0-Cresol Mannich reaction

Thus, reduction of the Mannich reaction product (65) from acetophenone leads to alcohol 66. Replacement of the hydroxyl group by chlorine (67) followed by displacement of halogen with the anion from o-cresol affords the ether 68. Removal of one of the methyl groups on nitrogen by means of the von Braun reaction or its modem equivalent (reaction with alkyl chloroformate followed by saponification) leads to racemic 69 which is then resolved with L-(+)-mandelic acid to give the levorotary antidepressant tomoxetine (69) [16]. 

Aromatic Mannich reactions have been reviewed290. Recent examples are the formation of 254 from p-cresol, paraformaldehyde and 1-methylpiperazine and of 255 from salicylaldehyde, aqueous formalin and 1-methylpiperazine291. 

Methylthymol blue and methylxylenol blue, prepared by the Mannich reaction from thymol-sulfonphthalein and p- xylenol blue respectively, have been intensively studied and resemble xylenol orange in many respects. If only one chelating group is introduced into cresol red, semi-xylenol orange results which is a common contaminant in XO and proves to be a more sensitive reagent for zirconium. 

Other modifications of the polyamines include limited addition of alkylene oxide to yield the corresponding hydroxyalkyl derivatives (225) and cyanoethylation of DETA or TETA, usuaHy by reaction with acrylonitrile [107-13-1/, to give derivatives providing longer pot Hfe and better wetting of glass (226). Also included are ketimines, made by the reaction of EDA with acetone for example. These derivatives can also be hydrogenated, as in the case of the equimolar adducts of DETA and methyl isobutyl ketone [108-10-1] or methyl isoamyl ketone [110-12-3] (221 or used as is to provide moisture cure performance. Mannich bases prepared from a phenol, formaldehyde and a polyamine are also used, such as the hardener prepared from cresol, DETA, and formaldehyde (228). Other modifications of polyamines for use as epoxy hardeners include reaction with aldehydes (229), epoxidized fatty nitriles (230), aromatic monoisocyanates (231), or propylene sulfide [1072-43-1] (232). 

Saheki. Y.. Kimura, M., and Negoro, K., Meashutkin reaction of Mannich bases derived from p-cresol and antimicrobial activities of their quaternary ammonium. salts, Nippon Kaguku Kaishi. 1123, 1978 Chem. Ahstr.. 89, 163167, 1978. 

The use of a zirconium catalyst derived from BINOL (Lj in Scheme 11.4 10 mol%) as promoter for the three-component Mannich-type reaction of 5-hexynal, 2-amino-m-cresol and the ketene silyl ketal derived from phenyl propionate provided an efficient and simple protocol for the preparation of a new p-amino acid derivative (>99% yield, 82% de, 99% ee), which was essential for the total synthesis of onchidin, a cytotoxic, C2-symmetric, cyclic decadepsipeptide isolated from a marine mollusk [16]. 

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