Amine nucleophiles homologation

Disadvantages of the silver-promoted method for Amdt-Eistert homologation are the large excess of nucleophile required and also the requirement for the use of the free amine during peptide formation procedures. 13 Activation of the diazo ketone by UV light has been shown to be suitable for this type of procedure and good yields are obtained using only 1.2 equivalents of a hydrochloride salt of an amino ester in the presence of triethylamine (Scheme 5). 14 ... 

The Arndt-Eistert Synthesis allows the formation of homologated carboxylic acids or their derivatives by reaction of the activated carboxylic acids with diazomethane and subsequent Wolff-Rearrangement of the intermediate diazoketones in the presence of nucleophiles such as water, alcohols, or amines. 

The key step of the Amdt-Eistert Homologation is the Wolff-Rearrangement of the diazoketones to ketenes, which can be accomplished thermally (over the range between r.t. and 750°C, photochemically or by silver(I) catalysis. The reaction is conducted in the presence of nucleophiles such as water (to yield carboxylic acids), alcohols (to give alcohols) or amines (to give amides), to capture the ketene intermediate and avoid the competing formation of diketenes. 

The reaction was extensively studied for cinnamyl esters (acetate and carbonate) as allylic substrates, with some examples given for allyl acetate and its homologs, and a wide range of nucleophiles including N-nucleophiles (primary and secondary amines, hydroxylamine and its derivatives, and sodium azide), C-nucleophiles (malonates, ethyl acetoacetate, acetylacetone, sodium tetraphenylborate) and an S-nucleophile (sodium p-toluenesulfinate) (Scheme 5.4). 

Ley and coworkers have been quite active in this field, and have found that 30 or its homolog could efficiently promote asymmetric Michael addihon reactions using various Michael acceptors and donors [164b, 175]. In these cases, the reactions require the use of a basic amine such as fran.s-4,5-dimethylpiperazine as a co-catalyst to increase the nucleophilicity of donor molecules by deprotonation. Typical examples are shown in Scheme 1.9. 

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