Synthesis and Structural Evaluation of 5-Methyl-6-acetyl Substituted Indole and Gramine

Abstract

The synthesis and crystal structures of 1-(5-methyl-1H-indol-6-yl)ethan-1-one (7), C 11 H 11 NO, and 1-{3-[(dimethylamino)methyl]-5-methyl-1H-indol-6-yl}ethan-1-one (8), C 14 H 18 N 2 O, are reported. The synthesis is based on the Diels-Alder cycloaddition of a substituted 2H-pyran-2-one derivative, followed by an acid-catalyzed cyclization and concomitant deprotection (the last two steps were carried out as a one-pot domino process) yielding substituted indole 7, which was further derivatized via Mannich reaction to the gramine derivative 8. Both structures 7 and 8 were determined on the basis of IR, 1 H NMR and mass spectroscopy, as well as by the elemental analysis and melting point determination. According to the single-crystal X-Ray diffraction analysis, the structure 7 has a single unique molecule in the asymmetric unit whereas the structure 8 contains four unique molecules in the asymmetric unit. Molecules 7 are linked via N-H···O hydrogen bonds between the secondary amine group and carbonyl moiety of the acetyl group of adjacent molecules, whereas molecules 8 are linked via N-H···N hydrogen bonds between the secondary and tertiary amine groups of adjacent molecules. Both structures are further stabilized by weak C-H···O, C-H···π and π···π interactions.

Recent Developments of Gramine: Chemistry and Biological Activity

“…In 2016, compound 27 was prepared using the Diels-Alder cycloaddition reaction, with compound 26 as the dienophile. Then, the substituted indole 28 was obtained via acid-catalyzed cyclization and concomitant deprotection, which further derivatized to the gramine analogue 29 via the Mannich reaction [22]. Scheme 4.…”

A 26-Membered Macrocycle Obtained by a Double Diels–Alder Cycloaddition Between Two 2H-Pyran-2-one Rings and Two 1,1'-(Hexane-1,6-diyl)bis (1H-pyrrole-2,5-dione)s

“…[27][28][29][30][31] Namely, it was already observed that 2H-pyran-2-ones can act as "double" dienes, reacting in two consecutive Diels-Alder reactions with two distinctive molecules of the dienophiles, yielding bicyclo[2.2.2]octenes. 30 The initial cycloaddition step leads to the formation of CO 2 -bridged oxabicyclo[2.2.2]octenes that in the next step eliminate a molecule of CO 2 (via a retro-hetero-Diels-Alder reaction) providing cyclohexadiene systems that act as new dienes for another molecule of dienophile finally providing the double cycloadducts.…”

Vilsmeier reagent, NaHSe and diclofenac acid chloride: one-pot synthesis of a novel selenoindolinone with potent anticancer activity

“…The chlorination of diclofenac (1) (Scheme 1, step 1) was attempted under three conditions, as previously reported in the literature: [10][11][12] (i) reux conditions with an excess of thionyl chloride (SOCl 2 ) for 2 h, 10 resulting in the degradation of diclofenac (1), observed by 1 H-NMR spectra; (ii) reaction with oxalyl chloride [Cl(CO) 2 Cl] in methylene chloride (DCM) at room temperature, 11 that did not yield the acid chloride 2 even at long periods of time (up to 72 h); and (iii) the use of few drops of N,N-dimethylformamide (DMF) as catalyst for the reaction for oxalyl chloride, which turned out to be the optimal conditions with quantitative yields (99%). 12 Regarding to molecular cyclization to render the lactam 1-(2,6-dichlorophenyl)indolin-2-one (3) (Scheme 1, step 2), several procedures have been published on the literature: radical photoredox cyclization, 13,14 acid catalyzed cyclization 15,16 and Mn(III)-based oxidative cyclization methods, 17 as well as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-based carboxyl activation cyclization, 18 among others. Nevertheless, these methods present limitations, including multiple steps, complex catalysis and use of expensive reagents.…”