A Convenient Method to Obtain 4,5-Dihydro-1H-Methylpyrazoles by A Ring Transformation Reaction

A convenient method for the synthesis of alkyl[aryl]-substituted 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-methylpyrazole (2) from a new ring transformation reaction of alkyl[aryl]-substituted-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-pyrazolethiocarboxyamide (1) with methylhydrazine in THF, and the thermal dehydration of 2, are reported.     

Synthesis of pyrimido[4,5-b]quinolines in the reaction of 6-aminopyrimidines with dimedone and benzaldehydes

The reaction of 6-aminopyrimidines 1a, b with dimedone ( 2 ) and p-substituted benzaldehydes 3a-d in ethanol afforded in all cases new regiospecific synthesis of tricyclic, linear 5-aryl-5,6,7,8,9,10-hexahydropyrimido[4,5-b]quinolines 4a-h in good yields. The linear structures and hence the regiospecificity of the reaction were established by nmr measurements.     

1,2,4-triazines. 1. A convenient synthesis of 4,5-dihydro-1,2,4-triazin-3-(2H)one and its 6-substituted derivatives

A facile synthesis of 4,5-dihydro-1,2,4-triazin-3-(2H)one (2a) from 5-methylthio-1,2,4-triazin-3-(2H)one (1a) with sodium borohydride is described. The reaction provides a convenient method for its 6-substituted derivatives (2b-h).     

Facile and convenient strategy towards synthesis of 4-substituted 2-aminothiazolo[4,5-d]pyridazinones

Convenient synthesis of 4-substituted 2-aminothiazolo[4,5-d]pyridazinones has been achieved in 12 steps with overall yield of 19% by employing Grignard reaction as the key step. The route utilizes well established thiazole ring formation followed by Grignard reaction to introduce substitution at 4-position effectively. In addition to the use of inexpensive chemicals, the present route first time gave access to the 4-substituted 2-aminothiazolo [4,5-d]pyridazinones with free amino group at C-2 position.     

3(2H)isoquinolones. 2. Studies on the structure and formation of aminonaphthols obtained in the preparation of 3(2H)isoquinolones

The reaction of a 2-acylphenylacetic acid derivative (I) with primary amines in glacial acetic acid produces novel, colorless aminonaphthols (III) which are isomeric with the brilliant yellow 3(2H)isoquinolones (II) obtained in the same reaction. A combination of chemical and spectral techniques allowed identification of the isomers as derivatives of 4-amino-2-naphthol. A plausible mechanism of formation of aminonaphthols versus 3(2H)isoquinolones is discussed and supported by chemical synthesis of N-substituted 2-aeylphenylacetamides (VIII) and a 1,4-dihydro-1-hydroxy-3(2H)isoquinolone derivative (IX).     

New liquid crystalline 3-methyl-6-(4-substituted phenyl)-4,5-dihydrobenzo [ d ] isoxazoles and 3,5-disubstituted 4,5-dihydroisoxazoles: synthesis and mesomorphic properties

The synthesis and mesomorphic properties of new liquid crystalline 3-methyl-6-(4-substituted phenyl)-4,5-dihydrobenzo [ d ] isoxazoles and 3,5-disubstituted 4,5-dihydroisoxazoles are reported. These compounds have been synthesized by the reaction of 6-(4-substituted phenyl)-3-acetyl cyclohex-2-enones with hydroxylamine hydrochloride and of the corresponding oximes with unsaturated compounds in the presence of N -chlorosuccinimide and triethylamine, respectively.     

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.     

Synthesis of Imidazo[4,5-b]quinoxaline Ribonucleosides as Linear Dimensional Analogs of Antiviral Polyhalogenated Benzimidazole Ribonucleosides

We have recently found that 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB) and the corresponding 2-bromo analog have better in vitro activities against HCMV than the clinically used agents ganciclovir and foscarnet. These benzimidazole nucleosides act by a unique mechanism, however, their biological target has not been completely identified. As an approach to probing the target, we have designed imidazo[4,5-b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole nucleosides to study the spatial limitation of the binding site in the target enzyme. A convenient route was developed for the synthesis of 2-substituted 6,7-dichloroimidazo[4,5-b]quinoxalines involving a reaction of 2,3,6,7-tetrachloroquinoxaline with ammonia followed by a ring annulation as the key step. This furnished the versatile heterocycle 6,7-dichloroimidazo[4,5-b]quinoxalin-2-one. Ribosylation of 2-substituted imidazo[4,5-b]quinoxalines was influenced by the functional group at the 2-position and the 2-one compound was found to smoothly undergo ribosylation. The 2-one group of the nucleoside was converted into specifically selected 2-substituted compounds. Evaluation of the compounds for activity against two herpesviruses and for cytotoxicity showed they were less active and/or more cytotoxic than TCRB. We conclude therefore, that the binding pocket on the protein target of TCRB will tolerate some electronic and size changes.     

New method for the synthesis of 4,5-dihydro-1,4-benzothiazepin-3(<Emphasis Type="Italic">2H</Emphasis>)-ones derivatives

A new method has been developed for the synthesis of 4,5-dihydro-1,4-benzothazepin-3(2H)ones derivatives by the acylation of N-substituted 2-chloro-5-nitrobenzylamines with acetylmercaptoacetyl chloride and α-acetylmercaptopropionyl chloride with subsequent removal of the S-acetyl protecting group and intramolecular nucleophilic substitution. The oxidation of 4,5-dihydro-1,4-benzothiazepin-3(2H)-ones to the corresponding 1,1-dioxides has been investigated.     

Synthesis of Some amino-4,5-dihydropyrazolo[3,4-a]acridines as potential cholinesterase inhibitors

A synthesis of the 4,5-dihydro derivatives of the previously known pyrazolo[3,4-a]acridine ring system is described. The reaction of a 3,4-dihydroacridin-1(2H)-one with N,N-dimethylformamide dimethyl acetal gave a reactive enamino ketone, which yielded the desired heterocycle upon reaction with hydrazine. Using this chemistry, 11-amino-4,5-dihydro-2H-pyrazolo[3,4-a)acridine ( 3 ) and a number of its 2-substituted derivatives 4a-k were synthesized and evaluated as acetylcholinesterase inhibitors, based on their relationship to 1,2,3,4-tetrahydro-9-acridinamine (THA). 1-Amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine ( 11a ) and 2-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine ( 11b ) were also synthesized and investigated as potential cholinesterase inhibitors.     

Pyrimidones. 2. Synthesis and reactions of 2-chloropyrimidines

The treatment of 1-alkyl-5-aryl and 1-alkyl-4,5-diaryl-2-(1H)pyrimidones with phosphorus oxychloride and phosphorus pentachloride resulted in chlorination and dealkylation to furnish 2-chloro-5-aryl (or 4,5-diaryl)-pyrimidines. These chlorpyrimidines were reacted with a variety of nitrogen, oxygen, sulfur, and carbon nucleophiles to produce the corresponding 2-substituted pyrimidines. In the case of phenyllithium, attack occurred at the 4-position of the pyrimidine ring yielding 11 . Triazolopyrimidine 9 was synthesized via the treatment of 2d with hydrazine followed by reaction with triethyl orthoformate.     

Synthesis of 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones

The reactions of 1-substituted 2-nitro-3-phenylaminoprop-2-en-1-ones with cyanothioacetamide afforded the corresponding 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones, which were used for the synthesis of 6-substituted 3-cyano-2-methylthio-5-nitropyridines and 7-substituted 4-hydroxy-8-nitropyrido[2",3":4,5]thieno[2,3-b]pyridin-2(1H)-ones.     

3-Alkylthio and 3-aminopyrazolo[3,4-D]pyridazines. Ring contraction of pyridazino[4,5-e][1,3,4]thiadiazines via extrusion of sulfur

Reaction of 4-chloro-2-methyl-5-(1-methylhydrazino)-3(2H)-pyridazinone ( 1 ) with carbon disulfide followed by alkylation yielded 2-alkylthio-4H-pyridazino[4,5-e][1,3,4]thiadiazine derivatives 2 . Oxidative cyclization of 5-(4-substituted 1-methylthiosemicarbazido)-3(2H)-pyridazinone derivatives 4 with N-bromosuccinimide also gave 2-substituted amino-4H-pyridazino[4,5-e][1,3,4]thiadiazine derivatives 5 . Heating of 2 and 5 resulted in ring contraction to afford the corresponding pyrazolo[3,4-d]pyridazine derivatives 6, 7 via sulfur extrusion. A possible mechanism for the desulfurization reaction is discussed, comparing with a structural difference between a type of pyridazino[4,5-e][1,3,4]thiadiazine ( 2,5 ) and another one ( 9,11,13,15 ).     

The synthesis of imidazo[4,5-c] - and v-triazolo[4,5-c] pyridazines

The parent imidazo[4,5-c]pyridazine (IV) has been prepared for the first time by three different routes. 1-Methylimidazo[4,5-c]pyridazine (XX) and 3-methylimidazo[4,5-c]pyridazine (XXVII) have been prepared by unequivocal syntheses. The constitution of the methylation product of imidazo[4,5-c]pyridazine-2-thiol (VIII) has been shown to be 2-methylthioimidazo[4,5-c]-pyridazine (IX) by the unequivocal syntheses of 1-methylimidazo[4,5-c]pyridazine-2-thiol (XXIII) and 3-methylimidazo[4,5-c]pyridazine-2-thiol (XXXIII). Likewise, the structure of the methylation product (XIII) was shown to be S-methylation by the unequivocal syntheses of 1-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXIV) and 3-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXXI), respectively. Several 7-substituted amino-v-triazolo-[4,5-c]pyridazines (XXXVIII) have been prepared from 7-chloro-v-triazolo[4,5-c]pyridazine (XXXVII).     

Reaction of carbonyl compounds with dimethyl 3-ketoglutarate. Synthesis of bicyclic furan derivatives

Acid catalyzed reaction of cyelododecane-1,2-dione VI with dimethyl,3-ketoglutarate II led to the formation of methyl (E)-6,7,8,9,10,11,12,13-octahydro-3-(methoxycarbonyl)cyclododeca-[b]furan-2-aeetate IX, presumably formed through the dihydrodihydroxy furan VIII. This dihydrofuran intermediate VIII was shown to be characteristic of the reaction of 2-substituted carbonyl-compounds with 11 for both α-chlorocyclohexanone and α-chlorocyclopentanone furnished furans XVIa and XX, respectively, when treated with 11. The effect of dihydrodihydroxy-furan intermediates on the course of such reactions is discussed.     

An application of the mannich reaction using hydroxylamine and some of its derivatives. 6-Substituted-2,4-diamino-5,6,7,8-tetrahydropyrimido[4,5-dpyrimidines

Hydroxylamine and some of its O -substituted derivatives ( 2 ) have been used as the amine component in Mannich reactions with 2,4,6-triaminopyrimidine ( 1 ). The resulting 6-substituted tetrahydropyrimido[4,5-d]-pyrimidines ( 3 ) contain an N-0 bond linking the substituent to the ring. These results extend the utility of this modified Mannich reaction to otherwise inaccessible substituents. Reaction conditions, spectral data and certain limitations of the reaction are discussed.     

4,5-Dihydroisoxazole and 4,5-dihydro-1,2,4-oxadiazole derivatives from cycloaddition reactions of nitrile oxides to alkyl N-(diphenylmethylene)-α,β-dehydroamino acids

The alkyl N-(diphenylmethylene)-α,β-dehydroamino acids 1 have been submitted to 1,3-dipolar cycloadditions with nitrile oxides. The reactivity of these compounds depends on the type and on the stereochemistry of the β-substituents. With the unsubstituted terms 1a,b the reaction occurs on the C,C double bond, providing a good method for the synthesis of the 4,5-dihydroisoxazole derivatives 3a,b,c and for the gem-functionalized 4,5-dihydroisoxazoles amino carboxylic ester 5. The β-substituted compounds 1c,d,e , inert to 1,1-dimethylethylnitrile oxide, undergo the reaction to the N,C double bond, thus giving with 2a,b the 4,5-dihydro-1,2,4-oxadiazole derivatives 4. All the reactions occur with high site- and regioselectivity.     

New process for the synthesis of imidazo[4,5-b]pyridine derivatives as potent orally active thromboxane a2 receptor antagonists

A new synthetic route to prepare the 4-[3-(4-chlorophenyl)methyl-6-chloroimidazo[4,5-b]pyridin-2-yl]-3,3-dimethylbutanoic acid (UP 116-77) is described. UP 116-77 is a potent orally active TXA₂/PGH₂ receptor antagonist currently under pharmacological investigation. Its development needed a suitable synthesis for industrial processing. The cyclization of 3-amino-5-chloro-2-(4-chlorophenyl)methylaminopyridine 4 with 3,3-dimethylglutaric anhydride in refluxing acetic acid affords a new efficient and simple way to UP 116-77 and subsequently to various 2-substituted imidazo[4,5-b]pyridine derivatives.     

Reactions of 2,2,4,4-tetramethyl-1,3-cyclobutanedione with amines and other nucleophiles. II

The reaction of 2,2,4,4-tetramethyl-1,3-cyclobutanedione with various nucleophiles has been demonstrated to be dependent on the reaction conditions, steric factors and the nucleophilicity of the attacking species. In the reaction with primary amines the intermediate has been established as the N-substituted imine which is hydrolyzed to the corresponding amide in the presence of water. The reaction of diamines with the dione has been shown to be a method of synthesizing 2-substituted imidazolines and 1 H-4,5-dihydropyrimidines.     

On the formation and reactivity of N(2),N(2′)-tetrasubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles

By the reaction of weak bases with N(2)-disubstituted 2-amino-4-thiazoliniminium chlorides 3, easily available by the reaction of thioureas 1 with α-chloroacetonitrile 2, N(2),N(2′)-persubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles 8 are formed. These new bis-thiazoles react, as exemplified with the dimorpholino derivative 8a, with different electrophilic reagent, such as phenyl isothiocyanate 9, 4-nitro-phenyldiazonium salt 11, or 4-dialkylaminobenzaldehydes 13 at their 5H-substituted thiazole moieties to give the corresponding thioanilides 10, azo compounds 12, and methine dyes 14, respectively. With sodium nitrite and the Vilsmeier reagent the thiazole 8a is transformed, via unstable intermediates, into the tricyclic 2,7-dimorpholinothiazolo[4,5-c]thiazolo[4,5-e]pyridazine 16 and 2,7-dimorpholinothiazolo[4,5-b]thiazolo[4,5-d]pyridine 19, respectively.