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

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  2. 2 ,
  3. 3 ,
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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
3Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
  1. Corresponding author email
Associate Editor: I. R. Baxendale
Beilstein J. Org. Chem. 2018, 14, 2907–2915. https://doi.org/10.3762/bjoc.14.269
Received 17 Sep 2018, Accepted 09 Nov 2018, Published 22 Nov 2018
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Abstract

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.

Keywords: cycloalkyl[b]pyridine-3-carbonitrile; cyclododecanone; 3-(1H-indol-3-yl)-3-oxopropanenitrile; tandem reaction

Introduction

The syntheses of novel heterocycles through greener protocols have received a great deal of attention of the synthetic organic chemists in view of environmental concerns [1-3]. The multicomponent tandem/domino reaction is one among several green chemical protocols widely employed for the synthesis of myriad of natural products and hybrid heterocycles [4-13]. These reactions are one-pot processes involving several bond forming steps under identical reaction conditions affording the desired product in a single transformation [14-22]. Hence, multicomponent tandem reactions minimize the number of steps to synthesize complex heterocycles, avoid the isolation and purification of the intermediates, allow less waste to the environment, shorten the reaction time and are also cost effective.

Carbocyclic or heterocyclic fused pyridine derivatives are an important class of compounds omnipresent in natural products and biologically relevant synthetic compounds [23-27]. For example, imiquimod is an immune response modifier used to treat warts on the skin and certain type of skin cancer called superficial basal cell carcinoma (Figure 1) [28,29]. Loratadine is a second-generation histamine H1 receptor antagonist used to treat allergic rhinitis and urticarial [30,31]. Blonanserin is an atypical antipsychotic drug used to treat schizophrenia [32], whereas the decahydrocyclododeca[b]pyridine has been reported as inhibitors of cytochrome P450 [33]. Furthermore, muscopyridine is being used in perfume industry [34].

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Figure 1: Examples of biologically important cycloalkyl-fused pyridines.

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 scaffolds bearing an indole side chain have received less attention. For instance, the multicomponent reactions of aldehydes, 3-(1H-indol-3-yl)-3-oxopropanenitriles and 5-aminopyrazol or naphthylamine afforded indole substituted fused pyridine derivatives [56]. 2-Indole substituted pyridine derivatives have also been prepared through AlCl3-induced C–C bond forming reaction [57] and three-component reactions of aromatic aldehydes, 3-(1H-indol-3-yl)-3-oxopropanenitrile and malononitrile [58,59], 2-acetylpyridine [60] or 3-amino-2-enones [61]. Incidentally, the indole scaffold is found in several natural products and bioactive synthetic compounds [62-67]. For example, the synthetic drug sumatriptan used for the treatment of migraine and cluster headaches belongs to the triptan class, whereas indomethacin is a non-steroidal anti-inflammatory drug used to relieve pain, swelling and joint stiffness caused by arthritis [68,69].

Recently we reported the synthesis of pyridine/benzo-fused cyclododecanes through a four-component tandem reaction [70]. In continuation we herein report the synthesis of novel indole substituted cycloalkyl[b]pyridine-3-carbonitriles from a one-pot six-step tandem protocol involving 3-(1H-indol-3-yl)-3-oxopropanenitriles, aromatic aldehydes, cycloalkanones and ammonium acetate. This work also stems from our continuous effort in synthesizing novel cycloalkyl[b]pyridine-3-carbonitrile hybrid heterocycles via tandem/domino reaction [71,72].

Results and Discussion

Initially the precursors viz. 3-(1H-indol-3-yl)-3-oxopropanenitriles 3 were synthesized from the reaction of indoles 1 and 2-cyanoacetic acid (2) in acetic anhydride under heating conditions (Scheme 1) [73].

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Scheme 1: Synthesis of 3-oxopropanenitriles 3.

Subsequently the one-pot four-component reaction of 3-(1H-indol-3-yl)-3-oxopropanenitrile (3a), 4-chlorobenzaldehyde (4f), cyclododecanone (5a) and ammonium acetate (6) was chosen as a model in order to identify the optimum conditions for this reaction (Table 1). To begin with, a 1:1:1:2 mixture of the above reactants was refluxed in toluene for 4 h which led to the formation of indole–cyclododeca[b]pyridine-3-carbonitrile 7f and the intermediate (E)-3-(4-chlorophenyl)-2-(1H-indole-3-carbonyl)acrylonitrile (8) in 10 and 80% yields, respectively. Intermediate 8 was formed exclusively when the reaction was carried out in refluxing acetonitrile or isopropanol. The yield of 7f increased up to 60% in refluxing methanol. However, the same reaction in refluxing ethanol afforded solely the desired product 7f in 93% yield within 2 h (Table 1). Furthermore, after completion of the reaction as evident from the TLC, the mixture was set aside for 6 h and the resultant precipitate was filtered, washed with ethanol and dried under vacuum to obtain pure 7f without the need for additional purification methods.

Table 1: Synthesis of indole–cyclododeca[b]pyridine-3-carbonitrile 7f.

[Graphic 1]
entry conditions yield (%)a
7f 8
1 toluene, reflux, 4 h 10 80
2 CH3CN, reflux, 3 h – 96
3 iPrOH, reflux, 3 h – 98
4 MeOH, reflux, 6 h 60 21
5 EtOH, reflux, 2 h 93 –

aIsolated yield.

The structure of 7f was elucidated with the help of one- and two-dimensional NMR spectroscopy. In the 1H NMR of 7f the 5- and 14-CH2 protons appeared as triplets at 2.56 and 3.01 ppm (J = 9.0 Hz), respectively. From the H,H-COSY correlation of 14-CH2 protons, the multiplets in the range 2.03–2.18 ppm was assigned to the 13-CH2 protons. The CH2 protons of C-6 to C-12 appeared as multiplets in the range 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 8.58 ppm is coupled to a doublet at 8.16 ppm (J = 3.0 Hz) due to 2′-CH proton.

A persuasive mechanism to justify the formation of indole–cyclododeca[b]pyridine-3-carbonitrile hybrid 7f is depicted in Scheme 2. Initially, the Knoevenagel condensation of 3-(1H-indol-3-yl)-3-oxopropanenitrile (3a) and 4-chlorobenzaldehyde (4f) leads to the formation of (E)-3-(4-chlorophenyl)-2-(1H-indole-3-carbonyl)acrylonitrile (8). Simultaneously, the reaction of cyclododecanone (5a) with ammonium acetate affords the enamine 9. The Michael addition of 8 and the enamine 9 yields the intermediate 10. Then the amino group of 10 undergoes intramolecular cyclization with the carbonyl to give 11, which subsequently undergoes dehydration to yield the cyclododeca[b]pyridine-3-carbonitrile 12. The intermediate 12 upon oxidative aromatization by molecular oxygen as the sole oxidant yields the indole–cyclododeca[b]pyridine-3-carbonitrile 7f. This four-component multistep tandem reaction afforded 7f in 93% yield involving the formation of two new C–N and C–C bonds in a single transformation without the need to isolate or purify the intermediates. Furthermore, the above reaction occurred stereoselectively to afford indole–cyclododeca[b]pyridine-3-carbonitrile 7f exclusively, which is evident from the fact that the decahydrocyclododeca[b]pyridin-2-amine 13 anticipated through the intramolecular cyclization of the amino group and the CN in intermediate 10 was not formed in the reaction (Scheme 2).

[1860-5397-14-269-i2]

Scheme 2: Proposed mechanism for the formation of 7f.

This one-pot four-component strategy was then employed to synthesize twenty-three novel indole–cyclododeca[b]pyridine-3-carbonitrile hybrid heterocycles 7 by varying the 3-(1H-indol-3-yl)-3-oxopropanenitrile 3 and aromatic aldehyde 4 (Scheme 3 and Table 2). In all the cases, the reaction occurred smoothly affording excellent yields of the product 7 (85–95%). However, the reaction failed to occur with aliphatic aldehydes viz. formaldehyde, heptanal, pentanal and hexanal. The structure of all the indole–cyclododeca[b]pyridine-3-carbonitrile hybrid heterocycles 7 was elucidated by NMR spectroscopy.

[1860-5397-14-269-i3]

Scheme 3: Synthesis of indole–cyclododeca[b]pyridine-3-carbonitriles 7 and 14.

Table 2: Yields and melting points of 7 and 14.

entry comp Ar R yield (%)a mp (°C)
1 7a C6H5 H 90 165–166
2 7b 4-CH3C6H4 H 93 153–154
3 7c 4-CH3OC6H4 H 85 216–217
4 7d 4-iPrC6H4 H 91 202–203
5 7e 4-FC6H4 H 92 198–199
6 7f 4-ClC6H4 H 93 241–242
7 7h 4-CNC6H4 H 85 214–215
8 7i 4-O2NC6H4 H 95 212–213
9 7j 2-CH3C6H4 H 94 268–269
10 7l 2-BrC6H4 H 92 254–255
11 7m 3-O2NC6H4 H 94 214–215
12 7n 2,4-Cl2C6H3 H 93 232–234
13 7s 3,4-(OCH3)2C6H3 H 91 228-229
14 7t 3,4,5-(OCH3)3C6H2 H 92 199–200
15 7u thiophene-2-yl H 90 206–207
16 14b 4-CH3C6H4 Br 92 272–273
17 14d 4-iPrC6H4 Br 90 280–281
18 14f 4-ClC6H4 Br 95 289–290
19 14g 4-BrC6H4 Br 92 299–300
20 14m 3-O2NC6H4 Br 95 297–298
21 14p 2-F,4-ClC6H3 Br 89 304–305
22 14s 3,4-(OCH3)2C6H3 Br 90 294–295
23 14t 3,4,5-(OCH3)3C6H2 Br 94 264–265

aIsolated yield.

Furthermore, the analysis of 1H NMR spectra revealed that the indole–cyclododeca[b]pyridine-3-carbonitriles 7 with ortho/ortho-para/ortho-meta substituted phenyl ring at C-4, exhibited axial chirality. For instance, in the case of 7f with p-Cl substituted phenyl ring at C-4, the 5- and 14-CH2 protons appeared as triplets at 2.56 and 3.01 ppm, respectively. However, in 7l wherein C-4 is bearing an o-Br substituted phenyl, the 5-CH2 protons appeared as multiplets in the range of 2.37–2.46 and 2.61–2.71 ppm, whereas the 14-CH2 protons appeared as multiplets in the range of 2.91–3.01 and 3.06–3.16 ppm. The diastereotopic behavior of 5- and 14-CH2 protons of indole–cyclododeca[b]pyridine-3-carbonitrile hybrid heterocycles 7 with an ortho/ortho-para/ortho-meta substituted phenyl ring at C-4 may be attributed to the axial chirality induced in these molecules due to the restricted rotation of the C–C single bond. The steric hindrance exerted between the nitrile group at C-3 and the ortho/ortho-para/ortho-meta substitution in the phenyl ring at C-4 restricts the free rotation of the C-4–phenyl C–C single bond thereby inducing axial chirality in these molecules (representative examples, Figure 2).

[1860-5397-14-269-2]

Figure 2: Axial chirality due to restricted C–C bond rotation (representative cases).

Interestingly in some cases this reaction afforded the unaromatized indole–cyclododeca[b]pyridine-3-carbonitriles 12 (Table 3). These experiments were repeated thrice in order to ascertain the exclusive formation of 12. The structure of 12 was confirmed from the 1H NMR spectra, wherein the characteristic singlet around 4.6–5.1 ppm due to the 4-CH proton was observed. In addition, in the case of 12r the structure was confirmed from the single crystal X-ray studies (Figure 3) [74]. A careful analysis of the reaction progress revealed that in these reactions the corresponding product 12 precipitated from the reaction mixture within 2 h of reflux (Table 3), which was also an indication of the completion of the reaction. Further increment in the reaction time had no influence on the reaction to afford the aromatized product 7. However, in other cases (Table 2) the reaction was complete within 2 h (TLC analysis) but the product 7 precipitated after 6–8 h.

Table 3: Synthesis of indole–cyclododeca[b]pyridine-3-carbonitriles 12.

[Graphic 2]
entry comp Ar yield (%)a mp (°C)
1 12g 4-BrC6H4 89 222–223
2 12k 2-ClC6H4 95 265–266
3 12o 2-Cl,3-CH3OC6H3 92 221–222
4 12p 2-F,4-ClC6H3 87 264–265
5 12q 2,5-(OCH3)2C6H3 85 224–225
6 12r 2,6-F2C6H3 89 269–270

aIsolated yield.

[1860-5397-14-269-3]

Figure 3: ORTEP diagram of 12r.

Gratified by the above results and, also to demonstrate the general applicability of this protocol, the reaction of 3-(1H-indol-3-yl)-3-oxopropanenitriles 3, aromatic aldehydes 4 and ammonium acetate (6) with lower ring-size cycloalkanones, viz. cyclooctanone (5b), cycloheptanone (5c) and cyclohexanone (5d) was investigated (Scheme 4). Under the previously established conditions, the reaction led to the formation of the respective cycloalkane-fused pyridine–indole hybrid heterocycles in excellent yields (80–95%). However, the reaction failed to occur with cyclopentanone. In total thirty-five indole–cycloalkyl[b]pyridine-3-carbonitrile hybrids 15–18 were isolated (Table 4). The structure of all the hybrid heterocycles 15–18 was elucidated using NMR spectroscopy and in the case of 16f the structure was further confirmed from single crystal X-ray studies (Figure 4) [74].

[1860-5397-14-269-i4]

Scheme 4: Synthesis of indole–cycloalkyl[b]pyridine-3-carbonitrile hybrids 15–18.

Table 4: Yields and melting points of 15–18.

entry comp Ar R yield (%)a mp (°C)
1 15a C6H5 H 92 189–190
2 15b 4-CH3C6H4 H 93 201–202
3 15d 4-iPrC6H4 H 92 198–199
4 15e 4-FC6H4 H 94 225–226
5 15f 4-ClC6H4 H 90 214–215
6 15g 4-BrC6H4 H 91 234–235
7 15h 4-CNC6H4 H 82 235–236
8 15i 4-O2NC6H4 H 92 245–246
9 15jb 2-CH3C6H4 H 91 222–223
10 15lb 2-BrC6H4 H 94 259–260
11 15m 3-O2NC6H4 H 92 236–237
12 15n 2,4-Cl2C6H3 H 85 254–255
13 15p 2-F,4-ClC6H3 H 94 237–238
14 15rb 2,6-F2C6H3 H 92 261–262
15 15s 3,4-(OCH3)2C6H3 H 92 267–268
16 15t 3,4,5-(OCH3)3C6H2 H 95 198–199
17 15u thiophene-2-yl H 94 200–201
18 16a C6H5 Br 88 186–187
19 16b 4-CH3C6H4 Br 89 268–269
20 16c 4-CH3OC6H4 Br 89 274–275
21 16d 4-iPrC6H4 Br 90 276–277
22 16e 4-FC6H4 Br 92 289–290
23 16f 4-ClC6H4 Br 91 278–279
24 16g 4-BrC6H4 Br 95 288–289
25 16ob 2-Cl,3-CH3OC6H3 Br 90 279–280
26 16p 2-F,4-ClC6H3 Br 90 297–298
27 16t 3,4,5-(OCH3)3C6H2 Br 95 259–260
28 17b 4-CH3C6H4 H 80 165–166
29 17f 4-ClC6H4 H 82 184–185
30 17lb 2-BrC6H4 H 89 210–211
31 17v 4-CH3SC6H4 H 84 170–171
32 18a C6H5 H 81 174–175
33 18b 4-CH3C6H4 H 80 164–165
34 18f 4-ClC6H4 H 80 158–159
35 18v 4-CH3SC6H4 H 85 162–163

aYield of isolated product. bThe unaromatized product was obtained.

[1860-5397-14-269-4]

Figure 4: ORTEP diagram of 16f.

Conclusion

The syntheses of a library of novel indole–cycloalkyl[b]pyridine-3-carbonitrile hybrid heterocycles have been achieved through a facile one-pot four-component strategy. This reaction occurred through a six-step tandem Hantzsch-like process involving Knoevenagel–Michael–nucleophilic addition–intramolecular cyclization–elimination–oxidative aromatization sequence of reactions in a single transformation leading to the formation of two new C–N and C–C bonds. The structure of all the indole–cycloalkyl[b]pyridine-3-carbonitrile hybrid heterocycles 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.

Supporting Information

Supporting Information File 1: Experimental procedure, compound characterization data and copies of NMR spectra.
Format: PDF Size: 9.5 MB Download

Acknowledgements

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 acknowledge the Deanship of Scientific Research at King Saud University for funding this work through the Research Grant No. RG-1438-052.

References

  1. Ritter, S. K. Chem. Eng. News 2013, 91 (22), 22–23. doi:10.1021/cen-09122-buscon
    Return to citation in text: [1]
  2. Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 13197–13202. doi:10.1073/pnas.0804348105
    Return to citation in text: [1]
  3. Ojima, I. Front. Chem. (Lausanne, Switz.) 2017, 5, No. 52. doi:10.3389/fchem.2017.00052
    Return to citation in text: [1]
  4. Chanda, T.; Zhao, J. C.-G. Adv. Synth. Catal. 2018, 360, 2–79. doi:10.1002/adsc.201701059
    Return to citation in text: [1]
  5. Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390–2431. doi:10.1021/cr400215u
    Return to citation in text: [1]
  6. Hayashi, Y. Chem. Sci. 2016, 7, 866–880. doi:10.1039/c5sc02913a
    Return to citation in text: [1]
  7. Cheng, C.; Zhang, J.; Wang, X.; Miao, Z. J. Org. Chem. 2018, 83, 5450–5457. doi:10.1021/acs.joc.8b00352
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  10. Niharika, P.; Ramulu, B. V.; Satyanarayana, G. ACS Omega 2018, 3, 218–228. doi:10.1021/acsomega.7b01553
    Return to citation in text: [1]
  11. Bisht, S.; Peddinti, R. K. J. Org. Chem. 2017, 82, 13617–13625. doi:10.1021/acs.joc.7b02207
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  13. Biswas, S.; Majee, D.; Guin, S.; Samanta, S. J. Org. Chem. 2017, 82, 10928–10938. doi:10.1021/acs.joc.7b01792
    Return to citation in text: [1]
  14. Ho, T.-L. Tandem Organic Reactions; John Wiley & Sons, 1992.
    Return to citation in text: [1]
  15. Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18, 115–122. doi:10.1016/s0160-9327(05)80086-9
    Return to citation in text: [1]
  16. Zhu, J.; Bienaymé, H., Eds. Multicomponent Reactions; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005. doi:10.1002/3527605118
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  18. Dömling, A. Chem. Rev. 2006, 106, 17–89. doi:10.1021/cr0505728
    Return to citation in text: [1]
  19. Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234–6246. doi:10.1002/anie.201006515
    Return to citation in text: [1]
  20. Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135. doi:10.1021/cr100233r
    Return to citation in text: [1]
  21. Anastas, P. T.; Warner, J. C. Green Chemistry, Theory and Practice; Oxford University Press: Oxford, UK, 2000; p 135.
    Return to citation in text: [1]
  22. Matlack, A. S. Introduction to Green Chemistry; Marcel Dekker: New York, NY, USA, 2001; p 570.
    Return to citation in text: [1]
  23. Shkil', G. P.; Sagitullin, R. S. Chem. Heterocycl. Compd. (Engl. Transl.) 1998, 34, 507–528. doi:10.1007/bf02290931
    Return to citation in text: [1] [2]
  24. Michael, J. P. Nat. Prod. Rep. 2005, 22, 627–646. doi:10.1039/b413750g
    Return to citation in text: [1] [2]
  25. Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Chem. Rev. 2014, 114, 10829–10868. doi:10.1021/cr500099b
    Return to citation in text: [1] [2]
  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.
    Return to citation in text: [1] [2]
  27. Khan, M. M.; Khan, S.; Saigal; Iqbal, S. RSC Adv. 2016, 6, 42045–42061. doi:10.1039/c6ra06767k
    Return to citation in text: [1] [2]
  28. Van Egmond, S.; Hoedemaker, C.; Sinclair, R. Int. J. Dermatol. 2007, 46, 318–319. doi:10.1111/j.1365-4632.2007.03200.x
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  31. See, S. Am. Fam. Physician 2003, 68, 2015–2016.
    Return to citation in text: [1]
  32. Deeks, E. D.; Keating, G. M. CNS Drugs 2010, 24, 65–84. doi:10.2165/11202620-000000000-00000
    Return to citation in text: [1]
  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.
    Return to citation in text: [1]
  34. Biemann, K.; Büchi, G.; Walker, B. H. J. Am. Chem. Soc. 1957, 79, 5558–5564. doi:10.1021/ja01577a061
    Return to citation in text: [1]
  35. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1881, 14, 1637–1638. doi:10.1002/cber.18810140214
    Return to citation in text: [1]
  36. Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9, 2265–2319. doi:10.3762/bjoc.9.265
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  38. Hill, M. D. Chem. – Eur. J. 2010, 16, 12052–12062. doi:10.1002/chem.201001100
    Return to citation in text: [1]
  39. Elgemeie, G. E. H.; Attia, A. M. E.; Hussain, B. A. W. Nucleosides Nucleotides 1998, 17, 855–868. doi:10.1080/07328319808003458
    Return to citation in text: [1]
  40. Al-Issa, S. A. Molecules 2012, 17, 10902–10915. doi:10.3390/molecules170910902
    Return to citation in text: [1]
  41. Scriven, E. F. V. Pyridines: From Lab to Production; Elsevier Ltd.: Oxford, OX5 1GB, UK, 2013.
    Return to citation in text: [1]
  42. Oda, K.; Nakagami, R.; Haneda, M.; Nishizono, N.; Machida, M. Heterocycles 2003, 60, 2019–2022. doi:10.3987/com-03-9828
    Return to citation in text: [1]
  43. Upadhyay, A.; Sharma, L. K.; Singh, V. K.; Singh, R. K. P. Tetrahedron Lett. 2016, 57, 5599–5604. doi:10.1016/j.tetlet.2016.10.111
    Return to citation in text: [1]
  44. Latham, E. J.; Murphy, S. M.; Stanforth, S. P. Tetrahedron 1995, 51, 10385–10388. doi:10.1016/0040-4020(95)00605-8
    Return to citation in text: [1]
  45. Khalili, D. Tetrahedron Lett. 2016, 57, 1721–1723. doi:10.1016/j.tetlet.2016.03.020
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  47. Radi, M.; Vallerini, G. P.; Petrelli, A.; Vincetti, P.; Costantino, G. Tetrahedron Lett. 2013, 54, 6905–6908. doi:10.1016/j.tetlet.2013.10.054
    Return to citation in text: [1]
  48. Afradi, M.; Pour, S. A.; Dolat, M.; Yazdani-Elah-Abadi, A. Appl. Organomet. Chem. 2018, 32, e4103. doi:10.1002/aoc.4103
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  50. Kambe, S.; Saito, K.; Sakurai, A.; Midorikawa, H. Synthesis 1980, 366–368. doi:10.1055/s-1980-29021
    Return to citation in text: [1]
  51. Kankala, S.; Pagadala, R.; Maddila, S.; Vasam, C. S.; Jonnalagadda, S. B. RSC Adv. 2015, 5, 105446–105452. doi:10.1039/c5ra16582b
    Return to citation in text: [1]
  52. Khaksar, S.; Yaghoobi, M. J. Fluorine Chem. 2012, 142, 41–44. doi:10.1016/j.jfluchem.2012.06.009
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  54. Wang, J.; Li, Z.; Wang, X.; Zhou, Y.; Guo, C. Heterocycles 2015, 91, 49–63. doi:10.3987/com-14-13104
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  57. Pal, M.; Batchu, V. R.; Dager, I.; Swamy, N. K.; Padakanti, S. J. Org. Chem. 2005, 70, 2376–2379. doi:10.1021/jo047944h
    Return to citation in text: [1]
  58. Thirumurugan, P.; Perumal, P. T. Tetrahedron Lett. 2009, 50, 4145–4150. doi:10.1016/j.tetlet.2009.04.121
    Return to citation in text: [1]
  59. Thirumurugan, P.; Mahalaxmi, S.; Perumal, P. T. J. Chem. Sci. 2010, 122, 819–832. doi:10.1007/s12039-010-0070-3
    Return to citation in text: [1]
  60. Thirumurugan, P.; Perumal, P. T. Tetrahedron 2009, 65, 7620–7629. doi:10.1016/j.tet.2009.06.097
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  62. Bariwal, J.; Voskressensky, L. G.; Van der Eycken, E. V. Chem. Soc. Rev. 2018, 47, 3831–3848. doi:10.1039/c7cs00508c
    Return to citation in text: [1]
  63. Hamid, H. A.; Ramli, A. N. M.; Yusoff, M. M. Front. Pharmacol. 2017, 8, No. 96. doi:10.3389/fphar.2017.00096
    Return to citation in text: [1]
  64. Sravanthi, T. V.; Manju, S. L. Eur. J. Pharm. Sci. 2016, 91, 1–10. doi:10.1016/j.ejps.2016.05.025
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  67. Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010, 47, 491–502. doi:10.1002/jhet.349
    Return to citation in text: [1]
  68. Freidank-Mueschenborn, E.; Fox, A. W. Headache 2005, 45, 632–637. doi:10.1111/j.1526-4610.2005.05129a.x
    Return to citation in text: [1]
  69. Ferreira, S.; Moncada, S.; Vane, J. R. Nature (London), New Biol. 1971, 231, 237–239. doi:10.1038/newbio231237a0
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  71. Maharani, S.; Ranjith Kumar, R. Tetrahedron Lett. 2015, 56, 179–181. doi:10.1016/j.tetlet.2014.11.052
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  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
    Return to citation in text: [1]
  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.
    Return to citation in text: [1] [2]

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