1-sulfonyl-1,2,3-triazoles: versatile carbene precursors for the functionalisation of simple building blocks

Williams, Matthew B. (2023) 1-sulfonyl-1,2,3-triazoles: versatile carbene precursors for the functionalisation of simple building blocks. PhD thesis, University of Glasgow.

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Electronically biased 1,2,3-triazoles undergo ring–chain tautomerisation which allows access to the corresponding diazoimine intermediates. In the presence of suitable catalysts, these intermediates undergo metal-catalysed denitrogenation to generate metallocarbenes. In particular, metallocarbenes generated from 1-sulfonyl-1,2,3-triazoles (1-STs) are capable of undergoing a diverse range of synthetically useful transformations and have emerged as a new staple in metallocarbene chemistry (Scheme A). 1-STs with a substituent at the 4-position are commonly prepared from readily available sulfonyl azides and terminal alkynes by the copper-catalysed alkyne azide cycloaddition (CuAAC) reaction, whereas 1-STs that have 5- or 4,5-substitution are more challenging to prepare and are underutilised compared to 4-substituted 1-STs.

In this work, strained cyclic alkynes were investigated as a means of preparing 1-STs. Cyclooctyne and exo-BCN underwent strain-promoted alkyne azide cycloaddition (SPAAC) with sulfonyl azides, yielding the corresponding 1-sulfonylcyclooctatriazoles in excellent yield (Scheme B). When treated with a chiral rhodium(II) carboxylate catalyst, cyclooctyne derived 1-STs underwent a 1,5- C–H insertion reaction to generate [3.3.0]-bicyclic products diastereoselectively with good yield and very high ee. For 1-STs prepared from exo-BCN, a 1,2-H shift occurred in moderate yield. The relative rate of cycloaddition between different sulfonyl azides and these cyclic alkynes was investigated using a combination of 1H NMR experiments and in situ reaction monitoring using IR spectroscopy, revealing that more electron poor sulfonyl azides reacted faster. The transition state structures for the cycloadditions involving mesyl azide were evaluated computationally and frontier molecular orbital analysis was carried out, showing that electron-poor sulfonyl azides were a better energy match for the strained alkynes in an inverse electron demand mechanism.

Separately, the use of a polymer-supported sulfonyl azide was investigated in 1-ST preparation (Scheme C). A polymer-supported sulfonyl azide was successfully prepared but CuAAC with terminal alkynes was very challenging. Successful cycloaddition was carried out with cyclooctyne at elevated temperatures although the polymer-supported 1-ST did not undergo any denitrogenative transformation.

Additionally, the reactivity of acceptor/acceptor carbenoids generated 1-STs with a 4-acyl substituent was investigated. The 4-acyl substitution meant that the metallocarbenes were highly electrophilic and underwent insertion into aromatic C(sp2 )–H bonds (Scheme D). Functionalisation of polycyclic aromatic systems was investigated but the regioselectivity proved difficult to control. Functionalisation of alkene π-bonds was also investigated and similar problems with regioselectivity were encountered.

When electron-rich alkenes such as enol ethers were used, an interesting change in chemoselectivity was observed that gave rise to dihydrofuran motifs. This mode of reactivity was unprecedented for 1-STs and was extended to the preparation of other oxygen heterocycles including furans and oxazoles (Scheme E). Control over the chemoselectivity was examined by careful tuning of the stereoelectronics of both the sulfonyl group and substituent at the 4-position. Using a large sulfonyl group and gold(I) additive was important for controlling the selectivity in the transannular reaction with nitriles to afford oxazoles.

Finally, a new approach to 3-azapyrroles was established. The 3-azapyrrole scaffold makes up the core of several biologically active compounds but there are few existing synthetic approaches. A general three step sequence was developed consisting of CuAAC between sulfonyl azides and terminal alkynes, rhodium(II)-catalysed N–H bond insertion and Lewis acid promoted cyclodehydration (Scheme F). These three steps could be telescoped into a single pot and the method was highly efficient with good functional group tolerance. The ready availability of individual substrates means that this method represented a modular approach to pyrroles allowing each position on the product heterocycle to be customised based on judicious choice of starting materials.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Boyer, Dr. Alistair
Date of Award: 2023
Depositing User: Theses Team
Unique ID: glathesis:2023-83518
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 03 Apr 2023 10:11
Last Modified: 20 Apr 2023 11:56
Thesis DOI: 10.5525/gla.thesis.83518
URI: https://theses.gla.ac.uk/id/eprint/83518
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