2//,6//-Pyrimido thiazines

In a review article Delia presents 88 references for the synthesis of pyrimidooxazines and pyrimido-thiazines [Pg.765]

Tile tautomeric equilibrium of pyrimido[4,5-h][4, 5 -e]thiazine 157 was studied in DMSO-dg by NMR spectroscopy (92CHE1219). Based on and NMR chemical shifts, fast proton exchange was concluded to occur between 157b and 157c. Monoprotonation of 157 has been assumed to form... 

Of the possible 16 pyridazino-, pyrimido-, and pyrazino-oxazines, 10 are known with 19 benzo-fused derivatives. Literature over the past 10 years reports 10 bicyclic and 9 tricyclic systems and these are shown in Table 2. Of the possible 16 N-bridgehead pyridazino-, pyrimido-, and pyrazino-thiazines, 7 are known along with 13 benzo-fused derivatives. In this review five bicyclic and four tricyclic systems are discussed and these are shown in Table 3. One bicyclic system has been reported with a Se heteroatom and this is shown in Table 4. 

Single crystal X-ray analysis of the pyrimido[2,l-3][l,3]thiazine 293 was performed to verify the structure and the regioselectivity of the synthesis from diazadiene <2002S403>. 

Mass spectra of the cis- and /ram-isomers of the pyrimido[2,TA [l,3]thiazin-6-ones 294 and 295 were studied. Retro-Diels-Alder fragmentation of the hydrocarbon ring was of medium to low stereospecificity. A number of highly selective processes were discovered allowing differentiation between stereoisomers <1996RCM721>. The mass spectral fragmentation pattern of 296 was studied in detail <1996PS(113)67>. 

Hydroxy-perhydropyrimido[2,Tr-][l,4]oxazine condensed into the pentacyclic compound 319 on heating in aqueous solution. The 9-OH-9-Me analogue did not undergo this reaction < 1996H(43) 1991 >. 7,8-Diamino-3,4-dihydro-277-pyrimido[2,1 -b [ 1,3]thiazin-6-one and 8,9-diamino-3,4-dihydro-2/7,6/7-pyrimido[6, -b][ 1,3]thiazin-6-one when reacted with benzamidine. HC1 in a melt at 220 °C in the presence of anhydrous NaOAc formed the purine derivatives 320 and 321, respectively <1996JME2529>. 

The pyrimido[6,l-F][l,4]oxazine-6,8-diones 164 (Y = O) and pyrimido[6,l-c][l,4]thiazine-6,8-diones 164 (Y = S) were synthesized by treating 6-chloromethyl-uracil with methyl glycolate 162 (Y = O) or methyl thioglycolate 162 (Y = S), respectively, and reacting the resulting 163 with DMF-dimethyl acetal (Scheme 20) <2004W02004/014354>. 

Benzyl-9-phenyl-3,4-dihydro-27/,677-pyrimido[6,l-A [l,3]thiazine-6,8-(7//)-dione was prepared from 3-benzyl-6-chloro-l-(3-chloropropyl)-5-phenylpyrimidine-2,4-(17/,3//)-dione and NaSH hydrate in DMF in 27% yield <1995W035296>. 

In a similar manner, 2,2,4-trimethyl-27/,677-pyrimido[2,T4][l,3]thiazines with 7-formyl, 7-acetyl, or 7-C02Me substituents were obtained in good to excellent yields by reacting Ar,Ar-dimethyl-Ar -(4,6,6-trimethyl-6//-l,3-thia-zin-2-yl)formamidine with acrolein, methyl vinyl ketone, or methyl acrylate, respectively <2002S403>. 

Dihydro-4//,8//-pyrimido[2,l-3][l,3]thiazine-7-carboxylic esters and amides exhibited high activity on antiinflammatory and antipyretic tests <1996EJM663>. 8-(Benzoylbenzyloxy) and (benzoylbenzylthio)-7-methyl-3,4-dihydro-2//,6//-pyrimido[2,l-3][l,3]thiazin-6-ones exhibit antitumor activity <1996EPP0733633>. 9-Amino- or 9-methyl-3.4-dihydro-2//,6//-pyrimido[2,l -3, 1,3]thiazin-6-oncs have anticorrosive effect <2003RUP2198245>. 

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... 

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. 

Reactions of pyrimido[4,5-3] [l,4]thiazines were discussed in CHEC-II(1996) <1996CHEC-II(7)737> more recently, reported reactions of this system involve nucleophilic substitution in a number of guises. Hemiaminals at C-3 react with ammonium acetate to form aminals (Equation 166) <1999CHE97>. The formation of acyl hydrazides from pyrimido[4,5-3][l,4]thiazine-2-carboxylic acids, along with their subsequent conversion to acyl azides and Curtius... 

Pyrimido[4,5-c][l,2]thiazines have been synthesized by formation of 4-(alkanesulfonamido)pyrimidine bearing an electrophilic substitutent at C-5, and cyclization of an anion generated adjacent to the sulfonamide. The 5-sub-stituent can be a ketone (Equation 171) <2003W003/062246>, or a carboxylate or nitrile, in which case the product contains a carbonyl group at C-4 (Scheme 89) <2002W002/076463>. 

The formation of a pyrimido[5,4-f][l,2]thiazine by annulation of a pyrimidine ring onto a benzoH[l,2]thiazin-4-one has been reported, involving condensation with dimethylformamide dimethyl acetal followed by Bredereck s reagent (Scheme 90), and reaction of the resultant vinylogous amide with guanidine <2005W02005/037843>. Essentially, the same approach has been used to prepare annulated forms of the isomeric pyrimido[4,5-< ][l,2]thiazines, as outlined in Scheme 91 <1998W098/28281>. 

No pyrimidothiazines have been marketed in their own right. However, the pyrimido[5,4-f][l,2]thiazine 147 is reported as a metabolite of meloxicam 148 <1995MI1219>. Pyrimido[4,5-f][l,2]thiazine 149 and related compounds ate claimed as inhibitors of cyclin-dependent kinases <2003W003/062246>, while 150 is reported to be in clinical evaluation as an antineoplastic agent <1997JME2502>. 

A recent report describes the formation of benzo derivatives of the pyrimido[4,5- ][l,4]thiazine system by cyclization (Scheme 109) <2007BMC2120>. The compounds prepared have some 5-lipoxygenase inhibitory activity, the active inhibitor being the corresponding sulfoxide, which has been prepared by oxidation of the parent (Scheme 109). 

---