Regioselective synthesis of 1-alkyl-5-(indol-3-yl- and -2-yl)pyrrolidin-2-ones from available reagents

Abstract

It is known that the combination of pharmacophoric fragments in a single molecule often leads to a strengthening and/or to a change in the pharmacological properties of the molecule. In this connection there is significant interest in studying compounds which contain indole and -aminobutyric acid (e.g. -butyrolactone) fragments in the molecule. A single compound of this type has been synthesized previously [1] but the method proposed by the authors is inconvenient and is not sufficiently general. Some time ago we carried a simple synthesis of the 2-alkyl-3-(indol-3-yl-and -2-yl)isoindol-2-ones 1 and 2 [2]. N O R 4 N R 1 R 2 N N O R 4 R 3 R 1 1 2We suggested that using this method can also prove useful for synthesizing the 1-alkyl-5-(indol-3-yl)-pyrrolidin-2-ones 3a-k. The 5-hydroxypyrrolidin-2-ones 4a-d needed for this were prepared from succinic anhydride and the corresponding amines 5a-d.The intermediate succinamic acids 6a-d were readily prepared by mixing succinic anhydride with the corresponding amine in stoichiometric quantities in chloroform. Their cyclization to the corresponding imides 7a-d occurs with prolonged refluxing in benzene in a DeanStark apparatus in the presence of equivalent

Condensations based on 5‐(indol‐3‐yl)‐pyrrolidin‐2‐thiones

“…Tetrahydrofuran (THF) was distilled from lithium aluminum hydride in a nitrogen atmosphere prior to use; methylene chloride from calcium hydride. The starting indolylpyrrolidones 1a ‐ f were synthesized according to method . The reaction mixtures were separated by flash chromatography on a dry column with L grade (5/40) silica gel according to; the eluent was benzene.…”

“…The starting indolylpyrrolidones 1a-f were synthesized according to method. [8] The reaction mixtures were separated by flash chromatography on a dry column with L grade (5/40) silica gel according to [21] ; the eluent was benzene. The reaction progress, column chromatography fractions, and the purity of compounds were controlled by TLC on Silufol UV-254 plates, eluent benzene-EtOAc, 10:1 and 2:1, visualization with iodine vapor or UV light.…”

“…In recent years, demand for modification of these biologically significant molecules has increased. [5][6][7] Previously, we found a convenient method of preparative synthesis of 5-(indolyl-3)-pyrrolidones [8] and showed reduced reactivity of the carbonyl group of these compounds in organic synthesis. [9] Synthesized derivatives of indole were of interest in terms of pharmacology, by analogy with the known structures.…”

Zinc‐Catalyzed Selective Reduction of Cyclic Imides with Hydrosilanes: Synthesis of ω‐Hydroxylactams

“…[2] The reduction of cyclic imides is commonly used to access w-hydroxylactams. [3] The reduction can also provide access to other heterocycles such as lactams, [4] substituted pyrroles, [5] pyrrolidines [6] or 4-hydroxybutyric amides [7] (ring-opening products) which proceed through the w-hydroxylactam as an intermediate (Scheme 1). Use of typical reducing reagents in the reduction of cyclic imides to w-hydroxylactams, such as LiAlH 4 or NaBH 4 , always results in undesired byproducts, so these reductions require careful temperature control.…”

Umpolung of Hemiaminals: Titanocene‐Catalyzed Dehydroxylative Radical Coupling Reactions with Activated Alkenes

“…We began our study with the treatment of hemiaminal 1 [12] and methyl acrylate (2.0 equiv) with [Cp 2 TiCl 2 ] (0.025 equiv), Mg powder (2.0 equiv), and TMSCl (2.0 equiv); the desired cross-coupling product 2 a was obtained in 54 % yield ( Table 1, entry 1). The influence of other reaction factors, including Lewis acids, protic additives, and metals, was systematically investigated.…”