Synthesis of 3-substituted and 3,4-disubstituted 3,4-dihydro-1(2H)-isoquinolones by condensation of lithiated N,N-diethyl-o-toluamide with imines

Clark, Robin D.; Jahangir, _

doi:10.1021/jo00233a013

Cited by 43 publications

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“…Furthermore, their procedures could not accommodate imines with hydrogens α to the imine carbon, due to suspected competing proton transfer. A related synthetic strategy, based upon the addition of lithiated N,N -diethyl- o -toluamide to imines, was used to prepare a series of dihydroisoquinolones . The yields of dihydroisoindolones were, however, modest to poor.…”

Section: Introductionmentioning

confidence: 99%

Addition of Transiently-Generated Methyl o-Lithiobenzoate to Imines. An Isoindolone Annulation

1996

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Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF(3).etherate at -105 degrees C gives good to excellent yields of isoindolones. The transient formation of methyl o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated anions can then be captured by the BF(3)-activated imines to form the isoindolones in good to high yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be tolerated.

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Section: Introductionmentioning

confidence: 99%

Addition of Transiently-Generated Methyl o-Lithiobenzoate to Imines. An Isoindolone Annulation

1996

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“…The one‐pot cycloaddition procedure was exploited in 1987 by Clark, to prepare 3,4‐dihydro‐1(2 H )‐ iso ‐quinolones (Scheme 20). [64] Starting from a N , N ‐diethyl‐ o ‐toluamide, this was lithiated by lithium diisopropylamide (LDA) and then reacted with an imine in THF at −70 °C. The reaction was then quenched at low temperature to minimise side products.…”

Section: Addition Reactionsmentioning

confidence: 99%

Main Group Metal‐Mediated Transformations of Imines

Orr

Andrews

Blair

2020

Chemistry A European J

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Main‐group‐metal‐mediated transformations of imines have earned a valued place in the synthetic chemist's toolbox. Their versatility allows the simple preparation of various nitrogen containing compounds. This review will outline the early discoveries including metallation, addition/cyclisation and metathesis pathways, followed by the modern‐day use of imines in synthetic methodology. Recent advances in imine C−F activation protocols are discussed, alongside revisiting “classic” imine reactivity from a sustainable perspective. Developments in catalytic methods for hydroelementation of imines have been reviewed, highlighting the importance of s‐block metals in the catalytic arena. Whilst stoichiometric transformations in alternative reaction media such as deep eutectic solvents or water have been summarised. The incorporation of imines into flow chemistry has received recent attention and is summarised within.

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“…We speculated that the tert-butylamido anion 2 might react further by intraor intermolecular proton transfer to form an eneamido anion with extended conjugation (3), and this anion did appear to be a reasonable candidate to account for the red color we observed. [12][13][14] To test this hypothesis methyl iodide (2 equiv) was added to the deep red solution shortly after its formation at À78 8C, and an orange solution was produced within minutes. Addition of trifluoroacetic acid after 30 minutes, also at À78 8C, followed by warming to room temperature, aqueous work-up, and purification by flash column chromatography provided 4-methyl-3-phenylisoquinoline in 80 % yield.…”

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confidence: 99%

A Versatile Synthesis of Substituted Isoquinolines

Myers

2011

Angewandte Chemie

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In the context of a broader program directed toward the synthesis of analogues of the isoquinoline-containing natural product cortistatin A, [1,2] we wished to prepare a diverse array of highly substituted isoquinoline coupling partners, but routes to the complex heterocyclic structures we envisioned were lengthy or impractical using classical [3] or moremodern [4][5][6] methods. Herein we report a method for the rapid construction of highly substituted isoquinolines of extraordinary structural versatility; this method proceeds by the convergent assembly of as few as two or as many as four components in a single operation. Further substitutional diversification can be achieved by modification of the workup conditions and by subsequent transformations, as detailed below.The present work was based on two important precedents. The first was the synthesis of 3-substituted isoquinolones by Poindexter; this synthesis proceeded by the addition of nitriles to o-tolylbenzamide dianions followed by work-up in the presence of ammonium chloride (Scheme 1). [7] The second was the method of Forth et al. for the preparation of ortho-substituted benzaldehyde derivatives by metalation of o-tolualdehyde tert-butylimines, followed by alkylation of the resulting anions, and then hydrolysis (Scheme 1). [8,9] We imagined and quickly brought to practice the idea that the trapping of metalated o-tolualdehyde tert-butylimines with nitriles might provide a highly direct route to 3-substituted isoquinolines. As we will show, the chemistry proved to be much more versatile than we initially imagined; this versatility is due to the transformations that ensue subsequent to the addition of the nitrile.Initial experiments established the feasibility of the proposed construction in a simple system and provided insights for expansion of the method. o-Tolualdehyde tertbutylimine was metalated under the reaction conditions specified by Forth et al., using stoichiometric n-butyllithium and a catalytic amount of 2,2,6,6-tetramethylpiperidine in tetrahydrofuran (THF) at 0 8C for 40 minutes, thus forming the corresponding benzyl anion as a deep purple solution, as previously reported. [8] Addition of this anion to a solution of benzonitrile (1.5 equiv) in THF at À78 8C produced a dark red solution within 3 minutes. [10] Upon warming to 23 8C the reaction mixture became dark brown. Addition of saturated aqueous ammonium chloride followed by extraction and purification by flash column chromatography provided 3-Scheme 1. The synthesis of isoquinolones reported by Poindexter and the method of Forth et al. for metalation/alkylation of o-tolualdehyde tert-butylimine. TMP = 2,2,6,6-tetramethylpiperidine.Scheme 2. A method for the direct condensation of o-tolualdehyde tertbutylimines with nitriles to form substituted isoquinolines. The mechanistic pathway depicted accounts for the fact that addition of an alkyl halide subsequent to condensation leads to the formation of 4-alkyl substituted isoquinolines, exemplified by the formation of 4-methyl-3phenylisoquinol...

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Synthesis of 3-substituted and 3,4-disubstituted 3,4-dihydro-1(2H)-isoquinolones by condensation of lithiated N,N-diethyl-o-toluamide with imines

Cited by 43 publications

References 0 publications

Addition of Transiently-Generated Methyl o-Lithiobenzoate to Imines. An Isoindolone Annulation

Addition of Transiently-Generated Methyl o-Lithiobenzoate to Imines. An Isoindolone Annulation

Main Group Metal‐Mediated Transformations of Imines

A Versatile Synthesis of Substituted Isoquinolines

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