Facile Generation and Synthetic Utility of Nitrogen-Centered Aziridinyl Radicals

Abstract

Nitrogen-centered aziridinyl radicals can be generated through homolysis of N-haloaziridines, which can be easily produced upon treatment of NH aziridines with N-bromo- or N-iodo­succinimide. This methodology allows synthesis of a variety of β-haloaziridines in moderate to good yields. Further transformation into piperazine scaffolds can be achieved via nucleophilic substitution at the β-position and aziridine ring opening initiated by oxalyl chloride.

N-aziridinyl radicals - β-haloaziridines - nucleophilic substitution - aziridine ring opening - piperazine synthesis

References and Notes

1 Aziridines and Epoxides in Organic Synthesis   Yudin AK. John Wiley and Sons; New York: 2006. 

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For recent reviews, see:

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9

Typical Procedure for the NXS-Facilitated N -Aziridinyl Radical Reaction with Olefins
In a flame-dried Schlenk flask, equipped with septum, magnetic stir bar, and nitrogen inlet, were placed NIS (235 mg, 1.33 mmol), powdered 4 Å MS (200 mg), anhyd CH₂Cl₂ (10 mL) under nitrogen atmosphere at 0 °C. After 10 min, aziridine-2-carboxylate methyl ester (100 µL, 1.11 mmol) was added via syringe. After 30 min, when TLC showed no aziridine remaining, 2-bromostyrene (138 µL, 1.11 mmol) was added via syringe. The reaction mixture was allowed to warm up to r.t. and stirred for 8 h. When TLC showed no methyl 1-iodoaziridine-2-carboxylate remaining, the reaction mixture was filtered and concentrated in vacuo, the residue oil was subjected to chromatography on silica gel, eluted with hexane-EtOAc (60:40), to give the product as light yellow oil.
Methyl 1-[2-(2-Bromophenyl)-2-iodoethyl]aziridine-2-carboxylate (4)
Yield 96%. First diastereomer: ¹H NMR (400 MHz, CDCl₃): δ = 7.58-7.56 (m, 1 H), 7.51-7.49 (m, 1 H), 7.33-7.29 (m, 1 H), 7.13-7.09 (m, 1 H), 5.77-5.74 (t, J = 6.8 Hz, 1 H), 3.68 (s, 3 H), 3.18-3.13 (m, 1 H), 2.91-2.86 (m, 1 H), 2.31-2.30 (d, J = 3.2 Hz, 1 H), 2.03-2.00 (m, 1 H), 1.86-1.84 (d, J = 6.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.7, 140.7, 133.5, 130.1, 129.7, 128.4, 122.9, 77.6, 77.2, 76.9, 67.7, 52.4, 37.3, 34.5, 27.5. Second diastereomer: ¹H NMR (400 MHz, CDCl₃): δ = 7.59-7.57 (m, 1 H), 7.51-7.49 (m, 1 H), 7.32-7.28 (m, 1 H), 7.12-7.08 (m, 1 H), 5.76-5.72 (t, J = 7.2 Hz, 1 H), 3.72 (s, 3 H), 3.19-3.14 (m, 1 H), 2.91-2.86 (m, 1 H), 2.34-2.32 (m, 1 H), 2.34-2.31 (m, 1 H), 2.20-2.19 (d, J = 2.8 Hz, 1 H), 1.67-1.66 (d, J = 6.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.8, 140.7, 133.4, 130.1, 130.0, 128.4, 122.9, 67.7, 52.5, 38.3, 33.8, 27.5.

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11

In a flame-dried Schlenk flask, equipped with septum, magnetic stir bar, and nitrogen inlet, were placed NIS (1.2 equiv), powdered 4 Å MS (180 mg/mol aziridine), anhyd CH₂Cl₂ (0.11 mmol/mL) under nitrogen atmosphere at 0 °C. Aziridine-2-carboxylate methyl ester (1.0 equiv) was added via syringe. After 30 min, when TLC showed no aziridine remaining, galvinoxyl (1.0 equiv) was added, followed by the addition of styrene. The reaction mixture was allowed to warm up to r.t. and stirred for 8 h. A control experiment was set up at the same time to compare the effect of the radical trap. After 8 h, the control experiment in the absence of galvinoxyl proceeded smoothly and the anti-Markovnikov product was afforded, while no desired product was formed in the presence of galvinoxyl.

12

Typical Procedure for the Nucleophilic Substitution of β-Haloaziridines with Amines
To a mixture of 4 (50 mg, 0.122 mmol) and DMF (2.5 mL) was added allylamine (91.5 µL, 12.2 mmol) at r.t. and the mixture stirred for 12 h. When TLC showed no 4 remaining, H₂O (4 mL) and Et₂O (2 mL) were added, the layers were then separated. The ether layer was washed with H₂O followed by drying over Na₂SO₄. The solvent was removed in vacuo and the oily residue was subjected to chromatography on alumina, eluted with hexane-EtOAc (80:20), to give the product 15 as light yellow oil.
Methyl 1-[2-Allylamino-2-(2-bromophen-yl)ethyl]azir-idine-2-carboxylate (15)
Yield 75%. ¹H NMR (400 MHz, CDCl₃): δ = 7.63-7.62 (m, 1 H), 7.52-7.49 (m, 1 H), 7.32-7.28 (m, 1 H), 7.13-7.09 (m, 1 H), 5.92-5.84 (m, 1 H), 5.19-5.06 (m, 2 H), 4.34-4.31 (m, 1 H), 3.71 (s, 3 H), 3.12-3.07 (m, 2 H), 2.76-2.71 (m, 2 H), 2.22-2.16 (m, 1 H), 2.03-2.00 (m, 1 H), 1.73-1.71 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.36, 140.20, 136.91, 133.02, 129.02, 127.91, 127.89, 124.12, 116.00, 65.72, 60.72, 52.37, 50.11, 38.13, 34.16.
Typical Procedure for the Nucleophilic Substitution of β-Haloamines with Alcohols Facilitated by Silver Salts
To a mixture of 4 (100 mg, 0.302 mmol), allyl alcohol (205 µL, 0.302 mmol), K₂CO₃ (50.0 mg, 0.362 mmol), and anhyd CH₂Cl₂ (10 mL), was added AgOTf (77.6 mg, 0.302 mmol) at r.t. and the mixture was stirred for 30 min. When TLC showed no 4 remaining, the mixture was filtered and concentrated in vacuo. The oily residue was subjected to chromatography on silica gel, eluted with hexane-EtOAc (70:30), to give the product 23 as light yellow oil.
Methyl 1-[2-(Allyloxy)-2-(2-bromophenyl)ethyl]azir-idine-2-carboxylate (23)
Yield 36%. ¹H NMR (400 MHz, CDCl₃): δ = 7.53-7.47 (m, 4 H), 7.45-7.32 (m, 2 H), 7.16-7.12 (m, 2 H), 5.92-5.86 (m, 2 H), 5.30-5.24 (m, 2 H), 5.18-5.15 (d, J = 10.4 Hz, 2 H), 3.99-3.83 (m, 4 H), 3.72 (s, 6 H), 3.00-2.98 (m, 1 H), 2.69-2.67 (m, 1 H), 2.50-2.45 (m, 1 H), 2.27-2.26 (m, 2 H), 2.15-2.13 (m, 1 H), 2.13-2.08 (m, 1 H), 2.08-2.04 (m, 1 H), 1.80-1.78 (d, J = 6.8 Hz, 1 H), 1.59-1.57 (d, J = 6.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.5, 139.4, 134.8, 134.7, 133.0, 129.5, 129.4, 128.3, 128.3, 127.9, 123.1, 123.1, 117.1, 117.0, (79.9, 79.62), (70.5, 70.3), (65.3, 65.2), (52.3, 52.2), (39.1, 36.7), (35.4, 32.8).

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19

Procedure for the Synthesis of 30
In a 5 mL Schlenk tube, equipped with septum and magnetic stir bar, were placed 19 (0.1 mmol), K₂CO₃ (0.22 mmol), and anhyd MeCN (1 mL). Oxalyl chloride was added via syringe and the solution was stirred at 60 °C for 2 h. When TLC showed no starting material remaining, the solution was filtered and the filtrated was washed with H₂O. The organic layer was dried over anhyd Na₂SO₄ and filtered. The filtrated was concentrated in vacuo and the light brown residue was directly used in the next step without purification.
Reduction with LiAlH ₄
To a suspension of 300 mg LiAlH₄ (7.91 mmol) in 40 mL THF, 264 mg crude product of diketopiperazine 29 (0.66 mmol) dissolved in 5 mL THF was added. The mixture was stirred at 60 °C for 12 h. After cooling to 0 °C, H₂O (0.4 mL), 15% NaOH (0.4 mL), and H₂O (0.4 mL) were added dropwise while stirring. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was subjected to silica gel chromatography, eluted with CH₂Cl₂-MeOH (90:10). Yield 40%.
Reduction with BH ₃ ·SMe ₂
To a solution of crude product of diketopiperazine 29 in anhyd THF (10 mL/mmol) under reflux was added dropwise 9 equiv of a 2 M solution of BH₃·SMe₂ in THF. The mixture was refluxed for 7 h, the solvent was evaporated under reduced pressure, and 4 equiv of a 0.2-0.4 M HCl solution were added. The mixture was stirred for 30 min at 100 °C, and then it was cooled to 0 °C, and 6 equiv of a 0.2-0.4 M solution of NaOH were added. Then, the mixture was stirred for a further 90 min. The aqueous mixture was saturated with solid K₂CO₃ and extracted with CH₂Cl₂ (3-4 times, 5 mL/mmol), and the combined organic extracts were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluted with CH₂Cl₂-MeOH (90:10). Yield 20%.
3-(4-Benzyl-3-phenylpiperazin-1-yl)propan-1-ol (30)
Yield 40%. ¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.19 (m, 10 H), 3.82-3.77 (m, 3 H), 3.03-2.78 (m, 4 H), 2.64-2.57 (m, 2 H), 2.42-2.11 (m, 2 H), 0.89-0.87 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 141.9, 139.1, 129.0, 128.9, 128.8, 128.4, 128.2, 127.9, 127.0, 67.6, 64.9, 62.3, 59.1, 53.6, 51.9, 27.2, 9.7.