Synthesis of fused dihydro-pyrimido[4,3-d]coumarins using Biginelli multicomponent reaction as key step

Article abstract of DOI:10.1016/j.tet.2009.05.088

A new efficient approach for the synthesis of functionalized dihydro-pyrimido[4,3-d]coumarins is described. Use of benzyl- or tert-butyl acetoacetate and various salicyl aldehydes in typical Biginelli multicomponent reactions provides esters that can be e

Full text of DOI:10.1016/j.tet.2009.05.088

Tetrahedron 65 (2009) 5949–5957
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of fused dihydro-pyrimido[4,3-d]coumarins using Biginelli
multicomponent reaction as key step
,
,
,
Mihaela Matache a b, Cristian Dobrota a b, Niculina D. Bogdan a, Ioana Dumitru a b, Lavinia L. Ruta b,
Codruta C. Paraschivescu b, Ileana C. Farcasanu b, Ion Baciu b, Daniel P. Funeriu a
,
*
a Technical University of Munich, Department of Chemistry, Marie Curie Excellence Team, 4 Lichtenbergstr., 85747 Garching, Germany
b University of Bucharest, Department of Chemistry, Division of Organic Chemistry, 90-92 Panduri Street, 050663, District 5, Bucharest, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2009
Received in revised form 23 May 2009
Accepted 28 May 2009
Available online 6 June 2009
A new efficient approach for the synthesis of functionalized dihydro-pyrimido[4,3-d]coumarins is de-
scribed. Use of benzyl- or tert-butyl acetoacetate and various salicyl aldehydes in typical Biginelli mul-
ticomponent reactions provides esters that can be easily deprotected to yield the corresponding hydroxy
acids. Annelation of the latter leads to the target dihydro-pyrimido[4,3-d]coumarins. Formation of some
unexpected oxo-bridged tetrahydro-pyrimidines is also described. Spectral properties of the synthesized
dihydro-pyrimido[4,3-d]coumarins indicate the necessity to revisit some compounds previously re-
ported as products of direct one-pot Biginelli condensation involving 4-hydroxycoumarin as dicarbonyl
component.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
solution, solvent-free conditions or in microwave conditions.11
However, despite the versatility of 1,3-dicarbonyl derivatives as
Functionalized nitrogen-heterocycles play a proeminent role in
medicinal chemistry and they have been intensively used as scaf-
folds for drug development.1 In this context pyrimidine derivatives
are of particular interest because of their pharmacological profile.2
4,5,6-Trisubstituted-3,4-dihydropyrimidin-2(1H)-ones of type 1,
also known as Biginelli compounds (Fig. 1), are easily accessible via
a multicomponent condensation process, first reported more than
a century ago.3 Almost ignored for eight decades,4 their popularity
recently increased. Structurally, they can be considered as 3-aza-
analogs of dihydropyridines of Hantzsch type. Based on this
similarity, pharmacological studies initially focused on their
demonstrated calcium channel modulating properties.5 More
recently, some Biginelli derivatives proved to be promising anti-
cancer leads, such as monastrol 2, which is an inhibitor of a mitotic
kinesin.6 Other compounds, such as 3, demonstrated inhibitory
activity of heat-shock protein Hsp707,8 whereas compounds such as
4 exhibited a1a-adrenoceptor antagonist properties.9
participants into multicomponent reactions,12 far less attention has
been paid to the scoping of the b-ketoesters in the Biginelli con-
densation13 as well as to the further functionalization of the Bigi-
nelli adducts,14 in spite of the fact that the structures thus obtained
may present significant biological activity.
OH
Ar
RO2C
EtO2C
NH
NH
N
H
O
N
H
S
1
2
F
F
Br
O
The easiest way to prepare the 3,4-dihydropyrimidin-2(1H)-one
N
F
core involves a b-ketoester, aldehyde, and urea derivatives in the
N
NH
presence of an acidic catalyst,10 process known as the Biginelli re-
action. In the study of this multicomponent process much emphasis
was placed on catalysts screening: a plethora of Bronsted and Lewis
acids were reported to mediate the Biginelli reaction, either in
H
EtO2C
NH
N
H
O
MeO
N
O
CO2Me
3
4
* Corresponding author. Tel.: þ49 892 891 3133; fax: þ49 892 891 4512.
E-mail address: daniel.funeriu@ch.tum.de (D.P. Funeriu).
Figure 1. General formula (1) and examples of biologically active (2–4) Biginelli
pyrimidinones.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.088

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M. Matache et al. / Tetrahedron 65 (2009) 5949–5957
Since numerous reports demonstrated the potential in medici-
11. The choice of the esters was dictated by the effectiveness of their
available deprotection methods. Since the alkaline hydrolysis of
Biginelli alkyl esters is known to be a low-yielding process,13,19 we
turned our sights to benzyl esters. Indeed, they are known to be
easily deprotected by hydrogenolysis, even in the notoriously dif-
ficult context of Biginelli-type compounds.13,19,20 We therefore
nal chemistry of fused heterocyclic structures including the py-
rimidine core15 we considered of interest their synthesis. In
particular, fused pyrimidocoumarins were shown to exhibit a wide
pharmacological profile,16 underlying the importance of new syn-
thetic methods for facile access into this class of compounds.
Herein, we describe an efficient approach for the preparation of
functionalized benzopyrano[4,3-d]dihydropyrimidinone derivatives
5 (Scheme 1) via a short synthetic sequence that uses the Biginelli
condensation as key step.
decided to use the benzyl acetoacetate 10a as b-ketoester moiety.
Additionally, in order to use the same methodology in presence of
hydrogenolysis-incompatible functional groups (compounds
11c–e), we also chose tert-butyl acetoacetate 10b as a potential
Biginelli-reaction candidate,21 since tert-butyl esters are readily
hydrolyzed under acidic conditions. For the mediation of the
multicomponent reaction, we used both Bronsted and Lewis acids.
Generally, we employed para-toluenesulfonic acid (PTSA) as
a cheap and accessible catalyst for the Biginelli process.22 By
2. Results and discussion
2.1. Initial approach and revision
To prepare the benzopyranopyrimidines core, we initially used
the most direct approach, a Biginelli-type condensation with 4-
hydroxycoumarin 6 as 1,3-dicarbonyl component. This methodo-
logy implies the use of preformed benzopyrane derivative and the
subsequent formation of the pyrimidinone ring in a multicompo-
nent reaction step (Scheme 1a). Literature survey disclosed the ex-
istence of a few precedents dealing with this transformation.17
However, all attempts to prepare the tricyclic target 7 by multi-
condensation using various reaction conditions,18 including those
previously reported, failed. We were only able to isolate the adducts
8 resulting from the condensation of the aldehyde with 4-hydroxy-
coumarin (Scheme 1a), as proved by physical and spectral charac-
teristics.18 Indeed, treatment of 6 with urea and various aldehydes in
presence of acid catalysts led to compounds identical to those
obtained in the same reaction conditions in absence of urea (also see
discussion in Section 2.4), further substantiating the proposal that
the obtained compounds are, in fact adducts of type 8.
refluxing the b-ketoester, aldehyde, and urea in ethanol in a molar
ratio of 1:1:1.5 in presence of 50 mol % of PTSA, we prepared the
desired Biginelli adducts 11a–g in medium to good isolated yields
(Table 1, entries 1–7).
Table 1
Preparation of Biginelli adducts 11 from
b
-ketoesters 10 using salicyl aldehydes 9
R3
R4
R2
CHO
R5
R4
OR1
R2
R5
RO2C
OR1
O
O
urea
solvent, catalyst
NH
OR
R3
9a-l
N
H
O
10a,b
11a-l
To overcome this apparent failure, we envisaged an alternative
synthetic pathway: first the dihydropyrimidine ring is synthesized
by multicomponent condensation and followed by the benzopyr-
ane ring closure reaction in the final step (Scheme 1b). This strategy
proposes the Biginelli-type condensation using salicyl aldehydes 9
Entry
R
R1 R2
R3
R4
R5
Product Conditionsa Yieldb
(%)
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
H
OEt
H
H
H
H
H
H
H
H
H
H
OMe
OBn
H
H
H
H
H
Br
Cl
NO2
Me
H
H
H
H
H
H
11a
11b
11c
11d
11e
11f
11g
11h
11i
A
A
A
A
A
A
A
B
C
B
C
C
76
90
65
40
60
65
40
67
75
70
62
78
and suitable b-ketoesters 10 to produce the dihydropirimidinone
core 11. Deprotection of the esters 11 to the corresponding free
acids 12 followed by lactonization in the last step should yield the
target benzopyranopyrimidinones 5. This approach gives the pos-
sibility to conveniently functionalize the coumarin ring, due to the
large variety of salicyl aldehydes 9 that are easily available.
H
H
–CH]CH–CH]CH–
H
H
Br
Cl
Bn Bn
Bn Bn
H
H
H
H
H
H
H
9
10
11
12
tBu
tBu
tBu
H
H
H
H
H
H
11j
11k
11l
NO2
2.2. Preparation of Biginelli adducts
a
A: 50 mol % PTSA, EtOH, reflux, 16 h; B: 10 mol % Sc(OTf)3, MeCN, reflux, 16 h; C:
The first step of the synthesis involves the preparation of a series
of various (2-salicyl)-3,4-dihydropyrimidin-2-one 5-carboxylates
10 mol % La(OTf)3, MeCN, reflux, 16 h.
b
Isolated yields of pure products.
O
O
as previously reported
OH
R
O
R
O
O
(a)
NH
O
R
CHO
R
CHO
urea, catalyst
urea, catalyst
O
N
H
OH HO
O
O
8
6
7
R3
R3
R3
O
O
R2
O
R4
R4
R2
R4
R5
R2
CHO
OR
R5
R4
OR1
R2
R5
NH
R5
HO2C
OH
NH
OR1
10
(b)
RO2C
O
O
NH
R3
H2N
NH2
N
H
O
N
H
O
N
H
O
5
12
11
9
Scheme 1. (a) Initial approach to synthesis of benzopyranopyrimidines 7; (b) revised retrosynthetic analysis.

M. Matache et al. / Tetrahedron 65 (2009) 5949–5957
5951
For some salicyl aldehydes (i.e., R3¼OMe or R3¼OH) isolation of
the target Biginelli dihydropyrimidine failed both under Bronsted
(PTSA) and Lewis acid [Sc(OTf)3] catalysis. For this reason, in these
cases, we decided to prepare the target adducts 11 using the cor-
responding benzyl-protected salicyl aldehydes 9h and 9i and Lewis
acids as catalysts23 (Table 1, entries 8 and 9). Thus, reflux of the
reagents in acetonitrile, in the same molar ratio as above, in the
presence of 10 mol % of Sc(OTf)3 or La(OTf)3 led to the products 11h
and 11i in good yields. Moreover, we successfully employed the
same Lewis acid catalyzed conditions in order to obtain the tert-
butyl Biginelli esters 11j–l (Table 1, entries 10–12).
orientation. However, deprotection of bulky tert-butyl or benzyl
esters led to compounds 13 under basic or acidic conditions, ex-
cept for the compound 11g, that bears a naphthyl ring. This could
be explained by the increased barrier for the inversion of the
dihydropyrimidine ring and for the rotation of the ortho-
substituted aryl groups as described by Kappe.25 The observed
stability of the benzyl 11c and tert-butyl 11j esters in strong basic
medium (0.5 M aq NaOH in 1,4-dioxane) substantiates the steric
hindrance hypothesis.
The annelation process is accompanied in our case by de-
carboxylation. Furthermore, attempted deprotection by
hydrogenolysis of the halogen- and nitro-substituted dihy-
dropyrimidines benzyl esters (i.e., 11c–e) resulted, as expected,
in halogen removal or nitro group reduction, respectively. Use
of the corresponding tert-butyl esters 11j–l under typical
acidic deprotection [trifluoroacetic acid (TFA)] prevented these
side-reactions, but unfortunately formation of the oxo-bridged
pyrimidines 13 could not be avoided (Scheme 4, compounds
13j–l).
R3
R
R4
R2
OR1
NH
R5
HOOC
OH
BnOOC
10% Pd/C, HCO2NH4
NH
MeOH, 4h, r.t.
N
H
O
N
H
O
11
12
2.4. Preparation of the tricyclic dihydro-benzopyrano
[4,3-d]pyrimidinones
12a: R2=R3=R4=R5=H (83%)
12b: R2=OEt, R3=R4=R5=H (90%)
12f: R2=R3=H, R4=Me, R5=H (92%)
12g: R2=R3=H, R4=R5=benzo (70%)
With the hydroxy acids 12a,b and 12f–h in hand, we proceeded
to the formation of the target benzopyrano[4,3-d]pyrimidines 5.
This final step was effectively achieved under the standard condi-
tions employed for amide bond formation: 2 equiv of TBTU (2-(1H-
benzotriazolyl)-1,1,3,3-tetramethyluronium as activation reagent
and 4 equiv of DIPEA (N,N-diisopropylethylamine) as base, in
dichloromethane. Under these conditions, all substrates gave the
desired products in high isolated yields (Scheme 5).
The benzopyrano[4,3-d]pyrimidines 5 deserve a brief discussion
with respect to their spectral properties. Our final target com-
pounds 5 are structurally similar to the previously reported com-
pounds 7 (Scheme 1a), claimed to have been obtained directly by
a multicomponent cyclization involving the 4-hydroxycoumarin 6
as enolized dicarbonyl.
12h: R2=H, R3=OMe, R4=R5=H (60%)
Scheme 2. Deprotection of benzyl esters 11a, 11b, and 11f–h.
2.3. Deprotection of the Biginelli esters
The benzyl-protected Biginelli adducts 11 thus obtained were
subjected to the palladium catalyzed hydrogenolysis as described
by Kappe.13a Hydrogenolysis of compounds 11 yielded the desired
products 12 provided that no basic work-up was used (Scheme 2).
Basic treatment of the hydrogenolysis reaction led to isolation of
the decarboxylated tricyclic oxo-bridged tetrahydro-pyrimidines
13 usually in good yields (Scheme 4). A similar type of compounds
(with the carboxy functionality preserved) has previously been
reported24 under different reaction conditions: the one-pot Bigi-
nelli condensation between salicyl aldehydes, ethyl acetoacetate,
and urea in presence of hydrogen chloride yielded directly 14
(Scheme 3) without isolation of the intermediate Biginelli
compound.24
It must be mentioned that all these reports17 present only
incomplete spectral characterization of the products 7 (i.e., in-
completely resolved proton NMR spectra and sometimes mi-
croanalysis). Although we repeatedly attempted to reproduce
these results under various reaction conditions (catalysts, sol-
vents) and different aldehyde components18 we have never
isolated products that presented similar spectral properties to
the tricyclic adducts 5. Moreover, the NMR spectra of the com-
pound resulted from the typical three one-pot multicomponent
reaction and the one resulted from condensation between 4-
hydroxycoumarin and aldehyde (in absence of urea) were
identical.18
CHO
O
O
OH
EtO2C
OEt
urea, HCl cat
NH
O
N
H
O
We comparatively show in Table 2 some selected NMR data for
examples of products of series 11, 12, 13, and 5 to those of products
8 and 7 (reported for the latter). Unlike the data reported for the
claimed products 7 (identified by us to be in fact condensation
adducts 8 between 4-hydroxycoumarin 6 and aldehydes), which
exhibit a chemical shift for the benzyl protons (denoted as 4-H in
Table 2) well above 6 ppm, the chemical shifts for the benzyl pro-
tons in our series of products (denoted 6-H for 11 and 12 and 12-H
for 5, respectively, in Table 2) lay between 5.1 and 5.8 ppm. We
consider this to be a diagnostic feature of the spectrum for these
families of compounds and this is supported by the different
chemical shifts for the benzylic proton peaks shown by the oxo-
bridged compounds 13 (denoted as 11-H for products 13 in Table 2),
which shift downfield by approximately 1 ppm. Further, each
proton belonging to the two NH groups in compounds 5 exhibit
different well-defined signals in the 7–10 ppm range. This is in
14
Scheme 3. Tricyclic oxo-bridged pyrimidines obtained from ethyl acetoacetate and
salicyl aldehydes.
The formation of 14 is assumed to take place via an attack of
the phenol to the double bond of the dihydropyrimidine ring. This
attack is possible only if the dihydropyrimidine ring adopts
a boat-like conformation with a diequatorial arrangement of the
methoxycarbonyl and hydroxyphenyl group.24 In our case
(Scheme 4), due to steric hindrance caused by the use of the more
bulky tert-butyl, benzyl
b-ketoesters or the 2-hydroxy-1-napht-
aldehyde in the multicomponent reaction, the positioning of the
phenol hydroxyl for such an attack was unfavorable and thus
Biginelli adducts 11 exclusively formed. 4-Aryl-dihydropyrimidine
derivatives were described25 to adopt a boat-like conformation
with the aryl substituent in position 4 having an axial, orthogonal
disagreement with the reported spectra of
7 showing the

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M. Matache et al. / Tetrahedron 65 (2009) 5949–5957
R3
R
R
R2
O
R4
R5
i) 10% Pd/C, HCO2NH4
OR1
NH
HO
HN
TFA, DCM
MeOH, 4h, r.t.
BnOOC
COOtBu
NH
ii) aq. NaOH
10 min., r.t.
N
H
O
N
H
O
O
N
H
11j-l
11a,b,f,h,i
13
13a:R2=R3=R4=R5=H (71%)
13i:R2=H, R3=OH, R4=R5=H (40%)
13j: R2=R3=H, R4=Br, R5=H (78%)
13k:R2=R3=H, R4=Cl, R5=H (64%)
13l:R2=R3=H, R4=NO2, R5=H (76%)
13b:R2=OEt,R3=R4=R5=H (75%)
13f:R2=R3=H, R4=Me, R5=H (73%)
13h:R2=H, R3=OMe,R4=R5=H (72%)
Scheme 4. Preparation of oxo-bridged pyrimidines 13 from adducts 11.
R3
R
3. Conclusions
R2
O
R4
R5
To summarize, we prepared a series of functionalized dihydro-
pyrimido[4,3-d]coumarines 5 bearing different substituents on the
aromatic ring. The approach is based on a Biginelli multicomponent
reaction with benzyl acetoacetate as dicarbonyl precursor. The
adducts 11 resulted from this process are easily transformed into
the desired fused pyrimido[4,3-d]coumarins 5 via an ester hydro-
genolysis–lactonization sequence. The hydrogenolysis step requires
particular attention with respect to the isolation of products 12,
since formation of the oxo-bridged pyrimidines 13 can easily occur.
Although we employed only benzyl acetoacetate as model
O
OH
NH
TBTU, DIPEA
DCM
HO
O
NH
N
H
O
N
H
O
12
5
5a:R2=R3=R4=R5=H (87%)
5b:R2=OEt,R3=R4=R5=H (90%)
5f: R2=R3=H, R4=Me, R5=H (87%)
5g:R2=R3=H, R4=R5=benzo (93%)
5h:R2=H, R3=OMe,R4=R5=H (92%)
b
-ketoester for this study, other benzyl b-ketoester derivatives may
Scheme 5. Lactonization of hydroxy acids 12 to fused tricyclic compounds 5.
be used as building blocks, in order to generate functional diversity
on the pyrimidine core.
corresponding NH protons being magnetically equivalent and dis-
playing a chemical shift higher than 11 ppm. These signals should
be assigned to the enols belonging to the simple 4-hydroxy-
coumarin-aldehyde condensation adducts 8 shown in Table 2.
Moreover, both mass spectra and elemental analysis of compounds
8 confirm the structure we proposed.18
4. Experimental
4.1. General
All commercial reagents were purchased from Acros and Aldrich
and used without additional purification. Melting points were
Table 2
Selected 1H NMR data (DMSO-d6) for compounds 5, 11, 12, 13, 5 reported 7 and compounds 8
R
R
R
R
9
9
9
8
10
11
8
7
8
10
11
10
11
8
7
7
9
10
O
O
O
R
H
HN
O
NH
7
6
O
OH
OH
6a
6a
O
O
H
H
H
H
6
BnO2C
HOOC
12
R
1
6
6
3
11
3
12
3
O
NH1
NH1
NH1
O
NH1
5
5
5
O
H4
O
3
OH HO
4
4
4
N
O
N
O
4
N
N
O
4a
H
H
H
H
7
8
5
11
12
13
7a: R=Ph
7b: R=4-Cl-C6H4
8a: R=Ph
8b: R=4-MeO-C6H4
Product
NMRa
d
(ppm)
Product
NMRa
d
(ppm)
Product
NMRa
d
(ppm)
Product
NMRa
d
(ppm)
Product
NMRa
d (ppm)
11a
5.53 (6-H)
7.11 (NH1)
9.62 (NH3)
12a
5.42 (6-H)
6.94 (NH1)
9.01 (NH3)
5a
5.50 (12-H)
8.12 (NH1)
9.60 (NH3)
13a
4.23 (11-H)
7.16 (NH1)
7.42 (NH3)
7a17a
6.1 (4-H)
11.5 (NH)
11b
11f
5.58 (6-H)
7.21 (NH1)
8.56 (NH3)
12b
12f
12g
5.47 (6-H)
6.94 (NH1)
9.02 (NH3)
5b
5f
5.46 (12-H)
8.08 (NH1)
9.58 (NH3)
13b
13f
4.20 (11-H)
7.14 (NH1)
7.39 (NH3)
7b17c
6.1 (4-H)
11.51 (NH)
5.48 (6-H)
7.05 (NH1)
9.14 (NH3)
5.39 (6-H)
6.73 (NH1)
8.98 (NH3)
5.45 (12-H)
8.03 (NH1)
9.58 (NH3)
4.18 (11-H)
6.94 (NH1)
7.11 (NH3)
8a
6.32 (1-H)
11.8 (OH)
11g
5.13 (6-H)
7.69 (NH1)
7.65 (NH3)
5.08 (6-H)
7.62 (NH1)
7.53 (NH3)
5g
5.70 (12-H)
7.83 (NH1)
10.05 (NH3)
13h
4.17 (11-H)
7.09 (NH1)
7.42 (NH3)
8b
6.31 (1-H)
11.9 (OH)
a
Numbering refers to NMR spectra assignment.

M. Matache et al. / Tetrahedron 65 (2009) 5949–5957
5953
determined in open capillary tubes using an electric melting point
STUART SMP3 apparatus and are uncorrected. The IR spectra were
recorded on a JASCO Fourier Transform Infrared Spectrometer 460
Plus in KBr pellets in the range of 4000–400 cmꢀ1. A JEOL–Delta
400 or Bruker DPX-400 spectrometer (operating at 400 MHz for 1H
and 100 MHz for 13C, respectively) was used for NMR recordings
129.7, 128.2, 127.5, 127.0, 117.7, 108.8, 96.5, 64.5, 49.3, 17.8; IR (KBr),
cmꢀ1: 3404, 3215, 3089, 2951, 1890, 1687, 1646, 1493, 1235, 1084;
MS (CI, 150 eV) m/z: 418.7 ([MþH]þ, 100).
4.2.4. 6-Methyl-4-(5-chloro-2-hydroxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid benzyl ester 11d
White crystals, mp 249–250 ꢁC (EtOH/AcOEt), Rf¼0.25 (silica,
(1H, 13C, 2D) using DMSO-d6 or CDCl3 as solvents. Chemical shifts (
d)
are reported in parts per million values using residual solvent peak
as internal reference. Multiplicities are abbreviated as follows:
brdbroad; sdsinglet; dddoublet; tdtriplet; qdquadruplet; and
mdmultiplet (stands for overlapped peaks and complex signals).
Mass spectra were obtained on Finnigan MAT 90 spectrometer
using CI technique (150 eV, isobutane) or by ESI technique using
a Finnigan LCQ instrument. Elemental analysis was performed on
a CHN Elementar Vario EL apparatus. Thin layer chromatography
(TLC) was performed on Merck Silica 60 F254 plates, visualized by
a UV lamp at 254 nm.
DCM/MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
d ppm: 9.96 (s,
1H, OH), 9.23 (s, 1H, 3-NH), 7.27–7.24 (m, 4H, 1-NH, CHarom), 7.13–
7.09 (m, 3H, CHarom), 6.89 (d, 1H, J¼2.4 Hz, 11-H), 6.81 (d, 1H,
J¼8.0 Hz, 9-H), 5.47 (d, 1H, J¼2.4 Hz, 6-H), 5.04 [d, 1H, J¼13.2 Hz,
CHH(Bn)], 4.96 [d, 1H, J¼13.2 Hz, CHH(Bn)], 2.29 (s, 3H, 4-CH3); 13
C
NMR (100 MHz, DMSO-d6)
d ppm: 164.8, 153.6, 151.7, 149.8, 136.5,
131.7, 128.1, 127.9, 127.4, 127, 126.9, 122.0, 117.0, 96.4, 64.4, 49.1, 17.7;
IR (KBr), cmꢀ1: 3406, 3227, 3101, 2938, 1697, 1647, 1496, 1220, 1085;
MS (CI, 150 eV) m/z: 372.7 ([M]þ, 46), 352.8 (100).
4.2.5. 6-Methyl-4-(5-nitro-2-hydroxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid benzyl ester 11e
Light yellow crystals, mp 249–251 ꢁC (EtOH), Rf¼0.3 (silica,
4.2. Synthesis of the esters 11a–l
A solution of 1 mmol of aldehyde,1 mmol of benzyl acetoacetate
10a or tert-butyl acetoacetate 10b, 1.2 mmol urea and catalyst
[PTSA, Sc(OTf)3 or La(OTf)3] in EtOH or MeCN (see Table 1) was
heated to reflux overnight, under stirring. The precipitate that
formed upon cooling or after addition of water was filtered, washed
with ice-water, and 95% EtOH, dried and recrystallized from EtOH
or EtOH/AcOEt to yield the pure products 11a–l.
DCM/MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.38 (s,
1H, OH), 9.32 (s, 1H, 3-NH), 8.03 (dd, 1H, J¼8.8, 2.8 Hz, 9-H), 7.80 (d,
1H, J¼2.8 Hz, 11-H), 7.45 (d, 1H, J¼2.0 Hz, 1-NH), 7.23–7.20 (m, 3H,
CHarom), 7.08–7.05 (m, 2H, CHarom), 6.96 (d, 1H, J¼8.8 Hz, 8-H), 5.51
(d, 1H, J¼2.8 Hz, 6-H), 5.05 [d, 1H, J¼13.2 Hz, CHH(Bn)], 4.93 [d, 1H,
J¼13.2 Hz, CHH(Bn)], 2.31 (s, 3H, 4-CH3); 13C NMR (100 MHz,
DMSO-d6) d ppm: 164.6,161.4,151.4,150.5,138.9,136.2,130.6, 130.4,
127.8, 127.3, 126.9, 115.6, 99.9, 64.4, 49.4, 17.5; IR (KBr), cmꢀ1: 3415,
3104, 2951, 1698, 1455, 1345, 1242, 1091; MS (CI, 150 eV) m/z: 383.8
([M]þ, 100).
4.2.1. 6-Methyl-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylic acid benzyl ester 11a
Light yellow crystals, mp 228–230 ꢁC (EtOH), Rf¼0.24 (silica,
DCM/MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
d
ppm: 9.62 (s,
4.2.6. 6-Methyl-4-(5-methyl-2-hydroxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid benzyl ester 11f
White crystals, mp 238–240 ꢁC (EtOH/AcOEt), Rf¼0.26 (silica,
1H, 3-NH), 9.17 (s, 1H, OH), 7.24–7.22 (m, 2H, CHarom), 7.11 (s, 1H, 1-
NH), 7.10–7.05 (m, 4H, CHarom), 6.96 (d, 1H, J¼7.2 Hz, 11-H), 6.81 (d,
1H, J¼8.0 Hz, 8-H), 6.71 (t, 1H, J¼7.2 Hz, 10-H), 5.53 (d, 1H, J¼2.8 Hz,
6-H), 5.02 [d, 1H, J¼13.2 Hz, CHH(Bn)], 4.96 [d, 1H, J¼13.2 Hz,
CHH(Bn)], 2.29 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
DCM/MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
d ppm: 9.36 (s,
1H, OH), 9.14 (s, 1H, 3-NH), 7.25–7.23 (m, 3H, CHarom), 7.10–7.08 (m,
2H, CHarom), 7.05 (br, 1H, 1-NH), 6.87 (dd, 1H, J¼8.0, 1.6 Hz, 8-H),
6.72 (d, 1H, J¼1.6 Hz, 11-H), 6.70 (d, 1H, J¼8.0 Hz, 9-H), 5.48 (d, 1H,
J¼2.4 Hz, 6-H), 5.03 [d, 1H, J¼13.2 Hz, CHH(Bn)], 4.96 [d, 1H,
J¼13.2 Hz, CHH(Bn)], 2.29 (s, 3H, 4-CH3), 2.11 (s, 3H, 10-CH3); 13C
d
ppm: 165.0, 154.6, 152.1, 149.5, 136.6, 129.7, 128.2, 128.0, 127.3,
127.0, 126.9, 118.7, 115.4, 97.1, 64.3, 48.9, 17.7; IR (KBr), cmꢀ1: 3415,
3238, 3128, 2980,1916,1698,1644,1459,1218,1096; MS (CI,150 eV)
m/z: 339.3 ([MþH]þ, 100).
NMR (100 MHz, DMSO-d6)
d ppm: 165.0, 152.3, 151.9, 149.4, 136.6,
129.3, 128.5, 128.0, 127.4, 127.3, 126.9, 126.9, 115.2, 96.9, 64.2, 49.1,
20.2, 17.7; IR (KBr), cmꢀ1: 3398, 3349, 3213, 3093, 2953, 1697, 1652,
1337; MS (CI, 150 eV) m/z: 352.9 ([M]þ, 100).
4.2.2. 6-Methyl-4-(3-ethoxy-2-hydroxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid benzyl ester 11b
White-yellowish powder, mp 223–224 ꢁC (EtOH/AcOEt),
Rf¼0.44 (silica, DCM/MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
4.2.7. 6-Methyl-4-(2-hydroxynaphtyl)-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylic acid benzyl ester 11g
d
ppm: 9.16 (s, 1H, OH), 8.56 (s, 1H, 3-NH), 7.24–7.22 (m, 2H,
CHarom), 7.21 (s, 1H, 1-NH), 7.09–7.05 (m, 3H, CHarom), 6.85 (dd, 1H,
J¼8.0, 1.2 Hz, 11-H), 6.67 (t, 1H, J¼8.0 Hz, 10-H), 6.61 (dd, 1H, J¼8.0,
1.2 Hz, 9-H), 5.58 (d, 1H, J¼2.8 Hz, 6-H), 5.03 [d, 1H, J¼13.2 Hz,
CHH(Bn)], 4.96 [d, 1H, J¼13.2 Hz, CHH(Bn)], 4.03 (q, 2H, J¼7.2 Hz,
CH2CH3), 2.29 (s, 3H, 4-CH3), 1.34 (t, 3H, J¼7.2 Hz, CH2CH3); 13C
White powder, mp 257–259 ꢁC (EtOH), Rf¼0.77 (silica, DCM/
MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
d ppm: 8.04 (d, 1H,
J¼8.0 Hz, CHarom), 7.86 (d, 1H, J¼8.0 Hz, CHarom), 7.80 (d, 1H,
J¼8.0 Hz, CHarom), 7.69 (s, 1H, 3-NH), 7.65 (br, 1H, 1-NH), 7.57–7.53
(m, 1H, CHarom), 7.46–7.35 (m, 6H, CHarom), 7.05 (d, 1H, J¼8.0 Hz,
CHarom), 5.25 [s, 2H, CH2(Bn)], 5.13 (d, 1H, J¼1.6 Hz, 6-H), 1.80 (s, 3H,
NMR (100 MHz, DMSO-d6)
d ppm: 165.0, 151.9, 149.3, 146.6, 143.7,
136.6, 130.3, 128.0, 129.2, 126.8, 118.8, 118.5, 111.6, 99.3, 64.2, 64.0,
49.7, 17.6, 14.6; IR (KBr), cmꢀ1: 3413, 3220, 3101, 2976, 2360, 1694,
1646, 1474, 1276, 1095; MS (CI, 150 eV) m/z: 382.8 ([M]þ, 100).
4-CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm: 168.5, 154.4, 148.2,
135.8, 130.6, 129.7, 128.5, 128.4, 128.3, 128.0, 127.0, 126.8, 123.6,
121.7, 118.4, 116.7, 99.3, 83.1, 66.1, 43.7, 23.8; IR (KBr), cmꢀ1: 3236,
3101, 2922, 1739, 1689, 1182, 1094; MS (CI, 150 eV) m/z: 388.8 ([M]þ,
100).
4.2.3. 6-Methyl-4-(5-bromo-2-hydroxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid benzyl ester 11c
White powder, mp 245–246 ꢁC (EtOH/AcOEt), Rf¼0.22 (silica,
4.2.8. 6-Methyl-4-(2-benzyloxy-4-methoxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid benzyl ester 11h
DCM/MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
d ppm: 9.23 (s,
1H, OH), 7.27–7.22 (m, 5H, 1-NH, 3-NH, CHarom), 7.11–7.09 (m, 3H,
CHarom), 7.01 (d, 1H, J¼2.8 Hz, 11-H), 6.77 (d, 1H, J¼8.0 Hz, 9-H), 5.45
(d, 1H, J¼2.4 Hz, 6-H), 5.04 [d, 1H, J¼13.2 Hz, CHH(Bn)], 4.96 [d, 1H,
J¼13.2 Hz, CHH(Bn)], 2.29 (s, 3H, 4-CH3); 13C NMR (100 MHz,
White powder, mp 154–155 ꢁC (EtOH), Rf¼0.57 (silica, DCM/
MeOH¼95:5); 1H NMR (400 MHz, CDCl3)
d ppm: 7.35–7.33 (m, 5H,
CHarom), 7.23–7.21 (m, 2H, CHarom), 7.04–7.02 (m, 2H, CHarom), 6.98
(d, 1H, J¼8.4 Hz, 11-H), 6.72 (d, 1H, J¼2.0 Hz, 8-H), 6.38 (dd, 1H,
J¼8.4, 2.0 Hz, 10-H), 5.75 (d, 1H, J¼2.0 Hz, 6-H), 5.10–4.95 (m, 4H,
DMSO-d6) d ppm: 164.9,154.2, 151.9, 151.9,149.9,136.6, 132.3, 130.9,

5954
M. Matache et al. / Tetrahedron 65 (2009) 5949–5957
CH2Bn), 3.77 (s, 3H, OCH3), 2.38 (s, 3H, 4-CH3); 13C NMR (100 MHz,
CDCl3) ppm: 165.4, 160.5, 156.9, 136.4, 136.3, 128.6, 128.2, 128.1,
127.7,127.6,127.4,127.4,104.4,100.1, 98.1, 70.2, 65.4, 55.3, 49.8,18.4;
IR (KBr), cmꢀ1: 3248, 3131, 2934, 1697, 1643, 1456, 1381, 1219, 1085;
MS (ESI, m/z) 459.1 [MþH]þ, 917.0 [2MþH]þ, 939.0 [2MþNa]þ. Anal.
Calcd for C27H26N2O5 (458.18): C, 70.73; H, 5.72; N, 6.11. Found: C,
70.42; H, 6.04; N, 5.84.
monitored by TLC (MeOH/DCM). Methanol was then removed in
vacuo and the residue was partitioned between 30 mL ethyl
acetate and 10 mL water. The two phases were separated, the
organic phase dried over MgSO4, and evaporated. The resulted
white solid was recrystallized from ethanol to yield the pure
hydroxy acid 12.
d
4.3.1. 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-(2-hydroxyphenyl)-
pyrimidine-5-carboxylic acid 12a
4.2.9. 6-Methyl-4-(2,4-benzyloxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid benzyl ester 11i
White powder, mp 143–146 ꢁC (EtOH), Rf¼0.93 (silica, DCM/
White powder, mp 255–258 ꢁC (EtOH), Rf¼0.25 (silica, DCM/
MeOH¼8:2); 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.73 (br, 1H,
MeOH¼95:5); 1H NMR (400 MHz, CDCl3)
d
ppm: 7.36–7.29 (m, 10H,
COOH), 9.60 (s, 1H, OH), 9.01 (s, 1H, 3-NH), 7.05 (ddd, 1H, J¼8.0, 7.6,
1.6 Hz, 9-H), 6.96–6.94 (br, 1H, 1-NH), 6.96–6.93 (m, 1H, 11-H), 6.80
(d, 1H, J¼8.0 Hz, 8-H), 6.72 (t, 1H, J¼7.6 Hz, 10-H), 5.42 (d, 1H,
J¼2.8 Hz, 6-H), 2.80 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
CHarom), 7.21–7.18 (m, 3H, CHarom), 7.03–7.00 (m, 2H, CHarom), 6.85
(d, 1H, J¼9.6 Hz, 11-H), 6.82 (dd, 1H, J¼9.6, 3.2 Hz, 10-H), 6.72 (d, 1H,
J¼3.2 Hz, 8-H), 5.79 (d, 1H, J¼2.8 Hz, 6-H), 5.66 (br, 1H, 1-NH), 5.08–
4.95 (m, 4H, 5,7-OCH2Bn), 4.19 (s, 2H, 9-OCH2Bn), 2.38 (s, 3H, 4-
d
ppm: 167.1, 154.5, 152.4, 148.3, 129.6, 128.1, 126.7, 118.7, 115.4, 98.0,
CH3); 13C NMR (100 MHz, DMSO-d6)
d
ppm: 165.2, 153.1, 150.2,
48.9, 17.8; IR (KBr), cmꢀ1: 3495, 3241, 2618, 2499, 1694, 1460, 1280,
149.2,137.0,136.7,136.1,131.6,128.6,128.5,128.2,128.0, 127.9,127.6,
127.4, 127.4, 127.3, 114.6, 114.0, 113.1, 97.6, 70.8, 70.5, 65.4, 50.0, 18.5;
IR (KBr), cmꢀ1: 3220, 3089, 2947, 1700,1641, 1494, 1382, 1225, 1091;
MS (CI, 150 eV) m/z: 534.7 ([M]þ, 2.5), 317.6 (26), 192.6 (100). Anal.
Calcd for C33H30N2O5 (534.60): C, 74.14; H, 5.66; N, 5.24. Found: C,
73.80; H, 5.74; N, 5.11.
110, 1041 MS (CI, 150 eV) m/z: 205.8 ([MꢀCOOH]þ, 100).
4.3.2. 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-(3-ethoxy-2-
hydroxyphenyl)-pyrimidine-5-carboxylic acid 12b
White powder, mp 275–280 ꢁC (EtOH), Rf¼0.41 (silica, DCM/
MeOH¼8:2); 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.72 (br, 1H,
COOH), 9.02 (s, 1H, 3-NH), 8.62 (br, 1H, OH), 6.94 (d, 1H, J¼2.8 Hz, 1-
NH), 6.82 (dd, 1H, J¼8.0, 1.6 Hz, 11-H), 6.68 (t, 1H, J¼8.0 Hz, 10-H),
6.60 (dd, 1H, J¼8.0, 1.6 Hz, 9-H), 5.47 (d, 1H, J¼2.8 Hz, 6-H), 4.02 (q,
2H, J¼8.0 Hz, CH2CH3), 2.27 (s, 3H, 4-CH3), 1.34 (t, 3H, J¼8.0 Hz,
4.2.10. 6-Methyl-4-(5-bromo-2-hydroxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid tert-butyl ester 11j
White powder, mp 221–223 ꢁC (EtOH), Rf¼0.38 (silica, DCM/
MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
d
ppm: 7.63 (s, 1H,
CH2CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm: 167.2, 152.3, 148.0,
OH), 7.36 (d, 1H, J¼2.4 Hz, 11-H), 7.33 (dd, 1H, J¼8.4, 2.8 Hz, 9-H),
7.22 (d, 1H, J¼2.8 Hz, 1-NH), 6.75 (d, 1H, J¼8.4 Hz, 8-H), 4.48–4.46
(m,1H, 6-H), 4.35 (br, 1H, 3-NH), 1.72 (s, 3H, 4-CH3), 1.44 (s, 9H, tBu);
146.6, 143.5, 130.5, 119.0, 112.1, 98.4, 64.0, 49.1, 17.3, 14.3; IR (KBr),
cmꢀ1: 3224, 3090, 2980, 2360, 1698, 1585, 1391, 1344, 1289, 1217,
1089; MS (CI, 150 eV) m/z: 248.9 ([MꢀCOOH]þ, 100).
13C NMR (100 MHz, DMSO-d6)
d ppm: 167.2, 154.2, 150.0, 131.6,
130.9, 127.8, 118.8, 111.3, 83.6, 81.0, 47.3, 44.1, 27.5, 23.7; IR (KBr),
cmꢀ1: 3499, 3232, 3088, 2973, 1743, 1699, 1506, 1475, 1243, 1162,
1085; MS (CI, 150 eV) m/z: 384.5 ([M]þ, 10), 157.7 (100).
4.3.3. 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-(5-methyl-2-
hydroxyphenyl)-pyrimidine-5-carboxylic acid 12f
White powder, mp 273–275 ꢁC (EtOH), Rf¼0.3 (silica, DCM/
MeOH¼9:1); 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.73 (br, 1H,
4.2.11. 6-Methyl-4-(5-chloro-2-hydroxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid tert-butyl ester 11k
White powder, mp 209–211 ꢁC (EtOH), Rf¼0.84 (silica, DCM/
COOH), 9.36 (s, 1H, OH), 8.98 (s, 1H, 3-NH), 6.88–6.84 (m, 2H, 9-H,
11-H), 6.73 (s, 1H, 1-NH), 6.68 (d, 1H, J¼8.0 Hz, 8-H), 5.39 (s, 1H, 6-
H), 2.28 (s, 3H, 4-CH3), 2.14 (s, 3H, 10-CH3); 13C NMR (100 MHz,
MeOH¼95:5); 1H NMR (400 MHz, CDCl3)
d
ppm: 7.13 (dd, 1H, J¼9.6,
DMSO-d6) d ppm: 167.2, 152.3, 152.1, 148.1, 129.5, 128.4, 126.9, 115.3,
2.8 Hz, 9-H), 7.10 (d, 1H, J¼2.8 Hz, 11-H), 6.74 (d, 1H, J¼9.6 Hz, 8-H),
6.33 (d, 1H, J¼3.2 Hz, 1-NH), 6.11 (s, 1H, 3-NH), 4.52–4.50 (m, 1H, 6-
H), 1.85 (s, 3H, 4-CH3), 1.46 (s, 9H, tBu); 13C NMR (100 MHz, DMSO-
99.3, 48.9, 20.3, 17.7; IR (KBr), cmꢀ1: 3398, 3225, 3106, 2925, 1688,
1630, 1467, 1224, 1153, 1046; MS (ESI, m/z): 263.0 [MþH]þ, 809.0
[3MþNa]þ, 825.0 [3MþK]þ, 525.1 [2MþH]þ, 547.1 [2MþK]þ.
d6)
d ppm: 167.0, 151.3, 149.6, 129.8, 127.7, 125.8, 125.4, 118.7, 99.7,
83.1, 48.6, 45.1, 27.9, 24.7; IR (KBr), cmꢀ1: 3400, 3239, 3089, 2975,
1740, 1693, 1510, 1480, 1326, 1244, 1162, 1082; MS (CI, 150 eV) m/z:
338.6 ([M]þ, 100).
4.3.4. 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-(2-hydroxynaphtyl)-
pyrimidine-5-carboxylic acid 12g
White powder, mp 295–296 ꢁC (EtOH), Rf¼0.16 (silica, DCM/
MeOH¼8:2); 1H NMR (400 MHz, DMSO-d6)
d ppm: 12.93 (br, 1H,
4.2.12. 6-Methyl-4-(5-nitro-2-hydroxyphenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylic acid tert-butyl ester 11l
White powder, mp 221–223 ꢁC (EtOH), Rf¼0.4 (silica, DCM/
COOH), 8.05 (d, 1H, J¼8.0 Hz, CHarom), 7.86 (d, 1H, J¼8.0 Hz, CHarom),
7.79 (d, 1H, J¼7.2 Hz, CHarom), 7.62 (d, 1H, J¼2.8 Hz, 1-NH), 7.55 (t,
1H, J¼7.2 Hz, CHarom), 7.53 (s, 1H, 3-NH), 7.39 (t, 1H, J¼7.2 Hz,
CHarom), 7.05 (d, 1H, J¼8.0 Hz, CHarom), 5.09–5.07 (m, 1H, 6-H), 3.20
(br, 1H, OH), 1.82 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
MeOH¼95:5); 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.34 (s, 1H,
OH), 9.12 (s,1H, 3-NH), 8.05 (d,1H, J¼8.0 Hz, 8-H), 7.87 (s,1H,1-NH),
7.34 (d, 1H, J¼2.4 Hz, 11-H), 6.97 (dd, 1H, J¼8.0, 2.4 Hz, 9-H), 5.42 (s,
d
ppm: 169.9, 154.3, 148.2, 130.6, 129.5, 128.4, 128.2, 126.7, 123.4,
t
1H, 6-H), 2.25 (s, 3H, 4-CH3), 1.24 (s, 9H, Bu); 13C NMR (100 MHz,
121.6, 118.3, 116.9, 83.2, 44.1, 23.7; IR (KBr), cmꢀ1: 3400, 3257, 3056,
2552, 1680, 1515, 1241, 1092; MS (CI, 150 eV) m/z: 254.9
([MꢀCOOH]þ, 40), 145 (100), 111 (65).
DMSO-d6) d ppm: 167.1, 161.1, 151.2, 147.9, 136.5, 130.7, 124.4, 123.4,
115.4, 97.4, 78.6, 49.6, 27.3, 17.1; IR (KBr), cmꢀ1: 3457, 3382, 3243,
3092, 2927, 1696, 1676, 1521, 1496, 1335, 1240, 1169, 1093; MS (CI,
150 eV) m/z: 349.7 ([MþH]þ, 12), 249.7 (81), 189.7 (100).
4.3.5. 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-(4-methoxy-2-
hydroxyphenyl)-pyrimidine-5-carboxylic acid 12h
4.3. Preparation of hydroxy acids 12a,b and 12f–h
by hydrogenolysis
White powder, mp 201–203 ꢁC (EtOH), Rf¼0.41 (silica, DCM/
MeOH¼8:2); 1H NMR (400 MHz, DMSO-d6)
d ppm: 11.70 (br, 1H,
COOH), 9.63 (s, 1H, OH), 8.97 (s, 1H, 3-NH), 6.87 (br, 1H, 1-NH),
6.64 (d, 1H, J¼8.8 Hz, 11-H), 6.37 (d, 1H, J¼2.4 Hz, 8-H), 6.31 (dd,
1H, J¼8.8, 2.4 Hz, 10-H), 5.34 (d, 1H, J¼2.8 Hz, 6-H), 3.66 (s, 3H,
Dihydropyrimidine benzyl ester 11 (1 mmol), 5% Pd/C (10%
w/w), 10 mmol ammonium formate (630 mg), and 10 mL
methanol were stirred at rt until the completion of the reaction,
OCH3), 2.27 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm:

M. Matache et al. / Tetrahedron 65 (2009) 5949–5957
5955
167.2, 159.3, 155.5, 152.5, 129.4, 127.5, 122.5, 118.2, 101.4, 48.6, 44.0,
4.4.5. 5-Hydroxy-9-methyl-11-oxo-8-oxa-10,12-diazatricyclo-
26.4, 17.7; IR (KBr), cmꢀ1: 3495, 3238, 3105, 2933, 1699, 1645,
1445, 1231, 1127, 1034; MS (CI, 150 eV) m/z: 234.6 ([MꢀCOOH]þ,
100).
[7,3,1,02,7]trideca-2,4-6-triene 13i
Brown powder, mp 286–290 ꢁC, Rf¼0.73 (silica, DCM/
MeOH¼8:2); 1H NMR (400 MHz, DMSO-d6)
d ppm: 8.89 (br, 1H,
8-OH), 7.29 (br, 1H, 3-NH), 7.11 (br, 1H, 1-NH), 6.55 (s, 3H, 7-H, 9-H,
10-H), 4.10 (dd, 1H, J¼7.2, 2.8 Hz, 11-H), 2.06 (dd, 1H, J¼12.8, 2.8 Hz,
12-CHH), 2.03–1.99 (m, 1H, 12-CHH), 1.56 (s, 3H, 4-CH3); 13C NMR
4.4. Synthesis of the oxo-bridged pyrimidines 13a, 13b, 13f,
13h, 13i, and 13j–l
(100 MHz, DMSO-d6)
d ppm: 155.1, 150.4, 143.6, 125.8, 116.8, 115.6,
114.6, 81.5, 44.5, 32.4, 26.4; IR (KBr), cmꢀ1: 3228, 3123, 1659, 1510,
Dihydropyrimidine benzyl ester 11 (1 mmol), 5% Pd/C (10% w/w),
10 mmol ammonium formate (630 mg), and 10 mL methanol were
stirred at room temperature until the completion of the reaction, as
monitored by TLC (MeOH/CH2Cl2¼2:8). Methanol was then re-
moved in vacuo and the reaction mixture was treated with 10 mL
0.5 M sodium hydroxide and allowed to stir for 30 min. Filtration
under gravity was then performed and the filtrate was acidified
with 2 N HCl until pH 3–4. In short time, a precipitate formed, which
was filtered and dried. No further purification was necessary.
1383, 1193, 1079; MS (CI, 150 eV) m/z: 220.0 ([M]þ, 100).
4.5. Synthesis of the oxo-bridged pyrimidines 13j–l
Dihydropyrimidine tert-butyl esters 11j–l (1 mmol) and 10 mL
of a mixture of 25% trifluoracetic acid in dichloromethane were
stirred at rt until the completion of the reaction (10 min), as
monitored by TLC (MeOH/CH2Cl2¼2:8). The solvent was then re-
moved in vacuo and the reaction mixture was triturated with ethyl
ether. The precipitate formed was filtered and dried. No further
purification was necessary.
4.4.1. 9-Methyl-11-oxo-8-oxa-10,12-diazatricyclo[7,3,1,02,7]-
trideca-2,4-6-triene 13a
White powder, mp 297–298 ꢁC, Rf¼0.74 (silica, DCM/
4.5.1. 4-Bromo-9-methyl-11-oxo-8-oxa-10,12-diazatricyclo-
[7,3,1,02,7]trideca-2,4-6-triene 13j
MeOH¼4:1); 1H NMR (400 MHz, DMSO-d6)
d ppm: 7.42 (s, 1H, 3-
NH), 7.17–7.16 (br, 1H, 1-NH), 7.16–7.12 (m, 2H, CHarom), 6.86 (ddd,
1H, J¼8.0, 7.2, 1.2 Hz, 8-H), 6.75 (d, 1H, J¼8.0 Hz, 7-H), 4.23 (dd, 1H,
J¼7.2, 3.2 Hz, 11-H), 2.13 (dd, 1H, J¼12.8, 3.2 Hz, 12-CHH), 2.07 (dd,
1H, J¼12.8, 7.2 Hz, 12-CHH), 1.61 (s, 3H, 4-CH3); 13C NMR (100 MHz,
White powder, mp 293–296 ꢁC, Rf¼0.57 (silica, DCM/
MeOH¼9:1); 1H NMR (400 MHz, DMSO-d6)
d ppm: 7.53 (s, 1H, 3-
NH), 7.32 (s, 1H, 10-H), 7.30 (d, 1H, J¼8.4 Hz, 7-H), 7.14 (s, 1H, 1-NH),
6.74 (d, 1H, J¼8.4 Hz, 8-H), 4.28 (s, 1H, 11-H), 2.15 (d, 1H, J¼12.8 Hz,
12-CHH), 2.07 (d, 1H, J¼12.8 Hz, 12-CHH), 1.61 (s, 3H, 4-CH3); 13C
DMSO-d6)
d ppm: 154.7, 151.1, 128.5, 128.4, 125.3, 119.7, 116.4, 81.9,
44.2, 31.9, 26.0; IR (KBr), cmꢀ1: 3242, 3097, 1676, 1503, 1322, 1252,
NMR (100 MHz, DMSO-d6)
d ppm: 155.6, 151.4, 132.5, 128.7, 120.3,
1134, 1069; MS (CI, 150 eV) m/z: 205.3 ([MþH]þ, 100).
118.6, 111.6, 83.3, 43.9, 32.6, 26.8; IR (KBr), cmꢀ1: 3232, 3106, 2928,
1696, 1510, 1305, 1166, 1076; MS (ESI, m/z): 283.1 [M]þ.
4.4.2. 4-Ethoxy-11-oxo-8-oxa-10,12-diazatricyclo[7,3,1,02,7]-
trideca-2,4-6-triene 13b
4.5.2. 4-Chloro-9-methyl-11-oxo-8-oxa-10,12-diazatricyclo-
[7,3,1,02,7]trideca-2,4-6-triene 13k
White powder, mp 259–262 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d
ppm: 7.39 (br, 1H, 3-NH), 7.14 (br, 1H, 1-NH), 6.82 (dd, 1H, J¼7.6,
White powder, mp 287–292 ꢁC, Rf¼0.57 (silica, DCM/
1.2 Hz, CHarom), 6.78 (td, 1H, J¼7.6, 1.2 Hz, CHarom), 6.72 (dd, 1H,
J¼7.6, 1.2 Hz, CHarom), 4.21–4.19 (m, 1H, 11-H), 3.97 (q, 2H, J¼6.8 Hz,
CH2CH3), 2.11 (dd, 1H, J¼12.8, 2.0 Hz, 12-CHH), 2.07–2.03 (m, 1H,
12-CHH),1.63 (s, 3H, 4-CH3),1.31 (t, 3H, J¼6.8 Hz, CH2CH3); 13C NMR
MeOH¼9:1); 1H NMR (400 MHz, DMSO-d6)
d ppm: 7.52 (s, 1H, 3-
NH), 7.19–7.16 (m, 2H, CHarom), 7.14 (s, 1H, 1-NH), 6.79 (d, 1H,
J¼8.0 Hz, 7-H), 4.28–4.27 (m, 1H, 11-H), 2.15–2.12 (m, 1H, 12-CHH),
2.09–2.05 (m, 1H, 12-CHH), 1.60 (s, 3H, 4-CH3); 13C NMR (100 MHz,
(100 MHz, DMSO-d6)
d ppm: 155.0, 147.1, 140.9, 126.3, 120.5, 119.7,
DMSO-d6) d ppm: 154.8, 150.3, 128.4, 128.2, 127.5, 123.3, 118.2, 111.6,
112.5, 82.0, 63.5, 44.4, 32.2, 26.5, 14.7; MS (CI, 150 eV) m/z: 248.3
82.6, 44.0, 31.7, 26.0; IR (KBr), cmꢀ1: 3225, 3076, 2932, 2602, 1701,
1465, 1226, 1110; MS (CI, 150 eV) m/z: 205 ([MꢀCl]þ, 100), 238.9
([M]þ, 48).
([MþH]þ, 100).
4.4.3. 4,9-Dimethyl-11-oxo-8-oxa-10,12-diazatricyclo-
[7,3,1,02,7]trideca-2,4-6-triene 13f
4.5.3. 9-Methyl-4-nitro-11-oxo-8-oxa-10,12-diazatricyclo-
[7,3,1,02,7]trideca-2,4-6-triene 13l
White powder, mp 295–297 ꢁC, Rf¼0.66 (silica, DCM/
MeOH¼9:1); 1H NMR (400 MHz, DMSO-d6)
d ppm: 7.37 (s, 1H, 10-
White powder, mp 261–263 ꢁC, Rf¼0.36 (silica, DCM/
H), 7.11 (s, 1H, 3-NH), 6.95 (d, 1H, J¼7.6 Hz, 8-H), 6.94 (br, 1H, 1-NH),
6.64 (d,1H, J¼7.6 Hz, 7-H), 4.18 (d,1H, J¼3.2 Hz,11-H), 2.20 (s, 3H, 9-
CH3), 2.11 (dd, 1H, J¼12.8, 3.2 Hz, 12-CHH), 2.06–2.02 (m, 1H, 12-
MeOH¼9:1); 1H NMR (400 MHz, DMSO-d6)
d ppm: 8.15 (d, 1H,
J¼2.8 Hz, 10-H), 8.07 (dd, 1H, J¼8.8, 2.8 Hz, 8-H), 7.75 (s, 1H, 3-NH),
7.27 (s, 1H, 1-NH), 6.90 (d, 1H, J¼8.8 Hz, 7-H), 4.48–4.46 (m, 1H, 11-
H), 2.13 (dd, 1H, J¼13.2, 2.8 Hz,12-CHH), 2.08–2.05 (m,1H, 12-CHH),
CHH), 1.59 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm:
154.8, 148.8, 128.9, 128.8, 128.3, 125.0, 115.9, 81.7, 44.2, 32.1, 26.1,
19.7; IR (KBr), cmꢀ1: 3223, 3216, 3071, 2931, 1700, 1657, 1513, 1313,
1254, 1176, 1072; MS (ESI, m/z): 219.1 [MþH]þ, 437 [2MþH]þ.
1.67 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm: 154.53,
150.73, 126.25, 123.70, 123.47, 123.28, 117.21, 82.43, 43.80, 31.67,
25.93; IR (KBr), cmꢀ1: 3226, 3081, 2933, 1700, 1587, 1509, 1342,
1172, 1086; MS (ESI, m/z): 250.0 [MþH]þ.
4.4.4. 5-Methoxy-9-methyl-11-oxo-8-oxa-10,12-diazatricyclo-
[7,3,1,02,7]trideca-2,4-6-triene 13h
White powder, mp 253–255 ꢁC, Rf¼0.13 (silica, DCM/
4.6. Preparation of 5 by lactonization of the hydroxy acids 12
MeOH¼98:2); 1H NMR (400 MHz, DMSO-d6)
d ppm: 7.42 (br, 1H, 3-
NH), 7.09 (br, 1H, 1-NH), 7.03 (d, 1H, J¼8.4 Hz, 10-H), 6.44 (d, 1H,
J¼8.4 Hz, 9-H), 6.32 (s,1H, 7-H), 4.17 (s,1H,11-H), 3.68 (s, 3H, OCH3),
2.09 (d, 1H, J¼12.8 Hz, 12-CHH), 2.03 (d, 1H, J¼12.8 Hz, 12-CHH),
The corresponding dihydropyrimidine carboxylic acid 12
(1 mmol) and 2 mmol of TBTU (650 mg) were suspended in 150 mL
of DCM. DIPEA (4 equiv, 1 mL) was added and the solution became
clear. After 20 min of stirring at rt, a white precipitate formed. The
reaction was allowed to stir for 2 h (completed as monitored by
TLC), and then the solvent removed was in vacuo. The white pre-
cipitate was recrystallized from ethanol to yield the pure adducts 5.
1.59 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm: 159.7,
155.1, 152.4, 129.3, 118.2, 106. 6, 82.2, 55.0, 43.9, 32.5, 26.3; IR (KBr),
cmꢀ1: 3236, 3107, 2940, 1688, 1621, 1507, 1287, 1069; MS (ESI, m/z):
235.1 [MþH]þ, 257.1 [MþNa]þ, 469.1 [2MþH]þ, 491.1 [2MþNa]þ.

5956
M. Matache et al. / Tetrahedron 65 (2009) 5949–5957
4.6.1. 4-Methyl-1H-chromeno[4,3-d]pyrimidine-2,5(3H,10bH)-
dione 5a
Grant 25085 as well as from Romanian Ministry of Education and
Research Grant IDEI 965/2007 is acknowledged. M.M. thanks
Bayerische Forschungstiftung for scholarship funding.
White powder, mp 245–249 ꢁC (EtOH), Rf¼0.4 (silica, AcOEt); 1H
NMR (400 MHz, DMSO-d6) d ppm: 9.60 (s, 1H, 3-NH), 8.12 (br, 1H, 1-
NH), 7.59 (d, 1H, J¼8.0 Hz,11-H), 7.32 (t,1H, J¼8.0 Hz, 9-H), 7.15 (t,1H,
Supplementary data
J¼8.0 Hz,10-H),7.05(d,1H, J¼8.0 Hz, 8-H),5.50(d,1H, J¼3.2 Hz,12-H),
2.21 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm: 160.8,151.6,
Experimental details for the preparation of compounds 8. Se-
lected 1H and 13C NMR spectra of relevant examples of compounds
11,12,13, and 5. Supplementary data associated with this article can
be found in the online version at, doi:10.1016/j.tet.2009.05.088.
150.7, 148.2, 128.0, 124.5, 123.8, 123.4, 115.4, 89.3, 47.5, 17.0; IR (KBr),
cmꢀ1: 3356, 3233, 3165, 2967, 1699, 1621, 1460, 1396, 1257, 1084; MS
(CI, 150 eV) m/z: 231.2 [(MþH]þ, 100). Anal. Calcd for C12H10N2O3
(230.07): C, 62.60; H, 4.38; N,12.17. Found: C, 60.64; H, 4.42; N,12.18.
References and notes
4.6.2. Ethoxy-4-methyl-1H-chromeno[4,3-d]pyrimidine-
2,5(3H,10bH)-dione 5b
1. (a) Hulme, C. In Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley:
Weinheim, 2005; pp 311–341; (b) Garuti, L.; Roberti, M.; Pizzirani, D. Mini-Rev.
Med. Chem. 2007, 7, 481–489; (c) Gil, C.; Braese, S. J. Comb. Chem. 2009,11,175–197.
2. (a) Baraldi, P. G.; Tabrizi, M. A.; Gessi, S.; Borea, P. A. Chem. Rev. 2008, 108,
238–263; (b) Petricci, E.; Mugnaini, C.; Radi, M.; Togninelli, A.; Bernardini, C.;
Manetti, F.; Parlato, M. C.; Renzulli, M. L.; Alongi, M.; Falciani, C.; Corelli, F.;
Botta, M. ARKIVOC 2006, 7, 452–478; (c) Lagoja, I. M. Chem. Biodivers. 2005,
2, 1–50; (d) For Biginelli-type dihydropyrimidines, most relevant for our
work see: Kappe, C. O. Eur. J. Med. Chem. 2000, 1043–1052; (e) Ralevic, V.;
Burnstock, G. Pharmacol. Rev. 1998, 50, 413–492.
3. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–416. For general reviews see: (a)
Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1–116; (b) Kappe, C. O. Acc. Chem.
Res. 2000, 33, 879–888; (c) Kappe, C. O. Tetrahedron 1993, 49, 6937–6963.
4. Very few relevant papers dealt with the Biginelli condensation and its mech-
anism before the end of the 1980’s: (a) Folkers, K.; Johnson, T. B. J. Am. Chem.
Soc. 1933, 55, 3784–3791; (b) Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95,
8741–8749.
5. Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gou-
goutas, J. Z.; O’Reilly, B. C.; Schwatz, J.; Smillie, K. M.; Malley, M. F. J. Med. Chem.
1992, 35, 2629–2635 and the references cited therein.
6. (a) Kapoor, T. M.; Mayer, T. U.; Coughlin, M. L.; Mitchison, T. J. J. Cell Biol. 2000,
150, 975–988; (b) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. L.; Mitchison, T. J. Science 1999, 286, 971–974.
7. (a) Wisen, S.; Androsavich, J.; Evans, C. G.; Chang, L.; Gestwicki, J. E. Bioorg. Med.
Chem. Lett. 2008, 18, 60–65; (b) Evans, C. G.; Wisen, S.; Gestwicki, J. E. J. Biol.
Chem. 2006, 281, 33182–33191.
8. (a) Rodina, A.; Vilenchik, M.; Moulick, K.; Aguirre, J.; Kim, J.; Chiang, A.; Litz, J.;
Clement, C. C.; Kang, Y.; She, Y.; Wu, N.; Felts, S.; Wipf, P.; Massague, J.; Jiang, X.;
Brodsky, J. L.; Krystal, G. W.; Chiosis, G. Nat. Chem. Biol. 2007, 3, 498–507; (b)
Fewell, S. W.; Smith, C. M.; Lyon, M. A.; Dumitrescu, T. P.; Wipf, P.; Day, B. W.;
Brodsky, J. L. J. Biol. Chem. 2004, 279, 51131–51140.
White powder, mp 260–264 ꢁC (EtOH), Rf¼0.41 (silica, DCM/
MeOH¼8:2); 1H NMR (400 MHz, DMSO-d6)
d ppm: 9.58 (s, 1H, 3-
NH), 8.08 (s, 1H, 1-NH), 7.13 (dd, 1H, J¼7.6, 2.0 Hz, 10-H), 7.10 (d, 1H,
J¼7.6 Hz, 11-H), 7.00 (dd, 1H, J¼7.6, 2.0 Hz, 9-H), 5.46 (s, 1H, 12-H),
4.06 (q, 2H, J¼6.8 Hz, CH2CH3), 2.20 (s, 3H, 4-CH3), 1.35 (t, 3H,
J¼6.8 Hz, CH2CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm: 161.3,
151.7,151.1,146.0,137.9,126.5,123.9,115.3,112.7, 89.8, 63.9, 48.3,17.4,
14.5; IR (KBr), cmꢀ1: 3212, 3145, 2979, 1708, 1605, 1487, 1278, 1076;
MS (CI, 150 eV) m/z: 274.8 ([M]þ, 100). Anal. Calcd for C14H14N2O4
(274.10): C, 61.31; H, 5.14; N, 10.21. Found: C, 61.49; H, 5.03; N, 9.89.
4.6.3. 4,9-Dimethyl-1H-chromeno[4,3-d]pyrimidine-2,5-
(3H,10bH)-dione 5f
White powder, mp 288–291 ꢁC (EtOH), Rf¼0.65 (silica, AcOEt);
1H NMR (400 MHz, DMSO-d6)
d ppm: 9.58 (s, 1H, 3-NH), 8.03 (s, 1H,
1-NH), 7.42 (s, 1H, 11-H), 7.11 (d, 1H, J¼8.0 Hz, 9-H), 6.93 (d, 1H,
J¼8.0 Hz, 8-H), 5.45 (s, 1H, 12-H), 2.29 (s, 3H, 4-CH3), 2.21 (s, 3H, 10-
CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm: 161.5, 151.9, 151.2,
146.6, 132.9, 124.6, 90.1, 48.1, 20.3, 17.7; IR (KBr), cmꢀ1: 3352, 3241,
3171, 2922, 1719, 1697, 1465, 1260, 1147; MS (ESI, m/z): 245 [MþH]þ.
Anal. Calcd for C13H12N2O3 (244.08): C, 63.93; H, 4.95; N, 11.47.
Found: C, 63.86; H, 5.01; N, 11.62.
9. Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle, K. E.; Gilbert, K.
F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.; Ransom, R. W.; Kling, P.; Reiss,
D.; Broten, T. P.; Schorn, T. W.; Chang, R. S. L.; O’Malley, S. S.; Olah, T. V.; Ellis, J.
D.; Barrish, A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. J. Med.
Chem. 2000, 43, 7203–7218 and the references cited therein.
4.6.4. 4-Methyl-1H-benzo[5]chromeno[4,3-d]pyrimidine-
2,5(3H,10bH)-dione 5g
White powder, mp 249–251 ꢁC (EtOH), Rf¼0.5 (silica, AcOEt); 1H
NMR (400 MHz, DMSO-d6)
d ppm: 10.05 (s, 1H, 3-NH), 8.00–7.95
10. For mechanistic insights of the process, see: Kappe, C. O. J. Org. Chem. 1997, 62,
7201–7204.
(m, 3H, CHarom), 7.83 (s, 1H, 1-NH), 7.66–7.63 (m, 1H, CHarom), 7.52
(td, 1H, J¼8.0, 1.2 Hz, CHarom), 7.25 (d, 1H, J¼8.8 Hz, CHarom), 5.70 (s,
11. The overwhelming number of papers concerning catalysts of the Biginelli
reaction has been recently reviewed in a report that lists the catalysts used to
mediate the condensation and even introduces the concept of ‘placebo catalyst’
for the Biginelli reaction (sodium chloride): Kolosov, M. A.; Orlov, V. D.; Belo-
borodov, D. A.; Dotsenko, V. V. Mol. Diversity 2009, 13, 5–25.
12. Simon, C.; Constantineux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957–4980.
13. (a) Desai, B.; Dollinger, D.; Kappe, C. O. Tetrahedron 2006, 62, 4651–4664; (b)
Kappe, C. O.; Uray, G.; Roshger, P.; Lindner, W.; Kratky, C.; Keller, W. Tetrahedron
1992, 48, 5473–5480.
1H,12-H), 2.47 (s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm:
158.6, 153.0,148.0,130.9, 130.6,130.1,128.3,127.2,124.9,124.0,117.1,
110.0, 91.8, 46.0, 18.4; IR (KBr), cmꢀ1: 3287, 3117, 3063, 2952, 1705,
1601, 1464, 1281, 1128; MS (CI, 150 eV) m/z: 206.7 (3), 129.8 (100).
Anal. Calcd for C16H12N2O3 (280.08): C, 68.56; H, 4.32; N, 9.99.
Found: C, 68.65; H, 4.20; N, 10.06.
14. (a) Singh, K.; Singh, S. Tetrahedron 2008, 64, 11718–11723; (b) Gholap, A. R.;
Toti, K. S.; Shirazi, F.; Deshpande, M. V.; Srinivasan, K. V. Tetrahedron 2008,
64, 10214–10223; (c) Werner, S.; Turner, D. M.; Lyon, M. A.; Huryn, D. M.;
Wipf, P. Synthesis 2006, 2334–2338; (d) Singh, K.; Singh, S.; Mahajan, A.
J. Org. Chem. 2005, 70, 6114–6117; (e) Prez, R.; Beryozkina, T.;
Zbruyev, O. I.; Haas, W.; Kappe, C. O. J. Comb. Chem. 2002, 4, 501–
510; (f) Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.; Kappe, C. O.
Tetrahedron: Asymmetry 2000, 11, 1449–1453.
15. For examples of recent reviews on synthesis and pharmacological evaluation of
some fused pyrimidines classes see: (a) Hill, M. D.; Movassaghi, M. Chem.dEur.
J. 2008, 6836–6844; (b) Szczepankiewicz, B. G.; Kurukulasuriya, R. Curr. Top.
Med. Chem. 2007, 7, 569–578; (c) De Clercq, E. In Herpes Zoster. Monogr. Virol.;
Gross, G., Doerr, H. W., Eds.; Karger: Basel, 2006; Vol. 26, pp 131–142; (d)
Baraldi, P. G.; Romagnoli, R.; El-Kashef, H.; Tabrizi, M. A.; Preti, D.; Pavani, M. G.;
Zanella, L.; Fruttarolo, F. In Targets in Heterocyclic Systems d Chemistry and
Properties; Attanasi, O. A., Spinelli, D., Eds.; Royal Society of Chemistry: 2006;
Vol. 10, pp 175–196.
4.6.5. 8-Methoxy-4-Methyl-1H-chromeno[4,3-d]pyrimidine-
2,5(3H,10bH)-dione 5h
White powder, mp 262–264 ꢁC (EtOH), Rf¼0.73 (silica, AcOEt); 1H
NMR (400 MHz, DMSO-d6) d ppm: 9.60 (s, 1H, 3-NH), 8.04 (s, 1H, 1-
NH), 7.51 (d, 1H, J¼8.0 Hz, 11-H), 6.77 (dd, 1H, J¼8.0, 2.4 Hz, 10-H),
6.64 (d,1H, J¼2.4 Hz, 8-H), 5.42 (s,1H,12-H), 3.75 (s, 3H, OCH3), 2.23
(s, 3H, 4-CH3); 13C NMR (100 MHz, DMSO-d6)
d ppm: 159.4, 152.6,
151.5, 149.6, 146.3, 125.4, 116.4, 109.9, 101.5, 90.1, 55.3, 47.5, 17.6; IR
(KBr), cmꢀ1: 3358, 3232, 3165, 2965, 1698, 1628, 1444, 1267, 1084;
MS (CI, 150 eV) m/z: 260.5 ([M]þ, 100). Anal. Calcd for C13H12N2O4
(260.08): C, 60.00; H, 4.65; N,10.76. Found: C, 59.74; H, 4.39; N,10.48.
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The authors thank Mrs. Ulrike Ammari for performing micro-
analyses. Financial support from European Commission by the EXT

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