Pd-mediated new synthesis of pyrroles: Their evaluation as potential inhibitors of phosphodiesterase 4

Article abstract of DOI:10.1039/c1cc12321a

A sequential Pd-mediated multi-component reaction followed by Suzuki or Heck or Sonogashira coupling in a single pot has been developed for the synthesis of functionalized pyrroles as potential inhibitors of PDE4.

Full text of DOI:10.1039/c1cc12321a

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COMMUNICATION
Pd-mediated new synthesis of pyrroles: their evaluation as potential
inhibitors of phosphodiesterase 4w
G. Rajeshwar Reddy,ab T. Ram Reddy,a Suju C. Joseph,a K. Sateesh Reddy,a
L. Srinivasula Reddy,a P. Mahesh Kumar,a G. Rama Krishna,c C. Malla Reddy,c
D. Rambabu,d Ravikumar Kapavarapu,d Chandana Lakshmi,d Teja Meda,d K. Krishna Priya,d
Kishore V. L. Parsad and Manojit Pal*d
Received 21st April 2011, Accepted 17th May 2011
DOI: 10.1039/c1cc12321a
A sequential Pd-mediated multi-component reaction followed by
Suzuki or Heck or Sonogashira coupling in a single pot has been
developed for the synthesis of functionalized pyrroles as potential
inhibitors of PDE4.
Pyrrole derivatives have attracted particular attention in the
area of drug discovery.1 For example, anticancer drug candi-
Fig. 1 Design of pyrrole based novel inhibitors (C) of PDE4.
date tallimustine and blockbuster cholesterol lowering agent
and bronchodilatory effects via elevation of the c-AMP level
and therefore have potential to provide relief of symptoms,
prevent complications and/or progression of these diseases.
Indeed, the most advanced PDE4 inhibitors e.g. cilomilast
and roflumilast have shown promising results in Phase III
clinical trials. As part of our ongoing effort on the identification
of novel inhibitors of PDE4 we report the evaluation of a series
of pyrroles (C, Fig. 1) designed from the known inhibitors A11a
and B.11b The synthesis and functionalization of C was carried
out using a Pd-based new MCR in a single pot.
atorvastatin (or lipitor) belong to this class. The classical
methods for the synthesis of pyrroles e.g. Hantzsch,2 Knorr,3
and Paal–Knorr4 reactions though effective suffer from several
drawbacks. Recently, multi-component reactions (MCRs)
have found wide applications in the synthesis of pyrroles.5
MCRs not only allow union of three or more starting materials
in a single synthetic operation with high atom economy and
bond-forming efficiency, but also avoid isolation and purifica-
tion of any intermediates thereby minimizing waste, labor, and
cost.6 Thus, synthesis of functionalized pyrroles has been
reported via an Fe(III)-catalyzed four-component coupling
reaction of 1,3-dicarbonyl compounds, amines, aldehydes,
and nitroalkanes.7 More recently, we have observed that
Pd-mediated8 MCR provides a more versatile and direct route
to functionalized pyrroles of potential medicinal value.
To synthesize C in a single pot we examined the reaction of
3-bromobenzaldehyde (3a), benzylamine (1), acetyl acetone (2a)
and nitromethane (4) in the presence of a Pd catalyst. Our goal
was to identify a suitable Pd catalyst that would allow further
functionalization via other key Pd-catalyzed reactions such as
Suzuki, Sonogashira, Heck, etc. Accordingly, PdCl2 was chosen
as an initial catalyst for four component reactions (step 1)
followed by Suzuki coupling (step 2) using 4-methoxyphenyl
boronic acid in the same pot (Table 1). No product was formed
when the reaction was performed at room temperature using
DMF as a solvent in the first step (entry 1, Table 1). Increase in
reaction temperature to 80–85 1C afforded the desired product 6a
along with 5 (entry 2, Table 1). Changing the solvent from DMF
to 1,4-dioxane did not improve the yield of 6a (entry 3, Table 1).
However, the use of additional Pd-catalyst in step 2 especially
(PPh3)2PdCl2 improved the yield of 6a significantly (entry 4,
Table 1). Moreover, conducting step 1 in the absence of the
solvent was found to be beneficial (entry 5, Table 1). Based on
these observations we replaced PdCl2 by (PPh3)2PdCl2 (entry 6,
Table 1). The step 1 was performed under neat conditions and no
additional catalyst was used in step 2. The reaction proceeded
well affording 6a in 85% yield. The MCR did not proceed in the
absence of a Pd catalyst (entry 7, Table 1).
The phosphodiesterase 4 (PDE4) inhibitors are known to be
beneficial for the potential treatment of asthma and chronic
obstructive pulmonary disease (COPD).9 The existing therapies
e.g. steroids, b2 agonists and antimuscarinics10 are effective but
do not address the long-term decline of lung function, the
hallmark of COPD. PDE4 inhibitors exert anti-inflammatory
a Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited,
Bollaram Road, Miyapur, Hyderabad 500 049, India
b Chemistry Division, Institute of Science and Technology, JNT
University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India
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
w Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, results of docking
study. CCDC 822229 and 822101. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c1cc12321a
c
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Table 2 Synthesis of 4-biaryl substituted pyrroles (6)a
Table 1 Effect of reaction conditions on Suzuki coupling based MCR
for the preparation of pyrrole derivativesa
Entry ArB(OH)2; ArQ
Pyrrole (6) Timeb/h %Yieldc
1
2
3
4
5
6
7
8
C6H4OMe-p
C6H4CF3-m
C6H4OMe-o
C6H4OMe-m
C6H4Cl-o
C6H4Cl-m
C6H4Cl-p
C6H4CF3-p
6a
6b
6c
6d
6e
6f
5.0
3.5
5.5
5.0
5.5
5.0
5.5
3.5
5.5
5.0
5.0
85
83
81
83
79
78
80
78
75
80
80
%Yieldb
6g
6h
5
6a
0c
15
10
70d
75d
85
0
Entry
Pd catalyst (step 1)
Solvent (step 1)
1
2
3
4
5
6
7
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
(PPh3)2PdCl2
No Pd cat.
DMF
DMF
1,4-Dioxane
DMF
No solvent
No solvent
No solvent
0
9
10
11
6-Methoxypyridin-3-yl 6i
C6H3(Cl-m)Cl-p
C6H4(CH2OH)-m
67
50
20
0
0
10
6j
6k
a
All the reactions were carried out using compound 1 (1.5 mmol), 2a
(1.0 mmol), 3a (1.0 mmol) and 4 (3.0 mL) in the presence of a
PdCl2(PPh3)2 (0.05 mol%) at 80–85 1C followed by addition of
b
aryl boronic acid (1.2 mmol). After addition of aryl boronic acid.
c
Isolated yield.
a
All the reactions were carried out using compound 1 (1.5 mmol), 2
(1.0 mmol), 3a (1.0 mmol) and 4 (3.0 mL) in the presence of a
Pd-catalyst (0.05 mol%) at 80–85 1C followed by addition of
b
c
4-methoxyphenyl boronic acid (1.2 mmol). Isolated yield. The
d
reaction was carried out at room temp. 0.05 mol% of PdCl2(PPh3)2
was added after completion of the first step.
Scheme 1 Synthesis of pyrroles 6l and 6m.
Fig. 2 X-Ray crystal structure of 6a (ORTEP diagram). Thermal
ellipsoids are drawn at a 50% probability level.
Compound 6a was characterized by spectral and analytical
data and this was supported by its molecular structure being
confirmed by X-ray analysis12 (Fig. 2).
Scheme 2 Synthesis of pyrrole 6n.
To demonstrate the utility of present MCR a variety of
4-biaryl substituted pyrroles (6) were synthesized (Table 2).
The use of ethylacetoacetate (2b) in place of 2a and 4-bromo-
benzaldehyde (3b) in place of 3a was examined and found to be
effective (Scheme 1). The use of an aryl dioxaborolane deriva-
tive in place of aryl boronic acid was also examined (Scheme 2).
Further functionalization of one of the pyrrole derivatives
synthesized was carried out (Scheme 3). We then examined
the feasibility of pyrrole synthesis via MCR based on the Heck
(Scheme 4) as well as Sonogashira reaction (Tables 3 and 4).
The selective inhibition of PDE4A and/or PDE4B without
affecting the other isoforms (thought to be responsible for
undesired side effects such as nausea and emesis) is the emerging
strategy to develop a safer drug.9a We therefore evaluated some
of the pyrroles synthesized initially for their PDE4B inhibitory
potential in vitro. In a cell based cAMP reporter assay fold
Scheme 3 Functionalization of pyrrole 7.
c
7780 Chem. Commun., 2011, 47, 7779–7781
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Scheme 4 Synthesis of pyrrole (10) via MCR based on Heck coupling.
Table 3 Synthesis of 4-alkynyliaryl substituted pyrroles (11)a
Fig. 4 Docking of 6n at the active site of PDE4B.
elevation of the cAMP level caused by the test compounds over
forskolin control was determined. Compounds 6n, 6m and 6g
showed significant fold increase at 30 mM whereas 6n showed
dose-dependent fold increase with an EC50 value of 8.69 mM
(Fig. 3). This was supported by the docking results of 6n with
PDE4B protein (Fig. 4) that showed H-binding of –CQO and
–CN groups of 6n with –NH (imidazole) of Histidine234
and –OH of SER282 residues of PDE4B protein respectively
(binding energy: ꢀ10.93 Kcal molꢀ1, see ESIw for further details).
In conclusion, a general synthesis of novel 1,2,3,4-tetra
substituted pyrrole derivatives has been accomplished via a
Pd-based MCR followed by Suzuki, Heck and Sonogashira
coupling in the same pot. This research has led to the
identification of a pyrrole-based new inhibitor of PDE4B.
GRR thanks Dr V. Dahanukar, U. K. Syam Kumar and the
analytical group of DRL MP and KVLP thanks Prof J. Iqbal.
Entry
HCRCR0; R0Q
Pyrrole (11)
Timeb/h
%Yieldc
1
2
3
4
5
CH2CH2CH2OH
CH2CH2OH
(CH2)5CH3
(CH2)3CH3
CH2OH
11a
11b
11c
11d
11e
5.5
5.0
4.5
4.0
6.0
81
86
81
94
80
a
All the reactions were carried out using compound 1 (1.5 mmol), 2a
(1.0 mmol), 3a (1.0 mmol) and 4 (3.0 mL) in the presence of a
PdCl2(PPh3)2 (0.10 mol%) at 80–85 1C followed by addition of
DMF (6 mL), a terminal alkyne (1.5 mmol), CuI (0.1 mmol), Et3N
b
c
(3.0 mmol). After addition of terminal alkyne. Isolated yield.
Table 4 Synthesis of 4-alkynylaryl substituted pyrroles (12)a
Notes and references
1 For an excellent review, see: V. Este0vez, M. Villacampa and
J. C. Mene0ndez, Chem. Soc. Rev., 2010, 39, 4402.
2 A. Hantzsch, Ber. Dtsch. Chem. Ges., 1890, 23, 1474.
3 L. Knorr, Ber. Dtsch. Chem. Ges., 1884, 17, 1635.
4 C. Pall, Ber. Dtsch. Chem. Ges., 1885, 18, 367.
5 For a review, see: G. Balme, Angew. Chem., Int. Ed., 2004, 43, 6238
and references therein.
6 For recent reviews, see: (a) B. B. Toure and D. G. Hall, Chem. Rev.,
´
2009, 109, 4439; (b) G. Balme, E. Bossharth and N. Monteiro,
Eur. J. Org. Chem., 2003, 4101; (c) C. Hulme and V. Gore, Curr.
Med. Chem., 2003, 10, 51; (d) R. V. A. Orru and M. de Greef,
Synthesis, 2003, 1471; (e) J. Zhu, Eur. J. Org. Chem., 2003, 1133;
Entry
HCRCR0; R0Q
Pyrrole (12)
Timeb/h
%Yieldc
1
2
3
4
CH2CH2CH2OH
CH2CH2OH
(CH2)5CH3
12a
12b
12c
12d
5.5
5.0
4.5
5.5
83
82
85
80
´
(f) H. Bienayme, C. Hulme, G. Oddon and P. Schmitt, Chem.–Eur. J.,
2000, 6, 3321.
C(CH3)2OH
7 S. Maiti, S. Biswas and U. Jana, J. Org. Chem., 2010, 75, 1674.
8 For Pd-mediated synthesis of pyrroles, see: (a) R. K. Dieter and H. Yu,
Org. Lett., 2001, 3, 3855; (b) R. Grigg and V. Savic, Chem. Commun.,
2000, 873; (c) B. Gabriele, G. Salerno and A. Fazio, J. Org. Chem.,
2003, 68, 7853; (d) K. K. A. D. S. Kathriarachchi, A. I. Siriwardana,
I. Nakamura and Y. Yamamoto, Tetrahedron Lett., 2007, 48, 2267.
9 (a) A. Kodimuthali, S. S. L. Jabaris and M. Pal, J. Med. Chem.,
2008, 51, 5471; (b) S. G. Dastidar, D. Rajagopal and A. Ray, Curr.
Opin. Invest. Drugs, 2007, 85, 364.
a
b
c
See the footnote of Table 3. See the footnote of Table 3. See the
footnote of Table 3.
10 A. M. Vignola, Respir. Med., 2004, 98, 495.
11 (a) G. L. Card, L. Blasdel, B. P. England, C. Zhang, Y. Suzuki,
S. Gillette, D. Fong, P. N. Ibrahim, D. R. Artis, G. Bollag,
M. V. Milburn, S. H. Kim, J. Schlessinger and K. Y. J. Zhang,
Nat. Biotechnol., 2005, 23, 201; (b) F. Suzuki, T. Kuroda, T. Tamura,
S. Sato, K. Ohmori and S. Ichikawa, J. Med. Chem., 1992, 35, 2863.
12 Crystallographic data (excluding structure factors) for 6a and 6h.
CCDC 822229 and 822101, respectively (see ESIw).
Fig. 3 PDE4B HEK 293 cell based reporter screen of 6 and EC50 of 6n.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7779–7781 7781