Furopyridines. XII . Reaction of 3-bromo, 2-phenylthio and 2-phenylthio-3-bromo derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine with several alkyllithiums

This paper describes reactions of 3-bromo- 1a-d , 2-phenylthio- 5a-d and 2-phenylthio-3-bromofuropyridines 6a-d with n-butyl-, t-butyl- and methyllithium and lithioacetonitrile. Lithiation of compounds 1a-d with n-butyl- or methyllithium gave the parent furopyridines 2a-d and o-ethynylpyridinols 3a-d. Reaction of compounds 5a-d with methyllithium afforded o-(phenylthioethynyl)pyridinols 7a-d , which were also yielded by reaction of compounds 6a-d with t-butyl- or methyllithium. The phenylthio group in compounds 7a-d were substituted with t-butyl group by the reaction with excess t-butyllithium. In contrast, 2-phenylthio group in compounds 5a-d and 6a-d was substituted with cyanomethyl group by reaction with lithioacetonitrile to give compounds 11a-d and 10b, c respectively.     

Synthesis of 5H-Tetrazolo[1,5-d] [1,4]benzodiazepin-6(7H)ones

Syntheses of 5H-tetrazolo [1,5-d] [1,4 ]benzodiazepin-6(7H)ones 2a-d from 5-(o-aminophenyl)-tetrazoles 1a-d and bromoacetyl bromide are described. Compounds 2a-d are representatives of a novel tricyclic ring system. Several alternate methods for the synthesis of 2a-d were attempted without success. Spectral evidence for structural assignments 2a-d is presented. Chemical evidence for these assignments includes the transformation of 2a to 6-(2,2-dimethylhydrazino)-5H-tetrazolo[1,5-d] [1,4]benzodiazepine ( 19 ) via the thione analog of 2a ( 18 ).     

Substituted γ-lactones: On the structural elucidation of the reaction products from 4-aroyl-3-hydroxy-2(5H)-furanones and 1,2-diamines

The reaction pathway of 4-aroyl-3-hydroxy-2(5H)-furanones 1 with diamines depends on the nature of the amine as well as on the applied reaction conditions. Thus, the reaction of 1a-d with 5,6-diamino-1,3-dimethyluracil 5 led to the formation of two isomeric Schiff bases 7a-d and 8a-d . Conversely type 1 compounds reacted with 4,5-diaminopyrimidine 9 or 2,3-diaminopyridine 10 to form the mono acid-base adducts 11a and 11b respectively. When type 1 compounds were reacted with aliphatic diamines 13a-d or p-phenylenediamine and p-xylenediamine, respectively also an immediate formation of acid-base adducts 15a-f was observed. The reaction of a number of O-methylated type 1 compounds with 1,2-ethylenediamine afforded the novel seven-membered ring compounds 18a-d in good yields. The analogous reaction of O-alkylated 1a with o-phenylenediamine 2 or 2,3-diaminonaphthalene gave the expected tricyclic ring systems 19 or 20 .     

Pyrimidine derivatives. VI. Synthesis of mono-, di-, tri-, and tetrabromo-substituted pyrimidine derivatives

The following bromo-2,4(1H,3H)-pyrimidinediones possessing a bromo substituent at the 5-position and side chains at the 1- and 6-positions were prepared. The three types of mono-bromo derivatives are: 1-(bromoalkyl)-3,6-dimethyl- 3a-d , 5-bromo-3,6-dimethyl-1-(hydroxyalkyl)- 4a-d , and 1-(acetoxyalkyl)-5-bromo-3,6-dimethyl-2,4(1H,3H)-pyrimidinediones 11a-d . The three types of dibromo derivatives are: 5-bromo-1-(bromoalkyl)-3,6-dimethyl- Sa-d , 1-(acetoxyalkyl)-5-bromo-6-bromomethyl- 8a, 8c , and 8d , and 5-bromo-6-bromomethyl 1-(hydroxyalkyl)-2,4(1H,3H)-pyrimidinediones 9a, 9c , and 9d . Likewise one group of tribromo and one group of tetrabromo derivatives are: 5-bromo-1-(bromoalkyl)-6-bromomethyl -7a-d and 5-bromo-1-(bromoalkyl)-6-dibromomethyl-2,4(1H,3H)-pyrimidinediones 6a-d .     

Reaction of lumichrome or 2-thiolumichrome with alkylamines

The reaction of lumichrome ( 2 ) with alkyl (or allyl)amines such as n-butylamine, n-hexylamine and allylamine gave 2,3-disubstituted 6,7-dimethylquinoxalines 4a-d, 5a-d, 6a-d, 7a-d and 8a-d . Similar reaction of 2-thiolumichrome ( 3 ) with alkyl (or allyl)amines gave 2,3-disubstituted 6,7-dimethylquinoxalines 6a-c, 9a-c and 10a-c , 2-alkyl (or allyl)amino-6,7-dimethyl-3,4-dihydrobenzo[g]pteridine-4-ones 11a-c and 2,4-dialkyl (or allyl)amino-6,7-dimethylbenzo[g]pteridines 12a-c .     

Furopyridines. XXII. Elaboration of the C-substituents alpha to the heteronitrogen atom of furo[2,3-b] -, -[3,2-b] -, -[2,3-c]- and -[3,2-c]pyridine

The Grignard reaction of fused ring cyanopyridine derivatives 1a-d with methyl- and phenylmagnesium bromide yielded the corresponding acylpyridine compounds 2a-d and 3a-d . Furopyridine N-oxides 4a-d were converted into the compounds having a phenyl group at the α-position to the ring nitrogen 5a-d . Reduction of 1a-d and the carboxylic esters 6a-d with diisobutylaluminium hydride yielded the corresponding amines 7a-d and aldehydes 9a-d . The aldehydes were converted to nitroethanol derivatives 10a-d by condensation with nitromethane and acrylic ester compounds 11a-d by the Wittig-Horner reaction with methyl diethyl phosphonoacetate.     

Synthesis and anti-HIV-1 activity of 1,5-dialkyl-6-(arylselenenyl)uracils and -2-thiouracils

The 1,5-dialkyl-6-(arylselenenyl)uracils 10a-h and -2-thiouracils 10i-p have been synthesized as potential anti-HIV-1 agents. Cyclization of N-alkyl-N'-[3,3-di(methylthio)-2-alkylacryloyl]ureas 6a-d and -thioureas 6e-h in acetic acid either containing a catalytic amount of methanesulfonic acid at 80°or containing 1 equivalent of methanesulfonic acid at room temperature afforded 1,5-dialkyl-6-(methylthio)uracils 7a-d in 84–96% yields and 1,5-dialkyl-5,6-dihydro-6,6-di(methylthio)-2-thiouracils 11a-d in 88–99% yields, respectively. Oxidation of 7a-d and 11a-d with either 3-chloroperoxybenzoic acid in benzene or aqueous sodium periodate solution in methanol gave 1,5-dialkyl-6-(methylsulfonyl)uracils 8a-d in 88–98% yields and 1,5-dialkyl-6-(methylsulfinyl)-2-thiouracils 12a-d in 57–73% yields, respectively, which were subsequently treated with arylselenol 9a-b in ethanolic sodium hydroxide solution to afford 10a-p in 6099% yields. Of these compounds, 6-[(3,5-dimethylphenyl)selenenyl]-5-isopropyl-1-(3-phenylpropyl)uracil ( 10h ) inhibited HIV-1 replication in MT-4 cells at a 50% effective concentration (EC₅₀) of 0.0006 μM with a selective index of 44833, which is 7.7-fold more potent than AZT.     

Saturated heterocycles, 248. Synthesis of 2,4-dioxo and 4-oxo-2-thioxo derivatives of octahydrocyclopenta[d]pyrimidines

Unsubstituted and 1-benzyl-substituted cis-cyclopenta[d]pyrirnidine-2,4-diones and cis-2-thioxo-cyclopenta[d]pyrimidin-4-ones 9a,b and 10a,b were prepared from the corresponding cis-2-amino-1-cyclopentanecarboxylates 3 and 5 with potassium cyanate and thiocyanate. It was found that the cis derivatives 7a-h readily underwent ring closure, resulting in 3-substituted cis-2,4-cyclopenta[d]pyrimidinediones and cis-2-thioxocyclopenta[d]pyrimidin-4-ones 11a-d and 12a-d , whereas the trans counterparts 8a-d failed to cyclize, but gave hydrolysed amino acid derivatives 13a,b and 14 . This difference in the reactivities of the cis and trans isomers is a further example of the difficulty of preparing cyclopentane trans-fused six-membered 1,3-heterocycles by ring closure.     

Furopyridines. XIV. Synthesis of 2-aminoalkyl derivatives of furo[2,3-b]-, furo[3,2-b], furo[2,3-c]- and furo[3,2-c]pyridine

The preparation of 2-aminomethyl- 3a-d , 2-acetamidomethyl- 4a-d , 2-N,N-dimethylaminomethyl- 5a-d , 2-(1-hydroxy-2-nitroethyl)- 6a-d , 2-(1-hydroxyl-2-aminoethyl)- 7a-d and 2-(1-hydroxy-2-N,N-dimethylaminoethyl)- 8b-d derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine is described.     

Ylides of heterocycles. VII.. I-, N-, P- and S-ylides of pyrimidones

The reaction of pyrimidone derivatives 1a-d with iodosobenzene prepared in situ from diacetoxyiodobenzene or dichloroiodobenzene afforded the iodonium-ylides 2a-d in good yields. Their thermal rearrangement produced 5-iodo-4-phenoxy-pyrimidin-6(1H)-ones 3a-c . Reductive deiodination of 3 gave the corresponding 4-phenoxypyrimidin-6(1H)-ones 4a-c . Acid catalized treatment of the iodonium-ylides 2a-d with nucleophiles such as pyridine, nicotinamide, isoquinoline, or triphenylphosphine produced the corresponding N- or P-ylides 7, 8, 9 , and 10 , respectively. The thiophanium-ylides 11a,c were obtained from the iodonium-ylides 2 without the use of a catalyst. The pyridinium-ylides 7 have been also prepared from the 5-halopyrimidones 5 or 6 which in turn could be obtained from the reactive iodonium-ylides 2 with hydrochloric or hydrobromic acid, respectively.     

Synthese von 4-halogensubstituierten Analogen von Trimethoprim

The Synthesis of 4-Halogen-substituted Analogs of Trimethoprim The four 2,4-diamino-5-(4-halo-3,5-dimethoxybenzyl)pyrimidines 20a-d have been synthesized along known routes, i.e. form the corresponding aldehydes 17a-d via the aminomethylidene-derivatives 18a-d and 19a-d , respectively (Scheme 4). All four aldehydes were prepared from a common intermediate, methyl 4-amino-3,5-dimethoxybenzoate ( 3 ), which was obtained from dimethyl 2,6-dimethoxyterephthalate ( 2 ) and hydroxylamine in a regioselective Lossen-type rearrangement mediated by polyphosphoric acid (Scheme 1). Under identical rearrangement conditions 2,6-diethoxyterephthalate ( 12 ) led, in addition to the amine 14 , to the benzoxazolone 15 (Scheme 2). Scope and mechanism of this reaction are discussed. - The antimicrobial activity of the diamino-pyrimidines 20a-d , expressed as the inhibition of E. coli-dihydrofolate reductase, has been measured and compared with that of trimethoprim ( 1 ), an established antimicrobial agent.     

Furopyridines. XXIX. Reactions of furo[2,3-b:4,5-c‘]-, -[3,2-b:-4,5-c’]-, -[2,3-c:4,5-c‘]- and -[3,2-c:3,2-c’]dipyridine

Furo[2,3-b:4,5-c‘]- 1a , -[3,2-b:4,5-c’]- 1b , -[2,3-c:4,5-c‘]- 1c and -[3,2-c:4,5-c’]dipyridine 1d were derived to the N-oxides 2a-d , N‘-oxides 2′b , 2′c or N,N’-dioxide 3b-d by N-oxidation with m-chloroperbenzoic acid. Chlorination of these N-oxides, N′-oxide and N,N′-dioxides with phosphorus oxychloride afforded compounds chlorinated at the α-position(s) to the ring nitrogen 4a-d , 4′c , 14b-d and 14′b . Acetoxylation of N-oxides 2a-d and 2′c with acetic anhydride gave the corresponding pyridone compounds 6a-d and 6′c in good yields, while the acetoxylation of N,N′-dioxides gave a complex mixture from which no compound could be isolated. Cyanation of 2a-d, 2′c and 3b-d with trimethylsilyl cyanide yielded the cyano compounds 7a-d , 7′c , cyano-N-oxides 15b-d and dicyano compounds 15′c and 15′d . Monocyano compounds 7a-d and 7′c were converted to the imino esters 8a-d and 8′c by treatment with sodium ethoxide. Imino esters were derived to the carboxylic esters 9a-d and 9′c , from which the corresponding alde hydes 10a-d and 10′c were obtained by reduction with diisobutylaluminum hydride. Dicyanide 15′c was converted to dialdehyde 19 by the treatment with sodium ethoxide, and the subsequent hydrolysis of the imino ester and reduction of the carboxylic ester with diisobutylaluminum hydride.     

Synthesis and biological activity of (3,5-disubstituted-1H-1,2,4-triazol-1-yl)benzophenone derivatives

The synthesis of (5-acylaminomethyl-3-carbamoyl-1H-1,2,4-triazol-1-yl)benzophenone derivatives 4a-i, 14a-d, 15a-d, 16a-c , is described. Acylation of the key intermediate, 1-benzoylphenylazo-1-aminoacetamide 7, followed by cyclization in the presence of acid afforded 1H-1,2,4-triazole derivatives. These compounds were evaluated for their central nervous system (CNS) activity. Some of these compounds exhibited high activities in anti-pentylene tetrazole and rotarod test in mice when orally administered.     

Synthesis and reactivity of 1,2,4-triazolo[1,5-c]quinazolines

The preparation of 1,2,4-triazolo[1,5-c]quinazolines 4a-d , 5 , 8a-d by cyclocondensation of 1a-c with carboxylic acids and carboxylic anhydrides, respectively, is described. By different pathways, the 5-thioxo-5,6-dihydro-1,2,4-triazolo[1,5-c]quinazolines 4a-d react with hydrazine hydrate or amines with the formation of 5-substituted 1,2,4-triazolo[1,5-c]quinazolines 9 and 10a-d . Cyclocondensation of 9 with carboxylic acids, carboxylic anhydrides, and nitrous acid, respectively, leads to the new anellated heterocycles bis-1,2,4-triazolo[4,3-a:1,5-c]quinazoline 13 and tetrazolo [1,5-a]-1,2,4-triazolo[1,5-c]quinazoline ( 14 ).     

Synthesis of some triazole,tetrazole, and tetrazine derivatives from N-β-naphthalenesulfonylbenzohydrazidoyl chlorides

A series of N-β-naphthalenesulfonylbenzohydrazidoyl chlorides 8a-d has been prepared by the action of thionyl chloride on the corresponding hydrazides 7a-d . Treatment of 8 with triethylamine and morpholine afforded the tetrazines 10 and the amidrazones 11 respectively. Acid hydrolysis of 11 yielded the hydrazides 7 . Reaction of 8 with phenylhydrazine gave 3,5-diaryltetrazoles 14 . However, reaction of 8 with aroylhyrazines yielded 3,5-diaryl-4-β-naphthalenesulfonylamino-4H-1,2,4-triazoles 15 . The structures of the products were assigned upon the basis of their spectra, elemental analyses and alternate synthesis whereever possible.     

Mechanistic aspects of the bromination of 10-substituted phenothiazines

The addition of 1 and 2 molar equivalents of bromine to a series of 10-alkylphenothiazines, 1a-d (methyl, ethyl, n-propyl, and isopropyl, respectively), yields the corresponding 3-bromo- and 3,7-dibromo-10-alkylphenothiazines ( 11a-d and 12a-d , respectively). Evidence which supports the typical clectrophilic aromatic substitution mechanism is presented. Radical cations ( 12a-d^.+ ) arc produced when 12a-d are treated with 1 or 2 molar equivalents of bromine. Upon boiling in acetic acid these radical cations are converted predominantly to 1,3,7,9-lelrabromophenothiazine ( 5 ) and the parent 3,7-dibromo-10-alkylphenothiazine ( 12a-d ) with the evolution of hydrogen bromide. The 10-methyl radical ( 12a ) gives, in addition, 1,3,7-tribromo-10-methylphenothiazine ( 15 ). A mechanism if proposed for these reactions in which initial dealkylution of 12b-d^.+ to 3.7-dibromophenothiazine radical cation ( 13 ) occurs followed by reduction of 13^.+ by bromide ion to parent 3,7-dibromophenothiazine ( 13 ). Subsequent bromination of 13 by molecular bromine produced in the previous redox reaction yields 1,3,7-tribromo-( 14 ) and 1,3,7,9-tetra-bromo-( 5 ) phenothiazines. The small size of the methyl group allows 12a to be brominated at the 1-position prior to dealkylation. In addition to undergoing bromination at the 3- and 7-position, 10-isopropylphenothiazine ( 1d ) is oxidized to the radical cation 12e^.+ when treated with bromine. 10-Benzylphenothiazine ( 1e ), however, undergoes oxidation to radical cation 1e^.+ exclusively. This radical cation debenzylates readily at room temperature and is converted finally into phenothiazine.     

A new tautomeric zwitterion form of 2-acylamino-4H-1,3,4-oxadiazino[5,6-b]quinoxalines in solution

The reaction of 2-acyiamino-8-chloro-4-methyl-4H-1,3,4-oxadiazino[5,6-b]quinoxalines 2a-d with methyl iodide/base gave the 8-chloro-4,10-dimethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxalin-10-ium-2-acylamidates 4a-d , respectively. Comparison of the nmr spectral data between compounds 2a-d and 4a-d in deuteriodimethyl sulfoxide or in deuteriotrifluoroacetic acid established that compounds 2a-d existed as the zwitterionic tautomers 2′a-d in solution.     

Synthesis of 3,3′-biisoxazoles from cyanogen N,N′-dioxide and trimethylsilyl enol ethers via the corresponding 5,5′-bis(trimethylsilyloxy)-3,3′-Δ2-biisoxazolines

Regioselective 1,3-dipolar cycloaddition of Cyanogen N,N′-dioxide ( 2 ) to trimethylsilyl enol ethers 3a-d, 6 and 7 gave the corresponding 5,5′-bis(trimethylsilyloxy)-3,3′-Δ²-biisoxazolines which upon short heating with 10% hydrochloric acid afforded 3,3′-biisoxazoles 5a-d , 8 and 9. Only the intermediate 5,5′-bis(trimethylsilyloxy)-derivative 4a was isolated and studied. Reaction of 2 with vinyl methyl ketone ( 10 ) gave biisoxazoline 11 which by oxidation with γ-manganese dioxide gave biisoxazole 12.     

Synthesis and reaction of 6-substituted 3-methoxycarbonyl-4-methylthio-2H-pyran-2-one derivatives

Reaction of aryl and styryl methyl ketones 1a-m with dimethyl bis(methylthio)methylenemalonate ( 2 ) in the presence of potassium hydroxide in dimethyl sulfoxide gave the corresponding methyl 6-aryl- and 6-styryl-4-methylthio-2-oxo-2H-pyran-3-carboxylates 3a-m . 6-Aryl derivatives 3a-d,g were treated with sodium methoxide in methanol to give the corresponding 6-aryl-4-methoxy-2H-pyran-2-ones 8a-d and 9. Phenylcoumalin ( 7a ) and paracotoin ( 7b ) were synthesized by the desulfurization of 6-aryl-4-methylthio-2H-pyran-2-ones 4a,b. Similarly, anibine ( 8e ) was also synthesized from 3g . Treatment of 3 with hydrogen peroxide or 3-chloroperoxybenzoic acid gave the corresponding 4-methylsulfiny-2H-pyran-2-ones 10a-f in good yields. Displacement reactions of 10a-f with nucleophilic reagents are also described.     

Thiophene systems. 7. Pyrido[3,2-b]thieno[3,4-e][1,4]diazepine derivatives with potential cns activity

Pyrido[3,2-b]thieno[3,4-e][1,4]diazepines ( 1a-d ) were synthesized to investigate their potential CNS activity. Synthesis of the desired ring system was effected by condensation of 2,3-diaminopyridine ( 3 ) with methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 4 ). Structural assignment of the major condensation product 5 was determined by comparison of ¹H nmr absorptions of 5 with those of related methyl lactam derivatives 11 and 14. A discussion of the possible mechanism leading to 5 in preference to isomeric lactam 6 is presented. Biological evaluation of 1a-d revealed no interesting properties.