Synthesis of 4-Aryl Pyrrolo[1,2-α]quinoxalines via Iron-Catalyzed Oxidative Coupling from an Unactivated Methyl Arene

Article abstract of DOI:10.1021/acs.joc.1c00371

Herein, we describe the direct synthesis of pyrrolo[1,2-α]quinoxaline via oxidative coupling between methyl arene and 1-(2-aminophenyl) pyrroles. Oxidation of the benzylic carbon of the methyl arene was achieved by di-t-butyl peroxide in the presence of an iron catalyst, followed by conversion to an activated aldehyde in situ. Oxygen played a crucial role in the oxidation process to accelerate benzaldehyde formation. Subsequent Pictet-Spengler-type annulation completed the quinoxaline structure. The protocol tolerated various kinds of functional groups and provided 22 4-aryl pyrrolo[1,2-α]quinoxalines when various methyl arene derivatives were used. The developed method proceeded in air, and all catalysts, reagents, and solvents were easily accessible.

Full text of DOI:10.1021/acs.joc.1c00371

pubs.acs.org/joc
Article
Synthesis of 4‑Aryl Pyrrolo[1,2-α]quinoxalines via Iron-Catalyzed
Oxidative Coupling from an Unactivated Methyl Arene
Jiwon Ahn, Seok Beom Lee, Injae Song, Simin Chun, Dong-Chan Oh, and Suckchang Hong*
Cite This: J. Org. Chem. 2021, 86, 7390−7402
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Herein, we describe the direct synthesis of pyrrolo-
[1,2-α]quinoxaline via oxidative coupling between methyl arene
and 1-(2-aminophenyl) pyrroles. Oxidation of the benzylic carbon
of the methyl arene was achieved by di-t-butyl peroxide in the
presence of an iron catalyst, followed by conversion to an activated
aldehyde in situ. Oxygen played a crucial role in the oxidation
process to accelerate benzaldehyde formation. Subsequent Pictet−
Spengler-type annulation completed the quinoxaline structure. The
protocol tolerated various kinds of functional groups and provided
22 4-aryl pyrrolo[1,2-α]quinoxalines when various methyl arene derivatives were used. The developed method proceeded in air, and
all catalysts, reagents, and solvents were easily accessible.
are of great importance in the synthesis of biomarkers, dyes,
and materials.8
INTRODUCTION
■
Among nitrogen-containing heterocycles, pyrrolo[1,2-α]-
quinoxalines are important building blocks found in bio-
logically active compounds and are considered to be privileged
substructures for drug design.1 In particular, substitution at the
C-4 position of the pyrrolo[1,2-α]quinoxaline motif results in
derivatives that possess a variety of biological activities (Figure
1), such as anticancer,2 antimalarial,3 and antiproliferative
activities.4 They can also act as human protein kinase CK2
inhibitors,5 glucagon receptor antagonists,6 and 5-HT3
receptor antagonists.7 In addition to exhibiting biological
activity, some derivatives of 4-aryl pyrrolo[1,2-α]quinoxalines
have excellent fluorescence and photophysical properties that
Owing to these characteristic features, various methods have
been developed for the synthesis of 4-aryl pyrrolo[1,2-
α]quinoxalines (3) in recent decades (Scheme 1). The most
common synthetic approach is oxidative cyclization of 1-(2-
aminophenyl)pyrrole (1) with aromatic aldehyde.9 These
modified Pictet−Spengler reactions can be achieved under
aerobic heating,9a catalyzed by Lewis or Brønsted acids,9b−e or
mediated by TEMPO oxoammonium salts.9f Even though
aldehyde substrates have been applied well for the synthesis of
pyrrolo[1,2-α]quinoxalines, they have some shortcomings
because of their lability. Several research groups have reported
the synthesis of 4-aryl pyrrolo[1,2-α]quinoxalines from benzyl
amine instead of aldehyde.10 In addition, the condensation of
1-(2-aminophenyl)-pyrrole with ketone,11 carboxylic acid,12
1,3-diketone,13 amino acid,14 or ether15 was also reported for
the synthesis of 4-aryl pyrrolo[1,2-α]quinoxalines. Although
the various synthetic methods mentioned above have provided
4-aryl pyrrolo[1,2-α]quinoxalines, they also involve an electro-
philic carbon synthon with specific functional groups such as
carbonyl, hydroxyl, and amine groups, which limits the
substrate scope. To the best of our knowledge, no direct
synthetic strategy has been explored for 4-aryl pyrrolo[1,2-
α]quinoxalines by employing unactivated methyl arene. Over
Received: February 15, 2021
Published: May 24, 2021
Figure 1. Selected examples of biologically active pyrrolo[1,2-
α]quinoxalines.
https://doi.org/10.1021/acs.joc.1c00371
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 7390−7402
7390

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Scheme 1. Synthesis of 4-Aryl Pyrrolo[1,2-α]quinoxalines
Table 1. Optimization of the Reaction Conditions
(3) from 1-(2-Aminophenyl)-pyrrole (1)
b
oxidant
(equiv)
time
(h)
yield
entry
catalyst
T (°C)
(%)
1
2
3
4
5
6
7
8
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl2·4H2O
Fe(NO3)3·9H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
no catalyst
DTBP (3)
110
110
110
110
110
110
110
110
120
120
120
16
41
46
19
22
18
18
20
40
44
40
61
49
10
57
53
62
68
57
77
47
29
c
TBHP (3)
d
H2O2 (3)
DTBP (3)
DTBP (3)
DTBP (2)
DTBP (1)
DTBP (0.5)
DTBP (1)
DTBP (1)
DTBP (2)
9
10
11
no catalyst
a
Reaction conditions: 1a (0.3 mmol), 2a (18 mmol), the catalyst (15
b
mol %), and the oxidant in DMSO (0.5 mL) in air. Isolated yield.
c
d
70% aqueous solution. 35% aqueous solution.
achieved when the reaction temperature was increased to 120
°C and the reaction time was increased to 40 h (entry 9). A
control experiment was also performed, and a significant
decrease in yield was observed in the absence of the catalyst
(entries 10 and 11). Similar to the iron catalytic system
(entries 6−7), excess DTBP showed a lower yield of 3aa with a
messy mixture in TLC. We predicted that this excessive use of
DTBP induces various side reactions via a radical pathway.
Based on the above results, we chose 1-(2-aminophenyl)-
pyrrole 1 (0.3 mmol), methyl arene 2 (18 mmol), FeCl3·6H2O
(15 mol %), and DTBP (0.3 mmol) in dimethyl sulfoxide
(DMSO, 0.5 mL) at 120 °C for 40 h in air as the optimal
reaction conditions.
We applied the optimized conditions for the annulation of
1a with a wide range of methyl arenes 2 to explore the reaction
scope (Table 2). A diverse array of methyl arenes bearing
electron-donating and electron-withdrawing groups could react
with 1a, and the corresponding quinoxaline products 3 were
obtained. Generally, methyl arenes with electron-donating
groups, such as methyl groups, showed better results than
those with electron-withdrawing groups (3ab−3ae vs 3ag−
3al). This tendency might occur because the electron-donating
group could stabilize the benzyl cationic charge that is
generated during benzylic carbon activation. However, methyl
arene substituted with a methoxy group gave the desired
product 3af in low yield with many side products. Strong
electron-withdrawing groups, such as nitrile-substituted methyl
arene, could also be applied in the reaction system to afford
quinoxaline product 3al in moderate yield. The steric effect
also influenced the formation of the desired product. The para-
substituted methyl arene showed higher yields than ortho- and
meta-substituted analogues (3ab−3ae). Additionally, naph-
thalene and heteroaromatic groups, such as thiophene and
pyridine, could be substituted at the 4-position of pyrrolo[1,2-
α]quinoxalines (3am−3ao).
the years, various types of base-metal-catalyzed oxidative
annulations using peroxide have been applied to the
construction of heterocycles.16 Recently, our group also
reported the direct synthesis of quinazolinone and quinolone
via iron-catalyzed oxidative cyclization from unactivated
methyl arene.17 In this strategy, direct functionalization of
C−H bonds forms C−C or C−heteroatom bonds and offers
substantial benefits owing to the remarkable potential for atom
economy and environmental sustainability. In particular, iron
has attracted considerable attention because of its low cost,
abundance, and low toxicity. As part of our program on
developing a new synthetic method for N-heterocycles, we
investigated iron-catalyzed oxidative reactions for the synthesis
of pyrrolo[1,2-α]quinoxalines. In this report, we disclose a new
one-pot annulation between 1-(2-aminophenyl)pyrrole and
methyl arene through in situ oxidative activation of a benzylic
sp3 C−H bond (Scheme 1 down).
RESULTS AND DISCUSSION
■
We began our studies by optimizing various parameters of the
reaction of 1-(2-aminophenyl)-pyrrole (1a) with toluene (2a).
Based on our previous study on the synthesis of quinazolino-
ne,17a FeCl3·6H2O and di-t-butyl peroxide (DTBP) were
employed as a preliminary catalyst and oxidant, respectively, in
an air environment. As shown in Table 1, the desired
quinoxaline product 3aa was obtained in 61% yield when 15
mol % FeCl3·6H2O and 3 equiv of DTBP were used in the
reaction (entry 1). Based on this promising result, various
types of catalysts and oxidants were employed in the reaction
to improve the formation of 3aa (entries 2−5). However, we
could not find more efficient ones. Interestingly, the yield of
3aa could be increased depending on the amount of DTBP. As
we decreased the amount of DTBP to 1 equiv relative to 1a,
clear conversion was observed by thin-layer chromatography
(TLC), and 3aa was obtained in higher yield (entries 6−7).
However, at least 1 equiv of DTBP was necessary to achieve
satisfactory conversion (entry 8). The highest yield of 3aa was
Next, we employed various types of 2-aminophenyl-pyrroles
for further extension of the reaction scope (Table 3). 6-
Methyl-substituted 1b afforded the corresponding products
3ba in good yield. Regardless of the electron density, the
position of the substituent played a crucial role in the reaction.
7391
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
3ia). Additionally, 1-(2-amino-6-pyridyl)-pyrrole could also be
applied in the reaction to yield annulated product 3ja. We
hypothesized that the 3-position of the pyrrole can participate
in the annulation instead of the 2-position of pyrrole. However,
because of the low nucleophilicity of the 3-position of the
pyrrole, 1-methyl-2-(2-aminophenyl)-pyrrole gave pyrrolo[3,2-
c]quinoline product 3ka in low yield. In addition to pyrrole
substrates, 1-(2-aminophenyl)-indole substrates were also
explored in the reaction system. Depending on the substituents
on the indole moiety, the corresponding 4-phenyl indolo[1,2-
α]quinoxaline products were synthesized in a wide range of
yields. The desired products were obtained in moderate to
good yields from simple and 3-methyl/5-methoxy indole
substrates (3la, 3ma, 3oa), whereas very poor yields were
observed from 5-bromo indole and pyrrolo[2,3-b]pyridine
substrates (3na, 3pa). Based on these results, we expected that
the electron density of indole is significantly influenced in the
annulation step, which would affect the whole reaction
procedure.
Table 2. Scope of Methyl Arenes 2
After exploration of the reaction scope, the fluorescence
characteristics of 3aa, 3af, 3ah, 3ak, 3al, 3ao, 3ga, 3ia, and 3la
were evaluated systematically (Figures 2 and 3). The maximum
a
b
All presented yields are isolated yields. 1 mmol scale reaction of 1a,
DTBP (1.2 mmol) was used.
a
Table 3. Scope of 2-Aminoaryl-pyrroles and -Indoles (1)
Figure 2. Normalized fluorescence emission spectra of pyrrolo[1,2-
α]quinoxalines in DMSO.
a
All presented yields are isolated yields.
The 4-substituted 1-(2-aminophenyl)-pyrroles were more
reactive than the 5-substituted analogues (3ca−3ea vs 3fa−
Figure 3. Fluorescence emission spectra of pyrrolo[1,2-α]-
quinoxalines in DMSO.
7392
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
wavelengths and intensities of the emission spectra varied
depending on the substituents. As shown in Figure 2, these
quinoxaline products showed fluorescence within the range of
445−515 nm. A red shift was induced by electron-withdrawing
substituents. For example, nitrile- or pyridine-substituted
pyrrolo[1,2-α]quinoxalines showed a large red shift to give
maximum wavelengths over 500 nm (3al, 3ao). In the case of
indolo[1,2-α]quinoxaline, a red shift in the emission was also
observed over 500 nm (3la). Interestingly, most of the
quinoxaline derivatives exhibited stronger fluorescence emis-
sion than simple pyrrolo[1,2-α]quinoxaline 3aa (Figure 3).
Substitution at the 7-position (para-position to pyrrole)
pyrrolo[1,2-α]quinoxalines appeared to enhance the fluores-
cence intensity, regardless of the electron density (3ga, 3ia). In
the case of the substituent of the 4-phenyl group, electron-
withdrawing groups increased the fluorescence emission (3al,
3ao, 3ak, 3ah), whereas electron-donating groups decreased
the fluorescence emission (3af). Moreover, indolo[1,2-α]-
quinoxaline 3la showed more than 10 times higher emission
than pyrrolo[1,2-α]quinoxaline 3aa. All these findings suggest
potential applications of the products in the design of
functional materials or biosensors.
as a coupling partner rather than being an oxidizing agent
under similar reaction conditions. Since a carbon radical
adjacent to the sulfur was generated by DTBP, the radical
directly participated in the intermolecular annulation. Based on
this hypothesis, we illustrated a correlation graph showing the
aldehyde formation depending on the oxygen and the iron
catalyst as shown in Figure 4. Both the iron catalyst and the
oxygen affected the oxidation process. Comparing the two
variables, the role of oxygen was more important.
To show the additional synthetic applications, we also tried
to convert pyrrolo[1,2-α]quinoxaline products 3al and 3ll to
antiproliferative compounds4 (Scheme 2). Large-scale (1
Scheme 2. Synthetic Application for Antiproliferative
Compounds
Figure 4. Formation of 2-naphthaldehyde depending on reaction
parameters.
Further control experiments were also performed to
understand the mechanism (Scheme 3). The radical scavenger
TEMPO disrupted the reaction, and benzylated TEMPO was
obtained (eq 1). This result confirmed that a benzyl radical
intermediate was generated during oxidation. We presumed
that t-butoxy benzyl ether 2a−OtBu might be another possible
intermediate that can be generated from benzyl radicals.
However, it gave a lower yield of 3aa (eq 2, left). Thus, we can
assume that the oxidation pathway via 2a−OtBu is not
preferred under the reaction conditions. In addition, since the
reaction did not proceed at all without DTBP, the direct N-
alkylation of 2a−OtBu could be excluded. When preoxidized
benzaldehyde reacted with 1a without DTBP, 3aa was
obtained in a yield similar to that obtained under standard
conditions (eq 2, right). Therefore, the final oxidation and
aromatization process readily occurred under aerobic con-
ditions to afford a pyrrolo[1,2-α]quinoxaline structure. To
explore synthetic possibility for dihydropyrrolo[1,2-α]-
quinoxaline, we also applied ethylbenzene and diphenyl-
methane under standard conditions instead of toluene
substrates (eq 3). As expected, the oxidation process occurred,
and a significant amount of ketones was obtained. However, no
dihydropyrrolo[1,2-α]quinoxaline products were observed in
the reaction. This result indicates that the ketone intermediate
could not participate in the subsequent annulation process.
Next, the reaction was performed in the presence of argon gas.
Significant formation of 3aa was observed, and benzylated 1a−
mmol) reaction was carried out to prepare quinoxaline 3al
and 3ll. DIBAL-H reduction of the nitrile group afforded the
corresponding aldehydes 4al and 4ll, respectively. After
reductive amination with 6, antiproliferative compound
JG454 (5al) and its indole analogue 5ll were obtained.
Compared with the previous synthesis, the total yield is
relatively low. However, the strength of this synthetic method
is a shortcut to the integrated route for the JG454 family.
To investigate the mechanism of the reaction, we focused on
the aldehyde intermediate because the corresponding
aldehydes were observed in most reactions. The representative
substrate, toluene, was alternated to 2-methylnaphthalene 2m
due to the volatility and instability of benzaldehyde. Initially,
we assumed oxygen as an oxidizing agent along with DTBP
and not DMSO. According to our previous synthesis of
quinazolinone,17a DMSO reacted with nucleophilic substrates
7393
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 3. Investigation of the Reaction Mechanism
Scheme 4. Proposed Mechanism
Bn was also obtained as a side product (eq 4). In the absence
of oxygen, we could not observe clear benzaldehyde spots by
TLC during the reaction. Thus, direct N-alkylation from
benzyl radicals, followed by annulation, could not be ruled out
as a background reaction. Additionally, it was supposed that
anilic amine reacts faster in the annulation than the pyrrole
group. Our hypothesis was confirmed by the formation of 3aa
from 1a−Bn under the standard conditions.
Based on the above control experiments and previous
studies,17 we proposed a rational mechanism (Scheme 4).
There are two possible pathways to generate benzaldehyde
intermediates from toluene 2a (path a and path b). First, a t-
butoxy radical is generated from DTBP with the assistance of
an iron catalyst. The t-butoxy radical abstracts H•, which is
located at the benzyl position of toluene 2a, to form a benzyl
radical. As mentioned above, DMSO, used as a solvent, can
also generate a methyl radical by DTBP. We expected that this
radical species helps to form the benzyl radical through radical
propagation. In pathway a, t-butoxy benzyl ether 2a−OtBu can
be formed as an intermediate by the coupling of benzyl radicals
with the iron t-butoxy salt. One more oxidation process occurs
by DTBP and the iron catalyst to produce benzaldehyde A.
However, 2a−OtBu is considered an insufficient substrate in
the oxidation process (refer to eq 2 in Scheme 2), and 2 equiv
of DTBP is required theoretically in pathway a, whereas only 1
equiv of DTBP was used in the developed reaction; another
alternative oxidation pathway b is suggested. In the presence of
oxygen gas, benzyl hydrogen peroxide was generated via the
coupling of benzyl radicals with O2, followed by the abstraction
of H• from the solvent (2a or DMSO). Then, benzyl hydrogen
peroxide liberates water and is converted to benzaldehyde A
under the reaction conditions. Based on the results shown in
Figure 4, oxygen played a crucial role in oxidation; thus,
pathway b is more preferred than pathway a under an air
atmosphere. After the formation of benzaldehyde A, it reacted
with 1-(2-aminophenyl)pyrrole 1a, and imine B was generated.
Subsequently, annulation of imine B through intramolecular
electrophilic aromatic substitution of the pyrrole moiety,
followed by aerobic oxidation, gave final product 3aa.
However, we could not exclude direct amination of 1a with
a benzyl radical intermediate.
CONCLUSIONS
■
In summary, we have developed an iron-catalyzed oxidative
annulation of 1-(2-aminophenyl)pyrrole with an unreactive
methyl arene for the synthesis of 4-aryl pyrrolo[1,2-α]-
quinoxalines. Benzaldehyde was suggested as a key inter-
mediate generated by oxidation of methyl arene in the
presence of DTBP and an iron catalyst, and we found that
oxygen plays a crucial role in this oxidative process. The
benzaldehyde intermediate underwent Pictet−Spengler-type
annulation, condensation with 1-(2-aminophenyl)pyrrole,
followed by electrophilic aromatic substitution, to afford the
annulated pyrrolo[1,2-α]quinoxaline product. Based on
control experiments and previous studies, we suggested a
possible reaction mechanism, especially describing the
oxidation process, including the formation of benzaldehyde
7394
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
7.19 (m, 2H), 6.84 (t, J = 2.2 Hz, 2H), 6.77−6.82 (m, 2H), 6.34 (t, J
= 2.2 Hz, 2H), 3.71 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ
141.6, 128.7, 128.0, 127.3, 121.9, 119.0, 116.6, 109.6; HRMS (FAB)
m/z: [M]+ calcd for C10H10N2, 158.0844; found, 158.0845.
3-Methyl-2-(1H-pyrrol-1-yl)aniline (1b). Following method A, 1-
(2-methyl-6-nitrophenyl)-1H-pyrrole (4.95 mmol, 1 g) was used as
the starting material. After recrystallization, 1b was obtained as a
white solid (791 mg, 93% yield); mp 37−39 °C; 1H NMR (400 MHz,
CDCl3): δ 7.08 (t, J = 7.8 Hz, 1H), 6.64−6.67 (m, 4H), 6.36 (d, J =
1.8 Hz, 2H), 3.51 (s, 2H), 2.00 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 144.0, 137.1, 128.9, 126.9, 121.6, 119.9, 113.3, 109.4, 17.3;
HRMS (FAB) m/z: [M + H]+ calcd for C11H13N2, 173.1079; found,
173.1074.
as a key intermediate. Importantly, this is the first report on the
synthesis of 4-aryl pyrrolo[1,2-α]quinoxalines via intermolec-
ular oxidative coupling from methyl arene. The reaction was
performed under an air atmosphere, and all reagents and
catalysts are inexpensive and readily available. The developed
method also tolerates various functional groups, allowing
further functionalization. Further expansion of the oxidative
annulation from methyl arene to approach other aryl-
substituted N-heterocycles is under investigation by our group.
EXPERIMENTAL SECTION
■
General Information. Experimental Details. All commercially
available reagents and solvents (purchased from Sigma-Aldrich, TCI,
Alfa Aesar, Acros, Combi-Blocks) were used without further
purification unless otherwise noted. All reactions were carried out
in an oven-dried round-bottom flask or borosilicate glass tubes
purchased from Fisher Scientific (Fisherbrand disposable borosilicate
glass tubes with threaded end). Reactions were monitored by TLC on
a silica gel 60 F254 plate (Merck, Darmstadt, Germany) using UV
illumination at 254 and 365 nm (VL-4.LC, Vilber Lourmat,
Eberhardzell, Germany). Column chromatography was performed
on silica gel (230−400 mesh; Zeochem, Lake Zurich, Switzerland)
using a mixture of hexane and EtOAc as eluents.
4-Methyl-2-(1H-pyrrol-1-yl)aniline (1c). Following method A, 1-
(5-methyl-2-nitrophenyl)-1H-pyrrole (8.41 mmol, 1.7 g) was used as
the starting material. After recrystallization, 1c was obtained as a white
1
solid (525 mg, 36% yield); mp 59−60 °C; H NMR (400 MHz,
CDCl3): δ 6.98 (d, J = 6.4 Hz, 2H), 6.83 (t, J = 2.1 Hz, 2H), 6.73 (dd,
J = 6.7, 2.1 Hz, 1H), 6.33 (t, J = 2.1 Hz, 2H), 3.59 (s, 2H), 2.27 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 139.5, 129.2, 128.1,
127.7, 127.6, 121.8, 116.4, 109.4, 20.4; HRMS (FAB) m/z: [M]+
calcd for C11H12N2, 172.1000; found, 172.0997.
4-Methoxy-2-(1H-pyrrol-1-yl)aniline (1d). Following method B, 1-
(5-methoxy-2-nitrophenyl)-1H-pyrrole (4.583 mmol, 1 g) was used as
the starting material. After column chromatography (hexane/EtOAc =
10:1), 1d was obtained as a white solid (385 mg, 45% yield); mp 91−
Spectral Data. Melting points were measured on a Buchi B-540
̈
1
melting point apparatus and were not corrected. Nuclear magnetic
resonance (1H NMR and 13C NMR) spectra were recorded on a
JEOL JNM-ECZ400s [400 MHz (1H), 100 MHz (13C), 376 MHz
(19F)] spectrometer. The chemical shifts are given in parts per million
on the delta (δ) scale. The solvent peak was used as a reference value;
93 °C; H NMR (400 MHz, CDCl3): δ 6.86 (t, J = 2.3 Hz, 2H),
6.75−6.81 (m, 3H), 6.35 (q, J = 2.0 Hz, 2H), 3.75 (s, 3H), 3.46 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3): δ 152.6, 135.5, 128.2,
121.8, 117.4, 114.9, 112.5, 109.6, 56.0; HRMS (FAB) m/z: [M]+
calcd for C11H12N2O, 188.0950; found, 188.0949.
1
for H NMR: CDCl3 = 7.26 ppm, DMSO-d6 = 2.50 ppm; for 13C
4-Chloro-2-(1H-pyrrol-1-yl)aniline (1e). Following method B, 1-
(5-chloro-2-nitrophenyl)-1H-pyrrole (2.695 mmol, 600 mg) was used
as the starting material. After column chromatography (hexane/
EtOAc = 10:1), 1e was obtained as a white solid (306 mg, 59% yield);
mp 92−95 °C; 1H NMR (400 MHz, CDCl3): δ 7.11−7.15 (m, 2H),
6.82 (t, J = 2.1 Hz, 2H), 6.73 (d, J = 8.7 Hz, 1H), 6.34 (t, J = 2.3 Hz,
2H), 3.73 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 140.8,
128.5, 128.2, 127.1, 122.7, 121.6, 117.0, 110.0; HRMS (FAB) m/z:
[M]+ calcd for C10H9ClN2, 192.0454; found, 192.0454.
5-Methyl-2-(1H-pyrrol-1-yl)aniline (1f). Following method A, 1-
(4-methyl-2-nitrophenyl)-1H-pyrrole (7.42 mmol, 1.5 g) was used as
the starting material. After recrystallization, 1f was obtained as a beige
solid (1.08 g, 85% yield); mp 88−90 °C; 1H NMR (400 MHz,
CDCl3): δ 7.04 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 2.1 Hz, 2H), 6.59−
6.63 (m, 2H), 6.33 (t, J = 2.1 Hz, 2H), 3.64 (s, 2H), 2.31 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 141.9, 138.8, 127.1, 125.3,
122.0, 119.3, 116.7, 109.3, 21.3; HRMS (FAB) m/z: [M + H]+ calcd
for C11H13N2, 173.1079; found, 173.1081.
NMR: CDCl3 = 77.16 ppm, DMSO-d6 = 39.52 ppm. Coupling
constants (J) are expressed in hertz. All high-resolution mass spectra
(HRMS) were recorded using the fast atom bombardment (FAB)
ionization method on a JMS-700 MStation mass spectrometer (JEOL,
Tokyo, Japan).
Optical Characterization. The UV−vis absorption spectra of the
synthesized compounds were recorded at ambient temperature using
a Lambda 25 UV−vis spectrometer (PerkinElmer, Waltham, MA,
United States). Fluorescence emission spectra were recorded with an
FP-6500 spectrofluorometer (JASCO, Tokyo, Japan) with slit widths
of 3 nm for excitation and also 3 nm for emission. UV−vis absorption
and fluorescence emission spectra were both recorded at a
concentration of 10 μM in the DMSO solvent.
Preparation of 2-Aminoaryl-pyrroles Substrate. Starting
compounds 1a−1f and 1h−1l were synthesized from the correspond-
ing 2-nitroaryl-pyrroles through the similar procedures with the
literature. 1g is commercially available.
Method A:18 Dissolve 1-(2-nitrophenyl)-1H-pyrroles in ethanol
(0.3 M), and add Pd/C (10 mol % Pd) to the mixture. Purge the
reaction with H2 (1 atm) for 10 min, and hold under a H2 atmosphere
at room temperature overnight. After complete consumption of 1-(2-
nitrophenyl)-1H-pyrrole, filtrate the reaction mixture over Celite, and
then remove the solvent under reduced pressure thoroughly.
Recrystallization of the mixture was performed using diethylether.
Method B:9a 1-(2-Nitrophenyl)-1H-pyrroles were dissolved in
ethanol (0.08 M), and powdered zinc (10.2 equiv) was added to
the vigorously stirred solution. 90% formic acid (11.8 equiv) was
slowly added to the reaction mixture at room temperature while
stirring vigorously. After refluxing at 80 °C for 2 h, cool it to room
temperature and filtrate the reaction mixture over Celite. After
removing the solvent under reduced pressure thoroughly, the reaction
mixture was poured into water (100 mL) and extracted with EtOAc
three times. The residue was purified by flash column chromatog-
raphy using hexane/EtOAc as the eluent.
5-Chloro-2-(1H-pyrrol-1-yl)aniline (1h). Following method B, 1-
(4-chloro-2-nitrophenyl)-1H-pyrrole (2.695 mmol, 600 mg) was used
as the starting material. After column chromatography (hexane/
EtOAc = 10:1), 1h was obtained as a white solid (447 mg, 86% yield);
1
mp 85−87 °C; H NMR (400 MHz, CDCl3): δ 7.06 (d, J = 8.3 Hz,
1H), 6.79 (q, J = 1.4 Hz, 3H), 6.74 (dd, J = 8.3, 2.3 Hz, 1H), 6.34 (t, J
= 2.1 Hz, 2H), 3.79 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ
143.3, 134.1, 128.3, 126.1, 121.8, 118.4, 115.7, 109.9; HRMS (FAB)
m/z: [M]+ calcd for C10H9ClN2, 192.0454; found, 192.0453.
2-(1H-Pyrrol-1-yl)-5-(trifluoromethyl)aniline (1i). Following meth-
od A, 1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-pyrrole (5.62 mmol,
1.44 g) was used as the starting material. After recrystallization, 1i was
1
obtained as a white solid (772 mg, 61% yield); mp 91−93 °C; H
NMR (400 MHz, CDCl3): δ 7.23 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.4
Hz, 2H), 6.85 (t, J = 2.1 Hz, 2H), 6.38 (t, J = 2.1 Hz, 2H), 3.94 (s,
2
2H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.3, 131.2 (q, JC−F
=
2
2
32.6 Hz), 130.9 (q, JC−F = 32.6 Hz), 130.5 (q, JC−F = 32.6 Hz),
130.2 (q, 2JC−F = 32.6 Hz), 129.9, 128.1 (q, 1JC−F = 271.0 Hz), 127.5,
125.4 (q, 1JC−F = 271.0 Hz), 122.7 (q, 1JC−F = 271.0 Hz), 121.5, 119.9
(q, 1JC−F = 271.0 Hz), 115.2 (q, 3JC−F = 3.8 Hz), 115.1 (q, 3JC−F = 3.8
2-(1H-Pyrrol-1-yl)aniline (1a). Following method A, 1-(2-nitro-
phenyl)-1H-pyrrole (12.8 mmol, 2.41 g) was used as the starting
material. After recrystallization, 1a was obtained as a white solid (1.58
g, 78% yield); mp 93−94 °C; 1H NMR (400 MHz, CDCl3): δ 7.14−
3
3
Hz), 115.1 (q, JC−F = 3.8 Hz), 115.0 (q, JC−F = 3.8 Hz), 112.9 (q,
7395
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4JC−F = 3.8 Hz), 112.9 (q, 4JC−F = 3.8 Hz), 112.8 (q, 4JC−F = 3.8 Hz),
(dd, J = 4.6, 1.5 Hz, 1H), 8.06 (dd, J = 8.0, 1.8 Hz, 1H), 7.55 (d, J =
3.7 Hz, 1H), 7.14−7.20 (m, 2H), 7.09 (dd, J = 7.7, 1.5 Hz, 1H), 6.92
(dd, J = 8.0, 1.2 Hz, 1H), 6.68−6.72 (m, 2H), 4.79 (s, 2H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ 147.5, 144.5, 142.9, 130.2, 129.0,
128.7, 128.5, 123.6, 120.4, 116.5, 116.3, 116.2, 101.2; HRMS (FAB)
m/z: [M + H]+ calcd for C13H12N3, 210.1031; found, 210.1033.
Preparation of 2-(5-Bromo-1H-indol-1-yl)aniline (1n).20 To a
stirred solution of 5-bromoindole (1.18 g, 6 mmol) in DMSO (6 mL),
NaOH (6.0 mmol) and 1-fluoro-2-nitrobenzene (6 mmol) were
added slowly. The reaction mixture was stirred vigorously for 2 h at
room temperature. After completion of the reaction, the reaction
mixture was extracted with EtOAc and saturated brine. Then, the
organic layer was combined and dried with anhydrous Na2SO4. The
solvent was evaporated to obtain the desired product which was
directly used for the next step without further purification. The
residue was added to iron powder (24 mmol) and NH4Cl (2.4 mmol)
in water (72 mL) and refluxed for overnight. After cooling, the
reaction mixture was poured into water (100 mL) and extracted with
EtOAc three times (3 × 60 mL). The combined organic layers were
dried with anhydrous Na2SO4, and the solvent was removed in vacuo
to afford the residue. The residue was purified by flash column
chromatography on silica gel using hexane/EtOAc (30:1 to 20:1) as
the eluent to provide the desired product 1n as a pale-yellow oil
(1.162 g, 67% yield); 1H NMR (400 MHz, DMSO-d6): δ 7.84 (d, J =
1.8 Hz, 1H), 7.45 (d, J = 3.1 Hz, 1H), 7.24 (dd, J = 8.6, 1.8 Hz, 1H),
7.17−7.21 (m, 1H), 7.06 (dd, J = 7.9, 1.2 Hz, 1H), 6.96 (d, J = 8.6
Hz, 1H), 6.91 (dd, J = 8.6, 1.2 Hz, 1H), 6.65−6.70 (m, 2H), 4.79 (s,
2H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 144.5, 134.8, 130.9,
130.1, 129.1, 128.1, 124.2, 122.8, 116.4, 116.0, 112.6, 112.2, 102.3;
HRMS (FAB) m/z: [M]+ calcd for C14H11BrN2, 286.0106; found,
286.0105.
General Procedure for the Synthesis of Quinoxaline
Products. To a mixture of anilines 1 (0.3 mmol) and FeCl3·6H2O
(0.045 mmol, 12.16 mg) in 0.5 mL of DMSO, methyl arenes 2 (18
mmol) were added in borosilicate glass tubes. While stirring the
mixture, DTBP (0.3 mmol, 55 μL) was added in a dropwise manner.
The reaction tube was capped with a rubber septum, and two needles
(18/24 gauge) were injected on top of the septum to induce air
circulation. The reaction mixture was stirred at 120 °C and monitored
by TLC. After stirring for 40 h, the reaction mixture was cooled to
room temperature and diluted with diethyl ether (5 mL). The mixture
was extracted with diethyl ether (5 mL × 3), and the organic phase
was washed with water (1 mL). The combined organic phase was
dried over anhydrous MgSO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel using
hexane/EtOAc as the eluent.
4-Phenylpyrrolo[1,2-a]quinoxaline (3aa). Following the general
procedure, 2-(1H-pyrrol-1-yl)aniline 1a (47.46 mg) was used as
aniline and toluene (2a, 1.913 mL) was used as methyl arene. After
column chromatography (hexane/EtOAc = 20:1), 3aa was obtained
as a pale-yellow solid (56.3 mg, 77% yield); mp 88−90 °C; 1H NMR
(400 MHz, CDCl3): δ 8.05 (dd, J = 8.0, 1.6 Hz, 1H), 7.99−8.02 (m,
3H), 7.90 (dd, J = 8.0, 1.4 Hz, 1H), 7.51−7.57 (m, 4H), 7.45−7.49
(m, 1H), 7.00 (dd, J = 4.1, 1.4 Hz, 1H), 6.91 (dd, J = 4.0, 2.6 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.5, 138.5, 136.3,
130.3, 130.0, 128.7, 128.7, 127.6, 127.3, 125.5, 125.4, 114.8, 114.1,
113.7, 108.9; HRMS (FAB) m/z: [M + H]+ calcd for C17H13N2,
245.1079; found, 245.1080.
4-(o-Tolyl)pyrrolo[1,2-a]quinoxaline (3ab). Following the general
procedure, 1a (47.46 mg) was used as aniline and o-xylene (2b, 2.17
mL) was used as methyl arene. After column chromatography
(hexane/EtOAc = 20:1), 3ab was obtained as a pale-yellow solid
(53.1 mg, 69% yield); mp 111−113 °C; 1H NMR (400 MHz,
CDCl3): δ 8.09 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 1.4 Hz, 1H), 7.92
(dd, J = 8.0, 1.1 Hz, 1H), 7.56 (td, J = 7.8, 1.4 Hz, 1H), 7.46−7.51
(m, 2H), 7.30−7.42 (m, 3H), 6.87 (q, J = 2.3 Hz, 1H), 6.61 (d, J =
3.7 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
155.6, 136.6, 131.0, 130.1, 129.3, 129.1, 127.8, 127.3, 126.4, 125.8,
125.5, 114.9, 114.3, 113.9, 109.3, 19.9; HRMS (FAB) m/z: [M + H]+
calcd for C18H15N2, 259.1235; found, 259.1229.
4
112.8 (q, JC−F = 3.8 Hz), 110.2; 19F NMR (376 MHz, CDCl3): δ
−62.68 ppm; HRMS (FAB) m/z: [M + H]+ calcd for C11H10F3N2,
227.0796; found, 227.0797.
2-(1H-Pyrrol-1-yl)pyridin-3-amine (1j). Following method A, 3-
nitro-2-(1H-pyrrol-1-yl)pyridine (6.872 mmol, 1.3 g) was used as the
starting material. After recrystallization, 1j was obtained as a brown
1
solid (646 mg, 59% yield); mp 84−87 °C; H NMR (400 MHz,
DMSO-d6): δ 7.72 (dd, J = 4.6, 1.4 Hz, 1H), 7.25 (dd, J = 8.0, 1.6 Hz,
1H), 7.18 (t, J = 2.3 Hz, 2H), 7.10 (q, J = 4.1 Hz, 1H), 6.24 (t, J = 2.3
Hz, 2H), 5.11 (s, 2H); 13C{1H} NMR (100 MHz, DMSO-d6): δ
138.3, 137.1, 136.1, 124.0, 122.9, 120.0, 109.1; HRMS (FAB) m/z:
[M + H]+ calcd for C9H10N3, 160.0875; found, 160.0873.
2-(1-Methyl-1H-pyrrol-2-yl)aniline (1k). Following method A, 1-
methyl-2-(2-nitrophenyl)-1H-pyrrole (7.418 mmol, 1.5 g) was used as
the starting material. After recrystallization, 1k was obtained as a
white solid (1.21 g, 95% yield); mp 38−40 °C; 1H NMR (400 MHz,
CDCl3): δ 7.20 (td, J = 7.7, 1.6 Hz, 1H), 7.15 (dd, J = 7.4, 1.8 Hz,
1H), 6.77−6.84 (m, 3H), 6.27 (t, J = 3.1 Hz, 1H), 6.21 (q, J = 1.6 Hz,
1H), 3.77 (s, 2H), 3.52 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 145.9, 131.8, 130.6, 129.2, 122.7, 118.8, 118.0, 115.1, 108.8, 107.7,
34.3; HRMS (FAB) m/z: [M + H]+ calcd for C11H13N2, 173.1079;
found, 173.1082.
2-(1H-Indol-1-yl)aniline (1l). Following method B, 1-(2-nitro-
phenyl)-1H-indole (4.197 mmol, 1.0 g) was used as the starting
material. After column chromatography (hexane/EtOAc = 10:1), 1l
1
was obtained as a yellow oil (536 mg, 61% yield); H NMR (400
MHz, CDCl3): δ 7.69−7.71 (m, 1H), 7.14−7.29 (m, 6H), 6.86−6.93
(m, 2H), 6.70 (d, J = 3.2 Hz, 1H), 3.40 (br s, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 143.2, 136.5, 129.3, 128.7, 128.7, 128.7, 124.9,
122.3, 121.1, 120.3, 118.6, 116.3, 110.9, 103.3; HRMS (FAB) m/z:
[M]+ calcd for C14H12N2, 208.1000; found, 208.0999.
Preparation of 2-Aminoaryl-indole Substrates.19 To a screw-
cap pressure tube, indole (1.0 equiv), CuI (20 mol %), 2-iodoaniline
(1.5 equiv), N,N′-dimethylethylenediamine (80 mol %), K3PO4 (2.1
equiv), and toluene (0.6 M) were added. The reaction vessel was
fitted with a rubber septum and was evacuated and backfilled with
argon gas. The reaction tube was sealed and stirred in a preheated oil
bath at 110 °C for 24 h. After completion of the reaction, the mixture
was cooled to room temperature. The reaction mixture was diluted
with ethyl acetate and filtered through Celite. The filtrate was
concentrated under reduce pressure, and the resulting residue was
purified by flash column chromatography on silica gel to give the
desired substrates.
2-(5-Methoxy-1H-indol-1-yl)aniline (1m). Following the proce-
dure above, 5-methoxyindole (9.0 mmol, 1.325 g) was used as the
starting material. After column chromatography (hexane/EtOAc =
25:1), 1m was obtained as a sticky orange oil (1.90 g, 89% yield); 1H
NMR (400 MHz, CDCl3): δ 7.16−7.27 (m, 4H), 7.06 (d, J = 8.6 Hz,
1H), 6.83−6.88 (m, 3H), 6.63 (d, J = 3.1 Hz, 1H), 3.88 (s, 3H), 3.53
(br s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.7, 143.2, 131.8,
129.2, 129.2, 129.1, 128.7, 125.1, 118.6, 116.3, 112.6, 111.6, 103.0,
102.8, 56.0; HRMS (FAB) m/z: [M]+ calcd for C15H14N2O,
238.1106; found, 238.1100.
2-(3-Methyl-1H-indol-1-yl)aniline (1o). Following the procedure
above, 3-methylindole (9.0 mmol, 1.18 g) was used as the starting
material. After column chromatography (hexane/EtOAc = 25:1), 1o
was obtained as a pale-orange oil (1.926 g, 96% yield); 1H NMR (400
MHz, DMSO-d6): δ 7.59 (dd, J = 6.7, 1.2 Hz, 1H), 7.03−7.19 (m,
5H), 7.00 (dd, J = 6.7, 1.2 Hz, 1H), 6.94 (dd, J = 8.6, 1.2 Hz, 1H),
6.69 (td, J = 7.7, 1.2 Hz, 1H), 4.73 (s, 2H), 2.34 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ 144.3, 136.3, 128.6, 128.5, 127.9,
126.6, 123.6, 121.8, 119.1, 118.8, 116.4, 115.9, 111.0, 110.4, 9.5;
HRMS (FAB) m/z: [M]+ calcd for C15H14N2, 222.1157; found,
222.1154.
2-(1H-Pyrrolo[2,3-b]pyridin-1-yl)aniline (1p). Following the pro-
cedure above, 1H-pyrrolo[2,3-b]pyridine (12.0 mmol, 1.418 g) was
used as the starting material. After column chromatography (hexane/
EtOAc = 25:1), 1p was obtained as a pale-pink solid (971 mg, 39%
1
yield); mp 103−106 °C; H NMR (400 MHz, DMSO-d6): δ 8.22
7396
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4-(m-Tolyl)pyrrolo[1,2-a]quinoxaline (3ac). Following the general
procedure, 1a (47.46 mg) was used as aniline and m-xylene (2c, 2.21
mL) was used as methyl arene. After column chromatography
(hexane/EtOAc = 20:1), 3ac was obtained as a sticky yellow oil (53.8
mg, 69% yield); 1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 7.8 Hz,
1H), 8.00 (t, J = 1.4 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.80 (d, J =
11.9 Hz, 2H), 7.41−7.54 (m, 3H), 7.34 (d, J = 7.4 Hz, 1H), 7.01 (d, J
= 4.1 Hz, 1H), 6.90 (t, J = 3.2 Hz, 1H), 2.48 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 154.6, 138.6, 138.1, 136.0, 130.9, 130.1, 129.4,
128.5, 127.6, 127.2, 125.9, 125.5, 115.0, 114.2, 113.8, 109.3, 21.7;
HRMS (FAB) m/z: [M + H]+ calcd for C18H15N2, 259.1235; found,
259.1240.
4-(p-Tolyl)pyrrolo[1,2-a]quinoxaline (3ad). Following the general
procedure, 1a (47.46 mg) was used as aniline and p-xylene (2d, 2.21
mL) was used as methyl arene. After column chromatography
(hexane/EtOAc = 20:1), 3ad was obtained as a sticky yellow oil (61.8
mg, 80% yield); 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.0 Hz,
1H), 8.01 (d, J = 1.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.88 (dd, J =
8.0, 1.2 Hz, 1H), 7.44−7.54 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.04
(d, J = 3.7 Hz, 1H), 6.91 (t, J = 3.4 Hz, 1H), 2.46 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 154.4, 140.3, 135.8, 135.2, 130.0, 129.5,
128.8, 127.6, 127.2, 125.5, 125.4, 115.1, 114.3, 113.8, 109.5, 21.6;
HRMS (FAB) m/z: [M + H]+ calcd for C18H15N2, 259.1235; found,
259.1234.
For 1 mmol Scale Reaction (3ad in Table 2). To a mixture of 2-
(1H-pyrrol-1-yl)aniline 1a (1.0 mmol, 158.2 mg) and FeCl3·6H2O
(0.15 mmol, 40.14 mg) in 1.7 mL of DMSO, p-xylene 2d (18.0 mmol,
7.40 mL) was added in an Ace pressure tube. While stirring the
mixture, DTBP (1.2 mmol, 224 μL) was added in a dropwise manner.
The reaction mixture was stirred at 120 °C under open air conditions
and monitored by TLC. After stirring for 40 h, the reaction mixture
was cooled to room temperature and diluted with diethyl ether (20
mL). The mixture was extracted with diethyl ether (10 mL × 3), and
the organic phase was washed with water (10 mL). The combined
organic phase was dried over anhydrous MgSO4 and concentrated in
vacuo. The residue was purified by flash column chromatography on
silica gel using hexane/EtOAc (20:1) as the eluent. After purification,
3ad was obtained as a sticky yellow oil (193.4 mg, 75%).
1JC−F = 249.2 Hz), 162.7 (d, 1JC−F = 249.2 Hz), 153.3, 136.0 (d, 2JC−F
4
= 156.2 Hz), 134.4 (d, 2JC−F = 156.2 Hz), 130.8 (d, JC−F = 8.7 Hz),
130.7 (d, 4JC−F = 8.7 Hz), 130.1, 127.8, 127.2, 125.6, 125.2, 115.9 (d,
3
3JC−F = 21.1 Hz), 115.7 (d, JC−F = 21.1 Hz), 115.1, 114.3, 113.8,
109.0; 19F NMR (376 MHz, CDCl3): δ −110.52 ppm; HRMS (FAB)
m/z: [M + H]+ calcd for C17H12FN2, 263.0985; found, 263.0979.
4-(4-Chlorophenyl)pyrrolo[1,2-a]quinoxaline (3ah). Following
the general procedure, 1a (47.46 mg) was used as aniline and 4-
chlorotoluene (2h, 2.13 mL) was used as methyl arene. After column
chromatography (hexane/EtOAc = 20:1), 3ah was obtained as a
1
white solid (46.8 mg, 56% yield); mp 172−173 °C; H NMR (400
MHz, CDCl3): δ 8.01−8.05 (m, 2H), 7.96−7.98 (m, 2H), 7.88 (dd, J
= 8.3, 0.9 Hz, 1H), 7.45−7.55 (m, 4H), 6.97 (dd, J = 3.9, 1.1 Hz, 1H),
6.91 (dd, J = 3.7, 2.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
153.2, 136.9, 136.1, 136.1, 130.3, 130.1, 129.0, 127.9, 127.2, 125.6,
125.2, 115.1, 114.3, 113.8, 108.8; HRMS (FAB) m/z: [M + H]+ calcd
for C17H12ClN2, 279.0689; found, 279.0698.
4-(4-Bromophenyl)pyrrolo[1,2-a]quinoxaline (3ai). Following the
general procedure, 1a (47.46 mg) was used as aniline and 4-
bromotoluene (2i, 2.21 mL) was used as methyl arene. After column
chromatography (hexane/EtOAc = 20:1), 3ai was obtained as a pale-
1
yellow solid (51.5 mg, 53% yield); mp 157−159 °C; H NMR (400
MHz, CDCl3): δ 8.01−8.04 (m, 2H), 7.88−7.91 (m, 3H), 7.68 (d, J =
7.9 Hz, 2H), 7.52−7.56 (m, 1H), 7.45−7.49 (m, 1H), 6.96 (d, J = 4.3
Hz, 1H), 6.91 (t, J = 3.4 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 153.3, 137.4, 136.2, 131.9, 130.4, 130.3, 127.9, 127.3,
125.6, 125.1, 124.4, 115.0, 114.3, 113.8, 108.7; HRMS (FAB) m/z:
[M + H]+ calcd for C17H12BrN2, 323.0184; found, 323.0190.
4-(4-Iodophenyl)pyrrolo[1,2-a]quinoxaline (3aj). Following the
general procedure, 1a (47.46 mg) was used as aniline and 4-
iodotoluene (2j, 2.34 mL) was used as methyl arene. After column
chromatography (hexane/EtOAc = 20:1), 3aj was obtained as a pale-
1
yellow solid (55.7 mg, 50% yield); mp 116−118 °C; H NMR (400
MHz, CDCl3): δ 8.07 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H),
7.89 (d, J = 8.6 Hz, 3H), 7.76 (d, J = 8.6 Hz, 2H), 7.52−7.56 (m,
1H), 7.45−7.49 (m, 1H), 6.98 (d, J = 3.7 Hz, 1H), 6.92 (t, J = 3.4 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.3, 137.9, 137.9,
136.1, 130.5, 130.3, 127.9, 127.2, 125.5, 125.1, 115.0, 114.3, 113.8,
108.7, 96.3; HRMS (FAB) m/z: [M + H]+ calcd for C17H12IN2,
371.0045; found, 371.0048.
4-(3,5-Dimethylphenyl)pyrrolo[1,2-a]quinoxaline (3ae). Follow-
ing the general procedure, 1a (47.46 mg) was used as aniline and
1,3,5-trimethylbenzene (2e, 2.5 mL) was used as methyl arene. After
column chromatography (hexane/EtOAc = 20:1), 3ae was obtained
as a yellow solid (53.1 mg, 69% yield); mp 83−85 °C; 1H NMR (400
MHz, CDCl3): δ 8.06 (dd, J = 7.8, 1.4 Hz, 1H), 7.99 (q, J = 1.2 Hz,
1H), 7.88 (dd, J = 8.3, 1.4 Hz, 1H), 7.60 (s, 2H), 7.51 (td, J = 7.7, 1.5
Hz, 1H), 7.46 (td, J = 7.6, 1.2 Hz, 1H), 7.16 (s, 1H), 7.00 (q, J = 1.8
Hz, 1H), 6.89 (dd, J = 3.8, 2.9 Hz, 1H), 2.44 (s, 6H); 13C{1H} NMR
(100 MHz, CDCl3): δ 154.9, 138.3, 136.3, 131.7, 130.3, 127.5, 127.3,
126.5, 125.6, 125.4, 114.8, 114.1, 113.8, 109.2, 21.6; HRMS (FAB)
m/z: [M + H]+ calcd for C19H17N2, 273.1392; found, 273.1392.
4-(4-Methoxyphenyl)pyrrolo[1,2-a]quinoxaline (3af). Following
the general procedure, 1a (47.46 mg) was used as aniline and 4-
methoxytoluene (2f, 2.3 mL) was used as methyl arene. After column
chromatography (hexane/EtOAc = 20:1), 3af was obtained as a pale-
4-(4-(Trifluoromethyl)phenyl)pyrrolo[1,2-a]quinoxaline (3ak).
Following the general procedure, 1a (47.46 mg) was used as aniline
and 4-methylbenzotrifluoride (2k, 2.51 mL) was used as methyl
arene. After column chromatography (hexane/EtOAc = 20:1), 3ak
was obtained as a pale-yellow solid (28.5 mg, 30% yield); mp 151−
1
153 °C; H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 7.9 Hz, 2H),
8.04 (dd, J = 8.1, 1.4 Hz, 1H), 8.02 (q, J = 1.3 Hz, 1H), 7.88 (dd, J =
8.3, 1.2 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.52−7.57 (m, 1H), 7.46−
7.50 (m, 1H), 6.96 (dd, J = 4.0, 1.2 Hz, 1H), 6.92 (dd, J = 4.1, 2.6 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.0, 142.0, 136.2, 132.2
2
2
2
(q, JC−F = 32.6 Hz), 131.9 (q, JC−F = 32.6 Hz), 131.6 (q, JC−F
=
32.6 Hz), 131.2 (q, 2JC−F = 32.6 Hz), 130.5, 129.1, 128.1, 127.3, 125.7
3
3
3
(q, JC−F = 3.8 Hz), 125.7 (q, JC−F = 3.8 Hz), 125.7 (q, JC−F = 3.8
3
1
1
Hz), 125.6 (q, JC−F = 3.8 Hz), 125.6, 125.5 (d, JC−F = 271.2 Hz),
125.1, 122.8 (d, 1JC−F = 271.2 Hz), 120.1, 115.1, 114.4, 113.8, 108.5;
19F NMR (376 MHz, CDCl3): δ −62.67 ppm; HRMS (FAB) m/z:
[M + H]+ calcd for C18H12F3N2, 313.0953; found, 313.0953.
yellow solid (26.0 mg, 32% yield); mp 111−113 °C; H NMR (400
MHz, CDCl3): δ 8.00 (ddd, J = 12.6, 7.4, 1.6 Hz, 4H), 7.86 (dd, J =
8.0, 1.1 Hz, 1H), 7.49 (td, J = 7.6, 1.4 Hz, 1H), 7.44 (td, J = 7.5, 1.4
Hz, 1H), 7.06 (dt, J = 9.5, 2.5 Hz, 2H), 7.00 (dd, J = 3.9, 1.1 Hz, 1H),
6.88 (dd, J = 4.0, 2.9 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 161.1, 154.0, 136.5, 131.2, 130.2, 127.3, 127.2,
125.5, 125.4, 114.6, 114.1, 114.0, 113.7, 108.7, 55.6; HRMS (FAB)
m/z: [M + H]+ calcd for C18H15N2O, 275.1184; found, 275.1183.
4-(4-Fluorophenyl)pyrrolo[1,2-a]quinoxaline (3ag). Following
the general procedure, 1a (47.46 mg) was used as aniline and 4-
fluorotoluene (2g, 1.98 mL) was used as methyl arene. After column
chromatography (hexane/EtOAc = 20:1), 3ag was obtained as a pale-
4-(Pyrrolo[1,2-a]quinoxalin-4-yl)benzonitrile (3al). Following the
general procedure, 1a (47.46 mg) was used as aniline and p-tolunitrile
(2l, 2.15 mL) was used as methyl arene. After column
chromatography (hexane/EtOAc = 20:1), 3al was obtained as a
1
light-yellow solid (35.9 mg, 44% yield); mp 224−226 °C; H NMR
(400 MHz, CDCl3): δ 8.13 (d, J = 8.7 Hz, 2H), 8.02−8.04 (m, 2H),
7.91 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.57 (td, J = 7.8,
1.4 Hz, 1H), 7.47−7.51 (m, 1H), 6.94−6.95 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 152.3, 142.8, 136.1, 132.5, 130.5, 129.4, 128.4,
127.3, 125.7, 124.9, 118.8, 115.2, 114.5, 113.9, 113.4, 108.4; HRMS
(FAB) m/z: [M + H]+ calcd for C18H12N3, 270.1031; found,
270.1033.
1
yellow solid (45.7 mg, 58% yield); mp 154−156 °C; H NMR (400
MHz, CDCl3): δ 8.01−8.12 (m, 4H), 7.90 (d, J = 8.3 Hz, 1H), 7.55
(t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.22−7.27 (m, 2H),
6.94−7.01 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.2 (d,
7397
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4-(Naphthalen-2-yl)pyrrolo[1,2-a]quinoxaline (3am). Following
the general procedure, 1a (47.46 mg) was used as aniline and 2-
methylnaphthalene (2m, 2.56 g) was used as methyl arene. After
column chromatography (hexane/EtOAc = 20:1), 3am was obtained
as a pale-yellow solid (38.7 mg, 44% yield); mp 93−94 °C; 1H NMR
(400 MHz, CDCl3): δ 8.53 (s, 1H), 8.13 (qd, J = 4.1, 1.6 Hz, 2H),
8.01−8.03 (m, 2H), 7.99 (t, J = 4.8 Hz, 1H), 7.94 (t, J = 4.6 Hz, 1H),
7.90 (dd, J = 8.3, 1.4 Hz, 1H), 7.47−7.60 (m, 4H), 7.10 (dd, J = 3.9,
1.1 Hz, 1H), 6.93 (q, J = 2.3 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 154.4, 136.2, 135.7, 134.2, 133.3, 130.2, 128.9, 128.6,
128.5, 127.9, 127.7, 127.2, 127.1, 126.6, 126.2, 125.6, 125.5, 115.0,
114.3, 113.8, 109.2; HRMS (FAB) m/z: [M + H]+ calcd for
C21H15N2, 295.1235; found, 295.1229.
CDCl3): δ 159.3, 152.1, 138.8, 131.6, 130.9, 129.6, 128.7, 128.1,
125.5, 114.2, 114.2, 113.0, 108.3, 97.7, 56.0; HRMS (FAB) m/z: [M
+ H]+ calcd for C18H15N2O, 275.1184; found, 275.1180.
8-Chloro-4-phenylpyrrolo[1,2-a]quinoxaline (3ea). Following the
general procedure, 4-chloro-2-(1H-pyrrol-1-yl)aniline (1e, 57.8 mg)
was used as aniline and toluene (2a, 1.913 mL) was used as methyl
arene. After column chromatography (hexane/EtOAc = 20:1), 3ea
was obtained as a pale-yellow solid (46.0 mg, 55% yield); mp 179−
181 °C; 1H NMR (400 MHz, CDCl3): δ 7.95−8.00 (m, 3H), 7.94 (q,
J = 1.4 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.52−7.58 (m, 3H), 7.42
(dd, J = 8.7, 2.3 Hz, 1H), 7.02 (dd, J = 3.9, 1.1 Hz, 1H), 6.93 (dd, J =
3.9, 3.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 154.7, 138.3,
135.0, 133.0, 131.6, 130.2, 128.8, 128.7, 127.9, 125.9, 125.4, 115.0,
114.7, 114.0, 109.4; HRMS (FAB) m/z: [M + H]+ calcd for
C17H12ClN2, 279.0689; found, 279.0694.
7-Methyl-4-phenylpyrrolo[1,2-a]quinoxaline (3fa). Following the
general procedure, 5-methyl-2-(1H-pyrrol-1-yl)aniline (1f, 51.67 mg)
was used as aniline and toluene (2a, 1.913 mL) was used as methyl
arene. After column chromatography (hexane/EtOAc = 20:1), 3fa
was obtained as a yellow solid (44.4 mg, 57% yield); mp 87−90 °C;
1H NMR (400 MHz, CDCl3): δ 7.98−8.01 (m, 2H), 7.96 (q, J = 1.4
Hz, 1H), 7.85 (d, J = 0.9 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.49−
7.57 (m, 3H), 7.34 (dd, J = 8.3, 1.8 Hz, 1H), 6.97 (q, J = 1.8 Hz, 1H),
6.88 (q, J = 2.3 Hz, 1H), 2.51 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 154.5, 138.7, 136.3, 135.2, 130.2, 129.9, 128.7, 128.7,
125.5, 125.2, 114.5, 113.8, 113.5, 108.6, 21.3; HRMS (FAB) m/z: [M
+ H]+ calcd for C18H15N2, 259.1235; found, 259.1233.
4-(Thiophen-2-yl)pyrrolo[1,2-a]quinoxaline (3an). Following the
general procedure, 1a (47.46 mg) was used as aniline and 2-
methylthiophene (2n, 1.74 mL) was used as methyl arene. After
column chromatography (hexane/EtOAc = 20:1), 3an was obtained
1
as a yellow solid (37.7 mg, 50% yield); mp 102−104 °C; H NMR
(400 MHz, DMSO-d6): δ 8.58 (q, J = 1.3 Hz, 1H), 8.32 (dd, J = 8.1,
1.1 Hz, 1H), 8.14 (dd, J = 3.8, 1.1 Hz, 1H), 7.89 (dd, J = 7.8, 1.4 Hz,
1H), 7.85 (dd, J = 5.0, 1.1 Hz, 1H), 7.57−7.62 (m, 1H), 7.50 (ddd, J
= 8.3, 6.9, 1.1 Hz, 1H), 7.46 (dd, J = 4.0, 1.2 Hz, 1H), 7.29 (dd, J =
5.2, 3.7 Hz, 1H), 7.04 (dd, J = 4.3, 2.8 Hz, 1H); 13C{1H} NMR (100
MHz, DMSO-d6): δ 146.3, 142.1, 134.9, 130.1, 129.1, 128.9, 128.5,
127.9, 126.6, 125.7, 122.6, 116.8, 114.8, 114.6, 108.1; HRMS (FAB)
m/z: [M + H]+ calcd for C15H11N2S, 251.0643; found, 251.0636.
4-(Pyridin-4-yl)pyrrolo[1,2-a]quinoxaline (3ao). Following the
general procedure, 1a (47.46 mg) was used as aniline and 4-
methylpyridine (2o, 1.75 mL) was used as methyl arene. After column
chromatography (hexane/EtOAc = 20:1), 3ao was obtained as a light-
7-Methoxy-4-phenylpyrrolo[1,2-a]quinoxaline (3ga). Following
the general procedure, 5-methoxy-2-(1H-pyrrol-1-yl)aniline (1g,
56.47 mg) was used as aniline and toluene (2a, 1.913 mL) was
used as methyl arene. After column chromatography (hexane/EtOAc
= 20:1), 3ga was obtained as a pale-yellow solid (61.4 mg, 75% yield);
1
yellow solid (46.1 mg, 63% yield); mp 188−190 °C; H NMR (400
MHz, CDCl3): δ 8.81 (q, J = 2.1 Hz, 2H), 8.03−8.05 (m, 2H), 7.90
(d, J = 6.1 Hz, 3H), 7.56 (t, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H),
6.99 (d, J = 4.3 Hz, 1H), 6.93 (t, J = 2.8 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 151.9, 150.4, 145.8, 136.0, 130.6, 128.5, 127.4,
125.7, 124.8, 123.1, 115.2, 114.5, 113.9, 108.3; HRMS (FAB) m/z:
[M + H]+ calcd for C16H12N3, 246.1031; found, 246.1034.
1
mp 129−130 °C; H NMR (400 MHz, CDCl3): δ 7.98−8.00 (m,
2H), 7.94 (m, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.52−7.57 (m, 4H), 7.14
(dd, J = 8.7, 2.8 Hz, 1H), 6.97 (dd, J = 4.1, 0.9 Hz, 1H), 6.87 (dd, J =
3.7, 2.8 Hz, 1H), 3.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
157.3, 154.9, 138.7, 137.5, 129.9, 128.7, 125.3, 121.6, 116.9, 114.7,
114.4, 113.8, 111.5, 108.5, 55.9; HRMS (FAB) m/z: [M + H]+ calcd
for C18H15N2O, 275.1184; found, 275.1188.
9-Methyl-4-phenylpyrrolo[1,2-a]quinoxaline (3ba). Following
the general procedure, 3-methyl-2-(1H-pyrrol-1-yl)aniline (1b, 51.67
mg) was used as aniline and toluene (2a, 1.913 mL) was used as
methyl arene. After column chromatography (hexane/EtOAc = 20:1),
3ba was obtained as a light-yellow solid (52.5 mg, 68% yield); mp
7-Chloro-4-phenylpyrrolo[1,2-a]quinoxaline (3ha). Following the
general procedure, 5-chloro-2-(1H-pyrrol-1-yl)aniline (1h, 57.8 mg)
was used as aniline and toluene (2a, 1.913 mL) was used as methyl
arene. After column chromatography (hexane/EtOAc = 20:1), 3ha
was obtained as a white solid (54.8 mg, 66% yield); mp 145−147 °C;
1H NMR (400 MHz, DMSO-d6): δ 8.61 (q, J = 1.4 Hz, 1H), 8.39 (d,
J = 8.6 Hz, 1H), 7.97−8.00 (m, 3H), 7.67 (dd, J = 9.2, 2.4 Hz, 1H),
7.58−7.62 (m, 3H), 7.07 (dd, J = 4.3, 1.2 Hz, 1H), 7.02 (q, J = 2.2
Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 154.4, 137.5,
136.6, 130.3, 129.3, 128.6, 128.5, 128.4, 127.6, 125.7, 124.2, 117.3,
116.7, 114.8, 109.2; HRMS (FAB) m/z: [M + H]+ calcd for
C17H12ClN2, 279.0689; found, 279.0687.
4-Phenyl-7-(trifluoromethyl)pyrrolo[1,2-a]quinoxaline (3ia). Fol-
lowing the general procedure, 2-(1H-pyrrol-1-yl)-5-(trifluoromethyl)-
aniline (1i, 67.86 mg) was used as aniline and toluene (2a, 1.913 mL)
was used as methyl arene. After column chromatography (hexane/
EtOAc = 20:1), 3ia was obtained as a light-yellow solid (66.3 mg, 71%
yield); mp 96−98 °C; 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H),
7.99−8.03 (m, 3H), 7.92 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.6 Hz,
1H), 7.54−7.59 (m, 3H), 7.06 (d, J = 3.7 Hz, 1H), 6.94 (t, J = 3.4 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.8, 138.0, 136.1,
1
121−123 °C; H NMR (400 MHz, CDCl3): δ 8.39 (q, J = 1.4 Hz,
1H), 7.96−7.99 (m, 2H), 7.93 (dd, J = 7.4, 2.3 Hz, 1H), 7.50−7.56
(m, 3H), 7.31−7.37 (m, 2H), 7.00 (dd, J = 4.1, 0.9 Hz, 1H), 6.88 (dd,
J = 4.1, 3.2 Hz, 1H), 2.99 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 154.4, 138.6, 138.1, 131.1, 129.8, 128.9, 128.8, 128.7,
127.6, 126.9, 125.4, 124.8, 120.4, 113.4, 108.3, 24.1; HRMS (FAB)
m/z: [M + H]+ calcd for C18H15N2, 259.1235; found, 259.1240.
8-Methyl-4-phenylpyrrolo[1,2-a]quinoxaline (3ca). Following the
general procedure, 4-methyl-2-(1H-pyrrol-1-yl)aniline (1c, 51.67 mg)
was used as aniline and toluene (2a, 1.913 mL) was used as methyl
arene. After column chromatography (hexane/EtOAc = 20:1), 3ca
1
was obtained as a yellow oil (35.9 mg, 46% yield); H NMR (400
MHz, CDCl3): δ 7.99 (dq, J = 6.2, 1.9 Hz, 2H), 7.96 (q, J = 1.4 Hz,
1H), 7.93 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.49−7.56 (m, 3H), 7.27
(dd, J = 8.5, 1.6 Hz, 1H), 6.97 (q, J = 1.8 Hz, 1H), 6.88 (q, J = 2.3 Hz,
1H), 2.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.6,
138.7, 138.1, 134.4, 130.1, 129.8, 128.7, 128.7, 127.0, 126.7, 125.6,
114.4, 114.0, 113.8, 108.5, 22.0; HRMS (FAB) m/z: [M + H]+ calcd
for C18H15N2, 259.1235; found, 259.1231.
2
2
130.4, 129.3, 128.8 (d, JC−F = 8.6 Hz), 128.7 (d, JC−F = 8.6 Hz),
127.9 (q, 4JC−F = 3.8 Hz), 127.9 (q, 4JC−F = 3.8 Hz), 127.8 (q, 4JC−F
=
8-Methoxy-4-phenylpyrrolo[1,2-a]quinoxaline (3da). Following
the general procedure, 4-methoxy-2-(1H-pyrrol-1-yl)aniline (1d,
56.47 mg) was used as aniline and toluene (2a, 1.913 mL) was
used as methyl arene. After column chromatography (hexane/EtOAc
= 20:1), 3da was obtained as a yellow solid (35.9 mg, 46% yield); mp
4
3.8 Hz), 127.8 (q, JC−F = 3.8 Hz), 127.7, 127.4, 127.4, 125.6, 125.5
(d, 1JC−F = 270.2 Hz), 123.9 (q, 3JC−F = 3.9 Hz), 123.9 (q, 3JC−F = 3.9
3
3
Hz), 123.8 (q, JC−F = 3.9 Hz), 123.8 (q, JC−F = 3.9 Hz), 122.8 (d,
1JC−F = 270.2 Hz), 121.4, 115.4, 115.0, 114.4, 110.2, 110.0; 19F NMR
(376 MHz, CDCl3): δ −61.89 ppm; HRMS (FAB) m/z: [M + H]+
calcd for C18H12F3N2, 313.0953; found, 313.0953.
1
98−100 °C; H NMR (400 MHz, CDCl3): δ 7.96−7.99 (m, 3H),
7.90 (q, J = 1.4 Hz, 1H), 7.48−7.56 (m, 3H), 7.29 (d, J = 2.7 Hz,
1H), 7.06 (dd, J = 8.9, 2.5 Hz, 1H), 6.97 (dd, J = 4.1, 0.9 Hz, 1H),
6.90 (q, J = 2.3 Hz, 1H), 3.98 (s, 3H); 13C{1H} NMR (100 MHz,
6-Phenylpyrido[3,2-e]pyrrolo[1,2-a]pyrazine (3ja). Following the
general procedure, 2-(1H-pyrrol-1-yl)pyridin-3-amine (1j, 47.76 mg)
7398
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
was used as aniline and toluene (2a, 1.913 mL) was used as methyl
arene. After column chromatography (hexane/EtOAc = 20:1), 3ja
was obtained as a pale-yellow solid (36.1 mg, 49% yield); mp 139−
114.7, 110.1, 10.9; HRMS (FAB) m/z: [M + H]+ calcd for C22H17N2,
309.1392; found, 309.1388.
6-Phenylpyrido[3′,2′:4,5]pyrrolo[1,2-a]quinoxaline (3pa). Fol-
lowing the general procedure, 2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-
aniline (1p, 62.8 mg) was used as aniline and toluene (2a, 1.913
mL) was used as methyl arene. After column chromatography
(hexane/EtOAc = 20:1), 3pa was obtained as a yellow solid (8.8 mg,
1
141 °C; H NMR (400 MHz, CDCl3): δ 8.55 (dd, J = 4.8, 1.6 Hz,
1H), 8.48 (q, J = 1.4 Hz, 1H), 8.32 (dd, J = 8.0, 1.6 Hz, 1H), 7.99−
8.04 (m, 2H), 7.54−7.59 (m, 3H), 7.46 (q, J = 4.3 Hz, 1H), 7.07 (q, J
= 1.8 Hz, 1H), 6.94 (dd, J = 3.7, 2.7 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 155.4, 146.8, 139.4, 138.1, 137.5, 131.2, 130.3,
128.8, 128.8, 126.9, 121.8, 116.1, 114.6, 110.5; HRMS (FAB) m/z:
[M + H]+ calcd for C16H12N3, 246.1031; found, 246.1031.
1
10% yield); mp 178−180 °C; H NMR (400 MHz, CDCl3): δ 9.93
(dd, J = 7.9, 1.2 Hz, 1H), 8.73 (q, J = 2.0 Hz, 1H), 8.23 (dd, J = 8.3,
1.5 Hz, 1H), 8.07 (dd, J = 7.9, 1.2 Hz, 1H), 8.01−8.05 (m, 2H), 7.68
(td, J = 7.8, 1.4 Hz, 1H), 7.56−7.62 (m, 3H), 7.47−7.51 (m, 1H),
7.40 (q, J = 4.3 Hz, 1H), 7.15 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 155.9, 145.7, 145.1, 137.9, 135.7, 130.6, 130.3, 129.8,
129.2, 128.9, 128.8, 128.3, 125.0, 121.3, 118.8, 117.7, 99.5; HRMS
(FAB) m/z: [M + H]+ calcd for C20H14N3, 296.1188; found,
296.1186.
1-Methyl-4-phenyl-1H-pyrrolo[3,2-c]quinoline (3ka). Following
the general procedure, 2-(1-methyl-1H-pyrrol-2-yl)aniline (1k, 60.66
mg) was used as aniline and toluene (2a, 1.913 mL) was used as
methyl arene. After column chromatography (hexane/EtOAc = 20:1),
3ka was obtained as a beige solid (9.9 mg, 13% yield); mp 123−125
1
°C; H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 8.6 Hz, 1H), 8.33
Synthetic Procedure for JG454 and Its Indole Analogue.
Piperidine compound 6 was synthesized through known procedures,
and characterization data were consistent with the literature.21
For 1 mmol Scale Reaction (3al in Scheme 2). To a mixture of 2-
(1H-pyrrol-1-yl)aniline 1a (1.0 mmol, 158.2 mg) and FeCl3·6H2O
(0.20 mmol, 54.06 mg) in 1.7 mL of DMSO, p-tolunitrile 2l (18.0
mmol, 7.11 mL) was added in an Ace pressure tube. While stirring the
mixture, DTBP (1.2 mmol, 224 μL) was added in a dropwise manner.
The reaction mixture was stirred at 120 °C under open air conditions
and monitored by TLC. After stirring for 40 h, the reaction mixture
was cooled to room temperature and diluted with diethyl ether (20
mL). The mixture was extracted with diethyl ether (10 mL × 3), and
the organic phase was washed with water (10 mL). The combined
organic phase was dried over anhydrous MgSO4 and concentrated in
vacuo. The residue was purified by flash column chromatography on
silica gel using hexane/EtOAc (10:1) as the eluent. 3al was obtained
as a light-yellow solid (110.5 mg, 41% yield).
4-(Indolo[1,2-a]quinoxalin-6-yl)benzonitrile (3ll). Following the
above procedure of 1 mmol scale reaction for 3al, 2-(1H-indol-1-
yl)aniline 1l (1.0 mmol, 208.3 mg) was used as the starting material.
After column chromatography (hexane/EtOAc = 20:1), 3ll was
obtained as an orange solid (122.7 mg, 38% yield); mp 253−255 °C;
1H NMR (400 MHz, CDCl3): δ 8.51 (dd, J = 11.9, 8.7 Hz, 2H), 8.15
(d, J = 8.3 Hz, 2H), 8.06 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H),
7.87 (d, J = 8.3 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.59 (t, J = 7.6 Hz,
1H), 7.47 (t, J = 7.6 Hz, 2H), 7.18 (s, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 154.2, 142.5, 136.0, 133.2, 132.6, 130.9, 130.3,
129.5, 129.3, 129.2, 128.5, 125.0, 124.6, 123.2, 123.0, 118.7, 114.9,
114.7, 113.7, 102.2; HRMS (FAB) m/z: [M + H]+ calcd for
C22H14N3, 320.1188; found, 320.1184.
4-(Pyrrolo[1,2-a]quinoxalin-4-yl)benzaldehyde (4al). Diisobuty-
laluminium hydride [0.297 mmol, 297 μL, 1 M solution in
dichloromethane (DCM)] was added dropwise to a solution of 3al
(0.149 mmol, 40.0 mg) in tetrahydrofuran (THF, 6.4 mL) using a
syringe pump for 1 h at −78 °C. After stirring for additional 1 h at
−78 °C, the mixture continued to stir for 3 h at room temperature.
Then, 1 M HCl was slowly added to the mixture to adjust the pH to
4−5. The mixture was filtered on Celite, washed with DCM (20 mL),
and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel using hexane/EtOAc (7:1) as the eluent.
4al was obtained as a light-yellow solid (19.5 mg, 48% yield); mp
149−152 °C; 1H NMR (400 MHz, CDCl3): δ 10.13 (s, 1H), 8.18 (d,
J = 8.3 Hz, 2H), 8.03−8.07 (m, 4H), 7.90 (dd, J = 8.3, 1.4 Hz, 1H),
7.56 (td, J = 7.7, 1.5 Hz, 1H), 7.46−7.51 (m, 1H), 6.98 (q, J = 1.8 Hz,
1H), 6.93 (q, J = 2.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
192.1, 153.0, 144.1, 137.2, 136.1, 130.5, 130.1, 129.5, 128.3, 127.3,
125.7, 125.1, 115.1, 114.5, 113.9, 108.6; HRMS (FAB) m/z: [M +
H]+ calcd for C18H13N2O, 273.1028; found, 273.1022.
(dd, J = 8.6, 1.2 Hz, 1H), 8.04−8.07 (m, 2H), 7.62−7.66 (m, 1H),
7.53−7.58 (m, 3H), 7.47−7.51 (m, 1H), 7.07 (d, J = 3.1 Hz, 1H),
6.82 (d, J = 3.1 Hz, 1H), 4.25 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 154.8, 144.8, 140.4, 134.9, 130.8, 129.8, 129.2, 128.9,
128.6, 126.4, 125.4, 120.5, 120.3, 118.4, 103.2, 38.2; HRMS (FAB)
m/z: [M + H]+ calcd for C18H15N2, 259.1235; found, 259.1241.
6-Phenylindolo[1,2-a]quinoxaline (3la). Following the general
procedure, 2-(1H-indol-1-yl)aniline (1l, 62.48 mg) was used as
aniline and toluene (2a, 1.913 mL) was used as methyl arene. After
column chromatography (hexane/EtOAc = 20:1), 3la was obtained as
a yellow solid (68.7 mg, 78% yield); mp 162−165 °C; 1H NMR (400
MHz, CDCl3): δ 8.48−8.53 (m, 2H), 8.09 (dd, J = 7.7, 1.5 Hz, 1H),
8.01−8.05 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.54−7.64 (m, 5H),
7.43−7.47 (m, 2H), 7.25 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.4, 138.4, 136.4, 133.2, 130.7, 130.3, 130.2, 129.3,
129.3, 128.8, 128.8, 128.5, 124.5, 124.3, 122.9, 122.8, 114.8, 114.7,
102.6; HRMS (FAB) m/z: [M + H]+ calcd for C21H15N2, 295.1235;
found, 295.1238.
9-Methoxy-6-phenylindolo[1,2-a]quinoxaline (3ma). Following
the general procedure, 2-(5-methoxy-1H-indol-1-yl)aniline (1m, 71.5
mg) was used as aniline and toluene (2a, 1.913 mL) was used as
methyl arene. After column chromatography (hexane/EtOAc = 20:1),
3ma was obtained as a light-yellow solid (46.4 mg, 48% yield); mp
167−169 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.67 (dd, J = 15.3,
8.6 Hz, 2H), 7.99−8.04 (m, 3H), 7.68−7.72 (m, 1H), 7.63 (t, J = 3.4
Hz, 3H), 7.51 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.26 (s,
1H), 7.21 (dd, J = 9.2, 2.4 Hz, 1H), 3.87 (s, 3H); 13C{1H} NMR (100
MHz, DMSO-d6): δ 155.4, 154.7, 137.7, 135.4, 130.2, 130.1, 129.9,
129.1, 129.1, 128.6, 128.5, 127.7, 124.3, 116.0, 115.7, 114.8, 102.6,
101.8, 55.4; HRMS (FAB) m/z: [M + H]+ calcd for C22H17N2O,
325.1341; found, 325.1347.
9-Bromo-6-phenylindolo[1,2-a]quinoxaline (3na). Following the
general procedure, 2-(5-bromo-1H-indol-1-yl)aniline (1n, 86.15 mg)
was used as aniline and toluene (2a, 1.913 mL) was used as methyl
arene. After column chromatography (hexane/EtOAc = 20:1), 3na
was obtained as a light-yellow solid (6.6 mg, 6% yield); mp 234−237
°C; 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 7.8 Hz, 1H), 8.38 (d,
J = 9.2 Hz, 1H), 8.10 (dd, J = 7.8, 1.4 Hz, 1H), 8.06 (d, J = 1.8 Hz,
1H), 8.00−8.02 (m, 2H), 7.57−7.67 (m, 5H), 7.47−7.51 (m, 1H),
7.18 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.2, 138.1,
136.5, 131.8, 131.0, 131.0, 130.3, 130.1, 129.9, 128.9, 128.8, 128.7,
127.3, 125.2, 124.8, 116.3, 116.1, 114.7, 101.7; HRMS (FAB) m/z:
[M + H]+ calcd for C21H14BrN2, 373.0340; found, 373.0332.
7-Methyl-6-phenylindolo[1,2-a]quinoxaline (3oa). Following the
general procedure, 2-(3-methyl-1H-indol-1-yl)aniline (1o, 66.7 mg)
was used as aniline and toluene (2a, 1.913 mL) was used as methyl
arene. After column chromatography (hexane/EtOAc = 20:1), 3oa
was obtained as a light-yellow solid (65.6 mg, 71% yield); mp 162−
163 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.71 (t, J = 8.3 Hz, 2H),
7.97 (d, J = 7.9 Hz, 1H), 7.90 (dd, J = 7.6, 1.5 Hz, 1H), 7.57−7.70
(m, 7H), 7.45−7.51 (m, 2H), 2.00 (s, 3H); 13C{1H} NMR (100
MHz, DMSO-d6): δ 157.0, 139.2, 135.1, 131.4, 129.7, 129.7, 129.6,
129.3, 129.0, 128.6, 128.3, 125.2, 125.0, 124.1, 122.3, 120.8, 114.9,
4-(Indolo[1,2-a]quinoxalin-6-yl)benzaldehyde (4ll). Following
the above procedure of 4al, diisobutylaluminium hydride (0.188
mmol, 188 μL, 1 M solution in DCM) was added dropwise to a
solution of 3ll (0.125 mmol, 40.0 mg) in THF (5.4 mL) using a
syringe pump for 1 h at −78 °C. After column chromatography
(hexane/EtOAc/DCM = 10:1:1), 4ll was obtained as an orange solid
7399
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(27.1 mg, 54% yield); mp 191−193 °C; 1H NMR (400 MHz,
CDCl3): δ 10.15 (s, 1H), 8.52 (dd, J = 8.3, 0.9 Hz, 1H), 8.49 (d, J =
8.7 Hz, 1H), 8.20 (d, J = 8.3 Hz, 2H), 8.07−8.10 (m, 3H), 7.94 (d, J
= 7.8 Hz, 1H), 7.65 (td, J = 7.9, 1.5 Hz, 1H), 7.56−7.60 (m, 1H),
7.44−7.49 (m, 2H), 7.21 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 192.0, 154.9, 143.9, 137.3, 136.2, 133.2, 130.9, 130.3,
130.1, 129.5, 129.2, 129.1, 128.7, 124.8, 124.5, 123.1, 123.0, 114.9,
114.7, 102.4; HRMS (FAB) m/z: [M + H]+ calcd for C22H15N2O,
323.1184; found, 323.1182.
Seok Beom Lee − Research Institute of Pharmaceutical
Sciences, College of Pharmacy, Seoul National University,
Seoul 08826, Republic of Korea
Injae Song − Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul
08826, Republic of Korea
Simin Chun − Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul
08826, Republic of Korea
Dong-Chan Oh − Natural Products Research Institute,
College of Pharmacy, Seoul National University, Seoul
08826, Republic of Korea; orcid.org/0000-0001-6405-
5535
1-(1-(4-(Pyrrolo[1,2-a]quinoxalin-4-yl)benzyl)piperidin-4-yl)-1,3-
dihydro-2H-benzo[d]imidazole-2-one (5al/JG454). 4al (0.045
mmol, 12.0 mg), 6 (0.053 mmol, 11.6 mg), MeOH (2.5 mL), and
acetic acid (2 drops) were added to an oven-dried round-bottom
flask. Sodium cyanoborohydride (0.225 mmol, 13.9 mg) was added to
the mixture, and then, the reaction mixture was heated to 85 °C for 5
h. After finishing reaction, the mixture was concentrated in vacuo. The
residue was diluted with DCM (5 mL) and washed with H2O (2 mL)
and sat. NaHCO3 (2 mL) sequentially. The organic phase was dried
over anhydrous MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel using DCM/
MeOH (96:4) as the eluent. 5al was obtained as a white solid (14.7
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00371
Author Contributions
J.A. and S.B.L. contributed equally to this work. The
manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
1
mg, 69% yield); mp 275−278 °C; H NMR (400 MHz, CDCl3): δ
10.17 (s, 1H), 8.06 (dd, J = 8.0, 1.6 Hz, 1H), 7.99−8.01 (m, 3H),
7.89 (dd, J = 8.0, 1.1 Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.50−7.54
(m, 1H), 7.46 (td, J = 7.6, 1.4 Hz, 1H), 7.31 (s, 1H), 7.02−7.10 (m,
4H), 6.91 (dd, J = 3.7, 2.8 Hz, 1H), 4.43 (t, J = 11.7 Hz, 1H), 3.69 (s,
2H), 3.11 (d, J = 6.9 Hz, 2H), 2.52−2.62 (m, 2H), 2.25 (s, 2H), 1.84
(d, J = 10.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 155.3,
154.3, 140.5, 137.5, 136.4, 130.3, 129.4, 129.2, 128.7, 128.2, 127.6,
127.3, 125.5, 125.4, 121.3, 121.2, 114.8, 114.1, 113.8, 110.0, 109.8,
108.9, 62.7, 53.3, 50.9, 29.4; HRMS (FAB) m/z: [M + H]+ calcd for
C30H28N5O 474.2294; found, 474.2293.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
Government (2021R1C1C1007657 and 2021R1A4A2001251)
and the Creative-Pioneering Researchers Program through
Seoul National University (SNU).
1-(1-(4-(Indolo[1,2-a]quinoxalin-6-yl)benzyl)piperidin-4-yl)-1,3-
dihydro-2H-benzo[d]imidazole-2-one (5ll). Following the above
procedure of 5al, sodium cyanoborohydride (0.310 mmol, 19.0 mg)
was added to a mixture of 4ll (0.062 mmol, 20.0 mg), 6 (0.074 mmol,
16.2 mg), MeOH (3.4 mL), and acetic acid (2 drops). After column
chromatography (hexane/EtOAc/DCM = 1:5:1), 5ll was obtained as
a yellow solid (16.3 mg, 50% yield); mp 284−286 °C; 1H NMR (400
MHz, DMSO-d6): δ 10.87 (s, 1H), 8.74 (d, J = 8.7 Hz, 2H), 7.98−
8.04 (m, 4H), 7.68−7.73 (m, 1H), 7.58−7.61 (m, 3H), 7.46−7.53
(m, 2H), 7.39 (s, 1H), 7.25 (d, J = 6.4 Hz, 1H), 6.96−7.02 (m, 3H),
4.19 (tt, J = 12.2, 4.2 Hz, 1H), 3.66 (s, 2H), 3.03 (d, J = 11.5 Hz, 2H),
2.42 (qd, J = 12.2, 3.2 Hz, 2H), 2.17 (t, J = 11.0 Hz, 2H), 1.68 (d, J =
9.6 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 155.0, 153.8,
141.0, 136.3, 135.6, 132.4, 129.3, 129.3, 129.0, 128.9, 128.8, 128.5,
128.3, 128.1, 124.7, 124.5, 122.9, 120.5, 120.4, 115.2, 115.0, 108.8,
108.7, 102.4, 61.7, 52.7, 50.2, 28.8; HRMS (FAB) m/z: [M + H]+
calcd for C34H30N5O, 524.2450; found, 524.2452.
REFERENCES
■
(1) (a) Huang, A.; Ma, C. Recent Progress in Biological Activities
and Synthetic Methodologies of Pyrroloquinoxalines. Mini-Rev. Med.
Chem. 2013, 13, 607−616. (b) Alleca, S.; Corona, P.; Loriga, M.;
Paglietti, G.; Loddo, R.; Mascia, V.; Busonera, B.; La Colla, P.
Quinoxaline chemistry. Part 16. 4-Substituted anilino and 4-
substituted phenoxymethyl pyrrolo[1,2-a]quinoxalines and N-[4-
(pyrrolo[1,2-a]quinoxalin-4-yl)amino and hydroxymethyl]benzoyl
glutamates. Synthesis and evaluation of in vitro biological activity.
Farmaco 2003, 58, 639−650.
̀
(2) (a) Parrino, B.; Carbone, A.; Ciancimino, C.; Spano, V.;
Montalbano, A.; Barraja, P.; Cirrincione, G.; Diana, P.; Sissi, C.;
Palumbo, M.; Pinato, O.; Pennati, M.; Beretta, G.; Folini, M.; Matyus,
P.; Balogh, B.; Zaffaroni, N. Water-soluble isoindolo[2,1-a]quinoxalin-
6-imines: In vitro antiproliferative activity and molecular mecha-
nism(s) of action. Eur. J. Med. Chem. 2015, 94, 149−162. (b) Desplat,
V.; Geneste, A.; Begorre, M.-A.; Fabre, S. B.; Brajot, S.; Massip, S.;
Thiolat, D.; Mossalayi, D.; Jarry, C.; Guillon, J. Synthesis of New
Pyrrolo[1,2-a]quinoxaline Derivatives as Potential Inhibitors of Akt
Kinase. J. Enzyme Inhib. Med. Chem. 2008, 23, 648−658. (c) Aiello,
F.; Carullo, G.; Giordano, F.; Spina, E.; Nigro, A.; Garofalo, A.;
Tassini, S.; Costantino, G.; Vincetti, P.; Bruno, A.; Radi, M.
Identification of Breast Cancer Inhibitors Specific for G Protein-
Coupled Estrogen Receptor (GPER)-Expressing Cells. ChemMed-
Chem 2017, 12, 1279−1285. (d) You, W.; Rotili, D.; Li, T.-M.;
Kambach, C.; Meleshin, M.; Schutkowski, M.; Chua, K. F.; Mai, A.;
Steegborn, C. Structural Basis of Sirtuin 6 Activation by Synthetic
Small Molecules. Angew. Chem., Int. Ed. 2017, 56, 1007−1011.
(3) (a) Guillon, J.; Cohen, A.; Gueddouda, N. M.; Das, R. N.;
Moreau, S.; Ronga, L.; Savrimoutou, S.; Basmaciyan, L.; Monnier, A.;
Monget, M.; Rubio, S.; Garnerin, T.; Azas, N.; Mergny, J.-L.; Mullié,
C.; Sonnet, P. Design, synthesis and antimalarial activity of novel
bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine
derivatives. J. Enzyme Inhib. Med. Chem. 2017, 32, 547−563.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00371.
■
sı
1H and 13C NMR spectra and details for mechanism
studies (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Suckchang Hong − Research Institute of Pharmaceutical
Sciences, College of Pharmacy, Seoul National University,
Seoul 08826, Republic of Korea; orcid.org/0000-0003-
4975-9192; Email: schong17@snu.ac.kr
Authors
Jiwon Ahn − Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul
08826, Republic of Korea
7400
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(b) Guillon, J.; Mouray, E.; Moreau, S.; Mullié, C.; Forfar, I.; Desplat,
V.; Belisle-Fabre, S.; Pinaud, N.; Ravanello, F.; Le-Naour, A.; Léger,
J.-M.; Gosmann, G.; Jarry, C.; Déléris, G.; Sonnet, P.; Grellier, P. New
ferrocenic pyrrolo[1,2-a]quinoxaline derivatives: Synthesis, and in
vitro antimalarial activity - Part II. Eur. J. Med. Chem. 2011, 46, 2310−
2326.
(4) (a) Desplat, V.; Moreau, S.; Gay, A.; Fabre, S. B.; Thiolat, D.;
Massip, S.; Macky, G.; Godde, F.; Mossalayi, D.; Jarry, C.; Guillon, J.
Synthesis and evaluation of the antiproliferative activity of novel
pyrrolo[1,2-a]quinoxaline derivatives, potential inhibitors of Akt
kinase. Part II. J. Enzyme Inhib. Med. Chem. 2010, 25, 204−215.
(b) Desplat, V.; Moreau, S.; Belisle-Fabre, S.; Thiolat, D.; Uranga, J.;
Lucas, R.; Moor, L. d.; Massip, S.; Jarry, C.; Mossalayi, D. M.; Sonnet,
P.; Déléris, G.; Guillon, J. Synthesis and evaluation of the
antiproliferative activity of novel isoindolo[2,1-a]quinoxaline and
indolo[1,2-a]quinoxaline derivatives. J. Enzyme Inhib. Med. Chem.
2011, 26, 657−667.
(5) Guillon, J.; Le Borgne, M.; Rimbault, C.; Moreau, S.;
Savrimoutou, S.; Pinaud, N.; Baratin, S.; Marchivie, M.; Roche, S.;
Bollacke, A.; Pecci, A.; Alvarez, L.; Desplat, V.; Jose, J. Synthesis and
biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline
derivatives as inhibitors of the human protein kinase CK2. Eur. J. Med.
Chem. 2013, 65, 205−222.
(6) Guillon, J.; Dallemagne, P.; Pfeiffer, B.; Renard, P.; Manechez,
D.; Kervran, A.; Rault, S. Synthesis of new pyrrolo[1,2-a]quinoxalines:
potential non-peptide glucagon receptor antagonists. Eur. J. Med.
Chem. 1998, 33, 293−308.
2019, 30, 2148−2152. (f) Huo, H.-r.; Tang, X.-Y.; Gong, Y.-f. Metal-
Free Synthesis of Pyrrolo[1,2-a]quinoxalines Mediated by TEMPO
Oxoammonium Salts. Synthesis 2018, 50, 2727−2740. (g) Sharma, A.;
Singh, M.; Rai, N. N.; Sawant, D. Mild and efficient cyanuric chloride
catalyzed Pictet−Spengler reaction. Beilstein J. Org. Chem. 2013, 9,
1235−1242. (h) Kamal, A.; Babu, K. S.; Kovvuri, J.; Manasa, V.;
Ravikumar, A.; Alarifi, A. Amberlite IR-120H: an efficient and
recyclable heterogeneous catalyst for the synthesis of pyrrolo[1,2-
a]quinoxalines and 5′H-spiro [indoline-3,4′-pyrrolo[1,2-a]-
quinoxalin]-2-ones. Tetrahedron Lett. 2015, 56, 7012−7015.
(10) (a) Ramamohan, M.; Sridhar, R.; Raghavendrarao, K.; Paradesi,
N.; Chandrasekhar, K. B.; Jayaprakash, S. Simple and Highly Efficient
Synthesis of Indolo- and Pyrrolo[1,2-a]quinoxalines Promoted by
Molecular Iodine. Synlett 2015, 26, 1096−1100. (b) Wang, C.; Li, Y.;
Guo, R.; Tian, J.; Tao, C.; Cheng, B.; Wang, H.; Zhang, J.; Zhai, H.
Iodine-Catalyzed Facile Synthesis of Pyrrolo- and Indolo[1,2-
a]quinoxalines. Asian J. Org. Chem. 2015, 4, 866−869. (c) Patil, B.
N.; Lade, J. J.; Pardeshi, S. D.; Patil, P.; Chaskar, A. C. Polyethylene-
Glycol-(PEG-400) Mediated Environmentally Benign Protocol for
the Synthesis of Pyrrolo[1,2-a]quinoxalines from Benzyl Amines at
Room Temperature. ChemistrySelect 2019, 4, 11362−11366.
(d) Pardeshi, S. D.; Patil, B. N.; Patil, P.; Chaskar, A. C. A highly
divergent Pictet-Spengler approach for pyrrolo[1,2-a] quinoxalines
from aryl amine using 1,2-dinitrobenzene as an oxidant. Tetrahedron
Lett. 2019, 60, 151250.
(11) (a) Mani, G. S.; Rao, A. V. S.; Tangella, Y.; Sunkari, S.; Sultana,
F.; Namballa, H. K.; Shankaraiah, N.; Kamal, A. Molecular iodine-
catalysed oxidative CO−C(alkyl) bond cleavage of aryl/heteroaryl
alkyl ketones: an efficient strategy to access fused polyheterocycles.
New J. Chem. 2018, 42, 15820−15829. (b) Jiang, G.; Wang, S.; Zhang,
J.; Yu, J.; Zhang, Z.; Ji, F. Palladium-Catalyzed Primary Amine-
Directed Decarboxylative Annulation of α-Oxocarboxylic Acids:
Access to Indolo[1,2-a]quinazolines. Adv. Synth. Catal. 2019, 361,
1798−1802.
(12) (a) Lade, J. J.; Patil, B. N.; Vhatkar, M. V.; Vadagaonkar, K. S.;
Chaskar, A. C. An Efficient Synthesis of Pyrrolo[1,2-a]quinoxalines by
Copper-Catalyzed C−H Activation of Arylacetic Acids. Asian J. Org.
Chem. 2017, 6, 1579−1583. (b) Lecomte, M.; Lipshultz, J. M.; Kim-
Lee, S.-H.; Li, G.; Radosevich, A. T. Driving Recursive Dehydration
by PIII/PV Catalysis: Annulation of Amines and Carboxylic Acids by
Sequential C−N and C−C Bond Formation. J. Am. Chem. Soc. 2019,
141, 12507−12512.
(13) Xie, C.; Feng, L.; Li, W.; Ma, X.; Ma, X.; Liu, Y.; Ma, C.
Efficient synthesis of pyrrolo[1,2-a]quinoxalines catalyzed by a
Brønsted acid through cleavage of C−C bonds. Org. Biomol. Chem.
2016, 14, 8529−8535.
(14) Liu, H.; Zhou, F.; Luo, W.; Chen, Y.; Zhang, C.; Ma, C.
Application of α-amino acids for the transition-metal-free synthesis of
pyrrolo[1,2-a]quinoxalines. Org. Biomol. Chem. 2017, 15, 7157−7164.
(15) An, Z.; Zhao, L.; Wu, M.; Ni, J.; Qi, Z.; Yu, G.; Yan, R. FeCl3-
Catalyzed synthesis of pyrrolo[1,2-a]-quinoxaline derivatives from 1-
(2-aminophenyl)-pyrroles through annulation and cleavage of cyclic
ethers. Chem. Commun. 2017, 53, 11572−11575.
(16) (a) Wang, X.; Liu, H.; Xie, C.; Zhou, F.; Ma, C. Terminal
methyl as a one-carbon synthon: synthesis of quinoxaline derivatives
via radical-type transformation. New J. Chem. 2020, 44, 2465−2470.
(b) Kumar, G. R. Y.; Begum, N. S.; Imran, K. M. Mn-mediated
oxidative radical cyclization of 2-(azidomethyl)phenyl isocyanides
with carbazate: access to quinazoline-2-carboxylates. New J. Chem.
2020, 44, 7001−7006. (c) Zhao, J.; Li, P.; Xu, Y.; Shi, Y.; Li, F.
Nickel-Catalyzed Transformation of Diazoacetates to Alkyl Radicals
Using Alcohol as a Hydrogen Source. Org. Lett. 2019, 21, 9386−9390.
(d) Wei, W.-T.; Teng, F.; Li, Y.; Song, R.-J.; Li, J.-H. Oxidative [4+2]
Cycloaddition of α-(N-Arylamino) Carbonyls with Aryl Alkenes by
Multiple C−H Functionalizations and [1,2]-Aryl Shifts. Org. Lett.
2019, 21, 6285−6288. (e) Morel, B.; Franck, P.; Bidange, J.; Sergeyev,
S.; Smith, D. A.; Moseley, J. D.; Maes, B. U. W. Concise Xanthine
Synthesis through a Double-Amidination Reaction of a 6-Chlorouracil
(7) Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini, S.;
Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.; Goegan, M.;
Cervo, L.; Dalla Valle, F.; Fracasso, C.; Caccia, S.; Mennini, T.
Pyrroloquinoxaline Derivatives as High-Affinity and Selective 5-HT3
Receptor Agonists: Synthesis, Further Structure-Activity Relation-
ships, and Biological Studies. J. Med. Chem. 1999, 42, 4362−4379.
(8) (a) Gemma, S.; Colombo, L.; Forloni, G.; Savini, L.; Fracasso,
C.; Caccia, S.; Salmona, M.; Brindisi, M.; Joshi, B. P.; Tripaldi, P.;
Giorgi, G.; Taglialatela-Scafati, O.; Novellino, E.; Fiorini, I.;
Campiani, G.; Butini, S. Pyrroloquinoxaline hydrazones as fluorescent
probes for amyloid fibrils. Org. Biomol. Chem. 2011, 9, 5137−5148.
̈
(b) Çarbas,̧ B. B.; Kivrak, A.; Zora, M.; Onal, A. M. Synthesis of a
novel fluorescent and ion sensitive monomer bearing quinoxaline
moieties and its electropolymerization. React. Funct. Polym. 2011, 71,
̈
579−587. (c) Carbas, B. B.; Kivrak, A.; Zora, M.; Onal, A. M.
Synthesis and electropolymerization of a new ion sensitive ethyl-
enedioxy-substituted terthiophene monomer bearing a quinoxaline
moiety. J. Electroanal. Chem. 2012, 677−680, 9−14. (d) Patil, B. N.;
Lade, J. J.; Vadagaonkar, K. S.; Chetti, P.; Chaskar, A. C. Pyrrolo[1,2-
a]quinoxaline-Based Bipolar Host Materials for Efficient Red
Phosphorescent OLEDs. ChemistrySelect 2018, 3, 10010−10018.
(e) Lade, J. J.; Patil, B. N.; Sathe, P. A.; Vadagaonkar, K. S.; Chetti, P.;
Chaskar, A. C. Iron Catalyzed Cascade Protocol for the Synthesis of
Pyrrolo[1, 2-a]quinoxalines: A Powerful Tool to Access Solid State
Emissive Organic Luminophores. ChemistrySelect 2017, 2, 6811−
6817.
(9) (a) Wang, C.; Li, Y.; Zhao, J.; Cheng, B.; Wang, H.; Zhai, H. An
environmentally friendly approach to pyrrolo[1,2-a]quinoxalines
using oxygen as the oxidant. Tetrahedron Lett. 2016, 57, 3908−
3911. (b) Verma, A. K.; Jha, R. R.; Sankar, V. K.; Aggarwal, T.; Singh,
R. P.; Chandra, R. Lewis Acid-Catalyzed Selective Synthesis of
Diversely Substituted Indolo- and Pyrrolo[1,2-a]quinoxalines and
Quinoxalinones by Modified Pictet−Spengler Reaction. Eur. J. Org.
Chem. 2011, 2011, 6998−7010. (c) Krishna, T.; Reddy, T. N.;
Laxminarayana, E.; Kalita, D. Copper-Catalyzed One-Pot Synthesis of
Pyrrolo[1,2-a]quinoxaline Derivatives from 1-(2-Aminophenyl)-pyr-
roles and Aldehydes. ChemistrySelect 2019, 4, 250−253. (d) Preetam,
A.; Nath, M. An eco-friendly Pictet−Spengler approach to pyrrolo-
and indolo[1,2-a]quinoxalines using p-dodecylbenzenesulfonic acid as
an efficient Brønsted acid catalyst. RSC Adv. 2015, 5, 21843−21853.
(e) Allan, P. N. M.; Ostrowska, M. I.; Patel, B. Acetic Acid Catalysed
One-Pot Synthesis of Pyrrolo[1,2-a]quinoxaline Derivatives. Synlett
7401
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
with Amidines using Base-Metal Catalysis. ChemSusChem 2017, 10,
624−628.
(17) (a) Jang, Y.; Lee, S. B.; Hong, J.; Chun, S.; Lee, J.; Hong, S.
Synthesis of 2-aryl quinazolinones via iron-catalyzed cross-dehydro-
genative coupling (CDC) between N−H and C−H bonds. Org.
Biomol. Chem. 2020, 18, 5435−5441. (b) Lee, S. B.; Jang, Y.; Ahn, J.;
Chun, S.; Oh, D.-C.; Hong, S. One-Pot Synthesis of 4-Quinolone via
Iron-Catalyzed Oxidative Coupling of Alcohol and Methyl Arene. Org.
Lett. 2020, 22, 8382−8386.
(18) Inamdar, S. M.; Chakrabarty, I.; Patil, N. T. A unified approach
to pyrrole-embedded azaheterocyclic scaffolds based on the RCM/
isomerization/cyclization cascade catalyzed by a Ru/B-H binary
catalyst system. RSC Adv. 2016, 6, 34428−34433.
(19) Rubio-Presa, R.; Pedrosa, M. R.; Fernández-Rodríguez, M. A.;
Arnáiz, F. J.; Sanz, R. Molybdenum-Catalyzed Synthesis of Nitro-
genated Polyheterocycles from Nitroarenes and Glycols with Reuse of
Waste Reduction Byproduct. Org. Lett. 2017, 19, 5470−5473.
(20) Ni, J.; Jiang, Y.; Qi, Z.; Yan, R. TFAA-Catalyzed Annulation
Synthesis of Spiro Pyrrolo[1,2-a]quinoxaline Derivatives from 1-(2-
Aminophenyl)pyrroles and Benzoquinones/Ketones. Chem.Asian J.
2019, 14, 2898−2902.
(21) Schramm, S.; Agnetta, L.; Bermudez, M.; Gerwe, H.; Irmen,
M.; Holze, J.; Littmann, T.; Wolber, G.; Tränkle, C.; Decker, M.
Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands:
Orthosteric Carbachol Differentially Regulates Partial Agonism.
ChemMedChem 2019, 14, 1349−1358.
7402
https://doi.org/10.1021/acs.joc.1c00371
J. Org. Chem. 2021, 86, 7390−7402