Synthesis of alkynyl/alkenyl-substituted pyridine derivatives via heterocyclization and Pd-mediated Sonogashira/Heck coupling process in one-pot: A new MCR strategy

Article abstract of DOI:10.1039/c4ra01053a

A new class of 2-amino-4-(3/2-(alkynyl)/3-(alkenyl)phenyl)-6- phenylnicotinonitriles (6, 7 & 9) has been synthesized with good to excellent isolated yields by the multi-component reaction (MCR) of bromobenzaldehyde (1), malononitrile (2), acetophenone (3), NH₄OAc (4) and a series of terminal alkynes (5)/alkenes (8) in the presence of pyrrolidine and Pd-catalyst in a mixture of H₂O-DME (1:4 ratio) under reflux conditions in a single step. The Heck-type coupling with terminal olefins takes place stereoselectively with exclusive formation of E-isomers. This new MCR strategy opens new avenues in the development of (i) a diversity-oriented new cyanopyridine based compound library and (ii) new chemical entities other than the present reported molecules.

Full text of DOI:10.1039/c4ra01053a

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Synthesis of alkynyl/alkenyl-substituted pyridine derivatives via heterocyclization and Pd-
mediated Sonogashira/Heck coupling process in one-pot: A new MCR strategy
Reddy Bodireddy Mohan,a N. C. Gangi Reddy,a* Sangita D. Kumarb
5
aDepartment of chemistry, School of Physical Sciences, Yogi Vemana University, Kadapa-516 003, A.P., India.
Analytical Chemistry Division, Bhabha Atomic Research Centre (BARC), Trombay-400 085, Mumbai, India.
b
Fax:+91-8562-225419;Tel:+91-8562-225410
E-mail: ncgreddy@yogivemanauniversity.ac.in
Abstract: A new class of 2ꢀaminoꢀ4ꢀ(3/2ꢀ(alkynyl)/3ꢀ(alkenyl)phenyl)ꢀ6ꢀphenylnicotinonitriles (6, 7
10 & 9) has been synthesized with good to excellent isolated yields by the multiꢀcomponent reaction
(MCR) of bromobenzaldehyde (1), malononitrile (2), acetophenone (3), NH4OAc (4) and a series of
terminal alkynes(5)/alkenes(8) in presence of pyrrolidine and Pdꢀcatalyst in a mixture of H2OꢀDME
(1:4 ratio) under reflux conditions in a single step. The Heckꢀtype coupling with terminal olefins takes
place stereoselectively with exclusive formation of E-isomers. This new MCR strategy opens new
15 avenues in the development of i) diversityꢀoriented new cyano pyridine based compound library and ii)
new chemical entities other than the present reported molecules.
Key words: Multiꢀcomponent reaction (MCR), Pyridines, heterocyclization, CꢀC coupling,
Sonogashira reaction, Heck reaction
20 1. Introduction
The pyridine ring system is an ‘Important structural motif’ in a large number of natural
products and also in clinically useful molecules. Among this plethora of compounds, cyanopyridine
derivatives have attracted great attention due to their wide range of biological activities such as
antimicrobial,1,2 antipyretic,3 antiꢀhyperglycemic properties,4 Ca2+ꢀchannel blockers,5 vasodilator,6
25 antitumor,7,8 antiꢀdiabetic agents.9 In addition, they have been evaluated as IKKꢀβ inhibitors,10 Protein
Kinase B (PKB/Akt) inhibitors,11 protein kinase Cθ (PKCθ) inhibitors,12 melaninꢀconcentrating
hormone receptor 1 (MCHꢀR1) antagonists,13 A2A adenosine receptor antagonists,14 carbonic anhydrase
inhibitors,15 dipeptidyl peptidaseꢀIV (DPPꢀIV) inhibitors with antiꢀhyperglycemic activity,16
analgesic agents,17 monoamine oxidases (MAO), cholinesterase inhibitors for the treatment of
30 Alzheimer’s disease,18 metabotropic glutamate receptor5 (mGluR5) negative allosteric modulators,19
CꢀJun NH2 terminal kinase (JNKs) inhibitors,20 prion disease therapeutics21 and RET tyrosine kinase
inhibitors22 and also useful in the development of nonꢀlinear optical (NLO) materials23 and nondoped
organic lightꢀemitting devices (OLEDs) too.24 As a result, cyanopyridine derivatives are regarded as
“significant structural motif” and a huge number of strategies are developed for their synthesis.25, 26 In
35 addition, the development of multiꢀcomponent reactions (MCRs) strategies have attracted great
attention from organic chemists27ꢀ34 to prepare these useful pyridine frameworks. Multiꢀcomponent
reactions (MCRs) are powerful strategies for the quick synthesis of diverse and complex organic

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molecules of potential interest particularly in the area of material science and drug discovery.35ꢀ39
MCRs have attracted much attention owing to their excellent synthetic efficiency, intrinsic atom
economy, high selectivity, procedural simplicity and environmental friendliness.40ꢀ43 Therefore, the
development of new multiꢀcomponent reaction (MCR) strategies for the preparation of diversityꢀ
5 oriented complex molecules have recently gained considerable interest from the organic chemists.45ꢀ49
In particular, structural elaboration on heterocyclic compounds with terminal alkynyl/alkenyl
functionalities using Sonogashira and Heck coupling reactions is quite interesting.50ꢀ56 However,
attempts are not made to investigate the structural elaboration of cyano pyridine derivatives using Pdꢀ
mediated Sonogashira and Heck coupling reactions via a oneꢀpot multicomponent reaction (MCR).
10
Herein, we report a new MCR strategy for the synthesis of 2ꢀaminoꢀ4ꢀ(3/2ꢀ(alkynyl)/3ꢀ
(alkenyl)phenyl)ꢀ6ꢀphenylnicotinenitriles (6, 7 & 9) with 80ꢀ90% isolated yields via heterocyclization
from bromobenzaldehyde (1), malononitrile (2), acetophenone (3) and NH4OAc (4) in the presence of
pyrrolidine followed by Pdꢀmediated Sonogashira and Heck coupling reactions using a variety of
terminal alkynes(5)/alkenes (8) in a mixture of H2OꢀDME (1:4 ratio) under reflux conditions as shown
15 in scheme 1. The present communication addresses several challenging issues e.g. (i) MCR based
synthesis of alkynyl/alkenyl substitutedꢀheterocyclic molecules via heterocyclization followed by CꢀC
coupling in oneꢀpot, (ii) the optimal base, catalyst system and reaction conditions and (iii) synthesis in
view to develop alkynyl/alkenyl substituted heterocyclic compounds based synthetic precursors
suitable for further functional group transformations in the development of diversity oriented new
20 compound library.
NH2
New CꢀC triple/
double bond
N
CHO
O
Pyrrolidine
H2OꢀDME (1:4 ratio)
PdCl2(PPh3)2
N
functionalities
CN
Various
alkynyl/alkenyl
+
+
+
NH4OAc
4
R
CN
2
groups
Br
R"
~75ꢀ90%
or
(5), CuI
R'
Sonogashira reaction
Reflux
(8)
1
3
R= alkynyl (6) & (7) or
alkenyl (9)
Heck reaction
Scheme 1 Synthesis of 2ꢀaminoꢀ4ꢀ(3/2ꢀ(alkynyl)/3ꢀ(alkenyl)phenyl)ꢀ6ꢀphenylnicotinenitriles via
multiꢀcomponent reaction.
2. Experimental
25 Melting points of various products obtained are determined (uncorrected). 1H and 13C NMR spectra are
recorded on a Varian 400 MHz. Chemical shifts are reported in ppm with the internal TMS signal at
0.0 ppm as a standard. The data are reported as follows: chemical shift (ppm) and multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad singlet), coupling

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constant(s) in Hz, integration assignment. Highꢀresolution mass spectra (HRMS) and compound purity
data are acquired on a Waters LCT premier XE TOF HRMS single quadrupole system equipped with
electro spray ionization (ESI) source. Thinꢀlayer chromatography is performed on 0.25 mm Merck
silica gel plates and visualized with UV light. Column chromatography is performed on silica gel (200ꢀ
5 300 mesh). Chemicals and solvents are purchased from Sigma Aldrich and Merck. Isolated compounds
are characterized by physical and spectroscopic data.
Typical experimental procedure for the preparation of 2-amino-4-(3-(3-hydroxyprop-1-
ynyl)phenyl)-6-phenylnicotinonitrile (6a):
A mixture of 3ꢀbromobenzaldehyde (1) [10.0 mmol], malononitrile (2) [11.0 mmol], acetophenone (3)
10 [11.0 mmol] and NH4OAc (4) [20.0 mmol] in presence of pyrrolidine (5.0 mmol) in a mixture of H2Oꢀ
DME (1:4 ratio) (10 vol) is stirred at reflux for 1.0 hr. The first phase progress of the reaction is
monitored by TLC. After the completion of the reaction, the reaction mixture is cooled to RT and then,
propꢀ2ꢀynꢀ1ꢀol 5a [15.0 mmol], PdCl2(PPh3)2 [0.002 mmol] and CuI [0.005 mmol] are added. Again
the entire reaction mixture is kept under reflux condition for 3.0 hrs in open air. Final stage progress is
15 monitored by TLC. After the completion of the reaction, the whole reaction mixture is cooled to RT
and the solvent is removed under reduced pressure. The obtained crude product is purified by column
chromatography using silica gel and 1:9 ratio of EtOAc ꢀ Petroleum ether (PE) to obtain pure
compound 6a. The isolated yield of product 6a is 91%. The same procedure is followed for the
preparation of 2ꢀaminoꢀ4ꢀ(3ꢀ(alkynyl)phenyl)ꢀ6ꢀphenylnicotinonitrile derivatives (6b-k) listed in
20 Table-2. All the synthesised compounds (6a-k) gave satisfactory spectroscopic data in accordance
with their proposed structures.
Typical experimental procedure for the preparation of 2-amino-4-(2-(3-hydroxyprop-1-
ynyl)phenyl)-6-phenylnicotinonitrile (7a):
A mixture of 2ꢀbromobenzaldehyde (1a) [10.0 mmol], malononitrile (2) [11.0 mmol], acetophenone
25 (3) [11.0 mmol] and NH4OAc (4) [20.0 mmol] in the presence of pyrrolidine (5.0 mmol) in a mixture
of H2OꢀDME (1:4 ratio) (10 vol) is stirred at reflux for 1.0 hr. The first phase progress of the reaction
is monitored by TLC. After the completion of the reaction, the reaction mixture is cooled to RT and
then, propꢀ2ꢀynꢀ1ꢀol 5a [17.0 mmol], PdCl2(PPh3)2 [0.002 mmol] and CuI [0.005 mmol] are added.
Again the entire reaction mixture is kept under reflux condition for 3.5 hrs in open air. Final stage
30 progress is monitored by TLC. After the completion of the reaction, the whole reaction mixture is
cooled to RT and the solvent is removed under reduced pressure. The obtained crude product is
purified by column chromatography using silica gel and 1:9 ratio of EtOAc ꢀ Petroleum ether (PE) to
obtain pure product 7a. The isolated yield of product 7a is 80%. The same procedure is followed for
the preparation of 2ꢀaminoꢀ4ꢀ(2ꢀ(alkynyl)phenyl)ꢀ6ꢀphenylnicotinonitrile derivatives (7b-d) listed in

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Table-3. Synthesized compounds (7a-d) gave satisfactory spectroscopic data in accordance with their
proposed structures.
Typical experimental procedure for the preparation of (E)-methyl 3-(3-(2-amino-3-cyano-6-
5 phenylpyridin-4-yl)phenyl)acrylate (9a):
A mixture of 3ꢀbromobenzaldehyde (1) [10.0 mmol], malononitrile (2) [11.0 mmol], acetophenone (3)
[11.0 mmol] and NH4OAc (4) [20.0 mmol] in presence of pyrrolidine (5.0 mmol) in a mixture of H2Oꢀ
DME (1:4 ratio) (10 vol) is stirred at reflux for 1.0 hr. The first phase progress of the reaction is
monitored by TLC. After the completion of the reaction, the reaction mixture is cooled to RT and then,
10 methyl acrylate (8a) [16.0 mmol] and PdCl2(PPh3)2 [0.002 mmol] are added. Again, the entire
reaction mixture is kept under reflux condition for 3.0 hrs in open air. Final stage progress is
monitored by TLC. After the completion of the reaction, the whole reaction mixture is cooled to RT
and the solvent is removed under reduced pressure. The obtained crude product is purified by column
chromatography using silica gel and 1:9 ratio of EtOAc ꢀ Petroleum ether (PE) to obtain pure
15 compound (9a). The isolated yield of product 9a is 88%. The same procedure is followed for the
preparation of 2ꢀaminoꢀ4ꢀ(3ꢀ(alkenyl)phenyl)ꢀ6ꢀphenylnicotinonitrile derivatives (9b-f) listed in
Table-4. Synthesized compounds (9a-f) gave satisfactory spectroscopic data in accordance with their
1
proposed structures. Based on H NMR data, all the prepared alkenes (9a-f) are confirmed as ‘E’
isomers (J= 16.0 ꢀ 16.5 Hz).
20 3. Results and discussion
In the present study, our initial objective is to identify wellꢀsuited reaction conditions for the
heterocyclization along with Pdꢀmediated CꢀC coupling process in a single step operation.
Accordingly, we have studied the effect of bases, solvents, reaction temperature and Pdꢀcatalysts as
well as effect of concentration of base for the construction of pyridine frame work followed by
25 Sonogashira/Heck coupling in oneꢀpot. Therefore, in an initial experiment, 3ꢀbromobenzaldehyde (1),
malononitrile (2), acetophenone (3) and NH4OAc (4) in presence of K2CO3 in H2O is stirred at reflux
for 10.0 hrs. After the completion of the reaction, the reaction mixture is cooled to RT and then, propꢀ
2ꢀynꢀ1ꢀol [5a], PdCl2(PPh3)2 and CuI are added. After workup and purification, the desired product 2ꢀ
aminoꢀ4ꢀ(3ꢀ(3ꢀhydroxypropꢀ1ꢀynyl)phenyl)ꢀ6ꢀphenylnicotinonitrile (6a) is isolated in 5.0% yield
30 (entry 1, Table 1). The obtained yield of the product (6a) is not impressive; this may be due to
insolubility of the reactants. To improve the solubility of the reactants and thereby the yield of the
product (6a), H2O is replaced by organic solvents such as THF, Dioxane, DME, mixture of H2OꢀDME
(1:4 ratio), DMF and DMSO. The obtained yields are 48%, 56%, 64%, 71% and 62%, respectively
(entries 2ꢀ7, Table 1). Initial effect of solvent study revealed that mixture of H2OꢀDME (1:4 ratio)

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provided acceptable yield (71%) of the product 6a (entry 5). To increase the yield of the product (6a)
further, various bases such as Na2CO3 (entry 8), Et3N (entry 9) and pyrrolidine (entry 10) are
employed which resulted a yield of 56%, 78% and 91%, respectively in a mixture of H2OꢀDME (1:4
ratio). The evaluation of suitable base revealed that pyrrolidine is more efficient in producing the
5 maximum yield (91%) of product 6a (entry 10) in a mixture of H2OꢀDME (1:4 ratio). Subsequently,
the effects of temperature, Pdꢀcatalyst and concentration of base and terminal alkyne, propꢀ2ꢀynꢀ1ꢀol
(5a) are investigated on the course of MCR. Lower yields (25ꢀ72%) are obtained when the same
reaction is conducted at less than 80°C in a mixture of H2OꢀDME (1:4 ratio). In this case, it is
observed that some portions of the reactants are still remaining and resulting lower yields of the
10 desired product (6a). Then, the same reaction has been conducted at reflux temperature and the
obtained yield of the product (6a) has dramatically increased to 91%. In order to study the effect of
other Pdꢀcatalysts on the course of the CꢀC coupling reaction, various Pdꢀcatalysts such as Pd(PPh3)4,
Pd(dppf)Cl2 and 20% Pd(OH)2 have been employed which afforded 72%, 68% and 75% yields,
respectively (entries 11ꢀ14). The results show the superiority of the PdCl2(PPh3)2 catalyst to obtain
15 maximum yield (91%) of the product (6a) within 4.0 hrs. The effect of pyrrolidine base load is studied
on the course of MCR reaction; for example 2.0, 5.0, 10.0, 15.0 and 20.0 mmol of pyrrolidine provided
72%, 91%, 78%, 71% and 65% yields of product (6a), respectively. From the results, it is concluded
that 5.0 mmol of pyrrolidine offered best yield (91%) of product (6a). Variation of terminal alkyne
concentration also effected the yields significantly; 10.0, 15.0, 20.0 and 25.0 mmol of propꢀ2ꢀynꢀ1ꢀol
20 5a resulted 68%, 91%, 84% and 78% yields and the optimum concentration of terminal alkyne
concentration is 15.0 mmol for maximum yield.
Table 1. Optimization of reaction conditions for the MCR based synthesis of 2ꢀaminoꢀ4ꢀ(3ꢀ(3ꢀ
hydroxypropꢀ1ꢀynyl)phenyl)ꢀ6ꢀphenylnicotinonitrile (6a) through heterocyclization followed by
Sonogashira reaction[a]
NH2
CHO
O
N
OH
Pdꢀcatalyst
Base
CN
CN
2
N
+
+
+
NH4OAc
Br
(5a), CuI
HO
1
Solvent
Temp'
6a
3
4
25
Entry
Catalyst
Solvent
Base
Time(hrs)/Temp(°C) Yield[b]
(%)
1
2
3
4
5
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
H2O
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
24.0; reflux
16.0; reflux
12.0; reflux
9.0; reflux
7.0; reflux
5
48
56
64
71
Dioxane
DME
H2OꢀDME (1:4 ratio)

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6
7
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
DMF
K2CO3
K2CO3
Na2CO3
Et3N
8.0; 90ꢀ100
6.0; 90ꢀ100
9.0; reflux
6.0; reflux
4.0; reflux
10; reflux
8.0; reflux
7.0; reflux
6.0; reflux
62
65
56
78
91
68
72
68
75
DMSO
8
H2OꢀDME (1:4 ratio)
H2OꢀDME (1:4 ratio)
9
10
11
12
13
14
H2OꢀDME (1:4 ratio) Pyrrolidine
H2OꢀDME (1:4 ratio) Pyrrolidine
H2OꢀDME (1:4 ratio) Pyrrolidine
H2OꢀDME (1:4 ratio) Pyrrolidine
Pd(PPh3)4
Pd(dppf)Cl2
[c]
20%Pd(OH)2
H2OꢀDME (1:4 ratio)
ꢀ
[a]Reagents and conditions: 3ꢀbromobenzaldehyde 1 (10.0 mmol), malononitrile 2 (11.0 mmol), acetophenone 3 (11.0
mmol), NH4OAc 4 (20.0 mmol), base (5.0 mmol); propꢀ2ꢀynꢀ1ꢀol 5a (15.0 mmol), PdCl2(PPh3)2 (0.002 mmol)and CuI
(0.005 mmol) in a solvent or mixture of solvents (10 vol) at specified temperature; [b] Isolated yield; [c] Act as catalyst
cum base.
5
Having prepared 2ꢀaminoꢀ4ꢀ(3ꢀ(3ꢀhydroxypropꢀ1ꢀynyl)phenyl)ꢀ6ꢀphenylnicotinonitrile (6a) through
heterocyclization followed by Sonogashira reaction efficiently under optimized reaction conditions, it
is further investigate the further substrate scope and generality of this process using various terminal
alkynes i.e. 6a-k and the obtained results are presented in Table 2. From this study, it is found that
10 various functional groups of terminal alkyne substrates (6a-k) are well tolerated to the reaction
conditions and provided good yields of the desired products (6a-k).
Table 2. MCR based synthesis of 2ꢀaminoꢀ4ꢀ(3ꢀ(alkynyl)phenyl)ꢀ6ꢀphenylnicotinonitriles (6) via
heterocyclization followed by Sonogashira reaction[a]
15
CHO
O
NH2
PdCl2(PPh3)2
Pyrrolidine
N
CN
CN
2
N
R'
+
+
+
NH4OAc
(5), CuI
R'
Br
H2OꢀDME (1:4 ratio)
Reflux
1
3
4
6

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[c]
Entry
R' of terminal
Product (6)
Time Yield[b] Rƒ
alkyne (5) substrate
(hrs)
(%)
NH2
N
OH
N
1
CH2OH (5a)
4.0
91
0.4
6a
NH2
OH
N
N
2
3
CH2CH2OH (5b)
4.0
3.5
89
85
0.45
6b
ΟΗ
ΝΗ2
Ν
Ν
CH2CH2CH2OH (5c)
0.5
6c
Cl
NH2
N
N
4
5
CH2CH2CH2Cl (5d)
CH2CH(OH)CH3(5e)
3.5
4.0
87
89
0.7
0.4
6d
NH2
N
OH
N
6e
NH2
N
OH
N
6
(OH) C (CH3)2 (5f)
5.0
85
0.4
6f

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NH2
N
N
7
8
CH2(CH2)2CH3 (5g)
4.5
4.5
88
86
0.75
6g
NH2
N
N
CH2(CH2)3CH3 (5h)
0.8
6h
NH2
N
N
9
CH2(CH2)4CH3 (5i)
4.5
88
0.85
6i
NH2
N
10
CH2(CH2)6CH3 (5j)
4.5
87
0.85
N
6j
NH2
N
N
OH
11
1ꢀHydroxyꢀ1ꢀ
5.0
85
0.45
cyclohexyl (5k)
6k
[a]Reagents and conditions: 3ꢀbromobenzaldehyde 1 (10.0 mmol), malononitrile 2 (11.0 mmol), acetophenone
3 (11.0 mmol), NH4OAc 4 (20.0 mmol), Pyrrolidine (5.0 mmol); terminal alkynes 5a-k (15.0 mmol),
PdCl2(PPh3)2 (0.002 mmol)and CuI (0.005 mmol) in a mixture of H2OꢀDME (1:4 ratio) (10 vol) at reflux; [b]
Isolated yield.; [c] Retention factor: 40% EtOAc in PE.

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The results obtained reveal that 3ꢀbromobezaldehyde (1) can act as an efficient key starting
material in the formation of 2ꢀaminoꢀ4ꢀ(3ꢀ(alkynyl)phenyl)ꢀ6ꢀphenylnicotinonitriles (6a-k)
via heterocyclization followed by Sonogashira reaction (Table 2); further it is found that the
scope of the same reaction with 2ꢀbromobenzandehyde (1a) as a key starting material
resulted in the production of desired products(7a-d) presented in Table 3. The study reveal
that lower yields of final products (7a-d) are obtained due to steric hindrance in the course of
the CꢀC coupling process. It is found that lower yields of products (7a-d) are offered in all
cases (entries 1ꢀ4, Table 3) irrespective of the nature of substituents present on terminal
alkyne substrates (5a, 5b, 5f and 5i) when 2ꢀbromobenzandehyde (1a) is used instead of 3ꢀ
bromobenzandehyde (1).
Table 3: MCR based synthesis of 2ꢀaminoꢀ4ꢀ(2ꢀ(alkynyl)phenyl)ꢀ6ꢀphenylnicotinonitriles
(7) via heterocyclization followed by Sonogashira reaction[a]
CHO
O
PdCl2(PPh3)2
Pyrrolidine
N
Br
CN
CN
R'
+
+
+
NH4OAc
(5), CuI
R'
H2N
N
H2OꢀDME (1:4 ratio)
Reflux
2
3
4
1a
7
[c]
Entry
R' of terminal
Product (7)
Time
(hrs)
Yield[b]
Rƒ
alkyne(5) substrate
(%)
N
NH2
N
1
CH2OH (5a)
4.5
81
0.35
HO
7a
N
NH2
2
CH2CH2OH (5b)
4.5
78
0.4
HO
N
7b

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N
NH2
N
0.4
HO
3
(OH)C(CH3)2 (5f)
5.5
76
7c
N
NH2
4
CH2(CH2)4CH3 (5i)
5.0
79
0.85
N
7d
[a] Reagents and conditions: 2ꢀbromobenzaldehyde 1a (10.0 mmol), malononitrile 2 (11.0 mmol),
acetophenone 3 (11.0 mmol), NH4OAc 4 (20.0 mmol), Pyrrolidine (5.0 mmol); terminal alkynes 5a/b/f/i (15.0
mmol), PdCl2(PPh3)2 (0.002 mmol)and CuI (0.005 mmol) in a mixture of H2OꢀDME (1:4 ratio) (10 vol) at
reflux; [b] Isolated yield.; [c] Retention factor: 40% EtOAc in PE.
Further substrate scope is investigated to assess the generality of the proposed MCR
under Heck reaction conditions as shown in Table 4. Towards this direction, a mixture of 3ꢀ
bromobenzaldehyde (1) malononitrile (2), acetophenone (3), NH4OAc (4) and methyl
acrylate (8a) in presence of PdCl2(PPh3)2 and pyrrolidine in a mixture of H2OꢀDME (1:4
ratio) (10 vol) are stirred for 5.0 hrs at reflux temperature to obtain product 9a. The yield
(88%) of product 9a is good (entry 1, Table 4). Further, a series of terminal alkenes i.e. 8b-f
are tested for the preparation of desired alkenylꢀsubstituted pyridine derivatives (9b-f) and
found that various sensitive functional groups of terminal alkenes (8a-f) are well tolerated to
the reaction conditions and provided good yields of the desired products (9b-f) (entries 2ꢀ6,
Table 4). Based on the obtained 1H NMR data, all the prepared 2ꢀaminoꢀ4ꢀ(3ꢀ
(alkenyl)phenyl)ꢀ6ꢀphenylnicotinonitrile derivatives (9a-f) are confirmed as ‘E’ isomers (J=
16.0 ꢀ 16.5 Hz).

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Table 4: MCR based synthesis of 2ꢀaminoꢀ4ꢀ(3ꢀ(alkenyl)phenyl)ꢀ6ꢀphenylnicotinonitriles (9)
via heterocyclization followed by Heck reaction[a]
CHO
O
NH2
PdCl2(PPh3)2
Pyrrolidine
N
CN
CN
2
N
+
+
+
NH4OAc
R"
8
( )
Br
R"
1
3
4
H2OꢀDME (1:4 ratio)
Reflux
9
[c]
Entry R'' of terminal
Alkene (8)
Product (9)
Time Yield[b]
Rƒ
(hrs)
(%)
substrate
N
H2N
N
1
COOCH3 (8a)
5.0
88
0.55
O
O
9a
9b
9c
2
COOCH2CH3
5.5
82
0.55
O
N
(8b)
O
NH2
N
3
COOC(CH3)3
5.0
83
0.6
O
N
(8c)
O
NH
N

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NH2
N
N
O
4
5
COCH3 (8d)
5.5
5.5
86
87
0.4
9d
CONH2 (8e)
0.1
O
N
H2N
NH2
N
9e
NH2
N
N
N
6
CN (8f)
4.5
85
0.3
9f
[a]Reagents and conditions: 3ꢀbromobenzaldehyde 1 (10.0 mmol), malononitrile 2 (11.0 mmol), acetophenone
3 (11.0 mmol), NH4OAc 4 (20.0 mmol), pyrrolidine (5.0 mmol) and terminal alkenes 8a-f (16.0 mmol),
PdCl2(PPh3)2 (0.002 mmol) in a mixture of H2OꢀDME (1:4 ratio) (10 vol) at reflux; [b] Isolated yield.; [c]
Retention factor: 30% EtOAc in PE.
4. Conclusions
In summary, general syntheses of a new library of structurally diverse
alkynyl/alkenylꢀsubstituted pyridine derivatives (6, 7 & 9) have been accomplished via
heterocyclization and subsequent Pdꢀmediated structural elaboration under Sonogashira and
Heck coupling reactions in single step. Interestingly, the Heck coupling with terminal alkenes
takes place stereoselectively with exclusive formation of the E-isomers. This MCR strategy
offers advantages like easy isolation of products, simple construction of diversity oriented
library of highly substituted pyridine derivatives and wide applications in the synthesis of
valuable heterocyclic synthetic precursors bearing carbonꢀcarbon triple and double bond
functionalities other than the present reported molecules. The prepared synthetic precursors

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will be suitable for further functional group transformations in the development of new and
novel heterocyclic molecules of potential pharmacological interest.
Acknowledgments
We gratefully acknowledge for the financial support from Council of Scientific and
Industrial Research (CSIR), New Delhi, Govt. of India through a major research Project
No. 01 (2391)/10/EMRꢀII and Department of Atomic EnergyꢀBoard of Research in Nuclear
Sciences (DAEꢀBRNS), Mumbai, Govt. of India through a major research project
No. 2011/37C/52/BRNS/2264.
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