Pyrimidine betaines

It was assumed that pyridine derivative 181 yielded pyrido[l,2-c]pyrimidine betaine 182 under catalytic hydrogenation conditions over (5,S)-Et-DuPHoS-Ph catalyst (99TL1211). 6,7-Dehydro derivative 184 of trequinsin (3) was obtained from pyrimidinone 183 by heating in an 1 1 mixture of MeOH and cone. HCl under reflux (97IJC(B)349). 

These compounds offer interesting possibilities for further elaboration as they enter into addition reactions with, for example, the 1,2-quinone (60), yielding tricyclic compounds (61) (79TL237), and their bicyclic analogues (62) combine with phenyl isocyanate to give adducts (63), which eliminate carbon dioxide to afford pyrimidine betaines (64). Similarly, dialkyl acetylenedicarboxylates produce quinolizinones (65) (Scheme 19) (79CB1585). 

Cycloadditions to mesomeric pyrimidine betaines (234 and 235) with DMAD in refluxing chlorobenzene gave high yields of the pyridones 237 and 238 via the intermediate cycloadducts 236, which were not... 

Potts and Hsia219 prepared unsaturated 6-oxo-6H-pyrido [ 1,2-a] pyrimidines (165) by the 1,4-dipolar cycloaddition of dipolarophilic acetylene derivatives to pyrimido[l,2-a]pyrimidine betaines (164). 

A novel type of heteroannulation reaction has been reported by Wamhoff, Schmidt et al. <91TL4473, 93JOC6976). Uracil-iminophosphoranes (108) are converted into pyrimido[4,5-rf]pyrimidine betaines (109) in a one-pot three-component reaction with isocyanates and hetarenes (double bonds) (Equation (14)). 

Fusion of a thiazole to pyrimidine betaines does not change the tendency of the latter for cycloaddition reactions, e.g. (306) forms adducts with alkynes (73JHC487). Similarly 1,3-thiazine betaines (399) react as 1,4-dipoles with aryl isocyanate with elimination of COS to produce pyrimidine betaines (400) (76CB3668). 

Thermolysis of pyrimidine betaines of type (138) yields quinolones (139) via keten intermediates (Scheme 57), and the vapour-phase reaction of indole and... 

Oxidopyridazinium betaines isomerize photochemically into pyrimidin-4(3H)-ones (33). Irradiation of 3-oxidopyridazinium betaine or 1-oxidophthalazinium betaine in water affords similarly the corresponding pyridazin-3(2H)-one (35) and phthalazin-l(2H)-one derivative (37). However, photolysis in acetonitrile affords stable diaziridines (34) and (36) which can be converted in the presence of water to the final products (35) and (37) (Scheme 12) (79JCS(P1)1199). 

Dipolar cycloadditions of dihydropyrimidine-fused mesomeric betaines 389, 391 and 394 with different dipolarophiles afforded 6-oxo-6H-pyrido[l,2-n]pyrimidine-3-carboxylates 390, 392, 393 and 396 (97JOC3109). 

The hexahydropyrimido[l,2-r ]pyrimidines 33 and 34 reacted with chloropentafluorobenzene with loss of HF, as depicted in Scheme 2 <2003JOC3139>. Compound 33 formed the mesomeric triazaphenalene betaines 51 with 2-substituted malonates. From the benzene solution of 33 and methane tricarboxylate, the salt 50 was isolated which on heating also converted into 51 (Scheme 3) <2004JHC717>. 

The Diels-Alder cycloaddition potential of fused 4-aryldihydropyrimidine mesomeric betaines has been studied. The cross-conjugated thiazinium betaine 317 underwent 1,4-dipolar cycloaddition with electron-rich dipolaro-philes, and thus 1-diethylaminoprop-l-ine gave the pyrido[l,2-tf]pyrimidine 318 by loss of carbonyl sulfide (Equation 34). Reaction of 317b with 1,1-diethoxyethene resulted in the 8-ethoxy analogue of 318 (R = H) <1997JOC3109>. 

Compound 248 treated with (EtOhP in refluxing xylene provides an 89% yield of 19 (Equation 37) <2005AGE7089>. Similarly, [l,2,3]triazolo[4,5- /]pyridazine 249 provided a 68% yield of the corresponding mesomeric betaine 250 (Equation 38). However, reductive cyclizations of the analogous 3-(2-nitrophenyl)-377-[l,2,3]triazolo[4,5-//Jpyrimidine, 3-(3-nitropyridin-2-yl)-3//-[l,2,3]triazolo[4,5-. 

Of the four possible azaquinolizinium systems, only the 1-aza- (pyrido[l,2-a]pyrimidin-5-ium, 234), the 2-aza- (pyrido[l,2-a]pyrazin-5-ium, 235) and the 4-aza- (pyrido[l,2- ]pyridazin-9-ium, 237) quir olizinium systems are known in at least a betaine form. No example of the fully aromatic 3-azaquinoIizinium system (pyrido[l,2-c]pyrimidin-9-ium, 236) has been found. 

Special cases of this reaction are the syntheses of TP betaines (53, see below) from pyrimidin-2-ylcarbamoyl chlorides and trimethylsilyl azide [89JCS(P1)1727] and of TP-1-oxides (31, see below) form pyrimidin-2-yl sulfimides and nitrile oxides [76JCS(P1)2166]. 

Oxidopyridiniums (26 Z = NR, Y = O) are converted photochemically into the bicycle (27) corresponding 3-oxidopyryliums and especially 4-oxidoisochromyliums isomerize more easily (cfi 44 — 45). 5-Oxidopyridazinium betaines are isomerized photochemically into corresponding pyrimidin-4-ones by a similar path (Scheme 6). 

Dipolar cycloaddition of anhydro pyrido[2,l-b][l,3]thiazinium hydroxides (128) with aryl isocyanates and dimethyl acetylenedicarboxylate gave pyrido[l,2]pyrimidines (129) and quinolizine-l,2-dicarboxylates (130), respectively (76CB3668). 1,4-Dipolar cycloaddition of pyrido[2,l-h][l,3]thi-azinium betaine (131, R = Me) with 1-diethylamino-l-propyne afforded cycloadduct 132, from which quinolizin-4-one 133 formed by a rapid cheletropic extrusion of carbonyl sulfide (93TL5405 95T6651). 1,4-Dipolar cycloaddition of anhydro 4-hydroxyl-2-oxo-6,7,8,9-tetrahydro-2//-pyrido-[2,l-b][l,3]thiazinium hydroxides (131) and 4-phenyl-l,2,4-triazoline-3,5-dione yielded 135 via 134 [94H(39)219 95H(41)1631] and 136 (95T6651). 

Mesomeric betaines (116) and isocyanates gave rise to 4-oxo-4//-pyrido-[l,2- ]pyrimidines (117) in 36-64°/, yield.175 177... 

Oxo-3,4-dihydro-2//-pyrido[l,2-a]pyrimidines (142) may easily be converted (e.g., by heating in water) to the betaines (143)200,204 The latter can also be prepared from 2-aminopyridines with propiolactone,206 acrylic acid,18 3-substituted propionitriles, and other acrylic acid derivatives.207,208 The betaines (143) revert to the bicyclic compounds (142) upon heating in acid 200 204-206-207... 

Adams and Pachter18 synthesized the 3-hydroxy derivative of (142 R = H) by reacting 2-aminopyridine and 3-bromo-2-hydroxypropionic acid in in chloroform and also by heating the appropiate hydroxy derivative of the betaine (143) in concentrated hydrobromic acid. The authors then amended their earlier conclusions,209 in which incorrect structures were assigned to the betaine and to the pyrido[l,2-u]pyrimidine. 

Amino-5-halopyridines displayed different behavior. According to Hurd and Hayao,206 with propiolactone in acetone, 2-amino-5-bromopyridine gives the betaine (143 R = 5-Br), whereas with 3-bromopropionic acid at 100 C without solvent, the hydrobromide of 4-oxo-2,3-dihydro-4//-pyrido-[l,2- ]pyrimidine (147 X = Br) is formed. 

On the action of water200-204-205 or ammonia,200 2-oxo-3,4-dihydro-2//-pyrido[l,2-a]pyrimidines (142) undergo a facile ring opening. The betaine-type products (143) can be recyclized to the parent pyridopyrimidines by heating with acids. Treatment with alkalis leads to 2-aminopyri-dines.200,205,208... 

The structure of the reaction product of 2-aminopyridine and diethyl malonate, described by Chichibabin as 2,4-dioxo-3,4-dihydro-2//-pyrido-[l,2-<7]pyrimidine,96 was first questioned by Snyder and Robison253 on the basis of the high melting point and poor solubility of the compound. They suggested the tautomeric 2-hydroxy-4-oxo-4H-pyrido[l,2-a]pyrimidine structure. The problem was solved by Katritzky and Waring273 who compared the UV spectrum of the product with that of fixed tautomers and found that the product may best be described as anhydro- 2-hydroxy-4-oxo-4/f-pyrido[l,2- ]pyrimidinium)hydroxide (63). Because of the chemical behavior of these compounds, however, the contribution of other mesomeric forms to the structure has also been considered.122 Thus, PPP-SCF quantum chemical calculations suggest that 1,4-dipolar cycloadditions to the C-3 and C-9a atoms are to be expected.352 This type of reaction does in fact occur (see Section III,C,10). Katritzky and Waring273 estimated the ratio of the mesomeric betaine (63 R = H) and the 2-hydroxy-4-oxo tautomers to be about 20 1. 

The ease of oxidation depends on the electron availability on the sulfur. In quinoline and pyrimidine analogues of (459) the rate of the reaction is decreased, and in these betaine systems sulfone formation is not observed using peracids in the oxidations. A 2-carboxy group as in (463 R = H) promotes the Pummerer-type rearrangement. The initially formed hemimercaptal mainly eliminates water to give the thiazole (464) a minor product (465) may be formed by ring opening (81H(15)1349). 

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