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Title: Silicon-containing catalysts and reagents for the direct amidation of carboxylic acids
Author: Rowley, Ben
ISNI:       0000 0004 9350 1487
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The work described in this thesis addresses the problems associated with direct amide synthesis using silicon compounds as catalysts or reagents. This thesis has been separated into five major parts and includes appendices, catalogued experimental procedures and spectroscopic data. Initial investigations concerned the study and development of molecular silanols as novel direct amidation catalysts. Reactivity screening of architecturally varied silanols against the identified model reaction between phenylacetic acid and 4-methylbenzylamine in refluxing toluene revealed Ph3SiOH as the most active silanol examined compared to the background amide conversion (25 vs 11% respectively). Synthesis of conceivable intermediates, triphenylsilyl 2-phenylacetate and N-(4-methylbenzyl)-triphenylsilanamine was conducted, and their implication during catalysis was assessed, revealing a plausible catalytic pathway via the aminolysis of catalytically generated silylesters. Further synthesis and assessment of a variety of electronically diverse tri-aryl silanols was conducted, revealing a substituent-reactivity relationship in which more electron-deficient silanols provided greater model amide conversion in this system, although, increased silanol decomposition was accompanied by increased silanol electrophilicity, measured by DFT calculations and Hammett substituent constants. This discovery led to the application of the relatively inexpensive and commercially available tetramethylorthosilicate (Si(OMe)4), as an overlooked direct amidation coupling reagent, providing a variety of amides in excellent to quantitative isolated yields and high purity upon simple work up. The methodology was also successfully applied to the synthesis of the antidepressant, moclobemide and the viable anti-arrhythmic procainamide precursor, N-(2-(diethylamino)ethyl)-4-nitrobenzamide. Furthermore, optimisation of this method, utilising 4Ǻ molecular sieves, allowed the generally difficult coupling of benzoic acids and anilines in quantitative yields within 24 h.
Supervisor: Braddock, D. Christopher ; Lickiss, Paul D. Sponsor: Pfizer Ltd ; Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral