Synthesis of corrosion preventive long-chain N -alkyl-2-(phenylthio)-acetohydrazides and 2-oxo-2-phenylethyl-2-alkanoylhydrazinecarbodithioates

Long-chain N-alkyl-2-(phenylthio)acetohydrazides were synthesized via the reactions of 2-(phenylthio)acetohydrazide with long-straight-chain aldehydes and then reduction with sodium borohydride. The reactions of long-straight-chain hydrazides with carbon disulfide in alkaline media give the corresponding carbodithioate salts. Heating of potassium 2-alkanoylhydrazinecarbodithioates with phenacyl bromide do not yield cyclization and failed to give the corresponding long-chain thiazolidine-2-thiones, but gave the corresponding 2-oxo-2-phenylethyl-2-alkanoylhydrazinecarbodithioates via nucleophilic substitution reaction. In addition, the synthesized compounds were tested for their corrosion prevention capabilities in acidic or in mineral oil media.     

Synthesis of 4-Alkoxy-1,3-oxazol-5(2H)-ones,Precursors of 1-alkoxy substituted nitrile ylides

4-Alkoxy-1,3-oxazol-5(2H)-ones of type 4 and 7 were synthesized by two different methods: oxidation of the 4-(phenylthio)-1,3-oxazol-5(2H)-one 2a with m-chloroperbenzoic acid in the presence of an alcohol gave the corresponding 4-alkoxy derivatives 4 , presumably via nucleophilic substitution of an intermediate sulfoxide (Scheme 2). The second approach is the BF₃-catalyzed condensation of imino-acetates of type 6 and ketones (Scheme 3). The yields of this more straightforward method were modest due to the competitive formation of 1,3,5-triazine tricarboxylate 8. At 155°, 1,3-oxazol-5(2H)-one 7b underwent decarboxylation leading to an alkoxy-substituted nitrile ylide which was trapped in a 1,3-dipolar cycloaddition by trifluoro-acetophenone to give the dihydro-oxazoles cis- and trans- 9 (Scheme 4). In the absence of a dipolarophile, 1,5-dipolar cyclization of the intermediate nitrile ylide yielded isoindole derivatives 10 (Schemes 4 and 5).     

Synthesis of <Emphasis Type="Italic">N</Emphasis><Superscript>2</Superscript>-Arylisocytidines and <Emphasis Type="Italic">N</Emphasis><Superscript>2</Superscript>-Aryl-2′-deoxyisocytidines

Summary. 2-(Arylamino)pyrimidin-4-ones were synthesized, silylated, and condensed with l,2,3,5-tetra-O-acetyl-β- d-ribofuranoside to afford the corresponding N ²-aryl protected isocytidines. Deprotection of the acetylated isocytidines using saturated NH₃ in MeOH solution gave 1-(β-d-ribofuranosyl)-2-(arylamino)-4-pyrimidinones. Methyl 2-deoxy-3,5-di-O-toluyl-α/β-d-ribofuranoside was prepared and condensed with the previously silylated bases to afford the anomeric mixture of protected nucleosides. The pure β-anomers were synthesized with better yield by treating the sodium salts of N ²-arylisocytosine derivatives with 2-deoxy-3,5-di-O-toluyl-α-d-ribofuranosyl chloride. Deprotection of the latter anomers afforded the corresponding free hydroxyl derivatives. The synthesized free nucleosides are under antiviral and oligonucleotide investigations.     

Behavior of 3‐benzylamino‐5‐aryl‐2(3H)‐furanones towards some nitrogen nucleophiles

Ring closure of 2‐N‐benzylamino‐3‐aroylpropionic acids ( 3 ) with acetic anhydride afforded 3‐N‐benzylamino‐5‐aryl‐2(3H)‐furanones ( 4 ). The reaction of the furanones ( 4 ) with benzylamine in benzene was found to be time dependent. Thus refluxing the reaction mixture for 1 h only afforded the open‐chain amides ( 5a‐c ). When the reaction was conducted for 3 h the 2(3H)‐pyrrolones ( 6 ) were obtained. Hydrazine hydrate affected ring opening of the furanones to give the hydrazides ( 5d‐f ). Also, semicarbazide converted ( 4 ) into the corresponding semicarbazide derivatives ( 5g‐i ). The hydrazides ( 5d‐f ) were reacted with benzoyl chloride to give the corresponding diaroylhydrazines ( 5j‐l ). The open‐chain derivatives ( 5 ) were converted into a variety of heterocycles: isothiazolones ( 7 ), dihydropyridazinones ( 8 ), 1,3,4‐oxadiazoles ( 9 ) and 1,2,4‐triazole derivatives ( 10 ) via cyclization reactions.     

Study of synthesis of 2‐(2‐alkoxyphenyl)‐1H‐imidazoles. Comparison of oxidative aromatization reactions of imidazolines

The reaction of methyl salicylate with ethane‐1,2‐diamine has been used to prepare 2‐(2‐hydroxyphenyl)‐1H‐imidazoline. This compound was alkylated with alkyl halides to give five new 2‐(2‐alkoxyphenyl)‐1H‐imidazolines (alkyl = propyl, isopropyl, isobutyl, sec‐butyl, benzyl). Seven types of transformation reactions of imidazolines into the respective imidazoles were tested. Out of them successful were the dehydrogenation on palladium in toluene (several‐day refluxing), oxidation with activated manganese dioxide in toluene (several‐hour heating at 60 °C), and the oxidation with potassium nitrosodisulfonate (Fremy's salt) at room temperature. Seven new 2‐(2‐alkoxyphenyl)‐1H‐imidazoles were synthesized (alkyl = ethyl, propyl, isopropyl, butyl, isobutyl, sec‐butyl, benzyl) via mentioned methods. Comparison of individual oxidative aromatization reactions is discussed from the point of view of experimental arrangement, reaction time and conditions, purity of the products obtained, and yields.     

Nitro derivatives of cyclic sulfoximides of the 1,2-benzoisothiazole series

Nitro derivatives of 1-R-1,2-benzoisothiazol-3-one 1-oxide were synthesized by the reactions of 2-alkyl(phenyl)thio-4-nitro- and 4,6-dinitro-2-(phenylthio)benzamides with chlorine in 60% acetic acid. Analogous reactions of 2-(n-butylthio)-4-nitro- and 2-(tert-butylthio)-4-nitrobenzamides with chlorine afforded 2-butyl- and 2-H-1,2-benzoisothiazol-3-one 1-oxides, respectively. The proposed reaction mechanism includes the formation and subsequent transformations of S-alkyl-S-aryl- and S,S-diarylchlorosulfonium chlorides.     

Design, synthesis and hypoglycemic activity of 3-methyl-1-phenyl-4-{4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzylene(benzyl)}-2-pyrazol-5-one

Based on the SAR (structure activity relationship) of TZDs (thiazolidinediones), 3-methyl-1-phenyl-2-pyrazoline-5-one was selected as a substitute for TZD. Compounds of 3-methyl-1-phenyl-4-{4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzylene(benzyl)}-2-pyrazol-5-one were designed and synthesized to find some more hypoglycemic active agents and further investigate the SAR of this class of compounds. Butanedione monoxime reacted with (substituted) benzaldehyde via cyclization and chlorination to give 4-(chloromethyl)-5-methyl-2-phenyloxazole derivatives, which condensed with 4-hydroxybenzaldehyde or vanillin, and was followed by the Knoevenagel reaction with 3-methyl-1-phenyl-2-pyrazol-5-one to give compounds Ia-Ih. Compounds Ia-Ih were hydrogenated with Pd-C to give IIa-IIh, and their hypoglycemic activity was evaluated with a glucose oxidase kit and insulin load test on normal mice. Sixteen new target compounds were synthesized. All the compounds were characterized by ¹H NMR, IR, MS and elemental analysis. The preliminary pharmacological tests show that the compounds have good hypoglycemic activity and can enhance the action of insulin, especially Ib, Id and If. __________ Translated from Chemical Journal of Chinese Universities, 2007, 28(4): 672–677 [译自: 高等学校化学学报]     

Bildung tricyclischer Thietan-Derivate durch intramolekulare(2+2)-Cycloaddition

Formation of Thietane Derivatives via Intramolecular (2+2) Cycloaddition On irradiation, the two 4-vinyl-1,3-thiazole-5(4H)-thiones 1a, b , synthesized from thiobenzoic acid and the corresponding 3-amino-2H-azirines 2a , b , undergo an intramolecular (2+2)-cycloaddition reaction of the C?S and C?C bonds to give the tricyclic thietane derivatives 3a , b .     

Novel Synthesis of 2‐Alkylquinolizinium‐1‐olates and Their 1,3‐Dipolar Cycloaddition Reactions with Acetylenes

Several 2‐alkylquinolizinium‐1‐olates 9 , i.e., heterobetaines, were prepared from ketone 11 , the latter being readily available either from pyridine‐2‐carbaldehyde via a Grignard reaction, followed by oxidation with MnO₂, or from 2‐picolinic acid (=pyridine‐2‐carboxylic acid) via the corresponding Weinreb amide and subsequent Grignard reaction. Mesoionic heterobetaines such as quinolizinium derivatives have the potential to undergo cycloaddition reactions with double and triple bonds, e.g., 1,3‐dipolar cycloadditions or Diels? Alder reactions. We here report on the scope and limitations of cycloaddition reactions of 2‐alkylquinolizinium‐1‐olates 9 with electron‐poor acetylene derivatives. As main products of the reaction, 5‐oxopyrrolo[2,1,5‐de]quinolizines (=‘[2.3.3]cyclazin‐5‐ones’) 19 were formed via a regioselective [2+3] cycloaddition, and cyclohexadienone derivatives, formed via a Diels? Alder reaction, were obtained as side products. The structures of 2‐benzylquinolizinium‐1‐olate ( 9a ) and two ‘[2.3.3]cyclazin‐5‐ones’ 19i and 19l were established by X‐ray crystallography.     

Synthesis and electrochemical characterization of complexes of 1,2-bis[2-(pyridylmethylideneamino)phenylthio]ethanes with transition metals (CoII, NiII, CuII)

Transition metal (Ni^II, Co^II, and Cu^II) complexes with 1,2-bis[2-(3-pyridylmethylideneamino)phenylthio]ethane (1) and 1,2-bis[2-(4-pyridylmethylideneamino)phenylthio]ethane (2) were synthesized for the first time by slow diffusion of solutions of compounds 1 or 2 in CH₂Cl₂ into solutions of MX₂ · nH₂O (M = Ni, Co, or Cu; X = Cl or NO₃; n = 2 or 6) in ethanol. The reactions with Co^II and Cu^II chlorides afford complexes of composition M(L)Cl₂ (L = 1 or 2). The reactions of compound 1 with Ni^II salts produce complexes with 1,2-bis(2-aminophenylthio)ethane. The molecular structure of dinitrato[1,2-bis(2-aminophenylthio)ethane]nickel(ii) was confirmed by X-ray diffraction. The ligands and the complexes were investigated by cyclic voltammetry and rotating disk electrode voltammetry. The initial reduction of the complexes proceeds at the metal atom. The oxidation of the chlorine-containing complexes proceeds at the coordinated chloride anion. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 350–355, February, 2008.     

Reactions of Thioketones Possessing a Conjugated CC Bond with Diazo Compounds

The reactions of several thioketones containing a conjugated C?C bond with diazo compounds were investigated. All of the selected compounds reacted via a 1,3‐dipolar cycloaddition with the C?S group and subsequent N₂ elimination to yield thiocarbonyl ylides as intermediates, which underwent a 1,3‐dipolar electrocyclization to give the corresponding thiirane 25 , or, by a subsequent desulfurization, to give the olefins 33a and 33b . None of the intermediate thiocarbonyl ylides reacted via 1,5‐dipolar electrocyclization. If the α,β‐unsaturated thiocarbonyl compound bears an amino group in the β‐position, the reactions with diazo compounds led to the 2,5‐dihydrothiophenes 40a – 40d . In these cases, the proposed mechanism of the reactions led once more to the thiocarbonyl ylides 36 and thiiranes 38 , respectively. The thiiranes reacted via an S_Ni′‐like mechanism to give the corresponding thiolate/ammonium zwitterion 39 , which underwent a ring closure to yield the 2,5‐dihydrothiophenes 40 . Also in these cases, no 1,5‐dipolar electrocyclization could be observed. The structures of several key products were established by X‐ray crystallography.     

Synthesis and anticancer evaluation of some novel N,O,S heterocyclic compounds pendant to 3-methyl-5-cyano-6-(3,4-dimethoxyphenyl)pyrimidine and other related fused pyrimidines

The key starting compound 5-cyano-6-(3,4-dimethoxyphenyl)-2-thiouracil ( 1 ) was synthesized and allowed to undergo electrophilic substitution with methyl iodide to give the corresponding 6-(3,4-dimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile ( 2 ). Nucleophilic substitution on compound 2 with hydrazine hydrate led to the corresponding 2-hyrazinopyrimidone intermediate 3 . Compound 3 underwent several substitution and cyclization reactions with β-ketoester, β-ketone, alkyl halides, arylisothiocyanate, or aromatic aldehydes followed by cyclization reactions to give the corresponding N,O,S heterocyclic compounds incorporated into pyrimidine moiety and/or the related S-triazino[3,4-b]pyrimidine derivatives 4 - 18 . Anticancer evaluation of some representative examples of newly synthesized compounds was carried out against MCF-7, HCT116 cell lines. Some of the newly synthesized compounds showed significant activity.     

Preparation of α- or β-trifluoromethylated vinylstannanes and their cross-coupling reactions

α- or β-Trifluoromethylated vinylstannanes 1, 2a, 3 and 4 were prepared form 1,1-bis(phenylthio)-2,2,3,3,3-pentafluoropropylbenzene (5) via several steps. The cross-coupling arylation reactions of 1–4 with aryl iodides bearing a bromo, methoxy, methyl, nitro or trifluoromethyl group on para- or meta-position of benzene ring afforded the corresponding coupling products in good yields. Compounds 1, 2a and 4 underwent the acylation reaction with various types of acyl chlorides to give the corresponding trifluoromethylated enone derivatives in good yields. Reduction of trifluoromethylated enone derivatives with LiAlH₄, followed by Fridel-Craft’s type of cyclization with AlCl₃ provided trifluoromethylated indene derivatives in good yields.     

Synthesis and chemical transformation of fused tetrazoles derived from 2‐bromomethyl‐ and 2‐iodomethyl‐3,5,6,7‐tetrahydro‐4(2H)‐benzofuranones

The 2‐bromomethyl‐3,5,6,7‐tetrahydrobenzofuranones 1a‐d were subjected to triazidochlorosilanesodium azide‐mediated Schmidt rearrangement to afford the corresponding tetrazolofuroazepine derivatives 2a‐d via methylene shift. Under similar reaction conditions, the 2‐iodomethyl‐3,5,6,7‐tetrahydrobenzofuranones 1e‐h afford mixtures of the corresponding tetrazolofuroazepines 2e‐h and the 4‐azido‐2‐iodomethyl‐2,3‐dihydrobenzofuran derivatives 3a‐c . A mechanism is proposed to account for the divergence in the reactivity of these 2‐halogenomethyltetrahydrobenzofuranones (X = Br versus I). In turn, the 2‐halogenomethyltetrazolofuroazepines 2a,b,d‐h and the 4‐azido‐2‐iodomethyl‐2,3‐dihydrobenzofurans 3a,b underwent nucleophilic substitution with triethyl phosphite and dehydrohalogenation using DBU in refluxing toluene to give the corresponding tetrazolofuroazepines 4a‐d and 5a‐c and benzofurans 6a,b .     

Intramolecular [4+2] cycloaddition of furfurylsubstituted homoallylamines to allylhalides,acryloyl chloride and maleic anhydride

Acylation of 4‐(furyl‐2)‐4‐R‐aminobut‐1‐enes and 4‐R‐4‐furfurylaminobut‐1‐enes with maleic anhydride, acryloyl chloride or allylhalides provided 3‐aza‐10‐oxatricyclo[5.2.1.0^1,5]decenes. The tricycles are formed via an initial amide formation followed by a stereoselective exo‐IMDAF (Intramolecular Diels‐Alder of Furan). In case of competing cycloaddition (for compounds possessing two furan or two dienophilic moieties) the most substituted fivemembered cycle is preferably annulated. Refluxing of 4‐R‐4‐furfurylaminobut‐1‐enes in acetic anhydride led to exo‐3‐aza‐11‐oxatricyclo[6.2.1.0^1,6]undecenes with the pseudoequatorial substituent R‐4. Treatment of 3‐aza‐10‐oxatricyclo[5.2.1.0^1,5]decenes with PPA at 90?110°C promoted cyclic ether opening, aromatization and intramolecular cyclization reactions sequence to give the corresponding tetracyclic compounds — tetrahydroisoindolo[2,1‐a]quinolines and tetrahydroisoindolo[2,1‐b][2]benzazepines in good yields. Unusual products of ipso‐substitution in aromatic ring were obtained on cyclization of N‐p‐R‐substituted 2‐allyl‐4‐oxo‐3‐aza‐10‐oxatricyclo[5.2.1.0^1,5]dec‐8‐enes.     

Preparation of 6-(nitron-c-yl)- and 6-(1,3-butadienyl)-2-pyrones and their cycloaddition reactions

6-(N-Substituted nitron-C-yl)-2-pyrones 1 and 6-(4-substituted 1,3-butadienyl)-2-pyrone 2 were prepared and their cycloaddition reactions with three kinds of diene systems were investigated. Namely, the reactions of 1 with methyl acrylate, vinyl crotonate and divinylsulfone took place at the nitrone moiety to afford 3-substituted isoxazolidines 9–14 , and that of 2 with maleimide took place at the 2-pyrone moiety to give a bis-adduct 17 via elimination of carbon dioxide.     

An unusual cascade of <Emphasis Type="Italic">S</Emphasis><Subscript>N</Subscript> reactions of benzotetrazine 1,3-dioxide derivatives

An unusual cascade of S _NAr reactions was discovered in the series of benzo-1,2,3,4-tetrazine 1,3-dioxides containing two adjacent nucleofuges X and Y in the benzene ring. First, the 1,2,3-triazole anion displaces the anion X^s- from the more reactive site. Then the nucleo-phile X^s- displaces the adjacent group Y. For instance, 1,2,3-triazole reacts with 6-azido-5-nitrobenzotetrazine 1,3-dioxide to give 5-azido-6-(1,2,3-triazol-2-yl)benzotetrazine 1,3-dioxide, with 8-azido-7-nitrobenzotetrazine 1,3-dioxide to give 7-azido-8-(1,2,3-triazol-2-yl)benzotetrazine 1,3-dioxide and 7-azido-8-(1,2,3-triazol-1-yl)benzotetrazine 1,3-dioxide, and with 7-bromo-6-(phenylthio)benzotetrazine 1,3-dioxide to give 7-phenylthio-6-(1,2,3-triazol-2-yl)benzotetrazine 1,3-dioxide.     

Alternative Synthesis of 2‐Hydroxy‐3,5,5‐trimethylcyclopent‐2‐en‐1‐one

The 2‐hydroxy‐3,5,5‐trimethylcyclopent‐2‐en‐1‐one ( 1 ) was synthesized in 42% yield by rearrangement of epoxy ketone 10 on treatment with BF₃⋅Et₂O under anhydrous conditions. Intermediate 10 was available from the known enone 8 , either via direct epoxidation (60% H₂O₂, NaOH, MeOH; yield 50%), or via reduction to the corresponding allylic alcohol 14 (LiAlH₄, THF), followed by epoxidation ([VO(acac)₂], ^tBuOOH) and reoxidation under Swern conditions, in 37% total yield.     

Thermische und photochemisch induzierte intramolekulare, 1,3-dipolare Cycloadditionen von 4-Phenyl-3-(2-allylphenyl)-sydnon. Vorläufige Mitteilung. 53. Mitteilung über Photoreaktionen

Thermal and photochemically induced intramolecular 1,3-dipolar cycloaddition reactions of 4-phenyl-3-(2-allylphenyl)-sydnone The title compound 9 was synthesised in the usual way, starting from 2-allylaniline and ethyl 2-bromo-2-phenylacetate, via the nitrosaminacid 8 (Scheme 2). 9 reacts at room temperature with its potential azomethinimine-function in an intramolecular [3+2]-cycloaddition to give the tricyclic compound 11 (Scheme 2). On irradiation, 9 yields the dihydro-3H-pyrazolo[2,3-a]indole 10 which probably arises by intramolecular [3+2]-cycloaddition of the corresponding intermediate nitrilimine.     

Synthesen und Ringerweiterungsreaktionen von 2-(4-Hydroxyalkyl)-2-nitrocycloalkanonen

Syntheses and Ring-Enlargement Reactions of 2-(4-Hydroxyalkyl)-2-nitrocycloalkanones Syntheses of the title compounds were achieved by [Pd{P(C₆H₅)₃}₄]-catalyzed reaction of 2-nitrocycloalkanones 3 with vinyloxirane followed by catalytic hydrogenation. By another route, the known methyl 4-(1-nitro-2-oxocycloalkyl)butanoates 6 were reduced to the corresponding aldehydes 7 which by NaBH₄ reduction or methylation with (CH₃)₂Ti(i-Pr)₂ were transformed to the alcohols 5 and 8 , respectively (Saheme 1). Treatment of 5 and/or 8 with KH/THF under reflux gave, via a 7-membered intermediate, the nitrolactones 12 and oxolactones 13 (Scheme 3). Compared with similar reactions running via 5- or 6-membered intermediates (see 1 and 2 ), the yields are distinctly lower. The natural occurring 12-tridecanolid ( 14 ) was synthesized.