Synthesis of 3-substituted indoles via N-acylindolium ions

Comins, Daniel L.; Stroud, Eric D.

doi:10.1016/s0040-4039(00)84397-x

Cited by 21 publications

(6 citation statements)

References 8 publications

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“…5-Bromoindole ( 7 ) was N -arylated by iodobenzene via a coupling reaction catalyzed by ligand-free copper to afford the intermediate ( 8 ), which then underwent Friedel–Crafts acylation with benzoyl chloride at position 3 . Reduction of the carbonyl group of the C3-acylated intermediate ( 9a ) to methylene was carried out in a stepwise manner using NaBH 4 and Et 3 SiH; the C3-benzyl derivative ( 10a ) was then obtained via the corresponding alcohol intermediate . Methyl acrylate was introduced at position 5 by the Heck reaction, and the C5 propenoate side chain was formed .…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A₂α Inhibitors

Tomoo¹,

Nakatsuka²,

Katayama³

et al. 2014

J. Med. Chem.

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This article describes the design, synthesis, and biological evaluation of new indole-based cytosolic phospholipase A2α (cPLA2α, a group IVA phospholipase A2) inhibitors. A screening-hit compound from our library, (E)-3-{4-[(4-chlorophenyl)thio]-3-nitrophenyl}acrylic acid (5), was used to design a class of 3-(1-aryl-1H-indol-5-yl)propanoic acids as new small molecule inhibitors. The resultant structure-activity relationships studied using the isolated enzyme and by cell-based assays revealed that the 1-(p-O-substituted)phenyl, 3-phenylethyl, and 5-propanoic acid groups on the indole core are essential for good inhibitory activity against cPLA2α. Optimization of the p-substituents on the N1 phenyl group led to the discovery of 56n (ASB14780), which was shown to be a potent inhibitor of cPLA2α via enzyme assay, cell-based assay, and guinea pig and human whole-blood assays. It displayed oral efficacy toward mice tetradecanoyl phorbol acetate-induced ear edema and guinea pig ovalbumin-induced asthma models.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A₂α Inhibitors

Tomoo¹,

Nakatsuka²,

Katayama³

et al. 2014

J. Med. Chem.

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“…Indolyl-substituted carbenium ions have recently been employed as prochiral intermediates in asymmetric Diels–Alder reactions, Friedel–Crafts reactions, , additions to aliphatic π-systems, α-alkylations of aldehydes and other CH acidic compounds, hydrogenation reactions, and several asymmetric syntheses . They are commonly generated by treatment of readily available precursors with Brønsted or Lewis acids (Scheme ) and subsequently trapped by hydride donors, organometallic reagents, and other nucleophiles to give a wide variety of functionalized indole derivatives. − …”

Section: Introductionmentioning

confidence: 99%

Structure and Reactivity of Indolylmethylium Ions: Scope and Limitations in Synthetic Applications

et al. 2015

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Eight substituted aryl(indol-3-yl)methylium tetrafluoroborates 3(a-h)-BF4 and three bis(indol-3-yl)methylium tetrafluoroborates 3(i-k)-BF4 have been synthesized and characterized by NMR spectroscopy and X-ray crystallography. Their reactions with π-nucleophiles 8(a-j) (silylated enol ethers and ketene acetals) were studied kinetically using photometric monitoring at 20 °C. The resulting second-order rate constants were found to follow the correlation log k(20 °C) = sN(N + E), in which nucleophiles are characterized by the two solvent-dependent parameters N and sN, and electrophiles are characterized by one parameter, E. From the previously reported N and sN parameters of the employed nucleophiles and the measured rate constants, the electrophilicities of the indol-3-ylmethylium ions 3(a-k) were derived and used to predict potential nucleophilic reaction partners. A discrepancy between published rate constants for the reactions of morpholine and piperidine with the (2-methylindol-3-yl)phenylmethylium ion 3h and those calculated from E, N, and sN was analyzed and demonstrated to be due to a mistake of the value reported in the literature.

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“…Furthermore, many natural products incorporating this structural key element are known . As a result of their biological and synthetic importance, a variety of methods have been reported for the preparation of 3-substituted indoles . Although these methods constitute a valuable addition to the chemical literature, a truly efficient, diverse synthetic scheme 6 for type 1 indoles is still required to construct further indole libraries for medicinal chemistry.…”

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confidence: 99%

Carboxylic Acid Catalyzed Three-Component Aza-Friedel−Crafts Reactions in Water for the Synthesis of 3-Substituted Indoles

2006

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Synthesis of 3-substituted indoles via N-acylindolium ions

Cited by 21 publications

References 8 publications

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A₂α Inhibitors

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A₂α Inhibitors

Structure and Reactivity of Indolylmethylium Ions: Scope and Limitations in Synthetic Applications

Carboxylic Acid Catalyzed Three-Component Aza-Friedel−Crafts Reactions in Water for the Synthesis of 3-Substituted Indoles

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Synthesis of 3-substituted indoles via N-acylindolium ions

Cited by 21 publications

References 8 publications

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A2α Inhibitors

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A2α Inhibitors

Structure and Reactivity of Indolylmethylium Ions: Scope and Limitations in Synthetic Applications

Carboxylic Acid Catalyzed Three-Component Aza-Friedel−Crafts Reactions in Water for the Synthesis of 3-Substituted Indoles

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Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A₂α Inhibitors

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A₂α Inhibitors