- Metal-Free Synthesis of Heteroaryl Amines or Their Hydrochlorides via an External-Base-Free and Solvent-Free C-N Coupling Protocol
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Herein, a metal-free and solvent-free protocol was developed for the C-N coupling of heteroaryl halides and amines, which afforded numerous heteroaryl amines or their hydrochlorides without any external base. Further investigations elucidated that the basicity of amines and specific interactions derived from the X-ray crystallography analysis of 3j′·HCl played pivotal roles in the reactions. Moreover, this protocol was scalable to gram scales and applicable to drug molecules, which demonstrated its practical value for further applications.
- Fan, Guang-Gao,Jiang, Bo-Wen,Sang, Wei,Cheng, Hua,Zhang, Rui,Yu, Bao-Yi,Yuan, Ye,Chen, Cheng,Verpoort, Francis
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p. 14627 - 14639
(2021/11/01)
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- Novel N-heterocyclic carbene cyclic palladium compound as well as preparation method and application thereof
-
The invention discloses a novel N-heterocyclic carbene cyclic palladium compound as well as a preparation method and application thereof, and belongs to the technical field of organic catalysis. The novel N-heterocyclic carbene cyclic palladium compound is prepared by the following steps: heating, stirring and mixing N-(4-butoxybenzyl)-N-ethylethylamine, palladium chloride and an organic solvent in an inert gas atmosphere, then adding potassium carbonate, performing stirring and mixing, and finally adding 1-(2,6-diisopropyl phenyl)-3-butyl-brominated imidazole for reflux reaction; and after the reaction is finished, performing quenching with an acid solution, performing extracting to obtain a crude product, and performing column chromatography separation and purification to obtain the novel N-heterocyclic carbene cyclic palladium compound. The N-heterocyclic carbene cyclic palladium compound provided by the invention has high catalytic activity, can catalyze cross-coupling reactions between aryl chloride and aryl phenylboronic acid and between aryl chloride and secondary amine in a catalytic amount of 1 mol%, and can be used as a high-efficiency catalyst for the coupling reactions.
- -
-
Paragraph 0044-0046
(2021/06/26)
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- Large-steric-hindrance N-heterocyclic carbene palladium complex, preparation method and application thereof, and synthesis method of sonidegib based on large-steric-hindrance N-heterocyclic carbene palladium complex
-
The invention belongs to the technical field of organic synthesis and chemical catalysis, and discloses a large-steric-hindrance N-heterocyclic carbene palladium complex, a preparation method thereof,an application of the complex in efficient catalysis of a C-N coupling reaction under a room-temperature air condition, and a synthesis method of sonidegib based on the complex. According to the large-steric-hindrance N-heterocyclic carbene palladium complex, diphenyl imidazole serves as a main ligand framework, functionalized allyl serves as an auxiliary ligand, the functionalized allyl is introduced beside a metal center of a catalyst to serve as an auxiliary ligand, the catalytic activity and stability are remarkably improved, the large-steric-hindrance N-heterocyclic carbene palladium complex can be applied to efficient catalysis of a CN coupling reaction, particularly, the CN coupling reaction can be efficiently catalyzed under the room temperature condition, and the yield can reachup to 99%. The invention also provides a method for synthesizing sonidegib by taking aryl/aliphatic amine and aryl chloride as reactants and a three-step method at room temperature under the catalysisof a palladium catalytic system, the synthetic method has few steps, and the total yield can reach 74.5%.
- -
-
Paragraph 0195; 0205-0207
(2021/01/24)
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- Bisulfite Addition Compounds as Substrates for Reductive Aminations in Water
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Highly valued products resulting from reductive aminations utilizing shelf-stable bisulfite addition compounds of aldehydes can be made under aqueous micellar catalysis conditions. Readily available α-picolineborane serves as the stoichiometric hydride source. Recycling of the aqueous reaction medium is easily accomplished, and several applications to targets in the pharmaceutical industry are documented.
- Bailey, J. Daniel,Iyer, Karthik S.,Leahy, David K.,Li, Xiaohan,Lipshutz, Bruce H.,Thakore, Ruchita R.
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p. 7205 - 7208
(2021/09/22)
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- Photocatalytic Water-Splitting Coupled with Alkanol Oxidation for Selective N-alkylation Reactions over Carbon Nitride
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Photocatalytic water splitting technology (PWST) enables the direct use of water as appealing “liquid hydrogen source” for transfer hydrogenation reactions. Currently, the development of PWST-based transfer hydrogenations is still in an embryonic stage. Previous reports generally centered on the rational utilization of the in situ generated H-source (electrons) for hydrogenations, in which photogenerated holes were quenched by sacrificial reagents. Herein, the fully-utilization of the liquid H-source and holes during water splitting is presented for photo-reductive N-alkylation of nitro-aromatic compounds. In this integrate system, H-species in situ generated from water splitting were designed for nitroarenes reduction to produce amines, while alkanols were oxidized by holes for cascade alkylating of anilines as well as the generated secondary amines. More than 50 examples achieved with a broad range scope validate the universal applicability of this mild and sustainable coupling approach. The synthetic utility of this protocol was further demonstrated by the synthesis of existing pharmaceuticals via selective N-alkylation of amines. This strategy based on the sustainable water splitting technology highlights a significant and promising route for selective synthesis of valuable N-alkylated fine chemicals and pharmaceuticals from nitroarenes and amines with water and alkanols.
- Xu, Yangsen,Zhang, Zhaofei,Qiu, Chuntian,Chen, Shaoqin,Ling, Xiang,Su, Chenliang
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p. 582 - 589
(2020/12/09)
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- BF3·Et2O as a metal-free catalyst for direct reductive amination of aldehydes with amines using formic acid as a reductant
-
A versatile metal- and base-free direct reductive amination of aldehydes with amines using formic acid as a reductant under the catalysis of inexpensive BF3·Et2O has been developed. A wide range of primary and secondary amines and diversely substituted aldehydes are compatible with this transformation, allowing facile access to various secondary and tertiary amines in high yields with wide functional group tolerance. Moreover, the method is convenient for the late-stage functionalization of bioactive compounds and preparation of commercialized drug molecules and biologically relevant N-heterocycles. The procedure has the advantages of simple operation and workup and easy scale-up, and does not require dry conditions, an inert atmosphere or a water scavenger. Mechanistic studies reveal the involvement of imine activation by BF3and hydride transfer from formic acid.
- Fan, Qing-Hua,Liu, Xintong,Luo, Zhenli,Pan, Yixiao,Xu, Lijin,Yang, Ji,Yao, Zhen,Zhang, Xin
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supporting information
p. 5205 - 5211
(2021/07/29)
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- An integrated console for capsule-based, automated organic synthesis
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The current laboratory practices of organic synthesis are labor intensive, impose safety and environmental hazards, and hamper the implementation of artificial intelligence guided drug discovery. Using a combination of reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions with prepacked capsules. The machine conducts coupling reactions and delivers the purified products with minimal user involvement. Two desirable reaction classes-the synthesis of saturated N-heterocycles and reductive amination-were implemented, along with multi-step sequences that provide drug-like organic molecules in a fully automated manner. We envision that this system will serve as a console for developers to provide synthetic methods as integrated, user-friendly packages for conducting organic synthesis in a safe and convenient fashion. This journal is
- Bode, Jeffrey W.,Bordi, Samuele,Chen, Kuang-Yen,Jiang, Tuo,McMillan, Angus E.,Nichols, Paula L.,Saito, Fumito,Wanner, Benedikt M.
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p. 6977 - 6982
(2021/06/06)
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- Homoleptic Bis(trimethylsilyl)amides of Yttrium Complexes Catalyzed Hydroboration Reduction of Amides to Amines
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Homoleptic lanthanide complex Y[N(TMS)2]3 is an efficient homogeneous catalyst for the hydroboration reduction of secondary amides and tertiary amides to corresponding amines. A series of amides containing different functional groups such as cyano, nitro, and vinyl groups were found to be well-tolerated. This transformation has also been nicely applied to the synthesis of indoles and piribedil. Detailed isotopic labeling experiments, control experiments, and kinetic studies provided cumulative evidence to elucidate the reaction mechanism.
- Ye, Pengqing,Shao, Yinlin,Ye, Xuanzeng,Zhang, Fangjun,Li, Renhao,Sun, Jiani,Xu, Beihang,Chen, Jiuxi
-
supporting information
p. 1306 - 1310
(2020/02/22)
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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
-
supporting information
p. 4151 - 4158
(2020/08/21)
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- Scalable preparation of stable and reusable silica supported palladium nanoparticles as catalysts for N-alkylation of amines with alcohols
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The development of nanoparticles-based heterogeneous catalysts continues to be of scientific and industrial interest for the advancement of sustainable chemical processes. Notably, up-scaling the production of catalysts to sustain unique structural features, activities and selectivities is highly important and remains challenging. Herein, we report the expedient synthesis of Pd-nanoparticles as amination catalysts by the reduction of simple palladium salt on commercial silica using molecular hydrogen. The resulting Pd-nanoparticles constitute stable and reusable catalysts for the synthesis of various N-alkyl amines using borrowing hydrogen technology without the use of any base or additive. By applying this Pd-based catalyst, functionalized and structurally diverse N-alkylated amines as well as some selected drug molecules were synthesized in good to excellent yields. Practical and synthetic utility of this Pd-based amination protocol has been demonstrated by upscaling catalyst preparation and amination reactions to several grams-scales as well as recycling of catalyst. Noteworthy, this Pd-catalyst preparation has been up-scaled to kilogram scale and catalysts prepared in both small (1 g) and large-scale (kg) exhibited similar structural features and activity.
- Alshammari, Ahmad S.,Natte, Kishore,Kalevaru, Narayana V.,Bagabas, Abdulaziz,Jagadeesh, Rajenahally V.
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p. 141 - 149
(2020/01/06)
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- Chemoselective Reductive Aminations in Aqueous Nanoreactors Using Parts per Million Level Pd/C Catalysis
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Condensation in recyclable water between aldehydes or ketones and amines occurs smoothly within the hydrophobic cores of nanomicelles, resulting in imine formation that is subject to subsequent reduction leading, overall, to reductive amination. This micellar technology enables the synthesis of several types of pharmaceuticals, a new procedure that relies on only 2000 ppm (0.20 mol %) palladium from commercially available Pd/C. A broad range of substrates can be used under mild conditions, leading to high chemical yields of the desired secondary and tertiary amines.
- Casotti, Gianluca,Gao, Eugene S.,Jin, Henry S.,Lipshutz, Bruce H.,Takale, Balaram S.,Thakore, Ruchita R.
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supporting information
(2020/09/09)
-
- Direct Catalytic Reductive N-Alkylation of Amines with Carboxylic Acids: Chemoselective Enamine Formation and further Functionalizations
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Direct reductive N-alkylation of secondary amines with carboxylic acids using molybdenum hexacarbonyl (5 mol %) as catalyst and diethoxymethylsilane as reducing agent generate enamines in a straightforward fashion in high yields. The formed enamines are without the need for isolation or purification further reacted with trimethylsilyl cyanide in the same reaction flask to yield α-amino nitriles in good yields. In the optimized reaction conditions equimolar amounts of carboxylic acid and amine are reacted under neat conditions, and a catalytic amount of trifluoroethanol (0.1 mol %) is added along with TMSCN for the cyanation step. The reductive N-alkylation reaction is demonstrated to be highly chemoselective, tolerating a multitude of different functional groups present in the starting carboxylic acids and amines. The reaction is scalable and the generated α-amino nitriles are converted to other useful compounds, e.g., α-amino acids or amino-tetrazoles. In addition, the intermediate enamines are further transformed into triazolines, sulfonylformamidines, pyrimidinediones, and TMS-propargylamines, respectively, in high yields under mild reaction conditions. Benzoic acids react with secondary amines under similar conditions to give tertiary amines in high yields, and using this methodology, the biologically active compound Piribedil was isolated in 80% yield in a direct one-pot reaction setup.
- Trillo, Paz,Adolfsson, Hans
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p. 7588 - 7595
(2019/08/20)
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- Fast continuous alcohol amination employing a hydrogen borrowing protocol
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A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl2]2 and DPEPhos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct dimethylamination of alcohols using commercial dimethylamine solution are reported. The synthesis of two pharmaceutical agents Piribedil (5) and Buspirone (25) were accomplished in good yields employing these new methods.
- Labes, Ricardo,Mateos, Carlos,Battilocchio, Claudio,Chen, Yiding,Dingwall, Paul,Cumming, Graham R.,Rincón, Juan A.,Nieves-Remacha, Maria José,Ley, Steven V.
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supporting information
p. 59 - 63
(2019/01/11)
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- Iridium-Catalyzed Alkylation of Amine and Nitrobenzene with Alcohol to Tertiary Amine under Base- and Solvent-Free Conditions
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Herein, an efficient and green method for the selective synthesis of tertiary amines has been developed that involves iridium-catalyzed alkylation of various primary amines with aromatic or aliphatic alcohols. Notably, the catalytic protocol enables this transformation in the absence of additional base and solvent. Furthermore, the alkylation of nitrobenzene with primary alcohol to tertiary amine has also been achieved by the same catalytic system. Deuterium-labeling experiments and a series of control experiments were conducted, and the results suggested that an intermolecular borrowing hydrogen pathway might exist in the alkylation process.
- Li, Chao,Wan, Ke-Feng,Guo, Fu-Ya,Wu, Qian-Hui,Yuan, Mao-Lin,Li, Rui-Xiang,Fu, Hai-Yan,Zheng, Xue-Li,Chen, Hua
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p. 2158 - 2168
(2019/05/16)
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- Pd-PEPPSI-IPentAn Promoted Deactivated Amination of Aryl Chlorides with Amines under Aerobic Conditions
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We report herein a highly efficient Pd-catalyzed amination by "bulky-yet-flexible" Pd-PEPPSI-IPentAn complexes. The relationship between the N-heterocyclic carbenes (NHCs) structure and catalytic properties was discussed. Sterically hindered (hetero)aryl chlorides and a variety of aliphatic and aromatic amines can be applied in this cross-coupling, which smoothly proceeded to provide desired products. The operationally simple protocol highlights the rapid access to CAr-N bond formation under mild conditions without the exclusion of air and moisture.
- Huang, Fei-Dong,Xu, Chang,Lu, Dong-Dong,Shen, Dong-Sheng,Li, Tian,Liu, Feng-Shou
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p. 9144 - 9155
(2018/07/21)
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- Expedient Synthesis of N-Methyl- and N-Alkylamines by Reductive Amination using Reusable Cobalt Oxide Nanoparticles
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N-Methyl- and N-alkylamines represent important fine and bulk chemicals that are extensively used in both academic research and industrial production. Notably, these structural motifs are found in a large number of life-science molecules and play vital roles in regulating their activities. Therefore, the development of convenient and cost-effective methods for the synthesis and functionalization of amines by using earth-abundant metal-based catalysts is of scientific interest. In this regard, herein we report an expedient reductive amination process for the selective synthesis of N-methylated and N-alkylated amines by using nitrogen-doped, graphene-activated nanoscale Co3O4-based catalysts. Starting from inexpensive and easily accessible nitroarenes or amines and aqueous formaldehyde or aldehydes in the presence of formic acid, this cost-efficient reductive amination protocol allows the synthesis of various N-methyl- and N-alkylamines, amino acid derivatives, and existing drug molecules.
- Senthamarai, Thirusangumurugan,Murugesan, Kathiravan,Natte, Kishore,Kalevaru, Narayana V.,Neumann, Helfried,Kamer, Paul C. J.,Jagadeesh, Rajenahally V.
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p. 1235 - 1240
(2018/02/09)
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- Piribedil preparation method
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The invention provides a piribedil preparation method which is characterized in that N-Methylpiperazine, 2-hydroxypyrimidine and 4-Bromo-1,2-(methylenedioxy)benzene are used as raw materials, reaction steps are short, reaction conditions are mild, side reactions in the reaction process are few, and purity of a finished product is high. The process is simple in operation, and the preparation process is little in pollutant emission, little in pollution and is favorable for environment protection.
- -
-
Paragraph 0012; 0013; 0014; 0015
(2017/07/21)
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- Cyclometalated palladium pre-catalyst for N-alkylation of amines using alcohols and regioselective alkylation of sulfanilamide using aryl alcohols
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Simple pyrazole based palladacycle-phosphine with a high turnover has been developed and applied for the N-alkylation of amines and sulfanilamide using alcohols as substrates by hydrogen borrowing strategy. N-alkylation of primary and secondary amines resulted in high isolated yields at 100–130 °C, under solvent free conditions. More challenging secondary aliphatic as well as aromatic alcohols were also successfully utilized as alkylating agents under similar reaction conditions. The turn over number reached up to 43000 for N-benzylation of aniline using benzyl alcohol. Notably, regioselective N-alkylation of 2-aminobenzothiazole and 4-aminobenzenesulfonamide to the corresponding 2-N-(alkylamino)azoles and 4-amino-(N-alkyl)benzenesulfonamides using alcohols as alkylating agents have been achieved using our new pre-catalyst-phosphine system.
- Mamidala, Ramesh,Mukundam, Vanga,Dhanunjayarao, Kunchala,Venkatasubbaiah, Krishnan
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supporting information
p. 2225 - 2233
(2017/03/24)
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- Synthetic method of piribedil
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The invention relates to a synthetic method of piribedil. The synthetic method is a brand new process comprising the steps of synthesizing piperonyl piperazine in one step under the effects of pentamethyleneamine, piperazine pyrimidine and paraformaldehyde, and reacting by virtue of piperonyl piperazine and dichloropyrimidine so as to synthesize piribedil. Piperonyl piperazine has not been synthesized by virtue of the synthetic method before. Compared with a traditional synthetic method of piribedil, the synthetic method has the advantages that synthetic steps are simplified, the three wastes are reduced, the utilization ratio of pentamethyleneamine is remarkably increased, and the after-treatment is relatively environment-friendly.
- -
-
Paragraph 0015
(2017/04/03)
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- Preparation method of piribedil
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The invention provides a preparation method of piribedil. The preparation method comprises the following steps of: preparing piperonyl chloride; preparing piperazinyl pyrimidine; and preparing piribedil. The preparation method of piribedil is simple, low in production cost, high in integral yield of reaction and convenient for industrial production, and has huge promotional meaning.
- -
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Paragraph 0022; 0025; 0028
(2017/10/13)
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- Preparation method of high-quality piribedil
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The invention provides a preparation method of high-quality piribedil. The preparation method of the high-quality piribedil comprises preparation of piperonyl chloride, preparation of piperazinyl pyrimidine and preparation of piribedil. The method is simple and brief, the production cost is low, the reaction overall yield is high, industrialized production is facilitated, and great popularization significance is achieved.
- -
-
Paragraph 0022; 0025; 0028
(2018/01/09)
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- Oxidation-Reduction Condensation of Diazaphosphites for Carbon-Heteroatom Bond Formation Based on Mitsunobu Mechanism
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An efficient oxidation-reduction condensation reaction of diazaphosphites with various nonacidic pronucleophiles in the presence of DIAD as a weak oxidant has been developed for carbon-heteroatom bond formation. This mild process affords structurally diverse tertiary amines, secondary amines, esters, ethers, and thioethers in moderate to excellent yields. The selective synthesis of secondary amines from primary amines has been achieved. Importantly, a practical application to the synthesis of antiparkinsonian agent piribedil has been demonstrated.
- Huang, Hai,Kang, Jun Yong
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supporting information
p. 544 - 547
(2017/02/10)
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- A method for synthesizing piribedil
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The invention relates to a method for synthesizing piribedil represented by a following formula. According to the method, stable, cheap and easy-to-obtain piperic acid and 1-(2-pyrimidinyl)piperazine are adopted as initial raw materials; a nonmetal boron compound is adopted as a catalyst; an organosilane compound is adopted as a reducing agent; and the needed product is synthesized with a one-step method through a reductive coupling process. The method provided by the invention is simple and is easy to operate. The raw materials have wide sources and low costs. The synthesis does not require a metal catalyst, such that metal residue in drugs is avoided. The method is safe and environment-friendly, and meets the requirements of green chemistry.
- -
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Paragraph 0050; 0051; 0055; 0058; 0060-0062; 0064; 0067
(2017/09/26)
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- Mitsunobu Reaction Using Basic Amines as Pronucleophiles
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A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C-N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C-N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43-93% yields. Importantly, C-N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system.
- Huang, Hai,Kang, Jun Yong
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p. 6604 - 6614
(2017/07/15)
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- Nickel-Catalyzed N-Alkylation of Acylhydrazines and Arylamines Using Alcohols and Enantioselective Examples
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A borrowing-hydrogen reaction between amines and alcohols is an atom-economic way to prepare alkylamines, ideally with water as the sole byproduct. Herein, nickel catalysts are used for direct N-alkylation of hydrazides and arylamines using racemic alcohols. Moreover, a nickel catalyst of (S)-binapine was used for an asymmetric N-alkylation of benzohydrazide with racemic benzylic alcohols.
- Yang, Peng,Zhang, Caili,Ma, Yu,Zhang, Caiyun,Li, Aijie,Tang, Bo,Zhou, Jianrong Steve
-
supporting information
p. 14702 - 14706
(2017/10/20)
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- Expanding Water/Base Tolerant Frustrated Lewis Pair Chemistry to Alkylamines Enables Broad Scope Reductive Aminations
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Lower Lewis acidity boranes demonstrate greater tolerance to combinations of water/strong Br?nsted bases than B(C6F5)3, this enables Si?H bond activation by a frustrated Lewis pair (FLP) mechanism to proceed in the presence of H2O/alkylamines. Specifically, BPh3has improved water tolerance in the presence of alkylamines as the Br?nsted acidic adduct H2O–BPh3does not undergo irreversible deprotonation with aliphatic amines in contrast to H2O–B(C6F5)3. Therefore BPh3is a catalyst for the reductive amination of aldehydes and ketones with alkylamines using silanes as reductants. A range of amines inaccessible using B(C6F5)3as catalyst, were accessible by reductive amination catalysed by BPh3via an operationally simple methodology requiring no purification of BPh3or reagents/solvent. BPh3has a complementary reductive amination scope to B(C6F5)3with the former not an effective catalyst for the reductive amination of arylamines, while the latter is not an effective catalyst for the reductive amination of alkylamines. This disparity is due to the different pKavalues of the water–borane adducts and the greater susceptibility of BPh3species towards protodeboronation. An understanding of the deactivation processes occurring using B(C6F5)3and BPh3as reductive amination catalysts led to the identification of a third triarylborane, B(3,5-Cl2C6H3)3, that has a broader substrate scope being able to catalyse the reductive amination of both aryl and alkyl amines with carbonyls.
- Fasano, Valerio,Ingleson, Michael J.
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supporting information
p. 2217 - 2224
(2017/02/18)
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- Boron-Catalyzed N-Alkylation of Amines using Carboxylic Acids
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A boron-based catalyst was found to catalyze the straightforward alkylation of amines with readily available carboxylic acids in the presence of silane as the reducing agent. Various types of primary and secondary amines can be smoothly alkylated with good selectivity and good functional-group compatibility. This metal-free amine alkylation was successfully applied to the synthesis of three commercial medicinal compounds, Butenafine, Cinacalcet. and Piribedil, in a one-pot manner without using any metal catalysts.
- Fu, Ming-Chen,Shang, Rui,Cheng, Wan-Min,Fu, Yao
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supporting information
p. 9042 - 9046
(2015/08/03)
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- Alkylation of Amines with Alcohols and Amines by a Single Catalyst under Mild Conditions
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An efficient catalytic system for the alkylation of amines with either alcohols or amines under mild conditions has been developed, using cyclometallated iridium complexes as catalysts. The method has broad substrate scope, allowing for the synthesis of a diverse range of secondary and tertiary amines with good to excellent yields. By controlling the ratio of substrates, both mono- and bis-alkylated amines can be obtained with high selectivity. In particular, methanol can be used as the alkylating reagent, affording N-methylated products selectively. A strong solvent effect is observed for the reaction.
- Zou, Qingzhu,Wang, Chao,Smith, Jen,Xue, Dong,Xiao, Jianliang
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supporting information
p. 9656 - 9661
(2015/06/30)
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- Reusable supported ruthenium catalysts for the alkylation of amines by using primary alcohols
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Efficient and recyclable ruthenium catalysts were synthesized from readily available polystyrene-or silica-supported phosphine ligands. Catalysts bound to the polymer support through an ether linkage showed good to excellent activity towards the N-alkylation of primary and secondary amines to afford the alkylated products in 62-99 % yield at 120-140°C. The supported phosphine ligand/ruthenium ratio was found to be crucial for higher catalytic activity and lower ruthenium leaching. The continuous flow N-alkylation of amines was demonstrated by using the supported catalyst in a column reactor. By adopting the hydrogen-borrowing strategy, the synthesis of the anti-Parkinson agent Piribedil was established in 98 % yield at 140°C. Support group steals the show: An efficient Ru-based heterogeneous catalyst from readily available supported phosphine ligands is developed. The nature of the linkage and the extent of ruthenium incorporation are crucial in determining the catalytic activity. The catalyst can be recycled and used under continuous flow in a packed-bed reactor. The alkylation of cyclic amines is achieved in excellent yield at moderate temperatures in the absence of any external base.
- Peishan, Siah,Dang, Tuan Thanh,Seayad, Abdul Majeed,Ramalingam, Balamurugan
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p. 808 - 814
(2014/03/21)
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- Reinvestigating Raney nickel mediated selective alkylation of amines with alcohols via hydrogen autotransfer methodology
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An efficient, cost-effective use of Raney nickel (R-Ni) a widely used industrial catalyst for N-alkylation using alcohols is highlighted here. The work describes the scope and capability of R-Ni in hydrogen autotransfer reactions enabling its widespread use in the Chemical and Pharmaceutical industry. R-Ni of W4, T4, and W7 grades were prepared and evaluated for alkylation of amines. The best activity and selectivity for mono alkylation of amines were obtained using W4 R-Ni at 1:4 moles of amine to alcohol in xylene at reflux. T4 R-Ni also showed ability to form stable imines. The prepared R-Ni was also recycled and reused for N-alkylation reaction. The optimized methodology was applied for synthesis of Active Pharmaceutical ingredients Piribedil and Mepyramine. The simplicity and wide substrate scope makes this method a preferred Hydrogen Auto-transfer protocol for the alkylation of amines.
- Mehta, Astha,Thaker,Londhe,Nandan, Santosh R.
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p. 241 - 251
(2014/05/20)
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- Development of a general non-noble metal catalyst for the benign amination of alcohols with amines and ammonia
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The N-alkylation of amines or ammonia with alcohols is a valuable route for the synthesis of N-alkyl amines. However, as a potentially clean and economic choice for N-alkyl amine synthesis, non-noble metal catalysts with high activity and good selectivity are rarely reported. Normally, they are severely limited due to low activity and poor generality. Herein, a simple NiCuFeOx catalyst was designed and prepared for the N-alkylation of ammonia or amines with alcohol or primary amines. N-alkyl amines with various structures were successfully synthesized in moderate to excellent yields in the absence of organic ligands and bases. Typically, primary amines could be efficiently transformed into secondary amines and N-heterocyclic compounds, and secondary amines could be N-alkylated to synthesize tertiary amines. Note that primary and secondary amines could be produced through a one-pot reaction of ammonia and alcohols. In addition to excellent catalytic performance, the catalyst itself possesses outstanding superiority, that is, it is air and moisture stable. Moreover, the magnetic property of this catalyst makes it easily separable from the reaction mixture and it could be recovered and reused for several runs without obvious deactivation. Copyright
- Cui, Xinjiang,Dai, Xingchao,Deng, Youquan,Shi, Feng
-
supporting information
p. 3665 - 3675
(2013/03/29)
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- Catalysis in flow: Au-catalysed alkylation of amines by alcohols
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By using a greater reaction space afforded by a flow reactor, commercially available Au/TiO2 can be used for highly selective direct alkylation of amines by alcohols, without the need for an inert atmosphere or base. A brief survey of substrates includes the alkylation of aromatic, aliphatic and chiral amines by a number of primary and secondary alcohols, in high yield and selectivity. The synthesis of Piribedil, a drug used in the treatment of Parkinson's disease, can be achieved in a single synthetic operation without the need for column chromatography. Mechanistic aspects of the reaction were revealed through modelling of reaction profiles, and the origin of selectivity is attributed to the accessibility of high temperature. The presence of water was found to be crucial for catalyst activity.
- Zotova, Natalia,Roberts, Felicity J.,Kelsall, Geoffrey H.,Jessiman, Alan S.,Hellgardt, Klaus,Hii, King Kuok Mimi
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experimental part
p. 226 - 232
(2012/04/04)
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- Borrowing hydrogen methodology for amine synthesis under solvent-free microwave conditions
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Application of microwave heating to the Borrowing Hydrogen strategy to form C-N bonds from alcohols and amines is presented, removing the need for solvent and reducing the reaction times while still yielding results comparable with those using thermal heating.
- Watson, Andrew J. A.,Maxwell, Aoife C.,Williams, Jonathan M. J.
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supporting information; experimental part
p. 2328 - 2331
(2011/05/17)
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- Ruthenium-catalyzed /V-alkylation of amines and sulfonamides using borrowing hydrogen methodology
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The alkylation of amines by alcohols has been achieved using 0.5 mol percent [Ru(p-cymene)CI2]2 with the bidentate phosphines dppf or DPEphos as the catalyst. Primary amines have been converted into secondary amines, and secondary amines into tertiary amines, including the syntheses of Piribedil, Tripelennamine, and Chlorpheniramine. A/-Heterocyclization reactions of primary amines are reported, as well as alkylation reactions of primary sulfonamides. Secondary alcohols requiremore forcing conditions than primary alcohols but are still effective a lkylating agents in the presence of this catalyst.
- Hamid, M. Haniti S. A.,Allen, C. Liana,Lamb, Gareth W.,Maxwell, Aoife C.,Maytum, Hannah C.,et al.
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supporting information; experimental part
p. 1766 - 1774
(2009/07/25)
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- Ruthenium-catalysed synthesis of tertiary amines from alcohols
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Secondary amines have been converted into tertiary amines by reactions with primary alcohols. A catalytic system of [Ru(cymene)Cl2]2 with dppf has been shown to be effective for this transformation for a range of primary alcohols and secondary amines. The methodology has been applied to the one pot synthesis of Piribedil and other piperazine and morpholine-containing products.
- Hamid, M. Haniti S.A.,Williams, Jonathan M.J.
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p. 8263 - 8265
(2008/03/14)
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- Parallel synthesis of N-arylpiperazines using polymer-assisted reactions
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A series of N-arylpiperazines were prepared in a parallel fashion using palladium-catalyzed cross-coupling, or nucleophilic aromatic displacement chemistries, and polymer-assisted sequestration and purification techniques as key steps.
- Duncton, Matthew A. J.,Roffey, Jonathan R. A.,Hamlyn, Richard J.,Adams, David R.
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p. 2549 - 2552
(2007/10/03)
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- Method for the purification of piribedil
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A method for purifying Piribedil includes mixing Piribedil solid having a purity of 98% by weight with water, boiling the mixture, adding slowly 95% ethanol to the boiling mixture to form a clear liquid, filtering the hot clear liquid, cooling the filtrate to obtain a white crystal having a purity of 99.8% by weight of Piribedil.
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Page/Page column 1; 2
(2008/06/13)
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- N-(3,3-diphenylpropyl)-n'-aralkyl-substituted piperazines
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N-(3,3-Diphenylpropyl)-N'-aralkyl-substituted piperazines which have a structure in which a hydrogen in the N'-benzene ring has been substituted for by --(OCH3)n (in which n represents an integer from 0 - 3) were synthesized. These compounds are novel compounds that are not found in literature, and have a coronary blood flow increasing action in considerably lower amounts than do conventional piperazine compounds having similar effects.
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