3-Oxo-1,2-benzoisothiazoline-2-acetic acid 1,1-dioxide derivatives. I. Reaction of esters with alkoxides

Reaction of 3-oxo-1,2-benzoisothiazoline-2-acetic acid alkyl esters 1,1-dioxide ( 1a-d ) with alkaline alkoxides was carried out under various conditions. Under mild conditions, o-(N-carboxymethylsulfamyl)benzoic acids dialkyl esters ( 2a-d ) were obtained with good yields. Reaction of 1a-d or 2a-d with sodium alkoxides under drastic conditions afforded 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid alkyl esters 1,1-dioxide ( 3a-d ). Transesterification was observed when esters 1b-d were treated with sodium methoxide in methanol. Esters 3a-d were hydrolyzed in concentrated aqueous sodium hydroxide affording the acid 6 . Attempts to recrystallize 6 from water resulted in its decarboxylation to give 2H-1,2-benzothiazine-4-(3H)one 1,1-dioxide (7). Compound 6 could not be obtained by acid hydrolysis of esters 3a-d or by rearrangement of 3-oxo-1,2-benzoisothiazoline-2-acetic acid 1,1-dioxide ( 8 ). Different experimental evidence supports the suggestion that rearrangement took place by ethanolysis of the carboxamide linkage affording the open sulfonamides (fast step) followed by a Dieckmann cyclization (slow step). It was demonstrated that transesterification took place in the open sulfonamides 2 .     

Synthesis and biological evaluation of novel (99m)Tc-labelled bisphosphonates as superior bone imaging agents

A series of novel zoledronic acid (ZL) derivatives 1-hydroxy-3-(2-methyl-1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid (MIPrDP), 1-hydroxy-4-(2-methyl-1H-imidazol-1-yl)butane-1,1-diyldiphosphonic acid (MIBDP), and 1-hydroxy-5-(2-methyl-1H-imidazol-1-yl)pentane-1,1-diyldiphosphonic acid (MIPeDP) were prepared and successfully labeled with (99m)Tc in high labeling yields. The in vitro stability and in vivo biodistribution of (99m)Tc-MIPrDP, (99m)Tc-MIBDP and (99m)Tc-MIPeDP were investigated and compared. The biodistribution studies indicate that the radiotracer (99m)Tc-MIPrDP has highly selective uptake in the skeletal system and rapid clearance from soft tissues. The present findings indicate that (99m)Tc-MIPrDP holds great potential for use in bone imaging.     

Lithiation of 1-chloromethylbenzotriazole: generation and elaboration of benzotriazolyloxiranes

1-Benzotriazolylchloromethyllithium generated from 1-chloromethylbenzotriazole (1) and LDA reacts with enolizable and nonenolizable ketones to give benzotriazolyloxiranes 2a-g in good yields. The oxiranyllithiums 4a-d generated from 2a-d and n-BuLi at -78 degrees C were trapped by a variety of electrophiles to give oxiranyl derivatives 5a-j in good to excellent yields. Lewis-acid-promoted nucleophilic ring opening of benzotriazolyloxiranes 2a,f,g with allyltrimethylsilane gave the corresponding 1,7-octadien-4-ols 6a-c in 68-75% yield. Hydrolysis of alpha-acylbenzotriazolyloxiranes 5g,h provided 3-hydroxy-1,2-diones 7a and 7b in 73 and 86% yield, respectively.     

The synthesis of 1-amino-2-hydroxy- and 2-amino-1-hydroxy-substituted ethylene-1,1-bisphosphonic acids and their N-methylated derivatives

A synthesis of 2-amino-1-hydroxyethylene-1,1-bisphosphonic acid 3 has been developed from N-phthaloylglycine via dimethyl 2-(N-phthaloylamino)acetylphosphonate 1. The preparation of the N-methylated and N,N-dimethylated derivatives 4 and 5 has been achieved by the reaction of 3 with formic acid and formaldehyde. The synthesis of 1-amino-2-hydroxyethylene-1,1-bisphosphonic acid 9 (R=R′=H) and its N-methylated and N,N-dimethylated analogues has been achieved by the reaction of phosphorus trichloride and phosphorous acid with the appropriate O-benzyl protected hydroxyacetamide, followed by catalytic hydrogenolysis of the protecting group.     

Synthesis of cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives by use of the [2 + 8] cycloaddition reaction of indolizines and dimethyl acetylenedicarboxylate

The reaction of 1-ethoxycarbonylmethylpyridinium bromides 5a-k with nitro ketene dithioacetal, 1,1-bis-(methylthio)-2-nitroethylene ( 2 ), in the presence of triethylamine in ethanol gave the desired ethyl 2-methyl-thioindolizine-3-carboxylates 3a-k in good yields, along with ethyl 2-methylthio-1-nitroindolizine-3-carboxyl-ates 4a-d . Deesterification of 3 using sodium hydroxide in methanol followed by treatment with polyphosphoric acid gave the corresponding 2-methylthioindolizines 5a-d in good yields. The desulfurization of 5 with Raney-nickel in ethanol occurs smoothly to give the 1,2,3-unsubstituted indolizines 6a-c (a , parent indolizine; b , 8-methylindolzine; c , 6,8-dimethylindolizine). Similarly, pyrrolo[2,1-a]isoquinoline ( 19 ) was also synthesized. These indolizine and pyrrolo[1,2-a]isoquinoline derivatives were allowed to react with dimethyl acetylene to give the corresponding cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives in good results.     

Asymmetric [2 + 1] Cycloaddition Reactions of 1-Seleno-2-silylethene

The reaction of (E)-1-(phenylseleno)-2-(trimethylsilyl)ethene (1) and vinyl ketones 2a-d in the presence of a chiral Lewis acid prepared from TiCl(4), Ti(O(i)Pr)(4), (R)- or (S)-1,1'-binaphthol (BINOL), and MS4A gave enantiomerically enriched cis cyclopropane products 3a-d. The enantiomeric excess and chemical yield varied depending on the ratio of TiCl(4) and Ti(O(i)Pr)(4) to 1. Reproducible results (43-47% ee/33-41% yields) for cis-1-acetyl-2-[(phenylseleno)(trimethylsilyl)methyl]cyclopropane (3a) were obtained using 1.1 equiv of TiCl(4), 0.54-0.65 equiv of Ti(O(i)Pr)(4), and 1.65 equiv of BINOL. The observed enantioselectivity was explained by consideration of the structure of the postulated intermediates, alkoxy titanium-carbonyl complexes, via ab initio MO calculations.     

Synthesis of 2-(3-tropolonyl)-1-benzopyrylium perchlorates and related compounds

3-Acetyltropolone ( 1 ) reacted with 2-hydroxybenzaldehyde ( 3a ) in the presence of perchloric acid in ethyl orthoformate to afford 2-(3-tropolonyl)-1-benzopyrylium perchlorate ( 4a ). The reactions with 2-hydroxy-5-methylbenzaldehyde ( 3b ), 5-chloro-2-hydroxybenzaldehyde ( 3c ), and 2-hydroxy-1-naphthalde-hyde ( 3d ) gave respectively the corresponding products 4b-d . The reactions of 2-acetyl-7-methylamino-tropone ( 2 ) with 3a-d also gave the corresponding products 5a-d , respectively.     

beta-acylvinyl anion and dianion equivalents: lithiation of 1-[(2EZ)-3-chloroprop-2-enyl]-1H-1,2,3-benzotriazole: preparation and elaboration of 1-(2-oxiranylvinyl)-1H-benzotriazoles

The allyllithium generated from 1-[(2EZ)-3-chloroprop-2-enyl]-1H-1,2,3-benzotriazole (5) and LDA, in the presence of HMPA, reacts with enolizable and nonenolizable carbonyls solely at the CCl terminus to give 1-(2-oxiranylvinyl)benzotriazoles 6a-g in 61-82% yields. Allyllithiums generated from 6a,c reacted exclusively at the CBt terminus to give 10a-d in 68-88% yields. Acidic hydrolysis of (oxiranylvinyl)benzotriazoles 6a-g and 10a-d provided 4-hydroxyalk-2-en-1-one derivatives 12a,b,c,e,g, 13a-d, and furan 14 in 54-86% yields.     

α-Pyrones. II . Synthesis of tetrahydroquinoline derivatives of 4-aminobutanoic and 2-amino-2-pentenedioic acids

Ethyl 3-benzoylamino-2-oxo-6-triphenylphosphoranylidenemethyl-2H-pyran-5-carboxylate ( 1 ) reacts with 2- nitrobenzaldehydes ( 2 ) to give 6-(2-nitrostyryl)-2H-pyran-2-ones ( 3 ), as the E stereoisomers, in good yields. The reduction of compounds 3 , performed with hydrogen over Pd/C at room temperature and 1 atmosphere, leads to a mixture of 2-amino-4-tetrahydroquinolinylidene-2-pentenedioic acid derivatives 5a-d as the main products, the corresponding 3-butenoic acid derivatives 6 and a minor amount of pyrano[2,3-c]benzazocines 9a-c. At 40 atmospheres and 90°, the reduction gives 4-amino-2-tetrahydroquinolinylbutanoic acid derivatives 8a-d as the main products and their precursors 7a,b,d as the minor ones. Amines 4c,d are isolated by stopping the reduction after the uptake of 3 equivalents of hydrogen.     

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.     

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.     

Transformed steroids. 141. Iodosobenzene diacetate for theα-hydroxylation of [17,16a]-2′-methyloxazoline derivatives of 20-ketosteroids

Using the [17,16a-d]-2′-methyloxazoline derivatives of 3β-hydroxypregn-5-en-20-one (I) as an example, the α-hydroxylation reaction has been studied with the use of rodosobenzene diacetate in a methanolic solution of NaOH as the α-hydroxylating reagent. The reaction took place successfully through the stage of the formation and isolation of the corresponding [17,16a-d]-2′-methyloxazoline derivative of 20, 20-dimethylpregn-15-ene-3β,21-diol (II), the dimethyl acetal protection of which was eliminated by acid hydrolysis in methanol. The results of physicochemical investigations and biological trials of the [17,16a-d]-2′-methyloxazoline derivatives of 21-hydroxy-21-acetoxy-20-ketosteroids obtained are given.     

Synthesis and antiviral activities of some 4,4'-dihydroxytriphenylmethanes

4,4'-Dihydroxytriphenylmethanes were synthesized using Br?nsted acid or Lewis acid in yields of 24-86% as target compounds for developing antiviral agents. Most of the 4,4'-dihydroxytriphenylmethanes showed significant activity against herpes simplex virus type 1 (anti-HSV-1 activity) in a plaque reduction assay. Higher cytotoxicity was observed generally in halogenated 4,4'-dihydroxytriphenylmethanes (2a-d) than in non-halogenated derivatives. The non-halogenated derivative, 4,4',4"-trihydroxy-3"-methoxytriphenylmethane (3), showed remarkable antiviral activity with an EC(50) value of 1.8 microg/ml.     

Synthesis of alpha-amino acids via asymmetric phase transfer-catalyzed alkylation of achiral nickel(II) complexes of glycine-derived Schiff bases

Achiral, diamagnetic Ni(II) complexes 1 and 3 have been synthesized from Ni(II) salts and the Schiff bases, generated from glycine and PBP (7) and PBA (11), respectively, in MeONa/MeOH solutions. The requisite carbonyl-derivatizing agents pyridine-2-carboxylic acid(2-benzoyl-phenyl)-amide 7 (PBP) and pyridine-2-carboxylic acid(2-formyl-phenyl)-amide 11 (PBA) were readily prepared from picolinic acid and o-aminobenzophenone or picolinic acid and methyl o-anthranilate, respectively. The structure of 1 was established by X-ray crystallography. Complexes 1 and 3 were found to undergo C-alkylation with alkyl halides under PTC conditions in the presence of beta-naphthol or benzyltriethylammonium bromide as catalysts to give mono- and bis-alkylated products, respectively. Decomposition of the complexes with aqueous HCl under mild conditions gave the required amino acids, and PBP and PBA were recovered. Alkylation of 1 with highly reactive alkyl halides, carried out under the PTC conditions in the presence of 10% mol of (S)- or (R)-2-hydroxy-2'-amino-1,1'-binaphthyl 31a (NOBIN) and/or its N-acyl derivatives and by (S)- or (R)-2-hydroxy-8'-amino-1,1'-binaphthyl 32a (iso-NOBIN) and its N-acyl derivatives, respectively, gave rise to alpha-amino acids with high enantioselectivities (90-98.5% ee) in good-to-excellent chemical yields at room temperature within several minutes. An unusually large positive nonlinear effect was observed in these reactions. The Michael addition of acrylic derivatives 37 to 1 was conducted under similar conditions with up to 96% ee. The (1)H NMR and IR spectra of a mixture of the sodium salt of NOBIN and 1 indicated formation of a complex between the two components. Implications of the association and self-association of NOBIN for the observed sense of asymmetric induction and nonlinear effects are discussed.     

Anion-exchange separation and determination of bisphosphonates and related analytes by post-column indirect fluorescence detection

Bisphosphonic acids and their salts can be detected after their liquid chromatographic separation by post-column indirect fluorescence detection (IFD). After separation the analyte is combined with the highly fluorescent Al³⁺–morin (2′,3,4′,5,7-pentahydroxyflavone) solution and fluorescence decreases because of the formation of the nonfluorescent Al³⁺–bisphosphonate complex. The decrease in fluorescence is proportional to the amount of bisphosphonate present. Separation of the multivalent anionic bisphosphonate analytes from other anions and sample matrix is achieved on a strong base anion-exchange column with a strong, basic eluent. The post-column reaction variables, which influence IFD, are identified and optimized for the detection of the bisphosphonates after separation on the anion exchanger. The method is selective, since only a few anions will undergo a reaction with the Al³⁺–morin solution, and sensitive, detection limit for difluoromethylene bisphosphonate, F₂MDP, is 4 ng for S/N=3. The separation–IFD method can be applied to the determination of bisphosphonates, such as F₂MDP, ethane-1-hydroxy-1,1-bisphosphonic acid, dichloromethylene bisphosphonic acid, 4-amino-1-hydroxybutane-1,1-bisphosphonic acid, in biological samples. The separation–IFD method is also applicable to the detection of inositol phosphate anions.     

Syntheses of 4-(2-hydroperoxy-2,2-diarylethyl)-3,5-dimethylpyrazoles, 4-(2-hydroxy-2,2-diarylethyl)-3,5-dimethylpyrazoles and the related compounds

The reactions of 1,1-disubstituted ethenes with 2,4-pentanedione in the presence of manganese(III) acetate and atmospheric oxygen yielded 4-acetyl-6,6-diaryl-3-methyl-1,2-dioxan-3-ols. The latter gave 4-(2-hydroperoxy-2,2-diarylemyl)-3,5-dimethylpyrazoles by the reaction with hydrazines in methanol-acetic acid (1:1 v/v) at 50° in 15-77% yields, or 4-(2-hydroxy-2,2-diarylethyl)-3,5-dimethylpyrazoles by the reaction with hydrazines in methanol in 2-78% yields. The acid-catalyzed reaction of 4-(2-hydroperoxy-2,2-diarylethyl)-3,5-dimethylpyrazoles yielded 4-(aroylmethyl)-3,5-dimethylpyrazoles (15-55%) and 4-(2,2-diarylethenyl)-3,5-dimethylpyrazoles (9-29%).     

Head-to-tail regioregular oligothiophene-functionalized 9,9'-spirobifluorene derivatives. 1. Synthesis

Two series of novel fully conjugated oligomers, oligothiophene-functionalized 9,9'-spirobifluorene derivatives, have been developed in this contribution. First, four 9,9'-spirobifluorene bromide derivatives (compounds 1a-d) are prepared through various synthetic routes. Oligothiophene derivatives with or without substituents are synthesized through the Grignard and Suzuki coupling reactions. The Negishi coupling reactions between oligothienylzinc chloride and various 9,9'-spirobifluorene bromides with Pd(PPh(3))(4) as catalyst successfully produce the desired compounds, unsubstituted oligothiophene-functionalized 9,9'-spirobifluorene derivatives, compounds 2 to 4a-d. Since the Negishi coupling reactions afford regioregularly head-to-tail (H-T) oligo(4-n-hexylthiophene)-functionalized 9,9'-spirobifluorene derivatives in poor yields, the Suzuki coupling reactions between sodium 4-n-hexylthienyl-2-boronate 8, and various 9,9'-spirobifluorene-based bromides 1a-d and 9-16 are employed to produce highly regioregular head-to-tail oligothiophene-functionalized 9,9'-spirobifluorene derivatives (compounds 5 to 7a-d) in very high yields. We also investigate the effect of solvents on the Suzuki coupling reactions. The structure and purity of all compounds are verified by FT-IR, (1)H and (13)C NMR, MS, and elemental analysis.     

Alkoxide-induced reactions of N-substituted saccharins. Synthesis of 1,2-benzothiazocine 1,1-dioxide and 2,3-dihydropyrrolo[1,2-b]-[1,2]benzisothiazole 5,5-dioxide derivatives

The reactions of saccharin derivatives 1 with sodium alkoxides were studied. Under mild conditions, compounds 1a-f gave the corresponding open sulfonamides 5a-f . Under drastic conditions, β-(saccharin-2)propionic acid derivatives 1a,b reacted with sodium ethoxide affording saccharin and β-ethoxypropionic acid derivatives 4a,b . γ-(Saccharin-2)butyric acid derivatives 1c,d and γ-(saccharin-2)-butyrophenone 1f reacted with sodium t-butoxide in dimethyl sulfoxide affording 5-substituted 6-hydroxy-3,4-dihydro-2H-1,2-benzothiazocine 1,1-dioxides 9 . From mother liquors, 1-substituted 2,3-dihydro-pyrrolo[1,2-b][1,2]benzisothiazole 5,5-dioxides 10 were isolated several hours later, though not detected immediately after completing the reaction. When the reactions were carried out in t-butyl alcohol, the yields of 9 diminished and those of 10 increased with product ratio inversion. Different experimental observations on the possible pathway generating 9 and 10 are discussed.     

New multi-1,2,3-selenadiazole aromatic derivatives

The aromatic polyketones 3a-d are versatile compounds for the synthesis of the multi-1,2,3-selenadiazole aromatic derivatives 1a-d. The preparation starts with the reaction between the multi-bromomethylene benzene derivatives 2a-d and 4-hydroxy- acetophenone to give compounds 3a-d which are transformed through the reaction with semicarbazide hydrochloride or ethyl hydrazine carboxylate into the corresponding semicarbazones derivatives 4a-d or hydrazones 5a-d. The reaction with selenium dioxide leads to regiospecific ring closure of semicarbazones or hydrazones to give the multi- 1,2,3-selenadiazole aromatic derivatives in high yield.     

Synthetic antibacterials. VIII. 7-(1′-alkylhydrazino)-1,8-naphthyridines and related compounds

Synthesis and in vitro antibacterial activity of 7-(1′-alkylhydrazino)-1,8-naphthyridines related to nalidixic acid were investigated. Namely, treatment of 7-alkylamino-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids 1a-d with sodium nitrite in the presence of hydrochloric acid gave the 1-ethyl-1,4-dihydro-7-(N-nitrosoalkylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acids 2a-d , which upon reacting with zinc dust in acetic acid gave the 7-(1′-alkylhydrazino)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacids 3a-d. The compound 3a was alternately obtained by the reaction of 7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphth-yridine-3-carboxylic acid ( 4 ) with methylhydrazine. The reaction of 7-chloro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid ( 5 ) with methylhydrazine gave the 4-hydroxy-7-(1′-methylhydrazino)-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 6 ), which upon treatment with alkyl halides afforded the 1-alkyl-1,4-dihydro-7-(1′-methyl-hydrazino)-4-oxo-1,8-naphthyridines 3a and 3e-g. The reaction of the appropriate 3 with ketones gave the corresponding 7-(1′-methylalkylidenehydrazino)-1,8-naphthyridines 7a-c and 8a-b. Among the compounds prepared, certain 3 and 7 exhibited good activity against Gram-negative bacteria.