18880-00-7Relevant articles and documents
Stereochemistry of solvation of benzylic lithium compounds: Structure and dynamic behavior
Fraenkel, Gideon,Duncan, Joseph H.,Martin, Kevin,Wang, Jinhai
, p. 10538 - 10544 (1999)
Several sec-benzylic lithium compounds, both externally coordinated, [α-(trimethylsilyl)benzyl]-lithium·PMDTA (12) and p-tert-butyl-α-(dimethylethylsilyl)benzyllithium·TMEDA (13), and internally coordinated, [α-[[[cis-2,5-bis(methoxymethyl)-1-pyrrolidinyl]methyl]dimethylsilyl]-p- tert-butylbenzyl]lithium (14) and [α-[[[(S)-2-(methoxymethyl)-1-pyrrolidinyl]methyl]dimethylsilyl]benzyl] lithium (15), have been prepared. Ring 13C NMR shifts indicate that 12-15 have partially delocalized structures. Externally solvated allylic lithium compounds are found to be delocalized, and only some internally coordinated species are partially delocalized. Compound 15 exists as > 95% of one stereoisomer of the two invertomers at Cα. This is in accord with a published ee of > 98% in products of the reactions of 15 with aldehydes. All four compounds show evidence of one-bond 13C-6Li spin coupling, ca. 3 Hz, which indicates a small detectable C-Li covalence. Averaging of the 13C-6Li coupling of 12 with increasing temperature provides the dynamics of intermolecular C-Li bond exchange, with ΔH?ex = 9 ± 0.5 kcal mol-1. Carbon-13 NMR line shape changes due to geminal methyls, and ligand carbons gave similar rates of inversion at Cα in 13 (externally solvated) and 14 (internally solvated), ΔH?inv ≈ 4.9 ± 0.5 kcal mol-1. By contrast, barriers to rotation around the ring-Cα bonds vary widely, depending on the mode of lithium coordination, ΔH?rot ≈ 8 ± 0.5 to 19 ± 1.0 kcal mol-1. Some mechanisms for these processes are proposed.
Partial oxidation of 4-tert-butyltoluene catalyzed by homogeneous cobalt and cerium acetate catalysts in the Br-/H2O 2/acetic acid system: Insights into selectivity and mechanism
Van De Water, Leon G. A.,Kaza, Arati,Beattie, James K.,Masters, Anthony F.,Maschmeyer, Thomas
, p. 8037 - 8044 (2007)
The partial oxidation of 4-fert-butyltoluene to 4-tert-butylbenzaldehyde by hydrogen peroxide in glacial acetic acid, catalyzed by bromide ions in combination with cobalt(II) acetate or cerium(III) acetate, has been studied in detail. Based on the observed differences in reaction rates and product distributions for the different catalysts, a reaction mechanism involving two independent pathways is proposed. After the initial formation of a benzylic radical species, either oxidation of this intermediate by the metal catalyst or reaction with bromine generated in situ occurs, depending on which catalyst is used. The first pathway leads to the exclusive formation of 4-tert- butylbenzaldehyde, whereas reaction of the radical intermediate with bromine leads to formation of the observed side products 4-tert-butylbenzyl bromide and its hydrolysis and solvolysis products 4-tertbutylbenzyl alcohol and 4-tert-butylbenzyl acetate, respectively. The cobalt(II) catalysts Co(OAc) 2 and Co(acac)2 are able to quickly oxidize the radical intermediate, thereby largely preventing the bromination reaction (i.e., side-product formation) from occurring, and yield the aldehyde product with 75-80% selectivity, In contrast, the cerium catalyst studied here exhibits an aldehyde selectivity of around 50% due to the competing bromination reaction. Addition of extra hydrogen peroxide leads to an increased product yield of 72% (cerium(III) acetate) or 58% (cobalt(II) acetate). Product inhibition and the presence of increasing amounts of water in the reaction mixture do not play a role in the observed low incremental yields.
Readily Reconfigurable Continuous-Stirred Tank Photochemical Reactor Platform
Blacker, A. John,Francis, Daniel,Kapur, Nikil,Marsden, Stephen P.
supporting information, (2022/01/12)
A new modular photochemical continuous stirred-tank reactor (CSTR) design is described, based upon the development of light-source units that can be fitted to the previously described fReactor CSTR platform. In addition to use in homogeneous photochemical reactions (e.g., photoredox-catalyzed hydroamination), these units are especially well suited to handling multiphasic mixtures, exemplified here in solid-liquid (Wohl-Ziegler bromination) and gas-liquid (photocatalytic oxidative decarboxylation) reactions. The use of slurries as input feeds allows for the intensification of photochemical brominations, while the modular nature of the system facilitates the simple integration of downstream reaction steps, exemplified here in a continuous synthesis of an intermediate for the antihypertensive drug valsartan.
Thiourea-Catalyzed C?F Bond Activation: Amination of Benzylic Fluorides
Houle, Camille,Savoie, Paul R.,Davies, Clotilde,Jardel, Damien,Champagne, Pier Alexandre,Bibal, Brigitte,Paquin, Jean-Fran?ois
supporting information, p. 10620 - 10625 (2020/07/24)
We describe the first thiourea-catalyzed C?F bond activation. The use of a thiourea catalyst and Ti(OiPr)4 as a fluoride scavenger allows the amination of benzylic fluorides to proceed in moderate to excellent yields. Preliminary results with S- and O-based nucleophiles are also presented. DFT calculations reveal the importance of hydrogen bonds between the catalyst and the fluorine atom of the substrate to lower the activation energy during the transition state.
Photochemical benzylic bromination in continuous flow using BrCCl3 and its application to telescoped p-methoxybenzyl protection
Otake, Yuma,Williams, Jason D.,Rincón, Juan A.,De Frutos, Oscar,Mateos, Carlos,Kappe, C. Oliver
supporting information, p. 1384 - 1388 (2019/02/14)
BrCCl3 represents a rarely used benzylic brominating reagent with complementary reactivity to other reagents. Its reactivity has been revisited in continuous flow, revealing compatibility with electron-rich aromatic substrates. This has brought about the development of a p-methoxybenzyl bromide generator for PMB protection, which was successfully demonstrated on a pharmaceutically relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br space-time-yield of 1.27 kg L?1 h?1
Nucleophilic Substitutions of Alcohols in High Levels of Catalytic Efficiency
Stach, Tanja,Dr?ger, Julia,Huy, Peter H.
supporting information, p. 2980 - 2983 (2018/05/28)
A practical method for the nucleophilic substitution (SN) of alcohols furnishing alkyl chlorides, bromides, and iodides under stereochemical inversion in high catalytic efficacy is introduced. The fusion of diethylcyclopropenone as a simple Lewis base organocatalyst and benzoyl chloride as a reagent allows notable turnover numbers up to 100. Moreover, the use of plain acetyl chloride as a stoichiometric promotor in an invertive SN-type transformation is demonstrated for the first time. The operationally straightforward protocol exhibits high levels of stereoselectivity and scalability and tolerates a variety of functional groups.
Selective C-H halogenation over hydroxylation by non-heme iron(iv)-oxo
Rana, Sujoy,Biswas, Jyoti Prasad,Sen, Asmita,Clémancey, Martin,Blondin, Geneviève,Latour, Jean-Marc,Rajaraman, Gopalan,Maiti, Debabrata
, p. 7843 - 7858 (2018/10/31)
Non-heme iron based halogenase enzymes promote selective halogenation of the sp3-C-H bond through iron(iv)-oxo-halide active species. During halogenation, competitive hydroxylation can be prevented completely in enzymatic systems. However, synthetic iron(iv)-oxo-halide intermediates often result in a mixture of halogenation and hydroxylation products. In this report, we have developed a new synthetic strategy by employing non-heme iron based complexes for selective sp3-C-H halogenation by overriding hydroxylation. A room temperature stable, iron(iv)-oxo complex, [Fe(2PyN2Q)(O)]2+ was directed for hydrogen atom abstraction (HAA) from aliphatic substrates and the iron(ii)-halide [FeII(2PyN2Q)(X)]+ (X, halogen) was exploited in conjunction to deliver the halogen atom to the ensuing carbon centered radical. Despite iron(iv)-oxo being an effective promoter of hydroxylation of aliphatic substrates, the perfect interplay of HAA and halogen atom transfer in this work leads to the halogenation product selectively by diverting the hydroxylation pathway. Experimental studies outline the mechanistic details of the iron(iv)-oxo mediated halogenation reactions. A kinetic isotope study between PhCH3 and C6D5CD3 showed a value of 13.5 that supports the initial HAA step as the RDS during halogenation. Successful implementation of this new strategy led to the establishment of a functional mimic of non-heme halogenase enzymes with an excellent selectivity for halogenation over hydroxylation. Detailed theoretical studies based on density functional methods reveal how the small difference in the ligand design leads to a large difference in the electronic structure of the [Fe(2PyN2Q)(O)]2+ species. Both experimental and computational studies suggest that the halide rebound process of the cage escaped radical with iron(iii)-halide is energetically favorable compared to iron(iii)-hydroxide and it brings in selective formation of halogenation products over hydroxylation.
Systematic Evaluation of Sulfoxides as Catalysts in Nucleophilic Substitutions of Alcohols
Motsch, Sebastian,Schütz, Christian,Huy, Peter H.
supporting information, p. 4541 - 4547 (2018/09/13)
Herein, a method for the nucleophilic substitution (SN) of benzyl alcohols yielding chloro alkanes is introduced that relies on aromatic sulfoxides as Lewis base catalysts (down to 1.5 mol-%) and benzoyl chloride (BzCl) as reagent. A systematic screening of various sulfoxides and other sulfinyl containing Lewis bases afforded (2-methoxyphenyl)methyl sulfoxide as optimal catalyst. In contrast to reported formamide catalysts, sulfoxides also enable the application of plain acetyl chloride (AcCl) as reagent. In addition, it was demonstrated that weakly electrophilic carboxylic acid chlorides like BzCl promote Pummerer rearrangement of sulfoxides already at room temperature. This side-reaction also provided the explanation, why sulfoxide catalyzed SN-reactions of alcohols do not allow the effective production of aliphatic and electron deficient chloro alkanes. Comparison experiments provided further insight into the reaction mechanism.
Copper-Mediated Trifluoromethylation of Benzylic Csp3?H Bonds
Paeth, Matthew,Carson, William,Luo, Jheng-Hua,Tierney, David,Cao, Zhi,Cheng, Mu-Jeng,Liu, Wei
, p. 11559 - 11563 (2018/07/31)
Trifluoromethyl-containing compounds play a significant role in medicinal chemistry, materials and fine chemistry. Although direct C?H trifluoromethylation has been achieved on Csp2?H bonds, direct conversion of Csp3?H bonds to Csp3?CF3 remains challenging. We report herein an efficient protocol for the selective trifluoromethylation of benzylic C?H bonds. This process is mediated by a combination CuIII?CF3 species and persulfate salts. A wide range of methylarenes can be selectively trifluoromethylated at the benzylic positions. A combination of experimental and theoretical mechanistic studies suggests that the reaction involves a radical intermediate and a CuIII?CF3 species as the CF3 transfer reagent.
Preparation and properties of a novel solution of hydrogen bromide (HBr) in 1,4-dioxane: An alternative reagent to HBr gas without protic solvents
Nishio, Yuya,Mifune, Ryota,Sato, Taisuke,Ishikawa, Shin-ich,Matsubara, Hiroshi
, p. 1190 - 1193 (2017/03/02)
A solution of hydrogen bromide (HBr) in 1,4-dioxane was prepared and investigated for its ability to brominate alcohols, and hydrobrominate alkenes. This study revealed that the brominating ability of this HBr/1,4-dioxane solution is equal or superior to that of hydrobromic acid or HBr in acetic acid. The solution of HBr in 1,4-dioxane is robust, exhibiting no decomposition of the solvent, and retaining 97% of its original concentration, when kept at ?25 °C for 30 days. This solution is a liquid alternative to HBr gas without protic solvents.
