- Highly Diastereoselective Synthesis of Medium-Sized Carbocycle-Fused Piperidines via Sequential Hydride Shift Triggered Double C(sp3)-H Bond Functionalization
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Herein we report a diastereoselective synthesis of medium-sized carbocycle-fused piperidines via [1,n (n = 6, 7)]-[1,5]-sequential hydride shift triggered double C(sp3)-H bond functionalization. When cinnamylidene malonates having N,N-dibenzyl propylamine moiety were treated with 5 mol % of Yb(OTf)3, a [1,6]-[1,5]-sequential hydride shift/cyclization process proceeded to afford seven-membered carbocycle-fused piperidines with excellent diastereoselectivities. This sequential system was applicable to the synthesis of eight-membered carbocycle-fused piperidines by an unprecedented [1,7]-[1,5]-sequential hydride shift/cyclization process.
- Kataoka, Miyabi,Otawa, Yuna,Ido, Natsuki,Mori, Keiji
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supporting information
p. 9334 - 9338
(2019/11/19)
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- Construction of seven-and eight-membered carbocycles by Lewis acid catalyzed C(sp3)-H bond functionalization
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We achieved a concise construction of seven-and eight-membered carbocycles via Lewis acid catalyzed C(sp3)-H bond functionalization. In these reactions, a quite rare [1,6 (or 7)]-hydride shift/cyclization process proceeded smoothly to afford seven-and eight-membered carbocycles with good chemical yields starting from substrates with high conformational freedom.
- Otawa, Yuna,Mori, Keiji
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supporting information
p. 13856 - 13859
(2019/11/21)
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- Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via Palladium-Catalyzed Intramolecular C–N Cross-coupling
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A number of β-enaminones with secondary amino group (alkyl, cyclopropyl, and aryl) were prepared from corresponding β-diketones. Two general protocols for their palladium-catalyzed intramolecular C–N cross-coupling were established to give corresponding N-substituted condensed tetrahydropyridines in good yields. The methodology is applicable for a wide variety of structural motifs. The work also extends the applicability of novel, recently established, palladium precatalysts to new substrates.
- Dou?ová, Hana,R??i?ková, Zdeňka,?im?nek, Petr
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supporting information
p. 670 - 684
(2018/01/22)
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- Regioselectivity inversion tuned by iron(iii) salts in palladium-catalyzed carbonylations
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Impactful regioselectivity control is crucial for cost-effective chemical synthesis. By using cheap and abundant iron(iii) salts, the hydroxycarbonylations of both aromatic and aliphatic alkenes were significantly enhanced in both reactivity and selectivity (iso/n or n/iso up to >99:1). Moreover, Pd-catalyzed carbonylation selectivity can be switched from branched to linear by using different Fe(iii) salts. In addition, similar results were obtained for the carbonylation of secondary alcohols.
- Huang, Zijun,Cheng, Yazhe,Chen, Xipeng,Wang, Hui-Fang,Du, Chen-Xia,Li, Yuehui
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supporting information
p. 3967 - 3970
(2018/04/23)
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- An intramolecular C-N cross-coupling of β-enaminones: A simple and efficient way to precursors of some alkaloids of Galipea officinalis
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2-Aroylmethylidene-1,2,3,4-tetrahydroquinolines with the appropriate substituents can be suitable precursors for the synthesis of alkaloids from Galipea officinalis (cuspareine, galipeine, galipinine, angustureine). However, only two, rather low-yielding procedures for their synthesis are described in the literature. We have developed a simple and efficient protocol for an intramolecular, palladium or copper-catalysed amination of both chloro- and bromo-substituted 3-amino-1,5-diphenylpent-2-en-1-ones leading to the above-mentioned tetrahydroquinoline moiety. The methodology is superior to the methods published to date.
- Douov, Hana,Hork, Radim,Ruikov, Zdeka,imunek, Petr
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supporting information
p. 884 - 892
(2015/08/24)
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- Effect of chain length on radical to carbanion cyclo-coupling of bromoaryl alkyl-linked oxazolines: 1,3-Areneotropic migration of oxazolines
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(Chemical Equation Presented) 2-Halophenylalkyl-2-oxazolines with alkyl chain spacers of two to six C atoms (n = 0-4) were prepared and their S RN1-type reactions with several base systems examined. The best conditions to promote cyclocoupling to the corresponding benzocycloalkane derivatives involved use of LDA in THF. The precursors with 3-C-atom and 4-C-atom spacers gave good yields of 2-(1′-phenylindan-1′-yl)-2- oxazolines and 2-(1-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-2-oxazoline, respectively. The major products from the precursor with a 5-C-atom spacer were derivatives of benzocycloheptane in which the oxazoline group had undergone a novel areneotropic migration from the end of the spacer to the benzo ring. The product from reaction of the corresponding 2-C-atom precursor was a 9-oxazolinophenanthrene derivative. EPR spectroscopy showed the intermediates of the LDA-promoted reactions to be radical anions of the product benzocycloalkanes. This supported an SRN1-type chain mechanism involving initial production of aryl radicals connected to azaenolate ions via the spacer groups. Intramolecular radical to carbanion coupling then generated ring-closed benzocycloalkane radical anions that transferred an electron to more precursor. Diastereoselective radical to carbanion cyclo-coupling reactions were carried out with 2-bromophenylpropyl precursors containing chiral 2-oxazolines. The diastereoselectivity achievable was modest, but the product diastereoisomeric Indane derivatives were easily separable by chromatography.
- Marshall, Laura J.,Roydhouse, Mark D.,Slawin, Alexandra M. Z.,Walton, John C.
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p. 898 - 911
(2007/10/03)
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- Heteroatom bridged metallocene compounds for olefin polymerization
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This invention relates to a transition metal compound represented by the formula: wherein M is a group 3, 4, 5 or 6 transition metal atom, or a lanthanide metal atom, or actinide metal atom; E is: 1) a substituted or unsubstituted indenyl ligand that is bonded to Y through the four, five, six or seven position of the indenyl ring, or 2) a substituted or unsubstituted heteroindenyl ligand that is bonded to Y through the four, five or six position of the heteroindenyl ring, provided that the bonding position is not the same as the position of the ring heteroatom, or 3) a substituted or unsubstituted fluorenyl ligand that is bonded to Y through the one, two, three, four, five, six, seven or eight position of the fluorenyl ring, or 4) a substituted or unsubstituted heterofluorenyl ligand that is bonded to Y through the one, two, three, four, five or six position of the heteroindenyl ring, provided that the bonding position is not the same as the position of the ring heteroatom; A is a substituted or unsubstituted cyclopentadienyl ligand, a substituted or unsubstituted heterocyclopentadienyl ligand, a substituted or unsubstituted indenyl ligand, a substituted or unsubstituted heteroindenyl ligand, a substituted or unsubstituted fluorenyl ligand, a substituted or unsubstituted heterofluorenyl ligand, or other mono-anionic ligand; Y is a Group 15 or 16 bridging heteroatom substituent that is bonded via the heteroatom to E and A; and X are, independently, univalent anionic ligands, or both X are joined and bound to the metal atom to form a metallocycle ring, or both X join to form a chelating ligand, a diene ligand, or an alkylidene ligand. This invention further relates to catalyst systems comprising the above transiotioon metal compounds, activators and optional supports and their use to polymerize or oligomerize olefins.
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- Radical-carbanion cyclo-coupling in armed aromatics: Overriding steric hindrance to ring closure
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ω-(2-Halophenyl)alkyl-2-oxazolines were prepared and reacted via base promoted intramolecular coupling of radical with carbanionic centres to yield 1-phenyl-1-oxazolino-indan and -tetralin derivatives containing quaternary C-atoms. The Royal Society of Chemistry 2005.
- Roydhouse, Mark D.,Walton, John C.
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p. 4453 - 4455
(2007/10/03)
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- A Convergent Method for the Synthesis of Highly Enantiomerically Enriched Cyclic Silanes with Silicon-Centered Chirality
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A preparatively straightforward methodology has been developed which allows the assembly of silicon-containing carbocycles as mixtures of diastereomers with silicon as the sole center of stereogenic information. One-step construction of the chiral cyclic silanes is realized by reaction of equimolar amounts of a dibromide and a chirally modified dichlorosilane under Barbier conditions giving access to several monofunctionalized 1-sila-1,2,3,4-tetrahydronaphthalenes and a corresponding phenanthrene derivative. Facile large scale syntheses of 3-(2-bromoaryl)propyl bromides as well as dichlorosilanes have been elaborated. This highly convergent methodology relies on the novel (-)-menthyloxy-substituted dichlorosilanes, which have the chiral auxiliary for the subsequent optical resolution installed. These enantiopure dichlorosilanes are useful building blocks for a general and modular one-step approach to silanes with silicon-centered chirality since this strategy avoids the linear sequences reported in literature. The optical resolution has been exemplarily optimized for the 1-phenyl-1-sila-1,2,3,4- tetrahydronaphthalene derivative and the absolute configuration has been established by X-ray crystallography. The chiral auxiliary is stereospecifically displaced by simple reduction providing the highly enantioenriched silane (er = 98:2) which is enantiospecifically chlorinated as verified by a Walden inversion at silicon.
- Oestreich, Martin,Schmid, Ulrike K.,Auer, Gertrud,Keller, Manfred
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p. 2725 - 2739
(2007/10/03)
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- Amine- and ether-chelated aryllithium reagents - Structure and dynamics
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Chelation and aggregation in phenyllithium reagents with potential 6- and 7-ring chelating amine (2, 3) and 5-, 6-, and 7-ring chelating ether (4, 5, 6) ortho substituents have been examined utilizing variable temperature 6Li and 13C NMR spectroscopy, 6Li and 15N isotope labeling, and the effects of solvent additives. The 5- and 6-ring ether chelates (4, 5) compete well with THF, but the 6-ring amine chelate (2) barely does, and 7-ring amine chelate (3) does not. Compared to model compounds (e.g., 2-ethylphenyllithium 7), which are largely monomeric in THF, the chelated compounds all show enhanced dimerization (as measured by K = [D]/[M]2) by factors ranging from 40 (for 6) to more than 200 000 (for 4 and 5). Chelation isomers are seen for the dimers of 5 and 6, but a chelate structure could be assigned only for 2-(2-dimethylaminoethyl)phenyllithium (2), which has an A-type structure (both amino groups chelated to the same lithium in the dimer) based on NMR coupling in the 15N, 6Li labeled compound. Unlike the dimer, the monomer of 2 is not detectably chelated. With the exception of 2-(methoxymethyl)phenyllithium (4), which forms an open dimer (12) and a pentacoordinate monomer (13), the lithium reagents all form monomeric nonchelated adducts with PMDTA.
- Reich, Hans J.,Goldenberg, Wayne S.,Sanders, Aaron W.,Jantzi, Kevin L.,Tzschucke, C. Christoph
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p. 3509 - 3521
(2007/10/03)
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- Ortho-substituted benzofused macrocyclic lactams as zinc metalloprotease inhibitors
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The design and preparation of ortho-substituted benzofused macrocyclic lactams are described. The benzofused macrocyclic lactams were designed as neutral endopeptidase 24.11 (NEP) inhibitors. Docking studies were carried out in a model of thermolysin (TLN) using the MACROMODEL and QXP modeling programs to select suitable ring sizes. These studies predicted that the 11- , 12-, and 13-membered ring macrocyclic lactams would be active in both enzymes TLN and NEP. Good predictability of experimental results, within this series, of binding to thermolysin and to a lesser extent to NEP was observed. A visual comparison, docked at the active site of TLN, is presented for thiorphan, a 10-membered ring macrocycle and an 11-membered ring benzofused macrocyclic lactam. Potent inhibition of both NEP and thermolysin was obtained. The 11-membered ring macrocycle 25a is the most potent inhibitor from this series of compounds (TLN IC50 = 68 nM; NEP IC50 = 0.9 nM). The effects of prodrug 44b administered at 10 mg/kg po on plasma atrial natriuretic peptide (ANP) levels in conscious rats was greater than 200% over a 4 h period.
- Ksander, Gary M.,De Jesus, Reynalda,Yuan, Andrew,Ghai,Trapani,McMartin, Colin,Bohacek, Regine
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p. 495 - 505
(2007/10/03)
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- DIAZEPINE CONTAINING DUAL ACTION INHIBITORS
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Compounds of the formula STR1 wherein: STR2 A is are dual inhibitors of NEP and ACE. Compounds wherein A is STR3 are selective ACE inhibitors.
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- THIAZOLO BENZAZEPINE CONTAINING DUAL ACTION INHIBITORS
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Compounds of the formula STR1 wherein A is STR2 are dual inhibitors of NEP and ACE. Compounds wherein A is STR3 are selective ACE inhibitors.
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- Benzo-fused lactams
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Compounds of the formula STR1 wherein A is STR2 are useful as ACE and NEP inhibitors and those wherein A is STR3 are useful as ACE inhibitors. Methods of preparation and intermediates are also disclosed.
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- COMPOUNDS CONTAINING A FUSED MULTIPLE RING LACTAM
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Compounds of the formula STR1 wherein A is STR2 are useful as ACE and NEP inhibitors and those wherein A is STR3 are useful as ACE inhibitors. Methods of preparation and intermediates are also disclosed.
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- COMPOUNDS CONTAINING A FUSED BICYCLE RING AND PROCESSES THEREFOR
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Compounds of the formula STR1 wherein X is O or S--(O) t ; n is one or two; m is zero or one; Y is CH 2, O, or S--(O) t provided that Y is O or S--(O) t only when m is one; and A is STR2 are dual inhibitors of NEP and ACE. Compounds wherein A is STR3 are selective ACE inhibitors. Also disclosed are methods of preparation and intermediates.
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- SUBSTITUTED AZEPINONE DUAL INHIBITORS OF ANGIOTENSIN CONVERTING ENZYME AND NEUTRAL EXDOPEPTIDASE
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Compounds of the formula STR1 are disclosed as possessing inhibitory activity against angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) and thus being useful as cardiovascular agents. Processes for preparing these compounds are also disclosed.
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- Synthesis and hydrogen bonding capabilities of biphenyl-based amino acids designed to nucleate β-sheet structure
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The syntheses of 3′-(aminoethyl)-2-biphenylpropionic acid (1) and 2-amino-3′-biphenylcarboxylic acid (2) are described. These residues were designed to nucleate β-sheet structure in aqueous solution when incorporated into small, amphiphilic peptides in place of the backbone of the i + 1 and i + 2 residues of the β-turn. N-Benzyl-3′-(2-(benzylamido)ethyl)-2-biphenylpropamide (3) and N-benzyl-(2-benzylamido)-3′-biphenylamide (4) were synthesized and studied as model compounds to investigate the hydrogen-bonding capabilities of residues 1 and 2, respectively. The X-ray crystal structure of 3 indicates that a 13-membered intramolecular hydrogen-bonded ring is formed, while the remaining amide proton and carbonyl are involved in intermolecular hydrogen bonding. Infrared and variable-temperature NMR experiments indicate that, in solution (CH2Cl2), 3 exists as an equilibrium mixture of the 13- and the 15-membered intramolecularly hydrogen-bonded conformers with the 15-membered ring conformer being favored. Amide 4 was shown to exist in solution (CH2Cl2) as an equilibrium mixture of the 11-membered intramolecular hydrogen-bonded ring and a nonbonded conformation. No contribution from the 9-membered hydrogen-bonded ring conformation was observed. The X-ray crystal structure of 4 indicated the absence of intramolecular hydrogen bonding in the solid state.
- Nesloney, Carey L.,Kelly, Jeffery W.
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p. 3127 - 3137
(2007/10/03)
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- Free-Radical Chemistry of Imines
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Aryl radicals bearing an aldimino functional group as part of an ortho substituent cyclized by addition to C and/or N of the imino group.When the choice was between 5-exo closure to C and 6-endo closure to N, the former predominated.However, 6-endo closure to C predominated over 5-exo cyclization to N in isomeric imines.Absolute values of cyclization rate constants were determined and an explanation for the unusual 6-endo preference is offered.Chiral induction in 6-endo cyclization to C of an aldimine from D-glyceraldehyde acetonide was observed, and its sense was determined.
- Tomaszewski, Miroslaw J.,Warkentin, John,Werstiuk, Nick H.
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p. 291 - 322
(2007/10/02)
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- SUBSTITUTED AZEPINO[2,1-A]ISOQUINOLINE COMPOUNDS
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Compounds of the formula STR1 wherein A is STR2 are dual inhibitors of NEP and ACE. Compounds wherein A is STR3 are selective as ACE inhibitors. Methods of preparation and intermediates are also disclosed.
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- Displacements at the Nitrogen of Lithioalkoxylamides by Organometallic Reagents
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The conversions of N-(o-bromobenzyl)methoxylamine to N-acetylbenzoazetine (1), of N-methoxylamine to N-acetyltetrahydroquinoline (2), and N-methoxylamine to N-acetylbenzazapine (3) illustrate the use of this displacement reaction to form nitrogencontaining rings in an exocyclic reaction mode.An X-ray structural determination is reported for 1.The formations of anilides by amination of aromatic organolithium reagents with lithium methoxylamide is also reported.Lithium reagents are found to be more effective than Grignard, copper, or zinc reagents in these displacement, and the yields decrease as the size of the substituents around nitrogen increases.The endocyclic restriction test is used to show that this displacement on nitrogen cannot occur within the endocyclic confines of a seven-membered ring.A SN2 reaction pathway in a lithium complex is considered to be supported by these results.
- Beak, Peter,Selling, Gordon W.
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p. 5574 - 5580
(2007/10/02)
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- Lithium-Halogen Exchange-Initiated Cyclization Reactions. 3. Intramolecular Conjugate Addition Reactions of Unsaturated Acylphosphoranes
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The lithium-halogen exchange-initiated intramolecular conjugate addition reactions of some model unsaturated acylphosphoranes have been examined.The effects of halide type, chain length, and acceptor substitution pattern on the feasibility of ring construction were studied.The lithium-bromine exchange reactions in two 2-bromooaryl acceptors were found to be too slow, relative to competing side reactions, to allow practical carbocycle syntheses while 3-,4-,5-, and 6-membered carbocycles are formed in good to excellent yields from precursors that are vinyl and saturated primary iodides.Highly efficient intramolecular conjugate addition reactions to β,β-disubstituted acceptor units are possible, and intermediate anions from intramolecular conjugate addition reactions are readily captured with electrophiles.
- Cooke, Manning P.,Widener, Rexford K.
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p. 1382 - 1396
(2007/10/02)
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- Synthesis of Biological Markers in Fossil Fuels. 2. Synthesis and 13C NMR Studies of Substituted Indans and Tetralins
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Unambiguous syntheses of all possible methyl, ethyl, n-propyl, and n-butyl derivatives of indan and tetralin were developed using the Kumada coupling procedure involving the reaction of aryl or vinyl halides with Grignard reagents in the presence of nickel(II) chloride.An analysis of the 13C NMR spectra of these compounds was also completed.
- Adamczyk, Maciej,Watt, David S.,Netzel, Daniel A.
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p. 4226 - 4237
(2007/10/02)
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