Studies on the Phthalidation of Heteroarenes: A Facile Preparation of 3-(Heteroaryl)phthalides via Triflic Acid Mediated Phthalidation

Nandakumar, Meganathan; Sankar, Elumalai; Mohanakrishnan, Arasambattu K.

doi:10.1055/s-0033-1340551

Cited by 7 publications

(2 citation statements)

References 5 publications

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“…To date, phthalidyl esters are routinely prepared via reactions of carboxylic acids with 3-bromophthalides (Fig. 1b) 16 . This method is efficient but unfortunately has no controls over the stereoselectivity for the newly created chiral center.…”

Section: Introductionmentioning

confidence: 99%

Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs

et al. 2019

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Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules.

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Section: Introductionmentioning

confidence: 99%

Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs

et al. 2019

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“…5,20 Of the various strategies, Friedel-Crafts/ lactonization of 2-formylbenzoates and nucleophiles is probably the most easily conceivable mode for formation of 3substituted phthalides. [21][22][23][24][25] On the other hand, the benzofuran core is associated with many commercially available drugs including Dronedarone, Amiodarone, Benzbromarone, Methoxsalen, Fruquintinib. 26,27 Due to the wide range of biological profiles of benzofurans and 3-substituted phthalides, compounds containing the benzofuran and phthalide moieties can exhibit potential biological activities.…”

Section: Introductionmentioning

confidence: 99%

A convenient and efficient synthesis of 3-benzofuryl-substituted phthalides

Zang,

Xu,

et al. 2024

Arkivoc

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A highly efficient and convenient procedure for straightforward synthesizing structurally diverse 3-benzofurylsubstituted phthalides is developed with moderate to excellent yields via cyclization reactions of benzofurans with 2-carbonyl-benzoic acid. The reaction features readily available starting materials, a broad scope, and a high atom economy. Besides, an interesting regioselective was observed in some cases.

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N‐Heterocyclic Carbene‐Catalyzed Asymmetric C−O Bond Construction Between Benzoic Acid and o‐Phthalaldehyde: Mechanism and Origin of Stereoselectivity

Deng

Qiao

et al. 2021

Chemistry An Asian Journal

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A computational study was contributed to explore the origin of stereoselectivity of NHC‐mediated cyclization reaction between benzoic acid and o‐phthalaldehyde for asymmetric construction of phthalidyl ester. The most energetically favorable pathway mainly includes the following steps: (1) nucleophilic attack on carbonyl carbon of o‐phthalaldehyde by catalyst NHC, (2) formation of Breslow intermediate, (3) oxidation by DQ, (4) asymmetric formation of dual C−O bonds, and (5) dissociation of catalyst with the product. The C−O bond formation was testified as the stereoselectivity‐determining step, the R‐configurational pathway is more energetically favorable than the S‐configurational one. The non‐covalent interaction (NCI) and atom‐in‐molecule (AIM) analyses were performed to reveal that the O−H ⋅⋅⋅ O and C−H ⋅⋅⋅ O hydrogen‐bond interactions are the key factors for controlling the stereoselectivity. The detailed mechanism and origin of stereoselectivity give useful insights for understanding organocatalytic reactions for asymmetric construction of C−O bond.

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Studies on the Phthalidation of Heteroarenes: A Facile Preparation of 3-(Heteroaryl)phthalides via Triflic Acid Mediated Phthalidation

Cited by 7 publications

References 5 publications

Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs

Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs

A convenient and efficient synthesis of 3-benzofuryl-substituted phthalides

N‐Heterocyclic Carbene‐Catalyzed Asymmetric C−O Bond Construction Between Benzoic Acid and o‐Phthalaldehyde: Mechanism and Origin of Stereoselectivity

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