- Visible-Light-Induced Regioselective Deaminative Alkylation of Coumarins via Photoredox Catalysis
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3-Alkylated coumarins have many applications in medicinal chemistry, however, methods access to such structures are still limited. Herein, we report a site-selective photocatalytic deaminative alkylation of coumarins utilizing pyridinium-activated aliphatic primary amines as alkylation reagents. The protocol was highlighted by its mild reaction conditions, operational simplicity, and broad functional group compatibility. Moreover, this strategy enables late-stage modification of some pharmaceuticals and natural products, thus providing an appealing approach to valuable molecules in medicinal chemistry. (Figure presented.).
- Tao, Maoling,Wang, An-Jun,Guo, Peng,Li, Weipiao,Zhao, Liang,Tong, Jie,Wang, Haoyang,Yu, Yanbo,He, Chun-Yang
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supporting information
p. 24 - 29
(2021/10/19)
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- Sulfinates from Amines: A Radical Approach to Alkyl Sulfonyl Derivatives via Donor-Acceptor Activation of Pyridinium Salts
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Synthetically versatile alkyl sulfinates can be prepared from readily available amines, using Katritzky pyridinium salt intermediates. In a catalyst-free procedure, primary, secondary, and benzylic alkyl radicals are generated by photoinduced or thermally induced single-electron transfer (SET) from an electron donor-acceptor (EDA) complex, and trapped by SO2 to generate sulfonyl radicals. Hydrogen atom transfer (HAT) from Hantzsch ester gives alkyl sulfinate products, which are used to prepare a selection of medicinal chemistry relevant sulfonyl-containing motifs.
- Andrews, Jonathan A.,Pantaine, Lo?c R. E.,Palmer, Christopher F.,Poole, Darren L.,Willis, Michael C.
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supporting information
p. 8488 - 8493
(2021/11/01)
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- The Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3–sp3 Carbon–Carbon Bonds
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We have developed a deaminative–decarboxylative protocol to form new carbon(sp3)–carbon(sp3) bonds from activated amines and carboxylic acids. Amines and carboxylic acids are ubiquitous building blocks, available in broad chemical diversity and at lower cost than typical C?C coupling partners. To leverage amines and acids for C?C coupling, we developed a reductive nickel-catalyzed cross-coupling utilizing building block activation as pyridinium salts and redox-active esters, respectively. Miniaturized high-throughput experimentation studies were critical to our reaction optimization, with subtle experimental changes such as order of reagent addition, composition of a binary solvent system, and ligand identity having a significant impact on reaction performance. The developed protocol is used in the late-stage diversification of pharmaceuticals while more than one thousand systematically captured and machine-readable reaction datapoints are reposited.
- Cernak, Tim,Zhang, Zirong
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supporting information
p. 27293 - 27298
(2021/11/22)
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- Continuous-Flow Synthesis of Pyrylium Tetrafluoroborates: Application to Synthesis of Katritzky Salts and Photoinduced Cationic RAFT Polymerization
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Katritzky salts have emerged as effective alkyl radical sources upon metal- or photocatalysis. These are typically prepared from the corresponding triarylpyrylium ions, in turn an important class of photocatalysts for small molecules synthesis and photopolymerization. Here, a flow method for the rapid synthesis of both pyrylium and Katrizky salts in a telescoped fashion is reported. Moreover, several pyrylium salts were tested in the photoinduced RAFT polymerization of vinyl ethers under flow and batch conditions.
- Sambiagio, Carlo,Ferrari, Matteo,Van Beurden, Koen,Ca', Nicola Della,Van Schijndel, Jack,Noel, Timothy
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supporting information
p. 2042 - 2047
(2021/04/05)
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- Biocompatible Photoinduced Alkylation of Dehydroalanine for the Synthesis of Unnatural α-Amino Acids
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A site-selective alkylation of dehydroalanine to access protected unnatural amino acids is described. The protocol is characterized by the wide nature of alkyl radicals employed, mild conditions, and functional group compatibility. This protocol is further extended to access peptides, late-stage functionalization of pharmaceuticals, and enantioenriched amino acids.
- Delgado, José A. C.,Correia, José T. M.,Pissinati, Emanuele F.,Paix?o, Márcio W.
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supporting information
p. 5251 - 5255
(2021/07/20)
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- Metal-free synthesis of unsymmetrical selenides from pyridinium salts and diselenides catalysed by visible light
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We report the first metal-free selenolations of pyridinium salts with diselenides to prepare unsymmetrical organoselenides catalysed by visible light. This protocol is an efficient and green method for the preparation of unsymmetrical organoselenides because metal-free conditions and readily accessible diselenides are used.
- Ji, Liangshuo,Qiao, Jiamin,Li, Ankun,Jiang, Zeyi,Lu, Kui,Zhao, Xia
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supporting information
(2021/05/04)
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- C-H Alkylation of Aldehydes by Merging TBADT Hydrogen Atom Transfer with Nickel Catalysis
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Catalyst controlled site-selective C-H functionalization is a challenging but powerful tool in organic synthesis. Polarity-matched and sterically controlled hydrogen atom transfer (HAT) provides an excellent opportunity for site-selective functionalization. As such, the dual Ni/photoredox system was successfully employed to generate acyl radicals from aldehydes via selective formyl C-H activation and subsequently cross-coupled to generate ketones, a ubiquitous structural motif present in the vast majority of natural and bioactive molecules. However, only a handful of examples that are constrained to the use of aryl halides are developed. Given the wide availability of amines, we developed a cross-coupling reaction via C-N bond cleavage using the economic nickel and TBADT catalyst for the first time. A range of alkyl and aryl aldehydes were cross-coupled with benzylic and allylic pyridinium salts to afford ketones with a broad spectrum of functional group tolerance. High regioselectivity toward formyl C-H bonds even in the presence of α-methylene carbonyl or α-amino/oxy methylene was obtained.
- Murugesan, Vetrivelan,Ganguly, Anirban,Karthika, Ardra,Rasappan, Ramesh
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supporting information
p. 5389 - 5393
(2021/07/21)
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- Visible-Light-Induced Deaminative Alkylation/Cyclization of Alkyl Amines with N-Methacryloyl-2-phenylbenzoimidazoles in Continuous-Flow Organo-Photocatalysis
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Herein, we present a metal-free visible-light-induced eosin-y-catalyzed deaminative strategy for the sequential alkylation/cyclization of N-methacryloyl-2-phenylbenzoimidazoles with alkyl amine-derived Katritzky salts, which provides an efficient avenue for the construction of various benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one derivatives in moderate to excellent yields under mild reaction conditions. The key enabling feature of this novel reaction includes utilization of redox-active pyridinium salts from abundant and inexpensive primary amine feedstocks that were converted into alkyl radicals via C-N bond scission and subsequent alkylation/cyclization with N-methacryloyl-2-phenylbenzoimidazoles by the formation of two new C-C bonds. In addition, we implemented this protocol for a variety of amino acids, affording the products in moderate yields. Moreover, the novel, environmentally benign batch protocol was further carried out in a continuous-flow regime by utilizing a perfluoroalkoxy alkane tubing microreactor under optimized reaction conditions with a blue light-emitting diode light source, enabling excellent yields and a shorter reaction time (19 min) versus the long reaction time (16 h) of the batch reaction. The reaction displays excellent functional group tolerance, easy operation, scalability, mild reaction conditions, and broad synthetic utility.
- Ramesh, Vankudoth,Gangadhar, Maram,Nanubolu, Jagadeesh Babu,Adiyala, Praveen Reddy
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supporting information
p. 12908 - 12921
(2021/09/18)
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- Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts
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A ruthenium-catalyzed photoredox coupling of substituted N-aryltetrahydroisoquinolines (THIQs) and different bench-stable pyridinium salts was successfully developed to give fast access to 1-benzyl-THIQs. Furthermore, secondary alkyl and allyl groups were also successfully introduced via the same method. Additionally, the typically applied N-phenyl group in the THIQ substrate could be replaced by the cleavable p-methoxyphenyl (PMP) group and successful N-deprotection was demonstrated.
- No?l, Timothy,Sambiagio, Carlo,Sch?nbauer, David,Schnürch, Michael
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supporting information
p. 809 - 817
(2020/05/18)
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- Nickel-Catalyzed Cross-Coupling of Alkyl Carboxylic Acid Derivatives with Pyridinium Salts via C-N Bond Cleavage
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The electrophile-electrophile cross-coupling of carboxylic acid derivatives and alkylpyridinium salts via C-N bond cleavage is developed. The method is distinguished by its simplicity and steers us through a variety of functionalized ketones in good to excellent yields. Besides acid chlorides, carboxylic acids were also employed as acylating agents, which enabled us to incorporate acid-sensitive functional groups such as MOM, BOC, and acetal. Control experiments with TEMPO revealed a radical pathway.
- Pulikottil, Feba Thomas,Pilli, Ramadevi,Suku, Rohith Valavil,Rasappan, Ramesh
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supporting information
p. 2902 - 2907
(2020/04/09)
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- Copper-Catalyzed Deaminative Difluoromethylation
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The difluoromethyl group (CF2H) is considered to be a lipophilic and metabolically stable bioisostere of an amino (NH2) group. Therefore, methods that can rapidly convert an NH2 group into a CF2H group would be of great value to medicinal chemistry. We report herein an efficient Cu-catalyzed approach for the conversion of alkyl pyridinium salts, which can be readily synthesized from the corresponding alkyl amines, to their alkyl difluoromethane analogues. This method tolerates a broad range of functional groups and can be applied to the late-stage modification of complex amino-containing pharmaceuticals.
- Cai, Aijie,Liu, Wei,Wang, Yufei,Yan, Wenhao,Yang, Dongqi,Yang, Kundi,Zacate, Samson B.,Zeng, Xiaojun
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supporting information
p. 16398 - 16403
(2020/07/17)
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- Visible Light-Driven α-Alkylation of N-Aryl tetrahydroisoquinolines Initiated by Electron Donor-Acceptor Complexes
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The visible light-driven α-alkylation of N-aryl tetrahydroisoquinolines was initiated through electron donor-acceptor complex photochemistry. The reaction can proceed smoothly without the addition of any photocatalysts, transition-metal catalysts, or additional oxidants. The proposed mechanism was supported by various mechanistic studies, and the reactive open-shell alkyl radicals were generally produced from an alkylamine and underwent radical coupling for alkylating a wide range of N-aryl tetrahydroisoquinolines.
- Dai, Peng,Deng, Hongping,Li, Yufei,Wang, Xinmin,Xia, Qing,Zhang, Wei-Hua
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supporting information
p. 7290 - 7294
(2020/10/12)
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- Method for difluoroalkylation after fatty amine deamination
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The invention discloses a method for difluoroalkylation after fatty amine deamination in the field of organic synthesis. Particularly the method comprises the following steps: by taking simple and easily available fatty amine represented by a formula A as a raw material, reacting the fatty amine with pyranyl tetrafluoroborate represented by a formula B under a heating or room temperature conditionto obtain alkyl pyridinium represented by a formula C; and under the illumination condition, obtaining various difluoroalkyl substituted alkanes, cycloalkanes and derivatives thereof with high yieldby selecting commercially available [Ir(dtbbpy)(ppy)2]PF6 as a catalyst and difluoroenol silyl ether D as a difluoroalkylation reagent. According to the invention, the method is simple and convenientto operate, simple and mild in reaction condition, excellent in functional group compatibility and suitable for large-scale production and synthesis; and fluorine-containing amino acid with potentialapplication value can be obtained through the catalytic synthesis method, and various difluoroalkyl-containing compounds with novel structures and important significance in the fields of medicines, pesticides and materials can be easily obtained through further conversion of the obtained product.
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Paragraph 0143; 0144; 0145
(2020/11/23)
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- Visible light promoted deaminative difluoroalkylation of aliphatic amines with difluoroenoxysilanes
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A visible light promoted deaminative strategy for the difluoroalkylation reaction utilizing pyridinium-activated aliphatic primary amines and difluoroenoxysilane as substrates has been developed. This protocol is characteriazed by its mild reaction conditions and broad substrate scope, which converted a diverse array of amine-containing molecules to the alkyl-CF2COPh products. Moreover, the resulting products can be easily transformed into a vast array of structurally novel and interesting difluoro-containing moieties, therefore providing a facile route for applications in medicinal chemistry and the life sciences. This journal is
- Huang, Yang,Jia, Jia,Huang, Qi-Ping,Zhao, Liang,Wang, Pan,Gu, Jiwei,He, Chun-Yang
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supporting information
p. 14247 - 14250
(2020/11/24)
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- Transition-Metal-Free Deaminative Vinylation of Alkylamines
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The amino group is one of the most fundamental structural motifs in natural products and synthetic chemicals. However, amines potential as effective alkylating agents in organic synthesis is still problematic. A unified strategy has been established for deaminative vinylation of the alkylamines with vinyl boronic acids by C?N bond activation under catalyst-free conditions. The key to the high reactivity is the utilization of pyridinium salt-activated alkylamines, with a base as a promoter. The transformation exhibits good functional group compatibility, and includes inexpensive primary amine feedstocks and amino acids. The proposed method can serve as a powerful synthetic method for late-stage modification of complex compounds. Mechanistic experiments suggest that free radical processes are involved in this system. (Figure presented.).
- Hu, Jiefeng,Cheng, Bo,Yang, Xianyu,Loh, Teck-Peng
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supporting information
p. 4902 - 4908
(2019/09/13)
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- Engaging Alkenes and Alkynes in Deaminative Alkyl-Alkyl and Alkyl-Vinyl Cross-Couplings of Alkylpyridinium Salts
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An alkyl-alkyl cross-coupling of Katritzky alkylpyridinium salts and organoboranes, formed in situ via hydroboration of alkenes, has been developed. This method utilizes the abundance of both alkyl amine precursors and alkenes to form C(sp3)-C(sp3) bonds. This strategy is also effective with alkynes, enabling a C(sp3)-C(sp2) cross-coupling. Under these mild conditions, a broad range of functional groups, including protic groups, is tolerated. As seen with previous alkylpyridinium cross-couplings, mechanistic studies support an alkyl radical intermediate.
- Baker, Kristen M.,Lucas Baca, Diana,Plunkett, Shane,Daneker, Mitchell E.,Watson, Mary P.
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supporting information
p. 9738 - 9741
(2019/12/02)
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- Photoinduced Deaminative Borylation of Alkylamines
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An operationally simple deaminative borylation reaction of primary alkylamines has been developed. The formation of electron-donor-acceptor complexes between N-alkylpyridinium salts and bis(catecholato)diboron enables photoinduced single-electron transfer and fragmentation to carbon-centered radicals, which are subsequently borylated. The mild conditions allow a diverse range of readily available alkylamines to be efficiently converted into synthetically valuable alkylboronic esters under catalyst-free conditions.
- Wu, Jingjing,He, Lin,Noble, Adam,Aggarwal, Varinder K.
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supporting information
p. 10700 - 10704
(2018/09/06)
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- Alkylation of Monosubstituted Malonate Anions With Pyridinium and Quinolinium Salts
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Monosubstituted malonate anions are alkylated at room temperature with 1-(sec-alkyl)quinolinium salts.Hindered disubstituted malonate esters can thus be prepared under very mild conditions.
- Katritzky, Alan R.,Aurrecoechea, Jose M.
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p. 342 - 345
(2007/10/02)
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- Carbon-Nitrogen Bond Cleavage in ?-Radicals derived by Reduction of N-Benzyl- and N-Allyl-pyridinium Salts
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Certain 1-alkyl-2,4,6-trisubstituted pyridinium salts form ?-radicals by electrochemical reduction which are stable in dimethylformamide on the time scale of cyclic voltammetry, whereas the corresponding 1-benzyl and 1-allyl compounds undergo carbon-nitrogen bond cleavage at measured rates which are dependent on the size of the 2,6-substituents.
- Grimshaw, James,Moore, Shirley,Thompson, Norris,Trocha-Grimshaw, Jadwiga
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p. 783 - 784
(2007/10/02)
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- Kinetics and Mechanisms of Nucleophilic Displacements with Heterocycles as Leaving Groups. Part 4. 2,4,6-Triaryl-N-benzylpyridinium Cations: Rate Variation with Electronic Effects in the Leaving Group
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Electron-withdrawing groups in the 4-phenyl ring of 2,4,6-triphenylpyridine modestly increase its activity as a leaving group.Replacement of 2-phenyl by heteroaryl has a small effect for monoheteroaryl groups, but significantly larger for 2-benzimidazol-2-yl and especially for 2-benzothiazol-1-yl.
- Katritzky, Alan R.,Adamson, Jeffrey,Elisseou, E. Michael,Musumarra, Giuseppe,Patel, Ranjan C.,et al.
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p. 1041 - 1048
(2007/10/02)
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- Kinetics and Mechanism of the Reactions of Primary Amines with Pyrylium Cations
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The initial reaction of primary amines with pyrylium cations to give the ring-opened intermediate is fast for strongly basic amines and is base-catalysed for weak amines.Ring-closure of the intermediate to give the pyridinium derivative is subject to ster
- Katritzky, Alan R.,Manzo, Ruben H.
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p. 571 - 575
(2007/10/02)
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- The Synthesis and Reactions of Sterically Constrained Pyrylium and Pyridinium Salts
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Efficient syntheses are developed for several pyrylium cations with substitution patterns more sterically demanding than 2,4,6-triphenyl and these are examined as reagents for the conversion of primary amino into a leaving group.The 2-mesityl-4,6-diphenyl derivative did not react smoothly with amines.The 2,6-di-t-butyl-4-phenyl-pyrylium cation gave the corresponding pyridinium derivatives, but they resisted nucleophilic attack. 2-t-Butyl-4,6-diphenylpyridinium cations suffer nucleophilic attack with about the same ease as the 2,4,6-triphenyl analogues.Dihydrobenzopyrylium (6) and tetrahydrodibenzoxanthylium cations (7) gave pyridinium cations which underwent much easier nucleophilic attack: thus they alkylate xanthate anion in ethanol solution and acetate anion in acetic acid.
- Katritzky, Alan R.,Thind, Sukhpal S.
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p. 1895 - 1900
(2007/10/02)
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- The Preparation of Primary Alkyl and Benzyl Fluorides from the Corresponding Primary Amines
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N-substituted 2,4,6-triphenylpyridinium fluorides (in contrast to these and other tetrafluoroborates) thermolyse to the corresponding primary alkyl and benzyl fluorides.The pyridinium fluorides are made from 2,4,6-triphenylpyrylium fluoride and the relevant amine.
- Katritzky, Alan R.,Patel, Ranjan C.
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p. 2901 - 2903
(2007/10/02)
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- Reductive Deamination of Primary Amines
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1-Alkyl-1,2-dihydropyridines thermolyse to complex mixtures, but 1-alkyl-2,3,5,6-tetraphenyl-1,4-dihydropyridines (prepared from the amine and 2,3,5,6-tetraphenylpyrylium salts followed by NaBH4) give alkanes smoothly at ca.200 deg C.Thermolysis of 1-benzyl-2-deuterio-2,4,6-triphenyl-1,2-dihydropyridine gives ω-monodeuteriotoluene (as shown by 2H n.m.r. spectroscopy) indicating a radical mechanism.
- Katritzky, Alan R.,Horvath, Karoly,Plau, Bernard
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p. 2554 - 2560
(2007/10/02)
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- A C-13 study of the reaction of 2,4,6-triarylpyrylium cations with amines
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The reaction of primary and secondary amines with 2,4,6-triarylpyryliums is shown by C-13 NMR to proceed by fast ring opening to a vinylogous amide; in the case of primary amines this closes slowly to a pyridinium salt. The reaction in DMSO gives the pyridinium salt quantitatively when 2 moles of amines are used, with less amine significant quantities of a diketone intermediate are produced which results in slower conversion.
- Katritzky, Alan R.,Brownlee, Robert T.C.,Musumarra, Giuseppe
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p. 1643 - 1647
(2007/10/02)
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- Heterocycles in Organic Synthesis. Part 42. Preparation of Azides, Phthalimides, and Sulphonamides from Primary Amines
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N-Alkyl and N-benzyl substituents are displaced from 2,4,6-triphenylpyridinium cations by nucleophilic azide, phthalimide, succinimide, and sulphonamide anions.This enables the conversion of primary alkyl- and benzylamines into azides, and primary (with potential for inversion or labelling) and secondary amines.
- Katritzky, Alan R.,Liso, Gaietano,Lunt, Edward,Patel, Ranjan C.,Thind, Sukhpal S.,Zia, Abid
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p. 849 - 851
(2007/10/02)
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