- A Green and Simple Process for Preparation of Tetraalkylammonium Azide with Excellent Environmental Factor: Comparison of Batch and Flow Column Reactor
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This study presents a green and efficient process for the preparation of tetraalkylammonium azide applicable in large scale under mild conditions. Moreover, the purity of the product and the reaction yield were significantly high. In this regard, two reactors are compared: batch and flow column reactor. Results demonstrated the greater efficiency of the flow column reactor. Strong base anion exchange resin was used as catalyst. The reusability of the resin was excellent. The environmental factor of this process is 0.85, which is excellent for a chemical process in industrial scale. Accordingly, this method involved almost all principles of Green Chemistry, which is unique for its type.
- Shalibor, Abdolrahman,Modarresi-Alam, Ali Reza
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- Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines
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Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of itsin vivoactive form (by iterative α-C-H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecularN-arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.
- Askey, Hannah E.,Grayson, James D.,Tibbetts, Joshua D.,Turner-Dore, Jacob C.,Holmes, Jake M.,Kociok-Kohn, Gabriele,Wrigley, Gail L.,Cresswell, Alexander J.
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supporting information
p. 15936 - 15945
(2021/10/12)
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- Photocatalytic α-Tertiary Amine Synthesis via C?H Alkylation of Unmasked Primary Amines
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A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C?H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 percent atom-economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α-tertiary primary amines.
- Alder, Catherine M.,Ballantyne, George,Cresswell, Alexander J.,Cunningham, William B.,Edwards, Lee J.,Grayson, Matthew N.,Kinsella, Anna G.,McKay, Blandine S. J.,Mules, Tom,Ryder, Alison S. H.,Turner-Dore, Jacob
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supporting information
p. 14986 - 14991
(2020/06/20)
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- The challenge of palladium-catalyzed aromatic azidocarbonylation: From mechanistic and catalyst deactivation studies to a highly efficient process
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Azidocarbonylation of iodoarenes with CO and NaN3, a novel Heck-type carbonylation reaction, readily occurs in an organic solvent-H 2O biphasic system to furnish aroyl azides at room temperature and 1 atm. The reaction is catalyzed by Xantphos-Pd and exhibits high functional group tolerance. The catalyst deactivation product, [(Xantphos)PdI2], can be reduced in situ with PMHS to Pd(0) to regain catalytic activity. In this way, the catalyst loading has been lowered to 0.2% without any losses in selectivity at nearly 100% conversion to synthesize a series of aroyl azides in 80-90% isolated yield on a gram scale. Alternatively, the ArCON3 product can be used without isolation for further transformations in situ, e.g., to isocyanates, ureas, benzamides, and iminophosphoranes. A detailed experimental and computational study has identified two main reaction pathways for the reaction. For both routes, Ar-I oxidative addition to Pd(0) is the rate-determining step. In the presence of CO in excess, the Ar-I bond is activated by the less electron-rich Pd center of a mixed carbonyl phosphine complex. Under CO-deficient conditions, a slightly lower energy barrier pathway is followed that involves Ar-I oxidative addition to a more reactive carbonyl-free (Xantphos)Pd0 species. Mass transfer in the triphasic liquid-liquid-gas system employed for the reaction plays an important role in the competition between these two reaction channels, uniformly leading to a common aroyl azido intermediate that undergoes exceedingly facile ArCO-N 3 reductive elimination. Safety aspects of the method have been investigated.
- Miloserdov, Fedor M.,McMullin, Claire L.,Belmonte, Marta Martinez,Benet-Buchholz, Jordi,Bakhmutov, Vladimir I.,Macgregor, Stuart A.,Grushin, Vladimir V.
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supporting information
p. 736 - 752
(2014/03/21)
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- A total synthesis of (+)-negamycin through isoxazolidine allylation
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The β-amino acid antibiotic (+)-negamycin has been synthesised in ten steps from epichlorohydrin via Sakurai allylation of an isoxazolidine intermediate. The key allylation reaction proceeded with complete trans-selectivity, which is attributed to electrostatic attraction between the chlorine atom and the iminium ion in the Sakurai intermediate. This journal is the Partner Organisations 2014.
- Bates, Roderick W.,Khanizeman, Rab'Iah Nisha,Hirao, Hajime,Tay, Yu Shan,Sae-Lao, Patcharaporn
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p. 4879 - 4884
(2014/07/07)
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- Stereoselective synthesis of α- And β-glycofuranosyl amides by traceless ligation of glycofuranosyl azides
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A highly stereoselective synthesis of α- or β-glycofuranosyl amides based on the traceless Staudinger ligation of glycofuranosyl azides of the galacto, ribo, and arabino series with 2-diphenylphosphanyl-phenyl esters has been developed. Both α- and β-isomers can be obtained with excellent selectivity from a common, easily available precursor. The process does not depend on the anomeric configuration of the starting azide but appears to be controlled by the C2 configuration and by the protection/deprotection state of the substrates. A mechanistic interpretation of the results, supported by 31P NMR experiments, is offered and merged with our previous mechanistic analysis of pyranosyl azide ligation reactions. Copyright
- Nisic, Filippo,Speciale, Gaetano,Bernardi, Anna
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experimental part
p. 6895 - 6906
(2012/07/31)
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- Replacement of imidazoles by azide at an iron(III) porphyrin center: Part 1 replacement of N-methylimidazole in bis-(N-methylimidazole) tetraphenylporphyrinato iron(III)
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Addition of tetra-n-butylammonium azide to acetone solutions of the tetraphenylporphyrinato iron(III) complex [Fe(TPP)(MeIm)2] +N-3 formed in situ from the reaction of N-methylimidazole and [Fe(TPP)N3] afforded equilibrium amounts of [Fe(TPP)(MeIm)2]+ and [Fe(TPP)(MeIm)N3]. Equilibrium experiments made using a range of known concentrations of added tetra-n-butylammonium azide and N-methylimidazole using stopped-flow apparatus gave an estimate of about 50 for the equilibrium constant for the formation of [Fe(TPP)(MeIm)N3] from the addition of azide to [Fe(TPP)(MeIm) 2]+. Kinetic studies indicated that the substitution of azide ion by N-methylimidazole is a dissociative process, and the results were interpreted using a stationary state approach in which [Fe(TPP)(MeIm)] + was the transient intermediate that discriminated in favor of the reaction with azide as opposed to the reaction with N-methylimidazole by about a factor of two. Loss of N-methylimidazole from [Fe(TPP)(MeIm)2] + is at least 50 times faster than that from the product [Fe(TPP)(MeIm)N3]. Using calculated values of free azide concentrations from experimentally determined ion-pair formation constants led to success in rationalizing results obtained under different conditions.
- Jones, John G.,McKnight, John,Twigg, Martyn V.
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experimental part
p. 2766 - 2778
(2010/12/25)
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- Bicyclic carbohydrate-derived scaffolds for combinatorial libraries
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A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several diversity sites, was linked to various resins through the primary (C-6) hydroxyl and decorated on the solid phase: the hydroxyl group at C-4 was functionalized a
- Cervi, Giovanni,Peri, Francesco,Battistini, Carlo,Gennari, Cesare,Nicotra, Francesco
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p. 3349 - 3367
(2007/10/03)
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- Methods and materials for the synthesis of modified peptides
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Methods and protected amino acids useful as building blocks (protected monomers) for the synthesis of peptides and proteins that are selectively modified at one or more side-chain hydroxyl groups. Azide-bearing protecting groups allow the selective deprotection of side-chain hydroxyl groups of amino acids after synthesis of a peptide. Reaction conditions for removal of the azide-bearing protecting group can be selected which are substantially orthogonal to those that will remove α-amino protecting groups typically employed in peptide synthesis, such that hydroxyl groups protected with the azide-bearing protecting group remain protected during synthesis of the peptide chain. Various protecting groups which are readily available can be used for protecting potentially reactive side chain groups of amino acids in the peptide or protein to be modified. Preferred side-chain protecting groups are chemically distinguishable from the azide-bearing protecting group and substantially orthogonal reaction conditions can be selected such that side-chain protection of other amino acids is maintained when the azide-bearing protecting group is removed. The use of the azide-bearing protecting group of this invention for one or more hydroxy amino acids during peptide synthesis allows the selective unmasking of those azide-protected side-chain hydroxyl groups and selective modification of the hydroxyl groups that are selectively unmasked. The methods and materials herein are particularly used in synthesis of sulfated, phosphorylated and glycosylated peptides and proteins. Kits and methods of synthesizing a modified peptide or protein using the kits are also provided.
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- AZIDE AND FLUORIDE EXCHANGE REACTIONS OF HALODIAZIRINES
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Reactions of 3-aryl-3-bromodiazirines (11) with molten tetrabutylammonium fluoride at 25degC provide 65-74percent isolated vields of the novel corresponding 3-aryl-3-fluorodiazirines (12) Related reactions of 11 with tetrabutylammonium azide afford high yields of aryl nitriles.The latter reactions are believed to proceed through unstable intermediate 3-aryl-3-azidodiazirines (7).These reactions involve rate-determining formation of 7 and display kinetics which are first order in azide ion and bromodiazirine.The likely intermediacy of aryldiazirinium bromide ion pair between 11 and 7 is supported by a combination of salt effect, leaving group effect and Hammett studies.Molecular orbital calculations are employed to characterize azidodiazirines as well as the mode of their decomposition to nitriles.In particular, we consider the possible itermediacy of a 3-nitrenodiazirine or an azidocarbene.
- Moss, Robert A.,Terpinski, Jacek,Cox, D. Phillip,Denneey, Dorothy Z.,Krogh-Jespersen, Karsten
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p. 2743 - 2748
(2007/10/02)
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