Diverse synthesis of pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles via CuI-catalyzed decarboxylic multicomponent reactions of heterocyclic azoles,aldehydes and alkynecarboxylic acids

We have developed a straightforward approach to diverse synthesis of 2,3-, 2,4-disubstituted pyrimido [1,2-a]benzimidazoles, 2,4,10-trisubstituted 2,10-dihydropyrimido [1,2-a]benzimidazoles and 2,3-disubstituted imidazo [2,1-b]benzothiazoles via multicomponent reactions (MCRs) of heterocyclic azoles, aldehydes with easily storable and handling alkynecarboxylic acids. In the presence of a catalytic amount of CuI and K₂CO₃, the pyrimido [1,2-a]benzimidazole or imidazo [2,1-b]benzothiazole scaffold could be rapidly constructed through a 6-endo-dig or 5-exo-dig cyclization, respectively. The preliminary mechanistic study suggested that the formation of 2,3- disubstituted pyrimido [1,2-a]benzimidazoles, which completes the assembly of the scaffold and its C-3 position functionalization in one pot, undergoes a novel cascade process involving a decarboxylation, A [3] coupling, 6-endo-dig cyclization, nucleophilic addition and dehydration.     

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.     

Solid-phase synthesis of imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines

The synthesis of imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives by condensation between an α-bromoketone bound to solid support and various 2-aminopyridine or 2-aminopyrimidine derivatives was described. Either an acid labile linker or a base labile linker was used in this study.     

A new, one-pot, multi-component synthesis of imines of 3-amino-2-arylimidazo[1,2-a]pyridines, 3-amino-2-arylimidazo[1,2-a]pyrazines, and 3-amino-2-arylimidazo[1,2-a]pyrimidines

An efficient, one-pot, multi-component synthesis of 3-amino-2-arylimidazo[1,2-a]pyridines, 3-amino-2-arylimidazo[1,2-a]pyrazines, and 3-amino-2-arylimidazo[1,2-a]pyrimidines is described. Heating a mixture of a 2-aminopyridine, 2-aminopyrazine or 2-aminopyrimidine, a benzaldehyde, and imidazoline-2,4,5-trione under solvent-free conditions afforded imine derivatives of the title compounds in excellent yields. Single-crystal X-ray analysis conclusively confirms the structure of these bridgehead bicyclic 5-6 heterocycles.     

A convenient synthesis of linear pyridinoimidazo[1,2-a]pyridine and pyrroloimidazo[1,2-a]pyridine cores

Two new imidazo[1,2-a]pyridine derivatives, pyridinoimidazo[1,2-a]pyridine (10) and pyrroloimidazo[1,2-a]pyridine (16), were synthesised from 2-amino-4-methyl-5-nitropyridine (1) by linear cyclisation, making use of dimethylformamide dimethylacetal (DMFDMA) as an agent of vinylamine functionalisation. This report describes first the formation of pyridine and pyrroloimidazopyridine from (1), and then the formation of pyridine-fused and pyrrolo-fused pyridine by the Friedländer method and reductive cyclisation followed by treatment of the resulting adduct with chloroacetaldehyde.     

Highly efficient synthesis of triazolo[1,2-a]indazole-triones and novel spiro triazolo[1,2-a]indazole-tetraones under solvent-free conditions

A new, convenient, and high yielding procedure for the synthesis of triazolo[1,2-a]indazole-triones by the condensation reaction between dimedone, aryl aldehydes, and ueazoles in the presence of a catalytic amount of sulfonated polyethylene glycol (PEG-SO₃H) as a highly stable and reusable eco-friendly degradable polymeric catalyst is described under solvent-free conditions. This procedure has also been applied successfully for the synthesis of novel spiro triazolo[1,2-a]indazole-tetraones.     

Diversity-oriented decoration of pyrrolo[1,2-a]pyrazines

Diversity-oriented synthesis of a chemical library based on a pyrrolo[1,2-a]pyrazine core is described by using palladium-catalyzed direct C6 arylation of pyrrolo[1,2-a]pyrazines with various aryl bromides. The starting materials, pyrrolo[1,2-a]pyrazines, were easily synthesized by the base-mediated N-alkylation of pyrrole-2-carboxaldehyde with several 2-bromoacetophenones followed by dehydrative cyclization with incorporation of nitrogen by the action of ammonium acetate. Introduction of other functional groups on this chemical scaffold is also discussed herein.     

Expeditious synthesis of 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones

A convenient synthesis of new 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones from the Baylis-Hillman adducts of acrylonitrile and their derivatives is described. A common strategy employed to achieve the syntheses of title compounds involved generation of diamines from different Baylis-Hillman derivatives followed by treatment with cyanogen bromide at reflux temperature to trigger a double intramolecular cyclization.     

The synthesis of 3-pyrazinyl-imidazo[1,2-a]pyridines from a vinyl ether

A new method has been developed for the synthesis of 3-pyrazinyl-imidazo[1,2-a]pyridines. 2-Chloro-6-[(Z)-2-ethoxyethenyl]pyrazine was treated with N-bromosuccinimide in dioxane-water to generate the 2-bromo-2-(6-chloropyrazin-2-yl)-1-ethoxyethanol intermediate. In a subsequent one-pot step, optional treatment with various 2-aminopyridines provided the cyclized 3-pyrazinyl-imidazo[1,2-a]pyridines in 31-76% yields.     

Synthesis and rearrangement of cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones: an access to cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones

2-Substituted-4a-hydroxy-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 2a-c were synthesized by an one-step cyclocondensation from the 5-substituted-2-amino-2-oxazolines 1a-c with ethyl 2-oxocyclohexanecarboxylate in ethanol at room temperature, and easily dehydrated to provide 2-substituted-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 3. In refluxing xylene, the reaction conducted with various ethyl 2-oxocycloalkanecarboxylates led to the two isomeric 2-substituted-8/9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones 3 and 2-substituted-5H-cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones 4. The structure of some compounds was unambiguously established using X-ray crystallography. According to results from the DSC analysis of compound 2a, formation of the thermodynamically stable pyrimidinones 4 could be related to an intramolecular rearrangement of kinetically controlled pyrimidinones 3.     

Cyclisation of 3-alkenylpyrido[1,2-a]pyrimidines to furo[2,3-d]pyrido[1,2-a]pyrimidines

3-Alkenylpyrido[1,2-a]pyrimidines react under mild conditions to give novel tricyclic furo[2,3-d]pyrido[1,2-a]pyrimidines in high yields. The cyclisation takes place in the presence of an acid catalyst. The product yield is affected by the type and the strength of the acid used. Exceptionally high yields were obtained when an organic acid like trifluoromethanesulfonic acid and trifluoroacetic acid were used. On the other hand, sulfuric acid gave the best results of the inorganic acids examined.     

Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives

Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl₂(PPh₃)₂] or [Cu(Phen)(PPh₃)₂]NO₃.     

Synthesis of pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles by Curtius reaction in Morita-Baylis-Hillman derivatives

Synthesis of substituted pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles from the Morita-Baylis-Hillman derivatives of acrylates via saponification followed by Curtius reaction is described.     

Synthesis of novel 1,2-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives

The iodolactonization product obtained from methyl 7-allylpyrrolo[2,3-d]pyrimidine-6-carboxylate was used for the synthesis of novel 1,2-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives, containing carboxamide- and methylamine-groups on the pyrrole ring of the heterocycle.     

A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

New multi-component reaction accessing 3-aminoimidazo[1,2-a]pyridines

The novel one step solution phase synthesis of an array of 3-aminoimidazo[1,2-a]pyridines is reported. Reactions were performed in methanol by mixing a α-amino-pyridine, aldehyde and trimethylsilylcyanide (TMSCN) to give the desired product. Mediated by microwave irradiation and catalyzed by scandium triflate, the methodology represents the first one pot preparation of 3-aminoimidazo[1,2-a]pyridines that avoids the use of an isonitrile and subsequent de-protection strategy. The reaction is an example of a formal three-centre-three-component multi-component reaction.     

Intramolecular N-arylation in heterocyclization: synthesis of new pyrido-fused pyrrolo[1,2-a][1,4]diazepinones

Alkylation of l-prolinamide with 3-(chloromethyl)-2-halopyridines, followed by cyclization through an intramolecular Pd-catalysed amidation, provided an entry to the pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10-one scaffold. Furthermore, a synthetic route towards diverse new pyrido[f]pyrrolo[1,2-a][1,4]diazepin-7-ones has been developed by acylation of contiguously substituted (aminomethyl)halopyridines with Boc-l-proline followed by intramolecular amination.     

Synthesis of sulfur-substituted quinolizidines and pyrido[1,2-a]azepines by ring-closing metathesis

Sulfur-substituted quinolizidines and pyrido[1,2-a]azepines (7) can be prepared by ring-closing metathesis (RCM) of 4-(phenylthio)-1,2,5,6-tetrahydropyridin-2-ones (6) bearing terminal alkenyl groups at both N-1 and C-6 positions, which are obtained from 3-(phenylthio)-3-sulfolene (1) in four steps. Some synthetic transformations of 2-(phenylthio)-1,6,9,9a-tetrahydroquinolizin-4-one (7a) and 2-(phenylthio)-1,6,9,10,10a-pentahydropyrido[1,2-a]azepin-4-one (7d) are also reported.     

Synthesis and X-ray crystal structure of pyrrolo[1,2-a]benzimidazoles

Reaction of nitrilimines 1 with 2-cyanomethylbenzimidazole 2 gave the 3-arylazo-2-methylpyrrolo[1,2-a]benzimidazole 4a rather than the reported 2-arylazo-3-methylpyrrolo[1,2-a]benzimidazole 3a. The correct structure of the product was determined using X-ray crystal structure analysis. The similar reaction of nitrilimines with 2-aminobenzimidazole 5 gave the acyclic nucleophilic addition product 6.     

Regioselective two step synthesis of 3-substituted 2-aminoimidazo[1,2-a]pyrimidines

A two step procedure for the regioselective synthesis of 3-substituted-2-aminoimidazo[1,2-a]pyrimidines is described. The key step is a Dimroth rearrangement of a mixture of 2 and 3-substituted aminoimidazo[1,2-a]pyrimidines that yields quantitatively one regioisomer. Reaction screening for the rearrangement step is reported. A multicomponent isocyanide based reaction is chosen as the preferred way for the synthesis of the precursors. Elucidation of regiochemistry has been done by X-ray determination of some representative compounds.