What Is Julia-Kocienski Olefination?
The classic Julia olefination reaction, also known as the Julia-Lythgoe olefination reaction, consists of α-deprotonation of phenyl sulfone, addition of carbanions to aldehydes and ketones, acetylation of hydroxyl groups, and elimination of sodium-amalgam desulfonation groups. consists of steps. This synthesis is an important method for synthesizing trans (E-formula) hydrocarbons starting from aldehydes and ketones. After this method was reported by Marc Julia and Jean-Mare Paris in 1973, it was systematically developed by Lythgoe and Kocienski.
In 1991, S.A.Julia creatively used benzothiazol-2yl-sulfone (BT) to replace phenylsulfone for Julia olefin synthesis. This improvement not only enables the original multi-step olefin synthesis method to be carried out in a "one-bottle reaction" manner, but the improved method is also easy to scale up. This constitutes an important development of the Julia olefin synthesis method, which is called the improved Julia olefin synthesis method.
Subsequently, Kocienski reported in 1998 that the use of 1-tert-butyl-1H-tetrazol-5-yl sulfone (PT) in the improved Julia olefin synthesis method could significantly improve the trans stereoselectivity of olefins and also Reactions that were originally difficult to carry out can be carried out. This modification is therefore called the Julia-Kocienski olefin synthesis method. Heteroaryl groups used to replace the classic Julia method include pyridin-2-yl (PYR), 1-tert-butyl-1H-tetrazol-5-yl (TBT) and 3,5-bis (trifluoromethyl)phenyl (BTFP).
Fig 1. Julia-Kocienski olefination reaction and its commonly used activators. [1]
Mechanism of Julia-Kocienski Olefination
The Julia-Lythgoe olefination reaction is usually carried out in a two-pot method:
- metallation of alkylaryl sulfone 4;
- addition of the resulting carbanion 5 to aldehyde or ketone 6;
- adduct 7 O-acylation (sulfonylation);
- Eliminate β-acyl (sulfonyl)oxysulfone 8 intermediate.
The mechanism of the Julia-Kocienski olefination reaction includes the steps:
- metallation;
- addition of metallated sulfone 11 to aldehyde 12;
- β-alkoxysulfone adduct 13 can occur spontaneously Smiles rearranges to form adduct 15;
- followed by β-elimination of SO2 in 15 and aryloxy anion (17).
Fig 2. The Julia-Lythgoe olefination vs. Julia-Kocienski olefination reaction. [1]
Application Examples of Julia-Kocienski Olefinization
- Example 1: Using chiral 1-(α-methylbenzyl)-aziridine-2-carboxylate as raw material, one-pot reduction ring-opening, debenzylation, and intramolecular N - Alkylation to obtain the key piperidine ring, and Julia–Kociensky olefination, enabled the total synthesis of Microgrowiapine A and its stereoisomers. [2]
- Example 2: Ryan M. Friedrich et al. developed a unified strategy for the synthesis of 1,5,9- and 1,5,7-triols via configurationally encoded 1,5-polyols, in which coupling events exploit the Julia-Kocienski reaction of enantiomerically pure α-siloxy-γ-sulfonitrile. [3]
- Example 3: The Julia-Kocienski reaction can be used to synthesize fluorine-containing olefins, which can be widely used in medicinal chemistry and materials science. Examples of various types of fluorovinyl compounds synthesized using Julia-Kocienski olefination as a key step include fluorostilbene-like and fluorostyrene-like derivatives, fluoroalkylidenes, α-fluoroacrylates, α-fluoroacrylonitriles, α-fluorovinyl phenyl sulfones, α-fluorovinyl Weinreb amide, and α-fluoroenones, etc. [4]
Fig 3. Synthetic examples via Julia-Kocienski olefinization reaction.
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References
- Chrenko, Daniel, et al. Molecules, 2024, 29(12), 2719.
- Macha, Lingamurthy, et al. The Journal of Organic Chemistry, 2018, 84(1), 94-103.
- Friedrich, Ryan M., et al. The Journal of Organic Chemistry, 2018, 83(22), 13636-13649.
- Zajc, Barbara, et al. Synthesis, 2010, 11, 1822-1836.
