Vinylic amino group activation: A new and general strategy leading to functionalized fused heteroaromatics

Article abstract of DOI:10.1039/c3cc41337c

A conceptually new and general strategy has been developed for the construction of a benzimidazole or a benzoxazole ring fused with isoquinolinone affording a diverse and unique class of small molecules as potential and novel inhibitors of PDE4.

Full text of DOI:10.1039/c3cc41337c

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Vinylic amino group activation: a new and general
strategy leading to functionalized fused
heteroaromatics†
Rajnikanth Sunke,a Raju Adepu,a Ravikumar Kapavarapu,b Swetha Chintala,a
Chandana Lakshmi Teja Meda,a Kishore V. L. Parsaa and Manojit Pal*a
Cite this: Chem. Commun., 2013,
49, 3570
Received 22nd February 2013,
Accepted 11th March 2013
DOI: 10.1039/c3cc41337c
www.rsc.org/chemcomm
A conceptually new and general strategy has been developed for
the construction of a benzimidazole or a benzoxazole ring fused
with isoquinolinone affording a diverse and unique class of small
molecules as potential and novel inhibitors of PDE4.
The development of new and powerful chemical methodologies
leading to fused heteroaromatics is of immense value as
it allows access to the diversity based novel chemical space
useful for pharmaceutical/drug discovery efforts. Through the
generation of a combinatorial library of small molecules these
methodologies often provide crucial breakthroughs in the
discovery of new chemical entities (NCEs) required by pharma-
ceutical/agrochemical industries.
Fig. 1 Design of A/B as novel inhibitors of PDE4.
While benzimidazole or benzoxazole and isoquinolinone are
well known structural motifs in drug discovery/medicinal chemistry
their combined form i.e. (benzimidazo or benzoxazolo)iso-
quinolinones largely remained unexplored perhaps due to the
limited or no accessibility of this class of compounds.1 This
prompted us to explore2 a new and general method of accessing
benzimidazo[1,2-b]isoquinolin-11-one/benzoxazolo[3,2-b]iso-
quinolin-11-one derivatives as potential inhibitors of phospho-
diesterase 4 (PDE4). PDE4 inhibitors are known to be useful
anti-inflammatory agents for the potential treatment of chronic
obstructive pulmonary disease (COPD) and asthma.3 Our target
molecules B derived from a known anti-inflammatory agent4
CP-77059 (Fig. 1) were designed based on the in silico docking studies
of a representative compound A (Fig. 1) into the active site of PDE4B
(Fig. 2). The study showed binding of A deep into the active site
Fig. 2 Binding mode of A in PDE4B (PDB code-1XMY).
In view of the central role played by heterogeneous catalysts
(docking score À22.07) along with an H-bond interaction of carbonyl in various organic transformations,5 inexpensive and commer-
oxygen of ester with the side chain amino group of Gln 443 (see ESI†). cially available Amberlyst-15 attracted our attention due to its
non-hazardous nature and easy removal from the reaction mixture
e.g. via simple filtration. We anticipated that Amberlyst-15
mediated activation of the vinylic amino group of 3-amino-2-
(2-hydroxy/aminophenyl)isoquinolin-1(2H)-one could trigger its
intramolecular cyclization leading to our target compounds
A/B. Herein we report our preliminary results on intramolecular
cyclization of 3-amino-2-(2-amino/hydroxyphenyl)isoquinolin-
1(2H)-one derivative 3 leading to benzimidazo[1,2-b]isoquinolin-
11-ones/benzoxazolo[3,2-b]isoquinolin-11-ones 4 (or B, Scheme 1).
a Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500 046, India. E-mail: manojitpal@rediffmail.com;
Tel: +91 40 6657 1500
b Doctoral Programme in Experimental Biology and Biomedicine, Center for
Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra,
Portugal
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectral data for all new compounds, results of in vitro and docking
studies. See DOI: 10.1039/c3cc41337c
c
3570 Chem. Commun., 2013, 49, 3570--3572
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yield (entry 5, Table 1). The reaction, however, did not proceed
in the absence of Amberlyst-15 (entry 6, Table 1) or in the
presence of another catalyst i.e. Amberlite (entry 7, Table 1)
indicating the key role played by Amberlyst-15 in the present
reaction. To test the recyclability of the catalyst, Amberlyst-15
was recovered by simple filtration and reused additional three
times when 4a was isolated without significant loss of its yield
(entry 1, Table 1). Notably, all these reactions were performed
without using any inert atmosphere. Overall, Amberlyst-15 in
MeCN was found to be optimum for the preparation of 4a.
We then examined the generality and substrate scope of the
present reaction. A range of substituents e.g. Me, OMe, Cl on
the N-aryl ring and ester, CN, amide on the isoquinolinone ring
of 3 were well tolerated (Table 2). Moreover, the reaction
proceeded well irrespective of the nature of participating amino
groups (e.g. primary or secondary) on the N-aryl ring of 3.
Secondary amines possessing various R3 groups like allyl,
propargyl, benzyl, cyanomethyl or 2-ethoxy-2-oxoethyl partici-
pated well in the reaction. The generality of this methodology
was demonstrated further by synthesizing benzoxazolo[3,2-b]iso-
quinolin-11-ones (4v–y) where the phenolic hydroxyl group of the
N-aryl ring of 3 participated in the reaction. All the desired
products were synthesized in good to excellent yields8 and well
characterized by spectral (NMR, IR and MS) data (see ESI†).
Scheme 1 Amberlyst-15 mediated activation of a vinylic amino group.
Scheme 2 Preparation of key starting material 3.
Table 2 Amberlyst-15 mediated synthesis of 4a
To the best of our knowledge the use of this strategy leading to 4 is
unprecedented.1,6 The key starting material 3 (3a–m; X = NH and
3v–y; X = O) required was prepared via Cu-mediated2f,7 coupling–
cyclization of 2-iodobenzamides 1 with appropriate cyano deriva-
tives 2 in the same pot (followed by selective N-alkylation to
prepare 3n–u) (Scheme 2).
The Amberlyst-15 mediated intramolecular cyclization of 3a
was examined initially in a variety of solvents (Table 1). The
reaction proceeded well in MeCN, PEG and MeOH (entries 1, 2
and 4, Table 1) but not in DMF (entry 3, Table 1). Notably, the
reaction proceeded in water affording product 4a albeit in lower
Entry X, R, R1, R2 substrate (3)
t/h
Product (4) Yieldb (%)
1
2
3
4
NH, H, H, CO2Et 3a
1.5 4a
2.0 4b
98
87
71
63
65
91
83
75
61
92
91
93
90
89
91
89
86
95
95
96
91
90
85
72
93
NH, H, H, CO2Me 3b
NH, H, H, CN 3c
7.0 4c
11.5 4d
8.5 4e
1.5 4f
2.0 4g
7.0 4h
12.0 4i
1.5 4j
2.0 4k
2.0 4l
2.0 4m
3.5 4n
3.5 4o
3.0 4p
3.0 4q
4.5 4r
4.0 4s
5.0 4t
6.0 4u
5.0 4v
8.0 4w
8.0 4x
5.0 4y
NH, H, H, morc 3d
Table 1 Effect of conditions on Amberlyst-15 mediated synthesis of 4aa
5
6
7
8
NH, H, H, CONH2 3e
NH, CH3, H, CO2Et 3f
NH, CH3, H, CO2Me 3g
NH, CH3, H, CN 3h
9
NH, CH3, H, mor 3i
10
11
12
13
14
15
16
NH, OCH3, H, CO2Et 3j
NH, OCH3, H, CO2Me 3k
NH, Cl, Cl, CO2Et 3l
NH, Cl, Cl, CO2Me 3m
N-Allyl, H, H, CO2Et 3n
N-Allyl, CH3, H, CO2Et 3o
N-Propargyl, H, H, CO2Et 3p
N-Propargyl, CH3, H, CO2Et 3q
NBn, H, H, CO2Et 3r
NBn, OCH3, H, CO2Et 3s
NCH2CN, CH3, H, CO2Et 3t
NCH2CO2Et, CH3, H, CO2Et 3u
O, OCH3, H, CO2Et 3v
O, OCH3, H, CONH2 3w
O, OCH3, H, mor 3x
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
No cat.
MeCN
PEG-800
DMF
MeOH
H2O
MeCN
MeCN
98 (95, 90, 88)c 17
92
47
18
19
20
21
22
23
24
25
90
75d
No reaction
No reaction
Amberlite
a
Reaction was carried out using 3a (1.0 mmol), catalyst (10%, w/w) in
O, CH3, H, CO2Et 3y
b
c
solvent (5 mL) at 60 1C. Isolated yield. Catalyst was reused for
a
additional three runs and figures within parentheses indicate the
All the reactions were carried out using compound 3 (1 mmol) and
b
d
corresponding yields for each run. The reaction was carried out Amberlyst-15 (10%, w/w) in CH3CN (5 mL) at 60 1C. Isolated yield.
c
at 75 1C.
mor = morpholine-4-carbonyl.
c
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RS and RA thank CSIR, for research fellowships. The authors
thank Prof. J. Iqbal and DST (Grant SR/S1/OC-53/2009) for
support.
Notes and references
1 For the only report on biological activities of benzimidazoiso-
quinolinone, see: M. Bollini, J. J. Casal, D. E. Alvarez, L. Boiani,
´
M. Gonzalez, H. Cerecetto and A. M. Bruno, Bioorg. Med. Chem.,
2009, 17, 1437.
Scheme 3 The proposed reaction mechanism.
2 For our earlier effort on the synthesis of functionalized hetero-
aromatics, see: (a) 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. S. Kumar, K. K. Priya, K. V. L.
Parsa and M. Pal, Chem. Commun., 2011, 47, 5010; (b) K. S. Kumar,
P. M. Kumar, M. A. Reddy, M. Ferozuddin, M. Sreenivasulu,
A. A. Jafar, G. R. Krishna, C. M. Reddy, D. Rambabu, K. S. Kumar,
S. Pal and M. Pal, Chem. Commun., 2011, 47, 10263; (c) G. R. Reddy,
T. R. Reddy, S. C. Joseph, K. S. Reddy, L. S. Reddy, P. M. Kumar,
G. R. Krishna, C. M. Reddy, D. Rambabu, R. Kapavarapu,
C. Lakshmi, T. Meda, K. K. Priya, K. V. L. Parsa and M. Pal, Chem.
Commun., 2011, 47, 7779; (d) P. M. Kumar, K. S. Kumar,
P. K. Mohakhud, K. Mukkanti, R. Kapavarapu, K. V. L. Parsa and
M. Pal, Chem. Commun., 2012, 48, 431; (e) B. Prasad, R. Adepu,
S. Sandra, D. Rambabu, G. R. Krishna, C. M. Reddy, G. S. Deora,
P. Misra and M. Pal, Chem. Commun., 2012, 48, 10434; ( f ) R. Adepu,
R. Sunke, C. L. T. Meda, D. Rambabu, G. R. Krishna, C. M. Reddy,
G. S. Deora, K. V. L. Parsa and M. Pal, Chem. Commun., 2013, 49,
190.
Fig. 3 Dose dependent inhibition of PDE4B by 4n.
3 A. Kodimuthali, S. S. L. Jabaris and M. Pal, J. Med. Chem., 2008,
51, 5471.
Amberlyst-15 (Scheme 3), a macro-reticular polystyrene-based
ion exchange resin, possesses strongly acidic sulfonic groups.
Thus, mechanistically (Scheme 3), the intramolecular cyclization
of 3 seemed to proceed via a two-step process involving (i) a
nucleophilic attack by the –XH moiety9a of E-1 on its activated
and nearby –CQN– affording the intermediate E-2 followed by (ii)
elimination of ammonia to give the desired compound 4.9b An
attempt to isolate the intermediate E-1 or E-2 from the reaction of
3a under the conditions employed however failed, perhaps due to
its rapid participation in the next step leading to 4a.
Some of the compounds synthesized were tested against
PDE4B using an in vitro enzyme assay.10 The compounds 4a
(A in Fig. 1 and 2), 4f, 4g, 4d and 4n showed 62, 53, 57, 48 and
85% inhibition, respectively, at 30 mM and 4n (IC50 B 3 mM,
Fig. 3) was comparable with rolipram (IC50 B 1 mM). Since
COPD and asthma are the major health burden worldwide, the
present class of compounds is of further interest.
4 J. A. Lowe, III, R. L. Archer, D. S. Chapin, J. B. Cheng, D. Helweg,
J. L. Johnson, B. K. Koe, L. A. Lebel, P. F. Moore, J. A. Nielsen,
L. L. Russo and J. T. Shirley, J. Med. Chem., 1991, 34, 624.
5 (a) S. H. Lee, D. R. Park, H. Kim, J. Lee, J. C. Jung, S. Y. Woo,
W. S. Song, M. S. Kwon and I. K. Song, Catal. Commun., 2008,
9, 1920; (b) S. Park, K. M. Cho, M. H. Youn, J. G. Seo, S. H. Baeck,
T. J. Kim, Y. M. Chung, S. H. Oh and I. K. Song, Catal. Lett.,
2008, 122, 349; (c) I. K. Song and W. Y. Lee, Appl. Catal., A, 2003,
256, 77.
6 For earlier methods, see: (a) J. Lu, X. Gong, H. Yang and H. Fu,
Chem. Commun., 2010, 46, 4172; (b) A. Senthilvelan, D. Thirumalai
and V. T. Ramakrishnan, Tetrahedron, 2005, 61, 4213; (c) K.-Q. Ling,
X.-Y. Chen, H.-K. Fun, X.-Y. Huang and J.-H. Xu, J. Chem. Soc., Perkin
Trans. 1, 1998, 4147. See also ref. 1.
7 For a similar Cu-mediated coupling, see: T. Liu, C. Zhu, H. Yang and
H. Fu, Adv. Synth. Catal., 2012, 354, 1579; see also ref. 6a.
8 Except 4c–e, 4h, 4i, 4w and 4x other compounds do not require any
chromatographic purification after isolation.
9 (a) The possibility of the –XH moiety to play the role of a leaving
group (cf. ref. 6a where Br was used as a leaving group) was ruled out
as the corresponding benzimidazo[1,2-b]isoquinolin-11-ones was
not isolated in the case of 3v–y instead of benzoxazolo[3,2-b]iso-
quinolin-11-ones 4v–y (see Table 2). Indeed, the present role of –XH
allowed us to introduce further diversity i.e. the R3 group into the
product 4; (b) Alternatively, protonation of R2 (i.e. ester, CN or
amide) of 3 followed by intramolecular nucleophilic attack of XH
on the –CQN– moiety could also lead to the formation of product 4.
10 P. Wang, J. G. Myers, P. Wu, B. Cheewatrakoolpong, R. W. Egan and
M. M. Billah, Biochem. Biophys. Res. Commun., 1997, 234, 320.
In conclusion, a facile assembly of a benzimidazole or a
benzoxazole ring with isoquinolinone has been achieved via a
conceptually new and general strategy involving Amberlyst-15
mediated activation of a vinylic amino group leading to a
diverse and unique class of small molecules as potential
inhibitors of PDE4.
c
3572 Chem. Commun., 2013, 49, 3570--3572
This journal is The Royal Society of Chemistry 2013