Synthesis and structural analysis of 5‐cyanodihydropyrazolo[3,4‐<i>b</i>]pyridines

Quiroga, Jairo; Cruz, Silvia; Insuasty, Braulio; Abonı́a, Rodrigo; Cobo, Justo; Sánchez, Adolfo; Nogueras, Manuel; Low, John N.

doi:10.1002/jhet.5570380108

Cited by 65 publications

(20 citation statements)

References 30 publications

(18 reference statements)

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“…This preference of the 1 H tautomer in pyrazolopyridines agrees with structural analysis of 4‐aryl‐5‐cyano‐pyrazolo[3,4‐ b ]pyridines [22], theoretical studies of pyrazolo[3,4‐ b ]pyridines bearing a variety of substituents [23], and crystallographic data of protein–ligand complexes [24], which indeed confirm that in this class of compounds, the (N1)H forms key H‐bonds with the enzymes (cyclin‐dependent kinases).…”

Section: Resultssupporting

confidence: 82%

Studies on the acetylation of 3,6‐diamino‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitrile derivatives

Chioua

Soriano

Samadi

et al. 2010

Journal of Heterocyclic Chem

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in Wiley InterScience (www.interscience.wiley.com).The acetylation reaction of the differently substituted 3,6-diamino-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile derivatives 1-6 is reported. The structure of the resulting acetamides has been investigated and confirmed by analytical, spectroscopic, and chemical transformations. From these studies, we conclude that, in general, under mild conditions, and using acetic anhydride, when free, the N(1)H moiety is a more reactive center respect to the C(3)NH 2 and C(6)NH 2 groups. This trend is reversed when no steric hindrance due to presence of a phenyl group at C4 drives the preferred acetylation to C(3)NH 2 , as it is evident by comparing the observed results from precursor 1 with 3. When N1 is blocked, the (C3)NH 2 group undergoes preferential acetylation over the (C6)NH 2 site, which only has been mono (or diacetylated) at reflux. Computational analyses based on DFT studies have been extensively used to explain the observed reactivities.

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Section: Resultssupporting

confidence: 82%

Studies on the acetylation of 3,6‐diamino‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitrile derivatives

Chioua

Soriano

Samadi

et al. 2010

Journal of Heterocyclic Chem

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“…In all cases, either complex mixtures of products were obtained or the initial compound remained unchanged. It should be noted that 5(3)-amino-3(5)-methyl-1H-pyrazole having no substituent in position 4 reacts with dimedone and aldehydes in boiling ethanol with high regioselectivity to produce tricyclic compounds with different structure, 4,7,8,9-tetrahydro-2H-pyrazolo[3,4-b]quinolin-5(6H)-ones [23]; here, the reaction centers in the initial pyrazole molecule are nitrogen atom in the exocyclic amino group and C 4 . On the other hand, three-component condensation of 5(3)-amino-3(5)-phenyl-1H-pyrazole with a cyclic 1,3-diketone and aromatic aldehydes in ethanol at 20°C under ultrasonic activation afforded 9-aryl-2-phenyl-4,5,6,7,8,9-hexahydropyrazolo[5,1-b]quinazolin-8-ones in good yields [24].…”

Section: Ia Idmentioning

confidence: 99%

α-Amino azoles in the synthesis of heterocycles: VI. Synthesis and structure of cycloalkane-annulated pyrazolo[1,5-a]pyrimidines

et al. 2009

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Reactions of 4-aryl-1H-pyrazol-5(3)-amines with 2-acylcycloakanones and 2-acyl-5,5-dimethylcyclohexane-1,3-diones led to the formation of regioisomeric 6,7,8,9-tetrahydropyrazolo[1,5-a]quinazoline, 5,6,7,8-tetrahydropyrazolo[5,1-b]quinazoline, and 7,8-dihydro-6H-cyclopenta[e]pyrazolo[1,5-a]pyrimidine derivatives. The product structure was determined by X-ray analysis and 1 H and 13 C NMR spectroscopy. * For communication V, see [1]. Extensive development of synthetic approaches to polyfunctional pyrazolo[1,5-a]pyrimidine derivatives is stimulated by the fact that compounds possessing pyrazole and pyrimidine fragments are promising as potential biologically active substances. Several efficient medical agents exhibiting sedative and soporific activity (such as Zaleplon [2], Indiplon [3], and Ocinaplon [4]) are known; some compounds of this series have been patented as antidiabetic [5] and antiphlogistic agents [6], antidepressants [7], and analgesics [8,9]. Pronounced biological activity of pyrazolo-[1,5-a]pyrimidine derivatives was noted in [10][11][12][13][14][15][16][17].The goal of the present work was to study regioselectivity in the formation of cycloalkane-annulated pyrazolo[1,5-a]pyrimidines and determine characteristic 13 C NMR spectral parameters of particular regioisomers. We examined reactions of 5(3)-amino-4-aryl-1H-pyrazoles Ia-Id with 2-acylcycloalkanones III-VII and three-component condensation of 5(3)-amino-4-aryl-1H-pyrazoles Ia and Id with dimedone and aldehydes.Aminopyrazoles I reacted with 2-ethoxymethylidene-5,5-dimethylcyclohexane-1,3-dione (II) and 2-acetyl-5,5-dimethylcyclohexane-1,3-dione (III) to give only substituted 6,7,8,9-tetrahydropyrazolo-[1,5-a]quinazolines which may be regarded as pyrazolopyrimidines fused at the C 6 -C 7 bond to cyclohexene ring. The reaction begins with nucleophilic attack by the amino nitrogen atom of pyrazole I at the carbon atom of the ethoxymethylidene or acetyl group in II or III, respectively. In the first case, the primary linear adduct, 5,5-dimethyl-2-{[(3-methyl-4-phenyl-1H-pyrazol-5-yl)amino]methylidene}cyclohexane-1,3-dione (A), was isolated as individual substance, while in the second case, 3-hydroxy-5,5-dimethyl-2-{1-[(4-phenyl-1H-pyrazol-3-yl)imino]ethyl}cyclohex-2-en-1-one (B) was detected as intermediate product by 1 H NMR (Scheme 1). The formation of an analogous intermediate compound was observed previously in the reaction of 5-methoxymethylidene-2,2-dimethyl-1,3-dioxane-4,6-dione with 5(3)-aminopyrazoles [18]. In the 1 H NMR spectrum of compound A, the NH proton in the pyrazole ring resonated at δ 12.82 ppm, and the exocyclic CH= and NH protons gave doublets at δ 8.65 and 12.76 ppm, respectively, with a coupling constant 3 J of 13.1 Hz. The downfield position of the latter NH signal indicates formation of intramolecular hydrogen bond NH · · · O. The structure of intermediate B was determined by 1 H NMR monitoring of the reaction of aminopyrazole Id with acetyldimedone III in DMSO-d 6 at 20°C. After 2 days, the 1 H NMR spectrum of the reaction...

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“…Several reactions were developed in the last decades for which the reactivity of hetarylacetonitriles towards diverse reagents was exploited for the synthesis of nitrogen bridged heterocycles. [1][2][3] From the point of view for biological activities, acetonitrile derivatives are useful intermediates and subunits for the development of molecules having pharmaceutical or biological interests. [4][5][6] Nitrogen containing heteroaromatic compounds have received considerable attention in the literature over the years.…”

Section: Introductionmentioning

confidence: 99%

“…From the synthetic point of the view, it is known that heteroaromatic acetonitrile derivatives undergo Knoevenagel condensation reactions with arylaldehydes to yield 3-aryl-2hetarylacrylonitriles. [1][2][3][5][6][7][8][9] Substituted acrylonitriles have been found to possess interesting biological properties, among them, antifungal and antitumor activities. 7,10,11 Although acrylonitrile derivatives are an-easy-to synthesize template, a great diversity of the methods is available in literature that describe their synthesis under different conditions making use of conventional thermal energy and microwave irradiation conditions.…”

Section: Introductionmentioning

confidence: 99%

“…7,10,11 Although acrylonitrile derivatives are an-easy-to synthesize template, a great diversity of the methods is available in literature that describe their synthesis under different conditions making use of conventional thermal energy and microwave irradiation conditions. [1][2][3][12][13][14][15][16][17] Typically, Knoevenagel adducts have been obtained under conventional heating conditions for extended periods of reaction in the presence of catalytic amounts of base, obtaining generally from good to very low yields. [18][19][20][21][22][23] Condensation reactions leading to heterocyclic systems have been performed with great success under Vol.…”

Section: Introductionmentioning

confidence: 99%

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Microwave-assisted synthesis under solvent-free conditions of (E)-2-(Benzo[d]thiazol-2-yl)-3-arylacrylonitriles

Trilleras¹,

Velásquez²,

Pacheco³

et al. 2011

J. Braz. Chem. Soc.

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Uma série de (E)-2-(benzo[d]tiazol-2-il)-3-arilacrilonitrilas foi sintetizada pela condensação de Knoevenagel assistida por microondas, na ausência de solvente, partindo do correspondente 2-(benzo[d]tiazo-2-il)acetonitrila e aldeídos aromáticos, contendo tanto grupos doadores de elétrons, como retiradores. Os tempos de reação foram consideravelmente curtos e os produtos, obtidos em rendimentos moderados (50-75%) e boa pureza. A configuração da dupla ligação da acrilonitrila não pôde ser estabelecida por métodos comuns de RMN. No entanto, estudos teóricos sugerem que nesses compostos o isômero E é mais estável do que o Z, o que está de acordo com algumas evidências experimentais.A series of (E)-2-(benzo[d]thiazol-2-yl)-3-arylacrylonitriles was synthesized by microwave assisted Knoevenagel condensation under solvent-free conditions from the corresponding 2-(benzo[d]thiazol-2-yl)acetonitrile and aromatic aldehydes with electrondonating/electronwithdrawing groups. The reaction times were considerably short and the products obtained in moderate yields (50 to 75%) and good purity. The configuration of the acrylonitrile double bond could not be established by regular NMR methods. However, theoretical studies suggest that the E isomer is more stable than Z, which is in good agreement with some experimental evidences.

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Synthesis and structural analysis of 5‐cyanodihydropyrazolo[3,4‐b]pyridines

Cited by 65 publications

References 30 publications

Studies on the acetylation of 3,6‐diamino‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitrile derivatives

Studies on the acetylation of 3,6‐diamino‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitrile derivatives

α-Amino azoles in the synthesis of heterocycles: VI. Synthesis and structure of cycloalkane-annulated pyrazolo[1,5-a]pyrimidines

Microwave-assisted synthesis under solvent-free conditions of (E)-2-(Benzo[d]thiazol-2-yl)-3-arylacrylonitriles

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