- Lewis Base-Catalyzed Amino-Acylation of Arylallenes via C-N Bond Cleavage: Reaction Development and Mechanistic Studies
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Lewis base-catalyzed transformations of allenes have received much attention over the last decades. However, this type of reaction has so far been limited to activated allenes bearing an electron-withdrawing group. On the other hand, cleavage of an amide C-N bond to forge other chemical bonds has been widely reported but restricted to low atom economy due to the waste of the amine moiety of amides. We initiated a project of metal-catalyzed amino-acylation of allenes via cleavage of amide C-N bonds. Surprisingly, an amino-acylation of weakly activated aryl allenes was discovered via Lewis base catalysis, providing 2-methyl-3-aroylindole products, "privileged structures"in drug discovery. This is a unique example of Lewis base catalysis of weakly activated allenes, which was not reported yet. Extensive experimental and computational studies have been conducted to provide insight into the reaction mechanism. The nucleophilic addition of Lewis base catalyst to aryl allene is the rate-limiting step. A challenging [1,3]-proton transfer is realized by nitrogen anion intermediate assisted sequential [1,4]- and [1,6]-proton transfer in the reaction pathway.
- Xia, Ji-Bao,Yang, Yusheng,Yu, Zhi-Xiang,Zhang, Zheng-Bing
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p. 5419 - 5429
(2020/09/02)
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- Palladium-catalyzed cyclization reaction of N-(2-Haloaryl)alkynylimines: Synthesis of 3-acylindoles using water as the sole solvent and oxygen source
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A simple and efficient strategy for the preparation of 3-acylindoles via palladium-catalyzed cyclization reaction of N-(2-haloaryl)alkynylimines in water has been developed. The reaction tolerates a wide range of functional groups, and the corresponding 3-acylindoles were obtained in high yields using water as the sole solvent and oxygen sources. Additionally, this method could provide a short synthesis route for Pravadoline, a phase II analgesic drug.
- Zhang, An-An,Meng, Tuanjie,Wang, Wenli,Liu, Xueli,Zhu, Yupei,Liu, Lantao
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- Cyclooctatetraene: A Bioactive Cubane Paradigm Complement
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Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.
- Xing, Hui,Houston, Sevan D.,Chen, Xuejie,Ghassabian, Sussan,Fahrenhorst-Jones, Tyler,Kuo, Andy,Murray, Cody-Ellen P.,Conn, Kyna-Anne,Jaeschke, Kara N.,Jin, Da-Yun,Pasay, Cielo,Bernhardt, Paul V.,Burns, Jed M.,Tsanaktsidis, John,Savage, G. Paul,Boyle, Glen M.,De Voss, James J.,McCarthy, James,Walter, Gimme H.,Burne, Thomas H. J.,Smith, Maree T.,Tie, Jian-Ke,Williams, Craig M.
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p. 2729 - 2734
(2019/02/03)
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- Metal-free 3-acyl indole compound synthetic method
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The invention relates to a metal-free 3-acyl indole compound synthetic method. The metal-free 3-acyl indole compound synthetic method comprises following steps: a N-tert-butoxycarbonyl-N-acyl-2-allenephenyl amine compound, and a nucleophilic organic small molecular catalyst are introduced into a reaction container, at nitrogen atmosphere, an organic solvent is added, reaction is carried out for 24 to 48h at 50 to 120 DEG C, and separation and purification are carried out to obtain the 3-acyl indole compound. According to the synthetic method, the nucleophilic organic small molecular catalystis taken as a catalyst, no additive is added, and cost is low; reaction atom economy is excellent, and generation of unnecessary waste is avoided; reaction conditions are mild; the operationality is high; and potential industrialized application prospect is achieved.
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Paragraph 0061
(2019/12/09)
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- Application of hypervalent iodine reagent-mediated in preparation of indole derivatives
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The invention relates to application of hypervalent iodine reagent-mediated in preparation of indole derivatives, in particular to the application of organic trivalent iodine reagent iodoyl benzene aminosulfonate in preparing N-protected 2-substituted indole compounds and indomethacin, zidometacin, pravadoline. The invention relates to the application of organic trivalent iodine reagent iodoyl benzene aminosulfonate in preparing N-protected 2-substituted indole compounds, and the reaction undergoes functional group exchange of a substrate. In addition, iodoyl benzene aminosulfonate plays two important roles in this application, as an oxidant and as Bronsted acid. The application has the advantages of good regioselectivity, wide substrate range, mild conditions, simple operation and amplification of experimental steps. The application of the organic trivalent iodine reagent iodoyl benzene aminosulfonate in the preparation of indomethacin, zidomeprin and pravadoline provided by the invention has the advantages of high synthesis efficiency, simple operation and the like.
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- Direct Synthesis of 3-Acylindoles through Rhodium(III)-Catalyzed Annulation of N-Phenylamidines with α-Cl Ketones
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In the present study, a novel synthetic strategy to directly produce versatile 3-acylindoles through Rh(III)-catalyzed C-H activation and annulation cascade of N-phenylamidines with α-Cl ketones was developed, in which α-Cl ketones serve as unusual one-carbon (sp3) synthons. This strategy features high regioselectivity, efficiency, wide substrate tolerance, and mild reaction conditions, which further underscore its synthetic utility in drug molecule synthesis.
- Zhou, Jianhui,Li, Jian,Li, Yazhou,Wu, Chenglin,He, Guoxue,Yang, Qiaolan,Zhou, Yu,Liu, Hong
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p. 7645 - 7649
(2018/12/11)
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- [3 + 2]-Annulations of N-hydroxy allenylamines with nitrosoarenes: One-pot synthesis of substituted indole products
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In the presence of O2 and an IPrCuCl additive (5 mol %), [3 + 2]-annulation reactions of N-hydroxyaniline with nitrosobenzenes in cold toluene form isoxazolidin-5-ol derivatives. Heating the same reaction mixture with DBU in toluene affords highly functionalized indole products efficiently. This method provides short synthesis of several bioactive molecules including WIN 48098, WIN 53365, and JWH 015.
- Sharma, Pankaj,Liu, Rai-Shung
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p. 412 - 415
(2016/02/18)
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- Synthesis of indoles through Rh(III)-catalyzed C-H cross-coupling with allyl carbonates
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A practical Rh-catalyzed reaction was developed to achieve 2-alkyl-substituted indole synthesis. The reaction can tolerate a variety of synthetically important functional groups. The indole products can also be transformed into other important skeletons. Two bioactive compounds, that is indomethacin and pravadoline were prepared using the new method.
- Gong, Tian-Jun,Cheng, Wan-Min,Su, Wei,Xiao, Bin,Fu, Yao
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p. 1859 - 1862
(2014/03/21)
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- Transfer of Activation from Indoles to Alcohols: A New Method for the Synthesis of Aminoethylindoles.
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Transfer of a sulfonyl group from an indole nitrogen to a β-amino alkoxide generates an indole anion and an aminoethylsulfonate which react to give aminoethylindoles.
- Eissenstat, Michael A.,Weaver, John D.
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p. 2029 - 2032
(2007/10/02)
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- Antinociceptive (Aminoalkyl)indoles
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The (aminoalkyl)indole (AAI) derivative pravadoline (1a) inhibited prostaglandin (PG) synthesis in mouse brain microsomes in vitro and ex vivo and exhibited antinociceptive activity in several rodent assays.In vitro structure-activity relationship studies of this new class of PG synthesis inhibitors revealed a correspondence in three respects to those reported for the arylacetic acids: (1) "α-methylation" caused an increase in PG inhibitory potency, (2) the (R)-α-methyl isomer was more active than the S isomer, (3) the hypothesized aroyl group conformation of the 2-methyl derivatives corresponded to the proposed and reported "active" conformations of the aroyl and related aromatic acetic acid derivatives.The 1H NMR chemical shift of the C-4 hydrogen of pravadoline in comparison to the deshielding seen with 50, which lacks a substituent at C-2, suggested that the carbonyl group of pravadoline is located near C-2 but is located near C-4 in 50.Associated with this conformational change of the carbonyl group of 1a is a diminution of PG synthetase inhibitory activity.The results of UV and difference nuclear Overhauser studies of the two compounds were consistent with these conformational assignments.The low eudismic ratios of the α-methyl derivatives and the observation that the side chain may be extended by three methylene groups without significant loss of PG inhibitory potency suggests that this class of inhibitors bound less strongly and less selectively to the active site of PG synthetase than do the arylacetic acids.Two AAIs, 1a and 30, were found to be metabolized to the corresponding acetic acid derivatives, both of which inhibited PG synthesis.An exception to the observation that the antinociceptive activity of the AAIs was associated with PG synthetase inhibitory activity was the 1-naphthoyl derivative 67 since neither it nor its acetic acid metabolite 74 inhibited PG synthesis.Yet 67 was antinociceptive in four different rodent assays.This naphthoyl derivative, like opioids, also inhibited electrically stimulated contractions in the mouse vas deferens (MVD) preparation.Unlike opioids, however, the inhibition was not antagonized by naloxone.A subseries of AAIs was identified, of which 67 was prototypic.These compounds lacked PG synthetase inhibitory activity, but their inhibitory potency in MVD preparations correlated roughly with their antinociceptive potency in vivo.Pravadoline was also inhibitory in MVD.Is antinociceptive activity, therefore, may be a consequence of both its PG synthease inhibitory potency and another antinociceptive mechanism, the latter associated with its inhibitory potency in the MVD.The evidence is summarized which suggests that this second antinociceptive mechanism is associated with binding to the recently characterized cannabinoid receptor.
- Bell, Malcolm R.,D'Ambra, Thomas E.,Kumar, Virendra,Eissenstat, Michael A.,Herrmann, John L.,et al.
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p. 1099 - 1110
(2007/10/02)
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