Synthesis of 2,3-Disubstituted 4-Ethoxycarbonyl-β-carbolin-1-ones: Application to the Synthesis of SL651498 and Its Analogue

Abstract

Synthesis of 2,3-disubstituted 4-ethoxycarbonyl-β-carbolin-1-ones is developed using palladium-catalyzed intramolecular amination of 3-amino-4-(2-bromophenyl)-2-pyridones prepared by the conjugate addition reaction of diethyl 2-aminomalonate to alkynyl imines. The method was applied to the total syntheses of SL651498 exhibiting anxiolytic activity and its analogue.

Synthesis of 2,3,6‐Trisubstituted β‐Carbolin‐1‐ones Utilizing 3‐Amino‐2‐pyridone Synthesis

“…Initially, we examined the one‐pot synthesis of 3‐amino‐2‐pyridone 7 under the similar reaction conditions previously reported by us [12] . The results are summarized in Table 1.…”

“…In 2020, we reported the synthesis 2,3,6‐trisubstituted 4‐ethoxycarbonyl‐β‐carbolin‐1‐ones 5 using palladium‐catalyzed intramolecular amination of 3‐amino‐4‐(2‐bromophenyl)‐2‐pyridones 4 prepared by the conjugate addition reaction of diethyl 2‐aminomalonate 2 a possessing an amidine moiety to alkynyl imines 1 and application to the synthesis of SL651498 and its analogue (Scheme 1a) [12] . On the other hand, we also found the conjugate addition reaction of diethyl 2‐aminomalonate 2 b having a bulkier ketimine moiety to alkynyl imine 1 a (R 1 =R 2 =Ph, R 3 =H) gave the dealkoxycarbonyl 3‐amino‐4‐(2‐bromophenyl)‐2‐pyridone 6 [12,13] . Herein, we report the synthesis of 2,3,6‐trisubstituted β‐carbolin‐1‐ones 8 utilizing 3‐amino‐4‐(2‐bromophenyl)‐2‐pyridone 7 synthesis via 2‐pyridone 6 (Scheme 1b).…”

“…Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.202201737 ChemistrySelect www.chemistryselect.org having a bulkier ketimine moiety to alkynyl imine 1 a (R 1 = R 2 = Ph, R 3 = H) gave the dealkoxycarbonyl 3-amino-4-(2-bromophenyl)-2-pyridone 6. [12,13] Herein, we report the synthesis of 2,3,6-trisubstituted β-carbolin-1-ones 8 utilizing 3-amino-4-(2bromophenyl)-2-pyridone 7 synthesis via 2-pyridone 6 (Scheme 1b).…”

The Construction of Nitrogen‐Containing Heterocycles from Alkynyl Imines

“…In this process, imidoyl halides could be smoothly prepared by the treatment of amides with SOCl 2 or PCl 5 [7] . Considering the instability of imidoyl halides, an alternative approach is the copper‐catalyzed coupling of nitrones with terminal alkynes (Scheme 1b) [8,26] . Besides, condensation of alkynyl ketones with amines could also afford the corresponding alkynyl imines, in which almost quantitative yields are achieved (Scheme 1c) [9] .…”

“…Prompted by these results, Hachiya and co‐workers further explored the nucleophilic addition of malonic esters to ( Z )‐alkynyl imines (Scheme 15a) [26] . This transformation employed brominated ( Z )‐alkynyl imines and diethyl 2‐aminomalonates as substrate, producing multifunctional 2‐pyridones in good to excellent yields.…”