A direct access to bioactive fused N-heterocyclic acetic acid derivatives

Article abstract of DOI:10.1039/c3ob42535e

A Cu-catalyzed new sequence involving the Ullmann type intermolecular C-C followed by an intramolecular C-N coupling and then intramolecular aza-Michael type addition (and oxidation) in a single pot afforded various fused N-heterocyclic acetic acid derivatives as inhibitors of PDE4. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ob42535e

Organic &
Biomolecular Chemistry
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A direct access to bioactive fused N-heterocyclic
acetic acid derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 2514
Raju Adepu,a A. Rajitha,a Dipali Ahuja,a Atul Kumar Sharma,a B. Ramudu,a
Received 19th December 2013,
Accepted 23rd January 2014
Ravikumar Kapavarapu,b Kishore V. L. Parsaa and Manojit Pal*a
DOI: 10.1039/c3ob42535e
www.rsc.org/obc
A Cu-catalyzed new sequence involving the Ullmann type inter-
molecular C–C followed by an intramolecular C–N coupling and
then intramolecular aza-Michael type addition (and oxidation) in a
single pot afforded various fused N-heterocyclic acetic acid deriva-
tives as inhibitors of PDE4.
The development of direct, simple and efficient strategies that
offer ample flexibilities is of high demand in modern organic
synthesis. The use of metal catalyzed domino reactions1 has
attracted considerable interest for this purpose, because of
their ability to produce diverse and novel classes of com-
pounds in a single synthetic operation.
The N-heterocyclic acetic acid framework A (Fig. 1) is preva-
lent in many bioactive compounds, including non-steroidal
anti-inflammatory drugs2 (NSAIDs) e.g. indomethacin, tolmetin,
zomepirac etc. The impressive and proven anti-inflammatory
activities of these drugs prompted us to explore fused N-hetero-
cyclic acetic acids as a novel class of potential inhibitors3 of phos-
phodiesterase 4 (PDE4). The development of PDE4 inhibitors4 is
beneficial, as in addition to chronic obstructive pulmonary
Fig. 2 Docking of C into the active site of PDE4B (PDB code 1XMY).
Fig. 1 Design of novel bioactive molecules B/C (as potential PDE4
inhibitors) derived from A.
aDr 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
bDoctoral 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
procedures, spectral data for all new compounds, copies of spectra, results of
in vitro and docking studies. See DOI: 10.1039/c3ob42535e
Scheme 1 Synthesis of 3 via Cu-catalyzed domino reactions.
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Table 1 Effect of conditions on domino reaction of 1a with 2aa
disease (COPD) and asthma, PDE4 has been reported as a poten-
tial therapeutic target for neurodegenerative diseases, cancer
and memory loss. Most of the leading PDE4 inhibitors, including
the marketed drug roflumilast (Daxas®, Nycomed), suffer from
side effects including nausea and emesis.4 It is therefore desir-
able to identify novel PDE4 inhibitors having fewer side effects.
In our effort, initial in silico docking studies of a representative
compound C, in the active site of PDE4B, aided us in the design
of the target molecules B (Fig. 1 and 2). To obtain B we have
developed a direct, Cu-mediated domino reaction, leading to the
one-pot synthesis of B (or 3 and 4, Scheme 1) under mild con-
ditions without using any co-catalyst, ligand or additive. Herein,
we report our preliminary results.
While more simple heterocyclic acid derivatives have been
prepared via a number of efficient methods,5 none of them
appeared to be useful for the synthesis of 3 or 4. In view of the
recent success of Cu-catalyzed domino reactions6 to construct
tri- and tetracyclic ring systems, we envisioned3f that a
Cu-mediated Ullmann type intermolecular C–C coupling of 1
with 2 (e.g. E-1), followed by an intramolecular nucleophilic
addition of the amidic NH to CN, would afford the initial
Entry
Catalyst
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
K2CO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMSO
1,4-Dioxane
DMF
DMF
DMF
89
79
88
88
53
80
71
78
80
0c
CuI
CuBr
CuCl
Cu(OAc)2
Cu(OTf)2
CuI
9
10
11
DMF
DMF
DMF
—
0
a Reactions were carried out using 1a (1 mmol), 2a (1.2 mmol), catalyst
(0.1 mmol) and base (3 mmol) in a solvent (2 mL) at 80 °C for 0.5 h
under anhydrous conditions (no inert atmosphere). b Isolated yield.
c Reaction performed at room temperature.
Table 2 Cu-catalyzed synthesis of 2-(12-oxo-6,12-dihydro-5H-isoquinolino[2,3-a]quinazolin-5-yl)acetate (3)a
Entry
1
Halide (1) R1, R2, R3, R4, X
Nitrile (2) Z
Time (h)
0.5
Product (3) R1, R2, R3, R4, Z
Yieldb (%)
H, H, Me, H, I
1a
1a
CO2Et
2a
CO2Me
H, H, Me, H, CO2Et
3a
H, H, Me, H, CO2Me
3b
89
84
81
81
87
83
79
81
76
73
73
80
75
68
85
2
0.5
2b
3
1a
1a
PO(OEt)2
2c
2.0
H, H, Me, H, PO(OEt)2
3c
t
t
4
CO2 Bu
0.5
H, H, Me, H, CO2 Bu
2d
2a
3d
5
H, H, Et, H, I
1b
1b
0.5
H, H, Et, H, CO2Et
3e
H, H, Et, H, CO2Me
3f
6
2b
2c
2d
2a
2b
2c
2a
2c
0.5
7
1b
1b
1.5
H, H, Et, H, PO(OEt)2
3g
t
8
0.5
H, H, Et, H, CO2 Bu
3h
9
H, H, Me, NO2, Cl
1c
1c
1.5
H, H, Me, NO2, CO2Et
3i
H, H, Me, NO2, CO2Me
3j
10
11
12
13
14
15
1.5
1c
2.5
H, H, Me, NO2, PO(OEt)2
3k
F, H, tBu, H, Br
1d
1d
2.0
F, H, tBu, H, CO2Et
3l
2.5
F, H, tBu, H, PO(OEt)2
3m
F, H, Me, NO2, Cl
1e
Cl, H, Me, H, I
CN
2e
2a
2.5
F, H, Me, NO2, CN
3n
Cl, H, Me, H, CO2Et
0.5
1f
3o
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Table 2 (Contd.)
Entry
16
Halide (1) R1, R2, R3, R4, X
Nitrile (2) Z
Time (h)
0.5
Product (3) R1, R2, R3, R4, Z
Yieldb (%)
1f
1f
1f
1f
2b
2c
2d
2e
2a
2b
2c
2a
2b
2c
Cl, H, Me, H, CO2Me
3p
Cl, H, Me, H, PO(OEt)2
81
78
77
72
87
84
82
86
81
78
17
1.5
3q
t
18
1.0
Cl, H, Me, H, CO2 Bu
3r
19
1.0
Cl, H, Me, H, CN
3s
Me, H, Et, H, CO2Et
3t
Me, H, Et, H, CO2Me
3u
Me, H, Et, H, PO(OEt)2
3v
Me, Me, Me, H, CO2Et
3w
Me, Me, Me, H, CO2Me
3x
20
Me, H, Et, H, I
1g
1g
0.5
21
0.5
22
1g
2.0
23
Me, Me, Me, H, I
1h
1h
0.5
24
0.5
25
1h
1.5
Me, Me, Me, H, PO(OEt)2
3y
a All the reactions were carried out using 1 (1 mmol), 2 (1.2 mmol), CuI (0.1 mmol) and K2CO3 (3 mmol) in DMF (2 mL) at 80 °C under
anhydrous conditions (no inert atmosphere). b Isolated yield.
6-membered ring in situ (E-3 via E-2, Scheme 1). A subsequent
intramolecular aza-Michael type addition7 of E-3 would Table 3 Cu-catalyzed synthesis of (Z)-alkyl 2-(7-cyano-12-oxo-
6,12-dihydro-5H-isoquinolino[2,3-a]quinazolin-5-ylidene)acetate (4)a
furnish 3 (or 4 after aerial oxidation).8
The required starting material, 1, was prepared via an
amide bond formation between a 2-haloaryl carboxylic acid
chloride and 3-(2-aminoaryl)acrylate ester, produced via a
Heck reaction (see the ESI†). Initially, the coupling of iodo
compound 1a with ethyl cyanoacetate (2a) was examined
(Table 1) using a range of bases (e.g. K2CO3, Na2CO3 and
Cs2CO3), solvents (e.g. DMSO, DMF and 1,4-dioxane) and cata-
lysts [e.g. CuI, CuBr, CuCl, Cu(OAc)2 and Cu(OTf)2]. While
good results were obtained in several cases (entries 1, 3, 4, 6
and 9), the combination of CuI and K2CO3 in DMF (entry 1,
Table 1) was chosen for further studies. All these reactions
were performed at 80 °C. The reaction did not proceed at room
temperature or in the absence of a catalyst (entries 10 and 11,
Table 1).
Halide (1)
R1, R2, R3, X
Product (4)
R1, R2, R3
Yieldb
(%)
Entry
Time/h
4.0
1
2
3
4
5
6
7
8
H, H, Me, I
1a
H, H, Et, I
H, H, Me
4a
H, H, Et
72
71
49
56
48
65
73
72
4.0
1b
4b
F, H, tBu, Br
5.0
F, H, tBu
4c
1d
F, H, Me, I
1i
Cl, H, Me, I
1f
Me, H, Et, I
1g
Me, Me, Me, I
1h
6.0
F, H, Me
4d
Cl, H, Me
4e
Me, H, Et
To expand the scope of the present Cu-catalyzed domino
reaction, compound 3 was prepared with a variety of substi-
tution patterns (Table 2). The reaction proceeded well with
5.0
4.0
t
various substituents on 1 including F, Cl, Me, Et, Bu, or NO2,
4f
4.0
Me, Me, Me
4g
Me, Me, Et
irrespective of X being either I, or Br, or Cl. The use of various
nitriles (2a–e) was also successful. Notably, the reaction of 1
with malononitrile 2e in DMSO for a longer period afforded
the compound 4 containing an exocyclic double bond with
a Z-stereochemistry (Table 3). Moreover, the formation of the
Me, Me, Et, I
1j
6.0
4h
a Reactions were carried out using 1 (1 mmol), 2e (1.2 mmol), CuI
(0.1 mmol) and K2CO3 (3 mmol) in DMSO (2 mL) at 80 °C under
Z-isomer was found to be exclusive and was supported by a anhydrous conditions (no inert atmosphere). b Isolated yield.
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a rapid access to novel, fused N-heterocyclic acetic acid deriva-
tives. The reaction proceeds via a Cu-catalyzed domino reac-
tion involving (i) an Ullmann type intermolecular C–C
followed by (ii) an intramolecular C–N coupling and then (iii)
an intramolecular aza-Michael type addition (and subsequent
aerial oxidation). Several of these compounds showed promis-
ing PDE4B inhibition in vitro and seem to have potential for
related medical applications. Overall, the one-pot methodo-
logy, presented here, may find wide use in constructing a
diversity based library of small molecules for chemical and
medicinal applications.
Fig. 3 (A) NOE study of 4g and (B) complexation of 3 with Cu-catalyst.
RA thank the CSIR, for research fellowships. The authors
thank Prof. J. Iqbal and the CSIR [grant 02(0127)/13/EMR-II]
for support.
Scheme 2 Role of CuI in the generation of compound 4.
Notes and references
1 For selected in-depth reviews, see: (a) L. F. Tietze, Chem.
Rev., 1996, 96, 115; (b) H. Pellissier, Tetrahedron, 2006, 62,
2143; (c) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger,
Angew. Chem., Int. Ed., 2006, 45, 7134; (d) D. M. D’Souza and
T. J. J. Muller, Chem. Soc. Rev., 2007, 36, 1095;
(e) S. F. Kirsch, Synthesis, 2008, 3183; (f) D. J. Gorin,
B. D. Sherry and F. D. Toste, Chem. Rev., 2008, 108, 3351;
(g) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008, 108, 3395;
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Fig. 4 Dose dependent inhibition of PDE4B by compound 3e.
2 A. Kar, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
in Medicinal Chemistry, New Age International (P) Ltd.,
New Delhi, India, 2005, ISBN: 81-224-1565-2.
NOE study of 4g (Fig. 3A). Mechanistically, the Z-isomer of 4
seemed to have been formed in situ via the generation of 3
(Scheme 1) and then a Cu-complex E-4 (Fig. 3B) which on
aerial oxidation afforded the olefin 4. To gain further evidence,
3s was treated with K2CO3 and CuI + K2CO3, separately,
whereby a mixture of products was obtained in the first case
and the desired 4e (62% yield) in the second case (Scheme 2).
Several of the synthesized compounds showed promising
inhibition of PDE4B [e.g. 3b (71%), 3e (93%), 3f (86%), 3i
(66%), 3j (66%), 3k (78%), 3o (62%), 3p (62%), 3t (83%), 3u
(93%), 3w (71%) and 3x (88%)] when tested in vitro9 at 30 µM
(see the ESI†). This result was further supported by the results
of the docking of 3e (Fig. 2) and 3u (see the ESI†) into the
PDE4B protein (Glide score −23.05 and −22.05 vs. rolipram’s
−24.61). The ester carbonyl group participated in H-bonding
with the Gln443 of the Q pocket in the case of 3e and the
His234 of the metal binding pocket in case of 3u, respectively.
Additionally, both 3e and 3u showed a common Ar–Ar inter-
action with the Phe446 of PDE4B (see the ESI†). The com-
pound 3e showed a dose dependent inhibition of PDE4B with
an IC50 (the half maximal inhibitory concentration) ∼ 1.06 µM
comparable to rolipram’s IC50 ∼ 1.0 µM (Fig. 4).
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