One-pot synthesis of trans-7-aryl-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepines

Article abstract of DOI:10.3987/COM-05-10485

Green chemical approaches for the condensation reaction of benzenethiols and 3-arylidenenchroman-4-ones as synthons for the synthesis of a series of newtrans-7-aryl-6H-6a,7-dihydro[1]benzo pyrano[3,4-c][1,5]benzothiazepines which may possess potential biological activity are described.{A figure is presented}.

Full text of DOI:10.3987/COM-05-10485

HETEROCYCLES, Vol. 65, No. 10, 2005
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HETEROCYCLES, Vol. 65, No. 10, 2005, pp. 2493 - 2503
Received, 20th June, 2005, Accepted, 10th August, 2005, Published online, 12th August, 2005
ONE-POT SYNTHESIS OF trans-7-ARYL-6H-6a,7-DIHYDRO[1]BENZO-
PYRANO[3,4-c][1,5]BENZOTHIAZEPINES
Ramadas Sathunuru, Benjamin Koh, Hongming Zhang, and Ed Biehl*
Department Chemistry, Southern Methodist University, Dallas, TX 75275,
U. S. A.
Communicating Author: ebiehl@smu.edu
Abstract – Green chemical approaches for the condensation reaction of
benzenethiols and 3-arylidenenchroman-4-ones as synthons for the synthesis of a
series of newtrans-7-aryl-6H-6a,7-dihydro[1]benzo pyrano[3,4-c][1,5]benzo-
thiazepines which may possess potential biological activity are described.
INTRODUCTION
Certain derivatives of 1,5-benzothiazepines, e.g. diltiazem, are used extensively as cardiovascular drugs
by acting as calcium channel blockers.1-5 Extensive synthetic studies have shown that certain substituents
on the aromatic ring fused to the 1,5-benzothiazepine nucleus may behave as potential pharmacophores.6,7
Taking into account the pharmacological activities of the chromane group8-10 and arylidenechroman-4-
ones11-13 and encouraged by our previous success in the synthesis of potentially biologically active
1,3-thiazoles,14 we have carried out a one-pot synthesis of tetracyclic [1,5]benzothiazepines with
substituents on the fused phenyl ring by the cyclization of 3-arylidenechroman-4-ones with 2-amino-
thiophenols with the goal of preparing benzothiazepines with improved cardiovascular activity. The
results are reported herein.15
RESULTS AND DISCUSSION
As shown in Table 1, the trans-3-arylidenyl derivatives of chroman-4-ones (3a–i) were prepared in
87-96% yields by treating 4-chromanone (1) with various aromatic aldehydes (2a–i) in the presence of
AcOH and HCl.16 The absence of cis-3-arylindinyl compounds was ascertained by HPLC. As shown in
Scheme 1, the arylidenes (3a–i) and 2-aminobenzenethiol (4) were then refluxed in a 1:1 (v:v) solution of
ethanol/toluene for 2 h in the presence of a strong acid, such as TFA with conc HCl, for 2 h to give trans-

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HETEROCYCLES, Vol. 65, No. 10, 2005
Table 1
O
O
O
O
O
Ar
AcOH / HCl
H
Ar
+
0 oC / 24 h
3a-i
1
2a-i
a
b
c
Ph-
4-MeO-C6H4-
4-Me-C6H4-
a
b
c
H
H
H
H
Ph-
4-MeO-C6H4-
4-Me-C6H4-
96
92
94
84
S
S
d
d
e
f
g
h
i
e
f
g
h
i
H
H
H
H
H
90
80
91
87
95
4-Cl-C6H4-
4-Br-C6H4-
2,5-diMeO-C6H3-
2,3,4-tri-MeO-C6H2-
3,4,5-tri-MeO-C6H2-
4-Cl-C6H4-
4-Br-C6H4-
2,5-diMeO-C6H3-
2,3,4-tri-MeO-C6H2-
3,4,5-tri-MeO-C6H2-
7-aryl-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepines (5a–i) in 87-97% yields. The yields
are shown in Table 2. Interestingly these reactions did not require the usual work-up since the products
(5a-i) precipitated from the reaction medium in pure state upon standing.
Ar
8
Ar
9
S
8a
H
H
H'
6
10
11
7
SH
H"
5
H
EtOH/toluene (1:1)
12a
6a
14
O
+
NH2
O
O
N
12
Conc. HCl 1 mL
TFA
13
4a
14a
1
4
4
Reflux, 2 h
3
2
R
5a-i
3a-i
Scheme 1
During the course of our work, the synthesis of 10-substitutedarylidene-6H-6a,7-dihydro-6-pheny-
l[1]-benzopyrano-[3,4-c][1,5]benzothiazepines (5) by the reaction of the corresponding chroman-4-one
(3) and 4 was reported.16 However, the yields in that study were significantly lower (60-70%) and reaction
times were longer (6 h) than those reported here. One of the major differences between the two syntheses
is that our method uses dry toluene and ethyl alcohol as co-solvents, whereas the other uses neat toluene.
Presumably the ethyl alcohol aids in the formation of and the subsequent precipitation of the benzothi-

HETEROCYCLES, Vol. 65, No. 10, 2005
2495
Table 2. Preparation of 1,5-Benzothiazepines (5a–i)
Entry 1,5-Benzothiazines (5) Yield, % Entry 1,5-Benzothiazines (5) Yield, %
Ph
Br
S
N
O
S
N
97
6
92
O
1
5a
5f
MeO
OMe
OMe
S
N
S
N
O
2
90
92
7
O
5g
5b
MeO
OMe
OMe
Me
S
N
S
N
3
O
O
90
8
94
89
5c
5h
MeO
OMe
MeO
S
S
S
N
O
94
9
O
N
4
5d
5i
Cl
S
87
5
O
N
5e

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HETEROCYCLES, Vol. 65, No. 10, 2005
azepines.
The structures of 5a–i were confirmed by1H NMR, 13C NMR spectroscopy and in the case of 5a and 5g,
by X-Ray crystallography. The ORTEP drawings of 5a and 5g, which are shown in Figures 1 and 2,
respectively, reveal that the H7 and H6a atoms are trans to each other with the H7–C7–C6a–H6a angles
being 175.09° and 170.62°, respectively. Additionally, the aromatic ring at C7 occupies the quasi
equatorial position. Moreover, the ORTEP drawings for 5a and 5g reveal that the H7 atom is located at
the quasi axial position and is gauche to the two diastereotopic protons, H6’ and H6”, and that the
diasterotopic protons are quasi equatorial. The dihedral angles for H6a—C6a–C6–H6’’ and
H6a—C6a–C6–H6” in compound (5a) are -64.1° and 53.4°, respectively, whereas those in compound
(5g) are –64.9° and 52.1°, respectively. The ORTEP drawings in Figures 1 and 2 also reveal that the
seven-membered ring in 5a and in 5g exists in a half-chair conformation. These results confirm the
structural assignments for 5a which were made previously on the basis of 1H NMR spectral analysis.18-20
We further confirmed the trans, ee configuration of the other 1,5-benzothiazepines (5b–5j) by comparing
the multiplicities and coupling constants of the diastereotopic protons H6’, H6” and the H6a and H7
protons. These are summarized in Table 3. For example, the 12.0–12.4 Hz splittings of the H7signals of
Figure 1 ORTEP of Compound (5a)

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2497
Figure 2 ORTEP of Compound (5g)
5g are –64.9° and 52.1°, respectively. The ORTEP drawings in Figures 1 and 2 also reveal that the
seven-membered ring in 5a and in 5g exists in half-chair conformations. These results confirm the
structural assignments for 5a which were made previously on the basis of 1H NMR spectral analysis.18-20
We further confirmed the trans, ee configuration of the other 1,5-benzothiazepines (5b–f, 5h,i) by
comparing the multiplicities and coupling constants of the diastereotopic protons H6’, H6” and the H6a
and H7 protons. These are summarized in Table 3. For example, the 12.0–12.4 Hz splittings of the H7
signals at δ 4.79–5.23 ppm are split into a doublet by the H6aprotons. This indicates that the H7 and H6a
are trans to each other and that the aryl groups attached to C7 exist in the quasi equatorial position.
Additionally, the diastereotopic protons, H6’ and H6” appear as ABqx2 patterns in the range of δ
3.90–4.10 and 3.76–3.99 ppm, respectively. Furthermore, the geminal couplings of these protons, which
are in the range of 11.8–11.9 Hz, are further split by H6a with coupling constants of 2.7 and 1.6 Hz,
respectively. The 1H NMR spectral data for 5a are in agreement with those previously reported.18
The IR spectra of the final products (5a–i) were devoid of the characteristic carbonyl absorption peak in
the range of 1690–1710 cm-1 and the absorption bands in the region of 1710-1690 and 3445-3200 cm-1
characteristic of primary amino groups. However, all compounds exhibited strong absorption band in the
range of 1602–1618 cm-1 indicative of C=N stretching.
A possible mechanism for the formation of titled compounds is given in Scheme 2. Thus, compound (1)
reacts with 2 by a Michael-type addition to give the adduct (6) which then undergoes an intramolecular
nucleophilic addition of amino group to the carbonyl moiety to give intermediate (7). This intermediate
then undergoes dehydration to give 5.

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1
Table 3 H Chemical Shifts (δ, Multiplicities and Coupling Constants (Hz) for H7’, H6a, H6’ and
H6” of Compounds (5a)
5
H7 (d)
J (Hz)
H6a (ddd)
H6’ (dd)
J (Hz)
H6” (dd)
J (Hz)
δ
δ
J (Hz)
δ
δ
a
b
c
d
e
f
4.92
4.89
4.89
5.23
4.88
4.87
4.09
4.09
4.79
12.3
12.3
12.3
12.0
12.2
12.1
12.4
12.3
12.4
3.09
12.3, 2.7, 1.6
12.3, 2.7, 1.5
12.3, 2.7, 1.6
12.0, 2.7, 1.5
12.1, 2.7, 1.6
12.1, 2.7. 1.6
12.4, 2.7, 1.6
12.4, 2.7, 1.6
12.4, 2,7, 1.6
4.04
4.04
4.04
4.10
4.05
4.05
3.90
3.90
4.06
11.8, 2.7
11.8, 2.7
11.8, 2.7
11.8, 2.7
11.9, 2.5
11.8, 2.5
11.8, 2.7
11.8, 2.7
11.9, 2.6
3.79
3.79
3.81
3.99
3.77
3.76
3.81
3.81
3.05
11.8, 1.6
11.9, 1.6
11.8, 1.6
11.9, 1.6
11.8, 1.6
11.7, 1.6
11.9, 1.6
11.9, 1.6
11.9, 1.6
3.03
3.01
2.99
3.04
3.05
3.01
3.01
3.05
g
h
i
O
O
O
O
O
R
H
R
R
3
H
!
O
S
!
S
..
..
H2N
H
H2N
S
..
7
NH2
6
4
_
H2O
R
S
O
N
5
Scheme 2
CONCLUSIONS
In conclusion, we have shown that a variety of 1,5-benzothiazepines can be prepared in excellent yields.
by the acid catalyzed cyclization of 3-benzylidinechroman-4-ones with 2-aminothiophenol. To our
knowledge this is the best method in terms of yields and ease of work-up for the synthesis of
seven-membered ring compounds.

HETEROCYCLES, Vol. 65, No. 10, 2005
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EXPERIMENTAL
Melting points were determined using a Mel-Temp capillary apparatus and were uncorrected. NMR
spectra were recorded on a Bruker Avance DRX400 instrument at 400 MHz (1H) or 100 MHz (13C NMR)
in CDCl3. Chemical shifts (δ values) were reported in parts per million and coupling constants (J
values) in Hz. IR spectra were recorded in a KBr pellet on a Perkin-Elmer spectrophotometer FT
Paragon 1000 PC. Elemental analyses were obtained from SMU Analytical Laboratories. Flash
chromatography was performed on silica gel (Ultrapure 230-400 mesh). TLC was performed on
pre-coated silica gel plates (silica gel 60, F254, 20 x 20 cm). Solvents were HPLC grade or were purified
by standard procedures. All reagents were of commercial quality and were purified before use. The
glassware was heated overnight in an oven at 125 ºC prior to use. The reactions were carried out under
an atmosphere of dry O2-free Ar via balloon.
Preparation of Arylidenechroman-4-ones (3a-j).
These compounds were synthesized by a literature method.16 The following have been reported and were
identified on the basis of their mp.
3-Benzylidenechroman-4-one (3a): mp 109 °C (MeOH); lit.,21110 °C.
3-(4’-Methoxybenzylidene)chroman-4-one (3b): mp 131–132 °C (MeOH); lit.,21 132 °C.
3-(4’-Methylbenzylidene)chroman-4-one (3c): mp 117–118 °C (MeOH); lit.,21 118 °C.
3-(Thiophen-2-ylmethyl)chroman-4-one (3d): mp 79 °C (MeOH); lit.,22 80–81 °C.
3-(4’-Chlorobenzylidene)chroman-4-one (3e): mp 160–162 °C (MeOH): lit.,21 168 °C.
3-(4’-Bromobenzylidene)chroman-4-one (3f): mp 174–175 °C (MeOH); lit.,21 174 °C.
3-(3’, 4’, 5’-Trimethoxybenzylidene)chroman-4-one (3i): mp 108-109 °C (MeOH); lit.,21107 °C.
The physical and spectral properties of new arylidenechroman-4-ones (3g, 3h, and 3j) follow.
3-(2’, 5’-Dimethoxybenzylidene)chroman-4-one (3g): Yellow solid, mp 77–79 °C (EtOH). 1H NMR
(400 MHz, CDCl3): δ 3.67 (s, 3 H), 3.77 (s, 3 H), 5.23 (s, 2 H), 6.66 (s, 1H), 6.90–6.98 (m, 4H), 7.07 (d, J
= 7.45 Hz, 1 H), 7.49 (d, J = 7.45 Hz, 1 H), 7.97 (s, 1H), 8.04–8.06 (m, 1 H). 13C NMR (100 MHz,
CDCl3): δ 56.3, 55.5, 68.5, 112.4, 116.1, 116.6, 118.1, 118.3, 122.2, 122.6, 124.6, 128.4, 131.6. 134.0,
136.1, 152.9, 153.5, 161.8. Anal. Calcd for C18H16O4: C, 72.96; H, 5.44. Found: C, 73.05; H, 5.50.
1
3-(2’, 3’, 4’-Trimethoxybenzylidene)chroman-4-one (3h): viscous oil. H NMR (400 MHz, CDCl3):
δ 3.76 (s, 3 H), 3.86 (s, 3 H), 4.01 (s, 3 H), 5.23 (s, 2 H), 7.00-7.04 (m, 2H), 6.64 (d, J = 7.5 Hz, 1 H),
6.21–6.24 (m, 2 H), 6.17 (d, J = 7.5 Hz, 1 H), 7.97 (s, 1H). Anal. Calcd for C19H18O5: C, 69.93, H, 5.56.
Found: C, 70.13; H, 5.63.

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General Procedure for the Synthesis of trans-7-Phenyl-6H-6a,7-dihydro [1]benzopyrano-
[3,4-c]-[1,5]-benzothiazepine (5a).
A mixture of 3-arylidenechroman-4-one (2a) (200 mg, 0.84 mmol) and 2-aminothiophenol (4a) (106 mg,
0.84 mmol) was solubilized in ethanol/toluene (1:1) (20 mL) with 1 mL of conc. HCl with a catalytic
amount of TFA (0.2 mL). The resulting solution was refluxed until TLC revealed the absence of reactants.
The solvent was removed under reduced pressure, and the residue left was recrystallized to give 5a (280
mg, 97%) as light yellow crystals, mp 170–172 0C (EtOH). IR (KBr, νmax) 1602 cm-1 (C=N); 1H NMR
(400 MHz, CDCl3): δ 3.09 (ddd, J = 12.3, 2.7, 1.6 Hz, H-6a), 3.79 (dd, J = 11.7,1.2 Hz, H-6” ), 4.04 (dd,
J = 11.8, 2.7 Hz, H-6’), 4.92 (d, J = 12.3 Hz, H-7), 7.00–8.40 (m, 13H, ArH); 13C NMR (100 MHz,
CDCl3): δ 44.1(C-6a), 59.7(C-7), 67.1(C-6), 118.0(C-4), 120.4(C-4a), 122.4(C-2), 124.4(C-8a),
125.7(C-12), 125.8(C-10), 127.2(C-1), 127.4(C-2’, C-6’), 128.5(C-4’), 129.3(C-3’, C- 5’), 130.4(C-9),
133.7(C-3), 135.5(C-11), 143.2(C-1’), 152.1(C-12a), 158.4(C-4a), 163.3(C-14). Anal. Calcd for
C22H17NOS: C, 76.94; H, 4.99; N, 4.08. Found: C, 76.85; H, 4.82; N, 4.15.
General Procedure for the HPLC Analysis of 5a-i.
The purity of compounds (5a-1) was ascertained by HPLC analysis. The HPLC analysis wee performed
on a Waters 484UV detector using a (S,S)Whelk-O 1 column obtained from Regis Technologies. The
flow rate was 1 ml/min and the solvent composition was hexane-isopropyl in a ratio of 75:25. The
compounds were detected at 254 nm.
The physical and spectral of compounds 5b-i follow.
trans-7-(4’-Methoxyphenyl)-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepine (5b):
Colorless crystals, mp 193–195 ºC (EtOH). IR (KBr, νmax): 1615.2 cm-1 (C=N). 1H NMR (400 MHz,
CDCl3): δ 3.03 (ddd, J = 12.4, 2.7, 1.5 Hz, H-6a), 3.79 (dd, J = 11.9, 1.6 Hz, H-6”), 3.82 (3H, MeO-4’),
4.04 (dd, J = 11.9, 2.7 Hz, H-6’), 4.89 (d, J = 12.4 Hz, H-7), 6.86–8.38 (m, 12H, ArH); 13C NMR (100
MHz, CDCl3): δ 44.3(6a), 55.7(MeO-4’), 59.3(C-7), 67.1(C-6), 114.6(C-4), 118.0(C-14a), 120.4(C-2),
122.4(C-8a), 124.4(C-12), 125.6(C-10), 125.8(C-1), 127.4(C-2’, 6’), 128.3(C-1’), 130.3(C-3’, 5’),
133.7(C-9), 135.5(C-3), 136.7(C-11), 152.1(C-12a), 158.4(C-4’), 159.7(C-4a), 163.3(C-14). Anal.
Calcd for C23H19NO2S: C, 73.97; H, 5.13; N, 3.75. Found: C, 74.11; H, 5.10; N, 3.69.
trans-7-(4’-Tolyl)-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepine (5c): Yellow crystals,
mp 153–155 ºC (EtOH-EtOAc). IR (KBr, νmax): 1618 cm-1 (C=N). 1H NMR (400 MHz, CDCl3): δ
2.36 (3H, Me-4’), 3.07 (ddd, J = 12.3, 2.7, 1.6 Hz, H-6a), 3.81 (dd, J = 11.8 Hz, 1.6 H-6”), 4.04 (dd, J =
11.8, 2.7 Hz, H-6’), 4.89 (d, J = 12.3 Hz, H-7), 7.00–8.39 (m, 12H, ArH); 13C NMR (100 MHz, CDCl3): δ
21.6(Me-4’), 44.1(C-6a), 59.5(C-7), 67.1(C-6), 118.0(C-4), 120.4(C-14a), 122.4(C-2), 124.5(C-8a),
125.6(C-12), 125.8(C-10), 127.0(C-1), 127.4(C-2’, 6’), 130.0(C-1’), 130.3(C-3’, 5’), 133.7(C-9),

HETEROCYCLES, Vol. 65, No. 10, 2005
2501
135.5(C-3), 138.3(C-11), 140.3(C-12a), 152.1(C-4’), 158.4(C-4a), 163.3(C-14). Anal. Calcd for
C23H19NOS: C, 77.28; H, 5.36; N, 3.92. Found: C, 77.18; H, 5.29; N, 3.89.
trans-7-(Thiophen-2-yl)-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepine (5d): Yellow
solid, mp 136–138 ºC (EtOH). IR (KBr, νmax): 1613 cm-1 (C=N). 1H NMR (400 MHz, CDCl3): δ 2.97
(ddd, J = 12.0, 2.7, 1.5 Hz, H-6a), 3.99 (dd, J = 11.9, 1.6 Hz, H-6”), 4.10 (dd, J = 11.8, 2.7 Hz, H-6’),
5.23 (d, J = 12.0 Hz, H-7), 6.96–8.38 (m, 11H, thiophene and ArH); 13C NMR (100 MHz, CDCl3): δ
45.2(C-6a), 55.2(C-7), 67.2(C-6), 118.1(C-4), 120.4(C-14a), 122.5(C-2), 123.3(C-8a), 125.4(C-10, C-12),
125.5(C-1), 125.6(C-4’), 126.9(C-2’), 127.4(C-3’), 130.7(C-9), 133.8(C-3), 136.1(C-11), 146.8(C-1’),
152.2(C-12a), 158.4(C-4a), 162.9(C-14). Anal. Calcd for C20H15NOS2: C, 68.74; H, 4.33; N, 4.01.
Found: C, 68.68; H, 4.26; N, 3.97.
trans-7-(4’-Chlorophenyl)-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepine (5e):
Colorless crystals mp 178–180 ºC (EtOH). IR (KBr, νmax): 1617 cm-1 (C=N). 1H NMR (400 MHz,
CDCl3): δ 3.04 (ddd, J = 12.2, 2.7, 1.6 Hz, H-6a), 3.77 (dd, J = 11.8, 1.6 Hz, H-6”), 4.05 (dd, J = 11.9, 2.5
Hz, H-6’), 4.88 (d, J = 12.2 Hz, H-7), 7.00–8.39 (m, 12H, ArH); 13C NMR (100 MHz, CDCl3): δ
44.0(C-6a), 58.9(C-7), 67.0(C-6), 118.1(C-4), 120.4(C-14a), 122.6(C-2), 124.0(C-8a), 125.8(C-12),
126.0(C-10), 127.5(C-1), 128.6(C-2’, 6’), 129.5(C-3’, 5’), 130.6(C-9), 133.9(C-3), 134.2(C-4’),
135.5(C-11), 141.7(1’), 152.2(C-12a), 158.4(C-4a), 163.0(C-14). Anal. Calcd for C22H16NClS: C, 69.92;
H, 4.27; N, 3.71. Found: C, 69.97; H, 4.35; N, 4.78.
trans-7-(4’-Bromophenyl)-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepine (5f): Light
yellow solid, mp 153-155 ºC (EtOH). IR (KBr, νmax): 1618 cm-1 (C=N). 1H NMR (400 MHz, CDCl3):
δ 3.05 (ddd, J = 12.1, 2.7, 1.6 Hz, H-6a), 3.76 (dd, J = 11.7, 1.6 Hz, H-6”), 4.05 (dd, J = 11.8, 2.5 Hz,
H-6’), 4.87 (d, J = 12.1 Hz, H-7), 7.05–8.41 (m, 12H, Ar H); 13C NMR (100 MHz, CDCl3): δ 44.0(C-6a),
58.7(C-7), 67.2(C-6), 118.4(C-4), 120.1(C-14a), 122.5(C-2), 124.3(C-8a), 125.6(C-12), 126.2(C-10),
127.8(C-1), 128.4(C-2’, 6’), 129.8(C-3’, 5’), 130.2(C-9), 133.6(C-3), 134.5(C-4’), 135.8(C-11),
141.6(C-1’), 152.7(C-12a), 158.5(C-4a), 163.2(C-14). Anal. Calcd for C22H16NOBrS: C, 62.56; H, 3.82;
N, 3.32. Found: C, 62.54; H, 3.79; N, 3.30.
trans-7-(2’,5’-Dimethoxyphenyl)-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepine (5g):
Yellow crystals, mp 180–183 ºC (EtOH). IR (KBr, νmax): 1615 cm-1 (C=N). 1H NMR (400 MHz,
CDCl3): δ 3.01 (ddd, J = 12.4, 2.7, 1.6 Hz, H-6a), 3.73 (3H, OMe), 3.74 (3H, OMe), 3.81 (dd, J = 11.9,
1.6 Hz, H-6”), 3.90 (dd, J = 11.8, 2.7 Hz, H-6’), 4.09 (d, J = 12.4 Hz, H-7), 6.75 (s, 1H, Ar H), 6.79–8.37
(m, 8H, Ar H), 8.38 (d, J = 6.8 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3): δ 44.1(C-6a), 56.0(C-7),
61.2(C-6), 67.3(C-4), 112.9(C-4a), 113.7(C-2), 118.0(C-8a), 120.5(C-12), 122.2(C-10), 123.7(C-5’),
125.3(C-1)), 125.6(C-2’), 127.4(C-9), 130.2(C-3), 133.6(C-11), 135.7(C-1’), 152.2(C-12a), 154.0(C-3’,

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6’), 158.5(C-4a), 163.5(C-14). Anal. Calcd for C24H21NO3S: C, 71.44; H, 5.25; N, 3.47. Found: C,
71.49; H, 5.31; N, 4.51.
trans-7-(3’, 4’, 5’-Trimethoxyphenyl)-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepine
(5h): Light yellow solid, mp 151–153 ºC (EtOH). IR (KBr, νmax): 1612 cm-1 (C=N). 1H NMR (400
MHz, CDCl3): δ 3.01 (ddd, J = 12.4, 2.7, 1.6 Hz, 1H, H-6a), 3.73 (3H, OMe), 3.74 (3H, OMe), 3.74 (3H,
OMe), 3.81 (dd, J = 11.9, 1.6 Hz, 1H, H-6”), 3.90 (dd, J = 11.9, 2.7 Hz, 1H, H-6’), 4.09 (d, J = 12.3 Hz,
1H, H-7), 6.75 (s, 1H, ArH), 6.79–8.37 (m, 8H, Ar H), 8.38 (d, J = 6.8 Hz, 2H, ArH); 13C NMR (100
MHz, CDCl3): δ 44.1(C-6a), 56.5(MeO x 3), 60.0(C-7), 67.1(C-6), 104.0(C-4), 118.0(C-14a), 120.4(C-2),
122.4(C-8a), 124.4(C-12), 125.5(C-10), 125.8(C-1), 127.3(C-2’, 6’), 130.6(C-4’), 133.8(C-9), 135.4(C-3),
138.0(C-11), 139.0(C-1’), 152.3(C-3’, 5’), 153.7(C-12a), 158.5(C-4a), 163.3(C-14). Anal. Calcd for
C25H23NO4S: C, 69.26; H, 5.35; N, 3.23. Found: C, 69.29; H, 5.38; N, 3.26.
trans-7-(2’,3’,4’-Trimethoxyphenyl)-6H-6a,7-dihydro[1]benzopyrano[3,4-c][1,5]benzothiazepine
(5i): Light yellow crystals, mp 158–160 ºC (EtOH). IR (KBr, νmax): 1617 cm-1 (C=N). 1H NMR (400
MHz, CDCl3): δ 3.05 (ddd, J = 12.4, 2.7, 1.6 Hz, H-6a), 3.82 (3H, OMe), 3.84 (3H, OMe), 3.85 (3H,
OMe), 3.87 (dd, J = 11.9, 1.6 Hz, H-6”), 4.06 (dd, J = 11.9, 2.6 Hz, H-6’), 4.79 (d, J = 12.4 Hz, H-7),
6.64 (d, J= 8.6 Hz, 1H, ArH), 6.86 (d, J = 8.5 Hz, 1H, ArH), 7.00–8.39 (m, 8H, ArH); 13C NMR (100
MHz, CDCl3): δ 43.2(C-6a), 56.3(MeO x 3), 61.1(C-7), 67.2(C-6), 108.4(C-4), 118.0(C-14a), 120.4(C-2),
120.7(C-8a), 122.3(C-12), 123.9(C-10), 125.4(C-3’), 125.6(C-1’), 127.4(C-2’), 129.2(C-1), 130.2(C-9),
133.7(C-3), 135.8(C-11), 142.5(C-5’), 150.9(C-4’), 152.2(C-6’), 153.5(C-12a), 158.4(C-4a), 163.3(C-14).
Anal. Calcd for C25H23NO4S: C, 69.26; H, 5.35; N, 3.23. Found: C, 69.30; H, 5.38; N, 3.26.
ACKNOWLEDGEMENTS
This work was supported in part by grant from the Welch Foundation, Houston, TX.
REFERENCES
1. A. Fleckenstein, Annu. Rev. Pharmacol. Toxicol., 1977, 17, 149.
2. T. Magararibuchi, H. Nakajima, and A. Kiyomoto, Japan J. Pharmacol., 1977, 27, 361.
3. H. Nakajima, M. Hoshiyama, K. Yamashita, and A. Kiyomoto, Japan J. Pharmacol., 1975, 25, 383.
4. M. Amblard, I. Daffix, P. Bedos, G. Berge, D. Pruneau, J. L. Paquet, J. M. Luccarini, P. Belichard, P.
Dogey, and J. Martinez, J. Med. Chem., 1999, 42, 4185.
5. D. Kantoci, Jr. E. D. Murray D. D. Quiggle, and W. J. Wechter, J. Med. Chem., 1996, 39, 1196.
6. A. Lochead, J. C. Muller, C. Denys, and H. Dumas, Eur. Pat. Appl. 88/5, 1988, 131 (Chem. Abstr.,
1990, 112, 158278m).
7. K. S. Atwal, S. Z. Ahmed, D. M. Floyd, S. Moreland, and A. Hedberg, Biorg. Med. Chem. Lett.,
1993, 3, 2797.

HETEROCYCLES, Vol. 65, No. 10, 2005
2503
8. G. P. Ellis, ‘Chromenes, Chromanones, and Chromones,’ John Wiley, New York, 1977.
9. P. J. Houghton, T, Z. Woldemarian, A. I. Khan, A. Burke, and N. Mahmood, Antiviral Res., 1994, 25,
235.
10. V. P. Kamboj, S. Ray, and B. N. Dhawan, Drugs Today, 1992, 28, 227.
11. P. M. Daniel, P. Sara, F. A. Maria, and R. Giulio, J. Med. Chem., 2004, 47, 4258.
12. Z. Ping, I. Yuko, K. Isao, E. Yasukuni, and Y. Hirobumi, Phytochemistry, 2004, 65, 2455.
13. R. Bernard, G. Catherine, J. Yves, G. Corinne, F. Herve, B. Francoise, R. Jean-Francois, H. Bruno,
M. Georges, R. Lysiane, and X. Alain, Eur. J. Med. Chem., 2004, 39, 931.
14. R. Sathunuru and E. Biehl, Heterocycles, 2004, 63, 2805.
15. This work was presented at the 229th ACS National Meeting, Division of Medicinal Chemistry,
Abstract #559, March-13-17, 2005, San Diego, CA.
16. A. E.-F. G. Hammam, A. F. M. Fahmy, A.-G. E. Amr, and A. M. Mohamed, Indian J. Chem. Sect. B,
2003, 42B, 1985.
17. U. C. Pant, A. Dandia, H. Chandra, S. Goyal, and S. Pant, Phosphorus, Sulfur and Silicon Relat.
Elem., 2005, 180, 559.
18. G. Toth , A. Szollosy, A. Levai, and H. Duddeck, Org. Magn. Reson., 1982, 20, 133.
19. (a) A. Lenai, G. Toth, and A. Szollosy, ‘Proceedings of the International Bioflavonoid Symposium,’
Munich, Germany, 1981, 41.
20. (a) A. Nefzi, N. A. Ong, M. A. Giulianotti, J. M. Osfresh, and R. A. Houghten, Tetrahedron Lett.,
1999, 40, 4939; (b) M. K. Schwarz, D. Tumelty, and M. A. Gallop, J. Org. Chem., 1999, 64, 2219;
(c) S. Yamada, Y. Mori, K. Morimatsu, Y. Ishizu, Y. Ozaki, R. Yoshioka, T. Nakatani, and H.
Seko, J. Org. Chem., 1996, 61, 8586.
21. P. Bennett, J. A. Donnelly, D. C. Meaney, and P. O’Boyle, J. Chem. Soc. Perkin, Trans 1, 1972, 12,
1554.
22. T. A. Nakib, V. Bezjak, S. Rashid, B. Fullam, and M. J. Meegan, Eur. J. Med. Chem., 1991, 26, 221.