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:

1a Comprehensive Organic Synthesis   Vol. 7:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  p.357-372  

1b Paquette L. Encyclopedia of Reagents for Organic Synthesis   Vol. 2:  John Wiley and Sons; New York: 1995.  p.1192-1198  

2 Prilezhaev N. Ber.  1909,  42:  4811 

For the well-known ‘butterfly’ mechanism of epoxidation see:

3a Bartlett PA. Rec. Chem. Prog.  1957,  18:  111 

For some recent reports on the radical hypothesis see:

3b Yamabe S. Kondou C. Minato T. J. Org. Chem.  1996,  61:  616 

3c Okovytyy S. Gorb L. Leszczynski J. Tetrahedron  2002,  58:  8751 

3d Bach RD. Glukhovtsev MN. Gonzalez C. J. Am. Chem. Soc.  1998,  120:  9902 

4a Warrener RN. Elsey GM. Pitt IG. Russell RA. Aust. J. Chem.  1995,  48:  241 

For the synthesis of α-haloepoxides see also:

4b Ono T. Henderson P. Tetrahedron Lett.  2002,  43:  7961 

4c Taber DF. Mitten JV. J. Org. Chem.  2002,  67:  3847 

4d Benayoud F. Begue JP. Bonnet-Delpon D. Fischer-Durand N. Sdassi H. Synthesis  1993,  1083 

5 Kocienski P. J. Chem. Soc., Perkin Trans. 1  1983,  945 

6 Nakayama J. Kamiyama H. Tetrahedron Lett.  1992,  49:  7539 

7a Benfatti F. Cardillo G. Fabbroni S. Gentilucci L. Perciaccante R. Piccinelli F. Tolomelli A. Synthesis  2005,  61 

7b Cardillo G. Fabbroni S. Gentilucci L. Perciaccante R. Piccinelli F. Tolomelli A. Org. Lett.  2005,  4:  533 

7c Cardillo G. Fabbroni S. Gentilucci L. Perciaccante R. Tolomelli A. Adv. Synth. Catal.  2005,  6:  833 

7d Benfatti F. Cardillo G. Fabbroni S. Gentilucci L. Perciaccante R. Tolomelli A. ARKIVOC  2005,  (vi):  136 

8

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.

9a Alcaide B. Almendros P. Curr. Med. Chem.  2004,  11:  1921 

9b Deshmukh ARAS. Bhawal BM. Krishnaswamy D. Govande Vidyesh V. Shinkre Bidhan A. Jayanthi A. Curr. Med. Chem.  2004,  11:  1889 

9c Singh GS. Tetrahedron  2003,  59:  7631 

9d Miller MJ. Hsiao CN. Huang NZ. Kalish VJ. Peterson K. Rajendra G. Recent Adv. Chem. β-Lactam Antibiot.  1989,  70:  273 ; special publication of the Royal Society of Chemistry, London

9e Ojima I. Shimizu N. Qiu Xiaogang C. Hauh JC. Nakahashi K. Bull. Soc. Chim. Fr.  1987,  4:  649 

10a Hayes BL. Aldrichimica Acta  2004,  37:  66 

10b Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 

11a Hanzlik RP. Shearer GO. J. Am. Chem. Soc.  1975,  97:  5231 

11b Kropf H. Yazdanbachsch MR. Tetrahedron  1974,  30:  3455 

12 Zhang HY. Sun YM. Wang XL. J. Org. Chem.  2002,  67:  2709 

13 Ogata Y. Tabushi I. J. Am. Chem. Soc.  1961,  83:  3440 

14

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.

15a Cardillo G. Fabbroni S. Gentilucci L. Perciaccante R. Tolomelli A. Tetrahedron: Asymmetry  2004,  15:  593 

15b Cardillo G. De Simone A. Mingardi A. Tomasini C. Synlett  1995,  1131 ; and reference cited therein

16

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.

17 Fujita M. Ishizuka H. Ogura K. Tetrahedron Lett.  1991,  32:  6355 

18a Bonini C. Righi G. Synthesis  1994,  225 

18b Wang S. Howe GP. Mahal RS. Procter G. Tetrahedron Lett.  1992,  33:  3351 

19

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.