- Mechanistic Studies of Cobalt-Catalyzed C(sp2)-H Borylation of Five-Membered Heteroarenes with Pinacolborane
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Studies into the mechanism of cobalt-catalyzed C(sp2)-H borylation of five-membered heteroarenes with pinacolborane (HBPin) as the boron source established the catalyst resting state as the trans-cobalt(III) dihydride boryl, (iPrPNP)Co(H)2(BPin) (iPrPNP = 2,6-(iPr2PCH2)2(C5H3N)), at both low and high substrate conversions. The overall first-order rate law and observation of a normal deuterium kinetic isotope effect on the borylation of benzofuran versus benzofuran-2-d1 support H2 reductive elimination from the cobalt(III) dihydride boryl as the turnover-limiting step. These findings stand in contrast to that established previously for the borylation of 2,6-lutidine with the same cobalt precatalyst, where borylation of the 4-position of the pincer occurred faster than the substrate turnover and arene C-H activation by a cobalt(I) boryl is turnover-limiting. Evaluation of the catalytic activity of different cobalt precursors in the C-H borylation of benzofuran with HBPin established that the ligand design principles for C-H borylation depend on the identities of both the arene and the boron reagent used: electron-donating groups improve catalytic activity of the borylation of pyridines and arenes with B2Pin2, whereas electron-withdrawing groups improve catalytic activity of the borylation of five-membered heteroarenes with HBPin. Catalyst deactivation by P-C bond cleavage from a cobalt(I) hydride was observed in the C-H borylation of arene substrates with C-H bonds that are less acidic than those of five-membered heteroarenes using HBPin and explains the requirement of B2Pin2 to achieve synthetically useful yields with these arene substrates.
- Obligacion, Jennifer V.,Chirik, Paul J.
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Read Online
- C(sp2)-H Borylation of Heterocycles by Well-Defined Bis(silylene)pyridine Cobalt(III) Precatalysts: Pincer Modification, C(sp2)-H Activation, and Catalytically Relevant Intermediates
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Well-defined bis(silylene)pyridine cobalt(III) precatalysts for C(sp2)-H borylation have been synthesized and applied to the investigation of the mechanism of the catalytic borylation of furans and 2,6-lutidine. Specifically, [(ArSiNSi)CoH3]·NaHBEt3 {ArSiNSi = 2,6-[EtNSi(NtBu)2CAr]2C5H3N, where Ar = C6H5 (1-H3·NaHBEt3) or 4-MeC6H4 (2-H3·NaHBEt3)} and trans-[(ArSiNSi)Co(H)2BPin] {Ar = C6H5 [1-(H)2BPin] or 4-MeC6H4 [2-(H)2BPin], and Pin = pinacolato} were prepared and employed as single-component precatalysts for the C(sp2)-H borylation of 2-methylfuran, benzofuran, and 2,6-lutidine. The cobalt(III) precursors, 2-H3·NaHBEt3 and 2-(H)2BPin, also promoted C(sp2)-H activation of benzofuran, yielding [(ArSiNSi)CoH(Bf)2] {Ar = 4-MeC6H4 [2-H(Bf)2], and Bf = 2-benzofuranyl}. Monitoring the catalytic borylation of 2-methylfuran and 2,6-lutidine by 1H NMR spectroscopy established the trans-dihydride cobalt(III) boryl as the catalyst resting state at low substrate conversions. At higher conversions, two distinct pincer modification pathways were identified, depending on the substrate and the boron source.
- Arevalo, Rebeca,Pabst, Tyler P.,Chirik, Paul J.
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Read Online
- Mono-Phosphine Metal-Organic Framework-Supported Cobalt Catalyst for Efficient Borylation Reactions
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We report a metal-organic framework (MOF) supported monoligated phosphine-cobalt complex, which is an active heterogeneous catalyst for aromatic C?H borylation and alkene hydroboration. The mono(phosphine)-Co catalyst (MOF?P?Co) was prepared by metalation of a porous triarylphosphine-functionalized MOF (MOF?P) with CoCl2 followed by activation with NaEt3BH. The MOF catalyst has a broad substrate scope with excellent functional group tolerance to afford arene- and alkyl-boronate esters in excellent yields and selectivity. MOF?P?Co gave a turnover number (TON) of 30,000 and could be recycled and reused at least 13 times in arene C?H borylation. Importantly, the attempt to prepare the homogeneous control (Ph3P?Co) using triphenylphosphine was unsuccessful due to the facile disproportionation reactions or intermolecular ligand exchanges in the solution. In contrast, the site isolation of the active mono(phosphine)-Co species within the MOF affords the robust and coordinatively unsaturated metal complexes, allowing to explore their catalytic properties and the reaction mechanism.
- Akhtar, Naved,Antil, Neha,Balendra,Begum, Wahida,Chauhan, Manav,Gupta, Poorvi,Kumar, Ajay,Malik, Jaideep,Manna, Kuntal,Newar, Rajashree
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supporting information
(2022/03/15)
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- Sequential Ir/Cu-Mediated Method for the Meta-Selective C-H Radiofluorination of (Hetero)Arenes
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This article describes a sequential Ir/Cu-mediated process for the meta-selective C-H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp2)-H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [18F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a benchtop without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FXFN module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [18F]1-fluoro-3,5-dimethoxybenzene and an 18F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24 GBq/μmol) molar activity (Am), respectively.
- Wright, Jay S.,Sharninghausen, Liam S.,Preshlock, Sean,Brooks, Allen F.,Sanford, Melanie S.,Scott, Peter J. H.
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supporting information
p. 6915 - 6921
(2021/05/29)
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- Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis
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Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.
- Klug, Dana M.,Mavrogiannaki, Eftychia M.,Forbes, Katherine C.,Silva, Lisseth,Diaz-Gonzalez, Rosario,Pérez-Moreno, Guiomar,Ceballos-Pérez, Gloria,Garcia-Hernández, Raquel,Bosch-Navarrete, Cristina,Cordón-Obras, Carlos,Gómez-Li?án, Claudia,Saura, Andreu,Momper, Jeremiah D.,Martinez-Martinez, Maria Santos,Manzano, Pilar,Syed, Ali,El-Sakkary, Nelly,Caffrey, Conor R.,Gamarro, Francisco,Ruiz-Perez, Luis Miguel,Gonzalez Pacanowska, Dolores,Ferrins, Lori,Navarro, Miguel,Pollastri, Michael P.
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supporting information
p. 9404 - 9430
(2021/07/25)
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- Understanding the Activation of Air-Stable Ir(COD)(Phen)Cl Precatalyst for C-H Borylation of Aromatics and Heteroaromatics
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A newly developed robust catalyst [Ir(COD)(Phen)Cl] (A) was used for the C-H borylation of three dozen aromatics and heteroaromatics with excellent yield and selectivity. Activation of the catalyst was identified by the use of catalytic amounts of water, alcohols, etc., when B2pin2 was used in noncoordinating solvents, while for THF catalytic use of HBpin was required. The results were on par with the in situ based expensive system [Ir(OMe)(COD)]2/dtbbpy or Me4Phen.
- Slack, Eric D.,Colacot, Thomas J.
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supporting information
p. 1561 - 1565
(2021/02/20)
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- Single-Site Cobalt-Catalyst Ligated with Pyridylimine-Functionalized Metal-Organic Frameworks for Arene and Benzylic Borylation
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We report a highly active single-site heterogeneous cobalt-catalyst based on a porous and robust pyridylimine-functionalized metal-organic frameworks (pyrim-MOF) for chemoselective borylation of arene and benzylic C-H bonds. The pyrim-MOF having UiO-68 topology, constructed from zirconium-cluster secondary building units and pyridylimine-functionalized dicarboxylate bridging linkers, was metalated with CoCl2 followed by treatment of NaEt3BH to give the cobalt-functionalized MOF-catalyst (pyrim-MOF-Co). Pyrim-MOF-Co has a broad substrate scope, allowing the C-H borylation of halogen-, alkoxy-, alkyl-substituted arenes as well as heterocyclic ring systems using B2pin2 or HBpin (pin = pinacolate) as the borylating agent to afford the corresponding arene- or alkyl-boronate esters in good yields. Pyrim-MOF-Co gave a turnover number (TON) of up to 2500 and could be recycled and reused at least 9 times. Pyrim-MOF-Co was also significantly more robust and active than its homogeneous control, highlighting the beneficial effect of active-site isolation within the MOF framework that prevents intermolecular decomposition. The experimental and computational studies suggested (pyrim?-)CoI(THF) as the active catalytic species within the MOF, which undergoes a mechanistic pathway of oxidative addition, turnover limiting σ-bond metathesis, followed by reductive elimination to afford the boronate ester.
- Akhtar, Naved,Antil, Neha,Balendra,Begum, Wahida,Kumar, Ajay,Manna, Kuntal,Newar, Rajashree,Shukla, Sakshi
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supporting information
p. 10473 - 10481
(2020/08/05)
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- Pyridine N-oxidation derivative as well as preparation method and application thereof
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The invention relates to a pyridine N-oxidation derivative as well as a preparation method and an application thereof, in particular to a compound shown in a general formula (I), a preparation methodof the compound, pharmaceutical composition containing the compound and an application of the compound as a BRD4 inhibitor in treating related diseases such as cancer, inflammation, chronic liver diseases, diabetes, cardiovascular diseases, AIDS and the like, wherein in the general formula (I), all substituent groups are the same as definitions in the description.
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Paragraph 0301-0307
(2019/08/06)
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- meta-Nitration of Arenes Bearing ortho/para Directing Group(s) Using C?H Borylation
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Herein, we report the meta-nitration of arenes bearing ortho/para directing group(s) using the iridium-catalyzed C?H borylation reaction followed by a newly developed copper(II)-catalyzed transformation of the crude aryl pinacol boronate esters into the corresponding nitroarenes in a one-pot fashion. This protocol allows the synthesis of meta-nitrated arenes that are tedious to prepare or require multistep synthesis using the existing methods. The reaction tolerates a wide array of ortho/para-directing groups, such as ?F, ?Cl, ?Br, ?CH3, ?Et, ?iPr ?OCH3, and ?OCF3. It also provides regioselective access to the nitro derivatives of π-electron-deficient heterocycles, such as pyridine and quinoline derivatives. The application of this method is demonstrated in the late-stage modification of complex molecules and also in the gram-scale preparation of an intermediate en route to the FDA-approved drug Nilotinib. Finally, we have shown that the nitro product obtained by this strategy can also be directly converted to the aniline or hindered amine through Baran's amination protocol.
- Li, Xuejing,Deng, Xingwang,Coyne, Anthony G.,Srinivasan, Rajavel
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supporting information
p. 8018 - 8023
(2019/05/29)
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- Sterically controlled C-H/C-H homocoupling of arenes: Via C-H borylation
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A mild one-pot protocol for the synthesis of symmetrical biaryls by sequential Ir-catalyzed C-H borylation and Cu-catalyzed homocoupling of arenes is described. The regiochemistry of the biaryl formed is sterically controlled as dictated by the C-H borylation step. The methodology is also successfully extended to heteroarenes. Some of the products obtained by this approach are impossible to obtain via the Ullmann or the Suzuki coupling protocols. Finally, we have shown a one-pot sequence describing C-H borylation/Cu-catalyzed homocoupling/Pd-catalyzed Suzuki coupling to obtain π-extended arene frameworks.
- Pei, Xiaocong,Zhou, Guan,Li, Xuejing,Xu, Yuchen,Panicker, Resmi C.,Srinivasan, Rajavel
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supporting information
p. 5703 - 5707
(2019/06/19)
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- METHODS OF USING SUBSTITUTED PYRAZOLE AND PYRAZOLE COMPOUNDS AND FOR TREATMENT OF HYPERPROLIFERATIVE DISEASES
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Disclosed are methods of treating hyperproliferative disorders such as cancer, methods of arresting the cell cycle in cancer cells, methods of inhibiting glutathione synthesis in cancer cells, and associated compounds for use and uses in medicaments. In certain embodiments, the methods, uses and compounds are provided with reference to compounds of the structural formula (I), in which X1, X2, Z1, Z2, the ring system denoted by "a", R1, L1, L2, Q, L3, R3, L4, R4, L5, and R5 are as described herein. In certain embodiments, compounds disclosed herein are especially active against cancers having a mutant KRAS gene.
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Paragraph 258; 259
(2018/06/21)
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- METHODS FOR FORMING SATURATED (HETERO)CYCLIC BORYLATED HYDROCARBONS AND RELATED COMPOUNDS
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The disclosure relates to methods for forming at least partially saturated cyclic and heterocyclic borylated hydrocarbons, as well as related compounds, which can be precursor compounds in the synthesis of any of a variety of pharmaceutical or medicinal compounds with a desired structure and/or stereochemistry for drug synthesis or drug candidate evaluation. The methods generally include reduction of an unsaturated cyclic or heterocyclic borylated hydrocarbon having a boron-containing substituent at an sp2-carbon, where such reduction converts the sp2-carbon to an sp3-carbon at the point of attachment of the boron-containing substituent. The methods can exhibit a selectivity for syn-addition during reduction, which can provide stereospecific products, such as when the unsaturated cyclic or heterocyclic reactant is multiply substituted with boron groups and/or other functional groups.
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Paragraph 0053
(2018/03/25)
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- Cobalt-Catalyzed Regioselective Borylation of Arenes: N-Heterocyclic Silylene as an Electron Donor in the Metal-Mediated Activation of C?H Bonds
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C?H Borylation of arenes has been a subject of great interest recently because of its atom-economy and the wide applicability of borylated products in value-added synthesis. A new bis(silylene)cobalt(II) complex bearing a bis(N-heterocyclic silylene)-pyridine pincer ligand (SiNSi) has been synthesized and structurally characterized. It enabled the regioselective catalytic C?H borylation of pyridines, furans, and fluorinated arenes. Notably, it exhibited complementary regioselectivity for the borylation of fluorinated arenes compared to previously known catalytic systems, demonstrating that N-heterocyclic silylene donors have enormous potential in metal-catalyzed catalytic applications.
- Ren, Hailong,Zhou, Yu-Peng,Bai, Yunping,Cui, Chunming,Driess, Matthias
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supporting information
p. 5663 - 5667
(2017/04/28)
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- Cobalt-Catalyzed C(sp2)-H borylation with an air-stable, readily prepared terpyridine cobalt(II) Bis(acetate) precatalyst
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A bench-stable, 4-aryl-substituted terpyridine supported, high-spin cobalt(II) bis(acetate) complex, (ArTpy)Co- (OAc)2 (ArTpy = 4′-(4-N,N′-dimethylaminophenyl)-2,2′:6′,2″- Terpyridine), is active for the C(sp2)-H borylation of arenes and heteroarenes with B2Pin2 (Pin = pinacolato). Optimization of the catalytic borylation reaction revealed improved performance in the presence of LiOMe and turnover numbers of up to 100 have been observed using all air-stable components. EPR specstroscopy identified formation of inactive cobalt species, promoted by excess HBPin. A high-spin cobalt(II) bis[(diacetoxy)- pinacolatoborate-κ3O,O,O] compound has been isolated and characterized by X-ray diffraction and is the result of catalyst deactivation.
- Léonard, Nadia G.,Bezdek, Máté J.,Chirik, Paul J.
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p. 142 - 150
(2017/04/04)
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- SUBSTITUTED PYRAZOLE AND PYRROLE COMPOUNDS AND METHODS FOR USING THEM FOR INHIBITION OF INITIATION OF TRANSLATION AND TREATMENT OF DISEASES AND DISORDERS RELATING THERETO
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Disclosed are pyrazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure (I) and pharmaceutically acceptable salts and /V-oxides thereof, wherein X1, X2, Z1, Z2, the ring system denoted by "a", R1, A1A, L1B, A1B, L1A, L2, Q, L3, R3, A4A, L4B, A4B, L4A, R4, L5, and R5 are as described herein. In certain embodiments, compounds disclosed herein disrupt the elF4E/eiF4G interaction, and can be used to treat hyperproliferative disorder, a neurological disease or disorder, or autism.
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Paragraph 274; 275
(2017/01/31)
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- Cobalt-Catalyzed C(sp2)-H Borylation: Mechanistic Insights Inspire Catalyst Design
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A comprehensive study into the mechanism of bis(phosphino)pyridine (PNP) cobalt-catalyzed C-H borylation of 2,6-lutidine using B2Pin2 (Pin = pinacolate) has been conducted. The experimentally observed rate law, deuterium kinetic isotope effects, and identification of the catalyst resting state support turnover limiting C-H activation from a fully characterized cobalt(I) boryl intermediate. Monitoring the catalytic reaction as a function of time revealed that borylation of the 4-position of the pincer in the cobalt catalyst was faster than arene borylation. Cyclic voltammetry established the electron withdrawing influence of 4-BPin, which slows the rate of C-H oxidative addition and hence overall catalytic turnover. This mechanistic insight inspired the next generation of 4-substituted PNP cobalt catalysts with electron donating and sterically blocking methyl and pyrrolidinyl substituents that exhibited increased activity for the C-H borylation of unactivated arenes. The rationally designed catalysts promote effective turnover with stoichiometric quantities of arene substrate and B2Pin2. Kinetic studies on the improved catalyst, 4-(H)2BPin, established a change in turnover limiting step from C-H oxidative addition to C-B reductive elimination. The iridium congener of the optimized cobalt catalyst, 6-(H)2BPin, was prepared and crystallographically characterized and proved inactive for C-H borylation, a result of the high kinetic barrier for reductive elimination from octahedral Ir(III) complexes.
- Obligacion, Jennifer V.,Semproni, Scott P.,Pappas, Iraklis,Chirik, Paul J.
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supporting information
p. 10645 - 10653
(2016/09/04)
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- 2-(PYRAZOLOPYRIDIN-3-YL)PYRIMIDINE DERIVATIVES AS JAK INHIBITORS
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New 2-(pyrazolopyridin-3-yl)pyrimidine derivatives are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 68-69; 105
(2016/12/26)
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- Evaluation of Cobalt Complexes Bearing Tridentate Pincer Ligands for Catalytic C-H Borylation
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Cobalt(II) dichloride complexes supported by a variety of neutral, tridentate pincer ligands have been prepared and, following in situ activation with NaBEt3H, evaluated for the catalytic borylation of 2-methylfuran, 2,6-lutidine, and benzene using both HBPin and B2Pin2 (Pin = pinacolate) as boron sources. Preparation of well-defined organometallic compounds in combination with stoichiometric experiments with HBPin and B2Pin2 provided insight into the nature and kinetic stability of the catalytically relevant species. In cases where sufficiently electron donating pincers are present, such as with bis(phosphino)pyridine chelates, Co(III) resting states are preferred and catalytic C-H borylation is efficient. Introduction of a redox-active subunit into the pincer reduces its donating ability and, as a consequence, the accessibility of a Co(III) resting state. In these cases, unusual mixed-valent μ-hydride cobalt complexes have been crystallographically and spectroscopically characterized. These studies have also shed light on the active species formed during in situ activated cobalt alkene hydroboration catalysis and provide important design criteria in base metal catalyzed C-B bond forming reactions. (Chemical Presented).
- Schaefer, Brian A.,Margulieux, Grant W.,Small, Brooke L.,Chirik, Paul J.
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p. 1307 - 1320
(2015/04/27)
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- SULFONAMIDE DERIVATIVE AND MEDICINAL USE THEREOF
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Provided are sulfonamide derivatives of a specific chemical structure in which a sulfonamide group having, as a substituent, a phenyl group or a heterocyclic group having a hetero atom(s) as a constituent element(s) is present at its terminal, and pharmaceutically acceptable salts thereof. These compounds are novel compounds having excellent α4 integrin-inhibitory action.
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Paragraph 0275-0276
(2015/02/25)
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- BASE METAL CATALYZED BORYLATION OF ARENES AND AROMMATIC HETEROCYCLES
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In one aspect, cobalt complexes are described herein. In some embodiments, such cobalt complexes employ bis(phosphine) or bis(imine) ligand and are operable as catalysts for borylation of arenes and aromatic heterocycles.
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Page/Page column 34
(2015/06/25)
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- Cobalt-catalyzed C-H borylation
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A family of pincer-ligated cobalt complexes has been synthesized and are active for the catalytic C-H borylation of heterocycles and arenes. The cobalt catalysts operate with high activity and under mild conditions and do not require excess borane reagents. Up to 5000 turnovers for methyl furan-2-carboxylate have been observed at ambient temperature with 0.02 mol % catalyst loadings. A catalytic cycle that relies on a cobalt(I)-(III) redox couple is proposed.
- Obligacion, Jennifer V.,Semproni, Scott P.,Chirik, Paul J.
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supporting information
p. 4133 - 4136
(2014/04/03)
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- Iridium-catalyzed C-H borylation of pyridines
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The iridium-catalysed C-H borylation is a valuable and attractive method for the preparation of aryl and heteroaryl boronates. However, application of this methodology for the preparation of pyridyl and related azinyl boronates can be challenged by low reactivity and propensity for rapid protodeborylation, particularly for a boronate ester ortho to the azinyl nitrogen. Competition experiments have revealed that the low reactivity is due to inhibition of the active catalyst through coordination of the azinyl nitrogen lone pair at the vacant site on the iridium. This effect can be overcome through the incorporation of a substituent at C-2. Moreover, when this is sufficiently electron-withdrawing protodeborylation is sufficiently slowed to permit isolation and purification of the C-6 boronate ester. Following functionalization, reduction of the directing C-2 substituent provides the product arising from formal ortho borylation of an unhindered pyridine ring. This journal is the Partner Organisations 2014.
- Sadler, Scott A.,Tajuddin, Hazmi,Mkhalid, Ibraheem A. I.,Batsanov, Andrei S.,Albesa-Jove, David,Cheung, Man Sing,Maxwell, Aoife C.,Shukla, Lena,Roberts, Bryan,Blakemore, David C.,Lin, Zhenyang,Marder, Todd B.,Steel, Patrick G.
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supporting information
p. 7318 - 7327
(2014/11/07)
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- Microwave-assisted, Ir-catalyzed aromatic C-H borylation
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One-step conversions of 1,3-disubstituted benzenes to aryl boronates and 2,6-disubstituted pyridines to heteroaryl boronates are described. Microwave heating was used for all reactions. [(COD)Ir(μ-OMe)]2 and 4,4′-di-tert-butyl-2,2′-bipyridine w
- Zeqing, Li,Zhibin, Liang,Yuqiang, Wang,Pei, Yu
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p. 1917 - 1926
(2013/06/05)
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- Sterically controlled iodination of arenes via iridium-catalyzed C-H borylation
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A mild method to prepare aryl and heteroaryl iodides by sequential C-H borylation and iodination is reported. The regioselectivity of this process is controlled by steric effects on the C-H borylation step and is complementary to existing methods to form aryl iodides. The iodination of boronic esters has potential for the synthesis of radiolabeled aryl iodides, as demonstrated by the concise synthesis of a potential tracer for SPECT imaging.
- Partridge, Benjamin M.,Hartwig, John F.
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supporting information
p. 140 - 143
(2013/03/28)
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- 1,2,4-TRIAZINE-4-AMINE DERIVATIVES
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According to the invention there is provided a compound of formula A1 which may be useful in the treatment of a condition or disorder ameliorated by the inhibition of the A1- A2b or, particularly, the A2a receptor wherein the compound of formula A1 has the structure, wherein, A represents Cy1 or HetA; Cy1 represents a 5- to 14-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one, two or three rings, which Cy1 group is optionally substituted by one or more R4a substituents; HetA represents a 5- to 14-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one, two or three rings and which HetA group is optionally substituted by one or more R4b substituents; B represents a Cy2 or HetB; Cy2 represents a 3- to 10-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one or two rings, which Cy2 group is optionally substituted by one or more R4c substituents; HetB represents a 3- to 10-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one or two rings and which HetB group is optionally substituted by one or more R4d substituents.
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Page/Page column 115
(2011/09/14)
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- 5-AMINO- 4-HYDROXYPENTOYL AMIDES
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HIV inhibitors of formula (I) wherein R1 is halo, C1-4alkoxy, trifluoromethoxy; R2 is a group of formula (A); R3 is a group of formula (B); R4 is a group of formula (C); n is 0 or 1; A is CH or N; R5 and R6 are hydrogen, C1-4alkyl, halo; R7 and R8 are C1-4alkyl or C1-4alkoxyC1-4alkyl; R9 is C1-4alkyl, cyclopropyl, trifluoromethyl, C1-4alkoxy, or dimethylamino; R10 is hydrogen, C1-4alkyl, cyclopropyl, trifluoromethyl, C1-4alkoxy, or dimethylamino; pharmaceutically acceptable addition salts and solvates thereof; pharmaceutical compositions containing these compounds as active ingredient and processes for preparing said compounds.
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Page/Page column 43
(2011/06/26)
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- Cyanation of arenes via iridium-catalyzed borylation
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We report a method to conduct one-pot meta cyanation of arenes by iridium-catalyzed C-H borylation and copper-mediated cyanation of the resulting arylboronate esters. This process relies on a method to conduct the cyanation of arylboronic esters, and conditions for this new transformation are reported. Conditions for the copper-mediated cyanation of arylboronic acids are also reported. By the resulting sequence of borylation and cyanation, 1,3-disubstituted and 1,2,3-trisubstituted arenes and heteroarenes containing halide, ketone, ester, amide, and protected alcohol functionalities are converted to the corresponding meta-substituted aryl nitriles. The utility of this methodology is demonstrated through the conversion of a protected 2,6-disubstituted phenol to 4-cyano-2,6-dimethylphenol, which is an intermediate in the synthesis of the pharmaceutical etravirine. The utility of the method is further demonstrated by the conversion of 3-chloro-5-methylbenzonitrile, produced through the one-pot C-H borylation and cyanation sequence, to the corresponding 3,5-disubstituted aldehydes, ketones, amides, carboxylic acids, tetrazoles, and benzylamines.
- Liskey, Carl W.,Liao, Xuebin,Hartwig, John F.
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supporting information; experimental part
p. 11389 - 11391
(2010/10/01)
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- "One-pot" tandem C - H borylation/1,4-conjugate addition/reduction sequence
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A microwave-assisted, one-pot, iridium-catalyzed aromatic C - H borylation/rhodium-catalyzed 1,4-conjugate addition sequence provides a highly robust protocol suitable for high-throughput array synthesis. Selective formation of either β-aryl-substituted ketones or the corresponding alcohols can be achieved in good overall yields by simple variation of the reaction conditions.
- Tajuddin, Hazmi,Shukla, Lena,Maxwell, Aoife C.,Marder, Todd B.,Steel, Patrick G.
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supporting information; experimental part
p. 5700 - 5703
(2011/03/19)
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- Microwave-accelerated iridium-catalyzed borylation of aromatic C-H bonds
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Image Persented Microwave heating accelerates the Ir-catalyzed C-H borylation of aromatic substrates when compared with reactions carried out at the same temperature under standard heating conditions. Application to a one-pot single solvent process for ta
- Harrisson, Peter,Morris, James,Marder, Todd B.,Steel, Patrick G.
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supporting information; experimental part
p. 3586 - 3589
(2011/02/22)
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- Meta halogenation of 1,3-disubstituted arenes via iridium-catalyzed arene borylation
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We report the meta halogenation of 1,3-disubstituted arenes to form 3,5-disubstituted aryl bromides and chlorides by using iridium-catalyzed arene borylation chemistry. Iridium-catalyzed borylation of arenes with B2pin2, followed by reaction of the boronic ester with copper(II) bromide or chloride converts arylboronic esters to the corresponding aryl halides. A variety of arenes containing alkoxy, alkyl, halogen, nitrile, ester, amide, and pivaloyl and TIPS-protected alcohols were converted to the corresponding 3,5-disubstituted aryl bromides and chlorides in yields ranging from 46% to 85%. In addition, 2,6-disubstituted and 3-substituted pyridines were converted to the 4-halo and 5-halopyridines, respectively. The utility of this methodology was demonstrated by the formal conversion of nicotine to Altinicline in three steps with an overall yield of 61% using meta bromination of nicotine as the first step. Copyright
- Murphy, Jaclyn M.,Liao, Xuebin,Hartwig, John F.
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p. 15434 - 15435
(2008/09/19)
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