A one-pot synthesis of novel sugar derived 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones: an entry towards highly functionalized sugar-heterocyclic hybrids

Article abstract of DOI:10.1016/j.tetlet.2006.07.064

An efficient and practical one-pot method for the synthesis of novel diversified sugar derived dihydro-quinazolino[4,3-b]quinazolin-8-ones has been reported. Various protected sugar hemiacetals were used to synthesize the hybrid tetracyclic ring system. The one-step reductive transformation of 2-(2-nitrophenyl)-3H-quinazolin-4-one with different sugar hemiacetals furnished the desired tetracyclic product in good yields and with high purity.

Full text of DOI:10.1016/j.tetlet.2006.07.064

Tetrahedron Letters 47 (2006) 6857–6860
A one-pot synthesis of novel sugar derived
5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones: an entry
towards highly functionalized sugar-heterocyclic hybridsI
Abhijeet Deb Roy,a Arunachalam Subramanian,a Balaram Mukhopadhyayb,*
and Raja Roya,*
aDivision of SAIF, Central Drug Research Institute, Lucknow 226001, India
bDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
Received 24 May 2006; revised 29 June 2006; accepted 13 July 2006
Available online 4 August 2006
Abstract—An efficient and practical one-pot method for the synthesis of novel diversified sugar derived dihydro-quinazolino-
[4,3-b]quinazolin-8-ones has been reported. Various protected sugar hemiacetals were used to synthesize the hybrid tetracyclic ring
system. The one-step reductive transformation of 2-(2-nitrophenyl)-3H-quinazolin-4-one with different sugar hemiacetals furnished
the desired tetracyclic product in good yields and with high purity.
Ó 2006 Elsevier Ltd. All rights reserved.
Over the past decade, the synthesis of privileged classes
of heterocyclic molecules has become one of the prime
areas of research in synthetic organic chemistry.1 These
privileged structures have gained much attention, owing
to their potential role as ligands, which are capable of
binding multiple biological targets.2 Among the nitro-
gen-containing privileged class of molecules, substituted
quinazolinones and quinazolines are considered as
important therapeutic scaffolds.3 Quinazolinone based
compounds have shown considerable activity as antican-
cer, diuretic, anti-inflammatory, anticonvulsant, hypo-
glycemic and antihypertensive agents.4
intramolecular reductive N-heterocyclization.10 How-
ever, these methods often involve multistep syntheses,11
use expensive and toxic catalysts12 and harsh reaction
conditions,13 and therefore are commercially undesir-
able. Although the use of new catalytic methodology
and microwave assisted synthesis provides some techni-
cal advantages over existing methods, they lack versatil-
ity and do not employ any new chemistry in the
construction of the ring system. Hence, there is a need
to develop novel methods that are more efficient for
the synthesis of these privileged molecules.
Various biologically active compounds are either glyco-
sides, or compounds containing glycosidic residues
along with different heterocyclic aglycon moieties.14
Often the glycol-residue plays an important role that
governs the activity as well as improves the pharmaco-
kinetic profile of the compound. The natural abundance
and the diverse chirality of the sugar have made
compounds of this type attractive targets for novel syn-
thetic methodologies. It was therefore envisioned that a
scaffold consisting of a privileged class of molecule
conjugated with a naturally occurring sugar entity might
increase the bioavailability of an active molecule. In
order to achieve this goal we sought to synthesize the
pharmacologically important quinazolinones by conju-
gating the heterocyclic aglycon part with a glycosyl
moiety.
Conventionally, the quinazolinone ring has been gener-
ated by the amidation of 2-aminobenzonitrile, 2-amino-
benzoic acid or 2-aminobenzamide followed by acid- or
base-catalyzed ring closure,5 by the condensation of imid-
ates with anthranilic acid,6 and by aza-Wittig reactions
of a-azido-substituted aromatic imides.7 The synthesis
of quinazolines has been achieved by chlorinating the
oxygen atom of quinazolinone, either using phosphorus
oxychloride8 or thionyl chloride9 followed by substitu-
tion with a primary amine, or by palladium-catalyzed
q CDRI Communication No. 7000.
*
Corresponding authors. Fax: +91 522 2623405; e-mail addresses:
sugarnet73@hotmail.com; rajaroy_cdri@yahoo.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.064

6858
A. D. Roy et al. / Tetrahedron Letters 47 (2006) 6857–6860
1
Our group has recently reported a novel method for the
preparation of biheterocyclic 5,6-dihydro-quinazol-
ino[4,3-b]quinazolin-8-ones.15 In continuation of our
efforts to develop newer methods to synthesize privileged
heterocyclic molecules,16 we herein report an efficient
one-pot method for the synthesis of novel glycosyl 5,6-
dihydro-quinazolino[4,3-b]quinazolin-8-ones wherein a
set of cyclic sugar hemiacetals have been used along with
2-(2-nitrophenyl)-3H-quinazolin-4-one. In the present
strategy, various sugar hemiacetals have been used, as
an aldehyde source which are involved in cyclization
with the resulting 2-(2-aminophenyl)-3H-quinazolin-4-
one to furnish a highly functionalized glycoconjugated
quinazolino[4,3-b]quinazolinone molecule. To the best
of our knowledge this is the first report dealing with
the formation of a glycosylated quinazolino[4,3-b]-
quinazolin-8-one heterocyclic system utilizing a sugar
molecule.
The H NMR spectrum of the product 4 showed all the
glycosyl protons between 3.8 and 6.4 ppm apart from
the anomeric H-6 proton which was shifted to
6.30 ppm because of its flanked position between two
nitrogen atoms. Apart from the four-acetate proton sig-
nals and the H-5 amine proton at 4.83 ppm, eight aro-
matic protons were clearly observable. From the 13C
and HSQC spectrum, the position of the anomeric car-
bon was assigned at 61.8 ppm. In the HMBC spectrum
the anomeric H-6 proton provided three long range cor-
relations with the aglycon portion, namely, with the
amide carbonyl at 160.3 ppm, the quaternary carbon
(C2) at 146.5 ppm, and the NH-substituted aromatic
quaternary carbon at 143.3 ppm, which confirmed the
linkage between the sugar moiety and the intermediate
diamine. Long-range heteronuclear proton carbon cor-
relations established the structure as a novel 6-glycosyl
substituted 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-
one.
The strategy for the synthesis of 6-glycosyl substituted
5,6-dihydro-quinazolino[4,3-b]quinazolin-8-one is de-
picted in Scheme 1. The synthesis commenced with the
amidation of anthranilamide 1 using 2-nitrobenzoyl
chloride and triethylamine to give the amide intermedi-
ate 2. Subsequently, 2-(2-nitrophenyl)-3H-quinazolin-4-
one 3 was prepared by ring closure of 2 under basic
conditions, using potassium hydroxide in ethanol, in
excellent yield and purity. Further, to obtain the amine
functionality for the synthesis of the 2-(2-aminophenyl)-
3H-quinazolin-4-one, product 3 was treated with 5 equiv
of stannous chloride in methanol at 80 °C which showed
complete conversion (TLC) to the corresponding amine
in about 1 h. Next, 1.2 equiv of 2,3,4,6-tetra-O-acetyl-D-
glucopyranose was added in the same pot and the reac-
tion mixture was allowed to stir at 80 °C for another 2 h
to furnish the desired product as a diastereomeric
mixture in 84% yield. The final products were purified
by column chromatography and the structures were
elucidated using various 1D and 2D NMR spectroscopic
experiments.
Prompted by a recent literature report17 it was envi-
sioned that the excess of stannous chloride present in
the system might trigger the formation of the cyclic sys-
tem utilizing the aldehydic property of the various sugar
hemiacetals. It could be postulated that, in the present
method, SnCl2Æ2H2O firstly reduces the nitro group to
an amine functionality and also acts as an acid source
that drives the formation of the Schiff base of the amine
with the sugar hemiacetal which ultimately cyclizes in
one-pot to furnish the 6-glycosyl-5,6-dihydro-quinazol-
ino[4,3-b]quinazolinone.
Hemiacetals having benzyl protecting groups were also
examined and provided the 6-glycosylated products in
excellent yields and purity, but in longer reaction times
than their acetylated counterparts. Based on the success
towards the preparation of 6-gluco-derivatives, and in
order to create more diversity and provide generality
to the present protocol, the scope and limitations of
the strategy was explored using three more acetylated
O
O
Cl
CONH2
O
O
NO2
NH NO2
NO2
b
NH2
N
a
H
N
NH2
2
1
3
OR
OR
OR
OR
OR
HO
RO
O
HO
RO
RO
O
OR
O
OH
+
H
H
c
N
NH
N
NH
N
N
4'
4
R= CH3CO- or C6H5CH2-
Scheme 1. Reagents and conditions: (a) 2 equiv of TEA, CHCl3, rt, 2 h, 80–85% (b) 2 equiv of KOH, EtOH, reflux, 10 min, 90% and (c) 5 equiv of
SnCl2Æ2H2O, MeOH, 80 °C, 1.2 equiv of sugar, 1–2 h, 70–88% of 4 and 40 (Table 1).

A. D. Roy et al. / Tetrahedron Letters 47 (2006) 6857–6860
6859
Table 1. Summary of the diversity and conditions used to synthesize the tetracyclic compounds 4a–g
Compound no.
Sugar hemiacetal
Product
Time (h)
Yield (%)
OAc
OAc
OAc
NH
HO
OAc
AcO
O
O
4a
4
84
AcO
OH
AcO
N
N
OAc
OBn
OBn
OBn
NH
HO
OBn
BnO
O
O
BnO
BnO
4b
5
75
OH
N
N
OBn
OAc
OAc
HO
OH
AcO
O
Me
AcO
O
4c
3
86
N
N
NH
AcO
OAc
OBn
OBn
HO
OH
BnO
O
Me
BnO
O
4d
3.5
88
N
N
NH
BnO
OBn
OH
AcO
AcO
O
OH
AcO
O
OAc
4e
5
86
N
N
NH
OAc
AcO
OH
BnO
BnO
O
OH
BnO
O
OBn
4f
6
70
N
N
NH
OBn
BnO
OAc
OAc
OAc
NH
HO
AcHN
O
OAc
O
4g
6
76
AcO
OH
AcO
N
N
NHAc
and benzylated sugar hemiacetals, viz. L-arabinose,
L-rhamnose and N-acetyl-D-glucosamine. In each case,
the target product was obtained in excellent yield and
with a high degree of purity. In all cases, diastereomeric

6860
A. D. Roy et al. / Tetrahedron Letters 47 (2006) 6857–6860
Eds.; Pergamon: Oxford, 1999; Vol. 11, p 21; (c) Joule, J.
A.; Mills, K. Heterocyclic Chemistry; Blackwell Science:
Oxford, 2000; (d) Katritzky, A. R.; Pozharskii, A. F.
Handbook of Heterocyclic Chemistry; Pergamon: Oxford,
2003.
products were obtained as was evident by two close
spots on the TLC. However, the NMR spectra of the
mixtures proved to be too complex for detailed charac-
terization of the products. Thus, the mixtures were sep-
arated by rigorous column chromatography to obtain
single diastereomers of adequate purity. For the glu-
cose-derivative (4a), detailed NMR studies on both the
faster and slower moving spots on TLC are reported
separately (see Supplementry data). For other deriva-
tives, only faster moving purified components are
reported.
2. For reviews see: (a) Horton, D. A.; Bourne, G. T.; Smythe,
M. L. Chem. Rev. 2003, 103, 893; (b) Nicolaou, K. C.;
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Int. Ed. 2000, 39, 44; (c) Arya, P.; Chou, D. T. H.; Back,
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Further, the reactivity of the protected sugar hemiace-
tals followed the general pattern as the deoxy sugars re-
acted at a much faster rate than the pentopyranose and
the hexopyranose sugars. Having thus prepared a series
of 6-glycosylated 5,6-dihydro-quinazolino[4,3-b]quin-
azolin-8-ones, it was observed that the final products
contained a free hydroxyl group in the glycon portion,
which may be successfully utilized further as a potential
acceptor for the glycosylation reaction, and could fur-
ther create diversity in the molecule. A summary of
the sugar hemiacetals utilized and the reaction condi-
tions employed are presented in Table 1.
4. (a) Chan, J. H.; Hong, J. S.; Kuyper, L. F.; Jones, M. L.;
Baccanari, D. P.; Tansik, R. L.; Boytos, C. M.; Rudolph,
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In summary, the present method provides a convenient
one-step synthesis of novel sugar-heterocycle hybrid
molecules leading to the formation of sugar-derived
biheterocyclic 5,6-dihydro-quinazolino-[4,3-b]quinazol-
in-8-ones. The products not only represent a privileged
class of structures but also have a glycosyl linker
attached for improved bioavailability and bioactivity.
Further work is in progress for the utilization of these
compounds as glycosyl acceptors in glycosylation reac-
tions for the synthesis of heterocycles containing biolog-
ically active oligosaccharides.
7. (a) Takeuchi, H.; Haguvara, S.; Eguchi, S. Tetrahedron
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Acknowledgements
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A.D.R. is thankful to CSIR, New Delhi, for providing a
fellowship.
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Supplementary data
11. For a review see. Connoly, D. J.; Cusack, D.; O’Sullivan,
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General experimental procedure and copies of NMR
spectra of all the compounds are included. Supplemen-
tary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2006.07.064.
´
´
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References and notes
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