FeCl3 and morpholine as efficient cocatalysts for the one-step synthesis of quinoxalines from α-hydroxyketones and 1,2-diamines

Article abstract of DOI:10.1080/00397911.2010.523489

One-step conversion including intramolecular hydrogen bond decomposition, aerobic oxidation, and condensation from α-hydroxyketones and 1,2-diamines into quinoxalines is reported using FeCl₃ and morpholine as cocatalysts. Taylor & Francis Group, LLC.

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FeCl3 and Morpholine as Efficient
Cocatalysts for the One-Step Synthesis
of Quinoxalines from α-Hydroxyketones
and 1,2-Diamines
Weibin Song a , Peng Liu a , Min Lei a , Hanyun You a , Xubing Chen a ,
Hu Chen a , Lei Ma a & Lihong Hu a b
a School of Pharmacy, East China University of Science and
Technology, Shanghai, China
b Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, Shanghai, China
Accepted author version posted online: 26 Jul 2011.Published
online: 14 Sep 2011.
To cite this article: Weibin Song , Peng Liu , Min Lei , Hanyun You , Xubing Chen , Hu Chen , Lei
Ma & Lihong Hu (2012): FeCl3 and Morpholine as Efficient Cocatalysts for the One-Step Synthesis of
Quinoxalines from α-Hydroxyketones and 1,2-Diamines, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:2, 236-245
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Synthetic Communications1, 42: 236–245, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523489
FeCl3 AND MORPHOLINE AS EFFICIENT COCATALYSTS
FOR THE ONE-STEP SYNTHESIS OF QUINOXALINES
FROM a-HYDROXYKETONES AND 1,2-DIAMINES
Weibin Song,1 Peng Liu,1 Min Lei,1 Hanyun You,1
Xubing Chen,1 Hu Chen,1 Lei Ma,1 and Lihong Hu1,2
1School of Pharmacy, East China University of Science and Technology,
Shanghai, China
2Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai, China
GRAPHICAL ABSTRACT
Abstract One-step conversion including intramolecular hydrogen bond decomposition,
aerobic oxidation, and condensation from a-hydroxyketones and 1,2-diamines into
quinoxalines is reported using FeCl3 and morpholine as cocatalysts.
Keywords Cocatalyst; FeCl3; morpholine; quinoxaline
INTRODUCTION
As an important heterocycle core, quinoxaline has gained attention in recent
years. Quinoxaline derivatives exhibit different biological activities, which have
been used in anticancer,[1a] antibacterial,[1b] antidepressant,[1c] anticonvulsants,[1d]
antiviral,[1e] insecticidal,[1f] and anti-osteoclast[1g] reagents. In addition, it is also
applied in dyes,[2a] fluorescent materials,[2b] organic semiconductors,[2c] chemical
switches,[2d] DNA cleaving agents,[2e] and asymmetric catalysis.[2f]
Over the years, a number of methods have been developed for the synthesis of
quinoxalines. The most common one is the condensation of 1,2-diamines with
1,2-diketones,[3] among which some efficient catalysts were employed according to
the concept of green chemistry. In recent years, some new synthetic procedures
were developed, such as a-hydroxyketone oxidation trapping with 1,2-diamines,[4]
a-bromoketone cyclization–oxidation with 1,2-diamines,[5] epoxide oxidation
coupling with 1,2-diamines,[6] and chloroquinoxaline homocoupling reaction with
Received June 12, 2010.
Address correspondence to Lei Ma or Lihong Hu, School of Pharmacy, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China. E-mail: malei@ecust.edu.cn;
simmhulh@mail.shcnc.ac.cn
236

FeCl3 AND MORPHOLINE AS COCATALYSTS
237
Scheme 1. FeCl3 and morpholine as a cocatalyst for the synthesis of quinoxalines.
aromatic compounds.[7] However, these reported methods were limited by one or
more drawbacks, such as long reaction time, tedious workup, poor yield, use of toxic
and expensive reagents, and the use of expensive metal salts as catalysts. Therefore,
developing a more practical, environmentally friendly, and economical method for
the synthesis of quinoxalines is greatly needed.
Recently, iron cocatalysts have emerged as powerful catalysts in various
organic transformations because of their environmentally friendly, cheap, and
efficient character, including the Mizoroki–Heck cross-coupling reaction,[8a]
N-arylation of pyrazoles,[8b] alkene epoxidation,[8c] sulfide oxidation,[8d] enantio-
selective oxidation of racemic benzoins,[8e] asymmetric hydrogenation of ketones,[8f]
and synthesis of 2H-1-benzopyran derivatives.[8g] In this article, we report our recent
work using FeCl3and morpholine as cocatalysts, for the synthesis of quinoxaline
derivatives in good yields (Scheme 1).
RESULTS AND DISCUSSION
At first, a systematic study on the screening of catalysts for the synthesis of quin-
oxaline was carried out using o-phenylenediamine 1a and benzoin 2a (Table 1). As
shown in Table 1, a blank reaction was conducted in EtOH at 80 ꢀC, which resulted
in only a trace amount of quinoxaline after 3 h (Table 1, entry 1). The same reaction
using 10 mol% of CuSO4 ꢁ 5H2O and (NH4)2Ni(SO4)2 ꢁ 6H2O afforded poor yields of
the desired product (Table 1, entries 2 and 3), while the reaction gave 77% yield of 3a
in the presence of 10 mol% of FeCl3 (Table 1, entry 5). Furthermore, adding different
amounts of FeCl3 indicated that 10 mol% catalyst was the best ratio for this reaction
(Table 1, entries 5–8). To our surprise, although the quinoxaline yield was rather
poor when using 20 mol% of morpholine as a catalyst (Table 1, entry 4), we found
that huge amounts of benzoin 2a were oxidized to benzil because of the presence of
oxygen. Hence, we hypothesized that using FeCl3 and morpholine as cocatalysts
would get better results.
To test this hypothesis, we initially performed the reaction of o-phenylenedia-
mine 1a with benzoin 2a in EtOH at room temperature in the presence of 10 mol% of
FeCl3 and 20 mol% of morpholine; however, only 17% yield of 3a was obtained after
3 h (Table 1, entry 9). To our delight, the same reaction conducted in EtOH at 80 ꢀC
afforded the desired product of 3a in 95% yield within 1.5 h (Table 1, entry 11).
Decreasing or increasing the additive amount of morpholine showed no significant
effect on the yields (Table 1, entries 10–13). Therefore, 10 mol% of FeCl3 with
20 mol% of morpholine was considered to be the most optimal condition. Besides,
some other organic bases, such as triethylamine (TEA) and pyridine, were tested
under the same conditions and afforded the product in good yields also (90–93%)
(Table 1, entries 14 and 15).

238
W. SONG ET AL.
Table 1. Optimization of the reaction conditionsa
Entry
Catalyst (mol%)
Time (h)
Yield (%)b
1
2
—
3
Trace
11
13
26
77
54
73
71
27
87
95
96
96
93
90
CuSO4 ꢁ 5H2O (10)
(NH4)2Ni(SO4)2 ꢁ 6H2O (10)
Morpholine (20)
2
3
2
4
3
5
FeCl3 (10)
FeCl3 (5)
2
6
2
7
FeCl3 (15)
FeCl3 (20)
2
8
2
9c
10
11
12
13
14
15
FeCl3 (10), morpholine (20)
FeCl3 (10), morpholine (10)
FeCl3 (10), morpholine (20)
FeCl3 (10), morpholine (30)
FeCl3 (10), morpholine (40)
FeCl3 (10), TEA (20)
FeCl3 (10), pyridine (20)
3
1.5
1.5
1.5
1.5
1.5
1.5
aReaction conditions: o-phenylenediamine 1a (2 mmol), benzoin 2a (2 mmol), EtOH (5 mL), 80 ꢀC.
bIsolated yield after column chromatography.
cThe reaction was performed in EtOH at room temperature.
To evaluate the efficiency of this methodology, a series of 1,2-aryldiamines
and a-hydroxyketones were further subjected to condensation using 10 mol% of
FeCl3 with 20 mol% of morpholine as the catalyst (Table 2). Results in Table 2
showed that different aromatic substituents of a-hydroxyketones had no significant
effect on the yields (93–96%) of products (Table 2, entries 1–5), but using acetoin 2f
afforded only the desired products in 65–77% yields within 2 h (Table 2, entries 6, 9,
and 12). Furthermore, electron-donating groups at the phenyl ring of 1,2-diamine
favored the formation of products in greater yields (77–96%) (Table 2, entries
10–12), while electron-withdrawing groups gave slightly lesser yields (65–90%) and
needed longer times (Table 2, entries 7–9). The present catalyst was also suitable
for the reaction of 1,2-alkyldiamines and a-hydroxyketones. When 1,2-ethanedia-
mine 1d was treated with a-hydroxyketones, dihydropyrazines 3 m and 3n were
obtained in excellent yields (97–99%) within 0.3 h (Table 2, entries 13 and 14). We
also found that 10 mol% of FeCl3 alone could catalyze the reaction efficiently,
because 1,2-ethanediamine 1d itself also acted as an organic base catalyst in this
reaction. However, when we attempted to condense 1d with acetoin 2f, no product
was detected even after 3 h (Table 2, entry 15). In the case of (ꢂ)-trans-1,2-diamino-
cyclohexane 1e, steric factors and reaction temperature played key roles in affecting
the rate of the reaction and the structure of products. For example,
5,6,7,8-tetrahydro-2,3-diphenylquinoxaline 3p was obtained in 92% yield within 2 h

FeCl3 AND MORPHOLINE AS COCATALYSTS
239
Table 2. Synthesis of quinoxaline derivatives catalyzed by 10 mol% of FeCl3 and 20 mol% of morpholinea
Time (h) Yield (%)b
Entry
Diamine
Alcohol
Product
1
1.5
1.5
95[3c,3k]
2
3
1a
1a
95[3c]
1.5
1.5
94
4
1a
96[3k]
5
6
1a
1a
1.5
93[3g]
2
72[3c]
7
2
90[3k]
8
9
1b
1b
2
3
90[3g]
65[3i]
(Continued )

240
W. SONG ET AL.
Table 2. Continued
Entry
Diamine
Alcohol
Product
Time (h) Yield (%)b
10
1.5
96[3k]
11
12
1c
1c
1.5
1.5
94[3g]
77[3i]
13
0.3
>99[3g]
14
15
1d
1d
0.3
97[3g]
3
NRd
16
2
92[3l]
17c
12
42[3b]
aReaction conditions: o-phenylenediamine la (2 mmol), benzoin 2a (2 mmol), EtOH (5 mL), 80 ꢀC.
bIsolated yield.
cThe reaction was performed in CH2C12 at room temperature.
dNo reaction was observed.

FeCl3 AND MORPHOLINE AS COCATALYSTS
241
at 80 ꢀC (Table 2, entry 16), while the same reaction performed in CH2Cl2 at room
temperature afforded 4a,5,6,7,8,8a-hexahydro-2,3-diphenylquinoxaline 3q in only
42% yield after 12 h (Table 2, entry 17).
To probe the mechanism of the reaction catalyzed by the iron cocatalyst, we
designed the following experiment, and the results are summarized in Table 3. As
shown in Table 3, a blank reaction was conducted using benzoin 2a in EtOH at
80 ꢀC, and no reaction product was detected after 1 h (Table 3, entry 1). In addition,
the reaction catalyzed by aniline gave only a trace amount of the desired product 4a
(Table 3, entry 7), while moderate yields of benzil 4a were obtained in the presence of
20 mol% of morpholine, diethylamine, and n-butylamine (56–58%) (Table 3, entries 2,
9, and 10), which seemed a little better than the yields of TEA and pyridine (47–56%)
(Table 3, entries 6 and 8). However, when the reaction was catalyzed by morpholine
under Ar protection conditions, only a trace amount of benzil 4a was detected
(Table 3, entry 3). The reaction catalyzed by FeCl3 afforded the desired product 4a
in only 18% yield, but the yield of benzil 4a was improved to 93% when using FeCl3
and morpholine as cocatalysts.
Even though the exact reaction mechanism is not quite clear at the moment,
the reaction most probably proceeds through intramolecular hydrogen bond
breaking, oxidation, and condensation (Scheme 2). At the beginning, there are
two catalytic cycles in the process of intramolecular hydrogen bond breaking
and oxidation. In the first cycle, the intramolecular hydrogen bond of a-hydroxy-
ketone 2 is ruptured by a lone pair electrons on the nitrogen of morpholine
and generates a Schiff base intermediate state 4. Then, 4 is easily oxidized to
Table 3. Benzoin 2a was oxidized in different reaction conditionsa
Entry
Catalyst (mol%)
Yield (%)b
1
2
—
Morpholine (20)
Morpholine (20)
FeCl3 (10)
NRd
58
3c
4
Trace
18
93
5
FeCl3 (10), morpholine (20)
TEA (20)
Aniline (20)
6
56
7
Trace
47
57
8
Pyridine
Diethylamine
n-Butylamine
9
10
56
aUnless otherwise specified, all reactions were performed with 2a (1 mmol) and 20 mol% of catalyst in
EtOH (2 mL) at 80 ꢀC for 1 h.
bIsolated yield.
cThe reaction was performed under Ar protection conditions.
dNo reaction was observed.

242
W. SONG ET AL.
Scheme 2. Proposed mechanism for the synthesis of quinoxalines.
1,2-diketone 5 and releases morpholine, which is ready to start another catalytic
cycle. When using a tertiary amine as the catalyst, the lone pair of electrons on
the nitrogen of TEA and pyridine can also break the intramolecular hydrogen
bond of a-hydroxyketone 2 and generates an unstable intermolecular hydrogen
bond intermediate, which is easily oxidized to 1,2-diketone 5. When compared
with the naked a-hydroxyl of Schiff base intermediate state 4, the a-hydroxyl of
the intermolecular hydrogen bond intermediate is a little harder to oxidize by
O2, which is why TEA and pyridine are less effective than secondary and primary
amines. In the second cycle, 2 is directly oxidized to 5 under the effects of Fe3þ
and O2. Although these two cycles happen at the same time, it is worth noting
that the first cycle is the main mechanism of the oxidation process. Subsequently,
the 1,2-diketone 5 binds with o-phenylenediamine 1a, gives rise to the intermediate
6 under the catalysis of Fe3þ, loses two H2O molecules quickly, and generates
the final quinoxaline derivative 3. This pathway is well supported by the
experiment.
CONCLUSIONS
In summary, we describe a practical method for the one-step synthesis of
quinoxalines from a-hydroxyketones and 1,2-diamines in the presence of FeCl3
and morpholine. The present protocol is simple, environmentally friendly, and
economical and generates good yields.
EXPERIMENTAL
Melting points were measured with an SGWX-4 apparatus. NMR spectra
were recorded with a Bruker ARX 500 spectrometer at 500 MHz (1H) and at
125 MHz (13C), and chemical shifts are given in parts per million (ppm) relative to
tetramethysilane (TMS) using the residual CHCl3 peak in CDCl3 solution as internal
standard (7.26 and 77.0 ppm, respectively, relative to TMS). High-resolution mass
spectra (HRMS) were recorded with the electron impact (EI) mode. Substrates are
commercially available and used without further purification.

FeCl3 AND MORPHOLINE AS COCATALYSTS
243
Preparation of Quinoxaline Derivatives: General Procedure
To a stirred solution of a-hydroxyketones (2 mmol), morpholine (35 mg) in
EtOH (5 mL), FeCl3 (34 mg) was added under an air atmosphere. Then the mixture
was heated to 80 ꢀC, 1,2-diamines (2 mmol) were added, and the reaction process
was monitored by thin-layer chromatography (TLC). After completion of the reaction,
the mixture was diluted with water (5 mL) and extracted with ethylacetate (2ꢃ 5 mL).
The combined organic layers were then washed with brine (2ꢃ 5 mL) and dried over
MgSO4. The solvent was evaporated under reduced pressure and the solid residue.
The pure products of 3a–3e, 3g–3h, 3j–3k, and 3m–3p were obtained by crystallization
from ethanol; 3f, 3i, 3l, and 3q were obtained by column chromatography.
2,3-Di(2,4-dichlorophenyl)quinoxaline (3c)
Mp 144–146 ꢀC; IR (KBr) v: 3425, 3076, 2923, 1591, 1556, 1479, 1371, 1331,
1
1082, 980, 841, 769 cmꢄ1. H NMR (CDCl3, 500 MHz): d 7.27 (dd, 2H, J1 ¼ 1.6 Hz,
J2 ¼ 7.8 Hz), 7.36 (d, 2H, J ¼ 1.6 Hz), 7.40 (d, 2H, J ¼ 7.8 Hz), 7.88 (dd, 2H,
J1 ¼ 3.4 Hz, J2 ¼ 6.4 Hz), 8.22 (dd, 2 H, J1 ¼ 3.4 Hz, J2 ¼ 6.4 Hz). 13C NMR (CDCl3,
125 MHz): d 127.73, 130.10, 130.26, 131.62, 132.85, 134.47, 136.36, 136.38, 141.98,
152.15. HRMS (EI): m=z [M]þ calcd. for C20H10Cl4N2: 417.9598. Found: 417.9596.
ACKNOWLEDGMENTS
This work was supported by the Chinese National Science and Technology
Major Project ‘‘Key New Drug Creation and Manufacturing Program’’ (Grants
2009ZX09301-001 and 2009ZX09102), the Chinese National High-Tech Research
and Development Program (Grant 2007AA02Z147), the National Natural Science
Foundation of China (Grants 90713046, 30772638, and 30925040), and the Chinese
Academy of Sciences (CAS) Foundation (Grant KSCX2-YW-R-179).
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