New frontiers in allylic C––H amination via palladium/sulfoxideoxazoline catalysis

Direct allylic C––H functionalization of terminal olefin represents an orthogonal approach to traditional methods to build C––O, C––N and C—C bond due to less oxidation state manipulation and synthetic overhead. In particular, site, chemo- and stereoselective methods for Pd(II)-catalyzed allylic C––H amination exists. However, all these reactions proceed via near ligandless conditions (e.g. reversibly coordinating sulfoxide ligands) and require benzoquinone oxidant to coordinate to Pd metal to promote the functionalization step (known as “serial ligand catalysis). This mechanism with sulfoxide ligands renders catalyst deactivation and the ability to tune the functionalization step limited. This work describes the development of racemic sulfoxide-oxazoline (SOX) ligands for Pd(II) catalyzed allylic C––H amination. By combining sulfoxide moiety, known for promoting heterolytic allylic C—H cleavage and oxazoline moiety, a stronger coordinating element that can keep the ligand associating with the Pd metal, we create a highly modular, oxidative stable ligand platform that is capable to support both Pd(II) and Pd(0) processes in allylic C––H amination. The first chapter of this dissertation describes the development of a general strategy for C––H to C––N coupling of sulfonamides with olefins via Pd(II)/ (±)-MeO-SOX catalysis. Due to the ubiquity of C—N bonds in natural products and pharmaceuticals, the cross-coupling of amines with hydrocarbons under fragment coupling conditions (1 equivalent) stands to significantly impacted chemical synthesis. Herein, we disclose a C(sp3)—N fragment coupling reaction between abundant terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/(±)-MeO-SOX catalyzed intermolecular allylic C––H amination. A range of (56) allylic amines are furnished in good yields (avg. 76%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E:Z). For the first time, a variety of singly activated aromatic and aliphatic nitrogen nucleophiles, including ones with stereochemical elements, can be used in fragment coupling stoichiometries for intermolecular C––H amination reactions. Mechanistic studies reveal that the SOX ligand framework is effective in promoting functionalization by supporting cationic -allyl Pd intermediates. The second chapter of this dissertation describes the development of a Pd(II)/(±)-MeO-SOX/2,5-dimethylbenzoquinone condition for intramolecular C––H amination that enables unprecedented access to anti-1,3 amino alcohols in good yields (33 substrates, avg. 66%) and high selectivities (avg. 10:1 dr). Switching ligand to (±)-CF3-SOX using a less bulky quinone oxidant (BQ), the kinetic syn- 1,3 amino alcohol motif can be accessed in comparable yields and selectivities. Advantages of stereodivergent nature of this allylic C––H amination method are showcased in the synthesis of anti- and syn- 1,3-amino alcohol Vitamin D3 analogue intermediates in half the steps and higher overall yield of previous route. Moreover, all eight possible stereoisomers of a medicinally important chiral diamino alcohol core are generated from two chiral pool amino acids. Mechanistic studies revealed that the anti-oxazinanone is furnished through C—H amination that furnishes the syn-isomer followed by Pd(0)-isomerization process promoted by the electron rich (±)-MeO-SOX ligand and a bulky quinone oxidant.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2019

Author dc:creator

• Ma, Rulin

Contributors dc:contributor

• White, Maria Christina
• Burke, Martin D.
• Hergenrother, Paul J.
• Sarlah, David

• ALLYLIC C––H AMINATION
• PALLADIUM/SULFOXIDE-OXAZOLINE CATALYSIS
• anti-1,3 amino alcohol
• syn- 1,3-amino alcohol
• Vitamin D3 analogue
• chiral diamino alcohol
• quinone oxidant
• (±)-MeO-SOX
• (±)-CF3-SOX
• 2,5-dimethylbenzoquinone
• 1,4 benzoquinone

Statement dc:rights

• Copyright 2019 Rulin Ma

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/105195

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/105195