Synthesis and Dopamine Receptor Binding of 3‐Phenylazepino[5,4,3‐<i>c</i>,<i>d</i>]indole Derivatives

Gmeiner, Peter; Sommer, J.; Höfner, Georg

doi:10.1002/ardp.19953280407

Cited by 10 publications

(5 citation statements)

References 18 publications

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“…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.…”

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confidence: 94%

Regiocontrolled Annellation Reactions Starting from Diethoxymethyl Protected Indole

Kraxner¹,

Gmeiner²

2000

Synthesis

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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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confidence: 94%

Regiocontrolled Annellation Reactions Starting from Diethoxymethyl Protected Indole

Kraxner¹,

Gmeiner²

2000

Synthesis

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“…The latter common precursor 2a [6] is then converted, via enzymatic hydroxylation, into 2b which is subsequently cyclized by internal displacement to give 1a,b [2,3,7]. Efficient biomimetic pathways toward synthesis of 1a,b [8] and 1c [5,9] were reported; other synthetic routes for 1a,b [3,7,10] and related derivatives [11][12][13][14] were also documented. Some of these derivatives were described as selective dopamine D-1 receptor ligands [12], useful for the treatment of circulatory and digestive tract disorders [13], as psychotropics [13], diuretics and smooth muscle relaxants [14].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of pyrazole‐fused azepino[5,4,3‐cd]indoles

Safieh

El‐Abadelah

Zarga

et al. 2001

Journal of Heterocyclic Chem

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The synthesis of some new pyrazolo [3',4':6,7]azepino [5,4,3-cd]indoles (10a-c) was achieved via regioselective cyclization of the respective 3-(4-acylaminopyrazol-5-yl)indoles (9a-c) under Bischler-Napieralski reaction conditions. The latter compounds were obtained by acylation of the corresponding 3-(4-aminopyrazol-5-yl)indoles (8a,b) which, in turn, were prepared by reduction of the 3-(4-nitropyrazol-5-yl)indoles precursors (7a,b). The latter synthons were accessible from the reaction of indolylzinc chlorides (5a,b) with 5-chloro-1,3-dimethyl-4-nitropyrazole. Ms and nmr spectral data of 10a-c are in agreement with the assigned azepino-indole structure as determined for 10a by X-ray crystal measurements which demonstrate that the azepine ring is almost completely planar with the indole and pyrazole rings.

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“…Application of this strategy to the phenylbenzazepines of type 3 leads to phenylazepinoindole derivatives [8] . As an extension of recent investigations of the peri-fused congener 4 [9] , we herein describe our studies on the synthesis and dopamine receptor binding properties of regioisomeric analogs (Scheme 1). Since we were intrigued by the SARs produced by the spatial relationships between the indole nucleus, the amino group and the phenyl ring as the potential pharmacophoric substructures, we planned to approach the test compounds of type 1, 2, 5 [10] , and 6.…”

Section: Introductionmentioning

confidence: 99%