Stereoselective Double Friedel−Crafts Alkylation of Indoles with Divinyl Ketones

Silvanus, Andrew C.; Heffernan, Stephen J.; Liptrot, David J.; Kociok‐Köhn, Gabriele; Andrews, Benjamin I.; Carbery, David R.

doi:10.1021/ol900014a

Cited by 46 publications

(12 citation statements)

References 71 publications

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“…[6a] During our recent study on the chiral Brønsted acid catalyzed Friedel-Crafts reaction, we found that a chiral phosphoric acid could catalyze the Friedel-Crafts reaction of indole with 2-formylbiphenyl derivatives. Interestingly, this reaction proceeded through a double Friedel-Crafts alkylation process, [12] providing the 9-(3-indolyl)fluorene derivatives with high ee values (Scheme 1). [13] To the best of our knowledge, despite their significant applications in organic synthesis, [14] this represents the first asymmetric synthesis of fluorene derivatives.…”

mentioning

confidence: 99%

Enantioselective Synthesis of Fluorene Derivatives by Chiral Phosphoric Acid Catalyzed Tandem Double Friedel–Crafts Reaction

Sun

Zeng

et al. 2009

Chemistry A European J

158

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The asymmetric Friedel-Crafts reaction is one of the most powerful methods to synthesize optically active aromatic compounds, [1] and chiral Brønsted acids have recently emerged as efficient catalysts.[2] Chiral phosphoric acids, first introduced by Akiyama et al. and Terada and Uraguchi as organocatalysts, [3] were shown to be effective in the FriedelCrafts alkylation reactions of indoles and pyrroles by several groups. However, electrophilic partners that can be activated by chiral phosphoric acids in Friedel-Crafts reactions have, so far, been limited to imines, [4] enamides, [5] a,b-unsaturated carbonyls, [6] and nitroolefins. [7] Developing new, suitable electrophilic partners and novel catalytic models for chiral phosphoric acid catalyzed reactions are extremely desirable. In this regard, vinyl ether [8] and nitroso compounds [9] have recently been developed successfully.[10] Alcohols are among the most abundant chemicals and synthetic intermediates, however, their use in enantioselective FriedelCrafts reactions has only appeared recently.[11] To the best of our knowledge, the only example involving the use of alcohols in the Brønsted acid catalyzed asymmetric FriedelCrafts reaction was carried out by Rueping et al., in which chiral N-triflylphosphoramide was used and a moderate enantiomeric excess (ee) value was obtained.[6a]During our recent study on the chiral Brønsted acid catalyzed Friedel-Crafts reaction, we found that a chiral phosphoric acid could catalyze the Friedel-Crafts reaction of indole with 2-formylbiphenyl derivatives. Interestingly, this reaction proceeded through a double Friedel-Crafts alkylation process, [12] providing the 9-(3-indolyl)fluorene derivatives with high ee values (Scheme 1).[13] To the best of our knowledge, despite their significant applications in organic synthesis, [14] this represents the first asymmetric synthesis of fluorene derivatives. More interestingly, the current reaction proceeds with the activation of both carbonyl and hydroxy groups by a chiral phosphoric acid. The enantiocontrol is likely to be made possible through the close proximity of the chiral phosphate counterion to the 3-benzylidene-3H-indolium ion.[15] Herein, we report a tandem double FriedelCrafts reaction of indoles with 2-formylbiphenyls, leading to 9-(3-indolyl)fluorene derivatives with up to 96 % ee.We first examined the reaction between 3',5'-dimethoxybiphenyl-2-carbaldehyde (2 a) and 2-methyl indole (3 a) catalyzed by different, readily available, chiral phosphoric acids.[16] To our delight, reaction of 2 a and 3 a in the presence of (S)-1 (5 mol %) and 5 molecular sieves (MS), in toluene at room temperature, proceeded smoothly to afford fluorene 4 aa in 70 % yield with 75 % ee (Table 1, entry 1). Optimization of the reaction conditions was carried out and the results are summarized in Table 1. Lowering the temperature to 0 8C resulted in an increase of enantioselectivity (81 % ee; Table 1, entry 2). Several solvents, namely, benzene, dichloromethane, and carbon tetrachloride, were scree...

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confidence: 99%

Enantioselective Synthesis of Fluorene Derivatives by Chiral Phosphoric Acid Catalyzed Tandem Double Friedel–Crafts Reaction

Sun

Zeng

et al. 2009

Chemistry A European J

158

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“…This section exclusively deals with the construction of this structure motif. Formation of benzocyclohepta[ b ]indoles, ,− and carbocycle-fused indoles, also suitable for the generation of cyclohepta[ b ]indoles, are not covered here. − …”

Section: Methodologies For Construction Of Cyclohepta[b]indolesmentioning

confidence: 99%

Cyclohepta[b]indoles: A Privileged Structure Motif in Natural Products and Drug Design

2016

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Seven-membered rings fused with an indole are termed cyclohepta[b]indoles. Compounds exhibiting this structure motif display a broad spectrum of biological activities, ranging from inhibition of adipocyte fatty-acid-binding protein (A-FABP), deacetylation of histones, inhibition of leukotriene production p53, antituberculosis activities, and anti-HIV activities. These biological profiles are found in natural products containing the cyclohepta[b]indole motif, as well as in pharmaceuticals that contain this structure motif. Therefore, the biology of molecules derived from the skeleton of cyclohepta[b]indoles, as well as cyclopenta- and cyclohexa[b]indoles, has attracted considerable interest from the pharmaceutical industry as potential therapeutics in recent years. This is reflected by more than two dozen patents that have been issued in the past decade, solely based on the cyclohepta[b]indole structure motif. The efficient preparation of highly functionalized and unsymmetrically substituted cyclohepta[b]indoles has therefore become of central interest for synthetic organic chemists. Historically, this structure motif most often has been prepared by means of a Fischer indole synthesis. Although very robust and useful, this reaction poses certain limitations. Especially unsymmetrically functionalized cyclohepta[b]indoles are not suitable for a Fischer indole type synthesis, since product mixtures are inevitable. Therefore, novel methodologies to overcome these synthetic obstacles have been developed in recent years. This Account introduces all natural products and pharmaceutical compounds exhibiting the cyclohepta[b]indole motif. The structural variability within cyclohepta[b]indole alkaloids in combination with the broad range of organisms where these alkaloids have been isolated from, strongly suggests that the cyclohepta[b]indole is somehow a "privileged" structure motif. The organisms producing these compounds range from evergreen trees (actinophyllic acid) to cyanobacteria (ambiguinines). The synthetic methodologies to construct these molecular scaffolds (natural and unnatural in origin) are in turn highlighted and discussed with regard to their potential to access highly functionalized and unsymmetrical cyclohepta[b]indoles, for which they specifically have been designed. The methods are classified with respect to reaction type and whether or not they are enantioselective. Finally, the syntheses of cyclohepta[b]indole natural products are presented, thereby in each case, focusing on the construction of this structure motif in the course of the respective total synthesis. As a conclusion, we end by contrasting the methodological progress in the field with the actual successful application of the newly developed methods to the synthesis of complex structures to pinpoint the urgent requirement for further synthetic development for efficient synthetic design of this "privileged" structure motif.

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“…Remarkably, its formation formally involves two consecutive and selective Friedel–Crafts‐type reactions of a C‐2,C‐3‐unsubstituted indole with a bis(electrophile) bearing an alcohol as sp 3 ‐type acceptor and an acetal as carbonyl‐type acceptor. Interestingly, whereas the preparation of annulated indolic frameworks by the formal C‐2‐hydroarylation of indoles with sp 2 ‐ or sp ‐type acceptors, such as Michael substrates17 or gold‐activated alkynes,18 has been well established, the corresponding reactions with sp 3 ‐type acceptors like halides or alcohols through the Ciamician–Plancher rearrangement have been scarcely reported 19…”

Section: Methodsmentioning

confidence: 99%

Brønsted Acid‐Catalyzed Straightforward Synthesis of Benzo[b]carbazoles from 2,3‐Unsubstituted Indoles

et al. 2014

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Abstract. Described is a general and efficient synthesis of valuable benzo [b]carbazoles by Brønsted acid-catalyzed reaction between simple C2,C3-unsubstituted indoles and o-(-(hydroxy)benzyl)benzaldehyde acetals. Highly selective migration processes are involved as key steps in the overall cascade sequence that implies the one-pot formation of two new bonds and a cycle in a regioselective fashion.

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Stereoselective Double Friedel−Crafts Alkylation of Indoles with Divinyl Ketones

Cited by 46 publications

References 71 publications

Enantioselective Synthesis of Fluorene Derivatives by Chiral Phosphoric Acid Catalyzed Tandem Double Friedel–Crafts Reaction

Enantioselective Synthesis of Fluorene Derivatives by Chiral Phosphoric Acid Catalyzed Tandem Double Friedel–Crafts Reaction

Cyclohepta[b]indoles: A Privileged Structure Motif in Natural Products and Drug Design

Brønsted Acid‐Catalyzed Straightforward Synthesis of Benzo[b]carbazoles from 2,3‐Unsubstituted Indoles

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