Methylglyoxal bis-(N,N-dimethylhydrazone): Synthesis and some reactions

Article abstract of DOI:10.1134/S1070363212010124

Methods were proposed for the synthesis of the methylglyoxal 1,2-bis-(N,N-dimethylhydrazone). A possibility was shown for the first time of its participation in the Diels-Alder reaction with maleic anhydride as an electron-rich diene. The second reaction of these reagents, which is observed in a wet media, is the formation of the hydrazinium salt of the initial diene with maleic acid. The most probable structure of the protonated diene among the four possible forms was revealed by the quantum-chemical calculations of the energy of the molecules and by the analysis of the ¹³C NMR chemical shifts.

Full text of DOI:10.1134/S1070363212010124

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 1, pp. 77–81. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © N.A. Keiko, N.V. Vchislo, L.I. Larina, K.A. Chernyshev, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 1, pp.
8
1–85.
Dedicated to the 90th Anniversary of Academician M.G. Voronkov
Methylglyoxal Bis-(N,N-dimethylhydrazone):
Synthesis and Some Reactions
N. A. Keiko, N. V. Vchislo, L. I. Larina, and K. A. Chernyshev
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: keiko@irioch.irk.ru
Received July 21, 2011
Abstract—Methods were proposed for the synthesis of the methylglyoxal 1,2-bis-(N,N-dimethylhydrazone). A
possibility was shown for the first time of its participation in the Diels–Alder reaction with maleic anhydride as
an electron-rich diene. The second reaction of these reagents, which is observed in a wet media, is the
formation of the hydrazinium salt of the initial diene with maleic acid. The most probable structure of the
protonated diene among the four possible forms was revealed by the quantum-chemical calculations of the
13
energy of the molecules and by the analysis of the C NMR chemical shifts.
DOI: 10.1134/S1070363212010124
The methylglyoxal bishydrazones, in particular,
H C
C
C
H
NNMe2
NNMe2
3
substituted bisguanylhydrazones and bisthiosemi-
carbazones, show pronounced biological activity, and
some of them are used as drugs [1–5]. Earlier [6] by
the reaction of 2-ethoxypropenal with equimolar amount
of 1,1-dimethylhydrazine we obtained in a yield of 8%
the previously poorly studied methylglyoxal bis-(N,N-
dimethylhydrazone) (II) potentially possessing a
pharmacological action.
NNMe2
CH COCHO +
II
3
2
H NNMe
2
H O
2
H C
C
C
H
3
O
III
The aim of this work was an optimization of the
methods for the synthesis of this compound in diverse
ways and the study its properties.
bishydrazone II and the related product of the
hydrolysis at the ketone imine group.
By the reaction of 50% aqueous solution of
methylglyoxal (I) (commercial reagent) with
dimethylhydrazine (molar ratio 1:4) the methylglyoxal
bis-(N,N-dimethylhydrazone) (II) was produced.
Depending on the experimental conditions and the
method of binding water, the yield of bishydrazone II
To eliminate the water medium we performed the
synthesis of methylglyoxal from 2-ethoxypropenal in
acetonitrile by the method of [7]. In the subsequent
reaction of methylglyoxal with dimethylhydrazine
MgSO or molecular sieves 4 Å were used for binding
4
1
before distillation (according to H NMR spectra) was
the water formed at the condensation.
3
7–54%. A by-product of the reaction is methylglyoxal
mono-N,N-dimethylhydrazone (III). Molar content of
this compound in the reaction mixture was 13–22%
depending on the experimental conditions.
OEt
+
H O , 60°C, 50 min
3
O
CH COCHO
3
CH
H NNMe + K CO or MgSO
4
CN
3
The formation of monohydrazone III is due to the
reversible equilibrium in the water medium of the
4
2
2
2
3
II + III
7
7

7
8
KEIKO et al.
But even at twofold excess of N,N-dimethylhyd-
The bishydrazone II is a poorly studied [9]
representative of a class of diaza-1,3-dienes used in the
diene synthesis [10]. Among them, 1,4-diaza-1,3-
butadienes have been used as potential intermediates in
the study of transformations of methylglyoxal in the
body [11] or as ligands in metallocomplex catalysts
[12, 13]. But they only seldom have been studied in the
reactions of [4+2]-cycloaddition as the dienes [14–17].
The possible Diels–Alder reaction for 1.4-diamino-
substituted 1.4-diaza-1,3-dienes IV, having at positions
razine over the stoichiometric amount the bishyd-
razone II yield was no more than 65% (according to
1
H NMR data). The monohydrazone III was formed in
1
8–25% yield.
A surprising feature of the methylglyoxal bis-N,N-
dimethylhydrazone II is the ability to exist as two
stereoisomers, major IIa and minor IIb, in a ratio of
1
1
.9–4: 1, as we judged from the H NMR spectra and
GC-MS. At heating the mixture with the isomers ratio
.9:1 for 15 min at 50°C in the NMR ampule the ratio
1
1
and 4 electron-donor and electron-acceptor sub-
changed to 2.7:1. In gas chromatography-mass spec-
trum of the authentic sample of methylglyoxal
bisdimethylhydrazone also two geometric isomers
were observed with molecular weight 156, with the
retention time of 8.801 and 9.164 min. The ratio of the
isomers cannot be estimated from the GC-MS data due
to their mutual transformations. The configurational
assignment of the isomers was carried out on the basis
stituents, with dienophiles with an electron-deficient
double bond, in particular, with acrolein was
calculated in [14]. It is known that the introduction of
the NMe substituent in the imino group of azadiene
2
leads to an increase in its reactivity with respect to
electrophilic dienophiles [18]. However, it was shown
in [19] that the steric repulsion of methyl groups in the
Me NN=C(Me) fragment does not activate the
2
of experimental measurements and ab initio
1
molecule of vinylmethylketone hydrazone V to
participate in the diene synthesis, as was in the case of
the acrolein hydrazone VI, but hinders by violating the
coplanarity of the diene fragment.
calculations of the spin–spin coupling constants J
CC
1
and J [8]. The calculations showed that bishyd-
CH
razone methylglyoxal exists as a mixture of EE and ZE
isomers [8].
NR
H
N
N
N
Me
N:
NR
IV
Me
V
, OH, CH , OCH
Me
Me Me
VI
R = NH
2
3
3
, H, Cl, CN, NO .
2
Thus, the presence of two dimethylamino groups in
reaction takes place at the temperature –15 to –20°C
within 20 minutes with full conversion of initial
reagents. In the reaction mixture the expected
anhydride of 1,4-bis(dimethylamino)-1,4-dihydropyra-
zine-2,3-dicarboxylic acid VII formed in a yield of up
studied diazadiene II activates the diene not explicitly
(
not proportional to the number of groups), so the ease
of diene synthesis is not obvious a priori. It should be
borne in mind that molecule II should participate in
the diene synthesis in the s-cis form, which in this case
is energetically less favorable [8].
1
to 77% (according to H NMR data).
The dehydrogenation of the primary adduct A with
the air oxygen, accompanying the diene synthesis, is
not unexpected [6]. Unfortunately, we failed to isolate
the anhydride VII in pure form, since it is readily
hydrolyzed like other anhydrides [20] at the
chromatography on silica gel and decomposes at the
vacuum distillation. However, in the reaction mixtures,
Carrying out the reactions of diene synthesis of α,β-
unsaturated N,N-dimethylhydrazones with methyl-
vinylketone or methacrylate often requires prolonged
heating at high temperature [18]. We failed to carry out
the reaction of diene synthesis of bishydrazone II with
methyl vinyl ketone at heating (140°C, 2 h). However,
we first showed that this electoron-rich bisdimethyl-
amino-1,4-diazadiene II can enter the diene synthesis
with the electron-deficient maleic anhydride. The
1
it is stored for several weeks, as confirmed by H and
1
3
C NMR spectra.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 1 2012

METHYLGLYOXAL BIS-(N,N-DIMETHYLHYDRAZONE)
79
O
O
II
NMe2
O
NMe
N
2
O
O
O
O
O
O
N
O
N
N
NMe2
NMe2
A
VII
The second product in the reaction of compound II
tonation of the main stereoisomer VIII of the parent
compound II [8] by a proton of the maleic acid formed
from the original anhydride in situ in the presence of
some water in the reaction mixture. The scheme below
with maleic anhydride was a crystalline substance
1
containing (according to H NMR spectrum) the frag-
ments similar in structure to the parent compounds.
13
13
But the C NMR resonance signals are shifted compared
shows the experimental values of the C NMR
2
3
with compound II, which may be a consequence of pro-
chemical shifts (ppm) of carbon atoms C and C .
NMe2
N1
O
O
O
H
N
NMe2
N+
1
62.56
H
H
H
H
H
2
O−
HO
HO
169.34
CH3
3
CH3
H
1
32.21
+
N4
117.15
HO
Me N
2
Me N
2
O
VIII
IX
To prove the structure of the hydrazinium salt IX
for the medium effects, in this case chloroform. The
chemical shifts were calculated also accounting for the
GIAO-B3LYP/DZP field of the solvent. The results of
1
3
we calculated the energy characteristics and the
C
NMR chemical shifts of four possible protonated
forms of the bishydrazone VIIIa–VIIId. The geometry
optimization was performed within the B3LYP/6-
–
1
the calculations [relative energies (kcal mol ) and
theoretical values of the δ , ppm] for the four forms of
C
3
11G(d,p) method using the PCM model to account
compound VIII are shown below.
+
NMe2
H
NMe2
NMe
2
+
N
NHMe2
N
N
N
1
74.91
CH3
120.70
CH3
124.22
CH3
H
1
72.57
H
12.37
H
149.42
H
17.14
168.96
1
CH3
1
N
N
N
+
N
Me N
+
Me HN
2
Me N
H
2
Me N
2
2
VIIIa, 7.1
VIIIb, 0.0
VIIIc, 12.0
VIIId, 12.2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 1 2012

8
0
KEIKO et al.
According to the calculations of the 13C NMR
hydrazones II and III was distilled in a vacuum. The
chemical shifts, the best agreement with experiment is
found for the forms VIIIa and VIIIb, for which the
difference between calculated and experimental values
does not exceed 5 ppm. In contrast, for VIIIc and
VIIId the agreement with experiment is much worse:
the difference is 50 ppm, which clearly favors the
structures VIIIa and VIIIb. In addition, the data on the
relative energies of four possible forms VIIIa–VIIId
show clearly that the protonation proceeds with the
formation of cation VIIIb. The relative energies of the
distillation provided 0.7 g (32.2%) of substance with
2
0
1
bp 70–76°C (4 mm Hg), n 1.5248. According to H
D
NMR, the fraction contains isomers of methylglyoxal
bis-(N,N-dimethylhydrazone) II in a ratio of 2.35: 1
and 13.15 mol % of methylglyoxal N,N-dimethylhyd-
1
razone III described in [23]. The H NMR spectrum of
major isomer IIa (CDCl ), δ, ppm: 2.12 s (3H, CH ),
3
3
2.53 s (6H, NMe ), 2.93 s (6H, NMe ), 6.91 s (1H,
2
2
1
=CH). The H NMR spectrum of minor isomer IIb
(CDCl ), δ, ppm: 2.08 s (3H, CH ), 2.47 s (6H, NMe ),
3
3
2
–
1
13
other forms are higher than 7 kcal mol , which
indicates their complete absence in the reaction
mixture. Thus, our calculations allow us an unequi-
vocal establishment of the structure of compound IX,
existing as a salt of maleic acid anion and the imine
3.01 s (6H, NMe ), 7.39 s (1H, =CH). C NMR
2
spectrum major isomer IIa (CDCl ), δ, ppm: 12.90
3
(CH ), 42.53 (C=NNMe ), 47.34 (CH=NNMe ),
3
2
2
1
3
132.85 (CH=N), 163.40 (C=N). C NMR spectrum of
minor isomer IIb (CDCl ), δ, ppm: 19.34 (CH ), 42.37
3
3
2
with the protonated nitrogen at the C atom of
(C=NNMe ), 47.88 (CH=NNMe ), 128.40 (CH=N),
2
2
methylglyoxal bisdimethylhydrazone. The yield is
varied in the range of 30–90% depending on water
content in the solvents (CH Cl , CHCl , CH CN).
162.15 (C=N). The assignment of the signals is made
1 13
on the basis of two-dimensional spectra H– C
HMBC-GP. The mass spectrum of major isomer IIa,
2
2
3
3
+
+
m/z (I , %): 156(56) [M] , 112(11) [M – NMe ] , 97
rel
2
+
+
EXPERIMENTAL
(
[
(
8) [M – NMe –CH ] , 83(10) [CCHNNMe ] , 70(22)
2
3
2
+ + +
C=NNMe ] , 58(7) [NNMe ] , 44(100) [NMe ] , 28
1
13
2
2
2
The H and C NMR spectra were recorded on a
Bruker DPX-400 spectrometer, at the resonance
frequency 400.13 and 100.61 MHz, respectively,
solvents CDCl , CD CN, and DMSO-d , internal
53), 18(17). The mass spectrum of minor isomer IIb,
+
+
m/z (I ,%): 156(49) [M] , 112(10) [M – NMe ] , 97
rel
2
+
+
(
10) [M – NMe – CH ] , 83(10) [CCHNNMe ] , 70
2
3
2
3
3
6
+ + +
(
20) [C=NNMe ] , 58(7) [NNMe ] , 44(100) [NMe ] ,
2
2
2
reference HMDS. The IR spectra were obtained on an
IR spectrometer Specord IR-75. Chromatography-mass
spectrometry analysis was performed on a gas
chromatograph-mass spectrometer Hewlett-Packard
HP 5971A (EI, 70 eV, mass-selective detector) with a
HP-5890 gas chromatograph, column Ultra-2 (5%
phenylmethylsilicone), evaporator temperature 250°C ,
oven temperature 70–280°C, the rate of heating
–1
2
8(28), 18(12). IR spectrum, ν, cm : 1590 and 1525
(
C = N).
Monohydrazone III. The H NMR spectrum
(CDCl ), δ, ppm: 2.27 s (3H, CH CO), 3.12 s (6H,
NMe ), 6.57 s (1H, =CH). The spectrum coincides
with the spectrum of this compound given in [23]. The
1
3
3
2
1
H NMR spectrum (CD
CO), 3.07 s (6H, NMe
NMR spectrum (CDCl
(NMe ), 124.21 (CH=N), 197.52 (C=O).
CN), δ, ppm: 2.16 s (3H, CH
), 6.51 s (1H, =CH). The
), δ, ppm: 18.91 (CH
3
3
–
1
13
2
0 deg min . The melting points were determined on a
2
C
Micro-Hot-Stage Poly Term A instrument (Warner and
Muzn). The geometry optimization of compounds
VIIIa–VIIIg was performed using the GAMESS
software package [21], calculations of shielding
constants was carried out with the ADF software
package [22].
3
3
), 67.90
2
Methylglyoxal bis-(N,N-dimethyl)hydrazone II
from α-ethoxyacrolein. To the solution of 0.07 g of
preliminary prepared catalyst (0.5 ml of concentrated
HCl was dissolved in 1 ml of acetonitrile) was added
0.002 g of hydroquinone in 0.38 g of water, at 55°C
was added 2.9 g of α-ethoxyacrolein, and the mixture
was heated for 50 min. After cooling to 25°C was
Reaction of methylglyoxal with dimethylhyd-
razine. To a solution of 0.5 g (1 ml) of 50% aqueous
methylglyoxal in 50 ml of ether was added 0.002 g of
hydroquinone and 1.67 g of dimethyl hydrazine. The
solution was stirred for 8 h at 18°C and left overnight.
The top layer of the reaction mixture was separated
added 3 g of MgSO , the mixture was stirred for
4
30 min, and 6.7 g of dimethylhydrazine was added
dropwise. The mixture was stirred for 4 h and left
overnight. The filtered reaction mixture was eva-
porated and distilled under nitrogen. Yield of com-
pound II 1.72 g (53%), bp 81–82°C (1 mm Hg).
and dried over CaCl , and then ether was removed in a
2
vacuum. The remaining reaction product (1.47 g)
1
containing mainly (according to H NMR data)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 1 2012

METHYLGLYOXAL BIS-(N,N-DIMETHYLHYDRAZONE)
81
Found, %: C 53.88, H 10.40; N 35.69. C H N .
3. Ekelund, S., Nygren, P., and Larsson, R., Biochem.
Pharm., 2001, vol. 61, no. 10, p. 1183.
7
16
4
Calculated, %: C 53.84, H 10.25; N 35.89. The spectra
correspond to the above listed.
4. Salvi, M. and Toninello, A., Biochem. Pharm., 2002,
vol. 63, no. 2, p. 247.
1
,4-Bis(dimethylamino)-1,4-dihydro-2-methylfuro-
5
6
7
. Mironov, E.A., Dilanyan, E.R., Moskaleva, I.V., and
Vol’pin, M.E., Koord. Khim., 1987, vol. 13, no. 12,
p. 1593.
. Keiko, N.A., Kuznetsova, T.A., Larina, L.I., Chuva-
shev, Yu.A., Klepikova, T.A., and Sherstyannikova, L.V.,
Zh. Org. Khim., 2006, vol. 42, no. 10, p. 1439.
. Mamashvili, T.N., Keiko, N.A., Sarapulova, G.I., and
Voronkov, M.G., Izv. Akad. Nauk, Ser. Khim., 1998,
no. 12, p. 2547.
pyrazin-5,7-dione (VII). To 0.29 g of maleic anhyd-
ride in 2 ml of methylene chloride (dried over 4A
sieves) at a temperature –15 to –20°C was added 0.46 g
of compound II, and the mixture was stirred until the
temperature reaches the room temperature. The yield
1
of crude product 77% ( H NMR). Yellow-brown oil.
1
H NMR spectrum (CDCl ), δ, ppm: 2.24 s (3H, CH ),
3
3
2
.70 s (6H, NNMe ), 3.21 s (6H, NNMe ), 7.90 s (H,
2
2
1
CH) . H NMR spectrum (CD CN), δ, ppm: 2.35 s
8. Krivdin, L.V., Larina, L.I., Keiko, N.A., and Cherny-
3
(
3H, CH ), 2.64 s (6H, NNMe ), 3.20 s (6H, NNMe ),
shev, K.A., Austral. J. Chem., 2006, vol. 59, no. 3, p. 211.
3
2
2
1
7
.10 s (1H, CH .) H NMR spectrum (DMSO-d ), δ,
9. Serè, V., Peri, F., Pollicino, S., and Ricci, A., Synlett.,
6
ppm: 2.18 s (3H, CH ), 2.54 s (6H, NNMe ), 7.3 s (6H,
1999, no. 10, p. 1585.
3
2
1
3
NNMe ), 6.84 s (1H, CH). The C NMR spectrum
(
1
10. Tietze, L.F. and Kettschau, G., in Topic in Current
Chemistry, Metz, P., Ed., Berlin, Heidelberg: Springer-
Verlag, 1997, vol. 189, p. 59.
2
CDCl ), δ, ppm: 15.7 (CH ), 46.0 and 46.3 (NMe ),
3
3
2
4a
7a
2
5
7
16.9 (C=NN), 121.4 (C , C ), 131.4 (C ), 171.7 (C , C ).
1
1. Brinkmann, E., Wells-Knecht, K.J., and Thorpe, S.R.,
1-{(E)-2-[(E)-2',2'-Dimethylhydrazino]-1-methyl-
J. Chem. Soc., Perkin Trans. 1, 1995, no. 22, p. 2817.
ethylidene}-2,2-dimethylhydrazinium maleate (IX).
To 0.242 g of maleic anhydride in 1.5 ml of methylene
chloride was added 0.385 g of compound II, and the
mixture was stirred at room temperature for 1 h and
1
2. Stoffelbach, F., Richard, P., Poli, R., Jenny, T., and
Savary, C., Inorg. Chim. Acta., 2006, vol. 359, no. 14,
p. 4447.
1
1
1
1
1
1
1
3. Nakamura, A. and Mashima, K.P., J. Organometal.
1
left overnight. A day later, according to H NMR
Chem., 2001, vol. 621, nos. 1–2, p. 224.
spectrum, the reaction mixture contained compounds
4. Lee, G.-Y., J. Korean Chem. Soc., 2001, vol. 45, no. 3,
p. 207; C. A., 2001, vol. 135, 256880.
VII and IX. The salt IX was isolated by recrystal-
lization from methylene chloride. Yield 0.566 g
5. Ganesan, A. and Heathcock, C.H., J. Org. Chem., 1993,
1
(
84.5%). Pale yellow needles, mp 102°C. H NMR
vol. 58, no. 22, p. 6155.
spectrum (CDCl ), δ, ppm: 2.49 s (3H, CH ), 2.70 s
3
3
6. Orsini, F. and Sala, J., Tetrahedron, 1989, vol. 45,
+
(
6H, NNMe ), 3.31 s (6H, N NMe ), 6.26 s (2H,
2
2
no. 20, p. 6531.
1
CH=CH), 7.31 s (1H, N=CH). H NMR spectrum
7. Weidenbruch, M. and Lesch, A., J. Organometal.
(
CD CN), δ, ppm: 2.32 s (3H, CH ), 2.64 s (6H,
3
3
Chem., 1991, vol. 407, no. 1, p. 31.
+
NNMe ), 3.34 s (6H, N NMe ), 6.16 s (2H , CH=CH),
2
2
8. Serkx-Ponkin, B., Hesbain –Frisque, A.M., and Ghosez, L.,
1
7
.27 s (1H, N= CH). H NMR spectrum (DMSO-d ), δ,
6
Tetrahedron Lett., 1982, vol. 23, no. 32, p. 3261.
ppm: 2.27 s (3H, CH ), 2.61 s (6H, NNMe ), 3.37 s
3
2
9. Beforous, M., Stelzer, L.S., Ahmadian, M., Haddad, J.,
and Scherschel, J.A., Tetrahedron Lett., 1997, vol. 38,
no. 13, p. 2211.
+
(
6H, N NMe ), 6.08 s ( 2H, CH=CH), 7.21 s (1H,
2
13
N=CH). C NMR spectrum (CDCl ), δ, ppm: 29.8
3
(
(
2
2
CH ), 46.3 and 46.7 (NMe ), 117.2 (N =CH), 136
3
2
2
2
0. Janey, J.M., Ywama, T., Kozmin, S.A., and Rawal, V.H.,
CH=CH), 169.4 (C=O). Found, %: C 48.77, H 7.8; N
J. Org. Chem., 2000, vol. 65, no. 26, p. 9059.
0.44. C H N O . Calculated, %: C 48.53, H 7.35; N
1
1
20
4
4
1. Schmidt, M.W., Baldridge, K.K., Boatz, J.A., Elbert, S.T.,
Gordon, M.S., Jensen, J.H., Koseki, S., Matsunaga, N.,
Nguyen, K.A., Su, S.J., Windus, T.L., Dupuis, M., and
Montgomery, J.A., J. Comput. Chem., 1993, vol. 14,
no. 11, p. 1347.
0.59.
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