Synthesis of Electron-Deficient N1-(Hetero)aryl 3,3,5,5-Tetramethyl Piperazinones

Abstract

An alternative synthesis of N1-(hetero)aryl 3,3,5,5-tetrasubstituted piperazin-2-ones is demonstrated using a copper-mediated Goldberg arylation of a common intermediate in good to fair yields. An improved synthesis of 3,3,5,5-tetramethyl piperazin-2-one is also described. This method allows for the synthesis of substituted piperazin-2-ones which are challenging or inaccessible using traditional Bargellini chemistry.

Key words

piperazin-2-ones - Bargellini - copper - Goldberg - hindered amines

• References and Notes

• 1a Patel RV, Won Park S. Mini-Rev. Med. Chem. 2013; 13: 1579
• 1b Nakhla JS, Wolfe JP. Org. Lett. 2007; 9: 3279
• 2a Zhou Z, Liu L. Curr. Org. 2014; 18: 459
• 2b Ciriminna R, Pagliaro M. Org. Process Res. Dev. 2010; 14: 245
• 2c Schoening K.-U. Chim. Oggi 2010; 28: 18
• 2d Schoening K.-U. Chim. Oggi 2010; 28: 18
• 2e Schoening K.-U. Chim. Oggi 2010; 28: 12
• 2f Schoening K.-U. Chim. Oggi 2010; 28: 15
• 2g Yoshida E. Polymers 2012; 4: 1125
• 3 Francavilla C, Turtle ED, Kim B, O’Mahony DJ. R, Shiau TP, Low E, Alvarez NJ, Celeri CE, D’Lima L, Friedman LC, Ruado FS, Xu P, Zuck ME, Anderson MB, Najafi R, Jain RK. Bioorg. Med. Chem. Lett. 2011; 21: 3029
• 4 McNally A, Haffemayer B, Collins BS. L, Gaunt MJ. Nature 2014; 510: 129
• 5a Bargellini G. Gazz. Chim. Ital. 1906; 36: 329

For a recent review, see:
• 5b Snowden TS. ARKIVOC 2012; (ii): 24
• 6 A survey of the literature on this class of compounds shows that out of the 730 reported examples, remarkably, only 23 bear an electron-withdrawing group on the lactam (Scifinder substructure search excluding prophetic in patents on 3,3,5,5-tetrasubstituted scaffolds, August 2016). Included are both piperazin-2-ones and 2,6-diketopiperazinones.
• 7a Lai JT. J. Org. Chem. 1980; 45: 754
• 7b Lai JT. Synthesis 1981; 40
• 7c Lai JT. Synthesis 1982; 71
• 8 We observed intractable mixtures with multiple products from side reactions, including decarboxylation and imidazoline formation.
• 9 Chern C.-Y, Huang Y.-P, Kan WM. Tetrahedron Lett. 2003; 44: 1039
• 10 Related hindered amines (3,3,5,5-tetramethyl morpholin-2-ones) have been shown to coordinate to palladium and undergo C–H activation processes. See ref. 4.
• 11 For substrate 3e, degradation was observed under the reaction conditions.
• 12 Compound 3k has been prepared by Lai (see ref. 7a,b) and 3l has been prepared by author TAA using the Bargellini reaction in 47% yield (unpublished results).
• 13 Synthesis of N1-(2,4-Dimethoxybenzyl)-2-methylpropane-1,2-diamine (1c) AcOH (0.260 mL, 4.54 mmol) was added to 2-methylpropane-1,2-diamine (0.595 mL, 5.67 mmol) and 2,4-dimethoxybenzaldehyde (943 mg, 5.67 mmol) in MeOH (20 mL) at r.t. under nitrogen. The resulting slurry turns yellow rapidly (CAUTION: exotherm). The reaction mixture was stirred at r.t. for 1 h. The reaction mixture was then diluted with MeOH (20 mL), NaBH₄ (429 mg, 11.34 mmol) was added portionwise, and the reaction mixture was stirred at r.t. for 1 h (CAUTION: gas evolution). The solvent was removed under reduced pressure, and the white residue was treated with H₂O (20 mL) and extracted with CH₂Cl₂ (2 × 30 mL). The combined organic layers were dried (MgSO₄), filtered, and the solvent removed under reduced pressure to give a 4:1 mixture of alkylation regioisomers. For characterisation, the crude yellow oil obtained was purified by flash silica chromatography, elution gradient 0–10% 7 N NH₃ in MeOH in CH₂Cl₂. Pure fractions were evaporated to dryness to afford the product as a 9:1 mixture of regioisomers in favor of 1c (1104 mg, 82%) as a colourless oil. R_f = 0.31 (CH₂Cl₂–7N NH₃ in MeOH = 9:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.14 (1 H, d, J = 8.0 Hz), 6.47–6.40 (2 H, m), 3.81 (3 H, s), 3.80 (3 H, s), 3.75 (2 H, s), 2.40 (2 H, s), 1.43 (3 H, s), 1.07 (6 H, s). ¹³C NMR (101 MHz, CDCl₃): δ = 160.1, 158.8, 130.3, 121.6, 103.9, 98.8, 61.7, 55.5, 55.5, 50.0, 49.9, 28.9 (2 C). IR: 3347, 2959, 2835, 1613, 1589, 1506, 1464, 1439, 1419, 1372, 1289, 1260, 1208, 1156, 1131, 1038 cm^–1. HRMS (TOF ES+): m/z calcd for C₁₃H₂₃N₂O₂ [M + H]⁺: 239.17540; found: 239.17560.
• 14 Synthesis of 1-(2,4-Dimethoxybenzyl)-3,3,5,5-tetramethylpiperazin-2-one (3b) 50% aq. NaOH (1.908 mL, 36.14 mmol) was added dropwise to 1,1,1-trichloro-2-methylpropan-2-ol (2.70 g, 14.46 mmol), 1c (2.36 g, 7.23 mmol), and N-benzyl-N,N-triethylammonium chloride (0.165 g, 0.72 mmol) in CH₂Cl₂ (70 mL) cooled to 0 °C. The resulting mixture was stirred at 0 °C and left to warm to r.t. over 20 h. The reaction mixture was treated with H₂O (50 mL) until any solid had dissolved. The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 50 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated under reduced pressure to give a pale yellow oil. The crude product was purified by flash silica chromatography, elution gradient 50–100% EtOAc in heptane, monitored at 280 nm. Pure fractions were evaporated to dryness to afford 3b (1.510 g, 68%) as a viscous pale yellow oil; R_f = 0.12 (EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 7.20 (1 H, d, J = 8.4 Hz), 6.49–6.39 (2 H, m), 4.58 (2 H, s), 3.80 (3 H, s), 3.79 (3 H, s), 3.09 (2 H, s), 1.39 (6 H, s), 1.35 (1 H, br s), 1.09 (6 H, s). ¹³C (101 MHz, CDCl₃): δ = 173.8, 160.5, 158.9, 131.4, 117.9, 104.5, 98.6, 58.9, 55.6, 55.5, 55.5, 48.9, 45.2, 30.6 (2 C), 27.8 (2 C). IR (): 3473, 1614, 1505, 1463, 1288, 1265, 1208, 1158, 1119, 1038 cm^–1. HRMS (TOF ES+): m/z calcd for C₁₇H₂₇N₂O₃ [M + H]⁺: 307.20162; found: 307.20157.
• 15 Synthesis of 2,2,6,6-Tetramethyl-3-oxopiperazin-1-ium 4-Methylbenzenesulfonate (5, p-TsOH Salt) Compound 3b (2.37 g, 7.73 mmol) was dissolved in toluene (23 mL) at r.t. p-TsOH (3.24 g, 17.02 mmol) was then added, and the resulting solution was stirred at 120 °C for 2.5 h. The reaction was quenched with MeOH. The purple residue was triturated with CH₂Cl₂ and filtered to give 5 (p-TsOH salt, 2.388 g, 94%) as an amorphous white powder. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.00 (2 H, br s), 8.31 (1 H, br s), 7.50 (2 H, d, J = 8.1 Hz), 7.13 (2 H, d, J = 7.8 Hz), 3.29 (2 H, d, J = 3.2 Hz), 2.29 (3 H, s), 1.51 (6 H, s), 1.40 (6 H, s). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 168.5, 145.6, 137.7, 128.1, 125.5, 57.8, 54.3, 48.1, 26.2, 22.9 (2 C), 20.8 (2 C). IR: 3276, 1688, 1610, 1585, 1507, 1463, 1395, 1343, 1294, 1213, 101, 1185, 1165, 1094, 1034 cm^–1. HRMS (TOF ES+): m/z calcd for C₈H₁₇N₂O [M + H]⁺: 157.13354; found: 157.13342.
• 16 Representative Synthesis of 3,3,5,5-Tetramethyl-1-(pyridin-3-yl)piperazin-2-one (3a) 1,10-Phenanthroline (10.97 mg, 0.06 mmol) was added to 3-iodopyridine (94 mg, 0.46 mmol), 5 (p-TsOH salt, 100 mg, 0.30 mmol), CuI (11.60 mg, 0.06 mmol), and K₃PO₄ (323 mg, 1.52 mmol) in DMF (3 mL) at r.t. under nitrogen. The resulting mixture was stirred at 110 °C for 1 d. The reaction mixture was filtered through a pad of Celite^®, and the filter cake was washed with EtOAc (3 × 5 mL). The filtrate was concentrated to dryness under reduced pressure to give a yellow residue which was purified by flash silica chromatography, elution gradient 0–10% MeOH in CH₂Cl₂. Pure fractions were evaporated to dryness to afford 3a (49 mg, 68%) as an amorphous waxy yellow solid. R_f = 0.41 (CH₂Cl₂–MeOH = 9:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.56 (1 H, d, J = 2.6 Hz), 8.48 (1 H, dd, J = 1.5, 4.8 Hz), 7.69 (1 H, ddd, J = 1.5, 2.6, 8.2 Hz), 7.32 (1 H, ddd, J = 0.7, 4.8, 8.2 Hz), 3.64 (2 H, s), 1.47 (7 H, s), 1.31 (6 H, s). N–H signal appeared under the methyl signal at δ = 1.47 ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 174.4, 147.5, 146.8, 140.0, 133.3, 123.6, 62.5, 56.1, 49.7, 30.7 (2 C), 27.9 (2 C). IR (): 3357, 3057, 2969, 2928, 1669, 1587, 1572, 1467, 1434, 1402, 1347, 1302, 1283, 1246, 1206, 1173, 1151, 1110 cm^–1. HRMS (TOF ES+): m/z calcd for C₁₃H₁₉N₃O [M + H]⁺: 234.16009; found: 234.15987.