Visible-light-accelerated pd-catalyzed cascade addition/ cyclization of arylboronic acids to γ- And β-ketodinitriles for the construction of 3-cyanopyridines and 3-cyanopyrrole analogues

Article abstract of DOI:10.1021/acs.joc.0c01703

The one-pot synthetic strategies for 2,4,6-triarylnicotinonitriles and 2,5-diaryl-1H-pyrrole-3-carbonitriles have been accomplished via a Pd-catalyzed coupling of arylboronic acid with 2-(3-oxo-1,3-diarylpropyl)malononitrile and 2-(2-oxo-2- arylethyl)malo

Full text of DOI:10.1021/acs.joc.0c01703

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Article
Visible-Light Accelerated Pd-Catalyzed Cascade Addition/
Cyclization of Aryl Boronic Acids to #- and #-Ketodinitriles for the
Construction of 3-Cyanopyridines and 3-Cyanopyrrole Analogues
Amitava Rakshit, Prashant Kumar, Tipu Alam, Hirendranath Dhara, and Bhisma K. Patel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01703 • Publication Date (Web): 09 Sep 2020
Downloaded from pubs.acs.org on September 10, 2020
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Visible-Light Accelerated Pd-Catalyzed Cascade Addition/Cyclization of
Aryl Boronic Acids to - and -Ketodinitriles for the Construction of 3-
Cyanopyridines and 3-Cyanopyrrole Analogues
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Amitava Rakshit, Prashant Kumar, Tipu Alam, Hirendranath Dhara and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, India.
Fax: (+91)361-26909762
E-mail: patel@iitg.ac.in
R1
R1
HO
OH
R2
NC
CN
B
O
Pd(OAc)2 (10 mol %)
,2'-bipyridyl (20 mol %)
n
2
1
N
HN
R2
R3
CN
CN or
R1
PTSA·H2O (2 equiv)
,2-DCE (2 mL), rt, 24 h
n = 0 or 1
R2 = H or aryl, heteroaryl
R3
R3
2
x10 W White LEDs
R2 = aryl, heteroaryl) (R2 = H)
n = 1 n = 0
42 examples 16 examples
(
photosensitizer-free mild reaction condition
selective attack at one CN group
formation of CC, CN, C=C and C=N bonds
Yields (35-79%) Yields (52-80%)
ABSTRACT
The one-pot synthetic strategies for 2,4,6-triarylnicotinonitriles and 2,5-diaryl-1H-
pyrrole-3-carbonitriles have been accomplished via a Pd-catalyzed coupling of arylboronic
acid with 2-(3-oxo-1,3-diarylpropyl)malononitrile and 2-(2-oxo-2-arylethyl)malononitrile,
respectively under mild reaction conditions followed by intramolecular cyclization of an
intermediate formed after the regeneration of catalyst under acidic rection conditions. The
cascade reactions proceed in 1,2-dichloroethane solvent under visible-light irradiation, and the
active catalyst is generated in situ in the presence of catalytic amounts of Pd(OAc) and 2,2′-
2
bipyridine. The active Pd-catalyst undergoes photoexcitation by the virtue of MLCT, and
subsequent redox trans-metalation occurs with arylboronic acid, thus obviating the necessity
of any exogenous photosensitizer. The targeted products, composed of a new CC, a CN, a
CN and two new CC bonds, were isolated in good yields.
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INTRODUCTION
Heteroaromatics are an essential class of molecules in the realm of organic chemistry,
among which the nitrogen-heterocycles comprised of pyridine and pyrrole-frameworks have
garnered the attention of chemists for several years. The widespread attention stems from the
fact that substituted pyridine scaffolds constitute an essential structural feature in several
natural products and other multipurpose molecules which find their applications in different
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fields of science ranging from biology to medicine to advanced materials. Besides, pyridine-
based structures also find utility in several other fields such as asymmetric catalysis,2
3
4
supramolecular chemistry, and cancer therapy. Likewise, the pyrrole moiety has been
identified in the structural frameworks of a wide array of natural products, unnatural products,
5
and drug molecules. The importance of pyrrole-based compounds can be substantiated by their
diverse applications in the field of materials chemistry pertaining to the development of
6
batteries, solar cells, and the exploration of diverse optoelectronic applications. Interestingly,
pyrrole and pyridine nuclei occur ubiquitously in a plethora of structurally diverse FDA
approved pharmaceutical drugs, so much so that they are the most aromatic nuclei in these
drugs (Figure 1 and 2).7
N
N
H
N
H
N
S
O
O
N
N
S
S
O
N
H
O
N
O
O
N
O
O
O
Nexium (esomeprazole)
Acid reflux)
Aciphex (rabeprazole)
(Duodenal ulcers
and acid reflux)
Avandia (Rosiglitazone A)
(
(Antidiabatic)
O
O
S
H
S
N
N
O
Cl
O
N
H
O
O
NH2
Actos (Pioglitazone B)
Amrinone D (Inocor)
N
Etoriocoxib E (Arcoxia)
(COX-2 inhibitor, Arthritis)
N
(Antidiabatic)
(PDE3 inhibitor)
acute heart failure)
(
N
H
O
N
NH2
N
N
Cl
O
N
F
N
H
O
N
N
N
Cl
CF3
NH
N
HN
N
Cl
O
N
N
N
O
Gleevec
(Chronic myeloid leukemia)
Sorafenib (nexovar)
(Chronic myeloid leukemia)
Crizotinib (Xalkori)
(Lung cancer)
H
HN
CF3
N
tBu
O
O
O
H
N
NH HN
OH
N
N
OMe
Altrazanavir
N
N
N
H
N
O
O
Nilotnib
(Chronic myeloid leukemia)
(Reyataz)
(HIV)
HN
tBu
OMe
NH
Figure 1. A few drugs bearing pyridine nucleus
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O
O
O
O
COOH
N
OH
OH
N
N
Ph NH
O
Me
Ph
Atorvastain (Lipitor)
Ketorolac
Tolmetin
(NSAIDs)
Anti-hyperlipidemic
(NSAIDs)
F
Ph
N
F
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HN
N
Et
N
O
HN
Et
N
O
N
H
Sunitinib
Treatment of Gastrointestinal Stromal Tumors)
Pyrvinium
(pinworm infestation)
(
Figure 2. A few drugs bearing pyrrole nucleus
Some of these marketed drugs along with their targets are listed in Figure 1 and 2. Some
renowned drugs bearing the pyridine moiety include nexium (esomeprazole) and aciphex
(
(
rabeprazole) for the treatment of acid reflux and duodenal ulcers (Figure 1);7a,b avandia
rosiglitazone A) and actos (pioglitazone B) as antidiabetic drugs;7c,d amrinone D (inocor) and
etoriocoxib E (arcoxia) for treating patients with acute heart failure and arthritis.7e,f Moreover,
7
g
7h
7i
some potent anticancer drugs such as gleevec, sorafenib (nexovar), crizotinib (xalkori),
7
j
7k
nilotnib, and the anti-HIV drug altrazanavir (reyataz) also contain the pyridine moiety
Figure 1). Similarly, few renowned drugs bearing the pyrrole moiety are atrovastatin, the best-
selling cholesterol lowering drug which functions by inhibiting the HMG-CoA reductase
(
8
a
enzyme; ketorolac and tolmetin are nonsteroidal anti-inflammatory drugs (NSAIDs) used for
treating acute pain and inflammation;8b-c sunitinib is a multi-targeted tyrosine kinase inhibitor
possessing antitumor and antiangiogenic activities, and pyrvinium is used for treating pinworm
infestation.8d-e
On account of several multifaceted applications of substituted pyridines and pyrroles,
synthetic chemists have long endeavoured the discovery of various pathways to achieve these
important structural motifs. Several classical methods for the synthesis of pyridine are based
upon the condensation of ammonia with a host of different carbonyl compounds.1d,9 Few of
9
b
these are the [5+1] condensation of 1,5-diketones with ammonia, the [2+2+1+1] Hantzsch
9c
9d
pyridine synthesis, and the Kröhnke synthesis. Later on, several transition metal-mediated
annulation protocols were explored which have been highlighted by Gulevich et al. in their
review article, and the references cited therein.10a Few of these cascade catalytic strategies
involve oxidative Michael condensation of oximes with α,β-unsaturated carbonyl
compounds.10b-c Others exploit the transition metal-assisted coupling/condensation of diverse
substrates to form the azatriene intermediates, which eventually follow the 6π-
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electrocyclization route affording pyridines.10a,d-f These methods possess several advantages
over the conventional condensation-based strategies, as highly substituted unsymmetrical
pyridines can be prepared from eclectic starting materials with high regioselectivity.
Nevertheless, many of these protocols suffer from disadvantages such as, the requirement of
elevated temperatures and employ expensive metal catalysts. The past couple of decades have
witnessed a surge in the thermal and transition metal-assisted [4+2] hetero Diels-Alder reaction
involving 1-azadienes and alkynes,11a-c though inverse electron demand Diels-Alder strategies
have also been explored.11d-e Earlier, researchers utilized the transition metals to catalyze the
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[
2+2+2] cycloadditions of alkynes and nitriles,11f-h however, later on, they discovered that the
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1i
annulation can also be achieved under metal-free condtions. Similarly, many other strategies
follow greener protocols by employing other readily available catalytic systems in place of
12
metal-based catalysts, or requiring solvent free conditions. Researchers, have also managed
to reap additional benefits by incorporating metal-free reaction conditions to multicomponent
strategies for the synthesis of pyridines as delineated by Allais et al. in their review, and the
1
b
references cited therein. Substituted pyridines synthesis have also been achieved under high
stereo- and regioselectivity via direct CH functionalization of the pyridine nucleus.13
Advancements in synthetic strategies for achieving pyrrole motifs follow similar trends akin to
the case of pyridines. Primeval strategies for the synthesis of pyrroles represent condensation-
based protocols such as the Knorr, Paal–Knorr, and Hantzsch reactions that gained immense
popularity. 14 Subsequently, the late 20 century marked an escalation in the transition metal-
catalysed cyclizations, and multicomponent tandem coupling reactions.15
th
In the last couple of decades, visible light-mediated organic syntheses have gained
immense popularity in the wake of several advantages associated with this regime. Several
organic, as well as transition metal-based photocatalysts, have been developed to harness the
energy of abundant visible light and transform it into chemical energy, thereby enabling the
generation of carbon-centred radicals under mild catalytic conditions, and hence tap the novel
16
reactivity of these intermediates. Unprecedented Pd-catalyzed transformations have been
achieved under visible-light irradiation, although an exogenous photo-catalyst may or may not
1
7
18a
be required. In the case of latter, the Pd-catalyst plays a dual role in several elegant
reactions, for instance, the C -C Heck coupling reaction,18b-e carbonylative cross coupling
sp3
sp2
reactions,18f-g and others.18h-j The successful underpinnings of these strategies can be attributed
to the fact that irradiation of Pd(0) catalyst induces a facile single electron transfer (SET)
oxidative addition of unactivated alkyl halide, and the subsequent photoexcitation of Pd(II)-
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alkyl complex restrains the undesired β-hydride elimination process, which otherwise plagues
the traditional reactions.18b
Recently, our group developed a cascade [4+2] Ru-catalyzed annulation strategy for
accessing fused isoquinolines, wherein, we noticed that one of the cyano groups, associated
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with malononitrile moiety, was selectively hydrolyzed. We envisioned that the five-carbon
core of the γ-ketomalononitrile (including this cyanide moiety) may act as a harbinger of
pyridine nucleus, if cross coupled with a suitable partner via a cascade [5+1] annulation
strategy. Thorough literature survey revealed that recently several protocols have been
developed for the synthesis of 5- and 6- membered nitrogen heterocycles. These studies are an
extension to the catalytic carbopalladation/carbonickelation of eclectic nitrile substrates with
suitable coupling partners such as arylboronic acids and arylhydrazines to obtain ketones and
20
21
imines, followed by intramolecular cyclization to afford diverse N-heterocycles. Few of
these recent works are highlighted in Scheme 1. For instance, in 2017 Wu’s group for the first
time utilized the nitrile N atom via Pd-catalyzed nucleophilic addition of arylboronic acids with
functionalized nitriles followed by an intramolecular cyclization to access biologically active
isoquinolines and isoquinolones [Scheme 1 (i)].21a Chen et al. reported a Ni(II)-catalyzed
cascade coupling of arylboronic acids to ketonitriles into substituted pyrroles and pyridines
[
Scheme 1 (ii)].21c A commonality that can be discerned from the mechanisms is that the initial
step engages arylboronic acids in a traditional two-electron trans-metalation with electron-
deficient Pd(II)-catalysts. The high activation energy barrier associated with this step
2
2
predisposes the necessity of elevated temperatures. Recently, Xu et al. discovered a Mn(III)-
triggered radical pathway involving the cyclization of 3-isocyano-[1,1′-biphenyl]-2-
carbonitriles with arylboronic acids to access pyrrolopyridine derivatives [Scheme 1 (iii)].23
Keeping in mind the natural propensity of Pd-catalyzed reactions to follow a facile SET
mechanistic pathway under visible-light irradiation, and arylboronic acids as readily available
2
4
radical progenitors, we envisaged the synthesis of 2,4,6-triaryl-3-cyanopyridines and 2,5-
diaryl-3-cyanopyrrole derivatives [Scheme 1 (iv)]. In our strategy, the starting materials γ-
ketomalononitriles and -ketomalononitriles were readily prepared via the addition of
malononitrile to various chalcones and -bromoacetophenones. Further, most arylboronic
acids are commercially available. This developed photocatalytic reaction proceeds at room
temperature without the usage of exogenous photosensitizer. The constructed pyridine and
pyrrole moiety having an inbuilt nitrile functionality can be further manipulated for various
applications. Therefore, our protocol bypasses the toxic chemical maneuvers and harsh reaction
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conditions generally associated with the introduction of a nitrile functionality in to aromatic
rings, consequently endows synthetic benefits in the form of functional group transformations
and derivatizations.
Scheme 1. Strategies for the Synthesis of Fused and Isolated Nitrogen-Heterocycles
from Substrates Containing Functionalized or Activated Cyano Groups
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Earlier reports
Cascade reaction with arylboronic acids
HO
OH
ref 21a
Pd(acac)2, bpy
B
N
O
(i)
CN
TsOH·H2O
80 C, 24 h
Synthesis of pyridines and pyrroles
R = COOEt
R = H
N
ref 21c
2
O
Ar B(OH)2
EtOOC
Ar1
Ar2
Ni(dppe)Cl2, ZnCl2
Ar1
n CN
(
ii)
THF, 100 C, 24 h
Ar1
Ar2
R
N
H
Ar1
Ar2
N
H
n = 1 or 2
Radical reaction of arylboronic acids
HO OH
ref 23
B
N
Mn(OAc)3·2H2O
radical addition
CN
(iii)
N
NC
Our approach
R2 = aryl
R2 = H
Ar
R1
R1
ArB(OH)2
Pd(OAc)2 (10 mol %)
,2'-bipyridyl (20 mol %)
CN
N
Ar
O
2
CN
HN
or
CN
PTSA·H2O (2 equiv)
(iv)
CN
n
R2
1,2-DCE (2 mL), rt, 24 h
2
x 10 W White LEDs
Ar
n = 0 or 1
R1
RESULT AND DISCUSSION
We embarked on our experimentation by selecting 2-(3-oxo-1,3-
diphenylpropyl)malononitrile (1) (0.25 mmol) and phenylboronic acid (a) (1 equiv) as the
rudimentary substrates; Pd(OAc) (5 mol %) as the precatalyst, 2,2′-bipyridine (10 mol %) as
2
the ligand, and PTSA·H O (1 equiv) as the additive. Toluene (2 mL) was employed as the
2
solvent, and the reaction mixture was irradiated by 20 W (2 x 10 W) white LEDs at room
temperature. The progress of the reaction was monitored via thin layer chromatography, which
indicated the formation of some new species in the mixture, in the form of a new fluorescent
blue spot in a 365 nm UV chamber. The new compound was isolated, characterized by standard
1
13
spectroscopic techniques (IR, H NMR, C NMR, and HRMS). Delightfully, the analysis
confirmed that the isolated compound was 2,4,6-triphenylnicotinonitrile (1a), and the yield was
estimated to be 33%. Subsequently, single crystal X-ray diffraction studies were performed on
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one of the derivatives (1f), which further validated the structure of the product (see the
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5
Supporting Information, Figure S1). It is imperative to mention that the formation of 2,4,6-
triphenylnicotinonitrile (1a) is associated with the genesis of a new C–C, a C–N, a CN and
two C=C bonds.
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After successfully characterizing the desired product, further screening process was
carried out to find the optimal reaction condition, for which 2-(3-oxo-1,3-
diphenylpropyl)malononitrile (1) (0.25 mmol) was chosen as the model substrate and
phenylboronic acid (a) (1 equiv) as the addition partner. Firstly, different solvents were
screened by replacing toluene (33%) with p-xylene (35%), m-xylene (32%), cyclohexane
(00%), 1,2-DCE (42%), MeOH (00%), CH CN (00%), DMF (00%) DMSO (00%), and H O
3 2
(00%) (Table 1, entries 110). In conclusion, 1,2-DCE (42%), was found to be the most
effective out of the lot (Table 1, entry 5). Next, the catalyst and ligands were screened by
selecting alternatives to Pd(OAc) and 2,2′-bipyridine. Although the replacement of Pd(OAc)
2
2
with Pd(TFA) resulted in a relatively lower yield (38%; Table 1, entry 11), no product was
2
isolated when the former was replaced with PdCl as the catalyst (Table 1, entry 12). Moreover,
2
the reaction completely failed in the absence of either Pd(OAc) , 2,2ꞌ-bipyridine or PTSA·H O
2
2
(Table 1, entries 1315). On the contrary, the yield of the isolated product enhanced to 56%
when the loadings of Pd(OAc) , 2,2ꞌ-bipyridine and PTSA·H O were increased from that of
2
2
the model reaction (Table 1, entry 16). Further increasing the amount of PTSA·H O from 2 to
2
5
1
equiv. did not significantly improve the isolated yield of the product (58%; Table 1, entries
6 and 17). After identifying Pd(OAc) (10 mol%) and 1,2-DCE as the suitable catalyst and
2
solvent, respectively, few ligands such as 1,10-phenanthroline (52%), L-proline (00%), PPh3
trace), XPhos (00%), 1,1ꞌ-bis-2-naphthol (00%) were also screened in lieu of 2,2′-bipyridine
(
(Table 1, entries 1822). Although the use of 1,10-phenanthroline as a ligand was able to
produce the desired product in an appreciable yield (Table 1, entry 18), nevertheless it was
unable to dethrone 2,2′-bipyridine as the favourable ligand, due to the higher yield of product
in case of latter. Further, experiments were carried out by replacing the additive, PTSA·H O
2
with other acids such as acetic acid and trifluoroacetic acid which produced (1a) in low yields
(25% and 23%, respectively) (Table 1, entries 2324). In contrast, the replacement of PTSA
with benzoic acid or sulfuric acid turned out to be futile as almost no significant amount of the
product obtained (Table 1, entries 2526). Further fine-tuning of the reaction was achieved by
increasing the amount of phenylboronic acid progressively from 1 to 5 equivalents. Adding 2
and 3 equivalents of phenylboronic acid resulted in escalated yields of (1a) to 66% and 72%,
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2
2
2
2
2
2
2
2
3
3
3
3
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5
5
5
5
6
respectively. Whereas, no further improvement was observed when 5 equiv. of the same were
used (Table 1, entries 2729). Reaction carried out in the presence of 2 x 5 W green LEDs light
(42%) and 2 x 5 W blue LEDs light (51%) were also quite favorable to the product formation
(Table 1, entries 30 and 31). The overall yield (42%) was decreased when the reaction stops
0
1
2
3
4
5
6
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8
9
0
1
2
3
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7
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9
0
1
2
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4
5
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3
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3
4
5
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8
9
0
after 12 h. (Table 1, entry 32). The reaction carried out in absence of LEDs is detrimental to
product formation and and only 22% of the desired product was obtained (Table 1, entry 33).
o
When the reaction was performed at a higher temperature (80 C) in the absence of light the
yield did not improve significantly. Further, the thermal reaction gave number of other side
products causing difficulties during the separation. As measure the temperature in the vicinity

of the reaction was near to the room temperature (2730 C) as it was performed in a well-
ventilated room below a fan. Here, the white LEDs is accelerating the reaction by reducing
Pd(II) to an active exited state Pd(0) in the presence of bipyridine ligand and enhance the
subsequent formation of aryl palladium species (I) via redox trans-metalation. On the other
hand in the absence of LEDs there might be competitive trans-metalation with Pd(II) species
there by giving only 22% yield of the product at room temperature. After screening of various
reaction parameters, the optimized standard conditions for this transformation were established
to be the use of 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1) (0.25 mmol), phenylboronic
acid (a) (3 equiv), Pd(OAc) (10 mol %), 2,2′-bipyridine (20 mol %) and PTSA·H O (2 equiv)
2
2
in 1,2-DCE (2 mL) as the solvent under irradiation by 20 W (2 x 10 W) white LEDs at room
temperature (Table 1, entry 28).
Table 1. Optimization of the Reaction Conditionsa-i
HO
OH
Catalyst, Ligand
Additive, Solvent
NC
CN
B
CN
O
N
2 x 10 W White LEDs
rt, 24 h
(1)
(a)
(1a)
yield (%)b
entry
catalyst (mol %)
ligand (mol %)
additive (equiv)
solvent
1
2
3
4
5
6
7
8
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
(5)
(5)
(10)
(5)
(5)
(5)
(5)
(5)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
2
2
2
2
2
2
2
2
O (1)
O (1)
O (1)
O (1)
O (1)
O (1)
O (1)
O (1)
toluene
33
35
32
00
42
00
00
00
p-xylene
m-xylene
cyclohexane
1,2-DCE
MeOH
CH
3
CN
DMF
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1
Pd(OAc)
Pd(OAc)
Pd(TFA)
2
2
2
(5)
(5)
(5)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (10)
---
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
---
2
2
2
2
2
2
O (1)
O (1)
O (1)
O (1)
O (1)
O (1)
DMSO
00
0
H
2
O
00
11
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
38
1
2
PdCl
---
2
(5)
00
13
00
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
1
1
1
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
(5)
00
(5)
2,2ꞌ-bipyridyl (10)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
1,10-phen (20)
L-proline (20)
00
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
(10)
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
2
2
2
2
2
2
2
O (2)
O (5)
O (2)
O (2)
O (2)
O (2)
O (2)
56
58
52
00
20
PPh
3
(20)
trace
00
2
1
XPhos (20)
22
1,1ꞌ-bi-2-naphthol (20) PTSA·H
00
2
2
2
2
3
4
5
6
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
2,2ꞌ-bipyridyl (20)
AcOH (2)
CF COOH (2)
PhCO
SO
PTSA·H
PTSA·H
25
3
23
2
H
trace
00
H
2
4
27
2
O (2)
66c
72d
73e
42f
2
8
Pd(OAc)
2
2
O (2)
O (2)
O (2)
O (2)
O (2)
O (2)
29
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
2
3
3
3
3
0
1
2
3
2
2
2
2
2
51g
2
2
2
42h
22i
aReaction condition: 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1) (0.25 mmol), phenylboronic acid (a) (0.25 mmol),
b
c
catalyst (mol %), ligand (mol %.), additive (equiv) at rt under 2 x 10 W white LEDs for 24 h. Isolated yields. 2 equiv
d
e
f
of (a) was used. 3 equiv of (a) was used. 5 equiv of (a) was used. Reaction performed using 2 x 5 W green LEDs
g
h
i
light. Reaction performed using 2 x 5 W blue LEDs light. Yield after 12 h. in the absence of LEDs.
With the optimized reaction conditions in hand, this photoreaction was subjected to further
studies for the elucidation of substrate scope. Firstly, various γ-keto-malononitriles bearing
electron-donating (EDGs) and electron-withdrawing groups (EWGs) were taken alongside
phenylboronic acid (a) in a series of different reactions to generate the corresponding
triarylsubstituted cyanopyridines (Scheme 2). The unsubstituted -keto-malononitrile (1)
coupled with phenylboronic acid (a), to yield 3-cyano-2,4,6-triphenylpyridine in (1a) in 72%
yield (Scheme 2). Next, a series of -keto-malononitriles containing unsubstituted benzoyl ring
alongside electron-rich phenyl ring bearing EDGs such as p-Me (2), p-OMe (3), p-OBu (4), p-
SMe (5), p-NMe (6), and p-Ph (7) were chosen to couple with the phenylboronic acid (a). The
2
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
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5
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5
5
5
5
5
6
corresponding products (2a, 74%), (3a, 72%), (4a, 73%), (5a, 61%), (6a, 68%), and (7a, 70%)
were obtained in good yields (Scheme 2). Moreover, when the phenyl ring bore EWGs such as
p-F (8), p-Cl (9), o-Br (10), and m-NO (11), the corresponding products (8a, 70%), (9a, 68%),
2
(10a, 65%), and (11a, 45%) were obtained in moderate to good yields (Scheme 2). Next, the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
effect of substitution on benzoyl ring was studied by choosing suitable -keto-malononitrile
substrates bearing an unsubstituted phenyl ring, and subjecting them to the optimized reaction
condition. Both the scenarios wherein the benzoyl ring possessed EDGs such as, p-Me (12)
and p-OMe (13), and EWGs such as, p-F (14), p-Cl (15), p-Br (16), p-NO (17), and o-NO
2
2
(18), resulted in the desired products (12a, 72%), (13a, 71%), (14a, 69%), (15a, 66%), (16a,
64%), (17a, 45%), and (18a, 42%) respectively (Scheme 2). It is interesting to note that akin
to the previous set of experiments, the presence of an electron-deficient benzoyl ring abated
the product formation. -Keto-malononitriles bearing the naphthyl moiety, (19) and (20), when
chosen as substrates for the developed protocol, responded well to afford the respective
products 3-cyano-4-(α-naphthyl)-2,6-diphenylpyridine (19a) and 3-cyano-4-(α-naphthyl)-6-
(β-naphthyl)-2-phenylpyridine (20a) with 72% and 70% yields, respectively (Scheme 2). The
protocol was also tested with -keto-malononitrile substrates bearing both substituted
benzoyl/phenyl moieties simultaneously with groups such as EDG p-Me/EWG p-Cl (21), EWG
p-Cl/EDG p-OMe (22), EWG p-Cl/EDG p-OH (23), and EWG p-NO /EDG p-OMe (24). All
2
of these substrates coupled well with phenylboronic acid (a) to yield the respective substituted
cyanopyridines (21a, 69%), (22a, 75%), (23a, 41%) and (24a, 46%), respectively. Further,
substrates containing some di-substituted phenyl rings such as 2,6-dichlorophenyl (25), and the
3,4-dimethoxyphenyl (26), reacted efficiently to give the products (25a, 64%) and (26a, 68%),
respectively, in good yields. The Michael adduct bearing 3,4-methylenedioxobenzoyl ring and
p-bromophenyl ring (27) reacted under the standard conditions to afford the desired pyridine
(27a, 63%). Besides, the cyclic -keto substrate (28) underwent efficient transformation to the
product (28a) in 61% yield. Furthermore, Michael adducts bearing other aryl rings such as,
furan (29) or a thiophene (30), were also compatible with the protocol and afforded the products
(29a, 65%) and (30a, 68%), respectively, in good yields. To determine the efficiency of this
photoinduced process and also to expand the scope of this method, 2-(3-oxo-1,3-
diphenylpropyl)malononitrile (1) (1.37 gm, 5 mmol), and phenylboronic acid (a) were reacted
on a gram scale which provided 2,4,6-triphenylsubstituted nicotinonitrile (1a) in 60% yield
(Scheme 2).
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Scheme 2. Substrate Scope for the Synthesis of 2,4,6-Triarylsubstituted Nicotinonitrile a,b
R1
Pd(OAc)2 (10 mol %)
R1
O
HO
OH
2,2'-bipyridyl (20 mol %)
PTSA·H2O (2 equiv)
N
CN
CN
R2
B
CN
2
x 10 W White LEDs
1
,2-DCE (2 mL), rt, 24 h
R2
(
130)
(a)
(1a30a)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R1 = H, R2 = p-Me (2a, 74%)
R2 = H, R1 = p-Me (12a, 72%)
= p-OMe (13a, 71%)
=
=
=
=
p-OMe (3a, 72%)
p-OBu (4a, 73%)
p-SMe (5a, 61%)
p-NMe2 (6a, 68%)
R1
R1
N
Ph
= p-F (14a, 69%)
= p-Cl (15a, 66%)
= p-Br (16a, 64%)
= p-NO2 (17a, 45%)
= o-NO2 (18a, 42%)
N
Ph
CN
CN
= p-Ph (7a, 70%)
= p-F (8a, 70%)
R2
R2
=
p-Cl (9a, 68%)
1a, 72%) (60 %)b
(
= o-Br (10a,65%)
= m-NO2 (11a, 45%)
Me
Cl
N
Ph
N
Ph
N
Ph
CN
N
Ph
CN
CN
CN
(19a, 72%)
(20a, 70%)
(21a, 69%)
(22a, 75%)
Cl
OMe
N
Cl
O2N
F
N
Ph
N
Ph
N
Ph
Ph
CN
CN
CN
Cl
CN
Cl
OMe
(
23a, 41%)
(24a, 46%) OMe
(25a, 64%)
(26a, 68%) OMe
OH
N
O
O
Ph
N
Ph
CN
N
Ph
CN
N
S
Ph
O
CN
CN
O
S
(
27a, 63%) Br
(28a, 61%)
(29a, 65%)
(30a, 68%)
Cl
aReaction conditions: (i) 130 (0.25 mmol), phenylboronic acid (a) (0.75 mmol), Pd(OAc)
(0.025 mmol), 2,2ꞌ-bipyridyl (0.05
2
b
mmol), PTSA·H
2
O (0.5 mmol), and 1,2-DCE (2 mL) at rt for 24 h. under 2 x 10 W white LEDs. Yield reported for 1 gm
scale.
After successfully employing diverse -ketomalononitriles (1-30) to the developed
strategy, the scope was further enhanced by reacting various arylboronic acids with 2-(3-oxo-
1
,3-diphenylpropyl)malononitrile (1) under standard conditions (Scheme 3). The reaction was
successful with 2-napthylboronic acid (b), which had produced 2-(naphthalen-2-yl)-4,6-
diphenylnicotinonitrile (1b) in 66% yield. Arylboronic acids possessing electron-donating
t
groups such as p-Me (c), o-Me (d), p-Et (e), p- Bu (f), p-OMe (g) and 3-Me-4-OMe (h) also
responded positively towards the protocol, and afforded the desired cyanopyridines (1c, 73%),
(1d, 43%), (1e, 75%), (1f, 77%), (1g, 79%), and (1h, 68%), respectively, in good yields.
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1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Arylboronic acids possessing electron-withdrawing groups such as p-F (i), p-Cl (j), m-Cl (k),
p-Br (l) and p-CF (m), also underwent efficient addition/cyclization with the -
3
ketomalononitrile (1) to afford the desired cyanopyridines (1i, 62%), (1j, 55%), (1k, 51%), (1l,
5
2%), and (1m, 35%), respectively, albeit the yields were moderate to good in these cases.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Unfortunately, the developed protocol turned out to be unsuccessful in case of few boronic
acids such as p-CHO-phenylboronic acid (n), cyclohexylboronic acid (o), 2-thienylboronicacid
(p), and allylboronic acid (q).
Scheme 3. Substrate Scope for Arylboronic Acidsa
Pd(OAc)2 (10 mol %)
R3
HO
OH
R3
2,2'-bipyridyl (20 mol %)
B
NC
CN
Ph
PTSA·H O (2 equiv)
2
O
CN
Ph
2
x 10 W White LEDs
N
Ph
1,2-DCE (2 mL), rt, 24 h
Ph
(
1)
(bq)
(1b1q)
tBu
Me
Et
OMe
Me
CN
N
CN
CN
Ph
CN
Ph
CN
Ph
CN
Ph
N
N
N
N
N
Ph
Ph
(1d, 43%)
Ph
Ph
Ph
Cl
Ph
(1e, 75%)
Ph
Ph
(
1b, 66%)
(1c, 73%)
(1f, 77%)
(1g, 79%)
OMe
F
Cl
Br
CF3
Me
Ph
CN
Ph
CN
CN
Ph
CN
Ph
CN
Ph
CN
Ph
N
N
N
N
N
N
Ph
Ph Ph
Ph
Ph
Ph
(1m, 35%)
(
1h, 68%)
(1i, 62%)
(1j, 55%)
(1k, 51%)
(1l, 52%)
unsuccessful substrates
CHO
S
N
CN
CN
Ph
CN
Ph
CN
Ph
N
N
N
Ph
Ph
Ph
Ph
Ph
(
1n, 00%)
(1o, 00%)
(1p, 00%)
(1q, 00%)
aReaction conditions: (i) 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1) (0.25 mmol), arylboronic acids (b-q) (0.75 mmol),
Pd(OAc) (0.025 mmol), 2,2ꞌ-bipyridyl (0.05 mmol), PTSA·H O (0.5 mmol), and 1,2-DCE (2 mL) at rt for 24 h. under 2 x 10
W white LEDs.
2
2
We speculate that the electron withdrawing substituents present in arylboronic acids
may potentially impede the trans-metalation and the carbopalladation/migration of aryl group
to the electrophilic carbon center of the nitrile moiety (Scheme 7). Perhaps, this might be the
reason for the lower yields with electron withdrawing substituents. For an electron-deficient
aryl moiety, p-CHO-phenylboronic acid (n), the carbopalladation does not occur efficiently
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due to the poor migrating ability of such aryl moieties to electrophilic centres. The failure of
3
boronic acids having a sp -C–B bond viz. cyclohexylboronic acid (o) and allylboronic acid (q)
hints towards a putative two electron carbanion based-mechanism, wherein β-hydride
16f
elimination reaction may be occurring. For thiophene based boronic acid, the adjacent S atom
may be depleting the electronic charge, built up at the C2-position by accepting electrons into
its vacant d-orbitals, leading to an inefficient carbopalladation. Moreover, strongly
coordinating sulfur atom in the thiophene ring is known to poison Pd(II) catalysts.
1
1
1
1
1
1
1
1
1
1
2
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2
2
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The synthetic utility of this photoreaction was further extended by investigating the
addition/cyclization of phenylboronic acids to few -ketomalononitriles under the optimized
reaction conditions to yield the substituted pyrroles (Scheme 4). To our delight, the reaction of
phenylboronic acid (a) with unsubstituted -ketomalononitrile, 2-(2-oxo-2-
phenylethyl)malononitrile (31) produced the five membered N-heterocycle, 2,5-diphenyl-1H-
pyrrole-3-carbonitrile (31a) in 73% yield under the standard conditions. The formation of
1
13
pyrrole skeleton was confirmed by the H NMR, C NMR and HRMS analysis. Later, -
ketomalononitriles bearing EDGs such as, p-Me (32) and p-OMe (33), and EWGs such as, p-
Cl (34), p-Br (35), and p-NO (36) were selected alongside the phenylboronic acid (a) to
2
participate in our reaction strategy. Fortunately, the desired 2,5-diaryl-3-cyanopyrrol products–
(32a, 76%), (33a, 78%), (34a, 71%), (35a, 67%), and (36a, 55%) were obtained in good to
moderate yields.
A
bicyclic substrate, 2-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-
yl)malononitrile (37) and a -ketomalononitrile containing thiophene moiety (38), also coupled
successfully with phenylboronic acid (a), and subsequently cyclized to afford the
corresponding pyrrole derivatives (37a, 71%) and (38a, 69%) in good yields. Naphthalen-2-
ylboronic acid (b) reacted with 2-(2-oxo-2-phenylethyl)malononitrile (31) to yield 2-(β-
naphthyl)-5-phenyl-1H-pyrrole-3-carbonitrile (31b) in 74% yield. Additionally, a host of
t
phenylboronic acids possessing EDGs such as, o-Me (d), p-Et (e), p- Bu (f), and p-OMe (g),
and EWGs such as, p-F (i), p-Cl (j), and p-Br (l) were reacted with 2-(2-oxo-2-
phenylethyl)malononitrile (31) under standard conditions to afford the corresponding pyrroles–
(31d, 54%), (31e, 78%), (31f, 75%), (31g, 80%), (31i, 60%), (31j, 55%), and (31l, 52%) in
moderate to good yields.
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6
Scheme 4. Substrate Scope for 2,5-Diarylsubstituted-3-cyano Pyrrolesa,b
Pd(OAc)2 (10 mol %)
R3
HO
OH
2
,2'-bipyridyl (20 mol %)
B
O
CN
HN
PTSA·H2O (2 equiv)
CN
CN
R3
2 x 10 W White LEDs
,2-DCE (2 mL), rt, 24 h
1
(
3138)
(a-l)
(31a38a)(31b31l)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
2
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
HN
HN
HN
CN
HN
HN
CN
CN
MeO
CN
Br
CN
Me
Cl
(31a, 73%) (65%)b
(32a, 76%)
(33a, 78%)
(34a, 71%)
(35a, 67%)
Me
HN
HN
HN
HN
HN
S
CN
CN
CN
CN
CN
O2N
(36a, 55%)
(37a, 71%)
(38a, 69%)
(31b, 74%)
(31d, 54%)
tBu
Et
OMe
F
Cl
Br
HN
HN
HN
HN
HN
HN
CN
CN
CN
CN
CN
CN
(
31e, 78%)
(31f, 75%)
(31g, 80%)
(31i, 60%)
(31j, 55%)
(31l, 52%)
aReaction conditions: (i) 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1) (0.25 mmol), arylboronic acids (b-q) (0.75 mmol),
Pd(OAc) (0.025 mmol), 2,2ꞌ-bipyridyl (0.05 mmol),PTSA·H O (0.5 mmol), and 1,2-DCE (2 mL) at rt for 24 h. under 2 x 10
W white LEDs. . Yield reported for mmol scale.
2
2
b
Intermolecular competition reactions were performed in order to study the electronic
influence of the substituents present on the aroyl/aryl moieties of -ketomalononitriles and
arylboronic acids. In our first experiment, an equimolar mixture of substrates (13) and (14),
composed of aroyl groups possessing an EDG, p-OMe and an EWG, p-F, respectively, were
reacted with phenylboronic acid (a) [Scheme 5 (i)]. The yields of the corresponding products
(13a, 25%) and (14a, 23%) were similar, which indicate that substrates possessing EDGs and
1
EWGs in the aroyl moiety (R ) show similar reactivity in our protocol. In the second
experiment, two -ketomalononitrile substrates wherein the aryl moiety contains either an EDG
p-OMe (3), or an EWG p-Cl (9) were chosen to react with the phenylboronic acid (a) under
standard conditions. It was again observed that the electronic nature of the substituent R2
present on the phenyl moiety had minimal effect on the outcome of reaction, as evident from
the almost equal yields of products (3a, 21%) and (9a, 20%), respectively [Scheme 5 (ii)].
3
Finally, the effect of the electronic nature of substituents (R ) present on the phenyl ring of the
boronic acids were investigated. An equimolar mixture of electron-rich p-
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methoxyphenylboronic acid (g), and a relatively electron-deficient p-fluorophenylboronic acid
(i) was reacted with (1) to afford the respective cyanopyridines (1g, 29%) and (1i, 20%). This
suggests that presence of an EDG on the phenyl ring of arylboronic acid renders higher
compatibility with the protocol [Scheme 5 (iii)].
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
3
3
3
4
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4
4
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4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Intermolecular Competition Experiments
F
MeO
F
MeO
O
O
N
Ph
N
Ph
CN
CN
CN
CN
PhB(OH)2
(a) (0.25 mmol)
CN
CN (i)
Standard Conditions
(13) (0.5 mmol)
(14)(0.5 mmol)
(13a, 25%)
(
14a, 23%)
O
N
Ph
N
Ph
O
CN
CN
PhB(OH)2
(
a) (0.25 mmol)
CN (ii)
CN
CN
CN
Standard Conditions
OMe
Cl
OMe
Cl
(
3) (0.5 mmol)
(9) (0.5 mmol)
(3a, 21%)
(9a, 20%)
OMe
F
HO
OH HO
OH
NC
CN
B
B
O
Standard Conditions
CN
CN
(iii)
N
N
OMe(g)
F (i)
(1)
(0.25 mmol)
(0.5 mmol) (0.5 mmol)
(1g, 29 %)
(1i, 20%)
Mechanistic Pathway
To understand the mechanistic underpinnings of the photoreaction, few control
experiments were performed as highlighted by Scheme 6. Our initial experiment was
performed under normal laboratory conditions at room temperature. It was observed that the
reaction proceeded slowly, and only 22% yield of the desired product was obtained after 24 h
[Scheme 6 (i)]. In the next experiment, the reaction flask was wrapped carefully with an
aluminium foil, and the reaction was carried out in complete dark conditions. This time, even
less than 16% of the product was isolated [Scheme 6 (ii)]. Hence, it can be concluded that light
does accelerate the desired reaction. Later, a radical scavenger 2,2,6,6-tetramethylpiperidine-
1
-oxyl (TEMPO) was added to the reaction mixture in varying quantities. Although the use of
2 equiv TEMPO resulted in poor yield (<20%), when 4 equiv TEMPO was added to the
reaction mixture, no desired product was obtained [Scheme 6 (iii)]. These results indicate that
a radical pathway may be operative. However, no TEMPO adducts were detected while
performing the HRMS analysis of the reaction mixture. Moreover, the alkylboronic acids such
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5
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as cyclohexylboronic acid (o) and allylboronic acid (q) did not yield the desired products 1o
and 1q when subjected to standard conditions (Scheme 3).16f Surprisingly, these observations
refute the existence of a radical pathway. According to the literature reports, there is a
possibility that TEMPO may oxidize Pd(0) to Pd(II), thereby inhibiting the reaction in the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
forward direction.26
Scheme 6. Control Experiments
Pd(OAc)2 (10 mol %)
O
HO
OH
2
,2'-bipyridyl (20 mol %)
PTSA·H2O (2 equiv)
N
CN
CN
B
CN
(i)
1,2-DCE (2 mL), rt, 24 h
absense of LEDs
(
1)
(a)
(1a, 22%)
Pd(OAc)2 (10 mol %)
O
HO
OH
2,2'-bipyridyl (20 mol %)
N
CN
CN
B
PTSA·H2O (2 equiv)
CN
(ii)
1,2-DCE (2 mL), rt, 24 h
dark condition
(
1)
(a)
(1a, 16%)
Pd(OAc)2 (10 mol %)
O
HO
OH
2,2'-bipyridyl (20 mol %)
N
CN
B
PTSA·H2O (2 equiv)
CN
CN
(iii)
1,2-DCE (2 mL), rt, 24 h
(1)
(a)
TEMPO (4 equiv): (1a, 00%)
TEMPO (2 equiv): (1a, <20%)
Based on these facts, the likelihood of conventional SET mechanism involving organic
radicals due to visible light irradiation is not obvious in our case, and a plausible reaction
mechanism is outlined in Scheme 7. Initially, Pd(OAc) combines with 2,2′-bipyridyl ligand
2
(L) to form a complex Pd(II)(bpy)(OAc) (detected by HRMS analysis of reaction mixture,
2
Figure S2). The protocol requires 3 equivalents of arylboronic acid with respect to the reacting
substrate. The requirement of excess boronic acid can be rationalized by the in situ generation
of Pd(0) by the reduction of Pd(II)(bpy)(OAc) , which is also accelerated under visible
2
2
7
irradiation. Another 2,2′-bipyridine ligand (L) combines with the in situ generated Pd(0)
species, which subsequently undergoes photoexcitation via MLCT to form an excited
palladium complex, [L Pd(0)*] (detected by HRMS analysis of reaction mixture, Figure S3).
2
Although the next step, that is, transmetalation is not fully understood, we speculate that a
redox reaction may be occurring, wherein the excited palladium complex, [L Pd(0)*] reduces
2
2
8
the phenylboronic acid (a). Concomitantly, transfer of aryl group (of boronic acid), and an
elimination of 2,2′-bipyridine ligand (L) occurs to give the intermediate (I) (detected by HRMS
analysis of reaction mixture, Figure S2). The redox step may involve the M→Z σ-interaction
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29
between the palladium centre and the boron centre of boronic acid. The Pd(II) centre of
intermediate (I) then cordinates with the γ-ketomalononitrile substrate (1) to give the
intermediate (II) (detected by HRMS analysis of reaction mixture, Figure S4). Next,
intramolecular carbopalladation of nitrile occurs via the insertion of the phenyl group to the
nitrile moiety followed by insertion of an acetate anion to the palladium centre which results
in the corresponding ketimine complex (III) (detected by HRMS analysis of reaction mixture,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure S5). Later, PTSA∙H O protonates this intermediate to release 2-(imino(phenyl)methyl)-
2
5
-oxo-3,5-diphenylpentanenitrile (IV) and coordination of PTSA to the Pd(II) centre forms the
intermediate (VIII) (detected by HRMS analysis of reaction mixture, Figure S6). The intial
Pd(II) species is regenerated via the intermidecy of (IX) (detected by HRMS analysis of
reaction mixture, Figure S7) and continues the catalytic cycle. Finally, PTSA∙H O triggers the
2
intramolecular cyclization of IV, which is followed by dehydration to form the intermediate
VII (detected by HRMS analysis of reaction mixture, Figure S8 and Figure S9). Finally,
aromatization of the intermediate VII affords the desired product, 3-cyano-2,4,6-
triphenylpyridine (1a).
Pd(II)(OAc)2
2
,2'-bypyridine (L)
PTSA
2
PhB(OH)2 (a), L
N
(II)
Pd
N
N (II) N
Pd
2 H2O 2 B(OH)3,
2 HOAc, Ph-Ph
O
Me
h
AcO
OAc
S
AcO
O
[
L2Pd(0)]*
O
H
(IX)
PhB(OH)2 (a)
AcO
AcOH
PTSA-
CN
h
HB(OH)2
PTSA
ligand exchange
AcOH
L
-
Ph
redox transmetalation
+ OAc
Ph
N
H
CN
LPd(II)Ph
(I)
+
HO
Ph
OH2
Ph
N
Ph
VI)
N (II) N
N
Ph
Ph
O
(
O
Me
(V)
Pd
AcO
S
O
O
N
O
N
CN
Ph (1)
Ph
(VIII)
O
(II)
Pd
Ph
NC
Ph
H2O
NH
Ph
(IV)
protonolysis
N (II) N
Pd
N
Ph
n
Ph
CN
Ph
Ph
OAc
N
CN
Ph
PTSA
CN
II)
NC
Ph
N
O
Ph
Ph
Ph
(
Aromatizatio
-
(
VII)
Ph
N
OAc
Ph
carbopalladation/
migration
(III)
(
1a)
Scheme 7. Proposed Mechanistic Pathway
CONCLUSION
In summary, we have devised an elegant strategy for the synthesis of 2,4,6-
triarylnicotinonitriles and 2,5-diaryl-1H-pyrrole-3-carbonitriles at ambient temperature via a
Pd-catalyzed reaction of arylboronic acid with - and -ketodinitriles under visible-light
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irradiation. The present one-pot synthetic protocol obviates the necessity of an external
photosensitizer, and provides a convenient access to the desired products in moderate to good
yields under mild reaction conditions. The desired products possess nitrile moiety which can
be later functionalized to generate useful molecules for diverse applications.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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0
EXPERIMENTAL SECTION
General information:
All the reagents were commercial grade and purified according to the established
procedures. All the reactions were carried out in oven-dried glassware under a degassed
atmosphere. Highest commercial quality reagents were purchased and were used without
further purification unless otherwise stated. Reactions were monitored by thin layer
chromatography (TLC) on a 0.25 mm silica gel plates (60F ) visualized under UV
2
54
illumination at 254 nm. Organic extracts were dried over anhydrous sodium sulfate (Na SO ).
2
4
Solvents were removed using a rotary evaporator under reduced pressure. Column
chromatography was performed to purify the crude product on silica gel 60120 mesh using a
mixture of hexane and ethyl acetate as eluent. All the isolated compounds were characterized
1
13
1
by H, C{ H} NMR and IR spectroscopic (HRMS-spectrometric) techniques. NMR spectra
for all the samples were recorded in deuterochloroform (CDCl ) or deuterated dimethyl
3
1
13
1
sulfoxide (DMSO-d6). H, C{ H} were recorded in 600 (150) or 400 (100) MHz spectrometer
1
and were calibrated using tetramethylsilane or residual undeuterated solvent for H NMR,
1
3
deuterochloroform for C NMR as an internal reference {Si(CH ) : 0.00 ppm or CHCl : 7.260
3
4
3
1
13
1
ppm for H NMR, 77.230 ppm for C NMR or (CH ) SO: 2.50 ppm for H NMR, 39.50 ppm
3
2
1
3
19
for C NMR}. F NMR was calibrated using hexafluorobenzene as internal standard. The
1
chemical shifts are quoted in δ units, parts per million (ppm). H NMR data is represented as
follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentat,
m = multiplet, br = broad, dd = doublet of doublet, tt = triplet of triplet), integration and
coupling constant(s) J in hertz (Hz). High resolution mass spectra (HRMS) were recorded on
a mass spectrometer using electrospray ionization-time of flight (ESI-TOF) reflection
experiments. FT-IR spectra were recorded in KBr or neat and reported in frequency of

1
absorption (cm ).
General Procedure for the Synthesis of 2-(3-Oxo-1,3-diarylpropyl)malononitriles (130).
Compounds (130) were synthesized by slightly modification of the literature
procedure.30
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To an oven-dried 50 mL round bottom flask was added chalcone, 1,3-diphenyl-2-propen-
1-one (1.04 g, 5.0 mmol.), malononitrile (0.66 g, 10.0 mmol), K CO (1.38 g, 10.0 mmol) and
2
3
DCE (10 mL). The reaction mixture was stirred at room temperature for 12 h. Then the reaction
mixture was admixed with ethyl acetate (50 mL) and the organic layer was washed with water
1
1
1
1
1
1
1
1
1
1
2
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2
2
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2
2
2
2
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2
3
4
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2
3
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6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2 x 10 mL). The organic layer was dried over anhydrous Na SO , and solvent was evaporated
2 4
under reduced pressure. The crude product so obtained was purified over a column of silica gel
hexane / ethyl acetate, 9:1) to give pure 2-(3-oxo-1,3-diaryllpropyl)malononitriles (1) (1.30 g,
5%).
(
9
General Procedure for the Synthesis of 2-(2-oxo-2-arylylethyl)malononitriles (3138).
Compounds (3138) were synthesized by slightly modification of the literature
procedures.31a,b
To an oven-dried 100 mL round bottom flask was added -bromoacetophenone (1.97 g,
1
0.0 mmol) and malononitrile (0.66 g, 10.0 mmol) were dissolved in EtOH (20 mL) and cooled
in an ice bath. On the other hand, NaOH (0.4 g, 10.0 mmol) was dissolved in H O (20 mL),
2
cooled in an ice bath and added to the above reaction mixture over a period of 5 min. After
o
letting the reaction mixture stir for 30 min at 0 C, H O (20 mL) was added from which
2
colorless residue appeared which was filtered off and dried under a constant stream of air.
Recrystallization from EtOH to give 2-(2-oxo-2-arylylethyl)malononitriles (31) as a white
solid (1.39 g, yield 76%).
General Procedure for the Synthesis of 2,4,6-Triarylnicotinonitriles (1a30a) from 2-(3-
Oxo-1,3-diarylpropyl)malononitriles (130) and Phenylboronic acid (a).
To an oven-dried 10 mL round bottom flask was added 2-(3-oxo-1,3-
diphenylpropyl)malononitrile (1) (68.5 mg, 0.25 mmol), phenylboronic acid (a) (90.6 mg, 0.75
mmol), Pd(OAc) (5.6 mg, 0.025 mmol), 2,2′-bipyridyl (7.8 mg, 0.05 mmol), PTSA·H O (95
2
2
mg, 0.5 mmol) and 1,2-DCE (2 mL). The reaction mixture was stirred at room temperature for
2
4
4 h, maintaining an approximate distance of ~6-8 cm from two 10W white LED bulbs (Flux
6 mw/cm2). After completion of the reaction (monitored by TLC analysis), the reaction
mixture was admixed with ethyl acetate (25 mL) and the organic layer was washed with
saturated sodium bicarbonate solution (1 x 5 mL). The organic layer was dried over anhydrous
Na SO , and solvent was evaporated under reduced pressure. The crude product so obtained
2
4
was purified over a column of silica gel using 2% ethyl acetate in hexane to give pure 2,4,6-
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triarylnicotinonitrile (1a) (60 mg, yield 72%). The identity and purity of the product was
confirmed by spectroscopic analysis.
General Procedure for the Synthesis of 2,5-diaryl-1H-pyrrole-3-carbonitriles (31a38a)
from 2-(2-oxo-2-arylethyl)malononitriles (3138) and Phenylboronic acid (a)
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To an oven-dried 10 mL round bottom flask was added 2-(2-oxo-2-
phenylethyl)malononitrile (31) (46 mg, 0.25 mmol), phenylboronic acid (a) (90.6 mg, 0.75
mmol), Pd(OAc) (5.6 mg, 0.025 mmol), 2,2′-bipyridyl (7.8 mg, 0.05 mmol), PTSA·H O (95
2
2
mg, 0.5 mmol) and 1,2-DCE (2 mL). The reaction mixture was stirred at room temperature for
2
4
4 h, maintaining an approximate distance of ~6-8 cm from two 10W white LED bulbs (Flux
2
6 mw/cm ). After completion of the reaction (monitored by TLC analysis), the reaction
mixture was admixed with ethyl acetate (25 mL) and the organic layer was washed with
saturated sodium bicarbonate solution (1 x 5 mL). The organic layer was dried over anhydrous
Na SO and solvent was evaporated under reduced pressure. The crude product so obtained
2
4
was purified over a column of silica gel using 5% ethyl acetate in hexane to give pure 2,5-
diaryl-1H-pyrrole-3-carbonitriles (31a) (45 mg, yield 73%). The identity and purity of the
product was confirmed by spectroscopic analysis.
Spectral Data
2
,4,6-Triphenylnicotinonitrile (1a):32
As a white solid (60 mg, 72% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.19 (d, 2H,
N
3,
J = 7.6 Hz), 8.06 (d, 2H, J = 7.8 Hz), 7.83 (s, 1H), 7.70 (d, 2H, J = 7.6
CN
1
3
1
Hz), 7.607.55 (m, 6H), 7.537.48 (m, 3H); C{ H} NMR (CDCl , 100
3
MHz): δ 162.6, 159.3, 155.6, 138.2, 137.7, 136.9, 130.7, 130.2, 130.1,
1
1
29.6, 129.17, 129.16, 128.9, 128.7, 127.8, 118.8, 117.9, 104.5; IR (KBr, cm ): 2924, 2858,
2215, 1727, 1571, 1530, 1488, 1372, 1276, 1171, 1073, 1025, 873, 748, 688, 616, 568, 485;
+
HRMS (ESI/Q-TOF) (m/z) calcd for C H N [M + H] 333.1386; found 333.1391.
24 17
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,6-Diphenyl-4-(p-tolyl)nicotinonitrile (2a):
As a white solid (64 mg, 74% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.19 (d, 2H,
3,
N
J = 7.8 Hz), 8.07 (d, 2H, J = 7.8 Hz), 7.82 (s, 1H), 7.627.52 (m, 8H),
CN
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
7
.39 (d, 2H, J = 8.0 Hz), 2.48 (s, 3H); C{ H} NMR (CDCl , 100
3
MHz): δ 162.5, 159.2, 155.6, 140.3, 138.2, 137.8, 134.0, 130.6, 130.2,
29.9, 129.6, 129.1, 128.8, 128.6, 127.7, 118.7, 118.1, 104.4,
Me
1

1
2
1.6; IR (KBr, cm ): 2925, 2862, 2214, 1578, 1511, 1377, 1290, 1247, 1170, 1072, 1024, 971,
+
8
75, 828, 762, 693, 609, 572, 520; HRMS (ESI/Q-TOF) (m/z) calcd for C H N [M + H]
2
5
19
2
347.1543; found 347.1558.
4
-(4-Methoxyphenyl)-2,6-diphenylnicotinonitrile (3a):32,33
As a white solid (65 mg, 72% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.18 (d, 2H,
N
3,
J = 7.8 Hz), 8.05 (d, 2H, J = 6.6 Hz), 7.80 (s, 1H), 7.67 (d, 2H, J = 8.4
CN
1
3
1
Hz), 7.597.49 (m, 6H), 7.09 (d, 2H, J = 8.8 Hz), 3.90 (s, 3H); C{ H}
NMR (CDCl , 100 MHz): δ 162.7, 161.2, 159.2, 155.2, 138.3, 137.8,
3
OMe
1
30.6, 130.4, 130.2, 129.2, 129.1, 128.6, 127.7, 118.6, 118.3, 114.6,

1
114.3, 104.3, 55.6; IR (KBr, cm ): 2924, 2861, 2218, 1669, 1582, 1514, 1459, 1373, 1253,
+
1
3
4
175, 1027, 819, 758, 690, 563; HRMS (ESI/Q-TOF) (m/z) calcd for C H N O [M + H]
25 19 2
63.1492; found 363.1497.
-(4-Butoxyphenyl)-2,6-diphenylnicotinonitrile (4a):
As a white solid (73 mg, 73% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.18 (d, 2H,
3,
N
J = 7.8 Hz), 8.05 (d, 2H, J = 7.6 Hz), 7.80 (s, 1H), 7.66 (d, 2H, J = 8.8
Hz), 7.597.49 (m, 6H), 7.08 (d, 2H, J = 8.4 Hz), 4.06 (t, 2H, J = 6.4
Hz), 1.871.80 (m, 2H), 1.591.50 (m, 2H), 1.02 (t, 3H, J = 7.4 Hz);
CN
OBu
1
3
1
C{ H} NMR (CDCl , 100 MHz): 162.7, 160.8, 159.2, 155.3, 138.3,
3
1
3
1
37.9, 130.6, 130.3, 130.2, 129.6, 129.1, 128.9, 128.6, 127.7, 118.5, 118.3, 115.1, 104.2, 68.1,
1
1.4, 19.4, 14.0; IR (KBr, cm ): 2919, 2857, 2213, 1660, 1574, 1529, 1455, 1373, 1237, 1179,
074, 1024, 880, 816, 754, 684, 588, 546, 494; HRMS (ESI/Q-TOF) (m/z) calcd for C H N O
2
8
25
2
+
[M + H] 405.1961; found 405.1976.
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-(4-(Methylthio)phenyl)-2,6-diphenylnicotinonitrile (5a):
As a white solid (57 mg, 61% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.18 (d, 2H,
3,
N
J = 7.4 Hz), 8.04 (d, 2H, J = 7.6 Hz), 7.80 (s, 1H), 7.63 (d, 2H, J = 8.4
CN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
Hz), 7.587.50 (m, 6H), 7.42 (d, 2H, J = 8.4 Hz), 2.56 (s, 3H); C{ H}
NMR (CDCl , 100 MHz): δ 162.7, 159.4, 154.9, 141.9, 138.2, 137.8,
3
SMe
1
33.2, 130.7, 130.3, 129.6, 129.23, 129.17, 128.7, 127.8, 126.4, 118.5,

1
1
18.0, 104.3, 15.4; IR (KBr, cm ): 2923, 2855, 2217, 1674, 1571, 1372, 1264, 1188, 1028,
+
8
12, 758, 690, 577, 497; HRMS (ESI/Q-TOF) (m/z) calcd for C H N S [M + H] 379.1263;
2
5
19
2
found 379.1265.
4
-(4-(Dimethylamino)phenyl)-2,6-diphenylnicotinonitrile (6a):34
As a white solid (63 mg, 68% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.17 (d, 2H,
N
3,
J = 7.2 Hz), 8.03 (d, 2H, J = 7.4 Hz), 7.80 (s, 1H), 7.66 (d, 2H, J = 8.8
CN
1
3
1
Hz), 7.587.48 (m, 6H), 6.85 (d, 2H, J = 8.8 Hz), 3.07 (s, 6H); C{ H}
NMR (CDCl , 100 MHz): δ 162.9, 158.9, 155.6, 151.6, 138.6, 138.2,
3
NMe2
1
30.4, 130.1, 130.0, 129.6, 129.1, 128.6, 127.7, 123.9, 118.8, 118.2,

1
103.8, 40.4; IR (KBr, cm ): 2922, 2854, 2216, 1677, 1615, 1573, 1453, 1369, 1523, 1200,
+
1
3
4
026, 815, 757, 692; HRMS (ESI/Q-TOF) (m/z) calcd for C H N [M + H] 376.1808; found
26 22
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76.1820.
-([1,1'-Biphenyl]-4-yl)-2,6-diphenylnicotinonitrile (7a):
As a white solid (71 mg, 70% yield); Purified over a column of silica gel
1
(
2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.20 (d, 2H, J =
N
3,
7
.8 Hz), 8.06 (d, 2H, J = 7.8 Hz), 7.88 (s, 1H), 7.79 (s, 4H), 7.68 (d, 2H,
CN
13
1
J = 7.2 Hz), 7.587.48 (m, 8H), 7.41 (t, 1H, J = 7.2 Hz); C{ H} NMR
(CDCl , 100 MHz): δ 162.7, 159.4, 155.2, 143.0, 140.3, 138.2, 137.8,
3
Ph
1
35.8, 130.8, 130.3, 129.6, 129.4, 129.20, 129.16, 128.7, 128.1,

1
1
1
27.9, 127.8, 127.4, 118.8, 118.1, 104.4,; IR (KBr, cm ): 2923, 2857, 2215, 1573, 1527, 1456,
372, 1266, 1074, 1024, 838, 754, 689, 575; HRMS (ESI/Q-TOF) (m/z) calcd for C H N
3
0
21
2
+
[M + H] 409.1699; found 409.1698.
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-(4-Fluorophenyl)-2,6-diphenylnicotinonitrile (8a):
As a white solid (61 mg, 70% yield); Purified over a column of silica
N
1
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.118.09
3
CN
(m, 2H), 7977.95 (m, 2H), 7.71 (s, 1H), 7.627.59 (m, 2H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
7
.497.43 (m, 6H), 7.217.17 (m, 2H); C{ H} NMR (CDCl , 100
3
MHz): δ 163.9 (d, J = 249.1 Hz), 162.7, 159.5, 154.6, 138.1,
F
137.6, 133.0 (d, J = 3.4 Hz), 130.9, 130.8 (d, J = 3.7 Hz), 130.4, 129.6, 129.2, 128.7, 127.8,
1
9
1
18.7, 117.8, 116.4 (d, J = 21.8 Hz), 104.5; F NMR (CDCl + hexafluorobenzene): δ 113.8
3

1
(s); IR (KBr, cm ): 2923, 2855, 2212, 1644, 1576, 1504, 1454, 1377, 1226, 1164, 1097, 1022,
+
8
76, 836, 751, 688, 548; HRMS (ESI/Q-TOF) (m/z) calcd for C H FN [M + H] 351.1292;
2
4
16
2
found 351.1304.
4-(4-Chlorophenyl)-2,6-diphenylnicotinonitrile (9a):
As a white solid (62 mg, 68% yield); Purified over a column of silica
N
1
gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.198.16
3
,
CN
(m, 2H), 8.058.03 (m, 2H), 7.79 (s, 1H), 7.63 (d, 2H, J = 8.8 Hz),
1
3
1
7.567.51 (m, 8H); C{ H} NMR (CDCl , 100 MHz): δ 162.7, 159.6,
3
1
54.4, 138.0, 137.6, 136.6, 135.4, 130.9, 130.4, 130.2,
Cl

1
1
1
29.6, 129.5, 129.2, 128.8, 127.8, 118.6, 117.8, 104.3; IR (KBr, cm ): 2923, 2858, 2216, 1677,
573, 1529, 1485, 1370, 1263, 1172, 1089, 1015, 822, 752, 688, 492; HRMS (ESI/Q-TOF)
+
(m/z) calcd for C H ClN2 [M + H] 367.0997; found 367.0999.
2
4
16
4-(2-Bromophenyl)-2,6-diphenylnicotinonitrile (10a):
As a white solid (66 mg, 65% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ 8.20 (d, 2H,
3
,
N
J = 7.2 Hz), 8.10 (d, 2H, J = 7.6 Hz), 7.79 (s, 2H), 7.597.48 (m, 7H),
CN
Br
13
1
7.457.44 (m, 1H), 7.417.37 (m, 1H); C{ H} NMR (CDCl , 100
3
MHz): δ 161.7, 159.2, 154.9, 137.98, 137.92, 137.6, 133.6, 131.2, 130.8,

1
1
2
30.6, 130.4, 129.5, 129.2, 128.8, 127.9, 127.8, 122.3, 119.4, 117.0, 105.9; IR (KBr, cm ):
923, 2855, 2219, 1572, 1532, 1470, 1404, 1262, 1078, 1374, 1024, 887, 755, 693; HRMS
+
(ESI/Q-TOF) (m/z) calcd for C H BrN [M + H] 411.0491; found 411.0474.
2
4
16
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-(3-Nitrophenyl)-2,6-diphenylnicotinonitrile (11a):
As a white solid (42 mg, 45% yield); Purified over a column of silica
1
N
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.53 (s, 1H),
3
8
7
.438.41 (m, 1H), 8.218.19 (m, 2H), 8.088.04 (m, 3H), 7.84 (s, 1H),
CN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
.78 (t, 1H, J = 8.0 Hz), 7.587.53 (m, 6H); C{ H} NMR (CDCl , 100
3
O N
2
MHz): δ 162.8, 159.9, 153.0, 148.8, 138.5, 137.8, 137.3, 134.9, 131.2,

1
130.6, 130.4, 129.6, 129.3, 128.8, 127.8, 124.8, 124.0, 118.5, 104.3; IR (KBr, cm ): 2924,
2
857, 2218, 1713, 1576, 1528, 1460, 1350, 1263, 1178, 1082, 1031, 882, 805, 693, 521; HRMS
+
(ESI/Q-TOF) (m/z) calcd for C H N O [M + H] 378.1237; found 378.1248.
2
4
16
3
2
,4-Diphenyl-6-(p-tolyl)nicotinonitriletrile (12a):35
2
As a white solid (62 mg, 72% yield); Purified over a column of silica
Me
1
N
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ
3
8
6
.118.06 (m, 4H), 7.80 (s, 1H), 7.717.68 (m, 2H), 7.607.53 (m,
CN
13
1
H), 7.33 (d, 2H, J = 8.4 Hz), 2.44 (s, 3H); C{ H} NMR (CDCl ,
3
100 MHz): δ 162.5, 159.3, 155.4, 141.1, 138.3, 137.1, 134.9, 130.2,

1
1
29.99, 129.87, 129.6, 129.1, 128.8, 128.6, 127.6, 118.4, 117.9, 104.1, 21.6; IR (KBr, cm ):
923, 2856, 2215, 1575, 1532, 1494, 1451, 1404, 1373, 1261, 1157, 1079, 1026, 881, 818, 766,
2
+
7
01, 620, 530; HRMS (ESI/Q-TOF) (m/z) calcd for C H N [M + H] 347.1543; found
2
5
19
2
347.1560.
6
-(4-Methoxyphenyl)-2,4-diphenylnicotinonitrile (13a):
As a white solid (64 mg, 71% yield); Purified over a column of
MeO
1
silica gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ
3
,
N
8.16 (d, 2H, J = 8.8 Hz), 8.04 (d, 2H, J = 7.6 Hz), 7.75 (s, 1H),
.68 (d, 2H, J = 7.6 Hz), 7.587.53 (m, 6H), 7.02 (d, 2H, J = 8.8
CN
7
1
3
1
Hz), 3.89 (s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 162.5,
3
1
1
61.9, 158.9, 155.4, 138.4, 137.2, 130.3, 130.2, 130.0, 129.6, 129.3, 129.2, 128.9, 128.7, 118.1,

1
17.9, 114.6, 103.6, 55.6; IR (KBr, cm ): 2923, 2856, 2211, 1575, 522, 1457, 1372, 1251,
1167, 1025, 879, 829, 761, 696, 542; HRMS (ESI/Q-TOF) (m/z) calcd for C H N O [M +
2
5
19
2
+
H] 363.1492; found 363.1500.
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-(4-Fluorophenyl)-2,4-diphenylnicotinonitrile (14a):
As a white solid (60 mg, 69% yield); Purified over a column of silica
F
1
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.228.18
N
3
(m, 2H), 8.068.04 (m, 2H), 7.77 (s, 1H), 7.707.68 (m, 2H),
CN
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
7
.597.55 (m, 6H), 7.20 (t, 2H, J = 8.6 Hz); C{ H} NMR (CDCl ,
3
1
00 MHz): δ 164.6 (d, J = 249.7 Hz), 162.6, 158.2, 155.7,
1
38.1, 136.9, 133.9 (d, J = 3.0 Hz), 130.3, 130.1, 129.8 (d, J = 8.6 Hz), 129.5, 129.2, 128.8,
1
9
128.7, 118.4, 117.8, 116.2 (d, J = 21.7 Hz), 104.5; F NMR (CDCl + hexafluorobenzene): δ
3

1

113.8 (s); IR (KBr, cm ): 2923, 2862, 2216, 1683, 1574, 1525, 1370, 1227, 1151, 1091, 1024,
+
8
30, 752, 690, 618, 527; HRMS (ESI/Q-TOF) (m/z) calcd for C H FN [M + H] 351.1292;
2
4
16
2
found 351.1298.
6-(4-Chlorophenyl)-2,4-diphenylnicotinonitrile (15a):
As a white solid (60 mg, 66% yield); Purified over a column of
Cl
1
silica gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ
3
,
N
8
.14 (d, 2H, J = 8.8 Hz), 8.048.02 (m, 2H), 7.79 (s, 1H),
CN
7.697.67 (m, 2H), 7.597.55 (m, 6H), 7.49 (d, 2H, J = 8.4 Hz);
1
3
1
C{ H} NMR (CDCl , 100 MHz): δ 162.7, 158.4, 155.8, 138.0,
3
1
1
37.0, 136.8, 136.1, 130.4, 130.2, 129.5, 129.4, 129.2, 129.0, 128.85, 128.75, 118.6, 117.8,
1
04.8; IR (KBr, cm ): 2923, 2862, 2217, 1652, 1573, 1528, 1489, 1369, 1260, 1172, 1091,
+
1018, 824, 753, 690, 492; HRMS (ESI/Q-TOF) (m/z) calcd for C H ClN [M + H] 367.0997;
2
4
16
2
found 367.0998.
6
-(4-Bromophenyl)-2,4-diphenylnicotinonitrile (16a):
As a white solid (65 mg, 64% yield); Purified over a column of
Br
1
silica gel (2% EtOAc in hexane). H NMR (CDCl 400 MHz): δ
N
3,
8.078.02 (m, 4H), 7.79 (s, 1H), 7.697.63 (m, 4H), 7.597.55 (m,
CN
1
3
1
6
1
H); C{ H} NMR (CDCl , 100 MHz): δ 162.7, 158.1, 155.9,
3
38.0, 136.8, 136.6, 132.4, 130.4, 130.2, 129.5, 129.24, 129.22,
1
1
28.8, 128.7, 125.5, 118.5, 117.7, 104.9; IR (KBr, cm ): 2922, 2862, 2218, 1681, 1573, 1528,
1486, 1367, 1272, 1169, 1071, 1004, 821, 753, 689, 622, 487; HRMS (ESI/Q-TOF) (m/z) calcd
+
for C H BrN [M + H] 411.0491; found 411.0499.
24 16
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2
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2
2
2
2
2
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6
-(4-Nitrophenyl)-2,4-diphenylnicotinonitrile (17a):
As a white solid (42 mg, 45% yield); Purified over a column of
O N
2
1
N
silica gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ
3
8
7
1
.36 (s, 4H), 8.058.03 (m, 2H), 7.89 (s, 1H), 7.717.68 (m, 2H),
CN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
.597.57 (m, 6H); C{ H} NMR (CDCl , 100 MHz): δ 162.9,
3
56.7, 156.4, 149.2, 143.5, 137.7, 136.5, 130.6, 130.5, 129.6,

1
129.4, 128.9, 128.6, 124.4, 119.6, 117.4, 106.1; IR (KBr, cm ): 2923, 2862, 2220, 1607, 1453,
+
1
3
6
406, 1272, 1094, 1039, 807, 692; HRMS (ESI/Q-TOF) (m/z) calcd for C H N O [M + H]
24 16 3 2
78.1237; found 378.1245.
-(2-Nitrophenyl)-2,4-diphenylnicotinonitrile (18a):
As a white solid (39 mg, 42% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl , 600 MHz): δ 7.96 (d,
N
3
NO2
1H, J = 7.8 Hz), 7.93 (d, 2H, J = 7.5 Hz), 7.727.68 (m, 4H),
CN
13
1
7
.627.59 (m, 2H), 7.577.55 (m, 3H), 7.547.51 (m, 3H); C{ H}
NMR (CDCl , 150 MHz): δ 162.4, 157.8, 155.9, 149.5, 137.4, 136.2,
3
1
1
1
34.0, 132.8, 131.2, 130.5, 130.44, 130.35, 129.5, 129.2, 128.9, 128.7, 124.9, 121.1, 117.4,

1
05.5; IR (KBr, cm ): 2922, 2856, 2216, 1694, 1567, 1522, 1453, 1340, 1235, 1159, 1076,
028, 901, 850, 751, 695, 616, 483; HRMS (ESI/Q-TOF) (m/z) calcd for C H N O [M +
2
4
16
3
2
+
H] 378.1237; found 378.1254.
-(Naphthalen-1-yl)-2,6-diphenylnicotinonitrile (19a):
4
As a white solid (68 mg, 72% yield); Purified over a column of silica
1
N
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.218.19
3
(m, 2H), 8.12 (d, 2H, J = 8.0 Hz), 8.03 (d, 1H, J = 8.0 Hz), 7.99 (d,
CN
1H, J = 8.0 Hz), 7.89 (s, 1H), 7.68 (d, 1H, J = 8.4 Hz), 7.64 (d, 1H, J
1
3
1
=
8.0 Hz), 7.617.56 (m, 5H), 7.547.51 (m, 4H); C{ H}
NMR (CDCl , 100 MHz): δ 162.1, 158.9, 155.1, 138.0, 137.6, 134.6, 133.9, 130.9, 130.8,
3
1
30.4, 130.2, 129.6, 129.2, 128.9, 128.8, 127.8, 127.44, 127.35, 126.7, 125.5, 125.0, 120.3,

1
117.3, 106.6; IR (KBr, cm ): 2921, 2853, 2215, 1732, 1656, 1569, 1528, 1446, 1374, 1262,
+
1
073, 1025, 906, 771, 692, 616, 533; HRMS (ESI/Q-TOF) (m/z) calcd for C H N [M + H]
28 19 2
3
83.1543; found 383.1548.
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-(Naphthalen-1-yl)-6-(naphthalen-2-yl)-2-phenylnicotinonitrile (20a):
As a white solid (75 mg, 70% yield); Purified over a column of silica
1
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.69 (s,
3
N
1
H), 8.33 (d, 1H, J = 8.8 Hz), 8.16 (d, 2H, J = 7.8 Hz), 8.057.94
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CN
(
(
m, 6H), 7.89 (d, 1H, J = 7.8 Hz), 7.72 (d, 1H, J = 8.0 Hz), 7.687.52
13
1
m, 8H); C{ H} NMR (CDCl , 100 MHz): δ 162.1, 158.8, 155.0,
3
138.1, 134.9, 134.7, 134.6, 133.9, 133.5, 130.4, 130.2,
29.6, 129.2, 128.9, 128.8, 127.89, 127.92, 127.6, 127.4, 127.3, 126.8, 126.7, 125.4, 125.0,
1

1
1
24.6, 120.4, 117.3, 106.6; IR (KBr, cm ): 2921, 2850, 2218, 1679, 1564, 1529, 1385, 1336,
+
1
233, 1168, 1026, 862, 763, 696, 628; HRMS (ESI/Q-TOF) (m/z) calcd for C H N [M + H]
3
2
21
2
433.1699; found 433.1730.
4
-(4-Chlorophenyl)-2-phenyl-6-(p-tolyl)nicotinonitrile (21a):
As a white solid (65 mg, 69% yield); Purified over a column of
Me
1
silica gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ
3
N
8.08 (d, 2H, J = 8.0 Hz), 8.048.02 (m, 2H), 7.75 (s, 1H), 7.62 (d,
CN
2
H, J = 8.4 Hz), 7.577.53 (m, 5H), 7.32 (d, 2H, J = 8.0 Hz), 2.44
1
3
1
(
s, 3H); C{ H} NMR (CDCl , 100 MHz): δ 162.6, 159.5, 154.2,
3
Cl
1
41.3, 138.1, 136.5, 135.5, 134.8, 130.3, 130.2, 129.9,

1
129.6, 129.5, 128.7, 127.7, 118.2, 117.9, 103.9, 21.6; IR (KBr, cm ): 2923, 2860, 2212, 1658,
1
575, 1531, 1486, 1455, 1370, 1266, 1174, 1089, 1016, 815, 753, 688, 628, 540, 495; HRMS
+
(ESI/Q-TOF) (m/z) calcd for C H ClN [M + H] 381.1153; found 381.1170.
2
5
18
2
6
-(4-Chlorophenyl)-4-(4-methoxyphenyl)-2-phenylnicotinonitrile (22a):
As a white solid (74 mg, 75% yield); Purified over a column of
Cl
1
silica gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ
3
N
8
2
.05 (d, 2H, J = 8.8 Hz), 7.967.93 (m, 2H), 7.68 (s, 1H), 7.58 (d,
H, J = 8.8 Hz), 7.497.47 (m, 3H), 7.40 (d, 2H, J = 8.4 Hz), 7.01
CN
13
1
(
d, 2H, J = 8.8 Hz), 3.82 (s, 3H); C{ H} NMR (CDCl , 100 MHz):
3
OMe
δ 162.7, 161.3, 157.9, 155.4, 138.1, 136.9, 136.2, 130.4, 130.3,

1
1
2
29.5, 129.3, 128.9, 128.7, 128.5, 118.3, 118.1, 114.7, 104.5, 55.6; IR (KBr, cm ): 2923, 2856,
216, 1727, 1574, 1514, 1459, 1373, 1177, 1259, 1089, 1025, 820, 689, 568, 514; HRMS
+
(ESI/Q-TOF) (m/z) calcd for C H ClN O [M + H] 397.1102; found 397.1106.
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6
6
-(4-Chlorophenyl)-4-(4-hydroxyphenyl)-2-phenylnicotinonitrile (23a):
As a white solid (39 mg, 41% yield); Purified over a column of
Cl
1
6
N
silica gel (5% EtOAc in hexane). H NMR (DMSO-d + CDCl ,
3
4
7
00 MHz): δ 10.07 (s, 1H), 8.30 (d, 2H, J = 8.4 Hz), 8.07 (s, 1H),
.967.94 (m, 2H), 7.67 (d, 2H, J = 8.4 Hz), 7.577.54 (m, 5H),
CN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
6
6.96 (d, 2H, J = 8.8 Hz); C{ H} NMR (DMSO-d + CDCl , 100
3
OH
MHz): δ 161.7, 159.3, 156.8, 154.9, 137.9, 135.8, 135.5, 130.6,

1
1
2
29.9, 129.3, 129.2, 128.9, 128.3, 126.7, 118.3, 117.9, 115.6, 103.9; IR (KBr, cm ): 3415,
955, 2922, 2853, 2215, 1667, 1594, 1565, 1491, 1462, 1387, 1308, 1262, 1219, 1090, 1017,
+
807, 702; HRMS (ESI/Q-TOF) (m/z) calcd for C H ClN O [M + H] 383.0946; found
2
4
16
2
3
83.0949.
-(4-Methoxyphenyl)-6-(4-nitrophenyl)-2-phenylnicotinonitrile (24a):
As a white solid (46 mg, 46% yield); Purified over a column of
4
O N
2
1
silica gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ
N
3
8
.35 (s, 4H), 8.038.01 (m, 2H), 7.86 (s, 1H), 7.67 (d, 2H, J = 8.8
CN
Hz), 7.587.56 (m, 3H), 7.10 (d, 2H, J = 8.8 Hz), 3.91 (s, 3H);
13
1
C{ H} NMR (CDCl , 100 MHz): δ 163.1, 161.6, 156.6, 155.9,
3
OMe
1
49.4, 149.2, 143.6, 137.8, 130.6, 130.4, 129.6, 128.8, 128.6, 124.3,

1
119.4, 117.8, 114.8, 105.8, 55.7; IR (KBr, cm ): 2923, 2854, 2218, 1727, 1602, 1568, 1513,
1
352, 1296, 1260, 1180, 1111, 1023, 825, 757, 691, 568, 511; HRMS (ESI/Q-TOF) (m/z) calcd
+
for C H N O [M + H] 408.1343; found 408.1347.
2
5
18
3
3
4
-(2,6-Dichlorophenyl)-6-(4-fluorophenyl)-2-phenylnicotinonitrile (25a):
As a white solid (66 mg, 64% yield); Purified over a column of silica
F
1
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.248.20
3
N
(
m, 2H), 8.138.10 (m, 2H), 7.69 (s, 1H), 7.597.57 (m, 3H),
CN
Cl
Cl
7
.547.52 (m, 2H), 7.437.39 (m, 1H), 7.22 (t, 2H, J = 8.8 Hz);
13
1
C{ H} NMR (CDCl , 100 MHz): δ 164.7 (d, J = 250.1 Hz), 161.8,
3
158.6, 151.4, 137.6, 134.8, 134.3, 133.6 (d, J = 3.1 Hz), 131.4, 130.5, 129.9 (d, J = 8.6 Hz),
1
9
1
29.4, 128.8 (d, J = 8.3 Hz), 118.9, 116.4, 116.2 (d, J = 21.6 Hz), 106.1; F NMR (CDCl +
3

1
hexafluorobenzene): δ 112.9 (s); IR (KBr, cm ): 2922, 2855, 2217, 1660, 1589, 1535, 1406,
1
369, 1230, 1151, 1094, 1013, 840, 778, 689, 512; HRMS (ESI/Q-TOF) (m/z) calcd for
+
C H Cl FN [M + H] 419.0513; found 419.0514.
2
4
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-(3,4-Dimethoxyphenyl)-2,6-diphenylnicotinonitrile (26a):
As a white solid (66 mg, 68% yield); Purified over a column of silica
N
1
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.21 (d, 2H,
3
CN
J = 7.8 Hz), 8.06 (d, 2H, J = 7.4 Hz), 7.85 (s, 1H), 7.597.54 (m, 6H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.337.26 (m, 2H), 7.07 (d, 1H, J = 8.4 Hz), 4.02 (s, 3H), 3.99 (s, 3H);
OMe
13
1
C{ H} NMR (CDCl , 100 MHz): δ 162.7, 159.2, 155.3, 150.8, 149.3,
3
OMe
1
38.3, 137.8, 130.6, 130.2, 129.6, 129.4, 129.2, 128.7, 127.7, 121.9,

1
118.6, 118.3, 112.0, 111.6, 104.3, 56.4, 56.2; IR (KBr, cm ): 2927, 2840, 2213, 1665, 1571,
1
515, 1452, 1376, 1321, 1256, 1180, 1140, 1077, 1020, 920, 858, 803, 756, 691, 594; HRMS
+
(ESI/Q-TOF) (m/z) calcd for C H N O [M + H] 393.1598; found 393.1598.
2
6
21
2
2
6
-(Benzo[d][1,3]dioxol-5-yl)-4-(4-bromophenyl)-2-phenylnicotinonitrile (27a):
As a white solid (71 mg, 63% yield); Purified over a column of silica
O
O
1
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.028.00
3
N
(m, 2H), 7.727.69 (m, 4H), 7.66 (s, 1H), 7.567.53 (m, 5H), 6.93 (d,
CN
13
1
1
H, J = 8.0 Hz), 6.05 (s, 2H); C{ H} NMR (CDCl , 100 MHz): δ
3
162.5, 158.8, 154.2, 150.2, 148.8, 138.0, 135.9, 132.4, 131.9, 130.42,
30.37, 129.5, 128.7, 124.8, 122.4, 117.84, 117.75, 108.8,
1
Br

1
1
07.9, 103.6, 101.9; IR (KBr, cm ): 2923, 2859, 2214, 1650, 1591, 1484, 1446, 1319, 1255,
+
1
106, 1039, 935, 810, 690, 488; HRMS (ESI/Q-TOF) (m/z) calcd for C H BrN O [M + H]
2
5
16
2
2
455.0390; found 455.0417.
4
-(4-Chlorophenyl)-2-phenyl-5,6-dihydrobenzo[h]quinoline-3-carbonitrile (28a):
As a white solid (59 mg, 61% yield); Purified over a column of silica
1
N
gel (2% EtOAc in hexane). H NMR (CDCl , 400 MHz): δ 8.518.49
3
(m, 1H), 8.03 (d, 2H, J = 7.8 Hz), 7.577.51 (m, 5H), 7.427.38 (m,
2H), 7.33 (d, 2H, J = 8.4 Hz), 7.26 (s, 1H), 2.912.87 (m, 2H), 2.792.76
CN
1
3
1
(
m, 2H); C{ H} NMR (CDCl , 100 MHz): δ 159.6, 155.4, 152.3,
3
Cl
1
38.9, 138.1, 135.7, 134.2, 133.7, 131.1, 130.3, 130.1, 129.5, 129.4,
1
1
28.7, 128.4, 128.0, 127.6, 126.9, 117.7, 105.9, 27.7, 25.5; IR (KBr, cm ): 2924, 2854, 2221,
1598, 1544, 1489, 1391, 1240, 1177, 1086, 1018, 836, 757, 699, 589, 485; HRMS (ESI/Q-
+
TOF) (m/z) calcd for C H ClN [M + H] 393.1153; found 393.1139.
2
6
18
2
ACS Paragon Plus Environment