Iminothioethers

In 2005, Kunieda et al. developed sterically congested 2-iminothioethers as novel and highly efficient chiral ligands for the test reaction, providing the product in excellent yield and enantioselectivity, as shown in Scheme 1.38. ... 

Scheme 1.38 Test reaction with congested 2-iminothioether ligand.

The thiazole ring has been found to be an occasional surrogate for a phenyl ring in certain antiinflammatory agents. Note that the side chain is restricted to a simple acetic acid in this series. Reaction of p-chloro-2-mercaptoacetophenone (198) with ethyl cyanoacetate in the presence of base affords thiazole 200. The reaction may involve an adduct such as the iminothioether 199 as an intermediate. Saponification of the ester moiety of 200 then gives the antiinflammatory agent fenclozic acid... 

The metal-bound RCN group is also activated on coordination towards nucleophilic attack by alcohols, thiols or amines to give stable N-bonded iminoether, iminothioether and amidine complexes respectively.332 Several cationic cyanobenzylpalladium(II) complexes have been prepared, and the reactivity of the CN group towards nucleophiles has been studied.333,334 The palladium complex (97) reacts with aromatic amines to give chelated amidino complexes (98) and the reaction has been studied kinetically.333 In this case intermediates with the nitrile group bonded side-on are considered to be involved. 

Another aspect of the reactivity of nitrilium salts has been employed in the synthesis of several heterocyclic systems. This entails their reaction with certain electron-rich functional groups, such as —OH, —SH, —NH2, etc.,27,30 according to the general scheme (67->68) yielding iminoethers (68, Z = 0), iminothioethers (68, Z = S),... 

Iminoethers have been hydrolyzed to esters and iminothioethers to thioesters. Some examples follow 2-cyano-3-(C-ethoxy-C-iminomethyl)-5,6-dimethylpyrazine [2-cyano-3-(C-ethoxyformidoyl)-5,6-dimethylpyrazine] (26) in boiling water gave... 

Iminothioethers have similarly been prepared from nitriles. 2-Amino-3-cyano-pyrazine with sodium methanethiolate (other alkanethiolates reached similarly) in ethanol gave 2-amino-3-(Cimino-C-methylthiomethyl)pyrazine (60) (792, 878, 1075) [which with guanidine hydrochloride and sodium methoxide in methanol gave 2-amino-3-(C-guanidino-C-iminomethyl)pyrazine (878)] 2-amino-5-chloro-3-cyanopyrazine with methanethiol and sodium hydroxide in methanol gave 2-amino-5-chloro-3-(C-imino-C-methylthiomethyl)pyrazine (877, 1218) [which with... 

Carboxy includes carboxy (carboxylic acids), alkoxycarbonyl (esters), carbamoyl (amides), thiocarbamoyl, hydrazinocarbamoyl (hydrazides), guanidinocarbonyl, azidocarbonyl (azides), chlorocarbonyl (acid chlorides), amidino, C-hydrazino-C-iminomethyl, C-alkoxy-C-iminomethyl (imino ethers), C-alkylthio-C-iminomethyl (iminothioethers), cyano (nitriles), C-formyl(aldehydes), dialkoxymethyl (acetals of aldehydes), C-acyl (ketones), isocyanato, and thiocyanato groups. 

Reactions between substituted allylic Grignard reagents and cyclic iminothioethers or iminoethers have been tried with 2-methylthio-2-thiazolines or 2-oxazolines. Interestingly, only one addition-elimination reaction is observed [77 Eq. (38)] ... 

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