On triazoles XLII . A new convenient method for the N‐alkylation of highly insoluble cyclic amides

Abstract

A simple N-alkylation method of highly insoluble cyclic amides based on the high solubility of their easily isolable tetraalkylammonium and tetraalkylphosphonium salts was elaborated. The method has a rather wide scope, it is not influenced by the identity of the different rings attached to the 1,2,4-triazolo[1,5-a]-pyrimidinone moiety of isomers 1 and 2, nor the presence of the triazole substituents. It proceeds smoothly without any unwanted by-products, at relatively low temperatures, and is not sensitive to moisture. The method allows an easy isolation of all possible N-alkylated derivatives 3, 7, and 8. Spectral analysis of isomers 3, 7, and 8 showed that our previous results concerning the formation of 3 type N-alkylated derivatives as main products of the N-alkylations as well as the tautomeric structure of the non-alkylated isomers 1 and 2 is correct. However, it also showed that the isolation of a single N-alkylated isomer 3 and its comparison with the corresponding non-alkylated derivative to prove its tautomeric structure may lead to mistakes. [4,5], and the corresponding nitrogen (1 and 2, R 1 + R 2 = (CH 2 ) n -NR-(CH 2 ) m ) [6][7][8] and sulphur (1 and 2, R 1 + R 2 = (CH 2 ) n -S-(CH 2 ) m ) [9,10] containing hetero analogues required model compounds of "fixed" tautomeric structures, like that of derivatives 3 and 4 (Scheme 1). They were synthesized by the N-alkylation of the corresponding sodium salts 5 and 6 (Scheme 2) prepared either in situ with sodium hydride in dimethylformamide [2,4,[6][7][8][9] or in advance in hot sodium hydroxide solution [3,6,10]. However, the yields of the above alkylations strongly depended on the solubility of the sodium salts in dimethylformamide, which can lead to difficulty during isolation of the products from the very diluted dimethylformamide containing solutions. Moreover the above methods enabled the isolation of the main Nalkylated products only. Luckily the isolated N-alkylated products of type 3 and 4 (Scheme 1) contain the same chromophore systems as derivatives 1 and 2, respectively, making their structure elucidation possible [2][3][4][5][6][7][8][9][10]. However, in spite of their similarities, doubts still remained concerning the validity of identifying the above structural pairs by comparing the spectral data. To solve this problem unambiguously we wanted to synthesize all possible N-alkylated isomers of type 1 and that of their O-alkylated analogues, i.e. derivatives 7-9 as well as compounds 3 (Scheme 3).It was known [11] that the N-alkylation of different cyclic amides can be performed in two-phase (liquidliquid or solid-liquid) systems using phase transfer catalysts (quaternary ammonium or phosphonium salts).Brändström [12] successfully isolated the stoichiometric crystalline tetrabutylammonium salts (10) of weak CH-acids like methyl 2,4-dioxovalerate (10z, X = COCH 3 , Y = COOMe) and methyl cyanoacetate (10w, X = CN,

On triazoles XLIV [1]. synthesis of new ring systems containing imidazo[2′,1′:3,4] [1,2,4] triazolo [1,5‐a]pyrimidine and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrimidine skeleton

“…The structure of derivatives 2 and 3 was also corroborated by the analogy of their cmr and uv spectra with those of isomeric compounds 15 and 16 (Scheme 6) prepared earlier [12]. Thus the chemical shifts of carbon atoms 4a and ωa of derivatives 2 were analogous with the chemical shifts of the corresponding carbon atoms 10a and 2, respectively, of derivative 15 (Scheme 6).…”

“…It was known from the literature [6] that heating of 2-cyanoimino-3-R-thiazolidine derivatives (11) with hydrazine hydrate in ethanol led to ring transformation to yield in case of R = electron donating group (EDG) the corresponding 3,5-diamino-1,2,4-triazole derivatives (12) (Scheme 4) isolated as disulfide dimers, while in case of R = electron withdrawing group (EWG) to the corresponding 5-amino-3-alkylthio-1,2,4-triazoles (13).…”

On triazoles XLVI. Synthesis of 1,3a,5,6,10c‐pentaazaacephenanthrylenes

“…The structure of derivatives 5 and 6 can easily be deduced by analogy of their pmr and cmr spectra with those of the 5-chloro-2-Q-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazoline derivatives 2 (Schemes 3 and 4) reported previously [2][3]. On the other hand the structure of the novel type 2,3,7,8,9,10-hexahydro-1,3a,5,6,10c-pentaazaacephenanthrylenes 9, which is consistent with all spectra recorded (Scheme 4, Tables III and IIIa), could be deduced by analogy of their triazole carbon atoms 4 and 5a with those of the corresponding carbon atoms 2 and 10a, respectively, of the 3-substituted-2-methylthio-6,7,8,9-tetrahydro-1,2,4-triazolo-[5,1-b]quinazolin-5(3H)-ones (10) (Scheme 4), reported Jul-Aug 2002 705 recently [6]. The structure of the novel type 2,3,7,8,9,10hexahydro-1,3a,5,6,10c-pentaazaacephenanthrylenes 9 was corroborated by X-ray diffraction spectra of two differently substituted derivatives 9/3 (Q = 1-methylethylthio) and 9/5 (Q = morpholin-4-yl), as well.…”

“…General Method for the Synthesis of 5-(2-Dialkylaminoethyl)amino-2-Q-6,7,8,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolines (4) from 5-(2-Chloroethyl)amino-2-Q-6,7,8,9-tetrahydro-1,2,4triazolo[5,1-b]quinazoline Derivatives (6).…”