One-pot synthesis of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines via palladium-catalyzed heteroannulation in water

Article abstract of DOI:10.1016/j.tetlet.2010.02.123

The reaction of N-alkyl-3-chloroquinoxaline-2-amines with 1-alkynes, catalyzed by Pd-Cu, in the presence of sodium lauryl sulfate as the surfactant in water, leads to the one-pot formation of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines in good-to-high yields.

Full text of DOI:10.1016/j.tetlet.2010.02.123

Tetrahedron Letters 51 (2010) 2409–2412
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Tetrahedron Letters
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One-pot synthesis of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines
via palladium-catalyzed heteroannulation in water
*
Ali Keivanloo , Mohammad Bakherad, Amin Rahimi, Sayed Ali Naghi Taheri
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of N-alkyl-3-chloroquinoxaline-2-amines with 1-alkynes, catalyzed by Pd–Cu, in the pres-
ence of sodium lauryl sulfate as the surfactant in water, leads to the one-pot formation of 1,2-disubsti-
tuted pyrrolo[2,3-b]quinoxalines in good-to-high yields.
Received 14 January 2010
Revised 10 February 2010
Accepted 19 February 2010
Available online 24 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Pyrroloquinoxaline
Alkyne
Sonogashira reaction
1. Introduction
eral examples of Pd-catalyzed Sonogashira reactions in aqueous
medium have been reported.18
Quinoxaline and its derivatives show a broad spectrum of bio-
logical activity including antitumor,1 antiviral,2 antituberculosis,3
and anti-inflammatory,4,5 and hence are an important class of
nitrogen-containing heterocycles, and useful intermediates in or-
ganic synthesis.6,7 Furthermore, pyrrolo[1,2-a]quinoxalines have
been shown to be potent and selective 5-HT3 receptor ligands.8
As a result, a number of synthetic strategies have been developed
for the preparation of substituted quinoxalines.9
The Sonogashira reaction catalyzed by palladium and copper is a
powerful andstraightforwardmethodforthe constructionofarylated
internal alkyne compounds.10 These are important intermediates in
organic synthesis and for the preparation of natural products,11 bio-
logically active molecules,12 molecular electronics,13 and polymers.14
Typical Sonogashira reactions are generally performed in the
presence of large amounts of palladium, and copper(I) iodide as a
co-catalyst in organic solvents, which can be expensive and are det-
rimental to the environment. This protocol has been improved by
several modifications, such as carrying out the reaction in aqueous
medium, in an ionic liquid or under microwave irradiation,15 along
with the use of promoters (Zn, Mg, and Sn) or effective ligands.16
The use of water or aqueous solutions represents a technique to
overcome the economical and the environmental problems caused
by the use of organic solvents for metal-catalyzed reactions.17 Sev-
In continuation of our recent studies19 on the Pd-catalyzed reac-
tion of acetylenes leading to heterocyclic compounds of biological
significance, we became interested in developing a synthetic route
to 1,2-disubstituted pyrrolo[2,3-b]quinoxalines in water.
In this Letter, a direct and convenient approach to the synthesis
of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines in water is pre-
sented. In order to introduce two substituents on the pyrrolo[2,3-
b]quinoxaline-fused system, our retrosynthetic analysis implicated
the use of 1-alkynes and N-alkyl-3-chloroquinoxaline-2-amines as
the starting materials. Palladium-catalyzed cross-coupling cycliza-
tion is the key step in this synthesis (Scheme 1).
The starting materials 2a–d were prepared from 2,3-dichloro-
quinoxaline 1 and primary alkyl amines in ethanol at reflux
(Scheme 2).20
1,2-Disubstituted pyrrolo[2,3-b]quinoxalines 4a–f were synthe-
sized by the reaction of N-alkyl-3-chloroquinoxaline-2-amines
2a–d with alkynes 3a–c in the presence of palladium chloride,
triphenylphosphine, copper(I) iodide, sodium lauryl sulfate, and
potassium carbonate at 70 °C in water under an argon atmosphere
(Scheme 3). The results are shown in Table 1.
Although PdCl2/PPh3 was the catalyst of choice, the addition of
copper(I) iodide was essential as the co-catalyst. The reactions car-
ried out with PdCl2 alone led to poor yields of mixtures of products.
Potassium carbonate was found to be a suitable base for the reac-
tion giving cleaner products and better yields. The choice of surfac-
tant was also critical for the success of the reaction as, without
surfactant, the yields were lower than 10%.
* Corresponding author. Fax: +98 2733395441.
E-mail addresses: akeivanloo@yahoo.com, keivanloo@shahroodut.ac.ir (A. Kei-
vanloo).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.123

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A. Keivanloo et al. / Tetrahedron Letters 51 (2010) 2409–2412
2
R
N
N
N
N
N
N
Cl
2
R2
C
CH
R
+
+
N
NH
NH
1
R
1
1
R
R
N
N
Cl
1
R
NH
2
Cl
Scheme 1. Reterosynthetic analysis of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines.
for 20 h. After completion of the reaction, the mixture was filtered,
and the remaining solid was washed with H2O and dried. The crude
product was purified by column chromatography using CHCl3–
CH3OH (98:2) as eluent.
N
N
Cl
N
N
Cl
EtOH
R1
NH2
+
NH
R1
Cl
2.1. 1-Methyl-2-phenyl-1H-pyrrolo[2,3-b]quinoxaline (4a)
1
2a-d
Mp 143–145 °C; 1H NMR (500 MHz, DMSO-d6): d 3.94 (s, 3H,
CH3), 6.97 (s, 1H, CH, pyrrole), 7.55 (m, 3H, 3CH), 7.67 (m, 2H,
2CH), 7.74 (m, 2H, 2CH), 8.10 (dd, J = 6.5, 3.5 Hz, 1H, CH), 8.18 (dd,
J = 6.5, 3.4 Hz, 1H, CH); IR (KBr): 3095, 2950, 1540, 1480, 1438,
695, 740 cmÀ1; MS (EI) m/z 259 (M+); Anal. Calcd for C17H13N3: C,
78.74; H, 5.05; N, 16.20. Found: C, 78.59; H, 5.11; N, 16.33.
R1 = Me, Bn,i-Bu, n-Pr
Scheme 2. Nucleophilic substitution of 2,3-dichloroquinoxaline with aliphatic
amines.
The 1H NMR spectrum of 4a exhibited an aromatic proton at d
6.97, which was the characteristic of a fused pyrrole ring. The other
nine aromatic protons appeared at 7.55–8.18 ppm. In the aliphatic
region, the singlet at d 3.94 was due to the N-methyl group. The
mass spectrum displayed the molecular ion peak at m/z 259.
The following steps can be postulated for the mechanism for the
formation of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines (Scheme
4): (i) oxidative addition of Pd(0) to the C–Cl bond; (ii) transmetal-
lation with the Cu salt of the alkyne to generate the alkynyl palla-
dium complex; (iii) reductive elimination results in the extrusion
of Pd(0) to yield the substituted alkyne, and (iv) finally nucleophilic
attack of the nitrogen on the triple bond activated by Cu(I) leads to
intermolecular cyclization and formation of products 4a–f.
2.2. 1-Benzyl-2-phenyl-1H-pyrrolo[2,3-b]quinoxaline (4b)
Mp 172–174 °C; 1H NMR (500 MHz, DMSO-d6): d 5.70 (s, 2H,
CH2), 6.92 (d, J = 6.8 Hz, 2H, 2CH), 7.03 (s, 1H, CH, pyrrole), 7.17–
7.22 (m, 3H, 3CH), 7.53–7.54 (m, 3H, 3CH), 7.65–7.67 (m, 2H, 2CH),
7.73–7.75 (m, 2H, 2CH), 8.09 (dd, J = 6.5, 3.5 Hz, 1H, CH), 8.17 (dd,
J = 6.5, 3.4 Hz, 1H, CH); IR (KBr): 3098, 1540, 1480, 1405, 740,
725 cmÀ1; MS (EI) m/z 335 (M+); Anal. Calcd for C23H17N3: C,
82.36; H, 5.11; N, 12.53. Found: C, 82.42; H, 5.05; N, 12.58.
2.3. 1-(2-Methylpropyl)-2-phenyl-1H-pyrrolo[2,3-
b]quinoxaline (4c)
In conclusion, we have developed a palladium-catalyzed, one-pot
reaction for the synthesis of 1,2-disubstituted pyrrolo[2,3-b]quinoxa-
lines from readily available starting materials in good-to-high yields.
Wax; 1H NMR (500 MHz, DMSO-d6): d 0.52 (d, J = 7.6 Hz, 6H,
2CH3), 1.87 (m, 1H, CH), 4.37 (d, J = 7.8 Hz, 2H, CH2), 6.90 (s, 1H,
CH, pyrrole), 7.48 (m, 3H, 3CH), 7.61 (m, 2H, 2CH), 7.69 (m, 2H,
2CH), 8.11 (dd, J = 6.5, 3.5 Hz, 1H, CH), 8.17 (dd, J = 6.5, 3.4 Hz,
1H, CH); IR (CCl4): 3096, 2950, 1540, 1480,1374, cmÀ1; MS (EI)
m/z 301 (M+); Anal. Calcd for C20H19N3: C, 79.70; H, 6.35; N,
13.94. Found: C, 79.53; H, 6.42; N, 14.07.
2. General procedure for the preparation of 1,2-disubstituted
pyrrolo[2,3-b]quinoxalines
A
mixture
of
N-alkyl-3-chloroquinoxaline-2-amine
1
(0.775 mmol), PdCl2 (0.0387 mmol, 5 mol %), CuI (0.0775 mmol,
10 mol %), PPh3 (0.0775 mmol, 10 mol %), sodium lauryl sulfate
(0.0543 mmol, 7 mol %), and K2CO3 (2.322 mmol) in H2O (5 mL)
2.4. 1-Propyl-2-phenyl-1H-pyrrolo[2,3-b]quinoxaline (4d)
Wax; 1H NMR (500 MHz, DMSO-d6): d 0.71 (t, J = 7.5 Hz, 3H,
CH3), 1.62 (m, 2H, CH2), 4.39 (t, J = 7.7 Hz, 2H, CH2), 6.88 (s, 1H,
under an argon atmosphere was treated with 1-alkyne
3
(1.55 mmol) slowly, and the reaction mixture was stirred at 70 °C
N
N
Cl
N
PdCl2, PPh3, CuI, SDS
K2CO3, H O, 70 ºC
R2
R2
C
CH
+
2
N
R1
NH
R1
N
2a-d
3a-c
4a-f
R1 = Me, Bn,i-Bu, n-Pr
R2 = Ph, n-C4H9, n-C3H7
Scheme 3. Sonogashira coupling of N-alkyl-3-chloroquinoxaline-2-amines 2a–d with 1-alkynes 3a–c.

A. Keivanloo et al. / Tetrahedron Letters 51 (2010) 2409–2412
2411
Table 1
Synthesis of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines
Entry
Amine 2
Alkyne 3
Product
Yield (%)
N
Cl
N
CH
CH
1
92
4a
4b
N
N
N
N
NH
N
N
N
CH
3
CH
Cl
3
N
NH
2
87
N
N
Cl
N
N
CH
CH
N
NH
3
75
H C
3
H C
3
4c
CH
CH
N
3
3
N
N
Cl
N
N
NH
4
70
4d
CH
CH
N
3
3
N
N
Cl
H C
3
N
N
NH
5
83
HC
CH
3
4e
N
N
Cl
H3C
N
N
CH
N
CH3
NH
6
78
4f
CuI, PPh3
R2
C
CH
R2 ( C C)2 R2
Pd0
PdCl2
2
+
+
K2CO3
R2
Cl
N
N
Cl
N
Pd
N
N
Pd
R2
C
CCu
Pd0
NH
R1
N
NH
R1
NH
R1
R2
-Pd0
N
N
Cu(I)
N
R2
K2CO3
N
R1
N
NH
R1
Scheme 4. Proposed mechanism for the formation of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines 4a–f.

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A. Keivanloo et al. / Tetrahedron Letters 51 (2010) 2409–2412
Chem. Commun. 1977, 9, 291; (c) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1980, 627.
CH, pyrrole), 7.44 (m, 3H, 3CH), 7.56 (m, 2H, 2CH), 7.63 (m, 2H,
2CH), 8.01 (dd, J = 6.4, 3.4 Hz, 1H, CH), 8.09 (dd, J = 6.4, 3.2 Hz,
1H, CH); IR (CCl4): 3098, 2930, 1545, 1480, 1428, 1120 cmÀ1; MS
(EI) m/z 287 (M+); Anal. Calcd for C19H17N3: C, 79.41; H, 5.96; N,
14.62. Found: C, 79.59; H, 5.79; N, 14.80.
11. (a) Nicolaou, K. C.; Dai, W. M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387; (b)
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Wang, L.; Namboodiri, V.; Pagni, R. M. Tetrahedron Lett. 2000, 41, 5151; (c)
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Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002,
124, 14127; (e) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed.
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2.5. 1-Benzyl-2-butyl-1H-pyrrolo[2,3-b]quinoxaline (4e)
Wax; 1H NMR (500 MHz, DMSO-d6): d 0.86 (t, J = 7.8 Hz, 3H,
CH3), 1.41 (m, 2H, CH2), 1.62 (m, 2H, CH2), 2.81 (t, J = 7.6 Hz, 2H,
CH2), 5.72 (s, 2H, CH2), 6.73 (s, 1H, CH, pyrrole), 7.12 (d, J = 6.8,
2H, 2CH), 7.22–7.27 (m, 3H, 3CH), 7.58–7.63 (m, 2H, 2CH), 8.05
(dd, J = 6.4, 3.4 Hz, 1H, CH), 8.12 (dd, J = 6.4, 3.5 Hz, 1H, CH); IR
(CCl4): 3060, 2920, 1543, 1418, cmÀ1; MS (EI) m/z 315 (M+); Anal.
Calcd for C21H21N3: C, 79.97; H, 6.71; N, 13.32. Found: C, 79.76; H,
6.88; N, 13.25.
2.6. 1-Benzyl-2-propyl-1H-pyrrolo[2,3-b]quinoxaline (4f)
Wax; 1H NMR (500 MHz, DMSO-d6): d 0.95 (t, J = 7.7, 3H, CH3),
1.60 (m, 2H, CH2), 2.73 (t, J = 7.2, 2H, CH2), 5.74 (s, 2H, CH2), 6.75 (s,
1H, CH, pyrrole), 7.10 (d, J = 6.7, 2H, 2CH), 7.20–7.25 (m, 3H, 3CH),
7.56–7.61 (m, 2H, 2CH), 8.07 (dd, J = 6.4, 3.5 Hz, 1H, CH), 8.13 (dd,
J = 6.5, 3.4 Hz, 1H, CH); IR (CCl4): 3073, 2925, 1548, 1420, cmÀ1; MS
(EI) m/z 301 (M+); Anal. Calcd for C20H19N3: C, 79.70; H, 6.35; N,
13.94. Found: C, 79.89; H, 6.27; N, 13.76.
17. (a) Lubineau, A.; Auge, J. In Modern Solvents in Organic Synthesis; Knochel, P.,
Ed.; Springer: Berlin, 1999; (b) Cornils, B.. In Herrmann, W. A., Ed.; Aqueous-
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Acknowledgment
The authors would like to thank the Research Council of Shah-
rood University of Technology for the financial support of this
work.
19. (a) Heravi, M. M.; Keivanloo, A.; Rahimizadeh, M.; Bakavoli, M.; Ghassemzadeh,
M. Tetrahedron Lett. 2004, 45, 5747; (b) Heravi, M. M.; Keivanloo, A.;
Rahimzadeh, M.; Bakavoli, M.; Ghassemzadeh, M.; Neumüller, B. Tetrahedron
Lett. 2005, 46, 1607; (c) Bakherad, M.; Isfahani, H. N.; Keivanloo, A.;
Doostmohammadi, N. Tetrahedron Lett. 2008, 49, 3819; (d) Bakherad, M.;
Isfahani, H. N.; Keivanloo, A.; Sang, G. Tetrahedron Lett. 2008, 49, 6188.
20. General procedure for the preparation of N-alkyl-3-chloroquinoxaline-2-amines: a
mixture of 2,3-dichloroquinoxaline (0.01 mmol) and primary alkyl amine
(0.02 mmol) in EtOH (5 mL) was heated under reflux for 4 h. The solvent was
then removed under reduced pressure, and the resulting solid was washed
with H2O and dried. The product so obtained was pure enough to be used in the
next step without any further purification.
References and notes
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Sonogashira, K.; Yatake, T.; Tohda, Y.; Takahashi, S.; Hagihara, N. J. Chem. Soc.,
3-Chloro-N-methylquinoxalin-2-amine (2a): yield, 95%; mp 89–90 °C; 1H NMR
(500 MHz, DMSO-d6): d 3.07 (d, J = 5.3 Hz, 3H, CH3), 7.51–8.13 (m, 5H, ArH,
NH), IR (KBr): 3410 (NH), 1580, 1080, 750 cmÀ1; Anal. Calcd for C9H8N3Cl: C,
55.83; H, 4.16; N, 21.70. Found: C, 55.68; H, 4.31; N, 21.88.
N-Benzyl-3-chloroquinoxalin-2-amine (2b): yield, 92%; mp 69–71 °C; 1H NMR
(500 MHz, DMSO-d6): d 4.75 (d, J = 6.1 Hz, 2H, CH2), 7.12–8.23 (m, 10H, ArH,
NH); IR (KBr): 3400 (NH), 1550, 1500, 1065 cmÀ1; Anal. Calcd for C15H12N3Cl:
C, 66.79; H, 4.48; N, 15.58. Found: C, 66.61; H, 4.61; N, 15.66.
3-Chloro-N-(2-methylpropyl)quinoxalin-2-amine (2c): yield, 86%; mp 40–41 °C;
1H NMR (500 MHz, DMSO-d6): d 0.95 (d, J = 6.6 Hz, 6H, 2CH3), 2.14 (m, 1H, CH),
3.23 (d, J = 5.9 Hz, 2H, CH2), 7.13–8.12 (m, 5H, ArH, NH), IR (KBr): 3400 (NH),
2800, 1540, 1520, 1080 cmÀ1; Anal. Calcd for C12H14N3Cl: C, 61.15; H, 5.99; N,
17.83. Found: C, 60.98; H, 5.88; N, 18.01.
N-Propyl-3-chloroquinoxalin-2-amine (2d): yield, 80%; mp 43–45 °C; 1H NMR
(500 MHz, DMSO-d6): d 1.04 (t, J = 7.2 Hz, 3H, CH3), 1.75 (m, 2H, CH2), 3.56 (t,
J = 6.6 Hz, 2H, CH2), 7.11–7.84 (m, 5H, ArH, NH); IR (KBr): 3390 (NH), 2900,
1555, 1525, 1080 cmÀ1; Anal. Calcd for C11H12N3Cl: C, 59.60; H, 5.46; N, 18.95.
Found: C, 59.80; H, 5.41; N, 18.87.