Diversity-oriented synthesis of ketoindoloquinoxalines and indolotriazoloquinoxalines from 1-(2-nitroaryl)-2-alkynylindoles

Article abstract of DOI:10.1021/jo402783p

A one-pot protocol for the diversity-oriented synthesis of two indole-based annulated polyheterocycles, ketoindoloquinoxalines and indolotriazoloquinoxalines, has been described. The salient features of the methodology involves either a metal/O₂-catalyzed aminooxygenation or a [3 + 2] cycloaddition pathway.

Full text of DOI:10.1021/jo402783p

Article
pubs.acs.org/joc
Diversity-Oriented Synthesis of Ketoindoloquinoxalines and
Indolotriazoloquinoxalines from 1‑(2-Nitroaryl)-2-alkynylindoles
Srinivas Samala,† Rajesh K Arigela,† Ruchir Kant,‡ and Bijoy Kundu*,†,§
‡
†Medicinal and Process Chemistry Division and Molecular and Structural Biology Division, CSIR-Central Drug Research Institute,
B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226001, India
§Academy of Scientific and Innovative Research, New Delhi 110001, India
S
* Supporting Information
ABSTRACT: A one-pot protocol for the diversity-oriented synthesis of two indole-based annulated polyheterocycles,
ketoindoloquinoxalines and indolotriazoloquinoxalines, has been described. The salient features of the methodology involves
either a metal/O2-catalyzed aminooxygenation or a [3 + 2] cycloaddition pathway.
In continuation of this, we next embarked on a search for a
one-pot synthesis of ketoindoloquinoxalines from N1-susbti-
tuted 2-alkynylindoles. The motivation stemmed from
following our exploratory experiments toward the synthesis of
indolotriazoloquinoxaline from the 2-alkynylindole derivative.
We made an unprecedented observation of an oxygen insertion
reaction affording a ketoindoloquinoxaline in a trace amount.
Indoloquinoxalines are bioactive compounds, and in particular,
indolo[1,2-a]quinoxalines exhibit antifungal activities13 in vitro
against phytopathogenic fungi. A careful survey of the literature
failed to report any synthesis for ketoindolo[1,2-a]quinoxalines
following incorporation of an oxygen as a keto group. The
reported strategies for indolo[1,2-a]quinoxalines involved the
usage of 1-(2-aminophenyl)indoles as a common substrate with
either alkenes14 or alkynes15 as the second reactant (Figure 1).
Herein, we report the diversity-oriented synthesis of two
indole-based annulated polyheterocycles, ketoindoloquinoxa-
lines 2 and indolotriazoloquinoxalines 3, from the common
intermediates 1-(2-nitroaryl)-2-alkynylindoles 1.
INTRODUCTION
■
The activated indole ring, owing to the presence of N1, C-2,
and C-3 as three nucleophilic centers, serves as a “versatile
scaffold” for the diversity-oriented synthesis1 of structurally
diverse indole-based annulated polyheterocycles. The indole-
derived polyheterocycles are widely present in many natural
products2 and are associated with pharmacological activities3
ranging from anticancer4 to antibacterial5 and antiviral
activities.6 In view of the therapeutic significance of these
species, developing one-pot syntheses7 via cascade8/domino
reactions9 has always remained an attractive task for chemists.
In recent years, electrophilic alkynes have been widely
employed as reactants in a one-pot reaction for the
construction of annulated polyheterocycles.10 This could be
attributed to their ability to undergo annulation via an
intramolecular nucleophilic attack in the presence/absence of
transition metals.
Following this clue, we reported several new routes for the
one-pot synthesis of indole-based natural products as well as
polyheterocycles11 by employing indole derivatives and
terminal/internal alkynes as reactants. Recently, we covalently
linked both the indole and alkyne into a single entity and the
resulting 2-alkynylindoles12 (comprising both nucleophilic and
electrophilic centers) were exploited as substrates for the
synthesis of structurally diverse heterocycles either in a one-pot
format or in two steps.
RESULTS AND DISCUSSION
■
In our effort directed toward azide−alkyne dipolar cyclo-
addition16 involving 6-((4-(tert-butyl)phenyl)ethynyl)-5-(2-ni-
trophenyl)-5H-[1,3]dioxolo[4,5-f ]indole (1a) and NaN3, we
Received: December 16, 2013
Published: February 26, 2014
© 2014 American Chemical Society
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and X-ray analyses17 (see the Supporting Information),
pointing to the unprecedented incorporation of oxygen in the
form of a keto group. The insertion of an oxygen atom18 in the
form of a keto group19 remains a powerful tool for the synthesis
of structurally diverse polyheterocycles. There are several
reports in the literature on polyheterocycle-based natural
products of therapeutic significance bearing a keto group
appended to their framework.20 Our findings thus demonstrate
the ability of the substrate 1a to afford the two distinct
structurally diverse indole-based annulated polyheterocycles 2a
(tricyclic) and 3a (tetracyclic) in a one-pot format.
Intrigued by these observations, we set out to study the
course of cyclization that led to the formation of 2a from 1a,
followed by the development of a method for the quantitative
and selective synthesis of 2a and 3a. We envisaged that the
products 2a and 3a could both originate from a single reactive
intermediate (having azide and alkyne moieties in close
proximity), with conversion preference for 3a over that of 2a.
Initially, our studies commenced with the treatment of 1a with
sodium azide in the presence of CuI as a catalyst, air/water as a
source of oxygen, and HMPA as a solvent. Though water as a
source of oxygen failed to afford 2a (Table 1, entry 5), the
presence of air furnished 2a in ∼5% isolated yield (Table 1,
entry 4). Nevertheless, 3a was formed under both conditions in
60% and 52% isolated yields, respectively. This prompted us to
carry out the reaction in the presence of oxygen, and to our
delight 2a was obtained in 78% isolated yield (entry 6) as a
major product along with the formation of 3a in traces (<5% as
evident by HPLC). Switching the solvent from HMPA to
DMSO (entry 7) and DMF (entry 8) produced a mixture of 2a
and 3a. Similarly, replacement of CuI with CuBr (entry 9) and
Figure 1. Reported strategies and our work involving the synthesis of
indolo[1,2-a]quinoxalines.
observed the formation of the minor side product 2a in ∼5%
isolated yield along with the major product indoloquinoxalino-
triazole 3a in 61% isolated yield (Table 1, entry 1). 2a was
characterized as [1,3]dioxolo[4′,5′:5,6]indolo[1,2-a]quinoxalin-
6-yl(4-(tert-butyl)phenyl)methanone on the basis of spectral
a
Table 1. Optimization of the Synthesis of Ketoindoloquinoxaline 2a and Indolotriazoloquinoxaline 3a
b
entry
reaction conditions
5 mol % CuI, HMPA
temp (°C)
time (h)
yield of 2a/3a (%)
c
1
120
120
120
100
120
120
120
120
120
120
120
120
120
120
120
120
80
10
10
24
10
10
10
24
24
24
24
24
24
24
12
7.5
10
24
<5 /61
2
5 mol % CuI, DMSO
5 mol % CuI, toluene
5 mol % CuI, HMPA, air
5 mol % CuI, HMPA, H2O
5 mol % CuI, HMPA, O2
5 mol % CuI, DMSO, O2
5 mol % CuI, DMF, O2
5 mol % CuBr, HMPA, O2
5 mol % CuCl, HMPA, O2
5 mol % AgI, HMPA, O2
5 mol % Pd(OAc)2, HMPA
5 mol % AuClPPh3/AgSbF6, HMPA
HMPA, O2
−/49
NR
3
4
5/52
-/60
5
c
6
78/<5
7
53/15
37/56
42/49
40/55
−/52
NR
8
9
10
11
12
13
14
15
16
17
NR
21/57
−/73
−/45
NR
HMPA
DMSO
ACN
a
b
c
NR = no reaction. All reactions were carried out with 5 equiv of NaN3. Isolated yields. Yield based on HPLC.
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Figure 2. Plausible mechanism for the formation of 2 and 3.
CuCl (entry 10) again resulted in poor selectivity, affording a
mixture of 2a and 3a approximately in the ratio of 1:1.
Surprisingly, the addition of AgI, in spite of the presence of
oxygen, completely failed to afford 2a and led to the selective
formation of 3a, albeit in 52% isolated yield (Table 1, entry 11).
Other transition-metal catalysts such as Pd and Au−Ag failed to
facilitate any transformation (entries 12 and 13), thereby
suggesting the crucial role of CuI as a catalyst in the
predominant transformation of 1a to 2a. This was further
evident from the fact that carrying out the reaction in the
presence of oxygen alone in HMPA without CuI produced a
mixture of 2a and 3a in the approximate ratio of 1:3 (Table 1,
entry 14). Interestingly, the absence of both CuI and oxygen in
HMPA led to the selective formation of only 3a in 73% isolated
yield (Table 1, entry 15) in 7.5 h. Replacing HMPA with
DMSO afforded 3a in reduced yield (entry 16), whereas use of
acetonitrile failed to produce any product (Table 1, entry 17).
Our optimization studies thus led to the preferential formation
of 2a via insertion of oxygen in the presence of CuI and oxygen,
whereas metal-free thermal conditions selectively afforded 3a in
satisfactory yields. To the best of our knowledge, this is the first
report of diversity-oriented synthesis involving metal-catalyzed
cascade annulation via aminooxygenation and metal-free
annulation via [3 + 2] cycloadditions under thermal conditions
from a single intermediate.
intermediate IV followed by isomerization to the intermediate
V. Then, the presence of iodide ion may regenerate the metal
catalyst to afford intermediate VI, which may at that point
undergo fragmentation to yield the final product 2 with the
liberation of N2O. While attempts to isolate the azide
intermediate I were not fruitful, carrying out the reaction in
the presence of TEMPO (free radical scavenger) afforded 3 as
the only product by suppressing the formation of amino-
oxygenation product 2. These preliminary findings suggest that
the reaction may be following a radical pathway where
intermediate IV may be getting blocked by the addition of
TEMPO.23 Formation of 2 as a minor product in HMPA in the
presence of oxygen alone (metal-free conditions; entry 14) may
be attributed to the in situ generation of HMPA peroxide.24
The latter species may be interacting25 with the intermediate I
to afford 2; however, in the absence of any literature precedent
involving hydroperoxide-mediated (non-metal-catalyzed) acti-
vation of alkynes, this needs detailed investigation.
Armed with the optimized reaction conditions leading to the
selective synthesis of 2a and 3a, we next examined the substrate
scope and limitation by introducing diversity in the three
aromatic rings present in the substrate 1 as R1, R2, and R3. Both
electron-withdrawing and -donating substitutents have been
introduced in the aromatic rings. R1 in the aromatic ring of the
indole has been substituted with 5-chloro, 5,6-dimethoxy, and
5,6-methylenedioxy groups, R2 in the aromatic ring of the
alkyne has been substituted with 4-tert-butyl and 4-methyl
groups, and R3 in the aromatic ring originating from the N of
the indole has been substituted with 4-methyl, 4-trifluor-
omethyl, 4-fluoro, and 4-bromo groups. Accordingly, 12
compounds (2a−l) were synthesized in moderate to good
yields (59−80%) (Scheme 1). The presence of electron-
donating substituents on R1 and R3 furnished 2 in ≥70%
isolated yields, whereas electron-withdrawing groups afforded 2
in reduced isolated yields ranging from 59 to 68%. Similarly, the
presence of electron-donating groups in the aromatic ring of
On the basis of earlier reports21 and our own optimization
studies, a plausible mechanism for the formations of 2 and 3 is
depicted in Figure 2. The first step of the mechanism may
involve aromatic nucleophilic substitution of the nitro group
with sodium azide22 to yield the intermediate I. Then, thermal
conditions may directly afford the cyclic compound 3 via
intramolecular [3 + 2] cycloaddition or the presence of a metal
catalyst may generate the metal alkyne π complex II followed
by an intramolecular nucleophilic attack by the nitrogen of the
azide to yield the cyclic intermediate III. Next, the addition of
oxygen to III may generate the organocopper peroxide
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a
Scheme 1. Synthesis of 2a−l
a
Corresponding 3 was obtained in <5% yield based on HPLC.
the alkyne as R2 afforded 2 in >70% isolated yield. However,
replacing R2 with an electron-withdrawing CN group or
replacing the aromatic ring in the alkyne with an aliphatic
group failed to produce the desired product. This may be
attibuted to the weak activation of the internal alkyne toward
nucleophilic attack. It is also noteworthy that products with R2
as a tert-butyl group afforded the corresponding 3 via [3 + 2]
cycloaddition in traces (<5% yield), as evidenced by HPLC.
Next, we examined the substrate scope and limitation for the
synthesis of indolotriazoloquinoxalines 3 using optimized
reaction conditions involving heating of substrates 1 in
HMPA under metal-free conditions. Altogether, 12 compounds
3a−l with 3 points of diversity were synthesized in isolated
yields ranging from 60 to 89% (Scheme 2). The nature of the
substituent (R1, R2, R3) had a significant effect on the cascade
cyclization, which was evidenced by the isolated yields of final
products. The substituents on substrate 1 with electron-
donating groups such as 5,6-dimethoxy and 5,6-methylenedioxy
groups as R1 and 4-tert-butyl as R2 afforded the final products in
good yields. In contrast, introducing electron-withdrawing
groups in R1 such as 5-chloro and in R3 such as 4-
trifluoromethyl, 4-fluoro, and 4-bromo produced 3 in reduced
yields.
CONCLUSION
■
In conclusion, we have demonstrated a diversity-oriented
synthesis of two indole-based annulated polyheterocycles,
ketoindoloquinoxalines and indolotriazoloquinoxalines, by
treating 1-(2-nitroaryl)-2-alkynylindoles with NaN3. The salient
features involved either a preferential cascade cyclization via
aminooxygenation with the elimination of nitrous oxide in the
presence of CuI/oxygen or a thermally induced metal-free
annulation via a [3 + 2] cycloaddition reaction.
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Scheme 2. Substrate Scope for Indolo Triazolo Quinoxalines 3
stirred at 120 °C. After it was stirred vigorously for the appropriate
time, the reaction mixture was removed from the oil bath, cooled to
room temperature, filtered through a bed of Celite-R, diluted with
water (50 mL), and extracted with ethyl acetate (3 × 30 mL). The
resulting organic solution was washed with brine (25 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting
residue was purified by silica gel flash column chromatography with
EtOAc/hexane as the eluent to afford 2.
Typical Procedure for the Synthesis of Indolotriazoloqui-
noxalines 3a−l. A 50 mL round-bottom flask equipped with a
magnetic stir bar was charged with the 1-(2-nitroaryl)-2-alkynylindole
(1 equiv) in 10 mL of HMPA, and to this clear solution was added
sodium azide (5 equiv) under a nitrogen atmosphere. The reaction
mixture was transferred to an oil bath and stirred at 120 °C. After it
was stirred vigorously for the appropriate time, the reaction mixture
was removed from the oil bath, cooled to room temperature, filtered
through a bed of Celite-R, diluted with water (50 mL), and extracted
with ethyl acetate (3 × 30 mL). The resulting organic solution was
washed with brine (25 mL), dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The resulting residue was purified by silica
gel flash column chromatography with EtOAc/hexane as the eluent to
afford 3.
EXPERIMENTAL SECTION
■
General Information and Methods. All reagents and solvents
were purchased from commercial sources and used without
purification. NMR spectra were recorded with 400 MHz spectrometers
for H NMR and 100 MHz spectrometers for 13C NMR. Chemical
1
shifts δ are given in ppm relative to the residual signals of
tetramethylsilane in CDCl3 or deuterated solvent DMSO-d6 for H
1
and 13C NMR. Multiplicities are reported as follows: singlet (s),
doublet (d), doublet of doublets (dd), doublet of triplets (dt), triplet
(t), quartet (q), multiplet (m). High-resolution mass spectra were
taken with a mass spectrometer. Column chromatography was
performed using silica gel (100−200 mesh) as the stationary phase.
All reactions were monitored by thin layer chromatography (TLC).
The purity and characterization of these compounds were further
established using HR/EI on Q-TOF, LC/MS Mass spectrometry.
Melting points were measured on a capillary melting point apparatus
and are uncorrected.
Typical Procedure for the Synthesis of Ketoindoloquinoxa-
lines 2a−l. A 50 mL round-bottom flask equipped with a magnetic
stir bar was charged with the 1-(2-nitroaryl)-2-alkynylindole (1 equiv)
in 10 mL of HMPA, and to this clear solution was added sodium azide
(5 equiv) and CuI (5 mol %) under an oxygen atmosphere at room
temperature. The reaction mixture was transferred to an oil bath and
Typical Procedure for the Synthesis of 1-(2-Nitroaryl)-2-
alkynylindoles 1a−p. A 50 mL round-bottom flask equipped with a
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magnetic stir bar was charged with the 2-alkynylindole (1 equiv) and
2-nitrofluorobenzene (1.1 equiv) in 20 mL of DMF; the reaction
mixture was cooled to 0 °C, and to this solution was added sodium
hydride (10 equiv) under a nitrogen atmosphere. The reaction mixture
was stirred at room temperature. After it was stirred vigorously for the
appropriate time, the reaction mixture was quenched with water and
extracted with ethyl acetate (4 × 25 mL). The resulting organic
solution was washed with brine (25 mL), dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The resulting residue was
purified by silica gel flash column chromatography with EtOAc/hexane
as the eluent to afford 1.
Characterization of all Final and Intermediate Compounds.
([1,3]Dioxolo[4′,5′:5,6]indolo[1,2-a]quinoxalin-6-yl)(4-(tert-butyl)-
phenyl)methanone (2a): red solid; Rf = 0.60 (10/90 ethyl acetate/
hexane); yield 78% (0.187 g); mp 186−188 °C; FT-IR (KBr) 3429,
3022, 2791, 2457, 1662, 1623, 1462, 1329 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.35 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.03 (d, J
= 7.9 Hz, 1H), 7.89 (s, 1H), 7.66 (t, J = 8.2 Hz, 1H), 7.51 (d, J = 8.4
Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 6.09 (s,
2H), 1.35 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 191.9, 157.8,
151.6, 147.8, 145.5, 135.2, 133.2, 131.4, 131.1, 130.6, 129.7, 128.1,
127.3, 125.6, 124.9, 124.3, 114.5, 102.8, 101.8, 100.0, 94.6, 35.4, 31.2
ppm; HRMS (ESI) calcd for C27H23N2O3 [M + H] 423.1708,, found
423.1703.
155−157 °C; FT-IR (KBr) 3431, 2795, 1660, 1624, 1461, 1327, 1215,
1160 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 8.8 Hz, 1H),
8.45 (d, J = 8.6 Hz, 1H), 8.32 (s, 1H), 8.17 (d, J = 7.3 Hz, 2H), 8.00
(d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.68−7.62 (m, 2H),
7.55−7.49 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): δ 191.6,
153.3, 135.5, 134.7, 134.2, 133.3, 133.0, 131.0, 129.8, 128.7, 127.4,
126.7, 125.7, 123.8, 123.7, 115.4, 114.4, 104.1 ppm; HRMS (ESI)
calcd for C22H15N2O [M + H] 323.1184, found 323.1192.
(Phenyl)(3-(trifluoromethyl)indolo[1,2-a]quinoxalin-6-yl)-
methanone (2g): red solid; Rf = 0.64 (10/90 ethyl acetate/hexane);
yield 62% (0.132 g); mp 162−164 °C; FT-IR (KBr) 3432, 3020, 2795,
1
1662, 1624, 1466, 1405, 1326 cm−1; H NMR (400 MHz, CDCl3): δ
8.62 (d, J = 8.7 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.19−
8.17 (m, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.95−7.92 (m, 1H), 7.69−7.63
(m, 2H), 7.56−7.50 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ
191.7, 153.4, 135.5, 134.8, 134.2, 133.4, 133.1, 131.1, 129.9, 128.7,
127.5, 126.8, 126.7, 126.4, 125.8, 125.2, 123.9, 123.8, 122.5, 115.4,
114.5, 104.1 ppm; HRMS (ESI) calcd for C23H14F3N2O [M + H]
391.1058, found 391.1053.
(3-Methylindolo[1,2-a]quinoxalin-6-yl)(phenyl)methanone (2h):
red solid; Rf = 0.62 (10/90 ethyl acetate/hexane); yield 70% (0.167
g); mp 179−181 °C; FT-IR (KBr) 3403, 3021, 2400, 1620, 1384,
1316, 1215 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 8.6 Hz,
1H), 8.37 (s, 1H), 8.19−8.17 (m, 2H), 7.99−7.93 (m, 2H), 7.66−7.57
(m, 2H), 7.53−7.45 (m, 4H), 7.29 (d, J = 8.1 Hz, 1H), 2.67 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 192.3, 150.9, 136.0, 133.8,
133.0, 132.8, 131.4, 131.1, 129.8, 128.5, 127.8, 125.6, 124.7, 123.3,
123.1, 115.3, 114.7, 114.2, 102.3, 22.6 ppm; HRMS (ESI) calcd for
C23H17N2O [M + H] 337.1340, found 337.1335.
(4-(tert-Butyl)phenyl)(indolo[1,2-a]quinoxalin-6-yl)methanone
(2i): red solid; Rf = 0.60 (10/90 ethyl acetate/hexane); yield 70%
(0.168 g); mp 156−158 °C; FT-IR (KBr) 3429, 3022, 1661, 1625,
1461, 1402, 1216, 1158 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.57−
8.55 (m, 1H), 8.50 (d, J = 8.7 Hz, 1H), 8.15−8.13 (m, 2H), 8.09−8.06
(m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.74−7.69 (m, 1H), 7.61−7.57 (m,
1H), 7.55−7.52 (m, 2H), 7.49−7.45 (m, 3H), 1.37 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3): δ 191.6, 157.8, 152.3, 134.8, 132.9, 132.7,
131.4, 131.0, 130.9, 130.2, 129.5, 127.5, 125.5, 124.7, 124.3, 123.2,
122.9, 114.9, 114.5, 102.4, 35.3, 31.1 ppm; HRMS (ESI) calcd for
C26H23N2O [M + H] 379.1810, found 379.1810.
([1,3]Dioxolo[4′,5′:5,6]indolo[1,2-a]quinoxalin-6-yl)(phenyl)-
methanone (2b): red solid; Rf = 0.62 (10/90 ethyl acetate/hexane);
yield 75% (0.179 g); mp 145−147 °C; FT-IR (KBr) 3431, 3020, 2795,
1
1663, 1624, 1466, 1405, 1215 cm−1; H NMR (400 MHz, CDCl3): δ
8.35 (d, J = 8.1 Hz, 1H), 8.17−8.15 (m, 2H), 8.03−8.01 (m, 1H), 7.89
(s, 1H), 7.68−7.61 (m, 2H), 7.52−7.42 (m, 3H), 7.36 (s, 1H), 7.22 (s,
1H), 6.10 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 192.4, 151.3,
148.0, 145.6, 136.0, 135.2, 133.9, 131.5, 131.3, 131.1, 129.9, 128.5,
127.3, 125.0, 124.4, 114.5, 102.8, 101.9, 100.1, 94.6 ppm; HRMS (ESI)
calcd for C23H15N2O3 [M + H] 367.1082, found 367.1076.
(4-(tert-Butyl)phenyl)(9,10-dimethoxyindolo[1,2-a]quinoxalin-6-
yl)methanone (2c): red solid; Rf = 0.58 (10/90 ethyl acetate/hexane);
yield 80% (0.182 g); mp 112−114 °C; FT-IR (KBr) 3403, 3021, 2960,
1
1606, 1402, 1323, 1215 cm−1; H NMR (400 MHz, CDCl3): δ 8.40
(d, J = 8.4 Hz, 1H), 8.13−8.11 (m, 2H), 8.06−8.03 (m, 1H), 7.85 (s,
1H), 7.70−7.66 (m, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.46−7.42 (m,
1H), 7.35 (s, 1H), 7.27 (s, 1H), 4.13 (s, 3H), 4.00 (s, 3H), 1.36 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3): δ 192.1, 157.9, 151.8, 149.4,
147.8, 135.3, 133.3, 131.4, 131.2, 130.9, 129.7, 127.7, 127.1, 125.7,
124.3, 123.8, 114.3, 102.5, 102.3, 96.9, 35.5, 31.3 ppm; HRMS (ESI)
calcd for C28H27N2O3 [M + H] 439.2021, found 439.2021.
(9,10-Dimethoxyindolo[1,2-a]quinoxalin-6-yl)(phenyl)-
methanone (2d): red solid; Rf = 0.52 (10/90 ethyl acetate/hexane);
yield 76% (0.192 g); mp 170−172 °C; FT-IR (KBr) 3399, 3021, 2957,
2921, 2401, 1667, 1540, 1460, 1402 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.39 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 7.4 Hz, 2H), 8.03 (d, J
= 7.1 Hz, 1H), 7.84 (s, 1H), 7.70−7.62 (m, 2H), 7.51 (t, J = 7.7 Hz,
2H), 7.44 (t, J = 7.5 Hz, 1H), 7.38 (s, 1H), 7.28 (s, 1H), 4.13 (s, 3H),
4.00 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 192.5, 151.4,
149.4, 147.8, 135.9, 135.2, 133.8, 131.4, 131.1, 130.8, 129.8, 128.5,
127.7, 127.0, 124.2, 123.8, 114.2, 102.4, 102.2, 96.8, 56.6, 56.2 ppm;
HRMS (ESI) calcd for C24H19N2O3 [M + H] 383.1395, found
383.1384.
(9-Chloroindolo[1,2-a]quinoxalin-6-yl)(p-tolyl)methanone (2e):
red solid; Rf = 0.60 (10/90 ethyl acetate/hexane); yield 68% (0.134
g); mp 167−169 °C; FT-IR (KBr) 3401, 3019, 2958, 2925, 2400,
1606, 1384 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 8.3 Hz,
1H), 8.41 (d, J = 9.1 Hz, 1H), 8.09−8.07 (m, 3H), 7.93 (d, J = 1.9 Hz,
1H), 7.75−7.71 (m, 1H), 7.53−7.47 (m, 2H), 7.39 (s, 1H), 7.32 (d, J
= 8.0 Hz, 2H), 2.46 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
191.6, 152.1, 145.2, 135.0, 133.1, 131.8, 131.3, 131.1, 130.8, 130.7,
129.4, 128.9, 128.6, 125.2, 124.9, 122.4, 115.7. 114.9, 101.8, 22.0 ppm;
HRMS (ESI) calcd for C23H16ClN2O [M + H] 371.0951, found
371.0958.
(3-Bromoindolo[1,2-a]quinoxalin-6-yl)(4-(tert-butyl)phenyl)-
methanone (2j): red solid; Rf = 0.64 (10/90 ethyl acetate/hexane);
yield 65% (0.156 g); mp 120−122 °C; FT-IR (KBr) 3430, 3022, 1663,
1
1625, 1458, 1402, 1327, 1215 cm−1; H NMR (400 MHz, CDCl3): δ
8.61 (d, J = 8.7 Hz, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 8.12
(d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H),
7.66−7.62 (m, 1H), 7.55−7.49 (m, 4H), 1.36 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3): δ 191.2, 158.3, 153.7, 134.8, 133.1, 132.8, 131.1,
129.9, 128.8, 128.7, 127.6, 126.7, 126.6, 125.8, 125.7, 123.9, 123.8,
115.4, 114.5, 104.1, 35.5, 31.3 ppm; HRMS (ESI) calcd for
C27H22F3N2O [M + H] 447.1684, found 447.1696.
(3-Bromoindolo[1,2-a]quinoxalin-6-yl)(4-(tert-butyl)phenyl)-
methanone (2k): red solid; Rf = 0.62 (10/90 ethyl acetate/hexane);
yield 60% (0.144 g); mp 146−148 °C; FT-IR (KBr) 3434, 3020, 1663,
1
1625, 1538, 1465, 1405 cm−1; H NMR (400 MHz, CDCl3): δ 8.40
(d, J = 8.8 Hz, 2H), 8.21 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H),
7.97 (d, J = 8.0 Hz, 1H), 7.79−7.77 (m, 1H), 7.62−7.58 (m, 1H), 7.53
(d, J = 8.5 Hz, 2H), 7.49−7.45 (m, 2H), 1.36 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3): δ 191.4, 158.2, 153.4, 136.3, 133.8, 132.9, 132.8,
131.1, 130.2, 129.7, 127.5, 125.8, 125.4, 123.7, 123.4, 116.7, 116.3,
114.5, 103.4, 35.5, 31.3 ppm; HRMS (ESI) calcd for C26H22BrN2O [M
+ H] 457.0915, found 457.0912.
(4-(tert-Butyl)phenyl)(3-fluoroindolo[1,2-a]quinoxalin-6-yl)-
methanone (2l): red solid; Rf = 0.64 (10/90 ethyl acetate/hexane);
yield 59% (0.123 g); mp 165−167 °C; FT-IR (KBr) 3400, 3023, 1625,
1541, 1503, 1386, 1266 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.57−
8.42 (m, 2H), 8.14−8.06 (m, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.79−7.69
(m, 1H), 7.62−7.52 (m, 3H), 7.49−7.44 (m, 3H), 1.37 (s, 9H) ppm;
13C NMR (100 MHz, CDCl3): δ 191.2, 158.3, 153.7, 134.7, 133.3,
(Indolo[1,2-a]quinoxalin-6-yl)(phenyl)methanone (2f): red solid;
Rf = 0.68 (10/90 ethyl acetate/hexane); yield 74% (0.149 g); mp
133.0, 132.7, 131.0, 129.8, 128.7, 128.6, 127.5, 126.6, 125.8, 123.8,
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123.7, 115.3, 114.4, 104.0, 35.5, 31.2 ppm; HRMS (ESI) calcd for
C26H22FN2O [M + H] 397.1716, found 397.1709.
g); mp 168−170 °C; FT-IR (KBr) 3400, 1613, 1385, 1216, 1157
1
cm−1; H NMR (400 MHz, CDCl3): δ 8.70 (d, J = 8.0 Hz, 1H), 8.51
1-(4-(tert-Butyl)phenyl)[1,3]dioxolo[4′,5′:5,6]indolo[1,2-a][1,2,3]-
triazolo[5,1-c]quinoxaline (3a): gray fluffy solid; Rf = 0.58 (10/90
ethyl acetate/hexane); yield 70% (0.172 g); mp 185−187 °C; FT-IR
(KBr) 3429, 1702, 1655, 1466, 1269 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.67 (d, J = 6.9 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.86 (d, J
= 8.2 Hz, 2H), 7.73 (s, 1H), 7.62−7.56 (m, 3H), 7.44 (t, J = 7.9 Hz,
1H), 7.21 (s, 1H), 7.08 (s, 1H), 6.06 (s, 2H), 1.43 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3): δ 152.0, 146.8, 144.8, 141.9, 128.7, 128.3,
128.2, 128.1, 127.4, 125.9, 124.5, 124.4, 123.9, 123.5, 122.7, 117.8,
115.7, 101.7, 100.9, 99.8, 94.5, 35.0, 31.5 ppm; HRMS (ESI) calcd for
C27H23N4O2 [M + H] 435.1821, found 435.1827.
6-Fluoro-1-phenyl[1,3]dioxolo[4′,5′:5,6]indolo[1,2-a][1,2,3]-
triazolo[5,1-c]quinoxaline (3b): gray fluffy solid; Rf = 0.54 (10/90
ethyl acetate/hexane); yield 67% (0.165 g); mp 191−193 °C; FT-IR
(KBr) 3400, 1627, 1462, 1386, 1215 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.94 (d, J = 1.5 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 7.91−
7.89 (m, 2H), 7.84−7.82 (m, 1H), 7.69 (s, 1H), 7.60 (t, J = 7.1 Hz,
2H), 7.54−7.50 (m, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.09
(s, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 151.2, 147.9, 145.6,
135.9, 135.2, 133.8, 131.5, 131.3, 131.1, 130.6, 129.8, 128.5, 128.4,
128.2, 127.3, 125.0, 124.4, 114.5, 102.8, 101.9, 100.1, 94.6 ppm;
HRMS (ESI) calcd for C23H14FN4O2 [M + H] 397.1100, found
397.1109.
1-(4-(tert-Butyl)phenyl)-11,12-dimethoxyindolo[1,2-a][1,2,3]-
triazolo[5,1-c]quinoxaline (3c): gray fluffy solid; Rf = 0.48 (10/90
ethyl acetate/hexane); yield 89% (0.220 g); mp 178−180 °C; FT-IR
(KBr) 3042, 1610, 1406, 1339, 1269 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.65 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.86 (d, J
= 8.1 Hz, 2H), 7.68 (s, 1H), 7.60 (d, J = 8.1 Hz, 3H), 7.42 (t, J = 7.9
Hz, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 4.06 (s, 3H), 3.95 (s, 3H), 1.43 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3): δ 151.9, 148.1, 146.9, 141.8,
128.3, 128.1, 127.5, 125.8, 124.1, 123.6, 123.4, 123.3, 122.7, 117.7,
115.2, 102.3, 100.4, 97.0, 56.6, 56.1, 35.0, 31.5 ppm; HRMS (ESI)
calcd for C28H27N4O2 [M + H] 451.2134, found 451.2135.
(d, J = 8.3 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 7.2 Hz, 2H),
7.76 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 3H), 7.56 (d, J = 7.3 Hz,
1H), 7.48 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 3.8
Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 142.8, 133.8, 130.9,
129.7, 129.0, 128.8, 128.5, 127.8, 124.8, 124.4, 124.3, 123.4, 123.0,
122.8, 122.0, 117.7, 116.2, 113.5, 100.6 ppm; HRMS (ESI) calcd for
C22H15N4 [M + H] 335.1296, found 335.1291.
6-Fluoro-1-phenylindolo[1,2-a][1,2,3]triazolo[5,1-c]quinoxaline
(3h): gray fluffy solid; Rf = 0.54 (10/90 ethyl acetate/hexane); yield
68% (0.168 g); mp 179−181 °C; FT-IR (KBr) 3427, 1645, 1468,
1275, 1156 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.95 (d, J = 1.4 Hz,
1H), 8.57 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.6 Hz, 1H), 7.93−7.91 (m,
2H), 7.87−7.84 (m, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.63−7.59 (m,
2H), 7.56−7.48 (m, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.31 (s, 1H) ppm;
13C NMR (100 MHz, CDCl3): δ 143.3, 134.2, 130.6, 130.2, 129.3,
129.1, 128.9, 126.9, 126.5, 125.5, 125.4, 125.2, 124.9, 123.6, 123.5,
123.0, 122.6, 116.7, 115.6, 115.5, 113.6, 102.0 ppm; HRMS (ESI)
calcd for C22H14FN4 [M + H] 353.1202, found 353.1214.
1-Phenyl-6-(trifluoromethyl)indolo[1,2-a][1,2,3]triazolo[5,1-c]-
quinoxaline (3i): gray fluffy solid; Rf = 0.58 (10/90 ethyl acetate/
hexane); yield 60% (0.148 g); mp 209−211 °C; FT-IR (KBr) 3401,
1
1627, 1384, 1232, 1158 cm−1; H NMR (400 MHz, CDCl3): δ 8.95
(d, J = 1.6 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H),
7.93−7.91 (m, 2H), 7.87−7.85 (m, 1H), 7.76 (d, J = 7.8 Hz, 1H),
7.63−7.59 (m, 2H), 7.56−7.48 (m, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.31
(s, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 143.3, 134.2, 130.5,
130.2, 129.3, 129.1, 128.9, 126.8, 126.5, 125.5, 125.4, 125.2, 124.9,
123.6, 123.5, 123.0, 122.5, 116.7, 115.6, 115.5, 113.6, 102.0 ppm;
HRMS (ESI) calcd for C23H14F3N4 [M + H] 403.1170, found
403.1158.
1-(4-(tert-Butyl)phenyl)indolo[1,2-a][1,2,3]triazolo[5,1-c]-
quinoxaline (3j): gray fluffy solid; Rf = 0.54 (10/90 ethyl acetate/
hexane); yield 72% (0.178 g); mp 169−171 °C; FT-IR (KBr) 3401,
1
1612, 1387, 1215, 1147 cm−1; H NMR (400 MHz, CDCl3): δ 8.68
11,12-Dimethoxy-1-phenyl-6-(trifluoromethyl)indolo[1,2-a]-
[1,2,3]triazolo[5,1-c]quinoxaline (3d): gray fluffy solid; Rf = 0.52 (10/
90 ethyl acetate/hexane); yield 78% (0.193 g); mp 192−194 °C; FT-
(d, J = 10.8 Hz, 1H), 8.49 (d, J = 11.2 Hz, 1H), 8.28 (d, J = 11.1 Hz,
1H), 7.88 (d, J = 10.6 Hz, 2H), 7.77 (d, J = 10.4 Hz, 1H), 7.61 (t, J =
9.9 Hz, 3H), 7.45 (d, J = 10 Hz, 2H), 7.37−7.33 (m, 2H), 1.43 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3): δ 152.0, 142.8, 133.8, 129.8,
128.4, 128.3, 127.8, 125.8, 125.0, 124.3, 124.2, 123.4, 122.6, 122.0,
117.7, 116.1, 113.4, 100.6, 34.8, 31.3 ppm; HRMS (ESI) calcd for
C26H23N4 [M + H] 391.1922, found 391.1920.
1-(4-(tert-Butyl)phenyl)-6-(trifluoromethyl)indolo[1,2-a][1,2,3]-
triazolo[5,1-c]quinoxaline (3k): gray fluffy solid; Rf = 0.56 (10/90
ethyl acetate/hexane); yield 65% (0.161 g); mp 165−167 °C; FT-IR
(KBr) 3400, 1627, 1462, 1386, 1215, 1184 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.68 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.5 Hz,
1H), 7.88 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.3
Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.32 (s,
1H), 1.44 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ
152.2, 143.1, 134.1, 130.0, 128.6, 128.5, 128.0, 126.0, 125.2, 124.6,
124.4, 123.7, 122.9, 122.8, 122.2, 117.9, 116.4, 113.7, 100.8, 35.1, 31.6
ppm; HRMS (ESI) calcd for C27H22F3N4 [M + H] 459.1796, found
459.1802.
1
IR (KBr) 3405, 1622, 1464, 1380, 1215 cm−1; H NMR (400 MHz,
CDCl3): δ 8.92 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.90−7.84 (m, 3H),
7.63−7.49 (m, 4H), 7.19 (s, 1H), 7.12 (s, 1H), 4.06 (s, 3H), 3.95 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 148.8, 147.6, 130.7, 129.9,
129.1, 129.0, 128.7, 128.5, 125.2, 123.7, 123.5, 123.4, 123.2, 115.8,
115.5, 102.8, 101.8, 97.2, 56.8, 56.2 ppm; HRMS (ESI) calcd for
C25H18F3N4O2 [M + H] 463.1381, found 463.1371.
12-Chloro-1-(p-tolyl)indolo[1,2-a][1,2,3]triazolo[5,1-c]-
quinoxaline (3e): gray fluffy solid; Rf = 0.58 (10/90 ethyl acetate/
hexane); yield 67% (0.165 g); mp 206−208 °C; FT-IR (KBr) 3425,
1
1625, 1459, 1217, 1158 cm−1; H NMR (400 MHz, CDCl3): δ 8.67
(d, J = 7.9 Hz, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H),
7.78 (d, J = 7.6 Hz, 2H), 7.68 (s, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.48−
7.36 (m, 4H), 7.18 (s, 1H), 2.49 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 143.5, 139.3, 132.4, 131.2, 129.8, 128.8, 128.6, 127.8, 127.6,
126.5, 125.0, 124.5, 123.7, 122.4, 121.4, 118.1, 116.2, 114.6, 99.9, 21.6
ppm; HRMS (ESI) calcd for C23H16ClN4 [M + H] 383.1063, found
383.1061.
6-Bromo-1-(4-(tert-butyl)phenyl)indolo[1,2-a][1,2,3]triazolo[5,1-
c]quinoxaline (3l): gray fluffy solid; Rf = 0.56 (10/90 ethyl acetate/
hexane); yield 70% (0.175 g); mp 170−172 °C; FT-IR (KBr) 3408,
6-Bromo-12-chloro-1-(p-tolyl)indolo[1,2-a][1,2,3]triazolo[5,1-c]-
quinoxaline (3f): gray fluffy solid; Rf = 0.56 (10/90 ethyl acetate/
hexane); yield 62% (0.153 g); mp 195−197 °C; FT-IR (KBr) 3041,
1
1617, 1385, 1245, 1167 cm−1; H NMR (400 MHz, CDCl3): δ 8.96
(d, J = 0.9 Hz, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.27 (d, J = 8.6 Hz, 1H),
7.88−7.86 (m, 3H), 7.80 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H),
7.53−7.50 (m, 1H), 7.42−7.39 (m, 2H), 1.44 (s, 9H) ppm; 13C NMR
(125 MHz, CDCl3): δ 153.1, 152.5, 143.8, 143.4, 134.2, 130.3, 128.5,
127.6, 126.8, 126.1, 125.4, 125.1, 123.6, 122.8, 122.6, 116.7, 115.5,
113.6, 102.1, 35.1, 31.5 ppm; HRMS (ESI) calcd for C26H22BrN4 [M +
H] 469.1027, found 469.1034.
6-((4-(tert-Butyl)phenyl)ethynyl)-5-(2-nitrophenyl)-5H-[1,3]-
dioxolo[4,5-f ]indole (1a): yellow solid; Rf = 0.54 (10/90 ethyl
acetate/hexane); yield 80% (0.276 g); mp 102−104 °C; FT-IR (KBr)
3400, 3021, 2962, 2401, 1608, 1533, 1466, 1395 cm−1; 1H NMR (400
1
1663, 1465, 1216, 1187 cm−1; H NMR (400 MHz, CDCl3): δ 8.67
(d, J = 8.1 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H),
7.79 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 1.9 Hz, 1H), 7.61 (t, J = 8.3 Hz,
1H), 7.47 (t, J = 7.7 Hz, 1H), 7.41−7.38 (m, 2H), 7.18 (s, 1H), 2.50
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 143.4, 139.2, 132.3,
131.1, 129.8, 128.7, 128.5, 127.7, 127.5, 126.3, 124.9, 124.4, 123.6,
122.3, 121.3, 118.0, 116.1, 114.5, 99.8, 21.6 ppm; HRMS (ESI) calcd
for C23H15ClBrN4 [M + H] 461.0168, found 461.0176.
1-Phenylindolo[1,2-a][1,2,3]triazolo[5,1-c]quinoxaline (3g): gray
fluffy solid; Rf = 0.58 (10/90 ethyl acetate/hexane); yield 70% (0.172
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MHz, CDCl3): δ 8.17−8.14 (m, 1H), 7.79−7.75 (m, 1H), 7.64−7.60
(m, 2H), 7.27 (t, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.99 (s,
1H), 6.86 (s, 1H), 6.53 (s, 1H), 5.94−5.92 (m, 2H), 1.27 (s, 9H)
ppm; 13C NMR (100 MHz, CDCl3): δ 151.8, 146.9, 144.3, 133.7,
132.9, 131.6, 131.1, 130.9, 129.1, 125.6, 125.3, 121.9, 120.8, 119.3,
110.3, 101.0, 99.4, 95.6, 90.8, 79.6, 34.8, 31.1 ppm; HRMS (ESI) calcd
for C27H23N2O4 [M + H] 439.1657, found 439.1649.
5-(2-Nitrophenyl)-6-(phenylethynyl)-5H-[1,3]dioxolo[4,5-f ]indole
(1b): yellow solid; Rf = 0.56 (10/90 ethyl acetate/hexane); yield 79%
(0.289 g); mp 99−101 °C; FT-IR (KBr) 3401, 3019, 2400, 1653,
1543,1476 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.19−8.16 (m, 1H),
7.81−7.77 (m, 1H), 7.67−7.62 (m, 2H), 7.26 (s, 5H), 7.00 (s, 1H),
6.89 (d, J = 0.52 Hz, 1H), 6.54 (s, 1H), 5.96−5.94 (m, 2H) ppm; 13C
NMR (100 MHz, CDCl3): δ 147.1, 144.5, 133.8, 133.1, 131.7, 131.2,
129.3, 128.5, 128.4, 125.8, 122.5, 122.0, 120.7, 110.7, 101.2, 99.5, 95.6,
91.0, 80.4 ppm; HRMS (ESI) calcd for C23H15N2O4 [M + H]
383.1031, found 383.1026.
1-(4-Bromo-2-nitrophenyl)-5-chloro-2-(p-tolylethynyl)-1H-indole
(1h): light red solid; Rf = 0.68 (10/90 ethyl acetate/hexane); yield 71%
(0.310 g); mp 102−104 °C; FT-IR (KBr) 3402, 3022, 2400, 1653,
1
1532, 1478, 1332 cm−1; H NMR (400 MHz, CDCl3): δ 8.58 (d, J =
2.2 Hz, 1H), 8.20−8.17 (m, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.77 (s,
1H), 7.52−7.44 (m, 4H), 7.39 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.7 Hz,
1H), 2.61 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 147.0, 139.6,
137.0, 135.6, 132.4, 131.5, 130.3, 129.3, 129.2, 128.9, 127.5, 124.7,
123.5, 122.6, 120.8, 118.7, 110.7, 109.9, 97.1, 78.7, 21.7 ppm; HRMS
(ESI) calcd for C23H15BrClN2O2 [M + H] 465.0005, found 464.9996.
1-(2-Nitrophenyl)-2-(phenylethynyl)-1H-indole (1i): yellow solid;
Rf = 0.62 (10/90 ethyl acetate/hexane); yield 75% (0.292 g); mp 89−
91 °C; FT-IR (KBr) 3406, 3021, 2401, 1627, 1545, 1449, 1383 cm−1;
1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 1.3 Hz, 1H), 7.98−7.96
(m, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.62−7.60 (m, 1H), 7.29−7.24 (m,
5H), 7.23−7.15 (m, 3H), 7.06 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H) ppm;
13C NMR (100 MHz, CDCl3): δ 146.5, 137.1, 134.8, 132.0, 131.5,
5-(4-Fluoro-2-nitrophenyl)-6-(phenylethynyl)-5H-[1,3]dioxolo-
[4,5-f]indole (1c): pale yellow solid; Rf = 0.58 (10/90 ethyl acetate/
hexane); yield 77% (0.290 g); mp 102−104 °C; FT-IR (KBr) 3402,
3021, 2965, 2401, 1613, 1537, 1490, 1383 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.45 (d, J = 1.6 Hz, 1H), 8.06−8.03 (m, 1H), 7.83 (d, J =
8.2 Hz, 1H), 7.30−7.27 (m, 5H), 7.00 (s, 1H), 6.93 (s, 1H), 6.56 (s,
1H), 5.98−5.96 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 147.5,
146.6, 144.9, 134.8, 132.6, 131.9, 131.3, 130.5, 128.9, 128.5, 123.5,
123.4, 122.3, 122.2, 120.4, 111.9, 101.4, 99.8, 96.2, 90.8, 79.8 ppm;
HRMS (ESI) calcd for C23H14FN2O4 [M + H] 401.0937, found
401.0931.
2-((4-(tert-Butyl)phenyl)ethynyl)-5,6-dimethoxy-1-(2-nitrophen-
yl)-1H-indole (1d): yellow solid; Rf = 0.54 (10/90 ethyl acetate/
hexane); yield 82% (0.280 g); mp 101−103 °C; FT-IR (KBr) 3411,
3019, 1626, 1532, 1385 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.36−
8.33 (m, 1H), 8.00−7.96 (m, 1H), 7.86−7.80 (m, 2H), 7.47 (d, J = 8.5
Hz, 2H), 7.43 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.08 (s, 1H), 6.72 (s,
1H), 4.12 (s, 3H), 3.99 (s, 3H), 1.46 (s, 9H) ppm; 13C NMR (100
MHz, CDCl3): δ 151.9, 149.0, 147.0, 146.5, 133.8, 132.1, 131.8, 131.2,
131.0, 129.0, 125.8, 125.4, 120.8, 120.6, 119.5, 110.1, 102.5, 95.7, 92.9,
79.9, 56.4, 56.3, 34.9, 31.2 ppm; HRMS (ESI) calcd for C28H27N2O4
[M + H] 455.1970, found 455.1962.
5,6-Dimethoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)-2-(phenyle-
thynyl)-1H-indole (1e): yellow solid; Rf = 0.56 (10/90 ethyl acetate/
hexane); yield 79% (0.332 g); mp 97−99 °C; FT-IR (KBr) 3401,
3020, 2957, 2406, 1633, 1536, 1484, 1387 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.44 (d, J = 3.4 Hz, 1H), 8.07−8.05 (m, 1H), 7.87 (d, J =
8.3 Hz, 1H), 7.30 (s, 5H), 7.08 (s, 1H), 6.96 (s, 1H), 6.56 (s, 1H),
3.95 (s, 3H), 3.48 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
149.1, 147.0, 146.5, 133.8, 132.2, 131.7, 131.2, 129.1, 128.5, 128.4,
125.8, 122.6, 120.8, 120.3, 110.4, 102.5, 95.5, 92.9, 80.6, 56.4, 56.3
ppm; HRMS (ESI) calcd for C25H18F3N2O4 [M + H] 467.1218, found
467.1210.
130.5, 130.4, 129.1, 128.5, 128.3, 124.9, 123.5, 123.4, 122.2, 121.7,
111.7, 109.6, 96.6, 79.6 ppm; HRMS (ESI) calcd for C22H15N2O2 [M
+ H] 339.1133, found 339.1139.
1-(4-Fluoro-2-nitrophenyl)-2-(phenylethynyl)-1H-indole (1j): yel-
low solid; Rf = 0.62 (10/90 ethyl acetate/hexane); yield 73% (0.295
g); mp 104−106 °C; FT-IR (KBr) 3401, 3020, 2959, 2400, 1604,
1384, 1215 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.89−7.86 (m, 1H),
7.63−7.60 (m, 3H), 7.50−7.45 (m, 1H), 7.24 (s, 1H), 7.20 (s, 2H),
7.18−7.15 (m, 2H), 7.06−6.98 (m, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 137.6, 133.2, 133.1, 131.5, 129.0, 128.5, 128.1, 124.6, 122.1,
121.8, 121.6, 121.2, 121.0, 113.6, 113.4, 110.7, 109.6, 96.1, 80.0 ppm;
HRMS (ESI) calcd for C22H14FN2O2 [M + H] 357.1039, found
357.1027.
1-(2-Nitro-4-(trifluoromethyl)phenyl)-2-(phenylethynyl)-1H-in-
dole (1k): yellow solid; Rf = 0.62 (10/90 ethyl acetate/hexane); yield
76% (0.290 g); mp 65−67 °C; FT-IR (KBr) 3402, 3021, 2401, 1628,
1543, 1384 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 1.4 Hz,
1H), 8.25−8.22 (m, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.3 Hz,
1H), 7.50 (s, 5H), 7.47−7.40 (m, 3H), 7.31 (d, J = 7.9 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3): δ 146.5, 137.1, 134.8, 132.0, 131.5,
130.5, 129.1, 128.6, 128.3, 124.9, 123.5, 123.4, 122.2, 121.9, 121.8,
121.7, 111.7, 109.6, 96.6, 79.6 ppm; HRMS (ESI) calcd for
C23H14F3N2O2 [M + H] 407.1007, found 407.1002.
1-(4-Methyl-2-nitrophenyl)-2-(phenylethynyl)-1H-indole (1l): yel-
low solid; Rf = 0.60 (10/90 ethyl acetate/hexane); yield 78% (0.295
g); mp 94−96 °C; FT-IR (KBr) 3401, 3020, 2958, 2401, 1603, 1527,
1453, 1348 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.3 Hz,
1H), 7.63 (d, J = 7.4 Hz, 1H), 7.41−7.36 (m, 2H), 7.29−7.23 (m,
5H), 7.22−7.14 (m, 2H), 7.10 (d, J = 7.7 Hz, 1H), 7.00 (s, 1H), 2.47
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 145.3, 144.4, 137.3,
131.5, 131.4, 131.3, 129.6, 128.6, 128.3, 127.9, 125.7, 124.2, 122.2,
121.9, 121.4, 121.3, 110.2, 109.8, 95.7, 80.1, 21.4 ppm; HRMS (ESI)
calcd for C23H17N2O2 [M + H] 353.1290, found 353.1285.
2-((4-(tert-Butyl)phenyl)ethynyl)-1-(2-nitrophenyl)-1H-indole
(1m): yellow solid; Rf = 0.60 (10/90 ethyl acetate/hexane); yield 88%
(0.298 g); mp 67−69 °C; FT-IR (KBr) 3400, 3021, 2959, 1608, 1533,
1385, 1216 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.45−8.42 (m, 1H),
8.06−8.02 (m, 1H), 7.92−7.86 (m, 3H), 7.55 (d, J = 8.4 Hz, 2H),
7.50−7.42 (m, 5H), 7.34 (d, J = 7.8 Hz, 1H), 1.53 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3): δ 152.3, 147.1, 137.5, 133.9, 131.7, 131.4,
131.3, 129.2, 128.2, 125.9, 125.5, 124.3, 122.4, 121.6, 121.5, 119.3,
110.3, 109.9, 96.2, 79.6, 35.0, 31.3 ppm; HRMS (ESI) calcd for
C26H23N2O2 [M + H] 395.1759, found 395.1755.
2-((4-(tert-Butyl)phenyl)ethynyl)-1-(4-fluoro-2-nitrophenyl)-1H-
indole (1n): yellow solid; Rf = 0.62 (10/90 ethyl acetate/hexane); yield
80% (0.301 g); mp 79−81 °C; FT-IR (KBr) 3402, 2927, 2402, 1633,
1535, 1487 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.18−8.16 (m, 1H),
7.92−7.89 (m, 2H), 7.78−7.74 (m, 1H), 7.59−7.57 (m, 2H), 7.51−
7.49 (m, 3H), 7.48−7.46 (m, 1H), 7.45−7.43 (m, 1H), 7.31−7.29 (m,
1H), 1.55 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 152.4, 137.5,
133.1, 133.0, 131.2, 128.1, 128.0, 127.9, 125.5, 124.4, 122.4, 121.7,
121.5, 121.2, 121.0, 119.1, 113.6, 113.3, 110.4, 109.6, 96.3, 79.3, 35.0,
5,6-Dimethoxy-1-(2-nitrophenyl)-2-(phenylethynyl)-1H-indole
(1f): yellow solid; Rf = 0.58 (10/90 ethyl acetate/hexane); yield 81%
(0.290 g); mp 103−105 °C; FT-IR (KBr) 3407, 3022, 1638, 1533,
1
1384 cm−1; H NMR (400 MHz, CDCl3): δ 8.17−8.15 (m, 1H),
7.82−7.78 (m, 1H), 7.68−7.62 (m, 2H), 7.25 (s, 5H), 7.06 (s, 1H),
6.91 (s, 1H), 6.54 (s, 1H), 3.93 (s, 3H), 3.81 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 149.0, 146.9, 146.4, 133.7, 132.1, 131.6, 129.0,
128.3, 125.6, 122.4, 120.6, 120.2, 110.3, 102.3, 95.4, 92.8, 80.5, 56.2,
56.1 ppm; HRMS (ESI) calcd for C24H19N2O4 [M + H] 399.1344,
found 399.1347.
5-Chloro-1-(2-nitrophenyl)-2-(p-tolylethynyl)-1H-indole (1g): pale
yellow solid; Rf = 0.64 (10/90 ethyl acetate/hexane); yield 74% (0.269
g); mp 91−93 °C; FT-IR (KBr) 3406, 2958, 2400, 1606, 1533, 1476,
1
1392 cm−1; H NMR (400 MHz, CDCl3): δ 8.19−8.17 (m, 1H),
7.82−7.77 (m, 1H), 7.67−7.61 (m, 3H), 7.19−7.16 (m, 3H), 7.09 (d, J
= 7.9 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 0.5 Hz, 1H), 2.32
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 146.9, 139.3, 135.8,
133.9, 131.4, 131.2, 129.5, 129.2, 129.1, 127.2, 125.8, 124.5, 123.7,
120.6, 118.8, 110.8, 109.4, 96.8, 79.0, 21.6 ppm; HRMS (ESI) calcd for
C23H16ClN2O2 [M + H] 387.0900, found 387.0892.
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Article
31.2 ppm; HRMS (ESI) calcd for C26H22FN2O2 [M + H] 413.1665,
found 413.1651.
5310. (b) Zhou, G.; Wu, D.; Snyder, B.; Ptak, R. G.; Kaur, H.; Gochin,
M. J. Med. Chem. 2011, 54, 7220−7231.
2-((4-(tert-Butyl)phenyl)ethynyl)-1-(2-nitro-4-(trifluoromethyl)-
phenyl)-1H-indole (1o): yellow solid; Rf = 0.62 (10/90 ethyl acetate/
hexane); yield 82% (0.300 g); mp 109−111 °C; FT-IR (KBr) 3407,
3020, 2961, 2401, 1628, 1545, 1451, 1382 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.44 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.2 Hz,
1H), 7.64 (d, J = 7.2 Hz, 1H), 7.32−7.30 (m, 4H), 7.23 (d, J = 1.4 Hz,
2H), 7.09 (d, J = 7.5 Hz, 1H), 7.02 (s, 1H), 1.27 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3): δ 152.2, 147.0, 137.5, 133.8, 131.7, 131.4,
131.2, 129.2, 128.1, 125.8, 125.5, 124.3, 122.4, 121.6, 121.4, 119.2,
110.2, 109.8, 96.2, 79.5, 35.0, 31.2 ppm; HRMS (ESI) calcd for
C27H22F3N2O2 [M + H] 463.1633, found 463.1630.
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1-(4-Bromo-2-nitrophenyl)-2-((4-(tert-butyl)phenyl)ethynyl)-1H-
indole (1p): light red solid; Rf = 0.60 (10/90 ethyl acetate/hexane);
yield 82% (0.305 g); mp 91−93 °C; FT-IR (KBr) 3399, 3020, 2962,
2401, 1603, 1537, 1490 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.56 (s,
1H), 8.15−8.13 (m, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.4 Hz,
1H), 7.58 (d, J = 8.3 Hz, 2H), 7.53−7.43 (m, 5H), 7.32 (d, J = 7.9 Hz,
1H). 1.55 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 152.5, 147.1,
137.3, 136.9, 132.6, 131.4, 130.8, 128.9, 128.3, 125.6, 124.6, 122.2,
122.1, 121.9, 121.6, 119.1, 110.8, 109.7, 96.5, 79.2, 35.0, 31.3 ppm;
HRMS (ESI) calcd for C26H22BrN2O2 [M + H] 473.0864, found
473.0857.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving 1H and 13C NMR spectra of all final compounds
and tables and a CIF file giving X-ray crystallographic data of
2a. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*B.K.: tel, +91 522 2612411-18; fax, +91 522 2623405; e-mail,
bijoy_kundu@yahoo.com, b_kundu@cdri.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.S. and R.K.A. are grateful to the CSIR, New Delhi, India, for
financial support. The authors would thank the SAIF, CDRI,
India, for providing analytical data.
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