Direct, Regioselective <i>N</i>-Alkylation of 1,3-Azoles

Chen, Shuai; Graceffa, Russell F.; Boezio, Alessandro A.

doi:10.1021/acs.orglett.5b02994

Cited by 34 publications

(29 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, having a sterically demanding t -Bu group at the indazole C-3 position ( 14 ) gave the N -1 substituted regioisomer 29 exclusively under both conditions A and B, respectively ( Table 2 , entry 3). Apart from the 1 H -indazole scaffold [ 36 – 37 ], the steric influence of adjacent substituent(s) on N -alkylation regioselectivity has previously been described for other nitrogen-containing heterocycles, such as pyrazole [ 38 ], purine, and related 1,3-azoles [ 39 ]. Although the N -alkylation of indazole 12, using conditions A (NaH in THF), proceeded with poor regioselectivity (ratio N -1 ( 25 ): N -2 ( 26 ) = 1:1.3), Bookser et al have obtained a similar regioselective outcome using a combination of NaHMDS and MeI instead of NaH and n -pentyl bromide ( Table 2 , entry 1), respectively [ 24 ].…”

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.

View full text Add to dashboard Cite

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.

show abstract

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.

View full text Add to dashboard Cite

show abstract

“…To retain similarity to the asmarines (N-6 and N-7 substituted), a series of analogs substituted at the N-6 and N-7 positions were first made. A regioselective N-7 alkylation 39 of 6-chloropurine ( 6 ) followed by displacement of the chlorides of compounds 7 and 8 with various hydroxylamines provided compounds 9-12 . Compounds 9-12 were designed to have varying values of logP as we had previously found this to be an important parameter.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Action of the Cytotoxic Asmarine Alkaloids

Lambrecht

Shenvi

2018

ACS Chem. Biol.

View full text Add to dashboard Cite

The asmarines are a family of cytotoxic natural products whose mechanism of action is unknown. Here, we used chemical synthesis to reverse engineer the asmarines and understand the functions of their individual components. We found that the potent asmarine analog "delmarine" arrested the mammalian cell cycle in the G1 phase and that both cell cycle arrest and cytotoxicity were rescued by cotreatment with ferric and ferrous salts. Cellular iron deprivation was clearly indicated by changes in iron-responsive protein markers, and cytotoxicity occurred independently of radical oxygen species (ROS) production. Chemical synthesis allowed for annotation of the distinct structural motifs required for these effects, especially the unusual diazepine, which we found enforced an iron-binding tautomer without distortion of the NCNO dihedral angle out of plane. With this information and a correlation of cytotoxicity with logP, we could replace the diazepine by lipophilic group appendage to N9, which avoided steric clash with the N6-alkyl required to access the aminopyridine. This study transformed the asmarines, scarce marine metabolites, into easily synthesized, modular chemotypes that may complement or succeed iron-selective binders in clinical trials and use.

show abstract

“…Thus, direct alkylation leads to both regioisomers predominating the N9-substituted isomer. To obtain the corresponding N7 isomers several strategies have been followed by different authors [ 40 , 77 , 115 , 116 , 117 , 118 ]. One of those relatively frequent strategies is to alkylate the N9 position with a protecting group, then to introduce the substituent at N7 and finally to deprotect N9, leading to the N7-substituted purines as summarised in the general Scheme 1 .…”

Section: Synthetic Approaches Towards the Natural Alkylpurines Andmentioning

confidence: 99%

“…One of those relatively frequent strategies is to alkylate the N9 position with a protecting group, then to introduce the substituent at N7 and finally to deprotect N9, leading to the N7-substituted purines as summarised in the general Scheme 1 . Other strategies include the Traube synthesis of purines [ 117 ] or the regioselective alkylation using alkylmagnesium reagents as recently described by Chen et al [ 118 ].…”

Section: Synthetic Approaches Towards the Natural Alkylpurines Andmentioning

confidence: 99%

Marine Alkylpurines: A Promising Group of Bioactive Marine Natural Products

et al. 2018

View full text Add to dashboard Cite

Marine secondary metabolites with a purine motif in their structure are presented in this review. The alkylpurines are grouped according to the size of the alkyl substituents and their location on the purine ring. Aspects related to the marine source, chemical structure and biological properties are considered together with synthetic approaches towards the natural products and bioactive analogues. This review contributes to studies of structure–activity relationships for these metabolites and highlights the potential of the sea as a source of new lead compounds in diverse therapeutic fields.

show abstract

Direct, Regioselective N-Alkylation of 1,3-Azoles

Cited by 34 publications

References 28 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

Mechanism of Action of the Cytotoxic Asmarine Alkaloids

Marine Alkylpurines: A Promising Group of Bioactive Marine Natural Products

Contact Info

Product

Resources

About