Synthesis and transformations of ethyl (2E)-3-N,N-dimethylamino-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-YL) propenoate

Article abstract of DOI:10.3987/COM-05-S(K)1

The reaction of amines (4a-g) with ethyl (2E)-3-N,N-dimethylamino- 2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)propenoate (3), prepared in two steps from ethyl (4,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-3-yl)acetate (1), gave ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyraz

Full text of DOI:10.3987/COM-05-S(K)1

HETEROCYCLES, Vol. 66, 2005
207
HETEROCYCLES, Vol. 66, 2005, pp. 207 – 218. © The Japan Institute of Heterocyclic Chemistry
Received, 16th March 2005, Accepted, 26th April, 2005, Published online, 28th April, 2005. COM-05-S(K)1
SYNTHESIS AND TRANSFORMATIONS OF ETHYL (2E)-3-N,N-
DIMETHYLAMINO-2-(5-ETHOXY-1-PHENYL-1H-PYRAZOL-3-
YL)PROPENOATE
David Bevk, Ljubo Golič, Amalija Golobič, Jurij Svete*, and Branko
Stanovnik*
Department of Organic Chemistry, Faculty of Chemistry and Chemical
Technology, University of Ljubljana, Aškerčeva 5, P.O. Box 537, 1000 Ljubljana,
Slovenia E-mail: Branko.Stanovnik@fkkt.uni-lj.si
Dedicated to Dr. Kenji Koga, Emeritus Professor of Tokyo University
Abstract – The reaction of amines (4a-g) with ethyl (2E)-3-N,N-dimethylamino-
2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)propenoate (3), prepared in two steps
from ethyl (4,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-3-yl)acetate (1), gave ethyl
(2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-(substituted amino)propenoates
(5a-g). The reaction of compound (3) with 2-aminopyridine (4h), 3 amino-1H-
pyrazole (4i), 2H-pyran-2-one (6a), and 5,5-dimethylcyclohexane-1,3-dione (6b)
afforded 3-(pyrazol-3-yl)pyridopyrimidinone (7a), 6-(pyrazol-3-yl)pyridopyri-
midinone (7b), 3-(pyrazol-3-yl)pyranopyrandione (7c), and 3-(pyrazol-3-yl)-
chromenedione (7d), respectively.
There are many methods for the synthesis of pyrazole ring construction described in the literature. Two
most important methods for practical purposes are the reaction between hydrazines and β-difunctional
compounds, and 1,3-dipolar cycloadditions. Both procedures are well documented. 1-6 Other methods are
1,2,3,4,5,6
alkylation at 4-position of 1-substituted pyrazoles with alkyl halides which is achieved in the presence of
aluminum trichloride, and alkylation at 5-position which can be achieved by lithiation followed by the
reaction with C-electrophiles.3 Only a few reports describe introduction of aryl or heteroaryl group into
pyrazole ring under Pd(0) catalysis.7,8 Recently, a novel and general approach of 5-aryl- and 5-heteroaryl-
substituted 1-benzyloxypyrazoles by combining directed ortho- metallation/transmetallation and
palladium catalyzed cross-coupling has been reported.9
Alkyl 3-dimethylaminopropenoates and related enaminones play an important role as building blocks for
the preparation of various heterocyclic systems and functionalized heterocycles, such as heteroaryl-

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HETEROCYCLES, Vol. 66, 2005
substituted α-amino- and α-hydroxy acid derivatives, fused pyridinones, pyrimidones, pyranones and
related systems, which are the basic structures of many alkaloids and their synthetic derivatives exhibiting
various biological activities.10-12
Among others, application of various 3-dimethylamino-2-
10
,
11
,
12
vinylaminopropenoates and dimethylaminomethylidene-substituted heterocycles as reagents for the
preparation of aplysinopsins and its analogues,13-16 and condensed indolyl pyrimidinones as meridianine
13,14,15,16
analogues have been reported.17
Recently, we reported some transformations of alkyl [(Z)-4-dimethylaminomethylidene-5-oxo-1-phenyl-
4,5-dihydro-1H-pyrazol-3-yl]acetate with N- and C- nucleophiles into alkyl 4-(substituted amino)-
methylidene- and (4-heteroarylmethylidene-4,5-dihydro-1H-pyrazol-3-yl)acetates followed by cyclization
into 2H-pyrazolo[4,3-c]pyridine-7-carboxylates.18,19
In continuation of our research in this area, we now report on the preparation of ethyl (2E)-3-N,N-
dimethylamino-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)propenoate (3) and its transformation with N- and
C- nucleophiles into ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-(substituted amino)propenoates
(5a-g), fused pyrazol-3-ylpyrimidinones (7a,b) and fused pyrazol-3-ylpyranones (7c,d), respectively.
Ph
N
Ph
N
Ph
N
EtBr, KI
HO
O
EtO
N
N
N
K2CO3
EtOH
COOEt
R-NH2
COOEt
COOEt
COOEt
1
1'
2
Ph
N
Ph
N
EtO
EtO
N
(4a-g)
N
DMFDMA
PhCH3
EtOH, HCl
COOEt
Me2N
HN
R
3
5
Reaction
4a→5a
4b→5b
4c→5c
4d→5d
R
Reaction
4e→5e
4f→5f
R
phenyl
-CH2COOMe
1H-indazol-3-yl
4-methylphenyl
4-methoxyphenyl
4-nitrophenyl
4g→5g
5-methylisoxazol-3-yl
Scheme 1.
Ethyl (2E)-3-dimethylamino-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)propenoate (3) was prepared in two
steps from ethyl (4,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-3-yl)acetate 20 (1) by treatment with ethyl

HETEROCYCLES, Vol. 66, 2005
209
bromide in ethanol under reflux to give ethyl 5-ethoxy-1-phenyl-1H-pyrazol-3-ylacetate (2), followed by
treatment with N,N-dimethylformamide dimethylacetal (DMF DMA) in toluene under reflux. Compound
(3) reacted with anilines (4a-d), methyl glycinate hydrochloride (4e), 3-amino-1H-indazole (4f), and 3-
amino-5-methylisoxazole (4g) in ethanol in the presence of hydrochloric acid under reflux for 1–3 h to
provide the corresponding ethyl (2E)-3-(arylamino)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)propenoates
(5a-d), ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-(methoxycarbonylmethyl)aminopropenoate
(5e), (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-[(1H-indazol-3-yl)amino]propenoate (5f), and (2E)-
2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-[(5-methylisoxazol-3-yl)amino]propenoate (5g). (Scheme 1)
Ph
N
Ph
N
EtO
EtO
N
N
O
O
N
N
NH
N
N
H
N
N
NH2
7b
7a
N
4i
NH2
4h
Ph
N
EtO
N
COOEt
O
Me
O
O
Me2N
6a
6b
O
3
OH
Ph
N
Ph
N
EtO
EtO
N
N
O
O
O
O
O
O
O
Me
7d
7c
Scheme 2.
On the other hand, when compound (3) was heated with 2-aminopyridine (4h) and 3-amino-1H-pyrazol
(4i) in acetic acid, the corresponding 3-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-4H-pyrido[1,2-a]pyrimidin-
4-one (7a) and 6-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7(1H)-one (7b) were
isolated in 70 % and 77 % yields, respectively. Similarly, the reaction of compound (3) with 4-hydroxy-6-

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HETEROCYCLES, Vol. 66, 2005
methyl-2H-pyran-2-one (6a) and 5,5-dimethylcyclohexane-1,3-dione (6b) acetic acid afforded 3-(5-
ethoxy-1-phenyl-1H-pyrazol-3-yl)-7-methyl-2H,5H-pyrano[4,3-b]pyran-2,5-dione (7c) and 3-(5-ethoxy-
1-phenyl-1H-pyrazol-3-yl)-7,8-dihydro-7,7-dimethyl-2H-chromene-2,5-dione (7d) in 26 % and 82 %
yields, respectively (Scheme 2).
Structure determination
The structures of all compounds were established on the basis of elemental analyses, IR, MS, and 1H and
13C NMR spectra. The orientation around the double bond in compounds (3) and (5b) were established on
the basis of 2D-HMBC NMR spectral techniques. The magnitude of heteronuclear coupling constants,
3JC-H, for the nuclei H-C=C-C=O with cis configuration around the C=C double bond are smaller (2-6
Hz) than those for the trans-orientated ones (8-12 Hz).10,11,21 Accordingly, the heteronuclear coupling
3
constants for compound (3), 3JC-H = 5 Hz, and for compound (5b), JC-H = 4 Hz, clearly indicates the (E)-
orientation. The structure of compound (5e) was confirmed also by X-Ray analysis. The ORTEP drawing
of 5e is shown in Figure 2.
Ph
N
Ph
N
EtO
N
EtO
N
COOEt
COOEt
HN
H
Me2N
H
3JC-H = 4 Hz (cis)
3JC-H = 5 Hz (cis)
Me
Figure 1. Determination of configuration around the C=C double bonds by NMR spectroscopy.
X-Ray structure analysis
Structure of compound (5e) was solved by X-Ray analysis.22
Fractional coordinates and equivalent displacement parameters (Å2) for compound (5e). Ueq is defined as
one third of the trace of the orthogonalized Uij tensor.
x/a
y/b
z/c
Ueq
O(31)
O(32)
0.2172(4)
0.3925(3)
0.2228(3)
0.3079(2)
1.1783(2)
1.2432(2)
0.075(1)
0.066(1)

HETEROCYCLES, Vol. 66, 2005
211
O(33)
O(34)
O(5)
N(1)
N(2)
0.9918(3)
1.1372(3)
0.3148(3)
0.5385(4)
0.5883(3)
0.7504(4)
0.6344(4)
0.7434(5)
0.8434(5)
0.8338(5)
0.7252(6)
0.6270(5)
0.4664(4)
0.4836(4)
0.3523(5)
0.2709(5)
0.3156(6)
0.6205(4)
0.8936(4)
1.0089(4)
1.2670(6)
0.3361(4)
0.3855(4)
0.1485(5)
0.0956(5)
0.3697(3)
0.4684(2)
0.0608(2)
0.1595(2)
0.2187(2)
0.3412(3)
0.1595(3)
0.2399(3)
0.2403(4)
0.1621(4)
0.0825(4)
0.0801(3)
0.2129(3)
0.2700(3)
0.2629(3)
0.3015(4)
0.3734(4)
0.3273(3)
0.4011(3)
0.4101(3)
0.4797(4)
0.1510(3)
0.1196(3)
0.0256(3)
-0.0393(4)
0.7622(2)
0.8344(2)
0.8032(2)
0.8033(2)
0.8716(2)
0.9581(2)
0.6909(3)
0.6446(3)
0.5365(3)
0.4735(3)
0.5199(3)
0.6284(3)
0.9674(3)
1.0570(3)
1.1618(3)
1.3513(3)
1.4200(3)
1.0469(3)
0.9537(3)
0.8391(3)
0.7300(3)
0.9607(3)
0.8575(3)
0.8618(3)
0.7885(3)
0.074(1)
0.066(1)
0.058(1)
0.048(1)
0.050(1)
0.055(1)
0.046(1)
0.056(1)
0.064(2)
0.069(2)
0.070(2)
0.063(2)
0.047(1)
0.047(1)
0.050(1)
0.070(2)
0.079(2)
0.048(1)
0.056(1)
0.053(1)
0.082(2)
0.050(1)
0.049(1)
0.058(1)
0.066(2)
N(3)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(3)
C(31)
C(32)
C(33)
C(34)
C(35)
C(36)
C(37)
C(38)
C(4)
C(5)
C(51)
C(52)
Figure 2. Ortep view of compound (5e) at the 50% probability level. H atoms are drawn as
ellipsoids of arbitrary radii.

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HETEROCYCLES, Vol. 66, 2005
Bond Distances (Å2)and Bond Angles (°) for compound (5e) with e.s.d.’s in parentheses
O(32)-C(32)
O(32)-C(33)
O(33)-C(37)
O(34)-C(37)
O(34)-C(38)
O(5)-C(5)
O(5)-C(51)
N(1)-C(5)
N(1)-N(2)
N(1)-C(11)
N(2)-C(3)
N(3)-C(35)
N(3)-C(36)
C(11)-C(16)
1.351(5)
1.449(4)
1.194(5)
1.331(5)
1.450(4)
1.339(5)
1.441(4)
1.366(4)
1.376(5)
1.416(4)
1.341(4)
1.325(4)
1.443(5)
1.376(6)
C(11)-C(16)
C(11)-C(12)
C(12)-C(13)
C(13)-C(14)
C(14)-C(15)
C(15)-C(16)
C(3)-C(4)
C(3)-C(31)
C(31)-C(35)
C(31)-C(32)
C(33)-C(34)
C(36)-C(37)
C(4)-C(5)
1.376(6)
1.380(5)
1.383(5)
1.375(7)
1.370(6)
1.379(5)
1.413(6)
1.463(5)
1.366(5)
1.458(4)
1.478(7)
1.489(5)
1.352(5)
1.487(7)
C(51)-C(52)
C(37)-O(34)-C(38) 117.1(3)
C(35)-C(31)-C(32) 118.9(3)
C(5)-O(5)-C(51)
C(5)-N(1)-N(2)
C(5)-N(1)-C(11)
N(2)-N(1)-C(11)
C(3)-N(2)-N(1)
C(35)-N(3)-C(36)
115.7(3)
109.4(3)
131.5(3)
118.7(3)
106.0(3)
123.7(3)
C(35)-C(31)-C(3)
C(32)-C(31)-C(3)
O(31)-C(32)-O(32) 120.7(3)
O(31)-C(32)-C(31) 125.7(4)
O(32)-C(32)-C(31) 113.6(3)
O(32)-C(33)-C(34) 108.9(4)
122.3(3)
118.7(3)
C(16)-C(11)-C(12) 119.3(3)
N(3)-C(35)-C(31)
N(3)-C(36)-C(37)
O(33)-C(37)-O(34) 124.2(3)
O(33)-C(37)-C(36) 125.4(4)
O(34)-C(37)-C(36) 110.4(3)
C(5)-C(4)-C(3)
O(5)-C(5)-C(4)
O(5)-C(5)-N(1)
C(4)-C(5)-N(1)
O(5)-C(51)-C(52)
126.5(3)
110.7(3)
C(16)-C(11)-N(1)
C(12)-C(11)-N(1)
122.5(3)
118.2(3)
C(11)-C(12)-C(13) 120.0(4)
C(14)-C(13)-C(12) 120.7(4)
C(15)-C(14)-C(13) 119.0(3)
C(14)-C(15)-C(16) 120.8(4)
C(11)-C(16)-C(15) 120.2(4)
105.4(3)
133.1(3)
118.1(3)
108.9(3)
107.1(3)
N(2)-C(3)-C(4)
N(2)-C(3)-C(31)
C(4)-C(3)-C(31)
110.3(3)
118.6(3)
131.1(3)
EXPERIMENTAL
1
13
Melting points were taken on a Kofler micro hot stage. The H NMR, C NMR and 2D NMR HMBC,
NOESY spectra were obtained on a Bruker Avance DPX 300 (300 MHz) spectrometer with DMSO-d6 or
CDCl3 as solvent and TMS as internal standard (δ in ppm, J in Hz). IR spectra were recorded with
Perkin–Elmer Spectrum BX FTIR and BIO RAD Excalibur Series FTS 3000 MX FTIR
spectrophotometers (KBr discs, ν in cm–1). MS spectra were obtained on an Autospeck Q spectrometer.
The microanalyses for C, H, and N were obtained on a Perkin Elmer CHN Analyser 2400 and Perkin
Elmer Series II CHN Analyser 2400.

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Ethyl (5-ethoxy-1-phenyl-1H-pyrazol-3-yl)acetate (2)23 2425
Ethyl (4,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-3-yl)acetate (2.46 g, 10 mmol), ethyl bromide (1 mL, 13
mmol), potassium iodide (1.66 g, 10 mmol), and potassium carbonate (1.38 g, 10 mmol) in ethanol (30
mL) were heated at the reflux temperature for 3 h. Solid residue was filtered off, solvent was evaporated
in vacuo. Oily residue was dissolved in ether (40 mL), and solution was shaken with 10 % NaOH (40
mL), and then with water (50 mL). Organic phase was dried with anhydrous sodium sulfate. Solvent was
evaporated in vacuo to give oily residue, which was further purified by column chromatography on silica
gel (EtOAc : hexane, 1 : 1). The compound was used without any additional purification in further
1
experiments. Colorless oil; yield: 42 % (1.151 g); H NMR (CDCl3): δ 1.27 (t, 3H, J = 7.2, OCH2CH3);
1.42 (t, 3H, J = 7.0, OCH2CH3); 3.66 (s, 2H, CH2); 4.11–4.22 (m, 4H, 2× OCH2CH3); 5.68 (s, 1H, 4-H);
7.19–7.25 (m, 1H, Ph); 7.35–7.42 (m, 2H, Ph); 7.68–7.72 (m, 2H, Ph).
Ethyl (2E)-3-(N,N-dimethylamino)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)propenoate (3)
Ethyl (5-ethyl-1-phenyl-1H-pyrazol-3-yl)acetate (2) and DMFDMA (2.16 mL, 15 mmol) in toluene (20
mL) were heated at the reflux temperature for 3 h. Solvent was evaporated in vacuo. Oily residue was
purified by column chromatography on silica gel (EtOAc : hexane, 1 : 2) to give white crystals. Yield:
42 % (1.157 g); mp 86–104°C (Ethanol). Anal. Calcd for C18H23N3O3: C 65.63; H 7.04; N 12.76. Found,
C 65.78; H 7.13; N 12.98. MS: m/z (M+, 329; MH+, 330). IR (cm–1): 1670, 1620, 1560, 1390, 1290, 1210,
1060, 770. 1H NMR (CDCl3): δ 1.26 (t, 3H, J = 7.2, OCH2CH3); 1,47 (t, 3H, J = 7.0, OCH2CH3); 2.87 (s,
6H, NMe2); 4.15–4.22 (m, 4H, 2 × OCH2CH3); 5.71 (s, 1H, 4-H); 7.20−7.25 (m, 1H, Ph); 7.38−7.43 (m,
13
2H, Ph); 7.65 (s, 1H, =CH); 7.75−7.81 (m, 2H, Ph). C NMR (CDCl3): δ 15.0; 15.1; 59.0; 68.1; 90.6;
91.4; 122.0; 125.9; 129.0; 139.5; 147.6; 148.5; 151.4; 154.6; 170.1.
General Procedures for the Preparation of Ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-
(substituted amino)propenoates (5a-g), fused pyrimidinones (7a,b) and fused pyranones (7c,d):
General Procedure A: 3 (165 mg, 0.5 mmol) and 4 (0.5 mmol) were dissolved in ethanol (5 mL) and
hydrochloric acid (3 drops, 33%, 1 mmol), and the solution heated at reflux temperature. The product was
filtered off, and recrystallized from ethanol.
General Procedure B: 3 (165 mg, 0.5 mmol) and nucleophile (4 or 6) (0.5 mmol) were dissolved in
acetic acid (3 mL), and the solution heated at reflux temperature. After cooling, the product was filtered
off, and recrystallized from ethanol.
Ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-phenylaminopropenoate (5a). This compound
was prepared from 3 (165 mg, 0.5 mmol) and aniline hydrochloride (4a) (65 mg, 0.5 mmol). (Procedure

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HETEROCYCLES, Vol. 66, 2005
A, 1 h reflux); grey needles; yield: 89% (168 mg); mp 142–144°C. Anal. Calcd for C22H23N3O3: C 70.01;
H 6.14; N 11.13. Found, C 70.27; H 6.26; N 10.85. MS: m/z (M+, 378; MH+, 377). IR (cm–1): 1690, 1640,
1560, 1510, 1400, 1260, 1060, 780. 1H NMR (CDCl3): δ 1.39 (t, 3H, J = 7.1, OCH2CH3); 1.48 (t, 3H, J =
7.0, OCH2CH3); 4.23–4.34 (m, 4H, 2 × OCH2CH3); 6.47 (s, 1H, 4-H); 7.01–7.11 (m, 3H, Ph); 7.24–7.37
(m, 3H, Ph); 7.44–7.49 (m, 2H, Ph); 7.76–7.79 (m, 2H, Ph); 8.36 (d, 1H, J = 12.9, =CH); 11.38 (br d, 1H,
13
J = 12.7; NH). C NMR (CDCl3): δ 15.3; 60.2; 68.9; 87.6; 95.7; 116.8; 121.8; 123.9; 126.9; 130.1;
130.7; 139.0; 140.7; 141.1; 149.5; 154.6; 167.2.
Ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-[(4-methylphenyl)amino]propenoate (5b). This
compound was prepared from 3 (165 mg, 0.5 mmol) and 4-methylaniline hydrochloride (4b) (72 mg, 0.5
mmol). (Procedure A, 2.5 h reflux); white crystals; yield: 84% (165 mg); mp 123–125°C. Anal. Calcd for
C23H25N3O3: C 70.75; H 6.44; N 10.73. Found, C 70.68; H 6.62; N 10.49. MS: m/z (M+, 391; MH+, 392).
IR (cm–1): 1680, 1650, 1560, 1510, 1330, 1260, 1070, 780, 760. 1H NMR (CDCl3): δ 1.38 (t, 3H, J = 7.2,
OCH2CH3); 1.48 (t, 3H, J = 7.0, OCH2CH3); 2.32 (s, 3H, CH3); 4.22–4.34 (m, 4H, 2 × OCH2CH3); 6.46
(s, 1H, 4-H); 7.00 (d, 2H, J = 8.5; Ph’); 7.14 (d, 2H, J = 8.5; Ph’); 7.24–7.29 (m, 1H, Ph); 7.43–7.48 (m,
13
2H, Ph); 7.76–7.79 (m, 2H, Ph); 8.33 (d, 1H, J = 12.9, =CH); 11.32 (br d, 1H, J = 12.9; NH). C NMR
(CDCl3): δ 14.6; 14.7; 20.7; 59.6; 67.9; 86.6; 94.6; 116.2; 121.2; 125.6; 128.9; 130.1; 132.5; 138.5: 138.9;
141.0; 149.4; 154.2; 167.7.
Ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-[(4-methoxyphenyl)amino]propenoate (5c).
This compound was prepared from 3 (165 mg, 0.5 mmol) and 4-methoxyaniline (4c) (62 mg, 0.5 mmol).
(Procedure A, 3 h reflux); white needles; yield: 38% (78 mg); mp 91–94°C. Anal. Calcd for C23H25N3O4:
C 67.80; H 6.18; N 10.31. Found, C 67.55; H 6.40; N 10.21. MS: m/z (M+, 407; MH+, 408). IR (cm–1):
1690, 1640, 1560, 1520, 1240, 780. 1H NMR (CDCl3): δ 1.37 (t, 3H, J = 7.0, OCH2CH3); 1.48 (t, 3H, J =
7.2, OCH2CH3); 3.80 (s, 3H, OCH3); 4.22–4.33 (m, 4H, 2 × OCH2CH3); 6.46 (s, 1H, 4-H); 6.90 (d, 2H, J
= 9.0; Ph’); 7.05 (d, 2H, J = 9.0; Ph’); 7.24–7.28 (m, 1H, Ph); 7.43–7.48 (m, 2H, Ph); 7.75–7.78 (m, 2H,
Ph); 8.28 (d, 1H, J = 12.9, =CH); 11.29 (br d, 1H, J = 12.9; NH). 13C NMR (CDCl3): δ 15.3; 56.2; 60.0;
68.9; 87.4; 94.4; 116.0; 118.4; 121.8; 126.8; 130.1; 134.6; 139.1; 141.8; 149.8; 154.6; 156.4; 167.2.
Ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-[(4-nitrophenyl)amino]propenoate (5d). This
compound was prepared from 3 (165 mg, 0.5 mmol) and 4-nitroaniline (4d) (69 mg, 0.5 mmol).
(Procedure A, 2 h reflux); yellow needles; yield: 91% (193 mg); mp 154–156°C. Anal. Calcd for
C22H22N4O5: C 62.55; H 5.25; N 13.26. Found, C 62.53; H 5.32; N 13.45. MS: m/z (M+, 422; MH+, 423).
IR (cm–1): 1680, 1640, 1590, 1560, 1510, 1330, 1260, 1110, 840, 780, 750, 690. 1H NMR (DMSO-d6): δ

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1.33 (t, 3H, J = 7.0, OCH2CH3); 1.41 (t, 3H, J = 7.2, OCH2CH3); 4.22–4.33 (m, 4H, 2 × OCH2CH3); 6.42
(s, 1H, 4-H); 7.33–7.39 (m, 1H, Ph); 7.39 (d, 2H, J = 9.4, Ph’); 7.53–7.58 (m, 2H, Ph); 7.78–7.81 (m, 2H,
Ph); 8.23 (d, 2H, J = 9.4, Ph’); 8.31 (d, 1H, J = 12.4, =CH); 11.42 (br d, 1H, J = 12.4; NH).
Ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-[(2-methoxy-2-oxoethyl)amino]propenoate (5e).
This compound was prepared from 3 (165 mg, 0.5 mmol) and methyl glycinate hydrochloride (4e) (63 mg,
0.5 mmol). (Procedure A, 3.5 h reflux); white crystals; yield: 66% (133 mg); mp 92–94°C. Anal. Calcd
for C19H23N3O5: C 61.11; H 6.21; N 11.25. Found, C 61.42; H 6.21; N 11.11. MS: m/z (M+, 373; MH+,
374). IR (cm–1): 1750, 1680, 1620, 1560, 1510, 1390, 1260, 1220, 1060, 760. 1H NMR (CDCl3): δ 1.33 (t,
3H, J = 7.2, OCH2CH3); 1.46 (t, 3H, J = 7.0, OCH2CH3); 3.80 (s, 3H, OCH3); 4.13 (d, 2H, J = 5.7, CH2);
4.20–4.25 (m, 4H, 2 × OCH2CH3); 6.41 (s, 1H, 4-H); 7.19−7.25 (m, 1H, Ph); 7.39–7.45 (m, 2H, Ph); 7.72
(d, 1H, J = 12.8, =CH); 7.77–7.81 (m, 2H, Ph); 9.43–9.51 (m, 1H, NH). 13C NMR (CDCl3): δ 15.0; 15.1;
50.3; 52.8; 59.8; 68.3; 86.7; 93.3; 121.6; 125.8; 129.1; 139.4; 149.4; 150.0; 154.5; 168.0; 170.3.
Ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-[(1H-indazol-3-yl)amino]propenoate (5f). This
compound was prepared from 3 (165 mg, 0.5 mmol) and 4-nitroaniline (4f) (67 mg, 0.5 mmol).
(Procedure B, 2 h); yellow needles; yield: 78% (163 mg); mp 175–194°C. Anal. Calcd for C23H23N5O3: C
66.17; H 5.55; N 16.78. Found, C 66.50; H 5.53; N 16.90. MS: m/z (M+, 417; MH+, 418). IR (cm–1): 1700,
1640, 1590, 1560, 1510, 1390, 1070, 780, 690. 1H NMR (CDCl3): δ 1.39 (t, 3H, J = 7.2, OCH2CH3); 1.49
(t, 3H, J = 7.0, OCH2CH3); 4.25–4.35 (m, 4H, 2 × OCH2CH3); 6.56 (s, 1H, 4-H); 7.11–7.16 (m, 1H, Ph’);
7.28–7.34 (m, 1H, Ph); 7.39–7.41 (m, 2H, Ph’); 7.47–7.52 (m, 2H, Ph); 7.67–7.70 (m, 1H, Ph’); 7.84–
7.88 (m, 2H, Ph); 8.76 (d, 1H, J = 12.4, =CH); 9.31 (br s, 1H, 1’-NH); 11.88 (d, 1H, J = 12.4; NH).
Ethyl (2E)-2-(5-ethoxy-1-phenyl-1H-pyrazol-3-yl)-3-[(5-methylisoxazol-3-yl)amino]propenoate (5g).
This compound was prepared from 3 (165 mg, 0.5 mmol) and 3-amino-5-methylisoxazole (4g) (49 mg,
0.5 mmol). (Procedure B, 2 h reflux); white needles; yield: 37% (75 mg); mp 123–125°C. Anal. Calcd for
C20H22N4O4 C 62.82; H 5.80; N 14.65. Found, C 62.73; H 5.99; N 14.49. MS: m/z (M+, 382; MH+, 383).
IR (cm–1): 2980, 1700, 1650, 1550, 1470, 1260, 1070, 790, 760, 680. 1H NMR (CDCl3): δ 1.37 (t, 3H, J =
7.2, OCH2CH3); 1.47 (t, 3H, J = 7.0, OCH2CH3); 2.39 (d, 3H, J = 0.8; CH3); 4.21–4.33 (m, 4H, 2 ×
OCH2CH3); 5.86 (d, 1H, J = 0.8; 4’-H); 6.46 (s, 1H, 4-H); 6.67 (s, 1H, 4’-H); 7.25–7.30 (m, 1H, Ph);
7.43–7.48 (m, 2H, Ph); 7.70–7.74 (m, 2H, Ph); 8.19 (d, 1H, J = 12.4, =CH); 11.23 (d, 1H, J = 12.4, NH).
13C NMR (CDCl3): δ 13.1; 14.9; 15.1; 60.4; 68.4; 87.4; 93.7; 98.9; 121.9; 126.4; 129.3; 139.0; 140.1;
148.9; 154.6; 160.8; 167.4; 170.8.

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3-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (7a). This compound was
prepared from 3 (165 mg, 0.5 mmol) and 2-aminopyridine (4h) (47 mg, 0.5 mmol). (Procedure B, 2 h
reflux); yellow needles; yield: 70% (116 mg); mp 175–176°C. Anal. Calcd for C19H16N4O2: C 68.66; H
4.85; N 16.86. Found, C 68.48; H 5.00; N 17.05. MS: m/z (M+, 332; MH+, 333). IR (cm–1): 1690, 1590,
1
1490, 1380, 1050, 770, 760, 680. H NMR (CDCl3): δ 1.49 (t, 3H, J = 7.0, OCH2CH3); 4.30 (q, 2H, J =
7.0, OCH2CH3); 6.67 (s, 1H, 4’-H); 7.21–7.31 (m, 2H, Ph, 7-H); 7.42–7.49 (m, 2H, Ph); 7.75–7.78 (m,
2H, 8-H, 9-H); 7.83–7.86 (m, 2H, Ph); 9.21–9.24 (m, 1H, 6-H); 9.28 (s, 1H, 2-H).
6-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-7(1H)-one (7b). This compound was
prepared from 3 (165 mg, 0.5 mmol) and 3-amino-1H-pyrazole (4i) (42 mg, 0.5 mmol). (Procedure B, 5 h
reflux); white needles; yield: 77% (123 mg); mp 291–293°C. Anal. Calcd for C17H15N5O2 C 63.54; H
4.71; N 21.79. Found, C 63.61; H 4.88; N 21.55. MS: m/z (M+, 321; MH+, 322). IR (cm–1): 1660, 1630,
1590, 1550, 1500, 1260, 1050, 770, 570. 1H NMR (DMSO-d6): δ 1.41 (t, 3H, J = 7.0, OCH2CH3); 4.29 (q,
2H, J = 7.0; OCH2CH3); 6.26 (d, 1H, J = 2.0, 3-H); 6.52 (s, 1H, 4’-H); 7.28–7.34 (m, 1H, Ph); 7.47–7.52
(m, 2H, Ph); 7.75–7.79 (m, 2H, Ph); 7.92 (d, 1H, J = 2.0, 2-H); 8.51 (s, 1H, 5-H); 12.8 (br s, 1H, NH). 13C
NMR (DMSO-d6): δ 15.3; 68.9; 87.8; 90.3; 102.1; 122.3; 126.9; 129.8; 137.2; 139.3; 141.8; 144.0; 145.6;
155.0; 156.0.
3-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)-7-methyl-2H,5H-pyrano[4,3-b]pyran-2,5-dione (7c). This
compound was prepared from 3 (165 mg, 0.5 mmol) and 4-hydroxy-6-methyl-2H-pyran-2-one (6a) (63
mg, 0.5 mmol). (Procedure B, 4 h reflux); white needles; yield: 26% (47 mg); mp 270–272°C. Anal.
Calcd for C20H16N2O5 C 65.93; H 4.43; N 7.69. Found, C 65.95; H 4.60; N 7.46. MS: m/z (M+, 364; MH+,
1
365). IR (cm–1): 1740, 1600, 1560, 1030, 770, 690. H NMR (DMSO-d6): δ 1.39 (t, 3H, J = 7.0,
OCH2CH3); 2.36 (s, 3H, CH3); 2.39 (s, 2H, CH2); 4.29 (q, 2H, J = 7.0; OCH2CH3); 6.72 (2 × s, 2 × 1H,
4’-H, 8-H); 7.33–7.38 (m, 1H, Ph); 7.49–7.54 (m, 2H, Ph); 7.75–7.78 (m, 2H, Ph); 8.37 (s, 1H, 4-H).
3-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)-7,8-dihydro-7,7-dimethyl-2H,6H-chromene-2,5-dione (7d).
This compound was prepared from 3 (165 mg, 0.5 mmol) and 5,5-dimethyl-1,3-cyclohexadione (6b) (70
mg, 0.5 mmol). (Procedure B, 8 h reflux); white needles; yield: 82% (155 mg); mp 226–229°C. Anal.
Calcd for C22H22N2O4 C 69.83; H 5.86; N 7.40. Found, C 69.79; H 6.01; N 7.17. MS: m/z (M+, 378; MH+,
1
379). IR (cm–1): 1710, 1690, 1670, 1600, 1510, 1370, 1230, 1170, 1050, 790, 700, 570. H NMR
(DMSO-d6): δ 0.83 (s, 6H, 2 × Me); 1.36 (t, 3H, J = 7.1, OCH2CH3); 2.36 (s, 2H, CH2); 2.39 (s, 2H,
CH2); 4.38 (q, 2H, J = 7.1; OCH2CH3); 5.95 (s, 1H, 4’-H); 7.29–7.32 (m, 2H, Ph); 7.45–7.54 (m, 3H, Ph);
8.37 (s, 1H, 4-H). 13C NMR (DMSO-d6): δ 15.0; 28.3; 33.3; 49.9; 62.2; 86.5; 114.3; 114.6; 125.9; 129.2;

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130.2; 133.4; 139.6; 150.5; 152.8; 164.0; 170.3; 193.7.
ACKNOWLEDGEMENTS
The financial support from the Ministry of Higher Education, Science and Technology, Slovenia through
grants P0-0502-0103, P1-0179, and J1-6689-0103-04 is gratefully acknowledged.
The diffraction data for compound (5e) were collected on the Kappa CCD Nonius diffractometer in the
Laboratory of Inorganic Chemistry, Faculty of Chemistry and Chemical Technology, University of
Ljubljana, Slovenia. We acknowledge with thanks the financial contribution of the Ministry of Higher
Education, Science and Technology, Republic of Slovenia through grants X-2000 and PS-511-103, which
thus made purchase of the apparatus possible.
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14. L. Selič and B. Stanovnik, Tetrahedron, 2001, 57, 3159.
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20. (a) H. V. Pechmann, Liebigs Ann. Chem., 1891, 261, 171; (b) Jpn. Kokai Tokkyo Koho JP 82 40,467
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22. A single crystal (0.16×0.12×0.08 mm) grown from ethanol was used for unit-cell determination and
data collection on a Nonius KAPPA CCD diffractometer, with graphite-monochromated MoKα
radiation (λ=0.7106 Å). Crystal data of 5e: C19H23N3O5; M=373.411; triclinic, space group P-1 (#2),
Z=2 with a=7.4886 (2) Å, b=11.8269 (3) Å, c=11.9923 (4) Å; α=73.355 (1)°, β=80.264 (1)°,
γ=71.993 (1)°; V=963.98 (5) Å3, and Dx=1.286 g/cm3. All calculations were performed using the
Xtal3.424 system. The structure was solved by direct method (SIR92).25 The non-hydrogen atoms
were refined anisotropically and the hydrogen atoms were refined isotropically. The final R- and
Rw- factors after full-matrix least-squares refinements were 0.047 and 0.042, respectively, for
1672 (I>2.50σ(I)) observed reflections.
23. H. Fujimura, M. Hori, S. Kojima, K. Kato, S. Sugiura, Jpn. Tokkyo Koho, 1974 JP 49011232
19740315 Showa. (Chem. Abstr., 1974, 81, 136138f)
24. S. R. Hall, G. S. D. King, and J. M. Stewart, The Xtal3.4 User's Manual, University of Western
Australia, Lamb, Perth, 1995.
25. C. K. Johnson, ORTEPII, Report ORNL-5138, Oak Ridge National Laboratory, Tennessee, USA,
1976.