Pyrrolo pyrimidine ring synthesis

The most common approach to the synthesis of a fused pyrimidine ring involves condensation reactions between adjacent carboalkoxy and amino groups. Therefore, it is not surprising that the majority of pyrrolo[3,2-4]pyrimidines that involve a pyrrole precursor follow this pathway. 

Molina, P., Eresneda, P.M., and Delgado, S. (2003) Carbodiimide-mediated preparation of the tricyclic pyrido[3, 2 4,5]pyrrolo[l,2-c] pyrimidine ring system and its application to the synthesis of the potent antitumoral marine alkaloid variolin B and analog. J. Org. Chem., 68, 489-499. 

Perhaps the most unique synthesis of a pyrrolo[2,3-, pyrimidine arises from a completely acyclic precursor. Thus, 180, upon reaction with guanidine in basic media, produces both rings, although undoubtedly one ring is formed first in situ (Equation 68). Good yields of 181 were obtained <1995CPB256>. 

A few less traditional approaches to the synthesis of pyrrolo[2,3-<7]pyrimidines are worthy of note. Ketene 5,A-acetals (136) serve as convenient precursors to pyrrolopyrimidines which are reduced in the pyrrole ring (137) (Equation (47)). Heating compound (136) in a 1 2 ratio with arylisothiocyanates affords the dithio products (137 X = S) <83S225>, whilst similar treatment with arylisocyanates leads to the dioxo compounds (137 X = O) <85CPB4299>. 

An ingenious procedure for the synthesis of 5H-pyrrolo(3,2-d)pyrimidines involves treatment of a 6-methyl-5-phenylazopyrimidine with t-butoxybls(di-methylamlno)methane or an orthoformate ester, followed by hydgogenolytic ring contraction of the resulting pyrlmido(4,3-c)pyridazlne. 

Additional examples of this fascinating chemistry are listed in Table 1 [9, 10]. For Entries 1-3, the initially formed m-chlorobenzoate product is methanolized to the methyl ether (not shown). Entry 3 represents an attractive synthesis of pyrrolo[3,2-d]pyrimidines [11]. Water is the nucleophile in Entry 4, not m-chlorobenzoate, in a sequence that provides pyrrolo[3,2-c]coumarins [12]. Entry 5 describes the preparation of pyrrolo[3,2-c] [1] benzothi-opyran-4-ones, which is a new ring system and where water has captured the intermediate 3-methylene-2-hydroxy indoline [13]. Entry 6 features the synthesis of pyrrolo[3,2-c]pyrones [14]. Entry 7 describes a similar rearrangement of A-alkyl-A-allenylmethylanihnes with magnesium monoperoxyphthalate (MMPP) to afford 2-vinylindoles [15], This reaction presumably follows the one described earlier, although none of the presumed intermediates could be isolated. 

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