1,3-AZOLES

N

X

E+ N

X

Few examplesReact. generally in benzene ring

E

N

NH

Imidazole

N

S

Thiazole

N

O

Oxazole

N

O2-Oxazoline

(4,5-Dihydrooxazol)

HN

OOxazolidine ON

O

HN

NO

LinesolidZyvoxTM

F

O

Oxazolidineone antibiotic

X

N

X=NH: 1H-BenzimidazoleX=O: BenzoxazoleX=S Benzotiazole

N

X

≈ pyridine

≈ pyrazolethiophenefuran

Reactivity towards E-files

N

X ≈ C2/C6 in pyridine

≈C3/C4 in pyrole etc+ inductive effect from N

≈C2/C5 in pyrole etc

Reaction with electrophiles on N - Protonation

N

XH+ N

X

H pKaX=NH: 7.1X=S: 2.5X=O: 0.8

N

N

HN

N

H

H Hstabilized Destabilized

N

O

H

N

NH

RHN

N

R

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

Taut.:

Reaction with electrophiles on NN-Alkylation

N

XR-X N

X

R

Reactivity:

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

N

NSO2Ph

low react.

N

NH

R

HN

N

R

R'-X

N

NH

R

HN

N

R

R'

'R

- H+

N

N

R

N

N

R

R'

'R

May be sterically favoured

N

NH

R

HN

N

R

Base

N

N

R

N

N

R - H+

N

N

R

N

N

R

R'

'R

R'-X

N

NH

HN

N

BaseN

N

O

steric control

1) Et3O+ BF4- N

N

O

EtN

N

EtPhCOCl

Reaction with electrophiles on NN-Acylation

Only rel. for imidazole

- H+

N

X

Ac2O N

X

OMe

X=O, SUnstable

N

NH

Ac2O N

NH

OMe

N

N

OMe

N

NOR

Readily hydrol./ attacked by Nu

Nu OR Nu

N

N

N

N

N NO

NN

Safe equiv. of phosgene

Reaction with electrophiles on C - protonation

N

NH

D+ / D2O NNH

HD

N

NH

DSlow reactReactivity C-5 > C4 > C2

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

N

X

D

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

N

X

D2O

H

DO

N

X

D

N

X

D

carbene

D2O N

X

D

D

DO

H

N

XD

Reactivity x = NH > S > O

N

X

R

H

DO

N

X

R

N

X

R

carbene

D2O N

X

R

D

Reactivity X = O > S > NR'

See 21.10

Reaction with electrophiles on C - Nitration N

X

Reactivity X = NH > S > O

N

NH

Conc. HNO3 / H2SO4HN

NH

N

NH

NO2

N

NH

Conc. HNO3 / H2SO4R

RNo react

N

SConc. HNO3 / H2SO4

RR ≠ H

N

SR NO2

Oxazoles: No react.

Reaction with electrophiles on C - BrominationReactivity X = NH > S > O

N

NH

Br2, NaOAc/AcOH

N

SRN

SR Br

Oxazoles: No react.

Br2

N

NH

Br

Br

BrNa2SO3 N

NH

Br

Reaction with electrophiles on C - AcylationNo Lewis acid cat react. (Friedel Craft, basic N)

N

XN

NR

RCOClH

B

N

X

N

X

RCOCl N

X

N

X

C.f. deuterium exchange

RO O

R

OR

Base

OR

OR

OR

Reaction with electrophiles on C - Condensation reactFew ex. comp. to pyrrole / thiophene / furan

N

STMSRCHO N

STMS

RHO

N

SHO

R

Ipso subst.

Reaction with NucleophilesNo Nu displacement of H Some ring opening react. on oxasole

N

X ≈ C2/C6 in pyridine

≈C3/C4 in pyrole etc+ inductive effect from N

≈C2/C5 in pyrole etc

N

X ClNu N

X Nu

N

X

Nu- N

X NuX

N

X

N

X LiBuLi

Deprotonation at N - Furter reactions

N

NH

R

HN

N

R

Base

N

N

R

N

N

R - H+

N

N

R

N

N

R

R'

'R

R'-X

C-metallation - Furter reactions

N

X

N

X Li

X= NR, S

BuLi N

X

N

XX= NR, SY=Br, I

BuLiY Li

•Transmetallation•Coupling react

Cycloaddition

N

O

N

O

BuLi

Oxazole

Li

N

OLi

Met-X

N

O Met

More stable

Decomp.

TMS-Cl N

OTMS

heat N

O TMS

N

X

Ph

X: S, O

RR

X

R Rcf synth of thiophene, furan

+ PhCN

Imidazole - only intramolec. examples

N

NR NR

ON

NR

NR

ORN

NR

O

- HCN

Alkylazoler

BuLiLi

N

X CH3

N

X CH2

N

X CH2

Li

E N

X CH2E

BuLiN

X

H3CN

XH3C

N

X

H3CLi

N CH3n

c.f. pyridines etc

BuLiN

X CH3

N

X CH2

N

X CH2

Li

R

R

R

Neutral form

more acidic

N

XLi

ONR2

H3C CH3

BuLi N

X

ONR2

H2C CH3

Other ODGreact in 2-pos

Quartenary 1,3-Diazolium Salts

N

XClCO2Et N

X

OO

EtY

Met

AllylstannanesAllylsilanesSilyl enol ethers

N

X

OO

Et

HY

Aqueous baseOxidizing agent N

X Y

N

O

MeOH N

O

MeHOH

H+ NMe

O

Also ring openings

N

N

RO

OR

N

N

N

N

XStable compounsIonic liquids(bmim)

N

N

R

R

NaH N

N

R

R

EN

N

R

R

N

N

R

R

E

N

N

Stable crystalline compds

N

N

N

N

Ph

Ph

N

N

Ph

Ph

Ph

Ph

Ph

Ph

N

N

Me

Me

N

N

Me

Me2

Pd(OAc)2

I2 AcOH

N

N

Me

Me

2 Pd2+

Pd NNN

NMe

Me Me

Me2 I

2 I

Pd NNN

NMe

Me Me

MeII

2Pd cat. for coupling reactGood for Heck

Amino 1,3-azoles

All as aminotautomers, all are protonated in the ring

N

S NH2

NH

S NH2

NH

S NH2

N

NR

NH2

NH

NR

NH2

NH

NR

NH2

NH

NR

NH2

More basic (≈guanidin)

N

X NH2

X≠O

NaNO2 N

X N2CuX N

X X

Oxy 1,3-azolesAll as oxo (carbonyl)Generally low aromaticity

NH

NH

OH+

NH

NH

O

NH

NH

O

NH

NH

OH

NHHN

OHH

- H+NH

NH

O

NHHN

OHH

H

StableNo rearomatisation

Enamin

iminium ion

NH

S O

E+

NH

SE

HO -H+

NH

S OE

Reacts as enamin

NH

S O

E+NH

S

EH

ONH

S O

E

Not as thio enol ether

NH

X O

POCl3Base

N

X Cl

Synthesis of 1,3-azoles

Carbonyl condensations N

X

A

B N

X

N

X

Strategy A

NH2X R'

X=NH, O, SR=H, Alkyl/aryl, NH2 etc

O

Cl

R

X R'

ORNH2

-H+X R'

OR NH NH

X

OHR

R' -H2ON

X R'

R H

-H+N

X

R

R'

R=H: O

ClUnstable

OEt

Cl

Clinsteadof

Strategy B Especially valuable for oxazoles

-H2ONH

O OR'R

N

OR

HOR'

N

O R'R'

JOC 2003, 9093

Cycloadditions

OR

N2EWG

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

cat. "Rh"

OR

EWGN

R'N

O

EWG

R R'

NTs

Ts-MIC

BaseN

Ts1,3-dipol

X

R

N

XRH

TsN

XR

carbenoid

CO2HH2NN

HN

Histidine (His)

Bioactive 1,3-azoles

H2NN

HN

Histamine

LO from plantsEpothilone A: R=HEpothilone B: R=MeFrom myxobacteriaPotential anticancer drugsMechanism ≈ taxol

N

NMe

OO H

protonert ved physiol pH(basisitet imidazoler)

Pilokarpin (Acetylkolin agonist)Glaukom

Isolert fra Pilocarpus jaborandi(Raintree) Sør-Amerika

NO

O

O H

ca. 5Å

N

S

N

N

HO

H2N

NH2

Thiamin(Vitamin B1)

Co-enzyme in biochem. prosesses:

Fermetation of glucose

Glucose O

OHO

N

S

N

N

HO

H2N

NH2

Base

N

S

N

N

HO

H2N

NH2

N

S

N

N

HO

H2N

NH2

O

OHO

± H+

N

S

N

N

HO

H2N

NH2

OH

OOCO2

N

S

N

N

HO

H2N

NH2

OH

H+

N

S

N

N

HO

H2N

NH2

OH

MeCHOEtOH

Chymotrypsin: Cleavage of peptides

RHN R'

O

O

O

NNH

H O

His

Ser

RHN R'

O

O

O

NN

O

His

SerH

H

R NH2O

O

NNH

O

His

Ser

O R'

AspAsp

Asp

1,2-AZOLES

Reaction with electrophiles on N: Protonation

NX

H+NH

X

NNH

NS

NO

pKa 2.5 -0.5 -3.0

NHNH

NHNH

NH3 NH2NH2 NH2OHpKa 9.3 7.9 5.8

N

NH

pKa 7.1

N

pKa 5.2

NNH

NS

NO

Pyrrazole Isothiazole Isoxazole12

34

5

NX

XN

X=S: 1,2-BenzisothiazolX=O; 1,2-Benzisoxazol

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

12

345

671

23

456

7NNH

NHN

Not detectable1H Benzindazol

Reaction with electrophiles on N: Alkylation and acylationGenerally more difficult than with 1,3-diazoles

NX

R-XN

XR

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

NN

R-XN

XR

R' R'

NNH

R

NHN

R

NNH

R

NHN

R

R

R

R-X -H+

NN

R

NN

R

R

R

sterical hindrance

Not reversible react++

NNH

R

NHN

R

NNH

R

NHN

R

R

R

-H+

NN

R

NN

R

COR

COR

ReversibleMost stable prod. formed

++RCOCl

Reaction with electrophiles on C

NX

Activation by X

XN

XN

NX X

NXN

Deactivation by N

NX

NX X

N

NX

E+N

X

E

Reaction may also occur in thebenzene ring

NX

X=S, NH

X=O: low reactivity

E

XN

EH

XN

EH

NX

Reactivity towards electrophiles

Most deactivatet(≈2-pos pyridine)

Weak deact. by NActivated by X

Deactivated by NActivated by X

Reaction with nucleophilesNot replacement of H

NX

X

Reactivity as PhX NX

X

Not reactivetowards Nu !?!

NX

Also activatedby EWGCl

EWG

Nu

Reaction with base

NNH

NaH NN

NN

pKa 14.2 (Imidazole17.5)

NX

NX

BuLiLi N

XN

XBuLi

But NB!

X= O, (S)

LiN

X

Reaction of metallated compounds

NNH

NaH NN

NN

Major isomerSterically favoured

R R RR-X

NN

R

R”C-Met”: Reactivity as expected

Cycloadditions

N

N

N

NNH

H2N

CO2Et

EtO2C CO2EtN

N

NEtO2C

EtO2CCO2Et

NH2NH

N- EtOCOCN

N

N NH

NH

H

NH2

-NH3

N

N NH

N

CO2Et

EtO2C

CO2Et

EtO2C

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

NOMe

HNNHPh

S BaseN

OMe

NNHPh

S

mech. ?

N

NS

NHPh

OMe

NNMe

CNhν

N

CN

NMe

N

CN

MeN

MeN N

CN

NNMe

CN

N

CNMeN

Two mechanismsLow yields

Alkyl 1,2-azoles

NX

CH3

H3C

Most acidic

Base

NX

CH3

H2C XN

CH2

NXH3C

CH2

XN

XNH3C

CH3

Oxy 1,2-diazoles

NX

OH

NHX

O

NHX

O

NXHO X

NO XNHO X

NHO

c.f. 2- or 4-oxopyridines

NX

HO

≈ Phenol

Amino 1,2-diazoles

-amino form-3 / 5-amino- ≈ anilin, diazotation etc

NNH

MeH2N

NN

MeN

Me

N

OHHNN

NN

Me

MeStable!

Synthesis of 1,2-azoles

O

R

RO

RH

R: few restrict

NH2H2N

NH

NHOH

RRH

HOR

- 2H2O NNH

RR

RNH2

HO NO

RR

R

NH2S

R OxN

SR

Carbonyl condensations

From oximes / hydrazones

NHO

H3CR

2 BuLiN

O

H2CR

O

NMe2(DMF)

NO

R

NHN

H3CR

R

NN

R

R

Cycloadditions

R

R

R'

NO

Nitril oxid

NO

R

R

R'R

R

R'

NN

Nitril imine

NN

R

R

R'

R'' R''

R

R

Diazo

NNH

R

R

CO2R

NN

CO2R