Simple and convenient approach to the kr€ohnke pyridine type synthesis of functionalized indol-3-yl pyridine derivatives using 3-cyanoacetyl indole

Article abstract of DOI:10.1021/cc9001394

Access to privileged heterocyclic scaffolds involving 4-aryl-6-(l H-indol-3-yl)-2,2-bipyridine-5-carbonitriles and 6-(2-fuiyl)-2-(lH-indol-3-yl)- 4-arylpyridine-3-carbonitriles frameworks has been achieved via a singlestep multicomponent reaction of structurally diverse aldehydes, 2-acetylpyridine (or) 2-acetylfuran and 3-cyanoacetyl indole in ammonium acetate under neat condition. Also a series of 6,6'-di(lH-indol-3-yl)4,4'-diaryl-2,2'-bipyridine-5, 5'-dicarbonitrile and 7,7,7',7'-tetrametliyl-4,4'-bis(aryl)-4,6,7,8,4',6',7',8'- octahydro-lH,lH-[2,2']biquinorinyl-5,5'-dione derivatives are synthesized using cinnamil, 3-cyanoacetyl indole (or) dimedone and ammonium acetate.

Full text of DOI:10.1021/cc9001394

J. Comb. Chem. 2010, 12, 161–167
161
Simple and Convenient Approach to the Kr€ohnke Pyridine Type
Synthesis of Functionalized Indol-3-yl Pyridine Derivatives Using
3-Cyanoacetyl Indole
Prakasam Thirumurugan, A. Nandakumar, D. Muralidharan, and
Paramasivan T. Perumal*
Organic Chemistry DiVision, Central Leather Research Institute, Adyar, Chennai, 600020 Tamilnadu, India
ReceiVed September 2, 2009
Access to privileged heterocyclic scaffolds involving 4-aryl-6-(1H-indol-3-yl)-2,2-bipyridine-5-carbonitriles
and 6-(2-furyl)-2-(1H-indol-3-yl)-4-arylpyridine-3-carbonitriles frameworks has been achieved via a single-
step multicomponent reaction of structurally diverse aldehydes, 2-acetylpyridine (or) 2-acetylfuran and
3-cyanoacetyl indole in ammonium acetate under neat condition. Also a series of 6,6′-di(1H-indol-3-yl)-
4,4′-diaryl-2,2′-bipyridine-5,5′-dicarbonitrile and 7,7,7′,7′-tetramethyl-4,4′-bis(aryl)-4,6,7,8,4′,6′,7′,8′-oc-
tahydro-1H,1H-[2,2′]biquinolinyl-5,5′-dione derivatives are synthesized using cinnamil, 3-cyanoacetyl indole
(or) dimedone and ammonium acetate.
1.0. Introduction
and structurally discrete biological receptors through ap-
propriate functional group modifications. Some of the
biologically active 3-substituted indole representatives are
shown in Figure 1.10-14
The structural diversity and biological importance of
nitrogen containing heterocycles have made them attractive
targets for synthesis over many years. They are found in
various natural products and have been identified as products
of chemical and biological importance. Multicomponent
reactions (MCR) have emerged as a powerful tool for
delivering the molecular diversity needed in the combina-
torial approaches for the preparation of bioactive heterocyclic
compounds.1 MCR, such as the Biginelli,2 Passerini,3 Ugi,4
and Hantzsch, provide a wide variety of important hetero-
cycles.5 For example, the Hantzsch reaction provides dihy-
dropyridines with activity against calcium channels, multi-
drug resistance (MDR) proteins, 5-hydroxytryptamine(5-HT)
receptors, and anti-inflammatory targets.6,7
The wide-ranging biological activity associated with many
pyridine and 3-substituted indole derivatives, both naturally
occurring and synthetic, ensures that the synthesis of this
important ring system remains a topic of current interest.
Various methods for the preparation of these compounds
have been reported. However, these methods suffer from
tedious synthetic routes, longer reaction time, drastic reaction
conditions, as well as narrow substrate scope.15-19 To the
best of our knowledge, there have been very few reports for
the synthesis of 6-(indol-3-yl)-2,2′-bipyridine derivatives.20
As part of our ongoing research on the development of novel
synthetic routes for the synthesis of biologically active
Pyridine derivatives occupy a central position in modern
heterocyclic chemistry particularly in the pharmaceutical and
agrochemical fields.8 Bipyridines have been well-known as
highly interesting organic ligands for transition metals for
more than a century. In particular, the 2,2′-bipyridines were
used in investigations in analytical chemistry, medical
chemistry, and energy conversion processes. Many applica-
tions of 2,2′-bipyridine derivatives have been reported in
fields such as supramolecular chemistry, artificial photosyn-
thesis systems, luminescent sensor materials, and non-linear
optical materials.9
On the other hand, 3-substituted indole is the one of the
“privileged medicinal scaffold” found in many natural
products10,11 and biologically active compounds especially
with anticancer, antitumor,12 hypoglycemic, anti-inflamma-
tory, analgesic, and antipyretic activities.13,14 These scaffolds
are capable of providing ligands for a number of functionally
* To whom correspondence should be addressed. E-mail: ptperumal@
gmail.com. Phone: +91 44 24913289. Fax: +91 44 24911589.
Figure 1. Representatives of 3-substituted indoles.
10.1021/cc9001394 CCC: $40.75  2010 American Chemical Society
Published on Web 11/11/2009

162 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Thirumurugan et al.
Scheme 1
Scheme 2. Synthesis of 6-(Indol-3-yl)-2,2′-bipyridine
Derivatives from Various Substituted Aldehydes
containing ether, nitro, halogens, heterocyclic and polyaro-
matic groups.(Scheme 2) Then, we next extended our
investigation to the microwave irradiated synthesis of 6-(in-
dol-3-yl)-2,2′-bipyridine derivatives. The yield of the product
is good on comparison with that obtained by the conventional
method. The results are summarized in Table 2, Method A.
On the basis of the above results, a tentative mechanistic
interpretation to explain the formation of 6-(indol-3-yl)-2,2′-
bipyridine derivatives (Scheme 3) is proposed. Initially, aryl
aldehyde 1 reacts with 3-(cyanoacetyl)indole 3 to form the
unsaturated ketone 3a, which in turn adds 2-acetylpyridine
(2, in its enol form 2′) to give compound 3b/3b′. Then, the
latter 3b′ reacts with ammonium acetate to form an inter-
mediate 3c/3c′, which by elimination of water gives the
Hantzsch 1,4-dihydropyridine 3d. Under the reaction condi-
tions the latter undergoes ready dehydrogenation to the
aromatized pyridine derivative 4.
Table 1. Screening of Various Solvents
entry
solvent
yield (%)a,b
1
2
3
4
5
6
DMF
64
79
78
83
72
87
Methanol
Acetonitrile
Water
Ethanol
Neat (120 °C)
a Isolated yield after column chromatography. b All the reactions
were carried out for 6 h.
heterocyclic compounds and use of green chemical tech-
niques in organic synthesis,21-23 herein, we report a simple
and facile one pot procedure for the synthesis of indol-3-yl
pyridine derivatives under neat condition.
2.0. Result and Discussion
Initial studies were carried out with a reaction of p-
tolualdehyde (1b), 2-acetylpyridine (2), and 3-cyanoacetyl
indole (3)24 in the presence of ammonium acetate in various
solvents at reflux temperature. (Scheme 1, Table 1) Excellent
results were obtained under neat condition at 120 °C with
high yield of the product in a shorter reaction time. (Table
1, entry 6) So we followed the reaction that employs the
heating of mixture of aldehyde, 2-acetylpyridine, 3-cy-
anoacetyl indole, and ammonium acetate at 120 °C. Under
these conditions, the reaction proceeded smoothly with a
wide range of functionalized aldehydes, including those
The structures of the products 4a-t were deduced from
1
their IR, H NMR, and 13C NMR spectral data. The mass
spectra of these compounds displayed (M+H+) peaks at the
appropriate m/z values. Finally, the structure of 4h was
confirmed unambiguously by single crystal X-ray analysis
(Figure 2).
On the other hand, the same reaction proceeding with 2,4-
dichlorobenzaldehyde under optimized conditions resulted
in Hantzsch 1,4-dihydropyridine derivatives, whereas all
other aldehydes yielded only pyridine derivatives. For entry
1u, the conventional heating gave 78% yield of Hantzsch
Table 2. Synthesis of 6-(Indol-3-yl)-2,2′-bipyridine Derivatives
method Ab
conventional heating microwave irradiation
producta time (h) yield (%)d time (min) yield (%)d time (h)
method Bc
conventional heating
microwave irradiation
entry
R
yield (%)d time (min) yield (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Phenyl (1a)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
6.0
5.5
6.0
5.5
5.5
6.5
6.5
6.5
6.0
6.5
6.5
5.5
7.5
7.5
6.5
6.5
6.5
7.5
6.5
6.0
86
87
81
88
89
87
80
79
78
76
76
72
71
71
79
71
76
78
67
69
17
14
15
14
13
18
16
17
16
17
17
18
18
18
15
18
16
18
16
17
88
88
82
90
91
90
81
82
79
77
78
77
76
75
81
75
81
82
72
72
5.0
4.5
5.5
5.5
5.0
6.0
6.0
5.5
6.0
5.5
5.5
4.5
6.5
6.5
5.5
6.0
6.0
6.5
5.0
5.0
90
91
86
92
92
91
88
86
87
86
82
81
76
80
82
81
82
86
77
78
12
11
12
14
12
18
14
15
16
13
14
14
14
14
12
13
14
14
12
13
93
94
88
94
92
92
90
89
87
86
84
83
78
84
85
82
85
89
84
81
4-Methylphenyl (1b)
3-Methylphenyl (1c)
4-Methoxyphenyl (1d)
4-Dimethoxyphenyl (1e)
1-Napthyl (1f)
4-Chlorophenyl (1g)
4-Bromophenyl (1h)
4-Fluorophenyl (1i)
3-Nitrophenyl (1j)
3-Nitrophenyl (1k)
3-Bromophenyl (1l)
2-Bromophenyl (1m)
2-Chrolophenyl (1n)
2-Furo (1o)
Indol-3-yl (1p)
4-Pyridyl (1q)
2-Pyridyl (1r)
1-Imadazolyl (1s)
2-Thienyl (1t)
4t
a All the products were characterized by IR, 1H NMR, 13C NMR, and mass spectroscopy. b All reaction were carried without urea nitrate under
optimized condition. c All reaction were carried with urea nitrate under optimized condition. d Isolated yield of the product.

Synthesis of Kr€ohnke Pyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 163
Scheme 3. Plausible Mechanism for the Formation of
6-(Indol-3-yl)-2,2′-bipyridine Derivatives
Figure 2. ORTEP diagram of compound 4h.
of the compound was confirmed by single crystal X-ray
diffraction analysis.29 (Figure 4).
We modified the protocol by adding urea nitrate in the
reaction mixture. (Table 2, entry 1-20) Addition of urea
nitrate 20 mol % helped to improve the yield product (4a-t)
considerably in a shorter reaction time. (Table 2, Method
B).
Many bis(bipyridyl) derivatives are capable of forming
multi nuclear complexes. Fused pyridines are useful sub-
structures in the design of supramolecular compounds. These
chelating ligands show high affinities for transition metal
ions and which frequently stabilize unusually low oxidation
state species because of both dπ*-pπ* back-bonding by the
cations and their capacity to form ligated anion radicals.26
We extended our protocol to the synthesis of bis(6-(indol-
3-yl)-2,2′-bipyridine) derivatives under optimized conditions.
Terephthaldialdehyde (0.5 mmol), 3-cyanoacetyl indole (1
mmol), and 2-acetyl pyridine under optimized conditions
gave bis(6-(indol-3-yl)-2,2′-bipyridine) derivative in good
yield. The reaction took a longer time for the complete
formation of the product. The crude product was precipitated
in ice cold water, filtered, washed with ethanol, and then
dried. The isolated product was further purified by recrys-
tallization with DMF, and the isolated yield was 68% in
Method A. By the addition of 20 mol % of urea nitrate to
the reaction mixture the yield of the product was increased
up to 76%. (Method B, Scheme 5).
dihydropyridine derivative in 6 h, and the microwave reaction
yielded up to 81% in 18 min. (Scheme 4).
The structure of Hantzsch 1,4-dihydropyridine (5) was
1
thoroughly investigated with spectral (IR, H NMR, 13C
NMR), elemental, and single crystal X-ray diffraction studies.
The ORTEP diagram of compound 5 shown in Figure 3.
Non-aromatized dihydropyridine derivative (5) was further
oxidized by using urea nitrate as the catalyst. Urea nitrate
in solvent slowly releases nitric acid which is involved in
the oxidation reaction. Since urea nitrate is inexpensive and
easy to prepare, we explored the ability to catalyze the
oxidation reaction in a shorter reaction time.25 A 20 mol %
of urea nitrate used for the oxidation of non-aromatized
product (5) in ethanol gave 86% yield of pyridine derivative
(6) under microwave irradiation.
The compound 6 was fully characterized by IR, 1H NMR,
13C NMR and mass spectrometry. The spectral data was in
good agreement with their structure. Further, the structure
Scheme 4. Synthesis of Dihydro Pyridine Derivative

164 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Thirumurugan et al.
To study the unique supramolecular properties of oligopy-
ridinyl derivatives, we extended our protocol to the synthesis
of bis(indol-3-yl pyridine) spacers under optimized condi-
tions. Oligopyridines are extremely versatile ligands for the
assembly of metallosupramolecular systems and enantiose-
lective asymmetric synthesis.27,28 1,6-Diarylhexa-l,5-diene-
3,4dione, 3-cyanoacetyl indole, and ammonium acetate under
reflux condition gave bis(3-indolyl pyridine) in good yield.
(Table 3, Method A and Scheme 6) To further explore the
utility of bis(indol-3-yl pyridine) derivative, reaction under
the optimized conditions were investigated, and the reaction
was amendable to a variety of substituent’s on cinnamils
bearing ethers, chloro, bromo, and hydrocarbons. Addition
of 20 mol % of urea nitrate was facilitated to improve the
yield of all the products 10a-g in a shorter reaction time.
(Table 3, Method B).
Figure 3. ORTEP diagram of compound 5.
The structures of compounds (10a-g) were evaluated
1
based on detailed IR, H NMR, 13C NMR, mass spectral
studies, and elemental analysis. The spectral data were in
good agreement with their structures.
In contrast, the reaction proceeded with 1,6-diarylhexa-
l,5-diene-3,4dione, dimedone, and ammonium acetate under
optimized condition to give bis(indol-3yl dihydropydine)
derivatives in moderate yields. The scope of the reaction was
further extended to various substituted cinnamils bearing
ethers, bromo, and hydrocarbons. (Table 4, Method A and
Scheme 7) However, addition of 20 mol % of urea nitrate
to reaction mixture of compounds 12a-f did not lead to the
formation of pyridine derivatives. The structures of com-
pounds (12a-f) were examined based on detailed spectro-
scopic studies like IR, 1H NMR, 13C NMR spectral studies,
and elemental analysis.
Figure 4. ORTEP diagram of compound 6.
The structure of bis(6-(indol-3-yl)-2,2′-bipyridine) deriva-
1
tive was thoroughly characterized based on IR, H NMR,
13C NMR spectral studies, and elemental analysis. The mass
spectra of products displayed (M+H+) peaks at the appropri-
ate m/z values.
Encouraged by the above results, we extended our protocol
to the synthesis of 2-(2-furo)6-(indol-3-yl)pyridine derivatives
Scheme 5. Synthesis of Bis(6-(indol-3-yl)-2,2′-bipyridine) Derivative
Table 3. Synthesis of 6,6′-Di(1H-indol-3-yl)-4,4′-diaryl-2,2′-bipyridine-5,5′-dicarbonitrile
method Ab
method Bc
yield (%)d
entry
Ar
producta
time (h)
yield (%)d
time (h)
1
2
3
4
5
6
7
Phenyl (9a)
10a
10b
10c
10d
10e
10f
12.0
11.0
12.0
10.0
11.0
12.0
12.0
65
66
62
68
70
58
55
11.0
10.5
11.0
9.0
11.5
11.0
11.0
72
74
68
74
76
66
64
4-Methylphenyl (9b)
3-Methylphenyl (9c)
4-Methoxyphenyl (9d)
3,4-Dimethoxyphenyl (9e)
4-Chlorophenyl (9f)
4-Bromophenyl (9g)
10g
a All the products were characterized by IR, 1H NMR, 13C NMR, and mass spectroscopy. b All reactions were carried without urea nitrate under
optimized conditions. c All reactions were carried with urea nitrate under optimized conditions. d Isolated yield of the product.

Synthesis of Kr€ohnke Pyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 165
Scheme 6. Synthesis of 6,6′-Di(1H-indol-3-yl)-4,4′-diaryl-2,2′-
bipyridine-5,5′-dicarbonitrile Derivatives
Scheme 7. Synthesis of 7,7,7′,7′-Tetramethyl-4,4′-bis(aryl)-4,6,7,
8,4′,6′,7′,8′-octahydro-1H,1H-[2,2′]biquinolinyl-5,5′-dione
Derivatives
Table 5. Synthesis of 2-(Furo)-6-(indol-3-yl) Pyridine Derivatives
method Ab
method Bc
Table 4. Synthesis of 7,7,7′,7′-Tetramethyl-4,4′-bis(aryl)-4,6,7,
8,4′,6′,7′,8′-octahydro-1H,1H-[2,2′]biquinolinyl-5,5′-dione derivatives
time yield time yield
method Ab
entry
Ar
producta
(h)
(%)d
(h)
(%)d
entry
Ar
producta time (h) yield (%)c
1
2
3
4
5
6
7
8
9
4-Methylphenyl (1a)
4-Chlorophenyl (1b)
3-Nitrophenyl (1c)
4-Fluorophenyl (1d)
4-Bromophenyl (1e)
3-Bromophenyl (1f)
4-Pyridinyl (1g)
2-Pyridinyl (1h)
2-Thienyl (1i)
Indol-3-yl (1j)
14a
14b
14c
14d
14e
14f
14g
14h
14i
6.0
7.0
7.5
7.0
7.0
7.5
7.0
6.5
7.0
7.5
74
71
68
70
76
76
79
73
76
77
5.0
6.0
6.5
6.5
6.5
6.0
5.5
6.0
6.5
6.0
79
77
74
75
81
78
79
81
81
82
1
2
3
4
5
6
a
Phenyl (9a)
12a
12b
12c
12d
12.0
11.0
11.5
12.0
11.0
14.0
55
56
48
58
52
42
4-Methylphenyl (9b)
3-Methylphenyl (9c)
4-Methoxyphenyl (9d)
3,4-Dimethoxyphenyl (9e) 12e
4-Bromophenyl (9f) 12f
All the products were characterized by IR, H NMR, 13C NMR, and
mass spectroscopy. b All reaction were carried without urea nitrate
under optimized conditions. c Isolated yield of the product.
1
10
14j
a
All the products were characterized by IR, H NMR, 13C NMR, and
mass spectroscopy. b All reaction were carried without urea nitrate
under optimized conditions. c All reaction were carried with urea nitrate
under optimized conditions. d Isolated yield of the product.
1
under optimized conditions. 2-Acetylfuran (1 mmol) and
aldehyde (1 mmol) in ammonium acetate were refluxed at
120 °C for 1-2 h (monitored by TLC). After complete
disappearance of both starting materials, 3-cyanoacetyl indole
(1 mmol) was added, and the refluxing was continued for
4-6 h. Finally the reaction mixture was poured into water
and extracted with ethyl acetate, and the organic layer was
dried with sodium sulfate. The crude product was purified
using column chromatography. The isolated product was
further purified by recrystallization in ethanol to obtain good
yield of 2-(2-furo)6-(indol-3-yl)pyridine derivatives. (Table
5 Method A and Scheme 8) The scope of the reaction was
further extended to various substituted aldehydes bearing
ether, chloro, bromo, nitro, and heterocycles. Addition of
20 mol % of urea nitrate to the reaction mixture enhanced
the yield of 14a-j considerably as shown Table 5, Method
B.
Scheme 8. Synthesis of 2-(Furo)-6-(indol-3-yl) Pyridine
Derivatives
spectral studies and elemental analysis. The mass spectra of
products displayed (M+H+) at the appropriate m/z values.
Furodihydropyridine derivative (15) was oxidized by using
urea nitrate as a catalyst. A 20 mol % of urea nitrate used
for the oxidation of non-aromatized product (15) in ethanol
gave 78% yield of pyridine derivative (16) under microwave
irradiation.
All aldehydes 1a-j reacted with 2-acetylfuran to form the
2-furopyridine derivatives, whereas 2, 4-dichlorobenzalde-
hyde reacted with 2-acetylfuran to yield 64% of 2-furodi-
hydropyridine derivative under optimized condition. (Scheme
9, Method A).
The structure and purity of the compound (16) was
thoroughly analyzed with IR, H NMR, 13C NMR spectral
1
studies and elemental analysis. The data was in agreement
with their structure.
The structure of furo Hantzsch 1,4-dihydropyridine (15)
1
was thoroughly characterized with IR, H NMR, 13C NMR
Scheme 9. Synthesis of 2-(Furo)-6-(indol-3-yl) Pyridine Derivatives

166 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Thirumurugan et al.
3.0. Conclusions
°C for an appropriate time as mentioned in Table 2, Method
B. After the completion of the reaction (as monitored by
TLC), it was poured into water and extracted with ethyl
acetate. The organic layer was dried over sodium sulfate and
concentrated under vacuum. The crude product was chro-
matographed, and the isolated yield is shown in Table 2,
Method B (90:10 petroleum ether/ ethyl acetate). The isolated
product was further purified by recrystallization in ethanol.
In summary, we have demonstrated a simple, facile, and
eco-friendly synthetic methodology for indol-3-yl pyridinyl
derivatives through multicomponent reaction. The versatility
of this chemistry offers a valuable addendum to methodology
for the synthesis of Kr€ohnke pyridines. Further studies to
delineate the scope and limitations of the present methodol-
ogy are underway.
(ii). Microwave Irradiation. A mixture of 3-cyanoacetyl
indole (1 mmol), aldehyde (1 mmol), 20 mol % of urea
nitrate and 2-acetylpyridine (1 mmol) in 5 g of ammonium
acetate under neat condition in a sealed tube was irradiated
in a microwave oven (BPL BMG 800 TS model) at 80W
for the appropriate time mentioned in the Table 2, Method
B. After completion of the reaction (as monitored by TLC),
it was poured into water and extracted with ethyl acetate.
The organic layer was dried over sodium sulfate and
concentrated under vacuum. The crude product was chro-
matographed, and the appropriate isolated yield is shown in
Table 2, Method B (90:10, petroleum ether/ethyl acetate).
The product was further purified by recrystallization in
ethanol.
4.3. Oxidation of 4-(2,4-Dichlorophenyl)-6-(1H-indol-
3-yl)-1,4-dihydro-2,2′-bipyridine-5-carbonitrile. A mixture
of 4-(2,4-dichlorophenyl)-6-(1H-indol-3-yl)-1,4-dihydro-2,2′-
bipyridine-5-carbonitrile 6a (1 mmol) and urea nitrate (20
mol %) was irradiated in a microwave oven in ethanol for 5
min. After completion of the reaction (as monitored by TLC),
it was poured into water and extracted with ethyl acetate.
The organic layer was dried over sodium sulfate and
concentrated under vacuum. The crude product was chro-
matographed and isolated in 86% yield (90:10 petroleum
ether/ethyl acetate).
4.0. Experimental Section
4.1. General Procedures. All the substituted aldehydes,
2-acetylpyridine, indole and DMSO-d6 were purchased from
Aldrich Chemicals. Acetic anhydride and other reagents were
procured from S. D. Fine. Chem. Limited and were used as
received. IR measurements were done as KBr pellets for
solids using Perkin-Elmer Spectrum RXI FT-IR. The 1H and
13C NMR spectra were recorded in DMSO-d6 using TMS as
internal standard with JEOL ECA-500 MHz and Bruker 400
and 500 MHz high resolution NMR spectrometer. Multiplici-
ties were abbreviated as follows: singlet (s), doublet (d),
triplet (t), multiplet (m), and broad (br). The mass spectra
were recorded using a Electrospray Ionization Method with
a Thermo Finnigan mass spectrometer. Melting points were
determined in capillary tubes and are uncorrected. Analytical
TLC was performed on precoated plastic sheets of silica gel
G/UV-254 of 0.2 mm thickness (Macherey-Nagel, Germany).
Elemental analysis data were recorded using Thermo Finni-
gan FLASH EA 1112 CHN instrument.
4.2. Synthesisof6-(Indol-3-yl)-2,2′-bipyridineDerivatives.
Method: A. (i). Conventional Heating. A mixture of
3-cyanoacetyl indole (1 mmol), aldehyde (1 mmol) and
2-acetylpyridine (1 mmol) in 5 g of ammonium acetate under
neat condition was refluxed at 120 °C for an appropriate time
mentioned as in Table 2, Method A. After the completion
of the reaction (as monitored by TLC), it was poured into
water and extracted with ethyl acetate. The organic layer
was dried over sodium sulfate and concentrated under
vacuum. The crude product was chromatographed, and the
isolated yield is shown in Table 2, Method A (90:10
petroleum ether/ethyl acetate). The isolated product was
further purified by recrystallization in ethanol.
4.4. Synthesis of Phenyl-1,4-bis(6-(1H-indol-3-yl)-2,2′-
bipyridine-5-carbonitrile). Method A. A mixture of 3-cy-
anoacetyl indole (1 mmol), aldehyde (0.5 mmol), and
2-acetylpyridine (1 mmol) in 5 g of ammonium acetate under
neat condition was refluxed at 120 °C for 8 h. After the
completion of the reaction (as monitored by TLC), it was
poured into water and then filtered. The residue was washed
with ethanol and then dried. The isolated product was further
purified by recrystallization in ethanol.
(ii). Microwave Irradiation. A mixture of 3-cyanoacetyl
indole (1 mmol), aldehyde (1 mmol) and 2-acetylpyridine
(1 mmol) in 5 g of ammonium acetate under neat condition
in a sealed tube was irradiated in microwave oven (BPL
BMG 800 TS model) at 80W for the appropriate time
mentioned in the Table 2, Method A. After completion of
the reaction (as monitored by TLC), it was poured into water
and extracted with ethyl acetate. The organic layer was dried
over sodium sulfate and concentrated under vacuum. The
crude product was chromatographed, and the appropriate
isolated yield is shown in Table 2, Method A (90:10,
petroleum ether/ethyl acetate). The product was further
purified by recrystallization in ethanol.
Method B. A mixture of 3-cyanoacetyl indole (1 mmol),
aldehyde (0.5 mmol), 20 mol % urea nitrate, and 2-acetylpy-
ridine (1 mmol) in 5 g of ammonium acetate under neat
condition was refluxed at 120 °C for 8 h. After the
completion of the reaction (as monitored by TLC), it was
poured into water and then filtered. The residue was washed
with ethanol and then dried. The isolated product was further
purified by recrystallization in ethanol.
4.5. Synthesis of 6,6′-bis-(1H-indol-3-yl)-4-4′-diaryl-
[2,2′]bipyridinyl-5,5′-dicarbonitrile. Method A. A mixture
of 3-cyanoacetyl indole or dimedone (2 mmol), cinnamil (1
mmol), and 5 g of ammonium acetate under neat condition
was refluxed at 120 °C for appropriate time mentioned as in
Table 3, Method A and Table 4. After the completion of the
reaction (as monitored by TLC), it was poured into water
and then filtered, washed with acetone, and then dried. The
obtained crude solid was purified further by recrystallization
Method: B. (i). Conventional Heating. A mixture of
3-cyanoacetyl indole (1 mmol), aldehyde (1 mmol), 20 mol
% of urea nitrate, and 2-acetylpyridine (1 mmol) in 5 g of
ammonium acetate under neat condition was refluxed at 120

Synthesis of Kr€ohnke Pyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 167
with DMF, and the appropriate isolated yield is shown in
Table 3, Method A and Table 4.
References and Notes
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(20 mol %) was irradiated in a microwave oven in ethanol
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Acknowledgment. One of the authors (P.T.) thanks the
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Supporting Information Available. Additional informa-
tion as noted in the text. This material is available free of
charge via the Internet at http://pubs.acs.org.
CC9001394