Preparation of Heterocycle-Masked β-Enamino Acids

Abstract

The preparation of masked N-substituted beta-enamino acid derivatives 3a-n by reaction of 2-alkyl-oxa(thia)zolines 2a,b with imidoylbenzotriazoles 1a-g in the presence of LDA was described.

Generation of Cyclic Ketene-N,X-Acetals (X = O, S) from 2-Alkyl-1,3-oxazo­lines and 2-Alkyl-1,3-thiazolines. Reactions with Acid Chlorides, 1,3-Diacid Chlorides andN-(Chlorocarbonyl) Isocyanate

“…17,18 Oxazolines and thiazolines have been employed in organic synthesis for about 70 years. [19][20][21][22][23][24][25][26][27][28][29][30][31][32] Herein, amino alcohols were used as starting materials for 2-alkyl-1,3oxazolines 3 and 2-alkyl-1,3-thiazolines 4 (Scheme 1), which were converted to cyclic ketene-N,X-acetals. [1][2][3]17,18 Amino alcohols reacted with carboxylic acids to afford 2alkyl-1,3-oxazolines 3 in 60-80% yield.…”

Synthesis of Heterocycles Mediated by Benzotriazole. 1. Monocyclic Systems

“…Lithiated 2-methyl-2-oxazoline reacts readily with compounds 431 to give enamines 433 in 82−96% yields. Imidoyl intermediates 432 are not detected by NMR in the product mixtures due to their rapid tautomerization to forms 433 that are stabilized by strong intramolecular hydrogen bonding between their nitrogen atoms (Scheme ) …”

“…As with the analogous reaction of 2-methyl-2-oxazoline (Scheme ), lithiated 2-methyl-2-thiazoline reacts with imines 431 to give substituted 2-(β-enamino)-2-thiazolines 442 in good yields (79−98%). Due to possible hydrolysis of the heterocyclic rings, thiazolines 442 and the previously described corresponding oxazolines 433 are considered as masked β-enamino carboxylic acids (Scheme ) …”

“…Imidoyl intermediates 432 are not detected by NMR in the product mixtures due to their rapid tautomerization to forms 433 that are stabilized by strong intramolecular hydrogen bonding between their nitrogen atoms (Scheme 119). 143 The anion derived from isonitrile 37 (BetMIC) on treatment with potassium tert-butoxide readily adds to the carbonyl groups of ketones. The benzotriazolyl moiety in the intermediates is substituted by an ethoxy group from the added ethanol to give 4-ethoxyoxazolines 434.…”

The facile one-pot synthesis of N-imidoylbenzotriazoles via a Beckmann rearrangement of ketoximes

“…1) such as enaminones, 2 N-substituted b-enamino acid derivatives, 3 polysubstituted amidines, 4 1,5-substituted tetrazoles, 5 amidrazones, 6 and triazoles. 6 Due to its synthetical importance, many efforts have been made to develop the synthetic methods by Katritzky 1e6 including the reaction of secondary amides under various reaction systems such as BtH/POCl 3 /Et 3 N, 1a Bt 2 SO, 1b BtCl/PPh 3 , 3 BtH/Pyridine/(COCl) 2 , 4 and BtH/SOCl 2 . 4 The reaction of isonitriles 7 with N-(aminoalkyl) benzotriazoles in the presence of BF 3 $Et 2 O and the reaction of isocyanates 8 with N-acylbenzotriazoles have also been reported to produce the imidoylbenzotriazoles.…”