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    1,3-AZOLES: Reactivity Towards E-Files

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    Luis Miguel Arellano Castellanos
    1. 1,2- and 1,3-azoles react with electrophiles at the nitrogen atoms through protonation and alkylation/acylation. Reactivity depends on the identity of the heteroatom (X = N, O, S). 2. 1,2-azoles react less readily than 1,3-azoles with electrophiles at nitrogen. Reaction at carbon is possible and activation/deactivation depends on the position and identity of heteroatoms. 3. Key reactions include cycloadditions, carbonyl condensations to form rings, and deprotonation/metallation at nitrogen followed by electrophilic substitution. Synthetic routes allow installation of different substituents on the

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    1,3-AZOLES: Reactivity Towards E-Files

    Uploaded by

    Luis Miguel Arellano Castellanos
    41 views28 pages
    1. 1,2- and 1,3-azoles react with electrophiles at the nitrogen atoms through protonation and alkylation/acylation. Reactivity depends on the identity of the heteroatom (X = N, O, S). 2. 1,2-azoles react less readily than 1,3-azoles with electrophiles at nitrogen. Reaction at carbon is possible and activation/deactivation depends on the position and identity of heteroatoms. 3. Key reactions include cycloadditions, carbonyl condensations to form rings, and deprotonation/metallation at nitrogen followed by electrophilic substitution. Synthetic routes allow installation of different substituents on the

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    Chapt21-22

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    1. 1,2- and 1,3-azoles react with electrophiles at the nitrogen atoms through protonation and alkylation/acylation. Reactivity depends on the identity of the heteroatom (X = N, O, S). 2. 1,2-azoles react less readily than 1,3-azoles with electrophiles at nitrogen. Reaction at carbon is possible and activation/deactivation depends on the position and identity of heteroatoms. 3. Key reactions include cycloadditions, carbonyl condensations to form rings, and deprotonation/metallation at nitrogen followed by electrophilic substitution. Synthetic routes allow installation of different substituents on the

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    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    41 views28 pages

    1,3-AZOLES: Reactivity Towards E-Files

    Uploaded by

    Luis Miguel Arellano Castellanos
    1. 1,2- and 1,3-azoles react with electrophiles at the nitrogen atoms through protonation and alkylation/acylation. Reactivity depends on the identity of the heteroatom (X = N, O, S). 2. 1,2-azoles react less readily than 1,3-azoles with electrophiles at nitrogen. Reaction at carbon is possible and activation/deactivation depends on the position and identity of heteroatoms. 3. Key reactions include cycloadditions, carbonyl condensations to form rings, and deprotonation/metallation at nitrogen followed by electrophilic substitution. Synthetic routes allow installation of different substituents on the

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    1,3-AZOLES

    N N H Imidazole N S Thiazole N O Oxazole Oxazolidineone antibiotic N


    N X

    HN O Oxazolidine

    O N F N O O H N O

    O 2-Oxazoline (4,5-Dihydrooxazol)

    X=NH: 1H-Benzimidazole X=O: Benzoxazole X=S Benzotiazole

    Linesolid ZyvoxTM

    Reactivity towards E-files


    N X

    pyridine

    E+
    X

    N E

    C3/C4 in pyrole etc + inductive effect from N


    N X

    pyrazole thiophene furan

    Few examples React. generally in benzene ring

    C2/C6 in pyridine

    C2/C5 in pyrole etc

    Reaction with electrophiles on N - Protonation


    N X H
    +

    H N X

    pKa X=NH: 7.1 X=S: 2.5 X=O: 0.8

    H N N H

    H N N H stabilized

    H N O Destabilized

    HN N

    Taut.:

    N H

    R= Me: ca 1 : 1 R=NO2: ca 400 : 1

    Reaction with electrophiles on N R N-Alkylation N


    N H

    'R

    R N N H

    'R

    R N N

    N X

    R-X

    R N X
    HN N

    R'-X R R HN N R' - H+ N N R' R May be sterically favoured

    Reactivity: X = N-Me 900 : X=S 15 : X=O 1

    R N N Base R'-X R N N - H+ 'R N N R'

    low react.

    N SO2Ph

    N H

    HN N

    R N N

    N N H Base PhCOCl Et Et

    N N O

    1) Et3O+ BF4-

    N N

    N N

    HN N steric control

    Reaction with electrophiles on N N-Acylation


    Only rel. for imidazole
    O N X Ac2O Me N X X=O, S Unstable N N H Ac2O Me N N H -H
    +

    O Me

    O N N

    N N N O Readily hydrol. / attacked by Nu R Nu R O Nu N N N N N O N N

    Safe equiv. of phosgene

    Reaction with electrophiles on C - protonation


    N N H D+ / D2O N N H H D N N H D

    Slow react Reactivity C-5 > C4 > C2

    Neutral / basic cond. - Faster excange - React. in the 2-pos.


    DO N D X

    N H X

    D2O H

    D N X

    D N X

    D2O D

    D N X

    pKa X=NH: 7.1 X=S: 2.5 X=O: 0.8

    DO D N X carbene

    Reactivity x = NH > S > O

    See 21.10 R N H X DO Reactivity X = O > S > NR'

    R N X

    D2O D

    R N X

    R N X carbene

    Reaction with electrophiles on C - Nitration


    N N H Conc. HNO3 / H2SO4 HN N H N N H NO2

    N X Reactivity X = NH > S > O

    N N H

    R R

    Conc. HNO3 / H2SO4

    No react

    N R S

    Conc. HNO3 / H2SO4 R RH

    N S NO2

    Oxazoles: No react.

    Reaction with electrophiles on C - Bromination


    Reactivity X = NH > S > O Br N N H N R S Br2 R Br2, NaOAc/AcOH Br N N H N S Br Br Na2SO3 N N H Br

    Oxazoles: No react.

    Reaction with electrophiles on C - Acylation


    No Lewis acid cat react. (Friedel Craft, basic N)
    O N N R R RCOCl H B O C.f. deuterium exchange R N X N X R O N X RCOCl R O O R N X R O Base N X

    Reaction with electrophiles on C - Condensation react


    Few ex. comp. to pyrrole / thiophene / furan
    N TMS S RCHO TMS HO R N S HO R N S

    Ipso subst.

    Reaction with Nucleophiles


    No Nu displacement of H Some ring opening react. on oxasole
    C3/C4 in pyrole etc + inductive effect from N
    N

    Nu
    Cl X

    N Nu

    N X

    C2/C6 in pyridine
    N X X

    C2/C5 in pyrole etc

    NuX

    N Nu

    Deprotonation at N - Furter reactions


    N N H R N N Base R HN N R R'-X - H+ 'R R N N R' R N N R

    N N

    C-metallation - Furter reactions


    N X

    BuLi
    X

    N Li

    Y X

    BuLi

    Li X

    X= NR, S

    X= NR, S Y=Br, I

    N X

    BuLi
    X

    N Li

    Transmetallation Coupling react

    Oxazole
    N O

    BuLi

    N O Li

    N OLi

    TMS-Cl

    N O TMS

    heat

    N O TMS

    Met-X
    N O Met

    Decomp.

    More stable

    Cycloaddition
    Ph N X R R X R R

    cf synth of thiophene, furan + PhCN

    X: S, O

    Imidazole - only intramolec. examples


    N N R O NR N N R O NR R N O NR

    - HCN

    Alkylazoler
    N N X CH3 N X
    N

    n
    CH2

    CH3

    BuLi

    Li E
    N X CH2E

    c.f. pyridines etc


    R N X CH2 R CH3 X

    Li
    CH2

    H3C N X H3C X

    N
    N

    BuLi
    R N

    BuLi

    H3C X

    Li

    Li
    CH2

    more acidic

    Neutral form

    NR2 O N H3C X CH3

    NR2

    BuLi

    Li
    H2C X

    N CH3

    Other ODG react in 2-pos

    Quartenary 1,3-Diazolium Salts


    O N X

    ClCO2 Et
    X

    Et Y

    O Met N X H O

    Et

    Aqueous base Oxidizing agent


    Y X

    N Y

    Allylstannanes Allylsilanes Silyl enol ethers

    Also ring openings


    O

    Me N O

    OH
    O

    Me H OH

    Me N O
    R N

    N N N

    X Stable compouns Ionic liquids (bmim)

    N N R

    NaH
    N R

    R N N R

    E
    N R

    R E

    Stable crystalline compds


    Ph N Ph N Ph Ph Ph N Ph N Ph Ph

    N N N

    Me

    Pd(OAc)2 2 AcOH

    Me N N Me

    Me

    N Me

    N Me

    Pd2+
    N Me

    Me Me N N Pd N Me

    2I

    2I
    Me Me N N N Me

    Pd cat. for coupling react Good for Heck

    2
    Pd I I

    N Me

    Amino 1,3-azoles
    All as aminotautomers, all are protonated in the ring
    N S NH2 S NH NH2 S NH NH2

    N N R NH2 N R

    NH NH2 N R

    NH NH2 N R

    NH NH2

    More basic (guanidin)

    N X NH2

    NaNO2
    X

    N N2

    CuX
    X

    N X

    XO

    Oxy 1,3-azoles
    All as oxo (carbonyl) Generally low aromaticity
    NH NH S O -H+ E S NH O

    NH N H O

    H+

    NH N H O

    E H

    iminium ion
    NH N H O

    E+

    Reacts as enamin E+
    NH S O H S E NH O S E NH O

    Stable No rearomatisation
    H H H N H HN O NH NH O H HN O NH NH N H

    Enamin

    Not as thio enol ether

    - H+

    H H

    NH X O

    POCl3 Base
    X

    N Cl

    Synthesis of 1,3-azoles
    Carbonyl condensations Strategy A
    X

    A
    N X

    B
    X

    O Cl X

    NH2 R'

    O NH2 X R'

    O NH X R'

    OH R NH X R' -H2 O

    R N X

    H R'

    R N

    -H+

    -H+

    R'

    X=NH, O, S R=H, Alkyl/aryl, NH2 etc R=H: Cl


    OEt Cl

    instead of

    Unstable
    Cl

    Strategy B

    Especially valuable for oxazoles

    JOC 2003, 9093

    NH R O O R'

    R HO

    N O R'

    -H2 O

    R'

    R'

    Cycloadditions

    Ts N

    Base

    Ts N R X Ts N X

    1,3-dipol

    Ts-MIC

    N R X

    R H

    N EWG R N2 O

    cat. "Rh"

    EWG R' R O

    EWG N R O R'

    R: Alkyl/aryl (ketone) R: OR' (ester)

    carbenoid

    Bioactive 1,3-azoles
    H N N H2N CO2H H2N Histamine H N N

    Histidine (His)

    LO from plants
    Epothilone A: R=H Epothilone B: R=Me From myxobacteria Potential anticancer drugs Mechanism taxol

    ca. 5
    Pilokarpin (Acetylkolin agonist) Glaukom
    O O H
    O

    N
    Me N O N H

    Isolert fra Pilocarpus jaborandi (Raintree) Sr-Amerika

    protonert ved physiol pH (basisitet imidazoler)

    Co-enzyme in biochem. prosesses:


    H2N N NH2 N HO S N

    Thiamin (Vitamin B1 )
    N HO S

    H2N N NH2 N

    Base
    H2N N NH2 N N H2N N NH2 N HO S HO O O N

    Fermetation of glucose

    HO

    Glucose EtOH MeCHO

    O HO O

    H+
    H2N N NH2 N HO S OH N HO S N OH H2N N NH2 N N N OH O HO S O H2N N NH2

    CO2

    H+

    Chymotrypsin: Cleavage of peptides

    His
    H N Asp O R O H N O N H O O R'

    His Ser
    Asp O H R H N O N N H O R'

    Ser

    His
    H N Asp O R NH2 O O N O R'

    Ser

    1,2-AZOLES
    4 3
    N H N

    Pyrrazole

    1 Isothiazole
    5 4

    N2

    Isoxazole
    3
    X N2

    5 6

    3
    X 2 N1

    N H

    NH

    1H Benzindazol

    Not detectable

    7 1 X=S: 1,2-Benzisothiazol X=O; 1,2-Benzisoxazol

    7 X=S: 2,1-Benzisothiazol X=O; 2,1-Benzisoxazol (Antranil)

    Reaction with electrophiles on N: Protonation


    N

    H+
    X

    NH

    N H

    N S

    pKa 2.5

    -0.5

    -3.0

    N H
    N N H N

    NH N H

    NH

    pKa 7.1

    pKa 5.2

    NH3 pKa 9.3

    NH2 NH2 7.9

    NH2 OH 5.8

    Reaction with electrophiles on N: Alkylation and acylation


    Generally more difficult than with 1,3-diazoles

    R-X
    N R' N X R' R N N R N R

    R-X
    X N X N R
    R N H N N H

    X=S: Ok with reactive RX X=O: Ring opening

    R N R

    sterical hindrance Not reversible react


    R

    R-X
    R N NH

    +
    R N R NH

    -H

    N R

    R N H N N H

    R N R N

    R N COR

    RCOCl

    +
    R N R NH

    -H+

    +
    R N COR N

    R N NH

    Reversible Most stable prod. formed

    Reaction with electrophiles on C


    Reactivity towards electrophiles
    Activation by X

    Weak deact. by N Activated by X


    X N

    Most deactivatet (2-pos pyridine)

    N X

    Deactivated by N Activated by X

    N X

    Deactivation by N

    E
    H X N

    E H X N

    E N
    X

    E
    N

    X=S, NH X=O: low reactivity

    Reaction may also occur in the benzene ring

    Reaction with nucleophiles


    Not replacement of H
    X X X

    EWG

    Reactivity as PhX N

    Not reactive towards Nu !?!

    Cl

    Also activated by EWG

    Nu

    Reaction with base


    N H N

    NaH
    N

    pKa 14.2 (Imidazole17.5)

    But NB!
    N

    Li

    BuLi
    Li X

    BuLi
    X

    N N X

    X= O, (S)

    Reaction of metallated compounds


    R N H N R R R

    NaH
    N

    R-X
    N N N N R N

    C-Met: Reactivity as expected

    Major isomer Sterically favoured

    Cycloadditions
    CO2Et N EtO2C N N CO2Et EtO2C EtO2C N N N CO2Et N CO2Et H CO2Et NH N N H NH2 N N N N H

    - EtOCOCN
    N NH2 N H

    EtO2C

    -NH3 EtO2C

    H2N

    N H

    No ex. Of 1,2-azoles as dienes in DA


    NHPh N N S Me O N N S NHPh

    NHPh HN S Me O N

    Base

    mech. ? Me

    O
    CN CN CN MeN N CN MeN N

    Two mechanisms Low yields

    N N Me CN

    N N Me CN

    N N Me

    MeN

    Alkyl 1,2-azoles
    CH3 CH3 H2C X N X CH2 H3C X N H3C X N CH2 N X CH3 N

    Base
    H3C X N

    Most acidic

    Oxy 1,2-diazoles
    OH X N X O NH O X NH

    c.f. 2- or 4-oxopyridines

    HO X N

    HO

    NH

    NH

    Phenol

    Amino 1,2-diazoles
    -amino form -3 / 5-amino- anilin, diazotation etc
    H2N N H Me N Me N N N H N Me N Me N N Me N

    Stable!

    OH

    Synthesis of 1,2-azoles
    Carbonyl condensations
    R: few restrict
    R H R O H2N R O NH2 H HO R N H R R OH NH R R N
    HO NH2 R O N R R

    - 2H2 O

    N H

    R S

    NH2

    Ox
    R S

    From oximes / hydrazones


    O R H3C HO R H3C N HN R N R N R

    (DMF)
    NMe2 O

    R N

    2 BuLi
    N

    H2C N O

    Cycloadditions
    R R' R O N R R R' N

    R R N N R''

    R' R

    R' N

    N R''

    Nitril oxid

    Nitril imine
    R R N N R R CO2R N H N

    CO2R

    Diazo

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