Guanidines, intramolecular arylation

The reaction may be carried out successfully by the conventional fusion-technique. In the course of the s5mthesis of numerous aryl- and alkyl-biguanides by this procedure, the substituted guanidine rather than the biguanide was occasionally formed in a side reaction. In such cases the biguanide first formed may be cleaved partially by way of an intramolecular hydrogen-bonded form (602) (cf. section VI, B3). 

Treatment of Af-[2-cyano(hct)aryl]-fV -phenylcarbodiimicles or iV-[2-(alkoxycarbonyl)phenylJ-AT-phenylcarbodiimides 3 with ammonia leads to intramolecular ring c o. ui of the initially formed guanidines to provide fused pyrimidin-4-amines 4a and fused pyrimidin-4(.l//)-ones 4b. In this procedure, a 2-guanidino functionality is generated under exceptionally mild conditions and consequently cyclizes very readily to the fused pyrimidine. ... 

Copper and palladium catalysed intramolecular C-N bond formation between an aryl halide and a guanidine moiety affords 2-aminobenzimidazoles. Inexpensive copper salts such as copper iodide (Cul) are generally superior to the use of palladium catalysts [76] (Table 4.12). 

An analogous reaction sequence can be used to generate benzimidazoles and aminobenzimidazoles, involving the palladium-catalyzed intramolecular cyclization of aryl bromide-substituted amidines and guanidines, respectively (e.g.. Scheme 6.37) [48]. With aryl bromides, simple Pd(PPh3)4 or Pd2dba3/PPh3 catalysts are sufficient to mediate cyclization. This same approach is equally applicable to indazoles and polycyclic benzimidazoles [49]. 

The ease of adduct formation depends largely on the electron density on the N atom of the imine and the electrophilicity of the center carbon atom of the isocyanate. Most reactive are persubstituted guanidines and amidines on one side and aryl isocyanates with electron withdrawing substituents on the other side. The initial attack occurs on the more nucleophilic center. Delocalization of the developing charges favors intermolecular [2-I-2-I-2] cycloaddition over intramolecular [2-1-2] cycloaddition or the exchange reaction. When a hydrogen shift can occur, the intramolecular isocyanate induced enurea reaction is faster than the intermolecular [2-I-2-I-2] cycloaddition reaction. Thermodynamically controlled equilibria are established above 100 °C and the thermodynamically more stable reaction product is isolated. 

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