Synthesis of N-substituted 6-trifluoromethyl-1,3-oxazinanes

Abstract

Este trabalho apresenta a síntese de duas novas séries de 6-trifluormetil-1,3-oxazinanas N-substituídas e 6-trifluormetil-1,3-oxazinan-2-onas N-substituídas, a partir da ciclização de 4-ilamino-1,1,1-trifluor-butan-2-óis com formaldeído e trifosgênio, respectivamente. Os 4-ilamino-1,1,1-trifluor-butan-2-óis foram obtidos através da reação de redução dos precursores 4-ilamino-1,1,1-trifluor-but-3-en-2-onas, utilizando hidrogênio e 10% Pd/C, com bons rendimentos.This work reports the synthesis of two new series of N-substituted 6-trifluoromethyl-1,3-oxazinanes and N-substituted 6-trifluoromethyl-1,3-oxazinan-2-ones from the cyclization of 4-ylamino-1,1,1-trifluoro-butan-2-ols with formaldehyde and triphosgene, respectively. The 4-ylamino-1,1,1-trifluoro-butan-2-ols were obtained in good yields from the reduction of the parent 4-ylamino-1,1,1-trifluoro-but-3-en-2-ones with hydrogen and 10% Pd/C. Keywords: γ-amino alcohols, β-enamino ketones, 1,3-oxazinanes, 1,3-oxazinan-2-ones, 1,3-oxazines Introduction 1,3-Oxazines belong to a class of compounds that have been largely studied due to their wide range of biological activities and easy synthetic accessibility. Special attention has been given to these compounds since the development of Efavirenz, a trifluoromethyl-1,3-oxazin-2-one, which is a non-nucleoside reverse transcriptase inhibitor that shows high activity against a variety of HIV-1 mutant strains. 1 Although, 1,3-oxazinanes have not been used as extensively as the parent 1,3-oxazines, probably due to the difficulties to synthesize the saturated 1,3-oxazine ring with a wide range of substituents, 1,3-oxazinanes exhibit a variety of biological activities. Just to mention a few, they are being explored as anti-inflammatory and agents for treating ulcers, allergies, asthma, arthritis, and diabetes. 2 1,3-Oxazinanes have been used as key intermediates in the synthesis of thrombolytic agents, 3 liquid crystal devices, 4 chiral auxiliaries in organic synthesis, 5,6 and 1,3-amino alcohols, 7-10 and β-carbolines. 11 The synthesis of 1,3-oxazinanes, is much less developed than the parent 1,3-oxazines and there are not many available synthesis for 1,3-oxazinanes described in the literature. One of the first methods reported to synthesize 5-nitro-5-alkyl-1,3-oxazinanes, from the reaction of a primary nitroalkane with formaldehyde and ammonia or primary amines, was explored in the fifties and sixties. 12 Another method to synthesize 1,3-oxazinanes is by peracid-induced ring opening of isoxazolidines derived from the reaction of nitrones and alkenes. 13 A chiral approach to the synthesis of 1,3-oxazinan-2-ones utilizes aspartic acid as the starting material in a multistep procedure that includes the formation of an epoxide containing a Cbz-protected arylamine as the key intermediate. The synthesis continues with the epoxide ring opening by sodium azide followed by an intramolecular cyclization of the hydroxy group with the benzylcarbamate group to give the desired 1,3-oxazinan-2-one. 14 1,3-Oxazinan-2-ones were also obtain...

Synthesis of New 1,3-Disubstituted-2,3-dihydro-1H-naphth[1,2e][1,3]oxazines

“…The Betti reaction, a Mannich-type aminoalkylation, offers a convenient route for preparing 1-(aminosubstituted methyl)-2-naphthols 2 under mild (rt) conditions. Access to these Mannich-type phenolic bases make the aminoalkylation reaction of naphthol derivatives a subject of current chemical interest [5][6][7]. Subsequent reaction of the aminobenzylnaphthtols with an equivalent amount of a substituted aldehyde in absolute MeOH at ambient temperature gave 1,3-naphthoxazines 3.…”

“…Investigation of the 1,3-oxazine heterocycles has shown that they possess varied biological properties such as analgesic, anticonvulsant, antitubercular, antibacterial and anticancer activity [1][2][3][4]. Particular attention has been paid to these compounds since the discovery of the non-nucleoside reverse transcriptase inhibitor trifluoromethyl-1,3-oxazine-2-one, which shows high activity against a variety of HIV-1 mutant strains [5]. In addition, naphthoxazine derivatives have exhibited therapeutic potential for the treatment of Parkinson's disease [6,7].…”

(+)-CSA Catalyzed Multicomponent Synthesis of 1-[(1,3-Thiazol-2-ylamino)methyl]-2-naphthols and Their Ring-Closure Reaction under Ultrasonic Irradiation

“…1,3-Oxazine derivatives have shown many biological properties such as analgesic, anticonvulsant, antitubular, antibacterial, antifungal, and anticancer activity [49][50][51][52][53][54][55][56]. Also, in the last decades, these compounds have been used in the treatment of AIDS and Parkinson's disease [57,58].…”

A solvent-free synthesis of beta-enamino trihalomethyl ketones

“…18 Unfortunately, in general, the processes to synthesize trihalomethyl substituted β-enamino ketones suffers from limitations, such as long reaction times, multi-step reactions and tedious work-up. 19,20 Thus, because of the applicability of β-enamino trihalomethyl ketones as a promising building blocks for the synthesis heterocycles, 21,22 a simple, general and high yielding onepot approach for the synthesis of this enaminones is highly desirable. In particular, it has been shown that syntheses which are carried out in solvent-free conditions are often rapid, regio-or chemoselective, occur in high yields and have environmental and economic advantages.…”