Improved preparation of sulfur substituted 3-vinylpyrrole and its application to the syntheses of chuangxinmycin derivatives

Article abstract of DOI:10.1248/cpb.49.1198

Sulfur substituted 3-vinylpyrrole 10 was prepared from 3-thio-acetylpyrrole 9 by alkylation with alkyl halide in the presence of propylene oxide. Functionalized 4-alkylthioindoles were made by Diels-Alder reaction of the 3-vinylpyrrole 10 with dienophiles

Full text of DOI:10.1248/cpb.49.1198

1198
Notes
Chem. Pharm. Bull. 49(9) 1198—1202 (2001)
Vol. 49, No. 9
Improved Preparation of Sulfur Substituted 3-Vinylpyrrole and Its
Application to the Syntheses of Chuangxinmycin Derivatives
Takuji YOSHIDA, Ai ITO, Kei IBUSUKI, Masayuki MURASE,* and Eiichi KOTANI
Showa Pharmaceutical University, Machida, Tokyo 194–8543, Japan. Received March 12, 2001; accepted June 3, 2001
Sulfur substituted 3-vinylpyrrole 10 was prepared from 3-thio-acetylpyrrole 9 by alkylation with alkyl
halide in the presence of propylene oxide. Functionalized 4-alkylthioindoles were made by Diels–Alder reaction
of the 3-vinylpyrrole 10 with dienophiles. Chuangxinmycin analogues were synthesized by using some of the
functionalized 4-alkylthioindoles as key intermediates.
Key words cycloaddition; 3-vinylpyrrole; alkylation; indole; 3-thioacetylpyrrole; propylene oxide
The Diels–Alder (D–A) reaction is one of the most useful atives Chuangxinmycin 1, isolated from the microorganism
reactions in synthetic organic chemistry. Recently, we re- Actinoplanes tsinanensis n. sp. of China,6) is an antibiotic al-
ported that thiocarbonyl compounds 2, 4, and 6 yielded di- kaloid bearing a sulfur substituent at the 4-position of the in-
enes 3, 5, and 7, respectively, through alkylation reactions, dole nucleus. This compound is known to be active against a
and these dienes underwent Diels–Alder reaction with appro- variety of Gram-positive and Gram-negative bacteria and is
priate dienophiles to give functionalized carbazoles, indoles, particularly effective in the treatment of Escherichia coli in-
and benzene derivatives.1—3) Previously, we found that 4- fections.7)
thioxo-4,5,6,7-tetrahydroindole 8, having a thioenaminone
Total synthesis of 1 has already been reported by several
moiety, gave dehydrochuangxinmycin through alkylation.4) groups.8) We also have reported two routes of formal synthe-
We also found that the cycloaddition reaction of N-methyl-3- sis.4,9) Our attention has now been focused on the synthesis
vinylpyrrole 5 proceeded smoothly, whereas the NH con- of Chuangxinmycin derivatives from the indole 11c.
gener 9 gave no cycloaddition product. This may be due to
the lability of vinylpyrrole 10, and the result was not investi- readily achieved by SnCl4-catalyzed Friedel–Crafts reaction
gated further. with acetyl chloride (quantitative yield). Compound 13 was
Acylation of 11c, leading to the 3-acetyl derivative 13, was
This paper describes an improved synthesis of sulfur sub- then heated in benzene in the presence of ammonium acetate
stituted 3-vinylpyrroles 10 and their application to the syn- monohydrate and acetic acid for 15 h to give 7,8-disubsti-
theses of chuangxinmycin having various substituents. In tuted dehydrochyangxinmycin methyl ester 14 in 65.6%
1978, E. J. Cory et al. reported the utility of intramolecular yield.
Diels–Alder reaction using propylene oxide as a hydrogen
The ester 14 could not be reduced with Mg–methanol.
We then examined the synthesis of the nor-methyl deriva-
chloride scavenger in the synthesis of gibberellic acid.5) The
application of propylene oxide as a scavenger prompted us to tive 17. Indole 11c was converted to 3-formyl derivative 15
examine its use in the preparation of 3-vinylpyrrole 10 from by the Vilsmeier reaction. Subsequently, without isolating 15,
3-thioacetylpyrrole 9 and alkyl halide. A preliminary study it was treated with NH4OAc in AcOH to give the cyclized
was done on the reaction of 10a, generated in situ by the re- product 16 in 51.6% yield. Reduction of 16 with Mg–
action of 3-thioacetylpyrrole 9 with methyl iodide in the
presence of a large excess of propylene oxide, with dimethyl
acetylenedicarboxylate (DMAD) in tetrahydrofuran (THF).
The indole 11a was indeed obtained in 20% overall yield.
Similarly, the reactions of 10b and 10c, generated in situ
with benzyl bromide and methyl bromoacetate, with DMAD,
gave the indoles 11b and 11c, in 17.2 and 27.3% yields re-
spectively. Figure 2 proposes a possible mechanism for the
generation of dienes 10. Reaction of the diene 10c with N-
methylmaleimide at 110 °C for 8 h, followed by treatment
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) for
30 min, gave the indole 12a in 27.3% yield. Similarly, the
reaction of the diene 10c with 3,4-dibromo-N-methyl-
maleimide in THF at room temperature for 8 h, followed by
direct in situ oxidation, gave 12a in 36.5% yield.
In general, the cycloaddition reaction of vinylpyrroles 10
with dienophiles were carried out in a fused glass tube at
100 °C under nitrogen for approximately 8 h. The results are
summarized in Table 1. The indoles 11c and 12a are the key
intermediates in the syntheses of substituted chuangxinmycin
derivatives.
Fig. 1
Synthesis of 7,8-Disubstituted Chuangxinmycin Deriv-
To whom correspondence should be addressed. e-mail: murase@ac.shoyaku.ac.jp
© 2001 Pharmaceutical Society of Japan

September 2001
1199
Fig. 2
Table 1. Cycloaddition Reaction of the Diene with Dienophiles
Entry
1)
Diene
10a
Dienophile
Temp. (°C)
Time (h)
Product
11a
Yield (%)a)
110
110
110
24
24
8
20
2)
10b
11b
17.2
27.3
3)
10c
11c
4)
5)
10c
10c
110
r.t.c)
8
8
12ab)
33.8
36.5
12a
6)
10c
r.t.
8
12b
33.7
a) Overall yield from 3-acetylpyrrole. b) Obtained by the oxidation of the cycloaddition product without purification. c) r.t., room temperature.
methanol gave 7,8-disubstituted nor-methylchuangxinmycin
We then examined the reduction of the olefinic bond of the
derivative 17 in 49.1% yield (Fig. 3).
unsaturated acid moiety of 22a and 22b with Mg–methanol.
Next, the synthesis of nor-methyl derivatives 22 from in- However, the desired product could not be obtained, probably
doles 12 was examined. Vilsmeier reaction of 12a with DMF because of the insolubility of 22a and 22b. Thus, 22a and
in the presence of POCl3 gave a mixture of 18a and 19a. This 22b were synthesized in 5 steps from 3-acetylpyrrole utiliz-
mixture was refluxed in DMF in the presence of ammonium ing propylene oxide. 3-Vinylpyrroles 10 can be prepared
acetate monohydrate and acetic acid for 6 h to give 19a in readily. Moreover, the Diels–Alder reaction of 10 with
68% yield. Compound 12b was allowed to react in a similar dienophiles provides functionalized 4-alkylthioindoles. Stud-
manner to give 19b in 88% yield. The reduction of the dou- ies on the antimicrobial activity of their derivatives are still in
ble bond of 19b has been found to be a troublesome problem. progress.
The reduction of the C–C double bond on vinyl sulfide
tended to accompany rapid desulfurization. Though the hy-
drogenation of 19b over palladium/charcoal did not proceed,
Experimental
All melting points (mp) were determined using a Yanagimoto micromelt-
ing point apparatus and are uncorrected. Infrared (IR) spectra were recorded
with a JASCO IR-700 spectrometer. 1H- and 13C-NMR spectra were ob-
tained on JNM-GX90, JNM-GX270 and JNM-a500 spectrometers. The
chemical shifts are given in ppm (d), and tetramethylsilane was used as an
internal standard (CDCl3, acetone-d6, DMSO-d6). Mass spectra were
recorded on JEOL JMS-D300, JMS-HX110, and Shimadzu QP-5000 spec-
trometers. Wako silica gel C-200 (200 mesh), and Fuji Silysia silica gel BW-
127 ZH, were used for column chromatography. Thin-layer chromatography
(TLC) was done on Merck Kieselgel 60F254, and spots were detected by ul-
reduction with NaBH4–NiCl2 led to rapid desulfurization
with the formation of 3-substituted-indole 21b. On the other
hand, reduction with Mg–MeOH proceeded with the cleav-
age of the C ring to furnish thiol 20b. Treatment of 19b with
LiI in pyridine afforded the hydrolyzed product 22b in 90.3%
yield. Similarly, 19a gave 22a in 81.5% yield under the same
condition.

1200
Vol. 49, No. 9
Fig. 3
1H-NMR (CDCl3) d: 3.73 (3H, s, CO2Me), 3.83 (2H, s, –SCH2), 3.93 (3H, s,
CO2Me), 3.95 (3H, s, CO2Me), 6.67—6.74 (1H, m, C-3H), 7.22 (1H, s, C-
5H), 7.36—7.42 (1H, m, C-2H), 9.79 (1H, br, NH). MS m/z: 337 (Mϩ).
Dimethyl-3-acetyl-4-methoxycarbonylmethylthio-1H-indole-6,7-dicar-
boxylate (13) SnCl4 (78 mg, 0.3 mmol) was slowly added to a solution of
11c (100 mg, 0.297 mmol) and acetyl chloride (24 mg, 0.3 mmol) in dry ben-
zene (5 ml), with stirring at 0 °C. Stirring was continued for 20 min at ambi-
ent temperature. Then, the whole mixture was stirred at room temperature
for 2 h more. The reaction mixture was poured into water, then extracted
with CHCl3. The organic layer was washed with saturated aqueous NaHCO3
and brine, then dried and concentrated.
traviolet (UV) illumination and by spraying 1% Ce(SO4)4 in 10% H2SO4,
followed by heating. The organic extract was dried over Na2SO4. THF was
distilled from sodium/benzophenone under nitrogen before use.
Preparation of the Diene 10 A mixture of 9, alkyl halide and propylene
oxide was heated in a fused glass tube under nitrogen atmosphere under ap-
propriate conditions to give the diene 10, which was used without purifica-
tion for the reaction with dienophiles under the condition mentioned in
Table 1.
Dimethyl-4-methylthio-1H-indole-6,7-dicarboxylate (11a) A mixture
of 9 (375 mg, 3 mmol), methyl iodide (1.278 g, 9 mmol), and propylene
oxide (2 ml) in dry THF (6 ml) was heated at 55 °C for 4 h in a fused glass
tube under nitrogen. The solvent was removed under reduced pressure. A so-
lution of DMAD (511 mg, 3.6 mmol) in dry THF (4 ml) was added to the
residue, and the mixture was heated at 110 °C for 24 h in a fused glass tube
under nitrogen. The reaction mixture was poured into water and extracted
with CHCl3. The organic layer was washed with brine, dried, and evaporated
in vacuo. The residue was subjected to silica gel column chromatography to
yield 167 mg (20%) of 11a from the chloroform eluate as colorless needles
The addition of ether to the concentrate caused the precipitation of 13,
which was separated through filtration. Recrystallization of the solid from
CH2Cl2–ether gave a quantitative yield of 13 as colorless needles. mp 182—
1
184 °C. 13: H-NMR (CDCl3) d: 2.57(3H, s, –Ac), 3.75 (3H, s, CO2Me),
3.82 (2H, s, –CH2–), 3.94 (3H, s, CO2Me), 3.95 (3H, s, CO2Me), 7.17 (1H,
s, C-5H), 7.92 (1H, d, Jϭ3.07 Hz, C-2H), 10.41(1H, br, NH). MS m/z: 379
(Mϩ).
1
(ether–hexane), mp 120—122 °C. 11a: H-NMR (CDCl3, 270 MHz) d: 2.62
9,10-Dimethoxycarbonyldehydrochuangxinmycin Methyl Ester (14)
A mixture of 13 (40 mg, 0.118 mmol), NH4OAc·H2O (360 mg, 4.74 mmol),
and acetic acid (510 mg, 10.68 mmol) in 3 ml of benzene and 3 ml of THF
was heated at 110 °C for 24 h in a fused glass tube. The reaction mixture was
cooled, poured into water, and extracted with CHCl3. The extract was dried
and evaporated, and the residue was chromatographed on silica gel with
CHCl3 as the eluent to yield 25 mg (65.6%) of 14 as yellow crystals. mp
(3H, s, –SMe), 3.94 (3H, s, CO2Me), 3.95 (3H, s, CO2Me), 6.63—6.69 (1H,
m, C-3H), 6.99 (1H, s, C-5H), 7.32—7.39 (1H, m, C-2H), 9.80 (1H, br,
NH). MS m/z: 279 (Mϩ).
Dimethyl-4-benzylthio-1H-indole-6,7-dicarboxylate (11b) A mixture
of 9 (375 mg, 3 mmol), benzyl chloride (419.1 mg, 3.3 mmol), and propylene
oxide (2 ml) in dry THF (6 ml) was heated at 55 °C for 4 h in a fused glass
tube under nitrogen. The solvent was removed under reduced pressure. A so-
lution of DMAD (511 mg, 3.6 mmol) in dry THF (4 ml) was added to the
residue, and the mixture was heated at 110 °C for 24 h in a fused glass tube
under nitrogen. The reaction mixture was poured into water and extracted
with CHCl3. The organic layer was washed with brine, dried, and evaporated
in vacuo. The residue was subjected to silica gel column chromatography to
yield 183 mg (17.2%) of 11b from the chloroform eluate as colorless nee-
dles (ether–hexane), mp 128—129 °C. 11b: 1H-NMR (acetone-d6, 270 MHz)
d: 3.85 (3H, s, CO2Me), 3.92 (3H, s, CO2Me), 4.42 (2H, s, benzyl H),
6.63—6.69 (1H, m, C-3H), 7.25—7.59 (7H, m, aromatic H), 10.79 (1H, br,
NH). MS m/z: 355 (Mϩ). High resolution (HR)-MS Calcd for C19H17NO4S:
355.0877. Found: 355.0857.
Dimethyl-4-methoxycarbonylmethylthio-1H-indole-6,7-dicarboxylate
(11c) A mixture of 9 (375 mg, 3 mmol), methyl bromoacetate (504.9 mg,
3.3 mmol), and propylene oxide (2 ml) in dry THF (6 ml) was heated at
110 °C for 8 h in a fused glass tube under nitrogen. The solvent was removed
under reduced pressure. A solution of DMAD (511 mg, 3.6 mmol) in dry
THF (4 ml) was added to the residue, and the mixture was heated at 110 °C
for 8 h in a fused glass tube under nitrogen. After the usual work up, the
crude product was subjected to silica gel column chromatography to yield
276 mg (27.3%) of 11c from the chloroform eluate as a brown liquid. 11c:
1
199—201 °C (ether–benzene). 14: H-NMR (CDCl3) d: 2.44(3H, s, –Me),
3.84 (3H, s, CO2Me), 3.90 (3H, s, CO2Me), 3.92 (3H, s, CO2Me), 6.62 (1H,
s, C-8H), 7.16 (1H, d, Jϭ2.14 Hz, C-2H), 9.52(1H, br, NH). MS m/z: 361
(Mϩ). HR-MS Calcd for C17H15NO6S: 361.0620. Found: 361.0633.
Nor-methyl-9,10-dimethoxycarbonyldehydrochuangxinmycin Methyl
Ester (16) POCl3 (0.28 ml) was slowly added to dry DMF (0.9 ml) at 0 °C,
with stirring under nitrogen. After 10 min, a solution of 11c (480 mg, 1.4
mmol) in THF (0.5 ml) was added, and the mixture was stirred at 35 °C for
1 h. The reaction mixture was poured into ice-water, 40% aq. NaOH (2 ml)
was added, then acidified with 10% HCl to pH 3 and extracted with AcOEt.
The extract was dried and evaporated in vacuo to give 15. A solution con-
taining 15, NH4OAc (485 mg, 6.3 mmol) and AcOH (756 mg, 12.6 mmol) in
DMF (20 ml) was heated at 100 °C for 1 h and then cooled to room tempera-
ture. The reaction mixture was poured into ice water and extracted with
AcOEt. The organic layer was washed with brine, dried, and evaporated in
vacuo. The residue was chromatographed over silica gel (AcOEt–hexane,
1 : 3) to give 16 (251 mg, 51.6%) as yellow needles. mp 228.5—229.5 °C.
16: IR (KBr) cmϪ1: 1726, 1703. 1H-NMR (CDCl3, 500 MHz) d: 3.65 (3H, s,
–CO2CH3), 3.90 (3H, s, –CO2CH3), 3.91 (3H, s, –CO2CH3), 6.62 (1H, s, C-
8H), 7.10 (1H, d, Jϭ2.2 Hz, C-2H), 7.66 (1H, s, C-4H), 9.50 (1H, br, NH).
HR-MS Calcd for C16H13NO3S: 347.0449. Found: 347.0469. MS m/z: 347

September 2001
1201
(Mϩ).
was poured into ice-water, neutralized with 40% aq. NaOH, and the resultant
precipitate was collected, washed with water, and dried to give a mixture of
18b and 19b (906 mg). A solution of 18b, 19b, NH4OAc (751 mg, 9.77
Nor-methyl-9,10-dimethoxycarbonylchuangxinmycin Methyl Ester
(17) Magnesium turning (49 mg, 2.04 mmol) was added to a mixture of 16
(59 mg, 0.17 mmol) and NH4Cl (445 mg, 10 mmol) in MeOH (1 ml), and the mmol) and AcOH (1.17 g, 19.53 mmol) in DMF (13 ml) was heated to reflux
resultant mixture was stirred at room temperature for 3 h. Then, 6 N HCl was
added to the reaction mixture and the mixture was extracted with CHCl3.
The organic layer was washed with brine, dried, and evaporated in vacuo.
for 5 h and then cooled to room temperature. The reaction mixture was
poured into ice-water and extracted with AcOEt. The organic layer was
washed with brine, dried, and concentrated in vacuo. The residue was re-
The residue was chromatographed over silica gel (ether–hexane, 1 : 2) to crystallized from acetone to give 19b (746 mg, 88.2%) as dark reddish
1
give 17 (29 mg, 49.1%) as a colorless liquid. 17: IR (KBr) cmϪ1: 1725. H- brown needles. mp 266—268 °C. 19b: IR (KBr) cmϪ1: 1740, 1692, 1576.
NMR (CDCl3, 270 MHz) d: 3.37 (1H, ddd, Jϭ15.8, 8.5, 1.2 Hz, C-4aH),
1H-NMR (DMSO-d6, 500 MHz) d: 3.77 (3H, s, –CO2CH3), 4.70 (2H, s,
3.47 (1H, dd, Jϭ15.8, 4.0 Hz, C-4bH), 3.75 (3H, s, –CO2CH3), 3.92 (3H, s, –CH2–), 6.94 (1H, s, C-6H), 7.25—7.35 (5H, m, aromatic H), 7.43 (1H, d,
–CO2CH3), 3.95 (3H, s, –CO2CH3), 4.20 (1H, dd, Jϭ8.5, 4.0 Hz, C-5H), Jϭ2.4 Hz, C-2H), 7.59 (1H, s, C-3H), 12.28 (1H, br, NH). 13C-NMR
7.05 (1H, s, C-8H), 7.15 (1H, d, Jϭ1.2 Hz, C-2H), 9.37 (1H, br, NH). MS (DMSO-d6, 125 MHz) d: 40.4, 52.6, 107.0, 111.1, 113.1, 120.7, 125.9,
m/z: 249 (Mϩ).
126.9, 127.1, 127.2, 127.9, 128.5, 130.4, 130.5, 136.9, 163.0, 166.8, 168.0.
7-Methyl-4-methoxycarbonylmethylthiopyrrolo[3,4-g]-1H-indole-6,8- HR-MS Calcd for C21H14N2O4S: 390.0674. Found: 390.0679. MS m/z: 390
dione (12a) Method a): A solution of 9 (500 mg, 4 mmol), methyl bro- (Mϩ).
moacetate (734 mg, 4.8 mmol), and propylene oxide (1.22 ml) in dry CH3CN
(10 ml) was heated at 110 °C for 8 h in a fused glass tube under nitrogen.
7-Benzyl-3-methoxycarbonylvinyl-4-mercaptopyrrolo[3,4-g]-1H-in-
dole-6,8-dione (20b) Magnesium turning (486 mg, 20 mmol) was added to
Then, N-methylmaleimide (532 mg, 4.8 mmol) was added to the reaction a mixture of 19b (195 mg, 0.5 mmol) and NH4Cl (445 mg, 10 mmol), in dry
mixture and heated at 110 °C for 8 h in a fused glass tube under nitrogen. THF (29 ml) and MeOH (24 ml), and the resultant mixture was stirred at
The solvent was removed under reduced pressure. The residue was treated room temperature for 30 min. A saturated NH4Cl solution was added to the
with DDQ (908 mg, 4 mmol) and the whole was stirred at room temperature reaction mixture and the mixture was extracted with AcOEt. The organic
for 30 min, then concentrated. CHCl3 was added to the residue, and insolu- layer was washed with brine, dried, and evaporated in vacuo. The residue
ble materials were filtered off. The filtrate was evaporated.
was recrystallized from THF to give 20b (126 mg, 64.3%) as yellow needles.
The residue was recrystallized from acetone to yield 411 mg (27.3%) of mp 226—228 °C. 20b: IR (KBr) cmϪ1: 1665, 1439, 1261. 1H-NMR
12a as yellow needles. Method b): A solution of 9 (250 mg, 2 mmol), methyl (DMSO-d6, 270 MHz) d: 3.38 (3H, s, Me), 4.59 (2H, ABq, Jϭ15.57, 15.57
bromoacetate (335 mg, 2.2 mmol), and propylene oxide (2 ml) in dry THF (6
Hz, –CH2–), 5.54 (1H, d, Jϭ8.9 Hz, olefinic H), 6.65 (1H, d, Jϭ8.9 Hz
ml) was heated at 80 °C for 2 d in a fused glass tube under nitrogen. The sol- olefinic H), 6.74 (1H, s, C-5H), 7.22—7.37 (5H, m, aromatic H), 7.65 (1H,
vent was removed under reduced pressure. A solution of 3,4-dibromo-N- s, C-2H), 11.97 (1H, br, NH). 13C-NMR (DMSO-d6, 125 MHz) d: 41.8,
methylmaleimide (2.9 g, 10.8 mmol) in dry THF (12 ml) was added to the 52.5, 80.6, 107.7, 112.2, 112.5, 120.0, 123.7, 126.9, 127.4, 127.9, 128.4ϫ2,
residue and the mixture was stirred at room temperature for 8 h. After the re- 133.1, 137.9, 144.8, 163.3, 165.5. HR-MS Calcd for C21H16N2O4S:
action, saturated aqueous NaHCO3 was added, and the reaction mixture was 392.0831. Found: 392.0845. MS m/z: 392 (Mϩ).
extracted with AcOEt. The organic layer was washed with brine, then dried
7-Benzyl-3-methoxycarbonylethylpyrrolo[3,4-g]-1H-indole-6,8-dione
and concentrated. Acetone was added to the concentrate, the insoluble mate- (21b) NiCl2·6H2O (35.7 mg, 0.15 mmol) and NaBH4 (56.7 mg, 1.5 mmol)
rial was filtered off, and the mother liquor was evaporated to dryness. The were added to a solution of 19b (39 mg, 1 mmol) in MeOH (70 ml) at 0 °C,
residue was recrystallized from acetone to yield 222 mg (36.5%) of 12a as and the mixture was stirred at the same temperature for 5 min. Saturated
yellow needles. mp 212.5—214 °C. 12a: IR (KBr) cmϪ1: 3284, 1741, 1683. NH4Cl solution was added to the reaction mixture and the mixture was ex-
1H-NMR (CDCl3, 270 MHz) d: 3.17 (3H, s, N–Me), 3.75 (3H, s, CO2Me), tracted with AcOEt. The organic layer was washed with brine, dried, and
3.88 (2H, s, –CH2–), 6.78 (1H, dd, Jϭ3.3, 2.2 Hz, C-3H), 7.47 (1H, dd,
evaporated in vacuo. The residue was chromatographed over silica gel
Jϭ3.3, 2.2 Hz, C-2H), 7.50 (1H, s, C-5H), 9.42 (1H, br, NH). HR-MS Calcd (AcOEt–hexane, 1 : 3) to give 21b (30.1 mg, 83.1%) as yellow needles. mp
for C16H12N2O4S: 304.0516. Found: 304.0516. MS m/z: 304 (Mϩ).
153—155 °C. 21b: IR (KBr) cmϪ1: 1760, 1736, 1695. H-NMR (CDCl3, 90
1
7-Benzyl-4-methoxycarbonylmethylthiopyrrolo[3,4-g]-1H-indole-6,8- MHz) d: 2.70 (2H, t, Jϭ4.7 Hz, –CH2–), 3.11 (2H, t, Jϭ4.7 Hz, –CH2–),
dione (12b) A mixture of the diene 10c and 3,4-dibromo-N-benzyl- 3.66 (3H, s, Me), 4.84 (2H, s, benzyl H), 7.24—7.45 (6H, m, aromatic H
maleimide (759 mg, 2.2 mmol) in dry THF (3 ml) was treated as described and C-2H), 7.56 (1H, d, Jϭ7.9 Hz, C-4H), 7.85 (1H, d, Jϭ7.9 Hz, C-5H),
for 12a to give 12b (256 mg, 33.7%) as yellow needles. mp 179—181 °C. 9.02 (1H, br, NH). HR-MS Calcd for C21H18N2O4: 362.1266. Found:
1
12b: IR (KBr) cmϪ1: 1739, 1680, 1429. H-NMR (DMSO-d6, 500 MHz) d: 362.1295. MS m/z: 362 (Mϩ).
3.66 (3H, s, N–Me), 4.23 (2H, s, –SCH2–), 4.78 (2H, s, –CH2Ph), 6.69 (1H,
4-Carboxy-3,4-dehydro-8-methylpyrrolo[3,4-g]thiopyrano[4,3,2-cd]-
1H-indole-7,9-dione (22a) Dry-LiI (540 mg, 3.6 mmol) was added to a so-
dd, Jϭ3.2, 1.7 Hz, C-3H), 7.25—7.36 (5H, m, aromatic H), 7.40 (1H, s, C-
5H), 7.69 (1H, t, Jϭ1.8 Hz, C-2H), 12.88(1H, br, NH). 13C-NMR (DMSO- lution of 19a (56.4 mg, 0.18 mmol) in dry pyridine (15 ml), and the mixture
d6, 125 MHz) d: 33.1, 40.6, 52.5, 101.4, 110.1, 112.1, 126.3, 127.6, 131.4,
was heated under reflux for 8 h. The reaction mixture was poured into ice-
131.8, 135.0, 137.1, 167.6, 168.7, 169.5. HR-MS Calcd for C20H16N2O4S: water, its pH adjusted to 1, and it was then extracted with AcOEt. The or-
380.0830. Found: 380.0829. MS m/z: 380 (Mϩ).
ganic layer was washed with brine, then dried and evaporated. The residue
3,4-Dehydro-4-methoxycarbonyl-8-methylpyrrolo[3,4-g]thiopyrano-
was recrystallized from THF to give 22a (44 mg, 81.5%) as dark reddish
1
[4,3,2-cd]-1H-indole-7,9-dione (19a) POCl3 (1.11 ml) was slowly added brown needles. mp Ͼ300 °C. 22a: IR (KBr) cmϪ1: 1754, 1690, 1574. H-
to dry DMF (3.67 ml) at 0 °C, with stirring under nitrogen. After 10 min, a NMR (DMSO-d6, 270 MHz) d: 2.97 (3H, s, Me), 6.91 (1H, s, C-6H), 7.04—
solution containing 12a (884 mg, 2.78 mmol) in dry DMF (11.1 ml) was
7.42 (1H, m, C-2H), 7.55 (1H, s, C-3H). 13C-NMR (DMSO-d6, 125 MHz) d:
added, and the mixture was stirred at 35 °C for 2 h. The reaction mixture was 23.3, 106.6, 111.3, 113.3, 122.4, 125.1, 126.8, 127.0, 130.3, 130.7, 136.5,
poured into ice-water, neutralized with 40% aq. NaOH, and the resultant 164.2, 167.2, 168.4. HR-MS Calcd for C14H8N2O4S1: 300.0204. Found:
precipitate was collected, washed with water, and dried to give a mixture of 300.0178. MS m/z: 300 (Mϩ).
18a and 19a (906 mg). A solution of 18a, 19a, NH4OAc (962 mg, 12.5
4-Carboxy-3,4-dehydro-8-benzylpyrrolo[3,4-g]thiopyrano[4,3,2-cd]-
mmol), and AcOH (1.5 g, 25 mmol) in DMF (16.7 ml) was heated to reflux 1H-indole-7,9-dione (22b) Dry-LiI (883 mg, 6.6 mmol) was added to a
for 6 h and then cooled to room temperature. The reaction mixture was solution of 19b (130 mg, 0.33 mmol) in dry pyridine (15 ml), and the mix-
poured into ice-water and the resultant precipitate was collected, washed ture was heated under reflux for 8 h. The reaction mixture was poured into
with water, dried, and recrystallized from THF to give 602 mg (69%) of 19a
ice-water, its pH adjusted to 1, and it was then extracted with AcOEt. The
as deep green needles. mp Ͼ300 °C. 19a: IR (KBr) cmϪ1: 1750, 1709, 1693. organic layer was washed with brine, then dried and evaporated. The residue
1H-NMR (acetone-d6, 500 MHz) d: 3.11 (3H, s, N–Me), 3.86 (3H, s, was recrystallized from THF to give 22b (112 mg, 90.3%) as dark reddish
–CO2CH3), 6.98 (1H, s, C-6H), 7.17 (1H, d, Jϭ2.4 Hz, C-2H), 7.62 (1H, s,
C-3H), 10.58 (1H, br, NH). HR-MS Calcd for C15H10N2O4S: 314.0361.
Found: 314.0369. MS m/z: 314 (Mϩ).
1
brown needles. mp Ͼ300 °C. 22b: IR (KBr) cmϪ1: 1755, 1680, 1572. H-
NMR (DMSO-d6, 500 MHz) d: 4.71 (2H, s, –CH2–), 6.97 (1H, s, C-6H),
7.25—7.35 (5H, m, aromatic H), 7.44 (1H, d, Jϭ2.4 Hz, C-2H), 7.57 (1H, s,
C-3H), 12.25 (1H, br, NH). 13C-NMR (DMSO-d6, 125 MHz) d: 40.5, 107.0,
111.1, 113.5, 122.9, 125.3, 126.9, 127.0, 127.2, 127.3, 128.6, 130.6, 130.7,
137.0, 137.3, 164.3, 166.9, 168.2. HR-MS Calcd for C20H12O4N2S1:
3,4-Dehydro-8-benzyl-4-methoxycarbonylpyrrolo[3,4-g]thiopyrano-
[4,3,2-cd]-1H-indole-7,9-dione (19b) POCl3 (2.6 ml) was slowly added to
dry DMF (8.6 ml) at 0 °C, with stirring under nitrogen.
After 10 min, a solution of 12b (825 mg, 2.17 mmol) in dry DMF (8.7 ml) 376.0517. Found: 376.0519. MS m/z: 376 (Mϩ).
was added, and the mixture was stirred at 35 °C for 6 h. The reaction mixture

1202
Vol. 49, No. 9
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