Synthesis of ethyl 6‐aryl‐4‐oxo‐4,6‐dihydro‐1(12)(13)h‐pyrimido‐[2′,1′:4,5][1,3,5]triazino[1,2‐a]benzimidazole‐3‐carboxylates

The synthesis of ethyl 6‐aryl‐4‐oxo‐4,6‐dihdro‐1(12)(13)H‐pyrimido[2′,1′:4,5][1,3,5]triazino[1,2‐a]‐benzimidazole‐3‐carboxylates ( 4a‐p ) was described via pyrimidine ring annulation to 4‐aryl‐3,4‐dihydro[1,3,5]triazino[1,2‐a]benzimidazole‐2‐amines ( 2a‐p ) which were obtained from 2‐guanidinobenzimidazole ( 1 ). Tautomerism in the prepared compounds was investigated using nmr spectroscopy. Compounds 2a‐p were found to be present in dimethyl sulfoxide solution predominantly as 3,4‐dihyhydro tautomeric form. Compounds 4a‐p existed in dynamic equilibrium of 1‐, 12‐ and 13H‐forms. It was found that methylation of 4a‐d led to 13‐methyl substituted derivatives 9a‐d exclusively.     

Green multicomponent synthesis of 1,2‐dihydro‐pyrimido[1,2‐a]‐benzimidazole‐3‐carbonitrile

1,2‐dihydro‐pyrimido[1,2‐a]benzimidazole‐3‐carbonitrile derivatives were synthesized via the three‐component reaction of aldehyde, malonodinitrile and 2‐aminobenzimidazole in water under microwave irradiation. The new protocol has the advantages of excellent yield, low cost, reduced environment impact, wide scope and convenient procedure.     

Synthesis and reactions of 2‐chloro‐2‐(hydroximino)‐1‐(4‐methyl‐2‐phenylthiazol‐5‐yl)ethanone

3‐Nitrosoimidazo[1,2‐a]pyridine, 3‐nitrosoimidazo[1,2‐a]pyrimidine, 3‐nitrosoquinoxaline, 2‐nitroso‐4H‐benzo[b]thiazine, 2‐nitroso‐4H‐benzo[b]oxazine, isoxazoles, isoxazolo[3,4‐d]pyridazines and pyrrolo[3,4‐d]isoxazole‐4,6‐dione were synthesized from 2‐chloro‐2‐(hydroximino)‐1‐(4‐methyl‐2‐phenylthiazol‐5‐yl)ethanone and different reagents. Structures of the newly synthesized compounds were confirmed by elemental analysis and spectral data.     

Synthesis and reactivity of 1‐amino‐4‐methyl‐3,4‐dihydro‐5H‐pyrazolo[3′,4′:4,5]pyrimido[1,6‐a]benzoimidazolo‐5‐one

Pyrimido[2“,1”:5′,6′]pyrazolo[3′,4′:4,5]‐pyrimido[1,6‐a]benzoimidazoloe‐2,8(1H,7H)‐diones, and [1,2,4]‐triazino‐[3“,4”:5′,6′]pyrazolo[3′,4′:4,5]pyrimido[1,6‐a]benzimidazol‐8(7H)‐ones were synthesized in a good yields via 1‐amino‐4‐methyl‐3,4‐dihydro‐5H‐pyrazolo[3′,4′:4,5]pyrimido[1,6‐a]benzoimidazolo‐5‐one and the appropriate active methylene compounds. Structures of the newly synthesized compounds were elucidated on the basis of elemental analyses, spectral data, and alternative synthesis methods whenever possible.     

Cyclocondensation reactions of heterocyclic carbonyl compounds XII. The double course of cyclization of 3‐(2‐aminobenzyl)‐1,2‐dihydro‐quinoxaline‐2‐one

The cyclocondensation reaction of compound 1 in boiling hydrochloric acid had an unexpected course. Instead of supposed 5,11‐dihydro‐quinoxalino[2,3‐b]quinoline 6a , 2‐(indol‐2‐yl)‐benzimidazole 4 was isolated as the major product.     

One pot synthesis of substituted dihydroindeno[1,2‐b]indoles and dihydrobenzo[a]carbazoles by photostimulated reactions of o‐iodoaniline with carbanions by the SRN1 mechanism

The photostimulated reaction of enolate anions of cyclic aromatic ketones such as substituted indan‐1‐ones and 3,4‐dihydro‐2H‐naphthalen‐1‐one with o‐iodoaniline in DMSO affords 1‐, 2‐, 3‐, and 4‐methoxy‐5,10‐dihydroindeno[1,2‐b]indoles (34‐40%), 1,2‐, 1,4‐, and 2,3‐dimethoxy‐5,10‐dihydroindeno[1,2‐b]‐indoles (31‐43%), and 1‐, 2‐, and 3‐methoxy‐5,11‐dihydro‐6H‐benzo[a]carbazoles (42‐61%) by the S_RN1 mechanism in one pot reactions.     

Ready access to 7,8‐dihydro‐ and 1,2,3,4‐tetrahydro‐1,6‐naphthyridine‐5(6H)‐ones from simple pyridine precursors

Short pathways are described for the synthesis of a representative example of each of the 7,8‐dihydro‐and 1,2,3,4‐tetrahydro‐1,6‐naphthyridine‐5(6H)‐one ring systems from simple pyridine precursors. An attempted synthesis of the related 4,6‐dihydro‐1,6‐naphthyridin‐5(1H)‐one ring system from a common intermediate was unsuccessful.     

Lithiation of N‐protected‐dihydro‐1,4‐benzoxaziness

Lithiation of N‐protected‐2,3‐dihydro‐1,4‐benzoxazines is described. Lithiation of N‐(tert‐butoxycarbonyl)‐2,3‐dihydro‐1,4‐benzoxazine ( 1 ) with BuLi/TMEDA occurred in the α‐position to nitrogen on the heterocyclic ring, leading to the unexpected ring‐opened product 3 . On the other hand, lithiation of N‐methyl‐2,3‐dihydro‐1,4‐benzoxazine ( 4 ) took place at the oxygen‐adjacent ortho‐position of the aromatic ring.     

Synthesis and tautomerization of 6,7‐dihydro‐(1,2,3)‐triazolo[1,5‐a]pyrimidines

The condensation of 5‐amino‐4‐phenyl‐1,2,3‐triazole ( 1 ) with chalcones 2a‐e or 3‐dimethylamino‐propiophenone ( 4f ) leads to the 6,7‐dihydro‐(1,2,3)‐triazolo[1,5‐a]pyrimidines 3a‐f. The equilibrium of 3 and the tautomeric 4,7‐dihydro‐(1,2,3)‐triazolo[1,5‐a]pyrimidines 3′ is described.     

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 and characterization of a series of 1,x‐bis‐(4‐oxo‐3,4‐dihydro‐1,2,3‐benzotriazin‐3‐yl)alkanes

Reaction of isatoic anhydride with an alkanediamine in DMF solution under mild conditions affords excellent yields of the 1,x‐bis‐{(2‐aminobenzoyl‐)amino}alkanes ( 2a‐k ), which have been characterized by IR and NMR spectroscopy, high resolution mass spectrometry and elemental analysis. Diazotization of the bis‐{(2‐aminobenzoyl‐)‐amino}alkanes in aqueous solution gives high yields of the 1,x‐bis‐(4‐oxo‐3,4‐dihydro‐1,2,3‐benzotriazin‐3‐yl)alkanes ( 1a‐k ), whch have also been characterized by IR and NMR spectroscopy, high resolution mass spectrometry and elemental analysis. The alkanediamines employed are as follows: ethylene diamine, 1,3‐propanediamine, 1,2‐propanediamine, 2‐methyl‐1,2‐propanediamine, 2,2‐dimethyl‐1,3‐propanediamine, 2‐hydroxy‐1,3‐propanediamine, 1,4‐diaminobutane, 1,5‐diaminopentane, 1,3‐diaminopentane (DYTEK® EP diamine), 1,6‐diaminohexane and 1,7‐diaminoheptane. The alternative method of synthesis of the bis‐(4‐oxo‐3,4‐dihydro‐1,2,3‐benzotriazin‐3‐yl)alkanes ( 1 ) via the diazonium salt from methyl anthranilate was explored.     

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).     

Synthesis of 1‐acyl‐1,2‐dihydro‐3H‐pyrazol‐3‐ones VIA lewis acid‐mediated rearrangement of 3‐acyloxypyrazoles

The unusual formation of 1‐acyl‐1,2‐dihydro‐3H‐pyrazol‐3‐ones starting from 3‐acyloxypyrazoles by Fries‐type rearrangement is described. Under normal conditions, acylation of 2,4‐dihydro‐3H‐pyrazol‐3‐ones 1 and 2 with acid chlorides or anhydrides in the presence of triethylamine gave the corresponding 3‐acyloxypyrazoles 3a‐f and 4a‐f . Treatment of 3a‐c and 4a‐f with Lewis acid, e.g. titanium(IV) chloride and tin(IV) chloride, caused migration of acyl groups to afford the corresponding 1‐acyl‐1,2‐dihydro‐3H‐pyrazol‐3‐ones 5a‐c and 6a‐f . Interestingly, the reactions of 3‐acyloxypyrazoles 3e and 3f with tin(IV) chloride provided the corresponding tin(IV) complexes 8e and 8f .     

FeCI3‐promoted [3+3] cycloaddition: Efficient preparation of 1,2‐dihydro‐2‐oxo‐3‐pyridinecarboxylate and 1,2‐dihydro‐2‐oxo‐3‐pyridinecarboxamide derivatives

A facile approach was developed on assembly of the 2‐pyridone nucleus by ferric chloride promoted [3+3] cycloaddition in propionic acid. The tandem process involves cyclization of Michael adduct followed by aromatization. Thus, different substituted 1,2‐dihydro‐2‐oxo‐3‐pyridinecarboxylate and 1,2‐dihydro‐2‐oxo‐3‐pyridinecarboxamide derivatives were prepared in good yields from various enones with malonamic ester and malonamide, respectively     

Simple synthesis of 2‐amino‐4‐(het)aryl‐4,6‐dihydro‐1(3)(11)H‐[1,3,5]triazino[2,1‐b]quinazolin‐6‐ones

The 2‐amino‐4‐(het)aryl‐4,6‐dihydro‐1(3)(11)H‐[1,3,5]triazino[2,1‐b]quinazolin‐6‐ones were prepared readily by cyclocondensation of anthranilic acid derived 4‐oxo‐3,4‐dihydroquinazolinyl‐2‐guanidine with a variety of aldehydes. The structures of the compounds were confirmed by nmr spectroscopy, including 2D NOESY experiments.     

Synthesis of novel 1‐substituted [1,3]thiazolo[3,2‐a]‐[1,5]benzodiazepine derivatives from 1,5‐benzodiazepine‐2‐thiones and α‐halogen carbonyl compounds

A number of substituted 4H,5H,6H‐thiazolo[3,2‐a][1,5]benzodiazepinium salts 2a‐h, 5, 9 , which are based on the novel thiazolobenzodiazepine system, were prepared by condensation‐cyclization of 1,5‐benzodiazepine‐2‐thiones 1a‐f, h, 4 with α‐haloketones, as well as with α‐bromoacetaldehyde diethyl acetal. The structure and stereochemistry of the ring system obtained were investigated by ¹H and ¹³C nmr spectroscopy: the additional heterocyclic nucleus was found to appreciably influence the conformational mobility of the heptatomic ring. Upon treatment of salt 2d with alkali the presence of the base enamine structure in solution has been postulated.     

Electrophilic aromatic substitution of 3‐alkoxy‐6‐alkyl‐2‐cyano‐4,5,6a,11‐tetraazabenzo[a]fluorene with orthoesters

Fused tetracycles, 6‐alkyl‐3‐alkoxy‐2‐cyano‐4,5,6a,11‐tetraazabenzo[a]fluorene derivatives ( 5a , b , c , d , e , f ), are synthesized from 2‐alkoxy‐5‐(benzimidazol‐2‐ylidene)‐3‐cyano‐6‐imino‐5,6‐dihydro‐pyridines ( 4b , c ), and when refluxed in ethyl orthoacetate or ethyl orthopropionate, the elecrophilic aromatic substitution occurs at the ortho position of the cyanopyridine ring in the fused tetracycles ( 5b , c , e , f ) to afford 6‐alkyl‐3‐alkoxy‐2‐cyano‐1‐ethyl‐4,5,6a,11‐tetraazabenzo[a]fluorenes( 6b , c , e , f ).     

Synthesis and antibacterial studies of 6‐aryl‐2,2a‐dihydro‐naphtho‐[2′,1′‐5,6]pyrano[4,3‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine and its derivatives

Chemoselective synthesis of novel hetero cyclopenta[b]chrysene derivatives, namely, 6‐Aryl‐2,2a‐dihydro‐naphtho[2′,1′‐5,6]pyrao[4,3‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine ( 4a‐j ) under neutral condition has been described. These molecules exhibited good to excellent anti‐bacterial activities.     

A facile synthesis of pyrazolo[3,4‐D]pyridazines Via the 1,3‐dipolar cycloaddition of 3‐arylsydnones. Synthesis and computational studies of 1‐aryl‐4,5‐dihydro‐1H‐pyrazolo[3,4‐D]pyridazine‐3,6‐diones and their 3,6‐dichloro derivatives.

The synthetic utility of 1,3‐dipolar cycloaddition of DMAD to sydnones has been exploited in the preparation of new 1‐aryl‐4,5‐dihydro‐1H‐pyrazolo[3,4‐d]pyridazine‐3,6‐diones 7a‐j and their aromatic 3,6‐dichloro analogues 8a‐j . The lactam‐lactim tautomerism of compound 7a has been studied by the semi emperical (PM3) and ab initio methods.     

Studies with S‐alkylpyrimidine: New route for the synthesis derivatives of isoxazol,pyrazolo[1,5‐a]pyrimidine,pyridazine, pyridine,thieno[2,3‐b]pyridine and thiophene of potential anti‐HIV

Derivatives of thiophene, thieno[2,3‐b]pyridine, pyridine, isoxazol, pyrazolo[1,5‐a]pyridine, pyridazine linked with s‐pyrimidine derivative have been synthesized and tested for antimicrobial and antifungal activities. The structure of the newly synthesized compounds have been established on the basis of their analytical and spectral data.