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

Takeshi Fujita; Kotaro Sakoda; Masahiro Ikeda; Masahiro Hattori; Junji Ichikawa

doi:10.1055/s-0032-1317709

Synlett, Table of Contents

Synlett 2013; 24(1): 57-60
DOI: 10.1055/s-0032-1317709

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

Takeshi Fujita

^aDivision 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

^bDepartment of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

,

Masahiro Ikeda

^aDivision 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

^aDivision 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*

^aDivision 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

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Abstract

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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

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References

References and Notes

For recent reviews, see:

1a Uneyama K. Organofluorine Chemistry . Chap. 2.3. Blackwell Publishing; Oxford: 2006
1b Amii H, Uneyama K. Chem. Rev. 2009; 109: 2119

2a Ichikawa J In Fluorine-Containing Synthons, ACS Symposium Series 911. Chap. 14. Soloshonok VA. Oxford University Press/ACS; Washington DC: 2005
2b Ichikawa J. Chim. Oggi 2007; 25 (4): 54

3a Wada Y, Ichikawa J, Katsume T, Nohiro T, Okauchi T, Minami T. Bull. Chem. Soc. Jpn. 2001; 74: 971
3b Wada Y, Mori T, Ichikawa J. Chem. Lett. 2003; 32: 1000
3c Mori T, Ichikawa J. Chem. Lett. 2004; 33: 590
3d Ichikawa J, Sakoda K, Moriyama H, Wada Y. Synthesis 2006; 1590

4a Ichikawa J, Wada Y, Miyazaki H, Mori T, Kuroki H. Org. Lett. 2003; 5: 1455
4b Ichikawa J, Mori T, Miyazaki H, Wada Y. Synlett 2004; 1219
4c Ichikawa J, Wada Y, Kuroki H, Mihara J, Nadano R. Org. Biomol. Chem. 2007; 5: 3956

For Baldwin’s rules, see:

5a Baldwin JE. J. Chem. Soc., Chem. Commun. 1976; 734
5b Baldwin JE, Cutting J, Dupont W, Kruse L, Silberman L, Thomas RC. J. Chem. Soc., Chem. Commun. 1976; 736
5c Baldwin JE, Thomas RC, Kruse L, Silberman L. J. Org. Chem. 1977; 42: 3846

6 Ichikawa J, Iwai Y, Nadano R, Mori T, Ikeda M. Chem. Asian J. 2008; 3: 393 ; and references cited therein

For recent reports on nucleophile-driven 5-endo-trig cyclization, see:

7a Anderson JC, Davies EA. Tetrahedron 2010; 66: 6300
7b Motto JM, Castillo Á, Greer A, Montemayer LK, Sheepwash EE, Schwan AL. Tetrahedron 2011; 67: 1002

For recent reports on electrophile-driven 5-endo-trig cyclization, see:

8a Stojanović M, Marković R. Synlett 2009; 1997
8b Kalamkar NB, Kasture VM, Dhavale DD. Tetrahedron Lett. 2010; 51: 6745
8c Saczewski J, Gdaniec M, Bednarski PJ, Makowska A. Tetrahedron 2011; 67: 3612

For recent reports on radical-initiated 5-endo-trig cyclization, see:

9a Pattarozzi M, Ghelfi F, Roncaglia F, Pagnoni UM, Parsons AF. Synlett 2009; 2172
9b Yu J.-D, Ding W, Lian G.-Y, Song K.-S, Zhang D.-W, Gao X, Yang D. J. Org. Chem. 2010; 75: 3232

For 5-endo-trig cyclization of substrates with difluoroalkene moieties, see:

10a Ichikawa J, Wada Y, Fujiwara M, Sakoda K. Synthesis 2002; 1917
10b Ichikawa J, Nadano R, Mori T, Wada Y. Org. Synth. 2006; 83: 111
10c Ichikawa J. Org. Synth. 2011; 88: 162
10d Ichikawa J, Wada Y, Okauchi T, Minami T. Chem. Commun. 1997; 1537
10e Ichikawa J, Fujiwara M, Wada Y, Okauchi T, Minami T. Chem. Commun. 2000; 1887
10f Tanabe H, Ichikawa J. Chem. Lett. 2010; 39: 248
10g Fuchibe K, Takahashi M, Ichikawa J. Angew. Chem. Int. Ed. 2012; 51: 12059

For selected examples of conventional synthetic methodologies for 2-alkylidene-2,3-dihydrofurans, see:

11a Tiecco M, Testaferri L, Tingoli M, Marini F. J. Org. Chem. 1993; 58: 1349 ; and references cited therein
11b Lattanzi A, Sagulo F, Scettri A. Tetrahedron: Asymmetry 1999; 10: 2023
11c Fang Y, Li C. Chem. Commun. 2005; 3574
11d Chen Y.-F, Wang H.-F, Wang Y, Luo Y.-C, Zhu H.-L, Xu P.-F. Adv. Synth. Catal. 2010; 352: 1163
11e Montel S, Bouyssi D, Balme G. Adv. Synth. Catal. 2010; 352: 2315

12 For the synthesis of 1,3-ketoaldehydes from enamines, see: Kuhlmey S.-R, Adolph H, Rieth K, Opitz G. Liebigs Ann. Chem. 1979; 617

For difluoromethylenation of aldehydes with dibromodifluoromethane and tris(trimethylamino)phosphine, see:

13a Naae DG, Burton DJ. Synth. Commun. 1973; 3: 197
13b Vinson WA, Prickett KS, Spahic B, deMontellano PR. O. J. Org. Chem. 1983; 48: 4661

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 H^a was observed. No NOE correlation was detected between the methyl protons and the allylic protons H^b (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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