Stereoselective synthesis of 2,4-disubstituted thiochromans using the supported reagent system 'Na2CO3/SiO2-PPA/ SiO2'

Article abstract of DOI:10.1055/s-2007-967935

A simple and efficient method has been developed for the stereoselective synthesis of 2,4-disubstituted thiochromans from arylthiols and α,β-unsaturated aldehydes by using an acid- and a base-supported reagent system, Na₂CO₃/SiO

Full text of DOI:10.1055/s-2007-967935

LETTER
387
Stereoselective Synthesis of 2,4-Disubstituted Thiochromans Using the
Supported Reagent System ‘Na2CO3/SiO2–PPA/SiO2’
Stereoselective
a
S
ynthesis
o
d
f
2,4-Disubs
a
tituted Thio
s
c
hromanshi Aoyama,*a Kazuyuki Okada,a Hideaki Nakajima,a Takuo Matsumoto,b Toshio Takido,a Mitsuo Kodomaric
a
Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Kanda Surugadai, Chiyoda-ku,
Tokyo 101-8308, Japan
Fax +81(3)32590818; E-mail: aoyama@chem.cst.nihon-u.ac.jp
b
c
Core Technology Research Laboratories, Sankyo Co., LTD., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Department of Applied Chemistry, Shibaura Institute of Technology, Toyosu, koto-ku, Tokyo 135-8548, Japan
Received 6 November 2006
a-haloketone to give a-sulfenyl ketone, and PPA/SiO2
catalyzes intramoleculer cyclocondensation of a-sulfenyl
ketone. Now, a significant improvement of the stereo-
selectivity has been achieved for a variety of organic reac-
Abstract: A simple and efficient method has been developed for
the stereoselective synthesis of 2,4-disubstituted thiochromans
from arylthiols and a,b-unsaturated aldehydes by using an acid- and
a base-supported reagent system, Na2CO3/SiO2–PPA/SiO2. Michael
addition of arylthiol to a,b-unsaturated aldehydes was promoted by tions by the use of supported reagents or by the adsorption
of substrates onto the surface of an inorganic solid.8 Here-
Na2CO3/SiO2, and then the product was cyclized in the presence of
PPA/SiO2.
in, we report the stereoselective synthesis of 2,4-disub-
Key words: stereoselective synthesis, thiochroman, supported
reagents
stituted thiochromans using supported reagents Na2CO3/
SiO2–PPA/SiO2.
First, we investigated a catalytic system for the synthesis
of thiochromans 3aa from p-toluenethiol (1a) and croton
aldehyde (2a). For instance, when a mixture of 1a (4.2
mmol), 2a (2 mmol) and PPA (0.3 g) was stirred in 1,2-
dichloroethane at 80 °C for 4 hours, 3aa was obtained in
42% yield (Table 1). On the other hand, in the reaction
The thiochroman ring system is very attractive, because a
variety of thiochromans possess biological activity. For
instance, thiochroman-6-acetic acid has anti-inflammato-
ry, antipyretic and analgesic activities, and 4-substituted
aminothiochromans are active as antidepressants, anti-
hypertensives and agents against angina paints, etc.1 In
general, thiochromans were synthesized via Claisen
rearrangement of allyl phenyl sulfide2 and acid-catalyzed
intramolecular cyclocondensation of thiol and b-arylthio
aldehyde which are synthesized from arylthiol and a,b-
unsaturated aldehyde under basic conditions.3 Jafarzadeh
et al.4 and Ishino et al.5 synthesized these thiochromans
directly from arylthiols and a,b-unsaturated aldehydes
under acidic conditions. These methods made it possible
to shorten the two-step reactions, but the neutralization of
the reaction mixture in order to obtain pure products could
not be avoided. Recently, we developed a silica gel
supported polyphosphoric acid (PPA/SiO2) as a hetero-
geneous acid catalyst for organic synthesis.6 The reaction
using PPA/SiO2 has some advantages: PPA/SiO2 can be
separated easily from the reaction mixture; recovered
PPA/SiO2 can be reused after drying; the filtrate need not
be neutralized after removing the catalyst by filtration. In
continuation of our work using PPA/SiO2, we found out
that both PPA/SiO2 and silica gel supported sodium
carbonate (Na2CO3/SiO2) coexist in the same vessel with-
out neutralization, and benzothiophenes were synthesized
from the reaction of arylthiol and a-haloketone using
PPA/SiO2–Na2CO3/SiO2 in the same vessel.7 In this reac-
tion, Na2CO3/SiO2 promotes the reaction of arylthiol and
9
using PPA/SiO2 instead of PPA, the yield of 3aa (%)
increased along with a small amount of by-product 4.
The reaction did not occur without the catalyst. The struc-
ture of 4, 1,1,3-tris(4-methylphenylthio)butane, was con-
firmed by spectroscopic means using NMR, IR and by
mass spectrometry. Because of acidic reaction conditions,
10
compound 4 was formed. Therefore Na2CO3/SiO2 was
added to the reaction mixture in order to prevent the
formation of 4. In the coexistent system of Na2CO3/SiO2
and PPA/SiO2, the reaction gave 3aa in 74% yield, and
compound 4 was not detected. We tried to optimize the
reaction conditions for the reaction using Na2CO3/SiO2–
PPA/SiO2.
The optimum amount of PPA on silica gel for the reaction
was investigated. Using a large amount of PPA loaded
onto silica gel, the yield of 3aa decreased, whereas the
yield increased with a higher amount of PPA. PPA/SiO2
(20 wt%) was the most suitable catalyst for the intramo-
lecular cyclocondensation. In order to determine the opti-
mum conditions for the synthesis of 3aa, molar ratio of
reagents, reaction time and temperature were investigat-
ed. When the reaction was carried out using 1.25 g of
Na2CO3/SiO2, the yield was the same as in the reaction us-
ing 2.0 g of Na2CO3/SiO2. However, in the reaction using
less than 1.0 g of Na2CO3/SiO2, the yield of 3aa de-
creased, and a small amount of 4 was obtained. The use of
a large amount of PPA/SiO2 did not affect the yield. The
rate of the intramolecular cyclocondensation was signifi-
cantly affected by the reaction temperature. When the
reaction was carried out at less than 70 °C, the intra-
SYNLETT 2007, No. 3, pp 0387–0390
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Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-967935; Art ID: U12906ST
© Georg Thieme Verlag Stuttgart · New York

388
T. Aoyama et al.
LETTER
Table 2 Preparation of 3aa in Various Solventsa
Table 1 Preparation of 3aa with Various Reagent Systemsa
Yield of 3aa (%)b
SH
O
Entry
Solvent
+
1
2
3
4
5
6
7
Hexane
73c
76
60c
80
80
86
4
H
1a
2a
S
Cyclohexane
Chloroform
Benzene
reagent system
DCE, 80 °C, 4 h
SAr
3aa
Toluene
Entry
Reagent system
None
Yield of 3aa (%)b
Monochlorobenzene
Butanol
1
2
3
4
0
PPA
42
67
74
a In all reaction were used 2 mmol of 2a, 4.2 mmol of 1a, 1.25 g of
Na2CO3/SiO2 (1.5 mmol/g), 3 g of PPA/SiO2 (20 wt%) and 15 mL of
solvent.
PPA/SiO2
Na2CO3/SiO2–PPA/SiO2
b Yield were determined by GLC.
c A small amount of 4 was observed.
a In all reactions were used 2 mmol of 2a, 4.2 mmol of 1a, 0.3 g of
PPA, 3.0 mmol of Na2CO3 and 15 mL of 1,2-dichloroethane.
b Yields were determined by GLC.
However, when 1,2-dichloroethane was used as a sol-
vent under these conditions, a small amount of 1,2-bis(4-
methylphenylthio)ethane (5) was formed as by-product
(Scheme 1). Compound 5 was formed in the reaction of
1,2-dichloroethane with 1a in the presence of Na2CO3/
SiO2. Therefore we examined another suitable solvent in
which 5 was not formed. The results are shown in Table 2.
The yield in aromatic solvents was higher than that in ali-
phatic solvents. Compound 4 was observed in the reaction
products when hexane and chloroform were used as
solvents (entries 1 and 3). Compound 3aa was obtained in
only 4% yield when a polar solvent such as butanol was
used (entry 7). A series of thiochromans was synthesized
by using various combinations of 1 and 2.11,12 The results
are summarized in Table 3. All thiochromans were syn-
thesized in moderate to high yield except for the reaction
using 3-methyl-2-butenal. In the reaction with 3-methyl-
2-butenal, a large amount of the starting material was re-
covered (entries 5, 10 and 15). The yield did not increase
even if the reaction was carried out using a large amount
of Na2CO3/SiO2 or at high reaction temperature.
molecular cyclocondensation did not proceed at all, but
Michael addition of 1a to 2a occurred. A shorter reaction
time resulted in a decreased yield, but long reaction time
and higher reaction temperature did not affect the yield.
From the results of these experiments, all reactions
were carried out using 2 mmol of 2, 4.2 mmol of 1, 1.25 g
of Na2CO3/SiO2 (1.5 mmol/g) and 3.0 g of PPA/SiO2
(20 wt%).
SH
O
+
H
1a
2a
3aa
Na2CO3/SiO2–PPA/SiO2
DCE, 80 °C, 4 h
+
ArS
SAr
5
Scheme 1
Figure 1 1H NMR spectra of compounds 3ba–3bc
Synlett 2007, No. 3, 387–390 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of 2,4-Disubstituted Thiochromans
389
a
Table 3 Preparation of 3 from 1 and 2 Using Na2CO3/SiO2–PPA/SiO2
R3
R1
S
R2
R2
O
Na2CO3/SiO2–PPA/SiO2
PhCl, 80 °C, 4 h
+
Ar SH
R1
H
R4
SAr
1
2
3
Entry
Ar
R1
R2
R3
R4
Product
Selectivity (%) Yield (%)b
(trans-isomer)
1
2
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
Ph
Me
Pr
H
H
Me
Me
Me
Me
Me
H
3aa
3ab
3ac
3ad
3ae
3ba
3bb
3bc
3bd
3be
3ca
3cb
3cc
3cd
3ce
90.9
96.2
>99.9
–
83
76
63
83
39
64
73
88
56
30
71
59
75
40
14
H
H
3
Ph
H
H
H
4
H
H
5
Me
Me
Pr
Me
H
H
–
6
H
80.0
84.7
>99.9
–
7
Ph
H
H
H
8
Ph
Ph
H
H
H
H
9
Ph
H
H
H
10
11
12
13
14
15
Ph
Me
Me
Pr
Me
H
H
H
–
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
Me
Me
Me
Me
Me
H
87.7
91.7
>99.9
–
H
H
Ph
H
H
H
H
H
Me
Me
H
–
a In all reactions were used 2 mmol of 2, 4.2 mmol of 1, Na2CO3/SiO2 (1.5 mmol/g), PPA/SiO2 (20 wt%) and 15 mL of PhCl.
b Isolated yield.
SH
and they found that p-toluene sulfonic acid (TsOH) was
the most effective catalyst for a stereoselective synthesis
of thiochromans. In the case of the reaction using TsOH,
the formation of the cis-isomer of the thiochromans has
priority over the trans-isomer. The method using support-
ed reagents, however, gave preferentially the trans-iso-
mer. The structure of the products and the ratio of cis- and
R2
O
Na2CO3/SiO2–PPA/SiO2
PhCl, 80 °C, 4 h
+
R1
H
R1
R2
Yield (%)
R1
R1
S
R2
S
R2
Me
Pr
H
H
68
59
80
49
21
+
Ph
H
H
H
1
trans-isomers were determined by H NMR and H–H
3da–de
3'da–de
SAr
SAr
Me
Me
COSY. A proton signal at the 4-position in the trans-iso-
mer showed a triplet (J = 2.9–3.2 Hz) whereas in the cis-
isomer a doublet of doublet (J = 11.0–11.2, 5.1–5.4 Hz;
see Figure 1) was observed. These results agreed with the
Karplus rule. The protons at the 4- and 3-positions of the
trans-isomer are located equatorial–axial and equatorial–
equatorial on the thiopyran ring. The corresponding
protons of the cis-isomer are located axial–equatorial and
axial–axial. The structure of trans-3aa was also deter-
mined by X-ray crystal structure analysis and is shown in
Figure 2. Preferential formation of the trans-isomer is due
to intramolecular cyclocondensation occurring on the
surface of PPA/SiO2. There was no stereoselectivity
observed when an intramolecular cyclocondensation was
Scheme 2
When m-toluenethiol was used for this reaction, intramo-
lecular cyclocondensation occurred at 2- and 4-positions
in the benzene ring, and both 5-methylthiochromans
(3da–de) and 7-methylthiochromans (3¢da–de) were
formed. Compounds 3 and 3¢ could not be isolated from
the mixture; therefore, these yields refer to a mixture of
3 and 3¢ (Scheme 2).
Ishino et al. have reported stereoselective synthesis of
thiochromans from arylthiols and a,b-unsaturated alde-
hydes in the presence of various protic and Lewis acids,
Synlett 2007, No. 3, 387–390 © Thieme Stuttgart · New York

390
T. Aoyama et al.
LETTER
Then, SiO2 [Wakogel C-200 (Wako Pure Chemical Ind.
Ltd.), 16.0 g], which was dried in vacuo (10 mmHg) at
160 °C for 2 h, was added to the mixture, and the mixture
was stirred for another 1 h. The CHCl3 was removed with
rotary evaporator and the resulting solid was dried in vacuo
(10 mmHg) at r.t. for 3 h.
carried out using PPA (see Figure 1), i.e. the reaction of
benzenethiol (1b) and cinnamaldehyde (2c) in the pres-
ence of PPA gave a mixture of cis- and trans-3bc, in
which the ratio of cis- and trans-isomer was 1.34:1.00.
The mechanism of intramolecular cyclocondensation is
now under investigation.
(10) Preparation of Na2CO3/SiO2.
Silica gel [Wakogel C-200 (Wako Pure Chemical Ind.
LTD.), 16.82 g] was added to a solution of Na2CO3 (30
mmol, 3.18 g) in distilled H2O (100 mL), and the mixture
was stirred at r.t. for 0.5 h. Then, H2O was removed by rotary
evaporator under reduced pressure, and the resulting reagent
was dried in vacuo (10 mmHg) at 160 °C for 5 h.
(11) Typical Procedure.
A mixture of arylthiols (4.20 mmol), a,b-unsaturated
aldehydes (2.00 mmol), Na2CO3/SiO2 (1.88 mmol, 1.25 g)
and PPA/SiO2 (20 wt%, 3.00 g) was stirred in PhCl (15 mL)
at 80 °C for 4 h, and then the used supported reagents were
removed by filtration. The filtrate was evaporated to leave
crude product, which was purified by column
chromatography eluted with hexane–EtOAc (300:1).
(12) Compound 3aa (trans:cis = 1.0:0.1): yellow solid; mp 59.4–
60.1 °C (hexane–EtOAc). Anal. Calcd for C18H20S2: C,
71.95; H, 6.71. Found: C, 71.91; H, 6.79. HRMS (EI): m/z
calcd for C18H20S2 [M+]: 300.1006; found: 300.0999. IR
(neat): 3015, 1489, 1479, 818, 780 cm–1. 1H NMR (400
MHz, CDCl3): d = 1.29 (0.27 H, d, J = 6.8 Hz), 1.31 (2.73 H,
d, J = 6.8 Hz), 1.85 (0.91 H, ddd, J = 14.1, 11.7, 3.1 Hz),
1.99 (0.09 H, dt, J = 13.7, 10.7 Hz), 2.19 (0.91 H, dt,
J = 14.1, 3.1 Hz), 2.22 (2.73 H, s), 2.27 (0.27 H, s), 2.32
(0.27 H, s), 2.35 (2.73 H, s), 2.50 (0.09 H, ddd, J = 13.7, 5.6,
2.9 Hz), 3.23–3.32 (0.09 H, m), 3.94–4.03 (0.91 H, m), 4.36
(0.09 H, dd, J = 10.7, 5.6 Hz), 4.47 (0.91 H, t, J = 3.1 Hz),
6.89–7.37 (7 H, m).
Figure 2 The molecular structure of trans-3aa
In conclusion, we developed a highly stereoselective syn-
thesis of 2,4-disubstituted thiochromans from commer-
cially available arylthiols and a,b-unsaturated aldehydes
using the supported reagent system Na2CO3/SiO2–PPA/
SiO2. It is particularly noteworthy that this method makes
the neutralization of the reaction mixture and the trans-
isomer of the products preferentially formed unnecessary.
Compound 3ab (trans:cis = 1.0:0.04): white solid; mp 77–
78 °C (EtOH). Anal. Calcd for C20H24S2: C, 73.12; H, 7.39.
Found: C, 73.03; H, 7.36. HRMS (EI): m/z calcd for
C20H24S2 [M+]: 328.1319; found: 328.1320. IR (neat): 3019,
1493, 1479, 814, 799 cm–1. 1H NMR (400 MHz, CDCl3):
d = 0.90 (0.12 H, t, J = 7.3 Hz), 0.95 (2.88 H, t, J = 7.3 Hz),
1.40–1.50 (2.00 H, m), 1.55–1.62 (2.00 H, m), 1.85 (0.96 H,
ddd, J = 14.1, 11.7, 3.2 Hz), 1.99 (0.04 H, dt, J = 13.7, 11.0
Hz), 2.23 (0.96 H, dt, J = 14.1, 3.2 Hz), 2.23 (2.88 H, s), 2.27
(0.12 H, s), 2.33 (0.12 H, s), 2.36 (2.88 H, s), 2.53 (0.04 H,
ddd, J = 13.7, 5.6, 3.7 Hz), 3.18–3.25 (0.04 H, m), 3.88–3.95
(0.96 H, m), 4.35 (0.04 H, dd, J = 11.0, 5.6 Hz), 4.46 (0.96
H, t, J = 3.3 Hz), 6.89–7.38 (7 H, m).
Acknowledgment
This research was partially supported by the Ministry of Education,
Science, Sports and Culture, Grant-in-Aid for Young Scientists (B),
18710066, 2006.
Compound 3ac (trans:cis = 1.0:0): white solid; mp 100–
102 °C (acetone–hexane). Anal. Calcd for C23H22S2: C,
76.24; H, 6.19. Found: C, 76.19; H, 6.12. HRMS (EI): m/z
calcd for C23H22S2 [M+]: 362.1163; found: 362.1163. IR
(neat): 3034, 1598, 1492, 1479, 807 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.26 (3 H, s), 2.31 (3 H, s), 2.34–2.37 (2
H, m), 4.57 (1 H, t, J = 3.0 Hz), 5.10 (1 H, dd, J = 9.3, 5.4
Hz), 6.93–7.42 (12 H, m).
Compound 3ad: oil. HRMS (EI): m/z calcd for C17H18S2
[M+]: 286.0850; found: 286.0851. IR (neat): 3016, 1597,
1491, 1482, 810 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.07
(1 H, ddt, J = 14.1, 12.4, 3.2 Hz), 2.22 (3 H, s), 2.22–2.29 (1
H, m), 2.32 (3 H, s), 2.69–2.75 (1 H, m), 3.68 (1 H, td,
J = 12.4, 3.2 Hz), 4.44 (1 H, t, J = 3.2 Hz), 6.87–7.36 (7 H,
m).
References and Notes
(1) Advances in Heterocyclic Chemistry, Vol. 18; Katrizky, A.
R.; Boulton, A. J., Eds.; Academic Press: New York, 1975,
76.
(2) Meyers, C. Y.; Rinaldi, C.; Bonoli, L. J. Org. Chem. 1963,
28, 2440.
(3) Nakazawa, T.; Sato, K.; Itabashi, K. Nihon Kagaku Kaishi
1990, 119.
(4) Jafarzadeh, M.; Amani, K.; Nikpour, F. Tetrahedron Lett.
2005, 46, 7567.
(5) Ishino, Y.; Mihara, M.; Kawai, H. Synlett 2001, 1317.
(6) Aoyama, T.; Takido, T.; Kodomari, M. Synlett 2004, 2307.
(7) Aoyama, T.; Takido, T.; Kodomari, M. Synlett 2005, 2739.
(8) (a) Mckillop, A.; Young, D. W. Synthesis 1979, 401.
(b) Posner, G. H. Angew. Chem., Int. Ed. Engl. 1978, 17,
487. (c) Cornelis, A.; Laszlo, P. Synthesis 1985, 909.
(9) Preparation of PPA/SiO2.
Compound 3ae: oil. HRMS (EI): m/z calcd for C19H22S2
[M+]: 314.1163; found: 314.1164. IR (neat): 3018, 1597,
1491, 1475, 810 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.33
(3 H, s), 1.38 (3 H, s), 2.14–2.25 (2 H, m), 2.30 (3 H, s), 2.33
(3 H, s), 4.42 (1 H, dd, J = 10.0, 6.4 Hz), 6.92–6.99 (2 H, m),
7.09 (2 H, d, J = 7.8 Hz), 7.26–7.29 (2 H, m), 7.65 (1 H, s).
PPA (4.0 g) and CHCl3 (100 mL) were placed in the round-
bottomed flask, and the mixture was stirred at 50 °C for 1 h.
Synlett 2007, No. 3, 387–390 © Thieme Stuttgart · New York