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Versatile and efficient solid-phase syntheses of pyrazoles and isoxazoles.
1Department of Molecular Design and Diversity, Merck Research Laboratories, P.O. Box 2000 RY800-C306, Rahway, New Jersey 07065, USA. dongming_shen@merck.com
Organic Letters
|August 31, 2000
Summary
A new synthetic route efficiently produces highly substituted pyrazoles and isoxazoles using resin-supported acetyl carboxylic acids. This method allows easy control over isomeric ratios and generates diverse heterocyclic compounds.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Heterocyclic Chemistry
Background:
- Pyrazoles and isoxazoles are important heterocyclic compounds with diverse applications.
- Efficient and controlled synthesis of highly substituted isomers remains a challenge.
Purpose of the Study:
- To develop a general and efficient method for synthesizing highly substituted, isomeric pyrazoles and isoxazoles.
- To achieve control over the ratio of isomers produced.
- To explore variations for generating specific substitution patterns.
Main Methods:
- Condensation of esters with resin-supported acetyl carboxylic acids.
- Cyclization with hydrazines or hydroxylamine.
- Linker activation and cleavage using amines, followed by optional reduction.
Main Results:
- The method provides highly substituted, isomeric pyrazoles or isoxazoles in excellent yields and purities.
- The ratio of the two isomers can be easily controlled.
- A variation allows the generation of 1,4,5- and 1,3,4-trisubstituted pyrazoles and related isoxazoles.
- Post-cleavage reduction converts pyrazole amides to amines.
Conclusions:
- This general method offers a versatile and efficient approach to substituted pyrazoles and isoxazoles.
- The ability to control isomer ratios and generate specific substitution patterns enhances its utility.
- The developed strategy is applicable to the synthesis of diverse heterocyclic structures.