Reaction of 3,5-carbonyl-substituted 1,4-dihydropyridines with hydrazine hydrate

Article abstract of DOI:10.1023/B:COHC.0000044569.14048.79

The interaction of 3,5-carbonyl-substituted derivatives of 1,4-dihydropyridine and some analogs of it with hydrazine hydrate occurs with fission of the heterocycle. In the case of alkoxycarbonyl-substituted compounds a reverse Michael reaction predominate

Full text of DOI:10.1023/B:COHC.0000044569.14048.79

Chemistry of Heterocyclic Compounds, Vol. 40, No. 7, 2004
REACTION OF 3,5-CARBONYL-
SUBSTITUTED 1,4-DIHYDROPYRIDINES
WITH HYDRAZINE HYDRATE
E. Bisenieks, J. Uldrikis, and G. Duburs
The interaction of 3,5-carbonyl-substituted derivatives of 1,4-dihydropyridine and some analogs of it
with hydrazine hydrate occurs with fission of the heterocycle. In the case of alkoxycarbonyl-substituted
compounds a reverse Michael reaction predominates leading to fragmentation of the molecules.
Keywords: 3-acyl- and 3-alkoxycarbonyl-5-oxo-1,4-dihydroindeno[1,2-b]pyridines, 3,5-acyl- and
3
,5-alkoxycarbonyl-1,4-dihydropyridines, pyrazole derivatives, fission of heterocycle with hydrazine.
The majority of the known derivatives of 1,4-dihydropyridine have electron-withdrawing substituents,
which usually contain a carbonyl group, in positions 3 and 5. Conjugation of the carbonyl substituents with the
NH group of the 1,4-dihydropyridine ring reduces the tendency of these compounds towards oxidation, and
simultaneously reduces the carbonyl reactivity and imparts weakly acidic properties to the ring NH group [1].
Consequently there is little information on the reactions of these compounds with hydrazines. For example, the
preparation of the 2,4-dinitrophenylhydrazone of 3,5-diacetyl-1,4-dihydropyridine is known [2], as is the
reaction of hydrazine with 2,3,5,6-tetraethoxycarbonyl-1,4-dihydropyridine, where the initial addition of
hydrazine to the substituents in positions 2 and 6 facilitates intramolecular cyclization with the substituents in
positions 3 and 5 [3]. This principle is also used in other syntheses of condensed heterocycles [4, 5]. The report
on the preparation of the dihydrazide of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid [6] proved to be
erroneous. It was later established that bis(5-methyl-3-oxo-4-pyrazolyl)methane is formed [7]. In the reactions of
3
4
4
,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine [7] and its 4-methyl, 4-ethyl, 4-phenyl, and
-(2-chlorophenyl) derivatives, and also of 3,5-diacetyl-2,6-dimethyl-1,4-dihydropyridine and its 4-methyl and
-phenyl derivatives [8], with a small excess of hydrazine hydrate without solvent, decomposition of the
heterocycle was observed and derivatives of bispyrazolylmethane were obtained. A large proportion of the
reactions required extended (up to 65 h) heating.
We have studied this reaction with a wider circle of related compounds, with tricyclic and pentacyclic
compounds containing the 1,4-dihydropyridine ring, and also with a tetrahydropyrimidine derivative. With the
aim of accelerating the process we carried out the reaction of the compounds being studied with an excess of
hydrazine hydrate in an autoclave at 100-150°C and in a solvent in order to avoid heterogeneous reactions.
Under these conditions the reaction of 3,5-acyl derivatives of 1,4-dihydropyridine 1a-f with hydrazine
hydrate proceeds more readily and pure bispyrazolylmethanes 2a-f are formed in high yield. Compound 2b [8]
was obtained previously on cyclization of methylene-3,3'-bisacetylacetone with hydrazine.
_
_________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV 1006; e-mail: gduburs@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 1014-1021. July, 2004. Original article submitted February 17, 2004.
0
009-3122/04/4007-0869©2004 Springer Science+Business Media, Inc. 869

R3
R2
R3
R2
O
O
R2
R2
2
H N–NH2
N
N
N
N
R1
R1
N
H
H
H
R1
R1
1
a–f
2a–f
1
2
3
1
2
3
1
2
3
1
, 2 a R = H, R = Me, R = H; b R = R = Me; R = H; c R = R = Me, R = 3-Py;
1
2
3
1
2
3
1
6 4 2 3 6 2
d R = R = Me, R = 2-С H OCHF ; e R = R = Me, R = 3,4,5-(MeO) C H ; f R = Me,
2
3
R = Ph, R = H
The reaction occurs even with compounds 1d and 1e, which have bulky substituents in position 4, and
also with the 3,5-dibenzoyl-substituted 1,4-dihydropyridine 1f. In difference to the data of [8] the solvent
(
ethanol) does not change the process.
Esters of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3a-d react with hydrazine hydrate
readily and unambiguously. The conversion of compound 3b was also successful on boiling in ethanolic
solution.
O
O
O
O
2
OR2
HN
NH
R O
H N NH2
2
N
N
Me
N
Me
H
H
Me Me
R1
a–e
4
3
1
2
1
2
1
2
1
2
3
a R = H, R = Me; b R = H, R = Et; c R = H, R = menthyl; d R = H, R = (CH
2
)13Me;
1
2
е R = Me; R = Et
Compound 4 was previously obtained on cyclization of methylene-2,2'-bisacetoacetic ester with
2
hydrazine. The size of the ester radical R has comparatively little influence on the reaction rate. Reaction with
the N-methyl-substituted compound 3e occurs more slowly. The formation of the second pyrazole ring requires
elimination of methylamine.
The reaction may be used for obtaining unsymmetrical bispyrazolylmethanes. Compound 6 is formed
from 3-acetyl-5-ethoxycarbonyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine (5) by reaction with hydrazine
hydrate.
Ph
Ph
O
O
O
Me
H N NH2
+
2
Me
OEt
N
NH
1
40°C, 4 h
N
N
Me
N
H
Me
H
H
Me Me
5
6
1
The structure of compound 6 was confirmed by the H NMR spectrum, but the IR spectrum is similar to
the spectra of bispyrazolylmethanes 2 and methylenebispyrazolone 4. In the IR spectrum of the latter the
-
1
stretching vibrations of the associated NH groups are displayed as bands in the 2400-3200 cm region due to
strengthening of the hydrogen bonds caused by resonance effects (of possible tautomeric bipolar structures). The
presence of NH and C=O (or C–OH) groups are thereby masked [9].
8
70

The reaction of hydrazine hydrate with compounds 1b and 3a-d unsubstituted at position 4 proceeds
significantly more rapidly than with their analogs substituted at position 4. This probably indicates the addition
of hydrazine to the carbonyl group as the first stage of the process with subsequent intramolecular addition of the
NH group at the C =C double bond, with fission of the 1,4-dihydropyridine ring and the formation of a
(
5)
(6)
pyrazole.
4
-Aryl-3,5-diethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines react poorly with hydrazine hydrate [8].
We carried out these reactions with an excess of hydrazine hydrate in alcohol solution at 130-150°C. In the case
of the bulky 5-norbornen-2-yl substituent at position 4 the initial dihydropyridine remains unchanged. The
1
,4-dihydropyridine ring is retained also in the case of the 4-phenyl-substituted compound, but its 4-(3-pyridyl)
analog 10 reacted with ring fission and the formation of bispyrazolylmethane 11. Reactions occurred readily
with methyl esters but frequently in addition to the expected bispyrazolonylmethane derivative such products as
5
-methyl-3-pyrazolone (8), and the hydrazone or azine of the aldehyde used for the synthesis of the
corresponding dihydropyridine were formed. Consequently, the so-called reverse Michael reaction is observed.
O
7
+
NH
Me
R2
N
H
O
O
F2HCO
OCHF
2
8
(47%)
1
OR1
H N NH2
H
N
N
H
R O
Me
2
9
1
50°C, 2 h
N
H
Me
N
O
7
, 10
1
0
O
O
+
NH
Me
N
HN
NH
H
8
N
N
H
H
Me Me
1 (~30%)
1
1
2
1
2
7
R = Me, R = 2-C H OCHF ; 10 R = Et, R = 3-Py
6
4
2
The yield of these side products in the reaction with dihydropyridine 7 exceeds the yield of the expected
bispyrazolonylmethane.
The 1,4-dihydropyridine ring is also broken on treatment of derivatives of 1,4-dihydroindeno[1,2-b]-
pyridine with hydrazine hydrate. It was possible to isolate compound 15 in the reaction with the 3-acetyl-
substituted compound 12. The reverse Michael reaction predominates in the reactions with the 3-alkoxycarbonyl
derivatives 13 and 14 under these conditions. It was possible to isolate 1,3-indanedione dihydrazone (16) in up
to 60% yield from the reaction mixture, and products of the recombination of fragments of the molecule, such as
3-pyridylbis(5-methyl-3-oxo-4-pyrazolyl)methane (11). Compound 13, unsubstituted at position 4, forms a
mixture of compounds even under less rigid conditions (Scheme 1).
In the case of 10,12-dioxo-11-phenyl-5,10,11,12-tetrahydrodiindeno[1,2-b:2',1'-e]pyridine (18), a
polycyclic derivative of 1,4-dihydropyridine, heating with hydrazine hydrate takes place without fission of the
heterocycle (Scheme 2).
Under the reaction conditions probably addition of hydrazine to a carbonyl group occurs, which is
accompanied by spontaneous aromatization of the heterocycle. Simultaneously a Wolff–Kishner reaction occurs
and 11-phenyl-10H,12H-diindeno[1,2-b:2',1'-e]pyridine (19) is formed. Compound 19 was obtained previously
from the product of oxidation of compound 18 [10].
8
71

Scheme 1
R2
O
O
R1
N
Me
H
2–14
1
+
H N NH2
2
1
2
150°C, 5 h
13
100°C, 2 h
14
125°C, 5 h
NNH2
NNH2
Me
O
Ph
N
N
NH
NH
NH
O
O
NNH2 Me
NNH2
Me
1
5 (23%)
HN
NH
1
7
N
N
+
NNH2
+
H
H
Me Me
16
1
1 (24%)
+
NNH2
16 (60%)
1
6
1
2
1
2
1
2
1
2 R = Me, R = Ph; 13 R = OEt, R = H; 14 R = OEt, R = 3-Py
Scheme 2
O
Ph
O
Ph
H N NH2
2
1
40°C, 5 h
N
N
H
18
19
Fission of the heterocycle and the formation of a pyrazole derivative also occurs on treatment of other
related system with hydrazine hydrate.
Ph
O
S
Ph
Me
H N NH2
HN
Me
2
H N
N
H
2
N
1
30°C, 5 h
N
S
Me
N
H
Me
H
2
0
21
3,5-Dimethyl-4-(α-thioureidobenzyl)pyrazole (21) is formed on interacting 5-acetyl-6-methyl-2-thioxo-
4-phenyl-1,2,3,4-tetrahydropyrimidine (20) with hydrazine hydrate.
8
72

TABLE 1. Reactions with Hydrazine Hydrate
Compound investigated
Hydrazine hydrate
mmol
Reaction conditions
Product obtained
amount, g
Ethanol, ml
No.
g
mmol
ml
t, °C
time, h
No.
yield, %
1
1
a
b
0.10
0.33
10.0
15.0
0.33
10.0
0.33
30
0.55
1.71
37.0
45.0
0.92
31.5
1.47
120
0.5
1.2
25
10.3
24.7
510
2.5
2.5
55
140
140
150
150
140
140
140
~80
140
140
140
140
150
150
140
100
125
6
2
2a
2b
2c
2d
2e
2f
4
0.05
0.28
7.69
14.10
0.20
8.80
0.25
21.73
0.12
0.19
0.12
0.23
2.50
0.91
0.10
52
80
74
91
59
85
82
88*
83
82
45
74
47
1
c
5
1
d
15
1.2
20
306
24.7
410
60
2.5
60
3
4
1
e
1
f
6
3
3
a
1.2
60
24.7
1240
24.7
10.4
24.7
24.7
410
2.5
200
2.5
2.2
2.5
2.5
60
0.5
6
b
4
3
c
0.33
0.66
0.34
0.33
10.0
10.0
0.33
0.33
10.0
0.70
1.12
1.27
1.10
27.2
30.3
1.05
1.23
30.1
1.2
0.52
1.2
1.2
20
1
4
3
d
1
6
4
4
3
e
5
4
6
7
1
5
5
8
2
0
2
3
4
20
410
60
11
15
16+17
16
11*
3
1
1
1
1.2
1.2
10
24.7
24.7
204
2.5
2.5
60
6
27*
2
5
Not isolated
3.16
1.04
0.02
9.90
60
24
36
37
1
1
1
2
8
0
0.06
10.0
0.17
40.6
0.5
25
10.3
510
2.5
55
140
130
5
5
19
21
_
*
*
*
______
Boiling in a flask under reflux.
2
A mixture (2.28 g) of compounds 11 and 8 was isolated in addition.
A mixture (0.23 g) of compounds 15 and 16 was obtained on evaporation.
3

EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker WH-90 (90 MHz) spectrometer in DMSO-d , internal
6
-
1
standard was HMDS (δ 0.055 ppm). The IR spectra were recorded in the region 1500-3600 cm on a Perkin-
Elmer 580B instrument as nujol suspensions.
The compounds being studied were synthesized by known methods. Reactions were carried out in thick-
walled glass vessels of volume 5 ml or in a 100 ml autoclave, in ethanol with an excess quantity of hydrazine
hydrate. The reaction conditions and results are collated in Table 1.
Bis(3-methyl-4-pyrazolyl)methane (2a). A mixture of 3,5-diacetyl-1,4-dihydropyridine monohydrate
(1a), hydrazine hydrate, and ethanol (see Table 1) was heated for 6 h at 140°C. The reaction mixture was
evaporated, the colorless compound 2a obtained was recrystallized from ethyl acetate–hexane. Yield 0.05 g
1
(
52%); mp 165-167°C. H NMR spectrum, δ, ppm: 2.07 (6H, s, 3,3'-CH ); 3.39 (2H, s, CH ); 7.16 (2H, s,
3
2
H-5,5'); 11.55-12.65 (2H, br. s, 1,1'-NH). Found, %: C 61.21; H 6.84; N 31.60. C H N . Calculated, %:
9
12
4
C 61.34; H 6.86; N 31.79.
Bis(3,5-dimethyl-4-pyrazolyl)methane (2b) was obtained from 3,5-diacetyl-2,6-dimethyl-1,4-
dihydropyridine 1b and was isolated after cooling the reaction mixture. The reaction also went well in dioxane
(1 h at 140°C or 3 h on boiling).
Bis(3,5-dimethyl-4-pyrazolyl)-3-pyridylmethane (2c) was obtained from 3,5-diacetyl-2,6-dimethyl-4-
(
3-pyridyl)-1,4-dihydropyridine (1c) on cooling the reaction mixture. The colorless compound had mp 320°C
1
(sublimes). H NMR spectrum, δ, ppm: 1.70 (12H, s, 4CH ); 5.26 (1H, s, CH); 7.20-7.50 (2H, m, H-4, H-5 Py);
3
8
.25-8.45 (2H, m, H-2, H-6 Py); 11.92 (2H, br. s, NH). Found, %: C 68.26; H 6.82; N 24.86. C H N .
16 19 5
Calculated, %: C 68.30; H 6.81; N 24.89.
2
-Difluoromethoxyphenylbis(3,5-dimethyl-4-pyrazolyl)methane (2d) was obtained from 3,5-diacetyl-
2
,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydropyridine (1d). Colorless substance with mp 297-300°C.
-
1
1
IR spectrum, ν, cm : 3170, 3120, 3060, 3040 (NH), 1587, 1510. H NMR spectrum, δ, ppm, (J, Hz): 1.67 (12H,
s, 4CH ); 5.35 (1H, s, CH); 7.02 (1H, t, J = 75, OCHF ); 6.90-7.45 (4H, m, C H ); 11.90 (2H, br. s, 2NH).
3
2
6
4
Found, %: C 62.44; H 5.85; N 16.27. C H F N O. Calculated, %: C 62.42; H 5.82; N 16.17.
1
8
20
2
4
Bis(3,5-dimethyl-4-pyrazolyl)-3,4,5-trimethoxyphenylmethane (2e) was obtained from 3,5-diacetyl-
,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-1,4-dihydropyridine (1e). The colorless substance had mp 279-281°C
2
(
DMF–water). A portion of the substance was isolated from the cooled reaction mixture, and the remainder on
1
evaporation. H NMR spectrum, δ, ppm: 1.72 (12H, s, 3,5,3',5'-CH ); 3.61 (9H, s, 3-CH O); 5.15 (1H, s, CH);
3
3
6
.33 (2H, s, C H ); 11.87 (2H, br. s, 2NH). Found, %: C 64.84; H 7.01; N 15.09. C H N O . Calculated, %:
6 2 20 26 4 3
C 64.85; H 7.07; N 15.12.
Bis(5-methyl-3-phenyl-4-pyrazolyl)methane (2f) was obtained from 3,5-dibenzoyl-2,6-dimethyl-1,4-
dihydropyridine 1f after evaporation of the reaction mixture as a colorless substance of mp 146-148°C (ethyl
1
acetate–hexane). H NMR spectrum, δ, ppm: 1.84 (6H, s, 2CH ); 3.80 (2H, s, CH ); 7.10-7.60 (10H, m, 2C H );
3
2
6
5
1
0.5-12.5 (2H, br. s, NH). Found, %: C 76.45; H 6.15; N 17.13. C H N . Calculated, %: C 76.80; H 6.14;
21 20 4
N 17.06.
Phenyl(3,5-dimethyl-4-pyrazolyl)(5'-methyl-3'-oxo-4'-pyrazolyl)methane (6) was obtained from
-acetyl-5-ethoxycarbonyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine 5. After evaporating the reaction mixture
the residue was washed with acetone, mp 281-282°C (decomp.). IR spectrum, ν, cm : 3310, 3160 (NH
3
-
1
pyrazole), 2500-3120 (band with weakly expressed maxima at 3020-3120 and 2600-2700, NH pyrazolone),
1
1
5
600, 1590, 1530, 1510. H NMR spectrum, δ, ppm: 1.68 (3H, s, CH pyrazolone); 1.73 (6H, s, 2CH pyrazole);
3
3
.13 (1H, s, CH); 6.95-7.50 (5H, m, C H ); 10.00-11.50 (3H, br. s, 3NH). Found, %: C 67.96; H 6.50; N 19.62.
6
5
C H N O. Calculated, %: C 68.06; H 6.43; N 19.84.
1
6
18
4
Bis(5-methyl-3-oxo-4-pyrazolyl)(3-pyridyl)methane (11) was obtained from 3,5-diethoxycarbonyl-
2
3
,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine (10). Colorless substance with mp >300°C (decomp.). 5-Methyl-
-oxo-4-pyrazole 8 is formed as a side product. Compound 11 was isolated in 24% yield from the reaction
8
74

mixture in the reaction of 3-ethoxycarbonyl-2-methyl-5-oxo-4-(3-pyridyl)-1,4-dihydroindeno[1,2-b]pyridine
1
(
14) with hydrazine hydrate, together with the dihydrazone of 1,3-indanedione (16) (60% yield). H NMR
spectrum, δ, ppm (J, Hz): 2.08 (6H, s, 2CH ); 4.88 (1H, s, CH); 7.24 (1H, dd, J = 8, J = 4.5, H-5 Py); 7.54 (1H,
3
1
2
dt, J = 8, J = 4.5, H-4 Py); 8.30-8.40 (2H, m, H-2, H-6 Py); 9.50-11.70 (4H, br. s, 4NH). Found, %: C 58.60;
1
2
H 5.39; N 24.72. C H N O . Calculated, %: C 58.94; H 5.30; N 24.55.
1
4
15
5
2
3
,5-Dimethyl-4-[α-(1,3-dihydrazono-2-indanyl)benzyl]pyrazole (15) was obtained from 5-oxo-4-
phenyl-1,4-dihydroindeno[1,3-b]pyridine 12 on cooling the reaction mixture. Yellow crystalline substance of mp
1
1
65°C (decomp.). H NMR spectrum, δ, ppm (J, Hz): 1.70 (6H, s, 2CH ); 4.67 (1H, d, J = 2, 2-H indanyl); 4.92
3
6 5 2 6 5
(1H, br. s, CHC H ); 6.40 (4H, s, 2NNH ); 7.00-7.80 (9H, m, C H and 4,5,6,7-H indanyl); 10.90-11.55 (1H, br.
s, NH pyrazole). After crystallization from ethanol: 1.05 (3H, m, J = 7, CH ); 3.45 (2H, m, CH ); 4.32 (1H, t, J =
3
2
5
, OH). Found, %: C 68.49; H 6.82; N 21.05. C H N ·C H OH. Calculated, %: C 68.29; H 6.92; N 20.79. An
21 22 6 2 5
additional amount of compound 15 was obtained mixed with 1,3-indanedione dihydrazone (16) on evaporating
the filtrate from the reaction mixture.
1
1-Phenyl-10H,12H-diindeno[1,2-b:2',1'-e]pyridine (19) was obtained from 10,12-dioxo-11-phenyl-
,10,11,12-tetrahydrodiindeno[1,2-b:2',1'-e]pyridine (18) after cooling the reaction mixture. Bright-yellow
substance with mp 293-295°C. Found, %: C 90.41; H 5.20; N 4.15. C H N. Calculated, %: C 90.60; H 5.17;
5
2
5
17
N 4.23.
3
,5-Dimethyl-4-[α-thioureidobenzyl)pyrazole (21) was obtained from 5-acetyl-6-methyl-2-thioxo-4-
phenyl-1,2,3,4-tetrahydropyrimidine (20). After evaporating, the reaction mixture was stirred with ethyl acetate.
1
Colorless crystalline solid 21 was precipitated; mp 189-191°C (acetone–ethyl acetate). H NMR spectrum,
δ, ppm (J, Hz): 1.95 (6H, s, 3,5-CH
3
); 6.60 (1H, d, J = 9, 4-CH); 6.90-7.45 (7H, m, C
6
H
5
2
and NH ); 8.05 (1H, d,
J = 9, 4-β-NH); 10.05 (1H, br. s, 1-NH). Found, %: C 59.68; H 6.11; N 21.76. C13
16 4
H N S. Calculated, %:
C 59.97; H 6.19; N 21.52.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
U. Eisner and J. Kuthan, Chem. Rev., 72, 1 (1972).
F. Michael and H. Dralle, Liebigs Ann. Chem., 670, 57 (1963).
R. Balicki, L. Kaczmarek, and P. Nantka-Namirski, Pol. J. Chem., 53, 893 (1979).
I. Meyers, P. D. Edwards, T. R. Balley, and G. E. Jr. Jagdman, J. Org. Chem., 50, 1019 (1998).
Y. Sato, BRD Patent 2629892; Chem. Abstr., 86, 189726 (1977).
Z. V. Esayan, S. G. Chshmarityan, N. A. Apoyan, and G. L. Papayan, Arm. Khim. Zh., 35, 178 (1982).
M. S. Mohamed, M. M. Ismail, and K. M. Ghoneim, J. Serb. Chem. Soc., 51, 405 (1986).
M. S. Mohamed, Egypt. J. Pharm. Sci., 34, 99 (1993).
L. Bellamy, New Data on the IR Spectra of Complex Molecules [Russian translation], Mir, Moscow
(
1971), p. 303.
10.
J. N. Chatterjea, S. C. Shaw, and S. N. Singh, J. Indian Chem. Soc., 55, 149 (1978).
8
75