Orthoesters malonate

Wolfbeis investigated the reactions of amines and orthoesters with different CH-acid molecules (81CB3471). When the reactions of aniline, ethyl orthoformate, and dialkyl malonates (2 mol) were carried out at 130-140°C for 4 hr, phenylaminomethylenemalonamates (245) were obtained (81CB3471). Similar reactions with aliphatic amines were unsuccessful. Phenylaminomethylenemalonic acid could not be prepared in the reactions of aniline, methyl orthoformate or orthoacetate, and malonic acid. When these reactions were carried out in 2-propanol, only amidines (246) were obtained. 

Scheme 1. Principle of cyanine dye synthesis leading to trimethine (n = l), pentamethine (n = 2) and heptamethine (n = 3) chromophores. Structures comprising indolic subunits are usually named indocarbocyanine, indodicarbocyanine and indotricarbocyanine, respectively. Formic acid, malonic aldehyde, glutaconic aldehyde are used in their protected dianUide or orthoester form. They can be applied as substituted derivatives to introduce residues into the polymethine unit. The indolic substructure might bear further residues or annelated aromatic rings...

Other examples are acetoacetates alkylamines and alkylhalides/acid halides ethers esters chloroformates ketones lactames lactones malonates mercaptanes and orthoesters in aliphatics catechol/hydroquinone/resorcinol, cresidines haloaromatics in aromatics and coumarines, cyanuric chloride, picolines, quinolines, and thiazoles in heterocylics. 

Reactivity is normally enhanced by quatemization [77HC(30)179]. In this case a methyl group at C-7 seems to be the most reactive toward both benzaldehydes (74KGS565) and orthoesters or malonic bisacetal (88UKZ880). Bis-quaternized methylene 2,2 -bis-TPs are attacked by benzaldehydes at the methylene carbon instead of the methyl group (82UKZ79). 

The alcohol 470 was prepared from the mesylate 469 by reaction with diethyl malonate followed by reduction to give 470, whose selective acetylation was carried out by reaction with trimethyl orthoacetate followed by acid hydrolysis of the cyclic orthoester intermediate. Bromination and then coupling gave 471 [88JCS(P1)2757]. 

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