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Synlett 2013; 24(1): 57-60
DOI: 10.1055/s-0032-1317709
letter
© Georg Thieme Verlag Stuttgart · New York

Nucleophilic 5-endo-trig Cyclization of 3,3-Difluoroallylic Ketone Enolates: Synthesis of 5-Fluorinated 2-Alkylidene-2,3-dihydrofurans

Takeshi Fujita
a   Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan   Fax: +81(29)8534237   Email: junji@chem.tsukuba.ac.jp
,
Kotaro Sakoda
b   Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
,
Masahiro Ikeda
a   Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan   Fax: +81(29)8534237   Email: junji@chem.tsukuba.ac.jp
,
Masahiro Hattori
a   Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan   Fax: +81(29)8534237   Email: junji@chem.tsukuba.ac.jp
,
Junji Ichikawa*
a   Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan   Fax: +81(29)8534237   Email: junji@chem.tsukuba.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 11 October 2012

Accepted after revision: 08 November 2012

Publication Date:
10 December 2012 (online)

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Abstract

3,3-Difluoroallylic ketones readily undergo nucleophilic 5-endo-trig cyclization through their metal enolates to afford 5-fluor­inated 2-alkylidene-2,3-dihydrofurans. O-Cyclization exclusively occurred via intramolecular substitution of the vinylic fluorines.

Key words

cyclization - fluorine - alkenes - furans - 5-endo-trig - ­ketone enolates - vinylic substitution

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes


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  • 14 Baldwin noted that when endocyclic alkylation of ketone enolates constructs five-membered rings, O-cyclization would be preferable because of an in-plane approach to enolates. The chemoselectivity in our case could be partially explained by a similar reasoning, albeit with the sp2-CF2 electrophile instead of sp3-C electrophiles. See: Baldwin JE, Kruse LI. J. Chem. Soc., Chem. Commun. 1977; 233
  • 15 (Z)-5-Fluoro-3,3-dimethyl-2-(2-phenylethylidene)-2,3-dihydrofuran (5b) To a suspension of KH (oil free, 46 mg, 1.2 mmol) in THF (11 mL) was added 6,6-difluoro-4,4-dimethyl-1-phenylhex-5-en-3-one (2b, 138 mg, 0.58 mmol), and the mixture was heated to reflux for 2 h. After cooling to r.t., the reaction was quenched with phosphate buffer (pH 7). Organic materials were extracted with Et2O three times. The combined extracts were washed with brine and dried over MgSO4. After removal of the solvent under reduced pressure, the residue was purified by TLC on silica gel (EtOAc–hexane, 1:5) to give 5b (122 mg, 97%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ = 1.26 (d, J HF = 1.1 Hz, 6 H), 3.45 (d, J = 7.5 Hz, 2 H), 4.20 (d, J HF = 5.4 Hz, 1 H), 4.73 (td, J = 7.5 Hz, J HF = 3.4 Hz, 1 H), 7.18–7.22 (m, 3 H), 7.27–7.30 (m, 2 H). 13C NMR (126 MHz, CDCl3): δ = 30.1 (d, J CF = 2 Hz), 30.9, 44.2 (d, J CF = 2 Hz), 79.7 (d, J CF = 8 Hz), 99.4, 125.9, 128.2, 128.4, 141.0, 157.5 (d, J CF = 276 Hz), 160.6 (d, J CF = 3 Hz). 19F NMR (470 MHz, CDCl3): δ = 46.2 (s). IR (neat): 3028, 2970, 2931, 1801, 1726, 1703, 1454, 1279, 1219, 1126, 1088, 993, 976, 748, 698 cm–1. Anal. Calcd for C14H15FO: C, 77.04; H, 6.93. Found: C, 76.80; H, 7.16%.
  • 16 3,3-Disubstituted 5-fluoro-2-alkylidene-2,3-dihydrofurans 5 are air- and heat-stable.
  • 17 In the NOESY experiment of dihydrofuran 5b, substantial correlation between the methyl protons and the vinylic proton Ha was observed. No NOE correlation was detected between the methyl protons and the allylic protons Hb (Figure 1).
  • 18 For a review on bioactivities of fluorinated compounds, see: Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
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