Transformations of phenylhydrazones of 5‐acyl‐1,2,4‐triazines to pyrazolo[4,3‐e][1,2,4]triazines or 4‐cyanopyrazole

A simple and high yielding preparation of pyrazolo[4,3‐e][1,2,4]triazines and 4‐cyano‐3‐methyl‐1‐phenylpyrazole derivatives from corresponding phenylhydrazones of 5‐acyl‐1,2,4‐triazines by melt under acidic medium and by thermal heating, respectively.     

Reaction of malonates with camphoranile synthesis of 4‐hydroxy‐2‐pyridones attached to the bornane ring system

The reaction of camphoraniles 3a,b with “magic malonates” (bis‐2,4,6‐trichlorophenylmalonates) 4a,b leads to 4‐hydroxy‐2(1H)‐pyridones attached to bornane ring system 6a‐c in good yields. Less satisfactory yields were obtained with the diethyl malonate 5b . The reaction of an excess of diethyl malonate 5 itself with 3b yields the pyrono derivative 7 , which can readily be degraded via the acetyl derivative 8 to the basic structure 9 .     

Preparation of 4,5‐dihydro‐1,3‐selenazoles by reaction of aromatic primary selenoamides with acetylenedicarboxylate

Reactions of primary selenoamides with dimethyl acetylenedicarboxylate afforded 2‐aryl‐5‐methoxy‐carbonylmethylene‐4,5‐dihydro‐1,3‐selenazol‐4‐ones in moderate to high yields. Reactions of the primary selenoamides with acetylenedicarboxylic acid gave 2‐aryl‐5‐carboxymethylene‐4‐ethoxy‐4,5‐dihydro‐1,3‐selenazol‐4‐ols in moderate yields.     

Synthesis of heterocyclic compounds using amidines as their ene‐1,1‐diamine tautomers. II. Synthesis of 2,3‐dihydropyridine, 3,4‐dihydropyridine and 3,4‐dihydropyrrol‐2‐one derivatives by the reaction of amidines with α, β‐unsaturated carbonyl compounds

N‐t‐Butylacetamidines 1 on heating with methyl vinyl ketone, acrolein or crotonaldehyde gave the 2,3‐dihydropyridine derivatives 4,5 or 6 via N‐alkylation of the acetamidines 1 . Reaction of amidines 1 with phenyl 1‐propenyl ketone, benzalacetone or chalcone gave 3,4‐dihydropyridine derivatives 8, 9 or 10 . These were obtained by C‐alkylation, achieved by Michael addition of the acetamidines 1 as their N,C‐tautomers ene‐1,1‐diamines 1 ′ to α,β‐unsaturated carbonyl compounds, and subsequent cyclodehydration of adducts. Reaction of 1 with ethyl 3‐benzoylacrylate gave 3,4‐dihydropyrrol‐2‐one derivatives 13 .     

Synthesis of 3‐(2‐hydroxy‐1‐phenylethyl)‐ and 3‐(2‐hydroxy‐2‐phenylethyl)adenine,DNA adducts derived from styrene

3‐(2‐Hydroxy‐2‐phenylethyl)‐ and 3‐(2‐hydroxy‐1‐phenylethyl)adenine, DNA adducts derived from styrene, along with their 9‐substituted analogues were prepared by alkylation of 8‐bromoadenine with corresponding allyl‐protected bromohydrins followed by a new deallylation procedure using tetrakis(triphenylphosphine)palladium catalyzed reductive cleavage by poly(methylhydrosiloxane) in the presence of p‐toluenesulphonic acid. This novel procedure proved to be useful for purine derivatives, which were resistant to other deallylation protocols. Structure of positional isomers was assigned using 2D NMR experiments HMBC and HMQC.     

A general synthesis of 8‐hydroxy‐6‐substituted‐1,7‐naphthyridines

A general method for the synthesis of 8‐hydroxy‐6‐substituted‐1,7‐naphthyridines is described using acylation of the dianion derived from tert‐butylamide 1 , followed by cyclization of the resulting intermediate ketones 2 with ammonium acetate.     

Transformation of 4‐oxo‐4H‐[1]‐benzopyran‐3‐carboxaldehydes into pyrazolo[3,4‐B]pyridines

Reaction of 6‐methyl‐4‐oxo‐4H‐[1]‐benzopyran‐3‐carboxaldehyde 1 with 5‐amino‐3‐methyl‐1‐phenylpyrazole 2 in alcoholic reaction media in the presence of 4‐toluenesulfonic acid as catalyst afforded 5‐(2‐hydroxy‐5‐methylbenzoyl)‐3‐methyl‐1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine 3 and 2‐methoxy‐6‐methyl‐3‐(3‐methyl‐1‐phenylpyrazol‐5‐ylaminomethylene)chroman‐4‐one 7 . We explain the mechanism of formation of both products on the basis of kinetic study of individual reaction steps.     

Studies with 3‐functionally substituted 2‐arylhydrazononitriles: A new route to 3‐substituted‐2‐arylhydrazononitriles, 4‐amino‐pyrazole‐5‐carbonitriles,azadienes and cinnolines

3‐Amino‐3‐phenyl‐2‐phenylazoacrylonitrile 6 is obtained in good yield via reaction of 5 with phenyl magnesium bromide. The compound 6 is readily converted into 4a . The so formed alkanenitrile reacted with phenylmagnesium bromide to yield 8 . Compound 8 could be also obtained from reaction of 9 with phenylmagnesium bromide. The arylhydrazononitriles 8 and 4a reacted with chloroacetonitrile to yield the 4‐aminopyrazoles 12a,b . Compound 12a reacted with acetic anhydride to yield the 15a and with benzoyl chloride to yield the pyrazole 16 which was converted into 15b . Refluxing 10 in acetic acid gave a mixture of the azadiene 21 and the cinnoline 22 is obtained. The azadiene 21 is converted into 22 either thermally or photochemically.     

A new synthesis of alkaloid (S)‐3‐hydroxypiperidin‐2‐one and its O‐TBS protected derivative

From the known lactone (S)‐ 4 , easily derived from L‐glutamic acid, a scalable approach to chiral building block O‐silylated 3‐hydroxypiperidin‐2‐one 3 and alkaloid 1 was achieved in five and six‐steps respectively. The key steps are a chemoselective amidation of lactone‐ester 5 and a one‐pot reductive borane‐decomplexation, N‐debenzylation and cyclization.     

Synthesis of N‐amino‐3‐hydroxy‐2‐phenyl‐4(1H)‐quinolinone

2‐[(Disubstituted‐methylene)‐hydrazino] benzoic acid phenacylesters 2a‐2d , prepared from anthranilic acid phenacylester 1 , were unsuccesfully tried as starting materials for the synthesis of N‐amino‐3‐hydroxy‐2‐phenyl‐4(1H)‐quinolinone 8 . The desired compound 8 was prepared by cyclization of N‐acetyl as well as N‐benzoyl‐hydrazinobenzoic acid phenacylester 6a or 6b in polyphosphoric acid to afford N‐acylamino‐3‐hydroxy‐2‐phenyl‐4(1H)‐quinolinone 7a or 7b , respectively. Surprisingly, the acyl group was resistant to attack by both hydrochloric acid as well as sodium hydroxide solution. It could be removed by boiling the compounds 7a or 7b respectively in 50% sulphuric acid to afford the the target compound 8 .     

A facile synthesis of 1‐alkyl‐5‐arylalkoxy‐6‐methoxy‐3,4‐dihydroisoquinolines

1‐Alkyl‐5‐arylalkoxy‐6‐methoxy‐3,4‐dihydroisoquinolines were synthesized by the alkylation of 1‐alkyl‐5‐hydroxy‐6‐methoxy‐3,4‐dihydroisoquinolines with arylalkyl halide in the presence of potassium carbonate. 1‐Alkyl‐5‐hydroxy‐6‐methoxy‐3,4‐dihydroisoquinolines as key precursor prepared from o‐vaniline via 6 steps.     

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 of [2‐aryl‐6‐oxo‐6H‐chromeno[6,7‐d]oxazol‐8‐yl]‐acetic acid ethyl esters

A number of coumarino[6,7‐d]oxazoles (nitrogen analogs of psoralens) have been synthesized from (7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl) acetic acid ethyl ester 1 . The synthetic route began with the nitration of 1 with nitric acid in acetic acid to give (6‐nitro‐7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl) acetic acid ethyl ester 2 ; (3,6‐dinitro‐7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl) acetic acid ethyl ester 3 and (3,6,8‐trinitro‐7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl) acetic acid ethyl ester 4 . The reduction of 2 was accomplished with tin(II) chloride, tin, and concentrated hydrochloric acid in ethanol giving (6‐amino‐7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl) acetic acid ethyl ester 5 . After the condensation of aminocoumarin 5 with aromatic aldehyde in glacial acetic acid medium, followed the dehydrocyclization to coumarino[6,7‐d]oxazoles 7a‐k . The intermediate Schiff's bases 6a‐k have been obtained from 5 with aromatic aldehyde in ethanol. Antibacterial and antifungal activities of the compounds have been evaluated.     

1,3‐Dipolar cycloadditions of 9‐diazofluorenes and diphenyldiazomethane to 2‐acyl‐2H‐1,2,3‐diazaphospholes

A series of 2‐acyl‐2H‐1,2,3‐diazaphospholes 3 underwent ready 1,3‐dipolar cycloaddition reactions with 9‐diazofluorenes as the 1,3‐dipole, yielding the respective bicyclic phosphiranes 5 or trimers 7 depending on the reaction conditions employed. The reaction is believed to proceed via the formation of the [3+2]‐cycloaddition adducts followed by elimination of nitrogen from the cyclic azo moiety. In the case of 3c , the phosphatetraazabicyclooctadiene compound 6 has been isolated with no loss of nitrogen. Likewise, the dipolar cycloaddition reaction of diphenyldiazomethane with the >C?P‐ moiety as the 1,3‐dipolarophile gave phosphadiazabicyclohexenes 8 in 32–68% yields.     

Synthesis of 9‐[1‐benzyl‐5‐(alkylsulfonyl)‐1H‐2‐imidazolyl]perhydro‐1,8‐acridinediones

Tricyclic dihydropyridines like ZM244085 are potential K_ATP channel openers. In this study 3‐cyanophenyl ring of ZM244085 was replaced with imidazolyl ring. So, 9‐[1‐benzyl‐5‐(alkylsulfonyl)‐1H‐2‐imidazolyl]perhydro‐1,8‐acridinediones ( 5d‐f ) were synthesized from 2‐alkylsulfonyl‐1‐benzyl‐5‐formylimidazole ( 4d‐f ) and cyclohexane‐1,3‐dione according to classical Hantzch synthesis as potential potassium channel modulators.     

Regioselective synthesis of pentacyclic polyheterocycles: Sequential [3,3] sigmatropic rearrangement of 4‐(4′‐aryloxybut‐2′‐ynyloxy)‐1‐phenyl‐1,8‐naphthyridin‐2(1H)‐ones

A number of 4‐aryloxymethyl‐6‐phenyl‐2H‐pyrano[3,2‐c][1,8]naphthyridin‐5(6H)‐ones ( 4a‐f ) are regioselectively synthesized in 72‐78% yield by the Claisen rearrangement of 4‐(4′‐aryloxybut‐2′‐ynyloxy)‐1‐phenyl‐1,8‐naphthyridin‐2(1H)‐ones ( 3a‐f ) in refluxing chlorobenzene for 4‐6 h. These products are then subjected to a second Claisen rearrangement catalyzed by anhydrous AlCl₃ at room temperature for 2 h to give hitherto unreported pentacyclic heterocycles ( 5a‐f ) in 78‐85% yield.     

Application of the acetate of baylis‐hillman adducts of salicylaldehydes in the synthesis of methyl 2‐oxo‐2,3‐dihydrobenzo[b]oxepine‐4‐carboxylates

A simple synthesis of several methyl 2‐oxo‐2,3‐dihydrobenzo[b]oxepine‐4‐carboxylates from Baylis‐Hillman adducts of O‐benzyl protected 2‐hydroxybenzadehydes has been described through the acetylation, cyanation, debenzylation, as well as acid assisted Pinner cyclization.     

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.