- Practical Chemoselective Acylation: Organocatalytic Chemodivergent Esterification and Amidation of Amino Alcohols with N-Carbonylimidazoles
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Chemoselective transformations are a cornerstone of efficient organic synthesis; however, achieving this goal for even simple transformations, such as acylation reactions, is often a challenge. We report that N-carbonylimidazoles enable catalytic chemodivergent aniline or alcohol acylation in the presence of pyridinium ions or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), respectively. Both acylation reactions display high and broad chemoselectivity for the target group. Unprecedented levels of chemoselectivity were observed in the DBU-catalyzed esterification: A single esterification product was obtained from a molecule containing primary aniline, alcohol, phenol, secondary amide, and N?H indole groups. These acylation reactions are highly practical as they involve only readily available, inexpensive, and relatively safe reagents; can be performed on a multigram scale; and can be used on carboxylic acids directly by in situ formation of the acylimidazole electrophile.
- Brown, Hailee,Heller, Stephen T.,Light, Christina,Medlin, Abigail,Nelson, Hope,Richard, William
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supporting information
p. 22818 - 22825
(2021/09/13)
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- BASE CONVERSION PROLIFERATOR
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PROBLEM TO BE SOLVED: To provide a photocurable composition with sufficient curability employing a photobase generator. SOLUTION: A base conversion proliferator comprises a compound represented by the specified general formula (1). The base conversion pro
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Paragraph 0174-0176
(2020/08/12)
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- Synthesis of Dithiolethiones and Identification of Potential Neuroprotective Agents via Activation of Nrf2-Driven Antioxidant Enzymes
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Oxidative stress is implicated in the pathogenesis of a wide variety of neurodegenerative disorders, and accordingly, dietary supplement of exogenous antioxidants or/and upregulation of the endogenous antioxidant defense system are promising for therapeutic intervention or chemoprevention of neurodegenerative diseases. Nrf2, a master regulator of the cellular antioxidant machinery, cardinally participates in the transcription of cytoprotective genes against oxidative/electrophilic stresses. Herein, we report the synthesis of 59 structurally diverse dithiolethiones and evaluation of their neuroprotection against 6-hydroxydopamine-or H2O2-induced oxidative damages in PC12 cells, a neuron-like rat pheochromocytoma cell line. Initial screening identified compounds 10 and 11 having low cytotoxicity but conferring remarkable protection on PC12 cells from oxidative-mediated damages. Further studies demonstrated that both compounds upregulated a battery of antioxidant genes as well as corresponding genes' products. Significantly, silence of Nrf2 expression abolishes cytoprotection of 10 and 11, indicating targeting Nrf2 activation is pivotal for their cellular functions. Taken together, the two lead compounds discovered here with potent neuroprotective functions against oxidative stress via Nrf2 activation merit further development as therapeutic or chemopreventive candidates for neurodegenerative disorders.
- Bai, Feifei,Fang, Jianguo,Song, Zi-Long,Zhang, Baoxin
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p. 2214 - 2231
(2020/03/06)
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- Ketoreductase catalyzed stereoselective bioreduction of α-nitro ketones
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We report here the stereoselective bioreduction of α-nitro ketones catalyzed by ketoreductases (KREDs) with publicly known sequences. YGL039w and RasADH/SyADH were able to reduce 23 class I substrates (1-aryl-2-nitro-1-ethanone (1)) and ten class II substrates (1-aryloxy-3-nitro-2-propanone (4)) to furnish both enantiomers of the corresponding β-nitro alcohols, with good-to-excellent conversions (up to >99%) and enantioselectivities (up to >99% ee) being achieved in most cases. To the best of our knowledge, KRED-mediated reduction of class II α-nitro ketones (1-aryloxy-3-nitro-2-propanone (4)) is unprecedented. Select β-nitro alcohols, including the synthetic intermediates of bioactive molecules (R)-tembamide, (S)-tembamide, (S)-moprolol, (S)-toliprolol and (S)-propanolol, were stereoselectively synthesized in preparative scale with 42% to 90% isolated yields, showcasing the practical potential of our developed system in organic synthesis. Finally, the advantage of using KREDs with known sequence was demonstrated by whole-cell catalysis, in which β-nitro alcohol (R)-2k, the key synthetic intermediate of hypoglycemic natural product (R)-tembamide, was produced in a space-time yield of 178 g L?1 d?1 as well as 95% ee by employing the whole cells of a recombinant E. coli strain coexpressing RasADH and glucose dehydrogenase as the biocatalyst.
- Wang, Zexu,Wu, Xiaofan,Li, Zhining,Huang, Zedu,Chen, Fener
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supporting information
p. 3575 - 3580
(2019/04/14)
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- A convenient synthesis of 2-acyl benzothiazoles/thiazoles from benzothiazole/thiazole and N,N'-carbonyldiimidazole activated carboxylic acids
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A convenient and efficient strategy for the synthesis of 2-acyl benzothiazoles/thiazoles has been developed. The treatment of benzothiazole/thiazole with allylic Grignard reagents readily generates the corresponding 2-Grignard reagents, which is followed by a reaction with N,N'-carbonyldiimidazole activated carboxylic acids to afford various 2-acyl benzothiazoles/thiazoles products. The synthetic method is applicable to a wide array of carboxylic acids and allows easy access to 2-acyl benzothiazoles/thiazoles with considerable yields under mild reaction conditions.
- Huang, Tonghui,Wu, Xin,Yu, Yongbo,An, Lin,Yin, Xiaoxing
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supporting information
p. 1667 - 1670
(2019/06/04)
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- Biology-oriented drug synthesis (BIODS): In vitro β-glucuronidase inhibitory and in silico studies on 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl carboxylate derivatives
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Current study is based on the biology-oriented drug synthesis (BIODS) of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl carboxylate derivatives 1–26, by treating metronidazole with different aryl and hetero-aryl carboxylic acids in the presence of 1,1'-carbonyl diimidazole (CDI) as a coupling agent. Structures of all synthetic derivatives were confirmed with the help of various spectroscopic techniques such as EI-MS,1H -NMR and13C NMR. CHN elemental analyses were also found in agreement with the calculated values. Synthetic derivatives were evaluated to check their β-glucuronidase inhibitory activity which revealed that except few derivatives, all demonstrated good inhibition in the range of IC50= 1.20 ± 0.01–60.30 ± 1.40 μM as compared to the standard D-saccharic acid 1,4-lactone (IC50= 48.38 ± 1.05 μM). Compounds 1, 3, 4, 6, 9–19, and 21–24 were found to be potent analogs and showed superior activity than standard. Limited structure-activity relationship is suggested that the molecules having electron withdrawing groups like NO2, F, Cl, and Br, were displayed better activity than the compounds with electron donating groups such as Me, OMe and BuO. To verify these interpretations, in silico study was also performed, a good correlation was observed between bioactivities and docking studies.
- Salar, Uzma,Khan, Khalid Mohammed,Taha, Muhammad,Ismail, Nor Hadiani,Ali, Basharat,Qurat-ul-Ain,Perveen, Shahnaz,Ghufran, Mehreen,Wadood, Abdul
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p. 1289 - 1299
(2016/12/06)
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- Ultrasound-assisted, convenient and widely applicable 1,1′-carbonyl-diimidazole-mediated "One-pot" syntheses of acyl/sulfonyl hydrazines
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Acyl / sulfonyl hydrazines were synthesized in a one-pot reaction from carboxylic acid/aryl sulfonic acid in the presence of 1,1′-carbonyl diimidazole (CDI) under ultrasound as well as under conventional heating. The reaction was performed on diverse organic molecules including simple benzoic acid (1), electron-donating and electron-withdrawing substituted benzoic acids, biologically active compounds like coumarin-3-carboxylic acid (12), 7-hydroxycoumarin-4-acetic acid (13), and therapeutic drugs like ibuprofen (14), flurbiprofen (15), naproxen (16) or tricyclic adamantane carboxylic acid (17). Benzene sulfonic acid (18) and its derivatives (19, 20, 21 and 22) were used to prepare corresponding sulfonyl hydrazide. All products were synthesized in very good yield via ultrasonic irradiation method and characterized by spectroscopic techniques including EIMS, 1H NMR, 13C NMR, IR. The method was found very simple, facile, efficient and high yielding (>90).
- Khan, Khalid Mohammed,Salar, Uzma,Fakhri, Muhammad Imran,Taha, Muhammad,Hameed, Abdul,Perveen, Shahnaz,Voelter, Wolfgang
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p. 637 - 644
(2015/11/09)
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- Modified McFadyen-Stevens reaction for a versatile synthesis of aliphatic/aromatic aldehydes: Design, optimization, and mechanistic investigations
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The traditional McFadyen-Stevens reaction requires harsh alkaline reaction conditions, thus precluding application to the synthesis of aliphatic aldehydes. Our modified McFadyen-Stevens reaction enables the transformation from the N,N-acylsulfonyl hydrazine to the corresponding aldehyde upon treatment with an imidazole-TMS imidazole combination without relying on oxidative or reductive reagents. The reduced basicity and in situ protection of the resulting aldehyde widens the substrate scope to include aliphatic aldehydes, even ones bearing an α-hydrogen atom. Close examination of the side reactions for particular substrates in combination with theoretical considerations via DFT calculations led to a mechanistic understanding of the McFadyen-Stevens reaction involving an acyl diazene and a hydroxy carbene as reasonable intermediates.
- Iwai, Yuri,Ozaki, Takashi,Takita, Ryo,Uchiyama, Masanobu,Shimokawa, Jun,Fukuyama, Tohru
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p. 1111 - 1119
(2013/06/04)
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- CDI-mediated monoacylation of symmetrical diamines and selective acylation of primary amines of unsymmetrical diamines
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A highly efficient and green protocol for monoacylation of symmetrical diamines and chemoselective acylation of primary amines of unsymmetrical diamines has been developed.
- Verma, Sanjeev K.,Ghorpade, Ramarao,Pratap, Ajay,Kaushik
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experimental part
p. 326 - 329
(2012/04/10)
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- Novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors
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A series of novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors was prepared via treatment of various diaryl amides with tetrachlorosilane/sodium azide. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles contained a methylsulfonyl or sulfonamide group as COX-2 pharmacophore displayed only low inhibitory potency towards COX-2. Most potent compounds showed IC50 values of 6 and 7 μM for COX-2. All compounds showed IC50 values greater 100 μM for COX-1 inhibition.
- Al-Hourani, Baker Jawabrah,Sharma, Sai Kiran,Suresh, Mavanur,Wuest, Frank
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supporting information; experimental part
p. 2235 - 2238
(2012/04/18)
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- Solvent free, N,N'-carbonyldiimidazole (CDI) mediated amidation
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The method involves CDI mediated amidation under solvent-free conditions. The protocol is green, simple, and scalable and has broad structural applicability. The protocol has also been used for BOC protection of amine. The protocol has reduced the time for CDI mediated amidation from 2-4 h to 5-10 min without the use of any dry organic solvent and nitrogen atmosphere.
- Verma, Sanjeev K.,Ghorpade, Ramarao,Pratap, Ajay,Kaushik
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experimental part
p. 2373 - 2376
(2012/05/31)
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- Asymmetric Rh(II)-catalyzed cyclopropanation of alkenes with diacceptor diazo compounds: P -methoxyphenyl ketone as a general stereoselectivity controlling group
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Different diacceptor diazo compounds bearing an α-PMP-ketone group were found to be effective carbene precursors for the highly stereoselective Rh2(S-TCPTTL)4-catalyzed cyclopropanation of alkenes (EWG = NO2, CN, CO2Me). The resulting products were readily transformed into a variety of biologically relevant enantiopure molecules, such as cyclopropane α- and β-amino acid derivatives. Different mechanistic studies carried out led to a rationale for the high diastereo- and enantioselectivity obtained, where the PMP-ketone moiety was found to play a critical role in the stereoinduction process. Additionally, the use of catalytic amounts of achiral Lewis bases to influence the enantioinduction of the reactions developed is documented.
- Lindsay, Vincent N. G.,Nicolas, Cyril,Charette, Andre B.
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supporting information; experimental part
p. 8972 - 8981
(2011/08/04)
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- Efficient synthesis of primary amides from carboxylic acids using n,n'-carbonyldiimidazole and ammonium acetate in ionic liquid
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A novel and efficient method for the conversion of carboxylic acids to primary amides using N,N'-carbonyldiimidazole in combination with ammonium acetate/triethyl amine system in [BMIM]BF4 is developed.
- Lee, Kwan Soo,Kim, Kee D.
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experimental part
p. 3497 - 3500
(2011/09/30)
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- Discovery of Benzamide Analogues as a Novel Class of 5-HT3 Receptor Agonists
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A 5-HT3 receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT3A receptor yielded substantial information concerning the analogues as 5-HT3 receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT3 receptor agonist, as it does not possess a positively charged functionality, which is essential for the binding of all orthosteric ligands to the receptor. Preliminary investigations suggest that the compounds may exert their effects on 5-HT3 receptors by binding to an allosteric site in the receptor complex.
- Jorgensen, Charlotte G.,Frolund, Bente,Kehler, Jan,Jensen, Anders A.
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scheme or table
p. 725 - 736
(2012/01/06)
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- Imidazole-catalyzed monoacylation of symmetrical diamines
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Figure Presented. An imidazole-catalyzed protocol for monoacylation of symmetrical diamines has been developed. The protocol gave selective monoacylation of aliphatic (cyclic and acyclic) primary and secondary diamines. In the reaction, imidazole acts as both catalyst and a leaving group. Different monoacylated piperazines and other diamines were synthesized at room temperature in an ethanol/water solvent system.
- Verma, Sanjeev K.,Acharya,Kaushik
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supporting information; experimental part
p. 4232 - 4235
(2010/11/04)
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- One-pot conversion of a representative series of carboxylic acids to the corresponding methyl ketones
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The use of imidazolide activation method for direct acylation of Meldrum's acid with carboxylic acids, and the subsequent acidic hydrolysis of the acylated products to methyl ketones, provide a simple and efficient method for a one-pot conversion of carboxylic acids to the corresponding methyl ketones.
- Hamilakis, Stylianos,Tsolomitis, Athanase
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p. 149 - 152
(2007/10/03)
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- Dissociation of Hydrogen Peroxide Adducts in Solution: the Use of Such Adducts for Epoxidation of Alkenes
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Solid adducts of hydrogen peroxide, when stirred with various solvents, provide equilibrium concentrations of anhydrous H2O2.The position of equilibrium is dependent on both the nature of the solvent and that of the adduct, so that controlled release of anhydrous H2O2 into solution can be arranged through proper choice of solvent and adduct.As one example of the advantage of such adducts, they have been used, in the presence of trichloroacetonitrile, carboxylic acid chlorides, imidazolides and anhydrides, as convenient means of epoxidising alkenes.
- Gonsalves, Antonio M. D'A. Rocha,Johnstone, Robert A. W.,Pereira, Mariette M.,Shaw, Jacqueline
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p. 2101 - 2118
(2007/10/02)
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- Facile Conversions of Carboxylic Acids into Amides, Esters, and Thioesters Using 1,1'-Oxalyldiimidazole and 1,1'-Oxalyldi(1,2,4-triazole)
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Aliphatic, aromatic, and heteroaromatic carboxylic acids react with 1,1'-oxalyldiimidazole (1) or 1,1'-oxalyldi(1,2,4-triazole) (2) in acetonitrile for 40 min at 40 degC to give the corresponding 1-acylazole intermediates (11), which promptly undergo aminolysis and alcoholysis to form amides (13) including dipeptides (14), esters (16), and thioesters (19).These findings show that both 1 and 2 can be utilized as condensing reagents for the synthesis of carboxylic acid derivatives.Keywords --- 1,1'-oxalyldiimidazole; 1,1'-oxalyldi(1,2,4-triazole); 1,1'-carbonyldiimidazole; 1-acylazole; condensing reagent; amidation; esterification; dipeptide; aminolysis; alcoholysis
- Kitagawa, Tokujiro,Kuroda, Hiroko,Sasaki, Hideaki,Kawasaki, Koichi
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p. 4294 - 4301
(2007/10/02)
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- α-Nitro Ketones and Esters from Acylimidazoles
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The anion of 2-(2-nitroethyl)-1,3-dioxolane (4), prepared from the corresponding 2-bromo compound (3), undergoes condensation with acylimidazoles to give the 3-nitro-4-oxobutanal acetals (9), which can serve as valuable polyfunctional intermediates.Condensation with 1-(methoxyoxalyl)imidazole gives the tetrafunctionalized methyl 4-(1,3-dioxolan-2-yl)-3-nitro-2-oxobutanoate (13), which, however, decomposed on attempted deprotection of the ester function.The syntheses in excellent yields of simple α-nitro ketones and α-nitro esters from acylimidazoles and nitroethane and 2-nitropropane are also described.
- Crumbie, Robyn L.,Nimitz, Jonathan S.,Mosher, Harry S.
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p. 4040 - 4045
(2007/10/02)
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- Solvent Effects on the Deacylation of Acylchymotrypsins: A Critical Comment on the Charge-Relay Hypothesis
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The pH dependencies for deacylation of a series of acyl-chymotrypsins, prepared by using peptide-free enzyme, are reported.The pKa' values exhibit considerable variation, from 7.63 for α-benzamide-trans-cinnamoyl-chymotrypsin to 6.6 for 3,5-din
- Hamilton, Susan E.,Zerner, Burt
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p. 1827 - 1831
(2007/10/02)
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