Facile synthesis and desulfurization of 5-(phenylthio)pyrano[3,2- c][1]benzopyrans starting from 5-phenylthio-4-penten-1-ols and salicylaldehyde via in situ intramolecular cycloaddition of substituted o- quinonemethides

Article abstract of DOI:10.1016/S0040-4039(00)00236-7

5-(Phenylthio)pyrano[3,2-c][1]benzopyrans (6) were successfully synthesized in high yield by the reaction of 5-phenylthio-4-penten-1-ol (5) and salicylaldehyde (1) in benzene in the presence of p-toluenesulfonic acid and trimethyl orthoformate, trans,trans-Isomer 6a and cis,cis-isomer 6d were produced as major products from (E)5 and (Z)-5, respectively. Treatment of 6a with lithium 4,4'-di-tert-butylbiphenyl or Raney Ni (W-4) lead to trans- pyrano[3,2-c][1]benzopyran 4b which is very difficult to make by direct cycloaddition using unsubstituted 4-penten-1-ol (2b). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00236-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2643–2647
Facile synthesis and desulfurization of 5-(phenylthio)pyrano-
3,2-c][1]benzopyrans starting from 5-phenylthio-4-penten-1-ols
and salicylaldehyde via in situ intramolecular cycloaddition of
substituted o-quinonemethides
[
∗
Hidekazu Miyazaki, Yoshinari Honda, Kiyoshi Honda and Seiichi Inoue
Department of Chemistry and Biotechnology, Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai,
Hodogayaku, Yokohama 240-8501, Japan
Received 12 January 2000; revised 3 February 2000; accepted 4 February 2000
Abstract
5-(Phenylthio)pyrano[3,2-c][1]benzopyrans (6) were successfully synthesized in high yield by the reaction of
5-phenylthio-4-penten-1-ol (5) and salicylaldehyde (1) in benzene in the presence of p-toluenesulfonic acid and
trimethyl orthoformate. trans,trans-Isomer 6a and cis,cis-isomer 6d were produced as major products from (E)-
0
5
and (Z)-5, respectively. Treatment of 6a with lithium 4,4 -di-tert-butylbiphenyl or Raney Ni (W-4) lead to
trans-pyrano[3,2-c][1]benzopyran 4b which is very difficult to make by direct cycloaddition using unsubstituted
-penten-1-ol (2b). © 2000 Elsevier Science Ltd. All rights reserved.
4
Keywords: cycloaddition; intramolecular Diels–Alder reaction; o-quinonemethide; 5-(phenylthio)pyrano[3,2-c][1]benzopyran;
pyrano[3,2-c][1]benzopyran.
We have been investigating the generation and reaction of o-quinonemethides under mild conditions
1
in order to widen their application in organic synthesis. Previously, we reported that salicylaldehyde
(
1) reacted with alcohol 2a in benzene in the presence of p-TsOH and trimethyl orthoformate at room
2
temperature to give trans-4a in high yield as a single stereoisomer (Scheme 1).
Scheme 1.
∗
Corresponding author. Fax: +81-45-335-1536; e-mail: s-inoue@ynu.ac.jp (S. Inoue)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00236-7
tetl 16516

2
644
In general, the cycloaddition between various salicylaldehydes and 5-methyl-4-alken-1-ols proceeds
very efficiently; however, the reaction between 1 and 4-penten-1-ol (2b) does not take place at all, even
3
in refluxing benzene for 5 days. The failure of the reaction with 2b may be attributed to the low electron
density at the olefinic moiety, as can be predicted from the mechanistic character of inverse electron
1
demanded [4+2] cycloaddition. We then anticipated that unsubstituted pyranobenzopyran 4b may be
obtained by employing phenylthio-substituted olefinic alcohol 5 instead of 2b followed by desulfurization
of the primary cyclization product. Furthermore, we were interested in the reactivity and stereochemical
nature of the cycloaddition of disubstituted olefins.
Simple radical addition of thiophenol to 4-pentyn-1-ol afforded 5-phenylthio-4-pentenol 5 as a ca.
4
1
:1 mixture of (E)- and (Z)-isomers. The individual stereoisomers were prepared by the stereoselective
5
hydrogenation of 5-(phenylthio)-4-pentyn-1-ol or its THP ether.
The cycloaddition reactions were carried out by stirring a solution of alcohol 5 (1.0 mmol), aldehyde
1
(1.2 mmol), trimethyl orthoformate (1.2 mmol), and p-TsOH (0.2 mmol) in benzene. The reaction
proceeded smoothly and the products 6a–d were isolated by silica gel column chromatography and were
characterized by spectroscopic data. The product 6a was easily isolated by silica gel column chroma-
tography; however, the others were difficult to separate from each other. The results are summarized in
6
Table 1.
Table 1
Reaction of salicylaldehyde (1) with alcohol 5
Reaction of salicylaldehyde with a 52:48 mixture of (E)- and (Z)-alcohols 5 afforded a mixture of
tricyclic stereoisomers 6a–d in 80% combined yield at room temperature, the isomeric ratio of 6 not
being correlated with that of 5 (entry 1). A long reaction period (entry 2), or high reaction temperature
(entry 3), did not greatly affect the diastereomer ratio of the products. Reaction of 1 with a 86:14 mixture
of (E)- and (Z)-5 afforded tricyclic compounds 6a as a major product at room temperature (entry 4) and
similar behavior was observed in refluxing benzene (entry 5). Interestingly, reaction of 1 with pure (Z)-5
afforded a considerable amount of 6a as well as 6d at both temperatures (entries 6 and 7).
Since the intramolecular cycloaddition by this method usually proceeds through an exo transition
state, such unusual stereoselectivities should be significant enough to attract much attention from both

2
645
synthetic and mechanistic viewpoints. To shed light on the unusual stereoselectivity of this cyclization,
we investigated the isomerization behavior of 5 and 6.
First, tricyclic compounds 6a and 6d were heated in benzene at reflux in the presence of p-TsOH.
1
According to H NMR measurements, 6a isomerized slowly to give a ca. 1:1 mixture of 6a and 6b after
3
6 h, whereas 6d completely changed to 6c in 5 h. According to the molecular orbital calculations (AM1,
7
kcal/mol), 6c (−25.42) has less heat of formation energy than 6d (−21.49), and that of 6b (–25.67) is
very close to that of 6a (−25.40). These data suggest that both 6a and 6d are the kinetic products of the
cycloaddition reaction. It is worth noting that the above isomerization took place only at the C-5 carrying
the phenylthio group, absolutely not at the B/C ring junction.
Next, we examined the isomerization of alcohol 5 (Scheme 2). The (E)- or (Z)-5 was isomerized to
a mixture of (E)- and (Z)-isomers at room temperature, and 2-(phenylthio)tetrahydro-2H-pyran 7 was
obtained from both the alcohols under refluxing conditions.
Scheme 2.
1
The reaction between 1 and the (E)- and (Z)-mixtures of 5 was monitored by H NMR spectra in
benzene-d at room temperature. Compound 6a was generated rapidly, whereas 6d was generated in
6
less than 5% of 6a at the early stage. It was observed that (E)-5 was consumed rapidly, whereas (Z)-5
remained until a later stage of the reaction.
Therefore, the stereochemical outcome of the cycloaddition reaction mentioned before could be
rationalized as follows. (E)-5 and (Z)-5 afforded 6a and 6d as major products, respectively; however,
6a was also obtained from the reaction of pure (Z)-5 with 1, as a result of the isomerization of (E)-5 to
(Z)-5 under the reaction conditions (Scheme 2).
The characteristic feature of the cycloaddition could be accounted for by assuming four transition
state models TS-1 (E-exo), TS-2 (E-endo), TS-3 (Z-exo), and TS-4 (Z-endo) in the concerted mechanism
Fig. 1). In general, exo-type transition states TS-1 and TS-3 may be more favored, and this is the case
(
for the reactions of alkyl substituted olefin. On the other hand, vinyl sulfide 5 afforded 6a and 6d as major
products through TS-1 and TS-4. Coefficient values calculated by the AM1 method are shown in Fig. 2.7
These results indicate that transition states are stabilized by an interaction between the sulfur atom and
the carbonyl carbon of o-quinonemethide in exo-type TS-1 and endo-type TS-4, whereas TS-2 and TS-3
8
have no orbital interaction. Consequently, vinyl sulfide would prefer TS-1 and TS-4 to provide 6a and
6d.
Fig. 1.

2
646
Fig. 2.
As mentioned earlier, direct cycloaddition of 1 and 2b does not take place at all. Therefore, if the
C-5 thiophenyl group of 6 can be removed efficiently, this approach should become a useful method for
9
producing 4b. Phenylthio-substituted compound 6a was treated with Raney Ni (W-4) in ethanol at room
10
temperature to give tricyclic compound 4b as a single stereoisomer in high yield (Scheme 3). The same
11
0
product was also obtained by treatment of 6a with LiDBB prepared from 4,4 -di-tert-butylbiphenyl
and lithium metal.
Scheme 3.
In summary, we have found that the reaction of (E)- and (Z)-alcohols 5 with 1 furnished phenylthio-
substituted tricyclic compounds 6a and 6d, respectively, as major products in high yields, and that 6d
can be efficiently isomerized to the more thermodynamically stable isomer 6c. By desulfurization of 6a,
unsubstituted product 4b was easily obtained, which was difficult to make from the reaction of 1 with 2b.
As phenylthio-substituted compounds can be reductively lithiated, as shown in Scheme 3 for example,
which makes them useful intermediates for a variety of transformations, the present method should be
applicable to the synthesis of substituted pyranobenzopyrans in natural products.
Acknowledgements
The authors would like to thank Assoc. Prof. Hiroko Suezawa, Instrumental Analysis Center, Yoko-
hama National University for NMR measurements. This work was supported in part by a Grant-in-Aid
for Scientific Research No. 09450339 from the Ministry of Education, Science, Sport and Culture, Japan.
References
1. (a) Inoue, T.; Inoue, S.; Sato, K. Chem. Lett. 1989, 653. (b) Inoue, T.; Inoue, S.; Sato, K. Chem. Lett. 1990, 55. (c) Inoue,
T.; Inoue, S.; Sato, K. Bull. Chem. Soc. Jpn. 1990, 63, 1062. (d) Inoue, T.; Inoue, S.; Sato, K. Bull. Chem. Soc. Jpn. 1990,
6
3, 1647. (e) Lu, Z. G.; Sato, N.; Inoue, S.; Sato, K. Chem. Lett. 1992, 1237. (f) Lu, Z. G.; Inoue, S. Heterocycles 1992, 34,
1
107.
2
3
4
. Inoue, S.; Asami, M.; Honda, K.; Miyazaki, H. Chem. Lett. 1996, 889.
. Miyazaki, H.; Honda, K.; Asami, M.; Inoue, S. J. Org. Chem. 1999, 64, 9507.
. Reaction of 4-pentyn-1-ol and thiophenol using AIBN as a radical initiator in benzene at reflux afforded alcohol 5 as a
mixture of (E)- and (Z)-isomers in 80% yield. Cf. Miyake, H.; Yamamura, K. Bull. Chem. Soc. Jpn. 1988, 61, 3752.

2
647
5
6
. To a solution of 4-pentyn-1-ol tetrahydropyranyl (THP) ether in THF was added hexane solution of n-butyllithium, followed
+
−
by a THF solution of PhS(Ph)(Me)S I to furnish 5-(phenylthio)-4-pentyn-1-ol THP ether. This was reduced with LiAlH
4
in THF at room temperature to give a 86:14 mixture of the corresponding (E)- and (Z)-olefins, which was treated with
pyridinium p-toluenesulfonate (PPTS) in methanol to give a mixture of (E)- and (Z)-5 in 88% yield. 5-(Phenylthio)-4-
pentyn-1-ol THP ether was treated with PPTS in methanol to give the parent alcohol in 95% yield, which was reacted with
trimethylaluminum followed by diisobutylaluminum hydride to give pure (Z)-5 in 42% yield. Cf. (a) Ma, S.; Negishi, E.
Tetrahedron Lett. 1997, 38, 3829. (b) Kabanyane, S. T.; MaGee, D. I. Can. J. Chem. 1992, 70, 2758. (c) Krief, A.; Kenda,
B.; Remacle, B. Tetrahedron 1996, 52, 7435.
. All compounds were purified by silica gel column chromatography, and were characterized by spectroscopic means. Physical
1
properties and selected H NMR spectral data (in CDCl
3
, 270 MHz, δ; TMS=0) are as follows. Compound 6a: mp.
1
1
=
20–121°C (hexane–EtOAc; colorless crystals) 1.36 (m, 1H), 1.68–1.88 (m, 3H), 2.30 (m, 1H), 3.61 (m, 1H), 4.16 (m,
H), 4.26 (d, J=10.2 Hz, 1H), 5.29 (d, J=10.9 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.94 (dd, J=7.3, 7.6 Hz, 1H), 7.17 (dd, J
7.3, 8.3 Hz, 1H), 7.25–7.33 (m, 3H), 7.36 (d, J=7.6 Hz, 1H), 7.60 (dd, J=1.7, 7.9 Hz, 2H). Compound 6b: (colorless oil;
60% pure) 1.70–2.06 (m, 3H), 2.27–2.38 (m, 2H), 3.71 (m, 1H), 4.18 (m, 1H), 4.50 (d, J=10.9 Hz, 1H), 5.67 (d, J=4.0 Hz,
1H), 6.85 (d, J=8.3 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 7.24–7.34 (m, 4H), 7.47 (d, J =7.6 Hz, 1H), 7.53 (dd, J=1.7, 7.9 Hz,
2H). Compound 6c: (colorless oil; 90% pure) 1.60–1.88 (m, 3H), 2.00 (m, 1H), 2.28 (m, 1H), 3.64–3.68 (m, 2H), 4.87 (d,
J=4.3 Hz, 1H), 5.68 (d, J=5.9 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 7.20–7.59 (m, 7H). Compound 6d:
colorless oil; 80% pure) 1.61–1.89 (m, 3H), 1.96 (m, 1H), 2.54 (m, 1H), 3.47 (m, 1H), 3.63 (m, 1H), 4.98 (d, J=5.9 Hz,
(
1
3
H), 5.50 (d, J=2.3 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 7.00 (t, J=7.3 Hz, 1H), 7.20 (dd, J=7.3, 8.3 Hz, 1H), 7.25–7.40 (m,
H), 7.43 (d, J=7.3 Hz, 1H), 7.55 (dd, J=1.7, 7.9 Hz, 2H).
7. The calculations were performed by using CAChe work system version 4.1.1 (PM3 and AM1).
8. Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 1724.
9. Adkins, H.; Pavlic, A. A. J. Am. Chem. Soc. 1947, 69, 3039.
1
0. Compound 4b: mp 83–84°C (hexane–EtOAc; colorless crystals) δ 1.24 (m, 1H), 1.68–2.04 (m, 4H), 3.68 (dt, J=3.0, 11.5
Hz,1H), 3.88 (t, J=11.5 Hz, 1H), 4.16 (dd, J=3.6, 10.9 Hz, 1H), 4.18 (t, J=10.9 Hz, 1H), 4.20 (d, J=9.9 Hz, 1H), 6.77 (d,
J=8.2 Hz, 1H), 6.90 (dd, J=7.3, 7.6 Hz, 1H), 7.14 (dd, J=7.3, 8.2 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H).
11. (a) Zhu, S.; Cohen, T. Tetrahedron 1997, 53, 17 607. (b) Rawson, D. J.; Meyers, A. I. Tetrahedron Lett. 1991, 32, 2095.
(
c) Rychnovsky, S. D.; Mickus, D. E. Tetrahedron Lett. 1989, 30, 3011. (d) Freeman, P. K.; Hutchinson, L. L. Tetrahedron
Lett. 1976, 22, 1849. (e) Shiner, C. S.; Tsunoda, T.; Goodman, B. A.; Ingham, S.; Lee, S.; Vorndam, P. E. J. Am. Chem. Soc.
989, 111, 1381.
1