Synthesis and transformations of ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate

Article abstract of DOI:10.1023/A:1014505209422

Ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate was prepared in one step from ethyl (2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)acetate and bis(dimethylamino)-tert-butoxymethane and treated with various amines and hydrazines to afford the corresponding amino substituted products. Reactions of the titled compound with N,N′-, C,N-, and C, O′-ambident nucleophiles in refluxing acetic acid furnished the corresponding fused pyrimidinones, quinolizinones, and pyranones.

Full text of DOI:10.1023/A:1014505209422

Chemistry of Heterocyclic Compounds, Vol. 37, No. 12, 2001
SYNTHESIS AND TRANSFORMATIONS
Z
OF ETHYL ( )-2-(2,3-DIHYDRO-1,3-DIOXO-
1H-ISOINDOL-2-YL)-3-(DIMETHYL-
AMINO)PROPENOATE*
D. Bevk, M. Kmetic, S. Recnik, J. Svete, L. Golic, A. Golobic, and B. Stanovnik
Ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate was prepared in
one step from ethyl (2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)acetate and bis(dimethylamino)-tert-
butoxymethane and treated with various amines and hydrazines to afford the corresponding amino
substituted products. Reactions of the titled compound with N,N'-, C,N-, and C,O'-ambident
nucleophiles in refluxing acetic acid furnished the corresponding fused pyrimidinones, quinolizinones,
and pyranones.
Keywords: amines, enaminones, isoindole, pyranones, pyrimidinones, quinolizinones, cyclizations.
Quinolizines [1], pyridopyrimidines [2], 2H-pyran-2-ones [3], and related systems are the constituents
of many naturally occurring compounds and their synthetic derivatives exhibiting various biological activities.
Such examples of important heterocyclic compounds are aminosubstituted fused heterocyclic systems with a
bridgehead nitrogen atom which have been utilized as versatile scaffolds and peptide mimetics [4] (Fig. 1).
Alkyl 2-acylamino-3-(dimethylamino)propenoates are an important subclass of 2-substituted alkyl
3-(dimethylamino)propenoates and their cyclic analogs which are easily available, efficient, and versatile
reagents for the preparation of
a
variety of heterocyclic systems. Alkyl 2-acylamino-3-
(dimethylamino)propenoates were employed as reagents in one step syntheses of alkyl 2-acylamino-3-
,β-dehydro-
(substituted amino)propenoates as
-amino acid derivatives, and heterocycles with incorporated
α
α
S
N
N
N
NH2
NH2
NH2
HOOC
O
O
HOOC
O
HOOC
quinolizine-type
thiazolo[3,2-a]pyridinone-type
indolizine-type
Fig. 1. Some examples of heterocyclic systems as scaffolds for peptide mimetics
_______
* Dedicated to Professor Edmunds Lukevics on the occasion of his 65th birthday.
__________________________________________________________________________________________
Faculty of Chemistry and Chemical Technology, University of Ljubljana, P.O.B. 537, Askerceva 5, 1001
Ljubljana, Slovenia; e-mail: branko.stanovnik@uni-lj.si, jurij.svete@uni-lj.si. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 12, pp. 1651-1663, December, 2001. Original article submitted July 20,
2001.
1498
0009-3122/01/3712-1493$25.00©2001 Plenum Publishing Corporation

-amino acid structural element. In this manner, various heterocyclic systems, such as acylamino-substituted
α
azolo- and azino-fused pyridinones, pyrimidinones, pyranones, and their tetrahydro analogs, have been
prepared. To date, several reviews on this topic have been published [5, 6]. In continuation of our research, we
report the preparation of ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate (1)
and its transformations with amines, hydrazines, and ambident 1,3-dinucleophiles into phthaloylimino
substituted propenoates and heterocyclic systems, which can be deprotected with hydrazine hydrate to give free
amino compounds.
Results and Discussion
Ester 1 was prepared in 93% yield from ethyl 2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)acetate (2) and
bis(dimethylamino)-tert-butoxymethane (Bredereck's reagent). Treatment of 1 with amines 3-8 or
3-hydrazinopyridazines 9, 10 in refluxing ethanol in the presence of equimolar amounts of hydrochloric acid
proceeded by substitution of the dimethylamino group.
Scheme 1
COOEt
R
NH
COOEt
NPhth
R
NH
NPhth
11–16
11'–14'
R-NH2, EtOH, HCl, reflux
3–8
NMe
NMe
2
-BuO
t
COOEt
COOEt
2
DMF, 120o
O
N
O
O
Me2N
N
N
NPhth =
O
O
O
1
2
R-NHNH2, EtOH, HCl, r.t.
9, 10
COOEt
NPhth
COOEt
HN
R
N
HN NH
R
NPhth
17,18
17',18'
Compound
R
Ratio of isomers (in DMSO-d6)
= 83 : 17
4-Methylphenyl
Thiazol-2-yl
4-Methylpyridin-2-yl
5-Chloropyridin-2-yl
4-Methylpyrimidin-2-yl
6-Chloropyridazin-3-yl
6-Chloropyridazin-3-yl
6-Phenylpyridazin-3-yl
3, 11, 11'
4, 12, 12'
5, 13, 13'
6, 14, 14'
7, 15, 15'
8, 16, 16'
9, 17, 17'
10, 18, 18'
11 11'
:
12 : 12' = 88 : 12
13 : 13' = 90 : 10
14 : 14' = 75 : 25
15 : 15' = 100 : 0
16 : 16' = 100 : 0
17 : 17' = 88 : 12
18 : 18' = 88 : 12
1499

With amines 3-8 the corresponding substitution products, ethyl 2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-
yl)-3-(substituted amino)propenoates 11-16, were prepared in 13-80% yields. Propenoates 11-14 exist in
DMSO-d6 solution as mixtures of the major (Z)-isomers (11-14) and the minor (E)-isomers (11'-14'), while
propenoates 2, 15, and 16 exist in DMSO-d6 solution as the (Z)-isomers, exclusively. Similarly, acid catalyzed
treatment of 1 with 3-hydrazinopyridazine derivatives 9, 10 in ethanol at room temperature afforded
3-hydrazinopropenoates 17, 18. In DMSO-d6 solution, equilibrium between the hydrazines 17, 18 as the major
and their hydrazono forms as the minor tautomers 17', 18', respectively, was established (Scheme 1).
On the other hand, heating of ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-
(dimethylamino)propenoate (1) in acetic acid with 2-aminothiazole (4), 2-amino-4-methylpyridine (5), and
2-aminopyridine (19) as N,N'-ambident nucleophiles afforded the corresponding pyrimidinones 20-22 in
15-64% yield. Similarly, treatment with ethyl 2-pyridineacetate (23) and 2-pyridineacetonitrile (24) as
C,N-ambident nucleophiles furnished quinolizinone derivatives 25, 26, while with C,O-ambident nucleophiles,
such as ethyl acetoacetate (27), 1,3-cyclohexanedione (28), 5,5-dimethyl-1,3-cyclohexanedione (29), 4-hydroxy-
2-pyridone (30), and 4-hydroxy-6-methyl-2H-pyran-2-one (31), the corresponding fused pyranones 32-36 were
obtained in 46-81% yield (Scheme 2).
Heating of 1 with 1,3-cyclopentanedione (37) or with 1,3-dimethylbarbituric acid (38) in acetic acid
under reflux resulted in decomposition of starting material giving inseparable mixtures as products. However,
upon heating at 80-100° the corresponding propenoates 39, 40 were obtained in the form of dimethylammonium
salts. Formation of salts 39, 40 offers additional evidence of the mechanism of dimethylamine substitution,
which, according to our previous observations, proceeds via addition-elimination mechanism. In some cases, the
adducts have also been isolated [7]. The difference between the propenoates 39, 40 and the adducts 41, 42 as
1
intermediates with the same molecular formula was clearly seen in the H NMR spectra, where the protons at
the 3-position, i.e., the proton attached to the double bond, in compounds 39 and 40 appeared as singlets with
chemical shifts 7.71 and 8.25 ppm, respectively (Scheme 3).
δ
3-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one
(21)
and
ethyl
3-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-4H-quinolizin-4-one-1-carboxylate (25) were treated with hydrazine
hydrate in refluxing ethanol in order to achieve the deprotection of the amino group at the 3-position. In both
cases, the corresponding free amino compounds, 3-amino-4H-pyrido[1,2-a]- pyrimidin-4-one (43) and 3-amino-
4H-quinolizin-4-one (44), were obtained in 86 and 28% yield, respectively (Scheme 4).
The structures of novel compounds 1, 11-18, 20-22, 25, 26, 32-36 were confirmed by spectroscopic
methods and by elemental analyses for C, H, and N. Their spectral data are in agreement with the literature data
for closely related compounds [5, 6].
The configuration around the C=C double bond in compound 1 was determined by NMR (HMBC
3
technique) on the basis of the magnitude of the long-range heteronuclear coupling constant, JC–H = 3.0 Hz,
which indicated the cis-relationship between the proton at the position 3 and the carbonyl carbon atom at the
position 1. For compound 13, which exists in DMSO-d6 solution as a mixture of the (Z)-isomer 13 and
(E)-isomer 13' in a ratio of 90:10, respectively, the isomerization around the C=C double bond in DMSO-d6
solution was also confirmed by HMBC experiment which showed different magnitudes of heteronuclear
3
3
3
coupling constants: JC–H = 2.5 Hz for the (Z)-isomer 13 and JC–H = 9.0 Hz for the (E)-isomer 13'. JC–H
Coupling constants are in agreement with previously observed 3J values for the (Z)- and (E)-isomers of closely
related propenoates [8-10] (Fig. 2). The structure of compound 1 was also confirmed by X-ray diffraction
(Fig. 3).
1500

Scheme 2
S
NH
2
N
S
4N
N
N
NPhth
NPhth
O
20
R
NH
2
N
R
N
19 (R = H)
5
(R = Me)
O
R
21 (R = H)
22 (R = Me)
N
R
23 (R = COOEt)
24 (R = CN)
N
NPhth
O
COOEt
25 (R = COOEt)
Me
O
26 (R = CN)
O
EtOOC
Me2N
N
AcOH, reflux
27
Me
O
O
O
R
R
O
EtOOC
NPhth
32
1
O
R
28 (R = H)
O
O
29 (R = Me)
R
NPhth
O
OH
33 (R = H)
HN
Me
34 (R = Me)
O
30
O
O
HN
O
NPhth
OH
O
O
35
O
O
31
Me
O
O
NPhth
36
1501

Scheme 3
Me
N
O
O
O
O
N
Me
38
37
AcOH, 100o
O
AcOH, 80o
1
O
N
O
Me
OH
COOEt
N
Me
OH
COOEt
O
O
Me2N
N
O
O
Me2N
N
O
41
42
O
Me2NH2
COOEt
O
Me
O
N
O
Me2NH2
COOEt
Me
N
O
O
O
N
O
O
N
39
40
Scheme 4
O
O
N2H4 H O,
.
EtOH, re2flux
N
N
NH
NH
O
O
+
N
N
N
N
NH2
O
O
O
43
45
21
COOEt
COOEt
N2H4 . H2O,
EtOH, reflux
+
45
N
NH2
N
O
44
O
25
O
1502

3JC–H = 3.0 Hz
3JC–H = 2.5 Hz
3JC–H = 9.0 Hz
H
H
COOEt
O
H
R
N
COOEt
O
COOEt
O
N
Me2N
N
N
R
N
H
H
O
O
O
13
(Z)-isomer
R = 4-methylpyrimidin-2-yl
1
13'
(E)-isomer
(Z)-isomer
Fig. 2. NMR determination of configuration around the C=C double bond
in compounds 1 and 13 by the 2D HMBC technique.
Fig. 3. Ortep view of the asymmetric unit of 1 with labelling of non-hydrogen atoms.
(Ellipsoids are drawn at 50% probability level.)
TABLE 1. Crystallographic data for compound 1
Crystal data
1
2
Chemical formula
Relative weight
Crystal system
C15H16N2O4
288.3
monoclinic
P21/c, No. 14
11.630(1)
8.343(1)
13.069(1)
96.49(1)
2978.7(8)
4
Space group
a, Å
b, Å
c, Å
β (°)
V, Å3
Z
1503

TABLE 1 (continued)
1
2
Calc. density Dx, Mg·m-3
Radiation type
Wavelength, Å
No. of refl. for cell param.
θ range (°) for cell param.
µ, mm-1
1.286
MoKα
0.71069
75
10.0-17.9
0.094
Temperature, K
Crystal shape
Crystal size, mm
Crystal color
293(1)
prism
0.40×0.32×0.32
yellow
Data collection
Diffractometer
Enraf Nonius CAD-4
ω-2θ scans
None
18826
5850
3108
I >2.5σ(I)
0.023
26
Data collection method
Absorption correction
No. of measured refl.
No. of independent refl.
No. of observed refl.
Criterion of observed refl.
Rint
θmax (°)
→
→
→
→
13
→
19
→
20
Range of h, k, l
-13
-13
-20
h
k
l
Intensity decay (%)
0.37
Refinement
Refinement on
R
F
0.068
0.073
4614
484
wR
No. of contributing refl.
No. of parameters
(∆/σ)max
0.0097
0.494
-0.457
∆ρmax, eA-3
∆ρmin, eA-3
TABLE 2. Bond distances with e.s.d.'s in parentheses for compound 1
Bond
1
d, Å
2
Bond
3
d, Å
4
C(1a)–C(2a)
1.456(6)
1.361(5)
1.474(6)
1.388(6)
1.378(6)
1.389(9)
1.37(1)
1.384(8)
1.377(7)
1.482(5)
C(1b)–C(2b)
1.442(6)
1.349(5)
1.485(5)
1.377(6)
1.376(5)
1.379(7)
1.375(8)
1.371(7)
1.377(6)
1.481(5)
C(2a)–C(3a)
C(6a)–C(7a)
C(7a)–C(8a)
C(7a)–C(12a)
C(8a)–C(9a)
C(9a)–C(10a)
C(10a)–C(11a)
C(11a)–C(12a)
C(12a)–C(13a)
C(2b)–C(3b)
C(6b)–C(7b)
C(7b)–C(8b)
C(7b)–C(12b)
C(8b)–C(9b)
C(9b)–C(10b)
C(10b)–C(11b)
C(11b)–C(12b)
C(12b)–C(13b)
1504

TABLE 2 (continued)
1
2
3
4
C(14a)–C(15a)
O(1a)–C(1a)
O(2a)–C(1a)
O(2a)–C(14a)
O(3a)–C(6a)
O(4a)–C(13a)
N(1a)–C(3a)
N(1a)–C(4a)
N(1a)–C(5a)
N(2a)–C(2a)
N(2a)–C(6a)
N(2a)–C(13a)
1.480(8)
1.210(5)
1.352(5)
1.451(6)
1.202(5)
1.210(5)
1.326(5)
1.449(7)
1.448(6)
1.424(4)
1.398(5)
1.391(5)
C(14b)–C(15b)
O(1b)–C(1b)
O(2b)–C(1b)
O(2b)–C(14b)
O(3b)–C(6b)
O(4b)–C(13b)
N(1b)–C(3b)
N(1b)–C(4b)
N(1b)–C(5b)
N(2b)–C(2b)
N(2b)–C(6b)
N(2b)–C(13b)
1.43(1)
1.213(5)
1.333(6)
1.451(9)
1.209(5)
1.193(5)
1.329(5)
1.459(6)
1.452(6)
1.436(4)
1.379(5)
1.407(5)
TABLE 3. Bond angles with e.s.d.'s in parentheses for compound 1
Angle
ω,deg.
Angle
ω,deg.
C(1a)–O(2a)–C(14a)
C(3a)–N(1a)–C(4a)
C(3a)–N(1a)–C(5a)
C(4a)–N(1a)–C(5a)
C(2a)–N(2a)–C(6a)
C(2a)–N(2a)–C(13a)
C(6a)–N(2a)–C(13a)
O(1a)–C(1a)–O(2a)
O(1a)–C(1a)–C(2a)
O(2a)–C(1a)–C(2a)
N(2a)–C(2a)–C(1a)
N(2a)–C(2a)–C(3a)
C(1a)–C(2a)–C(3a)
N(1a)–C(3a)–C(2a)
O(3a)–C(6a)–N(2a)
O(3a)–C(6a)–C(7a)
N(2a)–C(6a)–C(7a)
C(6a)–C(7a)–C(8a)
C(6a)–C(7a)–C(12a)
C(8a)–C(7a)–C(12a)
C(7a)–C(8a)–C(9a)
C(8a)–C(9a)–C(10a)
C(9a)–C(10a)–C(11a)
C(10a)–C(11a)–C(12a)
C(7a)–C(12a)–C(11a)
C(7a)–C(12a)–C(13a)
C(11a)–C(12a)–C(13a)
O(4a)–C(13a)–N(2a)
O(4a)–C(13a)–C(12a)
N(2a)–C(13a)–C(12a)
O(2a)–C(14a)–C(15a)
116.3(3)
119.6(4)
124.5(4)
115.9(4)
123.9(3)
123.3(3)
110.9(3)
122.4(4)
124.1(4)
113.5(3)
112.5(3)
124.6(3)
122.9(3)
131.8(4)
124.0(4)
129.9(4)
106.1(3)
130.8(4)
108.7(3)
120.5(4)
116.6(5)
122.6(6)
120.6(6)
117.3(5)
122.4(4)
107.5(3)
130.1(4)
125.0(4)
128.4(4)
106.6(3)
107.7(5)
C(1b)–O(2b)–C(14b)
C(3b)–N(1b)–C(4b)
C(3b)–N(1b)–C(5b)
C(4b)–N(1b)–C(5b)
C(2b)–N(2b)–C(6b)
C(2b)–N(2b)–C(13b)
C(6b)–N(2b)–C(13b)
O(1b)–C(1b)–O(2b)
O(1b)–C(1b)–C(2b)
O(2b)–C(1b)–C(2b)
N(2b)–C(2b)–C(1b)
N(2b)–C(2b)–C(3b)
C(1b)–C(2b)–C(3b)
N(1b)–C(3b)–C(2b)
O(3b)–C(6b)–N(2b)
O(3b)–C(6b)–C(7b)
N(2b)–C(6b)–C(7b)
C(6b)–C(7b)–C(8b)
C(6b)–C(7b)–C(12b)
C(8b)–C(7b)–C(12b)
C(7b)–C(8b)–C(9b)
C(8b)–C(9b)–C(10b)
C(9b)–C(10b)–C(11b)
C(10b)–C(11b)–C(12b)
C(7b)–C(12b)–C(11b)
C(7b)–C(12b)–C(13b)
C(11b)–C(12b)–C(13b)
O(4b)–C(13b)–N(2b)
O(4b)–C(13b)–C(12b)
N(2b)–C(13b)–C(12b)
O(2b)–C(14b)–C(15b)
115.7(4)
123.4(3)
120.5(3)
116.0(4)
125.0(3)
122.5(3)
111.4(3)
121.8(4)
124.5(4)
113.6(4)
113.2(3)
124.7(3)
122.0(3)
131.6(3)
125.1(3)
128.3(3)
106.6(3)
130.7(4)
107.8(3)
121.5(4)
117.4(4)
121.0(5)
121.4(5)
117.9(5)
120.8(4)
108.6(3)
130.6(4)
124.4(3)
130.0(4)
105.6(3)
110.0(6)
1505

EXPERIMENTAL
All starting materials and solvents were commercially available (in most cases from Fluka AG) and
purified following the standard techniques. Melting points were taken with a Kofler micro hot stage. The 1H and
13C NMR spectra were obtained with a Bruker Avance DPX 300 (300 MHz) spectrometer with DMSO-d6 and
CDCl3 as solvents and Me4Si as internal standard. IR spectra were recorded with a Perkin-Elmer Spectrum BX
FTIR instrument (KBr discs). The microanalyses for C, H, and N were obtained with a Perkin-Elmer CHN
Analyser 2400. TLC: Merck, Alufolien Kieselgel 60 F 254, 0.2 mm. Ethyl (2,3-dihydro-1,3-dioxo-1H-isoindol-
2-yl)acetate (2) was prepared according to the procedure described in the literature [11].
Z
A mixture
Ethyl ( )-2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate (1).
of ethyl (2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)acetate (2) (2.332 g, 10 mmol), bis(dimethylamino)-tert-
butoxymethane (3 ml, 15 mmol), and dimethylformamide (4 ml) was stirred under argon at 120°C for 4 h.
Volatile components were evaporated in vacuo and the oily residue was cooled to -15°C. Diethyl ether (5 ml)
and water (~5 drops) were added and the precipitate was collected by filtration and crystallized from
methanol–water to give 1. Yield 93% (2.685 g), yellow crystals; mp 124-126°C (methanol–water). IR, , cm-1:
ν
1780, 1680 (C=O). 1H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): 1.08 (3H, t, J = 7.0, OCH2CH3); 2.89 (6H,
δ
s, NMe2); 4.00 (2H, q, J = 7.0, OCH2CH3); 7.69 (1H, s, 3-H); 7.89- 7.97 (4H, m, phthaloyl). 13C NMR
(DMSO-d6, 75.5 MHz), , ppm, J (Hz): 15.3; 41.2; 60.1; 88.66; 124.5; 132.4; 135.8; 149.9; 166.0; 169.5.
δ
Found, %: C 62.78; H 5.39; N 9.44. C15H16N2O4. Calculated, %: C 62.49; H 5.59; N 9.72.
General Procedure for the Preparation of Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(N-
substituted amino)propenoates (11-16). Hydrochloric acid (37%, 3 drops, ~1 mmol) was added to a solution
of 1 (288 mg, 1 mmol) and amine 3-8 (1 mmol) in anhydrous ethanol (3 ml) and the reaction mixture was stirred
at 20-80°C for 1-12 h. The precipitate was collected by filtration, washed with a small amount of anhydrous
ethanol, and crystallized from an appropriate solvent. The following compounds were prepared in this manner:
Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-[(4-methylphenyl)amino]propenoate (11) was
prepared from 1 and 4-methylaniline (3); reflux for 1 h. Yield 80% (279 mg); mp 256-262°C (ethanol–water).
1
IR, , cm-1: 3310 (NH), 1710, 1670 (C=O). H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): major isomer 11:
ν
δ
1.17 (3H, t, J = 7.0, OCH2CH3); 2.26 (s, 3H, Me–Ar); 4.09 (2H, q, J = 7.0, OCH2CH3); 7.05 (2H, d, J = 8.3, 2H
of Ar); 7.14 (2H, d, JH2–H3 = 8.3, 2H of Ar); 7.89-7.98 (4H, m, phthaloyl); 8.19 (1H, d, J = 13.6, 3-H); 9.45 (1H,
d, J = 13.6, NH); minor isomer 11': 1.11 (3H, t, J = 7.0, OCH2CH3); 2.25 (3H, s, Me–Ar); 4,12 (2H, q, J = 7.0,
OCH2CH3); 8.02 (1H, d, J = 12.4, 3-H); 9.82 (1H, d, J = 12.4, NH). Found, %: C 68.87; H 5.04; N 7.92.
C20H18N2O4. Calculated, %: C 68.56; H 5.18; N 8.00.
Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-[(thiazol-2-yl)amino]propenoate (12) was
prepared from 1 and 2-aminothiazole (4); refluxed for 12 h. Yield 22% (75 mg); mp 223-225°C (ethanol). IR,
, cm-1: 3260 (NH), 1710, 1670 (C=O). 1H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): major isomer 12: 1.19
ν
δ
(3H, t, J = 7.0, OCH2CH3); 4.14 (2H, q, J = 7.0, OCH2CH3); 7.16 (1H, d, J = 3.4, 4'-H); 7.38 (1H, d, J = 3.4,
5'-H); 7.92-8.02 (4H, m, phthaloyl); 8.50 (1H, d, J = 9.4, 3-H); 11.00 (d, 1H, JCH–NH = 11.7, NH); minor isomer
12': 7.20 (1H, d, J = 3.4, 4'-H); 7.36 (d, 1H, J = 3.4, 5'-H). Found, %: C 55.62; H 3.97; N 11.94. C16H13N3O4S.
Calculated, %: C 55.97; H 3.82; N 12.24.
Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-[(4-methylpyridin-2-yl)amino]propenoate (13)
was prepared from 1 and 2-amino-4-methylpyridine (5); refluxed for 5 h. Yield 13% (45 mg), mp 254-258°C
1
(ethanol). IR, , cm-1: 3300 (NH), 1710, 1660 (C=O), 1300. H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz):
ν
δ
major isomer 13: 1.19 (3H, t, J = 7.0, OCH2CH3); 2.24 (3H, s, 4'-Me); 4.13 (2H, q, J = 7.0, OCH2CH3); 6.69
(1H, d, J = 1.5, 3'-H); 6.87 (1H, dd, J = 1.4; 5.2, 5'-H); 7.92-8.00 (4H, m, phthaloyl); 8.17 (1H, d, J = 5.2, 6'-H);
8.86 (1H, d, J = 12.8, 3-H); 9.94 (1H, d, J = 12.8, NH); minor isomer 13': 1.06 (3H, t, J = 7.0, OCH2CH3); 2.09
(3H, s, 4'-Me); 4.33 (2H, q, J = 7.0, OCH2CH3). Found, %: C 64.62; H 4.75; N 11.64. C19H17N3O4.
Calculated, %: C 64.95; H 4.88; N 11.96.
1506

Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-[(5-chloropyridin-2-yl)amino]propenoate (14)
was prepared from 1 and 2-amino-5-chloropyridine (6); refluxed for 10 h. Yield 45% (168 mg); mp 263-268°C
(methanol). IR, , cm-1: 3290 (NH), 1710, 1660 (C=O). 1H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): major
ν
δ
isomer 14: 1.18 (3H, t, J = 7.0, OCH2CH3); 4.17 (2H, q, J = 7.0, OCH2CH3); 6.90 (1H, d, J = 8.8, 3'-H); 7.81
(1H, dd, J = 2.6; 8.8, 4'-H); 7.93-8.01 (4H, m, phthaloyl); 8.36 (1H, d, J = 2.6, 6'-H); 8.78 (1H, d, J = 12.1, 3-H);
10.18 (1H, d, J = 12.1, NH); minor isomer 14': 1.12 (3H, t, J = 7.0, OCH2CH3); 4.17 (2H, q, J = 7.0, OCH2CH3);
7.44 (1H, d, J = 8.8, 3'-H); 8.29 (1H, d, J = 12.5, 3-H); 10.30 (1H, d, J = 12.4, NH). Found, %: C 57.85, H 3.65,
N 10.99. C18H14ClN3O4. Calcd., %: C 58.15, H 3.80, N 11.30.
Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-[(4-methylpyrimidin-2-yl)amino]propenoate
(15) was prepared from 2 and 2-amino-4-methylpyrimidine (7); refluxed for 2 h. Yield 31% (109 mg);
1
mp 233-246°C (ethanol). IR, , cm-1: 3280 (NH), 1710, 1670 (C=O). H NMR (DMSO-d6, 300 MHz), , ppm,
ν
δ
J (Hz): 1.19 (3H, t, J = 7.0, OCH2CH3); 4.14 (2H, q, J = 7.0, OCH2CH3); 7.00 (1H, d, J = 5.1, 5'-H); 7.88-7.96
(4H, m, phthaloyl); 8.46 (1H, d, J = 5.1, 6'-H); 8.80 (1H, d, J = 12.4, 3-H); 10.81 (1H, d, J = 12.4, NH).
Found, %: C 61.50; H 4.54; N 15.70. C18H16N4O4. Calculated, %: C 61.36; H 4.58; N 15.90.
Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-[(6-chloropyridazine-3-yl)amino]propenoate
(16) was prepared from 1 and 3-amino-6-chloropyridazine (8); refluxed for 7 h. Yield 13% (50 mg);
1
mp 328-330°C (ethanol). IR, , cm-1: 3300 (NH), 1710, 1670 (C=O). H NMR (DMSO-d6, 300 MHz), , ppm,
ν
δ
J (Hz): 1.21 (3H, t, J = 7.0, OCH2CH3); 4,17 (2H, q, J = 7.0, OCH2CH3); 7.29 (1H, d, J = 9.2, 4'-H); 7.76 (1H, d,
J = 9.2, 5'-H); 7.94-8.02 (4H, m, phthaloyl); 8.84 (1H, d, J = 12.0, 3-H); 10.32 (1H, d, J = 11.6, NH). Found, %:
C 54.61; H 3.35; N 14.52. C17H13ClN4O4. Calculated, %: C 54.78; H 3.52; N 15.03.
Ethyl 3-[(6-Chloropyridazin-3-yl)hydrazino]-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)propenoate
(17). A mixture of compound 1 (288 mg, 1 mmol), 6-chloro-3-hydrazinopyridazine (9) (129 mg, 1 mmol),
anhydrous ethanol (20 ml), and hydrochloric acid (37%, 3 drops, ~1 mmol) was stirred at room temperature for
3 h. Then water (5 ml) was added and the precipitate was collected by filtration, washed with anhydrous
ethanol, and crystallized from ethanol–water to give 17. Yield 21% (82 mg); mp 186-187°C (ethanol–water). IR,
, cm-1: 3480 (NH), 1740, 1720 (C=O). 1H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): major isomer 17: 1.14
ν
δ
(3H, t, J = 7.0, OCH2CH3); 4.05 (2H, q, J = 7.0, OCH2CH3); 7.00 (1H, d, J = 9.8, 4'-H); 7.72 (1H, d, J = 10.2,
3-H); 7.84-7.96 (4H, m, phthaloyl); 7.92 (1H, d, J = 9.8, 5'-H); 9.46 (1H, d, J = 10.2, Het–NH–NH); 9.63 (1H, s,
Het–NH–NH); minor isomer 17': 1.18 (3H, t, J = 7.0, OCH2CH3); 4.21 (2H, q, J = 7.0, OCH2CH3); 5.77 (1H, d,
J = 4.9, 2-H); 7.11 (1H, d, J = 9.8, 4'-H); 7.55 (1H, d, JH4–H5 = 9.8, 5'-H); 7.82 (1H, d, J = 4.5, 3-H); 11.65 (1H, s,
Het–NH). Found, %: C 52.41; H 3.50; N 17.85. C17H14ClN5O4. Calculated, %: C 52.65; H 3.64; N 18.06.
Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-[(6-phenylpyridazin-2-yl)hydrazino]propenoate
(18). A mixture of compound 1 (288 mg, 1 mmol), 3-hydrazino-6-phenylpyridazine (10) (171 mg, 1 mmol),
anhydrous ethanol (30 ml), and hydrochloric acid (37%, 3 drops, ~1 mmol) was stirred at room temperature for
4 h. The precipitate was collected by filtration, washed with anhydrous ethanol, and crystallized from
methanol/water to give 18. Yield 32% (136 mg); mp 214-216°C (from methanol water). IR, , cm-1: 3450 (NH),
ν
1
1750, 1720 (C=O). H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): major isomer 18: 1.15 (3H, t, J = 7.0,
δ
OCH2CH3); 4.05 (2H, q, J = 7.0, OCH2CH3); 7.04 (1H, d, J = 9.4, 4'-H); 7.42-7.54 (3H, m, 3H of Ph); 7.75 (1H,
d, J = 10.9, 3-H); 7.87-8.04 (6H, m, 4H of phthaloyl and 2H of Ph); 8.11 (1H, br d, J = 9.4, 5'-H); 9.50 (1H, d,
J = 10.9, Het–NH–NH); 9.52 (1H, s, Het–NH–NH); minor isomer 18': 1.20 (3H, t, J = 7.0, OCH2CH3); 4.22
(2H, q, J = 7.0, OCH2CH3); 5.80 (1H, d, J = 4.5, 2-H); 7.11 (1H, d, J = 9.4, 4'-H); 7.84 (1H, d, J = 4.9, 3-H);
11.58 (s, 1H, Het–NH). Found, %: C 64.39; H 4.46; N 16.31. C23H19N5O4. Calculated, %: C 64.33; H 4.46;
N 16.31.
General Procedure for the Preparation of Fused Pyrimidinones (20-22), Quinolizinones (25, 26),
and Pyranones (35, 36). A mixture of compound 1 (288 mg, 1 mmol), ambident nucleophile 4, 5, 19, 23, 24,
30, 31 (1 mmol), sodium acetate (328 mg, 4 mmol), and acetic acid (100%, 3 ml) was heated under reflux for
3-24 h. The reaction mixture was cooled, the precipitate was collected by filtration, and washed with water and
ethanol to give 20-22, 25, 26, 35, 36. The following compounds were prepared in this manner:
1507

a
was
6-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-5H-1,3-thiazolo[3,2- ]pyrimidin-5-one
(20)
prepared from 1 and 2-amino-1,3-thiazole (4); refluxed for 24 h. Yield 15% (44 mg); mp 330-334°C (washed
with hot methanol). IR, , cm-1: 1720, 1690 (C=O). 1H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): 7.75 (1H, d,
J = 4.9, 6-H); 7.94-8.04 (4H, m, phthaloyl); 8.18 (1H, d, J = 4.9, 7-H); 8.36 (s, 1H, 2-H). Found, %: C 56.73;
ν
δ
H 2.35; N 13.81. C14H7N3O3S. Calculated, %: C 56.56; H 2.37; N 14.13.
a
was prepared
3-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-4H-pyridino[1,2- ]pyrimidin-4-one (21)
from 1 and 2-aminopyridine (19); refluxed for 13 h. Yield 29% (75 mg); mp 344-346°C (washed with hot
methanol). IR, , cm-1: 1720, 1690 (C=O). H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): 7.55 (1H, deg dt,
1
ν
δ
J = 1.4; 6.9, 7-H); 7.90 (1H, dd, J = 1.4; 9.0, 9-H); 7.95-8.05 (4H, m, phthaloyl); 8.15 (1H, ddd, J = 1.6; 6.8; 8.9,
8-H); 8.60 (1H, s, 2-H); 9.07 (1H, dd, J = 1.6; 7.1, 6-H). Found, %: C 65.75; H 3.06; N 14.11. C16H9N3O3.
Calculated, %: C 65.98; H 3.11; N 14.43.
H
a
3-(2,3-Dihydro-1,3-dioxo-1 -isoindol-2-yl)-8-methyl-4H-pyridino[1,2- ]pyrimidin-4-one (22)
was
prepared from 1 and 2-amino-4-methylpyridine (5); refluxed for 13 h. Yield 64% (196 mg); mp 325-327°C
(washed with hot methanol). IR, , cm-1: 1730, 1680 (C=O). H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz):
1
ν
δ
2.55 (3H, s, 8-Me); 7.41 (1H, dd, J = 1.9, 7.2, 7-H); 7.72 (1H, d, J = 1.9, 9-H); 7.94-8.03 (4H, m, phthaloyl);
8.53 (1H, s, 2-H); 8.96 (1H, d, J = 7.2, 6-H). Found, %: C 66.88; H 3.50; N 13.46. C17H11N3O3. Calculated, %:
C 66.88; H 3.63; N 13.76.
Ethyl 3-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-4-oxo-4H-quinolizine-1-carboxylate (25) was
prepared from 1 and ethyl 2-pyridineacetate (23); refluxed for 5 h. Yield 58% (210 mg); mp 275-280°C
(ethanol). IR, , cm-1: 1720, 1680 (C=O). 1H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): 1.34 (3H, t, J = 7.0,
ν
δ
CH2CH3); 4.34 (2H, q, J = 7.0, CH2CH3); 7.59 (1H, ddd, J = 1.3; 6.9; 7.1, 7-H); 7.97-8.54 (4H, m, phthaloyl);
8.11 (1H, ddd, J = 1.1; 6.7; 9.3, 8-H); 8.65 (1H, s, 2-H); 9.24-9.28 (2H, m, 6-H and 9-H). Found, %: C 66.08;
H 3.86; N 7.56. C20H14N2O5. Calculated, %: C 66.30; H 3.89; N 7.73.
3-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-4-oxo-4H-quinolizine-1-carbonitrile (26) was prepared
from 1 and 2-pyridineacetonitrile (24); refluxed for 5 h. Yield 62% (196 mg), mp 307-310 C (from ethanol).
°
IR, , cm-1: 2360 (CN), 1720, 1680, 1650 (C=O). H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): 7.63 (1H,
1
ν
δ
ddd, J = 1.8; 6.5; 8.1, 7-H); 7.95-8.05 (4H, m, phthaloyl); 8.09-8.17 (2H, m, 8-H and 9-H); 8.47 (1H, s, 2-H);
9.23 (1H, dd, J = 1.1; 8.0; 6-H). Found, %: C 68.58; H 2.69; N 13.09. C18H9N3O3. Calculated, %: C 68.57;
H 2.88; N 13.33.
c
was
3-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-2H-pyrano[3,2- ]pyridin-2,5-(6H)-dione
(35)
prepared from 1 and 4-dihydroxypyridin-2-one (30); refluxed for 6 h. Yield 54% (167 mg); mp >350°C
(ethanol). IR, , cm-1: 3450 (NH), 1750, 1720, 1650 (C=O). H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz):
1
ν
δ
6.45 (1H, d, J = 7.3, 9-H); 7.77 (1H, d, J = 7.4, 8-H); 7.93-8.02 (4H, m, phthaloyl); 8.30 (1H, s, 4-H); 12.12 (1H,
br. s, NH). Found, %: C 62.2; H 2.69; N 8.89. C16H8N2O5. Calculated, %: C 62.34; H 2.62; N 9.09.
b
3-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-7-methyl-2H,5H-pyrano[4,3- ]pyran-2,5-dione
(36)
was prepared from 1 and 4-hydroxy-6-methyl-2H-pyran-2-one (31); refluxed for 7 h. Yield 81% (262 mg);
mp 297-300°C (ethanol). IR, , cm-1: 1720 (C=O). 1H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): 2.37 (s, 3H,
ν
δ
7-Me); 6.75 (1H, s, 8-H); 7.92-8.02 (4H, m, phthaloyl); 8.23 (1H, s, 4-H). Found, %: C 63.55; H 2.86; N 4.22.
C17H9NO6. Calculated, %: C 63.16; H 2.81; N 4.33.
General Procedure for the Preparation of Pyranones (32-34). A mixture of compound 1 (288 mg,
1 mmol), ambident nucleophile 27-29 (1 mmol), sodium acetate (328 mg, 4 mmol), and acetic acid (100%, 6 ml)
was heated under reflux for 2-3 h. Volatile components were evaporated in vacuo and ethanol (3 ml) was added
to the residue. The precipitate was collected by filtration and washed with water and ethanol to give 32-34. The
following compounds were prepared in this manner:
Ethyl 3-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-6-methyl-2-oxo-2H-pyran-5-carboxylate (32) was
prepared from 1 and ethyl acetoacetate (27); refluxed for 3 h. Yield 46% (150 mg); mp 184-186°C (decomp.)
(ethanol). 1H NMR (CDCl3, 300 MHz), , ppm, J (Hz): 1.35 (3H, t, J = 7.0, CH2CH3); 2.78 (s, 3H, 6-Me); 4.36
δ
1508

(2H, q, J = 7.0, CH2CH3); 7.76-8.13 (4H, m, phthaloyl); 8.04 (1H, s, 4-H). Found, %: C 61.95; H 3.85; N 4.28.
C17H13NO6. Calculated, %: C 62.39; H 4.00; N 4.28.
3-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-5,6,7,8-tetrahydro-2H-1-benzopyran-2,5-dione (33)
С
was prepared from 1 and cyclohexane-1,3-dione (28); refluxed for 2 h. Yield 57% (177 mg); mp 235-237.5°
1
(ethanol). H NMR (CDCl3, 300 MHz), , ppm, J (Hz): 2.0-3.1 (6H, m, 3 CH2); 7.73-8.18 (4H, m, phthaloyl);
δ
8.06 (1H, s, 4-H). Found, %: C 65.77; H 3.49; N 4.45. C17H11NO5. Calculated, %: C 66.02; H 3.59; N 4.53.
3-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-7,7-dimethyl-5,6,7,8-tetrahydro-2H-1-benzopyran-2,5-
dione (34) was prepared from 1 and 5,5-dimethyl-1,3-cyclohexanedione (29); refluxed for 3 h. Yield 56%
1
(95 mg); mp 226-228.5°C (ethanol). H NMR (CDCl3, 300 MHz), , ppm, J (Hz): 1.20 (6H, s, 2 Me); 2.48 (s,
δ
2H, CH2); 2.82 (s, 2H, CH2); 7.70-8.14 (4H, m, phthaloyl); 8.00 (1H, s, 4-H). Found, %: C 67.25; H 4.29;
N 4.27. C19H15NO5. Calculated, %: C 67.65; H 4.48; N 4.15.
Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(1,3-dioxo-2-cyclopentyl)propenoate Dimethyl-
ammonium Salt (39). A mixture of compound 1 (288 mg, 1 mmol), 1,3-cyclopentanedione (37) (98 mg,
1 mmol), and acetic acid (100%, 2 ml) was heated at 100°C for 2.5 h. Volatile components were evaporated in
vacuo, the residue was triturated with ethanol (3 ml), and the precipitate was collected by filtration to give 39.
1
С
Yield 68% (263 mg); mp 215-223.5° (decomp.) (ethanol). H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz):
δ
1.17 (3H, t, J = 7.1, OCH2CH3); 2.01 (4H, s, 2 CH2); 2.57 (6H, s, NMe2); 4.10 (2H, q, J = 7.1, OCH2CH3); 7.71
(s, 1H, 3-H); 7.87 (4H, s, phthaloyl). Found, %: C 62.01; H 5.61; N 7.22. C20H22N2O6. Calculated, %: C 62.17;
H 4.74; N 7.25.
Ethyl 2-(2,3-Dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(1,3-dimethyl-2,4,6-trioxo-1H,3H,5H-pyrimidin-
5-yl)propenoate Dimethylammonium Salt (40). A mixture of compound 1 (288 mg, 1 mmol),
1,3-dimethylbarbituric acid (38) (156 mg, 1 mmol), and acetic acid (100%, 3 ml) was heated at 80°C for 4 h.
Volatile components were evaporated in vacuo, the residue was triturated with diethyl ether (5 ml), and the
precipitate was collected by filtration to give 40. Yield 91% (405 mg); mp 194-202°C (decomp.) (ethanol).
1H NMR (DMSO-d6, 300 MHz), , ppm, J (Hz): 1.15 (3H, t, J = 7.1, CH2CH3); 2.56 (s, 6H, NMe2); 2.97 (6H, s,
δ
1'-Me and 3'-Me); 4.07 (2H, q, J = 7.1, CH2CH3); 7.83 (4H, s, phthaloyl); 8.25 (s, 1H, 3-H). Found, %: C 56.42;
H 5.29; N 12.39. C21H24N4O7. Calculated, %: C 56.75; H 5.44; N 12.61.
a
General Procedure for the Preparation of 3-Amino-4H-pyridino[1,2- ]pyrimidin-4-one (43) and
Ethyl 3-Amino-4-oxo-4H-quinolizine-1-carboxylate (44). A mixture of compound 21 (146 mg, 0.5 mmol) or
25 (181 mg, 0.5 mmol), anhydrous ethanol (4 ml), and hydrazine hydrate (100%, 0.05 ml, 1 mmol) was heated
at reflux temperature for 4 h. Volatile components were evaporated in vacuo and hydrochloric acid (10%, 5 ml)
was added. The precipitate was collected by filtration to give phthalohydrazide 45 as the side product. The
filtrate was neutralized with sodium hydrocarbonate, and the product was extracted with chloroform (3×15 ml).
Organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in
vacuo to give 43 or 44, respectively. The following compounds were prepared in this manner:
a
3-Amino-4H-pyridino[1,2- ]pyrimidin-4-one (43)
21
was prepared from . Yield 86% (69 mg), (lit.
yield: 85% [12], 40-94% [13, 14]). Mp 174-178°C, (lit. mp 176-179°C [12]; 176-178°C [13, 14]).
Ethyl 3-Amino-4-oxo-4H-quinolizine-1-carboxylate (44) was prepared from 25. Yield 28% (32 mg);
lit. yield 94% [15]. Mp 136-141°C (lit. mp 136-139°C [15]).
X-ray Structural Analysis. Diffraction data for compound 1 were collected on an Enraf-Nonius CAD4
diffractometer using graphite monochromated MoKα radiation. Structure was solved by direct methods using
the MULTAN88 [16] program. The Xtal3.4 [17] system of crystallographic programs was used for the
correlation and reduction of data, structure refinement, and interpretation. ORTEPII [18] was used to produce
molecular graphics. The resulting crystal data and details concerning data collection and refinement are quoted
in Table 1. Bond lengths and angles are presented in the Tables 2, 3. The crystallographic data for compound 2
have also been deposited with the Cambridge Crystallographic Data Centre as supplementary material with
deposition number CCDC 167581. Copies of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK.
1509

The asymmetric unit of compound 1 is shown in Fig. 1. It contains two molecules of (Z)-2-(2,3-dihydro-
1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate (1).
Acknowledgment
Financial support from the Ministry of Science, Slovenia, is gratefully acknowledged.
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