1.3- dimethyl-4-aminouracil

Treatment of aminoazines, in particular, 6-aminouracil 305, with cyclic oc,(3-unsaturated ketones was described in [235]. The authors showed that 1,3-dimethyl-6-aminouracil reacts easily with cyclooct-2-enone 313, cyclonon-2-enone 316 and other cyclic unsaturated carbonyls (cyclododec-2-enone, cycloundec-2-enon, etc.), forming the appropriate tricyclic compounds 314, 317 or analogues (Scheme 3.86). The interaction of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) with compound 314 leads to a rearrangement of the carbon skeleton and formation of another tricyclic structure 315, while in the... 

Reaction of arylidenecycloalkanones with derivatives of 6-aminouracil is not described in the literature but there are examples of multicomponent synthesis involving cyclic 1,3-diketones and aldehydes. In [244] the treatment of 1,3-dimethyl-6-aminouracil 305 with 1,3-diketones 320 and aliphatic aldehydes in boiling acetic acid was reported to lead to the formation of 1,3-dimethyl-8,9-dihydropyrimido[4,5-/ ]quinoline-2,4,6-trione 321 in yields of 50 60% (Scheme 3.87). 

One-step synthesis of 6-hydroxypyrimido[4,5-6]indole involves the condensation of 1,3-dimethyl-6-aminouracil with p-benzoquinone (66CB3524 81JOC4197) (Scheme 111). 

Treatment of 6-aminouracils 202 with dimethyl acetylenedicarboxylate (DMAD) affords the tricyclic pyrimidine derivatives 203 in excellent yields (Equation 20) <1998JCM502>. 

Reaction of the aminouracil (55) with thionyl chloride in dimethyl-formamide produced the isothiazolo[3,4-[Pg.65]

NICNAS. 1,3 Dimethyl 4-aminouracil, Full Public Report File No. STD/1029, National Indusitrial Chemicals Notification and Assessment Scheme, Commonwealth of Australia, 2003. 

However, treatment of 109a-d with maleic anhydride leads to the appropriately substituted 0x0 derivatives llla-d <1998T5753>. 6-Aminouracil and the iV-methyl or -dimethyl analogs proceed under identical conditions to form the corresponding iV-methylated analogs of 111 <1998T5753>. 

Amidines formed by condensation of 4-aminouracils with dimethylformamide dimethyl acetal are effective dienophiles, and form pyrimido[4,5-rflpyrimidines by [4-I-2] cycloaddition with isocyanates, isothiocyanates (Equation 83) <2005TL1433> and imines (Equation 84), A similar process has also been reported, using a nitrone as the dienophile (Equation 85) <2006BMCL3537>. 

The reaction of 6-aminouracils 157 with dimethyl Ai-cyanodithioimidocarbonate, shown in Scheme 27, gave the intermediates 158 which on coupling to phenyldiazonium salt, followed by elimination of methanethiol, gave the 5,7-disubstituted-2-phenylpyrimido[4,5- ]-l,2,4-triazines 159 (Ar = Ph) in the isolated yields shown in Table 10 (entries... 

Hayon447 to absorb in this UV region. Similar measurements have been made for a number derivatives of uracil (5,6-dihydro, 1-, 3-, and 6-methyl, 1,3-dimethyl-, and 5-aminouracil, orotic acid, barbituric and isobarbituric acids also see similar measurements448 on 5-bromouracil and its iV-methyl derivatives), thymine itself and its derivatives (5,6-dihydro, 2-methylthymine). In the case of cytosine, Hayon447 has very tentatively suggested that species 47 and 48 are obtained on pulse radiolysis of the solution at pH 5.5, and 49 at pH 13.3. 

Amino-7-methylthiopyrimido[4,5-d]pyrimidine-2,4-diones (261) can be prepared in one step from 6-aminouracils (255) using the versatile intermediate dimethyl cyanoimidodithiocarbonate (260). Condensation of the uracils (255) with (260) in the presence of potassium carbonate in DMF gives the desired products (261) (79H503). 

The reaction of l,3-dimethyl-6-aminouracil 305 with trifluorobenzylidenea-cetone, containing a strong a-acceptor group, in boiling DMSO, yielded a mixture of dihydro (307) and heteroaromatized (306) heterocycles, with a predominance of the latter [239] (Scheme 3.83). 

The reaction of 4-(2-hydroxyphenyl)-but-3-en-2-one 21 with l,3-dimethyl-6-aminouracil 305 in trifluoroacetic acid proceeds with the intramolecular addition of the hydroxyl group to the ethylene bond of dihydropyrido[2,3-J pyrimidines and yielded the appropriate tricyclic compounds 308 [230] (Scheme 3.84). 

A new synthesis of purines is illustrated by the reaction of l,3-dimethyl-6-aminouracil with MiV-dimethyldichloromethyleneiminium chloride (phosgeneiminium chloride), trimethylsilyl azide and arylamines in dry chloroform, followed by treatment with 20% aqueous potassium hydrogen carbonate. The reaction probably proceeds via a 4-amino-5-(chloroformamidin-l -yl)uracil (Scheme 10) [94JHC1185],... 

The most common synthetic approaches to both types of pyrimidopyrimidine have been described in CHEC-I and in review articles by Delia . In addition some new strategies in the preparation of pyrimido[4,5-rf]pyrimidines have been developed in the last few years. A new approach is the aza-Wittig-type reaction of iminophosphoranes of 5-aminouracils with aromatic isocyanates which leads to functionalized pyrimido[4,5-rf]pyrimidines. Ethyl 1,3-dimethyl-6-(triphenylphosphoranylideneamino)-uracil-5-carboxylate (105) reacts with isocyanates via adduct (106a) intermediates to afford 7-ethoxypyrimido[4,5-. 

The readiness of amidine formation in reactions of lactim ethers with amines has been used in the synthesis of 8,9-poly methylene-purines.97 Attempts to condense 2 (R = Me) with uramil and l,3-dimethyl-4,5-diaminouracil failed.97 Lactim ethers were also found not to react with derivatives of 5-aminouracil, probably due to the low basicity of the latter.97... 

Cycloaddition between electron rich 6-[(dimethylamino)methylene]amino-l,3-dimethyl uracil and various electron deficient substrates gave pyrido[2,3-i pyrimidine derivatives in a high regiospecific manner. The pyrido[2,3-i pyrimidinones 17 and their N-oxides 18, 5-deaza-5,8-dihydropterins 19 and pyrido[2,3-i (]pyrimidinone 20 were synthesized from 6-aminouracils, 6-hydroxyaminouracils, 2,6-diaminopyrimidin-4-one and 6-amino-l,3-dimethyl-5-formyluracil, respectively " . ... 

Aminouracil adds via its 5-position in low yields to dimethyl acetylenedicarboxylate in methanol at room temperature to furnish the corresponding dimethyl fumarate. This may then be cyclized in dimethylformamide at 150°C to give methyl l,3-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylate (4).142... 

The Michael addition of 6-aminouracils to dimethyl allene-l,3-dicarboxylate in methanol or dimethyl sulfoxide provides a pentenedioic acid side chain in the 5-position capable of further elaboration (Z-isomer in methanol, -isomer in dimethyl sulfoxide). Heating these adducts of 6-aminouracil or its 1-methyl derivative in dimethylformamide gives the corresponding pyri-do[2,3-d]pyrimidine-2,4,7(l//,3//,8//)-triones 7. 44... 

Activation by the cyano function is used to add C5 of l,3-dimethyl-6-aminouracil to the / -C of (3-(dimethylamino)acrylonitrile. Subsequent cyclization between the cyano and the 6-amino group, followed by elimination of dimcthylamine, leads to l,3-dimethyl-7-aminopyrido[2,3-rf]pyrimidine-2,4(l 77,3//)-dione (25).2 5 6... 

For the preparation of pyrido[2,3-d]pvrimidinc-2,4(l//,3//)-diones 28, an adaption of the Doebner-Miller quinaldine synthesis (cf. Houben-Weyl, Vol. E7a, p 363), can be used. The orientation of addition of oc,/5-unsaturated carbonyl compounds to pyrimidin-6-amines is governed by the attack of C5 of the pyrimidinamine at the carbon /5 to the carbonyl function.219 Besides pyrimidine-2,4,6-triamine,149 263 aminouracils are used as partners for the base-catalyzed reaction with a,/5-unsaturated ketones.148,219 264,570,571 Without the final oxidation step, which occurs mostly by air, the dihydro compounds are produced.265 Examples are the Michael additions of 4,4-dimethyl-l-phenylpent-l-en-3-one266 or of 1,3-diphenylprop-2-en-l-one264 to 6-amino-l,3-dimethylpyrimidine-2,4(l//,37T)-dione, which are followed by ring closure to give the corresponding pyrido[2,3-d]pyrimidme-2,4(l//,3//)-diones or their dihydro derivatives. 

With dimethyl acetylenedicarboxylate, the point of attack depends mainly on the solvent. In some cases, mixtures of 7-oxo and 5-oxo compounds together with the Michael adducts of the C5 or the 6-amino group of 6-aminouracil are obtained, e.g. with 6-(methylamino)uracil. On the other hand, in the case of 6-anilino-l,3-dimethyluracil, only the two possible pyrido[2,3-solvent dependence is remarkable and only partially understood. The reactions appear to be classifiable according to (a) presence or absence of an N1 substituent and (b) the availability of protons from the solvent.165... 

With 6-aminouracil, prop-2-ynal or 3-phenylprop-l-yn-3-one in aqueous alkali at 0°C reacts to furnish pyrido[2,3-phenyl derivative 232 similarly, methyl propiolate and l,3-dimethyl-6-aminouracil (33) in refluxing water give 1,3-dimethylpyrido[2,3-c/]pyrimidine-2,4,7(177,3//,8//)-trione (34).165 In protic media such as water or methanol, irrespective of the N1 substituent, the reaction with 6-aminouracils largely yields methyl 2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylates.I42,165,547,584... 

Aminouracil and its 1-inethyl derivative react with dimethyl allene-l,3-dicarboxylate in refluxing water by Michael attack of its C5 atom at the central allene carbon and subsequent ring closure to give the corresponding pyrido[2,3-<71pyrimidine-2,4,7(l //,37/.8/7)-triones 35.144... 

The product of the Michael addition of 5-aminouracil to dimethyl acetylenedicarboxylate in methanol is the fumarate resulting from the attack of the amino substituent whereas, in aprotic solvents such as dimethyl sulfoxide, the initial adduct is the maleate, which isomerizes within 1 hour to give predominantly the thermodynamically more stable Z-isomer. Upon heating a solution of the fumarate 1 in Dowtherm A at reflux temperature, cyclization occurs to give methyl 2,4,8-trioxo-l,2,3,4,5,8-hexahydropyrido[3,2-r/]pyrimidine-6-carboxylate... 

But-2-enal condenses with 5-aminouracil and its 1,3-dimethyl derivative,443 or with 2,5-di-aminopyrimidin-4(3//)-one (8)444 in the presence of hydrochloric acid to give the corresponding 6-methy lpyrido[3,2-rf]pyrirnidine-2,4(1/7,3/7)-diones 7 and 9, respectively. Because of the hydrolysis of the methoxy groups, the same procedure with 2,4-dimethoxypyrimidin-5-amine also yields 6-methylpyrido[3,2-c/]pyrimidine-2,4(1/7,3//)-dione, whereas with acetic acid as catalyst the methoxy groups are retained.443... 

The extension of the Nenitzescu reaction to l,3-dimethyl-6-aminouracil 212 gave the pyrimido[4,5-b]indole 214 in a much better yield in nitro-methane (41%) than in the conventional acetic acid (8%), Scheme 57 (81JOC4197). 

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