Telescoped diazo transfer and rhodium-catalysed S–H insertion in continuous flow

Kearney, Aoife M.; Lynch, Denis; Collins, Stuart G.; Maguire, Anita R.

doi:10.1016/j.tetlet.2021.153438

Cited by 5 publications

(11 citation statements)

References 34 publications

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“…As summarized in Table 1, generation of tosyl azide using Dowex resin 16 has been successfully telescoped with diazo transfer to a range of substrates including aryl acetates and diethyl malonate (25), adjusting the reaction conditions and specifically the reactant concentrations, relative to the preliminary investigations, to provide the α-diazo esters at higher concentration and increased throughput, while retaining a convenient residence time. In practice, this approach to the in situ generation of tosyl azide 12, in the absence of water, proved effective for the synthesis of a series of α-diazo-α-aryl-acetates (9, 20, 22, and 24), in addition to diethyl diazomalonate 26.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Building on our previous reports, − formation of methyl 2-diazo-2-chlorophenylacetate ( 9 ) was envisaged through telescoped generation of tosyl azide 12 in aqueous acetonitrile followed by diazo transfer in continuous flow, with subsequent incorporation of rhodium-mediated O–H insertion to form 10 (Scheme ). At the outset, the key challenge was to establish if the diazo transfer could be telescoped with a rhodium-mediated insertion into water, without isolation of the α-aryl-α-diazoacetate 9 .…”

Section: Resultsmentioning

confidence: 99%

“… 21 Furthermore, generation and use of sulfonyl azides in continuous flow has been demonstrated, obviating the requirement to isolate and handle these potential hazardous reagents. 20 , 22 − 25 While the Regitz diazo transfer from sulfonyl azides is a remarkably efficient and generally applicable process working with a wide variety of acceptors, the hazards associated with use and handling of sulfonyl azides are well documented. 4 , 5 While modified sulfonyl azides have been developed with improved safety profiles, none of these fully resolve the concerns in effecting diazo transfer at scale using a preprepared sulfonyl azide.…”

Section: Introductionmentioning

confidence: 99%

“… 4 , 5 , 26 − 31 In recent years, our team has developed a number of protocols for in situ generation of sulfonyl azides followed by diazo transfer, 22 together with telescoping with downstream reactions, including thermal Wolff rearrangement and ketene trapping, 23 copper catalyzed C–H insertion and aromatic additions, 24 and rhodium-mediated S–H insertion. 25 In parallel with our work on the synthesis and use of sulfonyl azides in flow, Krasavin has described in situ generation and use of sulfonyl azides as “sulfonyl azide-free” aqueous phase diazo transfer, under traditional batch conditions. 32 …”

Section: Introductionmentioning

confidence: 99%

“…The exploitation of α-diazocarbonyl chemistry has been a key beneficiary of advances in continuous processing. − ,− Continuous methodologies for the generation of diazomethane have been reported, including the use of tube-in-tube reactors . Furthermore, generation and use of sulfonyl azides in continuous flow has been demonstrated, obviating the requirement to isolate and handle these potential hazardous reagents. ,− While the Regitz diazo transfer from sulfonyl azides is a remarkably efficient and generally applicable process working with a wide variety of acceptors, the hazards associated with use and handling of sulfonyl azides are well documented. , While modified sulfonyl azides have been developed with improved safety profiles, none of these fully resolve the concerns in effecting diazo transfer at scale using a preprepared sulfonyl azide. ,,− In recent years, our team has developed a number of protocols for in situ generation of sulfonyl azides followed by diazo transfer, together with telescoping with downstream reactions, including thermal Wolff rearrangement and ketene trapping, copper catalyzed C–H insertion and aromatic additions, and rhodium-mediated S–H insertion . In parallel with our work on the synthesis and use of sulfonyl azides in flow, Krasavin has described in situ generation and use of sulfonyl azides as “sulfonyl azide-free” aqueous phase diazo transfer, under traditional batch conditions …”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Generation of Tosyl Azide in Continuous Flow Using an Azide Resin, and Telescoping with Diazo Transfer and Rhodium Acetate-Catalyzed O–H Insertion

O’Mahony

Lynch

O’Callaghan

et al. 2021

Org. Process Res. Dev.

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Generation of tosyl azide 12 in acetonitrile in flow under water-free conditions using an azide resin and its use in diazo transfer to a series of aryl acetates are described. Successful telescoping with a rhodium acetate-catalyzed O–H insertion has been achieved, thereby transforming the aryl acetate 8 to α-hydroxy ester 10 , a key intermediate in the synthesis of clopidogrel 11 , without requiring isolation or handling of either tosyl azide 12 or α-aryl-α-diazoacetate 9 , or indeed having significant amounts of either present at any point. Significantly, the solution of α-diazo ester 9 was sufficiently clean to progress directly to the rhodium acetate-catalyzed step without any detrimental impact on the efficiency of the O–H insertion. In addition, the rhodium acetate-catalyzed O–H insertion process is cleaner in flow than under traditional batch conditions. Use of the azide resin offers clear safety advantages and, in addition, this approach complements earlier protocols for the generation of tosyl azide 12 in flow; this protocol is especially useful with less acidic substrates.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Generation of Tosyl Azide in Continuous Flow Using an Azide Resin, and Telescoping with Diazo Transfer and Rhodium Acetate-Catalyzed O–H Insertion

O’Mahony

Lynch

O’Callaghan

et al. 2021

Org. Process Res. Dev.

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Process Development of Heterogeneous Rh Catalyzed Carbene Transfer Reactions Under Continuous Flow Conditions

Bayrakdar

Lescot

2023

ChemSusChem

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A very simple Rh‐based catalyst operates under heterogeneous flow conditions for the carbene transfer of methyl diazoacetate (MDA) with several substrates. Two different methods for heterogenizing the catalyst in a column reactor have been applied. Different X−H (X=O, S, Si, CH2) were successfully functionalized by the carbene and cyclopropenation was performed under very mild continuous flow conditions. Following these promising results, catalyst recycling experiments using both methodologies were conducted in which up to 5 catalytic cycles have been achieved for the carbene O−H insertion reaction and interestingly, a sequential transformation of different substrates with up to 10 consecutive runs per reactor were achieved with no loss in the catalytic activity, thus allowing the production of families of compounds.

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Continuous preparation and reaction of nonaflyl azide (NfN3) for the synthesis of organic azides and 1,2,3-triazoles

Green,

Broderick,

Wheelhouse

et al. 2024

J Flow Chem

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Organic azides are widely used in organic synthesis. Continuous flow processing can be used to bypass their isolation, and can therefore be useful in mitigating the hazards associated with these potentially toxic and explosive reagents. Nonaflyl azide has been reported as an effective, bench-stable, and relatively safe diazo transfer reagent that can be useful in the preparation of azides from amines and so avoid the use of alkyl halides. Here we demonstrate the synthesis and purification of nonaflyl azide in continuous flow with isolation of the neat, pure reagent by membrane filtration. The neat reagent was used in the preparation of organic azides from primary amines, and then applied to the synthesis of triazoles. A variety of triazoles, including the antiseizure drug Rufinamide, were prepared from primary amines and alkynes via the CuAAC click reaction in a semi-batch parallel array without isolation of alkyl azide intermediates. A telescoped two-stage continuous flow process was also designed and demonstrated to form triazoles via the same CuAAC reaction, which avoids the handling of the intermediate reactive azides.

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Telescoped diazo transfer and rhodium-catalysed S–H insertion in continuous flow

Cited by 5 publications

References 34 publications

Generation of Tosyl Azide in Continuous Flow Using an Azide Resin, and Telescoping with Diazo Transfer and Rhodium Acetate-Catalyzed O–H Insertion

Generation of Tosyl Azide in Continuous Flow Using an Azide Resin, and Telescoping with Diazo Transfer and Rhodium Acetate-Catalyzed O–H Insertion

Process Development of Heterogeneous Rh Catalyzed Carbene Transfer Reactions Under Continuous Flow Conditions

Continuous preparation and reaction of nonaflyl azide (NfN3) for the synthesis of organic azides and 1,2,3-triazoles

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