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DESIGN AND SYNTHESIS OF CHIRAL N-HETEROCYCLIC CARBENES WITH APPLICATIONS TO ASYMMETRIC SYNTHESES AND SYNTHESIS OF DIBENZAZEPINONES BY PALLADIUM¨CCATALYZED INTRAMOLECULAR ARYLATION OF O-(2¡¯-BROMOPHENYL)ANILIDE ENOLATES

pan, xiaohong (2011) DESIGN AND SYNTHESIS OF CHIRAL N-HETEROCYCLIC CARBENES WITH APPLICATIONS TO ASYMMETRIC SYNTHESES AND SYNTHESIS OF DIBENZAZEPINONES BY PALLADIUM¨CCATALYZED INTRAMOLECULAR ARYLATION OF O-(2¡¯-BROMOPHENYL)ANILIDE ENOLATES. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Chiral N-heterocyclic carbene (NHC) ligands were prepared and examined in three asymmetric syntheses (oxindole synthesis, pyrrolidine synthesis and cyanosilylation of aldehydes). The ligand generated from (4R,5R)-1,3-bis(ortho-cyclohexylphenyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborate provided the best asymmetric oxindole synthesis: yields of oxindoles up to 99% with enantioselectivities (ee) up to 80% were achieved in 3 h; catalyst loadings as low as 1 mol % could be used; the imidazolinium salt can be made efficiently in only two steps. A mechanism for this asymmetric oxindole synthesis was proposed. The rotation barrier of the N-aryl bond in the oxidative addition products was found crucial for the enantioselectivity.A new approach for the convenient synthesis of dibenzazepinones is reported. The key step is the formation of the seven-membered ring through palladium-catalyzed intramolecular arylation of an anilide enolate. The reactions were completed in 10 min at 100 ¡ãC with moderate to excellent yields. Aminodibenzazepinone, the core structure in secretase inhibitor LY411575, can be prepared in five steps from 2-bromophenylboronic acid and 2-iodoaniline in 60% overall yield. The synthesis reported here compares favorably with presently available approaches to this interesting ring system.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairWilcox, Craigdaylite@pitt.edu
    Committee MemberDoemling, Alexanderasd30@pitt.edu
    Committee MemberCurran, Denniscurran@pitt.edu
    Committee MemberNelson, Scottsgnelson@pitt.edu
    Title: DESIGN AND SYNTHESIS OF CHIRAL N-HETEROCYCLIC CARBENES WITH APPLICATIONS TO ASYMMETRIC SYNTHESES AND SYNTHESIS OF DIBENZAZEPINONES BY PALLADIUM¨CCATALYZED INTRAMOLECULAR ARYLATION OF O-(2¡¯-BROMOPHENYL)ANILIDE ENOLATES
    Status: Unpublished
    Abstract: Chiral N-heterocyclic carbene (NHC) ligands were prepared and examined in three asymmetric syntheses (oxindole synthesis, pyrrolidine synthesis and cyanosilylation of aldehydes). The ligand generated from (4R,5R)-1,3-bis(ortho-cyclohexylphenyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborate provided the best asymmetric oxindole synthesis: yields of oxindoles up to 99% with enantioselectivities (ee) up to 80% were achieved in 3 h; catalyst loadings as low as 1 mol % could be used; the imidazolinium salt can be made efficiently in only two steps. A mechanism for this asymmetric oxindole synthesis was proposed. The rotation barrier of the N-aryl bond in the oxidative addition products was found crucial for the enantioselectivity.A new approach for the convenient synthesis of dibenzazepinones is reported. The key step is the formation of the seven-membered ring through palladium-catalyzed intramolecular arylation of an anilide enolate. The reactions were completed in 10 min at 100 ¡ãC with moderate to excellent yields. Aminodibenzazepinone, the core structure in secretase inhibitor LY411575, can be prepared in five steps from 2-bromophenylboronic acid and 2-iodoaniline in 60% overall yield. The synthesis reported here compares favorably with presently available approaches to this interesting ring system.
    Date: 29 September 2011
    Date Type: Completion
    Defense Date: 18 May 2011
    Approval Date: 29 September 2011
    Submission Date: 28 May 2011
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-05282011-005856
    Uncontrolled Keywords: dibenzazepinone; N-heterocyclic carbene; oxindole
    Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
    Date Deposited: 10 Nov 2011 14:46
    Last Modified: 11 Jan 2012 11:58
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-05282011-005856/, etd-05282011-005856

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