- Isonitriles as source and fate of imidoyl radicals: A novel homolytic α-fragmentation
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Imidoyl radicals 4a-c react with phenylacetylene to give annulation products and nitrile 12, arising from β-scission of the intermediate iminyl radical that is involved in the rearrangement of azaspirocyclohexadienyl 8. In contrast, imidoyls 4d and 15 do not react with the alkyne and give good yields of the corresponding isonitriles through a novel example of homolytic α-fragmentation.
- Nanni, Daniele,Pareschi, Patrizia,Tundo, Antonio
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- Insertion reactions of small unsaturated molecules in the N-B bonds of boron guanidinates
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We report here 1,1- and 1,2-insertion reactions of small unsaturated molecules in the N-B bonds of two boron guanidinates, (Me2N)C(NiPr)2BCy2 (1) and {iPr(H)N}C(NiPr){N(p-tBu-C6H4)}BCy2 (2), and two bisboron guanidinates(2-), {iPr(BCy2)N}C(NiPr){N(p-tBu-C6H4)}BCy2 (3) and {iPr(C8H14B)N}C(NiPr){N(p-Me-C6H4)}BC8H14 (4), the latter being prepared for the first time by double deprotonation of the corresponding guanidine with the 9-borabicyclo[3.3.1]nonane dimer, (H-BC8H14)2. Compounds 1-4 easily insert aromatic isonitriles, XylNC (Xyl = 2,6-Me2-C6H3) and (p-MeO-C6H4)NC, to give the expected diazaboroles 5-12, some of them being structurally characterised by X-ray diffraction. Interestingly, the BC8H14 derivatives 11 and 12 are in a fast temperature-dependent equilibrium with the de-insertion products, whose thermodynamic parameters are reported here. A correlation between these equilibria and the puckered heterocyclic structure found in the solid state for 11, and confirmed by DFT calculations, is also established. Reactions of the aforementioned guanidinates with CO are more sluggish or even precluded, and only one product, {iPr(H)N}C{N(p-tBu-C6H4)}(NiPr)(CO)BCy2 (13), could be isolated in moderate yields. The 1,2-insertions of benzaldehyde in compounds 1, 2 and 4 are reversible reactions in all cases, and only one of the insertion products, {iPr(H)N}C{N(p-tBu-C6H4)}(NiPr)(PhHCO)BCy2 (16a), was isolated and diffractrometrically characterised. Likewise, CO2 reversibly inserts into a N-B bond of 2 to give {iPr(H)N}C{N(p-tBu-C6H4)}(NiPr)(CO2)BCy2 (19) with a conversion of ca. 9%. In all these equilibria, de-insertion is always favoured upon increasing the temperature.
- Ramos, Alberto,Anti?olo, Antonio,Carrillo-Hermosilla, Fernando,Fernández-Galán, Rafael,Montero-Rama, María Del Pilar,Villase?or, Elena,Rodríguez-Diéguez, Antonio,García-Vivó, Daniel
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- Bis-Selenoureas for Anion Binding: A 1H NMR and Theoretical Study
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The anion binding ability of a family of bis-selenoureas L1-L3 obtained by the reaction of 1,3-bis(aminomethyl)-benzene and phenylisoselenocyanate, p-methoxyphenylisoselenocyanate and naphtylisoselenocyanate, for L1, L2, and L3, respectively, has been tested and compared to that of previously described bis-urea analogues. Results suggest that the introduction of selenium leads to an increase in the acidity of the urea NH hydrogen atoms, and therefore to a stronger affinity (more than three-fold higher) towards anion species, in particular dihydrogen phosphate, in DMSO-d6. Theoretical calculations allowed for the optimization of the adducts receptors corroborating the experimental results.
- Caltagirone, Claudia,Ciancaleoni, Gianluca,Lippolis, Vito,Mocci, Rita,Picci, Giacomo,Zielińska-B?ajet, Mariola
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- Radical perfluoroalkylation - Easy access to 2-perfluoroalkylindol-3-imines-via electron catalysis
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Arylisonitriles (2 equivalents) react with alkyl and perfluoroalkyl radicals to form 2-alkylated indole-3-imines via two sequential additions to the isonitrile moiety followed by homolytic aromatic substitution. The three component reaction comprises three C-C bond formations. The endocyclic imine functionality in the products is more reactive in follow up chemistry and hydrolysis of the exocyclic imine leads to 3-oxindoles that show fluorescence properties.
- Leifert, Dirk,Artiukhin, Denis G.,Neugebauer, Johannes,Galstyan, Anzhela,Strassert, Cristian Alejandro,Studer, Armido
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- Novel hexakis(areneisonitrile)technetium(I) complexes as radioligands targeted to the multidrug resistance P-glycoprotein
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Transport substrates and modulators of the human multidrug resistance (MDR1) P-glycoprotein (Pgp) are generally lipophilic cationic compounds, many with substituted aryl moieties. We sought to synthesize aromatic technetium isonitrile complexes to enable
- Herman,Sharma,Kronauge,Barbarics,Herman,Piwnica- Worms
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- α-Keto Phenylamides as P1′-Extended Proteasome Inhibitors
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The major challenge for proteasome inhibitor design lies in achieving high selectivity for, and activity against, the target, which requires specific interactions with the active site. Novel ligands aim to overcome off-target-related side effects such as peripheral neuropathy, which is frequently observed in cancer patients treated with the FDA-approved proteasome inhibitors bortezomib (1) or carfilzomib (2). A systematic comparison of electrophilic headgroups recently identified the class of α-keto amides as promising for next generation drug development. On the basis of crystallographic knowledge, we were able to develop a structure-activity relationship (SAR)-based approach for rational ligand design using an electronic parameter (Hammett's σ) and in silico molecular modeling. This resulted in the tripeptidic α-keto phenylamide BSc4999 [(S)-3-(benzyloxycarbonyl-(S)-leucyl-(S)-leucylamino)-5-methyl-2-oxo-N-(2,4-dimethylphenyl)hexanamide, 6a], a highly potent (IC50=38 nM), cell-permeable, and slowly reversible covalent inhibitor which targets both the primed and non-primed sites of the proteasome's substrate binding channel as a special criterion for selectivity. The improved inhibition potency and selectivity of this new α-keto phenylamide makes it a promising candidate for targeting a wider range of tumor subtypes than commercially available proteasome inhibitors and presents a new candidate for future studies.
- Voss, Constantin,Scholz, Christoph,Knorr, Sabine,Beck, Philipp,Stein, Martin L.,Zall, Andrea,Kuckelkorn, Ulrike,Kloetzel, Peter-Michael,Groll, Michael,Hamacher, Kay,Schmidt, Boris
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- Synthesis of isonitriles from N-substituted formamides using triphenylphosphine and iodine
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Treatment of N-substituted formamides with the reagent combination of triphenylphosphine and molecular iodine, in the presence of a tertiary amine, quickly produces the corresponding isocyanides in high yields under ambient conditions. The process employs readily available and low-cost reagents, a convenient synthetic procedure, and mild reaction conditions for the synthesis of various alkyl and aryl isocyanides.
- Wang, Xia,Wang, Qing-Gang,Luo, Qun-Li
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- Mild C?F Activation in Perfluorinated Arenes through Photosensitized Insertion of Isonitriles at 350 nm
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Fluorinated compounds have become important in the fields of agrochemical industry, pharmaceutical chemistry and materials sciences. Accordingly, various methods for their preparation have been developed in the past. Fluorinated compounds can be accessed via conjugation with fluorinated building blocks, via C?H fluorination or via selective activation of perfluorinated compounds to give the partially fluorinated congeners. Especially the direct activation of C?F bonds, one of the strongest σ-bonds, still remains challenging and new strategies for C?F activation are desirable. Herein a method for the photochemical activation of aromatic C?F bonds is presented. It is shown that isonitriles selectively insert into aromatic C?F bonds while aliphatic C?F bonds remain unaffected. Mechanistic studies reveal the reaction to proceed via the indirect excitation of the isonitrile to its triplet state by photoexcited acetophenone at 350 nm. Due to the relatively mild light used, the process shows high functional group tolerance and various compounds of the class of benzimidoyl fluorides are accessible from aryl isonitriles and commercially available perfluorinated arenes. (Figure presented.).
- Weidlich, Frauke,Esumi, Naoto,Chen, Dongyang,Mück-Lichtenfeld, Christian,Zysman-Colman, Eli,Studer, Armido
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- Synthesis and cation-binding studies of gold(i) complexes bearing oligoether isocyanide ligands with ester and amide as linkers
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A series of dinuclear gold(i) isocyanide complexes of bis(alkynyl)calix[4]arene was designed and synthesized, and their photophysical and cation recognition properties were studied. Complex 1, [{calix[4]arene-(OCH2CONH-C6H4CC)2}{Au(CN-C6H4O(CH2CH2O)2CH3)}2], was found to show a high selectivity towards Al3+ in CH2Cl2-MeCN (1-1 v/v). Upon addition of Al3+, drastic changes in the electronic absorption, emission and 1H NMR spectra were observed. These changes have been attributed to the formation of Au(i)?Au(i) interactions induced by the high binding affinity of the amide site for the Al3+ ion, instead of the high binding affinity expected of the oligoether site for alkali and alkaline earth metal ions. Further studies with the control complex, [{calix[4]arene-(OOC-C6H4CC)2}{Au(CN-C6H4O(CH2CH2O)2CH3)}2] (4), indicated that the amide carbonyl oxygen in the flexible pendants is crucial for the binding of Al3+. The Royal Society of Chemistry 2016.
- Hau, Franky Ka-Wah,Yam, Vivian Wing-Wah
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- Visible-Light-Induced Radical Cascade Cyclization: Synthesis of the ABCD Ring Cores of Camptothecins
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A new strategy for constructing indolizino[1,2-b]quinolin-9(11H)-ones (ring cores of camptothecins) from readily available isocyanoarenes and N-(alkyl-2-yn-1-yl)pyridin-2(1H)-ones has been developed through a visible-light-induced radical cascade cyclization process. The reaction proceeds under mild conditions with fair to excellent yields. The easy introduction of substituents for both reactants and the broad functional group tolerance of the reaction make it a straightforward route to the cores of the marketed camptothecins and their derivatives.
- Yuan, Yao,Dong, Wuheng,Gao, Xiaoshuang,Gao, Huang,Xie, Xiaomin,Zhang, Zhaoguo
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- Thermal oligomerisation of aryl isocyanides: Formation of pyrazino[1,2-a:4,5-a′]diindoles and indigo diarylimines
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The aryl isocyanides 1-4 are converted at 150°C into the hexameric pyrazino[1,2-a:4,5-a′]diindoles 15-19. 4-Fluorophenyl isocyanide, when heated at 135°C, gave the hexamer 19 and the tetrameric indigo di-arylimine 9, and when kept at ambient temperature g
- Boeyens, Jan C.A.,Cook, Leanne M.,Ding, Yunxiang,Fernandes, Manuel A.,Reid, David H.
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- Synthesis of Imides, Imidates, Amidines, and Amides by Intercepting the Aryne-Isocyanide Adduct with Weak Nucleophiles
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New aryne-based multicomponent coupling reactions for the formation of functionalized aromatic compounds have been developed. Arynes generated from triynes or tetraynes through the hexadehydro Diels-Alder reaction readily react with isocyanide to generate nitrilium intermediate. Intercepting this nitrilium species with various weak nucleophile including carboxylic acids, alcohols, sulfonamides, or water generated the corresponding imides, imidates, amidines, or amides. The high regioselectivity of these transformations was mainly controlled by the substituents of the arynes.
- Ghorai, Sourav,Lee, Daesung
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- Visible-light-induced radical cascade cyclization of oxime esters and aryl isonitriles: Synthesis of cyclopenta[: B] quinoxalines
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A visible-light-induced radical cascade cyclization of aryl isonitriles and cyclobutanone oxime esters for the synthesis of cyclopenta[b]quinoxalines has been accomplished for the first time. The key to the success of this process was the integration of the in situ-formed nitrile radical followed by the cascade radical isonitrile/nitrile insertion-cyclization. The easy introduction of substituents for both substrates and the high functional group tolerance of the reaction make it an efficient strategy to give various quinoxaline derivatives in moderate to good yields.
- Yuan, Yao,Dong, Wu-Heng,Gao, Xiao-Shuang,Xie, Xiao-Min,Zhang, Zhao-Guo
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- Development of an Industrial Process Based on the Groebke-Blackburn-Bienaymé Multicomponent Reaction: Efficient Preparation- of 3-Aminoimidazo[1,2-a]pyrazines
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3-Aminoimidazo[1,2-a]pyrazine is an important scaffold that is found in many drugs. This scaffold is rapidly accessible through a Groebke-Blackburn-Bienaymé cyclisation starting from an aminopyrazine, an aldehyde and an isocyanide. A scale-up process of this multicomponent reaction has been achieved in high yield and with excellent purity. The scope and limitations of this process leading to various 3-aminoimidazo[1,2-a]pyrazines are disclosed.
- Baenziger, Markus,Durantie, Estelle,Mathes, Christian
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- Design, synthesis and anticancer evaluation of 3-methyl-1H-indazole derivatives as novel selective bromodomain-containing protein 4 inhibitors
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Bromodomain-containing Protein 4 (BRD4), an ‘epigenetic reader’, regulates chromatin structure and gene expression via recognizing and binding acetylated lysine in histones. BRD4 has become a therapeutic target for cancers because it promotes the expression of the tumor genes, such as c-Myc, NF-κB, and Bcl-2. In this study, a new series of 3-methyl-1H-indazole derivatives were designed via virtual screening and structure-based optimization. All compounds were synthesized and evaluated for their inhibitory activities to BRD4-BD1 and their antiproliferative effects in cancer cell lines. Among them, several compounds (such as 9d, 9u and 9w) exhibited strong BRD4-BD1 affinities and inhibition activities, and potently suppressed MV4;11 cancer cell line proliferation. Among them, compound 9d showed excellent selectivity for BRD4 and effectively suppressed c-Myc, the downstream protein of BRD4. This study provided new lead compounds for further biological evaluation on BRD4.
- Dong, Ru,Zhang, Cheng,Wang, Chao,Zhou, Xin,Li, Wen,Zhang, Jin-Yang,Wang, Min,Xu, Yong,Sun, Li-Ping
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- Access to Unsymmetrically Substituted Diaryl Gold N-Acyclic Carbene (NAC) and N-Heterocyclic Carbene (NHC) Complexes via the Isonitrile Route
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A variety of unsymmetric diaryl gold N-acyclic carbene (NAC) complexes was synthesized via the isonitrile route by three different methods: (a) solvent free in a melt, (b) mechanochemically and (c) in THF at room temperature. The latter method can also be used to synthesize unsaturated gold NHC complexes. These methods overall offer access to a broad array of new complexes and remove one of the previous limitations of the isonitrile route to NAC and NHC complexes of gold, namely the inability to react with the less nucleophilic aromatic amines. The new complexes also proved to be successful as pre-catalysts in the gold-catalyzed phenol synthesis. (Figure presented.).
- Vethacke, Vanessa,Claus, Vanessa,Dietl, Martin C.,Ehjeij, Daniel,Meister, Arne,Huber, Jonas F.,Paschai Darian, Leon K.,Rudolph, Matthias,Rominger, Frank,Hashmi, A. Stephen K.
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p. 536 - 554
(2021/10/20)
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- Method for preparing isonitrile compound
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The invention discloses a method for preparing an isonitrile compound, and belongs to the field of organic synthesis. According to the method, sodium chlorodifluoroacetate or potassium bromodifluoroacetate is used as a difluoromethyl source and is condensed with primary amine under the action of alkali to obtain an isocyanide target product, so that isocyanide is generated in situ on the primary amine. The reaction raw materials, alkali and solvent used in the method are simple and easy to obtain, wide in source and convenient to operate, do not need special storage and use conditions, the method has the advantages of safety, low cost, high yield, simple process, environmental friendliness and the like, and has important application value in the fields of medicine, protein and polypeptidepreparation, pesticides, high polymer materials, dyes and the like.
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Paragraph 0033; 0088-0089
(2021/01/30)
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- Synthesis of isocyanides by reacting primary amines with difluorocarbene
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A general, convenient, and friendly route for preparing a versatile building block of isocyanides from primary amines is developed. Difluorocarbene, generated in situ from decarboxylation of chlorodifluoroacetate, reacts efficiently with primary amines to produce isocyanides. Various primary amines are well tolerated, including aryl, heteroaryl, benzyl, and alkyl amines, as well as amine residues in amino acids and peptides. Late-stage functionalization of biologically active amines is demonstrated, showing its practical capacity in drug design and peptide modification.
- Si, Yi-Xin,Zhu, Peng-Fei,Zhang, Song-Lin
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supporting information
p. 9086 - 9090
(2020/11/30)
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- Silver-Catalyzed Selective Multicomponent Coupling Reactions of Arynes with Nitriles and Isonitriles
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Pathway selective aryne-based novel multicomponent coupling reactions with isonitriles and nitriles are described. Crucial to these reactions is the formation of a silver-aryne complex, which shows differential reactivity toward isonitriles and nitriles to form two different forms of ortho-nitrilium organosilver arene species. Interception of the nitrilium of an aryne-isonitrile adduct with another isonitrile leads to the formation of benzocyclobutene-1,2-diimines, whereas the nitrilium of an aryne-nitrile adduct renders selective formation of 3H-indol-3-imines or 3-iminoindolin-2-ol depending on the structure of the nitrile employed.
- Ghorai, Sourav,Lin, Yongjia,Xia, Yuanzhi,Wink, Donald J.,Lee, Daesung
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p. 642 - 647
(2020/01/31)
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- Palladium-Catalyzed Diarylation of Isocyanides with Tetraarylleads for the Selective Synthesis of Imines and α-Diimines
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Using tetraaryllead compounds (PbAr4) as arylating reagents, isocyanides undergo selective diarylation in the presence of palladium catalysts such as Pd(OAc)2 or Pd(PPh3)4 to afford imines and/or α-diimines based on the isocyanide employed. With aliphatic isocyanides, imines are obtained preferentially, whereas α-diimines are formed in the case of electron-rich aromatic isocyanides. The differences in imine/α-diimine selectivity can be attributed to the stability of imidoylpalladium intermediates formed in this catalytic reaction. Compared with other arylating reagents, tetraaryllead compounds are excellent candidates for use in the selective transformations to imines and/or α-diimines, especially in terms of inhibiting the oligomerization of isocyanides, which results in a lower product selectivity in many transition-metal-catalyzed reactions of isocyanides.
- Tran, Cong Chi,Kawaguchi, Shin-Ichi,Kobiki, Yohsuke,Matsubara, Hitomi,Tran, Dat Phuc,Kodama, Shintaro,Nomoto, Akihiro,Ogawa, Akiya
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p. 11741 - 11751
(2019/10/02)
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- Hexafluoroisopropanol as the Acid Component in the Passerini Reaction: One-Pot Access to β-Amino Alcohols
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A new Passerini-type reaction in which hexafluoroisopropanol functions as the acid component is reported. The reaction tolerates a broad range of isocyanides and aldehydes, and the formed imidates can be reduced toward β-amino alcohols under mild and metal-free conditions. In addition, the imidate products were shown to undergo an unprecedented retro-Passerini-type reaction under microwave conditions, providing valuable mechanistic information about the Passerini reaction and its variations.
- Saya, Jordy M.,Berabez, Rayan,Broersen, Pim,Schuringa, Imme,Kruithof, Art,Orru, Romano V. A.,Ruijter, Eelco
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supporting information
p. 3988 - 3991
(2018/07/15)
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- Palladium-Catalyzed One-Pot Synthesis of N -Sulfonyl, N -Phosphoryl, and N -Acyl Guanidines
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An efficient palladium-catalyzed cascade reaction of azides with isonitrile and amines is presented; it offers an alternative facile approach toward N -sulfonyl-, N -phosphoryl-, and N -acyl-functionalized guanidines in excellent yield. These series of substituted guanidines exhibit potential biological and pharmacological activities. In addition, the less reactive intermediate benzoyl carbodiimide could be isolated by silica gel column flash chromatography in moderate yield.
- Qiao, Guanyu,Zhang, Zhen,Huang, Baoliang,Zhu, Liu,Xiao, Fan,Zhang, Zhenhua
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p. 330 - 340
(2018/01/12)
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- Thermolysis-Induced Two- or Multicomponent Tandem Reactions Involving Isocyanides and Sulfenic-Acid-Generating Sulfoxides: Access to Diverse Sulfur-Containing Functional Scaffolds
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Direct reaction of isocyanides with some sulfenic-acid-generating sulfoxides led to the effective formation of the corresponding thiocarbamic acid S-esters in good to high yields. A multicomponent reaction involving isocyanide, sulfoxide, and a suitable nucleophile has also been developed, providing ready access to a diverse range of sulfur-containing compounds, including isothioureas, carbonimidothioic acid esters, and carboximidothioic acid esters.
- Wu, Shengfeng,Lei, Xiaofang,Fan, Erkang,Sun, Zhihua
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p. 522 - 525
(2018/02/10)
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- Selective Gold-Catalysed Synthesis of Cyanamides and 1-Substituted 1H-Tetrazol-5-Amines from Isocyanides
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The newly discovered gold-catalysed reaction of isocyanides with hydrazoic acid generated in situ from trimethylsilyl azide and methanol (or, alternatively, from NaN3/AcOH) produces either cyanamides or 1-substituted 1H-tetrazol-5-amines, depending on the amount of available HN3. The reaction proceeds selectively and in generally high yields of either product, thus providing a particularly convenient access to a wide range of substituted 1H-tetrazol-5-amines that are rather difficult to access otherwise.
- ?koch, Karel,Císa?ová, Ivana,?těpni?ka, Petr
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p. 13788 - 13791
(2018/09/14)
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- TEMPO-Catalyzed Aerobic Oxidative Selenium Insertion Reaction: Synthesis of 3-Selenylindole Derivatives by Multicomponent Reaction of Isocyanides, Selenium Powder, Amines, and Indoles under Transition-Metal-Free Conditions
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A novel and efficient approach for the selenium functionalization of indoles was developed with selenium powder as the selenium source, catalyzed by 2,2,6,6-tetramethylpiperidinooxy (TEMPO) and employing O2 as the green oxidant. This protocol provides a practical route for the synthesis of 3-selenylindole derivatives and has the advantages of readily available starting materials, mild reaction conditions, and a wide scope of substrates. Electron spin-resonance (ESR) studies reveal that the approach involves the formation of nitrogen-centered radicals and selenium radicals via oxidation of in situ generated selenoates.
- Liu, Huan,Fang, Yi,Wang, Shun-Yi,Ji, Shun-Jun
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supporting information
p. 930 - 933
(2018/02/22)
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- An isocyanide based multi-component reaction under catalyst- and solvent-free conditions for the synthesis of unsymmetrical thioureas
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A new and efficient method for the synthesis of thiourea derivatives by a sequential one-pot, three-component reaction between aromatic isocyanides, amines, and 1,2-di-tert-butyldisulfane (DTBS) was developed and 27 different examples were synthesized in good to excellent yields. DTBS was identified as an effective sulfur surrogate without the use of both catalysts and solvents. This protocol does not employ any transition metal catalyst or special experimental setup.
- Singh, Karandeep,Sharma, Siddharth
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p. 197 - 201
(2016/12/28)
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- Aerobic radical-cascade cycloaddition of isocyanides, selenium and imidamides: Facile access to 1,2,4-selenadiazoles under metal-free conditions
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A novel and facile metal-free method for the green synthesis of 1,2,4-selenadiazol-5-amine derivatives through the aerobic radical-cascade multi-component reactions of isocyanides, selenium powder and imidamides is reported herein. O2 in the air was employed as the green oxidant to achieve the cycloaddition with the generation of H2O as the sole by-product. It also features good functional group compatibility and broad substrate scope. In addition, this method was successfully applied to the functionalization of biologically active molecules.
- Fang, Yi,Zhu, Zheng-Lin,Xu, Pei,Wang, Shun-Yi,Ji, Shun-Jun
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supporting information
p. 1613 - 1618
(2017/06/05)
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- Palladium-Catalyzed Synthesis of α-Diimines from Triarylbismuthines and Isocyanides
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In this study, we report a highly selective coupling reaction between triarylbismuthines and isocyanides using palladium diacetate as the catalyst, affording α-diimines, with the formation of three C-C bonds. Among several aryl sources (Ar-YLn: Y = B, Sn, Pb, Sb, Bi, I), only triarylbismuthines successfully undergo coupling with isocyanides to selectively afford α-diimines. The coupling reaction exhibits the advantages of high atom economy and convenient operation, with no need for any additive.
- Kobiki, Yohsuke,Kawaguchi, Shin-Ichi,Ogawa, Akiya
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p. 3490 - 3493
(2015/07/28)
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- Palladium-catalyzed cross-coupling reaction of azides with isocyanides
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An efficient palladium-catalyzed cross-coupling reaction of azides with isocyanides is developed, providing a general synthetic route to unsymmetric carbodiimides with excellent yields. This method shows a broad substrate scope, including not only aryl azides, but also unactivated benzyl and alkyl azides. Furthermore, from readily available substrates, Pd-catalyzed coupling with a tandem amine insertion cascade to obtain unsymmetric trisubstituted guanidines has been achieved in a one-pot fashion.
- Zhang, Zhen,Li, Zongyang,Fu, Bin,Zhang, Zhenhua
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p. 16312 - 16315
(2015/11/16)
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- Synthesis of isocyanides through dehydration of formamides using XtalFluor-E
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The formation of isocyanides from formamides using XtalFluor-E, [Et2NSF2]BF4, is presented. A wide range of formamides can be used to produce the corresponding isocyanides in up to 99% yield. In a number of cases, the crude products showed good purity (generally >80% by NMR) allowing to be used directly in multi-component reactions.
- Keita, Massaba,Vandamme, Mathilde,Mahé, Olivier,Paquin, Jean-Fran?ois
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supporting information
p. 461 - 464
(2015/03/05)
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- C-F Activation in Perfluorinated Arenes with Isonitriles under UV-Light Irradiation
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Due to the great value of fluorinated arenes in agrochemistry, medicinal chemistry and materials science, development of methods for preparation of fluorinated arenes is of high importance. They can be either accessed by arene fluorination or by partial arene defluorination. However, the carbon-fluorine bond belongs to the strongest σ-bonds, which renders C-F activation highly challenging. Here it is shown that aryl and alkyl isonitriles efficiently activate the strong C-F bond in perfluoroarenes by simple UV irradiation under mild conditions. Reactions proceed by formal direct insertion of the isonitrile into the C-F bond without any transition metal. Activation occurs at arene C-F bonds whereas aliphatic C-F bonds remain unreacted. For selected perfluoroarenes C-F activation occurs with high regioselectivity and resulting imidoyl fluorides are transformed into other valuable compounds. Theoretical studies give insights into the reaction mechanism.
- Dewanji, Abhishek,Mück-Lichtenfeld, Christian,Bergander, Klaus,Daniliuc, Constantin G.,Studer, Armido
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supporting information
p. 12295 - 12298
(2015/08/25)
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- Combretastatin A-4 inspired novel 2-aryl-3-arylamino-imidazo-pyridines/ pyrazines as tubulin polymerization inhibitors, antimitotic and anticancer agents
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Based on the pharmacophoric features of the natural product combretastatin A-4 (CA-4) and its synthetic analogues that inhibit tubulin polymerization, a series of novel 2-aryl-3-arylamino-imidazo-pyridines/pyrazines as potential antitubulin anticancer agents were designed. They were synthesized by a one-pot method involving preparation of isocyanides from the anilines via formylation and subsequent dehydration followed by their reactions with heterocyclic-2- amidines and aldehydes. Compounds 1, 2, 14, and 15 were found to exhibit significant tubulin polymerization inhibition and disruption of tubulin-microtubule dynamics similar to that of CA-4. They showed potent anticancer activities in kidney, breast and cervical cancer cell lines, and relatively low toxicity to normal cells, compared to CA-4. The compounds induced DNA and chromosomal damage, and apoptosis via cell cycle arrest in the G2/M phase. The molecular docking and molecular dynamics (MD) simulation studies revealed that disruption of microtubule dynamics might occur by interaction of the compounds at the colchicine binding site of the α,β-tubulin heterodimer interface, similar to that of CA-4. Molecular modelling analysis showed that two of the three methoxy groups at ring A of all four potent compounds (1, 2, 14, and 15) were involved in bifurcated hydrogen bonding with Cysβ241, an important molecular recognition interaction to show tubulin inhibitory activity. In comparison to CA-4, the bridging NH and the imidazo-pyridine/pyrazine moieties in the title compounds provide flexibility for attaining the required dihedral relationship of two aryls and additional pharmacophoric features required for the interaction with the key residues of the colchicine binding site.
- Sanghai, Nitesh,Jain, Vaibhav,Preet, Ranjan,Kandekar, Somnath,Das, Sarita,Trivedi, Neha,Mohapatra, Purusottam,Priyadarshani, Garima,Kashyap, Maneesh,Das, Dipon,Satapathy, Shakti Ranjan,Siddharth, Sumit,Guchhait, Sankar K.,Kundu, Chanakya N.,Bharatam, Prasad V.
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p. 766 - 782
(2014/06/10)
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- Novel ultrasound-promoted parallel synthesis of trifluoroatrolactamide library via a one-pot passerini/hydrolysis reaction sequence and their fungicidal activities
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An ultrasound-promoted one-pot Passerini/hydrolysis reaction sequence has been developed for the synthesis of trifluoroatrolactamide derivatives using a diverse range of trifluoroacetophenones and isonitriles in acetic acid. Parallel synthesis in a centrifuge tube using a noncontact ultrasonic cell crusher was used in this study as an efficient method for the rapid generation of combinatorial trifluoroatrolactamide libraries, and subsequent biochemical evaluation of the resulting compounds indicated that they possessed excellent broad-spectrum fungicidal activities. N-(4-chlorophenyl)-2-(4-ethylphenyl)-3,3, 3-trifluoro-2-hydroxypropanamide and N-(4-chlorophenyl)-3,3,3-trifluoro-2- hydroxy-2-(4-methoxyphenyl)propanamide, in particular, showed significant fungicidal activities against all of the fungal species tested in the current study.
- Yu, Shu-Jing,Zhu, Cong,Bian, Qiang,Cui, Can,Du, Xiu-Jiang,Li, Zheng-Ming,Zhao, Wei-Guang
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supporting information
p. 17 - 23
(2014/02/14)
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- Multicomponent cascade cycloaddition involving tropone, allenoate, and isocyanide: A rapid access to a 7,6,5-fused tricyclic skeleton
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Multicomponent cascade cycloaddition of tropone, allenoate, and isocyanide has been disclosed. This method allows for the rapid construction of a highly unusual tricyclic skeleton in an efficient manner. The proposed transformation proceeds through [8 + 2 + 1] cycloaddition, [1,5]-H shift, and cyclization followed by an alkoxy group migration process.
- Jia, Shuanglong,Su, Shikuan,Li, Chunju,Jia, Xueshun,Li, Jian
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supporting information
p. 5604 - 5607
(2015/02/19)
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- A general simple methodology for synthesis of isonitriles using benzene-1,3-disulfonyl dichloride
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Isonitrile derivatives have been synthesized in good to high yields by dehydration of aliphatic and aromatic formamides in the presence of benzene-1,3-disulfonyl dichloride as easy and efficient reagent.
- Ghorbani-Vaghei, Ramin,Amiri, Mostafa,Veisi, Hojat
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- Odorless isocyanide chemistry: An integrated microfluidic system for a multistep reaction sequence
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Can't smell this: An integrated continuous-flow microfluidic setup enables in situ generation, extraction, separation, and reaction of foul-smelling isocyanides with little exposure to the surroundings. Isocyanides were generated by dehydration of the corresponding N-substituted formamides, and several representative isocyanide-based organic reactions were successfully performed. DIPEA=N,N-diisopropylethylamine. Copyright
- Sharma, Siddharth,Maurya, Ram Awatar,Min, Kyoung-Ik,Jeong, Guan-Young,Kim, Dong-Pyo
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supporting information
p. 7564 - 7568
(2013/07/26)
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- One-pot synthesis of 1-substituted-5-alkylselanyl-1H-tetrazoles from isoselenocyanates: Unexpected formation of N-alkyl-N-arylcyanamides and (Z)-Se-alkyl-N-cyano-N,N′-diarylisoselenoureas
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1-Substituted-5-alkylsulfanyl-1H-tetrazoles are well known class of organic substances with various applications in medicinal chemistry or photographic industry. Their selenium analogues, 1-substituted-5-alkylselanyl-1H-tetrazoles are, however, much less explored because of the lack of suitable methods for their preparation. In this work we investigated the synthesis of 1-alkyl/aryl-5-alkylselanyl-1H-tetrazoles from synthetically available alkyl/arylisoselenocyanates. One-pot reactions of arylisoselenocyanates with sodium azide and alkylating agent led to the target 5-alkylselanyl-1-aryl-1H- tetrazoles but also to interesting side products, namely N-alkyl-N- arylcyanamides and (Z)-Se-alkyl-N-cyano-N,N′-diarylisoselenoureas. Nevertheless, when alkylisoselenocyanates were utilized as the substrates, the reactions led exclusively to the formation of 1-alkyl-5-alkylselanyl-1H- tetrazoles in good yields. This simple one-pot procedure brings new possibilities for the preparation of variously substituted selenium compounds. It also opens the way to further investigations of selenium isosteres of the widely utilized 5-thiotetrazole moiety in biomedical applications.
- Karabanovich, Galina,Roh, Jaroslav,Padělková, Zdeňka,Novák, Zdeněk,Vávrová, Kate?ina,Hrabálek, Alexandr
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p. 8798 - 8808
(2013/09/23)
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- Silver hexafluoroantimonate-catalyzed three-component [2+2+1]cycloadditions of allenoates, dual activated olefins, and isocyanides
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The intermolecular [2+2+1]multicomponent cycloadditions from readily available allenoates, dual activated olefins and isocyanides catalyzed by silver hexafluoroantimonate were studied. This protocol allowed the syntheses of highly functionalized five-membered carbocycles with exclusive regioselectivity and stereoselectivity in an efficient and atom-economical manner.
- Li, Jian,Liu, Yuejin,Li, Chunju,Jia, Xueshun
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p. 913 - 917
(2011/06/18)
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- A practical synthesis of 5-aroyl-1-aryltetrazoles using an Ugi-like 4-component reaction followed by a biomimetic transamination
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Multicomponent reactions (MCRs), followed by subsequent transformations, are fascinating tools for the rapid and effective synthesis of molecular scaffolds with potential pharmacological relevance. We became interested in the preparation of novel 5-aroyl-1-aryltetrazoles as (1) they still represent challenging structures not easily accessible through the methods described in literature, and (2) the -ketotetrazolic framework may be considered as a potential bioisostere of the enonic linker of chalcones. In the present work, a novel, simple, effective and general synthesis for this class of compounds is described. Georg Thieme Verlag Stuttgart - New York.
- Giustiniano, Mariateresa,Pirali, Tracey,Massarotti, Alberto,Biletta, Beatrice,Novellino, Ettore,Campiglia, Pietro,Sorba, Giovanni,Tron, Gian Cesare
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experimental part
p. 4107 - 4118
(2011/03/17)
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- Discovery of novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes
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We describe herein the design, synthesis and pharmacological evaluation of novel 3-arylamine-imidazo[1,2-a]pyridine derivatives structurally designed as novel symbiotic prototypes presenting analgesic and anti-inflammatory properties. The derivatives obtained were submitted to in vivo assays of nociception, hyperalgesia and inflammation, and to in vitro assays of human PGHS-2 inhibition. These assays allowed the identification of compound LASSBio-1135 (3a) as an anti-inflammatory and analgesic symbiotic prototype. This compound inhibited moderately the human PGHS-2 enzyme activity (IC50 = 18.5 μM) and reverted the capsaicin-induced thermal hyperalgesia (100 μmol/kg, po) similarly to p38 MAPK inhibitor SB-203580 (2). Additionally, LASSBio-1135 (3a) presented activity similar to celecoxib (1) regarding the reduction of the carrageenan-induced rat paw edema (33% of inhibition at 100 μmol/kg, po). We also discovered derivatives LASSBio-1140 (3c) and LASSBio-1141 (3e) as analgesic and anti-inflammatory prototypes, which were able to attenuate the capsaicin-induced thermal hyperalgesia (100 μmol/kg, po) and reduce the carrageenan-induced paw edema (ED50 = 11.5 μmol/kg (3.3 mg/kg) and 14.5 μmol/kg (4.1 mg/kg), respectively), being both more active than celecoxib (1), despite the fact that their effects involve a different mechanism of action. Additionally, derivative LASSBio-1145 (3j) showed remarkable analgesic (ED50 = 22.7 μmol/kg (8.9 mg/kg)) and anti-inflammatory (ED50 = 8.7 μmol/kg (3.4 mg/kg)) profile in vivo (100 μmol/kg; po), in AcOH-induced abdominal constrictions in mice and carrageenan-induced rat paw edema models, respectively, being a novel orally-active anti-inflammatory drug candidate that acts as a selective PGHS-2 inhibitor (IC50 = 2.8 μM).
- Lacerda, Renata B.,de Lima, Cleverton K.F.,da Silva, Leandro L.,Romeiro, Nelilma C.,Miranda, Ana Luisa P.,Barreiro, Eliezer J.,Fraga, Carlos A.M.
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- Synthesis of sugar-derived isoselenocyanates, selenoureas, and selenazoles
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Aryl, alkyl, and sugar-derived isoselenocyanates were prepared by a one-pot procedure starting from the corresponding formamides, using triphosgene as a dehydrating agent, triethylamine, and black selenium powder. The preparation of sugar selenoureas by coupling of O-protected sugar-derived isoselenocyanates with different amines, and by coupling of unprotected glycopyranosyl amines with phenyl isoselenocyanate was also accomplished. The synthesis of a glucopyranos-2-yl-selenazole starting from O-protected 2-amino-2-deoxy-d-glucose by coupling with benzoyl isoselenocyanate, Se-alkylation with phenacyl bromide, and acid-catalyzed dehydration is also reported. Unprotected N-(β-d-glucopyranosyl)-N′-phenylselenourea was transformed into a 1,2-trans-fused bicyclic isourea upon treatment with aqueous hydrogen peroxide; the same isourea was prepared by a one-pot three-step procedure from β-d-glycopyranosylamine by thiophosgenation, coupling with aniline, and HgO-mediated desulfurization.
- López, óscar,Maza, Susana,Ulgar, Víctor,Maya, Inés,Fernández-Bola?os, José G.
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experimental part
p. 2556 - 2566
(2009/08/08)
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- Lewis acid-promoted imine synthesis by the insertion of isocyanides into C-H bonds of electron-rich aromatic compounds
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The Lewis acid-promoted insertion of isocyanides into aromatic C-H bonds is reported. An imine functionality containing an array of N-substituents can be introduced directly into electron-rich aromatics in good yields.
- Tobisu, Mamoru,Yamaguchi, Seiji,Chatani, Naoto
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p. 3351 - 3353
(2008/02/12)
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- Isonitrile trapping reactions under thermolysis of alkoxyamines for the synthesis of quinolines
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An efficient tandem radical process comprising a thermal alkoxyamine homolysis, an isonitrile trapping reaction, a 5-exo-trig cyclization, and a homolytic aromatic substitution leads to substituted dihydroquinolines. Depending on the substituent R1, oxidation to dihydro-1H-cyclopenta- [b]quinolines (for R1 = aryl) or tautomerization to tetrahydro-1H-cyclopenta[b]quinolines (for R1 = CO2Me, CN) occurs. The heterocycles are obtained in moderate to good yields. Upon using microwave-induced heating, the reaction time can be shortened from 3 days to 30 min.
- Janza, Birgit,Studer, Armido
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p. 1875 - 1878
(2007/10/03)
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- Solvent effect on the sensitized photooxygenation of cyclic and acyclic α-diimines
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The reaction of singlet molecular oxygen with a series of cyclic and acyclic α-diimines was studied. Time-resolved methods were used to measure total reaction rate constants and steady-state methods were used to determine chemical reaction rate constants. GC-MS was used to tentatively assign the reaction products. 5,6-Disubstituted cyclic α-diimines are singlet oxygen quenchers, but become more effective in polar solvents. A reaction mechanism involving a perepoxide intermediate or transition state leading to a hydroperoxide seems to be a key reaction path for product formation. A replacement of the phenyl substituent for a methyl substituent opens up an additional reaction involving a perepoxide-like exciplex, which increases singlet oxygen quenching of the cyclic α-diimines. The reactivity of 5,6-disubstituted cyclic α-diimines towards singlet oxygen is highly dependent on steric interactions arising from vicinal phenyl rings and from electronic effects. 1,4-Disubstituted acyclic α-diimines are, by comparison, moderate or poor singlet oxygen quenchers. Total rate constants are scarcely dependent on solvent properties, but instead correlate with the Hildebrand parameter. These results are explained in terms of a mechanism involving a dioxetane-like exciplex that gives rise to a charged intermediate leading to products.
- Lemp, Else,Zanocco, Antonio L.,Günther, German,Pizarro, Nancy
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p. 10734 - 10746
(2007/10/03)
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- Microwave-assisted synthesis of isonitriles: A general simple methodology
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(Chemical Equation Presented) A facile conversion of formamides to isonitriles under very mild conditions and microwave irradiation is described. This simple and efficient method has been applied for the synthesis of both aliphatic and aromatic isonitriles in high yields.
- Porcheddu, Andrea,Giacomelli, Giampaolo,Salaris, Margherita
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p. 2361 - 2363
(2007/10/03)
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- An improved approach for the synthesis of α,α-dialkyl glycine derivatives by the Ugi-Passerini reaction
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A general and simple strategy for routine peptide synthesis with α,α-dialkyl glycines taking advantage of the four-component Ugi-Passerini reaction is presented. The isonitrile required for the reaction can be relatively simple and its selection based on cost, as the group it generates is easily removed under acidic conditions; in addition, this removal is not visibly affected by the bulkiness of the α-alkyl groups. Being a good leaving group from the N-terminal amino group of the amino acid, 4-methoxybenzyl was the choice for the amine component of the reaction. The method is illustrated with the synthesis of a series of acyl derivatives of several α,α-dialkyl glycines. The preparation of the latter compounds is also reported.
- Costa, Susana P.G.,Maia, Hernani L.S.,Pereira-Lima, Silvia M.M.A.
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p. 1475 - 1479
(2007/10/03)
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- Radical Addition to Isonitriles: A Route to Polyfunctionalized Alkenes through a Novel Three-Component Radical Cascade Reaction
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The reaction of aromatic disulfides, alkynes, and isonitriles under photolytic conditions affords polyfunctionalized alkenes - β-arylthio-substituted acrylamides or acrylonitriles - in fair yields through a novel three-component radical cascade reaction. The procedure entails addition of a sulfanyl radical to the alkyne followed by attack of the resulting vinyl radical to the isonitrile. A fast reaction, e.g., scavenging by a nitro derivative or β-fragmentation, is necessary in order to trap the final imidoyl radical, since addition of vinyl radicals to isonitriles seems to be a reversible process. The stereochemistry of the reaction is discussed, particularly with respect to the stereochemical outcome of related hydrogen abstraction reactions by the same vinyl radicals. The lower or even inverted preference for either geometrical isomer observed in our cases with respect to that encountered in hydrogen abstraction reactions is explained in terms of transition-state interactions and/or isomerization of the final imidoyl radical. The latter possibility is supported by semiempirical calculations, which show that the spin distribution in the imidoyl radical can allow rotation of the adjacent carbon - carbon double bond prior to β-fragmentation.
- Leardini, Rino,Nanni, Daniele,Zanardi, Giuseppe
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p. 2763 - 2772
(2007/10/03)
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- 2-Chloro-1,3-dimethylimidazolinium chloride. 1. A powerful dehydrating equivalent to DCC
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2-Chloro-1,3-dimethylimidazolinium chloride (DMC) (3) can act as a powerful dehydrating agent, replacing DCC (1) under nearly neutral conditions. Its application to acylation and dehydration is described.
- Isobe, Toshio,Ishikawa, Tsutomu
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p. 6984 - 6988
(2007/10/03)
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