Preparation of substituted 1,3‐dihydro‐2H‐imidazo[4,5‐c]pyridin‐2‐ones

A new synthetic route to 6‐substituted‐imidazo[4,5‐c]pyridin‐2‐ons from 4‐aminopyridine has been investigated. 4‐Aminopyridine protected as alkyl carbamates were nitrated with dinitrogen pentoxide to the corresponding methyl, i‐propyl and t‐butyl 3‐nitropyridin‐4‐yl carbamates ( 5a‐c ) in 51‐63 % yields. Attempts to substitute these in the 6‐position by the ONSH and the VNS techniques succeeded with butyl‐amine and the t‐butyl carbamate 9 . From the methyl or t‐butyl 3‐nitropyridin‐4‐yl carbamates 5a, 5c 1,3‐dihydro‐2H‐imidazo[4,5‐c]pyridin‐2‐one ( 1 ) was formed in 73 and 39 % yields, respectively. t‐Butyl 6‐N‐butylamin‐3‐aminopyridin‐4‐yl carbamate ( 6 ) gave 6‐butylamino‐1,3‐dihydro‐2H‐imidazo[4,5‐c]‐pyridin‐2‐one (7) in 53 % yield.     

A simple and efficient synthesis of novel N,N′‐bis (1H‐pyrrol‐1‐yl)‐1‐[2‐(2‐aryl‐5‐methyl‐3‐oxo‐2,4‐dihydro‐3H‐1,2,4‐triazol‐4‐yl)ethyl]‐1H‐1,2,3‐triazole‐4,5‐dicarboxamides

One‐pot reaction of 3‐aryl‐5‐methyl‐1,3,4‐oxadiazolin‐2‐ones 1a‐g with ethanolamine yielded the 4‐(2‐hydroxyethyl)‐2‐aryl‐5‐methyl‐2,4‐dihydro‐3H‐1,2,4‐triazolin‐3‐ones 2a‐g which were converted to the azido compounds 6a‐g . These azides on 1,3‐dipolar cycloaddition with DMAD afforded the dimethyl‐1‐[2‐(2‐aryl‐5‐methyl‐3‐oxo‐1,2,4‐triazol‐4‐yl)ethyl]‐1H‐1,2,3‐triazol‐4,5‐dicarboxylates 7a‐g which on conversion to bishydrazides 8a‐g and further cyclisation with 2,5‐hexanedione afforded the title compounds 9a‐g . This new short route for the so far unkown bis‐(triazolinone‐triazole)ethanes involves mild and convergent 1,3‐dipolar cycloaddition reaction yielding overall good yields of the products.     

New fluorescent bis‐β‐cyclodextrin‐indolizine sensor. Synthesis and sensing ability

The synthesis of 1,3‐[bis‐N‐6A‐deoxy‐β‐cyclodextrin‐6A‐yl‐aminocabonyl]‐7‐pyridin‐4‐yl indolizine is reported. The reaction proceeds by an amidation between 6‐amino‐β‐cyclodextrin and 1,3‐[bis‐(‐4‐nitrophenoxycarbonyl)‐7‐[pyridine‐4‐yl)] and yields the first sensor having in its structure the fluorescent indolizine and two β‐cyclodextrin fragments. The sensing ability towards phenol, p‐cresol and adamantan‐1‐ol has been evaluated by fluorescence spectroscopy. The molecular modelling study realised by MM3 and AM1 methods shows that non cooperative conformations are favoured, thus explaining that inclusion ability is not increased by such dimer, and that sensitivity is not enhanced as compared to corresponding monomeric sensors.     

Synthesis of novel pyrazolo[3,4‐d]pyridazine,pyrido[1,2‐a]benzimidazole,pyrimido[1,2‐a]benzimidazole and triazolo[4,3‐a]pyrimidine derivatives

4‐Acetyl‐5‐methyl‐1‐phenyl‐1H‐pyrazole reacts with dimethylformamide dimethylacetal (DMF‐DMA) to afford the corresponding (E)1‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐3‐(N,N‐dimethylamino)‐2‐propen‐1‐one. The latter product undergoes regioselective 1,3‐dipolar cycloaddition with nitrilimines and nitrile oxides to afford the novel 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)carbonyl‐1‐phenylpyrazole and 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)carbonyl isoxazole derivatives, respectively. It reacts also with 1H‐benzimidazole‐2‐acetonitrile, 2‐aminobenzimidazole and 3‐amino‐1,2,4‐triazole to afford the novel pyrido[1,2‐a]benzimidazole, pyrimido[1,2‐a]benzimidazole and the triazolo[4,3‐a]pyrimidine derivatives, respectively. The reaction of 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl) carbonyl‐1‐phenylpyrazole derivatives with hydrazine hydrate led to a new pyrazolo[3,4‐d]pyridazine derivatives.     

Synthesis of new spiro‐[isothiochromene‐3,5′‐isoxazolidin]‐4(1H)‐ones

A series of seven new 2′,3′,4′‐substituted spiro[isothiochromene‐3,5′‐isoxazolidin]‐4(1H)‐ones ( 7‐13 ) has been prepared in the reaction of benzylidene(phenyl)azane oxide ( 5 ) or benzylidene(methyl)azane oxide ( 6 ) with (3Z)‐3‐(4‐substituted‐benzylidene)‐1H‐isothio‐ chromen‐4(3H)‐one ( 1‐4 ). The reaction occurs by a 1,3‐dipolar cycloaddition mechanism that leads to the regiospecific formation of various spiroisoxazolidines ( 7‐13 ).     

Generation of N‐Heterocycles via Tandem Reactions of N ′‐(2‐Alkynylbenzylidene)hydrazides

As a powerful synthon, N ′‐(2‐alkynylbenzylidene)hydrazides have been utilized efficiently for the construction of N‐heterocycles. Since N ′‐(2‐alkynylbenzylidene)hydrazides can easily undergo intramolecular 6‐endo cyclization promoted by silver triflate or electrophiles, the resulting isoquinolinium‐2‐yl amides can proceed through subsequent transformations including [3 + 2] cycloaddition, nucleophilic addition, and [3 + 3] cycloaddition. Several unexpected rearrangements via radical processes were observed in some cases, which afforded nitrogen‐containing heterocycles with molecular complexity. Reactive partners including internal alkynes, arynes, ketenimines, ketenes, allenoates, and activated alkenes reacted through [3 + 2] cycloaddition and subsequent aromatization, leading to diverse H‐pyrazolo[5,1‐a]isoquinolines with high efficiency. Nucleophilic addition to the in situ generated isoquinolinium‐2‐yl amide followed by aromatization also produced H‐pyrazolo[5,1‐a]isoquinoline derivatives when terminal alkynes, carbonyls, enamines, and activated methylene compounds were used as nucleophiles. Isoquinoline derivatives were obtained when indoles or phosphites were employed as nucleophiles in the reactions of N ′‐(2‐alkynylbenzylidene)hydrazides. A tandem 6‐endo cyclization and [3 + 3] cycloaddition of cyclopropane‐1,1‐dicarboxylates with N ′‐(2‐alkynylbenzylidene)hydrazides was observed as well. Small libraries of these compounds were constructed. Biological evaluation suggested that some compounds showed promising activities for inhibition of CDC25B, TC‐PTP, HCT‐116, and PTP1B.

     

Synthesis of the indole core structures of conophylline

Conophylline is a bisindole alkaloid of unique structure that shows anti‐cancer and anti‐diabetic activities. Two indole core structures of conophylline, namely 6,7‐dimethoxy‐5‐methoxymethoxy‐1H‐indole ( 1 ), and N‐benzoyl‐N‐[2‐(6‐methoxymethoxy‐2‐vinyl‐1H‐indol‐3‐yl)ethyl]amine ( 2 ) has been synthesized starting with substituted benzene derivatives.     

Metal‐Free,Regioselective Triazole Ligations that Deliver Locked cis Peptide Mimetics

Metal‐free triazole turns : 1,5‐Disubstituted peptidyl triazoles are obtained regioselectively from the 1,3‐dipolar cycloaddition of peptidyl phosphoranes and azides. Peptide turns are thus formed that contain a conformationally locked cis peptide bond. Being regioselective and free of heavy metals, this reaction may find broad application in chemical biology and medicinal chemistry.

     

Fast Alkene Functionalization In Vivo by Photoclick Chemistry: HOMO Lifting of Nitrile Imine Dipoles

Extremely fast fluorescence labeling (<1 min) of a recombinant alkene‐encoded protein in living Escherichia coli cells was observed with tetrazole 1 . The electron‐donating methoxy substituent raises the energy of the highest occupied molecular orbital of the nitrile–imine intermediate derived from 1 . This strategy greatly accelerates the functionalization of alkenes by 1,3‐dipolar cycloaddition in living systems.

     

1‐Arylsulfonyl‐2‐styrylsulfonylthenes — source for a new class of bis heterocycles

New and novel sulfone linked bis heterocycles_ bis pyrroles and pyrrolyl pyrazolines are prepared from 1‐arylsulfonyl‐2‐styrylsulfonylethenes by 1,3‐dipolar cycloaddition methodology.     

Diversity of Reactions of Isomeric Aminopyridine N‐Oxides with Chloronitropyridines: An Experimental and Theoretical Study

Reaction of 2‐aminopyridine N‐oxides 1a , 1b , 1c , 1d with chloronitropyridine 7a gave 2‐[(pyridin‐2‐yl)amino]pyridine N‐oxides 8a , 8b , 8c and 9 in good yield. The reactions of 4‐ and 3‐aminopyridine N‐oxides 12a , 12b and 24 with 7a , 7b , 7c proceed in the different manner involving initial formation of the intermediary 1‐pyridyloxypyridinium salts 13a , 13b , 13c , 13d and 26 , which rearrange to 4‐[(5‐nitropyridin‐2‐yl)amino]pyridine N‐oxide 22 and 1‐(3‐aminopyridin‐2‐yl)pyrid‐2‐one derivatives 27a , 27b , respectively. However, N‐protected 2‐aminopyridine N‐oxides 17 gave quaternary 1‐pyridyloxypyridinium salts 18a , 18b , which upon treatment with aqueous ammonia afforded 2‐[(pyridin‐2‐yl)amino]pyridine N‐oxides 8a and 20 . Quantum chemical calculations at the DFT/B3LYP/6‐311++G(d,p) level were performed to explain the differences in properties of the frontal orbitals and atomic charge distribution in isomeric aminopyridine N‐oxides.     

Synthesis and characterization of a novel heterocycle: 1‐Substituted‐4‐arylazamethylene‐6‐arylpyrazolo[5,4‐d]‐1,3‐oxazine

A series of novel heterocycles 1‐aryl‐ or alkyl‐substituted‐4‐arylazamethylene‐6‐arylpyrazolo[5,4‐d]‐1,3‐oxazines were synthesized from the acylation of (5‐amino‐1‐substituted‐pyrazol‐4‐yl)‐N‐carboxamide in 63‐89% isolated yields at room temperature within 12 hours. The structure was confirmed by X‐ray crystal analysis.     

A convenient one‐pot synthesis of new 3‐(4‐aryl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2‐yl)‐2H‐chromen‐2‐ones

Anhydrous zinc bromide catalysed reactions of arylidine‐3‐acetyl coumarins ( 1a‐c ) and 5,6‐benzoanalogs of arylidine 3‐acetyl coumarins ( 4a,4b ) with 1,3‐cyclohexanedione gives ‐(4‐aryl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2yl)‐2H‐chromen‐2‐ones ( 3a, 3c ) and 5,6‐benzoanalogs of 3‐(4‐aryl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2yl)‐2H‐chromen‐2‐one ( 5a,5b ). Under similar conditions arylidine‐3‐acetylcoumarins ( 1a, 1b,1d, 1e, 1f ) and 5,6‐benzoanalog of arylidine 3‐acetyl coumarin ( 4b ) react with 5,5‐dimethyl‐1,3‐cyclohexanedione (dimedone) yielding 3‐(4‐aryl‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2‐yl)‐2H‐chromen‐2‐ones ( 3d‐3h ) and the 5,6‐benzoanalog of 3.(4‐aryl‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2‐yl)‐2H‐chromen‐2‐one ( 5c ).     

Formation of aryl‐bis (6‐amino‐1,3‐dimethyluracil‐5‐yl) methanes by reaction of 6‐amino‐1, 3‐dimethyluracil with aromatic aldehydes

The synthesis of aryl‐bis(6‐amino‐1,3‐dimethyluracil‐5‐yl)‐methanes 3a‐m by condensation of 6‐amino‐1,3‐dimethyluracil ( 1 ) with aromatic aldehydes 2a‐m at room temperature is reported. The structures of the compounds were established using various spectroscopic analyses and X‐ray crystallography. The crystal structures of two aryl‐bis (6‐amino‐1,3‐dimethyluracil‐5‐yl) methanes are presented.     

Disubstituted Azidotetrazoles as Energetic Compounds

Base‐catalyzed activation of the C? F bond in the trifluoromethylazo‐substituted cyclic and acyclic alkanes provides a route to disubstituted azidotetrazoles. For example, the reaction of 1,2‐bis(trifluoromethylazo)ethane with four equivalents of NaN₃ gave the alkyl‐bridged bis(5‐azido‐1H‐tetrazol‐1‐yl)‐1,2‐dimine, N,N′‐bis(5‐azido‐1H‐tetrazol‐1‐yl)‐1,2‐diiminoethane, in 75 % yield (see scheme).

     

Synthesis and anti‐HIV activity of n‐(3‐amino‐3,4‐dihydro‐4‐oxopyrimidin‐2‐yl)‐4‐chloro‐2‐mercapto‐5‐methylbenzenesulfonamide derivatives

A series of N‐(3‐amino‐3,4‐dihydro‐4‐oxopyrimidin‐2‐yl)‐4‐chloro‐2‐mercapto‐5‐methylbenzenesulfonamide derivatives 10‐17 have been synthesized as potential anti‐HIV agents. The in vitro anti‐HIV‐1 activity of these compounds has been tested at the national Cancer Institute (Bethesda, MD), and the structure‐activity relationships are discussed. The selected N‐[3‐amino‐3,4‐dihydro‐6‐(tert‐butyl)‐4‐oxothieno[2,3‐e]pyrimidin‐2‐yl]‐4‐chloro‐2‐metcapto‐5‐methylbenzenesulfonamide ( 14 ) showed good anti‐HIV‐1 activity with 50% effective concentration (EC₅₀) value of 15 μM and weak cytotoxic effect (IC₅₀ = 106 μM).     

Reaction of 1‐acylthiosemicarbazides with ethenetetracarbonitrile

1‐Acylthiosemicarbazides 9a‐d reacted with ethenetetracarbonitrile (TCNE, 2 ) in ethyl acetate with formation of N′‐(4‐amino‐5,6‐dicyano‐2H‐1,3‐thiazin‐2‐ylidene) substituted hydrazide 10a‐d , N′‐(5‐amino‐3,4‐dicyano‐2H‐pyrrol‐2‐ylidene)‐2‐substituted hydrazide 11a‐d and 2‐substituted imidazo[2,1‐b][1,3,4]‐oxadiazole‐5,6‐dicarbonitrile 12a‐d . Rationales for the conversions observed are presented.     

Reactions of aroylthioureas with acetylenic esters and dibenzoyl ethylene. Selectivity towards the formation of new 1,3‐thiazines

A series of 1,3‐thiazines has been synthesized by the reactions of N‐aroylsubstituted thioureas with ethyl propiolate, dimethyl but‐2‐ynedioate and (E)‐1,4‐diphenyl‐but‐2‐ene‐1,4‐dione. The reaction of antipyrinylphenyl thiourea with π‐deficient acetylenic reagents did not afford the corresponding 1,3‐thiazines, whereas pyrrolo‐pyrazolopyrimidines were obtained.     

Synthesis of some thiazolyl and thiadiazolyl derivatives of substituted furan and pyrrole

Four series of substituted furan and pyrrole have been synthesized. The first series was prepared by cyclization of the key intermediates ethyl 5‐[(4‐substituted thiosemicarbazido)methyl]‐2‐methylfuran‐3‐carboxylates 2a‐2d and 1‐[(4‐acetyl‐5‐methyl‐1H‐pyrrol‐2‐yl)methylene]‐4‐substituted thiosemicarbazides 8a‐8d with chloroacetic acid or (ethyl bromoacetate) to afford the corresponding 4‐oxo‐3‐substituted thiazolidin‐2‐ylidene 3a‐3d or 3‐substituted thiazolidin‐4‐one 9a‐9d . On the other hand, heating of the intermediates 2a‐2d or 8a‐8d with acetic anhydride afforded the corresponding (N‐substituted acetylamino)‐2,3‐dihydro‐[1,3,4]thiadiazol‐2‐yl derivatives 4a‐4d and [1,3,4]thiadiazol‐2‐yl‐N‐substituted acetamide 10a‐10d respectively, while cyclization with p‐bromophenacyl bromide gave rise to the corresponding 3‐substituted thiazol‐2‐yl‐ylidene 5a‐5d and 11a‐11d respectively. Furthermore, 4‐oxo‐3‐substituted thioureido‐thiazolidin‐2‐yl 6a‐6d or 4‐oxo‐thiazolidin‐3‐yl‐3‐substituted thiourea 12a‐12d were obtained by reaction of the intermediates 2a‐2d or 8a‐8d with thioglycolic acid. Some of the synthesized compounds showed promising antimicrobial activities.     

Selective Iridium‐Catalyzed Alkylation of (Hetero)Aromatic Amines and Diamines with Alcohols under Mild Reaction Conditions

Selective amine alkylation : A P,N‐ligand‐stabilized iridium complex has been used as an efficient catalyst for the alkylation of (hetero)aromatic amines with alcohols at mild reaction temperatures and catalyst loadings as low as 0.1 mol % Ir (see scheme). The excellent selectivity of the catalyst for monoalkylation of the amine function has also been exploited for the N,N′‐dialkylation of diamines in both symmetric and nonsymmetric fashions.