Regioselective Formation of Substituted Indoles: Formal Synthesis of Lysergic Acid

Abstract

A Diels–Alder reaction‐based strategy for the synthesis of indoles and related heterocycles is reported. An intramolecular cycloaddition of alkyne‐tethered 3‐aminopyrones gives 4‐substituted indolines in good yield and with complete regioselectivity. Additional substitution is readily tolerated in the transformation, allowing synthesis of complex and non‐canonical substitution patterns. Oxidative conditions give the corresponding indoles. The strategy also allows the synthesis of carbazoles. The method was showcased in a formal synthesis of lysergic acid.

tert-Butyl(2-oxo-2H-pyran-5-yl)carbamate as the First Chameleon Diene Bearing an Electron-Donating Substituent

“…Ring substituents play a critical role in the cycloadditions of 2( H )pyran-2-ones. Generally speaking, the unsubstituted ring 2( H )pyran-2-one, 18 ( Figure 2 ), undergoes cycloadditions only under harsh conditions and with alkynes to afford benzenes following the tandem loss of CO 2 [ 1 , 2 , 3 , 4 , 5 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. Examples of cycloadditions of 2( H )pyran-2-one, 18, with alkenes to afford bridged bicyclic lactones do exist, but are rare [ 65 , 66 , 67 , 68 , 69 , 70 ].…”

“…In particular, cycloadditions of 2( H )pyran-2-one dienes to alkene dienophiles affords bridged bicyclic lactones, e.g., 2 which can then be transformed in few steps to highly substituted, six-membered rings, e.g., 3 ( Scheme 1 ) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Under more forcing conditions, typically at higher temperatures, cycloadditions to alkyne dienophiles and subsequent aromatization via loss of bridging CO 2 leads to substituted benzenes, e.g., 4 [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ].…”

Enantioselective Synthesis of Axially Chiral Biaryls by Diels–Alder/Retro-Diels–Alder Reaction of 2-Pyrones with Alkynes

“…The sequential Diels–Alder reaction of 2-pyrones with alkenes or alkynes followed by retro-Diels–Alder extrusion of CO 2 under thermal reaction conditions has been proved an efficient method for the synthesis of substituted benzenes (Scheme a) . In general, owing to the semi-aromaticity of 2-pyrones, these reactions are often conducted at high temperatures.…”

Regioselective Synthesis of Substituted Carbazoles, Bicarbazoles, and Clausine C

“…Specifically, we are investigating cyclizations where the substitution pattern of the starting material directly leads to substitution in the product . We recently found that substituted indolines and indoles can be prepared from N -butynyl-3-amino-2-pyrones in the presence of base . In this manuscript, we describe how alkyne-tethered 3-anilido-2-pyrones ( 10 ) undergo intramolecular cycloadditions, presumably giving intermediates 11 , which rapidly lose CO 2 to form substituted carbazoles 12 (Scheme , bottom) .…”

“…Alkynyl-aminopyrone 15 was coupled with bromoalkyne 21 to give non-symmetric diyne 22 . Heating this molecule gave a tandem pericyclic cascade, and in situ oxidation led to formation of 4-(4-indolyl)-carbazole 23 . Finally, alkyne 15 could be advanced to non-symmetric diyne 24 over four steps .…”