Traceless linking of diethoxymethyl (DEM)-protected 5- and 6-cyanoindoles and subsequent incorporation of phenylpiperazine derivatives led to the 2- and 3-piperazinylmethyl-substituted cyanoindoles 3a-m. Dopamine receptor binding studies on the final products 3a-m clearly indicated strong and selective recognition of the D(4) subtype which is known as a promising target for the treatment of neuropsychiatric disorders. The most interesting binding properties were observed for the 2-aminomethyl-5-cyanoindoles FAUC 299 (3f) and FAUC 316 (3j) (K(i) = 0.52 and 1.0 nM, respectively) when the fluoro derivative 3j proved extraordinary selectivity over D(1), D(2long), D(2short), and D(3) (>8600). To determine ligand efficacy, mitogenesis experiments were performed indicating partial agonist effects for the test compounds 3f,j (35% and 30%, when compared to the full agonist quinpirole).

Directed metallation of the diethoxymethyl protected indole 4 followed by treatment with b-nitrostyrene leads to the 1,2-disubstituted indole 5. Using 5 as a central intermediate, the tricyclic annellation products of type 2 and 3 were accessed when the regiochemical outcome of the reactions could be controlled.The selection of protecting groups preventing or modifying functional group transformations during a reaction sequence is crucial to the success of chemical syntheses. 1 Our interest was directed to the investigation of diethoxymethyl (DEM) for the nitrogen protection of lactams, amides and indoles. 2 Due to the simple introduction of DEM, its stability towards various reaction conditions and its ability to act as a N-directed metallation group the use of DEM turned out as an advantageous synthetic tool for the preparation of regioselectively substituted indolinones 3 and indoles. Very recently, we developed a traceless linkage route based on DEM protected indoles and demonstrated the practical utility of this methodology for the solid phase synthesis of 2-or 3-substituted indole derivatives. 4 Besides the above-mentioned talents, the DEM group should also be able to serve as a C-1 building block. Starting from DEM protected indole; our intention was to incorporate DEM into a fused ring system. Thus, we attempted to approach to pyrimido[1,6-a]indole derivatives, which can be considered as regioisomers and synthetic precursors of antipsychotically active g-carbolines. 5,6 As a part of our ongoing efforts to design selective dopamine receptor ligands 7 we envisaged the preparation of the phenyl substituted tetrahydropyrimido[1,6-a]indole 2 and the tetrahydro-g-carboline 3 which can be seen as heterocyclic analogs 8 of the selective D1 receptor agonist 3',4'-dihydroxynomifensine 1. 9In practice, directed metallation of the diethoxymethyl protected indole 4 by t-BuLi and subsequent trapping of the corresponding indole lithium intermediate by b-nitrostyrene provided the Michael addition product 5 (Scheme). Interestingly, treatment of 5 with zinc dust in a mixture of aqueous HCl and THF afforded the rearranged g-carboline derivative 3, exclusively. 8 The analytical data of the rearranged product 3 clearly indicate the rearranged ring system. In detail, the structure was elucidated by 1 H NMR and IR spectroscopy when a diagnostic signal at d = 7.74 ppm giving complete H/D exchange and a diagnostic absorption at 3400 cm -1 indicated the indole NH function. It is worthy to note, that the one-pot reaction sequence involving reduction of the nitro group, ring closure reaction to give a cyclic imine, further reduction and, finally, rearrangement yielded 89% of pure product. Migration reactions of this type have been reported in the literature, when a retro-Mannich type reaction leading to an iminium intermediate is reasonably assumed. 6In order to isolate synthetic intermediates including the tetrahydropyrimido[1,6-a]indole 2 which we initially seReagents and conditions: (a) 1. t-BuLi (1.1 equiv), THF, 0°C, 15 min....

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