2//-l,3,5-Thiadiazines

A variety of 2H- (121, X = O) and 4H- (122, X = O) 1,3,5-oxadiazines has been studied and eharaeterized, whereas 2//-l,3,5-thiadiazines 121 (X = S), unlike the 4H isomers 122 (X = S), are uneommon. The most eommon type of tautomerie intereonversions for sueh systems is ring-ehain tautomerism. A few studies on substituent tautomerism have also been earried out however, no data on annular tautomerism have yet appeared in the literature. 

Dihydro-2//-l,3,5-thiadiazines substituted at the 2 and 5 positions have been synthesized by treatment of TV-substituted tV,VV-fc(l//-l,2,3-benzotriazol-l-ylme-thyl)amines with thioamides and zinc bromide in dry CH2C12 (Scheme 27).54... 

The 2//-l,3,5-thiadiazine-2-thione 8 (1.66 mmol) in Me2S04 (4mL) was heated at 90°C for 2h and then allowed to stand at rt for 24 h. After addition of 70% aq HCIO, (0.8 mL), the mixture was treated with Et20 and the precipitated product separated by suction filtration. 

The strong IR absorptions at 3430 v(OH), 3230 v(NH), and 1520 cm" v(C=N) and the weak v(0=0) at 1630 cm , have been suggested to indicate that in the solid state 2,6-dimethyl-5,6-dihydro-2//-l,3,5-thiadiazin-4(37/)-one exists mainly as the lactim form (41). However, from the symmetry of the PMR spectrum in d -DMSO, which shows a solitary doublet methyl resonance at... 

Alkoxythiocarbonyl isothiocyanates (172 X = S) are also useful 47t components and with imines at room temperature furnish 6-alkoxy-2//-l,3,5-thiadiazine-4(3//)-thiones (173) albeit in variable yields <83CB2044>. In a similar manner ethoxythiocarbonyl isocyanate (172 R = Et, X = O) and benzylideneaniline produce 2,3-diphenyl-6-ethoxy-2/f-l,3,5-thiadiazin-4(3//)-one (174) <82CB1252>. In warm toluene the ethoxythiocarbonyl isocyanate dimerizes to give the 0-ethyl ester (175) of 6-ethoxy-3,4-dihydro-2,4-dioxo-2//-l,3,5-thiadiazine-3-thiocarboxylic acid (Scheme 24). 

If A-(trimethylsilylaminothiocarbonyl) derivatives (183) are used as the 47t components then cycloadditions with a carbonitrile followed by mild aqueous hydrolysis afford 2-imino-3,4-dihydro-2//-l,3,5-thiadiazines (184) in excellent yields (80-91%) (Equation (1 la)) <91SL93>. 

Phenylisocyanodichloride (PhN=CCl2) has been used as the one-carbon component in the synthesis of a number of 2,6-diimino-5,6-dihydro-2//-l, 3 5-thiadiazin-4(3 0 ones (203) (Equation (15)) <84JIC68, 84JIC781, 84JIC883>. 

Amino-2-hydrazino-l,6,6aA -trithia-3,4-diazapentalenes (233) in boiling toluene in the presence of a secondary amine suffer ring expansion to 4,6-diamino-2-hydrazono-2//-l,3,5-thiadiazines (234) as exemplified in Scheme 39 <93PS(84)83>. The 2//-l,3,5-thiadiazines are also formed by heating the... 

Whereas there appear to be no general synthetic routes to 2//-l,3,5-thiadiazines, the 2-thiones and the 2,4-dione derivatives are accessible by Dimroth rearrangement of l,3,5-oxadiazine-2-thiones (see Section 6.18.11.2) and by base-catalyzed cyclization of A -acyl-A -thioacylureas (see Section... 

A-1,3,5-Thiadiazines are prepared readily by (4-1-2) cycloaddition of A-thioacylimines with carbonitriles or cyanamides (see Section 6.18.10.2.2.iii). Analogous cycloadditions with alkoxy-thiocarbonyl isocyanates produce 2//-l,3,5-thiadiazine-4(3//)-thiones (see Section 6.18.10.2.2.iii). The boron-trifluoride etherate-catalyzed condensation of an aldehyde (or dialkyl ketone), a carbonitrile and a thioamide is also a versatile route to 4//-l,3,5-thiadiazines (see Section 6.18.10.3.2.2). 

Treatment of 6-amino-4-phenyl-2//-l,3,5-thiadiazine-2-thione 86 with aqueous NaOH or KOH, at room temperature, furnishes the 1,3,5-triazine 103, while reaction with aqueous HCl in methanol or reflux with water yields the Wbenzoylthiourea derivative 104 (Scheme 13) <2000NKK859>. 

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>. 

Dihydro-2/r-l,3>5-thiadiazines 270 can be synthesized via [3+3] cycloaddition reactions. Thus, starting from N-substituted A, A -bis(l//-l,2,3-benzotriazol-l-ylmethyl)amines 271 containing two leaving groups, as the equivalent of 1,3-bielectrophiles, and thioamides as 1,3-binucleophiles, these components undergo a Lewis acid-promoted condensation to afford 3,4-dihydro-2//-l,3,5-thiadiazines 270 (Scheme 56) <2002JOC4960>. 

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). 

Dihydro-2//-l,3,5-thiadiazines containing a ring carbonyl or thiocarbonyl group are synthesized from reaction of thioamides with phenoxycarbonyl isocyanate, dimerization of thiocarbamoylisothiocyanates, or dimerization of carbamoyl isocyanates. The latter two [4-1-2] cycloaddition reactions complement the tabulated list of dienes and dienophiles presented in Table 2 (Section 9.09.9.2). 3,6-Disubstituted-3,4-dihydro-2//-l,3,5-thiadiazines are synthesized by treatment of N-substituted A, Wbis(l//-l,2,3-benzotriazol-l-ylmethyl)-amines with thioamides and zinc bromide (Section 9.09.9.1.3). 

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