Pyrimidine formation guanidine

Treatment of 8-azidomethylperhydropyrido[l,2-c]pyrimidin-l-one 157 with methyl triflate and catalytic hydrogenation of the azide group led to the formation of tricyclic guanidine derivative 158 (01JA8851). Hydroxy group of 149 was protected with methoxymethyl chloride, and the p-methoxybenzyl protecting group (PMB) was eliminated by treatment with DDQ. 

The synthesis of pyrimidines under specific prebiotic conditions, at low temperature, has apparently been carried out successfully (Fig. 4.8). The formation of the DNA building blocks was carried out by freezing out a dilute solution of cyanoacetaldehyde (CAA) and urea or guanidine. The concentration of CAA was only 1(T3 M, that of guanidine 1M. The reaction took 2 months at 273 K and a pH of 8.1. Yields were as follows ... 

The first procedure involved starting with the methyl ketone 996, formation of the enamino ketone 997, and condensation with substituted guanidine derivatives to give the desired products 998, with substituent variation on the pyrimidine amino group. 

Methylene derivatives formed from alloxan can serve as bis-electrophiles and react with species such as guanidine to give pyrimido[4,5-tf pyrimidines directly (Equations 91 and 92). Formation of the Michael acceptor and the corresponding cyclization with thiourea can be carried out either in a single step (Equation 93) <2003RCB2457> or with isolation of the intermediate (Scheme 58) <2003SC3747> in either case, the process is reported to proceed most efficiently in the solid state under microwave irradiation. 

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>. 

Reaction of 103 with guanidine affords 4,6-diaminopyrazolo[3,4-d]-pyrimidine 111 as a main product (75JHC1199 79AP610 79AP873 79M11). Formation of 112 in 3-5% yields from reaction of 103 (R =... 

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]. 

When o-aminocarbonitriles 48 (R2 = R3 = Me) or 52 were reacted with jY-arylcyanamides in the presence of dry hydrogen chloride gas followed by aqueous workup, a mixture of 2-amino-3-aryl-4-iminothieno[2,3-d]-pyrimidines 65d and the corresponding thieno[2,3-d]pyrimidin-4(3//)-ones 66b was isolated. The formation of the latter as a minor product for each derivative was rationalized to proceed via the guanidine intermediate 67, which hydrolyzed through a Ritter-type reaction and then cyclized during workup (93JHC435). 

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 reactions of amidines or guanidines with a-functionalized carbonyl compounds continue to be utilized for the synthesis of imidazoles. Thus, the mixed anhydride of acetic and chloroacetic acids reacts with symmetrical diarylguanidines to give l-aryl-2-arylaminoimidazolin-4-ones, and there is competitive formation of imidazoles and pyrimidines in the reaction of benzamidine with 3-bromobenzo-4-pyrones (18). Imidazoles are minor products, but are favored in nonpolar solvents. The use of a-dicarbonyl compounds with guanidine gives 2-amino-4-hydroxy-4-methyl-4//-imid-azoles, which give excellent yields of 2-aminoimidazoles on catalytic hydrogenation. " ... 

Formylation with ethyl formate HCOOC2H5 and base gives hydroxy methylene derivative. Condensation of that intermediate with guanidine (H2N)2 C = NH gives pyrimidine. 

The main reaction products of prebiotic chemistry were H2, H20, CH4, CO, C02, NH3, and N2. These compounds formed many intermediates including ions and radicals. The more important molecules that formed were formaldehyde HCHO, hydrogen cyanide HCN, phosphate ions, and cyan amide NH2CN. The final spectrum of products encompassed glycerol, glyceraldehyde - the parent compounds of sugars - carboxylic acids, amino acids, urea, guanidine, purines, and pyrimidines. As an example for the many possible interactions the formation of the nucleobase, uracil is shown in Fig. 2.1. 

Nucleophilic cyclization reactions are widely used for the synthesis fluoroalkyl heterocycles. This process relies on the use of fluorinated building block for the introduction of perfluoroalkyl group into heterocycle. For example, heating of compound 30 with urea or guanidine results in the formation of the corresponding pyrimidines 31 and 32 in moderate yield (Fig. 7.10). 

A series of 4-amino-8-cyanoquinazolines 57 have been prepared by reaction of 2-aminobenzene-l,3-dicarbonitriles with formamide or guanidine [93H(36)2273j. Formation of a pyrimidine system 59 has been reported to occur by a ring transformation of 58 [93MI(130)737. ... 

Polysubstituted pyrimidines were synthesized from in situ generated a,p-unsaturated imines and the corresponding amidine or guanidine derivatives in a convenient one-pot procedure. It was proposed that the described transformations proceed via the initial formation of o,P-imsaturated imine that undergo nucleophilic attack by a bidentate nucleophile (amidine or guanidine). This step is then followed by elimination of ammonia and aromatization to yield the observed polysubstituted pyrimidine. 

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