General Reactivity of 2-Lithiobenzothiazole to Various Electrophiles and the Use as a Formyl Anion Equivalent in the Synthesis of α-Hydroxy Carbonyl Compounds

Abstract

The reaction of 2-lithiobenzothiazole with a variety of electrophiles such as aldehydes, ketones, carboxylic esters, lactones, nitriles, and amides afforded the expected addition and substitution products. Trimethylsilyl chloride readily reacted with the benzothiazolyl anion to give 2-trimethylsilylbenzothiazole, while common alkyl halides including primary iodide and benzyl halides, as well as epoxides, did not react with the anion. This characteristic nucleophilicity of the anion was also demonstrated by its reaction with phenacyl halides and 5-chloro-2-pentanone leading to the formation of benzothiazolyl-substituted small-ring ethers. In order to demonstrate the value of 2-lithiobenzothiazole as a masked formyl anion, 2-(α-hydroxyalkyl)benzothiazoles were transformed into α-hydroxy carbonyl compounds in three reaction steps without masking the α-hydroxy groups. Quaternization of various 2-(α-hydroxyalkyl)benzothiazoles with methyl iodide in DMF afforded the corresponding 2-(α-hydroxyalkyl)-3-methylbenzothiazolium iodides in high yields and the subsequent alkylation or reduction of the C=N+ link was readily accomplished with organolithium and Grignard reagents or sodium borohydride leading to the corresponding 2-(α-hydroxyalkyl)-3-methylbenzothiazolines with or without another 2-substituents. Hydrolysis of former compounds performed in aqueous acetonitrile, buffered to pH 7 and containing AgNO3, gave the desired α-hydroxy ketones.

Nickel‐Catalyzed CH Arylation of Azoles with Haloarenes: Scope, Mechanism, and Applications to the Synthesis of Bioactive Molecules

“…In line with this observation, Itoh and co-workers reported that the C2-lithiated benzothiazole (Li-1 A) is very unstable even at À50 8C. [26] To evaluate whether the deprotonation is taking place during nickel catalysis, we conducted the coupling in the presence of tBuOD (Scheme 5). When 1 A (1.5 equiv) was treated with 2 a (1.0 equiv), NiA C H T U N G T R E N N U N G (OAc) 2 (10 mol %), bipy (10 mol %), LiOtBu (2.0 equiv), and tBuOD (2.0 equiv), in 1,4-dioxane at 120 8C for 10 h, 42 % of recovered 1 A was deuterated at the C2 position (coupling product 3 Aa was formed in 44 % yield).…”

Hydroxybenzothiazoles as New Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1)

“…Then nucleophilic addition [67] of 5iiia (after in situ lithiation in the 2-position) to 5iiib in THF at −15°C for 90 minutes yielded the secondary alcohol 5ii . The latter was oxidized to the carbonyl derivative 5i using stabilized 2-iodoxybenzoic acid (SIBX) as oxidative reagent in THF at 60°C [68] prior to the removal of both silyl protecting groups under mild basic conditions (TBAF in THF at room temperature for 2 hours) [69] to afford compound 5 .…”

Synthesis of Rocaglamide Hydroxamates and Related Compounds as Eukaryotic Translation Inhibitors: Synthetic and Biological Studies

“…15 Encouraged by a report that 2-lithiobenzothiazole undergoes single addition to esters due to the formation of a stable tetrahedral intermediate, 16 we anticipated that heterocyclic aromatic ketone analogs may be prepared directly from methyl rocaglate (Chart 3). Indeed, 2-lithiobenzothiazole (3.1 equiv) was prepared and reacted with methyl rocaglate at -78 °C for 1 h to yield the desired benzothia-zole ketone 25 in 50% yield based on recovered starting material (BRSM).…”