Microwave-mediated regioselective synthesis of novel pyrimido[1,2-a]pyrimidines under solvent-free conditions

Article abstract of DOI:10.1016/S0040-4020(00)01157-1

Ethyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxylates readily react, under microwave irradiation and solvent-free conditions, with 3-formylchromone or diethyl (ethoxymethylene)malonate to yield novel pyrimido[1,2-a]pyrimidines. The structure of the final products, deduced from the spectral data and confirmed by X-ray analysis, allows us to suggest reaction pathways.

Full text of DOI:10.1016/S0040-4020(00)01157-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1785±1791
Microwave-mediated regioselective synthesis of novel
pyrimido[1,2-a]pyrimidines under solvent-free conditions
Jean Jacques Vanden Eynde,a,p Nancy Hecq,a Olga Kataevab and C. Oliver Kappec
aDepartment of Organic Chemistry, University of Mons-Hainaut, Place du Parc 20, B-7000 Mons, Belgium
bA.E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, A.E. Arbuzov Street 8,
Kazan 420083, Russian Federation
cInstitute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 9 October 2000; accepted 11 December 2000
AbstractÐEthyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxylates readily react, under microwave irradiation and solvent-
free conditions, with 3-formylchromone or diethyl (ethoxymethylene)malonate to yield novel pyrimido[1,2-a]pyrimidines. The structure of
the ®nal products, deduced from the spectral data and con®rmed by X-ray analysis, allows us to suggest reaction pathways. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
propenoates (1) and guanidine in DMF in the presence of
an inorganic base (sodium hydrogen carbonate). This pro-
cedure affords the desired heterocycles within reaction
times ranging from 8 to 48 h, but reported yields (not
optimized) do not exceed 40% because of a competitive
reaction yielding diethyl 2,4,6,8-tetraryl-4,6-dihydro-1H-
pyrimido[1,2-a]pyrimidine-3,7-dicarboxylates (3). As these
bicyclic derivatives arise from Michael-type condensations
between two molecules of ester (1) and guanidine,8 we
reasoned that their formation could perhaps be disfavored
when starting directly from arylaldehydes, ethyl benzoyl-
acetate, and guanidine. This proposal is veri®ed as the
three-component reactions enabled us to obtain derivatives
2a±e within 3 h in 75±90% yields whereas formation of 3
was not detected.
In recent years, there has been increasing interest in the
design of alkyl 1,4-dihydropyrimidine-5-carboxylates (1,4-
DHPMs) and related Biginelli-like compounds1 which are
presented as valuable substitutes2 for the well-known
Nifedipinew and other 1,4-dihydropyridine drugs,3
clinically used in the treatment of cardiovascular diseases.
This interest is illustrated, i.e. by the disclosure of elegant
protocols involving solid phase synthesis approaches4 as
well as (solvent-free) preparations under microwave
irradiation.5
The purpose of the present work is to extend the scope of
those studies to 2-amino derivatives, and especially to the
evaluation of their synthetic potential for the construction of
novel pyrimido[1,2-a]pyrimidines, a ring system that can
be found in marine-derived natural products such as
crambescidin6 and batzelladine7 alkaloids.
2.2. Reactions between the 2-amino-1,4-DHPMs 2a±e
and 3-formylchromone 4
Diamines are known to react with 3-formylchromone 4 to
yield pyrimidines.9 The reaction initially takes place on the
formyl group and is followed by an intramolecular attack of
the second amine function on the C-2 atom of the pyrone
ring followed by the opening of that ring (Scheme 2). In
such a sequence, derivatives 2 are excellent candidates for
the preparation of bicyclic systems but, due to the presence
of three nitrogen atoms in 2, formation of two isomeric
substances (4-aryl (5) or 2-aryl (6) derivatives) may be
foreseen as illustrated in Scheme 2.
2. Results and discussion
2.1. Preparation of the starting 2-amino-1,4-DHPMs
2a±e
A recent paper of Milcent8 describes the synthesis (Scheme
1) of ethyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimi-
dine-5-carboxylates (2) from ethyl 3-aryl-2-benzoyl-
Experimentally we observed (NMR) that only one series of
isomers (5 (2H), see Scheme 2) was obtained when the
reactants are heated in boiling ethanol for several hours.
However, we felt unsatis®ed with those experimental
Keywords: Biginelli compounds; pyrimidine; microwave; solvent-free
conditions.
Corresponding author. Tel.: 132-65-373338; fax: 132-65-373054;
e-mail: jjvde@umh.ac.be
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01157-1

1786
J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791
Scheme 1. Preparation of compounds 2a±e and 3.
Scheme 2. Reactions between 2-amino-1,4-DHPMs (2) and 3-formylchromone (4).

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791
1787
1
Figure 1. H NMR spectrum of compound 5b.
conditions, and we decided to perform the reactions under
microwave irradiation.10 In that way, we isolated the same
®nal products but advantageously in better yields, under
solvent-free conditions, and within a few minutes.
spectra of Biginelli-like 1,4-DHPMs and it allows to
attribute the signal to a proton on a sp3 carbon atom bearing
a (hetero)aryl group. As this position is constant whichever,
that (hetero)aryl substituent is, structures 5 (2H) or 6 (4H)
can be suggested (indeed, as illustrated by the values
collected in Table 1, the chemical shift of a Ar±CH proton
is highly dependent11 on the nature of the aromatic group:
such a dependence is also observed in the spectra of the
starting heterocycles (2). The second signal (H on a sp2
1
In the H NMR spectra (Fig. 1) of the ®nal products, there
are three signals (singlet) between 5.0 and 6.5 ppm. The less
deshielded signal in this range is located at 5.4 ppm: this is a
typical value for H chemical shifts observed in the NMR
1
1
Table 1. H chemical shifts of CH3 protons in various Ar±CH3 compounds
Ar in Ar±CH3
C6H5
2.40
4-(CH3)±C6H4
2.30
4-(OCH3)±C6H4
2.25
4-Cl±C6H4
2.35
2-thienyl
2.55
d CH3
Scheme 3. Reactions between 2-amino-1,4-DHPMs (2) and diethyl (ethoxymethylene)malonate (7).

1788
J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791
carbon atom) appears around 5.9 ppm when the substituent
on the system is a phenyl ring or a substituted phenyl ring,
and is shifted down®eld to 6.2 ppm when the substituent is a
thienyl group. The signal is therefore attributed to the H(6)
proton; the signal due to the H(8) proton is located at
6.0 ppm and its position does not vary with the nature of
the (hetero)aryl substituent on the system. Those data are
consistent with structures 5 (2H) only.
an aryl substituent (compounds a±d) to a thienyl substituent
(compound e), the bicyclic derivatives should belong to
series 8. This conclusion is con®rmed by the structure
(Fig. 2) obtained from the X-ray analysis of the product,
formed by the interaction between 2c and 7. According to
the X-ray single crystal diffraction study, the pyrimidinone
cycle is planar, the exocyclic ester group being twisted from
this plane by 26(2)8. The other unsaturated 6-membered ring
adopts an asymmetric boat conformation with a planar
C2C3N10C9 fragment, the pseudoaxial benzene ring
C20±C25 being perpendicular to this fragment. The phenyl
substituent attached to C2 is twisted around the C2±C11
bond by 74(2)8 to avoid steric interactions with the neigh-
bouring ethoxycarbonyl substituent at C3. In the crystal,
molecules 8c form centrosymmetric dimers via inter-
molecular hydrogen bonds: N8±H8´´´N1 [12x, 12y,
2.3. Reactions between the 2-amino-1,4-DHPMs 2a±e
and diethyl (ethoxymethylene)malonate 7
The situation is more complex when derivatives 2 are
allowed to react with diethyl (ethoxymethylene)malonate
(7). Indeed, four series of isomeric pyrimido[1,2-a]pyrimi-
dines can be formed (Scheme 3). Once again, when the
reactions are conducted in boiling ethanol, or under micro-
wave irradiation, only one series of compounds is obtained.
Ê
12z], N8±H8 0.99(4), H8´´´N1 1.97(5) A, /N8±H8´´´N1
1708.
1
In the H NMR spectra, there is no signal between 5.0 and
6.0 ppm. Therefore, the signal due to the proton on the sp3
carbon atom of the heterocyclic system is highly deshielded
when compared with the chemical shifts observed for the
starting heterocycles 2 (d C(4)± H in 2: between 5.2 and
5.6 ppm). Such a deshielding can be explained by the
in¯uence of the carbonyl moiety when it is in close vicinity
of the considered proton, and is therefore indicating a 6-oxo
structure 8 or 10.
2.4. Reaction pathways
We have not been able to isolate the uncyclized inter-
mediates, neither by reducing microwave irradiation
times, nor by performing the syntheses in a solvent at re¯ux
or at room temperature. Anyway, the structure of the ®nal
products 5 indicates that they result from the nucleophilic
attack of the exocyclic nitrogen atom of 2 on the formyl
function of 4 and that the ring closure involves the
N(3) nitrogen atom of the pyrimidine cycle. This situation
As the chemical shift of this proton varies when going from
Figure 2. Solid state structure of compound 8c.

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791
1789
Ê 3
parallels previous results, demonstrating a greater suscepti-
bility of the N(3) atom towards electrophiles, when
compared to the N(1) atom.1a Similarly, reactions performed
from diethyl (ethoxymethylene)malonate involve the same
exocyclic and N(3) nitrogen atoms of the starting hetero-
cycles 2.
1214.7(8) A , dcalcd 1.30 g/cm3, Z 2, space group P1bar. A
total of 5342 re¯ections were measured, of which only 992
were with I . 3s.
The phase problem was solved by direct methods using the
program sir.12 The structure was developed by difference-
Fourier calculations interspersed with cycles of full-matrix
least-squares re®nements. All non-hydrogen atoms were
re®ned anisotropically, and hydrogen atoms were located
from difference-Fourier maps and added to structure factor
calculations with ®xed positional and thermal parameters.
The ®nal agreement factors are R 0.088, Rw 0.099. All calcu-
lations were carried out using the MolEn package.13
3. Conclusion
In this work, we demonstrated that ethyl 2-amino-4-aryl-
1,4-dihydro-6-phenylpyrimidine-5-carboxylates (2) regio-
selectively react with 3-formylchromone (4) or diethyl
(ethoxymethylene)malonate (7) to afford pyrimido[1,2-
a]pyrimidines (5 and 8, respectively) which had not been
described previously. Interestingly, we observed that these
bicyclic derivatives can be prepared advantageously in a
microwave oven and in the absence of organic solvent,
thus contributing to the promotion of economical and
environmentally friendly experimental procedures.
4.3. Synthesis
4.3.1. Preparation of the starting 2-amino-1,4-DHPMs
2a±e. A mixture of aldehyde (20 mmol), ethyl benzoyl-
acetate (4.2 g, 3.8 mL, 22 mmol), guanidine hydrochloride
(2.3 g, 24 mmol), and sodium hydrogen carbonate (6.7 g,
80 mmol) in DMF (40 mL) was stirred at 708C for 3 h.
After cooling, the mixture was poured onto crushed ice.
The precipitate was ®ltered and thoroughly washed with
water. Compounds (Yield) 2a (75%), 2b (85%), 2c (75%),
and 2d (85%) have been described in the literature.8
4. Experimental
4.1. General
1H and 13C NMR spectra were obtained using a Jeol JNP-
PM X60 spectrometer (60 MHz for H at 1.4 T) and a
4.3.2. Ethyl 2-amino-1,4-dihydro-6-phenyl-4-(2-thienyl)-
pyrimidine-5-carboxylate 2e. Yield: 85%. Mp (EtOH):
1
Bruker AMX-300 spectrometer (300 MHz for 1H and
75 MHz for 13C at 7 T); chemical shifts (d) are given in
ppm using TMS as internal reference. IR spectra were
recorded on a Perkin±Elmer FTIR 1760 K spectro-
photometer. Melting points (not corrected) were determined
on an electrothermal 9100 apparatus. Solvents are com-
mercially available (Aldrich Co., Acros Organics) and
were used without further puri®cation. The elemental
analyses were carried out at the Station de Haute Belgique
(Libramont-Chevigny, Belgium). Crystallographic data
(excluding structure factors) of 7c have been deposited at
the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC 149469. Copies of the data
are available without charge from: The Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: 14412-
23336033; e-mail: deposit@ccdc.cam.ac.uk).
1
223±2258C. IR (KBr): 3395, 3357, 1673 cm21. H NMR
(DMSO): 0.7 (t, 3H, Jˆ7 Hz, CH3), 3.8 (q, 2H, Jˆ7 Hz,
CH2), 5.6 (s, 1H, H(4)), 6.7±7.5 (m, 10H, Ph, thienyl, and
NH2). 13C NMR (DMSO): 13.6, 47.4, 53.2, 58.2, 98.1,
123.1, 124.5, 126.5, 126.8, 127.2, 128.1, 150.4, 155.1,
160.0, 165.6. Anal. Calcd for C17H17N3O2S (327.40):
C, 62.37; H, 5.23; N, 12.84. Found: C, 62.27; H, 4.88; N,
12.65.
4.3.3. Reactions between the 2-amino-1,4-DHPMs 2a±e
and 3-formylchromone 4 in ethanol. A mixture of ethyl
2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxyl-
ate 2 (1.5 mmol) and 3-formylchromone 4 (0.27 g,
1.5 mmol) in ethanol was heated under re¯ux for 4 h.
After cooling, the precipitate was ®ltered and recrystallized.
Compounds (Yield): 5a (70%), 5b (80%), 5c (80%), 5d
(80%), 5e (60%).
4.2. X-Ray structure determination
4.3.4. Reactions between the 2-amino-1,4-DHPMs 2a±e
and 3-formylchromone 4 under microwave irradiation.
A mixture of ethyl 2-amino-4-aryl-1,4-dihydro-6-phenyl-
pyrimidine-5-carboxylate 2 (1.5 mmol) and 3-formyl-
chromone 4 (0.27 g, 1.5 mmol) was irradiated for 20 min
in a domestic microwave oven (Whirlpool AKL260,
400 W). The solid was recrystallized. Yields exceed 95%.
X-Ray data for crystals 8c were collected on a CAD4 Enraf-
Nonius automatic diffractometer with graphite mono-
chromated lMoKa radiation using v/2u-scan mode in the
range 28<u<278 at 208C. The stability of the crystal and
that of the experimental conditions were checked every 2 h
using three control re¯ections, while the orientation was
monitored every 200 re¯ections by centering three
standards. Neither decay, nor absorption correction (m Mo
0.87 cm21) was necessary. Corrections for Lorentz and
polarization effects were applied.
4.3.5. Ethyl 7-(2-hydroxybenzoyl)-2,4-diphenyl-2H-
pyrimido[1,2-a]pyrimidine-3-carboxylate
(EtOH): 225±2268C. IR (KBr): 3500±2500, 1697,
5a.
Mp
1
1666 cm21. H NMR (CDCl3): 0.7 (t, 3H, Jˆ7 Hz, CH3),
Crystals 8c,
0.4£0.1£0.1 mm3),
Ê
unit cell dimensions: a 7.147(3) A, b 11.969(3) A, c
C26H25O6N3
(colorless,
needles,
475.51, F(000) 500, triclinic.
3.9 (q, 2H, Jˆ7 Hz, CH2), 5.4 (s, 1H, H(2)), 5.9 (s, 1H,
H(6)), 6.0 (s, 1H, H(8)), 7.0±8.0 (m, 15H, Ar, and OH).
13C NMR (CDCl3): 13.5, 57.4, 60.2, 82.9, 103.3, 108.6,
119.2, 122.3, 124.1, 127.4, 127.6, 128.3, 128.5, 129.2,
130.2, 135.0, 135.7, 139.5, 140.2, 141.4, 146.9, 149.1,
M
Twenty-®ve centered re¯ections were used to determine
Ê
Ê
14.874(6) A, a 75.93(2)8, b 81.98(2)8, g 81.95(2)8, V

1790
J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791
155.9, 164.8, 179.6. Anal. Calcd for C29H23N3O4 (477.52):
C, 72.94; H, 4.86; N, 8.80. Found: C, 72.63; H, 4.85; N,
8.35.
Compounds (Yield): 8a (50%), 8b (50%), 8c (45%), 8d
(60%), 8e (40%).
4.3.11. Reactions between the 2-amino-1,4-DHPMs 2a±e
and diethyl (ethoxymethylene)malonate 7 under micro-
wave irradiation. A mixture of ethyl 2-amino-4-aryl-1,4-
dihydro-6-phenylpyrimidine-5-carboxylate 2 (1.5 mmol)
4.3.6. Ethyl 7-(2-hydroxybenzoyl)-4-(4-methylphenyl)-2-
phenyl-2H-pyrimido[1,2-a]pyrimidine-3-carboxylate 5b.
Mp (EtOH): 223±2248C. IR (KBr): 3500±2500, 1687,
1
1669 cm21. H NMR (CDCl3): 0.8 (t, 3H, Jˆ7 Hz, CH3),
and diethyl (ethoxymethylene)malonate
7
(0.32 g,
2.3 (s, 3H, ArCH3), 3.8 (q, 2H, Jˆ7 Hz, CH2), 5.4 (s, 1H,
H(2)), 5.9 (s, 1H, H(6)), 6.0 (s, 1H, H(8)), 7.0±8.0 (m, 14H,
Ar, and OH). 13C NMR (CDCl3): 14.0, 21.8, 57.7, 60.7,
83.4, 104.0, 109.2, 118.6, 123.1, 124.7, 127.9, 128.2,
128.8, 129.1, 130.4, 130.7, 135.6, 136.3, 137.1, 139.7,
141.6, 147.1, 149.6, 156.5, 165.4, 180.2. Anal. Calcd for
C30H25N3O4 (491.54): C, 73.31; H, 5.13; N, 8.55. Found:
C, 73.26; H, 5.36; N, 8.88.
0.30 mL, 1.5 mmol) was irradiated for 10 min in a domestic
microwave oven (Whirlpool AKL260, 400 W). The solid
was recrystallized. Yields exceed 95%.
4.3.12. Diethyl 6,9-dihydro-6-oxo-2,4-diphenyl-4H-
pyrimido[1,2-a]pyrimidine-3,7-dicarboxylate 8a. Mp
(CH3CN): 241±2438C. IR (KBr): 3400±2400 (br), 1718,
1
1708, 1664 cm21. H NMR (CDCl3): 0.9 (t, 3H, Jˆ7 Hz,
CH3), 1.4 (t, 3H, Jˆ7 Hz, CH3), 3.9 (q, 2H, Jˆ7 Hz, CH2),
4.3 (q, 2H, Jˆ7 Hz, CH2), 6.7 (s, 1H, H(8)), 7.0 (s, 1H,
H(4)), 7.3±7.7 (m, 11H, Ar, and NH). 13C NMR (CDCl3):
13.6, 14.5, 52.7, 60.6, 60.7, 104.3, 110.1, 127.7, 128.5,
128.7, 128.9, 130.6, 133.2, 139.7, 145.2, 151.5, 156.5,
157.8, 163.2, 163.6. Anal. Calcd for C25H23N3O5 (445.47):
C, 67.41; H, 5.20; N, 9.43. Found: C, 67.04; H, 5.11; N,
9.29.
4.3.7. Ethyl 7-(2-hydroxybenzoyl)-4-(4-methoxyphenyl)-
2-phenyl-2H-pyrimido[1,2-a]pyrimidine-3-carboxylate
5c. Mp (EtOH): 222±2248C. IR (KBr): 3500±2500, 1689,
1665 cm21. 1H NMR (CDCl3): 0.8 (t, 3H, Jˆ7 Hz, CH3), 3.8
(s, 3H, OCH3), 3.9 (q, 2H, Jˆ7 Hz, CH2), 5.4 (s, 1H, H(2)),
5.8 (s, 1H, H(6)), 6.0 (s, 1H, H(8)), 6.8±8.0 (m, 14H, Ar, and
OH). 13C NMR (CDCl3): 13.4, 55.3, 56.9, 60.6, 84.2, 103.5,
108.5, 114.5, 117.2, 123.0, 124.1, 127.4, 128.2, 128.4,
128.7, 128.9, 130.1, 131.5, 135.0, 135.7, 146.0, 148.9,
155.8, 160.2, 164.9, 179.6. Anal. Calcd for C30H25N3O5
(507.55): C, 71.00; H, 4.97; N, 8.28. Found: C, 70.67; H,
5.08; N, 7.98.
4.3.13. Diethyl 6,9-dihydro-4-(4-methylphenyl)-6-oxo-2-
phenyl-4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxyl-
ate 8b. Mp (CH3CN): 255±2578C. IR (KBr): 3400±2500
(br), 1720, 1705, 1665 cm21. 1H NMR (CDCl3): 0.9 (t, 3H,
Jˆ7 Hz, CH3), 1.4 (t, 3H, Jˆ7 Hz, CH3), 2.3 (s, 3H, Ar±
CH3), 3.9 (q, 2H, Jˆ7 Hz, CH2), 4.3 (q, 2H, Jˆ7 Hz, CH2),
6.7 (s, 1H, H(8)), 7.0 (s, 1H, H(4)), 7.2±7.6 (m, 10H, Ar, and
NH). 13C NMR (CDCl3): 13.6, 14.5, 21.2, 52.5, 60.6, 60.7,
104.4, 110.0, 127.6, 128.5, 128.6, 129.5, 130.5, 133.2,
136.9, 138.8, 145.0, 151.5, 156.5, 157.8, 163.2, 163.1.
Anal. Calcd for C26H25N3O5 (459.50): C, 67.96; H, 5.48;
N, 9.15. Found: C, 67.99; H, 5.28; N, 8.96.
4.3.8. Ethyl 4-(4-chlorophenyl)-7-(2-hydroxybenzoyl)-2-
phenyl-2H-pyrimido[1,2-a]pyrimidine-3-carboxylate 5d.
Mp (EtOH): 228±2298C. IR (KBr): 3500±2500, 1685,
1
1669 cm21. H NMR (CDCl3): 0.8 (t, 3H, Jˆ7 Hz, CH3),
3.9 (q, 2H, Jˆ7 Hz, CH2), 5.4 (s, 1H, H(2)), 5.9 (s, 1H,
H(6)), 6.0 (s, 1H, H(8)), 7.0±8.0 (m, 14H, Ar, and OH).
13C NMR (CDCl3): 13.4, 56.7, 60.3, 82.7, 103.0, 108.6,
117.9, 122.6, 123.9, 127.4, 128.1, 128.5, 128.9, 129.4,
130.2, 135.0, 135.1, 135.8, 137.9, 140.0, 147.2, 148.7,
155.8, 164.7, 179.4. Anal. Calcd for C29H22ClN3O4
(511.97): C, 68.04; H, 4.33; N, 8.21. Found: C, 67.95; H,
4.54; N, 8.29.
4.3.14. Diethyl 6,9-dihydro-4-(4-methoxyphenyl)-6-oxo-
2-phenyl-4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxyl-
ate 8c. Mp (CH3CN): 253±2558C. IR (KBr): 3400±2400
1
(br), 1715, 1708, 1664 cm21. H NMR (CDCl3): 0.9 (t,
3H, Jˆ7 Hz, CH3), 1.4 (t, 3H, Jˆ7 Hz, CH3), 3.8 (s, 3H,
OCH3), 3.9 (q, 2H, Jˆ7 Hz, CH2), 4.3 (q, 2H, Jˆ7 Hz,
CH2), 6.7 (s, 1H, H(8)), 7.0 (s, 1H, H(4)), 6.9±7.7 (m,
10H, Ar, and NH). 13C NMR (CDCl3): 13.6, 14.5, 52.3,
55.3, 60.5, 104.4, 110.0, 114.2, 128.5, 128.7, 129.2, 130.5,
131.9, 133.3, 144.9, 151.4, 156.5, 157.7, 159.9, 163.2,
163.6. Anal. Calcd for C26H25N3O6 (475.50): C, 65.68; H,
5.30; N, 8.84. Found: C, 65.55; H, 5.14; N, 8.66.
4.3.9. Ethyl 7-(2-hydroxybenzoyl)-2-phenyl-4-thienyl-
2H-pyrimido[1,2-a]pyrimidine-3-carboxylate 5e. Mp
(EtOH): 254±2578C. IR (KBr): 3500±2500, 1696,
1
1666 cm21. H NMR (CDCl3): 0.8 (t, 3H, Jˆ7 Hz, CH3),
3.9 (q, 2H, Jˆ7 Hz, CH2), 5.4 (s, 1H, H(2)), 6.0 (s, 1H,
H(8)), 6.2 (s, 1H, H(6)), 6.9±7.9 (m, 13H, Ar, thienyl, and
OH). 13C NMR (CDCl3): 13.5, 52.8, 60.3, 82.8, 103.4,
108.7, 118.1, 122.6, 124.0, 126.6, 126.7, 126.9, 127.4,
128.2, 128.5, 130.2, 135.1, 135.7, 140.0, 142.1, 147.5,
148.6, 155.9, 164.6, 179.4. Anal. Calcd for C27H21N3O4S
(483.54): C, 67.07; H, 4.38; N, 8.69. Found: C, 67.19; H,
4.02; N, 8.67.
4.3.15. Diethyl 6,9-dihydro-4-(4-chlorophenyl)-6-oxo-2-
phenyl-4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxyl-
ate 8d. Mp (CH3CN): 263±2658C. IR (KBr): 3400±2450
(br), 1715, 1708, 1664 cm21. 1H NMR (CDCl3): 0.9 (t, 3H,
Jˆ7 Hz, CH3), 1.3 (t, 3H, Jˆ7 Hz, CH3), 3.9 (q, 2H,
Jˆ7 Hz, CH2), 4.3 (q, 2H, Jˆ7 Hz, CH2), 6.7 (s, 1H,
H(8)), 7.0 (s, 1H, H(4)), 7.2±7.6 (m, 10H, Ar, and NH).
13C NMR (CDCl3): 13.6, 14.5, 52.4, 60.6, 103.9, 110.3,
128.4, 128.7, 129.1, 129.2, 130.7, 133.1, 134.8, 138.3,
145.3, 151.4, 156.2, 157.9, 163.1, 163.5. Anal. Calcd for
C25H22ClN3O5 (479.92): C, 62.57; H, 4.62; N, 8.76.
Found: C, 62.83; H, 4.64; N, 8.37.
4.3.10. Reactions between the 2-amino-1,4-DHPMs 2a±e
and diethyl (ethoxymethylene)malonate 7 in ethanol. A
mixture of ethyl 2-amino-4-aryl-1,4-dihydro-6-phenyl-
pyrimidine-5-carboxylate 2 (1.5 mmol) and diethyl (ethoxy-
methylene)malonate 7 (0.32 g, 0.30 mL, 1.5 mmol) in
ethanol (10 mL) was heated under re¯ux for 8 h. After
evaporation of the solvent, the residue was recrystallized.

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791
1791
4. (a) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,
7819±7822. (b) Kappe, C. O. Bioorg. Med. Chem. Lett.
2000, 10, 49±51.
4.3.16. Diethyl 6,9-dihydro-6-oxo-2-phenyl-4-(2-thienyl)-
4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxylate 8e. Mp
(EtOH): 225±2278C. IR (KBr): 3400±2400 (br), 1716,
1
1703, 1665 cm21. H NMR (CDCl3): 0.9 (t, 3H, Jˆ7 Hz,
5. (a) Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999,
1799±1803. (b) Stadler, A.; Kappe, C. O. J. Chem. Soc.,
Perkin Trans. 2 2000, 1363±1368.
CH3), 1.4 (t, 3H, Jˆ7 Hz, CH3), 3.9 (q, 2H, Jˆ7 Hz, CH2),
4.3 (q, 2H, Jˆ7 Hz, CH2), 6.7 (s, 1H, H(8)), 7.3 (s, 1H,
H(4)), 7.0±7.6 (m, 9H, Ph, thienyl, and NH). 13C NMR
(CDCl3): 13.7, 14.5, 47.6, 60.8, 103.9, 110.1, 126.0,
127.2, 127.4, 128.5, 128.7, 130.7, 133.0, 142.0, 145.8,
151.0, 156.4, 157.8, 163.2, 163.3. Anal. Calcd for
C23H21N3O5S (451.50): C, 61.19; H, 4.69; N, 9.31. Found:
C, 61.15; H, 5.05; N, 9.27.
6. Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828±3839.
7. (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;
Freyer, A. J.; De Brosse, C.; Mai, S.; Truneh, A.; Faulkner,
D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.;
Westley, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60, 1182±
1188. (b) Franklin, A. S.; Ly, S. K.; Mackin, G. H.; Overman,
L. E.; Shaka, A. J. J. Org. Chem. 1999, 64, 1512±1519.
(c) McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999,
64, 1520±1528.
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