The Reaction of Ethyl Bromoacetate with Dimethyl Sulfoxide

The reaction of excess dimethyl sulfoxide with ethyl bromoacetate has been shown to produce ethyl glyoxylate, hydrogen bromide, and dimethyl sulfide. The yield of glyoxylate at first was reduced because the dimethyl sulfide reacted with bromoacetate to form trimethylsulfonium bromide and ethyl (methylmercapto) acetate, presumably via carbethoxymethyldimethylsulfonium bromide. These side reactions were diminished in a thin-film reactor, but the result was not satisfiable, the yield was 51%, and the side reactions were prevented by addition of methyl bromide, which rapidly consumed the dimethyl sulfide with formation of trimethylsulfonium bromide. Addition of 1, 2-epoxy-3-phenoxypropane removed the hydrogen bromide, thereby preventing the deleterious effects casued by its reduction of dimethyl sulfoxide to dimethyl sulfide. In this way has been developed a convenient preparation of ethyl glyoxylate in yields averaging about 70%. Identification and stoichiometry of the reaction products are presented.     

Fluorinated heterocyclic compounds. 4-fluoro-2-pyridone

The uracil analog, 4-fluoro-2-pyridone was synthesized by ether cleavage of 4-fluoro-2-methoxypyridine with trimethylsilyl iodide. Improved procedures for the preparations of 2-methoxypyridine N-oxide hydrochloride and 2-methoxy-4-nitropyridine N-oxide are described.     

A Green Procedure for the Oxidation of Benzyl Halides to Aromatic Aldehydes or Ketones in Aqueous Media

Green oxidation of benzyl halides to the corresponding aldehydes or ketones was achieved in aqueous media using trimethylamine N-oxide generated in situ from trimethylamine and H₂O₂. The yield of the reaction was excellent and the workup was simple.     

Pyridine nucleosides related to 5-fluorocytosine

4-Amino-5-fluoro-2-pyridone ( 4 ) [5-fluoro-3-deazacytosine] was isolated as the hydrochloride salt from the dealkylation of 4-amino-5-fluoro-2-methoxypyridine ( 2 ), which was obtained from the reduction of 5-fluoro-2-methoxy-4-nitropyridine-N-oxide ( 1 ). Acetylation of 2 gave 4-acetamido-5-fluoro-2-methoxypyridine ( 3 ), which was condensed with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide to give the blocked nucleoside ( 8 ). Removal of the protecting groups gave 5-fluoro-3-deazacytidine. Fusion of the trimethylsilyl derivative of 4 (10), with 2-deoxy-3,5-di-O-p-toluoyl-D-erythro pentofuranosyl chloride gave a mixture of the β and α-anomers 12 and 13 , which were separated and deblocked to yield 5-fluoro-2′-deoxy-3-deazacytidine ( 14 ) and its α-anomer ( 15 ). Several alkylated and acetylated derivatives of 2 were prepared as model compounds for use in the proof of structure.     

4,7,10-三(叔丁氧碳酰甲基)-1,4,7,10-四氮杂环十二烷-1-乙酰肼的微波合成

以轮环藤宁为起始原料,依次与溴乙酸叔丁酯,溴乙酸乙酯和水合肼反应合成了一种核磁共振对比剂螯合前体--4,7,10-三(叔丁氧碳酰甲基)-1,4,7,10-四氮杂环十二烷-1-乙酰肼（4）,其结构经¹H NMR, ¹³C NMR, FT-IR和MS(ESI)表征。研究了溶剂、水合肼用量、微波功率和反应时间对4收率的影响。结果表明：乙醇为溶剂,水合肼10 eq.,于400 W微波反应10 min, 4（粉末固体）收率90%。     

Chinazolincarbonsäuren. XII. Mitteilung. Synthese von [2-(Ethoxycarbonyl)-3,4-dihydro-4-oxochinazolin-3-yl]-, [2-(Ethoxycarbonyl)chinazolin-4-yloxy]- und (5,6,7,8-Tetrahydro-2-phenylchinazolin-4-ylthio)alkansäure-estern

Quinazolinecarboxylic Acids. Synthesis of Alkyl [2-(Ethoxycarbonyl)-3,4-dihydro-4-oxoquinazolin-3-yl]-, [2-(Ethoxycarbonyl)quinazolin-4-yloxy]- and (5,6,7,8-Tetrahydro-2-phenylquinazolin-4-ylthio)alkanoates The [(2-aminobenzoyl)amino]alkanoic acids and their esters 1 showed a different reaction behaviour with diethyl oxalate. Compound 1 (n = 2,3) was converted into the quinazolinylalkanoates 3 . o-Aminohippurate yielded with ethyl (chloroformyl)formate a mixture of the amide 4 and the cyclized quinazolinone 7b . Ethyl 3,4-dihydro-4-oxoquinazoline-2-carboxylate ( 6 ) reacted with 2-bromoalkanoates, in the presence of NaH, to the [2-(ethoxycarbonyl)-3,4-dihydro-4-oxoquinazolin-3-y1]acetates 7 in the case of alkyl bromoacetate, and to the O-alkylated derivatives 8 with the ethyl 2-bromopropionate and -butyrate. 2-Aminobenzamide ( 5 ) gave with ethyl 3-(chloroformyl)-2-propenoate and methyl 3-(chloroformyl)propionate the amides 9 or 11 , respectively, and not the expected quinazolinones. The cyclized product 12 was obtained from 11 and ethyl bromoacetate. Tetrahydroquinazolin-4(3H)-thione 14 was synthesized by the reaction of 13 with NH₃, and it was alkylated at the S-atom with bromoalkanoates to 15 . The hydrazide 16 was synthesized from 15b with hydrazine hydrate.     

Pyridine nucleosides related to 5-fluorouracil

5-Fluoro-2-methoxypyridine ( 3 ) synthesized from 5-amino-2-methoxypyridine was converted to 4-benzyloxy-5-fluoro-2-methoxypyridine ( 12 ) and 2,4-dimethoxy-5-fluoropyridine ( 13 ) by a four step procedure employing the intermediate 5-fluoro-2-methoxy-4-nitropyridine N-oxide (7). Condensation of 3 , 12 , and 13 with 2,3,5-tri-O-benzoyl-D -ribofuranosyl bromide gave, after removal of the protecting groups, 4-deoxy-5-fluoro-3-deazauridine (20), 5-fluoro-3-deazauridine (23) and 5-fluoro-4-methoxy-3-deazauridine (25). Several alkylated and dealkylated derivatives of 3 and 12 were also prepared. Structure proof and anomeric configuration were determined from the uv, nmr, and CD data.     

4a-Alkyl Derivatives of 5-Oxo-4H-4a,5-dihydroindeno[1,2-b]pyridine

High selectivity has been discovered for the C-alkylation of ambident anions of 5-oxo-1H-4,5-dihydroindeno[1,2-b]pyridines with ethyl bromoacetate, allyl, propargyl, and phenacyl bromides, which leads to the formation of the corresponding 4a-substituted 5-oxo-4H-4a,5-dihydroindeno[1,2-b]pyridines in high yield.     

Bildung von 2-(1-Methyl-1, 4, 5, 6-tetrahydropyridyl-3)-2-oxazolin-4-on aus 1-Methyl-1, 4, 5, 6-tetrahydronicotinsäureamid und Bromessigsäureäthylester und seine Überführung in O-(1-Methylnipecotinoyl)glykolsäureamid via das dazu tautomere Cyclol

The main product of the reaction between 1-methyl-1, 4, 5, 6-tetrahydronicotin-amide and ethyl bromoacetate is shown to be the 2-(1-methyl-1, 4, 5, 6-tetrahydropyridyl-3)-2-oxazoline-4-one which on partial hydrogenation followed by reaction with alkali affords O-(1-methylnipecotinoyl)glycolic amide, presumably via the tautomeric cyclol.     

Tautomeric structure of 1-methyldihydropyridazino-[3,4-b]quinoxalines in solution

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 1 with ethyl 2-ethoxymethylene-2-cyano-acetate or ethoxymethylenemalononitrile gave 6-chloro-2-[2-(2-cyano-2-ethoxycarbonylvinyl)-1-methylhy-drazino]quinoxaline 4-oxide 3a or 6-chloro-2-[2-(2,2-dicyanovinyl)-1-methylhydrazino]quinoxaline 3b , respectively. The reaction of 3a with a base afforded 7-chloro-1-methyl-1,5-dihydropyridazino[3,4-b]quinoxaline 4 . From the NOE spectral data, the 1-methyldihydropyridazino[3,4-b]quinoxalines 2a, 2b and 4 were found to exist as the 1,5-dihydro form in a dimethyl sulfoxide or trifluoroacetic acid/dimethyl sulfoxide solution.     

Heterodiene synthesis. Synthesis of fused thiopyrano [2,3-d]thiazole,Benzopyrano[3′,4′:4,5]thiopyrano[2,3-d]thiazole and thiazolo[3,4-c]triazine derivative

5-Salicylidenethiazolidine-2,4-dithione ( 1 ) reacts with acrylonitrile, N-phenylmaleimide and dimethyl acet-ylenedicarboxylate to afford the fused thiopyrano[2,3-d]thiazolidinethione derivatives 2, 4 and 6 , respectively. The salicylidene derivative 1 reacts with ethyl acrylate and malononitrile to afford the fused [1]benzopyrano[3′,4′:4,5]thiopyrano[2,3-d]thiazoles 3 and 9 , respectively. 4-Phenylhydrazono-2-thiazolidinethione ( 11 ) reacts with ethyl bromoacetate and/or phenacyl bromide to yield the fused thiazolo[3,4-c]triazines 13 and 14.     

Synthesis,Antioxidant, Antituomer Activities of Some New Thiazolopyrimidines,Pyrrolothiazolopyrimidines and Triazolopyrrolothiazolopyrimidines Derivatives

Reaction of 6‐amino‐2‐thiouracil 1 with ethyl bromoacetate yielded ethyl 2‐(7‐amino‐2,5‐dioxo‐3,5‐dihydro‐2H‐thiazolo[3,2‐a]pyrimidin‐6‐yl)acetate 2 . Reaction of 2 with sodium ethoxide afforded the pyrrolothiazolopyrimidine derivative 3 . Compound 2 reacted with hydrazine hydrate to give 7‐amino‐thiazolopyrimidine‐carbohydrazide 4 . The latter compound 4 reacted with carbon disulphide to form 7‐amino‐6‐(oxadiazolylmethyl) thiazolopyrimidine 5 . Compound 5 was heated in methanol to yield 9‐thioxotriazolopyrrolothiazolopyrimidine 6 . Also, the reaction of 3 with aromatic aldehydes afforded the diarylmethylenepyrrolothiazolopyrimidine derivatives 7a‐c . The latter compounds 7a‐c underwent cyclocondensation with hydroxylamine to give diaryldioxazolopyrrolothiazolopyrimidine derivatives 8a‐c . The new prepared compounds were subjected for antioxidant and antituomer studies, some of these compounds exhibited promising activity.     

Heterocyclic Synthesis with 4-Benzoyl-1-cyanoacetylthiosemicarbazide: Selective Synthesis of Some Thiazole, Triazole, Thiadiazine, Pyrrylthiazole, and Pyrazolo[1,5-a]triazine Derivatives

4-Benzoyl-1-cyanoacetylthiosemicarbazide undergoes coupling reaction with aromatic diazonium chloride to afford (arylhydrazono)thiosemicarbazide, which was reacted with phenacyl bromide regioselectivity to afford the thiazoline. The (arylhydrazono)thiosemicarbazide could be transformed into the pyrazolo[1,5-a]triazine. Heterocyclization of 4-benzoyl-1-cyanoacetylthiosemicarbazide with α-haloketones (bromoacetone and phenacyl bromide), ethyl iodide, and ethyl bromoacetate furnished the pyrrylthiazoles, 1,2,4- triazole, and 1,3,4-thiadiazine. The latter was coupled with aromatic diazonium chloride to give the bis(arylhydrazono)‐thiadiazine. The mechanism for the formation of the title compounds was suggested and discussed.     

A novel synthesis of fused imidazo[5,1-c]-1,2,4-triazoles

The new fused imidazo[5,1-c]-1,2,4-triazoles 4 were obtained by cyclization of the corresponding 2-imidazolidinone 4-phenylhydrazones 2 which were obtained by the action of phenylhydrazine on the arylmethylene derivatives of 4-thioxo-2-imidazolidinone 1 . The benzylimino derivatives 6 were obtained by the reaction of benzylamine with 1 . Alkylation of 1 with phenacyl bromide and/or ethyl bromoacetate afforded the S-alkyl derivatives 7.     

Chemistry of thienopyridines. XLII. Three novel compounds derived from thienopyridine N-oxides

Extension of the Reissert-Henze reaction to treatment of thieno[2,3-b]pyridine 7-oxide with potassium thiocyanate and benzoyl chloride in water-methylene chloride gives a 2% yield of bis(6-thieno[2,3-b]pyridyl) disulfide. Peroxidation of 5-ethylthieno[2,3-b]pyridine ( 4 ) forms the 7-oxide 5 (53%), converted to a monopicrate 5a . Picrate 5a undergoes N-deoxygenation to 4 -picrate on drying at 78° in vacuo, but shows the expected additive mass spectrum of 5 (thermally stable) and picric acid. Nucleophilic displacement of chloride ion from 7-chlorothieno[3,2-b]pyridine (derived, in turn, from thieno[3,2-b]pyridine 4 -oxide) by the anion from ethyl cyanoacetate gives 7-(1-cyano-1-ethoxycarbonyl)methylene-4,7-dihydrothieno[3,2-b]pyridine (82%), stable in this iminodienic tautomeric form.     

Furopyridines. V. A simple synthesis of furo[2,3-c]pyridine and its 2-and 3-methyl derivatives

A simple synthesis of furo[2,3-c]pyridine and its 2- and 3-methyl derivatives from ethyl 3-hydroxyisonicotinate ( 2 ) is described. The hydroxy ester 2 was O-alkylated with ethyl bromoacetate or ethyl 2-bromopropionate to give the diester 3a or 3b . Cyclization of compound 3a afforded ethyl 3-hydroxyfuro [2,3-c]pyridine-2-carboxylate ( 4 ) which was hydrolyzed and decarboxylated to give furo[2,3-c]pyridin-3(2H)-one ( 5a ). Cyclization of 3b gave the 2-methyl derivative 5b . Reduction of 5a and 5b with sodium borohydride yielded the corresponding hydroxy derivative 6a and 6b , respectively, which were dehydrated with phosphoric acid to give furo[2,3-c]pyridine ( 7a ) and its 2-methyl derivative 7b . 4-Acetylpyridin-3-ol ( 8 ) was O-alkylated with ethyl bromoacetate to give ethyl 2-(4-acetyl-3-pyridyloxy) acetate ( 9 ). Saponification of compound 9 , and the subsequent intramolecular Perkin reaction gave 3-methylfuro[2,3-c]pyridine ( 10 ). Cyclization of 9 with sodium ethoxide gave 3-methylfuro[2,3-c]pyridine-2-carboxylic acid, which in turn was decarboxylated to give compound 10 .     

Furopyridines. III. A new synthesis of furo[3,2-b]pyridine

A convenient synthesis of furo[3,2-b]pyridine and its 2- and 3-methyl derivatives from ethyl 3-hydroxypiconate ( 1 ) is described. The hydroxy ester 1 was O-alkylated with ethyl bromoacetate or ethyl 2-bromopropionate to give the diester 2a or 2b . Cyclization of compound 2a afforded ethyl 3-hydroxyfuro[3,2-b]pyridine-2-carboxylate ( 3 ) which in turn was hydrolyzed and decarboxylated to give furo[3,2-b]pyridin-3-(2H)-one ( 4a ). Cyclization of 2b gave the 2-methyl derivative 4b . Reduction of 4a and 4b with sodium borohydride yielded the corresponding hydroxy derivative 5a and 5b respectively, which were dehydrated with phosphoric acid to give furo[3,2-b]pyridine ( 6a ) and its 2-methyl derivative ( 6b ). 2-Acetylpyridin-3-ol ( 8 ) was converted to the ethoxycarbonylmethyl ether ( 9 ) by O-alkylation with ethyl bromoacetate, which was cyclized to give 3-methylfuro[3,2-b]pyridine-2-carboxylic acid ( 10 ). Decarboxylation of 10 afforded 3-methylfuro[3,2-b]pyridine ( 11 ).     

Heterocyclic Synthesis with 4-Benzoyl-1-cyanoacetylthiosemicarbazide: Selective Synthesis of Some Thiazole,Triazole, Thiadiazine,Pyrrylthiazole, and Pyrazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]triazine Derivatives

Summary. 4-Benzoyl-1-cyanoacetylthiosemicarbazide undergoes coupling reaction with aromatic diazonium chloride to afford (arylhydrazono)thiosemicarbazide, which was reacted with phenacyl bromide regioselectivity to afford the thiazoline. The (arylhydrazono)thiosemicarbazide could be transformed into the pyrazolo[1,5-a]triazine. Heterocyclization of 4-benzoyl-1-cyanoacetylthiosemicarbazide with α-haloketones (bromoacetone and phenacyl bromide), ethyl iodide, and ethyl bromoacetate furnished the pyrrylthiazoles, 1,2,4- triazole, and 1,3,4-thiadiazine. The latter was coupled with aromatic diazonium chloride to give the bis(arylhydrazono)‐thiadiazine. The mechanism for the formation of the title compounds was suggested and discussed.     

Synthesis of 5-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione and its Reactions with Polyfunctional Electrophiles

Summary.  In the reaction of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with hydrazine hydrate, 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione was formed. The reactions of the latter with ethyl bromoacetate and chloroacetonitrile in the presence of triethylamine proceeded under formation of the corresponding S-alkylated derivatives, whereas from its reaction with ω-bromoacetophenone and ethyl 4-chloroacetoacetate triazolothiadiazines were obtained. Treatment of the title compound with ethyl 2-chloroacetoacetate led to the formation of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-N-acetylamino-(3-ethoxy-carbonylmethylthio)-1,2,4-triazole. Performing of the latter reaction without basic catalyst gave a triazolothiadiazine. Treatment of the S-alkylated derivatives with sodium methoxide resulted in triazolothiadiazines via a cyclocondensation reaction. Received November 20, 2000. Accepted January 15, 2001     

A flow injection electrospray ionization tandem mass spectrometric method for the simultaneous measurement of trimethylamine and trimethylamine N-oxide in urine

Key metabolites for the diagnosis of the genetic disorder trimethylaminuria are trimethylamine (TMA) and trimethylamine N-oxide (TMAO). A rapid, automatable flow injection ESI-MS/MS method for their measurement in urine has been developed. The TMA was derivatized with ethyl bromoacetate to form ethyl betaine bromide. The 2 min ESI-MS/MS analysis employed four multiple reaction monitoring (MRM) ion pairs for derivatized TMA (146.1, 118.1), derivatized (2)H(9)-TMA (155.1, 127.1), TMAO (76.1, 58.1) and (2)H(9)-TMAO (85.1, 66.1). In control urine samples (n = 27) referred for suspected metabolic problems TMA was 0.11-1.19 mmol/mol creatinine, TMAO was 13.5-181 mmol/mol creatinine and the TMA/TMAO ratio was 0.0025-0.055. In five patients with diagnosed trimethylaminuria, TMA was 5.3-230 mmol/mol creatinine, TMAO was 0.36-607 mmol/mol creatinine and the TMA/TMAO ratio was 0.20-134.