Transition-Metal-Free Approach for the Synthesis of N-Arylated Piperidones and their Ketals from Ketene Dithioacetals

Satya Narayan Sahu; Ranjay Shaw; Ismail Althagafi; Ramendra Pratap

doi:10.1055/a-2370-6625

Synlett, Table of Contents

Synlett 2025; 36(05): 488-495
DOI: 10.1055/a-2370-6625

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Transition-Metal-Free Approach for the Synthesis of N-Arylated Piperidones and their Ketals from Ketene Dithioacetals

Satya Narayan Sahu

^aDepartment of Chemistry, Swami Atmanand Government English Medium Model College Ambikapur, 497001, India

,

Ranjay Shaw

^bDepartment of Chemistry, GLA University, Mathura, U.P., 281406, India

,

Ismail Althagafi

^cDepartment of Chemistry, Faculty of Science, Umm Al-Qura University, Makkah, 21955, Saudi Arabia

,

Ramendra Pratap∗

^dDepartment of Chemistry, University of Delhi, Delhi, 110007, India

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Abstract

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Dedicated to Professor H. Ila on her 80^th birthday

Abstract

N-Arylated piperidones are present as pharmacophores in many pharmaceuticals and serve as useful precursors for the construction of important new molecules. We have developed a transition-metal-free, cost-effective, and mild approach for the synthesis of N-(hetero)arylated piperidones and their ketals by using ketals of piperidones and 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles as precursors. The desired products were obtained in two steps: amination of the 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile from piperidone, followed by ring transformation using a suitable nucleophile source. We have successfully tethered functionalized dihydrophenanthrenes, hydrobenzo[c]phenanthrenes, and benzoquinolines to piperidinone moieties under transition-metal-free conditions.

Key words

ketene dithioacetals - piperidone - dihydrophenanthrenes - chromenes - ring transformation - cyanoacetamides

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References

References and Notes
1 Ganellin CR, Spickett RG. W. J. Med. Chem. 1965; 8: 619
2 Dyakov MY, Sokolova TD, Peretokin AV, Moskovkin AS, Unkovskii BV. Chem. Heterocycl. Compd. 1991; 27: 183

3a Maryanoff CA, Reitz AB, Scott MK. US 5314885, 1994
3b Kerrigan F, Heal DJ, Martin KF. WO 9507274, 1995

4a Ziegler E, Roßmann U, Litvan F, Meier H. Monatsh. Chem. 1962; 93: 26
4b Ziegler E, Litvan F. US 3052678, 1959
4c Harfenist M, Magnien E. J. Org. Chem. 1963; 28: 538

5a Zirngibl U. DE 2142334, 1972 ; Chem. Abstr. 1972, 77, 36383
5b Wolfbeis OS, Ziegler E, Knierzinger A, Wipflee H, Trummer I. Monatsh. Chem. 1980; 111: 93

6 Rao TS, Reese CB, Serafinowska HT, Takaku H, Zappia G. Tetrahedron Lett. 1987; 28: 4897
7 Matasi JJ, Caldwell JP, Zhang H, Fawzi A, Higgins GA, Cohen-Williams ME, Varty GB, Tulshian DB. Bioorg. Med. Chem. Lett. 2005; 15: 3675
8 Maryanoff BE, Ho W, McComsey DF, Reitz AB, Grous PP, Nortey SO, Shank RP, Dubinsky B, Taylor RJ. Jr, Gardocki JF. J. Med. Chem. 1995; 38: 16
9 Cooper CS, Klock PL, Chu DT, Hardy DJ, Swanson RN, Plattner JJ. J. Med. Chem. 1992; 35: 1392
10 Schlienger N, Lund BW, Pawlas J, Badalassi F, Bertozzi F, Lewinsky R, Fejzic A, Thygesen MB, Tabatabaei A, Bradley SR, Gardell LR, Piu F, Olsson R. J. Med. Chem. 2009; 52: 7186
11 Lee J, Kim K.-H, Jeong S. Bioorg. Med. Chem. Lett. 2011; 21: 4203
12 Kumar RS, Rajesh SM, Perumal S, Banerjee D, Yogeeswari P, Sriram D. Eur. J. Med. Chem. 2010; 45: 411

13a Deng Z, Lin J.-H, Xiao J.-C. Nat. Commun. 2016; 7: 10337
13b Johnson CR, Ansari MI, Coop A. ACS Omega 2018; 3: 10886

14 Ullmann F. Ber. Dtsch. Chem. Ges. 1903; 36: 2382
15 Goldberg I. Ber. Dtsch. Chem. Ges. 1906; 39: 1691
16 Vantourout JC, Law RP, Isidro-Llobet A, Atkinson SJ, Watson AJ. B. J. Org. Chem. 2016; 81: 3942
17 Cai Q, Zhou W. Chin. J. Chem. 2020; 38: 879

18a Bariwal J, Van der Eycken E. Chem. Soc. Rev. 2013; 42: 9283
18b Sharma C, Srivastava AK, Sharma D, Joshi RK. New J. Chem. 2022; 46: 8551
18c Ranjan A, Varma A, Kumari S, Joshi RK. Synlett 2022; 33: 1065
18d Kommuri VC, Tadiparthi K, Pawar L, Arunachalampillai A. Polycycl. Aromat. Compd. 2023; 43: 665
18e Sharifi A, Moazami M, Ghonouei N, Abaee MS, Mirzaei M. Sci. Iran. 2016; 23: 2742

19a Hartwig JF. Acc. Chem. Res. 2008; 41: 1534
19b Surry DS, Buchwald SL. Chem. Sci. 2011; 2: 27
19c Zhou W, Liu Y, Yang Y, Deng G.-J. Chem. Commun. 2012; 48: 10678
19d Geng Q, Zhang H, Cao W, Chen Y. Chin. J. Chem. 2009; 27: 1995
19e Tan Y, Hu H, Zhu W, Wang T, Gao T, Wang H, Chen J, Xu J, Xu S, Zhu H. Eur. J. Med. Chem. 2023; 262: 115881
19f Geng Q, Zhang H, Cao W, Chen Y. Chin. J. Chem. 2009; 27: 1995
19g Quach TD, Batey RA. Org. Lett. 2003; 5: 4397
19h Chaudhary K, Subodh, Prakash K, Mogha NK, Masram DT. Arabian J. Chem. 2020; 13: 4869
19i Chen Y.-H, Graßl S, Knochel P. Angew. Chem. Int. Ed. 2018; 57: 1108

20a Borkin D, Morzhina E, Datta S, Rudnitskaya A, Sood A, Török M, Török B. Org. Biomol. Chem. 2011; 9: 1394
20b Pratap R, Ram VJ. Chem. Rev. 2014; 114: 10476
20c Pratap R, Ram VJ. Tetrahedron 2017; 73: 2529
20d Pratap R, Raghunandan R, Kumar A, Ram VJ. RSC Adv. 2012; 2: 2688

21a Singh K, Nawabjan SA, Zhang L, El-Nezami H, Annapureddy RR, Chow BK. C. Eur. J. Med. Chem. 2022; 242: 114642
21b Borlinghaus N, Ansari TN, von Garrel LH, Ogulu D, Handa S, Wittmann V, Braje WM. Green Chem. 2021; 23: 3955
21c Hou Y, Dong Y, Ye T, Jiang J, Ding L, Qin M, Ding X, Zhao Y. Bioorg. Med. Chem. Lett. 2019; 29: 126746
21d Gordeev MF, Yuan ZY. J. Med. Chem. 2014; 57: 4487
21e Tabarrini O, Sabatini S, Massari S, Pieroni M, Franzblau SG, Cecchetti V. Chem. Biol. Drug Des. 2012; 80: 781
21f Iyobe A, Uchida M, Kamata K, Hotei Y, Kusama H, Harada H. Chem. Pharm. Bull. 2001; 49: 822

22 Tortolani DR, Poss MA. Org. Lett. 1999; 1: 1261
23 Kim J, Stoltz BM. Tetrahedron Lett. 2012; 53: 4994
24 Jia XD, Chen XN, De Huo C, Peng FF, Qing C, Wang XC. Chin. Chem. Lett. 2012; 23: 309
25 Gallagher MJ, Mann FG. J. Chem. Soc. 1962; 5110
26 Jiang Y, Zhu W, Huang J, Luo F, Chen X, Fang C, Chen X, Liu S, Hu Y, Zhang S. Org. Chem. Front. 2024; 11: 12
27 Hili R, Yudin AK. Nat. Chem. Biol. 2006; 2: 284

28a Althagafi I, Shaw R, Tang C.-R, Panwar R, Sinha C, Kumar A, Zheng Y.-T, Pratap R. Org. Biomol. Chem. 2018; 16: 7477
28b Pratap R, Raghunandan R, Maulik PR, Ram VJ. Tetrahedron 2010; 66: 1458
28c Pratap R, Ram VJ. J. Org. Chem. 2007; 72: 7402

29a Yadav P, Shaw R, Panwar R, Sahu SN, Kumar A, Pratap R. Asian J. Org. Chem. 2017; 6: 1394
29b Pratap R, Raghunandan R, Maulik PR, Ram VJ. Tetrahedron Lett. 2007; 48: 7982

30a Pratap R, Kumar B, Ram VJ. Tetrahedron 2007; 63: 10309
30b Pratap R, Roy AD, Kushwaha SP, Roy R, Ram VJ. Tetrahedron Lett. 2007; 48: 5845

31 4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles 4; General Procedure A mixture of acrylate 1 (20 mmol), the appropriate 1-tetralone 2 (22 mmol), and powdered KOH (30 mmol) was stirred in DMSO (30 mL) for 10–14 h at rt. The mixture was then poured onto crushed ice with vigorous stirring, and the resulting precipitate was collected by filtration, washed (H₂O), dried, and crystallized from MeOH. The resulting intermediate 3 (4 mmol) was then refluxed with 1,4-dioxa-8-azaspiro[4.5]decane (4.4 mmol) in EtOH (15 mL) for 8 h until the reaction was complete (TLC). The mixture was then cooled to rt and the resulting precipitate was collected by filtration, dried, and crystallized from EtOH. 4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile (4a) Yellow solid; yield: 65%. ¹H NMR (400 MHz, CDCl₃): δ = 1.89 (t, J = 5.86 Hz, 4 H, CH₂), 2.65 (t, J = 8.05 Hz, 2 H, CH₂), 2.86 (t, J = 8.05 Hz, 2 H, CH₂), 3.64 (t, J = 5.86 Hz, 4 H, CH₂), 3.99 (s, 4 H, OCH₂), 7.22 (d, J = 7.32 Hz, 1 H, ArH), 7.30–7.39 (m, 2 H, ArH), 7.83 (d, J = 6.59 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.0, 27.6, 35.5, 49.7, 64.5, 81.5, 105.5, 108.7, 116.4, 124.5, 127.3, 127.4, 127.7, 131.4, 137.7, 157.2, 161.1, 167.2. 1-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-3-phenyl-9,10-dihydrophenanthrene-2-carbonitriles 7 and 1-(4-Oxopiperidin-1-yl)-3-phenyl-9,10-dihydrophenanthrene-2-carbonitriles 8; General Procedure The appropriate carbonitrile 4 (0.5 mmol), aryl methyl or aliphatic ketone 6 (0.5 mmol), and powdered KOH (0.75 mmol) were stirred in DMF (4 mL) for 5–6 h at rt until the reaction was complete (TLC). The mixture was then poured onto crushed ice and the solution was neutralized with 10% aq HCl. The precipitate was isolated by filtration, dried, and purified by chromatography (silica gel, 10% EtOAc–hexane) to give compound 7. The resulting compound 7 was stirred in formic acid for 1–2 h. The mixture was then poured into cold H₂O and the precipitate was collected by filtration, dried, and recrystallized from MeOH to give product 8. 1-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-3-phenyl-9,10-dihydrophenanthrene-2-carbonitrile (7a). White solid; yield: 81%. ¹H NMR (400 MHz, CDCl₃): δ = 1.91 (br s, 4 H, CH₂), 2.83–2.92 (m, 4 H, CH₂), 3.4 (br s, 4 H, CH₂), 4.00 (s, 4 H, OCH₂), 7.26–7.30 (m, 3 H, ArH), 7.41–7.55 (m, 6 H, ArH), 7.69–7.71 (m, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.8, 28.5, 36.0, 49.1, 64.3, 107.1, 107.9, 118.3, 121.8, 124.7, 127.2, 128.0, 128.4, 128.5, 128.8, 128.9, 133.7, 134.3, 137.8, 138.9, 139.9, 145.4, 153.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₇N₂O₂: 423.2068; found: 423.2058. 1-(4-Oxopiperidin-1-yl)-3-phenyl-9,10-dihydrophenanthrene-2-carbonitrile (8a) White solid; yield: 88%. ¹H NMR (400 MHz, CDCl₃): δ = 2.67 (br s, 4 H, CH₂), 2.86–2.90 (m, 2 H, CH₂), 2.93–2.97 (m, 2 H, CH₂), 3.62 (br s, 4 H, CH₂), 7.29–7.34 (m, 3 H, ArH), 7.42–7.50 (m, 3 H, ArH), 7.55–7.57 (m, 2 H, ArH), 7.62 (s, 1 H, ArH), 7.71–7.74 (m, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.8, 28.4, 42.9, 50.7, 108.3, 118.3, 122.6, 124.8, 127.3, 128.0, 128.6, 128.8, 129.1, 133.3, 134.5, 137.6, 138.5, 140.3, 145.6, 152.7, 208.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₃N₂O: 379.1805; found: 379.1809.

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