Chemistry and Chemical Biology ETDs

Publication Date

5-1-2018

Abstract

Development of sustainable synthetic technologies for molecular construction is an important but formidably challenging task in modern organic synthesis. Aldehyde synthesis represents a long-standing interest in synthesis because of the synthetic utility. Classic methods for aldehyde synthesis have the drawbacks of the use of harsh reaction conditions, poor atom-economy and multi-step operation, and production of stoichiometric amount of chemical wastes. The state-of-the-art strategies employ transition metal complexes as catalysts to promote formylation reactions. The concerns of catalyst cost, operation complexity and poor functional group tolerance demands more efficient synthetic technologies. My Ph.D. study focuses on design of conceptually novel catalytic systems, invention of reagents and exploration of new reactivities to create unprecedented processes the synthesis of fundamentally important class of chemicals - aldehydes with the emphasis on sustainability, selectivity, practicality and utility. A conceptually novel organocatalytic strategy for formylation of boronic acids is developed. In the process, a new reactivity is engineered into the α-amino acid forming Petasis reaction occurring between aryl boron acids, amines and glyoxylic acid. The feasibility and preparative power of the protocol has been demonstrated by its use to prepare aldehydes from broadly accessible aryl and alkenyl boronic acids, glyoxylic acid, and the cheap N-alkylaniline derivatives, tetrahydroquinoline and indoline, as catalysts. Furthermore, the operational simplicity of the process, which is performed by simply mixing these reagents under ambient conditions, and its ability to generate structurally diverse and valued aryl, heteroaryl and α,β-unsaturated aldehydes containing a wide array of functional groups, demonstrates the practical utility of the newly unveiled synthetic strategy. A simple formylation reaction of aryl halides, aryl triflates and vinyl bromides using synergistic nickel and organic dye mediated photoredox catalysis has been realized. Distinct from widely used palladium catalyzed formylation processes, this reaction proceeds by way of a two step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by 1,2,3,5-tetrakis-(carbazol-yl)-4,6-dicyanobenzene (4CzIPN) mediated photoredox reaction. The formyl radical equivalent then undergoes nickel catalyzed substitution reactions with aryl halides and triflate and vinyl bromides to form the corresponding aldehyde products. Significantly, in addition to aryl bromides, less reactive aryl chlorides and triflates and vinyl halides serve as effective substrates for this process. The fact that the mild conditions involved in this reaction tolerate a plethora of functional groups enables the process to be applied to the efficient preparation of diverse aromatic aldehydes. An unprecedented, chemo- and regio-selective, organo-photoredox catalyzed hydroformylation reaction of aryl olefins with diethoxyacetic acid as the formylation reagent is developed. In contrast to traditional transition metal promoted ionic hydroformylation reactions, the new process follows a unique photoredox promoted, free radical pathway. In this process, a formyl radical equivalent, produced from diethoxacetic acid through the same dye 4CzIPN photocatalyzed, sequential oxidation-decarboxylation route, regio- and chemo-selectively adds to a styrene substrate. Importantly, under the optimized reaction conditions the benzylic radical formed in this manner is reduced by SET from the anion radical of 4CzIPN to generate a benzylic anion. Finally, protonation produces the hydroformylation product. By using the new protocol, aldehydes can be generated regioselectively in up to 90% yield. A broad array of functional groups is tolerated in the process, which takes place under mild, metal free conditions. The broad synthetic utility of labile enol esters demands efficient methods for the stereo- and regio-selective synthesis of both Z and E isomers. The available synthetic methods dominated by metal catalysis cannot meet the challenge. Towards this end, we have developed a metal free organocatalytic divergent approach to both E and Z isomers of enol esters from the same reactant pools with the same catalytic system. A process involves an amine catalyzed conjugate addition of carboxylic acids to ynals, which triggers a rearrangement leading to enol esters. The reaction proceeds highly regio- and stereoselectivley. Simple manipulation of reaction temperatures enables to produce Z-isomers at 0°C (Z:E 15:1 - >20:1), whereas at higher 30°C to give E-isomers (E:Z 15:1 - >20:1). Furthermore, the mild reaction conditions accommodate a broad array of densely functionalized carboxylic acids including complex biologically relevant structures and ynals for the process. Therefore, synthetically valued, structurally diverse enol esters are efficiently synthesized. Preliminary mechanistic studies suggest an amine promoted conjugate addition-rearrangement pathway responsible for the formation of the enol esters.

Language

English

Keywords

Aldehyde, formylation, hydroformylation, photochemistry, organocatalysis, metal catalysis

Document Type

Dissertation

Degree Name

Chemistry

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Wei Wang

Second Committee Member

Patrick S. Mariano

Third Committee Member

Abhaya K. Datye

Fourth Committee Member

Fu-Sen Liang

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