Novel Base-Initiated Cascade Reactions of Hemiindigos to Produce Dipolar G-Carbolines and Cite This: RSC Adv.,2019,9,41402 Indole-Fused Pentacycles†
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RSC Advances View Article Online PAPER View Journal | View Issue Novel base-initiated cascade reactions of hemiindigos to produce dipolar g-carbolines and Cite this: RSC Adv.,2019,9,41402 indole-fused pentacycles† V. S. Velezheva, *a O. L. Babii,a A. A. Khodak,a E. A. Alekseeva,a Yu V. Nelyubina,a I. A. Godovikov,a A. S. Peregudov,a K. B. Majorovb and B. V. Nikonenkob Novel continuous-flow cascade reactions are developed for producing 1,4-diaryl-disubstituted dipolar g- carbolines 2 that contain a carboxylate group and their two pentacyclic precursors 6, 7 from Received 25th September 2019 hemiindigos 1. The nucleophilic and pro-electrophilic chemistry described is new to the hemiindigos 1, Accepted 4th December 2019 and it led to the discovery of antimycobacterial scaffold characteristic of rimino-type pentacycles 6, 7 DOI: 10.1039/c9ra07807j and potent drug clofazimine. The new scaffold like clofazimine appears to be useful in developing lead rsc.li/rsc-advances agents active against drug-resistant/dormant TB. Creative Commons Attribution 3.0 Unported Licence. Introduction was reported along with indigo in 1883 by A. Baeyer.10 However, photochromism of hemiindigos was demonstrated more than Studies of the cheap dye indigo and its analogs in the last two a century later.11 decades led to the design of novel indigoid photoswitches and Natural hemiindigos also include well-known indigoid dyes to the discovery of new approaches to cascade reactions that and natural medicinally important compounds such as indir- contributed largely to materials science and modern organic ubin, its family members, and a novel bioactive alkaloid (E)-2- 0 chemistry.1 Base-initiated cascade reactions of indigo using [(3 -indole)cyanomethylene]-3-indolinone (isolated from tetra- either allyl bromide or propargyl bromide provide rapid and ploidy banlangen (Isatis indigotica Fort)).12 Indirubins were This article is licensed under a unprecedented one-pot route to a diverse range of unique recognized as inhibitors of glycogen synthase kinase-3b and complex heterocyclic systems that are difficult to access by other CDK5/P25, the two protein kinases involved in abnormal tau means and that exhibit pronounced biological activities for phosphorylation in Alzheimer's disease.13 Indirubins were also several structures.2,3 Cascade synthesis of new bioactive spi- identied as potent ATP competitive protein kinase inhibitors.14 Open Access Article. Published on 13 December 2019. Downloaded 9/30/2021 11:16:03 PM. roindolinepyrido[1,2-a]indolediones from bioactive natural dye The indigo-like hemiindigos, 2-arylidene-1H-indol-3(2H)- indirubin, the 3,20-bisindole isomer of indigo, was reported.4 ones (2-arylmethylideneindoxyls, or indogenides according to The base-initiated cascade reactions of indigo with oxiranes and A. Baeyer) 1, were found to possess the challenging structural aziridines offered efficient access to dihydropyrazinodiindoles features as both enamines and a,b-enones show a unique dual and spiro-oxazocinodiindoles.5 nucleophilic and electrophilic reactivity. Earlier, we discovered Indigoid photoswitches cover a series of various hemi- that hemiindigos enter the ring-opening and ring enlargement thioindigo and hemiindigo chromophores, new studies and reactions of the indoxyl unit15,16 and that the exomethylidene applications of those are summarized by C. Petermayer and H. hydrogen atom can be replaced by nucleophilic and electro- Dube and described by Z. L. Pianowski.6,7 The available hemi- philic agents.17 We also reported, for the rst time, a number of indigo photoswitches show photochromism in the visible unexpected reactions, such as ring conversions and oxidative region so that the two isomeric states to be distinguished by the exomethylidene hydrogen substitution.15,18 Hemiindigos are naked eye. Substituted hemiindigos are therefore extremely readily available and versatile intermediates in the synthesis of – promising new photoswitches with excellent properties for fused indoles,19 22 4-quinolones,16 4-(2-acetylaminobenzoyl)-5- applications in biology, chemistry, or materials science.8,9 The aryl-1,2,3-triazoles,15 indoxyl alkaloid analogs,23 and pyridazino- rst hemiindigo indoxyl-based 2-phenylmethylideneindoxyl 1a [4,3-b]indoles exhibiting inhibitory activity against monoamine oxidases A and/or B and Mycobacterium tuberculosis.18 They also undergo the Diels–Alder and inverse electron demand Diels– aA. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Alder reactions24,25 as well as diverse cyclocondensations.26 Sciences, Vavilova St. 28, 119991 GSP-1, Moscow, Russia. E-mail: [email protected] Recently, some of us reported a photo-induced cyclo- bLaboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia dimerization of N-alkylhemiindigos (N-alkylindogenides) to † Electronic supplementary information (ESI) available. CCDC 1947196 and 1947197. For ESI and crystallographic data in CIF or other electronic format see spiropyrano[3,2-b]pseudoindoxyls rather than to cyclobutane 27,28 DOI: 10.1039/c9ra07807j adducts, as was reported by M. Hooper et al. The 41402 | RSC Adv.,2019,9,41402–41408 This journal is © The Royal Society of Chemistry 2019 View Article Online Paper RSC Advances spiropseudoindoxyl fragment of pseudoindoxyls is character- istic of many natural alkaloids. Over the last decade, the hem- iindigo scaffold has attracted considerable attention from synthetic chemists because of its unique reactivity and rele- vance to medicinal chemistry due to wide scope of bioactive properties.29–31 Our research in the eld of cascade reactions began with the discovery of a cationic domino reaction of hemiindigos that afford pentacyclic 3-hydroxyindolenines related to indolenine alkaloids in a diastereoselective fashion under the NMR experiment conditions.32 This is the rst example of the acid-catalyzed domino reaction that involved homocoupling of hemiindigos 1 followed by a reverse Wagner– Meerwein [1,2] type rearrangement of the intermediate 2-spi- 32 ropseudoindoxyls. We also described novel cationic domino Fig. 1 General view of 2a in representation of atoms via thermal reactions of hemiindigos 1 in the absence or in the presence of ellipsoids at 50% probability level. an external nucleophile.33 These reactions provide approaches to the dispiropseudoindoxyl system that represent structural core elements of natural spiroindoxyl alkaloids23,34 and a pyrrolo well as of 3 (see ESI†) was unambiguously conrmed by single- [1,2-a]indole core system of biologically active uorazones.33 crystal X-ray diffraction. Interesting results that we have obtained for homodimerization The g-carboline skeleton is widely used in the design of of hemiindigos 1 in acidic media inspired us to investigate agents against various diseases, and it represents a basic core of related reactions in base-induced conditions that remained many clinically successful drugs. These include antihistaminic Creative Commons Attribution 3.0 Unported Licence. unexplored until recently. Here we report novel alkaline- drugs mebhydroline (diazolin) and dimebon (latrepirdine) as initiated cascade reactions of hemiindigos 1 that lead to 1,4- well as neuroleptic carbidine. The last-two drugs are used in diaryl-disubstituted zwitterionic g-carbolinium derivatives 2 clinical practice in Russia. Flutroline and Gevotroline were with a carboxylate group and two new indole-fused pentacycles successfully tested in clinical trials as neuroleptics. Benzo-l- 6, 7 as well as to a spiropentacyclic compound 3. carboline alkaloid cryptosanguinolentine with highly conju- gated indolenine containing ring system showed anti- Results and discussion plasmodial properties.36 Various types activities of g-carbolines, such as neuropharmacological, antihistamine, anti-inamma- 32,33 In our ongoing research into the reactivity of hemiindigos 1, tory, anticancer, antiviral, antibacterial, antifungal and This article is licensed under a we studied their alkoxide-induced conversions. We observed antimalarial activity, were found in the recent years.37–39 Many that brightly colored orange solutions of hemiindigos 1a in methods for the synthesis of g-carboline ring systems were neutral media and dark-blue solutions of 1a in alkaline media elaborated.37 In addition, novel approaches from both – undergo decoloration during a short-term re ux in the alkaline traditional and modern chemistry continue to emerge.40 44 Open Access Article. Published on 13 December 2019. Downloaded 9/30/2021 11:16:03 PM. (KOH) EtOH or MeOH solution. Then we obtained a mixture of However, it is still a challenge to offer novel synthetic g-carboline 2a, fused spiroindoxyl 3, and 2-indolinone 4 in 2, 14, methods that provide functionalized g-carbolines from readily and 5% yields, respectively, upon re ux of 1a in alkaline EtOH available precursors. for 6 h (Scheme 1). Another byproduct, 2-indolinone 5, was also We put our efforts into the redirection of the process towards formed in 12% isolated yield using MeOH as a solvent. The g-carboline 2a as the major product. To this end, the reaction – starting indogenide 1a as well as its analogs 1b i were obtained was conducted under different conditions by varying the – in 68 95% yields by condensation of 1-acetylindoxyl and cor- solvents, temperature, and the nature and amount of bases. 27 responding benzaldehydes upon heating in alkaline EtOH. When sodium ethylate in DMSO was used in the reaction with The structures of 2, 3 and 5 were deduced from the elemental 1a, 2a was