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
X
H+ 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
X
R-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 N - N-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 N
O
NN
Safe equiv. of phosgene
Reaction with electrophiles on C - protonation (H / D exchange)
N
NH
D+ / D2O N
NH
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
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.
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
Acylation
No 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
Condensation reactFew ex. comp. to pyrrole / thiophene / furan
N
STMSRCHO N
STMS
RHO
N
SHO
R
Ipso subst.
Reaction with Nucleophiles
No 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
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
H
Y
Aqueous baseOxidizing agent N
X Y
N
O
Me
OH 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
N-heterocyclic carbenes as ligands in transition metal cat react.
Modified properties comp. to phosphile ligands
Amino 1,3-azolesAll 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
NH2
X 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
N CTs isocyanate
Base
N CTs
EWG
R'
N
EWG
Ts
R'HH
H
c.f. van Leusen synth. pyrrole
N
EWG
Ar
R'HH
NH
R' EWG
CO2HH2N
N
HN
Histidine (His)
Bioactive 1,3-azoles
H2N
N
HN
Histamine
Epothilone A: R=HEpothilone B: R=MeFrom myxobacteriaPotential anticancer drugsMechanism ≈ taxol
Imidazol common in nature
N
S
N
N
HO
H2N
NH2
Thiamin(Vitamin B1)
Co-enzyme in biochem. prosesses:
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
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
CycloadditionsNo ex. of 1,2-azoles as dienes in DA
N
N
N
NNH
H2N
CO2Et
EtO2C CO2EtN
N
NEtO2C
EtO2CCO2Et
NH2NH
N
N
N NH
NH
H
NH2
-NH3
N
N NH
N
CO2Et
EtO2C
CO2Et
EtO2C- EtOCOCN
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
R
NH2HO N
O
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