Regioselective synthesis of 2(1H)-pyridinones from β-aminoenones and malononitrile. Reaction mechanism

Article abstract of DOI:10.1021/jo991121o

The identification of some intermediates of the reactions between β- aminoenones and malononitrile to give 2(1H)-pyridinones has allowed us to obtain valuable information concerning its mechanism. These reactions begin with a conjugated addition of the nitrile to the enone followed by elimination. The compounds thus obtained cyclize to nonisolable 2H-pyran-2- imine. This afforded 2(1H)-pyridinones by ring opening to unsaturated aminoamides followed by cyclization (Dimroth-type rearrangement).

Full text of DOI:10.1021/jo991121o

J . Org. Chem. 1999, 64, 9493-9498
9493
Regioselective Syn th esis of 2(1H)-P yr id in on es fr om
â-Am in oen on es a n d Ma lon on itr ile. Rea ction Mech a n ism
Angel Alberola, Luis A. Calvo, Alfonso Gonza´lez Ortega, M. Carmen San˜udo Ru´ız,* and
Pedro Yustos
Departamento de Quı´mica Orga´nica, Universidad de Valladolid, Valladolid, Spain
Santiago Garc´ıa Granda and Esther Garc´ıa-Rodriguez
Departamento de Quı´mica Fı´sica y Analı´tica, Universidad de Oviedo, Oviedo, Spain
Received J uly 13, 1999
The identification of some intermediates of the reactions between â-aminoenones and malononitrile
to give 2(1H)-pyridinones has allowed us to obtain valuable information concerning its mechanism.
These reactions begin with a conjugated addition of the nitrile to the enone followed by elimination.
The compounds thus obtained cyclize to nonisolable 2H-pyran-2-imine. This afforded 2(1H)-
pyridinones by ring opening to unsaturated aminoamides followed by cyclization (Dimroth-type
rearrangement).
Sch em e 1
In tr od u ction
The reactions of â-dicarbonyl compounds or â-func-
tionalized R,â-unsaturated ketones with malononitrile
and related compounds have been described as a syn-
thetic method of 2(1H)-pyridinones.1-9 While the reaction
mechanism with cyanacetamide seems to be firmly
established,9-13 the process by which malononitrile acts
as a nucleophilic agent has been interpreted in according
to different hypothetical mechanisms.3,5,7,14-17
In this paper, we have investigated the reaction
pathway to 2(1H)-pyridinones from â-aminoenones and
malononitrile, using the identification of their intermedi-
ates as a basic methodology.
Resu lts a n d Discu ssion
Ta ble 1. Syn th esis of 3-Cya n o-2(1H)-p yr id in on es:
Research has been carried out with â-aminoenones
1a -g, 2a ,g,and 3a , whose reactions with malononitrile
(Scheme 1) afforded the results summarized in Table 1.
Rea ction Con d ition s
â-aminoenone
solvent
time (h) T (°C) pyridinonea (%)
1a
1b
1c
1d
1e
1f
1g
2a
2g
3a
THF
THF
2
72
70
24
24
120
120
2
120
1
65
20
80
20
80
80
80
65
80
65
4a (90)
4b (80)
4c (90)
4d (70)
4e (35)b,c
4f (70)d
4g (76)d
4a (90)
4g (65)d
4a (90)
(1) Bergmann, E. D.; Ginsburg, D.; Pappo, R. In Organic Reactions;
Adams, R., Ed.; J . Wiley and Sons: New York, 1967; Vol. 10, pp 258-
261.
EtOH
EtOH
EtOH
EtOH
EtOH
THF
(2) McKillop, A.; Boulton, A. In Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: New York,
1984; Vol. 2, pp 460-463.
(3) Freeman, F. Chem. Rev. 1969, 5, 591.
(4) Rastogi, R. R.; Kumar, A.; Ila, H.; J unjappa, H. J . Chem. Soc.,
Perkins Trans. 1 1978, 6, 549.
(5) Otto, H. H.; Schmelz, H. Arch. Pharm. 1982, 315, 526.
(6) Aggarwal, V.; Singh, G.; Ila, H.; J unjappa, H. Synthesis 1982,
214.
(7) Alberola, A.; Andre´s, C.; Gonza´lez-Ortega, A.; Pedrosa, R.;
Vicente, M. J . Heterocycl. Chem. 1987, 24, 709.
(8) Purkayastha, M. L.; Bhat, L.; Ila, H.; J unjappa, H. Synthesis
1995, 641.
(9) Krstic, V.; Misic-Vukovic, M.; Radojkovic-Velickovic, M. J . Chem.
Res., Synop. 1991, 82.
EtOH
THF
a
b
Isolated yield. Basic catalysis (NH4OH/Py) is necessary for
reaction to be produced. c Other isolated products: 2-amino-6-
tert-butyl-4-methylpyridine-3-carbonitrile 13 (38%) and 2-amino-
4-tert-butyl-6-methyl-1,3-benzenedicarbonitrile 14 (14%). See
Scheme 5.
d
The processes are highly regioselective, and each â-ami-
noenone regioisomer leads to its corresponding 2(1H)-
pyridinone (1b f 4b, 1c f 4c, 1d f 4d , 1e f 4e).
The reaction rate between â-aminoenones and malono-
nitrile depends on the nature of R1, R2, and L substitu-
ents and experimental conditions. Control of these factors
has allowed us to reduce the rate of some of the steps
and to identify the respective intermediates by spectro-
(10) Bardhan, J . C. J . Chem. Soc. 1930, 1509.
(11) Basu, U. J . Indian Chem. Soc. 1930, 7, 481.
(12) Dornow, A. Ber. 1940, 73, 153.
(13) Fanta, P. E.; Stein, R. A. J . Am. Chem. Soc. 1955, 77, 1045.
(14) Basu, U. J . Indian Chem. Soc. 1930, 7, 815.
(15) Dornow, A.; Neuse, E. Arch. Pharm. 1955, 288, 174.
(16) Ivanov, I. C.; Karagiosov, S. K.; Simeonov, M. F. Liebigs Ann.
Chem. 1992, 203.
(17) Al-Omran, F.; Al-Awadhi, N.; Khalik, M. M. A.; Kaul, K.; El-
Khair, A. A.; Elnagdi, M. H. J . Chem. Res., Synop. 1997, 84.
10.1021/jo991121o CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/03/1999

9494 J . Org. Chem., Vol. 64, No. 26, 1999
Alberola et al.
Sch em e 2
°C. When room temperature was reached, 7a was trans-
formed into the final 2(1H)-pyridinone (4a ), with release
of pyrrolidine. The comparative study of the evolution of
1
7a by H NMR (previously isolated) and, on the other
hand, of the reaction of 2a with malononitrile allowed
us to deduce that 5a is an intermediate prior to 7a in
1
the sequence (Scheme 3). The H NMR spectral study of
the reaction mixture also allowed us to confirm that the
transformation of 7 into pyridinone is fast when R2 is
different from H and, consequently, that the concentra-
tion of the said intermediate in the reaction mixture is
small. On the other hand, the conversion rate of 7 into 4
decreases with the volume of R1.
The average life of the intermediate 2H-pyran-2-imine
6 must be very low. In the literature, we found described
only those whose 2H-pyran-2-imine rings are stable to
nucleophilic attack because they are integrated in con-
densated polycyclic systems.5,21-24
The rapid evolution of 6 prevented us from directly
proving its presence in the reaction system. However,
some complementary transformations carried out with
â-aminoenones and their derivatives provide indirect
proof of its existence:
(a) The reactions of 1f and 1g with malononitrile in
excess yield type 8 compounds (Scheme 5), which afforded
4f,g, by treatment with aqueous hydrochloric acid with
release of malononitrile. The structure of 8f was con-
firmed by X-ray diffraction.
scopic means in the reaction mixture or by prior isola-
tion.
Monitoring of the reactions by H NMR indicates that
1
the process begins with a conjugated addition-elimina-
tion of the malonic dinitrile to the â-aminoenone to give
the intermediate 5 (Scheme 2), whose concentration in
the reaction mixture can reach values of between 30%
and 90%, according to the nature of R1, R2, and L. The
variations in the concentrations of the â-aminoenone (1),
the intermediate 5, and the final 2(1H)-pyridinone (4)
have been determined according to the intensity of the
signals due to their olefinic protons, which were recorded
at δ ) 4.87-5.12 (for 1-3), 5.43-5.59 (for 5), and 6.00-
6.21 (for 4).
The formation and disappearance rates of 5 depend on
the size of the R2 substituent: the more bulky this is,
the more slowly the intermediate is produced and the
more quickly it is transformed. In the case of the
â-aminoenone1g, in which R2 ) H, the lifetime of 5g
allows its complete identification by means of its 1H NMR
and 13C NMR spectra, which coincide with those of
sodium salt 9 (Table 2), obtained and isolated from the
reaction of the â-aminoenones 1g or 2g with malononi-
trile and sodium ethoxide in toluene.18
To establish the nature of the following steps of the
process by which 1-3 gives rise to 2(1H)-pyridinones (4),
we should point out that the transformations can be
carried out in dry THF or other inert water-free solvents.
This provides evidence that the oxygen atom at C-5
proceeds from the carbonyl group of the â-aminoenones
and is not produced during the process by any external
reagent. Consequently, 5 should be transformed by
means of the reactions that involve a change of position
of the initially ketonic oxygen and its integration in the
amide group present in the pyridinone.This would be
possible by the conversion of 5 in a 2H-pyran-2-imine
intermediate 6 (Scheme 3), whose opening by action of a
nucleophile (for example, that proceeding from the ni-
trogenate leaving group) would afford 7, and this would
give the 2(1H)-pyridinone (4) by cyclization.9-13
The transformation of 6 in 4 via 7 may be considered
a Dimroth-type rearrangement.19,20 When R2 ) H, 7g
(Scheme 4) may be isolated from the reaction mixture,
as a stable solid, whose structure was confirmed by X-ray
diffraction. The 1H NMR and 13C NMR spectra of 7g
coincided with those attributed to the other intermediates
7 in the monitoring of the reactions.
(b) The reactions of 9 with ethanol or ethanethiol, in
the presence of pyridinium 4-toluenesulfonate, yield 10
and 11, respectively (Scheme 6), transformable in the
pyridinone 4g by treatment with aqueous hydrochloric
acid.
The reaction mechanism proposed (Scheme 3) supposes
the existence of an easily reversible equilibrium between
the geometric isomers Z and E of 7 with respect to the
double bond C2-C3. The opening of the iminopyrone 6
must lead to (2Z)-7, but the configuration of the inter-
mediates 7, isolated and identified by X-ray, is 2E. On
the other hand, the formation of 4 starting from 7
demands that the last process of the conjugated addi-
tion-elimination takes place in the isomer (2Z)-7.
It has been described that those conjugated polyenes
that possess one donor group and one electron-attracting
group at their extremes (push-pull compounds) are
easily isomerized.25-29 This is due to the low energy
barrier between their configurations Z and E, which
allows an equilibrium between the isomers. The equilib-
rium is not shown in solutions of 7f,g (R2 ) H) but is
apparent in 7a (R2 ) Me) and its analogue 12 (Scheme
(21) Sakurai, A.; Motomura, Y.; Midorikawa, H. J . Org. Chem. 1972,
37, 1523.
(22) Reynolds, G. A.; Van Allan, J . A.; Petropoulos, C. C. J .
Heterocycl. Chem. 1970, 1061.
(23) O’Callagham, C. N.; Brian, T.; McMurry, H.; O’Brien, J . D.;
Draper, S. M.; Gormley, F. K. J . Chem. Res., Synop. 1997, 50.
(24) Darbarwar, M.; Sundaramurty V. Synthesis 1982, 368.
(25) Peseke, K.; Zahn, K.; Michalik, M. J . Prakt. Chem. 1994, 336,
357.
(26) Prokof’ev, E. P.; Krasnaya, Zh. A.; Kucherov, V. F. Org. Magn.
Reson. 1974, 6, 240.
(27) Sandstro¨m, J . In Topics in Stereochemistry: “Static and
Dynamic Stereochemistry of Push-Pull and Strained Ethylenes”;
Allinger, N. L., Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, 1983;
pp 83-181.
(28) Eberlin, M. N.; Takahata, Y.; Kascheres, C. THEOCHEM 1990,
207, 143.
Compound 7a (Scheme 4) was also obtained as the
major product from 2a and malononitrile in THF at -10
(18) Bellasoued-Fargeau, M. C.; Graffe, B.; Sacquet, M. C.; Maitte,
P. J . Heterocycl. Chem. 1985, 22, 713.
(19) Brown, D. J . In Mechanisms of Molecular Migrations; Thya-
garajan, B. S., Ed.; Wiley-Interscience: New York, 1968; Vol. 1, p 209.
(20) Wahren, M. Z. Chem. 1969, 9, 241.
(29) Kleinpeter, E.; Heydenreich, M.; Woller, J .; Wolf, G.; Koch, A.;
Kempter, G.; Pihlaja, K. J . Chem. Soc., Perkin Trans. 2 1998, 1877.

2(1H)-Pyridinones from â-Aminoenones and Malononitrile
J . Org. Chem., Vol. 64, No. 26, 1999 9495
Ta ble 2. Sign ifica n t Da ta for Com p ou n d s 9 a n d for Som e Typ e 5 In ter m ed ia tes
1H NMR δ (multiplicity, J , Hz)
13C NMR δ
compd
Ha
R2
C-1
C-2
C-3
C-4
C-5
C-6
5a
5.53 (s)
5.59 (s)
5.43 (d, 14.0)
5.43 (d, 14.0)
5.44 (d, 14.1)
2.22 (s)
2.35 (s)
7.19 (d, 14.1)
7.20 (d, 14.0)
7.19 (d, 14.1)
190.8
182.3
198.0
198.0
197.9
102.5
101.6
104.1
104.0
104.1
167.1
174.8
147.1
147.1
147.2
159.5
140.7
112.3
112.2
109.6
121.3
121.2
120.7
120.8
120.7
122.6
123.2
123.3
123.3
123.3
5b
5ga
5gb
9
a
b
From 1g. From 2g.
Sch em e 3
Sch em e 5
Sch em e 4
Sch em e 6
4), which was obtained in the reaction of 1f with ethyl
cyanoacetate. The NMR spectra of 12, starting from
single crystalline compounds (by X-ray), gave duplicated
signals.
Ch a r a cter iza tion of Rea ction In ter m ed ia tes. In
this section, we give a structural description of interme-
diates and an outline of the methodology used for the
structural assignment, especially for those intermediates
that have only been detected by spectroscopy and not
isolated as pure substances.
mediates, when R2 * H, have spectra referable to the
previous ones.
The IR spectrum (KBr) of 9 indicates an important
conjugation in all the molecules. It does not register the
Typ e 5 In ter m ed ia tes. Type 5 intermediates are an
example of those that have not been isolated. Their
structural assignment takes sodium salt 9 (R2 ) H) as a
reference. It is a stable, yellow solid with a melting point
of over 330 °C, soluble in water and insoluble in toluene
and diethyl ether. Its ionic mass spectrum, recorded on
a VG platform (Micromass Instrument) with electrospray
typical vibrations of enones at 1690-1630 cm-1(νCdO
)
although it does show a broad, intense signal at 1500
cm-1. On the other hand, the cyano groups, which
undoubtedly contribute to the great stability of the anion,
show four bands at frequencies characteristic of conju-
gated nitriles: 2207 (s), 2197 (s), 2180 (w), and 2166 cm-1
(m-w).
1
ionization interphase, indicates a M - 1 ) 161. Its H
NMR 13C NMR spectra practically coincide with those of
Typ e 7 In ter m ed ia tes. The stability of these inter-
the intermediate 5g (Table 2). The other type 5 inter-
mediates, when R2 ) H, allows them to be isolated as

9496 J . Org. Chem., Vol. 64, No. 26, 1999
Alberola et al.
F igu r e 1.
F igu r e 3.
Sch em e 7
superimposition of those corresponding to 8f (or 8g) and
to 4-hydroxy-4-methyl-2-pentanone.
Exp er im en ta l Section
Melting points are uncorrected. NMR spectra were recorded
at 300.1 (1H) and 75.0 MHz (13C). The chemical shifts are
reported as δ (ppm) referenced to the following: TMS as the
internal standard, for experiments in DMSO-d6 and CDCl3.
Definitive assignments of individual13C resonance were sup-
ported by DEPT experiments. Mass spectra were recorded at
an ionizing voltage of 70 eV by EI. All reactions were
monitored by TLC, which was performed on precoated sheets
of silica gel 60 F254, and flash column chromatography was
done in silica gel 60 (0.040-0.063 mm). Eluting solvents are
indicated in the text. THF was distilled from sodium-
benzophenone ketyl under argon, and toluene was distilled
from sodium under argon. The starting compounds 1b-e were
prepared by catalytic hydrogenation30,31 of isoxazoles, and
these were regioselectively prepared by the procedure of Nitz
et al.32 from oximes and N-methoxy-N-methylalkylamides. The
compounds 1-3a , 1f, 1g, and 2g have also been reported
previously.33
Gen er a l p r oced u r es for th e syn th esis of 2(1H)-p yr i-
d in on es. Meth od A. To a solution of 10 mmol of â-ami-
noenone (1-3) in 10 mL of dry THF was added 10 mmol of
malononitrile. The temperature for each reaction is indicated
in Table 1. The reaction was monitored by TLC until the
disappearance of starting materials. The pyridinone was
precipitated from the reaction mixture by cooling, and the solid
was separated by filtration and recrystallized from ethanol.
Meth od B. To a solution of 10 mmol of â-aminoenone in 10
mL of ethanol was added 10 mmol of malononitrile. The
temperature for each reaction is indicated in Table 1. The
reaction was monitored by TLC until the disappearance of
F igu r e 2.
stable solid compounds. The structure of these intermedi-
ates was established by X-ray diffraction of 7g (Figure
1). This compound is a yellow solid with a melting point
of 236-237 °C, soluble in acetone and ethanol and
insoluble in diethyl ether.
1H NMR and 13C NMR spectra of intermediate 7g
indicate a single compound coinciding with the configu-
ration 2E,4E of the solid state.
Other intermediates of the same type (when R2 ) H),
which are single compounds in a solid state, present in
solution (CDCl3) two structures in equilibrium. This
happens, for example, to ethyl 2-carbamoyl-5-(1-pyrro-
lidinyl)-2,4-heptadienate (12), which presents a 2E,4E
configuration in the solid state (X-ray, Figure 2) but is
seen in dissolution in equilibrium with the 2Z,4E isomer.
When R2 is different from H, the intermediates 7 are
less stable. They appear in low concentrations, and only
the intermediate 7a (R1 ) R2 ) Me) could be isolated as
an unstable solid. It also appears in dissolution as two
compounds in equilibrium: 2Z,4E and 2E,4E (push-pull
effect).
Typ e 8 In ter m ed ia tes. The unequivocal assignment
of this compound was carried out by X-ray diffraction of
8f2 (Figure 3). This is a cocrystallization adduct with a
molecule of 4-hydroxy-4-methyl-2-pentanone and was
obtained from the recrystallization of 8f in acetone
(Scheme 7). The NMR spectra of 8f2 (or 8g2) are a
(30) Lue, P.; Greenhill, J . Adv. Heterocycl. Chem. 1997, 67, 215.
(31) Kashima, C.; Tebe, S.; Sugiyama, N.; Yamamoto M. Bull. Chem.
Soc. J pn. 1973, 46, 310.
(32) Nitz, T. J .; Volkots, D. L.; Aldous, D. J .; Oglesby, R. C. J . Org.
Chem. 1994, 59, 5828.
(33) Greenhill, J . V. Chem Soc. Rev. 1977, 6, 277.

2(1H)-Pyridinones from â-Aminoenones and Malononitrile
J . Org. Chem., Vol. 64, No. 26, 1999 9497
starting materials. The solvent was evaporated in vacuo, and
the crude product was purified by flash chromatography (CH2-
Cl2/diethyl ether, 5:2).
Meth od C. A mixture of â-aminoenone (10 mmol), malono-
nitrile (10 mmol), pyridine (11 mmol), and 25% aqueous NH3
(1.7 mL) in 10 mL of ethanol was refluxed until TLC showed
the disappearance of starting materials and the pyridinone
was precipitated. The solid was separated by filtration and
recrystallized from ethanol.
malononitrile (10 mmol) in 10 mL of ethanol was refluxed until
TLC showed the disappearance of starting materials. The
intermediate 7f was precipitated from the reaction mixture
by cooling. The solid was separated by filtration and recrystal-
1
lized from ethanol: 59%; mp 225-226 °C; H NMR (DMSO-
d6) δ 1.08-1.12 (t, J ) 7.5 Hz, 3H), 1.88-1.96 (m, 4H), 2.59-
2.66 (q, J ) 7.5 Hz, 2H), 3.30-3.36 (m, 2H), 3.46-3.61 (m,
2H), 5.17-5.22 (d, J ) 13.0 Hz, 1H), 6.88 (s, 2H), 7.88-7.92
(d, J ) 13.0 Hz, 1H); 13C NMR (DMSO-d6) δ 13.3, 22.8, 24.3,
24.8, 48.5, 48.7, 85.9, 94.5, 119.5, 149.2, 165.0, 166.0; MS m/z
(rel intensity) 219 (M+, 8), 175 (20), 44 (100). Anal. Calcd for
C12H17N3O: C, 65.73; H, 7.81; N, 19.16. Found: C, 65.84; H,
7.79; N, 19.10.
3-Cya n o-4,6-d im eth yl-2(1H)-p yr id in on e (4a ) (method
1
A): 90%; mp 291-92 °C; H NMR (DMSO-d6) δ 2.23 (s, 3H),
2.31 (s, 3H), 6.13 (s, 1H), 11.89 (s, 1H); 13C NMR (DMSO-d6)
δ 18.8, 20.6, 99.3, 107.3, 115.9, 150.9, 160.2, 160.9; MS m/z
(rel intensity) 148 (M+, 77), 119 (100). Anal. Calcd for
C8H8N2O: C, 64.72; H, 5.46; N, 18.97. Found: C, 64.85; H,
5.44; N, 18.91.
2-Cya n o-6-m et h yl-5-(1-p yr r olid in yl)-2,4-h ep t a d ien a -
m id e (7g). By a procedure analogous to the previous one,
starting from 2g, 7g was obtained: 61%; mp 236-237 °C; 1H
NMR (DMSO-d6) δ 1.24-1.27 (d, J ) 7.1 Hz, 6H), 1.88-1.93
(m, 4H), 3.25-3.29 (m, 1H), 3.43-3.48 (m, 4H), 5.19-5.23 (d,
J ) 13.4 Hz, 1H), 6.63 (s, 2H), 8.08-8.13 (d, J ) 13.4 Hz, 1H);
13C NMR (DMSO-d6 + CDCl3) δ 20.5, 24.3, 29.9, 49.7, 85.7,
94.4, 118.8, 149.9, 165.4, 167.8; MS m/z (rel intensity) 233 (M+,
34), 44 (100). Anal. Calcd for C13H19N3O: C, 66.92; H, 8.21;
N, 18.01. Found: C, 66.97; H, 8.22; N, 17.94.
3-Cya n o-6-isop r op yl-4-m eth yl-2(1H)-p yr id in on e (4b)
(method A): 80%; mp 221-222 °C; 1H NMR (DMSO-d6) δ
1.21-1.23 (d, J ) 7.6 Hz, 6H), 2.36 (s, 3H), 2.81 (m, 1H), 6.09
(s, 1H), 12.25 (s, 1H); 13C NMR (DMSO-d6) δ 20.9, 21.0, 31.8,
100.2, 104.0, 115.0, 159.9, 160.3, 161.4; MS m/z (rel intensity)
176 (M+, 31), 161 (100). Anal. Calcd for C10H12N2O: C, 68.16;
H, 6.86; N, 15.90. Found: C, 68.07; H, 6.86; N, 15.95.
3-Cya n o-4-isop r op yl-6-m et h yl-2(1H )-p yr id in on e (4c)
(method B): 90%; mp 285-86 °C; 1H NMR (DMSO-d6) δ 1.23-
1.25 (d, J ) 7.6 Hz, 6H), 2.31 (s, 3H), 3.11-3.20 (m, J ) 7.6
Hz, 1H), 6.06 (s, 1H), 12.36 (s, 1H); 13C NMR (DMSO-d6) 19.4,
21.6, 33.0, 98.7, 103.1, 115.4, 151.2, 161.5, 169.6; MS m/z (rel
intensity) 176 (M+, 100), 161 (80). Anal. Calcd for C10H12N2O:
C, 68.16; H, 6.86; N, 15.90. Found: C, 68.04; H, 6.89, N, 15.97.
6-ter t-Bu t yl-3-cya n o-4-m et h yl-2(1H )-p yr id in on e (4d )
(method B): 70%; mp 285-286 °C; 1H NMR (DMSO-d6) δ 1.23
(s, 9H), 2.32 (s, 3H), 6.20 (s, 1H), 12.0 (s, 1H); 13C NMR
(DMSO-d6) δ 21.1, 28.3, 35.4, 100.2, 103.9, 116.1, 160.9, 161.5,
161.6; MS m/z (rel intensity) 190 (M+, 24), 175 (100). Anal.
Calcd for C11H14N2O: C, 69.45; H, 7.42; N, 14.72. Found: C,
69.43; H, 7.40; N, 14.74.
4-ter t-Bu t yl-3-cya n o-6-m et h yl-2(1H )-p yr id in on e (4e)
(method C): 35%; mp 247-248 °C; 1H NMR (DMSO-d6) δ 1.38
(s, 9H), 2.4 (s, 3H), 6.1 (s, 1H), 12.50 (s, 1H); 13C NMR (DMSO-
d6) δ 21.5, 28.6, 35.6, 101.1, 104.8, 115.1, 160.7, 161.7, 163.0;
MS m/z (rel intensity) 190 (M+, 19), 175 (100).; Anal. Calcd
for C11H14N2O: C, 69.45; H, 7.42; N, 14.72. Found: C, 69.48;
H, 7.44; N, 14.70.
3-Cya n o-6-eth yl-2(1H)-p yr id in on e (4f) (method C): 38%;
mp 255-256 °C; 1H NMR (CDCl3) δ 1.25-1.28 (t, J ) 7.6 Hz,
3H), 2.57-2.65 (q, J ) 7.6 Hz, 2H), 6.09-6.12 (d, J ) 7.4 Hz,
1H), 7.77-7.79 (d, J ) 7.4 Hz, 1H), 12.55 (s, 1H); 13C NMR
(CDCl3 + DMSO-d6) δ 12.5, 26.6, 101.2, 103.5, 116.3, 148.2,
158.4, 161.7; MS m/z (rel intensity) 148 (M+, 64), 147 (100).
Anal. Calcd for C8H8N2O: C, 64.85; H, 5.44; N, 18.91. Found:
C, 64.74; H, 5.46, N, 18.96.
5-Eth yl-2,6,6-tr icya n o-2,4-h exa d ien a m id e Am m on iu m
Sa lt (8f). A mixture of â-aminoenone 1f (10 mmol) and
malononitrile (20 mmol) in 10 mL of ethanol was refluxed until
TLC showed the disappearance of starting materials. 8f was
precipitated from the reaction mixture by cooling, and the
yellow solid was separated by filtration and recrystallized from
1
ethanol: 50%; mp 195-196 °C; H NMR (DMSO-d6) δ 1.08-
1.13 (t, J ) 7.3 Hz, 3H), 2.45-2.53 (q, J ) 6.9 Hz, 2H), 5.85-
5.89 (d, J ) 13.3 Hz, 1H), 6.69 (s, 2H), 7.10 (s, 4H), 7.78-7.82
(d, J ) 13.5 Hz, 1H); 13C NMR (DMSO-d6 + CDCl3) δ 15.1,
23.7, 49.8, 83.4, 102.6, 119.6, 119.9, 120.3, 146.5, 166.5, 166.9.
Anal. Calcd for C11H13N5O: C, 57.13; H, 5.67; N, 30.28.
Found: C, 57.23; H, 5.65; N, 30.19.
Ad d u ct of 5-Eth yl-2,6,6-tr icya n o-2,4-h exa d ien a m id e
a n d 4-Hyd r oxy-4-m eth yl-2-p en ta n on e (8f2). This adduct
was obtained by recrystallization of 8f in acetone affording a
stable yellow solid: mp 202-203 °C; 1H NMR (DMSO-d6) δ
1.02-1.07 (t, J ) 7.4 Hz, 3H), 1.24 (s, 6H), 2.12 (s, 3H), 2.40-
2.46 (q, J ) 7.4 Hz, 2H), 2.79 (s, 2H), 5.79-5.83 (d, J ) 13.3
Hz, 1H), 6.75 (s, 2H), 7.72 (s, 2H), 7.73-7.77 (d, J ) 13.3 Hz,
1H); 13C NMR (DMSO-d6 + CDCl3) δ 15.1, 23.7, 25.3, 31.2,
49.6, 49.9, 51.7, 83.8, 102.6, 119.6, 119.9, 120.3, 146.5, 166.5,
166.9, 207.3. Anal. Calcd for C17H22N4O3: C, 61.80; H, 6.71;
N, 16.96. Found: C, 61.78; H, 6.70; N, 16.94.
5-Isop r op yl-2,6,6-tr icya n o-2,4-h exa d ien a m id e Am m o-
n iu m Sa lt (8g). By a procedure analogous to that of 8f,
starting from 1g, 8g was obtained: 57%; mp 177-178 °C.
2E,4E isomer: 1H NMR (DMSO-d6) δ 1.21-1.24 (d, J ) 6.9
Hz, 6H); 3.21-3.36 (m, 1H), 5.85-5.89 (d, J ) 13.4 Hz, 1H),
6.78 (s, 2H), 7.12 (s, 4H), 7.91-7.95 (d, J ) 13.4 Hz, 1H); 13C
NMR (DMSO-d6) δ 20.8, 29.4, 48.3, 84.2, 102.9, 119.8, 120.1,
120.2, 145.7, 166.5, 170.2. Anal. Calcd for C12H15N5O: C, 58.77;
H, 6.16; N, 28.55. Found: C, 58.85; H, 6.15; N, 28.45.
Ad d u ct of 5-Isop r op yl-2,6,6-tr icya n o-2,4-h exa d ien a -
m id e a n d 4-Hyd r oxy-4-m eth yl-2-p en ta n on e (8g2). This
intermediate was obtained by recrystallization of 8g in acetone
affording a stable yellow solid: mp 181-182 °C; 1H NMR
(DMSO-d6) δ 1.21-1.24 (d, J ) 6.9 Hz, 6H),. 1.31 (s, 6H), 2.09
(s, 3H), 2.83 (s, 2H), 3.20-3.35 (m, 1H), 5.85-5.89 (d, J ) 13.4
Hz, 1H), 6.75 (s, 2H), 7.81(s, 2H), 7.90-7.94 (d, J ) 13.4 Hz,
1H); 13C NMR (DMSO-d6) δ 20.8, 25.3, 29.3, 31.2, 50.0, 50.1,
51.7, 84.2, 102.9, 119.9, 120.1, 120.2, 120.3, 145.8, 166.5, 170.2.
Anal. Calcd for C18H24N4O3: C, 62.77; H, 7.02; N, 16.27.
Found: C, 62.74; H, 7.05; N, 16.24.
3-Cya n o-6-isop r op yl-2(1H )-p yr id in on e (4g) (method
1
C): 30%; mp 226-227 °C; H NMR (DMSO-d6) δ 1.18-1.20
(d, J ) 6.9 Hz, 6H), 2.80-2.89 (m, 1H), 6.18-6.21 (d, J ) 7.5
Hz, 1H), 7.97-8.00 (d, J ) 7.5 Hz, 1H), 12.5 (s, 1H); 13C NMR
(CDCl3 + DMSO-d6) δ 20.8, 31.7, 100.4, 101.2, 116.2, 148.5,
160.9, 162.2; MS m/z (rel intensity) 162 (M+, 95), 147 (100).
Anal. Calcd for C9H10N2O: C, 66.66; H, 6.21; N, 17.27. Found:
C, 66.56; H, 6.23; N, 17.33.
2-Cya n o-3-m e t h yl-5-(1-p yr r olid in yl)-2,4-h e xa d ie n a -
m id e (7a ). To a solution of 10 mmol of â-aminoenone 2a in
ethanol was added 10 mmol of malononitrile at -20 °C. The
intermediate 7a was precipitated from the reaction mixture
and was separated by filtration as an unstable yellow solid,
90%. 2E,4E Isomer: 1H NMR (CDCl3) δ 1.83-1.95 (m, 4H),
2.23 (s, 3H), 2.50 (s, 3H), 3.41-3.49 (m, 4H), 5.43 (s, 1H), 5.89
(s, 2H); 13C NMR (CDCl3) δ 19.5, 20.6, 24.7, 46.1, 48.7, 89.8,
100.0, 121.5, 161.0, 164.0, 166.4. 2Z,4E isomer: 1H NMR
(CDCl3) δ 1.83-1.95 (m, 4H), 2.25 (s, 3H), 2.33 (s,3H), 3.41-
3.49 (m, 4H), 5.97 (s, 2H), 7.12 (s, 1H); 13C NMR (CDCl3) δ
19.8, 23.3, 25.0, 46.1, 49.0, 86.4, 100.8, 122.6, 157.1, 158.4,
166.9.
5-Meth yl-4-oxo-2-h exen e-1,1-dicar bon itr ile Sodiu m Salt
(9). To a solution of â-aminoenone 1g (10 mmol) in dry toluene
(100 mL) at 70 °C were added malononitrile (12 mmol) and
sodium ethoxide (12 mmol). The mixture was stirred at 70 °C
for 12 h, and new amounts of malononitrile (12 mmol) and
sodium ethoxide (12 mmol) were added and stirred at the same
temperature for another 12 h. The solid was separated by
filtration and recrystallized from acetone-ether: 71%; mp >
(2E ,4E )-2-Cya n o-5-(1-p yr r olid in yl)-2,4-h e p t a d ie n a -
m id e (7f). A mixture of â-aminoenone 2f (10 mmol) and

9498 J . Org. Chem., Vol. 64, No. 26, 1999
Alberola et al.
1
330 °C; H NMR (DMSO-d6) δ 0.92-0.94 (d, J ) 6.8 Hz, 6H);
42%; mp 181-182 °C. 2E,4E Isomer: 1H NMR (CDCl3) δ 1.01-
1.07 (t, J ) 7.1 Hz, 3H), 1.14-1.19 (t, J ) 7.0 Hz, 3H), 1.81-
1.86 (m, 4H), 2.44-2.51 (q, J ) 7.0 Hz, 2H), 3.26-3.44 (m,
4H), 4.00-4.08 (q, J ) 7.1 Hz, 2H), 5.36 (s, 1H), 6.85-6.89 (d,
J ) 13.4 Hz, 1H), 8.03-8.08 (d, J ) 13.4 Hz, 1H), 8.37 (s,1H);
13C NMR (CDCl3) δ 13.4, 14.4, 22.5, 24.4, 25.2, 48.5, 49.1, 59.6,
98.9, 100.7, 150.8, 166.8, 167.3, 169.5. 2Z,4E isomer: 1H NMR
(DMSO-d6) δ 1.01-1.07 (t, J ) 7.1 Hz, 3H), 1.21-1.26 (t, J )
7.1 Hz, 3H), 1.81-1.86 (m, 4H), 2.51-2.58 (q, J ) 7.5 Hz, 2H),
3.26-3.44 (m, 4H), 4.06-4.13 (q, J ) 7.1 Hz, 2H), 5.63 (s, 1H),
6.07-6.12 (d, J ) 14.0 Hz, 1H), 8.37 (s, 1H), 8.38-8.43 (d, J
) 14.0 Hz, 1H); 13C NMR (DMSO-d6) δ 13.6, 14.4, 22.7, 24.6,
25.2, 48.5, 48.8, 59.5, 98.7, 101.5, 150.4, 169.2, 169.5, 170.1;
MS m/z (rel intensity) 266 (M+, 11), 136 (100). Anal. Calcd for
C14H22N2O3: C, 63.13; H, 8.33; N, 10.52. Found: C, 63.08; H,
8.35; N, 10.48.
2-Am in o-6-t er t -b u t yl-4-m e t h ylp yr id in e -3-c a r b on i-
tr ile (13): 38%; mp 112-113 °C; 1H NMR (CDCl3 ) δ 1.27 (s,
9H), 2.41 (s, 3H), 5.04 (s, 2H), 6.60 (s, 1H); 13C NMR (CDCl3)
δ 20.6, 29.6, 37.6, 89.0, 110.8, 116.7, 152.6, 159.0, 172.9; MS
m/z (rel intensity) 189 (M+, 20), 174 (100). Anal. Calcd for
C11H15N3: C, 69.81; H, 7.99; N, 22.20. Found: C, 69.74; H,
7.97; N, 22.29.
2.52-2.54 (m, 1H), 5.41-5.46 (d, J ) 13.3 Hz, 1H), 7.16-7.21
(d, J ) 13.3 Hz, 1H); 13C NMR (DMSO-d6 ) δ 19.9, 37.9, 104.1,
109.6, 120.7, 123.3, 147.2, 197.9.
2-Cya n o-5-eth oxy-6-m eth yl-2,4-h ep ta d ien a m id e (10). A
mixture of sodium salt 9 (1 mmol) and pyridinium 4-toluene-
sulfonate (4 mmol) in dry ethanol was refluxed for 72 h. The
resulting mixture was allowed to reach room temperature and,
after dilution with CH2Cl2 (25 mL), was washed with a
saturated solution of NaOH (25 mL), extracted with CH2Cl2
(3 × 25 mL), and dried with MgSO4. The solvent was
evaporated in vacuo, and 10 was isolated after flash chroma-
1
tography (CH2Cl2): 44%; mp 130-131 °C; H NMR (DMSO-
d6) 1.11-1.13 (d, J ) 6.8 Hz, 6H); 1.34-1.39 (t, J ) 7.4 Hz,
3H), 3.23-3.32 (m, 1H), 3.99-4.06 (q, J ) 7.4 Hz, 2H), 5.69-
5.76 (d, J ) 12.5 Hz, 1H), 6.23 (s, 2H), 8.25-8.30 (d, J ) 12.5
Hz, 1H); 13C NMR (DMSO-d6) 14.0, 20.3, 30.0, 64.7, 96.6, 97.1,
117.0, 151.6, 164.4, 180.6; MS m/z (rel intensity) 208 (M+, 25),
137 (100). Anal. Calcd for C11H16N2O2: C, 63.45; H, 7.74; N,
13.45. Found: C, 63.49; H, 7.77; N, 13.41.
2-Cyan o-5-eth ylth io-6-m eth yl-2,4-h eptadien am ide (11).
A mixture of sodium salt 9 (1 mmol) and pyridinium 4-tolu-
enesulfonate (4 mmol) in dry ethanethiol was refluxed for 72
h. The resulting mixture was allowed to reach room temper-
ature and, after dilution with CH2Cl2 (25 mL), was washed
with a saturated solution of NaOH (25 mL), extracted with
CH2Cl2 (3 × 25 mL), and dried with MgSO4. The solvent was
evaporated in vacuo, and 11 was isolated after flash chroma-
tography (CH2Cl2): 65%; mp 149-150 °C; 1H NMR (CDCl3) δ
1.21-1.23 (d, J ) 6.8 Hz, 6H), 1.36-1.41 (t, J ) 7.4 Hz, 3H),
2.87-2.94 (q, J ) 7.4 Hz, 2H), 3.43-3.52 (m, 1H), 6.09 (s, 2H),
6.18-6.23 (d, J ) 12.5 Hz, 1H), 8.22-8.27 (d, J ) 12.5 Hz,
1H); 13C NMR (CDCl3) δ 12.4, 22.5, 25.3, 32.3, 98.8, 113.6,
116.7, 146.6, 163.4, 173.4. Anal. Calcd for C11H16N2SO: C,
58.90; H, 7.19; N, 12.49. Found: C, 58.81; H, 7.17; N, 12.52.
Eth yl 2-Ca r ba m oyl-5-(1-p yr r olid in yl)-2,4-h ep ta d ien a te
(12). A mixture of â-aminoenone 2f (10 mmol) and ethyl
cyanoacetate (10 mmol) in 10 mL of ethanol was refluxed until
TLC showed the disappearance of starting materials. 12 was
precipitated from the reaction mixture by cooling. The solid
was separated by filtration and recrystallized from ethanol:
2-Am in o-4-ter t-b u t yl-6-m et h yl-1,3-ben zen ed ica r b on i-
tr ile (14): 14%; mp 109-110 °C; 1H NMR (CDCl3 ) δ 1.47 (s,
9H), 2.48 (s, 3H), 5.21 (s, 2H), 6.66 (s, 1H); 13C NMR (CDCl3)
δ 21.7, 29.8, 36.1, 92.8, 95.9, 115.5, 117.0, 117.4, 147.6, 153.3,-
159.2; MS m/z (rel intensity) 213 (M+, 40), 198 (100). Anal.
Calcd for C13H15N3: C, 73.21; H, 7.09; N, 19.70. Found: C,
73.23; H, 7.12; N, 19.65.
Ack n ow led gm en t. Financial support from Spanish
CICYT (PB-1112) is gratefully acknowleged.
Su p p or tin g In for m a tion Ava ila ble: X-ray characteriza-
tion data for 7g, 12, and 8f2, including tables of experimental
details, ORTEP drawings, and selected bond lengths and bond
angles. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991121O