Cyclization routes for the synthesis of functionalized pyrano[2,3-b ]indolones, pyrazolo[3,4-b]indoles, and furo[2,3-b]indoles

Article abstract of DOI:10.1055/s-0032-1316870

The synthesis of biologically active core structures containing pyrano[2,3-b]indol-2(9H)-ones, pyrano[2,3-b]indol-4(9H)-ones, pyrazolo[3,4-b]indoles, and furo[2,3-b]indoles are described. Pyrano[2,3-b]indol-2(9H)-ones are synthesized by three different me

Full text of DOI:10.1055/s-0032-1316870

PAPER
▌1235
paper
Cyclization Routes for the Synthesis of Functionalized Pyrano[2,3-b]indolones,
Pyrazolo[3,4-b]indoles, and Furo[2,3-b]indoles
Cyclization Routes to Pyrano-, Pyrazolo-, and Furo-Fused Indoles
Arepalli Sateesh Kumar, Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Fax +91(40)23012460; E-mail: rnsc@uohyd.ernet.in
Received: 08.12.2012; Accepted after revision: 03.03.2013
As documented in the literature, some indole-fused pyra-
Abstract: The synthesis of biologically active core structures con-
none scaffolds act as inhibitors of hepatitis C virus NS5B
taining pyrano[2,3-b]indol-2(9H)-ones, pyrano[2,3-b]indol-4(9H)-
polymerase7 and are good precursors in the synthesis of
ones, pyrazolo[3,4-b]indoles, and furo[2,3-b]indoles are described.
Pyrano[2,3-b]indol-2(9H)-ones are synthesized by three different
pharmaceutically important β-carbolines.8 The core struc-
metal-free syntheses (DCC, DMSO; CDI, DBU, CH2Cl2; or Mukai- ture of furo[2,3-b]indole is also present in many natural
products9 that possess wide range of biological activity;
madindolines A and B are selective inhibitors of interleu-
yama’s reagent, Et3N, MeCN) and pyrano[2,3-b]indol-4(9H)-ones
are prepared by one-pot or two-step synthesis. Pyrazolo[3,4-b]in-
doles are synthesized by Fischer indole type cyclization and
kin-62 (Figure 2).10 Moreover this ring system and its de-
McMurry coupling is employed for the synthesis of furo[2,3-b]in-
doles. All these core structures are synthesized from simple, com-
rivatives are expedient as synthetic intermediates in the
synthesis of several alkaloids.
mon 3-acetylindol-2-ols.
The pyrazolo[3,4-b]indole skeleton also displays antiviral
Key words: pyrano[2,3-b]indolones, pyrazolo[3,4-b]indoles, fu-
ro[2,3-b]indoles, Mukaiyama’s reagent, Fischer indole type cycli-
zation
activity against HCMV (human cytomegalovirus).11
A
survey of literature disclosed, to the best of our knowl-
edge, that the synthesis pyrano[2,3-b]indol-2(9H)-ones,
pyrano[2,3-b]indol-4(9H)-ones, and pyrazolo[3,4-b]in-
doles have been reported sporadically.4f,12 Indeed, even
today there has been much interest in developing efficient
methods for the synthesis of these fused molecular core
structures.
‘Privileged’ indole ring structures are found in many bio-
logically active natural products, pharmaceutical agents,1
and synthetic compounds of vital medicinal value.2 As a
result, great efforts have been dedicated to the synthesis of
various fused indoles, and numerous efficient methods
have been documented.3 In addition, pyranones (pyran-2-
ones and pyran-4-ones)4 are also an important class of or-
ganic compounds, they form the backbone of many natu-
rally occurring, biologically active compounds.5 The
pyrazole motif is also found in a number of small mole-
cules that possess a wide range of agricultural and phar-
maceutical properties6 and some pyrazoles are used in
supramolecular and polymer chemistry, in the food indus-
try, and as cosmetic colorings. Remarkably, the pyrazole
motif is also present in the blockbuster drug, Sildenafil ci-
trate (Viagra),6g and a potent anticancer agent, WYE-
354,6h as well as in antifungal compounds. Therefore, a
fusion of these two core structures could potentially lead
to a series of biologically and structurally interesting com-
pounds (Figure 1).
The ubiquity of these molecular core structures in many
biologically and pharmaceutically important molecules
encouraged us to explore synthetic methods for their con-
struction. Keeping the reported synthetic methods in
mind,4f,12 we decided to explore metal-free synthetic
routes to pyrano[2,3-b]indol-2(9H)-ones, pyrano[2,3-
b]indol-4(9H)-ones (are also termed as isomeric pyra-
no[3,4-b]indolones or indolo[2,3-c]pyranones), and pyr-
azolo[3,4-b]indoles from one common substrate 1-
substituted 3-acetyl-1H-indol-2-ols 1, which were easily
prepared.13 Initially, we attempted the synthesis of pyra-
no[2,3-b]indol-2(9H)-ones 3a–g through Pechmann and
Perkin condensation procedures14 that involve the use of
excess acetic anhydride, acyl chlorides, high tempera-
tures, and strong acids, however, these routes gave the
O
N
O
O
NH
O
N
N
R
N
R
O
N
R
R
Figure 1 Indole fused with biologically active scaffolds
SYNTHESIS 2013, 45, 1235–1246
Advanced online publication: 27.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316870; Art ID: SS-2012-Z0947-OP
© Georg Thieme Verlag Stuttgart · New York

1236
A. S. Kumar, R. Nagarajan
PAPER
H2N
Cl
Cl
N
O
O
N
N
Cl
HO
OH
OH
NH
Cl
HO
N
N
N
N
O
O
O
O
O
O
OH
HO
OH
HO
madindoline B
pyrazolo[3,4-b]indole nucleosides having
madindoline A
antiviral and cytotoxic activity
O
O
CN
O
O
N
H
NH2
N
H
O
N
Et
O
N
H
HO2C
R
HO2C
Etodolac
(anti-inflammatory)
Pemedolac
(analgesic)
chromenopyrano[2,3-b]indole
dihydropyrano[2,3-b]indole
Figure 2 Various pyrazolo[3,4-b]indole nucleosides with antiviral and cytotoxic activity, novel bioactive microbial metabolites with furo[2,3-
b]indole core structures, and some important pyrano[2,3-b]indoles
products in very low yields (10–20%) with high reaction in dimethyl sulfoxide at 110 °C, gave 3a–g in moderate
times.
yields (55–63%) (Table 1).
To facilitate the reaction condition for the synthesis of py- In method A, we noticed that the reaction of phenylacetic
rano[2,3-b]indol-2(9H)-ones 3a–g, we developed three acids 2a–c with N,N′-dicyclohexylcarbodiimide provided
synthetic methods, methods A–C (Table 1). Method A, in insufficient activation to enabled them to react efficiently
which we used N,N′-dicyclohexylcarbodiimide15 as a de- with 1-substituted 3-acetyl-1H-indol-2-ols 1a–d. We then
hydrating agent in the reaction between 1-substituted 3- examined the use of various activating/dehydration agents
acetyl-1H-indol-2-ols 1a–d and phenylacetic acids 2a–c in this reaction and found that 1,1′-carbonyldiimidazole
Table 1 Synthesis of Pyrano[2,3-b]indol-2(9H)-ones and the Scope of the Different Reaction Protocols
R3
R2
DCC, DMSO, 110 °C, 6–8 h
HOOC
method A
Ac
CDI, DBU, CH2Cl2, 20–24 h, r.t.
+
OH
N
R1
method B
R3
O
O
R2
N
R1
Mukaiyama's reagent, Et3N
MeCN, reflux, 5–8 h
method C
1a R1 = Et
1b R1 = Bn
1c R1 = Bu
2a R2 = R3 = H
3a–g
2b R2 = H, R3 = NO2
2c R2 = NO2, R3 = H
method A 55–63%
method B 60–72%
method C 74–80%
1d R1 = hexyl
Product
Method A
Method B
Method C
Time (h)
R1
R2
R3
Time (h)
Yielda (%)
Time (h)
Yielda (%)
Yielda (%)
3a
3b
3c
3d
3e
3f
Et
H
H
8
7
6
6
8
8
8
59
61
62
63
57
55
60
24
22
20
20
24
24
24
69
70
70
72
65
60
68
8
6
5
5
8
8
7
74
76
78
80
77
74
79
Et
H
NO2
H
Bn
H
Bn
H
NO2
H
Bu
H
hexyl
hexyl
H
H
3g
NO2
H
a Isolated yields.
Synthesis 2013, 45, 1235–1246
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Cyclization Routes to Pyrano-, Pyrazolo-, and Furo-Fused Indoles
1237
O
O
O
O
N
Ar
Ar
H
+
O
O
N
N
Ar
O
N
HN
I
N
+
+
N
II
N
N
CO2
N
HN
R
2a–c
CDI
N
N
HO
1a–d
O
O
Ar
Ar
base
O
intramolecular
aldol reaction
O
O
N
R
O
N
R
III
3a–g
Scheme 1 Possible mechanism of the 1,1′-carbonyldiimidazole-mediated formation of 3
(CDI)16 was an attractive candidate. In method B, the re- ids 2a–c (1.2 equiv), and excess triethylamine in dry ace-
action of phenylacetic acids 2a–c with 1,1′-carbonyldi- tonitrile at reflux temperature. We were delighted to
imidazole provided sufficient activation, in comparison to obtain the desired products pyrano[2,3-b]indol-2(9H)-
N,N′-dicyclohexylcarbodiimide, and thus enabled them to ones 3a–g in good yields (74–80%) (Table 1).
react smoothly with 1-substituted 3-acetyl-1H-indol-2-ols
1a–d in the presence of organic base 1,8-diazabicy-
Method C was found to be general, and was almost equal-
ly successful in scope (Scheme 2) with both electron-rich
clo[5.4.0]undec-7-ene in dichloromethane (Scheme 1).
or electron-deficient substrates, and the yields were also
The reactions proceeded at room temperature and were
quite satisfactory. The possible mechanism for the reac-
complete in 20–24 hours, providing the desired pyra-
tion mediated by Mukaiyama’s reagent is depicted in
Scheme 2.
no[2,3-b]indol-2(9H)-ones 3a–g in good yields (60–72%)
(Table 1). The use of alternative bases (DABCO, Et3N,
t-BuOK, MeONa, Cs2CO3, K2CO3) was examined for a
model reaction under the conditions of method B, but
The reaction mechanism probably, in the first instance in-
volves phenylacetic acids 2a–c attacking the iminium
component of Mukaiyama’s reagent. Subsequent release
these were not as effective as 1,8-diazabicyclo[5.4.0]un-
of the chloride ion leads to the key acyloxy intermediate
dec-7-ene. The reaction conditions required 1-substituted
IV, which is highly susceptible to nucleophilic attack by
3-acetyl-1H-indol-2-ols 1a–d (1 equiv), phenylacetic
1a–d, providing III, which is undergoes intramolecular
acids 2a–c (1 equiv), 1,1′-carbonyldiimidazole (1.2
aldol reaction followed by dehydration to give pyra-
equiv), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5
no[2,3-b]indol-2(9H)-ones 3a–g.
equiv) in dichloromethane with stirring at room tempera-
ture. The proposed mechanism in method B using 1,1′-
carbonyldiimidazole is shown in Scheme 1, the first step
involves partial protonation of the basic imidazole nitro-
gen by 2a–c, protonated N-acetylimidazole has a pKa of
3.616i leading to an activated species that is then attacked
by the carboxylate. The resulting mixed anhydride I loses
carbon dioxide giving rise to N-acylimidazole II, which
on treatment with 1a–d leads to the formation of 3-acetyl-
2-(arylacetoxy)-1H-indoles III. After the formation of
III, intramolecular base catalyzed aldol reaction followed
by dehydration provided 3a–g.
Next, we focused to obtain the reaction condition for the
synthesis of 3-acetyl-2-(acyloxy)-1H-indole derivatives
4a–j; we screened various bases (NaOH, K2CO3, Cs2CO3,
DABCO, Et3N, DBU) and solvents (toluene, MeOH,
DMF, DMSO, THF, CH2Cl2, dioxane). Of these, triethyl-
amine and dichloromethane were suitable for the reaction
and the reaction condition found to involve 1-substituted
3-acetyl-1H-indol-2-ols 1a–d (1.0 equiv), triethylamine
(2.0 equiv), and freshly prepared acid chloride (2.0 equiv)
in dichloromethane that was stirred at room temperature
to afford 3-acetyl-2-(acyloxy)-1H-indoles 4a–j in good
yields (68–86%) (Table 2).
Inspired by the reports that 2-chloro-1-methylpyridinium
iodide (Mukaiyama’s reagent)17 can be used to bring
about esterification. We envisioned a similar reaction can
be effected between 1-substituted 3-acetyl-1H-indol-2-ols
1a–d and phenylacetic acids 2a–c in method C, which in-
volves Mukaiyama’s reagent (2.0 equiv), 1-substituted 3-
acetyl-1H-indol-2-ols 1a–d (1.0 equiv), phenylacetic ac-
Subsequently, we focused on the synthesis of pyrano[2,3-
b]indol-4(9H)-ones 5a–i. To synthesize these compounds,
we explored two methods (Table 3). Method I (which can
be also termed as a sequential acylation–base-mediated
cyclization), a one-pot synthesis, that started from 1a–d
using acid chloride and triethylamine, and dichlorometh-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1235–1246

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A. S. Kumar, R. Nagarajan
PAPER
O
O
O
base
– Cl–
Ar
H
+
N
Cl
+
O
Ar
I–
H
N
O
I–
N
Me
O
2a–c
1a–d
Me
R
IV
O
Ar
Ar
intramolecular aldol
base, reflux
O
O
O
O
N
N
R
R
3a–g
III
Scheme 2 Possible mechanism of the Mukaiyama’s reagent mediated formation of 3
ane in a reaction to give 4a–j, which was monitored by synthesis, the first step was the synthesis of 3-acetyl-2-
TLC until completion, then the reaction solvent was evap- (acyloxy)-1H-indole derivatives 4a–j (Table 2), and in the
orated under reduced pressure, and sodium hydride and second step sodium hydride in tetrahydrofuran was added
tetrahydrofuran were added directly, and the reaction was to the isolated 4a–j and the reaction was continued at re-
continued at reflux temperature. Method II, a two-step flux temperature. By using both of these methods, we syn-
thesized the various 2,9-substituted pyrano[2,3-b]indol-
Table 2 Synthesis of 3-Acetyl-2-(acyloxy)-1H-indoles and the
Scope of the Reaction Substrates
4(9H)-ones 5a–i in good yields (Table 3).
The 3-acetyl-2-(acyloxy)-1H-indole derivatives 4 were
also submitted to the McMurry18 titanium-promoted cou-
Ac
Ac
O
R2COCl, Et3N
pling reaction to prepare 2,3,8-trisubstituted furo[2,3-
R2
OH
CH2Cl2, r.t.
b]indoles, such as 8-ethyl-3-methyl-2-phenyl-8H-fu-
ro[2,3-b]indole (6a) and 8-benzyl-2,3-dimethyl-8H-fu-
ro[2,3-b]indole (6b) (Table 4). The yields were very low
(<10%) when the indole moiety contained alkyl substitu-
ents such as butyl and hexyl at the 8-position of the fu-
ro[2,3-b]indole.
N
R1
O
N
R1
1a R1 = Et
4a–j
1b R1 = Bn
1c R1 = Bu
1d R1 = hexyl
68–86%
Product
Time (h)
Yielda (%)
The initial approach to the synthesis of pyrazolo[3,4-b]in-
doles 7a–e from 1-substituted 3-acetyl-1H-indol-2-ols
1a–d examined the use of 1a and phenylhydrazine in var-
ious solvents [DMF or DMSO (at 110 °C); CH2Cl2, diox-
ane, toluene, MeOH, EtOH, t-BuOH (at reflux)]; ethanol
is the most suitable solvent for this reaction (Table 5).
R1
R2
4a
4b
4c
4d
4e
4f
Et
Me
Ph
6
4
81
81
77
80
78
68
80
82
86
86
Et
Bn
Me
Ph
6
On the reaction of 1-substituted 3-acetyl-1H-indol-2-ols
1a–d with hydrazine hydrochloride or phenylhydrazine
hydrochloride derivatives in acidic ethanol, pyrazolo[3,4-
b]indoles 7a–d were obtained in good yields as shown in
Table 6. Acetic acid or hydrochloric acid usage was ideal.
Bn
4
Bn
2-thienyl
6
Bu
Me
5
4g
4h
4i
Bu
Ph
10
10
10
12
The reaction mechanism probably follows the Fischer in-
dole type mechanism.19 Under acidic conditions the in-
dolic hydroxy group tautomerizes to a keto hydrazine,
which undergoes cyclodehydration to afford the pyrazo-
lo[3,4-b]indoles 7a–d as depicted in Scheme 3.
Bu
2-thienyl
Me
hexyl
hexyl
4j
Ph
a Isolated yields.
Synthesis 2013, 45, 1235–1246
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Cyclization Routes to Pyrano-, Pyrazolo-, and Furo-Fused Indoles
1239
Table 3 Synthesis of Pyrano[2,3-b]indol-4(9H)-ones and the Scope of the Reaction Substrates
method I: one-pot synthesis (i), (ii)
O
O
O
O
step 2
(ii)
step 1
(i)
R2
R2
O
O
N
R1
OH
N
N
R1
R1
5a–i
4a–j (isolated)
1a–d
method II: two-step synthesis
(i) R2COCl, Et3N, CH2Cl2, r.t.; (ii) NaH, THF, reflux
Product
Method I
Method II
Time (h)
R1
R2
Time (h)
Yielda (%)
Yieldb (%)
5a
5b
5c
5d
5e
5f
Et
Me
10
8
67
70
72
70
62
67
75
60
71
6
8
5
6
5
5
7
7
8
71
74
77
76
68
70
78
78
76
Et
Ph
Bn
Me
6
Bn
2-thienyl
Me
7
Bu
6
Bu
Ph
7
5g
5h
5i
Bu
2-thienyl
Me
7
hexyl
hexyl
9
Ph
10
a Isolated yield from 1.
b Isolated yield from 4.
Table 5 Effect of Solvent in the Formation of 8-Ethyl-3-methyl-1-
phenyl-1,8-dihydropyrazolo[3,4-b]indole (7b)
Table 4 Titanium-Mediated Coupling for the Preparation of Substi-
tuted Furo[2,3-b]indoles
Ac
N
PhNHNH2
O
N
OH
solvent, 110 °C or reflux
N
N
R2
O
TiCl4, Zn-Cu
DME, reflux
Et
Et
R2
O
1a
7b
O
N
N
R1
R1
Solvent
Temp (°C)
Yield (%)
4b,c
6a,b
DMSO
DMF
110
55
52
46
25
34
72
62
57
Product
R1
R2
Time (h)
Yielda (%)
110
6a
6b
Et
Ph
24
24
65
70
CH2Cl2
toluene
dioxane
EtOH
reflux
reflux
reflux
reflux
reflux
reflux
Bn
Me
a Isolated yield.
MeOH
t-BuOH
© Georg Thieme Verlag Stuttgart · New York
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A. S. Kumar, R. Nagarajan
PAPER
O
NNH2
OH
NH
NH2HCl
NH
NH2HCl
NH2NH2
HCl
OH
OH
N
N
N
O
N
R
R
R
R
1a–d
H+
H+
NH
N
N
H
N
N
N
N
N
R
N
R
H
H
H
OH
R
7a–e
Scheme 3 Possible mechanism for the synthesis of pyrazolo[3,4-b]indoles from 1-substituted 3-acetyl-1H-indol-2-ols 1a–d
Table 6 Preparation of Substituted Pyrazolo[3,4-b]indoles by
Fischer Indole Type Cyclization
on FT/IR-5300 spectrophotometer. Mass spectra were recorded us-
ing EI technique on a LCMS-2010A mass spectrometer. Elemental
analyses (C, H, and N) were recorded on EA 1112 analyzer in the
School of Chemistry, University of Hyderabad. Routine monitoring
of the reactions was performed using TLC silica gel plates 60 F254;
compounds were visualized with UV light at 254 nm with further
visualization by staining with I2. Column chromatography was car-
ried out employing neutral alumina. Commercially available re-
agents and solvents were used without further purification. Melting
points were measured in open capillary tubes and are uncorrected.
Ac
R2NHNH2 (excess)
acid, EtOH, reflux
N
N
OH
R2
N
N
R1
R1
1a–d
7a–d
Product
R1
R2
Time (h) Yielda (%)
Pyrano[2,3-b]indol-2(9H)-ones 3a–g; General Procedure,
Method A
7a
7b
7c
7d
7e
Et
H
12
14
15
18
16
77
72
65
68
65
A soln of 1a–d (1.0 equiv) and phenylacetic acid 2a–c (1.25 equiv)
in DMSO and DCC (1.5 equiv) was heated in an oil bath at 110 °C
for 6–8 h (see Table 1). Crushed ice (20 mL) and AcOH (3.0 mL)
were added to the mixture. The mixture was kept at r.t. for 2–4 h,
and then it was extracted with EtOAc (3 × 50 mL). The organic lay-
er was extracted with 5% NaHCO3 soln (50 mL) and then washed
with H2O (20 mL). The solvent was evaporated under vacuum and
the dry residue was purified by column chromatography (hexanes–
EtOAc, 9:1) to afford pure 3a–g.
Et
Ph
Bu
Bu
hexyl
4-NCC6H4
3-O2NC6H4
3-O2NC6H4
a Isolated yield.
Pyrano[2,3-b]indol-2(9H)-ones 3a–g; General Procedure,
Method B
In summary, three different metal-free synthetic routes for
the preparation of pyrano[2,3-b]indol-2(9H)-ones 3a–g
have been developed. The first approach is based on the
use of N,N′-dicyclohexylcarbodiimide in dimethyl sulfox-
ide, the second pathway involves the usage of 1,1′-carbon-
yldiimidazole and 1,8-diazabicyclo[5.4.0]undec-7-ene in
dichloromethane, and the third pathway involves the us-
age of the Mukaiyama’s reagent esterification protocol.
The pyrano[2,3-b]indol-4(9H)-ones 5a–i are prepared by
one-pot and two-step synthesis in good yields. Pyrazo-
lo[3,4-b]indoles 7a–d are synthesized by Fischer indole
type cyclization with hydrazine hydrate or phenylhydra-
zines. 3-Acetyl-2-(acyloxy)-1H-indoles 4a–j are used as
good precursors for the synthesis of furo[2,3-b]indoles
6a,b as well as pyrano[2,3-b]indol-4(9H)-ones 5a–i.
A soln of phenylacetic acid 2a–c (1.0 equiv) in CH2Cl2 (5 mL) and
CDI (1.2 equiv) was stirred at r.t. for 30 min. This soln was added
dropwise to a mixture of 1a–d (1.0 equiv) in CH2Cl2 (5 mL) and
DBU (1 equiv). The mixture was stirred for 20–24 h (see Table 1)
at r.t. The mixture was acidified with 10% HCl and stirred vigorous-
ly for 30 min. The organic phase was separated, dried (anhyd
Na2SO4), filtered, and evaporated to give the crude product. Purifi-
cation by column chromatography (hexanes–EtOAc, 9:1) afforded
pure 3a–g.
Pyrano[2,3-b]indol-2(9H)-ones 3a–g; General Procedure,
Method C
To a soln of 2-chloro-1-methylpyridinium iodide (Mukaiyama’s re-
agent) (2.0 equiv) in anhyd MeCN were added phenylacetic acid
2a–c (1.2 equiv), 1a–d (1.0 equiv), and Et3N (2.5 equiv). The reac-
tion was gently refluxed under N2 for 5–8 h (see Table 1). The mix-
ture was concentrated under reduced pressure and the residue was
treated with dilute HCl. The solid product obtained was filtered,
dried, and purified by column chromatography (hexanes–EtOAc,
9:1) to afford pure 3a–g.
1H and 13C NMR spectra were recorded on AV-400 spectrometer
operating at 400 and 100 MHz, respectively, relative to TMS (1H:
δ = 0.00) or CDCl3 (13C: δ = 77.0). Chemical shifts of common trace
1H NMR impurities (CDCl3): H2O, δ = 1.56; EtOAc, δ = 1.26, 2.05,
4.12; CH2Cl2, δ = 5.30; CDCl3, δ = 7.26. IR spectra were recorded
9-Ethyl-4-methyl-3-phenylpyrano[2,3-b]indol-2(9H)-one (3a)
Colorless solid; yield: 110 mg (74%, method C); mp 271–273 °C.
IR (KBr): 3055, 2926, 1718, 1563, 1531, 1494, 1454, 1323, 1157,
1113, 1022, 1005, 740, 696 cm–1.
Synthesis 2013, 45, 1235–1246
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cyclization Routes to Pyrano-, Pyrazolo-, and Furo-Fused Indoles
1241
1H NMR (400 MHz, TMS, CDCl3): δ = 7.77–7.75 (m, 1 H), 7.63–
7.52 (m, 2 H), 7.46–7.44 (m, 2 H), 7.31–7.24 (m, 4 H), 4.08 (q,
J = 8.0 Hz, 2 H), 2.68 (s, 3 H), 1.15–0.92 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 169.9, 151.8, 143.6, 142.4,
137.9, 136.0, 134.3, 130.5, 128.9, 128.4, 124.9, 123.4, 122.5, 122.2,
120.0, 110.9, 104.0, 45.4, 30.8, 13.6.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.16–8.14 (m, 2 H), 7.85–
7.83 (m, 1 H), 7.64–7.62 (m, 1 H), 7.59–7.55 (m, 2 H), 7.47–7.32
(m, 3 H), 4.42 (t, J = 8.0 Hz, 2 H), 2.72 (s, 3 H), 1.88–1.80 (m, 2 H),
1.32–1.25 (m, 2 H), 0.93–0.90 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 166.1, 143.6, 134.5, 133.2,
132.8, 128.9, 128.2, 128.0, 127.7, 127.6, 126.9, 125.0, 122.5, 122.3,
119.9, 111.0, 104.0, 45.8, 30.7, 30.6, 20.1, 13.7.
LC-MS (+ mode): m/z = 304.15 [M + H].
LC-MS (+ mode): m/z = 332.45 [M + H].
Anal. Calcd for C20H17NO2: C, 79.19; H, 5.65; N, 4.62. Found: C,
79.28; H, 5.71; N, 4.53.
Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found: C,
79.65; H, 6.31; N, 4.32.
9-Ethyl-4-methyl-3-(3-nitrophenyl)pyrano[2,3-b]indol-2(9H)-
one (3b)
Dirty colorless solid; yield: 130 mg (76%, method C); mp 271–
273 °C.
9-Hexyl-4-methyl-3-phenylpyrano[2,3-b]indol-2(9H)-one (3f)
Pale yellow solid; yield: 102 mg (74%, method C); mp 271–273 °C.
IR (KBr): 3032, 2911, 1768, 1590, 1434, 1363, 1257, 1133, 1015,
749, 670 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.85–7.83 (m, 2 H), 7.64–
7.62 (m, 1 H), 7.59–7.55 (m, 3 H), 7.48–7.45 (m, 1 H), 7.34–7.29
(m, 2 H), 4.42 (t, J = 8.0 Hz, 3 H), 2.73 (s, 3 H), 1.88–1.80 (m, 2 H),
1.30–1.28 (m, 2 H), 1.00–0.89 (m, 6 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 163.4, 156.5, 143.1, 136.8,
134.8, 131.8, 129.5, 126.3, 123.1, 122.6, 122.2, 120.2, 117.5, 116.9,
115.4, 110.5, 109.8, 46.8, 31.9, 30.9, 27.6, 24.6, 20.1, 13.6.
IR (KBr): 3021, 2913, 1745, 1538, 1361, 1212, 1131, 1232, 1035,
720, 630 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 9.36 (s, 1 H), 8.85–8.84 (m,
1 H), 8.42–8.40 (m, 1 H), 7.84–7.82 (m, 1 H), 7.51–7.47 (m, 2 H),
7.34–7.32 (m, 2 H), 4.39 (q, J = 8.0 Hz, 2 H), 2.71 (s, 3 H), 1.51 (t,
J = 8.0 Hz, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 165.2, 153.2, 149.5, 142.6,
136.0, 135.4, 134.4, 129.0, 128.6, 128.4, 124.9, 123.6, 122.7, 122.6,
120.0, 110.9, 104.2, 41.1, 30.5, 14.0.
LC-MS (+ mode): m/z = 360.60 [M + H].
LC-MS (+ mode): m/z = 349.25 [M + H].
Anal. Calcd for C24H25NO2: C, 80.19; H, 7.01; N, 3.90. Found: C,
80.06; H, 6.89; N, 3.98.
Anal. Calcd for C20H16N2O4: C, 68.96; H, 4.63; N, 8.04. Found: C,
68.81; H, 4.58; N, 8.12.
9-Hexyl-4-methyl-3-(3-nitrophenyl)pyrano[2,3-b]indol-2(9H)-
one (3g)
Pale brown solid; yield: 123 mg (79%, method C); mp 271–273 °C.
9-Benzyl-4-methyl-3-phenylpyrano[2,3-b]indol-2(9H)-one (3c)
Colorless solid; yield: 107 mg (78%, method C); mp 271–273 °C.
IR (KBr): 3065, 2956, 1748, 1598, 1542, 1494, 1450, 1348, 1151,
1127, 1020, 1095, 790, 656 cm–1.
IR (KBr): 3039, 2970, 1748, 1593, 1463, 1343, 1152, 1112, 1022,
677 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.13–8.11 (m, 2 H), 7.58–
7.35 (m, 4 H), 7.20–7.00 (m, 6 H), 6.98–6.96 (m, 1 H), 6.76–6.58
(m, 1 H), 4.86 (s, 2 H), 2.74 (s, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 167.6, 160.5, 140.8, 136.1,
134.3, 133.6, 130.5, 130.4, 129.7, 129.0, 128.8, 128.7, 128.6, 127.9,
127.5, 127.3, 127.1, 123.6, 122.8, 122.3, 121.9, 121.0, 116.7, 108.8,
43.5.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.84–7.81 (m, 1 H), 7.65–
7.63 (m, 1 H), 7.44–7.42 (m, 1 H), 7.34–7.29 (m, 1 H), 7.20–7.19
(m, 4 H), 4.39 (t, J = 8.0 Hz, 2 H), 2.71 (s, 3 H), 1.88–1.83 (m, 2 H),
1.33–1.28 (m, 6 H), 0.92–0.84 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 160.6, 143.2, 138.2, 136.8,
134.5, 132.4, 128.2, 127.6, 126.4, 125.0, 123.1, 122.6, 119.9, 116.9,
111.0, 109.8, 103.9, 46.0, 31.3, 30.5, 28.6, 26.5, 22.5, 13.9.
LC-MS (+ mode): m/z = 366.15 [M + H].
LC-MS (+ mode): m/z = 405.60 [M + H].
Anal. Calcd for C25H19NO2: C, 82.17; H, 5.24; N, 3.83. Found: C,
82.06; H, 5.32; N, 3.75.
Anal. Calcd for C24H24N2O4: C, 71.27; H, 5.98; N, 6.93. Found: C,
71.27; H, 5.91; N, 6.85.
9-Benzyl-4-methyl-3-(3-nitrophenyl)pyrano[2,3-b]indol-2(9H)-
one (3d)
3-Acetyl-2-(acyloxy)-1H-indoles 4a–j; General Procedure
To 1a–d (1.0 equiv) in CH2Cl2 was added Et3N (2.0 equiv), stirred
at r.t. for 15 min. Then the mixture was cooled in an ice bath and
freshly prepared acid chloride (2.0 equiv) was added dropwise. The
mixture was stirred for 15 min, and then it was brought up to r.t. and
stirred for up to 2 h. H2O was added to the mixture, and it and ex-
tracted with CH2Cl2, washed with brine (20 mL), and dried (anhyd
Na2SO4). The solvent was evaporated and the crude material was
purified by column chromatography (1% EtOAc–hexanes) to obtain
pure 4a–j.
Pale brown solid; yield: 123 mg (80%, method C); mp 271–273 °C.
IR (KBr): 3032, 2930, 1756, 1593, 1432, 1414, 1330, 1120, 1222,
1010, 790, 650 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.58 (s, 1 H), 7.68–7.64 (m,
4 H), 7.57–7.50 (m, 1 H), 7.47–7.40 (m, 4 H), 7.38–7.14 (m, 3 H),
4.55 (s, 2 H), 2.73 (s, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 168.7, 155.9, 142.9, 135.9,
131.4, 130.2, 128.9, 128.4, 128.2, 128.0, 127.9, 127.7, 126.5, 126.4,
126.2, 126.0, 124.2, 123.8, 123.1, 122.3, 121.7, 121.3, 109.6, 45.2,
14.3.
3-Acetyl-1-ethyl-1H-indol-2-yl Acetate (4a)
Colorless solid; yield: 97 mg (81%); mp 172–174 °C.
IR (KBr): 3292, 2976, 1752, 1739, 1689, 1417, 1267, 1159, 1105,
1022, 800, 748 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.51–7.49 (m, 1 H), 7.28–
7.25 (m, 1 H), 7.04–7.00 (m, 1 H), 6.85–6.83 (m, 1 H), 3.82 (q,
J = 4.0 Hz, 2 H), 2.71 (s, 3 H), 2.40 (s, 3 H), 1.28 (t, J = 4.0 Hz, 3
H).
LC-MS (+ mode): m/z = 410.13 [M + H].
Anal. Calcd for C25H18N2O4: C, 73.16; H, 4.42; N, 6.83. Found: C,
73.25; H, 4.51; N, 6.71.
9-Butyl-4-methyl-3-phenylpyrano[2,3-b]indol-2(9H)-one (3e)
Colorless solid; yield: 110 mg (77%, method C); mp 271–273 °C.
13C NMR (100 MHz, TMS, CDCl3): δ = 167.3, 167.0, 159.7, 140.8,
128.6, 123.4, 121.8, 121.1, 116.4, 107.8, 34.3, 21.2, 18.1, 12.7.
IR (KBr): 3022, 2956, 1748, 1523, 1494, 1328, 1127, 1110, 1052,
1035, 740, 666 cm–1.
LC-MS (+ mode): m/z = 246.15 [M + H].
Synthesis 2013, 45, 1235–1246
© Georg Thieme Verlag Stuttgart · New York

1242
A. S. Kumar, R. Nagarajan
PAPER
Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.45; H, 6.08; N, 5.82.
IR (KBr): 3059, 2959, 2930, 2866, 1752, 1730, 1554, 1462, 1419,
1269, 1153, 1108, 746 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.50–7.48 (m, 1 H), 7.39–
7.21 (m, 1 H), 7.10–7.00 (m, 1 H), 6.99–6.82 (m, 1 H), 3.74 (t,
J = 8.0 Hz, 2 H), 2.71 (s, 3 H), 2.40 (s, 3 H), 1.70–1.62 (m, 2 H),
1.45–1.36 (m, 2 H), 0.98–0.94 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 167.3, 159.7, 141.1, 138.2,
128.6, 123.3, 121.8, 121.0, 116.3, 108.0, 39.5, 29.7, 21.3, 20.2,
18.1, 13.7.
3-Acetyl-1-ethyl-1H-indol-2-yl Benzoate (4b)
Colorless solid; yield: 122 mg (81%); mp 176–178 °C.
IR (KBr): 3290, 2971, 1756, 1737, 1680, 1415, 1142, 1125, 742
cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.95–7.94 (m, 2 H), 7.82–
7.80 (m, 1 H), 7.65–7.44 (m, 3 H), 7.32–7.19 (m, 3 H), 4.40 (q,
J = 8.0 Hz, 2 H), 2.71 (s, 3 H), 1.50 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 170.9, 163.6, 160.7, 143.1,
142.4, 138.2, 134.4, 132.4, 130.7, 128.3, 125.0, 122.6, 122.4, 119.9,
110.8, 103.7, 41.2, 30.6, 14.1.
LC-MS (+ mode): m/z = 274.10 [M + H].
Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.21; H, 7.08; N, 5.07.
LC-MS (– mode): m/z = 306.30 [M – H].
3-Acetyl-1-butyl-1H-indol-2-yl Benzoate (4g)
Pale yellow solid; yield: 116 mg (80%); mp 167–169 °C.
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C,
74.12; H, 5.65; N, 4.46.
IR (KBr): 3271, 3057, 2961, 2930, 2866, 1765, 1724, 1548, 1462,
1417, 1373, 1271, 1228, 1155, 1107, 1022, 978, 800, 746, 709 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.16–8.14 (m, 2 H), 7.85–
7.83 (m, 1 H), 7.64–7.62 (m, 1 H), 7.59–7.55 (m, 2 H), 7.47–7.32
(m, 3 H), 4.40 (t, J = 8.0 Hz, 2 H), 2.72 (s, 3 H), 1.88–1.80 (m, 2 H),
1.32–1.25 (m, 2 H), 0.93–0.90 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 166.5, 164.9, 160.6, 143.6,
134.5, 133.8, 133.2, 132.8, 128.9, 128.0, 125.0, 122.5, 122.3, 119.9,
111.0, 104.0, 45.8, 30.7, 30.6, 20.1, 13.7.
3-Acetyl-1-benzyl-1H-indol-2-yl Acetate (4c)
Yellow solid; yield: 89 mg (77%); mp 183–185 °C.
IR (KBr): 3292, 2976, 1752, 1739, 1689, 1419, 1266, 1161, 1022,
748 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.52–7.50 (m, 1 H), 7.31–
7.25 (m, 6 H), 7.18–7.00 (m, 1 H), 6.98–6.71 (m, 1 H), 4.96 (s, 2 H),
2.76 (s, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 167.6, 167.3, 160.2, 143.2,
141.7, 140.8, 136.0, 128.7, 128.6, 127.5, 127.2, 123.4, 122.2, 121.0,
116.2, 108.7, 43.4, 21.3, 18.3.
LC-MS (+ mode): m/z = 336.25 [M + H].
Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18. Found: C,
75.32; H, 6.21; N, 4.07.
LC-MS (– mode): m/z = 306.30 [M – H].
3-Acetyl-1-butyl-1H-indol-2-yl Thiophene-2-carboxylate (4h)
Pale yellow solid; yield: 121 mg (82%); mp 196–198 °C.
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C,
74.12; H, 5.51; N, 4.68.
IR (KBr): 3271, 3057, 2961, 2930, 2866, 1781, 1734, 1462, 1417,
1373, 1271, 1228, 1155, 1107, 1022, 746 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.94–7.63 (m, 3 H), 7.43–
7.41 (m, 1 H), 7.31–7.18 (m, 3 H), 4.38 (t, J = 8.0 Hz, 2 H), 2.70 (s,
3 H), 1.83–1.69 (m, 2 H), 1.42–1.10 (m, 2 H), 0.84–0.81 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 171.4, 164.7, 160.6, 143.3,
138.2, 134.5, 132.4, 130.7, 128.2, 125.0, 122.6, 119.9, 111.0, 103.8,
46.1, 31.3, 26.5, 22.5, 13.9.
3-Acetyl-1-benzyl-1H-indol-2-yl Benzoate (4d)
Pale brown solid; yield: 111mg (80%); mp 201–203 °C.
IR (KBr): 3295, 2973, 1752, 1741, 1689, 1423, 1139, 1120, 749
cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.29–8.27 (m, 2 H), 7.74–
7.72 (m, 1 H), 7.62–7.59 (m, 2 H), 7.53–7.51 (m, 1 H), 7.36–7.29
(m, 5 H), 7.14–6.74 (m, 3 H), 5.02 (s, 2 H), 2.91 (s, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 167.5, 163.2, 160.4, 140.8,
136.1, 135.7, 134.3, 130.5, 130.4, 129.7, 129.0, 128.8, 128.7, 128.6,
127.5, 127.3, 127.1, 123.6, 122.3, 121.1, 116.8, 108.7, 43.5, 18.4.
LC-MS (+ mode): m/z = 342.30 [M + H].
Anal. Calcd for C19H19NO3S: C, 66.84; H, 5.61; N, 4.10. Found: C,
66.72; H, 5.53; N, 4.18.
LC-MS (– mode): m/z = 368.20 [M – H].
3-Acetyl-1-hexyl-1H-indol-2-yl Acetate (4i)
Colorless solid; yield: 100 mg (86%); mp 165–167 °C.
Anal. Calcd for C24H19NO3: C, 78.03; H, 5.18; N, 3.79. Found: C,
78.12; H, 5.09; N, 3.85.
IR (KBr): 3059, 2959, 2930, 2866, 1759, 1726, 1554, 1462, 1419,
1269, 1155, 1107, 1020, 746 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.89–7.81 (m, 1 H), 7.36–
7.24 (m, 3 H), 4.18 (t, J = 8.0 Hz, 2 H), 2.63 (s, 3 H), 2.30 (s, 3 H),
1.78–1.74 (m, 2 H), 1.25–1.22 (m, 6 H), 0.85 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 169.9, 168.2, 165.8, 142.3,
134.3, 124.9, 122.5, 120.0, 110.0, 104.1, 45.6, 31.3, 30.7, 28.6,
26.6, 24.4, 22.5, 13.9.
3-Acetyl-1-benzyl-1H-indol-2-yl Thiophene-2-carboxylate (4e)
Pale green solid; yield: 110 mg (78%); mp 192–194 °C.
IR (KBr): 3061, 2926, 1757, 1738, 1593, 1562, 1494, 1454, 1323,
1157, 1113, 1022, 1005, 740, 696 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.07–8.00 (m, 1 H), 7.77–
7.58 (m, 2 H), 7.34–7.13 (m, 7 H), 6.96–6.92 (m, 1 H), 6.75–6.73
(m, 1 H), 5.01 (s, 2 H), 2.89 (s, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 167.9, 159.9, 158.5, 156.6,
140.8, 136.0, 135.5, 135.3, 134.6, 132.0, 131.9, 129.7, 128.7, 128.5,
127.2, 123.9, 122.3, 121.0, 116.7, 108.7, 43.5, 18.3.
LC-MS (+ mode): m/z = 302.15 [M + H].
Anal. Calcd for C18H23NO3: C, 71.73; H, 7.69; N, 4.65. Found: C,
71.62; H, 7.76; N, 4.56.
LC-MS (– mode): m/z = 374.30 [M – H].
3-Acetyl-1-hexyl-1H-indol-2-yl Benzoate (4j)
Pale yellow solid; yield: 120 mg (86%); mp 176–178 °C.
Anal. Calcd for C22H17NO3S: C, 70.38; H, 4.56; N, 3.73. Found: C,
70.23; H, 4.48; N, 3.65.
IR (KBr): 3286, 3159, 2971, 2935, 2868, 1765, 1734, 1548, 1462,
1417, 1373, 1271, 1228, 1155, 1107, 1022, 978, 914, 802, 746, 712
cm–1.
3-Acetyl-1-butyl-1H-indol-2-yl Acetate (4f)
Colorless solid; yield: 80 mg (68%); mp 145–147 °C.
Synthesis 2013, 45, 1235–1246
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cyclization Routes to Pyrano-, Pyrazolo-, and Furo-Fused Indoles
1243
1H NMR (400 MHz, TMS, CDCl3): δ = 8.18–8.13 (m, 2 H), 7.85–
7.82 (m, 1 H), 7.64–7.44 (m, 3 H), 7.34–7.28 (m, 3 H), 4.40 (t,
J = 8.0 Hz, 2 H), 2.73 (s, 3 H), 1.92–1.81 (m, 2 H), 1.35–1.22 (m, 6
H), 0.91–0.82 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 166.1, 164.9, 154.9, 143.6,
134.6, 133.2, 132.7, 128.9, 128.0, 125.0, 122.5, 122.2, 119.8, 111.0,
109.3, 103.9, 46.1, 31.2, 30.6, 28.6, 26.5, 22.4, 13.9.
Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
78.96; H, 5.12; N, 4.97.
9-Benzyl-2-methylpyrano[2,3-b]indol-4(9H)-one (5c)
Pale brown solid; yield: 83 mg (77%, method II); mp >300 °C.
IR (KBr): 3219, 2910, 1722, 1590, 1489, 1320, 1160, 1022, 692
cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.73–7.24 (m, 7 H), 7.03–
LC-MS (+ mode): m/z = 364.40 [M + H].
7.02 (m, 2 H), 6.83 (s, 1 H), 5.10 (s, 2 H), 2.46 (s, 3 H).
Anal. Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85. Found: C,
76.12; H, 6.85; N, 3.91.
13C NMR (100 MHz, TMS, CDCl3): δ = 186.7, 167.6, 152.1, 139.5,
138.5, 133.8, 128.7, 128.5, 128.1, 127.9, 127.5, 126.5, 125.3, 120.7,
119.8, 117.6, 108.1, 42.4, 21.5.
2,9-Substituted Pyrano[2,3-b]indol-4(9H)-ones 5a–i; General
Procedure, Method I
LC-MS (– mode): m/z = 288.05 [M – H].
To 1a–d (1.0 equiv) in CH2Cl2 was added Et3N (2.0 equiv), and the
mixture was stirred at r.t. for 15 min. The mixture was cooled in an
ice bath and freshly prepared acid chloride (2.0 equiv) was added
dropwise. The mixture was stirred for 15 min, brought up to r.t. and
stirred for up to 2 h (TLC monitoring). The solvent was evaporated
under reduced pressure and then NaH (3.0 equiv) in THF (10 mL)
was added directly and the mixture was refluxed for the time given
in Table 3; the flask was removed from the oil bath and allowed to
cool to r.t. The mixture was then diluted with EtOAc. The resultant
mixture was extracted with EtOAc (20 mL), washed with H2O (100
mL), and dried (anhyd Na2SO4). The solvent was evaporated and
the crude material was purified by column chromatography (2%
EtOAc–hexanes) to obtain pure 5a–i.
Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
78.69; H, 5.31; N, 4.76.
9-Benzyl-2-(thiophen-2-yl)pyrano[2,3-b]indol-4(9H)-one (5d)
Pale yellow solid; yield: 102 mg (76%, method II); mp >300 °C.
IR (KBr): 3018, 2956, 1717, 1593, 1424, 1323, 1150, 1123, 1035,
691 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 77.57–7.54 (m, 1 H), 7.36–
7.22 (m, 9 H), 7.04–7.02 (m, 2 H), 6.84–6.82 (m, 1 H), 5.10 (s, 2 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 182.7, 168.8, 158.8, 137.1,
137.0, 134.0, 131.1, 129.8, 129.7, 129.4, 128.7, 128.6, 127.8, 127.1,
124.6, 122.7, 121.0, 118.4, 108.4, 103.8, 43.0.
2,9-Substituted Pyrano[2,3-b]indol-4(9H)-ones 5a-i; General
Procedure, Method II
LC-MS (+ mode): m/z = 358 [M + H].
An oven-dried, round-bottomed flask with a Teflon stir bar was
charged with 4a–j (1.0 equiv) and NaH (3.0 equiv) in anhyd THF
(10 mL) and the flask was placed in a preheated oil bath at reflux
temperature of the solvent and stirred for the time given in Table 3.
The flask was removed from the oil bath and allowed to cool to r.t.
The mixture was then diluted with EtOAc. The resultant mixture
was extracted with EtOAc (20 mL), washed with H2O (100 mL),
and dried (anhyd Na2SO4). The solvent was evaporated and the
crude material was purified by column chromatography (2%
EtOAc–hexanes) to obtain pure 5a–i.
Anal. Calcd for C22H15NO2S: C, 73.93; H, 4.23; N, 3.92. Found: C,
73.85; H, 4.12; N, 4.07.
9-Butyl-2-methylpyrano[2,3-b]indol-4(9H)-one (5e)
Colorless solid; yield: 75 mg (68%, method II); mp 262–263 °C.
IR (KBr): 3061, 2926, 1718, 1593, 1562, 1494, 1454, 1323, 1157,
1113, 1022, 1005, 740, 696 cm–1.
1H NMR (400 MHz, TMS, DMSO-d6): δ = 7.95–7.93 (m, 1 H),
7.54–7.52 (m, 1 H), 7.36–7.32 (m, 1 H), 7.20–7.16 (m, 1 H), 6.29
(s, 1 H), 4.32 (t, J = 8.0 Hz, 2 H), 2.68 (s, 3 H), 1.85–1.57 (m, 2 H),
1.31–1.20 (m, 2 H), 0.82–0.78 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 179.2, 162.9, 150.4, 145.6,
138.0, 124.0, 121.6, 121.1, 120.0, 109.7, 103.3, 41.2, 31.4, 22.4,
20.1, 14.3.
9-Ethyl-2-methylpyrano[2,3-b]indol-4(9H)-one (5a)
Colorless solid; yield: 79 mg (71%, method II); mp 277–279 °C.
IR (KBr): 3061, 2926, 1718, 1593, 1562, 1494, 1454, 1323, 1157,
1113, 1022, 1005, 740, 696 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.95–7.93 (m, 1 H), 7.55–
7.54 (m, 1 H), 7.37–7.34 (m, 1 H), 7.21–7.19 (m, 1 H), 6.30 (s, 1 H),
4.38 (q, J = 8.0 Hz, 2 H), 2.67 (s, 3 H), 1.29 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 176.3, 162.8, 149.5, 145.7,
137.6, 124.0, 121.2, 120.0, 109.5, 106.8, 103.3, 36.0, 20.0, 14.3.
LC-MS (+ mode): m/z = 256 [M + H].
Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C,
75.12; H, 6.81; N, 5.38.
9-Butyl-2-phenylpyrano[2,3-b]indol-4(9H)-one (5f)
Pale blue solid; yield: 96 mg (70%, method II); mp >300 °C.
LC-MS (+ mode): m/z = 228.20 [M + H].
IR (KBr): 3061, 2926, 1718, 1593, 1562, 1494, 1454, 1323, 1157,
1022, 1013, 740 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.28–8.27 (m, 1 H), 8.01–
8.00 (m, 2 H), 7.47–7.40 (m, 3 H), 7.37–7.36 (m, 1 H), 7.31–7.28
(m, 2 H), 6.98 (s, 1 H), 4.53 (t, J = 8.0 Hz, 2 H), 1.95–1.91 (m, 2 H),
1.46–1.41 (m, 2 H), 0.96–0.99 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 178.2, 160.6, 143.3, 138.2,
136.3, 135.9, 134.6, 133.2, 132.3, 130.7, 128.2, 125.0, 122.6, 122.3,
119.8, 111.0, 103.8, 46.1, 26.5, 22.4, 13.9.
Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C,
74.12; H, 5.72; N, 6.21.
9-Ethyl-2-phenylpyrano[2,3-b]indol-4(9H)-one (5b)
Pale yellow solid; yield: 105 mg (74%, method II); mp >300 °C.
IR (KBr): 3061, 2935, 1702, 1560, 1454, 1150, 1122, 1035, 745,
696 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.36–7.22 (m, 7 H), 7.04–
7.02 (m, 2 H), 6.84–6.82 (m, 1 H), 4.15 (q, J = 8.0 Hz, 2 H), 1.32–
1.29 (t, J = 8.0 Hz, 3 H).
LC-MS (+ mode): m/z = 318.15 [M + H].
13C NMR (100 MHz, TMS, CDCl3): δ = 183.8, 171.1, 164.9, 153.5,
152.5, 149.5, 142.6, 135.4, 134.4, 124.9, 122.7, 120.0, 110.9, 104.4,
41.1, 14.0.
Anal. Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C,
79.36; H, 6.12; N, 4.52.
9-Butyl-2-(thiophen-2-yl)pyrano[2,3-b]indol-4(9H)-one (5g)
Pale yellow solid; yield: 109 mg (78%, method II); mp >300 °C.
LC-MS (– mode): m/z = 291.15 [M – H].
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1235–1246

1244
A. S. Kumar, R. Nagarajan
PAPER
IR (KBr): 3052, 2926, 1719, 1562, 1490, 1320, 1137, 1022, 740,
cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.92–7.91 (m, 2 H), 7.65–
7.63 (m, 1 H), 7.40–7.29 (m, 4 H), 7.19–7.17 (m, 1 H), 4.33 (t,
J = 8.0 Hz, 2 H), 1.85–1.78 (m, 2 H), 1.28–1.26 (m, 2 H), 0.91–0.88
(m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 184.8, 171.2, 160.6, 142.2,
137.5, 136.3, 135.2, 134.5, 132.7, 130.8, 128.3, 125.4, 123.0, 117.7,
111.0, 45.6, 30.7, 20.0, 13.6.
13C NMR (100 MHz, TMS, CDCl3): δ = 167.1, 161.2, 154.1, 151.0,
138.0, 136.0, 128.7, 127.5, 127.2, 125.1, 122.3, 122.1, 119.7, 109.3,
103.7, 101.6, 43.2, 20.9, 20.3.
LC-MS (+ mode): m/z = 276 [M + H].
Anal. Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C,
82.68; H, 6.28; N, 5.16.
8-Benzyl-2,3-dimethyl-8H-furo[2,3-b]indole (6b)
Pale yellow solid; yield: 62 mg (70%); mp 175–177 °C.
IR (KBr): 3413, 2926, 1603, 1494, 1454, 1323, 740, 696 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.38–7.36 (m, 1 H), 7.31–
7.23 (m, 5 H), 7.12–7.04 (m, 2 H), 6.86–6.84 (m, 1 H), 5.04 (s, 2 H),
2.47 (s, 3 H), 2.04 (s, 3 H).
LC-MS (+ mode): m/z = 324.50 [M + H].
Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33. Found: C,
70.48; H, 5.21; N, 4.45.
13C NMR (100 MHz, TMS, CDCl3): δ = 173.2, 171.0, 161.1, 154.1,
138.0, 136.0, 128.7, 127.5, 127.2, 125.1, 122.3, 122.1, 119.7, 109.3,
103.7, 101.6, 43.2, 20.9, 20.3.
9-Hexyl-2-methylpyrano[2,3-b]indol-4(9H)-one (5h)
Colorless solid; yield: 71 mg (78%, method II); mp 267–269 °C.
IR (KBr): 3052, 2920, 1710, 1542, 1434, 1323, 1157, 1113, 740,
696 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.95–7.93 (m, 1 H), 7.54–
7.52 (m, 1 H), 7.36–7.32 (m, 1 H), 7.20–7.16 (m, 1 H), 6.29 (s, 1 H),
4.32 (t, J = 8.0 Hz, 2 H), 2.68 (s, 3 H), 1.85–1.57 (m, 2 H), 1.31–
1.20 (m, 6 H), 0.82–0.78 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 182.8, 162.9, 150.3, 145.6,
138.0, 124.0, 121.6, 121.1, 120.0, 109.7, 103.3, 41.2, 31.5, 28.8,
26.4, 22.4, 20.2, 14.2.
LC-MS (+ mode): m/z = 276.15 [M + H].
Anal. Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C,
82.98; H, 6.13; N, 4.96.
1,8-Substituted 3-Methyl-1,8-dihydropyrazolo[3,4-b]indoles
7a–e; General Procedure
To a soln of 1a–d (1.0 equiv) in EtOH (8 mL) and one drop of concd
HCl or AcOH was added hydrazine hydrochloride or phenylhydra-
zine hydrochloride (in excess or 10.0 equiv). The soln was refluxed
for 5–7 h and the solvent was distilled off under reduced pressure.
The resultant mixture was extracted with EtOAc (20 mL), washed
with H2O (100 mL), and dried (anhyd Na2SO4). The solvent was
evaporated and the crude material was purified by column chroma-
tography (EtOAc–hexanes) to obtain the pure products 7a–e. Spec-
troscopic (NMR) and analytical data (LCMS, CHN) matched those
in the literature.12t
LC-MS (+ mode): m/z = 284 [M + H].
Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C,
76.38; H, 7.36; N, 5.07.
9-Hexyl-2-phenylpyrano[2,3-b]indol-4(9H)-one (5i)
Colorless solid; yield: 101 mg (76%, method II); mp >300 °C.
IR (KBr): 3110, 2966, 1718, 1533, 1474, 1157, 1025, 742 cm–1.
1HNMR (400 MHz, TMS, CDCl3): δ = 8.13–8.12 (m, 2 H), 7.84–
7.82 (m, 1 H), 7.64–7.62 (m, 1 H), 7.58–7.55 (m, 2 H), 7.46–7.44
(m, 1 H), 7.33–7.28 (m, 3 H), 4.40 (t, J = 8.0 Hz, 2 H), 1.91–1.81
(m, 2 H), 1.34–1.22 (m, 6 H), 0.91–0.82 (m, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 182.8, 160.3, 148.5, 138.2,
129.2, 127.8, 125.8, 125.5, 125.0, 122.4, 119.7, 117.0, 114.0, 112.7,
111.1, 108.6, 101.7, 39.6, 31.4, 27.9, 26.6, 22.5, 14.0.
8-Ethyl-3-methyl-1,8-dihydropyrazolo[3,4-b]indole (7a)
Brown viscous liquid; yield: 75 mg (77%).
IR (KBr): 2924, 2860, 1633, 1599, 1452, 1375, 1269, 1091, 740
cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.70 (d, J = 8.0 Hz, 1 H),
7.32–7.24 (m, 2 H), 7.11 (t, J = 8.0 Hz, 1 H), 4.18 (q, J = 8.0 Hz, 2
H), 2.63 (s, 3 H), 1.45 (t, J = 4.2 Hz, 3 H).
LC-MS (+ mode): m/z = 346.15 [M + H].
13C NMR (100 MHz, TMS, CDCl3): δ = 157.8, 144.3, 130.9, 123.4,
Anal. Calcd for C23H23NO2: C, 79.97; H, 6.71; N, 4.05. Found: C,
79.85; H, 6.67; N, 4.10.
120.2, 119.5, 118.6, 108.6, 107.3, 38.1, 13.7, 11.5.
LC-MS (+ mode): m/z = 200 [M + H].
2,3,8-Trisubstituted Furo[2,3-b]indoles 6a,b; General Proce-
dure
Anal. Calcd for C12H13N3: C, 72.33; H, 6.58; N, 21.09. Found: C,
72.18; H, 6.51; N, 21.15.
To a slurry of low-valent titanium agent [generated by reduction of
TiCl4 (1.90 mL, 17.40 mmol) in anhyd DME (90 mL) with activated
Zn (2.27 g) and CuCl (0.34 g)] was added a soln of 4b or 4c (100
mg, 0.0325 mmol) in boiling DME (100 mL). The mixture was
heated under reflux for 20 min and then hydrolyzed by slow addi-
tion of 10% aq K2CO3 (47 mL). The mixture was filtered through
Celite to remove excess metal and washed with CH2Cl2. The wash-
ings were combined with the organic layer of the filtrate. The com-
bined organic solns were washed with CH2Cl2 and dried (Na2SO4),
and the solvent was removed on a rotary evaporator; the solid resi-
due was subjected to column chromatography (neutral alumina,
EtOAc–hexanes) to obtain pure 6a,b.
8-Ethyl-3-methyl-1-phenyl-1,8-dihydropyrazolo[3,4-b]indole
(7b)
Colorless viscous liquid; yield: 97 mg (72%).
IR (KBr): 3051, 2928, 2854, 1595, 1564, 1520, 1494, 1454, 1375,
1321, 1261, 1165, 1020, 742 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.67 (d, J = 7.2 Hz, 1 H),
7.62–7.61 (m, 2 H), 7.56–7.32 (m, 2 H), 7.46–7.44 (m, 1 H), 7.31–
7.24 (m, 3 H), 4.08 (q, J = 7.16 Hz, 2 H), 2.68 (s, 3 H), 1.13 (t,
J = 4.2 Hz, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 146.4, 142.5, 141.7, 139.3,
129.2, 127.8, 124.9, 121.9, 119.0, 110.0, 109.7, 38.6, 14.1, 13.8.
8-Ethyl-3-methyl-2-phenyl-8H-furo[2,3-b]indole (6a)
Colorless solid; yield: 58 mg (65%); mp 167–169 °C.
LC-MS (+ mode): m/z = 276 [M + H].
IR (KBr): 3411, 2926, 1608, 1454, 1323, 730 cm–1.
Anal. Calcd for C18H17N3: C, 78.52; H, 6.22; N, 15.26. Found: C,
78.46; H, 6.28; N, 15.12.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.77–7.74 (m, 1 H), 7.42–
7.40 (m, 1 H), 7.39–7.34 (m, 2 H), 7.28–7.24 (m, 2 H), 7.23–7.19
(m, 3 H), 4.15 (q, J = 8.0 Hz, 2 H), 2.07 (s, 3 H), 1.28 (t, J = 8.0 Hz,
3 H).
4-(8-Butyl-3-methylpyrazolo[3,4-b]indol-1(8H)-yl)benzonitrile
(7c)
Brown viscous liquid; yield: 92 mg (65%).
Synthesis 2013, 45, 1235–1246
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cyclization Routes to Pyrano-, Pyrazolo-, and Furo-Fused Indoles
1245
IR (KBr): 3251, 2926, 2854, 1590, 1564, 1520, 1494, 1375, 1280,
1166, 1110, 1020, 742 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 7.80–7.74 (m, 2 H), 7.72–
7.70 (m, 3 H), 7.31–7.24 (m, 3 H), 4.10–4.08 (q, J = 7.16 Hz, 2 H),
2.63 (s, 3 H), 1.50–1.42 (m, 2 H), 1.04–0.95 (m, 2 H), 0.72 (t,
J = 4.2 Hz, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 146.4, 143.8, 143.1, 142.8,
133.4, 124.1, 122.5, 120.8, 119.9, 118.3, 112.3, 111.3, 110.4, 44.3,
30.9, 29.3, 19.7, 13.7.
E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R.
M.; Whitter, W. L.; Lundell, G. F.; Verber, D. F.; Anderson,
P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. H.; Chen, T.
B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J.
J. Med. Chem. 1988, 31, 2235. (c) Horton, D. A.; Bourne, G.
T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; and
references therein.
(3) (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045. (b) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988,
25, 1. (c) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
2001, 2491. (d) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875.
(4) (a) Cavalieri, L. F. Chem. Rev. 1947, 41, 525. (b) Mehta, G.;
Singh, V. Chem. Rev. 1999, 99, 881. (c) Luo, T.; Schreiber,
S. L. Angew. Chem. Int. Ed. 2007, 46, 8250. (d) Luo, T.;
Schreiber, S. L. J. Am. Chem. Soc. 2009, 131, 5667.
(e) Finnegan, R. A.; Djerassi, C. J. Am. Chem. Soc. 1960, 82,
4342. (f) Chen, X.-Y.; Wen, M.-W.; Ye, S.; Wang, Z.-W.
Org. Lett. 2011, 13, 1138. (g) Geiseler, O.; Podlech, J.
Tetrahedron 2012, 68, 7280.
(5) (a) McGlacken, G. P.; Fairlamb, I. J. S. Nat. Prod. Rep.
2005, 22, 369. (b) Schlingmann, G.; Milne, L.; Carter, G. T.
Tetrahedron 1998, 54, 13013. (c) Barrero, A. F.; Oltra, J. E.;
Herrador, M. M.; Sanchez, J. F.; Quilez, J. F.; Rojas, F. J.;
Reyes, J. F. Tetrahedron 1993, 49, 141. (d) Fairlamb, I. J. S.;
Marrison, L. R.; Dickinson, J. M.; Lu, F.-J.; Schmidt, J. P.
Bioorg. Med. Chem. 2004, 12, 4285. (e) Wu, P.-L.; Hsu, Y.-
L.; Wu, T.-S.; Bastow, K. F.; Lee, K.-H. Org. Lett. 2006, 8,
5207.
(6) (a) Lahm, G. P.; Cordova, D.; Barry, J. D. Bioorg. Med.
Chem. 2009, 17, 4127. (b) Fustero, S.; Roman, R.; Sanz-
Cervera, J. F.; Simon-Fuentes, A.; Bueno, J.; Villanova, S.
J. Org. Chem. 2008, 73, 8545. (c) Vicentini, C. B.;
Romagnoli, C.; Andreotti, E.; Mares, D. J. Agric. Food
Chem. 2007, 55, 10331. (d) Li, Y.; Zhang, H.-Q.; Liu, J.;
Yang, X.-P.; Liu, Z.-J. J. Agric. Food Chem. 2006, 54, 3636.
(e) Shiga, Y.; Okada, I.; Ikeda, Y.; Takizawa, E.; Fukuchi, T.
J. Pestic. Sci. 2003, 28, 313. (f) Wyatt, P. G.; Woodhead, A.
J.; Berdini, V.; Boulstridge, J. A.; Carr, M. G.; Cross, D. M.;
Davis, D. J.; Devine, L. A.; Early, T. R.; Feltell, R. E.;
Lewis, E. J.; McMenamin, R. L.; Navarro, E. F.; O’Brien, M.
A.; O’Reilly, M.; Reule, M.; Saxty, G.; Seavers, L. A.;
Smith, D.-M.; Squires, M.; Trewartha, G.; Walker, M. T.;
Woolford, A. J.-A. J. Med. Chem. 2008, 51, 4986.
(g) Terrett, N. K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg.
Med. Chem. Lett. 1996, 6, 1819. (h) Yu, K.; Toral-Barza, L.;
Shi, C.; Zhang, W. G.; Lucas, J.; Shor, B.; Kim, J.;
Verheijen, J.; Curran, K.; Malwitz, D. J.; Cole, D. C.;
Ellingboe, J.; Ayral-Kaloustian, S.; Mansour, T. S.;
Gibbons, J. J.; Abraham, R. T.; Nowak, P.; Zask, A. Cancer
Res. 2009, 69, 6232.
LC-MS (+ mode): m/z = 329 [M + H].
Anal. Calcd for C21H20N4: C, 76.80; H, 6.14; N, 17.06. Found: C,
76.91; H, 6.08; N, 16.85.
8-Butyl-3-methyl-1-(3-nitrophenyl)-1,8-dihydropyrazolo[3,4-
b]indole (7d)
Colorless solid; yield: 102 mg (68%); mp 225–227 °C.
IR (KBr): 2959, 2930, 2866, 1614, 1554, 1475, 1352, 1165, 1107,
1026, 879, 798, 752 cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.46 (t, J = 4.0 Hz, 1 H),
8.27–8.25 (m, 1 H), 8.01–8.00 (m, 1 H), 7.99–7.77 (m, 2 H), 7.75–
7.25 (m, 3 H), 4.10 (t, J = 6.0 Hz, 2 H), 2.66 (s, 3 H), 1.56–1.53 (m,
2 H), 1.08–1.04 (m, 2 H), 0.73 (t, J = 9.2 Hz, 3 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 148.5, 146.4, 143.4, 142.9,
140.5, 130.2, 129.9, 122.4, 122.1, 121.7, 120.7, 119.7, 118.6, 115.2,
113.1, 111.0, 110.2, 109.0.
LC-MS (+ mode): m/z = 349.25 [M + H].
Anal. Calcd for C20H20N4O2: C, 68.95; H, 5.79; N, 16.08. Found: C,
68.86; H, 5.71; N, 16.21.
8-Hexyl-3-methyl-1-(3-nitrophenyl)-1,8-dihydropyrazolo[3,4-
b]indole (7e)
Red viscous liquid; yield: 94 mg (65%).
IR (KBr): 2926, 2854, 1622, 1529, 1462, 1350, 1150, 966, 875, 740
cm–1.
1H NMR (400 MHz, TMS, CDCl3): δ = 8.45 (t, J = 4.0 Hz, 1 H),
8.26–8.01 (m, 1 H), 7.99–7.77 (m, 1 H), 7.75–7.72 (m, 2 H), 7.61–
7.50 (m, 2 H), 7.34–6.95 (m, 1 H), 4.11–4.08 (m, 2 H), 2.66 (s, 3 H),
1.59–1.53 (m, 2 H), 0.91–0.90 (m, 5 H), 0.88–0.76 (m, 4 H).
13C NMR (100 MHz, TMS, CDCl3): δ = 130.2, 129.9, 128.3, 127.6,
122.4, 121.7, 120.7, 120.5, 119.1, 118.7, 113.2, 110.2, 109.0, 44.4,
31.9, 31.0, 30.2, 29.6, 22.6, 14.0.
LC-MS (+ mode): m/z = 377.35 [M + H].
Anal. Calcd for C22H24N4O2: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.28; H, 6.37; N, 14.75.
Acknowledgement
(7) (a) Gopalsamy, A.; Lim, K.; Ciszewski, G.; Park, K.;
Ellingboe, J. W.; Bloom, J.; Insaf, S.; Upeslacis, J.;
Mansour, T. S.; Krishnamurthy, G.; Damarla, M.; Pyatski,
Y.; Ho, D.; Howe, A. Y. M.; Orlowski, M.; Feld, B.;
O’Connell, J. J. Med. Chem. 2004, 47, 6603. (b) Queiroz,
M.-J. R. P.; Calhelha, R. C.; Vale-Silva, L. A.; Pinto, E.;
Sao-Jose, N. M. Eur. J. Med. Chem. 2009, 44, 1893.
(c) LaPorte, M. G.; Draper, T. L.; Miller, L. E.; Blackledge,
C. W.; Leister, L. K.; Amparo, E.; Hussey, A. R.; Young, D.
C.; Chunduru, S. K.; Benetatos, C. A.; Rhodes, G.;
Gopalsamy, A.; Herbertz, T.; Burns, C. J.; Condon, S. M.
Bioorg. Med. Chem. Lett. 2010, 20, 2968.
We gratefully acknowledge DST (Project number: SR/S1/OC-
70/2008) for financial support and for the single-crystal X-ray dif-
fractometer facility in our school. A.S.K. thanks UGC for a senior
research fellowship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
References
(1) (a) Sundberg, R. J. In The Chemistry of Indoles; Academic
Press: New York, 1970. (b) Brown, R. K. In Indoles;
Houlihan, W. J., Ed.; Wiley-Interscience: New York, 1972.
(2) (a) Joule, J. A. In Science of Synthesis; Vol. 10; Thomas, E.
J., Ed.; Chap. 10.13; Thieme: Stuttgart, 2000. (b) Evans, B.
(8) (a) Ngi, S. I.; Guilloteau, V.; Abarbri, M.; Thibonnet, J.
J. Org. Chem. 2011, 76, 8347. (b) Mali, R. S.; Manekar-
Tilve, A. Org. Prep. Proced. Int. 1994, 26, 573. (c) Praveen,
C.; Ayyanar, A.; Perumal, P. T. Bioorg. Med. Chem. Lett.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1235–1246

1246
A. S. Kumar, R. Nagarajan
PAPER
Z. Org. Process Res. Dev. 2007, 11, 731. Pyrazolo[3,4-
2011, 21, 4170. (d) Larsen, L. K.; Moore, R. E.; Patterson,
G. M. L. J. Nat. Prod. 1994, 57, 419. (e) Veale, C. A.;
Damewood, J. R. Jr.; Steelman, G. B.; Bryant, C.; Gomes,
B.; Williams, J. J. Med. Chem. 1995, 38, 86. (f) Mouaddib,
A.; Joseph, B.; Hasnaoui, A.; Merour, J.-Y. Synthesis 2000,
549. (g) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083.
(h) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318.
(i) Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi,
A. J. Org. Chem. 2003, 68, 7126. (j) Ding, S.; Shi, Z.; Jiao,
N. Org. Lett. 2010, 12, 1540. (k) Shi, Z.; Cui, Y.; Jiao, N.
Org. Lett. 2010, 12, 2908.
b]indoles, see: (p) Lande, B.; Soufiaoui, M.; Arriau, J.
J. Heterocycl. Chem. 1977, 14, 1183. (q) Daou, B.;
Soufiaoui, M. J. Heterocycl. Chem. 1989, 26, 1485.
(r) Monge, A.; Palop, J.; Ramirez, C.; Font, M.; Fernandez-
Alvarez, E. Eur. J. Med. Chem. 1991, 26, 179. (s) Kumar, S.;
Ila, H.; Junjappa, H. J. Org. Chem. 2009, 74, 7046.
(t) Kumar, A. S.; Rao, P. V. A.; Nagarajan, R. Synthesis
2011, 3878. Furo[2,3-b]indoles, see: (u) Trost, B. M.;
Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.
(v) Kawasaki, T.; Takamiya, W.; Okamoto, N.; Nagaoka,
M.; Hirayama, T. Tetrahedron Lett. 2006, 47, 5379.
(w) Rivera-Becerril, E.; Joseph-Nathan, P.; Pérez-Álvarez,
V. M.; Morales-Rios, M. S. J. Med. Chem. 2008, 51, 5271.
(x) Saito, I.; Morii, T.; Matsugo, S.; Matsuura, T. J. Am.
Chem. Soc. 1975, 97, 7191. (y) Saito, I.; Matsugo, S.;
Matsuura, T. J. Am. Chem. Soc. 1979, 101, 7332.
(9) (a) Salway, A. H. J. Chem. Soc. 1911, 99, 2148.
(b) Robinson, B. J. Chem. Soc. 1964, 1503. (c) Joule, J. A.
Indoles Part IV: The Monoterpenoid Indole Alkaloids, In
The Chemistry of Heterocyclic Compounds; Vol. 25; Saxton,
J. E., Ed.; John Wiley & Sons: Chichester, 1983, 244–259.
(d) Bohrmann, H.; Lau Cam, C.; Tashiro, J.; Youngken, H.
W. Jr. Phytochemistry 1969, 8, 645. (e) Morales-Ríos, M. S.;
Suárez-Castillo, O. R.; Joseph-Nathan, P. J. Org. Chem.
1999, 64, 1086. (f) Tius, M. A.; Wang, L. Org. Lett. 2007, 9,
647.
(10) (a) Saleh, A. Z. M.; Greenman, K. L.; Billings, S.; David, L.;
Vranken, V.; Krolewski, J. J. Biochemistry 2005, 44, 10822.
(b) Hayashi, M.; Kim, Y.-P.; Takamatsu, S.; Enomoto, A.;
Shinose, M.; Takahashi, Y.; Tanaka, H.; Komiyama, K.;
Ōmura, S. J. Antibiot. 1996, 49, 1091. (c) Takamatsu, S.;
Kim, Y.-P.; Enomoto, A.; Hayashi, M.; Tanaka, H.;
Komiyama, K.; Ōmura, S. J. Antibiot. 1997, 50, 1069.
(d) Hayashi, M.; Rho, M.-C.; Enomoto, A.; Fukami, A.;
Kim, Y.-P.; Kikuchi, Y.; Sunazuka, T.; Hirose, T.;
Komiyama, K.; Ōmura, S. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 14728. (e) Robinson, B. In The Alkaloids; Vol. X;
Manske, R. H. F., Ed.; Chap. 5; Academic Press: New York,
1968. (f) The Alkaloids; Vol. XIII; Manske, R. H. F., Ed.;
Chap. 4; Academic Press: New York, 1971. (g) Yu, Q.; Liu,
C.; Brzostowska, M.; Chrisey, L.; Brossi, A.; Greig, N. H.;
Atack, J. R.; Soncrant, T. T.; Rapoport, S. I.; Radunz, H.
Helv. Chim. Acta 1991, 74, 761. (h) Brzostowska, M.; He,
X.; Greig, N. H.; Stanley, S. I.; Brossi, A. Med. Chem. Res.
1992, 2, 238. (i) Kawashima, A.; Seto, H.; Kato, M.;
Yasuda, A.; Uchida, K.; Otake, N. J. Antibiot. 1986, 39,
1495.
(z) Morales-Rios, M. S.; Santos-Sànchez, N. F.; Joseph-
Nathan, P. J. Nat. Prod. 2002, 65, 136.
(13) (a) Bunnett, J. F.; Hrutfiord, B. F. J. Am. Chem. Soc. 1961,
83, 1691. (b) Etkin, N.; Babu, S. D.; Fooks, C. J.; Durst, T.
J. Org. Chem. 1990, 55, 1093. (c) Himbert, V. G.; Ruppich,
M. Angew. Chem. 1990, 102, 69. (d) Doyle, M. P.; Shanklin,
M. S.; Pho, H. Q.; Mahapatro, S. N. J. Org. Chem. 1988, 53,
1017. (e) Hugel, H. M.; Greenwood, R. J.; Mackay, M. F.
Aust. J. Chem. 1992, 45, 1953. (f) Jha, M.; Chou, T.-Y.;
Blunt, B. Tetrahedron 2011, 67, 982.
(14) (a) Perkin, W. H. J. Chem. Soc. 1868, 21, 53. (b) Johnson, J.
R. Org. React. 1942, 1, 210. (c) House, H. O. Modern
Synthetic Reactions, 2nd ed.; W. A. Benjamin: Menlo Park,
1972, 660–663. (d) Rosen, T. In Comprehensive Organic
Synthesis; Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, 395. (e) Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 4th ed.; Blackwell Science: Oxford, 2000.
(15) (a) Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589.
(b) Kurzer, F.; Douraghi-Zadeh, K. Chem. Rev. 1967, 67,
107.
(16) (a) Freyne, D.; Raeymaekers, A.; Venet, M.; Sanz, G.;
Wouters, W.; De Coster, R.; Wauwe, J. V. Bioorg. Med.
Chem. Lett. 1998, 8, 267. (b) Njar, V. C. O.; Nnane, I. P.;
Brodie, A. M. H. Bioorg. Med. Chem. Lett. 2000, 10, 1905.
(c) Aelterman, W.; Lang, Y.; Willemsens, B.; Vervest, I.;
Leurs, S.; De Knaep, F. Org. Process Res. Dev. 2001, 5, 467.
(d) Pouget, C.; Fagnere, C.; Basly, J. P.; Habrioux, G.;
Chulia, A. J. Bioorg. Med. Chem. Lett. 2002, 12, 2859.
(e) Tafi, A.; Costi, R.; Botta, M.; Di Santo, R.; Corelli, F.;
Massa, S.; Ciacci, A.; Manetti, F.; Artico, M. J. Med. Chem.
2002, 45, 2720. (f) Fischer, W. Synthesis 2002, 29. (g) Njar,
V. C. O. Synthesis 2000, 2019. (h) Totleben, M. J.; Freeman,
J. P.; Szmuszkovicz, J. J. Org. Chem. 1997, 62, 7319.
(i) Jencks, W. P.; Carriuolo, J. J. Biol. Chem. 1959, 234,
1272.
(17) This reagent is commercially available: (a) Mukaiyama, T.
Angew. Chem., Int. Ed. Engl. 1979, 18, 707. (b) Mukaiyama,
T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045.
(c) Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett.
2004, 6, 4579. (d) Babak Mokhtari, B.; Azadi, R.; Mardani,
E. Tetrahedron Lett. 2012, 53, 491. (e) Saigo, K.; Osaki, M.;
Mukaiyama, T. Chem. Lett. 1976, 163.
(11) Williams, J. D.; Drach, J. C.; Townsend, L. B. Nucleosides,
Nucleotides Nucleic Acids 2004, 23, 805.
(12) Pyranoindolones, see: (a) Lv, H.; Chen, X.-Y.; Sun, L-h.;
Ye, S. J. Org. Chem. 2010, 75, 6973. (b) Bestmann, H. J.;
Schmidt, G. Tetrahedron Lett. 1984, 25, 1441. (c) Ohnuma,
T.; Kasuya, H.; Kimura, Y.; Ban, Y. Heterocycles 1982, 17,
377. (d) Amiet, R. G.; Eastwood, F. W.; Rae, I. D. R. Aust.
J. Chem. 1972, 25, 1473. (e) Nakagawa, M.; Sodeoka, M.;
Yamaguchi, K.; Hino, T. Chem. Pharm. Bull. 1984, 32,
1373. (f) Feldman, K. S.; Karatjas, A. G. Org. Lett. 2004, 6,
2849. (g) Kam, T. S.; Tan, S. J.; Ng, S. W.; Komiyama, K.
Org. Lett. 2008, 10, 3749. (h) Feldman, K. S.; Vidulova, D.
B.; Karatjas, A. D. J. Org. Chem. 2005, 70, 6429. (i) Reh, S.;
Bergman, J. Tetrahedron 2005, 61, 3115. (j) Sabitha, G.;
Rao-Subha, A. V. Synth. Commun. 1987, 17, 341. (k) Ming,
Y.; Boykin, D. W. Heterocycles 1987, 26, 3229.
(l) Gallastegui, D. J.; Lago, J. M.; Palomo, C. J. Chem. Res.,
Synop. 1984, 170. (m) Potdar, M. K.; Mohile, S. S.;
Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285.
(n) Waldmann, H.; Kühn, M.; Liuab, W.; Kumar, K. Chem.
Commun. 2008, 1211. (o) Li, X.; Reuman, M.; Russell, R.
K.; Youells, S.; Beish, S.; Hu, Z.; Branum, S.; Jain, N.; Sui,
(18) Fürstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org.
Chem. 1994, 59, 5215.
(19) Gannon, W. F.; Benigni, J. D.; Dickson, D. E.; Minnis, R. L.
J. Org. Chem. 1969, 34, 3002; and references cited therein.
Synthesis 2013, 45, 1235–1246
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