Solid-phase synthesis of N-substituted 3,4-dihydroquinazolinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.03.034

An efficient solid-phase synthetic approach for the synthesis of N-substituted 3, 4-dihydroquinazolinone derivatives has been developed. Four different 2-nitrobenzoic acids and three different 2-phenylacetyl chlorides were employed in the synthesis of thi

Full text of DOI:10.1016/j.tetlet.2011.03.034

Tetrahedron Letters 52 (2011) 2627–2628
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Tetrahedron Letters
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Solid-phase synthesis of N-substituted 3,4-dihydroquinazolinone derivatives
⇑
Zhang Liu , Lili Ou, Marc A. Giulianotti, Richard A. Houghten
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient solid-phase synthetic approach for the synthesis of N-substituted 3, 4-dihydroquinazolinone
derivatives has been developed. Four different 2-nitrobenzoic acids and three different 2-phenylacetyl
chlorides were employed in the synthesis of this library. After purification, all products were obtained
in good yields.
Received 10 February 2011
Revised 2 March 2011
Accepted 4 March 2011
Available online 11 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Solid-phase organic synthesis (SPOS) is a powerful technique for
the rapid generation of structurally diverse compounds for the drug
discovery community.1 One major focus of this field is on the synthe-
sis of bioactive compounds and their derivatives on the solid phase.
Specifically heterocyclic compounds have received special attention
because of their broad range of biological activities.2 As a result, an
increasing number of pharmaceutically useful heterocyclic com-
pounds have been prepared using solid-phase methodology.3
The N-substituted 3,4-dihydroquinazolinone is an attractive
drug template because of its extensive biological activities in
various drug targets, such as p38 kinase inhibitor,4 5-HT2C ago-
nist,5 Aldose reductase inhibitor,6 CB2 agonist.7 Therefore, facile
preparation of diverse N-substituted 3,4-dihydroquinazolinones
for lead discovery is highly desirable. Although many solution-
phase methods have been explored for the synthesis of this use-
ful scaffold, to the best of our knowledge, no solid-phase syn-
thetic approaches have been reported.8 Herein, we would like
to present an efficient solid-phase synthetic approach for the
synthesis of N-substituted 3,4-dihydroquinazolinones.
Starting from p-methylbenzhydrylamine (MBHA) resin 1, 2-
nitrobenzoic acid was tethered to the resin under DIC/HOBt con-
ditions. Reduction of the aromatic nitro group of the resin-bound
2-nitrobenzamide 2 with tin(II) chloride yielded the correspond-
ing aniline 3. After coupling with 2-phenylacetyl chlorides, the
afforded amides 4 were reduced under BH3–THF conditions for
4 days, and then treated with piperidine for another 24 h.7 The
resulting diamines 5 were cyclized with carbonyliimidazole in
DCM at room temperature overnight to give the corresponding
O
O
O
c
b
a
N
H
HN
N
H
H2N
N
H
O2N
NH2
R1
R1
R1
O
1
2
3
4
R2
g
f
d, e
HN
N
N
H
HN
R1
R1
R1
O
N
O
N
7
6
5
R2
R2
R2
Scheme 1. Reagents and conditions: (a) 2-nitrobenzoic acid (6 equiv 0.1 M), HOBt (6 equiv, 0.1 M), DIC (6 equiv, 0.1 M) in DMF, rt, overnight; (b) SnCl2 (20 equiv, 2 M) in
DMF, rt, overnight; (c) 2-phenylacetyl chloride (6 equiv, 0.1 M), DIEA (6 equiv, 0.1 M) in DCM, rt, overnight; (d) BH3–THF, 65 °C, 4 days; (e) piperidine, 65 °C, 24 h; (f)
carbonyliimidazole (6 equiv 0.05 M), DCM, rt, overnight; (g) HF, 0 °C, 1.5 h.
⇑
Corresponding author.
E-mail addresses: zliu@tpims.org, zliu2003@sibs.ac.cn (Z. Liu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.034

2628
Z. Liu et al. / Tetrahedron Letters 52 (2011) 2627–2628
Table 1
References and notes
1. (a) Ziegert, R. E.; Torang, J.; Knepper, K.; Brase, S. J. Comb. Chem. 2005, 7, 147–
Entry
R1
R2
Yielda (%)
MWb
169; (b) Kundu, B. Curr. Opin. Drug Disc. Dev. 2003, 6, 815–826; (c) Feliu, L.; Vera-
Luque, P.; Albericio, F.; Alvarez, M. J. Comb. Chem. 2009, 11, 175–197.
2. Franzen, R. G. J. Comb. Chem. 2000, 2, 195–214.
3. Krchnak, V.; Holladay, M. W. Chem. Rev. 2002, 102–161.
4. Schlapbach, A.; Heng, R.; Di Padova, F. Bioorg. Med. Chem. Lett. 2004, 14, 357–
360.
5. Ahmad, S.; Ngu, K.; Miller, K. J.; Wu, G.; Hung, C.; Malmstrom, S.; Zhang, G.;
O’Tanyi, E.; Keim, W. J.; Cullen, M. J.; Rohrbach, K. W.; Thomas, M.; Ung, T.; Qu,
Q.; Gan, J.; Narayanan, R.; Pelleymounter, M. A.; Robl, J. A. Bioorg. Med. Chem.
Lett. 2010, 20, 1128–1133.
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
H
H
Phenyl
82
78
78
80
73
71
75
64
69
74
76
67
253 (M+1)
283 (M+1)
271 (M+1)
288 (M+1)
318 (M+1)
306 (M+1)
267 (M+1)
297 (M+1)
285 (M+1)
289 (M+1)
319 (M+1)
307 (M+1)
40-Methoxyl phenyl
40-Fluoro phenyl
Phenyl
4-Chloro
4-Chloro
4-Chloro
3-Methyl
3-Methyl
3-Methyl
4,5-Difluoro
4,5-Difluoro
4,5-Difluoro
40-Methoxyl phenyl
40-Fluoro phenyl
Phenyl
40-Methoxyl phenyl
40-Fluoro phenyl
Phenyl
6. Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492–1503.
7j
7k
7l
7. Omura, H.; Kawai, M.; Shima, A.; Iwata, Y.; Ito, F.; Masuda, T.; Ohta, A.; Makita,
N.; Omoto, K.; Sugimoto, H.; Kikuchi, A.; Iwata, H.; Ando, K. Bioorg. Med. Chem.
Lett. 2008, 18, 3310–3314.
40-Methoxyl phenyl
40-Fluoro phenyl
8. For example, see: (a) Ferraccioli, R.; Carenzi, D. Synthesis 2003, 9, 1383–1386; (b)
Jairo, P.; Carlos, P.; Beatriz, I.; Luis, M. J. Org. Chem. 2010, 75, 3037–3046; (c)
Chong, H.; John, P. Org. Lett. 2007, 9, 1517–1520; (d) Toru, Y.; Nobuki, K.; Shiniji,
M.; Noboru, S. Bull. Chem. Soc. Jpn. 1987, 60, 1793–1799.
a
Yields are based on the weight of purified product and relative to the initial
loading of the resin (1.1 mmol/g).
b
Determined by ESI–MS.
9. General procedure for the synthesis of N-substituted 3,4-dihydroquinazolinone
derivatives: 100 mg of p-methylbenzhydrylamine (MBHA) (loading: 1.1 mmol/g)
was sealed within a polypropylene mesh packet. Reactions were carried out in
polyethylene bottles. Starting from p-methylbenzhydrylamine (MBHA) resin 1,
2-nitrobenzoic acid was tethered to the resin in the presence of DIC (6 equiv)
and HOBt (6 equiv) with DMF as solvent at room temperature overnight. After
washing with DMF (three times), DCM (three times) and air dried, the resin-
bound nitrobenzoic amide was reduced by SnCl2 (20 equiv 2 M) in DMF at room
temperature overnight. The resin was then washed with DMF (10 times), DCM
(three times) and air dried. The afforded resin was reacted with phenylacetyl
chloride (6 equiv 0.1 M) in the presence of DIEA (6 equiv 0.1 M) in DCM at room
temperature overnight and then washed with DMF (three times) and DCM
(three times). The afforded resin was reduced with BH3–THF at 65 °C for 4 days,
washed with THF (once), MeOH (three times) and then treated with piperidine
for another 24 h at 65 °C. After washing with DMF (three times), DCM (three
times), MeOH (once) and air drying, the resulting diamine resin was cyclized
with carbonyliimidazole (6 equiv 0.05 M) in DCM at room temperature
overnight. The resin was then washed with DMF (three times), DCM (three
times) and MeOH (three times). The crude product was released from the resin
by HF at 0 °C for 1.5 h. The crude product was purified by preparative HPLC and
characterized by LC–MS under ESI condition and 1H NMR. Yield: 23 mg, 82%;
ESI–MS (m/z) of 7a: 253 (M+H); 1H NMR of 7a: (500 MHz, DMSO-d6): d 2.98 (t,
J = 7.8 Hz, 2H), 3.96 (t, J = 7.8 Hz, 2H), 4.40 (s, 2H), 6.75 (d, J = 8.0 Hz, 1H), 6.97
(m, 1H), 7.15–7.35 (m, 7H), 7.52 (m, 1H). 13C NMR of 7a: (125 MHz, DMSO-d6): d
33.7, 42.5, 54.2, 113.5, 122.3, 125.6, 126.0, 126.6, 126.9, 128.7, 135.3, 138.1,
138.4, 154.5.
resin-bound products 6, which were then released from the resin
by HF cleaving. After purifying by preparative HPLC, pure N-
substituted dihydroquinazolinone products 7 were obtained in
good yields (Scheme 1).9
To illustrate the versatility of this chemistry, a library of 12
compounds (7a–i) was prepared (Table 1). Four different 2-nitro-
benzoic acids and three different 2-phenylacetyl chlorides were
employed in the synthesis of this library.
In summary, we have developed an efficient solid-phase syn-
thetic approach for the synthesis of N-substituted 3,4-dihydroqui-
nazolinone derivatives. The methodology is of value for high
throughput synthesis of these potentially bioactive molecules.
Acknowledgment
This work was supported by the State of Florida, Executive Offi-
cer of the Governor’s Office of Tourism, Trade, and Economic
Development.