Direct Hydrodecarboxylation of Aliphatic Carboxylic Acids: Metal- and Light-Free

McLean, Euan B.; Mooney, David T.; Burns, David J.; Lee, Ai‐Lan

doi:10.1021/acs.orglett.1c04079

Cited by 14 publications

(15 citation statements)

References 46 publications

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“…Following our interest in 3-aryloxetane and azetidine derivatives involving carbocation intermediates, we envisaged that benzylic oxetane radicals would broaden the range of options for oxetane incorporation and provide access to valuable, unexplored, and medicinally relevant chemical space under mild photoredox conditions. However, tertiary benzylic radicals remain underinvestigated in photoredox catalysis and might be expected to display low reactivity in their addition reactions due to their relatively stabilized nature . Further, benzylic radicals are prone to oxidation to form stabilized carbocations through radical-polar crossover pathways .…”

Section: Introductionmentioning

confidence: 99%

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

et al. 2023

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Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible.

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Section: Introductionmentioning

confidence: 99%

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

et al. 2023

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“…Substrates with amide, ester or N ‐carbobenzyloxy functionalities also gave the corresponding products 18 , 19 and 20 in 72–94 % yields. The decarboxylation of more reactive benzylic substrates and an amino acid derivative similarly furnished 21 – 25 in good to high yields without the formation of undesired homocoupling products observed in the Lee's decarboxylation method using a strong oxidant [12i] . Remarkably, a dicarboxylic acid substrate can be doubly‐decarboxylated using these conditions, providing 82 % of 15 , albeit with the use of more solvent and 30 % TRIP disulfide to address its reduced solubility.…”

Section: Resultsmentioning

confidence: 96%

“…However, most of these methods still required the pre‐activation of aliphatic acids as redox‐active esters or carboxylates, superstoichiometric amounts of hydrogen atom donors such as dithiothreitol (DTT), Hantzsch ester or phenylsilane, and/or precious metals (Figure 1a). Significant strides have been made toward direct decarboxylative protonation to avoid the need for pre‐activation; however, the high potential of carboxylic acids remains a significant obstacle, requiring strong oxidants, harsh conditions, or stoichiometric photosensitizers to activate this otherwise stable functional group [12i,j] . In 2015, Nicewicz and co‐workers developed an elegant direct photocatalytic decarboxylative protonation leveraging the high reduction potential ( E 1/2 >2 vs SCE) of an acridinium photoredox catalyst in its excited state (Figure 1b) [13a] .…”

Section: Introductionmentioning

confidence: 99%

Chemoselective Decarboxylative Protonation Enabled by Cooperative Earth‐Abundant Element Catalysis

West

2022

Angewandte Chemie

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Decarboxylative protonation is a general deletion tactic to replace polar carboxylic acid groups with hydrogen or its isotope. Current methods rely on the pre-activation of acids, non-sustainable hydrogen sources, and/or expensive/highly oxidizing photocatalysts, presenting challenges to their wide adoption. Here we show that a cooperative iron/thiol catalyst system can readily achieve this transformation, hydrodecarboxylating a wide range of activated and unactivated carboxylic acids and overcoming scope limitations in previous direct methods. The reaction is readily scaled in batch configuration and can be directly performed in deuterated solvent to afford high yields of d-incorporated products with excellent isotope incorporation efficiency; characteristics not attainable in previous photocatalyzed approaches. Preliminary mechanistic studies indicate a radical mechanism and kinetic results of unactivated acids (KIE = 1) are consistent with a light-limited reaction.

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“…The decarboxylation of an organic acid to form its corresponding hydrocarbon (known as hydrodecarboxylation) and decarboxylative functionalization of C-H bond are two valuable processes in organic synthesis for creating diversity [1][2][3][4][5][6]. Several methods for decarboxylation generally occurring at high temperatures and strong acidic/ basic conditions are well reported.…”

Section: Introductionmentioning

confidence: 99%

Microwave‐assisted decarboxylation of 2H‐Pyran‐3‐carboxylic acid derivatives under basic condition

Mishra

Bal

2022

Journal of Heterocyclic Chem

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Despite the availability of several methods for decarboxylation, this area remains exploratory and requires new development. Here, we report a highly efficient microwave‐assisted hydrodecarboxylation of 4‐(methylthio)‐2‐oxo‐6‐aryl‐2H‐pyran‐3‐carboxylic acids (1a‐k) under basic condition to obtain 4‐(methylthio)‐6‐aryl‐2H‐pyran‐2‐ones (2a‐k) with >90% yield. The requirement of proton source from the solvent was observed by performing the reactions of 1b and 1e in CD3OD to obtain deuterated compounds 2 l and 2 m respectively. All compounds were characterized by spectroscopic analysis. Further, compounds 2b and 2e were analyzed by single‐crystal X‐ray diffraction studies.

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Direct Hydrodecarboxylation of Aliphatic Carboxylic Acids: Metal- and Light-Free

Cited by 14 publications

References 46 publications

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

Chemoselective Decarboxylative Protonation Enabled by Cooperative Earth‐Abundant Element Catalysis

Microwave‐assisted decarboxylation of 2H‐Pyran‐3‐carboxylic acid derivatives under basic condition

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