Solid-phase synthesis of 1,2,3,4-tetrahydro-2-pyridones via aza-annulation of enamines

An efficient solid-phase approach has been developed to prepare nitrogen heterocycles with a 1,2,3,4-tetrahydro-2-pyridone core via aza-annulation of enamines. Immobilized enamines were prepared from the reaction of primary amines with propynoic acid derivatives or ketones. Aza-annulation reactions were carried out by reacting resin-bound enamines with symmetrical alpha,beta-unsaturated acid anhydrides or alpha,beta-unsaturated acids in the presence of DPPA and TEA. The annulation products were isolated in good to high crude yields. Influence of sterically hindered amines as well as alpha- and beta-substituted acrylic acid derivatives on the annulation reaction was also investigated.     

Intramolecular rearrangement of α-amino acid amide derivatives of 2-aminobenzothiazoles

We have found that α-amino acid amide derivatives of 2-aminobenzothiazoles undergo a time-dependent, thermal rearrangement in which the amine group attacks the 2-position carbon of the thiazole ring to form a 5,5-spiro ring system. This is followed by sulfur leaving and air oxidation to the corresponding symmetrical disulfide. The isolated yields of such products are quite high (>70%) if there is conformational bias to further promote the intramolecular reaction such as for the 2-aminobenzothiazole amides derived from proline or 4-aminopiperidine-4-carboxylic acid. This rearrangement has not been described previously for α-amino acid amide derivatives of 2-aminobenzothiazoles. However, a related reaction involving 2-semicarbazido benzothiazoles has been recently reported.     

Synthesis and conversions of 2-substituted cinchoninic acid amides

Amides of 2-oxo- or 2-thiocinchoninic acid have been obtained by the reaction of substituted amides of 2-chlorocinchoninic acid with sodium acetate or sodium sulfide. The reaction of 2-thiocinchoninic acid amides with hydrazine hydrate or ethyl cyanoacetate leads to derivatives of 2-hydrazinocinchoninic acid or (4-carbamoyl-2-quinolyl)cyanoacetic ester respectively, which were also obtained from 2-chlorocinchoninic acid amides.Perm Pharmaceutical Academy, Perm 614600. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 697–700, May, 1997.     

Alkyl Esters of 2-[5-Chloro(bromo)-6-methoxy-4-methylpyrimidinyl-2-oxy]alkanoic Acids

The reaction of a mixture of formaldehyde and sodium cyanide or of lactic acid nitrile with trimethyl(6-methoxy-4-methylpyrimidinyl-2)ammonium chloride give the 2-(6-methoxy-4-methylpyrimidinyl-2-oxy)alkanoic acid nitriles. They were subsequently converted to the corresponding alkyl esters by a Pinner reaction and then to their 2-(5-halo-6-methoxy-4-methylpyrimidinyl-2-oxy) derivatives using N-halosuccinimides.     

Synthesis and properties of 2-(2-oxoindolin-3-ylidene)-2-cyanoacetic acid piperidides and morpholides

The reaction of isatins with cyanoacetic acid piperidide or morpholide gives the corresponding derivatives of 2-(2-oxoindolin-3-ylidene)-2-cyanoacetic acid, which may be reduced to give amides of 2-(2-oxoindolin-3-yl)-2-cyanoacetic acid and react with ethanolic alkali to give quinoline derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.12, pp. 1611–1613, December 1992.     

对称桥头二取代金刚烷衍生物的合成

以易得的1-金刚烷甲酸为原料, 合成了一系列对称桥头二取代金刚烷衍生物. 由1-金刚烷甲酸经Koch-Haaf羰基化反应得到1,3-金刚烷二甲酸(1); 化合物1经还原得到1,3-金刚烷二甲醇(2); 化合物2在HBr-ZnBr₂体系中经溴代反应得1,3-二(溴甲基)金刚烷(3); 同时经Apple-Lee反应将化合物2转化得到1,3-二(氯甲基)金刚烷(4). 采用红外光谱和核磁共振氢谱等手段表征了产物的结构, 提出了可能的反应机理, 并对合成条件进行了优化.     

Über eine neuartige Substitutionsreaktion am Chinoxalinsystem: nucleofuge Carbonamid- und Carbonester- Gruppen

The oximes or arylhydrazones of quinoxaline-2-carboxylic acid and its esters or amides substituted in position 3 by an aromatic acyl group are easily cyclized to form condensed isoxazole or pyrazole derivatives, respectively. In the reaction, the oxime oxygen or hydrazone nitrogen acts as a nucleophile; the eliminated carboxyl, carboxylic ester or carboxamide group is partly found as formic acid and CO. The reaction may proceed by an addition-elimination mechanism.     

Synthesis of isocyanates and carbodiimides

The reaction of 1,3-disubstituted ureas and 1-arylsulfonyl-3-alkylureas with phosgene permits the preparation of a number of isocyanates and sulfonyl isocyanates that had not previously been described, or that were difficult to prepare. 1,3-Disubstituted thioureas and 1-aryl-(or alkyl)sulfonyl-3-alkylthioureas give carbodiimides. Thionyl chloride and phosphorus pentachloride react with the urea derivatives in the same way as phosgene. Oxalyl chloride reacts with ureas to form parabanic acid derivatives, whereas with thiourea it gives 2-imino-1,3-thiazolidine-4,5-diones, which can isomerize to parabanic acid derivatives.     

Synthetic studies on diuretics. 5-(3,3-N,S-substituted-2-propenoyl)-2,3-dihydro-2- benzo[b]furancarboxylic acids

6,7-Dichloro-2,3-dihydro-2-benzo[b]furancarboxylic acid derivatives having a 3,3-N,S-disubstituted-2-propenoyl group at the 5-position were prepared by alkylation of 5-(thiocarbamoyl)acetyl derivatives of the 2,3-dihydro-2-benzo[b]furancarboxylic acid ester or by acetal exchange reaction of 5-[3,3-bis(alkylthio)-2-propenoyl] derivatives. Synthesis of 5-[4 and/or 5-(di)substituted-4-thiazolin-2-ylidene]acetyl-2,3- dihydro-2-benzo[b]furancarboxylic acids was also achieved by the reaction of 2-halo-1-methoxyethyl isothiocyanate with the 5-acetyl derivative in the presence of base or through sulfide contraction of 2-[[6,7-dichloro-2-methoxycarbonyl-2,3-dihydrobenzo[b]furan-5-yl) carbonyl)-methylthio]thiazolium bromide. Some of the compounds which were synthesized showed potent natriuretic activities in rats and mice. The structure-activity relationship is also discussed.     

Selective formation of either Tröger’s base or spiro Tröger’s base derivatives from [2-aminoporphyrinato(2-)]nickel by choice of reaction conditions

The article reports on the unique manipulation of the acid-catalyzed reaction of [2-aminoporphyrinato(2-)]nickel with formaldehyde to form selectively either the symmetric Tröger’s base or the asymmetric spiro Tröger’s base bis(metalloporphyrin) derivative. The reaction is driven by the choice of acid catalyst, formaldehyde source, and particularly, solvent, to give a mixture of both derivatives in preparative yields of about 90%, or to give selectively one of the derivatives in a yield of about 60%.     

Synthesis, and analgesic and antiparkinsonian activities of thiopyrimidine, pyrane, pyrazoline, and thiazolopyrimidine derivatives from 2-chloro-6-ethoxy-4-acetylpyridine

A series of substituted pyridine derivatives were prepared from 2-chloro-6-ethoxy-4-acetylpyridine, which was prepared from the corresponding citrazinic acid as starting material. Reaction of acetylpyridine with thiophene-2-carboxaldehyde afforded the 2-chloro-6-ethoxy-4-β-(2-thienyl)acryloylpyridine, which was reacted with malononitrile in refluxing ethanol in the presence of piperidine as a catalyst to afford the cyanoaminopyrane derivative. Acryloylpyridine was treated with urea or guanidine hydrochloride in refluxing ethanolic potassium hydroxide to give the corresponding pyrimidinone and aminopyrimidine derivatives. The latter was condensed with hydrazine hydrate or phenyl hydrazine to give pyrazoline and N-phenylpyrazoline derivatives. Finally, cycloaddition reaction of acryloylpyridine with thiourea yielded thioxopyrimidine, which was treated with 2-bromopropionic acid, 3-bromopropionic acid, or bromoacetic acid to yield methylthiazolo-, thiazino-, and thiazolopyrimidine derivatives. The arylmethylene derivative was prepared by reacting thiazolopyrimidine with benzaldehyde or by reacting thioxopyrimidine with benzaldehyde and bromoacetic acid in one step. The pharmacological screening showed that many of these compounds have good analgesic and antiparkinsonian activities comparable to Valdecoxib^® and Benzatropine^® as reference drugs.     

Design and synthesis of two triazonine-carbaldehyde derivatives using several chemical tools

Several triazonine-carbaldehyde derivatives have been prepared using different protocols; however, some require special reagents and conditions. The aim of study involved the synthesis of two triazonine-carbaldehyde derivative using testosterone or OTBS-testosterone as chemical tool. Triazonine-carbaldehyde derivatives were prepared by a series of reactions that involve the following: (1) synthesis of two nitrobenzamide derivatives by reaction of testosterone or OTBS-testosterone with p-nitrobenzoyl azide using Copper(II) as catalyst; (2) reaction of the nitrobenzamides with ethylenediamine to form two triazonine derivatives using boric acid as catalyst; (3) preparation of hexynyl-triazonine derivatives by the reaction of two triazonines 6-chlorohex-1-yne in basic medium; (4) reaction of hexynyl-triazonine derivatives with benzaldehyde to form two triazoninol analogs; (5) preparation of triazoninynal derivatives through oxidation of triazoninol analogs with dimethyl sulfoxide; and (6) synthesis of triazonine-carbaldehyde derivatives by the reaction of triazoninynal derivatives with hexyne-1 using Copper(II) as catalyst. The chemical structure of compounds was determined by spectroscopic and spectrometric methods. In conclusion, in this work were prepared two triazoninone derivatives using several chemical techniques, which are simple procedures and easy to handle.     

Novel isocyanide-based four-component reaction: a facile synthesis of fully substituted 3,4-dihydrocoumarin derivatives

A novel isocyanide-based four-component reaction between a 2-hydroxybenzaldehyde, Meldrum's acid, an isocyanide, and an aromatic or an aliphatic alcohol efficiently provide 3,4-dihydrocoumarin derivatives in good to excellent yields without using any catalyst or activation. The reaction can be carried out as a simple one-pot protocol at room temperature.     

Efficient, one-pot transformation of indoles into functionalized oxindole and spirooxindole systems under Swern conditions

The reaction of indole derivatives bearing a 3- or 4-hydroxyalkyl chain with dimethylsulfoxide and oxalyl chloride under Swern conditions led to a one-pot, three-component process involving three different synthetic transformations, namely oxidation of indole to oxindole, introduction of a chlorine substituent at the oxindole C-3 position and substitution of the hydroxyl group in the side chain by chlorine, in good to excellent overall yields. The same conditions, applied to a 2-methylindole, afforded a 2-formylindole derivative oxidized at its side chain. The reaction starting from one indole with a 2-hydroxyalkyl chain furnished 3-(2-hydroxyalkyl)oxindoles. Finally, application of the Swern conditions to derivatives of indole-3-propionic or -butyric acid afforded 3-spirooxindole lactones.     

Facile Synthesis of Nicotinic Acid Derivatives with Unsymmetrical Substitution Patterns

Abstract

Two novel methods for synthesis of nicotinic acid derivatives with unsymmetrical substitution patterns were presented via ketene dithioacetals. The ketene N,S-acetals 2 reacted with β-ketoesters or β-cyanoesters to give 4-amino-5-cyano-2-alkyl-6-methylthio-nicotinic acid derivatives 3 or 2,4-diamino-5-cyano-6-methylthio-nicotinic acid ethyl ester 4. However, 6-amino-5-cyano-2-alkyl-4-methylthio-nicotinic acid esters 6 were obtained by the reaction of the ketene dithioacetals 1 and β-amino-crotonates.     

Synthesis of Some Pyrimidine 2-Oxo(Thio)-4,6-Dione Derivatives

5-Arylidenes 1a and 1b, on reaction with ethyl cyanoacetate and diethyl malonate in the presence of ammonium acetate under Michael condensation, yield pyridine derivatives 2 and 3, respectively. Cyclopentapyrimidine derivative 4 can also be obtained by the reaction of 1a with malononitrile in the presence of piperidine. The reaction of 5-arylidene lb with monochloroacetic acid in an alkaline medium gives the thiazol derivative 5. Also, spiro-[3′, 5′]cyclohexenyl pyrimidine derivative 6 could be obtained from the reaction of 1d with maleic anhydride. On the other hand, 5-arylidene 1e reacts with maleic anhydride to give 2-thiobarbituric acid derivative 7. The condensation reaction of 2-thiovioluric acid 8 with some hydrazines affords the triazole derivatives 9a-d. Finally, barbituric acid condenses with isatin to give 5-arylidene 1f, which can be cyclized with phosphorous pentoxide to afford 10.     

Carbohydrate Phosphorylation with Diphenylphosphorochloridate

In connection with the synthesis directed toward 25-hydroxycholesterol,^1/ and other cholestane derivatives hydroxylated in the side chain, the research was undertaken in order to find the most effective method for the preparation of pregn-17/20/-en-21-oic acid derivatives.^2/ In the present communication we would like to report the observation that contrary to the literature data, such pregnenoic acid derivatives can be conveniently obtained in very good yields by the Wittig-Horner reaction of 17-ketoandrostane derivatives and estrone with trialkyl phosphonoacetates when alcohols or DME are used as the reaction medium. In the previous reports the following statements have been made: 1/ the Wittig-Horner reaction of steroidal 17-ketones with trialkyl phosphonoacetates is compleetely inhibited as a result of the steric shielding of the carbonyl group^3a, 2/ this reaction gives very low yields^3b/, 3/ in the case of 17-ketoanderostane derivatives this reaction requires drastic conditions and is completely inhibited in the case of estrone/irrespective of conditions/^3c/.     

The Ugi reaction with 2-substituted cyclic imines. Synthesis of substituted proline and homoproline derivatives

The Ugi three-component reaction with 2-substituted five-, six-, and seven-membered cyclic imines was investigated. The reaction opens a new route to substituted proline and homoproline derivatives. It was shown that the method is efficient for the one-step preparation of seminatural dipeptides containing natural amino acid residues, and fragments of substituted proline or pipecolinic acid. The scope and limitation of the approach are discussed.     

Lewis acid catalyzed cascade reactions of diarylvinylidenecyclopropanes and 1,1,3-triarylprop-2-yn-1-ols or their methyl ethers

The reactions of vinylidenecyclopropanes 1 with 1,1,3-triarylprop-2-yn-1-ols or their methyl ethers 2 in the presence of a Lewis acid selectively produce 4-dihydro-1H-cyclopenta[b]naphthalene derivatives 3 or 1,2,3,8-tetrahydrocyclopenta[a]indene derivatives 4 depending on the substituents on the cyclopropane. Good to high yields are obtained under mild conditions. A plausible cascade Meyer-Schuster rearrangement and Friedel-Crafts reaction mechanism has been proposed. Moreover, novel functionalized methylenecyclobutene derivatives 5 could also be obtained in moderate to good yields under similar conditions when strongly electron-donating methoxy groups were introduced into the benzene rings of 2.     

Derivatives of orotic acid and its analogs

The synthesis of oxo derivatives of pyrrolo[3, 4-d]pyrimidine has been effected by the reaction of the lactone of 5-(hydroxymethyl)-orotic acid with ammonia or primary amines. In a number of cases, in place of the free organic bases their salts with mineral acids were used successfully. A number of 2, 4, 7-trioxo derivatives of pyrrolo[3, 4-d]pyrimidine and some new derivatives of orotic acid have been synthesized.