Three-Component Assembly of Structurally Diverse 2-Aminopyrimidine-5-carbonitriles

Val, Cristina; Crespo, Abel; Yaziji, Vicente; Coelho, Alberto; Azuaje, Jhonny; Maatougui, Abdelaziz El; Sotelo, Eddy

doi:10.1021/co4000503

Cited by 17 publications

(7 citation statements)

References 46 publications

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“…The targeted 2-amino-4,6-disubstitutedpyrimidine-5-carbonitriles (18, 19, and 20) were assembled following an efficient and convergent three-component transformation (Scheme 1) described by our group. 45 The Biginelli-inspired preparative method relies on the reaction of α-cyanoketones (21), carboxaldehydes (22), and guanidines (23) in a one-pot sequence that renders 18−21 in moderate to excellent yields (45−89%) after purification by either column chromatography or crystallization (isopropanol or ethanol). The threecomponent transformation includes a sequence involving condensation, nucleophilic addition, cyclization, and spontaneous aromatization of the 2-amino-1,4-dihydropyrimidine-5carbonitrile intermediate.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

et al. 2022

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We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A 1 AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure–activity and structure–selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R 4 and R 6 of the pyrimidine core but most importantly the prominent role to the unprecedented A 1 AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure–activity relationship trends on both A 1 and A 2A ARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

et al. 2022

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“…This study was different from other studies in literature in terms of starting materials. According to literature, many substances were synthesized in different solvents by using different beginning reagents such as urea/thiourea and/or its derivatives or guanidine salts, different catalysts, and bases such as Na 2 CO 3, 45 K 2 CO 3 46 and ionic liquid, 47 etc. As a single‐pot reaction, this study obtained a series of the most efficient product in the piperidine.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of novel heterocyclic compounds containing pyrimidine nucleus using the Biginelli reaction: Antiproliferative activity and docking studies

Yavuz

Akkoç

Türkmenoğlu

et al. 2020

Journal of Heterocyclic Chem

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In a single reaction step, pyrimidine derivatives (4a‐p) were synthesized from the triple reaction of aromatic aldehydes (1), ethyl cyanoacetate (2), and some guanyl hydrazone derivatives (3a‐n). These compounds were tested as in vitro against two types of cancerous cell lines, namely, a human colon cancerous cell line (DLD‐1) and a human breast cancerous cell line (MDA‐MB‐231). According to the obtained results, nearly all the compounds have cytotoxic activity in the tested cell lines. Especially, the compounds 4j, 4k, and 4n had a significant effect against DLD‐1. Furthermore, compounds 4g, 4m, and 4o exhibited lower IC50 values compared to other synthesized compounds against MDA‐MB‐231. We hope that these compounds can be improved as anticancer agents in the future. Molecular docking was performed according to both topoisomerase I and N‐acetyltransferase 1 proteins to examine theoretically the binding mode and site of pyrimidine compounds having the best activity.

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“…Recently, we studied alkyne insertion reactions of cyclopalladated guanidines of the types [κ 2 ( C , N )Pd(μ-Br)] 2 and [κ 2 ( C , N )Pd(Lewis base)Br] to afford a variety of alkyne-inserted palladacycles with unanticipated frameworks, mainly due to ring contraction cum amine–imine tautomerization of alkyne-inserted palladacyclic intermediates in conjunction with the nature of the alkyne, coordinated anion, and other reaction conditions. , We have chosen the monoalkyne- and dialkyne-inserted cyclopalladated guanidines I – III for depalladation reactions following the first route, as such an attempt would afford guanidine-containing heterocycles/carbocycles (see Chart ) . We have also used the cyclopalladated guanidines IV and V as starting materials for more reactive substrates of the type [κ 2 ( C , N )PdL 2 ] + [WCA] − , which would enable us to isolate guanidine-containing hetero- and carbocycles through the second route, as outlined above (see Chart ). , Nitrogen-containing heterocycles are medicinally important compounds, and more importantly, guanidine-containing heterocycles are considered as privileged scaffolds in heterocyclic chemistry. , Line drawings of a few medicinally important guanidine-containing heterocycles are shown in Chart . , Herein, we report the synthesis and characterization of three new cationic cyclopalladated guanidines, four new heterocycles, and one carbocycle. Line drawings of the new compounds 1 – 8 are shown in Chart .…”

Section: Introductionmentioning

confidence: 99%

Depalladation of Neutral Monoalkyne- and Dialkyne-Inserted Palladacycles and Alkyne Insertion/Depalladation Reactions of Cationic Palladacycles Derived from N,N′,N″-Triarylguanidines as Facile Routes for Guanidine-Containing Heterocycles/Carbocycles: Synthetic, Structural, and Mechanistic Aspects

2014

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Depalladation of the monoalkyne-inserted cyclopalladated guanidines [κ 2 (C,N)Pd(2,6-Me 2 C 5 H 3 N)Br] (I and II) in PhCl under reflux conditions and that of the dialkyne-inserted cyclopalladated guanidine [κ 2 (C,N):η 2 (CC)PdBr] (III) in pyridine under reflux conditions afforded a guanidine-containing indole (1), imidazoindole (2), and benzazepine (3) in 80%, 67%, and 76%, yields, respectively. trans-[L 2 PdBr 2 ] species (L = 2,6-Me 2 C 5 H 3 N, C 5 H 5 N) were also isolated in the aforementioned reactions in 35%, 42%, and 40% yields. Further, the reaction of the cyclopalladated guanidine [κ 2 (C,N)Pd(μ-Br)] 2 (IV) with AgBF 4 in a CH 2 Cl 2 /MeCN mixture afforded the cationic pincer type cyclopalladated guanidine [κ 3 (C,N,O)Pd(MeCN)][BF 4 ] (4) in 85% yield and this palladacycle upon crystallization in MeCN and the reaction of [κ 2 (C,N)Pd(μ-Br)] 2 (V) with AgBF 4 in a CH 2 Cl 2 /MeCN mixture afforded the cationic palladacycles [{κ 2 (C,N)Pd(MeCN) 2 ][BF 4 ] (5 and 6) in 89% and 91% yields, respectively. The separate reactions of 4 with 2 equiv of methyl phenylpropiolate (MPP) or diphenylacetylene (DPA) and the reaction of 5 with 2 equiv of MPP in PhCl at 110 °C afforded the guanidine-containing quinazolinium tetrafluoroborate 7 in 25−32% yields. The reaction of 6 with 2 equiv of DPA under otherwise identical conditions afforded the unsymmetrically substituted guanidinium tetrafluoroborate 8, containing a highly substituted naphthalene unit, in 82% yield. Compounds 1−8 were characterized by analytical and spectroscopic techniques, and all compounds except 4 were characterized by single-crystal X-ray diffraction. The molecular structures of 2 and 3 are novel, as the framework in the former arises due to the formation of two C−N bonds upon depalladation while the butadienyl unit in the latter revealed cis,cis stereochemistry, a feature unprecedented in alkyne insertion chemistry. Plausible pathways for the formation of heterocycles/carbocycles are proposed. The influence of substituents on the aryl rings of the cyclopalladated guanidine moiety and those on alkynes upon the nature of the products is addressed. Heterocycles 1 and 7 revealed the presence of two rotamers in about a 1.00:0.43 ratio in CDCl 3 and in about a 1.00:0.14 ratio in CD 3 OD, respectively, as detected by 1 H NMR spectroscopy while in CD 3 CN and DMSO-d 6 (1) and CD 3 CN and CDCl 3 (7), these heterocycles revealed the presence of a single rotamer. These spectral features are attributed to the restricted C−N single-bond rotation of the CN 3 unit of the guanidine moiety, which possibly arises from steric constraint due to the formation of a N−H•••Cl hydrogen bond with CDCl 3 (1) and N−H•••O and O−D•••O hydrogen bonds with CD 3 OD (7).

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Three-Component Assembly of Structurally Diverse 2-Aminopyrimidine-5-carbonitriles

Abstract: An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization.

Cited by 17 publications

References 46 publications

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

Synthesis of novel heterocyclic compounds containing pyrimidine nucleus using the Biginelli reaction: Antiproliferative activity and docking studies

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Three-Component Assembly of Structurally Diverse 2-Aminopyrimidine-5-carbonitriles

Abstract: An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization.

Cited by 17 publications

References 46 publications

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists

Synthesis of novel heterocyclic compounds containing pyrimidine nucleus using the Biginelli reaction: Antiproliferative activity and docking studies

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Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A₁ Antagonists