Facile Synthesis of Diethyl Azodicarboxylate and Diethylhydrazodicarboxylate via the Sequential Bromination and Hofmann-Type Rearrangement of Ethyl Allophanate

Diethyl azodicarboxylate (DEAD) is a well-known coupling reagent that can be readily synthesized from diethylhydrazodicarboxylate (DEHD). The bromination of commercially available ethyl allophanate (1) in CHCl₃, followed by the Hofmann-type rearrangement reaction of the resulting N-brominated species 2 and 3 in C₂H₅OH in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), gave DEHD in good yield from a one-pot process. Interestingly, however, the bromination and Hofmann-type rearrangement reactions did not occur in the presence of N(C₂H₅)₃. These results therefore suggest that this reaction is reliant upon a high level of reactivity during the bromination reaction to give 2 and 3, and that these N-brominated species require the presence of a strong and nonnucleophilic base to undergo the Hofmann-type rearrangement to give DEHD.     

5-甲基-[(2E,6E)-3,7,11-三甲基-9-氧代十二碳二烯]苯醌和氢醌的首次全合成

以2-甲基对苯二酚和香叶基溴为起始原料, 经过酚羟基保护, 溴代, Li₂CuCl₄催化的芳基溴与Grignard试剂的偶联以及Julia偶联等一系列反应, 完成了裸鳃亚动物的代谢产物, 5-甲基-[(2E,6E)-3,7,11-三甲基-9-氧代十二碳二烯]苯醌(1)和氢醌(2)的首次全合成, 将1用NaBH₄还原, 得到(±)-3, (±)-3也是此类天然产物之一.     

二茂铁四唑和二茂铁甲醛缩3-取代丙二醇衍生物的合成

以甲酰基二茂铁6为原料, 通过与NH₄OH•HCl的缩合反应得到二茂铁肟7, 再经脱水剂脱水得到二茂铁腈8, 最后在(n-C₄H₉)₃SnCl的作用下与NaN₃反应生成新化合物二茂铁四唑(9). 以甲酰基二茂铁为原料, 在对甲苯磺酸(PTSA)的催化作用下与原甲酸三甲酯反应生成二甲基二茂铁缩醛(10), 然后与(R)-(－)-3-氯-1,2-丙二醇反应得到新的二茂铁缩醛衍生物12, 12再与NaN₃发生取代反应得到新的二茂铁缩醛衍生物13. 而新的二茂铁缩醛衍生物15的合成则是先由(R)-(－)-3-氯-1,2-丙二醇与CH₃OH在NaOH的作用下生成(R)-(－)-1-甲氧基-2,3-丙二醇(14), 再由14与二甲基二茂铁缩醛(10)反应得到的. 所合成的新化合物都用MS, ¹H NMR和IR谱确证了它们的结构.     

Synthesen von Heterocyclen, 133. Mitt.: Zur Chlorierung von 4-Hydroxy-2-pyridonen

Zusammenfassung Die Chlorierung des 5-Äthoxycarbonyl-4-hydroxy-6-methyl-2-pyridons (1) mit SO₂Cl₂ gibt bei unterschiedlichen Reaktionsbedingungen die chlorierten Derivate2,3 bzw.4. Bei der Reaktion des 4-Hydroxy-6-phenyl-2-pyridons (5) mit SO₂Cl₂ erhält man das 3,3,5-Trichlor-pyridin-2,4-dion (6), das mittels Zn/Eisessig zum Dichlorderivat7 reduziert wird. Durch Hydrolyse von6 und Decarboxylierung entsteht das Enaminketon8.

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Syntheses of heterocycles, CXXXIII: Concerning the chlorination of 4-hydroxy-2-pyridones

Chlorination of ethyl 4-hydroxy-6-methyl-2-pyridone-5-carboxylate (1) with SO₂Cl₂ gives, depending on the reaction conditions, the chlorinated derivatives2,3 and4. The reaction of 4-hydroxy-6-phenyl-2-pyridone5 with SO₂Cl₂ yields 3,3,5-trichloro-pyridin-2,4-dione (6), which can be reduced with Zn/AcOH to give 3,5-dichloro-4-hydroxy-2-pyridone (7). Hydrolysis of6 and decarboxylation leads to the enaminoketone8.

     

Pictet-Spengler reactions of Tryptamine and tryptophan with cycloalkanones and ketonicMannich bases

APictet-Spengler reaction of Tryptamine (1) with cyclopentanone under physiological conditions gave 3-(cyclopentylideneaminoethyl)indole (3), which was cyclized to the 1-spirocyclic 1,2,3,4-tetrahydro-2-carboline (4). Treatment of (±)-tryptophan with cyclopentanone and cyclohexanone in acidic medium afforded the spirocyclic systems5 and6, respectively. ThePictet-Spengler reaction was extended further using ketonic bis-Mannich bases, to give compounds7 and8. The possibility of using other types of ketonic bases was investigated.

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DiePictet-Spengler-Reaktion von Tryptamin and Tryptophan mit Cycloalkanonen und Keto-Mannich-Basen

Zusammenfassung DiePictet-Spengler-Reaktion von Tryptamin (1) mit Cyclopentanonen ergab unter physiologischen Bedingungen 30(Cyclopentylidenaminoethyl)indole (3), die zu den spirocyclischen Tetrahydro-2-carbolinen4 cyclisiert wurden. Die Behandlung von (±)-Tryptophan mit Cyclopentanon oder Cyclohexanon in saurem Milieu ergab die spirocyclischen Systeme5 oder6. DiePictet-Spengler-Reaktion wurde auch auf Keto-Bis-Mannich-Basen zur Synthese der Verbindungstypen7 und8 ausgeweitet. Die Möglichkeiten zur Nutzung anderer Keto-Basen wurde untersucht.

     

Reactions of 1,1-diaryl-2-isopropylidene-3-methylenecyclopropanes with C,N-diarylnitrones and nitrile oxides

The reactions of unactivated bis(methylene)cyclopropanes with nitrones and nitrile oxides have been investigated. The 1,1-diaryl-2-isopropylidene-3-methylenecyclopropanes react with the C,N-diarylnitrones to give a mixture of 2,2-dimethyl-1,6-diaryl-3-(diarylmethylene)piperidin-4-ones and 5-methyl-1-aryl-1-(arylamino)-4-(diarylmethylene)hex-5-en-3-ones. 2,3-Dihydro-3-methylenepyridin-4(1H)-ones are obtained by reaction of 1,1-diaryl-2-isopropylidene-3-methylenecyclopropanes with nitrile oxides.     

A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction

In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an S_N2-type nucleophilic substitution. First, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a reduction reaction of this compound using NaBH₄. Finally, 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the target compounds, were synthesized from the reaction of this compound (4), which is a secondary alcohol with various alkyl halides (5a-n) in the presence of sodium hydride (NaH). This study presents an interesting reaction mechanism related to the synthesis of aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in the literature.     

Synthesis of 2([Methyl-5-[(E)-2-aryl-1-ethenyl]-4-isoxazolyl]imino)-1,3-thiazolan-4-ones and Their Mannich Bases

Isoxazolyl chloroacetamides (2) were obtained from 4-amino-3-methyl-5-styrylisoxazoles (1) on reaction with chloroacetyl chloride. Cyclocondensation of 2 with NH₄SCN yielded 2([-methyl-5-(E)-2-aryl-1-ethenyl]-4-isoxazolylimino)-1,3-thiazolan-4-ones(3). Mannich reaction of 3 with formaldehyde and secondary amines gave isoxazolyl thiazolidinone Mannich bases (4 and 5).     

一种新的合成12-氧代-1,15-十五内酰胺的方法

设计了一种新的合成12-氧代-1,15-十五内酰胺(4)的方法, 即以α-硝基环十二酮(1)为原料, 经与丙烯腈的Michael加成, 氰基选择性还原为氨基后扩环, 再经Nef反应合成了4, 总收率为28%.     

An efficient method for the synthesis of 9-β-D-2′-deoxyribofuranosyl-6-methylpurine

A new method for the preparation of 9-β-D-2′-deoxyribofuranosyl-6-methylpurine from inosine (1) is described. Inosine was converted to 6-chloropurinenucleoside (4) via acetylation, chlorination, and deacetylation. Compound 4 was transformed to the key intermediate 6-methylpurinenucleoside (7) via protection of the 2′,3′,5′-hydroxy groups of 4 with 3,4-dihydropyran to give compound 5, then methylation at the 6-position of 5 with dimethyl copper lithium gave compound 6; depyranylation of 6 led to the subsequent selective protection of the 3′,5′-hydroxy groups of 7 with O[Si(I-Pr)₂Cl]₂ followed by reaction with phenyl chlorothionoformate to give compound 9. Compound 9 was then converted to the target compound 11 via 2′-deoxidation and 3′, 5′-desilylation. The structures of these products were identified by Mass Spectrum (MS), ¹H-NMR (Nuclear Magnetic Resonance) spectra and elemental analysis. Translated from Chinese Journal of Organic Chemistry, 2006, 26(10): 1394–1397 (in Chinese)     

Synthesis of Chloramphenicol via a new Intermediate 4-para-Nitrophenyl-5-formamido-1,3-dioxane

4-Phenyl-5-amino-1,3-dioxane 4, obtained from β-bromo styrene 2 was protected as formamido derivative 5. Nitration of 5 followed by regioselective acylative cleavage of the nitro product 12 gave N-formyl-N-acetyl hemiacetal diacetate 16, which on sequential base and acid hydrolysis followed by dichloroacetylation gave chloramphenicol 1.     

Ringschlussreaktionen mit 2-(β-Styryl)benzylaminen 5-Phenyl-1H-2-benzazepine. 23. Mitteilung über siebengliedrige Heterocyclen

Cyclization reactions with 2-(β-styryl)benzylamines 5-Phenyl-1H-2-benzazepines Cyclization of the urea derivative 3 with POCl₃ to give 2-(4-methyl-1-piperazinyl)-4-phenylquinoline ( 4 ) was carried out in analogy to the quinoline synthesis of Foulds & Robinson. This reaction was used for the preparation of 2-benzazepines. The trisubstituted ureas 6 and 8 , derived from the 2-(β-styryl)-benzylamines 5 , were cyclized with POCl₃ to yield the 3-amino-5-phenyl-1H-2-benzazepines 7 and 9 , respectively. Similarly, cyclization of the corresponding acetyl-derivatives 10 gave the 3-methyl-5-phenyl-1H-2-benzazepines 12 . On the other hand, the disubstituted urea 15 , cyclized under the same conditions to the 1-methyl-1-phenylisoindoline derivative 16 , and 2-(β-styryl)benzylamine ( 5a ) on treatment with phosgene gave the isoindoline 17 in an analogous manner.     

Synthesis and Reactions of Polynuclear Heterocycles: Azolothienopyrimidines and Thienothiazolopyrimidines

We prepared a thieno[2,3-d]pyrimidine compound fused with a thiazolo ring to produce biologicaly active compounds. In a one-step reaction, 2-arylmethylene derivative (3) was prepared via the reaction of a ternary mixture of 2-thioxo-1,2,3,4-tetrahydrocyclohepteno[4,5]thieno[2,3-d]pyrimi-dine-4-one (2), cloroacetic acid, and a proper aldehyde. The reaction of 2 with 3-chloropent-2,4-dione in ethanolic potassium hydroxide yielded the S-acetylacetone derivative 4e. The latter compound reacted with hydrazine hydrate and phenyl hydrazine to give 2-pyrazolthio derivatives 8a,b, respectively. Compound 4e also underwent cyclization on boiling with acetic anhydride/pyridine solution to form 2-acetyl-3-methyl thiazolo[3,2-a]cyclohepteno[4,5]thieno[2,3-d] pyrimidine-5-one (9). To support the structure 9, it gave a characteristic reaction for the 2-acetyl group. The 2-methylthio derivatives 4a underwent further alkylation at N₃ to give 6a,b. The purpose of the synthesis of thienopyrimidine derivatives is due to high biological activities. The 4-oxo-thienopyrimidine derivatives acted as inhibitors of adenosine kinase, platelet aggregation, antilukemia, and anticancer activities.     

Dienol-Benzol-Umlagerung von Penta-2,4-dienyl-benzocyclohexadienolen

1-Hydroxy-2-methyl-2-(penta-2,4-dienyl)-1,2-dihydronaphthalene ( 2 ), on treatment with 0,75N H₂SO₄ in ether at 0°, underwent a [1s, 2s]-sigmatropic rearrangement to give 2-methyl-1-(penta-2,4-dienyl)-naphthalene ( 5 ), cf. scheme 2. 2-Hydroxy-1-methyl-1-(penta-2,4-dienyl)-1,2-dihydronaphthalene ( 4 ) under the same conditions gave 38% of the [1s, 2s]-product 1-methyl-2-(penta-2,4-dienyl)-naphthalene ( 6 ), together with 26% 1-methylnaphthalene, 21% 1-methyl-4-(penta-2,4-dienyl)-naphthalene ( 7 ) and 1% 1-methyl-5-(penta-2,4-dienyl)-naphthalene ( 8 ), cf. scheme 2. Most likely the latter two naphthalene derivatives at least are products of an intermolecular process.     

Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized 2‐Pyrazolines

The styryl ketonic Mannich base 2 has been used as a precursor in the synthesis of 2‐pyrazolines having a basic side chain at C‐3 and a phenolic Mannich base at C‐5. Treatment of the bis(styryl ketonic bases) 6a and 8a with phenylhydrazine affords the bis(3‐functionalized 2‐pyrazolines) 7 and 9 . The transamination between the styryl keto base 10 and 4‐aminoantipyrine leads to 12 , which reacts with piperazine to give 13 . N‐Nitrosation of the sec‐Mannich bases 15a – d followed by reductive cyclization affords 2‐pyrazolines 17a – d . The keto base 14b has been used for the synthesis of 2‐pyrazolines having a phenolic Mannich base at C‐3 and its reaction with 3,5‐dimethyl‐1H‐pyrazole affords 23 . The alkylation of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one with the bis(Mannich base) 25 was investigated.     

1,2-双[2-甲基-5-(3,4-二氟苯基)噻吩-3-基]全氟环戊烯的合成

在冰浴条件下, 2-甲基噻吩(1)与液溴反应生成3,5-二溴-2-甲基噻吩(2); 在－78 ℃条件下, 硼酸三丁酯加入2, 得到2-甲基-3-溴-5-硼酸基噻吩(3); 3,4-二氟溴苯与3反应得到2-甲基-3-溴-5-(3,4-二氟苯基)噻吩(4); 在－78 ℃下全氟环戊烯与4反应, 得到一种新的二芳基乙烯类光致变色化合物1,2-双[2-甲基-5-(3,4-二氟苯基)噻吩-3-基]全氟环戊烯(DT-1). 用IR, NMR, MS和元素分析确定了化合物DT-1的结构, 并对该化合物的光致变色特性进行了初步研究.     

Synthesis of 4,6-(and 5,7-)dimethoxy-3,3-dimethyl-1-indanones

Grignard reaction of ethyl 3-(3,5-dimethoxyphenyl)-propionate (4) followed by cyclodehydration of the carbinol (5) with conc H₂SO₄ gave 4,6-dimethoxy-3,3-dimethylindane (6). Oxidation of the indane (6) with CrO₃-pyridine complex in methylene chloride gave 4,6-dimethoxy-3,3-dimethylindan-1- one (1) in high yield. Conjugate addition of methyl magnesium iodide to methyl α-cyano-β-methyl-3,5-dimethoxycinnamate (11), prepared from 3,5-dimethoxyacetophenone (10) by Knoevenagel condensation, resulted in methyl 2-cyano-3-(3,5-dimethoxyphenyl)-3,3-dimethylpropionate (12). Refluxing the ester (12) with aq DMSO containing sodium chloride gave the corresponding nitrile (15) which underwent Höesch reaction to yield 5,7-dimethoxy-3,3-dimethylindan-1-one (2).     

Dinuclear Zinc Hydride Supported by an Anionic Bis(N‐Heterocyclic Carbene) Ligand

Methylene‐linked bis(N,N′‐di‐tert‐butylimidazol‐2‐ylidene) 1 reacted with diethylzinc to give dinuclear zinc ethyl compound 2 , which contains a formally anionic bis(carbene) ligand as a result of deprotonation of the methylene bridge. The reaction of 2 with PhSiH₃ gave the phenylsilyl compound 3 . The zinc hydride 4 was obtained by the reaction of 2 with LiAlH₄ or Ph₃SiOH followed by treatment with PhSiH₃. X‐ray diffraction studies show that compounds 2 , 3 , and 4 all have a similar dimeric structure with D_2h symmetry. The reaction of hydride 4 with carbon dioxide and N,N′‐diisopropylcarbodiimide gave formato ( 5 ) and formamidinato ( 7 ) derivatives as a result of the insertion of the heterocumulene into both Zn? H bonds. Reaction with Ph₂CO gave the diphenylmethoxy compound 6 . Hydride 4 shows catalytic activity in the hydrosilylation of 1,1‐diphenylethylene and methanolysis of silanes.     

Transformations of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one under various conditions of cyclopropyldiazonium generation

Cyclopropyldiazonium generated by basic decomposition of N-cyclopropyl-N-nitrosourea easily entered into an azo coupling reaction with 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2) to give the corresponding cyclopropylhydrazone in up to 90% yield. Competitive processes occurring under the conditions of cyclopropyldiazonium generation by nitrosation of cyclopropylamine with butyl nitrite mainly include nitrosation of the starting pyrazolone 2. Subsequent transformations of the resulting heterocyclic 3-methyl-1-phenyl-1H-pyrazole-4,5-dione 4-oxime yield 4-[cyclopropyl(oxido)imino]-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2151–2155, December, 2006.     

A facile and novel synthesis of 1,6-naphthyridin-2(1H)-ones

A new and convenient procedure for the synthesis of 1,6-naphthyridin-2(1H)-ones and their derivatives is described. In the first scheme 5-acetyl-6-[2-(dimethylamino)ethenyl]-1,2-dihydro-2-oxo-3-pyridinecarbonitrile ( 4 ) obtained by the reaction of N,N-dimethylformamide dimethyl acetal with 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile ( 3 ) was cyclized to 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile ( 5 ) by the action of ammonium acetate. Thermal decarboxylation of acid 7 obtained from the hydrolysis of nitrile 5 led to a mixture of 5-methyl-1,6-naphthyridin-2(1H)-one ( 8 ) and its dimer 9 . Hydrazide 11 obtained from nitrile 5 in two steps was converted to 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one ( 12 ) by the Curtius rearrangement. The amino group of 12 was readily replaced by treatment with aqueous sodium hydroxide to yield 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one ( 13 ). In the second scheme, Michael reaction of enamines of type 20 with methyl propiolate, followed by ring closure gave 5-acyl(aroyl)-6-methyl-2(1H)-pyridinones ( 21 ) which in turn were treated with Bredereck's reagent to produce 5-acyl(aroyl)-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinones ( 22 ). Treatment of 22 with ammonium acetate led to the formation of 1,6-naphthyridin-2(1H)-ones 23 .