- Practical and Selective sp3 C?H Bond Chlorination via Aminium Radicals
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The introduction of chlorine atoms into organic molecules is fundamental to the manufacture of industrial chemicals, the elaboration of advanced synthetic intermediates and also the fine-tuning of physicochemical and biological properties of drugs, agrochemicals and polymers. We report here a general and practical photochemical strategy enabling the site-selective chlorination of sp3 C?H bonds. This process exploits the ability of protonated N-chloroamines to serve as aminium radical precursors and also radical chlorinating agents. Upon photochemical initiation, an efficient radical-chain propagation is established allowing the functionalization of a broad range of substrates due to the large number of compatible functionalities. The ability to synergistically maximize both polar and steric effects in the H-atom transfer transition state through appropriate selection of the aminium radical has provided the highest known selectivity in radical sp3 C?H chlorination.
- McMillan, Alastair J.,Sieńkowska, Martyna,Di Lorenzo, Piero,Gransbury, Gemma K.,Chilton, Nicholas F.,Salamone, Michela,Ruffoni, Alessandro,Bietti, Massimo,Leonori, Daniele
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supporting information
p. 7132 - 7139
(2021/03/03)
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- Site-Selective Aliphatic C-H Chlorination Using N-Chloroamides Enables a Synthesis of Chlorolissoclimide
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Methods for the practical, intermolecular functionalization of aliphatic C-H bonds remain a paramount goal of organic synthesis. Free radical alkane chlorination is an important industrial process for the production of small molecule chloroalkanes from simple hydrocarbons, yet applications to fine chemical synthesis are rare. Herein, we report a site-selective chlorination of aliphatic C-H bonds using readily available N-chloroamides and apply this transformation to a synthesis of chlorolissoclimide, a potently cytotoxic labdane diterpenoid. These reactions deliver alkyl chlorides in useful chemical yields with substrate as the limiting reagent. Notably, this approach tolerates substrate unsaturation that normally poses major challenges in chemoselective, aliphatic C-H functionalization. The sterically and electronically dictated site selectivities of the C-H chlorination are among the most selective alkane functionalizations known, providing a unique tool for chemical synthesis. The short synthesis of chlorolissoclimide features a high yielding, gram-scale radical C-H chlorination of sclareolide and a three-step/two-pot process for the introduction of the β-hydroxysuccinimide that is salient to all the lissoclimides and haterumaimides. Preliminary assays indicate that chlorolissoclimide and analogues are moderately active against aggressive melanoma and prostate cancer cell lines.
- Quinn, Ryan K.,K?nst, Zef A.,Michalak, Sharon E.,Schmidt, Yvonne,Szklarski, Anne R.,Flores, Alex R.,Nam, Sangkil,Horne, David A.,Vanderwal, Christopher D.,Alexanian, Erik J.
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p. 696 - 702
(2016/02/03)
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- Rhodium-catalyzed oxygenative addition to terminal alkynes for the synthesis of esters, amides, and carboxylic acids
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A gem of a couple: The title reaction of terminal alkynes with O and Nnucleophiles proceeds in the presence of [Rh(cod)Cl}2], P(4-FC 6H4)3, and 4-picoline N-oxide. Alcohols, amines, and water add to the terminal alkynes to give esters, amides, and carboxylic acids, respectively. The reaction involves formation of a rhodium vinylidene, oxidation to a ketene by oxygen transfer, and nucleophilic addition.
- Kim, Insu,Lee, Chulbom
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supporting information
p. 10023 - 10026
(2013/10/01)
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- Iridium-catalyzed oxidative methyl esterification of primary alcohols and diols with methanol
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Oxidative methyl esterification of primary alcohols and diols with methanol was successfully achieved, using acetone as a hydrogen acceptor, under the influence of an iridium complex combined with 2-(methylamino)ethanol (MAE) as catalyst.
- Yamamoto, Nobuyuki,Obora, Yasushi,Ishii, Yasutaka
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experimental part
p. 2937 - 2941
(2011/05/30)
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- Palladium(II)-catalyzed oxidation of aldehydes and ketones. 1. Carbonylation of ketones with carbon monoxide catalyzed by palladium(II) chloride in methanol
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Unsubstituted or alkyl-substituted cyclic ketones react with PdCl2 in methanol under a CO atmosphere to give mainly acyclic diesters along with some acyclic chloro-substituted monoesters. The monosubstituted cyclic ketones, 2-hydroxy- and 2-methoxycyclohexanone, do not give ring cleavage but rather produce 2-(carbomethoxy)cyclohex-2-en-1-one. 13CO labeling experiments indicate one CO is inserted in forming the diester product so the second ester group must arise from the original ketone group. Two mechanisms are possible for the diester reaction. One involves initial Pd(II)-CO2CH3 insertion across the double bond of the enol form of the ketone while the second involves initial addition of Pd(II)-OCH3 followed by CO insertion into the new Pd(II) carbon bond formed. Pd(II) elimination and acid-catalyzed ring cleavage produce the second methyl ester group in both routes. The chloro-substituted monoester is formed by initial Pd(II)-Cl insertion across the double bond followed by the acid-catalyzed ring cleavage. The 2-(carbomethoxy)cyclohex-2-en-1-one must result from elimination of water or methanol from the α-ketoester product formed by the initial methoxycarbonylation of the enol form of the ketone. As expected, the acyclic ketone 2-decanone, formed methyl acetate and a mixture of methyl nonanoate and products.
- Hamed,El-Qisairi,Henry
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p. 180 - 185
(2007/10/03)
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- Palladium(II) catalyzed carbonylation of ketones
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Cyclic ketones react with PdCl2 in methanol under a CO atmosphere to give mainly diesters by a ring cleavage reaction along with some chloro- substituted monoester, 13CO labeling experiments indicate the major product is formed by a mechanism involving Pd(II)-CO2CH3 insertion across the double bond of the enol form of the ketone. Pd(II) elimination and acid- catalyzed ring cleavage form a second methyl ester group. (C) 2000 Elsevier Science Ltd.
- Hamed, Othman,El-Qisairi, Arab,Henry, Patrick M.
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p. 3021 - 3024
(2007/10/03)
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- Decyclization of chlorocyclohexanone hydroperoxides under the action of ferrous salts
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The decomposition of 2-chloro-, 2,2-dichloro-, and 2,6-dichloro-substituted cyclohexanone hydroperoxides on treatment with ferrous chloride and sulfate to give chloro-substituted aliphatic acids was investigated. A method for the synthesis of 2,6,6-trichlorohexanoic and 2,6,7,11-tetrachlorododecane-1,12-dioic acids was elaborated.
- Starostin,Gushchin,Ignatenko,Aleksandrov,Nikishin
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p. 133 - 136
(2007/10/03)
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- MECHANISMS OF FREE-RADICAL REACTIONS. XXIV. QUANTITATIVE DESCRIPTION OF THE POLAR EFFECTS OF SUBSTITUENTS ON THE KINETICS OF THE FREE-RADICAL CHLORINATION OF ALIPHATIC COMPOUNDS BY N-CHLOROPIPERIDINE
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The free-radical chlorination of 1-substituted alkanes with electron-withdrawing substituents by N-chloropiperidine in trifluoroacetic acid was studied by the method of competing reactions, and the relative rate constants were obtained for all positions of the substrates.The data on the position selectivity can be described satisfactorily by means of an electrostatic model of the polar effect of the substituent, calculated according to the Kirkwood-Westheimer equation.The obtained characteristics of the electrostatic effect can be successfully applied to calculation of the substrate selectivity and the intermolecular relative rate constants for all the positions, beginning with the third.The Taft equation is unsuitable for description of the effect of substituents on the reaction rate.
- Dneprovskii, A. S.,Mil'tsov, S. A.,Arbuzov, P. V.
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p. 1826 - 1835
(2007/10/02)
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- Chlorination of Esters. I. Chlorination of Methyl Esters of Propanoic, Butanoic, Pentanoic and Hexanoic Acids. The Isomer Distribution of Monochloro Esters Formed
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The chlorination of methyl ester with chlorine in the liquid and vapor phase and with sulfuryl chloride in the liquid phase has been investigated.The chlorination yields all possible monochloro esters isomers with the 2-chloro isomer in the smallest amount.The products were identified by NMR and mass spectrometry.The isomer distribution and mass spectra of products were studied in detail.
- Korhonen, Ilpo O.O.,Korvola, Jorma N.J.
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p. 139 - 142
(2007/10/02)
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- Process for the production of even series ω-amino acids
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The invention relates to a process for the production of even-series ω-amino acids of the general empirical formula NH2 (CH2 CH2)n CH2 COOH /I/, where N = 1 or 2. The process of the invention comprises telomerizing ethylene with methyl esters of halogen acetic acids of the general empirical formula Xm CH3-m COOCH3 /II/, where X = Br and m = 1 or X = Cl and m = 2 or 3, at a temperature of from 100 to 145° C. and under ethylene pressure of from 25 to 40 gage atmospheres in the presence of initiators of free-radical reactions. The telomerization procedure gives telomers of the general empirical formula CH3 OOCCH3-m Xm-1 (CH2 CH2)n X /III/, where X, n and m are as in formulas /I/ and /II/. In case X = Br and m = 1, the telomers described by formula /III/ are subjected to ammonolysis with ammonia at a temperature of about 100° C to yield ammonolysis products; whereas, in case X = Cl and m = 2 or 3, the telomers described by formula /III/ are reduced to telomers of the same general formula, where X = Cl and m = 1, and the latter are subjected to ammonolysis with ammonia at a temperature from 135° to 140° C to yield ammonolysis products. Then the ammonolysis products are hydrolyzed with hydrochloric acid at a temperature of from 80° to 90° C., and the desired product is recovered from the resultant hydrolyzate by use of a styrene-divinylbenzene sulfocationite resin in the H form. The foregoing process uses widely available industrial raw materials, proceeds by a straightforward route and requires simple equipment; it is further characterized by high yields at all steps; all unreacted feedstocks can be completely recycled; and no non-utilizable wastes are produced.
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