on-water organic synthesis: L-proline catalyzed synthesis of pyrimidine-2,4-dione-, benzo[g]- and dihydropyrano[2,3-g]chromene derivatives in aqueous media

Article abstract of DOI:10.1007/s13738-012-0160-x

In this work, functionalized pyrimidine-2,4-dione-, benzo[g]-, and dihydropyrano[2,3-g]chromene derivatives have been synthesized via a Michael addition of 2-hydroxy-1,4-naphthoquinone or 2,5-dihydroxy-1,4-benzoquinone to the Knoevenagel condensation product of an aldehyde with Meldrum's acid, dimedone or barbituric acid in the presence of a catalytic amount of l-proline under refluxing conditions in water in good to excellent yields.

Full text of DOI:10.1007/s13738-012-0160-x

J IRAN CHEM SOC
DOI 10.1007/s13738-012-0160-x
ORIGINAL PAPER
‘‘On-water’’ organic synthesis: L-proline catalyzed synthesis
of pyrimidine-2,4-dione-, benzo[g]- and dihydropyrano
[2,3-g]chromene derivatives in aqueous media
•
Hamid Mofakham Rahim Ghadari
•
•
Ahmad Shaabani Milad Pedarpour
•
Sabrieh Ghasemi
Received: 31 July 2012 / Accepted: 18 August 2012
Ó Iranian Chemical Society 2012
Abstract In this work, functionalized pyrimidine-
2,4-dione-, benzo[g]-, and dihydropyrano[2,3-g]chromene
derivatives have been synthesized via a Michael addition
of 2-hydroxy-1,4-naphthoquinone or 2,5-dihydroxy-1,4-
benzoquinone to the Knoevenagel condensation product of
an aldehyde with Meldrum’s acid, dimedone or barbituric
acid in the presence of a catalytic amount of L-proline under
refluxing conditions in water in good to excellent yields.
Within the previous decade, green chemistry has
achieved the status of a major scientific discipline [14–17].
Cleaner and more benign chemical processes have been
developed using green chemistry philosophy and many
new technologies have been developed each year. Among
the 12 principles of green chemistry, utilizing ‘‘safer sol-
vents’’ and to ‘‘design for energy efficiency’’ can be con-
sidered the most important ones for the synthetic chemists.
Although there is widespread argument over the relative
‘‘greenness’’ of many reaction media, water can undoubt-
edly be considered as the cleanest solvent available;
therefore, the use and release of clean water will have the
least dreadful impact to the environment. For biological
chemistry, water is a green solvent that has been used by
nature; it is nonflammable and nontoxic. After the mas-
terful use of concept and language of ‘‘on-water’’ reactions
for cases where the reactants are insoluble in water by
Sharpless et al., the use of water as a reaction media for
organic synthesis has attracted many attractions [18, 19].
The use of aqueous media in organic reactions has
attracted a great deal of interest not only because of sig-
nificant environmental advantages, but also different ben-
eficial such as low cost and safety. Revolutionary studies of
organic reactions in aqueous media established that Claisen
rearrangement and Diels–Alder reactions of hydrophobic
reactants are accelerated in aqueous media. In addition to
these findings, higher reactivity and selectivity in aqueous
environments have been reported as well. Therefore, many
versatile and well-organized organic reactions have been
developed [19–34].
Keywords Pyrimidine-2,4-dione Á Benzo[g]chromene Á
Dihydropyrano[2,3-g]chromene Á Aqueous media
Introduction
Naturally occurring chromenes show a broad spectrum of
biological activities. This moiety is core fragment of dif-
ferent natural products including pyranokunthone A and B,
lambertellin B, b-lapachone C and a-xiloidone D [1–6].
Some derivatives of benzo[g]chromenes, such as com-
pounds E and F have been isolated from marine actino-
mycete CNQ-525 bacteria (Fig. 1). These latter materials
have shown significant anticancer and antibiotic activities
[7]. Because of broad pharmacological activities of
benzo[g]chromenes, different synthetic methods have been
introduced by research groups [8–12]. Usually, these syn-
thetic approaches are including a multi-step procedure.
A semi-synthetic method has also been introduced [13].
Small organic molecules like cinchona alkaloids,
L-proline and its derivatives are readily commercially
available catalysts and have been used in various trans-
formations in good yields [35, 36]. L-Proline has been
found to be very effective in enamine-based direct catalytic
H. Mofakham Á R. Ghadari Á A. Shaabani (&) Á
M. Pedarpour Á S. Ghasemi
Department of Chemistry, Shahid Beheshti University,
G. C., P. O. Box 19396-4716, Tehran, Iran
e-mail: a-shaabani@sbu.ac.ir
123

J IRAN CHEM SOC
OH
O
O
O
TLC). After completion, the reaction mixture was filtered
and washed with water and crystallized from EtOH/H2O
(v:v = 1:3) to afford pure product 4a. Yellow powder. m.p.
228–230 °C; IR (KBr) (mmax/cm-1): 3,451, 3,075, 2,956,
2,861, 1,664, 1,618, 1,586, 1,461, 1,366. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 0.95 (3H, s, CH3), 1.06
(3H, s, CH3), 2.10–2.50 (4H, m, 2CH2), 4.89 (1H, s, CH),
7.00–8.10 (9H, m, H–Ar); MS (m/z, %): 384 (M?, 80), 327
(10), 307 (65), 273 (30), 251 (45), 215 (50), 139 (70), 105
(30), 77 (100), 41 (70). Anal. Calcd for C25H20O4: C,
78.11; H, 5.24. Found: C, 78.08; H, 5.14.
O
O
HO
O
O
O
O
O
B
H
A
C
Cl
H
Cl
O
O
OH
OH
O
H
O
O
O
H
HO
HO
O
Cl
Cl
H
D
OH
O
OH
O
E
F
Typical procedure for the synthesis of 7,14-bis(2,4-
dimethoxyphenyl)-3,3,10,10-tetramethyl-3,4,10,11-tetrahydro-
chromeno[2,3-b]xanthene-1,6,8,13(2H,7H,9H,14H)-tetraone
(6b) A solution of 2,5-dihydroxycyclohexa-2,5-diene-
1,4-dione (0.17 g, 1.0 mmol), 2,4-dimethoxybenzaldehyde
(0.33 g, 2.0 mmol), 5,5-dimethylcyclohexane-1,3-dione
(0.28 g, 2.0 mmol) and L-proline (10 mol %) in refluxing
water (5 ml) was stirred for 8 h (the progress of the reac-
tion was monitored by TLC). After completion, the reac-
tion mixture was filtered and then crystallized from ethanol
to give 6b as pure products. Orange powder. m.p.
189–191 °C; IR (KBr) (mmax/cm-1): 3,390, 2,969, 2,838,
Fig. 1 Examples of biologically active benzo[g]chromene deriva-
tives
asymmetric aldol [37], Mannich [38, 39], Michael [40–42],
Diels–Alder [43], a-amination reactions [44], Knoevenagel
type reactions [45], and asymmetric Biginelli reactions [46,
47]. More recently, L-proline and its derivatives have been
used in multicomponent reactions [48–53].
1
Experiment
1,716, 1,639, 1,603. H NMR (300 MHz, DMSO-d6): dH
(ppm) 1.08 (12H, br s, 4CH3), 1.99–2.22 (8H, m, 4CH2),
2.98 (1H, s, CH), 3.5 (12H, br s, 4OMe), 4.42 (2H, s, 2CH),
6.28–6.76 (6H, m, H–Ar). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 27.0, 27.6, 28.1, 29.9, 31.7, 32.6, 33.1, 40.7, 42.7,
49.2, 50.9, 53.3, 55.4, 55.7, 97.9, 101.6, 104.0, 110.0,
115.6, 123.8, 129.9, 157.2, 158.7, 162.4, 167.2, 196.0,
205.5. MS (m/z, %): 680 (M?, 8), 678 (10), 606 (25), 577
(75), 565 (58), 551 (100), 537 (67), 523 (54), 500 (58).
Anal. Calcd for C40H40O10: C, 70.57; H, 5.92; O, 23.50.
Found: C, 70.47; H, 5.83; O, 23.40.
Materials
Melting points were measured on an Electrothermal 9200
apparatus. Mass spectra were recorded on a Shimadzu
GCMS-QP1100EX mass spectrometer operating at an
ionization potential of 70 eV. IR spectra were recorded on
1
a Shimadzu IR-470 spectrometer. H NMR spectra were
recorded on a Bruker DRX-300 Avance spectrometer
300.13 MHz; chemical shifts (d scale) are reported in parts
per million (ppm). H NMR spectra are reported in order:
1
Typical procedure for the synthesis of 4,9-dio-tolyl-3,4,8,9-
tetrahydropyrano[2,3-g]chromene-2,5,7,10-tetraone (19b) To
a magnetically stirred solution of 2-hydroxynaphthalene-
1,4-dione (0.17 g, 1.0 mmol), 4-methylbenzaldehyde
(0.24 g, 2.0 mmol), Meldrum’s acid (0.28 g, 2.0 mmol)
and L-proline (10 mol %) in refluxing water (5 ml) was
stirred for 4 h (the progress of the reaction was monitored
by TLC). After completion, the reaction mixture was fil-
tered and washed with 5 mL of n-hexane. The desired
product was obtained as a yellow powder. m.p. 300 °C. IR
(KBr) (cm-1): 2,938, 1,792, 1,673, 1,633. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 2.32 (6H, s, 2CH3),
number of protons, multiplicity and approximate coupling
constant (J value) in hertz (Hz); signals were characterized
as s (singlet), d (doublet), t (triplet), m (multiplet), br s
(broad signal) and Ar (aryl). The 13C NMR spectra were
recorded at 75.47 MHz; chemical shifts (d scale) are
reported in parts per million (ppm). The elemental analyses
were performed with an Elementar Analysensysteme
GmbH VarioEL. All the products are new compounds
(except 8a–f and 19a–e), which were characterized by IR,
1H NMR and 13C NMR spectra and mass spectral data.
Typical procedure for the synthesis of 3,3-dimethyl-12-
phenyl-3,4-dihydro-1H-benzo[b]xanthene-1,6,11(2H,12H)-
trione (4a) A solution of 2-hydroxynaphthalene-1,4-dione
(0.17 g, 1.0 mmol), benzaldehyde (0.11 g, 1.0 mmol), 5,5-
dimethylcyclohexane-1,3-dione (0.14 g, 1.0 mmol) and
L-proline (10 mol %) in refluxing water (5 ml) was stirred
for 4 h (the progress of the reaction was monitored by
3
2.87–3.06 (4H, m, CH2), 4.67 (2H, t, J = 8 Hz, 2CH),
7.02–7.40 (8H, m, H–Ar). 13C NMR (75 MHz, DMSO-
d6): dC (ppm) 18.0 (CH3), 29.7 (CH2), 32.1 (CH), 106.1,
118.1, 119.5, 120.2, 126.3, 126.5, 130.8, 131.3 (C-alkene
and aromatic), 157.1, 181.4 (C=O). MS (m/z, %): 430
(M?2, 11), 386 (4), 368 (7), 257 (25), 236 (21), 196 (11),
123

J IRAN CHEM SOC
149 (61), 83 (65), 69 (86), 57 (96), 43 (100). Anal. Calcd
for C26H20O6: C, 72.89; H, 4.71. Found: C, 72.79; H, 4.70.
3,3-Dimethyl-12-(4-nitrophenyl)-3,4-dihydro-1H-benzo[b]
xanthene-1,6,11(2H,12H)-trione (4e) Yellow powder.
m.p. 238–240 °C; IR (KBr) (mmax/cm-1): 3,432, 3,075,
2,960, 2,866, 1,664, 1,606, 1,518, 1,348. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 0.90 (3H, s, CH3), 1.03
(3H, s, CH3), 2.10–2.70 (4H, m, 2CH2), 4.96 (1H, s, CH),
7.00–8.10 (8H, m, H–Ar). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 27.0, 28.8, 32.8, 33.3, 50.3, 122.8, 123.7, 126.3,
126.5, 130.6, 131.0, 131.4, 134.7, 135.1, 146.7, 150.0,
150.6, 163.9, 177.4, 196.4. MS (m/z, %): 429 (M?, 25), 412
(30), 382 (25), 348 (15), 307 (60), 273 (80), 251 (60), 213
(40), 195 (25), 165 (25), 139 (85), 105 (25), 76 (70), 41
(100). Anal. Calcd for C25H19NO6: C, 69.92; H, 4.46; N,
3.26. Found: C, 69.87; H, 4.38; N, 3.19.
3,3-Dimethyl-12-phenyl-3,4-dihydro-1H-benzo[b]xanthene-
1,6,11(2H,12H)-trione (4a) Yellow powder. m.p.
228–230 °C; IR (KBr) (mmax/cm-1): 3,451, 3,075, 2,956,
2,861, 1,664, 1,618, 1,586, 1,461, 1,366. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 0.95 (3H, s, CH3), 1.06
(3H, s, CH3), 2.10–2.50 (4H, m, 2CH2), 4.89 (1H, s, CH),
7.00–8.10 (9H, m, H–Ar); MS (m/z, %): 384 (M?, 80), 327
(10), 307 (65), 273 (30), 251 (45), 215 (50), 139 (70), 105
(30), 77 (100), 41 (70). Anal. Calcd for C25H20O4: C,
78.11; H, 5.24. Found: C, 78.08; H, 5.14.
3,3-Dimethyl-12-p-tolyl-3,4-dihydro-1H-benzo[b]xanthene-
1,6,11(2H,12H)-trione (4b) Brown powder. m.p.
170–172 °C. IR (KBr) (mmax/cm-1): 3,435, 3,070, 2,958,
2,866, 1,732, 1,675, 1,590, 1,464, 1,372. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 0.94–1.26 (9H, m,
3CH3), 2.00–2.50 (4H, m, 2CH2), 4.29 (1H, s, CH),
6.90–8.10 (8H, m, H–Ar). MS (m/z, %): 398 (M?, 1), 349
(1), 330 (1), 308 (1), 192 (10), 174 (50), 146 (20), 105
(100), 77 (60), 41 (70). Anal. Calcd for C26H22O4: C,
78.37; H, 5.57. Found: C, 78.30; H, 5.47.
12-(4-Chlorophenyl)-3,3-dimethyl-3,4-dihydro-1H-benzo
[b]xanthene-1,6,11(2H,12H)-trione (4f) Pink powder.
m.p. 225–227 °C; IR (KBr) (mmax/cm-1): 3,391, 2,965,
1
2,835, 1,716, 1,641, 1,611. H NMR (300 MHz, DMSO-
d6): dH (ppm) 0.94 (3H, s, CH3), 1.07 (3H, s, CH3),
2.00–2.50 (4H, m, 2CH2), 4.88 (1H, s, CH), 7.00–8.10 (8H,
m, H–Ar). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 27.0,
28.9, 32.3, 33.5, 50.4, 113.3, 114.4, 123.6, 126.3, 126.5,
128.3, 128.6, 130.4, 131.0, 131.5, 131.9, 134.7, 135.1,
142.2, 163.6, 177.5, 196.5, 196.6. MS (m/z, %): 420 (M?,
37Cl, 20), 418 (M?, 35Cl, 60), 383 (20), 327 (10), 307 (75),
271 (25), 251 (70), 215 (50), 195 (25), 176 (25), 139 (100),
111 (65), 76 (80), 71 (80). Anal. Calcd for C25H19ClO4: C,
71.69; H, 4.57. Found: C, 71.59; H, 4.47.
12-(2-Hydroxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-benzo
[b]xanthene-1,6,11(2H,12H)-trione (4c) Yellow powder.
m.p. 237–239 °C. IR (KBr) (mmax/cm-1): 3,430, 3,188,
1
2,953, 2,866, 1,677, 1,635, 1,580, 1,490, 1,369. H NMR
(300 MHz, DMSO-d6): dH (ppm) 0.96 (3H, s, CH3), 1.05
(3H, s, CH3), 2.16 (2H, ABq, J = 16.0, CH2), 2.50 (2H,
ABq, J = 17.4, CH2), 5.34 (1H, s, CH), 6.90–8.10 (8H, m,
H–Ar), 11.35 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 26.6, 26.8, 32.2, 50.6, 110.1, 116.4, 125.2, 126.1,
128.3, 129.2, 130.2, 132.1, 133.7, 135.2, 149.8, 155.3,
166.0, 181.9, 183.8, 196.5. MS (m/z, %): 400 (M?, 10), 316
(65), 282 (30), 244 (10), 277 (100), 211 (40), 171 (70), 152
(10), 115 (80), 77 (50), 41 (40). Anal. Calcd for C25H20O5:
C, 74.99; H, 5.03. Found: C, 74.89; H, 5.00.
12-Phenyl-3,4-dihydro-1H-benzo[b]xanthene-1,6,11(2H,
12H)-trione (4g) Yellow powder. m.p. 234–236 °C; IR
(KBr) (mmax/cm-1): 3,446, 3,033, 2,948, 2,882, 1,664,
1
1,618, 1,586, 1,456, 1,368. H NMR (300 MHz, DMSO-
d6): dH (ppm) 1.50–2.70 (6H, m, 3CH2), 4.91 (1H, s, CH),
7.00–8.10 (9H, m, H–Ar). MS (m/z, %): 356 (M?, 60), 299
(8), 280 (25), 279 (100), 215 (27), 189 (10), 165 (20), 139
(40), 104 (20), 77 (60), 51 (40). Anal. Calcd for C23H16O4:
C, 77.52; H, 4.53. Found: C, 77.48; H, 4.43.
3,3-Dimethyl-12-(3-nitrophenyl)-3,4-dihydro-1H-benzo[b]
xanthene-1,6,11(2H,12H)-trione (4d) Brown powder.
m.p. 231–233 °C; IR (KBr) (mmax/cm-1): 3,348, 3,082,
3,3,10,10-Tetramethyl-7,14-diphenyl-3,4,10,11-tetrahydro-
chromeno[2,3-b]xanthene-1,6,8,13(2H,7H,9H,14H)-tetraone
(6a) Orange powder. m.p. 228–230 °C; IR (KBr) (mmax
/
1
2,961, 2,870, 1,668, 1,587, 1,526, 1,467, 1,349. H NMR
cm-1): 3,392, 2,971, 2,851, 1,720, 1,642, 1,615; H NMR
(300 MHz, DMSO-d6): dH (ppm) 0.86 (6H, bs, 2CH3), 0.99
(6H, bs, 2CH3), 2.13 (4H, bs, 2CH2), 2.25 (4H, bs, 2CH2),
5.70 (H, s, CH), 6.03 (H, s, CH), 6.84–7.17 (10H, m, H–
Ar). Anal. Calcd for C36H32O6: C, 77.12; H, 5.75. Found:
C, 77.04; H, 5.65.
1
(300 MHz, DMSO-d6): dH (ppm) 0.93 (3H, s, CH3), 1.07
(3H, s, CH3), 2.10–2.50 (4H, m, 2CH2), 6.09 (1H, s, CH),
7.00–8.20 (8H, m, H–Ar). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 26.6, 28.6, 32.2, 33.1, 50.2, 109.6, 112.8, 113.4,
117.3, 121.0, 122.2, 122.8, 123.8, 126.4, 129.8, 131.0,
131.4, 134.4, 134.7, 135.8, 148.0, (158.1, 158.6, 159.1,
159.6, CF3), 163.8, 175.4, (183.2), 196.3. MS (m/z, %): 429
(M?, 2), 412 (10), 395 (4), 378 (60), 348 (25), 307 (10),
273 (75), 217 (30), 161 (40), 105 (65), 77 (60), 41 (100).
Anal. Calcd for C25H19NO6: C, 69.92; H, 4.46; N, 3.26.
Found: C, 69.90; H, 4.36; N, 3.20.
7,14-Bis(2,4-dimethoxyphenyl)-3,3,10,10-tetramethyl-3,4,
10,11-tetrahydrochromeno[2,3-b]xanthene-1,6,8,13(2H,7H,
9H,14H)-tetraone (6b) Orange powder (yield 65 %). m.p.
189–191 °C; IR (KBr) (mmax/cm-1): 3,390, 2,969, 2,838,
1
1,716, 1,639, 1,603. H NMR (300 MHz, DMSO-d6): dH
123

J IRAN CHEM SOC
(ppm) 1.08 (12H, br s, 4CH3), 1.99–2.22 (8H, m, 4CH2),
2.98 (1H, s, CH), 3.5 (12H, br s, 4OMe), 4.42 (2H, s, 2CH),
6.28–6.76 (6H, m, H–Ar). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 27.0, 27.6, 28.1, 29.9, 31.7, 32.6, 33.1, 40.7, 42.7,
49.2, 50.9, 53.3, 55.4, 55.7, 97.9, 101.6, 104.0, 110.0,
115.6, 123.8, 129.9, 157.2, 158.7, 162.4, 167.2, 196.0,
205.5. MS (m/z, %): 680 (M?, 8), 678 (10), 606 (25), 577
(75), 565 (58), 551 (100), 537 (67), 523 (54), 500 (58).
Anal. Calcd for C40H40O10: C, 70.57; H, 5.92; O, 23.50.
Found: C, 70.47; H, 5.83; O, 23.40.
7,14-Bis(4-chlorophenyl)-3,4,10,11-tetrahydrochromeno
[2,3-b]xanthene-1,6,8,13(2H,7H,9H,14H)-tetraone (6g) Dark
powder. m.p.[290 °C; IR (KBr) (mmax/cm-1): 3,436, 2,945,
1
2,913, 2,877, 1,664, 1,529, 1,487, 1,441, 1,360. H NMR
(300 MHz, DMSO-d6): dH (ppm) 1.80–2.00 (4H, m, 2CH2),
2.26 (4H, m, 2CH2), 2.64 (4H, m, 2CH2), 4.54 (2H, s, 2CH),
7.00–7.30 (8H, m, H–Ar). MS (m/z, %): 328 (M?-244, 20),
293 (25), 217 (100), 152 (5), 111 (5), 55 (20). Anal. Calcd
for C32H22Cl2O6: C, 67.03; H, 3.87. Found: C, 67.03;
H, 3.77.
7,14-Bis(5-bromo-2-hydroxyphenyl)-3,3,10,10-tetramethyl-
3,4,10,11-tetrahydrochromeno[2,3-b]xanthene-1,6,8,13(2H,
7H,9H,14H)-tetraone (6c) Orange powder. m.p.[260 °C;
IR (KBr) (mmax/cm-1): 3,389, 2,962, 2,846, 1,721, 1,642,
1,612; 1H NMR (300 MHz, DMSO-d6): dH (ppm) 1.02
(12H, bs, 4CH3), 2.94 (8H, m, 4CH2), 5.00 (2H, s, 2CH),
6.90–725 (8H, m, H–Ar and 2OH). Anal. Calcd for
C36H30Br2O8: C, 57.62; H, 4.03. Found: C, 57.55; H, 3.93.
4-(3-Methoxyphenyl)-3,4-dihydro-2H-benzo[g]chromene-
2,5,10-trione (8a) Yellow powder. m.p. 191–192 °C; IR
1
(KBr) (cm-1): 2,990, 2,933, 1,792, 1,645, 1,582. H NMR
(300 MHz, DMSO-d6): dH (ppm) 2.89 (2H, bs, CH2), 3.70
(3H, s, OCH3), 4.55 (1H, bs, CH), 6.84–8.08 (8H, m, H–
Ar). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 34.9 (CH2),
36.2 (CH), 55.1 (OCH3), 113.1, 113.5, 119.2, 125.1, 126.4,
126.6, 130.6, 131.5, 134.7, 134.9, 141.5, 152.6, 160.1 (C-
alkene and aromatic), 165.9, 177.5, 183.2 (3C=O). MS (m/
z, %): 334 (M?, 100), 306 (40), 291 (14), 227 (38), 263
(27), 247 (20), 237 (19), 165 (18), 134 (35), 104 (32), 57
(40). Anal. Calcd for C20H14O5: C, 71.85; H, 4.22; Found:
C, 71.72; H, 4.19.
3,3,10,10-Tetramethyl-7,14-bis(3-nitrophenyl)-3,4,10,11-
tetrahydrochromeno[2,3-b]xanthene-1,6,8,13(2H,7H,9H,
14H)-tetraone (6d) Orange powder. m.p. [260 °C; IR
(KBr) (mmax/cm-1): 3,392, 2,966, 2,838, 1,718, 1,642,
1,612; 1H NMR (300 MHz, DMSO-d6): dH (ppm) 1.03
(12H, bs, 4CH3), 2.29 (8H, bs, 4CH2), 5.72 (2H, s, 2CH),
7.49–7.98 (8H, m, H–Ar); Anal. Calcd for C36H30N2O10:
C, 66.46; H, 4.65; N, 4.31. Found: C, 66.46; H, 4.55; N,
4.22.
4-(4-Methoxyphenyl)-3,4-dihydro-2H-benzo[g]chromene-
2,5,10-trione (8b) Yellow powder. m.p. 191–192 °C; IR
1
(KBr) (cm-1): 2,993, 2,930, 1,792, 1,648, 1,583. H NMR
(300 MHz, DMSO-d6): dH (ppm) 2.85 (1H, d,
2
2JHH = 15 Hz, CH2), 3.36 (1H, dd, JHH = 15 Hz,
3,3,10,10-Tetramethyl-7,14-bis(4-nitrophenyl)-3,4,10,11-
tetrahydrochromeno[2,3-b]xanthene-1,6,8,13(2H,7H,9H,14H)-
tetraone (6e) Brown powder. m.p. [260 °C; IR (KBr)
(mmax/cm-1): 3,316, 3,112, 3,075, 2,960, 2,874, 1,671,
3JHH = 7 Hz, CH2), 3.70 (3H, s, OCH3), 4.53 (1H, d,
3
3JHH = 7 Hz, CH), 6.86 (2H, d, JHH = 8.5 Hz, H–Ar),
7.21 (2H, d, 3JHH = 8.5 Hz, H–Ar), 7.82–8.11 (4H, m, H–
Ar). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 34.1 (CH2),
36.4 (CH), 55.5 (OCH3), 114.8, 125.7, 126.4, 126.6, 128.5,
131.4, 131.5, 131.7, 134.8, 135.0, 152.3, 159.0 (C-alkene
and aromatic), 166.1, 177.6, 183.2 (3C=O). Anal. Calcd for
C20H14O5: C, 71.85; H, 4.22; Found: C, 71.91; H, 4.26.
1
1,601, 1,522, 1,462, 1,350. H NMR (300 MHz, DMSO-
d6): dH (ppm) 0.89 (6H, s, 2CH3), 1.02 (6H, s, 2CH3), 2.17
(4H, ABq, J = 16.0, 2CH2), 2.55 (4H, ABq, J = 14.4,
2CH2), 4.62 (2H, s, 2CH), 7.40–7.80 (8H, H–Ar); 13C
NMR (75 MHz, DMSO-d6): dC (ppm) 27.0, 29.0, 32.3,
50.3, 113.8, 123.6, 124.7, 130.0, 131.1, 146.4, 152.3,
163.9, 196.5. MS (m/z, %): 395 (M?-255, 5), 378 (8), 348
(5), 273 (100), 217 (30), 178 (5), 161 (30), 133 (15), 115
(10), 77 (30), 55 (65). Anal. Calcd for C36H30N2O10: C,
66.46; H, 4.65; N, 4.31. Found: C, 66.36; H, 4.61; N, 4.31.
4-(4-Hydroxyphenyl)-3,4-dihydro-2H-benzo[g]chromene-
2,5,10-trione (8c) Yellow powder. m.p. 246–248 °C; IR
(KBr) (cm-1): 3,442, 3,095, 1,787, 1,666, 1,645, 1,603,
1,519. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 2.85
(1H, d, 2JHH = 16 Hz, CH2), 3.29–3.36 (1H, m, CH2), 4.47
3
(1H, d, JHH = 6.32 Hz, CH), 6.68–8.01 (8H, m, aro-
7,14-Diphenyl-3,4,10,11-tetrahydrochromeno[2,3-b]xanthene-
1,6,8,13(2H,7H,9H,14H)-tetraone (6f) Dark brown pow-
der. m.p. 262–264 °C; IR (KBr) (mmax/cm-1): 3,435, 2,946,
2,877, 1,659, 1,615, 1,494, 1,454. 1H NMR (300 MHz,
DMSO-d6): dH (ppm) 1.00–2.50 (12H, m, 6CH2), 4.48 (2H,
s, 2CH), 7.00–8.00 (10H, m, H–Ar). MS (m/z, %): 504
(M?, 1), 429 (1), 294 (25), 217 (100), 152 (8), 115 (8), 77
(25), 55 (25). Anal. Calcd for C32H24O6: C, 76.18; H, 4.79.
Found: C, 66.18; H, 4.70.
matic), 9.48 (1H, bs, OH). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 34.11 (CH2), 36.46 (CH), 116.1, 125.9, 126.4,
126.5, 128.4, 129.9, 131.3, 131.4, 134.7, 135.0, 152.1,
157.1 (C-alkene and H–Ar), 166.1, 177.5, 183.1 (3C=O).
MS (m/z, %): 320 (M?, 83), 292 (100), 263 (77), 249 (35),
222 (11), 165 (27), 120 (19), 104 (31), 76 (40), 50 (15).
Anal. Calcd for C19H12O5: C, 71.25; H, 3.78; Found: C,
71.31; H, 3.70.
123

J IRAN CHEM SOC
4-(2-Hydroxyphenyl)-3,4-dihydro-2H-benzo[g]chromene-
2,5,10-trione (8d) Yellow powder. m.p. 208–209 °C; IR
(300 MHz, DMSO-d6): dH (ppm) 2.32 (6H, s, 2CH3),
2.87–3.06 (4H, m, CH2), 4.67 (2H, t, J = 8 Hz, 2CH),
3
(KBr) (cm-1): 3,448, 3,195, 1,757, 1,677, 1,635. H NMR
7.02–7.40 (8H, m, H–Ar). 13C NMR (75 MHz, DMSO-d6):
dC (ppm) 18.0 (CH3), 29.7 (CH2), 32.1 (CH), 106.1, 118.1,
119.5, 120.2, 126.3, 126.5, 130.8, 131.3 (C-alkene and
aromatic), 157.1, 181.4 (C=O). MS (m/z, %): 430 (M?2,
11), 386 (4), 368 (7), 257 (25), 236 (21), 196 (11), 149
(61), 83 (65), 69 (86), 57 (96), 43 (100). Anal. Calcd for
C26H20O6: C, 72.89; H, 4.71. Found: C, 72.79; H, 4.70.
1
(300 MHz, DMSO-d6): dH (ppm) 2.49–2.96 (1H, m, CH2),
3.12–3.20 (1H, m, CH2), 4.85 (1H, bs, CH), 7.03–7.99 (8H,
m, H–Ar), 11.71 (1H, bs, OH). 13C NMR (75 MHz,
DMSO-d6): dC (ppm) 29.7 (CH2), 32.4 (CH), 116.8, 123.5,
124.5, 126.1, 126.3, 128.5, 130.4, 132.2, 133.7, 135.1,
151.6, 156.6 (C-alkene and aromatic), 167.1, 181.4, 184.3
(3C=O). Anal. Calcd for C19H12O5: C, 71.25; H, 3.78;
Found: C, 71.31; H, 3.69.
4,9-Bis(3-bromophenyl)-3,4,8,9-tetrahydropyrano[2,3-g]
chromene-2,5,7,10-tetraone (19c) Brown powder. m.p.
193–196 °C; IR (KBr) (cm-1): 3,059, 2,985, 2,922, 2,854,
4-(2-Hydroxy-3-methoxyphenyl)-3,4-dihydro-2H-benzo[g]
chromene-2,5,10-trione (8e) Yellow powder. m.p.
252–254 °C; IR (KBr) (cm-1): 3,357, 3,012, 2,922, 1,761,
1
1,723, 1,640, 1,566; H NMR (300 MHz, DMSO-d6): dH
(ppm) 2.07 (2H, bs, 2CH2), 2.88 (2H, bs, 2CH2), 4.49 (2H,
bs, CH), 7.26–7.44 (8H, m, H–Ar). Anal. Calcd for
C24H14Br2O6: C, 51.64; H, 2.53; Found: C, 51.54; H, 2.62.
1
1,649, 1,587. H NMR (300 MHz, DMSO-d6): dH (ppm)
2.92 (1H, dd, 2JHH = 16.0 Hz, 3JHH = 8.45 Hz CH2), 3.15
2
3
(1H, dd, JHH = 16 Hz, JHH = 8.45 Hz, CH2), 3.81 (3H,
s, OCH3), 4.83 (1H, dd, 3JHH = 8.45 Hz, 3JHH = 8.45 Hz,
CH), 6.69–7.99 (7H, m, H–Ar), 11.60 (1H, bs, OH). 13C
NMR (75 MHz, DMSO-d6): dC (ppm) 29.9 (CH2), 32.3
(CH), 56.1 (OCH3), 111.3, 119.7, 123.5, 124.1, 124.2,
126.2, 126.3, 130.4, 132.2, 133.7, 135.1, 140.8, 147.4,
156.5 (C-alkene and aromatic), 166.8, 181.4, 184.3
(3C=O). Anal. Calcd for C20H14O6: C, 68.57; H, 4.03;
Found: C, 68.48; H, 4.15.
4,9-Bis(2-hydroxy-3-methoxyphenyl)-3,4,8,9-tetrahydropyr-
ano[2,3-g]chromene-2,5,7,10-tetraone (19d) Pink powder.
m.p. 193 °C; IR (KBr) (cm-1): 3,427, 2,927, 2,854, 1,747,
1
1,645, 1,540; H NMR (300 MHz, DMSO-d6): dH (ppm)
2
3
2.66 (2H, dd, JHH = 16.35 HZ, JHH = 4 Hz, CH2),
2
2.88 (2H, t, JHH = 8 Hz, CH2), 4.50 (2H, bs, CH),
6.61–6.95 Hz (6H, m, H–Ar), 11.60 (1H, bs, OH). Anal.
Calcd for C26H20O10: C, 63.42; H, 4.09; Found: C, 63.51;
H, 4.14.
4-(5-Bromo-2-hydroxyphenyl)-3,4-dihydro-2H-benzo[g]
chromene-2,5,10-trione (8f) Yellow powder. m.p.
279–281 °C; IR (KBr) (cm-1): 3,345, 2,927, 2,859, 1,781,
1,651. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
2.91–2.96 (1H, m, CH2), 3.09–3.33 (1H, m, CH2), 4.84
(1H, bs, CH), 7.24–7.97 (7H, m, H–Ar), 11.65 (1H, bs,
OH). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 29.7
(CH2), 32.1 (CH), 116.1, 119.1, 122.4, 126.2, 126.3, 130.7,
130.9, 131.3, 132.4, 133.7, 134.9, 151.0, 157.1 (C-alkene
and aromatic), 166.7, 181.4, 184.3 (3C=O). MS (m/z, %):
399 (M?, 81Br, 10), 397 (M?, 79Br, 10), 396 (25), 388 (12),
386 (98), 371 (46), 368 (89), 353 (50), 351 (22), 343 (15),
341 (100). Anal. Calcd for C19H11BrO5: C, 57.17; H, 2.78;
Found: C, 57.32; H, 2.83.
4,9-Bis(5-bromo-2-hydroxyphenyl)-3,4,8,9-tetrahydropyr-
ano[2,3-g]chromene-2,5,7,10-tetraone (19e) Brown pow-
der. m.p. 332–334 °C. IR (KBr) (cm-1): 3,253, 2,912, 1,760,
1
1,623, 1,427. H NMR (300 MHz, DMSO-d6): dH (ppm)
2.87 (2H, bs, CH2), 3.08 (2H, bs, CH2), 4.59 (2H, bs, CH),
7.01–7.41 (6H, m, H–Ar), 11.55 (1H, bs, OH). MS (m/z, %):
588 (M?, 9), 580 (32), 577 (44), 565 (50), 262 (25), 551
(100), 548 (36), 537 (90), 534 (14), 523 (82), 521 (34), 368
(25), 326 (35), 85 (100), 57 (80). Anal. Calcd for
C24H14Br2O8: C, 48.84; H, 2.39; Found: C, 48.70; H, 2.45.
Product 21a Brownish powder. m.p. 217–219 °C. IR
1
(KBr) (cm-1): 3,443, 1,683, 1,634, 1,600, 1,573. H NMR
(300 MHz, DMSO-d6): dH (ppm) 3.47 (3H, s, OCH3), 6.22
(1H, s, CH), 6.75–7.95 (8H, m, H–Ar), 9.90 (1H, s, NH),
9.95 (1H, s, NH). 13CNMR (75 MHz, DMSO-d6): dH
(ppm) 29.3 (CH), 55.7 (OCH3), 88.4, 111.2, 119.8, 125.5,
126.1, 126.6, 129.5, 131.3, 132.0, 132.3, 133.2, 133.7,
134.2, 151.5, 157.6, 165.5, 184.3, 184.8. Anal. Calcd for
C22H14N2O6: C, 65.67; H, 3.51; N, 6.96; Found: C, 65.60;
H, 3.53; N, 6.89.
4,9-Bis(2,4-dimethoxyphenyl)-3,4,8,9-tetrahydropyrano
[2,3-g]chromene-2,5,7,10-tetraone (19a) Brown powder.
m.p. 180 °C; IR (KBr) (cm-1): 3,343, 3,001, 2,938, 2,838,
1
1,792, 1,650, 1,608, 1,588; H NMR (300 MHz, DMSO-
d6): dH (ppm) 2.94 (4H, bs, 2CH2), 3.54–3.92 (14H, m,
2CH and 4OMe), 6.01–7.28 (6H, m, H–Ar). Anal. Calcd
for C28H24O10: C, 57.17; H, 2.78; Found: C, 57.32; H, 2.83.
Anal. Calcd for C28H24O10: C, 64.61; H, 4.65; Found: C,
64.61; H, 4.55.
Product 21b Brownish powder. m.p. 198–200 °C. IR
1
(KBr) (cm-1): 3,409, 1,737, 1,695, 1,654, 1,617. H NMR
(300 MHz, DMSO-d6): dH (ppm) 6.07 (1H, s, CH),
7.24–8.81 (8H, m, H–Ar), 11.25 (1H, s, NH), 11.50 (1H, s,
NH). 13CNMR (75 MHz, DMSO-d6): dH (ppm) 29.2 (CH),
4,9-Dio-tolyl-3,4,8,9-tetrahydropyrano[2,3-g]chromene-2,5,
7,10-tetraone (19b) Yellow powder. m.p. 300 °C. IR
(KBr) (cm-1): 2,938, 1,792, 1,673, 1,633. 1H NMR
123

J IRAN CHEM SOC
90.8, 120.9, 123.6, 124.5, 126.5, 130.6, 130.8, 131.1,
132.1, 134.2, 138.0, 146.7, 150.7, 151.2, 152.9, 161.6,
162.8, 164.7. Anal. Calcd for C21H11N3O7: C, 60.44; H,
2.66; N, 10.07; Found: C, 60.48; H, 2.57; N, 10.11.
considering environmental aspects, H2O has been chosen
as a green solvent for the synthesis.
The effect of L-proline derivatives as catalysts in the
reaction has been investigated (Table 2). As indicated in
Table 2, the reaction could be progressed very efficiently in
the presence of a catalytic amount of L-proline in water.
In a pilot experiment, reaction between a mixture of 2-hy-
droxynaphthalene-1,4-dione 1, aldehydes 2, 5,5-dimethylcy-
clohexane-1,3-dione or cyclohexane-1,3-dione 3 in the
presence of a catalytic amount of L-proline as an inexpensive
and readily available catalyst proceeded smoothly in water
under reflux conditions for 2 h (Scheme 2). After completion
of the reaction (monitored by TLC), the reaction mixture was
filtered and the obtained precipitate was washed with water
and crystallized from EtOH/H2O (v:v = 1:3) to afford pure
2H-benzo[b]xanthene-triones 4a–g.
Product 21c Brownish red powder. m.p. 221–223 °C. IR
(KBr) (cm-1): 3,437, 1,686, 1,606, 1,468. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 6.42 (1H, s, CH),
7.13–8.00 (8H, m, H–Ar), 9.37 (1H, s, NH), 10.81 (1H, s,
NH). Anal. Calcd for C21H11ClN2O5: C, 62.01; H, 2.73; N,
6.89; Found: C, 62.14; H, 2.70; N, 6.81.
Product 21d Red powder. m.p. 217–219 °C. IR (KBr)
(cm-1): 3,569, 3,474, 1,698, 1,614, 1,572. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 4.91 (1H, bs, CH),
7.16–8.60 (7H, m, H–Ar), 10.94 (1H, s, NH), 11.21 (2H, s,
NH and OH). Anal. Calcd for C21H11BrN2O6: C, 53.98; H,
2.37; N, 6.00; Found: C, 53.91; H, 2.30; N, 6.12.
To explore the scope and limitations of this reaction,
various aldehydes with electron withdrawing and elec-
tron donating groups were employed under similar cir-
cumstances and the results have been shown in Fig. 2.
These reactions proceeded very cleanly under mild
reaction conditions and no undesirable side reactions
were observed.
Result and discussion
In view of our present study [54–60], and because of high
importance of pyrimidine-2,4-dione-, benzo[g]- and dihy-
dropyrano[2,3-g]chromene from pharmacological and
biological point of view, we wish to introduce a synthetic
method for the synthesis of these groups of compounds via
Michael addition of 2-hydroxy-1,4-naphthoquinone or 2,5-
dihydroxy-1,4-benzoquinone to the Knoevenagel conden-
sation product of an aldehyde with Meldrum’s acid,
dimedone or barbituric acid in the presence of a catalytic
amount of L-proline (10 mol %) under refluxing condi-
tions in water in good to excellent yields (Scheme 1).
The procedure is very simple and clean. Products are
separated from the reaction media with a simple filtration
and no more purification is needed. H2O use as a green
solvent increases the environment-friendly aspects of the
reaction.
To extend the chemical library, 2,5-dihydroxycyclo-
hexa-2,5-diene-1,4-dione 5 has been used instead of com-
pound 1. The reactions proceed efficiently and led to the
formation of the desired products 6a–g by a pathway
similar to the previously mentioned pathway (Scheme 3).
The results shown in Fig. 3 clearly indicate the scope and
limitations of the reaction.
In order to investigate the scope and limitations of this
reaction further, we decided to extend it to Meldrum’s acid
7 instead of 5,5-dimethylcyclohexane-1,3-dione or cyclo-
hexane-1,3-dione 3. In a pilot experiment (Scheme 4), a
mixture of 3-methoxybenzaldehyde 2 and Meldrum’s acid
7 in EtOH was stirred in the presence of a catalytic amount
of L-proline at room temperature for 1 h, then 2-hydroxy-
1,4-naphthoquinone 1 was added to the reaction mixture.
After completion of the reaction (after 24 h, monitored by
TLC), the precipitated product was separated from the
The effect of solvents in the reaction has been investi-
gated (Table 1). As indicated in Table 1, the reaction could
be progressed very efficiently in H2O and EtOH; by
R5
Scheme 1 Synthesis of
pyrimidine-2,4-dione-,
R4
benzo[g]-, and dihydropyrano
[2,3-g]chromene derivatives
R3
O
O
O
O
CHO
R5
R2
R2
R3
+
OH
O
2
O
O
X
X
L-proline (10 mol %)
2
+
R2
X
X
X
H2O, Reflux
4 h
R4
HO
X
O
R2
R2 R2
O
O
R3
R4
R5
123

J IRAN CHEM SOC
reaction mixture by filtration and washed with n-hexane
(5 mL) to afford product 8a in 78 % yield (Fig. 4).
As indicated in Fig. 4, various aldehydes with electron
withdrawing and electron donating groups have been used.
The reactions are very efficient and the corresponding
functionalized products could be obtained with good yields
under mild reaction conditions.
Table 1 Effect of solvents
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
PhCH3
CH2Cl2
CH3CN
EtOH
2
2
2
2
2
25
32
40
70
70
H2O
Although the mechanism of the reaction has not been
studied experimentally, at first, the initial formation of
iminium ion 10 in a reversible reaction between aldehydes
2 and L-proline 9 could be assumed, which finally lead to
the intermediate 13 after attack of Meldrum’s acid or
intermediate 14 through the attack of 5,5-dimethylcyclo-
hexane-1,3-dione or cyclohexane-1,3-dione. Then, 13 or 14
is attacked via a Michael-type addition reaction by the
2-hydroxynaphthalene-1,4-dione 1, which leads to the
intermediate 15 or 16, respectively. In the case of inter-
mediate 15, an intramolecular cyclization reaction gener-
ates intermediate 17, which undergoes decarboxylation and
tautomerization under the reaction conditions to produce
the fused heterocyclic systems 8a–f. Intermediate 16 could
be converted to the appropriate products 4a–g via intra-
molecular cyclization (Scheme 5) [45].
5,5-Dimethylcyclohexane-1,3-dione(1 mmol),benzaldehyde(1 mmol),
2-hydroxynaphthalene-1,4-dione (1 mmol) in the presence of L-proline
(10 mol %), under reflux conditions
Table 2 Effect of catalysts
Entry
Catalysts
Time (h)
Yield (%)
1
2
3
4
5
a
3,4-Dehydro-L-prolinea
4-Hydroxy-L-prolinea
L-Prolinea
2
2
25
32
70
–
2
L-Prolineb
24
24
–
–
5,5-Dimethylcyclohexane-1,3-dione (1 mmol), benzaldehyde (1 mmol),
2-hydroxynaphthalene-1,4-dione (1 mmol) in the presence of catalyst
(10 mol %), under reflux conditions in water
To extend the chemical library, 2,5-dihydroxy-1,4-
benzoquinone 5 has was instead of compound 1. As
b
Room temperature
Scheme 2 Synthesis of 2H-
benzo[b]xanthene-triones 4a–g
O
O
O
CHO
R2
R2
O
O
O
OH
L-proline (10 mol %)
+
+
H2O, Reflux
2 h
R1
R2 R2
O
O
1
3
2
R1
4a-g
65-75%
Fig. 2 The structure of 2H-
benzo[b]xanthene-triones 4a–g
NO2
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
4a
4c
4d
4b
Cl
NO2
O
O
O
O
O
O
O
O
O
O
O
O
4e
4f
4g
Product
Yield/%
4a 4b 4c 4d 4e 4f 4g
70 68 75 70 72 73 65
123

J IRAN CHEM SOC
R5
Scheme 3 Synthesis of
dodecahydrochromeno[2,3-b]
xanthene-1,6,8,13-tetraones
6a–g
R4
O
R3
O
O
CHO
R2
R2
R3
OH
O
O
O
L-proline (10 mol %)
+
R4
+
R2
R2
H2O, 4 h
HO
O
R2 R2
R5
O
O
O
R3
5
2
3
R4
R5
6a-g
65-70%
OMe
Fig. 3 The structure of
dodecahydrochromeno[2,3-b]
xanthene-1,6,8,13-tetraones
6a–g
Br
O2N
O
MeO
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OMe
O
O
O
O
O
6a
6b
6c
6d
OH
NO2
Cl
NO2
Br
OMe
O
O
O
O
O
O
O
O
O
O
O
O
O
O
6e
O
O
O
O
6f
6g
Cl
NO2
Product 6a 6b 6c 6d 6e 6f 6g
Yield/% 70 65 67 70 70 65 65
Scheme 4 Synthesis of the
products 8a–f
O
O
O
CHO
O
O
Z
O
O
OH
Z
L-proline (10 mol %)
H2O, 2 h
+
+
O
O
X
O
8a-f
2
7
1
Z = 2-H or 2-OH
X = 3-OMe, 4-OMe, 4-OH, 5-Br
X
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
O
OH
O
OH
O
8a
8b
8c
8e
8f
Br
8d
OMe
OMe
OMe
OH
Product 8a 8b 8c 8d 8e 8f
Yield/% 78 64 80 73 61 80
Fig. 4 Products 8a–f
123

J IRAN CHEM SOC
O
O
O
O
-
CO2
N+
O
O
O
or
R1
H
R2
R2
R1
H
7
3
10
2
-O2C
-O2C
or
O
O
O
N
N
N
H
9
OH
R1
O
R1
R2
R2
R2
H
H
R2
O
O
11
O
12
O
H O
R1
O
R1
O
O
O
R1
O
R1
O
O
O
O
or
O
-H2O
O
O
R2
R2
R2
R2
R2
R2
O
1
O
O
13
14
OH OH
16
4a-g
O
O
O
O
O
O
OH
Z
O
O
O
- CO2
H
- (CH3)2CO
O
O
H
O
18
O
O
Z
O
Z
15
17
X
X
X
tautomerization
O
O
O
Z
O
8a-f
X
Scheme 5 Proposed pathway for the formation of the products 4a–g and 8a–f
indicated in Fig. 5, the reactions proceed efficiently and led
to the formation of the desired products 19a–e.
and 2-hydroxy-1,4-naphthoquinone (Fig. 6). The product
of this procedure contains a pyrimidine-2,4-dione moiety
which introduces a variety of potential new biological
activities to the products. These potential pharmacological
activities merit further investigation. It is important to note
that some compounds which contain a pyrimidine-2,4-dione
The use of the barbituric acid in the proposed procedure
has also been investigated. In this case, similar to the
previous reactions, the desired product could be produced
via the reaction between barbituric acid 20, an aldehyde,
X
Fig. 5 Products 19a–e
O
Z
O
O
CHO
OH
O
2
O
O
O
Z
Z
+
L-Proline (10 mol %)
H2O, 4 h
2
+
O
O
HO
O
O
X
O
5
2
7
19a-e
OMe
X
Br
Br
O
MeO
MeO
O
O
O
O
O
O
O
HO
O
HO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OMe
O
OH
OH
Br
Br
OMe
OMe
19d
19e
19b
19c
19a
Product 19a 19b 19c 19d 19e
Yield/% 67 70 83 76 68
123

J IRAN CHEM SOC
Fig. 6 Products 21a–d
O
O
O
O
CHO
H
O
O
OH
+
O
N
O
Z
L-Proline (10 mol %)
H2O, 2 h
+
HN
NH
NH
X
O
O
Z
1
20
2
21a-d
X
O
O
O
H
N
H
N
O
O
H
O
O
NH
H
N
O
O
O
N
O
O
O
NH
NH
NH
O
O
NO2
O
OMe
O
O
OH
O
O
Br
21d
Cl
21b
21a
21c
Product 21a 21b 21c 21d
Yield/% 70 74 80 65
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