Synthesis of Selenopyrano[2,3-c]pyrazol-4(1H)-ones and Their C–H Activation

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Abstract

We disclose the synthesis of selenopyrano[2,3-c]pyrazol-4(1H)-ones and their aryl derivatives for the first time by using selenopyran ring formation via an in situ-generated selenide that reacts directly with α-halo-β-ynone-bearing substituted pyrazoles to provide the corresponding selenopyrano[2,3-c]pyrazol-4(1H)-ones. Subsequent direct C–H arylation of the latter compounds effected by palladium-catalyzed Heck reactions permits the incorporation of arene substituents onto the selenopyrano[2,3-c]pyrazol-4(1H)-ones scaffolds with moderate to good yields, and might be useful for biological screenings.

Key words

selenopyranopyrazolones - C–Se bond formation - C–H bond activation - Heck reaction - organoselenides - selenium heterocycles

Publication History

Received: 28 September 2020

Accepted after revision: 23 October 2020

Accepted Manuscript online:
23 October 2020

Article published online:
23 November 2020

• References and Notes

• 1a Srivastava PC, Robins RK. J. Med. Chem. 1983; 26: 445
• 1b Nogueira CW, Zeni G, Rocha JB. T. Chem. Rev. 2004; 104: 6255
• 1c Sarma BK, Mugesh G. J. Am. Chem. Soc. 2005; 127: 11477
• 1d Bhabak KP, Mugesh G. Chem. Eur. J. 2007; 13: 4594
• 1e Sarma BK, Mugesh G. Chem. Eur. J. 2008; 14: 10603
• 1f Bhabak KP, Mugesh G. Chem. Eur. J. 2009; 15: 9846
• 1g Sarma BK, Manna D, Minoura M, Mugesh G. J. Am. Chem. Soc. 2010; 132: 5364
• 1h Bhabak KP, Mugesh G. Acc. Chem. Res. 2010; 43: 1408
• 1i Koketsu M, Ishihara H, Wu W, Murakami K, Saiki I. Eur. J. Pharm. Sci. 1999; 9: 157
• 1j Takahashi H, Nishina A, Fukumoto R.-h, Kimura H, Koketsu M, Ishihara H. Eur. J. Pharm. Sci. 2005; 24: 291
• 1k Traiffort E, Ruat M, Arrang JM, Leurs R, Piomelli D, Schwartz JC. Proc. Natl. Acad. Sci. U.S.A. 1992; 89: 2649
• 1l van der Goot H, Eriks JC, Leurs R, Timmerman H. Bioorg. Med. Chem. Lett. 1994; 4: 1913
• 1m Sekiguchi A, Nishina A, Kimura H, Fukumoto RH, Kanoh K, Ishihara H, Koketsu M. Chem. Pharm. Bull. 2005; 53: 1439
• 1n Nam KN, Koketsu M, Lee EH. Eur. J. Pharmacol. 2008; 589: 53
• 2a Karabanovich G, Roh J, Padělková Z, Novák Z, Vávrová K, Hrabálek A. Tetrahedron 2013; 69: 8798
• 2b Pizzo C, Mahler SG. J. Org. Chem. 2014; 79: 1856
• 2c Choi Y.-S, Kim D.-M, Kim Y.-J, Yang S, Lee K.-T, Ryu J.-H, Jeong J.-H. Int. J. Mol. Sci. 2015; 16: 29574
• 3 Yang W.-R, Choi Y.-S, Jeong J.-H. Org. Biomol. Chem. 2017; 15: 3074
• 4 Klayman DL, Griffin TS. J. Am. Chem. Soc. 1973; 95: 197
• 5 MacLean MA, Diez-Cecilia E, Lavery CB, Reed MA, Wang Y, Weaver DF, Stradiotto M. Bioorg. Med. Chem. Lett. 2016; 26: 100
• 6 5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (5a); Typical Procedure POCl₃ (0.12 mol, 11.27 mL) was added dropwise to ice-cold DMF (0.52 mol, 4 mL). The cooling system was removed and replaced with a reflux system, and pyrazolone 6 (R¹ = Me; R² = Ph; 3.0 g, 17.22 mmol) was added. The mixture was heated at 120 °C for 20 min, then cooled and poured into ice-cold H₂O (200 mL) and stirred for 1 h. The mixture was extracted with EtOAc, and the extracts were washed with H₂O, dried (Na₂SO₄), and concentrated under vacuum. The product was purified by flash chromatography [silica gel, hexane–EtOAc (3:1)] to give a yellow solid; yield: 2.5 g (65.8%); mp 143–145 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.98 (s, 1 H), 7.53–7.46 (m, 5 H), 2.55 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 184.0, 151.9, 137.1, 133.6, 129.4, 129.3, 125.3, 117.6, 14.0. HRMS (ESI-QTOF): m/z [M + H]⁺ calcd for C₁₁H₁₀ClN₂O: 221.0482; found; 221.0480.
• 7 1-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)prop-2-yn-1-ol (4a); Typical Procedure A 0.5 M solution of ethynylmagnesium bromide in THF (8 mmol) was added to a solution of aldehyde 5a (1.3 g, 5.9 mmol) in anhyd THF (30 mL) at 0 °C. The mixture was stirred at 0 °C and then allowed to warm to rt for another 2 h. When the reaction was complete (TLC), the mixture was treated with sat. aq NH₄Cl and EtOAc, and then stirred for 30 min. The organic extracts were dried (Na₂SO₄), concentrated under vacuum, and purified by flash chromatography [silica gel, hexane–EtOAc (3:1)] to give a yellow solid; yield: 1.4 g (96%); mp 87–90 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.47–7.36 (m, 5 H), 5.43 (s, 1 H), 3.74 (s, 1 H), 2.56 (s, 1 H), 2.43 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 148.9, 137.8, 129.0, 128.3, 125.9, 125.1, 116.5, 82.2, 73.8, 55.3, 13.1. HRMS (ESI-QTOF): m/z [M + H]⁺ calcd for C₁₃H₁₂ClN₂O: 247.0638; found: 247.0646.
• 8 1-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)prop-2-yn-1-one (3a); Typical Procedure A solution of NaOCl (12%, 6 mmol) was added to a solution of NaBr (2 mmol), NaHCO₃ (4 mmol), TEMPO (0.1 mmol), and secondary alcohol 4a (500 mg, 2.03 mmol) in CH₂Cl₂ (10 mL) at 0 °C. When the reaction was complete (TLC), H₂O was added and organic layer was separated, dried (Na₂SO₄), concentrated under vacuum, and purified by flash chromatography [silica gel, hexane–EtOAc–CH₂Cl₂ (10:1:2)] to give a white solid; yield: 488 mg (98%); mp 96–99 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.52–7.49 (m, 5 H), 3.43 (s, 1 H), 2.59 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.7, 166.6, 152.7, 137.2, 129.5, 129.4, 125.6, 81.6, 80.7, 15.2. HRMS (ESI-QTOF): m/z [M + H]⁺ calcd for C₁₃H₁₀ClN₂O: 245.0482; found: 245.0479.
• 9 3-Methyl-1-phenylselenopyrano[2,3-c]pyrazol-4(1H)-one (2a); Typical Procedure A solution of NaHSe (1.2 mmol) was prepared by stirring Se powder (1.1 mmol) and NaBH₄ (1.2 mmol) in H₂O (10 mL) at 40 ℃ for 30 min. To this solution was added a solution of ketone 3a (100 mg, 0.409 mmol) in 1,4-dioxane (5 mL) in one portion, and the mixture was stirred for another 30 min. To remove the inorganics, the mixture was extracted with EtOAc and the extracts were washed with H₂O. The extracts were then dried (Na₂SO₄), concentrated, and purified by flash chromatography [silica gel, hexane–EtOAc (2:1)] to give a yellow solid; yield: 100 mg (85%); mp 133–135 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.79 (d, J = 8.0 Hz, 1 H), 7.63–7.43 (m, 5 H), 7.13 (d, J = 8.0 Hz, 1 H), 2.75 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 180.3, 152.7, 139.1, 136.2, 131.0, 129.9, 129.3, 128.7, 122.8, 118.1, 14.5. HRMS (ESI-QTOF): m/z [M + H]⁺ calcd for C₁₃H₁₁N₂OSe: 291.0037; found: 291.0040.
• 10 Lee K, Lee PH. Tetrahedron Lett. 2008; 49: 4302
• 11 Chen J, Chang HW, Kim HP, Park H. Bioorg. Med. Chem. Lett. 2006; 16: 2373
• 12 3-Methyl-1,6-diphenylselenopyrano[2,3-c]pyrazol-4(1H)-one (1a); Typical Procedure A two-necked flask fitted with reflux condenser and a septum was charged with Pd(OAc)₂ (20 mol%), XPhos (40 mol%), t-Bu₃PHBF₄ (40 mol%), PivOH (0.15 mmol), Cs₂CO₃ (0.3 mmol), and selenopyranopyrazolone 2a (30 mg, 0.104 mmol) in DMA (0.1 M). PhBr (0.2 mmol) was added, the flask was set on a heating block, the temperature was adjusted to 135 °C, and the mixture was stirred for 15 h. The cooled mixture was treated with H₂O and EtOAc, dried (Na₂SO₄), concentrated, and purified by flash chromatography [silica gel, hexane–EtOAc–CH₂Cl₂ (5:1:2)] to give a white solid; yield: 25.5 mg (75%); mp 192–193 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.67 (d, J = 8.0 Hz, 2 H), 7.57–7.53 (m, 4 H), 7.48–7.44 (m, 4 H), 7.23 (s, 1 H), 2.77 (s, 3 H). ^13C NMR (101 MHz, CDCl₃): δ = 180.7, 152.7, 147.3, 139.3, 137.8, 137.7, 130.8, 130.1, 129.5, 128.8, 127.2, 123.0, 117.4, 14.6. HRMS (ESI-QTOF): m/z [M + H]⁺ calcd for C₁₉H₁₅N₂OSe: 367.0350; found: 367.0347.