2 -Pyrimidinones 3,4-dihydro

Pyrimidinones, dihydro-NMR, 3, 62 synthesis, 3, 117 Pyrimidinones, methyl-thiation, 3, 89... 

Chemical Name 2,3-Dihydro-5-iodo-2-thioxo-4(1 H)-pyrimidinone Common Name lodothlouracll Structural Formula ... 

Treatment of l,3,4,6,7,llb-hexahydro[l,3]oxazino[3,4- ]quinazolin-l-one with LAH in boiling THF gave 2-(2-hydroxyethyl)-l-methylquinoline <2003T6785>. Pyrimidinone 107 was obtained from trequinsin 106 on the action of NaH, followed by the treatment with Mel (Equation 17) <1997IJB349>. The reaction of7-(benzotriazol-l-yl)-6,7-dihydro-l//,3/7,5//-pyrido[3,2,l-zy][3,l ]bcnzoxazine with PhMgBr led to ring-opened l-benzyl-4-(benzotriazol-l-yl)-8-hydroxymethyl-l, 2,3,4-tetrahydroquinoline < 1995JOC3993>. 

Synthesis of Enantiomerically Pure p-Amino Acid from 2-tert-Butyl-1-carbomethoxy-2,3-dihydro-4(1 H)-pyrimidinone (S)-p-Tyrosine-O-methyl Ether. 

Sodium borohydride can be used to reduce pyrimidinones to their dihydro derivatives, and the reduction of the axially chiral pyrimidinone 379 occurred stereoselectivily to give the dihydropyrimidinone 380 in 94% yield and 85% enantiomeric excess <2003AGE4360>. 

While all of the above examples have involved pyrimidinone derivatives, pyrimidines themselves can also be reduced to dihydro derivatives using triethylsilane and trifluoroacetic acid <2004TL2107>. Thus, a variety of 2-aminopyrimidines 390 were reduced to their 1,6-dihydro derivatives 391 in good yield by treatment with trifluoroacetic acid (TEA) and triethylsilane at room temperature, while 5-bromopyrimidine 392 similarly gave the dihydro derivative 393 in 81% yield under the same conditions <2004TL2107>. 

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>. 

The [4-I-2] cycloaddition of ketenes 628 with 1,3-diazabutadienes 629 is now a well-established route to 5,6-dihydro-4-pyrimidinones 630 and, when a leaving group is present, 4-pyrimidinones 631 <1997X13841, 1998H(47)933, 2001 H(55>2283, 2002ARK(vii)106, 2002J(P1)774>. 

The most important synthesis within this subgroup is the Biginelli reaction, which involves reaction between a methylene ketone 715, an aldehyde 716, and either a urea 717 (Z = 0) or thiourea 717 (Z = S) to give a dihydro-2-pyrimidinone 718 (Z = 0) or dihydro-2-pyrimidinethione 718 (Z=S) <1993T6937, 2000ACR879, 20040R1>. 

In a related three-component reaction procedure, aryl methyl ketones 724 have been combined with aryl aldehydes 725 and urea 726 at room temperature, using trimethylsilyl iodide as catalyst, to give 4,6-diaryl-3,4-dihydro-2(177)-pyrimidinones 727 <2005HCA2996>. A procedure using zinc iodide and microwave irradiation gave similar products <2007T1981>. 

The enzymes in the zebra fish pathway are presumably very similar to those of other vertebrates. However a completely different type of GTP cyclohydrolase has been identified in the hyperthermophilic euryarchaeon, Methanococcus jannashii <2002B15074>. This enzyme, in purified recombinant form, produced as a stable end product 2-amino-5-formylamino-6-ribofuranosylamino-4(3//)-pyrimidinone monophosphate, a compound that is an intermediate in the action of normal GTP cyclohydrolases. The biosynthesis of the incorporation of the pterin into methanopterin in Methanobacterium thermoautotrophicum has been proposed to occur via substitution of 7,8-dihydro-6-hydroxymethylpterin diphosphate 227 (Scheme 44) <1998BBA257>. 

The enantiomerically pure substituted 1,2-dihydro-4(3//)-pyrimidinone 11 has been employed as a chiral auxiliary for diastereoselective alkylation reactions2. Thus, acylation, followed by enolate formation and alkylation with reactive halides such as halomethanes. (balomethyl)benzenes, 3-halopropenes and 3-halopropynes, affords the alkylation products with high diastereoselectivity (d.r. 93 7 to 99 1) . 

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). 

Reduction ofpyrimidine-2(lH)-ones.1 The pyrimidinone 2 is reduced by metal hydrides such as lithium tri-f-butoxy aluminum hydride to a mixture of the 3,6- and 3,4-dihydro derivatives in the ratio 9 1. In contrast, Meerwein-Ponndorf-Verley reduction with 1 in isopropanol results only in the 3,4-dihydro derivative (3a) but the reaction is slow and stops after two days to provide only a 25% yield. However, introduction of a halo substituent at C5 results in enhanced yields of the 3,4-dihydro derivatives, with the highest yields obtained with the 5-chloro derivative. 

Dondoni and Massi9 executed a Bignelli synthesis to prepare dihydro-pyrimidinones starting from aldehydes, 1,3-dicarbonyl compounds, and urea with ytterbium(III) supported on Amberlyst 15 resin as a Lewis acid (entry 5). After condensation, the reaction mixture is treated with both strongly basic and acid resins to sequester reaction by-products. For more than 30 reported examples, dihydropyrimidones obtained directly from concentration of the filtrates are produced in high yields and in excellent purities. 

Dihydro-2//-pyrido[l,2-a]pyrimidin-2-one 675, a neutral hydrogen chloride acceptor, has been shown to give better yields in regio- and stereospecific thio- and selenolactonizations of hept-4-ynoic and hex-4-ynoic acids 683 with benzenesulfenyl and benzeneselenenyl chlorides than triethylamine [86JCS(P1)1999]. In the case of dihydropyrido[l,2-a] pyrimidinone 675, noncyclized products 685 and 686 were formed only in trace amounts. 

Basic catalysis of the reactions of urea with unsaturated ketones, as well as thiourea, can lead to heteroaromatization with the formation of oxidized pyrimidinones instead of their dihydro analogues [77] (Scheme 3.23). 

Cyclocondensation of asparagine with aromatic aldehydes gave 2-(substituted-phenyl)-6-carboxy-l,2,3,5,6-pcntahydro-4(l//)-pyrimidinones 55 <07MI2464>. A new approach to 3-alkyl(aryl)-2-thioxo-2,3-dihydro-1 //-benzofuro[3,2-c/]pyrimidin-4( I //)-oncs was developed,... 

SYNTHESIS OF ENANTIOMERICALLY PURE p-AMINO ACIDS FROM 2-tert-BUTYL-1 -CARBOMETHOXY-2,3-DIHYDRO-4(1 H)-PYRIMIDINONE (R)-3-AMINO-3-(p-METHOXYPHENYL)-PROPIONIC ACID... 

Several compounds derived from these libraries were identified as Hsp70 modulators and were further evaluated in cell proliferation assays such as the SK-BR-3 and MCF-7 breast cancer cell lines and the HT29 colon cancer cell line (Fig. 6) [26]. Compounds 22-24 were potent against all three cell lines. The dihydro-pyrimidinone libraries were also tested for replication inhibition of the malarial parasite, Plasmodium falciparum, where Hsp70 chaperones are believed to play an important role in the parasite s homeostasis [24]. Nine compounds that inhibit replication of the parasite were identified. Among them, compounds 25 and 26 were the most potent (Fig. 7) and were prepared by direct couplings of dihydropyrimidone acids 19 with a pyrrolo amine. 

DIHYDRO-6-PROPYX-2-THIOXO-4(IH)-PYRIMIDINONE see PNXOOO DIHYDROPSEUDOIONONE see GDE400 a-p-DIHYDROPSEUDOIONONE see GDE400... 

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