Heteroaromatic amidines

Based on this concept, Whitby and co-workers [110] reported an interesting palladium-catalyzed three-component synthesis of aromatic and heteroaromatic amidines 133 starting from unsaturated halides, amines, and t-butylisocyanide (Scheme 8.53). The catalytic cycle for this iminocarbonylative coupling reaction is analogous to the reactions incorporating carbon monoxide-isoelectronic with isocyanides-as the third partner [111]. 

There seems to be no major limitation regarding the selection of aldehydes and isonitriles. For 2-aminoazenes, both heteroaromatic amidines and heteroaromatic guanidines participated in this novel 3CR. Flowever, aliphatic amidines were found to be inactive. Many variants have since been reported by different research groups, both academic and industrial, due to the medicinal importance of this family of heterocycles [68]. 

Numerous applications have been found for the uses of imidazole derivatives as ionic liquids and A -heterocyclic carbenes and their use in organic chemistry has been well discussed in books or reviews. Thus, in this chapter, the use of non-heteroaromatic amidine compounds as functional tools in asymmetric synthesis and the related chemistry after presentation of the preparation method of amidines will mainly be discussed. 

Tautomer Ratio in Asymmetric Heteroaromatic Amidines 101 Table 5.2 pK Values for tautomers and model compounds of 12 and... 

The Field-Resonance Balance In VInylogous Heteroaromatic Amidines... 

The Field-Resonance Balance in Vinylogous Heteroaromatic Amidines 109... 

Figure 5.12 Tautomerism in heteroaromatic amidines 12 and their vinylogous 41. Table 5.6 pK Values for compounds 41a and 41c. ...

Another approach uses the reaction of 6-chloro-5-nitropyrimidines with a-phenyl-substituted amidines followed by base-catalyzed cyclization to pteridine 5-oxides, which can be reduced further by sodium dithionite to the heteroaromatic analogues (equation 97) (79JOC1700). Acylation of 6-amino-5-nitropyrimidines with cyanoacetyl chloride yields 6-(2-cyanoacetamino)-5-nitropyrimidines (276), which can be cyclized by base to 5-hydroxypteridine-6,7-diones (27S) or 6-cyano-7-oxo-7,8-dihydropteridine 5-oxides (277), precursors of pteridine-6,7-diones (278 equation 98) (75CC819). 

Diketene is of course a masked form of acetoacetic ester, and as such reacts in much the expected manner with a variety of mono- and di-nucleophiles. Aromatic and heteroaromatic amines, and phenols, for example, give acetoacetanilides and aryl acetoacetates the latter can be cyclized in excellent yield to coumarins while reaction of the former with excess of diketene followed by cyclization gives dioxopyridines (e.g. equation 164). Amidines, ureas, thioureas, S- alkylthioureas and carbodiimides also react with diketene to give pyrimidines e.g. equation 165), although in the case of amidines, S- alkylthioureas and carbodiimides the initially formed products are 1,3-oxazines which are converted into pyrimidines on subsequent treatment with acid or base. 

As already mentioned at the beginning of this chapter, one of the facile methods for the synthesis of dihydropyrimidine derivatives is the treatment of oc,(3-unsaturated carbonyls with urea and its analogues—thiourea, guanidine and amidines. However, the majority of the publications have dealt with syntheses involving thiourea. Most likely is the possibility of the modification of 3,4-dihydropyrimidine-2-thiones or their heteroaromatized analogues, which produces a diverse class of heterocycles. The reagent involved in this modification process can act like a,(3-unsaturated carbonyls [16] (Scheme 3.9). 

Some of these transformations were accompanied by additional reactions, e.g. formylation of the aromatic or heteroaromatic - nucleus or CH-acidic methyl groups further dehydration of amides to nitriles was observed. Adducts from amides and PCI3, sulfonyl halides or SO2CI2/SCXZI2 from which amidines can be obtained by reaction with amine derivatives (compare Section 2.7.2.5 and refs. 5 and 14) have not found wide application for this purpose. An interesting reaction is the preparation of the amidine (294 equation 158) from 7V-pentafluorophenylformamide. By thermal decomposition of the adducts from secondary amides and 7V,iV-dialkylcarbamoyl chlorides amidinium salts were synthesized from which the amidines (295 equation 159) were set free by treatment with bases. " ... 

The essential structure-activity requirements were the same as for the HI receptor except that the heteroaromatic ring had to contain an amidine unit (HN-CH-N ). These results are summarized in Fig. 13.7. 

Transition metal-catalyzed N-arylations of amidines and guanidines including those being part of a heteroaromatic system 12CSR2463. Transition metal-catalyzed C—C bond formation via C—S bond cleavage 13CSR5042. 

Reaction of 848 with amino heterocycles is a valuable approach to chain-fluorinated purines and their bioisosteres. It was found that cyclocondensation of 848 with electron-rich aromatic and heteroaromatic amines proceeded in two steps (Scheme 191) [543, 551-554]. First, amidines 913 were formed under mild conditions (EtgN, CH2CI2, ambient temperature) in moderate yields (44-60 %). Cyclization of 913 occurred under harsh conditions (toluene or xylene, reflux) however, the yields of the products 914 in this step were high (83-96 %). It should be noted that in the case of 5-methyhsoxazol-3-amine 915, triazine derivative 917 was formed instead of the corresponding pyrimidine [555]. 

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