Discovery, Development, and Applications of New Linchpin Reagents for NCO and NCS-Containing Molecules

Abstract

The NCO subunit is among the most prevalent structural motifs in natural products and pharmaceuticals. It is therefore surprising that no single existing method provides simple, modular access to all classes of NCO-containing products from a single, bench-stable reagent through sequential, chemoselective bond-forming events. This thesis presents the discovery, development, and application of three complementary linchpin reagents that address the unmet need of modular strategies for the synthesis of NCO- and NCS-containing molecules.

In Chapters 2 and 3, a first-generation biselectrophilic NCO linchpin strategy employing masked O-isocyanates was investigated through two distinct bond-forming sequences: C-C bond formation followed by C-N bond formation (Path A), or the opposite sequence (Path B). Conceivably, both pathways could form amides, motivating parallel exploration and development. Despite providing design principles for future linchpin reagents and establishing a proof-of-concept that masked O-isocyanates can be linchpin reagents, Path A was invalidated due to intrinsic chemoselectivity limitations of the Cu-mediated electrophilic amidation step (Chapter 2). Inversion of the bond-forming sequence to Path B enabled a Rh(III)-catalyzed electrophilic amination of aryl and alkenyl boronic acids, furnishing bench-stable masked C-isocyanates in near-quantitative yields (Chapter 3). These intermediates underwent controlled isocyanate release and subsequent Grignard addition to furnish sterically hindered and electron-deficient secondary amides, including products that are difficult to access from traditional amide bond-forming reactions. The reactive magnesium amidate formed during Grignard addition was further trapped with electrophiles, both inter- and intramolecularly, enabling the synthesis of tertiary amides and lactams, respectively. Moreover, the broad utility of the linchpin strategy was demonstrated by expanding the scope of accessible products to include unsymmetrical ureas.

To address the poor atom economy, need for an expensive Rh(III) catalyst, and incompatibility with N-sp³-C bond formation associated with the electrophilic amination step of the first-generation strategy, a second-generation amphoteric linchpin strategy was developed in Chapter 4. After initial experiments with cyanate salts (conceptually, the most atom-economical NCO linchpin reagent) revealed poor selectivity, efforts focused on development of phenyl carbamate as a "masked" cyanate equivalent that readily underwent amination reactions to provide N-alkyl carbamates as intermediates, which were converted into NCO-containing products. A proof-of-concept reaction established modular access to lactams via a Parham-type cyclization, which were inaccessible with the first-generation strategy. Moreover, two sets of selective conditions for the synthesis of N-alkyl unsymmetrical ureas were developed to address the limitations of the first-generation conditions with N-alkyl carbamates.

Chapter 5 extends the linchpin concept to the NCS subunit, motivated by the pharmaceutical importance of thioamides and thioureas. Thiocyanate salts were developed as NCS linchpin reagents because they are inexpensive, bench-stable, and highly atom-economical. Systematic optimization revealed that selective N-alkylation to form isothiocyanates is controlled by the substitution pattern of the electrophile and the nature of the alkylation mechanism. A two-step, one-pot protocol was developed for the synthesis of thioamides via Grignard addition to in situ generated isothiocyanates. The utility of the approach beyond thioamides was demonstrated with a preliminary scope of thioureas, and the formation of a 2-aminobenzimidazole heterocycle through intramolecular thiourea condensation.

Collectively, the three linchpin strategies presented in this thesis, first-generation masked O-isocyanates (biselectrophilic, NCO), second-generation phenyl carbamates (amphoteric, NCO), and thiocyanate salts (amphoteric, NCS), progressively satisfy the linchpin design criteria of bench stability, chemoselectivity, and product diversity. This work establishes linchpin strategies as powerful methods to access diverse classes of molecules containing a single similar recognizable core unit.