Multigram Synthesis of 4,4-Disubstituted 3-Oxopyrrolidones: Efficient Starting Materials for Diverse 3-Functionalized Pyrrolidones

Abstract

The practical, rapid development of chemical leads for drug discovery depends strongly on scalable building block synthesis procedures. N-Heterocyclic moieties, especially unsaturated ones, remain essential tools in the hands of screening and medicinal chemists. Here, we report four novel chemical block families and the interconversions between them. The synthesis of 4,4-disubstituted 3-oxopyrrolidones was an essential milestone in the diversity-oriented production of 3-aminopyrrolidones, 3-hydroxypyrrolidones, and 3,3′-difluoropyrrolidines. These compounds can be functionalized with conformationally flexible spirocyclic substituents. We developed a multigram procedure to access 4,4-disubstituted 3-oxopyrrolidones from commercially accessible and cost-saving reagents via a short three-step procedure. Here, we report the robust conversion of 3-oxopyrrolidones into 3-aminopyrrolidones, 3,3′-difluoropyrrolidones, and 3-hydroxypyrrolidones, involving a minimal number of steps. We demonstrate the scope and limitations and further perspectives for such synthetic approaches.

Key words

pyrrolidone derivatives - 3-oxopyrrolydones - 3-aminopyrrolidones - 3,3′-difluoropyrrolidines - building blocks

Publikationsverlauf

Eingereicht: 03. April 2024

Angenommen nach Revision: 06. Mai 2024

Accepted Manuscript online:
06. Mai 2024

Artikel online veröffentlicht:
28. Mai 2024

• References and Notes

• 1 Linusson A, Gottfries J, Lindgren F, Wold S. J. Med. Chem. 2000; 43: 1320
• 2 Zabolotna Y, Volochnyuk DM, Ryabukhin SV, Horvath D, Gavrilenko KS, Marcou G, Moroz YS, Oksiuta O, Varnek AA. J. Chem. Inf. Model. 2022; 62: 2171
• 3 Goldberg FW, Kettle JG, Kogej T, Perry MW. D, Tomkinson NP. Drug Discovery Today 2015; 20: 11
• 4 Wang J, Hou T. J. Chem. Inf. Model. 2010; 50: 55
• 5 Kerru N, Gummidi L, Maddila S, Gangu KK, Jonnalagadda SB. Molecules 2020; 25: 1909
• 6 Taylor AP, Robinson RP, Fobian YM, Blakemore DC, Jones LH, Fadeyi OM. Org. Biomol. Chem. 2016; 14: 6611
• 7 Börjesson M, Tortajada A, Martin R. Chem 2019; 5: 254
• 8 Baumann M, Baxendale IR. Beilstein J. Org. Chem. 2013; 9: 2265
• 9 Cozzini P, Kellogg GE, Spyrakis F, Abraham DJ, Costantino G, Emerson A, Fanelli F, Gohlke H, Kuhn LA, Morris GM, Orozco M, Pertinhez TA, Rizzi M, Sotriffer CA. J. Med. Chem. 2008; 51: 6237
• 10 Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. Lett. 2014; 24: 3673
• 11 Zheng YJ, Tice CM. T. Expert Opin. Drug Discovery 2016; 11: 831
• 12 Marson CM. Chem. Soc. Rev. 2011; 40: 5514
• 13 Abhijnhan A, Adams CE, David A, Ozbilen M. Cochrane Database Syst. Rev. 2007, 1 Art. No.: CD001718.
• 14 Keating GM. Drugs 2011; 71: 731
• 15 Melnykov KP, Artemenko AN, Ivanenko BO, Sokolenko YM, Nosik PS, Ostapchuk EN, Grygorenko OO, Volochnyuk DM, Ryabukhin SV. ACS Omega 2019; 4: 7498
• 16 Malykh AG, Sadaie MR. Drugs 2010; 70: 287
• 17 Ōmura S, Crump A. J. Antibiot. 2019; 72: 189
• 18 Noel GJ. Clin. Microbiol. Infect. 2007; 13: 25
• 19 Mashiko T, Kumagai N, Shibasaki M. Org. Lett. 2008; 10: 2725
• 20 Nitti A, Signorile M, Boiocchi M, Bianchi G, Po R, Pasini D. J. Org. Chem. 2016; 81: 11035
• 21 Zhu HL, Ling JB, Xu PF. J. Org. Chem. 2012; 77: 7737
• 22 Southwick PL, Crouch RT. J. Am. Chem. Soc. 1953; 75: 3413
• 23 Sundberg RJ, Pearce BC, Laurino JP. J. Heterocycl. Chem. 1986; 23: 537
• 24a Jones RC. F, Crockett AK. Tetrahedron Lett. 1993; 34: 7459
• 24b Pellegata R, Pinza M, Pifferi G. Synthesis 1987; 614
• 25 Camps P, Muñoz-Torrero D, Rull J, Mayoral JA, Calvet T, Font-Bardia M. Tetrahedron: Asymmetry 2010; 21: 2124
• 26 Compounds 3; General Procedure A solution of BuLi (2.5 M in hexane, 1.43 mol, 1.1 equiv) was added dropwise to a cooled (–40 °C) solution of NH(i-Pr)₂ (1.43 mol, 1.1 equiv) in THF (2000 mL) under Ar atmosphere and the mixture was stirred for 10–20 min. The mixture was kept at –78 °C, then nitrile 2 (1.30 mol, 1.0 equiv) was added and the mixture was stirred for another 15 min. A 50% solution of aldehyde 1 in toluene (1.43 mol, 1.1 equiv) was added and, after warming to room temperature, the reaction was quenched with a solution of NH₄Cl to pH~7. The organic layer was washed with water (3 × 200 mL) and brine (3 × 200 mL), separated, and the solvent was evaporated in vacuo. The crude product was used in next step without purification. Ethyl 2-(1-Cyanocyclobutyl)-2-hydroxyacetate (3e) Yield: 78% (221.1 g, 84% purity; analytical sample was obtained in 52% yield by chromatographic purification); colorless viscous oil. ¹H NMR (500 MHz, CDCl₃): δ = 4.38 (tt, J = 10.4, 5.5 Hz, 1 H), 4.35–4.20 (m, 3 H), 3.30 (s, 1 H), 2.58 (dq, J = 12.6, 5.7, 2.9 Hz, 1 H), 2.54–2.38 (m, 3 H), 2.36–2.15 (m, 1 H), 2.13–1.96 (m, 1 H), 1.42–1.22 (m, 3 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 168.7, 121.0, 70.9, 58.8, 37.4, 27.2, 27.0, 14.4, 12.2. LCMS (+ve): m/z = 184 [M + H]⁺. Anal. calcd. for C₉H₁₃NO₃: C, 59.00; H, 7.15; N, 7.65. Found: C, 58.61; H, 7.16; N, 8.03. Compounds 4; General Procedure Raney nickel (9.0 g) was added to a solution of nitrile 3 (1 mol) in methanol (2700 mL), the mixture was treated at 60 atm of H₂ pressure at 50 °C and left overnight. The mixture was then filtered, the solvent was evaporated in vacuo, and the solid was recrystallized from MeCN. 8-Hydroxy-6-azaspiro[3.4]octan-7-one (4e) Yield: 89% (125.6 g). ¹H NMR (500 MHz, DMSO-d ₆): δ = 7.46 (s, 1 H), 5.40 (s, 1 H), 3.68 (s, 1 H), 3.07 (s, 2 H), 2.31 (s, 2 H), 2.02 (s, 2 H), 1.55 (s, 2 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 176.0, 74.9, 50.2, 46.5, 28.2, 25.8, 15.8. LCMS (+ve): m/z = 142 [M + H]⁺. Anal. calcd. for C₇H₁₁NO₂: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.80; H, 8.19; N, 9.55. Compounds 5; General Procedure MnO₂ (1.8 mol, 2.0 equiv) was added to a solution of alcohol 4 (0.9 mol, 1.0 equiv) in DMF (800 mL). The mixture was stirred overnight at 50 °C, then the mixture was filtered and the solvent was evaporated in vacuo. The product was recrystallized from MeCN. 6-Azaspiro[3.4]octane-7,8-dione (5e) Yield: 71% (88.9 g). ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.51 (s, 1 H), 3.58 (s, 2 H), 2.29–2.16 (m, 2 H), 2.16–2.02 (m, 2 H), 2.01–1.85 (m, 2 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 204.6, 161.7, 49.8, 46.1, 30.7, 15.6. LCMS (+ve): m/z = 140 [M + H]⁺. Anal. calcd. for C₇H₉NO₂: C, 60.42; H, 6.52; N, 10.07. Found: C, 60.12; H, 6.14; N, 9.67. Compounds 6; General Procedure Sodium acetate (0.77 mol, 1.1 equiv) in methanol (560 mL) was added to a solution of ketone 5 (0.70 mol, 1.0 equiv) and hydroxylamine hydrochloride (0.77 mol, 1.1 equiv) in methanol (800 mL). The mixture was stirred overnight at 40 °C, then filtered to remove inorganic compounds and the solvent was evaporated in vacuo. 8-(Hydroxyamino)-6-azaspiro[3.4]octan-7-one (6e) Yield: 92% (99.3 g). ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.71 (s, 1 H), 8.29 (s, 1 H), 3.45 (s, 2 H), 3.28 (s, 1 H), 3.06–2.82 (m, 2 H), 2.21–2.00 (m, 1 H), 2.02–1.84 (m, 3 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 165.5, 154.2, 54.0, 42.1, 30.7, 15.8. LCMS (+ve): m/z = 155 [M + H]⁺. Anal. calcd. for C₇H₁₀N₂O₂: C, 54.54; H, 6.54; N, 18.17. Found: C, 54.51; H, 6.81; N, 18.49. Compounds 7; General Procedure Raney nickel (10.0 g) was added to solution of oxime 6 (0.40 mol) in a saturated solution of ammonia in methanol (1000 mL). The mixture was treated at 10 atm of hydrogen pressure at 60 °C and left overnight. The mixture was then filtered and the solvent was evaporated in vacuo. 8-Amino-6-azaspiro[3.4]octan-7-one hydrochloride (7e) Yield: 87% (48.8 g). ¹H NMR (500 MHz, D₂O): δ = 3.79 (s, 1 H), 3.56 (d, J = 10.3 Hz, 1 H), 3.35 (d, J = 10.6 Hz, 1 H), 2.19 (q, J = 9.6, 8.8 Hz, 1 H), 2.04 (q, J = 11.4, 10.1 Hz, 1 H), 1.88 (tt, J = 15.6, 9.0 Hz, 2 H), 1.69 (h, J = 8.3, 6.8 Hz, 2 H) (NH not observed due to exchange). ¹³C NMR (126 MHz, D₂O): δ = 172.1, 56.8, 51.7, 44.1, 28.0, 27.2, 15.4. LCMS (+ve): m/z = 141 [M-HCl + H]⁺. Anal. calcd. for C₇H₁₃ClN₂O: C, 47.60; H, 7.42; N, 15.86; Cl, 20.07. Found: C, 47.68; H, 7.18; N, 16.17; Cl, 20.38. 2-Azaspiro[4.4]nonan-4-ol (8f) Alcohol (0.25 mol, 1 equiv) in THF (200 mL) was added dropwise to a suspension of LAH (0.375 mol, 1.5 equiv) in THF (400 mL). The mixture was heated at reflux for 1 h and stirred overnight at room temperature. The reaction was then quenched with NaOH (2 M), the mixture was filtered, and the solvent was evaporated in vacuo. Yield: 89% (31.4 g); white crystalline powder; mp 63 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 4.57 (br, 2 H), 3.56 (dd, J = 5.3, 3.0 Hz, 1 H), 2.95 (dd, J = 11.3, 5.2 Hz, 1 H), 2.62 (d, J = 9.9 Hz, 1 H), 2.54 (dd, J = 11.3, 3.0 Hz, 1 H), 2.46 (s, 1 H), 1.83 (dt, J = 13.2, 7.3 Hz, 1 H), 1.66–1.41 (m, 4 H), 1.38–1.25 (m, 2 H), 1.21 (dt, J = 13.0, 6.8 Hz, 1 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 77.7, 57.3, 54.8, 54.6, 36.6, 30.1, 25.3, 25.2. LCMS (+ve): m/z = 142 [M + H]⁺. Anal. calcd. for C₈H₁₅NO: C, 68.04; H, 10.71; N, 9.92. Found: C, 68.07; H, 11.04; N, 10.25. tert-Butyl 4-Hydroxy-2-azaspiro[4.4]nonane-2-carboxylate (9f) Boc₂O (0.22 mol, 1 equiv) in THF (380 mL) was added dropwise to aminoalcohol 8 (0.22 mol, 1 equiv) in THF (250 mL). After stirring overnight, the solution was evaporated in vacuo. Yield: 98% (52.0 g); yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 3.84 (s, 1 H), 3.60–3.44 (m, 1 H), 3.42–3.08 (m, 3 H), 1.98 (s, 1 H), 1.92–1.78 (m, 1 H), 1.71–1.56 (m, 4 H), 1.56–1.29 (m, 12 H), 1.26 (s, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 154.3, 78.7, 76.0, 54.9, 54.1, 53.6–52.2 (m), 35.9*, 35.6, 30.7*, 29.6, 28.0, 24.7*, 24.6 (* - due to hindered rotation). LCMS (+ve): m/z = 186 [M-tBu + H]⁺. Anal. calcd. for C₉H₁₅NO₃: C, 58.36; H, 8.16; N, 7.56. Found: C, 58.61; H, 8.08; N, 7.68. tert-Butyl 4-Oxo-2-azaspiro[4.4]nonane-2-carboxylate (10f) A solution of DMSO (0.53 mol, 2.4 equiv) in CH₂Cl₂ (65 mL) was added dropwise to a cooled (–70 °C) solution of oxalyl chloride (0.26 mol, 1.2 equiv) in CH₂Cl₂ (400 mL) under Ar atmosphere. The reaction mixture was stirred for 30 min then alcohol 9 (0.22 mol, 1 equiv) in CH₂Cl₂ (65 mL) was added dropwise. The reaction mixture was stirred for 30 min and Et₃N (1.1 mol, 5 equiv) was added. The mixture was allowed to warm to room temperature and then washed with water (3 × 150 mL). The organic layer was dried over Na₂SO₄ and solvent was evaporated in vacuo. Yield: 91% (47.9 g); white crystalline powder; mp 60–61 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.90–3.75 (m, 2 H), 3.55 (s, 2 H), 1.87 (dt, J = 13.3, 6.3 Hz, 2 H), 1.76 (td, J = 9.8, 9.3, 3.9 Hz, 2 H), 1.73–1.61 (m, 2 H), 1.63–1.55 (m, 2 H), 1.47 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 214.9, 154.0, 79.8, 56.4, 55.9, 55.5, 52.2, 51.7, 35.2, 27.9, 25.4. EIMS (70 eV): m/z (%) = 239 (2) [M]⁺, 183 (12), 111 (15), 82 (12), 67 (25), 57 (100), 56 (21), 44 (21), 41 (46), 39 (21). Anal. calcd. for C₁₃H₂₁NO₃: C, 65.25; H, 8.85; N, 5.85. Found: C, 65.65; H, 9.16; N, 6.03. tert-Butyl 4,4-Difluoro-2-azaspiro[4.4]nonane-2-carboxylate (11f) DAST (0.4 mol, 2 equiv) in CH₂Cl₂ (250 mL) was added dropwise to cooled (–40 °C) ketone 10 (0.2 mol, 1 equiv) in CH₂Cl₂ (525 mL) under Ar atmosphere. The mixture was warmed to room temperature then poured onto ice and washed with Na₂CO₃ solution (2 × 150 mL) and brine (2 × 150 mL). The organic layer was dried over Na₂SO₄ and the solvent was evaporated in vacuo. The product was purified by flash chromatography. Yield: 87% (45.5 g). ¹H NMR (500 MHz, CDCl₃): δ = 3.65 (dt, J = 20.9, 13.2 Hz, 2 H), 3.42–3.21 (m, 2 H), 2.04–1.83 (m, 2 H), 1.81–1.61 (m, 4 H), 1.65–1.53 (m, 2 H), 1.46 (s, 9 H). ¹³C NMR (151 MHz, CDCl₃): δ = 154.2, 127.5, 80.1*, 80.0, 56.6, 55.8, 52.2, 31.1*, 31.0, 28.4, 27.9, 25.4*, 25.3 (* - due to hindered rotation). LCMS (+ve): m/z = 294 [M + Na]⁺. Anal. calcd. for C₁₃H₂₁F₂NO₂: C, 59.75; H, 8.10; N, 5.36. Found: C, 59.87; H, 8.11; N, 5.21. 4,4-Difluoro-2-azaspiro[4.4]nonane Hydrochloride (12f) Boc-protected ketone 11 (0.17 mol) in THF (120 mL) was mixed with a saturated solution of HCl in dioxane (150 mL) and stirred for 1 h. The solvent was evaporated in vacuo. Yield: 98% (32.9 g); yellow powder; mp 99–109 °C (decomp.). ¹H NMR (500 MHz, DMSO-d ₆): δ = 10.04 (s, 2 H), 3.66 (t, J = 12.9 Hz, 2 H), 3.27 (s, 2 H), 1.89–1.69 (m, 2 H), 1.72–1.56 (m, 6 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 128.2, 53.6, 52.8 (t, J = 20.4 Hz), 48.6 (t, J = 33.3 Hz), 30.5, 25.2. LCMS (+ve): m/z = 162 [M – HCl + H]⁺. Anal. calcd. for C₈H₁₄ClF₂N: C, 48.62; H, 7.14; N, 7.09; Cl, 17.94. Found: C, 48.36; H, 6.90; N, 6.86; Cl, 17.98.