Abstract:The preparation of 3.4-dihydro-1 -(p-tolylsulphonyl) benz[cd]indol-5(1 H)-one (2) and its conversion to a wide variety of 5-substituted tetrahydrobenz[cd] indoles are described, thus demonstrating the value of the N-tosyl protecting group in indole chemistry. Several reactions were also possible with the corresponding 1 -acetyl derivative (3).
THE chemistry of 3,4-dihydrobenz[cd]indol-5( 1H)-one (1)is dominated by the inherent tendency of the molecule to undergo isomerisation to the more stable naphthalenoid s… Show more
“…The synthesis of the tricyclic indole lactams utilizes the Leimgruber−Batcho indole cyclization to generate the key 4-carboxyindole intermediate ( 1 , Scheme ) and essentially follows procedures that have been published. , The [5,6,6]-tricyclic core, 2 , was prepared as described in the literature by Demerson et al (Scheme ). The [5,6,7]-tricyclic core, 3 , was prepared from the 4-carboxyindole by procedures described by Flaugh, Clark, Bowman, and Somei. , 1 Key Tricyclic Intermediates…”
A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.
“…The synthesis of the tricyclic indole lactams utilizes the Leimgruber−Batcho indole cyclization to generate the key 4-carboxyindole intermediate ( 1 , Scheme ) and essentially follows procedures that have been published. , The [5,6,6]-tricyclic core, 2 , was prepared as described in the literature by Demerson et al (Scheme ). The [5,6,7]-tricyclic core, 3 , was prepared from the 4-carboxyindole by procedures described by Flaugh, Clark, Bowman, and Somei. , 1 Key Tricyclic Intermediates…”
A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.
“…Stepwise conversion of the lactam into 32 (LAH reduction followed by N-methylation via the methoxycarbonyl derivative) was carried out essentially as previously described. 19 5-HT1A Radioligand Binding Assay. The radioligand receptor binding studies were performed by a modification of a previously described procedure.31 Male Sprague-Dawley rats were killed by a blow to the head and the brains were rapidly removed and dissected.…”
A number of 1,9-alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines were prepared and evaluated for 5-HT1A receptor and alpha 2-adrenoceptor affinity by using radioligand receptor binding techniques. Several compounds displayed 5-HT1A receptor affinity comparable to, or greater than, the known 5-HT1A ligand buspirone. The highest affinity 5-HT1A receptor ligands were N-alkyl-, N-allyl-5-chloro-, and 5-methoxy-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azapines (4c, 4m, 4n), which had pKi values of 7.9-8.1. The S enantiomer of 4c had a higher affinity for the 5-HT1A receptor than the corresponding R isomer (pKi of 8.2 for (S)-4c vs 7.7 for (R)-4c). These compounds had a relatively low affinity for the alpha 2-adrenoceptor (pKi of 7 or less). On the other hand, the closely related 5-chloro-2-methyl-2,3,4,8,9,9a-hexahydro-1H-indeno[1,7-cd]azepine (3b) had high affinity for both the alpha 2-adrenoceptor (pKi = 8.1) and 5-HT1A receptor (pKi = 7.6). These results indicate that the two receptors may share common recognition sites.
“…32 In this case, N-pivaloyl-Uhle's ketone 55, obtained in three steps from indole-3-propanoic acid according to the method of Goto (Scheme 8), 21 was chosen as the starting material and treated with bromine in 1,4-dioxane/CCl 4 to yield 4-bromo-Uhle's ketone. According to observations by Bowman and co-workers, 33 direct bromine-amine exchange is possible only with a weak base, e.g. aniline; therefore, they decided to synthesize amine hydrochloride 85 by substitution of the bromide with sodium azide followed by reduction with H 2 in the presence of Pd/C.…”
Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.1 Introduction2 Synthesis2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation3 Reactivity3.1 Use of Uhle’s Ketone for Lysergic Acid3.2 Use of Uhle’s Ketone for Rearranged Clavines3.3 Use of Uhle’s Ketone for Medicinal Chemistry4 Conclusion and Outlook
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