Efficient syntheses of ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate

Ethyl 2-chloroacetoacetate and its 4-chloro isomer react with cyanoacetamide in the presence of the mild, nonnucleophilic base, triethylamine under stoichiometric conditions to give high yields of ethyl 4-cyano-2-hydroxy-2-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (4-cyano-2-hydroxy-5-oxopyrrolidin-2-yl)acetate, respectively. These, under acid-catalyzed dehydration conditions, afforded ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate, respectively. Similarly, the 4-chloro isomer reacted with ethyl cyanoacetate to give the novel product, diethyl 2-cyano-4-oxohexanedioate. The use of triethylamine enables access to a whole new library of pyrrole derivatives from easily accessible, commercially available starting materials. The reactions described in this Letter enable access to libraries of important pyrrole systems in any of the isotopically enriched forms.     

Cesium fluoride and tetra-n-butylammonium fluoride mediated 1,4-N-->O shift of disubstituted phenyl ring of a bicalutamide derivative

A novel 1,4-N→O migration of a disubstituted phenyl ring was observed during N-methylation of a bicalutamide derivative, (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2-methylpropionamide, in the presence of CsF-Celite/acetonitrile and desilylation of (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2,N-dimethylpropionamide in tetra-n-butylammonium fluoride/THF. Both NMR and X-ray analysis confirmed the structure of the 1,4-N→O disubstituted phenyl ring migrated product.     

2-氰基-3-取代氨基-3-(2-甲基苯基)丙烯酸乙酯的合成和杀菌活性

2-甲基苯甲酰氯与氰乙酸乙酯反应得到2-氰基-3-羟基-3-(2-甲基苯基)丙烯酸乙酯, 经氯化得到2-氰基-3-氯-3-(2-甲基苯基)丙烯酸乙酯, 再用三乙胺处理合成了11个2-氰基-3-取代氨基-3-(2-甲基苯基)丙烯酸乙酯类目标化合物. 生物活性研究表明这类新化合物具有良好的杀菌活性.     

A one-pot synthesis and mild cleavage of 2-[2- or 5-(alkylsulfanyl)pyrrol-1-yl]ethyl vinyl ethers by t-BuOK/DMSO: a novel and facile approach to N-vinylpyrroles

Substituted N-[2-(vinyloxy)ethyl]pyrroles, prepared in good yield through an allenic or acetylenic carbanion/isothiocyanate one-pot methodology from 2-(vinyloxy)ethyl isothiocyanate and allyloxyallene, methoxyallene, N,N-dimethyl-2-propyn-1-amine, and 3-methoxy-1-(methylsulfanyl)-1-propyne, are smoothly converted into the corresponding N-vinylpyrroles using t-BuOK/DMSO (room temperature). The reaction proceeds via elimination of vinyl alcohol from the N-[2-(vinyloxy)ethyl] substituent and represents a novel approach to N-vinylpyrroles.     

An efficient synthesis of 4H,5H-pyrano[3,4-c]pyran-4,5-diones from a suitably functionalized 2H-pyran-2-one

An efficient synthesis of ethyl 7-aryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-dione-1-carboxylate 5, and ethyl 6-aryl-3-cyano-2H-pyran-2-one-4-acetate 6 has been delineated by reaction of suitably functionalized 2H-pyran-2-ones 1 with ethyl acetoacetate 2.     

Solution-phase parallel synthesis of new 2H-pyrimido-[4,5-e][1,2,4]triazin-3-ylidenecyanamides

A practical synthesis of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides has been developed. The key step is the coupling reaction of an aryldiazonium salt with 1-cyano-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylamino)-2-methylisothiourea followed by intramolecular cyclization. A library of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides was prepared in two steps from 6-aminouracils using this method.     

Synthesis of Benzo[<Emphasis Type="Italic">h</Emphasis>]quinazolines from Ethyl 1-Amino-3-cyclohexyl-3,4-dihydronaphthalene-2-carboxylate

The reaction of ethyl (2Z)-2-cyano-3-cyclohexylprop-2-enoate with benzylmagnesium chloride, followed by cyclization in the presence of sulfuric acid, provided an efficient method of synthesis of ethyl 1-amino-3-cyclohexyl-3,4-dihydronaphthalene-2-carboxylate which was converted to a number of new heterocyclic systems containing a benzo[h]quinazoline fragment.     

A facile domino protocol for the regioselective synthesis and discovery of novel 2-amino-5-arylthieno-[2,3-b]thiophenes as antimycobacterial agents

A series of novel 2-amino-5-arylthieno[2,3-b]thiophenes has been synthesized regioselectively from the reaction of 5-aryldihydro-3(2H)-thiophenones with ethyl cyanoacetate/malononitrile and sulfur powder in the presence of morpholine under thermal as well as microwave irradiation conditions. This transformation presumably occurs via domino Gewald reaction-dehydrogenation sequence. The 2-amino-5-arylthieno[2,3-b]thiophenes were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among 12 compounds screened, ethyl 2-amino-5-(1-naphthyl)thieno[2,3-b]thiophene-3-carboxylate was found to be the most active compound with MIC of 1.1 μM against MTB and MDR-TB.     

Design and synthesis of new series of 3-cyanopyridine and pyrazolopyridine derivatives

Reaction of 3-cyano-4,6-dimethyl-2-pyridone with ethyl chloroacetate afforded ethyl 2-([3-cyano-4,6-dimethylpyridin-2-yl]oxy)acetate 2 and ethyl 2-(3-cyano-4,6-dimethyl-2-oxopyridin-1[2H]-yl)acetate 3 , the reaction product yield depend on the reaction condition (potassium carbonate concentration and reaction time). These compounds used as precursors to synthesize pyridine derivatives 4 , 6-10 , 15, 17-20 , furopyridines 5, 16 , pyrazolopyridine 12 , pyridopyrazolopyrimidines 14a,b . The structure of the newly synthesized compounds was confirmed by spectral data (IR, NMR, and mass spectra) and elemental analysis.     

l-Proline-catalysed three-component domino reactions for the diastereoselective synthesis of 5,6-disubstituted 3-thiomorpholinones

l-Proline-catalysed three-component domino reactions of ethyl 2-[(2-oxo-2-arylethyl)sulfanyl]acetate, aromatic aldehydes and ammonia provide a rapid and facile access to novel trans-6-aroyl-5-aryl-3-thiomorpholinones. This diastereoselective reaction presumably proceeds via a domino sequence comprising enamine formation, Mannich reaction and intramolecular amidation individual steps and resulting in the generation of one C-C and two C-N bonds in a one-pot operation. The reaction also creates two contiguous stereocenters with complete diastereoselectivity.     

Convenient synthesis of novel N-(5-allyl-7,7-difluoro)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides

5-Allyl-7,7-difluoro-2-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-amine represents a fluorinated heterocyclic scaffold, potentially attractive. It was synthesized via Michael addition, Mannich reaction of the difluorinated ethyl bromoacetate with a benzotriazole derivative, followed by a Dieckmann condensation. Starting from simple materials, this efficient route which gives access to novel functionalized N-(5-allyl-7,7-dihalo)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides, was explored and adapted for parallel synthesis, resulting in a compound library.     

Bis-β-sulfanylethylester and cyclic disulfide-S-oxides as precursors of bifunctionalized anionic derivatives with two oxidized sulfurs

The cyclic disulfide and the bis-β-sulfanyl ethyl ester derived from dithiol, N,N′-1,2-phenylenebis(3-methyl-3-sulfanylbutanamide) were used as precursors to prepare upon oxidation the cyclic disulfide-S-oxides and the thioether sulfur oxidized species including thioether/sulfoxide, bis-sulfoxide, sulfoxide/sulfone, and bis-sulfone. Ring cleavage with KOH/EtOH of the cyclic disulfide-S-monooxide followed by reaction of the opened intermediate with ethyl acrylate afforded the sulfinate/β-sulfanyl ethyl ester derivative. Selective oxidation with 1 and 2 equiv of (3S)-3-tert-butyl-3-methyl-2-(phenylsulfonyl)oxaziridine or with 3 equiv of DMD led to the isolation of a series of compounds containing a sulfonate and a β-sulfanyl, a β-sulfinyl, and a β-sulfonyl ethyl ester. Retro-Michaël reaction applied to the β-sulfonyl/β-sulfinyl and bis-β-sulfonyl derivatives enabled to produce compounds containing a sulfinate and a β-sulfinyl or a β-sulfonyl ethyl ester as well as the bis-sulfinate dianion. DMD oxidation of the latter afforded the bis-sulfonate dianion. All these anionic species were characterized by ¹H NMR, mass spectrometry, HRMS or elemental analysis. Sulfenates in such pseudopeptidic structures could not be isolated from the ring cleavage of the cyclic disulfide-S-dioxide or from a retro-Michaël reaction applied to the β-sulfinyl ethyl ester. A cyclization reaction leading to an isothiazolidin-3-one is likely to occur as observed from the ring cleavage of the cyclic disulfide-S-dioxide. Finally, Ni(II) and Co(III) have been inserted into the disulfinate dianion leading to the corresponding diamidato/disulfinato complexes S-bonded to Ni(II) or Co(III) centers.     

Screening of N-Alkyl-Cyanoacetamido Oximes as Substitutes for N-Hydroxysuccinimide

Peptide-bond formation is a pivotal process in the synthesis of peptide oligomers. Among the various coupling methodologies described, carbodiimides combine strong acylation potency and smooth reaction conditions, and they are commonly used in the presence of N-hydroxylamine additives. In recent years, acidic oxime templates, mainly ethyl 2-cyano-2-(hydroxyimino) acetate (Oxyma), have emerged as highly reactive alternatives to the classic and explosive-prone benzotriazolic additives, 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt). However, to achieve certain biochemical targets, less reactive species, such as N-hydroxysuccinimide (HOSu) esters, are often required to obtain stability under aqueous conditions. In the present study, we report on a new family of water-soluble N-alkyl-cyanoacetamido oximes, most of which have proven useful in the construction of active carbonates for the introduction of fluorenylmethoxycarbonyl (Fmoc) with minimal impact of dipeptide impurities. We performed a direct comparison of these new N-alkyl-cyanoacetamido oximes with HOSu in order to evaluate their capacity to retain optical purity and their coupling efficiency in the assembly of bulky residues.     

2-氰基-3-N-烷氨基-3-(N-2-氟苯乙氨基)丙烯酸乙酯类化合物的合成及生物活性研究

把由氰基乙酸乙酯、二硫化碳、硫酸二甲酯在乙醇钠作用下反应得到的2-氰基.3,3-二甲硫基丙烯酸乙酯中间体用邻氟苯乙胺胺化,再和甲胺等烷胺进行胺化反应,合成了含氟2-氰基丙烯酸乙酯类化合物.结构经元素分析、IR、1H NMR、13C NMR等证实,抗烟草花叶病毒(TMV)生物活性的初步测定表明,所合成的化合物有一定抗TMV活性.     

Radical mediated stereoselective synthesis of (4R,8R)-4,8-dimethyldecanal, an aggregation pheromone of Tribolium flour beetles

(4R,8R)-4,8-Dimethyldecanal, a common aggregation pheromone of Tribolium flour beetles, has been synthesized from (R)-2,3-O-isopropylideneglyceraldehyde in 11 steps and 7% overall yield. The key step in the synthesis is the highly diastereoselective chelation-controlled radical reaction of ethyl (4S,5R)-4-benzyloxy-5,6-(isopropylidenedioxy)-2-methylenehexanoate with ethyl (R)-5-iodo-3-methylpentanoate performed in the presence of 7 equiv of MgBr₂·OEt₂.     

Tri-component reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones: synthesis of 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-[4,5-b:4,5-e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy) pyrimidine

Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones 4-9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-diones 11 as a novel heterocycle.     

A novel coenzyme NADH model 1-benzyl-1,4-dihydronicotinamide-mediated reaction: a single intermediate serves two mechanisms

Thermal reaction of ethyl (2Z)-4-bromo-2-cyano-3-(2-naphthyl)but-2-enoate (BCNB) with coenzyme NADH model 1-benzyl-1,4-dihydronicotinamide (BNAH) gives the debrominated cyclized product (E)-1-cyano-2-methyl-2-(2-naphthyl)cyclopropane-1-carboxylate (1), debrominated olefinic products ethyl (2E)-2-cyano-3-(2-naphthyl)but-2-enoate (2) and ethyl (2Z)-2-cyano-3-(2-naphthyl)but-2-enoate (3). The formation of 1 proceeds via partial concerted hydride transfer and debromocyclopropanation, whereas the formation of 2 or 3 proceeds via an electron transfer-debromination-hydrogen abstraction mechanism. Nonetheless, they all derived from the same electron-transfer intermediate complex.     

A convenient route to functionalized 3-amino-N-methylfuro[3,2-b]pyridine-2-carboxamides

The synthesis of novel functionalized 3-amino-N-methylfuro[3,2-b]pyridine-2-carboxamides is described from cyanopyridine intermediates. Based on the difference in halogen reactivity, ethyl [(5-bromo-2-chloropyridin-3-yl)oxy]acetate was functionalized by a palladium-catalyzed reaction, before the cyclization to the desired furo[3,2-b]pyridines.     

A highly diastereoselective five-component synthesis of 1-(alkylimino)-5,5-dicyano-3a-aryloctahydro-3-oxacyclobuta[cd]pentalene-1a,2,5a,5b(2H,3aH)-tetracarboxylates

A novel one-pot, five-component synthesis of 1-(alkylimino)-5,5-dicyano-3a-aryloctahydro-3-oxacyclobuta[cd]pentalene-1a,2,5a,5b(2H,3aH)-tetracarboxylates is described. A mixture of phenacyl bromide, malononitrile, isocyanide, and two equivalents of a dialkyl acetylenedicarboxylate undergoes a novel 1:1:1:2 addition reaction at ambient temperature in absolute ethanol to produce diastereoselectively the title compounds in good yields.     

New HA 14-1 analogues: synthesis of 2-amino-4-cyano-4H-chromenes

The synthesis of 2-amino-4-cyano-4H-chromene derivatives as new HA 14-1 analogues by a simple and efficient method is reported. In addition, the reaction of 2-amino-2H-chromene-3-carbonitriles, salicylaldehydes and amines results in the formation of new chromeno[2,3-d]pyrimidine derivatives.