torr), and the
individual components were quantified by HPLC on a Hypersil
MOS column (5 µm, 250 × 4.6 mm) with an isocratic eluent
Con clu sion
In summary, we have shown that the oxidation of
thiophene (1) with peracids in the presence of an excess
of acid leads to the formation of thiophene-S-oxide dimers
(47) Adam, W.; Bialas, J .; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377-2380.
J . Org. Chem, Vol. 67, No. 21, 2002 7265

Treiber
Oxid a tion of Th iop h en e (1) w ith An h yd r ou s H in
th e P r esen ce of N-P h en ylm a leim id e a n d Tr iflu or oa cetic
Acid . A solution of water-free trifluoroperacetic acid was
(
98:2 H
samples of all three analytes
calibration. Thiophen-2-one (4) was isolated from the organic
phase by drying over MgSO and evaporation of the solvent
at 20 °C/15 Torr. The crude product was submitted to a short
5 cm) silica gel column and eluted with methylene chloride.
2
O/CH
3
CN) and a flow rate of 1.0 mL/min. Authentic
2 2
O
2
6
were used for external
4
2 2
prepared by mixing 30% H O (125 µL, 1.10 mmol), trifluoro-
acetic anhydride (1.02 g, 4.86 mmol, 686 µL), and trifluoro-
acetic acid (1.14 g, 10.0 mmol, 780 µL) in 10 mL of methylene
chloride. To this mixture was added N-phenylmaleimide (190
mg, 1.10 mmol) and thiophene (1, 533 mg, 6.33 mmol, 0.5 mL).
The solution was stirred at ambient temperature for 3 h until
no more peroxide could be detected using KI/starch. The crude
reaction mixture was then washed twice with 10 mL of water
(
Thiophen-2-one (4) was quantified from the crude eluate by
1
H NMR spectroscopy using 1,2-dichloroethane as internal
standard. Thiophene-S-oxide dimers 2a and 2b, sesquioxide
3
comparison of their NMR and IR spectra with literature
data
, and thiophen-2-one (4) were structurally identified by
2
6,48
(for 2 and 3) and those of an authentic sample (for
and once with 10 mL of a saturated NaHCO
organic phase was dried over MgSO , and the solvent was
3
solution. The
2
7
4
). The results of the peracetic acid oxidations of thiophene
4
are summarized in Table 1.
removed at 15 Torr/20 °C. The product distribution of Diels-
Alder adduct 5 26 and thiophen-2-one (4) was determined as
75:25 directly from the crude reaction mixture by quantitative
Oxid a tion of Th iop h en e (1) w ith m -CP BA. To a solution
of thiophene (1, 533 mg, 6.33 mmol, 0.50 mL) in 10 mL of
methylene chloride was added a solution of m-CPBA (233 mg,
1
H NMR spectroscopy using 1,2-dichloroethane as internal
1
.35 mmol, 0.21 equiv) in 1.0 mL of methylene chloride. The
standard.
mixture was stirred at ambient temperature for 192 h until
no more peroxide could be detected by using KI/starch. After
addition of 0.1 mL of trifluoroacetic acid, the crude reaction
mixture was extracted three times with 10 mL of water. The
separation and quantification of Diels-Alder products (2 and
Oxid a tion of 2,5-Deu ter a ted Th iop h en e (1-D) w ith
An h yd r ou s H
To a solution of deuterated thiophene (1-D, 545 mg, 6.33 mmol,
.5 mL) in 10 mL of methylene chloride was added at ambient
temperature 30% H (125 µL, 1.10 mmol), trifluoroacetic
2 2
O a n d Deu ter a ted Tr iflu or oa cetic Acid .
0
2
O
2
3
) and thiophen-2-one (4) was performed as described in the
anhydride (1.02 g, 4.86 mmol, 686 µL), and deuterated tri-
fluoroacetic acid (1.14 g, 10.0 mmol, 780 µL). Stirring at
ambient temperature was continued for 17 h until no more
peroxide could be detected using KI/starch. The crude reaction
mixture was three times extracted with 10 mL of water, the
general method above and yielded sesquioxide 3 (136 mg, 76%)
as the only detectable product.
Oxid a tion of Th iop h en e (1) w ith m -CP BA in th e
P r esen ce of Tr iflu or oacetic Acid. To a solution of thiophene
(
1, 533 mg, 6.33 mmol, 0.5 mL) in 10 mL of methylene chloride
at ambient temperature was added trifluoroacetic acid (2.23
g, 19.5 mmol, 1.5 mL) and a solution of m-CPBA (229 mg 1.33
organic phase was dried over MgSO
evaporated at 15 Torr/20 °C. The residual oil was dissolved in
.8 mL of CDCl , and the yield and the extent of deuteration
in thiophen-2-one (4) were determined by quantitative
4
, and the solvent was
,
0
3
mmol, 0.21 equiv) in 1.0 mL of methylene chloride. The
reaction mixture was stirred for 15 h at ambient temperature
until no more peroxide could be detected using KI/starch. The
extraction and quantification of Diels-Alder products yielded
the thiophene-S-oxide dimers (2a ,b; 53.1 mg, 48%) but no
1
H
NMR spectroscopy using 1,2-dichloroethane as internal stand-
ard.
Deter m in a tion of H/D Exch a n ge Ra te of Th iop h en -2-
on e (4). Thiophene-2-one (4, 5.00 mg, 49.9 µmol) was dissolved
4
sesquioxide 3. The organic phase was dried over MgSO and
in 0.8 mL of CDCl , and 5.0 µL of 1,2-dichloroethane was added
3
cooled to -40 °C to precipitate the meta-chlorobenzoic acid.
as internal standard. After a reference spectrum had been
recorded, deuterated trifluoroacetic acid (285 mg, 2.50 mmol,
After filtration, the solvent was removed at 15 Torr/20 °C, and
1
thiophen-2-one (4, 15.9 mg, 14%) was quantified by H NMR
5
0 equiv) was added. H/D exchange in thiophen-2-one (4) was
spectroscopy.
monitored at regular time intervals. After 17 h, 12% and 72%
of H/D exchange was observed in positions 3 and 5, respec-
tively.
Oxid a tion of Th iop h en e (1) w ith Dim eth yld ioxir a n e.
Thiophene (1, 53.3 mg, 0.633 mmol, 50 µL) was added to a
solution of dimethyldioxirane (9.38 mg, 0.127 mmol, 0.20
equiv) in acetone. Stirring at room temperature was continued
for 0.5 h until no more peroxide could be detected using KI/
starch. The solvent was removed at 15 Torr/20 °C, and the
crude reaction mixture was taken up in 10 mL of methylene
chloride. Standard workup yielded sesquioxide 3 (6.3 mg, 23%)
as the only detectable product.
Ack n ow led gm en t. The author thanks the Deutsche
Forschungsgemeinschaft for a postdoctoral fellowship,
Dr. Patrick Dansette from the CNRS (URA400), Uni-
versit e´ Ren e´ Descartes, Paris for fruitful scientific
discussions, and Dr. Thomas Weller for reviewing the
manuscript.
(48) Merrill, R. E.; Sherwood, G. J . Heterocycl. Chem. 1977, 14,
1
251-1253.
J O0202177
7
266 J . Org. Chem., Vol. 67, No. 21, 2002