A facile synthesis of 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole and other pyrrolidine-fused aromatic ring systems via one-step cyclization from diols

Article abstract of DOI:10.3987/COM-12-12481

A facile synthetic method of 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole, which is a subunit of a potent factor Xa (fXa) inhibitor was developed. This new approach employs one-step cyclization from a diol and can be applied to the syntheses of other pyrrolidine-fused aromatic ring sytems.

Full text of DOI:10.3987/COM-12-12481

HETEROCYCLES, Vol. 57, No. 11, 2002, pp. 2045 - 2064, Received, 12th July, 2002
SYNTHESIS AND REACTIVITY OF (Z)-3-BENZOYLAMINO-4-
DIMETHYLAMINO-2-OXO-3-BUTENE. PREPARATION OF 1-ARYL-
AND
1-HETEROARYL-SUBSTITUTED
4-BENZOYLAMINO-5-
METHYL-1H-PYRAZOLES
Urška Bratušek, Simon Rečnik, Jurij Svete*, Ljubo Golič, and Branko
Stanovnik*
Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Aškerčeva 5, 1000 Ljubljana, Slovenia
Abstract
–
(Z)-3-Benzoylamino-4-dimethylamino-2-oxo-3-butene (4),
prepared from 1-benzoylamino-2-propanone (3) and N,N-dimethylformamide
dimethyl acetal, was converted regioselectively by reaction with a series of
hydrazines (5) into 1-substituted 4-benzoylamino-5-methyl-1H-pyrazoles (8).
Reactions of 4 with primary amines (10) and with dimethylbarbituric acid (12)
afforded the dimethylamine substitution products (11) and (13), respectively.
Treatment of the butenone (13) with ammonia furnished tetrahydropyrido[2,3–
d]pyrimidine derivative (14).
Pyrazoles are important class of heterocyclic compounds as constituents of natural and synthetic
products.1–3 Pyrazoles and their derivatives found a widespread use in various applications in last
decades.1b,4 They exhibit biological activity, and are applicable for industrial and synthetic purposes, such
as devolops in photographic applications6–8 as inhibitors of cyclooxygenase, lipooxygenase, and γ-
aminobutyrate transferase.9–14 The standard method of synthesis of pyrazoles consists in the condensation
of 1,3-bifunctional compound with hydrazine or its derivatives, and 1,3-dipolar cycloadditions.1b,5,15,16
The 4-nitrogen substituted 2-pyrazolin-5-ones are usually prepared by modification of already formed
pyrazolinones,17 while the 5-substituted 4-amino-3-hydroxypyrazoles have been synthesized by
transformation of β-keto esters, via oxime formation, into 2-amino-β-keto esters followed by treatment
with hydrazines18 and from methyl 2-benzoylamino-3-oxobutanoate and hydrazines.19 Recently,
pyrazolidinones have been used for regio- and stereoselective synthesis of rel-(2R,3R)-3-alkylamino-3-
phenylalanine amides20 and alanine esters,21,22 tetracyclic systems,23 rel-(4'R,5'S)-3-(5-aryl-3,4-

bis(hydrazinocarbonyl)-4,5-dihydro-1H-pyrazol-1-yl)-3-methylbutanohydrazides,24 and (1Z)-1-arylmeth-
ylidene-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ide azomethine imines.25 Several synthetic routes have
been developed in recent decades for their preparation by ring-switching methodology from (S)-3-
formylpyroglutamates and hydrazines,26-28 rel-(4R,5R)-4-benzoylamino-5-phenyl-3-pyrazolidinone,21,22 5-
substituted (S)-1-acyl-3-[(E)-dimethylaminomethylidene]pyrrolidin-2-ones, (S)-3-[(E)-dimethylamino-
methylidene]tetrahydrofuran-2-ones, and their 3-(E)-cyanomethylidene analogs.29-34
In this paper we present the synthesis and transformations of (Z)-3-benzoylamino-4-dimethylamino-2-
oxo-3-butene (4), prepared in 3 steps from hippuric acid (1). This was first treated with N,N-dimethyl-
acetamide and POCl3 to give the oxazolone (2), which was then transformed into 1-benzoylamino-2-
propanone (3) by treatment with a mixture of methanol and hydrochloric acid. Heating of 3 with N,N-
dimethylformamide dimethyl acetal (DMFDMA) in dry toluene for 45 min afforded (Z)-3-benzoylamino-
4-dimethylamino-2-oxo-3-butene (4) in 58% overall yield. In order to study the reactivity of compound
(4) a series of hydrazines (5a–l) were selected. Since 4 contains two functional groups, the carbonyl and
the enamino groups, which react easily with hydrazines, two intermediates can be formed: a) the ene-
hydrazine (6) by substitution of the dimethylamino group and b) the corresponding hydrazone (7) by the
reaction with the carbonyl group. From these two intermediates two isomeric pyrazole derivatives, either
1-substituted 4-benzoylamino-5-methyl-1H-pyrazole (8) or 1-substituted 4-benzoylamino-3-methyl-1H-
pyrazole (9) could be formed by cyclization. The isolation of intermediate was not possible, since further
cyclization occurs at room temperature to give pyrazole derivatives (Scheme 1).
The X-Ray structure of the product derived from 2-hydrazinopyrimidine (5j) was determined showing
that compound is 4-benzoylamino-5-methyl-1-(pyrimidin-2-yl)-1H-pyrazole (8j) (Figure 1).
Figure 1.
Ortep view at the 50% probability level for compound (8j) showing the labeling of the
non-hydrogen atoms. H atoms are drawn as circles of arbitrary radii.

O
Me
Me
COOH
NHCOPh
1
O
Ph
i
ii
iii
O
O
N
Me
NHCOPh
Me2N
NHCOPh
NMe2
2
3
4
O
R
N
Me
Me
N
HN NH
R
NHCOPh
Path A
Path B
O
PhOCHN
iv
Me
NHCOPh
8a-l
6
+
R
NHNH2
5a-l
Me2N
R
R
HN
N
4
N
N
Me
Me2N
NHCOPh
PhOCHN
Me
9
7
Compound
5a, 8a
5b, 8b
5c, 8c
5d, 8d
5e, 8e
5f, 8f
R
H
3-hydroxybenzyl
Ph
4-nitrophenyl
4-carboxyphenyl
pyridin-2-yl
5g, 8g
5h, 8h
5i, 8i
6-methylpyridazin-3-yl
6-chloropyridazin-3-yl
6-phenylpyridazin-3-yl
pyrimidin-2-yl
5j, 8j
5k, 8k
5l, 8l
1,2,4-triazolo[4,3–b]pyridazin-6-yl
3-phenyl-1,2,4-triazolo[4,3–b]pyridazin-6-yl
Reagents and Conditions: i) MeCONMe2, POCl3, 40–45°C; ii) MeOH, 36% HCl, reflux; iii)
Me2NCH(OMe)2, toluene, reflux; iv) EtOH, 36% HCl (1 equiv), reflux
Scheme 1

In the reactions of 4 with (hetero)aromatic amines (10a–n) in acetic acid, in most cases at room
temperature, the substitution of dimethylamino group took place to give 3-benzoylamino-4-substituted
amino-2-oxo-3-butenes (11a–n) (Scheme 2).
COMe
COMe
i
R
NH2
+
Me2N
NHCOPh
R
NH
NHCOPh
10a-n
4
11a-n
Compound
10a, 11a
10b, 11b
10c, 11c
10d, 11d
10e, 11e
10f, 11f
R
4-methoxyphenyl
3-chloro-4-fluorophenyl
phenyl
3-bromophenyl
2-methylphenyl
3-nitrophenyl
10g, 11g
10h, 11h
10i, 11i
5-chloropyridin-2-yl
4-methylpyridin-2-yl
pyridin-2-yl
10j, 11j
3-hydroxypyridin-2-yl
5-nitropyridin-2-yl
pyrimidin-2-yl
10k, 11k
10l, 11l
10m, 11m
10n, 11n
2,6-dimethylpyrimidin-2-yl
pyrazinyl
Reagents and Conditions: i) AcOH, rt.
Scheme 2
In the reaction of 4 with C-nucleophile, 1,3-dimethylbarbituric acid (12), in acetic acid at room
temperature the product (13) was isolated in the form of dimethylamine salt, from which free compound
(13a) was isolated by treatment with 2% hydrochloric acid. When 25% ammonia was added to the
solution of 13 in ethanol and the mixture was stirred at room temperature for three days, 6-benzoylamino-
1,3,7-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3–d]pyrimidine (14) was isolated in 15% yield
(Scheme 3).

Me
N
O
OH
NHCOPh
COMe
N
Me
O
13a
ii
H2NMe2
O
Me
N
Me
N
O
OH
O
COMe
i
NHCOPh
+
N
N
Me2N
NHCOPh
Me
Me
COMe
O
O
4
iii
13
12
Me
O
N
N
Me
N
Me
NHCOPh
O
14
Reagents and Conditions: i) AcOH, rt; ii) 2% HCl, rt; iii) NH3, H2O, EtOH, rt.
Scheme 3
The structures of compounds (4, 8a–l, 11a–n, 13, 13a, and 14) were determined by spectroscopic
methods and by analyses for C, H, and N. The configurations around the C=C double bond in compounds
(4, 11c, and 13a) were determined by NMR spectrometry. Since most of these compounds exist as single
isomers, differentiation between (Z)- and (E)-form is not possible on the basis of chemical shifts or J
values. However, the two isomeric forms can easily be differentiated on the basis of the magnitude of the
13
3
long-range heteronuclear C–1H coupling constants, JC–H, which have been used for determination of
conformations and configurations in various systems.35–37 Several methods for measuring JC–H, such as
3
TOCSY-based methods38–40 and methods based on HMBC correlation techniques,41–46 have been
described in the literature. Recently, the orientation around the double bond in alkyl 2,3-
(diamino)propenoates has been determined using the 2D HMBC method.47 Generally, the magnitude of
coupling constant 3JC–H for nuclei with cis-configuration around the C=C double bond is smaller (2–6 Hz)
than that for trans-oriented nuclei (8–12 Hz).45,47,48 Similar coupling constants have also been observed in
some oxazolone derivatives with an analogous structural element.49 For this reason, HMBC correlation
technique was selected as the most suitable for the determination of the configurations around the C=C
double bond in this study.50–52

Thus, in the case of compounds (4, 11c, and 13a), the magnitude of heteronuclear coupling constant, 3JC–
H = 3.2, 3.8, and 5.1 Hz, respectively, clearly indicates the (Z)-orientation. By comparison of the chemical
shifts δCH = 7.40–8.49 ppm and δNH = 9.69–11.42 ppm for protons of CH–NH structural element and the
magnitude of coupling constants, JCH–NH = 10.9 – 12.0 Hz one can conclude that the orientation around
the double bond in compounds (11) is (Z) and that the protons of the CH–NH structural element are trans-
oriented (Figure 2).
3JC-H = 3.2 Hz (cis)
3JC-H = 3.8 Hz (cis)
3JC-H = 5.1 Hz (cis)
Me
Me
Me
H
C
O
H
C
O
H
C O
HO
N
Me2N
NHCOPh
N
NHCOPh
NHCOPh
H
Me
O
N
Compound (4) (Z)
Compound (11c) (Z)
O
Me
Compound (13a) (Z)
Figure 2
1
The H NMR spectra of pyrazoles (8a–l) exhibit, besides the signals characteristic for substituents at
position 1 and benzoyl group, a signal for a proton at position 3 in the range of δ = 7.05–8.12 ppm and a
signal for a methyl group in the range of δ = 2.14–2.69 ppm. In NOESY spectra only the NOE effect
between the methyl protons and proton of the NH part of the benzoylamino group was observed. The
structure of pyrazoles (8) was unambigously determined by X–Ray analysis of compound (8j) (Figure 1).
X-Ray structure determination
Suitable crystals of the compound were obtained by slow evaporation of their solution in 8j. Structure of
compound (8j) was solved by direct method using the SIR9253 program. All hydrogen atoms were located
by difference Fourier synthesis and included in refinement with positional parameters and isotropic
displacement parameters. Full-matrix least-squares refinement on F of all non-hydrogen atoms with
anisotropic displacement parameters and an empirical weighting scheme: w = 14.99*w *w , w (F <2.3)
f
s
f
o
0.8
3
= (F /2.3), w (F >5.5) = (5.5/F ) , w (2.3<F <5.5)=1.0, w (sinθ/λ<0.52) = ((sinθ/λ)/0.52) ,
o
f
o
o
f
o
s
8
w (sinθ/λ>0.64) = (0.64/(sinθ/λ)) , w (0.52<sinθ/λ<0.64) = 1.0 was applied.
s
s

Crystal data
C15H13N5O
D
1.340 Mg m-3
x =
M = 279.301
Mo Kα radiation
Cell parameters from 100
reflections
r
Monoclinic, P21/c
a = 10.8084(9) Å
b = 13.757(1) Å
c = 10.0279(7) Å
θ = 8.39 - 14.86°
-1
µ = 0.0894 mm
β = 111.840(6)°
V = 1384.0(2) Å3
Z = 4
T = 293(1) K
Colorless prism
0.91 x 0.80 x 0.48 mm
Data collection
Enraf-Nonius CAD-4 diffractometer
θmax = 28°
Profile data from ω -2θ scans
Absorption correction: none
13395 measured reflections
3320 independent reflections
2826 reflections with I > 2.0σ(I)
Rint = 0.016
h = -14 → 14
k = -18 → 18
l = -13 → 13
3 standard reflections
frequency: 333 min
intensity decay -0.42 %
Refinement
Refinement on F
R = 0.042
(∆/σ)max = 0.00082
(∆/σ)aver = 0.00006
∆ρmax = 0.259 e Å-3
∆ρmin = -0.219 e Å-3
wR = 0.051
S = 0.937
2826 reflections
243 parameters
w = empirical
Extinction correction: equation 22
in Larson54
Extinction coefficient: 6933(1808)

The asymmetric unit of compound (8j) with atom-numbering scheme is shown in Figure 1. Final atomic
coordinates and isotropic displacement parameters with their e.s.d.’s are listed in Table 1. Bond lengths
and bond angles are presented in Table 2.
The Xtal3.455 system of crystallographic programs was used for the reduction of data, structure
refinement and interpretation. ORTEPII56 was used to produce molecular graphics.
Supplementary data for this structure are available from the IUCr electronic archives with reference
number CCDC 188862.
Table 1. Fractional Coordinates and Equivalent Displacement Parameters (Å2) for Compound (8j). Ueq is
defined as one third of the trace of the orthogonalized Uij tensor.
x/a
y/b
z/c
Ueq
O
0.09777(11) 0.59510(8) 0.43625(13) 0.0538(4)
0.43783(10) 0.82998(7) 0.57054(10) 0.0385(3)
0.31822(12) 0.84105(8) 0.58535(13) 0.0473(4)
0.27359(11) 0.62275(8) 0.37139(12) 0.0435(4)
0.50662(14) 0.96781(10) 0.71121(14) 0.0546(4)
0.64330(14) 0.89820(10) 0.59835(16) 0.0579(5)
0.24452(14) 0.76824(10) 0.51341(15) 0.0470(4)
0.31483(12) 0.70887(8) 0.45093(12) 0.0381(4)
0.43986(12) 0.74910(8) 0.49022(12) 0.0382(4)
0.16936(12) 0.56832(8) 0.37311(12) 0.0382(3)
0.15023(11) 0.47124(8) 0.30049(12) 0.0385(3)
0.19997(14) 0.44748(10) 0.19480(16) 0.0484(5)
0.18024(16) 0.35469(11) 0.13577(18) 0.0549(5)
0.11283(16) 0.28541(11) 0.18228(18) 0.0546(5)
0.06310(16) 0.30887(11) 0.28670(18) 0.0558(5)
0.08042(13) 0.40124(10) 0.34544(15) 0.0471(4)
0.55675(17) 0.71172(14) 0.46190(23) 0.0629(6)
0.53572(12) 0.90261(8) 0.63030(11) 0.0396(4)
0.73300(19) 0.96895(15) 0.65576(21) 0.0670(6)
0.71375(19) 1.04187(13) 0.73896(18) 0.0634(6)
0.59754(20) 1.03805(13) 0.76324(19) 0.0643(6)
N(1)
N(2)
N(4)
N(1')
N(3')
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(2')
C(4')
C(5')
C(6')

Table 2. Bond Distances (Å2)and Bond Angles (°) with e.s.d.’s in Parentheses for Compound (8j).
O-C(6)
1.2247(20)
1.3635(18)
1.3785(16)
1.4161(15)
1.3156(17)
1.3581(18)
1.4049(15)
1.3235(20)
1.3380(22)
1.3174(23)
1.3429(23)
1.4111(21)
C(4)-C(5)
C(5)-C(13)
C(6)-C(7)
C(7)-C(8)
C(7)-C(12)
C(8)-C(9)
C(9)-C(10)
C(10)-C(11)
C(11)-C(12)
C(4')-C(5')
C(5')-C(6')
1.3754(17)
1.4860(25)
1.4983(16)
1.3940(23)
1.3974(20)
1.3897(21)
1.3820(25)
1.381(3)
N(1)-N(2)
N(1)-C(5)
N(1)-C(2')
N(2)-C(3)
N(4)-C(6)
N(4)-C(4)
N(1')-C(2')
N(1')-C(6')
N(3')-C(2')
N(3')-C(4')
C(3)-C(4)
1.3837(21)
1.369(3)
1.366(3)
N(2)-N(1)-C(5)
N(2)-N(1)-C(2')
C(5)-N(1)-C(2')
C(3)-N(2)-N(1)
C(6)-N(4)-C(4)
C(2')-N(1')-C(6')
C(2')-N(3')-C(4')
N(2)-C(3)-C(4)
C(5)-C(4)-N(4)
C(5)-C(4)-C(3)
N(4)-C(4)-C(3)
C(4)-C(5)-N(1)
C(4)-C(5)-C(13)
N(1)-C(5)-C(13)
O-C(6)-N(4)
112.06(10)
N(4)-C(6)-C(7)
C(8)-C(7)-C(12)
C(8)-C(7)-C(6)
C(12)-C(7)-C(6)
C(9)-C(8)-C(7)
C(10)-C(9)-C(8)
C(11)-C(10)-C(9)
116.77(12)
117.68(11)
130.17(12)
105.10(12)
123.17(13)
114.89(17)
115.10(16)
111.59(13)
124.92(13)
105.90(11)
129.09(12)
105.35(12)
28.36(12)
119.40(12)
123.78(12)
116.80(13)
119.85(15)
120.43(18)
119.82(15)
C(10)-C(11)-C(12) 120.54(16)
C(11)-C(12)-C(7)
N(3')-C(2')-N(1')
N(3')-C(2')-N(1)
N(1')-C(2')-N(1)
N(3')-C(4')-C(5')
C(6')-C(5')-C(4')
N(1')-C(6')-C(5')
119.95(16)
127.80(12)
116.92(12)
115.28(13)
122.89(21)
116.00(17)
123.29(18)
126.19(12)
121.83(11)
121.33(12)
O-C(6)-C(7)

EXPERIMENTAL
Melting points were taken on a Kofler micro hot stage. The 1H NMR spectra were obtained on a Bruker
Avance DPX 300 (300 MHz) spectrometer with DMSO-d6 or CDCl3 as solvent and TMS as internal
standard. 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.
The following hydrazino compounds were prepared according to the procedures reported in the literature:
6-chloro-3-hydrazinopyridazine (5h),57 6-hydrazino-s-triazolo[4,3-b]pyridazine (5k),58 and 6-hydrazino-
3-phenyl-s-triazolo[4,3-b]pyridazine (5l).59
1-Benzoylamino-2-propanone (3). To a mixture of hippuric acid (1) (17.92 g, 0.1 mol) and phosphorus
oxychloride (22.9 mL, 0.25 mol) stirred on ice, N,N-dimethylacetamide (23.1 mL, 0.25 mol) was added
dropwise. The mixture was then stirred at 40–45°C for 2 h. The volatile components were evaporated in
vacuo and the oily residue was poured onto crushed ice (70 g). The precipitate was collected by filtration,
washed with cold water and dried at rt. The dried product (2) was dissolved in methanol (700 mL),
hydrochloric acid (36%, 130 mL) was added, and the mixture was heated under reflux for 4 h. The
solvent was evaporated in vacuo, water was added and the mixture was extracted with chloroform. The
organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. Ether was added to the
oily residue and the precipitate was collected by filtration to give 3 (10.283 g, 58%); mp 78–81°C (from
ethanol). 1H NMR (300 MHz, CDCl3): δ 2.27 (3H, s, Me), 4.36 (2H, d, JCH2–NH = 4.1 Hz, CH2NH), 6.93
(1H, br s, CH2NH), 7.42–7.55 (3H, m, Ph), 7.80–7.85 (2H, m, Ph). Anal. Calcd for C10H11NO2: C, 67.78;
H, 6.26; N, 7.90. Found: C, 67.76; H, 6.45; N, 7.76.
(Z)-3-Benzoylamino-4-dimethylamino-2-oxo-3-butene (4). A mixture of 1-benzoylamino-2-propanone
(3) (0.709 g, 4 mmol), N,N-dimethylformamide dimethyl acetal (1.07 mL, 8 mmol), and dry toluene (4
mL) was heated under reflux for 45 minutes. The volatile components were evaporated in vacuo, water
was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous
sodium sulfate and evaporated in vacuo, the residue was triturated with ethyl acetate, and the precipitate
1
was collected by filtration to give 4 (0.686 g, 74%); mp 120–122°C (from ethyl acetate). H NMR (300
MHz, CDCl3): δ 2.00 (3H, s, Me), 3.00 (6H, s, NMe2), 7.42 (1H, s, CH), 7.45–7.58 (3H, m, Ph), 7.88–
7.93 (2H, m, Ph), 9.05 (1H, br s, NHCO). Anal. Calcd for C13H16N2O2 ×·H2O: C, 62.38; H, 7.25; N, 11.19.
Found: C, 62.63; H, 7.49; N, 11.52.
General Procedure for the Preparation of 1-Substituted 4-Benzoylamino-5-methyl-1H-pyrazoles
(8a-l):

A mixture of a hydrazine (5) (1 mmol), (Z)-3-benzoylamino-4-dimethylamino-2-oxo-3-butene (4) (232
mg, 1 mmol), ethanol (5 mL), and catalytic amount of hydrochloric acid (36%, 5 drops) was stirred at rt
for several hours. The reaction was followed by TLC (DC-Alufolien Kieselgel 60 F 254, 0.2 mm, E.
Merck, and chloroform/methanol, 5:1 as solvent). The following compounds were prepared in this
manner:
4-Benzoylamino-5-methyl-1H-pyrazole (8a). This compound was prepared from hydrazine hydrate (5a)
(100%, 0.05 mL, 50 mg, 1 mmol), stirred for 4 h. Volatile components were evaporated in vacuo, the
residue was triturated with ether and ethanol, and the precipitate was collected by filtration to give 8a
1
(120 mg, 60% yield); mp 196–199°C (from methanol). H NMR (300 MHz, DMSO-d6): δ 2.18 (3H, s,
Me), 7.05 (1H, br s, H3), 7.46–7.59 (3H, m, Ph), 7.92–7.97 (2H, m, Ph), 9.66 (1H, s, NHCO), 12.38 (1H,
br s, NH). Anal. Calcd for C11H11N3O: C, 65.66; H, 5.51; N, 20.88. Found: C, 65.40; H, 5.39; N, 21.04.
4-Benzoylamino-1-(3-hydroxybenzyl)-5-methyl-1H-pyrazole (8b). This compound was prepared from
3-hydroxybenzylhydrazine dihydrochloride (5b) (211 mg, 1 mmol), stirred for 8 h. Volatile components
were evaporated in vacuo, the residue was triturated with water, and the precipitate was collected by
1
filtration to give 8b (201 mg, 65%); mp 198–201°C (from ethanol). H NMR (300 MHz, DMSO-d6): δ
2.14 (3H, s, Me), 5.21 (2H, s, CH2), 6.51–6.67 (3H, m, Ar), 7.12 (1H, t, J = 7.8 Hz, Ar), 7.46–7.56 (3H,
m, Ph), 7.59 (1H, s, H3), 7.92–7.95 (2H, m, Ph), 9.40 (1H, s, NHCO), 9.69 (1H, br s, OH). Anal. Calcd
for C18H17N3O2: C, 70.34; H, 5.57; N, 13.67. Found: C, 70.35; H, 5.57; N, 13.99.
4-Benzoylamino-5-methyl-1-phenyl-1H-pyrazole (8c). This compound was prepared from
phenylhydrazine (5c) (108 mg, 1 mmol), stirred for 4 h. Volatile components were evaporated in vacuo,
the residue was triturated with ether, and the precipitate was collected by filtration to give 8c (109 mg,
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39%); mp 170–173°C (from ether and ethanol). H NMR (300 MHz, DMSO-d6): δ 2.29 (3H, s, Me),
7.40–7.62 (8H, m, Ph), 7.82 (1H, s, H3), 7.96–8.00 (2H, m, Ph), 9.86 (1H, br s, NHCO). Anal. Calcd for
C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C, 73.43; H, 5.25; N, 15.26.
4-Benzoylamino-5-methyl-1-(4-nitrophenyl)-1H-pyrazole (8d). This compound was prepared from 4-
nitrophenylhydrazine (5d) (153 mg, 1 mmol), stirred for 1 h. The precipitate was, after cooling, collected
by filtration to give 8d (273 mg, 85%); mp 252–254°C (from ethanol). 1H NMR (300 MHz, DMSO-d6): δ
2.42 (3H, s, Me), 7.50–7.64 (3H, m, Ph), 7.91 (2H, d, J = 9.0 Hz, Ar), 7.95–8.02 (3H, m, Ph, H3), 8.39
(2H, d, J = 9.0 Hz, Ar), 9.95 (1H, br s, NHCO). Anal. Calcd for C17H14N4O3: C, 63.35; H, 4.38; N, 17.38.
Found: C, 63.35; H, 4.33; N, 17.19.

4-Benzoylamino-1-(4-carboxyphenyl)-5-methyl-1H-pyrazole (8e). This compound was prepared from
4-carboxyphenylhydrazine (5e) (152 mg, 1 mmol), stirred for 1.5 h. The precipitate was, after cooling,
1
collected by filtration to give 8e (100 mg, 31%); mp 248–251°C (from ethanol). H NMR (300 MHz,
DMSO-d6): δ 2.37 (3H, s, Me), 7.50–7.63 (3H, m, Ph), 7.72 (2H, d, J = 9.0 Hz, Ar), 7.91 (1H, s, H3),
7.97–8.01 (2H, m, Ph), 8.10 (2H, d, J = 9.0 Hz, Ar), 9.90 (1H, s, NHCO), 13.05 (1H, br s, OH). Anal.
Calcd for C18H15N3O3: C, 67.28; H, 4.71; N, 13.08. Found: C, 67.38; H, 4.86; N, 13.10.
4-Benzoylamino-5-methyl-1-(pyridin-2-yl)-1H-pyrazole (8f). This compound was prepared from 2-
hydrazinopyridine (5f) (109 mg, 1 mmol), stirred for 2 h. Volatile components were evaporated in vacuo,
the residue was triturated with water, and the precipitate was collected by filtration to give 8f (172 mg,
62%); mp 168–171°C (from ethanol). 1H NMR (300 MHz, DMSO-d6): δ 2.57 (3H, s, Me), 7.38 (1H, ddd,
J = 1.1, 4.9, 7.3 Hz, H5'), 7.50–7.63 (3H, m, Ph), 7.87 (1H, ddd, J = 0.9, 1.1, 8.4 Hz, H3'), 7.89 (1H, s, H3),
7.96–8.00 (2H, m, Ph), 8.02 (1H, ddd, J = 1.9, 7.3, 8.4 Hz, H4'), 8.50 (1H, ddd, J = 0.9, 1.9, 4.9 Hz, H6'),
9.87 (1H, br s, NHCO). Anal. Calcd for C16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found: C, 68.86; H,
5.03; N, 20.07.
4-Benzoylamino-5-methyl-1-(6-methylpyridazin-3-yl)-1H-pyrazole (8g). This compound was prepared
from 3-hydrazino-6-methylpyridazine (5g) (124 mg, 1 mmol), stirred for 3 h. The precipitate was, after
cooling, collected by filtration to give 8g (182 mg, 62%); mp 165–168°C (radial chromatography (Silica
gel 60), eluent chloroform/methanol; 5:1). 1H NMR (300 MHz, DMSO-d6): δ 2.59 (3H, s, Me), 2.67 (3H,
s, Me), 7.51–7.64 (3H, m, Ph), 7.79 (1H, d, J = 9.0 Hz, H5'), 7.96–8.01 (3H, m, Ph, H3), 8.05 (1H, d, J =
9.0 Hz, H4'), 9.95 (1H, s, NHCO). Anal. Calcd for C16H15N5O: C, 65.52; H, 5.15; N, 23.87. Found: C,
65.70; H, 5.41; N, 23.82.
4-Benzoylamino-1-(6-chloropyridazin-3-yl)-5-methyl-1H-pyrazole (8h). This compound was prepared
from 6-chloro-3-hydrazinopyridazine (5h) (145 mg, 1 mmol), stirred for 0.5 h. The precipitate was, after
1
cooling, collected by filtration to give 8h (241 mg, 77%); mp 195–197°C (from ethanol). H NMR (300
MHz, DMSO-d6): δ 2.61 (3H, s, Me), 7.51–7.65 (3H, m, Ph), 7.96–8.02 (2H, m, Ph), 8.06 (1H, s, H3),
8.07 (1H, d, J = 9.4 Hz, H4'), 8.25 (1H, d, J = 9.4 Hz, H5'), 10.01 (1H, br s, NHCO). Anal. Calcd for
C15H12N5OCl: C, 57.42; H, 3.85; N, 22.32. Found: C, 57.43; H, 3.63; N, 22.33.
4-Benzoylamino-5-methyl-1-(6-phenylpyridazin-3-yl)-1H-pyrazole (8i). This compound was prepared
from 3-hydrazino-6-phenylpyridazine (5i) (186 mg, 1 mmol), stirred for 0.5 h. The precipitate was, after
1
cooling, collected by filtration to give 8i (171 mg, 48%); mp 196–198°C (from ethanol). H NMR (300

MHz, DMSO-d6): δ 2.69 (3H, s, Me), 7.51–7.65 (6H, m, Ph), 7.99–8.04 (2H, m, Ph), 8.07 (1H, s, H3),
8.19–8.23 (2H, m, Ph), 8.25 (1H, d, J = 9.4 Hz, H5'), 8.46 (1H, d, J = 9.4 Hz, H4'), 9.99 (1H, br s, NHCO).
Anal. Calcd for C21H17N5O: C, 70.97; H, 4.82; N, 19.70. Found: C, 71.02; H, 4.53; N, 19.67.
4-Benzoylamino-5-methyl-1-(pyrimidin-2-yl)-1H-pyrazole (8j). This compound was prepared from 2-
hydrazinopyrimidine (5j) (110 mg, 1 mmol), stirred for 2 h. Volatile components were evaporated in
vacuo, the residue was triturated with water, and the precipitate was collected by filtration to give 8j (218
mg, 78%); mp 191–194°C (from ethanol). 1H NMR (300 MHz, DMSO-d6): δ 2.54 (3H, s, Me), 7.51 (1H,
t, J = 4.9 Hz, H5'), 7.50–7.63 (3H, m, Ph), 7.92 (1H, s, H3), 7.97–8.01 (2H, m, Ph), 8.92 (2H, d, J = 4.9 Hz,
H4', H6'), 9.91 (1H, br s, NHCO). Anal. Calcd for C15H13N5O: C, 64.51; H, 4.69; N, 25.07. Found: C,
64.36; H, 4.52; N, 25.10.
4-Benzoylamino-5-methyl-1-(s-triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole (8k). This compound was
prepared from 6-hydrazino-s-triazolo[4,3-b]pyridazine (5k) (150 mg, 1 mmol), stirred for 4 h. The
precipitate was, after cooling, collected by filtration to give 8k (226 mg, 71%); mp 244–246°C (from
1
ethanol). H NMR (300 MHz, DMSO-d6): δ 2.64 (3H, s, Me), 7.51–7.65 (3H, m, Ph), 7.98 (1H, d, J =
10.2 Hz, H7'), 7.97–8.02 (2H, m, Ph), 8.01 (1H, s, H3), 8.50 (1H, dd, J = 1.1, 10.2 Hz, H8'), 9.64 (1H, d, J
= 1.1 Hz, H3'), 10.02 (1H, br s, NHCO). Anal. Calcd for C16H13N7O: C, 60.18; H, 4.10; N, 30.70. Found:
C, 59.91; H, 3.99; N, 30.72.
4-Benzoylamino-5-methyl-1-(3-phenyl-s-triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole
(8l).
This
compound was prepared from 6-hydrazino-3-phenyl-s-triazolo[4,3-b]pyridazine (5l) (226 mg, 1 mmol),
stirred for 45 min. The precipitate was, after cooling, collected by filtration to give 8l (151 mg, 38%); mp
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244–245°C (from ethanol). H NMR (300 MHz, DMSO-d6): δ 2.66 (3H, s, Me), 7.51–7.68 (6H, m, Ph),
7.97–8.03 (2H, m, Ph), 8.04 (1H, d, J = 9.8 Hz, H7'), 8.12 (1H, s, H3), 8.31–8.36 (2H, m, Ph), 8.58 (1H, d,
J = 9.8 Hz, H8'), 10.03 (1H, br s, NHCO). Anal. Calcd for C22H17N7O: C, 66.82; H, 4.33; N, 24.79.
Found: C, 66.86; H, 4.34; N, 24.94.
General Procedure for the Preparation of 4-Substituted 3-Benzoylamino-2-oxo-3-butenes (11a–n):
A mixture of an amine (10) (1 mmol) and (Z)-3-benzoylamino-4-dimethylamino-2-oxo-3-butene (4) (232
mg, 1mmol) in acetic acid (2 mL) was stirred at rt for several hours. The reaction was followed by TLC
(DC-Alufolien Kieselgel 60 F 254, 0.2 mm, E. Merck, and chloroform/methanol, 5:1, 15:1 and 25:1 as
solvent). The following compounds were prepared in this manner:
(Z)-3-Benzoylamino-4-(4-methoxyphenyl)amino-2-oxo-3-butene (11a). This compound was prepared
from 4-methoxyaniline (10a) (123 mg, 1 mmol), stirred for 48 h. Volatile components were evaporated in

vacuo, the residue was triturated with ethanol and water, and the precipitate was collected by filtration to
give 11a (196 mg, 63%); mp 73–76°C (from water and ethanol). 1H NMR (300 MHz, CDCl3): δ 2.42 (3H,
s, Me), 3.81 (3H, s, OMe), 6.90 (2H, d, J = 9.0 Hz, Ar), 7.04 (2H, d, J = 9.0 Hz, Ar), 7.45–7.59 (3H, m, Ph),
7.50 (1H, d, J = 12.1 Hz, CHNH), 7.89–7.93 (2H, m, Ph), 8.95 (1H, br s, NHCO), 9.69 (1H, d, J = 12.1
Hz, CHNH). Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.40; H, 5.95; N, 9.23.
(Z)-3-Benzoylamino-4-(4-fluoro-3-chlorophenyl)amino-2-oxo-3-butene (11b). This compound was
prepared from 4-fluoro-3-chloroaniline (10b) (146 mg, 1 mmol), stirred for 8 h. Volatile components
were evaporated in vacuo, the residue was triturated with ethanol, and the precipitate was collected by
1
filtration to give 11b in (240 mg, 72%); mp 163–166°C (from ethanol). H NMR (300 MHz, CDCl3): δ
2.45 (3H, s, Me), 6.89–6.95 (1H, m, Ar), 7.08–7.15 (2H, m, Ar), 7.40 (1H, d, J = 11.7 Hz, CHNH), 7.47–
7.61 (3H, m, Ph), 7.89–7.93 (2H, m, Ph), 8.98 (1H, br s, NHCO), 9.98 (1H, d, J = 11.7 Hz, CHNH). Anal.
Calcd for C17H14N2O2FCl: C, 61.36; H, 4.24; N, 8.42. Found: C, 61.22; H, 4.31; N, 8.17.
(Z)-3-Benzoylamino-4-phenylamino-2-oxo-3-butene (11c). This compound was prepared from aniline
(10c) (93 mg, 1 mmol), stirred for 24 h. Volatile components were evaporated in vacuo, the residue was
triturated with ethanol, and the precipitate was collected by filtration to give 11c (224 mg, 80%); mp 155–
1
159°C (from ethanol and toluene). H NMR (300 MHz, CDCl3): δ 2.44 (3H, s, Me), 7.02–7.10 (3H, m,
Ph), 7.31–7.38 (2H, m, Ph), 7.46–7.59 (3H, m, Ph), 7.58 (1H, d, J = 12.1 Hz, CHNH), 7.90–7.94 (2H, m,
Ph), 8.95 (1H, br s, NHCO), 9.85 (1H, d, J = 12.1 Hz, CHNH). Anal. Calcd for C17H16N2O2: C, 72.84; H,
5.75; N, 9.99. Found: C, 73.20; H, 5.79; N, 10.08.
(Z)-3-Benzoylamino-4-(3-bromophenyl)amino-2-oxo-3-butene (11d). This compound was prepared
from 3-bromoaniline (10d) (172 mg, 1 mmol), stirred for 5 h. Volatile components were evaporated in
vacuo, the residue was triturated with ethanol, and the precipitate was collected by filtration to give 11d
1
(169 mg, 47%); mp 145–147°C (from ethanol). H NMR (300 MHz, CDCl3): δ 2.46 (3H, s, Me), 6.99
(1H, ddd, J = 1.9, 1.9, 7.2 Hz, Ar), 7.16 (1H, ddd, J = 1.9, 1.9, 7.9 Hz, Ar), 7.17–7.23 (2H, m, Ar), 7.48
(1H, d, J = 11.2 Hz, CHNH), 7.46–7.60 (3H, m, Ph), 7.89–7.93 (2H, m, Ph), 8.97 (1H, br s, NHCO),
10.01 (1H, d, J = 11.2 Hz, CHNH). Anal. Calcd for C17H15N2O2Br: C, 56.84; H, 4.21; N, 7.80. Found: C,
57.07; H, 4.13; N, 7.63.
(Z)-3-Benzoylamino-4-(2-methylphenyl)amino-2-oxo-3-butene (11e). This compound was prepared
from 2-methylaniline (10e) (107 mg, 1 mmol), stirred for 24 h. Volatile components were evaporated in
vacuo, the residue was triturated with water and ethanol, and the precipitate was collected by filtration to

1
give 11e (256 mg, 87%); mp 108–110°C (from ethanol). H NMR (300 MHz, CDCl3): δ 2.43 (3H, s, 2-
Me), 2.44 (3H, s, Me), 6.99 (1H, ddd, J = 1.1, 7.4, 7.4 Hz, Ar), 7.06 (1H, br d, J = 1.1 Hz, Ar), 7.17–7.24
(2H, m, Ar), 7.45–7.58 (3H, m, Ph), 7.59 (1H, d, J = 11.7 Hz, CHNH), 7.90–7.94 (2H, m, Ph), 8.94 (1H,
br s, NHCO), 9.80 (1H, d, J = 11.7 Hz, CHNH). Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52.
Found: C, 73.32; H, 6.11; N, 9.46.
(Z)-3-Benzoylamino-4-(3-nitrophenyl)amino-2-oxo-3-butene (11f). This compound was prepared from
3-nitroaniline (10f) (138 mg, 1 mmol), heated under reflux for 45 min. Volatile components were
evaporated in vacuo, the residue was triturated with ethanol, and the precipitate was collected by filtration
1
to give 11f (198 mg, 61%); mp 177–179°C (from ethanol). H NMR (300 MHz, CDCl3): δ 2.51 (3H, s,
Me), 7.36 (1H, ddd, J = 1.1, 2.2, 8.2 Hz, Ar), 7.46–7.62 (5H, m, Ph, Ar, CHNH), 7.85–7.96 (4H, m, Ph,
Ar), 9.03 (1H, br s, NHCO), 10.36 (1H, d, J = 10.9 Hz, CHNH). Anal. Calcd for C17H15N3O4: C, 62.76;
H, 4.65; N, 12.92. Found: C, 62.80; H, 4.73; N, 12.62.
(Z)-3-Benzoylamino-4-(5-chloropyridin-2-yl)amino-2-oxo-3-butene (11g). This compound was
prepared from 2-amino-5-chloropyridine (10g) (129 mg, 1 mmol), stirred for 24 h. The precipitate was
1
collected by filtration to give 11g (275 mg, 87%); mp 175–178°C (from ethanol). H NMR (300 MHz,
CDCl3): δ 2.51 (3H, s, Me), 6.81 (1H, dd, J = 0.7, 8.6 Hz, H3'), 7.46–7.61 (3H, m, Ph), 7.55 (1H, dd, J =
2.6, 8.6 Hz, H4'), 7.89–7.94 (2H, m, Ph), 8.23 (1H, dd, J = 0.7, 2.6 Hz, H6'), 8.34 (1H, d, J = 10.5 Hz,
CHNH), 9.05 (1H, br s, NHCO), 10.59 (1H, d, J = 10.5 Hz, CHNH). Anal. Calcd for C16H14N3O2Cl: C,
60.86; H, 4.47; N, 13.31. Found: C, 60.88; H, 4.50; N, 13.38.
(Z)-3-Benzoylamino-4-(4-methylpyridin-2-yl)amino-2-oxo-3-butene (11h). This compound was
prepared from 2-amino-4-methylpyridine (10h) (108 mg, 1 mmol), stirred for 48 h. Volatile components
were evaporated in vacuo, the residue was triturated with ethanol and water, and the precipitate was
1
collected by filtration to give 11h (80 mg, 27%); mp 170–173°C (from ethanol). H NMR (300 MHz,
CDCl3): δ 2.31 (3H, s, 4-Me), 2.50 (3H, s, Me), 6.68–6.76 (2H, m, H3', H5'), 7.46–7.60 (3H, m, Ph), 7.90–
7.95 (2H, m, Ph), 8.14 (1H, d, J = 5.3 Hz, H6'), 8.44 (1H, d, J = 11.7 Hz, CHNH), 9.03 (1H, br s, NHCO),
10.35 (1H, d, J = 11.7 Hz, CHNH). Anal. Calcd for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23. Found: C,
69.39; H, 5.81; N, 14.32.
(Z)-3-Benzoylamino-4-(pyridin-2-yl)amino-2-oxo-3-butene (11i). This compound was prepared from
2-aminopyridine (10i) (94 mg, 1 mmol), stirred for 48 h. Volatile components were evaporated in vacuo,
the residue was triturated with ethanol and water, and the precipitate was collected by filtration to give

11i (76 mg, 27%); mp 161–163°C (from ethanol). 1H NMR (300 MHz, CDCl3): δ 2.51 (3H, s, Me), 6.85
(1H, ddd, J = 0.8, 1.0, 8.2 Hz, H3'), 6.91 (1H, ddd, J = 1.0, 5.0, 7.3 Hz, H5'), 7.46–7.57 (3H, m, Ph), 7.59
(1H, ddd, J = 2.0, 7.3, 8.2 Hz, H4'), 7.90–7.95 (2H, m, Ph), 8.29 (1H, ddd, J = 0.8, 2.0, 5.0 Hz, H6'), 8.45
(1H, d, J = 10.9 Hz, CHNH), 9.03 (1H, br s, NHCO), 10.42 (1H, d, J = 10.9 Hz, CHNH). Anal. Calcd for
C16H15N3O2: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.46; H, 5.36; N, 14.82.
(Z)-3-Benzoylamino-4-(3-hydroxypyridin-2-yl)amino-2-oxo-3-butene (11j). This compound was
prepared from 2-amino-3-hydroxypyridine (10j) (110 mg, 1 mmol), stirred for 24 h. Volatile components
were evaporated in vacuo, the residue was triturated with ethanol, and the precipitate was collected by
1
filtration to give 11j (74 mg, 25%); mp 222–224°C (from ethanol). H NMR (300 MHz, CDCl3): δ 2.53
(3H, s, Me), 6.75 (1H, dd, J = 4.9, 7.5 Hz, H5'), 6.96 (1H, dd, J = 1.5, 7.5 Hz, H4'), 7.45–7.60 (3H, m, Ph),
7.84 (1H, dd, J = 1.5, 4.9 Hz, H6'), 7.92–7.96 (2H, m, Ph), 8.49 (1H, d, J = 12.0 Hz, CHNH), 9.02 (1H, br
s, NHCO), 10.22 (1H, d, J = 12.0 Hz, CHNH). Anal. Calcd for C16H15N3O3: C, 64.64; H, 5.06; N, 14.13.
Found: C, 65.01; H, 5.18; N, 14.26.
(Z)-3-Benzoylamino-4-(5-nitropyridin-2-yl)amino-2-oxo-3-butene (11k). This compound was
prepared from 2-amino-5-nitropyridine (10k) (139 mg, 1 mmol), stirred for 24 h. Volatile components
were evaporated in vacuo, the residue was triturated with ethanol, and the precipitate was collected by
1
filtration to give 11k (114 mg, 35%); mp 205–208°C (from ethanol and toluene). H NMR (300 MHz,
CDCl3): δ 2.56 (3H, s, Me), 6.88 (1H, d, J = 9.0 Hz, H3'), 7.49–7.63 (3H, m, Ph), 7.90–7.95 (2H, m, Ph),
8.36 (1H, dd, J = 2.6, 9.0 Hz, H4'), 8.37 (1H, d, J = 10.9 Hz, CHNH), 9.14 (1H, br s, NHCO), 9.17 (1H, d,
J = 2.6 Hz, H6'), 11.42 (1H, d, J = 10.9 Hz, CHNH). Anal. Calcd for C16H14N4O4: C, 58.89; H, 4.32; N,
17.17. Found: C, 58.97; H, 4.29; N, 17.22.
(Z) 3-Benzoylamino-4-(pyrimidin-2-yl)amino-2-oxo-3-butene (11l). This compound was prepared
from 2-aminopyrimidine (10l) (95 mg, 1 mmol), stirred for 48 h. Volatile components were evaporated in
vacuo, the residue was triturated with ethanol, and the precipitate was collected by filtration to give 11l
1
(116 mg, 41%); mp 168–170°C (from ethanol). H NMR (300 MHz, CDCl3): δ 2.52 (3H, s, Me), 6.88
(1H, t, J = 4.9 Hz, H5'), 7.46–7.59 (3H, m, Ph), 7.93–7.98 (2H, m, Ph), 8.31 (1H, d, J = 11.3 Hz, CHNH),
8.50 (2H, d, J = 4.9 Hz, H4', H6'), 8.94 (1H, br s, NHCO), 10.52 (1H, d, J = 11.3 Hz, CHNH). Anal. Calcd
for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.79; H, 4.93; N, 19.78.
(Z)-3-Benzoylamino-4-(4,6-dimethylpyrimidin-2-yl)amino-2-oxo-3-butene (11m). This compound
was prepared from 2-amino-4,6-dimethylpyrimidine (10m) (123 mg, 1 mmol), stirred for 48 h. Volatile

components were evaporated in vacuo, the residue was triturated with ethanol, and the precipitate was
1
collected by filtration to give 11m (124 mg, 40%); mp 178–180°C (from ethanol). H NMR (300 MHz,
CDCl3): δ 2.40 (6H, s, 2 × Me), 2.51 (3H, s, Me), 6.63 (1H, s, H5'), 7.45–7.59 (3H, m, Ph), 7.92–7.97
(2H, m, Ph), 8.39 (1H, d, J = 11.3 Hz, CHNH), 8.87 (1H, br s, NHCO), 10.09 (1H, d, J = 11.3 Hz,
CHNH). Anal. Calcd for C17H18N4O2: C, 65.79; H, 5.84; N, 18.05. Found: C, 65.76; H, 5.88; N, 17.91.
(Z)-3-Benzoylamino-4-(pyrazin-2-yl)amino-2-oxo-3-butene (11n). This compound was prepared from
2-aminopyrazine (10n) (95 mg, 1 mmol), stirred for 48 h. Volatile components were evaporated in vacuo,
the residue was triturated with ethanol, and the precipitate was collected by filtration to give 11n (175 mg,
1
62%); mp 159–161°C (from ethanol). H NMR (300 MHz, CDCl3): δ 2.52 (3H, s, Me), 7.48–7.62 (3H,
m, Ph), 7.91–7.96 (2H, m, Ph), 8.15 (1H, d, J = 2.6 Hz, H6'), 8.20 (1H, dd, J = 1.5, 2.6 Hz, H5'), 8.29 (1H,
d, J = 10.9 Hz, CHNH), 8.30 (1H, d, J = 1.5 Hz, H3'), 9.08 (1H, br s, NHCO), 10.84 (1H, d, J = 10.9 Hz,
CHNH). Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.67; H, 4.94; N, 19.89.
3-Benzoylamino-4-(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-oxo-3-
butene Dimethylamine (13). A mixture of 1,3-dimethylbarbituric acid (12) (156 mg, 1 mmol) and (Z)-3-
benzoylamino-4-dimethylamino-2-oxo-3-butene (4) (232 mg, 1 mmol) in acetic acid (2 mL) was stirred at
rt for 24 h. Volatile components were evaporated in vacuo, the residue was triturated with ether and
ethanol, and the precipitate was collected by filtration to give 13 (346 mg, 89%); mp 164–168°C (from
ethyl acetate and ethanol). 1H NMR (300 MHz, CDCl3): δ 2.32 (3H, s, Me), 2.77 (6H, s, NMe2), 3.31 (6H,
s, 2 × NMe), 6.97 (1H, s, CH), 7.43–7.57 (3H, m, Ph), 8.01–8.06 (2H, m, Ph), 11.64 (1H, br s, NHCO).
Anal. Calcd for C17H17N3O5 ×·NHMe2: C, 58.75; H, 6.23; N, 14.42. Found: C, 58.78; H, 6.27; N, 14.44.
3-Benzoylamino-4-(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl-)-2-oxo-3-
butene (13a). To the 3-benzoylamino-4-(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
dinyl-5)-2-oxo-3-butene dimethylamine (13) (388 mg, 1 mmol) hydrochloric acid (2%, 10 mL) was added
and stirred at rt for 15 min and the mixture was extracted with chloroform. The organic layer was dried
over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo to give 13a (295 mg,
1
86%); mp 127–130°C (from ethanol). H NMR (300 MHz, CDCl3): δ 2.60 (3H, s, Me), 3.38 (6H, s, 2 ×
NMe), 7.48–7.65 (4H, m, Ph, OH), 8.09–8.15 (2H, m, Ph), 8.54 (1H, s, CH) 14.09 (1H, br s, NHCO).
Anal. Calcd for C17H17N3O5: C, 59.47; H, 4.99; N, 12.24. Found: C, 59.28; H, 4.96; N, 11.93.
6-Benzoylamino-1,3,7-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine (14). To the 3-
benzoylamino-4-(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-oxo-3-butene

dimethylamine (13a) (388 mg, 1 mmol) in ethanol (4 mL) aqueus ammonia (25%, 2 mL) was added and
the mixture was stirred at rt for 3 days. The precipitate was collected by filtration to give 14 (48 mg, 15%
1
yield; mp 225–226°C (from ethanol). H NMR (300 MHz, CDCl3): δ 2.64 (3H, s, Me), 3.43 (3H, s,
NMe), 3.47 (3H, s, NMe), 7.50–7.59 (3H, m, Ph), 8.05–8.09 (2H, m, Ph), 8.43 (1H, s, H5), 14.04 (1H, br
s, NHCO). Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 62.94; H, 4.87; N, 17.00.
ACKNOWLEDGEMENTS
The financial support from the Ministry of Education, Science and Sport, Slovenia, through grant PS-
0502-0103, is gratefully acknowledged.
The crystallographic data 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 Education, Science and Sport,
Republic of Slovenia through grant Packet X-2000 and PS-511-103, which thus made the purchase of the
apparatus possible.
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