Efficient room-temperature one-pot synthesis of 2-amino-3-alkyl(3-aryl) quinazolin-4(3H)-ones

Article abstract of DOI:10.1002/ejoc.201100200

Starting from anthranilates, the one-pot successive addition of ethoxycarbonylisothiocyanate, alkyl- or arylamines, and the coupling reagent EDCI led to the clean, room-temperature formation of carbamate-protected 2-amino-3-alkyl(3-aryl)quinazolin-4(3H)-ones in up to 93% yield. This method provides a practical alternative to previously reported procedures for the synthesis of 2-amino-3-substituted quinazolin-4(3H)-ones.

Full text of DOI:10.1002/ejoc.201100200

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100200
Efficient Room-Temperature One-Pot Synthesis of 2-Amino-3-alkyl(3-aryl)-
quinazolin-4(3H)-ones
Cédric Lecoutey,[a] Christine Fossey,[a] Sylvain Rault,[a] and Frédéric Fabis*[a]
Keywords: Heterocycles / Fused-ring systems / Amination / Thioureas / Guanidines
Starting from anthranilates, the one-pot successive addition
of ethoxycarbonylisothiocyanate, alkyl- or arylamines, and
the coupling reagent EDCI led to the clean, room-tempera-
ture formation of carbamate-protected 2-amino-3-alkyl(3-
aryl)quinazolin-4(3H)-ones in up to 93% yield. This method
provides a practical alternative to previously reported pro-
cedures for the synthesis of 2-amino-3-substituted quinazo-
lin-4(3H)-ones.
bethoxy-protected arylguanidines,[21] the base-promoted in-
tramolecular ring closure of ortho-fluorobenzoylguanid-
ines,[22] and tandem amination/palladium-catalyzed cyclo-
carbonylation from carbodiimide derivatives.[23]
Introduction
Numerous quinazoline-containing compounds display
important biological activities; some are marketed such as
gefitinib (Iressa)[1] and erlotinib (Tarceva),[2] which are two
EGFR inhibitors used in the treatment of cancer. Among
quinazoline-containing compounds, 2-aminoquinazolin-
4(3H)-one derivatives are biologically relevant and have
been reported as dopamine agonists,[3] histamine H4 recep-
tor inverse agonists,[4] KATP channel modulators,[5] CCK-B
antagonists,[6] and antitumor,[7] anti-inflammatory,[8] anti-
hypertensive,[9] antihyperglycemic,[10] or antibacterial
agents.[11]
Although these methods offer multiple entries to the syn-
thesis of 2-aminoquinazolin-4(3H)-ones, most of them are
limited regarding the synthesis of 2-amino-3-substituted-
quinazolin-4(3H)-ones. Solid-phase approaches to their
synthesis have been reported using multistep procedures,
and the cleavage from the resin most often requires strongly
acidic conditions.[24] Moreover, in these methods, the ring-
closure reaction, mainly from guanidine intermediates, may
be nonregioselective depending on the nucleophilicity of
both the nitrogen atoms.[24b,24c] It has been shown that N-
acyl-protected guanidines can easily be obtained in a two-
step procedure involving the formation of a thiourea inter-
mediate with commercially available ethoxycarbonyliso-
thiocyanate followed by amination of the latter by using
EDCI as a coupling reagent.[25] We thought we could take
advantage of this procedure to synthesize diversely substi-
tuted 2-amino-3-substituted-quinazolin-4(3H)-ones in a
one-pot reaction according to Scheme 1.
For these reasons, several methodologies have been de-
veloped for their synthesis, which has been recently re-
viewed.[12] These methods can be classified into three main
groups including (1) nucleophilic substitution of 2-chloro-
quinazolin-4(3H)-ones,[13]
2-alkylthio-quinazolin-4(3H)-
ones,[14] or 2-cyanoquinazolin-4(3H)-ones[15] by amines;
(2) ring-closure reaction from anthranilic acid derivatives
with a number of one-carbon reagents such as isothio-
ureas,[3,16] guanidines,[9a] haloformamidines,[11,17] or di-
phenylcarbonimidates;[18] and (3) the tandem aza-Wittig re-
action using iminophosphoranes.[19] These procedures suf-
fer from some limitations such as multistep reactions, harsh
conditions, toxicity, or limited availability of reagents such
as isocyanates.
More recently, several new routes have been reported, in-
cluding the copper-catalyzed amination of 2-halobenzoic
acids,[20] intramolecular Friedel–Crafts acylation of N-car-
[a] Centre dЈEtudes et de Recherche sur le Médicament de
Normandie, UPRES EA 4258, INC3M FR-CNRS 3038, UFR
des Sciences Pharmaceutiques, Université de Caen Basse-
Normandie,
Boulevard Becquerel 14032 Caen cedex, France
Fax: +33-(0)231566803
E-mail: frederic.fabis@unicaen.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100200.
Scheme 1. One-pot synthesis of 3-alkyl(3-aryl)-2-aminoquinazolin-
4(3H)-ones.
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C. Lecoutey, C. Fossey, S. Rault, F. Fabis
SHORT COMMUNICATION
Table 1. Scope of amines in the one-pot synthesis of 3-alkyl(3-aryl)-
2-ethoxycarbonylaminoquinazolin-4(3H)-one derivatives from
methyl anthranilate.
Results and Discussion
We initiated our studies with methyl anthranilate (1a) as
starting material. The reaction of 1a with ethoxycarbonyl
isothiocyanate (1.2 equiv.) in acetonitrile at room tempera-
ture led to complete conversion into the corresponding
thiourea within 4 h.[26] Adding benzylamine (1.5 equiv.) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDCI, 2 equiv.) to the reaction mixture afforded quin-
azolinone 2a after 12 h at room temperature. The reaction
proceeded probably through the cyclization of the guani-
dine intermediate, which was not detected. The use of
1 equiv. of benzylamine led only to partial conversion of
the isothiocyanate into quinazolinone. It is noticeable that
quinazolinone 2a was obtained in 93% yield after a simple
extractive workup and crystallization from diethyl ether. We
then explored the reaction by using different primary
amines. The results are summarized in Table 1.
Aliphatic amines, even bulky 2,6-dichlorobenzylamine
(Table 1, Entry 2) led to the corresponding quinazolinones
in good yields. Interestingly, aromatic amines such as ani-
line proved to be efficient in this transformation (Table 1,
Entry 4), even if the use of less nucleophilic arylamines such
as methyl anthranilate (Table 1, Entry 5) and 3-nitroaniline
(Table 1, Entry 6) resulted in lower yields and prolonged
reaction times.[27] We then evaluated hexamethyldisilazane
(HMDS), which has already been shown to be a nitrogen
source in the synthesis of guanidines from thioureas.[28]
Using 10 equiv. of HMDS led to the formation of N-3 un-
substituted quinazolinone 2g in 71% yield (Table 1, En-
try 7). Complete conversion of the thiourea intermediate to
the quinazolinone varied from 12 h to 4 d depending on the
nucleophilicity of the amine and steric parameters.
We then evaluated this procedure with anthranilates sub-
stituted with either electron-donating or electron-with-
drawing groups to explore the generality of the reaction.
For each anthranilate, four representative amines were cho-
sen (benzylamine, isobutylamine, aniline, and HMDS). The
results are summarized in Table 2.
For each representative anthranilate substituted with
either an electron-donating (i.e., 1b) or an electron-with-
drawing group (i.e., 1c), the reaction worked well, leading
to the corresponding quinazolinones 2h–o in high yields. 5-
Chloro-substituted anthranilate 1d led to similar results,
and the lower yield observed with aniline was probably due
to the partial solubility of resulting quinazolinone 2r in di-
ethyl ether. However, purification of the quinazolinones by
flash chromatography appeared to be very easy and would
allow the loss of material due to crystallization workup to
be overcome.
[a] 10 equiv. were used.
The 2-aminoquinazolinones were obtained as ethyl car-
bamates; thus, we envisaged their deprotection on a repre-
sentative compound. Heating protected quinazolinone 2g at
reflux in a mixture of methanol and 1 m NaOH afforded 2-
aminoquinazolinone 3 in 67% yield. The free 2-amino
group could be further elaborated to create an additional
point of diversity (Scheme 2).
Scheme 2. Deprotection of the carbamate group on a representative
example.
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One-Pot Synthesis of 2-Amino-3-alkyl(3-aryl)quinazolin-4(3H)-ones
Table 2. Synthesis of 2-amino-3-substituted-quinazolin-4(3H)ones from diversely substituted anthranilates.
[a] 10 equiv. were used.
Conclusions
of appropriate anthranilate 1a–d (1 equiv., 1 mmol) in CH3CN
In summary, we have developed an efficient route
to diverse 2-amino-3-alkyl(3-aryl)quinazolin-4(3H)-ones
through a mild, room-temperature, three-step, one-pot pro-
cedure by combining a variety of anthranilates and primary
amines. Owing to the interest of the 2-aminoquinazoline
scaffold for the design of biologically relevant compounds,
this methodology offers a new practical route for the syn-
thesis of large and diverse chemical libraries. The synthetic
(10 mL). The reaction mixture was stirred at room temperature un-
der a nitrogen atmosphere until no starting material remained
(monitored by LC–MS). The amine (1.5 equiv.) or HMDS
(10 equiv.) and EDCI (2 equiv.) were then successively added. The
resulting mixture was stirred at room temperature for 24–96 h. The
solvent was then removed in vacuo, and the residue was dissolved
in EtOAc. The organic layer was successively washed with 1 n HCl/
H2O (2ϫ) and water (1ϫ), dried with MgSO4, filtered, and evapo-
applications of this procedure are under investigation in our rated under reduced pressure. The residue was either crystallized
from dry diethyl ether or purified by silica gel chromatography to
afford quinazolinones 2a–s.
laboratory.
Experimental Section
General Procedure for the Synthesis of Quinazolinones 2a–s:
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H and 13C NMR spectra of the compounds.
Ethoxycarbonyl isothiocyanate (1.2 equiv.) was added to a solution
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C. Lecoutey, C. Fossey, S. Rault, F. Fabis
SHORT COMMUNICATION
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Acknowledgments
We gratefully acknowledge the Institut de Recherches Servier
(IDRS) for financial support (C.L. postdoctoral fellow).
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[26] Times are determined by LC–MS analysis.
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Received: February 14, 2011
Published Online: April 1, 2011
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