Application of cyclic-1,3-diketones in domino and multicomponent reactions: Facile route to highly functionalized chromeno[2,3-d]pyrimidinones and diazabenzo[b]fluorenones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2010.09.017

A facile and efficient protocol for the synthesis of chromeno[2,3-d] pyrimidinones and diazabenzo[b]fluorenones has been developed by one-pot three-component cyclocondensation of aldehydes, cyclic-1,3-diketones and 1,3-dimethylbarbituric acid in the presence of InCl₃ or P ₂O₅ under solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2010.09.017

Tetrahedron Letters 51 (2010) 5933–5936
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Application of cyclic-1,3-diketones in domino and multicomponent
reactions: facile route to highly functionalized chromeno[2,3-d]pyrimidinones
and diazabenzo[b]fluorenones under solvent-free conditions
⇑
Ram Kumar, Keshav Raghuvanshi, Rajiv K. Verma, Maya S. Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2010
Revised 3 September 2010
Accepted 6 September 2010
Available online 21 September 2010
A facile and efficient protocol for the synthesis of chromeno[2,3-d]pyrimidinones and diazabenzo[b]flu-
orenones has been developed by one-pot three-component cyclocondensation of aldehydes, cyclic-1,3-
diketones and 1,3-dimethylbarbituric acid in the presence of InCl3 or P2O5 under solvent-free conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Chromeno[2,3-d]pyrimidinones
Diazabenzo[b]fluorenones
InCl3
P2O5
Solvent-free conditions
The interesting and diverse biological activities1,2 of dihydro-
pyrimidinones (DHPMs) have been explored through the genera-
tion of libraries of compounds via microwave, solid-phase, and
fluorous-phase technologies.2 Chromene derivatives are widely
present in plants including edible vegetables and fruits,3 and are
promising compounds in the field of medicinal chemistry.4 Stealt-
hins isolated from Streptomyces ciridochromogenes as potent radical
scavengers are the first known members of natural benzo[b]fluore-
nones, a recently discovered class of metabolites.5,6 Recently,
anthracene derivatives have been synthesized and screened for
their antibacterial and antifungal activities.7 Diazaanthracene
derivatives8 have been utilized as dye-forming components for
copying methods, whereas polyazaanthracenes are useful precur-
sors for preparing bioluminescent substrates and light-emitting
components for organic light-emitting devices,9 and are utilized
as potential DNA intercalators.10
Multicomponent reactions (MCRs) being highly flexible,
selective, and convergent in nature have a significant part of today’s
arsenal of methods in organic synthesis.11 MCRs leading to
interesting heterocyclic scaffolds are useful for the construction of
diverse chemical libraries of ‘drug like’ molecules.12,13 The possibil-
ity of performing chemical reactions in the absence of solvent has
been receiving more attention now-a-days.14 The examples
reported14–16 demonstrate that solvent-free reactions are generally
faster giving higher selectivities and excellent yields. It is evident
from the recent literature that indium trichloride17 has invoked
enormous interest as a green and potential Lewis acid catalyst for
theconstructionof carbon–carbonand carbon–heteroatombonds,18
due to its air and water compatibility, good reactivity19 and remark-
able ability to suppress side reactions in acid sensitive substrates.
Phosphorous pentoxide is a mild, selective, and readily biodegrad-
able reagent, which has also been utilized widely in various organic
transformations.20–22 Recently, chromeno[2,3-d]pyrimidinones
have been synthesized by one-pot three-component condensation
of barbituric acids, aldehydes, and cyclohexane-1,3-diones in reflux-
ing ethanolin the presence of p-toluenesulfonic acid.23 However, the
above method suffers from drawbacks such as longer reaction time
(4–8 h) and the need for an acidic catalyst in high mole percentage.
As part of our ongoing research program on the development of new
protocols in heterocyclic synthesis,24 we report herein a one-pot
three-component synthesis25 of chromeno[2,3-d]pyrimidinones
(4) and 6,10-dihydro-5-oxa-6,8-diazabenzo[b]fluorene-7,9,11-tri-
ones (5) promoted by InCl3 or P2O5 under solvent-free conditions
(Scheme 1).
Initially, the three-component cyclocondensation of 4-bromo-
benzaldehyde (1.0 mmol), dimedone (1.0 mmol), and 1,3-dimeth-
ylbarbituric acid (1.2 mmol) as a model reaction was performed
in refluxing dichloromethane in the presence of different catalysts
such as CAN (30 mol %, 22 h), P2O5 (20 mol %, 14 h), and InCl3
(10 mol %, 8 h) separately, resulting the desired product 4 in 42%,
58%, and 72% yields, respectively. Further, to optimize the reaction
⇑
Corresponding author. Fax: +91 542 2368127.
E-mail address: mssinghbhu@yahoo.co.in (M.S. Singh).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.017

5934
R. Kumar et al. / Tetrahedron Letters 51 (2010) 5933–5936
O
R
O
desired product 4 in 52%, 83%, and 88% yields, respectively. The re-
sults show that under solvent-free condition the catalytic activities
of InCl3 and P2O5 increased significantly. Thus, InCl3 was found to
be a better choice than P2O5 and provides the desired products
exclusively in good yields and high purity.
O
+
O
Me
O
N
R'
N
O
O
R'
R' = H, CH3
R'
R'
2a
InCl3 or P2O5
Me
Me
4
N
A test reaction using 4-nitrobenzaldehyde (1.0 mmol), dime-
done (1.0 mmol), and 1,3-dimethylbarbituric acid (1.2 mmol) at
100 °C in the absence of solvent and catalyst was performed to
establish the real effectiveness of the catalyst. It was found that
only trace amount of the desired product was obtained even after
8 h of heating (Table 1, entry 1). After optimization, 10 mol % of
InCl3 and 20 mol % of P2O5 were found to be effective for the pro-
gress of the reaction. The effect of temperature was also studied
and the optimum temperature of the reaction was found to be
100 °C (Table 1). The best results were obtained when the reactions
were carried out with 10 mol % of InCl3 or 20 mol % of P2O5 at
100 °C (Table 1, entry 6). In this process P2O5 not only acts as pro-
moter but also as water scavenger, which plays an important role
in accelerating the reactions.
or
+
solvent-free,
100 0C
RCHO
or
N
O
O
O
O
N
R
Me
1
O
Me
O
3
N
O
O
Me
5
2b
Scheme 1. Coupling of aldehydes (1), cyclic-1,3-diketones (2), and 1,3-dimethyl-
barbituric acid (3) to yield 4 and 5.
conditions, the above model reaction was carried out in the
absence of solvent at 100 °C with the above respective catalysts
to give 50%, 80%, and 85% yields within 25–45 min. Subsequently,
we carried out another set of reactions under similar conditions
taking 4-nitrobenzaldehyde (1.0 mmol), cyclohexan-1,3-dione
(1.0 mmol) and 1,3-dimethylbarbituric acid (1.2 mmol) giving the
To explore the generality of the reaction, we extended our study
with different aromatic aldehydes and cyclic-1,3-diketones. The
Table 1
Optimization of conditions for the synthesis of 4a
Entry Temp (°C)
Loading (mol %)
Time (min)
Yieldb (%)
Method A (InCl3) Method B (P2O5) Method A (InCl3) Method B (P2O5) Method A (InCl3) Method B (P2O5)
1
2
3
4
5
6
7
8
9
100
80
100
120
80
100
120
80
100
120
No catalyst
5
5
8 h
70
45
40
50
25
25
40
25
25
Trace
62
75
76
74
92
90
78
92
10
10
10
20
20
20
25
25
25
85
65
50
60
30
30
50
30
30
58
70
72
66
84
82
72
84
82
5
10
10
10
15
15
15
10
90
a
Reaction conditions: 4-nitrobenzaldehyde (1.0 mmol), dimedone (1.0 mmol), and 1,3-dimethylbarbituric acid (1.2 mmol).
Isolated yields.
b
Table 2
InCl3 and P2O5 promoted cyclocondensation of aldehydes, cyclic-1,3-diketones, and 1,3-dimethylbarbituric acida
Entry
R
1,3-Diketone (2)
Time (min)
Method A (InCl3) Method B (P2O5)
Yieldb (%)
Method A (InCl3) Method B (P2O5)
4a
4b
4c
4d
4e
4f
4g
4h
4i
p-FÁC6H4
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
30
25
35
30
35
40
28
25
30
35
25
25
40
25
35
28
30
35
25
35
32
35
40
30
38
40
45
50
36
37
35
45
32
30
60
35
40
38
42
40
35
40
40
42
85
92
89
82
78
74
86
84
80
78
85
88
78
88
75
82
78
78
85
55
57
53
81
84
85
78
74
72
82
75
78
75
80
84
73
83
72
78
75
76
78
50
52
48
p-NO2ÁC6H4
m-NO2ÁC6H4
o-NO2ÁC6H4
p-MeOÁC6H4
o-MeOÁC6H4
p-ClÁC6H4
m-ClÁC6H4
p-MeÁC6H4
m-OHÁC6H4
p-BrÁC6H4
C6H5
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
5a
5b
5c
2-OH-3-MeOÁC6H3
p-NO2ÁC6H4
p-MeÁC6H4
p-BrÁC6H4
2,4-Cl2ÁC6H3
o-ClÁC6H4
Dimedone
Cyclohexane-1,3-dione
Cyclohexane-1,3-dione
Cyclohexane-1,3-dione
Cyclohexane-1,3-dione
Cyclohexane-1,3-dione
Cyclohexane-1,3-dione
Indane-1,3-dione
Indane-1,3-dione
Indane-1,3-dione
C6H5
p-MeÁC6H4
p-NO2ÁC6H4
p-BrÁC6H4
a
For the experimental procedure, see Ref. 25.
Yield of isolated and purified products.
b

R. Kumar et al. / Tetrahedron Letters 51 (2010) 5933–5936
5935
11. For recent reviews, see: (a) Guillena, G.; Ramon, D. J.; Yus, M. Tetrahedron:
Asymmetry 2007, 18, 693–700; (b) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev.
2007, 36, 1095–1108; (c) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res.
2009, 42, 367–378; (d) Aliaga María, J.; Ramon Diego, J.; Yus, M. Org. Biomol.
Chem. 2010, 8, 43–46; (e) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15,
1300–1308; (f) Scheffelaar, R.; Paravidino, M.; Znabet, A.; Schmitz, R. F.; de
Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Guerra, C. F.; Bickelhaupt, F. M.; Groen, M.
B.; Ruijter, E.; Orru, R. V. A. J. Org. Chem. 2010, 75, 1723–1732; (g) Marek, I.
Tetrahedron 2005, 61, 11309–11519; (h)Multicomponent Reactions; Zhu, J.,
Bienaym’e, H., Eds.; Wiley-VCH: Weinheim, 2005; (i) Basso, A.; Banfi, L.; Riva,
R.; Guanti, G. J. Org. Chem. 2005, 70, 575–579.
12. (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80; (b) Sunderhaus, J. D.;
Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223–4226; (c) Armstrong, R.
W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Chem. Res. 1996, 29,
123–131; (d) Lieby-Muller, F.; Constantieux, T.; Jean Rodriguez, J. J. Am. Chem.
Soc. 2005, 127, 17176–17177; (e) Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.;
Chernenko, V. N.; Knyazeva, I. V.; Groth, U.; Glasnov, T. N.; Kappe, C. O. J. Org.
Chem. 2008, 73, 5110–5118.
13. (a) Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr. Med. Chem. 1999, 6, 255–270;
(b) Willy, B.; Muller, T. J. Eur. J. Org. Chem. 2008, 4157–4168; (c) Heravi, M. M.;
Baghernejad, B.; Oskooie, H. A.; Hekmatshoar, R. Tetrahedron Lett. 2008, 49,
6101–6103; (d) Dömling, A. Comb. Chem. High Throughput Screening 1998, 1, 1–
22; (e) Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Y.;
Magedov, I. V.; Kornienko, A. J. Org. Chem. 2007, 72, 3443–3453.
14. (a) Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975–2978; (b) Varma, R. S.
Green Chem. 1999, 43–55; (c) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–
1074; (d) Varma, R. S. Pure Appl. Chem. 2001, 73, 193–198; (e) Tanaka, K.; Toda,
F. In Solvent-free Organic Synthesis; Wiley-VCH, GmbH, 2003; (f) DeSimone, J.
M. Science 2002, 297, 799–803.
results of synthesis of a series of 9-oxa-1,3-diazaanthracene-2,4,5-
triones (4) and 5-oxa-6,8-diazabenzo[b]fluorene-7,9,11-triones (5)
are summarized in Table 2. This protocol tolerates a variety of aro-
matic aldehydes containing both electron-withdrawing and elec-
tron-donating substituents at ortho-, meta- or para-positions.
However, when some aliphatic aldehydes such as propionalde-
hyde, isobutyraldehyde, cinnamaldehyde, and cyclohexanecarbox-
aldehyde were used in this protocol under the above optimized
conditions, it led to a mixture of products in low yields. This may
be attributed to the aldol condensation as a side reaction.
In conclusion, we have developed a convenient one-pot three-
component cyclocondensation reaction between aromatic alde-
hydes, cyclic-1,3-diketones, and 1,3-dimethylbarbituric acid for
the preparation of 9-oxa-1,3-diazaanthracene-2,4,5-triones and
6,10-dihydro-5-oxa-6,8-diaza-benzo[b]fluorene-7,9,11-triones of
potential synthetic and pharmacological interest. Solvent-free con-
ditions, good yields of the products, and the use of simple and
readily available starting materials are the main advantages of this
method.
Acknowledgments
15. (a) Loh, T.-P.; Huang, J.-M.; Goh, S.-H.; Vittal, J. J. Org. Lett. 2000, 2, 1291–1294;
(b) Hajipour, A. R.; Arbabian, M.; Ruoho, A. E. J. Org. Chem. 2002, 67, 8622–
8624; (c) Yadav, L. D. S.; Singh, S. Synthesis 2003, 63–66; (d) Lee, J. C.; Bae, Y. H.
Synlett 2003, 507–508; (e) Xu, Z.-B.; Lu, Y.; Guo, Z.-R. Synlett 2003, 564–566.
16. (a) Azizi, N.; Saidi, M. R. Organometallics 2004, 23, 1457–1458; (b) Azizi, N.;
Saidi, M. R. Eur. J. Org. Chem. 2003, 4630–4633; (c) Azizi, N.; Saidi, M. R. Org.
Lett. 2005, 7, 3649–3651; (d) Khan, N. H.; Agrawal, S.; Kureshy, R. I.; Abdi, S. H.
R.; Singh, S.; Jasra, R. V. J. Organomet. Chem. 2007, 692, 4361–4366; (e) Khan, N.
H.; Agrawal, S.; Kureshy, R. I.; Abdi, S. H. R.; Singh, S.; Suresh, E.; Jasra, R. V.
Tetrahedron Lett. 2008, 49, 640–644; (f) Kureshy, R. I.; Singh, S.; Khan, N. H.;
Abdi, S. H. R.; Suresh, E.; Jasra, R. V. J. Mol. Catal. A: Chem. 2007, 264, 162–169.
17. For reviews see: (a) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149–11176; (b)
Sharma, S. D.; Hazarika, P.; Konwar, D. Tetrahedron Lett. 2008, 49, 2216–2220.
18. (a) Loh, T. P.; Pei, J.; Cao, G. Q. Chem. Commun. 1996, 1819–1820; (b) Li, Z.;
Zhang, J.; Li, C. J. Tetrahedron Lett. 2002, 44, 153–156; (c) Zhang, J.; Li, C. J. J. Org.
Chem. 2002, 67, 3969–3971; (d) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1997,
38, 5025–5026; (e) Loh, T. P.; Wei, L. L. Synlett 1998, 975–976; (f) Ranu, B. C.
Eur. J. Org. Chem. 2000, 2347–2356; (g) Ranu, B. C.; Hajra, A.; Jana, U. J. Org.
Chem. 2000, 65, 6270–6272.
This work was carried out under the financial support from
Council of Scientific and Industrial Research (Grant No. 01(2260)/
08/EMR-II) and Department of Science and Technology (Grant
No. SR/S1/OC-66/2009), New Delhi. R.K. is grateful to MDLLC,
Michigan, USA for the financial assistance. R.K.V. thanks CSIR,
New Delhi for his senior research fellowship.
References and notes
1. (a) Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624–630; (b) Wipf, P.;
Cunningham, A. Tetrahedron Lett. 1995, 36, 7819–7822; (c) Valverde, M. G.;
Dallinger, D.; Kappe, C. O. Synlett 2001, 741–744; (d) Rovnyak, G. C.; Atwal, K.
S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.;
Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254–3263; (e) Patil, A. D.;
Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; De Brosse, C.; Mai, S.;
Truneh, A.; Faulkner, D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.;
Westley, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60, 1182–1188; (f) Zorkun, I. S.;
Sarac, S.; Celebi, S.; Erol, K. Bioorg. Med. Chem. 2006, 14, 8582–8589.
2. (a) Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49–51; (b) Studer, A.; Jeger, P.;
Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62, 2917–2924; (c) 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,
2703–2718; (d) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052; (e) Folkers,
K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55, 3784–3791; (f) Sweet, F.; Fissekis, J.
D. J. Am. Chem. Soc. 1973, 95, 8741–8749; (g) Kappe, C. O. J. Org. Chem. 1997, 62,
7201–7204; (h) Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63,
3454–3457; (i) Vdovina, S. V.; Mamedov, V. A. Russ. Chem. Rev. 2008, 77, 1017–
1053.
19. Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141–1143.
20. (a) Eshghi, H.; Gordi, Z. Synth. Commun. 2003, 33, 2971–2978; (b) Mirjalili, B. F.;
Zolfigol, M. A.; Bamoniri, A.; Amrollahi, M. A.; Hazar, A. Phosphorus, Sulfur
Silicon 2004, 179, 1397–1401; (c) Eshghi, H.; Gordi, Z. Phosphorus, Sulfur Silicon
2005, 180, 619–623; (d) Massah, A. R.; Dabagh, M.; Shahidi, S.; Naghash, H. J.;
Momeni, A. R.; Aliyan, H. J. Iran. Chem. Soc. 2009, 6, 405–411; (e) Nandi, G. C.;
Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009, 50, 7220–7222; (f)
Kumar, R.; Nandi, G. C.; Verma, R. K.; Singh, M. S. Tetrahedron Lett. 2010, 51,
442–445.
21. (a) Ren, R. X.; Zueva, L. D.; Ou, W. Tetrahedron Lett. 2001, 42, 8441–8443; (b)
Eshghi, H.; Shafieyoon, P. Phosphorus, Sulfur Silicon 2004, 179, 2149–2152; (c)
Eshghi, H.; Gordi, Z. Phosphorus, Sulfur Silicon 2004, 179, 1341–1346; (d)
Hajipour, A. R.; Zarei, A.; Ruoho, A. E. Tetrahedron Lett. 2007, 48, 2881–2884.
22. (a) Hajipour, A. R.; Kooshki, B.; Ruoho, A. E. Tetrahedron Lett. 2005, 46, 5503–
5506; (b) Hajipour, A. R.; Ruoho, A. E. Tetrahedron Lett. 2005, 46, 8307–8310; (c)
Eshghi, H.; Rahimizadeh, M.; Saberi, S. Chin. Chem. Lett. 2008, 19, 1063–1067;
(d) Zarei, A.; Hajipour, A. R.; Khazdooz, L.; Mirjalili, B. F.; Zahmatkesh, S. J. Mol.
Catal. A: Chem. 2009, 301, 39–46.
3. Curini, M.; Cravotto, G.; Epifano, F.; Giannone, G. Curr. Med. Chem. 2006, 13,
199–222.
4. (a) Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.; Gorbunov, S. V.; Nasybullin,
R. F.; Stepanov, N. O.; Nikishin, G. I. Tetrahedron Lett. 2006, 47, 7629–7633; (b)
Sun, W.; Cama, L. J.; Birzin, E. T.; Warrier, S.; Locco, L.; Mosley, R.; Hammond, M.
L.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 1468–1472; (c)Coumarins:
Biology, Applications and Mode of Action; O’Kennedy, P., Thornes, R. D., Eds.; John
Wiley & Sons: Chichester, U.K., 1997.
5. For recent examples of biologically active chromene derivatives, see: Borges, F.;
Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem. 2005, 12, 887–
916.
6. (a) Tangmouo, J. G.; Meli, A. L.; Komguem, J.; Kuete, V.; Ngounou, F. N.; Lontsi,
D.; Beng, V. P.; Choudhary, M. I.; Sondengam, B. L. Tetrahedron Lett. 2006, 47,
3067–3070; (b) Gore, M. P.; Gould, S. J.; Weller, D. D. J. Org. Chem. 1991, 56,
2289–2291; (c) Mohri, S.; Stefinovic, M.; Snieckus, V. J. Org. Chem. 1997, 62,
7072–7073.
23. Ghahremanzadeh, R.; Fereshtehnejad, F.; Bazgir, A. Chem. Pharm. Bull. 2010, 58,
516–520.
24. (a) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron 2009, 65, 7129–
7134; (b) Samai, S.; Nandi, G. C.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009,
50, 7096–7098; (c) Samai, S.; Nandi, G. C.; Singh, P.; Singh, M. S. Tetrahedron
2009, 65, 10155–10161; (d) Nandi, G. C.; Samai, S.; Singh, M. S. Synlett 2010,
1133–1137; (e) Verma, R. K.; Ila, H.; Singh, M. S. Tetrahedron 2010, 66, 7389–
7398; (f) Samai, S.; Nandi, G. C.; Singh, M. S. Tetrahedron Lett. 2010, 51, 5555–
5558.
25. General procedure for the synthesis of compounds 4 and 5: To a ground mixture of
aldehyde (1.0 mmol), cyclic-1,3-diketone (1.0 mmol), and 1,3-dimethylbarbi-
turic acid (1.2 mmol), InCl3 (10 mol %) or P2O5 (20 mol %) was added and the
whole reaction mixture was heated at 100 °C for a set period of time (Table 2)
till the completion of the reaction (monitored by TLC). After the completion of
the reaction, water (20 mL) was added and the appeared precipitate was
extracted with ethyl acetate (3 Â 20 mL). The combined organic extract was
washed with water followed by brine, and dried over anhydrous MgSO4.
The solvent was evaporated under vacuum to give the product, which was
purified by column chromatography over silica gel using EtOAc–hexane (1:2)
as eluent.
7. Khafagy, M. M.; Ashraf, H. F.; Abd El-Wahab Eid, F. A.; El-Agrody, A. M.
ILFarmaco 2002, 57, 715–722.
8. Kast, H.; Dunkelmann, G. U.S. Patent 3931182, 1976.
9. Textbooks: (a) Industrial Dyes: Chemistry, Properties, Applications; Hunger, K., Ed.;
Wiley-VCH: Verlag GmbH
& Co. KGaA, Weinheim, 2003; (b) Hachiya, S.;
Hashizume, D.; Maki, S.; Niwa, H.; Hirano, T. Tetrahedron Lett. 2010, 51, 1401–1403.
10. Ebrahimlo, A. R. M.; Khalafy, J.; Marjani, A. P.; Prager, R. H. ARKIVOC 2009, 17–
30.

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R. Kumar et al. / Tetrahedron Letters 51 (2010) 5933–5936
Data for some selected compounds: 10-(4-Fluorophenyl)-1,3,7,7-tetramethyl-
10-(3-Hydroxyphenyl)-1,3,7,7-tetramethyl-6,7,8,10-tetrahydro-1H-9-oxa-1,3-di-
azaanthracene-2,4,5-trione (4j): white solid, mp 232–233 °C. 1H NMR (300 MHz,
CDCl3): d = 1.07, 1.13 (2s, 6H, 2 Â CH3), 2.26 (s, 2H, CH2), 2.57 (q, J = 6.3 Hz, 2H,
CH2), 3.26, 3.48 (2s, 6H, 2 Â NCH3), 4.84 (s, 1H, CH), 4.97 (s, 1H, OH), 6.62 (d,
J = 7.8 Hz, 2H, ArH), 6.85 (s, 1H, ArH), 7.08–7.13 (m, 2H, ArH). 13C NMR (75 MHz,
CDCl3): d = 27.6, 28.2, 28.9, 29.2, 32.3, 32.9, 40.5, 50.6, 92.1, 114.0, 115.8, 116.1,
6,7,8,10-tetrahydro-1H-9-oxa-1,3-diazaanthracene-2,4,5-trione (4a): white solid,
mp 177–178 °C. 1H NMR (300 MHz, CDCl3): d = 1.05, 1.14 (2s, 6H, 2 Â CH3), 2.25
(q, J = 4.5 Hz, 2H, CH2), 2.58 (s, 2H, CH2), 3.26, 3.48 (2s, 6H, 2 Â NCH3), 4.95 (s, 1H,
CH), 6.90–6.95 (m, 2H, ArH), 7.28–7.30 (m, 2H, ArH). 13C NMR (75 MHz, CDCl3):
d = 27.4, 28.1, 29.0, 29.1, 32.3, 40.5, 50.5, 92.0, 114.9, 115.2, 115.9, 129.7, 129.8,
138.9, 150.4, 151.1, 161.1, 161.2, 195.6. IR (KBr):
m
= 2954, 1721, 1675, 1660,
119.8, 129.3, 144.5, 150.4, 151.3, 155.8, 161.1, 161.2, 196.0. IR (KBr): m = 3493,
1518 cmÀ1. MS (m/z): 385 [M+1]+. Anal. Calcd for C21H21FN2O4 (384.4): C, 65.62;
H, 5.51; N, 7.29. Found: C, 65.50; H, 5.35; N, 7.46.
2943, 1711, 1692, 1671, 1529 cmÀ1. MS (m/z): 383 [M+1]+. Anal. Calcd for
C21H22N2O5 (382.4): C, 65.96; H, 5.80; N, 7.33. Found: C, 65.72; H, 5.59; N, 7.49.
6,8-Dimethyl-10-p-tolyl-6,10-dihydro-5-oxa-6,8-diazabenzo[b]fluorene-7,9,11-tri-
one (5a): red solid, mp 265–267 °C (dec). 1H NMR (300 MHz, CDCl3): d = 2.32 (s,
3H, ArCH3), 2.94, 3.37 (2s, 6H, 2 Â NCH3), 4.74 (s, 1H, CH), 6.94 (d, J = 7.8 Hz, 2H,
ArH), 7.10 (d, J = 7.5 Hz, 2H, ArH), 7.27–7.34 (m, 2H, ArH), 7.45–7.61 (m, 2H, ArH).
13C NMR (75 MHz, CDCl3): d = 21.3, 31.4, 31.9, 51.3, 120.9, 122.5, 123.8, 125.7,
10-(4-Methoxyphenyl)-1,3,7,7-tetramethyl-6,7,8,10-tetrahydro-1H-9-oxa-1,3-di-
azaanthracene-2,4,5-trione (4e): white solid, mp 205–207 °C. 1H NMR (300 MHz,
CDCl3): d = 0.99, 1.09 (2s, 6H, 2 Â CH3), 2.19 (q, J = 6.9 Hz, 2H, CH2), 2.45 (s, 2H,
CH2), 3.39, 3.41 (2s, 6H, 2 Â NCH3), 3.73 (s, 3H, OCH3), 4.69 (s, 1H, CH), 6.74 (d,
J = 8.4 Hz, 2H, ArH), 8.32 (d, J = 8.7 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3):
d = 27.4, 28.2, 28.9, 29.3, 32.4, 33.3, 40.5, 50.5, 56.1, 90.1, 115.3, 121.9, 122.1,
128.6, 129.2, 129.9, 131.0, 133.8, 134.0, 168.3, 193.4. IR (KBr):
m = 3129, 3081,
128.3, 135.7, 145.1, 147.3, 150.3, 152.4, 161.2, 161.5, 194.5. IR (KBr):
1699, 1634, 1623, 1567, 1501, 1475 cmÀ1. MS (m/z): 397 [M+1]+. Anal. Calcd for
22H24N2O5 (396.4): C, 66.65; H, 6.10; N, 7.07. Found: C, 66.39; H, 6.35; N, 7.29.
m
= 2923,
2951, 2867,1689, 1652,1649, 1642,1487 cmÀ1. MS (m/z):387 [M+1]+. Anal. Calcd
for C23H18N2O4 (386.4): C, 71.49; H, 4.70; N, 7.25. Found: C, 71.37; H, 4.41; N, 7.13.
6,8-Dimethyl-10-(4-nitrophenyl)-6,10-dihydro-5-oxa-6,8-diaza-benzo[b]fluorene-
7,9,11-trione (5b): red solid, mp 210–212 °C (dec). 1H NMR (300 MHz, CDCl3):
d = 2.99, 3.35(2s,6H, 2 Â NCH3),4.87(s, 1H, CH),7.37(d,J = 6.6 Hz, 2H, ArH),7.64–
7.81 (m, 4H, ArH), 8.17 (d, J = 8.7 Hz, 2H, ArH). 13C NMR (75 MHz, CDCl3): d = 31.9,
32.7, 53.2, 121.9, 122.1, 123.2, 125.9, 129.9, 130.1, 130.6, 131.9, 134.5, 134.9,
C
10-(4-Methylphenyl)-1,3,7,7-tetramethyl-6,7,8,10-tetrahydro-1H-9-oxa-1,3-diaza-
anthracene-2,4,5-trione (4i): white solid, mp 184–186 °C. 1H NMR (300 MHz,
CDCl3): d = 1.06, 1.13 (2s, 6H, 2 Â CH3), 2.24 (s, 3H, ArCH3), 2.25 (q, J = 4.8 Hz, 2H,
CH2), 2.57 (q, J = 2.7 Hz, 2H, CH2), 3.24, 3.47 (2s, 6H, 2 Â NCH3), 4.83 (s, 1H, CH),
7.05 (d, J = 7.8 Hz, 2H, ArH), 7.20 (d, J = 7.8 Hz, 2H, ArH). 13C NMR (75 MHz, CDCl3):
d = 21.0, 27.5, 28.1, 29.0,29.1, 32.3, 32.7, 40.5, 50.6, 92.4, 116.2, 128.0, 128.9,136.4,
167.9, 195.4. IR (KBr):
m = 3154, 3069, 2945, 2896, 1712, 1689, 1649, 1635,
1477 cmÀ1. MS (m/z): 418 [M+1]+. Anal. Calcd for C22H15N3O6 (417.3): C, 63.31; H,
140.1, 150.4, 151.1, 160.9, 161.3, 195.6. IR (KBr):
m
= 2941, 1709, 1689, 1668,
3.62; N, 10.07. Found: C, 63.45; H, 3.79; N, 10.31.
1533 cmÀ1. MS (m/z): 381 [M+1]+. Anal. Calcd for C22H24N2O4 (380.4): C, 69.46; H,
6.36; N, 7.36. Found: C, 69.36; H, 6.19; N, 7.49.