A Sulfonative rearrangement of N-Aryl Sulfamates to para-Sulfonyl Anilines

Zhou, Yifei; Jones, Alan M.

doi:10.26434/chemrxiv-2022-jc55l

Cited by 3 publications

(3 citation statements)

References 27 publications

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“…The sulfonation reaction has also been exemplified on a drug molecule, demonstrating this approach as a route to incorporate this functionality at a late stage in more complex scaffolds. This manuscript was previously a ChemRxiv pre-print [47].…”

Section: Discussionmentioning

confidence: 99%

Rearrangement of Arylsulfamates and Sulfates to Para-Sulfonyl Anilines and Phenols

Zhou,

Jones

2024

Molecules

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The C(sp2)-aryl sulfonate functional group is found in bioactive molecules, but their synthesis can involve extreme temperatures (>190 °C or flash vacuum pyrolysis) and strongly acidic reaction conditions. Inspired by the 1917 Tyrer industrial process for a sulfa dye that involved an aniline N(sp2)-SO3 intermediate en route to a C(sp2)-SO3 rearranged product, we investigated tributylsulfoammonium betaine (TBSAB) as a milder N-sulfamation to C-sulfonate relay reagent. Initial investigations of a stepwise route involving TBSAB on selected anilines at room temperature enabled the isolation of N(sp2)-sulfamate. Subsequent thermal rearrangement demonstrated the intermediary of a sulfamate en route to the sulfonate; however, it was low-yielding. Investigation of the N-sulfamate to C--sulfonate mechanism through control experiments with variation at the heteroatom positions and kinetic isotope experiments (KIEH/D) confirmed the formation of a key N(sp2)-SO3 intermediate and further confirmed an intermolecular mechanism. Furthermore, compounds without an accessible nitrogen (or oxygen) lone pair did not undergo sulfamation- (or sulfation) -to-sulfonation under these conditions. A one-pot sulfamation and thermal sulfonation reaction was ultimately developed and explored on a range of aniline and heterocyclic scaffolds with high conversions, including N(sp2)-sulfamates (O(sp2)-sulfates) and C(sp2)-sulfonates, in up to 99 and 80% (and 88% for a phenolic example) isolated yield, respectively. Encouragingly, the ability to modulate the ortho-para selectivity of the products obtained was observed under thermal control. A sulfonated analog of the intravenous anesthetic propofol was isolated (88% yield), demonstrating a proof-of-concept modification of a licensed drug alongside a range of nitrogen- and sulfur-containing heterocyclic fragments used in drug discovery.

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Section: Discussionmentioning

confidence: 99%

Rearrangement of Arylsulfamates and Sulfates to Para-Sulfonyl Anilines and Phenols

Zhou,

Jones

2024

Molecules

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“…[45] TBSAB has also found use as a reagent to install aniline N-sulfamates prior to their intermolecular rearrangement. [46] A summary of the scope and range of sulfated molecules achievable with Bu3NSO3 complex are listed in Table 3.…”

Section: Tributylsulfoammonium Betaine (Tbsab)mentioning

confidence: 99%

Approaches to the Sulfation of Small Molecules: Current Progress and Future Directions

Alshehri,

Jones

2024

Preprint

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Sulfation is one of the most important modifications that occur to a wide range of bioactive small molecules including polysaccharides, proteins, flavonoids, and steroids. In turn, these sulfated molecules have significant biological and pharmacological roles in diverse processes including cell signalling, modulation of immune and inflammation response, anti-coagulation, anti-atherosclerosis, and anti-adhesive properties. This essay summarises the most encountered chemical sulfation methods of small molecules. Sulfation reactions using sulfur trioxide amine/amide complexes are the most used method for alcoholic or phenolic groups in carbohydrates, steroids, proteins, and aliphatic or alicyclic scaffolds. Despite the effectiveness of these methods, they suffer from some issues such as multiple-purification steps, toxicity issues (eg pyridine contamination), purification challenges, stoichiometric excess of reagents which leads to increase of a reaction cost, and intrinsic stability issues of both the reagent and product. Recent advances including SuFEx, the Malins in situ reagent approach and TBSAB show the widespread appeal of novel sulfating approaches that will enable a larger exploration of the field in the years to come by simplifying the purification and isolation to access bespoke sulfated small molecules.

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“…[5][6][7][8][9][10][11][12][13][14][15][16] We have recently discovered a novel sulfuryl group transfer reagent with improved organic solubility properties for sulfation of organic substrates, tributylsulfoammonium betaine (TBSAB). [17][18][19][20][21][22][23] We identified TBSAB contains a novel N-S bond (not a dative complex as per Py-SO3) through single crystal X-ray crystallography. [22] The use of TBSAB would be detrimental for purification purposes in this chemistry when not isolating a sulfated intermediate due to its enhanced lipophilicity.…”

Section: Introductionmentioning

confidence: 99%

A modified all-in-one DMSO-activating and base releasing reagent for the Parikh-Doering-type benzylic oxidation reaction

Xie,

Male,

Jones

2024

Preprint

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The Parikh-Doering reaction, an example of the series of DMSO-mediated selective oxidation named reaction family, finds ongoing use in natural product synthesis when mild oxidative reaction conditions are required. The original conditions require the use of Py-SO3 and NEt3 along with DMSO and DCM. As part of our ongoing interest in sulfating agents, we recently disclosed the novel structure of tributylsulfoammonium betaine (TBSAB) that has a formal N-S bond (not dative) and may indicate that other N(sp3) amine-SO3 complexes have been misassigned. Herein, we explore a commercial sulfating agent, triethylamine-sulfur trioxide complex, as an all-in-one sulfation and base releasing reagent for a modified Parikh-Doering reaction. Single crystal X-ray crystallography further confirms our hypothesis than triethylamine-sulfur trioxide complex exists as triethylsulfoammonium betaine (TESAB). Employing TESAB as an all-in-one reagent, a range of primary and secondary alcohols were screened for competency. Reactivity was observed for the first time with 1) a non Py-SO3 sulfating agent and 2) without the need for additional base. Moderate to good yields of aldehydes and ketones can be prepared in an atom-efficient improvement with concomitant removal of toxic pyridine by-products.

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A Sulfonative rearrangement of N-Aryl Sulfamates to para-Sulfonyl Anilines

Cited by 3 publications

References 27 publications

Rearrangement of Arylsulfamates and Sulfates to Para-Sulfonyl Anilines and Phenols

Rearrangement of Arylsulfamates and Sulfates to Para-Sulfonyl Anilines and Phenols

Approaches to the Sulfation of Small Molecules: Current Progress and Future Directions

A modified all-in-one DMSO-activating and base releasing reagent for the Parikh-Doering-type benzylic oxidation reaction

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