1.2.6- Thiadiazines synthesis

Two Nitrogen Atoms and One Sulfur Atom Synthesis of 1,3,4-thiadiazines 98H(49)557. 

A precursor in the synthesis of a promising calcium sensitizing agent from E. Merck [33], a chiral thiadiazin-2-one EMD 53986, 3,6-Dihydro-5-[l,2,3,4-tetrahy-dro-6-quinolyl]-6-methyl-2H-l,3,4-thiadiazin-2-one [26]. The study was performed using Celluspher , a CSP prepared from cellulose tri(p-methylbenzoate) according to a patent from Ciba-Geigy [34]. The spherical particles had a mean particle diameter of 20 3 pm and the mobile phase was pure methanol. 

The first synthesis of pyrazolo[5,l-c]-l,2,4-thiadiazines 116 and pyrazolo[3,4-c]-l,2-thiazines 118 was reported by Aiello and co-workers <76JHC615>. Compound 115 was heated five degrees above its melting point to afford the novel ring system 116. However, compound 117 gave compound 118 when treated with triethylamine. 

Bakulev et al. reported the synthesis of 5//-[l,2,3]triazolo[5,l-i>] [l,3,4]thiadiazines starting from 5-N-nitrosylamino-l,2,3-thiadiazole 68. Reduction of 68 with SnCh and 1A/HC1 and then subsequent reaction with a ketone gave the imine 69. Treatment of 69 with thionyl chloride at -80 °C led to the formation of the isolable triazolothiazine 70 which on further reaction with thionyl chloride at room temperature gave the corresponding chloro derivative 71 <00MC19>. 

Table 4 Synthesis of [1,2,4]triazolo[3,4-b]thiadiazines by reaction of 3-mercapto-4-amino[1,2,4]triazoles with a-halo-oxo reagent...

More intensive investigations have been carried out with synthesis of t-fused [l,3,5]thiadiazines, and the transformations are shown in Scheme 32. 

Because of its importance in biological areas, special efforts have been made with the synthesis of the thiazolo[2,3-t]-[l,2,4]thiadiazole derivative 308 <2001BML1805>. The pathway started from the benzothiazole derivative 305 which was treated with chlorosulfonylacetyl chloride to form an intermediate 306, which underwent cyclization to a second intermediate 307 with hydrogen chloride elimination. The last step is the attack of the first intermediate 306 at the thiadiazine carbon atom to form the final product 308. 

Solid-phase library synthesis of triazolopyridazines via a [4+2] cycloaddition strategy has been accomplished <99TL619>. Intramolecular bis-Mannich reaction of 3-aryl-5-mercapto-13,4-triazole, formaldehyde and a-phenylethylamine yields chiral 5-aryltriazolo[3,4-ft]-[133]thiadiazine derivatives. These compounds have been screened for antibacterial activities and some of them show potent biological activity <99SC2027>. 

Synthesis and structural studies of new 3-alkylamino-pyrido[43-e][l,2,4]thiadiazine 1,1-dioxides have been reported <99T5419>. 

The synthesis of this ring system by condensation of 3,4,5-triamino-l,2,6-thiadiazine-l,1-dioxide with formic acid equivalents to give the fused imidazole ring dates back to the review by Montgomery and Secrist <1984GHEC(5)607>. This methodology was extended to cyclocondensation reactions of 3,4,5-triamino-l,2,6-thiadia-zine-1,1-dioxide with electrophiles such as methyl chloroformate and carbon disulfide to yield 6-oxo 98 and 6-thioxo 99 derivatives of 4-aminoimidazo[4,5-d-l,2,6-thiadiazine-2,2-dioxide respectively (Scheme 72) <1999BMC1617>. 

Fusion has also been employed in the synthesis of 3-cyclopentylpyrido[4,3- ]thiadiazine 1,1-dioxide 226 from the corresponding amide 225 (Scheme 33) <1996JME937>. 

Using the same methodology as they employed in the synthesis of the 3-oxopyrido[2,3-r ]-1.2,4-thiadiazines 268 <1998T13645>, Pirotte el al. prepared the 3-oxopyrido[4,3-r ]-l,2,4-thiadiazines 196 from the 4-aminopyridine-3-sulfonamide 224 and urea (Equation 31) <1993JME3211>. 

A review on the synthesis of 1,3,4-thiadiazines and 1,3,4-oxadiazines shows the formation of the diones 105 and 106 (Equation 57) <1998H(49)557>. TPHA3 was preparedby treatment of 107 with DBU in air (Scheme 10) <1998JA2989,... 

Electrophilic sulfur species such as thionyl chloride are frequently used in the synthesis of sulfur-containing heterocycles and, for example, reaction with N-N 1,5-dinucleophiles is a direct route to 1,2,6-thiadiazine 1-oxides. Thus the thiadiazines (138 n-1) are readily prepared by treatment of (231) with thionyl chloride in pyridine (81JCS(Pl)l89l), and the benzothiadiazine (232) is similarly made from (233) (64JOC2717). Reaction of (234) with thionyl chloride gives the dithiatriazine (235) (74ZOR488). 

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