Carboxamides of Dihydropyridin-2(1H)-ones

Article abstract of DOI:10.1007/s00706-003-0018-0

3-Carboxamides and 3-carboxanilides of 6-alkyl and 6-aryldihydropyridin- 2(1H)-ones have been prepared via different reaction pathways. All synthesized amides show hydrogen bonds in their NMR spectra. The 4-hydroxy compounds were obtained as a mixture of tautomers. Their configurations were elucidated by NMR experiments.

Full text of DOI:10.1007/s00706-003-0018-0

Monatshefte f€ur Chemie 134, 1129–1136 (2003)
DOI 10.1007/s00706-003-0018-0
Carboxamides of Dihydropyridin-2(1H)-ones
ꢀ
Robert Weis , Armin Presser, and Werner Seebacher
Institute of Pharmaceutical Chemistry and Pharmaceutical Technology,
University of Graz, A-8020 Graz, Austria
Received December 16, 2002; accepted December 20, 2002
Published online June 2, 2003 # Springer-Verlag 2003
Summary. 3-Carboxamides and 3-carboxanilides of 6-alkyl and 6-aryldihydropyridin-2(1H)-ones have
been prepared via different reaction pathways. All synthesized amides show hydrogen bonds in their
NMR spectra. The 4-hydroxy compounds were obtained as a mixture of tautomers. Their configura-
tions were elucidated by NMR experiments.
Keywords. Carboxamides; Hydrogen bonds; Dihydropyridin-2-ones; Tautomerism; Tetrahydro-
pyridine-3-carboxamides.
Introduction
Recently, we reported about the conversion of the 6-substituted dihydropyridin-
2(1H)-one 1 to the 3-acetyl derivatives 2 and 3 [1]. In the sequel we attempted to
synthesize the 3-carbamoyl analogues of the latter. Such compounds could be of
pharmacological interest since the structurally related 1,8-naphthyridine 4 and
quinoline-3-carboxamides 5 (Scheme 1) exhibit antiangiogenic [2], antiinflamma-
tory [3–7], anthelmintic [8], immunomodulatory [9], or gastric antisecretory activ-
ity [10]. This paper deals with the preparation of 3-carboxamides of 6-alkyl and
6-aryldihydropyridin-2(1H)-ones which were afforded via two completely different
reaction pathways.
Results and Discussion
Because carboxamides are readily available from the corresponding esters we
synthesized the 2-oxo-6-phenylpyridine-3-carboxylate 7a by Dieckmann conden-
sation of the 4-azaheptanedioic acid ester 6 following a known procedure [11]. A
mixture of the tautomeric amides 9a and 10a was obtained when ammonia was
bubbled through a boiling solution of the ester 7a in ethanol (Scheme 2). The
corresponding anilides 9b and 10b were formed in moderate yields when we
ꢀ
Corresponding author. E-mail: robert.weis@uni-graz.at

1130
R. Weis et al.
Scheme 1
refluxed 7a with 4-chloroaniline in DMF following a reported procedure [12].
However, almost quantitative amounts were obtained when the compounds were
fused together.
The synthesis of the 6,6-dimethyl analogues was accomplished via quite a
different pathway since the 6,6-dimethylpyridine-3-carboxylate 7b is not available
in acceptable yields by the above-mentioned method. Therefore, we tried to intro-
duce an alkoxycarbonyl substituent in ring position 3 of the readily available
tautomers 11, 12 [13], or 1. The 3-acetyl-4-hydroxypyridin-2-one 3 had to be
prepared by hydrolysis of its 4-methylamino analogue 2. It was not accessible from
compounds 11 and 12 because they were preferably O-acylated. In contrast, the 4-
methylamino analogue 2 has been prepared selectively from 1 under Friedel-Crafts
reaction conditions [1]. However, when 1 was treated with ethyl chloroformate in a
similar procedure we were not able to detect the formation of a carboxylated
product. Consequently, we changed the reaction conditions, but the carbamic acid
derivative 13 was the main product in each case. Evidence that the carboxylation
had taken place at the 4-amino nitrogen of 1 was given by a long-range coupling
from the methylamino protons to the carbonyl carbon of the ester in the HMBC
spectrum of 13. As expected compounds 11 and 12 gave selectively the carboxylic
acid ester 14. Saturation of the methyl groups in ring position 6 of compound 14
led to an NOE at the NH proton. In this way the possible formation of an 1-acyl
product was ruled out.
Another suitable way for the insertion of the carboxamido group in ring posi-
tion 3 of anellated 4-hydroxypyridin-2-ones is their addition to isocyanates [6, 8,
14]. The reaction of 4-chlorophenyl isocyanate with 1 gave the 3-carboxanilide 8a.
The synthesis of the corresponding primary amide succeeded in a two-step proce-
dure. Compound 1 was refluxed with benzoyl isocyanate, which has been prepared

Carboxamides of Dihydropyridin-2(1H)-ones
1131
Ph
Me
Me
Scheme 2
by the method of Weikert et al. [15] giving the imide 8b. Acid hydrolysis of the
latter afforded the amide 8c in good yields.
Analogous reactions with compounds 11 and 12 yielded mixtures of tautomers
in each case. The reaction with 4-chlorophenyl isocyanate gave the anilides 9c and
10c. The imides 9d and 10d were obtained upon treatment with benzoyl isocyanate
and their alkaline hydrolysis afforded the tautomers 9e and 10e.
The resonances of all compounds were assigned with the aid of 1D and 2D
NMR spectra. Special attention was directed to the distinction of the 3–8 NH and

1132
R. Weis et al.
1
OH signals in the H NMR spectra of compounds 7–10. The signals of their
protons in ring position 1 were indicated by NOEs which were observed upon
irradiation of the methyl groups in ring position 6. The resonances of the NH
protons of the methylamino groups of compounds 8 were identified from their
3J coupling with the methyl protons. Due to the hydrogen bonds in compounds
7–10 the signals of the concerning NH protons were shifted to 9–14 ppm and those
for OH protons to about 17 ppm. The shift difference of 3–4 Hz of the resonances
for the two geminal protons of the primary amides 8c, 9a, 9e, 10a, and 10e made
their distinction feasible.
When measured in CDCl3 the tautomers 9 and 10 predominantly exist in the
4-hydroxy form, whereas in DMSO-d6 the 2-hydroxy compound is the main con-
stituent in ratios of about 7:3. They were discriminated by means of HMBC experi-
ments. The OH protons of compounds 9 and 10 showed long-range couplings to the
adjacent ring carbons 2 and 4. Those were undoubtedly discernible from the cross-
peaks of 5-H to C-4 in their HMBC spectra.
The present paper provides an access to 3-carboxamides of 6-alkyl- and 6-
aryldihydropyridin-2-ones via two different reaction pathways. The structures of
the obtained tautomers were determined by NMR experiments.
Experimental
Melting points were obtained on a digital melting point apparatus Electrothermal IA 9200 and are
uncorrected. IR spectra: infrared spectrometer system 2000 FT (Perkin Elmer). NMR spectra: Varian
1
Inova 400 (298K) 5 mm tubes, TMS as internal standard. H- and 13C-resonances are numbered as
given in the formulae. Microanalyses: Microanalytical Laboratory at the Institute of Physical Chem-
istry, Vienna; their results agreed favourably with the calculated values. Column chromatography
˚
(CC): silica gel 60 (Merck 70–230 mesh, pore diameter 60A). Thin-layer chromatography (TLC):
TLC plates (Merck, silica gel 60 F254 0.2 mm, 200 ꢁ 200 mm).
(RS)-(ꢂ)-N-(2-(Methoxycarbonyl)-1-phenylethyl)malonamic acid methylester (6, C14H17NO5)
Modified procedure [11]: Triethylamine (0.02 mol) was added dropwise to a suspension of 0.02mol
of methyl 3-amino-3-phenylpropionate hydrochloride in 40cm3 of CH2Cl2 at 0ꢃC. Then 5 cm3 of
HClconc were added to a solution of the potassium salt of 0.06mol of monomethyl malonate in 25cm3
of H2O. The mixture was extracted repeatedly with CH2Cl2 and the combined organic layers
were dried over Na2SO4. The solution was concentrated to about 50cm3 and added dropwise at
0ꢃC to the solution of the aminoacid ester. Likewise a solution of 0.02 mol of DCC in 10cm3
of CH2Cl2 was added. The mixture was stirred for 2 h at room temperature, then the precipitated
N,N0-dicyclohexyl urea was filtered off. The filtrate was concentrated to 50 cm3, washed with soda,
H2O, and dried. Then the solvent was removed in vacuo and the residue was recrystallized from
ligroin yielding 5.52g (99%) of 6, mp 65ꢃC (Ref [11] 52–53ꢃC); IR (KBr): ꢀꢀ ¼ 3288 (s), 3092 (w),
2953 (w), 2931 (w), 1741 (s), 1652 (s), 1557 (s), 1439 (s), 1276 (s), 1224 (s), 1057 (m), 1029 (m),
1
852 (m), 710 (m) cmꢄ 1; H NMR (400MHz, CDCl3): ꢁ ¼ 2.85, 2.94 (2dd, J ¼ 15.5, 6.0 Hz, 2 20-H),
3.33, 3.38 (2d, J ¼ 17.8Hz, 2 2-H), 3.63 (s, OCH3-C30), 3.76 (s, OCH3-C1), 5.46 (ddd, J ¼ 8.0,
6.0, 6.0 Hz, 10-H), 7.25–7.36 (m, 5 aromatic H), 8.08 (d, J ¼ 8.0 Hz, NH) ppm; 13C NMR
(100 MHz, CDCl3): ꢁ ¼ 40.12 (C-20), 40.91 (C-2), 49.72 (C-10), 51.84 (OCH3-C30), 52.47
(OCH3-C1), 126.23, 127.68, 128.73, 140.22 (aromatic C), 164.13 (C-1), 169.79 (C-3), 171.27
(C-10) ppm.

Carboxamides of Dihydropyridin-2(1H)-ones
1133
(RS)-(ꢂ)-Methyl 1,2,5,6-tetrahydro-4-hydroxy-6-phenylpyridine-
3-carboxylate (7a, C12H13NO4)
7a was prepared according to Ref. [11]. From 5.02 g (0.018mol) of 6 we obtained 2.04 g (48%) of 7a
after recrystallization from benzene, mp 138ꢃC (Ref [11] 128–130ꢃC); IR (KBr): ꢀꢀ ¼ 3223 (m), 3095
(w), 2954 (w), 1677 (s), 1601 (s), 1448 (s), 1400 (s), 1340 (s), 1238 (s), 1217 (s), 1092 (s), 930 (s), 698
1
(m) cmꢄ 1; H NMR (400MHz, CDCl3): ꢁ ¼ 2.84 (dd, J ¼ 17.4, 5.5 Hz, 5-H), 2.92 (dd, J ¼ 17.4,
10.6Hz, 5-H), 3.93 (s, OCH3), 4.71 (dd, J ¼ 10.6, 5.5Hz, 6-H), 5.58 (s, NH), 7.33–7.41 (m, 5 aromatic
H), 14.10 (s, OH) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 38.14 (C-5), 52.56 (C-6), 52.71 (OCH3), 97.40
(C-3), 126.29, 128.71, 129.14, 139.48 (aromatic C), 168.28 (C-2), 172.03 (COO), 183.30 (C-4) ppm.
40-Chloro-1,2,5,6-tetrahydro-6,6-dimethyl-4-methylamino-2-oxopyridine-3-carboxanilide
(8a, C15H18ClN3O2)
4-Chlorophenyl isocyanate (0.03 mol) was added to a suspension of 0.02mol of 1 in 50cm3 of
acetonitrile. The mixture was heated on an oil-bath at 120ꢃC for 16h, cooled, and filtered with suction.
The residue was triturated with propan-2-ol, filtered, and recrystallized from propan-2-ol giving 5.42g
(88%) of 8a, mp 306ꢃC; IR (KBr): ꢀꢀ ¼ 3228 (w), 2964 (m), 1648 (m), 1606 (s), 1581 (s), 1539 (s),
1
1493 (m), 1475 (m), 1401 (s), 1307 (m), 1286 (m), 1225 (m), 838 (m), 812 (m) cmꢄ 1; H NMR
(400 MHz, DMSO-d6): ꢁ ¼ 1.20 (s, (CH3)2), 2.66 (s, 2 5-H), 2.99 (d, J ¼ 4.8 Hz, NCH3), 7.20 (s, N-H),
7.30 (d, J ¼ 8.8 Hz, 2 m-aromatic H), 7.55 (d, J ¼ 8.8Hz, 2 o-aromatic H), 11.19 (d, J ¼ 4.8 Hz,
NHCH3), 12.81 (s, NHAr) ppm; 13C NMR (100MHz, DMSO-d6): ꢁ ¼ 28.02 ((CH3)2), 29.85 (NCH3),
37.48 (C-5), 48.25 (C-6), 87.32 (C-3), 120.90, 125.77, 128.80, 138.51 (aromatic C), 168.12, 168.27,
168.39 (C-2, C-4, ArCO) ppm.
N-Benzoyl-1,2,5,6-tetrahydro-6,6-dimethyl-4-methylamino-2-oxopyridine-3-carboxamide
(8b, C16H19N3O3)
Compound 1 (5mmol) was dried twice by azeotropic removal of H2O with benzene and dissolved in
90cm3 of benzene in an Ar atmosphere at 100ꢃC. Then a solution of 15mmol of benzoyl isocyanate
in 10 cm3 of benzene was added dropwise. The mixture was refluxed for 3 h and the solvent removed
in vacuo. The residue was suspended in CH2Cl2 and filtered. The filtrate was concentrated and purified
by CC. The fractions containing 8b were collected, the solvent was evaporated, and the residue was
recrystallized from ethanol=ethyl acetate giving 1.14g (76%) of 8b, mp 253ꢃC; IR (KBr): ꢀꢀ ¼ 3235
(m), 2964 (m), 1710 (s), 1599 (s), 1501 (s), 1468 (s), 1417 (s), 1280 (s), 1206 (s), 840 (m), 711 (m)
cmꢄ 1; 1H NMR (400 MHz, CDCl3): ꢁ ¼ 1.32 (s, (CH3)2), 2.61 (s, 2 5-H), 3.05 (d, J ¼ 5.2Hz, NCH3),
5.91 (s, N1-H), 7.45 (t, J ¼ 8.0Hz, 2 m-aromatic H), 7.51 (t, J ¼ 8.0 Hz, p-aromatic H), 8.02 (d,
J ¼ 8.0 Hz, 2 o-aromatic H), 11.79 (d, J ¼ 5.2 Hz, NHCH3), 13.87 (s, NH(CO)2) ppm; 13C NMR
(100 MHz, CDCl3): ꢁ ¼ 28.52 ((CH3)2), 30.16 (NCH3), 38.05 (C-5), 48.81 (C-6), 88.79 (C-3),
127.82 (o-aromatic C), 128.51 (m-aromatic C), 132.07 (p-aromatic C), 134.64 (i-aromatic C),
165.35 (PhCO), 168.57, 168.69, 168.76 (C-2, C-4, CONH) ppm.
1,2,5,6-Tetrahydro-6,6-dimethyl-4-methylamino-2-oxopyridine-3-carboxamide
(8c, C9H15N3O2)
Compound 8b (0.4mmol) and 0.01 g of toluene-4-sulphonic acid were refluxed in 100 cm3 of ethanol
for 4 h. The mixture was cooled and the solvent evaporated. The residue was partitioned between
CH2Cl2 and H2O. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers
were washed with H2O and dried. The solvent was evaporated and the residue recrystallized from
ethanol=ethyl acetate giving 0.057 g (72%) of 8c, mp 252ꢃC; IR (KBr): ꢀꢀ ¼ 3348 (m), 3248 (w), 3184
(w), 1628 (s), 1596 (s), 1559 (s), 1462 (m), 1415 (m), 1391 (s), 1378 (s), 1276 (m), 816 (w) cmꢄ 1; 1H

1134
R. Weis et al.
NMR (400MHz, DMSO-d6): ꢁ ¼ 1.17 (s, (CH3)2), 2.55 (s, 2 5-H), 2.92 (d, J ¼ 4.8 Hz, NCH3), 6.51 (d,
J ¼ 4.4 Hz, 1 CONH2), 6.76 (s, N1-H), 9.37 (d, J ¼ 4.4 Hz, 1 CONH2), 11.39 (d, J ¼ 4.8 Hz, NHCH3)
ppm; 13C NMR (100 MHz, DMSO-d6): ꢁ ¼ 27.93 (CH3)2, 29.26 (NCH3), 37.09 (C-5), 47.94 (C-6),
87.44 (C-3), 167.06 (C-4), 168.04 (C-2), 171.85 (CONH2) ppm.
(RS)-(ꢂ)-1,2,5,6-Tetrahydro-4-hydroxy-2-oxo-6-phenylpyridine-3-carboxamide (9a)
and (RS)-(ꢂ)-1,4,5,6-tetrahydro-2-hydroxy-4-oxo-6-phenylpyridine-3-carboxamide
(10a, C8H12N2O3)
A stream of NH3 was bubbled through a boiling solution of 0.4 mmol of 7a in 60cm3 of dry EtOH for
10h. The mixture was cooled and the solvent was removed in vacuo. The colourless residue was
triturated with EtOH=H2O and recrystallized from EtOH yielding 0.076g (82%) of 9a and 10a, mp
186ꢃC; IR (KBr): ꢀꢀ ¼ 3355 (m), 3224 (m), 2963 (w), 1636 (s), 1594 (s), 1581 (s), 1321 (m), 1085 (m),
792 (m), 765 (m), 698 (s) cmꢄ 1
.
1
9a (main component): H NMR (400MHz, CDCl3): ꢁ ¼ 2.74–2.92 (m, 2 5-H), 4.69–4.76 (m,
6-H), 5.56 (s, N1-H), 5.69 (s, 1 CONH2), 7.35–7.41 (m, 5 aromatic H), 9.31 (s, 1 CONH2), 17.27 (s,
OH) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 38.89 (C-5), 52.92 (C-6), 94.00 (C-3), 126.28, 128.72,
129.17, 139.90 (aromatic C), 168.39 (C-2), 173.16 (CONH2), 186.73 (C-4) ppm.
1
10a (minor constituent): H NMR (400MHz, CDCl3): ꢁ ¼ 2.68–2.88 (m, 2 5-H), 4.69–4.76 (m,
6-H), 5.69 (s, 1 CONH2), 5.75 (s, N1-H), 7.35–7.41 (m, 5 aromatic H), 9.66 (s, 1 CONH2), 17.74
(s, OH) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 44.19 (C-5), 53.57 (C-6), 86.60 (C-3), 126.23, 128.66,
129.19, 139.82 (aromatic C), 173.18 (CONH2), 174.57 (C-2), 189.57 (C-4) ppm.
(RS)-(ꢂ)-40-Chloro-1,2,5,6-tetrahydro-4-hydroxy-2-oxo-6-phenylpyridine-3-carboxanilide (9b)
and (RS)-(ꢂ)-40-chloro-1,4,5,6-tetrahydro-2-hydroxy-4-oxo-6-phenylpyridine-3-carboxanilide
(10b, C18H15ClN2O3)
Compound 7a (0.2mmol) and 0.24 mmol of 4-chloroaniline were triturated with a pestle in a mortar.
The mixture was given in a round bottom flask and melted with agitation at 170ꢃC on an oil-bath for
3 h. The mixture was allowed to cool and the residue was recrystallized from EtOH=H2O giving
0.064 g (94%) of 9b and 10b, mp 228ꢃC; IR (KBr): ꢀꢀ ¼ 3192 (m), 3111 (w), 3069 (w), 3033 (w),
1651 (s), 1594 (s), 1548 (s), 1491 (s), 1405 (s), 1226 (m), 1092 (m), 1012 (m), 834 (m), 701 (m) cmꢄ 1
.
9b (minor constituent): 1H NMR (400 MHz, DMSO-d6): ꢁ ¼ 2.80–3.18 (m, 2 5-H), 4.73–4.83 (m,
6-H), 7.29–7.63 (m, 9 aromatic H), 8.31 (s, NH), 12.26 (s, NHAr), 16.35 (s, OH) ppm; 13C NMR
(100 MHz, DMSO-d6): ꢁ ¼ 36.90 (C-5), 50.41 (C-6), 95.14 (C-3), 122.30, 126.52, 127.92, 128.87,
129.16, 135.97, 141.28 (aromatic C), 167.55 (C-2), 169.05 (ArCO), 184.44 (C-4) ppm.
1
10b (main component): H NMR (400MHz, DMSO-d6): ꢁ ¼ 2.68–2.85 (s, 2 5-H), 4.81–4.91
(m, 6-H), 7.29–7.63 (m, 9 aromatic H), 9.41 (s, NH), 11.97 (s, NHAr), 17.50 (s, OH) ppm; 13C
NMR (100MHz, DMSO-d6): ꢁ ¼ 42.62 (C-5), 51.34 (C-6), 86.44 (C-3), 122.30, 126.52, 128.06,
128.87, 129.16, 136.32, 140.44 (aromatic C), 169.42 (ArCO), 173.46 (C-2), 189.11 (C-4) ppm.
40-Chloro-1,2,5,6-tetrahydro-4-hydroxy-6,6-dimethyl-2-oxopyridine-3-carboxanilide (9c)
and 40-chloro-1,4,5,6-tetrahydro-2-hydroxy-6,6-dimethyl-4-oxopyridine-3-carboxanilide
(10c, C14H15ClN2O3)
4-Chlorophenyl isocyanate (0.02 mol) was added to a suspension of 0.02mol of 11=12 in 50cm3 of
acetonitrile. After the addition of 0.3 cm3 of triethylamine the mixture was heated on an oil-bath at
120ꢃC over night. It was cooled and filtered with suction and the residue was triturated with propan-2-
ol, filtered, and recrystallized from propan-2-ol giving 5.35g (91%) of 9c and 10c, mp 202ꢃC; IR
(KBr): ꢀꢀ ¼ 3163 (m), 3117 (m), 3058 (m), 3025 (m), 2973 (m), 1655 (s), 1595 (s), 1557 (s), 1491 (s),
1427 (s), 1301 (m), 1261 (m), 1087 (m), 1009 (m), 825 (s), 798 (s) cmꢄ 1
.

Carboxamides of Dihydropyridin-2(1H)-ones
1135
9c (minor constituent): 1H NMR (400 MHz, DMSO-d6): ꢁ ¼ 1.26 (s, (CH3)2), 2.67 (s, 2 5-H), 7.38-
7.59 (m, 5 aromatic H), 7.88 (s, NH), 12.31 (s, NHAr), 16.31 (s, OH) ppm; 13C NMR (100 MHz,
DMSO-d6): ꢁ ¼ 28.18 ((CH3)2), 41.89 (C-5), 49.15 (C-6), 94.13 (C-3), 122.16, 128.27, 129.11, 136.03
(aromatic C), 166.58 (C-2), 169.16 (ArCO), 184.84 (C-4) ppm.
1
10c (main component): H NMR (400MHz, DMSO-d6): ꢁ ¼ 1.26 (s, (CH3)2), 2.49 (s, 2 5-H),
7.38–7.59 (m, 5 aromatic H), 8.99 (s, NH), 12.01 (s, NHAr), 17.22 (s, OH) ppm; 13C NMR (100 MHz,
DMSO-d6): ꢁ ¼ 27.29 ((CH3)2), 48.07 (C-5), 50.38 (C-6), 85.20 (C-3), 122.16, 127.84, 129.11, 136.49
(aromatic C), 169.50 (ArCO), 171.91 (C-2), 189.93 (C-4) ppm.
N-Benzoyl-1,2,5,6-tetrahydro-4-hydroxy-6,6-dimethyl-2-oxopyridine-3-carboxamide (9d)
and N-benzoyl-1,4,5,6-tetrahydro-2-hydroxy-6,6-dimethyl-4-oxopyridine-3-carboxamide
(10d, C15H16N2O4)
The tautomeric mixture 11=12 (5mmol) was dried twice by azeotropic removal of H2O with benzene
and dissolved in 100 cm3 of benzene in an Ar atmosphere at 100ꢃC. Then a solution of 0.6 mmol of
benzoyl isocyanate in 30cm3 of benzene was added dropwise. The mixture was refluxed for 3 h,
allowed to cool, and filtered. The residue was recrystallized from benzene giving 0.643 g (47%) of
9d and 10d, mp 170ꢃC; IR (KBr): ꢀꢀ ¼ 3257 (m), 2966 (m), 1715 (s), 1663 (s), 1614 (s), 1583 (s), 1490
(s), 1283 (m), 1228 (m), 783 (m), 699 (m) cmꢄ 1
.
9d (main component): 1H NMR (400 MHz, CDCl3): ꢁ ¼ 1.38 (s, (CH3)2), 2.70 (s, 2 5-H), 5.79 (s,
N1-H), 7.45–8.07 (m, 5 aromatic H), 13.37 (s, NH(CO)2), 16.26 (s, OH) ppm; 13C NMR (100 MHz,
CDCl3): ꢁ ¼ 28.83 ((CH3)2), 42.82 (C-5), 49.87 (C-6), 95.10 (C-3), 127.97 (o-aromatic C), 128.85
(m-aromatic C), 133.05 (p-aromatic C), 133.18 (i-aromatic C), 164.64 (PhCO), 167.14 (C-2), 170.42
(CONH), 187.37 (C-4) ppm.
10d (minor constituent): 1H NMR (400 MHz, CDCl3): ꢁ ¼ 1.40 (s, (CH3)2), 2.59 (s, 2 5-H), 6.17 (s,
N1-H), 7.45–8.07 (m, 5 aromatic H), 13.31 (s, NH(CO)2), 17.40 (s, OH) ppm; 13C NMR (100 MHz,
CDCl3): ꢁ ¼ 28.06 (CH3)2, 48.79 (C-5), 51.20 (C-6), 87.41 (C-3), 128.04 (o-aromatic C), 128.85
(m-aromatic C), 132.95 (p-aromatic C), 133.22 (i-aromatic C), 164.72 (PhCO), 170.81 (CONH),
172.93 (C-2), 190.91 (C-4) ppm.
1,2,5,6-Tetrahydro-4-hydroxy-6,6-dimethyl-2-oxopyridine-3-carboxamide (9e)
and 1,4,5,6-tetrahydro-2-hydroxy-6,6-dimethyl-4-oxopyridine-3-carboxamide
(10e, C8H12N2O3)
Compounds 9d=10d (1mmol) were refluxed in 50cm3 of 2 M NaOH solution for 3 h. The mixture was
cooled to 0ꢃC and acidified with HClconc. Then the mixture was extracted repeatedly with CH2Cl2. The
combined organic layers were washed with H2O and dried. The solvent was evaporated and the residue
was recrystallized from EtOH=H2O giving 0.116 g (63%) 9e and 10e, mp 109ꢃC; IR (KBr): ꢀꢀ ¼ 3269
(s), 2972 (m), 1654 (s), 1599 (s), 1571 (s), 1260 (m), 1075 (m), 796 (m) cmꢄ 1
.
9e (main component): 1H NMR (400MHz, CDCl3): ꢁ ¼ 1.33 (s, (CH3)2), 2.58 (s, 2 5-H), 5.29 (s,
N1-H), 5.63, 9.32 (2s, CONH2), 17.14 (s, OH) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 28.95 ((CH3)2),
43.20 (C-5), 49.64 (C-6), 93.28 (C-3), 167.17 (C-2), 173.11 (CONH2), 186.55 (C-4) ppm.
10e (minor constituent): 1H NMR (400MHz, CDCl3): ꢁ ¼ 1.33 (s, (CH3)2), 2.49 (s, 2 5-H), 5.44 (s,
N1-H), 5.63, 9.58 (2s, CONH2), 17.79 (s, OH) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 28.49 ((CH3)2),
48.91 (C-5), 50.54 (C-6), 85.53 (C-3), 173.03, 173.11 (C-2, CONH2), 190.14 (C-4) ppm.
Ethyl N-methyl-N-(1,2,3,6-tetrahydro-2,2-dimethyl-6-oxopyridin-4-yl)carbamate
(13, C11H18N2O3)
Compound 1 (1mmol) was dried twice by azeotropic removal of H2O with benzene and was dissolved
in 20cm3 of THF and 0.5 cm3 of HMPA in an Ar atmosphere. The solution was cooled to ꢄ 78ꢃC, then

1136
R. Weis et al.: Carboxamides of Dihydropyridin-2(1H)-ones
2 cm3 of a 1.5 M solution of lithium diisopropylamide monotetrahydrofuran in cyclohexane were
added through a dropping funnel. The mixture was allowed to reach room temperature and was stirred
for 1 h. Then ethyl chloroformate was added dropwise at ꢄ 78ꢃC and the mixture was again allowed to
warm up. After addition of 15 cm3 of H2O the mixture was repeatedly extracted with CH2Cl2 and the
combined organic layers were washed with H2O to remove HMPA, dried, and the solvent was
evaporated. The mixture was purified by CC eluting with CH2Cl2:MeOH¼ 29:1. Recrystallization
from benzene=n-heptane gave 0.176 mg (78%) of 13, mp 133ꢃC, IR (KBr): ꢀꢀ ¼ 3176 (w), 2966 (w),
1716 (s), 1667 (s), 1605 (m), 1374 (s), 1324 (s), 1170 (s), 837 (m) cmꢄ 1; 1H NMR (400 MHz, CDCl3):
ꢁ ¼ 1.32 (s, (CH3)2), 1.32 (t, J ¼ 7.0 Hz, CH3), 2.77 (s, 2 5-H), 3.21 (s, NCH3), 4.22 (q, J ¼ 7.0 Hz,
OCH2), 5.50 (s, 3-H), 6.64 (s, NH) ppm; 13C NMR (100 MHz, CDCl3): ꢁ ¼ 14.25 (CH3), 28.34
((CH3)2), 35.80 (NCH3), 41.03 (C-5), 51.44 (C-6), 62.36 (OCH2), 107.31 (C-3), 153.34 (C-4),
153.99 (COO), 167.27 (C-2) ppm.
Ethyl (1,2,3,6-tetrahydro-2,2-dimethyl-6-oxopyridin-4-yl) carbonate (14, C10H15NO4)
Compounds 11=12 (2mmol) and 2 mmol of DMAP were dissolved in 50cm3 of CH2Cl2 in an Ar
atmosphere. Ethyl chloroformate (2.2mmol) was diluted with 5 cm3 of CH2Cl2 and was added drop-
wise to the solution. The mixture was stirred over night and partitioned between H2O and CH2Cl2. The
aqueous layer was once extracted with CH2Cl2 and the combined organic layers were washed 5 times
with H2O, dried, and the solvent was removed in vacuo. The residue was recrystallized from
benzene=n-heptane yielding 0.371 g (87%) of 14, mp 94ꢃC; IR (KBr): ꢀꢀ ¼ 3194 (m), 2986 (m),
1
1770 (s), 1761 (s), 1666 (s), 1631 (s), 1402 (m), 1231 (s), 1046 (m), 865 (m) cmꢄ 1; H NMR
(400 MHz, CDCl3): ꢁ ¼ 1.28 (t, J ¼ 7.2 Hz, CH3), 1.29 (s, (CH3)2), 2.45 (s, 2 5-H), 4.20 (q, J ¼ 7.2 Hz,
Hz, OCH2), 5.78 (s, 3-H), 7.44 (s, NH) ppm; 13C NMR (100MHz, CDCl3): ꢁ ¼ 13.68 (CH3), 28.34
((CH3)2), 39.16 (C-5), 51.08 (C-6), 64.80 (OCH2), 108.54 (C-3), 150.89 (COO), 159.33 (C-4), 166.65
(C-2) ppm.
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