- THE BORONIC ACID MANNICH REACTION: A NEW METHOD FOR THE SYNTHESIS OF GEOMETRICALLY PURE ALLYLAMINES
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Reaction of vinyl boronic acids with the adducts of secondary amines and paraformaldehyde gives tertiary allylamines with the same geometry.This simple and practical method was used for the synthesis of geometrically pure naftifine, a potent antifungal agent.
- Petasis, Nicos A.,Akritopoulou, Irini
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- Preparation method for synthesizing amine compound through co-catalysis and hydrosilylation of amide by iridium and boron reagents
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The invention relates to a preparation method for synthesizing amine compounds from amide through co-catalysis and hydrosilylation of iridium and boron reagents, which comprises the following steps: reacting amide and silane in an organic solvent under the catalysis of an iridium complex and a boron reagent, and then concentrating and purifying to obtain amine, the molar ratio of the amide to the iridium complex to the boron reagent to the silane is 1: (0.0001-0.001): (0.01-0.05): (2-4); according to the invention, the amide which is stable and easy to obtain is used as a raw material, the iridium complex with very low catalyst loading capacity and the boron reagent are co-catalyzed for hydrosilylation, and the amine compound is efficiently synthesized. The method has the advantages of simple operation and separation of each step, fast reaction rate, mild reaction conditions, cheap and easily available commercial reagents, high yield and good functional group tolerance.
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Paragraph 0035-0038
(2022/04/03)
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- Amine compound as well as preparation method and application thereof
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The invention discloses an amine compound containing allyl or benzyl as well as a preparation method and application of the amine compound. The preparation method comprises the steps of sequentially adding a raw material 1, amine, a catalyst and an additive into a reaction solvent, and stirring and reacting for 12-24 hours in an air atmosphere at the temperature of 50-120 DEG C to obtain a reaction solution, wherein the raw material 1 is allyl alcohol or benzyl alcohol, and the molar volume ratio of the raw material 1 to the amine to the catalyst to the additive to the reaction solvent is (0.2 to 8) mmol: (0.4 to 12) mmol: (0.01 to 0.4) mmol: (0.01 to 0.4) mmol: (2 to 40) mL; and removing the reaction solvent of the reaction solution, and then carrying out purification through thin layer chromatography/column chromatography, wherein a developing solvent system is petroleum ether/ethyl acetate, and the amine compound containing allyl or benzyl is obtained. The amine compound can be applied to preparation of framework of biological and pharmaceutical active molecules. The preparation method disclosed by the invention is wide in applicable substrate range, convenient to operate, green and environment-friendly.
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- N -Butylpyrrolidone (NBP) as a non-toxic substitute for NMP in iron-catalyzed C(sp2)-C(sp3) cross-coupling of aryl chlorides
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Although iron catalyzed cross-coupling reactions show extraordinary promise in reducing the environmental impact of more toxic and scarce transition metals, one of the main challenges is the use of reprotoxic NMP (NMP = N-methylpyrrolidone) as the key ligand to iron in the most successful protocols in this reactivity platform. Herein, we report that non-toxic and sustainable N-butylpyrrolidone (NBP) serves as a highly effective substitute for NMP in iron-catalyzed C(sp2)-C(sp3) cross-coupling of aryl chlorides with alkyl Grignard reagents. This challenging alkylation proceeds with organometallics bearing β-hydrogens with efficiency superseding or matching that of NMP with ample scope and broad functional group tolerance. Appealing applications are demonstrated in the cross-coupling in the presence of sensitive functional groups and the synthesis of several pharmaceutical intermediates, including a dual NK1/serotonin inhibitor, a fibrinolysis inhibitor and an antifungal agent. Considering that the iron/NMP system has emerged as one of the most powerful iron cross-coupling technologies available in both academic and industrial research, we anticipate that this method will be of broad interest.
- Bisz, Elwira,Koston, Martina,Szostak, Michal
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supporting information
p. 7515 - 7521
(2021/10/12)
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- Oxidative Rearrangement of MIDA (N-Methyliminodiacetic Acid) Boronates: Mechanistic Insights and Synthetic Applications
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Herein we report that coordinative hemilability allows the MIDA (N-methyliminodiacetic acid) nitrogen to behave as a nucleophile and intramolecularly intercept palladium π-allyl intermediates. A mechanistic investigation indicates that this rearrangement proceeds through an SN2-like displacement at tetrasubstituted boron to furnish novel DABN boronates. Oxidative addition into the N-C bond of the DABN scaffold furnishes borylated π-allyl intermediates that can then be trapped with a variety of nucleophiles, including in a three-component coupling.
- Kaldas, Sherif J.,Tien, Chieh-Hung,Gomes, Gabriel Dos Passos,Meyer, Stephanie,Sirvinskas, Martynas,Foy, Hayden,Dudding, Travis,Yudin, Andrei K.
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supporting information
p. 324 - 328
(2021/01/26)
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- Direct N-Alkylation/Fluoroalkylation of Amines Using Carboxylic Acids via Transition-Metal-Free Catalysis
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A scalable protocol of direct N-mono/di-alkyl/fluoroalkylation of primary/secondary amines has been constructed with various carboxylic acids as coupling agents under the catalysis of a simple air-tolerant inorganic salt, K3PO4. Advantageous features include 100 examples, 10 drugs and drug-like amines, fluorinated complex tertiary amines, gram-scale synthesis and isotope-labelling amine, thus demonstrating the potential applicability in industry of this methodology. The involvement of relatively less reactive silicon-hydride compared with the traditional reactive metal-hydride or boron-hydride species required to reduce the amide intermediates presumably contributes to the remarkable functional group compatibility. (Figure presented.).
- Lu, Chunlei,Qiu, Zetian,Xuan, Maojie,Huang, Yan,Lou, Yongjia,Zhu, Yiling,Shen, Hao,Lin, Bo-Lin
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supporting information
p. 4151 - 4158
(2020/08/21)
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- A General Acid-Mediated Hydroaminomethylation of Unactivated Alkenes and Alkynes
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In comparison to the extensively studied metal-catalyzed hydroamination reaction, hydroaminomethylation has received significantly less attention despite its considerable potential to streamline amine synthesis. State-of-the-art protocols for hydroaminomethylation of alkenes rely largely on transition-metal catalysis, enabling this transformation only under highly designed and controlled conditions. Here we report a broadly applicable, acid-mediated approach to the hydroaminomethylation of unactivated alkenes and alkynes. This methodology employs cheap, readily available, and bench-stable reactants and affords the desired amines with excellent functional group tolerance and impeccable regioselectivity. The broad scope of this transformation, as well as mechanistic investigations and in situ domino functionalization reactions are reported.
- Kaiser, Daniel,Tona, Veronica,Gon?alves, Carlos R.,Shaaban, Saad,Oppedisano, Alberto,Maulide, Nuno
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supporting information
p. 14639 - 14643
(2019/09/17)
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- Metal-Organic Capsules with NADH Mimics as Switchable Selectivity Regulators for Photocatalytic Transfer Hydrogenation
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Switchable selective hydrogenation among the groups in multifunctional compounds is challenging because selective hydrogenation is of great interest in the synthesis of fine chemicals and pharmaceuticals as a result of the importance of key intermediates. Herein, we report a new approach to highly selectively (>99%) reducing C=X (X = O, N) over the thermodynamically more favorable nitro groups locating the substrate in a metal-organic capsule containing NADH active sites. Within the capsule, the NADH active sites reduce the double bonds via a typical 2e- hydride transfer hydrogenation, and the formed excited-state NAD+ mimics oxidize the reductant via two consecutive 1e- processes to regenerate the NADH active sites under illumination. Outside the capsule, nitro groups are highly selectively reduced through a typical 1e- hydrogenation. By combining photoinduced 1e- transfer regeneration outside the cage, both 1e- and 2e- hydrogenation can be switched controllably by varying the concentrations of the substrates and the redox potential of electron donors. This promising alternative approach, which could proceed under mild reaction conditions and use easy-to-handle hydrogen donors with enhanced high selectivity toward different groups, is based on the localization and differentiation of the 2e- and 1e- hydrogenation pathways inside and outside the capsules, provides a deep comprehension of photocatalytic microscopic reaction processes, and will allow the design and optimization of catalysts. We demonstrate the advantage of this method over typical hydrogenation that involves specific activation via well-modified catalytic sites and present results on the high, well-controlled, and switchable selectivity for the hydrogenation of a variety of substituted and bifunctional aldehydes, ketones, and imines.
- Wei, Jianwei,Zhao, Liang,He, Cheng,Zheng, Sijia,Reek, Joost N. H.,Duan, Chunying
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p. 12707 - 12716
(2019/09/04)
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- Design of two alternative routes for the synthesis of naftifine and analogues as potential antifungal agents
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Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues 16 and 20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, theγ-aminoalcohols 15 and 19 were obtained as the key intermediates and their subsequent dehydration catalyzed either by Br?nsted acids like H2SO4 and HCl or Lewis acid like AlCl3, respectively, led to naftifine, along with the target allylamines 16 and 20. The antifungal assay results showed that intermediates 18 (bearing both a β-aminoketo- and N-methyl functionalities in their structures) and products 20 were the most active. Particularly, structures 18b, 18c, and the allylamine 20c showed the lowest MIC values, in the 0.5-7.8 μg/mL range, against the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Interesting enough, compound 18b bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against Candida albicans and Cryptococcus neoformans with MIC80 = 7.8 μg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 μg/mL against C. neoformans.
- Abonia, Rodrigo,Garay, Alexander,Castillo, Juan C.,Insuasty, Braulio,Quiroga, Jairo,Nogueras, Manuel,Cobo, Justo,Butassi, Estefanía,Zacchino, Susana
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- Combining Copper-Catalyzed Hydroboration with Palladium-Catalyzed Suzuki Coupling for the One-pot Synthesis of Arylallylamines under Micellar Conditions
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Herein we report the one-pot dual-metal catalytic synthesis of arylallylamines, by combination of a Cu-catalyzed hydroboration with a Pd-catalyzed Suzuki arylation, using a broad range of aryl halides. Importantly, the reaction sequence was entirely performed in water, in the presence of small amounts of SPGS-550M, without the need of solvent switch or addition of organic co-solvents, rendering it operationally simple and environmentally benign. The usefulness of this methodology was highlighted in a short synthesis of the pharmaceutically important compound naftifine. (Figure presented.).
- Horn, Pedro A.,Braun, Roger K.,Isoppo, Victória G.,Costa, Jessie S. da,Lüdtke, Diogo S.,Moro, Angélica V.
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p. 2322 - 2328
(2017/07/07)
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- Direct use of allylic alcohols and allylic amines in palladium-catalyzed allylic amination
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Allylic alcohols and allylic amines were directly utilized in a Pd-catalyzed hydrogen-bond-activated allylic amination under mild reaction conditions in the absence of any additives. The cooperative action of a Pd-catalyst and a hydrogen-bonding solvent is most likely responsible for its high reactivity. The catalytic system is compatible with a variety of functional groups and can be used to prepare a wide range of linear allylic amines in good to excellent yields. Furthermore, this methodology can be easily applied to the one-step synthesis of two drugs, cinnarizine and naftifine, on a gram scale.
- Jing, Jiangyan,Huo, Xiaohong,Shen, Jiefeng,Fu, Jingke,Meng, Qinghua,Zhang, Wanbin
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p. 5151 - 5154
(2017/07/12)
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- Decarboxylative alkenylation
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Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.
- Edwards, Jacob T.,Merchant, Rohan R.,McClymont, Kyle S.,Knouse, Kyle W.,Qin, Tian,Malins, Lara R.,Vokits, Benjamin,Shaw, Scott A.,Bao, Deng-Hui,Wei, Fu-Liang,Zhou, Ting,Eastgate, Martin D.,Baran, Phil S.
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p. 213 - 218
(2017/05/19)
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- Methylation method of amines
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The invention provides a methylation method of amines. The method is characterized by comprising the steps that under the protection of nitrogen or inert gas, organic amines, a reductive agent polymethyl hydrogen siloxane or diphenyl silane, a catalyst potassium phosphate and an additive 18-crown-6 are added into a reaction container, and an reaction is made with carbon dioxide as a C1 source to obtain methylated products of amines. According to the method, potassium phosphate serves as the catalyst, the carbon dioxide serves as the C1 source, polymethyl hydrogen siloxane or diphenyl silane serves as the reductive agent, and 18-crown-6 serves as the additive. Various kinds of amines are converted into the corresponding methylated products in an acetonitrile solvent or without solvents. Two waste materials including the carbon dioxide and polymethyl hydrogen siloxane (PMHS) serve as the C1 source and the reductive agent in the method respectively, phosphate serves as the catalyst, the cost is low, and the conversion efficiency is high. Thus, the method makes an important contribution to the development of green chemistry.
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Paragraph 0091; 0092; 0093; 0094; 0095; 0096
(2017/12/04)
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- Iron-Catalyzed Allylic Amination Directly from Allylic Alcohols
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Allylic amination, directly from alcohols, has been demonstrated without any Lewis acid activators using an efficient and regiospecific molecular iron catalyst. Various amines and alcohols were employed and the reaction proceeded through the oxidation/reduction (redox) pathway. A direct one-step synthesis of common drugs, such as cinnarizine and nafetifine, was exhibited from cinnamyl alcohol that produced water as side product. The iron way! A direct amination of allylic alcohols has been demonstrated without the need of Lewis acid activators using an efficient and regiospecific molecular iron catalyst. A range of amines and alcohols were tolerated, and the reaction was found to procced through an oxidation/reduction (redox) pathway (see scheme).
- Emayavaramban, Balakumar,Roy, Moumita,Sundararaju, Basker
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supporting information
p. 3952 - 3955
(2016/03/16)
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- ADENYLYL CYCLASE INHIBITORS FOR NEUROPATHIC AND INFLAMMATORY PAIN
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The invention generally relates to adenylyl cyclase inhibitor compounds and methods for treating neuropathic or inflammatory pain by using those compounds.
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Paragraph 0317-0318; 0344-0345
(2016/10/11)
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- Efficient ruthenium-catalyzed N-methylation of amines using methanol
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An in situ-generated complex from [RuCpCl2]2 and dpePhos ligand is reported as an efficient catalyst in the presence of 5 mol % of LiOtBu for the N-methylation of amines using methanol as the methylating agent at moderate conditions, following hydrogen borrowing strategy. This simple catalyst system provides selective N-monomethylation of substituted primary anilines and sulfonamides as well as N,N dimethylation of primary aliphatic amines in excellent yields at 40-100 °C with good tolerance to reducible functional groups. The catalytic intermediate CpRu(dpePhos)H was isolated and was shown to be active for methylation in the absence of base.
- Dang, Tuan Thanh,Ramalingam, Balamurugan,Seayad, Abdul Majeed
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p. 4082 - 4088
(2015/11/11)
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- Palladium-catalyzed regio- and stereoselective β-arylation of tertiary allylic amines: Identification of potent adenylyl cyclase inhibitors
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Substituted allylic amines and their derivatives are key structural motifs of many drug molecules and natural products. A general, mild, and practical palladium-catalyzed β-arylation of tertiary allylic amines, one of the most challenging Heck arylation substrates, has been developed. The β-arylation products were obtained in excellent regio- and stereoselectivity. Moreover, novel and potent adenylyl cyclase inhibitors with the potential for treating neuropathic and inflammatory pain have been identified from the β-arylation products.
- Ye, Zhishi,Dai, Mingji,Brust, Tarsis F.,Watts, Val J.
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supporting information
p. 892 - 895
(2015/03/30)
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- Metal-free catalyst for the chemoselective methylation of amines using carbon dioxide as a carbon source
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N-methylation of amines is an important step in the synthesis of many pharmaceuticals and has been widely applied in the preparation of other key intermediates and chemicals. Therefore, the development of efficient methylation methods has attracted considerable attention. In this respect, carbon dioxide is an attractive C1 building block because it is an abundant, renewable, and nontoxic carbon source. Consequently, we developed a highly chemoselective, metal-free catalytic system that operates under ambient conditions for the N-methylation of amines. The methylation of amines with CO2 as C1 source and Ph2SiH2 as reducing agent was achieved with an N-heterocyclic carbene (NHC) as the catalyst. The catalyst is tolerant toward a variety of functional groups (including esters and ethers, nitro, nitrile, and carbonyl groups, and unsaturated C-C bonds); the reaction uses commercially available reagents and can be performed on a gram scale.
- Das, Shoubhik,Bobbink, Felix D.,Laurenczy, Gabor,Dyson, Paul J.
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supporting information
p. 12876 - 12879
(2016/02/18)
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- Stereoselective synthesis of allylamines by iron-catalyzed cross-coupling of 3-chloroprop-2-en-1-amines with grignard reagents. Synthesis of naftifine
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A general procedure for the synthesis of trans- and cis-allylamines has been developed on the basis of iron-catalyzed cross-coupling of Grignard reagents with stereochemically pure 3-chloroprop-2-en-1-amines prepared by allylation of amines with commercially available 1,3-dichloropropene isomers.
- Shakhmaev,Sunagatullina,Zorin
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p. 322 - 331
(2014/06/09)
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- An efficient and convenient palladium catalyst system for the synthesis of amines from allylic alcohols
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A novel catalyst system for efficient amination of allylic alcohols with aryl and alkyl amines is presented. By applying a convenient combination consisting of Pd(OAc)2/1,10-phenanthroline, a variety of allylic alcohols reacted smoothly to give the corresponding secondary and tertiary amines in good to excellent yields with high regioselectivity. The usefulness of our protocol is demonstrated in the one-step synthesis of the antifungal drug naftifine and the calcium channel blocker flunarizine. One pot is all it takes: By applying a convenient combination consisting of Pd(OAc)2/1,10- phenanthroline, a variety of allylic alcohols reacts smoothly to give the corresponding secondary and tertiary amines in good to excellent yields with high regioselectivity (see picture).
- Banerjee, Debasis,Jagadeesh, Rajenahally V.,Junge, Kathrin,Junge, Henrik,Beller, Matthias
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p. 2039 - 2044
(2013/01/15)
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- Substrate-directable heck reactions with arenediazonium salts. The regio- and stereoselective arylation of allylamine derivatives and applications in the synthesis of naftifine and abamines
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The palladium-catalyzed, substrate-directable Heck-Matsuda reaction of allylamine derivatives with arenediazonium salts is reported. The reaction proceeds under mild conditions, with excellent regio- and stereochemical control as a function of coordinating groups present in the allylamine substrate. The distance between the olefin moiety and the car-bonylic system seems to play a key role regarding the regiocontrol. The method presents itself as robust, as simple to carry out, and with wide synthetic scope concerning the allylic substrates and the type of arenediazonium employed. The synthetic potential of the method is illustrated by the short total syntheses of the bioactive compounds naftifine, abamine, and abamine SG.
- Prediger, Patricia,Barbosa, Lais Ferreira,Genisson, Yves,Correia, Carlos Roque Duarte
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experimental part
p. 7737 - 7749
(2011/12/01)
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- Amination of allylic alcohols in water at room temperature
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The "trick" to carrying out regiocontrolled aminations of allylic alcohols in water as the only medium is use of a nanomicelle's interior as the organic reaction solvent. When HCO2Me is present, along with the proper base and source of catalytic Pd, allylic amines are cleanly formed at room temperature.
- Nishikata, Takashi,Lipshutz, Bruce H.
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supporting information; experimental part
p. 2377 - 2379
(2009/12/01)
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- Aminations of allylic phenyl ethers via micellar catalysis at room temperature in water
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Especially mild, organic solvent-free conditions have been found that allow for allylic ethers to undergo Pd-catalyzed aminations.
- Nishikata, Takashi,Lipshutz, Bruce H.
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supporting information; experimental part
p. 6472 - 6474
(2010/03/04)
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- Direct use of allylic alcohols for platinum-catalyzed monoallylation of amines
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A new direct catalytic amination of allylic alcohols promoted by the combination of platinum and a large bite-angle ligand DPEphos was developed in which the allylic alcohol was effectively converted to a π-allylplatinum intermediate without the use of an activating reagent. The use of the DPEphos ligand was essential for obtaining high catalyst activity and high monoallylation selectivity of primary amines, allowing the formation of a variety of monoallylation products in good to excellent yield.
- Utsunomiya, Masaru,Miyamoto, Yoshiki,Lpposhi, Junji,Ohshima, Takashi,Mashima, Kazushi
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p. 3371 - 3374
(2008/02/12)
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- A one-pot oxidation-imine formation-reduction route from alcohols to amines using manganese dioxide-sodium borohydride: The synthesis of naftifine
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A new procedure for the one-pot conversion of alcohols into amines is described which utilises manganese dioxide in the presence of sodium borohydride; the scope of this process is outlined, as is its application to the preparation of the topical antifungal agent, naftifine.
- Kanno, Hisashi,Taylor, Richard J.K.
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p. 7337 - 7340
(2007/10/03)
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- Synthesis and Structure-Activity Relationships of Naftifine-Related Allylamine Antimycotics
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Naftifine (1) is the first representative of the new antifungal allylamine derivatives.Its biological activity is strictly bound to specific structural requirements that are unrelated to those of known antifungals.A tertiary allylamine function seems to be a prerequisite for activity against fungi.By systematic variation of the individual structural elements in 1, detailed structure-activity relationships are defined in which the phenyl ring is the structural feature permitting the widest variations.Versatile synthetic routes to allylamine derivatives and comparative biological data are presented.
- Stuetz, Anton,Georgopoulos, Apostolos,Granitzer, Waltraud,Petranyi, Gabor,Berney, Daniel
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p. 112 - 125
(2007/10/02)
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- REDUKTIVE METHYLIERUNG PRIMAERER UND SEKUNDAERER AMINE MIT HILFE VON FORMALDEHYD UND SALZEN DER PHOSPHORIGEN SAEURE
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Salts of phophorous acid were found to be useful alternative reducing agents for the reductive methylation of amines.
- Loibner, H.,Pruckner, A.,Stuetz, A.
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p. 2535 - 2536
(2007/10/02)
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