1.2.6- Thiadiazines reactivity

The compound 7-(4-chloro-benzyl)-2-(4-chloro-phenyl)-3,8a-dihydro-pyridazino[4,3-( ][l,3,4] thiadiazin-8-one 42 has been reported to be active against Bacillus Escherchia coli, Staphylococcus aureus, and Pseudomonas aeruginosa by a serial dilution method <2001IJB475>. Triazino-thiadiazines 24f, 25b, 25c, and 25f <2002IJH287> have been reported to be active against S. aureus-, sydnone derivatives of triazino-thiadiazine 24f <2002IJH287> are more reactive than coumarin derivatives. 

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). 

REACTIVITY OF FULLY-CONJUGATED RING SYSTEMS 7.17.5.1 1 //-Pyrido[2,3-c]-1,2,6-thiadiazines... 

In Section II, the chemistry of 1,2,6-thiadiazine 1,1-dioxides and fused systems will be described, but no attempt has been made to cover all the literature dealing with benzothiadiazinones. Numerous derivatives related to the herbicide bentazone (3-isopropyI-lH-2,l,3-benzothiadiazin-4-one 2,2-dioxide) have been prepared and are described in various patents, which will not be included. The reactivity of bentazone and related 2,1,3-benzo-thiadiazinones has also been extensively studied (81AG(E)151). 

The chemical behavior of the 1,2,6-thiadiazine 1,1-dioxide system is characterized by an enhanced reactivity of the 4-position toward electrophiles. Other important reactions are those which take place at the ring nitrogens and those of the functional groups of the 3-, 4-, and 5-positions. 

Benzoin undei goes a cyclocondensation with the aminothiolactam (11.4) to form a new thiadiazine ring while the reactive chlorine atoms of 2,3-dichloro-quinoxaline under mildly basic conditions react to form a doubly fused thiadiazine. 

A reactive side-chain methylene condenses with a nitroso group in a basic medium in this example, the methylene is joined to the ring through a sul-phonamide group. The chemistry of thiadiazines containing adjacent S and N atoms has been reviewed [3904J. 

Of the different thiadiazines, the 1,3,4-thiadiazines have been most extensively studied. They are best prepared by condensation of thiohydrazides with a-halocarbonyl compounds. This ring system was first reported from the reaction of phenacyl bromide with thiosemicarbazide or its 4-substituted derivatives.26 Similar reactions were later investigated,27 29 and important details about the synthesis and reactivity of 1,3,4-thiadiazines were reported in the following years by Beyer etal., Sandstrom, and Bulka et al.7,8... 

A detailed comparative study of the chemistry of 1,2,6-thiadiazine 1,1-dioxides and related pyrazoles has been carried out <82JOC536>. Useful comparisons can be made regarding tautomeric equilibria, C NMR chemical shifts, and the general reactivity of the 4-positions. As expected however, the lack of aromaticity of the 1,2,6-thiadiazine 1,1-dioxide system (Section 6.16.4.1) imparts substantial differences to their general chemistry. 

Other than the condensations of aminothiadiazine 1,1-dioxides with various mono- and dicarbonyl compounds (Section 6.16.7.3), surprisingly little work has been published on the reactivity of substituents attached to the thiadiazine nucleus. 

The striking difference in reactivity and stability of the 4//-l,3,4-thiadiazin-5(67/)-one (15 X = O) and the 5-ol (16) have been discussed in terms of resonance stabilization based on spectral data and extended Hiickel MO calculations <87NKZ1312>. The lactam exhibits typical amide resonance (15<- 15a) and is resistant to attack by electrophiles, nucleophiles, and free radicals, whereas the reactivity of the 5-ol (16) towards displacement of the hydroxy group by nucleophiles is attributed to resonance stabilization of the thiadiazinium cation (16a) formed by heterolysis of the C—OH bond. Extended Hiickel MO calculations on the thione analogue of the thiadiazinone, coupled with spectroscopic data, indicate that this system is best represented as the thione (15 X = S) <89CE797>. 

Thiadiazine 1,1-dioxides (389) have been synthesized by Ochoa s group and a comparative study of their physiochemical properties with that of pyrazoles 390 has been made371,372. Rough parallels are observed in the tautomeric equilibria of (389) and (390) with 13C chemical shifts and the reactivity of the 4-position while differences in their aromaticity have been observed. The 1,2,6-thiadiazine-1,1-dioxides 389 are prepared either by reaction of sulphamide or substituted sulphamides with 1,3-dicarbonyl compounds or their acetal derivatives or by AT-alkylation of the unsubstituted derivatives. 

Similar to the reactivity of the fully conjugated rings, there have been no developments in the chemistry related to the reactivity of nonconjugated rings of the 1,2,3-oxadiazine and 1,2,3-thiadiazine systems since CHEC-II(1996) <1996CHEC-II(6)637>. 

Pyrazino[2.3-f][l,2,6]thiadiazine 2,2-dioxides were prepared by condensation of 4,5,6-triamino-l,2,6-thiadiazine 1,1-dioxide with 1,2-diketones. Regioselectivity was achieved as the more reactive carbonyl reacted with the 4-amino group. Alternately, selectivity could be attained by use of a-oximino ketones (Section 9.07.7.2). 

Reaction of thiadiazine 86 with primary or secondary amines in DMF proceeds smoothly to give N -substituted A -thiocarbamoylbenzamidines 87. It has been found that the amidino group of 86 is the most reactive site and nucleophiles attack the 4-position of the 1,3,5-thiadiazine ring (Scheme 9) <2000NKK859>. 

Decarboxylation of P-keto-esters is facile in aqueous DMSO, but in less reactive cases decarboxylation is accelerated by sodium chloride. Condensation reactions of dibenzocycloheptadienone (334) with aromatic aldehydes have been reported. Syntheses of the heterocyclic carboxylic acids (335) have been described. No effect of the heterocycle s ring current on the chemical shifts of the methylene protons could be detected in the n.m.r. spectrum of the nonamethylene-thiadiazine dioxide (336), which was prepared from cyclododecane-l,3-dione. ... 

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