The Suzuki Reaction Applied to the Synthesis of Novel Pyrrolyl and Thiophenyl Indazoles

Migliorini, Antonella; Oliviero, Chiara; Gasperi, Tecla; Loreto, M. Antonietta

doi:10.3390/molecules17044508

Cited by 20 publications

(9 citation statements)

References 37 publications

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“…As literature precedence shows, the combination of Cs 2 CO 3 in DMF has been commonly employed to achieve indazole N -alkylation [ 17 , 34 – 35 ]. For comparison with our previously optimized N -alkylation protocol ( Table 1 , entry 22; conditions A), conditions that provided less favorable N -1 regioselectivity ( Table 1 , entry 3, henceforth referred to as “conditions B” in Table 2 ) were also included as a part of this investigation.…”

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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“…Variously substituted anilines at C3 were introduced using Buchwald conditions to afford 3‐anilines 4a–4g in relatively low yield. Suzuki coupling at C5 with pyridine‐3‐boronic acid was performed to give compounds 5a‐5g . The potency of 2‐chloro compound 5b (IC 50 = 4.87 μM) was similar to that of unsubstituted compound 5a (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…To remove the N ‐protecting group of pyrazole easily, 4‐methoxybenzyl (PMB) group was introduced at N1 of compound 2 to provide compound 6 , as shown in Scheme . Following Buchwald conditions, Suzuki coupling, and subsequent deprotection of PMB gave compound 9a–9d . Substitution of 1‐(2‐chlorobenzyl) of 5c to 1‐(4‐methoxybenzyl) 8a was deleterious in inhibitory activity on MELK (Table ).…”

Section: Resultsmentioning

confidence: 99%

3‐Amino‐1H‐pyrazolopyridine Derivatives as a Maternal Embryonic Leucine Zipper Kinase Inhibitor

Park

Jadhav

Song

et al. 2017

Bulletin Korean Chem Soc

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Maternal embryonic leucine zipper kinase (MELK) has been implicated in various cellular processes and is highly upregulated in diverse cancers, then it is thought to be a promising anticancer target. 3‐Anilino‐1H‐pyrazolo[3,4‐b]pyridine scaffold was identified as a novel scaffold for MELK kinase inhibitors in high throughput screening (HTS). From exploration for structure–activity relationship (SAR) studies mainly by the modification of the 3 (C3), and 5‐positions (C5), 4‐(4‐methylpiperazin‐1‐yl)‐N‐{5‐[1‐(piperidin‐4‐yl)‐1H‐pyrazol‐4‐yl]‐1H‐pyrazolo[3,4‐b]pyridin‐3‐yl}benzamide (21a) was found to exhibit good activity (IC50 = 0.15 μM) on MELK as a lead in early state.

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“…C-5 Heteroarylation of N-substituted 5-bromo 1Hand 2H-indazoles (17 a and 17 b) by Suzuki crosscoupling reaction has been developed by Loreto et al The couplings were done with N-boc-2-pyrrole or 2thiopheneboronic acids in presence of Pd(dppf)Cl 2 as a catalyst, K 2 CO 3 as a base in dimethoxyethane at 80°C which produced C-5 heteroarylated 1H-and 2Hindazole derivatives (17 c and 17 d) respectively with very good yields (Scheme 17). [81] But 2-pyrroleboronic acid afforded lower yields than that of 2-thiopheneboronic acid due to the tendency of thiopheneboronic acids to undergo protodeboronation and the formation of a side-product. Both 1H-and 2H-indazoles were compatible with the cross-coupling reactions.…”

Section: Arylationmentioning

confidence: 99%

Direct Catalytic Functionalization of Indazole Derivatives

2020

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Indazoles are a very important class of N‐containing heterocycles with a wide range of biological and medicinal properties. The presence of different functionalities on indazole moieties enhances its biological activities. Hence, the preparation of indazole compounds bearing functional groups has gained a significant interest to the organic synthetic chemists. A large effort has been made to develop efficient and new methods for the functionalization of indazoles. Direct catalytic functionalization is a very powerful tool for facile synthesis of important indazole derivatives due to its straightforwardness. This review summarizes developments on direct functionalizations of indazoles published in the last two decades.

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The Suzuki Reaction Applied to the Synthesis of Novel Pyrrolyl and Thiophenyl Indazoles

Cited by 20 publications

References 37 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

3‐Amino‐1H‐pyrazolopyridine Derivatives as a Maternal Embryonic Leucine Zipper Kinase Inhibitor

Direct Catalytic Functionalization of Indazole Derivatives

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