Synthesen auf der Basis von 2-Oxoglutarsäure. II Zur Synthese von Heterocyclen durch Reaktionen von 3-Brom-2-oxoglutarsäuredimethylester mit Binucleophilen

Organic Syntheses Based on 2-Oxoglutaric Acid. II. On the Synthesis of Heterocycles by Reactions of Dimethyl 3-bromo-2-oxoglutarate with Binucleophiles Reactions of dimethyl 3-bromo-2-oxoglutarate 2 with binucleophiles to form heterocycles proceed on two different pathways depending on the type of reactant. Thus, strong S-nucleophiles like thioureas and thiocarbohydrazide substitute initially the bromine atom and form 2-aminothiazoles 3 – 7 and the 1,3,4-thiadiazine 8 . However, o-phenylendiamines reacted to form the brominated quinoxaline-2(1H)-one derivatives 9 and 10 , resp.     

Reaktionen von Aroyl(Hetaroyl)iminodithiokohlesäureestern mit Carbanionen CH-acider Verbindungen

Reactions of Dimethyl N-Aroyl(Hetaroyl)carbimidodithioates with Carbanions CH-acidic Compounds Reactions of dimethyl N-aroyl(hetaroyl)carbimidodithioates 1 with carbanions 2 present new possibilities to synthesize 3-acyl-amino-3-methylthio-2-subst.-acrylnitriles 3 by monosubstitution of methylthiogroup. The reaction of 1 with 2-alkyl-benzothiazolium salts 4 yield deeply coloured N-acyl-(2,3-dihydrobenzothiazole-2-yliden) thioacetimido acid-methylates 5 of the 2-subst.-benzothiazoliumperchlorates 6 . The structures of the final products are determined by i.r.-, ¹H.-n.m.r.- and u.v.-spectra.     

Reaktion von Acetophenonmonomethyl‐ und ‐dimethylhydrazonen mit dem Vilsmeier‐Reagenz; Bildung von Pyrazol‐4‐carbiminiumsalzen: ein Beitrag zum Mechanismus

Reactions of Acetophenonmonomethyl‐ and ‐dimethylhydrazones with the Vilsmeier‐Reagent; Formation of Pyrazol‐4‐carbiminium Salts: A Contribution to the Mechanism Kira discovered the formation of ( 4e ) N,N‐Dimethyl‐N‐[1,3‐diphenylpyrazol‐4‐ylmethylen]ammonium perchlorat by the reaction from acetophenonphenylhydrazone 1e with the Vilsmeier‐Reagent 2 . On the example of the Acetophenonmonomethylhydrazone 1a we represent the mechanism of this reaction. 1a reacts with the Vilsmeier‐Reagent 2 firstly to 3a (scheme 1). 3a is formylated in the secondary step by 2 on the methyl group of the acetophenon part followed of a ring conclusion to the pyrazol 4a containing a carbiminium group in position 4 as substituent. 3a doesN′t react to 6a directly. Hydrolysis of 4a gives 5a . We found moreover, that acetophenondimethylhydrazones 8 react with 2 to 4 , too (scheme 2, eq 2). But here the proton of the methylamino group in 1 is occupied by the methyl group in 8 . Therefore, the reaction starts in this case with an attack on the methyl group of the acetophenon part followed of the ringconclusion to the intermediate 6 accompanied of the eli‐mination of the methyl group. In the last step the not isolated pyrazol 6 is formylated by 2 in 4‐position to 4 . In a secondary reaction from 8 with 2 the compounds 9 are formed (scheme 2, eq. 3). 9 are intermediates in the reaction from 8 to 4 only in a small extent.     

The STOBBE condensation. X. The cyclisation of (E)-3-methoxycarbonyl-4-(5′-methyl-2′-furyl)-but-3-enoic acid,and (E)−3-methoxycarbonyl-4-(2′-furyl)-pent-3-enoic acid,to Benzofuran Derivatives

The condensation of 5-methyl-furan-2-aldehyde and 2-furyl-methyl ketone with dimethyl succinate using either potassium t-butoxide or sodium hydride as condensing agents, gives predominantly (E)-3-methoxycarbonyl-4-(5′-methyl-2′-furyl)-but-3-enoic acid 1a and (E)-3-methoxy-carbonyl-4-(2′furyl)-pent-3-enoic acid 5 respectively. Their configurations are inferred by cyclisation with sodium acetate in acetic anhydride to the corresponding benzofuran derivatives 2,6 . Alcoholysis of (E)-3-carboxy-4-(5′-methyl-2′-furyl)-but-3-enoic anhydride 3 gives the half-ester 1c which is isomeric with the half-ester 1a . A competing side reaction also gives the self-condensation product of the succinic ester 4 .     

3-羟基-4-苯基-2-丁酮的合成

分别以(E)-1-苯基-1-丁烯-3-酮和4-苯基-2-丁酮为起始原料合成了3-羟基-4-苯基-2-丁酮。以(E)-1-苯基-1-丁烯-3-酮为起始原料,经过环氧化和还原两步反应得到产物;第1步环氧化反应,用双氧水作氧化剂,产率64%;第2步α,β-环氧酮在Pd/C催化作用下用甲酸还原,得到产物3-羟基-4-苯基-2-丁酮,产率67%;该路线总产率为43%。以4-苯基-2-丁酮为起始原料,经过烯醇硅醚中间体氧化得到产物;4-苯基-2-丁酮在六甲基二硅胺作用下与三甲基碘硅烷反应得到4-苯基-2-丁烯-2-基三甲基硅醚,产率为75%;第2步烯醇硅醚用间氯过氧苯甲酸氧化,得到产物3-羟基-4-苯基-2-丁酮,产率达71%;该路线总产率为53%。以(E)-1-苯基-1-丁烯-3-酮为起始原料的合成路线总产率略低,但操作简单,试剂价廉易得,是更为实用可行的合成路线。     

Struktur und Isomerisierung der 1,3-dipolaren Cycloaddukte von Malein- und Fumarsäure-dimethylester an Pyrazolidon-(3)-azomethinimine

Structures and Isomerisation of the 1,3-Dipolar Cycloadducts of Dimethyl Maleate and Fumarate to 3-Pyrazolidone-azomethinimines The 1,3-dipolar cycloaddition of dimethyl maleate 1b and fumarate 5b to the 3-pyrazolidone-azomethinimine 2 is a stereospecific cisoid reaction yielding the perhydropyrazolo[1,2-a] pyrazoles 3b/4b in the molar ratio of 2:1, and 6 b/7b in the molar ratio 1:1. Starting with each of the 4 stereoisomers, epimerization, catalysed by alcoholate, results in all 4 of them 3b, 4b, 6b and 7b with 7b as sterically favoured main product. During the addition reaction no epimerization is occurring. ¹H- and ¹³C-n.m.r. data are discussed.     

Sulfochlorierung von 1,2-Naphthochinondiazid-(2) mit Chlorsulfonsäure

Sulfochlorination of 1,2-Naphthoquinone-(2)-diazide by Chlorosulfonic acid . The sulfochlorination of 1,2-naphthoquinone diazide-(2) ( 1 ) by chlorosulfonic acid was investigated. The yields of the formed products (1,2-naphthoquinone diazide-(2)-4-sulfonic acid ( 4 ), 1,2-naphthoquinone diazide-(2)-5-sulfonic acid ( 5 ), 1,2-naphthoquinone diazide-(2)-4-sulfochloride ( 2 ) and 1,2-naphthoquinone diazide-(2)-5-sulfochloride ( 3 )) depend on the temperature and on the time of reaction. The highest yields of the favoured 1,2-naphthoquinone diazide-(2)-4-sulfochloride ( 2 ) are obtained at 63°C and after a reaction time of 80 minutes (50%).     

Der Substituenteneinfluß auf IR-Spektrenparameter von 4′-phenylsubstituierten (E)-Styryl-methyl-sulfonen

The Influence of Substituents on the I.R. Spectral Parameters of 4′-Phenylsubstituted (E)-Styryl-methyl-sulphones The positions and integrated intensities of the bands corresponding to characteristic vibrations of eight 4′-phenylsubstituted (E)-styryl-methyl-sulphones were determined and correlated with substituent constants. The results demonstrate a linear dependence of the wavenumbers of vSO₂ and VCC vibrations, respectively, with the electrophilic substituent constants σ. Otherwise the square roots of the integrated intensities A^1/2 (v^sso₂) and σ gave no linear correlation. The influence of the substituents on the i.r. spectral parameters is discussed and compared with π-bond orders and π-electron densities. These magnitudes reflect qualitatively the behaviour of i.r. frequencies and intensities of selected absorption bands.     

Engineering 2-oxoglutarate dehydrogenase to a 2-oxo aliphatic dehydrogenase complex by optimizing consecutive components

Multienzyme complexes have the potential for green catalysis of sequential reactions. The Escherichia coli 2-oxoglutarate dehydrogenase complex (OGDHc) was converted from a 2-oxoglutarate dehydrogenase to a 2-oxo aliphatic dehydrogenase complex by engineering consecutive components. OGDHc catalyzes succinyl-CoA synthesis in the Krebs cycle. OGDHc is composed of three components: E1o, 2-oxoglutarate dehydrogenase; E2o, dihydrolipoylsuccinyl transferase; E3, dihydrolipoyl dehydrogenase. There are three substrate checkpoints. One is in E1o and two in E2o. OGDHc was reprogrammed to accept alternative substrates by evolving the E1o and E2o components. Wt-ODGHc does not accept aliphatic substrates. E1o was previously engineered to accept a non-natural aliphatic substrate, 2-oxovalerate (2-OV). E2o also required engineering to accept 2-OV in the overall reaction. Hence, saturation mutagenesis libraries of E2o were screened for 2-OV activity. E2o-S333M, E2o-H348F, E2o-H348Q, and E2o-H348Y were identified to show activity for 2-OV in the reconstituted complex. Variants also displayed activity for larger aliphatic substrates.     

Friedel-Crafts-Acylierungen aliphatischer Verbindungen. VII. Friedel-Crafts-Acylierungen von Carbonsäurechloriden mit Maleinsäureanhydrid - ein neuartiger Zugang zu Tetronsäuren

Friedel-Crafts-Acylations of Aliphatic Compounds. VII. Friedel-Crafts-Acylations of Carboxylic Acid Chlorides with Maleic Acid Anhydride — a New Access to Tetronic Acids Reaction of succinic acid with propionyl chloride under Friedel-Crafts-reaction conditions yields 2-methyl-cyclopentan-1,3-dione. The related reaction of maleic acid anhydride with propionyl chloride does not yield 2-methyl-cyclopent-4-en-1,3-dione 7 , but a E/Z-mixture of the lactones 5 and 8 . By treating with hydrogen chloride in methanol or with thionylchloride in methanol the lactone mixture is converted to dimethyl (2Z, 4E)-3-hydroxy-2-methyl-hexa-2,4-diendioate 10 . By reaction with excessive sodium hydroxide the mixture of lactones is transformed into tetronic acid 11 . Structure determinations are based on u.v.-, i.r.-, m.s.- and n.m.r.-spectroscopy and on further chemical transformations. This tetronic acid synthesis represents an intramolecular addition of a carboxylate anion to an α, β-unsaturated carbonyl compound.     

Addition von α-Ketoenaminen an 2-Acetyl-p-benzochinon

Addition of α-Ketoenamines to 2-Acetyl-p-benzoquinone Addition of 2-morpholino-2-cyclohex-1-en-one 2 to 2-acetyl-quinone 1 yields benzo[c][4 H]chromen-4,7,10-trion 4 which is unstable and rearranges to 5. 4 is converted to 3-(2,5-dihydroxy-phenyl)-2-morpholino-2-cyclohex-1-en-on 3 thermically and to dibenzo[b,d]furan-4-on 7 acid catalyzed. The structure of 7 is secured by independent synthesis. Dibenzo[b,d]furan-4-on 14 is the product of reaction from 2-(p-toluidino)-2-cyclohex-1-en-on 9 and 1 with benzo[c][4 H]chromen-4,7,10-trion 10 as intermediate. By proton catalysis 5-acetyl-6-hydroxy-carbazol-1-on 13 and 4-oxo-cyclohexa[c]isochinolinium hydrochlorid 15 is obtained from 10 . 1 H-cyclopenta[d]furan-3-on 17 is formed by addition of 2-(p-toluidino)-2-cyclopent-1-en-on 16 to 1 . It is rearranged by proton catalysis to 3-oxo-1 H-cyclopenta[c]isochinolinium salt 18 . Reaction of cyclopentan-1,2-dione and 1 yields 3 aH-cyclopenta[c]isochromen-3,6,9-trion 20 , rearranging to 1 H-cyclopenta[b]benzo[d]furan-3-on 21 . The stereochemistry of adducts is discussed in connection with the course of the reaction, spectroscopical evidence, molecular modelling and calculation of HOMO/LUMO and AO-coefficients.     

The STOBBE condensation. XI. The cyclisation of (Z)- and (E)-3-methoxycarbonyl-2-methyl-4-(2′-naphthyl)-4-phenyl-but-3-enoic acids to the corresponding polysubstituted phenanthrene and naphthalene derivatives

(Z)- and (E)-3-methoxycarbonyl-2-methyl-4-(2′-naphthyl)-4-phenyl-but-3-enoic acids 1 a and 4 a have been converted into methyl-4-acetoxy-3-methyl-1-phenylphenanthrene-2-carboxylate 2 a and methyl 4-acetoxy-3-methyl-1-(2′-naphthyl)-2-naphthoate 5 a . The derived phenolic acids 2 b and 5 b are converted to methyl 4-methoxy-3-methyl-1-phenyl-phenanthrene-2-carboxylate 2 c and methyl 4-methoxy-3-methyl-1-(2′-naphthyl)-2-naphthoate 5 c ; which are saponified to the corresponding methoxy acids 2 d and 5 d . Alcoholysis of the anhydrides 3 and 6 gives the corresponding half-esters 1 c and 4 c , respectively.     

The STOBBE Condensation,Part IX. The cyclisation of (E)-3-Methoxycarbonyl-4-(5′-methyl-2′-thienyl)-but-3-enoic acid,and α,β-bis-(5-methyl thenylidene)-succinic anhydride,to benzothiophen derivatives

The condensation of 5-methyl-thiophen-2-aldehyde with dimethyl succinate in the presence of potassium t-butoxide or sodium hydride gave predominantly (E)-3-methoxy-carbonyl-4-(5′-methyl-2′-thienyl)-but-3-enoic acid 1a , whose configuration is proved by cyclisation with sodium acetate in acetic anhydride to the corresponding benzothiophen derivatives 2 . Alcoholysis of the derived (E)-carboxy-4-(5′-methyl-2′-thienyl)-but-3-enoic anhydride 3 gives the half-ester 1c which is isomeric with the half-ester 1a . Condensation also gave the α,β-bis-(5-methyl thenylidene)-succinic acid 4a in small amounts. The derived anhydride 5 yields on pyrolysis 4-(5′methyl-2′-thienyl)-2-methyl-benzothiophen-5,6-dicarboxylic anhydride 6 .     

Synthese von Glutaconaldehyden aus Quadratsäure-Pyridiniumbetainen

Synthesis of Glutaconaldehydes from Pyridinium Betaines of Squaric Acid The pyridinium ring of squaric acid betaines ( 2 ) is opened by hydroxide ions. Electronegative substituents (RCl, CN) at C-3 promote this reaction. The stereochemistry of the resulting 5-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)aminopenta-2,4-dienales ( 3 ) is confirmed by NMR-spectroscopy. Treatment of 3 with sodium hydroxide results in further hydrolysis to the sodium salts of glutaconaldehydes ( 5 ) and 3-amino-4-hydroxycyclobut-3-ene-1,2-dione ( 6 ). These products are also directly obtained from the nicotinic acid derivates 2 d (RCOOEt) and 2 e (RCONH₂), in the latter case cyclisation of the glutaconic acid derivate to the known 3-formylpyrid-2-one ( 10 ) is observed.     

Substitution Reactions of 2-(Aroyl,Methylidene)-thiazolidine-4-on Derivatives

The reaction of 2-(aroyl, methylidene)-3-arylthiazolidine-4-ones 1 with trifluoromethylsulfenyl chloride yields a mixture of geometric (Z, E) isomers of 2(aroyl, trifluorosulfenylmethylen)-3-aryl-thiazolidine-4-ones 2 . The bromination of 1 leads to 2-(aroyl, methylidene)-3-aryl-5-bromothiazolidine-4-ones 3 which on reaction with nitrosobenzene formes nitrones 4 . The structures of the compounds 2 – 4 were determined by means of n.m.r. and i.r. spectroscopy.     

Untersuchungen zur Hydrolysestabilität von 4-Arylmethyliden-2-pyrazolin-5-onen

Investigations on the Hydrolytic Stability of 4-Arylmethylidene-2-pyrazolin-5-ones The 4-Arylmethylidene-2-pyrazoline-5-ones S are not stable under aqueous alkaline conditions. By the substitution of R³ with electron donor substituents S reacts preferably yielding aldehyde A and 2-pyrazoline-5-one P , while with electron acceptor substituents S forms 4,4′-aryl-methylidene-bis-2-pyrazoline-5-one B . The intermediate of hydrolysis is 4-(arylhydroxymethyl)-2-pyrazoline-5-one SOH . The second order rate constants of the reaction of S with hydroxidions and with 2-pyrazoline-5-ones P ⁻ are determined. The dependence of the hydrolytic decomposition of S on the pH vaue substituents and temperature is suitable for the intermediate formation of SOH .     

Umsetzung von (Z/E)-1-Aryl-4-arylmethylen-pyrrolidin-2,3,5-trionen mit Enaminocarbonylverbindungen

Reaction of (Z/E)-1-Aryl-4-arylmethylene-pyrrolidine-2,3,5-triones with Enaminocarbonyl Compounds Treatment of the α, β-unsaturated ketones (Z/E)- 1a–e with alicyclic or aliphatic enamines afforded cyclic Michael adducts 2 and 3a–e , respectively. By dehydration of the N,O-hemiacetals 3b–d the corresponding 1,4-dihydropyridines 4a–c were obtained. The acid-catalyzed reaction of aminosubstituted maleimides with (Z/E)- 1e , aldehydes or indan-1,2,3-trione led to 5a–c , 6a–c , 7a–c and 8 . O-Methylation of the aryl-bis(maleinimidyl)methanes 5c , 6c by using diazomethane gave 5d , 6d , whereas 5a cyclized spontaneously to the 1,4-dihydropyridine 9a . Further 1,4-dihydropyridines were prepared by cyclocondensation of 6a , b in the presence of ammonium acetate and oxidized to the pyridine derivative 10 .     

Über die Katalyse der Cooxidation von cis-Oct-4-en und n-Butyraldehyd

The Catalysis of the Co-Oxidation of cis-Oct-4-ene and n-Butyric Aldehyde The co-oxidation of cis-oct-4-ene and n-butyric aldehyde in the absence of catalysts, or in the presence of molybdenum and Co(acac)₃, resp., was studied in dependence on the aldehyde/olefin ratio, on the temperature and other reaction conditions. Under the same conditions, the noncatalyzed co-oxidation converted 50%, the MoO₂(acac)₂-catalyzed one 68%, and the Co(acac)₃-catalyzed one 40% of the reacted olefin into the epoxide. The cis/trans-epoxide ratio in the molybdenum-catalyzed co-oxidation was nearly 2 independent of the aldehyde/olefin ratio. In the non-catalyzed co-oxidation the cis/trans-epoxide ratio depends linearly on the aldehyde/olefin ratio (cis/trans E. = 0,58 + 0,90 n/n). From these dependences we can conclude that the homolytic mechanism of epoxide formation decreases and the polar mechanism (Priležaev-reaction) increases with increasing aldehyde/olefin ratio. Optimization of the epoxide yields according to a Box-Hunter experimental plan gave the following reaction conditions to yield 95% epoxide based on reacted olefin: 70°C, Δn_S/n = 0,49, n/n = 3,5 · 10⁻³, n/n = 0,53. The co-oxidation in the presence of other molybdenum catalysts of the chloro-nitrosyl-complex type and of the carbonyl-complex type as well as the co-oxidation with other aldehydes were studied, too.     

(2S,4E)-5-氯-2-异丙基-4-戊烯酸乙酯的简易合成

以异戊酸乙酯与(E)-1,3-二氯丙烯为原料,通过烷基化反应得到(±)-(4E)-5-氯-2-异丙基-4-戊烯酸乙酯,经猪肝酯酶催化(进行动力学拆分)得到纯阿利克仑(Aliskiren)中间体(2S,4E)-5-氯-2-异丙基-4-戊烯酸乙酯。通过回收拆分母液以88%的收率得到(2R,4E)-5-氯-2-异丙基-4-戊烯酸。该方法绿色环保,操作简洁易行,具有工业化应用前景。     

Ringöffnung von 2-Oxocyclohexancarboxamid zu 2-Hydroximinopimelinsäure-1-amid

Ring Opening of 2-Oxocyclohexane Carboxamide to 2-Hydroximinopimelic-1-amide Reaction of 2-oxocyclohexane carboxamide ( 1 ) and sodium nitrite in 1n hydrochloric acid yields 2-hydroximinopimelic-1-amide ( 2 ). 2 and dimethylsulphate react to give compounds 3 and 4 , respectively, 2 and 1.6-diamino hexane form salt 5, 2 and cyclohexanone (resp. cyclopentanone) yield imidazoline-N-oxide 6 (and 7 , resp.) 2 and hydrazine afford pimelic hydrazide ( 8 ).