Novel solid-phase synthesis of 2,6-disubstituted 4(3H)-quinazolinones for combinatorial library generation

Article abstract of DOI:10.1016/S0040-4039(02)00419-7

A novel procedure for the synthesis of 6-alkoxy-2-amino-4(3H)-quinazolinones from 2,4-dichloro-6-hydroxyquinazoline, amines and alcohols using Wang resin is described.

Full text of DOI:10.1016/S0040-4039(02)00419-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2971–2974
Novel solid-phase synthesis of 2,6-disubstituted
4(3H)-quinazolinones for combinatorial library generation
Csaba We´ber,* Attila Bielik, Gyo¨rgyi I. Szendrei and Istva´n Greiner
Chemical and Biotechnological Research and Development, Gedeon Richter Ltd, PO Box 27, H-1475 Budapest, Hungary
Received 7 February 2002; revised 15 February 2002; accepted 28 February 2002
Abstract—A novel procedure for the synthesis of 6-alkoxy-2-amino-4(3H)-quinazolinones from 2,4-dichloro-6-hydroxyquinazo-
line, amines and alcohols using Wang resin is described. © 2002 Elsevier Science Ltd. All rights reserved.
2-Amino-4(3H)-quinazolinones are of pharmacological
interest as histamine H2-antagonists,1 antibacterial2 and
antihypertensive3 agents. Antimicrobial,4 anticonvul-
sant,5 antitumor6 and potential antiinflammatory7
activities of 4(3H)-quinazolinones have also been dis-
closed. Some 2-amino-4(3H)-quinazolinones have been
isolated from natural products.8 In the course of our
efforts directed towards the solid-phase synthesis of
structurally diverse heterocycles having potential bio-
logical activity, we have developed a method for the
preparation of compounds containing this structural
element.
anthranilic acids. The second one is that the cyclization
occurs under solid-phase conditions.
There have been a number of combinatorial chemistry
applications reported of trichlorotriazines,13,14 di- and
trichloropyrimidines15,16 and dichloropurines.17–19 The
common feature of these methods is the selective
replacement of the halogens by nucleophiles.
Our approach is based on 2,4-dichloroquinazoline
derivatives having a functional group (Y) on the ben-
zene ring available for further modification on solid
support. The two chlorines at C-2 and C-4 can be
replaced selectively by nucleophiles. This type of com-
pound can be coupled to solid supports at C-4 via a
nucleophilic linker, while the second nucleophile (the
first diversity element) can be introduced into C-2
(Scheme 1). The second diversity element (Z) can be
coupled via the functional group of the benzene ring
(Y).
There have been a number of syntheses reported of
4(3H)-quinazolinone derivatives on solid support.9–11
More recently Yang and co-workers12 described a solid-
phase synthesis approach to this type of compound.
This two-step method is based on the acylation of
resin-bound thiourea by isatoic anhydride, followed by
cleavage of the product via an intramolecular cycliza-
tion. All of these procedures have two common fea-
tures. The first one is that the diversity of the benzene
ring of the molecule derives from substituted
Following the retrosynthetic strategy, amines and alco-
hols were used as building blocks and 2,4-dichloro-6-
Scheme 1.
Keywords: 4(3H)-quinazolinones; solid phase; Mitsunobu.
* Corresponding author. Fax: 36 1 4326002; e-mail: cs.weber@richter.hu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00419-7

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C. We´ber et al. / Tetrahedron Letters 43 (2002) 2971–2974
hydroxyquinazoline† as the core structure. The protected
form of the core was prepared from 6-hydroxy-
2,4(1H,3H)-quinazolinedione20 in four steps (Scheme 2).
with BF3·Et2O in the presence of thiophenol (PhSH) in
THF followed by alkylation of the resulting phenol with
alcohols under Mitsunobu conditions.22–24 Our experi-
mental results with diethyl azodicarboxylate (DEAD)/
triphenylphosphine (PPh3) were in accordance with the
observations made by Krchna´k et al.25 They found that
fast addition of undiluted DEAD to the reaction mixture
resulted in the formation of a side product, the corre-
sponding ethyl ether. We could not fully avoid this side
product using diluted reagents and slow addition. How-
ever, the experiments carried out with diisopropyl azod-
icarboxylate DIAD/PPh3 worked well providing the
expected ethers of primary and secondary alcohols with-
out isopropyl ether impurity. The final products were
cleaved from the resin with 20% TFA in CH2Cl2 (Table
1, entries 6–9).
The general approach for the solid-phase synthesis of
6-alkoxy-2-amino-4(3H)-quinazolinones is shown in
Scheme 3. Wang resin21 was deprotonated by BuLi in
THF and was then reacted with 1 to give 2. Reaction of
2 with secondary amines in DMF at 100°C afforded
resin-bound 2-aminoquinazolines 3. These compounds
were cleaved from the resin to give 7. We observed that
alkyl and cyclic secondary amines gave the substituted
6-hydroxy-4(3H)-quinazolinone derivatives in high yield
and excellent purity (Table 1, entries 1–3). On the other
hand primary or aryl amines yielded the desired product
in only trace amounts even under aggressive conditions
(70 h with a 15-fold excess of amine) (Table 1, entries 4
and 5). In these multicomponent products the 2-chloro-6-
hydroxy-4(3H)-quinazolone derivative was detected.
The second step of diversification was achieved by
removing the THP (tetrahydropyran-2-yl) group of 3
A representative set of 4(3H)-quinazolinones synthesized
by this approach is summarized in Table 1. As shown,
most compounds gave a fair overall yield and good to
excellent purity.
Scheme 2. Reagents and conditions: (i) Ac2O, pyridine, reflux, 3 h, 94% (ii) POCl3, PhNEt2, reflux, 2 h, 72% (iii) MeOMgCl,
MeOH, THF, reflux, 3 h, 91% (iv) 3,4-dihydro-2H-pyran, THF, cat. H2SO4, reflux, 84%.
Scheme 3. Reagents and conditions: (i) 2.2 equiv. BuLi, 3 equiv. 1, rt, 5 h; (ii) 5 equiv., HNR1R2, DMF, 24 h, 100°C; (iii) 20%
TFA/DCM (iv) 1 equiv. BF3·Et2O, PhSH, THF, rt, 1 h; (v) 10 equiv. PPh3, 10 equiv. DIAD, 10 equiv. R3OH, rt, 16 h; (vi) 20%
TFA/DCM.
† Physical and spectroscopic data for compound 1 (Scheme 2) and their precursors: 6-Acetoxy-2,4(1H,3H)-quinazolindione: mp 321–324°C; 1H
NMR (DMSO-d6, TMS) l 2.28 (s, 3H), 7.20 (d, 1H, J=8.7 Hz ), 7.42 (dd, 1H, J=8.7 Hz and 2.7 Hz), 7.61 (d, 1H, J=2.7 Hz), 11.27 (br s,
1
2H); MS (EI) 220 (M+). 6-Acetoxy-2,4-dichloroquinazoline: mp 143–144°C; H NMR (CDCl3, TMS) l 2.40 (s, 3H), 7.74 (dd, 1H, J=9.3 Hz and
2.4 Hz), 8.00 (d, 1H, J=2.4 Hz ), 8.03 (d, 1H, J=9.3 Hz); MS (EI) 256 (M+). 2,4-Dichloro-6-hydroxyquinazoline: mp 171–172°C; 1H NMR
(DMSO-d6, TMS) l 7.42 (d, 1H, J=2.4 Hz), 7.69 (dd, 1H, J=9.3 Hz and 2.4 Hz), 7.93 (d, 1H, J=9.3 Hz), 10.96 (s, 1H); MS (EI) 214 (M+).
1
2,4-Dichloro-6-(tetrahydropyran-2-yloxy)quinazoline: mp 116–117°C; H NMR (CDCl3, TMS) l 1.58–1.84 (m, 3H), 1.91–2.13 (m, 3H), 3.64–3.74
(m, 1H), 3.80–3.92 (m, 1H), 5.65 (t, 1H, J=3.3 Hz), 7.71 (dd, 1H, J=9.0 Hz and 2.7 Hz), 7.76 (d, 1H, J=2.7 Hz), 7.92 (d, 1H, J=9.0 Hz);
MS (EI): 298 (M+).

C. We´ber et al. / Tetrahedron Letters 43 (2002) 2971–2974
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Table 1.
Entry
Compound
NR1R2
R3
Yield (%)a
Purity (%)b
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
6a
6b
6c
6d
Piperidin-1-yl
–
–
–
–
75
69
74
–
99
94
88
15
12
97
98
92
96
Morpholin-4-yl
Bis(n-butyl)amino
n-Hexylamino
N-Methylphenylamino
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
–
–
Methyl
Ethyl
Isopropyl
2-Methylbutyl
57
71
67
62
a The overall yield was determined by weight based on the loading of 2. The yields refer to compounds purified by flash chromatography.
b The purities of the crude products were determined by HPLC–MS at 254 nm. The structures of the purified products were confirmed by 1H
NMR and MS spectroscopy. Compound 7a: 1H NMR (DMSO-d6, TMS) l 1.50–1.78 (br m, 6H), 3.58–3.70 (br m, 4H), 7.21 (dd, 1H, J=8.9 Hz
and 2.6 Hz), 7.28 (d, 1H, J=2.6 Hz), 7.40 (d, 1H, J=8.9 Hz), 9.94 (br s, 1H); MS (EI) 245 (M+). Compound 7b: 1H NMR (DMSO-d6, TMS)
l 3.69–3.84 (br m, 8H), 7.29 (dd, 1H, J=9.0 Hz and 3.0 Hz), 7.34 (d, 1H, J=3.0 Hz), 7.81 (d, 1H, J=9.0 Hz), 10.20 (br s, 1H); MS (EI) 247
(M+). Compound 7c: 1H NMR (DMSO-d6, TMS) l 0.91 (t, 6H, J=7.2 Hz), 1.26–1.40 (m, 4H), 1.49–1.62 (m, 4H), 3.55 (t, 4H, J=7.5 Hz), 7.20
(dd, 1H, J=9.0 Hz and 3.0 Hz), 7.28 (d, 1H, J=3.0 Hz), 7.44 (d, 1H, J=9.0 Hz), 9.82 (br s, 1H); MS (EI) 289 (M+). Compound 7d: MS (EI)
261 (M+). Compound 7e: MS (EI) 267 (M+). Compound 6a: 1H NMR (MeOH-d4, TMS) l 1.70–1.85 (br m, 6H), 3.70–3.80 (br m, 4H), 3.89 (s,
3H), 7.41 (dd, 1H, J=9.0 Hz and 2.7 Hz), 7.50–7.56 (m, 2H); MS (EI) 259 (M+). Compound 6b: 1H NMR (DMSO-d6, TMS) l 1.34 (t, 3H, J=6.9
Hz), 1.48–1.66 (br m, 6H), 3.49–3.60 (br m, 4H), 4.05 (q, 2H, J=6.9 Hz), 7.15–34 (m, 3H), 11.23 (s, 1H); MS (EI) 273(M+). Compound 6c: 1H
NMR (DMSO-d6, TMS) l 1.28 (d, 6H, J=6.0 Hz), 1.46–1.68 (br m, 6H), 3.50–3.62 (br m, 4H), 4.54–4.68 (m, 1H), 7.11–7.34 (m, 3H), 11.22
(s, 1H); MS (EI) 287 (M+). Compound 6d: 1H NMR (MeOH-d4, TMS) l 0.98 (t, 3H, J=7.2 Hz), 1.04 (d, 3H, J=6.6 Hz), 1.22–1.36 (m, 1H),
1.52–1.78 (m, 7H), 1.78–1.97 (m, 1H), 3.60–3.74 (m, 4H), 3.76–3.92 (m, 2H), 7.24 (dd, 1H, J=9.0 Hz and 3.0 Hz), 7.35 (d, 1H, J=9.0 Hz), 7.46
(d, 1H, J=3.0 Hz); MS (EI) 315 (M+).
Our approach is especially attractive for combinatorial
synthesis due to the wide range of commercially avail-
able alcohols and secondary amines which can be used
as diversity elements. Considering the fact that it is the
enol–ether form of 4(3H)-quinazolinone that is coupled
to solid support allows us to use Mitsunobu conditions
without alkylation of N-3 or C4-O.
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In summary, we have developed a new solid-phase
method for the synthesis of 2,6-disubstituted-4(3H)-
quinazolinones. Simple and mild reaction conditions
and the huge number of commercially available build-
ing blocks permit us to synthesize large combinatorial
libraries.
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Acknowledgements
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