- Regioselective 2-alkylation of indoles with α-bromo esters catalyzed by Pd/P,P=O system
-
A palladium-catalyzed 2-alkylation of indoles with α-bromo esters is developed by employing a P,P=O ligand. The method features excellent regioselectivities, mild reaction conditions, and good functional group compatibility. The employment of the P,P=O ligand as well as 4? molecular sieves were crucial for the success of the transformation. Mechanistic studies indicate the reaction proceed through a radical pathway.
- Tian, Wei,Li, Bowen,Tian, Duanshuai,Tang, Wenjun
-
supporting information
p. 197 - 200
(2021/08/13)
-
- Rhodium(III)-Catalyzed Regioselective C?H Allylation and Prenylation of Indoles at C4-Position
-
Herein, Rh(III)-catalyzed C4-selective C?H allylation and prenylation of indoles by using a weak carbonyl coordination directing group have been reported. By employing 5-methylene-1,3-dioxan-2-ones, 4-vinyl-1,3-dioxolan-2-ones and 2-methyl-2,3-butadiene as scalable cross-coupling partners, these divergent synthesis protocols proceed smoothly under redox-neutral reaction conditions, delivering various allylated and prenylated indoles in moderate to satisfied yields. This transformation exhibits high functional-groups compatibility and broad substrate scope. Scale-up experiment and mechanistic studies were also accomplished. (Figure presented.).
- Zhang, Shang-Shi,Liu, Yan-Zhi,Zheng, Yi-Chuan,Xie, Hui,Chen, Shao-Yong,Song, Jia-Lin,Shu, Bing
-
supporting information
p. 64 - 70
(2021/11/03)
-
- Copper-Catalyzed Synthesis of Indolyl Benzo[b]carbazoles and Their Photoluminescence Property
-
A copper-catalyzed cascade cyclization of dihydroisobenzofurans with indoles for the rapid construction of indoly benzo[b]carbazoles has been reported, providing the desired products in moderate to good yields under mild conditions along with a broad substrate scope and good functional group tolerance. The photoluminescence property of these indoly benzo[b]carbazoles has also been investigated.
- Hao, Tonggang,Huang, Long,Wei, Yin,Shi, Min
-
supporting information
p. 5133 - 5137
(2021/07/19)
-
- ARYL HYDROCARBON RECEPTOR ACTIVATORS
-
Small molecule AhR ligands are disclosed. The ligands can induce the differentiation of Tr1 cells to suppress pathogenic immune responses without inducing nonspecific immune suppression. Methods of treatment of autoimmune diseases using the AhR ligands are also disclosed.
- -
-
Page/Page column 24
(2021/02/05)
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- Tandem iridium-catalyzed decarbonylative c-h activation of indole: Sacrificial electron-rich ketone-assisted bis-arylsulfenylation
-
Described herein is a decarbonylative tandem C-H bis-arylsulfenylation of indole at the C2 and C4 C-H bonds through the use of pentamethylcyclopentadienyl iridium dichloride dimer ([Cp?IrCl2]2) catalyst and disulfides. A new sacrificial electron-rich adamantoyl-directing group facilitates indole C-H bis-functionalization with a traceless in situ removal. Various differently substituted disulfides can be easily accommodated in this reaction by a coordination to Ir(III) through the formation of six- and five-membered iridacycles at the C2 and C4 positions, respectively. Mechanistic studies show that a C-H activation-induced C-C activation is involved in the catalytic cycle.
- Kathiravan, Subban,Anaspure, Prasad,Zhang, Tianshu,Nicholls, Ian A.
-
supporting information
p. 3331 - 3336
(2021/05/29)
-
- Assembly of polycyclic N-heterocycles: Via copper-catalyzed cycloamination of indolylquinones and aromatic amines
-
The copper-catalyzed cycloamination of indolylquinones and various (hetero)aromatic amines under ligand-free conditions for the synthesis of polycyclic N-heterocycles has been developed. This method allows facile access to polycyclic N-heterocycles with the tolerance of chloride, bromide, amino, thio, etc. groups in moderate to high yields (60-89%).
- Dong, Yu,Mei, Ting,Ye, Ji-Xian,Chen, Xiang-Long,Jiang, Hui,Chang, Bo,Wang, Zhi-Fan,Shi, Zhi-Chuan,Li, Zhong-Hui,He, Bing
-
supporting information
p. 4593 - 4598
(2021/05/31)
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- Salicylaldehyde-Promoted Cobalt-Catalyzed C-H/N-H Annulation of Indolyl Amides with Alkynes: Direct Synthesis of a 5-HT3 Receptor Antagonist Analogue
-
A cobalt-catalyzed annulation of the C(sp2)-H/N-H bond of indoloamides with alkynes assisted by 8-aminoquinoline is reported for the synthesis of six-membered indololactams. The use of salicylaldehyde as the ligand is crucial for this transformation. The protocol has a broad scope for both alkynes and indoles. Preparing an active Co complex illustrates that salicylaldehyde plays a key role in the C-H activation step. The synthetic applications are proven by the gram-scale reaction and one-step construction of the multicyclic 5-HT3 receptor antagonist.
- Huang, Mao-Gui,Shi, Shuai,Li, Ming,Liu, Yue-Jin,Liu, Yue-Jin
-
supporting information
p. 7094 - 7099
(2021/09/14)
-
- Synthesis of 3-halogenated 2,3′-biindoles by a copper-mediated 2,3-difunctionalization of indoles
-
A copper-mediated 2,3-difunctionalization of indoles to afford 3-halogenated 2,3′-biindoles is described herein. The protocol uses readily available feedstocks and a naturally abundant copper catalyst system, which allows the regioselective formation of C-C and C-X (X = Cl & Br) bonds in one single operation. Here the copper metal salt serves not only as a catalyst but also as a reactant to provide the source of halogen. This operationally simple procedure avoids the utilization of environmentally unfriendly reagents and displays good functional group compatibility. Noteworthily, the introduction of halogen into molecules would offer great potential for further chemical transformations. This journal is
- Gu, Xiaoting,Liang, Taoyuan,Wei, Wanxing,Zhang, Xiaoxiang,Zhang, Yingying,Zhang, Zhuan
-
supporting information
p. 10403 - 10407
(2021/12/17)
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- Preparation method of nitrogen-alkyl (deuterated alkyl) aromatic heterocycle and alkyl (deuterated alkyl) aryl ether compound
-
The invention provides a method for preparing nitrogen-alkyl(deuterated alkyl)aromatic heterocycle and alkyl(deuterated alkyl)aryl ether compounds. The method adopted in the invention specifically comprises the following steps: firstly, adding an alkoxy base (MOR') or a combination reagent Q (comprising a base M'X, an alcohol C and a molecular sieve E) into a solvent B to be stirred; then, addingan aromatic compound D of nitrogen sulfonyl or oxygen sulfonyl into a mixture; separating and purifying after reaction to obtain nitrogen-alkyl(deuterated alkyl)aromatic heterocycle or alkyl(deuterated alkyl)aryl ether. The method can realize one-step conversion from an electron withdrawing benzenesulfonyl protecting group on a nitrogen or oxygen atom to an electron donating alkyl protecting group, avoids using highly toxic alkyl halide, and has advantages of being efficient, economical, environmentally friendly, mild in condition, good in substrate universality and high in yield; the prepareddeuterated compounds can be widely applied to the fields of pharmaceutical chemistry and organic chemistry synthesis.
- -
-
Paragraph 0087-0091
(2021/04/03)
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- Visible-Light-Induced, Base-Promoted Transition-Metal-Free Dehalogenation of Aryl Fluorides, Chlorides, Bromides, and Iodides
-
We report a simple and efficient visible-light-induced transition-metal-free hydrogenation of aryl halides. The combined visible light and base system is used to initiate the desired radical-mediated hydrogenation. A variety of aryl fluorides, chlorides, bromides, and iodides could be reduced to the corresponding (hetero)arenes with excellent yields under mild conditions. Various functional groups and other heterocyclic compounds are tolerated.
- Ding, Ting-Hui,Qu, Jian-Ping,Kang, Yan-Biao
-
supporting information
p. 3084 - 3088
(2020/04/10)
-
- Electrosynthesis of Dihydropyrano[4,3-b]indoles Based on a Double Oxidative [3+3] Cycloaddition
-
Oxidative [3+3] cycloadditions offer an efficient route for six-membered-ring formation. This approach has been realized based on an electrochemical oxidative coupling of indoles/enamines with active methylene compounds followed by tandem 6π-electrocyclization leading to the synthesis of dihydropyrano[4,3-b]indoles and 2,3-dihydrofurans. The radical–radical cross-coupling of the radical species generated by anodic oxidation combined with the cathodic generation of the base from O2 allows for mild reaction conditions for the synthesis of structurally complex heterocycles.
- Choi, Subin,Park, Cheol-Min,Park, Jinhwi,Sim, Jeongwoo,Yu, Eunsoo
-
supporting information
p. 11886 - 11891
(2020/05/22)
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- Isothiourea-Catalyzed Enantioselective Synthesis of Tetrahydro-α-carbolinones
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An isothiourea-catalyzed enantioselective annulation protocol using indolin-2-imines with a series of α,β-unsaturated p-nitrophenyl esters for the synthesis of tetrahydro-α-carbolinones was developed. Using 5 mol % of the isothiourea HyperBTM as the Lewis base catalyst, this process allows the enantioselective preparation of a range of C(4)-substituted tetrahydro-α-carbolinones in good to excellent yield and with high enantioselectivity (20 examples, 32-99% yield and up to 99:1 er).
- Liu, Honglei,Slawin, Alexandra M. Z.,Smith, Andrew D.
-
supporting information
p. 1301 - 1305
(2020/02/25)
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- Synthesis of Cyclopenta[b]indoles via a Formal [3+2] Cyclization of N-Sulfonyl-1,2,3-triazoles and Indoles
-
Annulation of benzoxy-tethered N-sulfonyl-1,2,3-triazoles and indoles has been developed in this paper, providing an efficient and convenient access to valuable cyclopenta[b]indoles in moderate to good yields. α,β-Unsaturated imine, which generated in situ from denitrogenation and 1,2-OBz migration of triazole, provided three carbons for the formal [3+2] cyclization reaction for the first time. (Figure presented.).
- Duan, Shengguo,Zhang, Wan,Hu, Yuntong,Xu, Ze-Feng,Li, Chuan-Ying
-
supporting information
p. 3570 - 3575
(2020/08/05)
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- γ-Carboline synthesis enabled by Rh(iii)-catalysed regioselective C-H annulation
-
A redox-neutral Rh(iii)-catalyzed C-H annulation of indolyl oximes was developed. Relying on the use of various alkynyl silanes as the terminal alkyne surrogates, the reaction exhibited a reverse regioselectivity, thus giving an exclusive and easy way for the synthesis of a wide range of substituent free γ-carbolines at C3 position with high efficiency. Deuterium-labelling experiments and kinetic analysis have preliminarily shed light on the working mode of this catalytic system. This journal is
- Jiang, Bo,Jia, Jingwen,Sun, Yufei,Wang, Yichun,Zeng, Jing,Bu, Xiubin,Shi, Liangliang,Sun, Xiaoying,Yang, Xiaobo
-
supporting information
p. 13389 - 13392
(2020/11/10)
-
- Cobalt-Catalyzed Cycloamination: Synthesis and Photophysical Properties of Polycyclic N-Heterocycles
-
The first earth-abundant cobalt-catalyzed cycloamination of indolylquinones and various (hetero)aromatic amine under ligand-free conditions for the synthesis of polycyclic N-heterocycles has been developed. The process allows facile access to polycyclic N-heterocycles with tolerance of chloride, bromide, amino, thio, etc. groups in moderate to high yields (up to 89percent). In addition, The photophysical properties of the synthesized products were evaluated. These products exhibit interesting fluorescence properties, which is promising for fluorescent probes.
- Dong, Yu,He, Shuai,Shi, Zhi-Chuan,Wang, Ji-Yu,Yang, Jian,Zhan, Xiao-Yu,Zhang, Hua,Zhang, Xiao-Mei
-
supporting information
(2020/07/15)
-
- Ir-Catalyzed Reversible Acceptorless Dehydrogenation/Hydrogenation of N-Substituted and Unsubstituted Heterocycles Enabled by a Polymer-Cross-Linking Bisphosphine
-
The polystyrene-cross-linking bisphosphine ligand PS-DPPBz was effective for the Ir-catalyzed reversible acceptorless dehydrogenation/hydrogenation of N-heterocycles. Notably, this protocol is applicable to the dehydrogenation of N-substituted indoline derivatives with various N-substituents with different electronic and steric natures. A reaction pathway involving oxidative addition of an N-adjacent C(sp3)-H bond to a bisphosphine-coordinated Ir(I) center is proposed for the dehydrogenation of N-substituted substrates.
- Zhang, Deliang,Iwai, Tomohiro,Sawamura, Masaya
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p. 5240 - 5245
(2020/07/03)
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- Catalytic Aerobic Dehydrogenatin of N-Heterocycles by N-Hydoxyphthalimide
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Catalytic methods for the aerobic dehydrogenation of N-heterocycles are reported. In most cases, indoles are accessed efficiently from indolines using catalytic N-hydroxyphthalimide (NHPI) as the sole additive under air. Further studies revealed an improved catalytic system of NHPI and copper for the preparation of other heteroaromatics, for example quinolines. (Figure presented.).
- Chen, Weidong,Tang, Hao,Wang, Weilin,Fu, Qiang,Luo, Junfei
-
supporting information
p. 3905 - 3911
(2020/08/10)
-
- Method for preparing indole compound through air oxidation catalyzed by N-hydroxyphthalimide
-
The invention discloses a method for preparing an indole compound through non-transition metal catalyzed air oxidation. According to the method, the low-cost N-hydroxyphthalimide is used as a catalystand air is used as an oxidizing agent, wherein indoline compounds are oxidized in an organic solvent, and synthesis of the indoline compounds is achieved. The method has the advantages of simple reaction operation, low reaction cost, high yield, mild conditions, no heavy metal pollution and the like.
- -
-
Paragraph 0050-0052
(2020/11/23)
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- Cross-Coupling of Chloro(hetero)arenes with Thiolates Employing a Ni(0)-Precatalyst
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A general and efficient Ni-catalyzed coupling of challenging aryl chlorides and in situ generated aliphatic and aromatic thiolates is described. The employed on-cycle, air-stable defined Ni precatalysts allow for transformation of a broad scope of substrates. A variety of functional groups and heterocyclic motifs as well as structurally varied thiols are tolerated at unprecedented moderate catalyst loadings and reaction temperatures. Depending on reaction conditions, aryl thiols can selectively undergo C-S or C-C couplings.
- Gehrtz, Paul H.,Geiger, Valentin,Schmidt, Tanno,Sr?an, Laura,Fleischer, Ivana
-
supporting information
p. 50 - 55
(2019/01/11)
-
- NaNO2/K2S2O8-mediated Selective Radical Nitration/Nitrosation of Indoles: Efficient Approach to 3-Nitro- and 3-Nitrosoindoles
-
JPZ acknowledges financial support from the National Natural Science Foundation of China (No. 21172163, 21472133), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Key Laboratory of Organic Synthesis of Jiangsu Province (KJS1749). (Figure presented.).
- Shoberu, Adedamola,Li, Cheng-Kun,Tao, Ze-Kun,Zhang, Guo-Yu,Zou, Jian-Ping
-
supporting information
p. 2255 - 2261
(2019/04/13)
-
- Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis
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A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ- or δ,δ-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
- Jeon, Jinwon,Ryu, Ho,Lee, Changseok,Cho, Dasol,Baik, Mu-Hyun,Hong, Sungwoo
-
supporting information
(2019/07/03)
-
- Site-Selective 1,1-Difunctionalization of Unactivated Alkenes Enabled by Cationic Palladium Catalysis
-
A palladium(II)-catalyzed 1,1-difunctionalization of unactivated terminal and internal alkenes via addition of two nucleophiles was developed using a cationic palladium(II) complex. The palladacycle generated in situ as a result of a regioselective addition of a nucleophile to the alkene can readily undergo regioselective β-hydride elimination and migratory insertion with a cationic palladium catalyst. The resulting η 3-π-allyl palladium(II) complex is the key intermediate that reacts with a second nucleophile to furnish the desired 1,1-difunctionalization of the alkene. Under the optimized reaction conditions, a wide range of indoles and anilines add to alkene units of 3-butenoic or 4-pentenoic acid derivatives to afford the synthetically useful γ,γ-or ?,?-difunctionalized products with excellent regiocontrol. Furthermore, by employing internal hydroxyl or acid groups and external carbon nucleophiles, this transformation enables unsymmetric 1,1-difunctionalization to forge challenging and important oxo quaternary carbon centers. Combining experiments and DFT calculations on the mechanism of the reaction is investigated in detail.
- Jeon, Jinwon,Ryu, Ho,Lee, Changseok,Cho, Dasol,Baik, Mu-Hyun,Hong, Sungwoo
-
supporting information
p. 10048 - 10059
(2019/07/04)
-
- Electrochemically Enabled C3-Formylation and -Acylation of Indoles with Aldehydes
-
Reported herein is an effective strategy for oxidative cross-coupling of indoles with various aldehydes. The strategy is based on a two-step transformation via a well-known Mannich-type reaction and a C-N bond cleavage for carbonyl introduction. The key step - the C-N bond cleavage of the Mannich product - was enabled by electrochemistry. This strategy (with over 40 examples) ensures excellent functional-group tolerance as well as late-stage functionalization of pharmaceutical molecules.
- Yang, Liquan,Liu, Zhaoran,Li, Yujun,Lei, Ning,Shen, Yanling,Zheng, Ke
-
supporting information
p. 7702 - 7707
(2019/10/19)
-
- Detosylative (Deutero)alkylation of Indoles and Phenols with (Deutero)alkoxides
-
An efficient strategy for N/O-(deutero)alkylation of indoles and phenols with alkoxides/alcohols as the alkylation reagents is described. The consecutive detosylation/alkylation transformations feature mild reaction conditions, high ipso-selectivity, and good functional group tolerance (>50 examples). A one-pot selective N-alkylation of unprotected indoles with alcohols and TsCl is also realized. The application of this method is demonstrated by the introduction of isotope-labeled (CD3 and 13CH3) groups using the readily accessible labeled alcohols and the synthesis of pharmaceuticals.
- Zhu, Ming-Hui,Yu, Cheng-Long,Feng, Ya-Lan,Usman, Muhammad,Zhong, Dayou,Wang, Xin,Nesnas, Nasri,Liu, Wen-Bo
-
supporting information
p. 7073 - 7077
(2019/09/30)
-
- Replacement of Stoichiometric DDQ with a Low Potential o-Quinone Catalyst Enabling Aerobic Dehydrogenation of Tertiary Indolines in Pharmaceutical Intermediates
-
A transition-metal/quinone complex, [Ru(phd)3]2+ (phd = 1,10-phenanthroline-5,6-dione), is shown to be effective for aerobic dehydrogenation of 3° indolines to the corresponding indoles. The results show how low potential quinones may be tailored to provide a catalytic alternative to stoichiometric DDQ, due to their ability to mediate efficient substrate dehydrogenation while also being compatible with facile reoxidation by O2. The utility of the method is demonstrated in the synthesis of key intermediates to pharmaceutically important molecules.
- Li, Bao,Wendlandt, Alison E.,Stahl, Shannon S.
-
supporting information
p. 1176 - 1181
(2019/02/14)
-
- Metal-Free Oxidative Cross Coupling of Indoles with Electron-Rich (Hetero)arenes
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A new method for the synthesis of bi-heteroaryls is reported, based on the umpolung of indoles with benziodoxol(on)e hypervalent iodine reagents (IndoleBX). The oxidative coupling of IndoleBX with an equimolar amount of electron-rich benzenes, indoles, pyrroles, and thiophenes proceeded under mild transition-metal-free conditions. Functionalized non-symmetrical bi-indolyl heterocycles were accessed efficiently. Introduction of a new type of C2-substituted indole benziodoxole reagents further allowed extending the scope of the reaction to NH unprotected and C3-alkylated indoles. The obtained bi-heterocycles are important building blocks in synthetic and medicinal chemistry, and could be easily transformed into more complex heterocyclic systems.
- Caramenti, Paola,Nandi, Raj Kumar,Waser, Jerome
-
supporting information
p. 10049 - 10053
(2018/07/29)
-
- Practical and Scalable Synthesis of Borylated Heterocycles Using Bench-Stable Precursors of Metal-Free Lewis Pair Catalysts
-
A practical and scalable metal-free catalytic method for the borylation and borylative dearomatization of heteroarenes has been developed. This synthetic method uses inexpensive and conveniently synthesizable bench-stable precatalysts of the form 1-NHR2-2-BF3-C6H4, commercially and synthetically accessible heteroarenes as substrates, and pinacolborane as the borylation reagent. The preparation of several borylated heterocycles on 2 and 50 g scales was achieved under solvent-free conditions without the use of Schlenk techniques or a glovebox. A kilogram-scale borylation of one of the heteroarene substrates was also achieved using this cost-effective green methodology to exemplify the fact that our methodology can be conveniently implemented in fine chemical industries.
- Jayaraman, Arumugam,Misal Castro, Luis C.,Fontaine, Frédéric-Georges
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supporting information
p. 1489 - 1499
(2018/10/26)
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- Myoglobin-Catalyzed C?H Functionalization of Unprotected Indoles
-
Functionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal-catalyzed carbene transfer has provided an attractive route to afford C3-functionalized indoles, these protocols are viable only in the presence of N-protected indoles, owing to competition from the more facile N?H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C?H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α-diazoacetate to give the corresponding C3-functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti-inflammatory drug indomethacin.
- Vargas, David A.,Tinoco, Antonio,Tyagi, Vikas,Fasan, Rudi
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supporting information
p. 9911 - 9915
(2018/07/31)
-
- Thioether-Directed Selective C4 C-H Alkenylation of Indoles under Rhodium Catalysis
-
A thioether-directed Rh(III)-catalyzed C4 selective C-H alkenylation of indoles via the formation of 5-membered metallacycle intermediates is reported. This protocol allows a wide functional group compatibility and broad substrate scope. The directing group can be readily removed or transformed into other functional groups after the C-H functionalization event. The catalytic method is also applicable to related heterocyclic systems involving benzo[b]thiophene and benzo[b]furan scaffolds.
- Kona, Chandrababu Naidu,Nishii, Yuji,Miura, Masahiro
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supporting information
p. 4898 - 4901
(2018/08/24)
-
- Indole- and Pyrrole-BX: Bench-Stable Hypervalent Iodine Reagents for Heterocycle Umpolung
-
The one-step synthesis of the bench-stable hypervalent iodine reagents IndoleBX and PyrroleBX using mild Lewis acid catalyzed conditions is reported. The new reagents are stable up to 150 °C and were applied in the C?H arylation of unactivated arenes using either rhodium or ruthenium catalysts. A broad range of heterocyclic systems of high interest for synthetic and medicinal chemistry was accessed in high yields. The developed C?H functionalization could not be achieved using reported reagents or methods, highlighting the unique reactivity of Indole- and Pyrrole-BX.
- Caramenti, Paola,Nicolai, Stefano,Waser, Jerome
-
supporting information
p. 14702 - 14706
(2017/09/11)
-
- Site-Selective Copper-Catalyzed Amination and Azidation of Arenes and Heteroarenes via Deprotonative Zincation
-
Arene amination is achieved by site-selective C-H zincation followed by copper-catalyzed coupling with O-benzoylhydroxylamines under mild conditions. Key to this success is ortho-zincation mediated by lithium amidodiethylzincate base that is effective for a wide range of arenes, including nonactivated arenes bearing simple functionalities such as fluoride, chloride, ester, amide, ether, nitrile, and trifluoromethyl groups as well as heteroarenes including indole, thiophene, pyridine, and isoquinoline. An analogous C-H azidation is also accomplished using azidoiodinane for direct introduction of a useful azide group onto a broad scope of arenes and heteroarenes. These new transformations offer rapid access to valuable and diverse chemical space of aminoarenes. Their broad applications in organic synthesis and drug discovery are demonstrated in the synthesis of novel analogues of natural product (-)-nicotine and antidepressant sertraline by late-stage amination and azidation reactions.
- Hendrick, Charles E.,Bitting, Katie J.,Cho, Seoyoung,Wang, Qiu
-
supporting information
p. 11622 - 11628
(2017/08/30)
-
- Gold-catalyzed oxidative couplings of two indoles with one aryldiazo cyanide under oxidant-free conditions
-
Gold-catalyzed oxidative couplings of two indoles and one α-cyano gold carbene to form bis(indolyl)methane derivatives are described. Two different indoles are compatible with these reactions to provide reasonable yields. A plausible mechanism is postulated to rationalize the experimental data including product distributions, D2O labeling, and the significant effects of gold catalysts and cyano groups.
- Singh, Rahulkumar Rajmani,Liu, Rai-Shung
-
supporting information
p. 4593 - 4596
(2017/04/28)
-
- Copper-mediated trifluoroacetylation of indoles with ethyl trifluoropyruvate
-
Direct trifluoroacetylation of indoles with ethyl trifluoropyruvate as a trifluoroacetylating reagent has been developed. This novel protocol provides an attractive route for the preparation of 3-trifluoroacetylindole derivatives, due to its operational simplicity and practicability as well as mild reaction conditions.
- Yan, Guobing,Cao, Xihan,Zheng, Wanbin,Ke, Qiumin,Zhang, Jieyu,Huang, Dayun
-
supporting information
p. 5904 - 5907
(2017/07/25)
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- Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5-Oxo-6,8,11,14-eicosatetraenoic Acid (5-Oxo-ETE)-Induced Granulocyte Activation in Monkeys
-
The potent eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is
- Cossette, Chantal,Chourey, Shishir,Ye, Qiuji,Nagendra Reddy, Chintam,Gore, Vivek,Gravel, Sylvie,Slobodchikova, Irina,Vuckovic, Dajana,Rokach, Joshua,Powell, William S.
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p. 10127 - 10146
(2016/12/07)
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- OXADIAZINE COMPOUNDS AND METHODS OF USE THEREOF
-
The present disclosure relates to oxadiazine compounds, pharmaceutical compositions comprising an effective amount of an oxadiazine compound and methods for using an oxadiazine compound in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of an oxadiazine compound.
- -
-
Paragraph 0906; 0907
(2016/12/26)
-
- GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES
-
Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).
- -
-
Paragraph 000335
(2015/04/15)
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- Synthesis and antiproliferative activity of substituted 3[2-(1h-indol-3-yl)- 1,3-thiazol-4-yl]-1h-pyrrolo[3,2-b]pyridines, marine alkaloid nortopsentin analogues
-
A large number of indolyl-4-azaindolyl thiazoles, nortopsentin analogues, were conveniently synthesized. The antiproliferative activity of the new derivatives was examined against four human tumor cell lines with different histologic origin. Seven derivatives consistently reduced the growth of the experimental models independently of TP53 gene status and exhibited the highest activity against the malignant peritoneal mesothelioma (STO) cell line. The most active compound of this series acts as a CDK1 inhibitor, and was found to cause cell cycle arrest at G2/M phase, to induce apoptosis by preventing the phosphorylation of survivin in Thr34 and to increase the cytotoxic activity of paclitaxel in STO cells.
- Carbone,Pennati,Barraja,Montalbano,Parrino,Spanò,Lopergolo,Sbarra,Doldi,Zaffaroni,Cirrincione,Diana
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p. 1654 - 1666
(2014/05/20)
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- Dearomative indole [5+2] cycloaddition reactions: Stereoselective synthesis of highly functionalized cyclohepta[b]indoles
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The first dearomative indole [5+2] cycloaddition reaction with an oxidopyrylium ylide resulted in efficient and diastereoselective construction of some highly functionalized and synthetically challenging oxacyclohepta[b]indoles. The protocol proceeds unde
- Mei, Guangjian,Yuan, Hao,Gu, Yueqing,Chen, Wei,Chung, Lung Wa,Li, Chuang-Chuang
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supporting information
p. 11051 - 11055
(2015/03/30)
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- Magnesium oxide as a heterogeneous and recyclable base for the N-methylation of indole and O-methylation of phenol using dimethyl carbonate as a green methylating agent
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This work reports a mild efficient and sustainable protocol for N-methylation of indole and O-methylation of phenol using dimethylcarbonate as an environmentally safe, non-toxic, biodegradable and green methylating agent under microwave conditions. Magnesium oxide (MgO) has been employed as a heterogeneous and recyclable base for clean N-methylation of indole and O-methylation of phenol with dimethylcarbonate. Basic properties of the fresh and recycled MgO were measured by temperature programmed desorption (CO2-TPD) analysis. The CO2-TPD runs suggested that both strong and moderately basic sites are present on the oxide, while only the moderately basic sites are responsible for the N-and O-methylation of indole and phenol, respectively, using DMC as a methylating agent. The CO2-TPD analysis showed that the basic sites on fresh and recycled MgO were comparable. The MgO was isolated by simple filtration and recycled efficiently without loss in activity and selectivity.
- Gadge, Sandip T.,Mishra, Ashish,Gajengi, Aravind L.,Shahi, Nileshkumar V.,Bhanage, Bhalchandra M.
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p. 50271 - 50276
(2014/12/10)
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- Copper-promoted decarboxylative direct C3-acylation of N-substituted indoles with α-oxocarboxylic acids
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A novel and efficient Cu-promoted decarboxylative direct C3-acylation of N-substituted indoles with α-oxocarboxylic acids for the synthesis of 3-acylindoles was developed. The Royal Society of Chemistry.
- Yu, Lin,Li, Pinhua,Wang, Lei
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supporting information
p. 2368 - 2370
(2013/06/27)
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- C2-selective direct alkynylation of indoles
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The first C2-selective alkynylation of indoles using the hypervalent iodine reagent triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) with Pd(II) as a catalyst is described. This convenient and robust method gives a single-step access to substituted alkynyl indoles with very high C2 selectivity. The reaction is orthogonal to classical Pd(0) cross-coupling reactions, as it is tolerant to bromide and iodide substituents. The used silyl protecting group can be easily removed to give terminal acetylenes.
- Tolnai, Gergely L.,Ganss, Stephanie,Brand, Jonathan P.,Waser, Jerome
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supporting information
p. 112 - 115
(2013/03/28)
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- Novel 1H-pyrrolo[2,3-b]pyridine derivative nortopsentin analogues: Synthesis and antitumor activity in peritoneal mesothelioma experimental models
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In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3- thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol- 4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H- indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the active Thr34- phosphorylated form of the antiapoptotic protein survivin. Moreover, the combined treatment of DMPM cells with 3f derivative and paclitaxel produced a synergistic cytotoxic effect, which was paralleled by an enhanced apoptotic response. In the mouse model, i.p. administration of 1f, 3f, and 1l derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts (range, 58-75%) at well-tolerated doses, and two complete responses were observed in each treatment group.
- Carbone, Anna,Pennati, Marzia,Parrino, Barbara,Lopergolo, Alessia,Barraja, Paola,Montalbano, Alessandra,Spanò, Virginia,Sbarra, Stefania,Doldi, Valentina,De Cesare, Michelandrea,Cirrincione, Girolamo,Diana, Patrizia,Zaffaroni, Nadia
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supporting information
p. 7060 - 7072
(2013/10/01)
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- Identification of trans-4-[1-[[7-fluoro-2-(1-methyl-3-indolyl)-6- benzoxazolyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid as a potent, orally active VLA-4 antagonist
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For the purpose of obtaining orally potent VLA-4 inhibitors, we have carried out structural modification of the (N′-phenylureido)phenyl group in compound 1, where the group was found to be attributed to poor pharmacokinetic profile in our previous research. Through modification, we have identified several compounds with both potent in vitro activity and improved oral exposure. In particular, compound 7e with 7-fluoro-2-(1-methyl-1H-indol-3- yl)-1,3-benzoxazolyl group as a novel replacement of the (N′-phenylureido) phenyl group significantly inhibited eosinophil infiltration into bronchoalveolar lavage fluid at 15 mg/kg in an Ascaris-antigen-induced murine bronchial inflammatory model, and its efficacy was comparable to that of the anti-mouse α4 antibody (R1-2).
- Setoguchi, Masaki,Iimura, Shin,Sugimoto, Yuuichi,Yoneda, Yoshiyuki,Chiba, Jun,Watanabe, Toshiyuki,Muro, Fumihito,Iigo, Yutaka,Takayama, Gensuke,Yokoyama, Mika,Taira, Tomoe,Aonuma, Misato,Takashi, Tohru,Nakayama, Atsushi,MacHinaga, Nobuo
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experimental part
p. 1201 - 1212
(2012/03/26)
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- A continuous methylation of phenols and N, H -heteroaromatic compounds with dimethyl carbonate
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The methylation of phenolic substrates has been reevaluated using sulfolane as solvent instead of DMF. The change of solvent gave in all cases cleaner production of the anisole products in very good yields. The reaction requires 0.1 equiv of DBU, 2-3 equiv of DMC, and 2-5 vols of sulfolane depending on the substrate. At 220 C the reaction time is 10 min. Sulfolane is completely stable under the reaction conditions, excluding unwanted impurities from the solvent. The reaction could also be extended to NH-indole and NH-imidazole derivatives utilizing 0.1 equiv of DBU and 2-3 equiv of DMC in 2 vols of sulfolane. All NH-heteroaromatic compounds gave clean N-methylation.
- Tilstam, Ulf
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p. 1974 - 1978
(2013/02/25)
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- A selective, tin-free radical mediated synthesis of indoles based on a sulfonate template
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A synthesis of indoles based on a vinyl sulfonate template is described. The approach employs a sulfonate group which plays three discrete roles in the synthetic sequence. Firstly the highly electron-withdrawing sulfonate group behaves as an activating group for a 1,4-addition of an aniline to the unsaturated system. Secondly, the electron-withdrawing nature of the same group also allows it to behave as a radical stabilising group which facilitates radical cyclisation to an aromatic ring to yield a transient indoline. Finally, the pendant sulfonate group behaves as a leaving group to yield the indole.
- Gray, Vincent James,Wilden, Jonathan D.
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supporting information; experimental part
p. 41 - 44
(2012/01/05)
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- Cooperative catalytic activation of Si-H bonds by a polar Ru-S bond: Regioselective low-temperature c-h silylation of indoles under neutral conditions by a Friedel-crafts mechanism
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Merging cooperative Si-H bond activation and electrophilic aromatic substitution paves the way for C-3-selective indole C-H functionalization under electronic and not conventional steric control. The Si-H bond is heterolytically split by the Ru-S bond of a coordinatively unsaturated cationic ruthenium(II) complex, forming a sulfur-stabilized silicon electrophile. The Wheland intermediate of the subsequent Friedel-Crafts-type process is assumed to be deprotonated by the sulfur atom, no added base required. The overall catalysis proceeds without solvent at low temperature, only liberating dihydrogen.
- Klare, Hendrik F. T.,Oestreich, Martin,Ito, Jun-Ichi,Nishiyama, Hisao,Ohki, Yasuhiro,Tatsumi, Kazuyuki
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supporting information; experimental part
p. 3312 - 3315
(2011/04/24)
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- Synthesis and antitumor activity of 2,5-bis(3′-indolyl)-furans and 3,5-bis(3′-indolyl)-isoxazoles, nortopsentin analogues
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A series of novel 2,5-bis(3′-indolyl)furans and 3,5-bis(3′-indolyl)isoxazoles were synthesized as antitumor agents. The antiproliferative activity was evaluated in vitro toward diverse human tumor cell lines. Initially 5 isoxazoles and 3 furan derivatives were tested against a panel of 10 human tumor cell lines and the most active derivatives 3c and 4a were selected to be evaluated in an extended panel of 29 cell lines. By exhibiting mean IC50 values of 17.4 μg/mL (3a) and 20.5 μg/mL (4c), in particular 4c showed a high level of tumor selectivity toward the 29 cell lines.
- Diana, Patrizia,Carbone, Anna,Barraja, Paola,Kelter, Gerhard,Fiebig, Heinz-Herbert,Cirrincione, Girolamo
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experimental part
p. 4524 - 4529
(2010/08/22)
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- From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3βinhibitors that suppress proliferation and survival of pancreatic cancer cells
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Recent studies have demonstrated that glycogen synthase kinase 3β (GSK-3β) is overexpressed in human colon and pancreatic carcinomas, contributing to cancer cell proliferation and survival. Here, we report the design, synthesis, and biological evaluation of benzofuran-3-yl-(indol-3-yl) maleimides, potent GSK-3β inhibitors. Some of these compounds show picomolar inhibitory activity toward GSK-3β and an enhanced selectivity against cyclin-dependent kinase 2 (CDK-2). Selected GSK-3β inhibitors were tested in the pancreatic cancer cell lines MiaPaCa-2, BXPC-3, and HupT3. We determined that some of these compounds, namely compounds 5, 6, 11, 20, and 26, demonstrate antiproliferative activity against some or all of the pancreatic cancer cells at low micromolar to nanomolar concentrations. We found that the treatment of pancreatic cancer cells with GSK-3β inhibitors 5 and 26 resulted in suppression of GSK-3β activity and a distinct decrease of the X-linked inhibitor of apoptosis (XIAP) expression, leading to significant apoptosis. The present data suggest a possible role for GSK-3β inhibitors in cancer therapy, in addition to their more prominent applications in CNS disorders.
- Gaisina, Irina N.,Gallier, Franck,Ougolkov, Andrei V.,Kim, Ki H.,Kurome, Toru,Guo, Songpo,Holzle, Denise,Luchini, Doris N.,Blond, Sylvie Y.,Billadeau, Daniel D.,Kozikowski, Alan P.
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experimental part
p. 1853 - 1863
(2009/12/31)
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- Site-selective sp2 and benzylic sp3 palladium-catalyzed direct arylation
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Palladium-catalyzed site selective arylation reactions of both sp2 and benzylic sp3 sites on azine and diazine N-oxide substrates are described that occur in good to excellent yield and with complete selectivity for reaction at the desired position. These studies have uncovered the need to properly control the metal to ligand ratio in sp2 arylation and necessitated a complete reinvestigation of all reaction parameters for sp3 arylation. From these studies, the choice of base emerged as a pivotal component for site selectivity, pointing to its intimate involvement in the mechanism of direct arylation. These site selective reactions have been validated in both divergent and sequential derivatizations of heterocyclic compounds represent an attractive alternative to other routes to this class of molecule. Copyright
- Campeau, Louis-Charles,Schipper, Derek J.,Fagnou, Keith
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p. 3266 - 3267
(2008/10/09)
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- Synthesis and antitumor properties of 2,5-bis(3′-indolyl)thiophenes: Analogues of marine alkaloid nortopsentin
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A series of 11 bis-indolylthiophenes of type 8-10 were obtained by cyclization of diketones 4 and 7 using Lawesson's reagent. Derivatives 8c, 9c, 9d, and 10c were selected to be evaluated in the full panel of about 60 human tumor cell lines derived from nine human cancer cell types and showed antiproliferative activity generally in the micromolar range. The most sensitive cell lines were: CCRF-CEM, MOLT-4, HL60 (TB), and RPMI-8226 of the leukemia subpanel, HT29 and HCC-2998 cell lines of the colon sub-panel, NCI-H522 of the non-small cell lung cancer sub-panel, LOX IMVI of the melanoma sub-panel, and UO-31 of the renal cancer sub-panel.
- Diana, Patrizia,Carbone, Anna,Barraja, Paola,Montalbano, Alessandra,Martorana, Annamaria,Dattolo, Gaetano,Gia, Ornella,Via, Lisa Dalla,Cirrincione, Girolamo
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p. 2342 - 2346
(2008/02/03)
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