A regioselective synthesis of 2,6-diarylpyridines

Article abstract of DOI:10.1039/c3ra41575a

A regioselective synthesis of 2,6-diarylpyridines through base (sodium hydroxide in DMSO) catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones with benzamide has been delineated. However, similar reaction of 2H-pyran-2-ones with benzam

Full text of DOI:10.1039/c3ra41575a

View Article Online
View Journal
RSC Advances
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
www.rsc.org/advances
Registered Charity Number 207890

Page 1 of 9
RSC Advances
View Article Online
RSC Advances
Graphical Abstract:
A regio selective synthesis of 2,6-diarylpyridines
Hardesh K Maurya, Prema G. Vasudev and Atul Gupta*
A regioselective synthesis of 2,6-diarylpyridines through base (sodium hydroxide in DMSO) catalyzed ring transformation of suitably
functionalized 2H-pyran-2-ones with benzamide has been delineated. However, similar reaction of 2H-pyran-2-ones with benzamide using base
sodium hydroxide in absolute ethanol have yielded highly congested delta keto esters with active methylene centre instead of 2,6-
diarylpyridines.
X
X
X
N
O
N
O
N
N
CN
H2N
O
NaOH
DMSO
NaOH
EtOH
CN
CN
Ar
+
O
O
Ar
OCH2CH3
Ar

RSC Advances
Page 2 of 9
Dynamic Article Links ►
RSC Advances
View Article Online
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/advances
PAPER
A Regio Selective Synthesis of 2,6-Diarylpyridines †
Hardesh K. Maurya,a Prema G. Vasudevb and Atul Guptaa,*
A regio selective synthesis of 2,6-diarylpyridines through base (sodium hydroxide in DMSO) catalyzed
ring transformation of suitably functionalized 2H-pyran-2-ones with benzamide has been delineated.
However, similar reaction of 2H-pyran-2-ones with benzamide using base sodium hydroxide in absolute
ethanol have yielded highly congested delta keto esters with active methylene centre instead of 2,6-
diarylpyridines.
5
Cl
Introduction
HO
OH
CN
F
10 Among other nitrogen heterocycles, pyridine is an important
building block of many biologically active compounds with
established medicinal values.1 It is present in various bioactive
heterocycles, starting from simple to complex molecules such as
nicotinaamide (Vitamin B-3, I), pyridoxine (Vitamin B-6, II),
N
O
N
R
Cl
F
IX; Sch-21418,
Interleukin-6(IL-6) inhibitor, 73 % inhibition @ 10 μM,
VIII; Canabinoid receptor Type-1 (hCB- 1) antagonists,
R = Cl, IC50 1.3 nM: R = H; IC50 8 nM
O
N
NH2
CN
15 Fuzanin
C (III) and D
(IV),2 Haminol A and B (V),3
O
N
N
OH
N
O
Goniothalins A, B (VI),4 euoverrine A and B (VII),5 and
euophelline (VII)5 (Figure 1).
O
O
N
N
O
H
R1
R1
XI; IκB Kinase B (IKK-β) inhibitor, IC50 =1.5 nM
OH
X; Acetyl-CoA Carboxylase Inhibitor,
R1= H: IC50 126 nM, R1= Me: IC50 76nM
O
OH
OH
N
NH2
HO
OMe
N
OH
III; Fuzanin C
OR
N
I; Nicotinamide (Vitamin B3)
O
II; Pyridoxine (Vitamin B6)
N
N
OH
N
N
N
N
N
V; Haminol A (R=H)
Haminol B (R=CH3CO)
Me
N
OH
IV; Fuzanin D
OAc
XIII; Cholecystokinin 1 (CKK1) receptor agonist,
IC50 = 35nM
HO
BzO
OAc
OR2
XII; Estrogen Receptor ligand for ERa and b
Ki = 20 nM at ERa and 110 nM at ERb
O
35
O
OR
N
HO
O
OBz
O
CH3
Fig. 2 Some substituted diarylpyridine lead biologically active molecules.
O
O
O
H3C
O
N
Immunosuppressants, acetyl-CoA carboylase inhibitors (X),8 IκB
kinase β (IKK-β) inhibitors (XI),9 Estrogen receptor modulators
(XII)10 and cholecystokinin-1 receptor agonists (XIII),11 (Figure
VII; Euoverrine A; R1=Ac, R2=Ac
Euoverrine B; R1=Ac, R2=CH3CH2CO
Euophelline; R1=H, R2=Ac
VI; Goniothaline A; R=CH3
Goniothaline B; R=H
20
Fig. 1 Pyridine containing natural products.
40 2). 2,6-diarylpyridines have also been reported as herbicide,12
defoliating,12 antimalarial,13 diuretics,14a and neurotropic factor
for Alzheimer’s disease.14b These have also been found their use
in industrial applications as dye precursor in photographic
copying process,15 as a substructure in organic electroluminescent
45 element for EL devices.16
Substituted diarylpyridine derivatives such as 2,3-diarylpyridines,
3,5-diarylpyridines, 4,6-diarylpyridines, 5,6-diarylpyridines have
been reported to acts as canabinoid-1 receptor antagonists
(VIII),6 Interleukin-6 (IL-6) inhibitors (IX),7
25
aMedicinal Chemistry Department, Central Institute of Medicinal and
aromatic Plants, PO. CIMAP, Kukrail Road, Lucknow-226015, India
Tel.: 0915222718556, E-mail: atul_gupta04@yahoo.co.in (A. G.),
hardesh11@yahoo.co.in (H. K. M.)
Numerous protocols for the construction of 2,6-diarylpyridines
varying substitution patterns around the ring are delineated in the
chemical literature.7,8,12,13,17,23 For our ongoing project on
development of novel estrogen receptor modulators, we were
50 fascinated to synthesize 2,6-diarylpyridines as important
intermediates starting from suitably substituted 2H-pyran-2-ones.
2H-pyran-2-ones were chosen owing to their interesting
chemistry and their use as a widespread synthon for the
development of diversified heterocycles of medicinal interest.18,19
55 Structurally, 2H-pyran-2-ones has three electrophilic centres such
30 bMetabolic & Structural Biology Department, Central Institute of
Medicinal and Aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow-
226015,
† Electronic Supplementary Information (ESI) available: [crystallographic
information files (CIF) of 10a]. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [2013]
RSC Adv., 2013, XXX, 01–09 | 1

Page 3 of 9
RSC Advances
View Article Online
as E1, E2 and E3 (Figure 3). Due to the presence of three
electrophilic centres, it produces different reaction products 40 The product 8a was formed after decarboxylation of a reaction
hydrochloride (5a) using KOH as a base in DMF (Figure 4).22
regio-selectively when reacted with a nuclephile under different
reaction conditions. The reactivity order of these electrophilic
centre is E3>E2>E1 (Figure 3).. E3 is the most electron deficient
due to extended conjugation and the presence of an electron-
intermediate followed by ring closure via nitrogen insertion and
subsequently elimination of amine substituent from 4-position of
pyranone ring.22 While Bhosale et. al. have reported synthesis of
2,6-diarylpyridine 7a under similar reaction conditions with
5
withdrawing substituent at position 3 of the pyran ring.18b Thus, 45 modified N-arylbenzamidines (5b-d). The reaction of 4a with N-
C-6 (position E3) of the pyran ring is attacked by nucleophiles
more readily and in situ yields cyclicarenes and heteroarenes.
arylbenzamidines (5b-d) using KOH as a base in DMF at room
temperature yielded compound 7a in moderate to poor yields
(48%, 42% and 26%) respectively (Figure 4 and Table 1).23 The
plausible reaction mechanism shows that presence of aryl group
50 on nitrogen atom (NH group) in N-arylbenzamidines provided the
selective attack of imine group on C-6 postion of 2H-pyran-2-one
nucleus followed by expulsion of aniline anion, which facilitated
formation of 2,6-diarypyridine.23 The leaving group from
benzamidine (5a) was amino group rather aniline anion due to
55 low bond energy of C-N bond compared to C-C bond energy.
From these observations, it was realized that presence of an
aromatic group on nitrogen atom was essential for the formation
of 2,6-diarylpyridines.
10
Fig. 3 2H-pyran-2-ones (3 and 4); a versatile synthon
Results and discussion
Chemistry
Literature survey and study of various reactions of 2H-pyran-
X
X
15 2-ones revealed that the pyranone ring is very sensitive towards
reaction conditions. A minor change in the reaction conditions
such as change of solvent, temperature and nucleophile leads to
different products.18 Therefore, it was planned to study the
synthesis of diarylpyridines (7) through the modification of 2H-
20 pyran-2-ones via its reaction with a suitable nucleophile i.e
benzamide under different reaction conditions. We herein report
the solvent selective synthesis of 2,6-diarylpyridines (7) and also
highly congested delta keto esters with an active carbon center
(10) under mild reaction conditions.
NC
Ar
H2N
HN
NH
N
O
N
N
N
CN
O
CN
NH
N
KOH/DMF
KOH/DMF
Ar
Ar
R
7
Bhosale et. al. (Ref. 23)
8
R. Pratap et. al. (Ref. 22)
60
Fig.
4
Benzamidine selective syntheses of diarylpyridines and
diarylpyrimidines.22,23
In our synthetic strategy, 2H-pyran-2-ones (4) and inexpensive
commercially available benzamide (6) instead of expensive N-
25
65 arylbenzamidines (5b-d) were selected as starting precursors. To
find out an appropriate reaction condition for syntheses of 2,6-
diarylpyridines (7), different reaction conditions were attempted
through change of the solvent as well as use of different bases.
For this purpose, various reactions of 6-(4-bromophenyl)-2-oxo-
70 4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (4a) with benzamide
(6) under different reaction conditions were explored (Table 1).
In our initial attempts, we started reaction of 4a with
benzamide (6) using potassium hydroxide (KOH) in
dimethylformamide (DMF) at room temperature with stirring for
75 24 h, which yielded compound 7a in 25 % yield, while with
sodium hydride (NaH) in tetrahydrofuran (THF), an aprotic
solvent, at room temperature with stirring for 35 h, yielded
compound 7a in 7 % yield. Reaction of compound 4a and 6 using
NaH in DMF for 54 h at 100 °C yielded 2,6-diarylpyridine (7a) in
80 54%. However, use of potassium hydride (KH) at 60°C gave
product 7a in 35 % yield. Further change in aprotic solvent such
as benzene, toluene and ether did not improve the product yield.
Our further effort have been performed with the use of 1.2 eq.
sodium hydroxide (NaOH) as base in dimethylsuphoxide
85 (DMSO) which gave diarylpyridine 7a in 48% yield in 48 h at
room temperature and 53% at 120oC leaving behind unreacted
starting material 4a in 24 % and 19 % quantity respectively.
Using the 3 equivalent of base; reaction yielded compound 7a in
69% yield in DMSO at room temperature for 35 h superior than
90 previously reported method23 (Table 1).
Scheme 1 Synthesis of precursor 2H- pyran-2-ones 3 and 4.
The desired precursor for syntheses of target compounds, 6-
aryl-4-methylsulfanyl-2H-pyran-2-one-3-carbonitriles (3) were
30 obtained from the reaction of aryl methyl ketones (2) and methyl
2-cyano-3,3-dimethylthioacrylate20 1 followed by amination of 3
with secondary amines in boiling methanol afforded 6-aryl-4-
(sec-amino)-2H-pyran-2-one-3-carbonitriles (4) as shown in
Scheme 1.21
35 In an attempt to synthesize 2,6-diarylpyridines, R. Pratap et. al.
have reported synthesis of diarylpyrimidine 8a as exclusive
product instead of 2,6-diarylpyridines (7) under the typical
reaction conditions involved stirring of 4a with benzamidine
2
| RSC Adv., 2013, XXX, 01–09
This journal is © The Royal Society of Chemistry [2013]

RSC Advances
Page 4 of 9
View Article Online
X
Table 1 Optimization of reaction conditions for 2,6-diarylpyridine
synthesis from 7a.
N
O
CN
O
H2N
O
NaOH/DMSO
+
Ar
6
4
X
X
O
CN
O
N
N
O
O
CN
product Base
Solvent Timeb Temp.b
(h)
Yields (%)g
of 7a
N
N
OH
H
O
H
Ar
Ar
(ii)
(i)
6a
6a
6a
6a
6a
6e
6e
6a
6a
6a
6a
KOH
NaH
KH
DMF
THF
THF
DMF
24
35
4
rt
25
07
32
54
05
48
53
69
f
X
-CO2
X
rt
60 oC
100oC
rt
N
N
CN
OH
CN
NaH
54
35
N
-H2O
H
Ba(OH)2.8H2O DMF
N
Ar
Ar
(iii)
NaOH
NaOH
NaOH
K2CO3
NaOH
NaOH
DMSO 48
DMSO 10
DMSO 35
rt
7
110 oC
X
H2SO4
120 o
10 min.
C
rt
N
EtOH
8
80-85 oC
rt
120 oC
CONH2
EtOH 10
EtOH 10
c
N
Ar
d
9
a
b
reactant 4a used 1 eq., 6 used 1.5 eq. and base used 3 eq.;
Scheme 2 Synthesis and plausible mechanism of diarylpyridines (7)
c
optimized time and temperature; instead of 7, product 10 obtained;
d instead of 7 and 10, product 11 was obtained. e reactant 4a and 6
used 1 eq. and base used 1.2 eq.; fnot formed; g separated yields
Table
diarylpyridines (7)
Entry Product
2 Products, yields and melting points of
Yield (%)
Mp (oC)a
5
The plausible mechanism of 6 on 4 for the formation of 7a
reveals that reaction starts by the attack of amino group followed
by decarboxylation of intermediate ii and subsequently
elimination of water from intermediate iii leads to product 7
(Scheme 2). In general, it was observed that prolonged reaction at
10 high temperature or heating yielded inseparable side products.
Therefore, reaction at room temperature was found to be more
suitable for product formation.
Further, to improve the yield of reaction product and shorten the
reaction time, it was thought to use Ba(OH)2.8H2O instead of
15 NaOH in the same solvent i.e. DMSO which yielded compound
7a only in traces (5% yield) even after stirring the reactants for
35 h at room temperature.
In order to simplify the method, after exploring various
reactions in nonprotic solvents, we explored the reaction of 2H-
20 pyran-2-one 4a with benzamide (6) in a protic solvent i.e.
absolute EtOH using potassium carbonate (K2CO3) as base for 8 h
180-181
N
CN
69
7a.
7b
7c
N
Br
167-169
N
CN
CN
CN
65
61
63
N
Cl
N
N
160-161
N
o
at 80-85 C which did not yield product 7a. In contrast, when a
mixture of 4a and 6 was stirred in absolute ethanol with sodium
hydroxide for 24 h at room temperature (18-20 C), it did not
25 yield the product 7a, instead the reaction mixture lead to the
166
7d
7e
N
o
Me
O
formation of a regio-selective product, highly congested delta
N
keto ester24 10a in 71% yield (Scheme 3) which was
CN
58
209
characterized after single X-ray crystallographic analysis (Figure
N
6).
Me
30
continued…...
Table 2 continued…...
This journal is © The Royal Society of Chemistry [2013]
RSC Adv., 2013, XXX, 01–09
|
3

Page 5 of 9
RSC Advances
View Article Online
O
amide derivative was also attempted and successfully achieved
after heating it for 10 minute in concentrated sulphuric acid at
N
N
120 oC (Scheme 2).
CN
60
63
168
7f
X
O
N
H2N
CN
+
N
N
O
6
CN
O
O
Ar
169-170
167-168
7g
4
NaOH/EtOH
rt
X
reflux
X
MeO
X
N
7
N
O
CN
O
N
N
CN
OCH2CH3
CN
OCH2CH3
59
7h
O
Ar
i
Ar
O
10
MeO
X
OH
X
N
O
N
N
CN
CN
59
95
126-127
261
7i
9
N
OCH2CH3
O
CN
Ar
HO
Ar
OCH2CH3
ii
O
O
X
iv
N
CON H
2
N
OH
CN
N
Ar
OCH2CH3
O
Br
O
Ar
O
11
iii
amelting points (mp) were recorded from Buchi melting point
M560 apparatus.
H
X
X
N
The plausible explanation for the formation of compound 10a
could be that under the given reaction conditions an ethoxide
nulcleophile attacked on C2 of pyranone ring regioselectively
rather than on C6 of ring which subsequently, undergoes to keto-
enol tautomerism leading to formation of product 10a as depicted
in scheme 3.
Thus, the reaction of 4a with 6 showed solvent selectivity for a
same base NaOH, in DMSO and ethanol respectively and
10 produced diarylpyridine 7a and delta keto ester 10a in a solvent
dependent regioslective manner (Figure 5).
O
N
CN
CN
OCH2CH3
Ar
OCH2CH3
O
O
Ar
O
10
35
5
Scheme 3 Synthesis and plausible mechanism of delta keto ester (10)
X
X
X
N
O
N
CN
N
N
H2N
O
NaOH
DMSO
NaOH
EtOH
CN
Ar
CN
+
O
O
Ar
O
OCH2CH3
6
4
Ar
10
On the basis of yield optimization of diarylpyridine 7a in
NaOH/DMSO at room temperature, we have further explored
reaction of various 2H-pyran-2-ones (4) with benzamide (6) in
15 NaOH/DMSO which gave reaction products in fairly good yields
as shown in Table 2 (Scheme 2). We had also attempted the
synthesis of title compounds i.e. diarylpyridines (7) starting from
compounds 4j and 4k under the similar experimental conditions.
However, mainly starting material was recovered instead of
20 diarylpyridines. Reaction of 2H-pyran-2-ones (4) with benzamide
(6) in NaOH/EtOH produced highly congested delta keto ester
(10), Scheme 3 (Table 3). Formation of 10 was also observed by
A. Kumar et. al.24 by the use of a strong base ethoxide in DMSO.
Formation of 10 was observed with a variety of 2H- pyran-2-one
25 in the presence of benzamide in NaOH/DMSO as shown in Table
3.
7
Fig. 5 Solvent selective syntheses of diarylpyridines (7) and delta keto esters (10).
40
Crystals of X-ray25 quality for 10a was obtained by slow
evaporation of solvent (chloroform : hexane; 1 : 1) at room
temperature. The molecular structures of the compounds with
arbitrary numbering are presented in Figure 6 illustrating the non-
planar, Z-configuration of the molecule.
The crystal structure reveals that the nitrile group and
piperidine ring are on the same side of the double bond and the
phenyl bromide ring orients perpendicular to the plane of the
double bond. In the crystal structure, a weak Br....N interaction
(N...Br = 3.17Å) along the crystallographic c-axis is observed.
45
50 Furthermore, aromatic-aromatic interactions involving the phenyl
bromide rings of both symmetry-related and translated molecules
stabilize the molecular packing in crystals.
From the above observations, it was established that use NaOH
in DMSO at room temperature is the medium of choice compared
to other solvents and bases (Table 1) which regioselectively
30 yields diarylpyridines 7.
Conclusion
Further modification of diarylpyridine 7a to the corresponding
In conclusion, we have developed a solvent driven efficient
4
| RSC Adv., 2013, XXX, 01–09
This journal is © The Royal Society of Chemistry [2013]

RSC Advances
Page 6 of 9
View Article Online
method for syntheses of various 2,6-diarylpyridines using readily
commercially available benzamide in presence of sodium
hydroxide-DMSO. Our synthetic approach opened a new avenue
for the regioselective synthesis of medicinally useful and
functionalized 2,6-diarylpyridines. The protocol also provides an
approach for the preparation of delta keto esters with active
methylene centre for further exploration of various Michel type
reactions. Our synthetic approach has immediate practical
implications.
in parts per million shift (δ-value) based on the middle
30 peak of the solvent (CDCl3/DMSO-d6) (δ 100.00 ppm for
13C NMR) as the internal standard. Signal patterns are
indicated as s, singlet; bs, broad singlet; d, doublet; dd,
double doublet; t, triplet; m, multiplet; brm, broad
multiplet. Coupling constant (J) are given in Hertz.
35 Infrared (IR) spectra were recorded on a Perkin-Elmer AX-
1 spectrophotometer in KBr disc and reported in wave
number (cm-1). ESI mass spectra were recorded on
Shimadzu LC-MS after dissolving the compounds in
acetonitrile.
5
10
Table 3 Products, yields and melting points of delta keto
ester (10)
40
.
Entry
Product24
Yield (%)
Mp (oC)a
General procedure for the synthesis of methyl 2-cyano-3,3-
dimethylthioacrylate3 (1a):
142
O
N
O
10a.
63
CN
O
First prepared sodium methoxide in a 2 litre two neck round
Br
bottam flask by adding pieces of sodium metal ( 24 g) at cold (0-
o
45 5 C) in dry methanol (400 mL) for 2 h. In this mixture methyl
cyanoacetate (80 mL) was added by a dropping funnel in 30
minutes, a white precipitate was formed. Further on addition of
carbon disulphide (62 mL) by a dropping funnel in the reaction
mixture in 30 minutes, a yellow liquid was formed. Chilled
50 methyl iodide (108 mL) was added to it by a dropping funnel in
30 minute and stirred reaction mixture for 2 h at room
temperature a yellow precipitate is formed. The reaction mixture
was poured in chilled water (2 Litre) and stirred, filter the
precipitate. Precipitate was washed with chilled water (3 Litre)
55 and dried. Further crystallization of precipitate with methanol
O
N
O
119
CN
O
10b
65
Cl
O
N
O
CN
10c
10d
72
70
153
155
MeO
O
O
N
CN
O
(500 mL) yielded 85
g
of methyl 2-cyano-3,3-
dimethylthioacrylate (1a).
O
amp is recorded from buchi melting point M560 apparatus.
General procedure for the synthesis of 2H-pyran-2-one3,4 (3
and 4)
60 A mixture of acetophenone 2 (0.14 mmol) and methyl 2-cyano-
3,3-dimethylthioacrylate 1 (0.14 mol) in DMSO (54 mL) in the
presence of powdered KOH (0.15 mol) was stirred at room
temperature for 5-8 h with monitoring TLC. After consumption
of 1, the residue poured onto crushed ice with vigorous stirring.
65 The aqueous suspension was neutralized with dil. HCl (if
required) and the precipitate obtained was filtered, washed with
water and dried. Further purification by washing with cold
methanol yielded (50-80%) yellow solid of 3. A mixture of 3
(0.26 mol) and secondary amine (0.39 mol) was refluxed in
70 methanol for 6-8 h with monitoring the consumption of 3. During
this period precipitate separated out which was filtered after
cooling. The precipitate was washed with cold methanol which
yielded aminated 2H-pyran-2-one (4).
15 Fig. 6 Perspective view of delta keto ester (10a) with atom numbering.
Experimental Section
General
6-(4-methoxy-phenyl)-4-methylsulfanyl-2-oxo-5-phenyl-2H-
75 pyran-3-carbonitrile (3i). Yellow solid; Rf: 0.73 (DCM); mp
172-173 oC; IR (KBr, νmax/cm-1):1660 (C=O), 2210 (CN); 1H
NMR (CDCl3, 300 MHz, δ ppm): 2.84 (s, 3H, SCH3), 3.77 (s, 3H,
OCH3), 6.71-6.68 (d, 2H, J=7.2, Ar-H), 7.21-7.19 (m, 4H, Ar-H),
7.44 (bs, 3H, Ar-H); 13C NMR (CDCl3, 100 MHz, δ ppm): 18.8,
80 55.7, 92.6, 114.0 (2C), 115.1, 118.0, 123.3, 129.6 (2C), 129.7,
131.7, 131.8 (2C), 131.9 (2C), 132.6, 157.6, 162.0, 171.1; m/z:
350.1 [M+1]+; Anal. Calcd. for C20H15NO3S (349.4): C, 68.75; H,
4.33; N, 4.01 S, 9.18 Found: C, 68.65; H, 4.31; N, 3.99 S, 9.16
The reagents and the solvents used in this study were
of analytical grade and were used without further
20 purification. All the reactions were monitored on Merck
aluminium thin layer chromatography (TLC, UV254nm
)
plates. Column chromatography was carried out on silica
gel (60-120 mesh). The melting points were determined on
Buchi melting point M560 apparatus in open capillaries
25 and are uncorrected. Commercial reagents were used
without purification. 1H and 13C NMR spectra were
recorded on a Bruker WM-300 (300 MHz) using CDCl3
and DMSO-d6 as the solvent. Chemical shift are reported
6-(4-methoxyphenyl)-2-oxo-5-phenyl-4-(piperidin-1-yl)-2H-
This journal is © The Royal Society of Chemistry [2013]
RSC Adv., 2013, XXX, 01–09
| 5

Page 7 of 9
RSC Advances
View Article Online
pyran-3-carbonitrile (4i). White solid after washing with ether;
3'-carbonitrile (7d): white solid; Rf: 0.20 (5% EtOAc in
o
1
Rf: 0.45 (5% methanol/DCM); mp 220-221 oC; IR (KBr, νmax/cm-
Hexane); mp 166-167 C; IR (KBr, νmax/cm-1): 2214 (CN); H
1
1): 1662 (C=O), 2204 (CN); H NMR (CDCl3+DMSO-d6, 300
NMR (CDCl3, 300 MHz, δ ppm): 1.71 (bs, 2H, CH2), 1.81 (bs,
MHz, δ ppm): 1.55 (bs, 2H, CH2), 1.68 (bs, 4H, 2xCH2), 2.93 (bs, 60 4H, 2xCH2), 2.41 (s, 3H, CH3), 3.51 (bs, 4H, 2xNCH2), 7.14 (s,
5
4H, 2xNCH2), 3.73 (s, 3H, OCH3), 6.36-6.39 (m, 2H, Ar-H),
7.10-7.24 (m, 7H, Ar-H); 13C NMR (CDCl3+DMSO-d6, 100
MHz, δ ppm): 27.3, 27.4 (2C), 49.7 (2C), 60.3, 81.6, 118.2 (2C),
123.3, 124.8, 130.5, 132.1, 133.1 (2C), 135.9 (2C), 136.5 (2C),
1H, CH), 7.27 (m, 2H, Ar-H), 7.50 (m, 3H, Ar-H), 7.95 (m, 4H,
Ar-H); 13C NMR (CDCl3, 100 MHz, δ ppm): 21.7, 24.4, 26.2
(2C), 52.2 (2C), 96.4, 106.4, 119.0, 127.7 (2C), 128.6 (2C), 129.7
(2C), 129.8 (2C), 130.1, 136.2, 139.1, 140.5, 159.9, 163.1, 164.2;
139.5, 162.8, 165.2, 170.3, 186.0; m/z : 387.3 [M+1]+; Anal. 65 m/z: 354.3 [M+1]+; Anal. Calcd. for C24H23N3 (353.4): C, 81.55;
10 Calcd. for C24H22N2O3 (386.4): C, 74.59; H, 5.74; N, 7.25 Found:
C, 74.46; H, 5.71; N, 7.20.
H, 6.56; N, 11.89 Found: C, 81.46; H, 6.53; N, 11.85.
4-Morpholin-4-yl-2-phenyl-6-p-tolyl-nicotinonitrile
(7e): white solid; Rf: 0.13 (10% EtOAc in Hexane); mp
209 oC; IR (KBr, νmax/cm-1): 2215 (CN); 1H NMR (CDCl3,
70 300 MHz, δ ppm): 2.44 (s, 3H, CH3), 3.54 (bs, 4H,
2xNCH2), 3.96 (bs, 4H, 2xOCH2), 7.18 (s, 1H, CH), 7.30-
7.32 (m, 2H, Ar-H), 7.52-7.54 (m, 3H, Ar-H), 7.95-8.01
(m, 4H, Ar-H); 13C NMR (CDCl3, 100 MHz, δ ppm): 21.8,
51.0 (2C), 67.0 (2C), 96.6, 106.3, 118.6, 127.7 (2C), 128.7
75 (2C), 129.7 (2C), 129.9 (2C), 130.3, 135.8, 138.7, 140.9,
160.5, 162.8, 164.2; m/z: 356.3 [M+1]+; Anal. Calcd. for
C23H21N3O (355.4): C, 77.72; H, 5.96; N, 11.82 Found: C,
77.59; H, 5.92; N, 11.79.
General procedure for the synthesis of diarylpyridines (7).
A mixture of benzamide 6 (1.5 mmol) and powdered sodium
hydroxide (3 mmol) in DMSO (9 mL) was stirred at room
15 temperature for 15 minutes and in it aminated 2H-pyran-2-one 4
(1.0 mmol) was added and stirred for 32-35 h at room
temperature. After completion, reaction mixture was poured onto
crushed ice and neutralized with dil. HCl. The crude product was
filtered, washed with water and finally purified by a silica gel
20 column chromatography using 5 to 10% ethylacetate in hexane.
6'-(4-Bromo-phenyl)-2'-phenyl-3,4,5,6-tetrahydro-2H-
[1,4']bipyridinyl-3'-carbonitrile (7a). white solid; Rf: 0.21 (5%
4-Morpholin-4-yl-2,6-diphenyl-nicotinonitrile (7f): white solid;
o
EtOAc in Hexane); mp 180-181 C; IR (KBr, νmax/cm-1): 2214
80 Rf: 0.3 (20% EtOAc in Hexane); mp 168 oC; IR (KBr, νmax/cm-1):
1
1
(CN); H NMR (CDCl3, 300 MHz, δ ppm): 1.51 (bs, 2H, CH2),
2217 (CN); H NMR (CDCl3, 300 MHz, δ ppm): 3.61 (bs, 4H,
25 1.62 (bs, 4H, 2xCH2), 3.44 (bs, 4H, 2xNCH2), 7.40-7.52 (m, 5H,
Ar-H), 7.81-7.86 (m, 4H, Ar-H); 13C NMR (CDCl3, 100 MHz, δ
ppm): 24.3, 26.2 (2C), 52.2 (2C), 96.6, 106.5, 118.8, 124.8, 128.7
(2C), 129.3 (2C), 129.7 (2C), 130.3, 132.2, 137.9, 138.8, 158.6,
163.0, 164.4; m/z: 419.2 [M+1]+; Anal. Calcd. for C23H20BrN3
30 (418.3): C, 66.04; H, 4.82; N, 10.04 Found: C, 65.90; H, 4.80; N,
9.99.
2xNCH2), 4.01 (bs, 4H, 2xOCH2), 6.98 (s, 1H, CH), 7.57 (m, 6H,
Ar-H), 8.02 (d, 2H, J=3.3 Hz, Ar-H), 8.14 (d, 2H, J=3.9 Hz, Ar-
H); 13C NMR (CDCl3, 100 MHz, δ ppm): 51.0 (2C), 67.0 (2C),
85 97.2, 106.7, 118.5, 119.0, 127.8 (2C), 128.8 (2C), 129.2, 129.7
(2C), 130.3, 130.6, 138.7, 160.5, 162.8, 164.3; m/z: 342.3 ; Anal.
Calcd. for C22H19N3O (341.4): C, 77.40; H, 5.61; N, 12.31 Found:
C, 77.37; H, 5.58; N, 12.26.
6-(4-Methoxy-phenyl)-4-morpholin-4-yl-2-phenyl-
6'-(4-Chloro-phenyl)-2'-phenyl-3,4,5,6-tetrahydro-2H-
[1,4']bipyridinyl-3'-carbonitrile (7b). white solid; Rf: 0.19 (5%
35 EtOAc in Hexane); mp 167 oC; IR (KBr, νmax/cm-1): 2213 (CN);
1H NMR (CDCl3, 300 MHz, δ ppm): 1.74 (bs, 2H, CH2), 1.75
(bs, 4H, 2xCH2), 3.55 (bs, 4H, 2xNCH2), 7.14 (s, 1H, CH), 7.44-
7.52 (m, 5H, Ar-H), 7.93-8.04 (m, 4H, Ar-H); 13C NMR (CDCl3,
100 MHz, δ ppm): 24.3, 26.2 (2C), 52.2 (2C), 96.6, 106.5, 118.8,
40 128.7 (2C), 129.0 (2C), 129.3 (2C), 129.7(2C), 130.3, 136.5,
137.4, 138.8, 158.6, 163.1, 164.4; m/z: 374.1[M+1]+; Anal.
Calcd. for C23H20ClN3 (373.8): C, 73.89; H, 5.39; N, 11.24.
Found: C, 73.76; H, 5.36; N, 11.22.
90 nicotinonitrile (7g). White solid; Rf: 0.02 (20% EtOAc in
o
1
Hexane); mp 169-170 C; IR (KBr, νmax/cm-1): 2212 (CN); H
NMR (CDCl3, 300 MHz, δ ppm): 3.51 (bs, 4H, 2xNCH2), 3.86 (s,
3H, OCH3), 4.01 (bs, 4H, 2xOCH2) 6.99 (m, 2H, Ar-H), 7.12 (s,
1H, CH), 7.5 (m, 3H, Ar-H), 7.93 (m, 2H, Ar-H), 8.04 (m, 2H,
95 Ar-H); ; 13C NMR (CDCl3, 100 MHz, δ ppm): 55.7 (2C), 60.5,
71.6 (2C), 101.0, 110.7, 118.8 (2C), 119.3, 133.1 (2C), 133.4,
134.1, 134.4, 134.9, 135.6, 136.3, 143.7, 162.8, 164.5, 165.9,
166.6; m/z : 372.3; Anal. Calcd. for C23H21N3O2 (371.4): C,
74.37; H, 5.70; N, 11.31 Found: C, 74.24; H, 5.68; N, 11.25.
100 6'-(4-Methoxy-phenyl)-2'-phenyl-3,4,5,6-tetrahydro-2H-
[1,4']bipyridinyl-3'-carbonitrile (7h): white solid; Rf: 0.48
6'-Naphthalen-2-yl-2'-phenyl-3,4,5,6-tetrahydro-2H-
45 [1,4']bipyridinyl-3'-carbonitrile (7c). White solid; Rf: 0.16 (5%
o
(20% EtOAc in hexane); mp 167 C; IR (KBr, νmax/cm-1): 2211
o
EtOAc in Hexane); mp 160-161 C; IR (KBr, νmax/cm-1): 2212
1
(CN); H NMR (CDCl3, 300 MHz, δ ppm): 1.43 (bs, 2H, CH2),
1
(CN); H NMR (CDCl3, 300 MHz, δ ppm): 1.75 (bs, 2H, CH2),
1.60 (bs, 4H, 2xCH2), 3.48 (bs, 4H, 2xNCH2), 3.86 (s, 3H,
105 OCH3), 6.99 (d, 2H, J=8.7, Ar-H), 7.10 (s, 1H, CH), 7.48 (m, 3H,
Ar-H), 7.93 (d, 2H, J=3.3, Ar-H), 8.03 (d, 2H, J=8.7, Ar-H); 13C
NMR (CDCl3, 100 MHz, δ ppm): 24.4, 26.2 (2C), 52.2 (2C), 55.8
(2C), 96.0, 105.8, 114.4, 119.1, 128.6 (2C), 129.2 (2C), 129.7
(2C), 130.1, 131.5, 139.1, 159.5, 161.6, 163.2, 164.1; m/z: 370.3
110 [M+1]+; Anal. Calcd. for C24H23N3O (369.4): C, 78.02; H, 6.27;
N, 11.37 Found: C, 77.91; H, 6.26; N, 11.34.
1.86 (bs, 4H, 2xCH2), 3.58 (bs, 4H, 2xNCH2), 7.32 (s, 1H, CH),
7.55 (m, 5H, Ar-H), 7.93 (m, 5H, Ar-H), 8.19 (m, 1H, Ar-H),
50 8.67 (s, 1H, Ar-H); 13C NMR (CDCl3, 100 MHz, δ ppm): 24.4,
26.2 (2C), 52.2 (2C), 96.6, 107.0, 119.0, 125.0, 126.8, 127.4,
127.6, 128.1, 128.7, 128.8 (2C), 129.3, 129.8 (2C), 130.2, 133.7,
134.5, 136.3, 139.1, 159.8, 163.1, 164.4; m/z: 390.3 [M+1]+;
Anal. Calcd. for C27H23N3 (389.4): C, 83.26; H, 5.95; N, 10.79
55 Found: C, 83.16; H, 5.92; N, 10.75.
2',6'-Diphenyl-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-3'-
2'-Phenyl-6'-p-tolyl-3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-
6
| RSC Adv., 2013, XXX, 01–09
This journal is © The Royal Society of Chemistry [2013]

RSC Advances
Page 8 of 9
View Article Online
carbonitrile (7i). White solid; Rf: 0.19 (5% EtOAc in hexane);
mp 126-127 oC; IR (KBr, νmax/cm-1): 2211 (CN); 1H NMR
(CDCl3, 300 MHz, δ ppm): 1.61 (bs, 2H, CH2), 1.72 (bs, 4H,
2xCH2), 3.53 (bs, 4H, 2xNCH2), 7.17 (s, 1H, CH), 7.46-7.49 (m,
ArH); 13C NMR (CDCl3, 100 MHz, δ ppm): 14.7, 24.1, 26.7
(2C), 41.6, 52.7, 60.8 (2C), 74.3, 119.9, 129.5 (2C), 130.1 (2C),
134.6, 140.6, 167.5, 168.4, 193.1; m/z: 361.7 [M+1]+; Anal.
Calcd. for C19H21ClN2O3 (360.8): C, 63.24; H, 5.87; N, 7.76
5
6H, Ar-H), 7.93 (m, 2H, Ar-H), 8.05 (m, 2H, Ar-H); 13C NMR 60 Found: C, 63.15; H, 5.84; N, 7.74.
(CDCl3, 100 MHz, δ ppm): 24.4, 26.2 (2C), 52.2 (2C), 96.6,
2-Cyano-5-(4-methoxy-phenyl)-5-oxo-3-piperidin-1-yl-pent-2-
106.9, 118.9, 127.8 (2C), 128.7 (2C), 129.1 (2C), 129.8 (2C),
130.2 (2C), 130.3, 139.0, 160.0, 163.1, 164.3; m/z: 340.3 [M+1]+;
Anal. Calcd. for C23H21N3 (339.4): C, 81.38; H, 6.24; N, 12.38
o
enoic acid ethyl ester (10c): white solid; mp 153 C; IR (KBr,
1
νmax/cm-1): 1670 (CO), 2191 (CN); H NMR (CDCl3, 300 MHz,
δ ppm):1.22 (t, 3H, J = 6.0 Hz, CH3), 1.71 (bs, 6H, 3xCH2), 3.62
65 (bs, 4H, 2xNCH2), 3.86 (s, 3H, OCH3), 4.10 (q, 2H, J = 6.0 Hz,
CH2), 4.84 (s, 2H, CH2), 6.95 (d, 2H, J = 9.0 Hz, ArH), 7.96 (d,
2H, J = 9.0 Hz, ArH); 13C NMR (CDCl3, 100 MHz, δ ppm): 14.7,
24.1, 26.6 (2C), 41.3, 52.7, 55.9, 60.7 (2C), 74.0, 114.4 (2C),
120.1, 129.3, 131.0 (2C), 164.4, 167.5, 169.2, 192.7; m/z: 357.3
70 [M+1]+; Anal. Calcd. for C20H24N2O4 (356.4): C, 67.40; H, 6.79;
N, 7.86 Found: C, 67.31; H, 6.75; N, 7.83.
10 Found: C, 81.26; H, 6.21; N, 12.34.
General procedure for the synthesis of diarylpyridines (9).
Diarylpyridine 7a (1 mmol) was heated in concentrated sulphuric
acid (5 mL) for 10 minute at 120 oC. Then pour the reaction
mixure in chilled water (50 mL) and neutralized with N/10 HCl.
15 A white ppt formed, filter and dried.
6'-(4-Bromo-phenyl)-2'-phenyl-3,4,5,6-tetrahydro-2H-
[1,4']bipyridinyl-3'-carboxylic acid amide (9). White solid; Rf:
0.05 (DCM); mp 261 oC; IR (KBr, νmax/cm-1): 1664 (C=O), 3449
(NH2); H NMR (CDCl3, 300 MHz, δ ppm): 1.57 (bs, 2H, CH2),
20 1.66 (bs, 4H, 2xCH2), 2.28 (bs, 4H, 2xNCH2), 6.05 & 6.16 (s, 2H,
2-Cyano-5-oxo-5-phenyl-3-piperidin-1-yl-pent-2-enoic
acid
ethyl ester (10d). white solid; mp 155 oC; IR (KBr, νmax/cm-
1):1686 (CO), 2194 (CN); 1H NMR (CDCl3, 300 MHz, δ
75 ppm):1.23 (t, 3H, J = 6.0 Hz, CH3), 1.72 (bs, 6H, 3xCH2), 3.63
(bs, 4H, 2xNCH2), 4.09 (q, J = 6.0 Hz, 2H, OCH2), 4.88 (s, 2H,
CH2), 7.47-7.59 (m, 3H, ArH), 7.96–7.98 (m, 2H, ArH); 13C
NMR (CDCl3, 100 MHz, δ ppm): 14.7, 24.1, 26.6 (2C), 41.7,
52.7, 60.7 (2C), 74.0, 120.0, 128.6 (2C), 129.2, 134.1, 136.2,
80 167.5, 168.8, 194.2; m/z: 327.2 [M+1]+; Anal. Calcd. for
C19H22N2O3 (326.4): C, 69.92; H, 6.79; N, 8.58 Found: C, 69.81;
H, 6.68; N, 8.57.
1
NH2), 7.14 (s, 1H, CH), 7.32 (m, 3H, Ar-H), 7.50 (d, 2H, J=6.0,
Ar-H), 7.82 (d, 2H, J=1.2, Ar-H), 7.97 (d, 2H, J=6.0, Ar-H) ; 13
C
NMR (CDCl3, 100 MHz, δ ppm): 24.3, 26.4 (2C), 52.7 (2C),
108.3, 122.0, 123.9, 128.3 (2C), 128.7 (2C), 129.0 (4C), 132.0,
25 138.6, 141.0, 156.9, 158.0, 158.7, 171.15; m/z: 436.2 [M+1]+,
438.2 [M+3]+; Anal. Calcd. for C23H22BrN3O (436.3): C, 63.31;
H, 5.08; N, 9.63 Found: C, 63.20; H, 5.04; N, 9.60.
Crystallography
General procedure for the synthesis of delta keto esters (10).
Crystal data for 5-(4-Bromo-phenyl)-2-cyano-5-oxo-3-
85 piperidin-1-yl-pent-2-enoic acid ethyl ester (10a).
A mixture of benzamide 6 (1.5 mmol) and powdered sodium
30 hydroxide (3 mmol) in absolute ethanol (25 mL) was stirred for
o
Crystal data of 10a with molecular formula C19H21N2O3Br, was
collected at room temperature (293K) on a Bruker Apex-II CCD
diffractometer, using MoKα radiation (0.71073 Å). M = 405.3,
orthorhombic, P212121, a = 4.921 (1) Å, b =13.804 (2) Å, c =
90 26.079 (3) Å, V = 1771.7 (4) Å3, Z = 4, Dc = 1.519g cm-3, rod
crystals 0.5 x 0.3 x 0.3 mm. F(000) = 832. The structure was
solved by direct methods using SHELXS and was refined against
F2 with full-matrix least squares method by using SHELXL. All
the H-atoms were located from the difference Fourier maps and
95 were refined isotropically. R = 0.0224, wR = 0.0573 for 4105
observed reflection and 310 parameters. Crystallographic data
(excluding structure factors) have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 932166. Copies of the data can be
100 obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk)
15 minutes at room temperature (18-20 C) and subsequently
added aminated 2H-pyran-2-one 4 (1.0 mmol) and stirred for 24
h. After completion of the reaction, excess ethanol was removed
under reduced pressure and residue was poured in cold water with
35 stirring. The aqueous phase was neutralized with N/10 HCl. The
crude product obtained was filtered, washed with water and
finally purified by a silica gel column chromatography using
chloroform: hexane (1:1).
5-(4-Bromo-phenyl)-2-cyano-5-oxo-3-piperidin-1-yl-pent-2-
40 enoic acid ethyl ester (10a). White solid; Rf: 0.55 (DCM); mp
o
1
142 C; IR (KBr, νmax/cm-1): 1686 (CO), 2210 (CN); H NMR
(CDCl3, 300 MHz, δ ppm):1.23 (t, 3H, J = 6.3 Hz, CH3), 1.73 (bs,
6H, 3xCH2), 3.63 (bs, 4H, 2xNCH2), 4.10 (q, 2H, J = 6.3 Hz,
OCH2), 4.82 (s, 2H, CH2), 7.64 (d, 2H, J =8.4 Hz, ArH), 7.86 (d,
45 2H, J=8.4 Hz, ArH); 13C NMR (CDCl3, 100 MHz, δ ppm):14.7,
24.1, 26.7 (2C), 41.5, 52.8, 60.8 (2C), 74.3, 119.9, 129.4, 130.2
(2C), 132.5 (2C), 135.0, 167.5, 168.3, 193.3; m/z: 406.2 [M+1]+,
408.2 [M+3]+; Anal. Calcd. for C19H21BrN2O3 (405.3): C, 56.31;
H, 5.22; N, 6.91 Found: C, 56.19; H, 5.19; N, 6.88.
Acknowledgements
H.K.M. acknowledges DST, New Delhi, India for financial
105 support as DST fast track young scientist fellowship [No
SR/FT/CS-20/2011].
50 5-(4-Chloro-phenyl)-2-cyano-5-oxo-3-piperidin-1-yl-pent-2-
o
enoic acid ethyl ester (10b). white solid; mp 119 C; IR (KBr,
ν
max/cm-1): 1678 (CO), 2198 (CN); 1H NMR (CDCl3, 300 MHz,
Notes and references
δ ppm):1.22 (t, 3H, J = 6.6 Hz, CH3), 1.72 (bs, 6H, 3xCH2), 3.63
(bs, 4H, 2xNCH2), 4.10 (q, 2H, J = 6.6 Hz, CH2), 4.82 (s, 2H,
55 CH2), 7.47 (d, 2H, J = 7.5 Hz, ArH), 7.93 (d, 2H, J = 8.4 Hz,
1.
a) J. A. Joule, G. Smith, K. Mills, Heterocyclic Chemistry, 3rd Ed.,
Chapman and Hall, London,1995, pp. 72-119; b) H. J. Roth,
This journal is © The Royal Society of Chemistry [2013]
RSC Adv., 2013, XXX, 01–09
| 7

Page 9 of 9
RSC Advances
View Article Online
Kleeman, A. Pharmaceutical Chemistry, Drug Synthesis, Eds.,
Prentice Hall Europe, London 1988, Vol. 1, 407; c) S. Kumar, P.
K. Sharma, R. Dudhe, N. Kumar, J. Chrono. Drug Deliv. 2011, 2,
71; d) A. Chaubey, S. N. Pandey, Asian J. Pharma.Clini. Res.
2011, 4, 5.
13. A. B. Ash, Detroit, C. L. Stevens, Troy, A. Markovac, US Patent
3600396, 1971; b) D. J. Schipper, M. El-Salfiti, C. J. Whipp, K.
Fagnou, Tetrahedron 2009, 65, 4977.
14. a) L. L. Skaletzky, P. Mich, US Patent 4377586, 1983; b) H. Shirai,
K. Hanabusa, Y. Takahashi, F. Mizobe, K. Hanada, US Patent
5922743, 1999.
40
5
2.
W. Aida, T. Ohtsuki, X. Li, M. Ishibashi Tetrahedron 2009, 65,
369-373.
45 15.
U. Mayer, F.W. Raulfs, US Patent 4908447, 1990.
3.
10 4.
5.
J. M. Storvick, E. Ankoudinova, B. R. King, H. V. Epps, G. W.
O’Neil. Tetrahedron Lett. 2011, 52, 5858.
C. Levrier, M. Balastrier, K. D. Beattie, A. R. Carroll, F. Martin,
Phytochemistry 2013, 86, 121-126.
Z. Jinbo, W. Mingan, W. Wenjun, J. Zhiqing, I. Zhaonong,
Phytochemistry 2002, 61, 699-704.
C. B. Madsen-Duggan, J. S. Debenham, T. F. Walsh, R. B.
Toupence, S. X. Huang, J. Wang, X. Tong, J. Lao, T. M. Fong, M.
T. Schaeffer, J. C. Xiao, C. R.-R. C. Huang, C.-P. Shen, S.
Stribling, L. P. Shearman, A. M. Strack, D. E. MacIntyre, L. H. T.
V. d. Ploeg, M. T. Goulet, Bioorg. Med. Chem. Lett. 2007, 17,
2031.
U. Luning, R. Baumstark, W. Schyja, Tetrahedron Lett. 1993, 34,
5063.
T. Chonan, H. Tanaka, D. Yamamoto, M. Yashiro, T. Oi, D.
Wakasugi, A. Ohoka-Sugita, F. Io, H. Koretsune, A. Hiratate,
Bioorg. Med. Chem. Lett. 2010, 20, 3965-3968.
16. K. Takahiro, K. Masaki, Y. Toshihiro, M. Megumi, Patent EP
2535957 A1, 2012.
17. a) P. Babczinski, U. Heinemann, K. Lϋrssen, H.-J. Santel, R. R.
Schmidt, A. Yanagi, Patent EP0463492 A1, 1992; b) K. T. Potts,
M. J. Cipullo, P. Ralli, G. Theodoridis, J. Org. Chem. 1982, 47,
3027; c) V. Y. Sosnovskikh, B. I. Usachev, A. Y. Sizov, M. A.
Barabanov Synthesis 2004, 942-948; d) J. Satyanarayana, H. Ila, H.
Junjappa, Synthesis 1991, 889-890.
18. a) A. Goel, V. J. Ram, Tetrahedron 2009, 65, 7865-7913; b) V. K.
Tandon, H. K. Maurya, B. Kumar, B. Kumar, V. J. Ram, Synlett
2009, 2992.
19. F. Pozgan, M. Kocevar, Heterocycles 2009, 77, 657-678.
20. a) Y. Tominaga, A. Ushirogochi, Y. Matsuda, J. Heterocycl. Chem.
1987, 24, 1557; b) V. J. Ram, M. Verma, F. A. Hussaini, A. Shoeb,
J. Chem. Res. (S) 1991, 98; (c) V. J. Ram, M. Verma, F. A.
Hussaini, A. Shoeb, Liebigs Ann. Chem.1991, 1229.
21. V. J. Ram, M. Nath, P. Srivastava, S. Sarkhel, P. R. Maulik, J.
Chem. Soc. Perkin Trans 1 2000, 3719.
22. a) R. Pratap, S. P. Kushwaha, A. Goel, V. J. Ram, Tetrahedron
Lett. 2007, 48, 549; b) R. Pratap, B. Kumar, V. J. Ram,
Tetrahedron 2007, 63, 10309.
23. S. V. Bhosle, U. D. Patil, M. B. Kalynkar, S. V. Nalage, V. S. Patil,
K. R. Deslale, J. Heterocycle. Chem. 2010, 47, 691-696.
24. A. Kumar, S. P. Singh, D. Verma, R. Kant, P. R. Maulik, A.
Goel, Tetrahedron Lett. 2010, 51, 961.
25. Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 932166. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033
or e-mail: deposit@ccdc.cam.ac.uk).
50
55
60
65
70
75
6.
15
20 7.
8.
25 9.
T. Murata, M. Shimada, S. Sakakibara, T. Yoshino, H. Kadono, T.
Masuda, M. Shimazaki, T. Shintani, K. Fuchikami, K. Sakai, H.
Inbe, K. Takeshita, T. Niki, M. Umeda, K. B. Bacon, K. B.
Ziegelbauer, T. B. Lowinger, Bioorg. Med. Chem. Lett. 2003, 13,
913-918.
30 10.
B. R. Henke, D. H. Drewry, S. A. Jones, E. L. Stewart, S. L.
Weaver, R. W. Wiethe, Bioorg. Med. Chem. Lett. 2001, 11, 1939.
11. L. Wang, J. A. Hubert, S. J. Lee, J. Pan, S. Qian, M. L. Reitman, A.
M. Strack, D. T. Weingarth, D. J. MacNeil, A. E. Weber, S. D.
Edmondson, Bioorg. Med. Chem. Lett. 2011, 21, 2911.
35 12.
a) P. Schaefer, G. Hamprecht, E. Heistracher, H. Koenig, R. Klintz,
P. Muenster, H. Rang, K.-O. Westphalen, M. Gerber, H. Walter,
US Patent 5783522, 1998; b) S. Kawamura, Y. Sanemitsu, T.
Hamada, R. Yoshida, US Patent 4849011, 1989.
8
| RSC Adv., 2013, XXX, 01–09
This journal is © The Royal Society of Chemistry [2013]