- A visible-light mediated three-component radical process using dithiocarbamate anion catalysis
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We report a photoinduced three-component radical process, which couples readily available alkyl chlorides, maleimides, and heteroaromatic fragments to rapidly generate complex chiral products with high diastereocontrol. This method generates radicals via an SN2-based photochemical catalytic mechanism, which is not reliant on the redox properties of the precursors. It therefore grants access to open-shell intermediates from substrates that would be incompatible with or inert to classical radical-generating strategies. The redox-neutral conditions of this process make it tolerant of redox-sensitive substrates and allow the installation of multiple biologically relevant heterocycles within the cascade products.
- Cuadros, Sara,Horwitz, Matthew A.,Schweitzer-Chaput, Bertrand,Melchiorre, Paolo
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- Investigation of Straightforward, Photoinduced Alkylations of Electron-Rich Heterocompounds with Electron-Deficient Alkyl Bromides in the Sole Presence of 2,6-Lutidine
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Alkylations of simple electron-rich heterocompounds deliver valuable target structures in bioorganic and medicinal chemistry. Herein, we present a straightforward and photosensitizer free approach for the photoinduced C–C coupling of electron-rich unsaturated heterocompounds with alkyl bromides using 405 nm and 365 nm irradiation. Comprehensive mechanistic studies indicate the involvement of 2,6-lutidine in the formation of a non-covalently bound intermediate to which the function of a photosensitizer is attributed. UV/Vis spectra reveal the formation of a bathochromic shifted band when the electron-deficient alkyl bromide is mixed with the structural motif of 2,6-substituted pyridine. Upon photochemical excitation of this band, we find the initiation of the C–C bond-forming reaction. Using this approach highly versatile alkylation products, e.g. α-substituted ketones and 2-substituted furan, thiophene, and pyrrole derivatives, are obtained in high selectivity. Furthermore, this synthetic methodology can be applied to access substituted indoles, which cannot be obtained by other transformations.
- Fuks, Elina,Huber, Laura,Schinkel, Thea,Trapp, Oliver
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supporting information
p. 6192 - 6198
(2020/08/19)
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- Visible-light induced disproportionation of pyrrole derivatives for photocatalyst-free aryl halides reduction
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As a green synthetic approach, visible light-driven photosynthesis is highly desirable in arylation of inert alkyl halides, as they are important precursors in the total synthesis of natural products and pharmaceuticals. However, the high bond dissociation energy of aryl halides is typically out of the range of a single visible-light photon. Here, we propose an essential initiation and subsequent electron-transfer step process for visible light-driven aryl halide reduction, and identify the key pyrrole radical anion intermediate, that acts as the strong reduction species. We propose a photoinduced disproportionation (PDP) approach without the addition of any photocatalysts or additives to afford radical anions of pyrrole derivatives, which have enough reduction power to transfer an electron to aryl halide, giving rise to the corresponding aryl radical to afford the desired C-H arylated heterocyclic product. Once generated, the heterocyclic product can undergo the same photoinduced disproportionation (PDP) process to activate aryl halides, thereby promoting the reaction rate. This unprecedented initiation step, which was carried out in the absence of photocatalysts and additives under ambient conditions, can also be used for coupling a wide range of (hetero)aryl halides and pyrrole derivatives, as well as the synthesis of drug intermediates and biorelevant compounds.
- Li, Zhi-Jun,Li, Shuya,Hofman, Elan,Hunter Davis, Andrew,Leem, Gyu,Zheng, Weiwei
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supporting information
p. 1911 - 1918
(2020/04/07)
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- Photochemical generation of radicals from alkyl electrophiles using a nucleophilic organic catalyst
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Chemists extensively use free radical reactivity for applications in organic synthesis, materials science, and life science. Traditionally, generating radicals requires strategies that exploit the bond dissociation energy or the redox properties of the precursors. Here, we disclose a photochemical catalytic approach that harnesses different physical properties of the substrate to form carbon radicals. We use a nucleophilic dithiocarbamate anion catalyst, adorned with a well-tailored chromophoric unit, to activate alkyl electrophiles via an SN2 pathway. The resulting photon-absorbing intermediate affords radicals upon homolytic cleavage induced by visible light. This catalytic SN2-based strategy, which exploits a fundamental mechanistic process of ionic chemistry, grants access to open-shell intermediates from a variety of substrates that would be incompatible with or inert to classical radical-generating strategies. We also describe how the method’s mild reaction conditions and high functional group tolerance could be advantageous for developing C–C bond-forming reactions, for streamlining the preparation of a marketed drug, for the late-stage elaboration of biorelevant compounds and for enantioselective radical catalysis.
- Schweitzer-Chaput, Bertrand,Horwitz, Matthew A.,de Pedro Beato, Eduardo,Melchiorre, Paolo
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p. 129 - 135
(2018/12/13)
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- Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals: A Fast and Scalable Protocol for Trifluoromethylation
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We report an operationally simple and rapid continuous flow radical C?C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H2O2) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeIIcatalyst. For electron-rich aromatic and heteroaromatic substrates, C?C bond formation proceeds satisfactorily with electrophilic radicals including.CF3,.C4F9,.CH2CN, and.CH2CO2Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3I and C4F9I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.
- Monteiro, Júlia L.,Carneiro, Paula F.,Elsner, Petteri,Roberge, Dominique M.,Wuts, Peter G. M.,Kurjan, Katherine C.,Gutmann, Bernhard,Kappe, C. Oliver
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supporting information
p. 176 - 186
(2017/01/09)
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- Rhodium(II) catalyzed intramolecular insertion of carbenoids derived from 2-pyrrolyl and 3-indolyl α-diazo-β-ketoesters and α-diazoketones
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α-Diazo-β-ketoesters and α-diazoketones derived from 2-pyrrolylacetic, 2-pyrrolylpropionic, 3-indolylacetic and 3-indolylpropionic acids afforded carbenoid derived cyclization products on treatment with catalytic rhodium(II) acetate.
- Cuevas-Ya?ez, Erick,Muchowski, Joseph M.,Cruz-Almanza, Raymundo
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p. 1505 - 1511
(2007/10/03)
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- Simple synthetic approach to arylacetic NSAIAs via TosMIC procedure
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Preparation of 1-methylpyrrole-2-acetonitrile, 1-methyl-5-(4-methylbenzoyl) pyrrole-2-acetonitrile and 2-(6-methoxy-2-naphthyl)propionitrile by treatment of 1-methylpyrrole-2-carboxaldehyde, 1-methyl-5-(4-methylbenzoyl)pyrrole-2-carboxaldehyde and, respectively, 6-methoxy-2-acetylnaphthalene with tosylmethylisocyanide (TosMIC) is described. This one-step synthetic procedure is very useful to obtain the nitrile precursors of tolmetin and naproxen, two clinically important non-steroidal antiinflammatory agents (NSAIAs).
- Di Santo,Costi,Massa,Artico
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p. 787 - 793
(2007/10/02)
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- SELECTIVITY IN THE REACTIONS OF ELECTRON-RICH PENTATOMIC HETEROAROMATIC COMPOUNDS WITH CARBON-CENTRED FREE RADICALS
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The relative reactives of pyrrole, N-methylpyrrole, furan and thiophene with electrophilic carbon-centred free radicals .CH2CN, .CH2CO2Et and .CH(CO2Et)2 have been determined.The results have indicated a relatively low intermolecular selectivity, with a reactivity order N-methylpyrrole > pyrrole ca. furan > thiophene.The intramolecular selectivities (relative reactivity of the α and β positions) of these reactions, as well as that of indole with .CH2CN and .CH2CO2Et have also been determined.The α/β ratio is very high (> 50) with N-methylpyrrole, pyrrole, furan and thiophene, but becomes lower (between 6 and 12) with indole.These results can be rationalized by suggesting that in the homolytic substitutions of electrophilic carbon radicals with electron-rich pentatomic heteroaromatics, the SOMO of the radical probably interacts with both the HOMO and the LUMO of the substrate, and not only with the HOMO as expected.
- Baciocchi, Enrico,Manna, Livia,Muraglia, Ester
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p. 249 - 252
(2007/10/02)
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- Synthesis of some new pyrrolic derivatives
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The synthesis of some new disubstituted pyrrolic derivatives bearing an imine 2a-2d or amine 3b function in α-positions of the nitrogen atom is reported.Some oxazoles 5b, 7 oxadiazoles 12a-12c, oxadiazolines 14a-14b heterocycles substituted by a pyrrolic moiety have been also prepared.The N-substituted 2,5-diformylpyrroles 1b and 1c and the 2,5-bispyrrole 2d are mainly in the s-trans conformation, established by dipole moment measurements and 1H or 2D NMR spectroscopy. Key Words: pyrrole / conformation
- Oussaid, B.,Hubert, C.,Fayet, J. P.,Garrigues, B.
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- Preparation of Pyrroles from Pyroglutamic Acid Derivatives
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Heating of the vinylogs of N-acyl N,O-acetals 3 in acetic acid, preferably in the presence of acetic anhydride and pyridine, yields pyrroles 4 in good yields.
- Rigo, Benoit,Fasseur, Dominique,Leduc, Catherine,Couturier, Daniel
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p. 1769 - 1776
(2007/10/02)
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- SYNTHESIS OF N-UNSUBSTITUTED α-ALKYLATED PYRROL-2-ACETONITRILES
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Nucleophilic addition of alkyllithium compounds to in situ generated 6-dimethylamino-1-azafulvene produced the α-alkylated pyrrole Mannich bases (3).Reaction of the p-toluenesulfonic acid salt of such bases with excess sodium cyanide in wet acetonitrile, at reflux temperature, provided the corresponding α-alkylpyrrol-2-acetonitriles (5) via the putative 6-alkyl-1-azafulvenes.
- Muchowski, Joseph M.,Scheller, Marcus E.
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p. 863 - 876
(2007/10/02)
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- Preparation of 1-methylpyrrole-2-acetonitrile
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1-Methylpyrrole-2-acetonitrile is prepared by the reduction of α-imino-1-loweralkylpyrrole-2-acetonitrile using hydrogen sulfide as the reducing agent.
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- Preparation of pyrrole-2-acetic acid derivatives
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Catalytic dehydrogenation of Δ-2,α-pyrrolidenemalonates and Δ-2,α-pyrrolidenemalononitriles yields pyrrole-2-acetates and pyrrole-2-acetonitriles, respectively. Subsequent hydrolysis of the latter affords pyrrole-2-acetic acids.
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