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Regioselectivity of Michael Additions to 3‐(Pyridin‐3‐yl or Pyrimidin‐2‐yl)propenoates and Their N ‐Oxides – Experimental and Theoretical Studies
Author(s) -
Lewandowska Elzbieta,
Chatfield David C.
Publication year - 2005
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200500058
Subject(s) - regioselectivity , chemistry , substituent , nucleophile , adduct , michael reaction , medicinal chemistry , nucleophilic addition , double bond , addition reaction , stereochemistry , organic chemistry , catalysis
We demonstrate that nucleophilic addition to α,β‐unsaturated carbonyl compounds can be redirected from the usual β‐carbon (Michael) to an α‐carbon regioselectivity by attaching a π‐deficient aromatic substituent to the β‐carbon atom. In particular, propanethiol addition to 3‐(pyridin‐3‐yl or pyrimidin‐2‐yl)propenoate gives a β‐carbon adduct, while addition to the corresponding more π‐deficient N ‐oxides gives the α‐adduct or a mixture of α‐ and β‐adducts. This adds to the number of carbon–carbon bond‐forming reactions at the α‐position of Michael receptors documented recently. Density functional calculations reveal that the regioselectivity is due to a combination of reduction of the barrier for α‐addition and increase of the barriers for β‐addition and carbonyl addition as the π‐deficient character of the aromatic substituent is increased. The calculations predict a significant solvent effect on the regioselectivity in some cases. The regioselectivity is also consistent with Hammett constants σ – . (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)