A versatile and efficient synthesis of 2-alkyl and 2-aryl-6-alkyl-2,3-dihydro-1H-pyridin-4-ones

Article abstract of DOI:10.1055/s-2002-33648

A versatile and efficient method for the preparation of 2-alkyl and 2-aryl-6-alkyl-2,3-dihydro-1H-pyridin-4-ones is described. The sequence involved the condensation of β-amino acids and t-butyl ketoester to give enaminoesters whose intramolecular cyclisation followed by an hydrolysis step afforded the expected products.

Full text of DOI:10.1055/s-2002-33648

1740
PAPER
A Versatile and Efficient Synthesis of 2-Alkyl and 2-Aryl-6-alkyl-2,3-dihydro-
1H-pyridin-4-ones
A
Versatile and
E
f
i
ficient
c
Synthesis
o
o
f
S
ubstituted
l
Pyridi
anones s Leflemme, Patrick Dallemagne,* Sylvain Rault
Centre d'Etudes et de Recherche sur le Medicament de Normandie, UFR des Sciences Pharmaceutiques, 1 rue Vaubénard 14032 CAEN
Cedex, France
Fax +33(2)31931188; E-mail: dallemagne@pharmacie.unicaen.fr
Received 4 April 2002; revised 21 May 2002
tempted dihydropyridinones 4 by adapting a method very
Abstract: A versatile and efficient method for the preparation of 2-
recently described by Ma6 in a preliminary report.
alkyl and 2-aryl-6-alkyl-2,3-dihydro-1H-pyridin-4-ones is de-
scribed. The sequence involved the condensation of -amino acids
and t-butyl ketoester to give enaminoesters whose intramolecular
cyclisation followed by an hydrolysis step afforded the expected
products.
Apart from its implementation on great quantities of start-
ing material the other interest of this method lies in the
possibility of introducing in position 6 various others sub-
stituents than the methyl group (Scheme 2).
Key words: -amino ester, enaminoester, dihydropyridinone, ring
closure, heterocycle
Dihydropyridinones are interesting building blocks for a
large variety of heterocycle syntheses because their ami-
noenone moiety can be used in various reactions leading
to key intermediates particularly useful in the synthesis of
alkaloids and pharmacologicaly active agents.1 Further,
we have recently pointed out the interest of the dihydro-
pyridinones of the type 1 (Scheme 1) as memory enhanc-
ers in relation to their nicotinic acetylcholine receptor
affinity.2 Two general methods for synthesizing these
compounds have been reported. The first consists in ap-
plying Comins’ methodology by the use of organometal-
lics and 1-acyl salts of 4-methoxypyridines,3 the second
employed a Schiff base and a -diketone in the presence
of potassium amide in liquid ammonia.4 Recently, we de-
veloped a new method for the synthesis of 1 starting from
-aryl- -amino acids 2 converted in four steps into the hy-
drochloric salts of -aryl- -amino- -ketoketones 3 before
being cyclised to 1 (Scheme 1).5 In spite of the versatility
of this method and the good yields obtained, the use of
powdered samarium limited the quantities of starting ma-
terial and we therefore sought an alternative method to
achieve the desired conversion.
Scheme 2
The reaction sequence proposed by Ma6 involved the ace-
tate salts of -amino esters 5 which were condensed with
ethyl -ketoesters. The intermediates were cyclized with
sodium ethoxide to afford 6 whose the ester moiety was
removed by treatment in a mixture of ethanol and aqueous
sodium hydroxide to give the dihydropyridinones 4
(Scheme 3). Because of the difficulties encountered dur-
ing the application of this method to our compounds and
in particular because of the low yields obtained during the
hydrolysis of the ethyl carboxylate group we preferred to
replace the ethyl -ketoesters by t-butylesters.
The acetate salts of the -aryl- -amino esters 7a–c were
readily prepared via an esterification step of the corre-
sponding -aryl- -amino acids 2a–c,7 using thionyl chlor-
ide in ethanol. The hydrochloric salts thus obtained were
then displaced with ammonia and converted into the de-
sired acetate salts 7a–c by the use of acetic acid
(Scheme 4).
The method we now describe was developed starting from
the same -amino acids 2 and leads in four steps to the at-
Scheme 1
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1740,1746,ftx,en;T03702SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
A Versatile and Efficient Synthesis of Substituted Pyridinones
1741
Scheme 3
(Scheme 6, Table 2). As Baraldi has described for the
preparation of enaminones12 and as we checked by using
hydrochloric salts of -amino ester instead of the acetates,
the reaction was slower and did not go to completion in
the absence of acetic acid.
Scheme 4
The enaminoesters 9–12 were then cyclized with potassi-
um t-butoxide in t-butanol to afford the t-butyl 4-ketodi-
hydropyridine-3-carboxylates
13–16
(Scheme 7).13
The required acetate salt of -homophenylalanine ethyl
ester 7d was prepared from -phenylalanine as shown in
Scheme 5. Among the numerous methods for the conver-
sion of an -amino acid to its homologous -amino acid,
including the Arndt-Eistert reaction,8 the opening of azir-
idine-2-carboxylates9 and a more recently described pro-
cedure via BtCH2TMS,10 we favored an approach
involving nucleophilic displacement of a tosylate by cya-
nide.11 Under acidic condition, in ethanol, the resulting ni-
trile 8 was hydrolyzed and the BOC group was removed.
The corresponding -amino ester was finally reacted with
acetic acid to give the acetate salt 7d (Table 1).
Removal of the t-butyl ester group of the latter was finally
performed by refluxing in dichloromethane in the pres-
ence of TFA to give the title 2,6-disubstituted-2,3-dihy-
dropyridin-4-ones 17–20 in high yields (Table 3).
In summary, we have developed a versatile and efficient
methodology for the preparation of 2-alkyl or 2-aryl-6-
alkyl-2,3-dihydro-1H-pyridin-4-ones. The interaction of
these new compounds with the neuronal nicotinic receptor
and their pharmacological properties is now under inves-
tigation.
Commercial reagents were used as received without additional pu-
rification. Melting points were determined on a Kofler melting
point apparatus and are uncorrected. The NMR spectra were record-
ed in CDCl3 or in DMSO-d6 with a JEOL Lambda 400 spectrome-
ter, the chemical shifts ( ) are expressed in ppm relative to TMS for
1H and 13C nuclei, the coupling constants (J) are given in Hz, con-
ventional abbreviations are used. IR spectra were recorded on a
Genesis Series FTIR spectrometer. A typical example of IR spec-
trum is given for each series of compounds. Element microanalyses
were obtained from the ‘Institut de Recherche en Chimie Fine’
(Rouen). Analytical TLC was carried out on 0.25 precoated silica
gel plates (POLYGRAN SIL G/UV254) with viualization by UV ir-
radiation. Silica gel 60 (70–230 mesh) was ued for column chroma-
tography. Petroleum ether (PE) used had a bp 40–60°C.
Scheme 5
Table 1 Preparation of Acetates 7a–d
Table 2 Preparation of Enamino Esters 9–12
Product
7a
R
Yield (%)
Mp (°C)
97
R1
Yield (%)
Ph
95
93
92
63
Product
9a
R
7b
3-ClPh
Py
94
Ph
Me
Et
85
80
82
86
80
82
81
7c
62
9b
Ph
7d
Bn
86
10a
10b
11a
11b
12
3-ClPh
3-ClPh
Py
Me
Et
The resulting acetate salts 7a–d were then treated either
by t-butylacetoacetate or t-butylpropionylacetate in the
presence of an equivalent amount of acetic acid in reflux-
ing benzene with azeotropic removal of water to give the
enamino esters 9–12 in good yields after purification
Me
Et
Py
Bn
Me
Synthesis 2002, No. 12, 1740–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

1742
N. Leflemme et al.
PAPER
Scheme 6
Ethyl 3-Amino-3-arylpropanoate Acetate 7a-c, General Proce-
dure
d the product as white powder.
SOCl2 (0.44 mL, 6 mmol) was added dropwise to a soln of -amino
acid 2 (5 mmol) in EtOH (20 mL) cooled in an ice-bath. The mixture
was stirred for 12 h at r.t. After removal of solvent, the residue was
poured into H2O (20 mL), neutralized with NH4OH and extracted
with CH2Cl2 (2 20 mL). The combined organic layers were dried
(CaCl2), and concentrated in vacuo. The crude amino ester was dis-
solved in MeOH (10 mL), and HOAc (0.57 mL, 10 mmol), was add-
ed. The mixture was stirred for 0.5 h at r.t. and the solvents were
removed in vacuo. Recrystallization in an appropriate solvent yield-
Ethyl 3-amino-4-phenylbutanoate acetate (7d)
A stirred soln of 3-[(t-butoxycarbonyl)amino]-4-phenylbutane-
nitrile 8 (10 mmol), in anhyd EtOH (10 mL) and anhyd dioxane (10
mL) was saturated with HCl gas. The mixture was refluxed for 12 h
and concentrated in vacuo. The residue was dissolved in CH2Cl2 (20
mL), washed with 10% aq NaHCO3 ( 2 20 mL), dried over CaCl2
and concentrated in vacuo. The crude amino ester was dissolved in
MeOH (10 mL), and HOAc (0.92 mL,16 mmol) was added. The
mixture was stirred for 0.5 h at r.t. and the solvents were removed
in vacuo. Recrystallization with appropriated solvent yielded the
product as white powder.
The 1H and 13C NMR data of 7 are recorded in Table 4. Satisfactory
microanalyses were obtained for 7a d, C 0.40, H 0.29, N
0.33.
7a
IR (KBr): 3190, 3055, 2977, 2883, 1736, 1601, 1519, 1439, 1382,
1
1248, 1193, 789, 695 cm .
tert-Butyl 3-(1-Alkyl or Aryl-3-ethoxy-3-oxopropylamino)but-
2-enoate 9a,10a,11a,12 and tert-Butyl 3-(1-Aryl-3-ethoxy-3-oxo-
propylamino)pent-2-enoate 9b,10b,11b; General Procedure
To a stirred suspension of acetate 7a d (5 mmol), in anhyd benzene
(20 mL), was added HOAc (0.29 mL, 5 mmol), and -ketoester (6
mmol). The mixture was heated under reflux and the H2O formed
was removed azeotropically using a Dean–Stark apparatus. After
cooling to r.t., CHCl3 (25 mL) was added and the soln was washed
with sat. NaHCO3 soln (2 20 mL). The organic layer was dried
(CaCl2), the solvents were removed in vacuo and the residue was
purified by chromatography on silica gel eluting with variable
amounts of Et2O–PE to give the pure corresponding enamine. The
Scheme 7
e
Table 3 Preparation of 2,6-Disubstituted-2,3-dihydropyridin-4-ones 17–20
Product
13a
R
R1
Yield (%)
Mp (°C)
163
Product
17a
Yield (%)
Mp (°C)
160
141
160
132
148
96
Ph
Me
Et
85
78
84
84
84
79
84
92
93
94
93
78
79
92
13b
14a
Ph
104
17b
18a
3-ClPh
3-ClPh
Py
Me
Et
207
14b
15a
76
18b
19a
Me
Et
172
15b
16
Py
102
19b
20
Bn
Me
119
96
Synthesis 2002, No. 12, 1740–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Versatile and Efficient Synthesis of Substituted Pyridinones
1743
Table 4 1H and 13C NMR Data of Compounds 7a d
Product
1H NMR (DMSO-d6),
, J (Hz)
13C NMR (DMSO-d6),
, J (Hz)
7a
1.04 (t, 3 H, J = 7.0 Hz, CH3CH2O), 1.84 (s, 3 H, CH3C=O), 2.84 14.0 (CH3CH2O), 22.1 (CH3C=O), 40.4 (CH2C=O), 51.6
(dd, 1 H, J = 8.3, 15.6 Hz, CHHC=O), 3.01 (dd, 1 H, J = 5.8, 15.6 (CH), 60.4 (CH3CH2O), 127.5 128.4 128.7 (CHAr), 139.5
Hz, CHHC=O), 3.95 (q, 2 H, J = 7.0 Hz, CH3CH2O), 4.47 (dd, 1 (CAr), 169.9 (C=O), 173.5 (CH3C=O)
H, J = 5.8, 8.3 Hz, CH), 7.29–7.45 (m, 5 H, C6H5), 9.49 (br s, 3
H, NH3)
7b
1.10 (t, 3 H, J = 7.1 Hz, CH3CH2O), 1.86 (s, 3 H, CH3C=O), 2.61 13.9 (CH3CH2O), 21.6 (CH3C=O), 43.1 (CH2C=O), 51.9
(dd, 1 H, J = 6.6, 15.3 Hz, CHHC=O), 2.68 (dd, 1 H, J = 7.7, 15.3 (CH), 59.8 (CH3CH2O), 125.3, 126.5, 126.8, 129.9
Hz, CHHC=O), 3.99 (q, 2 H, J = 7.1 Hz, CH3CH2O), 4.25 (dd, 1 (CHAr), 132.9, 147.3 (CAr), 170.7 (C=O), 172.6
H, J = 6.6, 7.7 Hz, CH), 7.26 7.47 (m, 4 H, C6H4Cl), 9.21 (br s, (CH3C=O)
3 H, NH3)
7ca
1.24 (t, 3 H, J = 6.9 Hz, CH3CH2O), 2.06 (s, 6 H, CH3C=O), 2.73 13.7 (CH3CH2O), 21.8 (CH3C=O), 38.6 (CH2C=O), 49.3
(dd, 1 H, J = 4.3, 16.2 Hz, CHHC=O), 2.82 (dd, 1 H, J = 8.7, 16.2 (CH), 61.1 (CH3CH2O), 124.0 (CHAr), 133.6 (CAr),
Hz, CHHC=O), 4.14 (q, 2 H, J = 6.9 Hz, CH3CH2O), 4.53 (dd, 1 135.4, 147.9, 148.8 (CHAr), 169.8 (C=O), 176.5
H, J = 4.3 8.7 Hz, CH), 5.69 (br s, 3 H, NH3), 7.35 (dd, 1 H, J = (CH3C=O)
3.5, 7.2 Hz, ArH), 7.83 (d, 1 H, J = 7.2 Hz, HAr), 8.54 (d, 1 H,
J = 3.5, ArH), 8.63 (s, 1 H, ArH)
7da
1.24 (t, 3 H, J = 7.1 Hz, CH3CH2O), 2.02 (s, 3 H, CH3C=O), 2.62 13.8 (CH3CH2O), 22.4 (CH3C=O), 35.5 (CH2Ph), 38.8
(m, 2 H, CH2C=O), 2.86 (dd, 1 H, J = 8.5, 13.3 Hz, CHHPh),
(CH2C=O), 49.4 (CH), 60.9 (CH3CH2O), 127.0, 128.7,
3.07 (dd, 1 H, J = 6.1 13.3 Hz, CHHPh), 3.68 (m, 1 H, CH), 4.13 129.2 (CHAr), 135.7 (CAr), 171.1 (C=O), 176.8
(q, 2 H, J = 7.1 Hz, CH3CH2O), 7.20–7.34 (m, 5 H, C6H5), 8.38 (CH3C=O)
(br s, 3 H, NH3)
a 1H and 13C NMR in CDCl3.
1H and 13C NMR data of 9,10,11,12 are recorded in Table 5. Satis-
factory microanalyses were obtained for 9a b,10a b,11a b,12 C
0.40, H 0.25, N 0.24.
9a
IR (KBr): 3275, 3194,2977, 2930, 1736, 1649, 1613, 1451, 1366,
1264, 1152, 770, 699 cm–1.
Table 5 1H and 13C NMR Data of Compounds 9 12
Product
1H NMR (CDCl3),
13C NMR (CDCl3),
, J (Hz)
, J (Hz)
9a
1.16 (t, 3 H, J = 7.2 Hz, CH3CH2O), 1.43 [s, 9 H, C(CH3)3], 1.75 14.0 (CH3CH2O), 19.5 (CH3), 28.5 [C(CH3)3], 43.4
(s, 3 H, CH3), 2.70 (dd, 1 H, J = 6.4, 15.4 Hz, CHHC=O), 2.76 (CH2C=O), 53.9 (CH), 60.8 (CH3CH2O), 77.9 [C(CH3)3],
(dd, 1 H, J = 8.4, 15.4 Hz, CHHC=O), 4.03 (dq 1 H, J = 7.2, 10.7 85.9 (C=CH), 125.8 127.4 128.7 (CHAr), 142.1 (CAr),
Hz, CH3CHHO), 4.10 (dq, 1 H, J =7.2, 10.7 Hz, CH3CHHO),
4.37 (s, 1 H, C=CH), 4.95 (m, 1 H, CH), 7.20–7.30 (m, 5 H,
C6H5), 8.97 (d, 1 H, J = 8.8 Hz, NH)
160.0 (C=CH), 170.3 (C=O), 170.5 (C=O)
9b
1.02 (t, 3 H, J = 7.6 Hz, CH2CH3), 1.21 (t, 3 H, J = 7.1 Hz,
CH3CH2O), 1.49 [s, 9 H C(CH3)3], 2.02 (dq, 1 H, J = 7.6, 15.2
11.8 (CH2CH3), 14.0 (CH3CH2O), 25.0 (CH2CH3), 28.2
[C(CH3)3], 43.3 (CH2C=O), 52.9 (CH), 60.3 (CH3CH2O),
Hz, CHHCH3), 2.19 (dq, 1 H, J = 7.6, 15.2 Hz, CHHCH3), 2.74– 78.9 [C(CH3),3], 84.4 (C=CH), 125.7 127.9 128.5 (CHAr),
2.82 (m, 2 H CH2C=O), 4.10 (dq, 1 H, J = 7.1, 10.8 Hz,
CH3CHHO), 4.14 (dq, 1 H, J =7.1, 10.8 Hz, CH3CHHO), 4.45
(s, 1 H, C=CH), 5.01 (m, 1 H, CH), 7.26–7.36 (m, 5 H C6H5),
9.05 (d, 1 H, J = 9.2 Hz, NH)
141.6 (CAr), 163.9 (C=CH), 170.2 (C=O), 170.5 (C=O)
10a
1.19 (t, 3 H, J = 7.1 Hz, CH3CH2O), 1.45 [s, 9 H, C(CH3)3], 1.76 14.0 (CH3CH2O), 19.5 (CH3), 28.5 [C(CH3)3], 43.2
(s, 3 H, CH3), 2.70 (dd, 1 H, J = 5.8, 15.4 Hz, CHHC=O), 2.76 (CH2C=O), 53.5 (CH), 60.9 (CH3CH2O), 78.2 [C(CH3)3],
(dd, 1 H, J = 8.3, 15.4 Hz, CHHC=O), 4.07 (dq, 1 H, J = 7.2, 10.8 86.7 (C=CH), 124.1 126.2 127.7 130.1 (CHAr), 134.6
Hz, CH3CHHO), 4.11 (dq, 1 H, J =7.2, 10.8 Hz, CH3CHHO),
4.42 (s, 1 H, C=CH), 4.93 (m, 1 H, CH), 7.13–7.22 (m, 4 H,
C6H4Cl), 8.96 (d, 1 H, J = 8.6 NH)
144.3 (CAr), 159.6 (C=CH), 170.1 (C=O), 170.3 (C=O)
Synthesis 2002, No. 12, 1740–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

1744
N. Leflemme et al.
PAPER
Table 5 1H and 13C NMR Data of Compounds 9 12 (continued)
Product
1H NMR (CDCl3),
13C NMR (CDCl3),
, J (Hz)
, J (Hz)
10b
0.94 (t, 3 H, J = 7.6 Hz, CH2CH3), 1.13 (t, 3 H, J = 7.1 Hz,
11.8 (CH2CH3), 13.9 (CH3CH2O), 25.1 (CH2CH3), 28.4
CH3CH2O), 1.41 [s, 9 H, C(CH3)3], 1.92 (dq, 1 H, J = 7.6, 15.2 [C(CH3)3], 43.4 (CH2C=O), 52.9 (CH), 60.8 (CH3CH2O),
Hz, CHHCH3), 2.08 (dq 1 H, J = 7.6, 15.2 Hz, CHHCH3), 2.64 78.1 [C(CH3)3], 84.9 (C=CH), 123.9 126.1 127.5 130.0
(dd, 1 H, J = 5.9, 15.4 Hz, CHHC=O), 2.69 (dd, 1 H, J = 8.2, 15.4 (CHAr), 134.5 144.5 (CAr), 164.8 (C=CH), 170.1 (C=O),
Hz, CHHC=O), 4.02 (dq, 1 H, J = 7.1, 10.9 Hz, CH3CHHO),
4.06 (dq, 1 H, J =7.1, 10.9 Hz, CH3CHHO), 4.41 (s, 1 H,
C=CH), 4.90 (m, 1 H, CH), 7.09–7.22 (m, 4 H, C6H4Cl), 8.95 (d,
1 H, J = 9.3 Hz, NH)
170.6 (C=O)
11a
1.22 (t, 3 H, J = 7.2 CH3CH2O), 1.48 [s, 9 H C(CH3)3], 1.81 (s, 13.9 (CH3CH2O), 19.4 (CH3), 28.4 [C(CH3),3], 42.9
3 H CH3), 2.78 (dd, 1 H J = 6.0, 15.4 Hz, CHHC=O), 2.85 (dd, (CH2C=O), 51.6 (CH), 60.9 (CH3CH2O), 78.2 [C(CH3)3],
1 H J = 8.2, 15.4 Hz, CHHC=O), 4.10 (dq 1 H J = 7.2, 10.7 Hz, 86.8 (C=CH), 123.6, 133.5 (CHAr), 137.5 (CAr), 147.9,
CH3CHHO), 4.13 (dq 1 H J =7.2, 10.7 Hz, CH3CHHO), 4.46 (s, 148.9 (CHAr), 159.3 (C=CH), 169.9 (C=O), 170.2 (C=O)
1 H, C=CH), 5.04 (m, 1 H, CH), 7.30 (dd, 1 H, J = 3.9, 7.6 Hz,
ArH), 7.64 (dd, 1 H, J = 1.3, 7.8 Hz, ArH), 8.53 (d 1 H, J = 3.9
Hz, ArH), 8.57 (d 1 H, J = 1.3 Hz, ArH), 9.04 (d 1 H, J = 8.8 Hz,
NH)
11b
1.04 (t, 3 H, J = 7.6 Hz, CH2CH3), 1.22 (t, 3 H, J = 7.2 Hz,
CH3CH2O), 1.49 [s, 9 H, C(CH3)3], 2.02 (dq 1 H, J = 7.5, 15.0
11.8 (CH2CH3), 13.9 (CH3CH2O), 25.1 (CH2CH3), 28.4
[C(CH3)3], 43.1 (CH2C=O), 51.1 (CH), 60.9 (CH3CH2O),
Hz, CHHCH3), 2.20 (dq 1 H, J = 7.6, 15.2 Hz, CHHCH3), 2.78 78.2 [C(CH3)3], 85.1 (C=CH), 123.6 133.5 (CHAr), 137.7
(dd, 1 H, J = 5.9, 15.5 Hz, CHHC=O), 2.84 (dd, 1 H, J = 8.4, 15.5 (CAr), 147.8 148.8 (CHAr), 164.5 (C=CH), 169.9 (C=O),
Hz, CHHC=O), 4.11 (dq 1 H, J = 7.2, 10.7 Hz, CH3CHHO), 4.15 170.5 (C=O)
(dq 1 H, J =7.1 10.8 Hz, CH3CHHO), 4.49 (s, 1 H, C=CH), 5.06
Hz, (m, 1 H, CH), 7.29 (dd, 1 H, J = 4.6, 7.7 Hz, ArH), 7.64 (dd,
1 H, J = 1.7, 7.7 Hz, ArH), 8.53 (d, 1 H, J = 4.6 Hz, ArH), 8.57
(d, 1 H, J = 1.7 Hz, ArH), 9.07 (d, 1 H, J = 9.4 Hz, NH)
12
1.20 (t, 3 H, J = 7.1, CH3CH2O), 1.44 [s, 9 H, C(CH3)3], 1.60 (s, 14.0 (CH3CH2O), 19.1 (CH3), 28.5 [C(CH3)3], 40.6
3 H, CH3), 2.44 (dd, 1 H, J = 8.2, 15.6 Hz, CHHC=O), 2.53 (dd, (CH2Ph), 43.0 (CH2C=O), 51.7 (CH), 60.5 (CH3CH2O),
1 H, J = 5.3, 15.6 Hz, CHHC=O), 2.74 (dd, 1 H, J = 8.0, 13.6 Hz, 77.6 [C(CH3)3], 84.6 (C=CH), 126.5 128.2 129.3 (CHAr),
CHHPh), 2.79 (dd, 1 H, J = 6.1, 15.6 Hz, CHHPh), 4.07–4.10
(m, 3 H, CH, CH3CH2O), 4.23 (s, 1 H, C=CH), 7.12–7.26 (m, 5
H, C6H5), 8.52 (d, 1 H, J = 5.6 Hz, NH)
137.5 (CAr), 166.2 (C=CH), 170.3 (C=O), 170.9 (C=O)
tert-Butyl 6-Alkyl and 6-Aryl-2-alkyl-4-oxo-1,4,5,6-tetrahydro-
pyridine-3-carboxylate 13,14,15,16; General Procedure
compound. The 1H and 13C NMR data of 13,14,15,16 are recorded
in Table 6. Satisfactory microanalyses were obtained for
13a,b,14a,b,15a,b,16, C 0.35, H 0.20, N 0.19.
To a stirred soln of enamine 9,10,11, or 12 (5 mmol), in anhyd t-
BuOH (10 mL), was added t-BuOK (0.67 g 6 mmol), and the mix-
ture was heated at 50 °C. After completion (4 h monitored by TLC
analysis), the reaction mixture was quenched with HCl 10% (10
mL), poured into H2O (10 mL), and extracted with CHCl3 (2 20
mL). The combined organic fractions were dried (CaCl2), and con-
centred in vacuo. The crude product was chromatographed on silica
gel eluting with variable amounts of EtOAc–MeOH to give the pure
13a
IR (KBr),: 3232, 3071, 2974, 2932, 1694, 1621,1558, 1524, 1455,
1364, 1306, 1169, 765, 699 cm–1.
Table 6 1H and 13C NMR Data of Compounds 13-16
Product
1H NMR (CDCl3),
13C NMR (CDCl3),
J (Hz)
J (Hz)
13a
1.54 [s, 9 H, C(CH3)3], 2.27 (s, 3 H, CH3), 2.51 (dd, 1 H, J =
4.4, 15.9 Hz, CHHC=O), 2.74 (dd, 1 H, J = 14.5, 15.9, Hz,
21.3 (CH3), 28.4 [C(CH3),3], 43.6 (CH2C=O), 57.2 (CH),
80.4 [C(CH3),3], 106.5 (HN–C=C), 126.6 128.8 129.1
CHHC=O), 4.71 (dd, 1 H, J = 4.4, 14.5 Hz, CH), 5.35 (br s, 1 (CHAr), 139.1 (CAr), 163.7 (CO2t-Bu), 165.9 (HN–C=C),
H, NH), 7.34–7.40 (m, 5 H, C6H5) 187.6 (C=O),
13b
1.26 (t, 3 H, J = 7.6 Hz, CH2CH3), 1.53 [s, 9 H, C(CH3)3], 2.43 12.7 (CH2CH3), 27.3 (CH2CH3), 28.7 [C(CH3)3], 43.6
(dd, 1 H, J = 4.7, 15.9 Hz, CHHC=O), 2.59 (m, 2 H, CH2CH3), (CH2C=O), 56.9 (CH), 80.4 [C(CH3)3], 105.9 (HN–C=C),
2.63 (dd, 1 H, J = 14.3, 15.9 Hz, CHHC=O), 4.65 (dd, 1 H,
126.6 128.6, 129.1 (CHAr), 139.3 (CAr), 165.9 (CO2t-
J = 4.7, 14.3 Hz, CH), 5.68 (br s, 1 H, NH), 7.31–7.39 (m, 5 H, Bu), 168.1 (HN–C=C), 187.9 (C=O)
C6H5)
Synthesis 2002, No. 12, 1740–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Versatile and Efficient Synthesis of Substituted Pyridinones
1745
Table 6 1H and 13C NMR Data of Compounds 13-16 (continued)
Product
1H NMR (CDCl3),
13C NMR (CDCl3),
J (Hz)
J (Hz)
14a
1.52 [s, 9 H, C(CH3)3], 2.28 (s, 3 H, CH3), 2.46 (dd, 1 H, J =
4.7, 15.9 Hz, CHHC=O), 2.62 (dd, 1 H, J = 13.9, 15.9 Hz,
21.2 (CH3), 28.3 [C(CH3)3], 43.5 (CH2C=O), 56.6 (CH),
80.5 [C(CH3)3], 106.7 (HN–C=C), 124.8, 126.8, 128.8,
CHHC=O), 4.66 (dd, 1 H, J = 4.7, 13.9 Hz, CH), 5.72 (br s, 1 130.4 (CHAr), 134.9, 141.3 (CAr), 163.7 (CO2t-Bu),
H, NH), 7.21–7.33 (m, 4 H, C6H4Cl) 165.7 (HN–C=C), 187.1 (C=O),
14b
1.23 (t, 3 H, J = 7.5 Hz, CH2CH3), 1.48 [s, 9 H, C(CH3)3], 2.31 12.9 (CH2CH3), 27.4 (CH2CH3), 28.2 [C(CH3)3], 43.2
(dd, 1 H, J = 5.2, 15.9 Hz, CHHC=O), 2.43 (dd, 1 H, J = 12.8, (CH2C=O), 55.9 (CH), 80.3 [C(CH3)3], 105.4 (HN–C=C),
15.9 Hz, CHHC=O), 2.58 (m, 2 H, CH2CH3), 4.56 dd, 1 H, J = 124.8 126.7, 128.5, 130.2 (CHAr), 134.6, 141.5 (CAr),
5.2, 12.8 Hz, CH), 6.55 (br s, 1 H, NH), 7.16–7.26 (m, 4 H,
C6H4Cl)
165.7 (CO2t-Bu), 169.1 (HN–C=C), 187.5 (C=O)
15a
15b
1.50 [s, 9 H, C(CH3)3], 2.30 (s, 3 H, CH3), 2.49 (dd, 1 H, J =
5.3, 15.9 Hz, CHHC=O), 2.61 (dd, 1 H, J = 12.5, 15.9 Hz,
CHHC=O), 4.73 (dd, 1 H, J = 5.3, 12.5 Hz, CH), 6.79 (br s, 1 135.0 (CAr), 148.4, 149.8 (CHAr), 164.7 (CO2t-Bu),
H, NH), 7.29 (dd, 1 H, J = 4.9, 7.8 Hz, ArH), 7.68 (d, 1 H, J = 165.6 (HN–C=C), 187.0 (C=O)
7.8 Hz, ArH), 8.52 (m, 2 H, ArH)
21.3 (CH3), 28.4 [C(CH3)3], 42.9 (CH2C=O), 54.3 (CH),
80.5 [C(CH3)3], 106.2 (HN–C=C), 123.9, 134.4 (CHAr),
1.27 (t, 3 H, J = 7.5 Hz, CH2CH3), 1.53 [s, 9 H, C(CH3)3], 2.42 13.0 (CH2CH3), 27.4 (CH2CH3), 28.2 [C(CH3)3], 42.8
(dd, 1 H, J = 5.7, 15.9 Hz, CHHC=O), 2.51 (dd, 1 H, J = 11.7, (CH2C=O), 54.0 (CH), 80.4 [C(CH3)3], 105.7 (HN–C=C),
15.9 Hz, CHHC=O), 2.55 (m, 2 H, CH2CH3), 4.75 (dd, 1 H,
123.8 134.3 (CHAr), 135.2 (CAr), 148.2, 149.6 (CHAr),
J = 5.7, 11.7 Hz, CH), 5.81 (br s, 1 H, NH), 7.33 (dd, 1 H, J = 165.6 (CO2t-Bu), 168.9 (HN–C=C), 187.2 (C=O)
4.9, 7.8 Hz, ArH), 7.70 (d, 1 H, J = 7.8 Hz, ArH), 8.58 (m, 2
H, ArH)
16
1.51 [s, 9 H, C(CH3)3], 2.71 (s, 3 H, CH3), 2.39 (dd, 1 H, J =
11.2, 15.8 Hz, CHHC=O), 2.52 (dd, 1 H, J = 5.1, 15.8 Hz,
21.5 (CH3), 28.3 [C(CH3)3], 39.4 (CH2Ph), 40.5
(CH2C=O), 52.8 (CH), 79.9 [C(CH3)3], 104.8 (HN–C=C),
CHHC=O), 2.85 (dd, 1 H, J = 8.4, 13.4 Hz, CHHPh), 2.91 (dd, 126.9, 128.7, 129.1 (CHAr), 136.3 (CAr), 164.7 (CO2t-
1 H, J = 6.1, 13.4 Hz, CHHPh), 3.84 (m, 1 H, CH), 5.43 (br s, Bu), 165.8 (HN–C=C), 188.3 (C=O)
1 H, NH), 7.17–7.36 (m, 5 H, C6H5)
2-Alkyl and 2-Aryl-6-alkyl-1,2-dihydro-1H-pyridin-4-one
17,18,19,20; General Procedure
and 13C NMR data of 17,18,19,20 are recorded in Table 7. Satisfac-
tory microanalyses were obtained for 17a,b,18a,b,19a,b,20 C
0.40, H 0.18, N 0.20.
To a stirred soln of tetrahydropyridinone 13, 14, 15 or 16 (5 mmol),
in CH2Cl2 (10 mL), was added TFA (3.85 mL, 50 mmol), and the
mixture was heated at 50 °C. After completion (4 h monitored by
TLC analysis), the reaction mixture was neutralized with sat. aq
K2CO3 and extracted with CH2Cl2 (2 20 mL). The combined or-
ganic fractions were dried (CaCl2) and concentrated in vacuo. The
crude product was chromatographed on silica gel eluting with vari-
able amounts of EtOAc–MeOH to give the pure compound. The 1H
17b
IR (KBr),: 3218, 3060, 2965, 2925, 2878, 1616, 1601, 1532, 1450,
1351, 1264, 1237, 1107, 769, 702 cm–1.
Table 7 1H and 13C NMR Data of Compounds 17a 18, 19, 20
Product
1H NMR (CDCl3),
13C NMR (CDCl3),
, J (Hz)
, J (Hz)
17b
1.19 (t, 3 H, J = 7.6 Hz, CH2CH3), 2.28 (q, 2 H, J = 7.6 Hz,
CH2CH3), 2.42 (dd, 1 H, J = 4.9, 16.2 Hz, CHHC=O), 2.62
11.7 (CH2CH3), 27.8 (CH2CH3), 43.4 (CH2C=O), 57.9
(CH), 97.2 (C=CH), 126.5, 128.1, 128.7 (CHAr), 140.2
(dd, 1 H, J = 14.5, 16.2 Hz, CHHC=O), 4.67 (dd, 1 H, J = 4.9, (CAr), 167.8 (C=CH), 191.9 (C=O)
14.5 Hz, CH), 5.04 (s, 1 H C=CH), 5.15 (br s, 1 H, NH), 7.31–
7.40 (m, 5 H, C6H5)
18a
18b
1.98 (s, 3 H, CH3), 2.47 (dd, 1 H, J = 4.8, 16.0 Hz,
21.2 (CH3), 43.2 (CH2C=O), 57.9 (CH), 99.9 (C=CH),
CHHC=O), 2.60 (dd, 1 H, J = 14.2, 16.0 Hz, CHHC=O), 4.69 124.6, 126.8, 128.6, 130.6 (CHAr), 134.8, 142.2 (CAr),
(dd, 1 H, J = 4.8, 14.2 Hz, CH), 4.98 (s, 1 H, C=CH), 5.34 (br 162.4 (C=CH), 191.5 (C=O)
s, 1 H, NH), 7.24–7.39 (m, 5 H, C6H5)
1.19 (t, 3 H, J = 7.6 Hz, CH2CH3), 2.29 (q, 2 H, J = 7.6 Hz,
CH2CH3), 2.37 (dd, 1 H, J = 5.0, 16.1 Hz, CHHC=O), 2.50
11.7 (CH2CH3), 27.9 (CH2CH3), 43.4 (CH2C=O), 57.6
(CH), 97.8 (C=CH), 124.8, 126.7, 128.4, 130.2 (CHAr),
(dd, 1 H, J = 13.8, 16.1 Hz, CHHC=O), 4.62 (dd, 1 H J = 5.0, 134.6 142.4 (CAr), 167.7 (C=CH), 191.5 (C=O)
13.8 Hz, CH), 4.98 (s, 1 H, C=CH), 5.63 (br s, 1 H, NH),
7.24–7.36 (m, 4 H, C6H4Cl)
Synthesis 2002, No. 12, 1740–1746 ISSN 0039-7881 © Thieme Stuttgart · New York

1746
N. Leflemme et al.
PAPER
Table 7 1H and 13C NMR Data of Compounds 17a 18, 19, 20 (continued)
Product
1H NMR (CDCl3),
13C NMR (CDCl3),
, J (Hz)
, J (Hz)
19a
2.02 (s, 3 H, CH3), 2.42 (dd, 1 H, J = 5.3, 16.2 Hz,
21.0 (CH3), 42.7 (CH2C=O), 55.6 (CH), 99.6 (C=CH),
CHHC=O), 2.55 (dd, 1 H, J = 13.3, 16.2 Hz, CHHC=O), 4.69 123.9, 134.6 (CHAr), 136.0 (CAr), 147.9, 149.2 (CHAr),
(dd, 1 H, J = 5.3, 13.3 Hz, CH), 4.98 (s, 1 H, Hz, C=CH), 6.07 162.9 (C=CH), 190.9 (C=O)
(br s, 1 H, NH), 7.26 (dd, 1 H, J = 4.9, 7.8 Hz, ArH), 7.68 (d,
1 H, J = 7.8 Hz, ArH), 8.53 (d, 1 H, J = 4.9 Hz, ArH), 8.57 (s,
1 H, ArH)
19b
20
1.21 (t, 3 H, J = 7.5 Hz, CH2CH3), 2.31 (q, 2 H, J = 7.5 Hz,
CH2CH3), 2.51 (dd, 1 H, J = 4.6, 16.1 Hz, CHHC=O), 2.65
(dd, 1 H, J = 13.4, 16.1 Hz, CHHC=O), 4.75 (dd, 1 H, J = 4.6, 147.8 148.7 (CHAr), 168.6 (C=CH), 190.4 (C=O)
13.4 Hz, CH), 5.09 (s, 1 H, Hz, C=CH), 5.20 (br s, 1 H, NH),
7.34 (dd, 1 H, J = 4.8, 7.8 Hz, ArH), 7.75 (d, 1 H, J = 7.8 Hz,
ArH), 8.63 (m, 2 H, ArH)
11.6 (CH2CH3), 27.5 (CH2CH3), 42.3 (CH2C=O), 54.7
(CH), 96.6 (C=CH), 123.3, 134.0 (CHAr), 135.7 (CAr),
1.91 (s, 3 H, CH3), 2.28 (dd, 1 H, J = 11.6, 16.1 Hz,
20.9 (CH3), 39.9 (CH2Ph), 40.6 (CH2C=O), 54.1 (CH),
CHHC=O), 2.39 (dd, 1 H, J = 5.1, 16.1 Hz, CHHC=O), 2.86 98.8 (C=CH), 126.8, 128.7, 129.0 (CHAr), 136.7 (CAr),
(dd, 1 H, J = 6.2, 13.5 Hz, CHHPh), 2.91 (dd, 1 H, J = 7.9,
13.5 Hz, CHHPh), 3.81 (m, 1 H, CH), 4.92 (s, 1 H, C=CH),
5.54 (br s, 1 H, NH), 7.16–7.33 (m, 5 H, C6H5)
162.2 (C=CH), 191.9 (C=O)
a Description of 17a was already published.14
(5) (a) Renault, O.; Guillon, J.; Dallemagne, P.; Rault, S.
Tetrahedron Lett. 2000, 41, 681. (b) Leflemme, N.;
Dallemagne, P.; Rault, S. Tetrahedron Lett. 2001, 42, 8997.
(6) Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503.
(7) (a) Rodionov, V. M.; Postovskaja, E. A. J. Am. Chem. Soc.
1929, 51, 841. (b) Johnson, T. R.; Livak, J. E. J. Am. Chem.
Soc. 1936, 58, 299. (c) Seeman, J. I.; Secor, H. V.; Whidby,
J. F.; Bassfield, R. L. Tetrahedron Lett. 1978, 22, 1901.
(d) Secor, H. V.; Edwards, W. B. J. Org. Chem. 1979, 44,
3136.
(8) (a) Plucinska, K.; Liberek, B. Tetrahedron 1987, 43, 3509.
(b) Podlech, J.; Seebach, D. Liebigs Ann. Chem. 1995, 1217.
(9) Baldwin, J. E.; Adlington, R. M.; O’Neil, I. A.; Schofield,
C.; Spivey, A. C.; Sweeney, J. B. J. Chem. Soc., Chem.
Commun. 1989, 1852.
(10) Katritzky, A. R.; Zhang, S.; Haleem, A.; Hussein, A. H. M.;
Fang, Y. J. Org. Chem. 2001, 66, 5606.
(11) Sutherland, A.; Willis, C. L. J. Org. Chem. 1998, 63, 7764.
(12) Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983,
902.
(13) Becker, H. G. O. J. Prakt. Chem. 1961, 12, 294.
(14) Guarda, A.; Brandi, A.; Sarlo, F.; De Goti, A.; Pericciuoli, F.
J. Org. Chem. 1988, 53, 2426.
References
(1) (a) Coutts, R. T.; Scott, J. R. Can. J. Pharm. Sci. 1971, 6, 78.
(b) Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem.
Soc. 1988, 110, 7445; and references therein. (c) Comins,
D. L.; Fulp, A. B. Org. Lett. 1999, 1, 1941. (d) Stout, D.
M.; Meyers, A. I. Chem. Rev. 1982, 82, 223. (e) Sausins,
A.; Duburs, G. Heterocycles 1988, 27, 291. (f) Comins, D.
L.; O’Connor, S. Adv. Heterocycl. Chem. 1988, 44, 199.
(g) Yamaguchi, R.; Hata, E.; Matsuki, T.; Kawanisi, M. J.
Org. Chem. 1987, 52, 2094. (h) Ogawa, M.; Natsume, M.
Heterocycles 1985, 23, 831. (i) Natsume, M.; Utsunomiya,
I.; Yamaguchi, K.; Sakai, S. Tetrahedron 1985, 41, 2115.
(j) Ferles, M.; Pliml, J. Adv. Heterocycl. Chem. 1970, 12, 43.
(2) Rault, S.; Renault, O.; Guillon, J.; Dallemagne, P.; Pfeiffer,
B.; Lestage, P.; Lebrun, M. C. EP Patent 1,050,530, 2000.
(3) (a) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27,
4549. (b) Comins, D. L.; Killpack, M. O. J. Am. Chem. Soc.
1992, 114, 10972. (c) Comins, D. L.; Joseph, S. P.;
Goehring, R. R. J. Am. Chem. Soc. 1994, 116, 4719.
(4) Sugiyama, N.; Yamamoto, M.; Kashima, C. Bull. Chem.
Soc. Jpn. 1970, 43, 901; and references cited therein.
Synthesis 2002, No. 12, 1740–1746 ISSN 0039-7881 © Thieme Stuttgart · New York