Synthesis of 4-hydroxy-1-methylindole and benzo[b]thiophen-4-ol based unnatural flavonoids as new class of antimicrobial agents

Article abstract of DOI:10.1016/j.bmc.2004.12.032

Synthesis of nitrogen and sulfur heterocyclic mimics of furanoflavonoids have been achieved for the first time. Synthesized flavonoid alkaloids and thiophenyl flavonoids have been screened for antifungal and antibacterial activities. All the test compound

Full text of DOI:10.1016/j.bmc.2004.12.032

Bioorganic & Medicinal Chemistry 13 (2005) 1497–1505
Synthesis of 4-hydroxy-1-methylindole and
benzo[b]thiophen-4-ol based unnatural flavonoids as new class of
antimicrobial agentsq
Prem P. Yadav,a Prasoon Gupta,a A. K. Chaturvedi,b P. K. Shuklab and Rakesh Mauryaa,*
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
bDivision ofFermentation Technology, Central Drug Research Institute, Lucknow 226 001, India
Received 16 November 2004; revised 17 December 2004; accepted 18 December 2004
Available online 21January 2005
Abstract—Synthesis of nitrogen and sulfur heterocyclic mimics of furanoflavonoids have been achieved for the first time. Synthe-
sized flavonoid alkaloids and thiophenyl flavonoids have been screened for antifungal and antibacterial activities. All the test com-
pounds barring 25 exhibited antifungal activity. The compound 19 was the best and showed comparable MICs to the known
compound karanjin. Compounds 5, 12, 14 and 22 also showed comparable MIC to karanjin.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
bial12 activity and is used commercially in cosmetic and
sun-screen preparations.13
The clinical relevance of fungal diseases has increased
enormously in the second half of the 20th century,
mainly because of an increasing population of immuno-
compromised hosts, including individuals infected with
HIV, transplant recipients and patients with cancer.1,2
The fungal threat will continue to increase, as shown
by the occurrence of aspergillosis in severe acute respira-
tory syndrome (SARS)3 and by the inclusion of Coccid-
ioides immitis as a potent agent of bioterrorism.4 The
crude mortality from opportunistic fungal infections still
exceeds 50% in most human studies and has been re-
ported to be as high as 95% in a bone marrow transplant
recipients infected with Aspergillus spp.5
O
O
OCH3
O
OCH3
O
OH
O
Karanjin
Pongamol
The adequate treatment of mycotic infections is difficult
since fungi are eukaryotic organisms with a structure
and metabolism that is similar to those of eukaryotic
host. For this reason, there is a need to design new com-
pounds with good antifungal activity.
During our continuing efforts to identify antifungal
leads from plant sources we have isolated furanoflavo-
noids from Pongamia pinnata fruits.6,7 These com-
pounds possess various kind of biological activities.8
Among the compounds isolated by us most prominent
were karanjin, and pongamol. Karanjin has been re-
ported to be hypoglycemic,9 antifungal,10 synergist to
insecticides, antifeedent11 and pongamol has antimicro-
Therefore, in order to explore the potential of furano-
flavonoid nucleus as antifungal and antibacterial agents
we have devised an easy and efficient methodology to
introduce novel pyrrole and thiophene anellated mimics
to furanoflavonoids as their heterocyclic counterparts.
2. Results and discussion
2.1. Retrosynthetic scheme
Keywords: Unnatural flavonoids; Flavonoid alkaloids; Thiophenyl
flavonoids; Chalcones; Diketone; Flavones; Flavonols.
q CDRI communication no. 6582.
Various methods in the literature regarding synthesis of
furanoflavonoids reveal that these compounds can be syn-
thesized from degradation product of furanoflavonoids,
*
Corresponding author. Tel.: +91 522 2612411 18x4440; fax: +91 522
2623405/2623938/2629504; e-mail: mauryarakesh@rediffmail.com
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.12.032

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P. P. Yadav et al. / Bioorg. Med. Chem. 13 (2005) 1497–1505
that is, karanjic acid or total synthesis can be achieved
starting from cyclohexane-1,3-dione involving multi-
steps leading to furanoflavonoids.14 These methods
cannot be applied as such to the nitrogen and sulfur het-
erocyclic mimics of furanoflavonoids. Nitrogen can be
inserted to the 4-oxo-4,5,6,7-tetrahydrobenzofuran (1)
through ammonolysis whereas sulfur heterocyclic mim-
ics can not be generated from 1 as they lack any possible
step where sulfur can be inserted to the benzofuranoid
nucleus. Corresponding sulfur motif 6,7-dihydro-5H-
benzo[b]thiophen-4-one (3) can be generated from thio-
phene and succinic anhydride as depicted in the retro-
synthetic scheme. There is no literature report for
synthesis of these key intermediates as well as the final
compounds.
in quantitative yields by ammonolysis of tetra-
hydrobenzofuran (1) with methyl amine in aqueous eth-
anol contained in a sealed tube at 150 ꢁC for 14 h.19
As depicted in the retrosynthetic scheme, sulfur can be
inserted to the key intermediate while starting our strat-
egy from thiophene. Friedel–Crafts acylation of thio-
phene with succinic anhydride catalyzed by Lewis acid
AlCl3 and subsequent reduction of carbonyl group by
Clemmensen reduction, thereafter conversion of free
acid to acid chloride and again Friedel–Crafts acylation
afforded 3 in 64% overall yield as shown in Scheme 2.20
Enolate of 2/3 was generated with NaH and catalytic
amount of KH followed by coupling with ethyl acetate
and dimethyl carbonate in refluxing DME produced
4–7 (80–94%). Compound 4 and 5 existed as keto-enol
tautomers (9:1), as indicated from 1H NMR spectra.
Thereafter, DDQ mediated dehydrogenation of 4–7 in
refluxing dioxane, afforded 8–11 (64–85%) (Scheme
3).14 Compound 16 and 17 were prepared in quantitative
yield by methylation of the phenols 10 and 11 with
methyl iodide and K2CO3 in acetone (Scheme 5).
Furanoflavonoids
X
X
OR
OR
OMe
O
O
O
X= NMe / S
X= NMe / S
1, X=O
2, X=NMe
3, X=S
X
The synthesis of corresponding chalcones 12–15 were
achieved in good yield by subjecting intermediates 8/9
to Claisen–Schmidt condensation with substituted benz-
aldehydes in presence of barium hydroxide in ethanol
(Scheme 4).
O
O
O
O
O
OH
+
O
N
CH3
O
O
S
S
O
Propanedione analogue (18/19) were prepared in (35–
40%) yield by condensation of methyl ether 16/17 with
acetophenone in the presence of sodium amide in dry
2.2. Chemistry
We initiated our studies by preparing starting 4-oxo-
4,5,6,7-tetrahydrobenzofuran (1). Easy and efficient
methods are available for synthesis of 2-substituted-
tetrahydrobenzofurans, but these methods can only be
applied for synthesis of 2,3-dihydro-2-substituted-tetra-
hydrobenzofurans due to their limitations.15,16 Recent
studies have shown use of rhodium acetate in dipolar
cycloaddition of diazacyclohexane-1,3-diones with vinyl
acetates followed by acid catalyzed dehydration to pro-
duce 1 in 41–71% yield.17 Our attempt to synthesize 1,
commenced from commercially available cyclohexane-
1,3-dione as shown in Scheme 1. Aqueous solution of
cyclohexane-1,3-dione was stirred with bromoacetalde-
hyde in presence of catalytic amount of TBAI and
pH 6–7 was maintained by addition of sodium bicarbon-
ate. After 6 h the reaction mixture was subjected to acid
catalyzed dehydration to afford 1 in 78% yield.18 The
synthesis of key intermediate 2 (Scheme 1) was achieved
O
O
HO
+
a
O
S
S
O
O
b
O
O
HO
c
S
S
3
Scheme 2. Reagents and conditions: (a) AlCl3, nitrobenzene, 0–5 ꢁC;
(b) Zn–Hg, HCl; (c) SnCl4, CS2, 0 ꢁC.
O
O
O
OH
O
4
3
5
R
R
9
a
b
6
X
X 1
8
O
O
X
O
4, R=CH , X=NCH
5, R=CH , X=S
8, R=CH , X=NCH
3 3
9, R=CH , X=S
10, R= OCH , X=NCH
11, R= OCH , X=S
3
3
2, R=NMe
3, R=S
a
b
3
3
N
CH
6, R= OCH , X=NCH
O
1
3
3
3
3
O
2
7, R= OCH , X=S
3
3
3
Scheme 1. Reagents and conditions: (a) BrCH2CHO, NaHCO3, H2O,
rt, 6 h (78%); (b) ammonolysis with MeNH2, EtOH in sealed tube,
150 ꢁC, 14 h (90%).
Scheme 3. Reagents and conditions: (a) NaH (KH), EtOAc (for 4 and
5)/dimethyl carbonate (for 6 and 7), DME, reflux, 4 h; (b) DDQ,
dioxane, reflux, 2 h.

P. P. Yadav et al. / Bioorg. Med. Chem. 13 (2005) 1497–1505
1499
3''
3'
2''
R
3
N
O
OH
O
X
H3C
OH
R
X
O
O
α
a
a
1
12-15
+
5
5'
R1
1'
OH
β
X
O
O
Minor
8/ 9
12, R = H, X=NCH
13, R = OCH , X=NCH
14, R=H, X=S
15, R = OCH , X=S
3
25, R=H, X=NCH
26, R=H, X=S
27, R=OCH , X=S
3
28, R = H
1
3
3
29, R = OH
1
3
3
Scheme 6. Reagents and conditions: (a) 8% H2O2, 10% KOH, 0 ꢁC,
3 h.
Scheme 4. Reagents and conditions: (a) barium hydroxide, pR-
PhCHO, EtOH, reflux, 3 h.
culture plates using RPMI 1640 media buffered with
MOPS (3-[N-morpholino]propanesulfonic acid) (Sigma
Chemical Co.). All the test compounds barring 25 exhib-
ited antifungal activity. The compound 19 was the best
and showed comparable MICs to the known compound
karanjin. This compound showed activity of 6.25 lg/mL
as compared to standard antifungal drug fluconazole,
having MIC of 2 lg/mL against Trichophyton mentagro-
phytes. Against each test isolate including bacteria, com-
pound 19 showed good activity whereas the compound
22 exhibited good activity against fungal isolates only.
On the contrary compound 12 showed mild activity
against bacteria and fungi. Most of the compounds have
shown good antifungal activity against Trichophyton
mentagrophytes but compound 19, 22 and 12 exhibited
good activity against each fungal isolate. It can be in-
ferred from the activity results that substitution by sul-
fur has produced better results as compared to the
nitrogen analogues as revealed from activities of chal-
cones 12–15, propanediones (18/19) and flavonols 25–
27, whereas nitrogen analogue for flavone 22 was more
active then its sulfur counterpart 24. Methoxy substi-
tuted analogues for all these compounds in general have
shown decrease in activity. Two of the compounds 12
and 19 also had some antibacterial activity (Table 1).
2''
5
3''
3
X
O
OCH3
OCH3
4'
1
b
MeO
9
1'
7
X
a
O
O
H
16, X=NCH
17, X=S
3
18, X=NCH
19, X=S
3
10 /11
c
R
2''
3''
4'
X
OH
X
2
O
9
d
1'
7
S
O
4
5
O
O
20, X=NCH
21, X=S
3
22, R= H, X=NCH
23, R= OMe, X=NCH
24, R=H, X=S
3
3
Scheme 5. Reagents and conditions: (a) MeI, K2CO3, acetone, reflux,
2 h; (b) NaNH2, dry ether, acetophenone, 3 h; (c) NaH, DMSO, dry
benzene, 80 ꢁC; (d) piperidine, dry toluene, pR-PhCHO, first at 40 ꢁC,
2 h then at 110 ꢁC, 1h.
ether (Scheme 5). Reaction was tried with different bases
(NaH, KH, BuOK) and solvents (THF, DME) but no
t
improvement in yield was observed. Further esters 10/
11 were treated with dimsyl anion in DMSO to form
the b-ketosulfoxide 20/21 (Scheme 5), which on treat-
ment with benzaldehydes and piperidine in dry toluene
first at 40 ꢁC for 2 h, then at 110 ꢁC for 1h, produced
corresponding flavone analogues 22–24 (65–76%).14
3. Conclusion
In conclusion we have accomplished synthesis of novel
pyrrole and thiophene anellated flavonoid analogues of
furanoflavonoids, all the final compounds including
intermediates 4–11 are new and synthesized for the first
time. Synthesized compounds were evaluated for anti-
fungal and antibacterial activities. Biological studies of
heterocyclic analogues of these compounds have
revealed that substitution of the heterocyclic oxygen
by sulfur has produced marked increase in the anti-
fungal activity, as indicated by activity profile of the
compound 19. Compounds 5, 12, 14 and 22 also showed
comparable MIC to karanjin.
Synthesis of corresponding flavonols were achieved by
Algar–Flynn–Oyamada reaction (AFO)21 of chalcones
12–15. Reaction of sulfur heterocyclic chalcones (14
and 15) were neat and produced flavonol 25 and 26 in
good yields, whereas, AFO reaction of nitrogen anlogue
(12) was not efficient and chromatographic purification
of products revealed formation of flavonol analogue
25 (30%) as major product along with two minor prod-
ucts flavanone 28 (3%) and flavanonol 29 (5%) (Scheme
6), whereas with chalcone 13 reaction resulted in com-
plex mixture of products.
2.3. In vitro antifungal and antibacterial activity
4. Experimental
4.1. General
The minimum inhibitory concentration (MIC) of each
compound was determined against test isolates using
broth micro-dilution technique as described by the
NCCLS.22,23 MIC of standard antifungal (fluconazole)
and the compounds were determined in 96-well tissue
Melting points (mp) were taken in open capillaries on an
electrically heated melting point apparatus Complab
and are uncorrected. IR spectra were recorded on a

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P. P. Yadav et al. / Bioorg. Med. Chem. 13 (2005) 1497–1505
Table 1. Antimicrobial activity of heterocyclic analogues
Compound
Minimum inhibitory concentration (MIC) lg/mL against
Fungi
Bacteria
2
1
3
4
5
6
7
8
9
1
0
4
50
25
––
––
––
––
––
––
––
50
––
––
50
––
––
––
––
––
––
––
––
––
50
25
50
50
––
25
––
25
––
25
12.5
25
––
––
––
––
––
12.5
––
0.5
50
25
50
50
50
25
25
25
––
25
25
25
––
50
25
50
50
––
25
50
25
––
25
25
12.5
––
––
––
––
––
12.5
––
1.0
5
25
25
50
50
25
25
12.5
––
50
12.5
25
––
––
––
––
––
50
––
––
––
––
––
––
––
––
––
––
––
––
7
––
––
––
50
9
10
––
––
25
––
12
13
50
––
50
25
25
––
25
25
––
25
6.25
––
––
––
––
25
14
15
12.5
25
––
––
––
––
––
––
––
––
––
––
––
––
––
18
19
––
25
––
––
––
––
––
––
––
––
ND
25
25
50
50
6.25
6.25
6.25
22
23
––
––
––
––
––
––
––
––
––
––
––
––
––
––
––
––
ND
12.5
50
25
––
––
––
25
––
25
50
12.5
25
24
25
25
25
––
50
––
––
––
––
26
27
25
50
25
––
Karanjin
Pongamol
flu*
12.5
12.5
12.5
12.5
––
6.25
––
ND
––
ND
––
ND
12.5
2.0
1.0
1.0
2.0
(1) Streptococcus faecalis, (2) Klebsiella pneumoniae, (3) Escherichia coli, (4) Pseudomonas aeruginosa, (5) Staphylococcus aureus, (6) Candida albicans,
(7) Cryptococcus neoformans, (8) Sporothrix schenckii, (9) Trichophyton mentagrophytes, (10) Aspergillus fumigatus, (11) Candida parapsilosis (ATCC
22019), flu* = Fluconazole, ND = Not done.
Perkin–Elmer RX-1spectrophotometer using either
KBr pallets or in neat. The FAB-MS were recorded
using a beam of Argon (2–8 eV) on Jeol SX 102/DA-
6000 mass spectrometer. The NMR spectra were run
on an AVANCE DPX 200 and Bruker DRX 300
FTNMR spectrometers. The chemical shifts are re-
ported in d (ppm) downfield from TMS, which was used
as internal standard. Elemental analyses were obtained
in a Carlo-Erba-1108 CHN elemental analyzer. Silica
gel (60–120 mesh) was used for column chromatography
while silica gel (230–400 mesh) was used for flash chro-
matography. TLC was run either on precoated silica
gel 60F254 and RP-18 F254 (Merck) or hand made
plates. Detection of spots was done either by iodine
vapour, spraying with 1% cerric sulfate in 1 M H2SO4
followed by heating at 110 ꢁC, or spraying with 10%
methanolic sulfuric acid followed by heating at 110 ꢁC.
duced pressure. The crude product was purified by chro-
matography over silica gel (60–120 mesh), by isocratic
elution with chloroform: ethyl acetate (95:05) to afford
824 mg (84% yield) of 4; viscous, IR (KBr) mmax: 3452,
2944, 1709, 1636, 1514, 1473, 1413, 1354, 1257, 1167,
1
1080, 754, 729 cmꢀ1; H NMR (CDCl3, 200 MHz): d
16.17 (OH-chelated), 6.53 (1H, br s, H-2), 6.51(1H, br
s, H-3), 3.53 (3H, s, NCH3), 3.50 (1H, br dd, H-5),
2.47–2.95 (4H, m, H-6, H-7), 2.28 (3H, s, COCH3);
13C NMR (CDCl3, 50.32 MHz): d 206.2 (C-10), 189.6
(C-4), 186.5 (C-10-enol), 176.1 (C-4-enol), 144.2 (C-8),
142.0 (C-8-enol), 124.1 (C-2), 124.0 (C-2-enol), 120.2
(C-9), 106.1 (C-3), 105.9 (C-3-enol), 103.3 (C-5-enol),
60.6 (C-5), 33.8 (NCH3), 30.0 (COCH3), 25.6 (C-6),
24.0 (C-6-enol), 27.1(C-7-enol), 20.4 (CO CH3-enol),
20.0 (C-7); FAB-MS (+ve): 192 [M+H]+, 383 [2M+H]+.
4.3. 5-Acetyl-6,7-dihydro-5H-benzo[b]thiophen-4-one (5)
4.2. 5-Acetyl-1-methyl-4-oxo-4,5,6,7-tetrahydroindole (4)
The procedure for the synthesis of 4 was repeated (see
Section 4.2) with 3 (2.00 g, 0.013 mol) and ethyl acetate
(7.60 mL, 0.073 mol), afforded 5; 2.00 g, (80%); colour-
less needles, mp 80–81 ꢁC; IR (KBr) mmax: 3530, 2982,
1748, 1719, 1667, 1605, 1429, 1365, 1271, 11154, 1039,
To the stirred solution of sodium hydride (1.20 g,
50 mmol) and potassium hydride (100 mg, 2.5 mmol)
in dry DME (10 mL) added a solution of 2 (750 mg,
5.0 mmol) in dry DME (2 mL) at 0 ꢁC under nitrogen
atmosphere. The reaction mixture was stirred for
30 min and then ethyl acetate (2.40 mL, 25 mmol) was
slowly added over 10 min. The ice bath was removed
and the reaction mixture was heated to reflux for
2.30 h. Reaction mixture was quenched by dropwise
addition of ice cold ammonium chloride solution
(5 mL) and then poured over aqueous ammonium chlo-
ride solution (30 mL), extracted with ethyl acetate
(3 · 50 mL). The combined organic layers were washed
with brine, dried over Na2SO4 and evaporated under re-
1
908, 722 cmꢀ1; H NMR (CDCl3, 200 MHz): d 16.14
(1H, s, OH-chelated-enol form), 7.38 (1H, d,
J = 5.2 Hz, H-2-enol), 7.37 (1H, d, J = 5.3 Hz, H-2-
keto), 7.09 (1H, d, J = 5.1Hz, H-3-enol), 7.07 (1H, d,
J = 5.2 Hz, H-3-keto), 3.61(H1 , t,
J = 7.8 Hz, H-5-
keto), 3.01–3.29 (2H, m, H-7-keto), 2.94–3.0 (2H, m,
H-6-enol), 2.67–2.77 (2H, m, H-7-enol), 2.23–2.61(2H,
m, H-6-keto), 2.31(3H, s, CO CH3-keto), 2.14 (3H, s,
COCH3-enol); 13C NMR (CDCl3, 50.32 MHz):
d
205.3, (C-10-keto), 189.4 (C-4-keto), 182.9 (C-4-enol),

P. P. Yadav et al. / Bioorg. Med. Chem. 13 (2005) 1497–1505
1501
182.4 (C-10-enol), 156.9 (C-8-keto), 151.9 (C-8-enol),
136.6 (C-9-keto), 136.1 (C-9-enol), 125.3 (C-2-keto),
125.07 (C-2-enol), 124.0 (C-3-keto), 123.7 (C-3-enol),
104.0 (C-5-enol), 66.6 (C-5-keto), 30.5 (C–COCH3-
enol), 26.8 (C-6-keto), 24.7 (C-6-enol), 24.6 (C-7-enol),
23.9 (C-7-keto), 21.5 (COCH3-keto); FAB-MS (pos.):
m/z 195 [M+H]+ m/z 389 [2M+H]+.
(2.10 g, 9.20 mmol) gave 9 (1.26 g, 85%); white crystals,
mp 102–103 ꢁC; IR (KBr) mmax: 3455, 3092, 1629, 1544,
1
1443, 1410, 1368, 1267, 1164, 988, 717 cmꢀ1; H NMR
(CDCl3, 200 MHz): d 13.4 (1H, s, OH-chelated), 7.63
(1H, d, J = 5.5 Hz, H-200), 7.59 (1H, d, J = 8.7 Hz, H-
6), 7.36 (1H, d, J = 5.5 Hz, H-300), 7.33 (1H, d,
J = 8.8 Hz, H-5), 2.66 (3H, s, COCH3); FAB-MS
(pos.): m/z 193 [M+H]+, 385 [2M+H]+.
4.4. 1-Methyl-4-oxo-4,5,6,7-tetrahydroindole-5-carbox-
ylic acid methyl ester (6)
4.8. 4-Hydroxy-1-methyl-indole-5-carboxylic acid methyl
ester (10)
The procedure for the synthesis of 4 was repeated (see
Section 4.2) with 2 (1.00 g, 6.7 mmol) and dimethyl car-
bonate (3.00 g, 33.5 mmol), afforded 6; 1.30 g (94%);
brown crystals, mp 93–94 ꢁC; IR (KBr) mmax: 2950,
2912, 1733, 1649, 1512, 1465, 1362, 1309, 1219, 1167,
Procedure for the synthesis of 8 was repeated (see Sec-
tion 4.6) with 6 (1.00 g, 4.8 mmol) and DDQ (1.20 g,
5.3 mmol), gave 10 (0.84 g, 85%); white crystals, mp
87–88 ꢁC; IR (KBr) mmax: 3009, 2954, 1658, 1598, 1422,
1
1079, 729, 692 cmꢀ1; H NMR (CDCl3, 200 MHz): d
1342, 1310, 1257, 1143, 974, 740 cmꢀ1 1H NMR
;
6.66 (2H, br s, H-2, H-3), 3.86 (3H, s, OCH3), 3.68
(3H, s, NCH3), 3.58 (1H, dd, J = 8.1, 4.8 Hz, H-5),
3.05 (1H, td, J = 16.5, 6.0 Hz, H-7a), 2.84 (1H, td,
J = 16.8, 6.6 Hz, H-7b), 2.66 (1H, m, H-6a) 2.45 (1H,
m, H-6b); FAB-MS (pos.): m/z 208 [M+H]+, 41 5
[2M+H]+.
(CDCl3, 200 MHz): d 11.5 (1H, s, chelated hydroxyl),
7.63 (1H, d, J = 8.8 Hz, H-6), 6.94 (1H, d, J = 3.1Hz,
H-2), 6.80 (1H, d, J = 8.8 Hz, H-7), 6.72 (1H,
d, J = 3.1Hz, H-3), 3.93 (3H, s, COO CH3), 3.74
(3H, s, NCH3); FAB-MS (+ve): 206 [M+H]+, 41 1
[2M+H]+.
4.5. 4-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-5-car-
boxylic acid methyl ester (7)
4.9. 4-Hydroxy-benzo[b]thiophene-5-carboxylic acid
methyl ester (11)
The procedure for the synthesis of 4 was repeated (see
Section 4.2) with 3 (2.00 g, 0.013 mol) and dimethyl car-
bonate (6.55 mL, 0.073 mol) afforded 7 (2.30 g, 85%);
white needles, mp 92–94 ꢁC; IR (KBr) mmax: 2929,
1735, 1671, 1523, 1404, 1344, 1267, 1069, 990,
The procedure for the synthesis of 8 was repeated (see
4.6) with 7 (2.00 g, 9.5 mmol) and DDQ (3.09 g,
13.70 mmol) gave 11 (1.54 g, 78%); white needles, mp
98–99 ꢁC; IR (KBr) mmax: 3446, 2948, 1661, 1616, 1548,
1
1436, 1345, 1267, 1142, 1003, 933, 749, 683 cmꢀ1; H
1
747 cmꢀ1; H NMR (CDCl3, 200 MHz): d 7.42 (1H, d,
NMR (CDCl3, 200 MHz): d 11.59 (1H, s, OH-chelated),
7.79 (1H, d, J = 9.0 Hz, H-6), 7.66 (1H, d, J = 6.0 Hz,
J = 5.3 Hz, H-2), 7.10 (1H, d, J = 5.3 Hz, H-3), 3.77
(3H, s, COOCH3), 3.58 (1H, dd, J = 8.9, 4.8 Hz, H-5),
3.04–3.17 (2H, m, H-7), 2.43–2.63 (2H, m, H-6); FAB-
H-2), 7.41H(1, d,
J = 9 Hz, H-7), 4.00 (3H, s, OCH3); FAB-MS (pos.):
J = 6 Hz, H-3), 7.39(1H, d,
+
MS (pos.): m/z 211 [M+H]+, 421[2M+H] .
m/z 209 [M+H]+, 417 [2M+H]+, 175.
4.6. 5-Acetyl-4-hydroxy-1-methyl-indole (8)
4.10. 1-(4-Methoxy-1-methyl-1H-indol-5-yl)-3-phenyl-
propenone (12)
A mixture of 4 (1.20 g, 6.2 mmol) and DDQ (1.60 g,
7.44 mmol) in dry dioxane (20 mL) were heated under
reflux for 4 h. The resulting mixture was cooled in an
ice bath and solids were removed by filtration through
Celite. The filtrate was evaporated under reduced pres-
sure and purified by flash chromatography over silica
gel, eluted with hexane–ethyl acetate (9:1) afforded 8
(0.76 g, 64%); white crystals, mp 82–83 ꢁC; IR (KBr)
To a solution of 8 (200 mg, 1.05 mmol) in ethanol
(20 mL) and barium hydroxide (176 mg, 1.05 mmol)
was added benzaldehyde (0.42 mL, 4.2 mmol). The reac-
tion mixture was refluxed for 3 h, cooled to room tem-
perature and poured in to water (50 mL). The reaction
mixture was extracted with ethyl acetate (3 · 50 mL)
and combined ethyl acetate extract was washed with
satd NH4Cl solution and brine, dried over Na2SO4
and concentrated to afford crude product, which was
purified by column chromatography over deactivated
silica gel eluted with hexane–ethyl acetate (1:9) afforded
12 (202 mg, 68% yield); yellow crystals, mp 145–146 ꢁC;
IR (KBr) mmax: 3411, 2934, 1630, 1583, 1496, 1359, 1306,
m
max: 3430, 2980, 1630, 1601, 1356, 1322, 1264, 1163,
1
739 cmꢀ1; H NMR (CDCl3, 200 MHz): d 13.65 (1H,
s, chelated hydroxyl), 7.48 (1H, d, J = 8.8 Hz, H-6),
6.95 (1H, d, J = 3.0 Hz, H-2), 6.75–6.81(2H, m, H-3,
H-7), 3.76 (3H, s, NCH3), 2.62 (3H, s, COCH3); 13C
NMR (CDCl3, 50.32 MHz): d 203.9 (COCH3), 159.9
(C-4), 141.7 (C-8), 128.6 (C-2), 124.4 (C-6), 118.3 (C-
9), 111.5 (C-5), 101.9 (C-3), 101.7 (C-7), 33.4 (NCH3),
1
1199, 753, 723 cmꢀ1; H NMR (CDCl3, 200 MHz): d
14.19 (OH-chelated), 7.90 (1H, d, J = 15.5 Hz, H-b),
90 7.64–7.74 (4H, m, H-a, 60, 2, 6), 7.40–7.44 (3H, m, H-
3, 4, 5), 6.96 (1H, d, J = 3.1Hz, H-2 00), 6.84 (1H, d,
J = 8.9 Hz, H-50), 6.79 (1H, d, J = 3.1Hz, H-3 00), 3.78
(3H, s, NCH3); 13C NMR (CDCl3, 50.32 MHz): d
193.2 (C@O), 161.6 (C-20), 143.9 (C-b), 141.7 (C-40),
135.5 (C-1), 130.7 (C-200), 129.3 (C-3, 5), 128.8 (C-2,
6), 128.6 (C-4), 123.4 (C-a), 121.7 (C-60), 118.6 (C-10),
27.0 (COCH3); FAB-MS (+ve): 189 [M]+,
1
[M+H]+, 379 [2M+H]+.
4.7. 1-(4-Hydroxy-benzo[b]thiophen-5-yl)-ethanone (9)
The procedure for the synthesis of 8 was repeated (see
Section 4.6) with 5 (1.50 g, 7.7 mmol) and DDQ

1502
P. P. Yadav et al. / Bioorg. Med. Chem. 13 (2005) 1497–1505
111.7 (C-30), 102.1 (C-50), 101.9 (C-300), 33.5 (NCH3);
FAB-MS (+ve): 278 [M+H]+. Elemental analysis: calcd
for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C,
78.32; H, 5.03; N, 5.35.
50.32 MHz): d 193.9 (C@O), 162.3 (C-20), 161.3 (C-4),
147.8 (C-40), 145.3 (C-b), 130.9 (C-1), 130.9 (C-2, 6),
127.9 (C-30), 125.7 (C-200), 124.7 (C-a), 122.3 (C-60),
118.4 (C-300), 114.9 (C-10), 114.9 (C-3, 50), 113.2(C-50),
55.8 (OCH3); FAB-MS (+ve): 311 [M+H]+, 621
[2M+H]+. Elemental analysis: calcd for C18H14O3S: C,
69.66; H, 4.55; S, 10.33. Found: C, 69.53; H, 4.72; S,
10.55.
4.11. 1-(4-Methoxy-1-methyl-1H-indol-5-yl)-3-(4-meth-
oxy-phenyl)-propenone (13)
Procedure for the synthesis 12 (see Section 4.10) was re-
peated with 8 (200 mg, 1.05 mmol) and p-methoxy-benz-
aldehyde (0.51mL, 4.2 mmol), produced 13 (211 mg,
65% yield); yellow crystals, mp 183–184 ꢁC; IR (KBr)
4.14. 4-Methoxy-1-methyl-indole-5-carboxylic acid
methyl ester (16)
m
max: 2925, 2851, 1635, 1603, 1507, 1440, 1359, 1248,
1170, 1126, 1029, 774 cmꢀ1 1H NMR (CDCl3,
200 MHz): 14.30 (OH-chelated), 7.80 (1H, d,
To a stirred mixture of phenol 10 (0.50 g, 1.2 mmol) and
potassium bicarbonate (0.60 g, 6 mmol) in acetone
(20 mL) was added methyl iodide (1.70 g, 12 mmol)
and the reaction mixture was refluxed for 4 h. The reac-
tion mixture was cooled, filtered through Celite. The fil-
trate was concentrated and purified by column
chromatography over silica gel, eluted with hexane–
ethyl acetate (9:1) afforded quantitative yield of 16
(0.50 g) as a sticky mass; IR (KBr) mmax: 3014, 2948,
1712, 1605, 1572, 1488, 1310, 1257, 1195, 1051, 951,
;
d
J = 15.3 Hz, H-b), 7.54–7.66 (3H, m, H-60, 2, 6), 6.93
(2H, d, J = 8.4 Hz, H-3, 5), 6.68–6.83 (3H, m, H-a, 200,
50), 6.34 (1H, br s, H-300), 3.85 (3H, s, OCH3), 3.63
(3H, s, NCH3); 13C NMR (CDCl3, 50.32 MHz): d
203.3 (C@O), 163.2 (C-20), 161.6 (C-4), 143.0 (C-40),
142.4 (C-b), 138.1 (C-1), 130.4 (C-2, 6), 127.7 (C-200),
124.5 (C-a), 119.6 (C-60), 116.6 (C-10), 114.7 (C-3, 5),
111.5 (C-30), 101.5 (C-300, 50), 55.5 (OCH3), 33.3
(NCH3); FAB-MS (+ve): 308 [M+H]+ 615 [2M+H]+.
Elemental analysis: calcd for C19H17NO3: C, 74.25; H,
5.58; N, 4.56. Found: C, 74.53; H, 5.37; N, 4.80.
1
753 cmꢀ1; H NMR (CDCl3, 200 MHz): d 7.74 (1H, d,
J = 8.6 Hz, H-6), 7.05 (1H, d, J = 8.6 Hz, H-7), 7.02
(1H, d, J = 3.0 Hz, H-2), 6.69 (1H, d, J = 3.0 Hz, H-3),
4.10 (3H, s, OCH3), 3.91 (3H, s, OMe-11), 3.76 (3H, s,
NCH3); FAB-MS (+ve): 219 [M]+, 220 [M+H]+.
4.12. 1-(4-Hydroxy-benzo[b]thiophen-5-yl)-3-phenyl-
propenone (14)
4.15. 4-Methoxy-benzo[b]thiophene-5-carboxylic acid
methyl ester (17)
The procedure for the synthesis of 12 (see Section 4.10)
was repeated with 9 (200 mg, 1.04 mmol) and benzalde-
hyde (0.52 mL, 5.2 mmol), produced 204 mg (70%) of
The procedure for the synthesis of 16 (see Section 4.14)
was repeated with 11 (0.50 g, 2.4 mmol), methyl iodide
(0.15 mL, 24 mmol) and potassium carbonate (1.65 g,
12 mmol), afforded 17 (0.47 g, 90%); white needles, mp
50–51 ꢁC; IR (KBr) mmax: 3021, 2930, 1719, 1591, 1454,
14; yellow needles, mp 144–145 ꢁC; IR (KBr) mmax
3490, 3090, 1637, 1590, 1499, 1446, 1361, 1205, 1092,
:
1
975, 749 cmꢀ1; H NMR (CDCl3, 200 MHz): d 14.14
(OH-chelated), 7.96 (1H, d, J = 15.4 Hz, H-b), 7.82
(1H, d, J = 8.7 Hz, H-60), 7.67–7.74 (4H, m, H-a, 2, 6,
200), 7.42–7.46 (4H, m, H-3, 4, 5, 50), 7.39 (1H, d,
J = 5.3 Hz, H-300); 13C NMR (CDCl3, 50.32 MHz): d
193.9 (C@O), 161.3 (C-20), 148.1 (C-40), 145.4 (C-b),
135.1 (C-1), 131.2 (C-4), 131.0 (C-30), 129.4 (C-3, 5),
129.0 (C-2, 6), 125.8 (C-200), 124.7 (C-a), 122.3 (C-60),
120.9 (C-300), 114.8 (C-10), 113.3 (C-50); FAB-MS
(+ve): 281[M+H] +. Elemental analysis: calcd for
C17H12O2S: C, 72.83; H, 4.31; S, 11.44. Found: C,
73.04; H, 4.51; S, 11.69.
1335, 1193, 1018, 757 cmꢀ1 1H NMR (CDCl3,
;
200 MHz): d 7.80 (1H, d, J = 8.5 Hz, H-6), 7.63 (1H,
d, J = 8.4 Hz, H-7), 7.54 (1H, d, J = 5.5 Hz, H-2), 7.44
(1H, d, J = 5.5 Hz, H-3), 4.04 (3H, s, OCH3), 3.95
(3H, s, COOCH3); FAB-MS (pos.): m/z 222, 223
[M+H]+, 445 [2M+H]+.
4.16. 3-Hydroxy-1-(4-methoxy-1-methyl-1H-indol-5-yl)-
3-phenyl-propenone (18)
To
a
stirred solution of acetophenone (1.36 g,
0.011 mol) and sodium amide (0.53 g, 0.013 mol) in
ether (80 mL) was added 16 (0.50 g, 0.002 mol) in ether
(15 mL) at room temperature. The reaction mixture was
refluxed for 4 h. Cooled reaction mixture was quenched
by drop wise addition of aqueous ammonium chloride
solution (10 mL), poured over ice cold saturated solu-
tion NH4Cl (50 mL) and extracted with ethyl acetate
(4 · 50 mL). The combined organic layer was washed
with brine, dried over Na2SO4, evaporated under re-
duced pressure. The resulting residue was purified by
column chromatography over silica gel eluting with
5% ethyl acetate in hexane to give 18 (300 mg, 40%); vis-
cous, IR (KBr) mmax: 3439, 2934, 1660, 1601, 1499, 1450,
4.13. 1-(4-Hydroxy-benzo[b]thiophen-5-yl)-3-(4-methoxy-
phenyl)-propenone (15)
The procedure for the synthesis of 12 (see Section 4.10)
was repeated with 9 (200 mg, 1.04 mmol) and p-meth-
oxy-benzaldehyde (0.63 mL, 5.2 mmol), produced
210 mg (65%) of 15; yellow needles, mp 163–164 ꢁC;
IR (KBr) mmax: 3424, 2930, 1645, 1602, 1509, 1439,
1
1357, 1263, 1175, 1089, 1024, 788, 678 cmꢀ1; H NMR
(CDCl3, 200 MHz): d 14.25 (OH-chelated), 7.89 (1H,
d, J = 15.3 Hz, H-b), 7.81(H1 , d,
J = 8.7 Hz, H-60),
7.61–7.69 (3H, m, H-2, 6, 200), 7.57 (1H, d,
J = 15.2 Hz, H-a), 7.38 (1H, d, J = 8.9 Hz, H-50), 7.37
(1H, d, J = 5.3 Hz, H-300), 6.95 (2H, d, J = 8.6 Hz, H-
3, 5), 3.86 (3H, s, OCH3); 13C NMR (CDCl3,
1272, 1218, 760, 696 cmꢀ1
;
1H NMR (CDCl3,
200 MHz): d 17.0 (1H, s, chelated hydroxyl), 8.00 (2H,
br dd, H-20, 60), 7.86 (1H, d, J = 8.7 Hz, H-6), 7.52

P. P. Yadav et al. / Bioorg. Med. Chem. 13 (2005) 1497–1505
1503
(3H, m, H-30, 40, 50), 7.34 (1H, s, H-8), 7.13 (1H, d,
4.19. 1-(4-Hydroxy-benzo[b]thiophen-5-yl)-2-methane-
sulfinyl-ethanone (21)
J = 8.7 Hz, H-5), 7.06 (1H, d, J = 2.9 Hz, H-20), 6.72
(1H, d, J = 2.86 Hz, H-300), 4.02 (3H, s, OCH3), 3.81
(3H, s, NCH3); 13C NMR (CDCl3, 50.32 MHz): d
186.9 (C-7), 183.5 (C-9), 154.4 (C-2), 140.9 (C-4),
133.0 (C-100), 131.7 (C-20), 128.9 (C-40), 128.3 (C-20, 60),
126.9 (C-3 , 50), 123.5 (C-6), 121.1 (C-1), 118.6 (C-3),
105.2 (C-300), 100.4 (C-5), 97.6 (C-8), 33.5 (NCH3);
FAB-MS (+ve): 308 [M+H]+. Elemental analysis: calcd
for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C,
74.72; H, 5.63; N, 4.66.
The procedure for the synthesis of 20 (see Section 4.18)
was repeated with 11 (250 mg, 1.12 mmol) and enolate
of DMSO in DMSO (1.5 mL), produced 228 mg (80%)
of 21; white crystals, mp 120–121 ꢁC; IR (KBr) mmax
3455, 3092, 1629, 1544, 1443, 1410, 1368, 1267, 1164,
:
1
988, 717 cmꢀ1; H NMR (CDCl3, 200 MHz): 13.4 (1H,
s, OH-chelated), 7.75 (1H, d, J = 8.7 Hz, H-6), 7.64
(1H, d, J = 5.5 Hz, H-200), 7.50 (1H, d, J = 5.5 Hz, H-
300), 7.44 (1H, d, J = 8.7 Hz, H-5), 4.63 (1H, d,
J = 14.2 Hz, H-8a), 4.52 (1H, d, J = 14.2 Hz, H-8b),
2.80 (3H, s, SOCH3); FAB-MS (pos.): m/z 255
[M+H]+, 509 [2M+H]+.
4.17. 3-Hydroxy-1-(4-methoxy-benzo[b]thiophen-5-yl)-3-
phenyl-propenone-4-oxo-4-thiophen-2-yl-butyric acid (19)
The procedure for the synthesis of 18 (see Section 4.16)
was repeated with 17 (200 mg, 0.90 mmol) and enolate
of acetophenone (0.52 mL, 4.5 mmol), produced
4.20. 7-Methyl-2-phenyl-7H-pyrano[2,3-e]indol-4-one
(22)
82.5 mg (35% yield) of 19; viscous; IR (KBr) mmax
3432, 3019, 1594, 1459, 1416, 1331, 1217, 1013,
:
Benzaldehyde (1.4 mL, 14 mmol) in dry toluene was
slowly added to a warm solution of 20 (350 mg,
1.4 mmol) in dry toluene (15 mL) containing catalytic
amount of piperidine (four drops) and the resulting mix-
ture was allowed to reflux for 3 h. After distillation of
solvent, residue was purified by column chromatogra-
phy over silica gel (eluting with 15% ethyl acetate and
hexane) to afford 22 (268 mg, 70%); yellow crystals,
mp 178–179 ꢁC; IR (KBr) mmax: 2950, 1631, 1594,
1
761cm ꢀ1; H NMR (CDCl3, 300 MHz): d 16.87 (1H,
s, OH-chelated), 8.02 (3H, br d, J = 7.2 Hz, H-20, 60,
H-2), 7.90 (1H, d, J = 8.4 Hz, H-6), 7.74 (1H, d,
J = 8.4 Hz, H-7), 7.57 (3H, m, H-30, 40, 50), 7.50 (1H,
s, H-11), 7.49 (1H, d, J = 5.7 Hz, H-3), 4.03 (3H, s,
OCH3); 13C NMR (CDCl3, 50.32 MHz): d 186.1 (C-
10), 185.1 (C-12), 155.6 (C-4), 145.4 (C-8), 135.9 (C-
10), 134.9 (C-9), 132.7 (C-40), 129.0 (C-30, 50), 127.6
(C-20, 60), 127.3 (C-2), 125.9 (C-6), 124.7 (C-5), 121.5
(C-3), 118.9 (C-7), 98.1 (C-11), 63.1 (OCH3); FAB-MS
(pos.): m/z 311 [M+H]+, 621[2M+H] +. Elemental analy-
sis: calcd for C18H14O3S: C, 69.66; H, 4.55; S, 10.33.
Found: C, 69.39; H, 4.73; S, 10.17.
1499, 1414, 1355, 1251, 1133, 1051, 769, 677 cmꢀ1; H
1
NMR (CDCl3, 200 MHz): d 7.95–8.03 (3H, m, H-20,
60, 5), 7.51–7.54 (3H, m, H-30, 40, 50), 7.33 (1H, d,
J = 8.7 Hz, H-6), 7.14 (1H, d, J = 3.0 Hz, H-20), 6.92
(1H, d, J = 3.0 Hz, H-300), 6.86 (1H, s, H-3), 3.86 (3H,
s, NCH3); 13C NMR (CDCl3, 50.32 MHz): d 179.2 (C-
4), 162.3 (C-2), 151.5 (C-9), 140.2 (C-7), 132.6 (C-10),
131.5 (C-20), 129.6 (C-40), 129.4 (C-30, 50), 126.5 (C-20,
60), 118.7 (C-5), 117.6 (C-10), 116.9 (C-8), 108.5 (C-30),
108.2 (C-6), 100.1 (C-3), 33.7 (NCH3); FAB-MS (+ve):
276 [M+H]+. Elemental analysis: calcd for
C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C,
78.74; H, 4.43; N, 5.37.
4.18. 1-(4-Hydroxy-1-methyl-1H-indol-5-yl)-2-methane-
sulfinyl-ethanone (20)
A mixture of dry DMSO (1.5 mL) and sodium hydride
(280 mg, 11.6 mmol) in dry benzene (20 mL) was heated
at 80 ꢁC under nitrogen atmosphere for 2 h. The solu-
tion was cooled to room temperature and added drop
wise 10 (200 mg, 0.97 mmol) in dry benzene (5 mL).
The reaction mixture was then stirred for 1h, diluted
with ether (40 mL) and quenched with saturated solu-
tion of NH4Cl (20 mL). Organic and aqueous layers
were separated and the aqueous layer was further ex-
tracted with ether (3 · 30 mL). Combined organic layer
was washed with brine, dried over Na2SO4, filtered and
evaporated under reduced pressure. The resulting resi-
due was purified by column chromatography on silica
gel eluting with ethyl acetate, afforded 20 (195 mg,
4.21. 2-(4-Methoxy-phenyl)-7-methyl-7H-pyrano[2,3-e]-
indol-4-one (23)
The procedure for the synthesis of 22 (see Section 4.18)
was repeated with p-methoxy-benzaldehyde (1.4 mL,
12.3 mmol) and 20 (310 mg, 1.23 mmol), afforded 23
(280 mg, 74%); yellow crystals, mp 208–209 ꢁC; IR
(KBr) mmax: 2951, 1625, 1597, 1352, 1175, 1055, 767,
1
80%); white crystals, mp 138–139 ꢁC; IR (KBr) mmax
3422, 2951, 1628, 1602, 1499, 1435, 1349, 1271, 1198,
:
586 cmꢀ1; H NMR (CDCl3, 200 MHz): d 7.97 (1H, d,
J = 8.7 Hz, H-5), 7.88 (2H, br d, J = 8.9, 2.0 Hz, H-20,
60), 7.27 (1H, br d, J = 8.7, 1.7 Hz, H-6), 7.10 (1H, d,
J = 3.7 Hz, H-20), 7.00 (2H, br d, J = 8.9, 1.9 Hz H-30,
50), 6.88 (1H, br d, J = 3.02, 0.34 Hz, H-300), 6.73 (1H,
s, H-3), 3.86 (3H, s, OCH3), 3.82 (3H, s, NCH3); 13C
NMR (CDCl3, 50.32 MHz): d 179.1 (C-4), 162.4 (C-2),
162.3 (C-40), 151.6 (C-9), 140.1 (C-7), 129.5 (C-20),
128.0 (C-20, 60), 124.9 ( C-10), 118.6 (C-5), 117.5 (C-
10), 116.7 (C-8), 114.7 (C-30, 50), 108.3 (C-6), 106.7 (C-
300), 100.0 (C-3), 55.8 (OCH3), 33.6 (NCH3); FAB-MS
(+ve): 306 [M+H]+. Elemental analysis: calcd for
1
1016, 774 cmꢀ1; H NMR (CDCl3, 200 MHz): d 7.46
(1H, d, J = 8.9 Hz, H-6), 6.98 (1H, d, J = 3.1Hz, H-2),
6.86 (1H, d, J = 8.9 Hz, H-7), 6.77 (1H, d, J = 3.0 Hz,
H-3), 4.52 (1H, d, J = 13.8 Hz, H-11a), 4.26 (1H, d,
J = 13.8 Hz, H-11b) 3.78 (3H, s, NCH3), 2.77 (3H, s,
Me-13); 13C NMR (CDCl3, 50.32 MHz): d 195.4 (C-
10), 160.9 (C-4), 142.2 (C-8), 129.1 (C-2), 124.2 (C-6),
118.2 (C-9), 111.4 (C-5), 103.1 (C-3), 102.2 (C-7), 62.6
(C-11), 39.9 (SOCH3), 33.6 (NCH3); FAB-MS (+ve):
252 [M+H]+, 503 [2M+H]+.

1504
P. P. Yadav et al. / Bioorg. Med. Chem. 13 (2005) 1497–1505
C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C, 74.92;
H, 5.13; N, 4.75.
(2H, m, H-6, 20), 6.69 (1H, d, J = 3.1Hz, H-3 00), 5.62
(1H, dd, Jaa = 12.8 Hz, Jee = 3.3 Hz, H-2ax), 3.79 (3H,
s, NCH3), 3.13 (1H, dd, Jgem = 16.7 Hz Jaa = 12.9 Hz,
H-3ax), 2.91(1H, dd, Jgem = 16.7 Hz Jea = 3.3 Hz, H-
3eq); 13C NMR (CDCl3, 50.32 MHz): d 191.7 (C-4),
152.4 (C-9), 141.9 (C-7), 139.7 (C-10), 129.0 (C-30, 50),
128.9 (C-20), 128.8 (C-40), 126.4 (C-20, 60), 120.7 (C-5),
118.2 (C-10), 112.9 (C-8), 104.5 (C-6), 101.1 (C-300),
80.3 (C-2), 44.7 (C-3), 33.5 (NCH3); FAB-MS (pos.):
m/z 278 [M+H]+.
4.22. 8-Phenyl-9-oxa-3-thia-cyclopenta[a]naphthalen-6-
one (24)
The procedure for the synthesis of 22 (see Section 4.18)
was repeated with benzaldehyde (0.80 mL, 7.80 mmol)
with 21 (200 mg, 0.78 mmol) afforded 24 (166 mg,
76%); white crystals, mp 194–195 ꢁC; IR (KBr) mmax
3060, 2928, 1653, 1596, 1491, 1447, 1385, 1353, 1093,
808, 767, 676 cmꢀ1 1H NMR (CDCl3, 200 MHz): d
:
;
4.23.3. Compound 29. White crystals, mp 208–209 ꢁC, tR
12.36 min, RP-HPLC on ODS column (Whatman,
5 lm, 6.35 · 250 mm, k 254 nm) using isocratic system
comprised of MeOH–H2O–AcOH (85:15:1) in 20 min
at flow rate of 0.5 mL/min; 1H NMR (CDCl3,
200 MHz): d 7.75 (1H, d, J = 8.7 Hz, H-5), 7.64–7.68
(2H, m, H-20, 60), 7.44–7.53 (3H, m, H-30, 40, 50), 7.03
(1H, d, J = 8.8 Hz, H-6), 7.00 (1H, d, J = 3.2 Hz, H-
8.10 (1H, d, J = 8.6 Hz, H-5), 7.95 (2H, m, H-20, 60),
7.82 (1H, d, J = 5.4 Hz, H-20), 7.80 (1H, dd, J = 8.7,
0.5 Hz, H-6), 7.58 (1H, d, J = 5.4 Hz, H-300), 7.54 (3H,
m, H-30, 40, 50), 6.87 (1H, s, H-3); 13C NMR (CDCl3,
50.32 MHz): d 178.5 (C-4), 162.7 (C-2), 152.3 (C-9),
146.8 (C-7), 132.2 (C-8), 132.1 (C-10), 131.9 (C-40),
129.6 (C-20), 129.5 (C-30, 50), 128.2 (200), 126.5 (C-20,
60), 121.1 (C-5), 120.6 (C-300), 120.4 (C-10), 119.9 (C-
6), 108.6 (C-3); FAB-MS (+ve): 279 [M+H]+. Elemental
analysis: calcd for C17H10O2S: C, 73.36; H, 3.62; S,
11.52. Found: C, 73.54; H, 3.86; S, 11.39.
0
20), 6.66 (1H, d, J = 3.1Hz, H-3 ), 5.28 (1H, d,
Jaa = 12.2 Hz, H-2ax), 4.64 (1H, d, Jaa = 12.2 Hz, H-
3ax), 3.81(3H, s, NCH 3); 13C NMR (CDCl3,
50.32 MHz): d 193.7 (C-4), 161.6 (C-9), 142.3 (C-7),
137.4 (C-10), 129.4 (C-20, 40), 128.9 (C-30, 50), 128.0 (C-
20, 60), 120.7 (C-5), 118.5 (C-10), 110.0 (C-8), 105.2 (C-
6), 101.3 (C-300), 84.7 (C-2), 73.5 (C-3), 33.6 (NCH3);
FAB-MS (pos.): m/z 294 [M+H]+.
4.23. 3-Hydroxy-7-methyl-2-phenyl-7H-pyrano[2,3-e]-
indol-4-one (25)
To a stirred solution of chalcone 12 (200 mg, 0.72 mmol)
in ethanol (10 mL) at 0 ꢁC, was added 10% aqueous
potassium hydroxide (3.6 mL) and 8% hydrogen perox-
ide (0.40 mL). The reaction mixture was stirred at 0 ꢁC
for 5 h. The reaction mixture was diluted with water
(25 mL), extracted with ethyl acetate (3 · 50 mL) and
the extract was washed with water, saturated NH4Cl
and finally with brine. The organic layer separated,
dried over Na2SO3, concentrated and purified by chro-
matographic separation over deactivated silica gel using
benzene as eluent to afford flavonols, 25 (124 mg, 59%)
along with two minor products flavanone, 28 (6 mg,
3%) and flavanonol, 29 (10.5 mg, 5%).
4.23.4. 7-Hydroxy-8-phenyl-9-oxa-3-thia-cyclopenta[a]-
naphthalen-6-one (26). The procedure for the synthesis
of 25 (see Section 4.23) was repeated with chalcone 14
(200 mg, 0.71mmol) and hydrogen peroxide (0.40 mL),
afforded 26 (143 mg, 68%); brown needles, mp 224–
226 ꢁC; IR (KBr) mmax: 3284, 2924, 1639, 1605, 1589,
1
1491, 1377, 1218, 1122, 1033, 748, 689 cmꢀ1; H NMR
(CDCl3, 300 MHz): d 8.29 (2H, br d, J = 7.7 Hz, H-20,
60), 8.11 (1H, d, J = 8.6 Hz, H-5), 7.88 (1H, d,
J = 5.3 Hz, H-200), 7.81(1H, d, J = 8.6 Hz, H-6), 7.61
(1H, d, J = 5.4 Hz, H-300), 7.47–7.56 (3H, m, H-30, 40,
50); 13C NMR (CDCl3, 50.32 MHz): d 173.6 (C-4),
151.7 (C-2), 145.6 (C-9), 144.1 (C-7), 139.3 (C-3),
131.6 (C-10), 130.4 (C-40), 129.6 (C-8), 129.1 (C-30, 50),
128.2 (C-20), 127.9 (C-20, 600), 120.8 (C-30), 120.8 (C-5),
119.6 (C-6), 117.0 (C-10); FAB-MS (pos.): m/z 295
[M+H]+, 589 [2M+H]+. Elemental analysis: calcd for
C17H10O3S: C, 67.37; H, 3.42; S, 10.89. Found: C,
67.55; H, 3.46; S, 11.03.
4.23.1. Compound 25. Yellow crystals, mp 196–197 ꢁC;
1H NMR (CDCl3, 300 MHz):
d
8.32 (2H, d,
J = 7.8 Hz, H-20, 60), 8.00 (1H, d, J = 8.7 Hz, H-5),
7.56 (2H, t, J = 7.8 Hz, H-30, 50), 7.46 (1H, br t,
J = 7.5 Hz, H-40), 7.36 (1H, d, J = 8.7 Hz, H-6), 7.15
(1H, d, J = 3.0 Hz, H-20), 6.98 (1H, d, J = 2.4 Hz, H-
300), 3.89 (3H, s, NCH3); 13C NMR (CDCl3,
50.32 MHz): d 194.0 (C-4), 151.6 (C-2), 143.3 (C-9),
142.4 (C-7), 138.7 (C-3), 132.0 (C-10), 129.9 (C-20),
129.4 (C-40), 128.9 (C-30, 50), 127.8 (C-20, 60), 118.5 (C-
5), 118.2 (C-10), 113.7 (C-8), 108.6 (C-6), 100.4 (C-300),
33.7 (NCH3); FAB-MS (pos.): m/z 292 [M+H]+. Ele-
mental analysis: calcd for C18H13NO3: C, 74.22; H,
4.50; N, 4.81. Found: C, 74.46; H, 4.25; N, 4.99.
4.24. 7-Hydroxy-8-(4-methoxy-phenyl)-9-oxa-3-thia-
cyclopenta[a]naphthalen-6-one (27)
The procedure for the synthesis of 25 (see Section 4.23)
was repeated with chalcone 15 (200 mg, 0.64 mmol) and
hydrogen peroxide (0.40 mL), afforded 27 (135 mg,
65%); dirty yellow amorphous powder; IR (KBr) mmax
3448, 2925, 1630, 1598, 1459, 1418, 1350, 1259, 1179,
1114, 1028, 749, 693 cmꢀ1 1H NMR (CDCl3 +
:
4.23.2. Compound 28. Yellow crystals, mp 149–150 ꢁC,
tR 12.88 min, RP-HPLC on ODS column (Whatman,
5 lm, 6.35 · 250 mm, k 254 nm) using isocratic system
comprised of MeOH–H2O–AcOH (85:15:1) in 20 min
at flow rate of 0.5 mL/min; 1H NMR (CDCl3,
200 MHz): d 7.79 (1H, d, J = 8.7 Hz, H-5), 7.55 (2H,
m, H-20, 60), 7.38–7.49 (3H, m, H-30, 40, 50), 6.96–7.01
;
DMSO-d6, 200 MHz): d 8.85 (1H, br s, OH), 8.31 (2H,
d, J = 8.5 Hz, H-20, 60), 8.08 (1H, d, J = 8.6 Hz, H-5),
7.94 (1H, d, J = 4.8 Hz, H-20), 7.88 (1H, br d, H-6),
7.77 (1H, d, J = 4.6 Hz, H-300), 7.07 (2H, d, J =
8.7 Hz, H-30, 60), 3.90 (3H, s, OCH3); 13C NMR
(CDCl3, 75 MHz): d 173.0 (C-4), 161.0 (C-40), 151.1

P. P. Yadav et al. / Bioorg. Med. Chem. 13 (2005) 1497–1505
1505
(C-9), 145.0 (C-2), 144.3 (C-7), 138.1 (C-3), 132.3 (C-10),
129.3 (C-20, 60), 127.7 (C-20), 123.7 (C-8), 120.4 (C-30, 50
and C-5), 119.1 (C-300), 116.7 (C-10), 114.2 (C-6),
55.4 (OCH3); FAB-MS (pos.): m/z 325 [M+H]+, 649
[2M+H]+. Elemental analysis: calcd for C18H12O4S: C,
66.65; H, 3.73; S, 9.89. Found: C, 66.94; H, 3.58; S,
9.97.
6. Yadav, P. P.; Ahmad, G.; Maurya, R. Phytochemistry
2004, 65, 439–443.
7. Ahmad, G.; Yadav, P. P.; Maurya, R. Phytochemistry
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Anderson, W.; Hope, W.; Meyers, K.; Coffey, J. W. In
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4.25. Biological evaluation
The fungal and the bacterial strains were grown on Sab-
roaud dextrose agar and nutrient agar media respec-
tively. After the incubation fungal and bacterial
growth were suspended in normal saline and maintained
at 1.0–5.0 · 103 cfu/mL. The activity of compounds was
determined by the NCCLS method for fungus using
RPMI-1640 media buffered with MOPS (3-[N-morpho-
lino]propanesulfonic acid) (Sigma Chemical Co.) and
Mueller Hinton broth for bacteria. The 96-well tissue
culture plates were used for twofold serial dilution.
The proper growth control, drug control and the blank
were adjusted onto the plate. Compounds were dis-
solved in DMSO at a concentration of 1mg/mL and
20 lL of this was added to 96-well tissue culture plate
having 180 lL RPMI-1640 so the maximum concentra-
tion of the compound became 50 lg/mL. From here the
solution was serially diluted resulting into the half of the
concentration of test compounds and then inoculum was
added and kept for incubation. Micro-titer plates were
incubated at 35 ꢁC in a moist, dark chamber and MICs
were recorded spectrophotometrically.
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Authors are thankful to ICMR, New Delhi for financial
assistance.
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1997. Reference method for broth dilution antifungal
susceptibility testing of yeast, Approved standard docu-
ment M 27-A. National Committee for Clinical Labora-
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1998. Reference method for broth dilution antifungal
susceptibility testing of conidium-forming filamentous
fungi: proposed standard. Document M 38-P. National
Committee for Clinical Laboratory Standards, Wayne,
PA, USA.