Organophotocatalytic late-stage N-CH3 oxidation of trialkylamines with O2 in continuous flow

Mark John P.  Mandigma; Jonas  Žurauskas; Callum I. MacGregor; Lee J. Edwards; Ahmed  Shahin; Ludwig  d’Heureusea; Philip Yip; David J. S. Birch; Thomas  Gruber; Jörg  Heilmann; Matthew P. John; Joshua P. Barham

doi:10.33774/chemrxiv-2021-zpfxf

Organophotocatalytic late-stage N-CH3 oxidation of trialkylamines with O2 in continuous flow

Mark John P. Mandigma, Jonas Žurauskas, Callum I. MacGregor, Lee J. Edwards, Ahmed Shahin, Ludwig d’Heureusea, Philip Yip, David J. S. Birch, Thomas Gruber, Jörg Heilmann, Matthew P. John, Joshua P. Barham

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Abstract

We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for processing in flow which allowed harnessing of O2 as a benign reagent for late-stage photocatalytic N-CH3 oxidation of natural products and active pharmaceutical ingredients. These substrates bear functional groups which are not tolerated by previous methods. The organophotocatalytic process benefited from the flow
parameters, affording cleaner reactions in short residence time of 13.5 mins and productivities of up to 0.65 g / day. Mechanistic studies found that catalyst derivatization not only enhanced solubility of the new catalyst compared to DCA, it profoundly diverted the photocatalytic reaction mechanism from singlet
electron transfer (SET) reductive quenching with amines to energy transfer (EnT) with O2.

Original language	English
Place of Publication	Cambridge, UK
Number of pages	10
DOIs	https://doi.org/10.33774/chemrxiv-2021-zpfxf
Publication status	Published - 20 Sept 2021

Keywords

medicinal chemistry
diversity-oriented synthesis
bioactive molecules

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10.33774/chemrxiv-2021-zpfxfLicence: CC BY 4.0

organophotocatalytic-late-stage-n-ch3-oxidation-of-trialkylamines-with-o2-in-continuous-flowFinal published version, 1.17 MBLicence: CC BY 4.0

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title = "Organophotocatalytic late-stage N-CH3 oxidation of trialkylamines with O2 in continuous flow",

abstract = "We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for processing in flow which allowed harnessing of O2 as a benign reagent for late-stage photocatalytic N-CH3 oxidation of natural products and active pharmaceutical ingredients. These substrates bear functional groups which are not tolerated by previous methods. The organophotocatalytic process benefited from the flowparameters, affording cleaner reactions in short residence time of 13.5 mins and productivities of up to 0.65 g / day. Mechanistic studies found that catalyst derivatization not only enhanced solubility of the new catalyst compared to DCA, it profoundly diverted the photocatalytic reaction mechanism from singletelectron transfer (SET) reductive quenching with amines to energy transfer (EnT) with O2. ",

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author = "Mandigma, {Mark John P.} and Jonas {\v Z}urauskas and MacGregor, {Callum I.} and Edwards, {Lee J.} and Ahmed Shahin and Ludwig d{\textquoteright}Heureusea and Philip Yip and Birch, {David J. S.} and Thomas Gruber and J{\"o}rg Heilmann and John, {Matthew P.} and Barham, {Joshua P.}",

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AU - Mandigma, Mark John P.

AU - Žurauskas, Jonas

AU - MacGregor, Callum I.

AU - Edwards, Lee J.

AU - Shahin, Ahmed

AU - d’Heureusea, Ludwig

AU - Yip, Philip

AU - Birch, David J. S.

AU - Gruber, Thomas

AU - Heilmann, Jörg

AU - John, Matthew P.

AU - Barham, Joshua P.

PY - 2021/9/20

Y1 - 2021/9/20

N2 - We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for processing in flow which allowed harnessing of O2 as a benign reagent for late-stage photocatalytic N-CH3 oxidation of natural products and active pharmaceutical ingredients. These substrates bear functional groups which are not tolerated by previous methods. The organophotocatalytic process benefited from the flowparameters, affording cleaner reactions in short residence time of 13.5 mins and productivities of up to 0.65 g / day. Mechanistic studies found that catalyst derivatization not only enhanced solubility of the new catalyst compared to DCA, it profoundly diverted the photocatalytic reaction mechanism from singletelectron transfer (SET) reductive quenching with amines to energy transfer (EnT) with O2.

AB - We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for processing in flow which allowed harnessing of O2 as a benign reagent for late-stage photocatalytic N-CH3 oxidation of natural products and active pharmaceutical ingredients. These substrates bear functional groups which are not tolerated by previous methods. The organophotocatalytic process benefited from the flowparameters, affording cleaner reactions in short residence time of 13.5 mins and productivities of up to 0.65 g / day. Mechanistic studies found that catalyst derivatization not only enhanced solubility of the new catalyst compared to DCA, it profoundly diverted the photocatalytic reaction mechanism from singletelectron transfer (SET) reductive quenching with amines to energy transfer (EnT) with O2.

KW - medicinal chemistry

KW - diversity-oriented synthesis

KW - bioactive molecules

U2 - 10.33774/chemrxiv-2021-zpfxf

DO - 10.33774/chemrxiv-2021-zpfxf

M3 - Working paper

BT - Organophotocatalytic late-stage N-CH3 oxidation of trialkylamines with O2 in continuous flow

CY - Cambridge, UK

ER -

Organophotocatalytic late-stage N-CH3 oxidation of trialkylamines with O2 in continuous flow

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Keywords

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