Facile synthesis of novel pyrimido[1,2-a]pyrimidin-4-ones from highly reactive malonates

Article abstract of DOI:10.1002/ejoc.200901419

A very simple and efficient procedure for the synthesis of novel 2-hydrox.y-4H-pyrimido[1,2-a]pyrimidin-4-ones is described. Title compounds were obtained from the room temperature reaction of 2-aminopyrimidine and its substituted derivatives with bis(2,4,6-trichlorophenyl) malonates. High product yields were observed under optimized conditions. Applicability and reactivity of a range of substituted and unsubstituted phenyl malonates were also investigated. Structural identification of all new compounds was accomplished by spectroscopic methods and elemental analysis.

Full text of DOI:10.1002/ejoc.200901419

FULL PAPER
DOI: 10.1002/ejoc.200901419
Facile Synthesis of Novel Pyrimido[1,2-a]pyrimidin-4-ones from Highly
Reactive Malonates
Mustafa Güllü,*[a] Ali Dinçsönmez,[a] and Öznur Özyavas[a]
¸
Keywords: Nitrogen heterocycles / Fused-ring systems / Cyclization / Condensation / Malonates
A very simple and efficient procedure for the synthesis of
novel 2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-ones is de-
scribed. Title compounds were obtained from the room tem-
perature reaction of 2-aminopyrimidine and its substituted
derivatives with bis(2,4,6-trichlorophenyl) malonates. High
product yields were observed under optimized conditions.
Applicability and reactivity of a range of substituted and un-
substituted phenyl malonates were also investigated. Struc-
tural identification of all new compounds was accomplished
by spectroscopic methods and elemental analysis.
imidine derivatives have been successfully prepared from
the corresponding starting materials by thermal cyclization,
there are only a few methods for the synthesis of pyrimido-
[1,2-a]pyrimidines in the literature.[3]
Introduction
Novel bi- or tricyclic pyrimidine derivatives are impor-
tant and such compounds have always been at the center of
interest in the search for new pharmaceutical candidates.
Many pyrimidine and pyrimidopyrimidine derivatives show
interesting pharmaceutical properties, such as: antiviral, an-
tibacterial, anti-HIV, antiallergic, and antitumoral activi-
ties. For instance, pyrimidine ring containing sulfonamides
constitute one of the oldest groups of antibacterial agents.
Aminopyrimidines and their derivatives, especially those
having substituents on the pyrimidine ring, are also valu-
able drug intermediates in addition to possessing significant
biological activities.[1]
Pyrimidopyrimidines are bicyclic pyrimidine derivatives
containing two fused pyrimidine rings, and have four struc-
tural isomers. Pyrimido[4,5-d]pyrimidine and pyrimido-
[5,4-d]pyrimidine ring systems have been the main focus of
drug investigations due to the ease of access to this type
of compound by various simple synthetic methods.[2] For
example, the reaction of 1,3-dimethyl-6-aminouracil with
formaline and benzylamine in ethanol produced a pyrim-
ido[4,5-d]pyrimidine derivative that was found to have anti-
depressant activity.[2] Sanghvi and coworkers reported that
isopropylidene ribofuranosylamine derivatives of several
pyrimido[5,4-d]pyrimidines have antitumoral and antiviral
activities.[2]
Hurd and Hayao[3] were the first researchers to introduce
examples of pyrimido[1,2-a]pyrimidines, which were made
in the salt form by the reaction of 2-amino-4,6-dimethyl-
pyrimidine with 3-bromopropionic acid. In another
method, it was shown that cyclization of guanidine with
some α,β-unsaturated nitriles or carbonyl compounds pro-
duced hindered derivatives of pyrimido[1,2-a]pyrimidines,
although in low yields.[3] A pyrimido[1,2-a]pyrimidine syn-
thesis was also described by Eynde et al.[3] that involved the
reaction of 3-formylchromone or diethyl ethoxymalonate
(EMME) with highly substituted 2-aminopyrimidines. Un-
der microwave heating without a solvent, this procedure re-
sulted in the formation of some highly substituted pyrim-
ido[1,2-a]pyrimidines in good yields. In a few other syn-
thetic procedures, pyrimido[1,2-a]pyrimidines were synthe-
sized in low to moderate yields by the reaction of 2-amino-
pyrimidines with reagents such as 2-fluorobenzoyl chlorides
and iminopropadienones[3] under thermal conditions by
either classical or microwave heating. Other methods that
are described in the literature are specific examples of the
synthesis of some simple pyrimido[1,2-a]pyrimidines.[3]
Thomas Kappe[4] reported the synthesis of a pyrimido-
[1,2-a]pyrimidinium derivative by the reaction of bis(2,4,6-
trichlorophenyl) ethylmalonate, one of the so-called “magic
malonates” (or active malonates), with 2-(methylamino)-
pyrimidine for the first time. This is the sole example of the
use of an active malonate in the synthesis of pyrimido[1,2-a]-
pyrimidines. No detailed study on the applicability of
Kappe’s or any other method for the production of pyr-
imido[1,2-a]pyrimidine derivatives has yet been presented in
the literature. Therefore, the development of a methodology
for the synthesis of such compounds would be highly desir-
able for providing new bicyclic pyrimidine heterocycles that
On the other hand, pyrimido[1,2-a]pyrimidines are a less
known group of bicyclic pyrimidine heterocycles, probably
because of the lack of a widely applicable method for the
synthesis of these compounds. Although many bicyclic pyr-
[a] Department of Chemistry, Faculty of Science, Ankara Univer-
sity,
Tandog˘an, 06100 Ankara, Turkey
Fax: +90-312-2232395
E-mail: gullu@science.ankara.edu.tr
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M. Güllü, A. Dinçsönmez, Ö. Özyavas
¸
FULL PAPER
can be applied in different fields of chemistry such as che- was confirmed from its spectroscopic data and elemental
lating compounds, as bases, as well as in the search for new analysis, several reaction parameters (type of the solvent,
drug candidates.
presence and type of a catalyst, reaction period and tem-
In this study, as part of our ongoing research on the syn- perature) were investigated to improve the product yield.
thesis of fused pyrimidine ring systems, we have developed The results of these optimization experiments showed that
a method that is widely applicable, simple and uses easily a high yield (82%) of the desired compound could be
accessible starting materials for the synthesis of pyrim- achieved by simply stirring the starting materials in diethyl
ido[1,2-a]pyrimidines. The synthesis of several 2-aminopyr- ether for 12 h at room temperature without any catalyst
imidines and their reaction with a range of malonates was (Table 1).
investigated in detail.
With these initial results in hand, similar cyclization reac-
tions of other 2-aminopyrimidine derivatives with bis(2,4,6-
trichlorophenyl) malonate and bis(2,4,6-trichlorophenyl)
alkylmalonates were carried out both to obtain novel pyr-
Results and Discussion
Herein, we report the results of our attempts to prepare imido[1,2-a]pyrimidine derivatives and to determine the ap-
pyrimido[1,2-a]pyrimidines from malonates and 2-amino- plicability of this procedure in more detail (Scheme 1). The
pyrimidines. Initially, we investigated the reaction of 2- results obtained from the optimized reaction are summa-
aminopyrimidines with diethyl malonate and diethyl alkyl- rized in Table 1.
malonates by thermal condensation. However, our efforts
As seen in Table 1, this method was very successful for
did not produce even trace amounts of pyrimido[1,2-a]pyr- the synthesis of the desired pyrimido[1,2-a]pyrimidine het-
imidine derivative under thermal conditions even after long erocycles. The reactions were carried out simply by stirring
reaction periods; e.g., temperature range 120–250 °C and the starting materials in a suitable solvent at room tempera-
reaction times of 1–50 h. In most cases, whereas starting ture. In some cases, refluxing the solution increased the re-
materials were recovered at lower temperatures (below 170– action rate but did not improve the yield due to rapid de-
180 °C), decomposition of reaction mixture and formation composition of the active malonates. Hence, long reaction
of tar-like masses at higher temperatures were observed. Al- periods at room temperature was preferred in order to avoid
though, thermal condensation of diethyl malonates with 2- thermal decomposition of the esters. Reaction times needed
aminoheterocycles is known to be very successful for the to be extended in some cases, although in most cases the
synthesis of several bicyclic compounds (including pyr- reactions were complete in 5–10 h.
ido[1,2-a]pyrimidines[5]), unfortunately, similar results were
Some aliphatic and aromatic amines, namely triethyl-
not observed with 2-aminopyrimidines.
amine, N,N-dimethylaniline and 4-(dimethylamino)pyridine
The application of controlled microwave heating (120– (DMAP), were used as basic catalysts in these reactions.
250 °C) with a single mod microwave oven (CEM Discovery Only in the preparation of compounds 3a, 3h, and 3o were
S Model) to a mixture of diethyl malonate and 2-aminopyr- higher yields obtained in the presence of catalyst than in
imidine, either in the presence of a few drops of a suitable the absence of catalyst. Triethylamine was observed to be a
solvent (e.g. DMF, DMSO etc.) or without any solvent, also better catalyst than others and can be used in excess due to
produced none of the desired pyrimido[1,2-a]pyrimidine its low cost.
type of compound. Again, either recovery of starting mate-
rials or formation of a tarry mass was observed in micro- been effectively used in previous cyclization reactions.[4–5]
wave-assisted reactions. However, except 3b and 3h, low product yields were ob-
Acetone was the first choice of solvent because it had
As an alternative, we used active malonates to synthesize served in acetone for some pyrimido[1,2-a]pyrimidines. In
the pyrimido[1,2-a]pyrimidines. These highly reactive mal- order to find a solvent system that was more suitable for
onates, namely bis(2,4,6-trichlorophenyl) or bis(pentachlo- these types of product and starting material, several other
rophenyl) esters of malonates, were introduced by Thomas common solvents were also investigated. From the solvents
Kappe around 1967 and used effectively for the synthesis of tested, tetrahydrofuran (THF) and diethyl ether were found
a range of fused heterocycles,[4,6] especially fused pyrimidine to be very successful and even better than acetone in some
systems. This method involves the reaction of an amino- cases. Chloroform was fairly good only in cases where the
heterocycle with an active malonate in an inert solvent desired product was not soluble in chloroform because,
either with or without a tertiary amine (e.g. triethylamine) otherwise, it was difficult to separate the pyrimido[1,2-a]-
catalyst. As a fine example of this method, in our earlier pyrimidine derivatives from 2,4,6-trichlorophenol and 2-
work, high yields of 2-hydroxy-4H-pyrido[1,2-a]pyrimidin- aminopyrimidines, which were the main by-product and
4-ones were obtained from the reaction of bis(2,4,6-tri- minor impurity, respectively, in the reaction media.
chlorophenyl) malonates with 2-aminopyridines.[5]
As a result of these investigations, a common solvent
In a similar manner, the reaction of 2-aminopyrimidine with an average polarity was found to be optimal for the
with bis(2,4,6-trichlorophenyl) butylmalonate[5] was per- synthesis of pyrimido[1,2-a]pyrimidines. Ideally, both start-
formed in acetone in the presence of triethylamine as a cata- ing materials were soluble in the solvent and the product
lyst. Although low in yield, formation of 3-butyl-2-hydroxy- was less soluble, so that the target pyrimido[1,2-a]pyrimid-
4H-pyrimido[1,2-a]pyrimidin-4-one (3f) was realized in suf- ine derivatives could be easily purified. One other impor-
ficiently pure state. After the structure of this compound tant point to mention about the solvent is its hygroscopic
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Pyrimido[1,2-a]pyrimidin-4-ones from Reactive Malonates
Table 1. Reaction of 2-aminopyrimidines with bis(2,4,6-trichlorophenyl) malonates.[a]
R1
R2
R3
R4
Solvent
Time [h]
Product (%)
H
CH3
H
CH3
CH3
H
CH3
H
H
CH3
H
CH3
CH3
H
H
H
H
H
H
H
H
H
butyl
H
H
H
H
H
H
H
H
Cl
H
CH3
CH3
H
OCH3
OCH3
H
CH3
CH3
H
H
H
H
butyl
butyl
butyl
butyl
H
H
H
butyl
allyl
allyl
CHCl3
acetone
acetone
CHCl3
Et2O
Et2O
THF
acetone
THF
THF
THF
THF
THF
THF
CHCl3
CHCl3
Et2O
DMF
DMSO
6
4
2
8
24
12
2
2
12
6
12
8
24
16
10
5
3
24
48
3a (84)[b]
3b (87)
3c (75)
3d (78)
3e (86)
3f (82)
3g (62)
3h (72)[b]
3i (57)
H
morpholin-4-yl
morpholin-4-yl
morpholin-4-yl
morpholin-4-yl
H
CH3
H
CH3
H
OH
3j (41)
3k (46)
3l (46)
3m (51)
3n (85)
3o (79)[b]
3p (84)
3r (75)
H
H
Cl
H
cyclohex-2-en-1-yl
cyclohex-2-en-1-yl
H
H
H
[c]
–
[c]
CH3
–
[a] Bis(2,4,6-trichlorophenyl) malonates were used. All reactions were carried out at room temperature. [b] Triethylamine was used as a
catalyst. [c] No product could be isolated.
regioisomeric product was formed in each case, respectively:
2-hydroxy-8-methyl-4H-pyrimido[1,2-a]pyrimidin-4-one (3a),
3-butyl-2-hydroxy-8-methyl-4H-pyrimido[1,2-a]pyrimidin-
4-one (3h), and 3-(cyclohex-2-enyl)-2-hydroxy-8-methyl-4H-
pyrimido[1,2-a]pyrimidin-4-one (3o) (Figure 1).
Scheme 1.
nature. In our experience, a well dried, less hygroscopic sol-
vent is much better than a polar, hygroscopic solvent be-
cause the presence of moisture in the system decreased the
Figure 1. Regioselectively formed isomers 3a and 3h.
yield of product by provoking decomposition of the
bis(2,4,6-trichlorophenyl) malonates.
In a similar manner, 2-hydroxy-8-methoxy-6-methyl-4H-
Several 2-aminopyrimidines and malonates were used as pyrimido[1,2-a]pyrimidin-4-one (3d), 3-butyl-2-hydroxy-8-
starting materials to provide information on the applica- methoxy-6-methyl-4H-pyrimido[1,2-a]pyrimidin-4-one (3e),
bility of this reaction. However, since only 2-aminopyrimid- 2-hydroxy-6-methyl-8-(morpholin-4-yl)-4H-pyrimido[1,2-a]-
ine and 2-amino-4-methylpyrimidine are commercially pyrimidin-4-one (3j), 3-butyl-2-hydroxy-6-methyl-8-(mor-
available, a number of other starting materials were pre- pholin-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one (3l), and 3-
pared using known literature methods.[7] Cyclization of all allyl-2-hydroxy-6-methyl-8-(morpholin-4-yl)-4H-pyrimido-
the 2-aminopyrimidine derivatives with the active malon- [1,2-a]pyrimidin-4-one (3m) were obtained, respectively,
ates were carried out under the optimized conditions de- from the reaction of 2-amino-4-methoxy-6-methylpyrimid-
scribed above. However, a number of starting materials did ine or 2-amino-4-methyl-6-(morpholin-4-yl)pyrimidine with
not produce the desired product in high yields under similar bis(2,4,6-trichlorophenyl) malonates, even though two
conditions. Therefore, reaction parameters (solvent, tem- structural isomers are possible in all cases (Figure 2). It was
perature, duration, and presence of a catalyst) were re- understood that the steric effect of both methoxy and mor-
evaluated and optimized for each set.
pholinyl groups decreased the reactivity of the neighboring
Most of the 2-aminopyrimidines gave the corresponding nitrogen towards the cyclization reaction in the second part
target compounds in good yields. The presence of one or of the two-step process of pyrimido[1,2-a]pyrimidin-4-one
two substituents (CH3, OCH3, Cl, and/or morpholinyl) at formation. However, a bulky butyl group at the 5-position
the 4- and/or 6-positions, which are adjacent to the ring of pyrimidine ring did not much influence the cyclization
nitrogen atoms of the pyrimidine, did not much hinder the (3i).
cyclization. In the reaction of 2-amino-4-methylpyrimidine
These results showed that the presence of several dif-
with bis(2,4,6-trichlorophenyl) malonate, butylmalonate, or ferent substituents on the 2-aminopyrimidine ring did not
(cyclohex-2-en-1-yl)malonate, it was observed that only one preclude the formation of desired pyrimido[1,2-a]pyrim-
Eur. J. Org. Chem. 2010, 2113–2120
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M. Güllü, A. Dinçsönmez, Ö. Özyavas
¸
FULL PAPER
prepared in a similar manner and used in the synthesis of
pyrimido[1,2-a]pyrimidines. Their reactions with 2-amino-
pyrimidines were investigated under a range of conditions
and the results are given in Table 2.
As seen in Table 2, reactions of the new malonates with
2-amino-4-methylpyrimidine and 2-amino-4,6-dimethylpyr-
imidine gave the expected pyrimido[1,2-a]pyrimidines 3a
and 3b, respectively, but in lower yields than those obtained
with bis(2,4,6-trichlorophenyl) malonate. These reactions
could not be realized at room temperature in common sol-
vents, but were successful at higher temperatures in solvents
such as DMF or THF. On the other hand, 2-amino-5-chlo-
ropyrimidine and 2-amino-4-hydroxy-6-methylpyrimidine
did not give any corresponding bicyclic pyrimidine deriva-
tive from the reaction with either diphenyl malonate or
bis(4-chlorophenyl) malonates, even at elevated tempera-
tures (150 °C) in polar solvents such as DMF. These results
showed that neither of the malonates were as reactive as
bis(2,4,6-trichlorophenyl) malonate and that both produced
the target compounds in lower yields even under more vig-
orous conditions. Although 2,4,6-trichlorophenol is not a
desired by-product of any reaction due to its toxic and un-
pleasant nature, its malonate ester, in contrast to ethyl,
phenyl or 4-chlorophenyl esters of malonate, has the unique
property of producing the bicyclic pyrimido[1,2-a]pyrimid-
ine derivatives described above.
Structural identification of these novel pyrimido[1,2-a]-
pyrimidines were satisfactorily completed by studying the
FTIR, NMR and mass spectroscopic data and the elemen-
tal analysis results. In the IR spectra, a medium strength,
broad, hydrogen-bonded enolic O–H band between 3400
and 2600 cm–1 and two bands at around 1680 and
1630 cm–1, together with the absence of any N–H stretching
band around 3300–3100 cm–1, were accepted as characteris-
tic bands that could be used for monitoring 2-hydroxy-4H-
pyrimido[1,2-a]pyrimidin-4-one formation.
Figure 2. Examples of regioselectively formed pyrimido[1,2-a]pyr-
imidines.
idin-4-ones. The presence of a hydroxy group on the pyrim-
idine ring, on the other hand, gave rise to decomposition
of active malonates due its acidic and nucleophilic nature.
Therefore, the reaction of 2-amino-4-hydroxy-6-methylpyr-
imidine with active malonates did not result in formation
of the corresponding pyrimido[1,2-a]pyrimidine derivatives.
Another unsuccessful outcome was observed from the reac-
tions of 2-amino-5-chloropyrimidine with malonates; in
these cases, the electron-withdrawing effect of the chlorine
substituent on the ring nitrogen of the pyrimidine moiety
reduced the nucleophilicity and, hence, disfavored the ring-
closure in the second step of the cyclization.
The effect of alkyl or alkenyl groups at the C-2 carbon
of malonate was also investigated by studying the reaction
of bis(2,4,6-trichlorophenyl) esters of butyl, allyl and cyclo-
hexenyl malonate with a range of 2-aminopyrimidines.
These esters were prepared by using a modification of
Kappe’s method,[4–5] and all successfully gave the corre-
sponding pyrimido[1,2-a]pyrimidines (Table 1). The pres-
ence of an alkyl or alkenyl group at the 3-position of the
target compounds improved the solubility of the pyrimido-
[1,2-a]pyrimidine in common solvents.
The ambiguous position of the methyl group in the prod-
ucts 3a, 3h, and 3o (Figure 1), i.e., whether it was at the 6-
The use of bis(2,4,6-trichlorophenyl) malonates was or 8-position, was revealed by proton NMR spectroscopic
found to be very successful for preparing the desired pyrim- data. The chemical shifts of the methyl hydrogen atoms in
ido[1,2-a]pyrimidines at room temperature in high yields. the products were consistent with the methyl group occupy-
However, their unstable nature combined with problems as- ing the 8-position in all cases. The chemical shifts of the
sociated with toxicity and the separation of 2,4,6-tri- methyl hydrogen atoms for 6,8-dimethyl-2-hydroxy-4H-pyr-
chlorophenol from the products, led us to study the pos- imido[1,2-a]pyrimidin-4-one (3b) and 3-butyl-6,8-dimethyl-
sibility of replacing it with an alternative phenol. To this 2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one (3g) were
end, malonates with phenol and 4-chlorophenol were also observed to be distinct; the 6-methyl hydrogen atoms
Table 2. Reactions of diphenyl malonate (2e) and bis(4-chlorophenyl) malonate (2f) with 2-aminopyrimidines.
Ar
2-Aminopyrimidine
Temperature [°C]
Solvent
Product (%)
Phenyl
Phenyl
Phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-Cl-phenyl
4-methyl
4,6-dimethyl
5-chloro
4-methyl
4,6-dimethyl
5-chloro
110
120
150
60
60
150
150
DMF
DMF
DMF
THF
THF
DMF
DMF
3a (56)
3b (62)
[a]
–
3a (68)
3b (65)
[a]
–
[a]
4-hydroxy-6-methyl
–
[a] No product formation was observed.
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Pyrimido[1,2-a]pyrimidin-4-ones from Reactive Malonates
showed higher chemical shifts than those of the 8-methyl
hydrogen atoms, owing to the deshielding effect of the
neighboring carbonyl group (Figure 3).
Conclusions
In summary, a highly efficient and simple synthetic pro-
cedure has been developed for the synthesis of 2-hydroxy-
4H-pyrimido[1,2-a]pyrimidin-4-one derivatives in high
yields by the reaction of different 2-aminopyrimidines with
bis(2,4,6-trichlorophenyl) malonates at room temperature.
This method was found to be applicable to a wide selection
of starting materials, even sterically hindered 2-aminopyr-
imidines. 2,4,6-Trichlorophenol was found to be a better
leaving group than ethanol, phenol and 4-chlorophenol in
comparable experiments with a range of malonates that
were conducted to determine the optimal leaving group in
terms of the reactivity, stability, ease of removal, and toxic-
ity. Although 2,4,6-trichlorophenol can be difficult to work
with due to its toxicity and pungent odor, its malonate ester
was preferred in these reactions because of its high reactiv-
ity and stability. Such “magic malonates” were found to be
the only malonates capable of reacting to produce bicyclic
pyrimidine derivatives, 2-hydroxy-4H-pyrimido[1,2-a]pyr-
imidin-4-ones, in high yields under mild conditions.
Figure 3. Structures of 3a, 3b and 3g.
1
An H-13C HMBC experiment was carried out with 3a
(Figure 3) to confirm the position of the methyl group
1
(Table 3). In the H-13C HMBC spectrum, the H-3 hydro-
gen at δ = 4.82 ppm coupled with both the C-2 (δ =
168.40 ppm) and C-4 (δ = 150.24 ppm) carbon atoms. A
1
long-range H-13C coupling was also observed between the
C-4 carbon atom and a hydrogen atom other than H-3. This
result indicates that a proton must be attached to the C-6
carbon. It follows that, because two different hydrogen
atoms (H-3 and H-6) couple with the C-4 carbon, the
methyl group should be attached to the C-8 carbon (δ =
176.38 ppm). Additionally, the 1H-13C coupling between
the methyl hydrogen atoms (δ = 2.63 ppm) with the C-8 (δ
= 176.38 ppm) and C-7 (δ = 114.28 ppm) carbon atoms is
also clearly indicative of the position of methyl group.
Experimental Section
General: Melting points were determined with an Electrothermal
melting point apparatus. Infrared spectra were recorded on a Per-
kin–Elmer Spectrum 100 FTIR spectrometer. 1H and 13C NMR
spectra were recorded with a Varian Mercury 400–400 MHz High
Performance Digital FT-NMR spectrometer. Chemical shifts (δ)
are expressed relative to tetramethylsilane (TMS). Mass spectra
were recorded with a Shimadzu GC–MS QP2010 mass spectrome-
ter operating at an ionization potential (EI) of 70 eV. Samples were
injected into the MS using a DI-2010 direct inlet probe. Elemental
analyses for C, H and N were performed with a EuroVector
CHNS-O Elemental Analyser.
1
1
Table 3. 13C and H assignments for 3a and H-13C HMBC corre-
lations.
General Procedure for the Synthesis of Active Malonates: To malo-
nic acid (0.1 mol) and 2,4,6-trichlorophenol (0.21 mol) in a round-
bottomed flask, was added freshly distilled POCl3 (20 mL) and the
solution was heated to reflux until HCl evolution stopped. Then,
excess POCl3 was removed by vacuum distillation. Residual crude
product was neutralized by controlled addition of saturated
Na2CO3 to the cooled flask and then extracted with chloroform.
After drying the solution with MgSO4, it was filtered and the sol-
vents evaporated to dryness under reduced pressure. The crude
product was recrystallized from a suitable solvent. Bis(2,4,6-tri-
chlorophenyl) malonate (2a) and bis(2,4,6-trichlorophenyl) butyl-
malonate (2b), diphenyl malonate (2e) and bis(4-chlorophenyl) ma-
lonate (2f) were identified by comparing their melting points and
spectroscopic data (FTIR and 1H NMR) with those reported in
the literature.[4,5,8]
Position
13C
δ [ppm]
1H
δ [ppm]
1H-13C HMBC correlation
2
3
4
6
7
8
10
8Ј
168.40
81.30
–
4.82
–
9.08
7.36
–
–
C3, C4, C2
–
C6, C7, C8, C4
C7, C6, C8, C8Ј
–
–
150.24
138.25
114.28
176.38
155.92
25.55
–
2.63
C8, C7, C8Ј
In a similar manner, 3d and 3e (Figure 2) formed as cycli-
zation products from the reaction of 2-amino-4-methoxy-6-
methylpyrimidine with bis(2,4,6-trichlorophenyl) malonate
and bis(2,4,6-trichlorophenyl) butylmalonate, respectively.
The position of the methyl and methoxy groups were estab-
lished from the proton NMR spectra by comparison of
chemical shifts of the methyl group protons, which were
found at δ = 2.87 and 2.82 ppm, proving that the methyl
group occupied the 6-position and the methoxy group the
8-position of the target compounds. Both the spectroscopic
data and the elemental analysis supported the structures of
the isolated products of the condensation–cyclization reac-
tions.
Bis(2,4,6-trichlorophenyl) Allylmalonate (2c): The product was
recrystallized from acetone/water. White solid (47.69 g, 95%); m.p.
80–85 °C. FTIR (KBr): ν
= 3082, 3010 (C=C–H), 2984, 2822,
˜
max
1770 (C=O), 1631 (C=C), 1569, 1515, 1450, 1384, 1336, 1320 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.0 (t, J = 7.2 Hz, 2 H, CH2),
4.15 (t, J = 7.2 Hz, 1 H, CH), 5.23 (dd, J = 10.4, 1.2 Hz, 1 H,
CH=), 5.32 (dd, J = 14.8, 1.2 Hz, 1 H, CH=), 5.95 (m, 1 H, CH=),
7.48 (s, 4 H, ArH) ppm.
Bis(2,4,6-trichlorophenyl) (Cyclohex-2-en-1-yl)malonate (2d): The
product was recrystallized from acetone/water. White solid (42.5 g,
Eur. J. Org. Chem. 2010, 2113–2120
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2117

M. Güllü, A. Dinçsönmez, Ö. Özyavas
¸
FULL PAPER
78%); m.p. 115 °C. FTIR (KBr): ν
= 3080 (C=C–H), 2938, the product was purified by column chromatography (SiO2; EtOAc/
˜
max
2835, 1789 (C=O), 1654 (C=C), 1565, 1448, 1384, 1328, 1228 cm–1.
hexane, 1:1). Yellow solid (1.13 g, 86%); m.p. 265–267 °C. FTIR
(KBr): ν = 3365–2650 (O-H), 3086, 2945, 2853, 1671 (C=O),
1H NMR (400 MHz, CDCl3): δ = 1.45–2.00 (m, 6 H, cyclo-CH2),
˜
max
3.2 (m, 1 H, cyclo-CH), 4.1 (d, J = 6 Hz, 1 H, CH), 5.89 (m, 1 H, 1612 (C=C), 1537 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 0.80
cyclo CH=), 5.84 (dd, J = 11.2 Hz, 1 H, CH=), 7.2 (s, 4 H, ArH)
ppm.
(t, J = 7 Hz, 3 H, 4Ј-CH3), 1.27 (m, J = 7 Hz, 2 H, 3Ј-CH2), 1.35
(m, J = 7 Hz, 2 H, 2Ј-CH2), 2.23 (m, J = 7 Hz, 2 H, 1Ј-CH2), 2.82
(s, 3 H, 6-CH3), 3.9 (s, 3 H, 8-OCH3), 6.25 (s, 1 H, 7-H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 14.69 (C4Ј), 22.92 (C3Ј), 24.02
(C1Ј), 24.25 (C6-CH3), 30.68 (C2Ј), 55.22 (C8-OCH3), 94.25 (C3),
105.1 (C7), 151.35 (C6), 156.80 (C4), 160.97 (C2), 164.21 (C10),
168.15 (C8) ppm. MS: m/z (%) = 264 (100) [M + H]+. C13H17N3O3
(263): calcd. C 59.30, H 6.51, N 15.96; found C 59.48, H 6.19, N
15.65.
General Procedure for the Synthesis of 2-Hydroxy-4H-pyrimido[1,2-
a]pyrimidin-4-ones: 2-Aminopyrimidine derivative (5 mmol) and
bis(2,4,6-trichlorophenyl) butylmalonate (5 mmol) were dissolved
in an appropriate anhydrous solvent (see Table 1, 20 mL), under
nitrogen, in a dried reaction flask fitted with a reflux condenser.
The homogeneous solution was stirred at room temperature and
the progress of the reaction was monitored with TLC. If the reac-
tion did not start, triethylamine (1 mL) was added slowly into the
solution. After completion of the reaction, precipitated solids were
filtered by suction, washed with solvent (2 ϫ 20 mL) and dried at
room temperature. The crude product was purified either by
recrystallization from ethanol, acetone, ethanol/water or by column
chromatography.
3-Butyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one (3f): The re-
action was carried out in diethyl ether and the pure product was
obtained by column chromatography (SiO2; EtOAc). Yellow solid
(0.89 g, 82%); m.p. 178–181 °C. FTIR (KBr): ν
= 3400–2500
˜
max
(O–H), 3055, 2949 and 2868 (aliphatic C–H), 1687 (C=O), 1635,
1577, 1477, 1365, 775 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
0.89 (t, J = 7.6 Hz, 3 H, 4Ј-CH3), 1.28 (m, J = 7.6 Hz, 2 H, 3Ј-
CH2), 1.4 (m, J = 7.6 Hz, 2 H, 2Ј-CH2), 2.4 (m, J = 7.6 Hz, 2 H,
1Ј-CH2), 7.39 (q, J = 2 Hz, 1 H, 7-H), 9.02 (q, J = 2 Hz, 1 H, 8-
H), 9.2 (q, J = 2 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 14.67 (C4Ј), 22.83 (C3Ј), 24.09 (C2Ј), 30.74 (C1Ј),
95.26 (C3), 113.07 (C6), 138.72 (C7 and C9), 149.41 (C4), 156.17
(C10), 164.16 (C2) ppm. MS: m/z (%) = 220 (100) [M + H]+.
C11H13N3O2 (219): calcd. C 60.26, H 5.98, N 19.17; found C 60.79,
H 6.02, N 18.73.
2-Hydroxy-8-methyl-4H-pyrimido[1,2-a]pyrimidin-4-one (3a): The
reaction was carried out in CHCl3 and the product was recrys-
tallized from ethanol. Yellow solid (0.74 g, 84%); m.p. 256–268 °C.
FTIR (KBr): ν
= 3400–2600 (O–H), 3074, 2901 and 2864 (ali-
˜
max
phatic C–H), 1675 (C=O), 1627, 1540, 1465, 1236 cm–1. H NMR
(400 MHz, [D6]DMSO): δ = 2.43 (s, 3 H, 8-CH3), 4.62 (s, 1 H, 3-
H), 7.17 (d, J = 7 Hz, 1 H, 7-H), 8.4 (d, J = 7 Hz, 1 H, 6-H), 12.3
(s, 1 H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 25.55
(C8-CH3), 81.30 (C3), 114.28 (C7), 138.25 (C6), 150.24 (C4),
155.92 (C10), 168.40 (C2), 176.38 (C8) ppm. MS: m/z (%) = 178
(100) [M + H]+. C8H7N3O2 (177): calcd. C 53.73, H 4.14, N 23.15;
found C 54.18, H 4.70, N 21.96.
1
3-Butyl-6,8-dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one
(3g): The reaction was carried out in THF and the product was
recrystallized from ethanol/water. Yellow solid (0.83 g, 62%); m.p.
6,8-Dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one
(3b): 136–138 °C. FTIR (KBr): νmax = 3400–2500 (O–H), 3078, 2961 and
˜
The reaction was carried out in acetone and the product was recrys-
tallized from ethanol/water. Yellow solid (0.83 g, 87%); m.p. 167–
2859 (aliphatic C–H), 1673 (C=O), 1650, 1560, 1535, 1488, 1469
1
cm–1. H NMR (400 MHz, [D6]DMSO): δ = 0.95 (t, J = 7.2 Hz, 3
169 °C. FTIR (KBr): νmax = 3300–2600 (O–H), 2935 and 2853 (ali-
H, 4Ј-CH3), 1.44 (m, J = 7.2 Hz, 2 H, 3Ј-CH2), 1.55 (m, J = 7.2 Hz,
2 H, 2Ј-CH2), 2.55 (t, J = 7.2 Hz, 2 H, 1Ј-CH2), 2.58 (s, 3 H, 8-
CH3), 3.14 (s, 3 H, 6-CH3), 6.7 (s, 1 H, 7-H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 14.12 (C4Ј), 22.92 (C3Ј), 24.02 (C2Ј),
24.40 (C1Ј), 24.67 (C8-CH3), 30.36 (C6-CH3), 96.79 (C3), 116.69
(C7), 128.38 (C6), 156.08 (C4), 159.93 (C5), 162.47 (C10), 172.64
(C2) ppm. MS: m/z (%) = 248 (100) [M + H]+. C13H17N3O2 (247):
calcd. C 63.14, H 6.93, N 16.99; found C 62.80, H 6.98, N 16.90.
˜
phatic C–H), 1708 (C=O), 1625, 1432, 1365, 1240, 1163, 1032, 945,
783 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 2.25 (s, 3 H, 8-
CH3), 2.7 (s, 3 H, 6-CH3), 4.4 (s, 1 H, 3-H), 6.9 (s, 1 H, 7-H), 11.95
(1 H, enolic OH) ppm. MS: m/z (%) = 192 (100) [M + H]+.
C9H9N3O2 (191): calcd. C 56.54, H 4.74, N 21.98; found C 56.39,
H 5.62, N 21.67.
2-Hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one (3c): The reaction
was carried out in acetone and the product was recrystallized from
3-Butyl-2-hydroxy-8-methyl-4H-pyrimido[1,2-a]pyrimidin-4-one
(3h): The reaction was carried out in acetone and the crude product
was purified by column chromatography (SiO2; CHCl3). Yellow so-
water. Red solid (0.61 g, 75%); m.p. Ͼ300 °C. FTIR (KBr): ν
=
˜
max
3300–2600 (O–H), 3092, 1697 (C=O), 1617, 1531, 1357, 1350, 1317
1
cm–1. H NMR (400 MHz, [D6]DMSO): δ = 4.9 (s, 1 H, 3-H), 7.4
lid (0.83 g, 72%); m.p. Ͼ300 °C. FTIR (KBr): ν
= 3400–2500
˜
max
(q, J = 3 Hz, 1 H, 7-H), 9.15 (q, J = 3 Hz, 1 H, 8-H), 9.35 (q, J =
3 Hz, 1 H, 6-H), 12.3 (s, 1 H, OH) ppm. MS: m/z (%) = 164.45
(100) [M + H]+. C7H5N3O2 (163.134): calcd. C 51.54, H 3.09, N
25.76; found C 51.28, H 3.40, N 25.63.
(O–H), 3082, 2953 and 2855 (aliphatic C–H), 1673 (C=O), 1648,
1
1558, 1535, 1488, 1465 cm–1. H NMR (400 MHz, [D6]DMSO): δ
= 0.88 (t, J = 7 Hz, 3 H, 4Ј-CH3), 1.29 (m, J = 7 Hz, 2 H, 3Ј-CH2),
1.42 (m, J = 7 Hz, 2 H, 2Ј-CH2), 2.15 (t, J = 7.2 Hz, 2 H, 1Ј-CH2),
2.5 (s, 3 H, 8-CH3), 7.33 (d, J = 7 Hz, 1 H, 7-H), 9.09 (d, J = 7 Hz,
1 H, 6-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 14.71 (C4Ј),
24.11 (C3Ј), 25.50 (C2Ј), 30.87 (C1Ј), 22.87 (C8-CH3), 94.04 (C3),
114.02 (C7), 138.01 (C6), 148.70 (C4), 155.55 (C5), 168.43 (C10),
175.24 (C2) ppm. MS: m/z (%) = 234 (100) [M + H]+. C12H15N3O2
(233): calcd. C 61.79, H 6.48, N 18.01; found C 61.50, H 6.78, N
17.85.
2-Hydroxy-8-methoxy-6-methyl-4H-pyrimido[1,2-a]pyrimidin-4-one
(3d): The reaction was carried out in CHCl3 and the product was
recrystallized from ethanol. Yellow solid (0.81 g, 72%); m.p. 190–
192 °C. FTIR (KBr): νmax = 3400–2500 (O–H), 2965 and 2823 (ali-
˜
1
phatic C–H), 1693 (C=O), 1643, 1457, 1365, 1210, 1163 cm–1. H
NMR (400 MHz, [D6]DMSO): δ = 2.87 (s, 3 H, 6-CH3), 4.02 (s, 3
H, 8-OCH3), 5.35 (s, 1 H, 3-H), 6.64 (s, 1 H, 7-H) ppm. MS: m/z
(%) = 207 (100) [M]+, 190 (15), 179 (40), 166 (95), 123 (30), 83 (60),
109 (45). C9H9N3O3 (207): calcd. C 52.17, H 4.38, N 20.28; found
C 52.48, H 4.50, N 19.76.
7-Butyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one (3i): The re-
action was carried out in THF and the product was recrystallized
from ethanol. Yellow solid (0.54 g, 57%); m.p. 226–228 °C. FTIR
3-Butyl-2-hydroxy-8-methoxy-6-methyl-4H-pyrimido[1,2-a]pyrim- (KBr): ν
= 3400–2400 (O–H), 2974, 2920 and 2863 (aliphatic
˜
max
idin-4-one (3e): The reaction was carried out in diethyl ether and
C–H), 1683 (C=O), 1589, 1547, 1513, 1444, 1372, 1310, 1242, 1117,
2118
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2113–2120

Pyrimido[1,2-a]pyrimidin-4-ones from Reactive Malonates
1013, 976, 796 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 0.92 44 (100). C10H9N3O2 (203): calcd. C 59.11, H 4.46, N 20.68; found
(t, J = 7 Hz, 3 H, 4Ј-CH3), 1.25 (m, J = 7.2 Hz, 2 H, 3Ј-CH2), 1.43
(m, J = 7 Hz, 2 H, 2Ј-CH2), 2.39 (t, J = 7.2 Hz, 2 H, 1Ј-CH2), 4.96
(s, 1 H, 3-H), 9.01 (d, J = 7 Hz, 1 H, 8-H), 9.21 (d, J = 7 Hz, 1 H,
6-H) ppm. MS: m/z (%) = 219.1 (30) [M]+, 207 (30), 190(10), 176
(100), 162 (5), 122 (80), 79 (75). C11H13N3O2 (219): calcd. C 60.26,
H 5.98, N 19.17; found C 60.39, H 5.91, N 18.97.
C 59.40, H 4.30, N 20.60.
3-(Cyclohex-2-en-1-yl)-2-hydroxy-8-methyl-4H-pyrimido[1,2-a]pyr-
imidin-4-one (3o): The reaction was carried out in chloroform and
the crude product was purified by column chromatography (SiO2;
EtOAc). Yellow solid (0.85 g, 79%); m.p. 232–234 °C. FTIR (KBr):
ν
= 3400–2200 (O–H), 3084, 2971 and 2878 (aliphatic C–H),
˜
max
1667 (C=O), 1613, 1566, 1433 cm–1. 1H NMR (400 MHz, [D6]-
DMSO): δ = 1.6–2.2 (m, 6 H, 2Ј-H, 3Ј-H, 4Ј-H), 2.75 (s, 3 H, 8-
CH3), 3.9 (m, 1 H, 1Ј-H), 5.6 (d, J = 10 Hz, 1 H, 6Ј-H), 5.85 (m,
J = 10 Hz, 1 H, 5Ј-H), 6.5 (d, J = 7 Hz, 1 H, 7-H), 7.12 (d, J =
7 Hz, 1 H, 6-H) ppm. MS: m/z (%) = 257 (50) [M]+, 229 (20), 203
(100), 175 (15), 136 (75), 109 (50), 93 (95). C14H15N3O2 (257):
calcd. C 65.35, H 5.88, N 16.33; found C 65.12, H 5.50, N 15.98.
2-Hydroxy-6-methyl-8-morpholin-4-yl-4H-pyrimido[1,2-a]pyrimidin-
4-one (3j): The reaction was carried out in THF and the crude
product was purified by column chromatography (SiO2; EtOAc).
Orange solid (0.62 g, 41%); m.p. 230–233 °C. FTIR (KBr): ν
=
˜
max
3300–2500 (O–H), 3098, 2963, 2873, 1691 (C=O), 1502 (C=C),
1
1445, 1425 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 2.79 (s, 3
H, 6-CH3), 3.67–3.69 (m, 6 H, 5Ј,6Ј-CH2), 3.84 (2 H, 6-H), 4.25 (t,
1 H, H2), 4.25 (s, 1 H, 3-H), 6.75 (s, 1 H, 7-H), 11.3 (s, 1 H, OH)
ppm. MS: m/z (%) = 262 (70) [M]+, 245 (5), 234 (20), 221 (100),
194 (30), 163 (65), 109 (45). C12H14N4O2 (262): calcd. C 54.96, H
5.38, N 21.36; found C 54.43, H 5.24, N 21.66.
3-(Cyclohex-2-en-1-yl)-2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-
one (3p): The reaction was carried out in CHCl3 and the product
was recrystallized from acetone/water. Yellow solid (1.02 g, 84%);
m.p. 212–214 °C. FTIR (KBr): ν
= 3400–2500 (O–H), 3020,
˜
max
2928 and 2858 (aliphatic C–H), 1650 (C=O), 1614, 1565, 1439
2-Hydroxy-8-morpholin-4-yl-4H-pyrimido[1,2-a]pyrimidin-4-one
(3k): The reaction was carried out in THF and the product was
recrystallized from ethanol/water. Yellow solid (0.57 g, 46%); m.p.
1
cm–1. H NMR (400 MHz, [D6]DMSO): δ = 1.3–2.04 (m, 6 H, 2Ј-
H, 3Ј-H, 4Ј-H), 2.75–3.65 (m, 1 H, 1Ј-H), 6.55 (d, J = 13 Hz, 1 H,
6Ј-H), 7.4 (m, J = 10 Hz, 1 H, 5Ј-H), 8.2 (q, J = 5 Hz, 1 H, 8-H),
9.02 (q, J = 5 Hz, 1 H, 7-H), 9.19 (q, J = 7 Hz, 1 H, 6-H) ppm.
MS: m/z (%) = 243 (60) [M]+, 228 (10), 215 (40), 200 (15), 161 (35),
122 (100), 73 (55). C13H13N3O2 (243): calcd. C 64.19, H 5.39, N
17.27; found C 64.43, H 5.14, N 16.95.
252–256 °C. FTIR (KBr): νmax = 3500–2300 (O–H), 2979, 2955 and
˜
2855 (aliphatic C–H), 1677 (C=O), 1627, 1587.1552, 1452, 1378,
1115 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 3.7–3.9 (m, 8 H,
5Ј,6Ј-H), 4.15 (s, 1 H, 3-H), 6.9 (d, J = 8 Hz, 1 H, 7-H), 8.6 (d, J
= 7.6 Hz, 1 H, 6-H) ppm. MS: m/z (%) = 248 (45) [M]+, 220 (30),
207 (40), 196 (100), 180 (75), 160 (25), 149 (80), 123 (35), 95 (60).
C11H12N4O3 (248): calcd. C 53.22, H 4.87, N 22.57; found C 53.39,
H 4.52, N 22.23.
6-Chloro-2-hydroxy-8-methyl-4H-pyrimido[1,2-a]pyrimidin-4-one
(3r): The reaction was carried out in diethyl ether and the product
was recrystallized from ethanol/water. Yellow solid (0.79 g, 75%);
m.p. 190–1192 °C. FTIR (KBr): ν
= 3400–2500 (O–H), 3074,
˜
max
3-Butyl-2-hydroxy-6-methyl-8-morpholin-4-yl-4H-pyrimido[1,2-a]-
pyrimidin-4-one (3l): The reaction was carried out in THF and the
product was recrystallized from acetone. Yellow solid (0.76 g,
2915 and 2888 (aliphatic C–H), 1693 (C=O), 1598, 1412, 1355,
1240, 783 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 1.97 (s, 3
H, 8-CH3), 5.59 (s, 1 H, 3-H), 8.05 (s, 1 H, 7-H), 12.03 (s, 1 H,
enolic OH) ppm. MS: m/z (%) = 211 (100) [M + H]+. C8H6ClN3O2
(211): calcd. C 54.41, H 2.86, N 19.86; found C 54.83, H 3.01, N
20.16.
46%); m.p. 231–233 °C. FTIR (KBr): ν
= 3200–2337 (O–H),
˜
max
1
2984, 2959, 2855, 1677 (C=O), 1552 (C=C), 1452 cm–1. H NMR
(400 MHz, CDCl3): δ = 0.90 (t, J = 5.6 Hz, 3 H, 4Ј-CH3), 1.38 (m,
J = 7 Hz, 2 H, 3Ј-CH2), 1.53 (m, J = 7 Hz, 2 H, 2Ј-CH2), 2.4 (m,
J = 7.6 Hz, 2 H, 1Ј-CH2), 3.0 (s, 3 H, 6-CH3), 3.6–4.05 (m, 8 H,
5Ј,6Ј-H), 6.1 (s, 1 H, 7-H) ppm. C16H22N4O3 (318): calcd. C 60.36,
H 6.97, N 17.60; found C 60.76, H 6.14, N 17.44.
Acknowledgments
We thank The Scientific and Technological Research Council of
3-Allyl-2-hydroxy-6-methyl-8-morpholin-4-yl-4H-pyrimido[1,2-a]-
pyrimidin-4-one (3m): The reaction was carried out in THF and
the pure product was obtained by column chromatography [SiO2;
EtOAc/hexane, 1:1]. Yellow solid (0.77 g, 51%); m.p. 233–235 °C.
˙
Turkey (TÜBITAK) (TBAG-106T066) for financial support. A. D.
˙
and Ö. Ö. also thank TÜBITAK for PhD and MSc scholarships,
respectively, throughout this project.
FTIR (KBr): ν
= 3500–2300 (O–H), 3077, 2971, 2922, 1681
˜
max
(C=O), 1561 (C=C), 1418, 1366, 1115 cm–1. H NMR (400 MHz,
CDCl3): δ = 3.0 (s, 3 H, 6-CH3), 3.6, 3.8 (6 H, 5Ј,6Ј-CH2), 3.2 (d,
J = 6 Hz, 2 H, 1Ј-CH2), 4.98 (d, J = 11 Hz, 1 H, 3Јa-CH-cis), 5.15
(d, J = 18 Hz, 1 H, 3Јb-CH-trans), 5.96 (m, 1 H, 2Ј-CH), 6.15 (s,
1 H, 7-H) ppm. MS: m/z (%) = 302 (100) [M]+, 274 (30), 259 (38),
245 (10), 221 (65), 163 (8), 109 (5). C15H18N4O3 (302): calcd. C
59.59, H 6.00, N 18.53; found C 59.50, H 5.94, N 18.82.
1
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3-Allyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one (3n): The re-
action was carried out in THF and the product was recrystallized
from THF. Yellow solid (0.86 g, 85%); m.p. 134–136 °C. FTIR
(KBr): ν
= 3400–2400 (O–H), 3080, 2995 and 2897 (aliphatic
˜
max
C–H), 1691 (C=O), 1643, 1537, 1450, 1313 cm–1 1H NMR
.
(400 MHz, [D6]DMSO): δ = 3.12 (d, J = 6 Hz, 2 H, 1Ј-CH2), 4.87
(d, J = 11 Hz, 1 H, 3Јa-CH-cis), 5.0 (d, J = 18 Hz, 1 H, 3Јb-CH-
trans), 5.85 (m, 1 H, 2Ј-CH), 7.33 (q, J = 8 Hz, 1 H, 7-H), 8.98 (q,
J = 8 Hz, 1 H, 8-H), 9.17 (q, J = 8 Hz, 1 H, 6-H) ppm. MS: m/z
(%) = 203 (10) [M]+, 188 (5), 160 (25), 134 (40), 120 (15), 95 (45),
Eur. J. Org. Chem. 2010, 2113–2120
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2119

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Received: December 6, 2009
Published Online: March 4, 2010
2120
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Eur. J. Org. Chem. 2010, 2113–2120