Microwave-accelerated Conjugate Addition of 2-Arylindoles to Substituted β-Nitrostyrenes in the Presence of Ammonium Trifluoroacetate: An Efficient Approach for the Synthesis of a Novel Class of CB1 Cannabinoid Receptor Allosteric Modulators

Article abstract of DOI:10.1002/jhet.2861

2-Arylindoles, in general, exhibit reduced reactivity towards the conjugate addition to substituted nitrostyrenes, when compared with indoles. We report here an efficient, expeditious, and high-yielding conjugate addition of 2-arylindoles to substituted β

Full text of DOI:10.1002/jhet.2861

Month 2017
Microwave-accelerated Conjugate Addition of 2-Arylindoles to
Substituted β-Nitrostyrenes in the Presence of Ammonium
Trifluoroacetate: An Efficient Approach for the Synthesis of a Novel Class
of CB1 Cannabinoid Receptor Allosteric Modulators
*
Pushkar M. Kulkarni, Ameya Ranade, Sumanta Garai, and Ganesh A. Thakur
Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University,
Boston, MA 02115, USA
*
E-mail: g.thakur@northeastern.edu
Additional Supporting Information may be found in the online version of this article.
Received October 29, 2016
DOI 10.1002/jhet.2861
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
2-Arylindoles, in general, exhibit reduced reactivity towards the conjugate addition to substituted
nitrostyrenes, when compared with indoles. We report here an efficient, expeditious, and high-yielding con-
jugate addition of 2-arylindoles to substituted β-nitrostyrenes in the presence of ammonium trifluoroacetate
under microwave irradiation. This method is mild with high and reproducible yields and is selective for ad-
dition of β-nitrostyrenes when compared with other electrophiles. The results obtained from the optimized
microwave method consistently provided improved yields in a shorter time compared with those of the con-
ventional heating synthetic route.
J. Heterocyclic Chem., 00, 00 (2017).
The cannabinoid 1 receptor (CB1R), a tractable target
for treating several pathologies affecting humans, is the
most abundant class-A G-protein coupled receptor in the
brain and is also expressed in many peripheral tissues [1].
CB1R-mediated signaling plays a vital role in many
important physiological functions including learning,
memory, cognition, nociception, cardiovascular function,
greatly limited their translational potential [1,2]. Recent
discovery of CB1R allosteric modulators has renewed
interest in CB1R by offering
a potentially safer
therapeutic avenue [3]. Exemplars of small-molecule
positive (PAMs) and negative (NAMs) allosteric
modulators are shown in Figure 1 [3,4]. CB1 PAMs such
as ZCZ011[4] and GAT211 (1) [5] hold promise of
greater and safer clinical utility than typical CB1R
orthosteric agonists because of the lack of intrinsic
activity of allosteric modulators in the absence of an
orthosteric ligand.
reproduction,
and
neuronal
development,
and
dysregulated CB1R activity has been implicated in the
pathogenesis of disease states related to these and other
physiological processes [1,2]. Although, several CB1R
targeting clinical candidates have demonstrated their
therapeutic utility, the undesirable on-target side effects
associated with such orthosteric agonists/antagonists have
Such compounds can be synthesized in one step by
Michael addition of 2-phenylindoles with suitable
β-nitrostyrenes. Although such conjugate addition of
© 2017 Wiley Periodicals, Inc.

P. M. Kulkarni, A. Ranade, S. Garai, and G. A. Thakur
Vol 000
active compounds [10]. In this regard, we attempted MW
irradiation for the reaction (Scheme 1) but unfortunately
did not obtain much improvement. Babu et al. reported
the synthesis of 1 by using tetrabutylammonium bromide
(TBAB) under reflux conditions in acetonitrile in
quantitative yields [7]. However, in our hands, even after
repeated attempts, this reaction did not provide yields
greater than 62%, and longer reaction times were
required. MW irradiation of this reaction yielded only
minor improvement, prompting us to search for
alternative conditions. Conjugate addition of β-
nitrostyrenes with indole and 2-methylindole has been
reported in superheated water at 150°C without any
catalyst [11]. Our attempt to extend the scope of this
method to 2-phenylindole, however, gave 1 in moderate
yields (~55%) with longer reaction time, presumably
because of solubility issues and thermal degradation of
starting materials in water. Several Lewis acids reported
for Michael addition of indoles on β-nitrostyrenes, zinc
triflate is a well-studied and high-yielding catalyst [12].
However, this catalyst has not been explored for Michael
addition of 2-phenylindole as a substrate. We followed
the reported protocol by carrying out above reaction at
Figure 1. Some representative CB1 PAM/NAMs.
unsubstituted indoles to β-nitrostyrenes or other
electrophiles at C-3 position has been studied in depth,
and a variety of methods have been reported [6],
relatively few conditions are available for extending such
additions to 2-phenylindoles in which the C-3 position is
less reactive and sterically hindered because of phenyl
substitution at C-2 position [7]. The reactivity mismatch
between the highly electrophilic/reactive β-nitrostyrene
and the sterically hindered/less reactive and relatively
electron deficient 2-phenylindoles often leads to longer
reaction times with poor yields. The acid-catalyzed
conjugate addition of such 2-phenylindoles to β-
nitrostyrene requires careful control of acidity to prevent
side reactions such as dimerization or polymerization of
indoles [8]. Thus, identification of an efficient catalyst
and development of better reactions conditions are
required for such an addition reaction.
Previously, we reported the synthesis of 1 by using
tetraethylammonium bromide (TEAB) (Scheme 1).
However, this method was relatively inefficient in terms
of time (12 h) and yield (56%). The need for rapid lead
optimization and scale up in gram quantities for profiling
the therapeutic utility of such modulators demanded our
focus towards the development of a more facile, high-
yield method for synthesis of 1 and its analogs.
room
temperature
in
presence
mol%).
of
zinc
trifluoromethanesulfonate
(20
Although
satisfactory yield (65%) was obtained, longer reaction
time (>24 h) prompted us to investigate further this
reaction under microwave conditions.
We attempted the optimization of the MW version of
this reaction using an array of solvents at 100°C
(Table 1), and we found EtOH to be the best solvent
(entry 11, Table 1). We further performed this reaction in
EtOH at various temperatures (50, 75, 125, and 150°C),
but no significant enhancement in yield was obtained.
To improve the yields, we also explored metal-free
conditions, which not only add commercial value but also
make the reaction environment friendly [13]. We used
Table 1
Optimization of reaction conditions for Michael addition of 2-
phenylindole to β-nitrostyrene in presence of zinc
trifluoromethanesulfonate.a
Microwave (MW) irradiation accelerates the rates and
yields of many chemical reactions, including conjugate
addition reactions [9]. Our laboratory is actively involved
in utilizing microwave-accelerated methodologies for
facilitating expeditious library synthesis of biological
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
Toluene
CHCl3
Ether
THF
DME
15
15
15
15
12
15
15
15
15
15
10
60
53
63
59
64
45
40
38
51
50
68
Scheme 1. Synthesis of 1 using our previously reported protocol.[5]
DMF
DMA
DMSO
CH3CN
H2O
9
10
11
EtOH
aMW irradiation at 100°C; 20 mol% (CF3SO3)2Zn.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Microwave-accelerated Conjugate Addition of 2-Arylindoles to Substituted Β-
Nitrostyrenes in the Presence of Ammonium Trifluoroacetate
several quaternary ammonium salts, which are
biodegradable [14], provide milder reaction conditions,
and are water as well as ethanol soluble at ambient
temperatures (Table 2). The best yield (80%) was
obtained with CF3COONH4 as a catalyst using absolute
ethanol as a solvent (entry 4, Table 2). CF3COONH4 is a
least explored catalyst [15], and this is the first report of
its application to such Michael addition reaction.
As the presence of water was found to favor the reaction
yield, we attempted use of different percentages of aqueous
ethanol as a solvent with ammonium trifluroacetate at
100°C (Table 3). The best yields were obtained with 25%
and 50% aqueous ethanol. We also altered the amount of
CF3COONH4 (Table 3), and 20 mol% was found to be
optimum. Reactions performed in aqueous ethanol when
cooled to room temperature led to product precipitation
in acceptable purity, which was an advantage especially
for reactions carried out on gram scale.
We applied these optimized conditions (25% aq EtOH,
100°C, and CF3COONH4) for the conjugate addition of
different 2-arylindoles on various nitroalkenes (Table 4).
β-nitrostyrenes bearing electron withdrawing groups
(entries 5, 7, and 8) required lesser time as compared
with electron-donating substrates (entries. 2, 3, 4, and
Table 2
Effect of different ammonium salts on reaction time and yield.a
Entry
Catalyst
TBAB
CF3SO3NH4
CH3COONH4
CF3COONH4
HCOONH4
Time (min)
Yield (%)
1
2
3
4
5
15
10
20
10
10
42
69
71
80
64
aMW, 100°C, EtOH; 20 mol% catalyst.
Table 3
Effect of different percentage of aq. ethanol on reaction yield.a
11).
A significant increase in reaction time was
Entry
mol% of CF3COONH4
% of aq. EtOH
Yield (%)
necessitated when a strong electron withdrawing group
like nitro group was present at 5-position of indole (entry
14, Table 4), which led to that the decreased
nucleophilicity at C3 position of indole. Heterocyclic and
polycyclic β-nitrostyrenes also provided corresponding
Michael adduct in good yields (entry 9–11, Table 4). To
1
2
3
4
5
20
20
20
10
50
100
50
25
25
25
80
87
88
81
89
aMW, 100°C, EtOH, 10 min.
Table 4
Michael addition of 2-arylindole to different β-nitrostyrenes on 6.50 mmol scale.
Microwave
Conventional heating
Time (h)
Isolated yield (%)b
Compound
R1
R2
R3
Time (min)
Isolated yield (%)b
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
10
20
20
18
10
25
9
88
87
86
81
84
81
85
80
89
76
77
78
91
89
79
3.5
6
6
8
4
14
4
3
12
12
24
6
78
76
74
70
72
77
74
70
76
71
62
69
83
38
69
2-CH3OPh
4-CH3OPh
3-CH3OPh
2CF3-Ph
2,6-diClPh
4-CNPh
2-NO2Ph
2-furyl
2-Naphthyl
4-(piperdinyl)Ph
Ph
Ph
Ph
8
9
22
15
35
15
10
65
20
10
11
12
13
14
15
2-Naphthyl
CH3
Ph
6
20
6
5-NO2
H
Ph
4-Cl Ph
aon 6.50 mmol scale;
bIsolated yield
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. M. Kulkarni, A. Ranade, S. Garai, and G. A. Thakur
Vol 000
Scheme 2. Gram scale synthesis of CB1PAM ZCZ011.
expand further the scope of this method, we utilized
napthyl and substituted phenyl ring well as methyl group
at C-2 of the indole. We observed bulky and electron
withdrawing groups took longer reaction time (entry 12)
whereas an electron-donating group such as methyl
favored the Michael addition acceleration in higher yield
(entry 13) with shorter reaction time.
To demonstrate further the selectivity of our method
towards different reactive Michael acceptors, we
performed the aforementioned reaction in the presence of
methylacrylate, ethyl cinnamate, acrylonitrile, and
nitrostyrene. Interestingly, the only Michael adduct of β-
nitrostyrene 4 was obtained, indicating the selectivity of
the reaction. To test the relative efficiency of microwave
acceleration, we also attempted a conventional heating
protocol. Microwave acceleration clearly demonstrated
higher yields in all examples (Table 4).
We then elaborated the utility of this method by
successful application to the rapid synthesis of compound
ZCZ011, which was produced in 65% yield in 15 min
(Scheme 2) under microwave irradiation as compared with
the literature reported yield [4] and time (3 days). Using
this optimized method, we made a library of analogs of 4
as potential CB1 PAMs, synthesis and biochemical
characterization of which will be published elsewhere.
In conclusion, we have developed an efficient, mild,
microwave-accelerated, and high-yielding method for
addition of varieties of 2-arylindoles to β-nitrostyrenes.
This approach is valuable and useful for rapid synthesis
of biologically significant compounds.
CF3COONH4 (0.2 eq.; 1.3 mmol) were taken in of 25%
aq. EtOH (12 mL). The tube was sealed and introduced in
the microwave reactor. The tube was irradiated for an
appropriate time at 100°C under stirring. After completion
of reaction, the reaction mixture was diluted with cold
water followed by extraction with dichloromethane (three
times). Combined dichloromethane layer was evaporated
under vacuum, the residue was purified by flash
chromatography using Biotage SP1 instrument using
normal phase GRACE™ columns (40 μm particle size) to
acquire pure product.
3-(2-Nitro-1-phenylethyl)-2-phenyl-1H-indole (1; GAT211).
1H NMR (CDCl3, 500 MHz) δ 8.13 (br s, 1H, NH), 7.51
(d, J = 8.0 Hz, 1H), 7.46–7.39 (m, 5H), 7.36 (br d,
J = 8.0 Hz, 1H), 7.34–7.31 (m, 2H), 7.31–7.26 (m, 2H),
7.25–7.18 (m, 2H, esp. 7.20, ddd, J = 8.0 Hz, J = 7.0 Hz,
J = 1.0 Hz, 1H), 7.10 (ddd, J = 8.0 Hz, J = 7.0 Hz,
J = 1.0 Hz, 1H), 5.31 (dd as t, J = 8.0 Hz, 1H), 5.17 (dd,
J = 12.5, 7.5 Hz, 1H), 5.12 (dd, J = 12.5, 7.5 Hz, 1H);
MS (ESI) (m/z): 343 [M + H]+. HRMS m/z calculated for
C22H18N2O2 [M]+ 342.1368, found 342.1364.
3-(1-(2-Methoxyphenyl)-2-nitroethyl)-2-phenyl-1H-indole
(2). 1H NMR (CDCl3, 500 MHz) δ 8.14 (br s, 1H, NH),
7.64 (dd, J = 8.0 Hz, 0.5 Hz, 1H), 7.45–7.36 (m, 6H), 7.35
(dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.28–7.18 (m, 2H, esp. 7.21,
ddd, J = 8.5 Hz, 7.5 Hz, 1.5 Hz, 1H), 7.13 (ddd,
J = 8.5 Hz, 7.5 Hz, 1.5 Hz, 1H), 6.89 (dd, J = 8.0 Hz,
1.0 Hz, 1H), 6.84 (td, J = 7.5 Hz, 1.0 Hz, 1H), 5.60 (dd,
J = 9.0 Hz, 6.5 Hz, 1H), 5.17 (dd, J = 12.5 Hz, 6.5 Hz,
1H), 5.14 (dd, J = 12.5 Hz, 9.0 Hz, 1H), 3.77 (s, 3H).
MS (ESI) (m/z): 373 [M + H]+. HRMS m/z calculated
for C23H20N2O3 [M]+ 372.1474, found 342.1471.
3-(1-(4-Methoxyphenyl)-2-nitroethyl)-2-phenyl-1H-indole
(3). 1H NMR (CDCl3, 500 MHz) δ 8.13 (br s, 1H, NH),
GENERAL REMARKS
Microwave reactions were conducted using a Biotage®
Initiator Classic microwave synthesizer (Biotage,
Charlotte, NC). Reactions were performed in glass
vessels (capacity, 5 to 20 mL) equipped with magnetic
stirring bar and sealed with a septum. The target
temperature was set and maintained constant during the
reaction.
7.53 (br d, J = 8.0 Hz, 1H), 7.48–7.39 (m, 5H), 7.38 (br d,
J = 8.5 Hz, 1H), 7.27–7.23 (m, 2H), 7.21 (ddd, J = 8.0 Hz,
7.0 Hz, 1.0 Hz, 1H), 7.11 (ddd, J = 8.0 Hz, 7.0 Hz, 1.0
Hz, 1H), 6.82 (d, J = 9.0 Hz, 2H), 5.26 (dd as br t,
J = 8.0 Hz, 1H), 5.14 (dd, J = 12.0 Hz, 7.0 Hz, 1H),
5.09 (dd, J = 12.5 Hz, 8.5 Hz, 1H), 3.76 (s, 3H); MS
(ESI) (m/z): 373 [M + H]+. HRMS m/z calculated for
C23H20N2O3 [M]+ 372.1474, found 342.1480.
GENERAL PROCEDURE
3-(1-(3-Methoxyphenyl)-2-nitroethyl)-2-phenyl-1H-indole
(4). 1H NMR (CDCl3, 500 MHz) δ 8.16 (br s, 1H, NH),
In a 20-mL microwave vial 2-arylindole derivative
(1.0 eq.; 6.5 mmol), nitro alkene (1.3 eq.; 8.45 mmol), of
7.54 (dd, J = 8.0 Hz, 0.5 Hz, 1H), 7.47–7.39 (m, 5H), 7.36
(br d, J = 8.0 Hz, 1H), 7.25–7.17 (m, 2H), 7.11 (ddd,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Microwave-accelerated Conjugate Addition of 2-Arylindoles to Substituted Β-
Nitrostyrenes in the Presence of Ammonium Trifluoroacetate
J = 8.5 Hz, 7.5 Hz, 1.0 Hz, 1H), 6.93 (br d, J = 8.0 Hz, 1H),
6.88 (t, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.5 Hz, 2.5 Hz, 1H),
5.28 (dd as br t, J = 8.0 Hz, 1H), 5.16 (dd, J = 12.5 Hz,
7.0 Hz, 1H), 5.12 (dd, J = 12.5 Hz, 8.5 Hz, 1H), 3.71 (s,
3H). MS (ESI) (m/z): 373 [M + H]+. HRMS m/z calculated
for C23H20N2O3 [M]+ 372.1474, found 342.1477.
3-(1-(Naphthalen-2-yl)-2-nitroethyl)-2-phenyl-1H-indole
(10). 1H NMR (CDCl3, 500 MHz) δ 8.19 (br s, 1H, NH),
7.82–7.73 (m, 4H), 7.55 (dd, J = 8.0 Hz, 0.5 Hz, 1H),
7.50–7.40 (m, 9H), 7.23 (ddd, J = 8.0 Hz, 7.0 Hz,
1.0 Hz, 1H), 7.10 (ddd, J = 8.0 Hz, 7.0 Hz, 1.0 Hz, 1H),
5.48 (dd as t, J = 7.0 Hz, 1H), 5.32 (dd, J = 12.5 Hz,
7.0 Hz, 1H), 5.22 (dd, J = 12.5 Hz, 8.5 Hz, 1H); MS
(ESI) (m/z): 393 [M + H]+. HRMS m/z calculated for
3-(2-Nitro-1-(2-(trifluoromethyl)phenyl)ethyl)-2-phenyl-1H-
indole (5). 1H NMR (CDCl3, 500 MHz) δ 8.16 (br s, 1H,
C26H20N2O2 [M]+ 392.1525, found 392.1530.
NH), 7.83 (br d, J = 8.0 Hz, 1H), 7.76 (dd, J = 8.0 Hz,
1.0 Hz, 1H), 7.68 (dd, J = 7.5 Hz, 1.0 Hz, 1H), 7.44–7.39
(m, 5H), 7.38–7.33 (m, 3H), 7.27–7.23 (m, 1H), 7.21 (ddd,
J = 8.5 Hz, 7.5 Hz, 1.5 Hz, 1H), 5.76 (dd, J = 10.5 Hz,
5.5 Hz, 1H), 5.34 (dd, J = 13.5 Hz, 10.5 Hz, 1H), 4.89 (dd,
J = 13.5, 5.5 Hz, 1H); MS (ESI) (m/z): 410.12 [M + H]+.
MS (ESI) (m/z): 411 [M + H]+. HRMS m/z calculated for
C23H17F3N2O2 [M]+ 410.1242, found 410.1248.
3-(2-Nitro-1-(4-(piperidin-1-yl)phenyl)ethyl)-2-phenyl-1H-
indole (11). 1H NMR (DMSO-d6, 500 MHz) δ 11.41 (br
s, 1H, NH), 7.64 (d, J = 8.0 Hz, 1H), 7.59–7.41 (m, 5H),
7.37 (d, J = 8.0 Hz, 1H), 7.18–7.04 (m, 3H), 6.98 (t,
J = 7.5 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 5.52–5.27 (m,
2H), 5.09 (dd as t, J = 8.5, 1H), 3.17–2.95 (m, 4H),
1.67–1.36 (m, 6H); MS (ESI) (m/z): 426 [M + H]+.
HRMS m/z calculated for C27H27N3O2 [M + H]+
3-(1-(2,6-Dichlorophenyl)-2-nitroethyl)-2-phenyl-1H-indole
(6). 1H NMR (CDCl3, 500 MHz) δ 8.02 (br s, 1H, NH),
426.2103, found 426.2120.
2-(Naphthalen-2-yl)-3-(2-nitro-1-phenylethyl)-1H–indole
7.41–7.27 (m, 7H), 7.19 (d, J = 8.0 Hz, 2H), 7.17 (dd,
J = 8.0 Hz, 1.0 Hz, 1H), 7.08–7.03 (m, 2H), 6.20 (dd,
J = 8.5 Hz, 7.0 Hz, 1H), 5.27 (dd, J = 13.5 Hz, 6.5 Hz, 1H),
5.24 (dd, J = 13.0 Hz, 9.0 Hz, 1H); MS (ESI) (m/z): 411
[M + H]+. HRMS m/z calculated for C22H16Cl2N2O2 [M]+
410.0589, found 410.0585.
4-(2-Nitro-1-(2-phenyl-1H-indol-3-yl)ethyl)benzonitrile (7).
1H NMR (CDCl3, 500 MHz) δ 8.22 (br s, 1H, NH), 7.58 (d,
J = 8.5 Hz, 2H), 7.52–7.46 (m, 3H), 7.46–7.39 (m, 6H),
7.25 (ddd, J = 8.0 Hz, 7.0 Hz, 1.0 Hz, 1H), 7.14 (ddd,
J = 8.0 Hz, 7.0 Hz, 1.0 Hz, 1H), 5.36 (dd as br t,
J = 8.0 Hz, 1H), 5.23 (dd, J = 12.5 Hz, 8.0 Hz, 1H), 5.11
(dd, J = 12.5 Hz, 7.5 Hz, 1H); MS (ESI) (m/z): 368
[M + H]+. HRMS m/z calculated for C23H17N3O2 [M]+
367.1321, found 367.1323.
(12). 1H NMR (CDCl3, 500 MHz) δ 8.27 (br s, 1H, NH),
7.94 (d, J = 8.5 Hz, 1H), 7.91–7.87 (m, 2H), 7.86–7.81 (m,
1H), 7.61–7.51 (m, 4H), 7.44 (d, J = 8.0 Hz, 1H), 7.40–
7.35 (m, 2H), 7.35–7.29 (m, 2H), 7.28–7.22 (m, 2H),
7.15 (ddd, J = 8.0 Hz, 7.0 Hz, 1.0 Hz, 1H), 5.41 (dd as t,
J = 8.0 Hz, 1H), 5.21 (dd, J = 12.5 Hz, 7.5 Hz, 1H), 5.18
(dd, J = 12.5 Hz, 8.5 Hz, 1H); MS (ESI) (m/z): 393
[M + H]+. HRMS m/z calculated for C26H20N2O2 [M]+
392.1525, found 392.1530.
2-Methyl-3-(2-nitro-1-phenylethyl)-1H–indole (13).
1H
NMR (CDCl3, 500 MHz) δ 7.85 (br s, 1H, NH), 7.36
(dd, J = 8.0 Hz, 0.5 Hz, 1H), 7.34–7.25 (m, 5H), 7.24–
7.20 (m, 1H), 7.11 (ddd, J = 8.5 Hz, 7.5 Hz, 1.0 Hz, 1H),
7.02 (ddd, J = 8.0 Hz, 7.0 Hz, 1.0 Hz, 1H), 5.26–5.16
(m, 2H), 5.11 (dd, J = 10.5 Hz, 7.5 Hz, 1H), 2.40 (s,
3H); MS (ESI) (m/z): 281 [M + H]+. HRMS m/z
calculated for C17H16N2O2 [M]+ 280.1212, found
3-(2-Nitro-1-(2-nitrophenyl)ethyl)-2-phenyl-1H-indole (8). 1H
NMR (CDCl3, 500 MHz) δ 8.18 (br s, 1H, NH), 7.84 (dd,
J = 8.0 Hz, 1.5 Hz, 1H), 7.77 (dd, J = 8.0 Hz, 1.0 Hz, 1H),
7.64 (dd, J = 8.0 Hz, 0.5 Hz, 1H), 7.49 (td, J = 7.5 Hz,
1.5 Hz, 2H), 7.45–7.37 (m, 5H), 7.33–7.28 (m, 2H), 7.27–
7.22 (m, 1H), 7.18 (ddd, J = 8.0 Hz, 7.0 Hz, 1.0 Hz, 1H),
5.93 (dd, J = 9.0 Hz, 7.0 Hz, 1H), 5.30 (dd, J = 13.5 Hz,
9.0 Hz, 1H), 5.16 (dd, J = 13.5 Hz, 7.0 Hz, 1H); MS (ESI)
(m/z): 388 [M + H]+. HRMS m/z calculated for C22H17N3O4
[M + H]+ 388.1219, found 388.1223.
280.1220.
5-Nitro-3-(2-nitro-1-phenylethyl)-2-phenyl-1H-indole
(14). 1HNMR (DMSO-d6, 500MHz) δ12.27 (brs, 1H,
NH), 8.46(d, J=2.0Hz, 1H), 8.03(dd, J=9.0Hz, 2.0Hz,
1H), 7.63–7.49 (m, 6H), 7.37–7.30 (m, 4H), 7.27–7.22
(m, 1H), 5.64 (dd, J = 13.5 Hz, 7.5 Hz, 1H), 5.44 (dd,
J=13.0Hz, 9.0Hz, 1H), 5.27(ddast,J=8.0Hz,1H);MS
(ESI) (m/z): 388 [M + H]+. HRMS m/z calculated for
1H
C22H17N3O4 [M + H]+ 388.1219, found 388.1300.
2-(4-Chlorophenyl)-3-(2-nitro-1-phenylethyl)-1H–indole
(15). 1H NMR (DMSO-d6, 500 MHz): δ 11.50 (br s, 1H,
3-(1-(Furan-2-yl)-2-nitroethyl)-2-phenyl-1H-indole (9).
NMR (CDCl3, 500 MHz) δ 8.17 (br s, 1H, NH), 7.56 (dd,
J = 8.0 Hz, 0.5 Hz, 1H), 7.54–7.47 (m, 4H), 7.47–7.42 (m,
1H), 7.39 (br d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H),
7.22 (ddd, J = 8.5 Hz, 7.5 Hz, 1.5 Hz, 1H), 7.12 (ddd,
J = 8.0 Hz, 7.0 Hz, 1.0 Hz, 1H), 6.30 (dd, J = 3.5 Hz,
2.0 Hz, 1H), 6.14 (dt, J = 3.5 Hz, 1.0 Hz, 1H), 5.36 (td,
J = 7.5 Hz, 0.5 Hz, 1H), 5.24 (dd, J = 12.5 Hz, 7.5 Hz, 1H),
4.92 (dd, J = 12.5 Hz, 7.5 Hz, 1H); MS (ESI) (m/z): 333
[M + H]+. HRMS m/z calculated for C20H16N2O3 [M]+
332.1161, found 332.1168.
NH), 7.68–7.59 (m, 3H, esp. 7.63 (d, J = 8.5 Hz, 2H), 7.54
(d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.34–7.27 (m,
4H), 7.21 (tt, J = 7.0 Hz, 1.5 Hz, 1H), 7.12 (br t, J = 8.0 Hz,
1H), 6.98 (br t, J = 8.0 Hz, 1H), 5.56 (dd, J = 13.5 Hz,
7.5 Hz,1H), 5.44 (dd, J = 13.5 Hz, 9.5 Hz, 1H), 5.17 (dd
as br t, J = 8.0 Hz, 1H); MS (ESI) (m/z): 377 [M + H]+.
HRMS m/z calculated for C22H17ClN2O2 [M]+ 376.0979,
found 376.0959.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. M. Kulkarni, A. Ranade, S. Garai, and G. A. Thakur
Vol 000
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6-Methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-
indole (ZCZ011).. 1H NMR (CDCl3, 500 MHz) δ 8.04 (br
s,1H, NH), 7.52–7.45 (m, 4H), 7.45–7.38 (m, 2H),
7.21–7.18 (m, 2H), 6.96 (dd, J = 8.0 Hz, 1.5 Hz, 1H),
6.95–6.91 (m, 2H), 5.47 (t, J = 8.0 Hz, 1H), 5.19 (dd,
J = 12.5 Hz, 7.0 Hz, 1H), 5.07 (dd, J = 12.5 Hz, 8.0 Hz,
1H), 2.46 (s, 3H); MS (ESI) (m/z): 363 [M + H]+. HRMS
m/z calculated for C21H18N2O2S [M]+ 362.1089, found
362.1090.
Acknowledgments. The work was supported by grants from
National Eye Institute (EY024717 to GAT). P.M.K. is thankful
to “Hilda and Preston Davis Foundation” for their support. We
are thankful to Drs. David Janero and Abhijit Kulkarni for their
useful comments.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet