3-Formyl-47/-pyrido pyrimidin-4-ones

Appropriate pyrido[2,3-d]pyrimidin-5-ones with formyl groups in the 6-position have been oxiized to piromidic (68) and pipemidic (69) acids, or to intermediates for these, using moist silver oxide, chromium trioxide (potassium dichromate), potassium permanganate or, alternatively, sodium chlorite/hydroxylamine-O-sulfonic acid. 6-Acetyl groups have been similarly oxidized using sodium hypobromite in aqueous dioxane, whilst 2-acetyl groups give dimethylaminomethylene derivatives en route to 2-pyrazolylpyrido[2,3-d]pyrimidines. 

Oxidation of 9-(4-pyridylvinyl)-7-methyl-2-morphohno-4//-pyrido[l, 2-a -pyrimidin-4-one with cetyltrimethylammonium permanganate in CH2CI2 at room temperature for 5 h yielded a 9-formyl derivative (01MIP9). 

Vilsmeier-Haack formylation of 2-(4-methyl-l-piperazinyl)-4//-pyrido-[l,2-n]pyrimidin-4-one with a mixture of POCI3 and DMF at 95°C gave a 3-formyl derivative (93FES1225) while ethyl 4-oxo-6,7,8, 9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-2-acetate at 50 °C yielded a 9-dimethylaminomethylene-3-formyl derivative (01MI4). 3-Formyl-2-hydroxy-8-[2-(4-isopropyl-l,3-thiazol-2-yl)-l-ethenyl]-4//-pyrido[l,2-n]pyri-midin-4-one was obtained from the 3-unsubstituted derivative with oxalyl chloride-DMF reagent in CH2CI2 at room temperature for 3h (OlMIPl). 

The 3-formyl group of 8-substituted 3-formyl-2-hydroxy-4//-pyrido[l,2-n]pyrimidin-4-one was reacted with (cyanomethyl)- and (terr-butoxycarbo-nylmethylene)triphenylphosphorane in THF, and with 5-aminotetrazole in boiling MeOH for 9h to yield ( )-3-propenenitrile, terr-butyl ( )-3-propenoate and 3-[(2//-tetrazol-5-yl)imino]methyl derivatives, respectively (OlMIPl). 

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). 

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 3-formyl-2-[A-(2-alkenyl)-A-benzylamino]-4//-pyrido[l, 2-n]-pyrimidin-4-ones 252 and primary amines in the presence of MS (4 A) afforded pyrido[l, 2 l,2]pyrimido[4,5-Z)]azepin-6-ones 253 (96T13081). 

Reaction of 2-(A -alkyl-A -benzylamino)- and 2-[A -(rraM-crotyl)-A -ben-zylamino]-3-formyl-4/7-pyrido[l,2-n]pyrimidin-4-ones (260, R = H, Me) with tosylamine gave compounds 268 via compounds 266 and 267 (96T13097). The results of kinetic studies and MP3 calculations on the 3-formyl derivatives 252, 260 and the imines 262, 263 suggested a concerted nature for azepine-ring formation. 

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. 

For all 4//-pyrido[l, 2- ]pyrimidin-4-ones the formyl-enamine is the predominant form both in solid and solutions [83JCS(P 1)369, 83JCS(P2)1153 85JCS(P2)1873, 85JCS(P2)1881]. 

Protonation of 9-formyltetrahydropyrido[l,2-a]pyrimidinones takes place at the formyl oxygen, and the protonated enol-imine tautomers on the N(l) atom became the predominant tautomer forms [86JCS)P2)1911]. Similar phenomena were observed for the 9-formyltetrahydro-2// pyrido[l,2-a]pyrimidin-2-ones and their homologs [85JCS)P2)1873 88MI7]. 

Methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-a]pyrimidin-4-ones 340 were also prepared from 9-formyl-1,6,7,8-tetrahydro-4//-pyrido[l,2-a] pyrimidin-4-ones 339 by catalytic hydrogenation in acidified ethanol over palladium-on-charcoal (83JMC1126 86JOC394). 

Formyl derivative 362 was prepared when 9-hydroxymethylpyrido-pyrimidin-4-one 361 in dichloromethane was added to a cooled mixture of oxalyl chloride and dimethyl sulfoxide at - 50°C/ - 60°C in the presence of triethylamine. 9-Formyl derivative 362 was oxidized with silver nitrate in aqueous ethanol, and after 15 minutes of stirring the reaction mixture was treated with aqueous potassium nitrate for 2 hours at ambient temperature to give pyrido[ 1,2-a]pyrimidine-9-carboxylic acid 363 (91EUP453042). 

The amino group of 2-amino-3-formyl-4//-pyrido[l,2-a]pyrimidin-4-one was acylated with chloroacetyl chloride in benzene at ambient temperature to give 2-(chloroacetylamino)-3-formyl-4//-pyrido[ 1,2-a]pyrimidin-4-one (92MI23). 

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. 

When 2-phenylamino derivative 474 reacted under the above conditions, unsaturated 12 -pyrido[l 2 l,2]pyrimido[4,5-Z>]quinolin-12-one 476 and 3-formyl-2-phenylamino-4//-pyrido[ 1,2-u]pyrimidin-4-one 475 were isolated in 57% and 11% yields, respectively. When the reaction was carried... 

Dipyrido[l,2-a 2, 3 -(i]pyrimidine-2,5(l//)-diones 477 were prepared when 2-acylamido-4//-pyrido[l,2-a]pyrimidin-4-ones 382 were heated in a mixture of phosphoryl chloride and dimethylformamide (92JHC25). When the reaction period was only 15 minutes, 2-acetamido derivative 382 (R = Me, R1 = H) gave 3-formyl derivative 478 and tricyclic compound 477 (R = Me, R1 = H) in 31% and 53% yields, respectively. 

Nitro-4-oxo-l, 6,7,8-tetrahydro-4/f-pyrido[l, 2-a]pyrimidines 534 (R = 6-, 7-, and 8-Me) or 538 were also obtained from 9-formyl-4-oxo-1,6,7,8-tetrahydro-4i/-pyrido[l,2-a]pyrimidine-3-carboxylates 536 with Clayfen in 24-54% yields (90JOC6198), or from 9-bromo-6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidin-4-ones 537 with sodium nitrite in 40-62% yields (87H869). From the reaction mixture of 9-formyl-6-methyltetrahydropyridopyrimidine-3-carboxylate 536 (R = 6-Me) both 32% of 9-nitro derivative 534 (R = 6-Me) and 5% of dinitro compound 535 (R = Me) were isolated following column chromatography (90JOC6198). 

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