Studies toward the synthesis of alpha-fluorinated phosphonates via tin-mediated cleavage of alpha-fluoro-alpha-(pyrimidin-2-ylsulfonyl)alkylphosphonates. Intramolecular cyclization of the alpha-phosphonyl radicals

J Org Chem. 2002 May 3;67(9):3065-71. doi: 10.1021/jo0111560.

Abstract

Treatment of the alpha carbanions generated from several alpha-(pyrimidin-2-ylsulfonyl)alkylphosphonates with Selectfluor gave high yields of the alpha-fluoro-alpha-(pyrimidin-2-ylsulfonyl)alkylphoshonates, which were desulfonylated [Bu(3)SnH/2,2'-azobisisobutyronitrile (AIBN)/benzene or toluene/Delta] to give alpha-fluoroalkylphosphonates. "Catalytic" tin hydride, generated from tributyltin chloride and excess polymethylhydrosiloxane in the presence of potassium fluoride, also effected removal of the pi-deficient alpha-(pyrimidin-2-ylsulfonyl) group from the phosphonate esters. Substitution of Bu(3)SnD for Bu(3)SnH gave access to alpha-deuterium-labeled phosphonates. Prolonged treatment of alpha-(pyridin-2-ylsulfonyl)alkylphosphonate with excess Bu(3)SnH/AIBN or catalytic tin hydride also effected desulfonylation but in moderate yields. This represents a mild new methodology for removal of the synthetically useful pi-deficient heterocyclic sulfone moiety and an alternative route for the preparation of alpha-fluorinated phosphonates. Desulfonylation is suggested to proceed via attack of tin radical at an oxygen (or sulfur) atom of the sulfonyl group to give a stabilized alpha-phosphonyl radical intermediate. The latter was found to undergo 5-exo-trig ring closure to give the corresponding 2-methylcyclopentylphosphonates. Treatment of diethyl 1-bromohex-6-enylphosphonate with Bu(3)SnH/AIBN produced an analogous mixture of ring-closure products. Treatment of [(2-bromo-5- methoxyphenyl)(fluoro)(pyrimidin-2-ylsulfonyl)]methylphosphonate with Bu(3)SnH resulted in an intramolecular radical [1,5]-ipso substitution reaction and migration of the pyrimidinyl ring to give fluoro[5-methoxy-2-(pyrimidin-2-yl)phenyl]methylphosphonate.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkanes / chemistry
  • Alkylation
  • Catalysis
  • Chromatography, High Pressure Liquid
  • Cyclization
  • Esters / chemistry
  • Hydrocarbons, Fluorinated / chemical synthesis*
  • Hydrocarbons, Fluorinated / chemistry
  • Magnetic Resonance Spectroscopy
  • Models, Chemical
  • Molecular Structure
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Oxidation-Reduction
  • Pyridines / chemical synthesis
  • Pyrimidines / chemical synthesis
  • Stereoisomerism
  • Sulfones / chemical synthesis
  • Sulfones / chemistry
  • Tin / chemistry*

Substances

  • Alkanes
  • Esters
  • Hydrocarbons, Fluorinated
  • Organophosphonates
  • Pyridines
  • Pyrimidines
  • Sulfones
  • Tin