Novel approach to 3-methyl-1H-quinoxalin-2-ones

Article abstract of DOI:10.1080/00397910500213880

A novel approach to the synthesis of 3-methyl-1H-quinoxalin-2-ones has been described. These compounds were regioselectively prepared by starting from substituted phenylamines and α-chloropropionyl chloride through the efficient procedures of acylation, nitration, reduction, intramolecular alkylation, and oxidation. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500213880

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Novel Approach to
3‐Methyl‐1H‐quinoxalin‐2‐ones
Xun Li a , Donghua Wang b , Jifeng Wu c & Wenfang
Xu a
a School of Pharmacy , Shandong University , Ji'nan,
China
b College of Pharmaceuticals and Biotechnology ,
Tianjin University , Tianjin, China
c Jinan Public Security Bureau , Ji'nan, China
Published online: 18 Aug 2006.
To cite this article: Xun Li , Donghua Wang , Jifeng Wu & Wenfang Xu (2005)
Novel Approach to 3‐Methyl‐1H‐quinoxalin‐2‐ones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:19,
2553-2560
To link to this article: http://dx.doi.org/10.1080/00397910500213880
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Synthetic Communicationsw, 35: 2553–2560, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500213880
Novel Approach to
3-Methyl-1H-quinoxalin-2-ones
Xun Li
School of Pharmacy, Shandong University, Ji’nan, China
Donghua Wang
College of Pharmaceuticals and Biotechnology, Tianjin University,
Tianjin, China
Jifeng Wu
Jinan Public Security Bureau, Ji’nan, China
Wenfang Xu
School of Pharmacy, Shandong University, Ji’nan, China
Abstract: A novel approach to the synthesis of 3-methyl-1H-quinoxalin-2-ones has
been described. These compounds were regioselectively prepared by starting from sub-
stituted phenylamines and a-chloropropionyl chloride through the efficient procedures
of acylation, nitration, reduction, intramolecular alkylation, and oxidation.
Keywords: a-Chloropropionyl chloride, 3-methyl-1H-quinoxalin-2-ones, regio-
selective synthesis, substituted phenylamine
3-Methyl-1H-quinoxalin-2-ones have been postulated as important intermedi-
ates for the synthesis of various useful heterocyclic compounds.[1–3]Hence,
preparation of 3-methyl-1H-quinoxalin-2-ones 6 has attracted considerable
attention in recent years.
Received in Japan March 22, 2005
Address correspondence to Wenfang Xu, School of Pharmacy, Shandong University,
Ji’nan 250012, China. Tel.:/Fax: þ 86-531-8382264; E-mail: tjulx2004@sdu.edu.cn
2553

2554
X. Li et al.
These compounds are generally prepared by the condensation of
o-phenylene-diamine with pyruvic acid, but multiple of by-products are
obtained when asymmetrical diamines were used as starting materials.[4] in
addition, these compounds also can be obtained by some other regioselective
methods,[5–7] however, there are issues associated with each approach.
Makino et al. reported the synthesis of 3-methyl-quinoxalin-2-ones 6 in
1985, which involved C-methylation of quinoxalin-2-ones to give the target
compound.[5]
[6]
Van Dusen and Schultz
reported the synthesis of 3-methyl-6- and
-7-bromo-2-quinoxalinols, which involved condensation of dl-a-alanine
with 2,5-dibromonitrobenzene, followed by reductive cyclization with
alcoholic hydrochloric acid and iron in the presence of a Raney nickel
catalyst, and subsequent oxidation with basic hydrogen peroxide solution
gave the desired product. Yet these reactions either had long tedious routes,
and low yields or were not easily executed, which limited their applications.
Therefore, alternative regioselective methods need to be developed for the
preparation of a wide variety of the 3-methyl-1H-quinoxalin-2-one deri-
vatives. However, a review of the literature revealed that no effectively
regioselective synthesis of 3-methyl-quinoxalin-2-ones 6 or its substituted
analogue has been published.
We have reported our preliminary investigation concerning the syntheses
of 6,7-disubstituted-1H-quinoxalin-2-ones.[8] We expected to expand its
application to an efficient and practical route for the synthesis of 3-methyl-
1H-quinoxalin-2-ones 6. We chose commercially available substituted pheny-
lamines and a-chloropropionyl chloride as the starting materials for efficient
procedures of acylation, nitration, reduction, intramolecular alkylation, and
oxidation (see Scheme 1). Compared with the other reactions, the conditions
of these reactions were mild, easily executed, and more regioselective.
Reaction of substituted phenylamines with a-chloropropionyl chloride in
toluene under refluxing afforded acetamide 2 in almost quantitative yield and
the hydrogen chloride generated in the reaction was absorbed in another flask
containing sodium hydroxide solution. Acetamide 2 was nitrated by KNO3/
H2SO4 or mild nitrating reagent HNO3/CH3COOH according to the substi-
tuted groups of benzene ring to give single o-nitroacetamide 3 in 80–93%
Scheme 1.

3-Methyl-1H-quinoxalin-2-ones
2555
yield. 3 was quantitatively transferred to 4 within 15 min by ferrous powder
reduction in 50–70% yield. Other reductive methods such as hydrazine
hydrate in the presence of an iron oxide/hydroxide catalyst,[9]Zn/
NH4Cl,[10] Pd-C/H2,[11] SnCI2,[12]and so on were less efficient. The
optimum experimental conditions have been developed, and N,N-dimethyl-
formamide was chosen as solvent to improve dissolution of 3 in a ferrous
powder reductive suspension, which could increase reaction efficiency. In
addition, mild reaction temperature was used to decrease the dechlorinating
by-products. Subsequent intramolecular cyclization of 4 in the presence of
sodium iodide and sodium bicarbonate gave substituted 3-methyl-3,4-
dihydro-lH-quinoxalin-2-one 5 in 51–62% yield separated by column chrom-
atography on silica gel. Sodium iodide was used as a catalyst to promote the
nucleophilic substitution reaction. 5 was readily transformed to the corre-
sponding 3-methyl-lH-quinoxalin-2-ones 6 by treatment with hydrogen
peroxide in 5% NaOH solution in 51–86% yield. The desired compounds
1
have been fully characterized by IR, H NMR, MS, and elemental analysis
and the analytical results are shown in Table 1 and Table 2.
In summary, we have developed an efficient five-step synthesis of 3-methyl-
1H-quinoxalin-2-ones 6 from substituted phenylamines, which overcomes the
limitations of previous syntheses. Moreover, the new procedure is simple, inex-
pensive, and regioselective, and gives good yield. This convenient method can
be a useful method to obtain more series of such compounds.
EXPERIMENTAL
Melting points were determined on an X-6 type digital apparatus, and
are uncorrected. Elemental analyses were carried out on a Perkin-Elmer
Table 1. Synthesis of 3-methyl-1H-quinoxalin-2-ones
Mp
(8C)
Total yield
(%)
Product
R1
R2
6a
6b
6c
6d
6e
6f
H
CH3
C4H9
CH3O
C2H5O
Me
Cl
257–258
162–163
253–254
34
27
31
28
39
24
33
37
12
39
41
H
H
H
237–238
276–277
Me
H
263–264
256–257
273–274
6g
6h
6i
H
Br
F
H
Cl
Cl
F
CH3
F
292–293 dec.
328–329 dec.
318–319 dec.
6j
6k
F
Note: 6a–6e: nitrated with HNO3/AcOH; 6f–6k: nitrated with KNO3/H2SO4.

2556
X. Li et al.
d

3-Methyl-1H-quinoxalin-2-ones
2557

2558
X. Li et al.
C, H, and N elemental analyzer. Low-resolution electron-ionization (EI) mass
spectra were obtained from an API4000 instrument using fast atom bombard-
ment (FAB) as ionization mode with meta-nitrobenzyl alcohol (NBA) as a
matrix support. Infrared spectra (IR) were measured on Nicolet Nexus 470
FT infrared spectrophotometer in the range of 4000–400 cm21, and the
solid products and were palletized in KBr. All 1H NMR spectra were
recorded on a Bruker AMX-400 spectrometer and were referenced to TMS
(Me4Si) as an internal standard; chemical shifts (d) are listed in ppm against
deuterated solvent peaks as an internal reference. Coupling constants (J) are
reported in hertz, and the abbreviations for splitting include the following: s,
single; d, doublet; t, triplet; q, quartet; m, multiplet. The purity of
compounds was .95% as determined by HPLC analysis using an analytical
C18 reversed-phase column. Flash chromatography was performed using
200–300-mesh silica gel and the solvent system indicated in the procedure.
All reactions except those in aqueous media were carried out by standard tech-
niques for the exclusion of moisture. Reaction courses and product mixtures
were routinely monitored by thin-layer chromatography (TLC) on silica gel
(precoated GF254 plates). Visualization on TLC was achieved using UV
light, iodine vapor, KMnO4, triketohydrindene hydrate, and/or 5% phospho-
molybdic acid in 95% ethanol. Toluene and tetrahydrofuran were used
freshly distilled from sodium benzophenone. Other chemicals and solvents
purchased commercially were reagent grade and were purified according to
the standard procedures before use.
Typical procedures for the synthesis of 6-chloro-3-methylquinoxalin-
2(1H)-one (6f) was as follows.
2-Chloro-N-(4-chlorophenyl)acetamide (2f): A stirred solution of p-chloro-
aniline (l0 mmol) in toluene (20 mL) was treated with a-chloropropionyl
chloride (12 mmol). After refluxing for 1 h, the reaction mixture was
allowed to cool down to room temperature. The solvent was removed under
vacuum and the residue was recrystallized from an ethyl acetate–petroleum
ether (1:2) mixture to afford the product as white crystal. Yield 99%, mp
1
175–1768C. H NMR (DMSO-d6) d 3.28 (s, 3H, CH3), 4.24 (m, 1H, CH),
7.38 (d, 2H, J ¼ 8.8Hz, ArH), 7.61 (d, 2H, J ¼ 8.8 Hz, ArH), 10.39 (s, 1H,
NH). Elemental analyses calculated for C8H7NOCl2: C, 47.06; H, 3.43; N,
6.86. Found: C, 47.87; H, 2.99; N, 6.93. ESI-MS: m/z (rel intensity) 203.3
[M-H]þ.
2-Chloro-N-(4-chloro-2-nitrophenyl)propanamide(3f): Concentratednitric
acid (1 mL) was added to the solution of 2f(4.2-mmol) in acetic acid (5 mL)
and water (2 mL) (or a stirred solution of 2f in concentrated sulfuric acid
was treated with 1.05 equiv of potassium nitrate). About 5 min later, concen-
trated sulfuric acid (6.3 mmol) was added dropwise within 20 min at 08C, and
then stirred for another 1 h at room temperature. The resulting yellow-brown
solution was poured into crushed ice (50 g). The resultant solid was collected

3-Methyl-1H-quinoxalin-2-ones
2559
by filtration and then washed successively with water (3 ꢀ 10 mL) to afford
the crude product 3f as a pale yellow solid, which was purified by recrystalli-
zation from methanol and dried under vacuum. Yield 86%, mp 137–1388C. 1
H NMR (DMSO-d6) d 2.09 (s, 3H, CH3), 4.53 (m, 1H, CH), 7.77–7.83 (m, 2H,
ArH), 8.09 (d, 1H, J ¼ 2.0 Hz, ArH), 10.72 (s, 1H, NH). Elemental analyses
calculated for C8H6N2O3Cl2: C, 38.55; H, 2.41; N, 11.24. Found: C, 39.46;
H, 2.52; N, 10.66. ESI-MS: m/z (rel intensity) 248.1 [M-H]þ.
N-(2-Amino-4-chlorophenyl)-2-chloropropanamide (4f): A mixture of
reductive ferrous powder (2.0 g, 35.7 mmo1), ammonium chloride (0.1 g,
1.9 mmol), and acetic acid (0.5 mL, 8.7 mmol) in water (30 mL) was vigor-
ously stirred with a mechanical stirrer at 508C for 10–15 min. To this
reaction mixture, a solution of 3f (4 mmol) in dimethylformamide (10 mL)
was added. After the reaction was over (monitored by TLC, about 15 min),
the mixture was basified to pH ¼ 8–9 by the addition of 10% aqueous sodium
carbonate. The resulting slurry was filtered, and the residue was washed
with water (2 ꢀ 20 mL) and ethyl acetate (2 ꢀ 30 mL) successively. After
the washings, the organic materials were separated and the aqueous phase
was extracted three times with ethyl acetate (3 ꢀ 10 mL). The combined
organic extracts were washed successively with water (3 ꢀ 25 mL) and
brine (25 mL), and dried over anhydrous sodium sulfate. After removal of the
solvent, the crude product was dried under reduced pressure and purified by
flash chromatograsphy (ethyl acetate–petroleum ether ¼ 2:3 to 3:2, v/v) to
give 4f as brown solid. It is noteworthy that the amino product is sensitive
to oxygen in open air, so it should be used immediately for the next
1
procedure after purification. Yield 56%, mp 157–1588C. H NMR (DMSO-
d6) d 1.07 (s, 3H, CH3), 2.34 (m, 1H, CH), 5.29 (s, 2H, CH2), 6.89 (s, 1H,
ArH), 7.33 (s, 1H, ArH), 7.54 (s, 1H, ArH), 9.02 (s, 1H, NH). Elemental
analyses calculated for C8H8N2OCl2: C, 43.84; H, 3.65; N, 12.79. Found: C,
44.35; H, 3.09; N, 12.14. ESI-MS: m/z (rel intensity) 218.3 [M-H]þ.
6-Chloro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (5f): Sodium iodide
dihydrate (1.6 mmol) and sodium bicarbonate (6.5 mmol) were added to a
acetonitrile under nitrogen atmosphere. The resulting solution was allowed
to reflux until completion while the reaction was monitored by TLC. After
cooling to room temperature, the solvent was removed under reduced
pressure. The residue was treated with water (100 mL) and was stirred at
room temperature for l0 min, and acidified by the addition of 2N hydrochloric
acid to pH ¼ 5–6. The pale gray solid was collected by filtration and washed
with water (2 ꢀ 20 mL), dried in vacuum to afford the crude product 5f,
1
ether ¼ 2:3 v/v). Yield 60%, mp 217–2188C. HNMR (DMSO-d6) d 2.49
(s, 3H, CH3), 3.73 (m, 1H, CH), 6.21 (s, 1H, NH), 6.56 (m, 1H, ArH), 6.68
(s, 2H, ArH), 10.33 (s, 1H, NH). Elemental analyses calculated for
C9H9N2OCl: C, 54.96; H, 4.58; N, 14.25. Found: C, 54.03; H, 4.66; N,
15.02. ESI-MS: m/z (rel intensity) 195.1 [M-H]þ.

2560
X. Li et al.
6-Chloro-3-methylquinoxalin-2(1H)-one (6f): To a 5% sodium hydroxide
solution (10 mL) of 5f (1 mmol) was sequentially added 30% hydrogen
peroxide (1 mL) and water (2 mL). The solution was stirred at 608C for 6 h,
then allowed to cool down to room temperature. The precipitate was filtered
and washed with water (5 mL), and dried under reduced pressure to afford
the crude product 6f, which was purified by flash-column chromatography
(ethyl acetate–petroleum ether ¼ 2:3 to 3:2 v/v) as silvery white solid.
Yield 83%, mp 263–2648C.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Grant No.
20272033), and the Doctoral Foundation of Ministry of Education of the
People’s Republic of China (Grant No. 20020422024) for financial support.
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