Synthesis of pyrrolo[2,3-b]quinoxalines by the Pd/C-catalyzed multicomponent reaction of 1,2-dichloroquinoxaline with hydrazine hydrate, phenylacetylene, and a variety of aldehydes in water

Article abstract of DOI:10.1016/j.tet.2012.01.045

The one-pot, Pd/C-catalyzed, multicomponent reaction of 1,2-dichloroquinoxaline with hydrazine hydrate, phenylacetylene, and a variety of aldehydes provides an efficient and direct method for the preparation of N-substituted pyrrolo[2,3-b]quinoxalines in

Full text of DOI:10.1016/j.tet.2012.01.045

Tetrahedron 68 (2012) 2107e2112
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Tetrahedron
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Synthesis of pyrrolo[2,3-b]quinoxalines by the Pd/C-catalyzed multicomponent
reaction of 1,2-dichloroquinoxaline with hydrazine hydrate, phenylacetylene,
and a variety of aldehydes in water
*
Mohammad Bakherad , Ali Keivanloo, Saeideh Jajarmi
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 one-pot, Pd/C-catalyzed, multicomponent reaction of 1,2-dichloroquinoxaline with hydrazine hy-
drate, phenylacetylene, and a variety of aldehydes provides an efficient and direct method for the
preparation of N-substituted pyrrolo[2,3-b]quinoxalines in water at 70 ꢀC.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 19 November 2011
Received in revised form 1 January 2012
Accepted 16 January 2012
Available online 21 January 2012
Keywords:
Pyrroloquinoxaline
Sonogashira reaction
Palladium catalyzed
Aldehydes
1. Introduction
coupling reactions have been applied to the synthesis of quinoxa-
line derivatives from haloquinoxalines, and an intramolecular Heck
Multicomponent reactions (MCRs) have become important tools
in modern preparative synthetic chemistry because they increase
the reaction efficiency by combining several operational steps
without isolation of the reaction intermediates or changing the
reaction conditions.1 These approaches allow an overall reduction
of the time required to obtain the desired product with an advan-
tageous economy of solvents and an overall reduction of waste
production. MCRs have been widely used for the preparation of
heterocyclic structures2 as well as the key steps in the total syn-
thesis of natural products.3 The quinoxaline nucleus is present in
many pharmaceutical agents, exhibiting a broad spectrum of bi-
ological activities, such as antitumor,4 antiviral,5 antiglucoma,6
antituberculosis,7 antiinflammatory,8,9 and anticancer10 activities.
Furthermore, pyrrolo[1,2-a]quinoxalines have been shown to be
potent and selective 5-HT3 receptor ligands.11 There has been
growing interest in developing a general and versatile method for
the synthesis of pyrrolo[2,3-b]quinoxaline derivatives. A number of
synthetic approaches to this class of compounds have been in-
troduced in recent years.12
reaction16 on aminoquinoxaline scaffolds has been used in the
synthesis of 3-substituted pyrrolo[2,3-b]quinoxalines.
Our and other recent success in this area encouraged us to ex-
amine the possibility of preparing pyrrolo[2,3-b]quinoxalines by
the palladium/copper-catalyzed alkyne coupling followed by nu-
cleophilic cyclization.
Acardi and co-workers have previously reported an approach for
the synthesis of pyrrolo[2,3-b]quinoxalines by the reaction of 2-
alkynyl-3-trifluoroacetamidoquinoxalines with aryl and vinyl ha-
lides or triflates.17 Unfortunately, the protecting and deprotecting
steps required to synthesize alkynylaminoquinoxaline are not
particularly attractive, synthetically.
Recently, our group has prepared pyrrolo[2,3-b]quinoxaline
derivatives by heteroannulation of N-alkyl-3-chloroquinoxaline-2-
amines with phenylacetylene18 and propargyl bromide19 under
mild conditions in one-pot reactions catalyzed by PdeCu. We
attempted to make this overall approach more attractive synthet-
ically by examining the preparation of pyrrolo[2,3-b]quinoxalines
using MCRs.
Rather surprisingly, palladium catalysis, despite its remarkable
versatility and efficiency in the synthesis of heterocyclic com-
pounds,13 has very rarely been mentioned in this area. Extensive
literature search revealed that the Suzuki14 and Stille15 cross-
2. Results and discussion
To introduce diversified pyrrolo[2,3-b]quinoxaline derivatives,
our retrosynthetic analysis implicated the use of 1,2-
dichloroquinoxaline, hydrazine, a suitable aldehyde, and phenyl-
acetylene as the starting materials, and palladium-catalyzed
* Corresponding author. E-mail address: m.bakherad@yahoo.com (M. Bakherad).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.045

2108
M. Bakherad et al. / Tetrahedron 68 (2012) 2107e2112
cascade cross coupling-cyclization as the key step, extensively used
in the synthesis of indoles (Scheme 1).20
surfactant, Pd/C turns out to be the best catalyst in terms of
yields (entries 1e5). Other parameters, such as the base, catalyst
loading, and reaction temperature were also examined. The re-
action was influenced significantly by the base employed; it
worked very well when inorganic bases, such as K2CO3 and
Cs2CO3 were used (entries 5 and 6), with the best results ob-
tained in the case of potassium carbonate (entry 5). No satis-
factory results were obtained with organic bases, such as Et3N,
diisopropylethylamine (DIPEA), pyridine, and piperidine (entries
9e12). When the catalyst loading was decreased to 3 mol %, the
yield of N-(phenylmethanimine)-2-phenyl-1H-pyrrolo[2,3-b]qui-
noxaline 4a was 62% (entry 13). Increasing the amount of palla-
dium catalyst did not increase the yield (entry 14). Only a trace
amount of the desired product 4a was obtained when the re-
action was carried out without CuI as a co-catalyst (entry 15).
Decreasing the temperature to 25 ꢀC caused the yield to decrease
to 45% (entry 16).
Ph
N
N
N
N
N
N
Cl
Ph
Ph
+
N
NH
N
NH
N
CHAr
CHAr
N
CHAr
N
N
Cl
Cl
Cl
NH2NH2
ArCHO
+
+
NH
N
N
NH2
Scheme 1. Retrosynthetic analysis of diversified pyrrolo[2,3-b]quinoxalines.
As indicated in Table 1, the reaction conditions mentioned in
entry 5 were used for further examination of the scope of this re-
action with various benzaldehydes, 1,2-dichloroquinoxaline, hy-
drazine, and phenylacetylene. The reactions were carried out under
an argon atmosphere, and water was degassed prior to use. The
typical results are summarized in Table 2. As shown in this table,
nature of the aldehydes used plays a key role in controlling the
reaction outcome, the best results being obtained in the presence of
electron-withdrawing (entries 2e4) or slightly electron-
withdrawing (entries 5e9) substituents. With aldehydes contain-
ing electron-neutral (entry 1) or electron-donating (entries 10 and
11) groups, products 4a, 4j, and 4k are isolated in moderate yields,
respectively.
The use of Pd/CeCuI as a catalytic system for the efficient
Sonogashira coupling of aryl halides with terminal alkynes has also
been reported.21 Compared to the frequently used expensive pal-
ladium catalysts [e.g., Pd(PPh3)4, (PPh3)2PdCl2, etc.], Pd/C-based
methods have an economic advantage, and hence remain attrac-
tive in large or industrial scale preparations.
Herein, we describe the Pd/C-catalyzed MCR of 1,2-
dichloroquinoxaline, hydrazine, phenylacetylene, and a variety of
aldehydes, which provides an efficient route for the synthesis of
pyrrolo[2,3-b]quinoxalines from simple starting materials.
In an initial research work, we found that the reaction of 1,2-
dichloroquinoxaline (1 equiv) with hydrazine (1 equiv), benzalde-
hyde (1 equiv), and phenylacetylene (1 equiv) in the presence of
Pd/C (mol %), CuI (10 mol %), and K2CO3 (2 equiv) in water at 70 ꢀC
provides the desired product 4a in high yield (Table 1, entry 5).
It was found that while Pd/C, PdCl2(PPh3)2, PdCl2/PPh3, PdCl2,
and Pd(dba)2 all catalyze the reaction without the aid of any
Decrease in the reaction yield could be due to the low yield of 2-
(arylhydrazino)-3-chloroquinoxaline 3 when aldehydes bearing
electron-donating groups are used. Our reason for drawing this
conclusion is that when dichloroquinoxaline and hydrazine, in
turn, react with 4-methoxybenzaldehyde, 4-methylbenzaldehyde,
Table 1
Effect of base, catalyst, and temperature in heterocyclization during the Sonogashira reaction of 1,2-dichloroquinoxaline 1 with hydrazine hydrate, benzaldehyde, and
phenylacetylenea
N
N
Cl
Cl
N
Cat, CuI
NH2NH2
PhCHO
+
+
Ph
Ph
+
Base, H2O, 70 oC
N
N
1
2a
4a
N
CHPh
Entry
Catalyst (mol %)
Base
Yieldb (%)
1
2
3
4
5
6
7
8
PdCl2 (5)/PPh3(10)
PdCl2(PPh3)2(5)
Pd(dba)2(5)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KOH
65
63
55
75
80
75
40
53
42
23
25
30
62
80
Trace
45
PdCl2(5)
10% Pd/C (5)
10% Pd/C (5)
10% Pd/C (5)
10% Pd/C (5)
10% Pd/C (5)
10% Pd/C (5)
10% Pd/C (5)
10% Pd/C (5)
10% Pd/C (3)
10% Pd/C (10)
10% Pd/C (5)
10% Pd/C (5)
Na2CO3
Et3N
9
10
11
12
13
14
15d
16e
DIPEAc
Pyridine
Piperidine
K2CO3
K2CO3
K2CO3
K2CO3
a
Reaction conditions: 1 (1.0 mmol), hydrazine hydrate (2.0 mmol), benzaldehyde (1.0 mmol), phenylacetylene (1.0 mmol), K2CO3 (2.0 mmol), CuI (10 mol %), at 70 ꢀC for
10 h.
b
c
Isolated yields.
Diisopropylethylamine.
Without CuI.
Reaction at 25 ꢀC.
d
e

M. Bakherad et al. / Tetrahedron 68 (2012) 2107e2112
2109
Table 2
Yields of N-substituted pyrrolo[2,3-b]quinoxalines 4aek
N
Cl
Cl
N
N
Pd/C, CuI
NH2NH2
ArCHO
+
+
Ph
Ph
+
K2CO3, H2O, 70 oC
N
N
N
CHAr
1
2
4
Entry
Ar
Product
Yieldb (%)
N
N
Ph
N
N
1
80
4a
NO2
2
86
2b
2c
3
94
NO2
4
95
NO2
2d
F
5
94
2e
N
N
Ph
N
N
6
95
F
4f
2f
F
N
N
Ph
N
N
7
91
Cl
(continued on next page)

2110
M. Bakherad et al. / Tetrahedron 68 (2012) 2107e2112
Table 2 (continued )
Entry
Ar
Product
Yieldb (%)
N
N
Ph
N
N
8
94
Cl
4h
2h
Cl
N
Ph
Cl
Cl
Cl
N
N
N
9
85
4i
2i
Cl
N
N
Ph
N
N
10
72
Me
11
66
OMe
2k
aReaction conditions: 1 (1.0 mmol), hydrazine hydrate (2.0 mmol), 2aek (1.0 mmol), phenylacetylene (1.0 mmol), K2CO3 (2.0 mmol), 10% Pd/C (5 mol %), CuI (10 mol %),
degassed water (5 mL), at 70 ꢀC for 10 h.
b
Isolated yields.
and 4-nitrobenzaldehyde, the reaction yields for the formation of
product 3 are 60, 68, and 95%, respectively (Scheme 2).
3. Conclusion
A plausible reaction mechanism is depicted in Scheme 3. The
Pd(0) species generated in situ from Pd/C catalyzes the coupling of
2-(arylhydrazino)-3-chloroquinoxaline 3 with copper(I) acetylide
(generated in situ from phenylacetylene) via intermediate [A]
leading to 2-(arylhydrazino)-3-alkynylquinoxaline [B]. This sub-
sequently affords the corresponding pyrrolo[2,3-b]quinoxalines 4
via activation of the triple bond through its complexation with the
copper(I) salt followed by intramolecular cyclization22 with re-
generation of the Cu(I) catalyst.23
In conclusion, we demonstrated a very simple, efficient, clean,
and straightforward method for the synthesis of pyrrolo[2,3-b]
quinoxaline derivatives via the Pd/C-catalyzed reaction of readily
available dichloroquinoxaline with hydrazine, phenylacetylene and
a variety of aldehydes. This methodology does not involve the use
of expensive reagents or catalysts, and thus permits a new and
practical access to pyrrolo[2,3-b]quinoxalines.
4. Experimental section
4.1. General method
N
N
N
Cl
Cl
Cl
Melting points were uncorrected. The 1H NMR spectra were
recorded at 400 MHz, and the 13C NMR spectra were recorded at
100 MHz in DMSO-d6. The chemical shifts are reported in parts per
H2O
r.t
NH2NH2
ArCHO
+
+
NH
N
N
CHAr
1
2
3
million (d), and referenced to the residual proton signal for DMSO-
d6 2.49). The J-coupling constants are reported in hertz. High
(
d
Ar = 4-MeO-C6H4-
Ar = 4-Me-C6H4-
Ar = 4-NO2-C6H4-
60%
68%
95%
resolution mass spectrometry was performed on a Bruker micro-
TOF instrument using ESI. The reagents used were purchased from
commercial suppliers, and used without further purification. Merck
silica gel 60 was used for chromatography (230e400 mesh).
Scheme 2. Synthesis of 2-(arylhydrazino)-3-chloroquinoxaline 3.

M. Bakherad et al. / Tetrahedron 68 (2012) 2107e2112
2111
A
N
N
N
Pd Cl
N
N
Cl
Pd(0)
Pd
Ph
Ph
CuI
NH
N
NH
N
NH
N
N
CHAr
CHAr
ArHC
3
Pd(0)
Cu
Ph
B
N
N
N
N
-
CuI
Ph
NH
N
N
N
CHAr
CHAr
4
Scheme 3. A plausible mechanism for the formation of N-substituted pyrrolo[2,3-b]quinoxalines 4.
4.2. Experimental procedures
7.60e7.65 (m, 3H), 7.81e7.86 (m, 3H), 8.17e8.19 (m, 1H), 8.24e8.26
(m, 1H), 8.27e8.29 (m, 1H), 8.35 (dd, J¼8.4, 2.4 Hz, 1H), 8.69 (t,
4.2.1. Synthesis of N-(arylmethamimine)-2-phenyl-1H-pyrrolo[2,3-b]
quinoxaline 4. A mixture of 1,2-dichloroquinoxaline (199 mg,
1.0 mmol), hydrazine hydrate 99% (0.1 mL, 2.0 mmol), and a suitable
aldehyde (1.0 mmol) was stirred in H2O (5 mL) at room tempera-
ture under an argon atmosphere for 30 min. Phenylacetylene
(0.11 mL, 1 mmol), 10% Pd/C (53 mg, 0.05 mmol), CuI (19 mg,
0.1 mmol), and K2CO3 (276 mg, 2.0 mmol) were added, and the
resulting solution was heated in 70 ꢀC for 10 h and cooled to room
temperature. The reaction mixture was filtered, and the filtrate was
concentrated in vacuo. The residue was purified by chromatogra-
phy, eluting with CHCl3/CH3OH (50/1) to afford the pure product
(Table 2).
J¼3.6 Hz, 1H), 10.63 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 100.6,
122.2, 125.5, 128.4, 128.9, 128.9, 128.9, 129.2, 130.2, 130.4, 130.6,
131.1, 133.9, 136.6, 138.4, 140.9, 141.6, 142.3, 148.7, 151.5, 151.7. HRMS
(ESI): 393.1205; calcd for C23H15N5O2, 393.1226. Anal. Calcd for
C23H15N5O2: C, 70.22; H, 3.84; N, 17.80. Found: C, 70.02; H, 3.69; N,
17.95.
4.2.1.4. 2-Phenyl-N-[(4-nitrophenyl)methylene]-1-H-pyrrolo[2,3-
b]quinoxaline-1-amine 4d. Purification by silica gel column chro-
matography (chloroform/methanol¼50/1): TLC (chloroform/
methanol¼50/1) Rf¼0.54; solid; mp¼267e269 ꢀC;
n
(KBr): 3060,
d 7.25 (s, 1H),
1595, 1540, 1350 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
7.60e7.65 (m, 3H), 7.81e7.84 (m, 2H), 7.97 (dd, J¼8.4, 2.0 Hz, 2H),
4.2.1.1. 2-Phenyl-N-phenylmethylene-1-H-pyrrolo[2,3-b]quinoxa-
line-1-amine 4a. Purification by silica gel column chromatography
(chloroform/methanol¼50/1): TLC (chloroform/methanol¼50/1)
8.11 (d, J¼8.8 Hz, 2H), 8.17e8.19 (m, 1H), 8.21e8.23 (m, 1H), 8.36 (d,
J¼8.8 Hz, 2H), 10.63 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 100.9,
124.7, 128.5, 128.9, 128.9, 128.9, 129.0, 129.2, 130.2, 130.4, 130.5,
132.0, 138.3, 140.9, 141.7, 142.4, 148.8, 151.6, 151.6. HRMS (ESI):
393.1208; calcd for C23H15N5O2, 393.1226. Anal. Calcd for
C23H15N5O2: C, 70.22; H, 3.84; N, 17.80. Found: C, 70.41; H, 3.65; N,
17.62.
Rf¼0.55; solid; mp¼176e178 ꢀC;
n
(KBr): 3065, 1595 cmꢁ1; 1H NMR
(400 MHz, DMSO-d6)
d 7.20 (s, 1H), 7.54e7.58 (m, 3H), 7.59e7.63
(m, 3H), 7.76 (d, J¼4.8 Hz, 1H), 7.81 (d, J¼4.1 Hz, 1H), 7.86e7.89 (m,
3H), 7.97 (dd, J¼6.4, 1.6 Hz, 1H), 8.14e8.19 (m, 2H), 10.39 (s, 1H); 13C
NMR (100 MHz, DMSO-d6)
d 99.9, 128.1, 128.2, 128.7, 128.8, 128.9,
129.2, 129.5, 130.3, 130.4, 131.6, 134.6, 138.4, 140.8, 142.1, 151.5,
155.5. HRMS (ESI): 348.1349; calcd for C23H16N4, 348.1375. Anal.
Calcd for C23H16N4: C, 79.29; H, 4.63; N, 16.08. Found: C, 79.05; H,
4.77; N, 16.25.
4.2.1.5. 2-Phenyl-N-[(2-fluorophenyl)methylene]-1-H-pyrrolo
[2,3-b]quinoxaline-1-amine 4e. Purification by silica gel column
chromatography (chloroform/methanol¼50/1): TLC (chloroform/
methanol¼50/1) Rf¼0.53; solid; mp¼193e195 ꢀC;
n (KBr): 3060,
1595 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 7.20 (s, 1H), 7.32e7.34
4.2.1.2. 2-Phenyl-N-[(2-nitrophenyl)methylene]-1-H-pyrrolo[2,3-
b]quinoxaline-1-amine 4b. Purification by silica gel column chro-
matography (chloroform/methanol¼50/1): TLC (chloroform/
(m, 1H), 7.41e7.44 (m, 1H), 7.56e7.63 (m, 4H), 7.77e7.81 (m, 2H),
7.86e7.88 (m, 1H), 7.90 (dd, J¼8.0, 1.6 Hz, 1H), 8.09e8.11 (m, 1H),
8.15e8.17 (m, 1H), 10.67 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
methanol¼50/1) Rf¼0.53; solid; mp¼262e264 ꢀC;
n
(KBr): 3070,
7.22 (s, 1H),
d 100.3, 116.6, 116.9, 122.2, 122.3, 125.6, 125.6, 125.6, 126.6, 128.3,
1600, 1545, 1350 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
128.8, 128.9, 129.2, 130.3, 130.5, 133.5, 133.5, 138.2, 140.8, 141.5,
142.3, 147.2, 147.3, 151.6, 160.4, 162.9. HRMS (ESI): 366.1261; calcd
for C23H15FN4, 366.1281. Anal. Calcd for C23H15FN4: C, 75.40; H,
4.13; N, 15.29. Found: C, 75.23; H, 4.22; N, 15.47.
7.56e7.63 (m, 3H), 7.73e7.75 (m, 1H), 7.80e7.87 (m, 3H), 7.94 (dd,
J¼8.0, 2.0 Hz, 2H), 8.05e8.10 (m, 2H), 8.16e8.19 (m, 2H), 11.03 (s,
1H); 13C NMR (100 MHz, DMSO-d6)
d 100.9, 125.4, 128.1, 128.5,
128.8, 128.9, 129.0, 129.1, 129.2, 130.2, 130.4, 130.5, 131.9, 134.4,
138.2, 140.9, 141.7, 142.3, 149.1, 149.4, 151.7. HRMS (ESI): 393.1202;
calcd for C23H15N5O2, 393.1226. Anal. Calcd for C23H15N5O2: C,
70.22; H, 3.84; N, 17.80. Found: C, 70.39; H, 3.97; N, 17.67.
4.2.1.6. 2-Phenyl-N-[(4-fluorophenyl)methylene]-1-H-pyrrolo
[2,3-b]quinoxaline-1-amine 4f. Purification by silica gel column
chromatography (chloroform/methanol¼50/1): TLC (chloroform/
methanol¼50/1) Rf¼0.54; solid; mp¼200e202 ꢀC;
n (KBr): 3060,
4.2.1.3. 2-Phenyl-N-[(3-nitrophenyl)methylene]-1-H-pyrrolo[2,3-
b]quinoxaline-1-amine 4c. Purification by silica gel column chro-
matography (chloroform/methanol¼50/1): TLC (chloroform/
1600 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 7.20 (s, 1H), 7.37e7.41
(m, 2H), 7.58e7.63 (m, 3H), 7.78e7.81 (m, 2H), 7.92e7.98 (m, 4H),
8.15e8.19 (m, 2H), 10.39 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
methanol¼50/1) Rf¼0.52; solid; mp¼258e260 ꢀC;
n
(KBr): 3070,
d 7.24 (s, 1H),
d
99.9,116.6,116.8,128.2,128.7,128.8,128.9,129.2,130.3,130.4,131.2,
1600, 1530, 1355 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
131.2,138.4,140.8,141.3,142.1,151.5,154.3,162.9,165.4. HRMS (ESI):

2112
M. Bakherad et al. / Tetrahedron 68 (2012) 2107e2112
366.1259; calcd for C23H15FN4, 366.1281. Anal. Calcd for C23H15FN4:
C, 75.40; H, 4.13; N, 15.29. Found: C, 75.62; H, 4.03; N, 15.07.
156.3, 162.4. HRMS (ESI): 378.1460; calcd for C24H18N4O, 378.1481.
Anal. Calcd for C24H18N4O: C, 76.17; H, 4.79; N, 14.81. Found: C,
76.37; H, 4.65; N, 14.62.
4.2.1.7. 2-Phenyl-N-[(2-chlorophenyl)methylene]-1-H-pyrrolo
[2,3-b]quinoxaline-1-amine 4g. Purification by silica gel column
chromatography (chloroform/methanol¼50/1): TLC (chloroform/
Acknowledgements
methanol¼50/1) Rf¼0.56; solid; mp¼190e192 ꢀC;
n
(KBr): 3070,
We are grateful to the Research Council of Shahrood University
of Technology for the financial support of this work.
1600 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
7.18 (s, 1H), 7.43 (t,
J¼7.0 Hz,1H), 7.50 (t, J¼5.2 Hz,1H), 7.57e7.63 (m, 4H), 7.78e7.81 (m,
2H), 7.90 (dd, J¼8.0,1.6 Hz,1H), 7.96 (dd, J¼8.1,1.6 Hz,1H), 8.06e8.08
(m,1H), 8.12e8.14 (m,1H),10.92 (s,1H); 13C NMR (100 MHz, DMSO-
Supplementary data
The copies of 1H NMR and 13C NMR spectra for all products.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.045.
d6) d 100.5, 126.8, 128.4, 128.9, 128.9, 129.2, 130.3, 130.6, 132.1, 132.8,
134.7, 138.1, 140.8, 141.5, 142.3, 149.9, 151.6. HRMS (ESI): 382.0966;
calcd for C23H15ClN4, 382.0985. Anal. Calcd for C23H15ClN4: C, 72.16;
H, 3.95; N, 14.63. Found: C, 72.37; H, 3.73; N, 14.85.
References and notes
4.2.1.8. 2-Phenyl-N-[(4-chlorophenyl)methylene]-1-H-pyrrolo
[2,3-b]quinoxaline-1-amine 4h. Purification by silica gel column
chromatography (chloroform/methanol¼50/1): TLC (chloroform/
ꢀ
1. (a) Zhu, J.; Bienayme, H. In Multicomponent Reactions; Wiley-WCH: Weinheim,
2006; (b) Litvinov, V. P. Russ. Chem. Rev. 2003, 72, 69e85.
2. (a) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471e1499; (b) d Souza, D. M.;
Muller, T. J. Chem. Soc. Rev. 2007, 36, 1095e1108; (c) Sunderhaus, J. D.; Martin, S.
F. Chem.dEur. J. 2009, 15, 1300e1308.
ꢁ
methanol¼50/1) Rf¼0.57; solid; mp¼196e198 ꢀC;
n (KBr): 3075,
€
1595 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 7.19 (s, 1H), 7.57e7.62
3. Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439e4486.
(m, 5H), 7.72e7.81 (m, 2H), 7.86e7.88 (m, 2H), 7.96 (dd, J¼8.0,
4. Hazeldine, S. T.; Polin, L.; Kushner, J.; Paluch, J.; White, K.; Edelstein, M.; Pal-
omino, E.; Corbett, T. H.; Horwitz, J. P. J. Med. Chem. 2001, 44, 1758e1776.
5. Rong, F.; Chow, S.; Yan, S.; Larson, G.; Hong, Z.; Wu, J. Bioorg. Med. Chem. Lett.
2007, 17, 1663e1666.
1.6 Hz, 2H), 8.15e8.18 (m, 2H), 10.41 (s, 1H); 13C NMR (100 MHz,
DMSO-d6)
d 100.1, 128.3, 128.8, 128.8, 128.9, 129.2, 129.6, 129.6,
130.3, 130.4, 133.5, 136.0, 138.3, 140.8, 141.4, 142.2, 151.5, 153.7.
HRMS (ESI): 382.0962; calcd for C23H15ClN4, 382.0985. Anal. Calcd
for C23H15ClN4: C, 72.16; H, 3.95; N, 14.63. Found: C, 72.40; H, 3.84;
N, 14.47.
6. David, R. Exp. Opin. Invest. Drug 1998, 7, 1063e1086.
7. Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. J. Med. Chem. 2005, 48, 2019e2025.
8. Smits, R. A.; Lim, H. D.; Hanzer, A.; Zuiderveld, O. P.; Guaita, E.; Adami, M.;
Coruzzi, G.; Leurs, R.; de Esch, I. J. P. J. Med. Chem. 2008, 51, 2457e2467.
9. Burguete, A.; Pontiki, E.; Hadjipavlou-Litina, D.; Villar, R.; Vicente, E.; Solano, B.;
Ancizu, S.; Perez-Silanes, S.; Aldana, I.; Monge, A. Bioorg. Med. Chem. Lett. 2007,
17, 6439e6443.
10. Naylor, M. A.; Stephen, M. A.; Nolan, J.; Sutton, B.; Tochcer, J. H.; Fielden, E. M.;
Adams, G. E.; Strafford, I. J. Anticancer Drug Res. 1993, 8, 439e461.
11. (a) Campiani, G.; Cappelli, A.; Nacci, V.; Anzini, M.; Vomero, S.; Hamon, M.;
Cagnotto, A.; Fracasso, C.; Uboldi, C.; Caccia, S.; Consolo, S.; Mennini, T. J. Med.
Chem. 1997, 40, 3670e3678; (b) 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. J. Med. Chem. 1999, 42,
4362e4379.
4.2.1.9. 2-Phenyl-N-[(2,6-dichlorophenyl)methylene]-1-H-pyrrolo
[2,3-b]quinoxaline-1-amine 4i. Purification by silica gel column
chromatography (chloroform/methanol¼50/1): TLC (chloroform/
methanol¼50/1) Rf¼0.52; solid; mp¼186e188 ꢀC;
n (KBr): 3070,
d 7.21 (s, 1H), 7.48e7.55
1600 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
(m, 4H), 7.62e7.64 (m, 2H) 7.79e7.83 (m, 2H), 7.95 (dd, J¼7.6,1.6 Hz,
1H), 8.11e8.13 (m, 1H), 8.15e8.19 (m, 1H), 10.92 (s, 1H); 13C NMR
12. Yuan, Q.; Ma, D. J. Org. Chem. 2008, 73, 5159e5162.
(100 MHz, DMSO-d6) d 101.0, 128.6, 128.7, 128.9, 129.0, 129.2, 129.9,
13. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry. A Guide for Synthetic
Chemists; Baldwin, J. E., Williams, R. M., Eds.; Pergamon: Amsterdam, 2000.
14. Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507e4510.
15. Dinsmore, A.; Garner, C. D.; Joule, J. A. Tetrahedron 1998, 54, 3291e3302.
16. Li, J. J. J. Org. Chem. 1999, 64, 8425e8427.
130.1, 130.3, 130.5, 130.7, 132.3, 134.4, 138.2, 140.9, 141.9, 142.9,
142.4, 150.2, 151.9. HRMS (ESI): 416.0577; calcd for C23H14Cl2N4,
416.0596. Anal. Calcd for C23H14Cl2N4: C, 66.20; H, 3.38; N, 13.43.
Found: C, 66.02; H, 3.50; N, 13.62.
17. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Parisi, L. M. Tetrahedron Lett. 2004, 45,
2431e2434.
18. Keivanloo, A.; Bakherad, M.; Rahimi, A.; Taheri, S. A. N. Tetrahedron Lett. 2010,
51, 2409e2412.
4.2.1.10. 2-Phenyl-N-[(4-methylphenyl)methylene]-1-H-pyrrolo
[2,3-b]quinoxaline-1-amine 4j. Purification by silica gel column
chromatography (chloroform/methanol¼50/1): TLC (chloroform/
19. Keivanloo, A.; Bakherad, M.; Rahimi, A. Synthesis 2010, 10, 1599e1602.
20. (a) Palimkar, S. S.; Kumar, P. H.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron 2006,
62, 5109e5115; (b) Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.; Mar-
yanoff, B. E. Org. Lett. 2000, 2, 89e92; (c) Hong, K. B.; Lee, C. W.; Yum, E. K.
Tetrahedron Lett. 2004, 45, 693e697; (d) Zhang, H.-C.; Hong, Y.; White, K. B.;
Maryanoff, B. E. Tetrahedron Lett. 2001, 42, 4751e4754; (e) Sun, L. P.; Wang, J. X.
Synth. Commun. 2007, 37, 2187e2193; (f) Palimkar, S. S.; More, V. S.; Kumar, P.
H.; Srinivasan, K. V. Tetrahedron 2007, 63, 12786e12790; (g) Oskooie, H. A.;
Heravi, M. M.; Behbahani, F. K. Molecules 2007, 12, 1438e1446; (h) McLaughlin,
M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307e3310; (i) Dooleweerdt, K.;
Ruhland, T.; Skrydstrup, T. Org. Lett. 2009, 11, 221e224.
21. (a) Raju, S.; Kumar, P. R.; Mukkanti, K.; Annamalai, P.; Pal, M. Bioorg. Med. Chem.
Lett. 2006, 16, 6185e6189; (b) Reddy, E. A.; Barange, D. K.; Islam, A.; Mukkanti,
K.; Pal, M. Tetrahedron 2008, 64, 7143e7150; (c) Pal, M.; Subramanian, V.; Ye-
leswarapu, K. R. Tetrahedron Lett. 2003, 44, 8221e8225; (d) Batchu, V. R.;
Subramanian, V.; Parasuraman, K.; Swamy, N. K.; Kumar, S.; Pal, M. Tetrahedron
2005, 61, 9869e9877; (e) Novak, Z.; Szabo, A.; Repasi, J.; Kotschy, A. J. Org. Chem.
2003, 68, 3327e3329.
22. (a) McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.; Erichsen, J. T.; Andrei,
G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2000, 43, 4993e4997;
(b) McGuigan, C.; Brancale, A.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini,
J. Bioorg. Med. Chem. Lett. 2000, 10, 1215e1217; (c) McGuigan, C.; Yarnold, C.
J.; Jones, G.; Velazquez, S.; Barucki, H.; Brancale, A.; Andrei, G.; Snoeck, R.;
De Clercq, E.; Balzarini, J. J. Med. Chem. 1999, 42, 4479e4484; (d) Robins, M.
J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854e1862; (e) Janeba, Z.; Balzarini, J.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Robins, M. J. J. Med. Chem. 2005, 48,
4690e4696.
methanol¼50/1) Rf¼0.55; solid; mp¼142e144 ꢀC;
n (KBr): 3080,
1600 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 2.39 (s, 3H), 7.21 (s, 1H),
7.36 (d, J¼8.0 Hz, 2H), 7.58e7.62 (m, 3H), 7.77e7.82 (m, 4H), 7.97
(dd, J¼8.0, 1.6 Hz, 2H), 8.15e8.19 (m, 2H), 10.33 (s, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 21.6, 99.7, 124.5, 128.1, 128.7, 128.8, 128.9,
129.2, 130.1,130.3, 130.4, 130.5, 131.8,138.4, 140.8, 141.3, 141.7, 142.0,
151.5, 155.9. HRMS (ESI): 362.1510; calcd for C24H18N4, 362.1531.
Anal. Calcd for C24H18N4: C, 79.54; H, 5.01; N,15.46. Found: C, 79.71;
H, 5.14; N, 15.63.
4.2.1.11. 2-Phenyl-N-[(4-methoxyphenyl)methylene]-1-H-pyrrolo
[2,3-b]quinoxaline-1-amine 4k. Purification by silica gel column
chromatography (chloroform/methanol¼50/1): TLC (chloroform/
methanol¼50/1) Rf¼0.53; solid; mp¼154e156 ꢀC;
n (KBr): 3050,
1600 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 3.85 (s, 3H), 7.10 (d,
J¼8.7 Hz, 2H), 7.20 (s, 1H), 7.54e7.66 (m, 3H), 7.68e7.72 (m, 1H),
7.73e7.81 (m, 2H), 7.84 (d, J¼8.0 Hz, 2H), 7.97 (dd, J¼8.0, 1.6 Hz, 2H),
7.16e8.18 (m, 2H), 10.25 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d
55.9, 99.4, 115.0, 127.0, 128.0, 128.6, 128.8, 128.9, 129.1, 129.2,
129.9, 130.3, 130.4, 130.6, 132.0, 132.1,138.4, 140.8, 141.1,142.0,151.4,
23. Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4531e4534.