Synthesis of 3-acylamino-2-oxazolidinone derivatives through cyclic transformations of 5-aryl (or benzyl)-1,3,4-oxadiazol-2(3H)-one derivatives

New 3-acylamino-2-oxazolidinone derivatives 3 were obtained in good yields by reaction of 5-aryl (or benzyl)3-(2-hydroxyethyl)1,3,4-oxadiazol-2(3H)ones 1 with sodium ethylate. Treatment of ethyl 5-aryl-2-oxo-1,3,4-oxadiazole-3(2H)-acetates 7 with aromatic aldehydes in the presence of sodium ethylate or sodium hydride afforded 3-acylamino-5-aryl-4-ethoxycarbonyl-2-oxazolidinone derivatives as two trans- 5 and cis- 6 racemics. Only RS,SR-racemates were obtained with acetophenone under the same conditions.     

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 .     

Degradative ring opening of pyrido and pyrazino 3-benzenesulfonyloxyuracils and their conversion to condensed pyrazolones and triazolones

Ring opening, followed by an immediate Lossen rearrangement, of 3-benzenesulfonyloxypyrido[3,2-d, 3,4-d and 4,3-d]pyrimidine-2,4(1H,3H)diones with sodium methoxide in methanol furnished good yields of the methyl esters of 3-[2-(methoxycarbonyl)hydrazino]-2-, 3-[2-(methoxycarbonylhydrazino]-4- and 4-[2-(methoxycarbonyl)hydrazino]-3-pyridinecarboxylic acids, respectively. These hydrazino esters were cyclized to the corresponding pyridopyrazolones. However, the reaction of 3-benzenesulfonyloxypyrido[2,3-d]pyrimidine-2,4(1H,3H)dione with sodium methoxide produced 8-methoxycarbonyl-s-triazolo[4,5-a]pyridin-3(2H)one. In similar fashion, sodium methoxide converted 3-benzenesulfonyloxylumazine to 8-methoxycarbonyl-s-triazolo[4,3-a]pyrazin-3(2H)one.     

Synthesis of 5-aryl-2-oxazolepropionic acids and analogs. Antiinflammatory agents

Condensation of 2-bromoacetophenones with sodium succinimide gave N-phenacylsuccinimides ( 1 ) which were opened with sodium hydroxide to N-phenacylsuccinamic acids ( 2 ). The latter were cyclized to 5-aryl-2-oxazolepropionic acids ( 3 ) in sulfuric acid. Similar cyclization of N-phenacylphthalamic acid ( 5 ) and succinic acid 2-benzoylhydrazide ( 7 ) gave o-(5-phenyl-2-oxazolyl)benzoic acid ( 6 ) and 5-phenyl-1,3,4-oxadiazole-2-propionic acid ( 8 ). The succinamic acids 2 and the phthalamic acid 5 were observed to recyclize to the corresponding imides ( 1 and 4 ) on heating, and the succinic acid hydrazide 7 was similarly cyclized to N-benzamidosuccinimide ( 9 ) with acetic anhydride. Antiinflammatory screening data are reported for 3 , 6 and 8 .     

p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> Determinations for Montelukast Sodium and Levodropropizine

The pK _a constants and relative abundances of unionized and ionized forms of Montelukast sodium {the sodium salt of 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl] phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetic acid} and Levodropropizine {(2S)-3-(4-phenylpiperazin-1-yl)propane-1,2-diol} were determined potentiometrically from measurements at various pHs. These determinations were in order to relate their pK _a values with their bioavailability and to provide chemical data to be used in their analysis.     

Reactions of α,β-unsaturated ketones with cyanoacetamide

3-Aryl-1-phenyl-2-propen-1-ones Ia-f and aroylphenylacetylenes Va-d reacted under reflux for 3 hours with cyanoacetamide in the presence of sodium ethoxide to give the corresponding 4-aryl-3-cyano-6-phenyl-2-(1H)pyridones VI. However, when ketones Ia-e were refluxed with cyanoacetamide for one hour in the presence of sodium ethoxide or piperidine, they gave the corresponding 4-aryl-3-cyano-3,4-dihydro-6-phenyl-2-(1H)pyridones IIIa-e, which upon heating with selenium gave the corresponding 2-pyridones VI. The structures of the products are based on chemical and spectroscopic evidence.     

Synthesis,phosphodiesterase inhibition and antiinflammatory activity of 2-aryl-3-hydroxythieno[2,3-b]quinoline 1,1-dioxides. Application of sodium chlorite as a novel reagent for the (Stepwise) oxidation of sulfides to sulfones

Synthesis of five 2-aryl-3-hydroxythieno[2,3-b]quinoline 1,1-dioxides (38-42) from 3-formylquinoline-2-thiol ( 3 ) via a facile oxidation-cyclization sequence is reported. Reaction of appropriate benzyl chlorides with the thiol ( 3 ) in the presence of sodium methoxide gave excellent yields of the corresponding benzyl 2-(3-formylquinolyl) sulfides (4-8) . Direct oxidation of these sulfides to the corresponding sulfones (23-27) was effected with excess sodium chlorite in aqueous pyridine. Esterification of these sulfone-acids followed by brief treatment of the resulting esters 28-32 with sodium methoxide gave the desired compounds 38-42 after acidification. The benzyl 2-(3-formylquinolyl) sulfides were also selectively oxidized to the corresponding sulfoxides (13-17) . Thus sodium chlorite has proved to be an effective reagent for the stepwise oxidation of sulfides to sulfones. The title compounds were potent inhibitors of cyclic AMP phosphodiesterase, but failed to display significant antiinflammatory effects in the carrageenan rat paw edema test or significant activity in the phenylquinone induced writhing test for analgesia.     

Synthetic approaches to 2-substituted 1-oxo- and 3-oxotetrahydroisoquinolines

2-Substituted homophthalimides 2a-c were reduced regioselectively with sodium borobydride to carbinol-lactam intermediates 3a-c , which were dehydrated, followed by hydrogenation, to give 1-oxo-tetrabydroisoquinolines or 3,4-dihydroisoquinolin-1(2H)ones 5a-c . The isomeric 3-oxo-tetrahydro-isoquinolines or 1,4-dihydroisoquinolin-3(2H)-ones 8a-i were obtained in satisfactory yields via heating 3-isochromanone ( 6 ) with the corresponding amines 7a-i in the presence of aluminum chloride.     

Reactions of 1,2,3-Triazoles with Trifluoromethanesulfonyl Chloride and Trifluoromethanesulfonic Anhydride

Reactions of 4,5-dibromo-1,2,3-triazole, 1H-1,2,3-benzotriazole, and 2-phenyl-2H-1,2,3-triazole-4-carbonyl chloride with trifluoromethanesulfonyl chloride and trifluoromethanesulfonic anhydride were studied. 4,5-Dibromo-1,2,3-triazole sodium salt reacted with CF₃SO₂Cl in tetrahydrofuran to give 4,5-dibromo-2-(2-tetrahydrofuryl)-2H-1,2,3-triazole rather than expected 4,5-dibromo-2-trifluoromethylsulfonyl-2H-1,2,3-triazole. The latter was synthesized by treatment of 4,5-dibromo-1,2,3-triazole sodium salt with trifluoromethanesulfonic anhydride. The reaction of benzotriazole with (CF₃SO₂)₂O afforded 1-trifluoromethylsulfonyl-1H-1,2,3-benzotriazole and 1,2,3-benzotriazolium trifluoromethanesulfonate. 2-Phenyl-2H-1,2,3-triazole-4-carbonyl chloride reacted with trifluoromethanesulfonamide sodium salt in DMF, yielding N-(dimethylaminomethylene)trifluoromethanesulfonamide. Possible ways for formation of the unexpected products were proposed.     

Reactions of thioquinanthrene with sodium alkanethiolates. The smiles rearrangement of diquinolinyl sulfides

Reactions of thioquinanthrene 1 with sodium alkanethiolates or S-alkylisothiouronium salts (in the presence of sodium hydroxide) at 70° in DMSO or DMF yielded 4,4′-dialkylthio-3,3′-diquinolinyl sulfides 3 , which were results of the S-S type of the Smiles rearrangement of primary reaction products - sodium 3-quinoline-thiolates 6. When the reactions were carried out at 20° the products were 3′,4-dialkylthio-3,4′-diquinolinyl sulfides 2.     

Synthesis of 1‐acyl‐2‐oxo‐3‐pyrrolidinecarbonitriles by the reaction of 2‐acylamino‐4,5‐dihydro‐3‐furancarbonitriles with sodium iodide

The reaction of 2‐acylamino‐4,5‐dihydro‐3‐furancarbonitriles 1 with sodium iodide in N,N‐dimethyl‐formamide gave the corresponding 1‐acyl‐2‐oxo‐3‐pyrrolidinecarbonitriles 2 in good yields. Successive treatment of 1 with titanium(IV) chloride and potassium carbonate resulted in the formation of N‐acyl‐1‐cyanocyclopropanecarboxamides 4 . The same compounds 2 were also obtained by treatment of 4 with sodium iodide. The starting compounds 1 were synthesized by the reaction of 2‐amino‐4,5‐dihydro‐3‐furan‐carbonitrile with acyl chlorides in pyridine.     

STEREOCHEMISTRY OF SIX-COORDINATE OCTAHEDRAL SILICON(IV) COMPLEXES CONTAINING 2,2-BIPYRIDINE

Abstract

[Si(bpy)₃]⁴⁺ (bpy = 2,2′-bipyridine), synthesized from Sil₄ and 2′.-bipyndine. was optically resolved by a chromatographic method using an SP-Sephadex C-25 column as an adsorbent and a 0.16M aqueous solution of sodium (2R,3R)-(-)-O,O′-dibenzoyltartrate as an eluent. The optical isomers were characterized by measurement of their electronic absorption, circular dichroism, and ¹H NMR spectra. The chromatographic resolution of [SKbpyb]⁴⁺ was also attempted with an aqueous solution of potassium [(2R,3R)-(+)-tartrato]antimonate(III). sodium (2R,3R)-(+)-hydrogentartrate, and sodium (2R,3R)-(+)-tartrate as eluents. Force-field calculations were used to elucidate the chromatographic elution mechanism. [Si(OH)₂(bpy)₂]I₂was also synthesized from Sil₄ and 2′,-bipyridine. The optical resolution of this complex was achieved with sodium [(2R,3R)-(+)-tartrato]antimonate(III).     

3-Substituted 2-trifluoromethylimidazo [1,2-a] pyridines

3-Fluoro-2-trifluoromethylimidazo[1,2-a]pyridines were obtained by reactions of hexafluoroacetone 2-pyridylimines with trimethyl phosphite and studied in reactions with sodium methoxide. This gave the corresponding 3-methoxy-2-trifluoromethylimidazo[1,2-a]pyridines.     

Acetylinic ketones. Part II.. Reaction of acetylenic ketones with nucleophilic nitrogen compounds

Aroylphenylacetylenes (I) reacted with ethyl and phenyl hydrazinecarboxylates (II) to give ω-aroylacetophenone-N-ethoxycarbonyl-(Vla-f) and N-phenoxycarbonyl-(VIg-l) hydrazones, respectively. When these were healed with acetic anhydride they were converted to 5-aryl-1-ethoxycarbonyl-and 1-phenoxycarbonyl-3-phenylpyrazoles (VII), respectively, which on hydrolysis with rnethanolic potassium hydroxide gave the corresponding 5(3)aryl-3(5)phenylpyrazoles (VIII). Reaction of the above acetylenic ketones with guanidine hydrochloride in the presence of sodium carbonate gave the corresponding 2-amino-6-aryl-4-phenylpyrimidines (XII). Similarly, reaction of benzoylphenylacetylene with thiourea and with urea in the presence of sodium ethoxide gave rise to 2,4-diphenylpyrimidine-2-thione (XVIII) and 2,4-diphenyl-2(1H)pyrimidin-one (XV), respectively.     

Synthesis of monoalkenylated crown ethers and C-pivot cryptands

The synthesis of two N-(2-allyloxy)ethyl-substituted diaza-crowns and two C-pivot (allyloxy)methyl-substi-tuted cryptands is described. Controlled etherization of N,N-bis(2-hydroxyethyl)-4,13-diaza-18-crown-6 with allyl bromide and sodium hydride gave N-(2-allyloxy)ethyl-N-(2-hydroxyethyl)-4,13-diaza-18-crown-6 in a good yield. This macrocycle was reacted with sodium hydride and tetrahydrofurfuryl chloride or 3,3-dimeth-ylbutyl tosylate to give expected N-(2-allyloxy)ethyl-N'-tetrahydrofurfuryloxy)ethyl-[or (3,3-dimethylbutoxy)-ethyl]-substituted products 3 or 4 . 6,13-Dimethylenyl-14-crown-4 ( 9 ) and 9,19-dimethylenyl-20-crown-6 ( 10 ) were treated with mercuric acetate, followed by sodium borohydride in strong base to give macrocyclic diols 11 and 12 , respectively. These diols were reacted with sodium hydride and the ditosylate derivative of allyloxymethyl-substituted triethyleneglycol 13 to produce the C-pivot (allyloxy)methyl-substituted macrotri-cycles 6 and 7 .     

THE CRYSTAL STRUCTURES OF AMMONIUM AND SODIUM 2-AMINO-3,5-DICHLOROBENZOATES

Abstract

The crystal structures of ammonium and sodium 2-amino-3,5-dichlorobenzoates were determined by the X-ray diffraction method. The ammonium salt crystallizes in the monoclinic system (space group P2₁/c) with a = 13.941(3), b = 9.128(3), c = 7.349(2) Å, β = 90.80(3)° and Z = 4. The structure consists of an ammonium cation hydrogen bonded to a carboxylate oxygen of the 2-amino-3,5-dichlorobenzoate anion. The sodium salt of 2-amino-3,5-dichlorobenzoic acid crystallizes in the triclinic system (space group P 1) with a = 8.033(2), 6 = 8.944(2), c = 17.350(3) Å, α = 76.72(3)°, β = 79.69(3)°, γ = 72.54(3)° and Z = 4. The compound is a polymer in which the sodium ions are coordinated by carboxylate oxygen atoms of the organic ligand and water molecules in an octahedral arrangement. IR spectra of the salts are discussed.     

The chemistry of polycyclic arene imines. V. Reactions of phenanthrene 9,10-imine with nucleophiles under phase transfer conditions

Reactions of phenanthrene 9,10-imine (1) with alkyl halides, sodium azide and ammonium thiocyanate in two liquid phase systems were investigated. In the presence of aqueous sodium hydroxide and alkyl halides triethylbenzylammonium (TEBA) salts promote N-alkylation of 1 with preservation of the aziridine ring. Tetrabutylammonium (TBA) salts catalyze nucleophilic substitutions in which the three membered ring is cleaved. Aqueous sodium azide reacts with 1 to give trans-10-azido-9,10-dihydro-9-phenanthrenamine (2) . Ammonium and potassium thiocyanate cause expansion of the aziridine ring; while the unsubstituted imine 1 yields the 2-thiazolamine derivative 4 , N-butylphenanthrene 9,10-imine (8) froms trans-3a,11b-dihydro-3-butylphenanthro[9,10-d]thiazol-2-imine (9) with an exocyclic CN bond. The structure of 9 was established by X-ray crystal analysis.     

Synthesis of 4,6,8-Trisubstituted Methyl Azulene-2-carboxylates

It is shown that sodium (methoxycarbonyl)cyclopentadienide ( 1 ), which is easily accessible from sodium cyclopentadienide and dimethyl carbonate in THF, reacts with 2,4,6-trisubstituted pyrylium tetrafluoroborates 2a–d in boiling MeOH to afford the corresponding methyl azulene-2-carboxylates 4a–d in good yields. The corresponding 1-carboxylates 3 were not found (cf. Schemes 1 and 2).     

Studies on phenothiazines. Part 11. Synthesis and spectral studies of substituted 1-chloro/methyl/nitrophenothiazines

Synthesis of the title compounds by the Smiles rearrangement has been reported. 1-Nitrophenothiazines have been prepared by the reaction of 2-amino-3-chloro/methyl/methoxythiophenol with substituted o-halonitrobenzenes in ethanolic sodium hydroxide, in which Smiles rearrangement occurs in situ. 1-chloro/methyl-7-substituted phenothiazines have been prepared by Smiles rearrangement of 3-chloro/methyl-2-formamido-2′-nitro-4′-substituted diphenyl sulphides. The latter were prepared by the formylation of the diphenyl sulphides obtained by the condensation of 2-amino-3-chloro/methylthiophenols with substituted o-halogenonitrobenzenes in ethanolic sodium acetate. Spectral studies are also included.     

Kolbe-Schmitt reaction of sodium 2-naphthoxide

The mechanism of the Kolbe-Schmitt reaction of sodium 2-naphthoxide is examined by means of the B3LYP/LANL2DZ method. After the initial formation of sodium 2-naphthoxide-CO₂ complex, the carbon of the CO₂ moiety performs an electrophilic attack on the naphthalene ring. Further transformations lead to the formation of sodium 2-hydroxy-1-naphthoate. Sodium 3-hydroxy-2-naphthoate is formed by a 1,3-rearrangement of the CO₂Na group. Our findings are in good agreement with the experimental results on the carboxylation reaction of sodium 2-naphthoxide. Correspondence: Svetlana Marković, Faculty of Science, University of Kragujevac, 34000 Kragujevac, Serbia