- Catalytic SNAr Hydroxylation and Alkoxylation of Aryl Fluorides
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Nucleophilic aromatic substitution (SNAr) is a powerful strategy for incorporating a heteroatom into an aromatic ring by displacement of a leaving group with a nucleophile, but this method is limited to electron-deficient arenes. We have now established a reliable method for accessing phenols and phenyl alkyl ethers via catalytic SNAr reactions. The method is applicable to a broad array of electron-rich and neutral aryl fluorides, which are inert under classical SNAr conditions. Although the mechanism of SNAr reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addition followed by elimination), experimental data that support this hypothesis is still under exploration. Mechanistic studies and DFT calculations suggest either a stepwise or stepwise-like energy profile. Notably, we isolated a rhodium η5-cyclohexadienyl complex intermediate with an sp3-hybridized carbon bearing both a nucleophile and a leaving group.
- Kang, Qi-Kai,Li, Ke,Li, Yuntong,Lin, Yunzhi,Shi, Hang,Xu, Lun
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supporting information
p. 20391 - 20399
(2021/08/13)
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- N-Phenyl-1,2,3,4-tetrahydroisoquinoline: An Alternative Scaffold for the Design of 17β-Hydroxysteroid Dehydrogenase 1 Inhibitors
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17β-Hydroxysteroid dehydrogenases catalyse interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less-active estrone to estradiol, and inhibitors have therapeutic potential in estrogen-dependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N-phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ) template was pursued by using Pomeranz-Fritsch-Bobbitt, Pictet-Spengler and Bischler-Napieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structure-activity relationships are discussed. THIQs possessing a 6-hydroxy group, lipophilic substitutions at the 1- or 4-positions in combination with N-4′-chlorophenyl substitution were most favourable for activity. Of these, one compound had an IC50 of ca. 350 nM as a racemate, testifying to the applicability of this novel approach.
- Mottinelli, Marco,Sinreih, Ma?a,Ri?ner, Tea L.,Leese, Mathew P.,Potter, Barry V. L.
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p. 259 - 291
(2020/12/07)
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- Synthesis of Benzo[ b]furans by Intramolecular C-O Bond Formation Using Iron and Copper Catalysis
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One-pot processes for the synthesis of benzo[b]furans from 1-aryl- or 1-alkylketones using nonprecious transition metal catalysts have been developed. Regioselective iron(III)-catalyzed halogenation of the aryl ring, followed by iron- or copper-catalyzed O-arylation allowed the synthesis of various structural analogues, including the benzo[b]furan-derived natural products corsifuran C, moracin F, and caleprunin B.
- Henry, Martyn C.,Sutherland, Andrew
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supporting information
p. 2766 - 2770
(2020/03/30)
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- Nickel-Catalyzed Mono-Selective α-Arylation of Acetone with Aryl Chlorides and Phenol Derivatives
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The challenging nickel-catalyzed mono-α-arylation of acetone with aryl chlorides, pivalates, and carbamates has been achieved for the first time. A nickel/Josiphos-based catalytic system is shown to feature unique catalytic behavior, allowing the highly selective formation of the desired mono-α-arylated acetone. The developed methodology was applied to a variety of (hetero)aryl chlorides including biologically relevant derivatives. The methodology has been extended to the unprecedented coupling of acetone with phenol derivatives. Mechanistic studies allowed the isolation and characterization of key Ni0 and NiII catalytic intermediates. The Josiphos ligand is shown to play a key role in the stabilization of NiII intermediates to allow a Ni0/NiII catalytic pathway. Mechanistic understanding was then leveraged to improve the protocol using an air-stable NiII pre-catalyst.
- Amgoune, Abderrahmane,Derhamine, Sary Abou,Krachko, Tetiana,Monteiro, Nuno,Pilet, Guillaume,Schranck, Johannes,Tlili, Anis
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supporting information
p. 18948 - 18953
(2020/09/01)
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- An Efficient Palladium-Catalyzed α-Arylation of Acetone below its Boiling Point
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The monoarylation of acetone is a powerful transformation, but is typically performed at temperatures significantly in excess of its boiling point. Conditions described for performing the reaction at ambient temperatures led to significant dehalogenation when applied to a complex aryl halide. We describe our attempts to overcome both issues in the context of our drug-discovery program.
- Ledgard, Andrew J.,Martin, Fionna M.,Mutton, Simon P.,Richardson, Jeffery,Walton, Lesley
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- Expeditious Synthesis of Isoquinolone Derivatives by Rhodium(I)-Catalyzed Annulation Reaction through C-C Bond Cleavage
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A Rh(I)-catalyzed intermolecular cyclization between isocyanates and benzocyclobutenols leading to isoquinolin-1(2H)-ones through selective cleavage of a C-C bond has been realized. Exploiting the same strategy, we developed a Rh(I)-catalyzed three-component reaction of benzocyclobutenols, isonitriles, and sulfonyl azides to access isoquinolin-1(2H)-imines. These procedures provide unique and expeditious access to isoquinolone derivatives which are otherwise difficult to prepare in satisfactory yields with excellent functional-group tolerance under mild reaction conditions.
- He, Yiyi,Yuan, Chengsha,Jiang, Zeqi,Shuai, Li,Xiao, Qing
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supporting information
p. 185 - 189
(2019/01/04)
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- Porphyrins as Photoredox Catalysts in Csp2-H Arylations: Batch and Continuous Flow Approaches
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We have investigated both batch and continuous flow photoarylations of enol-acetates to yield different α-arylated aldehyde and ketone building blocks by using diazonium salts as the aryl-radical source. Different porphyrins were used as SET photocatalysts, and photophysical as well as electrochemical studies were performed to rationalize the photoredox properties and suggest mechanistic insights. Notably, the most electron-deficient porphyrin (meso-tetra(pentafluorophenyl)porphyrin) shows the best photoactivity as an electron donor in the triplet excited state, which was rationalized by the redox potentials of excited states and the turnover of the porphyrins in the photocatalytic cycle. A two-step continuous protocol and multigram-scale reactions are also presented revealing a robust, cost-competitive, and easy methodology, highlighting the significant potential of porphyrins as SET photocatalysts.
- De Souza, Aline A. N.,Silva, Nathalia S.,Müller, Andressa V.,Polo, André S.,Brocksom, Timothy J.,De Oliveira, Kleber T.
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p. 15077 - 15086
(2019/01/03)
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- Synthesis of Functionalized Dihydrobenzofurans by Direct Aryl C?O Bond Formation under Mild Conditions
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A method for the synthesis of dihydrobenzofurans by a direct aryl C?O bond formation is described. A mechanistic pathway for the reaction, distinct from previously described similar transformations, allows for mild reaction conditions that are expected to be compatible with functionalized substrates.
- Alvarado, Joseph,Fournier, Jeremy,Zakarian, Armen
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supporting information
p. 11625 - 11628
(2016/10/24)
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- Direct Asymmetric Reductive Amination for the Synthesis of Chiral β-Arylamines
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The highly efficient and direct asymmetric reductive amination of arylacetones catalyzed by an iridium complex for the preparation of enantiomerically pure β-arylamines is described. The monodentate phosphoramidite ligand exhibits superb reactivity (TONs of up to 20 000) and enantioselectivity (up to 99 % ee). Additives played important roles in this reductive coupling reaction. Asymmetric reductive coupling of a ketone and an amine is a straightforward and atom-economic approach for preparing optically enriched amines. The highly efficient and direct asymmetric reductive amination of arylacetones, catalyzed by an iridium complex, supplies enantiomerically pure β-arylamines. The new phosphoramidite ligands reported show superb reactivity and enantioselectivity in this reductive coupling. M.S.=molecular sieves, TFA=trifluoroacetic acid.
- Huang, Haizhou,Liu, Xiaoyan,Zhou, Le,Chang, Mingxin,Zhang, Xumu
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supporting information
p. 5309 - 5312
(2016/04/26)
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- Palladium-Catalyzed Mono-α-arylation of Acetone at Room Temperature
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The first examples of acetone mono-α-arylation at room temperature are described, enabled by use of a [Pd(cinnamyl)Cl]2/JosiPhos catalyst system. (Hetero)aryl chloride, bromide, and iodide electrophiles featuring or lacking ortho-substitution, and comprising a range of functionalities (e.g., alkoxy, cyano, fluoro, trifluoromethyl, or alkenyl) and heteroaryl motifs (e.g., pyrrole, pyridine, isoquinoline, quinoline, quinaldine, (benzo)thiophene, benzothiazole, or benzodioxole) were successfully accommodated. Proof-of-principle experiments confirm that other (hetero)aryl methyl ketones can also be employed in such room temperature mono-α-arylations. The established substrate scope is the most extensive reported to date for acetone mono-α-arylation under any conditions, and more generally represents the first room temperature ketone mono-α-arylations employing a structurally diverse set of (hetero)aryl chlorides. Chill out: The first examples of acetone mono-α-arylation at room temperature are described. The substrate scope is the most extensive reported to date for acetone mono-α-arylation under any conditions, and represents the first room temperature ketone mono-α-arylations employing a diverse set of (hetero)aryl chlorides.
- Macqueen, Preston M.,Chisholm, Alicia J.,Hargreaves, Breanna K. V.,Stradiotto, Mark
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supporting information
p. 11006 - 11009
(2015/11/10)
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- Zheda-phos for general α-monoarylation of acetone with aryl chlorides
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A new, readily available, and air-stable monophosphine ligand, i.e., Zheda-Phos, has been developed for the general and highly effective palladium-catalyzed monoarylation of acetone with aryl chlorides. The reaction rate is of first-order dependence with the aryl chloride. Copyright
- Li, Pengbin,Lue, Bo,Fu, Chunling,Ma, Shengming
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supporting information
p. 1255 - 1259
(2013/06/27)
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- Palladium-catalyzed mono-α-arylation of acetone with aryl imidazolylsulfonates
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Set the ace(tone): A palladium catalyst derived from the bidentate XantPhos ligand and Pd(OAc)2 has enabled broadly applicable mono-α-arylations of acetone to be performed with air- and moisture-stable aryl imidazolylsulfonates as most user-friendly electrophiles (see scheme). Copyright
- Ackermann, Lutz,Mehta, Vaibhav P.
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supporting information; experimental part
p. 10230 - 10233
(2012/09/22)
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- Palladium-catalyzed selective carboelimination and cross-coupling reactions of benzocyclobutenols with aryl bromides
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The palladium-catalyzed selective β-carboelimination and cross-coupling chemistry of benzocyclobutenols is described. In contrast to the base-mediated ring-opening reactions of benzocyclobutenols, this variant proceeds with exclusive cleavage of the proximal bond.
- Chtchemelinine, Andrei,Rosa, David,Orellana, Arturo
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supporting information; experimental part
p. 9157 - 9162
(2011/12/16)
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- Palladium-catalyzed mono-α-arylation of acetone with aryl halides and tosylates
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We report the first example of selective Pd-catalyzed mono-α- arylation of acetone employing aryl chlorides, bromides, iodides, and tosylates. The use of appropriately designed P,N-ligands proved to be the key to controlling the reactivity and selectivity. The reaction affords good yields with substrates containing a range of functional groups at modest Pd loadings using Cs2CO3 as the base and employing acetone as both a reagent and the solvent.(Figure Presented)
- Hesp, Kevin D.,Lundgren, Rylan J.,Stradiotto, Mark
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supporting information; experimental part
p. 5194 - 5197
(2011/06/10)
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- β-fluoroamphetamines via the stereoselective synthesis of benzylic fluorides
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A range of substituted aryl epoxides undergo efficient ring-opening hydrofluorination upon treatment with 0.33 equiv of BF3-OEt 2 in CH2Cl2 at -20 -°C to give the corresponding syn-fluorohydrins, consistent with a mechanism involving a stereoselective SN1-type epoxide ring-opening process. The benzylic fluoride products of these reactions are valuable templates for further elaboration, as demonstrated by the preparation of a range of aryl-substituted β-fluoroamphetamines.
- Cresswell, Alexander J.,Davies, Stephen G.,Lee, James A.,Roberts, Paul M.,Russell, Angela J.,Thomson, James E.,Tyte, Melloney J.
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supporting information; experimental part
p. 2936 - 2939
(2010/09/10)
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- Catalytic electrosynthesis in ionic liquid: Performance of nickel-2,2′-bipyridine) complexes for production of aryl propan-2-ones
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The nickel-catalyzed electroreductive coupling of a benzylicchloride with an acyl donor reagent in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate has been studied in the preparative scale to obtain aryl propan-2-ones in galvanostatic mode. Poor solubility of metallicsalts prevents the use of the sacrificial anode process in an undivided cell. Moderate chemical yields are obtained withinadivided cell configuration using an anionic membrane as a separator, which shows the compatibility ofionic liquids with thiskind of electrochemical device. Aryl propan-2-ones were prepared with chemical yieldup to65%. Cyclicvoltammetry and UV-vis spectroscopy confirm that the mechanism is the same in the ionic liquid and inaclassical molecular solvent such as DMF. Nevertheless, degradation of the imidazolium cation induced by redox catalysis involving the bipyridine ligand has been observed, which explains the low faradaic yields.
- Barhdadi, Rachid,Maekawa, Hirofumi,Comminges, Clement,Troupel, Michel
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experimental part
p. 1510 - 1513
(2010/04/01)
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- Efficient synthesis of chiral β-arylisopropylamines by using catalytic asymmetric hydrogenation
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(Chemical Equation Presented) Direct condensation of β-arylketones with acetamide afforded both Z and E enamides. The Z-configured substrates underwent hydrogenation with excellent enantioselectivity by using the Rh/tang-phos catalytic system (see scheme; tangphos = 1,1′-di-tert-butyl- [2,2′]-diphospholanyl). The product β-arylisopropylamines are important precursors to several drugs.
- Chen, Jian,Zhang, Weicheng,Geng, Huiling,Li, Wei,Hou, Guohua,Lei, Aiwen,Zhang, Xumu
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supporting information; experimental part
p. 800 - 802
(2009/05/06)
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- Development of a robust and practical process for the Darzens condensation and α,β-epoxide rearrangement: Scope and limitations of the methodology
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A practical and robust process for the Darzens condensation of substituted benzaldehydes and subsequent α,β-epoxy rearrangement is reported. The process developed is both amenable to large scale and parallel synthesis. While electron-poor benzaldehydes gave mixtures of aryl ketones and 2-substituted aryl ketones in mediocre to low yields, electron-rich benzaldehydes were found to react in high yields with complete regioselectivity to form 2-substituted aryl ketones. Georg Thieme Verlag Stuttgart.
- Zimbron, Jeremy Malcolm,Seeger-Weibel, Manuela,Hirt, Hans,Gallou, Fabrice
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p. 1221 - 1226
(2008/12/22)
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- Nickel-catalyzed direct electrochemical cross-coupling between aryl halides and activated alkyl halides
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The electrochemical reduction of a mixture of aryl halides and activated alkyl halides in DMF in the presence of catalytic amount of NiBr2bipy leads to cross-coupling products in good to high yields. The method applies to the synthesis of α-aryl ketones, α-aryl esters, and allylated compounds from readily available organic halides. Optimization of the process has been obtained by slowly adding the most reactive organic halide (usually the activated alkyl halide) during the electrolysis which is best conducted at 70 °C when aryl bromides are involved.
- Durandetti, Muriel,Nedelec, Jean-Yves,Perichon, Jacques
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p. 1748 - 1755
(2007/10/03)
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- ALPHA, ALPHA DIALKYLBENZYL DERIVATIVES
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The invention concerns (alpha),(alpha)-dialkylbenzyl derivatives of the formula I wherein Ar1 is phenyl or naphthyl, or a 10-membered bicyclic heterocyclic moiety containing one or two nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur; A1 is a direct link to X1 or is (1-3C)alkylene; X1 is oxy, thio, sulphinyl or sulphonyl; the phenylene group may optionally bear one or two substituents R3; each of R1 and R2, which may be the same or different, is (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, fluoro-(1-4C)alkyl, phenyl or phenyl-(1-4C)alkyl, provided that both of R1 and R2 are not methyl or fluoromethyl; and Q is cyano, amino, nitro, formyl, (1-4C)alkoxy, thiazolyl or (2-4C)alkanoyl; or a pharmaceutically-acceptable salt thereof; processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors
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- A novel method of arylation of α-chloroketones
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α-Arylated ketones were obtained in moderate to good yields by one-step electroreductive coupling of α-chloroketones and arylhalides in DMF and in the presence of a Al- or Zn-sacrificial anode and a catalytic amount of a nickel complex.
- Durandetti,Sibille,Nedelec,Perichon
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p. 145 - 151
(2007/10/02)
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- Mass spectrometric investigations on phenylacetic acid derivatives, IV: Loss of ortho-substituents from ionized phenyl-2-propanones upon electron impact
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In the gas phase, the phenyl-2-propanone molecules 2a-4a lose upon electron impact chloro-, bromo-, and iodo-radicals specifically at the orthopOsition of the phenyl group giving rise to strong (M-Hal.)+-ions (70/12 eV; 1st and 2nd FFR) of identical structure as confirmed by their MIKE-CAD-spectra. The daughter ions at m/z 133 from o-chlorophenyl-2-propanone (2a) and 2,2-dimethyl-2,3-dihydro[b]furane (11) are structurally similar but not identical (similarity index 99.8). The collisionally activated (2nd FFR) (M-Br.)+-ions from o-bromophenyl-2-propanone (3a) and 1-bromo-1-phenyl-2-propanone (12) produce virtually congruent spectra. The most impOrtant subsequent fragmentation of the (M-Hal-)+-ions from 2a-4a is the loss of CO which incorporates the C-atom of the carbonyl group exclusively (13C labelling). Mechanistic aspects of the fragmentation sequences are discussed (Figs. 5 and 8).
- Striegel,Mayer,Wiegrebe,Schlunegger,Siegrist,Aebi
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p. 751 - 760
(2007/10/02)
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- Behaviour of Arylazo tert-Butyl Sulfides with Ketone Enolates. Competition between SRN1 α-Arylation and Azocoupling Reactions.
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(Z)-Arylazo tert-butyl sulfides 1a-i react, in DMSO and at room temperature, with potassium acetone enolate to give good yields of 1-aryl-2-propanones via spontaneous SRN1 dark reactions. α-Phenylation of pincolone and acetophenone enolates by 1a likewise occurs in excellent yields.In agreement with the involvement of an electron-transfer catalyzed chain process, the reaction of the 4-bromo derivative 1n with pinacolone enolate gives mainly the bis-substitution product 13.With azosulfides 1j-m the arylation pathway competes with a base-induced thiol elimination eventually leading, depending on the structure of the azosulfide, to indazoles 8 or 11 and/or to 2-oxopropanal arylhydrazones 9, 10 or 12.
- Dell'Erba, Carlo,Novi, Marino,Petrillo, Giovanni,Tavani, Cinzia
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p. 325 - 334
(2007/10/02)
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- SYNTHESIS, TAUTOMERIZATION AND ACYLATION OF 1-PHENYLPROPANE-2-IMINES
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1-Phenylpropane-2-imines and its derivatives substituted in a benzene ring were synthesized in reaction of proper ketones with ammonia.The keto-enol and imine-enamine tautomerisms in starting compounds and reaction products, respectively, were examined by proton nuclear magnetic resonance spectrometry and chemical methods.The determined constants of tautomeric equilibria were correlated with the Hammett ? constants.Electronic effects occurring in the systems under study were discussed basing on the correlations found.A possible use of 1-phenylpropane-2-imines in synthesis of N-acyl derivatives of 2-phenyl-1-methylvinylamines was examined.
- Zielinski, W.,Mazik, M.
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p. 661 - 668
(2007/10/02)
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- ACETONYLATION AROMATIQUE HOMOLYTIQUE
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Treatment of monosubstituted benzene derivatives with acetone and manganese(III) acetate in acetic acid gave rise to products of homolytic aromatic substitution in fairly good yields and high purity except for toluene.Isomer distribution, relative rates and partial rate factors were determeined for toluene, anisole, chlorobenzene, bromobenzene and benzonitrile.A Hammet plot of the logarithm of the partial rate factors for meta and para positions vs. ?-constants gave a slope ρ of -1.74 +/- 0.40 (confidence interval at the level 95percent).When using ?+-constants the slope becomes ρ+ = -1.25 +/- 0.36.The negative velues of ρ and ρ+ indicated that the acetonyl radical has an appreciable electrophilic character.
- Gardrat, C.
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p. 897 - 902
(2007/10/02)
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- Aromatic Acetonylation Promoted by Manganese(III) and Cerium(IV) Salts
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Treatment of aromatic hydrocarbons with acetone and manganese(III) acetate gave rise to arylacetones in yields ranging from 25 percent with chlorobenzene to 74 percent with anisole.Cerium(IV) salts were also successfully used as promoters but gave lower yields.The reactions were relatively free of side products except with toluene.Isomer distributions, relative rates, and partial rate factors were determined for acetonylation of anisole, toluene, chlorobenzene, and fluorobenzene.A Hammett plot of the log of the partial rate factors for the manganese(III) system vs. ?-constants gave a slope, ρ, of -2.4 +/- 0.3.An isotope effect kH/kD = 3.8 was observed for the manganese(III)-promoted reaction with acetone-d6, indicating rate-determining proton loss from acetone.The overall mechanism involves formation and attack of acetonyl radicals onto the aromatic hydrocarbon followed by subsequent oxidative deprotonation of the resulting ?-radical complex.The acetonyl radical exhibits appreciable electron-deficient character in its substitution behavior with aromatic hydrocarbons.
- Kurz, Michael E.,Baru, Vijayalakshmi,Nguyen, P-Nhi
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p. 1603 - 1607
(2007/10/02)
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- Intramolecular Alkylation of Phenols. Part 4. Base-catalysed Cyclisation of Phenolic Enones. Scope and Limitations
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The phenolic enones (4), (5), (8), (9), and (13) cyclise readily under acidic conditions.However, neither these nor the thio-substituted phenols (11a), (13a), (14a), and (15a) closed under basic conditions.Involvement of unfavourable equilibria is disproved.Comparison is made with related successful cyclisations of the saturated ketone (38) and aldehyde (39).Preliminary results suggest that strict stereo-electronic requirements are necessary for enone ring closure and that these conditions are not met in base-catalysed 5-Endo- and 6-Endo-Trigonal ring closures of the phenols of general type (2; n=0 and n=1).
- Murphy, William S.,Wattanasin, Sompong
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p. 1555 - 1566
(2007/10/02)
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