Preparation of Benzothiopyrano[2,3-b]indoles by thereaction of 1,3-dihydroindole-2-thiones with certain dienophiles

Article abstract of DOI:10.3987/COM-04-10219

Benzothiopyrano[2,3-b]indoles were prepared by the cyclization of 1,3-dihydroindole-2-thiones with varions dienophiles. The 1,3-dihydroindole-2- thiones were readily synthesized by the reaction of oxindole with P₂S₅ followed by a piperidine-mediated condensation of the resulting thioindole with a suitable aromatic aldehyde.

Full text of DOI:10.3987/COM-04-10219

HETEROCYCLES, Vol. 63, No. 12, 2004, pp. 2785 - 2795
Received, 3rd September, 2004, Accepted, 7th October, 2004, Published online, 8th October, 2004
PREPARATION OF BENZOTHIOPYRANO[2,3-b]INDOLES BY THE
REACTION OF 1,3-DIHYDROINDOLE-2-THIONES WITH CERTAIN
DIENOPHILES
Sukanta Kamila and Ed Biehl*
Department of Chemistry, Southern Methodist University, Dallas, TX 75275
U. S. A. ebiehl@smu.edu
Abstract – Benzothiopyrano[2,3-b]indoles were prepared by the cyclization of
1
,3-dihydroindole-2-thiones with various dienophiles. The 1,3-dihydroindole-2-
thiones were readily synthesized by the reaction of oxindole with P S followed
2
5
by a piperidine-mediated condensation of the resulting thioindole with a suitable
aromatic aldehyde.
INTRODUCTION
-Substituted 1-alkylidine-3H-benzo[b]indolin-2-ones have been shown to exhibit inhibitory properties
3
1
,2
3
against various receptor tyrosine kinases (RTKs). We recently expanded the chemical diversity of this
structural type by developing a new strategy towards the synthesis of 3-1-alkylidine-3H-
benzo[b]thiophene-2-ones in which the nitrogen atom has been replaced by a sulfur atom. We were also
interested in exploring the possibility of these benzo[b]thiophene-2-ones serving as dienes in Diels–Alder
4
cyclization reactions since we had shown that selonoazadienes react with benzynes to give 4H-1,3-
benzoselenazines. However, our attempts to carrying out Diels–Alder
reactions with
benzo[b]thiophene-2-ones failed. We subsequently prepared the pyrrole analogs, benzo[b]pyrrole-2-
thiones (in which the carbonyl oxygen atom of the indolin-2-one ring was placed by a sulfur atom) and
found that 2-thiones did reaction with benzynes and dimethyl acetylenedicarboxylate to give new
benzothiopyrano[2,3-b]indoles. The results are reported herein.
RESULTS AND DISCUSSION

5
As shown in Scheme 1, the starting benzo[b]-2-thiones (4 and 5) were prepared by the conversion of 2H-
indol-2-one (1), commonly called oxindole, to the thioindole (2) with P S followed by a piperidine-
2
5
mediated condensation of 2 with aldehydes (3a–e) in refluxing benzene. The results are listed in Table 1.
R'
H
R'
H
S
RCHO (3a–e)
P S
2
5
S
+
O
S
N
Piperidine, Benzene
Reflux
N
N
N
H
H
H
H
5
2
4
1
Scheme 1
As shown, (Z)-1,3-dihydro-3-(pyrrol-2-ylmethylene)indole-2-thione (4b) (Entry 2), (Z)-3-(furan-2-
ylmethylene)-1,3-dihydroindole-2-thione (4e) (Entry 5), and (E)-1,3-dihydro-3-(thien-2-
ylmethylene)indole-2-thione (5d) (Entry 4) were obtained essentially as single products. However, a
mixture of (Z )-(4a)- and (E)-1,3-dihydro-3-(4-isopropylbenzylidine)indole-2-thione (5a), were obtained
in a ratio of 72:15, respectively (Entry 1) and a mixture of (Z)- (4c)- and E-1,3-dihydro-3-(4-N,N-
dimethylaminobenzylidine)indole-2-thione (5c) was obtained in a ratio of 78:18, respectively (Entry 3).
Since analytical samples of 4a,c and 5a,c were obtained by subjecting a small portion of each mixture
to column chromatography. Diasteromeric assignments of the indole-2-thiones (4 and 5) were made on
the basis of their olefinic proton chemical shifts with the Z isomers occurring around δ 7.8 ppm and the
E isomers appearing around 7.5 ppm. These chemical shifts were similar to those previously reported for
4
similarly structured indol-2-ones. In addition, the structure of compound (4b) was confirmed by X-
Ray crystallography; the ORTEP drawing of 4b is shown in Figure 1.
Figure 1. ORTEP of Compound (4b)

Table 1. Preparation of Z- (4) and E-Pyrrol-2-thiones (5)
Entry
1
3
4 (yield, %)
5 (yield, %)
i-Pr
H
Pr-i
OHC
Pr-i
H
S
N
S
3
a
H
N
4
a (72)
H
5
a (15)
H
H
N
NH
H
2
CHO
N
H
S
N
H
S
3
b
N
H
b (trace)
4
b (83)
5
Me N
2
H
NMe2
3
OHC
NMe2
H
S
N
S
3
c
H
N
4
c (78)
H
5
c (18)
S
H
S
H
S
4
5
CHO
S
S
N
H
N
3
d
H
4
d (trace)
5
d (82)
H
O
O
H
S
S
CHO
O
N
3
e
H
e (79)
N
H
4
5
e trace
With the indole-2-thiones on hand, their reactions with 4,5-dimethoxybenzyne (6a), 3-methoxybenzyne
6b), and dimethyl acetylenedicarboxylate (8) were carried out. Since dienophiles (6a and 8) would
(

yield a single adduct, the mixtures (4a/5a and 4c/5c) were used as is. The overall reactions schemes are
shown in Scheme 1. We first studied the reaction of indole-2-thiones with 6a since the identification of
1
13
the structure of Diels–Alder adducts by H NMR and C NMR spectroscopy would be simplified, and
the
R
R
G
R1
R1
6
S
N
H
1
a) R = OMe R = OMe
1
b) R = H R = OMe
7
H
G
S
N
H
4
,5
CO Me
G
2
i-Pr
H
MeO2C
CO Me
2
N
CO Me
2
8
G =
S
,
,
N
H
Me N
2
9
O
S
,
,
Scheme 2
introduction of the dimethoxy groups might induce some biological activity in the resulting adducts. As
shown in Scheme 1, compounds (4a/5a,4b, 4c/5c) indeed reacted with 6a to yield single adducts, i.e., 2,3-
dimethoxy[1]benzothiopyrano[2,3-b]indoles (7a–c) in 52–65% yields. The results listed in Table 2
(
Entries 1–3)) were obtained by generating 4,5-dimethoxybenzyne (6a) in situ from a mixture of 2-
6
diazonio 4,5-dimethoxybenzenecarboxylate hydrochloride in refluxing benzene. The yields of 7a–c
were lower when 6 was generated by the addition of isoamyl nitrite to a refluxing benzene solution
7
(
~80 °C) containing 4,5-dimethoxyanthranilic acid.
Interestingly, these indole-2-thiones, unlike
1
selonoazadienes, failed to react when 6 was generated by the reaction of (phenyl)[o-
7
(
trimethylsilyl)phenyl]iodonium triflate and Me NF at room temperature, or by the reaction of anthranilic
4
8
acid and isoamyl nitrite in THF 0 °C. Subsequently, the reaction of 3-methoxybenzyne (6b) with (Z)-
1
,3-dihydro-3-(pyrrol-2-ylmethylene)indole-2-thione (4b) afforded a 1:1 mixture of 3-methoxy- and 4-
methoxyindoles (7d) (Entry 4). This indicates that 4b adds non-regioselectively and in a concerted
manner to 3-methoxybenzyne which is consistent with other reports of Diels-Alder cycloadditions to
9
unsymmetric arynes.

Lastly, the reaction of 4 and 5 with dimethyl acetylenedicarboxylate (8) gave the indole-2,3-dicarboxylic
acid dimethyl esters (9a–e) in yields of 68–78% (Entries 5–9). These reactions also required refluxing
1
13
MeCN for 6 h. The structures of 7 and 9 were confirmed by H NMR and C NMR spectral analysis. For
1
example, in the H NMR spectra of compounds (7a–c) the benzylic hydrogen (H-11) exhibited a singlet
in the vicinity of δ 3.8–4.0 ppm whereas the allylic hydrogen (H-1) in 9a–e exhibited a singlet in the
Table 2. Yields of Diels-Alder Adducts (7 and 9)
Entry Diene Dieno-
Phile
Adduct, Yield
(%)
Entry Diene Dieno-
phile
Adduct, Yield
(%)
OMe
i-Pr
i-Pr
CO Me
2
H
H
OMe
CO Me
1
4a/5a
6a
6
4a/5a
8
2
S
N
H
S
N
7
a (56)
H
9
a (21)
H
H
N
OMe
N
H
CO Me
2
H
OMe
CO2Me
2
3
4b
6a
6a
7
8
4b
8
8
S
S
N
H
N
H
7
b (45)
9
b(78)
Me N
OMe
2
S
H
CO Me
2
H
OMe
4c/5c
4c/5c
CO Me
2
S
N
H
S
N
H
7
c (56)
9
c (72)
H
S
H
CO2Me
CO2Me
N
H
OMe
S
S
N
H
N
H
9
1
8
8
5d
4e
9
d (73)
7
d (21)
4
4b
6b
O
+
CO Me
H
2
H
CO Me
OMe
2
N
H
S
0
N
H
S
9
e (68)
N
H
7
e (22)
range of 3.9–4.3ppm. Additionally, the structure of 9d was confirmed by X-Ray spectroscopy; an
ORTEP drawing of 9d is shown in Figure 2.

In conclusion, we have shown that 1,3-dihydroindole-2-thiones undergo reaction with 4,5-
dimethoxybenzyne and dimethyl acetylendicarboxylate to give benzothiopyrano[2,3-b]indoles in modest
yields. We are not aware of other synthetic methodology that would allow the facile synthesis of these
multi-substituted heterocycles.
Figure 2. ORTEP of Compound (9d)
EXPERIMENTAL
General Data: Melting points were taken on a Mel-Temp capillary apparatus and are uncorrected with
1
13
respect to stem correction. H and C NMR spectra were recorded on a 400 MHz Bruker AVANCE
DRX-400 Multinuclear NMR spectrometer. Chemical shifts are reported in reference to TMS as
internal standard.
1
,3-Dihydroindole-2-thione (2)
To a solution of oxiindole (5 g, 37 mmol) in 30 mL of dry THF was added P S (16.6 g, 37 mmol).
2
5
The resulting mixture was stirred at rt for 45 min then NaHCO (10.41 g, 123 mmol) was added in
3
three portions and the resulting mixture stirred at rt for an additional 3 h. The solid material, which
precipitated during stirring, was separated by vacuum filtration and the mother liquor was concentrated to
dryness. The residue was treated with 100 mL of ice water, extracted with CHCl (3X 60 mL) and
3
purified by column chromatography on SiO to give 2 (4.5 g, 82%) as a light yellow solid (EtOAc-
2
°
1
hexane), mp 79–82 C. H NMR (CDCl ) δ 4.10 (s, 2H, -CH -), 7.10 (m, 2H, Ar-H-5, H-6), 7.27 (m, 2H,
3
2
1
3
Ar-H-4, H-7), 10.80 (br s, 1H, NH). C NMR (CDCl ) δ 36.7, 110.3, 122.6, 124.9, 125.7, 128.3, 143.1,
3
1
78.9. Anal. Calcd for C H NS: C, 64.39; H, 4.73; N, 9.39. Found: C, 64.47; H, 4.80; N, 9.45.
8 7
General Procedure for the Preparation of 1,3-Dihydroindole-2-thiones (4 ,5)

A reaction mixture of 2 (0.5 g, 3.3 mmol), the appropriate aldehyde (3) (4.0 mmol) and piperidine (0.09 g,
°
1
mL, 0.3 mmol) in dry benzene (6 mL) was stirred at 90 C for 4 h. The reaction mixture was then cooled
to rt, during which time a precipitate was obtained. The precipitate was filtered, washed (benzene), and
dried. The dried solid was subjected to column chromatography on SiO with EtOAc-hexane (1:4, v/v)
2
to give 4 and 5.
(
Z)- 1,3-Dihydro-4-isopropylbenzylidineindole-2-thione (4a)
°
1
This compound was isolated as a light yellow solid (EtOAc-hexane), mp 213–215 C. H NMR (CDCl ) δ
3
1
2
1
1
6
.13 (d, J=8.0 Hz, 6H), 2.80 (m, 1H), 6.35 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.1 Hz,
H), 7.23 (dd, J=7.5, 7.8 Hz, 1H), 7.35 (dd, J=7.5, 7.8 Hz, 1H), 7.80 (s, 1H, vinylic H), 7.91 (d, J=7.8 Hz,
1
3
H), 8.02 (br s, 1H, NH). C NMR (CDCl ) δ 24.1, 24.3, 33.9, 110.2, 119.8, 121.5, 122.5, 125.5, 126.2,
3
29.3, 130.4, 131.9, 132.2, 132.4, 134.7, 147.7, 149.4, 186.5. Anal. Calcd for C H NS: C, 77.38; H,
1
8
17
.13; N, 5.01. Found: C, 77.29; H, 6.09; N, 4.99.
E)-1,3-Dihydro-3-(4-isopropylbenzylidine)indole-2-thione (5a)
This compound was isolated as a light red solid (EtOAc-hexane), mp 214–216 C. H NMR (CDCl ) δ
(
°
1
3
1
2
.17 (d, J=8.0 Hz, 6H), 2.74 (m, 1H), 6.30 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz,
H), 7.13 (dd, J=7.5, 7.8 Hz, 1H), 7.23 (dd, J=7.5 Hz, 7.8 Hz, 1H), 7.50 (s, 1H, vinylic-H), 7.88, (d,
1
3
J=7.8 Hz, 1H), 8.01 (br s, 1H, NH). C NMR (CDCl ) δ 24.1, 24.2, 33.9, 110.2, 119.8, 121.5, 123.2,
3
1
7
25.5, 126.2, 129.2, 130.4, 131.9, 132.2, 132.3, 134.6, 147.7, 149.4, 183.5. Anal. Calcd for C H NS: C,
18 17
7.38; H, 6.13; N, 5.01. Found: C, 77.39; H, 6.07; N, 4.97.
Z)-1,3-Dihydro-3-pyrrol-2-ylmethyleneindole-2-thione (4b)
This compound was isolated as light red needles (EtOAc-hexane), mp 193–195 C. H NMR (CDCl ) δ
(
°
1
3
6
.53 (s, 1H), 7.00 (d, J=7.5 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.18 (dd, J=7.5, 8.0 Hz, 1H), 7.23 (d, J=7.5
Hz, 1H), 7.32 (dd, J=2.5, 7.5 Hz, 1H), 7.60 (dd, J=2.1, 8.0 Hz, 1H), 7.73 (s, 1H, vinylic-H), 8.40 (s, 1H,
1
3
NH), 8.50 (s, 1H, NH). C NMR (CDCl ) δ 109.7, 113.6, 118.4, 123.1, 125.2, 125.3, 126.9, 127.0, 129.8,
3
1
4
30.0, 130.9, 139.6, 184.2. Anal. Calcd for C H N S: C, 69.00; H, 4.45; N, 12.38. Found: C, 69.10; H,
13 10 2
.42; N, 12.33.
(
Z)-1,3-Dihydro-3-(4-N,N-dimethylaminobenzylidine)indole-2-thione (4c)
°
1
This compound was isolated as a light red solid (EtOAc-hexane), mp 210–213 C. H NMR (CDCl ) δ
3
2
2
1
.85 (s, 6H), 6.22 (d, J=8.0 Hz, 1H), 7.02 (dd, J=7.8, 8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.0 Hz,
1
3
H), 7.98 (s, 1H, vinyl-H), 8.0 (d, J=8.0 Hz, 1H), 8.37 (br s, 1H, NH). C NMR (CDCl ) δ 40.4, 110.4,
3
21.4, 123.2, 125.5, 125.7, 127.6, 128.9, 131.9, 132.9, 135.5, 136.0, 141.0, 141.1, 152.2, 153.1, 195.4.
Anal. Calcd for C H N S: C, 72.82; H, 5.75; N, 9.99. Found: C, 72.83; H, 5.77; N, 10.02.
1
7
16
2
(
E)-1,3-Dihydro-3-(4-N,N-dimethylaminobenzylidine)indole-2-thione (5c)

°
1
This compound was isolated as a purple solid (EtOAc-hexane), mp 209–210 C. H NMR (CDCl ) δ 2.85
3
(
s, 6H), 6.18 (d, J=8.0 Hz, 1H), 6.36 (d, J=8.0 Hz, 2H), 6.50 (dd, J=7.8, 8.0 Hz, 2H), 6.68 (d, J=8.0 Hz,
1
3
2
1
H), 7.45 (s, 1H, vinylic-H), 7.98 (d, J=8.0 Hz, 1H). C NMR (CDCl ) δ 42.1, 111.5, 121.4, 123.3, 125.1,
3
25.5, 127.6, 127.9, 131.9, 133.1, 135.5, 136.1, 141.1, 142.3, 152.3, 153.1, 194.4. Anal. Calcd for
C H N S: C, 72.82; H, 5.75; N, 9.99. Found: C, 72.80; H, 5.78; N, 9.98.
1
7
16
2
(
E)-1,3-Dihydro-3-thien-2-ylmethyleneindole-2-thione (5d)
°
1
This compound was isolated as a light brown solid (EtOAc-hexane), mp 217–218 C. H NMR (CDCl ) δ
3
6
8
1
.18 (d, J=8.0 Hz, 1H), 6.70 (d, J=7.5 Hz, 2H), 6.90 (s, 1H), 7.01–7.14 (m, 3H), 7.45 (s, 1H, vinylic-H),
1
3
.02 (br s, 1H, NH). C NMR (CDCl ) δ 109.3, 110.2, 110.5, 119.0, 119.6, 121.5, 123.7, 126.2, 127.9,
3
28.5, 129.6, 194.4. Anal. Calcd for C H NS : C, 64.16; H, 3.73; N, 5.78. Found: 64.18; H, 3.78; N, 5.80.
1
3
9
2
(
Z)-3-Furan-2-ylmethylene-1,3-dihydroindole-2-thione (4e)
°
1
This compound was obtained as a light red solid (EtOAc-hexane), mp 180–183 C. H NMR (CDCl ) δ
3
6
.60 (d, J=7.8 Hz, 1H), 7.03 (d, J=5.5 Hz, 1H), 7.10–7.14 (m, 2H), 7.29 (dd, J =2.3, 7.5 Hz, 1H), 7.81 (s,
1
3
1
H, vinylic-H), 8.05 (dd, J=2.1, 7.8 Hz, 1H), 8.57 (br s, 1H, NH). C NMR (CDCl ) δ 110.2, 114.3, 123.6,
3
1
23.8, 124.7, 125.7, 126.3, 129.7, 130.6, 143.1, 147.1, 152.2, 193.6. Anal. Calcd for C H NOS: C, 68.70;
1
3
9
H, 3.99; N, 6.16. Found: C, 68.73; H, 3.97; N, 6.19.
General Procedure for the Preparation of 2,3-Dimethoxy[1]benzothiopyrano[2,3-b]indoles (7a–c) A
well stirred solution containing 4a/5a (0.52 g, 0.18mmol) and a catalytic amount of trichloroacetic acid in
dry benzene (10 mL) was heated under reflux in a three-necked flask fitted with a reflux condenser and
two addition funnels under argon atmosphere. At this point the dropwise addition of solutions of 4,5-
dimethoxyanthranilic acid (1.4 g, 6.9 mmol) and isoamyl nitrite (0.96 g, 6.9 mmol) in dry benzene (5 mL)
from the addition funnels was started. The addition was stopped when the starting materials were no
longer detected in the reaction mixture by TLC (∼1.5 h). ßThe resulting solution was cooled to rt and
evaporated to dryness. The residue was dissolved in CH Cl , washed with 5% HCl solution, 5% NaOH
2
2
and water and finally dried over Na SO . Evaporation of the solvent under reduced pressure afforded the
2
4
crude compound which was purified by column chromatography using SiO with EtOAc-hexane (1:4,
2
v/v) as eluent. The physical and spectral data are given below for compounds (7a–c).
6
,11-Dihydro-11-(4-isopropylphenyl)-2,3-dimethoxy[1]benzothiopyrano[2,3-b]indole (7a)
1
This compound was obtained as a light yellow viscous oil. H NMR (CDCl ) δ 1.01 (d, J=8.0 Hz, 6H),
3
2
7
5
.81 (m, 6H), 3.86 (s, 3H), 3.89 (s, 3H), 3.94 (s, 1H), 6.59 (s, 1H), 6.80 (s, 1H), 7.25 (d, J=7.8 Hz, 2H),
1
3
.40 (d, J=7.8 Hz, 2H), 7.41–7.45 (m, 4H), 8.03 (br s, 1H, NH). C NMR (CDCl ) δ 24.2, 32.1, 38.0, 55.9,
3
6.1, 111.1, 112.2, 115.1, 120.1, 121.0, 122.2, 123.3, 125.7, 127.0, 128.3, 133.5, 138.1, 155.4, 155.9.
Anal. Calcd for C H NO S: C, 75.15; H, 8.06; N, 3.37. Found: C, 75.26; H, 6.05; N, 3.40.
2
6
25
2
6
,11-Dihydro-2,3-dimethoxy-11-(pyrrol-2-yl)[1]benzothiopyrano[2,3-b]indole (7b)

1
This compound was obtained as a light red viscous liquid. H NMR (CDCl ) δ 3.92 (s, 3H), 3.95 (s, 1H,
3
H-11), 3.98 (s, 3H), 6.38 (d, J=1.1 Hz, 1H), 6.80 (s, 1H), 6.90 (dd, J=7.5, 8.0 Hz, 1H), 7.12 (d, J=1.1 Hz,
1
H), 7.28–7.35 (m, 3H), 7.39 (s, 1H), 7.69 (dd, J=2.1, 8.0 Hz, 1H), 8.01 (br s, 1H NH), 8.16 (br s, 1H,
1
3
NH). C NMR (CDCl ) δ 41.5, 55.9, 56.0, 107.3, 108.5, 110.9, 111.8, 114.9, 117.5, 118.3, 120.5, 121.2,
3
1
23.5, 126.8, 130.1, 131.9, 138.1, 152.1, 153.1. Anal. Calcd for C H N O S: C, 69.59; H, 5,01; N, 7.73.
21 18 2 2
Found: C, 69.56; H, 4.96; N, 7.78.
6
,11-Dihydro-2,3-dimethoxy-11-(thien-2-yl)[1]benzothiopyrano[2,3-b]indole (7c)
1
This compound was obtained as a yellow viscous oil. H NMR (CDCl ) δ 3.98 (s), 4.01 (s, 1H, H-11),
3
4
7
3
1
3
.02 (s, 3H), 6.18 (s, 1H), 6.90 (s, 1H), 7.03 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.16 (dd, J=7.8, 8.0 Hz, 1H),
1
3
.27–7.30 (m, 2H), 7.49 (s, 1H), 7.80 (dd, J=2.5, 8.0 Hz, 1H), 8.06 (br s, 1H, NH). C NMR (CDCl ) δ
3
8.9, 54.5, 56.3, 107.5, 109.1, 110.9, 111.3, 115.0, 117.3, 118.9, 120.8, 121.1, 123.2, 126.3, 130.1, 131.3,
39.3, 154.1, 155.0. Anal. Calcd for C H NOS : C, 66.46; H, 4.52; N, 3.69. Found: C, 66.42; H, 4.58; N,
2
1
17
2
.81.
General Procedure for the Preparation of Thiopyrano[2,3-b]indole-2,3-dicarboxylic Acid Dimethyl
Esters (9)
To a well stirred solution of a diasteromeric mixture of 4 and 5 (0.35 mmol) in dry MeCN (5 mL)
contained in a round bottom flask fitted with a reflux condenser under argon atmosphere, a solution of
dimethyl acetylenedicarboxylate (0.25 g, 1.7 mmol) in MeCN (1 mL) was added through a needle syringe
system. The mixture was heated to reflux for 6 h then cooled to rt. The solvent was removed under
reduced pressure to afford he crude product (9) which was purified by column chromatography using
SiO with EtOAc-hexane (1:4, v/v).
2
1
,5-Dihydro[1](4-isopropylphenyl)thiopyrano[2,3-b]indole-2,3-dicarboxylic Acid Dimethyl Ester
9a)
This compound was obtained as a light red viscous oil. H NMR (CDCl ) δ 1.19 (d, J=8.0 Hz, 6H), 2.82
(
1
3
(
m, 1H), 3.69 (s, 3H), 3.87 (s, 3H), 4.16 (s, 1H, vinylic-H, H-9), 7.03 (dd, J=7.8, 8.0 Hz, 1H), 7.11 (d,
1
3
J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.20–7.28 (m, 3H), 8.01 (br s, 1H, NH). C NMR (CDCl ) δ 24.3,
3
3
1
1
4.1, 43.5, 52.9, 53.7, 109.9, 110.8, 118.3, 120.7, 122.7, 123.3, 127.2, 128.0, 128.3, 129.2, 134.2, 137.6,
48.7, 164.2. Anal. Calcd for C H NO S: C, 68.39; H, 5.50; N, 3.32. Found: C, 68.45; H, 5.53; N, 3.29.
2
4
23
4
,5-Dihydro-9-pyrrol-2-ylthiopyrano[2,3-b]indole-2,3-dicarboxylic Acid Dimethyl Ester (9b)
1
This compound was obtained as a light red viscous oil. H NMR (CDCl ) δ 3.79 (s, 3H), 3.8 (s, 3H), 4.71
3
(
s, 1H, vinylic-H, H-9), 6.61 (s, 1H), 6.98 (d, J=1.1 Hz, 1H), 7.07 (dd, J=7.8, 8.0 Hz, 1H), 7.08 (dd, J=7.8,
8
.0 Hz, 1H), 7.19 (d, J=1.1 Hz, 1H), 7.31-7.39 (m, 2H), 8.02 (br s, 1H, NH), 8.12 (br s, 1H, NH).
1
3
C NMR (CDCl ) δ 36.6, 53.2, 53.7, 107.2, 108.6, 110.9, 118.2, 118.5, 121.0, 123.0, 165.0, 165.1. Anal.
3
Calcd for C H N O S: C, 61.94; H, 4.38; N, 7.60. Found: C, 61.98; H, 4.37; N, 7.69.
1
9
16
2
4

1
,5-Dihydro[1](4-N,N-dimethylaminophenyl)thiopyrano[2,3-b]indole-2,3-dicarboxylic Acid Di-
methyl Ester (9c)
This compound was obtained as colorless oil. H NMR (CDCl ) δ 2.86 (s, 6H), 3.71 (s, 3H), 3.82 (s, 3H),
1
3
4
.26 (s, 1H, vinylic-H, H-9), 7.02 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H),
1
3
7
.30–7.38 (m, 3H), 8.16 (br s, 1H, NH). C NMR (CDCl ) δ 24.3, 43.2, 52.8, 53.6, 109.8, 110.8, 119.3,
3
1
21.6, 122.6, 123.3, 126.9, 127.9, 128.3, 129.2, 134.2, 137.6, 147.9, 165.1. Anal. Calcd for C H N O S:
2
3
22
2
4
C, 65.38; H, 5.25; N, 6.63. Found: C, 65.42; H, 5.27; N, 6.60.
1
,5-Dihydro-9-thien-2-ylthiopyrano[2,3-b]indole-2,3-dicarboxylic Acid Dimethyl Ester (9d)
°
1
This compound was obtained as a light orange solid (CH Cl -hexane), mp 150–153 C. H NMR
2
2
(
CDCl ) δ 3.78 (s, 3H), 3.86 (s, 3H), 4.16 (s, 1H, H-9), 7.04–7.18 (m, 3H), 7.28 (dd, J=7.8 Hz, 8.0 Hz,
3
1
H), 7.37 (dd, J=2.1, 7.8 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 8.05 (br s, 1H, NH).
1
3
C NMR (CDCl ) δ 37.9, 53.2, 53.8, 109.5, 110.1, 118.0, 120.8, 121.9, 122.9, 125.3, 125.6, 126.0, 127.1,
3
1
30.4, 131.5, 137.7, 145.8, 165.4, 167.1. Anal. Calcd for C H NO S: C, 61.78; H, 4.09; N, 3.79. Found:
1
9
15
5
C, 61.89; H, 4.18; N, 3.85.
9
-Furan-2-yl-1,5-Dihydrothiopyrano[2,3-b]indole-2,3-dicarboxylic Acid Dimethyl Ester (9e)
1
This compound was obtained as a tan viscous oil. H NMR (CDCl ) δ 3.77 (s, 3H), 3.87 (s, 3H), 3.89 (s,
3
1
H, H-9), 6.99 (d, J=5.6 Hz, 1H), 7.24 (d, J=5.6 Hz, 1H), 7.32 (dd, J=7.8, 8.0 Hz, 1H), 7.36 (dd, J
1
3
=
7.8, 8.0 Hz, 1H), 7.48 (m, 2H), 7.54 (dd, J=1.5, 7.8 Hz, 1H), 8.17 (br s, 1H, NH). C NMR (CDCl ) δ
3
3
7.0, 53.2, 53.8, 106.9, 107.1, 110.7, 111.0, 118.2, 120.8, 122.2, 122.8, 126.3, 129.8, 131.0, 137.6, 142.6,
1
53.7, 165.2, 167.2. Anal. Calcd for C H NO S: C, 61.78; H, 4.09; N, 3.79. Found: C, 61.78; H, 4.08;
2
1
17
3
N, 3.80.
ACKNOWLEDGEMENTS
This work was sponsored in part by a grant from the Robert Welch Foundation, Houston, TX, U. S. A.
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