Synthesis of Some Novel Heterocyclic Xylidinyl Amines and Carboxamides

The xylidines 1a , 1b undergo condensation with ethyl cyanoacetate 2 and ethyl benzoyl acetate 15 to afford the cyano acetanilides 3a , 3b and the β‐diketones 16a , 16b , respectively. Compounds 3a , 3b react with hydrazine and phenyl hydrazine to afford the azine‐bis derivatives 5a , 5b and 7a , 7b , whereas 16a , 16b react with the same reagents to afford the pyrazolyl amine derivatives 17a , 17b and 18a , 18b , respectively. Compounds 3a , 3b react also with dimethylformamide dimethylacetal to afford the enaminonitriles 8a , 8b , whereas 16a , 16b react with the same reagent to afford only the enaminone 19b . The enaminonitriles 8a , 8b react with hydrazine and phenyl hydrazine to afford also the azine‐bis derivatives 11a , 11b and 14a , 14b , respectively.     

Synthesis and reactions of thiosemicarbazides, triazoles, and Schiff bases as antihypertensive α-blocking agents

Methyl 2-(thiazol-2-ylcarbamoyl)acetate was synthesized and used as starting material. It was treated with hydrazine hydrate to afford the hydrazide, which was reacted with nitromethane and formaldehyde to give the saturated nitropyrimidine. The hydrazide was reacted with phenyl isothiocyanate to afford the thiosemicarbazide, which was cyclized with ethyl bromoacetate, sodium hydroxide, or sulfuric acid to afford N-phenylthiazolidinone, N-phenyltriazole, and thiadiazolyl derivatives. The methyl 2-(thiazol-2-ylcarbamoyl)acetate was coupled with diazonium salts of aniline, 4-chloroaniline, 4-bromoaniline, or 4-aminobenzenesulfonamide to afford the carbamoyl acetates, which were reacted with 2-aminobenzimidazole, 1,2,4,5-tetrachlorophthalic anhydride, and hydrazine hydrate to afford the corresponding thiazolylmalonamide, tetrachloroisoindolylimide, and tri-azole derivatives. Schiff bases and imides are newly synthesized candidates obtained via simple condensation of the hydrazide with aldehydes, 2,3-pyridinedicarboxylic anhydride, or 1,8-naphthalenedicarboxylic anhydride. The pharmacological screening showed that many of these compounds have good antihypertensive α-blocking activity and low toxicity.     

A Novel Synthesis of Some 1,4‐Phenylene‐bis‐heterocyclic Derivatives and of Some Pyran,Pyrano[2,3‐c]pyrazole,and Pyrano[2,3‐d]pyrimidine Derivatives [1]

p‐Diacetyl benzene 1 undergoes bromination to afford p‐bromoacetyl phenacyl bromide 2 . Compound 2 reacts with twofold excess of malononitrile to afford 2‐{2‐[4‐(3,3‐Dicyanopropionyl)‐phenyl]‐2‐oxo‐ethyl}‐malononitrile 3 . Compound 3 could be cyclized to afford the 1,4‐phenylene‐bis‐furan derivative 4 . Compound 3 reacts also with a twofold excess of hydrazine hydrate and phenyl hydrazine under dry conditions at RT to afford the bis‐pyrazole derivatives 5a , 5b , respectively. The reaction of 5a , 5b with the same reagents in refluxing dioxane afforded the bis‐pyrazolopyridazine derivatives 7a , 7b , respectively. The azo coupling of compound 3 with arene diazonium salts afforded the bis‐pyrazole derivatives 9a , 9b , 9c . The β‐keto esters 10a , 10b react with benzaldehyde and malononitrile in a one pot synthesis to afford the pyran derivatives 11a , 11b . These latter compounds react with hydrazine hydrate and urea derivatives to afford the pyrano[2,3‐c]pyrazoles 15a , 15b and the pyrano[2,3‐d]pyrimidine derivatives 17a , 17b , respectively.     

Preparation of 1,5-methano-2,3,4,5- tetrahydro-1H-3-benzazepine via Pd-catalyzed cyclization

[reaction: see text] A new approach to prepare 1,5-methano-2,3,4,5-tetrahydro-1H-3-benzanepine (1) is discussed. This strategy utilized a tandem Michael addition and Pd-catalyzed cyclization to afford cyanobenzofulvene acetal 13. This indene intermediate (13) was subjected to hydrogenolysis to provide an amino ester (12) and was cyclized with base to afford lactam 5. The lactam (5) was reduced with borane to afford the desired benzazepine (1).     

Synthesis of Some New Pyrazole,Pyrimidine, Pyridazine,and Their Fused Derivatives from 3‐Oxo‐3,N‐diphenylpropionamide

The title compounds were obtained from the reactions of 3‐oxo‐3,N‐diphenylpropionamide 3 with dimethylformamide dimethylacetal followed by hydrazine to afford the pyrazole 7 , condensation with benzaldehyde followed by cyclocondensation with guanidine to afford the pyrimidine derivative 13 , condensation with active methylenes followed by azo coupling of the products followed by cyclization to afford the pyridazines 17a , 17b . The pyridazinone 17b was explored for the synthesis of some novel pyridazine‐fused heterocyclic compounds 19 , 21 , 24a , 24b , 24c , and 26 . All structures were proved via their elemental analyses and spectral data.     

Synthesis and Reactions of Some Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives with a Thiophene Ring as Analgesic, Anticonvulsant, and Antiparkinsonian Agents

A series of 2,6-disubstituted pyridine ester derivatives and the corresponding amides were prepared. The esters were hydrolysed to the sodium salts, which were treated with acetic anhydride to afford oxazinone derivatives. These were treated with ammonium acetate to afford 2-methylpyrimidinone derivatives, which were methylated to yield 2,3-dimethylpyrimidinone derivatives. In addition, they were reacted with aniline or hydrazine hydrate to give 3-phenyl- or 3-aminopyrimidinone derivatives. The latter reacted with 2-thiophenecarbaldehyde or phthalic anhydride to afford the corresponding Schiffs base and imide derivatives. Diazotization of amides gave thienotriazinone derivatives, which were treated with ethyl iodide to afford the corresponding 3-ethyltriazinone derivatives. Also, they were reacted with phenyl isothiocyanate to give the corresponding thiopyrimidinone derivatives, which were alkylated with ethyl iodide or chloroacetic acid to afford the corresponding thioethyl- or thioglycolic acid pyrimidinone derivatives.The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Voltarene®, Carbamazepine®, and Benzotropene® as reference drugs.     

Synthesis and reactions of thiosemicarbazides,triazoles, and <Emphasis Type="Italic">Schiff</Emphasis> bases as antihypertensive α-blocking agents

Methyl 2-(thiazol-2-ylcarbamoyl)acetate was synthesized and used as starting material. It was treated with hydrazine hydrate to afford the hydrazide, which was reacted with nitromethane and formaldehyde to give the saturated nitropyrimidine. The hydrazide was reacted with phenyl isothiocyanate to afford the thiosemicarbazide, which was cyclized with ethyl bromoacetate, sodium hydroxide, or sulfuric acid to afford N-phenylthiazolidinone, N-phenyltriazole, and thiadiazolyl derivatives. The methyl 2-(thiazol-2-ylcarbamoyl)acetate was coupled with diazonium salts of aniline, 4-chloroaniline, 4-bromoaniline, or 4-aminobenzenesulfonamide to afford the carbamoyl acetates, which were reacted with 2-aminobenzimidazole, 1,2,4,5-tetrachlorophthalic anhydride, and hydrazine hydrate to afford the corresponding thiazolylmalonamide, tetrachloroisoindolylimide, and tri-azole derivatives. Schiff bases and imides are newly synthesized candidates obtained via simple condensation of the hydrazide with aldehydes, 2,3-pyridinedicarboxylic anhydride, or 1,8-naphthalenedicarboxylic anhydride. The pharmacological screening showed that many of these compounds have good antihypertensive α-blocking activity and low toxicity. Correspondence: Abd El-Galil E. Amr, National Research Center, Applied Organic Chemistry, Dokki, Cairo, Egypt.     

Direct Synthesis of Multi‐functional Pyrimidine,Pyrazine, and Pyridine Scaffolds via Inter‐ and Intramolecular Annulations of 3‐Amino‐thieno[2,3‐b]pyridine‐2‐carboxylate

The synthesis of a new series of annulated thieno[2,3‐b]pyridines was performed. Ester compound 1 underwent heterocyclization upon reaction with phenylisothiocyanate and formamide to afford pyrimidines 2 and 3 , respectively. Thienopyrimidine 5 was resulted via reaction of amino derivative 1 with triethyl orthoformate to afford the non‐isolable intermediate 4 , which allowed hydrazinolysis with hydrazine hydrate to afford the target compound. Pyrimidine type 5 was condensed with p‐nitrobenzaldehyde to afford Schiff base 6 . Refluxing of ester 1 with ethyl cyanoacetate and diethyl malonate followed by base‐mediated heterocyclization afforded condensed pyridines 8 and 9 , respectively. The tetracyclic pyrazine derivative 14 was obtained from the reaction of amino compound 1 with 2,5‐dimethoxytetrahydrofuran followed by hydrazinolysis to give carbohydrazide 11 , which undergo diazotization followed by Curtius rearrangement. The antibacterial results illustrated no significant results for the investigated compounds except compound 5 , which has moderate activity against Gram‐positive bacteria.     

Reactions of dimethoxycarbene with dimethyl 2,3-dicycanomaleate and fumarate

Dimethoxycarbene, in 2-fold or larger excess, reacts with dimethyl 2,3-dicyanomaleate and fumarate to afford an unstable dihydrofuran 1:1 adduct that was shown to react further with the carbene to afford a 2:1 adduct reported previously. In an astonishing process, the dihydrofuran reacts with water to afford a mixture of (d,l and meso) dimethyl 2,3-dicyanosuccinates in which both hydrogen atoms of water were used to hydrogenate a C=C bond.     

Synthesis of 1,8- and 2,8-dihydrocycloheptapyrazol-8-one derivatives by the reactions of 3-acetyltropolone and its methyl ethers with phenylhydrazine

3-Acetyltropolone ( 1 ) reacted with phenylhydrazine to give 3-acetyltropolone phenylhydrazone ( 3 ) and 3-methyl-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one ( 4 ). The former ( 3 ) cyclized to afford the latter ( 4 ). The reaction of 3-acetyl-2-methoxytropone ( 2a ) with phenylhydrazine gave 4 , 3-methyl-2-phenyl-2,8-dihydrocyclo-heptapyrazol-8-one ( 5 ), and 3-methyl-2-phenyl-2,8-dihydrocycloheptapyrazol-8-one phenylhydrazone ( 6 ). The compound ( 5 ) reacted with phenylhydrazine to afford 6 . The reaction of 7-acetyl-2-methoxytropone ( 2b ) with phenylhydrazone gave 7-acetyl-2-methoxytropone phenylhydrazone ( 7 ), 7-acetyl-2-(N′-phenylhydrazino)-tropone phenylhydrazone ( 8 ), 3-methyl-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one phenylhydrazone ( 9 ), and 6 . The compound ( 7 ) was heated to afford 4 and reacted with phenylhydrazine to afford 8 and 9 . The compound ( 8 ) was also refluxed to give 9 .     

Nucleophilic addition to (3-methylpentadienyl)iron(1+) cations: counterion control of regioselectivity; application to the enantioselective synthesis of 4,5-disubstituted cyclohexenones

The regioselectivity of malonate addition to (3-methylpentadienyl)Fe(CO)3+ is controlled by the malonate-counterion association. The Li+ salt of malonate proceeds via C1 nucleophilic attack to afford the 1,3Z-diene complex 4a, while reaction of highly dissociated ion pair (i.e., Na+ or Li+/12-crown-4) salt proceeds at the C2 internal carbon to eventually afford cyclohexenone products 6. Reaction of 1a with the sodium salt of bis(8-phenylmenthyl)malonate proceeds with excellent diastereocontrol to afford a single diastereomeric cyclohexenone.     

Optically active poly(hydroxyurethane)s derived from cyclic carbonate and L-lysine derivatives

The polyaddition of L -lysine hydrochloride and bifunctional five-membered cyclic carbonate 1 was carried out in DMAc in the presence of 1 equiv of DBU or 2 equiv of sodium hydride for 24 h to afford optically active polyurethane 2 bearing hydroxy and carboxyl group. The polyaddition of L -lysinol and 1 was also carried out in NMP to afford higher molecular weight of optically active polyurethane 3 bearing hydroxy group in quantitative yield. These polyurethanes reacted with cupric acetate, sodium tetrahydroborate, and titanium tetraisopropoxide to afford the corresponding crosslinked gels immediately. © 1996 John Wiley & Sons, Inc.     

Synthesis and Reactions of Some Fused Oxazinone,Pyrimidinone, Thiopyrimidinone,and Triazinone Derivatives with a Thiophene Ring as Analgesic,Anticonvulsant, and Antiparkinsonian Agents

Summary. A series of 2,6-disubstituted pyridine ester derivatives and the corresponding amides were prepared. The esters were hydrolysed to the sodium salts, which were treated with acetic anhydride to afford oxazinone derivatives. These were treated with ammonium acetate to afford 2-methylpyrimidinone derivatives, which were methylated to yield 2,3-dimethylpyrimidinone derivatives. In addition, they were reacted with aniline or hydrazine hydrate to give 3-phenyl- or 3-aminopyrimidinone derivatives. The latter reacted with 2-thiophenecarbaldehyde or phthalic anhydride to afford the corresponding Schiffs base and imide derivatives. Diazotization of amides gave thienotriazinone derivatives, which were treated with ethyl iodide to afford the corresponding 3-ethyltriazinone derivatives. Also, they were reacted with phenyl isothiocyanate to give the corresponding thiopyrimidinone derivatives, which were alkylated with ethyl iodide or chloroacetic acid to afford the corresponding thioethyl- or thioglycolic acid pyrimidinone derivatives.The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Voltarene®, Carbamazepine®, and Benzotropene® as reference drugs.Received January 23, 2003; accepted (revised) March 17, 2003 Published online September 15, 2003     

Highly-functionalised difluorinated (hydroxymethyl)conduritol analogues via the Diels-Alder reactions of a difluorinated dienophile

A difluorodienophile, synthesised using a Stille coupling reaction underwent tin(iv)-catalysed cycloaddition with three furans to afford oxa[2.2.1]bicycloheptenes in good yield. Reduction of ester and carbamate carbonyl groups and diol protection as the acetonide set the stage for palladium-catalysed hydrostannylation in two cases. Treatment of the stannanes with methyllithium triggered ring-opening to afford highly-functionalised difluorinated cyclohexenols which could be deprotected to afford (hydroxymethyl)conduritol analogues.     

Synthesis, Reactions, and Anti-inflammatory Activity of Heterocyclic Systems Fused to a Thiophene Moiety Using Citrazinic Acid As Synthon

Summary. A series of pyridines, pyrimidinones, and oxazinones were synthesized as anti-inflammatory agents using citrazinic acid (2,6-dihydroxyisonicotinic acid) as a starting material. Acryloyl pyridine was treated with cyanothioacetamide to give cyano pyridine-thione, which was reacted with ethyl chloroacetate to yield the corresponding amino ester. The ester was hydrolysed to the sodium salt, which was treated with acetic anhydride to afford 2-methyloxazinone, which was treated with ammonium acetate to afford 2-methylpyrimidinone followed by methylation with methyl iodide to yield 2,3-dimethylpyrimidinone. In addition, the oxazinone derivative was reacted with aniline or hydrazine hydrate to give 3-phenyl- or 3-aminopyrimidinones. The latter reacted with thiophene-2-carboxaldehyde or phenylisothiocyanate to afford Schiff’s bases or thiosemicarbazides. 3-Aminopyrimidinone was treated with phthalic anhydride or 1,2,4,5-benzenetetracarboxylic acid dianhydride or toluene-3,5-diisocyanate to afford the corresponding imide, bis-imide, and bis-semicarbazide derivatives. The pharmacological screening showed that many of these compounds have good anti-inflammatory activity comparable to Prednisolone^? as reference drug.     

Synthesis of Some Thienotetrahydroquinoline Derivatives

2‐Thioxo‐1,2,5,6,7,8‐hexahydroquinoline‐3‐carbonitrile ( 2 ) was easily S‐alkylated to produce alkyl mercapto derivatives 3a‐g . The latter compounds were cyclized to afford thienotetrahydroquinolines 4a‐g . Several pyrimidothienotetrahydroquinolines 5a‐d , and 6a‐d were obtained from the condensation of compounds 4c‐f with different reagents. o‐Aminocarbohydrazide derivative 11 was reacted with aromatic aldehydes, acetylacetone, nitrous acid and CS₂ to afford compounds 12–15 . Compound 24 was coupled with aryldiazonium chloride to afford arylazo derivatives 25 . Also it condensed with aromatic aldehydes to give arylidene derivatives 26 . The latter compounds were reacted with malononitrile to give pyrano derivative 27 .     

Syntheses of selectively fluorinated cyclodecenones: the first deployment of the neutral oxy-Cope rearrangement in organofluorine chemistry

Metallated haloalkenes were used to open epoxides in moderate to good yield. The homoallylic alcohols obtained underwent Swern oxidation to afford three gamma,gamma-difluorinated beta,gamma-enones, which reacted with either vinyllithium,2-lithio-2H-dihydropyran or another metallated haloalkene to afford substituted trans-1,2-divinylcyclohexanols of different degrees of stability. These intermediates underwent neutral thermal oxy-Cope rearrangements when heated in xylene in Ace tubes. The first-formed enols ketonised without loss of HF to afford a range of cyclodecenones in moderate to good yield; X-ray crystallography was used extensively for product characterisation. All substrates rearranged more rapidly than a cis/trans mixture of 1,2-divinylcyclohexanols.     

Heterocyclic synthesis via enaminones: Regioselective synthesis of some novel pyrazole,isoxazole, pyrimidine,pyrido[1,2‐a]benzimidazole and pyrazolo[1,5‐a]‐pyrimidine derivatives

2‐Acetylbenzothiazole ( 1 ) reacts with dimethylformamide dimethylacetal (DMF‐DMA) to afford the enaminone 2. Compound 2 reacts regioselectively with some nitrilimines 5a–d and nitrile oxides 6b–d to afford the novel pyrazole and isoxazole derivatives 11a–d and 12b–d, respectively, which react with hydrazine hydrate to give the new pyrazolo[3,4‐d]pyridazine and isoxazolo[3,4‐d]pyridazine derivatives 13a–d and 14b–d, respectively. The enaminone 2 reacts with 1H‐benzimidazole‐2‐acetonitrile ( 17 ) to afford the pyrido[1,2‐a]benzimidazole derivatives 19. Compound 2 reacts also with 5‐amino‐3‐phenylpyrazole ( 20 ) and with guanidine to afford the new pyrazolo[1,5‐a]pyrimidine and the 2‐aminopyrimidine derivatives 22 and 24, respectively. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 417–422, 1999     

Reaction of alpha-(N-carbamoyl)alkylcuprates with enantioenriched propargyl electrophiles: synthesis of enantioenriched 3-pyrrolines

Enantioenriched propargyl mesylates or perfluorobenzoates react with alpha-(N-carbamoyl)alkylcuprates to afford scalemic alpha-(N-carbamoyl) allenes which undergo N-Boc deprotection and AgNO3-promoted cyclization to afford N-alkyl-3-pyrrolines. The synthetic sequence proceeds under optimal conditions with no loss of enantiopurity relative to the starting propargyl alcohols prepared by asymmetric addition of terminal alkynes to aldehydes.     

Apply peptide C-terminal semicarbazides to peptide segment coupling using transfer active ester condensation technology

Peptide C-terminal semicarbazides are used as the starting materials in transfer active ester condensation technology to prepare HOCt active esters intermediates, which react with other peptide segments or reagents to afford long chain peptides, branch peptides and peptide C-terminal derivatives. The semicarbazido derivatives afford reliable results and avoid side reactions efficiently.