Synthesis of substituted quinazolines

Article abstract of DOI:10.1016/S0040-4039(02)00558-0

A novel and flexible synthetic route is described for the synthesis of 5,6,8-alkyl-7-methoxy-2-aminoquinazolines using dihydrobenzenes as key intermediates.

Full text of DOI:10.1016/S0040-4039(02)00558-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3295–3296
Synthesis of substituted quinazolines
Yadagiri Bathini,a,* Inderjit Sidhu,a Rajeshwar Singh,a Ronald G. Miceticha and Peter L. Toogoodb
aNAEJA Pharmaceutical Inc., c2, 4290-91A Street, Edmonton, Alberta, Canada T6E 5V2
bPfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
Received 8 February 2002; revised 13 March 2002; accepted 15 March 2002
Abstract—A novel and flexible synthetic route is described for the synthesis of 5,6,8-alkyl-7-methoxy-2-aminoquinazolines using
dihydrobenzenes as key intermediates. © 2002 Elsevier Science Ltd. All rights reserved.
The many and varied biological properties of quinazo-
lines have engendered widespread interest in their syn-
thesis.1,2 This group of compounds exhibits numerous
pharmacological activities such as sedative, analgesic,
diuretic, antihypertensive, antibiotic and antitumoral
properties and many quinazolines have been demon-
strated to inhibit kinases by competing with ATP for
the kinase active site.3,4 During a project directed at
the discovery of new quinazoline-based kinase
inhibitors, we required a synthetic route that would
facilitate the introduction of substituents at the 2, 5, 6,
7, and 8 positions of the quinazoline core. Frequently,
quinazolines are synthesized starting from 2-aminoben-
zoic acid or its derivatives.5 Alternatively, the fused
phenyl ring may be assembled via a cycloaddition
strategy.6
R1
R1
R1
R1
R2
Li/NH3
OCH3
R2
R2
R2
nBuLi, R3X
OCH3
2.5 M HCl
MeOH
OCH3
CH3O
CH3O
CH3O
CH3O
O
R3
R3
1
2
3
4
a, b: R1 = H, R2 = H
c : R1 = CH3, R2 = H
d: R1 = H, R2 = CH3
a, b: R1 = H, R2 = H
c : R1 = CH3, R2 = H
d: R1 = H, R2 = CH3
R1
R1
R1
R2
R2
R2
CH3O
NaOCH3
HCO2Et, NaH
Benzene
O
Guanidine carbonate
DMF
OH
N
MeOH/THF
CH3O
CH3O
O
N
NH2
R3
R3
R3
6
5
7
R1
For compounds 3 - 8
a: R1 = H, R2 = H, R3 = 2-propyl
b: R1 = H, R2 = H, R3 = cyclopentyl
c : R1 = CH3, R2 = H, R3 = cyclopentyl
d: R1 = H, R2 = CH3, R3 = cyclopentyl
R2
CH3O
10% Pd-C
N
nitrobenzene
150 oC, 2 days
N
NH2
R3
8
Scheme 1.
* Corresponding author. Tel.: (780) 462 4044; fax: (780) 461 0196; e-mail: ybathini@naeja.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00558-0

3296
Y. Bathini et al. / Tetrahedron Letters 43 (2002) 3295–3296
Recently, the reaction of 2-fluoroacetophenones with
guanidine carbonate was used for the synthesis of 2-
amino-4-alkylsubstituted quinazolines.7 Separately,
regioselective metallation at the peri position of quina-
zolines has been reported using LTMP.8 Surprisingly,
quinazolines bearing substitution at positions 2, 7, and
8 as we needed were not previously known in the
literature and none of the previously reported
approaches to quinazolines were generally useful for
the synthesis of our target compounds. Here we
describe the synthesis of various substituted quinazoli-
nes using dihydrobenzenes as key intermediates. Dihy-
drobenzenes are readily available from Li/NH3
reduction of benzenoid precursors. This approach also
allows for the introduction of alkyl groups at what will
become position C-8 in the final quinazoline target
(Scheme 1).
In conclusion, we report here a convenient synthesis of
2, 5/6, 7, 8-tetrasubstituted quinazolines that employs
dihydrobenzenes as key intermediates. This route offers
flexibility to introduce a variety of alkyl groups at the
C-5, C-6 and C-8 positions either by choosing the
appropriate starting material or through the choice of
alkylating agent. The intermediate 6 is a 1,3-dicarbonyl
compound that may have utility in the synthesis of
various heterocyclic compounds. To our knowledge this
is the first application of dihydroaromatic compounds
in the synthesis of 2-aminoquinazolines.
Acknowledgements
The authors thank Ellen Dobrusin and Mark Barvian
for helpful suggestions. This manuscript is respectfully
dedicated to Professor Henry Rapoport in memoriam.
1,3-Dimethoxybenzenes 1a–d were reduced to cyclo-
hexa-1,4-dienes 2a–d using lithium metal in liquid
ammonia. Compounds 2a–d then were alkylated with
either 2-iodopropane or cyclopentyl bromide to give
compounds 3a–d using n-BuLi as the base. The alkyl-
ated products were obtained in 80–95% yield. With
some care, partial hydrolysis of dienolethers 3a–d could
be achieved with 2.5% HCl in methanol at 0°C to give
b, g, unsaturated ketones 4a–d in high yield. It should
be noted that only the trisubstituted enolether in 3d was
hydrolyzed to give 4d exclusively. The non-conjugated
double bond in compounds 4a–d was isomerized using
NaOMe in methanol at room temperature to give a,b-
unsaturated ketones 5a–d. Compounds 5a–d then were
formylated with ethyl formate in the presence of
sodium hydride in benzene to give compounds 6a–d in
moderate yield. The condensation of 6a–d with
guanidine carbonate at 140°C in DMF provided 5,6-
dihydroquinazolines 7a–d as the major products. 1H
NMR analysis indicated that the 5,6-dihydroquinazo-
line products were isolated with a small amount (ꢀ
10%) of the corresponding 5,8-dihydroquinazolines.
These dihydroquinazoline mixtures could be aroma-
tized without separation to cleanly produce compounds
8a–d by heating them in nitrobenzene at 150°C in the
presence of 10% Pd–C.9 The overall yields of 8 from 6
ranged from 40 to 50%.† It is noteworthy that the
guanidine amino group was stable under the aromatis-
ing conditions.
References
1. Jhone, S. In Progress In Drug Research; Jucker, E., Ed.;
Birkauser Verlag: Basel, 1982; Vol. 26, pp. 259–341.
2. Brown, D. J. The Chemistry of Heterocyclic Compounds; J.
Wiley & Sons: New York, 1996.
3. Boschelli, D. H. Drugs Future 1999, 24, 515–537.
4. Dumas, J. Expert Opin. Therapeut. Pat. 2001, 11, 405–429.
5. (a) Curd, F. H. S.; Landquist, J. K.; Rose, F. L. J. Chem.
Soc. 1948, 1759; (b) Clark-Lewis, J. W.; Singh, R. P. J.
Chem. Soc. 1962, 3162; (c) Armarego, W. L. F. J. Chem.
Soc. 1961, 2697; (d) Sen, A. B.; Gupta, S. K. J. Indian
Chem. Soc. 1962, 32, 368; (e) Downes, A. M.; Lions, F. J.
Am. Chem. Soc. 1950, 72, 3053; (f) Katritzky, A. R.;
Pozharski, A. F. Handbook of Heterocyclic Chemistry, 2nd
ed.; Pergamon: New York, 2000.
6. See for example: Wada, A.; Yamamoto, K.; Ohki, K.;
Nagai, S.; Kanamoto, S. J. Heterocyclic Chem. 1992, 29,
911.
7. Hynes, J. B.; Campbell, J. P.; Hynes, J. D. J. Heterocyclic
Chem. 1995, 32, 1185–1187.
8. Ple, N.; Truck, A.; Chapoulaud, V.; Quegueguiner, G.
Tetrahedron 1997, 53, 2871–2890.
9. Yadagiri, B.; Lown, J. W. Synth. Commun. 1990, 20,
955–963.
† All new compounds showed satisfactory spectral and analytical
data, e.g. 8a: Off-white solid; mp 112–113°C, 1H NMR (CDCl3) l:
1.38 (d, 6H, 2×CH3), 3.95 (s, 3H, OCH3), 4.24 (m, 1H, CH), 5.0 (s,
2H, NH2), 7.02 (d, 1H, Ar-H, J=9 Hz), 7.55 (d, 1H, Ar-H, J=9
Hz), 8.87 (s, 1H, Ar-H); MS: m/z 218.05 (MH+). 8b: Off-white
solid; mp 181–183°C, 1H NMR (CDCl3) l: 1.6–2.2 (complex, 8H,
4×CH2), 3.9 (s, 3H, OCH3), 4.27 (m, 1H, CH), 5.02 (s, 2H, NH2),
7.02 (d, 1H, Ar-H, J=9 Hz), 7.54 (d, 1H, Ar-H, J=9 Hz), 8.87 (s,
1H, Ar-H); MS: m/z 244.07 (MH+). 8c: Off-white solid; mp 200–
201°C, 1H NMR (CDCl3) l: 1.6–2.1 (complex, 8H, 4×CH2), 2.63 (s,
3H, CH3), 3.93 (s, 3H, OCH3), 4.24 (m, 1H, CH), 5.02 (s, 2H,
NH2), 6.81 (s, 1H, Ar-H), 9.06 (s, 1H, Ar-H); MS: m/z 258.17
(MH+). 8d: Off-white solid; mp 144–145°C, 1H NMR (CDCl3) l:
1.6–2.3 (complex, 8H, 4×CH2), 2.36 (s, 3H, CH3), 3.8 (s, 3H,
OCH3), 3.87 (m, 1H, CH), 4.99 (s, 2H, NH2), 7.34 (s, 1H, Ar-H),
8.85 (s, 1H, Ar-H); MS: m/z 258.06 (MH+).