Guanidine pyrimidine ring

A number of methods have been published for the annulation of a pyrimidine ring onto an existing 1,4-oxazine. All involve the reaction of guanidine with an oxazine-based three-carbon system, as in Equation (154) <2001PS(175)129>. In more elaborate examples, the guanidine derivative is a heterocyclic amine <2004HC0163, 2004ZNB424>. 

The formation of a pyrimido[5,4-f][l,2]thiazine by annulation of a pyrimidine ring onto a benzoH[l,2]thiazin-4-one has been reported, involving condensation with dimethylformamide dimethyl acetal followed by Bredereck s reagent (Scheme 90), and reaction of the resultant vinylogous amide with guanidine <2005W02005/037843>. Essentially, the same approach has been used to prepare annulated forms of the isomeric pyrimido[4,5-< ][l,2]thiazines, as outlined in Scheme 91 <1998W098/28281>. 

The bicyclic system has also been prepared by annulation of a pyrimidine ring onto an existing thiazine (Scheme 97) the cyclization fails with acetamidine or d -methylthiourea <1996JHC235>. Alternatively, a pyrimidine ring is formed by reaction of guanidine with the lactim ether formed by 0-methylation of a 2-methoxycarbonyl-l,4-thiazin-2-one (Scheme 98)<1997JME2502>. 

The reactions of thiourea and guanidine with cycloalkanones are carried out in the same manner [101]. But it is worthwhile noting that muticomponent reactions of urea-like compounds with ketones, containing an activated methyl or methyle-negroup, often do not stop after the formation of a pyrimidine ring. In fact numerous derived condensation processes can lead to more complicated polycyclic compounds, which are especially typical for the reaction of cycloalkanones [101]. 

More complex, but still feasible, is the synthesis of pyrimidine bases from simple prebiotic substrates, although the reported yields of these reactions are relatively low. In this context, two main prebiotic precursors have been identified cyanoethine and a primary product of its hydrolysis, cyanoacetaldehyde. These compounds contain a preformed C-C bond which is incorporated in the C5-C6 position of the pyrimidine ring. In 1968 Ferris and co-workers reported that the reaction of cyanoethine with cyanate at 30 °C yields cytosine and, after its hydrolysis, uracil in acceptable yield [27]. trans-Cyanovinylurea was recovered as a key intermediate for this transformation. However, this reaction requires relatively high concentrations of cyanate (>0.1 mol/1), unlikely to occur in aqueous media due to its rapid degradation to carbon dioxide and ammonia. Cyanoethine also reacts with cyanate and yields cytosine and uracil at elevated temperatures. In this reaction urea or guanidine (also considered as prebiotic organic compounds) can easily replace cyanate (Figure 8.8) [26]. 

Condensation with ethyl formate (HC02Et) and cyclization with guanidine gives the pyrimidine ring system but with an OH instead of the required amino group. Aromatic nucleophilic substitution in the pyrimidone style from Chapter 43 gives trimethoprim. 

The most general pyrimidine ring synthesis involves the combination of a 1,3-dicarbonyl component with an N-C-N fragment snch as a urea, an amidine or a guanidine. 

The third example (190) of a steroid in which ring-A is a substituted pyrimidine ring has been prepared by condensation of the trisnor-seco-ester (189) with methyl guanidine sulphate. 

The pyrimidine rings of 970 were built on the 2-formyl-3-()8-D-ribofurano-syl)propanoate enol ether derivative 969 by reaction with urea, thiourea, or guanidine (79MI2, 79TL3669 83BCJ2700) (Scheme 279). 

Functionalization of UPy derivatives in order to prepare bi- or multifunctional telechelics is not limited to reactions on the ureido-substituent, but may also use a functionality at the 5- or 6-position of the pyrimidine ring (Scheme 2). Oleflnic UPy derivatives have been obtained by condensation of an ethylenically unsaturated /3-ketoester with guanidine. The resulting UPy 2f has been used to end-functionalize telechelic poly(dimethylsiloxane) via hydrosilylation with a Karstedt s catalyst [17]. 

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