From Amidines

AM3-Chlorophenyl)aminomethylenemalonate (250) was obtained in pure form in 94% yield when /V,A, -bis(3-chlorophenyl)formamidine (248) (1 mol), diethyl malonate (I mol), and ethyl orthoformate (1.2 mol) were reacted for 20 hr at 126°C, the ethanol evolved being continuously distilled off. More diethyl malonate (1 mol) was then added to the half-converted reaction mixture, and the reaction mixture was stirred at 126°C for 48 hr (65MIP1 66JOC4003). Under these conditions, the formation of N- 3-chlorophenyl)aminomethylenemalonamate (252, R = 3-C1) could be excluded because the 3-chloroaniline formed in the reaction of amidine and malonate was simultaneously converted to amidine by ethyl orthoformate. 

Starting from the appropriate amidines (254, R = 3-C1, R1 = H, and R = R1 = 3,4-diisobutyl), diethyl malonate and ethyl orthoformate, N-(3-chlorophenyl)- and N-( 3,4-diisobutylphenyl)aminomethylenemalonates (250 and 257, R = diisobutyl) were prepared in 92% yields, respectively (69M1P1). 

N-(6-Methyl-2-pyridyl)aminomethylenemalonate (306) was prepared in 94% yield in the reaction of N,N -bis(6-methyl-2-pyridyl)formamidine and diethyl malonate in the presence of ethyl orthoformate at I50°C for 1 hr, the ethanol formed being removed [74JAP(K) 101380]. 

)V -Bis(cyclohexylaminocarbonyl)formamidine (310) was reacted with diethyl malonate in ethanol at 70°C for 60 hr to give N-(cyclohexylami-nocarbonyl)aminomethylenemalonate (311, R = Et) in 24% yield (53-JA671). The similar reaction of malonic acid at room temperature for 3-4 min afforded (cyclohexylaminocarbonyl)aminomethylenemalonic acid (311, R = H) in 65% yield. When bis(cyclohexylaminocarbonyl)for-mamidine (310) was reacted with 1 1 molar mixture of diethyl malonate and malonic acid in ethanol at 70°C for 5 min, only malonic acid (311, R = H) was obtained, in 76% yield. 

In 1969, Cherkasov and co-workers252 showed that the condensation of benzaldehyde with benzamidine gives 2,4,6-triphenyl-1,2-dihydro-1,3,5-triazine (154b) rather than benzylidenebenzamidine (159) (as was reported incorrectly in the early work of Pinner253) [Eq. (74)]. 

These Soviet workers also prepared a series of l,2-dihydro-l,3,5-triazines by reaction of aryl aldehydes,252,254 Shiff bases,255-257 or ketimines258 with amidines of different acids (usually benzoic, trichloro-, or trifluoroacetic). They proposed that the dihydrotriazines form via intermediate azadienes, which undergo cyclization via [4 + 2] cycloaddition, accompanied by elimination of an akylidenimine [Eq. (75)]. 

Smith et al. demonstrated the formation of 2-aryl-4,6-diphenyl- 1,2-dihydro- 1,3,5-triazines (154b, 162) by thermolysis of ylides 161 [Eq. (77)] 

Moreover, considering the mechanistic similarities between dihydro-1,2-triazine formation via ylide thermolysis and the condensation of aryl aldehydes with benzamidine or IV-alkylbenzamidines, the [4 + 2] cycloaddition 

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In conclusion, a scaleable process for the preparation of 2,4-subsituted imidazole from amidines and a-halo ketones is described. This method avoids the use of chloroform as solvent and affords the desired products in consistently good to excellent yields. 

Scheme 6.247 Synthesis of2,4,6-trisubstituted pyrimidines from amidine and alkyne building blocks.

RCN From amide % yield from thioamide From amidine... 

S-benzyl-zso-thiuronium chlorides 164 with sulfur monochloiide provides a convenient method for preparing S-benzyl-l,2,3,5-dithiadiazolium chlorides 165 (2002ARK224). Based on the formation of similar products from amidines and guanidines with sulfur dichloride, the authors proposed a mechanism which included the addition of two S2CI2 molecules to amidine 164 followed by HCI and sulfur extrusion (Scheme 86). 

TABLE 7.9. SYNTHESIS OF 4-(A,A-DIALKYLAMINO)-5(2H)-OXAZOLONES FROM AMIDINES AND CARBON DIOXIDE ... 

The heterocyclic system in compound 63 was prepared in 40% yield from amidine 61 as shown in Scheme 12 <2001CHE1183>. Although the intermediate 62 was not isolated on this occasion, related compounds, for example, 64, can be isolated if care is taken to exclude moisture (Scheme 13) <2001HAC658>. 

In 1954, Goerdeler6 introduced a general synthesis of 1,2,4-thia-diazoles from amidines. This versatile method has since been widely extended and has made a great variety of 1,2,4-thiadiazole derivatives readily accessible. Basically, an amidine is converted into its i T-thio-cyanato derivative, which cyclizes spontaneously to the 5-amino-1,2,4-thiadiazole. 

Synthesis from amidines, isocyanates, aldehydes and ketones 512... 

Azomethine ylids derived from amidines undergo internal [3 + 2]cyclization reactions with a styrenic double bond present in the starting amidine. This strategy has been applied to the synthesis of physostigmine and erythramine. 

Nitriles are also the usual products of oxidation of aliphatic amines RCH2NH2 by nickel peroxide and lead(IV) acetate. Aliphatic azo compounds can be prepared from these primary amines by first converting them into ulfamides (6), these then being oxidized with sodium hypochlorite or (better) r butyl hypochlorite (Scheme 9). A few aliphatic azo compounds can be formed in good yield by direct oxidation of r-alkylamines for example, AIBN was formed (86%) by oxidation of the amine Me2C(CN)NH2 with sodium hypochlorite. A special case of azoalkane foimation is the synthesis of chlorodiazirines (7) from amidines RC(= NH)NH2 by oxidation with sodium hypochlorite. ... 

Imidazoles (1) prepared from amidines derived from o -amino acids ... 

An electron-deficient carbon bearing a trifluoromethyl group becomes part of an imidazole ring when Schiff bases (18) made from amidines and hexa-fluoroacetonc are reduced by tin(U) chloride (Scheme 2.2.7). The 5-fluoro-4-trifluoromethylimida2olcs (19) are isolated in 58-65% yields [9-11]. The fluoro substituents in the 5-position are readily displaced by nucleophiles such as alkoxy or cyanide, thereby extending the versatility of these syntheses [9j. 

Imidazoles can be made by 1,5-dipolar cyclization of suitable 2-azavinamidinium salts [6. 7]. Such salts (10) are readily made from amidines (or guanidines) and amido or ureido chlorides (9), and in the presence of sodamide in liquid ammonia they cyclize to form electron-rich imidazoles... 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

Imidazolines have been prepared starting from amidines and guanidines. Reaction of amidine 1348 with 2-chloro-acrylonitrile gives the imidazoline 1349 in 79% yield, aromatization giving the imidazole 1350 (Scheme 346) <2000JME3168>. 

Amidines with a more complicated substitution pattern have been prepared from amidines by alkylation—either at nitrogen or at nitrogen substituents. - Variations at these positions have been achieved by heteroarylation, acylation,vinylation or carboxylation with phosgene, thio-phosgene, isocyanide dichlorides or isothiocyanates. Some interesting amidines, e.g. (347)-(3S2) (Scheme 59), have been prepared in this manner. The amidine skeleton can also be varied by halogen-ation, - hydrolysis, isomerization or catalytic hydrogenation or other addition reactions if there are C=—C double bonds present as in (353 equation 173) for example. ... 

Acyltriazolium salts 522, generated in situ from amidines 294, are transformed to 3-substituted 1,2,4-triazoles 523 on heating in nitromethane or acetonitrile (69JPR477, 69JPR646). In this case, the presence of alkali... 

Yamada T, Lukac PJ, George M, Weiss RG (2007) Reversible, room-temperature ionic liquids. Amidinium carbamates derived from amidines and aliphatic primary amines with carbon dioxide. Chem Mater 19 967-969... 

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