Benzylic Reagents Research Articles

Access to Substituted 1,1-Diarylalkanes by Friedel-Crafts Benzylations Mediated by FeCl3-based Deep Eutectic Solvents.

The development of new, more efficient Friedel-Crafts benzylation methodologies that provide access to 1,1-diarylalkanes is an important objective of interest for the production of pharmaceuticals and fine chemical products. In this regard, this study introduces a novel synthetic route to 1,1-diarylalkanes conducted in the Deep Eutectic Solvent (DES) 3 FeCl3 ⋅ 6 H2O/Gly, which serves as both a reaction medium and promoter. Under these conditions, Friedel-Crafts benzylations of various arenes bearing activating and deactivating ortho-/para-directing groups, can be performed using diverse benzylating reagents such as styrenes, alcohols, acetates, ethers, and chlorides. Importantly, highly electronically deactivated electrophiles, including those with CF3 and NO2 groups, are suitable substrates. This methodology provides a wide range of asymmetric 1,1-diarylalkanes (up to 132 examples) with generally good yields and high regioselectivities. The efficiency of this approach was demonstrated with the multigram-scale synthesis (10 mmol) of 1-phenyl-1-xylyl ethane (PXE), a liquid with great industrial applicability. Moreover, the Fe(III)-based DES could be reused for 20 consecutive cycles with no appreciable erosion of the yields.

Photochemical Benzylation of White Phosphorus.

Organophosphorus compounds (OPCs) have wide application in organic synthesis, material sciences, and drug discovery. Generally, the vast majority of phosphorus atoms in OPCs are derived from white phosphorus (P4). However, the large-scale preparation of OPCs mainly proceeds through the multistep and environmentally toxic chlorine route from P4. Herein, we report the direct benzylation of P4 promoted by visible light. The cheap and readily available benzyl bromide was used as a benzylation reagent, and tetrabenzylphosphonium bromide was directly synthesized from P4. In addition, the metallaphotoredox catalysis strategy was applied to functionalize P4 for the first time, which significantly improved the application range of the substituted benzyl bromide.

Visible-Light-Induced Stoichiometric Coupling of Alkylarenes and Trifluoromethyl Ketones.

A visible-light induced direct C(sp3)-H functionalization of alkylarenes with trifluoromethyl ketones has been reported to access valuable benzyl-substituted trifluoromethyl alcohols in a stoichiometric manner. Readily available petroleum-derived alkylarenes are employed as latent benzylation reagents. With a bromine radical as the hydrogen atom transfer reagent, primary, secondary, and tertiary benzyl C-H bonds are suitable coupling partners. Additionally, the late-stage modification of bioactive molecules highlights the potential application of this approach.

Catalytic asymmetric Tsuji-Trost α-benzylation reaction of N-unprotected amino acids and benzyl alcohol derivatives.

Catalytic asymmetric Tsuji–Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.

Rapid Benzylation of Wood Powder without Heating.

Converting wood waste into thermoplastic materials is an attractive means of increasing its utilization. A promising method for imparting thermoplasticity to wood is chemical modification, in which the hydroxyl groups in wood are substituted with benzyl groups. In the common method, wood powder is first treated with a highly concentrated aqueous NaOH solution, and then reacted with a benzylation reagent by heating for a long time under stirring. In this study, a 50% aqueous tetra-n-butylphosphonium hydroxide solution was used for the pretreatment of wood powder. This modified alkaline treatment enhanced the efficiency of the subsequent benzylation reaction, which could be conducted without heating over a shorter time. The effects of various conditions on the efficiency of the benzylation reaction were evaluated. Both the alkali pretreatment and the subsequent benzylation required only ~5–10 min of stirring without heating to obtain benzylated wood with a similar degree of benzylation as that achieved by the common method. The chemical structure of the benzylated wood powder was characterized by Fourier-transform infrared and solid-state NMR spectroscopies, and its thermal softening characteristics were evaluated by thermomechanical analysis. Finally, a translucent film could be obtained by hot-pressing the benzylated wood powder.

Recent Advances in Triarylmethane Synthesis

Triarylmethanes are important molecules in organic chemistry. This review discusses advances in their synthesis summarized in five categories according to the starting materials: (1) benzyl reagents with different leaving groups, such as benzyl alcohols, ethers, esters, phosphates, sulfones, thioethers, sulfonamide, 1,3-dicarbonyls, and ammonium salts; (2) reactions via para- or ortho-quinone methides; (3) arylation of benzyl halides; (4) C–H activation of methylenes; and (5) reactions of aldehydes or N-tosylhydrazones. Triarylmethane derivatives such as 9-arylxanthenones, 9-arylfluorenes, and aryloxepines are also discussed.1 Introduction2 Benzyl Reagents with Leaving Groups3 Quinone Methide Mediated Reactions4 Arylation of Benzyl Halides5 C–H Activation of Methylene6 Reactions of Carbonyl Compounds7 Conclusions

Catalytic Deoxygenative Coupling of Aromatic Esters with Organophosphorus Compounds.

We have developed a deoxygenative coupling of aromatic esters with diarylphosphine oxides/dialkyl phosphonates under palladium catalysis. In this reaction, aromatic esters can work as novel benzylation reagents to give the corresponding benzylic phosphorus compounds. The key of this reaction is the use of phenyl esters, an electron-rich diphosphine as a ligand, and sodium formate as a hydrogen source. Arylcarboxylic acids were also applicable in this reaction using (Boc)2O as an additive. Palladium/dcype worked to activate the acyl C-O bond of the ester and to support the reduction with sodium formate.

Preparation of Alkyl Ethers with Diallyltriazinedione‐Type Alkylating Agents (ATTACKs‐R) Under Acid Catalysis

Diallyltriazinedione‐type acid‐catalyzed alkylating agents (ATTACKs‐R) with 10 different alkyl groups (R), including benzyl, substituted benzyl, allyl, and methyl groups were synthesized. The palladium‐catalyzed intramolecular O‐to‐N allylic rearrangement of 2,4‐bis(allyloxy)‐6‐chloro‐1,3,5‐triazine was developed to introduce various alkoxy groups into the N,N′‐dialkylated triazinedione skeleton. O‐Alkylation of alcohols with ATTACKs‐R was carried out in 1,4‐dioxane in the presence of 2,6‐di‐tert‐butylpyridinium trifluoromethanesulfonate or trifluoromethanesulfonic acid as a catalyst. Six selected ATTACKs‐R bearing benzylic R groups were employed to prepare alkyl ethers from primary, secondary, and tertiary alcohols. The reactions of ATTACKs‐R bearing an o‐nitro‐substituted benzyl group tended to afford low yields. Comparison of four different triazinedione‐based benzylating reagents suggested that the N,N′‐substituents affected the reactivity.

Highly conductive anion exchange membranes based on one-step benzylation modification of poly(ether ether ketone)

Side-chain-type quaternized aromatic polyelectrolytes named QBz-PEEK-x have been synthesized via one-step benzylation modification of commercial poly(ether ether ketone) (PEEK). By controlling the molar ratio between the benzylation reagent and PEEK, the substitution degree x could be tuned in a wide range (51.1%~ 91.6%). A series of five anion exchange membranes (AEMs) with high mechanical strength were facilely prepared via solution-casting of QBz-PEEK-x. Water uptake, swelling ratio and ion conductivity of these AEMs were investigated in detail. Of particular interest is that, at 60 °C, the AEM of QBz-PEEK-76.0% exhibited a moderate water uptake of 56%, a low swelling ratio of 15%, and an exceptionally high OH– conductivity of 155 mS cm−1 which was comparable to the top values ever reported. Moreover, a promising peak power density of 391 mW cm−2 was achieved when assembling QBz-PEEK-76.0% AEM in a H2/O2 single cell operated at 70 °C. This unprecedented “benzylation” method opens a new door to novel high performance side-chain-type AEMs.

Cu-catalyzed deoxygenative gem-hydroborylation of aromatic aldehydes and ketones to access benzylboronic esters

Organoboron compounds are widely used in synthetic chemistry, pharmaceutical chemistry and material chemistry. Among various organoboron compounds, benzylboronic esters are unique and highly reactive, making them suitable benzylation reagents. At present, the synthetic methods for the syntheses of benzylboronic esters are still insufficient to meet their demands. It is necessary to develop novel and practical methods for their preparation. In this work, a novel copper-catalyzed deoxygenative gem-hydroborylation of aromatic aldehydes and ketones has been developed. This direct and operationally simple protocol provides an effective approach for the synthesis of a variety of primary and secondary benzylboronates, in which broad functional group tolerance was presented. Widely available B2pin2 (pin = pinacol) was used as the boron source and alcoholic proton was applied as the hydride source.

Development of Triazine-Based Benzylating Reagents Possessing t-Butyl Group on the Triazine Core: Thermally Controllable Reagents for the Initiation of Reaction.

Benzylating reagents, 4-(4,6-di-t-butyl-1,3,5-triazin-2-yl)-4-benzylmorpholinium triflate, and related derivatives have been developed. The reagents release benzyl triflate as a benzyl cation equivalent upon heating the solution to 40°C under neutral conditions. The O-benzylation of alcohols using a stoichiometric amount of these reagents afforded corresponding benzyl ethers in good to high yields. This was due to the presence of a bulky t-butyl group on the triazine ring of these reagents that prevents the consumption of benzyl triflate via a side reaction with a morpholinotriazine derivative.

A Novel Brønsted-Lewis acidic catalyst based on heteropoly phosphotungstates: Synthesis and catalysis in benzylation of p-xylene with benzyl alcohol

A novel Brønsted-Lewis acidic catalyst, Hf0.5[TEAPS]PW12O40, has been prepared by the replacement of protons in neat phosphotungstic acid with both organic and metal cations and characterized by FT-IR, Py-IR, XRD, TG-DTG, ICP-AES, BET, elemental analysis and n-butylamine potentiometeric titration techniques. This hybrid heterogeneous catalyst with both Brønsted and Lewis acidity can efficiently promote the conversion of dibenzyl ether, the self-condensation product of benzyl alcohol, to the benzylation products, as well restrain the polybenzylation of aromatics. As a result, it exhibits excellent catalytic activity and selectivity in the benzylation of p-xylene with clean benzylation reagent benzyl alcohol. Thus, an environmentally friendly route for the benzylation reaction of p-xylene with high atomic economy has been developed by this reusable Hf0.5[TEAPS]PW12O40 catalyst.

Organotin-catalyzed regioselective benzylation of carbohydrate trans-diols

A convenient approach to regioselective benzylation of carbohydrate trans-diols was developed, where 0.1equiv. of Bu2SnCl2 and 0.1equiv. of TBABr were used as the catalysts and 2.0equiv. of BnCl was used as the benzylation reagent. In most cases, similar or better benzylation regioselectivities and isolated yields were obtained by using catalytic amounts of Bu2SnCl2, rather than stoichiometric amounts of organotin reagents required.

Addition of novel benzylmagnesium “ate” complexes of BnR2MgLi type to 2-(thio)pyridones and related compounds

Novel benzylation reagents BnR2MgLi were obtained by mixing benzylmagnesium chloride (BnMgCl) and appropriate organolithium compounds (RLi). As BnR2MgLi complexes are more nucleophilic than the parent Grignard compound they enabled regioselective C6-addition to electrophilic N-substituted 2-(thio)-pyridones and C4-addition to poorly reactive NH 2-(thio)pyridones in high and good yields, respectively. Thus, the application of these new reagents in efficient synthesis of 6-benzyl-3,6-dihydro- and 4-benzyl-3,4-dihydropyridin-2(1H)-ones is described. The prospect of wider application of BnR2MgLi in 1,4-addition to other electrophiles, comprising six-membered α,β-unsaturated systems is also presented.

Specific reactivity of 2,4,6-tri-tert-butylanilide anions and its application to benzylation reagent

The reaction of methyl iodide with an anilide anion prepared from 2,4,6-tri-tert-butylanilide and NaH in CH3CN gave N-methyl anilide (N-alkylation product) as a major product, while in the reaction of benzyl bromide with the anilide anion in DMF, O-benzyl imidate (O-alkylation product) was obtained with almost complete selectivity. The treatment of O-benzyl imidate with alcohols and carboxylic acids in the presence of trifluoromethane sulfonic acid gave benzyl ethers and benzyl esters, respectively.

ChemInform Abstract: Development of Acid‐Catalyzed Fluorous Benzylating Reagents Based on a Triazinedione Core.

Abstract Acid-catalyzed fluorous benzylating reagents have been developed based on the unique π-electron deficient properties of triazinedione. Alcohols and carboxylic acids could be converted into the corresponding fluorous-benzyl ether and ester derivatives, respectively, in good yield by using the reagents in the presence of a catalytic amount of trifluoromethanesulfonic acid.

Development of acid-catalyzed fluorous benzylating reagents based on a triazinedione core

Acid-catalyzed fluorous benzylating reagents have been developed based on the unique π-electron deficient properties of triazinedione. Alcohols and carboxylic acids could be converted into the corresponding fluorous-benzyl ether and ester derivatives, respectively, in good yield by using the reagents in the presence of a catalytic amount of trifluoromethanesulfonic acid.

Mild Amide-Cleavage Reaction Mediated by Electrophilic Benzylation.

An extremely mild method for amide-cleavage by using the triazine-based benzylating reagent 4-(4,6-diphenoxy-1,3,5-triazin-2-yl)-4-benzylmorpholinium trifluoromethanesulfonate (DPT-BM), which spontaneously releases benzyl cation species when being dissolved at room temperature, has been developed. O-Benzylation of the amide with DPT-BM and the subsequent hydrolysis of the resulting intermediate benzyl imidate salt afford the corresponding amine and benzyl ester, which can be converted by hydrogenolysis into a carboxylic acid under neutral conditions. O-Benzylation proceeds depending on both steric and electronic factors around the amide group. Thus, some amides have been selectively cleaved over other amides. Furthermore, intramolecular chemoselective cleavage of an amide group in the presence of an ester group was achieved. Such selective hydrolytic reactions cannot be performed with Meerwein reagents as well as under acidic or basic hydrolytic conditions.

ChemInform Abstract: Development of a New Benzylating Reagent Spontaneously Releasing Benzyl Cation Equivalents at Room Temperature.

AbstractBenzyl cations are generated from the novel reagent (I) by solvation in a suitable solvent under non‐acidic conditions.

Organic carbonates: sustainable and environmentally-friendly ethylation, allylation, and benzylation reagents

Diallyl, dibenzyl, and diethyl carbonate are shown to be non-toxic, sustainable and efficient reagents for the alkylation of phenols as well as for an esterification of carboxylic acids under microwave irradiation in the presence of sub-stoichiometric quantities of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or potassium carbonate. Comparative studies with diethyl carbonate (DEC), diallyl carbonate (DAC), and dibenzyl carbonate (DBC) were performed for the etherification of phenol. Moreover, the reaction of these organic carbonates with hydrogenated ferulic acid show that ester formation is significantly faster and requires lower temperatures if compared to the etherification. Generally, DBC and DAC show a higher reactivity than DEC. Moreover, the use of DBC and DAC under optimized reaction conditions allowed a selective protection of carboxyl groups in the presence of phenols.