Pyrimidinone, cyclized

The aminomethylenemalonates can be cyclized at high temperature as in the formation of pyrido[3,2-. With the aminomethylene-malonate group in the 4-/6-position in a free 2-pyrimidinone, cyclization is to the adjacent ring nitrogen <82JHC1581>. 

The hydroxymethyl derivatives 194 undergo one-pot intramolecular cyclization to form pyrimidinone derivatives 195 in excellent yields (Equation 18) <2006T1433>. 

The ring closure of )V-(a-N-heterocyclic)aminomethylenemalonates may lead to the formation of nitrogen bridgehead pyrimidinones when the ring nitrogen is involved in the cyclization. Ring closure may also lead to the formation of condensed pyridines when the ring carbon is involved (Scheme 46). 

During initiation with metal ions, a solvent can play the role of a donor ligand to this metal ion and thus enforce its activity. An example from Smij chemistry is as follows In mixtures of HMPA and l,3-dimethyl-3,4,5,6-tetrahydro-2(l//)pyrimidinone with AN (but not with THF), the rate of reductive cyclization of o-allyloxyiodobenzene with Sml2 sharply increases (Hasegawa and Curran 1993). 

The addition of organometaiiics to unactivated pyrimidines normally produces unstable dihydro derivatives which readily oxidize back to the pyrimidine oxidation level, although successful conjugate addition to pyrimidinone derivatives can occur. Thus, the addition of lithium trimethylsilyldiazomethane [TMSC(Li)N2] to 1,3-dimethyluracil 418 occurred at the 6-position to produce a mixture of the two pyrazolo[4,3-rf]pyrimidine-5,7-diones 419 and 420, where the initial addition had been accompanied by cyclization <1997T7045>. 

It has been reported that 357, prepared via condensing 356 with oxalic acid (no yield was given), cyclizes into pyrazolo[3,4-f]pyrimidinone 358 on reflux in nitrobenzene in the presence of stannic chloride (Scheme 29) <2001BMC715>. 

The pyrido[2,3- pyrimidinones 380 and 381 were thermally obtained from boiling the ethyl acrylate derivatives 378 and 379, respectively, with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and EtNHPd in THF (Scheme 13) <2001W02001055148, 2004USP2004009993>. The acrylates were obtained from reaction of the corresponding pyrimidine-5-carbaldehyde with (carbethoxymethylene)triphenylphosphorane. On the other hand, acrylate 382 was converted into 383 via aza-Wittig cyclization (Equation 32) <1997LA1619>. 

In another cyclization procedure for the 1,5-benzodiazodne system, the nitriles (296) are converted to the aminodihydrodiazocines (297) (79CPB2589). Attack of nucleophiles on (297) occurs at the N-5—C-6 bond to give the 3,4,5,6-tetrahydrodiazodnes (298) with NaBH4 and the jS-aminoethylquinazolines (301) on hydrolysis. The diazocines (297) behave as typical amidines. Oxidation leads to the amidoximes (300) which on hydrolysis are converted to 2,1-benzisoxazoles (302), and reaction with diketene leads to the fused pyrimidinones (299 and l-methyl-3-one isomer) (79CPB2927). 

Cyclization of 2-hydrazinocyanopyrimidinone 392 with triethyl orthoformate afforded the triazolopyrimidin-5-one 394 rather than 396, together with its A-ethylated derivative 395, whose amount increased with time. Here the orthoester acts as a novel alkylating agent. The products from reaction with N-substituted pyrimidinones (393) were the triazolopyrimidin-7-ones 146 (98UP1) (Scheme 74). 

Reaction of 2-amino-4-pyrimidinone (229) with an excess of acrylonitrile gives the intermediate (230). This intermediate can be cyclized to the product (231) in excellent yield by heating in glacial acetic acid (6UOC1891). Similarly, 3,4-dihydro-6,8-dimethyl-pyrimido[ 1,2-a ]pyrimidin-2-one hydrobromide (233) is prepared by the reaction of 2-amino-4,6-dimethylpyrimidine (232) with 3-bromopropionic acid. This reaction also proceeds via a pyrimidinylpropionic acid intermediate (61JOC1891). 

Carboxy)methoxy]-3-formylpyrido[l, 2-a]pyrimidin-4-one 377 was cyclized by heating in acetic anhydride to give furo[2,3-d]pyrimidinone 461 [91IJC(B)839]. 

This kind of TCRT is also observed in the reactions of nitropyrimidinone 3 with ketones and methanolic ammonia, which leads to 4,5-disubstituted pyrimidines 26 [44,45]. This reaction is initiated by the successive addition of ammonia and ketone at the 2- and the 6-positions of pyrimidinone 3. The intramolecular cyclization between the amino and the carbonyl groups furnishes bicyclic intermediate 27, and then anionic nitroacetamide is eliminated to afford pyrimidine 26 (Scheme 12). 

These compounds are also known as thiapteridines. Most syntheses of pyrimido[5,4-/>] [l,4]thiazines were developed for pteridines and then adapted for the thio analogues. Thus, the cyclization of polyfunctionalized pyrimidinones (e.g. (268) - (269)) is a well-known method (Equation (41)) <92H(34)729>. 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

In addition to the Hilbert-Johnson reaction, the so-called mercuri process,37 and, less frequently, the cyclization procedure of Shaw et a/.,53 64 have been used for the synthesis of nucleosides and their derivatives. l-Peracylglycosyl-4-alkoxy-2(l//)-pyrimidinones, the intermediates of the Hilbert-Johnson reaction, can be, in principle, prepared 56,56 also by the mercuri process, namely by reaction of 4-ethoxy-2(lZ/)-pyrimidinone chloromercuri salt with the corresponding halogenoses, but this method is of less importance because of the contamination of iV-l-glycosyl derivatives with the 0-2 isomers, namely, with 2-peracylglycosyloxy-4-alkoxypyrimidines. The advantageous features of the mercuri process in comparison with the Hilbert-Johnson reaction might be formulated as follows. 

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