Transformation of 5,5-diaryl-4,5-dihydro-1,2,4-oxadiazoles to 4-arylquinazolines

Article abstract of DOI:10.1016/S0040-4039(03)00229-6

The transformation of 5,5-diaryl-4,5-dihydro-1,2,4-oxadiazoles to 4-arylquinazolines in boiling acetic anhydride via acyclic 1-acetyloxy-4-aryl-1,3-diaza-1,3-butadienes is described.

Full text of DOI:10.1016/S0040-4039(03)00229-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2015–2017
Transformation of 5,5-diaryl-4,5-dihydro-1,2,4-oxadiazoles to
4-arylquinazolines
Wojciech Szczepankiewicz,* Paweł Wagner, Mirosław Danicki and Jerzy Suwin´ski
Institute of Organic Chemistry and Technology, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland
Received 15 October 2002; revised 17 January 2003; accepted 24 January 2003
Abstract—The transformation of 5,5-diaryl-4,5-dihydro-1,2,4-oxadiazoles to 4-arylquinazolines in boiling acetic anhydride via
acyclic 1-acetyloxy-4-aryl-1,3-diaza-1,3-butadienes is described. © 2003 Elsevier Science Ltd. All rights reserved.
The discovery of the strong anticancer activity of some
quinazoline derivatives1 has caused increased interest in
the synthesis of quinazolines.2 A search through the
review literature concerning quinazolines shows that
only very little is known about synthesis of the system
via the formation of the 1,8a bond.3 For example, in
Brown’s monograph on quinazolines4 this route was
called ‘unappealing’ and only half a page was dedicated
to it. The reason seems to be connected with the poor
availability of the starting materials, namely 4-aryl-1,3-
diaza-1,3-butadiene derivatives 1 suitable for quinazo-
line ring formation (Fig. 1).
Though compounds 1a (X=H) are rather easily pre-
pared by condensing benzamidines with aldehydes, on
heating they unfortunately form 1,3,5-triazines5 and not
quinazolines. In contrast, some derivatives, e.g. 1b (X=
OH) or 1c (X=OAc) are practically unknown. Until
now we have found only one example of the synthesis
of 1b (R1=Ph, R2=R3=H, X=OH, 10% yield),6
which involves the dehydration of benzaldoxime on
molecular sieves in the presence of RuS2 as a catalyst.
The acetate 1c of this compound remains unknown.
It is worth mentioning that quinolines7 and
quinoxalines8 have been successfully obtained in high
yields by heating easily available O-acetates of b,b-
diphenyl-a,b-unsaturated ketoximes and a-arylimino-
ketoximes in non-polar solvents, by formation of the
respective 1,8a-bonds.
Looking for a convenient approach to 1c (X=OAc) we
noticed the formal tautomerism between 1b and 5-aryl-
4,5-dihydro-1,2,4-oxadiazoles 2 (Scheme 1).
Figure 1.
We considered that 2 would react with acetic anhydride
to yield the desired 1c which on heating should be
further transformed to quinazolines 3.
Compounds 2 are reasonably easy to prepare.9 We
obtained several such 4,5-dihydro-1,2,4-oxadiazoles by
the 1,3-dipolar cycloaddition reaction of arenenitrile
N-oxides to benzophenone imines: R1=Ar, R2=Ph,
R3=H10 or R1=Ar, R2=p-MeC6H4, R3=Me11
(Scheme 2). The N-oxides were prepared from areneox-
imoyl chlorides12 using triethylamine.13
Scheme 1.
Keywords: oxadiazoles; quinazolines; dipolar cycloaddition; transfor-
mation; electrocyclization; imines; nitrile oxides.
* Corresponding author. Tel.: +48-32-2372635; fax: +48-32-2372094;
e-mail: wojtex@polsl.gliwice.pl
Heating 2 in an excess of boiling acetic anhydride for
six hours followed by careful treatment of the resulting
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00229-6

2016
W. Szczepankiewicz et al. / Tetrahedron Letters 44 (2003) 2015–2017
Scheme 2.
Scheme 3.
solution with water afforded solid products, which were
collected and recrystallized from methanol (Scheme 3,
Table 1).
Figure 2. Crystal structure of 3g. Displacement ellipsoids are
drawn at the 50% probability level.
MS and NMR analyses showed that compounds 2 in
boiling acetic anhydride afford the expected quinazoli-
nes 3 with yields from low to satisfactory. In the case of
3f–3i the position of the R3 substituent was uncertain.
X-Ray analysis of a single crystal of 3g unequivocally
proved that R3 occupies position 7 of the quinazoline
system (Fig. 2).15 This indicates 1,8a bond formation
via direct attack of the oxime nitrogen atom on one of
the ortho positions of the benzene rings. Such a reaction
can occur as a thermal electrocyclic disrotatory process.
The intermediate 1,8a-dihydroquinazoline derivative
can then thermally eliminate acetic acid to give the
aromatic product (Scheme 4).
A radical mechanism recently proposed by Maroulis et
al.8 for the formation of quinoxalines from a-(N-
arylimino)oxime acetates seems not to operate in this
reaction. In the syntheses of quinolines and quinoxa-
lines phenolic radical scavengers affect neither the com-
Scheme 4.
have not found 6-substituted quinazolines in the
product mixtures.
position nor yields of the products.16 Also
a
reaction-path including a spiro intermediate formed as
a result of an ipso attack of the oxime nitrogen atom on
the benzene ring (Scheme 5) can be ruled out since we
To conclude, our results show that readily available
5,5-diaryl-4,5-dihydro-1,2,4-oxadiazoles transform in
Table 1. Yields and melting points of quinazolines obtained by heating 5,5-diaryl-4,5-dihydro-1,2,4-oxadiazoles in boiling
acetic anhydride
Compound
R1
R2
R3
Yield (%)
Mp (°C)
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ph
Ph
Ph
H
H
H
H
64
66
79
45
81
33
78
30
80
120–121a
164–166
181–183
116–118
191–194
119–121
153–155
152–154
147–148
4-MeC6H4
3-NO2C6H4
3-ClC6H4
4-BrC6H4
Ph
4-MeC6H4
3-ClC6H4
4-ClC6H4
Ph
H
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Me
Me
Me
Me
a 119–120°C.14

W. Szczepankiewicz et al. / Tetrahedron Letters 44 (2003) 2015–2017
2017
3. Undheim, K.; Benneche, T. In Pyrimidines and their
Benzo Derivatives in Comprehensive Heterocyclic Chem-
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Eds.; Elsevier Science: Oxford, 1996; Vol. 6 (Boulton, A.
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4. Brown, D. J. Quinazolines. Supplement I; John Wiley &
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5. Gund, P.; Berkelhamer, G.; Wayne, R. S. Tetrahedron
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6. Gieren, A.; Dederer, B.; Ugi, I.; Stu¨ber, S. Tetrahedron
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Scheme 5.
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boiling acetic anhydride into 4-arylquinazolines via 4,4-
diaryl-1,3-diaza-1,3-butadiene
derivatives,
which
undergo thermal electrocyclization to form the 1,8a-
bond of the quinazoline system.
10. (a) Solladie´, G.; Saint Clair, J.-F.; Philippe, M.; Semeria,
D.; Maignan, J. Tetrahedron: Asymmetry 1996, 7, 2359;
(b) Product of Sigma-Aldrich Co., no. 29,373-3.
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Chem. Soc. (A) 1970, 2019.
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13. Procedure: Triethylamine (0.01 mol) in chloroform (10
ml) was dropped into the oximoyl chloride (obtained
from 0.01 mol of a respective benzaldoxime)9 in chloro-
form (30 ml) at 0°C followed by addition of the imine
(0.01 mol) solution in chloroform (15 ml). The resulting
solution was stirred for 1 h at 0°C and then overnight at
ambient temperature. The mixture was extracted with
dilute aqueous hydrochloric acid, then with water, dried
over anhydrous magnesium sulfate and evaporated to
dryness. The solid residues were recrystallized from
methanol.
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+44(0)1223-336033
or
e-mail:
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