Some reactions of fluorosulfonyldifluoroacetic acid with N-heterocyclic compounds

Difluorocarbene generated from the decomposition of fluorosulfonyldifluoroacetic acid (2)reacted with various sodium salts of N-heterocyclic compounds(1) giving the corresponding difluoro-methylated products in acetonitrile at 10—40℃.Benzotriazole(1a),benzimidazole(1b) and imidazole(1c) were converted into 1-(difluoromethyl)benzotriazole(3a),1-(difluoromethyl)benzimidazole(3b) and1-(difluoromethyl)imidazole(3c)respectively.Indole(1d)reacted with 2 to give -(fluorosulfonyldifluoro-acetate)indole(2d) rather than the expected difluoromethylated derivatives.     

The reactions of perfluoro- and α,α-dichloropolyfluoroalkanesulfinates

Sodium perfluoroalkanesulfinate, R_FSO₂Na [R_F?Cl(CF₂)₄, 1a; CF₃(CF₂)₅, 1b; Cl(CF₃)₆, 1c] reacted with bromine in aqueous solution to give the corresponding sulfonyl bromide R_FSO₂Br (2a-2c) and in acetonitrile or acetic acid, to form perfluoroalkyl bromide R_FBr (3a-3c). Heating in acetonitrile at 80°C, 2a-2c were converted smoothly into 3a-3c. However, reaction of sodium α,α-dichloropolyfluoroalkanesulfinate RCCl₂SO₂Na (R?CF₃, Cl(CF₂)n, n=2, 4, 6, 5a-5d) with bromine in aqueous solution gave directly the corresponding bromoalkanes 1-bromo-1,1-dichloropolyfluoroalkane RCCl₂Br (6a-6d). In aqueous potassium iodide solution, 1a-1c, 5a and 5b also reacted with iodine to form the corresponding iodo-polyfluoroalkane 4a-4c, 7a and 7b directly. 6a and 7a underwent free radical addition to alkene readily in the presence of free radical initiator and reacted with Na₂S₂O₄ in the usual way to form α,α-dichloropolyfluoroethane sulfinate (5a). 5a was stable in strong acid, but reacted with strong base to yield 10. 5a was oxidised by hydrogen peroxide to the sulfonate 11 and reduced by zinc in dilute acid to from the α-chloro sulfinate 12.     

Functionalization and cyclization reactions of 4-benzoyl-1,5-diphenyl- 1H-pyrazole-3-carboxylic acid

The 1H-pyrazole-3-carboxylic acid 2 or its remarkably stable acid chloride 3 can easily be converted into the corresponding ester or amide derivatives 4 or 5, respectively, from reaction with alcohols or N-nucleophiles. Pyrazolo[3,4-d]pyridazines 6a,b are obtained from cyclocondensation reactions of the pyrazoles 2 and 3, respectively, with phenylhydrazine or hydrazine hydrate, while 6c is formed in an one-pot procedure from the furan-2,3-dione 1 and hydrazine hydrate.     

Synthese von Trifluoromethyl-substituierten Schwefel-Heterocyclen unter Verwendung von 3,3,3-Trifluorobrenztraubensäure-Derivaten

Synthesis of Trifluoromethyl-Substituted Sulfur Heterocycles Using 3,3,3-Trifluoropyruvic-Acid Derivatives The reaction of methyl 3,3,3-trifluoropyruvate ( 1 ) with 2,5-dihydro-1,3,4-thiadiazoles 4a, b in benzene at 45° yielded the corresponding methyl 5-(trifluoromethyl)-1,3-oxathiolane-5-carboxylates 5a, b (Scheme 1) via a regioselective 1,3-dipolar cycloaddition of an intermediate ‘thiocarbonyl ylide’ of type 3 . With methyl pyruvate, 4a reacted similarly to give 6 in good yield. Methyl 2-diazo-3,3,3-trifluoropropanoate ( 2 ) and thiobenzophenone ( 7a ) in toluene underwent a reaction at 50°; the only product detected in the reaction mixture was thiirane 8a (Scheme 2). With the less reactive thiocarbonyl compounds 9H-xanthene-9-thione ( 7b ) and 9H-thioxanthene-9-thione ( 7c ) as well as with 1,3-thiazole-5(4H)-thione 12 , diazo compound 2 reacted only in the presence of catalytic amounts of Rh₂(OAc)₄. In the cases of 7a and 7b , thiiranes 8b and 8c , respectively, were the sole products (Scheme 3). The crystal struture of 8c has been established by X-ray crystallography (Fig.). In the reaction with 12 , desulfurization of the primarily formed thiirane 14 gave the methyl 3,3,3-trifluoro-2-(4,5-dihydro-1,3-thiazol-5-ylidene)propanoates (E)-and (Z)- 15 (Scheme 4). A mechanism of the Rh-catalyzed reaction via a carbene addition to the thiocarbonyl S-atom is proposed in Scheme 5.     

Design,Synthesis, and Characterization of 1, 3‐disubstituted‐1,4‐benzodiazepine Derivatives

The 2‐amino‐4′‐flouro‐benzophenone ( 1 ) that was reacted with chloroacetylchloride to afford 2‐chloro‐N‐(2‐(4′‐fluorobenzoyl) phenyl)acetamide ( 2 ) was subsequently converted to 1,4‐benzodiazepines ( 3 ) by the modification of the known hexamethylenetetramine based cyclization reaction developed by Blazevic and Kajfez. Thus, obtained product ( 3 ) was reacted with a variety of alkyl halide using KOH in DMF to give 1‐substituted‐5‐(4‐fluorophenyl)‐1H‐benzo[e][1,4]diazepin‐2(3H)‐one ( 4a , 4b ). To achieve 1, 3‐disubstituted 1, 4‐benzodiazepines ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l , 5m , 5n , 5o , 5p , 5q , 5r , 5s , 5t ), 1‐substituted‐5‐(4‐fluorophenyl)‐1H‐benzo[e][1,4]diazepin‐2(3H)‐one ( 4a , 4b ) was treated with various aromatic aldehydes in the presence of KOH in toluene.     

Chemoselectivity of the Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine

The reactions of 5‐benzylidene‐3‐phenylrhodanine ( 2 ; rhodanine=2‐thioxo‐1,3‐thiazolidin‐4‐one) with diazomethane ( 7a ) and phenyldiazomethane ( 7b ) occurred chemoselectively at the exocyclic C?C bond to give the spirocyclopropane derivatives 9 and, in the case of 7a , also the C‐methylated products 8 (Scheme 1). In contrast, diphenyldiazomethane ( 7c ) reacted exclusively with the C?S group leading to the 2‐(diphenylmethylidene)‐1,3‐thiazolidine 11 via [2+3] cycloaddition and a ‘two‐fold extrusion reaction’. Treatment of 8 or 9b with an excess of 7a in refluxing CH₂Cl₂ and in THF at room temperature in the presence of [Rh₂(OAc)₄], respectively, led to the 1,3‐thiazolidine‐2,4‐diones 15 and 20 , respectively, i.e., the products of the hydrolysis of the intermediate thiocarbonyl ylide. On the other hand, the reactions with 7b and 7c in boiling toluene yielded the corresponding 2‐methylidene derivatives 16, 21a , and 21b . Finally, the reaction of 11 with 7a occurred exclusively at the electron‐poor C?C bond, which is conjugated with the C?O group. In addition to the spirocyclopropane 23 , the C‐methylated 22 was formed as a minor product. The structures of the products (Z)‐ 8, 9a, 9b, 11 , and 23 were established by X‐ray crystallography.     

An efficient synthesis and reactions of novel indolylpyridazinone derivatives with expected biological activity

Reaction of 4-anthracen-9-yl-4-oxo-but-2-enoic acid (1) with indole gave the corresponding butanoic acid 2. Cyclocondensation of 2 with hydrazine hydrate, phenyl hydrazine, semicarbazide and thiosemicarbazide gave the pyridazinone derivatives 3a-d. Reaction of 3a with POCl(3) for 30 min gave the chloropyridazine derivative 4a, which was used to prepare the corresponding carbohydrate hydrazone derivatives 5a-d. Reaction of chloropyridazine 4a with some aliphatic or aromatic amines and anthranilic acid gave 6a-f and 7, respectively. When the reaction of the pyridazinone derivative 3a with POCl(3) was carried out for 3 hr an unexpected product 4b was obtained. The structure of 4b was confirmed by its reaction with hydrazine hydrate to give hydrazopyridazine derivative 9, which reacted in turn with acetyl acetone to afford 10. Reaction of 4b with methylamine gave 11, which reacted with methyl iodide to give the trimethylammonium iodide derivative 12. The pyridazinone 3a also reacted with benzene- or 4-toluenesulphonyl chloride to give 13a-b and with aliphatic or aromatic aldehydes to give 14a-g. All proposed structures were supported by IR, (1)H-NMR, (13)C-NMR, and MS spectroscopic data. Some of the new products showed antibacterial activity.     

The reaction of homophthalic acid and some aza analogues with vilsmeier reagent: a reinvestigation

Homophthalic acid and its pyrido and 8‐methylquinolino analogues with dimethylformamide/phosphoryl chloride at 0 ° give the appropriate 4‐(dimethylaminomethylene)isochroman‐1,3‐dione ( 2a, 2b, 2c , respectively). Under the literature conditions for conversion of 2a to 2‐methyl‐1‐oxo‐1,2‐dihydroisoquinoline‐4‐carboxylic acid ( 3a ), the aza analogues give instead 7‐hydroxy‐5‐oxo‐5H‐pyrano[4,3‐b]pyridine‐8‐carbox‐aldehyde ( 5b ) and 3‐hydroxy‐6‐methyl‐1‐oxo‐1H‐pyrano[4,3‐b]quinoline‐4‐carboxaldehyde ( 5c ), respectively. Modified conditions were required to isolate analogues 3b and 3c . Further, while reaction of 2a with hydrogen chloride in methanol gave the known change to methyl 1‐oxo‐1H‐isochromene‐4‐carboxylate ( 4 ), 2b and 2c gave only products of oxa‐ring cleavage. Methyl 2‐(cis‐2‐hydroxyvinyl)‐8‐methylquinoline‐3‐carboxylate ( 8 ) was the main product from 2c , while a novel quinolizinium species ( 11 ) was formed in good yield from 2b.     

Furopyridines. XIII. Reaction of 2-methylfuro[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridines with lithium diisopropylamide

Lithiation of 2-methylfuro[2,3-b]- 1a , -[2,3-c]- 1c and -[3,2-c]pyridine 1d with lithium diisopropylamide at ?75° and subsequent treatment with deuterium chloride in deuterium oxide afforded 2-monodeuteriomethyl compounds 2a, 2c and 2d , while 2-methylfuro[3,2-b]pyridine 1b gave a mixture of 1b, 2b , 2-methyl-3-deuteriofuro[3,2-b]pyridine 2′b and 2-(1-proynyl)pyridin-3-ol 5 . The same reaction of 1a at ?40° gave 3-(1,2-propadienyl)pyridin-2-ol 3 and 3-(2-propynyl)pyridin-2-ol 4 . Reaction of the lithio intermediates from 1a, 1c and 1d with benzaldehyde, propionaldehyde and acetone afforded the corresponding alcohol derivatives 6a, 6c, 6d, 7a, 7c, 7d, 8a, 8c and 8d in excellent yield; while the reaction of lithio intermediate from 1b gave the expected alcohols 6b and 8b in lower yields accompanied by formation of 3-alkylated compounds 9, 11, 12 and compound 5 . While reaction of the intermediates from 1a, 1b and 1d with N,N-dimethylacetamide yielded the 2-acetonyl compounds 13a, 13b and 13d in good yield, the same reaction of 1c did not give any acetylated product but recovery of the starting compound almost quantitatively.     

Synthesis of diverse novel compounds with anticipated antitumor activities starting with biphenyl chalcone

The chalcone as (E)-1-([1,1′-biphenyl]-4-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one ( 3 ) was reacted with various active methylene compounds via Michael addition reaction under different conditions. In one hand, chalcone 3 reacted with isatin and glycine in one pot reaction via 1,3-dipolar cycloaddition reaction. On the other hand, chalcone 3 was also reacted with different N-nucleophiles via direct addition on the carbonyl group to award cyclic and/or acyclic products. Meanwhile, the reaction of chalcone 3 with S-benzylthiuronium chloride afforded the thio-Michael addition product. Chalcone 3 and 10 novel synthesized compounds were screened against two cell lines (HepG2 and MCF-7). Among of them, thiosemicarbazone 16 , oxime 14 and pyrimidine-2(1H)-thione 19 derivatives revealed an excellent activity against both cell lines (IC₅₀ values = 6.79-12.91 μM), whereas thiosemicarbazone 16 (6.79 ± 0.5 and 7.58 ± 0.6 μM) showed the highest activity.     

The reaction of lithium phenylacetylide and phenyllithium with N-(ω-Bromoalkyl)phthalimides

Lithium phenylacetylide reacted with short-chain N-(ω-bromoalkyl)phthalimides 1b and 1c to give tricyclic products 2b and 2c in moderate yields. Likewise, tricyclic products 3a-c were obtained when short-chain imides 1a-c were treated with phenyllithium. When longer-chain imides 1d-f in this series were treated with lithium phenylacetylide only tertiary alcohols 4d-f could be isolated. Partial hydrogenation of 2b and 2c yielded the corresponding alkenes 5b and 5c , products which corroborated the structural assignment of 2b and 2c .     

A Ring Enlargement from Seven- to Ten-Membered-Ring sulfonamide derivatives

The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1a ) with 4,5-dihydro-7,8-dimethoxy-1,2-benzothiazepin-3-one 1,1-dioxide ( 4 ) in dioxane at room temperature gave the correspondingly substituted 4H-1,2,5-benzothiadiazecin-6-one 1,1-dioxide 5a in 64% yield (Scheme 2). The structure of this novel ten-membered ring-enlargement product was established by X-ray crystallography (Fig.). Under more vigorous conditions (refluxing dichloroethane), 5a was formed together with the isomeric 6a , both in low yield. The 3-(dimethylamino)-2H-azirines 1b and 1c reacted sluggishly to give the two isomeric ring-enlargement products of type 5 and 6 in yields of 24–29% and 2–4%, respectively (Table 1). Even less reactive is 2,2-dimethyl-3-(N-methyl-N-phenylamino)-2H-azirine ( 1d ), which reacted with 4 in MeCN only at 65°. Under these conditions, besides numerous decomposition products, only traces of 5d and 6d were formed. No ring enlargement was observed with the sterically crowded 1e , which bears an isopropyl group at C(2).     

Intramolecular and intermolecular diels-alder reactions of acylhydrazones derived from methacrolein and ethylacrolein

The intramolecular Diels-Alder reactions of hydrazones derived from methacrolein or ethylacrolein and terminally unsaturated N-acyl-N-methylhydrazines have been investigated. The hydrazones 7b and 7c derived from N-methyl-N-pent-4-enoylhydrazine 3b were found to undergo intramolecular [4 + 2] cycloaddition above 140 °C and the pyridopyridazines 12 were isolated. The corresponding hydrazones 8b and 8c from N-methyl N-pent-4-ynoylhydrazone 4a reacted similarly and gave as the final products the pyridines 13. The scope of the reaction is limited, as was shown by the failure of several other terminally unsaturated hydrazones of β-unsaturated aldehydes to undergo intramolecular cycloaddition. These hydrazones did, however, undergo intermolecular [4 + 2] cyctoaddition to N-phenylmaleimide. Other hydraiones 15 of methacrolein. including the benzoylhydrazone and the phenylhydrazone, also reacted with N-phenylmaleimide to give the pyridine 14b by way of an isolable dihydropyridine 16.     

The behavior of 2‐substituted‐1,3‐diphenylpropane‐1,3‐tione toward organophosphorus reagents

The reaction of 2‐benzylidene‐1,3‐diphenylpropanetrione ( 1a ) with phosphorus ylides 2a–c afforded the new phosphonium ylides 4a–c . Trialkyl phosphites 3a–c react with 1a to give the respective dialkyl phosphonate products 5a–c . On the other hand, the olefinic compounds 6 and 7 were isolated from the reaction of 1b with Wittig reagents 2 . Moreover, trialkyl phosphites reacted with 1b to give products 8a–c . Possible reaction mechanisms are considered, and the structural assignments are based on analytical and spectroscopic evidence. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:57–64, 2000     

Palladaphosphacyclobutenes as catalysts in Heck and Suzuki reactions

Heck reactions of aryl halides with various olefins and Suzuki reactions of aryl halides with phenylboronic acid catalyzed by palladaphosphacyclobutene have been investigated. The scope of the Heck reaction has been investigated in N,N‐dimethylacetamide at 140 °C using NaOAc as base. Using 0.1% molar ratio of palladaphosphacyclobuyenes, aryl bromides were converted into 1,2‐substitutedethene products in good to high yields through coupling with both vinylarenes and acrylates. Actived aryl chloride reacted with styrene to afford 1,2‐substitutedethene products in moderate yields. The scope of the Suzuki reaction has been conducted in toluene at 110 °C using Cs₂CO₃ as base. Using 0.1% molar ratio of palladaphosphacyclobutene, aryl bromides reacted with phenylboronic acid to afford diaryl derivatives in excellent yield. Copyright © 2008 John Wiley & Sons, Ltd.     

Studies on the synthesis of heterocyclic compounds. Part VI. The action of methyl salicylate on some 5-aminopyrazoles

Some 1-phenyl-3-R-5-aminopyrazoles reacted with methyl salicylate to give N-(1-phenyl-3-R-pyrazol-5-yl)-2-methoxybenzamides ( 3a,b,c ), 1-phenyl-2-methyl-3-R-salicyloilimino-3-pyrazolines ( 4a,b,c ) together with 1-phenyl-3-R-5-methylamino pyrazoles ( 5a,b,c ). The structures of the new compounds 3 and 4 were determined on the basis of analytical and spectroscopic data as well as on the acid hydrolysis products.     

The reactions of ethyl 3,4-dihydro-4-quinazolylacetate and its derivatives with cyclopentanone. An attempt at the synthesis of the 6,8-diazasteroid system VII

The reaction of ethyl 3,4-dihydro-4-quinazolylacetate ( 1a ) with cyclopentanone in the presence of trifluoroacetic acid gave mainly two decomposition products, carbostyril (VIII) and ethyl 2-aminocinnamate (IX). Two compounds which are suggested to have the 6,8-diazasteroid skeleton were also obtained in poor yield. Ethyl 3,4-dihydro-2-p-methoxyphenyl-4-quinazolylacetate (1b), however, gave 2-p-methoxyphenylquinazoline (XII) as a decomposition product and did not condense with cyclopentanone. Furthermore, two ethyl 3,4-dihydroquinazolylacetates substituted at the 2-position with cyclohexyl (1c) and methyl (1d) groups could not be converted to the expected diazasteroid system.     

Ring-opening reactions of 3-substituted 1-azabicyclo[1.1.0]butane with dichlorocarbene

Reaction of 3-ethyl-1-azabicyclo[1.1.0]butane ( 1a ) with chloroform-potassium tert-butoxide afforded a ring-opened product, 1,1-dichloro-2-aza-4-ethylpenta-1,4-diene ( 4a ), which was characterized via conversion to the corresponding N-substituted 5-chloro-1,2,3,4-tetrazole, Sa . Reaction of 3-phenyl-1-azabicyclo-[1.1.0]butane ( 1b ) with “Seyferth's reagent” (PhHgCCl₂Br) afforded 1,1-dichloro-2-aza-4-phenylpenta-1,4-diene ( 4b ), which also was characterized via conversion to a tetrazole derivative, i.e., 5b . Finally, the reaction of 1b with dichlorocarbene generated under phase transfer conditions (chloroform-sodium hydroxide-TEBA) was studied. At short reaction times (0.5 hour), the major reaction product was 4b . However, at longer reaction times (20–30 hours), two secondary products, 8 and 9 , were formed which resulted via subsequent dichlorocyclopropanation of 4b .     

Synthesis and Reactivity of Six‐Membered Oxa‐Nickelacycles: A Ring‐Opening Reaction of Cyclopropyl Ketones

Cyclopropanecarboxaldehyde ( 1 a ), cyclopropyl methyl ketone ( 1 b ), and cyclopropyl phenyl ketone ( 1 c ) were reacted with [Ni(cod)₂] (cod=1,5‐cyclooctadiene) and PBu₃ at 100 °C to give η²‐enonenickel complexes ( 2 a – c ). In the presence of PCy₃ (Cy=cyclohexyl), 1 a and 1 b reacted with [Ni(cod)₂] to give the corresponding μ‐η²:η¹‐enonenickel complexes ( 3 a , 3 b ). However, the reaction of 1 c under the same reaction conditions gave a mixture of 3 c and cyclopentane derivatives ( 4 c , 4 c′ ), that is, a [3+2] cycloaddition product of 1 c with (E)‐1‐phenylbut‐2‐en‐1‐one, an isomer of 1 c . In the presence of a catalytic amount of [Ni(cod)₂] and PCy₃, [3+2] homo‐cycloaddition proceeded to give a mixture of 4 c (76 %) and 4 c′ (17 %). At room temperature, a possible intermediate, 6 c , was observed and isolated by reprecipitation at ?20 °C. In the presence of 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene (IPr), both 1 a and 1 c rapidly underwent oxidative addition to nickel(0) to give the corresponding six‐membered oxa‐nickelacycles ( 6 ai , 6 ci ). On the other hand, 1 b reacted with nickel(0) to give the corresponding μ‐η²:η¹‐enonenickel complex ( 3 bi ). The molecular structures of 6 ai and 6 ci were confirmed by X‐ray crystallography. The molecular structure of 6 ai shows a dimeric η¹‐nickelenolate structure. However, the molecular structure of 6 ci shows a monomeric η¹‐nickelenolate structure, and the nickel(II) 14‐electron center is regarded as having “an unusual T‐shaped planar” coordination geometry. The insertion of enones into monomeric η¹‐nickelenolate complexes 6 c and 6 ci occurred at room temperature to generate η³‐oxa‐allylnickel complexes ( 8 , 9 ), whereas insertion into dimeric η¹‐nickelenolate complex 6 ai did not take place. The diastereoselectivity of the insertion of an enone into 6 c having PCy₃ as a ligand differs from that into 6 ci having IPr as a ligand. In addition, the stereochemistry of η³‐oxa‐allylnickel complexes having IPr as a ligand is retained during reductive elimination to yield the corresponding [3+2] cycloaddition product, which is consistent with the diastereoselectivity observed in Ni⁰/IPr‐catalyzed [3+2] cycloaddition reactions of cyclopropyl ketones with enones. In contrast, reductive elimination from the η³‐oxa‐allylnickel having PCy₃ as a ligand proceeds with inversion of stereochemistry. This is probably due to rapid isomerization between syn and anti isomers prior to reductive elimination.     

Furopyridines. IX. Syntheses and properties of 3-ethoxy derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

Reaction of ethyl 3-ethoxycarbonylmethoxyfuropyridine-2-carboxylates 2a-2d with sodium ethoxide afforded 3-ethoxy derivatives 3a-3d which converted to 3-ethoxyfuropyridines 5a-5d by hydrolysis and decarboxylation of the ester group. Vilsmeier reaction of 5a and 5b gave 2-formyl-3-ethoxy derivatives 6a and 6b and 2-formyl-3-chloro derivatives 7a and 7b , while 5c and 5d did not give any formyl compound. Bromination of 3-ethoxyfuropyridines with 1 equivalent mole of bromine gave 2-bromo-3-ethoxyfuropyridines 9a-9d , whereas reaction with 3 equivalents of bromine yielded 2,2-dibromo-3,3-diethoxy-2,3-dihydrofuropyridines ( 10a and 10b ) and/or 2-bromo-3,3-diethoxy-2,3-dihydrofuropyridines 11b , 11c and 11d . Treatment of compounds 5a-5d with n-butyllithium in hexane-tetrahydrofuran at ?70° and subsequent addition of N,N-dimethylformamide yielded 2-formyl derivatives 6a-6d .