Article | Published:

Switchable selectivity in an NHC-catalysed dearomatizing annulation reaction

Nature Chemistry volume 7, pages 842847 (2015) | Download Citation

Abstract

The development of general catalytic methods for the regio- and stereoselective construction of chiral N-heterocycles in a diversity-oriented fashion remains a formidable challenge in organic synthesis. N-heterocyclic carbene (NHC) catalysis has been shown to produce a variety of outcomes, but control of the reactivity has rarely been demonstrated. Here we report a switchable catalytic activation of enals with aromatic azomethine imines that provides high selectivity using NHC organocatalysts. The original selectivity corresponds to the acidity of the base used in the reaction. The catalytically generated chiral homoenolate or enol intermediate undergoes enantioselective annulation with electrophiles such as N-iminoquinolinium ylides, N-iminoisoquinolinium ylides and β-N-iminocarboline ylides. The good-to-high overall yields, high regioselectivities and excellent enantioselectivities observed are controlled by the catalyst and reaction conditions.

  • Compound C9H8O

    Cinnamaldehyde

  • Compound C9H7FO

    (E)-3-(4-Fluorophenyl)acrylaldehyde

  • Compound C9H7ClO

    (E)-3-(4-Chlorophenyl)acrylaldehyde

  • Compound C10H10O

    (E)-3-(p-Tolyl)acrylaldehyde

  • Compound C10H10O2

    (E)-3-(4-Methoxyphenyl)acrylaldehyde

  • Compound C7H6O2

    (E)-3-(Furan-2-yl)acrylaldehyde

  • Compound C6H10O

    (E)-Hex-2-enal

  • Compound C4H6O

    (E)-But-2-enal

  • Compound C3H4O

    Acrylaldehyde

  • Compound C16H14N2O2S

    Isoquinolin-2-ium-2-yl(tosyl)amide

  • Compound C17H16N2O2S

    (6-Methylisoquinolin-2-ium-2-yl)(tosyl)amide

  • Compound C16H13BrN2O2S

    (6-Bromoisoquinolin-2-ium-2-yl)(tosyl)amide

  • Compound C16H13BrN2O2S

    (5-Bromoisoquinolin-2-ium-2-yl)(tosyl)amide

  • Compound C16H13BrN2O2S

    (4-Bromoisoquinolin-2-ium-2-yl)(tosyl)amide

  • Compound C16H13BrN2O2S

    (8-Bromoisoquinolin-2-ium-2-yl)(tosyl)amide

  • Compound C22H18N2O2S

    (3-Phenylisoquinolin-2-ium-2-yl)(tosyl)amide

  • Compound C16H14N2O2S

    Quinolin-1-ium-1-yl(tosyl)amide

  • Compound C16H13BrN2O2S

    (6-Bromoquinolin-1-ium-1-yl)(tosyl)amide

  • Compound C16H13ClN2O2S

    (6-Chloroquinolin-1-ium-1-yl)(tosyl)amide

  • Compound C17H16N2O2S

    (6-Methylquinolin-1-ium-1-yl)(tosyl)amide

  • Compound C17H16N2O2S

    (4-Methylquinolin-1-ium-1-yl)(tosyl)amide

  • Compound C23H23N3O4S

    (9-(tert-Butoxycarbonyl)-9H-pyrido[3,4-b]indol-2-ium-2-yl)(tosyl)amide

  • Compound C14H14N2O4S

    (4-(Methoxycarbonyl)pyridin-1-ium-1-yl)(tosyl)amide

  • Compound C25H22N2O3S

    (1R,11bR)-1-Phenyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C25H21FN2O3S

    (1R,11bR)-1-(4-Fluorophenyl)-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C25H21ClN2O3S

    (1R,11bR)-1-(4-Chlorophenyl)-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C26H24N2O3S

    (1R,11bR)-1-(p-Tolyl)-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C26H24N2O4S

    (1R,11bR)-1-(4-Methoxyphenyl)-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C23H20N2O4S

    (1S,11bR)-1-(Furan-2-yl)-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C22H24N2O3S

    (1S,11bR)-1-Propyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C20H20N2O3S

    (1S,11bR)-1-Methyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C19H18N2O3S

    (S)-4-Tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C26H24N2O3S

    (1R,11bR)-9-Methyl-1-phenyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C25H21BrN2O3S

    (1R,11bR)-9-Bromo-1-phenyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C25H21BrN2O3S

    (1R,11bR)-8-Bromo-1-phenyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C25H21BrN2O3S

    (1R,11bR)-7-Bromo-1-phenyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C25H21BrN2O3S

    (1R,11bR)-11-Bromo-1-phenyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C31H26N2O3S

    (1R,11bR)-1,6-Diphenyl-4-tosyl-4,11b-dihydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C25H22N2O3S

    (4R,4aS)-4-Phenyl-1-tosyl-4,4a-dihydro-1H-pyridazino[1,6-a]quinolin-2(3H)-one

  • Compound C25H21BrN2O3S

    (4R,4aS)-8-Bromo-4-phenyl-1-tosyl-4,4a-dihydro-1H-pyridazino[1,6-a]quinolin-2(3H)-one

  • Compound C25H21ClN2O3S

    (4R,4aS)-8-Chloro-4-phenyl-1-tosyl-4,4a-dihydro-1H-pyridazino[1,6-a]quinolin-2(3H)-one

  • Compound C26H24N2O3S

    (4R,4aS)-8-Methyl-4-phenyl-1-tosyl-4,4a-dihydro-1H-pyridazino[1,6-a]quinolin-2(3H)-one

  • Compound C26H24N2O3S

    (4R,4aS)-6-Methyl-4-phenyl-1-tosyl-4,4a-dihydro-1H-pyridazino[1,6-a]quinolin-2(3H)-one

  • Compound C27H29N3O5S

    (1S,12bR)-tert-Butyl 1-methyl-3-oxo-4-tosyl-1,3,4,12b-tetrahydropyridazino[1',6':1,2]pyrido[3,4-b]indole-12(2H)-carboxylate

  • Compound C18H20N2O5S

    (4S,4aR)-Methyl 4-methyl-2-oxo-1-tosyl-2,3,4,4a-tetrahydro-1H-pyrido[1,2-b]pyridazine-6-carboxylate

  • Compound C25H22N2O3S

    (1S,10bS)-1-Benzyl-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C25H21FN2O3S

    (1S,10bS)-1-(4-Fluorobenzyl)-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C25H21ClN2O3S

    (1S,10bS)-1-(4-Chlorobenzyl)-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C26H24N2O3S

    (1S,10bS)-1-(4-Methylbenzyl)-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C26H24N2O4S

    (1S,10bS)-1-(4-Methoxybenzyl)-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C23H20N2O4S

    (1S,10bS)-1-(Furan-2-ylmethyl)-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C22H24N2O3S

    (1S,10bS)-1-Isobutyl-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C22H24N2O3S

    (1S,10bS)-1-Butyl-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C20H20N2O3S

    (1S,10bS)-1-Ethyl-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C26H24N2O3S

    (1S,10bS)-1-Benzyl-8-methyl-3-tosyl-1,10b-dihydropyrazolo[5,1-a]isoquinolin-2(3H)-one

  • Compound C25H24N2O3S

    (1R,11bR)-1-Phenyl-4-tosyl-4,6,7,11b-tetrahydro-1H-pyridazino[6,1-a]isoquinolin-3(2H)-one

  • Compound C26H28N2O4S

    (R)-Methyl 3-((R)-2-(4-methylphenylsulfonamido)-1,2,3,4-tetrahydroisoquinolin-1-yl)-3-phenylpropanoate

  • Compound C18H17NO

    (1R,10bR)-1-Phenyl-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one

  • Compound C21H24BF4N3O

    (S)-5-Benzyl-2-mesityl-6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-2-ium tetrafluoroborate

  • Compound C19H18ClN3O

    (5aR,10bS)-2-(p-Tolyl)-4,5a,6,10b-tetrahydroindeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium chlorine

  • Compound C21H22ClN3O

    (5aR,10bS)-2-Mesityl-4,5a,6,10b-tetrahydroindeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium chlorine

  • Compound C22H24BF4N3O

    (5aR,10bS)-2-(2,6-Diethylphenyl)-4,5a,6,10b-tetrahydroindeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate

  • Compound C20H20ClN3O3

    (5aR,10bS)-2-(2,6-Dimethoxyphenyl)-4,5a,6,10b-tetrahydroindeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium chlorine

  • Compound C18H11ClF5N3O

    (5aR,10bS)-2-(Perfluorophenyl)-4,5a,6,10b-tetrahydroindeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium chlorine

  • Compound C27H28BF4N3O

    (S)-5-(Hydroxydiphenylmethyl)-2-mesityl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate

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Acknowledgements

The authors acknowledge financial support from the Alexander von Humboldt Foundation (C.G.), the Deutsche Forschungsgemeinschaft IRTG 2027 (M.F.) and the Deutsche Forschungsgemeinschaft (SPP 1179, Leibniz award; F.G.). The authors also thank M.N. Hopkinson, K. Chepiga and J. Neugebauer for discussions and corrections during the preparation of the manuscript. This work is dedicated to the memory of C. Djerassi.

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Affiliations

  1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, Münster 48149, Germany

    • Chang Guo
    • , Mirco Fleige
    • , Daniel Janssen-Müller
    • , Constantin G. Daniliuc
    •  & Frank Glorius

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Contributions

C.G. and F.G. conceived and designed the study, and co-wrote the paper. C.G. and M.F. performed the experiments and analysed the data. C.G., M.F. and D.J.-M. performed the mechanism study. C.G.D. performed the crystallographic studies. All the authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Frank Glorius.

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https://doi.org/10.1038/nchem.2337

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