Rapid microwave-assisted solution phase synthesis of substituted 2-pyridone libraries

Article abstract of DOI:10.1016/j.tet.2004.05.100

2-Pyridone and 2-quinolone analogues are well-known biologically active heterocyclic scaffolds. Libraries of 3,5,6-substituted 2-pyridone derivatives are generated by rapid microwave assisted solution phase methods using a one-pot, two-step protocol. The three-component condensation of CH-acidic carbonyl compounds, N,N-dimethylformamide dimethylacetal and methylene active nitriles, leads to 2-pyridones and fused analogues in moderate to good overall yields and high purities. The proposed mechanism of this novel multi-component reaction, structure elucidation of products and intermediates are discussed.

Full text of DOI:10.1016/j.tet.2004.05.100

Tetrahedron 60 (2004) 8633–8644
Rapid microwave-assisted solution phase synthesis of substituted
2-pyridone libraries
*
Nikolay Yu. Gorobets, Behrooz H. Yousefi, Ferdinand Belaj and C. Oliver Kappe
Institute of Organic Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 5 November 2003; accepted 4 May 2004
Available online 25 June 2004
Dedicated to Professor Peter Stanetty on the occasion of his 60th birthday
Abstract—2-Pyridone and 2-quinolone analogues are well-known biologically active heterocyclic scaffolds. Libraries of 3,5,6-substituted 2-
pyridone derivatives are generated by rapid microwave assisted solution phase methods using a one-pot, two-step protocol. The three-
component condensation of CH–acidic carbonyl compounds, N,N-dimethylformamide dimethylacetal and methylene active nitriles, leads to
2-pyridones and fused analogues in moderate to good overall yields and high purities. The proposed mechanism of this novel multi-
component reaction, structure elucidation of products and intermediates are discussed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Several synthetic approaches to 2-pyridones of this type are
described in the literature. Some of them include rearrange-
ment from a pyrimidine heterocycle,17–19 others involve
ring-opening of 3-formyl-4-hydroxycoumarine20 and
3-formyl-21 or 3-cyano-4-oxo-4H-1-benzopyran22 deriva-
tives by the action of enamines or malonodiamide. On the
other hand, many literature sources23–31 describe more
general approaches involving the condensation of unsatu-
rated ketones 4 with methylene active amides 5 (Scheme 1).
Using cyanoacetamide, a number of Milrinone analogues 7
have been obtained.24–31
Many naturally occurring and synthetic compounds contain-
ing the 2-pyridone1 or 2-quinolone2–4 scaffold possess
interesting pharmacological properties. Pyridone 1, for
example, has been identified as specific non-nucleoside
reverse transcriptase inhibitor of human immunodeficiency
virus-1 (HIV-1).5,6 Milrinone (2), Amrinone (3)7 and their
analogues8–10 are cardiotonic agents for the treatment of
heart failure. Some 2-pyridones are also reported to possess
antitumor,11,12 antibacterial13 and other biological
activities.14–16
A few reports31–33 describe the use of malonodinitrile
instead of cyanoacetamide in condensations with enones 4
leading to 3-cyano-2-pyridones 7. Alternatively, it has been
shown that Milrinone can be obtained by the condensation
of ethoxymethylene malonodinitrile with 1-(4-pyridyl)-2-
propanone 8.31 In all cases, strong basic catalysts such as
sodium hydride or alkoxides were required for this
transformation. However, in earlier work by Junek and
In this work we aimed to develop a rapid microwave-
assisted protocol for the solution phase synthesis of highly
substituted 2-pyridone derivatives (including fused
analogues) which could be applied to a high-throughput
format. In view of the structures of several known drugs, we
have specified our target 2-pyridone molecules to be
unsubstituted in both N1 and C4 positions (Chart 1).
Chart 1.
Keywords: Microwave synthesis; Multi-component reactions; 2-Pyridones; 2-Quinolones.
*
Corresponding author. Tel.: þ43-316-380-5352; fax: þ43-316-380-9840; e-mail address: oliver.kappe@uni-graz.at
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.100

8634
N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
co-workers,34 it has been shown that the reaction between
enamines 9 and cyanoacetamide catalyzed by piperidine
readily leads to the desired pyridine-3-carboxamides 10.
Herein, we introduce general microwave-assisted35 three-
component one-pot synthesis of highly substituted
2-pyridones of type 15, utilizing CH–acidic substrates
11a–h, dimethylformamide dimethylacetal (DMFDMA) 12
and diverse methylene active nitriles 14A–J as building
blocks (Scheme 2).36
2. Results and discussion
2.1. Building blocks and their preparation
All CH–acidic building blocks 11a–h, DMFDMA 12 and
methylene active nitriles 14A–C, 14J were obtained from
commercial sources (Scheme 2). 2-Cyano-N-propyl-acet-
amide 14D was obtained by direct condensation of the
methyl cyanoacetate 14B and n-propylamine at room
Scheme 1.
Scheme 2.
Scheme 3.

N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
8635
Scheme 4.
temperature. The other representatives of various cyano-
acetylated aliphatic, aromatic and heterocyclic amines
14E–I were prepared by trans-cyanoacetylation of the
corresponding amines with 1-cyanoacetyl-3,5-dimethyl-
pyrazole in refluxing toluene following known strategies
(Scheme 3).37
the final compound was obtained when a mixture of adduct
13d, nitrile 14H and catalytic amounts of piperidine in
i-PrOH was irradiated at 100 8C for 5 min. Upon cooling,
product 15dH could be isolated by simple filtration in
moderate yield (45%) but excellent purity (.98%). In a
comparison experiment with salicylaldehyde 17 and
nitrile 14H, 1 min of microwave irradiation at 100 8C
gave the corresponding 2-iminocoumarin 18H in virtually
quantitative yield (Scheme 4).41
2.2. Optimization of reaction conditions
For comparison purposes we have initially looked at the
formation of 2-iminocoumarin derivatives from salicyl-
aldehydes. It is well known that salicylaldehyde derivatives
react with methylene active nitriles of type 14 under
Knoevenagel reaction conditions (alcoholic media, weak
base) to give 2-iminocoumarine derivatives.38,39 In our
reactions, we have considered a similar approach under
microwave conditions (MW) (see Scheme 4).
2.3. Library preparation
Optimized conditions for the synthesis of the key enamine
intermediates 13 are shown in Table 1. In case of 1,3-
dicarbonyl compounds 11c,d, the initial condensation with
DMFDMA was completed within 5 min at room tempera-
ture. For other building blocks the reaction took place at
elevated-temperature microwave conditions (Table 1).
As representative building blocks for CH–acidic com-
pounds 11 and methylene active nitriles 14 (Scheme 2),
dimedone 11d and cyanoacetylated p-anisidine 14H were
chosen as starting components. For the first reaction step
leading to enamine 13d (See Scheme 4), initially, we have
applied an excess of DMFDMA (1.2 equiv.) at room
temperature for 1 min.40 However, we found that excess
of unreacted DMFDMA would effectively react with the
third building block, that is, 14H, to form an adduct 16H,
which would not undergo the desired condensation with
dimedone (11d). Therefore, it was necessary to carry out
this three-component condensation in a two-step fashion
and to avoid excess of DMFDMA.
Table 1. Enamine 13a–h preparation under solvent-free conditions
Reagentsa
Adduct
Time (min)
Tempb (8C)
Conversionc (%)
11aþ12
11bþ12
11cþ12
11dþ12
11eþ12
11fþ12
11gþ12
11hþ12
13a
13b
13c
13d
13e
13f
10
5
5
5
5
5
5
5
170
100
rt
95
.99
.99
.99
.99
.99
69d
rt
100
100
150
150
13g
13h
68d
a
Equimolar amounts (2 mmol each).
b
c
d
Microwave irradiation (single-mode, for details see Section 4).
Determined by RP-HPLC.
Isolated yield of compound.
The second step of the two-step sequence (13þ14!15) was
optimized by varying reaction time and temperature under
microwave irradiation conditions, and using different
solvents (MeOH, EtOH, i-PrOH) or solvent-free conditions.
The best result with respect to isolated yields and purities of
Initially, the transformation of adducts 13a–h to 2-
pyridones 15 was studied using model nitrile 14H with
the previously optimized conditions (MW, 100 8C, 5 min).
While compounds 15bH–15eH were isolated in good yield,
Scheme 5.

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N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
Table 2. Conditions and yields for synthesized compounds
Compound
Scalea (mmol)
Temp (8C)
Time (min)
Yieldb (%)
15bH
15cC
15cD
15cG
15cH
15cI
15dA
15dBd
15dC
15dD
15dE
15dF
15dG
15dH
15dI
4
2
4
2
2
2
0.38
4
4
4
4
4
4
4
1
4
1.24
2
1
2
4
4
4
2
2
2
2
2
2
2
2
2
4
2
0.5
100
100
100
100
100
100
25
100
100
100
100
100
100
100
150
100
150
150
100
100
0
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
10
10
5
1
2
12
5
5
5
5
5
5
5
2
2
2
5
5
67
78
72
81
55
54
85c
53
43d
31
55
58
27
55
57d
65
70
79
65
96
64
78
68
68
89
75
55
48
58
53
58
56
55
78
47
15eH
15fHd
15hHd
16H
18H
19dA
19dC
19dI
Chart 2.
25
100
100
100
100
150
150
150
120
120
120
100
100
130
there were particular cases that showed the limitations of
this protocol. Thus, the reaction between acetophenone
adduct 13a and nitrile 14H unexpectedly led to cyano-
enamine 16H and acetophenone (Scheme 5).
19fH
19gH
19hH
20fH
20gH
20hH
21fH
21gH
21hH
22dA
23dJ
24dC
In cases of 1,3-dimethylbarbituric acid 11f, 4-hydroxy-
coumarine 11g and 4-hydroxy-1-methyl-1H-quinolin-2-one
11h, it was found that the catalyst (piperidine) was
selectively consumed from the reaction medium leading to
complex mixtures. When 1.0 equiv. of piperidine was used
in these transformations the stoichiometric salts 19fH, gH,
hH were formed as crystalline solids. When the reaction
temperature was increased to 150 8C to force cyclization,
only the undesired enamines 20fH, gH, hH were obtained.
Adding concentrated aqueous HCl to the final reaction
mixtures or to isolated salts 19fH, gH, hH in i-PrOH and
irradiating again at 120 8C for 2 min furnished the
corresponding pyran derivatives 21fH, gH, hH. Only in
the case of 1,3-dimethylbarbituric acid 11f and 4-hydroxy-
1-methyl-1H-quinolin-2-one 11h the desired 2-pyridones
15fH and 15hH were obtained by microwave irradiation of
the isolated salt 19fH and 19hH in i-PrOH at 150 8C for
10 min, respectively (Chart 2).
3
a
Equimolar amounts of 11, 12 and 14 in i-PrOH (2 mL).
Isolated yield of pure (.98% by HPLC) compound.
Starting from 22dA.
b
c
d
See text for details.
materials 13d, 14C and 14I. Similarly, under solvent free
conditions (100 8C, 5 min), 3-carbomethoxy-2-pyridone
15dB was obtained without any open chain impurity.
Utilizing malonodinitrile 14A as building block, the initially
formed salt 22dA was extraordinarily stable and was
isolated both directly from 13d and 14A (100 8C, 5 min)
and also via irradiation of intermediate salt 19dA under
microwave conditions (130 8C, 10 min) (Scheme 6).
Another unusual result was obtained when 2-cyanomethyl-
benzimidazole 14J was utilized as building block. In this
case, cyclization involved the imidazole ring to furnish
tetracyclic product 23dJ (Scheme 6).
In order to synthesize all the desired 2-pyridone library
compounds 15, methylene active nitriles 14A–J were
employed in condensations with cyclohexanedione 13c
and dimedone 13d enamine adducts. In cases of compounds
15cC, cD, cE, cG, cH, cI, dA, dB, dC, dE, dF (Table 2), the
desired 2-pyridone products were formed. Surprisingly,
however, cyclohexanedione 13c and dimedone 13d
enamine adducts showed somewhat different reactivity
toward cyanoacetoamide 14C and 2-cyano-N-pyridin-2-yl-
acetamide 14I. Under the applied conditions in case of
cyclohexanedione 13c, the expected 2-pyridones 15cC and
15cI were formed. On the other hand, dimedone adduct 13d
gave the open chain salts 19dC and 19dI which produced
the desired pyridone products 15dC and 15dI only by
irradiation at higher temperature (Scheme 6). Interestingly,
applying a solvent-free protocol (100 8C, 5 min), products
15dC and 15dI were obtained directly from starting
2.4. Structure elucidation
In the course of this work different spectroscopic methods
for structure elucidation of all intermediates and products
have been used. Here some model cases are discussed. Full
spectral data for all new compounds are presented in the
Section 4. The distinction of structure 15dH from the
possible isomeric structures 2-iminopyran 15p and the open-
chain unsaturated hydroxy nitrile 15p p was performed by
NOE NMR experiments. Irradiation at 2.84 ppm (C8–H)
produced a distinct NOE effect at 13.09 ppm (NH).
Furthermore, full assignment of the 13C NMR spectrum

N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
8637
Scheme 6.
by performing HMBC experiments confirmed structure
15dH, where the key signal at d 161.7 ppm was assigned to
the lactam carbonyl group. In the solid phase IR spectra of
compounds 15 no nitrile absorption band was present. For
product 23dJ two isomeric structures (23dJ, 23dJp) can be
proposed. HMBC experiments have confirmed a correlation
between the nitrile carbon and the alkene proton in the
pyridine ring, which is possible only for structure 23dJ
(Chart 3).
crystallography (Fig. 1)42 in addition to a full spectroscopic
analysis.
To confirm the structure of the open-chain salt for the
example of dimedone derivative 19dC and also to add
another diversity point to the final 2-pyridone libraries the
reaction with p-anisidine was performed (Scheme 7). The
structure of the N-arylated product 24dC was confirmed by
all routine spectral data and NOE.
The structure of salt 22dA was determined by X-ray
Based on all the above results and the structure elucidation
of isolated reaction intermediates we propose the following
reaction mechanism for the formation of 2-pyridones
(Scheme 8).
After the formation of 2-iminopyrane intermediate 26 the
next step is the ring opening with base (26!27) and
subsequent ring-closure to the pyridine in a Dimroth-type
rearrangement. In case of 2-iminocoumarine (where R1/R2
constitutes a fused benzene cycle, see Scheme 4) this is not
possible. In the aliphatic cases, nucleophilic attack on the
C-6 position of the 2-iminolactone 26 becomes viable and
after Dimroth-like rotation the thermodynamically more
stable 2-pyridone 15 is formed.
3. Conclusion
In conclusion, we have demonstrated that libraries of densly
substituted 2-pyridones of type 15 can be rapidly prepared
by solution-phase methods, employing a one pot, two step
protocol, that involves the condensation of CH–acidic
carbonyl compounds with N,N-dimethylformamide
dimethylacetal (DMFDMA) and methylene active nitriles.
The isolated yields in this microwave-assisted protocols
Chart 3.

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N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
Figure 1. ORTEP plot of the hydrogen bonded salt 22dA.
Scheme 7.
Scheme 8.
were moderate to high (27–96%) and provided the desired
target compounds in high purity after simple workup by
filtration.
photometer in KBr pellets. Mass spectra were taken on a
Hewlett–Packard LC/MSD 1100 series instrument in the
atmospheric pressure chemical ionization (negative or
positive APCI) mode. Micro-analyses were obtained on a
Fisons Mod. EA 1108 elemental analyzer. For reaction
monitoring, kinetic investigations, and quality (purity)
control of the synthesized library compounds a Shimadzu
LC-10 system, that included LC10-AT(VP) pumps, an
autosampler (S-10AXL), and a dual wavelength UV
detector set at 215 and 280 nm was used. The separations
were carried out using a C18 reversed phase analytical
column, LiChrospher 100 (E. Merck, 100£3 mm, particle
size 5 mm) at 25 8C and a mobile phase from (A) 0.1% TFA
in 90:10 water/MeCN and (B) 0.1% TFA acid in MeCN (all
solvents were HPLC grade, Acros; TFA was analytical
4. Experimental
Starting materials were obtained from commercial suppliers
and used without further purification. TLC analysis was
performed on Merck precoated 60 F254 plates. Melting
points were obtained on a Gallenkamp melting point
apparatus, Model MFB-595 in open capillary tubes. 1H
NMR and 13C NMR spectra were recorded on a Bruker
AMX360 and 500 MHz instruments in CDCl3 or DMSO-d6.
IR spectra were taken on a Perkin–Elmer 298 spectro-

N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
8639
reagent grade, Aldrich). The following gradients were
applied at a flow rate of 0.5 mL/min: linear increase from
solution 30% B to 100% solution B in 7 min, hold at 100%
solution B for 1 min. Sample preparation was done by
diluting approximately 5 mL of the MeCN solution with
0.5 mL of MeCN. 5 mL of the solutions were injected onto
the HPLC system.
precipitate was formed. Otherwise, precipitation was
initiated by cooling (4 8C). After several hours of stirring
the precipitate was filtered, washed with i-PrOH (2£1 mL),
Et2O and subsequently dried. Additional amounts of
product can be collected from the filtrate after further
precipitation overnight. All compounds had .98%
purity by HPLC and were identified by mp, NMR, IR, MS
and elemental analysis. For yields see Table 2. When
appropriate (see below), analytical samples were obtained
by re-crystallization from a suitable solvent.
4.1. Microwave irradiation experiments
All microwave irradiation experiments were carried out
using the Emryse Synthesizer from PersonalChemistry AB
(Uppsala). All experiments were performed in sealed
microwave process vials utilizing the standard absorbance
level (300 W maximum power). Reaction times under
microwave conditions reflect the time the reaction mixture
was kept at the designated temperature (fixed hold time). A
detailed description of this single-mode microwave reactor
with integrated robotics was recently published.43
4.4.1. N3-(4-Methoxyphenyl)-5-acetyl-6-methyl-2-oxo-
1,2-dihydro-3-pyridinecarboxami-de (15bH). Mp 328 8C
dec. Anal. Calcd (C16H16N2O4) C, 63.99; H, 5.37; N, 9.33.
1
Found: C, 64.24; H, 5.40; N, 9.43; H NMR (DMSO-d6) d
2.51 (s, 3H), 2.60 (s, 3H), 3.74 (s, 3H), 6.92 (d, J¼9.0 Hz,
2H), 7.61 (d, J¼9.0 Hz, 2H), 8.79 (s, 1H), 11.55 (s, 1H),
13.00 (s, 1H); MS (pos. APCI) m/z 301 (Mþ1); IR (KBr),
cm21: n 1368, 1511, 1564, 1622, 1679, 1700, 2913, 3000,
3281.
4.2. Preparation of N1-propyl-2-cyanoacetamide (14D)
4.4.2. 2,5-Dioxo-1,2,5,6,7,8-hexahydro-3-quinoline-
carboxamide (15cC). Mp 330 8C dec. (lit.45 340 8C dec.).
Anal. Calcd (C10H10N2O3): C, 58.25; H, 4.89; N, 13.59.
Found: C, 57.99; H, 4.84; N, 13.48; 1H NMR (DMSO-d6) d
2.03 (quintet, J¼6.1 Hz, 2H), 2.48 (t, J¼6.7 Hz, 2H), 2.87
(t, J¼5.9 Hz, 2H), 7.65 (s, 1H), 8.63 (s, 1H), 8.67 (s, 1H),
12.68 (s, 1H); MS (pos. APCI) m/z 207 (Mþ1); IR (KBr),
cm21: n 1394, 1559, 1664, 1684, 2958, 3099, 3359, 3500.
An equimolar mixture of n-propylamine (2.96 g, 50 mmol)
and methyl cyanoacetate 14B (4.95 g, 50 mmol) was stirred
at room temperature overnight. The formed crystalline
product was filtered, washed with Et2O, and dried (5.95 g,
yield 94%), mp 48 8C.
4.3. General procedure for the preparation of N1-
substituted 2-cyanoacetamides (14E–I)37
4.4.3. N3-Propyl-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-
quinolinecarboxamide (15cD). Mp 328 8C dec. (recrystal-
lized analytical sample). Anal. Calcd (C13H16N2O3): C,
62.89; H, 6.50; N, 11.28. Found: C, 63.11; H, 6.45; N, 11.24.
1H NMR (DMSO-d6) d 0.88 (t, J¼7.4 Hz, 3H), 1.50 (hextet,
J¼7.2 Hz, 2H), 2.03 (quintet, J¼6.2 Hz, 2H), 2.48 (t,
J¼6.9 Hz, 2H), 2.88 (t, J¼6.0 Hz, 2H), 3.25 (quartet,
J¼6.4 Hz, 2H), 8.63 (s, 1H), 9.35 (s, 1H), 12.83 (s, 1H); MS
(pos. APCI) m/z 249 (Mþ1); IR (KBr), cm21: n 1398, 1545,
1559, 1661, 1685, 3119.
Cyanoacetic acid hydrazide was obtained by careful
addition of 19.82 g (0.20 mol) of methyl cyanoacetate to
hydrazine hydrate (10.01 g, 0.20 mol) with stirring at room
temperature. The formed cyanoacetic acid hydrazide was
filtered, washed with Et2O, and dried (yield 93%). To a
stirred solution of the cyanoacetic acid hydrazide (9.91 g,
0.10 mol) in water (25 mL) containing conc. HCl (1 mL) at
room temperature, acetylacetone (10.01 g, 0.10 mol) was
added. The mixture was stirred for about 1 h, until the
precipitation was complete. 1-Cyanoacetyl-3,5-dimethyl-
pyrazole was removed by filtration, washed with water, and
dried (mp 118 8C, yield 90%). This product (4.08 g,
25.0 mmol) was added to a solution of 1.0 equiv. of amine
derivative in toluene (10–15 mL), the mixture was refluxed
for 1 min, and then stirred at room temperature. The
N-substituted 2-cyanoacetamides (14E–I) were filtered,
washed with Et2O and dried (14E mp 120 8C, 14F mp 88 8C,
14G mp 198 8C, 14H mp 136 8C, 14I mp 155 8C; with ca.
90% yields).37,44
4.4.4. N3-Phenyl-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-
quinolinecarboxamide (15cG). Mp 339 8C. Anal. Calcd
(C16H14N2O3): C, 68.07; H, 5.00; N, 9.92. Found: C, 67.88;
1
H, 4.84; N, 9.90; H NMR (DMSO-d6) d 2.06 (quintet,
J¼6.1 Hz, 2H), 2.44–2.55 (m, 2H), 2.93 (t, J¼5.9 Hz, 2H),
7.13 (t, J¼7.4 Hz, 1H), 7.36 (t, J¼7.8 Hz, 2H), 7.68 (d,
J¼7.8 Hz, 2H), 8.74 (s, 1H), 11.64 (s, 1H), 13.09 (s, 1H);
MS (pos. APCI) m/z 283 (Mþ1); IR (KBr), cm21: n 1394,
1554, 1597, 1627, 1683, 2964.
4.4. General procedure for the synthesis of 2-pyridones
15
4.4.5. N3-(4-Methoxyphenyl)-2,5-dioxo-1,2,5,6,7,8-hexa-
hydro-3-quinolinecarboxamide (15cH). Mp 323 8C dec.
Anal. Calcd (C17H16N2O4): C, 65.38; H, 5.16; N, 8.97.
1
An equimolar mixture of carbonyl compound 11b–e and
DMFDMA 12 (2.0/4.0 mmol, see Table 2) in a 2.5 mL
(small) Emryse microwave process vial was stirred under
the conditions specified in Table 1 to form enamines 13b–e.
Subsequently, methylene active nitriles 14A–I (1.0 equiv.),
2.0 mL of i-PrOH (for 15dB and 15dC without i-PrOH) and
piperidine (2 drops, ca. 28 mg) were added to the vial and
the mixture was irradiated under microwave conditions at
100 8C for 5 min. After cooling, in most cases a crystalline
Found: C, 64.99; H, 5.01; N, 9.28; H NMR (DMSO-d6) d
2.05 (quintet, J¼6.0 Hz, 2H), 2.44–2.55 (m, 2H), 2.92 (t,
J¼5.9 Hz, 2H), 3.74 (s, 3H), 6.92 (d, J¼8.9 Hz, 2H), 7.61
(d, J¼8.9 Hz, 2H), 8.72 (s, 1H), 11.50 (s, 1H), 13.00 (br s,
1H); MS (pos. APCI) m/z 313 (Mþ1); IR (KBr), cm21: n
1235, 1510, 1558, 1680, 2910, 3154.
4.4.6. N3-(2-Pyridyl)-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-
quinolinecarboxamide (15cI). Mp 335 8C (recrystallized

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N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
analytical sample). Anal. Calcd (C15H13N3O3): C, 63.60; H,
4.63; N, 14.83. Found: C, 63.72; H, 4.26; N, 14.60; 1H NMR
(DMSO-d6) d 2.06 (quintet, J¼6.1 Hz, 2H), 2.51 (t,
J¼6.6 Hz 2H), 2.93 (t, J¼5.8 Hz, 2H), 7.15 (t, J¼6.1 Hz,
1H), 7.83 (t, J¼7.8 Hz, 1H), 8.26 (d, J¼8.3 Hz, 2H), 8.34
(d, J¼4.6 Hz, 1H), 8.77 (s, 1H), 12.04 (s, 1H), 13.12 (br s,
1H); MS (pos. APCI) m/z 284 (Mþ1); IR (KBr), cm21: n
1433, 1530, 1633, 1680, 3245.
2H), 7.20–7.44 (m, 5H), 8.66 (s, 1H), 9.72 (t, J¼5.8 Hz,
1H), 12.90 (s, 1H); 13C NMR (DMSO-d6) d 28.1, 33.1, 42.8,
50.5, 113.0, 118.8, 127.4, 127.8, 128.9, 139.7, 140.3, 159.1,
163.1, 163.6, 193.7; MS (pos. APCI) m/z 325 (Mþ1); IR
(KBr), cm21: n 1398, 1570, 1667, 2958, 2958, 3091.
4.4.12. N3-(4-Fluorophenethyl)-7,7-dimethyl-2,5-dioxo-
1,2,4a,5,6,7,8,8a-octahydro-3-quinolinecarboxamide
(15dF). Mp 251 8C. Anal. Calcd (C20H21FN2O3) C, 67.40;
H, 5.94; N, 7.86. Found: C, 67.47; H, 5.86; N, 7.90;
1H NMR (DMSO-d6) d 1.01 (s, 6H), 2.39 (s, 2H), 2.77
(s, 2H), 2.80 (t, J¼7.2 Hz 2H), 3.52 (q, J¼7.2 Hz, 2H),
7.07–7.12 (m, 2H), 7.25–7.29 (m, 2H), 8.61 (s, 1H), 9.36
(s, 1H), 12.80 (s, 1H); 13C NMR (DMSO-d6) d 28.1, 33.0,
34.7, 39.2, 40.7, 50.5, 112.9, 115.4 (d, J¼20.8 Hz), 118.9,
130.9 (d, J¼7.6 Hz), 135.9, 140.0, 158.9, 161.3 (d,
J¼239.9 Hz), 162.9, 163.5, 193.7; MS (pos. APCI) m/z
357 (Mþ1); IR (KBr), cm21: n 1508, 1557, 1618, 1678,
2361, 3057.
4.4.7. 7,7-Dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-
quinolinecarbonitrile (15dA). The product was obtained
by decomposition of salt 22dA (100 mg, 0.38 mmol) in
DMF (0.5 mL) with conc. HCl (0.5 mL) at room tempera-
ture. After addition of 1 mL water the mixture was filtered
and the product washed with Et2O (2£1 mL). Yield: 85%,
mp 310–311 8C (lit.45 298 8C); 1H NMR (CDCl3) d 1.19 (s,
6H), 2.50 (s, 2H), 2.90 (s, 2H), 8.51 (s, 1H), 12.60 (b s, 1H);
IR (KBr), cm21: n 955, 1154, 1407, 1597, 1669, 2218, 2785,
2947, 3000, 3055.
4.4.8. Methyl-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-hexa-
hydro-3-quinolinecarboxylate (15dB). The compound
was obtained as white solid by a solvent free protocol
under microwave conditions at 100 8C for 5 min (yield
53%), mp 232 8C. Anal. Calcd (C13H15NO4): C, 62.64; H,
4.4.13. N3-Phenyl-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-
hexahydro-3-quinolinecarboxamide
(15dG).
Mp
332 8C. Anal. Calcd (C18H18N2O3): C, 69.66; H, 5.85;
N, 9.03. Found: C, 69.87; H, 5.74; N, 9.19; 1H
NMR (DMSO-d6) d 1.04 (s, 6H), 2.44 (s, 2H), 2.85
(s, 2H), 7.12 (t, J¼7.5 Hz, 1H), 7.37 (t, J¼7.7 Hz, 2H), 7.69
(d, J¼7.9 Hz, 2H), 8.73 (s, 1H), 11.64 (s, 1H); MS (pos.
APCI) m/z 311 (Mþ1); IR (KBr), cm21: n 1392, 1484,
1599, 1626, 1683, 2751, 2799, 2876, 2920, 2965, 3012,
3027, 3081.
1
6.07; N, 5.62. Found: C, 62.86; H, 6.07; N 5.56; H NMR
(CDCl3) d 1.16 (s, 6H), 2.48 (s, 2H), 2.92 (s, 2H), 3.92 (s,
3H), 8.80 (s, 1H); MS (pos. APCI) m/z 250 (Mþ1); IR
(KBr), cm21: n 1395, 1641, 1690, 1744, 2962, 3069, 3213,
3146. The same compound was obtained by a solvent free
protocol under microwave conditions at 100 8C for 5 min
(yield 53%).
4.4.14. N3-(4-Methoxyphenyl)-7,7-dimethyl-2,5-dioxo-
1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (15dH).
Mp 300 8C dec. Anal. Calcd (C19H20N2O4) C, 67.05; H,
4.4.9. 7,7-Dimethyl-2,5-dioxo-1,2,5,6,7,8-hexahydro-3-
quinolinecarboxamide (15dC). The compound was
obtained by irradiation of 200 mg (0.7 mmol) of salt 19dC
in i-PrOH (1 mL) under microwave conditions at 150 8C for
5 min, yielding 78 mg (48%) of product, mp 346 8C dec.
1
5.92; N, 8.23. Found: C, 66.99; H, 5.95; N, 8.43; H NMR
(DMSO-d6) d 1.04 (s, 6H), 2.43 (s, 2H), 2.84 (s, 2H), 3.74 (s,
3H), 6.93 (d, J¼9.0 Hz, 2H), 7.61 (d, J¼9.0 Hz, 2H), 8.71
(s, 1H), 11.47 (s, 1H), 13.09 (s, 1H); 13C NMR (DMSO-d6)
27.2 (2Me), 37.4 (CH2-6), 41.3 (CH2-8), 50.1 (C-7), 54.4
(OMe), 111.5 (C-4a), 0114.2 (CH-30,50), 120.3 (C-3), 122.5
(CH-20,60), 131.2 (C-1 ), 139.1 (CH-4), 154.3 (C-40), 158.6
(C-8a), 160.4 (CONHAr), 161.7 (CO-2), 180.2 (CO-5); MS
(pos. APCI) m/z 341 (Mþ1); IR (KBr), cm21: n 1511, 1556,
1596, 1630, 1675, 2966.
1
(lit.45a 340 8C dec.); H NMR (DMSO-d6) d 2.39 (s, 2H),
2.79 (s, 2H), 7.67 (s, 1H), 8.62 (s, 1H), 8.66 (s, 1H), 12.74 (s,
1H); 13C NMR (DMSO-d6) d 28.1, 33.1, 50.5, 112.8, 119.4,
140.4, 159.2, 163.5, 164.5, 193.7; MS (pos. APCI) m/z 235
(Mþ1); IR (KBr), cm21: n 1407, 1598, 1669, 2874, 2958,
3350. The same compound was obtained as white solid by a
solvent free protocol under microwave conditions at 100 8C
for 5 min (yield 43%).
4.4.15. N3-(2-Pyridyl)-7,7-dimethyl-2,5-dioxo-
1,2,5,6,7,8-hexahydro-3-quinolinecarbox-amide (15dI).
The compound was obtained by irradiation of 356 mg
(1 mmol) of salt 19dI in i-PrOH (2 mL) under microwave
conditions at 150 8C for 5 min, yielding 178 mg (57%)
of product; mp 328 8C dec. Anal. Calcd (C17H17N3O3):
C, 65.58; H, 5.50; N, 13.50. Found: C, 65.71; H, 5.26;
N, 13.69. 1H NMR (DMSO-d6) d 1.04 (s, 6H), 2.44
(s, 2H), 2.85 (s, 2H), 7.16 (t, J¼6.0 Hz, 1H), 7.65 (d,
J¼7.7 Hz, 1H), 7.84 (t, J¼6.7 Hz, 1H), 8.26 (d, J¼7.8 Hz,
1H), 8.76 (s, 1H), 12.02 (s, 1H), 13.32 (br s, 1H); MS (pos.
APCI) m/z 312 (Mþ1); IR (KBr), cm21: n. 1492, 1540,
1573, 1633, 1681, 2756, 2792, 2839, 2869, 2896, 2935,
2955, 3018.
4.4.10. N3-Propyl-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-
hexahydro-3-quinolinecarboxamide (15dD). Mp 325 8C
dec. (recrystallized analytical sample). Anal. Calcd
(C15H20N2O3): C, 65.20; H, 7.30; N, 10.14. Found: C,
1
65.15; H, 7.47; N, 10.28. H NMR (DMSO-d6) d 0.88 (t,
J¼7.4 Hz, 3H), 1.01 (s, 6H), 1.49 (hextet, J¼7.2 Hz, 2H),
2.39 (s, 2H), 2.77 (s, 2H), 3.25 (quartet, J¼6.4 Hz, 2H), 8.61
(s, 1H), 9.38 (t, 1H), 12.65 (br s, 1H); MS (pos. APCI) m/z
277 (Mþ1); IR (KBr), cm21: n 1312, 1430, 1551, 1615,
1663, 2795, 2834, 2940, 2963, 3115, 3324.
4.4.11. N3-Benzyl-7,7-dimethyl-2,5-dioxo-1,2,5,6,7,8-
hexahydro-3-quinolinecarboxamide (15dE). Mp 271–
273 8C. Anal. Calcd (C19H20N2O3) C, 70.35; H, 6.21; N,
8.64. Found: C, 70.55 H, 6.20 N, 8.60; 1H NMR (DMSO-d6)
d 1.02 (s, 6H), 2.41 (s, 2H), 2.80 (s, 2H), 4.53 (d, J¼5.8 Hz,
4.4.16. Methyl 3-(4-methoxyphenylcarbamoyl)-6-
methyl-2-oxo-1,2-dihydro-5-pyridinecarboxylate
(15eH). Mp 326 8C dec. Anal. Calcd (C16H16N2O5) C,

N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
8641
60.75; H, 5.10; N, 8.86. Found: C, 60.87; H, 5.22; N, 8.90;
1H NMR (DMSO-d6) d 2.65 (s, 3H), 3.74 (s, 3H), 3.81 (s,
3H), 6.93 (d, J¼9.0 Hz, 2H), 7.61 (d, J¼9.0 Hz, 2H), 8.79
(s, 1H), 11.53 (s, 1H), 13.04 (br s, 1H); MS (pos. APCI) m/z
317 (Mþ1); IR (KBr), cm21: n 1374, 1509, 1559, 1682,
1715, 2913, 3000, 3127.
Emryse Synthesizer process vial. Workup as described in
the general procedure 4.4. gave pure 2-iminocoumarine
18H, mp 208 8C.46 Anal. Calcd (C17H14N2O3): C, 69.38; H,
4.79; N, 9.52. Found: C, 69.43; 4.77; 9.46; 1H NMR
(CDCl3) d 3.82 (s, 3H), 6.91 (d, J¼8.9 Hz, 2H) 7.16 (d,
J¼8.2 Hz, 1H), 7.23 (t, J¼7.5 Hz, 1H), 7.41–7.59 (m, 2H),
7.63–7.82 (m, 3H), 8.57 (s, 1H), 12.42 (s, 1H); MS (pos.
APCI) m/z 295 (Mþ1); IR (KBr), cm21: n 1509, 1559,
1569, 1670, 3276.
4.4.17. N-(4-Methoxyphenyl)-1,3-dimethyl-2,4,7-trioxo-
1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidine-6-car-
boxamide (15fH). The title compound was obtained as pale
yellow solid by microwave irradiation of 546 mg
(1.24 mmol) of salt 19fH in i-PrOH (2 mL) at 150 8C for
10 min, yield 312 mg (70%), mp 334 8C dec. Anal. Calcd
(C17H16N4O5): C, 57.30; H, 4.53; N, 15.72. Found: C,
4.4.21. Dimethylammonium 2-(2,2-dicyanovinyl)-5,5-
dimethyl-3-oxo-1-cyclohexen-1-olate (19dA). To enamine
13d (4.0 mmol) 2 mL of i-PrOH was added and the stirred
mixture was cooled to 0 8C. Malonodinitrile (1.0 equiv.,
264 mg) was added to the mixture, and within 2 min a white
precipitate was formed that was filtered off after 2 h, washed
with i-PrOH (1 mL), Et2O and dried to give 670 mg (64%)
of a white solid, mp 134 8C. Anal. Calcd (C14H19N3O2): C,
64.35; H, 7.33; N, 16.08. Found: C, 64.49; H, 7.48; N,
1
57.18; H, 4.36; N, 15.58; H NMR (DMSO-d6) d 2.49 (s,
6H), 3.72 (s, 3H), 4.19 (br, s, 2H), 6.86 (d, J¼9.0 Hz, 2H),
7.53 (d, J¼9.0 Hz, 2H), 8.25 (s, 1H), 8.91 (s, 1H); MS (pos.
APCI) m/z 356; IR (KBr), cm21: n 1290, 1342, 1425, 1468,
1515, 1630, 1712.
1
15.99; H NMR (DMSO-d6) d 0.92 (s, 6H), 2.15 (s, 4H),
4.4.18. N3-(4-Methoxyphenyl)-6-methyl-2,5-dioxo-
1,2,5,6-tetrahydrobenzo[h][1,6]naphthyridine-3-carbox-
amide (15hH). The title compound was obtained as pale
yellow solid by microwave irradiation of 2 mmol (920 mg)
of salt 19hH in i-PrOH (2 mL) at 150 8C for 10 min. The
same product was isolated when after the general procedure
4.4. the reaction mixture was irradiated at 150 8C for 10 min
in 48% yield, mp 340 8C dec. (recrystallized analytical
sample). Anal. Calcd (C21H17N3O4): C, 67.19; H, 4.56; N,
11.19. Found: C, 67.11; H, 4.33; N, 11.41. 1H NMR
(DMSO-d6) d 3.71 (s, 3H), 3.75 (s, 3H), 6.95 (d, J¼9.0 Hz,
2H), 7.48 (t, J¼7.3 Hz, 1H), 7.65 (d, J¼9.1 Hz, 2H), 7.71
(d, J¼8.9 Hz, 1H), 7.88 (t, J¼7.3 Hz, 1H), 8.16 (d,
J¼7.8 Hz, 1H), 8.83 (s, 1H), 10.35 (s, 1H); MS (pos.
APCI) m/z 376 (Mþ1); IR (KBr), cm21: n 1023, 1175,
1259, 1296, 1325, 1422, 1479, 1494, 1608, 1650, 2878,
2985, 3010.
2.55 (s, 6H), 7.33 (s, 1H), 7.50 (br s,2H); 13C NMR (DMSO-
d6) d 28.7 (2Me), 30.7, 34.9 (NMe2), 51.8 (2CH2), 59.6,
113.0, 117.4, 122.2, 148.8 (CH), 193.7 (DEPT 135); MS
(pos. APCI) m/z 217 (Mþ1-HNMe2), MS (pos. ESI) m/z 262
(Mþ1); IR (KBr), cm21: n 1403, 1502 1537, 1593, 2199,
2208, 2869, 2950.
4.4.22. Dimethylammonium 2-(2-carbamoyl-2-cyano-1-
ethenyl)-5,5-dimethyl-3-oxo-1-cyclohexen-1-olate
(19dC). The title compound was obtained from dimedone
11d and cyanoacetomide 14C, following general procedure
4.4., using 2.0 mmol of starting materials, with an additional
purification step: the crude isolated product in 2.0 mL of
i-PrOH was irradiated under microwave conditions at
100 8C for 2 min. After cooling, the white precipitate was
filtered off, washed with Et2O and dried to give 312 mg
(56%) of pure (1H NMR) product. The same product was
obtained when the equimolar mixture (4.0 mmol, each) of
enamine 13d and cyanoacetamide 14C, containing piper-
idine (2 drops, ca. 28 mg) was stirred overnight at room
temperature. The pure product (868 mg, 78%) was worked
up as described in procedure 4.4, mp 138 8C. Anal. Calcd
(C14H21N3O3): C, 60.20; H, 7.58; N, 15.04. Found: C,
4.4.19. N1-(4-Methoxyphenyl)-2-cyano-3-dimethyl-
amino-2-propenamide (16H). A mixture of 1.0 mmol
(190 mg) of N-(cyanoacetyl)-4-methoxyaniline 14H,
1.0 equiv. (119 mg) of DMFDMA, 0.5 mL of i-PrOH and
piperidine (2 drops ca. 28 mg) was irradiated under
microwave conditions at 100 8C for 5 min in a 2.5 mL
(small) Emryse process vial. After cooling, a white
crystalline precipitate was formed, that was filtered off,
washed with Et2O and dried to give 160 mg (65%) yield of
16H as a white solid. The same product was isolated when
the general procedure 4.4. was applied to acetophenone 11a
and nitrile 14H. The formation of the intermediate adduct
13a was confirmed by HPLC (Table 1) and mass
spectrometry (pos. APCI) m/z 176 (Mþ1). Acetophenone
was detected in the second reaction mixture by HPLC
analysis. Product 16H: 1H NMR (DMSO-d6) d 3.20 (s, 3H),
3.26 (s, 3H), 3.71 (s, 3H), 6.84 (d, J¼9.0 Hz, 2H), 7.45 (d,
J¼9.0 Hz, 2H), 7.79 (s, 1H), 8.91(s, 1H). MS (pos. APCI)
m/z 246 (Mþ1).
1
60.43; H, 7.28; N, 15.22; H NMR (DMSO-d6) d 0.93 (s,
6H), 2.10 (s, 4H), 2.55 (s, 6H), 6.55 (br, s, 2H), 8.05 (s, 1H);
MS (pos. API-ES) m/z 280 (Mþ1). IR (KBr), cm21: n 1355,
1505, 1533, 1667, 2189, 2785, 2949, 3050, 3234, 3411.
4.4.23. Dimethylammonium 2-[2-cyano-2-(pyridin-2-
ylcarbamoyl)-ethenyl]-5,5-dimethyl-3-oxo-cyclohexen-
1-olate (19dI). Mp 136 8C. Anal. Calcd (C19H24N4O3): C,
64.03; H, 6.79; N, 15.72. Found: C, 64.13; H, 6.45; N,
1
15.94; H NMR (DMSO-d6) d 0.93 (s, 6H), 2.10 (s, 4H),
2.55 (s, 6H), 6.55 (br, s, 2H), 8.05 (s, 1H); MS (pos. API-ES)
m/z 357 (Mþ1). IR (KBr), cm21: n 1287, 1309, 1408, 1583,
1667, 2197, 2954, 3025, 3246, 3361.
4.4.24. Open-chain piperidine salts (19fH, gH, hH).
These salts were obtained as pale yellow solids from
building blocks 11f–h, DMFDMA 12 and the nitrile 14H,
following the general procedure 4.4., using 2.0 mmol of
starting materials and 1.0 equiv. of piperidine. Yields: 19fH
68%, 19gH 89%, 19hH 75%.
4.4.20. N3-(4-Methoxyhenyl)-2-iminocoumarin-3-car-
boxamide (18H). An equimolar mixture of salicylaldehyde
17, methylene active nitrile 14H (2.0 mmol), i-PrOH (2 mL)
and piperidine (2 drops, ca. 28 mg) was irradiated under
microwave conditions at 100 8C for 1 min in a 5.0 mL

8642
N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
4.4.25. Piperidinium 5-[2-cyano-2-(4-methoxyphenyl-
carbamoyl)-1-ethenyl]-1,3-dimethyl-2,4-barbiturate
(19fH). Mp 134 8C. Anal. Calcd (C22H27N5O5): C, 59.85;
H, 6.16; N, 15.86. Found: C, 60.13; H, 6.21; N, 15.65;
1H NMR (DMSO-d6) d 1.58 (m, 6H), 2.48 (s, 6H), 2.94
(m, 4H), 3.72 (s, 3H), 4.75 (br s, 2H), 6.86 (d, J¼9.0 Hz,
2H), 7.53 (d, J¼9.0 Hz, 2H), 8.25 (s, 1H), 8.92 (s, 1H); MS
(pos. API-ES) m/z 442 (Mþ1). IR (KBr), cm21: n 1508,
1550, 1599, 1640, 1660, 2175, 2340, 2363, 2879, 2984,
3020.
again with microwaves at 120 8C for 2 min and worked up
as described in procedure 4.4.
4.4.30. N6-(4-Methoxyphenyl)-1,3-dimethyl-2,4,7-trioxo-
1,3,4,7-tetrahydro-2H-pyrano-[2,3-d]pyrimidine-6-car-
boxamide (21fH). Mp 262 8C. Anal. Calcd (C17H15N3O6):
C, 57.17; H, 4.23; N, 11.76. Found: C, 56.89; H, 4.33; N,
1
12.05; H NMR (DMSO-d6) d 3.12 (s, 6H), 3.71 (s, 3H),
6.85 (d, J¼9.0 Hz, 2H), 7.52 (d, J¼9.0 Hz, 2H), 8.24 (s,
1H), 8.90 (s, 1H); MS (neg. APCI) m/z 356.
4.4.26. Piperidinium 3-[2-cyano-2-(4-methoxy-phenyl-
carbamoyl)-ethenyl]-2-oxo-2H-chromen-4-olate (19gH).
Evaporation of solvent from the reaction mixture gave a
viscous oil. HPLC/MS (pos. API-ES) m/z 448 (Mþ1) and
the m/z for starting enamine 13g and nitrile 14H were not
detected.
4.4.31. N3-(4-Methoxyphenyl)-2,5-dioxo-2H,5H-
pyrano[3,2-c]chromene-3-carboxamide (21gH). Mp
259 8C. Anal. Calcd (C20H13NO6): C, 66.12; H, 3.61; N,
3.86. Found: C, 66.32; H, 3.57; N, 4.01; 1H NMR (DMSO-
d6) d 3.75 (s, 3H), 6.95 (d, J¼9.0 Hz, 2H), 7.58 (m, 2H),
7.64 (d, J¼9.0 Hz, 2H), 7.88 (t, J¼6.5 Hz, 1H), 8.10 (d,
J¼6.7 Hz, 1H), 8.61 (s, 1H), 10.26 (s, 1H); MS (pos. APCI)
m/z 364 (Mþ1).
4.4.27. Piperidinium 3-[2-cyano-2-(4-methoxyphenyl-
carbamoyl)-1-ethenyl]-1-methyl-2-oxo-1,2-dihydro-4-
quinolinolate (19hH). Mp 138 8C. Anal. Calcd
(C26H28N4O4): C, 67.81; H, 6.13; N, 12.17. Found: C,
4.4.32. N3-(4-Methoxyphenyl)-6-methyl-2,5-dioxo-5,6-
dihydro-2H-pyrano[3,2-c]quinoli-ne-3-carboxamide
(21hH). Mp 256 8C dec. Anal. Calcd (C21H16N2O5): C,
67.02; H, 4.28; N, 7.44. Found: C, 66.72; H, 4.24; N, 7.55.
1H NMR (DMSO-d6) d 3.61 (s, 3H), 3.74 (s, 3H), 6.94 (d,
J¼8.9 Hz, 2H), 7.45 (t, J¼7.1 Hz, 1H), 7.63 (d, J¼8.9 Hz,
2H), 7.69 (d, J¼8.7 Hz, 1H), 7.85 (t, J¼7.1 Hz, 1H), 8.15
(d, J¼7.1 Hz, 1H), 8.88 (s, 1H), 10.33 (s, 1H); MS (pos.
APCI) m/z 377 (Mþ1).
1
67.63; H, 5.90; N, 11.94; H NMR (DMSO-d6) d 1.58 (m,
6H), 2.49 (s, 2H), 2.99(m, 4H), 3.44 (s, 3H), 3.72 (s, 3H),
6.87 (d, J¼8.7 Hz, 2H), 7.05 (t, J¼7.3 Hz, 1H), 7.23 (d,
J¼8.3 Hz, 1H), 7.47 (t, J¼7.2 Hz, 1H), 7.56 (d, J¼8.7 Hz,
2H), 8.00 (d, J¼7.6 Hz, 1H), 8.47 (s, 1H), 9.03 (s, 1H); MS
(pos. APCI) m/z 461 (Mþ1); IR (KBr), cm21: n 1037, 1178,
1225, 1304, 1409, 1508, 1555, 1592, 1667, 2190, 2345,
2366, 2879, 2984, 3019.
4.4.33. Dimethylammonium 3-cyano-7,7-dimethyl-5-
oxo-1,2,5,6,7,8-hexahydro-2-quinolin-4-olate
4.4.28. 5-(4-Methoxyanilinomethylene)-1,3-dimethyl-
barbituric acid (20fH), 3-[(4-methoxyphenyl)amino]-
methylene-2H-chromene-2,4(3H)-dione (20gH) and 3-
[1-(4-methoxyanilino)methylidene]-1-methyl-1,2,3,4-
tetrahydro-2,4-quinolinedione (20fH). The title com-
pounds were obtained as pale yellow solids from building
blocks 11f–h and 14H, following general procedure 4.4.,
using 2.0 mmol of starting materials, and microwave
conditions in the second step at 150 8C for 5 min. Product
20fH: mp 161 8C. Anal. Calcd (C14H15N3O4): C, 58.13; H,
5.23; N, 14.53. Found: C, 58.11; H, 5.23; N, 14.52; 1H NMR
(DMSO-d6) d 3.16 (s, 3H), 3.17 (s, 3H), 3.75 (s, 3H), 6.97
(d, J¼8.9 Hz, 2H), 7.45 (d, J¼8.9 Hz, 2H), 8.45 (s, 1H),
11.88 (br s, 1H); MS (pos. APCI) m/z 290 (Mþ1); IR (KBr),
cm21: n 797, 834, 1028, 1176, 1205, 1314, 1341, 1426,
1475, 1634, 1657, 2950, 3012, 3410. Product 20gH: mp
156 8C. Anal. Calcd (C17H13NO4): C, 69.15; H, 4.44; N,
4.74. Found: C, 69.01; H, 4.23; N, 4.50; 1H NMR (DMSO-
d6) d 3.79 (s, 3H), 7.03 (d, J¼8.9 Hz, 2H), 7.35 (m, 2H),
7.62 (d, J¼8.9 Hz, 2H), 7.70(t, J¼7.7 Hz, 1H), 7.97 (d,
J¼7.2 Hz, 2H), 8.79 (s, 1H), 11.90 (br, 1H); MS (pos.
APCI) m/z 290 (Mþ1); IR (KBr), cm21: n 1195, 1250,
1308, 1442, 1505, 1602, 1637, 1667, 2965, 3005, 3035,
3328. Product 20hH, mp 154 8C; HPLC/MS (pos. API-ES)
m/z 309 (Mþ1), the m/z for starting enamine 13g and nitrile
14H were not detected.
(22dA).
The title compound was obtained as white solid from 13d
and malonodinitrile 14A, following general procedure 4.4.,
using 4.0 mmol of starting materials; yield 575 mg (55%).
The same compound was obtained by irradiation of 430 mg
(1.76 mmol) of salt 19dA in i-PrOH (2 mL) with microwave
irradition at 130 8C for 10 min, yield 260 mg (50%), mp
214 8C. Anal. Calcd (C14H19N3O2): C, 64.35; H, 7.33; N,
16.08. Found: C, 64.17; H, 7.28; N, 16.36; 1H NMR
(CDCl3) d 1.11 (s, 6H), 2.44 (s, 2H), 2.74 (s, 2H), 2.80 (s,
6H), 6.36 (br s, 2H), 8.34 (s, 1H); 13C NMR (DMSO-d6) d
28.4 (2Me), 32.6, 34.7 (NMe2), 45.6 (CH2), 51.2 (CH2),
96.7, 113.0, 119.2, 142.1, 167.2, 170.1, 193.5 (DEPT 135);
MS (pos. APCI) m/z 217 (Mþ1-HNMe2), MS (pos. ESI) m/z
217, 234, 239, 262 (Mþ1), 433, 455; IR (KBr), cm21: n
1415, 1488, 1579, 1667, 2206, 2789, 2385, 2949, 3051.
4.4.34. 2,2-Dimethyl-4-oxo-1,2,3,4-tetrahydro-
benzo[4,5]imidazo[1,2-a]quinolin-6-yl cyanide (23dJ).
The title compound was obtained as pale green–yellow
solid from dimedone 11d, DMFDMA 12 and 2-cyano-
methylbenzoimidazole (14J), following general procedure
4.4., using 2.0 mmol of starting materials. Yield 450 mg
(78%); mp 330–333 dec. Anal. Calcd (C18H15N3O): C,
74.72; H, 5.23; N 14.52. Found: C, 74.66; H, 5.22; N 14.50;
1H NMR (DMSO-d6) d: 1.19 (s, 6H), 2.62 (s, 2H), 3.73 (s,
2H), 7.54 (t, J¼7.8 Hz, 1H), 7.69 (t, J¼7.7 Hz, 1H), 8.00 (d,
J¼8.1 Hz, 1H), 8.46 (d, J¼8.5 Hz, 1H), 8.51 (s, 1H); 13C
NMR (DMSO-d6) d 28.5 (2Me), 33 (C-2), 41 (CH2-1), 50
(CH2-3), 99 (C-6), 115 (CN), 116 (C-4a), 117 (CH-11), 120
(CH-8), 123 (CH-10), 127 (CH-9), 131 (C-11a), 135
(CH-5), 145 (C-7a), 147 (C-6a), 154.5 (C-12a), 194
4.4.29. One-pot procedure for the synthesis of 2-pyrans
(21fH, gH, hH). The intermediate salts were obtained as
pale yellow solids from building blocks 11f–h and 14H,
following general procedure 4.7. To the final reaction
mixture conc. HCl (1 mL) was added and it was irradiated

N. Yu. Gorobets et al. / Tetrahedron 60 (2004) 8633–8644
8643
(CO-4); MS (pos. APCI) m/z 290 (Mþ1); IR (KBr), cm21
n1515, 1558, 1592, 1688, 2279, 2962, 2865.
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2H), 2.45 (s, 2H), 3.91 (s, 3H), 5.73 (br s, 1H), 7.12 (s, 4H),
8.94 (br s, 1H), 9.20 (s, 1H); 13C NMR (DMSO-d6) (CDCl3)
d 28.3, 29.7, 32.9, 42.9, 50.1, 55.6, 114.2, 115.7, 128.4,
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Acknowledgements
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This work was supported by the Austrian Science Fund
(FWF, P15582). We thank Personal Chemistry AB
(Uppsala, Sweden) for the use of the Emrys Synthesizer.
We also acknowledge Prof. H. Sterk, and Drs. K. Zangger
and C. Reidlinger for assisting in the spectroscopic analysis
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