l-Proline-Mediated One-Pot Synthesis of 3-Exomethylene β-Lactams via Kinugasa Reaction

Abstract

Synthetically important 3-exomethylene β-lactams 4a-f were obtained in a single step via Cu(I)-mediated cycloaddition ­between propargyl alcohol/butyn-2-ol and nitrones 2a-d, in the presence of l-proline (Kinugasa reaction).

Kinugasa reaction - β-lactams - isoxazoline - amino acids - proline

References

<A NAME="RD04604ST-1A">1a</A> Kinugasa M. Hashimoto S. J. Chem. Soc., Chem. Commun.  1972,  466 

<A NAME="RD04604ST-1B">1b</A> Miura M. Enna M. Okura K. Nomura N. J. Org. Chem.  1995,  60:  4996 

<A NAME="RD04604ST-2A">2a</A> Basak A. Bhattacharya G. Bdour HMM. Tetrahedron  1998,  54:  6529 

<A NAME="RD04604ST-2B">2b</A> Basak A. Mahato T. Bhattacharya G. Mukherjee B. Tetrahedron Lett.  1997,  38:  643 

<A NAME="RD04604ST-2C">2c</A> Basak A. Rudra KR. Ghosh SC. Bhattacharya G. Indian J. Chem., Sect. B  2001,  41:  244 

<A NAME="RD04604ST-3A">3a</A> Shintani R. Fu GC. Angew. Chem. Int. Ed.  2003,  42:  4082 

<A NAME="RD04604ST-3B">3b</A> Lo MM.-C. Fu GC. J. Am. Chem. Soc.  2002,  124:  4572 

<A NAME="RD04604ST-4">4</A> Basak A. Ghosh SC. Bhowmick T. Das AK. Bertolasi V. Tetrahedron Lett.  2002,  43:  5499 

<A NAME="RD04604ST-5">5</A> Ding LK. Irwin WJ. J. Chem. Soc. Perkin Trans. 1  1976,  2382 

<A NAME="RD04604ST-6A">6a</A> List B. Tetrahedron  2002,  58:  5573 

<A NAME="RD04604ST-6B">6b</A> List B. Lerner RA. Barbas CF. J. Am. Chem. Soc.  2000,  122:  2395 

<A NAME="RD04604ST-6C">6c</A> List B. Pojarliev P. Castello C. Org. Lett.  2001,  3:  573 

<A NAME="RD04604ST-6D">6d</A> Sakthiviel K. Notz W. Bui T. Barbas CF. J. Am. Chem. Soc.  2001,  123:  5260 

<A NAME="RD04604ST-7A">7a</A> Basak A. Bdour HM. Bhattacharya G. Tetrahedron Lett.  1997,  38:  2535 

<A NAME="RD04604ST-7B">7b</A> Baldwin JE. Otsuka M. Wallace PM. Tetrahedron  1986,  42:  3097 

<A NAME="RD04604ST-8">8</A>

General Procedure: To a solution of 1a in DMSO under argon at r.t., l-proline (1 equiv) was added and stirred for 30 min. Cuprous iodide (1 equiv) was added and the solution was stirred for another 5 min after which a DMSO solution of the nitrone [10] (0.75 equiv) was added slowly over a period of 5 min. The reaction was stirred at r.t. for 16 h. The mixture was diluted with H₂O and filtered through celite. The celite bed was washed with EtOAc. The combined filtrate and washings were extracted with EtOAc. The residue, obtained after evaporation, afforded a mixture of exo-methylene β-lactam and the cis-β-lactam. These two were easily separated by column chromatography over silica gel using hexane-EtOAc (4:1) as eluent.

<A NAME="RD04604ST-9">9</A>

Spectroscopic data: All new compounds were characterised by spectroscopic and analytical data. Some of these are mentioned below (the ¹H NMR and ¹³C NMR were recorded in CDCl₃ at 200 MHz and 50 MHz, respectively):
For 4a: mp 115 °C. ¹H NMR: δ = 5.16 (1 H, t, J = 1.3 Hz,
H-4), 5.39 (1 H, t, J = 1.33 Hz, =CH), 5.84 (1 H, t, J = 1.9 Hz, =CH), 7.08-7.00 (1 H, m, Ar-H), 7.40-7.21 (9 H, m,
Ar-H). ¹³C NMR: δ = 63.46, 110.77, 117.07, 124.08, 126.53, 128.72, 129.03, 136.42, 137.53, 149.82, 160.88. Anal. Calcd for C₁₆H₁₃NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.52; H, 5.54; N, 6.12. For 4b: mp 102 °C. ¹H NMR: δ = 5.34 (1 H, t, J = 1.3 Hz, H-4), 5.50 (1 H, br s, =CH), 5.93 (1 H, t, J = 1.9 Hz, =CH), 6.37 (1 H, dd, J = 1.9, 3.3 Hz, furyl-H), 6.46 (1 H, d, J = 3.0, furyl-H), 7.06-7.02 (1 H, m, Ar-H), 7.33-7.25 (2 H, m, Ar- and furyl-H), 7.46-7.41 (3 H, m,
Ar-H). ¹³C NMR: δ = 56.60, 96.14, 109.62, 110.71, 111.29, 116.79, 124.21, 129.09, 137.67, 143.34, 147.15, 149.73, 160.32. MS (EI): m/z = 225 [M⁺]. For 4c: mp 86 °C. ¹H NMR: δ = 5.31 (1 H, t, J = 1.6 Hz, H-4), 5.71 (1 H, br s, =CH), 5.91 (1 H, t, J = 1.8 Hz, =CH), 7.43-7.01 (8 H, m,
Ar-H). ¹³C NMR: δ = 59.02, 96.05, 111.22, 117.0, 124.32, 126.29, 126.67, 126.96, 128.60, 129.02, 137.32, 140.10, 149.72, 160.28. MS (EI): m/z = 241 [M⁺]. For 4d: mp 95 °C. ¹H NMR: δ = 3.79 (3 H, s, OCH₃), 5.13 (1 H, br s, H-4), 5.34 (1 H, br s, =CH), 5.82 (1 H, br s, =CH), 6.87 (2 H, d, J = 8.6 Hz, Ar-H), 7.03 (1 H, m, Ar-H), 7.35-7.19 (6 H, m, Ar-H). ¹³C NMR: δ = 55.17, 63.22, 96.15, 110.50, 114.51, 117.12, 124.04, 128.00, 128.39, 129.07, 137.67, 150.44, 160.22, 160.90. MS (EI): m/z = 265 [M⁺]. For 4e: mp 99 °C. ¹H NMR: δ = 3.76 (3 H, s, OCH₃), 5.30 (1 H, br s, H-4), 5.47 (1 H, br s, =CH), 5.89 (1 H, t, J = 1.7 Hz, =CH), 6.38 (1 H, d, J = 1.4 Hz, furyl-H), 6.46 (1 H, d, J = 3.3 Hz, furyl-H), 6.85 (2 H, d, J = 9.1 Hz, Ar-H), 7.41-7.36 (3 H, m, Ar-H and furyl-H). MS (EI): m/z = 255 [M⁺]. For 4f: ¹H NMR: δ = 1.59 (3 H, d, J = 7.2 Hz, CH₃), 5.42 (1 H, s, H-4), 6.30 (1 H, q, J = 7.2 Hz, =CH), 6.99 (1 H, m, Ar-H), 7.78-7.18 (9 H, m, Ar-H). For 5f: ¹H NMR: δ = 2.09 (3 H, d, J = 7.2 Hz, CH₃), 5.28 (1 H, s, H-4), 5.62 (1 H, q, J = 7.2 Hz, =CH), 7.03 (1 H, m, Ar-H), 7.36-7.20 (9 H, m, Ar-H). For 4g: ¹H NMR: δ = 1.70 (3 H, d, J = 7.1 Hz, CH₃), 5.50 (1 H, s, H-4), 6.37 (2 H, m, =CH and furyl-H), 6.44 (1 H, d, J = 3.1 Hz, furyl-H), 7.03 (1 H, t, J = 7.3 Hz, Ar-H), 7.27 (2 H, t, J = 7.5 Hz, Ar-H), 7.44-7.39 (3 H, m, Ar-H and furyl-H). Anal. Calcd for C₁₅H₁₃NO₂: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.01; H, 5.62; N, 5.92. For 5g: ¹H NMR: δ = 2.14 (3 H, d, J = 7.2 Hz, CH₃), 5.39 (1 H, br s, H-4), 5.80 (1 H, q, J = 7.2 Hz, =CH) 6.35 (1 H, m, furyl-H), 6.41 (1 H, d, J = 3.2 Hz, furyl-H), 7.03 (1 H, t, J = 7.3 Hz, Ar-H), 7.31-7.23 (2 H, m, Ar-H), 7.45-7.39 (3 H, m, Ar-H). For 8: ¹H NMR: δ = 1.20 (3 H, d, J = 5.6 Hz, Me, minor isomer), 1.21 (3 H, d, J = 4.7 Hz, Me, major isomer), 1.24 (3 H, d, J = 7.5 Hz, Me, major isomer), 1.37 (3 H, d, J = 6.9 Hz, Me, minor isomer), 2.63 (1 H, m, CHCO, major isomer), 2.71 (1 H, m, CHCO, minor isomer), 4.88 (2 H, br s, PhNH, both isomers), 5.01 (2 H, m, CHPh, both isomers), 5.64 (1 H, d, J = 7.6 Hz, NHCHPh, major isomer), 5.72 (1 H, d, J = 7.4 Hz, NHCHPh, minor isomer), 6.52 (4 H, m, Ar-H, both isomers), 6.66-6.62 (2 H, m, Ar-H, both isomers), 7.08-7.02 (6 H, m, Ar-H and amide NH, both isomers), 7.31-7.15 (20 H, m, Ar-H, both isomers). MS (EI): m/z = 358 [M⁺]. The spectroscopic data for the hydroxy methyl β-lactams and 3-methyl 4-phenyl β-lactam 6 have already been reported from our laboratory.^2a

<A NAME="RD04604ST-10">10</A> All the nitrones were prepared according to the procedure described: Bhattacharya G. Ph. D. Thesis   Indian Institute of Technology; Kharagpur India: 1997.