- Controlling Enantioselectivity and Diastereoselectivity in Radical Cascade Cyclization for Construction of Bicyclic Structures
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Radical cascade cyclization reactions are highly attractive synthetic tools for the construction of polycyclic molecules in organic synthesis. While it has been successfully implemented in diastereoselective synthesis of natural products and other complex compounds, radical cascade cyclization faces a major challenge of controlling enantioselectivity. As the first application of metalloradical catalysis (MRC) for controlling enantioselectivity as well as diastereoselectivity in radical cascade cyclization, we herein report the development of a Co(II)-based catalytic system for asymmetric radical bicyclization of 1,6-enynes with diazo compounds. Through the fine-tuning of D2-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process, which proceeds in a single operation under mild conditions, enables asymmetric construction of multisubstituted cyclopropane-fused tetrahydrofurans bearing three contiguous stereogenic centers, including two all-carbon quaternary centers, in high yields with excellent stereoselectivities. Combined computational and experimental studies have shed light on the underlying stepwise radical mechanism for this new Co(II)-based cascade bicyclization that involves the relay of several Co-supported C-centered radical intermediates, including α-, β-, γ-, and ?-metalloalkyl radicals. The resulting enantioenriched cyclopropane-fused tetrahydrofurans that contain a trisubstituted vinyl group at the bridgehead, as showcased in several stereospecific transformations, may serve as useful intermediates for stereoselective organic synthesis. The successful demonstration of this new asymmetric radical process via Co(II)-MRC points out a potentially general approach for controlling enantioselectivity as well as diastereoselectivity in synthetically attractive radical cascade reactions.
- Lee, Wan-Chen Cindy,Mckillop, Alexander M.,Wang, Duo-Sheng,Zhang, Congzhe,Zhang, X. Peter
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supporting information
p. 11130 - 11140
(2021/07/31)
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- Pd-catalyzed regioselective C?H alkenylation and alkynylation of allylic alcohols with the assistance of a bidentate phenanthroline auxiliary
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A Pd-catalyzed regioselective C?H alkenylation of allylic alcohols with electron-deficient alkenes has been developed. The key to success is the introduction of bidentately coordinating phenanthroline directing group, which enables the otherwise challenging and regioselective C?H activation at the proximal alkenyl C?H bonds over the conceivably competitive allylic C?O bond activation. The same Pd/phenanthroline system is efficient for the C?H alkynylation of allylic alcohols with alkynyl bromides.
- Hirano, Koji,Miura, Masahiro,Xu, Shibo
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supporting information
p. 9059 - 9064
(2020/12/02)
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- Visible-Light Mediated Hydrosilylative and Hydrophosphorylative Cyclizations of Enynes and Dienes
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Described herein is a visible-light mediated intermolecular radical cyclization approach to access heterocycles. Heteroatom radicals, such as silicon and phosphorus atom radicals, were generated via direct hydrogen atom abstraction by the photoexcited catalyst species with hydro-silanes and phosphine oxides. The radical addition/cyclization/HAT (hydrogen atom transfer) reaction sequences of 1,6-enynes and 1,6-dienes were highly efficient delivering the desired heterocycles in good yields.
- Chen, Xiaoyun,Hou, Hong,Shi, Yaocheng,Xu, Yue,Yan, Chaoguo,Yang, Haibo,Zhu, Shaoqun
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- Visible-Light-Promoted Intramolecular α-Allylation of Aldehydes in the Absence of Sacrificial Hydrogen Acceptors
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We report herein an unprecedented protocol for radical cyclization of aldehydes with pendant alkenes via synergistic photoredox, cobaloxime, and amine catalysis. The transformation was achieved in the absence of external oxidants, providing a variety of 5-, 6-, and 7-membered ring products with alkene transposition in satisfactory yields. The reaction exhibits wide functional group compatibility and occurs under mild conditions with extrusion of H2.
- Liu, Feng,Liu, Jia-Li,tu, Jia-Lin
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p. 7369 - 7372
(2020/10/05)
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- Reusable and highly enantioselective water-soluble Ru(II)-Amm-Pheox catalyst for intramolecular cyclopropanation of diazo compounds
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A reusable and highly enantioselective catalyst for the intramolecular cyclopropanation of various diazo ester and Weinreb amide derivatives was developed. The reactions catalyzed by a water-soluble Ru(II)-Amm-Pheox catalyst proceeded smoothly at room temperature, affording the corresponding bicyclic cyclopropane ring-fused lactones and lactams in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). After screening of various catalysts, the Ru(II)-Amm-Pheox complex having an ammonium group proved to be crucial for the intramolecular cyclopropanation reaction in a water/ether biphasic medium. The water-soluble catalyst could be reused at least six times with little loss in yield and enantioselectivity.
- Mandour, Hamada S.A.,Nakagawa, Yoko,Tone, Masaya,Inoue, Hayato,Otog, Nansalmaa,Fujisawa, Ikuhide,Chanthamath, Soda,Iwasa, Seiji
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p. 357 - 363
(2019/02/20)
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- A Sequential Acyl Thiol-Ene and Thiolactonization Approach for the Synthesis of δ-Thiolactones
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A novel strategy for the synthesis of δ-thiolactones from inexpensive and readily available ?-unsaturated esters has been developed. This strategy incorporates a radical acyl thiol-ene reaction as the key C-S bond forming step. Cyclization is achieved via a Steglich-type thiolactonization of 5-mercaptopentanoic acids. We report the facile and scalable synthesis of δ-thiolactones in moderate to good yield under mild reaction conditions with tolerance for a range of functional groups.
- McCourt, Ruairí O.,Scanlan, Eoin M.
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supporting information
p. 3460 - 3464
(2019/05/10)
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- Synthesis of Cyclobutene-Fused Eight-Membered Carbocycles through Gold-Catalyzed Intramolecular Enyne [2+2] Cycloaddition
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Cationic gold(I) complexes with hollow-shaped triethynylphosphine ligands efficiently catalyzed intramolecular [2+2] cycloaddition of 1,9-enynes to afford cyclobutene-fused eight-membered carbocycles that were difficult to synthesize by other catalytic systems. Various 1,9-enynes with carbon linkers with or without a fused ring underwent efficient [2+2] cycloaddition with 5 mol% of the Au catalyst bearing the triarylmethyl-end-capped triethynylphosphine in CH2Cl2 at rt in the presence of MS 4A as an additive. More challenging 1,9-enyne substrates with fully saturated acyclic carbon linkers underwent eight-membered ring formation at 60 °C in ClCH2CH2Cl in the absence of MS 4A, forming monocyclic 1,3-dienes as major products. (Figure presented.).
- Iwai, Tomohiro,Ueno, Masahiro,Okochi, Hiori,Sawamura, Masaya
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p. 670 - 675
(2017/12/26)
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- Transition-Metal-Free Formylation of Allylzinc Reagents Leading to α-Quaternary Aldehydes
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The first example of formylation of allylzinc reagents using S-phenyl thioformate is presented. The reaction proceeded under mild conditions without any transition-metal catalyst, forming quaternary carbon centers with reactive functionalities, such as formyl and vinyl groups. Moreover, Barbier-type formylation of an allylic bromide with a sterically demanding thioformate was achieved. As a preliminary result, asymmetric formylation was conducted using a menthol-derived chiral thioformate.
- Haraguchi, Ryosuke,Kusakabe, Akinori,Mizutani, Nakaba,Fukuzawa, Shin-Ichi
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p. 1613 - 1616
(2018/03/23)
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- Rapid Access to Thiolactone Derivatives through Radical-Mediated Acyl Thiol-Ene and Acyl Thiol-Yne Cyclization
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A new synthetic approach to thiolactones that employs an efficient acyl thiol-ene (ATE) or acyl thiol-yne (ATY) cyclization to convert unsaturated thiocarboxylic acid derivatives into thiolactones under very mild conditions is described. The high overall yields, fast kinetics, high diastereoselectivity, excellent regiocontrol, and broad substrate scope of these reaction processes render this a very useful approach for diversity-oriented synthesis and drug discovery efforts. A detailed computational rationale is provided for the observed regiocontrol.
- McCourt, Ruairi O.,Dénès, Fabrice,Sanchez-Sanz, Goar,Scanlan, Eoin M.
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p. 2948 - 2951
(2018/05/28)
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- Transition Metal Free Cycloamination of Prenyl Carbamates and Ureas Promoted by Aryldiazonium Salts
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Upon treatment with aryldiazonium salts, prenyl carbamates and ureas undergo redox-neutral azocycloamination. In general, N-aryl O-prenyl carbamates cyclize in a photocatalytic reaction with visible light and an organic dye. With electron-deficient diazonium salts, electronic matching with an electron-rich N-aryl substituent results in a reaction proceeding in the ground state, without either light or photocatalyst. Cyclic voltammetry suggests that this radical reaction is initiated by hydrogen-atom abstraction mediated by an aryl radical, followed by a radical addition cascade and proton-coupled hole propagation. The reaction proceeds at room temperature in short reaction times, and a range of functional groups is tolerated.
- Abrams, Roman,Lefebvre, Quentin,Clayden, Jonathan
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p. 13587 - 13591
(2018/09/25)
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- Copper-catalyzed [1,2]-rearrangements of allylic iodides and aryl α-diazoacetates
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The [1,2]- and [2,3]-rearrangements of iodonium ylides are synthetically useful reactions for the generation of functionalized α-iodoesters. Allylic iodides are coupled with α-diazoesters in the presence of a copper catalyst and a ligand to generate iodonium ylides, which undergo metal-mediated rearrangements. By fine-tuning the structure of the ligand, we have reversed the regioselectivity of copper-catalyzed reactions of iodonium ylides from [2,3]- to [1,2]-rearrangements with the use of alternate bipyridine ligands. The preference for [1,2]-rearrangements was further improved by using bulky aryl α-diazoester substrates. Several α-iodoesters with a diverse range of functional groups were generated in good yields (up to 88% yield) and high regioselectivities (up to >95:5 regioisomeric ratio). A deuterium-labeled substrate was utilized to gain insight into the mechanism of the reaction.
- Xu, Bin,Gartman, Jackson A.,Tambar, Uttam K.
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p. 4150 - 4159
(2017/06/29)
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- Copper-Catalyzed Enantio-, Diastereo-, and Regioselective [2,3]-Rearrangements of Iodonium Ylides
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The first highly enantioselective, diastereoselective, and regioselective [2,3]-rearrangement of iodonium ylides has been developed as a general solution to catalytic onium ylide rearrangements. In the presence of a chiral copper catalyst, substituted allylic iodides couple with α-diazoesters to generate metal-coordinated iodonium ylides, which undergo [2,3]-rearrangements with high selectivities (up to >95:5 r.r., up to >95:5 d.r., and up to 97 % ee). The enantioenriched iodoester products can be converted stereospecifically into a variety of onium ylide rearrangement products, as well as compounds that are not accessible by classical onium ylide rearrangements.
- Xu, Bin,Tambar, Uttam K.
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p. 9868 - 9871
(2017/08/08)
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- Amide-Group-Directed Protonolysis of Cyclopropane: An Approach to 2,2-Disubstituted Pyrrolidines
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Regioselective protonolytic C-C bond cleavage of acylated aminomethyl cyclopropanes can be achieved using trifluoroacetic acid. The intermediate tertiary carbenium ion undergoes an intramolecular amination to give 2,2-substituted pyrrolidines. The strength of the acid and the amine substituent are important factors to achieve high regioselectivity, suggesting intramolecular proton transfer from the protonated amide function. Preliminary mechanistic studies revealed that cyclopropane cleavage proceeds with retention of configuration at the carbon to which the proton is attached. This observation is consistent with the "edge" protonation trajectory of the C-C bond.
- Skvorcova, Marija,Jirgensons, Aigars
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supporting information
p. 2478 - 2481
(2017/05/24)
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- Hydropyridylation of Olefins by Intramolecular Minisci Reaction
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An unprecedented cheap, mild and easy methodology for an intramolecular Minisci reaction based on a hydrogen atom transfer (HAT) initiated hydrofunctionalization of olefins was developed. The method is suitable for the construction of unusual dihydropyrano-pyridine and 1,2,3,4-tetrahydronaphthiridine structures and, unlike most similar reactions, does not require exclusion of air from the reaction medium.
- Bordi, Samuele,Starr, Jeremy T.
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supporting information
p. 2290 - 2293
(2017/05/12)
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- The synthesis of α,α-disubstituted α-amino acids via ichikawa rearrangement
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An approach to α,α-disubstituted α-amino acids is reported. The key step is allyl cyanate-to-isocyanate rearrangement. As demonstrated, the resultant allyl isocyanates can be directly trapped with various nucleophiles, for instance, alcohols, amines, and organometallic reagents, to provide a broad range of N-functionalized allylamines. The developed method has been successfully applied in the synthesis of two bioactive peptides: 2-aminoadamantane-2-carboxylic acid derived P2X7-evoked glutamate release inhibitor and 4-amino-tetrahydropyranyl-4-carboxylic acid derived dipeptide GSK-2793660, which is currently in clinical trials as cathepsin C inhibitor for the treatment of cystic fibrosis, noncystic fibrosis bronchiectasis, ANCA-associated vasculitis and bronchiectasis.
- Szczes?niak, Piotr,Pieczykolan, Micha?,Stecko, Sebastian
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p. 1057 - 1074
(2016/02/19)
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- Carbene-catalyzed desymmetrization of 1,3-diols: Access to optically enriched tertiary alkyl chlorides
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The introduction of a chlorine atom to a carbon center in an enantioselective manner via conventional C-Cl bond formation is difficult. Here we report a new approach to this class of tertiary alkyl chlorides with high optical purities. Instead of forming a new C-Cl bond, our approach involves carbene-catalyzed desymmetrization of 2-chloro-1,3-diols as the key step to set up the chiral carbon center with excellent enantiomeric excess.
- Li, Bao-Sheng,Wang, Yuhuang,Proctor, Rupert S. J.,Jin, Zhichao,Chi, Yonggui Robin
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p. 8313 - 8316
(2016/07/06)
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- Ligand-Controlled Regiodivergence in the Copper-Catalyzed [2,3]- and [1,2]-Rearrangements of Iodonium Ylides
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Despite the importance of allylic ylide rearrangements for the synthesis of complex molecules, the catalyst control of [2,3]- and [1,2]-rearrangements remains an unsolved problem. We developed the first regiodivergent [2,3]- and [1,2]-rearrangements of iodonium ylides that are controlled by copper catalysts bearing different ligands. In the presence of a 2,2′-dipyridyl ligand, diazoesters and allylic iodides react via a [2,3]-rearrangement pathway. Alternatively, a phosphine ligand favors the formation of the [1,2]-rearrangement product. A series of α-iodoesters containing a broad range of functional groups were obtained in high yields, regioselectivities, and diastereoselectivities. Deuterium-labeling studies suggest distinct mechanisms for the regioselective rearrangements.
- Xu, Bin,Tambar, Uttam K.
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p. 12073 - 12076
(2016/09/28)
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- Preparation of polycyclic compounds by intramolecular photospirocyclization and photocycloaddition reactions of 4-alkenyl-1-cyanonaphthalene derivatives
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Photoreactions of 4-pentenyl-1-cyanonaphthalenes yield spirocyclic products along with [4?+?2] cycloadducts. Photoreactions of 5-phenyl derivatives produce a product having tricyclo[6.3.0.01,4]undecadiene skeleton. Formation of angular triquinanes takes place in photoreactions of cycloalkene-linked cyanonaphthalenes. The observation demonstrates that π–π arene ring interactions, steric hindrance, and suitable locations of reaction sites in syn and anti singlet exciplexes govern the modes followed in intramolecular photoreactions of 4-alkenyl-1-cyanonaphthalenes.
- Maeda, Hajime,Wada, Hidenori,Mukae, Hirofumi,Mizuno, Kazuhiko
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- Synthetic spirocyclic endoperoxides: New antimalarial scaffolds
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Here we report the development of a straightforward synthetic procedure for the preparation of spirocyclic endoperoxides as synthetic analogues of the natural product dihydroplakortin. The peroxides presented here are more potent antiplasmodials than dihydroplakortin itself and we proved for the first time their antimalarial activity in vivo. This journal is
- Brindisi, Margherita,Gemma, Sandra,Kunjir, Sanil,Di Cerbo, Luisa,Brogi, Simone,Parapini, Silvia,D'Alessandro, Sarah,Taramelli, Donatella,Habluetzel, Annette,Tapanelli, Sofia,Lamponi, Stefania,Novellino, Ettore,Campiani, Giuseppe,Butini, Stefania
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p. 357 - 362
(2015/03/31)
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- NOVEL PROCESS FOR TOTAL SYNTHESIS OF VENLAFAXINE
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There is a need for short, resolution free asymmetric process for synthesis of one isomer of venlafaxine, (-)-venlafaxine. The invention provides a novel, short process of synthesis of (-)-venlafaxine, with yield greater than 50% and ee> 99%. This process can be used for racemic synthesis of venlafaxine with overall yield 65%.
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- Dialkylzinc-mediated allylic polyfluoroarylation reaction
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Abstract We present an allylic polyfluoroarylation reaction with broad substrate scope and excellent functional group tolerance, using organozinc reagents under mild conditions. A catalytic amount of triphenylphosphine oxide efficiently promotes iodine-zinc exchange reaction between polyfluoroaryl iodide and dimethylzinc, and the resulting phosphine oxide-activated polyfluoroarylzinc undergoes substitution reaction with allylic halides to afford the corresponding polyfluoroarylated products.
- Kurauchi, Daisuke,Hirano, Keiichi,Kato, Hisano,Saito, Tatsuo,Miyamoto, Kazunori,Uchiyama, Masanobu
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p. 5849 - 5857
(2015/08/03)
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- A protecting group free and scalable approach towards total synthesis of (-)-venlafaxine
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A protecting group free asymmetric total synthesis of (-)-venlafaxine is reported. The strategy employs Sharpless epoxidation and regio-selective epoxide ring opening by an in situ generated Gilman reagent as key steps. This paper reports a 53% overall yield in 6 steps for total synthesis of (-)-venlafaxine. This journal is the Partner Organisations 2014.
- Chavan, Subhash P.,Pawar, Kailash P.,Garai, Sumanta
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p. 14468 - 14470
(2014/04/17)
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- Selectivity control by silver catalysts in the cycloisomerization of 1,6-enynes derived from propiolamides
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Silver-catalyzed cycloisomerizations of 1,6-enynes derived from propiolamides led to a selective formation of Alder-ene type 1,4-dienes. Interestingly, AgNTf2 outperformed gold or platinum catalysts in terms of selectivity and reactivity, providing the 1,4-dienes at room temperature. The presence of C(5) carbonyl group in combination with Ag salts is key to the selectivity and the β-oxo coordinated silver carbenoids were proposed as an intermediate based on the reaction profiles.
- Koo, Jaeyoung,Park, Hyun-Sub,Shin, Seunghoon
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p. 834 - 839
(2013/02/25)
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- GERANYLGERANYLACETONE DERIVATIVES
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Provided herein are geranylgeranylacetone derivatives and methods of using them.
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- Enantioselective intramolecular aldehyde α-alkylation with simple olefins: Direct access to homo-ene products
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A highly selective method for the synthesis of asymmetrically substituted carbocycles and heterocycles from unactivated aldehyde-olefin precursors has been achieved via enantioselective SOMO-catalysis. Addition of a catalytically generated enamine radical cation across a pendent olefin serves to establish a general asymmetric strategy toward the production of a wide range of formyl-substituted rings with alkene transposition. Conceptually, this novel mechanism allows direct access to "homo-ene"-type products.
- Comito, Robert J.,Finelli, Fernanda G.,Macmillan, David W. C.
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p. 9358 - 9361
(2013/07/26)
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- α,β-Unsaturated imines via Ru-catalyzed coupling of allylic alcohols and amines
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A convenient synthesis of α,β-unsaturated imines requiring only an allylic alcohol, an amine and a Ru catalyst has been developed. The use of large excesses of oxidant and the purification of sensitive intermediates can be avoided.
- Rigoli, Jared W.,Moyer, Sara A.,Pearce, Simon D.,Schomaker, Jennifer M.
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p. 1746 - 1749
(2012/04/23)
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- Gold-catalysed activation of epoxides: Application in the synthesis of bicyclic ketals
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Gold-catalysed generation of diol equivalents from epoxides and their intramolecular reaction with Ca≡C bonds to generate bicyclic ketals is presented. This reaction essentially involves the formation of an acetonide, which subsequently cyclises on the alkyne intramolecularly under gold catalysis conditions. This method could be extended to make optically pure bicyclic ketals. Deuterium incorporation experiments were carried out to ascertain the mechanism of the reaction. Sequential activation of epoxide and alkyne moieties by a gold catalyst in acetone as solvent has been achieved. This strategyhas been employed to synthesise bicyclic ketals from epoxy alkynes. Copyright
- Balamurugan, Rengarajan,Kothapalli, Raveendra Babu,Thota, Ganesh Kumar
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p. 1557 - 1569
(2011/04/25)
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- Synthesis of N-heterocycles, beta-amino acids, and allyl amines via aza-payne mediated reaction of ylides and hydroxy aziridines
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An ylide-based aza-Payne rearrangement of 2,3-aziridin-1-ols leads to an efficient process for the preparation of pyrrolidines. The aza-Payne rearrangement under the basic reaction conditions favors the formation of epoxy amines. Subsequent nucleophilic attack of the epoxide by the ylide yields a bis-anion, which upon a 5-exo-tet ring closure yields the desired pyrrolidine, thus completing the relay of the 3-membered the 5-membered nitrogen containing ring system. This process takes place with complete transfer of stereochemical fidelity, and can be applied to sterically hindered aziridinols.
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Page/Page column 55
(2009/01/23)
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- Synthesis and biological activity of permethrinic acid analogs containing various substituents in position 2 of the cyclopropane ring
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A number of permethrinic acid ethyl ester derivatives having various substituents [Et, Pr, Ph, Ph(CH2) n (n = 1, 2), etc.] in position 2 of the cyclopropane ring were synthesized, and their insecticidal acivity against typhoid flies, rice weevils, and bean aphides, as well as juvenoid activity on flour beetle chrysalises, was studied. The newly synthesized compounds turned out to exhibit weak insecticidal activity against standard insects but pronounced juvenile hormone activity, which differentiates them from permethrinic acid esters.
- Mirzabekova,Kuz'mina,Lukashov,Sokolova,Golosov,Kazakov,Perlova,Potapova,Kheinman,Ivanova
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experimental part
p. 1139 - 1149
(2009/09/25)
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- Diastereomerically and enantiomerically pure 2,3-disubstituted pyrrolidines from 2,3-aziridin-1-ols using a sulfoxonium ylide: A one-carbon homologative relay ring expansion
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An ylide-based aza-Payne rearrangement of 2,3-aziridin-1-ols leads to an efficient process for the preparation of pyrrolidines. The aza-Payne rearrangement under basic reaction conditions favors the formation of epoxy amines. Subsequent nucleophilic attack of the epoxide by the ylide yields a bis-anion, which upon a 5-exo-tet ring-closure yields the desired pyrrolidine, thus completing the relay of the three-membered to the five-membered nitrogen-containing ring system. This process takes place with complete transfer of stereochemical fidelity and can be applied to sterically hindered aziridinols.
- Schomaker, Jennifer M.,Bhattacharjee, Somnath,Yan, Jun,Borhan, Babak
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p. 1996 - 2003
(2007/10/03)
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- An RCM based approach to (±)-herbertene-l, 14-diol and (±)-tochuinyl acetates
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A sequence comprising of Johnson's ortho ester Claisen rearrangement, alkylation and RCM reactions has been developed for the synthesis of cyclopentenes containing vicinal quaternary carbon atoms. The versatility of the sequence has been demonstrated by the efficient total synthesis of sesquiterpenes tochuinyl acetates and herbertene-1,14-diol.
- Srikrishna,Rao, M Sreenivasa
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p. 1308 - 1317
(2008/09/18)
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- Ligand-accelerated vanadium-catalysed epoxidation in water
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Vanadium-catalysed epoxidation of allylic alcohols, a classical example of ligand-decelerated catalysis, in water it turns into a ligand-accelerated process. The Royal Society of Chemistry 2005.
- Bourhani, Zainaba,Malkov, Andrei V.
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p. 4592 - 4594
(2007/10/03)
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- Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes
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Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of β-quaternary amino acid linked L-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the β-position of α-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zuckerfa/fa rats. Extension of this approach to adamantylglycine- derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
- Augeri, David J.,Robl, Jeffrey A.,Betebenner, David A.,Magnin, David R.,Khanna, Ashish,Robertson, James G.,Wang, Aiying,Simpkins, Ligaya M.,Taunk, Prakash,Huang, Qi,Han, Song-Ping,Abboa-Offei, Benoni,Cap, Michael,Xin, Li,Tao, Li,Tozzo, Effie,Welzel, Gustav E.,Egan, Donald M.,Marcinkeviciene, Jovita,Chang, Shu Y.,Biller, Scott A.,Kirby, Mark S.,Parker, Rex A.,Hamann, Lawrence G.
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p. 5025 - 5037
(2007/10/03)
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- Synthesis of diastereomerically and enantiomerically pure 2,3-disubstituted tetrahydrofurans using a sulfoxonium ylide
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Nucleophilic substitution reactions of 2,3-epoxy alcohols, easily prepared via Sharpless asymmetric epoxidation chemistry, offer access to a wide variety of enantiomerically pure compounds. In this communication, we describe the use of a Payne rearrangement to control regioselectivity in the ring-opening of a series of 2,3-epoxy alcohols with dimethylsulfoxonium methylide to yield diastereomerically and/or enantiomerically pure disubstituted tetrahydrofuran rings. The factors influencing the success and substitution pattern of the THF ring products are discussed, including steric, electronic, and solvent effects. Copyright
- Schomaker, Jennifer M.,Pulgam, Veera Reddy,Borhan, Babak
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p. 13600 - 13601
(2007/10/03)
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- Anomalous intramolecular C-H insertion reactions of rhodium carbenoids: Factors influencing the reaction course and mechanistic implications
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The intramolecular insertion of rhodium carbenoids into the α-C-H bonds of allylic ethers to give 3(2H)-furanones has been explored. Cyclopropanation is favored irrespective of the complex used for carbenoid generation or the substitution pattern of the allylic ether, unless a substituent is placed on the tether connecting the ether to the α-diazo ketone. Unusual acetal products resulting from an anomalous C-H insertion process are obtained in addition to the expected 3(2H)-furanones formed by conventional carbenoid C-H insertion. These acetals are the favored C-H insertion products in certain circumstances and particularly in cases where carbenoid generation is effected using an electron-deficient rhodium complex. Experiments with simple deuterium labeled substrates reveal that anomalous C-H insertion products arise by a mechanism that is distinct from that leading to the formation of conventional C-H insertion products. The formation of acetal products and the outcome of reactions performed using deuterium-labeled substrates suggest that a mechanism involving hydride migration to the rhodium center of the carbenoid is operative.
- Clark, J. Stephen,Dossetter, Alexander G.,Wong, Yung-Sing,Townsend, Robert J.,Whittingham, William G.,Russell, C. Adam
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p. 3886 - 3898
(2007/10/03)
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- Claisen rearrangement based methodology for the spiroannulation of a cyclopentane ring. Formal total synthesis of (±)-acorone and isoacorones
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A Claisen rearrangement based methodology for spiroannulation of a cyclopentane ring to cyclic precursors and its application in the formal total synthesis of acorones 1 is described. Thus, Claisen rearrangement of 2-cycloalkylideneethanols 12 with 2-methoxypropene and a catalytic amount of mercuric acetate generates 4,4-substituted hex-5-en-2-ones 13. Ozonolytic cleavage of the terminal olefin in the enones 13 and intramolecular aldol condensation of the resulting keto-aldehydes 14 furnishes the spiroannulated compounds 15. (C) 2000 Elsevier Science Ltd.
- Srikrishna,Praveen Kumar
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p. 8189 - 8195
(2007/10/03)
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- Spiroannulation of a cyclopentane ring. Synthesis of spiro[4.n](n+5)alk-2-en-1-ones
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A methodology based on Claisen rearrangement-Wacker oxidation and intramolecular aldol condensation strategy starting from cyclic ketones leading to spiro[4.n](n+5)alk-2-en-1-ones has been developed. Thus one-pot Claisen rearrangement of the allyl alcohols 6a-c furnished the aldehydes 8a-c, which on regiospecific oxidation using Wacker conditions generated the keto-aldehydes 9a-c. Finally, intramolecular aldol condensation transformed the keto-aldehydes 9a-c into spiroannulated products 10a-c.
- Srikrishna,Kumar, P. Praveen
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p. 521 - 526
(2007/10/03)
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- Pesticidal compounds
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This invention relates to 1,1,1,4-substituted naphthaline compounds, compositions, processes for their preparation and processes for their use as pesticides, especially insecticides, acaricides and fungicides.
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- Stereocontrol in organic synthesis using silicon-containing compounds. A formal synthesis of prostaglandins controlling the stereochemistry at C-15 using a silyl-to-hydroxy conversion following a stereochemically convergent synthesis of an allylsilane
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Hydrosilylation of isoprene with chloro(diphenyl)silane gave (Z)-chloro(2-methylbut-2-enyl)-diphenylsilane 7. The cuprate reagent derived from this chloride underwent conjugate addition to methyl cinnamate 11, 1,2-silylcupration with hex-1-yne 16 and allene 18, and allylic displacement reactions with 1-vinylcyclohexyl acetate 20 and (Z)-1-cyclopentyloct-2-en-1-yl acetate 22. The silyl group in each of the products was converted into a hydroxy, with the removal of the 2-methylbut-2-enyl group taking place under much milder acidic conditions than those needed to remove the phenyl group from the dimethyl(phenyl)silyl group, and making this group suitable for the conversion of an allylsilane into an allyl alcohol. A stereospecifically anti conjugate displacement of the allylic benzoate group in (Z)-(1S,5R,6R,7R,1′S)-7-benzoyloxy-6-(1′-benzoyloxyoct-2′- enyl)-2-oxabicyclo[3.3.0]octan-3-one 52, and a stereospecifically syn conjugate displacement of the carbamate group in (Z)-(1S,5R,6R,7R,1′R)-7-benzoyloxy-6-(1′-N-phenylcarbamoyloxyoct- 2′-enyl)-2-oxabicyclo[3.3.0]octan-3-one 51, gave stereo-convergently the same allylsilane (1′ E,2″Z)-(1S,5S,6R,7R,3′S)-7-benzoyloxy-6-[3′-(2″- methylbut-2″-enyl)-diphenylsilyloct-1′-enyl]-2-oxabicyclo[3.3.0] octan-3-one 53. Silyl-to-hydroxy conversion gave the allyl alcohol (E)-(1S,5S,6R,7R,3′S)-7-benzoyloxy-6-(3′-hydroxyoct-1′-enyl)- 2-oxabicyclo[3.3.0]octan-3-one 54, having the relative and absolute stereochemistry at C-15 of the prostaglandins.
- Fleming, Ian,Winter, Stephen B. D.
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p. 2687 - 2700
(2007/10/03)
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- Complementary regioselective cyclopropyl ring openings of 6- formyl-spirobicyclo[5.2]octane mediated by TMSC1 and TBAI
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Absolute control over the regioselectivity of trimethylsilyl halide-induced cyclopropane fragmentation of a spirofused cyclopropyl carboxaldehyde has been achieved by simply varying the reaction stoichiometry and the nature of the halide. Treatment of 6-formyl- spirobicyclo[5.2]octane with a large excess of TMSC1 gave 3-(1- chlorocyclohexyl)propanal (84% yield), whereas 2-(1- iodomethylcyclohexyl)ethanal (86% yield) was obtained using 10 equivalents each TMSC1 and n-Bu4NI (TBAI). Use of only a moderate excess of TMSC1 or TMSC1 and TBAI gave the rearranged product 3-(1- cyclohexenyl)-propanal.
- Huang, He,Forsyth, Craig J.
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p. 16341 - 16348
(2007/10/03)
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- Synthetic applications of functionalized silyl anions: Aminosilyl anions as hydroxy anion equivalent
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An (aminosilyl)lithium and the corresponding copper and magnesium reagents serve as a hydroxy anion equivalent through (1) allylic substitution, (2) addition to vinyloxirane, and (3) addition to acetylene, followed by oxidative cleavage of the silicon-carbon bonds. Highly regio- and stereoselective transformations have been achieved in all cases.
- Tamao, Kohei,Kawachi, Atsushi,Tanaka, Yoko,Ohtani, Hitoshi,Ito, Yoshihiko
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p. 5765 - 5772
(2007/10/03)
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- A simple strategy for spirocyclopentannulation of cyclic ketones. Formal total synthesis of (±)-acorone
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A general and simple methodology for spirocyclopentannulation of cyclic ketones (or 4,4-disubstituted cyclopentenones from acyclic ketones) and its application in the synthesis of the spirodienone 7 via a prochiral precursor constituting a formal total synthesis of (±)-acorone (6), are described.
- Srikrishna, Adusumilli,Kumar, P. Praveen,Viswajanani, Ranganathan
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p. 1683 - 1686
(2007/10/03)
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- Conformationally restricted TRH analogs: The compatibility of a 6,5-bicylic lactam-based mimetic with binding to TRH-R
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A pair of conformationally restricted TRH analogs have been synthesized. Both analogs have the central histidine of TRH replaced by a cyclohexylalanine unit, and both analogs contain a 6,5-bicyclic lactam ring fusing the proline peptide bond into a trans conformation. The analogs differ at the bridgehead stereocenter. The synthesis of the analogs utilized an anodic amide oxidation reaction to selectively functionalize a proline derivative and a titanium tetrachloride-initiated cyclization-rearrangement sequence to assemble the desired bicyclic ring skeleton. The analogs were compared with the unrestricted cyclohexyalanine-containing TRH analog (cyclohexyl-Ala2-TRH) in order to determine how the added lactam ring affected the affinity and the potency of the analog for TRH-R. Both the affinity and potency of the restricted analogs were found to be critically dependent on the bridgehead stereochemistry of the bicyclic ring. The analog having R stereochemistry at the bridgehead was 478 times more potent than the S isomer. In addition, the R isomer was found to be approximately 4.7 times more potent than its unrestricted counterpart. Similarly, the R isomer was found to have an affinity for TRH-R that was approximately 3.4 times the affinity of the unrestricted cyclohexyl-Ala2-TRH.
- Li, Wenhao,Moeller, Kevin D.
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p. 10106 - 10112
(2007/10/03)
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- Application of Microwave Heating Technique for Rapid Synthesis of γ,δ-Unsaturated Esters
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The use of microwave heating technique for the acceleration of ortho ester Claisen rearrangement (a three step transformation) is described.Irradiation of a DMF solution of the allyl alcohol 5, triethyl orthoacetate and propionic acid (catalytic) in an Erlenmeyer flask for 10 minutes in a microwave oven generated the ester 8 in 83percent yield.Analogously, ortho ester Claisen rearrangement of a variety of allyl and propargyl alcohols (9, 12-22) were achieved.The formation of the diester 10 from 2-butyne-1,4-diol (9) via the ortho ester Claisen rearrangement of two allyl alcohol moieties (involving six steps) in 15 minutes, demonstrates the versatility of the microwave heating technique.
- Srikrishna, Adusumilli,Nagaraju, Sankuratri,Kondaiah, Paturu
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p. 1809 - 1816
(2007/10/02)
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- Regioselective Photocycloadditions of Benzoquinones to Alkylidenecyclohexanes: A New Synthetic Resource
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Benzoquinones add regioselectively to alkylidenecyclohexanes.The photoadducts are converted into useful building blocks in good yield.
- Ciufolini, Marco A.,Rivera-Fortin, M. Angelica,Byrne, Norman E.
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p. 3505 - 3508
(2007/10/02)
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- The 2-methylbut-2-enyl(diphenyl)silyl group: A silyl group easily converted to hydroxyl in the presence of a 1,2-disubstituted C=C double bond
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The 2-methylbut-2-enyl(diphenyl)silyl group can be introduced into a variety of organic structures by way of the cuprate reagent 4, and it can then be converted into a hydroxyl group, even in the presence of a C=C double bond, unlike the dimethyl(phenyl)silyl group.
- Fleming, Ian,Winter, Stephen B. D.
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p. 7287 - 7290
(2007/10/02)
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- New Syntheses of Isomerically Pure Allyl and Propargyl Cyanides by Isocyanide-Cyanide Rearrangement
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A new route for the synthesis of isomerically pure allyl and propargyl cyanides has been developed.Allylic amines are synthesized from the corresponding alcohols by Mitsunobu or by Overman reaction.Formylation with formic acid derivatives provides N-substituted formamides, which are dehydrated to isocyanides. 1,2-Sigmatropic rearrangement by flash pyrolysis provides the isomerically pure allyl and propargyl cyanides. Key Words: Isocyanide-cyanide rearrangment / Cyanides, allyl- and propargyl-
- Wolber, Erwin K. A.,Schmittel, Michael,Ruechardt, Christoph
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p. 525 - 532
(2007/10/02)
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