6943-00-6Relevant academic research and scientific papers
Studies of hydrogen isotope scrambling during the dehalogenation of aromatic chloro-compounds with deuterium gas over palladium catalysts
Lockley, William J.S.,Venanzi, Niccolò A. E.,Crane, Georgie J.
, p. 531 - 552 (2020/09/22)
Catalytic dehalogenation of aromatic halides using isotopic hydrogen gas is an important strategy for labelling pharmaceuticals, biochemicals, environmental agents and so forth. To extend, improve and further understand this process, studies have been carried out on the scrambling of deuterium isotope with protium during the catalytic deuterodehalogenation of model aryl chlorides using deuterium gas and a palladium on carbon catalyst in tetrahydrofuran solution. The degree of scrambling was greatest with electron-rich chloroarene rings. The tetrahydrofuran solvent and the triethylamine base were not the source of the undesired protium; instead, it arose, substantially, from the water content of the catalyst, though other sources of protium may also be present on the catalyst. Replacement of the Pd/C catalyst with one prepared in situ by reduction of palladium trifluoroacetate with deuterium gas and dispersed upon micronised polytetrafluoroethylene led to much reduced scrambling (typically 0–6% compared with up to 40% for palladium on carbon) and to high atom% abundance, regiospecific labelling. The improved catalytic system now enables efficient polydeuteration via the dehalogenation of polyhalogenated precursors, making the procedure viable for the preparation of MS internal standards and, potentially, for high specific activity tritium labelling.
Identification of two arylimides as cholinesterase inhibitors and testing of propranolol addition on impaired rat memory
Ciprés-Flores, Fabiola J.,Farfán-García, Eunice D.,Andrade-Jorge, Erik,Cuevas-Hernández, Roberto I.,Tamay-Cach, Feliciano,Martínez-Archundia, Marlet,Trujillo-Ferrara, José G.,Soriano-Ursúa, Marvin A.
, p. 256 - 266 (2019/12/30)
Alzheimer's disease (AD) is clearly linked to the decline of acetylcholine (ACh) effects in the brain. These effects are regulated by the hydrolytic action of acetylcholinesterase (AChE). Therefore, a central palliative treatment of AD is the administration of AChE inhibitors although additional mechanisms are currently described and tested for generating advantageous therapeutic strategies. In this work, we tested new arylamides and arylimides as potential inhibitors of AChE using in silico tools. Then, these compounds were tested in vitro, and two selected compounds, C7 and C8, as well as propranolol showed inhibition of AChE. In addition, they demonstrated an advantageous acute toxicity profile compared to that of galantamine as a reference AChE inhibitor. in vivo evaluation of memory performance enhancement was performed in an animal model of cognitive disturbance with each of these compounds and propranolol individually as well as each compound combined with propranolol. Memory improvement was observed in each case, but without a significant additive effect with the combinations.
Late-stage oxidative C(sp 3)–H methylation
Feng, Kaibo,Kohrt, Jeffrey T.,Oderinde, Martins S.,Quevedo, Raundi E.,Reilly, Usa,White, M. Christina
, p. 621 - 627 (2020/05/04)
Frequently referred to as the ‘magic methyl effect’, the installation of methyl groups—especially adjacent (α) to heteroatoms—has been shown to dramatically increase the potency of biologically active molecules1–3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)–H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C–H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C–H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)–H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites—including drugs (for example, tedizolid) and natural products—are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates—an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1—via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.
A one pot protocol to convert nitro-arenes into: N-aryl amides
Massolo, Elisabetta,Pirola, Margherita,Puglisi, Alessandra,Rossi, Sergio,Benaglia, Maurizio
, p. 4040 - 4044 (2020/02/04)
A two-step one pot, experimentally simple protocol, based on readily available and inexpensive reagents allowed the conversion of nitro-arenes directly to N-aryl amides. A metal-free reduction of the nitro group, mediated by trichlorosilane, followed by the addition of an anhydride afforded the corresponding N-aryl carboxyamide, that was isolated after a simple aqueous work up in good-excellent yields. When the methodology was applied to the reaction with γ-butyrolactone, the desired N-aryl butanamide derivative was obtained, featuring a chlorine atom at the γ-position, a functionalized handle that can be used for further synthetic manipulation of the reaction product. Such an intermediate has already been employed as a key advanced precursor of pharmaceutically active compounds.
Synthesis of 3-(5-amino-1: H -1,2,4-triazol-3-yl)propanamides and their tautomerism
Lim, Felicia Phei Lin,Tan, Lin Yuing,Tiekink, Edward R. T.,Dolzhenko, Anton V.
, p. 22351 - 22360 (2018/07/03)
Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5) were proposed and successfully realized in the synthesis of 20 representative examples. These methods use the same types of starting material
Direct Synthesis of Cyclic Imides from Carboxylic Anhydrides and Amines by Nb2O5 as a Water-Tolerant Lewis Acid Catalyst
Ali, Md. A.,Moromi, Sondomoyee K.,Touchy, Abeda S.,Shimizu, Ken-Ichi
, p. 891 - 894 (2016/03/15)
In the 20 types of heterogeneous and homogenous catalysts screened, Nb2O5 showed the highest activity for the synthesis of N-phenylsuccinimide by dehydrative condensation of succinic anhydride and aniline. Nb2O5 was used in the direct imidation of a wide range of carboxylic anhydrides with NH3 or amines with various functional groups and could be reused. Kinetic studies showed that the Lewis acid Nb2O5 catalyst was more water tolerant than both the Lewis acidic oxide TiO2 and the homogeneous Lewis acid ZrCl4, which resulted in higher yields of imides through the use of Nb2O5. Int-imidation tactics: A general method for the direct synthesis of cyclic imides from cyclic anhydrides with amines (or ammonia) under solvent-free conditions is reported. Kinetic studies indicate that the Lewis acid sites of Nb2O5 are highly water tolerant, which results in high catalytic activity for imidation even in the presence of water formed during the reaction. The catalyst can be recovered and reused four times without a marked decrease in yield.
Synthesis of novel N-aryl-3-dialkylamino-4-substituted maleimides
Patil, Nilesh S.,Deshmukh, Ganesh B.,Mahale, Keshao A.,Gosavi, Kirankumar S.,Patil, Sambhaji V.
, p. 272 - 278 (2015/03/04)
The syntheses of several novel 3-dialkylamino-N-aryl-maleimides 3a-i and 6 are described via a conjugate elimination addition-elimination pathway. Syntheses of their various 4-substituted derivatives 4a-i, 5a-c and 7-12 are also described. Introduction of a secondary amino group at C-3 position in N-arylmaleimides leads to the formation of enaminones 3a-i and 6, which undergo facile electrophilic substitutions at C-4 position in good to excellent yields to provide the highly functionalized maleimides 4a-i, 5a-c and 7-12.
An expeditious synthesis of imides from phthalic, maleic and succinic anhydrides and chemoselective C=C reduction of maleic amide esters
Kumar, Padam Praveen,Reddy, Y. Dathu,Kumari, Y. Bharathi,Devi, B. Rama,Dubey
, p. 392 - 398 (2014/05/06)
Phthalic, maleic and succinic anhydrides have been reacted with aromatic amines to obtain the corresponding monoacid monoamides. The latter have been each transformed into the corresponding cyclic imide derivatives by treating with SOCl2. Alternatively, anhydrides have been reacted with methanolic KOH to obtain monomethyl ester derivatives which on reaction with aromatic amines in the presence of EDC. HCl and HOBt give cyclic imide derivatives. Reaction of monoacid monoamides independently, with SOCl 2 at 0-5°C give the monoamide monoester derivatives. Treatment of monoamide monoester of malic anhydride with NaBH4 leads to the unusual reduction of C=C grouping as well as the carbonyl group of the ester group to from monoamide monoalcohol of succinic anhydride. Preparation of monoamide monoalcohol of succinic anhydride can also be achieved by chemoselective reduction of monoamide monoester of malic anhydride with Mg turnings yielding monoamide monoester of succinic anhydride followed by reduction of the latter with NaBH4.
A convenient one-pot synthesis of polysubstituted pyrroles from N-protected succinimides
Kobeissi, Marwan,Yazbeck, Ogaritte,Chreim, Yamama
supporting information, p. 2523 - 2526 (2014/05/06)
The dienamine products formed by the reaction between polysubstituted succinimides and the Petasis reagent were subjected to isomerization under mild acidic conditions to give polysubstituted pyrroles in excellent yields (85-95%). The scope and limitations of this methodology are explored.
Versatile and sustainable synthesis of cyclic imides from dicarboxylic acids and amines by Nb2O5 as a base-tolerant heterogeneous lewis acid catalyst
Ali, Md. Ayub,Siddiki, S. M. A. Hakim,Kon, Kenichi,Hasegawa, Junya,Shimizu, Kenichi
supporting information, p. 14256 - 14260 (2015/01/09)
Catalytic condensation of dicarboxylics acid and amines without excess amount of activating reagents is the most atom-efficient but unprecedented synthetic method of cyclic imides. Here we present the first general catalytic method, proceeding selectively and efficiently in the presence of a commercial Nb2O5 as a reusable and base-tolerant heterogeneous Lewis acid catalyst. The method is effective for the direct synthesis of pharmaceutically or industrially important cyclic imides, such as phensuximide, N-hydroxyphthalimide (NHPI), and unsubstituted cyclic imides from dicarboxylic acid or anhydrides with amines, hydroxylamine, or ammonia.
