An Investigation of the Reactivity of MCPBA and α-Bromoalkenes under ­Traditional or Microwave-Assisted Conditions: Selective Formation of ­Epoxides or Allylic Bromides

Abstract

The reaction of α-bromo-β,γ-unsaturated lactams and ­esters with m-chloroperbenzoic acid has been studied to find experimental conditions that could afford exclusively epoxide formation or bromide 1,3-shift. The results show a strong dependence of reactivity on the dilution and on the amount of peracid used, suggesting a radical mechanism for the bromine rearrangement. This last reaction is also strongly favored by microwave-assisted conditions.

epoxidation - rearrangements - radical reactions - microwaves - α-bromo derivatives

References

For general accounts on MCPBA reactions, see:

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<A NAME="RG16405ST-3A">3a</A> Bartlett PA. Rec. Chem. Prog.  1957,  18:  111 

For some recent reports on the radical hypothesis see:

<A NAME="RG16405ST-3B">3b</A> Yamabe S. Kondou C. Minato T. J. Org. Chem.  1996,  61:  616 

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<A NAME="RG16405ST-8">8</A>

Typical Experimental Procedure.
To a stirred solution of 1 (1 mmol) in the solvent of choice at r.t. (see Table [1] ), MCPBA was added in one portion. The reaction was stirred overnight and then diluted with H₂O and CH₂Cl₂ (5 mL). The two phases were separated and the organic layer was dried over Na₂SO₄ and solvent was removed under reduced pressure. Compounds 2 and 3 were isolated by flash chromatography on silica gel (cyclo-hexane-ethyl acetate, 9:1 as eluent). The characterization of compound 3 is reported in ref. 7d. Commercially available MCPBA was used in the reactions. Purified peracid (according to J. Am. Chem. Soc. 1987, 109, 2770) was less reactive in the epoxidation, due to the lack of acid impurities.
Compound 2a: first diastereomer: R _f = 0.44 (9:1, cyclo-hexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 1.02 (3 H, t, J = 7.6 Hz), 1.45-1.81 (2 H, m), 2.89 (1 H, dt, J = 1.8, 5.6 Hz), 3.45 (1 H, d, J = 1.8 Hz), 3.93 (1 H, d, J = 15.0 Hz), 4.59 (1 H, s), 4.97 (1 H, d, J = 15.0 Hz), 7.16-7.44 (10 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 9.4 (CH₃), 24.2 (CH₂), 44.9 (CH₂), 57.3 (CH), 58.9 (CH), 59.5 (CH), 68.8 (quat), 127.8 (CH), 127.9 (CH), 128.1 (CH), 128.4 (CH), 128.7 (CH), 128.9 (CH), 133.8 (quat), 134.0 (quat), 164.5 (CO). LC-ESI-MS (t _R 15.2 min): m/z = 386/388 [M + 1], 408/410 [M + Na]. IR (film): 2962, 2928, 1775, 1494, 1454, 1392, 1351, 1147, 1072 cm^-1. Second diastereomer: R _f = 0.30 (9:1, cyclohexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 1.05 (3 H, t, J = 7.2 Hz), 1.53-1.77 (2 H, m), 3.27 (1 H, d, J = 2.2 Hz), 3.57 (1 H, dt, J = 2.2, 5.6 Hz), 3.91 (1 H, d, J = 15.0 Hz), 4.78 (1 H, s), 4.99 (1 H, d, J = 15.0 Hz), 7.18-7.43 (10 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 9.6 (CH₃), 24.6 (CH₂), 44.9 (CH₂), 57.6 (CH), 58.7 (CH), 59.4 (CH), 68.4 (quat), 127.7 (CH), 127.9 (CH), 128.2 (CH), 128.4 (CH), 128.7 (CH), 129.0 (CH), 133.7 (quat), 133.9 (quat), 163.4 (CO). LC-ESI-MS (t _R 14.5 min): m/z = 386/388 [M + 1], 408/410 [M + Na]. IR (film): 3073, 2959, 2930, 1771, 1654, 1455, 1395, 1355, 1157, 1077 cm^-1.

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<A NAME="RG16405ST-14">14</A>

Microwave-assisted reactions have been performed on a Milestone Microsynth Labstation, dual magnetron system with pyramid diffuser, 1600 W power (800X2), maximum delivered power 1000 W, Easywave software. Conditions: 200 W fixed power, 5 min irradiation.

<A NAME="RG16405ST-15A">15a</A> Cardillo G. Fabbroni S. Gentilucci L. Perciaccante R. Tolomelli A. Tetrahedron: Asymmetry  2004,  15:  593 

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<A NAME="RG16405ST-16">16</A>

Compound 5: R _f = 0.66 (8:2, cyclohexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 1.03 (3 H, t, J = 7.2 Hz), 1.53-1.74 (2 H, m), 2.87 (1 H, dt, J = 1.5, 5.4 Hz), 3.34 (1 H, dd, J = 1.5, 8.4 Hz), 3.85 (1 H, d, J = 8.4 Hz), 5.25 (2 H, s), 7.38 (5 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 9.6 (CH₃), 24.3 (CH₂), 43.9 (CH₂), 57.0 (CH), 60.5 (CH), 67.9 (CH), 128.2 (CH), 128.4 (CH), 128.6 (CH), 134.8 (quat), 167.5 (CO). IR (film): 3021, 2968, 1744, 1498, 1456, 1380, 1296, 1257, 1157, 1010 cm^-1.
Compound 6: R _f = 0.57 (8:2, cyclohexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 1.04 (3 H, t, J = 7.4 Hz), 1.91-2.06 (2 H, m), 4.24-4.54 (1 H, m), 5.21 (2 H, s), 6.00 (1 H, d, J = 15.4 Hz), 7.03 (1 H, dd, J = 15.4, 9.2 Hz), 7.25 (5 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 12.1 (CH₃), 31.2 (CH₂), 52.9 (CH₂), 66.6 (CH), 121.8 (CH), 128.6 (CH), 128.9 (CH), 129.9 (CH), 134.3 (quat), 135.7 (CH), 163.0 (CO). IR (film): 2955, 1867, 1755, 1442, 1252, 1218, 1994 cm^-1.

<A NAME="RG16405ST-17">17</A> Fujita M. Ishizuka H. Ogura K. Tetrahedron Lett.  1991,  32:  6355 

<A NAME="RG16405ST-18A">18a</A> Bonini C. Righi G. Synthesis  1994,  225 

<A NAME="RG16405ST-18B">18b</A> Wang S. Howe GP. Mahal RS. Procter G. Tetrahedron Lett.  1992,  33:  3351 

<A NAME="RG16405ST-19">19</A>

Ring-Opening of Epoxide 5.
To a stirred solution of epoxide 5 (1 mmol) in 5 mL of dry CH₂Cl₂ at -78 °C, TiCl₄ (1 mL, solution 1 M in CH₂Cl₂) was added. The reaction was stirred at this temperature for 3 h and then quenched with H₂O. After diluting with CH₂Cl₂, the two phases were separated, the organic one was dried over Na₂SO₄ and solvent was removed under reduced pressure. Compound 7 was isolated, by flash chromatography on silica gel (cyclohexane-EtOAc, 8:2 as eluant).
Compound 7: R _f = 0.52 (8:2, cyclohexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 1.08 (3 H, t, J = 7.5 Hz), 1.68-1.85 (1 H, ddq, J = 7.5, 9.3, 14.4 Hz), 1.95-2.09 (1 H, ddq, J = 7.5, 3.0, 14.4 Hz), 3.25 (1 H, d, J = 7.8 Hz), 4.04 (1 H, ddd, J = 3.0, 9.3, 3.0 Hz), 4.12 (1 H, ddd, J = 3.0, 7.8, 5.4 Hz), 4.65 (1 H, d, J = 5.4 Hz), 5.25 (2 H, s), 7.39 (5 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 10.7 (CH₃), 25.0 (CH₂), 43.9 (CH₂), 65.0 (CH), 68.0 (CH), 76.0 (CH), 128.2 (CH), 128.3 (CH), 128.7 (CH), 134.6 (quat), 169.0 (CO). IR (film): 3457, 2953, 2919, 1734, 1261, 1013 cm^-1 Formation of Epoxide 8.
To a stirred solution of 7 (1 mmol) in 5 mL of dry THF at 0 °C, NaH (1.1 equiv, 26.5 mg) was added. The reaction was stirred at r.t. for 2 h and then quenched by addition of H₂O. After removing THF under reduced pressure, the residue was diluted with EtOAc, and washed twice with H₂O. The organic layer was separated, dried over Na₂SO₄ and solvent was removed under reduced pressure. Compound 8 was isolated, by flash chromatography on silica gel (cyclohexane-EtOAc, 9:1 as eluent).
Compound 8: R _f = 0.54 (8:2, cyclohexane-EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 1.10 (3 H, t, J = 8.1 Hz), 1.63-1.96 (2 H, m), 3.39 (1 H, dd, J = 1.5, 4.5 Hz), 3.48 (1 H, d, J& nbsp;= 1.5 Hz), 3.50 (1 H, dt, J = 4.5, 8.1 Hz), 5.26 (2 H, s), 7.39 (5 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 10.2 (CH₃), 28.9 (CH₂), 52.8 (CH₂), 59.9 (CH), 61.6 (CH), 67.5 (CH), 128.2 (CH), 128.4 (CH), 128.7 (CH), 134.9 (quat), 167.9 (CO). IR (film): 3034, 2963, 1747, 1497, 1455, 1381, 1264, 1190, 1026 cm^-1.