A Convenient One-Pot Synthesis of Pyrazolo[3,4-d]pyrimidines and s-Triazolo[3,4-b][1,3,5]thiadiazines

Abstract

The reaction of 5-am ino-3-aryl-l-phenylpyrazoles (la-d) with formaldehyde and secondary amines in boiling ethanol gave the corresponding 4-alkylaminomethyl derivatives (2a-f) and bis-(4-pyrazolyl)methane (4a,b) as byproduct. Such reaction with primary aliphatic and aro matic amines at room temperature afforded 1,3,5-trisubstituted (5a-h) and 1,3.5,7-tetrasubstituted tetrahydropyrazolo[3,4-d]pyrimidines (8a-k) respectively in good yield. Similarily, the Mannich reaction of 5-m ercapto-3-phenyl-l,2,4-triazole (9) with secondary amines, in boiling ethanol, and primary aromatic amines, at room temperature, gave 2 -substituted aminomethyl derivatives (lOa-c) and (14a-g) respectively,while with primary aliphatic amines, p-toluidine and p-anisidine,at room temperature,and with other primary aromatic amines, in boiling etha nol, afforded the cyclized products l,2,4-triazolo[3,4-b]thiadiazines (13a-e); (15f,g) and (15a-e), respectively. * Reprints requests to Dr. Z. A. Hozien. phenylpyrazoles (la-d) and 5-m ercapto-3-phenyl-1,2,4-triazole (9) as bifunctional nucleophiles with both secondary and prim ary amines. T reatm ent of la-d with m orpholine or piperidine and form aldehyde in boiling ethanol afforded 5-am ino-3-aryl-l-phenyl-4-m orpholinom ethyl/ piperidinom ethylpyrazoles (2 a-f) which revealed the C4 center is m ore nucleophilic than the am ino group at C5. The IR spectra of 2a-f displayed the N H 2 stretching bands at 3380-3200 cm -1. The !H N M R spectra of 2a-f lacked the H -C 4 p ro to n (at <3 5.6 ppm ) [14] and show ed the -N H 2 signal at d 4.85-4.55 ppm , in addition to the o th e r p roton which appeared at the expected chem ical shifts, Table IV. Side reaction products w ere obtained, in som e cases, due to the condensation of la,b with form aldehyde, which was identified as 4a,b. The structures of 4a-b w ere established for the reaction products based on their analytical and spectral data. The IR spectra lacked N H 2 signals. The !H N M R spectrum of 4a show ed two doublets at d 3.85 (J = 16 H z) and d 4.56 (J = 16 H z) integrated for 4 protons attrib u ted to the vinylic protons, in addition to a singlet at d 4.62 ppm a ttrib u te d to the o th er m ethylene protons. The form ation of 4a,b m ay be rationalized in term s of the initial form ation [15-16] of 3 fol lowed by condensation with form aldehyde to give 4. The 13C N M R spectrum of 4a was in accordance

The Mannich reaction in the synthesis of N,S-containing heterocycles. 7. Effective one-pot synthesis of derivatives of spiro[3,5,7,11-tetraazatricyclo-[7.3.1.02,7]tridec-2-ene-13,4′-piperidine]

“…It follows from multitudinous data in the literature that aminomethylation of 2-mercaptoazoles and -azines is a general method for the preparation of condensed derivatives of 1,3,5-thiadazines. In particular, derivatives of sym-triazolo [3,4-b][1, 3,5]thiadiazine [9][10][11][12][13][14][15][16], thiazolo [3',4':1,5][1,2,4]triazolo [3,4-b][1, 3,5]thiadiazine [17], imidazo[2,1-b][1, 3,5]thiadiazine [18,19], 1,2,4-triazino [3,2- 3,5]thiadiazine [19], and 1,3,5-thiadiazino[3,2-a]benzimidazole [20] have been obtained by "double" Mannich condensations. We have shown previously with a series of 2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates that, depending on the structure of the substrate, aminomethylation can lead to the formation of _______ * For 3,5]thiadiazine [21,22], 3,7-diazabicyclo[3.3.1]nonane [23], or tricyclic products [24].…”

Synthesis of partially hydrogenated 1,3,5-thiadiazines by Mannich reaction

“…Chemistry of Heterocyclic Compounds 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] were observed, and the major products were dithiazines 20. Aniline and meta-substituted anilines under these conditions tended to form mixtures of compounds 13, 20, and 22 in various ratios (Scheme 5), with the fraction of dithiazines 20 increasing after longer reaction time; complete conversion of amine was achieved after 10 h. In general, it was noted 37а that 3,5-diaryl-substituted perhydro-1,3,5-thiadiazines were more stable than 3,5-dialkyl analogs, which readily disproportionated with the formation of dithiazines.…”

“…The reaction was sensitive both to the reactant ratio and reaction temperature, as well as the amount of catalyst used. Derivatives of perhydro-1,3,5-thiadiazine 38 could be Chemistry of Heterocyclic Compounds 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] obtained in up to 66% yield by heating (thio)urea with a mixture of CH 2 O and H 2 S (1 : 2 : 1 ratio) in the presence of n-BuONa (4 equiv) (Scheme 12). 43,84 It has been noted 43 that mostly macrocyclic condensation products were obtained under different conditions.…”

“…15 The most widely used compound of THTT series is 3,5-dimethyltetrahydro-1,3,5-thiadiazine-2-thione (5), known by the trade names Dazomet, Tiazone (in USSR), Basamid, Mylone, DMTT, and applied as highly potent soil fumigant, fungicide, herbicide, and powerful insecticide, as well as for the prevention of biofilm accumulation in paper industry. 16 Chemistry of Heterocyclic Compounds 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2015, 51 (2), [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127] rapidly decomposes by forming MeNCS, MeNH 2 , СН 2 О, and Н 2 S, which provide for its fumigant activity. 18, 19 It has also been reported that thiazone 5 has ovicidal activity against...…”

Efficient one‐pot synthesis of s‐triazolo[3,4‐b]‐[1,3,5]thiadiazines containing a chiral side chain by double mannich type reaction

“…Derivatives of phenothiazine [7] are also a group of valuable drugs. Therefore, the apparently specific role for the triazolothiadiazine derivatives [8][9] in medicinal chemistry suggests they may be suitable targets for antibiotic design. We present here the first report of a new and efficient method for the synthesis of 7.…”