2-alkoxypropenals as synthetic equivalents of methylglyoxal in the synthesis of heterocycles

Article abstract of DOI:10.1134/S1070428013030196

One-pot synthesis of 2-methylquinoxaline, 3-hydroxy-2-methylimidazo[1,2-a] pyridine, and 2-methyl-3,7-dihydroimidazo[1,2-a]pyrazin-3-one via cycloaddition of N,N-binucleophilic o-phenylenediamine, 2-aminopyridine, and 2-aminopyrazine, respectively, to methylglyoxal generated in situ by hydrolysis of 2-alkoxypropenals is reported for the first time. Thus 2-alkoxypropenals in weakly acidic medium (25-80 C, 1-4 h) are convenient synthetic equivalents of methylglyoxal in the synthesis of heterocyclic compounds.

Full text of DOI:10.1134/S1070428013030196

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 3, pp. 428–431. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © N.A. Keiko, N.V. Vchislo, L.I. Larina, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 3, pp. 440–443.
Dedicated to Full Member of the Russian Academy of Sciences
I.P. Beletskaya on her jubilee
2-Alkoxypropenals as Synthetic Equivalents of Methylglyoxal
in the Synthesis of Heterocycles
N. A. Keiko, N. V. Vchislo, and L. I. Larina
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: keiko@irioch.irk.ru
Received December 24, 2012
Abstract—One-pot synthesis of 2-methylquinoxaline, 3-hydroxy-2-methylimidazo[1,2-a]pyridine, and
2-methyl-3,7-dihydroimidazo[1,2-a]pyrazin-3-one via cycloaddition of N,N-binucleophilic o-phenylenedi-
amine, 2-aminopyridine, and 2-aminopyrazine, respectively, to methylglyoxal generated in situ by hydrolysis
of 2-alkoxypropenals is reported for the first time. Thus 2-alkoxypropenals in weakly acidic medium (25–80°C,
1–4 h) are convenient synthetic equivalents of methylglyoxal in the synthesis of heterocyclic compounds.
DOI: 10.1134/S1070428013030196
Unlike acrolein, 2-alkoxypropenals characteristi-
cally undergo facile hydration of the C=C bond in acid
medium according to Markovnikov with formation of
methylglyoxal (2-oxopropanal) [1]. The latter is
a strong endogenous bielectrophile generated in vivo
by mammalian cells [2–4], some microorganisms
[5–7], and plants [8]. Methylglyoxal participates in
numerous biochemical transformations and acts as
low-molecular-weight cell growth regulator which
inhibits cell division [7, 9] and favors cell death
[5, 10]. Researchers’ interest in the properties of
methylglyoxal and its role in biological processes con-
tinuously increases [11].
necessary to extend the series of methylglyoxal deriv-
atives that could be used as new reference compounds
in the monitoring of biological substrates.
Apart from fundamental research, heterocyclic
compounds derived from methylglyoxal are used in
fine organic synthesis [21]. Quinoxaline heteroring
constitutes a structural fragment of a number of bio-
logically active compounds and drugs exhibiting anti-
bacterial, antitumor, and antiviral activity [22, 23].
Quinoxaline derivatives were recently reported as ef-
ficient electroluminescent materials [24] and fluores-
cent dyes [25]. Imidazopyrazinones were shown to act
as potential antioxidants [26]. 3-Hydroxy-2-methyl-
imidazo[1,2-a]pyridine turned out to be active toward
some enzymes, in particular toward Oplophorus and
Cypridina luciferases) [27].
Methylglyoxal is used as starting compound in the
synthesis of various heterocycles, in particular β-car-
bolines [12], dihydroimidazoles and their derivatives
[13], functionalized pyrimidines [14], dihydropyra-
zines [3], quinoxalines [15], and imidazopyrazines
[16]. Some of these were found to be formed in living
cells [12, 17], as well as in foods [8, 12, 14] and drinks
[18]. In biochemistry, the concentration of methyl-
glyoxal in blood serum is determined by converting it
into 2,3-diphenyl-2,3-dihydropyrazine [19] or dihydro-
pyrazine [3]. However, detection of methylglyoxal and
tracing of its transformation constitute a fairly difficult
problem, for its concentration in biological liquids
amounts to nanomoles per liter, e.g., 100 nM in blood
plasma of healthy humans [16, 20]. Therefore, it is
Commercially available methylglyoxal in the form
of a 40–50% aqueous solution contains a lot of im-
purities, and it cannot be used as reference compound
without preliminary purification which is difficult
because of its high reactivity and strong tendency to
undergo polymerization [17]. Methylglyoxal in solu-
tion may exist as different species (mono- and dihy-
drates, dimers and trimers, and enol tautomers) [28]
whose ratio depends on the solvent, temperature, con-
centration of water, and pH and strongly affects the
reaction direction and yield.
428

2-ALKOXYPROPENALS AS SYNTHETIC EQUIVALENTS OF METHYLGLYOXAL
429
In continuation of our studies on the properties of
2-alkoxypropenals as synthetic equivalents of methyl-
glyoxal [1, 29], in the present work we examined the
possibility of using these compounds in the synthesis
of some fused heterocycles which were obtained previ-
ously from aqueous methylglyoxal. The hydrolysis of
aldehydes Ia and Ib in the presence of HCl, followed
by treatment with an equimolar amount of o-phenyl-
enediamine (II), gave 2-methylquinoxaline (III) in 48–
61% yield as a result of condensation at both carbonyl
groups of methylglyoxal (Scheme 1). Thus, unlike the
reaction of 2-alkoxypropenals with o-phenylenedi-
amine under basic conditions, which afforded 2-(1-al-
koxyvinyl)benzimidazoles [30], the proposed proce-
dure ensures preparation of 2-methylquinoxaline
from a different initial compound than methylglyoxal
(cf. [31]).
(δN –141.2 ppm) and protons in the methyl group,
while the N4 nucleus (δN –180.2 ppm) displayed cou-
plings with 5-H, 6-H, and 8-H. These findings, in com-
1
bination with the H and 13C NMR data, unambigu-
ously confirmed the assumed enol structure of V.
According to published data, methylglyoxal reacts
with 2-aminopyrazine [16] under argon in ethanol in
the presence of 37% hydrochloric acid at room tem-
perature (18 h) or at 80°C (4 h) [26] to produce
2-methyl-3,7-dihydroimidazo[1,2-a]pyrazin-3-one as
hydrochloride. We found that the reaction of 2-ethoxy-
propenal (Ia) with 2-aminopyrazine (VI) in ethanol in
the presence of 29% aqueous HCl at 80°C yields 70%
of 2-methyl-3,7-dihydroimidazo[1,2-a]pyrazin-3-one
(VII) in 4 h (Scheme 3).
Scheme 3.
O
Scheme 1.
MeCN, H+, H2O
Me
H+, H2O, EtOH
80°C, 4 h
N
N
OEt
CHO
N
OR
O
50–60°C, 2 h
N
+
H2C
NH2
HN
H2C
CHO
H3C
CHO
Ia
VI
VII
Ia, Ib
C6H4(NH2)2-o (II)
25°C, 1 h
To conclude, we have shown that fused heterocyclic
compounds, which were previously available only with
the use of methylglyoxal, can be synthesized by reac-
tion of 2-alkoxypropenal with o-phenylenediamine,
2-aminopyridine, and 2-aminopyrazine in weakly
acidic aqueous medium.
N
N
Me
III
R = Et (a), Me (b).
The reaction of 2-alkoxypropenals Ia and Ib with
equimolar amounts of 2-aminopyridine (IV) and water
in the presence of HCl smoothly afforded 2-methyl-
imidazo[1,2-a]pyridin-3-ol (V), which was isolated in
50% yield after recrystallization from methanol
(Scheme 2). In this case, there was no need of prelim-
inary hydrolysis of aldehydes Ia and Ib.
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
1
a Bruker DRX-400 spectrometer at 400 and
100.6 MHz, respectively, using hexamethyldisiloxane
as internal reference. The mass spectra (electron im-
pact, 70 eV) were obtained on a Hewlett Packard
5971A mass-selective detector coupled with an HP
5890 gas chromatograph (Ultra-2 column, 5% of phe-
nylmethylsilicone; injector temperature 250°C, oven
temperature programming from 70 to 280°C at a rate
of 20 deg/min). The melting points were measured on
a Micro-Hot-Stage PolyTherm A instrument (Wagner
and Munz). The elemental compositions were deter-
mined on a Thermo Fisher Scientific FlashEA 1112
automatic analyzer. Column chromatography was per-
formed on silica gel 60 (70–200 mesh, Merck). Initial
2-alkoxypropenals were synthesized according to [32].
Compound V showed in the two-dimensional
1H–15N NMR spectrum a cross peak between N1
Scheme 2.
OR
+
H2C
CHO
Ia, Ib
N
NH2
IV
OH
5
8
MeCN, H+, H2O
50–60°C, 4 h
3
4
N
6
7
2
Me
1
N
8a
Reaction of 2-ethoxypropenal (Ia) with o-phenyl-
enediamine in the presence of HCl. Concentrated
hydrochloric acid, 0.5 ml, was mixed with 1 ml of
V
R = Et (a), Me (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

KEIKO et al.
430
acetonitrile, 0.04 g of that mixture and 0.002 g of
hydroquinone were dissolved in 0.18 g (10 mmol) of
water, the solution was heated to 55°C, 0.3 g (3 mmol)
of aldehyde Ia was added, and the mixture was heated
for 50 min. The mixture was cooled to 25°C, MgSO4
and a solution of 0.36 g (3 mmol) of o-phenylenedi-
amine in 2 ml of acetonitrile were added, and the
mixture was stirred for 1 h at room temperature and
K2CO3, and filtered, and the solvent was removed
under reduced pressure to isolate compound V in 60%
yield (1H NMR). Recrystallization from methanol gave
0.52 g (47%) of 2-methylimidazo[1,2-a]pyridin-3-ol
(V) as orange crystals with mp 149°C; published data
1
[33]: mp 148–151°C. H NMR spectrum (DMSO-d6),
δ, ppm: 2.22 s (3H, CH3), 6.81 t (1H, 7-H, J = 6.6 Hz),
7.18 t (1H, 6-H, J = 8.8 Hz), 7.48 d (1H, 8-H, J =
13
1
8.8 Hz), 7.82 d (1H, 5-H, J = 6.6 Hz). C NMR spec-
filtered from MgSO4. According to the H NMR data,
trum (DMSO-d6), δC, ppm: 12.8 (CH3), 111.1 (C8),
the mixture contained 80% of III. The solvent was
removed under reduced pressure, and the residue was
subjected to column chromatography on silica gel
using hexane–ethyl acetate (9:1) as eluent to isolate
0.20 g (48%) of 2-methylquinoxaline (III) as a dark
116.2 (C6), 118.5 (C2), 123.0 (C7), 123.4 (C5), 136.5
15
(C3), 141.2 (C8a). N NMR spectrum (DMSO-d6), δC,
ppm: –141.2 (N1), –180.2 (N4). Found, %: C 64.88;
H 5.70; N 18.75. C8H8N2O. Calculated, %: C 64.85;
H 5.44; N 18.91.
1
red liquid. H NMR spectrum (CDCl3), δ, ppm: 2.77 s
(3H, CH3), 7.71 m (2H, 6-H, 7-H), 8.01 d (1H, 5-H,
J = 8.0 Hz), 8.06 d (1H, 8-H, J = 8.0 Hz), 8.73 s (1H,
3-H). 13C NMR spectrum (CDCl3), δC, ppm: 21.3
(CH3), 127.4, 127.5, 127.9, 128.7, 139.7 (C2), 144.7
(C3), 152.5 and 155.9 (C4, C8a). Mass spectrum, m/z
(Irel, %): 144 (100) [M]+·, 129 (1) [M – CH3]+, 117 (76)
[M – CCH3]+, 104 (1), 90 (8), 76 (31), 50 (14). Found,
%: C 74.91; H 5.31; N 18.98. C9H8N2. Calculated, %:
C 74.97; H 5.59; N 19.43. M 144.17.
Reaction of 2-methoxypropenal (Ib) with
2-aminopyridine (IV) in the presence of HCl. Alde-
hyde Ib, 0.25 g (2.9 mmol), was dissolved in 2 ml of
acetonitrile, 0.05 g (2.8 mmol) of water, 0.015 g
(0.1 mmol) of 28.6% aqueous HCl, and 0.27 g
(2.9 mmol) of 2-aminopyridine were added, and the
mixture (pH 6) was heated for 4 h at 50–60°C. The
mixture was dried over MgSO4, neutralized with
K2CO3, and filtered, and the solvent was removed from
the filtrate under reduced pressure. Yield of V 60%
(1H NMR). Recrystallization from methanol gave
0.215 g (50%) of V. Its 1H and 13C NMR spectra were
identical to those given above.
Reaction of 2-methoxypropenal (Ib) with
o-phenylenediamine in the presence of HCl. Con-
centrated hydrochloric acid, 0.5 ml, was mixed with
1 ml of acetonitrile, 0.05 g of that mixture and 0.002 g
of hydroquinone were dissolved in 0.144 g (8 mmol)
of water, the solution was heated to 55°C, 0.7 g
(8 mmol) of aldehyde Ib was added, and the mixture
was heated for 50 min. After cooling to 25°C, MgSO4
and a solution of 0.89 g (8 mmol) of o-phenylenedi-
amine in 2 ml of acetonitrile were added, and the
mixture was stirred for 1 h at room temperature and
Reaction of 2-ethoxypropenal (Ia) with 2-amino-
pyrazine (VI) in the presence of HCl. 2-Ethoxypro-
penal (Ia), 0.2 g (2 mmol), and 28.6% aqueous HCl,
0.175 g (1.37 mmol), were added to 0.13 g (1.3 mmol)
of 2-aminopyrazine (VI) in 8 ml of ethanol, and the
mixture was heated for 4 h at 80°C. The solvent was
removed under reduced pressure, and the residue was
recrystallized from methanol. Yield of 2-methyl-3,7-di-
hydroimidazo[1,2-a]pyrazin-3-one (VII) 0.13 g (68%),
mp 251°C; published data [33]: mp 243°C. The spec-
tral parameters of the product were consistent with
1
filtered from MgSO4. According to the H NMR data,
the mixture contained 80% of compound III. The
solvent was removed under reduced pressure, and the
residue was subjected to column chromatography on
silica gel using hexane–ethyl acetate (9:1) as eluent to
isolate 0.7 g (61%) of 2-methylquinoxaline (III) as
a dark red liquid whose 1H and 13C NMR spectra fully
coincided with those given above.
1
those given in [26]. H NMR spectrum (DMSO-d6), δ,
ppm: 2.07 s (3H, CH3), 7.73 d (1H, 6-H, J = 5.3 Hz),
8.27 d (1H, 5-H, J = 5.3 Hz), 8.98 s (1H, 8-H).
13C NMR spectrum (DMSO-d6), δC, ppm: 13.07 (CH3),
114.5 (C5), 119.5 (C6), 129.0 (C8a), 130.3 (C8), 137.7
(C2), 143.2 (C3). Found, %: C 56.46; H 4.66; N 27.92.
C7H7N3O. Calculated, %: C 56.36; H 4.73; N 28.18.
Reaction of 2-ethoxypropenal (Ia) with 2-amino-
pyridine (IV) in the presence of HCl. Aldehyde Ia,
0.75 g (7.5 mmol), was dissolved in 5 ml of acetoni-
trile, 0.135 g (7.5 mmol) of water, 0.07 g (0.55 mmol)
of 28.6% aqueous HCl (0.73 mol %), and 0.7 g
(7.5 mmol) of 2-aminopyridine were added, and the
mixture (pH 6) was heated for 4 h at 50–60°C. The
mixture was dried over MgSO4, neutralized with
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