Synthesis 2007(8): 1209-1213  
DOI: 10.1055/s-2007-965972
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Substituted Tetrahydropyrans via Intermolecular Reactions of δ-Halocarbanions with Aldehydes

Michał Barbasiewicz, Aneta Brud, Mieczysław Mąkosza*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, P. O. Box 58, 01-224 Warsaw 42, Poland
Fax: +48(22)6326681; e-Mail: [email protected];
Further Information

Publication History

Received 4 January 2007
Publication Date:
28 February 2007 (online)


Intramolecular substitution in δ-halocarbanions leading to cyclobutanes is a relatively slow process, thus they readily add to carbonyl groups; the thus-produced anionic adducts cyclize to tetrahydropyran derivatives. A simple mechanistic discussion, optimization of the reaction conditions, and scope of the reaction is presented.


  • 1a Mąkosza M. Przyborowski J. Klajn K. Kwast A. Synlett  2000,  773 
  • 1b Mąkosza M. Judka M. Chem. Eur. J.  2002,  4234 
  • 1c Barbasiewicz M. Judka M. Mąkosza M. Russ. Chem. Bull.  2004,  53:  1771 
  • 2 Barbasiewicz M. Mąkosza M. Synthesis  2006,  1190 
  • 3 Mąkosza M. Judka M. Helv. Chim. Acta  2005,  88:  1676 
  • 4 Mąkosza M. Judka M. Synlett  2004,  717 
  • 5 Winnik MA. Chem. Rev.  1981,  81:  491 
  • 6 Eliel EL. Whilen SH. Stereochemistry of Organic Compounds   John Wiley & Sons; New York: 1994. 
  • 7 Barbasiewicz M. Marciniak K. Fedoryński M. Tetrahedron Lett.  2006,  47:  3871 
  • 8 Fleming FF. Shook BC. Tetrahedron  2002,  58: 
  • 10 For example of reactions of nonstabilized δ-halocarbanion equivalents, see: Mudryk B. Cohen T. J. Am. Chem. Soc.  1991,  113:  1866 
  • 11 Fleming FF. Gudipati V. Steward OW. J. Org. Chem.  2003,  68:  3943 
  • 12 Basil LF. Meyers AI. Hassner A. Tetrahedron  2002,  58:  207 
  • 13 Smet M. van Oosterwijck C. van Hecke K. van Meervelt L. Vandendriessche A. Dehaen W. Synlett  2004,  2388 
  • 14 Our attempts to synthesize a substituted dihydropyran in reactions from 4-chlorobut-2-enyl phenyl sulfone with benzaldehyde under a plethora of conditions were unsuccessful. For similar attempts using an imine, see: Balasubramanian T. Hassner A. Tetrahedron: Asymmetry  1998,  9:  2201 
  • The erythro-isomer gave product 3a exclusively, while the threo-isomer gave a mixture of 3a/3b (9:1, according to 1H NMR). This observation may lead to the conclusion, that erythro-isomer cyclizes relatively rapidly, while this process is slower for the threo-isomer and competitive retro-aldol reaction gives cross product 3b. The conformational preference for the cyclization of diastereomers of analogous aldol-type adducts 2a on the basis of their 1H-1H coupling constants and reactivity pattern were discussed in:
  • 17a Mąkosza M. Barbasiewicz M. Krajewski D. Org. Lett.  2005,  7:  2945 
  • 17b Hassner A. Usak D. Kumareswaran R. Friedman O. Eur. J. Org. Chem.  2004,  2421 
  • 19 During the optimization process, we observed that excess benzaldehyde (>1.25 equiv) inhibits the second step of the reaction(cyclization), which causes contamination of product 3a with aldol-type adducts 2a and decreases the reaction yield. We assume that this effect is based on interaction of the O-anion of 2a with the carbonyl group of excess aldehyde and formation of a hemiacetal-type adduct. This type of equilibrium operates, for example, in the reaction of the anion of 2-chloroethanol with aldehydes: Barbasiewicz M. Mąkosza M. Org. Lett.  2006,  8:  3745 
  • 22 Yu J.-W. Huang SK. Org. Prep. Proced. Int.  1997,  29:  214 
  • 23 Decesare MJ. Corbel B. Durst T. Blount JF. Can. J. Chem.  1981,  59:  1415 
  • 24 Shinriki N. Nambara T. Chem. Pharm. Bull.  1963,  11:  178 

Fedoryński M., manuscript in preparation.


The behavior of 1a and 1b without an electrophile under basic conditions [t-BuOK (2 equiv), THF, -50 °C or 0 °C, 1 h] revealed that, in contrast to γ-halocarbanions, intramolecular substitution in δ-halocarbanions leading to cyclobutanes is a slow process disturbed by competitive elimination and oligomerization reactions.


The ratio of the diastereomers of 2a remains almost constant, in the range 1:0.55-1:0.70 (erythro/threo, according to 1H NMR), during the course of the reaction.


In an independent experiment we performed the reaction of PhCHO (1 mmol), 4-MeOC6H4CHO (1 mmol), and 1b (1 mmol) under standard conditions to evaluate the effect of the relative electrophilicity of aldehydes. This experiment gave an approximately 1: 1 mixture of 3a and 3b (according to 1H NMR of the crude reaction mixture), leading to the conclusion that complete equilibration of adduct 2a with 4-MeOC6H4CHO in the aldol dissociation-addition sequence should lead to an equimolar mixture of 3a and 3b.


Reaction of 1c with benzaldehyde (-40 °C, 1 h) led to a mixture of the expected product 3f and uncyclized aldol-type adduct 2f (according to 1H NMR analysis of the crude reaction mixture). To force the cyclization process the temperature was increased to -25 °C. Similar behavior was observed for analogous reactions of γ-halocarbanions: an aldol-type adduct of 3-chloropropyl phenyl sulfone carbanion and benzaldehyde cyclizes much faster to the tetrahydrofuran derivative than its ester or cyano congeners: Barbasiewicz M., Mąkosza M., unpublished results.


Probably due to the less favorable equilibrium of addition of stabilized enolate of ketone to the carbonyl group under these conditions, as compared to other less stabilized carbanions, see ref. 2 for details. The only isolable compound was the product of reaction of the expected tetrahydropyran derivative with the second molecule of aldehyde and/or its subsequent transformations (yield ˜20%).