- Large-bite diboranes for the μ(1,2) complexation of hydrazine and cyanide
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As part of our interest in the chemistry of polydentate Lewis acids as hosts for diatomic molecules, we have investigated the synthesis and coordination chemistry of bidentate boranes that feature a large boron-boron separation. In this paper, we describe the synthesis of a new example of such a diborane, namely 1,8-bis(dimesitylboryl)triptycene (2) and compare its properties to those of the recently reported 1,8-bis(dimesitylboryl)biphenylene (1). These comparative studies reveal that these two diboranes feature some important differences. As indicated by cyclic voltammetry, 1 is more electron deficient than 2; it also adopts a more compact and rigid structure with a boron-boron separation (4.566(5) ?) shorter by ~1 ? than that in 2 (5.559(4) ?). These differences appear to dictate the coordination behaviour of these two compounds. While 2 remains inert toward hydrazine, we observed that 1 forms a very stable μ(1,2) hydrazine complex which can also be obtained by phase transfer upon layering a solution of 1 with a dilute aqueous hydrazine solution. The stability of this complex is further reflected by its lack of reaction with benzaldehyde at room temperature. We have also investigated the behaviour of 1 and 2 toward anions. In MeOH/CHCl3 (1/1 vol) both compounds selectively bind cyanide to form the corresponding μ(1,2) chelate complexes with a B-CN-B bridge at their cores. Competition experiments in protic media show that the anionic cyanide complex formed by 1 is the most stable, with no evidence of decomplexation even in the presence of (C6F5)3B.
- Chen, Chang-Hong,Gabba?, Fran?ois P.
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- Functionalization of Sn/S Clusters with Hetero- and Polyaromatics
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We report a mild and all-purpose method to synthesize several hydrazone-functionalized homo- and heteroaromatic molecules, as well as the attachment of the latter to organic functionalized Sn/S clusters. It turned out that the size of the aromatic system has a great influence on the crystallization tendency of the products, which were characterized by NMR spectroscopy, mass spectrometry, and/or single-crystal X-ray diffraction. The last technique indicates the presence of intramolecular or intermolecular stacking of the aromatic rings.
- Leusmann, Eliza,Schneck, Felix,Dehnen, Stefanie
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- Ruthenium catalyzed β-selective alkylation of vinylpyridines with aldehydes/ketonesviaN2H4mediated deoxygenative couplings
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Umpolung (polarity reversal) tactics of aldehydes/ketones have greatly broadened carbonyl chemistry by enabling transformations with electrophilic reagents and deoxygenative functionalizations. Herein, we report the first ruthenium-catalyzed β-selective alkylation of vinylpyridines with both naturally abundant aromatic and aliphatic aldehyde/ketonesviaN2H4mediated deoxygenative couplings. Compared with one-electron umpolung of carbonyls to alcohols, this two-electron umpolung strategy realized reductive deoxygenation targets, which were not only applicable to the regioselective alkylation of a broad range of 2/4-alkene substituted pyridines, but also amenable to challenging 3-vinyl and steric-embedded internal pyridines as well as their analogous heterocyclic structures.
- Lv, Leiyang,Li, Chao-Jun
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p. 2870 - 2875
(2021/03/14)
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- Addition reactions of organic carbanion equivalents via hydrazones in water
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The addition of organometallic reagents to unsaturated bonds is one of the most powerful tools for carbon–carbon bond formations. Alkylation through organometallic reagents requires stoichiometric quantity of metal and tedious anhydrous operation in most cases. Here, we report “umpolung” nucleophilic additions of hydrazones to Michael acceptors, carbonyls and imines in water. Under the catalysis of ruthenium(II), the addition reactions could be carried out in pure water to provide various alkylation products in moderate to good yields.
- Wang, Yi-Zhan,Liu, Qi,Cheng, Liang,Yu, Song-Chen,Liu, Li,Li, Chao-Jun
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supporting information
(2021/01/11)
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- Solid phase submonomer azapeptide synthesis
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Azapeptides contain at least one aza-amino acid, where the α-carbon has been replaced by a nitrogen atom, and have found broad applicability in fields ranging from medicinal chemistry to biomaterials. In this chapter, we provide a step-by-step protocol for the solid phase submonomer synthesis of azapeptides, which includes three steps: (1) hydrazone activation and coupling onto a resin-bound peptide, (2) chemoselective semicarbazone functionalization for installation of the aza-amino acid side chain, and (3) orthogonal deprotection of the semicarbazone to complete the monomer addition cycle. We focus on semicarbazone functionalization by N-alkylation with primary alkyl halides, and describe conditions for coupling onto aza-amino acids. Such divergent methods accelerate the synthesis of peptidomimetics and allow the rapid introduction of a wide variety of natural and unnatural side chains directly on solid support using easily accessible submonomers.
- Bowles, Maxwell,Proulx, Caroline
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p. 169 - 190
(2021/05/26)
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- Palladium-Catalyzed Defluorinative Alkylation of gem-Difluorocyclopropanes: Switching Regioselectivity via Simple Hydrazones
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Conventional approaches for Pd-catalyzed ring-opening cross-couplings of gem-difluorocyclopropanes with nucleophiles predominantly deliver the β-fluoroalkene scaffolds (linear selectivity). Herein, we report a cooperative strategy that can completely switch the reaction selectivity to give the alkylated α-fluoroalkene skeletons (branched selectivity). The unique reactivity of hydrazones that enables analogous inner-sphere 3,3′-reductive elimination driven by denitrogenation, as well as the assistance of steric-embedded N-heterocyclic carbene ligand, are the key to switch the regioselectivity. A wide range of hydrazones derived from naturally abundant aryl and alkyl aldehydes are well applicable, and various gem-difluorocyclopropanes, including modified pharmaceutical and biological molecules, can be efficiently functionalized with high value alkylated α-fluorinated alkene motifs under mild conditions.
- Lv, Leiyang,Li, Chao-Jun
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supporting information
p. 13098 - 13104
(2021/05/03)
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- Submonomer synthesis of peptoids containingtrans-inducingN-imino- andN-alkylamino-glycines
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The use of hydrazones as a new type of submonomer in peptoid synthesis is described, giving access to peptoid monomers that are structure-inducing. A wide range of hydrazones were found to readily react with α-bromoamides in routine solid phase peptoid submonomer synthesis. Conditions to promote a one-pot cleavage of the peptoid from the resin and reduction to the correspondingN-alkylamino side chains were also identified, and both theN-imino- andN-alkylamino glycine residues were found to favor thetrans-amide bond geometry by NMR, X-ray crystallography, and computational analyses.
- Davern, Carolynn M.,Ison, Elon A.,Lowe, Brandon D.,Proulx, Caroline,Rosfi, Adam
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p. 8401 - 8410
(2021/06/28)
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- Copper-Catalyzed Conjugate Addition of Carbonyls as Carbanion Equivalent via Hydrazones
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Copper-catalyzed conjugate addition is a classic method for forming new carbon-carbon bonds. However, copper has never showed catalytic activity for umpolung carbanions in hydrazone chemistry. Herein, we report a facile conjugate addition of hydrazone catalyzed by readily available copper complexes at room temperature. The employment of mesitylcopper(I) and electron-rich phosphine bidentate ligand is a key factor affecting reactivity. The reaction allows various aromatic hydrazones to react with diverse conjugated compounds to produce 1,4-adducts in yields of about 20 to 99%.
- Luo, Siyi,Peng, Marie,Querard, Pierre,Li, Chen-Chen,Li, Chao-Jun
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p. 13111 - 13117
(2021/09/18)
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- N-Amino-1,8-Naphthalimide is a Regenerated Protecting Group for Selective Synthesis of Mono-N-Substituted Hydrazines and Hydrazides
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A new route to synthesis of various mono-N-substituted hydrazines and hydrazides by involving in a new C?N bond formation by using N-amino-1,8-naphthalimide as a regenerated precursor was invented. Aniline and phenylhydrazines are reproduced upon reacting these individually with 1,8-naphthalic anhydride followed by hydrazinolysis. The practicality and simplicity of this C?N dihalo alkanes; developed a synthon for bond formation protocol was exemplified to various hydrazines and hydrazides. N-amino-1,8-naphthalimide is suitable synthon for transformation for selective formation of mono-substituted hydrazine and hydrazide derivatives. Those are selective mono-amidation of hydrazine with acid halides; mono-N-substituted hydrazones from aldehydes; synthesis of N-aminoazacycloalkanes from acetohydrazide scaffold and inserted to hydroxy derivatives; distinct synthesis of N,N-dibenzylhydrazines and N-benzylhydrazines from benzyl halides; synthesis of N-amino-amino acids from α-halo esters. Ecofriendly reagent N-amino-1,8-naphthalimide was regenerated with good yields by the hydrazinolysis in all procedures.
- Manoj Kumar, Mesram,Venkataramana, Parikibanda,Yadagiri Swamy, Parikibanda,Chityala, Yadaiah
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p. 17713 - 17721
(2021/11/10)
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- Switch in Selectivity for Formal Hydroalkylation of 1,3-Dienes and Enynes with Simple Hydrazones
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Controlling reaction selectivity is a permanent pursuit for chemists. Regioselective catalysis, which exploits and/or overcomes innate steric and electronic bias to deliver diverse regio-enriched products from the same starting materials, represents a powerful tool for divergent synthesis. Recently, the 1,2-Markovnikov hydroalkylation of 1,3-dienes with simple hydrazones was reported to generate branched allylic compounds when a nickel catalyst was used. As part of the effort, shown here is that a complete switch of Markovnikov to anti-Markovnikov addition is obtained by changing to a ruthenium catalyst, thus providing direct and efficient access to homoallylic products exclusively. Isotopic substitution experiments indicate that no reversible hydro-metallation across the metal-π-allyl system occurred under ruthenium catalysis. Moreover, this protocol is applicable to the regiospecific hydroalkylation of the distal C=C bond of 1,3-enynes.
- Li, Chao-Jun,Lv, Leiyang,Qiu, Zihang,Yu, Lin
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supporting information
p. 6466 - 6472
(2020/03/13)
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- Structural studies of 2,5-disubstituted 1,3,4-thiadiazole derivatives from dithioesters under the mild condition: Studies on antioxidant, antimicrobial activities, and molecular docking
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A series of 2,5-disubstituted 1,3,4-thiadiazole was synthesized and evaluated for their antioxidant and molecular docking studies. These molecules were efficiently synthesized under mild and inexpensive starting material. Construction of these molecules developed using substituted aldehydes and substituted dithioesters in presence of NCS (N-Chorosuccinimide). The compounds 4a, 4b, 4c, 4f, and 4k showed good antibacterial and antioxidant activity among which, 4k possess excellent antibacterial and antioxidant activity. The results of antioxidant activity studies revealed that compound 4k manifested profound antioxidant potential. The molecular docking study was performed with respective newly synthesized compounds to ascertain the binding mode of 4k with respect to the critical proteins involved in biosynthesis and metabolic pathways.
- Gowda, Kemparaje,Kanchugarkoppal, Rangappa S.,Kempegowda, Mantelingu,Nagarakere, Sandhya C.,Rangappa, Shobith,Swarup, Hassan A.
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- Palladium-Catalyzed Formal Hydroalkylation of Aryl-Substituted Alkynes with Hydrazones
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We have developed an unprecedented Pd-catalyzed formal hydroalkylation of alkynes with hydrazones, which are generated in situ from naturally abundant aldehydes, as both alkylation reagents and hydrogen donors. The hydroalkylation proceeds with high regio- and stereoselectivity to form (Z)-alkenes, which are more difficult to generate compared to (E)-alkenes. The reaction is compatible with a wide range of functional groups, including hydroxy, ester, ketone, nitrile, boronic ester, amine, and halide groups. Furthermore, late-stage modifications of natural products and pharmaceutical derivatives exemplify its unique chemoselectivity, regioselectivity, and synthetic applicability. Mechanistic studies indicate the possible involvement of Pd-hydride intermediates.
- Yu, Lin,Lv, Leiyang,Qiu, Zihang,Chen, Zhangpei,Tan, Ze,Liang, Yu-Feng,Li, Chao-Jun
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supporting information
p. 14009 - 14013
(2020/06/10)
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- Palladium-catalyzed hydroalkylation of methylenecyclopropanes with simple hydrazones
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A palladium-catalyzed hydroalkylation reaction of methylenecyclopropanes via highly selective C-C σ-bond scission was achieved under mild conditions, in which simple hydrazones served as carbanion equivalents. This method featured good functional group compatibility, affording high yields of C-alkylated terminal alkenes.
- Cao, Dawei,Chen, Zhangpei,Li, Chao-Jun,Lv, Leiyang,Yao, Jinzhong,Yu, Lin
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p. 10759 - 10763
(2020/10/26)
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- Denitrative imino-diaza-Nazarov cyclization: Synthesis of pyrazoles
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An iodine-catalyzed denitrative imino-diaza-Nazarov cyclization (DIDAN) methodology has been developed for the synthesis of pyrazoles with high to excellent yields by using α-nitroacetophenone derivatives and in situ generated hydrazones. The key transformation of this oxidative 4π-electrocyclization proceeds through an enamine-iminium ion intermediate. This rapid one-pot DIDAN protocol results in the selective generation of C-C and C-N bonds and cleavage of a C-N bond. This journal is
- Aegurla, Balakrishna,Jarwal, Nisha,Peddinti, Rama Krishna
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p. 6100 - 6107
(2020/10/21)
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- Novel pyranopyrazole derivatives comprising a benzoxazole core as antimicrobial inhibitors: Design, synthesis, microbial resistance and machine aided results
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From a medical point of view lot of existing antibiotics became unusable because microbial gained strong antibiotic resistance. The combination of two compounds in one core may lead to kill such type of pathogens. Herein, we developed pyranopyrazole derivatives comprising benzoxazole moiety by green approach strategy and studied their antimicrobial performance on four bacteria and two fungi. As a result, most of the compounds delivered reliable toxicity to kill the pathogens. In those, 6a exhibited considerable activity against the microbial pathogens. Moreover, compounds 6d, 6l, and 6n showed prominent antibacterial activity. In addition, molecular docking studies of docked compounds revealed the strong bonding interaction with DNA-Gyrase and were docked into the intercalation location of DNA of the DNA-gyrase complex. The molecule bounded to the DNA stabilized by the H bonds, hydrophobic interactions, and π-π interaction. In addition, the linked 5-chlorobenazoxazole structure stabilized by the DT-8 and DG2009 of the F chain with pi-pi interactions. From the computer-aided results, it was observed that compound 6a demonstrated maximum docking score ?10.0 kcal/mole towards DNA-gyrase. Overall, this investigation suggested that these biologically active compounds can be utilized as leads for preclinical studies with the goal of developing newer antimicrobial drugs.
- Garcia, Jarem Raul,Kumari, Avula Krishna,Reddy, Guda Mallikarjuna,Reddy, Vemulapati Hanuman
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- Synthesis and comparison of copper(ii) complexes with various: N -aminotetrazole ligands involving trinitrophenol anions
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Due to the ongoing research on lead-free energetic materials, two different ligand systems (1-amino-5H-tetrazole (1-AT), 2-amino-5H-tetrazole (2-AT), 1-amino-5-methyltetrazole (1-AMT), and 2-amino-5-methyltetrazole (2-AMT)) were applied for the synthesis of 12 new energetic coordination compounds (ECC) with copper(ii) as the central metal. Different anions based on trinitrophenols (picric acid (HPA), styphnic acid (H2TNR), and trinitrophloroglucinol (H3TNPG)) were used for the specifical tuning of the energetic and physico-chemical properties of the complexes. Through the choice of ligand, the characteristics of the resulting products can be easily adjusted either towards sensitive primary explosives usable for classical initiation setups or towards laser-ignitable explosives with decreased sensitivities. The ECC were extensively characterized by e.g., X-ray diffraction (XRD), elemental analysis (EA), IR, differential thermal analysis (DTA), and UV/vis. In addition, the most promising compounds were analyzed by TGA and in classical initiation tests using nitropenta (PETN). Furthermore, the sensitivities towards external stimuli (impact, friction, and electrostatic discharge) were determined by standard methods and the influence of the anions towards them was investigated. Compounds [Cu(TNR)(1-AMT)2] and [Cu(HTNPG)(1-AMT)2] both possess appropriate sensitivities as well as thermal stabilities above 200 °C and show promising results to be used as potential lead azide replacements. In addition, all ECC were irradiated with a near infrared light (NIR) laser diode leading to different responses.
- Wurzenberger, Maximilian H. H.,Bissinger, Benjamin R. G.,Lommel, Marcus,Gruhne, Michael S.,Szimhardt, Norbert,Stierstorfer, J?rg
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supporting information
p. 18193 - 18202
(2019/12/03)
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- Nickel-catalyzed alkyl-alkyl cross-coupling reactions of non-activated secondary alkyl bromides with aldehydes as alkyl carbanion equivalents
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A novel nickel-catalyzed alkyl-alkyl cross coupling of non-activated secondary alkyl bromides with aldehydes via hydrazone intermediates has been developed. Aldehydes as alkyl carbanion equivalents replace traditional organometallic reagents. This coupling occurs on the carbon of the hydrazone rather than the nitrogen. In addition, non-activated primary and tertiary alkyl bromides also undergo the cross-coupling reaction to form new C(sp3)-C(sp3) bonds in moderate yields.
- Zhu, Chenghao,Zhang, Junliang
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supporting information
p. 2793 - 2796
(2019/03/06)
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- Nickel-catalyzed cross-coupling of umpolung carbonyls and alkyl halides
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An effective nickel-catalyzed cross-coupling of Umpolung carbonyls and alkyl halides was developed. Complementary to classical alkylation techniques, this reaction utilizes Umpolung carbonyls as the environmentally benign alkyl nucleophiles, providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.
- Zhu, Dianhu,Lv, Leiyang,Qiu, Zihang,Li, Chao-Jun
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- Nickel-Catalyzed Cross-Coupling of Umpolung Carbonyls and Alkyl Halides
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An effective nickel-catalyzed cross-coupling of Umpolung carbonyls and alkyl halides was developed. Complementary to classical alkylation techniques, this reaction utilizes Umpolung carbonyls as the environmentally benign alkyl nucleophiles, providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.
- Zhu, Dianhu,Lv, Leiyang,Qiu, Zihang,Li, Chao-Jun
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p. 6312 - 6322
(2019/05/24)
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- Denitrogenative Hydrotrifluoromethylation of Benzaldehyde Hydrazones: Synthesis of (2,2,2-Trifluoroethyl)arenes
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Reacting hydrazones of arylaldehydes with Togni's CF3-benziodoxolone reagent, in the presence of potassium hydroxide and cesium fluoride, induces a denitrogenative hydrotrifluoromethylation event to produce (2,2,2-trifluoroethyl)arenes. This novel reaction was tolerant to many electronically-diverse functional groups and substitution patterns, as well as naphthyl- and heteroaryl-derived substrates. Advantages of this process include the easy access to hydrazone precursors on a large scale, speed and operational simplicity, and being transition metal-free.
- Zhao, Zhensheng,Ma, Kevin C. Y.,Legault, Claude Y.,Murphy, Graham K.
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supporting information
p. 11240 - 11245
(2019/08/20)
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- Metal-Free Construction of the C(sp3)-CF3 Bond: Trifluoromethylation of Hydrazones with Togni's Reagent under Mild Conditions
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A metal-free trifluoromethylation of hydrazones with Togni's reagent under mild conditions was developed. Various functional groups including ester, methoxy, dimethoxy, nitro, halogen, and heterocyclic compounds were tolerated. This simple and green strategy provides a practical tool to construct C(sp3)-CF3 bonds.
- Zeng, Huiying,Luo, Zhen,Han, Xinlong,Li, Chao-Jun
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supporting information
p. 5948 - 5951
(2019/08/29)
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- Umpolung cross-coupling of polyfluoroarenes with hydrazones: Via activation of C-F bonds
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An umpolung strategy for the cross-coupling of polyfluoroarenes with various substituted hydrazones to construct C(sp2)-C(sp3) bonds is developed. In this strategy, the C-F bond of polyfluoroarenes is cleaved and coupled with moisture- and air-stable hydrazones under mild conditions with good to excellent yields. This method provides a useful tool for synthesizing polyfluorinated pharmaceuticals and functional materials.
- Cao, Dawei,Pan, Pan,Zeng, Huiying,Li, Chao-Jun
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supporting information
p. 9323 - 9326
(2019/08/08)
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- Nickel-Catalyzed Regioselective Hydrobenzylation of 1,3-Dienes with Hydrazones
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Hydroalkylation of unsaturated hydrocarbons with unstabilized carbon nucleophiles is difficult and remains a major challenge. The disclosed examples so far have mainly focused on the involvement of heteroatom and/or stabilized carbon nucleophiles as efficient reaction partners. Reported here is an unprecedented regioselective nickel-catalyzed hydrobenzylation of 1,3-dienes with hydrazones, generated in situ from abundant aryl aldehydes and ketones and acting as both the sources of unstabilized carbanion equivalent and hydride. With this strategy, both terminal and sterically hindered internal dienes are hydroalkylated efficiently in a highly selective manner, thus providing a reliable catalytic method to construct challenging C(sp3)-C(sp3) bonds.
- Lv, Leiyang,Zhu, Dianhu,Qiu, Zihang,Li, Jianbin,Li, Chao-Jun
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p. 9199 - 9205
(2019/10/14)
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- Metal-Free Synthesis of 5-Trifluoromethyl-1,2,4-Triazoles from Iodine-Mediated Annulation of Trifluoroacetimidoyl Chlorides and Hydrazones
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A metal-free approach for the synthesis of 5-trifluoromethyl-1,2,4-triazoles from trifluoroacetimidoyl chlorides and hydrazones has been achieved under aerobic oxidative conditions. The reaction proceeds through a cascade base-promoted intermolecular C?N bond formation and iodine-mediated intramolecular C?N bond oxidative coupling sequence. The protocol features broad substrate scope and can be scaled up to gram scale. (Figure presented.).
- Hu, Sipei,Yang, Zuguang,Chen, Zhengkai,Wu, Xiao-Feng
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p. 4949 - 4954
(2019/11/03)
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- Reactivity of Z- and E-isomers of 2-benzamido-3-phenylacrylohydrazide towards some carbon electrophiles. A comparative study
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Z- and E-isomers of 2-benzamido-3-phenylacrylohydrazide 2a, 2b have different relative reactivities towards some carbon electrophiles had been discussed.The Z-isomer underwent cyclization to give imidazole derivative 3 and triazine derivative 4, whereas the latter E-isomer does not undergo such cyclization. The reaction of 2a and/or 2b with 1,2-dibenzylidene hydrazine at different reaction conditions afforded the Schiff bases 6, 8 and the triazolidine derivative 9. Reactions of 2a, 2b with formic acid and phthalic anhydride gave the different cyclization products 10–14, respectively. The structures of all the new synthesized compounds were established from their IR, 1H-NMR and mass spectra as well as elemental analyses.
- Abou-Elregal, Mohsen K.,Youssef, Ahmed S. A.,Hemdan, Magdy M.,Samir, Sandy S.
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p. 2369 - 2378
(2019/07/03)
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- Maximization of the energy capability level in transition metal complexes through application of 1-amino- and 2-amino-5: H -tetrazole ligands
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Toxic lead compounds (especially lead azide and lead styphnate), reliable but highly harmful compounds, still dominate the field of primary explosives used in most ignition and initiation systems to this day. Therefore, an extensive investigation into energetic materials with similar performance and minimized toxicity led to the very promising strategy of developing energetic coordination compounds (ECC). For the first time in literature, two isomeric amino-5H-tetrazoles with sensitivities already in the range of primaries, which could be obtained via practicable, easily scalable synthesis, proved to be very promising new energetic ECC ligands. By variation of the respective isomer (1-AT, 2-AT), metal(ii) center (MnII, FeII, CuII, ZnII) and the corresponding counter-anion (Cl-, NO3-, ClO3-, ClO4-, styphnate, trinitrophloroglucinate) desired properties could be tailored gradually, yielding 20 new, highly energetic and easily accessible transition metal(ii) complexes. In addition to comprehensive characterization by XRD, IR, EA, solid-state UV/Vis, DTA and TGA, BAM standard sensitivity measurements as well as ESD and ball drop impact sensitivities were determined. Classical initiation tests (nitropenta filled detonator) validated the present approach to be extraordinarily promising for potential use in advanced initiation systems. Beyond successfully achieving set goals in terms of sensitivity and toxicity, investigated complexes match or even outperform lead-based primaries' high performance and, more importantly, do not necessarily depend on initiation by mechanical stimuli. Laser irradiation of the received primary explosives with near-infrared light (NIR) yielded initiation reliably and safely, further extending their potential for future applications.
- Szimhardt, Norbert,Wurzenberger, Maximilian H. H.,Zeisel, Lukas,Gruhne, Michael S.,Lommel, Marcus,Stierstorfer, J?rg
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supporting information
p. 16257 - 16272
(2018/08/28)
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- Cross-Coupling of Phenol Derivatives with Umpolung Aldehydes Catalyzed by Nickel
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A nickel-catalyzed cross-coupling to construct the C(sp2)-C(sp3) bond was developed from two sustainable biomass-based feedstocks: phenol derivatives with umpolung aldehydes. This strategy features the in situ generation of moisture/air-stable hydrazones from naturally abundant aldehydes, which act as alkyl nucleophiles under catalysis to couple with readily available phenol derivatives. The avoidance of using both halides as the electrophiles and organometallic or organoboron reagents (also derived from halides) as the nucleophiles makes this method more sustainable. Water tolerance, great functional group (ketone, ester, free amine, amide, etc.) compatibility, and late-stage elaboration of complex biological molecules exemplified its practicability and unique chemoselectivity over organometallic reagents.
- Lv, Leiyang,Zhu, Dianhu,Tang, Jianting,Qiu, Zihang,Li, Chen-Chen,Gao, Jian,Li, Chao-Jun
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p. 4622 - 4627
(2018/05/22)
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- Nickel-catalyzed cross-coupling of aldehydes with aryl halides: Via hydrazone intermediates
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Traditional cross-couplings require stoichiometric organometallic reagents. A novel nickel-catalyzed cross-coupling reaction between aldehydes and aryl halides via hydrazone intermediates has been developed, merging the Wolff-Kishner reduction and the classical cross-coupling reactions. Aromatic aldehydes, aryl iodides and aryl bromides are especially effective in this new cross-coupling chemistry.
- Tang, Jianting,Lv, Leiyang,Dai, Xi-Jie,Li, Chen-Chen,Li, Lu,Li, Chao-Jun
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supporting information
p. 1750 - 1753
(2018/02/21)
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- Synthesis, antiproliferative and pro-apoptotic effects of nitrostyrenes and related compounds in Burkitt’s lymphoma
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Background: Cancers of the lymphatic cells (lymphomas) account for approximately 12% of malignant diseases worldwide. The nitrostyrene scaffold is identified as a lead target structure for the development of particularly effective compounds targeting Burkitt’s lymphoma (BL). Objectives: The aims of the curent study were to synthesise a panel of nitrostyrene compounds and to evaluate their activity in Burkitt’s lymphoma (BL). Methods: A panel of structurally varied compounds were designed and synthesised using Henry Knoevenagel condensation reactions. Single crystal X-Ray analysis confirmed the E configuration for six examples of these novel structures. A number of nitrostyrene-related compounds were also investigated including 1,3-bis(aryl)-2-nitropropenes together with heterocyclic scaffolds containing the nitrovinyl pharmacophore such as 3-nitro-2-phenyl-2H-chromenes. The antiproliferative activities of the compounds were evaluated using the BL cell lines EBV- MUTU-1 and EBV+ DG-75 (chemoresistant) to establish preliminary structure-activity relationships. Results: Lead compounds with optimized nitrostyrene scaffolds and 3-nitro-2-phenyl-2Hchromene structures were successfully established with typical IC50 values of 0.45 μM and 0.47 μM in MUTU-1 cells and 1.41 μM and 1.92 μM, respectively, in DG-75 cells. The mechanism of cell death was identified as apoptotic and the lead compound was found to elicit comparable apoptotic effects to Taxol in Burkitt’s lymphoma cell lines MUTU-1 and DG-75. Conclusion: This class of pharmaceutically active compounds with potential for the treatment of Burkitt’s lymphoma suggest a potential role for nitrostyrene based agents in chemotherapy.
- Byrne, Andrew J.,Bright, Sandra A.,Fayne, Darren,McKeown, James P.,McCabe, Thomas,Twamley, Brendan,Williams, Clive,Meegan, Mary J.
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p. 181 - 199
(2018/03/13)
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- Iron-Catalyzed Nucleophilic Addition Reaction of Organic Carbanion Equivalents via Hydrazones
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Earth-abundant and well-defined iron complexes are found to be cheap and effective catalysts for a series of "umpolung" nucleophilic additions of hydrazones. The new catalytic system not only maintains the broad substrate scope of an earlier expensive ruthenium system but also attains chemoselectivity of different kinds of carbonyl groups. Furthermore, the iron catalyst enables this reaction at ambient temperature.
- Li, Chen-Chen,Dai, Xi-Jie,Wang, Haining,Zhu, Dianhu,Gao, Jian,Li, Chao-Jun
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supporting information
p. 3801 - 3805
(2018/07/25)
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- Green, Catalyst-Free Reaction of Indoles with β-Fluoro-β-nitrostyrenes in Water
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The reaction of 2-fluoro-2-nitrostyrenes with various indoles was investigated. We found that the reaction proceeds as a Michael addition in a highly regioselective manner to form 3-(1-aryl-2-fluoro-2-nitroethyl)-1H-indoles. Thus, a green and catalyst-free synthesis of these compounds was developed using water as a reaction medium. The high effectiveness of this approach was demonstrated through the preparation of target products in up to 92 % isolated yield. Subsequent reduction of the nitro group was investigated. We found that due to the instability of the intermediate α-fluoro amines, the reduction led to non-fluorinated tryptamine derivatives.
- Aldoshin, Alexander S.,Tabolin, Andrey A.,Ioffe, Sema L.,Nenajdenko, Valentine G.
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p. 3816 - 3825
(2018/07/31)
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- Umpolung of Carbonyl Groups as Alkyl Organometallic Reagent Surrogates for Palladium-Catalyzed Allylic Alkylation
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Palladium-catalyzed allylic alkylation of nonstabilized carbon nucleophiles is difficult and remains a major challenge. Reported here is a highly chemo- and regioselective direct palladium-catalyzed C-allylation of hydrazones, generated from carbonyls, as a source of umpolung unstabilized alkyl carbanions and surrogates of alkyl organometallic reagents. Contrary to classical allylation techniques, this umpolung reaction utilizes hydrazones prepared not only from aryl aldehydes but also from alkyl aldehydes and ketones as renewable feedstocks. This strategy complements the palladium-catalyzed coupling of unstabilized nucleophiles with allylic electrophiles by providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.
- Zhu, Dianhu,Lv, Leiyang,Li, Chen-Chen,Ung, Sosthene,Gao, Jian,Li, Chao-Jun
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supporting information
p. 16520 - 16524
(2018/11/23)
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- Solvent-free ring cleavage hydrazinolysis of certain biginelli pyrimidines
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Certain Biginelli pyrimidines with ester substitution in C5 were subjected to unexpected ring opening upon solvent-free reaction with hydrazine hydrate to give three products: pyrazole, arylidenehydrazines, and urea/thiourea, respectively. The nonisolable carbohydrazide intermediates are formed firstly followed by the intermolecular nucleophilic attack of terminal amino group of hydrazide function on sp2 C6 rather than the sp3 C4 to give the ring adduct which was produced as a final product.
- Said, Mohamed A.,Eldehna, Wagdy M.,Ghabbour, Hazem A.,Kabil, Maha M.,Al-shakliah, Nasser S,Abdel-Aziz, Hatem A
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- Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds
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Nucleophilic addition reactions of organometallic reagents to carbonyl compounds for carbon-carbon bond construction have played a pivotal role in modern chemistry. However, this reaction's reliance on petroleum-derived chemical feedstocks and a stoichiometric quantity of metal have prompted the development of many carbanion equivalents and catalytic metal alternatives. Here, we show that naturally occurring carbonyls can be used as latent alkyl carbanion equivalents for additions to carbonyl compounds, via reductive polarity reversal. Such 'umpolung' reactivity is facilitated by a ruthenium catalyst and diphosphine ligand under mild conditions, delivering synthetically valuable secondary and tertiary alcohols in up to 98% yield. The unique chemoselectivity exhibited by carbonyl-derived carbanion equivalents is demonstrated by their tolerance to protic reaction media and good functional group compatibility. Enantioenriched tertiary alcohols can also be accessed with the aid of chiral ligands, albeit with moderate stereocontrol. Such carbonyl-derived carbanion equivalents are anticipated to find broad utility in chemical bond formation.
- Wang, Haining,Dai, Xi-Jie,Li, Chao-Jun
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p. 374 - 378
(2017/04/03)
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- Carbonyls as Latent Alkyl Carbanions for Conjugate Additions
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Conjugate addition of carbon nucleophiles to electron-deficient olefins is one of the most powerful methods for forming carbon–carbon bonds. Despite great achievements in controlling the selectivity, variation of the carbon nucleophiles remains largely underexplored, with this approach relying mostly on organometallic reagents. Herein, we report that naturally abundant carbonyls can act as latent carbon nucleophiles for conjugate additions through a ruthenium-catalyzed process, with water and nitrogen as innocuous byproducts. The key to our success is homogeneous ruthenium(II) catalysis, combined with phosphines as spectator ligands and hydrazine as the reducing agent. This chemistry allows the incorporation of highly functionalized alkyl fragments into a vast array of electron-deficient olefins under mild reaction conditions in a reaction complementary to the classical organometallic-reagent-based conjugate additions mediated or catalyzed by “soft” transition metals.
- Dai, Xi-Jie,Wang, Haining,Li, Chao-Jun
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supporting information
p. 6302 - 6306
(2017/05/19)
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- Umpolung Addition of Aldehydes to Aryl Imines
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One of the classical ways to synthesize amines involves the coupling of carbonyl compounds and imines, either through enolate chemistry or acyl-based carbanion equivalents. We herein report an alternative strategy that is based on the use of aldehydes as alkyl carbanion equivalents in a reductive coupling with aryl imines. A wide array of secondary amines can be synthesized in moderate to high yields. This reaction is mediated by hydrazine and catalyzed by ruthenium(II) complexes, and it tolerates various functional groups, such as esters, amides, and nitriles.
- Chen, Ning,Dai, Xi-Jie,Wang, Haining,Li, Chao-Jun
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supporting information
p. 6260 - 6263
(2017/05/19)
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- Synthesis of Aryldihalomethanes by Denitrogenative Dihalogenation of Benzaldehyde Hydrazones
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We report a denitrogenative dihalogenation reaction of phenyldiazomethanes in which the hypervalent iodine reagents PhICl2 and TolIF2 act as surrogates for elemental chlorine and fluorine. Halogen transfer from iodane to aryldiazomethane is described, as is a tandem oxidative dihalogenation reaction between iodane and hydrazone. This is the first use of non-α-stabilized diazo compounds in this reaction, which provided an efficient synthesis of aryldifluoromethane (ArCHF2) and aryldichloromethane (ArCHCl2) derivatives. (Figure presented.).
- Zhao, Zhensheng,Kulkarni, Kaivalya G.,Murphy, Graham K.
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supporting information
p. 2222 - 2228
(2017/07/07)
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- Ruthenium(II)-catalyzed olefination: Via carbonyl reductive cross-coupling
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Natural availability of carbonyl groups offers reductive carbonyl coupling tremendous synthetic potential for efficient olefin synthesis, yet the catalytic carbonyl cross-coupling remains largely elusive. We report herein such a reaction, mediated by hydrazine under ruthenium(ii) catalysis. This method enables facile and selective cross-couplings of two unsymmetrical carbonyl compounds in either an intermolecular or intramolecular fashion. Moreover, this chemistry accommodates a variety of substrates, proceeds under mild reaction conditions with good functional group tolerance, and generates stoichiometric benign byproducts. Importantly, the coexistence of KOtBu and bidentate phosphine dmpe is vital to this transformation.
- Wei, Wei,Dai, Xi-Jie,Wang, Haining,Li, Chenchen,Yang, Xiaobo,Li, Chao-Jun
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p. 8193 - 8197
(2017/11/27)
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- The diaza-Nazarov cyclization involving a 2,3-diaza-pentadienyl cation for the synthesis of polysubstituted pyrazoles
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An unprecedented iodine-mediated diaza-Nazarov (DAN) type cyclization for the construction of substituted pyrazoles from easily available starting materials via an enamine-iminium ion intermediate is described. The oxidative cyclization worked under green conditions with remarkable regioselectivity. This one-pot, efficient and operationally simple three-component intramolecular regioselective DAN cyclization displayed a wide range of substrate scope. The dichotomy of reaction pathways has been explored with density functional theory in the gas phase and solution phase. Of the possible 1,5-, 1,6-, and 1,7-electrocyclizations, the DAN cyclization, i.e., the 1,5-pathway offers the lowest activation energy barrier supporting our experimental observations.
- Aegurla, Balakrishna,Peddinti, Rama Krishna
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p. 9643 - 9652
(2017/11/30)
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- DOPAMINE D3 RECEPTOR ANTAGONISTS COMPOUNDS
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The disclosure is directed to novel dopamine D3 receptor antagonists, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, including treating drug dependency and psychosis.
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Page/Page column 88
(2016/05/19)
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- Synthesis of esters by in situ formation and trapping of diazoalkanes
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A general method has been developed for the in situ formation and trapping of diazoalkanes by carboxylic acids to form esters. The method is applicable to a large variety of carboxylic acids using diazo compounds that are formed from the hydrazones of benzaldehydes and aryl ketones. In situ reaction monitoring with IR spectroscopy (ReactIR) was used to demonstrate that slow addition of the hydrazone to a mixture of oxidant and carboxylic acid avoids the buildup of the diazo compound. This method enables the safe preparation of esters from simple precursors without isolation of diazo compounds.
- Squitieri, Richard A.,Shearn-Nance, Galen P.,Hein, Jason E.,Shaw, Jared T.
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p. 5278 - 5284
(2016/07/14)
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- The p: K a of Br?nsted acids controls their reactivity with diazo compounds
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We study the O-alkylation of phosphate groups by alkyl diazo compounds in a range of small molecules and biopolymers. We show that the relatively high pKa of phosphate in comparison to the other naturally occurring Br?nsted acids can be exploited to control alkylation selectivity. We provide a simple protocol for chemical modification of some of the most important instances of phosphates in natural compounds including in small molecule metabolites, nucleic acids, and peptides.
- Fei, Na,Sauter, Basilius,Gillingham, Dennis
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supporting information
p. 7501 - 7504
(2016/06/14)
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- 1,2,4-Triazolyl 5-Azaspiro[2.4]heptanes: Lead Identification and Early Lead Optimization of a New Series of Potent and Selective Dopamine D3 Receptor Antagonists
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A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.
- Micheli, Fabrizio,Bacchi, Alessia,Braggio, Simone,Castelletti, Laura,Cavallini, Palmina,Cavanni, Paolo,Cremonesi, Susanna,Dal Cin, Michele,Feriani, Aldo,Gehanne, Sylvie,Kajbaf, Mahmud,Marchió, Luciano,Nola, Selena,Oliosi, Beatrice,Pellacani, Annalisa,Perdonà, Elisabetta,Sava, Anna,Semeraro, Teresa,Tarsi, Luca,Tomelleri, Silvia,Wong, Andrea,Visentini, Filippo,Zonzini, Laura,Heidbreder, Christian
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p. 8549 - 8576
(2016/10/03)
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- Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): Cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities
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Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 ? resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.
- Witschel, Matthias C.,Rottmann, Matthias,Schwab, Anatol,Leartsakulpanich, Ubolsree,Chitnumsub, Penchit,Seet, Michael,Tonazzi, Sandro,Schwertz, Geoffrey,Stelzer, Frank,Mietzner, Thomas,McNamara, Case,Thater, Frank,Freymond, Céline,Jaruwat, Aritsara,Pinthong, Chatchadaporn,Riangrungroj, Pinpunya,Oufir, Mouhssin,Hamburger, Matthias,M?ser, Pascal,Sanz-Alonso, Laura M.,Charman, Susan,Wittlin, Sergio,Yuthavong, Yongyuth,Chaiyen, Pimchai,Diederich, Fran?ois
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supporting information
p. 3117 - 3130
(2015/04/27)
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- Fluorogenic Strain-Promoted Alkyne-Diazo Cycloadditions
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Fluorogenic reactions, in which non- or weakly fluorescent reagents produce highly fluorescent products, are attractive for detecting a broad range of compounds in the fields of bioconjugation and material sciences. Herein, we report that a dibenzocyclooctyne derivative modified with a cyclopropenone moiety (Fl-DIBO) can undergo fast strain-promoted cycloaddition reactions under catalyst-free conditions with azides, nitrones, nitrile oxides, as well as mono- and disubstituted diazo-derivatives. Although the reaction with nitrile oxides, nitrones, and disubstituted diazo compounds gave cycloadducts with low quantum yield, monosubstituted diazo reagents produced 1H-pyrazole derivatives that exhibited an approximately 160-fold fluorescence enhancement over Fl-DIBO combined with a greater than 10 000-fold increase in brightness. Concluding from quantum chemical calculations, fluorescence quenching of 3H-pyrazoles, which are formed by reaction with disubstituted diazo-derivatives, is likely due to the presence of energetically low-lying (n,π?) states. The fluorogenic probe Fl-DIBO was successfully employed for the labeling of diazo-tagged proteins without detectable background signal. Diazo-derivatives are emerging as attractive reporters for the labeling of biomolecules, and the studies presented herein demonstrate that Fl-DIBO can be employed for visualizing such biomolecules without the need for probe washout.
- Friscourt, Frédéric,Fahrni, Christoph J.,Boons, Geert-Jan
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supporting information
p. 13996 - 14001
(2015/09/28)
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- Azapeptides as CD36 binding compounds
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An azapeptide compound of Formula I: A-(Xaa)a-N(RA)—N(RB)—C(O)-(Xaa′)b-B??I.
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Page/Page column 102-103
(2015/09/23)
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- N -aminoimidazolidin-2-one peptidomimetics
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The synthesis of N-aminoimidazolidin-2-one (Aid) peptidomimetics has been achieved by alkylation of the urea nitrogen of a semicarbazone residue using ethylene bromide. The Aid scaffold combines electronic and structural constraints to rigidify the peptide backbone in the equivalent of an aza variant of a Freidinger-Veber lactam. The syntheses and isolation of 25 Aid peptides, including eight GHRP-6 analogues, are reported to demonstrate the utility of this method for controlling conformation.
- Doan, Ngoc-Duc,Hopewell, Robert,Lubell, William D.
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supporting information
p. 2232 - 2235
(2014/05/06)
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- Diversity-oriented synthesis of azapeptides with basic amino acid residues: Aza-lysine, aza-ornithine, and aza-arginine
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Aza-peptides with basic amino acid residues (lysine, ornithine, arginine) and derivatives were synthesized by an effective approach featuring alkylation of a hydrazone-protected aza-glycine residue with α-bromo ω-chloro propane and butane to provide the corresponding alkyl chloride side chains. Displacement of the chloride with azide and various amines gave entry to azaOrn, azaLys, and azaArg containing peptides as demonstrated by the solution and solid-phase syntheses of 29 examples, including an aza-library of Growth Hormone Releasing Peptide-6 analogs.
- Traore, Mariam,Doan, Ngoc-Duc,Lubell, William D.
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supporting information
p. 3588 - 3591
(2014/07/21)
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- Submonomer synthesis of azapeptide ligands of the Insulin Receptor Tyrosine Kinase domain
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Azapeptide ligands of the Insulin Receptor Tyrosine Kinase (IRTK) were developed by solid-phase submonomer azapeptide synthesis in sufficient isolated yields (36-55%) and purities >95% for structure-activity relationship studies. The azapeptides adopted folded geometries with some proportion of random coil according to CD and NMR spectroscopy. In vitro phosphorylation of the IRTK domain in the presence of azapeptides produced a lead inhibitor, Ac-DIazaYET-NH2 (~50% at 400 μM) whereas the [aza-DOPA 3] and [aza-Glu4] analogs were found to stimulate IRTK phosphorylations. Thus, azapeptide ligands of the IRTK provide important modulatory activity of this important class of enzymes for anti-cancer and related applications in drug discovery.
- Kurian, Lathamol A.,Silva, Tammy A.,Sabatino, David
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supporting information
p. 4176 - 4180
(2014/12/09)
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- A novel one pot multi-component strategy for facile synthesis of 5-aryl-[1,2,4]triazolidine-3-thiones
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We have disclosed an efficient, one pot, novel multi-component approach for the synthesis of 5-aryl-[1,2,4]triazolidine-3-thiones from aldehyde, hydrazine hydrate, and trimethylsilyl isothiocyanate (TMSNCS) in the presence of catalytic amount of sulfamic acid. High yields, easy work-up procedure, no chromatographic separation, and novelty in multi-component strategy are the main merits of the present strategy.
- Mane,Pore
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supporting information
p. 6601 - 6604
(2015/01/09)
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