Zur Synthese von Octahydrochinazolinonen und deren Reaktion mit Persäure

The Synthesis of Octahydroquinazolinones and their Reaction with Peracid By reaction of cyclohexanone-2-carboxamide with ammonia and aldehydes, octahydroquinazolinones 2a–f , and with Schiff bases octahydroquinazolinones 3a–c are formed. 2-Hydroxycyclohexanone-2-carboxamide forms with ammonia and butyraldehyde the hydroxyocta-hydroquinazolinone 4 . Compound 2e reacts with monoperoxiphthalic acid to the hydroxyoxaziridine 5e which reacts with alkali hydroxide to compound 6. 8 yields with peroxy acid the hydroperoxy epoxide 9 .     

Die Nitril-Carboxamid-Umlagerung

The Nitrile Carboxamide Rearrangement By reaction of cyclohexanone-2-carboxamide ( 4 ) with cyan amide 1-cyano-cyclohex-1-en-2-yl-urea ( 6 ) is formed via nitrile carboxamide rearrangement. Whilst compound 6 with 1,2-diaminobenzene hydrochloride forms 11-amino-1 H-2,3,4,5-tetrahydrodibenzo[b,e][1,4]diazepin hydrochloride ( 8 and 8a ), compound 6 and 1,2-diaminobenzene form hexahydro-benzimidazo[1,2-c]-quinazolin-6-one ( 12 ). Compound 8 with sodium hydroxide yields 11-amino-1 H-2,3,4,11a-tetrahydrodibenzo[b,e]-[1,4]diazepin ( 9 ). Compound 6 reacts with cyclohexylamine to form N-(1-cyanocyclohex-1-en-2-yl)-N′-cyclohexyl urea ( 10 ). Compound 10 with 1,4- or 1,2-diaminobenzene hydrochloride yields compound 7 and 8 . In alkaline solution 10 cyclises to 4-amino-3-cyclohexyl-2,3,5,6,7,8-hexahydroquinazolin-2-one ( 11 ). Compound 4 and malonitrile form either 3-amino-4-cyano-1,2,5,6,7,8-hexahydro-isoquinol-1-one ( 13 ) or 1-amino-4-cyano-2,3,5,6,7,8-hexahydro-isoquinol-3-one ( 14 ). Compound 13 and alkaline formaldehyde react to cyanooctahydroisoquinoline-[2,3-c] [1,3,5]oxdiazin-6-one ( 17 ). 2-Cyanoethyl-cyclohexan-one-2-carboxamide ( 22 ), prepared by Michael-reaction from 4 and acrylonitrile, forms via nitrile carboxamide rearrangement 10-cyano-1,2,3,4,5,6,7,10-octahydroquinolin-2-one ( 24 ) and 2-(1′-cyano-cyclohexyl-2′-one)-propionic acid ( 25 ). Nucleophilic attack of the NH₂-group at the cyanogroup of compound 22 forms 5-(spirocyclohexan-2′-one)-hexahydropyridin-2,6-dione ( 27 ).     

Über die Synthese von Pyrimidindionen-(2,4) aus Ketonen und Harnstoff

The Synthesis of Pyrimidine-2,4-diones from Ketones and Urea By reaction of urea with 2-alkylcyclohexanones or with 2-alkylcyclohexanonecarboxamides 8-alkyl-5,6,7,8-tetrahydrobenzo-[1,2-d]pyrimidine(1H,3H)-2,4-diones ( 5a–i ) are formed. Cyclohexanone or cyclohexanone-2-carboxamide with urea form 5,6,7,8-tetrahydro-benzo-[1,2-d]pyrimidine(1H,3H)-2,4-dione ( 3 ). Menthone, 2,6-dimethylcyclohexanone, 3,5-diphenylcyclohexanone, cyclooctanone and cyclododecanone with urea yield pyrimidinediones 9, 10, 11, 12a and 12b .     

Zur Bromierung des Cyclohexanon-2-carbonsäureamids

The Bromination of Cyclohexanone-2-carboxamide Cyclohexanone-2-carboxamide with bromine forms 6-bromo-cyclohexanone-2-carboxamide ( 2 ) or 2-bromo-cyclohexanone-2-carboxamide ( 3 ). Via Faworski-rearrangement the reaction of 2 and ammonia or amines gives trans-cyclopentanedicarboxamides ( 5a – f ). 3 and thiourea form the aminothiazole derivative 6 . Pyridinium salt 7 is formed by reaction of 2 and pyridine. 7 and phenylhydrazine form the phenyl-indazolonoyl-hydrazine 8. 1 and sodiumhypochlorite yield 2-hydroxy-cyclohexanone-2-carboxamide ( 9 ).     

Synthese von 6-(pyrid-4-yl)-substituierten Pyrido[: 3-d]pyrimidinen und 1,8-Naphthyridinen

Synthesis of 6-(4-pyridinyI)-substituted Pyrido[2,3-d]pyrimidines and 1,8-Naphthyridinms A series of new 6-(4-pyridinyl)-substituted pyrido-[2,3-d]pyrimidines 2 – 4 and 1,8-naphthyridines 6 , respectively, is described. Cyclisation of 2-amino-5-(4-pyridinyl)-pyridinm-3-carboxamide 1a with diethyl oxalate gives the pyrido-[2,3-d]pyrimidinm 2a . Alkylation of( 2a ) yields the 3-ethylaminoxyrido[2,3-d]pyrimidine derivative 2b . Saponification of 2a , b gives the corresponding carboxylic acids 3a , b , which are decarboxylated by heating above the melting point to give 4a , b . The 2-amino-5-(4-pyridinyl)-pyridinm carboxylic acid derivatives 1 b – e react with ethylmalonylchloridm and diethyl malonate to afford the 1,8-naphthyridines 6b – e . The 1-oxide 7 in a similar reaction gives 8 and the oxdiazole( 9 ) which is converted by ring transformation to the 1,8-naphthyridine 10 .     

Synthese und Reaktionsverhalten von N-(3-Chlorbenzo[b]-thiophen-2-carbonyl)imino-Dithiokohlensäure-Derivaten

Synthesis and Reaction Behaviour of N-(3-Chlorobenzo[b]thiophene-2-carbonyl)-imino-dithiocarbonic Derivatives 3-Chlorobenzo[b]thiophene-2-carbonyl-chloride 1 was treated with potassium rhodanide to afford the appropriate acyl isothiocyanate 3 , which adds nucleophilic agents as amines and thioles in good yields. Addition of methanethiole and subsequent alkylation of the dithiocarbamate 7 gives S, S-dimethylimino-dithiocarbonate 8 . 3-Chlorobenzo[b]thiophene-2-carboxamide 2 reacts with carbon disulphide and phenyl isothiocyanate by chlorine substitution and cyclisation to benzo[b]thieno[2, 3-e]thiazines 9, 10 or 11 . The structure of the final products were determined by analytical and spectroscopical dates.     

Reactions with the Arylhydrazones of some α-cyanoketones

Ethereal diazomethane reacts with the arylhydrazones of mesoxalic acid dinitrile 1a–c and of ethyl α-cyanoglyoxalate 2b, d–g to yield the methylarylhydrazones 3a–c and 4a–e respectively. Treatment of 4b–e with phenylmagnesium bromide results in the formation of the imino derivatives 5a–d . Whereas 2a–g react with phenylhydrazine to yield the aminopyrazoles 8a–g , the hydrazides 10a, b are formed on treatment of 4c, e with hydrazine hydrate. 1a–c react with hydrazine hydrate and with phenylhydrazine to yield 3-amino-4-arylhydrazono-5-imino-2-pyrazoline derivatives 11a–f 11a, b react with acrylonitrile to yield 3-amino-1(β-cyanoethyl)-4-arylhydrazono-5-imino-2-pyrazoline derivatives 12a, b which can be readily cyclised to the pyrazolo[3,2-b]pyrimidine derivatives 13a, b by the action of hot acetic acid.     

α-substituierte Phosphonate. 47. P?C-Spaltungen bei geminalen Trisphosphorylverbindungen

α-Substituted Phosphonates. 47. Splitting of P C-Bonds from Trisphosphoryl Compounds Hexaethyldimethylaminomethyl-trisphosphonate ( 2a ) reacts with HCl or trimethylsilylbromid/water by splitting off one phosphoryl group, giving dimethylaminomethyl-bisphosphonic acid ( 7 ). The result of methylation of 2a depends on the reagent: with methyliodide one phosphoryl group is split off, and the ammonium salt 11a is formed, while with methyl toluene sulfonate or dimethylsulfate the expected quarternary ammonium salts 10b or 10c are formed. One phosphoryl group of 10c is split off under acidic as well as alkalinous conditions: acidic hydrolysis gives the bisphosphonic acid 15 , while under alkalinous conditions the known ylid 16 is formed.     

Umsetzungen substituierter 1-Thiochromone und 4(1H)-Chinolone mit Nucleophilen

Reactions of Substituted 1-Thiochromones and 4(1H)-Quinolones with Nucleophiles 1-Thiochromone 1a and 4(1H)-quinolone 1b react with nucleophiles to substitute the methylthio group. Compounds of type 1 are suitable C₃-fragments for the synthesis of novel heterocycles. Hydroxylamine leads to 2-amino-1-thiochromone-3-carboxamide 7 , whereas 1c gives 2-methylthio-1-thiochromone-oxime 8 .     

Front Cover: Structure-Based Design,Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors (ChemMedChem 7/2020)

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole-based hydroxamate 2 b (N-hydroxy-1-phenyl-1H-1,2,3-triazole-4-carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b /smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2 b led to the discovery of 4-fluorophenoxy derivative 21 (1-[5-chloro-2-(4-fluorophenoxy)phenyl]-N-hydroxy-1H-1,2,3-triazole-4-carboxamide), a nanomolar smHDAC8 inhibitor (IC₅₀=0.5 μM), exceeding the smHDAC8 inhibitory activity of 2 b and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole-based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis.     

Orthoamide. LI. Push-Pull-Butadiene und Heterocyclen aus CH2-aciden Verbindungen und Orthoamiden von Alkincarbonsäuren

Orthoamides. LI. Push-Pull-Butadienes and Heterocycles from Alkyne Carboxylic Acid Orthoamides and CH₂-acidic Compounds The acetylides 4b, 4f react with N,N,N′,N′,N″,N″-hexamethylguanidiniumchloride ( 5 ) to give the orthoamides 6b, 6f , resp. From CH₂-acidic compounds and the orthoamides 6a, c, e can be obtained the push-pull-substituted butadienes 8a–8aj . The 2,3,5-trimethyl-thiadiazolium salt 9 does not condense with 6e , as other CH₂-acidic compounds do, instead the vinylogous guanidinium salt 10a is produced. On heating, the ketenaminals 8d, aa cyclize to give the pyridone-carbonitriles 11a, b , resp. From 4-amino-coumarins 12 and the orthocarboxylic acid amideacetals 13a, b and the ketenaminal 16 resp., the amidines 14a–c and the heterocyclic compounds 15a–c resp., are formed. The enamines 17a–c, 19a, b react with the orthoamides 6a–f to give the pyridine derivatives 18a–1, 20a–h and 21a, b , resp. Analogously, from 6-aminouracil 22 and 6a, b, e, f are formed the pure 7-dimethylaminopyrido[2,3-d] pyrimidines 23a, b or mixtures of compounds 23c, d and the isomeric 4-dimethylamino-pyrido[2,3-d]pyrimidines 24a, b resp., which can be separated via their salts 25a,b/26a,b . The heterocyclic compounds 30a–d, 32a,b can be prepared from the pyrazole derivatives 28, 31 resp. and the orthoamides 6a–f .     

Photochemische Reaktionen von Pyrazolidon-(3)-betainen. V. Photooxydation heteroaromatischer N-Ylide

Photochemical Reactions of 3-Pyrazolidone Betains. V. Photooxidation of Heteroaromatic N-Ylids The dye-sensitized photooxidation of the heteroaromatic N-ylids 3a and 3b yields 1-isoquinolone 8 together with ethyl mesoxalate 13 and bis(benzoyl-isoquinol-1-on-2-yl-methyl)ether 10 , respectively. These are decomposition products of fivemembered ring peroxides, formed by reaction of singlet oxygen with the N-ylids. One mole of the ylids 3c, 4 and 5 gives complete conversion with 0.5 moles of singlet oxygen, yielding the corresponding heteroaromatic and mesoxalic acid derivatives, respectively. The products and the oxygen consumption are discussed to be due to reaction of one molecule of the ylid with one molecule of alkylhydroperoxide 18 , formed as a primary product. N-Ylids 3c, 4 and 5 react in the same manner with hydrogen hydroperoxide or perbenzoic acid to the corresponding heteroaromatic and mesoxalic acid derivatives. For the reaction between 3c and substituted perbenzoic acids the HAMMETT correlation gives ϱ = +0.94.     

3,4-Dihydro-benz[1,3]oxazine Derivatives from 2-Acyl(or aroyl)-cyanatobenzenes

3,4-Dihydro-2H-benz[1,3]oxazin-2-ones 3 are obtained from 2-acyl(or aroyl)-cyanatobenzenes 2 and anisole. The reaction proceeds under Friedel-Crafts conditions via DIMROTH rearrangement. Compounds 2 , dissolved in diethyl ether, react with 1 in the presence of finely powdered KOH at ambient temperature leading to 8 . The structure of 8b is confirmed by X-ray structure analysis. (Z)-4-Ethylidene - 3,4 - dihydro -2H-benz[1,3] oxazin-2-one 9 is formed upon treatment of 2-cyanatopropiophenone 2b with diluted hydrochloric acid. The ethylene derivative 5 is obtained from 4 upon reaction with cyanogen bromide/triethyl amine.     

Folgeprodukte halogenierter Aldehyde. XVI [1]. Untersuchungen über Chloralammoniak

Derivatives of Halogenated Aldehydes. XVI. Investigations of Chloralammonia N-(1,2,2,2-Tetrachloroethyl)trichloroacetaldimine 8 is formed by heating of chloral-ammonia 2 with thionyl chloride. The reaction of 2 with phosphorus pentachloride in ether leads to a mixture of aldimine 8 , 1,2,2,2-tetrachloroethyl-phosphorodichloridate 5 , N-(1,2,2,2-tetrachloroethyl)-phosphorimidic acid trichloride 6 and N-(1,2,2,2-tetrachloroethyl)-phosphoramidic acid dichloride 7 . From compound 7 , the phosphoramidic acid ester 9 , the substituted phosphoric acid triamide 10 and the N-dichlorophosphoryl trichloroacetaldimine 11 are obtained on treatment with methanol, isopropyl amine or triethyl amine, respectively. Compound 9 is also formed from 6 by reaction with methanol. The data of i. r. spectra are concordant with the assigned structures of the compounds 6–11 .     

Synthesis of Bitopic Ligands as Potent Dopamine D2 Receptor Agonists

In this study, we designed and synthesized twelve bitopic ligands as dopamine D₂ receptor (D₂R) agonists. The forskolin-induced cAMP accumulation assay revealed that all the finial compounds are able to activate D₂R. Furthermore, bitopic ligand N-((trans)-4-(((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclo-hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide ( 11 b ) showed 21-fold higher potency than lead compound propyl aminoindane ( 2 ) and 17-fold higher subtype selectivity for D₂R over D₄R, indicating that the optimal length of spacer affects the D₂R functionality. Molecular modeling study exhibited that 11 b formed an electrostatic interaction and two H-bonds with amino acid Asp114, which contributes significantly to the D₂R functional activity. Taken together, we discovered a bitopic ligand 11 b as potent D₂R agonist, which may be used as a tool compound for further study.     

The Reaction of Syringol with Chlorine Dioxide

Syringol 2 (R=H) reacted with chlorine dioxide to give the dione 7 and its benzilic acid rearrangement product 8a as the major products. Other products were the dimethoxybenzoquinones 3a and 3b, 3-chlorosyringol 4b, chlorocyclopropenone 5, 2-furoic acid 6a and the dichioromethylenefuranones 10a and 10b. Two samples of effluent from chlorine dioxide bleaching contained the dione 7, while one sample contained the furanone 10a, and one contained the isomer 10b.     

Strukturvariationen durch Reaktionen der Thiocarbonylgruppe

Structural Variations by Reactions of the Thiocarbonyl Group The 2,3‐dihydrothiazol‐2‐thiones 1a—c have been methylated to the 2‐methylsulfanylthiazolium iodides 2a—c , which could be reacted with double activated CH‐acidic compounds like 4‐nitrophenylacetonitrile ( 3 ) to yield 5 and 6a,b , with malonic acid derivatives 7a—c to yield the push pull substituted ketene‐S,N‐acetales 8a—c or with 3‐aminorhoda‐nine derivatives to yield 12a,b . Vinylogous CH‐acidic compounds like 9a—d reacted with 2b to the push‐pull substituted butadienes 10a—d . With p‐phenethidine 2b formed depending on the reaction conditions either the rare structure of an ortho‐dithiocarbonic diester diamide ( 14 ) or the isothiourea 15 . With hydrazino compounds, 16a—c with hydrazono partial structure resulted. Efforts to acylate the unsubstituted nitrogen of 17 with carbonic acid ester derivatives always yielded the S‐acylated products 18 and 20a,b .     

不同构型的2’-O,4’-C-亚甲基桥双环核苷（锁核酸单体）的合成

分别以L-核糖(3a)和D-核糖(3b)为原料,经过甲磺酰基化、脱异丙叉保护基、乙酰基化得到L-五呋喃糖衍生物(4a)和D-五呋喃糖衍生物(4b),然后分别与3-羟基吡嗪-2-酰胺进行Vorbruggen偶合,再经过闭环、脱甲磺酰基、脱苄基等合成了两种不同构型的锁核酸单体1-羟甲基-3[4-(3-氧代吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(2a,2b),总收率分别高达24.6%,31.5%。对闭环、脱除甲磺酰基以及脱除苄基等步骤的反应条件进行了优化,收率分别达到83.5%,62.5%,86.9%。目标产物的结构经过红外光谱、核磁共振氢谱、质谱、元素分析等进行确证。     

不同构型的2’-O,4’-C-亚甲基桥双环核苷（锁核酸单体）的合成

分别以L-核糖(Ⅲa)和D-核糖(Ⅲb)为原料,经过甲磺酰基化、脱异丙叉保护基、乙酰基化得到L-五呋喃糖衍生物(Ⅳa)和D-五呋喃糖衍生物(Ⅳb),然后分别与3-羟基吡嗪-2-酰胺进行Vorbruggen偶合,再经过闭环、脱甲磺酰基、脱苄基等合成了两种不同构型的锁核酸单体1-羟甲基-3[4-(3-氧代吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(Ⅱa,Ⅱb),总收率分别高达24.6%,31.5%。对闭环、脱除甲磺酰基以及脱除苄基等步骤的反应条件进行了优化,收率分别达到83.5%,62.5%,86.9%。目标产物的结构经过红外光谱、核磁共振氢谱、质谱、元素分析进行确证。     

Lewis acid induced additions to unsaturated fatty compounds IV: Synthesis of cyclopentenones from Friedel- Crafts acylation products of unsaturated fatty compounds with α,β-unsaturated acyl chlorides

The ethylaluminium dichloride induced Friedel- Crafts acylation of unsaturated fatty compounds such as oleic acid ( 1a ), methyl oleate ( 1b ) and 10-undecenoic acid ( 9b ) and furthermore of 1-octene ( 9a ) with α,β-unsaturated acyl chlorides e.g. crotonic acid chloride ( 2a ) and acrylic acid chloride ( 2b ) gave the corresponding allyl vinyl ketones. Nazarov cyclizations of the acylation products 3a/4a, 3b/4b, 10a and 10b afforded the alkyl substituted 2-cyclopentenones 5a/6a, 5b/6b, 11a/12a and 11b/12b . Catalytic hydrogenation of 5b/6b and 11b/12b gave the respective saturated cyclic products 7b/8b and 13b/14b as diastereomeric mixtures.