2- and 3-phenylsulfonylindoles – synthetic equivalents of unsubstituted indole in N-alkylation reactions

Abstract

The N-alkylation of 2-and 3-phenylsulfonylindoles under various conditions and the subsequent removal of the activating phenylsulfonyl group by reductive desulfonylation using Raney nickel leads to N-alkylindoles in high yield. 2-Phenylsulfonylindole readily undergoes the Mitsunobu reaction, while isomeric 3-phenylsulfonylindole is relatively inert under these conditions.In medicinal chemistry, indole derivatives form one of the most important classes of heterocyclic compounds [1]. This importance is due to the wide distribution of the indole fragment in the structures of natural and synthetic biologically active compounds with a broad range of activities. An enormous variety of efficient synthetic methods for construction of the bicyclic indole system and its modifications is already known [2, 3]. Nevertheless, the search for new, reliable, and simple synthetic transformations for indole derivatives remains a subject of current research.The direct N-alkylation of indole is clearly the most attractive method for obtaining N-alkyl derivatives. The initial generation of the indolyl anion is usually required for the success of this reaction. However, the ambident properties of the indolyl anion facilitate formation of N-alkylation, C-alkylation, and N,C-dialkylation products [2,4,5]. The selectivity of the reaction of the indolyl anion and the alkylating agent depends significantly on the nature of the cation, solvent, and structure of the alkylating agent. Although high selectivity for this reaction may be achieved by varying these factors, the problem of selective preparation of an indole N-alkylation product requires a specific solution in each concrete case [2, 6-8]. Special synthetic methods based on the use of phase-transfer catalysis [9][10][11], ionic liquids as the solvent [12,13], other special solvents [14,15], bases [16], and alkylating agents [17], as well as microwave irradiation have been proposed to resolve this problem. Furthermore, generation of the indolyl anion from an N-unsubstituted indole and indole derivatives lacking electron-withdrawing substituents requires the use of a stoichiometric amount of strong bases, which significantly limits the range of functional group tolerating the reaction conditions. It is also important to note _______ * Dedicated to Professor V. I. Minkin on the occasion of his seventieth birthday.

Iodine-Catalyzed Regioselective 2-Sulfonylation of Indoles with Sodium Sulfinates

“…Indolyl aryl sulfones can be found in various drugs, such as SR 33805 oxalate, a Ca 2+ antagonist with length-dependent Ca 2+ -sensitizing properties in cardiac myocytes (Figure ) . Indolyl aryl sulfones are generally prepared by oxidation of the corresponding arylthioindoles . In recent years, alternative approaches have been developed for 3-arylsulfonyl indoles using aryl sulfonyl halides or aryl sulfonic acids as sulfonylation reagents .…”

One-pot, three-component Fischer indolisation–N-alkylation for rapid synthesis of 1,2,3-trisubstituted indoles

“…It is also plausible that reaction of the indole anion itself through C-3 was further compromising regioselectivity, despite the kinetic and thermodynamic favourability of N-alkylation. 42,43 In either case, there is an argument to suggest that higher reaction Organic & Biomolecular Chemistry Paper temperatures should favour alkylation through nitrogen; accordingly, we repeated our protocol (hydride addition, DMF addition, stir 5 minutes then BnBr addition) with heating applied to the reaction vessel following DMF addition. Whilst reactions at 50°C and 65°C offered modest improvements in regioselectivity, we were delighted to observe complete N-alkylation at 80°C, and this corresponded to 91% isolated yield (96% per step) of the desired 1,2,3-trisubstituted indole 4a.…”

Redox Amination Scope of Benzylic Ketones with Indoline: Synthetic and Mechanistic Insights

“…for C 16 H 17 N: C, 86.05; H, 7.67; N, 6.27, found: C, 86.11; H, 7.64; N, 6.30. N ‐(1‐Phenylethyl)‐1 H ‐indole ( 6c ) . 145 mg, 14%, yellow viscous liquid, eluent: EtOAc/hexane (20%), Rf = 0.53 (254 nm).…”

“…5H 2 O (0.1 m M )‐Catalyzed reaction of indoline ( 1 ; 500 mg, 4.2 m M ) with N ‐Boc‐2‐acetylpyrrole ( 27 ; 878 mg, 4.2 m M ) was performed at 120°C for 6 h in MeCN according to GP1. tert ‐Butyl indoline‐1‐carboxylate ( 28 ) . 615 mg, 45%, yellow viscous liquid, eluent: EtOAc/hexane (10%), Rf = 0.71 (254 nm).…”