Efficient syntheses of thiochromans via cationic cycloadditions

Article abstract of DOI:10.1021/jo001571c

α-(Benzotriazolyl)methyl thioethers 1a-e reacted with styrenes under Lewis acid catalysis to give novel polysubstituted thiochromans (3,4-dihydro-2H-1 -benzothiopyrans) 3-14 and 16-20 in generally high yields. Most thiochromans were isolated as one diastereomer following recrystallization. The configuration and conformation of the products are predicted on the basis of their NMR data. A stepwise reaction, proceeding via a [4⁺ + 2] cationic polar cycloaddition mechanism, is proposed.

Full text of DOI:10.1021/jo001571c

J . Org. Chem. 2001, 66, 5595-5600
5595
Efficien t Syn th eses of Th ioch r om a n s via Ca tion ic Cycloa d d ition s
Alan R. Katritzky* and Martin A. C. Button‡
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received November 6, 2000
R-(Benzotriazolyl)methyl thioethers 1a -e reacted with styrenes under Lewis acid catalysis to give
novel polysubstituted thiochromans (3,4-dihydro-2H-1-benzothiopyrans) 3-14 and 16-20 in
generally high yields. Most thiochromans were isolated as one diastereomer following recrystalli-
zation. The configuration and conformation of the products are predicted on the basis of their NMR
data. A stepwise reaction, proceeding via a [4+ + 2] cationic polar cycloaddition mechanism, is
proposed.
Sch em e 1
In tr od u ction
The chemistry of sulfur based six-membered rings,
thiopyrans, has, to date, been less extensively studied
than that of the analogous pyrans.1 Although not par-
ticularly common throughout nature, this class of sulfur-
containing heterocycles is of synthetic and biological
interest. 3,4-Dihydro-2H-1-benzothiopyrans, more com-
monly known as thiochromans, exhibit antiinflammatory,
antipyretic, antidepressant, and analgesic activity.1a
Thiochromans have previously been synthesized from the
corresponding 2H-1-benzothiopyrans (thiochromens),2
benzothiopyranones,3 and by Claisen rearrangement of
phenyl allyl sulfides.4 Another approach to the synthesis
of thiochromans utilizes cycloadditions of stabilized sulfur
carbocations.5 While other cationic polar cycloadditions
have become well-known,6 relatively few examples of
sulfur stabilized cationic cycloadditions have been re-
ported.5,7 However, in our application of benzotriazole
methodology to organic synthesis,8 we have used R-(ben-
zotriazolyl)alkyl thioethers as precursors to thionium
ions.9 Such thioethers are simple to prepare and easily
structurally modified.9c,f We now report the Lewis acid
generation of R-thionium ion dienes, precursors of sub-
stituted thiochromans, from R-(benzotriazolyl)methyl
thioethers 1a -e. These thionium ions undergo efficient
cationic cycloadditions to afford thiochromans 3-14 and
16-20 in generally high yields.
Resu lts a n d Discu ssion
R-(Benzotriazolyl)methyl thioether starting materials
1a -c were easily prepared by the condensation of ben-
zotriazole, thiophenol, and benzaldehyde derivatives as
previously reported.9c,f Novel compounds 1d ,e were ob-
tained in 51% and 60% yields, respectively, using the
same method as for 1a -c. Reactions of substrates 1a -e
with styrenes, under Lewis acid conditions, afforded
thiochroman derivatives 3-14 and 16-20 in yields
ranging from 40 to 99% (Scheme 1, Table 1). The
reactions were either carried out in dichloromethane at
room temperature for 14 to 18 h, or at reflux for ca. 4 h.
The reaction temperature had negligible effect on yield
or diastereoselectivity. The workup, following the reac-
‡ Present address: Charnwood Catalysis, PO Box 5775, Loughbo-
rough, Leicestershire, LE11 3WE, UK.
(1) (a) Schneller, S. W. Adv. Heterocyclic Chem. 1975, 18, 59. (b)
Ingall, A. H. In Comprehensive Heterocyclic Chemistry, Vol 3; Boulton,
A. S.; Mckillop, A., Eds.; Oxford: Pergamon Press, 1984; p 855.
(2) Tilak, B. D.; Vaidya, V. M. Tetrahedron Lett. 1963, 8, 487.
(3) Takido, T.; Takagi, Y.; Itabashi, K. J . Heterocycl. Chem. 1995,
32, 687.
(4) Meyers, C. Y.; Rinaldi, C.; Bonoli, L. J . Org. Chem. 1963, 28,
2440.
(5) (a) Ishibashi, H.; Okada, M.; Sato, K.; Ikeda, M.; Ishiyama, K.;
Tamura, Y. Chem. Pharm. Bull. 1985, 33, 90. (b) Ishibashi, H.; So, T.
S.; Nakatani, H.; Minami, K.; Ikeda, M. J . Chem. Soc., Chem. Commun.
1988, 827. (c) Tamura, Y.; Ishiyama, K.; Mizuki, Y.; Maeda, H.;
Ishibashi, H. Tetrahedron Lett. 1981, 22, 3773.
(6) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1973, 12, 212.
(7) (a) Abis, L.; Giordano, C. J . Chem. Soc., Perkin Trans. 1 1973,
771. (b) Giordano, C. Synthesis 1972, 34. (c) Thakur, D. K.; Vankar,
Y. D. Synthesis 1983, 223. (d) Hori, M.; Kataoka, T.; Shimizu, H.;
Narita, K.; Ohno, S.; Aoki, H. Chem. Lett. 1974, 1101. (e) Giordano, C.
Gazz. Chim. Ital. 1974, 104, 849.
(9) (a) Katritzky, A. R.; Yang, Z.; Lam, J . N.; Cundy, D. J .
Heterocycles 1993, 36, 1367. (b) Katritzky, A. R.; Perumal, S.; Kuzmierk-
iewicz, W.; Lue, P.; Greenhill, J . V. Helv. Chim. Acta 1991, 74, 1924.
(c) Katritzky, A. R.; Xie, L.; Afridi, A. S.; Fan, W.-Q.; Kuzmierkiewicz,
W. Synthesis 1993, 47. (d) Katritzky, A. R.; Wang, Z.; Henderson, S.
A. Heterocycles 1998, 48, 295. (e) Katritzky, A. R.; Afridi, A. S.;
Kuzmierkiewicz, W. Helv. Chim. Acta 1991, 74, 1931. (f) Katritzky,
A. R.; Fang, Y.; Feng, D.; Silina, A.; Prakash, I. Heterocycles 2000, 53,
331.
(8) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem. Rev.
1998, 98, 409.
10.1021/jo001571c CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/18/2001

5596 J . Org. Chem., Vol. 66, No. 16, 2001
Ta ble 1. Yield s a n d Dia ster eom er ic Ra tios for Th ioch r om a n s 3-20
Katritzky and Button
1
R1
R2
R3
R4
R5
prod.
dra
yieldb (%)
yieldc (%)
a
a
c
e
d
b
b
a
a
e
c
d
a
a
a
e
d
a
a
H
H
2-Cl
3-Cl
H
4-MeO
4-MeO
H
H
H
H
H
Me
H
H
H
H
H
H
Me
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Ph
H
H
H
H
Ph
H
Ph
4-MeC6H4
Ph
Ph
4-MeC6H4
Ph
4-MeC6H4
4-MeOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
3
4
5
6
7
12:1
exclusive
23:1
20:1
20:1
1.9:1
1.3:1
exclusive
5.5:1
8:1
7:1
7:1
N/A
6:4:2:1
1.4:1
1.3:1
1:1
6:1
4:1
95
96
94
92
96
94
97
40
85
95
96
99
0
84
99
98
91
41
40
84
96
92
84
90
8
9
72 (1.2:1)d
76 (2.5:1)d
10
11
12
13
14
15
16
17
18
19
20
20
20e,h
H
65
3-Cl
2-Cl
H
H
H
H
3-Cl
H
H
H
75 (7:1)e,g
79
81
0
38
H
Me
Me
Me
Me
Ph
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
H
54
36f
80 (10:1)d
30e,h,i
24e,h,i
Ph
a
Ratio determined by GC and NMR. b Yield of isolated mixture. c Yield of pure diastereomer, isolated by recrystallization (unless stated).
Purified by recrystallization to give two isomers, ratio in parentheses. e Could not be separated by recrystallization. f Recrystallized to
give minor diastereomer only. Crude product was an oil, column chromatography afforded pure product as a mixture of diastereomers.
As g but as one pure diastereomer. The same 2,3-trans-3,4-trans isomer of 20 was produced from both cis- and trans-stilbene.
d
g
h
i
tion of 1a -e with ZnBr2 and a suitable alkene, consisted
of simple filtration and solvent removal to afford the
desired crude thiochromans 3-14 and 16-20, either as
pure isomers, or as mixtures of up to four diastereomers.
Interestingly, in all cases apart from 16, only one or two
isomers were detected (Table 1). Most crude products
were g90% pure, and frequently the major isomer was
isolated in good yield following recrystallization, but
column chromatography was occasionally necessary.
Variation of the functionality of the starting materials
allowed the syntheses of three different major classes of
thiochromans: (i) 2,4- (3-6, 8-10) and 2,4,8- (7); (ii)
2,4,4- (11-13) and 2,4,4,8- (14), and; (iii) 2,3,4- (16-18,
20) and 2,3,4,8- (19) substituted thiochromans (Table 1).
Each of the classes (i) to (iii) are discussed in more detail
below.
a half-chair or “sofa” conformation.11,12 Large values, ca.
16.0 Hz, for the overall coupling constants for both the
H-2 and H-4 resonances, are consistent with trans-diaxial
proton orientations and corresponding interactions with
the C-2 and C-4 substituents both pseudoequatorial.13,14
This predicted stereochemistry is highlighted in Figure
1, where the cis-configuration of the 2,4-diarylthiochro-
man is shown in both half chair (I) and “sofa” (II)
conformations.11,12,13b Unfortunately, despite many at-
tempts, only imperfect crystals of 3 could be obtained:
however, partial X-ray results support the cis stereo-
chemistry.
The coupling constants for compound 7 were J 3a,4
)
9.3 Hz and J 2,3a ) 8.7 Hz, compared with values of
between 10.0 and 12.0 Hz for 3-6. The slightly lower
vicinal coupling constants for 7 may be a result of
conformation averaging; however, the values are still
large enough to support the presence of a single pre-
dominant conformation, i.e., the protons are pseudoaxial
for a majority of the time. From the observed coupling
constants, it was not possible to confirm whether the
thiochromans exist predominantly in the half chair (I)
or the “sofa” (II) form, or as a mixture of both. In the
cases of 3 and 5-7, i.e., whenever a mixture of two
diastereomers were present, the minor trans-isomers,
which were not isolated, could be unambiguously identi-
fied by their characteristic 1:2:1 triplet for the H-4
protons which resonate at approximately 4.37-4.43 ppm
(J = 4 Hz). This NMR pattern is typical for that observed
in reported trans-4-substituted thioflavans.2,13a
(i) 2,4-Dia r yl-Su bstitu ted Th ioch r om a n s. Com-
pounds 3-7 were each obtained as single diastereomers
following recrystallization. The large J 2,3a and J 3a,4 cou-
pling constants for compounds 3-7 (ca. 10-12 Hz, see
Table 2) suggest that the C-2 and C-4 substituents are
both equatorial and therefore cis to each other.5a The
overlap of signals and complex splitting patterns in some
cases precluded measurement of accurate coupling con-
stants (as demonstrated for 3 and 4). However, we could
determine the product stereochemistry by considering the
10
overall coupling constants for J 2,3a + J 2,3e and J 3e,4 + J 3a,4
(where a and e represent axial and equatorial orienta-
tions, respectively). The total sums for J 2,3a + J 2,3e and
J 3e,4 + J 3a,4 were obtained by taking the values of the
outermost lines for the H-2 and H-4 multiplets. The sum
of these coupling constants was 16.8 Hz (J 3e,4 + J 3a,4) for
3 and 15.0 Hz (J 2,3a + J 2,3e) for 4, thus supporting the
cis-diequatorial relationship between the substituents at
C-2 and C-4 in thiochromans 3 and 4. However, the
coupling constants for H-4 in compound 3 and H-2 in
compound 4 were found to be easier to define using
(CD3)2CO as the NMR solvent (Table 2). Moreover,
chroman skeletons are known to exist preferentially in
Using 4-methoxyphenyl-R-(benzotriazolyl) methylthio
ether (1b), 2,4-diaryl substituted thiochromans 8 and 9
were each obtained as a mixture of two diastereomers
after recrystallization (Table 1). The configurations for
(11) Bolger, B. J .; Hirwe, A.; Marathe, K. G.; Philbin, E. M.; Vickars,
M. A.; Lillya, C. P. Tetrahedron 1966, 22, 621.
(12) Katekar, G. F.; Moritz, A. G. Aust. J . Chem. 1967, 20, 2235.
(13) (a) Katekar, G. F. Aust. J . Chem. 1966, 19, 1251. (b) Clark-
Lewis, J . W. Aust. J . Chem. 1968, 21, 2059. (c) Lillya, C. P.; Drewes,
S. E.; Roux, D. G. Chem. Ind. 1963, 783. (d) Hanaya, K.; Muramatsu,
T.; Onodera, S.; Ikegami, Y.; Hirota, M. Bull. Chem. Soc. J pn. 1984,
57, 1695.
(10) Pople, J . A.; Schneider, W. G.; Bernstein, H. J . In High
Resolution Nuclear Magnetic Resonance; McGraw-Hill: New York,
1960; p 135.
(14) (a) Karplus, M. J . Am. Chem. Soc. 1963, 85, 2870. (b) Karplus,
M. J . Chem. Phys. 1959, 30, 11.

Syntheses of Thiochromans
J . Org. Chem., Vol. 66, No. 16, 2001 5597
Ta ble 2. Selected NMR Da ta for Th ioch r om a n s 3-14,
16-20
the cis- or the trans-isomers of compound 8, present in a
ratio of 1.2:1.0. Attempts to improve signal separation
using high-temperature NMR (up to 60 °C) were not
successful.
δ (CDCl3) H2 + H4
compd
and multiplicity
J /Hza,b
Reaction of 4-methoxystyrene with 1a gave the cis-2,4-
diarylthiochroman 10, but only in a low yield (20%)
following column chromatography, together with bis-
(phenylthio)methyl benzene15 (24) as a major byproduct
(Table 1, Table 2). The cis-stereochemistry was once
again assigned on the basis of the high coupling constants
for J 2,3a and J 3a,4 which were 10.2 and 10.5 Hz, respec-
tively. Interestingly, in contrast to the previous 2,4-
diarylthiochromans, no other isomer was observed.
(ii) 2-Ar yl-4-m eth yl-4-p h en ylth ioch r om a n s. Com-
pounds 11-14, from R-methylstyrene, were all obtained
as mixtures of 2 diastereomers in 5.5-8:1 ratios (Table
1). For compounds 11, 13, and 14, the major isomer was
obtained pure after recrystallization. Thiochroman 12
was isolated as an oil, and attempts to remove the last
traces of minor isomer failed by both crystallization or
chromatography. In both major and minor diastereomers
of 11-14, the 2-aryl substituent was again assigned to
occupy the pseudoequatorial orientation on the basis of
the H-2 coupling constants of ca. 2.5 and 12.5 Hz, the
latter representing the trans-diaxial J 2,3a proton interac-
tions (Table 2). This observation is analogous to the
results observed for similar 2,4,4-substituted chromans.16
3
H-4 4.20-4.28 (m)
[H-4 4.36 (dd)]c
H-2 4.62 (dd)
H-4 4.21 (dd)
H-2 4.61-4.66 (m)
[H-2 4.73 (dd)]c
H-4 4.27 (dd)
H-2 5.18 (dd)
H-4 4.22 (dd)
H-2 4.58 (dd)
H-4 4.26 (dd)
H-2 4.59 (dd)
H-4 4.10-4.27 (m)
H-2 4.56-4.65 (m)
H-4 4.15-4.24 (m)
[H-4, 4.29 (dd)]e
H-2 4.55-4.63 (m)
[H-2 4.70 (dd)]e
H-4 4.20 (dd)
H-2 4.63 (dd)
H-3e 2.21 (dd)
H-3a 2.66 (dd)
H-2 4.64 (dd)
H-3e 2.18 (dd)
H-3a 2.60 (dd)
H-2 4.58 (dd)
H-3e 2.22 (dd)
H-3a 2.52 (dd)
H-2 5.22 (dd)
H-3e 2.21 (dd)
H-3a 2.66 (dd)
H-2 4.58 (dd)
H-4 3.83 (d)
J 3a,4 + J 3e,4) 16.8
[J 3e,4 ) 5.7, J 3a,4 ) 11.1]c
J 2,3e ) 4.5, J 2,3a ) 10.2
J 3e,4 ) 6.6, J 3a,4 ) 9.9
J 2,3a + J 2,3e) 15
4
[J 2,3e) 3.9, J 2,3a ) 10.8]c
J 3e,4 ) 4.5, J 3a,4 ) 12
J 2,3e) 3.0, J 2,3a ) 11.4
J 3e,4 ) 4.8, J 3a,4 ) 11.4
J 2,3e ) 3.9, J 2,3a ) 11.1
J 3e,4 ) 7.2, J 3a,4 ) 9.3
J 2,3e ) 6.3, J 2,3a ) 8.7
sd
5
6
7
8
9
sd
sd
[J 3e,4 ) 5.1, J 3a,4 ) 12.0]e
sd
[J 2,3e ) 3.6, J 2,3a ) 11.1]e
J 3e,4 ) 6.0, J 3a,4 ) 10.5
J 2,3e) 4.5, J 2,3a ) 10.2
J 2,3e ) 2.7, J 3e,3a ) 13.8
J 2,3a ) 12.6, J 3a,3e ) 13.8
J 2,3e ) 2.7, J 2,3a ) 12.6
J 2,3e ) 2.4, J 3e,3a ) 13.5
J 2,3a ) 12.6, J 3a,3e ) 13.5
J 2,3e ) 2.4, J 2,3a ) 12.6
J 2,3e ) 2.4, J 3e,3a ) 13.8
J 2,3a ) 12.3, J 3a,3e ) 13.8
J 2,3e ) 2.4, J 2,3a ) 12.3
J 2,3e ) 2.4, J 3e,3a ) 13.8
J 2,3a ) 12.6, J 3a,3e ) 13.8
J 2,3e ) 2.4, J 2,3a ) 12.6
J 3a,4 ) 10.2
10
11
12
13
14
1
From the crude H NMR spectra, it appears that the C-2
aryl substituents of the minor isomers in 11-14 were
also pseudoequatorial since the J 2,3a coupling constants
varied over the range of 9.6-12.3 Hz; the minor isomer
signals were present as doublet of doublets at higher field
than those for the major products. The major diastere-
omers for compounds 11-14 were predicted to be cis with
respect to the 2- and 4-aryl groups. This was based on
the assumption that the more bulky C-2 aryl and C-4
phenyl groups would preferentially occupy the equatorial
position, with the less bulky C-4 methyl axial. Spectral
16
17
18
19
20c
H-2 4.15 (d)
H-4 3.68-3.85 (m)
H-2 4.14 (d)
H-4 3.76 (d)
H-2 4.10 (d)
H-4 3.98 (d)
H-2 4.27 (d)
H-3 3.84 (dd)
H-4 4.55 (d)
H-2 4.92 (d)
J 2,3a ) 10.5
sf
J 2,3a ) 10.5
J 3a,4 ) 10.5
J 2,3a ) 10.5
J 3a,4 ) 10.8
J 2,3a ) 10.5
J 3a,4 ) 10.8, J 2,3a) 11.1
J 3a,4 ) 10.8
1
evidence supports this conclusion, the H NMR chemical
J 2,3a ) 11.1
shifts for the C-2 protons of the major diastereomers in
2-aryl-4-methyl-4-phenylthiochromans 11-14 are exactly
identical to those observed for the C-2 protons of the cis-
2,4-diarylthiochromans 3-6. This compares with the
significant upfield shift of >0.6 ppm observed for the
chemical shift of the minor diastereomers. Moreover,
further conclusive evidence was obtained by carrying out
NOE experiments on compound 11. When the axial H-2
proton at 4.64 ppm was irradiated, a significant NOE was
observed at the 4-methyl substituent as well as at the
H-3 equatorial proton and at the ortho protons on the
C-2 phenyl ring (Figure 2, A). Similarly, irradiation of
the C-4 methyl protons at 1.81 ppm led to an NOE with
the C-2 proton as well as the geminal equatorial C-3
proton and the ortho protons on the C-4 phenyl ring
(Figure 2, B). These strong NOE enhancements, observed
between H-2 and the C-4 methyl substituent, verify that
the methyl group is axial and are caused by the 1,3-
diaxial type interaction as highlighted in Figure 2.
When 1,1-diphenylethylene was employed as an alk-
ene, the desired thiochroman 15 was not obtained; only
a
Total coupling constants for J 2,3a + J 2,3e or J 3a,4 + J 3e,4 quoted
when the signal is not a clear doublet of doublets.10 Abbrevia-
b
tions: a ) axial and e ) equatorial. c Carried out in (CD3)2CO.
Overlap of signals for diastereomers. e Carried out in (CD3)2CO
d
to separate signals for two diastereomers [slight overlap of isomers
still observed]. f Overlap of signals.
F igu r e 1. Conformation of cis-2,4-diarylthiochromans.
8 and 9 were difficult to determine by 1H NMR since the
signals for the H-2 and H-4 protons of both diastereomers
overlapped. However, the signals for 9, present in a ratio
of 2.5:1.0, were resolved significantly using (CD3)2CO as
the NMR solvent to reveal a doublet of doublets for the
major diastereomer with coupling constants of ca. J )
3.6, 11.1 Hz (4.70 ppm) for H-2 and J ) 5.1, 12.0 Hz (4.29
ppm) for H-4 (Table 2). The major diastereomer was
therefore assigned to be the cis-isomer. However, it was
not possible to get good separation of the signals for either
(15) Brinksma, J .; Van der Deen, H.; Van Oeveren, A.; Feringa, B.
L. J . Chem. Soc., Perkin Trans. 1 1998, 24, 4159.
(16) (a) Adam, W.; Peters, K.; Sauter, M. Synthesis 1994, 111. (b)
Adam, W.; Hadjiarapoglou, L.; Peters, K.; Sauter, M. J . Am. Chem.
Soc. 1993, 115, 8603. (c) Adam, W.; Hadjiarapoglou, L.; Peters, K.;
Sauter, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 735.

5598 J . Org. Chem., Vol. 66, No. 16, 2001
Katritzky and Button
Sch em e 2
F igu r e 2. Diagnostic NOEs for major isomer of 11.
decomposition of the starting material and formation of
byproducts, such as bis(phenylthio)methylbenzene (23),15
was observed.
(iii) 2,3,4-Su bstitu ted Th ioch r om a n s. Thiochroman
16 was produced as a mixture of four diastereomers,
while 17, 18, and 20 were each obtained as mixtures of
two diastereomers. However, single isomers for each of
them were isolated after recrystallization of 16-18 and
column chromatography of 20. Compound 19, produced
as a 1:1 mixture of isomers, was obtained as a 10:1
mixture of diastereomers following recrystallization.
Coupling constants of between 10.2 and 11.1 Hz for both
the H-2 and H-4 protons were observed for compounds
16-20 (Table 2), consistent with those previously re-
ported for 2,3,4-substituted thiochromans,17 thus con-
firming the all trans-triaxial conformation for the H-2,
H-3, and H-4 protons. Consequently, all the substituents
must be pseudoequatorially arranged in the major iso-
mers of thiochromans 16-20. The minor isomers were
not isolated, and their stereochemistry could not be
confirmed since the axial-equatorial and equatorial-
equatorial coupling constants are very similar.
Sch em e 3
crystallization, presumably by a reversal of the reaction
from 22 back to 21 (route B, Scheme 2). A control
experiment was carried out by refluxing cis-stilbene with
ZnBr2 in DCM without inclusion of substrate 1a -e; after
the workup, only cis-stilbene was recovered. This result
again suggests that this reaction proceeds in a stepwise
manner as highlighted in Scheme 2.
The major products from the reactions of 1a with both
trans- and cis-stilbene were identical, each composed of
a mixture of diastereomers as indicated by the NMR
spectra and GC-MS analyses (Table 1). Purification of
the major trans-isomer of 20 was achieved by column
chromatography. The lack of stereochemical retention
during the reaction of 1a with both stilbene isomers
indicates that the reaction mechanism is not completely
concerted. Further evidence to support a stepwise mech-
anism includes the regiospecificity resulting from the use
of unsymmetrical styrene derivatives with R-(benzotria-
zolyl)methyl thioethers 1a -e. The electrophilic attack of
the thionium ion 21 on unsymmetrical alkenes led to the
most stable benzylic carbocation prior to cyclization. The
resulting diastereoselectivity also supports the stepwise
mechanism: when using both cis- and trans-stilbene, the
intermediate 22 cyclized to give the most stable and
favorable thiochroman diastereomer (route A, Scheme 2).
The stereochemistry of the alkene is not retained during
this reaction. When recrystallization was used in an
attempt to purify the crude reaction mixture obtained
from the reaction of 1a with trans-stilbene, only trans-
stilbene was recovered. Moreover, the reaction mixture
resulting from the reaction of 1a with cis-stilbene, which
is not crystalline, also afforded pure trans-stilbene after
The use of other Lewis acids, such as BF3‚Et2O, ZnCl2
and SnCl4 also afforded the desired products 3 and 4 after
reaction with 1a , although attempts with AlCl3 or TiCl4
did not. With BF3‚Et2O, the diastereoselectivities were
comparable to those observed using ZnBr2. However, the
yields were lower, and significant amounts of byproducts,
such as bis(phenylthio)methylbenzene (23)15 and phenyl
disulfide (24),18 were obtained. Compound 23 was also
used instead of R-(benzotriazolyl)methyl thioethers 1a -e
as a precursor for this cycloaddition type reaction (Scheme
3). Although we obtained the desired thiochroman 3, the
yield was only ca. 40%, considerably less than the yields
obtained using benzotriazole substrates 1a -e, and with
significant amounts of unreacted 23 (ca. 50%) and
byproduct 24 (ca. 10%), thus making the purification
more difficult.
R-(Benzotriazolyl)alkyl thioether (1a ) was alkylated
with methyl iodide to give 1-[(phenyl)(methyl)phenyl-
thiomethyl]-1H-benzotriazole (25) in 95% yield (Scheme
4). However, no significant amount of the desired thio-
chroman 26 was observed using the cycloaddition reac-
tion conditions previously discussed. This lack of reac-
tivity may be a consequence of steric hindrance resulting
from the R-methyl substituent on the thionium ion
intermediate (Scheme 4).
(17) (a) Baruah, P. D.; Mukherjee, S.; Mahajan, M. P. Tetrahedron
1990, 46, 1951. (b) Takahashi, H.; Kubota, Y.; Miyazaki, H.; Onda, M.
Heterocycles 1984, 22, 1147. (c) Funicello, M.; Spagnolo, P.; Zanirato,
P. J . Chem. Soc., Perkin Trans. 1 1990, 2971.
(18) Barton, D. H. R.; Chen, C.; Wall, G. M. Tetrahedron 1991, 47,
6127.

Syntheses of Thiochromans
Sch em e 4
J . Org. Chem., Vol. 66, No. 16, 2001 5599
for 16 h before quenching with saturated ammonium chloride
solution. The solution was worked up by extracting the product
into ethyl acetate (3 × 20 mL), washing with water and brine,
and drying over MgSO4. Following removal of the desiccant
by filtration and solvent under reduced pressure, a yellow oil
was obtained. Crystallization from methanol afforded 25 as
1
white macroprisms (95%), mp 111-112 °C; H NMR (CDCl3)
δ 2.40 (s, 3H), 6.73 (d, J ) 7.8 Hz, 2H), 7.09 (t, J ) 6.9 Hz,
2H), 7.22-7.40 (m, 9H), 8.10 (d, J ) 7.5 Hz, 1H). 13C NMR
(CDCl3) δ 32.4, 76.0, 114.5, 119.9, 124.0, 125.6, 126.6, 128.4,
128.8, 128.9, 129.9, 130.0, 132.2, 136.6, 141.8, 146.9. Anal.
Calcd for C20H17N3: C, 72.48; H, 5.17; N, 12.68. Found: C,
72.44; H, 5.16; N, 12.75.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th ioch r o-
m a n s (3-14, 16-20). To a solution of ZnBr2 (4 mmol) in dry
DCM (10 mL) at room temperature under nitrogen atmosphere
was added a suitable alkene (2.1 mmol) in DCM (5 mL),
followed by 1-[(aryl)arylthiomethyl]-1H-benzotriazoles (1a -
e) (2 mmol). This reaction mixture was either heated at reflux
for 4 h or left at room temperature for 14-18 h. A precipitate
formed and was removed by filtration followed by solvent
removal under vacuum to afford the desired crystalline
products. Further purification was achieved by recrystalliza-
tion using ethyl acetate/hexanes, or occasionally by column
chromatography. In some cases, where a mixture of diaste-
reomers was obtained, the NMR data for the minor diastere-
omers are bracketed.
Con clu sion
A new and efficient synthesis of novel thiochromans
is described which utilizes R-benzotriazolyl sulfides 1d -e
in place of the R-chloro sulfides as previously employed
by Ishibashi.5a Compounds 1d -e are easier to prepare
and undergo the cycloadditions with a less toxic catalyst
and in significantly high yields. A majority of the present
reactions proceeded with high diastereoselectivity. Most
of the thiochromans could be purified by recrystallization,
often affording the major diastereoisomer. A stepwise,
rather than concerted, [4+ + 2] cationic cycloaddition
mechanism is proposed.
Exp er im en ta l Section
cis-2,4-Dip h en ylth ioch r om a n (3): pale yellow plates, mp
127 °C from EtOAc/hexanes; 1H NMR (CDCl3) δ 2.47-2.61 (m,
2H), 4.20-4.28 (m, J 3a,4 + J 3e,4 ) 16.8 Hz, 1H), 4.62 (dd, J )
4.5, 10.2 Hz, 1H), 6.72 (d, J ) 7.8 Hz, 1H), 6.88 (dt, J ) 1.5,
7.5 Hz, 1H), 7.05 (t, J ) 7.5 Hz, 1H), 7.14 (dd, J ) 1.2, 7.8 Hz,
1H), 7.20-7.44 (m, 10H). 13C NMR (CDCl3) δ 41.5, 46.1, 47.7,
124.2, 126.1, 126.6, 126.7, 127.5, 127.8, 128.7, 130.0, 134.6,
136.8, 141.1, 145.0. Anal. Calcd for C21H18S: C, 83.40; H, 6.00.
Found: C, 83.09; H, 6.03.
Gen er a l Com m en ts. Melting points were determined on
a hot-stage microscope and are uncorrected. H NMR spectra
1
were recorded on a 300 MHz spectrometer using tetrame-
thylsilane as the internal standard. The 13C NMR spectra were
recorded at 75 MHz on the same instrument with the solvent
CDCl3 or (CD3)2CO peak as internal reference. The GC-MS
instrument used was Hewlett-Packard 5890 series II gas
chromatograph coupled to a 5972 mass selective detector.
Elemental analyses (C, H, N) were carried out on a Carlo Erba-
1106 instrument. Column chromatography was carried out on
silica gel (200-425 mesh). Dichloromethane was distilled over
calcium hydride prior to use. THF was dried by distillation in
the presence of Na and benzophenone under a nitrogen
atmosphere.
P r ep a r a tion of R-(Ben zotr ia zolyl)m eth yl Th ioeth er s
1d , 1e, a n d 25. The starting thioethers 1a -e were prepared
in good yields using previously reported condensations of
benzotriazole, thiophenol, and benzaldehydes in the presence
of catalytic PTSA in refluxing toluene with azeotropic water
removal.9f Compounds 1a -c were previously reported, but
1d -e are novel and satisfactory analytical data are given
below.
1-[(P h en yl)-2-m eth ylp h en ylth iom eth yl]-1H-ben zotr ia -
zole (1d ). Compound 1d was obtained following recrystalli-
zation from ether to afford white plates (51%), mp 82-83 °C;
1H NMR (CDCl3) δ 2.33 (s, 3H), 6.84-6.92 (m, 1H), 6.97 (d, J
) 7.5 Hz, 1H), 7.07-7.14 (m, 2H), 7.29-7.42 (m, 6H), 7.46-
7.53 (m, 2H), 7.62 (d, J ) 8.4 Hz, 1H), 8.02 (d, J ) 8.1 Hz,
1H). 13C NMR (CDCl3) δ 20.4, 69.6, 111.8, 120.2, 124.0, 126.6,
126.9, 127.2, 128.9, 129.0, 129.1, 130.5, 130.6, 131.7, 134.1,
135.6, 141.0, 146.7. Anal. Calcd for C20H17N3: C, 72.48; H, 5.17;
N, 12.68. Found: C, 72.36; H, 5.25; N, 12.59.
cis-4-(4-Meth ylph en yl)-2-ph en ylth ioch r om an (4): white
1
needles, mp 148 °C from EtOAc/hexanes; H NMR (CDCl3) δ
2.34 (s, 3H), 2.46-2.60 (m, 2H), 4.21 (dd, J ) 6.6, 9.9 Hz, 1H),
4.61-4.66 (m, J 2,3a + J 2,3e ) 15 Hz, 1H), 6.74 (d, J ) 7.8 Hz,
1H), 6.88 (dt, J ) 1.5, 7.5 Hz, 1H), 7.05 (t, J ) 7.5 Hz, 1H),
7.08-7.43 (m, 10H). 13C NMR (CDCl3) δ 21.1, 41.5, 46.1, 47.3,
124.2, 126.0, 126.5, 127.5, 127.8, 128.6, 128.7, 129.4, 130.0,
134.6, 136.3, 137.0, 141.2, 142.0. Anal. Calcd for C22H20S: C,
83.50; H, 6.37. Found: C, 83.28; H, 6.51.
cis-2-(2-Ch lor op h en yl)-4-p h en ylth ioch r om a n (5): pale
yellow plates, mp 103-104 °C from EtOAc/hexanes; 1H NMR
(CDCl3) δ 2.39-2.63 (m, 2H), 4.27 (dd, J ) 4.5, 12 Hz, 1H),
5.18 (dd, J ) 3, 11.4 Hz, 1H), 6.73 (d, J ) 7.8 Hz, 1H), 6.91
(dt, J ) 1.5, 7.5 Hz, 1H), 7.08 (t, J ) 7.5 Hz, 1H), 7.15-7.38
(m, 9H), 7.60 (dd, J ) 1.8, 7.8 Hz, 1H). 13C NMR (CDCl3) δ
40.6, 41.9, 47.6, 124.4, 126.4, 126.6, 126.8, 127.4, 128.6, 128.7,
129.7, 129.9, 133.5, 134.2, 137.1, 138.7, 144.7. Anal. Calcd for
C
21H17ClS: C, 74.87; H, 5.09. Found: C, 74.53; H, 5.16.
cis-2-(3-Ch lor oph en yl)-4-ph en ylth ioch r om an (6): white
plates, mp 133-134 °C from EtOAc/hexanes. 1H NMR (CDCl3)
δ 2.42-2.59 (m, 2H), 4.22 (dd, J ) 4.8, 11.4 Hz, 1H), 4.58 (dd,
J ) 3.9, 11.1 Hz, 1H), 6.72 (d, J ) 7.8 Hz, 1H), 6.89 (dt, J )
1.5, 7.5 Hz, 1H), 7.07 (t, J ) 7.5 Hz, 1H), 7.13 (dd, J ) 1.5, 7.8
Hz, 1H), 7.20-7.37 (m, 8H), 7.41 (s, 1H). 13C NMR (CDCl3) δ
41.4, 45.6, 47.5, 124.4, 125.8, 126.1, 126.7, 126.8, 127.7, 128.0,
128.7, 128.8, 130.0, 134.1, 134.5, 136.8, 143.3, 144.7. Anal.
Calcd for C21H17ClS: C, 74.87; H, 5.09. Found: C, 74.68: H,
5.05.
1-[(3-Ch lor op h en yl)p h en ylth iom eth yl]-1H-ben zotr ia -
zole (1e). Compound 1e was obtained following recrystalli-
zation from ether to afford white plates (60%), mp 106-107
1
°C; H NMR (CDCl3) δ 7.13-7.47 (m, 11H), 7.54 (s, 1H), 7.64
(d, J ) 8.1 Hz, 1H), 8.05 (d, J ) 8.1 Hz, 1H). 13C NMR (CDCl3)
δ 69.8, 111.6, 120.4, 124.2, 125.1, 127.3, 127.5, 129.2, 129.29,
129.31, 130.2, 130.9, 131.6, 133.6, 134.9, 137.5, 146.7. Anal.
Calcd for C19H14N3: C, 64.91; H, 4.01; N, 11.95. Found: C,
64.90; H, 4.01; N, 11.95.
8-Me t h yl-cis-4-(4-m e t h ylp h e n yl)-2-p h e n ylt h ioch r o-
m a n (7): pale yellow plates, mp 158-159 °C from EtOAc/
1
hexanes. H NMR (CDCl3) δ 2.28 (s, 3H), 2.35 (s, 3H), 2.52-
2.58 (m, 2H), 4.26 (dd, J ) 7.2, 9.3 Hz, 1H), 4.59 (dd, J ) 6.3,
8.7 Hz, 1H), 6.62 (d, J ) 7.5 Hz, 1H), 6.81 (t, J ) 7.6 Hz, 1H),
6.97 (d, J ) 8.1 Hz, 1H), 7.09-7.17 (m, 4H), 7.24-7.37 (m,
3H), 7.41-7.46 (m, 2H). 13C NMR (CDCl3) δ 20.1, 21.1, 41.1,
45.9, 47.7, 123.3, 127.6, 127.7, 127.8, 127.8, 128.5, 128.7, 129.3,
133.9, 134.1, 136.2, 136.8, 141.3, 142.5. Anal. Calcd for
1-[(P h en yl)(m eth yl)p h en ylth iom eth yl]-1H-ben zotr ia -
zole (25). To a solution of thioether 1a (9.46 mmol) in dry
THF (20 mL) was added n-BuLi (10 mmol) at -78 °C. The
reaction mixture was left stirring for 1 h at -78 °C before
addition of methyl iodide (10.4 mmol) in dry THF (10 mL).
The reaction mixture was allowed to warm to 25 °C and left
C
23H22S: C, 83.59; H, 6.71. Found: C, 83.61; H, 7.02.

5600 J . Org. Chem., Vol. 66, No. 16, 2001
Katritzky and Button
2-(4-Meth oxyp h en yl)-4-p h en ylth ioch r om a n (8): pale
orange plates, mp 134-135 °C from EtOAc/hexanes; all signals
4,8-Dim et h yl-2,4-d ip h en ylt h ioch r om a n (14): white
plates, mp 150-151 °C from EtOAc/hexanes; 1H NMR (CDCl3):
δ 1.82 (s, 3H), 2.21 (dd, J ) 2.4, 13.8 Hz, 1H), 2.29 (s, 3H),
2.66 (dd, J ) 12.6, 13.8 Hz, 1H), 4.58 (dd, J ) 2.4, 12.6 Hz,
1H), 6.63 (d, J ) 7.8 Hz, 1H), 6.80 (t, J ) 7.7 Hz, 1H), 6.96 (d,
J ) 7.5 Hz, 1H), 7.16-7.37 (m, 8H), 7.43-7.47 (m, 2H). 13C
NMR (CDCl3) δ 20.3, 28 0.8, 42.0, 44.9, 48.5, 123.2, 126.0,
127.2, 127.5, 127.8, 127.9, 128.1, 128.2, 128.7, 133.2, 133.7,
141.0, 141.1, 150.6. Anal. Calcd for C23H22S: C, 83.59; H, 6.71.
Found: C, 83.85; H, 7.04.
2,3-t r a n s-3,4-t r a n s-3-Me t h yl-2,4-d ip h e n ylt h ioch r o-
m a n (16): white plates, mp 164-165 °C from EtOAc/hexanes;
1H NMR (CDCl3) δ 0.66 (d, J ) 6.3 Hz, 3H), 2.55-2.69 (m,
1H), 3.83 (d, J ) 10.2 Hz, 1H), 4.15 (d, J ) 10.5 Hz, 1H), 6.67
(d, J ) 8.1 Hz, 1H), 6.88 (dt, J ) 1.5, 7.5 Hz, 1H), 7.03 (t, J )
7.2 Hz, 1H), 7.12 (dd, J ) 1.5, 7.8 Hz, 1H), 7.19-7.40 (m, 10H).
13C NMR (CDCl3) δ 18.6, 42.9, 52.2, 55.0, 124.4, 126.0, 126.1,
126.5, 127.7, 128.3, 128.6, 128.7, 129.5, 131.2, 134.4, 137.7,
140.1, 145.1. Anal. Calcd for C22H20S: C, 83.50; H, 6.37.
Found: C, 83.28; H, 6.71.
1
for mixture of both diastereomers (1.2:1.0) unless stated; H
NMR (CDCl3) δ 2.45-2.59 (m, 2H), [3.78 (s, 3H, minor
diastereomer)], 3.79 (s, 3H, major diastereomer), 4.10-4.27
(m, 1H), 4.56-4.65 (m, 1H), 6.73 (t, J ) 8.0 Hz, 1H), 6.83-
6.92 (m, 3H), 7.05 (t, J ) 7.4 Hz, 1H), 7.10-7.16 (m, 2H), 7.20-
7.44 (m, 6H). 13C NMR (CDCl3) δ 41.6, 41.7 45.4, 46.1, 46.8,
47.8, 55.2, 55.3, 114.1, 124.2, 124.1, 126.0, 126.5, 126.7, 127.5,
127.8, 128.6, 128.7, 129.6, 129.9, 130.0, 133.1, 134.6, 134.8,
136.7, 137.0, 137.2, 141.1, 145.1, 158.3, 159.1. Anal. Calcd for
C
22H20OS: C, 79.48; H, 6.06. Found: C, 79.18; H, 6.38.
4-(4-Me t h ylp h e n yl)-2-(4-m e t h oxyp h e n yl)t h ioch r o-
m a n (9): pale orange plates, mp 152-153 °C from EtOAc/
hexanes; 1H NMR (CDCl3) δ (all signals for both diastereomers
(2.5:1.0) unless stated) 2.32 (s, 3H, major diastereomer), [2.34
(s, 3H, minor diastereomer)], 2.47-2.56 (m, 2H), [3.78 (s, 3H,
minor diastereomer)], 3.80 (s, 3H, major diastereomer), 4.15-
4.24 (m, 1H), 4.55-4.63 (m, 1H), 6.73 (d, J ) 7.8 Hz, 1H),
6.83-6.92 (m, 3H), 7.04 (t, J ) 7.7 Hz, 1H), 7.09-7.17 (m, 5H),
7.28-7.35 (m, 2H). Figures in {parentheses} are unassigned
to either diastereomer. 13C NMR (CDCl3) δ [21.0], 21.1, 41.6,
[41.7], [45.5], 45.8, 46.9, [47.4], {55.2, 114.0, 124.1, 126.0, 126.4,
127.4, 128.5, 128.6, 129.4, 129.6, 129.9, 130.0}, [133.2], 134.7,
[134.8], [136.2], [136.9], 137.1, 137.2, [137.4], 138.2, [142.1],
158.3, [159.1]. Anal. Calcd for C23H22OS: C, 79.73; H, 6.40.
Found: C, 80.51; H, 6.38.
cis-4-(4-Met h oxyp h en yl)-2-p h en ylt h ioch r om a n (10):
white plates, mp 158-159 °C following column chromato-
graphic separation using EtOAc/hexanes as an eluent. 1H
NMR (CDCl3) δ 2.44-2.60 (m, 2H), 3.81 (s, 3H), 4.20 (dd, J )
6.0, 10.5 Hz, 1H), 4.63 (dd, J ) 4.5, 10.2 Hz, 1H), 6.75 (d, J )
7.8 Hz, 1H), 6.84-6.93 (m, 3H), 7.06 (t, J ) 7.5 Hz, 1H), 7.05-
7.18 (m, 3H), 7.22-7.36 (m, 3H), 7.42 (d, J ) 7.2 Hz, 2H). 13C
NMR (CDCl3) δ 41.6, 46.1, 46.9, 55.3, 114.1, 124.2, 126.0, 126.5,
127.5, 127.8, 128.7, 129.6, 129.9, 134.6, 137.0, 137.2, 141.2,
158.4. Anal. Calcd for C22H20OS: C, 79.48; H, 6.06. Found: C,
79.12; H, 6.46.
2,3-tr a n s-3,4-tr a n s-4-(4-Met h oxyp h en yl)-3-m et h yl-2-
p h en ylth ioch r om a n (17): pale yellow plates, mp 155-200
°C (decomp) from EtOAc/hexanes; 1H NMR (CDCl3) δ 0.66 (d,
J ) 6.3 Hz, 3H), 2.48-2.64 (m, 1H), 3.68-3.85 (m, 1H), 3.81
(s, 3H), 4.14 (d, J ) 10.5 Hz, 1H), 6.69 (d, J ) 7.8 Hz, 1H),
6.84-6.92 (m, 3H), 7.03 (t, J ) 7.4 Hz, 1H), 7.12 (d, J ) 8.4
Hz, 3H), 7.24-7.40 (m, 5H). 13C NMR (CDCl3) δ 18.6, 42.9,
52.2, 54.2, 55.2, 114.0, 124.4, 125.9, 126.1, 127.7, 128.3, 128.7,
130.3, 131.1, 134.4, 137.1, 138.0, 140.3, 158.2. HRMS (EI)
Calcd for C23H22OS: 346.1391. Found: 346.1420. Anal. Calcd
for C23H22OS: C, 79.73; H, 6.40. Found: C, 79.33; H, 6.56.
2,3-tr a n s-3,4-tr a n s-(4-Met h oxyp h en yl)-3-m et h yl-2-(2-
ch lor op h en yl)th ioch r om a n (18): white plates, mp 144-
1
146 °C from EtOAc/hexanes; H NMR (CDCl3) δ 0.67 (d, J )
6.6 Hz, 3H), 2.46-2.59 (m, 1H), 3.76 (d, J ) 10.5 Hz, 1H), 3.81
(s, 3H), 4.10 (d, J ) 10.5 Hz, 1H), 6.70 (d, J ) 7.8 Hz, 1H),
6.84-6.93 (m, 3H), 7.04 (t, J ) 7.4 Hz, 1H), 7.08-7.14 (m, 3H),
7.25 (d, J ) 1.5 Hz, 3H), 7.37 (s, 1H). 13C NMR (CDCl3) δ 18.7,
42.9, 51.8, 54.0, 55.2, 114.0, 124.6, 126.0, 126.2, 126.5, 127.9,
128.4, 130.0, 130.3, 131.0, 133.8, 134.5, 136.7, 137.9, 142.5,
158.3. HRMS (EI) Calcd for C23H21ClOS: 380.1002. Found:
380.0971.
4-Meth yl-2,4-d ip h en ylth ioch r om a n (11): white plates,
mp 151-152 °C from EtOAc/hexanes; 1H NMR (CDCl3) δ 1.81
(s, 3H), 2.21 (dd, J ) 2.7, 13.8 Hz, 1H), 2.66 (dd, J ) 12.6,
13.8 Hz, 1H), 4.64 (dd, J ) 2.7, 12.6 Hz, 1H), 6.76 (dd, J )
1.5, 8.1 Hz, 1H), 6.89 (dt, J ) 1.2, 7.5 Hz, 1H), 7.05 (dt, J )
1.2, 7.5 Hz, 1H), 7.14 (dd, J ) 1.2, 7.8 Hz, 1H), 7.18-7.36 (m,
8H), 7.43 (d, J ) 8.2 Hz, 2H). 13C NMR (CDCl3) δ 28.5, 42.2,
44.6, 49.0, 124.2, 126.0, 126.1, 126.2, 127.3, 127.7, 127.8, 128.1,
128.7, 130.5, 133.6, 140.8, 141.2, 150.1. Anal. Calcd for
8-Met h yl-2,3-tr a n s-3,4-tr a n s-4-(4-m et h oxyp h en yl)-3-
m eth yl-2-p h en ylth ioch r om a n (19): white plates, mp 140-
142 °C from EtOAc/hexanes; all signals for major diastereomer
unless stated; 1H NMR (CDCl3) δ 0.84 (d, J ) 6.6 Hz, 3H),
2.45 (s, 3H), 2.58-2.82 (m, 1H), 3.98 (s, 3H), 3.98 (d, J ) 10.8
Hz, 1H), 4.27 (d, J ) 10.5 Hz, 1H), 6.76 (d, J ) 7.8 Hz, 1H),
6.96-7.14 (m, 4H), 7.29 (d, J ) 8.7 Hz, 2H), 7.42-7.60 (m,
5H). The only signals identifiable for minor diastereomer
(<10%) are [1.14 (d, J ) 6.6 Hz, 3H)], [2.57 (s, 3H)], [4.60 (d,
J ) 3.0 Hz, 1H)]. 13C NMR (CDCl3) δ 18.7, 20.7, 42.6, 52.1,
54.6, 55.2, 113.9, 123.6, 127.4, 127.7, 128.3, 128.7, 128.8, 130.3,
133.7, 134.0, 137.6, 137.9, 140.4, 158.1. Anal. Calcd for
C
22H20S: C, 83.50; H, 6.37. Found: C, 83.37; H, 6.66.
2-(3-Ch lor op h e n yl)-4-m e t h yl-4-p h e n ylt h ioch r om a n
(12): colorless oil, purified by column chromatography using
EtOAC/hexanes 20:1 as eluent to give the product as a 7:1
1
mixture of isomers; H NMR (CDCl3) δ (major isomer), 1.78
(s, 3H), 2.18 (dd, J ) 2.4, 13.5 Hz, 1H), 2.60 (dd, J ) 12.6,
13.5 Hz, 1H), 4.58 (dd, J ) 2.4, 12.6 Hz, 1H), 6.75 (dd, J )
1.5, 8.1 Hz, 1H), 6.87 (dt, J ) 1.5, 8.1 Hz, 1H), 7.03 (dt, J )
1.5, 7.5 Hz, 1H), 7.12 (dd, J ) 1.5, 8.1 Hz, 1H), 7.12-7.32 (m,
8H), 7.43 (s, 1H); (minor isomer, selected signals) [1.82 (s, 3H)],
[3.94 (dd, J ) 3.6, 12.3 Hz, 1H)], [2.39 (dd, J ) 12, 13.5 Hz,
1H)], [2.50 (dd, J ) 3.3, 13.5 Hz, 1H)]. 13C NMR (CDCl3) δ
28.4, 41.8, 44.5, 48.8, 124.3, 125.9, 126.0, 126.2, 126.8, 127.2,
127.9, 128.0, 128.2, 129.9, 130.5, 133.1, 134.4, 141.0, 142.9,
149.7. Anal. Calcd for C22H19ClS: C, 75.30; H, 5.46. Found:
C, 75.27; H, 5.35.
C
24H24OS: C, 79.96; H, 6.71. Found: C, 79.56; H, 7.09.
2,3-tr a n s-3,4-tr a n s-2,3,4-Tr ip h en ylt h ioch r om a n (20):
white plates, mp 145-146 °C following column chromatogra-
phy using EtOAc/hexanes (20:1) as an eluent followed by
washing resultant colorless oil with hexanes; 1H NMR (CD3)2-
CO δ 3.84 (dd, J ) 11.1, 10.8 Hz, 1H), 4.55 (d, J ) 10.8 Hz,
1H), 4.92 (d, J ) 11.1 Hz, 1H), 6.72 (d, J ) 8.1 Hz, 1H), 6.80-
7.34 (m, 18H). 13C NMR (CDCl3) δ 51.1, 55.3, 56.3, 125.1, 126.6,
126.7, 126.9, 127.1, 128.0, 128.5, 128.9, 129.0, 129.6, 130.3,
132.1, 135.3, 139.3, 140.5, 142.8, 145.5. Anal. Calcd for
C
27H22S: C, 85.67; H, 5.86. Found: C, 85.98: H, 6.67.
2-(2-Ch lor op h e n yl)-4-m e t h yl-4-p h e n ylt h ioch r om a n
(13): white plates, mp 154 °C from EtOAc/hexanes; 1H NMR
(CDCl3) δ 1.86 (s, 3H), 2.22 (dd, J ) 2.4, 13.8 Hz, 1H), 2.52
(dd, J ) 12.3, 13.8 Hz, 1H), 5.22 (dd, J ) 2.4, 12.3 Hz, 1H),
6.77 (dd, J ) 1.5, 7.8 Hz, 1H), 6.90 (dt, J ) 1.5, 7.5 Hz, 1H),
7.05 (dt, J ) 1.5, 7.5 Hz, 1H), 7.13-7.38 (m, 9H), 7.65 (dd, J
) 1.8, 7.8 Hz, 1H). 13C NMR (CDCl3) δ 28.3, 38.3, 44.9, 48.5,
124.3, 126.18, 126.24, 126.3, 127.26, 127.32, 128.1, 128.7,
128.8, 129.7, 130.6, 133.1, 133.5, 138.2, 141.3, 149.9. Anal.
Calcd for C22H19ClS: C, 75.30; H, 5.46. Found: C, 75.31; H,
5.82.
Ack n ow led gm en t. The authors thank Dr. Peter J .
Steel (University of Canterbury, New Zealand) for
carrying out preliminary X-ray studies on compound 3.
They are also grateful to Dr. Sergey N. Denisenko (UF)
and Dr. Ion Ghiriviga (UF) for helpful discussions, and
Dr. Novruz G. Akhmedov (UF) for assistance with NOE
studies.
J O001571C