An optimized procedure for direct access to 1<i>H</i>-indazole-3-carboxaldehyde derivatives by nitrosation of indoles

Chevalier, Arnaud; Ouahrouch, Abdelaaziz; Arnaud, Alexandre; Gallavardin, Thibault; Franck, Xavier

doi:10.1039/c8ra01546e

Cited by 17 publications

(10 citation statements)

References 42 publications

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“…No evident 1 H- 13 C correlation was observed between the n-alkyl CH 2 proton pair proximal to the With a set of optimal conditions for the regioselective N-1 alkylation of methyl ester 9 in hand (Table 1, entry 22), our attention turned to probing the influence of a variety of indazole C-3 substituents on the regiochemical N-alkylation outcome. A series of C-3 substituted indazoles (12-24) (Figure 3) were thus assembled [28][29][30][31][32][33] to investigate the effects of electronic and steric factors on indazole N-alkylation (Table 2) using our optimized conditions from Table 1 (entry 22) (referred to as "conditions A" in Table 2).…”

Section: Resultsmentioning

confidence: 99%

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

Alam¹,

Keating²

2021

Beilstein J. Org. Chem.

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The indazole scaffold represents a promising pharmacophore, commonly incorporated in a variety of therapeutic drugs. Although indazole-containing drugs are frequently marketed as the corresponding N-alkyl 1H- or 2H-indazole derivative, the efficient synthesis and isolation of the desired N-1 or N-2 alkylindazole regioisomer can often be challenging and adversely affect product yield. Thus, as part of a broader study focusing on the synthesis of bioactive indazole derivatives, we aimed to develop a regioselective protocol for the synthesis of N-1 alkylindazoles. Initial screening of various conditions revealed that the combination of sodium hydride (NaH) in tetrahydrofuran (THF) (in the presence of an alkyl bromide), represented a promising system for N-1 selective indazole alkylation. For example, among fourteen C-3 substituted indazoles examined, we observed > 99% N-1 regioselectivity for 3-carboxymethyl, 3-tert-butyl, 3-COMe, and 3-carboxamide indazoles. Further extension of this optimized (NaH in THF) protocol to various C-3, -4, -5, -6, and -7 substituted indazoles has highlighted the impact of steric and electronic effects on N-1/N-2 regioisomeric distribution. For example, employing C-7 NO2 or CO2Me substituted indazoles conferred excellent N-2 regioselectivity (≥ 96%). Importantly, we show that this optimized N-alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate electrophiles, while maintaining a high degree of N-1 regioselectivity.

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Section: Resultsmentioning

confidence: 99%

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

Alam¹,

Keating²

2021

Beilstein J. Org. Chem.

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“…1 was readily prepared in two steps, starting from indole 12 (Scheme 1), the first reaction being a nitrosation providing in one step indazole-3-carboxaldehyde 7; this transformation was achieved in excellent yield according to our previously described protocol [48]. Then a Knoevenagel condensation was performed using 1-Ethyl-2,3,3-trimethyl-3H-indolium iodide 6 as the nucleophile to give the cationic dye 1 with 64% yield.…”

Section: Synthesismentioning

confidence: 99%

Indazole versus indole-based cationic merocyanines with red shifted in-cellulo emission for selective mitochondria imaging

et al. 2022

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“…The 1 H -pyrazolo[3,4- d ]pyrimidin-4-amine motifs 12a–12t were synthesized through a Suzuki–Miyaura coupling reaction of 11 . On the other hand, 6-chloroindole 13 was treated with NaNO 2 in an acidic condition for rendering a rearrangement to deliver 3-formyl indazole 14 , and 14 was involved in the Grignard reaction to deliver alcohols 15a and 15b . 15a and 15b were oxidized by activated MnO 2 to give ketones 16a and 16b , and the following Ullman-coupling reaction provides indazoles 17a–17d .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

Tang,

Zheng,

Bao

et al. 2023

J. Med. Chem.

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PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amine-tethered 3-methyl-1-aryl-1H-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages. ( S )-29 was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivo administration of ( S )-29 at 10 mg/kg dosage could significantly ameliorate histopathological changes and attenuate lung inflammation in lung tissues of LPS-challenged mice. Molecular docking demonstrated the success of scaffold hopping design. Overall, ( S )-29 is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.

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An optimized procedure for direct access to 1H-indazole-3-carboxaldehyde derivatives by nitrosation of indoles

Abstract: The nitrosation of indoles under slightly acidic conditions and reverse addition conditions leads to the preparation of the corresponding indazole-3-carboxaldehydes in high yields and greatly minimizes side reactions.

Cited by 17 publications

References 42 publications

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

Indazole versus indole-based cationic merocyanines with red shifted in-cellulo emission for selective mitochondria imaging

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

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