A new one-pot strategy for the synthesis of a series of new N-substituted 3-trifluoroacetyl pyrroles is presented. These compounds were obtained by the reaction of 3-trifluoroacetyl-4,5-dihydrofuran with primary amines, which generated 1,1,1-trifluoro-3-(2-hydroxyethyl)-4-alkylaminobut-3-en-2-one intermediates. In most cases these intermediates were not stable enough to be isolated. Thus, in the same reaction vessel they were directly submitted to oxidation with PCC (Corey's reagent) to furnish 1,1,1-trifluoro-3-(2-ethanal)-4-alkylaminobut-3-en-2-ones, which under reflux underwent intramolecular cyclization to give the desired N-substituted 3-trifluoroacetyl pyrroles, in moderate yields. All of these pyrroles were tested against pan-susceptible Mycobacterium tuberculosis H37Rv and clinical isolates INH-and RMP-resistant strain and some of these compounds showed significant in vitro antimicrobial activity.
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...
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A simple and efficient one-pot synthesis of tetrahydrooxazolo[3,2-a]pyridines and hexahydroimidazo[1,2-a]pyridines, and some related oxa-and aza-condensed tetrahydropyridines, from the reaction of 2-alkoxy-5-(trifluoroacetyl)-2,3-dihydro-2H-pyrans (cyclic enones) with amino alcohols and primary diamines, is reported. Products were isolated with high purity and in very good yields.Cyclic enones have been extensively used for the last few decades to obtain various heterocyclic compounds, such as isoxazoles, 1 pyrazoles, 2 pyrimidines, 3 3-(aminomethylene)dihydrofuran-2-ones, 4 analogues of cyclophosphamide, 5 furan-3-carboxamides, 6 3-alkoxy-3-cyanocarboxylic acids, 7 pyrroles, 8 and tetrahydropyridines. 9 The use of cyclic enones such as 4-(trihaloacetyl)-2,3-dihydrofuran and 5-(trihaloacetyl)-3,4-dihydro-2H-pyran has attracted much attention because these compounds can easily react with nucleophiles, generating new aliphatic or heterocyclic systems by a process that involves opening of the furan or pyran ring by the nucleophile, and subsequent closure of the alkyl-hydroxy side chain. [8][9][10][11][12][13] However, 2-alkoxy-5-(trifluoroacetyl)-3,4-dihydro-2H-pyrans have rarely been explored as starting reagents in organic synthesis. 10 In a recent publication our group reported an important application of 2-alkoxy-5-(trifluoroacetyl)-3,4-dihydro-2H-pyrans as a highly chemoselective method for the synthesis of a large series of novel 2-alkoxy-1-alkyl(aryl)-5-(trifluoroacetyl)-1,2,3,4-tetrahydropyridines and 1-alkyl(aryl)-2-amino-5-(trifluoroacetyl)-1,2,3,4-tetrahydropyridines. 9In this study we wish to report a simple and efficient onepot synthesis of a series of new tetrahydrooxazolo[3,2-a]pyridines and hexahydroimidazo[1,2-a]pyridines, and some related oxa-and aza-condensed tetrahydropyridines, from the cyclocondensation reaction of 2-alkoxy-5-(trifluoroacetyl)-3,4-dihydro-2H-pyrans with amino alcohols and diamines.Very few reports on the synthesis of tetrahydrooxazolopyridines are described in the literature. 13-16 Tetrahydrooxazolopyridines have been prepared from the condensation between unsaturated carbonyls and carboxylic esters and N-(hydroxyethyl)enamines, 14 by iodocyclization of 1,4-dihydropyridines with properly attached substituents at the nitrogen atom, 15 or through the self-cyclization of Nphenylglycinol substituted dihydropyridines, derived from the reaction of Zincke salts 16 with (-)-(R)-phenylglycinol. 17 Recently, the synthesis of chiral 6-carbonyl-2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridines through the condensation of (S)-phenylglycinol with tricarbonyl compounds derived from the Michael addition of b-dicarbonyl compounds to acrolein and methyl vinyl ketones, was reported. 18 More recently the same group reported an interesting one-pot synthesis of tetrahydrooxazolopyridines by a multicomponent reaction. 19 Chiral 6-carbonyl-2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridines have been used to prepare (-)-deoxocassine, which is an analogue of natural alkaloid (-)-cassine 20 and a quinolizidine ...
A simple and convenient one-pot procedure for the synthesis of 5-and 6-substituted 2-phenyl-3H-pyrimidin-4-ones by the condensation of 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones with benzamidine hydrochloride is described.
A convenient selective protection of the a-amino carboxyl group of amino acids bearing reactive side chain groups such as arginine, asparagine, glutamine, cysteine, histidine, serine and lysine, using 4-alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones is reported. The reactions were performed without esterification of the carboxyl group and N-deprotection was carried out using a six molar solution of hydrochloric acid.
Three methods for the regiospecific bromination of 2-phenyl-3H-pyrimidin-4-ones are presented: bromination of the 5-position of the pyrimidine ring, bromination of the 6-benzylic position and simultaneous bromination of both the 5-position of the pyrimidine ring and 6-benzylic position. Reactions were carried out using simple protocols and the brominated pyrimidines were obtained in good yields.
The synthesis of a novel series of twelve 4-(trihalomethyl)dipyrimidin-2-ylamines, from the cyclocondensation reaction of 4-(trichloromethyl)-2-guanidinopyrimidine, with β-alkoxyvinyl trihalomethyl ketones, of general formula: X 3 C-C(O)-C(R 2 )=C(R 1 )-OR, where: X = F, Cl; R = Me, Et, -(CH 2 ) 2 -, -(CH 2 ) 3 -; R 1 = H, Me; R 2 = H, Me, -(CH 2 ) 2 -, -(CH 2 ) 3 -, is reported. The reactions were carried out in acetonitrile under reflux for 16 hours, leading to the dipyrimidin-2-ylamines in 65-90% yield. Depending on the substituents of the vinyl ketone, tetrahydropyrimidines or aromatic pyrimidine rings were obtained from the cyclization reaction. When X = Cl, elimination of the trichloromethyl group was observed during the cyclization step. The structure of 4-(trihalomethyl)dipyrimidin-2-ylamines was studied in detail by 1 H-, 13 C-and 2D-nmr spectroscopy. J. Heterocyclic Chem., 39, 943(2002).Dipyrimidin-2-ylamines have been the subject of few publications. In a search from the literature only two methods were found for the synthesis of dipyrimidin-2-ylamines. The first method was reported in 1969 and relies on the condensation of 2-guanidinopyrimidine sulfate with diethyl malonate to obtain a series of hydroxydipyrimidin-2-ylamines [1]. Several other alkoxy-and amino-dipyrimidin-2-ylamine derivatives were reported in the same paper and they were obtained by derivatization of hydroxydipyrimidin-2-ylamines. The second method to obtain dipyrimidin-2-ylamines, reported by Akhemerov et al. , consists on the interamination of amnooxypyrimidines with its hydrochloride or another aminooxypyrimidine hydrchloride [2].The applications and biological activities of dipyrimidin-2-ylamines are largely unknown, although several reports have described 2-guanidinopyrimidines and bipyrimidines as metal-cage complexes [3,4] and potential potassium-sparing diuretics [5].In this work, we wish to report the synthesis of a new series of 4-(trihalomethyl)dipirimidin-2-ylamines obtained from the cyclo-condensation reaction of 4-(trichloromethyl)-2-guanidinopyrimidine with a series of β-alkoxyvinyl trihalomethyl ketones. The importance of β-alkoxyvinyl trihalomethyl ketones as potential building blocks for the synthesis of many heterocyclic systems such as isoxazoles [6][7][8][9][10][11][12], pyrazoles [13][14][15][16][17][18], pyrimidines [19][20][21][22][23], diazepines [24,25], and aliphatic compounds [26,27] has been demonstrated in previous publications of our group and by other groups [28].The 4-(trichloromethyl)-2-guanidinopyrimidine (1) was prepared from 4-(trichloromethyl)pyrimidin-2(1H)-one by treatment with phosphorus oxychloride followed by nucleophilic substitution of the 2-chloropyrimidine derivative by guanidine hydrochloride in the presence of potassium t e rtbutoxide in t e rt-butyl alcohol, according to reference [29].The synthesis of dipyrimidin-2-ylamines 4 a -e, 5 a,c,e, and 6a-d, were carried out by refluxing the 4-(trichloromethyl)-2-guanidinopyrimidine (1) with β-alkoxyvinyl trihalomethyl ketones 2a-e and 3a-e ...
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