Facile assembly of two 6-membered fused N-heterocyclic rings: A rapid access to novel small molecules via Cu-mediated reaction

Article abstract of DOI:10.1039/c2cc37070k

A rapid, versatile and one-pot Cu-mediated domino reaction has been developed for facile assembly of two six membered fused N-heterocyclic rings leading to novel small molecules as potential inhibitors of PDE4. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2cc37070k

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Facile assembly of two 6-membered fused
N-heterocyclic rings: a rapid access to novel small
molecules via Cu-mediated reaction†
Raju Adepu,a Rajnikanth Sunke,a Chandana L. T. Meda,a D. Rambabu,a
G. Rama Krishna,b C. Malla Reddy,b Girdhar Singh Deora,a
Kishore V. L. Parsaa and Manojit Pal*a
Cite this: Chem. Commun.,
2013, 49, 190
Received 28th September 2012,
Accepted 5th November 2012
DOI: 10.1039/c2cc37070k
www.rsc.org/chemcomm
A rapid, versatile and one-pot Cu-mediated domino reaction has been
developed for facile assembly of two six membered fused N-heterocyclic
rings leading to novel small molecules as potential inhibitors of PDE4.
The development of elegant, versatile and new synthetic metho-
dologies leading to the diversity based N-heterocycles is of enor-
mous importance. Metal catalyzed cascade/domino reactions1 have
occupied the center stage due to their ability to provide an array
of diverse and novel compounds especially for medicinal/
pharmaceutical uses or early drug discovery effort.
Evaluation of phosphodiesterase 4 (PDE4) inhibition for the
potential treatment of CNS related diseases in addition to COPD
and asthma has underlined the importance of development of PDE4
inhibitors.2 Only one drug i.e. roflumilast (Daxass, Nycomed) has
been launched so far and side effects including nausea and emesis2
have delayed the market launch of cilomilast. Thus, discovery of novel
PDE4 inhibitors having fewer side effects is desirable. In pursuance of
our research on identification of fused N-heterocycle based PDE-4/
TNF-a inhibitors3 we required new routes to access our target
compound C that was derived from our earlier inhibitors3a,b A/B
(Fig. 1). Accordingly, we have developed a new and versatile Cu-
Scheme 1 Synthesis of 3 via Cu-catalyzed domino reactions.
mediated domino reaction4 leading to one-pot synthesis of C (or 3 and
5, Scheme 1) under mild conditions without using any co-catalyst,
ligand or additive. Herein we report our preliminary results.
While chemistry of quinazolin-4(3H)-ones and isoquinolin-
1(2H)-ones is well documented their combined form C (3 and 5)
remained unexplored.5 Thus, in addition to evaluating their
Table 1 Effect of conditions on domino reaction of 1a with 2aa
Entry
Catalyst
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
No cat.
K2CO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMF
1,4-Dioxane
Toluene
DMSO
DMSO
DMSO
87 (60, 32)c
Fig. 1 Design of novel PDE-4/TNF-a inhibitors (C) derived from A/B.3a,b
71
86
74
46
0
81
69
0
a Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad
500 046, India. E-mail: manojitpal@rediffmail.com; Tel: +91 40 6657 1500
b Department of Chemical Sciences, Indian Institute of Science Education and
Research, Kolkata, West Bengal 741252, India
† Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, and results of in vitro and
docking study. CCDC 902761. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc37070k
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) under anhydrous
conditions. Isolated yield. 0.05 and 0.02 mmol of CuI used.
b
c
c
190 Chem. Commun., 2013, 49, 190--192
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Table 2 Cu-catalyzed synthesis of 5H-isoquinolino[2,3-a]quinazoline-5,12(6H)-
dione (3)a
Table 3 Cu-catalyzed synthesis of 4H-pyrido[1,2-a]thieno[3,2-e]pyrimidine-
4,9(5H)-dione (5)a
Halide (4)
Entry R1, R3, X, Y
Nitrile
(2) R2 T/h R1, R3, R2, Y
Product (5)
Yieldb
(%)
Halide (1)
R1, R3, X,
Entry Y, Z
Nitrile (2)
R2
Product (3)
T/h R1, Y, Z, R2
Yieldb
(%)
1
2
3
R1, R3 = –(CH2)4–,
I, CH
4a
CO2Et 6.0 R1, R3 = –(CH2)4–,
2a
75
64
69
CO2Et, CH
5a
7.0 R1, R3 = –(CH2)4–,
CN, CH
1
2
3
4
5
H, CH3, I,
CH, CH
1a
H, CH3, Br,
CH, CH
1b
H, CH3, Cl,
CH, CH
1c
CO2Et
2a
3.0 H, CH, CH,
87
84
0
CO2Et
3a
3.5 3a
4a
CN
2c
2a
2a
5b
4a
2d
6.5 R1, R3 = –(CH2)4–,
6.0 3a
5c
1a
CO2Me
2b
3.0 H, CH, CH,
86
76
4
5
R1, R3 = –(CH2)4–,
Cl, N
4b
2a
2d
8.0 R1, R3 = –(CH2)4–,
61
60
CO2Me
3b
4.0 H, CH, CH, CN
CO2Et, N
5d
6.5 R1, R3 = –(CH2)4,
1a
1a
CN
2c
4b
3c
–
H, CH, CH,
3.5
6
7
77
63
5e
6
7
8
R1, R3 = –(CH2)2–
N(Boc)–CH2–, I, CH
4c
2a
2c
2a
6.0 R1, R3 = –(CH2)2–
N(Boc)–CH2–,
CO2Et, CH
5f
7.0 R1, R3 = –(CH2)2–
N(Boc)–CH2–,
CN, CH
70
61
71
2d
3d
H, CH, CH,
3.0
1a
4c
2e
2a
3e
5g
8
9
H, CH3, Cl,
N, CH
4.0 H, N, CH,
CO2Et
73
85
R1, R3 = –(CH2)2–
N(CO2Et)–CH2–, I,
CH
4d
R1, R3 = –(CH2)3–,
I, CH
4e
R1, R3 = –(CH2)5–,
I, CH
4f
6.0 R1, R3 = –(CH2)2–
N(CO2Et)–CH2–,
CO2Et, CH
5h
6.0 R1, R3 = –(CH2)3–,
CO2Et, CH
5i
6.0 R1, R3 = –(CH2)5–,
CO2Et, CH
5j
1d
3f
t
t
R
R
Bu , CH3, 2a
I, CH, CH
1e
3.0 Bu , CH, CH,
CO2Et
9
2a
2a
68
70
72
61
63
68
69
3g
t
R
10
11
1e
2c
3.5 Bu , CH, CH, CN 72
3h
t
10
11
12
13
14
15
R
1e
2d
3.5 Bu , CH, CH,
72
4f
CO2Me 6.5 R1, R3 = –(CH2)5–,
2b
3i
CO2Me, CH
5k
7.0 R1, R3 = –(CH2)5–,
CN, CH
5l
8.5 R1, R3 = –(CH2)5–,
CO2Et, N
5m
6.0 R1, R3 = –(CH2)6–,
CO2Et, CH
5n
6.5 R1, R3 = –(CH2)6–,
12
13
14
Ph, CH3, I,
CH, CH
1f
1f
2a
2b
2d
3.0 Ph, CH, CH,
74
69
68
CO2Et
3j
3.0 Ph, CH, CH,
CO2Me
4f
2c
R1, R3 = –(CH2)5–,
Cl, N
4g
R1, R3 = –(CH2)6–,
I, CH
4h
4h
2a
2a
2b
3k
1f
3.5 Ph, CH, CH,
3l
15
2-Thienyl,
CH3, I,
CH, CH
1g
H, C2H5, I,
CH, N
1h
NO2, CH3, I, 2a
CH, CH
1i
2a
2a
3.0 2-Thienyl, CH,
CH, CO2Et
3m
72
CO2Me, CH
5o
6.0 Ph, H, CO2Et, CH
16
17
18
19
Ph, H, I, CH
4i
Ph, H, Cl, N
4j
H, H, I, CH
4k
4k
2a
2a
2a
2d
70
62
72
59
5p
16
17
a
3.0 H, CH, N, CO2Et
63
65
8.0 Ph, H, CO2Et, N
3n
5q
6.5 H, H, CO2Et, CH
3.5 NO2, CH, CH,
5r
CO2Et
3o
7.5
H,H,
,CH
All the reactions were carried out using 1 (1 mmol), 2 (1.2 mmol), CuI
(0.1 mmol) and K2CO3 (3 mmol) in DMSO (2 mL) under anhydrous
conditions (no inert atmosphere). Isolated yield.
5s
b
a
b
For reaction conditions, see footnote of Table 2. Isolated yield.
c
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Scheme 2 Preparation of intermediate 6 and its conversion to 3a.
favorable role played by the catalyst in the cycloaddition step
(perhaps via coordination with CN) in addition to C-arylation.
Some of the synthesized compounds showed promising
inhibition of PDE4B [e.g. 3f (51%), 3n (57%) and 5e (62%)]
when tested in vitro7 at 30 lM (see ESI†). This was further
supported by the docking results of 5e (Fig. 2) (and 3n, see ESI†)
with PDE4B protein (Glide score À7.4). The oxygen atom of the
morpholine ring of 5e along with the CO group participated in
H-bonding with NH of His-278 and OH of Tyr 233 respectively. A
pi–pi stacking between 5e and Phe-446 was also observed (Fig. 2).
The morpholine ring of 5e was found to be well occupied in the
partially charged pocket of active sites (see ESI†).
In conclusion, a new, one pot and versatile Cu-mediated
domino reaction has been developed that allowed rapid access
to a library of small molecules based on novel structural motifs.
Three of these compounds showed inhibition of PDE4B in vitro
and may have potential for therapeutic applications.
Fig. 2 Binding mode and interactions of 5e with PDE4B active sites.
PDE4 inhibiting properties the development of a suitable
methodology leading to C was a major challenge. We envisioned
that Cu-mediated C-arylation of nitriles (e.g. E-1) followed by an
intramolecular nucleophilic addition of NH to CN would afford
the initial 6-membered ring in situ (E-3 via E-2, Scheme 1). A
subsequent intramolecular nucleophilic attack by the 3-amino
moiety of E-3 on its ester group would allow the formation of a
fused pyrimidone ring leading to 3 or 5.
The key starting material 1 or 4 required for our synthesis was
prepared via amide bond formation between 2-halo (het)aryl car-
boxylic acid chloride and 2-amino (het)aryl carboxylate ester (see
ESI†). We then examined the coupling of iodo compound 1a with
ethyl cyanoacetate (2a) under various conditions. After assessing a
range of bases e.g. K2CO3, Na2CO3 and Cs2CO3 (entries 1–3, Table 1),
solvents e.g. DMSO, DMF, 1,4-dioxane and toluene (entries 1 and
4–6, Table 1) and catalysts e.g. CuI, CuBr and CuCl (entries 1, 7 and 8,
Table 1) a combination of CuI and K2CO3 in DMSO was found to be
optimum. A decrease in CuI loading decreased the product yield and
RA and RS thank CSIR for research fellowships. The authors
thank Prof. J. Iqbal and DST (Grant SR/S1/OC-53/2009) for support.
Notes and references
ˆ
1 For excellent reviews, see: (a) V. Michelet, P. Y. Toullec and J.-P. Genet,
´
˜
Angew. Chem., Int. Ed., 2008, 47, 4268; (b) E. Jimenez-Nu´nez and
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62, 2143; (i) L. F. Tietze, Chem. Rev., 1996, 96, 115.
no reaction in the absence of CuI (entries 1 and 9, Table 1) indicated 2 For reviews, see: (a) A. Kodimuthali, S. L. Jabaris and M. Pal, J. Med.
Chem., 2008, 51, 5471; (b) M. D. Houslay, P. Schafer and K. Y. Zhang,
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3 (a) K. S. Kumar, P. M. Kumar, K. A. Kumar, M. Sreenivasulu, A. A. Jafar,
the key role played by the catalyst.
We then examined the scope of the present Cu-catalyzed domino
reaction which afforded compound 3 with a variety of substitution
patterns (Table 2). The reaction proceeded well with various sub-
stituents on 1 e.g. R1 = alkynyl (entries 9–11, Table 2), phenyl (entries
12–14, Table 2), 2-thienyl (entry 15, Table 2), or NO2 (entry 17,
Table 2) group irrespective of X being I or Br (entry 1 vs. 2, Table 2)
except Cl (entry 3, Table 2) unless it is attached to an azomethine
carbon (entry 8, Table 2). In addition to the use of various nitriles
(2a–e) the reaction was also successful for thiophene analogues of 1
(Table 3) i.e. 4 containing various substituents e.g. R1, R3 represent-
ing a fused alicyclic (entries 1–5 and 9–15, Table 3) or azaalicyclic
(entries 6–8, Table 3) ring or hydrogens (entries 18 and 19, Table 3)
or R1 = Ph and R3 = H (entries 16 and 17, Table 3). All the
compounds synthesized were well characterized by spectral (NMR,
IR and MS) data and the molecular structure of 5k was confirmed
unambiguously by single crystal X-ray diffraction study (see ESI†).6
Mechanistically, the intermediacy of E-1 (Scheme 1) was
confirmed by isolation of 6 from the reaction of 1a with 2a at
room temperature (Scheme 2). The shorter reaction time (2 h) for
the conversion of 6 to 3a in the presence of CuI indicated the
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;
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5 Only two synthesis of isoquino[2,3-a]quinazolines have been
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6 CCDC 902761 (5k)†.
7 P. Wang, J. G. Myers, P. Wu, B. Cheewatrakoolpong, R. W. Egan and
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c
192 Chem. Commun., 2013, 49, 190--192
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