Reaktionen mit γ-Chloracetessigesterderivaten

Reactions with derivatives of γ-chloroacetoacetic acid Ethyl γ-chloroacetoacetate reacts with ammonia to give ethyl β-amino-γ-chloro-crotonate; with aniline, however, β-anilino-crotonic acid γ-lactone is formed. The reaction of ethyl α-cyano-γ-chloro-acetoacetate with arylamines yields 1-aryl-2-amino-3-ethoxycarbonyl-pyrrolin-4-ones.     

Sydnone Compounds XXX. The Syntheses and Reactions of 3-Aryl-4-Cyanosydnones and 3-Aryl-4-Formylsydnone Oximes

In the presence of pyridine, 3-aryl-4-formylsydnone (II) reacts with hydroxyl-amine hydrochloride to produce 3-aryl-4-formylsydnone oxime (III). This reaction was performed in ethanol solution with reflux or at room temperature; the latter procedure gave an excellent yield (74-98%) and high purity. (III) reacts in acetic anhydride at room temperature to give 3-aryl-4-formylsydnone oxime O-acetate (IV). A convenient method for the synthesis of 3-aryl-4-cyanosydnone (V) is to dehydrate (III) with acetic anhydride at reflux. When (IV) was refluxed with acetic anhydride, (V) was similarly obtained. Another convenient method to prepare (V) from (III), dehydration with thionyl chloride at room temperature, was also investigated.     

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.     

Exploratory chemistry of 3-aroylformamido-4-aryl-1,2,5-thiadiazoles

Apart from the previous report, the reaction of 3-(4-nitrobenzoylformamido)-4-(4-nitrophenyl)-1,2,5-thiadiazole ( 2a ) with m-chloroperbenzoic acid in chloroform at room temperature did not proceed, whereas at reflux temperature the same reaction gave 4-nitrobenzoic acid ( 5 ) (86%) and a minute amount of a mixture of 4-nitrobenzoylformamide ( 6 ) and 3-amino-4-(4-nitrophenyl)-1,2,5-thiadiazole ( 7a ). On the other hand the same reaction in a mixture of ethanol and chloroform (1:4) at room temperature gave 3-ethoxycarbamoyl-4-(4-nitrophenyl)-1,2,5-thiadiazole ( 8a ) (24%) as an isolable product. When 3-aroylformamido-4-aryl-1,2,5-thiadiazoles 2 in tetrahydrofuran were treated with various alkoxides in the corresponding alcohols at room temperature, 3-amino-4-aryl- 7 , 3-alkoxycarbamoyl-4-aryl- 8 , and 3-aryl-4-(aryl)(hydroxy)acetamido-1,2,5-thiadiazoles 9 were isolated. The ratios of which were dependent on the kind of bases and the solvent employed. Selected compounds 2 were allowed to react with phosphorus pentasulfide in the presence of pyridine at reflux to give 3-aryl-4-arylacetarnido-1,2,5-thiadiazoles 17 (55–64%), which were also produced by the reaction of 2 with either Lawesson's reagent or hydrogen sulfide gas in the presence of pyridine at reflux.     

Room‐temperature Suzuki–Miyaura cross‐coupling reaction with α‐diimine Pd(II) catalysts

An α‐diimine Pd(II) complex containing chiral sec‐phenethyl groups, {bis[N,N′‐(4‐methyl‐2‐sec‐phenethylphenyl)imino]‐2,3‐butadiene}dichloropalladium (rac‐ C1 ), was synthesized and characterized. rac‐ C1 was applied as an efficient catalyst for the Suzuki–Miyaura cross‐coupling reaction between various aniline halides and arylboronic acid in PEG‐400–H₂O at room temperature. Among a series of aniline halides, rac‐ C1 did not catalyze the cross‐coupling of aniline chlorides and fluorides but efficiently catalyzed the cross‐coupling of aniline bromides and iodides with phenylboronic acid. The catalytic activity reduced slightly with increasing steric hindrance of the aniline bromides. The complexes {bis[N,N′‐(4‐fluoro‐2,6‐diphenylphenyl)imino]‐2,3‐butadiene}dichloropalladium and {bis[N,N′‐(4‐fluoro‐2,6‐diphenylphenyl)imino]acenaphthene}dichloropalladium were also found to be efficient catalysts for the reaction. Copyright © 2015 John Wiley & Sons, Ltd.     

[18O]-Studien zur Carboxylbeteiligung bei der sauren Hydrolyse von γ-substituierten Carbonsäuren. 1. Mitteilung: Zum Sauerstoffaustausch von γ-Lactonen in saurer Lösung

Specifically [¹⁸O]-labelled γ-valerolactone and 4-methyl-γ-valerolactone were submitted to tracer equilibration in dilute mineral acid at reflux temperature. Though under these conditions the two lactones are known to be hydrolyzed to the extent of about 25% to the corresponding γ-hydroxy acids only the «tertiary» 4-methyl derivative lost its alkoxyl label whereas the unsubstituted «secondary» one retained it. – This may be understood on the base of two alternative mecanisms possible for lactone reformation. The results permit a quantitative evaluation of the amount of carboxyl-participation during acid hydrolysis of 4-substituted carboxylic acids to 4-monoalkylated γ-butyrolactones.     

C-Nucleosides. 8. Synthesis of 5-hydroxy-2-(β-D-ribofuranosyl)pyridine

The synthesis of 5-hydroxy-2-(β-D-ribofuranosyl)pyridine ( 12 ) from 2-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)furan ( 1 ) is described. Treatment of 1 with α-methoxycarbamate in the presence of p-toluenesulfonic acid in benzene at reflux temperature afforded furfurylcarbamate ( 2 ) and its α-isomer in a 5/1 ratio. The anomerization was circumvented by treatment of 1 with α-methoxycarbamate in the presence of boron trifluoride in benzene at room temperature. Compound 2 was electrochemically oxidized to give dihydrofuran 4 . However, conversion of 4 into 11 was unsuccessful. Treatment of azide 8 with bromine and methanol afforded 9 . Reduction of 9 with zinc powder gave dihydrofurfurylamine 10 , in 80% yield. Treatment of this with concentrated hydrochloric acid in methanol yielded 11 , which on deblocking with 5% sodium hydroxide aqueous solution gave 12.     

Cyclization of ylidenemalononitriles. X. Synthesis of benzazapropellane derivatives from α-Cyano-β-chloroalkylcinnamonitriles

The reaction of nucleophilic and non-nucleophilic bases wtih 2-carbamoyl-3-(γ-chloropropyl)-1-indenone ( 5 ) have been investigated. Condensation of γ-chlorobutyrophenone with malono-nitrile afforded α-cyano-β-(3-ehloropropyl)cinnamonitrile which was cyclized in concentrated sulfurie acid to produce 5 . Two other products obtained from the cyclization reaction were 2-carbamoyl-3-(γ-ehloropropylidene)-1-indanone ( 4 ) and α-carbamoyl-β-(3-chloropropyl)cinnam-amide. Treatment of a solution of 4 in ethyl acetate with piperidine resulted in cyclization of the γ-chloropropyl side chain to give 2-carbamoyl-3-cycIopropyl-1-indanone. The same compound was obtained in improved yield by the treatment of 4 or 5 with sodium hydroxide solution. The reaction of dirnethylamine with 5 in benzene gave initial Michael addition of the amine followed by internal alkylation of the carbanion so formed to yield 3a-dimethylamino-2,3,3a,8-tetrahydro-8-oxoeyclopent[a]indene-8a(lH)earboxamide ( 7a ). Similarly addition of ammonia, pyrrolidine, piperidine, benzenethiol, p-toluenethiol, 2-naphthalenethiol and nitromethane to the indenone I gave respective analogs of type 7 . Treatment of 5 with sodium cyanide in aqueous t-butyl alcohol resulted in a similar Michael addition followed by internal alkylation. In addition, cyclization between the nitrile and the carbamoyl functions occurred in the same step to give 2-oxo-4-imino-7,8-benzo-3-aza[3.3.3]-propellan-6-one ( 13a ). Hydrolysis of the iminopyrrolido ring in 13a to the corresponding suecin-irnide gave 2,4-dioxo-7,8-benzo-3-aza[3.3.3]propellan-6-one ( 13b ). Reactión of 13b with methyl iodide, allyl bromide, benzyl bromide, and diethyluminoethyl chloride afforded the corresponding N-alkylated products. A similar sequence starling with δ-ehlorovalerophenone led to 5,6-fused ring systems, including a [4.3.3]propellane. 2,9-Dioxo-4-methyl-7,8-benzo-3-aza[4.3.3]propell-4-ene was obtained by the reaction of 5 with acetone in dilute alkali.     

THE STEREOSELECTIVE SYNTHESIS OF N-ARYL-TRANS,TRANS-α-CARBOXYL-β-METHOXYCARBONYL-γ-ARYL-γ-BUTYROLACTAMS

Cis-1-methoxycarbonyl-2-aryl-6,6-dimethyl-5,7-diox-spiro-[2,5]-4,8-octadiones (1) in dimethyl ethylene glycol at room temperature react with anilines (2) to give N-aryl-trans,trans-α-carboxyl-β-methoxycarbonyl-γ-aryl-γ-butyrolactams (3) in good to excellent yields and high stereoselectivity.     

Determination of Enantiomer Purity of β‐ and γ‐Amino Acids by NMR Analysis of Diastereoisomeric Palladium Complexes

Like α‐amino acids, β‐ and γ‐amino acids form spirobicyclic complexes (see 2 and 3 ) by reaction with the chiral di‐μ‐chlorobis{2‐[1‐dimethylamino‐ϰN)‐ethyl]phenyl‐ϰC}dipalladium complexes 1 under basic conditions (Scheme 1 and X‐ray structures in Fig. 1). The diastereoisomeric complexes formed with mixtures of enantiomers of either the amino acids or the dichloro‐dipalladium complexes give rise to marked chemical‐shift differences in the ¹H‐ and ¹³C‐NMR spectra (Figs. 2 – 4) to allow determination of the enantiomer purities. A simple procedure is described by which β‐ and γ‐amino acids (which may be generated in situ from Boc‐ or Fmoc‐protected precursors) are converted to the Pd complexes and subjected to NMR measurements. The effects of solvent, temperature, and variation of the aryl group in the chiral derivatizing Pd reagent are described (Figs. 4 and 5). The methyl esters of β‐amino acids can also be employed, forming diastereoisomeric chloro[(amino‐ϰN)aryl‐ϰC][(amino‐ϰN)alkanoate]palladium complexes 6 for determining enantiomer ratios (Scheme 6). The new method has great scope, as demonstrated for β²‐, β³‐, β^2,3‐, β^2,2,3‐, γ²‐, γ³‐, γ⁴‐, and γ^2,3,4‐amino acid derivatives.     

Stereoselectivity of the Diels-Alder Reaction of (E)-γ-Oxo-α,β-Unsaturated Thioesters with Cyclopentadiene

The stereoselectivity of the Diels-Alder reaction of (E)-γ-oxo-α,β-unsaturated thioesters 3a-3d with cyclopentadiene is greatly enhanced in the presence of Lewis acids favoring the endo acyl isomers 4a-4d . In the absence of Lewis acid, Diels-Alder reaction of 3a-3d with cyclopentadiene at 25 °C gave two adducts 4a-4d and 5a-5d in a ratio of 1:1 respectively. In the presence of Lewis acids, Diels-Alder reaction of 3a-3d with cyclopentadiene gave 4a-4d and 5a-5d in ratios of 75-94:25-6 respectively. The stereoelectivity was enhanced to ratios of 95-98:5-2 with lowering the reaction temperature. The stereochemistry of the cycloadducts 4 and 5 was confirmed by iodocyclization. Reaction of the endo-thioester 5c with I₂ in aqueous THF at 0 °C gave the novel methylthio group rearranged product 6c in 80% yield, the first example of iodo-lactonization of endo-thioesters. Reaction of the endo-acyl isomer 4b with I₂ under the same reaction conditions gave an isomeric mixture of 7b and 8b in 1:2 ratio. The stereochemistry of the thioester group in 8b was proved by X-ray single-crystal analysis. The solvent effect on the endo selectivity of (Z)-γ-oxo-α,β-unsaturated thioester 2b was also examined.     

Haloacetylated enol ethers. 7 . Synthesis of 3-aryl-5-trihalomethylisoxazoles and 3-aryl-5-hydroxy-5-trihalomethyl-4,5-dihydroisoxazoles

β-Aryl-β-methoxyvinyl trihalomethyl ketones 1a-g, 2a-g [aryl = p-YC₆H₄ where Y= H, Me, OMe, F, Cl, Br, NO₂] are cyclocondensed with hydroxylamine hydrochloride to afford the 3-aryl-5-hydroxy-5-trihalomethyl-4,5-dihydroisoxazoles 3a-g, 4a-f in good yield. The dehydratation of compounds 3a-g with concentrated sulfuric acid, led the corresponding 3-aryl-5-trichloromethylisoxazoles 5a-g . An alternative one-pot procedure yields 3-aryl-5-trihalomethylisoxazoles 5,6a-g directly by cyclocondesation of 1,2a-g with hydroxylamine hydrochloride in the presence of an excess of concentrated hydrochloric acid.     

The synthesis of 3-deazaorotidine and related nucleoside derivatives of 4-hydroxy-2-pyridone

Condensation of 6-earbethoxy-4-hydroxy-2-pyridone or a silyl derivative of 5-earbomethoxy-4-hydroxy-2-pyridone with 2′,3′,5′-tri-O-benzoyl-D-ribofuranosyl halide has provided the 3-deaza analogs of orotidine and uridine-5-carboxylic acid. The corresponding amides have also been prepared in view of their possible structural relationship to l-β-D-ribohiranosyl nicotinamide. Tri-O-benzoyl-3-deazauridine was treated with N-bromosuccinimide to give, after deblocking, 3-bromo-4-hydroxy-1-(β-D-ribofuranosyl)-2-pyridone. The anomeric configuration of these nuclcosides was confirmed by pmr spectroscopy.     

Thermische Lactonisierung von Estern γ-Brom-α, β-ungesättigter Carbonsäuren zu Δα-Butenoliden. Direkte γ-Bromierung von α, β-ungesättigten Säuren

By heating with iron powder at 120–150° some γ-bromo-α, β-unsaturated carboxylic methyl esters, and, less smothly, the corresponding acids, were lactonized to Δ^7alpha;-butenolides with elimination of methyl bromide. The following conversions have thus been made: methyl γ-bromocrotonate ( 1c ) and the corresponding acid ( 1d ) to Δ^α-butenolide ( 8a ), methyl γ-bromotiglate ( 3c ) and the corresponding acid ( 3d ) to α-methyl-Δ^α-butenolide ( 8b ), a mixture of methyl trans- and cis-γ-bromosenecioate ( 7c and 7e ) and a mixture of the corresponding acids ( 7d and 7f ) to β-methyl-Δ^α-butenolide ( 8c ). The procedure did not work with methyl trans-γ-bromo-Δ^α-pentenoate ( 5c ) nor with its acid ( 5d ). Most of the γ-bromo-α, β-unsaturated carboxylic esters ( 1c, 7c, 7e and 5c ) are available by direct N-bromosuccinimide bromination of the α, β-unsaturated esters 1a, 7a and 5a ; methyl γ-bromotiglate ( 3c ) is obtained from both methyl tiglate ( 3a ) and methyl angelate ( 4a ), but has to be separated from a structural isomer. The γ-bromo-α, β-unsaturated esters are shown by NMR. to have the indicated configurations which are independent of the configuration of the α, β-unsaturated esters used; the bromination always leads to the more stable configuration, usually the one with the bromine-carrying carbon anti to the carboxylic ester group; an exception is methyl γ-bromo-senecioate, for which the two isomers (cis, 7e , and trans, 7d ) have about the same stability. The N-bromosuccinimide bromination of the α,β-unsaturated carboxylic acids 1b , 3b , 4b , 5b and 7b is shown to give results entirely analogous to those with the corresponding esters. In this way γ-bromocrotonic acid ( 1 d ), γ-bromotiglic acid ( 3 d ), trans- and cis-γ-bromosenecioic acid ( 7d and 7f ) as well as trans-γ-bromo-Δ^α-pentenoic acid ( 5d ) have been prepared. Iron powder seems to catalyze the lactonization by facilitating both the elimination of methyl bromide (or, less smoothly, hydrogen bromide) and the rotation about the double bond. α-Methyl-Δ^α-butenolide ( 8b ) was converted to 1-benzyl-( 9a ), 1-cyclohexyl-( 9b ), and 1-(4′-picoly1)-3-methyl-Δ^α-pyrrolin-2-one ( 9 c ) by heating at 180° with benzylamine, cyclohexylamine, and 4-picolylamine. The butenolide 8b showed cytostatic and even cytocidal activity; in preliminary tests, no carcinogenicity was observed. Both 8b and 9c exhibited little toxicity.     

Synthesis of pyridazino[4,5-b]indole derivatives from 2-(3-carboxy-1-methylindole)acetic acid anhydride

2-(3-Carboxy-1-methylindole)acetic acid anhydride ( 1 ) reacts with aryldiazonium salts to give 85–95% of the corresponding α-hydrazono anhydrides 2 . Treating 2 with boiling hydrazine hydrate in xylene, the respective 2-aryl-4-carbohydrazido-5-methyl-1-oxo-1,2-dihydro-5H/-pyridazino[4,5-b]indoles 3 were obtained (47–67%), and these compounds characterized as the respective benzylidene derivatives 4 . Compounds 2 react with amines (aniline, morpholine, piperidine) to give the respective 2-(3-carboxy-1-methylindole)aceta-mide 5 or the respective 2-aryl-4-carboxamido-5-methyl-5H-pyridazino[4,5-b]indole 6 , the product obtained depending on the structure of the aryl substituent. Boiling 2b (aryl = 4-chlorophenyl) with 5% sodium hydroxide gave (80%) 2-(3-carboxy-1-methylindole)acetic acid ( 7 ). Hydrolysis of 2b gave a mixture of 7 and 2-(3-carboxy-1-methylindolyl)-2-(4-chlorophenylhydrazono)acetic acid ( 8 ).     

Chemoselective anti-Markovnikov hydroamination of α,β-ethylenic compounds with amines using montmorillonite clay

The catalytic activity of montmorillonite clays as a catalyst for the hydroamination of α,β-ethylenic compounds with amines was tested. Aniline and substituted anilines reacted with α,β-ethylenic compounds in the presence of catalytic amount of commercially available clay to afford exclusively anti-Markovnikov adduct in excellent yields. Aniline reacted with ethyl acrylate to yield only anti-Markovnikov adduct N-[2-(ethoxycarbonyl)ethyl]aniline (mono-addition product). No Markovnikov adduct (N-[1-(ethoxycarbonyl)ethyl]aniline and double addition product N,N-bis[2-(ethoxycarbonyl)ethyl]aniline were formed under selected reaction conditions. For a better exploitation of the catalytic activity in terms of increased activity and improved selectivity for the mono-addition product, the reaction parameters were optimized in terms of temperature, solvent, reactant mole ratio. Under optimized reaction conditions, montmorillonite clay K-10 showed a superior catalytic performance in the hydroamination of ethyl acrylate with aniline with a conversion of aniline to mono-addition product (almost 100% chemoselectivity) with a high rate constant 0.3414 min⁻¹ compared to the reported protocols. The dependence of conversion of aniline over different types of montmorillonite clays (K-10, K-20, K-30, Al-Pillared clay and untreated clay) has also been discussed. The activities of clay for the hydroamination of different aromatic and aliphatic amines have also been investigated. Under harsh reaction conditions (increased temperature and long reaction time) small amounts of di-addition products were observed. The kinetics data has been interpreted using the initial rate approach model.     

Synthèse et propriétés des aroylhydrazones du benzoate d'éthyle. Synthèses d'hétéroscycles azotes

The aroylhydrazones of ethyl benzoate have been prepared in fair yield by the action of aroylhydrazines on ethyl benzimidate hydrochloride. These products give rise, quantitatively, at their melting point, to 5-aryl-2-phenyl-1,3,4-oxadiazoles, and, in the presence of hydrazine hydrate, in boiling 1-propanol to 4-amino-5-aryl-3-phenyl(4H)-1,2,4-triazoles (Yields 50%). The addition of methylmagnesium iodide to these products give aroylhydrazones of acetophenone.     

3-芳基-1,2,3,4-噁三唑-5-亚胺与阿司匹林偶联物的合成和抗血栓活性研究

取代苯胺经重氮化、还原得苯肼盐酸盐, 与硫氰酸钾作用得苯基取代的氨基硫脲, 再在亚硝酸异戊酯、盐酸的作用下环合、成盐, 加碱中和后生成3-芳基-1,2,3,4-噁三唑-5-亚胺, 最后与乙酰水杨酰氯反应得目标物6a～6l, 其结构经MS, IR, ¹H NMR和元素分析确证. 体外血小板聚集试验和小鼠肺血栓生成试验结果表明, 部分目标物在体内、外均显示出较好的抗血栓活性, 值得深入进行研究.     

Effective synthesis of <Emphasis Type="Italic">N</Emphasis>-substituted 1,3,5-dithiazinanes by reactions of <Emphasis Type="Italic">N</Emphasis>-methyl-1,3,5-dithiazinane and 1,3,5-trithiane with aromatic amines

A novel procedure has been developed for selective synthesis of N-aryl-1,3,5-dithiazinanes, 1,2,6,7-tetrahydro-3,5,1,7-benzodithiadiazonine, and 6,7-dihydro-1,3,5,7-benzotrithiazonine by reactions of aniline derivatives with N-methyl-1,3,5-dithiazinane or 1,3,5-trithiane in the presence of transition and rare earth metal salts and complexes.     

RAFT Polymerization of N‐Isopropylacrylamide and Acrylic Acid under γ‐Irradiation in Aqueous Media

Summary: The ambient temperature (20 °C) reversible addition fragmentation chain transfer (RAFT) polymerization of N‐isopropylacrylamide (NIPAAm) and acrylic acid (AA) conducted directly in aqueous media under γ‐initiation (at dose rates of 30 Gy · h⁻¹) proceeds in a controlled fashion (typically, < 1.2) to near quantitative conversions and up to number‐average molecular weights of 2.5 × 10⁵ g · mol⁻¹ for PNIPAAm and 1.1 × 10⁵ g · mol⁻¹ for PAA via two water‐soluble trithiocarbonate chain transfer agents, i.e., S,S‐bis(α,α′‐dimethyl‐α″‐acetic acid)trithiocarbonate (TRITT) and 3‐benzylsulfanylthiocarbonylsulfanyl propionic acid (BPATT). The generated polymers are successfully chain extended, which suggests that the RAFT agents are stable throughout the polymerization process so that complex and well‐defined architectures can be obtained.

An increase of the monomer/CTA ratio leads to an increase of the molecular weight for the RAFT polymerization of NIPAAm under γ‐radiation in water using TRITT at ambient temperature.