A synthesis of 6-functionalized 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines

6-Unsubstituted 7-R-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines (R = H or Me) were synthesized via two pathways: (a) deacylation of the corresponding 5-acetyl Biginelli-like precursors in KOH/H₂O and (b) reduction of the corresponding 1,2,4-triazolo[1,5-a]pyrimidines using LiAlH₄. The products could be easily formylated at position 6, which is promising for the further synthesis of functionalized 6-substituted derivatives of 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. In contrast, 6-acetyl-7-(4-(N,N-dimethylaminophenyl))-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine undergoes a cascade process in KOH/H₂O, leading to the formation of a 4,5,8,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline derivative.     

A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines

A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by N-(2-heteroaryl)amides to yield a ketenimine intermediate, which was cyclized and then rearranged under the reaction conditions to afford the title compounds under mild reaction conditions in good yields. Single-crystal X-ray analysis conclusively confirms the structure of the obtained bridgehead bicyclic 6-6 heterocyclic compounds.     

New Facile Route to Synthesize Furo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine and Furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives

A new facile route for synthesis of 3-(aryl)-8,9-diphenylfuro[3,2-e][1,2,4]triazolo pyrimidines derivative from the same starting material, 2-amino-4,5-diphenylfuran-3-carbonitrile, has been developed through heterocyclization of the corresponding arylidene-hydrazono-5,6-diphenylfuro[2,3-d]pyrimidine and N-(arylmethylene)-4-imino-5,6-diphenylfuro[2,3-d]pyrimidin-3(4H)-amine under refluxing condition with acetic anhydride followed by air oxidation. The products were obtained in good yield with an easy workup along with the purification of products by a nonchromatographic method. This general synthetic procedure can be extended to the preparation of a wide range of isomeric triazoles using 2-amino 3-carbonitrile bifunctional derivatives.     

A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

Synthesis of derivatives of 3-acetyl-2-aminopyrrole and pyrolo[2,3-d]pyrimidine from monoacetylketene aminals

A new scheme for the synthesis of pyrrolo[2,3-d]pyrimidines from monoacetylketene animals was proposed. Reactions of monoacetylketeneN-benzoyl- andN-acetylaminals with -bromoacetophenone afforded the corresponding 3-acetyl-2-acylamino-5-phenyl- lH-pyr-roles, which underwent cyclization to 2,4,6-trisubstituted 7Hl-pyrrolo[2,3-d]pyrimidines under the action of ammonium acetate in boiling BuOH.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp, 1808–1811, July, 19W     

Studies on uracils: a facile one-pot synthesis of oxazino[4,5-d]-, pyrano[2,3-d]-, pyrido[2,3-d]- and pyrimido[4,5-d]pyrimidines using microwave irradiation in the solid state

N,N-Dimethyl-5-formylbarbituric acid 1 reacts with maleimide 2 and phenyl isocyanate/phenyl isothiocyanate 4 under microwave-assisted conditions in the solid phase to afford pyrano[2,3-d]pyrimidines 3 and oxazino[4,5-d]pyrimidines 5 in excellent yields. Under identical conditions, N,N-dimethyl-6-amino-5-formyluracil 6 reacts with 2 and 4 to give pyrido[2,3-d]pyrimidine derivative 7 and pyrimido[4,5-d]pyrimidines 8 in high yields.     

Synthesis and some properties of N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d]pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1??,2??:4,5]pyrazino[1,2-a]pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2??,1??:3,4]pyrazino[1,2-a]pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7]triazacycloundecin-8(9H)-one.     

Recent synthetic methodologies for pyrazolo[1,5-a]pyrimidine

The development of new synthetic routes towards pyrazolo[1,5-a]pyrimidines for their biological and medicinal exploration is an attractive area for researchers. This review focuses on various synthetic routes developed in the last decade for the synthesis of differently substituted pyrazolo[1,5-a]pyrimidines by a broad range of organic reactions by means of 5-aminopyrazole as a precursor.     

Synthesis of 6-hydrazino-3,4-dimethyl-1H-pyrazolo[3,4-d]pyrimidine and its application for the construction of a pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidine system

A new representative of heterocyclic hydrazines, viz., 6-hydrazino-3,4-dimethyl-1H-pyrazolo[3,4-d]pyrimidine (3) was synthesized from diacetyl ketene N,S-acetal. A condensation of hydrazine 3 with amide acetals or aldehydes and subsequent cyclization furnished pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines, whose structure was confirmed by ¹H, ¹³C, and ¹H/¹⁵N HMBC NMR spectroscopy. Reactions of hydrazine 3 with acetylacetone, ethyl acetoacetate, diethyl malonate, and acetic anhydride were studied.     

Efficient and regioselective N-1 alkylation of 4-chloropyrazolo[3,4-d]pyrimidine

Efficient and N-1 selective alkylation of 4-chloropyrazolo[3,4-d]pyrimidine can be achieved when the heterocycle is reacted with alcohols under Mitsunobu conditions. The 1-alkyl-pyrazolo[3,4-d]pyrimidines formed can be functionalized further according to known methods, to give a variety of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines. The first example of a palladium-catalyzed coupling reaction on a 4-halopyrazolo[3,4-d]pyrimidine is described.     

Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines

General, high-yielding MAOS protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyrimidines, as well as their pyrazole precursors, are described amenable to an iterative analogue library synthesis strategy for lead optimization.     

One-pot synthesis and antiproliferative evaluation of pyrazolo[3,4-d]pyrimidine derivatives

An efficient one-pot methodology for the synthesis of pyrazolo[3,4-d]pyrimidines was developed by using 5-aminopyrazoles with formamide in presence of PBr₃ as the coupling agent. Among the examples presented in this work, compounds 41 and 54-56 with phenyl or 2-quinolinyl groups at N-1 and p-Me-Ph, p-Cl-Ph, or p-OMe-Ph group at C-3 position in the pyrazole ring possessed better potency against NCI-H226 and NPC-TW01 cancer cells with GI₅₀ values between 18 μM and 39 μM.     

Syntheses of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines from methyl tetrahydro-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-3-oxo-2-thiophenecarboxylate,respectively

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 13 ) was condensed with 6-aminonicotinic acid ( 18 ) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 19 ). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 17 ). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate ( 21 ) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid ( 25 ) by an analogous route.     

Polycyclic N-hetero compounds. XXXVII. A convenient synthesis and evaluation of anti-platelet aggregation activity of 1,2,4,5-tetrahydro[1]- benzothiepino[4,5-e]imidazo[1,2-c]pyrimidine and its related compounds

A simple and highly efficient methodology for the synthesis of 1,2,4,5-tetrahydro[1]benzothiepino[4,5-e]-imidazo[1,2-c]pyrimidine ( XI ) having a novel ring system via 4-substituted 5,6-dihydro[1]benzothiepino-[5,4-d]pyrimidines VII-X is described. The anti-platelet aggregation activity for it and its related compounds against collagen-induced aggregation of rabbit blood platelets in vitro was found.     

Regioselective formylation of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine systems using Vilsmeier-Haack conditions

Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via Vilsmeier-Haack conditions. While the 4,5- and 6,7-dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5-carbaldehydes and 4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, respectively, the aromatic analogs rendered the pyrazolo[1,5-a]pyrimidine-3-carbaldehyde only, and no reaction took place at the pyrazolopyridine derivatives.     

Microwave-assisted synthesis of substituted 2-amino-1H-imidazoles from imidazo[1,2-a]pyrimidines

An efficient method for the synthesis of mono- and disubstituted 2-amino-1H-imidazoles via microwave-assisted hydrazinolysis of substituted imidazo[1,2-a]pyrimidines is reported. This protocol avoids strong acidic conditions and is superior to the classical cyclocondensation of α-haloketones with N-acetylguanidine.     

Studies on 6-[(dimethylamino)methylene]aminouracil: a facile one-pot synthesis of novel pyrimido[4,5-d]pyrimidine derivatives

The reactions of 6-[(dimethylamino)methylene]aminouracil 1, with various heterocumulenes such as aryl isocyanates and isothiocyanates give rise to novel pyrimido[4,5-d]pyrimidines in excellent yields, after elimination of dimethylamine from the (1:1) cycloadducts and tautomerisation. This procedure provides a convenient method for direct synthesis of pyrimido[4,5-d]pyrimidine derivatives under thermal conditions.     

Synthesis of N-Alkylated Derivatives of Pyrazolo[1,5-a]pyrimidine and Their Reaction with Methylamine

With the object of studying the factors influencing the course of enamine rearrangements, we have carried out the N-alkylation of alkyl- and aryl-substituted pyrazolo[1,5-a]pyrimidines. Using the NOEDIF NMR spectroscopic method for the cases of 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidines it was found that addition of the alkyl group occurs at the N₍₄₎ atom of the pyrimidine fragment in the pyrazolo[1,5-a]pyrimidine. It was shown that, when reacting with an alcoholic solution of methylamine, the 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidine iodomethylates undergo decomposition to give 5-methylamino-3-phenylpyrazole and 5-(1,3-diphenyl-3-methylamino-2-propenylid-1-ene)amino-3-phenylpyrazole.     

Synthesis of 7H-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines and their reductive ring cleavage to 4-aminopyrrolo[2,3-d]pyrimidines

Some new 7,9-disubstituted 7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 5 have been synthesized either by diazotization of 4-hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 4 obtained by hydrazinolysis of 4-chloro-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 3 or via a substitution reaction between 3 and sodium azide. 5,7-Disubstituted-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-ones 2 were obtained by cyclocondensation of 2-amino-3-cyano-1,4-disubstituted pyrroles 1 with formic acid which on chlorination using phosphorus oxychloride afforded 3 . A novel route for the synthesis of 4-amino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 6 by the reductive ring cleavage of 5 has been reported.