122-28-1Relevant articles and documents
SN2 mechanism for alcoholysis, aminolysis, and hydrolysis of acetyl chloride
Bentley, T. William,Llewellyn, Gareth,McAlister, J. Anthony
, p. 7927 - 7932 (1996)
First-order solvolysis rate constants are reported for solvolyses of acetyl chloride in methanol and MeOD, and in binary aqueous mixtures with acetone, acetonitrile, ethanol, methanol, and trifluoroethanol at 0°C. Product selectivities (S = [MeCOOR]/[MeCOOH] x [water]/[alcohol]) are reported for solvolyses in ethanol/ and methanol/water at 0°C. Solvolyses of acetyl chloride show a high sensitivity to changes in solvent ionizing power, consistent with C-Cl bond cleavage. As the solvent is varied from pure ethanol (or methanol) to water, S values and rate-rate profiles show no evidence for the change in reaction channel observed for solvolyses of benzoyl and trimethylacetyl chlorides. However, using rate ratios in 40% ethanol/water and 97% trifluoroethanol/ water (solvents of similar ionizing power but different nucleophilicities) to compare sensitivities to nucleophilic attack, solvolyses of acetyl chloride are over 20-fold more sensitive to nucleophilic attack than benzoyl chloride. The solvent isotope effect of 1.29 (MeOH/MeOD) for acetyl chloride is similar to that for p-methoxybenzoyl chloride (1.22) and is lower than for benzoyl chloride (1.55). Second-order rate constants for aminolyses of acetyl chloride with m-nitroaniline in methanol at 0°C show that acetyl chloride behaves similarly to p-methoxybenzoyl chloride, whereas benzoyl chloride is 40-fold more sensitive to the added amine. The results indicate mechanistic differences between solvolyses of acetyl and benzoyl chlorides, and an SN2 mechanism is proposed for solvolyses and aminolyses by m-nitroaniline of acetyl chloride (i.e. these reactions are probably not carbonyl additions, but a strong sensitivity to nucleophilic attack accounts for their high rates).
2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
Bayliss, Richard,Boxall, Kathy,Carbain, Benoit,Coxon, Christopher R.,Fry, Andrew M.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Harnor, Suzannah J.,Mas-Droux, Corine,Matheson, Christopher J.,Newell, David R.,Richards, Mark W.,Sivaprakasam, Mangaleswaran,Turner, David,Cano, Céline
supporting information, p. 707 - 731 (2020/08/24)
Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2. This journal is
SO2F2-Activated Efficient Beckmann Rearrangement of Ketoximes for Accessing Amides and Lactams
Zhang, Guofu,Zhao, Yiyong,Xuan, Lidi,Ding, Chengrong
supporting information, p. 4911 - 4915 (2019/07/31)
A novel, mild and practical protocol for the efficient activation of the Beckmann rearrangement utilizing the readily available and economical sulfuryl fluoride (SO2F2 gas) has been developed. The substrate scope of the operationally simple methodology has been demonstrated by 37 examples with good to nearly quantitative isolated yields (over 90 % yield in most cases) in a short time, including B(OH)2, COOH, NH2, and OH substituted substrates. A tentative mechanism was proposed involving formation and elimination of key intermediate, sulfonyl ester.
