5-Methyl-2-furylglyoxal, 5-methyl-4-nitro-2-furylglyoxal, and their derivatives. Nitration of 2-(5-methyl-2-furyl)quinoxaline

Article abstract of DOI:10.1023/A:1020669301326

The oxidation of 2-acetyl-5-methyl-4-R-furans (R = H, NO₂) by selenious acid was studied. Derivatives substituted at the C=O groups of the corresponding glyoxals were obtained. The nitration of 2-(5-methyl-2-firyl)quinoxaline was carried out at C₍₄₎. Oxidative splitting of the β-nitrofuryl group occurs at the C₍₄₎-C₍₅₎ and C₍₅₎-O bonds.

Full text of DOI:10.1023/A:1020669301326

Chemistry of Heterocyclic Compounds, Vol. 38, No. 7, 2002
5-METHYL-2-FURYLGLYOXAL,
5-METHYL-4-NITRO-2-FURYLGLYOXAL,
AND THEIR DERIVATIVES. NITRATION
OF 2-(5-METHYL-2-FURYL)QUINOXALINE
N. O. Saldabol, J. Popelis, and V. Slavinska
The oxidation of 2-acetyl-5-methyl-4-R-furans (R = H, NO2) by selenious acid was studied. Derivatives
substituted at the C=O groups of the corresponding glyoxals were obtained. The nitration of
. Oxidative splitting of the β-nitrofuryl group
2-(5-methyl-2-furyl)quinoxaline was carried out at C(4')
occurs at the C(4)–C(5) and C(5)–O bonds.
Keywords: 2-acetyl-5-methyl-4-R-furans (R = H, NO2), glyoxals, 2-(5'-methyl-2-furyl)quinoxaline,
nitric acid nitration, oxidation, H2SeO3.
The α-methyl groups of ketones and methyl groups in the α-position relative to the heteroatom of
heterocyclic compounds may be oxidized by selenium dioxide to formyl or carboxylic acid groups [1].
5-R-2-Furylglyoxals (R = H, NO2) were thereby obtained from the corresponding methyl ketones [2], while the
5-methyl group in 1-methyl-(5-methyl-3-furyl)benzimidazole was oxidized to a formyl group [3].
In the present work, we compared the reactivity of the methyl groups of the ring and ketone part of
2-acetyl-5-methylfuran (1a) and 2-acetyl-5-methyl-4-nitrofuran (1b) relative to oxidation by selenious acid and
also obtained oxidation products of these compounds with transformed carbonyl groups.
The oxidation of 1a and 1b by an equimolar amount of H2SeO3 proceeds selectively at the ketone group
to give 5-methyl-2-furylglyoxal (2a) and 5-methyl-4-nitro-2-furylglyoxal (2b), respectively.
R
H2SeO3
Me
O
COCHO
H2O2
2a,b
R = NO2
O2N
R
2H2SeO3
COMe
R = NO2
Me
O
Me
COOH
O
1a,b
4b
H
N
O2N
Me
O
O2N
o-C6H4(NH2)2
COCOOH
1, 2 a R = H, b R = NO2
O
N
Me
O
3b
5b
__________________________________________________________________________________________
Latvian Institute of Organic Chemistry, LV-1006, Riga; e-mail: dzsile@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 889-899, July, 2002. Original article submitted November 28, 2000.
0009-3122/02/3807-0783$27.00©2002 Plenum Publishing Corporation
783

The 1H NMR spectrum of glyoxal 2a after vacuum distillation showed a trace of the monohydrate form.
Glyoxal 2a readily polymerizes to give a glassy mass. In contrast to 2-furylglyoxal, which forms a crystalline
monohydrate upon heating at reflux with water (1:4 ratio) in high yield, 5-methyl derivative 2a after heating at
reflux with water (1:2 ratio) does not crystallize out in the hydrate form upon maintenance of the solution over a
week at 3-5°C.
Nitro ketone 1b did not react completely under the conditions selected. 1H NMR spectroscopy indicated
that the crude product contained 15 mol % starting ketone, 80 mol % glyoxal hydrate 2b·H2O, and 3 mol %
5-methyl-4-nitro-2-furylglyoxylic acid (3b) along with traces of anhydrous glyoxal and 5-methyl-4-nitro-2-
furancarboxylic acid (4b).
The action of two molar equivalents of H2SeO3 on ketone 2b under the same conditions led to a mixture
containing 50 mol % glyoxylic acid 3b, 15 mol % glyoxal 2b, and 15 mol % carboxylic acid 4b contaminated
1
by products of reaction with the trisubstituted furan ring as indicated by H NMR spectroscopy. This mixture
was not studied in detail. The presence of nitroglyoxylic acid 3b was shown by treatment of the mixture with
o-phenylenediamine, subsequent heating of the precipitate obtained with ethanol at reflux to remove the
5-methyl-4-nitro-2-furyl derivatives of quinoxaline and benzimidazole, and recrystallization of the residue from
DMF to give 3-(5-methyl-4-nitro-2-furyl)quinoxal-2-one (5b). The signals for the quinoxalone fragment of 5 are
found in the same regions as for 3-(5-nitro-2-furyl)quinoxal-2-one [4].
Furancarboxylic acid 4b was obtained by oxidation of glyoxal 2b using hydrogen peroxide by analogy
to 5-nitro-2-furylglyoxal [2].
R
H2X
2a,b
Me
COCH=X
O
6a,b X = NNMe2
7 X = NNHCONH2
2 NH2NHCONH2
R
R
H
H
N
Me
O
Me
C
C
C
O
C
N
N
N
N
CONH2
HN
CONH2
H
H2NOC
NH
H2NOC
NH
8a,b E,Z-furyl (syn)
Z,E-furyl (anti)
a R = H, b R = NO2
Glyoxals 2a and 2b were characterized by their conversion into aldehydo-N,N-dimethylhydrazones 6a
and 6b and bissemicarbazones 8a and 8b. Glyoxal 2a reacts with one molar equivalent of semicarbazide to form
aldehydosemicarbazone 7a, while glyoxal 2b reacts with one molar equivalent of semicarbazide to give
bissemicarbazone 8b, i.e., an analogy is seen with 2-furylglyoxal and its 5-nitro derivative [2].
1H NMR spectroscopy indicated that nitrobissemicarbazone 8b has two isomers, namely, with E,Z- and
Z,E-configuration of the furyl group in 2:1 ratio. The configuration of the aldehydosemicarbazone group was
established relative to the position of the CH=N proton in accord with the data for other semicarbazones and
thiosemicarbazones [5-7] and oximes [7], while the configuration of the ketosemicarbazone group was
determined relative to the chemical shift of ring 3-H by analogy to the chemical shifts of the same proton in the
E- and Z-isomers of oximes of 2-acetyl- and 2-formyl-5-methyl-4-nitrofuran [8,9].
784

2a
2b
o-C6H4(NH2)2
o-C6H4(NH2)2
O2N
N
N
HNO3
H2SO4
Me
N
Me
N
O
O
9b
9a
[O]
dil.
HNO3–H2SO4
polymer
NO2
[MeCHO]
N
11
O2N
HOCH2
N
O
10
MeCH=NNH
12
The reaction of glyoxals 2a and 2b with o-phenylenediamine gave 2-(5-methyl-2-furyl)quinoxaline (9a)
and its 4-nitro derivative 9b, respectively. Quinoxaline 9b is also formed by the action of 1.1 molar equivalent
of 70% aq. HNO3 on the denitro analog 9a in concentrated sulfuric acid. The nitration did not proceed to
completion and was accompanied by oxidation of the starting compound to 2-(5-hydroxymethyl-2-
furyl)quinoxaline (10), apparently after pouring the reaction mixture onto ice, and formation of a polymer from
a portion of the precipitate upon filtration of the reaction product.
TABLE 1. Physical Characteristics of Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
(method)
Calculated, %
(solvent)
C
H
N
C7H6O3
60.49
60.87
4.73
4.37
—
—
42
79
2a
2b·Н2О
C7H5NO5·Н2О
41.64
3.28
7.08
6.96
89-92
(H2O)
41.85
3.51
C6H5NO5
C13H9N3O4
C9H12N2O2
C9H11N3O4
C8H9N3O3
C9H12N6O3
C9H11N7O5
C13H10N2O
C13H9N3O3
42.08
42.11
2.87
2.95
8.09
160-161
85
95
63
70
90
95
95
81
4b
5b
6a
6b
7a
8a
8b
9a
9b
8.19
(H2O)
57.18
3.60
15.23
15.50
>300
57.57
3.34
(DMF)
59.72
59.98
6.59
6.71
15.71
90-91
15.55
(H2O)
47.88
4.83
18.57
18.66
146-148
(EtOH)
48.00
4.92
49.03
49.21
4.53
4.65
21.77
208-209
21.53
(EtOH)
42.63
4.68
33.09
33.32
227-228
(EtOH)
42.86
4.80
36.21
36.33
3.67
3.76
32.97
>300
33.36
(DMF–H2O)
74.43
4.75
13.21
13.32
80-81
74.25
4.81
(EtOH)
61.03
61.18
3.47
3.53
16.23
203-204
95 (A)
16.48
(EtOH–DMF)
31 (B)*
_______
* Relative to 9a consumed.
785

Hydroxymethyl derivative 10 could not be separated from the starting compound by preparative
1
chromatography. The structure of this product was demonstrated only by H NMR spectroscopy. Nitro
derivative 9b was isolated from the mixture by crystallization from 6:1 ethanol–DMF. The yield of this product
1
calculated using the H NMR spectrum of the mixture was 23% relative to starting 9a and 31% relative to the
starting compound consumed.
The success of the nitration is attributed to the strong electron-withdrawing effect of the quinoxaline
group, which imparts stability to the furan ring, while complete polymerization is observed upon heating
2-(5-methyl-2-furyl) derivatives of imidazo[1,2-a]pyridine [10] and imidazo[1,2-a]pyrimidine. Partial
polymerization occurs in the nitration of the nitrile of 5-methyl-2-furancarboxylic acid [5].
In the latter case, after separation of the nitro nitrile and polymer, a precipitate of the
2,4-dinitrophenylhydrazone of acetaldehyde formed upon addition of 2,4-dinitrophenylhydrazine to the filtrate
and not of the nitrile of 5-formyl-2-furancarboxylic acid as might have been expected by analogy with the
nitration of the ethyl ester of 5-methyl-2-furancarboxylic acid but this was not reflected in our previous
communication [5].
After separation of quinoxaline 9b and polymer, 2,4-dinitrophenylhydrazone 12 was also obtained upon
addition of the same hydrazine to the filtrate. The structure of 12 was indicated by its melting point, elemental
analysis, and 1H NMR spectrum.
TABLE 2. 1H NMR Spectra of Compounds Synthesized
Chemical shifts, δ, ppm., J (Hz)*
5-CH3 Other protons
Com-
pound
3-H
4-H
7.76
7.50
8.10
7.90
8.06
7.66
8.15
6.50
6.36
—
2.42
2.42
2.77
2.75
2.76
2.75
2.90
9.48 (1H, s, CHO)
5.45 (1H, s, CH); 5.6 (2H, br. s, 2OH)
9.40 (1H, s, CHO)
5.42 (1H, s, CH); 5.6 (2H, br. s, 2OH)
—
2a
2а·Н2О
2b
2b·Н2О
—
—
—
—
3b
12.11 (1H, br. s, СОOH)
4b
7.4-7.8 (3H, m, 5-H−7-H); 7.95 (1H, ddd,
5b
J = 8.4, 1.1, 0.4, 8-H); 12.05 (1H, br. s, NH)
6a*2
6b
7a
7.46
7.87
7.65
6.32
—
6.40
2.36
2.75
2.40
3.18 (6Н, s, NMe2); 6.93 (1H, s, CH=N)
3.71 (6H, s, NMe2), 6.95 (1H, s, CH=N)
6.65 (2H, br. s, NH2); 7.68 (1H, s, CH=N);
10.94 (1H, br. s, NH)
7.24
7.42
7.55
6.31
2.30
2.73
2.73
6.30 (2H, br. s, NH2); 6.72 (2H, br. s, NH2);
7.60 (1H, s, CH=N); 9.83 (1H, s, NH);
10.72 (1H, s, NH)
8a
E,Z-8b
Z,E-8b
—
6.24 (2H, br. s, NH2); 6.50 (2H, br. s, NH2);
7.66 (1H, s, CH=N); 10.02 (1H, s, NH);
10.51 (1H, s, NH)
—
6.50 (2H, br. s, NH2); 6.90 (2H, br. s, NH2);
8.01 (1H, s, CH=N); 10.62 (1H, s, NH);
11.21 (1H, s, NH)
7.53
8.18
7.75
6.46
—
2.50
2.85
—
7.84 (2H, m, 6-H, 7-H); 8.05 (2H, m, 5-H, 8-H);
9a
9b
10
9.43 (1H, s, 3-H)
7.85 (2H, m, 6-H, 7-H); 8.05 (2H, m, 5-H, 8-H);
9.49 (1H, s, 3-H)
4.58 (2H, d, CH2OH); 4.8 (1H, t, J = 4.8, CH2OH);
7.8 (2H, m, 6-H, 7-H); 7.95-8.1 (2H, m, 5-H, 8-H);
9.38 (1H, s, 3-H)
6.62
_______
* For compounds 2-9a J (3,4-CH3) = 3.3-3.5, J (3,5-CH3) = 0.4,
J (4,5-CH3) = 0.9 Hz; for compounds 2-9b J (3,5-CH3) = 0.4 Hz.
*2 In acetone-d6.
786

The formation of aldehyde indicates the oxidative cleavage of the 5-methyl-4-nitro-2-furyl group at the
C(4)–C(5) and C(5)–O bonds in contrast to the 5-nitro-2-furyl group, which is attached to the oxidation-resistant
heterocycle (imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine). The 5-nitro-2-furyl group is lost upon nitric
acid oxidation only at the C(5)–O bonds to give hetarylacrylic acids (HetCOCH=CHCO2H) [10, 11].
EXPERIMENTAL
The purity of the products was checked by thin-layer chromatography on Silufol UV-254 plates using
3:1 benzene–ethyl acetate and 25:4:1 benzene–dioxane–acetic acid as the eluents and by 1H NMR spectroscopy.
The 1H NMR spectra were taken on a Bruker WH-90/DS spectrometer at 90 MHz in DMSO-d6 with TMS as the
internal standard. The IR spectra were taken on a Perkin–Elmer 580B spectrometer for vaseline mulls. The
melting points were taken on a Boetius block.
The physical characteristics of these compounds are given in Tables 1 and 2.
5-Methyl-2-furylglyoxal (2a). A sample of ketone 1a (62 g, 0.5 mol) was added to a solution of
H2SeO3 (64.5 g) in dioxane (300 ml) and water (20 ml) prepared at 45-50°C. The mixture was heated at reflux
for 4 h with stirring, left stand overnight, and filtered to remove selenium. The solvent was distilled off the
filtrate and the residue was distilled in vacuum with a 2-cm-high rod-and-disk type fractionating column, taking
the fraction distilling at 100-103°C (20 hPa). Yield of compound 2a 29 g.
5-Methyl-4-nitro-2-furylglyoxal (2b). A sample of compound 1b (6.76 g, 40 mmol) was added to a
solution of H2SeO3 (5.16 g, 40 mmol) in a mixture of water (3 ml) and acetic acid (20 ml) at 50°C, heated at
reflux with stirring for 4 h, left stand overnight, and filtered to remove selenium. The filtrate was evaporated in
vacuum to give 6.6 g of orange oil. The crude product was heated with water (20 ml) and after maintenance at
2-3°C for 48 h, filtered to yield yellow crystals, which were dried over P2O5 to give 5.86 g of a mixture of 80%
glyoxal monohydrate, 15% ketone 1b, and 3% glyoxylic acid 3b as well as traces of unhydrated glyoxal and
carboxylic acid 4b.
A sample of o-phenylenediamine (1 g) was added to the filtrate after removal of the precipitate, warmed
for 10 min, and filtered after 24 h to give 0.92 g of 2-(5-methyl-4-nitro-2-furyl)quinoxaline 9b, which accounts
for 0.72 g of glyoxal 2b·H2O. The total yield of glyoxal monohydrate was 6.36 g.
Recrystallization of crude glyoxal twice from 10 parts water gave pure product. IR spectrum, ν, cm-1:
1360 and 1542 (NO2), 1692 (C=O), 3000-3400 (CO2H).
5-Methyl-4-nitro-2-furancarboxylic Acid (4b). Three samples of 26% aq. H2O2 (2 ml) were added to
a solution of glyoxal 2b (0.5 g, 2.5 mmol) in a mixture of water (15 ml) and acetic acid (3 ml). The mixture was
maintained for 1 h at room temperature after each of the three additions. The mixture was extracted with ether to
give 0.36 g 4b. IR spectrum, ν, cm-1: 1340 and 1555 (NO2), 1705 (CO2H).
3-(5-Methyl-4-nitro-2-furyl)quinoxal-2-one (5b). A sample of ketone 1b (3.38 g, 20 mmol) was
oxidized in a mixture of acetic acid (20 ml) and water (3 ml) upon heating at reflux for 5 h and the reaction
products were removed as described above. The product was analyzed by thin-layer chromatography and
1H NMR spectroscopy. A sample of o-phenylenediamine (2.16 g, 20 mmol) in water (30 ml) was added to the
crude product containing 50-60 mol % 5-methyl-4-nitro-2-furylglyoxylic acid 3b and heated for several minutes.
The precipitate was filtered off and heated at reflux with ethanol (100 ml). The portion which did not dissolve
was recrystallized from DMF to give 1.3 g of compound 5b.
N,N-Dimethylhydrazone of 5-Methyl-2-furylglyoxal (6a). A sample of N,N-dimethylhydrazine
(0.30 g, 4.4 mmol) was added to glyoxal 2a (0.56 g, 4 mmol) in water (4 ml) and maintained for 3 h at room
temperature. The solvent was evaporated off to give 0.45 g of hydrazone.
N,N-Dimethylhydrazone of 5-Methyl-4-nitro-2-furylglyoxal (6b) was obtained analogously from
compound 2b (0.4 g, 2 mmol). The precipitate formed was filtered off. Yield of hydrazone 0.32 g.
787

Semicarbazone 7a and Bissemicarbazones 8a and 8b were obtained by the standard procedures.
2-(5-Methyl-4-nitro-2-furyl)quinoxaline (9a). A mixture of freshly prepared glyoxal 2a (1.38 g,
10 mmol), o-phenylenediamine (1.08 g, 10 mmol), water (10 ml), and ethanol (5 ml) was heated at reflux for
several minutes. The initial oily product crystallized and was filtered and washed with dilute ethanol to give
1.71 g of compound 9a.
2-(5-Methyl-4-nitro-2-furyl)quinoxaline (9b). A. A mixture of glyoxal 2b·H2O (1 g, 5 mmol),
o-phenylenediamine (0.54 g, 5 mmol), ethanol (5 ml), and water (5 ml) was heated for several minutes. The
precipitate was filtered off to give 1.08 g of yellow crystals, which sublimate above 150°C.
B. A sample of 9a (2.1 g, 10 mmol) was added in portions to concentrated sulfuric acid (50 ml)
vigorously stirred at from -18 to -15°C. Then, a mixture of 70% HNO3 (0.70 ml, 11 mmol) and concentrated
sulfuric acid (2 ml) was added at the same temperature over 50 min. The mixture was stirred at the same
temperature for 1 h and then poured with vigorous stirring onto a mixture of ice and water (500 g). The
precipitate was filtered off and washed thoroughly with water to give 0.72 g of product consisting of 15 mol %
of compound 9a, 80 mol % of compound 9b, and 5 mol % of 2-(hydroxymethyl-2-furyl)quinoxaline (10) as
1
indicated by H NMR spectroscopy. A portion of the product formed a tar upon filtration and hardened over
1
time. A precipitate of 0.21 g of a 1:1 mixture of compounds 9a and 10 as indicated by H NMR spectroscopy
was obtained from one-half of the filtrate after neutralization by sodium hydroxide and standing for 24 h.
Crystallization of the first precipitate from 6:1 ethanol–DMF gave pure nitro compound 9b. The yield
calculated by means of 1H NMR spectroscopy was 0.60 g.
A solution of 2,4-dinitrophenylhydrazine (0.5 g) in concentrated sulfuric acid was added to the second
half of the filtrate after removal of crude quinoxaline 9b. The 2,4-dinitrophenylhydrazone of acetaldehyde 12
1
was filtered off and washed with hot ethanol to give 0.08 g of compound 12; mp 144-146°C [12]. H NMR
spectrum (DMSO-d6), δ, ppm, J (Hz): 2.03 (3H, d, J = 5, CH3); 7.75 (1H, d, J = 9.7, 6-H); 8.03 (1H, q, J = 5,
CH=N); 8.31 (1H, ddd, J = 9.7, 2.6, 0.4, 5-H); 8.83 (1H, d, J = 2.6, 3-H); 11.39 (1H, s, NH). Found, %: C 42.58;
H 3.72; N 25.23. C8H8N4O8. Calculated, %: C 42.85; H 3.60; N 24.98.
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788