- HDAC6 INHIBITORS AND USES THEREOF
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Provided herein are compounds that inhibit HDAC6, a protein whose activity is associated with a variety of diseases (e.g., cancer, neurological disorders). Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of tre
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Paragraph 00534
(2021/02/05)
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- Asymmetric "clip-Cycle" Synthesis of Pyrrolidines and Spiropyrrolidines
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The development of an asymmetric "clip-cycle"synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activate
- Maddocks, Christopher J.,Ermanis, Kristaps,Clarke, Paul A.
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supporting information
p. 8116 - 8121
(2020/11/02)
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- Palladium(II)-Catalyzed Aminotrifluoromethoxylation of Alkenes: Mechanistic Insight into the Effect of N-Protecting Groups
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An efficient palladium-catalyzed regioselective 5-exo aminotrifluoromethoxylation of alkenes has been established herein, which provides a practical route towards the synthesis of OCF3-containing pyrrolidines. tert-Butyloxycarbonyl (Boc) as an amino protecting group plays a significant role in both the chemo- and regioselectivities. In addition, preliminary mechanistic studies reveal that the amino protecting group of substrates and the counter anion of palladium catalyst play critical roles in reaction efficiency presumably due to an isomerization of alkyl- Pd(II) intermediates. Moreover, the asymmetric 5-exo aminotrifluoromethoxylation reaction has also been achieved by introducing a sterically bulky pyridinyl-oxazoline ligand.
- Chen, Chaohuang,Chen, Pinhong,Hou, Chuanqi,Liu, Guosheng
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supporting information
p. 346 - 350
(2020/05/25)
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- 3-(Triflyloxy)benzynes Enable the Regiocontrolled Cycloaddition of Cyclic Ureas to Synthesize 1,4-Benzodiazepine Derivatives
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A versatile synthesis of 1,4-benzodiazepine derivatives through the reaction of various 3-(trifluoromethanesulfonyloxy)benzynes with N -(p -toluenesulfonyl)imidazolidin-2-ones is reported. This reaction system provides a 1,4-benzodiazepine bearing a trifluoromethanesulfonyloxy group as a single regioisomer among the four possible regioisomers.
- Kaneko, Hideki,Ikawa, Takashi,Yamamoto, Yuta,Arulmozhiraja, Sundaram,Tokiwa, Hiroaki,Akai, Shuji
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supporting information
p. 943 - 948
(2018/02/26)
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- One-pot Construction of Difluorinated Pyrrolizidine and Indolizidine Scaffolds via Copper-Catalyzed Radical Cascade Annulation
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A convenient approach to the synthesis of diverse difluorinated nitrogen-containing polycycles via a copper-catalyzed radical cascade annulation of amine-containing olefins and ethyl bromodifluoroacetate was developed. Three new bonds, including a Csp3 ?CF2 and two C?N bonds, are forged simultaneously in this strategy. Through this strategy, a series of difluorinated pyrrolizidine and indolizidine derivatives have been conveniently synthesized in good yields. (Figure presented.).
- Wang, Xiaoyang,Li, Miao,Yang, Yanyan,Guo, Minjie,Tang, Xiangyang,Wang, Guangwei
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supporting information
p. 2151 - 2156
(2018/04/26)
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- Enantioselective Pd(II)-Catalyzed Intramolecular Oxidative 6- endo Aminoacetoxylation of Unactivated Alkenes
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A novel asymmetric 6-endo aminoacetoxylation of unactivated alkenes by palladium catalysis, which yields chiral β-acetoxylated piperidines with excellent chemo-, regio- and enantioselectivities under very mild reaction conditions, has been established herein by employing a new designed pyridine-oxazoline (Pyox) ligand. Importantly, introducing a sterically bulky group into the C-6 position of Pyox is crucial to enhance the reactivity of the aminoacetoxylation of alkenes.
- Qi, Xiaoxu,Chen, Chaohuang,Hou, Chuanqi,Fu, Liang,Chen, Pinhong,Liu, Guosheng
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supporting information
p. 7415 - 7419
(2018/06/08)
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- Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles
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The first general sulfone–metal exchange is described. Treating substituted 2-pyridylsulfonylacetonitriles with either BuLi or Bu3MgLi generates metalated nitriles that efficiently intercept a variety of electrophiles to afford quaternary nitriles. The 2-pyridylsulfone is critical for the sulfone–metal exchange because chelation anchors the organometallic proximal to the electrophilic, tetrasubstituted sulfone to override complex-induced deprotonation. Alkylating commercial 2-pyridinesulfonylacetonitrile with mild bases, either K2CO3 or DBU, and subsequent sulfone–metal exchange and alkylation rapidly assembles quaternary nitriles by three alkylations, only one of which requires an organometallic reagent.
- Yang, Xun,Nath, Dinesh,Gau, Michael R.,Steward, Omar W.,Fleming, Fraser F.
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supporting information
p. 7257 - 7260
(2017/06/13)
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- Pd-Catalyzed Intramolecular Aminoalkylation of Unactivated Alkenes: Access to Diverse N-Heterocycles
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A highly efficient palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes in the absence of an external ligand and oxidant is described. New C-N and C(sp3)-C(sp3) bonds are formed simultaneously. This general transformation allows for construction of diverse N-heterocycles. Mechanistic studies show that the process may involve a four-membered Pd(alkyl)amido intermediate.
- Ye, Liu,Lo, Kai-Yip,Gu, Qiangshuai,Yang, Dan
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supporting information
p. 308 - 311
(2017/04/21)
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- Enantioselective Palladium-Catalyzed Oxidative Cascade Cyclization of Aliphatic Alkenyl Amides
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The catalyst system of Pd(TFA)2/(S,S)-diPh-pyrox is reported to promote the highly efficient enantioselective oxidative cascade cyclization of alkene-tethered aliphatic acrylamides under mild aerobic conditions. A series of pyrrolizidine derivatives have been synthesized in good yield and excellent enantioselectivity. Deuterium-labeling experiments have revealed that the reaction proceeded through an anti-aminopalladation (anti-AP) pathway with high selectivity. The transition states for the anti-AP step have been calculated to account for the observed enantioselectivity.
- Du, Wei,Gu, Qiangshuai,Li, Yang,Lin, Zhenyang,Yang, Dan
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supporting information
p. 316 - 319
(2017/04/21)
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- I2-Mediated oxidative bicyclization of 4-pentenamines to prolinol carbamates with CO2 incorporating oxyamination of the C=C bond
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A metal-free oxyamination reaction of alkenes with ambient CO2 is reported. In the presence of I2 and DBU, CO2 is applied in situ as a protecting group to regulate the nucleophilicity of the amino group and facilitate the bicyclization of 4-pentenamines with high chemoselectivity. Moreover, this reaction provided a feasible approach to prepare prolinol carbamates with good tolerance of functional groups and high efficiency under mild conditions.
- Wang, Sheng,Zhang, Xiaowei,Cao, Chengyao,Chen, Chao,Xi, Chanjuan
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supporting information
p. 4515 - 4519
(2017/10/13)
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- Copper(II)-catalyzed enantioselective intramolecular cyclization of N-alkenylureas
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The first Cu(II)-catalyzed highly enantioselective intramolecular cyclization of N-alkenylureas was developed for the concise assembly of chiral vicinal diamino bicyclic heterocycles. Facile removal of carbonyl group of the carbamido moiety allowed for ready access to enantioenriched cyclic vicinal diamines.
- Fu, Shaomin,Yang, Honghao,Deng, Yuanfu,Jiang, Huanfeng,Zeng, Wei,Li, Guoqiang
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supporting information
p. 1018 - 1021
(2015/03/30)
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- Photoredox-Catalyzed Intramolecular Aminodifluoromethylation of Unactivated Alkenes
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A photoredox catalyzed aminodifluoromethylation of unactivated alkenes has been developed in which HCF2SO2Cl is used as the HCF2 radical source. Sulfonamides were active nucleophiles in the final step of a tandem addition/oxidation/cyclization process to form pyrrolidines, and esters were found to cyclize to form lactones. Thus, a variety of pyrrolidines and lactones were obtained in moderate to excellent yield. In order for the cyclization reactions to be efficient, a combination of a copper catalyst (Cu(dap)2Cl) and silver carbonate was crucial to suppressing a competing chloro, difluoroalkylation process.
- Zhang, Zuxiao,Tang, Xiaojun,Thomoson, Charles S.,Dolbier, William R.
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supporting information
p. 3528 - 3531
(2015/07/28)
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- Arylthio-metal exchange of α-arylthioalkanenitriles
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The addition of BuLi, Bu3MgLi, Et2ZnBuLi, or Me 2CuLi to α-arylthioalkanenitriles triggers an arylthio-metal exchange. NMR spectroscopic analyses implicate organometallic attack on sulfur forming a three-coordinate sulfidate as the key intermediate. Electrophilic trapping affords tertiary and quaternary nitriles in high yield. The method addresses the challenge of improving the functional group tolerance and preventing polyalkylations.
- Nath, Dinesh,Skilbeck, Melanie C.,Coldham, Iain,Fleming, Fraser F.
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supporting information
p. 62 - 65
(2014/01/23)
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- TEMPO-mediated allylic C-H amination with hydrazones
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TEMPO-mediated reactions of alkenyl hydrazones afforded azaheterocycles via sp3 C-H allylic amination. The transformation is featured by a sequence of remote allylic H-radical shift and allylic homolytic substitution with hydrazone radicals. This journal is
- Zhu, Xu,Chiba, Shunsuke
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supporting information
p. 4567 - 4570
(2014/06/24)
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- Regioselective copper(II)-mediated bromoamination of unfunctionalized olefins: An efficient route to N-heterocyclic compounds
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Bromoamination of unfunctionalized olefins was realized under mild conditions using copper(II) bromide (CuBr2) as both reaction promoter and bromine source. The reactions could be carried out under open air at ambient temperature, and both N-alkylated and N-tosylated substrates could be converted to the corresponding N-heterocyclic compounds in high regioselectivity and good isolated yields. A variety of biologically important structures could be obtained via subsequent nucleophilic substitution reactions.
- Liu, Gong-Qing,Ding, Zhen-Ying,Zhang, Li,Li, Ting-Ting,Li, Lin,Duan, Lili,Li, Yue-Ming
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supporting information
p. 2303 - 2310
(2014/07/21)
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- Efficient copper-catalyzed direct intramolecular aminotrifluoromethylation of unactivated alkenes with diverse nitrogen-based nucleophiles
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A mild, convenient, and step-economical intramolecular aminotrifluoromethylation of unactivated alkenes with a variety of electronically distinct, nitrogen-based nucleophiles in the presence of a simple copper salt catalyst, in the absence of extra ligand
- Lin, Jin-Shun,Xiong, Ya-Ping,Ma, Can-Liang,Zhao, Li-Jiao,Tan, Bin,Liu, Xin-Yuan
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supporting information
p. 1332 - 1340
(2014/04/03)
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- Sulfinylnitriles: Sulfinyl-metal exchange-alkylation strategies
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Adding organolithiums, Grignard reagents, or zincates to sulfinylnitriles triggers a facile sulfinyl-metal exchange to afford N- or C-metalated nitriles. Sulfinyl-magnesium exchange-alkylations efficiently install quaternary and tertiary centers, even in
- Nath, Dinesh,Fleming, Fraser F.
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supporting information
p. 2023 - 2029
(2013/03/14)
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- Palladium- and ruthenium-catalyzed cycloisomerization of enynamides and enynhydrazides: A rapid approach to diverse azacyclic frameworks
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I want to ride my azacycle: The title reaction of enynamides affords a wide diversity of azacycles. The reactions are high-yielding, highly stereoselective, and proceed rapidly under mild reaction conditions. Equivalent transformations using enynhydrazides offer new routes to pyrazole and indazole scaffolds. Boc=tert-butoxycarbonyl, EWG=electron-withdrawing group, Ns=4-nitrobenzenesulfonyl, Ts=4-toluenesulfonyl. Copyright
- Walker, P. Ross,Campbell, Craig D.,Suleman, Abid,Carr, Greg,Anderson, Edward A.
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supporting information
p. 9139 - 9143
(2013/09/12)
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- A new method for intramolecular chloroamination of unfunctionalized olefins
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A new method for the intramolecular chloroamination of unfunctionalized olefins is reported. The reactions were carried out at room temperature for 3 h using hydrated copper(II) chloride as both promoter and chlorine source, and the corresponding vincinal haloamines were obtained in good isolated yields.
- Liu, Gong-Qing,Li, Wei,Li, Yue-Ming
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supporting information
p. 395 - 402
(2013/05/08)
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- Cu(II)-mediated aminooxygenation of alkenylimines and alkenylamidines with TEMPO
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A method for the synthesis of oxymethyl dihydropyrroles (pyrrolines) and dihydroimidazoles has been developed via Cu(II)-mediated intramolecular aminooxygenation of alkenylimines and alkenylamidines, respectively, with 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO). Georg Thieme Verlag Stuttgart · New York.
- Sanjaya, Stephen,Chua, Sze Hui,Chiba, Shunsuke
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supporting information; experimental part
p. 1657 - 1661
(2012/07/17)
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- Ligand acceleration in ZnI2-catalyzed intramolecular hydroamination of unfunctionalized olefins
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Zinc halide-promoted hydroamination of 4-penten-1-amine compounds was studied. Preliminary results indicated that both steric and electronic factors are crucial for this Lewis acid-promoted reaction. ZnI2 gave the most promising results and the reactivity could be further increased upon addition of a suitable ligand. Up to 95% isolated yields were obtained when the reactions were carried out in 1,4-dioxane in the presence of 10 mol % of ZnI2 and 8-hydroxyquinoline.
- Liu, Gong-Qing,Li, Wei,Wang, Yu-Mei,Ding, Zhen-Ying,Li, Yue-Ming
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supporting information; experimental part
p. 4393 - 4396
(2012/09/22)
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- Nitrile alkylations through sulfinyl-metal exchange
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Triple alkylation: Phenylsulfinyl- and phenylthioacetonitrile can function as trianion equivalents of acetonitrile by sequential alkylation and sulfinyl-metal exchange (see scheme; mCPBA=meta-chloroperoxybenzoic acid). The metalated nitriles alkylate a range of electrophiles to obtain nitriles with quaternary centers. The sulfinyl-metal exchange proceeds under very mild conditions and has a high functional-group tolerance. Copyright
- Nath, Dinesh,Fleming, Fraser F.
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supporting information; experimental part
p. 11790 - 11793
(2012/01/06)
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- PhI(OAc)2-mediated iminobromination for synthesis of bromomethyl cyclic imines starting from alkenyl carbonitriles and Grignard reagents
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PhI(OAc)2-mediated iminobromination was developed starting from alkenyl carbonitriles and Grignard reagents. The present transformation is carried out by a sequence of nucleophilic addition of Grignard reagents to alkenyl carbonitriles to form
- Sanjaya, Stephen,Chiba, Shunsuke
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experimental part
p. 590 - 596
(2011/03/19)
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- A cascade approach to cyclic aminonitrones: reaction discovery, mechanism and scope
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Treatment of ω-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful s
- Sharma, Rojita,Bulger, Paul G.,McNevin, Michael,Dormer, Peter G.,Ball, Richard G.,Streckfuss, Eric,Cuff, James F.,Yin, Jingjun,Chen, G-Yi
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supporting information; experimental part
p. 3194 - 3197
(2009/12/01)
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- Intramolecular hydroamination of aminoalkenes by calcium and magnesium complexes: A synthetic and mechanistic study
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The β-diketiminate-stabilized calcium amide complex [{ArNC(Me)CHC(Me)NAr}Ca{N(SiMe3)2}-(THF)] (Ar = 2,6-diisopropylphenyl) and magnesium methyl complex [{ArNC(Me)CHC(Me)NAr}Mg(Me) (THF)] are reported as efficient precatalysts for hydroamination/cyclization of aminoalkenes. The reactions proceeded under mild conditions, allowing the synthesis of five-, six-, and seven-membered heterocyclic compounds. Qualitative assessment of these reactions revealed that the ease of catalytic turnover increases (i) for smaller ring sizes (5 > 6 > 7), (ii) substrates that benefit from favorable Thorpe-Ingold effects, and (iii) substrates that do not possess additional substitution on the alkene entity. Prochiral substrates may undergo diastereoselective hydroamination/cyclization depending upon the position of the existing stereocenter. Furthermore, a number of minor byproducts of these reactions, arising from competitive alkene isomerization reactions, were identified. A series of stoichiometric reactions between the precatalysts and primary amines provided an important model for catalyst initiation and suggested that these reactions are facile at room temperature, with the reaction of the calcium precatalyst with benzylamine proceeding with ΔG°(298 K) = -2.7 kcal mol-1. Both external amine/amide exchange and coordinated amine/amide exchange were observed in model complexes, and the data suggest that these processes occur via low-activation-energy pathways. As a result of the formation of potentially reactive byproducts such as hexamethyldisilazane, calcium-catalyst initiation is reversible, whereas for the magnesium precatalyst, this process is nonreversible. Further stoichiometric reactions of the two precatalysts with 1-amino-2,2-diphenyl-4-pentene demonstrated that the alkene insertion step proceeds via a highly reactive transient alkylmetal intermediate that readily reacts with N-H σ bonds under catalytically relevant conditions. The results of deuterium-labeling studies are consistent with the formation of a single transient alkyl complex for both the magnesium and calcium precatalysts. Kinetic analysis of the nonreversible magnesium system revealed that the reaction rate depends directly upon catalyst concentration and inversely upon substrate concentration, suggesting that substrate-inhibited alkene insertion is rate-determining.
- Crimmin, Mark R.,Arrowsmith, Merle,Barrett, Anthony G. M.,Casely, Ian J.,Hill, Michael S.,Procopiou, Panayiotis A.
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supporting information; experimental part
p. 9670 - 9685
(2011/03/20)
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- PROCESS FOR PREPARING GABAPENTIN
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A process for preparing gabapentin of formula 1, which comprises Formula (I) converting 1-allyl-cyclohexanecarboxaldehyde into 1-allyl-cyclohexanecarbonitrile; ozonizing 1-allyl-cyclohexanecarbonitrile to obtain 1-cyano-cyclohexaneacetaldehyde; acetalizing 1-cyano-cyclohexaneacetaldehyde with a suitable acetalizing agent to give the corresponding acetal and converting the latter into gabapentin.
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Page/Page column 12
(2008/06/13)
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- Utilization of achiral alkenyl amines for the preparation of high affinity Grb2 SH2 domain-binding macrocycles by ring-closing metathesis
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A family of previously reported ring-closing metathesis (RCM)-derived macrocycles that exhibit potent Grb2 SH2 domain-binding affinity is characterized by stereoselectively-introduced upper ring junctions that bear bicyclic aryl substituents. However, the synthetic complexity of these macrocycles presents a potential limit to their therapeutic application. Therefore, the current study was undertaken to simplify these macrocycles through the use of achiral 4-pentenylamides as ring-forming components. A series of macrocycles (5a-f) was prepared bearing both open and cyclic constructs at the upper ring junction. The Grb2 SH2 domain-binding affinities of these macrocycles varied, with higher affinities being obtained with cyclo-substituents. The most potent analogue (5d) contained a cyclohexyl group and exhibited Grb2 SH2 domain-binding affinity (KD = 1.3 nM) that was nearly equal to the parent macrocycle (2), which bore a stereoselectively- introduced naphthylmethyl substituent at the upper ring junction (KD = 0.9 nM). The results of this study advance design considerations that should facilitate the development of Grb2 SH2 domain-binding antagonists. This journal is The Royal Society of Chemistry.
- Liu, Fa,Worthy, Karen M.,Bindu, Lakshman,Giubellino, Alessio,Bottaro, Donald P.,Fisher, Robert J.,Burke Jr., Terrence R.
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p. 367 - 372
(2008/03/27)
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- MACROCYCLIC SH2 DOMAIN BINDING INHIBITORS
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Disclosed are compounds for inhibiting the binding of an SH2 domain-containing protein, for example, a compound of formula (I): FORMULA (I) wherein R1 is a lipophile; R2, in combination with the phenyl ring, is a phenylphosphate mimic group or a protected
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Page/Page column 25
(2010/10/20)
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- Enantioselective intramolecular hydroamination catalyzed by lanthanide ate complexes coordinated by N-substituted (R)-1,1′-binaphthyl-2,2′- diamido ligands
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Ytterbium and lutetium ionic complexes derived from enantiopure substituted (R)-binaphthylamine ligands, of the general formula [Li(THF) n][Ln[(R)-C20H12(NR)2]2], have been investigated for the hydroa
- Riegert, David,Collin, Jacqueline,Meddour, Abdelkrim,Schulz, Emmanuelle,Trifonov, Alexander
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p. 2514 - 2517
(2007/10/03)
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- Base-catalysed asymmetric hydroamination/cyclisation of aminoalkenes utilising a dimeric chiral diamidobinaphthyl dilithium salt
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A dimeric proline derived diamidobinaphthyl dilithium salt represents the first example of a chiral main group metal based catalyst for asymmetric hydroamination/cyclisation reactions of aminoalkenes. The Royal Society of Chemistry 2006.
- Martinez, Patricia Horrillo,Hultzsch, Kai C.,Hampel, Frank
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p. 2221 - 2223
(2007/10/03)
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- Metalated nitriles: Organolithium, -magnesium? and -copper exchange of α-halonitriles
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(Chemical Equation Presented) α-Halonitriles react with alkyllithium, organomagnesium, and lithium dimethylcuprate reagents generating reactive, metalated nitriles. The rapid halogen-metal exchange with alkyllithium and Grignard reagents allows selective exchange in the presence of reactive carbonyl electrophiles, including aldehydes, providing a high-yielding alkylation protocol. Lithiated and magnesiated nitriles react with propargyl bromide by SN2 displacement whereas organocopper nitriles react by S N2′ displacement, correlating with the formation of a C-metalated nitrile.
- Fleming, Fraser F.,Zhang, Zhiyu,Liu, Wang,Knochel, Paul
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p. 2200 - 2205
(2007/10/03)
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- Palladium(II)-catalyzed intramolecular diamination of unfunctionalized alkenes
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Intramolecular diamination reactions are described which yield cyclic ureas as direct products of an oxidative alkene transformation in the presence of palladium acetate and iodosobenzene diacetate as terminal oxidant. The reaction is truly catalytic in metal catalyst and represents the proof of principle for this elusive type of alkene oxidation. Copyright
- Streuff, Jan,Hoevelmann, Claas H.,Nieger, Martin,Muniz, Kilian
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p. 14586 - 14587
(2007/10/03)
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- Platinum-catalyzed intramolecular hydroamination of unactivated olefins with secondary alkylamines
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Reaction of benzyl-2,2-diphenyl-4-pentenylamine with a catalytic 1:2 mixture of [PtCl2(H2C=CH2)]2 (2.5 mol %) and PPh3 in dioxane at 120 °C for 16 h led to isolation of 1-benzyl-2-methyl-4,4-diphenylp
- Bender, Christopher F.,Widenhoefer, Ross A.
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p. 1070 - 1071
(2007/10/03)
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- Metalated Nitriles: Halogen - Metal Exchange with α-Halonitriles
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(Equation presented) α-Halonitriles react with organometallic reagents in a facile halogen-metal exchange. The halogen-metal exchange is extremely fast with Grignard and alkyllithium reagents, generating metalated nitriles in situ with aldehyde, ketone, a
- Fleming, Fraser F.,Zhang, Zhiyu,Knochel, Paul
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p. 501 - 503
(2007/10/03)
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