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.     

Studies with 2‐arylhydrazononitriles: A novel simple,efficient route to 5‐acyl‐2‐substituted‐1,2,3‐triazol‐4‐amines

Efficient route to 5‐acyl‐2‐substituted‐1,2,3‐triazol‐4‐amines via reaction of 3‐oxo‐2‐(arylhydrazono)‐pentanenitrile with hydroxylamine hydrochloride is reported. X‐ray crystal structure has been made to confirm the structure of reaction products.     

Studies with functionally substituted N‐alkylazoles: The reactivity of 1‐(3,5‐dimethylpyrazol‐1‐yl)‐acetone towards electrophilic reagents

The reaction of 1‐(3,5‐dimethylpyrazol‐1‐yl)acetone 4 with aromatic diazonium salts afforded the corresponding arylhydrazones 5a,b that were converted into pyridazines 6a,b and 8 via condensation with active methylene nitriles and dimethylformamide dimethylacetal, respectively. Condensation of 4 with phenylhydrazine afforded the phenylhydrazone 10 , which could be converted into the indolylpyrazole 11 on treatment with ethanolic hydrochloric acid. Compound 4 also reacted with nitrous acid, benzyl‐idenemalononitrile to yield a variety of substituted new pyrazoles.     

Studies with enaminonitriles: Synthesis and chemical reactivity of 2‐phenyl‐3‐piperidin‐1‐yl acrylonitrile under microwave heating

Benzyl cyanide reacts with triethylorthoformate and piperidine in DMF solution to yield the title compound 2 . This reacted with aromatic amines to yield either aminoacrylonitriles or quinoline depending on reaction conditions and substitution pattern on the aromatic amine. The reaction of compound 2 with hydrazine hydrate could only be effected in the microwave oven and resulted in the formation of aminopyrazole 7 . Diazotization of 7 and coupling with an active methylene reagent afforded pyrazolo[5,1‐c]‐[1,2,4]triazine derivatives.     

Studies with enamines and azaenamines: Synthesis and reactivity of 3‐dimethylamino‐2‐[(3‐indolyl) carbonyl]propenonitrile

2‐Oxo‐3‐(indol‐3‐yl)propanonitrile 2 condensed with dimethylformamide dimethylacetal to yield the enaminonitrile 3 . The latter reacted with 4‐chloroaniline to yield the 4‐chlorophenylaminoacrylonitrile 5 . Reaction of 3 with hydrazine hydrate led to formation of pyrazole‐4‐carbonitrile 6 . Compound 3 reacted with ethyl acetoacetate in refluxing acetic acid and in presence of ammonium acetate to yield the indolylpyridine 10 . Enamine 3 reacted with 5(1H)‐aminotriazole 13 and 3(5)‐aminopyrazole 17 to yield the pyrimidine derivatives 15 and 19 , respectively.     

Studies towards the Synthesis of Alkyl N‐(4‐Nitrophenyl)‐3/2‐oxomorpholine‐2/3‐carboxylates

The syntheses of methyl 4‐(4‐nitrophenyl)‐3‐oxomorpholine‐2‐carboxylate ( 3a ) and ethyl 4‐(4‐nitrophenyl)‐2‐oxomorpholine‐3‐carboxylate ( 5b ), important building blocks for the synthesis of factor Xa inhibitor rivaroxaban analogs with potential dual antithrombotic activity, via Rh₂(OAc)₄‐catalyzed O? H and N? H carbene insertion reactions are described.     

Further Studies with Ethyl 5‐Amino‐3‐phenyl‐lH‐pyrazole‐4‐carboxylate1

The newly synthesized ethyl 3‐amino‐5‐phenylpyrazole‐4‐carboxylate 1 was diazotized and coupled with β‐naphthol, active methylene reagents 6 , 9 , 12 , 15 , and the active methine 19 to afford the pyrazolo[5,1‐c]triazines 5 , 8 , 11 , 14 , 17 , 18 , and the pyrazolo[5,1‐ c ]‐1,2,4‐triazoles 21 , 22 , and 23 , respectively. Structures are elucidated and mechanisms are discussed.     

Studies with enaminones: Synthesis and chemical reactivity of 2‐(4‐dimethylamino‐2‐oxobut‐3‐enyl)‐isoindole‐1,3‐dione and of 4‐(4‐dimethylamino‐2‐oxobut‐3‐enyloxy)‐2H‐phthalazin‐1‐one

The title compounds were synthesized via condensing acetonylphthalimide and 4‐acetonyloxyphthalazine‐1‐one with dimethylformamide dimethylacetal (DMFDMA). The reaction of these enaminones with electrophiles and nucleophiles is reported as a route to polyfunctional heteroaromatics.     

Studies on the reactivity of new types of tetracyclic‐1,5‐benzoxazepines: Part V

The syntheses of tetracyclic 1,5‐benzoxazepines 3a‐e from heterocyclic (3‐chloroaldehydes 1a‐e and 2‐aminophenol are reported herein (Scheme I). Attempted lithium aluminium hydride (LiAlH₄) reduction of the imine double bond in 3a‐e failed to furnish the corresponding saturated compounds 5a‐e. Attempted catalytic hydrogenation of 3a‐e in the presence of acetic acid and acetic anhydride gave surprisingly only the acetoxy derivatives 6a‐e in high yields (Scheme II). Base catalysed hydrolysis of acetoxy derivatives 6a‐e furnished, as expected, the corresponding phenolic derivatives 7a‐e , in moderate yields. Attempted cyclofunctionalization of 3a‐e either with mercaptoacetic acid or its methyl ester to obtain the new penta‐cyclic heterocycles 4a‐e was, however, not successful.     

New results on the reactivity of 5,6‐diamino‐4‐hydroxy‐2‐mercaptopyrimidine

The reaction of 5,6‐diamino‐4‐hydroxy‐2‐mercaptopyrimidine with mono‐ and α,ω‐dihalocompounds has been reinvestigated. Alkyl derivatives of 5‐amino group, not previously described, have been obtained as reaction products. A comparison with the reactivity of 6‐amino‐4‐hydroxy‐2‐mercaptopyrimidine has been also performed.     

New synthesis and reactivity of 3‐bromoacetyl‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one with binucleophilic amines

3‐(Bromoacetyl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one was synthesized by the reaction of dehydroacetic acid (DHAA) with bromine in glacial acetic acid. Novel heterocyclic products were synthesized from the reaction of bromo‐DHAA with alkanediamines, phenylhydrazines, ortho‐phenylenediamines, and ortho‐aminobenzenethiol. The obtained new products 3‐(2‐N‐substituted‐acetyl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐ones, 4‐hydroxy‐3‐[1‐hydroxy‐2‐(2‐phenylhydrazinyl)vinyl]‐6‐methyl‐2H‐pyran‐2‐one, 1‐(2,4‐dinitrophenyl)‐7‐methyl‐2,3‐dihydro‐1H‐pyrano[4,3‐c]pyridazine‐4,5‐dione, 3‐(3,4‐dihydroquinoxalin‐2‐yl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one/3‐(3,4‐dihydroquinoxalin‐2‐yl)‐6‐methyl‐2H‐pyran‐2,4(3H)‐dione, 6‐methyl‐3‐(3,4‐dihydroquinoxalin‐2‐yl)‐2H‐pyran‐2,4(3H)‐dione, and (E)‐3‐(2H‐benzo[b][1,4]thiazin‐3(4H)‐ylidene)‐6‐methyl‐2H‐pyran‐2,4(3H)‐dione were fully characterized by IR, ¹H and ¹³C NMR, and mass spectra. J. Heterocyclic Chem., 2011.     

Studies with enamines: Reactivity of N,N‐dimethyl‐N‐[(E)‐2‐(4‐nitrophenyl)‐1‐ethenyl]amine towards nitrilimine and aromatic diazonium salts

In the presence of triethylamine, cycloaddition reaction of enamine 1 with hydrazonoyl halides 2 followed by dimethylamine elimination was achieved, yielding the corresponding 1,3,4‐trisubstituted pyrazoles 4 . Coupling of enamine 1 with aromatic diazonium salts afforded 2‐(arylhydrazono)‐2‐(4‐nitrophenyl)acetaldehyde 9 in good yield. Refluxing the phenyl hydrazone 9a with chloroacetone in ethanol in the presence of triethylamine afforded 1,3,5‐trisubstituted pyrazole 12a , formed via intermediate 11a. Reaction of 9a with hydroxylamine hydrochloride in ethanol in the presence of anhydrous sodium acetate yielded oxime 13a which was irradiated in a microwave oven in the presence of acetic acid to afford a mixture of 15a and 16a.     

Synthesis and chemical reactivity of 3‐oxo‐2‐arylhydrazono‐propanenitriles

2‐Formyl‐2‐arylhydrazonoethanenitriles 6b‐d where prepared via reacting enaminonitrile 2b,c with aromatic diazonium salts. These reacted with phenylhydrazine to yield bis hydrazones that were converted to arylazopyr‐azoles via a novel Vilsmeier‐Haack reaction type. Reaction of 6c with hydroxylamine afforded oxime that could be successfully cyclised into arylazoisoxazole. Reaction of 6c with hydrazine hydrate to yield arylazoamino‐pyrazole that proved to be excellent precursors for synthesis functional substituted pyrazolopyrimidines.     

4‐hydroxy‐6‐methyl‐3‐(5‐phenyl‐2E,4E‐pentadien‐1‐oyl)‐2H‐pyran‐2‐one: Synthesis and reactivity with amines

The synthesis and reactivity studies of 4‐hydroxy‐6‐methyl‐3‐(5‐phenyl‐2E,4E‐pentadien‐1‐oyl)‐2H‐pyran‐2‐one 2 with nucleophiles are reported. Reactions of 2 with hydrazine derivatives gave new pyrazole‐type com pounds while the reaction with ortho‐phenylenediamines yielded 1,5‐benzodiazepines. The reaction of 2 with ethylamine implies the 2H‐pyran‐2‐one ring opening and the formation of a strong conjugated compound 3.     

Olefin Cross‐Metathesis: Studies towards the Total Synthesis of (+)‐Bitungolide F

A stereoselective synthesis of (5S,6S)‐6‐[(2S,5S,7R,8E,10E)‐5‐(benzyloxy)‐7‐{[(tert‐butyl)dimethylsilyl]oxy}‐11‐phenylundeca‐8,10‐dien‐2‐yl]‐5‐ethyl‐5,6‐dihydro‐2H‐pyran‐2‐one (=(+)‐9‐O‐benzyl‐11‐O‐[(tert‐butyl)dimethylsilyl]bitungolide F) is reported. The strategy involves Gilman reaction, olefin cross‐metathesis, and Horner? Wadsworth? Emmons olefination as key steps.     

Reaction of β-keto ethyleneacetals with hydroxylamine: A correction

A reaction of 2-(2-nitrobenzoylmethyl)-1,3-dioxolane ( 3 ) with hydroxylamine, followed by acid catalyzed cyclization, produced 5-(2-nitrophenyl)isoxazole ( 5 ) as the only isolable product, whereas 2-(benzoylmethyl)-1,3-dioxolane ( 9 ) under identical conditions produced a 2.5:1 mixture of 3-phenyl and 5-phenylisoxazoles 10 and 11 . These findings contradict the literature report that β-keto ethyleneacetals on treatment with hydroxylamine produce exclusively 3-substituted isoxazoles. As an additional proof, 3-(2-nitrophenyl)isoxazole ( 8 ) was prepared by an unambiguous method via the nitrile oxide route for comparison. The intermediate obtained on treatment of 2-(2-nitrobenzoylmethyl)-1,3-dioxolane ( 3 ) with hydroxylamine was found to be an isomeric mixture of 5-hydroxy-5-(2-nitrophenyl)-2-isoxazoline ( 4 ) and the syn and anti mono-oximes 19 (at least in solution), either of which could give 5-(2-nitrophenyl)isoxazole ( 5 ) on acid treatment. A mechanistic rationale is provided to explain the anomalous results.     

Enaminones in heterocyclic synthesis: Synthesis and chemical reactivity of 3‐anilino‐1‐substituted‐2‐propene‐1‐ one

The 3‐anilinoenones 3a,b were prepared from the corresponding 3‐dimemyl‐aminopropenones. The reactivity of 3a,b towards a variety of carbon and nitrogen nucleophiles as well as naphthoquinones is reported.