Azide 1,3-Dipolar Cycloadditions to N-Propynoyl and N-Propenoyl (5R)-5-Phenylmorpholin-2-one: Diastereocontrolled Aziridine Formation

Abstract

N-Propynoyl (5R)-5-phenylmorpholin-2-one undergoes nonregioselective cycloaddition with aromatic azides to furnish mixtures of the corresponding triazoles, whereas N-propenoyl (5R)-5-phenylmorpholin-2-one reacts to furnish the corresponding dia­stereoisomerically pure aziridines in moderate to good yields, presumably via the intermediate triazolines.

(5R)-5-phenylmorpholin-2-one - triazole - triazoline - aziridine

References and Notes

1

Current address: Department of Environmental Science and Engineering, Nanjing University of Information Science and Technology, 210044, Nanjing, P. R. of China.

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4

Synthesis of N -Propynoyl (5 R )-5-Phenylmorpholin-2-one (2): To a solution of (5R)-5-phenylmorpholin-2-one (0.53 g, 3 mmol) in anhyd CH₂Cl₂ (40 mL) was added propynoic acid (0.21 g, 3 mmol), and then dicyclohexyl-carbodiimide (0.68 g, 3.3 mmol) in anhyd CH₂Cl₂ (10 mL) was added over 10 min. The resulting solution was stirred for 12 h. The solids were removed by filtration through a short pad of Celite^® and washed with CH₂Cl₂ (10 mL). The solvent was removed under reduced pressure and the crude material was purified by flash column chromatography on silica, eluting with PE-EtOAc (3:1) to furnish the title compound as colourless needles (1.81 g, 84%); mp 125-126 ˚C; [α]_D ^²0 -50.5 (c = 1.08, CHCl₃). IR (film): 3243, 1738, 1635 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 7.26-7.47 (m, 5 H), 5.60-5.66 (m, 1 H), 4.94 (d, J = 17.5 Hz, 0.5 H), 4.80 (d, J = 17.5 Hz, 0.5 H), 4.69-4.76 (m, 2 H), 4.33 (d, J = 17.5 Hz, 0.5 H), 4.16 (d, J = 17.5 Hz, 0.5 H), 3.29 (s, 0.5 H), 3.08 (s, 0.5 H). MS: m/z = 230 [M + 1]⁺, 178, 148, 104, 99, 45.Synthesis of N -Propenoyl (5 R )-5-Phenylmorpholin-2-one (3): To a mixture of (5R)-5-phenylmorpholin-2-one (0.531 g, 3 mmol), Et₃N (9 mmol) and anhyd CH₂Cl₂ (40 mL), propenoyl chloride (0.408 g, 4.5 mmol) was added dropwise over 10 min. The resulting solution was stirred for 5 h under an atmosphere of nitrogen. The reaction was quenched by the addition of sat. Na₂CO₃ (40 mL), the aqueous phase was extracted with Et₂O (2 × 30 mL) and the combined extracts were dried over MgSO₄. The solvent was removed under reduced pressure and the crude material was purified by flash column chromatography on silica, eluting with PE-Et₂O (1:5) to furnish the title compound as an oil. Crystallization from Et₂O produced colourless crystals (0.54 g 78%); mp 51-52 ˚C; [α]_D ^²0 -69.9 (c = 4.65, CHCl₃). IR (film): 1747, 1651 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 7.28-7.51 (m, 7 H), 6.50 (m, 1 H), 6.01 (m, 1 H), 4.02-4.50 (m, 4 H). MS: m/z = 231, 178, 148, 104, 99, 45.

5

X-ray data of 3: C₁₃H₁₃NO₃, MW = 231.2; T = 293(3) K; monoclinic, P2(1), a = 7.0336(1), b = 7.1121(6), c = 11.7883(7) Å; β = 91.464(7)˚; Z = 2; D _x = 1.303 g˙cm^-³; F(000) = 244; µ(Mo-K_α) = 0.093 mm^-¹. The number of independent reflections used in the analysis was 1860 with
I 2σ(I). Data were measured (θ_max = 30.13˚) on an Oxford Diffraction Gemini S Ultra instrument using Mo-K_α radiation; final R1 = 3.12, wR2 = 7.78. 5a: C₁₉H₁₈N₂O₃, M = 322.3; T = 293 (3) K; monoclinic, P2(1), a = 7.2342(1), b = 11.7560(2), c = 9.9218(2) Å; β = 106.408(2)˚; Z = 2; D _x = 1.321 g×cm^-³; F(000) = 340; µ(Cu-K_α) = 0.735 mm^-¹. The number of independent reflections used in the analysis was 2107 with I 2σ(I). Data were measured (θ_max = 66.13˚) on an Oxford Diffraction Gemini S Ultra instrument using CuK_α radiation; final R1 = 2.44, wR2 = 6.81. Atomic coordinates and further crystallographic details have been deposited at the Cambridge Crystallographic Data Centre, deposition numbers CCDC 689449 (3), CCDC 689448 (5a) and copies of these data can be obtained by applying to CCDC, University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK; [fax: [phone]; email: [e-mail]).

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8

Synthesis of Aziridine Adducts 5: A solution of N-propenoyl (5R)-5-phenylmorpholin-2-one (3; 231 mg, 1 mmol) and the requisite aryl azide (1.5 mol) in toluene was heated to reflux for 2-3 h until TLC analysis indicated the absence of dipolarophile. Solvent was removed under reduced pressure and the crude material was purified by flash column chromatography on silica, eluting with PE-Et₂O (1:7) to furnish the compounds 5 as colourless solids.
Analytical Data for 5a: mp 67-69 ˚C; [α]_D ^²0 -112.7 (c = 1.0, CHCl₃). IR (film): 1762, 1663 cm^-¹. ^¹H NMR (250 MHz, CDCl₃): δ = 7.10-7.50 (m, 5 H), 6.80-7.05 (m, 3 H), 6.20 (d, J = 7.5 Hz, 2 H), 5.35 (br t, J = 5.0 Hz, 1 H), 4.89 (d, J = 17.5 Hz, 1 H), 4.69 (dd, J = 11.0 Hz, J′ = 3.0 Hz, 1 H), 4.35-4.60 (m, 2 H), 2.50-2.70 (m, 2 H), 2.10-2.25 (m, 1 H). MS: m/z = 323 [M + 1]⁺, 178, 148, 104, 99, 45.

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