A facile and efficient one-pot synthesis of thiochromans from bis(2-formylphenyl) disulfide and alkenols via iodine-promoted generation and subsequent intramolecular cycloaddition of ortho-thiobenzoquinone methides

Article abstract of DOI:10.1016/S0040-4039(03)01510-7

Stereoselective synthesis of tetrahydrofuro- and tetrahydropyrano[3,2-c]benzothiopyrans was achieved by intramolecular [4+2]cycloaddition of o-thiobenzoquinone methides that were generated in situ from bis(2-formylphenyl) disulfide and alkenols in the presence of iodine under mild reaction conditions.

Full text of DOI:10.1016/S0040-4039(03)01510-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6513–6517
A facile and efficient one-pot synthesis of thiochromans from
bis(2-formylphenyl) disulfide and alkenols via iodine-promoted
generation and subsequent intramolecular cycloaddition of
ortho-thiobenzoquinone methides
Takao Saito,a,* Takahiro Horikoshi,a Takashi Otani,a Yosuke Matsudaa and Takayuki Karakasab
aDepartment of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
bChemistry Laboratory, The Nippon Dental University, Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan
Received 22 May 2003; revised 9 June 2003; accepted 13 June 2003
Abstract—Stereoselective synthesis of tetrahydrofuro- and tetrahydropyrano[3,2-c]benzothiopyrans was achieved by intramolecu-
lar [4+2]cycloaddition of o-thiobenzoquinone methides that were generated in situ from bis(2-formylphenyl) disulfide and alkenols
in the presence of iodine under mild reaction conditions.
© 2003 Elsevier Ltd. All rights reserved.
Chemistry of sulfur-containing six-membered heterocy-
cles, thiopyran derivatives,1 has been less extensively
studied than that of oxygen analogs, pyrans.2 This is
probably in part due to the fact that pyran derivatives,
e.g. flavonoids, catechins and pterocarpans, are found
abundant in nature and have been shown to possess a
wide range of physiological and biological activities.3
However, the interest in sulfur heterocycles of this class
such as thiopyrans is growing because of the recent
reports of their pharmacological and medicinal impor-
tance.4 Hence, the development of new and facile syn-
thetic methods for such heterocycles is considered to be
of great significance.5
substituent(s) are required for the isolation and treat-
ment of these o-thioquinone methide species.9
It has recently been reported that iodine plays an
interesting and specific role in various organic transfor-
mations.10 In the present study it has been found to be
an effective reagent for the generation of o-thiobenzo-
quinone methide. We report herein for the first time a
stereoselective one-pot synthesis of thiochromans from
bis(2-formylphenyl) disulfide and alkenols via iodine-
promoted generation and subsequent intramolecular
cycloadditions of o-thiobenzoquinone methides.
Keeping this and our continued interest in the hetero
Diels–Alder (HDA) reaction of 1-thiabuta-1,3-dienes in
view,6 we have initiated an investigation in search for
an effective method for the generation and subsequent
stereoselective cycloaddition of o-thiobenzoquinone
methides as the 4p-heterodiene component to obtain
benzothiopyrans. Hitherto reported successful methods
for the generation and subsequent cycloaddition of
o-thiobenzoquinone methides require rather stringent
reaction conditions such as thermolysis or photolysis of
their precursors,7 and hence result in less than satisfac-
tory yields, regio- and stereoselectivities and diversity of
the cycloadducts.8 Alternatively, specified stabilizing
* Corresponding author.
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01510-7

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T. Saito et al. / Tetrahedron Letters 44 (2003) 6513–6517
(1)
Initially, in view of the reported protocol for synthesis
of benzopyrans 6 from salicylaldehydes 4 (Scheme 1),11
it was envisaged that o-thiobenzoquinone methides 2
could be generated in situ by reacting o-mercaptobenz-
aldehydes 1 and alkenols under mild reaction condi-
tions and efficiently trapped to provide tricyclic
benzothiopyrans 3. Unfavorably, the required o-mer-
captobenzaldehyde 112 is very air-sensitive and readily
oxidized to disulfide 7. In any case, aldehyde 1 was
allowed to react with several alkenols according to
Inoue’s protocol conditions [CH(OMe)3, p-TsOH,
C6H6, rt, 2–24 h] (Eq. (1)). However, these efforts
resulted in the formation of dimerized bis-cycloadducts
8 and 9 as major products with a trace amount of the
desired thiochroman derivative 11a only in case of
R1=R2=R3=Me, n=2. This is probably due to the
instability and higher nucleophilicity of the mercapto
group of 1 as compared to the hydroxyl group of
analog 4. In order to overcome this problem, it was felt
that the disulfide 7, by virtue of its relative stability and
the fact that a disulfide bond is readily cleaved
reversibly by action of certain reagents under mild
conditions, could potentially be a convenient reagent
for in situ generation of o-thiobenzoquinone methides.
Keeping these facts in mind a number of efforts were
made in the desired direction (screening of promoters,
stoichiometry, solvent, and conditions), and it was
finally discovered that molecular iodine (300 mol%)
effectively promoted the desired reaction to afford the
trans-fused pyrano[3,2-c]benzothiopyran derivative 11a
as a single stereoisomer in good yield (93%, Table 1,
run 1)13 (Eq. (2)). In the absence of iodine, the reaction
did not afford any product even under reflux condi-
tions. Hydrogen iodide (runs 2 and 3), bromine (run 4),
and Ph3P/p-TosOH/H2O (run 5) also resulted in the
formation of compound 11a albeit in lower yields. The
reagents Ph3P/DMF–H2O–MeOH (run 6), by which
disulfide 7 is converted to o-mecaptobenzaldehyde 1 by
reduction,12 failed to form compound 11a.
Table 1. Screening of promoters for reaction of 7 with
10a to afford thiochroman 11a
Run Promoter
Conditions
Yield (%)a
1
2
3
4
5
6
I2
CH2Cl2, rt, 30 min 93
Aq. 57% HI
Aq. 57% HIb
Br2
Ph3P/p-TsOH–H2O
Ph3P/DMF–H2O
–MeOH
CH2Cl2, rt, 72 h
22 (81)
CH2Cl2, rt, 15 min 73
CH2Cl2, rt, 30 min 36 (67)
CH2Cl2, rt, 72 h
rt, 24 h
Trace
0
a Isolated yield. In parentheses, yield based on conversion percentage.
b In the presence of anhydrous MgSO4.
(2)
Table 2. The reaction of 7 with alkenols 10 to afford pyranobenzothiopyrans 11 or 12 and 13 (substituent effect)
Run
Alkenol
R1
R2
R3
R4
Time (h)
Product (yield %)a
trans:cisb
1
2
3
4
5
10a
10b
10c
10d
10e
Me
Me
Me
H
Me
Me
H
Me
H
Me
Me
H
H
H
H
Me
H
H
H
0.5
1.5
20
1
11a (93)
11b (73)
11c (70)
12 (85), 13d (92)
12 (96), 13e (90)
>95:5
>95:5
69:31
–
H
1
–
a Isolated yield.
b Ratio of stereoisomers determined by 1H NMR spectroscopy. Ratio >95:5 denotes that no cis isomer was detected.
(3)

T. Saito et al. / Tetrahedron Letters 44 (2003) 6513–6517
6515
Table 3. The reaction of 7 with alkenols 14 to afford furanobenzothiopyrans 15
Run
Alkenol
R1
R2
Time (h)
Product (yield %)a
trans:cisb
1
2
3
14a
14b
14c
Me
Et
H
Me
H
Et
4
24
24
15a (85)
15b (22)
15c (20)
78:22
23:77
5:95<
a Isolated yield.
b Ratio of stereoisomers determined by 1H NMR spectroscopy. Ratio 5:95< denotes that no trans isomer was detected.
(4)
Scheme 2. Possible pathways.
substituent(s) of alkenols 10a–c are absolutely essential
for the cycloaddition to proceed smoothly. These stud-
ies were extended to the reactions of 7 with some
unsaturated alcohols 14 having one-carbon shorter
chain length than 10. The reaction with 4-methyl-3-pen-
ten-1-ol (14a) proceeded cleanly in the presence of
iodine (300 mol%) at room temperature (4 h) to afford
tetrahydrofuro[3,2-c]benzothiopyran 15a in 85% yield
with a trans:cis ratio of 78:22 (Table 3, run 1). The
reaction with (E)-3-hexen-1-ol (14b) also afforded [5]-
ring-fused benzothiopyran 15b in 22% yield with a
trans:cis ratio of 23:77 (run 2). Interestingly, the forma-
tion of cis-15b as a major isomer in reaction of 7 with
In order to gain deeper insight into the scope, general-
ity, and the mechanism of this process, the reactions
were investigated with several other unsaturated alco-
hols 10b–e and 14a–c under the optimized conditions
and the results of these investigations are summarized
in Tables 2 and 3. The reactions with alkenols 10a–c
bearing a methyl substituent at the R1 position gave the
thiopyran cycloadducts 11a–c (Table 2, runs 1–3).
Whereas, the reactions with (Z)-hex-4-en-1-ol (10d) and
4-penten-1-ol (10e) afforded only condensed dimer 1214
and iodocyclization products 13d and 13e, respectively
(Table 2, runs 4 and 5). On the basis of the data above,
it is suggested that the terminal dimethyl or (E)-methyl

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T. Saito et al. / Tetrahedron Letters 44 (2003) 6513–6517
alkenol 14b is in sharp contrast with the formation of
trans-11c in reaction of 7 with alkenol 10c (Table 2, run
3) (Eq. (3)). Similar treatment with (Z)-3-hexen-1-ol
(14c) gave exclusively the cis stereomer of the cycload-
duct 15c in 20% yield (Table 3, run 3). It is also
noteworthy that the cycloaddition proceeds with the
retention of the E- or Z-stereochemistry of alkenes
(10c, 14c and 14b). Further, the reaction of 7 with
3-methyl-2-buten-1-ol (n=0) resulted only in the iodo-
cyclization product, formed via the hemiacetal of 7,
instead of the anticipated [4]-ring-fused benzo-
thiopyran.
S. J. Org. Chem. 2001, 66, 5333; (c) Hori, M.; Kataoka,
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1989, 37, 1282.
6. (a) Saito, T.; Furuie, H.; Ishigo-oka, Y.; Watanabe, I.;
Kobayashi, K. Heterocycles 2000, 53, 1685; (b) Saito, T.;
Takekawa, K.; Takahashi, T. Chem. Commun. 1999,
1001; (c) Saito, T.; Nishimura, J.; Akiba, D.; Kusuoku,
H.; Kobayashi, K. Tetrahedron Lett. 1999, 40, 8383; (d)
Saito, T.; Kawamura, M.; Nishimura, J. Tetrahedron
Lett. 1997, 38, 3231; (e) Saito, T.; Takekawa, K.;
Nishimura, J.; Kawamura, M. J. Chem. Soc., Perkin
Trans. 1 1997, 2957; (f) Saito, T.; Suda, H.; Kawamura,
M.; Nishimura, J.; Yamaya, A. Tetrahedron Lett. 1997,
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sushita, T.; Kato, H.; Kobayashi, K. J. Chem. Soc.,
Perkin Trans. 1 1996, 1897 and references cited therein.
7. Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: New
York, 1987; Chapter 8, p. 214.
8. (a) Meier, H.; Eckes, H.-L. Angew. Chem. 1987, 99, 1040;
(b) Kanakarajan, K.; Meier, H. J. Org. Chem. 1983, 48,
881; (c) Hortmann, A. G.; Aron, A. J.; Bhattacharya, A.
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1990, 2971.
On the basis of the experimental results and semi-
empirical calculations,15 a tentative pathway leading to
the benzothiopyrans (11 and 15) together with some of
the by-products is proposed in Scheme 2. In this scheme
it is assumed that the disulfide 7 reacts with iodine in
the presence of an alkenol to form the transient hemi-
acetalized sulfenyl iodide,16 and elimination of
hypoiodous acid from the sulfenyl iodide generates the
o-thiobenzoquinone methide, via its iodosulfonium ion
species. The latter ionic intermediate then preferentially
undergoes inverse electron-demanding intramolecular
exo or endo [4+2]cycloaddition to afford the trans or cis
ring-fused benzothiopyran, respectively (Eq. (4)).
In summary, we have developed a novel stereoselective
synthesis of ring-fused thiochromans via iodine-pro-
moted generation of o-thiobenzoquinone methides and
their subsequent intramolecular cycloaddition under
mild reaction conditions.
9. (a) Kang, K.-T.; Okazaki, R.; Inamoto, N. Bull. Chem.
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Inamoto, N. Bull. Chem. Soc. Jpn. 1978, 51, 309; (c)
Okazaki, R.; Sunagawa, K.; Kang, K.-T.; Inamoto, N.
Bull. Chem. Soc. Jpn. 1979, 52, 496.
10. Matsumoto, S.; Kishimoto, T.; Ogura, K. Chem. Lett.
2002, 134.
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12. o-Mercaptobenzaldehyde 1 was readily prepared from
commercially available thiosalicylic acid by (i) LAH-
reduction (95%),17 followed by (ii) PCC-oxidation of the
formed o-mercaptobenzyl alcohol (60%),18 and then (iii)
Ph3P/DMF–MeOH/H2O treatment of bis(2-formyl-
phenyl) disulfide 719 (90%).18
1
13. Compound 11a: colorless crystals; H NMR (400 MHz,
3. (a) Di Carlo, G.; Mascolo, N.; Izzo, A. A.; Capasso, F.
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CDCl3): l 1.29 (3H, d, J=6.1, 2-Me), 1.31–1.48 (2H, m,
H-3-ax, H-4-ax), 1.32 (3H, s, Me), 1.35 (3H, s, Me), 1.77
(1H, dddd, J=9.8, 4.1, 2.9, 2.0, H-3-eq), 1.98 (1H, ddd,
J=12.6, 11.2, 3.6, H-4a-ax), 2.04 (1H, dddd, J=12.7, 4.1,
3.6, 2.9, H-4-eq), 3.67 (1H, dqd, J=11.0, 6.1, 2.0, H-2-
ax), 4.31 (1H, d, J=11.2, H-10b-ax), 7.01 (1H, dd, J=
7.0, 2.1), 7.07 (1H, ddd, J=7.0, 7.0, 2.1), 7.09 (1H, ddd,
J=7.0, 7.0, 2.1), 7.62 (1H, dd, J=7.0, 2.1); 13C NMR
(125.65 MHz, CDCl3, DEPT): l 21.78 (q), 24.00 (q),
24.47 (t), 27.89 (q), 33.33 (t), 44.56 (s), 46.29 (d), 74.09
(d), 76.61 (d), 124.19 (d), 125.85 (d), 127.42 (d), 127.79
(d), 132.78 (s), 132.98 (s); MS m/z 248 (M+, 100%). Anal.
calcd for C15H20OS: C, 72.53: H, 8.12. Found: C, 72.34;
H, 8.15%.
14. Dickman, D. A.; Chemburkar, S.; Konopacki, D. B.;
Elisseou, E. M. Synthesis 1993, 573.
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2001, 66, 5595; (b) Ram, V. J.; Srivastava, P.; Saxena, A.

T. Saito et al. / Tetrahedron Letters 44 (2003) 6513–6517
6517
15. For example, a mixture of diphenyl disulfide and disulfide
7 in a 1:1 molar ratio undergoes disproportionation readily
at rt in the presence of iodine to give a mixture of diphenyl
disulfide: mixed disulfide: 7 in a ratio of ca. 1:2:1, which
suggests that a sulfenyl iodide species16 can be a key
transient intermediate in this process. The semi-empirical
MO calculations of (o-formylphenyl)sulfenyl iodides, o-
thiobenzoquinone methide and disulfide 7 (Keyword:
AM1, EF, PRECISE) and the transition state of
intramolecular [4+2]cycloaddition of o-thiobenzoquinone
methide (Keyword: AM1, TS, PRECISE) were performed
using a WinMOPAC version 3.0 program. Details as well
as further investigation of this process including its inter-
molecular cycloaddition variant will be reported in due
course.
16. (a) Goto, K.; Holler, M.; Okazaki, R. Chem. Commun.
1998, 1915; (b) Goto, K.; Yamamoto, G.; Tan, B.;
Okazaki, R. Tetrahedron Lett. 2001, 42, 4875.
17. Arnoldi, A.; Carughi, M. Synthesis 1988, 155.
18. Kasmai, H. S.; Mischke, S. G. Synthesis 1989, 763.
19. Brown, K. J.; Meth-Cohn, O. Tetrahedron Lett. 1974, 15,
4069.