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; Wen-Jie Cao; Jun-An Ma

doi:10.1055/s-0036-1588363

Synlett, Table of Contents

Synlett 2017; 28(06): 673-678
DOI: 10.1055/s-0036-1588363

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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

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Abstract

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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

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References

References and Notes

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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]⁺.

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