Tetrahydro-1,3,4-thiadiazines

Ring-chain tautomerism (32 33), which is well established for tetrahydro-l,3,4-oxadiazines <73CHE830> and for tetrahydro-1,3,4-thiadiazines <79CHE1314>, has been observed on heating the bicyclic 1,3,4-oxadiazines (33 R = C02Et or COAr) (Section 6.17.7.2.2.1) in boiling benzene <820335,... 

E. V. Karaseva, S. N. Dedyukhina, and A. A. Dedyukhin. Treatment of water-based drilling solution to prevent microbial attack— by addition of dimethyl-tetrahydro-thiadiazine-thione bactericide. Patent RU 2036216-C, 1995. 

Glutaraldehyde and the tetrahydro thiadiazine derivative are especially effective in cooling water systems with pH values above 7. The other active ingredients mentioned here are sensitive to hydrolysis and therefore are not recommended for cooling systems where the pH exceeds 8. An advantage of these compounds is that they are not persistent and in consequence do not cause significant waste water problems. 

This ring system could be prepared by thionation of benzil monohydrazone 172 with Lawesson s reagent (LR) followed by cyclization. The reaction gives 2,3-diphenyl-7,8,9,9a-tetrahydro-27/,677-pyrido[2,TA][l,3,4]thiadiazine 173 in a diastereoselective way, with the hydrogens at 2- and 9a-position in trans orientation. Benzil monohydrazone 172 was obtained by condensation of benzil 170 with 1 equiv of iV-aminopiperidine 171 (Scheme 23) <1998TA1531>. 

Most of the reported triazinothiadiazines have been prepared from 1,2,4-triazine derivatives. Treatment of amino-1,2,4-triazine 28 with chloroacetyl chloride in dioxane in the presence of triethylamine at 10 °C resulted in the formation of 6-methyl-4-(A -chloroacetamido)-3-thioxo-5-oxo-2,3,4,5-tetrahydro-l,2,4-triazine 29 and 3-methyl-4,7-dioxo-4,6,7,8-tetrahydro-l,2,4-triazino[3,4-A][l,3,4]thiadiazine 15 (Scheme 1) <2005JHC935>. 

The 1,2,5-thiadiazole system was also constructed from ketoximes and S4N4-SbCl5 and by rearrangement of 4-hydroxyimino-2,3,5,6-tetrahydro-3,5-dioxo-l,2,6-thiadiazines in the presence of acid. ... 

However, in many other series results have been obtained that are compatible with those from other methods and that gave the dipole-moment method an appearance of general reliability now known to be unjustified. Such compatible results include spiropiperidines (Section III,A,4), tropanes (Section III,B,4), 2-alkyltetrahydro-l,2-oxazines (Section III,C,2), perhydro-pyrido[l,2-c][l,3]oxazines (Section III,D,IX perhydropyrido[l,2-c][l,3]thi-azines (Section III,D,2), dialkylhexahydropyrimidines and perhydropyrido-[l,2-c]pyrimidines (Section III,D,3), 5-alkyldihydro-l,3,5-dithiazines (Section III,G,3), 3,5-dialkyltetrahydro-l,3,5-thiadiazines (Section III,G,4) and, in part, l,2,4,5-tetraalkylhexahydro-l,2,4,5-tetrazines (Section III,H,4) as well as piperidines, tetrahydro-l,3-oxazines, and tetrahydro-l,3-thiazines containing an N-H group. 

By analogy with the tetrahydro-l,3,5-oxadiazine system, the ae conformer 466 of 3,5-dialkyltetrahydro-l,3,5-thiadiazines (465) should predominate in the conformational equilibrium. Investigation of a series of 3,5-dialkyl derivatives by H-NMR disclosed ring-inversion barriers that decrease with increasing size of the substituent (465 R = Me, AG 12.1 + 0.3 R = Et, AG 12.0 + 0.2 R = iPr, AG 10.5 + 0.4 kcal mol ). No further changes in the H-NMR spectra on cooling were found. Dipole-moment data indicated that all the compounds existed predominantly in the ae conformation.356 It is difficult to draw conclusions for Jtem in this series. 

There are only a few reported members of this series. The first mentioned is 3,4,5,6-tetrahydro-3-phenyl-2//-l,2,3-thiadiazine 1,1-dioxide, which is prepared in low yield by cyclization of N-3-chloropropylsulfonyl-N -phenylhydrazine with base (62JPR56). The well-known property of azoalkenes to undergo [4 + 2] cycloaddition reactions with dienophiles can be exploited to give 1,2,3-thiadiazines. Thus, N-phenylazostilbene, PhCH=C(Ph)N=NPh, reacts slowly with sulfine 1 at room temperature to yield the trans (44%) and cis (13%) isomers 2 and 3... 

In cyclic sulfoximides such as 3-ethoxy-4,5-dihydro-3-oxo-l-phenyl-and 3,4,5,6-tetrahydro-3,5-dioxo-1 -phenyl-1H-1 A6,2,4-thiadiazine 1 -oxides (46), the C6 proton signals appear at much higher fields [4.35 and 4.9 ppm (2H)] than for aromatic systems [benzene, 7.27 ppm thiophene, 7.2 (C2-H) and 6.95 ppm (C3-H)]. Similarly, the, 3C-NMR signals of the C6 atom appear at higher fields. These facts suggest a degree of ylidic character (77JOC952), which can be demonstrated by the reactivity of such compounds towards electrophiles (see Section III, C,3,f). 

The main successful applications of monocyclic 1,2,4-thiadiazines in earlier years have been the use of bis[4-(3,4,5,6-tetrahydro-l,l-dioxo-2//-l,2,4-thiadiazinyl)]methane (62, Taurolidine, Taurolin, Drainsept) as an antibacterial agent and 3,4,5,6-tetrahydro-2//-l,2,4-thiadiazine 1,1-dioxide (63, Taurultam) as both an antibacterial and antifungal agent (66FRP1458701). Claimed uses of 1,2,4-thiadiazines are listed in Table 11. 

All the recorded derivatives of these systems have the sulfur atom in the fully oxidized state, the N—S02—N grouping being introduced by the use of sulfamide or a substituted derivative. The 3-unsubstituted 2,2-dioxopyrazolo[3,4-c][l,2,6]triazines (176) and (177 R = H) are formed by heating with sulfamide. With the substituted sulfamides, cyclization of the intermediate is achieved with either alcoholic sodium hydroxide or trifluoracetic acid in moderate yields (Scheme 17) <85S190>. In a similar synthesis (Equation (25)) the tetrahydro-2,2-dioxopyrazolo[4,3-c][l,2,6]thiadiazine (179) is formed from the aminopyrazole (178) <76IJC(B)766>. 

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