4-Hydroxyquinolones-2. 91. Synthesis and properties of ethyl 1-R-4-hydroxy-6-methyl-2-oxo-dihydropyridine-5-carboxylates

Article abstract of DOI:10.1007/s10593-006-0070-x

The reaction of ethyl aminocrotonates with derivatives of malonic acid is a suitable method for the preparation of ethyl 4-hydroxy-6-methyl-2-oxo-1,2- dihydropyridine-5-carboxylates. One of the synthesized materials has been studied by X-ray crystallograp

Full text of DOI:10.1007/s10593-006-0070-x

Chemistry of Heterocyclic Compounds, Vol. 42, No. 2, 2006
4
-HYDROXYQUINOLONES-2. 91*. SYNTHESIS
AND PROPERTIES OF ETHYL 1-R-4-HYDROXY-
-METHYL-2-OXO-DIHYDROPYRIDINE-5-CARBOXYLATES
6
1
1
1
2
I. V. Ukrainets , L. V. Sidorenko , O. V. Gorokhova , and O. V. Shishkin
The reaction of ethyl aminocrotonates with derivatives of malonic acid is a suitable method for the
preparation of ethyl 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-5-carboxylates. One of the
synthesized materials has been studied by X-ray crystallography.
Keywords: 4-hydroxy-2-oxopyridinecarboxylic acids, 1,2-dihydropyridin-2-ones, ethyl 3-
aminocrotonic acids, X-ray crystallography.
6
-Alkyl-substituted 1,2-dihydropyridin-2-ones are used in medicine as selective inhibitors of
2
phosphodiesterases [2,3] and AMPA-receptors* [4]. Highly effective vasodilators [5], anticoagulants [6],
fungicides [7], and anti-HIV agents [8] have been created based on them. To obtain these compounds a three
component condensation of the corresponding ketone, a dimethyl acetal of DMF or ethyl formate, and a
substituted amide of acetic acid is normally required. The ketone determines the nature of the substituents at
positions 5 and 6 of the ring formed, the substituted formic acid is the source of C , and the substituted
(
4)
acetamide forms the N –CO–C –R unit of the dihydropyridine ring. In some cases an alternative route – the
(
1)
(3)
reaction of pyran-2-ones with amines – is used [9].
In continuation of our study of the physicochemical and biological properties of
a
4
1
-hydroxyquinolones-2, we have connected reports of molecular systems similar to ours – 1-R-4-hydroxy-2-oxo-
,2-dihydropyridine. We have used the same principle as in obtaining 4-hydroxyquinolones-2, i.e., the acylation
of amino esters with ethoxymalonyl chloride with subsequent closing of the ring under Dieckman reaction
conditions. It is known [10] that N-acylanthranilates unambiguously form 3-ethoxycarbonyl-4-hydroxy-
quinolones -2 under these conditions. However after acylation of ethyl aminocrotonates 1 the cyclization of the
diesters 2 is theoretically possible by two routes since both carbonyl and active methylene groups are present in
both the malonyl and crotonyl fragments. Consequently the end products of the reaction studied may be ethyl
4
-hydroxy-6-methyl-2-oxo-1-propyl-1,2-dihydropyridine-3-carboxylate (3) or the isomeric ethyl 4-hydroxy-6-
1
methyl-2-oxo-1-propyl-1,2-dihydropyridine-5-carboxylate (4). Unfortunately neither H NMR spectroscopy nor
chromatomass spectrometry permitted an unambiguous conclusion on the structure of this substance.
Nevertheless a failure to prepare the benzamide 5 under normal conditions suggested that the ester produced is a
_
*
*
_
______
For part 90, see [1].
2
AMPA – α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.
_________________________________________________________________________________________
1
2
National Pharmaceutical University, Kharkov 61002, Ukraine; e-mail: uiv@kharkov.ua. Institute of
Scintillation Materials, Ukraine National Academy of Sciences, Kharkov 6101, Ukraine; e-mail:
shishkin@xray.isc.kharkov.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, 217-223,
February, 2006. Original article submitted September 16, 2004.
0
009-3122/06/4202-0191©2006 Springer Science+Business Media, Inc.
191

1
92

derivative pyridine-5-carboxylic acid, since it would be expected that the 3-ethoxycarbonyl isomer 3 would be
the more reactive because of its similarity to the esters of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-
carboxylates.
In fact, an X-ray crystallographic study confirmed this prediction and established that the pyridine ring
of the ester 4 (Fig. 1) has a strongly compressed bath conformation. The deviations of atoms C(1) and C(4) from
the mean-square plane of the remaining atoms of the ring are -0.05 and -0.04 A respectively. Contacts between
the methyl, propyl, and ethoxycarbonyl groups [shortest contacts H(6B)···C(7) 2.75 (sum of the van der Waals radii
[
11] 2.87), H(6C)···H(7B) 2.22 (2.32) and H(7A)···O(1) 2.37A (2.45A)] lead to lengthening of the bonds N ···C
(1) (5)
1
1
.400(3), N ···C 1.416 and N ···C 1.496 Å in comparison with average values [12] of 1.352, 1.385, and
(1) (1) (1) (7)
.469 Å respectively. The substituent at N(1) is in the ap-conformation and is rotated practically perpendicular
relative to the mean-square plane of the ring (torsion angles C –N –C –C 84.9(2)° and N –C –C –C
(9)
(
1)
(1)
(7)
(8)
(1)
(7)
(8)
1
80.0(2)°). Conjugation between the π-systems of the pyridine ring and the ester group is considerably decreased
as a result of rotation of the latter about the C –C bond (torsion angle C –C –C(10)–O(3) -64.3(3)°), which
(
4)
(10)
(5)
(4)
explains the stability of ester 4 to amidation. The ethyl substituent of the ester group is in the ap-conformation
torsion angle C(10)–O –C(11)–C(12) 166.1(2)°). In the crystal molecules of ester 4 form dimers via the
(
(4)
intermolecular hydrogen bonds O –H(2C)···O(1) (x + 0.5, -y - 0.5, -z + 2) (H···O 1.80(3) A, O···H···O'
(
2)
1
67(3)°).Probably as a result of this the C =O is lengthened to 1.272 A in comparison with the average value
(1) (1)
of 1.210 Å [12].
Interesting data which confirmed the formation of derivatives of pyridine-5-carboxylic acid during the
course of the reaction under discussion were obtained by using ethyl phenylmalonate in place of ethoxymalonyl
chloride. As in the first case two possible compounds are formed, but they are not isomers so that the
interpretation of their structures is eased considerably. Thus the formation of ethyl 4-hydroxy-6-methyl-2-oxo-3-
phenyl-1,2-dihydropyridine-5-carboxylate (6) indicates that in the ester condensation of the corresponding
diester of type 2 catalyzed by sodium ethoxide the electrophilic center is in the malonic unit while the
nucleophilic is in the crotonic unit. In the opposite case the cyclization should occur with elimination of the
ethoxycarbonyl groups of the malonic unit [13] to give as the final product 4-hydroxy-6-methyl-2-oxo-3-phenyl-
1
,2-dihydropyridine which does not correspond to the experimental data.
A complex result was obtained from the reaction aminocrotonic esters 1 with triethyl
methanetricarboxylate, the high reactivity of which allows closure of the pyridine ring without basic catalysis. In
the case of the unsubstituted aminocrotonic ester (1, R = H) it was not possible to stop the reaction at the stage of
diethyl pyridon-3,5-dicarboxylate even with a two-fold excess of triethyl methanetricarboxylate – the ester group
in position 3 is very easily amided by the aminocrotonates starting material to give ethyl 3-(2-ethoxycarbonyl-1-
methylvinylcarbamoyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-5-carboxylate
(7).
Fig. 1 Structure of the molecule of ester 4 showing numbering of the atoms.
193

TABLE 1. Bond Lengths (l) in the Structure of Ester 4
Bond
l, Å
Bond
l, Å
Bond
l, Å
N(1)–C(5)
N(1)–C(1)
N(1)–C(7)
О(1)–С(1)
О(2)–C(3)
О(3)–C(10)
1.400(3)
1.416(3)
1.496(3)
1.272(3)
1.347(3)
1.203(3)
О
(4)–C(10)
1.356(3)
1.474(3)
1.423(3)
1.388(3)
1.442(3)
1.385(3)
C
C
C
C
C
(4)–C(10)
(5)–C(6)
(7)–C(8)
(8)–C(9)
(11)–С(12)
1.525(3)
1.524(3)
1.532(3)
1.531(3)
1.510(4)
О(4)–С(11)
C
C
C
C
(1)–C(2)
(2)–C(3)
(3)–C(4)
(4)–C(5)
TABLE 2. Bond Angles (ω) in the Structure of Ester 4
Angle
ω, deg.
Angle
ω, deg.
Angle
ω,deg.
C
C
C
С
(5)–N(1)–C(1)
(5)–N(1)–C(7)
(1)–N(1)–C(7)
(10)–О(4)–С(11)
122.36(2)
121.37(2)
116.22(2)
115.46(2)
117.38(2)
125.53(2)
117.09(2)
121.62(2)
O
(2)–C(3)–C(2)
(2)–C(3)–C(4)
124.36(2)
116.49(2)
119.13(2)
120.23(2)
120.85(2)
118.92(2)
119.31(2)
122.77(2)
N
(1)–C(5)–C(6)
(1)–C(7)–C(8)
117.92(2)
113.78(2)
111.70(2)
123.40(2)
126.10(2)
110.49(2)
107.90(2)
O
N
C
C
C
C
C
C
(2)–C(3)–C(4)
(5)–C(4)–C(3)
(5)–C(4)–C(10)
(3)–C(4)–C(10)
(4)–C(5)–N(1)
(4)–C(5)–C(6)
C(9)–C(8)–C(7)
O(3)–C(10)–O(4)
O(3)–C(10)–C(4)
O(4)–C(10)–C(4)
O(4)–C(11)–C(12)
O
O
N
(1)–C(1)–N(1)
(1)–C(1)–C(2)
(1)–C(1)–C(2)
C
(3)–C(2)–C(1)
Similarly, N-propyl-substituted ethyl aminocrotonate (1, R = Pr) under the same conditions gave diethyl
-hydroxy-6-methyl-2-oxo–1-propyl-1,2-dihydropyridin-3,5-dicarboxylate (8) which can then be converted into
4
the amido ester 9 without complications.
EXPERIMENTAL
1
H NMR spectra of the compounds synthesized were recorded with a Varian Mercury VX-200 (200
6
MHz) in DMSO-d with TMS as internal standard. Mass spectra were recorded on a Finnigan MAT Incos 50
quadrupole spectrometer by direct insertion, with total scanning over the range 33-700 m/z, with an ionizing
voltage of 70 eV, and a rate of heating of 5°/s. The ethyl esters of the aminocrotonic acids were prepared by a
known method [14].
Ethyl 4-Hydroxy-6-methyl-2-oxo-1-propyl-1,2-dihydropyridine-5-carboxylate (4). Triethylamine
(
1.54 ml, 0.011 mol) was added to a solution of ethyl N-propylaminocrotonate (1.71 g, 0.01 mol) (1, R = Pr) in
CH Cl (30 ml), then ethoxymalonyl chloride (1.66 g, 0.011 mol) was added dropwise with cooling and
intensive stirring and the mixture was kept at room temperature for 4-5 h. The reaction mixture was diluted with
water and stirred thoroughly. The organic layer was separated and dried over anhydrous CaCl . The solvent was
2
2
2
evaporated (finally under reduced pressure. Sodium ethoxide (from metallic sodium (0.23 g, 0.01 mol) and
absolute ethanol (20 ml)) was added to the residue (the diester 2) and boiled for 1 h, after which the reaction
mixture was cooled, diluted with water, and acidified with 1:1 HCl to pH 4.5-5. The precipitated ester 4 was
1
filtered off, washed with water, and dried. Yield 1.98 g (83%); mp 107-109°C (ethanol). H NMR spectrum,
δ, ppm (J, Hz): 10.86 (1H, s, OH); 5.60 (1H, s, H-3); 4.23 (2H, q, J = 7.0, OCH ); 3.85 (2H, t, J = 7.6, NCH
.33 (3H, s, CH ); 1.53 (2H, m, NCH CH ); 1.26 (3H, t, OCH CH ); 0.89 (3H, t, J = 7.6, NCH CH CH ). Mass
3 6 3
spectrum, m/z (Irel, %): 239 [M ] (15), 224 [M - CH ] (18), 197 [M - C H ] (17), 178 [M - CH - EtOH] (15),
2
2
);
2
3
2
2
2
3
2
2
3
+
+
+
+
3
1
94

+
1
51 [M - C
. Calculated, %: C 60.24; H 7.16; N 5.85.
X-ray Crystallography. Crystals of the ester 4 are rhombic. At 20°C: a = 8.215(2), b = 10.956(4),
3 6
H - EtOH] (100), 137 (10), 123 (31), 69 (19), 42 (21). Found, %: C 60.41; H 7.10; N 5.73.
12 4
C H17NO
3
3
1 1 1
c = 14.154(5) Å; V = 1273.9(7) Å ; dcalc = 1.248 g/cm ; space group P2 2 2 ; Z = 4. Elementary cell parameters
and the intensities of 2104 independent reflexions (Rint = 0.03) were measured on a Siemens P3/PC four-circle
automatic diffractometer (λMoKα, graphite monochromator, θ/2θ scanning, 2θmax = 60°). The structure was
refined by direct methods using the SHELXTL PLUS suite of programs [15]. The positions of the hydrogen
atoms were found from difference syntheses of the electron density and refined by the "riding" method with
fixed Uiso = nUeq for the non-hydrogen atoms bonded to the hydrogen atoms (n = 1.5 for methyl groups and 1.2
2
for the remaining hydrogen atoms). Refinement according to F was carried out with full matrix least squares
analysis in the anisotropic approximation for non-hydrogen atoms using 2104 reflexions to wR
2
= 0.115
(R
1
= 0.049 for 1308 reflexions with F > 4σ(F), S = 0.98). Complete crystallographic information has been
deposited in the Cambridge Crystals Data Bank (deposit no. CCDC 250565). Interatomic distances and bond
angles are given in Tables 1 and 2.
Ethyl 4-Hydroxy-6-methyl-2-oxo-3-phenyl-1,2-dihydropyridine-5-carboxylate (6). A mixture of
ethyl aminocrotonate (1, R = H) (1.29 g, 0.01 mol) and diethyl phenylmalonate (2.60 g, 0.01 mol) was
maintained at 160°C for 5 h. The mixture was cooled, added to a solution of sodium ethoxide (from metallic
sodium (0.46 g, 0.02 mol) in absolute ethanol (40 ml)), boiled for 2 h, and then acidified with aqueous HCl. The
precipitate of ester 6 was filtered off, washed with water, and dried. Yield 1.55 g (57%); mp 300-302°C
1
(
4
2
ethanol). H NMR spectrum, δ, ppm (J, Hz): 11.97 (1H, s, OH); 11.78 (1H, s, NH
2
); 7.40 -7.12 (5H, m, C
). Mass spectrum, m/z (Irel, %):
73 [M] (36), 227 [M - EtOH] (100), 199 [M - EtOH - CO] (37), 143 (14), 128 (11). Found, %: C 65.80;
. Calculated, %: C 65.93; H 5.53; N 5.13.
3-(2-Ethoxycarbonyl-1-methylvinylcarbamoyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-
6 5
H );
2 3 2 3
.32 (2H, q, J = 7.0, OCH ); 2.58 (3H, s, CH ); 1.30 (3H, t, J = 7.0, OCH CH
+
+
+
H 5.42; N 5.20. C15
Ethyl
H15NO
4
pyridine-5-carboxylate (7). A mixture of ethyl 3-aminocrotonate (1, R = H) (1.29 g, 0.01 mol) and triethyl
methanetricarboxylate (4.64 g, 0.02 mol) was kept at 200-210°C for 15 min. It was cooled, hexane (30 ml) was
added, and the mixture was vigorously stirred. The amino ether 7 was filtered off, washed on the filter several
times with hexane, and dried. Yield 1.30 g (73% based on the aminocrotonate); mp 181-183°C (ethanol).
1
H NMR spectrum, δ, ppm (J, Hz): 15.50 (1H, s, OH); 13.02 (1H, s, NH); 12.09 (1H, s, NH); 5.19 (1H, s, =CH);
4
.28 (2H, q, J = 7.0, OCH
m, 2 OCH CH ). Mass spectrum, m/z (Irel, %): 352 [M] (3), 307 [M - OEt] (4), 279 [M - OEt - CO] (27), 233
11), 224 (16), 178 (100), 129 (18), 84 (21), 42 (25). Found, %: C 54.68; H 5.81; N 7.88. C16
Calculated, %: C 54.54; H 5.72; N 7.95.
2 2 3 3
); 4.09 (2H, q, J = 7.0, OCH ); 2.35 (3H, s, CH ); 2.27 (3H, s, CH ); 1.30-1.10 (6H,
+
+
+
2
3
(
20 2 7
H N O .
Diethyl 4-Hydroxy-6-methyl–2-oxo-1-propyl-1,2-dihydropyridine-3,5-dicarboxylate (8) was
prepared from ethyl N-propylaminocrotonate (1, R = Pr) and triethyl methanetricarboxylate in 1:1 molar ratio as
1
in the previous experiment. Yield 78%; mp 65-67°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 12.82 (1H, s,
OH); 4.27 (4H, q, J = 7.0, 2 OCH
.29 (6H, t, J = 7/0, 2 OCH CH ); 0.90 (3H, t, J = 7.4, NCH
. Calculated, %: C 57.87; H 6.80; N 4.50.
Ethyl 3-(4-Ethoxycarbonylphenylcarbamoyl)-4-hydroxy-6-methyl-2-oxo-propyl-1,2-dihydro-
pyridine-5-carboxylate (9). A mixture of ester 8 (3.11 g, 0.01 mol), benzocaine (1.65 g, 0.01 mol), and DMF
1 ml) was stirred an kept on a metal bath at 160-180°C for 3 min. The mixture was cooled, ethanol (30 ml) was
2
); 3.92 (2H, t, J =7.4, NCH
2
3 2 2
); 2.40 (3H, s, CH ); 1.56 (2H, m, NCH CH );
1
2
3
2
CH CH ). Found, %: C 57.78; H 6.87; N 4.63.
2
3
15 6
C H21NO
(
added, the mixture was thoroughly mixed and filtered. The amino ester 9 obtained was washed on the filter with
1
ethanol and dried. Yield 4.0 g (93%); mp 157-159°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 15.56 (1H, s,
OH); 12.64 (1H, s, NH); 7.96 (2H, d, J = 7.9, H-3',5'); 7.75 (2H, d, J = 7.9, H-2',6'), 4,32 (4H, m, 2 OCH
2H, t, J = 7.6, NCH ); 2.46 (3H, s, CH ); 1.62 (2H, m, NCH CH ); 1.30 (6H, m, 2 OCH CH ); 0.91 (3H, t,
). Found, %: C 61.47, H 6.18, N 6.44. C22 . Calculated, %: C 61.39; H 6.09;
2
); 4.00
(
2
3
2
2
2
3
J = 7.6, NCH
2
CH
2
CH
3
26 2 7
H N O
N 6.51.
195

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