Improve method for synthesis of 4-thioaryl-2,3,4-trihydro-1-benzo-thiopyrans: Acid-induced stereoselective intermolecular cycloaddition of α,β-unsaturated aldehydes with arenethiols

Article abstract of DOI:10.1055/s-2001-16071

A catalytic amount of acids catalyzed reaction of α,β-unsaturated aldehydes with arenethiols in 1,2-dichloroethane brought about intermolecular cycloaddition to give the corresponding 4-thioaryl-2,3,4-trihydro-1-benzothiopyrans (thiochromans) in good to e

Full text of DOI:10.1055/s-2001-16071

LETTER
1317
Improve Method for Synthesis of 4-Thioaryl-2,3,4-trihydro-1-benzo-
thiopyrans: Acid-induced Stereoselective Intermolecular Cycloaddition
of
-Unsaturated Aldehydes with Arenethiols
Yoshio Ishino,* Masatoshi Mihara, Hidehito Kawai
Osaka Municipal Technical Research Institute 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Fax +81-6-6963-8051; E-mail: ishino@omtri.city.osaka.jp
Received 4 June 2001
The reactions were usually carried out at 80 8 °C for 3 h
in anhydrous dichloroethane containing a catalytic
Abstract: A catalytic amount of acids catalyzed reaction of
-un-
saturated aldehydes with arenethiols in 1,2-dichloroethane brought
about intermolecular cycloaddition to give the corresponding
4-thioaryl-2,3,4-trihydro-1-benzothiopyrans (thiochromans) in
amount of acids,
-unsaturated aldehydes, and arene-
thiols.8 Detailed studies on the reaction of crotyl aldehyde
good to excellent yield. These reactions are assumed to proceed (1a) with thiophenol (2a) to 2-methyl-4-thiophenyl-1-
through allylic cationic intermediates generated in site.
benzothiopyran (3a) showed that this catalytic intermo-
lecular cycloaddition is considerably influenced by the
kinds of acids, the molar ratio of p-TsOH, and the solvents
used, as shown in Table 1.
Key words: benzothiopyrans, acids catalysts, unsaturated alde-
hydes, arenethiols, intermolecular cycloaddition
Fused thiochromans are interesting and useful synthetic
intermediates because of their strong activity toward
many kinds of reagents; a thiochroman’s ring system is
also found in many naturally occurring biologically active
compounds.1 A number of methods for the preparation of
thiochromans have been reported. The thio-Claisen rear-
rangement and its modified version represent a highly ef-
fective and general method for the intermolecular
Table 1 Catalytic Activities of Acids in the Reaction of Crotyl
Aldehyde (1a) and Thiophenol (2a)
cycloaddition products from
-unsaturated com-
pounds.2 - 7 Synthetic utility of these methods may be,
however, considerably limited because of the use of a
large excess of protonic acids or Lewis acids, high tem-
perature, multistep, and so on. To our knowledge, inter-
molecular cycloaddition of
-unsaturated aldehydes and
arenethiols to thiochromans by using a catalytic amount of
acids have not been reported.
Herein, we wish to describe an improved method for se-
lective ring formation through intermolecular cycloaddi-
a)Isolated yield based on 1a. 2-Methyl-1-benzothiopyran (4) was ad-
ditionally obtained at entry 2-5 in the yield of 7%, 2%, 4%, and 10%,
respectively.
tion of
presence of a catalytic amount of acids to give the corre-
sponding 4-thioaryl-2,3,4-trihydro-1-benzotiopyrans
-unsaturated aldehydes with arenethiols in the
b)3-Phenylthio-butanal was obtained in the yield of 46%.
c)Crotyl-dithiophenyl acetal was also obtained in 63%.
(thio-chromans, 3) in good to excellent yields (Scheme 1).
The present method may be characterized by use of a cat-
alytic amount of acids, highly simplicity and convenience
of reaction procedure, mild reaction conditions, selective
ring formation by easily available substrates, and good
yields of the products.
Noteworthy is the fact that the reaction in the absence of
acids did not give 3a, while the presence of a catalytic
amount of acids, especially p-TsOH and H2SO4, caused
a smooth reaction to give product 3a in good yields. As
shown in Table 1, the optimum reaction condition for the
formation of 3a is attained when the molar ratio of 1a : 2a:
p-TsOH is 1: 2.1: 0.1. A reaction with Lewis acids result-
ed in a low yield (36-0%). The use of propionic acid in-
stead of p-TsOH gave no chroman products. 1,2-
Dichloroethane is the best choice of solvents.
The intermolecular cycloaddition between
-unsaturat-
ed aldehydes with arenethiols led to stereoisomeric mix-
Scheme 1
Synlett 2001, No. 8, 1317–1319 ISSN 0936-5214 © Thieme Stuttgart · New York

1318
Y. Ishino et al.
LETTER
Table 2 Reaction of , -Unsaturated Aldehydes (1) with Arenethiols (2) in the
Presence of p-Toluenesulfornic Acid
Table 3 Stereochemistry of 2,3,4-Trihydro-1-Benzothiopyrans (3)
tures of cis and trans isomer. A molar ratio of cis to trans
1
isomer was determined by means of H NMR and GLC
analyses.9 Representative examples are given in Tables 2
and 3.
A catalytic amount of acids has been found to promote
smoothly the transformation of various unsaturated alde-
hydes with arenethiols to the corresponding intermolecu-
lar cycloaddition products, such as thiochromans 3 and
thiochromens 4, under mild reaction conditions. Several
comments are worth noting: (1) Various type of
-un-
saturated aldehydes reacted with 2, except 2-substituted
crotonaldehydes,10 and gave thiochromans (3) in good to
excellent yield; (2) the cis isomer was usually obtained as
major isomer; and (3) acetylenic aldehydes also reacted
smoothly with 2 under the same reaction conditions and
gave thiochromenes (5) in good yields.
Synlett 2001, No. 8, 1317–1319 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Improve Method for Synthesis of 4-Thioaryl-2,3,4-trihydro-1-benzothiopyrans
1319
(8) Typical reaction procedure: To a solution of 1a (350 mg, 5
mmol) and p-TsOH-H2O (100 mg, 0.5 mmol) in anhydrous
dichloroethane (15 mL) was added a solution of 2a (1.21 g, 11
mmol) in anhydrous dichloroethane (15 mL). The reaction
mixture was stirred at 80 °C for 4 h. After the usual work-up
of the reaction mixture, the crude products was purified by
chromatography column on silica gel to afford 2-methyl-4-
thiophnyl-2,3,4-trihydro-1-benzotiopyrans as a mixture of cis
and trans isomers (3a, 76%, ratio of cis/trans = 1.9/1). All new
compounds were fully characterized by 1H and 13C NMR (270
MHz; CDCl3), IR and MS. Selected spectral data: 3a-cis: 1H
NMR (270 Mz, CDCl3): 6.98-7.78 (m, 9H), 4.56 (t, J = 3.15
Hz, 1H), 3.95 (m, 1H), 2.24 (m, 1H), 1.86 (m, 1H), 1.30 (d,
J = 6.60 Hz. 3H); 13C NMR (270 Mz, CDCl3): 128-136, 48.8,
35.5, 30.8, 21.0; 3a-trans: 1H NMR (270 Mz, CDCl3): 6.98-
7.78 (m, 9H), 4.43 (m, 1H), 3.30 (m, 1H), 2.55 (m, 1H), 2.06
(m, 1H), 1.23 (d, J = 8.91 Hz. 3H); 13C NMR (270 Mz,
CDCl3): 128-136, 47.7, 40.8, 36.3, 21.5; HRMS Calcd for
C16H16S2 272.0693, Found 272.0690. 5a: 1H NMR (270 Mz,
CDCl3): 6.74-7.64 (m, 14H), 6.22 (d, J = 3.3 Hz, 1H), 5.92
(d, J = 3.3 Hz, 1H); HRMS Calcd for C21H16S2 332.0693,
Found 332.0689.
Although the details concerning the mechanism still re-
main ambiguous, the reaction may proceed through allylic
cationic intermediates generated in site. These allylic cat-
ionic intermediates gave the products thiochromans 3 or 4
through a subsequent cross-condensation of arenethiols.11
In conclusion, the present method using easily available
catalyzer is characterized by high operational simplicity
and mild reaction conditions. These reactions provide a
route to prepare 2,3,4-trihydro-1-benzothiopyrans with a
high stereoselectivity in good-to-moderate yields. We be-
lieve that this intermolecular cycloaddition offers one of
the most simple and very convenient methods for synthe-
sis of 1-benzothiopyrans.
References and Notes
(1) For example, Katrizky, A. R.; Bonlton, A. J. Advances in
Heterocyclic Chemistry; Academic Press: 1975, 18, 76.
(2) Tilak, B.D.; Desai, H. S.; Deshande, C. V.; Jain, S. K.; Vaiaya,
Y. M., Tetrahedron 1966, 22, 7.
(3) Meters, C.Y.; Rineldi, C.; Bonali, L., J. Org. Chem. 1963, 28,
2440.
(4) Tanaka, J.; Katagiri, T.; Takabe, K.; Takeshita, S., J. Synth.
Org. Chem, Japan 1971, 29, 788.
(5) Kwart, H.; Greoge, T. J., J. Chem. Soc., Chem. Comm 1970,
433.
(6) Gopalan, B.; Rajagopalan, K.; Swaminathan, S., Synthesis
1976, 409.
(7) Intermolecular cycloaddition catalyzed by aluminum chloride
to thiochromans are known. Manimaran, T.; Thiruvengadim,
T. K.; Ramakrishuan, V. T., Synthesis 1975, 739.
(9) Assignment of the cis and trans-isomers of the products, and
determination of the cis/trans ratio were accomplished by
means of 1H NMR and/or gas chromatography according to
the reported assignment. For example; Cotterill, W. D.;
France, C. J.; Livingstone, R.; Atkinson, J. R.; Cottan, J., J.
Chem. Soc., Perkin I 1972, 787.
(10) In the case of 2-substituted aldehydes, such as 2-ethyl-2-
butanal, diphenylthioacetals (2-ethyl-2-buta-
diphenylthioacetals) were obtained in 70% yield.
(11) For example, Ishino, Y.; Nakamura, M.; Nishiguchi, I.;
Hirashima, T. Synlett 1991, 633. Cossy, J.; Henin, F,; Leblanc,
C., Tetrahedron Lett. 1987, 28, 1417.
Article Identifier:
1437-2096,E;2001,0,08,1317,1319,ftx,en;Y10901ST.pdf
Synlett 2001, No. 8, 1317–1319 ISSN 0936-5214 © Thieme Stuttgart · New York