Prins fluorination cyclisations: Preparation of 4-fluoro-pyran and -piperidine heterocycles

Summary The Prins reaction was investigated using BF3·OEt2 as a Lewis acid. It has been recently demonstrated, that if BF3·OEt2 is used in stoichiometric amounts then these reactions generate fluorinated products where the BF3·OEt2 contributes fluoride ion to quench the intermediate carbocations. In this study oxa- and aza-Prins reactions for the synthesis of 4-fluoro-pyrans and -piperidines were investigated. The products were obtained in good yields, but only with moderate diastereoselectivity. These Prins fluorination reactions can be accelerated under microwave conditions. The study extends the Prins fluorination methodology for the generation of the C–F bond in heterocycles.

[1]  G. Sandford.  Organofluorine chemistry , 2021, Philosophical Transactions of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[2]  A. Slawin,et al.  Synthesis and structure of stereoisomeric multivicinal hexafluoroalkanes. , 2009, Angewandte Chemie.

[3]  L. F. Silva,et al.  An expeditious synthesis of hexahydrobenzo[f]isochromenes and of hexahydrobenzo[f]isoquinoline via iodine-catalyzed Prins and aza-Prins cyclization , 2009 .

[4]  J. Yadav,et al.  Heteropoly acid-catalyzed aza-Prins-cyclization : an expeditious synthesis of 4-hydroxypiperidines , 2009 .

[5]  S. Inagi,et al.  Prins Cyclization in Ionic Liquid Hydrogen Fluoride Salts: Facile and Highly Efficient Synthesis of 4-Fluorinated Tetrahydropyrans, Thiacyclohexanes, and Piperidines , 2008 .

[6]  S. Inagi,et al.  Facile and highly efficient synthesis of fluorinated heterocycles via Prins cyclization in ionic liquid hydrogen fluoride salts. , 2008, Chemical communications.

[7]  J. Yadav,et al.  Gallium iodide/iodine as a versatile reagent for the aza-Prins cyclization: an expeditious synthesis of 4-iodopiperidines , 2008 .

[8]  David O'Hagan,et al.  Understanding organofluorine chemistry. An introduction to the C-F bond. , 2008, Chemical Society reviews.

[9]  K. Uneyama.  Organofluorine Chemistry: Kenji/Organofluorine , 2007 .

[10]  F. Diederich,et al.  Fluorine in Pharmaceuticals: Looking Beyond Intuition , 2007, Science.

[11]  A. Armstrong,et al.  Aza-Prins-pinacol approach to 7-azabicyclo[2.2.1]heptanes: syntheses of (+/-)-epibatidine and (+/-)-epiboxidine. , 2007, The Journal of organic chemistry.

[12]  V. Martín,et al.  Iron(III)-promoted aza-Prins-cyclization: direct synthesis of six-membered azacycles. , 2006, Organic letters.

[13]  J. Iley,et al.  Monofluorinated di- and tetrahydropyrans via Prins-type cyclisations. , 2006, Chemical communications.

[14]  K. Kataoka,et al.  Convenient synthesis of highly optically active 2,3,4,6-tetrasubstituted tetrahydropyrans via prins cyclization reaction (PCR) of optically active homoallylic alcohols with aldehydes , 2006 .

[15]  A. Armstrong,et al.  aza-Prins-pinacol approach to 7-azabicyclo[2.2.1]heptanes and ring expansion to [3.2.1]tropanes. , 2005, Organic letters.

[16]  J. Yadav,et al.  Rapid and Efficient Protocol for the Synthesis of 4-Chlorotetrahydropyrans Using Niobium(V) Chloride , 2004 .

[17]  S. Coles,et al.  A versatile indium trichloride mediated Prins-type reaction to unsaturated heterocycles. , 2003, The Journal of organic chemistry.

[18]  Mark T. Oakley,et al.  Aromatic 4-tetrahydropyranyl and 4-quinuclidinyl cations. Linking Prins with Cope and Grob. , 2002, Journal of the American Chemical Society.

[19]  C. Willis,et al.  Oxonia-cope rearrangement and side-chain exchange in the Prins cyclization. , 2002, Organic letters.

[20]  S. Rychnovsky,et al.  Stereoselectivity and regioselectivity in the segment-coupling Prins cyclization. , 2001, The Journal of organic chemistry.

[21]  B. Rickborn,et al.  Kinetics and stereochemistry of LiNR2-induced 1,2-elimination of homoallylic ethers , 1989 .

[22]  L. A. Mikeska,et al.  The Olefin-Aldehyde Condensation. The Prins Reaction. , 1952 .

[23]  R. H. Baker,et al.  The Cleavage of Benzyl Ethers with Hydrogen , 1948 .

[24]  T. J. Simpson,et al.  Stereocontrolled synthesis of 2,4,5-trisubstituted tetrahydropyrans , 2001 .

[25]  M. Ashwell,et al.  Preparation of α-substituted S-phenylthio esters from 2-nitro-2-phenylthio oxiranes , 1990 .

[26]  M. Ashwell,et al.  Preparation and synthetic utility of 1-phenylthio-1-nitro epoxides. Facile preparation of α-substituted S-phenyl thio esters , 1988 .