With Amidines or Guanidine

Amidines were first condensed with o-aminoamides in 1965 when Baker and Kozma fused benzamide, 4-aminopyrazole-5-carboxamide, and sodium 

The corresponding hydrochlorides do not react, so that the acetates seem to form a steady source of the more volatile and thermolabile bases. The course of the reaction is revealed by trichloroacetamidine, which takes the triazole no farther than an ethylideneamino derivative (153). This can be cyclized rapidly in cold 0.5 N potassium hydroxide to 2-trifluoromethyl-8-azapurin-6-one.248 Formamidine acetate has also been used to convert 2-aminopyrazine-3-carboxamide to pteridin-4-one in good yield.213 

3-Aminopyridine-2-carboxamide, when fused with guanidine carbonate at 170°C, gave a moderate yield of 2-aminopyrido[3,2-d]pyrimidin-4-one (see 6).249 

---

The 1,2,4-oxadiazole dioxolanes 144 react with hydroxylamine and hydrazines to form the 5-pyrazole- and isoxazole-substituted 1,2,4-oxadiazoles 146 via the dioxolane ring-opened intermediates 145 (Scheme 17). Reaction of compounds 144 with amidine or guanidine salts allows access to pyrimidine substituted analogues 147, via intermediate 145 (X = C(NH)R1), albeit in lower yield <1996JHC1943, 1998JHC161>. 

Even heterocyclic fused aminomethyleneketones can be similarly cyclocondensed with amidines or guanidine to give fused pyrimidines, such as interesting diazacannabinols260 (equation 189). 

More recently it has been reported that even A -acyl-A, A -dimethylcarboximidamide.s react with amidines or guanidines in aprotic solvents (t-BuOK, dioxane or THF, reflux, 3-16 h, 40 94%) to give 1,3,5-triazines with three different substituents.476... 

Benzopyrano[3,4-with amidines or guanidine under basic conditions. Scheme 177 (86JHC1753). 

Apart from a,fl-unsaturated carbonyl compounds having 0-, N- and S-leaving groups at the p-position, compounds 706 with halogen nucleofuges (i.c. Cl, F) were also used in the synthesis of 4-fluoroalkylpyrimidines. In particular, reaction of aldehyde 775 [481], ketone 776 [482], or ester 777 [483] with amidines or guanidines gave pyrimidines 778-780 in 39-98 % yields (Scheme 154). 

We found 192 unique structures, with 252 recorded activities on 46 targets (see also Figure 2.3). A vast majority of them (176 structures) are likely to be charged at pH 7.4, as they are aliphatic amines, amidines or guanidines, and sometimes carboxylic acids. This indicates that low MW compounds are likely to require salt bridge interactions... 

Substituted malondialdehydes form pyrimidines substituted in the 5-position with an alkyl, aryl, halo, or hetero substituent. The pyrimidine is unsubstituted in the 4- and 6-positions. /3-Dialdehyde equivalents are frequently used in these reactions, for example, 3-alkoxy- or 3-aminoacroleins. With aldehydo ketones, the pyrimidine carries a substituent in the 4- or 6-position. The formyl group in the ketone is normally masked as an alkoxymethylene ketone or as an aminomethylene ketone. A commonly used procedure involves the preparation of a dimethylaminomethyl-ene ketone 645 by reaction of a methyl ketone 644 with DMF dimethylacetal and subsequent reaction with an amidine or guanidine to form the target pyrimidine 646 <2003MI237, 2004JHC461>. 

Further extension of this synthesis to guanidines leads to 3,5-diamino-l,2,4-thiadiazoles. Examples are so far confined to the conversion, by the usual procedure, of 2V,2V-disubstituted guanidines into 5-amino-3-dialkyl(or diphenyl)amino-l,2,4-thiadiazoles (66).84,87 In general, this variant of the reaction proceeds less uniformly than with amidines or iso(thio)ureas, and is performed without isolation of the intermediate AT-halogenoguanidines. In some cases (e.g. dimethyl and cyclopentamethylene homologs) the yields are low, and guanidine is formed as a by-product. The 3-dimethylamino homolog (66 R = R ... 

When amidines or guanidines cyclize in the presence of a-functionalized carbonyl reagents they form imidazoles with a variety of 1-, 2-, 4- and 5-substituents [1, 2]. Formamldine will react with a-hydroxy- [8] or a-halogenoketones [9], to give mixtures of oxazolcs and imidazoles. Usually, the formamidine is liberated from its hydrochloride by treatment with sodium butoxide in butanol. When the two-carbon synthon is an a-hydroxyketone the aliphatic members mainly form imidazoles (35-70%), while benzoins give oxazoles (67-80%) preferentially [8], The competing pathways are shown in Scheme 4.3.1. 

Methylisothiourea is formally analogous to an amidine or guanidine (see also reactions of amidine sulfinic acids earlier in this chapter). It reacts readily with acylvinylphosphonium salts in much the same way as amidines to give 2-methylthio-4-imidazolylphosphonium salts, which can be converted into multifunctional imidazoles with recovery of triphenylphosphine [28]. 

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. " ... 

Cyclization of a halonitrile with an amidine or guanidine usually needs a strongly basic mediiun, but heating in DMA may also be effective as in this example which uses guanidine-potassium carbonate. 

A carboxylic acid derivative which also contains an activated neighbouring halo atom may be cyclized by warming with an amidine (or guanidine) or 2-aminopyridine (a cyclic amidine). In some reactions of this type, it is advantageous to add a base such as TEA. The chlorine atom of the thienopyridine (6[Pg.422]

In a related conversion the synthesis of substituted diphenyl-1,3,5-triazines can be achieved in 47-64% by reaction of amidines or guanidines with 2-aza-l-(methylsulfanyl)-l,3-diphenyl-buta-l,3-diene-4,4-dicarbonitrile in the presence of sodium hydride.477... 

A convenient method for the synthesis of substituted pyrimidines involves the reaction of amidine or guanidine derivatives with a 1,3-dielectrophilic, three-carbon unit. Synthesis of 2,4,5-trisubstituted pyrimidines from Baylis-Hillman adducts and amidines is a good example. The ester group in the reactant can be replaced with acetyl and cyano groups, and the corresponding products are isolated in moderate to excellent yields. 

A phosgene-free process for preparing urethane and carbonate monomers and polymers has been reported [257]. The process involves reaction of CO2 with amines (e.g. 4,4 -methylenebis(cydohexylamine)), alcohols, or amino alcohols in the presence of an amidine- or guanidine-type base (e.g. N-cydohexyl-N, N, N",N"-tetra-ethylguanidine), followed by treatment of the resulting ammonium carbamate or carbonate salt with a primary or secondary hydrocarbyl halide of a specified structure in a polar, aprotic solvent (e.g. N-methylpyrroUdinone). When hydrocarbyl dihalides or -polyhalides are used in the second step, polyurethanes and polycarbonates are formed. 

---