An efficient synthesis of functionalized 2-pyridones by direct route or via amide/enolate ammonium salt intermediates

Article abstract of DOI:10.1055/s-1999-3531

A number of compounds with a 2-pyridone structure 3, which have different substituents and-are analogous to cardiotonic drugs like milrinone, have been synthesized in high yields from the appropriate enamino ketones 2 using different cyanomethylene active compounds (methyl cyanoacetate, benzoylacetonitrile and phenylsulfonylacetonitrile). In this synthetic route, the active role of the dimethylamine released in situ on the cyclization process has been underlined. In particular, its direct intervention; as a nucleophile or a base, was proven and intermediate amides 5 or enolate ammonium salts 6 were isolated and recognized by the analytical and spectral data.

Full text of DOI:10.1055/s-1999-3531

PAPER
1169
An Efficient Synthesis of Functionalized 2-Pyridones by Direct Route or via
Amide/Enolate Ammonium Salt Intermediates
Francesco Bondavalli, Olga Bruno, Eleonora Lo Presti, Giulia Menozzi, Luisa Mosti*
Dipartimento di Scienze Farmaceutiche, Viale Benedetto XV, 3, I-16132, Genova, Italy
Fax +39(10)3538358; E-mail:mosti@csita.unige.it
Received 21 October 1998; revised 21 December 1998
This paper is dedicated to the memory of Prof. Pietro Schenone
to obtain a variety of 5-acyl-1,2-dihydro-2-oxo-3-pyri-
Abstract: A number of compounds with a 2-pyridone structure 3,
dinecarbonitriles 1,3 some of which showed a significant
which have different substituents and are analogous to cardiotonic
inotropic activity.4 During some investigation on the reac-
tivity of (2-dimethylaminomethylene)cyclohexanone
drugs like milrinone, have been synthesized in high yields from the
appropriate enamino ketones 2 using different cyanomethylene ac-
tive compounds (methyl cyanoacetate, benzoylacetonitrile and phe- with methyl cyanoacetate we ascertained that the closure
nylsulfonylacetonitrile). In this synthetic route, the active role of the
dimethylamine released in situ on the cyclization process has been
underlined. In particular, its direct intervention, as a nucleophile or
investigate more closely the reactivity of some cyanome-
a base, was proven and intermediate amides 5 or enolate ammonium
salts 6 were isolated and recognized by the analytical and spectral
of a 2-pyridone ring could easily be achieved in good
yield. This interesting chemical behaviour prompted us to
thylene active compounds (methyl cyanoacetate, benzoy-
lacetonitrile and phenylsulfonylacetonitrile) with
a
data.
variety of open-chain and cyclic enamino ketones 2 to
verify the possibility of generalizing such results and to
find out a possible reaction pathway. In fact some malonic
derivatives were formerly reacted with bicyclic enamino
ketones in a basic medium5 followed by acid hydrolysis to
lead to a-pyrone derivatives. A unique example of reac-
tion of aliphatic enamino ketones with cyanoacetic esters
giving a pyridone derivative was reported by Krasnaya6
but this unexpected result was not generalized. In our
case, without adding a base, a number of compounds with
a 2-pyridone structure 3 with different substituents, name-
ly the simple substituted derivatives 3a–d, the 5,6-polim-
ethylene-1H-pyridin-2-ones 3e–h, the benzoquinolin-2-
ones 3i and finally the 1,5,6,7-tetrahydro-2H-ben-
zo[6,7]cyclohepta-[1,2-b]pyridin-2-ones 3j were obtained
by reaction of a variety of enaminones with activated ac-
etonitriles (Scheme, Table). These products may repre-
sent a new class of milrinone analogous lacking their
characteristic hydrogen bonding acceptor group opposite
to the lactamic function and therefore could be of interest
for a thorough investigation on the structure-activity rela-
tionship in the 2-pyridone family.7, 8
Key words: mono and polycyclic 2-pyridones, dimethylaminome-
thyleneketones, amide and enolate intermediates, cardiotonic
agents
Congestive heart failure (CHF) is a major cause of death
in patients with heart disease. For many years digitalis
glycosides have been used for the treatment of CHF. This
use, however, is limited by their narrow therapeutic index
and their propensity to cause life-threatening arrhythmias
(arrhythmogenic lability). The search for orally active
nonglycosidic cardiotonic drugs displaying a greater safe-
ty profile and improved efficacy comparable to digitalis
principles resulted in the discovery of a new class of
agents, the cyclic adenosine 3’,5’-monophosphate (cAMP)
specific phosphodiesterase (PDEIII) inhibitors. These
agents belong to a chemically composite group of com-
pounds, however almost all characterized by the presence
of a 2-pyridone nucleus, the prototypes being amrinone1
and particularly milrinone.2
Compounds 3 a–j were synthesized from the versatile pre-
cursors 2 a–j obtained in the past in very high yield from
the corresponding a-hydroxymethylene derivatives with
dimethylamine at room temperature (2a,9 2b,10 2c,11 2d,12
2e,13 2f,14 2g,15 2h,15 2i,16 2j17) or, more recently, directly
by refluxing a solution of the suitable ketone in amide ac-
etals (mainly N,N-dimethylformamide dimethylacetal)
(2a,18 2c,18 2d,19 2e,20 2f,20 2g,20 2i21 and by us in the case
of 2b, 2h and 2j). The reaction of enamino ketones 2a–j
with the above mentioned cyano compounds, having a
methylene active group, usually occurs first between the
nucleophilic methylenic group and the a-enamino carbon
atom, which is the most electrophilic site of the enamino-
ne. In few cases does the nucleophilic attack also occur on
the enaminone carbonyl function so as to give the meth-
In preceding papers we reported the facile reaction of
open-chain and cyclic sym-2-dimethylaminomethylene-
1,3-diones (enamine diones) with cyanoacetamide, a 1-3
dinucleophile with C–C–N structure, as a useful method
Synthesis 1999, No. 7, 1169–1174 ISSN 0039-7881 © Thieme Stuttgart · New York

1170
F. Bondavalli et al.
PAPER
Reagents and conditions: a) appropriate WCH2CN/anhyd MeOH or EtOH, r.t., or reflux (Table); b)AcOH, anhyd toluene,
reflux (Table); c) AcOH, 0 °C
Scheme
ylidene derivatives 4 as a by product or as the sole isolated Dimroth22 rearrangement of a preliminary a-iminopyran
product, even if in low yield (Scheme, Table). Subse- ring.23 The amide and salt nature of compounds 5 and 6 re-
1
quently the dimethylamine, when released in situ, mostly spectively has been clarified by IR, H NMR and 13C
causes the reaction to proceed towards the direct closure NMR spectral data. The formation of the isolated amides
of the 2-pyridone ring without isolation of intermediates.
5 was in agreement with the example reported by Kras-
naya.6 In particular, 1H NMR data of some amides 5 evi-
denced the presence of two isomeric forms due to an s-cis/
trans isomerism (the trans form being the prevalent).
In a few cases, we have been able to isolate intermediates
that confirm this direct intervention of the dimethylamine,
which may act as a nucleophile on the carbonyl group to
give amides 5,6 or, in particular cases, as a base to form After careful acidification, salts 6, which are very soluble
water-soluble salts 6, well enough soluble in diethyl ether/ in water, gave the corresponding unstable enols 7, which
ethyl acetate (3:1) (Scheme). These two types of interme- could not be cyclized to 2-pyridones, further proving the
diates, in turn, always gave the desired 2-pyridones 3 by active role of the dimethylamine in the cyclization pro-
refluxing in anhydrous toluene with a small quantity of cess. Similar enolates, having an alkaline rather than a
acetic acid. The formation of enolates 6 instead of amides dimethylammonium counter ion, have been mentioned by
5 is probably due to a stronger acidity of the enol form in- Maitte et al5 but their analytical and spectral data have not
volved, which protonates the released dimethylamine thus been recorded. The most interesting fact, however, is that
forming a stable salt that hinders the normal addition on those enolates, after acidification, always gave only a-py-
the keto group to give an amide. In the case of amides 5 rone and not 2-pyridone derivatives, exactly the opposite
the last step of the 2-pyridone ring closure might reason- of our present results.
ably result from the amide group attack to the masked
electrophilic carbonyl group, with loss of dimethylamine.
For the enolates 6, the cyclization process could not be as-
Some of these 2-pyridones, prepared by other routes with
lower or unreported yields, are already known (3a w1,6
3c–f w124) and consequently the identity of their mps, IR
certained through the identification of other intermediates
and 1H NMR spectral data compared to those of our com-
and probably results via amide formation or by a sort of
Synthesis 1999, No. 7, 1169–1174 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of Functionalized 2-Pyridones
1171
cm–1. 1H and 13C NMR spectra were recorded on a Varian Gemini
200 (200 and 50.30 MHz respectively) spectrometer. Chemical
shifts are reported in parts per million (ppm) on the d scale down-
field from TMS. Coupling constants (J) are expressed in Hertz (Hz).
The assignments of 13C signals were assisted by DEPT spectral da-
ta. Physical and chemical data of new pyridones derivatives are giv-
en in Table.
pounds unequivocally confirmed the pyridone structure of
compounds 3.
Finally, in view of the known biological activity of this
class of compounds, a selected set was also subjected to a
preliminary evaluation as cardiotonic agents. It is remark-
able that none of them showed significant activity,25 thus
confirming the essential role, in the biological interaction,
of the hydrogen bonding acceptor group located on the
opposite site to the lactamic moiety.
(N, N-Dimethylaminomethylene)ketones 2b, h, j; General
Procedure
The method of preparation was the same as the one previously de-
scribed for the other compounds 2 and realized directly by refluxing
a solution of the suitable ketone (20 mmol) in N,N-dimethylforma-
mide dimethylacetal (30 mmol) for 24 h. In the case of 3-methyl-
butan-2-one the reaction was carried out in sealed tube and the mix-
ture was heated at 100°C for 72 h.
2b: bp 105–110°C/0.2 mbar; yield: 60% (Lit.10 yield: 55%).
2h: bp 135–140 °C/0.2 mbar, yield 80% (Lit.15 yield: 91%).
Organic solvents and reagents were purified by the appropriate stan-
dard procedures. Drying of the organic extracts during the workup
of reactions was performed over anhyd MgSO4. Evaporation of sol-
vents was carried out under reduced pressure with a rotatory evap-
orator. Purification of high boiling oils was realized by bulb-to-bulb
distillation in vacuo. Mps were determined on a Fisher–Johns appa-
ratus and are uncorrected. Microanalyses were performed on a Car-
lo Erba elemental analyzer (model 1106) for C, H, N. IR spectra
were taken on a Perkin Elmer 398 instrument and are expressed in
2j: bp 185–190°C/0.3 mbar, mp 90–91°C (Et2O); yield: 91% (Lit.17
yield: 95%).
Table Physical and Chemical Data for Compounds 3a–j w1, 3b–h, j w2, 3b–j w3, 4a w3, 4i, j w1 and 4j w2 (w1=CO2Me, w2=COPh,
w3=SO2Ph)
Product
R1
R2
mp (°C) or
bp (°C)/mbar
Reaction Conditions
(anhyd solvent)
Synthetic Route
Yielda
(%)
3a w1
3b w1
3c w1
3d w1
3e w1
Me
i-Pr
Ph
H
H
H
Me
168–169b
144–145
reflux, 48h (toluene)
reflux, 6h (MeOH)
reflux, 48h (toluene)
reflux, 6h (MeOH)
reflux, 6h (MeOH)
reflux, 12h (toluene)
r.t., 4h (MeOH)
via amide
direct
via amide
direct
direct
via enolate
direct
direct
direct
direct
direct
direct
via amide
direct
direct
via enolate
direct
direct
direct
direct
via amide
via amide
direct
direct
via enolate
direct
direct
direct
direct
direct
84
20
87
67
23
97
70
85
79
29
25
18
76
61
21
55
52
53
50
22
89
71
71
20
58
93
95
99
83
68
16
40
54
80
176–177c
178–180c
175–177c (dec)
Ph
-(CH2)3-
3f w1
3g w1
3h w1
3i w1
3j w1
3b w2
3c w2
3d w2
3e w2
-(CH2)4-
-(CH2)5-
-(CH2)6-
C6H4(CH2)2
C6H4(CH2)3
H
H
Me
-(CH2)3-
197–199c
209–211
228–230
195–197
230–232
174–175
227–228
223–225
268–270 (dec)
r.t., 4h (MeOH)
r.t., 4h (MeOH)
reflux, 12h (MeOH)
reflux, 6h (MeOH)
reflux, 24h (EtOH)
reflux ,48h (toluene)
reflux, 24h (EtOH)
reflux, 6h (EtOH)
reflux, 12h (toluene)
r.t., 24h (EtOH)
i-Pr
Ph
Ph
3f w2
3g w2
3h w2
3j w2
3b w3
3c w3
3d w3
3e w3
-(CH2)4-
-(CH2)5-
-(CH2)6-
C6H4(CH2)3
H
H
Me
-(CH2)3-
251–252
230–232
242–244
245–247
212–213
318–320
268–270
273–275 (dec)
r.t., 24h (EtOH)
r.t., 24h (EtOH)
reflux, 24h (EtOH)
reflux, 48h (toluene)
reflux, 48h (toluene)
reflux, 6h (EtOH)
reflux, 6h (EtOH)
reflux, 12h (toluene)
reflux, 4h (EtOH)
reflux, 4h (EtOH)
reflux, 4h (EtOH)
reflux, 4h (EtOH)
reflux, 24h (EtOH)
reflux, 24h (EtOH)
see 3i w1
i-Pr
Ph
Ph
3f w3
3g w3
3h w3
3i w3
3j w3
4a w3
4i w1
4j w1
4j w2
-(CH2)4-
-(CH2)5-
-(CH2)6-
C6H4(CH2)2
C6H4(CH2)3
H
C6H4(CH2)2
C6H4(CH2)3
C6H4(CH2)3
278–279
308–310
365–367
>350
>350
Me
194–196
185–190/0.3
180–185/0.1
117–119
direct
direct
direct
direct
see 3j w1
see 3j w2
a Yield of isolated, purified products after recrystallization or distillation in vacuo.
b Lit.6 mp 165–166°C.
c Lit.24 3c w1: mp 172–173°C; 3d w1: mp 176–177°C; 3e w1: mp 174–175°C; 3f w1: mp 193–194°C.
Synthesis 1999, No. 7, 1169–1174 ISSN 0039-7881 © Thieme Stuttgart · New York

1172
F. Bondavalli et al.
PAPER
2(1H)-Pyridinones 3b,d–j w1, 3b,d–h,j w2 , 3d–j w3 and 4i,j w1,
4j w2, 4a w3; General Direct Procedure
Anal. Calcd for C18H15NO3S: C, 66.44; H, 4.65; N, 4.30. Found: C,
66.54; H, 4.61; N, 4.28.
The suitable cyanomethylene compound (22 mmol) was added to a
solution of enaminones 2a–j (20 mmol) in anhyd MeOH or EtOH
(10 mL). The mixture was stirred at r.t. or at reflux at different times
(Table), then the formed crude solid was filtered, washed thorough-
ly with anhyd Et2O and recrystallized (3b, d, i w1 from EtOAc; 3f–
h, j w1 from MeOH; 3b, d, f–h, j w2 from EtOH; 3d, f w3 from EtOH
and 3g–j w3 from EtOH/DMSO, (2:1). In the case of 2e, the final
reaction solution was evaporated under reduced pressure to give a
thick oily mixture of the desired compounds 3e and dimethyl am-
monium salts 6e. The pyridones 3e were isolated with difficulty and
in poor yield as solid residues after repeated washing and handling
with anhyd Et2O/EtOAc (3:1) at r.t. and recrystallized (3e w1 from
EtOAc; 3e w2 and 3e w3 from EtOH). In the case of 2a, the direct
procedure did not afford the desired 2-pyridones 3. Particularly,
when phenylsulfonylacetonitrile was used as the cyanomethylene
active compound 4a w3 was obtained which was filtered and puri-
fied by recrystallization from EtOAc. On the contrary, starting from
2i or 2j by reaction with methyl cyanoacetate or benzoylacetoni-
trile, respectively, an oily mixture of desired compounds 3 together
with opened derivatives 4 was obtained. This mixture was added to
Et2O (20 mL) and the derivatives 3i, j w1 and 3j w2 were isolated as
solids in poor yield, filtered and recrystallized as previously de-
scribed. The organic layer was dried and evaporated under reduced
pressure. The crude oily residues were purified by bulb-to-bulb dis-
tillation in vacuo (4i, j w1) or by final recrystallization from Et2O (4j
w2). Finally, the reaction between 2i and benzoylacetonitrile was
disappointing, since only an intractable tar was obtained.
1,5,6,7-Tetrahydro-3-phenylsulfonylcyclopenta[1,2-b]pyridin-
2-one (3e w3)
IR (KBr): n = 3200–2400, 1640, 1560 cm–1.
1H NMR (DMSO-d6): d = 1.80–2.30 (m, 2 H, 6-CH2), 2.50–3.00
(m, 4 H, 5,7-CH2), 7.50–7.80 (m, 3 H, 2 ArHm + ArHp), 7.90–8.20
(m, 2 H, ArHo), 8.29 (s, 1 H, 4-CH), 12.50 (br s, 1 H, NH, disap-
pears with D2O).
Anal. Calcd for C14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C,
61.00; H, 4.80; N, 5.21.
5,6-Dihydro-3-phenylsulfonylbenzo[h]quinolin-2(1H)-one (3i
w3)
IR (KBr): n = 3200–2700, 1648, 1558 cm–1.
1H NMR (DMSO-d6): d = 2.82 (near s, 4 H, 5,6-CH2), 7.30–8.20
(m, 9 H, Ar H), 8.34 (s, 1 H, 4-CH), 12.38 (br s, 1 H, NH, disappears
with D2O).
Anal. Calcd for C19H15NO3S: C, 67.64; H, 4.48; N, 4.15. Found: C,
67.37; H, 4.41; N, 4.10.
5-Dimethylamino-3-methyl-2-phenylsulfonyl-2,4-pentadieneni-
trile (4a w3)
IR (CHCl3): n = 2200, 1550 cm–1.
1H NMR (CDCl3): d = 2.29 (s, 3 H, CH3), 3.14, 3.26 [2 s, 6 H,
N(CH3)2], 5.41 (d, 1 H, J = 14 Hz, 4-CH), 7.65 (m, 3 H, 2 ArHm +
ArHp), 7.85 (d, 1 H, J = 14 Hz, 5-CH), 7.60–7.86 (m, 2 H, 2 ArHo).
Anal. Calcd for C14H16N2O2S: C, 60.85; H, 5.84; N, 10.14. Found:
C, 60.50; H, 6.16; N, 9.93.
1
IR and H NMR spectral data were fully consistent with the pro-
posed structures; only spectral and analytical data of 3i w1, 3d, e w2,
3d, e, i w3, 4a w3, 4i, j w1 and 4j w2 are described.
Methyl 1,2,3,4-tetrahydro-[2-(dimethylaminomethylene)-1-
naphthylidene]cyanoacetate (4i w1)
IR (CHCl3): n = 2218, 1708, 1546 cm–1.
Methyl 1,2,5,6-tetrahydro-2-oxo-3-benzo[h]quinoline carboxy-
late (3i w1)
1H NMR (CDCl3): d = 2.80–3.00 (m, 4 H, 5,6-CH2), 3.09 [s, 6 H,
N(CH3)2], 3.91 (s, 3 H, OCH3), 7.25–7.50 (m, 3 H, ArH), 7.82 (s, 1
H, =CHN), 8.25–8.35 (m, 1 H, ArH).
IR (KBr): n = 3200–3000, 1728, 1628, 1550 cm–1.
1H NMR (DMSO-d6): d = 2.82 (near s, 4 H, 5,6-CH2), 3.85 (s, 3 H,
OCH3), 7.30–7.60 (m, 3 H, ArH), 8.12 (m, 2 H, ArH + 4-CH), 11.80
(br s, 1 H, NH, disappears with D2O).
Anal. Calcd for C17H18N2O2: C, 73.32; H, 6.42; N, 9.92. Found: C,
73.11; H, 6.20; N, 9.96.
Anal. Calcd for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C,
70.51; H, 5.00; N, 5.60.
Methyl [6,7,8,9-tetrahydro-8-(dimethylaminomethylene)-5H-
benzocyclohepten-9-ylidene]cyanoacetate (4j w1)
IR (CHCl3): n = 1705, 1592, 1545 cm–1.
1H NMR (CDCl3): d = 2.18 (near qui 2 H, J = 6.6 Hz, 6-CH2), 2.40
(t, 2 H, J = 6.6 Hz, 7-CH2), 2.57 (t, 2 H, J = 6.6 Hz, 5-CH2), 3.07 [s,
6 H, N(CH3)2], 3.92 (s, 3 H, OCH3), 7.20–7.45 (m, 3 H, ArH), 7.75–
7.80 (m, 1 H, ArH), 7.82 (s, 1 H, =CHN).
3-Benzoyl-5-methyl-6-phenyl-2(1H)-pyridinone (3d w2)
IR (CHCl3): n = 3370, 1642, 1562 cm–1.
1H NMR (CDCl3): d = 2.13 (s, 3 H, CH3), 7.10–7.70 (m, 8 H, ArH),
7.75–8.10 (m, 3 H, ArH + 4-CH), 12.30 (br s, 1 H, NH, disappears
with D2O).
13C NMR (CDCl3): d = 29.34, 31.86, 33.46 (3 CH2), 41.62 (2 CH3),
52.48 (CH3), 110.05 (CN), 124.05 (C), 127.03 (CH), 129.12 (CH),
129.36 (CH), 140.45 (C), 140.64 (C), 141.37 (CH), 158.51 (C),
159.36 (C), 168.67 (CO).
Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
78.85; H, 5.23; N, 4.95.
3-Benzoyl-1,5,6,7-tetrahydro-2H-cyclopenta[1,2-b]pyridin-2-
one (3e w2)
IR (KBr): n = 3400, 3100–2500, 1638, 1562 cm–1.
Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C,
73.03; H, 6.87; N, 9.36.
1H NMR (DMSO-d6): d = 2.05 (qui, 2 H, J = 7.5 Hz, 6-CH2), 2.71
(t, 2 H, J = 7.5 Hz, 5-CH2), 2.83 (t, 2 H, J = 7.5 Hz, 7-CH2), 7.43–
7.78 (m, 6 H, ArH + 4-CH), 12.15 (br s, 1 H, NH, disappears with
D2O).
2-[6,7,8,9-Tetrahydro-8-(dimethylaminomethylene)-5H-benzo-
cyclohepten-9-ylidene]-2-benzoylacetonitrile (4j w2)
IR (CHCl3): n = 2225, 1640, 1590 cm–1.
1H NMR (CDCl3): d = 2.17 (near qui, 2 H, J = 6.8 Hz, 6-CH2), 2.39
(near t, 2 H, J = 6.8 Hz, 7-CH2), 2.60 (near t, 2 H, J = 6.8 Hz, 5-
CH2), 2.98 [s, 6 H, N(CH3)2], 7.20–7.65 (m, 3 H, ArH), 7.80–8.00
(m, 7 H, 6 ArH + =CHN).
Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C,
75.37; H, 5.65; N, 5.94.
5-Methyl-6-phenyl-3-phenylsulfonyl-2(1H)-pyridinone (3d w3)
IR (CHCl3): n = 3200–3000, 1650, 1552 cm–1.
1H NMR (CDCl3): d = 2.17 (s, 3 H, CH3), 7.00–7.90 (m, 10 H,
ArH), 8.37 (s, 1 H, 4-CH), 13.15 (br s, 1 H, NH, disappears with
D2O).
Anal. Calcd for C23H22N2O: C, 80.67; H, 6.47; N, 8.18. Found: C,
80.43; H, 6.67; N, 8.13.
Synthesis 1999, No. 7, 1169–1174 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of Functionalized 2-Pyridones
1173
Dimethyl Ammonium Salts of Enolate Anions 6e w1, 6e w2, 6e
w3; General Procedure
1H NMR (DMSO-d6): d = 1.90 (qui, 2 H, J = 8 Hz, 4-CH2), 2.55 (t,
2 H, J = 8 Hz, 3-CH2), 2.76 (t, 2 H, J = 8 Hz, 5-CH2), 3.74 (s, 3 H,
OCH3), 4.0–6.0 (very br s, 1 H, OH, disappears with D2O), 8.11 (s,
1 H, =CH).
As mentioned above, during the synthesis of pyridones 3e, the cor-
responding dimethylammonium salts 6e were obtained as main
products together with a small amount of the desired compounds.
Their isolation from thick crude oily residues of the reaction was re-
alized with a thorough washing and handling with anhyd Et2O/
EtOAc (3:1) at r.t. The organic layer was dried, filtered and evapo-
rated under reduced pressure: the solid residue was finally recrystal-
lized from EtOAc.
Anal. Calcd for C10H11NO3: C, 62.16; H, 5.74; N, 7.25. Found: C,
61.94; H, 5.77; N, 7.25.
2-Benzoyl-3-(2-oxocyclopentyl)propenenitrile (7e w2)
Yield: 1.94 g (81%); mp 128–130°C (dec).
IR (KBr): n = 3200–2300, 2215, 1665, 1560, 1175 cm–1.
1H NMR (DMSO-d6): d = 1.90 (qui, 2 H, J = 8 Hz, 4-CH2), 2.32 (t,
2 H, J = 8 Hz, 3-CH2), 2.92 (t, 2 H, J = 8 Hz, 5-CH2), 3.50–4.50
(very br s, 1 H, OH, disappears with D2O), 7.13 (near s, 1 H, =CH),
7.40–7.70 (m, 5 H, ArH).
Dimethylammonium salt of the enolate anion of methyl 2-cy-
ano-3-(2-oxocyclopentyl)propenoate (6e w1)
Yield: 3.53 g (74%); mp 109–111°C (dec).
IR (KBr): n = 3200–2300, 2185, 1675, 1585, 1500–1400 cm–1.
1H NMR (DMSO-d6): d = 1.71 (qui, 2 H, J = 7.4 Hz, 4-CH2), 1.99
(t, 2 H, J = 7.4 Hz, 5-CH2), 2.57 [s, 6 H, N(CH3)2], 2.72 (dt, 2 H, J
= 7.4, 1.7 Hz, 3-CH2), 3.51 (s, 3 H, OCH3), 7.36 (t, 1 H, J = 1.7 Hz,
=CH), 7.50–9.00 (very br s, 2 H, OH + NH, disappears with D2O).
Anal. Calcd for C15H13NO2: C, 75.29; H, 5.47; N, 5.85. Found: C,
74.63; H, 5.53; N, 5.96.
3-(2-Oxocyclopentyl)-2-phenylsulfonylpropenenitrile (7e w3)
Yield: 2.34 g (85%); mp 147–150°C (dec).
13C NMR (DMSO-d6): d = 20.09 (CH2), 27.08 (CH2), 34.65 (2
CH3), 37.80 (CH2), 50.20 (CH3), 63.99 (C), 112.04 (CN), 124.22
(C), 136.51 (CH), 169.29 (C), 201.29 (CO).
IR (KBr): n = 3300–2700, 2218, 1655, 1608, 1550 cm–1.
1H NMR not obtained owing its high instability in organic solvents.
Anal. Calcd for C14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C,
60.70; H, 4.77; N, 5.31.
Anal. Calcd for C12H18N2O3: C, 60.48; H, 7.61; N, 11.76. Found: C,
60.47; H, 7.61; N, 11.71.
Dimethylammonium salt of the enolate anion of 2-benzoyl-3-(2-
oxocyclopentyl)propenenitrile (6e w2)
Yield: 4.29 g (80%); mp 140–143°C (dec).
IR (KBr): n = 3200–2300, 2175, 1640, 1560, 1500–1400 cm–1.
1H NMR (DMSO-d6): d = 1.76 (qui, 2 H, J = 7.5 Hz, 4-CH2), 2.05
(t, 2 H, J = 7.5 Hz, 5-CH2), 2.55 [s, 6 H, N(CH3)2], 2.82 (dt, 2 H, J
= 7.5, 1.0 Hz, 3-CH2), 7.30–7.70 (m, 7 H, 5 ArH, and OH + NH,
which disappear with D2O).
Amides 5a w1, 5b w3, 5c w1, 5c w2, 5c w3; General Procedure
The proper cyanomethylene compound (11 mmol) was added to a
solution of enaminones 2a, 2b or 2c (10 mmol) in anhyd MeOH or
EtOH (20 mL). The mixture was refluxed for 24 h, then evaporated
under reduced pressure. The solid residue was added with Et2O/
EtOAc (1:1), filtered and recrystallized from a suitable solvent.
Methyl 2-carbamoyl-5-dimethylamino-2,4-hexadienoate (5a
w1)
Yield: 0.47 g (22%); mp 174–176°C (E+OAc).
IR (KBr): n = 3385, 3250–3100, 1655, 1635, 1520 cm–1.
1H NMR (DMSO-d6): d = 2.17, 2.21 (2 s, 3 H, CH3C), 3.11, 3.14
[2 s, 6 H, N(CH3)2], 3.64, 3.71 (2 s, 3 H, O CH3), 6.29, 6.93 (2 d, 1
H, J = 14, 12 Hz, 4-H trans, cis -form), 6.60, 6.76 (2 br s, 1 H, NH,
disappear with D2O), 7.90–8.00 (br s, 1 H, NH, disappears with
D2O), 7.99, 8.35 (2 d, 1 H, J = 12, 14 Hz, 3-H cis, trans -form).
13C NMR (DMSO-d6): d = 20.16 (CH2), 27.22 (CH2), 34.66 (2
CH3), 37.92 (CH2), 77.80 (C), 116.38 (CN), 127.80 (2 CH + C),
128.53 (C), 129.04 (2 CH), 129.29 (CH), 134.80 (CH), 142.58 (C),
203.39 (CO).
Anal. Calcd for C17H20N2O2: C, 71.80; H, 7.09; N, 9.85. Found: C,
71.67; H, 6.94; N, 9.53.
Dimethylammonium salt of the enolate anion of 3-(2-oxocyclo-
pentyl)-2-phenylsulfonylpropenenitrile (6e w3)
Yield: 5.25 g (82%); mp 116–118°C (dec).
Anal. Calcd for C10 H16N2O3: C, 56.60; H, 7.60; N, 13.20. Found:
C, 56.70; H, 7.73; N, 13.17.
IR (KBr): n = 3200–2300, 2175, 1642, 1588, 1500–1400 cm–1.
Methyl 2-carbamoyl-5-dimethylamino-5-phenyl-2,4-pentadi-
enoate (5c w1)
Yield: 1.73 g (63%); mp 195–197 °C (EtOAc).
IR (CHCl3): n = 3490, 3340, 1663, 1635, 1515 cm–1.
1H NMR (CDCl3): d = 2.70–3.30 [br s, 6 H, N(CH3)2], 3.48 (s, 3 H,
OCH3), 5.27 (br s, 1 H, NH, disappears with D2O), 7.15–7.27 (m, 2
H, 3,4 CH=), 7.38–7.50 (m, 5 H, ArH), 8.40 (br s, 1 H, NH, disap-
pears with D2O).
13C NMR (CDCl3): d = 42.00 (2 CH3), 51.49 (CH3), 101.79 (CH),
104.17 (C), 128.99 (CH), 129.20 (CH), 129.61 (CH), 129.67 (CH),
129.97 (CH), 134.75 (C), 155.52 (CH), 167.72 (enamine C), 168.96
(amide C=O), 169.83 (ester C=O). Only in 13C NMR spectrum a
smaller signal was present beside each signal, probably belonging
to a minor isomer.
1H NMR (DMSO-d6): d = 1.70 (qui, 2 H, J = 7.5 Hz, 4-CH2), 1.99
(t, 2 H, J = 7.5 Hz, 5-CH2), 2.56 [s, 6 H, N(CH3)2], 2.62 (dt, 2 H, J
= 7.4, 1.0 Hz, 3-CH2), 7.10 (near t, 1 H, J = 1.0 Hz, =CH), 7.50–7.60
(m, 3 H, 2 ArHm + ArHp), 7.65–7.75 (m, 2 H, 2 ArHo), 7.80–8.60
(very br s, 2 H, OH + NH, disappears with D2O).
13C NMR (DMSO-d6): d = 19.96 (CH2, 26.86 (CH2), 34.68 (2 CH3),
37.77 (CH2), 73.18 (C), 111.89 (CN), 121.70 (C), 125.34 (2CH),
129.26 (2CH), 131.33 (CH), 133.14 (CH), 146.33 (C), 201.45 (CO).
Anal. Calcd for C16H20N2O3S: C, 59.97; H, 6.29; N, 8.74. Found: C,
59.89; H, 6.29; N, 8.71.
Enol Forms 7e w1, 7e w2, 7e w3; General Procedure
A aq (20 mL) solution of the salts 6e (10 mmol) was carefully acid-
ified with AcOH at 0°C. The amorphous precipitate was filtered,
washed thoroughly with H2O, dried and purified with repeated
washings with anhyd Et2O.
Anal. Calcd for C15H18N2O3: C, 65.67; H, 6.61; N, 10.21. Found: C,
65.88; H, 6.81; N, 10.42.
2-Benzoyl-5-dimethylamino-5-phenyl-2,4-pentadienamide (5c
w2)
Yield: 1.83 g (57%); mp 224–226 °C (95% EtOH).
Methyl 2-cyano-3-(2-oxocyclopentyl)propenoate (7e w1)
Yield: 1.31 g (68%); mp 125–127 °C (dec).
IR (KBr): n = 3300–3000, 2218, 1722, 1610, 1544, 1215 cm–1.
IR (CHCl3): n = 3480, 3280, 1638, 1545, 1500 cm–1.
Synthesis 1999, No. 7, 1169–1174 ISSN 0039-7881 © Thieme Stuttgart · New York

1174
F. Bondavalli et al.
PAPER
1H NMR (CDCl3): d = 2.82, 3.25 [2 br s, 6 H, N(CH3)2], 5.38 (br s,
1 H, NH, disappears with D2O), 6.92 (d, 1 H, J = 13 Hz, 4-CH trans
form), 6.95–7.30 (m, 10 H, ArH), 7.39 (d, 1 H, J = 13 Hz, 3-CH
trans form), 9.08 (br s, 1 H, NH, disappears with D2O).
1H NMR (DMSO-d6): d = 6.80 (d, 1 H, J = 7 Hz, 5-H), 7.50–7.85
(m, 8 H, ArH), 7.90–8.15 (m, 2 H, ArH), 8.40 (d, 1 H, J = 7 Hz, 4-
CH), 12.60 (br s, 1 H, NH, disappears with D2O).
Anal. Calcd for C17H13NO3S: C, 65.58; H, 4.21; N, 4.50. Found: C,
65.71; H, 3.99; N, 4.44.
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C,
74.71; H, 6.26; N, 8.97.
Physical and spectral data of compound 3e are reported in the Table
6-Methyl-5-dimethylamino-2-phenylsulfonyl-2,4-heptadiena-
mide (5b w3)
and in the General Direct Procedure.
Yield: 0.26 g (8%); mp 176–178°C (EtOAc).
IR (CHCl3): n = 3500, 3370, 1640, 1530, 1380, 1140 cm–1.
Acknowledgement
We wish to thank Ministero Università e Ricerca Scientifica e Tec-
nologica and CNR (Roma) for the financial support.
1H NMR (CDCl3): d = 1.40 [d, 6 H, J = 7 Hz, (CH3)2CH], 2.97, 3.20
[2 s, 6 H, N(CH3)2], 2.80–3.80 [m, 1 H, (CH3)2CH], 6.63 (d, 1 H, J
= 13 Hz, 3-CH= trans form), 7.60 (m, 3 H, 2 ArHm + ArHp), 7.85
(m, 2 H, ArHo), 5.50 (br s, 1 H, NH, disappears with D2O), 8.30 (d,
1 H, J = 13 Hz, 4-CH = trans form), 8.50 (br s, 1 H, NH, disappears
with D2O).
References
(1) Farah, A.E.; Alousi, A.A. Life Sci. 1978, 22, 1139.
(2) Alousi, A.A.; Canter, J.M.; Montenaro, M.J.; Fort, D.J.;
Ferrari, R. A. J. Cardiovasc. Pharmacol. 1983, 5, 792.
(3) Mosti, L.; Schenone, P.; Menozzi, G. J. Heterocycl. Chem.
1985, 22, 1503.
(4) Dorigo, P.; Gaion, R.M.; Belluco, P.; Fraccarollo, D.;
Maragno, I.; Bombieri, G.; Benetollo, F.; Mosti, L.; Orsini, F.
J. Med. Chem. 1993, 36, 2475.
Anal. Calcd for C16H22N2O3S: C, 59.60; H, 6.88; N, 8.69. Found: C,
59.66; H, 6.89; N, 8.67.
5-Dimethylamino-5-phenyl-2-phenylsulfonyl-2,4-pentadiena-
mide (5c w3)
Yield: 2.64 g (74%); mp 232–234°C (95% EtOH).
IR (CHCl3): n = 3500, 3370, 1642, 1580, 1525 cm–1.
(5) Bellassoued-Fargeau, M.C.; Graffe, B.; Sacquet, M.C.;
Maitte, P. J. Heterocycl. Chem. 1985, 22, 713.
(6) Krasnaya, Zh.A.; Stytsenko, T.S.; Prokofev, E.P.; Kucherov,
V.F. Izv. Akad. Nauk. SSSR, Ser. Khim., 1973, 11, 2543;
Chem. Abstr. 1974, 80, 59832.
1H NMR (CDCl3): d = 2.85, 3.20 [2 br s, 6 H, N(CH3)2], 5.25 (br s,
1 H, NH, disappears with D2O), 6.93 (d, 1 H, J = 13 Hz, 4-CH=
trans form), 7.20–7.80 (m, 12 H, 10 ArH +3-CH=, and NH which
disappears with D2O).
Anal. Calcd for C19H20N2O3S: C, 64.02; H, 5.65; N, 7.86. Found: C,
64.30; H, 5.60; N, 7.92.
(7) Boggia, R.; Forina, M.; Fossa, P.; Mosti, L. Quant. Struct.-
Act. Relat. 1997, 16, 201.
(8) Fossa, P.; Boggia, R.; Mosti, L. J. Comput.-Aided Mol. Design
1998, 12, 1.
(9) Benary, E. Ber.Dtsch. Chem. Ges. 1930, 63, 1573.
(10) Bargagna, A.; Cafaggi, S.; Schenone, P. J. Heterocycl. Chem.
1980, 17, 507.
(11) Lienhard, U.; Fahrni, H.P.; Nevenschwander, M. Helv. Chim.
Acta 1978, 61, 1609, and references cited therein.
(12) Smith, L.I.; Engelhardt, V.A. J. Am. Chem. Soc. 1949, 71,
2671.
(13) Jutz, C.; Löbering, H.G.; Trinkl, K.H. Synthesis 1977, 326.
(14) Dabrowski, J.; Kamienska-Trela, K. Spectrochim. Acta 1966,
22 (2), 211.
(15) Minardi, G.; Schenone, P.; Bignardi, G. Ann. Chim. 1968, 58,
1320.
(16) Schenone, P.; Mosti, L.; Bignardi, G.; Tasca, A. Ann. Chim.
1974, 64, 603.
(17) Bargagna, A.; Longobardi, M.; Mariani, E.; Schenone, P.;
Cenicola, M.L.; Losasso, C.; Carnevale, M.; Marmo, E. Il
Farmaco 1991, 46, 461.
(18) Bredereck, H.; Effenberger, F.; Botsch, H. Chem. Ber. 1964,
97, 3397.
2(1H)-Pyridinones 3a, c, e w1, 3c, e w2 and 3b, c, e w3; Procedure
via Amide or Enolate Intermediates
A solution of 5 or 6 (10 mmol) and glacial AcOH (10 mmol, 0.6 g)
in anhyd toluene (250 mL) was refluxed in a Dean–Stark appparatus
for 12 h in the case of ammonium salts and 48 h in the case of
amides. The mixture was washed with 1 M aq NaOH solution and
H2O, dried and evaporated under reduced pressure. The residue was
recrystallized (3a, c w1 from EtOAc; 3c w2, 3b w3 from EtOH; 3c
w3 from EtOH/DMSO, 2:1; for 3e derivatives the crystallization
solvents have already been described).
3-Benzoyl-6-phenyl-2(1H)-pyridinone ( 3c w2)
IR (KBr): n = 3410, 1645 cm–1.
1H NMR (DMSO-d6): d = 6.82 (d, 1 H, J = 6 Hz, 5-H), 7.45–7.95
(m, 11 H, 10 ArH + 4-CH), 12.28 (br s, 1 H, NH, disappears with
D2O).
Anal. Calcd for C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C,
78.57; H, 4.55; N, 5.04.
6-Isopropyl-3-phenylsulfonyl-2(1H)-pyridinone (3b w3)
IR (KBr): n = 3200–2500, 1628, 1547 cm–1.
(19) Wasserman, H.H.; Ives, J.L. J. Org. Chem. 1985, 50, 3573.
(20) Shuda, P.F.; Ebner, C.B.; Morgan, T.M. Tetrahedron Lett.
1986, 27, 2567, and references cited therein.
(21) Wagner, R.M.; Jutz, C. Chem. Ber. 1971, 104, 2975.
(22) Wahren, M. Z. Chem. 1969, 241.
(23) Otto, H.H.; Schmelz, H. Arch. Pharm. 1982, 315, 526.
(24) Ito, K.; Yokokura, S.; Miyajima, S. J. Heterocycl. Chem.
1989, 26, 773.
1H NMR (DMSO-d6): d = 1.16 [d, 6 H, J=7 Hz, (CH3)2CH], 2.80
[sept, 1 H, J = 7 Hz, (CH3)2CH], 6.35 (d, 1 H, J = 7.7 Hz, 5-H),
7.53–7.74 (m, 3 H, 2 ArHm + ArHp), 7.92–7.99 (m, 2 H, 2 ArHo),
8.27 (d, 1 H, J = 7.7 Hz, 4-CH), 12.27 (near s, 1 H, NH, disappears
with D2O).
Anal. Calcd for C14H15NO3S: C, 60.63; H, 5.45; N, 5.05. Found: C,
60.42; H, 5.42; N, 5.05.
(25) Unpublished results.
6-Phenyl-3-phenylsulfonyl-2(1H)-pyridinone (3c w3)
IR (KBr): n = 3420, 1650, 1312, 1155 cm–1.
Article Identifier:
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Synthesis 1999, No. 7, 1169–1174 ISSN 0039-7881 © Thieme Stuttgart · New York