Solid-phase synthesis of 2-cyanoquinazolin-4(3H)-one and 2,3-dihydrooxazolo[2,3-b]quinazolin-5-one derivatives utilizing resin-bound anthranilic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.09.015

We were able to obtain 2-cyanoquinazolin-4(3H)-ones 11 in 35-60% four-step overall isolated yields and 2,3-dihydrooxazolo[2,3-b]quinazolin-5-ones 12 in 20-71% four-step overall isolated yields utilizing polymer-bound anthranilic acid derivatives 1, and 6-amino-2-cyanoquinazolin-4(3H)-ones 19 in 30-44% six-step overall isolated yields making use of anthranilic acid derivative resin 2 via dithiazole resins 10 and 17. The reactions on solid phase were monitored by single bead ATR-FTIR spectroscopic method.

Full text of DOI:10.1016/j.tetlet.2005.09.015

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7477–7481
Solid-phase synthesis of 2-cyanoquinazolin-4(3H)-one and
2,3-dihydrooxazolo[2,3-b]quinazolin-5-one derivatives utilizing
resin-bound anthranilic acid derivatives
Moon-Kook Jeon,a Dong-Su Kim,a,b Hyun Ju La,a,b Deok-Chan Hab and
Young-Dae Gonga,*
aKorea Research Institute of Chemical Technology, Medicinal Science Division, PO Box 107, Yuseong-gu, Daejeon 305-600,
Republic of Korea
bDepartment of Chemistry, Korea University, Seoul 151-742, Republic of Korea
Received 3 August 2005; revised 5 September 2005; accepted 7 September 2005
Abstract—We were able to obtain 2-cyanoquinazolin-4(3H)-ones 11 in 35–60% four-step overall isolated yields and 2,3-dihydro-
oxazolo[2,3-b]quinazolin-5-ones 12 in 20–71% four-step overall isolated yields utilizing polymer-bound anthranilic acid derivatives
1, and 6-amino-2-cyanoquinazolin-4(3H)-ones 19 in 30–44% six-step overall isolated yields making use of anthranilic acid derivative
resin 2 via dithiazole resins 10 and 17. The reactions on solid phase were monitored by single bead ATR-FTIR spectroscopic
method.
Ó 2005 Elsevier Ltd. All rights reserved.
Solid-phase synthesis of combinatorial libraries has
emerged as a powerful tool for efficient drug discovery
process.1 In particular, derivation of various core struc-
tures with the same or different substituents from a ver-
satile intermediate resin has been an interesting strategy
for construction of small molecule libraries on solid
phase in which varying scaffold as well as substituents
might further increase the diversity of the libraries com-
pared to depending on single scaffold.2 In this context,
resin-bound anthranilic acid derivatives have served
as important intermediates for the solid-phase synthe-
sis of some biologically interesting heterocyclic com-
pounds such as quinazolin-4(3H)-ones,3a–c quinazoline-
2,4(1H,3H)-diones,3d–f
pyrrolo[2,1-c][1,4]benzodiaze-
pines,3g and 3H-benzo[a][1,2,3]triazinones.3h In connec-
tion with our ongoing drug discovery project,4 we
O
O
R
N
O
NH2
OMe
NH2
X
2
1
N
N
O
NH2
HO
O
O
NH2
N
R
R2
OMe
N
R1
CO2HNEt3
O
O
N
O
R2
R1
3
6
4
5
Keywords: Solid-phase synthesis; Quinazolinone; Anthranilic acid; Dithiazole.
*
Corresponding author. Tel.: +82 42 860 7149; fax: +82 42 861 1291; e-mail addresses: ydgong@krict.re.kr; moteta@krict.re.kr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.015

7478
M.-K. Jeon et al. / Tetrahedron Letters 46 (2005) 7477–7481
O
O
O
O
.
SnCl2 2H2O
2-nitrobenzoic acid
NO2
NH2
OH
DMF
DIC, DMAP
DCM/DMF
rt
80 oC
7
X
X
1
8
H2NR or
O
O
Cl
_
Cl
O
X
O
R1
R1
R2
Cl
R
+
S
Cl
S
N
9
N
N
H2N
OH
R2
N
X
or X
pyr
THF
N
O
70 oC)
N
CN
N
(
rt
DCM
rt
S
S
10
11
12
Scheme 1.
intended to utilize some resin-bound anthranilic acid
derivatives such as 1 and 2 to develop solid-phase syn-
thetic methods for generation of drug-like heterocyclic
compound libraries. The resins 1 and 2 have been rarely
utilized for solid-phase synthesis of heterocyclic com-
pounds even though the former was reported5 and they
have possibilities other than the previously reported re-
sin-bound anthranilic acid derivatives 3,3a–c 4,3e,f 5,3h
and 6.3d Herein, we wish to describe the solid-phase syn-
thesis of 2-cyanoquinazolin-4(3H)-ones and 2,3-dihy-
drooxazolo[2,3-b]quinazolin-5-ones from polymer-
bound anthranilic acid derivatives 1 and 2 utilizing the
solution-phase chemistry of 5-arylimino-4-chloro-5H-
1,2,3-dithiazoles.6 There has been no report regarding
the solid-phase synthesis of 2-cyanoquinazolin-4(3H)-
ones and 2,3-dihydrooxazolo[2,3-b]quinazolin-5-ones
derivatives even though quinazolinone derivatives have
shown broad spectrum of biological activities and
numerous methodologies for solid-phase synthesis of
them have been reported.3a–c,7
Table 1. Yields and purities of the compounds 11 and 12
Compound
X
R
Yielda (%)
Purity (%)
11a
11b
11c
11d
11e
11f
11g
11h
11i
H
H
H
H
H
H
n-Pr
60
50
53
42
43
35
45
60
57
55
43
57
46
54
60
52
41
44
43
44
50
95b
98b
100b
100c
98b
100c
85b
95b
82c
MeOCH2CH2
Cyclohexanemethyl
4-Methoxybenzyl
Phenethyl
Furfuryl
n-Bu
MeOCH2CH2
Cyclohexanemethyl
4-Methylbenzyl
2-Methoxyphenethyl
Furfuryl
3-(2-Oxopyrrolidin-1-yl)propyl
MeOCH2CH2
Cyclohexanemethyl
4-Methylbenzyl
4-Chlorobenzyl
Phenethyl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
7-Me
11j
100b
90b
83b
84b
98b
98c
11k
11l
11m
11n
11o
11p
11q
11r
11s
11t
11u
95c
96c
99c
4-Fluorophenethyl
4-Methoxyphenethyl
Furfuryl
98c
99c
100b
R1
R2
12a
12b
12c
12d
12e
12f
12g
8-Cl
8-Cl
8-Cl
8-Me
8-Me
8-Me
8-Me
H
H
H
Me
H
H
71
69
37
32
40
25
20
91b
100c
99b
Me
Ph
H
Me
H
99c
100b
100b
100b
(R)-Ph
H
Ph
a Four-step overall isolated yield from Wang resin (loading capacity 0.92 mmol/g).
b Determined on the basis of LC–MS spectrum after column chromatography.
c Determined on the basis of GC–MS spectrum after column chromatography.

M.-K. Jeon et al. / Tetrahedron Letters 46 (2005) 7477–7481
7479
olamines in THF at rt to 70 °C afforded 2,3-dihydroox-
azolo[2,3-b]quinazolin-5-ones 12 in 20–71% yields and
91–100% purities. The results are summarized in Table
1.9 The progress of the reactions on solid phase was
monitored by single bead ATR-FTIR spectroscopy10
as shown in Figure 1, where the resins 8, 1, and 10
showed characteristic bands, that is, 1731 (C@O), 1533
(NO2), 1349 (NO2) cmÀ1 for 8 (X = H); 3489 (NH2),
3371 (NH2), 1688 (C@O) cmÀ1 for 1 (X = H); 1710
(C@O), 1601 (C@N) cmÀ1 for 10 (X = H). The final
products 11a–u and 12a–g were all unknown and char-
acterized on the basis of 1H NMR, 13C NMR, and
LC–MS (or GC–MS) spectral data.
On the other hand, resin-bound methyl 5-amino-2-nitro-
benzoate 15, prepared from reductive amination of
AMEBA resin 13 with the corresponding aniline 14,
gave benzoylated resin 16 by treatment with benzoyl
chloride in the presence of DIEA in CH2Cl2 (Scheme
2). Reduction of the resin 16 with SnCl2Æ2H2O in
DMF at 80 °C afforded the resin-bound anthranilic acid
derivative 2, which was converted to the dithiazole resin
17 under the same condition as that for the Wang resin-
bound 1. Cyclization of the resin 17 by the reactions
with various primary alkylamines in THF at rt followed
by cleavage from the resins 18 using 50% TFA/DCM at
rt gave the 2-cyanoquinazolin-4(3H)-ones 19 in 30–44%
yields and 85–100% purities. The results are summarized
in Table 2.11 The progress of the reactions on solid
phase was also monitored by single bead ATR-FTIR
spectroscopy as shown in Figure 2. The intermediate
resins exhibited distinguishing bands on the IR spectra,
that is, 3400 (NH), 1736 (C@O), 1504 (NO2),
1319 (NO2) cmÀ1 for 15; 1737 (C@O), 1655 (C@O),
1528 (NO2), 1342 (NO2) cmÀ1 for 16; 3489 (NH2),
3369 (NH2), 1691 (C@O), 1642 (C@O) cmÀ1 for 2;
1723 (C@O), 1646 (C@O), 1601 (C@N) cmÀ1 for 17;
1691 (C@O), 1646 (C@O) cmÀ1 for 18. The final prod-
ucts 19a–h were all unknown and characterized on the
basis of 1H NMR, 13C NMR, and LC–MS spectral data.
Figure 1.
The resin-bound anthranilic acid derivatives 1 were pre-
pared from coupling of Wang resin 7 with 2-nitrobenz-
oic acids in the presence of DIC and DMAP in
CH2Cl2/DMF (4/1) at rt and subsequent reduction of
the resultant resins 8 with SnCl2Æ2H2O in DMF at
80 °C (Scheme 1). Treatment of the resins 1 with 2,3-di-
chloro-5H-1,2,3-dithiazolium chloride (Appelꢀs salt)8 9
in the presence of pyridine in CH2Cl2 at rt gave the
dithiazole resins 10. Cyclative release from the resins
10 by the reactions with various primary alkylamines
in THF at rt gave the desired 2-cyanoquinazolin-
4(3H)-ones 11 in 35–60% yields and 82–100% purities.
In addition, treatment of the resins 10 with some ethan-
O
H2N
O
Ph
O
OMe
H
O
14
H
N
PhCOCl
DIEA
NO2
N
OMe
NO2
OMe
NO2
NaBH(OAc)3
O
DCM
DCE
rt
40 oC, sealed
13
16
15
O
Ph
O
N
Cl
_
Cl
O
Ph
N
O
.
+
S
OMe
Cl
Cl
S
N
SnCl2 2H2O
9
N
OMe
DMF
pyr
80 oC
DCM
rt
NH2
S
17
2
S N
O
O
Ph
H
O
Ph
N
R
H2NR
50% TFA
DCM
rt
N
N
N
R
N
THF
rt
O
CN
N
CN
19
18
Scheme 2.

7480
M.-K. Jeon et al. / Tetrahedron Letters 46 (2005) 7477–7481
Table 2. Yields and purities of the compounds 19
Compound
R
Yielda (%)
Purityb (%)
19a
19b
19c
19d
19e
19f
19g
19h
MeOCH2CH2
Cyclohexanemethyl
Benzyl
4-Methylbenzyl
4-Chlorobenzyl
Phenethyl
30
44
35
31
30
34
37
31
85
100
92
90
88
100
88
93
4-Methoxyphenethyl
4-Fluorophenethyl
a Six-step overall isolated yield from AMEBA resin (loading capacity 0.85 mmol/g).
b Determined on the basis of LC–MS spectrum after column chromatography.
ones 19 from 2 via dithiazole resins 10 and 17. The reac-
tions on solid phase were monitored by single bead
ATR-FTIR spectroscopic method. Now under way is
the construction of the corresponding compound li-
braries using structurally and functionally more diverse
building blocks. On the other hand, investigation is in
progress into efficient methods for another heterocyclic
compound utilizing the resin-bound anthranilic acid
derivatives 1 and 2.
Acknowledgements
We are grateful to Ministry of Commerce, Industry and
Energy of Korea, the Center for Biological Modulators,
and Korea Research Institute of Chemical Technology,
for financial support of this research.
Supplementary data
Representative procedure for preparation of compounds
1
11, 12, and 19, H NMR, 13C NMR, and MS spectral
data of compounds 11, 12, and 19. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2005.09.015.
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