An efficient one pot synthesis of 2-amino quinazolin-4(3H)-one derivative via MCR strategy

Article abstract of DOI:10.1016/j.tetlet.2015.08.040

A novel multi-component reaction strategy was developed for the construction of important building blocks, 2-amino 3-substituted quinazolinone derivatives from isatoic anhydride and amine with electrophilic cyanating compound, N-cyano-4-methyl-N-phenylbenzenesulfonamide (NCTS). The quinazolinone synthesis proceeds via a sequential series of reactions such as nucleophilic attack of the amine group on the carbonyl group of isatoic anhydride followed ring opening and subsequent decarboxylation, nucleophilic attack of amine to nitrile, followed by heterocyclization.

Full text of DOI:10.1016/j.tetlet.2015.08.040

Accepted Manuscript
An efficient one pot synthesis of 2-amino quinazolin-4(3H)-one derivative via
MCR strategy
V. Narayana Murthy, Satish P Nikumbh, S. Praveen Kumar, L. Vaikunta Rao,
Akula Raghunadh
PII:
S0040-4039(15)01342-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.08.040
TETL 46624
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 July 2015
14 August 2015
18 August 2015
Please cite this article as: Narayana Murthy, V., Nikumbh, S.P., Praveen Kumar, S., Vaikunta Rao, L., Raghunadh,
A., An efficient one pot synthesis of 2-amino quinazolin-4(3H)-one derivative via MCR strategy, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.08.040
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Tetrahedron Letters
1
Tetrahedron Letters
An efficient one pot synthesis of 2-amino quinazolin-4(3H)-one derivative via MCR strategy
V. Narayana Murthy,a Satish P Nikumbh,a S. Praveen Kumar,a L. Vaikunta Rao,b Akula Raghunadh,a*
aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India, bDepartment of Chemistry, GIS,
Gitam University, Visakhapatnam, 530 045, India.
*E-mail: raghunadha@drreddys.com
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel multi-component reaction strategy was developed for the construction of important
building blocks, 2-amino 3- substituted quinazolinone derivatives from isatoic anhydride and
amine with electrophilic cyanating compound, N-cyano-4-methyl-N-phenylbenzenesulfonamide
(NCTS). The quinazolinone synthesis proceeds via a sequential series of reactions such as
nucleophilic attack of amine group on carbonyl group of isatoic anhydride followed ring
opening and subsequent decarboxylation, nucleophilic attack of amine to nitrile, followed by
heterocyclization.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords: isatoicanhydride, N-cyano-4-
methyl-N-phenylbenzenesulfonamide, multi-
component reaction
Quinazolinone and their derivatives exhibit a wide range of
biological and pharmacological properties some of these
activities include anti-cancer,1 anti-inflammatory,2 anti-
fungal,3 anti-microbial and anti-malarial properties.4
Furthermore, the heterocyclic core constitutes more than 40
synthesis of 2-amino 3- substituted quinazolinone with free
amino group at 2nd position.11 Zeghida and co-workers
reported a novel synthetic method involving the Friedel-
craft type substitution from aniline.12 Kundu et al., reported
the synthesis of 2-amino quinazolinone via polymer-linked
anthranilamide with isothiocyanates followed by coupling
with secondary amines in the presence of DIC.13 Yang and
Kaplan reported solid-phase syntheses of quinazolin-4(3H)-
ones via cyclocondensation of anthranilic acid with amino
acids and aldehydes or by aza-wittig mediated annulation
involving o-azidobenzoic acid.14 Other methods reported
recently involves cyclocondensation of 2-nitrobenzyl
chloride with aryl amines and thioureas with isatoic
anhydride.15
alkaloids and various natural products like luotonon A 1, B
7
2, and
E
3,5 rutaecarpine 4,6 tryptanthrin 5,
8
9
macckinazolinone 6, vasicinone 7, deoxy vasicinone 8
and evodiamine 9, 10 (Fig 1).
The development of simple methodology for the synthesis
of 2-amino 3- substituted quinazolinone derivatives is
always in demand due to its extensive biological activity.
Multi-component reaction (MCRs) are highly desirable in
any process as the target products are directly yielded by
cascade or domino reaction sequences offer considerable
advantages over conventional linear –step synthesis. Herein
we wish to report a straight forward novel multi-component
Fig. 1. Examples of natural products which contain
quinazolinone skeleton
Because of varied biological properties of quinazolinone
derivatives,
a number of methodologies have been
developed for their synthesis. However a limited number of
synthetic strategy were reported in the literature for the

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2
reaction for the synthesis of 2-amino 3- substituted
quinazolinone derivatives.
The bases, namely K2CO3, DBU, DABCO, TEA, CS2CO3,
and LiHMDS wree screened.The best result was obtained
when the reaction was performed in the presence of
LiHMDS in 1,4 dioxane solvent (Table 2, entries 1-8),
solvents like DMSO, DMF, THF, Acetonitrile, Toluene and
1,4-Dioxane were screened in presence of LiHMDS. 1,4-
Dioxane had proven to be the best solvent for this MCR
(Table 1, entries 1–7).
Scheme 1: Retrosynthesis of 10.
Table 2: Screening of Bases.
The retro synthetic strategy employed for the synthesis of 2-
amino 3- substituted quinazolinone is depicted in Scheme 1.
The 2-amino quinazolinone could be easily obtained by a
reaction of isatoic anhydride 11 with amine 12 and NCTS
Isolated Yield
Entry
Base
(%)
45
K2CO3
DBU
1
2
3
4
5
6
7
8
(N-cyano-4-methyl-N-phenylbenzenesulfonamide)
13.
38
35
0
NCTS could be synthesized using the reported methodology
by Kurzer.16 NCTS are quite stable, non toxic, crystalline
solid, which is used as potential electrophilic cyanating
agent on indoles and pyrroles.17
DABCO
TEA
CS2CO3
52
72
68
62
LiHMDS(3.0 eq)
LiHMDS (2.0 eq)
LiHMDS (1.0 eq)
Table 1: Screening of solvents.
Isolated Yield
Entry
Solvents
(%)
Reaction and conditions: isatoic anhydride (1.0 eq), NCTS
(1.0 eq) and benzylamine (1.0 eq) at 100 °C.
1
2
3
4
5
6
7
DMSO
DMF
45
48
70
0
We chose a variety of structurally diverse amines possessing
a wide range of functional groups for our study to
understand the scope and the generality of this MCR and the
results are summarized in Table 3. The amines chosen for
the study include aliphatic, aromatic, hetero aromatic
amines
1,4-Dioxane
Ethanol
Acetonitrile
THF
48
55
40
Toluene
Reaction and conditions: isatoic anhydride (1.0 eq), NCTS
(1.0 eq), benzylamine (1.0 eq) and LiHMDS (3.0 eq) at
reflux .
When the reaction was conducted with 3,3-
dimethoxypropan-1-amine 12n the cyclized product 2-
hydroxy-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-
one 10n was obtained via the formation of the 2-amino 3-
substituted quinazolinone followed by intramolecular
cyclization. When the reaction was conducted with
Aromatic amines afforded lower yields compared to
aliphatic amines.
In an effort to develop an optimal conditions, various
reaction parameters were studied for the preparation of 10
via condensation of isotoic anhydride 11 (1.0 mmol) with N-
cyano-4-methyl-N-phenylbenzenesulfonamide
13
(1.0
mmol) and benzylamine (1.0 mmol). The base and solvent
had a pronounced effect on these reactions with respect to
yield.

3
Table 3: Synthesis of various 2-amino 3- substituted quinazolinone derivatives.
Isolated Yield
(%)
Entry
Isatoic anhydride
Amine
Product
1
71
2
3
4
5
72
67
78
77
11a
11a
11a
11a
6
52
11a
7
8
47
70
11a
11a
9
72
11a

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4
10
11
12
60
57
36
11a
11a
11a
13
14
52
68
50
11a
11a
11a
15
16
56
59
17
18
19
11b
11b
11b
62
69

5
The Scheme 2 represents a plausible mechanism for the
three component reaction leading to the compound 10. The
nucleophilic attack of primary amine on carbonyl group of
isatoic anhydride followed by ring opening and subsequent
decarboxylation will yield to compound 14. Deprotonation
of aromatic amine 15 in the presence of base followed by
nucleophilic attack to the nitrile group, 13 will yield imine
16; subsequent cyclization followed by elimination of N-
phenyl tosyl group will yield intermediate 17. Cyclization of
compound 18 will yield compound 19. The intermediate 19
will undergo tautomerization leading to the formation of 10.
Scheme 2: The proposed reaction mechanism for the formation of 10.
Bereznak, J. F.; Chang, Z. Y.; Sternberg, C. G.; PCT Int. Appl.
WO 9702262 (1997) [Chem. Abstr. 1998, 129, 132536w]; (c)
Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M.
L.; Conte, L.; Ramis, J.; Merlos, M.; Garcia-Rafanell, J.; Forn, J.
J. Med. Chem. 1998, 41, 1869-1882.
Conclusion:
In conclusion, we have developed a novel multi-component
reaction strategy for the synthesis of 2-amino 3- substituted
quinazolinone in good yields from isatoic anhydride, amine
and electrophilic cyanating agent, N-cyano-4-methyl-N-
phenylbenzenesulfonamide in a one pot process. The
synthesis of 2-amino 3- substituted quinazolinone proceeded
4.
5.
Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq, E. Pharm.Acta
Helv. 1999, 74, 11–17; (b) Shiba, S. A.; El-Khamry, A. A.;
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via
a
series of reactions such as ring opening,
dehydration, elimination and
decarboxylation,
heterocycloannulation.
Acknowledgments:
The authors would like to thank Dr. Vilas Dahanukar, Dr.
Rama Mohan, Dr. K. B. Shiva Kumar and the analytical
group of CPS-DRL for spectral data.
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General procedure for synthesis of 2-amino 3-
substituted quinazolinone derivatives (10a – 10s): To the
solution of isatoic anhydride (1.0 eq) in 1,4 dioxane (4.0
ml), Amine ( 1.0 eq) was added and then reaction mass
temperature was raised to 90-100°C and maintained for 3-4
hrs, LiHMDS solution (3.0 eq) followed by N-cyano -4-
methyl –N-phenyl benzene sulfonamide (NCTS) (1.0 eq)
was added and reaction mass was further maintained for 10-
12hrs at same temperature, reaction progress was monitored
by TLC. After completion of the reaction, 20% aqueous
ammonium chloride solution (5.0 ml) was added and
reaction mass was diluted with ethyl acetate (10.0 ml).
Ogranic layer was separated and aqueous layer extracted
with ethyl acetate (4.0 ml). Combined organic layer was
washed with water (4.0 ml) followed by 10% sodium
chloride solution (4.0 ml). Solvent was evaporated under
vacuum and crude material was purified by column
chromatography in Ethyl acetate / hexane (3:7).

Tetrahedron Letters
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An efficient one pot synthesis of 2-amino quinazolin-4(3H)-one derivative Via MCR strategy
V. Narayana Murthy,a Satish P Nikumbh,a S. Praveen Kumar,a L. Vaikunta Rao,b Akula Raghunadh,a*