Concise synthesis of 2-amino-4(3H)-quinazolinones from simple (hetero)aromatic amines

Article abstract of DOI:10.1021/jo7026883

(Chemical Equation Presented) A novel and simple method of preparation of 2-alkylaminoquinazolin-4-ones with fused heteroaromatic rings from easily accessible (hetero)aromatic amines is described. The method is very efficient, and the 2-alkylaminoquinazolinone derivatives are obtained in three steps without chromatographic purification. The key step is the ring closure of the N-protected guanidine intermediates by intramolecular Friedel-Craft's type substitution.

Full text of DOI:10.1021/jo7026883

have been involved in the synthesis and study of this family of
compounds. Despite their simple skeleton, 2-aryl- and 2-alky-
laminoquinazolinones are not easily accessible. Several synthetic
methodologies, including recent solid-phase applications, have
been reported.8 As shown in Figure 1, most of them are based
on three disconnections. Their major limitations are the avail-
ability of diversely substituted aromatic starting materials
(mainly anthranilic acid derivatives) and the reactivity and
toxicity of the reagents, such as the alkyl- or aryl isocyanates,
required in paths b or c.
Concise Synthesis of
2-Amino-4(3H)-quinazolinones from Simple
(Hetero)aromatic Amines
Walid Zeghida, Julien Debray, Sabine Chierici,
Pascal Dumy, and Martine Demeunynck*
De´partement Chimie Mole´culaire, UMR 5250, UniVersite´ Joseph
Fourier, BP 53, 38041 Grenoble cedex 9, France
martine.demeunynck@ujf-grenoble.fr
ReceiVed December 18, 2007
A novel and simple method of preparation of 2-alkylami-
noquinazolin-4-ones with fused heteroaromatic rings from
easily accessible (hetero)aromatic amines is described. The
method is very efficient, and the 2-alkylaminoquinazolinone
derivatives are obtained in three steps without chromato-
graphic purification. The key step is the ring closure of the
N-protected guanidine intermediates by intramolecular
Friedel-Craft’s type substitution.
FIGURE 1. Literature data for the preparation of 2-alkylamino-
quinazolin-4-one derivatives.8a-j
More recently, two new methods were reported (Scheme 1),
the palladium-catalyzed cyclocarbonylation of o-iodoanilines
with heterocumulenes9 and the base-promoted ring closure of
o-fluorobenzoylguanidines.10 This first strategy is dependent on
the availability and stability of carbodiimines and requires
prolonged heating and high temperature, whereas the other is
compatible with the presence of various substituents but gives
moderate to low yields of cyclization.
Introduction
The quinazoline skeleton is found in a number of biologically
active molecules. In particular, 2-amino-4(3H)-quinazolinone
derivatives display a large range of biological properties such
as antitumor (thymidylate synthase inhibition1), antibacterial
and antifungal activities,1 antihypertensive effects,2 or dopamine
agonist activity.3 Very recently this class of compounds was
shown to interfere with insulin secretion and smooth muscle
contractile activity by targeting KATP channel activity,4 and such
molecules were tested as analgesic and anti-inflammatory
agents.5 Leonard6 and, more recently, Kool7 have also used
imidazo[d]quinazoline (benzoguanine) as a fluorescent analogue
of guanine. Several groups (both from academy and industry)
SCHEME 1. Syntheses of 2-Alkylaminoquinazolin-4-one
Derivatives from o-Iodoanilines and
o-Fluorobenzoylguanidines
* Fax: +33 476 514946. Telephone: +33 476 514429.
(1) Pendergast, W.; Johnson, J. V.; Dickerson, S. H.; Dev, I. K.; Duch,
D. S.; Ferone, R.; Hall, W. R.; Humphrey, J.; Kelly, J. M.; Wilson, D. C.
J. Med. Chem. 1993, 36, 2279-2291.
(2) Chern, J.-W.; Tao, P.-L.; Wang, K.-C.; Gutcait, A.; Liu, S.-W.; Yen,
M.-H.; Chien, S.-L.; Rong, J.-K. J. Med. Chem. 1998, 41, 3128-3141.
(3) Grosso, J. A.; Nichols, E. D.; Kohli, J. D.; Glock, D. J. Med. Chem.
1982, 25, 703-708.
(4) Somers, F.; Ouedraogo, R.; Antoine, M.-H.; de Tullio, P.; Becker,
B.; Fontaine, J.; Damas, J.; Dupont, L.; Rigo, B.; Delarge, J.; Lebrun, P.;
Pirotte, B. J. Med. Chem. 2001, 44, 2575-2585.
Our research interests focus on the design of biologically
active nitrogen heterocycles. In the past years, taking advantage
of the regioselective reactivity of aminoacridines with electro-
philic reagents, we have prepared several acridine-fused het-
erocycles of biological interest.11 We are currently studying the
chemical and biological properties of guanidino-substituted
acridines. As exemplified in Scheme 2, these compounds are
(5) Alagarsamy, V.; Dhanabal, K.; Parthiban, P.; Anjana, G.; Deepa, G.;
Murugesan, B.; Rajkumar, S.; Beevi, A. J. J. Pharm. Pharmacol. 2007,
59, 669-677.
(6) (a) Leonard, N. J. Acc. Chem. Res. 1982, 15, 128-135. (b) Keyser,
G. E.; Leonard, N. J. J. Org. Chem. 1976, 41, 3529-3532.
(7) Liu, H.; Gao, J.; Kool, E. T. J. Org. Chem. 2005, 70, 639-647.
10.1021/jo7026883 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/22/2008
J. Org. Chem. 2008, 73, 2473-2475
2473

TABLE 1. Preparation of 2-Propylamino(3H)quinazolin-4-one
Derivatives from Aromatic Amines
SCHEME 2. Formation of Quinolino[2,3-f]quinazolin-1-one
Skeleton from 3-Aminoacridine
prepared following the Manimala and Anslyn’s12 methodology,
by condensing the aminoacridines with ethoxycarbonyl isothio-
cyanate followed by coupling with aliphatic amines and
deprotection of the guanidine function. It appeared to us that
the ethoxycarbonyl group of the N-protected guanidino inter-
mediates was ideally positioned to react by intramolecular
Friedel-Craft’s type substitution, to form, in one step, the fused
pyrimidinone ring of 2-alkylaminoquinolino[2,3-f]quinazolinone
3 (Scheme 2).
The first attempt of cyclization was performed with guani-
dinoacridine 2.13 The reaction was successfully achieved by
heating 2 at 80 °C in DMF in the presence of ClSiMe3 (5 equiv).
The desired quinazolinone 3 was isolated as the hydrochloride
salt in 95% yield.14
To assess the scope of this approach, we performed this
cyclization process with various N-aryl and N-heteroaryl N′-
propylguanidines. We report in this paper a new efficient
methodology for the synthesis of substituted 2-propylamino-
quinazolin-4-ones from simple aromatic and heteroaromatic
amines. The results are summarized in Table 1.
The preparation of the ethoxycarbonyl-guanidines 5a-g was
performed in one pot by careful control of the stoichiometry of
the reagents, successively added to the chosen aromatic amine
dissolved in CH2Cl2. In most cases, the resulting protected
guanidines 5a-g were easily isolated in excellent levels of purity
(>95% as shown by HPLC analysis) by simple precipitation
(8) (a) For a recent review, see: Vo¨gtle, M. M.; Marzinzik, A. L. QSAR
Comb. Sci. 2004, 23, 440-459. See also: (b) Kundu, B.; Partani, P.;
Duggineni, S.; Sawant, D. J. Comb. Chem. 2005, 7, 909-915. (c) We´ber,
C.; Demeter, A.; Szendrei, G. I.; Greiner, I. Tetrahedron Lett. 2003, 44,
7533-7536. (d) Yang, R.-Y.; Kaplan, A. Tetrahedron Lett. 2000, 41, 7005-
7008. (e) Gopalsamy, A.; Yang, H. J. Comb. Chem. 2000, 2, 378-381. (f)
Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Org. Chem. 2002, 67, 5831-
5834. (g) Wilson, L. J. Org. Lett. 2001, 3, 585-588. (h) Villalgordo, J.
M.; Obrecht, D.; Chucholowsky, A. Synlett 1998, 1405-1407. (i) Molina,
P.; Alajarin, M.; Vidal, A. Tetrahedron 1989, 45, 4263-4286. (j) Zhang,
W.; Mayer, J. P.; Hall, S. E.; Weigel, J. A. J. Comb. Chem. 2001, 3, 255-
256.
(9) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773-2777.
(10) Fray, M. J.; Mathias, J. P.; Nichols, C. L.; Po-Ba, Y. M.; Snow, H.
Tetrahedron Lett. 2006, 47, 6365-6368.
(11) (a) Fixler, N.; Demeunynck, M.; Duflos, A.; Lhomme, J. Hetero-
cycles 1998, 48, 755-767. (b) Charmantray, F.; Duflos, A.; Lhomme, J.;
Demeunynck, M. J. Chem. Soc., Perkin Trans.1 2001, 2962-2968. (c)
Tatiboue¨t, A.; Demeunynck, M.; Andraud, C.; Collet, A.; Lhomme, J. Chem.
Commun. 1999, 161-162.
a
b
ClSiMe3 (5 equiv), 5 h reaction. ClSiMe3 (10 equiv), overnight
reaction.
(12) Manimala, J. C.; Anslyn, E. V. Tetrahedron Lett. 2002, 43, 565-
from water. The same sequence of reactions was also performed
using DMF as the solvent, with similar results. The next step
of ring closure was achieved by heating the crude guanidines
5a-g in DMF in the presence of an excess of ClSiMe3. As
indicated by HPLC analysis, the guanidines have been fully
567.
(13) The synthesis and reactivity of compound 2 and other acridine
analogues will be described elsewhere. The spectroscopic data of compounds
2 and 3 are given in the Supporting Information.
(14) Zeghida, W. Ph.D. thesis, Universite´ Joseph Fourier, Grenoble,
France, 2007.
2474 J. Org. Chem., Vol. 73, No. 6, 2008

converted into the corresponding quinazolinone analogues (6a-
g), which were isolated as free bases in excellent yields by
evaporation of the solvent and trituration of the residue in water
in the presence of NH4OH. As observed previously in the
acridine series, the cyclization step was regioselective in the
indole series (entry 6) and occurred on the carbon adjacent to
the ring junction.15 With the aminoindane isomer 5d, a mixture
of two regioisomers (linear lin-6d and angular ang-6d) was
obtained. The two isomers were clearly characterized and
Experimental Section
General Procedure for One-Pot Synthesis of Guanidine
Derivatives. Ethyl isothiocyanatoformate (135 µL, 1.2 mmol) was
added to a solution of the (hetero)cyclic amine (1 mmol) in CH2-
Cl2 (10 mL). The solution was stirred at room temperature for 1.5
h. The disappearance of the starting amine was checked by TLC
or HPLC analysis. To the solution, Et3N (416 µL, 3 mmol),
propylamine (166 µL, 2 mmol), and EDCI (229 mg, 1.2 mmol)
were successively added. The resulting mixture was stirred for 6 h
at room temperature or 60 °C (depending on the solubility of the
thiourea intermediate). The solvent was then evaporated to dryness.
The resulting oily residue was diluted with water. The guanidines
were isolated either as solids by simple filtration or as oils after
dilution with water and extraction with CH2Cl2. The purity of the
guanidine was checked by HPLC analysis and was found to be
>95%. The guanidines were used in the next step without further
purification.
1
quantified by H NMR (two singlets for aromatic protons of
lin-6d and two doublets for ang-6d). A 10/8 ratio in favor of
the linear isomer was found.16 It is worth noting that the proton
NMR spectra of quinazolinones 6a-g are characterized by the
strong deshielding of the aromatic proton peri to the 4-oxo
substituent, and the broadening of the aromatic proton peri to
the N1 position, indicating an ongoing N1-H-N3-H tautom-
erism.
As shown in Table 1, the reaction is compatible with a wide
range of aromatic cycles: phenyl and five- or six-membered
fused heterocycles.
In conclusion, this unique cyclization process is very attractive
because diversely substituted aromatic amines are easily avail-
able. Large quantities of N-ethoxycarbonyl guanidine intermedi-
ates can be prepared in one pot in good to high yields. It may
be also worth isolating the thiourea intermediates (by simple
precipitation from the reaction mixture), as they are key
intermediates to build libraries of quinazolinones containing
various 2-alkyl or arylamino groups. This methodology allows
rapid preparation of large amounts of highly substituted
quinazolinones with excellent purity and in good to high yields.
General Procedure for the Synthesis of Quinazolinone
Derivatives. The protected guanidine 5a-g (1 mmol) was dissolved
in anhydrous DMF (3 mL), and ClSiMe3 (5 or 10 mmol) was added
to the solution and stirred at 80 °C. The reaction was monitored
by HPLC. When the reaction was completed, water (2 mL) was
added and the solvents were removed under reduced pressure. The
residue was stirred in water, and aq. NH4OH was added to reach
neutral pH. The precipitate thus formed was filtered, washed with
water, and dried to give the desired compound 6a-g.
Supporting Information Available: Experimental details and
1
full compound characterization data as well as copies of H and
13C spectra are given. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Cudero, J.; Pardo, C.; Ramos, M.; Gutierrez-Puebla, E.; Monge,
A.; Elguero, J. Tetrahedron 1997, 53, 2233-2240.
(16) The two isomers are not separated in our HPLC conditions (reversed-
phase C18 column, pH 2.5 H2O-MeOH solvent gradient) and give two
adjacent spots on TLC (silica gel, Et2O). No attempt of separation was
made as the mixture was well characterized and quantified by NMR.
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