Chromeno[2,3-d]pyrimidine-triones synthesis by a three-component coupling reaction

Article abstract of DOI:10.1248/cpb.58.516

A simple and one-pot synthesis of new chromeno[2,3-d]pyrimidine-triones by a three-component condensation reaction of barbituric acids, aldehydes and cyclohexane-1,3-diones in refluxing ethanol in the presence of p-toluenesulfonic acid (p-TSA) for 3-10 h is reported. Two cyclohexane-1,3-diones, four barbituric acids and six substituted aldehydes were chosen for the library validation. Prominent among the advantages of this new method are operational simplicity, good yields and easy work-up procedures employed.

Full text of DOI:10.1248/cpb.58.516

516
Chem. Pharm. Bull. 58(4) 516—520 (2010)
Vol. 58, No. 4
Chromeno[2,3-d]pyrimidine-triones Synthesis by a Three-Component
Coupling Reaction
Ramin GHAHREMANZADEH,a,b Fatemeh FERESHTEHNEJAD,a and Ayoob BAZGIR*,a
a Department of Chemistry, Shahid Beheshti University; General Campus, Tehran 1983963113, Iran: and b Nanobiotech-
nology Research Center, Avicenna Research Institute; ACECR, Tehran 19615–1177, Iran.
Received November 18, 2009; accepted January 19, 2010; published online January 26, 2010
A simple and one-pot synthesis of new chromeno[2,3-d]pyrimidine-triones by a three-component condensa-
tion reaction of barbituric acids, aldehydes and cyclohexane-1,3-diones in refluxing ethanol in the presence of
p-toluenesulfonic acid (p-TSA) for 3—10 h is reported. Two cyclohexane-1,3-diones, four barbituric acids and six
substituted aldehydes were chosen for the library validation. Prominent among the advantages of this new
method are operational simplicity, good yields and easy work-up procedures employed.
Key words chromeno[2,3-d]pyrimidine; cyclohexane-1,3-dione; barbituric acid; aldehyde
Multicomponent reactions (MCRs), an important subclass procedures for the synthesis of fused-pyrimidine heterocy-
of tandem reactions, are one-pot processes in which three or cles.43—51) Herein, we report a simple and efficient synthesis
more easily accessible components react to form a single of chromeno[2,3-d]pyrimidine-triones by a new three-com-
product that incorporates essentially most or all atoms in ponent coupling reaction.
starting materials.1) MCRs are highly flexible, (chemo) selec-
Experimental
tive, convergent, and atom-efficient processes of high ex-
General Melting points were measured on an Electrothermal 9100
ploratory power.2—5) As such they closely approach the con-
apparatus and are uncorrected. Mass spectra were recorded on a FINNI-
cept of ideal synthesis. Heterocyclic systems are common
GAN-MAT 8430 mass spectrometer operating at an ionization potential of
70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1H-
and 13C-NMR spectra were recorded on a BRUKER DRX-300 AVANCE
spectrometer at 300.13 and 75.47 MHz, respectively. Elemental analyses
were performed using a Heracus CHN-O-Rapid analyzer.
structural elements in many natural products and pharmaco-
logically active substances. Accordingly, the development of
efficient methods for the synthesis of (combinatorial libraries
of) heterocyclic compounds has been posing a real challenge
to organic chemists for over a century. In the course of time,
MCRs have proved to be a convenient tool for the construc-
tion of many heterocyclic compound classes.1—5)
The chromene moiety often appears as an important struc-
tural component in both biologically active and natural com-
pounds. Chromene fragments occur in alkaloids, flavonoids,
Typical Procedure for Preparation of 8,8-Dimethyl-5-phenyl-8,9-dihy-
dro-1H-chromeno[2,3-d]pyrimidine-2,4,6(3H,5H,7H)-trione 4a A mix-
ture of 5,5-dimethyl-cyclohexane-dione (0.14 g, 1 mmol), barbituric acid
(0.13 g, 1 mmol), benzaldehyde (0.13 g, 1 mmol) and p-toluenesulfonic acid
(p-TSA) (0.1 g) in refluxing ethanol (5 ml) was stirred for 4 h. After comple-
tion of the reaction confirmed by TLC (eluent: EtOAc/n-hexane, 1 : 3), the
reaction mixture was cooled to room temperature. Then, the precipitated
product was filtered and washed with water (10 ml) and ethanol (5 ml) to af-
tocopherols, and anthocyanins. Moreover, functionally sub- ford the pure 4a as a white powder (yield 84%). mp 160 °C (dec.). IR (KBr)
cmꢀ1: 3180, 2938, 2870, 1719, 1676, 1654. MS m/z: 338 (Mꢁ). 1H-NMR
stituted chromenes have played increasing roles in synthetic
(DMSO-d6) d: 0.92 (3H, s, CH3), 1.03 (3H, s, CH3), 2.07—2.57 (4H, m,
approaches to promising compounds in the field of medicinal
2CH2), 4.52 (1H, s, CH), 7.11—7.22 (5H, m, H-Ar), 11.03 (1H, s, NH),
chemistry.6—9)
12.04 (1H, br s, NH). 13C-NMR (DMSO-d6) d: 27.0, 28.9, 32.2, 32.3, 50.4,
Pyrimidine derivatives are well-known10—16) for their bio-
90.8, 115.2, 126.0, 126.8, 128.3, 128.5, 128.6, 144.3, 149.8, 153.1, 162.8,
163.3, 170.4, 196.3. Anal. Calcd for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28.
Found: C, 67.53; H, 5.30; N, 8.21.
logical activity. Numerous pyrimidine and uracil based com-
pounds have found application in medicine and therapeutics
e.g. some are used in the chemotherapy of cancer17) and some
are used against HIV and viral diseases.18—21) Usually func-
tionalization of uracil at the C-5 and C-6 positions leads to
biologically interesting molecules. A number of heterocyclic
compounds fused with pyrimidines are known for their
varied biological acivities.22—26) For example, the chromeno
[2,3-d]pyrimidine-2,4(3H)-diones (oxadeazaflavines), which
are biomimetic models of the 5-deazaflavin coenzyme, have
been shown to possess strong redox properties in the conver-
sion of alcohols to aldehydes or ketones.27—29) Novel meth-
ods for preparing heterocycle containing pyrimidine moiety
have attracted much interest in recent years.30—35) Despite the
5-(4-Chlorophenyl)-8,8-dimethyl-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H, 5H,7H)-trione 4b 79% yield. Yellow powder. mp
170 °C (dec.). IR (KBr) cmꢀ1: 2954, 2870, 2807, 1719, 1698. MS m/z: 372
1
(Mꢁ). H-NMR (DMSO-d6) d: 0.92 (3H, s, CH3), 1.04 (3H, s, CH3), 2.12,
3
2.26 (2H, ABq, JHHꢂ15.6 Hz, CH2), 2.56 (2H, s, CH2), 4.49 (1H, s, CH),
7.16—7.29 (4H, m, H-Ar), 11.02 (1H, s, NH). 13C-NMR (DMSO-d6) d:
26.9, 28.8, 31.9, 32.3, 50.4, 90.3, 114.4, 125.9, 128.3, 128.5, 130.5, 143.3,
149.8, 153.2, 162.9, 163.3, 163.5, 196.3. Anal. Calcd for C19H17ClN2O4: C,
61.21; H, 4.60; N, 7.51. Found: C, 61.11; H, 4.65; N, 7.57.
8,8-Dimethyl-5-(4-nitrophenyl)-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H, 5H,7H)-trione 4c 85% yield. Yellow powder. mp
200 °C (dec.). IR (KBr) cmꢀ1: 3259, 3201, 2938, 1722, 1685. MS m/z: 383
1
(Mꢁ). H-NMR (DMSO-d6) d: 0.91 (3H, s, CH3), 1.03 (3H, s, CH3), 2.11,
3
2.27 (2H, ABq, JHHꢂ16.1 Hz, CH2), 2.64 (2H, s, CH2), 4.62 (1H, s, CH),
7.10—8.10 (4H, m, H-Ar), 11.11 (1H, s, NH), 12.16 (1H, br s, NH). 13C-
available synthetic methods, there still exists a need for de- NMR (DMSO-d6) d: 27.1, 28.7, 32.3, 32.8, 50.3, 89.7, 114.0, 123.5, 130.1,
146.5, 149.8, 151.8, 153.4, 163.3, 163.4, 196.4. Anal. Calcd for C19H17N3O6:
C, 59.53; H, 4.47; N, 10.96. Found: C, 59.62; H, 4.40; N, 10.88.
8,8-Dimethyl-5-(3-nitrophenyl)-8,9-dihydro-1H-chromeno[2,3-
veloping more efficient procedures, which allow the ready
synthesis of pyrimidine polycyclic systems.
As part of our continuing efforts on the development of
d]pyrimidine-2,4,6(3H, 5H,7H)-trione 4d 83% yield. White powder. mp
180 °C (dec.). IR (KBr) cmꢀ1: 3180, 2959, 2812, 1729, 1694. MS m/z: 383
new routes for the synthesis of biologically active small het-
erocyclic compounds,36—42) we have already reported some
1
(Mꢁ). H-NMR (DMSO-d6) d: 0.94 (3H, s, CH3), 1.05 (3H, s, CH3), 2.13,
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: a_bazgir@sbu.ac.ir

April 2010
517
4.73 (1H, s, CH), 7.51—8.08 (4H, m, H-Ar). 13C-NMR (DMSO-d6) d: 27.0,
28.2, 28.8, 29.6, 32.5, 33.5, 50.3, 89.9, 114.1, 122.1, 123.4, 129.9, 135.5,
146.2, 147.8, 150.4, 152.3, 161.4, 163.4, 196.4. Anal. Calcd for C21H21N3O6:
C, 61.31; H, 5.14; N, 10.21. Found: C, 61.39; H, 5.19; N, 10.16.
5-(4-Bromophenyl)-1,3,8,8-tetramethyl-8,9-dihydro-1H-
chromeno[2,3-d]pyrimidine-2,4,6(3H,5H,7H)-trione 4m 78% yield.
White powder. mp 203 °C. IR (KBr) cmꢀ1: 1711, 1684, 1653. MS m/z: 446
(Mꢁ+2), 444 (Mꢁ). 1H-NMR (DMSO-d6) d: 0.93 (3H, s, CH3), 1.04 (3H, s,
CH3), 2.17—2.25 (2H, m, CH2), 2.64 (2H, br s, CH2), 3.07 (3H, s, NCH3),
4.58 (1H, s, CH), 7.21 (2H, br s, H-Ar), 7.39 (2H, br s, H-Ar). 13C-NMR
(DMSO-d6) d: 27.1, 28.2, 28.8, 29.5, 32.4, 32.8, 50.4, 90.4, 114.6, 120.0,
131.0, 131.1, 143.5, 150.4, 152.1, 161.3, 162.9, 163.1, 196.3. Anal. Calcd
for C21H21BrN2O4: C, 56.64; H, 4.75; N, 6.29%. Found: C, 56.72; H, 4.82;
N, 6.23%.
5-(4-Chlorophenyl)-1,3-dimethyl-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H,5H,7H)-trione 4n 65% yield. Yellow powder. mp
170 °C. IR (KBr) cmꢀ1: 1711, 1674, 1637. MS m/z: 372 (Mꢁ). 1H-NMR
(DMSO-d6) d: 1.92—1.97 (2H, m, CH2), 2.30—2.31 (2H, m, CH2), 2.73—
2.75 (2H, m, CH2), 3.09 (3H, s, NCH3), 3.35 (3H, s, NCH3), 4.62 (1H, s,
CH), 7.27 (4H, br s, H-Ar). 13C-NMR (DMSO-d6) d: 20.2, 26.7, 28.2, 29.5,
32.6, 36.8, 90.5, 115.8, 128.2, 130.6, 131.4, 143.2, 150.4, 152.1, 161.3,
164.8, 196.5. Anal. Calcd for C19H17ClN2O4: C, 61.21; H, 4.60; N, 7.51%.
Found: C, 61.11; H, 4.55; N, 7.43%.
3
2.29 (2H, ABq, JHHꢂ15.9 Hz, CH2), 2.61 (2H, s, CH2), 4.64 (1H, s, CH),
7.51—8.04 (4H, m, H-Ar), 11.10 (1H, s, NH), 12.16 (1H, br s, NH). 13C-
NMR (DMSO-d6) d: 27.0, 28.8, 32.4, 32.6, 50.3, 89.7, 114.1, 122.0, 123.3,
125.9, 129.9, 135.4, 146.4, 147.8, 149.8, 153.4, 163.3, 196.4. Anal. Calcd
for C19H17N3O6: C, 59.53; H, 4.47; N, 10.96. Found: C, 59.45; H, 4.41; N,
10.90.
8,8-Dimethyl-5-p-tolyl-8,9-dihydro-1H-chromeno[2,3-d]pyrimidine-
2,4,6(3H,5H,7H)-trione 4e 73% yield. Yellow powder. mp 185 °C (dec.).
IR (KBr) cmꢀ1: 3243, 3190, 2933, 1719, 1679. MS m/z: 352 (Mꢁ). 1H-NMR
(DMSO-d6) d: 0.92 (3H, s, CH3), 1.03 (3H, s, CH3), 2.07—2.29 (5H, m,
CH2, CH3), 2.56 (2H, s, CH2), 4.46 (1H, s, CH), 7.00—7.09 (4H, m, H-Ar),
11.02 (1H, s, NH). 13C-NMR (DMSO-d6) d: 21.0, 27.0, 28.9, 31.8, 32.3,
50.4, 90.9, 115.3, 128.4, 128.9, 135.8, 141.4, 149.8, 153.0, 162.6, 163.2,
196.3. Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C,
68.26; H, 5.67; N, 7.49.
5-Phenyl-8, 9-dihydro-1H-chromeno[2, 3-d]pyrimidine-
2,4,6(3H,5H,7H)-trione 4f 77% yield. Light yellow powder. mp ꢃ300 °C.
IR (KBr) cmꢀ1: 3190, 2938, 2817, 1723, 1682. MS m/z: 310 (Mꢁ). 1H-NMR
(DMSO-d6) d: 1.86—2.00 (2H, m, CH2), 2.22—2.23 (2H, m, CH2), 2.26—
2.73 (2H, m, CH2), 4.55 (1H, s, CH), 7.11—7.23 (5H, m, H-Ar), 11.03 (1H,
s, NH), 12.02 (1H, br s, NH). 13C-NMR (DMSO-d6) d: 20.2, 26.8, 32.1,
36.8, 90.8, 116.2, 126.8, 128.4, 128.5, 144.4, 149.8, 153.1, 163.3, 164.8,
196.5. Anal. Calcd for C17H14N2O4: C, 65.80; H, 4.55; N, 9.03. Found: C,
65.71; H, 4.48; N, 8.95.
5-(4-Chlorophenyl)-8,9-dihydro-1H-chromeno[2,3-d]pyrimidine-
2,4,6(3H,5H,7H)-trione 4g 74% yield. Light yellow powder. mp ꢃ300 °C.
IR (KBr) cmꢀ1: 3195, 3064, 2922, 1719, 1651. MS m/z: 344 (Mꢁ). 1H-NMR
(DMSO-d6) d: 1.94 (2H, br s, CH2), 1.28 (2H, br s, CH2), 2.65 (2H, br s,
CH2), 4.51 (1H, s, CH), 7.25 (4H, br s, H-Ar), 11.04 (1H, s, NH), 12.03 (1H,
br s, NH). 13C-NMR (DMSO-d6) d: 20.1, 26.8, 31.8, 36.7, 90.2, 115.7,
128.2, 130.5, 131.3, 143.4, 149.8, 153.1, 163.3, 164.9, 196.5. Anal. Calcd
for C17H13ClN2O4: C, 59.23; H, 3.80; N, 8.13. Found: C, 59.31; H, 3.84; N,
8.04.
1,3-Dimethyl-5-(4-nitrophenyl)-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H,5H,7H)-trione 4o 70% yield. Light yellow pow-
der. mp 222 °C (dec.). IR (KBr) cmꢀ1: 3069, 2959, 2938, 2870, 1724, 1635.
MS m/z: 383 (Mꢁ). 1H-NMR (DMSO-d6) d: 1.93—2.00 (2H, m, CH2),
2.31—2.33 (2H, m, CH2), 2.49—2.50 (2H, m, CH2), 3.07 (3H, s, NCH3),
3.38 (3H, s, NCH3), 4.74 (1H, s, CH), 7.55—8.09 (4H, m, H-Ar). 13C-NMR
(DMSO-d6) d: 20.2, 26.8, 28.2, 29.6, 33.5, 36.7, 89.9, 115.1, 123.5, 130.2,
146.6, 150.4, 151.7, 152.3, 161.3, 165.2, 196.5. Anal. Calcd for C19H17N3O6:
C, 59.53; H, 4.47; N, 10.96. Found: C, 59.64; H, 4.42; N, 11.04.
Due to very low solubility of the products 4p we can not report the 13C-
NMR data for this product.
5-(4-Nitrophenyl)-8,9-dihydro-1H-chromeno[2,3-d]pyrimidine-
2,4,6(3H,5H,7H)-trione 4h 72% yield. Orange powder. mp 275 °C. IR
(KBr) cmꢀ1: 1719, 1692, 1653. MS m/z: 355 (Mꢁ). 1H-NMR (DMSO-d6) d:
1.27 (2H, br s, CH2), 1.95 (2H, br s, CH2), 2.28 (2H, br s, CH2), 4.63 (1H, s,
CH), 7.53—8.07 (4H, m, H-Ar), 11.10 (1H, s, NH), 12.15 (1H, s, NH). 13C-
NMR (DMSO-d6) d: 20.1, 26.8, 32.7, 36.7, 89.6, 115.1, 123.5, 130.1, 146.5,
149.8, 151.9, 153.3, 163.3, 165.4, 196.5. Anal. Calcd for C17H13N3O6: C,
57.47; H, 3.69; N, 11.83%. Found: C, 57.33; H, 3.61; N, 11.90%.
5-(3-Nitrophenyl)-8,9-dihydro-1H-chromeno[2,3-d]pyrimidine-
2,4,6(3H,5H,7H)-trione 4i 81% yield. White powder. mp 210 °C (dec.).
IR (KBr) cmꢀ1: 3285, 3216, 3074, 1729, 1693. MS m/z: 355 (Mꢁ). 1H-NMR
(DMSO-d6) d: 1.90—1.98 (2H, m, CH2), 2.28—2.34 (2H, m, CH2), 2.69—
2.71 (2H, m, CH2), 4.66 (1H, s, CH), 7.50—8.07 (4H, m, H-Ar), 11.07 (1H,
s, NH), 12.11 (1H, br s, NH). 13C-NMR (DMSO-d6) d: 20.1, 26.8, 32.5,
36.7, 89.7, 115.1, 121.9, 123.4, 126.0, 129.9, 135.4, 146.5, 147.8, 149.8,
153.3, 163.3, 165.4, 196.6. Anal. Calcd for C17H13N3O6: C, 57.47; H, 3.69;
N, 11.83. Found: C, 57.41; H, 3.75; N, 11.89.
1,3-Dimethyl-5-(3-nitrophenyl)-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H,5H,7H)-trione 4p 68% yield. White powder. mp
ꢃ300 °C (dec.). IR (KBr) cmꢀ1: 2959, 2927, 2864, 1712, 1688, 1669. MS
1
m/z: 383 (Mꢁ). H-NMR (DMSO-d6) d: 1.18—1.37 (2H, m, CH2), 1.93—
2.00 (2H, m, CH2), 2.32—2.41 (2H, m, CH2), 3.08 (3H, s, NCH3), 3.38 (3H,
s, NCH3), 4.75 (1H, s, CH), 7.50—8.10 (4H, m, H-Ar). Anal. Calcd for
C19H17N3O6: C, 59.53; H, 4.47; N, 10.96. Found: C, 59.46; H, 4.41; N, 10.89.
8,8-Dimethyl-5-phenyl-2-thioxo-2,3,8,9-tetrahydro-1H-chromeno[2,3-
d]pyrimidine-4,6(5H,7H)-dione 4q 73% yield. Light brown powder. mp
180 °C. IR (KBr) cmꢀ1: 3495, 3190, 2958, 1715, 1692. MS m/z: 354 (Mꢁ).
1H-NMR (DMSO-d6) d: 0.93 (3H, s, CH3), 1.04 (3H, s, CH3), 2.12, 2.26
(2H, ABq, 3JHHꢂ13.3 Hz, CH2), 2.57 (2H, s, CH2), 4.53 (1H, s, CH), 7.13—
7.22 (5H, m, H-Ar), 12.46 (1H, s, NH), 13.54 (1H, br s, NH). 13C-NMR
(DMSO-d6) d: 27.1, 28.8, 32.3, 32.4, 50.4, 95.8, 114.8, 127.0, 128.4, 128.6,
143.6, 152.5, 161.0, 162.7, 174.1, 196.2. Anal. Calcd for C19H18N2O3S: C,
64.39; H, 5.12; N, 7.90. Found: C, 64.31; H, 5.08; N, 7.82.
Due to very low solubility of the products 4j, we can not report the 13C-
NMR data for this product.
5-Phenyl-2-thioxo-2,3,8,9-tetrahydro-1H-chromeno[2,3-d]pyrimidine-
4,6(5H,7H)-dione 4r 70% yield. Yellow powder. mp ꢃ300 °C (dec.). IR
(KBr) cmꢀ1: 3106, 3027, 2885, 1691, 1658. MS m/z: 326 (Mꢁ). 1H-NMR
(DMSO-d6) d: 1.88—1.98 (2H, m, CH2), 2.23—2.29 (2H, m, CH2), 2.67—
2.75 (2H, m, CH2), 4.56 (1H, s, CH), 6.99—7.24 (5H, m, H-Ar), 12.39 (1H,
s, NH), 13.51 (1H, br s, NH). 13C-NMR (DMSO-d6) d: 20.2, 26.8, 32.1,
36.8, 95.8, 115.9, 127.0, 128.4, 128.6, 143.7, 152.5, 161.0, 164.7, 174.1,
196.4. Anal. Calcd for C17H14N2O3S: C, 62.56; H, 4.32; N, 8.58. Found: C,
62.61; H, 4.28; N, 8.51.
1,3,8,8-Tetramethyl-5-phenyl-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H,5H,7H)-trione 4j 74% yield. Light yellow powder.
mp 197 °C. IR (KBr) cmꢀ1: 2964, 2870, 1703, 1635. MS m/z: 366 (Mꢁ). 1H-
NMR (DMSO-d6) d: 0.93 (6H, br s, 2CH3), 2.17—2.71 (4H, m, 2CH2), 2.97
(3H, s, NCH3), 3.11 (3H, s, NCH3), 4.64 (1H, s, CH), 7.00—7.47 (5H, m, H-
Ar). Anal. Calcd for C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C,
68.94; H, 6.01; N, 7.72.
8,8-Dimethyl-5-(4-nitrophenyl)-2-thioxo-2,3,8,9-tetrahydro-1H-
chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4s 80% yield. Orange pow-
1,3,8,8-Tetramethyl-5-(4-nitrophenyl)-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H,5H,7H)-trione 4k 79% yield. White powder. mp
1
der. mp 265 °C. IR (KBr) cmꢀ1: 1686, 1627, 1570. MS m/z: 399 (Mꢁ). H-
1
ꢃ300 °C. IR (KBr) cmꢀ1: 2959, 2870, 1707, 1645. MS m/z: 411 (Mꢁ). H-
NMR (DMSO-d6) d: 0.93 (3H, s, CH3), 1.07 (3H, s, CH3), 2.13, 2.27 (2H,
NMR (DMSO-d6) d: 0.94 (3H, s, CH3), 1.06 (3H, s, CH3), 2.16, 2.30 (2H,
ABq, 3JHHꢂ16.1 Hz, CH2), 2.59 (2H, s, CH2), 4.64 (1H, s, CH), 7.55 (2H, d,
ABq, 3JHHꢂ16.2 Hz, CH2), 2.68 (2H, s, CH2), 3.07 (3H, s, NCH3), 3.38 (3H,
3
3JHHꢂ8.7 Hz, H-Ar), 8.10 (2H, d, JHHꢂ8.7 Hz, H-Ar), 12.48 (1H, s, NH),
3
s, NCH3), 4.73 (1H, s, CH), 7.56 (2H, d, JHHꢂ8.6 Hz, H-Ar), 8.09 (2H, d,
13.65 (1H, s, NH). 13C-NMR (DMSO-d6) d: 27.2, 28.6, 32.4, 32.8, 50.3,
56.5, 94.6, 113.8, 123.5, 130.2, 146.6, 151.1, 152.7, 161.0, 163.3, 174.3,
196.2. Anal. Calcd for C19H17N3O5S: C, 57.13; H, 4.29; N, 10.52%. Found:
C, 57.04; H, 4.21; N, 10.44%.
3JHHꢂ8.6 Hz, H-Ar). 13C-NMR (DMSO-d6) d: 27.2, 28.2, 28.7, 29.6, 32.4,
33.6, 50.3, 89.9, 114.1, 123.5, 130.2, 146.6, 150.4, 151.6, 152.3, 161.3,
163.3, 196.3. Anal. Calcd for C21H21N3O6: C, 61.31; H, 5.14; N, 10.21.
Found: C, 61.42; H, 5.08; N, 10.29
5-(4-Nitrophenyl)-2-thioxo-2,3,8,9-tetrahydro-1H-chromeno[2,3-
d]pyrimidine-4,6(5H,7H)-dione 4t 82% yield. Brown powder. mp 270 °C
(dec.). IR (KBr) cmꢀ1: 1713, 1669, 1635. MS m/z: 371 (Mꢁ). 1H-NMR
(DMSO-d6) d: 1.90—1.99 (2H, m, CH2), 2.23—2.35 (2H, m, CH2), 2.73
(2H, br s, CH2), 4.77 (1H, s, CH), 7.52 (2H, d, 3JHHꢂ8.4 Hz, H-Ar), 8.09
1,3,8,8-Tetramethyl-5-(3-nitrophenyl)-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H,5H,7H)-trione 4l 81% yield. Light yellow pow-
der. mp 185 °C. IR (KBr) cmꢀ1: 2962, 2933, 2864, 1696, 1642. MS m/z: 411
1
(Mꢁ). H-NMR (DMSO-d6) d: 0.94 (3H, s, CH3), 1.06 (3H, s, CH3), 2.16,
2.30 (2H, ABq, 3JHHꢂ16.1 Hz, CH2), 2.69 (2H, s, CH2), 3.07 (3H, s, NCH3),

518
Vol. 58, No. 4
(2H, d, 3JHHꢂ8.3 Hz, H-Ar), 12.94 (1H, s, NH). 13C-NMR (DMSO-d6) d:
14.8, 20.2, 24.8, 27.2, 33.5, 36.7, 114.2, 123.6, 130.0, 146.5, 151.8, 166.7,
196.6. Anal. Calcd for C17H13N3O5S: C, 54.98; H, 3.53; N, 11.31%. Found:
C, 54.99; H, 3.46; N, 11.39%.
1,3-Diethyl-5-(4-nitrophenyl)-2-thioxo-2,3,8,9-tetrahydro-1H-
chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4bꢀ 73% yield. Light yel-
low powder. mp 207 °C. IR (KBr) cmꢀ1: 3106, 2985, 2927, 1614. MS m/z:
427 (Mꢁ). 1H-NMR (DMSO-d6) d: 1.08 (3H, s, CH3), 1.33 (3H, s, CH3),
1.99 (2H, br s, CH2), 2.33 (2H, br s, CH2), 2.79 (2H, br s, CH2), 4.27—4.68
(4H, m, 2NCH2), 4.79 (1H, s, CH), 7.47—8.13 (4H, m, H-Ar). Anal. Calcd
for C21H21N3O5S: C, 59.00; H, 4.95; N, 9.83. Found: C, 59.08; H, 4.99; N,
10.03.
8,8-Dimethyl-5-(3-nitrophenyl)-2-thioxo-2,3,8,9-tetrahydro-1H-
chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4u 81% yield. Light or-
ange powder. mp 190 °C. IR (KBr) cmꢀ1: 2959, 2870, 1691, 1624. MS m/z:
399 (Mꢁ). 1H-NMR (DMSO-d6) d: 0.95 (3H, s, CH3), 1.05 (3H, s, CH3),
3
1,3-Diethyl-8,8-dimethyl-5-(3-nitrophenyl)-2-thioxo-2,3,8,9-tetrahy-
dro-1H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4cꢀ 71% yield.
White powder. mp 154 °C. IR (KBr) cmꢀ1: 2975, 2915, 2868, 1690, 1670.
MS m/z: 455 (Mꢁ). 1H-NMR (DMSO-d6) d: 0.96 (3H, s, CH3), 1.07 (3H, s,
CH3), 1.14—1.18 (3H, m, CH3), 1.30—1.34 (3H, s, CH3), 4.25—4.53 (4H,
m, 2NCH2), 4.78 (1H, s, CH), 7.48—8.12 (4H, m, H-Ar). 13C-NMR
(DMSO-d6) d: 11.7, 12.7, 12.9, 27.1, 28.8, 32.4, 33.6, 43.3, 45.4, 50.3, 95.2,
95.8, 113.9, 121.3, 122.3, 123.6, 130.0, 135.5, 145.4, 148.0, 152.3, 159.2,
161.6, 163.4, 174.9, 196.2. Anal. Calcd for C23H25N3O5S: C, 60.64; H, 5.53;
N, 9.22. Found: C, 60.71; H, 5.58; N, 9.17.
2.14, 2.28 (2H, ABq, JHHꢂ15.7 Hz, CH2), 2.61 (2H, s, CH2), 4.65 (1H, s,
CH), 7.54—8.04 (4H, m, H-Ar), 12.46 (1H, s, NH), 13.60 (1H, br s, NH).
13C-NMR (DMSO-d6) d: 15.6, 27.1, 28.7, 32.4, 50.3, 65.4, 94.6, 113.8,
122.1, 123.4, 129.9, 135.5, 145.7, 147.9, 152.8, 161.1, 163.4, 174.3, 196.3
Anal. Calcd for C19H17N3O5S: C, 57.13; H, 4.29; N, 10.52. Found: C, 57.22;
H, 4.22; N, 10.46.
5-(3-Nitrophenyl)-2-thioxo-2,3,8,9-tetrahydro-1H-chromeno[2,3-
d]pyrimidine-4,6(5H,7H)-dione 4v 81% yield. Yellow powder. mp ꢃ300 °C
(dec.). IR (KBr) cmꢀ1: 3101, 2864, 1703, 1671, 1650. MS m/z: 371 (Mꢁ).
1H-NMR (DMSO-d6) d: 1.95 (2H, br s, CH2), 2.29 (2H, br s, CH2), 2.70
(2H, br s, CH2), 4.66 (1H, s, CH), 7.52—8.08 (4H, m, H-Ar), 12.48 (1H, s,
NH), 13.61 (1H, br s, NH). 13C-NMR (DMSO-d6) d: 20.1, 26.9, 32.6, 36.6,
94.6, 114.8, 122.1, 123.5, 130.0, 135.5, 145.7, 147.8, 152.7, 161.1, 165.4,
174.3, 196.5. Anal. Calcd for C17H13N3O5S: C, 54.98; H, 3.53; N, 11.31.
Found: C, 54.90; H, 3.59; N, 11.26.
Due to very low solubility of the product 6 we can not report the 13C-
NMR data for this product.
5-Phenyl-9,10-dihydropyrido[2,3-d:6,5-d]dipyrimidine-
2,4,6,8(1H,3H,5H,7H)-tetraone 6 White powder. mp ꢃ300 °C. IR (KBr)
cmꢀ1: 3230, 3089, 1691, 1668. MS m/z: 325 (Mꢁ). 1H-NMR (DMSO-d6) d:
4.64 (1H, s, CH), 7.04—7.25 (5H, m, H-Ar), 9.95 (2H, s, 2NH), 10.81 (2H,
s, 2NH). Anal. Calcd for C15H11N5O4: C, 55.39; H, 3.41, N, 21.53. Found: C,
55.40; H, 3.35; N, 21.42.
Due to very low solubility of the products 4w, we can not report the 13C-
NMR data for this product.
5-(4-Bromophenyl)-8,8-dimethyl-2-thioxo-2,3,8,9-tetrahydro-1H-
chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4w 78% yield. White pow-
der. mp 180 °C. IR (KBr) cmꢀ1: 2960, 2854, 1708, 1663. MS m/z: 432 (Mꢁ).
1H-NMR (DMSO-d6) d: 0.91 (3H, s, CH3), 1.07 (3H, s, CH3), 2.03—2.28
(2H, m, CH2), 2.55 (2H, s, CH2), 4.46 (1H, s, CH), 7.10—7.42 (4H, m, H-
Ar), 11.06 (1H, s, NH), 12.07 (1H, br s, NH). 13C-NMR (DMSO-d6) d: 13.7,
28.8, 29.1, 32.4, 50.4, 90.2, 95.2, 114.3, 120.1, 124.1, 131.0, 143.0, 149.1,
162.9, 196.3. Anal. Calcd for C19H17BrN2O3S: C, 52.66; H, 3.95; N, 6.46.
Found: C, 52.72; H, 3.89; N, 6.51.
Results and Discussion
The choice of an appropriate reaction media is of crucial
importance for successful synthesis. Initially, the three-com-
ponent reaction of barbituric acid 1a, benzaldehyde 2a and
dimedone 3a as a simple model substrate was investigated to
1,3-Diethyl-8,8-dimethyl-5-phenyl-2-thioxo-2,3,8,9-tetrahydro-1H- establish the feasibility of the strategy and optimize the reac-
chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4x 72% yield. White pow-
tion conditions (Table 1). Different solvents in the presence
of p-TSA as an inexpensive and available catalyst and vari-
ous Lewis acids were screened in the model reaction. As can
der. mp 180 °C. IR (KBr) cmꢀ1: 2962, 2933, 2870, 1683, 1625. MS m/z: 410
(Mꢁ). 1H-NMR (DMSO-d6) d: 0.95 (3H, s, CH3), 1.06—1.11 (6H, m,
2CH3), 1.29—1.33 (3H, m, CH3), 4.24—4.56 (4H, m, 2NCH2), 4.67 (1H, s,
CH), 7.13—7.26 (5H, m, H-Ar). 13C-NMR (DMSO-d6) d: 11.7, 12.9, 27.1,
28.9, 32.4, 33.1, 43.3, 45.3, 50.4, 96.3, 115.0, 127.1, 128.5, 128.7, 143.3,
152.1, 159.1, 162.9, 174.7, 196.0. Anal. Calcd for C23H26N2O3S: C, 67.29;
H, 6.38; N, 6.82. Found: C, 67.20; H, 6.33; N, 6.89.
be seen from Table 1, in the presence of p-TSA, ethanol is
the solvent of choice for the reaction and the desired product,
8,8-dimethyl-5-phenyl-8,9-dihydro-1H-chromeno[2,3-
d]pyrimidine-2,4,6(3H,5H,7H)-trione 4a, was obtained in
good yield (Entry 5), while without p-TSA and over long pe-
riod of time (20 h) the yield of product was trace (Entry 7).
Encouraged by this success, in regard to library construc-
tion and evaluation the substrate scope of this reaction, dif-
ferent barbituric acids 1a—d, cyclohexane-1,3-diones 3a, b
5-(4-Chlorophenyl)-1,3-diethyl-8,8-dimethyl-2-thioxo-2,3,8,9-tetrahy-
dro-1H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4y 70% yield.
Light yellow powder. mp 133 °C. IR (KBr) cmꢀ1: 2959, 2933, 2870, 1694,
1
1635. MS m/z: 444 (Mꢁ). H-NMR (DMSO-d6) d: 0.94 (3H, s, CH3), 1.07
(6H, br s, 2CH3), 1.31 (3H, s, CH3), 2.17, 2.27 (2H, ABq, 3JHHꢂ15.7 Hz,
CH2), 2.67 (2H, s, CH2), 3.77—4.65 (5H, m, 2NCH2, CH), 7.29 (4H, br s,
H-Ar). 13C-NMR (DMSO-d6) d: 11.7, 12.9, 27.2, 28.8, 32.4, 32.9, 43.3,
45.3, 50.4, 95.8, 114.5, 128.4, 130.6, 131.7, 142.3, 152.1, 159.1, 162.9,
174.8, 196.1. Anal. Calcd for C23H25ClN2O3S: C, 62.08; H, 5.66; N, 6.30.
Found: C, 62.17; H, 5.72; N, 6.39.
Table 1. Model Reaction, Conditions, and Yieldsa)
1,3-Diethyl-8,8-dimethyl-5-(4-nitrophenyl)-2-thioxo-2,3,8,9-tetrahy-
dro-1H-chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4z 74% yield.
Light orange powder. mp 190 °C. IR (KBr) cmꢀ1: 2964, 2927, 2875, 1692,
1
1650. MS m/z: 455 (Mꢁ). H-NMR (DMSO-d6) d: 0.95 (3H, s, CH3), 1.07
(6H, br s, 2CH3), 1.30—1.34 (3H, m, CH3), 2.17, 2.29 (2H, ABq, 3JHHꢂ
16.1 Hz, CH2), 2.69 (2H, s, CH2), 4.24—4.66 (4H, m, 2NCH2), 4.77 (1H, s,
CH), 7.57—8.12 (4H, m, H-Ar). 13C-NMR (DMSO-d6) d: 11.7, 12.9, 27.3,
28.7, 32.4, 33.7, 43.3, 45.4, 50.3, 95.1, 113.9, 123.6, 130.3, 146.7, 150.7,
152.3, 159.1, 163.3, 174.9, 196.2. Anal. Calcd for C23H25N3O5S: C, 60.64;
H, 5.53; N, 9.22. Found: C, 60.58; H, 5.49; N, 9.14.
Entry
Conditions
Catalyst
Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
CHCl3 (reflux)
Water (reflux)
CH3CN (reflux)
EtOH (reflux)
EtOH (reflux)
EtOH (reflux)
EtOH (reflux)
EtOH (reflux)
EtOH (reflux)
EtOH (reflux)
p-TSA (0.3 mmol)
p-TSA (0.3 mmol)
p-TSA (0.3 mmol)
p-TSA (0.2 mmol)
p-TSA (0.3 mmol)
p-TSA (0.4 mmol)
—
LiCl (0.3 mmol)
ZnCl2 (0.3 mmol)
AlCl3 (0.3 mmol)
4
4
4
Trace
Trace
64
Due to very low solubility of the products 4aꢄ we can not report the 13C-
NMR data for this product.
5-(4-Chlorophenyl)-1,3-diethyl-2-thioxo-2,3,8,9-tetrahydro-1H-
chromeno[2,3-d]pyrimidine-4,6(5H,7H)-dione 4aꢀ 72% yield. White pow-
der. mp 214 °C. IR (KBr) cmꢀ1: 3448, 3064, 2927, 1609. MS m/z: 416 (Mꢁ).
1H-NMR (DMSO-d6) d: 1.34 (8H, br s, 2CH3, CH2), 1.87 (2H, br s, CH2),
2.50 (2H, br s, CH2), 4.05—4.39 (5H, m, 2NCH2, CH), 6.99—7.23 (4H, m,
H-Ar). Anal. Calcd for C21H21ClN2O3S: C, 60.50; H, 5.08; N, 6.72. Found:
C, 6.59; H, 5.02; N, 6.64.
4
63
4
84
4
82
20
4
4
Trace
Trace
Trace
54
10
4
Due to very low solubility of the products 4bꢄ we can not report the 13C-
NMR data for this product.
a) Barbituric acid (1 mmol), benzaldehyde (1 mmol), dimedone (1 mmol).

April 2010
519
and aromatic aldehydes 2a—f were employed under similar hyde such as propionaldehyde or butanaldehyde in same con-
1
circumstances (Chart 1). Corresponding chromeno[2,3- ditions (EtOH/p-TSA), TLC and H-NMR spectra of the re-
d]pyrimidine-trione 4 were selectively synthesized by the action mixture showed a combination of starting materials
three-component condensation reaction of barbituric acids 1, and numerous by-products, the yield of the expected product
aldehydes 2 and cyclohexane-1,3-diones 3 in good yields at was very poor. This can be attributed to the aldol condensa-
refluxing ethanol in the presence of p-TSA for 3—10 h. The tion side reaction.
reaction can be represented as in Table 2. Aromatic alde-
Compounds 4 are stable solids whose structures were es-
1
hydes carrying different functional groups work satisfactorily tablished by IR, H-NMR, 13C-NMR spectroscopy, and ele-
in the reaction (Table 2). All compounds described in the mental analysis.
paper were synthesized for the first time. Prominent among
Finally, in order to investigate the formation of by-prod-
the advantages of this new method are operational simplicity, ucts in the reaction, we examined the reaction of barbituric
good yields, and an easy workup procedure without using acid 1a, benzaldehyde 2a and dimedone 3a in the optimized
any chromatographic methods.
conditions. Besides chromeno[2,3-d]pyrimidine-trione 4a
When this reaction was carried out with an aliphatic alde- (84%) as the main product, by-product 6 also identified in
10%. The by-product 6 was thought to be produced from the
reaction of heterodienes 5 and barbituric acid 1a. Although
by-product 7 seems to be a reasonable candidate, we did not
identify it in the reaction (Chart 2).
Therefore, the formation of products 4 can be rationalized
by initial formation of heterodiene 5 by standard Knoeve-
nagel condensation of barbituric acids 1 and aromatic alde-
hydes 2. Subsequent Michael-type addition of cyclohexane-
Chart 1. Synthesis of Chromeno[2,3-d]pyrimidinones 4
1,3-diones 3 to the heterodienes 5, followed by cyclization
afforded the corresponding products 4 and water (Chart
3).44,52—54)
Table 2. Chromeno[2,3-d]pyrimidinones 4
Product 4
R
Rꢄ
X
Ar
Time (h) Yield (%)a)
Conclusion
In conclusion, an efficient, one-pot and simple method for
the preparation of chromeno[2,3-d]pyrimidinones using read-
ily available starting materials is reported. Prominent among
the advantages of this new method are operational simplicity,
good yields and easy work-up procedures employed. Further
reactivity studies and synthetic application of this methodol-
ogy are in progress in our laboratory.
a
b
c
d
e
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Me
Me
Me
Me
H
H
H
H
Me
Me
Me
Me
H
H
H
Me
H
Me
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
S
C6H5
4
6
3
3
10
8
7
6
6
6
6
6
6
8
7
8
8
8
6
6
6
6
8
8
8
7
8
7
7
84
79
85
83
73
77
74
72
81
74
79
81
78
65
70
68
73
70
80
81
81
81
78
72
70
74
72
73
71
4-Cl-C6H4
4-NO2-C6H4
3-NO2-C6H4
4-Me-C6H4
C6H5
4-Cl-C6H4
4-NO2-C6H4
3-NO2-C6H4
C6H5
4-NO2-C6H4
3-NO2-C6H4
4-Br-C6H4
4-Cl-C6H4
4-NO2-C6H4
3-NO2-C6H4
C6H5
f
g
h
i
j
k
l
m
n
o
p
q
r
Acknowledgements We gratefully acknowledge financial support from
the Research Council of Shahid Beheshti University.
C6H5
s
t
4-NO2-C6H4
4-NO2-C6H4
3-NO2-C6H4
3-NO2-C6H4
4-Br-C6H4
C6H5
4-Cl-C6H4
4-NO2-C6H4
4-Cl-C6H4
4-NO2-C6H4
3-NO2-C6H4
u
v
w
x
y
z
aꢄ
bꢄ
cꢄ
Me
H
H
H
Me
Me
Me
Me
H
Et
Et
Et
Et
Et
Et
S
S
S
S
H
Me
a) Isolated yields.
Chart 2. Probable Products of the Reaction
Chart 3. Proposed Mechanism of the Reaction

520
Vol. 58, No. 4
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