3251-56-7Relevant articles and documents
Photochemical Methoxide Exchange in Some Nitromethoxybenzenes. The Role of the Nitro Group in SN2Ar* Reactions
Riel, H. C. H. A. van,Lodder, G.,Havinga, E.
, p. 7257 - 7262 (1981)
Photoinduced methoxide exchange has been measured for o-, m-, and p-nitromethoxybenzene as well as for the methoxy-labeled 4-nitroveratroles.In these reactions (of the SN23Ar* type), where the substituting and leaving groups are the same, the origin of the meta activation found cannot be otherwise than in the steps leading to the symmetrical ? complex.Next to considerations on the basis of charge distributions of the excited aromatic compounds and of electron densities in the HOMO and LUMO, a rationalization for the regioselectivity and activation is offered on the basis of the energy gap between the ground-state and the excited-state surfaces.Since the level of the ground-state ? complex corresponding to meta substitution as compared to that for ortho/para substitution is highest in energy and since the trajectory from the (triplet) excited state leading to the ? complex for meta substitution is lowest in energy, the energy gap between the excited-state and ground-state hypersurface is considerable smaller for the geometry that leads to the meta ? complex and thus to meta substitution.Meta direction and activation of photosubstitutions will therefore be outspoken in the case of a substituent that gives difficult or no substitution at the meta position in the ground state and brings with it low triplet energy.The NO2 group conforms nicely to these criteria.
Synthesis and Antileishmanial Evaluation of Arylimidamide-Azole Hybrids Containing a Phenoxyalkyl Linker
Abdelhameed, Ahmed,Feng, Mei,Joice, April C.,Zywot, Emilia M.,Jin, Yiru,La Rosa, Chris,Liao, Xiaoping,Meeds, Heidi L.,Kim, Yena,Li, Junan,McElroy, Craig A.,Wang, Michael Zhuo,Werbovetz, Karl A.
, p. 1901 - 1922 (2021/02/22)
Due to the limitations of existing medications, there is a critical need for new drugs to treat visceral leishmaniasis. Since arylimidamides and antifungal azoles both show oral activity in murine visceral leishmaniasis models, a molecular hybridization approach was employed where arylimidamide and azole groups were separated by phenoxyalkyl linkers in an attempt to capitalize on the favorable antileishmanial properties of both series. Among the target compounds synthesized, a greater antileishmanial potency against intracellular Leishmania donovani was observed as the linker length increased from two to eight carbons and when an imidazole ring was employed as the terminal group compared to a 1,2,4-triazole group. Compound 24c (N-(4-((8-(1H-imidazol-1-yl)octyl)oxy)-2-isopropoxyphenyl) picolinimidamide) displayed activity against L. donovani intracellular amastigotes with an IC50 value of 0.53 μM. When tested in a murine visceral leishmaniasis model, compound 24c at a dose of 75 mg/kg/day p.o. for five consecutive days resulted in a modest 33% decrease in liver parasitemia compared to the control group, indicating that further optimization of these molecules is needed. While potent hybrid compounds bearing an imidazole terminal group were also strong inhibitors of recombinant CYP51 from L. donovani, as assessed by a fluorescence-based assay, additional targets are likely to play an important role in the antileishmanial action of these compounds.
Engineering Orthogonal Methyltransferases to Create Alternative Bioalkylation Pathways
Bennett, Matthew R.,Cronin, Victoria A.,Herbert, Abigail J.,Micklefield, Jason,Shepherd, Sarah A.,Sung, Rehana
supporting information, p. 14950 - 14956 (2020/07/04)
S-adenosyl-l-methionine (SAM)-dependent methyltransferases (MTs) catalyse the methylation of a vast array of small metabolites and biomacromolecules. Recently, rare carboxymethylation pathways have been discovered, including carboxymethyltransferase enzymes that utilise a carboxy-SAM (cxSAM) cofactor generated from SAM by a cxSAM synthase (CmoA). We show how MT enzymes can utilise cxSAM to catalyse carboxymethylation of tetrahydroisoquinoline (THIQ) and catechol substrates. Site-directed mutagenesis was used to create orthogonal MTs possessing improved catalytic activity and selectivity for cxSAM, with subsequent coupling to CmoA resulting in more efficient and selective carboxymethylation. An enzymatic approach was also developed to generate a previously undescribed co-factor, carboxy-S-adenosyl-l-ethionine (cxSAE), thereby enabling the stereoselective transfer of a chiral 1-carboxyethyl group to the substrate.
ANTI-PARASITIC COMPOUNDS
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Paragraph 00124, (2018/03/25)
Provided are compounds, methods, and pharmaceutical compositions useful for treatment of parasites, e.g., Leishmania. For example, the compound may he represented by Ar—C(=NR1)NR2—A—X—Y—Het2, and pharmaceutically acceptable salts thereof. Ar may be an optionally substituted, aryl or nitrogen-containing heteroaryl. R1 and R2 may independently represent H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl. X may be O, S, amide, or a bond. Y may be optionally substituted C1-C14 alkyl or optionally substituted C2-C14 alkenyl. Het2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
Synthesis method of 2-amino-4-chloro-6-metoxyphenol
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Paragraph 0004; 0007, (2016/11/14)
The invention discloses a synthesis method of 2-amino-4-chloro-6-metoxyphenol, which belongs to the field of chemical synthesis. The method comprises the following steps of adding p-nitrophenol of nitrosonitric acid and sulfuric acid into phenol, adding methane chloride and anhydrous glacial acetic acid to obtain a mixture, then putting the mixture into a high-pressure autoclave, adding absolute ethyl alcohol and inputting hydrogen, performing pumping filtration to obtain filter residues after reaction, adding copper chloride into the filter residues, generating light green precipitation after adjusting pH through sodium hydroxide, filtering, washing the filter residues and drying to obtain the 2-amino-4-chloro-6-metoxyphenol.
Reactions of aryl 5-substituted-2-thiophenecarboxylates promoted by 4-Z-C6H4O-/4-Z-C6H4OH in 20 mol % DMSO(aq). Effect of nucleophile on acyl-transfer reaction
Pyun, Sang Yong,Paik, Kyu Cheol,Han, Man So,Cho, Bong Rae
, p. 2810 - 2814 (2016/02/05)
Nucleophilic substitution reactions of 5-XC4H2(S)C(O)OC6H3-2-Y-4-NO2 (1) promoted by 4-Z-C6H4O-/4-Z-C6H4OH in 20 mol % dimethyl sulfoxide (DMSO)(aq) have been studied kinetically. The reactions exhibited second-order kinetics with βacyl = -2.52 to -2.83, ρ(x) = 2.81-3.16, βnuc = 0.88-0.04 and βlg = -0.94, respectively. The results have been interpreted with an addition-elimination mechanism in which the nucleophilic attack occurs in the rate-determining step. Comparison with existing data reveals that the ratedetermining step changes from the second to the first step by the change in the nucleophile from R2NH/R2NH2+ to 4-Z-C6H4O-/4-Z-C6H4OH.
Elimination reactions of aryl furylacetates promoted by r 2NH-r2NH2 + in 70 mol% MeCN(aq). effects of β-aryl on the ketene-forming transition-state
Pyun, Sang Yong,Kim, Ju Chang,Cho, Bong Rae
supporting information, p. 2143 - 2147 (2014/12/10)
Ketene-forming elimination from 2-X-4-nitrophenyl furylacetates (1a-d) promoted by r2NH-r2NH2 + in 70 mol % MeCN(aq) has been studied kinetically. When X = Cl and NO2, the reactions exhibited second-order kinetics as well as Broensted β = 0.37-0.54 and |βlg| = 0.31-0.45. The Broensted β decreased with a poorer leaving group and |βlg| increased with a weaker base. The results are consistent with an E2 mechanism. When the leaving group was changed to a poorer one [X= H (1a) and OCH3 (1b)], the reaction mechanism changed to the competing E2 and E1cb mechanisms. A further change to the E1cb mechanism was realized for the reaction of 1a with i-Pr2NH/i-Pr2NH2 + in 70 mol % MeCN-30 mol % D2O. By comparing the kinetic results in this study with the existing data for ArCH2C(O)OC6H3-2-X-4-NO 2, the effect of the β-aryl group on the ketene-forming elimination was assessed.
A practical approach for regioselective mono-nitration of phenols under mild conditions
Chen, Ling-Yan,Liu, Tao,Zhou, Xiaokun,Sun, Zhihua
, p. 64 - 71 (2014/07/22)
Cu(NO3)2.3H2O was demonstrated to be an efficient, regioselective and inexpensive nitrating reagent for the synthesis of mono-nitro substituted phenolic compounds. 12 examples of different phenols were examined. Good yields (67-90%) have been achieved. ARKAT-USA, Inc.
A probable hydrogen-bonded meisenheimer complex: An unusually high S NAr reactivity of nitroaniline derivatives with hydroxide ion in aqueous media
Imoto, Mitsutaka,Matsui, Yasunori,Takeda, Motonori,Tamaki, Akihiro,Taniguchi, Hisaji,Mizuno, Kazuhiko,Ikeda, Hiroshi
experimental part, p. 6356 - 6361 (2011/10/05)
Observations show that nitroanilines exhibit an unusually high S NAr reactivity with OH- in aqueous media in reactions that produce nitrophenols. SNAr reaction of 4-nitroaniline (2a) in aqueous NaOH for 16 h yields 4-nitrophenol (4a) quantitatively, whereas a similar reaction of 4-nitrochlorobenzene (1a) gave 4a in 2% yield together with recovered 1a in 97%, suggesting that the leaving ability of the NH2 group far surpasses that of Cl under these conditions. An essential feature of SNAr reactions of nitroanilines is probably that the NH2 leaving group participates in a hydrogen-bonding interaction with H 2O. Density functional theory (DFT) calculations for a set of 4-nitroaniline, OH-, and H2O suggest a possible formation of a Meisenheimer complex stabilized by hydrogen-bonding interactions and a six-membered ring structure. The results obtained here contrast with conventional SNAr reactivity profiles in which nitroanilines are nearly unreactive with nucleophiles in organic solvents.
Fluoride-induced intermolecular excimer formation of bispyrenyl thioureas linked by polyethylene glycol chains
Thongkum, Duangrat,Tuntulani, Thawatchai
experimental part, p. 8102 - 8109 (2011/10/30)
New bispyrenyl thioureas linked by polyethylene glycol (PEG) chains, L1-L3, and methoxy benzene pyrene thiourea, L4, were synthesized. Upon binding with F- in CHCl3, L1-L3 exhibited strong excimer emission bands (IE) and weak monomer emission bands (IM), while L4 displayed the same intensity of both bands. However, little or no change was observed in fluorescence spectra of L1 upon adding OH-, AcO -, BzO-, H2PO4-, Cl -, Br-, and I-. Therefore, only F- induced the pyrene excimer formation. Job's plots showed 1/1 or 2/2 complexation of L1 with F-. Ratios of IE/IM of L1·F- complex were dependent on the concentration of L1, implying that the dimerization of L1 proceeded via the intermolecular excimer formation. Among L1-L4, L1 possessed the highest binding constant and sensitivity toward F- implying the importance of the linking PEG chain. L1 was demonstrated to be an excellent probe for F- in CHCl3 with the detection limit as low as 46.2 μg/L.
