Palladium-Catalyzed Trans-Selective Synthesis of Spirocyclic Cyclobutanes Using α,α-Dialkylcrotyl- and
Isaiah K Eckart-Frank1, Sidney M Wilkerson-Hill1
1Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Journal of the American Chemical Society
|August 8, 2023
Summary
This study showcases a novel method using crotylhydrazones to synthesize spirocyclic vinylcyclobutanes and spirocyclic alkylidene cyclobutanes. The reaction
Area of Science:
- Organic Synthesis
- Catalysis
- Stereoselective Reactions
Background:
- Spirocyclic compounds are valuable structural motifs in medicinal chemistry.
- Efficient and diastereoselective synthetic routes are crucial for accessing complex molecules.
Purpose of the Study:
- To develop a novel diastereoselective synthesis of spirocyclic vinylcyclobutanes and spirocyclic alkylidene cyclobutanes.
- To investigate the influence of reaction parameters on the outcome of tandem cyclization reactions.
Main Methods:
- Utilizing E/Z mixtures of α,α-disubstituted crotylhydrazones and allylated hydrazones.
- Employing a 1,1-insertion/4-exo-trig tandem process catalyzed by palladium.
- Exploring variations in aryl migrating groups and reaction partners like bromoenones.
Main Results:
- Successfully synthesized 24 examples of spirocyclic vinylcyclobutanes with high diastereoselectivity.
- Generated 11 examples of spirocyclic alkylidene cyclobutanes.
- Demonstrated that the aryl migrating group significantly impacts reaction pathways, enabling allylic C-H insertion or intramolecular cyclopropanation.
Conclusions:
- The developed method provides a versatile and diastereoselective route to complex spirocyclic frameworks.
- The study highlights the tunability of palladium-catalyzed tandem reactions for diverse synthetic outcomes.
- This work expands the synthetic toolbox for constructing valuable spirocyclic architectures.
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
Related Concept Videos
01:16Cycloaddition Reactions: Overview
2.6K
Cycloadditions are one of the most valuable and effective synthesis routes to form cyclic compounds. These are concerted pericyclic reactions between two unsaturated compounds resulting in a cyclic product with two new σ bonds formed at the expense of π bonds. The [4 + 2] cycloaddition, known as the Diels–Alder reaction, is the most common. The other example is a [2 + 2] cycloaddition.
2.6K
01:27Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation
2.2K
Robinson annulation is a base-catalyzed reaction for the synthesis of 2-cyclohexenone derivatives from 1,3-dicarbonyl donors (such as cyclic diketones, β-ketoesters, or β-diketones) and α,β-unsaturated carbonyl acceptors. Named after Sir Robert Robinson, who discovered it, this reaction yields a six-membered ring with three new C–C bonds (two σ bonds and one π bond).
2.2K
![[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2Ffiles%2Fmedia%2Fscience-education%2Fscience-education-thumbs%2F12417.jpg&w=3840&q=75)
01:16[4+2] Cycloaddition of Conjugated Dienes: Diels–Alder Reaction
10.3K
The Diels–Alder reaction is an example of a thermal pericyclic reaction between a conjugated diene and an alkene or alkyne, commonly referred to as a dienophile. The reaction involves a concerted movement of six π electrons, four from the diene and two from the dienophile, forming an unsaturated six-membered ring. As a result, these reactions are classified as [4+2] cycloadditions.
10.3K
01:29Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry
4.6K
Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.
4.6K
01:28Diels–Alder Reaction Forming Cyclic Products: Stereochemistry
3.9K
The Diels–Alder reaction is one of the robust methods for synthesizing unsaturated six-membered rings. The reaction involves a concerted cyclic movement of six π electrons: four π electrons from the diene and two π electrons from the dienophile.
3.9K
01:16Cycloaddition Reactions: MO Requirements for Thermal Activation
3.6K
Thermal cycloadditions are reactions where the source of activation energy needed to initiate the reaction is provided in the form of heat. A typical example of a thermally-allowed cycloaddition is the Diels–Alder reaction, which is a [4 + 2] cycloaddition. In contrast, a [2 + 2] cycloaddition is thermally forbidden.
3.6K