A facile one-pot synthesis of 2-thioxo-dihydropyrimidines and polyfunctionalized pyran derivatives as mimics of novel calcium channel modulators

Article abstract of DOI:10.1016/j.tetlet.2012.10.020

An efficient protocol for the synthesis of pharmacologically significant dihydropyrimidines and polyfunctionalized pyrans is described by performing a one-pot multicomponent reaction (MCR). A chemistry-driven drug discovery approach is implemented by keep

Full text of DOI:10.1016/j.tetlet.2012.10.020

Tetrahedron Letters 53 (2012) 6725–6728
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile one-pot synthesis of 2-thioxo-dihydropyrimidines and
polyfunctionalized pyran derivatives as mimics of novel calcium channel
modulators
Rama Krishna Yadlapalli a, O. P. Chourasia a, Ramu Sridhar Perali b,
⇑
a Department of Chemistry, Dr. Harisingh Gour University (A Central University), Sagar 470 003, MP, India
b School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient protocol for the synthesis of pharmacologically significant dihydropyrimidines and polyfunc-
tionalized pyrans is described by performing a one-pot multicomponent reaction (MCR). A chemistry-dri-
ven drug discovery approach is implemented by keeping an essential skeleton of calcium channel
modulators in all the synthesized derivatives.
Received 17 July 2012
Revised 1 October 2012
Accepted 4 October 2012
Available online 13 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Piperidinylamide
Dihydropyrimidines
Polyfunctionalized pyrans
Multi-component reaction
Calcium channel modulator
Recent investigations in the natural products’ chemistry of the
genus Piper have yielded numerous amide derivatives of diverse
molecular architectures exhibiting significant biological activities.1
This has spurred novel synthetic methodologies2 and encouraged
many chemists and biochemists to think on the possible biogenetic
interactions. One of the structural units that is common in these
bio-active compounds such as mGluR5 (metabotropic glutamate
receptor 5) antagonists,3 fatty acid amide hydrolase (FAAH) inhib-
itors,4 b-tryptase inhibitors for many inflammatory and allergic
On the other hand, 4H-pyran (an isoelectronic displacement
analogue of DHP, Fig. 1) pharmacophore is a key structural motif
present in several natural products15 and many bio-active com-
pounds.16–19 More importantly, 4H-pyrans can be transformed into
Ar
Ar
Ar
Ar = substituted aryl
E = ester, amide, acyl
R1, R2 = alkyl
E
E
E
E
E
NH
diseases, particularly for asthma5 and b- or -secretase inhibitors6
c
R1
N
H
Z
R1
N
H
R2
Z = O, S
R1
O
R2
is found to be a piperidinylamide unit.
Dihydropyrimidine (DHPM)7 derivatives are identified as inter-
esting molecular scaffolds for de-novo drug design. This was orig-
inally due to the apparent structural similarity of DHPMs to the
well-known Hantzsch type dihydropyridine (DHP) (Fig. 1) calcium
channel modulators8 like nifedipine and lacidipine.
DHPM
DHP
4H-pyran
Figure 1. Structural comparison of DHPM, DHP, and 4H-pyran.
DHPMs are also important structural motifs present in anti-
inflammatory agents,9 adrenergic antagonists,10 fatty acid trans-
porter FATP4 inhibitors,11 and anticancer agents.12 Several DHPM
and DHP derivatives possessing a lipophilic carbamoyl group were
shown to exhibit potential antitubercular activity.13 2-oxo and 2-
thioxo DHPMs are also present in nitractin 1, an antiviral agent
and monastrol 2, a mitotic kenesin EG5 inhibitor (Fig. 2).14
O2N
OH
O
O
O
O
NH
O
NH
N
H
S
N
H
O
Nitractin 1
(Antiviral)
Monastrol 2
(mitotic kenesin EG5 inhibitor )
⇑
Corresponding author.
E-mail address: prssc@uohyd.ernet.in (R.S. Perali).
Figure 2. DHPM based bio-active agents.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.020

6726
R. K. Yadlapalli et al. / Tetrahedron Letters 53 (2012) 6725–6728
O
O
H
N
O
O
Neat reaction
reflux, 80 0
O
O
N
O
piperidine
+
C
O
+
H
N
CN
CN
24 h, 70%
CN
CN
N
5
4
3
O
CHO
8
5
12
Thio urea,
p -TsOH, EtOH,
reflux, 7 h
R
R = H
R = 4-OMe (6b, 31%)
R = 4-OH (6c, 60%)
R = 3-Me
R = 2-Cl
R = 4-Cl
(6a, 76%)
R = 3-Br (6g, 82%)
R = 4-Br (6h, 57%)
(6i, 42%)
6j
R = 3-NO2 ( , 85%)
R = 4-NO2 (6k, 48%)
R = 4-CN (6l, 94%)
R
O
O
H
11a
O
CN
CN
NH
R = 4-F
N
N
6d
, 31%)
(
N
NH
_
O
(6e, 85%)
(6f, 52%)
O
N
N
H
S
14
13
6a 6l
-
Scheme 3. Proposed mechanism for the formation of 4H-pyran derivative.
Scheme 1. One-pot synthesis of 2-thioxo-dihydropyrimidines bearing piperidi-
nylamide moiety.
compounds. Therefore, herein we report a MCR approach towards
the synthesis of above target molecules.
The starting precursor 1-(piperidin-1-yl)butane-1,3-dione 5
was prepared by refluxing equimolar amounts of piperidine 4
and ethylacetoacetate 3 under solvent-free conditions. Refluxing
compound 5 along with differentially substituted aromatic alde-
hydes and excess thiourea (1.5 equiv) in ethanol under mild acidic
conditions provided the expected DHPMs (6a–6l) in good to excel-
lent yield (Scheme 1).
Better yields were obtained when the aromatic aldehyde pos-
sessed electron withdrawing groups. All the DHPMs showed an
asymmetric CH proton in 1H NMR spectrum between d 4.91 and
5.78 ppm, as well as a singlet at d 1.67–1.88 ppm equiv to the
methyl group on the dihydropyrimidine ring that confirms the for-
mation of DHPM derivative. Further, 13C NMR spectra showed
chemical shifts at d 174.0–174.7 ppm corresponding to C@S on
the dihydropyrimidine ring and d 165.6–166.5 ppm assigning to
C@O of the piperidinylamide. The asymmetric carbon was ob-
served in between d 56.4 and 58.5 ppm as expected and a peak
at d 15.6–16.0 ppm equiv to the methyl group on the dihydropy-
rimidine ring. However, all the peaks in 1H NMR were found to
be broadening due to the flipping of the piperidine moiety at room
temperature. A similar kind of observation was identified in 13C
NMR spectra especially for the peaks corresponding to methylene
groups of the piperidine ring. Moreover, the structure of compound
6e (Fig. 3)23 is confirmed by single crystal X-ray diffraction. The
crystal structure of 6e revealed that the phenyl ring is positioned
Figure 3. ORTEP diagram of compound 6e.
corresponding pyridines resulting in valuable DHP type calcium
channel modulators.20
Several reports are available for the synthesis of dihydropyri-
dines21 and 4H-pyrans.22 Further, developments in this area re-
quire diversity in selected building blocks to generate the target
libraries possessing different heterocyclic scaffolds. In our ongoing
medicinal chemistry program, we planned to synthesize DHPM
and 4H-pyran derivatives possessing piperidinylamide moiety as
a common substituent, due to its wide existence in bio-active
5
O
, NaOH
EtOH
CN
NC
CN
N
N
OC2H5 H2N
N
OC2H5
CN
CN
NaOH
expected
observed
10
(35%)
+
9
or
CN
CN
piperidine
O
H
7
8
O
5
, piperidine
CN
N
EtOH
O
11a
NH2
(63%)
Scheme 2. A multicomponent approach towards the synthesis of highly substituted pyridine/4H-pyran derivatives.

R. K. Yadlapalli et al. / Tetrahedron Letters 53 (2012) 6725–6728
6727
R
O
O
CHO
O
piperidine
+ NC
CN
+
N
CN
NH2
EtOH /+ acetonitrile
25 oC, 1 h
N
R
O
5
7
11a - 11l
R = H
(11a, 63%)
R = 3-Br (11g, 77%)
11b
11h
R = 4-OMe (
, 38%)
, 74%)
R = 4-Br
R = 4-F
(
, 36%)
11i
, 27%)
11c
R = 3-Me
(
(
R = 4-Me (11d, 39%)
R = 3-NO2 (11j, 58%)
11e
, 54%)
11k
( , 22%)
R = 2-Cl
R = 4-Cl
(
R = 4-NO2
R = 4-CN (11l, 50%)
(11f, 45%)
Scheme 4. Synthesis of polyfunctionalized pyran derivatives bearing piperidinylamide moiety.
39.9 and 40.8 ppm as expected and d 16.1–16.7 ppm equiv to the
methyl group on the pyran ring. The 13C NMR peaks of the cyano
group were found to be in between d 118.5 and 119.5 ppm. All
the final products were also confirmed by taking DEPT and LCMS.
The structures of compounds 11h and 11l (Fig. 4) were also con-
firmed by single crystal X-ray diffraction.27 These crystal structures
also fulfill the requirements to exhibit calcium channel modulator
properties in which the phenyl ring is positioned exactly perpen-
dicular to and bisecting the planar-like 4H-pyran ring.
In conclusion, a one-pot multicomponent reaction towards the
synthesis of dihydropyrimidines (DHPMs) and highly substituted
4H-pyran derivatives is revealed. The evaluation of these mole-
cules as calcium channel modulators is under investigation.
Figure 4. ORTEP diagrams of compounds 11h and 11l.
exactly perpendicular to and bisecting the planar-like dihydropy-
rimidine ring, with the 4-aryl substituent (Cl) with syn-periplanar
(relative to C4–H) orientation. Rovnyak et al. proposed24 that cal-
cium channel modulation depends on the absolute configuration
at C4, whereby the orientation of the C4-aryl group, acts as a
‘molecular switch’ between agonist and antagonist activity.
Towards the synthesis of polyfunctionalized pyridine and pyran
derivatives bearing piperidinylamide moiety, a diversity oriented
MCR was investigated. Thus, 1,3-dione 5 was stirred in the pres-
ence of malononitrile 7 and benzaldehyde in ethanol using NaOH
as a base. However, the reaction provided a highly substituted
3,5-dicyanopyridine derivative 1025 instead of an expected pipe-
ridinylamide substituted pyridine derivative 9. Very recently, a
similar kind of reaction was reported by using acetoacetanilide
as a 1,3-dione precursor resulting in the substituted pyridine deriv-
atives.26 On the other hand, changing the base to piperidine pro-
vided the expected pyran derivative 11a as a major product in
63% yield (Scheme 2).
Acknowledgements
Y.R.K. thank the UGC Networking Resource Centre in carrying
out the research work at the University of Hyderabad.
Supplementary data
Supplementary data (detailed experimental procedures, crystal
data, 1H, 13C NMR and DEPT NMR spectra of 5, 6a–6l, 10 and 11a–
11l) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2012.10.020.
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C19H20BrN3O2, chemical formula weight 402.29, monoclinic, unit cell
parameters: a 31.242(3) Å, b 7.4062(4) Å, c 17.4101(16) Å, b 106.338(9)° and
space group C2/c and the CCDC deposition number for 11l is 860869;
molecular formula: C20H20N4O2, chemical formula weight 348.40, triclinic,
unit cell parameters: a 6.158(2) Å, b 9.111(3) Å, c 18.017(6) Å,
87.71(3)°, 71.53(3)° and space group P-1.
a 76.44(3)°, b
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O.; Kozielski, F. J. Med. Chem. 2010, 53, 5676.
c