One-pot synthesis of 2H-pyrano[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.1007/s00706-011-0602-7

The reaction between dialkyl acetylenedicarboxylate and a 1,1-diactivated alkene in the presence of Ph₃P leads to 2H-pyrano[2,3-d]pyrimidine derivatives and highly substituted dialkyl (2E)-2-[(1,3-dimethyl-2,4,6- trioxotetrahydropyrimidin-5(2H)-ylidene)arylmethyl]-2-butenedioate in fair to good yields at room temperature and under neutral conditions.

Full text of DOI:10.1007/s00706-011-0602-7

Monatsh Chem (2012) 143:479–483
DOI 10.1007/s00706-011-0602-7
ORIGINAL PAPER
One-pot synthesis of 2H-pyrano[2,3-d]pyrimidine derivatives
•
Mohammad Bayat Yadollah Bayat
•
Soheila Shafei Asayesh
Received: 28 May 2010 / Accepted: 15 July 2011 / Published online: 16 August 2011
Ó Springer-Verlag 2011
Abstract The reaction between dialkyl acetylenedicar-
boxylate and a 1,1-diactivated alkene in the presence of Ph3P
leads to 2H-pyrano[2,3-d]pyrimidine derivatives and highly
substituted dialkyl (2E)-2-[(1,3-dimethyl-2,4,6-trioxote-
trahydropyrimidin-5(2H)-ylidene)arylmethyl]-2-butenedio-
ate in fair to good yields at room temperature and under
neutral conditions.
hepatoprotective [9, 10], antihypertensive [9, 10], anti-
bronchitic [11, 12], and antifungal activity [13]. Therefore,
for the preparation of these complex molecules, great efforts
have been directed towards synthetic manipulation of ura-
cils. They are accessible by a variety of methods, including
classical approaches and novel strategies [14–17]. A number
of reports usually require forcing conditions, long reaction
times, and complex synthetic pathways (for a recent review
see [18–27]). Thus, new routes for the synthesis of these
molecules have attracted considerable attention in the search
for rapid entry to these heterocycles.
Keywords Triphenylphosphine Á
2H-Pyrano[2,3-d]pyrimidine Á
Dimethyl acetylenedicarboxylate Á Aromatic aldehyde
In the development of highly expedient methods for the
synthesis of annelated uracil, herein we report a simple one-
pot reaction between a 1,1-diactivated alkene 1, prepared by
Knoevenagel reaction of N,N’-dimethylbarbituric acid with
aryl aldehydes [28], and dialkyl acetylenedicarboxylate 2 in
the presence of Ph3P leading to 2H-pyrano[2,3-d]pyrimidine
derivatives 3 and dialkyl (2E)-2-[(1,3-dimethyl-2,4,6-trioxo-
tetrahydropyrimidin-5(2H)-ylidene)arylmethyl]-2-butene-
dioate 4 (Scheme 1). The reaction proceeded via smooth
1:1:1 addition in CH2Cl2 at ambient temperature and under
neutral conditions to produce 3a–3g and 4a–4d in 70–88%
yield.
Introduction
Multicomponent processes are attractive for the achieve-
ment of high levels of diversity and brevity, as they allow
three or more simple and flexible building blocks to be
combined in practical, one-pot operations. Due to their
inherent simple experimental procedures and their one-pot
character, they are perfectly suited for drug synthesis [1–4].
The development of new and convenient synthetic
approaches to these scaffolds is therefore of great interest
to the medicinal chemistry community.
Pyrano[2,3-d]pyrimidines are annelated uracils which
have received considerable attention over the past decade
due to their wide range of biological activity. Compounds
with these ring systems have diverse pharmacological
activity such as antitumor [5–7], cardiotonic [8],
Results and discussion
The 1H and 13C nuclear magnetic resonance (NMR) spectra
of the crude reaction mixtures clearly indicated the for-
mation of compounds 3 and 4 in good yields. Although we
were not able to separate 3 and 4 in pure form, NMR data
could be extracted from the spectrum of the mixture of
products (see ‘‘Experimental’’). In the case of 1a–1d,
compound 3 was the major product, and for 1e–1g, com-
pound 3 was obtained as the only product. The 13C NMR
M. Bayat (&) Á Y. Bayat Á S. S. Asayesh
Chemistry Department,
Imam Khomeini International University,
Qazvin, Iran
e-mail: bayat_mo@yahoo.com
123

480
M. Bayat et al.
O
O
Ar
O
O
Ar
O
CO2R
H
Me
O
Me
O
CO2R
N
N
Me
O
CO2R
CO2R
Me
O
CH2Cl2
r.t.
N
N
Ph3P
+
+
+
O2N
CO2R
NO2
CO2Me
O
O
N
N
CO2R
H3C
H3C
Ar
H
Me
Me
CO2Me
CO2Me
1
4
N
2
3
N
CO2Me
H
O
N
O
O
N
O
H
1,3,4 Ar
R
Yield 3+4
Ratio
3:4
CH3
CH3
/%
76
70
72
80
85
88
80
3f-I
3f-II
a
b
c
d
e
f
Phenyl
Me
Me
Me
Me
Me
Me
Et
75:25
79:21
65:35
94:6
Scheme 3
4-Chlorophenyl
4-Methylphenyl
3-Nitrophenyl
Me
O
+
Ar
N
2,6-Dichlorophenyl
2-Nitrophenyl
3 only
3 only
3 only
Ph3P
_
+
Ph3P
2
O
RO2C
CO2R
N
H
g
2-Nitrophenyl
O
Me
5
1
Me
N
Scheme 1
Scheme 2
Me
N
O
O
O
O
_
H
N
_
Ar
CO2Me
H
Me
Ar
+
Ph3P
N
Ar
Me
O
CO2R
+
Ph3P
bond
rotation
[1,3]-H
O
CO2R
X
CO2R
CO2Me
X = O, C(CN)2, NTs
CO2R
6
7
H
Me
Me
O
N
O
O
chemical shift of the CH group in 3a appeared at about
1
N
O
75.10 ppm. The H and 13C NMR spectra of 3b–3g are
_
N
Ar
N
Ar
Me
Me
similar to those of 3a, except for the aryl and ester
moieties.
-Ph3P
O
CO2R
RO2C
O
RO2C
H
CO2R
H
+
Nair and coworker reported in 2005 that the chemical
shift for the E isomer of the substituted butadiene deriva-
tives (Scheme 2) varies between 6.7–7.2 ppm, and X-ray
analysis confirmed the structural assignment of the com-
pounds in the series [29]. Thus, observation of the vinyl H
atom (d = 6.8 ppm) indicates the (E)-configuration of the
C=C bond in 4 [30, 31].
PPh3
4
s-trans
8
Me
N
Me
N
O
O
O
O
N
Ar
N
Ar
Me
Me
O
O
RO2C
CO2R
1
The H and 13C NMR spectra of 3f–3g are consistent
RO2C
H
CO2R
3
with the presence of two rotational isomers in 90:10 ratio.
Although we were not able to separate these rotamers in
pure form, NMR data for each isomer could be extracted
from the spectrum of the mixture of rotational isomers.
The 1H and 13C NMR spectra of 3f clearly indicated the
presence of two rotational isomers 3f–I and 3f–II in 90:10
ratio (Scheme 3). We performed a temperature-dependent
NMR experiment in dimethyl sulfoxide (DMSO).
Increasing the temperature up to 95 °C did not lead to
coalescence of methine and methyl signals. The ratio of the
two isomers was measured by integration of the CH proton,
being between 0.1 at 18 °C and 0.66 at 95 °C.
s-cis 4
Scheme 4
for MeN (d = 3.15, 3.38 ppm), MeO groups (d = 3.51,
3.60 ppm), and CH group (d = 6.24 ppm).
Although the mechanism of the reaction between Ph3P
and dialkyl acetylenedicarboxylates 2 in the presence of a
1,1-diactivated alkene 1 (prepared from the reaction of
N,N’-dimethylbarbituric acid with aryl aldehydes) has not
yet been established in an experimental manner, a possible
explanation is proposed in Scheme 4.
1
The H NMR spectrum of the major isomer 3f–I exhib-
Based on the well-established chemistry of trivalent
phosphorus nucleophiles [32–36], it is reasonable to
assume that the initially formed 1,3-dipolar 5 can add to the
electrophilic C=C bond of 1 to provide a new zwitterion 6,
which can undergo a [1,3]-H shift to provide 7. The latter
ited five sharp singlets, readily recognizable as arising from
two MeN (d = 3.17, 3.49 ppm), two MeO (d = 3.61,
3.85 ppm), and one CH group (d = 6.28 ppm), and the
minor isomer 3f–II displayed the corresponding singlets
123

Synthesis of 2H-pyrano[2,3-d]pyrimidine derivatives
481
can exist in equilibrium with a more stable conformer 8.
Elimination of PPh3 from 8 will deliver the butadiene 4
with E configuration. It may be surmised that the stere-
oselectivity of the reaction is predicated on the elimination
of PPh3 occurring from the rotamer 8, which is stereo-
electronically disposed for the favorable trans elimination
[37]. Then, s-trans 4 in equilibrium with s-cis 4 can
undergo electrocyclic reaction and cyclize to 2H-chromene
derivatives 3.
m/z = 386 (M?, 5), 386 (15), 354 (15), 327 (100), 295
(34), 91 (8), 77 (14), 59 (35).
Dimethyl 1,3,4,7-tetrahydro-1,3-dimethyl-2,4-dioxo-5-
phenyl-2H-pyrano[2,3-d]pyrimidine-6,7-dicarboxylate
(3a, C19H18N2O7)
1H NMR (300 MHz, CDCl3): d = 3.20, 3.51 (6H, 2s, 2
MeN), 3.59, 3.81 (6H, 2s, 2 MeO), 6.26 (1H, s, H-7),
7.36–7.45 (5H, m, arom.) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 28.28, 29.77 (2 MeN), 51.83, 53.40 (2 MeO),
75.10 (C-7), 92.59 (C-4a), 109.23 (C-6), 127.31, 128.80,
129.61, 136.25 (arom. C), 146.58 (C-7), 150.13, 158.89 (2
C=O), 160.42, 164.34 (2 C=O ester), 168.35 (C-8a) ppm.
In conclusion, we have described a new, general, and
successful strategy for convenient synthesis of 2H-pyr-
ano[2,3-d]pyrimidine derivatives of potential synthetic and
pharmaceutical interest. The reactions were carried out
under neutral conditions at room temperature. In this
method the substrates can be mixed without any activation
or modification. The advantages of the present procedure
are experimental simplicity and easy work-up.
Dimethyl (2E)-2-[(1,3-dimethyl-2,4,6-
trioxotetrahydropyrimidin-5(2H)-ylidene)phenylmethyl]-2-
butenedioate (4a, C19H18N2O7)
1H NMR (300 MHz, CDCl3): d = 3.27, 3.32 (6H, 2s, 2
MeN), 3.67, 3.87 (6H, 2s, 2 MeO), 6.79 (1H, s, CH),
7.10–7.15 (5H, m, arom.) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 28.69, 29.78 (2 MeN), 52.24, 53.37 (2 MeO),
119.28 (Ar–C=C), 124.08 (C=CH), 128.10, 128.80, 130.10,
136.26 (arom. C), 147.80 (C=CH), 150.79 (Ar–C=C),
159.55, 161.38, 163.89, 164.86, 166.91 (5 C=O) ppm.
Experimental
Dimethyl acetylenedicarboxylates, aryl aldehydes, and
other reagents and solvents used in this work were obtained
from Fluka (Buchs, Switzerland) and used without further
purification. NMR spectra were recorded with a Bruker
DRX-300 Avance instrument with CDCl3 as solvent.
Chemical shifts are given in ppm (d) relative to internal
tetramethylsilane (TMS), and coupling constants (J) are
reported in Hz. Melting points were measured with a
Gallenkamp electrothermal 9100 apparatus. Elemental
analyses were performed using a Heraeus CHN-O-Rapid
analyzer. These results agreed favorably with the calcu-
lated values. Mass spectra (electrospray ionization, EI)
were recorded with a Shimadzu GC-Mass QP-5050 spec-
trometer operating at ionization potential of 70 eV.
Infrared (IR) spectra (KBr) were measured with a Bruker
Tensor 27 spectrometer.
Preparation of 3b and 4b
ꢀ
Orange oil; yield 0.294 g (70%); IR (KBr): m = 2,955 (C–
H), 1,753, 1,722, 1,667 (C=O), 1,618 (C=C), 1,138, 1,263
(C–O, C–N) cm-1; EI-MS: m/z = 420 (M?, 5), 388 (8),
361 (100), 329 (14), 304 (15), 272 (5), 244 (10), 163 (9),
139 (3), 59 (6).
Dimethyl 5-(4-chlorophenyl)-1,3,4,7-tetrahydro-1,3-
dimethyl-2,4-dioxo-2H-pyrano[2,3-d]pyrimidine-6,7-
dicarboxylate (3b, C19H17ClN2O7)
1H NMR (300 MHz, CDCl3): d = 3.19, 3.54 (6H, 2s, 2
MeN), 3.58, 3.80 (6H, 2s, 2 MeO), 6.25 (1H, s, H-7),
7.25–7.34 (4H, m, arom.) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 28.27, 29.79 (2 MeN), 51.49, 53.46 (2 MeO),
75.05 (C-7), 92.27 (C-4a), 109.61 (C-6), 127.67, 129.80,
133.84, 134.68 (arom. C), 145.35 (C-5), 150.00, 158.89 (2
C=O), 160.51, 164.08 (2 C=O ester), 168.17 (C-8a) ppm.
Typical procedure for the preparation of 3a and 4a
To a magnetically stirred solution of 0.244 g 5-benzyli-
dene-1,3-dimethylpyrimidine-2,4,6-trione (1 mmol) in
5 cm3 dry CH2Cl2 was added 0.262 g Ph3P (1 mmol) fol-
lowed by dropwise addition of a solution of 0.142 g
dimethyl acetylenedicarboxylate (1 mmol) in 2 cm3 dry
CH2Cl2 at r.t. over 10 min. The mixture was stirred for
24 h. The solvent was removed under reduced pressure,
and the residue was separated by column chromatography
(silica gel, Merck 230–400 mesh) using n-hexane-ethyl-
acetate (80:20) to give the products as orange oil. Yield
Dimethyl (2E)-2-[(4-chlorophenyl)(1,3-dimethyl-
2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)methyl]-2-
butenedioate (4b, C19H17ClN2O7)
1H NMR (300 MHz, CDCl3): d = 3.27, 3.31 (6H, 2s, 2
MeN), 3.67, 3.87 (6H, 2s, 2 MeO), 6.78 (1H, s, CH),
7.10–7.25 (4H, m, arom.) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 28.71, 29.80 (2 MeN), 52.26, 53.34 (2 MeO),
119.33 (Ar–C=C), 124.16 (C=CH), 128.03, 128.80, 135.75,
136.28 (arom. C), 147.81 (C=CH), 150.81 (Ar–C=C),
159.56, 161.37, 163.85, 164.96, 166.80 (5 C=O) ppm.
ꢀ
0.294 g (76%); IR (KBr): m = 2,955 (C–H), 1,750, 1,723,
1,665 (C=O), 1,620 (C=C), 1,264 (C–O) cm-1; EI-MS:
123

482
M. Bayat et al.
Preparation of 3c and 4c
Dimethyl (2E)-2-[(1,3-dimethyl-2,4,6-
trioxotetrahydropyrimidin-5(2H)-ylidene)-
(3-nitrophenyl)methyl]-2-butenedioate
(4d, C19H17N3O9)
1H NMR (300 MHz, CDCl3): d = 3.24, 3.31 (6H, 2s, 2
MeN), 3.74, 3.89 (6H, 2s, 2 MeO), 6.80 (1H, s, CH),
7.40–8.30 (4H, m, arom.) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 28.66, 30.09 (2 MeN), 52.53, 53.87 (2 MeO),
119.25 (Ar–C=C), 125.07 (C=CH), 123.25, 125.07, 129.12,
134.50, 136.26, 148.25 (arom. C), 148.30 (C=CH), 150.81
(Ar–C=C), 159.58, 161.40, 163.86, 164.85, 166.92 (5
C=O) ppm.
ꢀ
Orange oil; yield 0.288 g (72%); IR (KBr): m = 2,952 (C–
H), 1,752, 1,725, 1,668 (C=O), 1,625 (C=C), 1,259 (C–O)
cm-1; EI-MS: m/z = 400 (M?, 4), 368 (10), 341 (100),
309 (23), 284 (7), 252 (7), 224 (8), 91 (4), 59 (7).
Dimethyl 1,3,4,7-tetrahydro-1,3-dimethyl-5-
(4-methylphenyl)-2,4-dioxo-2H-pyrano[2,3-d]-
pyrimidine-6,7-dicarboxylate (3c, C20H20N2O7)
1H NMR (300 MHz, CDCl3): d = 2.38 (3H, s, Me), 3.20,
3.54 (6H, 2s, 2 MeN), 3.58, 3.80 (6H, 2s, 2 MeO), 6.24
(1H, s, H-7), 7.20–7.40 (4H, m, arom.) ppm; 13C NMR
(75.4 MHz, CDCl3): d = 21.55 (Me), 28.30, 29.75 (2
MeN), 51.84, 53.40 (2 MeO), 75.14 (C-7), 92.72 (C-4a),
109.02 (C-6), 128.17, 128.46, 133.07, 137.63 (arom. C),
146.93 (C-5), 150.14, 158.95 (2 C=O), 160.47, 164.28 (2
C=O ester), 168.40 (C-8a) ppm.
Dimethyl 5-(2,6-dichlorophenyl)-1,3,4,7-tetrahydro-
1,3-dimethyl-2,4-dioxo-2H-pyrano[2,3-d]pyrimidine-
6,7-dicarboxylate (3e, C19H16Cl2N2O7)
ꢀ
Orange oil; yield 0.387 g (85%); IR (KBr): m = 2,950 (C–
H), 1,757, 1,719, 1,660 (C=O), 1,630 (C=C), 1,138 (C–O)
cm-1; EI-MS: m/z = 455 (M?, 3), 454 (12), 419 (10), 395
(100), 338 (29), 213 (7), 180 (6), 155 (4), 82 (4), 59 (12);
1H NMR (300 MHz, CDCl3): d = 3.19, 3.57 (6H, 2s, 2
MeN), 3.59, 3.78 (6H, 2s, 2 MeO), 6.29 (1H, s, H-7),
7.20–7.35 (3H, m, arom.) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 28.21, 29.52 (2 MeN), 52.15, 53.17 (2 MeO),
74.55 (C-7), 90.66 (C-4a), 109.73 (C-6), 127.95, 130.91,
129.80, 134.89 (arom. C), 140.97 (C-5), 149.87, 158.38 (2
C=O), 160.65, 163.12 (2 C=O ester), 167.83 (C-8a) ppm.
Dimethyl (2E)-2-[(1,3-dimethyl-2,4,6-
trioxotetrahydropyrimidin-5(2H)-ylidene)-
(4-methylphenyl)methyl]-2-butenedioate
(4c, C20H20N2O7)
1H NMR (300 MHz, CDCl3): d = 2.36 (3H, s, Me), 3.27,
3.31 (6H, 2s, 2 MeN), 3.64, 3.84 (6H, 2s, 2 MeO), 6.78
(1H, s, CH), 7.00–7.15 (4H, m, arom.) ppm; 13C NMR
(75.4 MHz, CDCl3): d = 21.61 (Me), 28.68, 28.93 (2
MeN), 52.16, 53.25 (2 MeO), 118.62 (Ar–C=C), 123.93
(C=CH), 128.45, 128.72, 134.92, 140.30 (arom. C), 148.27
(C=CH), 150.89 (Ar–C=C), 159.76, 161.68, 164.02,
165.00, 167.99 (5 C=O) ppm.
Dimethyl 1,3,4,7-tetrahydro-1,3-dimethyl-5-
(2-nitrophenyl)-2,4-dioxo-2H-pyrano[2,3-d]pyrimidine-
6,7-dicarboxylate (3f, C19H17N3O9)
ꢀ
Orange oil; yield 0.379 g (88%); IR (KBr): m = 2,924 (C–
Preparation of 3d and 4d
H), 1,710, 1,661 (C=O), 1,312, 1,230 (C–O, C–N) cm-1
;
EI-MS: m/z = 431 (M?, 1), 372 (100), 326 (37), 311 (15),
277 (20), 183 (18), 113 (11), 91 (16), 77 (17), 59 (80), 43
(15).
ꢀ
Orange oil; yield 0.330 g (80%); IR (KBr): m = 2,958 (C–
H), 1,750, 1,664 (C=O), 1,625 (C=C), 1,140, 1,163 (C–O,
C–N) cm-1; EI-MS: m/z = 431 (M?, 2), 371 (20), 326
(35), 311 (15), 127 (11), 91 (18), 57 (16).
Major isomer (90%): 1H NMR (300 MHz, CDCl3):
d = 3.16, 3.49 (6H, 2s, 2 NMe), 3.61, 3.85 (6H, 2s, 2
OMe), 6.27 (1H, s, H-7), 7.02 (1H, d, J = 7.2 Hz, arom.),
7.52 (2H, m, arom.), 8.32 (1H, d, J = 7.2 Hz, arom.) ppm;
13C NMR (75.4 MHz, CDCl3): d = 28.25, 29.70 (2 MeN),
52.02, 53.55 (2 MeO), 74.99 (C-7), 91.55 (C-4a), 107.56
(C-6), 124.15, 127.42, 128.58, 133.20, 133.39, 143.60
(arom. C), 148.38 (C-5), 149.98, 158.69 (2 C=O), 160.45,
163.74 (2 C=O ester), 167.54 (C-8a) ppm.
Minor isomer (10%): 1H NMR (300 MHz, CDCl3):
d = 3.14, 3.38 (6H, 2s, 2 MeN), 3.51, 3.60 (6H, 2s, 2
MeO), 6.24 (1H, s, H-7), 7.12 (1H, d, J = 7.1 Hz, arom.),
7.66 (2H, m, arom.), 8.20 (1H, d, J = 7.2 Hz, arom.) ppm;
Dimethyl 1,3,4,7-tetrahydro-1,3-dimethyl-5-
(3-nitrophenyl)-2,4-dioxo-2H-pyrano[2,3-d]pyrimidine-
6,7-dicarboxylate (3d, C19H17N3O9)
1H NMR (300 MHz, CDCl3): d = 3.16, 3.52 (6H, 2s, 2
MeN), 3.59, 3.82 (6H, 2s, 2 MeO), 6.28 (1H, s, H-7),
7.40–7.65 (2H, m, arom.), 8.20–8.23 (2H, m, arom.) ppm;
13C NMR (75.4 MHz, CDCl3): d = 28.68, 30.09 (2 MeN),
52.52, 53.86 (2 MeO), 75.37 (C-7), 92.31 (C-4a), 110.54
(C-6), 123.28, 123.29, 134.50, 138.50, 138.51, 144.39
(arom. C), 146.98 (C-5), 150.28, 159.26 (2 C=O), 161.10,
163.94 (2 C=O ester), 168.35 (C-8a) ppm.
123

Synthesis of 2H-pyrano[2,3-d]pyrimidine derivatives
483
13C NMR (75.4 MHz, CDCl3): d = 29.81, 30.93 (2 MeN),
52.02, 55.23 (2 MeO), 68.35 (C-7), 93.34 (C-4a), 110.85
(C-6), 123.10, 124.26, 127.42, 128.45, 132.15, 146.12
(arom. C), 149.01 (C-5), 150.17, 158.70 (2 C=O), 160.62,
161.95 (2 C=O ester), 169.23 (C-8a) ppm.
6. Anderson GL, Shim JL, Broom AD (1976) J Org Chem 41:1095
7. Grivaky EM, Lee S, Siyal CW, Duch DS, Nichol CA (1980) J
Med Chem 23:327
8. Heber D, Heers C, Ravens U (1993) Pharmazie 48:537
9. Furuya S, Ohtaki T (1994) Eur Pat Appl EP 608565
10. Furuya S, Ohtaki T (1994) Chem Abstr 121:205
11. Sakuma Y, Hasegawa M, Kataoka K, Hoshina K, Yamazaki N,
Kadota T, Yamaguchi H (1989) PCT Int Appl WO 9105785
12. Sakuma Y, Hasegawa M, Kataoka K, Hoshina K, Yamazaki N,
Kadota T, Yamaguchi H (1991) Chem Abstr 115:71646
13. Ahluwalia VK, Batla R, Khurana A, Kumar R (1990) Indian J
Chem 29:1141
14. Manlove A, Groziak MP (2009). In: Progress in heterocyclic
chemistry, vol 20. Gribble GW, Joule JA (eds) Elsevier,
Amsterdam, p 333
15. Brown DJ (1984) Pyrimidines and their Benzo derivatives. In:
Katritzky AR, Rees CW (eds) Comprehensive heterocyclic
chemistry, vol 3. Pergamon, Oxford, p 57
Diethyl 1,3,4,7-tetrahydro-1,3-dimethyl-5-(2-nitrophenyl)-
2,4-dioxo-2H-pyrano[2,3-d]pyrimidine-6,7-dicarboxylate
(3g, C21H21N3O9)
ꢀ
Orange oil; yield 0.294 g (80%); IR (KBr): m = 2,924 (C–
H), 1,710, 1,661 (C=O), 1,312, 1,230 (C–O, C–N) cm-1
;
EI-MS: m/z = 459 (M?, 1), 444 (18), 413 (45), 386 (100),
340 (30), 91 (20), 77 (18), 73 (50).
Major isomer (88%): 1H NMR (300 MHz, CDCl3):
d = 0.85 (3H, t, J = 6.8 Hz, Me), 1.32 (3H, t, J = 6.5 Hz,
Me), 3.13, 3.59 (6H, 2s, 2 MeN), 3.90 (2H, q, J = 6.5 Hz,
OCH2), 4.20–4.40 (2H, m, OCH2), 6.25 (1H, s, H-7), 7.01
(1H, d, J = 7.5 Hz, arom.), 7.40–7.60 (2H, m, arom.), 8.28
(1H, d, J = 7.6 Hz, arom.) ppm; 13C NMR (75.4 MHz,
CDCl3): d = 13.99, 14.60 (2 Me), 28.60, 30.15 (2 MeN),
61.23, 63.30 (2 OCH2), 75.43 (C-7), 91.79 (C-4a), 108.81
(C-6), 124.42, 127.98, 128.84, 133.29, 134.06, 142.70
(arom. C), 149.06 (C-5), 150.42, 159.15 (2 C=O), 160.70,
164.04 (2 C=O ester), 167.46 (C-8a) ppm.
Minor isomer (12%): 1H NMR (300 MHz, CDCl3):
d = 1.29–1.30 (6H, 2t, J = 7.2 Hz, 2 Me), 3.11, 3.57 (6H,
2s, 2 MeN), 4.12 (2H, q, J = 7.2 Hz, OCH2), 4.20–4.40
(2H, m, OCH2), 6.21 (1H, s, H-7), 7.30 (1H, d, J = 7.5 Hz,
arom.), 7.50–7.70 (2H, m, arom.), 8.18 (1H, d, J = 7.5 Hz,
arom.) ppm; 13C NMR (75.4 MHz, CDCl3): d = 14.01,
14.38 (2 Me), 29.52, 30.22 (2 MeN), 63.05, 63.29 (2
OCH2), 75.14 (C-7), 91.70 (C-4a), 108.97 (C-6), 124.63,
128.90, 131.71, 132.47, 132.55, 142.75 (arom. C), 149.00
(C-5), 150.45, 159.18 (2 C=O), 160.75, 163.98 (2 C=O
ester), 167.50 (C-8a) ppm.
16. Erian AW (1993) Chem Rev 93:1991
17. Undheim K, Benneche T (1996) Pyrimidines and their Benzo
derivatives. In: Katritzky AR, Rees CW, Scriven EFV (eds)
Comprehensive heterocyclic chemistry II, vol 6. Pergamon,
Oxford, p 93
18. Kraljevic TG, Kristafor S, Suman L, Kralj M, Ametamey SM,
Cetina M, Malic SR (2010) Bioorg Med Chem 18:2704
19. Sasada T, Kobayashi F, Sakai N, Konakahar T (2009) Org Lett
11:2161
20. For a recent review see: Hill MD, Movassaghi M (2008) Chem
Eur J 14:6836
21. Ahluwalia VK, Kumar R, Khurana K, Bhatla R (1990) Tetrahe-
dron 46:3953
22. Ahluwalia VK, Sharma HR, Tyagi R (1986) Tetrahedron 42:4045
23. Ahluwalia VK, Aggarwal R, Alauddin M, Gill G, Khanduri CH
(1990) Heterocycles 31:129
24. Hirota K, Kuki H, Maki Y (1994) Heterocycles 37:563
25. Srivastava P, Saxena AS, Ram VJ (2000) Synthesis 541
26. Kranjc K, Kocevar M (2007) Bull Chem Soc Jpn 80:2001
27. Kranjc K, Kocevar M (2007) Heterocycles 73:481
28. Deb ML, Bhuyan PJ (2005) Tetrahedron Lett 46:6453
29. Nair V, Menon RS, Sreekumar V (2005) Pure Appl Chem
77:1191
30. Eliel EL, Wilen SH (1994) Stereochemistry of organic com-
pounds. Wiley, New York, p 570
31. Huisgen R, Herbig K, Siegl A, Huber H (1966) Chem Ber
99:2526
32. Becker KB (1986) Tetrahedron 36:1717
33. Ferrer P, Auendano C, Sollhuber M (1995) Liebigs Ann Chem
1895
References
34. Johnson AW (1966) Ylid chemistry. Academic, New York
35. Bestmann HJ, Vostrowsky O (1983) Top Curr Chem 109:85
36. Katritzky AR (1999) J Heterocycl Chem 36:1501
37. Nair V, Devi BR, Vidya N, Menon RS, Abhilash N, Rath NP
(2004) Tetrahedron Lett 45:3203
1. Hulme C (2005) In: Zhu J, Bienayme H (eds) Multicomponent
reactions. Wiley-VCH, Weinheim, p 311
2. Hulme C, Gore V (2003) Curr Med Chem 10:51
3. Hulme C, Nixey T (2003) Curr Opin Drug Discov Devel 6:921
¨
4. Domling A (2006) Chem Rev 106:17
5. Howells RE, Tinsley J, Devaney E, Smith G (1981) Acta Trop
38:289
123