Graduate Thesis Or Dissertation
 

Synthesis of novel ambifunctional atropisomeric 2,2',6,6'-tetrasubstituted biphenyls and investigation of their properties and organocatalytic activity

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  • Ambifunctional axially chiral 2,2',6,6'-tetrasubstituted biphenyls containing nucleophilic (or basic) functional groups juxtaposed with hydrogen-bond donors were synthesized and their properties studied. Applications for the prepared biaryls as potential organocatalysts for enantioselective carbon-carbon bond forming reactions were examined. Processes investigated included: aldol, Michael, nitroaldol (Henry), and Baylis-Hillman reactions. The novel amidoamine 2',6-dimethoxy-N-methyl-6'-[(methylamino)methyl]-biphenyl-2-carboxamide was prepared in 83% yield from m-anisic acid via a sequence of transformations comprising: conversion to the N-methyl-N-t-butyl amide; directed ortho-metalation (DoM) followed by FeCl₃ mediated oxidative coupling of the resulting aryllithium; removal of tert-butyl groups with TFA; and, conversion of the penultimate bis-2°-amide intermediate to the amidoamine by LiAlH₄ reduction. Single-crystal X-ray diffraction analysis revealed that the amidoamine (as TFA salt) and its bis-N-methyl-N-t-butylamide precursor, formed crystalline conglomerates. This spontaneous resolution phenomenon was exploited to obtain enantioenriched samples of both compounds by single crystal triage (100%ee for amidoamine•TFA; 20-80%ee for bisamide). The amidoamine (free base or acetate salt) catalyzed intermolecular aldol reactions between acetone and simple aldehydes in good to excellent yield (up to 84% at 10 mol% loading), but with barely discernable enantioselectivity (2-5%ee). Successful organocatalysis by the amidoamine was also observed for inter- and intra-molecular Michael reactions, including: 1,3-diketone addition to MVK and cyclization of 8-oxo-8-phenyloct-6-enal. An alternate ambifunctional biaryl containing phenolic and amino functionality, 3,3'-bis[(diethylamino)methyl]-2,2'-biphenol, was prepared in 64% yield from 2-amino-3-methoxybenzoic acid via coupling of the diazonium salt and thence bisamide formation, reduction with BH₃, and BBr₃ mediated demethylation. The same compound was also generated from m-anisic acid via the diethylamide and DoM/FeCl₃ mediated biaryl formation followed by reduction and demethylation as before. 3,3'-Bis[(diethylamino)-methyl]-2,2'-biphenol failed to catalyze the addition of nitromethane to simple aromatic aldehydes (Henry reaction). (R)-3,3'-Bis(diphenylphosphino)-2,2'-biphenol (HOBIPHEP) and its dimethyl ether [(R)-MeOBIPHEP] were evaluated as promotors for the Baylis-Hillman (BH) reaction between methyl acrylate and 5-pyrimidylcarboxaldehyde. (R)-HOBIPHEP (10 mol%) catalyzed formation of the expected BH-adduct in 47% yield but 0%ee after 20 h. Under identical conditions, (R)-MeOBIPHEP gave the same product in 23% yield and 31%ee. Bisphosphine oxides derived from HOBIPHEP and MeOBIPHEP were found to catalyze the addition of allyltrimethylsilane to N-acylhydrazones.
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