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1,3-AZOLES Reactivity Towards E-Files 1,3-AZOLES N N N N S O H Imidazole Thiazole Oxazole Oxazolidineone antibiotic N HN O N O N O O 2-Oxazoline Oxazolidine F N O X (4,5-Dihydrooxazol) H N X=NH: 1H-Benzimidazole Linesolid X=O: Benzoxazole ZyvoxTM O X=S Benzotiazole Reactivity towards E-files N E+ N N ≈ pyridine X X E X ≈C3/C4 in pyrole etc + inductive effect from N Few examples React. generally in benzene ring ≈ pyrazole thiophene N furan 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 pyrrole / 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. pyridines 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 aromaticity 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 (ketone) 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 Isoxazole 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.
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