Synthesis and selected reactions of 4-(diethoxyphosphorylmethyl)-3-furoic acid

Reduction of 4-(ethoxycarbonyl)-3-furoyl chloride with sodium borohydride in dioxane-DMF mixture leads to an ethyl 4-hydroxymethylfuran-3-carboxylate. The treatment of the latter with thionyl chloride at boiling yields the corresponding chloromethyl derivative. The obtained chloride reacts with one equivalent of sodium iodide in acetone at room temperature to form iodomethylfuran. Halomethylfurans synthesized are phosphorylated with sodium diethyl phosphite and triethyl phosphite to give ethyl 4-(diethoxyphosphorylmethyl)-3-carboxylate. The hydrolysis of this substance with one equivalent of potassium hydroxide in ethanol gives the corresponding furoic acid. Treating this substance in succession with ethyl chloroformate and sodium azide yields furoyl azide which while heating in toluene undergoes rearrangement to phosphorus-containing 3-furylisocyanate. Heating the latter with a mixture of acetic acid and acetic anhydride gives N-[4-(diethoxyphosphorylmethyl) furyl-3]acetamide. 4-(Diethoxyphosphorylmethyl)-3-furoic acid reacts with thionyl chloride to form the corresponding furoyl chloride. Its reduction with sodium borohydride in dioxane-DMF mixture leads to the phosphorylated 3-furylmethanol. Aminomethylation of its acetate with dimethylmethyleneiminium chloride in acetonitrile does not proceed at the ring. Instead of that the unstable ester of 3-(dimethylamino) propionic acid and the phosphorylated 3-furylmethanol are formed. In slightly basic medium free Mannich base decomposed to give the starting acetate.     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

Rearrangement in the series of 3-(2-aryl-2-oxoethyl)-3,4-dihydroquinoxalin-2(1H)-ones

4-Acetyl- and 4-succinyl-3-(2-aryl-2-oxoethyl)-3,4-dihydroquinoxalin-2(1H)-ones undergo the rearrangement into (Z)-2-(3-arylquinoxalin-2-ylidene)acetic acids accompanied by the elimination of the acyl groups. The nitration of 3-(2-oxo-2-phenylethyl)-3,4-dihydro-quinoxalin-2(1H)-one affords 5-nitro- and 7-nitro-2-carboxymethylidenequinoxalines. The bromination of quinoxalin-2-ones in AcOH gives 3-aryl-2-carboxymethylidenequinoxalines and the corresponding 7-bromo derivatives, with the former products predominating.     

Comparative study on the preparation of C(3)-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-ones

C(3)-Hydroxy-1,4-benzodiazepin-2-ones 1–3 have been prepared in high yields using a new, two step approach. In the first step, the 3-deoxy-precursors 4–6 were acetylated at C(3) using the redox-system lead tetraacetate and iodine, or potassium iodide, in acetic acid. The intermediary acetates 9–11 were quantitatively hydrolyzed into 1–3 in non-aqueous conditions, i.e. in a methanol-methylene chloride solvent mixture in the presence of sodium methoxide. Another route to the title compounds has been improved as follows. The yields of C(3)-bromination of compounds 4–6 has been significantly augmented in relation to the known methods using the strong trifluoroacetic acid in very dilute carbon tetrachloride solutions as a catalyst for NBS mediated bromination. The intermediary C(3)-bromo derivatives have been acetoxylated in situ, and compounds 9–11 have been isolated in over 80% yield. These compounds were solvolyzed into 1–3 as described above. The third part of this paper describes the search for feasible reaction conditions in the synthesis of 3 according to a known method (Scheme 1.); optimization of the yields in all steps was performed.     

Thiadiazole ring opening in the derivatives of 2-substituted 5-(1,2,3-thiadiazol-4-yl)-3-furoic acid under the action of bases

Transformations of the derivatives of 2-substituted 5-(1,2,3-thiadiazol-4-yl)-3-furoic acid under the action of bases has been studied. In the presence of potassium tert-butylate in THF, the studied compounds decompose with the cleavage of the thiadiazole ring, liberation of nitrogen, and formation of labile acetylene thiolates. In the presence of methyl iodide, these salts form stable 2-methylthioethynylfurans. Under the action of sodium ethylate in ethanol, thiadiazole ring of ethyl [2-methyl-5-(1,2,3-thiadiazol-4-yl)]-3-furoate is split to form the corresponding sodium acetylene thiolate. Under the action of ethanol, two molecules of this salt give bis(furyl)dithiafulvene. In the DMF–potassium carbonate system, acetylene thiolates react with primary and secondary amines giving thioamides of (4-ethoxycarbonyl-5-methylfur-2-yl)acetic acid. Treating of ethyl 2-methyland 2-N-morpholinomethyl-5-(1,2,3-thiadiazol-4-yl)-3-furoates with hydrazine hydrate leads to hydrazinolysis of the ester group and cleavage of thiadiazole ring resulting in the formation of hydrazides of 4-hydrazinocarbonylfur-2-ylacetic acid. In the case of ethyl 2-acetoxymethyl- and 2-(4-nitrophenoxy)methyl-5-(1,2,3-thiadiazol-4-yl)-3-furoates, thiadiazole ring is retained and exclusively hydrazinolysis of the ester groups is observed.     

Ring closure reaction of 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride. Synthesis of pyrimido[5,4-c] [1,5]benzoxazepin-5(11H)ones

Syntheses of 11-acety1-2-phenylpyrimido[5,4-c][1,5]benzoxazepin-5(11H)one ( 16a ) and analogs ( 16b,c, 22 ) were described. The reaction of 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 7 ) with 2-aminophenol afforded 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidine-carboxylic acid ethyl ester ( 8a ). The latter was also prepared by catalytic reduction of 4-(2-nitrophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 9 ), which was obtained from 7 and 2-nitrophenol. Involvement of 4-(2-aminophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 12a ) in this reduction as an intermediate was demonstrated by an independent synthesis of 12a and its subsequent rearrangement to 8a. Hydrolysis of 8a or 12a gave 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid ( 15a ). Reaction of 15a with acetic anhydride afforded 16a , the first member of a novel ring system, the pyrimido[5,4- c ][1,5]-benzoxazepin. Additional examples ( 16b,c ) were prepared similarly. The corresponding 11-ethyl derivative ( 22 ) was prepared in similar fashion, starting with 7 and 2-ethylaminophenol. A possible reaction mechanism for the formation of 16a-c from 15a-c and acetic anhydride was discussed.     

Synthetic experiments related to the indole alkaloids V. mercuric acetate oxidation of 2-[2-(3-indolyl)ethyl]-1,2,3,4-tetrahydroisoquinolines and the formation of benz[a]indolo[3,2-h]quinolizine derivatives

Oxidation of 2-[2-(3-indolyl)ethyl]-1,2,3,4-tetrahydroisoquinoline (I) with mercuric acetate gave 5,6,8,9,14,14b-hexahydrobenz[a]indolo[3,2-h]quinolizine (IV) and 8,9-dihydro-14H-benz[a]indolo[3,2-h]quinolizin-7-ium iodide (VI), as well as starting material. The base (IV) was oxidized with iodine and potassium acetate to VI and on Palladium carbon - maleic acid dehydrogenation yielded 5,6-dihydro-14H-benz[a]indolo[3,2-h]-quinolizin-7-ium iodide (IX), and 14H-benz[a]indolo[3,2-h]quinolizin-7-ium iodide (X). Heating the iodide (VI) with Palladium-carbon brought about an irreversible rearrangement to VII and both these salts with base yielded the red anhydro base 8, 9-dihydrobenz[a]indolo[3,2-h]quinolizine (VIII). This base was also obtained from IV by oxidation in air. The corresponding 8, 9-dehydroanhydro base (XI), benz[a]indolo[3,2-h]quinolizine, was readily obtained from X and alkali. The quinolizinium salts (VI), (VII), and (IX), on catalytic, zinc dust and acetic acid, or sodium borohydride reduction, regenerated the base (IV). Selenium degradation of IV gave, among other products, 1-(2-ethylphenyl)-β-carboline. An analogous series of products was obtained with the 6, 7-dimethoxy derivative of I. Various other aspects of these and related transformations are described.     

Synthesis of Novel New 2-(2-(4-((3,4-Dihydro-4-oxo-3-aryl quinazolin-2-yl)methyl)piperazin-1-yl)acetoyloxy)-2-phenyl Acetic Acid Esters

Stereoselective diazotization of (S)-2-amino-2-phenyl acetic acid (L-phenyl glycine) (4) with NaNO₂ in 6% H₂SO₄ in a mixture of acetone and water gave optically pure (S)-2-hydroxy-2-phenyl acetic acid (L-mandelic acid) (5). Esterification, gave (S)-2-hydroxy-2-phenyl acetic acid esters (6). The latter was treated with chloroacetyl chloride in the presence of triethylamine (TEA) in dichloromethane (DCM) to yield (S)-2-chloroacetyloxy phenyl acetic acid ester (2). In another sequence, the reaction of 2-(chloromethyl)-3-arylquinazolin-4(3H)-one (9) treated with N-Boc piperazine, followed by deprotection of the Boc group, to obtain 3-aryl-2-((piperazin-1-yl)methyl) quinazolin-4(3H)-one (3). Reaction of 2 with 3 in the presence of K₂CO₃ and KI gave the title compound, 2-(2-(4-((3,4-dihydro-4-oxo-3-arylquinazolin-2-yl)methyl)piperazin-1-yl) acetoyloxy)-2-phenyl acetic acid esters (1). The structures of all the new compounds obtained in the present work are supported by spectral and analytical data.     

Syntheses of substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines

Reaction of N-methyl-2-amino-4-nitroaniline ( 1 ) with lactic acid afforded 2-(1-hydroxyethyl)-1-methyl-5-nitrobenzimidazole ( 2 ). Oxidation of compound 2 with chromic acid in acetic acid gave 2-acetyl-1-methyl-5-nitrobenzimidazole ( 3 ). Reaction of compound 3 with substituted 2-aminobenzaldehyde ( 4 ) under basic conditions yielded substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines ( 5 ). Condensation and cyclization of o-aminoacetophenone (or substituted o-aminobenzophenones) with compound 3 under acetic condition afforded compound 7 . Condensation and cyclization of compound 1 with indole-3-carboxaldehyde ( 11 ) in ethanol in the presence of excess nitrobenzene gave 3-(1-methyl-5-nitro-2-benzimidazolyl)indole ( 12 ).     

3-[2-(8-Quinolinyl)benzoxazol-5-yl]alanine derivative—a specific fluorophore for transition and rare-earth metal ion detection

A novel aromatic amino acid, 3-[2-(8-quinolinyl)benzoxazol-5-yl]alanine derivative was synthesized as a potential Zn(II) and rare-earth metal, Eu(III) and Tb(III), ion chemosensor. The fluorophore was obtained using lead tetraacetate in DMSO to oxidize the Schiff base obtained from N-Boc-3-amino-tyrosine methyl ester and quinoline-8-carboxaldehyde. Preliminary photophysical properties of this ligand show that it possesses the properties necessary to be an effective chemosensor for Zn²⁺, Tb³⁺ and Eu³⁺ ions.     

Methyl (E)-2-(2-phenylcyclopropylidene)acetate: Synthesis, isomerization, and reaction with 1,3-diphenyl-2-benzofuran

Treatment of 3-methyl-2-phenylcycloprop-2-ene-1-carboxylic acid with potassium tert-butoxide induced its isomerization into trans-2-methylidene-3-phenylcyclopropane-1-carboxylic acid which was converted into methyl ester, and heating of the latter for 1 h in toluene gave methyl (E)-2-(2-phenylcyclopropylidene)acetate. Thermal isomerization of methyl (E)-2-(2-phenylcyclopropylidene)acetate on prolonged heating in toluene afforded 5-methoxy-3-methyl-2-phenylfuran, and the reaction with 1,3-diphenyl-2-benzofuran resulted in [4 + 2]-cycloaddition at the exocyclic double bond.     

Studies on 5-arylidene-3-phenyl-2-methylmercaptohydantoins

The action of ammonium acetate on 5-arylidene-3-phenyl-2-methylmercaptohydantoins 1g,h in acetic acid led to the formation of the 5-arylidene-3-phenylhydantoin derivatives 4a,b . In absence of a solvent, ring opening and rearrangement took place with the formation of the 5-arylidene-N²-phenylglycocyamidine derivatives 7a-c . Compounds 7a-c reacted with methyl iodide to afford the corresponding 3-methyl derivatives 9a-c . The structures of the synthesised products were established and the mechanism proposed for the rearrangement reaction was discussed.     

Substitutionen und oxidative Additionen an 2-Chlor-4, 4, 5, 5-tetrakis(trifluormethyl)-1, 3, 2-dioxaphospholan

Substitution Reactions and Oxidative Addition on 2-Chloro-4, 4, 5, 5-tetrakis (trifluoromethyl)-1, 3, 2-dioxaphospholane Substitution of chlorine in the title compound 1 yields the phosphites XP[OC(CF₃)₂C(CF₃)₂O] ( 2 : X = I, 4 : X = OCH(CF₃)₂, 5 : X = OC(O)CF₃, 7 : X = OSiMe₃). Compound 2 is easily reduced by hydrogen iodide and mercury to give HP[OC(CF₃)₂C(CF₃)₂O], 3 . The acylphosphite 5 decomposes into trifluoracetic acid anhydride and the μ-oxo diphosphite 6 at elevated temperatures. 6 is obtained also in the reaction of triphenylhydroxystannane and 1 , whereas trimethylhydroxystannane formes the phosphonic acid ester 11 which furnishes the phosphoric acid ester 12 upon reacting with hexafluoroacetone. 12 is obtained directly from the monoammonium-salt of hexafluoroacetonehydrate 13 and 1 exhibiting a prototropic rearrangement. Compound 7 is oxidized by chlorine to yield the trichlorophosphorane 9 and the diphosphate 10 . Antimony pentachloride and iodochloride oxidize 1 to give the dichlorophosphonium hexachloroantimonate 14 and the trichlorophosphorane 9 , respectively.     

The autoxidation of 2-(2-aminophenyl)-3- methylindole

Fischer indolisation of 2-aminophenyl ethyl ketone phenylhydrazone using glacial acetic acid saturated with hydrogen chloride as catalyst affords 3-methylindolo(l′:2′-3:4)2-methylquinazoline and 2-(2-aminophenyl)-3-methylindole. The latter compound is autoxidised to 2-(2-amino-phenyl)-3-hydroxy-3-methyl-3H-indole, a reaction which is shown to be dependent upon the presence of the primary amino group at the 2-position of the 2-phenyl substituent and which is much slower than the corresponding autoxidation of 2-(2-hydroxyphenyl)-3-methylindole to 3-hydroxy-2-(2-hydroxyphenyl)-3-methyl-3H-indole previously reported.Nitration of isopropyl phenyl ketone occurs preferentially at the ortho- rather than the meta- positions of the benzene nucleus.     

Synthesis and Reactions of Some Novel Nicotinonitrile,Thiazolotriazole, and Imidazolotriazole Derivatives for Antioxidant Evaluation

The novel 2-(1H)-pyridone, the lead compound of the pyridone derivative 1, reacted with an electrophilic reagent (ethyl chloroacetate) to give the corresponding ester 2. Condensation of compound 2 with thiosemicarbazide and/or hydrazine hydrate afforded the mercaptotriazole and the corresponding acetic acid hydrazide derivatives 3 and 4, respectively. The latter compound reacted with ethyl acetoacetate, ethyl cyanoacetate, and maleic anhydride to give compounds 5, 6, and 7, respectively. Alkylation of compound 3 with methyl iodide or chloroacetic acid afforded methylsulfanyltriazole and thiazolotriazole derivatives 8 and 9, respectively. Compound 8 reacted with glycine to afford the imidazotriazole derivative 10. Both compounds 9 and 10 reacted with glucose and benzaldehyde to give compounds 11, 12, 13, and 14, respectively. Some of the prepared products were selected and subjected to screening for their antioxidant activity.     

Synthesis 5-(pyrazolin-3-ylmethylidene)-2-thiohydantoins and 2-alkylsulfanyl-5-(pyrazolin-3-ylmethylidene)-3,5-dihydro-4<Emphasis Type="Italic">H</Emphasis>-imidazol-4-ones

A reaction of 3-allyl- and 3-phenylthiohydantoins with 1,5-diphenyl- and 1-phenyl-substituted 3-formyl-2-pyrazolines was used to obtain a series of 5-(pyrazolin-3-ylmethylidene)-2-thioxotetrahydro-4H-imidazol-4-ones, the subsequent alkylation of which with methyl iodide or ethyl chloroacetate gave the corresponding 2-alkylthio-5-(pyrazolin-3-ylmethylidene)-3,5-dihydro-4H-imidazol-4-ones in the yields from 30 to 77%. The oxidation of (5Z)-3-phenyl-5-[(1,5-diphenylpyrazolin-3-yl)methylidene]-2-methylsulfanyl-4,5-dihydroimidazol-4-one with lead tetraacetate led to the corresponding pyrazole in 48% yield.     

Synthesis of 2,3-dihydro-3-hydroxy-2-(pyrrol-1-ylmethyl)-1H-isoindol-1-one. An intermediate for the synthesis of tetracyclic systems

N-Chloromethylphthalimide 1 and the potassium salt of pyrrole gave N-(pyrrol-1-ylmethyl)pbthalimide 2 . Reduction of 2 led to the hydroxyisoindolone 3 . This hydroxylactam cyclized under acidic conditions to lead to a pyrroloimidazoloisoindolone 4 via an acyliminium ion. Transformation of 3 with acetic acid derivatives provided 5, 7 and 9 which gave by intramolecular cyclization, tetracyclic compounds 6, 10 and 11 .     

Amino acids in the synthesis of heterocyclic systems. Synthesis of γ-(5-(1,2,4-Triazinylidene))-α,β-dehydro-α-amino acid derivatives and 6H-pyrido[1,2-d][1,2,4]triazin-6-ones

5-(1,2,4-Triazinyl) substituted enamines 3 react with 5(4H)-oxazolones 4 in acetic anhydride to give acetylated products 5 , while in toluene-acetic acid mixture nonacetylated products 9 are formed. Both types of products were isolated as (E,Z) mixtures. Compounds 5 and 9 rearrange into 6H-pyrido[1,2-d]-[1,2,4]triazin-6-ones 12 by heating in formic acid or in xylene, respectively. Compounds 5 are transformed in the presence of nucleophiles, such as sodium alkoxides or sodium amides via anionic form 10 into corresponding esters 13 and amides 14 of γ-(5-(1,2,4-triazinylidene)) substituted derivatives of α-amino-2-butenoic acid, which exist in 2-(Z),4-(Z) form.     

α-pyrones. III Synthesis of 5,6-dihydro-1H-benzo[c]-quinolizin-1-ones from 6-(2-nitrostyryl)-2H-pyran-2-ones

The 6-(2-nitrostyryl)-2H-pyran-2-ones 1 were reduced with hydrogen over Pd/C at room temperature and atmospheric pressure giving the 2-benzoylamino-4-(1,2,3,4-tetrahydro-2-quinolinylidene-2-pentenedioic acid derivatives 2 which were converted, without isolation, into the 5,6-dihydro-1H-benzo[c]quinolizin-1-ones 4 in refluxing acetic anhydride. When α-aminoacids 2 were treated with acetic anhydride at room temperature oxazolones 3 were isolated, while by heating quinolizines 4 were found. Compounds 3 were transformed into 4 in refluxing acetic acid or anhydride.