One-pot synthesis of benzo[e]1,4-oxathiepin-5-ones under solvent-free condition via self-promoted thiolysis of 1,2-epoxides

Article abstract of DOI:10.1021/jo0487496

Under solvent-free conditions, thiosalicylic acid (2) efficiently self-promotes the thiolysis of 1,2-epoxides 1, anti-stereoselectively and generally totally β-regioselectively. The resulting β-hydroxysulfide products 3 have been obtained in very good yields. Benzo[e]1,4-oxathiepin-5-ones 4 have been easily prepared in a regio- and diasteroselective manner and in satisfactory yields under SFC by a one-pot protocol including nucleophilic ring opening of 1,2-epoxides 1 by thiosalicylic acid (2) and thermally induced lactonization of β-hydroxy arylsulfides 3. Solvent-free condition and the absence of any catalyst make this procedure atom-economical and environmentally friendly.

Full text of DOI:10.1021/jo0487496

One-Pot Synthesis of Benzo[e]1,4-oxathiepin-5-ones under
Solvent-Free Condition via Self-Promoted Thiolysis of
1,2-Epoxides
Francesco Fringuelli,* Ferdinando Pizzo,* Simone Tortoioli, and Luigi Vaccaro
CEMIN “Centro di Eccellenza Materiali Innovativi Nanostrutturati”, Dipartimento di Chimica,
Universita` di Perugia, Via Elce di Sotto, 8 I-06123 Perugia, Italia
frifra@unipg.it; pizzo@unipg.it
Received July 22, 2004
Under solvent-free conditions, thiosalicylic acid (2) efficiently self-promotes the thiolysis of 1,2-
epoxides 1, anti-stereoselectively and generally totally â-regioselectively. The resulting â-hydroxy-
sulfide products 3 have been obtained in very good yields. Benzo[e]1,4-oxathiepin-5-ones 4 have
been easily prepared in a regio- and diasteroselective manner and in satisfactory yields under SFC
by a one-pot protocol including nucleophilic ring opening of 1,2-epoxides 1 by thiosalicylic acid (2)
and thermally induced lactonization of â-hydroxy arylsulfides 3. Solvent-free condition and the
absence of any catalyst make this procedure atom-economical and environmentally friendly.
Introduction
many synthetic procedures have been proposed to pre-
pare a variety of derivatives.7 In contrast, the pharma-
cological properties of the isosterically related oxathie-
pinones have never been tested, supposedly because of
the lack of an efficient synthetic method for their
preparation. To our knowledge, only one paper has
reported the synthesis of a mixture of 2- and 3-phenyl
2,3-dihydro-1,4-benzoxathiepin-5-one, via thiolysis of sty-
rene oxide by thiosalicylic acid (2). The reaction was
carried out in refluxing benzene, catalyzed by p-toulene-
sulfonic acid (p-TsOH), and the overall yield was low.8
As a continuation of our research devoted to the
development of a green organic chemistry by using water
as reaction medium or by performing organic transfor-
mations under solvent-free conditions (SFC),9 we are
currently engaged in a project aimed at defining a
versatile, environmentally friendly, and atom-economical
synthesis of 1,4-oxathiepinones.
Heterocyclic small molecules play a pivotal role in the
search for new therapeutic and drug candidates1 and are
essential to elucidate the chemistry of living processes.2
Recent advances in biology have provided many poten-
tially useful targets for which new small-molecule modu-
lators have to be found.3 Starting from the concept of
“privileged structures”,4 synthetic methodologies have
been developed to synthesize natural productlike or
active druglike small molecules on the basis of a target-
oriented synthesis or a combinatorial approach.5a Schreiber
recently pointed out the urgent need to explore “new
chemical spaces” by accessing new structures having
unknown properties, namely, diversity-oriented synthe-
sis,5 and proposed a complete revolution in the approach
to pharmaceutical discovery.
Thiazepinones are a very interesting class of com-
pounds that show a wide spectrum of biological activity;6
(1) (a) Shu, Y.-Z. J. Nat. Prod. 1998, 61, 1053-1071. (b) Coula-
douros, E. A.; Strongilos, A. T. Angew. Chem., Int. Ed. 2002, 41, 3677-
3680.
(2) (a) Hung, D. T.; Jamison, T. F.; Schreiber, S. L. Chem. Biol. 1996,
3, 623-639. (b) Hinterding, K.; Alonso-D´ıaz, D.; Waldmann, H. Angew.
Chem., Int. Ed. 1998, 37, 688-749.
(3) (a) The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.;
Academic Press: London, 2003; Chapters 5 and 8. (b) Lenz, G. R.;
Nash, H. M.; Jindal, S. Drug Discovery Today 2000, 5, 145-156. (b)
Razvi, E. S.; Leytes, L. J. Mod. Drug Discovery 2000, 41-42. (c)
Rosamond, J.; Allsop, A. Science 2000, 287, 1973-1976.
(4) This term was first introduced by Evans et al. and originally
referred to benzodiazepines and benzazepines, to define a group of
compounds whose members bind on different classes of receptors. (a)
Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R.
M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.
A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235-2246.
(b) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.;
Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939-
9953.
(6) Hexahydro-1,4-thiazepin-5-ones: (a) Arakawa, M.; Sasaki, M.;
Ohmori, M.; Harada, K.; Fujimura, A. Eur. J. Clin. Pharmacol. 2001,
56, 775-779. (b) Lesuisse, D.; Deprez, P.; Albert, E.; Duc, T. T.; Sortais,
B.; Gofflo, D.; Jean-Baptiste, V.; Marquette, J. P.; Schoot, B.; Sarubbi,
E.; Lange, G.; Broto, P.; Mandine, E. Bioorg. Med. Chem. Lett. 2001,
11, 2127-2131. (c) Pieper, G. M.; Siebeneich, W. Eur. J. Pharmacol.
2000, 403, 129-132. (d) Yanagisawa, H.; Ishihara, S.; Ando, A.;
Kanazaki, T.; Miyamoto, S.; Koike, H.; Iijima, Y.; Oizumi, K.; Mat-
sushita, Y.; Hatat, T. J. Med. Chem. 1987, 30, 1984-1991. 1,5-
Benzoxathiepin-4-one and isosters: (d) Amblard, M.; Daffix, I.; Bedos,
P.; Berge´, G.; Pruneau, D.; Paquet, J. L.; Luccarini, J. M.; Be´lichard,
P.; Dodey, P.; Martinez, J. J. Med. Chem. 1999, 42, 4185-4192. (e)
Corbelli, F.; Monetti, F.; Tafi, A.; Campiani, G.; Nacci, V.; Botta, M. J.
Med. Chem. 1997, 40, 125-131. (f) Campiani, G.; Fiorini, I.; De Filippis,
M. P.; Ciani, S. M.; Garofano, A.; Nacci, V.; Giorni, G.; Sega, A.; Botta,
M.; Chiarini, A.; Budresi, R.; Bruni, G.; Romeo, M. R.; Manzoni, C.;
Pennini, T. J. Med. Chem. 1996, 39, 2922-2938.
(7) (a) Morcaccini, S.; Miguel, D.; Torroba, T.; Garc´ıa-Valverde, M.
J. Org. Chem. 2003, 68, 3315-3318. (b) Furutani, T.; Imashiro, R.;
Hatsuda, M.; Seki, M. J. Org. Chem. 2002, 67, 4599-4601. (c)
Katritzky, A. R.; Odens, H. H.; Zhang, S. J. Org. Chem. 2001, 66, 6792-
6796. (d) Lee, C. L.; Lam, Y.; Lee, S. Y. Tetrahedron Lett. 2001, 42,
109-111.
(5) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004,
43, 46-58. (b) Schreiber, S. L. Chem. Eng. News 2003, 81 (9), 51-61.
(c) Schreiber, S. L. Science 2000, 287, 1964-1969.
(8) Gelebe, A. C.; Kaye, P. T. Synth. Commun. 1996, 26, 4459-4475.
10.1021/jo0487496 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/16/2004
8780
J. Org. Chem. 2004, 69, 8780-8785

One-Pot Synthesis of Benzo[e]1,4-oxathiepin-5-ones
SCHEME 1. Synthesis of Benzo[e]1,4-oxathiepin-5-one 4a in Water
TABLE 1. Thiolysis of 1,2-Epoxides 1a,b with
Recently, we have approached the synthesis of a 1,4-
benzoxathiepin-5-one 4a by performing the thiolysis of
cyclohexene oxide (1a) under aqueous basic conditions
with thiosalicylic acid (2) and subsequent in situ lacton-
ization of the corresponding adduct 3a under acidic
refluxing conditions (Scheme 1).9h These promising re-
sults suggested that the one-pot synthetic strategy based
on the reaction of 1,2-epoxides with thiosalicylic acid (2)
and subsequent lactonization of the resulting hydroxy
carboxylic acids could be one of the most straightforward
ways to synthesize 1,4-oxathiepin-5-one moiety. There-
fore we decided to study these processes under different
conditions: (i) in the presence of a reaction medium, (ii)
under SFC, and (iii) in the presence and in the absence
of a Brønsted acid catalyst.
Thiosalicylic Acid (2) under Various Reaction Conditions
No-solvent reactions are generally fast, give high
selectivities and yields, and usually require easier work-
up procedures and simpler equipment.10-12
Under SFC, we reported the tetrabutylammonium
fluoride catalyzed 1,3-dipolar cycloaddition of nitriles
with trimethylsilyl azide,12a the tetrabutylammonium
bromide catalyzed O-trimethylsilylation of alcohols,12e the
[4 + 2] cycloaddition of 3-nitrocoumarins with vinyl
ethers and 1,3-dienes for the synthesis of chromenes
derivatives12d or dihydrobenzofurans,12c respectively, and
the thiolysis of 1,2-epoxides catalyzed by Lewis or Brøn-
sted acids and bases.12b On the basis of these results, we
a Conversion determined by GCL analyses. b trans-1,2-Cyclo-
hexandiol was formed in 79%. c 3a was isolated in 94% yield.
d Complement to 99% were decomposition products. e 2-Phenyl-
1,2-ethandiol was formed in 80%. f Products 3br and 3bâ were
isolated in 95% overall yield.
(9) (a) Li, C. J.; Chang, T. H. In Organic Reactions in Aqueous Media;
Wiley: New York, 1997. (b) Fringuelli, F.; Piermatti, O.; Pizzo, F. In
Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic and
Professional: London, 1998; pp 223-261. (c) Fringuelli, F.; Pizzo, F.;
Vaccaro, L. J. Org. Chem. 2001, 66, 3554-3558. (d) Amantini, D.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2001, 66, 4463-
4467. (e) Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2001, 66,
4719-4722. (f) Amantini, D.; Fringuelli, F.; Pizzo, F. J. Org. Chem.
2002, 67, 7238-7243. (g) Fringuelli, F.; Pizzo, F.; Rucci, M.; Vaccaro,
L. J. Org. Chem. 2003, 68, 7041-7045. (h) Fringuelli, F.; Pizzo, F.;
Tortoioli, S.; Vaccaro, L. Green Chem. 2003, 5, 436-440. (i) Amantini,
D.; Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. Synlett 2003,
2292-2296. (j) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.;
Vaccaro, L. J. Org. Chem. 2003, 68, 9263-9268. (k) Fioroni, G.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green Chem. 2003, 5, 425-428.
(l) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. J. Org. Chem. 2003,
68, 8258-8251.
have hypothesized that thiosalicylic acid (2) can behave,
in the nucleophilic ring opening of the oxirane, both as a
Brønsted acid and as a nucleophile, thereby avoiding the
use of any external catalytic species in contrast to what
usually happens.9c-e,h,12a,13 This paper reports the first
general route to 1,4-oxathiepin-5-one moiety starting
from 1,2-epoxides.
(10) (a) Tanaka, K.; Toda, F. In Solvent-free Organic Synthesis;
Wiley-VCH: 2003. (b) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem.
Commun. 2001, 2159-2169. (c) Varma, R. S. Pure Appl. Chem. 2001,
73, 193-198. (d) Tanaka, K.; Toda, F. Chem Rev. 2000, 100, 1025-
1074. (e) Varma, R. S. Green Chem. 1999, 43-55. (f) Metzger, J. O.
Angew. Chem., Int. Ed. 1998, 37, 2975-2978.
(11) (a) Yadav, L. D. S.; Singh, S. Synthesis 2003, 1, 63-66. (b) Lee,
J. C.; Bae, Y. H. Synlett 2003, 4, 507-508. (c) Xu, Z.-B.; Lu, Y.; Guo,
Z.-R. Synlett 2003, 4, 564-566. (d) Hajipour, A. R.; Arbabian, M.;
Ruoho, A. E. J. Org. Chem. 2002, 67, 8622-8624. (e) Loh, T.-P.; Huang,
J.-M.; Goh, S.-H.; Vittal, J. J. Org. Lett. 2000, 2, 1291-1294.
(12) (a) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro,
L. J. Org. Chem. 2004, 70, 2896-2898. (b) Fringuelli, F.; Pizzo, F.;
Tortoioli, S.; Vaccaro, L. Tetrahedron Lett. 2003, 44, 6785-6787. (c)
Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. J.
Org. Chem. 2003, 68, 9263-9268. (d) Amantini, D.; Fringuelli, F.;
Pizzo, F. J. Org. Chem. 2002, 67, 7238-7243. (e) Amantini, D.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2001, 66, 6734-
6737.
Results and Discussion
We have initially studied the thiolysis of two repre-
sentative 1,2-epoxides, cyclohexene oxide (1a) and sty-
rene oxide (1b), with thiosalicylic acid (2) in DCM, in
toluene, in water at pH 3.0 and 9.0, and under SFC, in
the presence and absence of p-TsOH as external Brønsted
catalyst. The results obtained are summarized in Table
1.
In DCM, the thiolysis occurred with complete conver-
sion and high regio- and stereoselectivity, but long
reaction times were required to obtain â-hydroxy aryl-
sulfides 3a and 3b (Table 1, entries 1 and 7). In toluene,
the reaction conversion and the regioselectivity of the
J. Org. Chem, Vol. 69, No. 25, 2004 8781

Fringuelli et al.
TABLE 2. Self-Promoted Thiolysis of 1,2-Epoxides 1a-h with Thiosalycilic Acid (2) under SFC
a Yield of the isolated products 3.
process were significantly lower even at reflux temper-
ature (Table 1, entries 2 and 8).
disappointing results in terms of conversion and selectiv-
ity (Table 1, entries 6 and 12).
The behavior of thiosalicylic acid (2) deserves a com-
ment. The thiolysis of 1,2-epoxides with thiophenol did
not occur in DCM or SFC unless Brønsted or Lewis acids
were used.12b,13b The thiol group of thiosalicylic acid (2)
is expected to be less nucleophilic than that of thiophenol.
Nevertheless, in DCM and SFC the thiolysis of 2 with
1a and 1b did not need to be catalyzed, and when a
Brønsted acid was used, disappointing results were
obtained.
When the reagents were mixed in water, an acidic
medium was generated (pH 3.0) and under these condi-
tions the reaction conversion was low, the nucleophilic
attack was poorly regioselective, and the hydrolysis
reaction prevailed over the thiolysis (Table 1, entries 3
and 9). In water at pH 9.0, the thiolysis was very fast,
gave high yields, but in the case of 1b, was poorly
regioselective (Table 1, entries 4 and 10).
The thiolysis of 1a carried out under SFC was complete
in 6 h at 30 °C and gave the adduct 3a with excellent
yield (Table 1, entry 5). Similarly the reaction of 1b with
2 in the absence of solvent required 4 h to be complete
and gave quantitatively the regioisomer adducts 3ar and
3aâ in a 85/15 ratio (Table 1, entry 11). The use of
p-TsOH (5 mol %) accelerated the reactions but gave
To better understand these results, we also carried out
thiolysis of 1a and 1b with o-carboxymethyl-thiophenol
and p-carboxy-thiophenol under the same reaction condi-
(13) (a) Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2004,
70, 2315-2321. (b) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L.
Adv. Synth. Catal. 2002, 344, 379-384.
8782 J. Org. Chem., Vol. 69, No. 25, 2004

One-Pot Synthesis of Benzo[e]1,4-oxathiepin-5-ones
TABLE 3. Lactonization Reaction of â-Hydroxy
tions illustrated in Table 1. The reactions worked only
in water at pH 9.0, whereas in DCM, PhMe, H2O (pH
3.0), and SFC in the absence and presence of p-TsOH,
no â-hydroxy arylsulfides were detected or disappointing
results were obtained. The reaction is only successful
when a carboxylic functionality is at the ortho position
to the mercapto group. This self-promoted thiolysis could
be the consequence of a favorable hydrogen bond between
the oxirane ring and the thiosalicylic acid (2), which
favors catalytically and geometrically the approach of the
reagents, particularly in aprotic solvents and under SFC.
Summarizing the results in Table 1, the simplest, most
convenient, and atom-economical protocol for the thiolysis
of 1a and 1b with 2 is that carried out under SFC without
catalyst. With the aim of developing a simple and fast
route to benzo[e]1,4-oxathiepin-5-ones, thiolysis under
SFC was extended to a variety of substituted 1,2-epoxides
1. The results obtained are reported in Table 2. All
reactions proceeded satisfactorily in short times, and the
resulting â-hydroxy arylsulfide products 3 were isolated
in 85-95% yields. All new products were fully character-
ized (see Supporting Information). In the case of alkyl-
1,2-epoxides, thiol 2 attacked almost exclusively at C-â
except in the case of 1e where the C-R regioisomer was
formed in an appreciable amount (15%, Table 2). The
thiolysis of 1b proceeded with the prevalent formation
of the 3br regioisomer (85%) as expected (Table 1, entry
11 and Table 2).
The second step in our synthetic approach to the benzo-
[e]1,4-oxathiepin-5-one ring was the lactonization of
hydroxy-thio carboxylic acids 3. Lactonization and es-
terification reactions are important processes and have
been largely investigated to find mild catalysts and
efficient procedures for 100% conversion of equimolecular
amounts of carboxylic acids and alcohols.14 The activation
of the carboxylic function in various solvents and/or high
temperatures is generally required.14 One of the most
efficient protocols has been realized by Yamamoto H. et
al. who have demonstrated that under dehydrating
conditions, hafnium(IV) chloride and alkoxide are very
efficient catalysts for this process.14a Sc(OTf)3,14c Ti(Oi-
Pr)414a and diphenylammonium triflate14b also efficiently
promoted esterification and lactonization reactions. In
our case the transformation can be more complicated
than usual because of the presence of a sulfide function-
ality. In fact it is known that acids promote the formation
of thiiranium ion, which can evolve to give [1,2] sulfanyl
migration by elimination or substitution reactions.15
Taking adduct 3a as a typical substrate, we studied
the lactonization process under various reaction condi-
tions. The results obtained are illustrated in Table 3. This
transformation required 24 h in refluxing water under
acidic conditions to furnish 4a in 70% yield (Scheme 1
and Table 3, entry 1).9h Ti(IV) and Hf(IV) chlorides (in
stoichiometric or catalytic amounts) in DCE at 50 °C were
not effective catalysts; their use resulted in the formation
of a 4/1 mixture of cis and trans-â-chloro sulfides 5. The
first one was derived from the direct hydroxyl substitu-
Arylsulfide 3a
T
t
yielda
(°C) (h) product (%)
entry medium
catalyst
1
2
3
4
5
6
H2O
DCE
DCE
DCE
SFC
SFC
pH ∼ 0
TiCl4 (1.0 equiv)
TiCl4 (THF)2 (1.0 equiv) 50
rfx 24
4a
5
70
50
8
8
8
5
5
59b
58b
58b
30
5
HfCl4 (0.3 equiv)
none
50
50
50
5
4a
4a
In(OTf)3 (0.05 equiv)
30
5Å MS
none
7
SFC
200
1
4a
95
a Isolated yield of 4a and 5 respectively. b 4/1 mixture of cis-
and trans-2-[(2′-carboxy)thiophenyl]-1-chloro cyclohexane 5.
tion by chloride, and the second was supposedly formed
by chloride nucleophilic attack on the 2,3-cyclohexane-
1-(2′-carboxyphenyl)thiiranium formed from 3a (Table 3,
entries 2-4).
The best result was obtained under SFC without using
any Lewis acid catalyst or dehydrating agent. The
lactonization of 3a, induced by simply heating at 200 °C
in an open vial to facilitate the elimination of water,
resulted in a very good yield of product 4a (Table 3, entry
7). Only 30% conversion was reached when the temper-
ature was lowered to 50 °C (Table 3, entry 5) and when
the reaction was carried out in the presence of molecular
sieves and In(OTf)3 at 50 °C (Table 3, entry 6). Longer
reaction times did not change the final conversion
percentage. In any case, the cyclization temperature used
under SFC (Table 3, entry 7) is quite low considering that
a temperature of 150 °C is usually required after anhy-
dride activation of the carboxylic functionality and in
many other esterification protocols. To the best of our
knowledge, this is the first example of the preparation
of a seven-membered thiolactone by simple thermal
cyclization of the corresponding hydroxy-thio carboxylic
acids. This result paves the way to a very simple one-
pot synthesis of a benzo[e]1,4-oxathiepin-5-one moiety
starting from 1,2-epoxides, which does not need a reaction
medium, a catalyst, dehydrating conditions, or activating
steps.
Equimolar amounts of 1,2-epoxides 1a-h and thiosali-
cylic acid 2 were initially heated at 30-65 °C for 2-8 h
in a closed vial, and then heating was continued at 100-
200 °C for 1-8 h in the open vial. The corresponding 1,2-
benzoxathiepin-5-ones 4a-h were produced in good to
excellent yields with the exception of 4f (Table 4, entry
6).16 The results obtained are reported in Table 4.
In the cases of 1c and 1g, the conversions to 4c and
4g were only 20% and 45%, respectively, after 8 h. No
improvements were observed by raising the lactonization
temperature or prolonging the reaction time. These
results were not completely unsatisfactory because 60%
(14) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000, 290,
1140-1142. (b) Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y.
Tetrahedron Lett. 2000, 41, 5249-5252. (c) Ishihara, K.; Kubota, M.;
Kurihara, H.; Yamamoto, H. J. Org. Chem. 1996, 61, 4560-4567.
(15) Fox, D. J.; House, D.; Warren, S. Angew. Chem., Int. Ed. 2002,
41, 2462-2482.
(16) Preparation of 4 can be performed directly by treating the 1,2-
epoxides 1 with thiol 2 at the temperature and for the time reported
for the lactonization process (Table 4), but sometimes slightly lower
yields were obtained apparently as a result of some decomposition of
1.
J. Org. Chem, Vol. 69, No. 25, 2004 8783

Fringuelli et al.
TABLE 4. One-Pot Synthesis of 1,4-Benzoxathiepin-5-ones 4 from 1,2-Epoxides 1a-h and Thiosalicylic Acid (2) under
SFC
a Thiolysis and lactonization temperatures, respectively. b Thiolysis and lactonization reaction times, respectively. c Yield of isolated
products. d See text. e Various reaction conditions.
of 3c and 40% of 3g could be recovered after silica gel
column chromatography resulting in a 43% and 73%
effective yield, respectively. Glycidol (1f) did not undergo
any reaction at 100 °C, and at higher temperatures a very
complex reaction mixture was obtained. This unfavorable
result is supposedly due to the presence of the free
hydroxyl functionality that causes side reactions in the
lactonization step. O-Allyl and the O-phenyl analogues
1g and 1h were satisfactorily converted to the corre-
sponding benzo[e]1,4-oxathiepin-5-ones 4g and 4h.
In addition, we also explored the use of â-mercapto-
propionic acid (6). Under SFC, at 50 °C and in the
absence of any catalyst, the reaction proceeded in 8 h,
and the â-hydroxysulfide product 7 was obtained in 65%
yield. After heating 7 in situ at 150 °C for 20 h, 8 was
isolated in 61% overall yield from 1a (Scheme 2). This
result shows that the one-pot SFC protocol can also be
conveniently applied to the thiolysis of 1,2-epoxides with
aliphatic thiols.
In conclusion, by reacting 1,2-epoxides 1 with thio-
salycilic acid (2) under SFC, in a one-pot procedure,
benzo[e]1,4-oxathiepin-5-ones 4 were prepared in a com-
pletely diasteroselective and generally C-â-regioselective
manner and with satisfactory yields. Starting materials
are cheap, and only heating is needed to complete the
whole synthesis. Because the procedure does not require
8784 J. Org. Chem., Vol. 69, No. 25, 2004

One-Pot Synthesis of Benzo[e]1,4-oxathiepin-5-ones
SCHEME 2. One-Pot Synthesis of trans-Octahydro-benzo[b]1,4-oxathiepin-2-one (8)
chromatography of the crude solid (3:7 EtOAc/Etp), product
the use of solvent or additional catalyst, drying of
glassware, or activating steps, this process is atom-
economical and particularly adequate for large-scale
production. Further studies are underway to extend this
synthetic strategy to polymer-supported mercapto car-
boxylic acids, with the intention of including this protocol
in a process aimed at the construction of more architec-
turally complex molecules.
4h was isolated in 96% yield (0.274 g).
Typical One-Pot Synthesis of 1,4-Benzoxathiepin-5-
ones. Preparation of 3-(Phenoxymethyl)-2,3-dihydro-5H-
benzo[e]1,4-oxathiepin-5-one (4h). A screw-capped vial
equipped with a magnetic stirrer was charged with thiosali-
cylic acid (2) (1.05 mmol, 0.165 g) and 2,3-epoxypropyl-phenyl
ether (1h) (1.0 mmol, 0.137 mL). The resulting mixture was
left under magnetic stirring at 65 °C for 2 h. The vial was then
opened, and the reaction mixture was heated to 200 °C for 1
h. By silica gel chromatography of the final mixture (3:7
EtOAc/Etp), 4h was isolated in 89% yield (0.254 g).
Experimental Section
Typical Thiolysis Procedure. Preparation of 3-[2′-
(Carboxy)phenylthio]-1-phenoxy-propan-2-ol (3h). A
screw-capped vial equipped with a magnetic stirrer was
charged with thiosalicylic acid (2) (1.05 mmol, 0.165 g) and
2,3-epoxypropyl-phenyl ether (1h) (1.0 mmol, 0.137 mL). The
resulting mixture was left under magnetic stirring at 65 °C
for 2 h. After silica gel chromatography of the final mixture
(3.8:6:0.2 EtOAc/Etp/AcOH) â-hydroxy sulfide 3h was isolated
in 94% yield (0.286 g).
Typical Lactonization Procedure. Preparation of 3-
(Phenoxymethyl)-2,3-dihydro-5H-benzo[e]1,4-oxathiepin-5-one
(4h). The â-hydroxy sulfide 3h (1.0 mmol, 0.304 g) was heated
in an open flask at 200 °C for 1 h. After direct silica gel
Acknowledgment. The Ministero dell’Istruzione
dell’Universita` e della Ricerca (MIUR) and the Univer-
sita` degli studi di Perugia are thanked for financial
support within the funding projects COFIN, COFINLAB
(CEMIN), and FIRB 2001.
Supporting Information Available: Full characteriza-
tion data (1H NMR, 13C NMR, IR, GC-MS, Rf) for compounds
3b-h, 4b-h, 5, 7, and 8 coming from the reactions of 1a with
6. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0487496
J. Org. Chem, Vol. 69, No. 25, 2004 8785