- Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
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Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
- Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
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p. 4623 - 4661
(2021/05/07)
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- Tandem Photoredox Catalysis: Enabling Carbonylative Amidation of Aryl and Alkylhalides
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We report a new visible-light-mediated carbonylative amidation of aryl, heteroaryl, and alkyl halides. A tandem catalytic cycle of [Ir(ppy)2(dtb-bpy)]+ generates a potent iridium photoreductant through a second catalytic cycle in the presence of DIPEA, which productively engages aryl bromides, iodides, and even chlorides as well as primary, secondary, and tertiary alkyl iodides. The versatile in situ generated catalyst is compatible with aliphatic and aromatic amines, shows high functional-group tolerance, and enables the late-stage amidation of complex natural products.
- Connell, Timothy U.,Forni, José A.,Micic, Nenad,Polyzos, Anastasios,Weragoda, Geethika
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supporting information
p. 18646 - 18654
(2020/08/21)
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- IrIII-Catalyzed direct syntheses of amides and esters using nitriles as acid equivalents: A photochemical pathway
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An unprecedented IrIII[df(CF3)ppy]2(dtbbpy)PF6-catalyzed simple photochemical process for direct addition of amines and alcohols to the relatively less reactive nitrile triple bond is described herein. Various amides and esters are synthesized as the reaction products, with nitriles being the acid equivalents. A mini-library of different types of amides and esters is made using this mild and efficient process, which uses only 1 mol% of photocatalyst under visible light irradiation (λ = 445 nm). The reaction strategy is also efficient for gram-scale synthesis.
- Talukdar, Ranadeep
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supporting information
p. 5303 - 5308
(2020/04/17)
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- Frustrated Lewis Pair Catalyzed Hydrogenation of Amides: Halides as Active Lewis Base in the Metal-Free Hydrogen Activation
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A method for the metal-free reduction of carboxylic amides using oxalyl chloride as an activating agent and hydrogen as the final reductant is introduced. The reaction proceeds via the hydrogen splitting by B(2,6-F2-C6H3)3 in combination with chloride as the Lewis base. Density functional theory calculations support the unprecedented role of halides as active Lewis base components in the frustrated Lewis pair mediated hydrogen activation. The reaction displays broad substrate scope for tertiary benzoic acid amides and α-branched carboxamides.
- Sitte, Nikolai A.,Bursch, Markus,Grimme, Stefan,Paradies, Jan
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supporting information
p. 159 - 162
(2019/01/04)
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- Cross-Dehydrogenating Coupling of Aldehydes with Amines/R-OTBS Ethers by Visible-Light Photoredox Catalysis: Synthesis of Amides, Esters, and Ureas
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A straightforward synthesis of amides, ureas, and esters is reported by visible-light cross-dehydrogenating coupling (CDC) of aldehydes (or amine carbaldehydes) and amines/R-OTBS ethers by photoredox catalysis. The reaction is found to be general and high yielding. A plausible mechanistic pathway has been proposed for these transformations and is supported by appropriate controlled experiments.
- Pandey, Ganesh,Koley, Suvajit,Talukdar, Ranadeep,Sahani, Pramod Kumar
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supporting information
p. 5861 - 5865
(2018/09/21)
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- Low-Pressure Radical11C-Aminocarbonylation of Alkyl Iodides through Thermal Initiation
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A radical11C-aminocarbonylation protocol characterized by excellent substrate compatibility was developed to transform alkyl iodides into11C-labelled amides, including the 11β-HSD1 inhibitor [carbonyl-11C]adamantan-1-yl(piperidin-1-yl)methanone. This protocol serves as a complementary extension of palladium-mediated11C-aminocarbonylation, which is limited to the preparation of11C-labelled compounds lacking beta-hydrogen atoms. The use of AIBN as a radical initiator and a low-pressure xenon–[11C]CO delivery unit represents a simple and convenient alternative to previous radical11C-carbonylation methodologies burdened with the need for a proprietary high pressure reactor connected to a light source.
- Chow, Shiao Y.,Odell, Luke R.,Eriksson, Jonas
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p. 5980 - 5989
(2016/12/26)
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- Mild and Low-Pressure fac-Ir(ppy)3-Mediated Radical Aminocarbonylation of Unactivated Alkyl Iodides through Visible-Light Photoredox Catalysis
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A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac-Ir(ppy)3-catalyzed radical aminocarbonylation protocol has been developed. Using a two-chambered system, alkyl iodides, fac-Ir(ppy)3, amines, reductants, and CO gas (released ex situ from Mo(CO)6), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.
- Chow, Shiao Y.,Stevens, Marc Y.,?kerbladh, Linda,Bergman, Sara,Odell, Luke R.
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supporting information
p. 9155 - 9161
(2016/07/14)
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- Mild Amide-Cleavage Reaction Mediated by Electrophilic Benzylation
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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.
- Yamada, Kohei,Karuo, Yukiko,Tsukada, Yuichi,Kunishima, Munetaka
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supporting information
p. 14042 - 14047
(2016/09/21)
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- PROCESSES USING MOLECULAR SIEVE SSZ-101
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This disclosure is directed to uses for a new crystalline molecular sieve designated SSZ-101. SSZ-101 is synthesized using a N-cyclohexylmethyl-N-ethylpiperidinium cation as a structure directing agent.
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- Metal–Organic Framework Based on Copper and Carboxylate-Imidazole as Robust and Effective Catalyst in the Oxidative Amidation of Carboxylic Acids and Formamides
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A metal–organic framework (MOF) based on copper and 1,3-bis(carboxymethyl)imidazole (bcmim) was prepared on a gram scale by using a precipitation method at room temperature. The Cu(bcmim)2MOF was shown to be an efficient catalyst for the preparation of amides through an oxidative coupling between carboxylic acids and formamides in the presence of an oxidant, such as tert-butyl hydroperoxide (TBHP). The method for the preparation of the amides is robust regardless of the carboxylic acid and gives good conversions with good selectivity. The heterogeneous catalyst was recovered unaltered after the reaction, was easily separated from the reaction mixture, and subsequently reactivated by suitable treatment. Moreover, the coupling reaction was scaled up to a gram scale, which allowed for the preparation of valuable products, such as fatty acid amides (i.e., 1-palmitoylpiperidine).
- Albert-Soriano, María,Pastor, Isidro M.
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supporting information
p. 5180 - 5188
(2016/10/26)
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- Light-enabled synthesis of anhydrides and amides
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Recently, we have demonstrated that the photogeneration of Vilsmeier-Haack reagents is possible using only dimethylformamide (DMF) and tetrabromomethane (CBr4) in the bromination of alcohols. Extending these findings to carboxylic acid substrates has produced a mild and facile approach to the in situ formation of symmetric anhydrides, which were conveniently converted to amide derivatives in a one-pot process. The efficient protocols discussed herein are marked by use of UVA LEDs (365 nm), which have reduced the reaction times and come with a low setup cost.
- Mccallum, Terry,Barriault, Louis
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p. 2874 - 2878
(2015/03/30)
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- Mild and selective Et2Zn-catalyzed reduction of tertiary amides under Hydrosilylation conditions
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Diethylzinc (Et2Zn) can be used as an efficient and chemoselective catalyst for the reduction of tertiary amides under mild reaction conditions employing cost-effective polymeric silane (PMHS) as the hydride source. Crucial for the catalytic activity was the addition of a substoichiometric amount of lithium chloride to the reaction mixture. A series of amides containing different additional functional groups were reduced to their corresponding amines, and the products were isolated in good-to-excellent yields.
- Kovalenko, Oleksandr O.,Volkov, Alexey,Adolfsson, Hans
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supporting information
p. 446 - 449
(2015/03/05)
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- Palladium-catalyzed aminocarbonylation of N-chloroamines with boronic acids
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Abstract Aryl (pseudo)halide-based (C-X) carbonylation reactions have been extensively studied during the past few decades. From both academic and synthetic points of view, the carbonylative transformation of N-X bonds represents an interesting and attractive area of investigation. In light of this, the first carbonylative cross-coupling between N-chloroamines and organoboronic acids has been developed. This new type of aminocarbonylation proceeds at mild temperatures (45-55 °C) with 2 mol % Pd/C (10 wt %) as the ligand-free catalyst. Not only arylboronic acids, but also alkenyl- and alkylboronic acids can be applied as the substrates and bromide and iodide substituents in the substrates are well tolerated. Initial mechanistic investigations have also been performed. Umpolung aminocarbonylation: The first palladium-catalyzed carbonylative cross-coupling between N-chloroamines and organoboronic acids has been realized. Various amides were isolated in moderate to excellent yields from reactions under mild temperatures with ligand-free Pd/C as the catalyst. Not only arylboronic acids, but also alkenyl- and alkylboronic acids are applied as the substrates and bromide and iodide substituents in the substrates are well tolerated.
- Li, Wanfang,Wu, Xiao-Feng
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supporting information
p. 7374 - 7378
(2015/05/27)
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- Organocatalytic oxidation of aldehydes to mixed anhydrides
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TEMPO catalyzes the direct oxidation of aldehydes to mixed anhydrides in the presence of a carboxylic acid. The anhydrides can be converted in situ to esters, secondary, tertiary or Weinreb amides in high yield. Oxidation of the aldehyde directly to 2-propyl esters is also possible using only catalytic amounts of acid. The oxidation reactions are rapid and take place under mild conditions.
- Toledo, Hila,Pisarevsky, Evgeni,Abramovich, Adi,Szpilman, Alex M.
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supporting information
p. 4367 - 4369
(2013/06/05)
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- Yttrium (amidate) complexes for catalytic C-N bond formation. Rapid, room temperature amidation of aldehydes
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Yttrium (amidate) precatalysts are highly active for the mild amidation of aldehydes with amines. Reactions occur at room temperature within 5 min in up to 98% isolated yield. These rare-earth systems are effective for this transformation in the absence of supplementary heat, light, base, or oxidants. The reaction proceeds with functionalized amines and/or aldehydes. A comparison of various amidate precatalysts in combination with reaction monitoring suggests that the targeted amide products formed during the reaction promote the formation of alternative catalytically active amidate species in situ.
- Thomson, Jaclyn A.,Schafer, Laurel L.
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experimental part
p. 7897 - 7904
(2012/08/07)
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- Pseudomonas stutzeri lipase: A useful biocatalyst for aminolysis reactions
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The use of Pseudomonas stutzeri lipase (PSL) as a biocatalyst for aminolysis reactions with bulky substrates has been investigated. PSL compared favorably to Novozym 435 (immobilized Candida antarctica lipase B, NOV435) in the aminolysis of various bulky methyl esters and amines. While NOV435 demonstrated a higher rate of aminolysis with methyl 2-phenylpropionic acid as the acyl donor, PSL outperformed NOV435 with secondary amines as the nucleophile. Methanol inhibition and a low affinity for bulky acyl donors were found to be the two main reasons for relatively low rates in the PSL-catalyzed aminolysis reactions. It was demonstrated that the use of molsieve 4A had a significant effect on the aminolysis rate and amide yield, since it enabled the effective removal of the inhibiting methanol from the reaction mixture.
- Van Pelt,Teeuwen,Janssen,Sheldon,Dunn,Howard,Kumar,Martinez,Wong
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experimental part
p. 1791 - 1798
(2011/10/09)
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- Zinc-catalyzed reduction of amides: Unprecedented selectivity and functional group tolerance
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(Chemical Equation Presented) A novel zinc-catalyzed reduction of tertiary amides was developed. This system shows remarkable chemoselectivity and substrate scope tolerating ester, ether, nitro, cyano, azo, and keto substituents. Copyright
- Das, Shoubhik,Addis, Daniele,Zhou, Shaolin,Junge, Kathrin,Beller, Matthias
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supporting information; experimental part
p. 1770 - 1771
(2010/04/25)
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- Tetrabenzylpyrophosphate: An efficient catalyst for the synthesis of carboxamides from carboxylic acids and amines
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An efficient method for the synthesis of simple and sterically hindered carboxamides from various carboxylic acids and amines using tetrabenzylpyrophosphate (TBPP) as a coupling agent in the presence of 4-(dimethylamino)pyridine (DMAP) is described. The r
- Thirupathi Reddy,Narsimha Reddy,Raghotham Reddy,Crooks, Peter A.
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p. 528 - 529
(2008/09/21)
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- Highly efficient method for the synthesis of carboxamides from carboxylic acids and amines using benzenesulfonic anhydride (BSA)
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A highly efficient method by using benzenesulfonic anhydride (BSA) in the presence of 4-(dimethylamino)pyridine (DMAP) to synthesize carboxamides from various carboxylic acids and amines including sterically hindered ones is established. This reaction proceeds smoothly to provide the desired product in high yield. Copyright
- Funasaka, Setsuo,Kato, Koji,Mukaiyama, Teruaki
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p. 1456 - 1457
(2008/03/14)
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- Mild, powerful, and robust methods for esterification, amide formation, and thioesterification between acid chlorides and alcohols, amines, thiols, respectively
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We developed two efficient practical methods for esterification, amide formation, and thioesterification between acid chlorides and alcohols, amines, thiols, respectively. The present mild and robust reaction was performed by two separate methods both by combining cheap and readily available amines, N-methylimidazole, and N,N,N′,N′-tetramethylethylenediamine (TMEDA). Method A uses catalytic N-methylimidazole and TMEDA with an equimolar amount of K2CO3, whereas Method B uses equimolar amounts of N-methylimidazole and TMEDA. The salient features are as follows. (i) With regard to reactivity, Method B was superior to Method A for esterification and thioesterification, whereas cost-effective Method A was superior to Method B for amide formation. (ii) Amide formation proceeded smoothly between acid chlorides and less nucleophilic and stereocongested amines such as 2,6-dichloroaniline. (iii) This protocol was applied to the successful synthesis of two agrochemicals, bromobutide and carpropamid.
- Nakatsuji, Hidefumi,Morimoto, Mami,Misaki, Tomonori,Tanabe, Yoo
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p. 12071 - 12080
(2008/03/13)
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- A convenient method for the synthesis of carboxamides and thioesters by using tetrakis(2-methylimidazol-1-yl)silane
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Tetrakis(2-methylimidazol-1-yl)silane [Si(2-Me-Im)4], a new dehydrating reagent having silicon-imidazole linkage, reacted readily with carboxylic acids at room temperature to form the corresponding 1-acyl-2-methylimidazole intermediates, which smoothly underwent subsequent condensation with nucleophiles such as amines or thiols to afford the corresponding carboxamides or thioesters in good to excellent yields, respectively.
- Tozawa, Takashi,Yamane, Yoshinobu,Mukaiyama, Teruaki
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p. 629 - 641
(2007/10/03)
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- Water solvent method for esterification and amide formation between acid chlorides and alcohols promoted by combined catalytic amines: Synergy between N-methylimidazole and N,N,N′,N′-tetramethylethylenediamine (TMEDA)
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An efficient method for esterification between acid chlorides and alcohols in water as solvent has been developed by combining the catalytic amines, N-methylimidazole and N,N,N′,N′-tetramethylethylenediamine (TMEDA). The present Schotten-Baumann-type reaction was performed by maintaining the pH at around 11.5 using a pH controller to prevent the decomposition of acid chlorides and/or esters and to facilitate the condensation. The choice of catalysts (0.1 equiv.) was crucial: the combined use of N-methylimidazole and TMEDA exhibited a dramatic synergistic effect. The catalytic amines have two different roles: (i) N-methylimidazole forms highly reactive ammonium intermediates with acid chlorides and (ii) TMEDA acts as an effective HCl binder. The production of these intermediates was rationally supported by a careful 1H NMR monitoring study. Related amide formation was also achieved between acid chlorides and primary or secondary amines, including less nucleophilic or water-soluble amines such as 2-(or 4-)chloroaniline, the Weinreb N-methoxyamine, and 2,2-dimethoxyethanamine.
- Nakatsuji, Hidefumi,Morita, Jun-Ichi,Misaki, Tomonori,Tanabe, Yoo
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p. 2057 - 2062
(2007/10/03)
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- An effective method for the synthesis of carboxamides by using tetrakis(pyridine-2-yloxy)silane as a mild coupling reagent
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Tetrakis(pyridin-2-yloxy)silane [Si(OPy)4] is easily prepared by trans-silylation between silicon tetrachloride and trimethyl(pyridin-2-yloxy) silane in the molar ratio of 1:4. This novel reagent is effectively employed as a mild dehydrating reagent in forming various carboxamides from the corresponding carboxylic acids and amines that involve secondary or tertiary alkyl substituted ones in good to high yields without using any basic promoters such as tertiary amines or 4-(dimethylamino)pyridine. Copyright
- Tozawa, Takashi,Yamane, Yoshinobu,Mukaiyama, Teruaki
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p. 1334 - 1335
(2007/10/03)
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- Indium-mediated mild and facile method for the synthesis of amides
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Indium-mediated coupling reactions of acyl chlorides and amines for the synthesis of amide bonds are described. The reaction afforded high yields of the desired amides under mild and neutral conditions, and it was applicable also to the preparation of peptides without epimerization.
- Cho, Dae Hyan,Jang, Doo Ok
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p. 2285 - 2287
(2007/10/03)
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- Simple, Mild, and Practical Esterification, Thioesterification, and Amide Formation Utilizing p-Toluenesulfonyl Chloride and N-Methylimidazole
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We have developed an efficient method for the esterification or thioesterification of equimolar amounts of carboxylic acids and alcohols or thiols using a novel reagent, p-toluenesulfonyl chloride (TsCl) together with N-methylimidazole. The present method is simple, mild, and reactive, uses readily available and economical reagents. The choice of amine is critical for the present method. The amine, N-methylimidazole, has two roles: (i) as an HCl scavenger for the initial smooth generation of mixed anhydrides between carboxylic acids and TsCl and (ii) successive formation of highly reactive ammonium intermediates from mixed anhydrides. This method could be applied to various types of carboxylic acids, alcohols, and thiols: a) several functionalities were tolerated; b) two N-Cbz amino acids were smoothly esterified without racemization; and c) the labile 1β-methylcarbapenem key intermediate and a pyrethroid insecticide, prallethrin, were successfully prepared. The related amide formation between carboxylic acids and primary or secondary amines was also performed. The proposed reaction mechanism involves a novel method for producing the reactive acylammonium intermediates. The production of these intermediates was rationally supported by a careful 1H NMR monitoring study.
- Wakasugi, Kazunori,Iida, Akira,Misaki, Tomonori,Nishii, Yoshinori,Tanabe, Yoo
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p. 1209 - 1214
(2007/10/03)
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- Novel and efficient method for esterification, amidation between carboxylic acids and equimolar amounts of alcohols, and amines utilizing Me2NSO2Cl and N,N-dimethylamines; Its application to the synthesis of coumaperine, a natural chemopreventive dieneamide
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Various carboxylic esters or amides were prepared in good to excellent yield between carboxylic acids and equimolar amounts of alcohols or amines under very mild conditions (0-45°C; within 3 h) using dimethylsulfamoyl chloride (Me2NSO2Cl; 1) combined with N,N-dimethylamines (Me2NR: 2a; R=Me, 2b; R=Bu). The choice of the sulfamoyl chloride and the amine is crucial for the reaction; that is, sterically uncrowded amines accelerated the present esterification and amidation. This agent had some advantages over methanesulfonyl chloride (3)/amines as for the atom-economy, avoidance of side reactions, and had very high chemoselectivity toward the carboxyl group vs the hydroxyl group; the experiment was performed by the addition of 1 to the mixture of carboxylic acids and alcohols. Application of this method to the synthesis of coumaperine, a chemopreventive natural product, was performed using the present amidation as a key step.
- Wakasugi, Kazunori,Nakamura, Atsushi,Iida, Akira,Nishii, Yoshinori,Nakatani, Nobuji,Fukushima, Shoji,Tanabe, Yoo
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p. 5337 - 5345
(2007/10/03)
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- Me2NSO2Cl and N,N-dimethylamines; a novel and efficient agent for esterification, amidation between carboxylic acids, and equimolar amounts of alcohols and amines
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Various carboxylic esters or amides were prepared in good to excellent yields between carboxylic acids and equimolar amounts of alcohols or amines under very mild conditions using dimethylsulfamoyl chloride (Me2NSO2Cl) combined with N,N-dimethylamines. The choice of the sulfamoyl chloride and the amine is crucial for the reactions.
- Wakasugi, Kazunori,Nakamura, Atsushi,Tanabe, Yoo
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p. 7427 - 7430
(2007/10/03)
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- Direct Aminolysis of Nonactivated and Thermally Unstable Esters at High Pressure
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The preparation of the amides 3 from a wide variety of nonactivated esters 1 and secondary amines 2 has been achieved at 8 kbar and around 45 deg C; scope and limitations are discussed.The method was also successfully applied for the aminolysis of alkyl 2-arylsulfinylacetates 7 that are relatively sensitive to heat. - Key Words: Aminolysis/ High-pressure synthesis
- Matsumoto, Kiyoshi,Hashimoto, Shiro,Uchida, Takane,Okamoto, Tadashi,Otani, Shinichi
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p. 1357 - 1364
(2007/10/02)
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