One-pot stereoselective synthesis of pyrano[3,2-c]benzothiopyrans: A new generation and [4+2] cycloaddition of ortho-thioquinonemethides

Article abstract of DOI:10.1055/s-2005-862379

Pyrano[3,2-c]benzothiopyrans are synthesized from thiosalicylaldehyde derivatives and unsaturated alcohols in the presence of trimethyl orthoformate and a catalytic amount of p-toluenesulfonic acid with complete trans-stereoselectivity via intramolecular [4+2] cycloaddition of ortho-thioquinonemethides. A more efficient generation and cycloaddition of ortho-thioquinonemethides with Lewis acid is also described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862379

LETTER
469
One-Pot Stereoselective Synthesis of Pyrano[3,2-c]benzothiopyrans:
A New Generation and [4+2] Cycloaddition of ortho-Thioquinonemethides
O
ne-Pot Stere
e
oselective
S
i
ynthes
i
is of Py
c
rano[3,2-
c
h
i
rans Inoue,*a Ping Wang,a Mami Nagao,a Yujiro Hoshino,a Kiyoshi Hondab
a
Department of Environment and Natural Sciences, Graduate School of Environment and Information Sciences, Yokohama National
University, 79–7, Tokiwadai, Hodogaya, Yokohama 240–8501, Japan
Fax +81(45)3351536; E-mail: s-inoue@ynu.ac.jp
Department of Chemistry and Biotechnology, Graduate School of Engineering, Yokohama National University, 79–7, Tokiwadai,
Hodogaya, Yokohama 240–8501, Japan
b
Received 16 December 2004
the presence of trimethyl orthoformate (1.2 equiv) and p-
toluenesulfonic acid (0.2 equiv) to give tricyclic com-
pound 4a (54%) along with a minor amount of substituted
Abstract: Pyrano[3,2-c]benzothiopyrans are synthesized from
thiosalicylaldehyde derivatives and unsaturated alcohols in the
presence of trimethyl orthoformate and a catalytic amount of p-tol-
uenesulfonic acid with complete trans-stereoselectivity via in-
tetrahydropyran 5a (18%, Table 1, entry 1). The struc-
1
tramolecular [4+2] cycloaddition of ortho-thioquinonemethides. A tures of 4a4 and 5a9 were easily confirmed by their H
NMR and 13C NMR spectra. It is worthwhile to note that
more efficient generation and cycloaddition of ortho-thioquinone-
methides with Lewis acid is also described.
4a had B/C-trans ring junction in high stereoselectivity.
Key words: stereoselective synthesis, [4+2] cycloaddition, Lewis
acid, sulfur, heterocycles
The stereoselectivity of this reaction can be explained on
the basis of steric repulsion in the exo-transition state of
the thiatriene system.6b
In the past decades, a number of studies on pyrans and
benzopyrans have been reported while those of their sul-
fur-containing analogs are rare.1,2 It is only lately that the
studies of benzothiopyrans have attracted attention of a
number of research groups.3 To the best of our knowledge
there are relatively few reports touched upon the synthesis
of polycyclic pyranobenzothiopyrans.2b,4 As a result of
advances in both synthetic chemistry and biology, there is
now an increased demand for an efficient and convenient
synthetic method for sulfur-containing polycyclic com-
pounds.5 On the other hand, intramolecular Diels–Alder
reaction is useful in the construction of fused polycyclic
compounds, but this reaction finds few application for the
sulfur-containing systems.
O
O
HO
CHO
SR
H
+
H
S
R2
R1
R2
R1
R1
R2
S
1
2
3
4
CH3
H
a: R1 = R2 = CH3
1a: R = H
b: R1 = (CH3)2C=CHCH2CH2,
R2 = CH3
1b: R = MOM
1c: R = THP
1d: R = MIP
O
H
c: R1 = CH3,
R1
R2 = (CH3)2C=CHCH2CH2
SMOM
5
Scheme 1
As an extension of our recent studies on the trans stereo-
selective synthesis of pyrano[3,2-c]benzopyrans from sal-
icylaldehydes and 5-methyl-4-hexen-2-ol,6 we anticipated
that polycyclic pyranobenzothiopyran 4 would be pre-
pared stereoselectively via ortho-thioquinonemethides
(3),2,7 generated in situ from thiosalicylaldehyde deriva-
tive 1 and olefinic alcohol 2 (Scheme 1). Here we report a
new generation of ortho-thioquinonemethides with acid
catalyst and an efficient one-pot trans stereoselective
synthesis of pyranobenzothiopyrans.
In the cases of increased reaction temperature or pro-
longed reaction time, 4a was obtained as the sole product;
no formation of 5a was observed (Table 1, entries 3 and
4). Furthermore, we found that 5a was completely con-
verted into 4a at a temperature above 50 °C in the pres-
ence of acid catalyst in benzene. These results suggested
two possible mechanisms for the formation of 4a from 2a
(Scheme 2), a concerted mechanism (path 1) which in-
volved ortho-thioquinonemethide 3 and a stepwise one
(path 2) which involved two cationic species (A and B).
We initially used thiosalicylaldehyde methoxymethyl
ether (1b) as the substrate, because thiosalicylaldehyde
(1a) was reported to be intractable and extremely suscep-
tible to air-oxidation.8 The reaction of 1b and 6-methyl-5-
hepten-2-ol (2a) was carried out at room temperature in
It then became necessary to thoroughly clarify the ste-
reospecificity of this cycloaddition reaction from synthet-
ic and mechanistic points of view. For this purpose, we
synthesized a stereoisomeric pair of alcohols 2b and 2c
from geraniol and nerol,6b respectively. These alcohols
were reacted with thiosalicylaldehyde 1b to give a mix-
ture of tricyclic compounds 4b,c, and substituted tetrahy-
dropyran 5b at room temperature for a prolonged period
SYNLETT 2005, No. 3, pp 0469–0472
1
6.
0
2.
2
0
0
5
Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862379; Art ID: U32004ST
© Georg Thieme Verlag Stuttgart · New York

470
S. Inoue et al.
LETTER
or under reflux in benzene within a short time (Table 1, Since the presence of relatively stable methoxymethyl
entries 5, 6 and 9). Similarly, we observed the conversion protective group seemed to lead to the preferential forma-
of 5b to a mixture of 4b and 4c under the same conditions tion of cation at the benzylic position (A, Scheme 2), we
as described above.
then tried to overcome the problem by removing the meth-
oxymethyl group before elimination of the methoxy group
in order to promote the formation of ortho-thioquinone-
methide (Scheme 3).
Table 1 Reactions of Thiosalicylaldehydes with p-TsOH
Entry
1
2
Conditions
Products (yield, %)
In the presence of a catalytic amount of p-toluenesulfonic
acid and a small amount of methanol, 1b reacted with tri-
methyl orthoformate at room temperature to give acetal
610 quantitatively. Then, the isolated acetal 6 reacted with
2b in benzene–methanol at 50–60 °C to furnish 4b as a
single tricyclic compound in 35% yield.
1
2
3
4
5
1b
1b
1b
1b
1b
2a
2a
2a
2a
2b
25 °C, 13 h
4a (54)
4a (56)
4a (68)
4a (67)
5a (18)
80 °C, 15 min
80 °C, 35 min
110 °C, 10 mina
25 °C, 18 h
5a (13)
–
–
4b (32),
4c (10)
5b (18)
MeO
OMe
MeO
OMe
2b
6
1b
2b
80 °C, 35 min
4b/4c
5b
O
S
a
b
1b
(48:22:30)b
4b
SMOM
SH
R2
R1
7
8
9
1b
1b
1b
2b
2b
2c
80 °C, 3 h
4b (43),
4c (18)
–
6
Scheme 3 a) CH(OMe)3, p-TsOH, MeOH, benzene, r.t., 10 min,
quant; b) p-TsOH, benzene–MeOH, 50–60 °C, 2 h, then 2b, 45 min,
35%.
110 °C, 30 min
25 °C, 24 h
4b (42),
4c (19)
–
4b (19),
4c (12)
5b (6)
In order to synchronize the deprotection of the SH protec-
tive group with elimination of methoxy group at the ben-
zylic position, we used more labile 2-tetrahydropyranyl as
a protective group for SH of thiosalicylaldehyde. The
results are shown in Table 1 (entries 10–13). The reaction
of 1c and (E)-alcohol 2b afforded trans-tricyclic 4b as a
single cyclic product, at room temperature in 42% yield
(Table 1, entry 11). By comparing with the reaction as
shown in entry 5, Table 1, this experiment suggested
strongly that the reaction proceeded solely via a concerted
intramolecular [4+2] cycloaddition of ortho-thioquinone-
methide (3). Increasing the reaction temperature im-
proved the yields of 4b or 4c (Table 1, entries 12 and 13).
The use of thiosalicylaldehyde 1-methyl-1-methoxy ethyl
(MIP) ether (1d) decreased the yield of 4a (Table 1, entry
14).
10
11
12
13
14
1c
1c
1c
1c
1d
2a
2b
2b
2c
2a
25 °C, 5.5 h
25 °C, 4 h
4a (72)
4b (42)
4b (59)
4c (50)
4a (<10)
–
–
–
–
–
80 °C, 15 min
80 °C, 45 min
80 °C, 45 min
a Reaction in toluene.
b The ratio was determined by GC.
1b + 2a
CH(OMe)3
p-TsOH
Lewis acids such as AlCl3, Sc(OTf)3, BF3·OEt2 and
Yb(OTf)3 have been found to be more efficient for the
generation and cycloaddition of ortho-quinonemethides
than Brønsted acids.11,12 In the line with our continued
interest on the use of BF3·OEt2 for studies on ortho-
quinonemethides, we then studied the generation of ortho-
thioquinonemethides utilizing BF3·OEt2. The results are
shown in Table 2.
O
O
O
MeO
H
path 1
H
S
S
S
3
4a
MOM
– MeO–
path 2
The reaction of 2a with 1b proceeded within 30 minutes
to give tricyclic compound 4a in 96% yield (Table 2, en-
try 1). No formation of substituted pyran 5a was observed
at all. This catalytic system was successfully applied to
reactions of alcohol 2b and 2c with 1b. The reaction pro-
ceeded smoothly at room temperature, to give only a sin-
gle tricyclic product 4b and 4c, respectively (Table 2,
entries 2 and 3). Again, no formations of substituted pyran
compounds were observed. These somewhat decreased
O
O
H
– H+
80 °C
H
+
H
S
H
H+
S
S
MOM
MOM
MOM
A
B
5a
Scheme 2
Synlett 2005, No. 3, 469–472 © Thieme Stuttgart · New York

LETTER
One-Pot Stereoselective Synthesis of Pyrano[3,2-c]benzothiopyrans
471
Acknowledgment
Table 2 Reactions of Thiosalicylaldehydes with BF3·OEt2
We are sincerely grateful to Dr. Hiroko Suezawa of Yokohama
National University, for carrying out NOE measurements. This
work was supported in part by a Grant-in-Aid for Scientific
Research (B) No. 09450339, 13555252, and Grant-in-Aid for
Scientific Research on Priority Areas No. 14044029 from the
Ministry of Education, Science, Sport and Culture, Japan.
Entry
1
2
Conditions
r.t., 15 min
r.t., 50 min
r.t., 2 h
Product
4a
Yield (%)
1
2
3
4
5
6
1b
1b
1b
1c
1c
1c
2a
2b
2c
2a
2b
2c
96
66
50
95
90
89
4b
4c
r.t., 30 min
r.t., 40 min
r.t., 60 min
4a
References
4b
(1) (a) Ellis, G. P.; Lockhart, I. M. In Chromans and
Tocopherols, Vol. 36; John Wiley and Sons: New York,
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(2) (a) Boger, D. L.; Weinreb, S. M. In Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: New
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4c
yields were due to the recovery of 1b. It is worthwhile to
note that the reaction utilizing 1c and 2a–c lead to the
corresponding 4a–c, as single cyclic products in excellent
yields (Table 2, entries 4–6). In these intramolecular
cycloaddition reactions the Lewis acid served not only to
accelerate the reaction but also to promote the cleavage of
the protective groups, methoxymethyl or 2-tetrahydro-
pyranyl, furnishing ortho-thioquinonemethides.
In conclusion, we have described a trans stereoselective
synthesis of pyrano[3,2-c]benzothiopyrans from thio-
salicylaldehyde derivatives and unsaturated alcohols in
the presence of trimethyl orthoformate and acid catalyst
via intramolecular [4+2] cycloaddition of ortho-thio-
quinonemethides. We have also found that BF3·OEt2 is a
very effective acid catalyst for the generation and the
reaction of ortho-thioquinonemethides.
(4) Saito, T.; Horikoshi, T.; Otani, T.; Matsuda, Y.; Karakasa, T.
Tetrahedron Lett. 2003, 44, 6513.
(5) Wermuth, C. G. The Practice of Medicinal Chemistry;
Academic Press: London, 1996, 258.
(6) (a) Inoue, S.; Asami, M.; Honda, K.; Miyazaki, H. Chem.
Lett. 1996, 889. (b) Miyazaki, H.; Honda, K.; Asami, M.;
Inoue, S. J. Org. Chem. 1999, 64, 9507. (c) Miyazaki, H.;
Honda, Y.; Honda, K.; Inoue, S. Tetrahedron Lett. 2000, 41,
2643.
(7) For a review of ortho-thioquinonemethide see: Inoue, S.;
Honda, K. Kagaku Kogyo 2004, 55, 212; Journal written in
Japanese.
(8) (a) Arnoldi, A.; Carughi, M. Synthesis 1988, 155.
(b) Kasmai, H. S.; Mischke, S. G. Synthesis 1989, 763.
(c) Toste, F. D.; Lough, A. J.; Still, I. W. J. Tetrahedron Lett.
1995, 36, 6619. (d) Gallagher, T.; Pardoe, D. A.; Porter, R.
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General Procedure for the Cycloaddition Reactions
A flask was charged with alcohol (10 mmol), thiosalicyclaldehyde
derivative (12 mmol), and trimethyl orthoformate (12 mmol), and
then acid catalyst (2 mmol) was dropped into the reaction mixture.
The mixture was stirred at r.t. (or 80 °C, 110 °C) and monitored by
TLC. The reaction mixture was treated with 10% aq NaOH (in the
case of BF3·OEt2, the reaction was treated with H2O), and the organ-
ic layer was separated. The aqueous layer was extracted with Et2O,
and the combined organic layer was washed with brine, dried over
anhyd MgSO4, and concentrated in vacuo to give crude products,
which were purified by silica gel chromatography.
Compound 4b: 1H NMR (400 MHz, C6D6): d = 0.93 (m, 1 H), 1.10
(m, 1 H), 1.21 (s, 3 H), 1.22 (d, J = 6.1 Hz, 3 H), 1.32–1.46 (m, 2
H), 1.52–1.67 (m, 2 H), 1.57 (s, 3 H), 1.66 (s, 3 H), 1.97 (m, 1 H),
2.14 (m, 1 H), 2.33 (m, 1 H), 3.30 (dqd, J = 2.2, 6.1, 11.7 Hz, 1 H),
4.23 (d, J = 10.3 Hz, 1 H), 5.11 (tt, J = 1.5, 7.1 Hz, 1 H), 6.96 (ddd,
J = 1.5, 7.3, 7.8 Hz, 1 H), 7.00 (ddd, J = 1.5, 7.3, 7.8 Hz, 1 H), 7.17
(m, 1 H), 7.89 (dd, J = 1.5, 7.8 Hz, 1 H). 13C NMR (100 MHz,
C6D6): d = 18.0, 22.4, 23.1, 24.1, 24.9, 26.1, 33.8, 41.1, 44.1, 48.8,
74.0, 76.8, 124.3, 124.4, 126.7, 127.9, 128.1, 131.7, 133.0, 134.2.
Compound 4c: 1H NMR (400 MHz, C6D6): d = 1.00–1.06 (m, 2 H),
1.09 (s, 3 H), 1.22 (d, J = 6.1 Hz, 3 H), 1.34 (m, 1 H), 1.50–1.68 (m,
3 H), 1.52 (s, 3 H), 1.61 (s, 3 H), 2.02–2.08 (m, 2 H), 2.56 (m, 1 H),
3.31 (dqd, J = 2.2, 6.1, 11.7 Hz, 1 H), 4.30 (d, J = 10.3 Hz, 1 H),
5.06 (tt, J = 1.5, 7.1 Hz, 1 H), 6.90 (ddd, J = 1.5, 7.3, 7.8 Hz, 1 H),
6.98 (ddd, J = 1.5, 7.3, 7.8 Hz, 1 H), 7.12 (dd, J = 1.5, 7.8 Hz, 1 H),
7.85 (dd, J = 1.5, 7.8 Hz, 1 H). 13C NMR (100 MHz, C6D6): d = 17.7,
22.2, 23.6, 24.6, 24.8, 25.8, 34.0, 35.2, 48.3, 48.9, 74.0, 76.3, 124.4,
124.8, 126.3, 127.8, 128.8, 131.5, 133.3, 134.1.
(9) Compound 5a: 1H NMR (400 MHz, CDCl3): d = 1.21 (d, J =
6.1 Hz, 3 H), 1.45 (m, 1 H), 1.50 (s, 3 H), 1.71–1.80 (m, 2
H), 1.92 (m, 1 H), 2.47 (ddd, J = 2.9, 10.0, 11.5 Hz, 1 H),
3.42 (s, 3 H), 3.67 (dqd, J = 2.0, 6.1, 11.1 Hz, 1 H), 4.60 (m,
2 H), 4.85 (d, J = 11.2 Hz, 1 H), 4.93 (d, J = 11.2 Hz, 1 H),
4.95 (d, J = 10.0 Hz, 1 H), 7.21 (ddd, J = 1.7, 7.3, 7.6 Hz, 1
H), 7.23 (ddd, J = 1.5, 7.3, 7.6 Hz, 1 H), 7.43 (dd, J = 1.7, 7.6
Hz, 1 H), 7.56 (dd, J = 1.5, 7.6 Hz, 1 H). 13C NMR (100
MHz, CDCl3): d = 21.4, 22.2, 30.7, 33.7, 48.5, 56.1, 74.4,
78.6, 79.5, 112.3, 127.2, 127.6, 128.0, 131.6, 135.5, 141.4,
145.8.
(10) Compound 6 was purified by silica gel column
chromatography, and was characterized by NMR.
Synlett 2005, No. 3, 469–472 © Thieme Stuttgart · New York

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S. Inoue et al.
LETTER
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Synlett 2005, No. 3, 469–472 © Thieme Stuttgart · New York