New regiospecific isothiazole C-C coupling chemistry

Regioselective palladium catalysed coupling reactions are achieved in good to high yields, starting from either 3,5-dichloro- or 3,5-dibromoisothiazole-4-carbonitriles 1 and 2, providing 3-halo-5-(hetero/aryl, alkenyl and alkynyl)isothiazoles 3, 4, 6-9 from Stille couplings, 3-halo-5-(hetero/arylethynyl)isothiazoles 14-19 from Sonogashira and 5,5'-bi(3-chloroisothiazole-4-carbonitrile) (13) from an Ullmann type coupling. 3,5-Dibromoisothiazole-4-carbonitrile 2 is more reactive than the dichloroisothiazole-4-carbonitrile 1 and effective enough for Stille, Negishi and Sonogashira couplings. 5,5-Bi(3-chloroisothiazole-4-carbonitrile) (13) is prepared by a palladium catalysed Ullmann coupling from 3-chloro-5-iodoisothiazole-4-carbonitrile (11). A variety of 3-substituted isothiazoles (3-substituents = Cl, Br, OMs, OTs and OTf) are less reactive and fail to give successful Suzuki couplings at the isothiazole C-3 position. The 3-iodo-5-phenyl-isothiazole-4-carbonitrile (28), prepared via Sandmeyer iodination, participates successfully in Suzuki, Ullmann type, Stille, Negishi and Sonogashira coupling reactions. All products are fully characterized.     

Synthesis and biodistribution of p-iodophenyl analogues of a naturally occurring imidazole ribonucleoside

A model iodophenyl imidazole ribonucleoside has been synthesized to study biodistribution properties in laboratory animals. The key intermediate 5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-[N-(p-iodophenyl)carboxamide] ( 5 ) was synthesized by coupling N-succinimidyl-5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxylate ( 4 ) and p-iodoaniline. Deacetylation of the intermediate compound gave 5-amino-1-β-D-ribofuranosylimidazole-4-[N-(p-iodophenyl)]carboxamide ( 6 ). Ring annulation via diazotization of 5 gave 7-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-[3-N-(p-iodophenyl)]-4-one ( 7 ). Subsequent deacetylation of 7 afforded 7-β-D-ribofuranosylimidazo[4,5-d]-v-triazin-[3-N-(p-iodophenyl)]-4-one ( 8 ). The radiolabeled compounds, [¹²⁵I] 5 and [¹²⁵I] 6 were prepared in a manner similar to the corresponding unlabeled compounds except that p-[¹²⁵I]iodoaniline was used for coupling with 4 . Biodistribution studies of iodine-125-labeled 5 and 6 were performed in female Fischer rats and tumor bearing nude mice. Compound 6 showed uptake in the brain and proliferating tissues such as tumor and bone-marrow.     

Synthesis of 6-bromo-2-arylindoles using 2-iodobenzoic acid as precursor

The synthesis of 6-bromo-2-arylindoles starting from readily available 2-iodobenzoic acid is presented. Regioselective bromination of the latter was followed by Curtius rearrangement and trapping of the isocyanate with benzyl alcohol led to the benzyl carbamate of 2-iodo-5-bromoaniline. Chemoselective Sonogashira coupling of this compound with arylacetylenes followed by TBAF induced 5-endo-dig cyclization gave the desired bromo indoles. The method allows selective introduction of a bromine atom at the indole C-6 position.     

Regioselective synthesis of thiophene fused sultam derivatives via iodocyclization approach and their application towards triazole linker

An efficient regioselective synthesis of 4-iodo-2,3-disubstituted-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide derivatives via iodocyclization approach using iodine under mild reaction condition described herein. This coupling–iodocyclization strategy tolerated a variety of functional groups such as alkyl, cycloalkyl, phenyl producing the six-membered heterocyclic ring selectively. The resulting 4-iodo-2,3-disubstituted-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide was coupled with a variety of boronic acids (Suzuki coupling) and activated alkenes (Heck coupling). The iodo group was utilized for Sonogashira coupling followed by efficient transformation to azido precursor, which was used for the synthesis of various thieno-sultam linked with triazole.     

Regiocontrolled Microwave Assisted Bifunctionalization of 7,8-Dihalogenated Imidazo[1,2-<em>a</em>]pyridines: A One Pot Double-Coupling Approach

The reactivity of the 7-chloro-8-iodo- and 8-chloro-7-iodoimidazo[1,2-a]pyridines 1a-e diversely substituted on the 2 position, towards Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig cross-coupling reactions as well as cyanation was evaluated. Various methodologies are proposed to introduce aryl, heteroaryl, alkyne, amine or cyano groups in the two positions depending on the nature of the substituent present in position 2. In both series, the substitution of the iodine atom was totally regioselective and the difficulty was to substitute the chlorine atom in a second step. Until now, only hetero(aryl) groups could be introduced though Suzuki-Miyaura cross-coupling. We overcame this problem evaluating both regioisomers in parallel. The double coupling approach was also studied allowing the one pot Suzuki/Suzuki, cyanation/Sonogashira and cyanation/Buchwald reactions leading to polyfunctionnalized imidazo[1,2-a]pyridines.     

Synthesis of New Highly Functionalized 1H-Indole-2-carbonitriles via Cross-Coupling Reactions

An approach for the preparation of polysubstituted indole-2-carbonitriles through a cross-coupling reaction of compounds 1-(but-2-ynyl)-1H-indole-2-carbonitriles and 1-benzyl-3-iodo-1H-indole-2-carbonitriles is described. The reactivity of indole derivatives with iodine at position 3 was studied using cross-coupling reactions. The Sonogashira, Suzuki–Miyaura, Stille and Heck cross-couplings afforded a variety of di-, tri- and tetra-substituted indole-2-carbonitriles.     

Chemoenzymatic Synthesis of Stannylated Metomidate as a Precursor for Electrophilic Radiohalogenations – Regioselective Alkylation of Methyl 1<Emphasis Type="Italic">H</Emphasis>-Imidazole-5-carboxylate [1]

Summary. Metomidate (ee 99%) substituted with iodine in the phenyl ring was prepared from (S)-1-(4-iodophenyl)ethanol (ee >98%) obtained by lipase-catalysed resolution and methyl 1H-imidazole- 5-carboxylate. The two fragments were joined highly regioselectively (alkylation only at N-1 of substituted imidazole) with inversion of configuration using the Mitsunobu reaction. Finally, p-iodometomidate was transformed into the p-trimethylstannyl derivative.     

Synthesis and some properties of 5-alkylamino-2-(phthalimidoalkyl)-1,3-oxazole-4-carbonitriles

5-Alkylamino-1,3-oxazole-4-carbonitriles containing a 2-phthalimidoethyl or 3-phthalimidopropyl substituent at position 2 of the oxazole ring were synthesized. In the reaction of 5-(morpholin-4-yl)-2-(2-phthalimidoethy)l-1,3-oxazole-4-carbonitrile with hydrazine hydrate, 2-(2-aminoethyl)-5-(morpholin-4-yl)-1,3-oxazole-4-carbonitrile is formed. In the case of the 3-phthalimidopropyl analog, the recyclization product 3-amino-2-(morpholin-4-ylcarbonyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole is formed.     

Crystal structure and mechanistic investigation of the reaction of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile with unsaturated carbonyl compounds

The crystal structure of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-ethyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile was obtained and determined by X-ray crystallography. The reaction mechanism of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile with unsaturated carbonyl compounds was further proposed.     

4-(对取代苯基)-2-[2-(取代苯基)呋喃-4-甲酰胺]-1',3',4'-均三唑[1,2-d]-1,3,4-噻二唑类衍生物的合成和生物活性

以1-氨基-5-巯基-2-(对取代苯基)-1,3,4-均三唑和5-取代苯基-2-呋喃甲酰异硫氰酸酯为原料, 合成了10个未见文献报道的含苯环连呋喃的均三唑并噻二唑类衍生物, 通过元素分析, ¹H NMR, IR和MS确定化合物的结构, 初步生物活性测试表明标题化合物具有一定的除草活性.     

Synthesis of novel 8-(het)aryl-6H-pyrano[4′,3′:4,5]thieno[3,2-b]pyridines by 6-endo-dig cyclization of Sonogashira products and halolactonizations with Cu salts/NXS. Preliminary antitumor evaluation

Novel 8-(het)aryl-6H-pyrano[4′,3′:4,5]thieno[3,2-b]pyridines were prepared in good to high yields by a tandem one-pot procedure of Sonogashira coupling and 6-endo-dig lactonization from 3-bromothieno[3,2-b]pyridine-2-carboxylic acid and (het)arylalkynes. Sonogashira coupling products were also prepared from the corresponding methyl ester giving in the same reaction the corresponding 6-endo-dig compounds as minor products. The Sonogashira phenyl ester product gave cyclization with electrophiles only in low to moderate yields. Nevertheless, halolactonizations using Cu(I) or (II) salts/N-halosuccinimides (NXS) from either the phenyl ester or the carboxylic acid derivatives occurred in good to high yields. The growth inhibition potential of the compounds was evaluated using human tumor cell lines, HCT-15 (colorectal adenocarcinoma) and NCI-H460 (non-small cell lung cancer) and studies of apoptosis induction were performed for the three most promising compounds in HCT-15?cells. Two of them caused almost 40% of cell death by apoptosis when tested at their 1.5?×?GI₅₀ concentrations. The tricyclic lactone with a F atom in the meta position showed to be the most promising one.     

Synthesis of monomeric and oligomeric 1,1′-methylenebis-(1H-pyrazoles) contaning ethynyl fragments

1,1′-Methylenebis(1H-pyrazole) and 1,1′-methylenebis(3,5-dimethyl-1H-pyrazole) reacted with iodine in the presence of iodic acid to give the corresponding 4,4′-diiodo derivatives. Polycondensation of the latter with p-diethynylbenzene led to the formation of oligomeric compounds. 1,1′-Methylenebis(4-iodo-1H-pyrazoles) were converted into 4,4′-diethynyl derivatives by the Sonogashira and reverse Favorskii reactions, and their oxidative polycondensation in the presence of copper(I) chloride in pyridine also gave oligomeric products with a molecular weight exceeding 9000.     

Synthesis of new annulated pyridazine derivatives and studying their antioxidant and antimicrobial activities

Benzil was reacted with cyanoacetohydrazide under microwave irradiation to give 3-oxo-5,6-diphenyl-2,3-dihydropyridazine-4-carbonitrile 1 which used as starting material for the synthesis of new heterocyclic compounds. Chlorination of pyridazinone 1 with POCl₃ afforded the chloro-pyridazine derivative 3, which then condensed with 2-aminothiazole or hydrazine hydrate to produce 3,4-diphenyl-5H-thiazolo[3′,2′:1,2]pyrimido[4,5-c]pyridazin-5-one 5 or 3-hydrazinyl-5,6-diphenylpyridazine-4-carbonitrile 6, respectively. New Schiff bases were obtained by condensation reactions of compound 6 with different aldehydes. On the other hand, compound 6 reacted with different carbon electrophiles naming acetyl acetone, diethyl malonate, and phenyl isothiocyanate producing new pyarazolo-pyridazine derivatives 11, 12, and 14, respectively. Chemical structures of all newly synthesized compounds were confirmed on the basis of spectral data and had been screened for antimicrobial and antioxidant activity.     

新颖的含乙炔桥键液晶分子设计与合成

为降低液晶分子的双折射率并获得宽液晶相区, 用环己基替代传统二苯乙炔液晶分子中的一个苯环, 得到一类结构新颖的含乙炔桥键的负介电各向异性液晶分子4a, 4b. 目标化合物采用1-trans-4-(trans-4-正戊基环己基)环己基乙炔与4-碘-2,3-二氟苯基醚进行Sonogashira偶联反应制备, 反应总产率27%～28%. 产物结构经MS, IR, NMR鉴定确认. 采用DSC结合偏光显微镜对液晶相变温度进行了测试, 结果表明新化合物4a, 4b清亮点分别为212, 216 ℃, 向列相温区均达到140 ℃, 与传统二苯乙炔类液晶的相变温区基本相当. 物理性能测试表明, 分子骨架共轭程度的削弱不仅使双折射率大幅降低, 而且介电各向异性绝对值还有所增大, 为分子设计提供了新的思路. 新化合物综合性能得到显著改善, 在大尺寸液晶电视领域具有非常好的应用前景.     

A dendrimer approach to high-spin polycarbenes. Conversion of connectivity from disjoint to non-disjoint by perturbation of nonbonding molecular orbital coefficients

[structure: see text] Pentakis(diazo) compound was prepared by coupling 3,5-bis[4-[diazo(4-tert-butyl-2,6-dimethylphenyl)methyl]-3,5-dibromophenylethynyl]phenylacetylene with bis(4-iodo-2,6-dimethylphenyl)diazomethane under Sonogashira reaction conditions. Pentakis(carbene) generated by irradiation of the pentakis(diazo) compound was shown to have a high-spin state with S = 4.4 at 2.0 K.     

The Pursuit of Perphenylterphenyls

Tetradecaphenyl-p-terphenyl ( 2 ) was synthesized from 2,3,5,6-tetraphenyl-1,4-diiodobenzene ( 11 ) by two methods. Ullmann coupling of 11 with pentaphenyliodobenzene ( 9 ) gave compound 2 in 1.7 % yield, and Sonogashira coupling of 11 with phenylacetylene, followed by a double Diels-Alder reaction of the product diyne 12 with tetracyclone ( 6 ), gave 2 in 1.5 % overall yield. The latter reaction also gave the monoaddition product 4-(phenylethynyl)-2,2′,3,3′,4′,5,5′,6,6′-nonaphenylbiphenyl ( 13 ) in 4 % overall yield. The X-ray structures of compounds 2 and 13 show them to possess core aromatic rings distorted into shallow boat conformations. Density functional calculations indicate that these unusual structures are not the lowest energy conformations in the gas phase and may be the result of packing forces in the crystal. In addition, while uncorrected DFT calculations indicate that the strain energy in compound 2 is approximately 50 kcal/mol, dispersion-corrected DFT calculations suggest that it is essentially unstrained, due to compensating, favorable, intramolecular interactions of its many phenyl rings. An attempted synthesis of tetradecaphenyl-o-terphenyl ( 4 ) by reaction of diphenylhexatriyne ( 14 ) with three equivalents of tetracyclone at 350 °C gave only the diadduct 2-(phenylethynyl)-2′,3,3′,4,4′,5,5′,6,6′-nonaphenylbiphenyl ( 15 ) in 17 % yield. Even higher temperatures failed to produce 4 and lowered the yield of 15 , perhaps due to rapid decomposition of the starting materials. Ullmann coupling of 3,4,5,6-tetraphenyl-1,2-diiodobenzene ( 16 ) and compound 9 also failed to give compound 4 .     

An unexpected product from the cyclodesulfurization of 5-[1-(3-methoxycarbonyl)thioureido]-1-(β-D-ribofuranosyl)imidazole-4- carboxamide with dicyclohexylcarbodiimide

The treatment of 5-[1-(3-methoxycarbonyl)thioureido]-1-(β-D-ribofuranosyl)imidazole-4-carboxamide with N,N'-dicyclohexylcarbodiimide in N,N-dimethylformamide has afforded 4-cyano-5-[1-(3-methoxycarbonyl)-ureido]-1-(β-D-ribofuranosyl)imidazole.     

N-[3-氰基-1-(2,6-二氯-4-三氟甲基苯基)-1H-吡唑-5-基]菊酰胺类化合物的合成及生物活性

为了寻求新的N-芳基吡唑类先导化合物, 用5种拟除虫菊酯类农药的活性基团——菊酸与高活性杀虫剂氟虫腈和其中间体5-氨基-3-氰基-1-(2,6-二氯-4-三氟甲基-苯基)吡唑在其氨基位置采用亚结构对接的方法合成得到了10个新的芳基吡唑菊酰胺类化合物. 经¹H NMR, ESI-MS和元素分析对化合物的结构进行了表征. 初步生物活性测定结果表明, 在37.5 mg/L浓度下, N-[3-氰基-1-(2,6-二氯-4-三氟甲基苯基)-4-(三氟甲基亚磺酰基)-1H-吡咯-5-基]-3-(2,2-二氯乙烯基)-2,2-二甲基环丙酰胺(3b)对小菜蛾Amaranthus spinosus抑制活性达到100%, LC₅₀为15.1 mg/L. 初步雌雄大鼠急性经口毒性综合评价属中毒级, 同时还检测了2-(4-氯苯基)-N-[3-氰基-1-(2,6-二氯-4-三氟甲基苯基)-1H-吡唑-5-基]-3-甲基丁酰胺(3i)的晶体结构.     

The preparation of some 1-(2-furyl)-2-arylethylenes

Some 1-(2-furyl)-2-arylethylenes, where the furan nucleus is substituted in position 5 with a methyl or p-chlorophenyl group and where the aryl group is phenyl, p-nitrophenyl, α-naphthyl or β-naphthyl, have been prepared by the Perkin reaction and subsequent decarboxylation of the acid. The compounds 1-12 were prepared lor of photochemistry and photoelectron spectroscopy studies. Their geometrical configurations has been established by ¹H nmr and ir spectra.     

A novel and efficient synthesis of the naturally occurring nucleoside doridosine

1-Methylisoguanosine was synthesized by a one-pot reaction involving a condensation of 5-amino-1-(β-$\text{D}$-ribofuranosyl)imidazole-4-carboxamide (1) with methyl isothiocyanate, treatment of the resulting thiourea derivative with DCC furnished 5-(3-methyl-1-ureido)-1-(β-$\text{D}$-ribofuranosyl)imidazole-4-carbonitrile (4) which was then annulated with ethanolic ammonia to furnish doridosine in a 68% yield from 1.