Donor synthons stabilization

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

It was shown that the cocrystallization yielded both the target stable and metastable tautomers of 1-deazapurine. In the case of halogen-bond donors, 1-deazapurine occurs as the >H tautomer and the predicted synthon pattern is dominant in the stabilization of their crystal architectures, with >H dimer intact. In the remaining four structurally characterized cocrystals with urea coformers, the H is obtained as an exclusive tautomeric species, with urea appearing at the predicted position, acting as a bridge between two H molecules (Scheme 13.6). As indicated by FTIR spectroscopy, the H tautomer was present in 6 out of 14 cocrystals obtained by milling. 

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