A simple and regioselective one-pot procedure for the direct N-acylation of some purine and pyrimidine nucleobases via carboxylic acids using cyanuric chloride

Rad, Mohammad Navid Soltani; Behrouz, Somayeh; Asrari, Zeinab; Khalafi-Nezhad, Ali

doi:10.1007/s00706-014-1270-1

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…In the purine series, however, the analogous reaction is regioselective and resulted in the formation of two products, i.e., N7-and N9-regioisomers (Scheme 1). In no case, the N1-, N3-, or N 6 -products were formed, which is comparable to the results reported for the reaction between benzoyl chloride (BzCl) and purine anions [25].…”

Section: Resultssupporting

confidence: 87%

Ferrocenoyl-adenines: substituent effects on regioselective acylation

Toma¹,

Zubčić²,

Lapić³

et al. 2022

Beilstein J. Org. Chem.

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A series of N6-substituted adenine–ferrocene conjugates was prepared and the reaction mechanism underlying the synthesis was explored. The SN2-like reaction between ferrocenoyl chloride and adenine anions is a regioselective process in which the product ratio (N7/N9-ferrocenoyl isomers) is governed by the steric property of the substituent at the N6-position. Steric effects were evaluated by using Charton (empirical) and Sterimol (computational) parameters. The bulky substituents may shield the proximal N7 region of space, which prevents the approach of an electrophile towards the N7 atom. As a consequence, the formation of N7-isomer is a kinetically less feasible process, i.e., the corresponding transition state structure increases in relative energy (compared to the formation of the N9-isomer). In cases where the steric hindrance is negligible, the electronic effect of the N6-substituent is prevailing. That was supported by calculations of Fukui functions and molecular orbital coefficients. Both descriptors indicated that the N7 atom was more nucleophilic than its N9-counterpart in all adenine anion derivatives. We demonstrated that selected substituents may shift the acylation of purines from a regioselective to a regiospecific mode.

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Section: Resultssupporting

confidence: 87%

Ferrocenoyl-adenines: substituent effects on regioselective acylation

Toma¹,

Zubčić²,

Lapić³

et al. 2022

Beilstein J. Org. Chem.

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“…In contrast to the regiospecific reaction in pyrimidine series, in the course of the reaction between purine anions and FcCOCl, the N7 - and N9 -isomers were detected and isolated thereafter. Neither N1- nor N3-products were observed, which is similar to the results reported for the benzoylation reaction of purines …”

Section: Resultsmentioning

confidence: 66%

“…Neither N1-nor N3-products were observed, which is similar to the results reported for the benzoylation reaction of purines. 31 NMR Spectroscopic Analysis. We observed that the N7isomer in a polar organic solvent, such as dimethyl sulfoxide (DMSO), was transformed to the more stable N9-isomer.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

“…We believe that N7 / N9 isomerization is a common type of rearrangement of acylated purines in DMSO. Therefore, care should be taken while discussing N7 / N9 -regioselectivity of acylation because the N7 / N9 -isomerization of acylated purines can bias the interpretation of the results. One should be also cautious about the stability of N9 - or N7 -acyl purines dissolved in DMSO as stock solution (regularly used in bioassays, etc.…”

Section: Resultsmentioning

confidence: 99%

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Transacylation in Ferrocenoyl-Purines. NMR and Computational Study of the Isomerization Mechanism

et al. 2019

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In the reaction of purines with ferrocenoyl chloride in dimethylformamide (DMF), a regioselective acylation occurred. The two products have been isolated and, according to detailed NMR analysis, identified as N7- and N9-ferrocenoylated isomers. In a more polar solvent, for example, in dimethylsulfoxide (DMSO), the two isomers interconvert to each other. The N7/N9 isomerization was followed by 1H NMR spectroscopy, until dynamic equilibrium was reached. Both kinetics and thermodynamics of the transacylation process are governed by a C6-substituent on the purine ring (R = NH2, Me, NHBz, OBz). The observed rate constant for the N7/N9-isomerization in the adenine system (R = NH2) is k obs = 0.3668 h–1, whereas the corresponding process in the C6-benzyloxypurine is 56 times slower. By use of density functional theory calculations and molecular dynamics simulations, several reaction pathways were considered and explored. Only the reaction mechanism involving DMSO as a nucleophilic reactant is in harmony with the experimental kinetic data. The calculated barrier (ΔG ⧧ = 107.9 kJ/mol; at the M06L/6-311+G(d,p)/SDD level of theory) for this SN2-like reaction in the adenine system agrees well with the experimental value of 102.7 kJ/mol. No isomerization was detected in other organic solvents, for example, acetonitrile, N,N-dimethylformamide, or acetone, which indicated the exceptional nucleophilicity of DMSO. Our results raise a warning when treating or dissolving acylated purines in DMSO as they are prone to isomerization. We observed that the N7/N9-group transfer was specific not only for the organometallic moiety only, but for other acyl groups in purines as well. The relevance of this isomerization may be expected for a series of nucleobases and heterocyclic systems in general.

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“…6-Chloropurine was selected as a substrate to achieve regioselective nucleophilic acyl substitution, assuming that chlorine at that position would hinder the N7 nucleophilic center. We first selected ochlorobenzoic acid as the electrophile, assisted by cyanuric chloride, 52 unsuccessfully. With the use of o-chlorobenzoyl chloride as the acylating reagent, several bases, for example, pyridine or TEA, and solvents such as DMF, CH 2 Cl 2 , or MeCN were probed, achieving the best yield (78%) for the synthesis of 2 with the TEA/DMAP system as the base in THF (Scheme 1).…”

Section: ■ Resultsmentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Novel Non-nucleotide Purine Derivatives as P2X7 Antagonists for the Treatment of Neuroinflammation

et al. 2021

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The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached clinical trials for this indication. In this work, we designed and synthesized novel blood−brain barrier (BBB)permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in Xenopus laevis oocytes, and in interleukin 1β release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and Pglycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound 6 (2-(6-chloro-9Hpurin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound 6 can be considered as a first non-nucleotide purine hit for future drug optimizations.

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A simple and regioselective one-pot procedure for the direct N-acylation of some purine and pyrimidine nucleobases via carboxylic acids using cyanuric chloride

Cited by 9 publications

References 34 publications

Ferrocenoyl-adenines: substituent effects on regioselective acylation

Ferrocenoyl-adenines: substituent effects on regioselective acylation

Transacylation in Ferrocenoyl-Purines. NMR and Computational Study of the Isomerization Mechanism

Synthesis and Pharmacological Evaluation of Novel Non-nucleotide Purine Derivatives as P2X7 Antagonists for the Treatment of Neuroinflammation

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