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Home , Oxazole, Oxazolidine, Oxazoline

1,3- N N N N S O H Oxazolidineone antibiotic N HN O N O N O O 2- F N O X (4,5-Dihydrooxazol) H N X=NH: 1H- Linesolid X=O: ZyvoxTM O X=S Benzotiazole

Reactivity towards E-files

N E+ N N ≈ X X E X ≈C3/C4 in pyrole etc + inductive effect from N Few examples React. generally in benzene ring ≈ pyrazole thiophene N X ≈ C2/C6 in pyridine

≈C2/C5 in pyrole etc Reaction with electrophiles on N - Protonation

H H pKa H N H+ N N N H X=NH: 7.1 N X X X=S: 2.5 N N X=O: 0.8 H H O stabilized Destabilized

R R N HN Taut.: N N H R= Me: ca 1 : 1 R=NO2: ca 400 : 1 Reaction with electrophiles on N R 'R R 'R R N-Alkylation N N N N N N H H R'-X R N R-X N - H+ R R R X X HN HN N May be sterically favoured Reactivity: N N N R' R' X = N-Me X=S X=O 900 : 15 : 1 R R R N N N N low react. N N N N H R' SO2Ph Base R'-X

- H+ R R 'R R HN N N N N N

N N H Base Et Et N + - N N PhCOCl 1) Et3O BF4 N N N O O HN N steric control Reaction with electrophiles on N N-Acylation

Only rel. for imidazole

O O O N Ac O Me N Ac O Me Me 2 N 2 N N X N - H+ X H N N X=O, S H Unstable

N N N Nu O O N N N R Nu N N R O Readily hydrol. N Safe equiv. of phosgene / attacked by Nu N Reaction with electrophiles on C - protonation

+ D / D2O N N N H Slow react D N D N Reactivity C-5 > C4 > C2 N H H H

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

DO D D D D O D2O N N N 2 N N D H X D X H X X X pKa DO See 21.10 X=NH: 7.1 R X=S: 2.5 D R R D O N N N N 2 X=O: 0.8 D H X Reactivity x = NH > S > O X X X carbene DO R Reactivity X = O > S > NR' N X carbene Reaction with electrophiles on C - Nitration N X

Reactivity X = NH > S > O

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

R Conc. HNO / H SO N 3 2 4 No react N R H

N Conc. HNO3 / H2SO4 N R NO R S S 2 R ≠ H

Oxazoles: No react. Reaction with electrophiles on C - Bromination

Reactivity X = NH > S > O

Br Br N Br2, NaOAc/AcOH N Na2SO3 N N Br N Br N H H H

N Br2 N R Br R S S

Oxazoles: No react.

Reaction with electrophiles on C - Acylation No Lewis acid cat react. (Friedel Craft, basic N)

O O O Base R R R RCOCl N N N RCOCl N N R R H X X N X X O O R B O C.f. deuterium exchange R N X Reaction with electrophiles on C - Condensation react

Few ex. comp. to / thiophene / furan

N N N RCHO TMS HO TMS S S S HO R R 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 N N Nu X Cl X X ≈ C2/C6 in pyridine

N Nu- N ≈C2/C5 in pyrole etc X X X Nu Deprotonation at N - Furter reactions

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

- H+ R R 'R R HN N N N N N

C-metallation - Furter reactions

N BuLi N Y N BuLi Li N X X Li X X X= NR, S X= NR, S Y=Br, I

N N BuLi •Transmetallation Li X X •Coupling react Oxazole TMS-Cl N BuLi N N N heat N TMS O O Li OLi O O TMS Met-X

N Decomp. O Met More stable

Cycloaddition

Ph R R N R R cf synth of thiophene, furan X X X: S, O + PhCN

Imidazole - only intramolec. examples

N N R O O O N N N R R NR NR NR - HCN Alkylazoler N CH3 N n CH X 2 Li N N c.f. BuLi E etc CH CH E X 3 X 2 Li N R CH X 2 N CH X 2 R N BuLi H3C N R N N BuLi H3C CH Li Li X 3 N H3C X X X more acidic CH X 2 Neutral form

NR 2 NR2 O O Other ODG N BuLi N Li react in 2-pos H C CH 3 X 3 H2C X CH3 Quartenary 1,3-Diazolium Salts O O Et Et O Met O N N Y N Aqueous base ClCO2Et H Oxidizing agent N X X X Y X Y Allylstannanes Allylsilanes Silyl enol ethers

Also ring openings O Me Me Me R N N + N OH H H N O O OH N O R O

N N

N N

X Stable compouns Ionic liquids (bmim) R R R R N NaH N N E N N N N N E R R R R

Stable crystalline compds

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

Me Me Me N Pd(OAc) N Me Me N 2 2+ 2 Pd N N 2 N N N I Me N N Me Pd Me 2 AcOH 2 I Me Me

2 I

Me Me N N Pd cat. for coupling react 2 N Good for Heck N Pd Me I I Me Amino 1,3-azoles

All as aminotautomers, all are protonated in the ring

N NH NH NH NH NH2 S 2 S 2 S

N NH NH NH

NH NH2 NH2 N NH2 N 2 N N R R R R More basic (≈guanidin)

N N N NaNO2 CuX N2 X X NH2 X X X≠O Oxy 1,3-azoles

All as oxo (carbonyl) Generally low NH NH NH E NH + S O O + O NH H H S -H E S O + O N E N H iminium ion Reacts as enamin H

NH E+ E E H NH NH N O NH H Enamin O O Stable S O S S No rearomatisation Not as thio enol ether O O HN HN H H NH NH H H H NH H NH - H+ N O N O H H NH POCl3 N Base O X X Cl Synthesis of 1,3-azoles

N A Carbonyl condensations X N B Strategy A X N X

OH R H R R O R O O N NH2 R R NH N NH2 NH + -H+ X R' -H X R' -H2O X R' X R' Cl X R' X R' X=NH, O, S R=H, Alkyl/aryl, NH2 etc

R=H: Cl OEt O instead of Unstable Cl Cl

Strategy B Especially valuable for oxazoles JOC 2003, 9093

N N NH R R R' O R' -H O R' O R' O O HO 2 Cycloadditions

Ts Base Ts N N 1,3-dipol Ts-MIC R

X Ts N N R R X X H

N EWG EWG EWG N2 N cat. "Rh" R' R R R' O R O O R: Alkyl/aryl () R: OR' (ester) carbenoid Bioactive 1,3-azoles

H H N N N N

H2N CO H 2 H2N Histidine (His) Histamine

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

ca. 5Å Pilokarpin (Acetylkolin agonist) Glaukom Isolert fra Pilocarpus jaborandi O (Raintree) Sør-Amerika N O Me N protonert ved physiol pH H O O N (basisitet imidazoler) O H Co-enzyme in biochem. prosesses:

H2N N NH2 N N

HO S

Thiamin H2N N (Vitamin B1) NH2 N N

HO S Base

H2N Fermetation of glucose N NH2 N N H2N N HO S NH2 N N Glucose O HO HO S O O HO EtOH MeCHO O

± H+

H2N H2N H2N N N N NH2 NH2 NH2 N N N N N N HO S HO S HO S OH OH OH CO2 O H+ O Chymotrypsin: Cleavage of peptides

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

His

H N N Ser Asp O O

O O R' NH R 2 1,2-AZOLES 4 3

N 5 N 2 N N S O H 1 Pyrrazole Isothiazole

4 4 5 3 5 3 6 N 2 6 X 2 N NH X N N N 7 1 7 1 H 1H Benzindazol Not detectable X=S: 1,2-Benzisothiazol X=S: 2,1-Benzisothiazol X=O; 1,2-Benzisoxazol X=O; 2,1-Benzisoxazol (Antranil) Reaction with electrophiles on N: Protonation

+ N N N H N S O N NH H X X pKa 2.5 -0.5 -3.0

NH NH N N H H N

N N H NH3 NH2NH2 NH2OH pKa 7.1 pKa 5.2 pKa 9.3 7.9 5.8 Reaction with electrophiles on N: Alkylation and acylation

Generally more difficult than with 1,3-diazoles R-X N N R R-X N X N N R R' R' X X

X=S: Ok with reactive RX R R R X=O: Ring opening N N R N R N N N H H sterical hindrance R-X -H+ + + Not reversible react

R R R

NH NH N N N N R R

R R R

N N R N COR N N N H H RCOCl -H+ + +

R R R Reversible NH NH N Most stable prod. formed N N N R COR Reaction with electrophiles on C

Reactivity towards electrophiles Activation by X

Weak deact. by N N N N X X Activated by X Most deactivatet X (≈2-pos pyridine) N X N N N Deactivated by N X X X Activated by X

Deactivation by N

N N N X X X

E E E E H H E+ N N N N N X X X X X X=S, NH Reaction may also occur in the X=O: low reactivity benzene ring Reaction with nucleophiles

Not replacement of H X EWG X Also activated Not reactive N Reactivity as PhX N Cl by EWG N X towards Nu !?! X X Nu Reaction with base

NaH N N N N N N H pKa 14.2 (Imidazole17.5)

But NB! Li N BuLi BuLi N Li N N N X X X X X

X= O, (S) Reaction of metallated compounds R R R R R-X NaH N N N N N N N N H R ”C-Met”: Reactivity as expected Major isomer Sterically favoured Cycloadditions CO Et 2 CO Et 2 CO Et N 2 N N EtO2C H N N N CO2Et NH N EtO2C N CO2Et EtO C N - EtOCOCN N N 2 EtO2C N -NH3 EtO2C N N H H NH N 2 NH2 H N H2N N H No ex. Of 1,2-azoles as dienes in DA

NHPh NHPh NHPh HN N N S Base S S N Me N Me N O O mech. ? Me O

CN CN CN hν N MeN N N Two mechanisms N N Me Me Low yields CN CN CN N MeN MeN N N N Me Alkyl 1,2-azoles

CH 3 CH2 CH3

N N N H2C CH3 X X X Base H C N 3 X CH2

N N Most acidic H3C X H3C X Oxy 1,2-diazoles

OH O O c.f. 2- or 4-oxopyridines N NH NH HO X X X

N X N N O NH NH HO X O X X O X ≈ Phenol

Amino 1,2-diazoles

N N -amino form H2N Me N Me N Me -3 / 5-amino- ≈ anilin, diazotation etc Stable! N N N N Me N Me N H OH H Synthesis of 1,2-azoles

Carbonyl condensations R: few restrict R R R R R R R R H H OH NH2 R O HO NH N HO - 2H2O R R N O R N N O NH2 H H H2N

Ox R NH 2 R N S S

From oximes / hydrazones

O R R R (DMF) 2 BuLi H C NMe2 H3C 2 N N N O HO O

R R H3C N N HN N R R Cycloadditions

R R R R' R R' R' R' R N R N R N R N N O O N R'' R'' Nitril oxid Nitril

R R CO2R CO2R

R N R N N N H

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