Visible‐Light‐Mediated Aerobic Tandem Dehydrogenative Povarov/Aromatization Reaction: Synthesis of Isocryptolepines

Schendera, Eva; Unkel, Lisa‐Natascha; Quyen, Phung Phan Huyen; Salkewitz, Gwen; Hoffmann, Frank; Villinger, Alexander; Brasholz, Malte

doi:10.1002/chem.201903921

Cited by 27 publications

(14 citation statements)

References 44 publications

(26 reference statements)

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“…14,136 Similarly to the synthesis of THQs, these reactions can be catalyzed by Lewis and Brønsted acids such as BF 3 •OEt 2 , 36,40,137-142 BF 3 •O(CH 3 ) 2 , 143,144 FeCl 3 , 145,146 InCl 3 , 147 trifluoromethanesulfonic acid, 148 p-toluenesulfonic acid, 146 CX4SO 3 H, 14,149 TFA, 150,151 camphorsulfonic acid, 152 tris(4-bromophenyl)aminium (TBPA + ), 140,[153][154][155] CBr 4 , 156 iron, 157 copper iodide 158 and iodine. [159][160][161][162][163][164][165][166][167] Furthermore, different triflates have been widely used such as Sc(OTf) 3 , 154,168,169 Yb(OTf) 3 , [170][171][172][173] Cu(OTf) 2 , 174,175 Ce(OTf) 3 , 176,177 Zn(OTf) 2 , 178 AgOTf, 22 In(OTf) 3 179 and Ca(OTf) 2 . 84 Heterogeneous catalysis was also described by using montmorillonite-supported perchloric acid (HClO 4 -Mont).…”

Section: Quinolinesmentioning

confidence: 99%

“…Regarding the reaction medium, various polar and nonpolar solvents have been explored, for example, acetonitrile, 2,4,6,[22][23][24][36][37][38] THF, 159,161 DMSO, 160,162,163,166,173 ethanol, 146,[181][182][183] DMF, 158 acetic acid, 157 dichloromethane, 97,138,145,148,150,179,180,184 TFE, 137,152 diethyl ether, 185 dichloroethane, 140,142,151,153,165,186 chloroform 174 and toluene. 147,171,177 Greener alternatives were also reported such as the absence of a solvent 84,149,174,176,178 or the use of a DES (Scheme 13).…”

Section: Scheme 12 Synthesis Of 2-arylquinoline Derivatives Through A...mentioning

confidence: 99%

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The Povarov Reaction: A Versatile Method to Synthesize Tetrahydroquinolines, Quinolines and Julolidines

et al. 2022

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Multicomponent Povarov reaction is a powerful approach for the construction of N-heterocyclic containing substances. By using Povarov reaction, in addition to accessing tetrahydroquinolines, quinolines and julolidines in a single step, it is possible to form, respectively, two new Csp3-Csp3 and one Csp3-Nsp3 bonds, two new Csp2-Csp2 and one Csp2-Nsp2 bonds and four Csp3-Csp3 and two Csp3-Nsp1 bonds. This review article reports the main features of the Povarov reaction such as its mechanism, the scope of such reaction concerning to different catalysts and substrates used on it as well as the stereoselective versions of Povarov reaction

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Section: Quinolinesmentioning

confidence: 99%

Section: Scheme 12 Synthesis Of 2-arylquinoline Derivatives Through A...mentioning

confidence: 99%

The Povarov Reaction: A Versatile Method to Synthesize Tetrahydroquinolines, Quinolines and Julolidines

et al. 2022

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“…In the second method, they developed a photocatalytic variant and through rigorous screening experiments observed optimal product formation by irradiating the starting materials together with triphenylpyrylium tetrafluoroborate (TPP•BF 4 ) and tetrabutylammonium iodide (TBAI) using a mixture of hexafluoroisopropanol (HFIP) and 1,2dichloroethane (DCE) as solvents. [221] Utilizing the same starting materials, Wu and coworkers have described a copper(II)-catalyzed visible-light-mediated C-H functionalization strategy to yield a range of various indolo [3,2-c]quinolines 38C (one example shown in Scheme 61b). [222] Despite photochemical synthesis being considered as one of the six major synthetic methods for the construction of the indolo[3,2-c]quinoline core, [101] the aforementioned publications demonstrate a decline in the development of novel synthetic approaches in recent literature.…”

Section: Photochemical Synthesis Of Indolo[32-c]quinolines 38mentioning

confidence: 99%

“…Scheme 61: Synthesis of some indolo[3,2-c]quinolines 38; (a) utilizing a visible-lightmediated tandem dehydrogenative Povarov/aromatization reaction as presented by Brasholz and colleagues; [221] (b) copper(II)-catalyzed C-H activation by Wu and coworkers. [222]…”

Section: Photochemical Synthesis Of Indolo[32-c]quinolines 38mentioning

confidence: 99%

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Håheim¹

2022

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Malaria is a devastating tropical disease, claiming approximately 627 000 lives in 2020. Due to the appearance of resistance towards artemisinin-based therapies, the discovery of novel treatments are of paramount importance. The indoloquinoline natural products cryptolepine, neocryptolepine and isocryptolepine, first discovered in the extracts of the African bush plant Cryptolepis sanguinolenta, have been found to exhibit potent antimalarial properties. More- over, several functionalized derivatives of these compounds have shown great promise as an- tiplasmodial agents. The indoloquinoline alkaloids have also been found to possess significant antiproliferative and antimicrobial properties, making them ideal targets for the development into novel drug candidates. The first project in this work details the application of a synthetic approach first devel- oped by Helgeland and Sydnes to assemble various tetracyclic ring systems. The key synthetic strategies being a Suzuki-Miyaura cross-coupling reaction followed by a palladium-catalyzed intramolecular cyclization. Though the approach was unsuitable to construct all the intended target molecules, it furnished the unexpected pyridophenanthridine scaffold. By further inves- tigating alternative protocols for the construction of indoloquinolines, a regiodivergent inter- mediate was discovered, which allowed for the synthesis of both novel pyridophenanthridine and pyridocarbazole scaffolds by utilizing two different reaction protocols. By subjecting this common intermediate to a diazotization-azidation-nitrene insertion approach, the novel pyrido- carbazoles could be furnished in excellent yields. The unexpected formation of a biquinoline bridged by an aniline during a Suzuki-Miyaura cross-coupling reaction, was deemed interesting for development into a transition metal com- plex for catalysis. Through a collaborative effort with Dr. Eugene Khaskin’s group at Oki- nawa Institute of Science and Technology, five quinoline/pyridine N,N,N ligands were designed and synthesized. The key synthetic tools utilized in their construction was either a sequential Suzuki-Miyaura cross-coupling reaction and Buchwald-Hartwig amination or reductive amina- tion. A novel two-step approach for the synthesis of the natural product neocryptolepine from commercially available bromoquinolines was developed. The key transformations being re- gioselective N-alkylations followed by a cascade Suzuki-Miyaura cross-coupling reaction and intramolecular nucleophilic C-N bond formation. The scope and limitations for the novel pro- tocol was evaluated through the preparation of 24 neocryptolepine derivatives, bearing a diverse range of functional groups, where electron-withdrawing group substitutions were generally su- perior. It became apparent that it would also be possible to prepare a library of indolo[3,2-c]quino- lines from the same starting material as the newly devised strategy to produce neocryptolepines. By utilizing a reaction sequence consisting of a Suzuki-Miyaura cross-coupling reaction, in- stallation of an azido moiety and finally photochemical cyclization, this goal was realized, producing a total of 19 indoloquinolines. This protocol was less robost towards substrate func- tionalizations than the neocryptolepine approach, with no apparent trend concerning electron- withdrawing and electron-donating groups being apparent. The photochemical cyclization was hypothesized to proceed via the formation of a reactive singlet nitrene intermediate. Finally, a selection of the prepared tetracyclic compounds assembled during this work was evaluated for their antiplasmodial, antiproliferative and antimicrobial activities by the help of various external collaborators. The most successful compound was revealed to be the novel pyridophenanthridines, displaying more potent antiproliferative activities than doxoru- bicin against human prostate cancer (IC50 = 24 nM). The novel pyridocarbazoles moreover showed excellent inhibition of biofilm formation, with the potential to be developed into a dual anticancer-antimicrobial agent. Of all the tested compounds, only N-methylated pyridocar- bazole was found to contain any significant activity against the evaluated Plasmodium falci- parum strain. The antimicrobial assays revealed the importance of the inclusion of a methyl group for activity, but not strictly in the form of an N-methyl unit, which is the general con- census in the literature thus far. Further, chlorinated indoloquinolines were revealed to contain excellent antimicrobial activity against both Gram-positive and Gram-negative bacterial cell lines.

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“…We envisaged that strongly oxidizing photoexcited 2,4,6-triphenyl pyrylium tetrafluoroborate (TPT) ( E red = +2.55 V vs SCE) , will not only oxidize 2 H -azirines but also may serve as dipolarophile in [3 + 2]-cycloaddition with the resulting 2-azaallenyl intermediate (Scheme b) . The pyrylium salts have been classically employed as photosensitizers in the photoinduced electron transfer (PET) mediated cycloadditions . Further, pyrylium salts or pyrylium intermediates have also found use as dienes in the hetero-Diels–Alder reactions and as dipolarophiles in cycloaddition reactions .…”

Section: Introductionmentioning

confidence: 99%

Redox-Neutral 1,3-Dipolar Cycloaddition of 2H-Azirines with 2,4,6-Triarylpyrylium Salts under Visible Light Irradiation

et al. 2021

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A novel visible light mediated redox-neutral 1,3-dipolar cycloaddition of 2H-azirines with 2,4,6-triarylpyrylium tetrafluoroborate salts providing tetrasubstituted pyrroles has been developed. The 2,4,6-triarylpyrylium salt acts as dipolarophile as well as photosensitizer in the reaction, under blue light irradiation. The control experiments indicated single electron oxidation of 2H-azirines by photoexcited pyrylium salts, followed by coupling between an azaallenyl radical cation and triarylpyranyl radical as the key mechanistic feature. The mild conditions, wide substrate scope, and complete regioselectivity are the noticeable attributes of the reaction.

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Visible‐Light‐Mediated Aerobic Tandem Dehydrogenative Povarov/Aromatization Reaction: Synthesis of Isocryptolepines

Cited by 27 publications

References 44 publications

The Povarov Reaction: A Versatile Method to Synthesize Tetrahydroquinolines, Quinolines and Julolidines

The Povarov Reaction: A Versatile Method to Synthesize Tetrahydroquinolines, Quinolines and Julolidines

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Redox-Neutral 1,3-Dipolar Cycloaddition of 2H-Azirines with 2,4,6-Triarylpyrylium Salts under Visible Light Irradiation

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