Kinugasa Reaction under Click Chemistry Conditions

Abstract

Various monocyclic β-lactams, both cis and trans, have been successfully prepared via Kinugasa reaction mimicking the click chemistry conditions.

Key word

Kinugasa reaction - nitrone - β-lactam - click chemistry

References and Notes

• 1a Chemistry and Biology of β-Lactam Antibiotics   Vol. 1:  Morin RB. Gorman M. Academic Press; New York: 1982. 
• 1b Chemistry and Biology of β-Lactam Antibiotics   Vol. 2:  Morin RB. Gorman M. Academic Press; New York: 1982. 
• 1c Chemistry and Biology of β-Lactam Antibiotics   Vol. 3:  Morin RB. Gorman M. Academic Press; New York: 1982. 
• 1d The Chemistry of β-Lactams   Page MI. Chapman & Hall; London: 1992. 
• 1e Antibiotics Containing the β-Lactam Structure, Part 1   Demain AL. Solomon NA. Springer; Berlin: 1983. 
• 1f Antibiotics Containing the β-Lactam Structure   Part 2:  Demain AL. Solomon NA. Springer; Berlin: 1983. 
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• 12a All the nitrones were prepared according to the procedure described in: Bhattacharya G. PhD Thesis   Indian Institute of Technology; Kharagpur, India: 1997. 
• 12b

  However, a general method of preparation is given below along with the spectroscopic data of some representative compounds:
  To a solution of EtOH (30 mL) and H₂O (20 mL) nitrobenzene or p-methoxynitrobenzene (50 mmol), benzaldehyde (or p-methoxybenzaldehyde or furfural or thienyl aldehyde; 50 mmol) and Zn dust (5 gm) were placed. The mixture was stirred at 5 °C. AcOH (30 mL) was slowly added in a span of 20 min. The reaction mixture was stirred for an additional 1.5 h at -5 °C. The mixture was filtered and the residue was washed with EtOAc. The filtrate was concentrated to 10 mL. H₂O was added and the products were extracted with EtOAc. The organic layer was washed with NaHCO₃, brine and dried over Na₂SO₄. The solvent was evaporated under vacuo and the crude mass was subjected to silica gel column chromatography. The products were eluted with hexane-EtOAc mixture.
  Compound 2a: ¹H NMR: δ = 7.39-7.52 (m, 6 H), 7.71-7.81 (m, 2 H), 7.90 (s, 1 H), 8.33-8.42 (m, 2 H).
  Compound 2b: ¹H NMR: δ = 6.62 (dd, J = 1.3 Hz, 3.2 Hz, 1 H), 7.39-7.44 (m, 3 H), 7.57 (d, J = 3.6 Hz, 1 H), 7.78-7.81 (m, 2 H), 8.0 (d, J = 3.3 Hz, 1 H), 8.14 (s, 1 H).
  Compound 2c: ¹H NMR: δ = 7.15 (dd, J = 4.0, 4.8 Hz, 1 H), 7.39-7.56 (m, 5 H), 7.76-7.81 (m, 2 H), 8.46 (s, 1 H).

• 14 Dess DB. Martin JC. J. Am Chem. Soc.  1991,  113:  7277 
• The spectral data for all the known compounds have been reported:
• 15a Basak A. Rudra KR. Ghosh SC. Bhattacharya G. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2001,  40:  974 
• 15b Ghosh SC. PhD Thesis   Indian Institute of Technology; Kharagpur, India: 2005. 
• 15c

  For the new compounds, the spectral data are given below:
  β-Lactam 8j: ¹H NMR: δ = 1.85 (s, 3 H), 3.90 (dd, J = 7.6, 14.4 Hz, 1 H), 3.98 (dd, J = 7.6, 14.4 Hz, 1 H), 4.14 (m, 1 H), 5.26 (d, J = 5.6 Hz, 1 H), 6.50 (br s, 2 H), 7.08-7.48 (m, 7 H), 8.64 (br s, 1 H). ¹³C NMR: δ = 12.18, 45.51, 50.95, 52.54, 110.41, 111.16, 111.26, 116.77, 124.45, 129.13, 137.09, 140.79, 143.60, 147.73, 150.60, 164.02, 164.29. MS (ES): m/z = 368 [MH⁺], 390 [MNa⁺].
  β-Lactam 7j: ¹H NMR: δ = 1.84 (s, 3 H), 3.76 (m, 1 H), 4.15 (dd, J = 5.6, 14.8 Hz, 1 H), 4.29 (dd, J = 6.6, 14.6 Hz, 1 H), 5.09 (d, J = 2.4 Hz, 1 H), 6.35 (d, J = 2.8 Hz, 1 H), 6.50 (m, 1 H), 7.06-7.48 (m, 7 H), 9.06 (br s, 1 H). ¹³C NMR: δ = 12.23, 45.75, 52.48, 55.86, 110.31, 110.71, 111.32, 116.88, 124.46, 129.10, 137.10, 140.62, 143.43, 148.71, 151.59, 164.08, 164.61. MS (ES): m/z = 368 [MH⁺], 390 [MNa⁺].
  β-Lactam 8k: ¹H NMR: δ = 1.82 (s, 3 H), 3.82-3.94 (m, 2 H), 4.13 (m, 1 H), 5.55 (d, J = 5.6 Hz, 1 H), 6.36 (s, 1 H), 6.99-7.40 (m, 8 H), 8.45 (br s, 1 H). ¹³C NMR: δ = 14.13, 24.83, 31.92, 45.64, 52.84, 53.38, 117.16, 124.55, 126.42, 127.18, 127.96, 129.43, 138.51, 140.99, 150.86, 164.31, 164.42. MS (ES): m/z = 384 [MH⁺], 406 [MNa⁺].
  β-Lactam 7k: ¹H NMR: δ = 1.90 (s, 3 H), 3.51 (m, 1 H), 4.10 (dd, J = 4.8, 14.8 Hz, 1 H), 4.35 (dd, J = 7.2, 14.8 Hz, 1 H), 5.30 (br s, 1 H), 6.92-7.61 (m, 9 H), 8.59 (br s, 1 H). ¹³C NMR: δ = 12.31, 22.69, 28.94, 46.01, 55.40, 60.49, 111.59, 117.29, 124.62, 126.09, 127.19, 127.41, 136.82, 140.31, 151.51, 164.32, 164.49. MS (ES): m/z = 384 [MH⁺], 406 [MNa⁺].
  β-Lactam 4k: ¹H NMR (DMSO-d ₆): δ = 4.18 (dd, J = 8.2, 13.8 Hz, 1 H), 4.35-4.46 (m, 2 H), 5.80 (d, J = 5.2 Hz, 1 H), 7.09-7.60 (m, 9 H), 8.12 (s, 1 H). ¹³C NMR (DMSO-d ₆): δ = 41.04, 56.27, 58.17, 116.78, 123.87, 125.91, 127.09, 128.37, 128.93, 129.17, 137.03, 137.17, 140.78, 149.49, 152.57, 155.95, 164.08. MS (ES): m/z = 377 [MH⁺], 399 [MNa⁺].
  β-Lactam 3k: ¹H NMR: δ = 3.49 (m, 1 H), 4.72 (d, J = 6.0 Hz, 2 H), 5.45 (br s, 1 H), 5.74 (br s, 2 H), 6.91-7.37 (m, 8 H), 7.93 (s, 1 H), 8.44 (s, 1 H). ¹³C NMR: δ = 52.71, 54.49, 60.18, 117.70, 124.12, 126.44, 126.46, 127.74, 127.84, 128.71, 136.91, 137.26, 140.85, 149.55, 152.60, 164.23, 165.00. MS (ES): m/z = 377 [MH⁺], 399 [MNa⁺].
  β-Lactam 4l: ¹H NMR (DMSO-d ₆): δ = 3.75 (s, 3 H), 3.97 (dd, J = 8.0, 14.4 Hz, 1 H), 4.20 (dd, J = 8.0, 14.4 Hz, 1 H), 4.39 (m, 1 H), 5.50 (d, J = 6.0 Hz, 1 H), 7.03-7.37 (m, 10 H), 8.08 (s, 1 H). ¹³C NMR (DMSO-d ₆): δ = 39.96, 55.23, 58.58, 59.70, 114.57, 119.28, 120.29, 124.92, 128.11, 128.99, 129.43, 136.95, 141.02, 149.71, 153.15, 155.69, 159.84, 164.03. MS (ES): m/z = 401 [MH⁺], 423 [MNa⁺].
  β-Lactam 3l: ¹H NMR: δ = 3.52 (m, 1 H), 3.84 (s, 3 H), 4.73 (αππ d, J = 6.0 Hz, 2 H), 4.97 (br s, 1 H), 6.02 (br s, 2 H), 7.00-7.43 (m, 9 H), 7.95 (s, 1 H), 8.42 (s, 1 H). ¹³C NMR: δ = 40.99, 52.73, 55.31, 56.88, 114.70, 117.91, 124.28, 126.51, 127.06, 128.11, 129.33, 133.43, 136.95, 140.02, 141.72, 152.72, 160.10, 164.25. MS (ES): m/z = 401 [MH⁺], 423 [MNa⁺].

13

General Procedure: To a solution of CuSO₄·5H₂O (1 mmol) in degassed H₂O (10 mL), sodium ascorbate (2 mmol) was added and the mixture was stirred for 30 min at r.t. (solution X). In another flask, to a solution of propargyl alcohol-3-butyn-2-ol-propargyl nucleobase (2 mmol) in DMF-MeCN (3 mL) under argon at 0 °C, Et₃N (2 mmol) was added and the mixture was stirred for 30 min (solution Y). Solution Y was added dropwise to the solution X at r.t. after which a 2 mL DMF or MeCN solution of the nitrones [12] 2a-2d (1 mmol) was added slowly over 10 min. The reaction was stirred at r.t. for 16-25 h. It was then diluted with H₂O and filtered through celite. The celite bed was washed with EtOAc. The combined filtrate and washings were extracted with EtOAc. The organic layer was washed with NH₄Cl, H₂O and brine and dried over Na₂SO₄ and evaporated. The residue, obtained after evaporation, upon chromatography afforded a mixture of trans and cis diastereomers. [15] These were easily separated by conventional chromatography over silica gel using hexane-EtOAc (2:1) as eluent. The various hydroxymethyl β-lactams [combined mixture of cis (3e-h) and trans (4e-h) products] could be oxidized to a single trans ketone by Dess-Martin oxidation [14] in quantitative yield.