Catalytic Strategies for Remote C-H Functionalization of Alcohols and Amines
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The Ohio State University / OhioLINK
2020
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1587554146078308 |
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English |
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Chemistry |
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Chemistry Stateman, Leah Marie Catalytic Strategies for Remote C-H Functionalization of Alcohols and Amines |
| author |
Stateman, Leah Marie |
| author_facet |
Stateman, Leah Marie |
| author_sort |
Stateman, Leah Marie |
| title |
Catalytic Strategies for Remote C-H Functionalization of Alcohols and Amines |
| title_short |
Catalytic Strategies for Remote C-H Functionalization of Alcohols and Amines |
| title_full |
Catalytic Strategies for Remote C-H Functionalization of Alcohols and Amines |
| title_fullStr |
Catalytic Strategies for Remote C-H Functionalization of Alcohols and Amines |
| title_full_unstemmed |
Catalytic Strategies for Remote C-H Functionalization of Alcohols and Amines |
| title_sort |
catalytic strategies for remote c-h functionalization of alcohols and amines |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2020 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1587554146078308 |
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AT statemanleahmarie catalyticstrategiesforremotechfunctionalizationofalcoholsandamines |
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1719457215059853312 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu15875541460783082021-08-03T07:14:39Z Catalytic Strategies for Remote C-H Functionalization of Alcohols and Amines Stateman, Leah Marie Chemistry The ability to exchange carbon-hydrogen (C-H) bonds with modular functional group handles represents a powerful strategy to expedite molecular diversification. Nonetheless, such transformations remain a major challenge in organic synthesis. The challenge lies within the inert nature of C-H bonds, as represented by their high bond dissociation energy (e.g. unactivated C-H bonds 98-100 kcal/mol). Additionally, as C-H bonds are the most common structural motif found in organic molecules, their selective differentiation (i.e. regio- and chemo- selectivity) is often problematic. To overcome these obstacles, we have developed a series of radical chaperones that facilitate C-H functionalization of beta or delta sites of readily available starting materials, thus expanding the toolbox of C-H functionalization.To achieve this goal, radical-mediated strategies were investigated, which were inspired by the century-old Hoffman-Loffler-Freytag (HLF) reaction. In this original example of remote C-H amination, the desired reactivity and selectivity was achieved by utilizing electrophilic N-centered radicals that undergo selective 1,5-hydrogen atom transfer (HAT). Thus, a C-H bond is abstracted and transposes the open-shell radical to the delta position relative to the nitrogen atom. With this knowledge in hand, we began strategizing methods to leverage electrophilic radicals for the development of selective C-H functionalizations: including beta-amination (Ch 2-3), delta-arylation (Ch 4), and delta-desaturation (Ch 5). Due to the prevalence of 1,2-amino alcohols in drugs, the beta-amination of readily available alcohols was investigated (Ch 2). In our first-generation protocol, it was discerned that imidates served as efficient radical chaperones, however, the transformation initially required super-stoichiometric oxidants. Therefore, an iodine-catalyzed protocol was developed, which we hypothesized would limit the amount of oxidative decomposition. After extensive investigation, it was determined that catalytic beta-amination of alcohols could be efficiently achieved with catalytic iodine (1-5%). Under this oxidative manifold, a series of imidate-mediated beta C-H aminations afforded a range of 1,2-amino alcohols and several mechanistic attributes of this transformation were studied.Next, we developed an enantioselective variant of this beta C-H amination (Ch 3). Whereas our iodine-catalyzed protocol provided a streamlined synthesis of a variety amino alcohol derivatives, the formation of the C-N bond was racemic due to the lack of chirality in C-radical trapping step. Therefore, we began exploring an alternate system to impart enantiocontrol. We found a dual catalytic manifold (Ir and CuL*) is effective in providing high yields of C-H amination, in addition to high enantioselectivities (up to 99% ee). Mechanistic experiments reveal triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity, enabling the synthesis of several important classes of chiral beta amines by enantioselective, radical C-H amination. In addition to beta-amino alcohols, many amine containing heterocycles are prevalent in top-selling drug motifs. Therefore, we sought to develop strategies to expedite the synthesis of amines through C-H functionalization (Ch 4). To this end, we have developed several methods to interrupt the HLF reaction, thus circumventing the typical products of an oxidative manifold, C-H amination or halogenation. Employing a reductive protocol and an N-F sulfonamide radical precursor, a Cu-catalyzed delta-arylation was achieved. The radical relay is both initiated and terminated by the Cu catalyst, which enables incorporation of arenes and heteroarenes by cross-coupling with boronic acids. The broad scope and utility of this catalytic method for delta C–H arylation is explored, along with mechanistic probes for selectivity of the HAT mechanism. A catalytic, asymmetric variant is also presented, as well as a method for accessing diaryl-pyrrolidines via iterative delta functionalizations.Finally, since alkenes provide a platform for di-functionalization, a remote desaturation of amines was developed using this Cu-catalyzed HAT strategy (Ch 5). This was achieved by cooperative catalysis via Ir and Cu and proceeds upon photoinitiation and reduction of Ir, which subsequently reduces the N-F bond. After the electrophilic radical undergoes an HAT, a Cu(II) catalyst traps the resulting carbon radical. Furthermore, elimination of the organometallic species can provide the unsaturated product and turnover the Cu(I) catalyst. The broad scope of this catalytic manifold for distal desaturation is showcased with a variety of aliphatic amines. Additionally, the utility of the unsaturated product was explored and a series of valuable heterocyclic cores and amine derivatives were synthesized.It is anticipated that these approaches will streamline the synthesis of biologically relevant pharmacophores and novel motifs, and the mechanistic findings will spur further development of C-H functionalization. 2020-09-25 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1587554146078308 http://rave.ohiolink.edu/etdc/view?acc_num=osu1587554146078308 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |