The catalytic enantioselective synthesis of tetrahydroquinolines containing all-carbon quaternary stereocenters via the formation of aza-ortho-xylylene with 1,2-dihydroquinoline as a precursor

Abstract

Tetrahydroquinolines (THQs) with an all-carbon quaternary stereocenter were effectively obtained via the in situ formation of aza-ortho-xylylene (AOX) with easily accessible 1,2-dihydroquinolines as precursors. The reaction was rationalized with chiral phosporic acid to afford chiral THQs with high yield and excellent enantioselectivity.Tetrahydroquinolines (THQs) belong to a class of nitrogen containing heterocycles, which have attracted the attention of medicinal and synthetic chemists because of their abundance in both natural products and drug molecules. 1 Therefore, methods for a rapid assembly of chiral THQs were very demanding despite the numerous synthetic approaches available. 2 Recently, our group reported an efficient way of synthesizing aza-ortho-xylylene (AOX) by dearomatization of 1,2-dihydroquinolines (DHQs) 1 with catalytic Brønsted acid. 3 The resulting intermediate formed in situ could be efficiently transfer hydrogenated with HEH to afford THQs with high yields and enantioselectivity (Scheme 1a). The advantages of this approach including the highly reactive AOX generated through a simple way, 4 the easily accessible substrates obtained from simple aromatic amines and ketones, and the high enantioselectivities of the corresponding chiral THQs, prompted us to investigate and develop more reaction types accordingly.As we know the preparation of compounds containing allcarbon quaternary stereocenters with catalytic enantioselective reactions are particularly demanding because of their wide distribution in natural products and bioactive substances. 5 However, catalytic enantioselective construction of these centers poses a daunting challenge in spite of the tremendous efforts made in this field. 6 One of the difficulties in constructing an all-carbon stereocenter is their congested nature. 7 Inspired by Van Straten's work 8 for constructing an all-carbon quaternary center at the C-4 of DHQs with AlCl 3 as well as our previous work of forming reactive AOX with Brønsted acid, 3 we challenged the Brønsted acid catalyzed Friedel-Craft reaction with indoles as substrates, 9 which could afford DHQs containing all-carbon quaternary centers. To our knowledge, access to THQs containing all-carbon quaternary chiral centers was rare. Herein we report an efficient strategy to form THQs with all-carbon quaternary stereocenters based on DHQs, in which the double bond was functionalized via the formation of AOX and subsequent nucleophilic substitution with indoles (Scheme 1b).Our previous work demonstrated that the electron properties of DHQs played an important role in the formation of an AOX intermediate. Enhancing the electron density of the alkene group by installing an electron donating group on the phenyl ring could make the alkene group easily protonated with Brønsted acid under mild reaction conditions. Therefore, we initiated this work by screening the DHQs accordingly. As a result, several DHQs with different substituents on the phenyl ring were prepared and subjected to indoles with 5 mol% TsOH in ...

Organocatalyzed Asymmetric Friedel‐Crafts Reactions: An Update

“…In 2016, Tang and co‐workers examined the generality of the Brønsted acid mediated F‐CA reaction for the production of different tetrahydroquinolines (THQs) with a chiral quaternary carbon center . Moreover, indole derivatives 14 containing electron‐donating substituents or electron‐withdrawing substituents have been reasonably applied to treat with 64 to attain the desired tetrahydroquinoline derivatives 66 c – e with moderate yields and good ee s. Instead, 1,2‐dihydroquinolines having various substituents have been tested.…”

“…In the meantime, 7,8‐benzo‐tetrahydroquinoline 66 q might be accomplished with moderate yield and good enantioselectivity. Although, 66 r that has a phenyl functionalized at 4‐position, was not produced because of the marginally large steric hindrance (Scheme ) …”

Lewis Säure‐katalysierte Transferhydromethallylierung für den Aufbau quartärer Kohlenstoffzentren

“…[7,8] Obwohl dieser Ansatz bereits im Rahmen der Erzeugung von Carbeniumionen durch Dehydratisierung tertiärer Alkohole mit katalytischen Mengen an starker Säure ausgenutzt worden ist, [5,6,9] ist der komplementäre Verlauf durch katalytische Protonierung von Alkenen weit weniger gut erforscht. [10,11] Wiru ntersuchen seit geraumer Zeit Cyclohexa-1,4-dienbasierte Surrogate schwer handhabbarer Verbindungen für metallfreie Tr ansferreaktionen. [12][13][14][15] Als Te il dieses Programms haben wir zuvor die Cyclohexa-1,4-diene 5 und 6 als Surrogate fürIsobutangas entwickelt und über deren Einsatz in der Transferhydro-tert-butylierung von Alkenen unter Verwendung der starken Bor-Lewis-Säure B(C 6 F 5 ) 3 berichtet (Schema 1, oben).…”

Hydroarylation of Alkenes by protonation/Friedel-Crafts Trapping – HFIP-Mediated Access to Per-Aryl Quaternary Stereocentres

“…enamines, enol ethers, o/pQM(I)s] may be arylated under milder conditions. 23 Pertinent recent (asymmetric) examples of this latter class include Sun's arylation of a pQM formed by chiral phosphoric acid (CPA)catalyzed dehydration (Scheme 1c), 24 Tang's arylation of an oQMI formed by protonation (Scheme 1d), 25 and Liu's arylation of a styrene-derived pQM via benzylic radical formation/oxidation (Scheme 1e). 26 However, in all these CPA-mediated transformations the only arene nucleophiles able to successfully trap the cationic intermediates were indoles and pyrroles due to their ability to H bond with the CPA promotors.…”