Amides are one of the most common functional groups in biological systems and in
bioactive molecules. Arguably the most direct way to form amides is via the condensation of an
amine onto a carboxylic acid. This reaction is notoriously difficult and has stimulated much
development, including the developments of new reagents and catalysts to perform this
transformation under milder conditions. More broadly, amide formation continues to be of high
importance and the incorporation of emerging transformations utilizing new disconnections are
complimentary to existing routes.
Isocyanates are the simplest electrophiles containing the desired NCO motif and have a
large presence in the polymer (e.g. polyurethane) and paint industries. In addition, isocyanates
have been utilized for amide formation with various nucleophiles in a stoichiometric and catalytic
fashion, but the inherent functional group intolerance associated with the high reactivity of
isocyanate largely remains. Efforts have been made to address such limitations of isocyanates,
including the use of a blocking group which allow for in situ release of the isocyanate while using
a bench stable masked (blocked) isocyanate precursor. Changes to the blocking group structure
have direct correlations to the stability and reactivity of the precursor, which helps in suppressing
common side reactions observed with free isocyanates such as polymerization or oligomerization.
Incorporation of a blocking group strategy in catalytic amide forming reactions has the
power to unlock the potential of isocyanates with reactivity that would not be attainable with free
isocyanates. Reports imparting this strategy exemplify the power of a blocking group with
increased applicability and functional group tolerance compared to reactions with the free
isocyanate counterpart. The implementation of this strategy for catalytic amide formation is sparse
including only two reports with a rhodium catalyst. Utilization of different metals could broaden
the scope of reactivity allowing for extensions that the rhodium (I) catalyst cannot do.
The development of a palladium-catalyzed amide synthesis via masked isocyanates was
targeted (Chapter 2). Indeed, implementation of a blocking group strategy with alkyl and aryl
isocyanates allowed for efficient synthesis of amides with electron rich and mildly deficient aryl
boroxine nucleophiles. Catalysis was achieved with 1 mol% of Pd(OAc)2 and 2 mol% of SPhos at
50 ℃ with Et3N to aid in the deblocking of the isocyanate. Several control experiments were
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conducted to obtain mechanistic insight including what mechanism may be operative as well as
the necessity of this blocking group strategy. Kinetic studies were performed using the variable
time normalization analysis method and have yielded the following information: 1) the presence
of catalyst decomposition, 2) that the rate determining step involved the catalyst, boroxine, and
masked isocyanate, and 3) that the rate determining step is likely the insertion into the isocyanate.
In summary, palladium catalysts can achieve catalysis with masked isocyanates to facilitate
amide formation under appropriate conditions. With limited reports of masked isocyanates in
catalysis, this reactivity could act as a steppingstone for developments of reactivity that are held back with the use of free isocyanates.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/41598 |
| Date | 22 December 2020 |
| Creators | Brzezinski, David |
| Contributors | Beauchemin, André |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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