BrΦnsted acid-promoted ‘on-water’ C(sp^3)-H functionalization fot the synthesis of isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine derivatives targeting the SKP2-CKS1 interaction

The isoindolinone and biaryl scaffolds are prevalent in natural products and drug molecules,which have showed broad and interesting biological activities.The efficient construction of such hybridized molecules and biological evaluation are of great interest to medicinal chemistry community.In this communication,we report an efficient BrΦnsted acid-promoted C(sp^3)-H functionalization approach that enables the rapid construction of biologically important isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine hybrids from 5-methyl-7-(2,4,6-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine,2-formylbenzoic acid and various anilines.The title compounds were generated in high to excellent yields(up to 96%)regardless of the electronic nature and steric effects of the substituents.In this reaction,an isoindolinone scaffold,one C-C single bond,and two C-N bonds were formed simultaneously with high atom economy.In this work,we have envisioned that the methyl group linked to the electron-deficient Nheterocycles could be used as a new synthetic handle for late-state diversification and may have broad applications in the field of organic and medicinal chemistry.Besides,the title compounds have exhibited promising activity against the SKP2-CKS1 interaction.     

A convenient synthesis of 2-aryl substituted benzo[f] [1,2,4]triazolo[1,5-a]azepine derivatives

A convenient synthetic pathway to 2-aryl-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[1,5-α]azepine derivatives 7 was developed. The synthesis was based on the cycloaddition of the 1,2,3,4-tetrahydronaphthalene a-acetoxy azo compounds 3 with Ar-CN in the presence of AlCl3 and the consecutive ring enlargement.     

Fluoroalkyl-containing lithium β-diketonates in the synthesis of 1,2,4-triazolo[1,5-a]pyrimidines

Cyclocondensation of fluorine-containing lithium -diketonates with 3-amino-1,2,4-triazoles afforded 7-fluoromethyl-1,2,4-triazolo[1,5-a]pyrimidines.     

Synthesis of 2-substituted 6,8-dinitro[1,2,4]triazolo[1,5-a]pyridines and the formation of the related zwitterionic σ-adducts

A method for the synthesis of 2-substituted 6,8-dinitro[1,2,4]triazolo[1,5-a]pyridines is proposed. The method includes the reaction of 2-chloro-3,5-dinitropyridine with the corresponding 5-substituted tetrazoles. The resulting compounds react with anhydro bases of α- and γ-methylazinium salts to give zwitterionic σ-adducts. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1405–1407, July, 1999.     

One-pot synthesis of 6H-pyrrolo[2,3-e[1,2,4]triazolo[1,5-a]pyrimidines on the basis of σH-adducts of 6-Nitro[1,2,4]triazolo[1,5-a]pyrimidine with carbonyl compounds

Aromatic, heteroaromatic, and aliphatic carbonyl compounds reacted with 6-nitro[1,2,4]triazolo[1,5-a]pyrimidine in the presence of a base to give stable σ^H-adducts at C⁷. Reduction of the nitro group in the latter is accompanied by tandem autoaromatization of the azine ring and intramolecular cyclocondensation with formation of the corresponding 6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyrimidines. Original Russian Text ? E.B. Gorbunov, G.L. Rusinov, R.I. Ishmetova, V.N. Charushin, O.N. Chupakhin, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 1, pp. 130–134. Dedicated to Full Member of the Russian Academy of Sciences G.A. Tolstikov on his 75th anniversary     

A simple and convenient synthesis of [1,2,4]triazolo/benzimidazolo ‎quinazolinone and [1,2,4]triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidine derivatives catalyzed by ‎DABCO-based ionic liquids

DABCO-based ionic liquids were utilized for the preparation of [1,2,4]triazolo/benzimidazolo quinazolinone and [1,2,4]triazolo[1,5-a]pyrimidine derivatives in the adequate procedures. These methods involve three-component reaction between aldehydes, β-diketones and 3-amino-1,2,4-triazole or 2-aminobenzimidazole in the presence of 1,4-disulfo-1,4-diazabicyclo[2.2.2]octane-1,4-diium chloride ([DABCO](SO₃H)₂(Cl)₂) and 1,4-disulfo-1,4-diazabicyclo[2.2.2]octane-1,4-diium dihydrogen sulfate ([DABCO](SO₃H)₂(HSO₄)₂) as reusable and economical catalysts at 100 °C. These methods also show eco-friendly characters by elimination of solvent. Any by-product was not prepared through this method, and products were separated by a simple workup procedure. The other noticeable benefits of these procedures are excellent yields, short reaction times, mild reaction conditions and use of available and inexpensive materials.     

Facile synthesis of azaarene-substituted 3-hydroxy-2-oxindoles via Brønsted acid catalyzed sp3 C-H functionalization

Br?nsted acid catalyzed functionalization of sp(3) C-H bonds in 2-methyl azaarenes has been achieved in the reaction with isatins. This method provides facile synthesis of biologically important azaarene-substituted 3-hydroxy-2-oxindoles in one step in moderate to good yields.     

Design of fused systems based on σH-adducts of 6-nitro-1,2,4-triazolo[1,5-a]pyrimidine with π-excessive heteroaromatic compounds

Russian Chemical Bulletin - A new method was developed for the construction of tetra- and pentacyclic fused systems based on σH-adducts of 6-nitro-1,2,4-triazolo[1,5-a]pyrimidine with...     

Synthesis of pyrido[3′,2′:4,5]thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-one derivatives

Some new pyrido[3′,2′:4,5]thieno[2,3-e]-[1,2,4]triazolo[4,3-a] pyrimidin-5(4H)-ones were prepared through heterocyclization of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate with phenyl or ethyl isothiocyanate followed by nucleophilic displacement with hydrazine, and finally cyclocondensation with orthoesters. Correspondence: Abolghasem Davoodnia, Department of Chemistry, School of Sciences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran.     

C–H Arylation using acyl thiourea ligands: Applications in the synthesis of 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

Synthesis of a series of new 3,6-diaryl-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles(5a–o) was achieved by phophine free, C–H arylative cross-coupling of 6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles(4a–o)with suitably substituted iodoanilines using 1-(2-naphthoyl)-3-(4-bromophenyl)thiourea as a ligand.The requisite triazolothiadiazoles(4a–o) were obtained by the condensation of 4-amino-1,2,4-triazole-3-thiol(3) with suitably substituted aromatic acids in the presence of phosphoryl chloride.     

Synthesis,Crystal Structure and Herbicidal Activity of O,O＇-Diethyl-N-[2-（5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yloxy）-benzoxyl]-1-amino-benzyl phosphonate

The crystal structure of the title compound (C25H28N5O5P,Mr=509.49) has been determined by single-crystal X-ray diffraction.The crystal is of monoclinic,space group P21/c with a=13.0726(4),b=13.4513(4),c=15.103(1),β=93.650(1)°,V=2650.29(14)3,Z=4,Dc= 1.277 g/cm3,F(000)=1072,μ(MoKα)=0.147 mm-1,the final R=0.0748 and wR=0.1956 for 3186 observed reflections (I 2σ(I)).The fused triazolopyrimidine system ring is coplanar,the dihedral angles between the triazolopyrimidine and C(1)-C(3)-C(5) phenyl,the triazolopyrimidine and C(17)-C(19)-C(21) phenyl,and the two phenyl rings are 66.87,58.79 and 80.11o,respectively.Intramolecular N(5)-H(5A)…O(3) and intermolecular C(2)-H(2)…N(4),C(18)-H(18)…O(3),C(19)-H(19)…O(2) and C(24)-H(24C)…N(4) hydrogen bonds together with C-H…π interactions contribute to the stability of the structure and result in a three-dimensional framework.The preliminary bioassay indicates that the title compound exhibits moderate herbicidal activity against dicotyledonous plants (Brassica campestris L) at the concentration of 100 mg/L.     

Iodine-catalyzed efficient synthesis of azaarene substituted 3-hydroxy-2-oxindole derivatives through sp3 C–H functionalization

Iodine-catalyzed benzylic sp³ C–H bond functionalization of lutidines or picolines to isatins is described. This synthetic method provides a rapid entry towards biologically interesting 3-azaarene substituted 3-hydroxy-2-oxindole derivatives.     

Anomeric Stereoauxiliary Cleavage of the C−N Bond of d-Glucosamine for the Preparation of Imidazo[1,5-a]pyridines

The targeted cleavage of the C−N bonds of alkyl primary amines in sustainable compounds of biomass according to a metal-free pathway and the conjunction of nitrogen in the synthesis of imidazo[1,5-a]pyridines are still highly challenging. Despite tremendous progress in the synthesis of imidazo[1,5-a]pyridines over the past decade, many of them can still not be efficiently prepared. Herein, we report an anomeric stereoauxiliary approach for the synthesis of a wide range of imidazo[1,5-a]pyridines after cleaving the C−N bond of d -glucosamine (α-2° amine) from biobased resources. This new approach expands the scope of readily accessible imidazo[1,5-a]pyridines relative to existing state-of-the-art methods. A key strategic advantage of this approach is that the α-anomer of d -glucosamine enables C−N bond cleavage via a seven-membered ring transition state. By using this novel method, a series of imidazo[1,5-a]pyridine derivatives (>80 examples) was synthesized from pyridine ketones (including para-dipyridine ketone) and aldehydes (including para-dialdehyde). Imidazo[1,5-a]pyridine derivatives containing diverse important deuterated C(sp²)−H and C(sp³)−H bonds were also efficiently achieved.     

An efficient and solvent-free one-pot multi-component synthesis of novel highly substituted pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives catalyzed by tetramethylguanidine

Abstract

An efficient solvent-free access towards highly substituted pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives has been established through multi-component reaction of 1H‐pyrazolo[3,4‐b]pyridin‐3‐amine, aldehyde, 3-(1H-indol-3-yl)-3-oxopropanenitrile catalyzed by 1,1,3,3-tetramethylguanidine (TMG). The reaction allows the formation of one C?C and two C?N bonds with high yield. The significant features of this solvent-free reaction include mild reaction condition, readily accessible substrates, short reaction time, excellent yield, and broad substrate scopes as well as simple one-pot operation, no column chromatographic purification, which makes this strategy highly attractive.     

Novel 2H-[1,2,4]thiadiazolo[2,3-a]pyrimidine derivatives bearing chiral S(−)-2-(4-chlorophenyl)-3-methylbutyric acid moiety: Design,synthesis and herbicidal activity

A series of S(?)-2-(4-chlorophenyl)-N-(5,7-disubstituted-2H-[1,2,4]-thiadiazolo[2,3-a]pyrimidin-2-ylidene)-3-methylbutanamide derivatives were designed and synthesized. The structures of all the newly synthesized compounds had been identified by elemental analysis, ¹H NMR, MS and optical rotation. Their herbicidal activities were evaluated against a variety of weeds. The preliminary results showed that most of the target compounds had moderate inhibitory activities and selectivities against root and stalk of monocotyledon and dicotyledon plants. More importantly, the chiral target compounds showed improved herbicidal activities to some extent over their racemic counterparts against a variety of tested weeds, which might be contributed by the introduction of chiral active unit. The present work provided a novel class of chirality-based thiadiazolopyrimidine derivatives with potent herbicidal activities for further optimization.     

One-pot synthesis of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives via the three-component reaction of 1,2-diamines,ethyl pyruvate and α-bromo ketones

A simple synthetic protocol has been developed involving the three-component reaction between 1,2-diamines, ethyl pyruvate and a-bromo ketones in the presence of Fe Cl3 as a catalyst. A number of pyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]pyrazine derivatives were synthesized in excellent yields using this protocol.     

Catalyst-free synthesis of 3-hydroxyimidazo[1,2-a]pyridine zwitterion derivatives via the three-component reaction of ethyl glyoxalate, 2‑aminopyridines and cyclic 1,3-dicarbonyls

The three-component reaction of ethyl glyoxalate, 2-aminopyridines, and cyclic 1,3-dicarbonyl compounds such as 4-hydroxycoumarin, N,N-dimethylbarbituric acid and 4-hydroxy-6-methyl-2H-pyran-2-one is described for the synthesis of 3-hydroxyimidazo[1,2-a]pyridine zwitterion derivatives.     

Facile synthesis and characterization of novel pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one and pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine incorporating 1,3-diarylpyrazole moiety

4-(3-(4-Hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-6-phenyl-2-thioxo-1,2-di hydro-pyridine-3-carbonitrile (1) reacted with ethyl chloroacetate (2) in ethanolic sodium acetate solution to yield the corresponding ethyl (3-cyanopyridin-2-ylsulphanyl)acetate derivative 3. Intramolecular cyclization of compound 3 was achieved by its heating in DMF containing potassium carbonate to afford the corresponding ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate derivative 4 which reacted with hydrazine hydrate in refluxing pyridine to yield the starting material 3-aminothieno[2,3-b]pyridine-2-carbohydrazide derivative 7. Compound 7 reacted with different reagents such as triethylorthoformate, formic acid, acetic acid and acetic anhydride to afford the target molecules pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives 8–10, 12 and 13 in good to excellent yields. On the other hand, pyridine-2(1H)-thione derivative 1 reacted with hydrazine hydrate in refluxing pyridine to give the other starting material 3-amino-1H-pyrazolo[3,4-b]pyridine derivative 20 which reacted with acetylacetone under reflux to afford the target molecule pyrido[2′,3′:3,4]pyrazolo[1,5-a]-pyrimidine derivative 21 in a good yield. The structures of target molecules were elucidated using elemental analyses and spectral data.     

Fused quinoline heterocycles X. First synthesis of new four heterocyclic ring systems 10-amino-6,9-disubstituted-[1,2,4]triazino[4′,3′:1,5]pyrazolo[4,3-c]quinoline derivatives

A novel, simple, and efficient synthetic methodology for the synthesis of hitherto unreported tetracyclic 10-amino-6,9-disubstituted-[1,2,4]triazino[4′,3′:1,5]pyrazolo[4,3-c]quinolines, in one step, has been developed by coupling of various active methylene compounds with diazotized heterocyclic amines. Reacting 2,4-dichloroquinoline-3-carbonitrile (1) with cyanoacetic acid hydrazide (2) in the presence of triethylamine in refluxing MeOH gave the unexpected 3-amino-4-chloro-1H-pyrazolo[4,3-c]quinoline (4), instead of the desired tetracyclic ring system 3 (Scheme 1). Refluxing 4 with excess of cyclic secondary amines 5a–c in boiling dimethylformamide yielded the corresponding 4-amino-pyrazolo[4,3-c]quinolines 6a–c. Diazotization of compounds 4 and 6a–c with sodium nitrite and concentrated HCl at ?5?°C gave the corresponding diazonium salts 17a–d, which were then subjected to couple with different active methylene nitriles, namely, 2-cyanothioacetamide (12), ethyl cyanoacetate (13), malononitrile (14), 2-cyanoacetamide (15), and 2-cyano-N-phenylacetamide (16), in aqueous ethanol containing sodium acetate as a buffer solution. The coupling reaction of diazonium salts 17 with 12, 13, and 14 leading to the novel perianellated tetracyclic ring system 10-amino-6,9-disubstituted-[1,2,4]triazino[4′,3′:1,5]pyrazolo[4,3-c]quinolines 19, 23, and 27, respectively, in one step, is described for the first time. On the other hand, coupling reaction of diazonium salt 17a with both 15 and 16 yielded the previously unknown tetracyclic 10-amino-6-chloro-[1,2,4]triazino[4′,3′:1,5]pyrazolo[4,3-c]quinoline-9-carboxamides 28a and 28b, respectively (Scheme 6). No chromatographic techniques have been used for the purification of the products. The structures of all the newly synthesized compounds were unambiguously confirmed by spectroscopic and analytical techniques.