5- Cyanouracil

An efficient preparation of 5-cyanouracils started from JV-ethoxycarbonylcyanoacetamide 47, the carbonyl of the urethane finally being incorporated into the uracil ring... 

The formation of the adduct between 86 and the nitrile, i.e., 89, occurs more readily than that between 86 and ketones, since an activated nitrile is a better nucleophile than a ketone. Since the ce-proton in the adduct 89 is more acidic than the ce-proton in the ketonic adduct, also the ring opening will occur more easily. The interchange of a nitrile carbon with the ring carbon of a pyrimidine ring was also observed with the 3-benzyloxymethyl-l-ribosyl-5-cyanouracil. With a series of activated nitriles, the protected bi-cyclic nucleosides are formed. After deprotection, the corresponding bi-cyclic nucleosides are obtained (Scheme IV.35). 

Cyanouracil — This pyrimidine (XXXV) can be synthesized either by the condensation of pseudoalkylthiourea with ethyl ethoxymethylenecyanoacetate followed by acid hydrolysis [300], or by the treatment of the corresponding cyanoethoxyacrylamide with aqueous ammonia [301,302]. 

In a study of the catabolic pathway of pyrimidines, it was found that the reduction of uracil was blocked almost completely by 5-cyanouracil (XXXV) in an in vitro test with the rat enzyme dihydropyrimidine dehydrogenase [303]. 5-Halogenated uracils and thymine are weakly active in this regard, and 5-acetyluracil and 5-trifluoromethyluracil are completely inert. 

When the methylene ketone component of the three-component reaction is replaced by ethyl cyanoacetate 729, 5-cyanouracils <19798287, 2003JHC213> or their 2-thioxo analogs <19798287, 2000T8631, 2006JHC821> are obtained under basic conditions. The reaction proceeds via initial condensation of the aldehyde and ester... 

The preferential reaction of uracil with HCN in aqueous solution3,7 (but not with Br", I", or SCN" 64) appears to go through a sequence140 uracil - A - B - other products, in which A is probably 5-cyano-5,6-dihydrouracil, and B is 5-cyanouracil. There were two final (unidentified) products. The reaction step A -> B is inhibited by oxygen. 

Surprisingly, only one example of the synthesis of thieno[3,4-,7 pyrimidines has been described starting from a pyrimidine ring. In CHEC-II(1996) <1996CHEC-II(7)229>, substituted 5-cyanouracils, upon reaction with elemental sulfur, led to the formation of compounds in this class. Now the use of a 5-cyanopyrimidino-2-thione 419 under similar conditions (Equation 156) leads to the thienopyrimidine 420 <1997HC0151>. 

Such a ring cleavage and ring closure mechanism is supported by the rearrangement of 5-cyanouracils into 6-aminouracils in the presence of sodium hydroxide and amines (Scheme 139) (see also Scheme 143). 

Uracil and thymine derivatives are obtained from cyanoacetic acid and A -alkylurethanes. An amide 16 is formed first, which condenses with orthoformic ester to give the enol ether 17 aminolysis of 17 leads to 18 which on cyclization yields 5-cyanouracil 19 Shaw synthesis) ... 

Treatment of 5-cyanouracil 100 with l-aminopropane-2-ol in anhydrous ethanol gave 6-aminouracil 101 [R = CH2CH(OH)Me] in 51% yield (Scheme 63) [130]. However, when ethanol was replaced with anhydrous DMF the course of the reaction was changed and compounds 102 were obtained in good yields. 

Walczak and co-workers employed an acid-catalyzed Dimroth rearrangement in their novel transformation of 5-cyanouracil derivatives. Treatment of 5-cyano uracil 150 with l-amino-2-hydroxypropanone in anhydrous ethanol at room temperature gave the corresponding Dimroth product 151 in 51% yield. 

A soln. of 5-cyanouracil in 5%-NaOH satd. with HgS, and heated in a sealed tube for 20 hrs. in a water bath ->. 2,4-dioxo-l,2,3,4-tetrahydro-5-pyrimidine-carbothionamide (Y 74.8%) dissolved in aq. 28%-NHg, Raney-Ni added, heated 2 hrs. on a water bath, and stored overnight at room temp. 5-aminomethyl-uracil (Y 60%). S. Yamada and K. Achiwa, Chem. Pharm. Bull. 9, 119 (1961). 

---