Recent advancements in the use of Bobbitt's salt and 4-acetamidoTEMPO

Abstract

This feature article provides a comprehensive overview of recent developments and applications of Bobbitt's salt and 4-acetamidoTEMPO in organic synthesis and fields beyond.

Asymmetric Synthesis of Nidulalin A and Nidulaxanthone A: Selective Carbonyl Desaturation Using an Oxoammonium Salt

“…This control experiment reinforced a desaturation mechanism involving the ester n(O)-to-σ*(C−H) activation rather than the allylic π(C�C)-to-σ*(C−H) activation. 36 At present, we cannot rule out a mechanism involving enol formation from substrate 2 followed by desaturation by oxoammonium salt 30 which was also proposed in the literature. 33,34 Although DFT computations (r 2 SCAN-3C/ CPCM (CH 2 Cl 2 )) showed that the enol desaturation is almost barrierless (TS-SB, 2.3 kcal/mol), 9 we were unable to identify an energetically reasonable enolization process.…”

“…Although allylic alcohols tend to be reactive toward such reagents, , we reasoned that the ester of 2 might prevent alcohol oxidation, as we only recovered starting material 2 after treatment with DDQ. Based on a literature search that identified Bobbitt’s oxoammonium salt 30 as a stoichiometric reagent for both oxidation of alcohols and desaturation of ketones, − we found that 30 cleanly converted allylic alcohol 2 to nidulalin A ( 1 ) in 78% yield in refluxing DCE without alcohol oxidation (Figure A). On the other hand, use of AZADO-BF 4 32 resulted in decomposition, and TEMPO-BF 4 31 only resulted in a lower yield of 1 along with unidentified byproducts.…”

“…Given that Bobbitt’s salt 30 is known to serve as a hydride acceptor, , together with the premise that an ester n­(O)-to-σ*­(C–H) interaction should activate the hydrogen β to the ketone based on computational analysis of 2 ( left inset , Figure ), we considered that desaturation of successful substrates 2 and 17 may occur by a hydride transfer mechanism which is facilitated by the adjacent ester moiety. Accordingly, we hydrogenated substrate 17 to 35 (Figure C) to remove the cyclohexenyl moiety.…”

The Catalytic Enantioselective [1,2]-Wittig Rearrangement of Allylic Ethers

“…As [1,2]-Wittig products are traditionally expected to be generated via a radical recombination mechanism the effect of adding 20 mol% of 4-NHAc-TEMPO as an additive was probed. Formation of the [1,2]-product was not significantly inhibited, giving 9 in 73% yield and improved 95:5 er, with no 4-NHAc-TEMPO adducts observed 33 . The mass balance consisted of the aldol side product 10 (>95:5 dr, 75:25 er) that was isolated in 5% yield; addition of 1.0 equivalent of 4-NHAc-TEMPO was also tested, affording 9 in a further reduced 59% yield but enhanced 97:3 er.…”

Oxoammonium Salt-Mediated On-DNA Alcohol Oxidation for DEL Synthesis

“…26,28 We focused on TEMPO-derived oxoammonium salts, specifically 4acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate, commonly known as "Bobbitt's salt", which is known in organic chemistry for its ability to selectively oxidize alcohols to aldehydes and carboxylic acids without the need of metal catalysis. 31,32 Notably, recent work by Xu et al demonstrated the use of Bobbitt's salt for the oxidation of a modified DNA base, 5-hydroxymethyl cytosine, to its corresponding aldehyde and their protocol showed no adverse effects of the integrity of DNA. 33 This oxoammonium saltmediated oxidation process does not rely on stoichiometric secondary or terminal oxidants, which lessens additional risks from potential DNA damage by an extra oxidant or unexpected scale effects from additional reaction turnover steps.…”