Dialkyl Diazomalonates in Transition-Metal-Free, Thermally Promoted, Diastereoselective Wolff β-Lactam Synthesis

Abstract

Metal-free, thermally promoted synthesis of 3-alkoxy-3-alkoxycarbonyl-2-azetidinones via the Wolff-Staudinger β-lactam synthesis using dialkyl diazomalonates is described. The reaction appears fairly general and delivers only one diastereomer.

Key words

β-lactam - diazomalonates - Wolff rearrangement - metal-free - thermal

• References and Notes

• 1a Fernandes R, Amador P, Prudencio C. Rev. Med. Microbiol. 2013; 24: 7
• 1b McGeary RP, Tan DT. C, Schenk G. Future Med. Chem. 2017; 9: 673
• 2 Synofzik J, Dar’in D, Novikov MS, Kantin G, Bakulina O, Krasavin M. J. Org. Chem. 2019; 84: 12101
• 3 Ohno M, Itoh M, Ohashi T, Eguchi S. Synthesis 1993; 793
• 4a Subba Reddy BV, Karthik G, Rajasekaran T, Antony A, Sridhar B. Tetrahedron Lett. 2012; 53: 2396
• 4b Mandler MD, Truong PM, Zavalij PY, Doyle MP. Org. Lett. 2014; 16: 740
• 4c Chen L, Wang K, Shao Y, Sun J. Org. Lett. 2019; 21: 3804
• 4d Chen L, Zhang L, Shao Y, Xu G, Zhang X, Tang S, Sun J. Org. Lett. 2019; 21: 4124
• 5a Fernandes R, Amador P, Prudencio CC. Rev. Med. Microbiol. 2013; 24: 7
• 5b McGeary RP, Tan DT. C, Schenk G. Future Med. Chem. 2017; 9: 673
• 6 Veinberg G, Potorocina I, Vorona M. Curr. Med. Chem. 2013; 21: 393
• 7 Tsuno T, Kondo K, Sugiyama K. J. Heterocycl. Chem. 2006; 43: 21
• 8 Golubev AA, Smetanin IA, Agafonova AV, Rostovskii NV, Khlebnikov AF, Starova GL, Novikov MS. Org. Biomol. Chem. 2019; 17: 6821
• 9 70 various dialkyl diazomalonates are listed as commercially available in SciFinder^® according to the search performed on February 16, 2020.
• 10 Egorova KS, Ananikov VP. Organometallics 2017; 36: 4071
• 11 Zeller K.-P. Chem.-Ztg. 1973; 97: 37
• 12 Richardson DC, Hendrick ME, Jones M. J. Am. Chem. Soc. 1971; 93: 3790
• 13 Dar'in D, Kantin G, Krasavin M. Chem. Commun. 2019; 55: 5239
• 14 Chany A.-C, Marx LB, Burton JW. Org. Biomol. Chem. 2015; 13: 9190
• 15 General Procedure for the Preparation of Lactams 6a–p In a 25 mL round-bottom flask, amine (0.8 mmol, 1.0 equiv) and aldehyde (0.9 mmol, 1.1 equiv) were dissolved in 10 mL of chlorobenzene and refluxed with azeotropic removal of water. After 1 h, half of the solvent was distilled off and 2-diazomalonates 4a–e (1.6 mmol, 2.0 equiv) was added. The mixture was then refluxed overnight, and the reaction progress was followed via TLC. When no more diazo compound was detectable (20–24 h), the solvent was evaporated in vacuo, and the resulting mixture was purified by column chromatography on silica gel with a linear gradient (0–20%) of acetone in n-hexane (total volume of eluent, 450 mL) to provide pure compounds 6a–p. In case of volatile aldehyde or amine, they were reacted in chlorobenzene at room temperature overnight in the presence of 4 Å MS. The latter was filtered off before proceeding with the addition of 4 and heating. Compounds 6a,d,g,l,n,p were prepared with the use of presynthesized imines.
• 16 Characterization Data of Representative Compounds Compound 6i: white powder (231 mg, 72%); mp 113–115 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.30 (d, J = 8.9 Hz, 2 H), 6.95 (d, J = 8.5 Hz, 1 H), 6.87–6.82 (m, 2 H), 6.49 (d, J = 2.4 Hz, 1 H), 6.35 (d, J = 8.5 Hz, 1 H), 5.50 (s, 1 H), 3.89 (s, 3 H), 3.78 (d, J = 2.0 Hz, 6 H), 3.75 (s, 3 H), 3.39 (s, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 166.3, 161.2, 161.1, 158.6, 156.5, 130.5, 128.6, 119.0, 114.4, 112.4, 104.0, 98.5, 94.5, 60.1, 55.9, 55.8, 55.5, 55.3, 51.9 ppm. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₁H₂₃NaNO₇: 424.1367; found: 424.1378. Compound 6l: yellow powder (202 mg, 66%); mp 97–99 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.21 (d, J = 8.7 Hz, 2 H), 7.01–6.68 (m, 2 H), 4.63 (s, 1 H), 4.08 (dq, J = 8.9, 7.0 Hz, 1 H), 3.92 (dq, J = 10.8, 7.1 Hz, 1 H), 3.81 (s, 3 H), 3.78–3.63 (m, 1 H), 2.93 (s, 3 H), 1.30 (t, J = 7.0 Hz, 3 H), 0.99 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 166.3, 165.0, 160.1, 128.6, 124.4, 113.9, 95.2, 67.8, 64.1, 61.4, 55.3, 27.4, 15.4, 13.8 ppm. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₃H₂₇NNaO₇: 452.1680; found: 452.1683. Compound 6n: yellow oil (206 mg, 42%). ¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.46 (m, 2 H), 7.42–7.26 (m, 8 H), 7.24–7.01 (m, 2 H), 6.80 (d, J = 8.0 Hz, 2 H), 5.35–5.09 (m, 2 H), 4.94 (d, J = 12.2 Hz, 1 H), 4.86–4.77 (m, 2 H), 4.54 (d, J = 18.0 Hz, 1 H), 3.81 (s, 3 H), 3.74 (s, 3 H), 3.65 (d, J = 18.0 Hz, 1 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 167.9, 165.9, 164.8, 160.2, 137.0, 134.7, 128.6, 128.4, 128.4, 128.3, 128.2, 128.0, 123.6, 114.1, 95.7, 70.3, 67.1, 66.4, 55.2, 52.5, 41.3 ppm. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₈H₂₇NNaO₇: 512.1680; found: 512.1700.
• 17 Jiao L, Liang Y, Xu J. J. Am. Chem. Soc. 2006; 128: 6060