Synthesis of indole-cycloalkyl[b]pyridine hybrids via a four-component six-step tandem process

Article abstract of DOI:10.3762/bjoc.14.269

The one-pot four-component reaction of 3-(1H-indol-3-yl)-3-oxopropanenitriles, aromatic aldehydes, cycloalkanones and ammonium acetate occurred via a six-step tandem Knoevenagel condensation-nucleophilic addition to carbonyl-Michael addition-N-cyclization-elimination-air oxidation sequence to afford structurally intriguing indole-cycloalkyl[b]pyridine-3-carbonitrile hybrid heterocycles in excellent yields.

Full text of DOI:10.3762/bjoc.14.269

Synthesis of indole–cycloalkyl[b]pyridine hybrids
via a four-component six-step tandem process
Muthumani Muthu1, Rakkappan Vishnu Priya2, Abdulrahman I. Almansour3,
Raju Suresh Kumar3 and Raju Ranjith Kumar*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2907–2915.
1Department of Organic Chemistry, School of Chemistry, Madurai
Kamaraj University, Madurai 625 021, Tamil Nadu, India,
2Department of Physics, Madura College, Madurai 625011, Tamil
Nadu, India and 3Department of Chemistry, College of Science, King
Saud University, Riyadh 11451, Saudi Arabia
doi:10.3762/bjoc.14.269
Received: 17 September 2018
Accepted: 09 November 2018
Published: 22 November 2018
Email:
Associate Editor: I. R. Baxendale
Raju Ranjith Kumar* - raju.ranjithkumar@gmail.com
© 2018 Muthu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
cycloalkyl[b]pyridine-3-carbonitrile; cyclododecanone;
3-(1H-indol-3-yl)-3-oxopropanenitrile; tandem reaction
Abstract
The one-pot four-component reaction of 3-(1H-indol-3-yl)-3-oxopropanenitriles, aromatic aldehydes, cycloalkanones and ammoni-
um acetate occurred via a six-step tandem Knoevenagel condensation–nucleophilic addition to carbonyl–Michael addition–N-cycli-
zation–elimination–air oxidation sequence to afford structurally intriguing indole–cycloalkyl[b]pyridine-3-carbonitrile hybrid
heterocycles in excellent yields.
Introduction
The syntheses of novel heterocycles through greener protocols size complex heterocycles, avoid the isolation and purification
have received a great deal of attention of the synthetic organic of the intermediates, allow less waste to the environment,
chemists in view of environmental concerns [1-3]. The multi- shorten the reaction time and are also cost effective.
component tandem/domino reaction is one among several green
chemical protocols widely employed for the synthesis of myriad Carbocyclic or heterocyclic fused pyridine derivatives are an
of natural products and hybrid heterocycles [4-13]. These reac- important class of compounds omnipresent in natural products
tions are one-pot processes involving several bond forming and biologically relevant synthetic compounds [23-27]. For ex-
steps under identical reaction conditions affording the desired ample, imiquimod is an immune response modifier used to treat
product in a single transformation [14-22]. Hence, multicompo- warts on the skin and certain type of skin cancer called superfi-
nent tandem reactions minimize the number of steps to synthe- cial basal cell carcinoma (Figure 1) [28,29]. Loratadine is a
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Beilstein J. Org. Chem. 2018, 14, 2907–2915.
Figure 1: Examples of biologically important cycloalkyl-fused pyridines.
second-generation histamine H1 receptor antagonist used to Results and Discussion
treat allergic rhinitis and urticarial [30,31]. Blonanserin is an Initially the precursors viz. 3-(1H-indol-3-yl)-3-oxopropaneni-
atypical antipsychotic drug used to treat schizophrenia [32], triles 3 were synthesized from the reaction of indoles 1 and
whereas the decahydrocyclododeca[b]pyridine has been re- 2-cyanoacetic acid (2) in acetic anhydride under heating condi-
ported as inhibitors of cytochrome P450 [33]. Furthermore, tions (Scheme 1) [73].
muscopyridine is being used in perfume industry [34].
Among the several methods available for the synthesis of
pyridines or cycloalkyl-fused pyridines [23-27,35-44], the one-
pot four-component reaction of cyclic/acyclic ketones,
malononitrile, aromatic aldehyde and ammonium acetate
affording 2-amino-3-cyanopyridine derivatives have been
explored extensively [45-55]. However, syntheses of pyridine
Scheme 1: Synthesis of 3-oxopropanenitriles 3.
scaffolds bearing an indole side chain have received less atten-
tion. For instance, the multicomponent reactions of aldehydes,
3-(1H-indol-3-yl)-3-oxopropanenitriles and 5-aminopyrazol or Subsequently the one-pot four-component reaction of 3-(1H-
naphthylamine afforded indole substituted fused pyridine deriv- indol-3-yl)-3-oxopropanenitrile (3a), 4-chlorobenzaldehyde
atives [56]. 2-Indole substituted pyridine derivatives have also (4f), cyclododecanone (5a) and ammonium acetate (6) was
been prepared through AlCl3-induced C–C bond forming reac- chosen as a model in order to identify the optimum conditions
tion [57] and three-component reactions of aromatic aldehydes, for this reaction (Table 1). To begin with, a 1:1:1:2 mixture of
3-(1H-indol-3-yl)-3-oxopropanenitrile and malononitrile the above reactants was refluxed in toluene for 4 h which led to
[58,59], 2-acetylpyridine [60] or 3-amino-2-enones [61]. Inci- the formation of indole–cyclododeca[b]pyridine-3-carbonitrile
dentally, the indole scaffold is found in several natural products 7f and the intermediate (E)-3-(4-chlorophenyl)-2-(1H-indole-3-
and bioactive synthetic compounds [62-67]. For example, the carbonyl)acrylonitrile (8) in 10 and 80% yields, respectively.
synthetic drug sumatriptan used for the treatment of migraine Intermediate 8 was formed exclusively when the reaction was
and cluster headaches belongs to the triptan class, whereas carried out in refluxing acetonitrile or isopropanol. The yield of
indomethacin is a non-steroidal anti-inflammatory drug used to 7f increased up to 60% in refluxing methanol. However, the
relieve pain, swelling and joint stiffness caused by arthritis same reaction in refluxing ethanol afforded solely the desired
[68,69].
product 7f in 93% yield within 2 h (Table 1). Furthermore, after
completion of the reaction as evident from the TLC, the mix-
Recently we reported the synthesis of pyridine/benzo-fused ture was set aside for 6 h and the resultant precipitate was
cyclododecanes through a four-component tandem reaction filtered, washed with ethanol and dried under vacuum to
[70]. In continuation we herein report the synthesis of novel obtain pure 7f without the need for additional purification
indole substituted cycloalkyl[b]pyridine-3-carbonitriles from a methods.
one-pot six-step tandem protocol involving 3-(1H-indol-3-yl)-3-
oxopropanenitriles, aromatic aldehydes, cycloalkanones and The structure of 7f was elucidated with the help of one- and
ammonium acetate. This work also stems from our continuous two-dimensional NMR spectroscopy. In the 1H NMR of 7f the
effort in synthesizing novel cycloalkyl[b]pyridine-3-carbo- 5- and 14-CH2 protons appeared as triplets at 2.56 and
nitrile hybrid heterocycles via tandem/domino reaction [71,72]. 3.01 ppm (J = 9.0 Hz), respectively. From the H,H-COSY
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Beilstein J. Org. Chem. 2018, 14, 2907–2915.
Table 1: Synthesis of indole–cyclododeca[b]pyridine-3-carbonitrile 7f.
entry
conditions
yield (%)a
7f
8
1
2
3
4
5
toluene, reflux, 4 h
CH3CN, reflux, 3 h
iPrOH, reflux, 3 h
MeOH, reflux, 6 h
EtOH, reflux, 2 h
10
–
80
96
98
21
–
–
60
93
aIsolated yield.
correlation of 14-CH2 protons, the multiplets in the range 13 anticipated through the intramolecular cyclization of the
2.03–2.18 ppm was assigned to the 13-CH2 protons. The amino group and the CN in intermediate 10 was not formed in
CH2 protons of C-6 to C-12 appeared as multiplets in the range the reaction (Scheme 2).
1.27–1.58 ppm. The H,H-COSY spectrum revealed that the
NH proton of indole ring, which appeared as a broad singlet at This one-pot four-component strategy was then employed to
8.58 ppm is coupled to a doublet at 8.16 ppm (J = 3.0 Hz) due synthesize twenty-three novel indole–cyclododeca[b]pyridine-
to 2′-CH proton.
3-carbonitrile hybrid heterocycles 7 by varying the 3-(1H-indol-
3-yl)-3-oxopropanenitrile 3 and aromatic aldehyde 4 (Scheme 3
A persuasive mechanism to justify the formation of and Table 2). In all the cases, the reaction occurred smoothly
indole–cyclododeca[b]pyridine-3-carbonitrile hybrid 7f is affording excellent yields of the product 7 (85–95%). However,
depicted in Scheme 2. Initially, the Knoevenagel condensation the reaction failed to occur with aliphatic aldehydes viz. form-
of 3-(1H-indol-3-yl)-3-oxopropanenitrile (3a) and 4-chloro- aldehyde, heptanal, pentanal and hexanal. The structure of all
benzaldehyde (4f) leads to the formation of (E)-3-(4-chloro- the indole–cyclododeca[b]pyridine-3-carbonitrile hybrid hetero-
phenyl)-2-(1H-indole-3-carbonyl)acrylonitrile (8). Simulta- cycles 7 was elucidated by NMR spectroscopy.
neously, the reaction of cyclododecanone (5a) with ammonium
acetate affords the enamine 9. The Michael addition of 8 and Furthermore, the analysis of 1H NMR spectra revealed that
the enamine 9 yields the intermediate 10. Then the amino group the indole–cyclododeca[b]pyridine-3-carbonitriles 7 with
of 10 undergoes intramolecular cyclization with the carbonyl to ortho/ortho-para/ortho-meta substituted phenyl ring at C-4,
give 11, which subsequently undergoes dehydration to yield the exhibited axial chirality. For instance, in the case of 7f with
cyclododeca[b]pyridine-3-carbonitrile 12. The intermediate 12 p-Cl substituted phenyl ring at C-4, the 5- and 14-CH2 protons
upon oxidative aromatization by molecular oxygen as the sole appeared as triplets at 2.56 and 3.01 ppm, respectively. Howev-
oxidant yields the indole–cyclododeca[b]pyridine-3-carbo- er, in 7l wherein C-4 is bearing an o-Br substituted phenyl, the
nitrile 7f. This four-component multistep tandem reaction 5-CH2 protons appeared as multiplets in the range of 2.37–2.46
afforded 7f in 93% yield involving the formation of two new and 2.61–2.71 ppm, whereas the 14-CH2 protons appeared as
C–N and C–C bonds in a single transformation without the need multiplets in the range of 2.91–3.01 and 3.06–3.16 ppm.
to isolate or purify the intermediates. Furthermore, the above The diastereotopic behavior of 5- and 14-CH2 protons of
reaction occurred stereoselectively to afford indole–cyclodo- indole–cyclododeca[b]pyridine-3-carbonitrile hybrid hetero-
deca[b]pyridine-3-carbonitrile 7f exclusively, which is evident cycles 7 with an ortho/ortho-para/ortho-meta substituted
from the fact that the decahydrocyclododeca[b]pyridin-2-amine phenyl ring at C-4 may be attributed to the axial chirality in-
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Beilstein J. Org. Chem. 2018, 14, 2907–2915.
Scheme 2: Proposed mechanism for the formation of 7f.
Scheme 3: Synthesis of indole–cyclododeca[b]pyridine-3-carbonitriles 7 and 14.
duced in these molecules due to the restricted rotation of the ascertain the exclusive formation of 12. The structure of 12 was
C–C single bond. The steric hindrance exerted between the confirmed from the 1H NMR spectra, wherein the characteristic
nitrile group at C-3 and the ortho/ortho-para/ortho-meta substi- singlet around 4.6–5.1 ppm due to the 4-CH proton was ob-
tution in the phenyl ring at C-4 restricts the free rotation of the served. In addition, in the case of 12r the structure was con-
C-4–phenyl C–C single bond thereby inducing axial chirality in firmed from the single crystal X-ray studies (Figure 3) [74]. A
these molecules (representative examples, Figure 2).
careful analysis of the reaction progress revealed that in these
reactions the corresponding product 12 precipitated from the
Interestingly in some cases this reaction afforded the unaro- reaction mixture within 2 h of reflux (Table 3), which was also
matized indole–cyclododeca[b]pyridine-3-carbonitriles 12 an indication of the completion of the reaction. Further incre-
(Table 3). These experiments were repeated thrice in order to ment in the reaction time had no influence on the reaction to
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Beilstein J. Org. Chem. 2018, 14, 2907–2915.
Table 2: Yields and melting points of 7 and 14.
entry
comp
Ar
R
yield (%)a
mp (°C)
1
7a
C6H5
H
90
93
85
91
92
93
85
95
94
92
94
93
91
92
90
92
90
95
92
95
89
90
94
165–166
153–154
216–217
202–203
198–199
241–242
214–215
212–213
268–269
254–255
214–215
232–234
228-229
199–200
206–207
272–273
280–281
289–290
299–300
297–298
304–305
294–295
264–265
2
7b
7c
4-CH3C6H4
4-CH3OC6H4
4-iPrC6H4
H
3
H
4
7d
7e
H
5
4-FC6H4
H
6
7f
4-ClC6H4
H
7
7h
7i
4-CNC6H4
H
8
4-O2NC6H4
2-CH3C6H4
2-BrC6H4
H
9
7j
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
7l
H
7m
7n
7s
3-O2NC6H4
2,4-Cl2C6H3
3,4-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
thiophene-2-yl
4-CH3C6H4
4-iPrC6H4
H
H
H
7t
H
7u
14b
14d
14f
14g
14m
14p
14s
14t
H
Br
Br
Br
Br
Br
Br
Br
Br
4-ClC6H4
4-BrC6H4
3-O2NC6H4
2-F,4-ClC6H3
3,4-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
aIsolated yield.
Figure 2: Axial chirality due to restricted C–C bond rotation (representative cases).
afford the aromatized product 7. However, in other cases Gratified by the above results and, also to demonstrate the
(Table 2) the reaction was complete within 2 h (TLC analysis) general applicability of this protocol, the reaction of 3-(1H-
but the product 7 precipitated after 6–8 h.
indol-3-yl)-3-oxopropanenitriles 3, aromatic aldehydes 4 and
2911

Beilstein J. Org. Chem. 2018, 14, 2907–2915.
Table 3: Synthesis of indole–cyclododeca[b]pyridine-3-carbonitriles
12.
entry comp Ar
yield (%)a
mp (°C)
1
2
3
4
5
6
12g
12k
12o
12p
12q
12r
4-BrC6H4
2-ClC6H4
89
95
222–223
265–266
221–222
264–265
224–225
269–270
2-Cl,3-CH3OC6H3 92
2-F,4-ClC6H3 87
2,5-(OCH3)2C6H3 85
2,6-F2C6H3 89
aIsolated yield.
Figure 3: ORTEP diagram of 12r.
ammonium acetate (6) with lower ring-size cycloalkanones, viz.
cyclooctanone (5b), cycloheptanone (5c) and cyclohexanone 15–18 was elucidated using NMR spectroscopy and in the case
(5d) was investigated (Scheme 4). Under the previously estab- of 16f the structure was further confirmed from single crystal
lished conditions, the reaction led to the formation of the X-ray studies (Figure 4) [74].
respective cycloalkane-fused pyridine–indole hybrid hetero-
cycles in excellent yields (80–95%). However, the reaction Conclusion
failed to occur with cyclopentanone. In total thirty-five The syntheses of a library of novel indole–cycloalkyl[b]pyri-
indole–cycloalkyl[b]pyridine-3-carbonitrile hybrids 15–18 were dine-3-carbonitrile hybrid heterocycles have been achieved
isolated (Table 4). The structure of all the hybrid heterocycles through a facile one-pot four-component strategy. This reaction
Scheme 4: Synthesis of indole–cycloalkyl[b]pyridine-3-carbonitrile hybrids 15–18.
2912

Beilstein J. Org. Chem. 2018, 14, 2907–2915.
Table 4: Yields and melting points of 15–18.
entry comp Ar
R
yield (%)a mp (°C)
1
15a
15b
15d
15e
15f
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
92
93
92
94
90
91
82
92
91
94
92
85
94
92
92
95
94
189–190
201–202
198–199
225–226
214–215
234–235
235–236
245–246
222–223
259–260
236–237
254–255
237–238
261–262
267–268
198–199
200–201
186–187
268–269
274–275
276–277
289–290
278–279
288–289
279–280
297–298
259–260
165–166
184–185
210–211
170–171
174–175
164–165
158–159
162–163
2
4-CH3C6H4
4-iPrC6H4
4-FC6H4
3
4
5
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-O2NC6H4
2-CH3C6H4
6
15g
15h
15i
7
8
9
15jb
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
15lb 2-BrC6H4
15m 3-O2NC6H4
15n
15p
2,4-Cl2C6H3
2-F,4-ClC6H3
15rb 2,6-F2C6H3
15s
15t
3,4-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
thiophene-2-yl
C6H5
15u
16a
16b
16c
16d
16e
16f
Br 88
Br 89
Br 89
Br 90
Br 92
Br 91
Br 95
4-CH3C6H4
4-CH3OC6H4
4-iPrC6H4
Figure 4: ORTEP diagram of 16f.
4-FC6H4
Supporting Information
4-ClC6H4
16g
4-BrC6H4
Supporting Information File 1
Experimental procedure, compound characterization data
and copies of NMR spectra.
16ob 2-Cl,3-CH3OC6H3 Br 90
16p
16t
2-F,4-ClC6H3
Br 90
3,4,5-(OCH3)3C6H2 Br 95
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-269-S1.pdf]
17b
17f
4-CH3C6H4
4-ClC6H4
2-BrC6H4
4-CH3SC6H4
C6H5
H
H
H
H
H
H
H
H
80
82
89
84
81
80
80
85
17lb
17v
18a
18b
18f
Acknowledgements
4-CH3C6H4
4-ClC6H4
4-CH3SC6H4
R.R.K. thanks the Department of Science and Technology, New
Delhi, for funds under IRHPA program for the high-resolution
NMR facility and PURSE programme. The authors acknowl-
edge the Deanship of Scientific Research at King Saud Univer-
sity for funding this work through the Research Grant No.
RG-1438-052.
18v
aYield of isolated product. bThe unaromatized product was obtained.
ORCID® iDs
occurred through a six-step tandem Hantzsch-like process in-
volving Knoevenagel–Michael–nucleophilic addition–intramo-
lecular cyclization–elimination–oxidative aromatization se-
quence of reactions in a single transformation leading to the for-
mation of two new C–N and C–C bonds. The structure of all the
indole–cycloalkyl[b]pyridine-3-carbonitrile hybrid hetero-
cycles was elucidated with the help of NMR spectroscopy and
supported by single crystal X-ray studies for two compounds.
The indole–cycloalkyl[b]pyridine-3-carbonitriles comprising
ortho/ortho-para/ortho-meta substituted phenyl rings exhibited
axial chirality due to restricted C–C single bond rotation.
Raju Suresh Kumar - https://orcid.org/0000-0003-3754-4223
Raju Ranjith Kumar - https://orcid.org/0000-0002-9926-7770
References
1. Ritter, S. K. Chem. Eng. News 2013, 91 (22), 22–23.
doi:10.1021/cen-09122-buscon
2. Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U. S. A. 2008, 105,
13197–13202. doi:10.1073/pnas.0804348105
3. Ojima, I. Front. Chem. (Lausanne, Switz.) 2017, 5, No. 52.
doi:10.3389/fchem.2017.00052
2913

Beilstein J. Org. Chem. 2018, 14, 2907–2915.
4. Chanda, T.; Zhao, J. C.-G. Adv. Synth. Catal. 2018, 360, 2–79.
doi:10.1002/adsc.201701059
33.Schilling, B.; Woggon, W. D.; Chougnet,, A.; Granier, T.; Frater, G.;
Hanhort, A. Organic Compounds. WO Patent WO 2008/116339 A2,
Feb 10, 2008.
5. Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114,
2390–2431. doi:10.1021/cr400215u
34.Biemann, K.; Büchi, G.; Walker, B. H. J. Am. Chem. Soc. 1957, 79,
5558–5564. doi:10.1021/ja01577a061
6. Hayashi, Y. Chem. Sci. 2016, 7, 866–880. doi:10.1039/c5sc02913a
7. Cheng, C.; Zhang, J.; Wang, X.; Miao, Z. J. Org. Chem. 2018, 83,
5450–5457. doi:10.1021/acs.joc.8b00352
35.Hantzsch, A. Ber. Dtsch. Chem. Ges. 1881, 14, 1637–1638.
doi:10.1002/cber.18810140214
8. Panday, A. K.; Mishra, R.; Jana, A.; Parvin, T.; Choudhury, L. H.
J. Org. Chem. 2018, 83, 3624–3632. doi:10.1021/acs.joc.7b03272
9. Kumar, M.; Chauhan, P.; Bailey, S. J.; Jafari, E.; von Essen, C.;
Rissanen, K.; Enders, D. Org. Lett. 2018, 20, 1232–1235.
doi:10.1021/acs.orglett.8b00175
36.Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9,
2265–2319. doi:10.3762/bjoc.9.265
37.Gattu, R.; Bagdi, P. R.; Sidick Basha, R.; Khan, A. T. J. Org. Chem.
2017, 82, 12416–12429. doi:10.1021/acs.joc.7b02159
38.Hill, M. D. Chem. – Eur. J. 2010, 16, 12052–12062.
doi:10.1002/chem.201001100
10.Niharika, P.; Ramulu, B. V.; Satyanarayana, G. ACS Omega 2018, 3,
218–228. doi:10.1021/acsomega.7b01553
39.Elgemeie, G. E. H.; Attia, A. M. E.; Hussain, B. A. W.
Nucleosides Nucleotides 1998, 17, 855–868.
11.Bisht, S.; Peddinti, R. K. J. Org. Chem. 2017, 82, 13617–13625.
doi:10.1021/acs.joc.7b02207
doi:10.1080/07328319808003458
12.Lin, W.; Zheng, Y.-X.; Xun, Z.; Huang, Z.-B.; Shi, D.-Q.
ACS Comb. Sci. 2017, 19, 708–713. doi:10.1021/acscombsci.7b00126
13.Biswas, S.; Majee, D.; Guin, S.; Samanta, S. J. Org. Chem. 2017, 82,
10928–10938. doi:10.1021/acs.joc.7b01792
40.Al-Issa, S. A. Molecules 2012, 17, 10902–10915.
doi:10.3390/molecules170910902
41.Scriven, E. F. V. Pyridines: From Lab to Production; Elsevier Ltd.:
Oxford, OX5 1GB, UK, 2013.
14.Ho, T.-L. Tandem Organic Reactions; John Wiley & Sons, 1992.
15.Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18, 115–122.
doi:10.1016/s0160-9327(05)80086-9
42.Oda, K.; Nakagami, R.; Haneda, M.; Nishizono, N.; Machida, M.
Heterocycles 2003, 60, 2019–2022. doi:10.3987/com-03-9828
43.Upadhyay, A.; Sharma, L. K.; Singh, V. K.; Singh, R. K. P.
Tetrahedron Lett. 2016, 57, 5599–5604.
16.Zhu, J.; Bienaymé, H., Eds. Multicomponent Reactions; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005.
doi:10.1002/3527605118
doi:10.1016/j.tetlet.2016.10.111
44.Latham, E. J.; Murphy, S. M.; Stanforth, S. P. Tetrahedron 1995, 51,
10385–10388. doi:10.1016/0040-4020(95)00605-8
45.Khalili, D. Tetrahedron Lett. 2016, 57, 1721–1723.
doi:10.1016/j.tetlet.2016.03.020
17.Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123–131.
doi:10.1021/ar9502083
18.Dömling, A. Chem. Rev. 2006, 106, 17–89. doi:10.1021/cr0505728
19.Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011,
50, 6234–6246. doi:10.1002/anie.201006515
46.Tang, J.; Wang, L.; Yao, Y.; Zhang, L.; Wang, W. Tetrahedron Lett.
2011, 52, 509–511. doi:10.1016/j.tetlet.2010.11.102
47.Radi, M.; Vallerini, G. P.; Petrelli, A.; Vincetti, P.; Costantino, G.
Tetrahedron Lett. 2013, 54, 6905–6908.
20.Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135.
doi:10.1021/cr100233r
doi:10.1016/j.tetlet.2013.10.054
21.Anastas, P. T.; Warner, J. C. Green Chemistry, Theory and Practice;
Oxford University Press: Oxford, UK, 2000; p 135.
48.Afradi, M.; Pour, S. A.; Dolat, M.; Yazdani-Elah-Abadi, A.
Appl. Organomet. Chem. 2018, 32, e4103. doi:10.1002/aoc.4103
49.Heravi, M. M.; Yahya Shirazi Beheshtiha, S.; Dehghani, M.;
Hosseintash, N. J. Iran. Chem. Soc. 2015, 12, 2075–2081.
doi:10.1007/s13738-015-0684-y
22.Matlack, A. S. Introduction to Green Chemistry; Marcel Dekker: New
York, NY, USA, 2001; p 570.
23.Shkil', G. P.; Sagitullin, R. S. Chem. Heterocycl. Compd. (Engl. Transl.)
1998, 34, 507–528. doi:10.1007/bf02290931
50.Kambe, S.; Saito, K.; Sakurai, A.; Midorikawa, H. Synthesis 1980,
366–368. doi:10.1055/s-1980-29021
24.Michael, J. P. Nat. Prod. Rep. 2005, 22, 627–646.
doi:10.1039/b413750g
51.Kankala, S.; Pagadala, R.; Maddila, S.; Vasam, C. S.;
Jonnalagadda, S. B. RSC Adv. 2015, 5, 105446–105452.
doi:10.1039/c5ra16582b
25.Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Chem. Rev.
2014, 114, 10829–10868. doi:10.1021/cr500099b
26.Tenti, G.; Ramos, M. T.; Menéndez, J. C. Chapter 1: Synthesis of
pyridines by multicomponent reactions. In Multicomponent Reactions:
Synthesis of Bioactive Heterocycles; Ameta, K. L.; Dandia, A., Eds.;
CRC Press, Taylor and Francis: 10.1201/9781315369754-2, 2017.
27.Khan, M. M.; Khan, S.; Saigal; Iqbal, S. RSC Adv. 2016, 6,
42045–42061. doi:10.1039/c6ra06767k
52.Khaksar, S.; Yaghoobi, M. J. Fluorine Chem. 2012, 142, 41–44.
doi:10.1016/j.jfluchem.2012.06.009
53.Maleki, A.; Jafari, A. A.; Yousefi, S.; Eskandarpour, V. C. R. Chim.
2015, 18, 1307–1312. doi:10.1016/j.crci.2015.09.002
54.Wang, J.; Li, Z.; Wang, X.; Zhou, Y.; Guo, C. Heterocycles 2015, 91,
49–63. doi:10.3987/com-14-13104
28.Van Egmond, S.; Hoedemaker, C.; Sinclair, R. Int. J. Dermatol. 2007,
46, 318–319. doi:10.1111/j.1365-4632.2007.03200.x
29.Hemmi, H.; Kaisho, T.; Takeuchi, O.; Sato, S.; Sanjo, H.; Hoshino, K.;
Horiuchi, T.; Tomizawa, H.; Takeda, K.; Akira, S. Nat. Immunol. 2002,
3, 196–200. doi:10.1038/ni758
55.Ghorab, M. M.; Ragab, F. A.; Hamed, M. M. Eur. J. Med. Chem. 2009,
44, 4211–4217. doi:10.1016/j.ejmech.2009.05.017
56.Zhu, S.-L.; Ji, S.-J.; Zhao, K.; Liu, Y. Tetrahedron Lett. 2008, 49,
2578–2582. doi:10.1016/j.tetlet.2008.02.101
57.Pal, M.; Batchu, V. R.; Dager, I.; Swamy, N. K.; Padakanti, S.
J. Org. Chem. 2005, 70, 2376–2379. doi:10.1021/jo047944h
58.Thirumurugan, P.; Perumal, P. T. Tetrahedron Lett. 2009, 50,
4145–4150. doi:10.1016/j.tetlet.2009.04.121
30.Menardo, J.-L.; Horak, F.; Danzig, M. R.; Czarlewski, W. Clin. Ther.
1997, 19, 1278–1293. doi:10.1016/s0149-2918(97)80005-7
31.See, S. Am. Fam. Physician 2003, 68, 2015–2016.
32.Deeks, E. D.; Keating, G. M. CNS Drugs 2010, 24, 65–84.
doi:10.2165/11202620-000000000-00000
59.Thirumurugan, P.; Mahalaxmi, S.; Perumal, P. T. J. Chem. Sci. 2010,
122, 819–832. doi:10.1007/s12039-010-0070-3
2914

Beilstein J. Org. Chem. 2018, 14, 2907–2915.
60.Thirumurugan, P.; Perumal, P. T. Tetrahedron 2009, 65, 7620–7629.
doi:10.1016/j.tet.2009.06.097
61.Chen, T.; Xu, X.-P.; Liu, H.-F.; Ji, S.-J. Tetrahedron 2011, 67,
5469–5476. doi:10.1016/j.tet.2011.05.065
62.Bariwal, J.; Voskressensky, L. G.; Van der Eycken, E. V.
Chem. Soc. Rev. 2018, 47, 3831–3848. doi:10.1039/c7cs00508c
63.Hamid, H. A.; Ramli, A. N. M.; Yusoff, M. M. Front. Pharmacol. 2017, 8,
No. 96. doi:10.3389/fphar.2017.00096
64.Sravanthi, T. V.; Manju, S. L. Eur. J. Pharm. Sci. 2016, 91, 1–10.
doi:10.1016/j.ejps.2016.05.025
65.Zhang, M.-Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015, 89,
421–441. doi:10.1016/j.ejmech.2014.10.065
66.Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.;
Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620–6662.
doi:10.3390/molecules18066620
67.Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010, 47,
491–502. doi:10.1002/jhet.349
68.Freidank-Mueschenborn, E.; Fox, A. W. Headache 2005, 45, 632–637.
doi:10.1111/j.1526-4610.2005.05129a.x
69.Ferreira, S.; Moncada, S.; Vane, J. R. Nature (London), New Biol.
1971, 231, 237–239. doi:10.1038/newbio231237a0
70.Vivek Kumar, S.; Rani, M. A.; Almansour, A. I.; Suresh Kumar, R.;
Athimoolam, S.; Ranjith Kumar, R. Tetrahedron 2018, 74, 4569–4577.
doi:10.1016/j.tet.2018.07.020
71.Maharani, S.; Ranjith Kumar, R. Tetrahedron Lett. 2015, 56, 179–181.
doi:10.1016/j.tetlet.2014.11.052
72.Maharani, S.; Almansour, A. I.; Suresh Kumar, R.; Arumugam, N.;
Ranjith Kumar, R. Tetrahedron 2016, 72, 4582–4592.
doi:10.1016/j.tet.2016.06.030
73.Fadda, A. A.; El-Mekabaty, A.; Mousa, I. A.; Elattar, K. M.
Synth. Commun. 2014, 44, 1579–1599.
doi:10.1080/00397911.2013.861915
74.Crystallographic data for compounds 12r and 16f have been deposited
with the Cambridge Crystallographic Data Center as supplementary
publication numbers CCDC 1859052 and 1859053, respectively.
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