Silver(i)-N-heterocyclic carbene catalyzed multicomponent reactions: A facile synthesis of multisubstituted pyridines

Article abstract of DOI:10.1039/c5ra16582b

A four component one-pot reaction between aromatic aldehyde, malononitrile, ammonium acetate and ketone mediated by Ag(i) N-heterocyclic carbene to produce multisubstituted and fused pyridines in a short reaction time (～10 min) in ethanol at room temperat

Full text of DOI:10.1039/c5ra16582b

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ARTICLE TYPE
Silver(I)-N-heterocyclic carbene catalyzed multicomponent reactions: a
facile synthesis of multisubstituted pyridines
Shravankumar Kankala,a Ramakanth Pagadala,a Suresh Maddila,a Chandra Sekhar Vasam*b,c and
Sreekantha B. Jonnalagadda*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
task such as the (i) use of additional coordinating ligands to
45 minimize the coordination of organocatalysts, (ii) sequential
addition of catalysts and (iii) use of early transition metals.7fꢀh
However, recent research reveals that the right selection of
metal/organo catalysts pair8 facilitates the cooperative dual
catalysis without the need for above mentioned precautions (i),
50 (ii) & (iii). Specifically the compatibility and cooperativity
between metal ion and organo Nꢀheterocyclic carbenes (organoꢀ
NHC) was found to be highly effective to achieve unprecedented
organic transformations particularly under ‘weak’ base
conditions.8 While the metal ion and in situ generated organoꢀ
55 NHC catalyst pair was found to coꢀexist with a significant level
of concentrations under weak base conditions, metalꢀtoꢀNHC
ligand coordination was noticed under strong base conditions.
We are interested to investigate the possible cooperativity
between Ag(I) and organoꢀNHC in catalyzing a multicomponent
60 oneꢀpot reaction of aromatic aldehyde, malononitrile, ammonium
acetate and ketone for efficient synthesis of highly substituted
pyridines. According to the previous reports, the metal and
organoꢀNHC catalysts were brought into the reaction system from
the two individual precursors.8 However, the generation of
65 organoꢀNHC from the corresponding imidazolium salt using an
external base (strong/mild) may possibly hamper the aldehyde
involving MCR. Mild base catalyzed aldol condensation reactions
are also known.9 We would like to employ the preꢀsynthesized
Ag(I)ꢀNHC complexes as source for both organoꢀNHCs and
70 Ag(I) ions for the MCR due to the following reasons.
A
four component one-pot reaction between aromatic
aldehyde, malononitrile, ammonium acetate and ketone
mediated by Ag(I) N-heterocyclic carbene to produce
10 multisubstituted and fused pyridines in short reaction time
(~10 min) in ethanol at room temperature is described.
Substituted pyridines are building blocks for many
pharmaceuticals,
agrochemicals,
organic
intermediates,
supramolecules, nanoparticles, OLED, solar cells and polymers.1
15 The two wellꢀknown synthetic pathways to afford substituted
pyridines are either by modifying the pyridine core (Scheme 1,
Path A)2 or by condensing the appropriately substituted (mostly
carbonyl and amine functionalities) precursors (Scheme 1, Path
B).3
20
3
3
R
R
4
5
2
1
4
5
2
1
R
R
R
R
R
Path B
Path A
OO
R
N
R
R
N
N-precursor
Scheme 1 Multicomponent approach to multifunctionalized
pyridines.
25
While the substitution reactions of the pyridine core pathꢀA
frequently suffer from the low reactivity of the electronꢀdeficient
heteroaromatic system, the synthetic protocols reported for pathꢀ
B in most cases are not ecoꢀfriendly. In this context, catalyzed
(metal or organo) multicomponent reactions (MCR), a special
i) Ag(I)ꢀNHC have been recognized as efficient organoꢀNHC
delivery agents in solution,10 despite of their prime role as
NHC transfer agents to other metal ions.11
30 class of tandem reactions, have emerged as highly atom and
resource efficient to obtain substituted pyridines in oneꢀpot.3g,4
Despite the myriad of organic transformations using transition
metal based catalysts,5 recently organocatalysis6 has witnessed a
spectacular rise in homogeneous catalysis. At this juncture it has
35 been envisaged that the cooperative dual catalysis7 i.e. combining
transition metal catalysis and organocatalysis enables
unprecedented organic transformations not currently possibly by
use of each catalytic systems alone (acidic/basic). Nevertheless,
one of the key challenges is catalysis compatibility i.e. the search
40 of metal and organic catalysts pair that can work together
cooperatively without quenching each other i.e. preventing the
possible metal coordination to organocatalysts.7 Various efforts
have been made to overcome metal/organocatalysts, quenching
ii) The reported equilibrium between ionic and neutral forms
75
80
85
of preꢀsynthesized Ag(I)ꢀNHCs10,11 in solution and the
soft/labile nature of Ag(I)ꢀNHC bond could facilitate the
intermediary of both Lewis basic organoꢀNHC and Lewis
acidic Ag(I) catalysts for cooperative catalysis. (i.e. it is not
necessary to introduce Ag(I) and NHC catalyst precursors
separately for cooperative catalysis since Ag(I)ꢀNHC bond
is labile in solution).
iii) Ag(I)ꢀNHCs can be obtained simply by mixing Ag2O with
imidazolium salt without the need for additional base and
solvent preꢀtreatment.11
The aptness of organoꢀNHC catalysis is mainly attributed to
their reactivity umpolung.12 While the NHC lone pair is highly
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nucleophilic, the empty pꢀorbital is able to accept electron density
mediating the MCR. The solid product of 3a obtained in our work
and stabilizes the accumulation of negative charge in the vicinity
was further identified and quantified on the basis of its analytical,
i.e. reactivity umpolung.12 As a consequence, the use of NHCs as 50 spectral and single crystal Xꢀray crystallographic data (ESI). The
Lewis/Brønsted base catalysts facilitate the formation various
reactive modes (acyl anions, homoenolates, acylvinyl anions and
enolate) to produce carboꢀ and heterocyclic compounds.
Furthermore, NHCs and their precursors (imidazolium salts) are
good example of conjugate acidꢀbase pairs. Protonꢀshuttling
strategy using NHCs as brønsted base in catalysis is also a wellꢀ
single crystals of 3a were grown from ethyl acetate/nꢀhexane.
The ORTEP drawing of 3a is show in Fig. 2.
5
10 known phenomenon. Based on this information, previously Wu
and coꢀworkers reported cooperativity between Ag(I) and organoꢀ
NHC catalysts during the umpolung reaction of hydrazides with
α, βꢀunsaturated aldehydes.13
In furtherance of our research work in the fields of (i) MCRs14
15 and (ii) NHCs11,15 herein we report for the first time the use of
Ag(I)ꢀNHCs as preꢀcatalysts i.e. as source of Ag(I) ion and
organoꢀNHC delivery agents (Fig. 1) to promote a clickꢀtype fast
MCR protocol for the synthesis of multisubstituted and fused
pyridines at room temperature (RT) in ethanol.
20
(e): R = adamentyl
Ag(I)ꢀNHC (a): R = mesityl
(b): R = isoꢀpropyl
R
55 Fig. 2 The ORTEP diagram of 3a
.
i
(f): R = 2,6ꢀdi propylphenyl
N
(c): R = cyclohexyl
Ag
Cl
Table 1 Optimization of reaction parameters for the synthesis of 3a.
(d): R = tertꢀbutyl
N
OCH3
R
O
CHO
(i) CH2(CN)2
(ii) CH3CO2NH4
Fig. 1 Ag(I)ꢀNHCs used in the present work.
NC
Catalyst, EtOH, 10 min, rt
25
Initially we choose to investigate a four component sequential
oneꢀpot reaction (MCR) between malononitrile, aromatic
aldehyde (1a), ammonium acetate and ketone (2a) in ethanol and
the scope of a variety of potential catalyst materials. The details
of the reaction and the results are given in Scheme 2 and Table 1
OCH3
H2N
N
3a
1a
2a
Entry
Catalyst
Yield (%)a
ꢀꢀ
ꢀꢀ
No Catalyst
AgOAc
1
2
3
30 respectively.
ꢀꢀ
AgOTf
Ar
O
ꢀꢀ
ꢀꢀ
AgSbF6
4
5
(i) CH (CN)
2
2
NC
AgNO3
(ii) CH CO NH
4
3
2
Ar CHO
94
86
90
Ag(I)-NHC (a)
Ag(I)-NHC (b)
6
7
cat. Ag(I)-NHC
H2N
N
EtOH, 10 min, rt
1a-g
3a-g
2a
Ag(I)-NHC (c)
8
9
Ar = 4ꢀOCH C H (3a), 4ꢀBrC H (3b), C H (3c),
3
6
4
6
4
6 5
90
Ag(I)-NHC (d)
Ag(I)-NHC (e)
Ag(I)-NHC (f)
2ꢀClC H (3d), 2ꢀBrC H (3e), 2ꢀOCH C H (3f),
6
4
6
4
3 6 4
88
91
10
11
4ꢀN(CH ) C H (3g).
3 2
6 4
32
84
Organo-NHC
12
13
Scheme 2 Synthesis of multifunctional pyridines (3a-g).
Organo-NHC + AgOAc
80
Organo-NHC + AgOTf
14
35
There was no MCR sequence observed without any catalyst
(Table 1, entry1). There was also no progress in the above MCR
at RT conditions, when silver salts, AgOAc, AgOTf, AgSbF6 or
AgNO3 were employed as catalysts (Table 2, entries 2ꢀ5).
However, when Ag(I)ꢀNHC ((a), Fig. 1) was employed a catalyst,
a GC Yields
60
Continuing the work, we have also investigated the above
MCR using various other Ag(I)ꢀNHC catalysts (b-f, Fig. 1) which
have different Nꢀsubstituents on NHC. The results summarised in
Table 1 (Entries 7ꢀ11) show higher yields of product 3a with
65 Ag(I)ꢀNHC (a) (Table 1, entry 6). Results of the effect of Ag(I)ꢀ
NHC (a) concentration on the reaction yields of 3a are also
summarised (ESI). The catalyzed MCRs of present study in
ethanol are found to be slightly exothermic in the beginning as
observed in other works. It is also important to note that the
70 above catalyzed reaction was observed to be sluggish and nonꢀ
40 the results were impressive producing the substituted pyridine
(3a) selectively just in 10 minutes and in good yields (94%, Table
1, entry 6). On the other hand, previous reports describe that a
similar MCR sequence (aldehydes, ketones, malononitrile, and
ammonium acetate) of both catalyzed16 and uncatalyzed
45 processes17 was
accomplished only under refluxing or
microwave conditions and longer reaction times. This
information indicates the efficiency of Ag(I)ꢀNHC preꢀcatalyst in
2
|
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selective in nonꢀprotic solvents, CH2Cl2, THF and CH3CN and
examination of the results and conditions depicted in Table 2 for
finally ended up with mixture of products. This information 60 the selective synthesis of multisubstituted pyridines (3a-i & 4a-d)
outlines that the choice of solvent is also one of the key factors in
this catalyzed MCR.
suggests our yields are comparable or even better than those for
the closely related multisubstituted pyridines in earlier reports3,4
by following metal or organo or base catalyzed MCRs, or the
methodologies following the Scheme 1.
5
The data presented in Table 1 suggests the possible mediation
of MCR by both Ag(I) and free organoꢀNHC, which were
released from soft/labile Ag(I)ꢀNHC in the MCR. To support this
hypothesis, we have conducted an additional experiment of the
title reaction using a preꢀgenerated free organoꢀNHC 1,3ꢀ
65
Table 2 Synthesis of multisubstituted pyridines by Ag(I)ꢀNHC
(a) (3a-i & 4a-d).a
10 dimesitylimidazolꢀ2ꢀylidene that obtained from the corresponding
imidazolium salt. We have noticed that the Ag(I) free organoꢀ
NHC is also able to facilitate the formation of substituted
pyridines under inert conditions, but the reaction was relatively
slow and the yields of pyridine were poor (Table 1, entry 12). We
15 have also conducted another experiment to confirm the role of
silver(I) in the free organoꢀNHC (1,3ꢀdimesitylimidazolꢀ2ꢀ
ylidene) mediated MCR. When the silver salts (AgOAc or
AgOTf) were introduced to the organoꢀNHC (1,3ꢀ
dimesitylimidazolꢀ2ꢀylidene) mediated MCR during the reaction
20 course, the MCR was accomplished fast and improved the yield
(Table 1, entry 13 & 14) than the free organoꢀNHC alone
mediated MCR. Besides, in order to expand the the scope of this
MCR, we have also investigated the abilities of various acidꢀbase
catalyst combinations (i) Ag(I) salts with bases (DABCO, DBU,
25 TEA, K2CO3, NaOAc) i.e. other than NHCs, (ii) other Lewis
acids (Cu(II), Sc(III), Al(III), Ni(II)) with NHC, (iii) Lewis acids
other than Ag(I) with bases other than NHCs. The results of MCR
obtained with above catalyst combinations are summarized in ESI
(Table S1). Only Knoevenagel condensed products instead of
30 MCR products (pyridines) were observed when the MCR was
conducted in the presence of (i) Ag(I) and bases other than NHC
(ESI) and (ii) other Lewis acids and bases (not Ag(I) and NHC).
On the other hand, the catalyst combination of NHC and Lewis
acids other than Ag(I) has also facilitated the MCR but produced
35 the pyridine 3a in less yields (ESI). At this juncture, it is rational
to propose that there could be a effective cooperative catalysis
between Ag(I) and organoꢀNHC catalysts those were released
from labile Ag(I)ꢀNHC during the course of MCR in solution. On
the other hand, unꢀdissociable metalꢀNHCs formation suppressed
40 the dual catalysis and decreased the yields of MCR products
(ESI) when Lewis acids other than Ag(I) were employed as
partner to NHC.
Ar
O
NC
H2N
N
(i) CH (CN)
2
2
2a-c
3a-i
(ii) CH CO NH
4
3
2
or
Ar
CHO
or
O
Ar
cat. Ag(I)ꢀNHC (a)
NC
CH3
CH3
EtOH, 10 min, rt
1a-g
H2N
N
2d
4a-d
b
yield (%)
94
Ar (1a-g)
Entry
1
Ketone
O
Product
3a
4ꢀOCH C H (1a)
3
6 4
(2a)
4-BrC6H4 (1b)
C6H5 (1c)
2
3
4
5
3b
3c
3d
3e
3f
90
92
89
2a
2a
2a
2a
2a
2-ClC6H4 (1d)
2-BrC6H4 (1e)
83
90
90
2-OCH3C6H4 (1f)
6
7
4-N(CH3)2C6H4 (1g)
2a
3g
O
8
9
1c
1c
3h
3i
86
91
(2b)
O
(2c)
O
1c
1d
4a
4b
92
88
10
11
(2d)
2d
1e
1a
4c
12
13
a
92
92
2d
2d
4d
All products were characterized by NMR and mass spectral analysis.
Isolated yields.
b
70
Based on previous reports16,17 and current results in the MCR
Employing the same reaction conditions for the synthesis of 3a
(RT, Ag(I)ꢀNHC (a) (2 mol%, 10 min, ethanol), we investigated
45 the scope of the reaction with a variety of structurally different
aldehydes (1b-g) in combination with cyclic (2a-c) and acyclic
ketones (2d), malononitrile and ammonium acetate for the four
component condensation reaction. The results are depicted in
Table 2. The substrates of MCR bearing electron donating or
50 electronꢀwithdrawing groups on the aromatic ring proceeded
smoothly and formed the corresponding multisubstituted
pyridines in good yields under the chosen conditions.
synthesis of multisubstituted pyridines, a plausible mechanism is
proposed in Scheme 3 by emphasizing the cooperativity between
Ag(I) and organoꢀNHC catalysts. The reaction may proceed via
75 forming enamine (A) (condensed product of ketone and
ammonium acetate), and then activated by Ag(I), which then
reacts with alkylidenemalononitrile (B) (Knoevenagel condensed
product of aldehyde with malononitrile) to give intermediate (C)
(Michael adduct). The Michael adduct then undergoes
80 cycloaddition and isomerisation to give 1,4ꢀdihydropyridine (D).
The subsequent oxidative aromatization of 1,4ꢀdihydropyridine
(D) under air atmosphere will produce the desired
multisubstituted and fused pyridines (3a-i & 4a-d) as shown in
Scheme 3. Tracking of the H of NH2 with D2O exchange study
85 and the results of D2O exchange are depicted in the ESI.
Furthermore, 15NNMR (GHSQC) data has also confirmed the
formation of the amino pyridine product.
Structures of the substituted pyridines (3a-i & 4a-d, Table 2)
were established on the basis of elemental analysis and spectral
55 data (1H NMR, 13C NMR and Mass). The details of the product
characterization are presented in the experimental and ESI.
Literature reports reveal that pyridines with 2,3,4,5 and 6
substitutions still remain
a
challenge to synthesise.3,4 An
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Ag
H
ESIꢀMS spectra were determined on a LCQ ion trap mass
45 spectrometer (Thermo Fisher, San Jose, CA, USA), equipped
with an ESI source. Elemental analyses were carried out using a
PerkinꢀElmer CHNS Elemental Analyzer model 2400. Melting
points were recorded on a hot stage melting point apparatus Ernst
Leitz Wetzlar, Germany and were uncorrected. The singleꢀcrystal
50 Xꢀray diffraction data was collected on a Bruker SMART 1K
CCD diffractometer.
N
Ag
Ar
(B)
CN
CN
Ar
NH
O
HN
NH
Ag-NHC
NC
NH4OAC
-H2O
NHC
(A)
(C)
CN
Ar
O
CN
NH2
NH2
NH
CN
Ar
CN
CN
Ar
HN
N
HN
O2 (air)
-H2
General procedure for the synthesis of polysubstituted
pyridines (3a-i & 4a-d). Aromatic aldehydes (1a-g) (1 mmol)
55 and malononitrile (1 mmol) was dissolved in EtOH (10 ml) and
added the ethanolic solution of cyclic ketone/ethyl methyl ketone
(2a-c or 2d) (1.5 mmol), Ag(I)ꢀNHC (a) (2 mol%) and
ammonium acetate (1.5 mmol) were stirred over a period of 2
minutes at room temperature and stirring was continued for 10
60 minutes. Complete consumption of starting material as judged by
TLC and GC analysis. The reaction mass was filtered and
obtained offꢀwhite solid crude product which was subjected to
column chromatography (silica gel, 60ꢀ120 mesh, eluent; nꢀ
hexane/EtOAc gradient) to afford pure products (3aꢀi & 4a-d).
65
Ar
H
(3 & 4)
(D)
Scheme 3 Possible mechanism for the formation of
multisubstituted pyridines via catalyzed by Ag(I)ꢀNHC.
5
Conclusions
In conclusion, we have demonstrated that using preꢀsynthesized
Ag(I)ꢀNHCs as source of both Ag(I) and organoꢀNHC catalyst
delivery agents, a room temperature and clickꢀtype fast MCR
protocol can be put into practice for the synthesis of
2-Amino-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine-3-carbonitrile (3a). Offꢀwhite solid: mp
10 multisubstituted and fused pyridines from simple starting
materials in ecoꢀfriendly ethanol. Further studies are warranted to
address the nature of the active catalysts under these conditions.
The soft and labile nature of Ag(I)ꢀNHC bond and the reported
equilibrium between neutral and ionic forms of Ag(I)ꢀNHCs in
15 solution11aꢀc indicate the possible intermediacy role of free NHC
and as well as Ag(I) cation in MCR for the cooperative dual
catalysis. Our results indicates that it is not necessary to introduce
Ag(I) and NHC catalyst precursors separately into MCR and the
use of preꢀsynthesized Ag(I)ꢀNHCs is a good choice for
20 cooperative dual catalysis.
o
223ꢀ224 C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.48ꢀ1.53
(m, 2H), 1.70ꢀ1.84 (m, 4H), 2.49 (t, 2H, J = 5.4 Hz), 2.91 (t, 2H,
70 J = 5.4 Hz), 3.85 (s, 3H, OCH3), 5.07 (s, 2H, NH2), 6.98 (d, 2H, J
= 8.6), 7.15 (d, 2H, J = 8.6) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 26.20, 28.06, 28.91, 32.0, 39.69, 55.28, 89.59,
114.03, 117.21, 126.69, 128.97, 129.82, 152.94, 157.24, 159.82,
167.86 ppm. IR (KBr): 3318 (NH2), 2213 (CN) cmꢀ1. MS (ESI),
75 m/z = 294 [M+H]+. EA calcd (%) for C18H19N3O (293.36): calcd.
C 73.69, H 6.53, N 14.32; found. C 73.72, H 6.55, N 14.39.
2-Amino-4-(4-bromo-phenyl)-6,7,8,9-tetrahydro-5H-
Acknowledgments
cyclohepta[b]pyridine-3-carbonitrile (3b). Offꢀwhite solid: mp
o
1
80 236ꢀ237 C; H NMR (400 MHz, CDCl3, 25 °C) δ = 1.48ꢀ1.51
(m, 2H), 1.70ꢀ1.84 (m, 4H), 2.44 (t, 2H, J = 5.4 Hz), 2.92 (t, 2H,
J = 5.4 Hz), 5.14 (s, 2H, NH2), 7.10 (d, 2H, J = 8.3), 7.60 (d, 2H,
J = 8.3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 26.14,
27.99, 28.97, 31.92, 39.67, 88.90, 116.76, 123.13, 126.26,
85 130.10, 131.93, 135.68, 151.73, 157.26, 168.25 ppm. IR (KBr):
3307 (NH2), 2213 (CN) cmꢀ1. MS (ESI), m/z = 343 [M+H]+. EA
calcd (%) for C17H16BrN3 (342.23): calcd. C 59.66, H 4.71, N
12.28; found. C 59.74, H 4.68, N 12.35.
Dr. S. Kankala thankful to the School of Chemistry & Physics
University of KwaZuluꢀNatal, South Africa for the facilities,
NRFꢀSouth Africa and DSTꢀIndia for financial support
25 (DST/INT/SA/Pꢀ15/2011 IndoꢀSouth Africa project). And also
thank Dr. Bernard Omondi Owaga, School of Chemistry &
Physics, University of KwaZuluꢀNatal, for providing Single
crystal Xꢀray data (Bruker SMART 1K CCD diffractometer).
30 Experimental Section
90 2-Amino-4-phenyl-6,7,8,9-tetrahydro-5H-
General
cyclohepta[b]pyridine-3-carbonitrile (3c). Offꢀwhite solid: mp
o
227ꢀ228 C; 1H NMR (400 MHz, CDCl3, 25 °C) δ = 1.47ꢀ1.52
All commercially available reagents were used without further
35 purification. Reaction solvents were dried by standard methods
before use. Purity of the compounds was checked by TLC using
Merck 60F254 silica gel plates. Elemental analyses were obtained
with an Elemental Analyser PerkinꢀElmer 240C apparatus. 1H
and 13C NMR spectra were recorded with a Mercuryplus 400
40 spectrometer (operating at 400 MHz for 1H and 100 MHz for
13C); chemical shifts were referenced to TMS. The FTꢀIR
spectroscopy of samples was carried out on a Perkin Elmer
Precisely 100 FTꢀIR spectrometer in the 400ꢀ4000 cmꢀ1 region.
(m, 2H), 1.69ꢀ1.82 (m, 4H), 2.46 (t, 2H, J = 5.4 Hz), 2.92 (t, 2H,
J = 5.5 Hz), 5.11 (s, 2H, NH2), 7.21ꢀ7.49 (m, 5H) ppm. 13C NMR
95 (100 MHz, CDCl3, 25 °C): δ = 26.18, 28.03, 28.97, 31.98, 39.67,
89.33, 116.94, 126.42, 128.38, 128.60, 128.68, 136.85, 153.11,
157.22, 167.96 ppm. IR (KBr): 3316 (NH2), 2212 (CN) cmꢀ1. MS
(ESI), m/z = 264 [M+H]+. EA calcd (%) for C17H17N3 (263.34):
calcd. C 77.54, H 6.51, N 15.96; found. C 77.62, H 6.49, N 15.98.
100
2-Amino-4-(2-chloro-phenyl)-6,7,8,9-tetrahydro-5H-
4
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DOI: 10.1039/C5RA16582B
cyclohepta[b]pyridine-3-carbonitrile (3d). Offꢀwhite solid: mp
Hz), 2.80 (t, 2H, J = 7.6 Hz), 6.66 (s, 2H, NH2), 7.42ꢀ7.51 (m,
o
1
273ꢀ274 C; H NMR (400 MHz, CDCl3, 25 °C) δ = 1.39ꢀ2.96 60 5H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 22.22, 28.78,
(m, 10H), 5.18 (s, 2H, NH2), 7.15ꢀ7.52 (m, 4H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 26.11, 27.57, 29.27, 32.01, 39.77,
89.24, 116.34, 126.78, 127.12, 129.87, 129.91, 130.20, 132.58,
135.81, 150.33, 157.21, 168.07 ppm. IR (KBr): 3313 (NH2), 2214
34.50, 85.52, 117.39, 123.02, 128.24, 128.49, 128.92, 135.92,
149.16, 160.99, 169.64 ppm. IR (KBr): 3301 (NH2), 2205 (CN)
cmꢀ1. MS (ESI), m/z = 236 [M+H]+. EA calcd (%) for C15H13N3
(235.28): calcd. C 76.57, H 5.57, N 17.86; found. C 76.59, H
5
(CN) cmꢀ1. MS (ESI), m/z = 298 [M+H]+. EA calcd (%) for 65 5.58, N 17.89.
C17H16ClN3 (297.78): calcd. C 68.57, H 5.42, N 14.11; found. C
68.65, H 5.46, N 14.09.
2-Amino-5,6-dimethyl-4-phenyl-nicotinonitrile (4a). Offꢀwhite
solid: mp 240ꢀ241 C; H NMR (400 MHz, CDCl3, 25 °C) δ =
1.95 (s, 3H, CH3), 2.44 (s, 3H, CH3), 5.05 (s, 2H, NH2), 7.23ꢀ7.50
o
1
10
2-Amino-4-(2-bromo-phenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine-3-carbonitrile (3e). Offꢀwhite solid: mp 70 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 15.30,
261ꢀ262 oC; 1H NMR (400 MHz, CDCl3, 25 °C) δ = 1.38ꢀ3.0 (m,
10H), 5.14 (s, 2H, NH2), 7.14ꢀ7.70 (m, 4H) ppm. 13C NMR (100
23.72, 89.72, 116.80, 119.69, 128.33, 128.64, 128.77, 136.79,
153.86, 157.23, 161.57 ppm. IR (KBr): 3330 (NH2), 2211 (CN)
cmꢀ1. MS (ESI), m/z = 224 [M+H]+. EA calcd (%) for C14H13N3
(223.27): calcd. C 75.31, H 5.87, N 18.82; found. C 75.37, H
15 MHz, CDCl3, 25 °C): δ = 26.11, 27.54, 29.27, 32.01, 39.80,
89.17, 116.28, 122.30, 126.58, 127.71, 129.79, 130.29, 133.03,
137.91, 151.86, 157.13, 168.14 ppm. IR (KBr): 3312 (NH2), 2214 75 5.89, N 18.78.
(CN) cmꢀ1. MS (ESI), m/z = 343 [M+H]+. EA calcd (%) for
C17H16BrN3 (342.23): calcd. C 59.66, H 4.71, N 12.28; found. C
20 59.69, H 4.76, N 12.32.
2-Amino-4-(2-chloro-phenyl)-5,6-dimethyl-nicotinonitrile
(4b). Offꢀwhite solid: mp 251ꢀ252 oC; 1H NMR (400 MHz,
CDCl3, 25 °C) δ = 1.88 (s, 3H, CH3), 2.46 (s, 3H, CH3), 5.03 (s,
80 2H, NH2), 7.17ꢀ7.53 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 14.89, 23.66, 116.20, 120.43, 127.0, 127.22, 129.81,
129.94, 130.16, 130.30, 132.45, 151.14, 157.13, 161.71 ppm. IR
(KBr): 3329 (NH2), 2211 (CN) cmꢀ1. MS (ESI), m/z = 258
[M+H]+. EA calcd (%) for C14H12ClN3 (257.72): calcd. C 65.25,
2-Amino-4-(2-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine-3-carbonitrile (3f). Offꢀwhite solid: mp
o
1
244ꢀ245 C; H NMR (400 MHz, CDCl3, 25 °C) δ = 1.42ꢀ2.94
25 (m, 10H), 3.78 (s, 3H, OCH3), 5.03 (m, 2H, NH2), 6.99ꢀ7.43 (m,
4H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 26.18, 27.65,
29.40, 32.13, 39.76, 55.46, 90.08, 111.11, 117.03, 120.74, 85 H 4.69, N 16.30; found. C 65.29, H 4.74, N 16.36.
125.59, 127.36, 130.0, 130.39, 150.33, 156.11, 157.16, 167.37
ppm. IR (KBr): 3296 (NH2), 2210 (CN) cmꢀ1. MS (ESI), m/z =
30 294 [M+H]+. EA calcd (%) for C18H19N3O (293.36): calcd. C
73.69, H 6.53, N 14.32; found. C 73.62, H 6.56, N 14.30.
2-Amino-4-(4-bromo-phenyl)-5,6-dimethyl-nicotinonitrile
(4c). Offꢀwhite solid: mp 265ꢀ266 oC; 1H NMR (400 MHz,
CDCl3, 25 °C) δ = 1.94 (s, 3H, CH3), 2.44 (s, 3H, CH3), 5.02 (s,
90 2H, NH2), 7.11 (d, 2H, J = 8.2 Hz), 7.63 (d, 2H, J = 8.1 Hz) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 15.3, 23.79, 89.94,
112.48, 119.53, 129.72, 130.07, 131.98, 132.12, 153. 68, 157.23,
161.92 ppm. IR (KBr): 3327 (NH2), 2212 (CN) cmꢀ1. MS (ESI),
m/z = 303 [M+H]+. EA calcd (%) for C14H12BrN3 (302.17): calcd.
2-Amino-4-(4-dimethylamino-phenyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine-3-carbonitrile (3g). Light yellow solid:
o
35 mp 230ꢀ231 C; 1H NMR (400 MHz, CDCl3, 25 °C) δ = 1.52ꢀ
1.81 (m, 6H), 2.56 (t, 2H, J = 5.3 Hz), 2.91 (t, 2H, J = 5.4 Hz),
3.01 (s, 6H, N(CH3)2), 4.96 (s, 2H, NH2), 6.76 (d, 2H, J = 8.6), 95 C 55.65, H 4.0, N 13.91; found. C 55.57, H 4.04, N 13.87.
7.11 (d, 2H, J = 8.6) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 26.25, 28.15, 28.90, 32.06, 39.73, 40.26, 88.90, 111.77, 123.13,
40 124.04, 126.79, 129.63, 135.68, 150.42, 153.68, 157.28, 167.58
ppm. IR (KBr): 3312 (NH2), 2210 (CN) cmꢀ1. MS (ESI), m/z =
2-Amino-4-(4-methoxy-phenyl)-5,6-dimethyl-nicotinonitrile
(4d). Offꢀwhite solid: mp 276ꢀ277 oC; 1H NMR (400 MHz,
CDCl3, 25 °C) δ = 1.97 (s, 3H, CH3), 2.44 (s, 3H, CH3), 3.86 (s,
307 [M+H]+. EA calcd (%) for C19H22N4 (306.40): calcd. C 100 3H, OCH3), 5.0 (s, 2H, NH2), 6.98 (d, 2H, J = 8.5 Hz), 7.17 (d,
74.48, H 7.24, N 18.29; found. C 74.56, H 7.28, N 18.32.
2H, J = 8.5 Hz) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
15.36, 23.78, 55.29, 89.94, 114.05, 119.95, 128.90, 129.58,
129.81, 153.68, 157.25, 159.89, 161.46 ppm. IR (KBr): 3320
(NH2), 2215 (CN) cmꢀ1. MS (ESI), m/z = 254 [M+H]+. EA calcd
45 2-Amino-4-phenyl-5,6,7,8,9,10-hexahydro-
cycloocta[b]pyridine-3-carbonitrile (3h). Offꢀwhite solid: mp
o
1
234ꢀ235 C; H NMR (400 MHz, CDCl3, 25 °C) δ = 1.27ꢀ1.38 105 (%) for C15H15N3O (253.30): calcd. C 71.13, H 5.97, N 16.59;
(m, 6H), 1.68 (s, 2H), 2.38ꢀ2.80 (m, 4H), 6.58 (s, 2H, NH2), 7.23ꢀ
7.51 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
50 25.26, 25.76, 26.01, 30.01, 30.56, 34.87, 88.35, 116.59, 121.64,
127.91, 128.29, 128.40, 137.14, 153.75, 158.21, 165.19 ppm. IR
(KBr): 3316 (NH2), 2216 (CN) cmꢀ1. MS (ESI), m/z = 278
[M+H]+. EA calcd (%) for C18H19N3 (277.36): calcd. C 77.95, H
6.90, N 15.15; found. C 77.98, H 6.92, N 15.18.
found. C 71.18, H 5.99, N 16.64.
Notes and references
a School of Chemistry & Physics, University of Kwazulu-Natal, Westville
110 Campus, Chiltern Hills, Durban-4000, South Africa. Fax: +27 31 260
3091; Tel: +27 31 260 7325/3090; E-mail: jonnalagaddas@ukzn.ac.za
b Department of Chemistry, Satavahana University, Karimnagar, India.
cDepartment of Pharmaceutical Chemistry, Telangana University,
Nizamabad, India. Fax: +91-878-2255933; Tel: +91-9000285433; E-
115 mail: vasamcs@yahoo.co.in
55
2-Amino-4-phenyl-6,7-dihydro-5H-[1]pyrindine-3-
carbonitrile (3i). Offꢀwhite solid: mp 220ꢀ221 oC; 1H NMR (400
MHz, CDCl3, 25 °C) δ = 1.90ꢀ1.98 (m, 2H), 2.60 (t, 2H, J = 7.3
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† Electronic Supplementary Information (ESI) available: Optimization of
reaction parameters, Catalayst load table, and all the spectra of
multisubstituted pyridine derivatives 3a-i & 4a-d and crystallographic
data of compound 3a. See DOI: 10.1039/b000000x/
‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
5
(a) S. H. A. M. Leenders, R. GramageꢀDoria, B. de Bruin and J. N.
H. Reek, Chem. Soc. Rev., 2015,44, 433; (b) Z. Huang, H. N. Lim, F.
Mo, M. C. Young and G. Dong, Chem. Soc. Rev., (2015), Advance
Article (DOI: 10.1039/C5CS00272A); (c) F. Chen, T. Wang and N.
Jiao, Chem. Rev., 2014, 114, 8613; (d) L. Huang, M. Arndt, K.
Gooßen, H. Heydt and L. J. Gooßen, Chem. Rev., 2015, 115, 2596;
(e) G. Fang and X. Bi, Chem. Soc. Rev., (2015), Advance Article,
(DOI: 10.1039/C5CS00027K); (f) J. Kan, S. Huang, J. Lin, M.
Zhang and W. Su, Angew. Chem. Int. Ed., 2015, 54, 2199.
(a) D. J. Liu and E. Y. ꢀX. Chen, Green Chem., 2014, 16, 964; (b) D.
W. C. MacMillan, Nature, 2008, 455, 304; (c) Z. Du and Z. Shao,
Chem. Soc. Rev., 2013, 42, 1337; (d) S. Bertelsen and K. A.
Jørgensen, Chem. Soc. Rev., 2009, 38, 2178; (e) C. F. Barbas III,
Angew. Chem. Int. Ed., 2008, 47, 42; (f) M. C. Holland and R.
Gilmour, Angew. Chem. Int. Ed., 2015, 54, 3862.
(a) C. Li, B. VillaꢀMarcos and J. Xiao, J. Am. Chem. Soc., 2009, 131,
6967; (b) C. S. Schindler and E. N. Jacobsen, Science, 2013, 340,
1052; (c) L. Stegbauer, F. Sladojevich and D. J. Dixon, Chem.
Sci., 2012, 3, 942; (d) R. Peters, Cooperative Catalysis, (ed.),
ISBN 978ꢀ3ꢀ527ꢀ33689ꢀ0ꢀWileyꢀVCH, 1st Edition 2015; (e) X.ꢀQ.
Dong, Q. Zhao, P. Li, C. Chen and X. Zhang, Org. Chem.
Front., (2015), Accepted Manuscrip, (DOI: 10.1039/C5QO00226E);
(f) R. Lebeuf, K. Hirano and F. Glorius, Org. Lett., 2008, 10, 4243;
(g) D. E. A. Raup, B. CardinalꢀDavid, D. Holte and K. A. Scheidt,
Nat. Chem., 2010, 2, 766; (h) J. Mo, X. Chen and Y. R. Chi, J. Am.
Chem. Soc., 2012, 134, 8810.
(a) N. Kayambu, Z. Tingshun, C. Jiajia, Z. Pengcheng, L. Xiangyang,
Y. Song, S. BaoꢀAn and R. C. Yonggui, Nat. Commun., 2014, 5,
3982; (b) N. T. Patil, Angew. Chem. Int. Ed., 2011, 50, 1759.
(a) V. Maya, M. Raj and V. K. Singh, Org. Lett., 2007, 9, 2593; (b)
A. Martínez, K. Zumbansen, A. Döhring, M. van Gemmeren and B.
List, Synlett, 2014, 25, 932; (c) Z. Tang, Z.ꢀH. Yang, X.ꢀH. Chen, L.ꢀ
F. Cun, A.ꢀQ. Mi, Y.ꢀZ. Jiang and L.ꢀZ. Gong, J. Am. Chem.
Soc., 2005, 127, 9285; (d) Y. Hayashi, T. Sumiya, J. Takahashi, H.
Gotoh, T. Urushima and M. Shoji, Angew. Chem. Int. Ed., 2006, 45,
958; (e) H.ꢀX. Wei, R. L. Jasoni, H. Shao, J. Hu and P. W.
Pare, Tetrahedron, 2004, 60, 11829.
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
1
(a) J. Rouden, M.ꢀC. Lasne, J. Blanchet and J. Baudoux, Chem.
Rev., 2014, 114, 712; (b) S. M. Parrish, W. Y. Yoshida, T. P.
Kondratyuk, E.ꢀJ. Park, J. M. Pezzuto, M. Kelly and P. G. Williams,
J. Nat. Prod., 2014, 77, 1644; (c) X. Yue, X. Yan, C. Wu, G. Niu, Y.
Ma, O. Jacobson, B. Shen, D. O. Kiesewetter and X. Chen, Mol.
Pharmaceutics, 2014, 11, 3875; (d) Y.ꢀH. Ye, L. Ma, Z.ꢀC. Dai, Y.
Xiao, Y.ꢀY. Zhang, D.ꢀD. Li, J.ꢀX. Wang and H.ꢀL. Zhu, J. Agric.
Food Chem., 2014, 62, 4063; (e) G. Desimoni, G. Faita and P.
Quadrelli, Chem. Rev., 2014, 114, 6081; (f) L. C. Morrill and A. D.
Smith, Chem. Soc. Rev., 2014, 43, 6214; (g) N. M. Barl, E.
SansiaumeꢀDagousset, G. Monzón, A. J. Wagner and P. Knochel,
Org. Lett., 2014, 16, 2422; (h) S. Zhou, G. M. Anderson, B. Mondal,
E. Doni, V. Ironmonger, M. Kranz, T. Tuttle and J. A. Murphy,
Chem. Sci., 2014, 5, 476; (i) X. Zhang, T. Nakanishi, T.
Ogawa, A. Saeki, S. Seki, Y. Shen, Y. Yamauchi and M.
Takeuchi, Chem. Commun., 2010, 46, 8752; (j) Y.ꢀY. Zhang, Y.ꢀJ.
Lin and G.ꢀX. Jin, Chem. Commun., 2014, 50, 2327; (k) K. Heo, C.
Miesch, T. Emrick and R. C. Hayward, Nano Lett., 2013, 13, 5297;
(l) N. Li, P. Wang, S.ꢀL. Lai, W. Liu, C.ꢀS. Lee, S.ꢀT. Lee and Z. Liu,
Adv. Mater., 2010, 22, 527; (m) B. Lim, J. T. Bloking, A. Ponec, M.
D. McGehee and A. Sellinger, ACS Appl. Mater. Interfaces, 2014, 6,
6905; (n) K.ꢀY. Shih, Y.ꢀC. Lin, T.ꢀS. Hsiao, S.ꢀL. Deng and S.ꢀW.
Kuo, J.ꢀL. Hong, Polym. Chem., 2014, 5, 5765.
6
7
85
90
95
8
9
100
2
(a) C.ꢀH. Lei, D.ꢀX. Wang, L. Zhao, J. Zhu and M.ꢀX. Wang, J. Am.
Chem.
C. Doebelin, P. Wagner, F. Bihel, N. Humbert, C.
A. Kenfack, Y. Mely, J.ꢀJ. Bourguignon and M. Schmitt, J. Org.
Soc., 2013, 135,
4708;
(b)
Chem., 2014, 79, 908; (c) B.ꢀT. Guan and Z. Hou, J. Am. Chem. 105
Soc., 2011, 133, 18066; (d) D. C. Mohan, S. N. Rao and S.
Adimurthy, J. Org. Chem., 2013, 78, 1266; (e) Q. Chen, T. León and
P. Knochel, Angew. Chem. Int. Ed., 2014, 126, 1; (f) X. Meng, Y.
Wang, C. Yu and P. Zhao, RSC Adv., 2014, 4, 27301; (g) A.
10 (a) A. C. Sentman, S. Csihony, R. M. Waymouth and J. L. Hedrick,
J. Org. Chem., 2005, 70, 2391; (b) J. Pytkowicz, S. Roland and P.
Mangeney, Tetrahedron: Asymmetry., 2001, 12, 2087; (c) A.
Piermattei, S. Karthikeyan and R. P. Sijbesma,, Nat. Chem., 2009, 1,
133; (d) W. Z.ꢀGuo, S. Z.ꢀXian, B. Q.ꢀQuan, L. S.ꢀMan, L. Ting,
Chinese J. Struct. Chem., 2011, 31, 1334; (e) R. Savka, Synlett, 2013,
24, 1735; (f) O. Coulembier, J. ꢀM. Raquez, P. Dubois, Polimery
2008, 53, 253; (g) N. E. Kamber, W. Jeong and R. M. Waymouth, R.
C. Pratt, B. G. G. Lohmeijer and J. L. Hedrick, Chem. Rev.,
2007, 107, 5813; (h) S. Karthikeyan, S. L. Potisek, A. Piermattei and
R. P. Sijbesma, J. Am. Chem. Soc., 2008, 130, 14968; (i) S. Naumann
and M. R. Buchmeiser, Catal. Sci. Technol., 2014, 4, 2466.
Dhakshinamoorthy and H. Garcia, Chem. Soc. Rev., 2014, 43, 5750.
(a) J. M. Neely and T. Rovis, J. Am. Chem. Soc., 2014, 136, 2735; (b)
S. Rostamnia and A. Morsali, RSC Adv., 2014, 4, 10514; (c) Y.
Jiang, CꢀM. Park and TꢀP. Loh, Org. Lett., 2014, 16, 3432; (d) Z. Shi
and T.ꢀP. Loh, Angew. Chem. Int. Ed., 2013, 52, 8584; (e) D. G.
110
3
Stark, L. C. Morrill, P.ꢀP. Yeh, A. M. Z. Slawin, T. J. C. O'Riordan 115
and A. D. Smith, Angew. Chem. Int. Ed., 2013, 52, 11642; (f) H. T.
AbdelꢀMohsen, J. Conrad and U. Beifuss, Green Chem., 2012, 14,
2686; (g) Z. He, D. Dobrovolsky, P. Trinchera and A. K. Yudin, Org.
Lett., 2013, 15, 334; (h) R. Ananthakrishnan and S. Gazi, Catal. Sci.
Technol., 2012, 2, 1463; (i) B. Jiang, W.ꢀJ. Hao, X. Wang, F. 120 11 (a) I. J. B. Lin and C. S. Vasam, Coord. Chem. Rev., 2007, 251, 642;
Shi and S.ꢀJ. Tu, J. Comb. Chem., 2009, 11, 846.
(b) I. J. B. Lin and C. S. Vasam, Comments Inorg. Chem., 2004, 25,
75; (c) H. M. J. Wang and I. J. B. Lin, Organometallics, 1998, 17,
972; (d) I. J. B. Lin and C. S. Vasam, Can. J. Chem., 2005, 83, 812;
(e) I. J. B. Lin and C. S. Vasam J. Organomet. Chem., 2005, 690,
3498; (f) H. M. J. Wang, C. S. Vasam, T. Y. R. Tsai, S.ꢀH. Chen, A.
H. H. Chang and I. J. B. Lin, organometallics, 2005, 24, 486; (g) J.
C. Garrison and W. J. Youngs, Chem. Rev., 2005, 105, 3978.
4
(a) X. Xin, Y. Wang, S. Kumar, X. Liu, Y. Lin and D. Dong, Org.
Biomol. Chem., 2010, 8, 3078; (b) B. Jiang, W.ꢀJ. Hao, X. Wang, F.
Shi and S.ꢀJ. Tu, J. Comb. Chem., 2009, 11, 846; (c) F. Zhou, X. Liu,
N. Zhang, Y. Liang, R.Zhang, X. Xin, and D. Dong, Org. 125
Lett., 2013, 15, 5786; (d) F. Sha, L. Wu and X. Huang, J. Org.
Chem., 2012, 77, 3754; (e) L. Zheng, J. Ju, Y. Bin and R. Hua, J.
Org. Chem., 2012, 77, 5794; (f) S.Yamamoto, K. Okamoto, M.
Murakoso, Y. Kuninobu, and K. Takai, Org. Lett., 2012, 14, 3182;
(g) Z. He, D. Dobrovolsky, P. Trinchera and A. K. Yudin, Org. 130
Lett., 2013, 15, 334; (h) C. Wang, D. Wang, F. Xu, B. Pan, and B.
Wan, J. Org. Chem., 2013, 78, 3065; (i) P. Thirumurugan, P. T.
Perumal, Tetrahedron, 2009, 65, 7620; (j) C. Wang, X. Li, F. Wu,
and B. Wan, Angew. Chem. Int. Ed., 2011, 50, 7162; (k) V. P. A.
Raja, G. Tenti, S. Perumal and J. C. Menéndez, Chem. Commun., 135
2014, 50, 12270; (l) Y. Hao, X. ꢀP. Xu, T. Chen, LꢀL. Zhao and SꢀJ.
Ji, Org. Biomol. Chem., 2012, 10, 724; (m) J. Hu, Z. Deng, X. Zhang,
F. Zhang and H. Zheng, Org. Biomol. Chem., 2014, 12, 4885; (n) K.
Shekarrao, P. P. Kaishap, S. Gogoi and R. C. Boruah, RSC Adv.,
2014, 4, 14013.
12 (a) M. N. Hopkinson, C. Richter, M. Schedler and F. Glorius, Nature,
2014, 510, 485; (b) L. He, H. Guo, YꢀZ. Li, GꢀF. Du and B.
Dai, Chem. Commun., 2014, 50, 3719; (c) L. R. Domingo, J. A. Sáez
and M. Arnó, Org. Biomol. Chem., 2014, 12, 895; (d) S. W. Youn, H.
S. Song and J. H. Park, Org. Biomol. Chem., 2014, 12, 2388; (e) M.
Fèvre, J. Pinaud, Y. Gnanou, J. Vignolle and D. Taton, Chem. Soc.
Rev., 2013, 42, 2142; (f) D. Enders, O. Niemeier, and A. Henseler,
Chem. Rev., 2007, 107, 5606; (g) B. Maji, M. Breugst and H. Mayr,
Angew. Chem. Int. Ed., 2011, 50, 6915; (h) X. Bugaut and F.
Glorius, Chem. Soc. Rev., 2012, 41, 3511; (i) N. Marion, S. Díezꢀ
González and S. P. Nolan, Angew. Chem. Int., Ed., 2007, 46, 2988.
13 Z. Chen, X. Yua and J. Wu, Chem. Commun., 2010, 46, 6356.
140 14 (a) R. Pagadala, S. Maddila, V. Moodley, W. E. Van Zyl and S. B.
Jonnalagadda, Tetrahedron Lett., 2014, 55, 4006; (b) R. Pagadala, S.
6
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Maddila, S. Rana and S. B. Jonnalagadda, RSC Adv., 2014, 4, 6602;
(c) R. Pagadala, S. Maddila, V. D. B. C. Dasireddy and S. B.
Jonnalagadda, Catal. Commun. 2014, 45, 148; (d) R. Pagadala, S.
Maddila and S. B. Jonnalagadda, Ultrasonics Sonochem., 2014, 21,
472; (e) R. Pagadala, D. R. Kommidi, S. Kankala, S. Maddila, P.
Singh, B. Moodley, N. A. Koorbanally and S. B. Jonnalagadda, Org.
Biomol. Chem., 2015, 13, 1800; (f) S. Maddila, S. Rana, R. Pagadala,
S. Kankala, S. Maddila and S. B. Jonnalagadda, Catal. Commun.,
2015, 61, 26.
5
10 15 (a) S. Kankala, R. K. Kankala, D. R. Kommidi, C. Mudithanapelli, R.
Balaboina, R. Vadde, S. B. Jonnalagadda and C. S. Vasam, RSC
Adv., 2014, 4, 40305; (b) S. Kankala, R. Vadde and C. S. Vasam,
Org. Biomol. Chem., 2011, 9, 7869; (c) S. Kankala, R. Edulla, S.
Modem, R. Vadde and C. S. Vasam, Tetrahedron Lett., 2011, 52,
15
3828; (d) S. Kankala, R. K. Kankala, R. Balaboina, N. S.
Thirukovela, R. Vadde and C. S. Vasam, Bioorg. Med. Chem. Lett.,
2014, 23, 1180; (e) S. Kankala, R. K. Kankala, P. Gundepaka, N.
Thota, S. Nerella, M. R. Gangula, H. Guguloth, M. Kagga, R. Vadde
and C. S. Vasam, Bioorg. Med. Chem. Lett., 2013, 23, 1306.
20 16 J. Tang, L. Wang, Y. Yao, L. Zhang and W. Wang, Tetrahedron
Lett., 2011, 52, 509.
17 (a) F. Shi, S. Tu, F. Fang and T. Li, ARKIVOC 2005, (i), 137; (b) D.
C. Mungra, M. P. Patel and R. G. Patel, ARKIVOC 2009, (xiv), 64.
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Graphilcal Abstract
Silver(I)-N-heterocyclic carbene catalyzed multicomponent reactions: a facile
synthesis of multisubstituted pyridines
Shravankumar Kankala,a Ramakanth Pagadala,a Suresh Maddila,a Chandra Sekhar
Vasam,*b Sreekantha B. Jonnalagadda*a
A room temperature four component reaction between aromatic aldehydes (1a-g),
malononitrile and ammonium acetate with ketones (2a-d) mediated by Ag(I) N-
heterocyclic carbene pre-catalysts to produce multisubstituted and fused pyridines in
short reaction time (~10 min) in eco-friendly ethanol was described.
O
R
N
AgCl
N
2a-c
Ar
Ar
R
NC
CH3
CH3
NC
or
catalyst (2 mol%)
or
Ar CHO
1a-g
O
(i) CH2(CN)2
(ii) CH3CO2NH4
EtOH, 10 min, rt
H2N
N
H2N
N
3a-i
2d
4a-d