- Facile reaction of o-carboranyllithium reagents with functionalized alkyl halides
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Unlike the normal organolithium reagents, o-carboroanyllithium derivatives can tolerate many functional groups, such as ketones, nitriles and esters. This chemoselectivity is utilized in synthesizing a wide variety of o-carborane derivatives containing fu
- Cai, Jianping,Nemoto, Hiaso,Singaram, Bakthan,Yamamoto, Yoshinori
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- Reductive cleavage of 1,3-dithiane systems anchored on polymers useful for supported organic syntheses
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Completely odourless reductions of ketones to alkanes through condensation with 1,3-propanedithiol copolymers and cleavage of the formed 1,3-dithiane units with sodium and ammonia or tributyltin hydride and AIBN, useful as a new synthetic methodology for combinatorial chemistry, is reported. Selective reductions of ketones in presence of an ester or a second ketone group are exemplified.
- Bertini, Vincenzo,Lucchesini, Francesco,Pocci, Marco,Alfei, Silvana,De Munno, Angela
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- Cobalt-catalyzed cross-coupling reactions of alkyl halides with aryl Grignard reagents and their application to sequential radical cyclization/cross-coupling reactions
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Reactions of alkyl halides with arylmagnesium bromides in the presence of cobalt(II)(diphosphine) complexes are discussed. Treatment of 1-bromooctane with phenylmagnesium bromide with the aid of a catalytic amount of CoCl 2(dppp) [DPPP=1,3-bis(diphenylphosphino)propane] yielded octylbenzene in good yield. The reaction mechanism would include single electron transfer from an electron-rich cobalt complex to alkyl halide to generate the corresponding alkyl radical. The mechanism was justified by CoCl 2(dppe)-catalyzed [DPPE=1,2-bis(diphenylphosphino)ethane] sequential radical cyclization/cross-coupling reactions of 6-halo-1-hexene derivatives that yielded benzyl-substituted cyclopentane skeletons.
- Ohmiya, Hirohisa,Wakabayashi, Katsuyu,Yorimitsu, Hideki,Oshima, Koichiro
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- Homolytic Reactions of Ligated Boranes. Part 9. Overall Addition of Alkanes to Electron-deficient Alkenes by a Radical Chain Mechanism
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Methyl bromoacetate and ethyl 2-bromopropanoate are reduced by Bun3P->BH3 or Bun3P->BH2Ph to methyl acetate and ethyl propanoate, respectively, in chlorobenzene at 80-110 deg C in the presence of dibenzoyl peroxide or t-butyl perbenzoate.Amine complexes of borane or phenylborane are much less effective reducing agents.The reductions may also be initiated photochemically and are inhibited by a phenolic radical scavenger.A homolytic chain mechanism is proposed in which the phosphine-boryl radical abstracts halogen from the bromo ester and is subsequently regenerated by reaction of an α-(alkoxycarbonyl)alkyl radical with the phosphine-borane.The latter propagation step, together with halogen abstraction from RI and addition of the derived alkyl radical to the C=C bond, is also involved in the chain reaction between Bun3P->BH2Ph, an alkyl iodide, and ethyl acrylate according to equation (A); Bun3P->BH3 reacts similarly but gives lower yields of ester.Reaction (A) proceeds smoothly at 110 deg C Bun3P->BH2Ph + RI + CH2=CHCO2Et -> RCH2CH2CO2Et + Bun3P->BHIPh (A) when initiated by t-butyl perbenzoate and moderate yields of isolated esters were obtained from n-butyl iodide, cyclohexyl iodide, and 3β-iodocholest-5-ene.This last iodide gives an epimeric mixture of 3α- and 3β-esters in total isolated yield of ca. 50 percent.Similar addition reactions take place between Bun3P->BH2Ph, BunI, and diethyl vinylphosphonate or phenyl vinyl sulphone.It is concluded that Bun3P->BH3 and particularly Bun3P->BH2Ph offer promise as alternatives to tin, mercury, and germanium hydrides in radical chain reactions of synthetic value.
- Baban, Jehan A.,Roberts, Brian P.
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- Reductive decyanation of α-cyano and α-alkoxycarbonyl substituted nitriles promoted by samarium(II) iodide
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Decyanation of geminal dinitriles and α-alkoxycarbonyl substituted nitriles promoted by samarium(II) iodide has been efficiently achieved. This method has advantages over the previously known radical route using tin hydride with respect to applicable substrates and the reaction temperature employed. This decyanation could broaden the synthetic applicability of the nitrile derivatives.
- Kang,Hong,Cho,Koh
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- One-step cross-coupling reaction of functionalized alkyl iodides with aryl halides by the use of an electrochemical method
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Organozinc compounds of functionalized alkyl iodide carrying an alkoxycarbonyl, cyano or alkenyl group were prepared in high yields under mild conditions (0°C-r.t., 10min in DMF) by the reaction of iodides with an electrogenerated reactive zinc (EGZn). Cross-coupling of the organozinc compounds with various aryl halides in the presence of 5 mol% Pd(P(o- Tol)3)2Cl2 in THF gave the corresponding cross-coupled products in moderate to high yields. These cross-coupling reactions can be also achieved in one step and in one pot by the use of an electrochemical method utilizing a Pt cathode and Zn anode.
- Kurono, Nobuhito,Sugita, Kazuya,Takasugi, Shingo,Tokuda, Masao
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- Microwave-assisted aqueous Krapcho decarboxylation
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The Krapcho decarboxylation of alkyl malonate derivatives has been adapted to aqueous microwave conditions. Various salt additives were examined, and both the cation and the anion impacted the facility of the reaction. A strong correlation was found between the pKa of the anion and the reaction rate, suggesting a straightforward base-catalyzed hydrolysis. Lithium sulfate gave the best results, obviating the need for DMSO co-solvent. Georg Thieme Verlag Stuttgart · New York.
- Mason, Jeremy D.,Murphree, S. Shaun
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- Facile preparation of organozinc bromides using electrogenerated highly reactive zinc and its use in cross-coupling reaction
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Highly reactive zinc was readily prepared by electrolysis of a DMF solution containing pyrene as a mediator with a platinum cathode and a zinc anode. Preferential reduction of pyrene occurred to generate the corresponding radical anion, which reduced zinc ions generated from anodic dissolution to give zero valent zinc with high reactivity. The reactive zinc was successfully used for an efficient transformation of bromoalkanes into the corresponding organozinc bromides. Organozinc bromides obtained were further used successfully in Pd-catalyzed cross-coupling reaction with various aryl iodides and bromides.
- Kurono, Nobuhito,Inoue, Tomio,Tokuda, Masao
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- Unprecedented alkylation of carboxylic acids by boron trifluoride etherate
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The alkylation of carboxylic acids by an ethyl moiety of boron trifluoride etherate in the absence of ethyl alcohol from the reaction system is unexpected and novel. Both aromatic and aliphatic carboxylic acids were clearly alkylated affording good yields in short reaction times with the exception of nicotinic acid that necessitated an overnight reaction. It was noted that while ortho-substituted hydroxyl groups of carboxylic acids investigated were not affected by alkylation, those of meta- and para-substituted carboxylic acids were partially etherified. Furthermore, the alkylation reaction was found to be compatible with a range of functional groups such as halogens, amino and nitro groups except for the alkene function of undecylenic acid that underwent polymerisation with concomitant alkylation of its carboxylic acid function.
- Jumbam, Ndze D.,Maganga, Yamkela,Masamba, Wayiza,Mbunye, Nomthandazo I.,Mgoqi, Esethu,Mtwa, Sphumusa
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- Cu(II)-Catalyzed Olefin Migration and Prins Cyclization: Highly Diastereoselective Synthesis of Substituted Tetrahydropyrans
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Metal-ligand complexes of Cu(OTf)2 with an appropriate bisphosphine ligand have been shown to effectively catalyze the formation of substituted tetrahydropyrans via a sequential olefin migration and Prins-type cyclization. This methodology provides convenient access to a variety of functionalized tetrahydropyrans in excellent diastereoselectivities and good to excellent yields.
- Ghosh, Arun K.,Nicponski, Daniel R.
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- Cobalt(i)-catalysed CH-alkylation of terminal olefins, and beyond
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Cobalester, a natural nontoxic vitamin B12 derivative, was found to catalyse unusual olefinic sp2 C-H alkylation with diazo reagents as a carbene source instead of the expected cyclopropanation.
- Giedyk, Maciej,Goliszewska, Katarzyna,ó Proinsias, Keith,Gryko, Dorota
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- Vinylation of benzylic quaternary ammonium salts catalyzed by palladium
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The palladium-catalyzed vinylation of benzylic tributylammonium salts with a variety of olefins has been studied. A possible free radical mechanism is proposed.
- Yi,Zhuangyu,Hongwen
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- Synthesis of 1-(3-phenylpropyl)-4-(pyridinylmethoxy)-[1,2,4]triazolo[4,3-a] quinoxalines
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Starting from 2,3-dichloroquinoxaline, a synthetic strategy for the preparation of 1-(3-phenylpropyl)-4-(pyridinylmethoxy)[1,2,4]triazolo[4,3-a]quinoxalines is described.
- Summer, Dominik,Matuszczak, Barbara
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- Ring opening of cyclopropanecarboxylates using samarium(ii) diiodide (SmI2)-HMPA-THF system
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Cyclopropane ring of 2- and 2,3-substituted cyclopropanecarboxylates (1) was regioselectively cleaved using SmI2-HMPA-THF system in the presence of tert-BuOH to give 4- and 3,4-substituted butyrates (2) in moderate to good yields.
- Yamashita,Okuyama,Ohhara,Kawasaki,Ohta
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- Free radical reaction of ω-allylsulfonylalkyl substituted aromatic derivatives
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Benzenesulfonyl radical can be generated from sodium benzenesulfinate in aqueous acetic acid or formic acid. A benzenesulfonyl radical induced radical reaction of ω-allylsulfonylalkyl substituted aromatic and heteroaromatic derivatives is described. Alkyl
- Wang, Sheow-Fong,Chuang, Che-Ping,Lee, Wan-Hua
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- Ruthenium pincer complex-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides: Substrate keeps the catalyst active
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The electron pair of the heteroatom in heterocycles will coordinate with metal catalysts and decrease or even inhibit their catalytic activity consequently. In this work, a pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed. Benefitting from the pincer ligand, a variety of heterocycles, such as thiophenes, morpholine, unprotected indoles, pyrrole, pyridine, pyrimidine, furan, thiazole, pyrazole, benzothiadiazole, and triazole, are compatible here. This journal is
- Ai, Han-Jun,Wu, Xiao-Feng,Yuan, Yang
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p. 2481 - 2486
(2022/03/08)
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- Electrochemical Tandem Olefination and Hydrogenation Reaction with Ammonia
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An electrochemical Horner-Wadsworth-Emmons/hydrogenation tandem reaction was achieved using ammonia as electron and proton donors. The reaction could give two-carbon-elongated ester and nitrile from aldehyde or ketones directly. This reaction could proceed with a catalytic amount of base or even without a base. The ammonia provides both the electron and proton for this tandem reaction and enables the catalyst-free hydrogenation of an α,β-unsaturated HWE intermediate. More than 40 examples were reported, and functional groups, including heterocycles and hydroxyl, were tolerated.
- Zhang, Xiaofeng,Jiang, Runze,Cheng, Xu
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supporting information
p. 16016 - 16025
(2021/08/24)
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- Visible-light induced metal-free cascade Wittig/hydroalkylation reactions
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Cascade reactions are green and powerful transformations for building multiple carbon-carbon bonds in one step. Through a relay olefination and radical addition process, we were able to develop the cascade Wittig/hydroalkylation reactions induced by visible light. This metal-free radical approach features mild conditions, robustness, and excellent functionality compatibility. It allows access to saturated C3 homologation products directly from aldehydes or ketones. The synthetic utility of this method is demonstrated by a two-step synthesis ofindolizidine 209D.
- Miao, Pannan,Li, Ruining,Lin, Xianfeng,Rao, Liangming,Sun, Zhankui
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supporting information
p. 1638 - 1641
(2021/03/09)
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- Mechanical metal activation for Ni-catalyzed, Mn-mediated cross-electrophile coupling between aryl and alkyl bromides
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Liquid-assisted grinding has been successfully applied to eliminate the requirements of chemical activators and anhydrous solvents in nickel-catalyzed, manganese-mediated cross-electrophile coupling between aryl and alkyl bromides. In addition to the traditional reaction parameters, mechanical ones,e.g.the rotational speed of mill, the filling degree of jar and ball size, have been found to affect the catalytic efficiency remarkably, implying the involvement of the regeneration of nickel(0) species in the rate-determining steps. A combined evaluation of the reaction and mechanical parameters led to an optimal condition under which a variety ofn-alky aromatics with various functional groups could be readily obtained in good yields with a 1 mol% catalyst loading. The practical application of liquid-assisted grinding-enabled aryl/alkyl cross-electrophile coupling has been demonstrated in the gram-scale synthesis of 6-methoxytetralone.
- Wu, Sisi,Shi, Weijia,Zou, Gang
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supporting information
p. 11269 - 11274
(2021/07/02)
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- Copper catalyzed C(sp3)-H bond alkylation via photoinduced ligand-to-metal charge transfer
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Utilizing catalytic CuCl2 we report the functionalization of numerous feedstock chemicals via the coupling of unactivated C(sp3)-H bonds with electron-deficient olefins. The active cuprate catalyst undergoes Ligand-to-Metal Charge Transfer (LMCT) to enable the generation of a chlorine radical which acts as a powerful hydrogen atom transfer reagent capable of abstracting strong electron-rich C(sp3)-H bonds. Of note is that the chlorocuprate catalyst is an exceedingly mild oxidant (0.5 V vs SCE) and that a proposed protodemetalation mechanism offers a broad scope of electron-deficient olefins, offering high diastereoselectivity in the case of endocyclic alkenes. The coupling of chlorine radical generation with Cu reduction through LMCT enables the generation of a highly active HAT reagent in an operationally simple and atom economical protocol.
- Treacy, Sean M.,Rovis, Tomislav
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supporting information
p. 2729 - 2735
(2021/03/01)
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- Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds
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One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2 CR2) across a carbon-carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.
- Su, Yong-Liang,Liu, Geng-Xin,Liu, Jun-Wen,Tram, Linh,Qiu, Huang,Doyle, Michael P.
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supporting information
p. 13846 - 13855
(2020/09/21)
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- Computer-Assisted Discovery and Structural Optimization of a Novel Retinoid X Receptor Agonist Chemotype
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As universal heterodimer partners of many nuclear receptors, the retinoid X receptors (RXRs) constitute key transcription factors. They regulate cell proliferation, differentiation, inflammation, and metabolic homeostasis and have recently been proposed as potential drug targets for neurodegenerative and inflammatory diseases. Owing to the hydrophobic nature of RXR ligand binding sites, available synthetic RXR ligands are lipophilic, and their structural diversity is limited. Here, we disclose the computer-assisted discovery of a novel RXR agonist chemotype and its systematic optimization toward potent RXR modulators. We have developed a nanomolar RXR agonist with high selectivity among nuclear receptors and superior physicochemical properties compared to classical rexinoids that appears suitable for in vivo applications and as lead for future RXR-targeting medicinal chemistry.
- Heitel, Pascal,Gellrich, Leonie,Kalinowsky, Lena,Heering, Jan,Kaiser, Astrid,Ohrndorf, Julia,Proschak, Ewgenij,Merk, Daniel
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supporting information
p. 203 - 208
(2019/01/25)
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- Rhodium Porphyrin Catalyzed Regioselective Transfer Hydrogenolysis of C-C σ-Bonds in Cyclopropanes with iPrOH
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A new rhodium porphyrin catalyzed regioselective transfer hydrogenolysis of both activated and unactivated cyclopropanes employing iPrOH as the hydrogen source was discovered. The reaction mechanism for the C-C σ-bond activation of cyclopropanes was identified through an initial radical substitution with rhodium(II) metalloporphyrin radical to give a rhodium porphyrin alkyl, followed by hydrogenolysis with iPrOH to give the corresponding acyclic alkanes and regenerate rhodium(II) metalloporphyrin radical.
- Chen, Chen,Feng, Shiyu,Chan, Kin Shing
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p. 2582 - 2589
(2019/07/02)
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- Efficient synthesis of esters through oxone-catalyzed dehydrogenation of carboxylic acids and alcohols
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Since esters are important organic synthesis intermediates, an environmentally friendly oxone catalyzed-esterification of carboxylic acids with alcohols has been developed. A series of carboxylic acid esters are obtained in high yield. This strategy requires mild reaction conditions, providing an attractive alternative for the construction of valuable carbonyl esters. Electron-rich and electron-deficient groups are compatible with the standard conditions and a variety of substrates are demonstrated. Moreover, the reaction could easily be adapted to typical prodrugs, drugs and gram-scale synthesis.
- Hou, Fei,Wang, Xi-Cun,Quan, Zheng-Jun
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supporting information
p. 9472 - 9476
(2019/01/03)
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- Mechanochemical Activation of Zinc and Application to Negishi Cross-Coupling
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A form independent activation of zinc, concomitant generation of organozinc species and engagement in a Negishi cross-coupling reaction via mechanochemical methods is reported. The reported method exhibits a broad substrate scope for both C(sp3)–C(sp2) and C(sp2)–C(sp2) couplings and is tolerant to many important functional groups. The method may offer broad reaching opportunities for the in situ generation organometallic compounds from base metals and their concomitant engagement in synthetic reactions via mechanochemical methods.
- Cao, Qun,Howard, Joseph L.,Wheatley, Emilie,Browne, Duncan L.
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p. 11339 - 11343
(2018/08/28)
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- Graphene Oxide: An Efficient Acid Catalyst for the Construction of Esters from Acids and Alcohols
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Graphene oxide was found to be an efficient and reusable acid catalyst for the esterification reaction. A wide range of aliphatic and aromatic acids and alcohols were compatible with the standard conditions and afforded the corresponding products in good yields. The heterogeneous catalyst can be easily recovered and recycled in dichloro-ethane solvent with good catalytic activity.
- Chen, Zhengwang,Wen, Yuelu,Fu, Yejuan,Chen, Hai,Ye, Min,Luo, Guotian
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supporting information
p. 981 - 985
(2017/05/05)
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- Enantioselective copper catalysed intramolecular C-H insertion reactions of α-diazo-β-keto sulfones, α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones; the influence of the carbene substituent
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Enantioselectivities in C-H insertion reactions, employing the copper-bis(oxazoline)-NaBARF catalyst system, leading to cyclopentanones are highest with sulfonyl substituents on the carbene carbon, and furthermore, the impact is enhanced by increased steric demand on the sulfonyl substituent (up to 91%ee). Enantioselective intramolecular C-H insertion reactions of α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones are reported for the first time.
- Shiely, Amy E.,Slattery, Catherine N.,Ford, Alan,Eccles, Kevin S.,Lawrence, Simon E.,Maguire, Anita R.
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supporting information
p. 2609 - 2628
(2017/04/01)
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- Nickel-Catalyzed Reductive Cross-Coupling of Aryl Bromides with Alkyl Bromides: Et3N as the Terminal Reductant
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Reductive cross-coupling has emerged as a direct method for the construction of carbon-carbon bonds. Most cobalt-, nickel-, and palladium-catalyzed reductive cross-coupling reactions to date are limited to stoichiometric Mn(0) or Zn(0) as the reductant. One nickel-catalyzed cross-coupling paradigm using Et3N as the terminal reductant is reported. By using this photoredox catalysis and nickel catalysis approach, a direct Csp2-Csp3 reductive cross-coupling of aryl bromides with alkyl bromides is achieved under mild conditions without stoichiometric metal reductants.
- Duan, Zhengli,Li, Wu,Lei, Aiwen
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supporting information
p. 4012 - 4015
(2016/08/30)
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- Iodobenzene Dichloride in the Esterification and Amidation of Carboxylic Acids: In-Situ Synthesis of Ph3PCl2
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A novel, in-situ synthesis of dichlorotriphenylphosphorane (Ph3PCl2) is accomplished upon combining PPh3and the easily prepared hypervalent iodine reagent iodobenzene dichloride (PhICl2). The phosphorane is selectively generated in the presence of carboxylic acid or alcohol residues to rapidly produce acyl chlorides and alkyl chlorides in high yields. Addition of EtOH, PhOH, BnOH, Et2NH or CH2N2results in the direct synthesis of esters, amides and diazo ketones from carboxylic acids.
- Carle, Myriam S.,Shimokura, Grace K.,Murphy, Graham K.
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supporting information
p. 3930 - 3933
(2016/08/24)
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- Regioselective Alkoxycarbonylation of Allyl Phenyl Ethers Catalyzed by Pd/dppb under Syngas Conditions
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A simple and regioselective synthesis of phenoxy esters and phenylthio esters is reported. The products are obtained by selective alkoxycarbonylation catalyzed by Pd2(dba)3, 1,4-bis(diphenylphisphino)butane (dppb), and syngas (CO/H2) in chloroform/alcohol. This methodology affords bifunctional products in good yield with excellent n-selectivity and without the need to use additives.
- Amézquita-Valencia, Manuel,Alper, Howard
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p. 3860 - 3867
(2016/05/24)
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- Synthesis and Characterization of 5-Hydroxy-2-(2-phenylethyl)chromone (5-HPEC) and Its Analogues as Non-nitrogenous 5-HT2B Ligands
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The involvement of the neurotransmitter serotonin (5-HT) in numerous physiological functions is often attributed to the diversity of receptors with which it interacts. Ligands targeting serotonin receptor 2B (5-HT2B) have received renewed interest for their potential to help understand the role of 5-HT2B in migraines, drug abuse, neurodegenerative diseases, and irritable bowel syndrome. To date, most of the ligands targeting 5-HT2B have been nitrogen-containing compounds. The natural product 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 5) has been shown previously to act as a non-nitrogenous antagonist for the 5-HT2B receptor (pKi = 5.6). This report describes further progress on the study of the structure-activity relationship of both naturally occurring and synthetic compounds bearing the 2-(2-phenylethyl)chromone scaffold at the 5-HT2B receptor. The inhibitory activity of the newly synthesized compounds (at 10 μM) was tested against each of the 5-HT2 receptors. Following this assay, the binding affinity and antagonism of the most promising compounds were then evaluated at 5-HT2B. Among all the analogues, 5-hydroxy-2-(2-phenylpropyl)chromone (5-HPPC, 22h) emerged as a new lead compound, showing a 10-fold improvement in affinity (pKi = 6.6) over 5-HPEC with reasonable antagonist properties at 5-HT2B. Additionally, ligand docking studies have identified a putative binding pocket for 5-HPPC and have helped understand its improved affinity. (Figure Presented).
- Williams, Dwight A.,Zaidi, Saheem A.,Zhang, Yan
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p. 1859 - 1867
(2015/09/08)
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- 2-SUBSTITUTED-5-HYDROXY-4H-CHROMEN-4-ONES AS NOVEL LIGANDS FOR THE SEROTONIN RECEPTOR 2B (5-HT2B)
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A family of compounds which function as selective ligands for the serotonin receptor 2B (5-HT2B) is identified. Some of the compounds are synthetic non-natural ligands which have a relatively strong interaction with 5-HT2B compared to naturally occurring compounds (some of which are identified for the first time herein as ligands for 5-HT2B). Because the compounds, both naturally occurring and synthetically produced, function as ligands for 5-HT2B they will have application in, for example, the treatment and/or prevention of nervous system disorders such as Alzheimer's disease.
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Page/Page column 30; 31
(2015/09/22)
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- Borontribromide-mediated C-C bond formation in cyclic ketones: A transition metal free approach
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Borontribromide (BBr3) is a well-known demethylating agent. The current investigation was focused on a new application of borontribromide as a C-C bond forming agent in cyclic ketones. In this study, borontribromide mediated C-C bond formation reactions of tetralones, chromenone, thiochromenone and indanones were explored. A methoxy group containing ketones showed selective C-C bond formation reaction instead of demethylation of the methoxy group. MM2 steric energy calculations for the final products showed that the reaction favored the formation of exo- or endo-cyclic double bond containing products, depending upon their low MM2 steric energy in a specific frame structure, as observed in X-ray crystallography. A comprehensive crystallographic and pi-stacking analysis of product 10a demonstrated the formation of 10a as an enantiomeric mixture, and its centre of inversion was stabilized by a set of three unique pi-pi interactions.
- Ahmad, Imran,Pathak, Vinay,Vasudev, Prema G.,Maurya, Hardesh K.,Gupta, Atul
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p. 24619 - 24634
(2014/07/07)
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- Suzuki-miyaura cross-coupling reactions of unactivated alkyl halides catalyzed by a nickel pincer complex
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A nickel(II) pincer complex, [(MeN2N)Ni-Cl], was used to catalyze alkyl-alkyl and alkyl-aryl Suzuki-Miyaura coupling reactions of unactivated alkyl halides. The coupling of 9-alkyl-9-borabicyclo[3.3.1]nonane and 9-phenyl-9-borabicyclo[3.3.1]nonane reagents with alkyl halides was achieved in modest to good yields. The reactions tolerated a variety of useful functional groups including ester, ether, furan, thioether, acetal, and Boc groups. Georg Thieme Verlag Stuttgart, New York.
- Di Franco, Thomas,Boutin, Nicolas,Hu, Xile
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p. 2949 - 2958
(2013/11/06)
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- α-Diazo-β-ketonitriles: Uniquely reactive substrates for arene and alkene cyclopropanation
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An investigation of the intramolecular cyclopropanation reactions of α-diazo-β-ketonitriles is reported. These studies reveal that α-diazo-β-ketonitriles exhibit unique reactivity in their ability to undergo arene cyclopropanation reactions; other similar acceptor-acceptor- substituted diazo substrates instead produce mixtures of C-H insertion and dimerization products. α-Diazo-β-ketonitriles also undergo highly efficient intramolecular cyclopropanation of tri- and tetrasubstituted alkenes. In addition, the α-cyano-α-ketocyclopropane products are demonstrated to serve as substrates for SN2, SN2′, and aldehyde cycloaddition reactions.
- Nani, Roger R.,Reisman, Sarah E.
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supporting information
p. 7304 - 7311
(2013/06/27)
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- Design and synthesis of novel lactate dehydrogenase a inhibitors by fragment-based lead generation
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Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.
- Ward, Richard A.,Brassington, Claire,Breeze, Alexander L.,Caputo, Alessandro,Critchlow, Susan,Davies, Gareth,Goodwin, Louise,Hassall, Giles,Greenwood, Ryan,Holdgate, Geoffrey A.,Mrosek, Michael,Norman, Richard A.,Pearson, Stuart,Tart, Jonathan,Tucker, Julie A.,Vogtherr, Martin,Whittaker, David,Wingfield, Jonathan,Winter, Jon,Hudson, Kevin
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scheme or table
p. 3285 - 3306
(2012/06/01)
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- Site-specific hydrogen exchange and hydrogen transfer processes preceding the fragmentation of long-lived radical cations of ethyl dihydrocinnamate and related arylalkanoates
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An electron ionisation study on the fragmentation of metastable molecular radical cations of ethyl 3-phenylpropanoate (ethyl dihydrocinnamate) and related arylalkanoic acid esters was performed by mass-analysed ion kinetic energy (MIKE) spectrometry. Six deuterium-labelled isotopomers of ethyl dihydrocinnamate were synthesised and studied by MIKE spectrometry. The fragmentation leading to ions C7H7O+ (m/z 107) involving migration of the alkoxycarbonyl group was also observed in the 70-eV mass spectra of related alkyl dihydrocinnamates, but it was found to be a high-energy process that does not compete at low energies in metastable molecular ions. Instead, the metastable ions of ethyl dihydrocinnamate undergo competing losses of carbon monoxide, ethanol and the combined loss of these neutral fragments, giving ionised styrene, C8H8 ?+ (m/z 104). A highly specific H/D interchange involving the four hydrogen atoms at the benzylic α- and ortho-positions was found to precede the losses of ethanol and [ethanol + CO]. This represents another striking case of complete 4H - scrambling that enables the molecular ion to fully equilibrate the interchanging hydrogen atoms prior to fragmentation. A mechanism rationalising these observations and extending previously suggested mechanisms is proposed involving a series of distonic ions and the intermediacy of an ion/neutral complex. The metastable ions of the related esters exhibit in part similar fragmentation behaviour, but the McLafferty reaction turns out to be more favourable with higher alkyl dihydrocinnamates. For example, n-propyl 3-phenylpropanoate and isopropyl 3-phenylpropanoate react through highly distinct fragmentation channels.
- Amick, Aaron W.,Hoegg, Edward,Harrison, Sean,Houston, Katelyn R.,Hark, Richard R.,Reingold, I. David,Barth, Dieter,Letzel, Matthias C.,Kuck, Dietmar
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experimental part
p. 206 - 215
(2012/07/01)
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- Replacing conventional carbon nucleophiles with electrophiles: Nickel-catalyzed reductive alkylation of aryl bromides and chlorides
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A general method is presented for the synthesis of alkylated arenes by the chemoselective combination of two electrophilic carbons. Under the optimized conditions, a variety of aryl and vinyl bromides are reductively coupled with alkyl bromides in high yields. Under similar conditions, activated aryl chlorides can also be coupled with bromoalkanes. The protocols are highly functional-group tolerant (-OH, -NHTs, -OAc, -OTs, -OTf, -COMe, -NHBoc, -NHCbz, -CN, -SO2Me), and the reactions are assembled on the benchtop with no special precautions to exclude air or moisture. The reaction displays different chemoselectivity than conventional cross-coupling reactions, such as the Suzuki-Miyaura, Stille, and Hiyama-Denmark reactions. Substrates bearing both an electrophilic and nucleophilic carbon result in selective coupling at the electrophilic carbon (R-X) and no reaction at the nucleophilic carbon (R-[M]) for organoboron (-Bpin), organotin (-SnMe3), and organosilicon (-SiMe2OH) containing organic halides (X-R-[M]). A Hammett study showed a linear correlation of σ and σ(-) parameters with the relative rate of reaction of substituted aryl bromides with bromoalkanes. The small ρ values for these correlations (1.2-1.7) indicate that oxidative addition of the bromoarene is not the turnover-frequency determining step. The rate of reaction has a positive dependence on the concentration of alkyl bromide and catalyst, no dependence upon the amount of zinc (reducing agent), and an inverse dependence upon aryl halide concentration. These results and studies with an organic reductant (TDAE) argue against the intermediacy of organozinc reagents.
- Everson, Daniel A.,Jones, Brittany A.,Weix, Daniel J.
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supporting information; experimental part
p. 6146 - 6159
(2012/05/07)
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- Reactions of CF3-substituted boranes with α-diazocarbonyl compounds
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Boranes substituted with a CF3-group can be generated from methyl boronic esters RB(OMe)2 and Me3SiCF3/KF followed by treatment with Me3SiCl. These boranes are stable only in coordinating solvents, and due to the increased Lewis acidity of boron, react rapidly with α-diazocarbonyl compounds to give the products of transfer of the organic group from boron. Alkyl, aryl, vinyl, and alkynyl boronic esters can be used in this reaction.
- Elkin, Pavel K.,Levin, Vitalij V.,Dilman, Alexander D.,Struchkova, Marina I.,Belyakov, Pavel A.,Arkhipov, Dmitry E.,Korlyukov, Alexander A.,Tartakovsky, Vladimir A.
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supporting information; experimental part
p. 5259 - 5263
(2011/10/31)
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- Nickel-catalyzed reductive cross-coupling of aryl halides with alkyl halides
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(Chemical Equation Presented) The direct reductive cross-coupling of alkyl halides with aryl halides is described. The transformation is efficient (equimolar amounts of the starting materials are used), generally high-yielding (all but one between 55 and 88% yield), highly functional-group-tolerant [OH, NHBoc, NHCbz, Bpin, C(O)Me, CO2Et, and CN are all tolerated], and easy to perform (uses only benchtop-stable reagents, tolerates small amounts of water and oxygen, changes color when complete, and uses filtration workup). The reaction appears to avoid the formation of intermediate organomanganese species, and a synergistic effect was found when a mixture of two ligands was employed.
- Everson, Daniel A.,Shrestha, Ruja,Weix, Daniel J.
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supporting information; experimental part
p. 920 - 921
(2010/03/31)
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- Functional group tolerant Kumada-Corriu-Tamao coupling of nonactivated alkyl halides with aryl and heteroaryl nucleophiles: Catalysis by a nickel pincer complex permits the coupling of functionalized Grignard reagents
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A nickel(II) pincer complex [(MeNN2)NiCl] (1) catalyzes Kumada-Corriu-Tamao cross coupling of nonactivated alkyl halides with aryl and heteroaryl Grignard reagents. The coupling of octyl bromide with phenylmagnesium chloride was used as a test reaction. Using 3 mol % of 1 as the precatalyst and THF as the solvent, and in the presence of a catalytic amount of TMEDA, the coupling product was obtained in a high yield. The reaction conditions could be applied to cross coupling of other primary and secondary alkyl bromides and iodides. The coupling is tolerant to a wide range of functional groups. Therefore, alkyl halides containing ester, amide, ether, thioether, alcohol, pyrrole, indole, furan, nitrile, conjugated enone, and aryl halide moieties were coupled to give high isolated yields of products in which these units stay intact. For the coupling of ester-containing substrates, O-TMEDA is a better additive than TMEDA. The reaction protocol proves to be efficient for the coupling of Knochel-type functionalized Grignard reagents. Thus aryl Grignard reagents containing electron-deficient and/or sensitive ester, nitrile, amide, and CF3 substituents could be successfully coupled to nonactivated and functionalized alkyl iodides. The catalysis is also efficient for the coupling of alkyl iodides with functionalized heteroaryl Grignard reagents, giving rise to pyridine-, thiophene-, pyrazole-, furan-containing molecules with additional functionalities. Concerning the mechanism of the catalysis, [(MeNN2)Ni-(hetero)Ar] was identified as an intermediate, and the activation of alkyl halides was found to take place through a radical-rebound process.
- Vechorkin, Oleg,Proust, Valerie,Hu, Xile
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supporting information; experimental part
p. 9756 - 9766
(2011/03/19)
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- NOVEL 2-AMINOPYRIMIDINONE DERIVATIVES AND THEIR USE
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This invention relates to novel compounds having the structural formula I below: (I) and to their pharmaceutically acceptable salts, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheim
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Page/Page column 127
(2008/06/13)
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- α-haloenol acetates: Versatile reactants for oxetan-2-one, azetidin-2-one and isoxazolidin-5-one synthesis
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New ketene equivalents, namely α-haloenol acetates, are investigated as both nucleophilic and electrophilic reactants in a tandem aldol-lactonization reaction. Diethylaluminum ethoxide proves to be an efficient promoter for the aldol reaction with a wide
- Bejot, Romain,Anjaiah, Siddam,Falck,Mioskowski, Charles
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p. 101 - 107
(2007/10/03)
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- Cobalt(diamine)-catalyzed cross-coupling reaction of alkyl halides with arylmagnesium reagents: Stereoselective constructions of arylated asymmetric carbons and application to total synthesis of AH13205
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A cobalt-diamine complex catalyzes the cross-coupling reactions of primary and secondary alkyl halides with aryl Grignard reagents. It is confirmed that oxidative addition of alkyl halide to cobalt proceeds via a radical process. Optically pure Ueno-Stork halo acetals undergo diastereoselective cross-coupling reactions, the products of which are transformed into optically active THF derivatives. A sequential radical cyclization/arylation reaction under cobalt catalysis provides extremely short access to a synthetic prostaglandin AH13205.
- Ohmiya, Hirohisa,Yorimitsu, Hideki,Oshima, Koichiro
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p. 1886 - 1889
(2007/10/03)
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- Mono- and bis-thiazolium salts have potent antimalarial activity
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Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC50 values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED50 ≤ 0.22 mg/kg), and low toxicity in mice infected by Plasmodium vinckei.
- Hamzé, Abdallah,Rubi, Eric,Arnal, Pascal,Boisbrun, Michel,Carcel, Carole,Salom-Roig, Xavier,Maynadier, Marjorie,Wein, Sharon,Vial, Henri,Calas, Michèle
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p. 3639 - 3643
(2007/10/03)
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- An Expedient and Practical Method for the Synthesis of A Diverse Series of Cyclopropane α-Amino Acids and Amines
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A practical synthesis for the preparation of a diverse series of cyclopropane α-amino acids is described. Nitrocyclopropane carboxylates can be readily prepared through treatment of α-nitroesters and iodobenzene diacetate or α-nitro-α-diazoesters with a R
- Wurz, Ryan P.,Charette, Andre B.
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p. 1262 - 1269
(2007/10/03)
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- The first example of alpha-thiomagnesiums generated from dithioacetal monoxides with Grignard reagent; their properties and some synthetic applications.
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Dithioacetal monoxides were synthesized from aldehydes and cyclohexanone, and reaction of the dithioacetal monoxides with Grignard reagents was investigated. The dithioacetal monoxide synthesized from alkylaldehyde and 4-chlorobenzenethiol reacted with i-
- Satoh, Tsuyoshi,Akita, Kiyoshi
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p. 181 - 186
(2007/10/03)
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- Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
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This invention provides novel radiopharmaceuticals that are radiolabeled cyclic compounds containing carbocyclic or heterocyclic ring systems which act as antagonists of the platelet glycoprotein IIb/IIIa complex; to methods of using said radiopharmaceuticals as imaging agents for the diagnosis of arterial and venous thrombi; to novel reagents for the preparation of said radiopharmaceuticals; and to kits comprising said reagents.
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- Stereoselective cyclopropanation and ring-opening: Application to the synthesis of pure (S)-2-methyl-3-arylpropylamines
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Stereoselective catalytic and stoichiometric cyclopropanation of styrenes 3a,3b was studied; the stoichiometric method turned out superior in the terms of enantioselectivity. The intermediate carboxymethyl cyclopropane 11a,11b, obtained on reduction of carbethoxy derivatives 4a,4b, were hydrogenolyzed to (S)-1,3-substituted-2-methylpropanes 15a,15b. The highest conversion and regioselectivity was obtained with 3% Pd/C as the catalyst. The final steps, chlorination of alcohol 15a into 19a, and alkylation of cyclic sec amines were already demonstrated by us (ref. 2c) to afford (S)-(- )-2-(4-tert-butylphenyl)-1-cis-2,6-dimethylmorpholyl)propane (S-1a) and (S)- (-)-2-(4-tert-butylphenyl)-1-piperidylpropane (S-2a), the (S)-enantiomers of two systemic fungicides presently commercialized as racemates, without any lost of enantiomeric purity.
- Roje, Marin,Vinkovic, Vladimir,Sunjic, Vitomir,Solladie-Cavallo, Arlette,Diep-Vohuule, Anh,Isarno, Thomas
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p. 9123 - 9128
(2007/10/03)
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- Ring opening of cyclopropanemonocarboxylates and 1,1- cyclopropanedicarboxylates using samarium(II) diiodide (SmI2)-HMPA-THF system
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The cyclopropane ring in 2-substituted 1,1-cyclopropanedicarboxylates was regioselectively opened by using samarium(II) diiodide (Sml2) in a hexamethylphosphoric triamide (HMPA)-tetrahydrofuran (THF) (1:10) system under mild and neutral conditions to give (2-substituted ethyl)malonates in moderate to good yields. The cyclopropane ring in 2-substituted cyclopropanecarboxylates or 2-substituted 3- (trimethylsilyl)cyclopropanecarboxylates was similarly cleaved regioselectively by using Sml2 in a HMPA-THF (1:1) system to give 4- arylbutyrates or 4-aryl-3-(trimethylsilyl)butyrates in 16-89% yields. The reaction mechanism of these ring-opening reactions is discussed.
- Yamashita,Okuyama,Ohhara,Kawasaki,Sakai,Nakata,Kawabe,Kusumoto,Ohta
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p. 2075 - 2081
(2007/10/03)
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