Modular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagents
<p>In this thesis, novel methods for the synthesis of sulfondiimines and sulfondiimidamides are described. The use of sulfinylamine linchpins in combination with commercially available organometallic reagents and amines provides access to a broad range of sulfondiimines and sulfondiimidamides....
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2022
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| _version_ | 1797112075067064320 |
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| author | Zhang, Z |
| author2 | Willis, M |
| author_facet | Willis, M Zhang, Z |
| author_sort | Zhang, Z |
| collection | OXFORD |
| description | <p>In this thesis, novel methods for the synthesis of sulfondiimines and sulfondiimidamides are described. The use of sulfinylamine linchpins in combination with commercially available organometallic reagents and amines provides access to a broad range of sulfondiimines and sulfondiimidamides.</p>
<p>Chapter 1 provides an overview of the properties of S(VI)-functionalities such as sulfoximines, sulfonimidamides, sulfondiimines and sulfondiimidamides, as well as synthetic strategies to access them.</p>
<p>Chapter 2 documents a novel strategy for the preparation of sulfondiimines. A stable sulfinylamine linchpin, N-sulfinyl-tert-octylamine (t-Oct-NSO), is selected as the starting reagent. The combination of two different organometallic reagents with t-Oct-NSO in the presence of Lewis acid generates the sulfilimine intermediate. This is followed by a rhodium-catalysed imination, providing a broad range of orthogonal N-protected sulfondiimines. Deprotection and various functionalisation reactions provide the most diverse range of sulfondiimines to date.</p>
<p>Chapter 3 describes the exploration of a novel functional group, sulfondiimidamides, which are the di-aza analogues of widely explored sulfonamides. The combination of t-Oct-NSO with LiHMDS, TMSCl and various organometallic reagents provides the corresponding N-t-Oct primary sulfinamidines. Protection with a nosyl group provides orthogonally N-protected sulfinamidines. Oxidative fluorination followed by Ca(NTf2)2-mediated amination converts the sulfinamidines to the corresponding sulfondiimidoyl fluorides and sulfondiimidamides, respectively. Imidazole-substituted sulfondiimidamides are also shown to be effective intermediates, allowing primary amines and challenging N-nucleophiles to be used. A series of deprotection and further functionalisation reactions using sulfondiimidamides are described, indicating the possible application of these interesting functional groups in the pharmaceutical industry. An analogue of the COX-2 inhibitor, Celecoxib, was prepared using this methodology.</p>
<p>Chapter 4 details the discovery of a novel sulfinylamine linchpin, N-sulfinyl-triisopropylsilylamine (TIPS-NSO). The reaction of the TIPS-NSO with LiHMDS, TMSCl and various organometallic reagents followed by N-protection and N-TIPS deprotection, enables the synthesis of N-substituted primary sulfinamidines. A robust sulfondiimidamide synthesis method is developed from these primary sulfinamidines via PhI(OAc)2-promoted amination. Celecoxib analogue is prepared using this methodology in only four steps, and a sulfondiimidamide analogue of Sildenafil is accessed in just two steps.</p>
<p>Chapter 5 discusses the conclusion of our research and future plans.</p>
<p>Chapter 6 presents the experimental procedures and data.</p> |
| first_indexed | 2024-03-07T08:19:20Z |
| format | Thesis |
| id | oxford-uuid:df671c83-f44e-41eb-8236-702c5511df38 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:19:20Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:df671c83-f44e-41eb-8236-702c5511df382024-01-17T08:42:35ZModular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagentsThesishttp://purl.org/coar/resource_type/c_db06uuid:df671c83-f44e-41eb-8236-702c5511df38Chemistry, OrganicEnglishHyrax Deposit2022Zhang, ZWillis, M<p>In this thesis, novel methods for the synthesis of sulfondiimines and sulfondiimidamides are described. The use of sulfinylamine linchpins in combination with commercially available organometallic reagents and amines provides access to a broad range of sulfondiimines and sulfondiimidamides.</p> <p>Chapter 1 provides an overview of the properties of S(VI)-functionalities such as sulfoximines, sulfonimidamides, sulfondiimines and sulfondiimidamides, as well as synthetic strategies to access them.</p> <p>Chapter 2 documents a novel strategy for the preparation of sulfondiimines. A stable sulfinylamine linchpin, N-sulfinyl-tert-octylamine (t-Oct-NSO), is selected as the starting reagent. The combination of two different organometallic reagents with t-Oct-NSO in the presence of Lewis acid generates the sulfilimine intermediate. This is followed by a rhodium-catalysed imination, providing a broad range of orthogonal N-protected sulfondiimines. Deprotection and various functionalisation reactions provide the most diverse range of sulfondiimines to date.</p> <p>Chapter 3 describes the exploration of a novel functional group, sulfondiimidamides, which are the di-aza analogues of widely explored sulfonamides. The combination of t-Oct-NSO with LiHMDS, TMSCl and various organometallic reagents provides the corresponding N-t-Oct primary sulfinamidines. Protection with a nosyl group provides orthogonally N-protected sulfinamidines. Oxidative fluorination followed by Ca(NTf2)2-mediated amination converts the sulfinamidines to the corresponding sulfondiimidoyl fluorides and sulfondiimidamides, respectively. Imidazole-substituted sulfondiimidamides are also shown to be effective intermediates, allowing primary amines and challenging N-nucleophiles to be used. A series of deprotection and further functionalisation reactions using sulfondiimidamides are described, indicating the possible application of these interesting functional groups in the pharmaceutical industry. An analogue of the COX-2 inhibitor, Celecoxib, was prepared using this methodology.</p> <p>Chapter 4 details the discovery of a novel sulfinylamine linchpin, N-sulfinyl-triisopropylsilylamine (TIPS-NSO). The reaction of the TIPS-NSO with LiHMDS, TMSCl and various organometallic reagents followed by N-protection and N-TIPS deprotection, enables the synthesis of N-substituted primary sulfinamidines. A robust sulfondiimidamide synthesis method is developed from these primary sulfinamidines via PhI(OAc)2-promoted amination. Celecoxib analogue is prepared using this methodology in only four steps, and a sulfondiimidamide analogue of Sildenafil is accessed in just two steps.</p> <p>Chapter 5 discusses the conclusion of our research and future plans.</p> <p>Chapter 6 presents the experimental procedures and data.</p> |
| spellingShingle | Chemistry, Organic Zhang, Z Modular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagents |
| title | Modular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagents |
| title_full | Modular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagents |
| title_fullStr | Modular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagents |
| title_full_unstemmed | Modular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagents |
| title_short | Modular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagents |
| title_sort | modular sulfondiimine and sulfondiimidamide synthesis using stable sulfinylamine reagents |
| topic | Chemistry, Organic |
| work_keys_str_mv | AT zhangz modularsulfondiimineandsulfondiimidamidesynthesisusingstablesulfinylaminereagents |