Imidoylation reactions at carbon

Methods used for imidoylation and aminoimidoylation at α -carbon atoms of ketones


Introduction 1.General
Imidoylations enable the preparation of a wide variety of compound classes.Thus, imidoylations at nitrogen are used for the preparation of amidines, guanidines, and N-substituted derivatives. 1 The present review covers imidoylations at carbon, which are defined as the formation of a C-C bond concomitant with the introduction of a (C=NR)Y group in a position previously occupied by a hydrogen (Scheme 1).

Imidoylation of ketones
C-Imidoylations of ketones to give β-enaminoketones 8 (Scheme 3) include (i) reactions of enolates derived from ketones 9 with imidoyl halides; this is only successful with fluorinated (R 1 ) imidoyl halides thus restricting its application; 10,11 (ii) a single example of a palladium catalyzed reaction of acetonyltributyltin 10 with an imidoyl chloride; 12 (iii) reactions of imidoylbenzotriazoles with ketones 11 or ketone-derived silyl enol ethers to give the desired imidoylation products 8 in 19-80% yield together with an amide as a byproduct; 9a (iv) reaction of an O-mesyloxime 12, a route that includes a C to N migration of the cis group but this is limited to symmetric oximes. 13(v) reactions of nitriles with methylketones 9 incorporating nitriles of aromatic 14a and fluorinated acids 14b in the presence of base.
Recently, we have reacted ester enolates (generated by treatment of esters with excess potassium t-butoxide in THF at room temperature) with imidoylbenzotriazoles 21 to give βenamino esters 22 in 77-88% yields.23a (Scheme 5).There seem to be no limitations to these fast and efficient reactions.

Imidoylation of nitriles
Condensation of a nitrile anion 23a with a neutral nitrile species effects imidoylations of many nitriles 23 (Scheme 6).23b,24 Products 24 can be obtained but reactions proceed more rapidly with R 1 = Ar in the neutral nitrile 23b, because reactions between two different aliphatic nitriles lead to the formation of side products.23b

Imidoylation of nitro compounds
A single C-imidoylation of a nitro compound has been reported. 25The reaction of ethyl nitroacetate 26 with imidoyl chloride 25 gives the enamine 27b (Scheme 7).A general C-imidoylation of nitro compounds was recently established in our group.23a β-Nitroenamines 28 (3 examples) were prepared in 34-60% yield from the reaction of imidoylbenzotriazoles 21 with nitroethane (Scheme 8).Yields were improved by using DMSO as a solvent rather than THF.

Scheme 9
Three C-imidoylations of sulfones by imidoylbenzotriazoles 21 to form β-iminosulfones 29 (53-97%) have been found recently, 23a but no examples were reported with aliphatic substituents in place of N-phenyl, which could be a limitation.

Imidoylation of sulfoxides
Imidoylations of sulfoxides to give β-iminosulfoxides 31 (Scheme 10) involve the reaction of sulfinylmethyl carbanion derived from methylsulfoxides 30 with (i) fluorinated imidoyl chlorides (R = CF 3 , CF 2 Cl, CF 2 CF 3 , CF 2 H, CFH 2 ) 29,30 or (ii) nitriles. 31Fluorinated imidoyl chlorides react well with sulfinylmethyl carbanions regardless of the substituents in the imidoyl chlorides (R = R F , R 1 = aryl or alkyl) and in the sulfoxide 30, and require an excess of LDA.The reaction does not affect the configuration of the sulfur atom, and gives β-iminosulfoxides with optical purities comparable to those of the starting sulfoxide.29a β-Iminosulfoxides can also easily be converted into the corresponding sulfinyl ketones by treatment with mineral acid.However, these methods do not provide a general route to C-imidoylation of sulfoxides because method (i) is limited mainly to fluorinated imidoyl chlorides, and the yields of method (ii) are greatly influenced by the nature of the methylsulfinyl carbanion (R 2 = alkyl, aryl) for reasons which are not explained by the authors.

Scheme 10
Recently, we have reported the reaction of sulfoxides with potassium t-butoxide followed by imidoylbenzotriazole 21 to give β-iminosulfoxides 32 in 48-78% yields (Scheme 11).23a The reaction required 2 h at 20 °C to reach completion and worked well with both alkyl and aryl substituents (R 1 , R 2 = alkyl, aryl).

Scheme 12
The benzotriazole methodology allows the one step preparation of ketene aminals 35 in 27-32% yields: 35 C-aminoimidoylations of ketones have been achieved at 20 °C using benzotriazole-1-carboxamidines 34 (Scheme 13); the reactions occurred with both aromatic and aliphatic substituents.

Conclusions
A short review of imidoylation reactions at carbon is presented and the most significant literature reactions considered and summarized.