Using Calcium Carbide as an Acetylene Source for Cascade Synthesis of Pyrrolo[2,3-b]quinoxalines via Copper-Free Sonogashira Coupling Reaction

Article abstract of DOI:10.1002/hlca.201800004

A palladium-catalyzed cascade protocol has been established for the synthesis of 4-methyl-1-(1H-pyrrolo[2,3-b]-quinoxalin-2-yl)cyclohexanols and 2-phenyl-1-(1H-pyrrolo[2,3-b]quinoxalin-2-yl)propan-1-ols through the reaction of N-alkyl(aryl)-3-chloroquinox

Full text of DOI:10.1002/hlca.201800004

Article Type: Full Paper
Using calcium carbide as an acetylene source for cascade synthesis of
pyrrolo[2,3-b]quinoxalines via copper-free Sonogashira coupling reaction
Mahsa Fakhariana, Ali Keivanloo,*a Mohammad Reza Nabidb
aFaculty of Chemistry, Shahrood University of Technology, Shahrood 36199-95161, Iran.
bDepartment of Chemistry and Petroleum Faculty of Sciences, Shahid Beheshti University,
Evin, Tehran, Iran.
E-mail addresses: akeivanloo@yahoo.com; keivanloo@shahroodut.ac.ir
Abstract
A palladium-catalyzed cascade protocol has been established for the synthesis of pyrrolo[2,3-
b]quinoxalin-2-yl)-4-methylcyclohexanols
and
pyrrolo[2,3-b]quinoxalin-2-yl)-2-
phenylpropan-1-ols through the reaction of N-alkyl(aryl)-3-chloroquinoxaline-2-amines with
calcium carbide and cyclohexanones or 2-phenylpropanal. This one-pot process, carried out
without any copper salt in the key step of the Sonogashira coupling reaction, provides an
efficient method for the synthesis of 2,3-disubstituted pyrrolo[2,3-b]quinoxalines in the
presence of catalytic amounts of Pd(PPh3)2Cl2 in DMSO/H2O with high yields. The benefit of
this strategy is the use of a commercially available, inexpensive, and less hazardous primary
chemical feedstock, calcium carbide, as an acetylene source in a wet solvent.
Keywords: Calcium carbide, Pyrrolo[2,3-b]quinoxalines, Copper-free, Sonogashira
coupling.
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lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/hlca.201800004
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Introduction
The chemistry of carbon-carbon triple bonds has been a permanent source of fundamentally
important processes and technologies.[1] Acetylene is one of the primary building blocks in
synthetic organic and industrial chemistry. It has been the main industrial source of vinyl
chloride, acrylonitrile, vinyl acetate, acetaldehyde, and several other important compounds
for many decades. Calcium carbide has a number of advantages over acetylene gas. Neither
oil nor natural gas is required to synthesize calcium carbide, its transportation does not have
the same risks as for acetylene, there is no need to use complicated high-pressure equipment,
and working with calcium carbide is safer and more convenient.[2] Furthermore, the use of
calcium carbide in organic synthesis is more cost-efficient and safer than the use of acetylene
gas. The use of calcium carbide in the presence of palladium catalyst is an efficient protocol
for the synthesis of various functional acetylene derivatives. However, its low solubility in
almost all solvents and the difficulty in controlling mono-substitution reactions are the major
challenges in the direct synthesis of functionalized acetylene derivatives from CaC2. Cheng
and co-workers have reported the synthesis of symmetric diarylethynes from aryl bromides
using CaC2.[3] This strategy was successfully applied for the synthesis of enaminones and
propargylic amines through the three-component coupling reaction of CaC2, aryl aldehydes,
and amines [4] as well as a convenient method for the preparation of propargyl alcohols by
reacting CaC2 with aldehydes and ketones in the presence of 50 mol% of cesium carbonate in
aqueous DMSO at 60 °C.[5] Novel protocols have already been developed for the synthesis of
various functional molecules such as propargylamines,[6] diarylethynes,[7] triazoles,[8] and
[9]
enaminones
from calcium carbide. The use of ethynylmagnesium bromide has also been reported recently
as a commercial acetylene surrogate in the Kumada-Negishi-type coupling reactions.[10,11] It
was further demonstrated in these protocols that, unlike the traditional methods, multiple
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protection and de-protection steps could be avoided with the direct usage of calcium carbide.
This greatly reduced the number of synthetic steps, resulting in a more efficient and greener
organic synthesis.
The Sonogashira reaction is an important process that is most widely used for the C(sp2)-
C(sp) bond-formation reactions in organic synthesis.[12] It provides an efficient method for
the synthesis of aryl alkynes, which are interesting intermediates for the preparation of a
[13]
variety of target compounds with applications ranging from natural products
and
[14]
pharmaceuticals
to molecular organic materials.[15] In the Sonogashira coupling reaction,
addition of a catalytic amount of copper(I) iodide, as a co-catalyst, greatly accelerates the
reaction, thus enabling the performance of alkynylation at room temperature.[16] The addition
of copper salts in the typical Sonogashira coupling reactions also have drawbacks such as
being environmentally unfriendly and difficult to recover reagent, and the in situ generation
of copper acetylides under the reaction conditions often generates homo-coupling products of
the terminal alkyne (Glaser coupling).[17] This side-reaction is especially problematic when
the terminal acetylene is difficult to obtain or expensive and usually difficult to separate from
the desired products,[18] and it has been shown that the presence of a reductive atmosphere
formed by difficult-to-handle hydrogen can diminish homocoupling [19] as well as the slow
addition of the acetylene.[20] In the recent years, a significant modification has been reported
for the Sonogashira coupling procedure, [21-24] and efficient copper-free reactions have been
developed.[25-27] These copper-free methodologies are usually called the copper-free
Sonogashira coupling reactions. Although copper-free Sonogashira coupling reactions of
terminal alkynes with aryl iodides have been widely investigated, few examples with aryl
chlorides [28–30] and heteroaryl chlorides [31-33] have been reported.
Multi-component reactions (MCRs) are one-pot reactions in which three or more starting
materials react sequentially in a single operation to form a single product, where basically all
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or most of the atoms of the starting materials contribute to the final product formed. In the
last decade, transition metals have been widely used for catalysis of new MCRs. Expectedly,
palladium-catalyzed processes have received a dominant position; yet, other transition metal
complexes such as the rhodium, ruthenium, and copper ones are catching up, implying
organometallic elementary steps that reach even further than the cross-coupling and
carbometallation reactions.[34-36]
Pyrroloquinoxalines have been extensively studied as bioactive compounds, and many of
them are known to be biologically and medicinally useful molecules such as anti-HIV agents,
anti-malarial agents, antagonist agents, anti-cancer agents, and PARP-1 inhibitors.[37]
Recently, we have reported the synthesis of pyrrolo[2,3-b]quinoxaline derivatives by the
Sonogashira coupling reaction of N-alkyl-3-chloroquinoxaline-2-amines with terminal
alkynes,[38] propargyl bromide,[39] and propargyl alcohols,[40] followed by the subsequent
cyclization in a one-pot process. In this work, we attempted to make this overall approach
more attractive synthetically using calcium carbide as an acetylene source for the preparation
of pyrrolo[2,3-b]quinoxalines.
Result and discussion
In continuation of our group’s efforts on the application of palladium catalyst for the
synthesis of heterocyclic compounds,[41] we have recently used calcium carbide (CaC2) as a
commercially available, low-cost feedstock, safe, and inexpensive reagent for the synthesis of
quinoxaline chalcones.[42] In the present work, we wish to report the use of CaC2 for the
synthesis of new 1,2-disubstituted pyrrolo[2,3-b]quinoxalines. A cascade palladium-catalyzed
reaction of N-alkyl(aryl)-3-chloroquinoxaline-2-amines 1a-i, calcium carbide 2, and carbonyl
compounds (3a-c) in DMSO/H2O afforded pyrrolo[2,3-b]quinoxalines substituted by
cyclohexanol or phenylpropan-1-ol at position 2 with high yields (Scheme1).
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Scheme 1: One-pot synthesis of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines from N-
alkyl(aryl)-3-chloroquinoxaline-2-amines (1), calcium carbide (2), and cyclohexanones (3a,
b) or 2-phenylpropionaldehyde (3c).
In 2013, Zhang and co-workers,[5] reported the synthesis of terminal acetylenic alcohols from
calcium carbide and a restricted number of ketones or aldehydes. According to this work, the
best conditions for the preparation of acetylenic alcohols were 2.5 eqiv. CaC2, 1 eqiv.
aldehyde or ketone, and 0.05 eqiv. Cs2CO3 in 2 vol% DMSO/H2O at 60 ᵒC. We used this
protocol for the synthesis of 1,2-disubstituted pyrrolo[2,3-b]quinoxalines
through palladium-catalyzed cascade reactions. In order to optimize the reaction
conditions, the reaction of cyclohexanone (3a), calcium carbide (2) and N-butyl-3-
chloroquinoxalin-2-amine (1c) was used as a model reaction. The investigation, aimed at
finding suitable conditions for this cascade transformation, was carried out by the reaction
with different bases, catalysts, temperatures, and reaction times in the second step of the
reaction. Studies were conducted using different bases including Cs2CO3, K2CO3, Et3N, and
morpholine for the Sonogashira reaction/heteroannulation. It was found that the organic bases
were more suitable than the inorganic ones, and that triethylamine was the most effective
base (Table 1, entry 2). Also we studied several palladium catalysts such as Pd(PPh3)2Cl2,
Pd(OAc)2, Pd(dba)2, and Pd/C in the presence and absence of copper salt. We observed that
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two side-reactions occurred in the presence of copper(I) iodide: one, homo-coupling reaction
of copper acetylide with N-butyl-3-chloroquinoxaline-2-amine 1c to afford
bisheteroarylethyne 6c and the other, hydrolysis of chloroquinoxalineamine 1c to 3-
(buthylamino)quinoxalin-2(1H)-one (7c). The use of inorganic bases or copper(I) salt
increased the hydrolyzed side-product 7ac (Table 1, entries 13-16). According to the
optimization table, Pd(PPh3)2Cl2 was the best catalytic system, and afforded the desired
product 4c with a high reaction yield (85%) (Table 1, entry 2). The product formed also
depended upon the reaction time. It is noteworthy that the uncyclized compound 5c was
isolated as a major product in low reaction times (2-3 h) (Table 1, entries 7 and 9).
Apparently, 5c is an intermediate of this reaction. The cyclized product 4c was formed as a
major product in a prolonged reaction time; after 6-8 h, it was the sole product (Table 1, entry
7). The suitable reaction temperature was 60 °C; increasing the reaction temperature to 80 °C
did not increase the reaction yield (Table 1, entry 8).
Table 1: Optimization reaction conditions for synthesis of 1,2-disubstituted pyrrolo[2,3-
b
]quinoxalines from cyclohexanone 3a, calcium carbide
2
, and N-butyl-3-chloroquinoxalin-2-
amine 1c a
.
T
Yield (%)
5c 6c
Time
(h)
Entry
Base
Catalyst
4c
(℃
7c
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1
2
Et3N
Et3N
6
6
3
6
6
6
6
6
6
3
6
3
6
6
6
6
60
60
60
60
60
60
80
60
60
60
60
60
60
60
60
80
40
85
20
60
30
50
80
75
40
10
60
40
30
15
25
15
-
-
40
-
-
-
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
3
Et3N
70
10
20
20
-
-
-
4
Et3N
Pd(OAc)2
Pd/C
-
-
5
Et3N
-
-
6
Et3N
Pd(dba)2
-
-
7
Et3N
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2/CuI
-
-
8
DIPEA
DIPEA
DIPEA
Morpholine
Morpholine
Cs2CO3
Cs2CO3
K2CO3
K2CO3
-
-
-
9
-
30
-
-
10
11
12
13
14
15
16
75
-
-
-
-
20
-
-
-
-
45
40
50
30
-
30
-
-
Pd(PPh3)2Cl2
-
35
Pd(PPh3)2Cl2/CuI
aReaction conditions: cyclohexanone (1 mmol), Cs2CO3 (0.5 mmol), calcium carbide (2.5 mmol)
DMSO/H2O (50:1 mL), at 60 ᵒC, 8 h; and then adding 1a (0.5 mmol), catalyst (0.05 mmol), base (3.0
mmol), reaction time (h), reaction temperature (ᵒC).
With the optimized reaction conditions in hand, we looked into expanding
the substrate scope of this reaction system. In the first step of the
reaction, only a few number of aldehydes and ketones were effective.
Straight-chain aldehydes, cyclopentanone, and aromatic aldehydes and
ketones failed to give the desired product. In 2015, Seidel and Schreiner
reported a simple method for the ethynylation of aldehydes and ketones by
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fluoride-assisted activation of calcium carbide. In this method, the
reaction of water with solid calcium carbide gives ethynylcalcium
hydroxide, which is activated by fluoride from TBAF·3H2O to form the
corresponding ate-complex that attacks the carbonyl compounds.[43] In this
article, the restrictions of procedure due to the aldol condensation of
carbonyl compounds in the basic medium or steric and torsional strains have
been explained. A pKa value of 26.4 for the carbonyl component was
considered as a lower limit to avoid an aldol condensation.[43]
After obtaining the best reaction conditions for the Sonogashira coupling/heteroannulation
step, we enhanced a facile cascade procedure for the synthesis of 1,2-disubstituted
pyrrolo[2,3-b]quinoxalines by the three component reaction of N-alkyl(aryl)-3-
chloroquinoxaline-2-amines (1a-i), calcium carbide (2), and cyclohexanone derivatives
(3a,b) or 2-phenylpropanal (3c) in the presence of Pd(PPh3)2Cl2 as the catalyst. The results
obtained are shown in Table 2.
Table 2: One-pot synthesis of 1,2-dsubstituted pyrrolo[2,3-b]quinoxalines from reaction of N-
alkyl(aryl)-3-chloroquinoxaline-2-amine, calcium carbide, and carbonyl compounds.a
Entry
1
Quinoxaline amine
Carbonyl
compound
Product
Yield
(%)
85
3a
3b
4a
1a
2
85
4b
1b
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3
4
70
85
3a
4c
1c
3a
3a
4d
4e
1d
5
7
85
84
1e
3a
4f
1f
8
9
75
3a
4g
1g
75
78
1h
1i
4h
3b
3b
10
4i
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11
12
70
70
3c
4j
1a
3c
1i
4k
aReaction conditions: Cyclohexanone (1 mmol), Cs2CO3 (0.5mmol), calcium carbide (2.5 mmol),
DMSO/H2O (50:1 mL), at 60 ᵒC, 8 h; and then adding 1a (0.5 mmol), catalyst (0.05 mmol), Et3N (3.0
mmol), reaction time (6-8 h), reaction temperature (60 ᵒC).
The coupling intermediates 5a and 5b were formed as major products in a stepwise reaction
manner in low reaction times (2-3 h). When these intermediates were slowly warmed in
CH3CN in the presence of morpholine, used as a base, cyclization occurred, and the
final products 4a and 4b were formed in excellent yields (Scheme 3).
Scheme 3: Synthesis of coupling intermediates 1-((3-(alkylamino)quinoxalin-2-
yl)ethynyl)cyclohexanols
5 and their cyclization to pyrrolo[2,3-b]quinoxalines 4.
The structural assignments of the products were based upon the NMR spectroscopic
1
and mass analysis data. The H NMR spectrum of 4c exhibited two multiplets for the
four aromatic protons of the quinoxaline ring at δ 8.10-8.18 and 7.60-7.70,
respectively. An aromatic proton at δ 6.38 was characteristic of the fused pyrrole ring.
In the aliphatic region, the triplet at δ 4.62 is due to the methylene protons of the butyl
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group. The singlet at δ 2.88 was assigned to the hydroxyl group proton. The multiplets
at δ 1.43-2.20 are due to the other seven methylene protons of the butyl and
cyclohexyl groups. The triplet at δ 0.97 is due to the methyl protons of the butyl group.
The 13C NMR spectrum for this compound showed 18 peaks for the carbon atoms. The
mass spectrometer used recorded the molecular ion peak at [M+H] 324 for this
compound.
2-
The acetylide ion in calcium carbide (C2 ) contains two nucleophilic carbons, which, in
principle, may react with two carbonyl molecules. However, propargyl alcohols with a
terminal alkynyl proton were formed exclusively, and no disubstituted acetylenes were
observed. A possible reaction mechanism probably includes the following steps, proposed
for the formation of propargyl alcohols from CaC2.5 The trace amount of water promotes the
reaction by breaking down the polymeric structure of calcium carbide to form calcium
acetylide A. The presence of base could stabilize the acetylide intermediate and prevent the
formation of acetylene. The cesium cation then activates the aldehyde or ketone, and induces
a nucleophilic attack of acetylide A on the carbonyl group to afford alkoxide C via
intermediate B. Propargyl alcohol D is formed by hydrolysis of C. In continuation, a copper-
free cross-coupling reaction takes place between heteroaryl 1 and propargyl alcohol D to
afford intermediate 5. Finally, ring closure by hydroamination/cyclization leads to the
formation of 2-substituted pyrrolo[2,3-b]quinoxalines 4 (Scheme 3).
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Scheme 3. Proposed mechanism for formation of 1,2-disubstituted pyrrolo[2,3-
b]quinoxalines.
Conclusion
We have developed a practical and efficient strategy for the synthesis of pyrrolo[2,3-
b]quinoxalines by the reaction of N-alkyl(aryl)-3-chloroquinoxaline-2-amines with calcium
carbide and cyclohexanones or 2-phenylpropanal under mild conditions. This one-pot
cascade reaction was carried out in the presence of catalytic amounts of Pd(PPh3)2Cl2 in
DMSO/H2O without any copper salt. The benefit of this strategy is the use of commercially
available calcium carbide, as an acetylene source, in a wet solvent.
General information
Melting points were recorded on a Thermocouple digital melting point apparatus. IR spectra
were recorded on a Shimadzu IR-435 grating spectrophotometer. For column
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chromatography, Merck Kieselgel 100 was used as the stationary phase. NMR spectra were
1
obtained as CDCl3 solutions using a Bruker 400 and 300 MHz NMR spectrometer. H NMR
13
signals were reported relative to Me4Si (δ 0.0) or residual CHCl3 (δ 7.26). C NMR signals
were reported relative to CDCl3 (δ 77.16). Multiplicities were described using the following
abbreviations: s = singlet, d = doublet, t = triplet, and m = multiplet. Mass spectra were
recorded using a 5975C spectrometer supplied from Agilent Technologies Company.
Typical experimental procedure for synthesis of 2,3-disubstituted pyrrolo[2,3-
b]quinoxalines (4)
The mixture of a ketone or aldehyde (1 mmol), Cs2CO3 (0.5 mmol), calcium carbide (2.5
mmol), and DMSO/H2O (5:0.1 mL) was stirred at 60 ᵒC for 8 h. After completion of the
reaction (monitored by TLC) an N-alkyl(Aryl)-3-chloroquinoxaline-2-amine (0.5 mmol),
Pd(PPh3)2Cl2 (0.05 mmol), and triethylamine (3.0 mmol) were added, respectively. Stirring
the reaction mixture was continued for another 6-8 h at 60 ᵒC. After completion of the
reaction (monitored by TLC), the solvent was evaporated, and the remaining solid was
washed with H2O and then dried. The crude product was purified by column chromatography
(silica gel 100) using n-hexane/ethyl acetate (80/20).
1-(1-methyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)cyclohexanol (4a)
1
yellow solid; mp, 193-195 ᵒC; H NMR (300 MHz, CDCl3): δ 1.54-1.92 (m, 8H, 4CH2),
2.08-2.11 (m, 2H, CH2), 3.34 (s, 1H, OH), 4.12 (s, 3H, CH3), 6.29 (s, 1H, CH of pyrrole),
13
7.55-7.64 (m, 2H, 2CH of quinoxaline), 8.06-8.12 (m, 2H, 2CH of quinoxaline); C NMR
(75 MHz, CDCl3): 21.5, 25.4, 30.8, 36.8, 70.9, 96.4, 126.3, 127.3, 128.1, 128.5, 128.5, 139.2,
140.3, 142.1, 158.1; IR (KBr): 3407, 2944, 2864, 1574, 1523, 1420, 1337, 1177, 966, 761
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cm–1; m/z [M+H], 282. Anal. Calcd. for C17H19N3O: C, 72.57; H, 6.81; N, 14.94; Found: C,
72.50; H, 6.84; N, 14.98.
1-(1-propyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)cyclohexanol (4b)
1
Yellow solid; mp, 140-142 ᵒC; H NMR (300 MHz, DMSO-d6): δ 0.98 (t, J = 7.4 Hz, 3H,
NCH2CH2CH3), 1.57-1.64 (m, 4H, CH2), 1.82-1.97 (m, 6H, CH2), 2.08-2.11 (m, 2H,
NCH2CH2CH3), 4.56 (t, J = 7.7 Hz, 2H, NCH2CH2CH3), 5.46 (s, 1H, OH), 6.62 (s, 1H, CH
of pyrrole), 7.66-7.72 (m, 2H, 2CH of quinoxaline), 8.07-8.12 (m, 2H, 2CH of quinoxaline);
13C NMR (75 MHz, DMSO-d6): 11.8, 12.6, 22.9, 25.6, 37.3, 46.1, 70.9, 96.2, 126.6, 127.6,
128.5, 129.0, 138.8, 140.6, 142.8, 143.3, 160.5; IR (KBr): 3317, 2956, 2932, 1582, 1532,
1465, 1414, 1096, 755 cm–1; m/z [M+H], 310. Anal. Calcd. for C19H23N3O: C, 73.76; H,
7.49; N, 13.58; Found: C, 73.79; H, 7.74; N, 13.59.
1-(1-butyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)cyclohexanol (4c)
1
Yellow solid; mp, 113-115 ᵒC; H NMR (300 MHz, CDCl3): δ 0.97 (t, J = 7.4 Hz, 3H,
NCH2CH2CH2CH3), 1.43-1.55 (m, 2H, CH2), 1.58-1.79 (m, 4H, 2CH2), 1.82-1.93 (m, 6H,
3CH2), 2.08-2.20 (m, 2H, CH2), 2.88 (s, 1H, OH), 4.62 (t,
J
= 7.9 Hz, 2H,
NCH2CH2CH2CH3), 6.38 (s, 1H, CH of pyrrole), 7.61-7.68 (m, 2H, 2CH of quinoxaline),
13
8.11-8.17 (m, 2H, 2CH of quinoxaline); C NMR (75 MHz, CDCl3): 13.8, 20.3, 21.5, 25.3,
31.9, 37.3, 44.5, 71.0, 96.4, 126.3, 127.1, 128.5, 130.5, 139.3, 140.3, 142.2, 143.6, 158.4; IR
(KBr): 3424, 3280, 2944, 2848, 1558, 1520, 1459, 1401, 1292, 1216, 1068, 956, 777 cm–1;
m/z [M+H], 324. Anal. Calcd. for C20H25N3O: C, 74.27; H, 7.79; N, 12.99; Found: C, 74.19;
H, 7.76; N, 12.95.
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1-(1-cyclohexyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)cyclohexanol (4d)
1
Yellow solid; mp, 196-197 ᵒC; H NMR (300 MHz, CDCl3): δ 1.49-2.13 (m, 20H, 10CH2)
2.51 (m, 1H, OH), 5.03-5.12 (m, 1H, -CH-N), 5.13 (m, 1H, CH), 6.44 (s, 1H, CH of pyrrole),
13
7.63-7.68 (m, 2H, 2CH of quinoxaline), 8.11-8.14 (m, 2H, 2CH of quinoxaline); C NMR
(75 MHz, CDCl3): 21.6, 25.4, 26.6, 30.4, 37.4, 57.8, 71.2, 96.9, 126.2, 126.9, 128.0, 128.6,
128.7, 129.6, 140.0, 157.4; IR (KBr): 3323, 2963, 2834, 1556, 1528, 1483, 1434, 1327, 1112,
755 cm–1; m/z [M+H], 350. Anal. Calcd. for C22H27N3O: C, 74.61; H, 7.79; N, 12.02; Found:
C, 74.56; H, 7.81; N, 12.04.
1-(1-(2-hydroxyethyl)-1H-pyrrolo[2,3-b]quinoxalin-2-yl)cyclohexanol (4e)
1
yellow solid; mp, 121-123 ᵒC; H NMR (300 MHz, CDCl3): δ 1.28-1.34 (m, 2H, 1CH2),
1.56-1.86 (m, 8H, 4CH2), 2.02-2.05 (m, 2H, 2OH), 4.13 (t, 2H, J = 4.7, -NCH2CH2OH), 4.90
(t, 2H, J = 4.7 Hz -NCH2CH2OH), 6.36 (s, 1H, CH of pyrrole), 7.56-7.62 (m, 2H, 2CH of
quinoxaline), 7.93-7.96 (m, 1H, CH of quinoxaline), 8.01-8.04 (m, 1H, CH of quinoxaline);
13C NMR (75 MHz, CDCl3): 21.4, 25.3, 38.0, 46.9, 61.8, 70.9, 97.1, 126.7, 127.6, 127.9,
128.4, 138.4, 140.2, 142.2, 143.5, 159.0; IR (KBr): 3468, 2954, 2934, 1534, 1513, 1445,
1415, 1130, 755 cm–1; m/z [M+H], 312. Anal. Calcd. for C18H21N3O2: C, 69.43; H, 6.80; N,
13.49; Found: C, 69.51; H, 6.75; N, 13.45.
1-(1-(p-tolyl)-1H-pyrrolo[2,3-b]quinoxalin-2-yl)cyclohexanol (4f)
1
Yellow solid; mp, 197-200 ᵒC; H NMR (300 MHz, CDCl3): δ 1.41-1.59 (m, 6H, 3CH2),
1.76-1.89 (m, 4H, 2CH2), 1.92 (m, 1H, OH), 6.72 (s, 1H, CH pyrrole), 7.29 (s, 4H, ArH),
7.32-7.57 (m, 2H, 2CH of quinoxaline), 7.89-7.93 (m, 1H, CH of quinoxaline), 8.07-8.10 (m,
1H, CH of quinoxaline); 13C NMR (75 MHz, CDCl3): 21.4, 21.6, 25.2, 37.3, 71.9, 98.7,
126.7, 127.3, 128.7, 128.8, 130.0, 130.1, 134.7, 139.1, 139.7, 141.0, 142.1, 145.5, 158.5; IR
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(KBr): 3296, 2944, 2848, 1641, 1513, 1414, 1337, 1132, 1065,755 cm–1; m/z [M+H], 358.
Anal. Calcd. for C23H23N3O: C, 77.28; H, 6.49; N, 11.76; Found: C, 77.33; H, 6.50; N, 11.79.
1-(1-phenyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)cyclohexanol (4g)
1
Yellow solid; mp, 195-198 ᵒC; H NMR (300 MHz, DMSO-d6): δ 1.09-1.32 (m, 2H, CH2),
1.39-1.69 (m, 5H, CH2), 1.73-1.87 (m, 3H, CH2), 5.27 (m, 1H, OH), 6.91 (s, 1H, CH pyrrole),
7.51-7.55 (m, 5H, ArH), 7.60-7.72 (m, 2H, 2CH of quinoxaline), 7.89-7.92 (m, 1H, CH of
quinoxaline), 8.13-8.16 (m, 1H, Ar-H); 13C NMR (75 MHz, DMSO-d6): 21.7, 25.5, 36.9,
70.6, 98.4, 127.0, 127.8, 128.5, 129.0, 129.1, 131.1, 138.0, 139.1, 140.8, 142.4, 145.2, 161.2;
IR (KBr): 3366, 2956, 2832, 1635, 1582, 1532, 1465, 1414, 1096, 755 cm–1; m/z [M+H],
344. Anal. Calcd. for C22H21N3O: C, 76.94; H, 6.16; N, 12.24; Found: C, 76.90; H, 6.20; N,
12.22.
1-(1-ethyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)-4-methylcyclohexanol (4h)
1
yellow solid; mp, 180-183 ᵒC; H NMR (300 MHz, CDCl3): δ 0.93 (d, 3H, CH3), 1.20-1.34
(m, 2H, CH2), 1.51 (t, 3H, NCH2CH3), 1.60-1.68 (m, 1H, CH), 1.70-1.95 (m, 4H, 2CH2),
2.38-2.50 (m, 2H, CH2), 2.72 (s, 1H, OH), 4.71 (q, 2H, J = 6.8, NCH2CH3), 6.60 (s, 1H, CH
pyrrole), 7.61-7.70 (m, 2H, 2CH of quinoxaline), 8.12-8.16 (m, 2H, 2CH of quinoxaline); 13C
NMR (75 MHz, CDCl3): 15.1, 20.3, 30.4, 30.8, 36.8, 39.5, 71.8, 99.0, 126.3, 127.3, 128.3,
128.7, 139.4, 140.5, 142.3, 143.4, 155.3; IR (KBr): 3398, 2954, 2824, 1530, 1512, 1469,
1415, 1167, 755 cm–1; m/z [M+H], 310. Anal. Calcd. for C19H23N3O: C, 73.76; H, 7.49; N,
13.58; Found: C, 73.66; H, 7.42; N, 13.65.
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1-(1-benzyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)-4-methylcyclohexanol (4i)
1
Yellow solid; mp, 200-203 ᵒC; H NMR (300 MHz, DMSO-d6): δ 0.88-2.92 (m, 13H, CH3,
4CH2, CH, OH), 3.57 (s, 2H, NCH2), 5.93 (s, 1H, CH of pyrrole), 6.93-7.43 (m, 5H, ArH),
13
7.61-7.72 (m, 2H, 2CH of quinoxaline), 7.99-8.17 (m, 2H, 2CH of quinoxaline); C NMR
(75 MHz, DMSO-d6): 20.4, 30.8, 36.7, 47.7, 66.8, 72.0, 100.1, 125.9, 126.5, 126.8, 127.5,
128.5, 128.9, 137.9, 138.8, 139.7, 140.9, 141.9, 148.2, 155.4; IR (KBr): 3421, 2945, 2812,
1643, 1616, 1587, 1545, 1476, 1423, 1045, 755 cm–1; m/z [M+H], 372. Anal. Calcd. for
C24H25N3O: C, 77.60; H, 6.78; N, 11.31; Found: C, 77.62; H, 6.82; N, 11.30.
1-(1-methyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)-2-phenylpropan-1-ol (4j)
Yellow solid; mp, 206-209 ᵒC; 1H NMR (300 MHz, DMSO-d6): δ 1.45 (d, 3H, J = 6.9 Hz, -
CHCH3), 3.78 (m, 4H, NCH3 and OH), 5.08 (m, 1H, CHCH3), 6.03 (d, 1H, J = 5.7 Hz, -
CHOH), 6.58 (s, 1H, CH of pyrrole) 7.11-7.31 (m, 5H, ArH), 7.67-7.72 (m, 2H, 2CH of
13
quinoxaline), 8.04-8.09 (m, 2H, 2CH of quinoxaline); C NMR (75 MHz, DMSO-d6): 16.4,
28.6, 45.6, 72.6, 98.3, 126.5, 127.1, 127.5, 127.6, 128.1, 128.5, 128.6, 128.7, 139.0, 140.4,
142.1, 142.4; IR (KBr): 3234, 2935, 2932, 1643, 1587, 1545, 1456, 1413, 1145, 755 cm–1;
m/z [M+H], 318. Anal. Calcd. for C20H19N3O: C, 75.69; H, 6.03; N, 13.24; Found: C, 75.60;
H, 6.06; N, 13.22.
1-(1-benzyl-1H-pyrrolo[2,3-b]quinoxalin-2-yl)-2-phenylpropan-1-ol (4k)
1
Yellow solid; mp, 206-209 ᵒC; H NMR (300 MHz, DMSO-d6): δ 1.35 (d, 3H, J = 6.9 Hz,
CHCH3), 3.38 (m, 1H, OH), 4.92 (m, 1H, CHCH3), 5.59 (s, 2H, NCH2), 6.04 (d, 1H, J = 6.3
Hz, CHOH), 6.77 (s, 1H, CH of pyrrole) 7.04-7.35 (m, 5H, ArH), 7.41-7.46 (m, 5H, ArH),
7.67-7.73 (m, 2H, 2CH of quinoxaline), 8.01-8.04 (m, 1H, CH of quinoxaline), 8.10-8.14 (m,
1H, 2CH of quinoxaline); 13C NMR (75 MHz, DMSO-d6): 16.7, 45.0, 45.1, 71.6, 99.2, 126.4,
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126.6, 126.7, 126.8, 127.6, 128.1, 128.3, 128.4, 128.5, 128.7, 128.8, 137.4, 139.3, 140.7,
141.9, 142.9, 153.9; IR (KBr): 3221, 2965, 2932, 1587, 1545, 1456, 1423, 1135, 755 cm–1;
m/z [M+H], 394. Anal. Calcd. for C26H23N3O: C, 79.36; H, 5.89; N, 10.68; Found: C, 79.38;
H, 5.88; N, 10.64.
Typical experimental procedure for synthesis of 1-((3-((cyclo)alkylamino)quinoxalin-2-
yl)ethynyl)cyclohexanol (5a-b)
The mixture of a cyclohexanone (1 mmol), Cs2CO3 (0.5 mmol) and calcium carbide (2.5
mmol) DMSO-H2O (5:0.1 mL) was stirred at 60 ᵒC for 8 hours. After completion of the
reaction (8 h) an N-alkyl-3-chloroquinoxaline-2-amine (0.5 mmol), Pd(PPh3)2Cl2 (0.05
mmol), and Triethylamine (3.0 mmol) were added, respectively. Stirring the reaction mixture
was continued for another 2-3 h at 60 ᵒC. After completion of the reaction (monitored by
TLC), the solvent was evaporated, and the remaining solid was washed with H2O and then
dried. The crude product was purified by column chromatography (silica gel 100) using n-
hexane/ethyl acetate (80/20).
1-((3-(butylamino)quinoxalin-2-yl)ethynyl)cyclohexanol (5a)
1
Yellow solid; mp, 103-106 ᵒC; H NMR (300 MHz, DMSO-d6): δ 0.95 (t, J = 7.5 Hz, 3H,
NHCH2CH2CH2CH3), 1.32-1.57 (m, 6H, 3CH2), 1.60-1.74 (m, 6H, CH2), 1.94-1.97 (m, 2H,
NHCH2CH2CH2CH3), 3.50-3.55 (m, 2H, NHCH2CH2CH2CH3), 5.83 (m, 1H, OH), 6.58 (t, J
= 6.0, 1H, NHCH2CH2CH2CH3), 7.35-7.40 (m, 1H, CH of quinoxaline), 7.58-7.61 (m, 2H,
2CH of quinoxaline), 7.75-7.77 (m, 1H, CH of quinoxaline); 13C NMR (75 MHz, DMSO-d6):
14.2, 20.2, 23.1, 25.2, 31.2, 39.5, 40.6, 67.5 78.5, 102.5, 124.6, 126.1, 128.6, 130.8, 130.9,
136.3, 141.2, 151.7; IR (KBr): 3424, 2928, 2848, 1696, 1600, 1516, 1408, 1318, 1110, 752
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cm–1; m/z [M+H], 324. Anal. Calcd. for C20H25N3O: C, 74.27; H, 7.79; N, 12.99; Found: C,
74.32; H, 7.81; N, 12.92.
1-((3-(cyclohexylamino)quinoxalin-2-yl)ethynyl)cyclohexanol (5b)
1
Yellow solid; mp, 110-113 ᵒC; H NMR (300 MHz, CDCl3): δ 1.28-2.18 (m, 21H, 10CH2
and OH), 4.11-4.17 (m, 1H, CH), 7.24-7.30 (m, 1H, CH of quinoxaline), 7.42-7.48 (m, 2H,
2CH of quinoxaline), 7.56-7.60 (m, 1H, CH of quinoxaline); 13C NMR (75 MHz, CDCl3):
20.5, 23.9, 24.8, 30.6, 30.9, 31.5, 49.2, 66.2, 85.6, 103.5, 123.6, 124.7, 127.6, 138.3, 138.6,
139.0, 139.4, 148.2; IR (KBr): 3423, 2963, 2834, 1656, 1568, 1523, 1483, 1414, 1112, 755
cm–1; m/z [M+H], 350. Anal. Calcd. for C22H27N3O: C, 75.61; H, 7.79; N, 12.02; Found: C,
75.66; H, 7.82; N, 11.98.
Characterization data for 6 and 7
3,3'-(ethyne-1,2-diyl)bis(N-ethylquinoxalin-2-amine) (6h)
1
Yellow solid; mp, 100-103 ᵒC; H NMR (300 MHz, DMSO-d6): δ 1.24 (t, J = 6.9 Hz, 3H,
NHCH2CH3), 3.51-3.55 (m, 2H, NHCH2CH3), 7.39-7.40 (m, 2H, CH of quinoxaline and
NHCH2CH3 ), 7.62-7.63 (m, 2H, 2CH of quinoxaline), 7.79-7.81 (m, 1H, CH of
quinoxaline); IR (KBr): 3388, 2954, 2821, 1520, 1512, 1469, 1418, 1167, 755 cm–1; m/z
[M+H], 369. Anal. Calcd. for C22H20N6: C, 71.72; H, 5.47; N, 22.81; Found: C, 71.75; H,
5.40; N, 22.79.
3-(propylamino)quinoxalin-2(1H)-one (7b)
1
Yellow solid; mp, 140-142 ᵒC; H NMR (300 MHz, CDCl3): δ 1.07 (t, J = 7.4 Hz, 3H,
NHCH2CH2CH3), 1.71-1.82 (m, 2H, NHCH2CH2CH3), 3.55 (t, J = 6.7 Hz, 2H,
NHCH2CH2CH3), 6.34 (s, 1H, NHCH2CH2CH3), 7.16-7.28 (m, 3H, CH of quinoxaline),
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7.54-7.57 (m, 1H, CH of quinoxaline), 11.16 (s, 1H, NH-CO); IR (KBr): 3408, 2976, 2928,
1667, 1574, 1526, 1497, 1465, 1382, 1241, 1206, 748 cm–1; m/z [M+H], 204. Anal. Calcd.
for C12H15N3: C, 71.61; H, 7.51; N, 20.88; Found: C, 71.58; H, 7.54; N, 20.86.
Acknowledgment
We gratefully acknowledge the financial support of the Research Council of the Shahrood
University of Technology.
Supporting information
Supporting information for this work is available: copies of 1H and 13C spectra of all the new
compounds.
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