Tetrahydro-l,3,5-thiadiazines

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. 

In the 3,5-diethyl compound, slow ring inversion renders the CH2 protons of the ethyl groups nonequivalent, and appropriate coalescence phenomena are observed.360 

In contrast to the other 1,3,5-trihetero systems just discussed, it is now believed that the conclusions originally reached361,362 regarding the conformations of l,3,5-trialkylhexahydro-l,3,5-triazines (467-469) are misleading it is no longer believed that di-N-axial conformations are appreciably populated for the trimethyl and triethyl derivatives. 

From the H-NMR spectra the barrier to ring inversion was estimated as AG1 13.2 0.2 kcal mol-1 at — 5°C and the barrier to /V-inversion as AG1 7.2 + 0.1 kcal moP1 at — 123.5°C.363 Barriers to ring inversion in 1,3,5-trialkyl derivatives 470 decrease with increasing size of substituent,297 365-366 and AG values for nitrogen inversion (determined by 13C-NMR spectroscopy355) follow a similar trend (Table XXIX). The barriers to N-inversion 

Compound Ring inversion AG (kcal mol ) TfC) N-inversion AG (kcal mol 1) T(°C) 

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THIADIAZINE-2-THIONE TETRAHYDRO-3,5-DIMETHYL-2H-1,3,5-THIADIAZINE-2-THIONE THIAZON THIAZONE 2-THIO-3,5-DIMETHYL-TETRAHYDRO-l,3,5-THIADIAZINE TIAZON TROYSAN 142 UCC 974... 

Thio-3,5-dimethyl-tetrahydro-l,3,5-thiadiazine A135 Industrial 171... 

Of the derivatives, 5-carboxymethyl-3-methyl-tetrahydro-l,3,5-thiadiazine-2-thione (thiadiazinethion, 17), its sodium salt, and 3,3 -ethylene-bistetrahydro-4,6-dimethyl-2H-l,3,5-thiadiazine-2-thione (milneb, 18) have been used in agriculture, the latter being effective also against apple scab, tobacco peronospora and potato blight. 

Sodium hydrogen sulfide Tetrahydro-l,3,5-thiadiazine-2-thiones from isothiocyanates... 

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. 

TETRAHYDRO-3,5-DIMETHYL-4H,l,3,5-OXADIAZINE-4-THIONE see TCQ275 TETRAHYDRO-2H-3,5-DIMETHYL-l,3,5-THIADIAZINE-2-THIONE see DSB200 TETRAHYDRO-3,5-DIMETHYL-2H-l,3,5-THIADIAZINE-2-THIONE see DSB200 TETRAHYDRO-p-DIOXIN see DVQOOO TETRAHYDRO-l,4-DIOXIN see DVQOOO TETRAHYDRO-2,5-DIOXOFURAN see SNCOOO... 

The full spectral characteristics including 5( H) and 5( C) chemical shifts and proton-proton couplings have been reported by Molero et for a series of derivatives of 3,5-disubstituted tetrahydro-2if-l,3,5-thiadiazine-2-thione, by Sonnenburg et for a series of bis-(2-chloroethyl)amino-... 

Oxidation of 3,5-dialkyl tetrahydro-4//-l,3,5-thiadiazin-4-ones with one equivalent of MCPBA in chloroform at room temperature yields the 1-oxides (91) in 31-60% yield. With an excess of oxidant, the 1,1-dioxides (92) are produced <72JHC23l>. 

Attachment of isoniazid (INH) to a tetrahydro-277-[l,3,5]thiadiazine-2-thione moiety has been carried out via the dithiocarbamate salt 239 using a similar approach (see Scheme 46) <2004MI35>. 

Delivery of amines through incorporation into tetrahydro-2//-l,3,5-thiadiazine-2-thione (THTT) structures has been demonstrated for two classes of pharmaceutically important molecules. As excellent substrates for the enzyme, monoamine oxidase, phenethylamine 242 ( = 2), and benzylamine 242 ( = 1) are known to be potent vasopressors. These two compounds were incorporated in highly lipid soluble and hydrolytically vulnerable THTT structures in order to modify their pharmacokinetics (Scheme 47) <1994EJM11>. 

In an attempt to suppress the toxic side effects of the antimicrobial drug, but retain or enhance the activity, the deacylated chloramphenicole amine D-(—)-/, rift>-2-amino-l-(4-nitrophenyl)-l,3-diol (o-amine, 247-d) and its enantiomer, the L-(- -)-/,4ri o-form (L-amine, 247-L) are introduced into a tetrahydro-2//-l,3,5-thiadiazine-2-thione skeleton (Scheme 49). Coupling between the D-amine and the diol 248 affords tetrahydro-2//-l,3,5-thiadiazine-2-thione derivatives 249 of moderate to good antibacterial activity <2000MI281>. 

Disubstituted tetrahydro-r-triazolo[3,4-3][l,3,5]thiadiazines 272 have been synthesized in 50-85% yield by the double Mannich reaction of 3-aryl-5-mercapto-l,2,4-triazoles 273 with various aromatic amines and formaldehyde in the presence of ethanolic HCl, as shown in Scheme 57 <1996MOL89>. 

Many of the methods used for the preparation of 1,3,5-oxadiazines also apply to the 1,3,5-thiadiazines. Similar to the oxygen analogs, the starting Wnitroguanidine can be treated with formaldehyde, but in the presence of sodium sulfide to afford the Mannich-type cyclization product 4-nitroimino-l,3,5-thiadiazines (Section 9.09.9.1.2). Primary amines react with carbon disulfide under basic conditions to form dithiocarbamate salts which react with 2 equiv of formaldehyde and a second primary amine to furnish tetrahydro-2//-l,3,5-thiadiazine-2-thiones (Section 9.09.9.1.3). 

Bromo-2-nitropropane-1,2-diol 2-bromo-4-hydroxy-acetophenone l,2-Dibromo-2,4-dicyanobutane 2,2-dibromo-3-nitrilopropionamide 3.5-Dimethyl tetrahydro-2H-l,3,5-thiadiazine-2-thione disodium ethylene) (1,5-Pentanedial) 2-hydroxypropyl... 

Tetrahydro-3,5-dimethyl-2//-l,3,5-thiadiazine-2-thione, see Dazomet Tetrahydro-2/f-3,5-dimethyl-l,3,5-thiadiazine-2-thione, see Dazomet... 

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