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

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

Publication History

Received: 11 May 2024

Accepted after revision: 22 July 2024

Accepted Manuscript online:
22 July 2024

Article published online:
21 August 2024

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• 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.