Development of an unexpected reaction pathway for the synthesis of 1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines through palladium-catalyzed cascade reactions

Article abstract of DOI:10.1016/j.tet.2017.02.018

1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines are synthesized through the multi-component reaction of 3-substituted 2-chloroquinoxalines, propargyl bromide, and excess secondary amines in the presence of a palladium copper catalytic system. This one-pot process provides an unexpected synthesis of new trisubstituted pyrrolo[1,2-a]quinoxalines by the introduction of two amine substituents onto the fused pyrrole rings in a single reaction procedure. The compounds formed are fully characterized by the analytical spectral data and X-ray analysis. A number of synthesized pyrrolo[1,2-a]quinoxaline derivatives are also screened against the three bacterial strains Micrococcus luteus, Pseudomonas aeruginos, and Bacillus subtilis. According to the results obtained, compounds 3b, 3c, and 3e are active against M.?luteus, compounds 3b and 3e are active against Ps. Aeruginos, and only compound 3f is active against all the three bacterial strains.

Full text of DOI:10.1016/j.tet.2017.02.018

Accepted Manuscript
Development of an unexpected reaction pathway for the synthesis of 1,2,4-
trisubstituted pyrrolo[1,2-a]quinoxalines through palladium-catalyzed cascade
reactions
Ali Keivanloo, Atena Soozani, Mohammad Bakherad, Mahdi Mirzaee, Hadi Amiri
Rudbari, Giuseppe Bruno
PII:
S0040-4020(17)30143-6
10.1016/j.tet.2017.02.018
TET 28459
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 November 2016
Revised Date: 25 January 2017
Accepted Date: 6 February 2017
Please cite this article as: Keivanloo A, Soozani A, Bakherad M, Mirzaee M, Rudbari HA, Bruno G,
Development of an unexpected reaction pathway for the synthesis of 1,2,4-trisubstituted pyrrolo[1,2-
a]quinoxalines through palladium-catalyzed cascade reactions, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.02.018.
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ACCEPTED MANUSCRIPT
Development of an unexpected reaction pathway for the synthesis of 1,2,4-
trisubstituted pyrrolo[1,2-a]quinoxalines through palladium-catalyzed cascade
reactions
Ali Keivanloo*a, Atena Soozania, Mohammad Bakherada, Mahdi Mirzaeea, Hadi Amiri
Rudbarib, Giuseppe Brunoc
N
N
NR1
NR2
2
R22NH
+
Pd(PPh3)2Cl2
CuI
N
N
NR1
Cl
2
Br
+
70 oC
R22N
R22NH
2
One-pot
R22NH: morpholine
piperidine
R12NH: morpholine
pyrrolidine
Multicomponent
Regioselective
pyrrolidine
piperidine
diethylamine

ACCEPTED MANUSCRIPT
Development of an unexpected reaction pathway for the synthesis of
1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines through palladium-
catalyzed cascade reactions
Ali Keivanloo*a, Atena Soozania, Mohammad Bakherada, Mahdi Mirzaeea, Hadi
Amiri Rudbarib, Giuseppe Brunoc
a
School of Chemistry, Shahrood University of Technology, Shahrood, 36199-95161
Iran. E-mails: akeivanloo@yahoo.com, keivanloo@shahroodut.ac.ir
b Department of Chemistry, University of Isfahan, 81746-73441 Iran.
c Department of Chemical Sciences, University of Messina, Via F. Stagno d’Alcontres
31, 98166 Messina, Italy.
Abstract- 1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines are synthesized through the
multi-component reaction of 3-substituted 2-chloroquinoxalines, propargyl bromide,
and excess secondary amines in the presence of a palladium copper catalytic system.
This one-pot process provides an unexpected synthesis of new trisubstituted
pyrrolo[1,2-a]quinoxalines by the introduction of two amine substituents onto the
fused pyrrole rings in a single reaction procedure. The compounds formed are fully
characterized by the analytical spectral data and X-ray analysis. A number of
synthesized pyrrolo[1,2-a]quinoxaline derivatives are also screened against the three
bacterial strains Micrococcus luteus, Pseudomonas aeruginos, and Bacillus subtilis.
According to the results obtained, compounds 3b, 3c, and 3e are active against M.
luteus, compounds 3b and 3e are active against Ps. Aeruginos, and only compound 3f
is active against all the three bacterial strains.
Introduction
Quinoxaline derivatives display a broad spectrum of biological activities
including anti-microbial,1-3 anti-inflammatory,4 anti-cancer,5-7 anti-malarial,8
1

ACCEPTED MANUSCRIPT
anti-tubercular9 and PI3Kα inhibitory properties.10 Some quinoxaline
derivatives have a cytotoxic effect on the human cancer cell lines,11 and in
addition, the quinoxaline moiety constitutes a part of the chemical structure of
various antibiotics such as echinomycin, levomycin, and actinoleutin.12
Pyrrolo[1,2-a]quinoxalines are an important class of organic compounds
present in various biologically active materials, which exhibit a wide variety of
important physiological and biological properties (Fig. 1). For example,
compound
A
exhibits a highly potent 5-HT3 receptor agonist activity.13
]quinoxaline is well-known as an anti-mycobacterial
Likewise, Pyrrolo[1,2-
a
B
agent.14 The anti-tumor activity of JG454 has been confirmed against the
human leukemic cell lines K562, U937, and HL60, and the breast cancer cell
line MCF7.15 Therefore, the development of a novel and highly efficient
strategy to construct these fused angular heterocyclic architectures is highly
desirable for drug discovery.
O
NH
NH2
N
N
N
N
F3C
N
N
CH3
5-HT3 receptor agonist
antimycobacterial activity
A
B
N
N
N
N
O
N
anticancer activity
JG454
Fig. 1 Structures of drugs based on pyrrolo[1,2-a]quinazoline scaffold.
2

ACCEPTED MANUSCRIPT
Many procedures have been reported for the synthesis of pyrrolo[1,2-
a]quinoxalines, although most of them feature disadvantages such as multi-step
reactions and of lack generality. The most common protocol for the synthesis of
pyrrolo[1,2-a]quinoxalines includes cyclization of functionalized pyrrole
derivatives.16-23 Two recent examples of this strategy include the one-pot
synthesis of pyrrolo[1,2-a]quinoxalines via a copper-catalyzed aerobic
oxidative domino reaction of α-amino acids with 1-(2-halophenyl)-1
H-
pyrroles24 and the iron-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from
1-(N-arylpyrrol-2-yl)ethanone O-acetyl oximes through N−O bond cleavage
and intramolecular directed C−H arylation reactions in acetic acid.25
The development of more efficient methods for the preparation of these
compounds is still an active research area. A literature survey shows that the
synthesis of pyrrolo[1,2-a]quinoxalines, starting from the quinoxaline moiety,
has been under explored. Consequently, the development of new synthetic
methods and strategies for the synthesis of pyrrolo[1,2-a]quinoxaline
derivatives from the quinoxaline scaffold are important.
The palladium-catalyzed coupling/annulation reactions of terminal alkynes with
aryl and hetero-aryl halides have been successfully employed for the synthesis
of a variety of heterocyclic compounds.26 This process involves a two-step
reaction, an initial palladium-catalyzed carbon-carbon bond formation and the
subsequent intramolecular hetero-annulation of the resulting internal alkynes
with suitable nucleophiles in proximity to the triple bond. In the present work,
we used this strategy for the successful synthesis of pyrrolo[1,2-a]quinoxalines
via palladium-catalyzed cascade reactions.
3

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Results and discussion
In continuation of our interest in exploring new strategies for the synthesis of
fused heterocyclic compounds through palladium-catalyzed reactions,27-32 we
decided to synthesize trisubstituted pyrrolo[1,2-a]quinoxalines 3a-g, from the
multi-component reactions of 3-substituted 2-chloroqunoxalines 1a-c
,
propargyl bromide , and secondary amines (Scheme 1). 3-Substituted 2-
2
chloroqunoxalines were prepared from the reaction of 2,3-dichloroquinoxaline
with secondary amines in acetonitrile at 80 °C.32
Scheme 1. Palladium-catalyzed synthesis of 1,2,4-trisubstituted pyrrolo[1,2-
a]quinoxalines from 3-substituted 2-chloroquinoxaline, propargyl bromide and
secondary amines.a
.
N
N
NR1
2
R2 NH
Pd(PPh3)2Cl2
CuI
2
N
NR1
Cl
2
Br
+
+
70 oC
N
R2 N
2
R2 NH
NR2
2
One-pot
2
2
3a-h
1a-c
R1 NH: morpholine, pyrrolidine, piperidine
2
R2 NH: morpholine, piperidine, pyrrolidine, diethylamine
2
a
Reaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), Pd(Ph3P)2Cl2 (0.05 mmol), CuI
(0.1 mmol), secondary amine as solvent (3 mL), 70 ºC, 18 h.
We have recently reported the synthesis of 1,4-disubstituted pyrrolo[1,2-
a]quinoxalines from 3-substituted 2-chloroquinoxaline, propargyl alcohol, and cyclic
secondary amines such as morpholine, piperidine and pyrrolidine, in which amine
substitution was carried out at position 1 of this fused heterocyclic system (Scheme
2).32 In that work, we used 3 equiv. of a secondary amine and 3 equiv. of K2CO3 in
water.
4

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Scheme 2. Synthesis of 1,4-disubstituted pyrrolo[1,2-a]quinoxalines from 3-
substituted 2-chloroquinoxalines, propargyl alcohol and secondary amine in the
presence of Pd/Cu in water
N
N
Nu
N
N
Nu
Cl
Pd/Cu
R2NH
+
+
OH
K2CO3
H2O
R2N
NuH: morpholine, pyrrolidine, piperidine, methanol, ethanol
R2NH: morpholine, piperidine, pyrrolidine
In the present work, we used propargyl bromide instead of propargyl alcohol, and
carried out the reactions with excess amounts of the amines, which acted,
simultaneously, as the reactant, base, and solvent. When 2-chloro-3-(morpholin-4-
yl)quinoxaline 2a was reacted with propargyl bromide 3 in the presence of 5 mol% of
Pd(PPh3)2Cl2 and 10 mol% of CuI in 3 mL of piperidine at 70 °C, surprisingly, a new
compound was formed, which was characterized as 4-(morpholin-4-yl)-1,2-
di(piperidin-1-yl)pyrrolo[1,2-a]quinoxaline (4d) (Scheme 3).
Scheme 3. Reaction of 2-chloro-3-(morpholin-4-yl)quinoxaline 1a with propargyl
bromide 2 in piperidine to afforded 4-(morpholin-4-yl)-1,2-di(piperidin-1-
yl)pyrrolo[1,2-a]quinoxaline (3d)
O
O
N
N
N
N
N
N
N
Pd(PPh3)2Cl2
+
Br
+
3d
CuI
70 °C
Cl
N
N
H
2
1a
1
The H NMR spectrum of this compound showed two multiplets at δ9.38-9.40 and
δ7.63-7.65, which were characteristics of two aromatic protons at positions 9 and 5 of
the quinxoline ring, respectively. The other two aromatic protons of this ring appeared
5

ACCEPTED MANUSCRIPT
at δ7.25–7.65. The singlet at δ6.62 was assigned to a proton at position 3 in the fused
pyrrole ring. In the aliphatic region, the 26 protons of the morpholine and piperidines
substituents appeared at δ1.38-3.92. Mass spectrometer recorded the molecular ion
peak at m/z 421 for this compound. It was also crystallized from ethanol in the form
of yellow needles and was characterized by single crystal X-ray crystallography. This
analysis showed that it was crystallized in monoclinic system with space group P21/n
and there was also four molecules in each unit cell. Fig. 2 shows a perspective view of
the molecular structure of 3d.
Figure 2 ORTEP representation for 3d. Displacement ellipsoids are drawn at the 50%
probability level and H atoms are shown as small spheres of arbitrary radii. CCDC
1488186 contains the supplementary crystallographic data for this article.
6

ACCEPTED MANUSCRIPT
In order to optimize the reaction conditions, we chose the reaction of 2-chloro-3-
(morpholin-4-yl)quinoxaline (1a) with propargyl bromide (2) and morpholine as the
model system. To find the optimal reaction conditions for the synthesis of 1,2,4-
tri(morpholin-4yl)pyrrolo[1,2-a]quinoxaline (3c), the effects of various parameters on
the reaction were studied, and the results obtained were tabulated in Table 1. Several
catalytic palladium sources such as Pd(PPh3)2Cl2, Pd(OAc)/PPh3, Pd(dba)2/PPh3, and
Pd/C/PPh3 were screened in the presence or absence of copper iodide in different
solvents and bases. It was obvious that the use of Pd(PPh3)2Cl2 in the presence of the a
copper salt in excess amounts of the secondary amine, were the best reaction
conditions. The use of a solvent such as CH3CN, DMF, and water, in addition to, the
use of a tertiary amine or K2CO3 as the base, changed the reaction pathway, and
produced 1,4-disubstituted pyrrolo[1,2-a]quinoxalines (3cc) as the major product on
the basis of chromatography separation.
Table 1: Optimization table for one-pot synthesis of 1,2,4-tri(morpholin-)pyrrolo[1,2-
a]quinoxaline.a
O
O
N
N
N
N
N
N
N
O
Br
O
N
N
N
Catalyst
+
+
+
Base
N
H
Cl
N
N
Solvent
3c
3cc
O
O
1a
O
2
Yield (%)
Co-
catalyst
Entry Solvent
Base
Catalyst
Pd/C/Ph3P
3cc
3c
10
1
2
3
4
Morpholine Morpholine
Morpholine Morpholine
Morpholine Morpholine
Morpholine Morpholine
-
-
-
-
-
Pd(dba)2/ Ph3P
Pd(OAc)2/Ph3P
Pd(PPh3)2Cl2
-
20
55
80
CuI
CuI
7

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5
Morpholine Morpholine
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
-
-
45
-
6
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Morpholine
Morpholine
Et3N
CuI
-
75
7
30
60
55
65
70
45
25
-
8
CuI
CuI
CuI
CuI
CuI
CuI
-
9
DIEA
-
10
11
12
13
Et3N
-
DMF
Morpholine
K2CO3
-
DMF
-
H2O
K2CO3
-
aReaction conditions: 1a (1.0 mmol), 2 (1.2 mmol), morpholine (3 mL), catalyst (0.05
mmol), CuI (0.1 mmol), 70 °C, 18 h.
In order to explore the scope and generality of this protocol, a number of 3-
substituted 2-chloroquinoxalines (1a-c) were reacted with propargyl bromide
(3) in the presence of Pd(PPh3)2Cl2 at 70 °C in an excess amount of a variety of
secondary amines such as morpholine, piperidine, pyrrolidine, and
diethylamine. The desired products, 1,2,4-trisubstituted pyrrolo[1,2-
a]quinoxalines (3a-g), were obtained in good-to-high yields. The results
obtained are shown in Table 2. The structural assignments of the products were
based upon the NMR spectroscopic and mass analysis data.
Table 2. Synthesis of 1,2,4-trisubstituted pyrrolo[1,2-a]quinoxalines.a
Entry
Substrate
1
Product
3
Yield
(%)
N
N
N
N
N
N
N
1
70
Cl
N
O
O
3a
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N
N
N
N
N
N
N
2
3
4
82
80
85
N
Cl
O
3b
O
O
N
N
N
N
O
N
N
N
Cl
N
O
O
3c
O
N
N
O
N
N
N
N
N
N
Cl
3d
N
N
N
N
N
N
5
70
80
60
N
Cl
N
3e
N
N
6
N
N
N
N
Cl
N
N
3f
O
N
N
O
N
N
N
7
N
Cl
N
N
3g
aReaction conditions: 1 (1.0 mmol), 2 (1.2 mmol), Pd(PPh3)2Cl2 (0.05 mmol), CuI
(0.1 mmol), secondary amine as solvent (3 mL), 70 ºC, 18 h, argon atmosphere.
9

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When 2-chloro-3-methoxyquinoxalines (1d) or 2-chloro-3-ethoxyquinoxalines (1e)
were used as the starting materials, as a result of a simultaneous nucleophilic
substitution, the alkoxy group was replaced by the secondary amines under the
specified reaction conditions, and the 1,2,4-triaminopyrrolo[1,2-a]quinoxalines 3d
and 3e were formed as the major products (Scheme 4).
Scheme 4. Reaction of 2-chloro-3-alkoxyquinoxalines with propargyl bromide and
secondary amines in the presence of Pd-Cu catalyst.
N
N
NR2
NR2
N
N
OR
Cl
Pd(PhPh3)2Cl2
+
Br
R2NH
+
CuI
70 °C
R2N
2
1d R = CH3
3d R2NH = morpholine (75%)
3e R2NH = piperidine (68%)
1e R = C2H5
A plausible multi-step mechanism can be proposed for the reaction (Scheme 5). First,
a standard Sonogashira coupling took place by a Pd(0)-catalyzed reaction to give the
hetero-aryl alkyne intermediate A. This was followed by the regioselective amine
nucleophilic attack on the triple bond of the conjugated alkyne to produce the allene
intermediate B, base-catalyzed isomerization to the amino dyne intermediate C,
isomerization to the iminimum ion D, and intramolecular cyclization to the fused ring
system E. Finally, the aerial oxidation and aromatization of E afforded the final
product (3).
Scheme 5. Proposed mechanism for formation of 1,2,4-trisubstituted pyrrolo[1,2-
a]quinoxalines from 3-substituted 2-chloroquinoxalines, propargyl bromide, and
secondary amines.
10

ACCEPTED MANUSCRIPT
N
N
Nu
Cl
Br
NR2
+
R2NH
Sonogashira coupling
N
Nu
N
Nu
C
N
Nu
H+
NHR2
H+
N
H
N
H
NR2
H
N
NR2
H
NR2
NR2
B
C
NR2
A
N
Nu
N
N
Nu
N
N
Nu
H+
H2
N
H
[O]
NR2
R2N
R2N
NR2
NR2
NR2
E
D
Anti-bacterial assay
A number of newly synthesized pyrrolo[1,2-a]quinoxalines were screened for their in
vitro anti-bacterial activity against the Gram-positive and Gram-negative bacteria
Micrococcus luteus (M. luteus), Pseudomonas aeruginos (Ps. aeruginos), and
Bacillus subtilis (B. subtilis) using the well-diffusion method. DMSO was used as the
negative control, showing no activity against the above-mentioned bacterial strains,
and tetracycline was used as the positive control. The results obtained were tabulated
in Table 3. Compounds 3b-f were evaluated for their anti-bacterial activity at a
concentration of 1000 ꢀg mL-1 in DMSO. The results obtained were reported as the
inhibition zone in mm. According to these results, the three compounds 3b, 3c, and 3e
were active against M. luteus. Compounds 3b and 3e showed anti-bacterial activities
against Ps. Aeruginos. Only 3f was active against all the three bacterial strains.
11

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Table 3: Anti-bacterial activities of selected compounds (1000 ꢀg mL-1) as inhibition
zone in mm.
Entry
Compound B. subtilis
M. luteus
Ps. aeruginos
1
2
3
4
5
6
7
8
-
9
8
-
8
-
3b
3c
-
-
3d
-
7
9
-
8
9
--
13
3e
8
-
3f
DMSO
tetracycline 15
41
Conclusion
We have successfully demonstrated a rare efficient palladium-catalyzed one-pot
reaction for the construction of a variety of novel 1,2,4-trisubstituted pyrrolo[1,2-
a]quinoxlines from 2-chloro-3-substituted quinoxalines, propargyl bromide, and
excess secondary amines. The Sonogashira coupling reaction, amine nucleophilic
addition to the triple bond, and cyclization were realized in a cascade. A number of
synthesized pyrrolo[1,2-a]quinoxaline derivatives were screened against the three
bacterial strains Micrococcus luteus (M. luteus), Pseudomonas aeruginos (Ps.
aeruginos), and Bacillus subtilis (B. subtilis). According to the results obtained,
compounds 3b, 3c, and 3e are active against M. luteus, compounds 3b and 3e are
active against Ps. Aeruginos, and only compound 3f is active against all the three
bacterial strains.
12

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Experimental
General method
Palladium(II) salts and propargyl bromide were supplied from Sigma-Aldrich
Chemical Company. Triphenylphosphine, secondary amines, thin-layer
chromatography (TLC) plates, silica gel (of particle size of 100 mesh), and all
the solvents used were obtained from Merck. Melting points were recorded on a
Thermocouple digital melting point apparatus. IR spectra were recorded on a
Shimadzu IR-435 grating spectrophotometer. NMR spectra were recorded on a
1
13
Bruker 400 MHz H NMR, 100 MHz C spectrometer. 1H NMR spectra were
reported relative to Me4Si (δ0.0 ppm) or residual CHCl3 (δ7.26 ppm). 13C NMR
spectra were reported relative to CDCl3 (δ77.16 ppm). Multiplicities were
described using the following abbreviations: s = singlet, d = doublet, t = triplet,
and m = multiplet. Mass spectra were recorded on a 5975C spectrometer
supplied from Agilent Technologies Company.
General procedure for synthesis of 3-amino-substituted 2-
chloroquinoxalines
A mixture of 2,3-dichloroquinoxaline (1 mmol) and a secondary amine (2
mmol) in acetonitrile was refluxed for 5 h until the complete consumption of
the starting materials (monitored by TLC). After evaporation of the solvent, the
resulting precipitate was washed with H2O; it did not require any further
purification.32
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General procedure for synthesis of 3-alkoxy-substituted 2-
chloroquinoxalines
A mixture of sodium (1 mmol) and an alcohol (3 mL) was stirred for 15 min at
room temperature. Then 2,3-dichloroquinoxaline (1 mmol) was added to the
mixture until the complete consumption of the starting materials (monitored by
TLC). After evaporation of the solvent, the resulting precipitate was washed
with H2O; it did not require any further purification.32
General procedure for preparation of 1,2,4-trisubstituted pyrrolo[1,2-
a]quinoxalines 3a-g
A mixture of a 3-substituted 2-chloroquinoxaline
amine (3 mL), Pd(PPh3)2Cl2 (0.05 mmol), and CuI (0.1 mmol) was stirred at 0
°C under an argon atmosphere for 15 min. Propargyl bromide (1.2 mmol) was
1 (1.0 mmol), a secondary
2
added, and the resulting mixture was stirred at 80 °C for 18 h. After completion
of the reaction, the solvent was evaporated, and the resulting solid was washed
with H2O and then dried. The crude product was purified by column
chromatography using CHCl3/CH3OH (98:2) as the eluent.
1,2-di(Morpholin-4-yl)-4-(pyrrolidin-1-yl)pyrrolo[1,2-a]quinoxaline 3a
1
Yellow solid; mp 248–249 °C; Rf (95% CHCl3/CH3OH) 0.57; H NMR (400
MHz, CDCl3): δ 9.37 (d,
J = 8.4, 1H, ArH), 7.66 (d, J = 7.6, 1H, ArH), 7.20–
7.33 (m, 2H, ArH), 6.86 (s, 1H, CH of pyrrole), 3.86–3.94 (m, 12H, 6CH2),
3.72–3.76 (m, 2H, NCH2), 3.00–3.29 (m, 2H, NCH2), 2.93–2.94 (m, 4H,
13
NCH2), 2.01 (m, 4H, CH2); C NMR (100 MHz, CDCl3): δ 49.1, 51.3, 55.2,
55.2, 67.3, 67.4, 99.1, 100.4, 116.3, 123.8, 124.7, 126.1, 126.5, 127.7, 134.2,
14

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136.0, 136.7, 153.0; IR ʋ (KBr): 3056, 2950, 2850, 1508, 1493, 1105, 728 cm-1.
m/z [M]+ 407. Anal. Calcd for C23H29N5O2: C, 67.79; H, 7.17; N, 17.19%.
Found: C, 67.68; H, 7.11; N, 17.15%.
1,2-di(Morpholin-4-yl)-4-(piperidin-1-yl)pyrrolo[1,2-a]quinoxaline 3b
1
Yellow solid; mp 237–239 °C; Rf (95% CHCl3/CH3OH) 0.51; H NMR (400
MHz, CDCl3) δ 9.35 (dd,
J = 8.4, 1.6 Hz, 1H), 7.64 (dd, J = 8.0, 1.4 Hz, 1H,
ArH), 7.20–7.30 (m, 2H, ArH), 6.66 (s, 1H, CH of pyrrole), 3.86–3.95 (m, 8H,
4OCH2), 3.71–3.77 (m, 2H, NCH2), 3.57–3.59 (m, 4H, 2NCH2), 2.99–3.02 (m,
13
2H, OCH2), 2.95 (t,
J = 4.4 Hz , 4H, 2NCH2), 1.71–1.77 (m, ,6H, 3CH2); C
NMR (100 MHz, CDCl3): δ 25.1, 26.1, 50.0, 51.3, 55.3, 67.4, 67.5, 76.7, 77.0,
77.3, 99.2, 115.6, 116.3, 123.2, 124.6, 127.5, 127.5, 134.0, 136.5, 137.1, 153.7;
IR ʋ (KBr): 3056, 2950, 2850, 1510, 1495, 1400, 1105, 929, 730 cm-1. m/z
[M]+ 421. Anal. Calcd for C24H31N5O2: C, 68.38; H, 7.41; N, 16.61%. Found:
C, 68.52; H, 7.28; N, 16.42%.
1,2,4-tri(Morpholin-4-yl)pyrrolo[1,2-a]quinoxaline 3c
1
Yellow solid; mp 269–271 °C; Rf (95% CHCl3/CH3OH) 0.60; H NMR (400
MHz, CDCl3) δ 9.34 (dd,
J = 8.2, 1.4 Hz, 1H, ArH), 7.63 (dd, J = 7.8, 1.8 Hz,
1H, ArH), 7.23–7.30 (m, 2H, ArH), 6.62 (s,1H, CH of pyrrole), 3.83-3.93 (m,
12H, 6OCH2), 3.69–3.75 (m, 2H, NCH2), 3.59–3.61 (m, 4H, 2NCH2), 2.98 (m,
13
2H, NCH2), 2.91 (t,
J = 4.8Hz, 4H, 2NCH2). C NMR (100 MHz, CDCl3): δ
49.4, 51.3, 55.3, 67.0, 67.3, 67.4, 99.1, 115.2, 116.3, 123.8, 124.7, 127.7, 127.8,
134.2, 136.7, 136.7, 153.0; IR ʋ (KBr): 3056, 2950, 2850, 1550, 1495, 1400,
15

ACCEPTED MANUSCRIPT
1105, 990, 730 cm-1. m/z [M]+ 423. Anal. Calcd for C23H29N5O3: C, 65.23; H,
6.90; N, 16.54%. Found: C, 64.98; H, 6.80; N, 16.60%.
4-(Morpholin-4-yl)-1,2-di(piperidin-1-yl) pyrrolo[1,2-a]quinoxaline 3d
1
Yellow solid; mp 170–171 °C; Rf (95% CHCl3/CH3OH) 0.66; H NMR (400
MHz, CDCl3) δ 9.38–9.41(m,1H, ArH), 7.63–7.65 (m, 1H, ArH), 7.24–7.28 (m,
2H, ArH), 6.61 (s, 1H, CH of pyrrole), 3.91 (t,
J
= 4.4 Hz, 4H, 2OCH2), 3.63 (t,
J
= 4.4 Hz, 4H, 2NCH2), 3.39–3.45 (m, 2H, NCH2), 3.14 (m, 2H, NCH2), 2.85
(t,
J
= 5.2 Hz, 4H, 2NCH2), 1.384–1.917 (m, 12H, 6CH2). 13C NMR (100 MHz,
CDCl3): δ 24.2, 24.2, 26.2, 26.4, 49.5, 51.9, 56.3, 67.1, 99.0, 114.4, 116.8,
123.5, 124.2, 127.4, 128.0, 135.8, 136.6, 137.8, 153.1; IR ʋ (KBr): 3056, 2950,
2850, 1510, 1493, 1400, 1105, 729 cm-1. m/z [M]+ 419. Anal. Calcd for
C25H33N5O: C, 71.57; H, 7.93; N, 16.69%. Found: C, 71.64; H, 7.68; N,
16.51%.
1,2,4-tri(Piperidin-1-yl)pyrrolo[1,2-a]quinoxaline 3e
1
Yellow solid; mp 134–135 °C; Rf (95% CHCl3/CH3OH) 0.63; H NMR (400
MHz, CDCl3) δ 9.37 (d,
J = 8.0 Hz, 1H, ArH), 7.61 (d, J = 7.6 Hz, 1H, ArH),
7.18–7.23 (m, 2H, ArH), 6.62 (s, 1H, CH of pyrrole), 3.57 (d,
J
= 4.8 Hz, 4H,
2NCH2), 3.41 (m, 2H, NCH2), 3.14 (m, 2H, NCH2), 2.86 (t,
J = 4.6 Hz, 4H,
13
2NCH2), 1.56–1.90 (m, 18H, 9CH2). C NMR (100 MHz, CDCl3): δ 24.2,
24.3, 25.1, 26.2, 26.3, 26.7, 50.1, 52.0, 56.2, 99.0, 114.8, 116.7, 122.9, 124.1,
127.1, 127.9, 135.5, 137.0, 137.7, 153.9; IR ʋ (KBr): 3056, 2950, 2850, 1510,
1495, 1385, 1103, 725 cm-1. m/z [M]+ 417. Anal. Calcd for C26H35N5: C, 74.78;
H, 8.45; N, 16.77%. Found: C, 74.57; H, 8.50; N, 16.71%.
16

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1,2-di(Piperidin-1-yl)-4-(pyrrolidin-1-yl)pyrrolo[1,2-a]quinoxaline 3f
1
Yellow solid; mp 160–161 °C; Rf (95% CHCl3/CH3OH) 0.55; H NMR (400
MHz, CDCl3) δ 9.36 (dd,
1H, ArH), 7.16-7.23 (m, 2H, ArH), 6.60 (s, 1H, CH of pyrrole), 3.55 (t,
Hz, 4H, 2NCH2), 3.40 (m, 2H, NCH2), 3.12 (m, 2H, NCH2), 2.84 (t, = 5.2 Hz,
J
=8.0, 1.6 Hz, 1H, ArH), 7.60 (dd,
J
= 8.0, 1.8 Hz,
J
= 5.5
J
4H, 2NCH2), 1.55–1.80 (m, 16H, 8CH2). 13C NMR (100 MHz, CDCl3): δ 24.2,
24.2, 26.2, 26.2, 26.3, 50.06, 51.3, 56.2, 99.1, 114.8, 116.7, 122.9, 124.0, 125.4,
127.0, 127.9, 135.5, 137.0, 137.7, 153.9; IR ʋ (KBr): 3056, 2950, 2850, 1510,
1495, 1400, 725 cm-1. m/z [M]+ 403. Anal. Calcd for C25H33N5: C, 74.40; H,
8.24; N, 17.35%. Found: C, C, 74.22; H, 8.28; N, 17.18%.
N1,N1,N2,N2-tetraethyl-4-(Morpholin-4-yl)pyrrolo[1,2-a]quinoxaline-1,2-
diamine 3g
Yellow viscos oil; Rf (95% CHCl3/CH3OH) 0.65; 1H NMR (400 MHz, CDCl3)
δ 9.42 (dd,
J = 8.5, 1.4 Hz, 1H, ArH), 7.66 (dd, J = 7.8, 1.4 Hz, 1H, ArH),
7.21–7.29 (m, 2H, ArH), 6.60 (s, 1H, CH of pyrrole), 3.89–3.93 (m, 4H,
2OCH2), 3.63–3.65 (m, 4H, 2NCH2), 3.42–3.48 (m, 2H, NCH2), 3.13–3.21 (m,
13
2H, NCH2), 2.94 (m, 4H, 2NCH2), 0.98–1.09 (m, 12H, 4CH3). C NMR (100
MHz, CDCl3): δ 13.0, 13.3, 47.9, 49.4, 49.5, 67.0, 99.9, 116.8, 117.2, 123.3,
124.0, 127.4, 128.0, 133.5, 136.4, 136.5, 152.9; IR ʋ (KBr): 3056, 2950, 2850,
1510, 1495, 1102, 730 cm-1. m/z [M]+ 395. Anal. Calcd for C23H33N5O: C,
69.84; H, 8.41; N, 17.60%. Found: C, 69.67; H, 8.52; N, 17.46%.
Anti-bacterial assay
17

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The anti-bacterial activities of pyrrolo[1,2-a]quinazolines were evaluated
biologically using a well-diffusion method. First the nutrient agar and nutrient
broth cultures were prepared according to the manufacturer’s instructions, and
◦
they were then incubated at 37 C. After incubation for the appropriate time
period, a suspension of 30 ꢀL of each bacterium was added to the nutrient agar
plates. Cups (5 mm in diameter) were cut in the agar using a sterilized glass
tube. Each well received 30 ꢀL of the test compounds at a concentration of
◦
1000 ꢀg
/
ml in DMSO. Then the plates were incubated at 37 C for 24 h, after
which time, the inhibition zone was measured. The values were expressed in
millimeters (mm). The anti-bacterial activity of each pyrrolo[1,2-a]quinazoline
was compared with that for PenicillinGand as the standard. DMSO was used as
the negative control.
Acknowledgment
The authors wish to express their thanks to the Research Council of Shahrood
University of Technology for the financial support of this research work.
Supplementary data
Supplementary data (Crystallography data and copies of the 1H and 13C spectra
of all new compounds were provided.) related to this article can be found
at………..
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