A practical approach towards synthesis of octahydroquinazolinone derivatives in water

Article abstract of DOI:10.2174/157017809789869555

A simple, efficient and green procedure has been developed for the synthesis of octahydroquinazolinone derivatives by Biginelli-type three-component cyclocondensation reactions of cyclic β-diketones, aldehydes and (thio)urea with p-TsOH catalysis in water

Full text of DOI:10.2174/157017809789869555

Letters in Organic Chemistry, 2009, 6, 557-559
557
A Practical Approach Towards Synthesis of Octahydroquinazolinone
Derivatives in Water
Hai-Xia Lin*, Xiao-Zhen Xie, Xiao-Hong Wang and Bin He
Department of Chemistry, Shanghai University, Shanghai, 200444, P. R. China
Received May 13, 2009: Revised August 17, 2009: Accepted August 27, 2009
Abstract: A simple, efficient and green procedure has been developed for the synthesis of octahydroquinazolinone
derivatives by Biginelli-type three-component cyclocondensation reactions of cyclic ꢀ-diketones, aldehydes and (thio)urea
with p-TsOH catalysis in water.
Keywords: Octahydroquinazolinone, biginelli reaction, cyclic ꢀ-diketones, p-toluenesulfonic acid, synthesis, catalysis.
One-pot multicomponent reactions (MCRs) are attracting
considerable interest for various reasons [1]. The production
of dihydropyrimidinones via the well established Biginelli
reaction certainly ranks as one of the most recognized and
often used MCRs for the generation of novel pyrimidine
scaffolds. This reaction involves the interaction of a ꢀ-
ketoester, a urea, and an aldehyde [2]. Some of the interest in
this heterocyclic synthesis is also due to the challenge of
redesigning and improving an old but useful preparative
method [3]. Very recently, the Biginelli reaction has been
employed for the synthesis of octahydroquinazolinones,
which used cyclic ꢀ-diketones instead of open-chain
dicarbonyl compounds, but with low yields of products (19-
approach for the synthesis of octahydroquinazolinone
derivatives by the multicomponent reactions of cyclic ꢀ-
diketones 1, (thio)urea 2 and aldehydes 3 using p-
toluenesulfonic acid (p-TsOH) as catalyst in water with good
yields and selectivity (Scheme 1).
In the present study we have selected benzaldehyde, 1,3-
cyclohexanedione, and urea as model compounds using p-
TsOH (10 mol%) as catalyst and have tested a variety of
reaction conditions. In order to drive the reaction to
completion, excess of 1,3-cyclohexanedione and urea has to
be employed in the reaction. The best results were obtained
with a 1.4:1.2:1 ratio of 1,3-cyclohexanedione, urea, and
R1
O
X
H
N
R1
R1
p-TsOH
H O,
R1
X
+
+
RCHO
H2N
NH2
reflux
2
NH
O
X = O, S
O
R
4
1
2
3
Scheme 1.
69%) under catalystic amount of conc. HCl [4]. Additional
scaffolds such as spiro-fused heterocycles and
aldehyde. The effect of various solvents on the yield of the
reaction was also studied. Results reported in Table 1 are
quite surprising since similar yields were observed by
carrying out the reaction in two solvents such as acetonitrile
and water. Particularly impressive is the good yield observed
in water despite the reaction requiring the elimination of two
water molecules. Based on the reaction yields and
environmental consideration, water was proved to be the best
solvent among the other solvents such as acetonitrile, ethanol
and toluene. Water insoluble solid products that separated
out were easily purified by recrystallization. All these
positive aspects make the reaction very compatible with
green chemistry requirements.
hexahydroxanthenes were formed in those reactions [5].
Moreover, octahydroquinazolinone derivatives exhibited
potent antibacterial activity and calcium antagonist activity
[4c, 6]. Therefore, improved procedures with better and
milder conditions have been under attention for the novel
Biginelli-like scaffold syntheses.
The toxicity and volatile nature of many organic solvents
that are widely used in huge amounts for organic reactions
have posed a serious threat to the environment. Water is a
medium that is fully compatible with green chemistry [7]. In
connection with our ongoing work on multicomponent
reactions [8], we now wish to report a practical and simple
With optimized protocol in hand, the condensation of
cyclic ꢀ-diketones, (thio)urea and aldehydes afforded
products 4 in good yield and purity [9]. The results are
reported in Table 2. A wide range of aromatic aldehydes
either electron-donating or electron-withdrawing are
*Address correspondence to this author at the Department of Chemistry,
Shanghai University, Shanghai, 200444, P. R. China; Tel: +86-21-
66132797; E-mail: haixialin@staff.shu.edu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

558 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Lin et al.
Table 1. Solvent Effect for Reaction of 1,3-Cyclohexanedione 1 (2.8 mmol), Urea 2 (2.4 mmol) and Benzaldehyde 3 (2.0 mmol)
Catalyzed by p-TsOH
Entry
Solvent
Time (h)
Yield of 4a (%)
1
2
3
4
Ethanol
Acetonitrile
Water
8
8
8
8
62
77
83
Toluene
Trace
Table 2. p-TsOH Catalyzed Synthesis of Octahydroquinazolinone Derivatives
Entry
R
R1
X
Product
Yield (%)a
1
2
C6H5
4-CH3C6H4
4-CHF2OC6H4
4-CH3OC6H4
4-NO2C6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-FC6H4
3a
3b
3c
3d
3e
3f
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
4a
4b
4c
4d
4e
4f
83 (46)
78 (43)
3
H
85 (58 [8c])
84 (48)
4
H
5
H
82 (46)
6
H
86 (62)
7
3g
3h
3i
H
4g
4h
4i
74 (54)
8
H
68 (44)
9
H
77 (45)
10
11
12
13
14
15
16
3j
H
4j
75 (44)
3k
3l
H
4k
4l
85 (19) [5d]
79 (68) [8b]
84 (95) [3d]
72 (43) [2c]
70 (74) [5c], (30) [5d]
61 (93) [7b]
3-FC6H4
H
2,4-Cl2C6H3
4-ClC6H4
4-FC6H4
3m
3n
3o
3p
H
4m
4n
4o
4p
CH3
H
4-ClC6H4
CH3
S
aNumbers in parentheses refer to reported yields in literature [4b] unless otherwise indicated.
tolerated in this procedure to provide a library of
octahydroquinazolinones. Thiourea also works well to give
the corresponding thio-derivatives. Compared to classical
Biginelli method, one additional important feature of the
present protocol is the ability to tolerate the variation in all
the three components. Besides 1,3-cyclohexanedione, and
5,5-dimethyl-1,3-cyclohexanedione can also be employed.
The three-component condensation reactions proceeded
smoothly and were completed within 5-10 h. All the
products were characterized on the basis of their
Academic Discipline Project of Shanghai Municipal
Education Commission (Project No. J50102) for their
support.
REFERENCES
[1]
[2]
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl., 2000, 39, 3168.
a) Biginelli, P. Gazz. Chim. Ital., 1893, 23, 360; b) Kappe, C.O.
Eur. J. Med. Chem., 2000, 35, 1043; c) Kappe, C.O. Acc. Chem.
Res., 2000, 33, 879.
[3]
a) Dondoni, A.; Massi, A.; Sabbatini, S.; Bertolasi, V. J. Org.
Chem., 2002, 67, 6979; b) Abelman, M. M.; Smith, S. C.; James,
D. R. Tetrahedron Lett., 2003, 44, 4559; c) Alexander Gross, G.;
Wurziger, H.; Schober, A. J. Comb. Chem., 2006, 8, 153. d) Tu, S.
J.; Fang, F.; Zhu, S. L.; Li, T. J.; Zhang, X. J.; Zhuang, Q. Y. J.
Heterocycl. Chem., 2004, 41, 253.
1
spectroscopic data such as H NMR, IR and EI-MS spectra
and physical data.
In conclusion, this study has demonstrated that the
synthesis of octahydroquinazolinone derivatives is achieved
in good yields and selectivity using p-toluenesulfonic acid as
catalyst to promote the Biginelli-type three component
reactions of aldehydes, cyclic ꢀ-diketones and urea in water.
[4]
[5]
a) Saraç, S.; Yar1m, M.; Ertan, M.; Kilic, F. S.; Erol, K.
Pharmazie, 2001, 56, 298; b) Saraç, S.; Yar1m, M.; Ertan, M.;
Boydag, S.; Erol, K. Pharmazie, 1998, 53, 91; c) Yar1m, M.;
Saraç, S.; Kilic, F. S.; Erol, K. I1 Farmaco, 2003, 58, 17.
a) Reddy, K.R.; Reddy, C.V.; Mahesh, M.; Raju, P. V. K.; Reddy,
V. V. N. Tetrahedron Lett., 2003, 44, 8173; b) Shanmugam, P.;
Sabastein, C.; Perumal, P. T. Indian J. Chem. B, 2004, 43, 135; c)
Zhu, Y. L.; Pan, Y. J.; Huang, S. L. Heterocycles, 2005, 65, 133; d)
Tonkikh, N. N.; Strakovs A.; Petrova, M. V. Chem. Heterocycl.
ACKNOWLEDGEMENTS
The authors are grateful to the National Natural Science
Foundation of China (Project No. 30672506) and Leading

A Practical Approach Towards Synthesis of Octahydroquinazolinone
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
559
Compd., 2004, 40, 43; e) Amini, M. M.; Shaabani, A.; Bazgir, A.
Catal. Commun., 2006, 7, 843.
Kidwai, M.; Saxena, S.; Khalilur Rahman Khan, M.; Thukral, S. S.
Eur. J. Med. Chem., 2005, 40, 816.
a) Bose, A. K.; Manhas, M. S.; Pednekar, S.; Ganguly, S. N.; Dang,
H.; He, W.; Mandadi, A. Tetrahedron Lett., 2005, 46, 1901; b)
Hassani, Z.; Islami, M. R.; Kalantari, M. Bioorg. Med. Chem. Lett.,
2006, 16 , 4479.
dione 4c. A mixture of cyclohexane-1,3-dione (1.57 g, 14 mmol),
urea (0.72 g, 12 mmol), 4-(difluoromethoxy)-benzaldehyde (1.72 g,
10 mmol), and p-toluenesulfonic acid (0.17 g, 1 mmol) in water (40
mL) was refluxed for 7 h. After completion of the reaction, as
monitored by TLC, the crude product, which precipitated on
cooling, was filtered and washed with H2O and recrystallized from
ethanol (2.62 g, 85% yield). Data for 4c: M.p. 266.3-266.6 oC; IR
[6]
[7]
1
(KBr): 3221, 3121, 1699, 1649, 1606 cm-1; H NMR (300 MHz,
[8]
[9]
a) Lin, H. X.; Zhao, Q. J.; Xu, B.; Wang, X. H. Chin. Chem. Lett.,
2007, 18, 502; b) Lin, H. X.; Zhao, Q. J.; Xu, B.; Wang, X. H. J.
Mol. Catal. A: Chem., 2007, 268, 221. c) Lin, H. X.; Wang, X. H.;
Xu, B.; Yuan, T. H.; Chen, M. Q. Acta Cryst. E, 2007, 63, o1565-
o1567.
DMSO-d6): ꢀ = 1.81-1.95 (m, 2H), 2.19-2.26 (m, 2H), 2.44-2.51
(m, 2H), 5.17 (d, J = 3.0 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 7.18 (t,
J = 74.3 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 7.76 (s, 1H), 9.50 (s,
1H); EI-MS: m/z (%) = 309 (26), 308 (M+, 38), 307 (12), 252 (12),
251 (8), 241 (31), 240 (15), 165 (100). See X-ray crystal structure
analysis of compound 4c in literature [8c].
Typical
procedure
for
the
preparation of
4-(4-Di-
fluoromethoxyphenyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-