Synthesis of 4,6-disubstituted dimethyl pyridazine-3,5-dicarboxylates

Article abstract of DOI:10.1023/B:RUJO.0000045199.21494.c7

Dimethyl pyridazine-3,5-dicarboxylates were synthesized by reaction of substituted 2-cyclo-propenecarboxylates with methyl diazoacetate, followed by oxidation of the resulting 1,4-dihydropyridazine-4,6-dicarboxylates.

Full text of DOI:10.1023/B:RUJO.0000045199.21494.c7

Russian Journal of Organic Chemistry, Vol. 40, No. 7, 2004, pp. 1033–1036. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 7, 2004,
pp. 1074–1077.
Original Russian Text Copyright © 2004 by Yakovlev, Razin.
Synthesis of 4,6-Disubstituted Dimethyl
Pyridazine-3,5-dicarboxylates
M. E. Yakovlev and V. V. Razin
St. Petersburg State University, Universitetskii pr. 26, St. Petersburg, 198904 Russia
Received September 24, 2003
Abstract—Dimethyl pyridazine-3,5-dicarboxylates were synthesized by reaction of substituted 2-cyclo-
propenecarboxylates with methyl diazoacetate, followed by oxidation of the resulting 1,4-dihydropyridazine-
4,6-dicarboxylates.
We proposed in [1] a procedure for the synthesis of
substituted methyl pyridazine-4-carboxylates on the
basis of cycloadducts derived from diazomethane and
2-cyclopropenecarboxylic acids. In the present work
we applied an analogous scheme to obtain substituted
dimethyl pyridazine-3,5-dicarboxylates using methyl
diazoacetate instead of diazomethane. The initial com-
pounds were known 2,3-disubstituted methyl 2-cyclo-
propenecarboxylates I–III. Cyclopropene I reacted
with methyl diazoacetate at a much lower rate than
with diazomethane; after 90 days at room temperature,
the conversion was ~40%, whereas the reaction with
diazomethane was complete in 10–12 days. We have
found more appropriate conditions for the reaction of
I with methyl diazoacetate: in dimethylformamide at
85°C, the reaction was complete in 30 h, and the
product was formed in high yield. Both at room tem-
perature and at 85°C, the same product was obtained,
1,4-dihydropyridazine IVa. Presumably [1], the corre-
sponding bicyclic adduct A is formed initially, and
its enhanced CH acidity favors the subsequent fast
isomerization with cleavage of the three-membered
carbon ring [2].
Like cyclopropene I, compounds II and III readily
reacted with methyl diazoacetate at 75–80°C in DMF.
From cyclopropene II we obtained 1,4-dihydropyrida-
zine derivative Va, and compound III gave rise to
two isomeric 1,4-dihydropyridazines VIa and VIIa at
a ratio of 5:1. Obviously, compounds Va–VIIa are
formed in a way similar to the formation of IVa, and
the isomer ratio VIa:VIIa is determined by regio-
selectivity of the cycloaddition of methyl diazoacetate
at the unsymmetrically substituted double bond of
cyclopropene III. It should be noted that in the reac-
tion with the same substrate (III), methyl diazoacetate
shows a lower regioselectivity than diazomethane (the
ratio of the isomeric adducts in the reaction with diazo-
methane was 11:1 [1]). However, the proposed scheme
of formation of compounds IVa–VIIa cannot be re-
garded as an unambiguous proof for their structure. In
fact, we showed in [1] that base-catalyzed isomeriza-
tion of 2,3-diazabicyclo[3.1.0]hexenes like A can take
two pathways leading to 1,4-dihydropyridazines IVa–
VIIa and tautomeric structures IVb–VIIb (Scheme 1).
Analysis of the spectral data (Table 1) confirmed
the 1,4-dihydropyridazine structure of compounds Va
Scheme 1.
H
N
H
N
R
R'
E
R
E
N
E
N
N2CHE
N
NH
E
R
or
R'
H
R
H
E
R'
R'
H
E
H
E
I–III
A
IVa–VIIa
IVb–VIIb
I–VII, E = COOMe; I, IVa, IVb, R = R' = Ph; II, Va, Vb, R = R' = Me; III, VIa, VIb, R = Me, R' = Ph;
III, VIIa, VIIb, R = Ph, R' = Me.
1070-4280/04/4007-1033 © 2004 MAIK “Nauka/Interperiodica”

YAKOVLEV, RAZIN
1034
Scheme 2.
E
H
E
H
E
H
H
Ph
–H+
H+
H+
–H+
H+
H+
Ph
E
Ph
Ph
Ph
Ph
IVa
IVb
–H+
–H+
N
N
N
N
E
N
E
N
D
B
C
E = COOMe.
1
and VIa. Their H NMR spectra contained singlets
from the 4-H protons and protons of the methyl
groups; alternative structures Vb and VIb should be
characterized by splitting of the corresponding signals.
It was more difficult to distinguish between structures
IVa/IVb and VIIa/VIIb on the basis of the available
spectral data. We have found that compound IVa
undergoes isomerization into IVb by the action of
sodium hydroxide in DMSO. The main difference
between isomers IVa and IVb is the presence of
a downfield (δ 7.8–8.0 ppm) two-proton signal in
boxylates VIII–XI were obtained in high yields
1
(Scheme 3). The H and 13C NMR spectra of com-
pounds VIII–XI (Table 2) were consistent with the
assumed structures.
The structure of regioisomers X and XI was proved
by comparing their spectral parameters. First of all,
these compounds were characterized by different
chemical shifts of the methyl protons and carbon
1
nuclei in the H and 13C NMR spectra: the corre-
sponding signals in the spectra of XI were located in
a weaker field due to effect of the neighboring azo
group. Second, the signal from the ortho-protons of
the phenyl group in X was displaced downfield for the
same reason. We believe that these data are sufficient
to distinguish between structures X and XI. In ad-
dition, we thus confirmed the assumed structures of
parent compounds VI and VII and hence the regio-
selectivity of cycloaddition of methyl diazoacetate to
cyclopropene III.
1
the H NMR spectrum of IVa; no such signal was
observed in the spectrum of IVb. This signal is typical
of ortho-protons of the 3-phenyl group in IVa [1]. The
choice between isomers VIIa and VIIb was made in
favor of the former, taking into account that the
chemical shifts of C4 and C5 in the 13C NMR spectrum
of VIIa were similar to those observed for IVa rather
than IVb. Probably, the isomerization of IVa into IVb
involves intermediate formation of 4,5-dihydropyrida-
zine B via intermolecular proton transfer. The driving
force of this process is likely to be clearly higher
stability of anion C as compared to D (Scheme 2).*
Taking into account accessibility of the initial
cyclopropene derivatives, the proposed two-step proce-
dure for the synthesis of 4,6-disubstituted pyridazine-
3,5-dicarboxylates seems to be an efficient alternative
to the known methods of preparation of pyridazine-
3,5-dicarboxylic acids [3].
1,4-Dihydropyridazines IV–VII were oxidized by
the action of potassium permanganate in aqueous
acetone. The reaction was fast, and the correspond-
ing 4,6-disubstituted dimethyl pyridazine-3,5-dicar-
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Scheme 3.
a Bruker DPX-300 spectrometer (300.13 and
75.47 MHz, respectively) from solutions in CDCl3.
The IR spectra were measured on a UR-20 instrument
from 1% solutions in CCl4. The elemental composi-
tions were determined on an HP-185B CHN-analyzer.
Silufol UV-254 plates were used for analytical thin-
layer chromatography. The products were separated
and purified by column chromatography on silica gel
L 40/100 µm (Chemapol). Esters I [4], II [5], and III
[6] were synthesized by known methods.
E
N
KMnO4
N
IVa–VIIa, IVb
R1
R2
E
VIII–XI
E = COOMe; VIII, R1 = R2 = Ph; IX, R1 = R2 = Me;
X, R1 = Me, R2 = Ph; XI, R1 = Ph, R2 = Me.
* We are now trying to prove the general character of prototropic
isomerization in the series of 1,4-dihydropyridazines. Unfortu-
nately, this work is complicated by high sensitivity of these
compounds to oxidants (especially in alkaline medium).
Dimethyl 3,5-diphenyl-1,4-dihydropyridazine-
4,6-dicarboxylate (IV). a. A solution of 0.25 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 7 2004

SYNTHESIS OF 4,6-DISUBSTITUTED DIMETHYL PYRIDAZINE-3,5-DICARBOXYLATES
1035
Table 1. 1H and 13C NMR spectra of 1,4-dihydropyridazines IV–VII
1H NMR spectrum, δ, ppm
4-H CH3 OCH3 NH
3.69 s, 8.80 br.s 7.30–7.45 (8H), 46.4 111.1
3.75 s, 7.80–7.90 (2H)
13C NMR spectrum, δC, ppm
CH3 OCH3 C=O
Comp.
no.
Ph
C4
C5
Ph, C3, C6
4.87 s
4.99 s
–
–
–
,52.2, ,163.3, 126.6 (2C), 127.6, 127.8
52.7 169.9 (2C), 127.9, 128.4 (2C),
129.0, 129.3 (2C), 134.6,
IV
135.0, 137.9
3.76 s, 8.53 br.s 7.12–7.18 (3H), 41.9 103.1
–
,52.5, ,164.3, 126.7, 127.8 (2C), 128.9
52.6 171.0 (2C), 129.2, 129.4 (2C),
129.8 (2C), 133.7, 136.4,
IVa
3.87 s,
7.18–7.24 (2H),
7.30–7.40 (5H)
137.0
3.77 s 2.11 s, 3.70 s, 7.87 br.s –
2.21 s, 3.85 s,
50.3 111.2 ,18.4, ,52.0, ,162.9, 126.7, 136.3
21.7 52.3 168.9
V
4.47 s 2.35 s, 3.69 s, 8.47 br.s 7.35–7.45 (3H), 46.9 112.3 18.5 ,52.0, ,162.6, 125.9 (2C), 126.3, 128.2
VI
VII
3.88 s,
7.75–7.83 (2H)
52.4 169.4 (2C), 128.6, 134.1, 135.4
a
4.14 s 2.22 s, 3.65 s,
3.75 s,
7.28–7.40
49.7 110.2 21.8 ,52.1, ,163.5, 127.6, 127.7 (2C), 129.1
52.5 169.3 (2C), 129.2, 136.8, 137.9
a
The NH signal was not detected in CDCl3; in DMSO-d6: δ 9.4 ppm, br.s.
Table 2. 1H and 13C NMR spectra of dimethyl pyridazine-3,5-dicarboxylates VIII–XI
1H NMR spectrum, δ, ppm
13C NMR spectrum, δC, ppm
OCH3 C=O
Ph, C4, C5
Comp.
no.
CH3
OCH3
Ph
C3, C6
CH3
–
–
3.48 s, 7.30–7.40 (2H), 151.5,
3.81 s, 7.43–7.57 (6H), 157.6,
7.73–7.80 (2H)
52.6, 52.9 164.9, 127.9 (2C), 128.3 (2C), 128.6 (2C),
165.5, 128.7 (2C), 129.4, 130.1, 131.8,
132.5, 135.4, 136.8
VIII
2.47 s, 3.99 s,
2.72 s 4.03 s,
–
151.1, 15.8, 20.4 52.9, 53.0 165.1, 133.2, 134.4
IX
X
156.6,
166.1,
2.55 s 3.73 s, 7.46–7.53 (3H), 151.1,
4.06 s, 7.65–7.72 (2H) 157.4,
15.7
20.4
52.6, 53.0 164.9, 128.3 (2C), 128.5 (2C), 129.4, 130.9,
166.3, 134.5, 136.3
2.82 s 3.64 s, 7.23–7.30 (2H), 151.5,
3.78 s, 7.42–7.48 (3H) 156.8,
52.6, 52.8 165.0, 127.7 (2C), 128.4 (2C), 129.3, 132.1,
165.6, 132.8, 135.9
XI
(1 mmol) of compound I and 0.5 g (5 mmol) of methyl
diazoacetate in 2 ml of DMF was kept for 30 h at 85°C
under argon. The mixture was cooled and diluted with
3 ml of water, and the precipitate was filtered off
and recrystallized from aqueous alcohol. Yield 0.29 g
(84%), mp 139°C. IR spectrum (CCl4), ν, cm–1: 3415
(N–H); 2955 (C–H); 1746, 1719 (C=O). Found, %:
C 68.48; H 5.28; N 7.91. C20H18N2O4. Calculated, %:
C 68.55; H 5.18; N 8.00.
0.32 g of initial compound I, Rf 0.42, and 0.15 g (21%)
of compound IVa, Rf 0.12.
Dimethyl 4,6-diphenyl-1,4-dihydropyridazine-
3,5-dicarboxylate (IVb). One drop of 50% aqueous
potassium hydroxide was added to a solution of 50 mg
(0.14 mmol) of compound IVa in 0.5 ml of dimethyl
sulfoxide, the mixture was stirred for 5 h at room
temperature and diluted with 15 ml of water, and
the precipitate was filtered off. Yield 27 mg (54%),
mp 153°C (from aqueous methanol). Found, %:
C 68.55; H 5.27; N 7.82. C20H18N2O4. Calculated, %:
C 68.56; H 5.18; N 8.00.
b. A solution of 0.5 g (2 mmol) of compound I and
0.5 g (5 mmol) of methyl diazoacetate in 2 ml of
benzene was placed in an ampule, and the ampule was
sealed and kept for 90 days at room temperature. The
mixture was subjected to column chromatography
using hexane–diethyl ehter (2:1) as eluent to isolate
Dimethyl 3,5-dimethyl-1,4-dihydropyridazine-
4,6-dicarboxylate (Va). A solution of 0.28 g
(2.2 mmol) of compound II and 1.0 g (10 mmol) of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 7 2004

YAKOVLEV, RAZIN
1036
methyl diazoacetate in 5 ml of DMF was heated for
20 h at 75°C under argon. The solvent and excess
methyl diazoacetate were removed under reduced
pressure, and the residue was recrystallized from
water. Yield 0.39 g (78%), mp 94°C. Found, %:
C 53.16; H 6.21; N 12.38. C10H14N2O4. Calculated, %:
C 53.09; H 6.24; N 12.38.
Dimethyl 4,6-diphenylpyridazine-3,5-dicar-
boxylate (VIII) was obtained from 1,4-dihydropyrida-
zine IVa. Yield 83%, mp 133°C (from aqueous
methanol). Found, %: C 68.79; H 4.77; N 7.80.
C20H16N2O4. Calculated, %: C 68.96; N 4.63; N 8.04.
According to the TLC data, the same product was
formed by oxidation of IVb.
Dimethyl 4,6-dimethylpyridazine-3,5-dicar-
boxylate (IX) was obtained from 1,4-dihydropyrida-
zine Va. Yield 77%, mp 97°C (from water). Found, %:
C 53.57; H 5.38; N 12.37. C20H12N2O4. Calculated, %:
C 53.57; H 5.40; N 12.50.
Reaction of ethyl 2-methyl-3-phenyl-2-cyclo-
propenecarboxylate (III) with methyl diazoacetate.
A solution of 0.75 g (4 mmol) of compound III and
1.5 g (15 mmol) of methyl diazoacetate in 8 ml of
DMF was heated for 25 h at 80°C under argon. The
mixture was cooled, diluted with 60 ml of water, and
extracted with methylene chloride (3×25 ml). The
combined extracts were washed with water, dried over
anhydrous sodium sulfate, and evaporated under
reduced pressure. The residue, 1.31 g, was a mixture of
compounds VIa and VIIa at a ratio of 5:1 (according
Dimethyl 4-methyl-6-phenylpyridazine-3,5-di-
carboxylate (X) was obtained from 1,4-dihydro-
pyridazine VI. Yield 91%, mp 70°C. Found, %:
C 62.84; H 4.93; N 9.74. C15H14N2O4. Calculated, %:
C 62.93; H 4.93; N 9.79.
Dimethyl 6-methyl-4-phenylpyridazine--3,5-di-
carboxylate (XI) was obtained from 1,4-dihydro-
pyridazine VII. Yield 88%, mp 64°C. Found, %:
C 63.12; H 4.92; N 9.56. C15H14N2O4. Calculated, %:
C 62.93; H 4.93; N 9.79.
1
to the H NMR data). It was subjected to column
chromatography using hexane–ethyl acetate–chloro-
form (3:1:1) as eluent.
Dimethyl 5-methyl-3-phenyl-1,4-dihydropyrida-
zine-4,6-dicarboxylate (VIa). mp 101°C, Rf 0.15.
IR spectrum (CCl4), ν, cm–1: 3405 (N–H); 2937 (C–H);
1741, 1715 (C=O). Found, %: C 62.56; H 5.64;
N 9.66. C15H16N2O4. Calculated, %: C 62.49; H 5.59;
N 9.72.
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Oxidation of 1,4-dihydropyridazines IVa–VIIa
(general procedure). Powdered potassium permanga-
nate, 1 mmol, was added in one portion to a solution of
1 mmol of 1,4-dihydropyridazine IVa–VIIa in aqueous
acetone, and the mixture was stirred for 1–5 h until the
initial compound disappeared (TLC). The precipitate
of MnO2 was filtered off and washed with acetone, the
filtrate was evaporated, and the residue was purified by
recrystallization or flash chromatography (compounds
X and XI).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 7 2004