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Synlett 2017; 28(06): 673-678
DOI: 10.1055/s-0036-1588363
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© Georg Thieme Verlag Stuttgart · New York

Thieme Chemistry Journals Awardees – Where Are They Now?
Stereoselective Cycloaddition of 2,2,2-Trifluorodiazoethane with α-Methylene-β-lactams: Facile Synthesis of Trifluoromethyl-Substituted Spirocyclic β-Lactams

Shen Li
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. of China   Email: majun_an68@tju.edu.cn
,
Wen-Jie Cao
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. of China   Email: majun_an68@tju.edu.cn
,
Jun-An Ma*
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. of China   Email: majun_an68@tju.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 11 October 2016

Accepted after revision: 06 November 2016

Publication Date:
28 November 2016 (online)

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Abstract

The cycloadditions of 2,2,2-trifluorodiazoethane with α-methylene-β-lactams were investigated. The reaction proceeded via a [3+2] cycloaddition mode under metal-free conditions, whereas the use of an iron catalyst enabled a cyclopropanation to occur. This protocol offers a facile access to a broad range of trifluoromethyl containing spirocyclic β-lactams.

Key words

2,2,2-trifluorodiazoethane - α-methylene-β-lactam - spirocyclic β-lactam - [3+2] cycloaddition - cyclopropanation

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1588363.
  • Supporting Information
 

  • References and Notes

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  • 13 The X-ray crystallographic structure for 3a has been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 1486595. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 15 The X-ray crystallographic structures for 4a and epi-4a have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 1486487 and 1486488. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 16 General Procedure for the [3+2] CycloadditionTo a Schlenk tube charged with 2 (81.3 mg, 0.60 mmol, 2.0 equiv) and NaNO2 (49.7 mg, 0.72 mmol, 2.4 equiv) was added MeCN (1.5 mL) and H2O (0.1 mL). The resulting mixture was stirred at 0 °C for 1 h before β-lactam 1 (0.30 mmol, 1.0 equiv) was added in one portion. Then the tube was sealed and heated at 60 °C until no β-lactam was observed by TLC. After cooling to r.t., the solvent was removed under reduced pressure, the residue was subjected to flash column chromatography on silica gel to give the desired product 3.
    • 17a Representative Analytical Data2,3-Diphenyl-7-(trifluoromethyl)-2,5,6-triazaspiro[3.4]oct-6-en-1-one (3a)Yield 95%, 98 mg; light yellow solid, mp 182–184 °C. 1H NMR (400 MHz, CDCl3): δ = 7.52–6.96 (m, 10 H), 6.66 (s, 1 H), 5.09 (s, 1 H), 3.10 (dd, J = 20.0, 1.2 Hz, 1 H), 2.43 (d, J = 20.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 165.1, 140.2 (q, J = 38.0 Hz), 136.2, 135.7, 135.4, 130.9, 129.7, 129.4, 125.2, 119.8 (q, J = 268.0 Hz), 117.8, 82.4, 68.8, 33.5. 19F NMR (376 MHz, CDCl3): δ –67.1. ESI-HRMS: m/z calcd for C18H14F3N3NaO+: 368.0981; found: 368.0986 [M + Na]+.
  • 18 General Procedure for the [2+1] CycloadditionTo a Schlenk tube charged with FeTPPCl (14.1 mg, 0.02 mmol, 0.1 equiv) and β-lactam 1 (0.20 mmol, 1.0 equiv) was added DMF (2.0 mL). The resulting mixture was allowed to cool to 0 °C, and then a DMF solution of CF3CHN2 (0.8 M, 1 mL, 0.8 mmol, 4.0 equiv) was added via syringe pump at speed of 0.2 mL/h. After completion of the addition, stirring was continued for a further 6 h. The reaction was quenched with H2O (3 mL), extracted with EtOAc (3 × 10 mL). The organic layer was combined, dried over anhydrous Na2SO4, concentrated under reduced pressure to give the crude product 4. The unpurified product was directly examined by 19F NMR analysis to determine the diastereomeric ratio, and then subjected to flash column chromatography on silica gel to give the major isomer.
  • 19 Representative Analytical Data5,6-Diphenyl-1-(trifluoromethyl)-5-azaspiro[2.3]hexan-4-one (4a)Yield 89%, 46 mg, 81:19 dr. Analytical data for the major isomer: white solid, mp 132–134 °C. 1H NMR (400 MHz, CDCl3): δ = 7.41–7.22 (m, 9 H), 7.06–7.02 (m, 1 H), 5.09 (s, 1 H), 2.30–2.21 (m, 1 H), 1.69 (t, J = 6.0 Hz, 1 H), 0.86–0.81 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 163.9, 137.6, 134.9, 129.4, 129.2, 129.1, 126.8, 124.5 (q, J =272.0 Hz), 124.0, 116.9, 61.5, 42.8, 24.2 (q, J = 39.0 Hz), 10.2 (q, J = 3.0 Hz). 19F NMR (376 MHz, CDCl3): δ = –63.0 (d, J = 7.5 Hz). ESI-HRMS: m/z calcd for C18H14F3NNaO+ 340.0920; found: 340.0948 [M + Na]+.