Microwave-assisted Niementowski reaction. Back to the roots

Article abstract of DOI:10.1016/S0040-4039(02)00619-6

In a search to speed up an aspect of the drug discovery processes, the Niementowski synthesis of the 3H-quinazolin-4-one core was reinvestigated using microwave irradiation. The experimental methodology and microwave conditions described here are well established, allowing significant rate enhancements and good yields compared to conventional reaction conditions.

Full text of DOI:10.1016/S0040-4039(02)00619-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3911–3913
Microwave-assisted Niementowski reaction. Back to the roots
Franc¸ois-Rene´ Alexandre,a,b Amaya Berecibara and Thierry Bessonb,*
aPFIZER Global Research & Development, Fresnes Laboratories, 3–9 rue de la Loge, BP100, F-94265 Fresnes cedex, France
bLaboratoire de Ge´nie Prote´ique et Cellulaire, EA3169, Groupe de Chimie Organique, UFR Sciences Fondamentales et Sciences
pour l’Inge´nieur, Baˆtiment Marie Curie, Universite´ de la Rochelle, F-17042 La Rochelle cedex 1, France
Received 21 March 2002; revised 27 March 2002; accepted 28 March 2002
Abstract—In a search to speed up an aspect of the drug discovery processes, the Niementowski synthesis of the 3H-quinazolin-4-
one core was reinvestigated using microwave irradiation. The experimental methodology and microwave conditions described here
are well established, allowing significant rate enhancements and good yields compared to conventional reaction conditions.
© 2002 Elsevier Science Ltd. All rights reserved.
The quinazoline skeleton, when selectively functional-
ized, is a building block for the preparation of numer-
ous alkaloids and substances with pronounced
biological activities.1
and proceeds usually via an o-amidine intermediate
(Scheme 1). This procedure usually needs high tempera-
tures and requires lengthy and tedious conditions.
Microwave irradiation is known to allow a striking
reduction in reaction times, good yields and cleaner
reactions than the purely thermal procedures. Our pre-
vious experience in the use of microwave in organic
synthesis,5 led us to check if there was any possibility
for improvement in the Niementowski method used for
the synthesis of the quinazoline skeleton.6 In this paper,
we report the benefits associated with this new method-
ology and we identify standard experimental
conditions.
In the course of our work on the preparation of new
polyheterocyclic systems with pharmaceutical value, we
recently described the synthesis of novel heterocycles in
which the quinazoline ring was fused with thiazole,
indole or benzimidazole rings.2 Following such a strat-
egy, we planned to prepare 3H-quinazolin-4-one
derivatives which can be employed as intermediates in
the synthesis of useful bioactive compounds. Quina-
zolin-4-ones have not been the object of new synthetic
developments in the last few years and recent reports
on their preparation use only classical procedures.3 The
most common synthetic method of the 3H-quinazolin-
4-one ring is based on the Niementowski reaction,4
which involves the fusion of anthranilic acid (or a
derivative, e.g. 2-aminobenzonitrile) with formamide
Following the strategy originally published by Niemen-
towski,4 synthesis of the 3H-quinazolin-4-one ring
involves long heating (several hours) of the anthranilic
acids with an excess of formamide at 130–150°C. The
amount of quinazolines obtained in such conditions is
Scheme 1. The Niementowski reaction:4 (a) conventional conditions: 130–150°C, average time 6 h; (b) microwave conditions: MW
(60 W), 150°C, average time 20 min.
Keywords: Niementowski reaction; microwave irradiation; quinazolin-4-ones.
* Corresponding author. Tel.: +33 (0)5 46 45 82 76; e-mail: tbesson@univ-lr.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00619-6

3912
F.-R. Alexandre et al. / Tetrahedron Letters 43 (2002) 3911–3913
Table 1. Synthesis of 3H-quinazolin-4-ones from various anthranilic acids7,9
Starting material
R1
R2
R3
Reaction time (min)
Product
Yield (%)
Mp (°C) (lit.8)
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
Me
Br
NO2
OMe
Br
H
H
H
H
OMe
H
H
H
H
H
H
H
Br
H
OMe
H
20
15
20
20
40
15
15
40
15
20
3a
3b
3c
3d
3e
3f
3g
3h
3i
90a
75
75
87
70
78
86
77
77
80
216b (215)
259b (260–261)
262b (261–267)
\260c (286)
\260d (296–297)
\260e (295–296)
\260e (\300)
231b (226–227)
\260e (273–274)
258e (258)
OH
OMe
–C2H4-
Pyridinef
OMe
1j
3j
a A conventional thermal heating (oil bath) of this reaction at 150°C for 6 h led to the expected product in a 59% yield.
b From EtOH.
c From MeOH.
d Not recrystallized.
e From H2O.
f Starting material: 2-aminonicotinic acid.
variable and sometimes low yields were observed
accompanied by complicated mixtures of carbonaceous
compounds and impurities which were difficult to elim-
inate, even by column chromatography or
recrystallization.
was extended to various anthranilic acids to give the
desired products in very good yields (Table 1). Here again
no by-products were detected and reactions were cleaner
than for the purely thermal procedures.
In conclusion we have reinvestigated the original work
by von Niementowski under microwave irradiation.
Using dedicated microwave instruments this reaction
could be easily and rapidly performed in very good yields,
providing a large quantity of various quinazolin-4-ones
which can be employed as intermediates in the synthesis
of useful bioactive compounds. We have also demon-
strated that previously difficult and traditional transfor-
mations can now be rapidly and safely completed by
microwave irradiation.
As we previously mentioned in similar studies, trans-
posing such a reaction under focused microwave irradi-
ation needs special attention. For this reason we
performed preliminary experiments in order to establish
the best experimental conditions.
(a) Irradiation power and temperature: condensation
of anthranilic acid with formamide was performed at
various temperatures (120–170°C) (with a power con-
trol) or at varying power (with infrared measurement
of the temperature reached in the mixture). A control
of the irradiation power and a fixed temperature led
to better yields and good experimental conditions.
(b) Heterogeneous or homogeneous mixtures: associ-
ation of liquid/solid reactants may involve uncon-
trolled reactions and is generally worse than in
comparative thermal reactions. As we previously pub-
lished in similar reactions, in the present study, exper-
iments in which the starting compounds were mixed on
graphite led to heterogeneous mixtures and resulted in
poor yields and hazardous bumping in the reactor. The
best alternative is to work with an excess of formamide
as fusion accelerator (by itself formamide is a good
candidate for microwave heating).
Acknowledgements
We thank R. Wrigglesworth (PFIZER) for helpful
discussion and CEM Corporation for financial support
and technical assistance.
References
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2. (a) Domon, L.; Le Coeur, C.; Grelard, A.; Thie´ry, V.;
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(c) Reactants: the ratio between the quantity of for-
mamide and anthranilic acid is very important. If it is
too small, lower yields were observed, probably due to
the resulting heavy syrup or gum which made the
work-up more difficult.
Among the various combinations tested, the best results
were obtained by treatment of the anthranilic acid with
5 equiv. of formamide with an irradiation programmed
at 60 W and a fixed temperature (150°C). Here again the
comparative study of this procedure by classical heating
(oil bath) and microwave irradiation showed that reac-
tion time was reduced from several hours to few minutes
(Scheme 1) by using the latter technique. This process

F.-R. Alexandre et al. / Tetrahedron Letters 43 (2002) 3911–3913
3913
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until completion (TLC monitoring, 20 min). After cooling
the reaction mixture was rinsed out with ethyl acetate
and evaporated under reduced pressure. Recrystallization
from ethanol afforded quinazolin-4-one 3a as a white
solid (960 mg, 90%).
Spectroscopic data for compounds 3: Quinazolin-4(3H)-
one 3a: MS (ESI, El+) m/z 147 (MH+); 1H NMR
(DMSO-d6) l 7.49 (dt, 1H, J=8.1, 1.0 Hz), 7.64 (d, 1H,
J=8.1 Hz), 7.78 (dt, 1H, J=8.1, 1.5 Hz), 8.07 (s, 1H),
8.10 (dd, 1H, J=8.1, 1.5 Hz), 12.29 (brs, 1H); 6-
methylquinazolin-4(3H)-one 3b: MS (ESI, El+) m/z 161
1
(MH+); H NMR (DMSO-d6) l 2.42 (s, 3H), 7.55 (d, 1H,
J=8.4 Hz), 7.62 (dd, 1H, J=8.4, 2.0 Hz), 7.90 (d, 1H,
J=2.0 Hz), 8.01 (s, 1H), 12.16 (brs, 1H); 6-bromoquina-
zolin-4(3H)-one 3c: MS (ESI, El+) m/z 225/227 (MH+);
1H NMR (DMSO-d6) l 7.61 (d, 1H, J=8.8 Hz), 7.95
(dd, 1H, J=8.8, 2.0 Hz), 8.13 (s, 1H), 8.17 (d, 1H, J=2.0
Hz), 12.45 (brs, 1H); 6-nitroquinazolin-4(3H)-one 3d: MS
6. Only one example of the synthesis of the quinazoline ring
via
a modified Niementowski reaction was recently
described: anthranilic acid and formanilide were mixed in
the presence of N,N-dimethylacetamide. See: Rad-
Moghadam, K.; Khajavi, M. S.; J. Chem. Res. (S) 1998,
702–703.
1
(ESI, El−) m/z 190 (M−H+); H NMR (DMSO-d6) l 7.83
7. Focused microwave irradiations were carried out at
atmospheric pressure with a CEM Discover™ focused
microwave reactor (300 W, monomode system) which has
in situ magnetic variable speed, irradiation monitored by
PC computer, infrared measurement and continuous feed-
back temperature control. Equipment of the oven was
completed by a condenser allowing conditions close to
those involved in classical methods; it is also possible to
work under dry atmosphere, in vacuo, or under pressure
(0–20 bar) if necessary.
8. Ref. for compound 3: (a) 3a, 3e, 3g: Le Mahieu, R. A.;
Carson, M.; Nazon, W. C.; Parrish, D. R.; Welton, A.
F.; Baruth, H. W.; Yaremko, B. J. Med. Chem. 1983, 26,
420–425; (b) 3b, 3c, 3d, 3f: Baker, B. R.; Schaub, Joseph,
J. P.; McEvoy, F. J.; Williams, J. H. J. Org. Chem. 1952,
17, 141–148; (c) 3h: Gavit, A.; Chen, J.; App, H.; McMa-
hon, G.; Hirth, P.; Chen, I.; Levitzki, A. Bioorg. Med.
Chem. 1996, 4, 1203–1208; (d) 3i: Baker, B. R.; Schaub,
Joseph, J. P.; McEvoy, F. J.; Williams, J. H. J. Org.
Chem. 1952, 17, 149–156; (f) 3j: Robins, R. K.; Hitchings,
G. H. J. Am. Chem. Soc. 1955, 77, 2256–2260.
(d, 1H, J=8.8 Hz), 8.29 (s, 1H), 8.51 (dd, 1H, J=8.8, 2.8
Hz), 8.76 (d, 1H, J=2.8 Hz), 12.75 (brs, 1H); 6,7-
dimethoxyquinazolin-4(3H)-one 3e: MS (ESI, El+) m/z
1
207 (MH+); H NMR (DMSO-d6) l 3.85 (s, 3H), 3.89 (s,
3H), 7.12 (s, 1H), 7.43 (s, 1H), 7.98 (s, 1H), 12.06 (brs,
1H); 6,8-dibromoquinazolin-4(3H)-one 3f: MS (ESI, El+)
m/z 304/308 (M−H+); 1H NMR (DMSO-d6) l 8.17 (d,
1H, J=2.4 Hz), 8.24 (s, 1H), 8.34 (d, 1H, J=2.4 Hz),
12.67 (brs, 1H); 6-hydroxy-4(3H)-quinazolin-4(3H)-one
1
3g: MS (ESI, El+) m/z 163 (MH+); H NMR (DMSO-d6)
l 7.43 (dd, 1H, J=8.8, 2.8 Hz), 7.39 (d, 1H, J=2.8 Hz),
7.52 (d, 1H, J=8.8 Hz), 7.89 (s, 1H), 10.07 (brs, 1H),
12.02 (brs, 1H); 6,7,8-trimethoxy-4(3H)-quinazolin-4(3H)-
one 3h: MS (ESI, El+) m/z 237 (MH+); 1H NMR
(DMSO-d6) l 3.85 (s, 3H), 3.88 (s, 3H), 23.93 (s, 3H),
7.33 (s, 1H), 7.99 (s, 1H), 12.18 (brs, 1H); benzo-
[g]quinazolin-4(3H)-one 3i: MS (ESI, El+) m/z 197
(MH+); 1H NMR (DMSO-d6) l 7.58 (m, 1H), 7.66 (m,
1H), 8.84 (m, 2H), 8.21 (m, 2H), 12.06 (brs, 1H);
pyrido[2,3-d]pyrimidin-4(3H)-one 3j:MS (ESI, El+) m/z
1
148 (MH+); H NMR (DMSO-d6) l 7.54 (dd, 1H, J=7.8,
9. Typical procedure for the synthesis of 3a: A mixture of
anthranilic acid (1 g, 7.3 mmol) and formamide (1.45 mL,
36.5 mmol) was irradiated at 150°C (power input: 60 W)
4.4 Hz), 8.30 (s, 1H), 8.49 (dd, 1H, J=7.8, 2.0 Hz), 8.94
(dd, 1H, J=4.4, 2.0 Hz), 12.55 (brs, 1H).