Imidazo thiazines

Imidazo[4,5-fi][l,3]thiazine, 6-amino-2-bromo-l,5-dihydro-synthesis, 5, 664... 

A ,A"-/i/. s,(dimcthylaminomcthylenc)thiourea (prepared by double condensation of AAY-dimethylformamide dimethyl acetal with thiourea) has been reacted with a-haloketones or acrylic dienophiles to give thiazolic and thiazinic diazadienes, respectively. These undergo cyclization reactions to yield imidazo[2,1-/ ][1,3] thiazoles, 5H-1,3-thiazolo[3,2-a]pyrimidines, 72/-imidazo[2,1 -/ ][ 1,3]thiazines and 2//,6//-pyrimido[2,l -/)][1,3]thiazines without any regioisomeric ambiguity (Scheme 61).144,145... 

Alkylation of W -(5-acetyl-67/-l,3-thiazin-2-yl)-WA -dimethylformamidine 113 with 2-bromo-l-(4-bromophenyl)etha-none resulted in attack at the nitrogen in the ring and formation of the N-alkylated salt (Scheme 4). The latter was not isolated but treated directly with 2 equiv of base to give, after loss of dimethylamine, the imidazo[2,l-/ ][l,3]thia-zine 114 <2003EJ0421>. 

The one-step synthesis of further tri- and tetracyclic pteridine derivatives from 2-aminopyrazine 153 has also been described <2001JHC1173>. Cyclic analogues of A -[bis(methylthio)methylene]amino reagents such as 2-(methylthio)-2-thiazoline, 5,6-dihydro-2-(methylthio)-4//-l,3-thiazine, 2-(methylthio)-2-imidazoline, 2-(methylthio)-l,4,5,6-tetrahydro-pyrimidine, 2-(methylthio)-2-pyrazine, and 2-chloropyrimidine reacted with aminopyrazine 153 to afford thiazolo/thia-zino[2,3-3]- 159 ( = 1 (53%), n = 2 (42%)), imidazo/pyrimidino[2,l-/ ]- 160 ( = 1 (53%), = 2 (57%)), pyrazino[2,l-/ ]-161 (21%), and pyrimido[2,l-/ ]-pteridine 162 (42%) derivatives, respectively. 

Fluor-phenylimino)-tetrahydro-l,3-oxazin bzw. -1,3-thiazin reagieren mit einem Uber-schuB an Butyllithium bei — 75° unter intermediarer Arin-Bildung zu 3,4-Dihydro-2H-(Jpenz-imidazo[2,l-b]-l,3-oxazin (X = O 90% Schmp. 115-118°) bzw. -2H-(benzimidazo[2,l-b]-1,3-thiazin> (X = S 62% Schmp. 181-183° s.a. S. 246)122 ... 

A number of penicillin sulfoxides 1 were heated in THF with two equivalents of ethoxycarbonyl isocyanate in the expectation that the corresponding sulfilimines would be obtained. The products, however, were shown to be the imidazo[5,l-c][l,4]thiazines 2, which were obtained in 31-54% yield. 

Oxo-l,3-imidazothiazines. A number of reactions have been used for the construction of imidazo[2,l-b]-l,3-thiazin-4-one. For example, reaction between acetylenic acid esters and imidazolinethione is the route to imida-zolino-TAs 187 [68JCS(C)2510] (Scheme 65). 

Some reduced derivatives of imidazo[2,l-b]-l,3-thiazin-4-one have been described. For example, the reaction of 2-mercaptobenzimidazole with acry-loyl chlorides results in TAs 188 (91MI2). A similar iodine-containing compound (R = H) was synthesized by the cyclization of acid 189 (92MI2) (Scheme 66). 

Of the six imidazothiazane systems pictured in the introduction, by far the most common is the imidazo[2,l-6][l,3]thiazine. 

The synthesis of the imidazo[2,l-6][l,3]thiazine system also has been approached starting with a thiazine. Treatment of (696) with an a-bromoketone such as phenacyl bromide (512) produced an N-alkylated material, which could then be cyclized by heating to (697) (70LA(742)85). An a-chloroketone has also been used in similar fashion (69ZC27). 

Ring expansion of the bicyclic isothiazole (698) occurred upon treatment with cyanide ion to give the imidazo[l,2-c][l,3]thiazine (699). The mechanism involves initial ring opening by attack on sulfur, and then ring closure. The anion of methyl propiolate also causes the same type of rearrangement (79TL1281). 

Synthesis of imidazo[2,l-c][l,4]thiazines has been carried out from the lactam ether... 

When the thiazine ester (708) was treated with an isocyanate such as (709), an imidazo[5,l-c][l,4]thiazine (710) was produced (8UAP8161384). Treatment of certain penicillin sulfoxide esters (711) with ethoxycarbonyl isocyanate results in a ring expansion of both rings to afford an imidazo[5,l-c][l,4]thiazine (712) (81JOC3026). 

In a similar sequence, treatment of (684) with 3-bromopropionic acid produced (685), which cyclized to imidazo[2,l-Z)][l,3]thiazine (686) upon heating with acetic anhydride (74JPR147). 

---