Regiocontrolled Annellation Reactions Starting from Diethoxymethyl Protected Indole

Abstract

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....

γ-Carbolines and their hydrogenated derivatives. 2.* Hydrogenated derivatives of γ-carbolines: methods of synthesis (review)

“…The Pictet-Spengler reaction was also used for the production of a structural analog of the alkaloid catharanthine containing a γ-carboline skeleton, which belongs to the ibogaine group [91] By using a diethoxymethyl group as protecting group for the indole nitrogen atom it is possible to realize regioselective metallation at position 2 with subsequent annelation of the piperideine ring with nitrostyrene. In this case the diethoxymethyl group also plays the role of a one-carbon building block, taking part in the formation both of tetrahydro-γ-carboline and of the isomeric tetrahydropyrimido[1,6-a]indole, which can also serve as precursor for the production of tetrahydro-γ-carboline according to the following scheme [92] A synthetic equivalent of the carbonyl compound for the Pictet-Spengler condensation can be not only an acetal fragment at the nitrogen atom of indole (as in the previous example) but also an aminal fragment in the side chain. Here, however, the yield of the bridged γ-carboline derivative 32 is low on account of the chemoselective transformation of the respective bicyclic aminal [93].…”

Tracelessness Unmasked: A General Linker Nomenclature

“…[35a±c] Amines attached to a benzylic carbon atom with the ability to stabilize a cation can be released under acidic conditions. Several such linkers possessing ortho-and para-alkoxy substituents, the Rink amide linker being one example, have been developed ( [36a] The acetal-derived linker in entry 7 of Table 8 has been applied to the release of indoles; [37] cleavage is effected in excellent yield and purity by hydrolysis and subsequent treatment with 2 n NaOH. A resin based on a tetrahydropyranyl (THP) protecting group for the linkage of substrates through an aminal (Table 8, entry 8) [38] is base stable and cleaved with weak acid.…”

Direct and Selective 3-Amidation of Indoles Using Electrophilic N-[(Benzenesulfonyl)oxy]amides

“…20 Encouragingly, when the reaction conditions were explored, the use of DMSO as the solvent instead of THF and the absence of a transmetallation step was found to improve the formation of the aminal product 6 to 78% yield. 21 With this modified protocol, different indoles all formed their respective aminal products 29 – 33 .…”