19692-45-6Relevant academic research and scientific papers
Mechanism of solvolysis of substituted benzyl chlorides in aqueous ethanol
Denegri, Bernard,Mati?, Mirela,Va?ko, Monika
supporting information, (2021/11/22)
The mechanism of solvolyses of activated ortho-, meta- and para-substituted benzyl chlorides in aqueous ethanol has been studied by using the Hammett-Brown and Yukawa-Tsuno treatments as well as by correlating logarithms of solvolysis rate constants with relative stabilities of corresponding benzyl carbocations in water calculated at the IEFPCM-M06–2X/6-311+G(3df,3pd) level of theory. Benzyl chlorides containing strong conjugative electron-donors in the para-position solvolyze by the SN1 mechanism, whereas other activated benzyl chlorides solvolyze by the SN2 mechanism via loose transition states.
Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors
Brotherton-Pleiss, Christine,Yue, Peibin,Zhu, Yinsong,Nakamura, Kayo,Chen, Weiliang,Fu, Wenzhen,Kubota, Casie,Chen, Jasmine,Alonso-Valenteen, Felix,Mikhael, Simoun,Medina-Kauwe, Lali,Tius, Marcus A.,Lopez-Tapia, Francisco,Turkson, James
supporting information, p. 695 - 710 (2021/01/14)
We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of (R)-azetidine-2-carboxamide analogues that have sub-micromolar potencies. 5a, 5o, and 8i have STAT3-inhibitory potencies (IC50) of 0.55, 0.38, and 0.34 μM, respectively, compared to potencies greater than 18 μM against STAT1 or STAT5 activity. Further modifications derived analogues, including 7e, 7f, 7g, and 9k, that addressed cell membrane permeability and other physicochemical issues. Isothermal titration calorimetry analysis confirmed high-affinity binding to STAT3, with KD of 880 nM (7g) and 960 nM (9k). 7g and 9k inhibited constitutive STAT3 phosphorylation and DNA-binding activity in human breast cancer, MDA-MB-231 or MDA-MB-468 cells. Furthermore, treatment of breast cancer cells with 7e, 7f, 7g, or 9k inhibited viable cells, with an EC50 of 0.9-1.9 μM, cell growth, and colony survival, and induced apoptosis while having relatively weaker effects on normal breast epithelial, MCF-10A or breast cancer, MCF-7 cells that do not harbor constitutively active STAT3.
Fine-tuning of the pharmacological potential of novel thiazolium ionic liquids by anion alteration
Alfaifi, Mohammad Y.,Elbehairi, Serag Eldin I.,Elshaarawy, Reda F. M.,Gad, Emad M.,Shati, Ali A.
, p. 458 - 469 (2022/01/19)
A novel series of thiazolium ionic liquids (TILs) bound to chloride (2a-c), tetrafluoroborate (BF4) (3a-c), and bis-(trifluoromethanesulfonimide) (Tf2N) anions (4a-c) was synthesized and their physicochemical characteristics were investigated using various microanalytical techniques. The pharmacological potential of the new TILs was assessed as chemotherapeutic agents for bacterial infections and ovarian cancer (SKOV-3). Notably, ILs with the same cations become more bactericidal upon their binding with the strongest chaotropic anion (TN2f). The in vitro toxicity of the TILs toward ovarian carcinoma cell lines (SKOV-3) and normal human skin fibroblast cells (HSF) revealed that all tested TILs have the capacity to induce a dose- and time-dependent decline in SKOV-3 cell viability, with Tf2N-linked TILs (4a-c) having a preferable efficacy. In addition, the new compounds showed excellent selectivity for cancer cells (SKOV-3) over healthy cells (HSF). [iPBzTh][Tf2N] (4b) is the most cytotoxic and specific one and may act as a promising anti-ovarian cancer agent.
Lewis Base Catalysis Enables the Activation of Alcohols by means of Chloroformates as Phosgene Substitutes
Zoller, Ben,Stach, Tanja,Huy, Peter H.
, p. 5637 - 5643 (2020/09/21)
Nucleophilic substitutions (SN) are typically promoted by acid chlorides as sacrificial reagents to improve the thermodynamic driving force and lower kinetic barriers. However, the cheapest acid chloride phosgene (COCl2) is a highly toxic gas. Against this background, phenyl chloroformate (PCF) was discovered as inherently safer phosgene substitute for the SN-type formation of C?Cl and C?Br bonds using alcohols. Thereby, application of the Lewis bases 1-formylpyrroldine (FPyr) and diethylcyclopropenone (DEC) as catalysts turned out to be pivotal to shift the chemoselectivity in favor of halo alkane generation. Primary, secondary and tertiary, benzylic, allylic and aliphatic alcohols are appropriate starting materials. A variety of functional groups are tolerated, which includes even acid labile moieties such as tert-butyl esters and acetals. Since the by-product phenol can be isolated, a recycling to PCF with inexpensive phosgene would be feasible on a technical scale. Eventually, a thorough competitive study demonstrated that PCF is indeed superior to phosgene and other substitutes.
Formamide-Catalyzed Nucleophilic Substitutions: Mechanistic Insight and Rationalization of Catalytic Activity
Hilt, Gerhard,Huy, Peter H.,Kohlmeyer, Corinna,Sch?fer, André
, p. 11567 - 11577 (2020/11/17)
Herein, detailed mechanistic investigations into formamide-catalyzed nucleophilic substitution (SN) of alcohols are reported. Alkoxyiminium chlorides and hexafluorophosphates were synthesized and characterized as a key intermediate of the catalytic cycle. The determination of reaction orders and control experiments indicated that the nucleophilic attack of the formamide catalyst onto the reagent BzCl is the rate-determining step. Linear free energy relationship revealed a correlation between the quantified Lewis basicity strength of formamides by means of 11B NMR spectroscopy and their catalytic activity in SN-transformations. The observed difference in catalytic ability was attributed to the natural bond order charge, dipole moment, and Sterimol parameter B5. Importantly, this rationalization enables the prediction of the capacity of formamides to promote SN-type transformations in general.
An efficient and convenient chloromethylation of some aromatic compounds catalyzed by zinc iodide
Tang, Jian,Liu, Hongtao,Zhou, Jing,Zhang, Xingxian
, p. 34 - 38 (2019/06/21)
Treatment of a series of aromatic hydrocarbons and O-carbethoxy phenol substrates with a mixture of chlorosulfonic acid and dimethoxymethane in CH2Cl2 catalyzed by zinc iodide affords the corresponding chloromethyl derivatives in good to excellent yields.
A practical and convenient Blanc-type chloromethylation catalyzed by zinc chloride under solvent-free conditions
Tang, Jian,Liu, Hongtao,He, Kailun,Zhang, Xingxian
, p. 925 - 932 (2019/03/17)
Chloromethylation of various aromatic hydrocarbons and substituted phenolic derivatives with dimethoxymethane and chlorosulfonic acid was carried out in the presence of 10 mol% of ZnCl2 in a mild and efficient manner under solvent-free conditions. In addition, 2,6-dimethyltyrosine was synthesized in high yield via this protocol.
Organocatalytic Chlorination of Alcohols by P(III)/P(V) Redox Cycling
Longwitz, Lars,Jopp, Stefan,Werner, Thomas
, p. 7863 - 7870 (2019/06/27)
A catalytic system for the chlorination of alcohols under Appel conditions was developed. Benzotrichloride is used as a cheap and readily available chlorinating agent in combination with trioctylphosphane as the catalyst and phenylsilane as the terminal reductant. The reaction has several advantages over other variants of the Appel reaction, e.g., no additional solvent is required and the phosphane reagent is used only in catalytic amounts. In total, 27 different primary, secondary, and tertiary alkyl chlorides were synthesized in yields up to 95%. Under optimized conditions, it was also possible to convert epoxides and an oxetane to the dichlorinated products.
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.
A General Catalytic Method for Highly Cost- and Atom-Efficient Nucleophilic Substitutions
Huy, Peter H.,Filbrich, Isabel
supporting information, p. 7410 - 7416 (2018/04/30)
A general formamide-catalyzed protocol for the efficient transformation of alcohols into alkyl chlorides, which is promoted by substoichiometric amounts (down to 34 mol %) of inexpensive trichlorotriazine (TCT), is introduced. This is the first example of a TCT-mediated dihydroxychlorination of an OH-containing substrate (e.g., alcohols and carboxylic acids) in which all three chlorine atoms of TCT are transferred to the starting material. The consequently enhanced atom economy facilitates a significantly improved waste balance (E-factors down to 4), cost efficiency, and scalability (>50 g). Furthermore, the current procedure is distinguished by high levels of functional-group compatibility and stereoselectivity, as only weakly acidic cyanuric acid is released as exclusive byproduct. Finally, a one-pot protocol for the preparation of amines, azides, ethers, and sulfides enabled the synthesis of the drug rivastigmine with twofold SN2 inversion, which demonstrates the high practical value of the presented method.
