Tetracyclic pyrido pyrimidines

Reaction of 2-(A -allylamino)-3-formyl-4//-pyrido[l, 2-u]pyrimidin-4-ones 219 in EtOH with HONH2 HCI yielded ( )-oximes 220 at 0°C and 221 (R = PhCH2) under reflux. Heating 220 (R = H) in a boiling solvent afforded cw-fused tetracyclic cycloadducts 221 (R = H). In an aprotic solvent (e.g., benzene or MeCN) the main a>fused cycloadducts 221 (R = H) were accompanied by a mixture of trauA-fused cycloadducts 222, A -oxides 223 and tetracyclic isoxazoline 224 (96T887). The basicity of the 2-allylamino moiety of compounds 219 affected the rate of the conversion. Cycloadditions were also investigated in dioxane and BuOH. 

Reaction of 2-[A -(2-alkenyl)amino]-3-formyl-4/f-pyrido[l, 2-n]pyrimidin-4-ones 235 with HONH2 HCl under both acidic and basic conditions (in the absence or in the presence of NEts) gave tetracyclic derivatives 236 in good yields. Higher yields were achieved in the presence of NEts (96T887). 

Intramolecular cycloadditions of 4/f-pyrido[l,2-n]pyrimidin-4-ones 235 (R = H, Me Ph) and MeNHOH HCl gave tetracyclic isoxazolo derivatives 237. In the case of 235 (R = Me) a minor epimer 238 was also isolated (00JCR(S)414). Similar reaction of 235 (R = H, Me, Ph) and sarcosine ethyl ester HCl afforded an isomeric mixture of epimeric tetracyclic pyrrolo derivatives 239 and 240. In the reaction of 235 (R = H) and PhCHjNHCHjCOOEt only one product 241 was obtained. 

The phenylhydrazones of 2-[(2-alkenyl)amino]-3-formyl-4//-pyrido-[1,2-n]pyrimidin-4-ones 242 underwent a thermally induced intramolecular 1,3-dipolar cycloaddition leading to a mixture of tetracyclic compounds 243 and 244 at room temperature or to 244 under reflux (96T901). Derivatives 243 were not stable and converted to compounds 244 gradually on standing or on heating their ethanolic solutions in air. The ( )-hydrazones 245 could be isolated only in the case of... 

Reaction of 2-[A -(rra -crotyl)-A -benzylamino]-3-formyl-4/f-pyrido[l,2-n]pyrimidin-4-one (269) with chiral primary amines 270 and 271 gave mixtures of diastereoisomers of tetracyclic compounds 273 and tricyclic 275 (96T131]]). The chiral centers in 272 and 274 did not provide any stereocontrol for the formation of diastereomers 273 and 275, respectively. 

Reaction of 4-cyano-3-imino-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyr-imidin-l-one 169 with 2-chloroethyl isocyanate at ambient temperature and under reflux gave N-acylated 170 and tetracyclic derivative 171, respectively (95MI1). Similar reaction of 3-amino-4-cyano-2,4a5,6,7,8-hexahydro-l// pyrido[l,2-c]pyrimidin-1-ones 172 afforded tricyclic compounds 173. 

Reaction of pyrido[ 1,2- pyrazin-4-one 304 with methyl cyanoacetate, cyanamide, and JI-oxo nitriles in AcOH at 70 °C gave imidazo[ l,2- ] pyridine 331, imidazo[l,2- ]-pyrimidine 332, and tetracyclic heterocycles 333, respectively <1996JHC639>. 

Ziegler et al. 3 reported that the reaction of 63 R = H) with bis-2,4-dichlorophenyl malonate at 230 C gave the tetracyclic compound (218), while with bis-2,4-dichlorophenyl benzylmalonate at 200 C the tricyclic compound (219) was formed. This means that the acylation involved both the 0-2 atom and the C-3 atom of the ring system. French workers transformed the pyrido[l,2-r/]pyrimidines (63 R = H) with dialkyl chloro-thiophosphate or its monoamide to 2-acy oxy-4-oxo-4//-pyrido[l,2- ]-pyrimidines.108-179180... 

Vielsmeier-Haack formylation of /-substituted 2-phenylamino-4/7-pyrido[ 1,2-a]pyrimidin-4-ones 470 with a mixture of phosphoryl chloride and dimethylformamide at 95°C for 90 minutes gave a near 1 1 mixture of pyrido[r,2 I,2]pyrimido[4,5-6]quinazolin-12-one 472and -12,13 dione 473 in 23-37% and 22-41% yields, respectively (87JHC329). Compounds 472 and 473 probably formed by the disproportionation of the tetracyclic hydroxyl derivatives 471. If the substituent (R) of 470 was the ethoxycar-bonyl group, only N-ethoxycarbonyl derivative 475 could be obtained (92JHC25). No tetracyclic derivative 472 and/or 473 (R = COOEt) was formed. 

Tetracyclic pyrimido[l, 2 l,2]pyrido[3,l- >]indole derivative 606 (R = H) was obtained when 9-bromotetrahydropyrido[ 1,2- ]pyrimidin-4-one 604 (R = H) reacted with Af-methylaniline in boiling ethanol for 8 hours under nitrogen in 37% yield (Scheme 40) (91JHC1405). In the reac-... 

A variety of other polycyclic systems of this type have been synthesised including the tetracyclic system pyrido 3, 2 4 5 ]thienol2 3, 5,6]pyrido 2,3-[Pg.267]

Reaction of pyrido[l,2-a]pyrazin-4-one 145 with methyl cyanoacetate, cyanamide, and /3-oxo nitriles in AcOH at 70°C gave imidazo[l,2-a]pyridine 147, imidazo[l,2-u]pyrimidine 148, and tetracyclic heterocycles 149, respectively (96JHC639). 

Cyclocondensation of l-methylthio-4,4a,5,6,7,8-hexahydro-3//-pyrido [l,2-c]pyrimidine (139) with anthranilic acids (71JMC878 72USP3631046 74USP3772230 75USP3868372) or with ethyl 5-amino-3-methylisothiazole-4-carboxylate [76IJC(B)391] afforded the tetracyclic derivatives 140 and 141, respectively. 

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