Yb(OTf)3 catalyzed new cascade reaction: A facile assembly of fused quinazolinones

Article abstract of DOI:10.1039/c1cc13695j

A one-pot Yb(iii)-mediated cascade reaction has been developed leading to small molecules based on a novel structural motif, i.e. quinazolin-4-one moiety fused with an isoquinoline ring, for potential inhibition of TNF-α.

Full text of DOI:10.1039/c1cc13695j

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COMMUNICATION
Yb(OTf)3 catalyzed new cascade reaction: a facile assembly of fused
quinazolinonesw
K. Siva Kumar,ab P. Mahesh Kumar,a M. Appi Reddy,a Md. Ferozuddin,a M. Sreenivasulu,a
Ahamed A. Jafar,b G. R. Krishna,c C. Malla Reddy,c D. Rambabu,d K. Shiva Kumar,d
Sarbani Pale and Manojit Pal*d
Received 21st June 2011, Accepted 1st August 2011
DOI: 10.1039/c1cc13695j
A one-pot Yb(III)-mediated cascade reaction has been developed
leading to small molecules based on a novel structural motif, i.e.
quinazolin-4-one moiety fused with an isoquinoline ring, for
potential inhibition of TNF-a.
Metal catalyzed cascade1a and multi-component reactions1b
(MCRs) have emerged as major strategies in heterocyclic
synthesis. Extending these reactions into combinatorial and
solid phase syntheses often provides an array of novel hetero-
Fig. 1 Design of novel TNF-a inhibitors (C) derived from A.
cyclic frameworks accessible to medicinal/pharmaceutical
chemists thereby facilitating identification of new lead structures
in the area of drug discovery. While transition metal catalysts
are being used extensively for this purpose the use of lanthanides
has also been explored.2 Several lanthanide triflates including
Yb(OTf)3 have shown excellent catalytic behavior in various
known MCRs such as the Biginelli and Hantzsch reaction.
Dysregulation of TNF-a (Tumor Necrosis Factor-a, a
multifunctional cytokine mediator for critical immune
functions, including inflammation, infection, and antitumor
responses)3 is implicated in autoinflammatory diseases such as
rheumatoid or psoriatic arthritis, and Crohn’s disease.4
A number of synthetic antibodies e.g. etanercept, infliximab,
and adalimumab have been approved for the treatment of
inflammatory diseases. However, due to their potential to
cause severe side effects effort has been devoted to identify
small molecules as inhibitors of TNF-a.5 Only few small
molecule based inhibitors have been reported till date.6 Herein
we report few small molecules as potential inhibitors of
TNF-a synthesized via a new three component as well as
cascade reaction catalyzed by Yb(OTf)3. In view of promising
TNF-a inhibitory properties of 6,6a-dihydroisoindolo-[2,1-
a]quinazoline-5,11-diones6b (A, Fig. 1) new chemical entities
were designed from A. Considering primarily the hydrophobic
interactions between A and the TNF-a protein as observed in
the related docking studies,6b the structure C was arrived via B
by introducing hydrophobicity into A (Fig. 1). Moreover, the
substituent R0 was introduced to expand the scope of library
generation.
Various pharmacological properties and synthesis of 2-aryl-
2,3-dihydroquinazolin-4(1H)-ones7 and 2,3-diaryl-1,2-dihy-
droisoquinolines have been reported.8 While the synthesis of
their combined form i.e. 12-aryl-4bH-isoquinolino[2,1-a]quin-
azolin-6(5H)-one has been disclosed recently9 corresponding
5-substituted analogues (C; R = alkyl or aryl) are not known.
Therefore, generation of a compound library based on C to
evaluate their TNF-a inhibiting property was the major goal
whereas development of a suitable methodology leading to the
heterocyclic structure
C was the major challenge. We
a Custom Pharmaceutical Services, Dr Reddy’s Laboratories Limited,
Bollaram Road Miyapur, Hyderabad 500 049, India
b PG and Research Department of Chemistry, Jamal Mohamed
College, Tiruchirappalli 620020, Tamil Nadu, India
envisaged that a combination of isatoic anhydride (1) and an
amine (2) could provide the required precursor of the quinazolin-
4-one moiety in situ and the use of o-alkynyl benzaldehyde (3)
could complete the construction of the fused isoquinoline ring
in the presence of a suitable catalyst. Accordingly, the reaction
of 1, methylamine (2a) and 2-(phenylethynyl)benzaldehyde
(3a) was examined under various conditions (Table 1). The
initial use of catalyst Cu(OTf)2 (entries 1–3, Table 1) was not
successful either at low or elevated temperatures in DCE or
acetonitrile as the desired product 4a was isolated in low or
poor yield. Replacing the transition metal catalyst by a
lanthanide triflate i.e. Eu(OTf)3 improved the product yield
c Department of Chemical Sciences, Indian Institute of Science
Education and Research, Kolkata, West Bengal 741252, India
d Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500 046, India.
E-mail: manojitpal@rediffmail.com
e Department of Chemistry, MNR Degree and PG College,
Kukatpally, Hyderabad, India
w Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, results of docking
study. CCDC 828186. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc13695j
c
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Table 1 Effect of reaction conditions on MCR using isatoic anhydride
(1) with methylamine (2a) and 2-(phenylethynyl)benzaldehyde (3a)a
Table 2 Synthesis of 5,12-disubstituted 4bH-isoquinolino[2,1-a]quin-
azolin-6(5H)-ones (4)a
Alkynes 3;
Entry Amines 2; R= R0=
%Yieldb
Entry
Catalyst
Solvent
T/1C
Time/h
%Yieldb
Products 4
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Eu(OTf)3
Eu(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
DCE
DCE
MeCN
DCE
DCE
DCE
MeCN
DCE
25–30
80–85
80–85
25–30
80–85
25–30
25–30
25–30
48
24
24
24
24
48
48
48
25
20
10
40
20
70
35
49c
1
2
2a; CH3
3a; C6H5
70
a
All the reactions were carried out using
(6.71 mmol), 3a (6.74 mmol) and a catalyst (0.61 mmol) in a solvent
1 (6.13 mmol), 2a
2bc
3a
72
64
b
c
(10 mL). Isolated yield. 0.30 mmol of Yb(OTf)3 was used. DCE =
1,2-dichloroethane.
marginally when the reaction was performed at 25–35 1C in
DCE (entry 4, Table 1) but not at higher temperatures
(entry 5, Table 1). Good yield of 4a however was obtained
when Yb(OTf)3 was used in DCE (entry 6, Table 1) but not in
MeCN (entry 7, Table 1). The use of lower quantity of catalyst
decreased the product yield (entry 8, Table 1). The MCR did
not provide 4a in the absence of Yb(OTf)3 confirming the key
role played by the catalyst.
3
4
5
6
2c; c-propyl
3a
The compound 4a was characterized by the appearance of
the CQO signal at 1706 cmꢀ1 in IR and 163.2 ppm in 13C
NMR spectra. A signal at 5.64d in the 1H NMR and 74.6 ppm
in the 13C NMR spectra confirmed the presence of C–H at the
vinylic and C-4b position of the isoquinoline ring respectively.
We examined the scope of the present Yb(III)-catalyzed
reaction using the optimized conditions which provided
4bH-isoquinolino[2,1-a]quinazolin-6(5H)-one with a variety
of substitution patterns (Table 2). The reaction proceeded
well with a variety of aliphatic and aromatic amines (2) and
o-alkynyl benzaldehydes (3) to give a range of 5,12-disubsti-
tuted derivatives (Table 2). All the compounds synthesized
were characterized by spectral and analytical data and this was
supported by the molecular structure of 4b being confirmed by
X-ray analysis (Fig. 2).10
2d; C6H4CH3-p 3a
74
72
78
2e; C6H4Cl-p
3a
2f; C6H5CH2
3b; C6H4CH3-p
Mechanistically, the reaction seems to proceed via (i)
generation of N-substituted o-aminobenzamide from 1 and 2
in situ which on (ii) condensation with 3 provides the
corresponding imine. (iii) A subsequent intramolecular and
regiospecific nucleophilic attack of the imine nitrogen at the
Yb-coordinated alkyne (E-1) generates the corresponding
(2-(2-carbamoylphenyl)isoquinolinium-4-yl)ytterbium ion (E-2,
Scheme 1) which (iv) undergoes further nucleophilic attack
by the amide nitrogen at C-1 in an intramolecular fashion to
give 4 (via E-3).11 Alternatively, 2-(o-alkynylphenyl)-2,3-dihydro-
7
8
2g; CH2CH2OH 3b
76
68
2h; C6H4F-p
3b
quinazolin-4-one
intramolecular cyclization of the iminoalkyne–Yb complex
undergoes Yb(III)-assisted regiospecific intramolecular
intermediate
formed
through
an
a
hydroamination reaction leading to the formation of 4
c
10264 Chem. Commun., 2011, 47, 10263–10265
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Table 2 (continued )
Alkynes 3;
Entry Amines 2; R= R0=
Products 4
%Yieldb
Scheme 2 Preparation of alkyne 6 and its reaction with Yb(OTf)3.
9
2a
3b
73
(see ESIw). To gain further evidence, the alkyne 6 prepared
from the iodide 5 (obtained via a known method11) was treated
with Yb(OTf)3 at 25–35 1C in DCE (Scheme 2). However,
formation of 4a was not observed even after 24 h indicating
that the present cascade reaction does not follow the alter-
native path as proposed.
10
2i; C6H5
3b
72
In conclusion,
a new cascade reaction catalyzed by
Yb(OTf)3 has been developed that allowed concurrent
construction of two six membered fused N-heterocyclic rings
thereby rapid access to a library of small molecules based on a
novel structural motif. Two of these compounds showed
inhibition of TNF-a in vitro12 and may have potential for
therapeutic applications.
11
2j; CH2C6H4F-p 3b
78
73
KSK thanks Dr Vilas Dahanukar and the analytical group
of DRL. MP thanks Prof. J. Iqbal for support.
Notes and references
12
2d
3b
1 (a) For a scholarly review, see: K. C. Nicolaou, D. J. Edmonds and
P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134; (b) For an
in-depth review, see: D. M. D’Souza and T. J. J. Muller, Chem.
Soc. Rev., 2007, 36, 1095.
2 P. J. Tambade, Y. P. Patil and B. M. Bhanage, Curr. Org. Chem.,
2009, 13, 1805.
3 H. Wajant, K. Pfizenmaier and P. Scheurich, Cell Death Differ.,
2003, 10, 45.
¨
a
All the reactions were carried out using 1 (6.13 mmol), 2 (6.71 mmol), 3
(6.74 mmol) and Yb(OTf)3 (0.61 mmol) in DCE (10 mL) at 25–30 1C for
48 h. Isolated yield. (NH4)2CO3 was used in place of RNH2.
b
c
4 B. B. Aggarwal, Nat. Rev. Immunol., 2003, 3, 745.
5 M. A. Palladino, F. R. Bahjat, E. A. Theodorakis and
L. L. Moldawer, Nat. Rev. Drug Discovery, 2003, 2, 736 and
references cited therein.
6 For leading references, see: (a) D. Shiu-Hin Chan, H.-M. Lee,
F. Yang, C.-M. Che, C. C. L. Wong, R. Abagyan, C.-H. Leung
and D.-L. Ma, Angew. Chem., Int. Ed., 2010, 49, 2860;
(b) K. S. Kumar, P. M. Kumar, K. A. Kumar, M. Sreenivasulu,
A. A. Jafar, D. Rambabu, G. R. Krishna, C. M. Reddy,
R. Kapavarapu, K. Shivakumar, K. K. Priya, K. V. L. Parsa
and M. Pal, Chem. Commun., 2011, 47, 5010.
7 M. Dabiri, P. Salehi, S. Otokesh, M. Baghbanzadeh,
G. Kozehgary and A. A. Mohammadi, Tetrahedron Lett., 2005,
46, 6123 and references cited therein.
8 M. Kihara, M. Ikeuchi and Y. Nagao, Drug Des. Discovery, 1995,
12, 259 and references cited therein.
9 N. T. Patil, A. K. Mutyala, P. G. V. V. Lakshmi, P. V. K. Raju and
B. Sridhar, Eur. J. Org. Chem., 2010, 1999.
10 Crystal data of 4b: molecular formula = C22H16N2O, formula
weight = 324.37, crystal system = monoclinic, space group =
P21/n, a = 9.388(6) A, b = 11.595(8) A, c = 15.005(10) A,
Fig. 2 X-Ray crystal structure of 4b (ORTEP diagram). Thermal
V = 1627.3(19) A3, T = 100(2) K, Z = 4, Dc = 1.324 Mg mꢀ3
,
= , 6728 reflections measured, 3152
0.08 mmꢀ1
ellipsoids are drawn at 50% probability level.
m(Mo-Ka)
independent reflections, 1525 observed reflections [I 4 2.0s(I)],
R1_obs = 0.079, goodness of fit = 0.765. CCDC 828186w.
11 M. Baghbanzadeh, P. Salehi, M. Dabiri and G. Kozehgary, Synthesis,
2006, 344.
12 Some of the compounds synthesized were tested for their TNF-a
inhibitory potential in vitro.6b Compounds 4h and 4i showed 29%
and 47% inhibition of TNF-a at 10 mM. The docking results of 4i
with TNF-a protein (see ESIw) showed good interactions with the
hydrophobic binding site (binding energy ꢀ5.6 kcal molꢀ1) con-
sisting primarily of H-bonding interaction of the CQO group of 4i
with the –NH group of W118 (tryptophan) residue of the TNF-a
protein.
Scheme 1 Proposed reaction mechanism.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10263–10265 10265