What Is Lawesson's Reagent?
Lawesson's reagent (LR for short) is a reagent commonly used to convert the carbonyl group of ketones, esters, and amides to thiocarbonyl groups. This transformation involves the replacement of an oxygen atom with a sulfur atom, leading to the formation of thiocarbonyl compounds.
The chemical name of LR is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide. This type of compound was first obtained by Lecher et al. in 1956 by reacting aromatic hydrocarbons with phosphorus pentasulfide. After that, Swedish chemist Sven-Olov Lawesson (1926-1988) and others developed it into a reagent that can convert the carbonyl group of ketones, esters and amides into thiocarbonyl groups.
To aid product separation, Soos et al. developed fluorine-containing LR (abbreviated as FLR). It should be pointed out that in addition to the above uses, Lawesson's reagent can also be used for the synthesis of heterocyclic compounds, deoxygenation of heteroaryl halobenzyl alcohols and other reactions. Electron-rich carbonyl groups are more reactive. When reacting with α,β-unsaturated aldehydes and ketones, the double bond is not affected.
- Reagent: Lawesson's reagent
- Reactants: Carbonyl compounds (e.g., amides, ketones, esters, lactams, quinones, etc.)
- Products: Thiocarbonyl compounds (e.g., thioamides, thioketones, thioesters)
- Reaction type: Formation of C-S bonds.
- Related reactions: Appel reaction, Corey-Fuchs reaction, Wittig reaction.
Fig 1. Lawesson's reagent and its rection mechanism. [1]
Mechanism of Lawesson's Reagent
Lawesson's reagent exists in the solution in an equilibrium state with the more active disulfide phosphorus ylide. It reacts with the carbonyl group to obtain a thiophosphine tetracyclic intermediate. The motor of the reaction is the formation of a stable phosphorus-oxygen double bond (P=O) during the ring cleavage process, which is a part of what's going on in the Wittig reaction mechanism.
In the reaction with Lawesson's reagent, ketones, amides, lactams and lactones are more reactive than esters, so in some selective reactions, the ester group can be excluded from the reaction under certain conditions. For example, thiophenes 74–78 in the figure below were obtained from diketones by microwave-assisted reactions, using Lawesson's reagent to introduce sulfur atoms. [2]
Fig 2. Preparation of thiophenes with Lawesson's reagent. [2]
Application Examples of Lawesson's Reagent
- Example 1: In the synthesis of 2-methylene-2,3-dihydro-1,4-thiazepines from N-propargylic β-enaminones, which were first thiolated with Lawesson's reagent, and the resulting N-propargyl β-enaminothiones were then electrophilically cyclized. This approach is very useful for the synthesis of a library of functionalized 1,4-thiazepines for pharmaceutical applications. [3]
- Example 2: In a synthetic strategy for a class of thiophosphinyl pseudopeptides, several fully protected thiophosphinate pseudodipeptides with the general formula PG-Phe-Ψ[P(S)(OX)CH2]-Gly-OY were prepared using Lawesson's reagent starting from the corresponding phosphinate pseudodipeptides. These compounds can be used as transition state mimetic inhibitors of several zinc metalloproteases. [4]
Fig 3. Synthetic examples with Lawesson's reagent.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 314-316.
- Minetto, Giacomo, et al. Eur. J. Org. Chem., 2005, 5277-5288.
- Kelgokmen, et al. The Journal of Organic Chemistry, 2018, 83(15), 8376-8389.
- Vassiliou, Stamatia, et al. The Journal of Organic Chemistry, 2013, 78(20), 10069-10076.
