Correlation between pK(a) and reactivity of quinuclidine-based catalysts in the Baylis-Hillman reaction: Discovery of quinuclidine as optimum catalyst leading to substantial enhancement of scope

VK Aggarwal*, Ingo Emme, SY Fulford

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

212 Citations (Scopus)

Abstract

The reactivity of a variety of quinuclidine-based catalysts in the Baylis-Hillman reaction has been examined, and a straightforward correlation between the basicity of the base and reactivity has been established, without exception. The following order of reactivity was established with pk(a)'s of the conjugate acids (measured in water) given in parentheses: quinuclidine (11.3), 3-hydroxy-quinuclidine (9.9), DABCO (8.7), 3-acetoxyquinuclidine (9.3), 3-chloroquinuclidine (8.9), and quinuclidinone (7.2). The higher than expected reactivity of DABCO, based on its pK(a), was analyzed by comparing the relative basicity of DABCO and 3-acetoxyquinuclidine in DMSO. It was found that in aprotic solvent, DABCO was 0.6 pK(a) units more basic than 3-acetoxyquinuclidine, thus establishing a direct link between pK(a) of the amine and its reactivity. In contrast to previous literature work that reported the contrary, quinuclidine, which has the highest pK(a), was found to be the most active catalyst. The reaction profile with quinuclidine showed significant autocatalysis, which suggested that the presence of proton donors might further enhance rates. Thus, a series of additives bearing polar X-H bonds were investigated and it was found that methanol, triethanolamine, formamide, and water all provided additional acceleration. Methanol was found to be optimum, and the powerful combination of quinuclidine with methanol was tested with a host of aldehydes and Michael acceptors. Not only were the reactions more efficient and faster than previously reported, but now new substrates that were previously unreactive could be employed. Notable examples include the use of acetylenic aldehydes and the employment of vinyl sulfones, acrylamides, delta-lactones, and even alpha,beta-unsaturated esters bearing a beta-substituent.

Original languageEnglish
Pages (from-to)692-700
Number of pages9
JournalJournal of Organic Chemistry
Volume68
Issue number3
DOIs
Publication statusPublished - 7 Feb 2003

Keywords

  • LIGAND-ACCELERATED CATALYSIS
  • CARBONYL-COMPOUNDS
  • ACID-DERIVATIVES
  • HIGH-PRESSURE
  • SUBSTITUTION
  • METAL
  • WATER

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