Heterocycles cont. more than 2 heteroatoms in one ring
Chapt. 26
5-membered rings
Triazoles and tetrazoles
N N
N
N
N
H
N N
N
N
H
N
H
X=O, S
X
N
N
N
N N
N
X
N N
X
N
N
X
X
N
Only X=S
unstable X=O
6-membered rings
Triazines and tetrazines
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
unknown
N
N
5-membered rings
Triazoles and tetrazoles (pentazoles highly unstable)
More acidic - less basic comp to diazoles
N
H
pKa (base): ca 0 (NB aromaticity)
pKa (Acid): 17.5
N
N
H
N
H
pKa (base): 2.5
pKa (Acid): ca 12
pKa (base): 7.1
pKa (Acid): 14.2
N N
N
H
N
N
N
N
H
N NH
N
N
NH
N
pKa (base): 1.2
pKa (Acid): 9.4
pKa (base): 2.2
pKa (Acid): 10.3
N N
N
N
H
N N
NH
N
pKa (base): ?
pKa (Acid): 4.9
Bioisostere - CO2H
1,2,3-Triazole
N
NH
N
N
N
N
H
More aromatic
(calculations)
React. at N
N
NH
N
N
N
N
H
pKa (base): 1.2
pKa (Acid): 9.4
- Also difficult to alkylate neutral cond
Base
N
N
N
N
N
N
R-X
N
N
N
R
+
N
N
N
H
N
N SiMe3
N
N
NH
N
RCOX
RX
N
N R
N
N
N SiMe3
N
COR
N
N SiMe3
N
R
- Me3Si+
N
N
N
R
- Me3Si+
N
N COR
N
N
N
N
COR
1,2,3-Triazole
React. at C
Br
N
N
N
R
N
N
N
R
Br2
N
N
N
Br
Br2
N
N R
N
N
N R
N
+ Fe-cat.
less reactive
O2N
N
N
N
HNO3 / H2SO4
Li N
R
N
N
N
NO2
+ N2
r.t.
N
N
N
R
n-BuLi
< -20 oC
Li
< -20 oC
IZn
Sn-comp. less stable
N
N
N
R
MeI
< -20 oC
ZnX2
N
N
N
R
Negishi,
higher temp
Me
N
N
N
R
Benzo-1,2,3-Triazole
N
N
N
N
R
usefull synthetic intermediates
N
N
N
N
R
N
N
N
R
R'
R'
R
Stabilized cation
Stabilized anion
Nu
N
R''
R'
Good leaving group
Reviews, see for instance:
Tetrahedron 2005, 2555
N
N
N
H
1) CH2O
2) SOCl2
N
N
N
N
N
BuLi
N
N
δ+
N
N
N
H
Li
N
R-X
δN
Cl
R2
R
N
R2MgX or R2ZnX
N
N
N
R
N
LiAlH4 or NaBH4
R
N
1,2,4-Triazole
React. at N
N
lone pair - lone
pair interact.
HN
N
N
H
RCOCl
RX
Base
Me3O+
N
N
N
R
N
N
N
N
COR
N
BF4-
Me
Me
N
Hydrol.
N
N
N
N
COR
N
React. at C
Br
N
N
H
N
Br2, Base
Br
N
N
R
N n-BuLi
N
N
N
H
N
N
H
N
N
Cl
N
Li
N
R
N
N
heat
Cl
N
N
Rel. stable
N
Cl2, Base
H2N
N
R
N
Diazotation etc
N
H
N
N N
N N
NH2
Me2N
N
N
N
N
R
TMS-Cl, pyridine
Nu
N
NMe2
N
N
N
N
R
Nu
N
N
N
N
R
Small diff. stab. taut.
Tetrazole
N N
NH
N
N N
N
N
H
Bioisostere - CO2H
pKa (base): ?
pKa (Acid): 4.9
React. at N
N N
NH
R
N
N N
N
R
N
H
N N
N SnBu3
R
N
R-X
N N
N SnBu3
R
N
R
Base
R-X
N N
N
R
N
R
+
N N
N R
R
N
R / Selectivity
Ca same selectivity in acylations
N N
N
R
N
R
React. at C
N N
N
N
R
N
N N
N
X
N
R
N N
N
N
R
Nu
Me2NH, HCl, CH2O
"Mannich"
N N
N
Nu
N
R
BuLi
- 65 oC
Li
N N
N
N
R
Also coupling react.
N N
N
N
R
N N
N
E
N
R
X2 etc
N N
N
X
N
R
N N
N
H2N
N
H
N2
-H+
> - 50 oC
N
Li N
R
+ N2
N N
N
N
H
N N
N N
N
N
3 N2 + C
Explosive
Oxadiazoles and thiadiazoles
X=O, S
X
N
N
N
N N
N
X
N N
X
N
N
X
X
N
Only X=S
unstable X=O
(thiatriazole)
O
O
- No acidic NH
-Generally low basicity
(cf triazoles)
-Some examles N-quart.
-Few ex. Introd of E-fils on C
-Prone to Nu attack
R
N
N
Sydnones
Mesoionic
Aromaticity (NMR shifts, bond lenghts)
N N
N
S
N
S
N
S
O
N
Ring opening (esp. O-cont. rings)
Reactiv. towards Nu (piperidine)
Cl
N
Cl
N N
S
N
Cl
S
N
S
N
Most aromatic
oxadiazole
H
N
C-lithiation easy, but often low stab of lithiated prod
O
N
aq.NaOH,
r.t.
t 1/2 = 4.3 min
N
N
ONa
6-membered rings
Triazines and tetrazines
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
unknown
Highly activated for Nu attack
No simple react with electrophiles
N
R
N
N
NH3 (l)
N
N
R
H
N
N
H
N
NH2
N
[ox]
NaNH2 in react with pyridine and diazines
N
R
N
N
NH2
N
N
N
N
X
R
N
N
MeS
SMe
N
X
R
N
N
RONa
(or amine)
SMe
MeLi
H+
N
N
N
OR
N
HN
N
N
SMe
N
Me
Nu attack on N
Nu
Nu
N
N
N
+ N2
NH
Diels Alder react. Leading to azines with fewer N
(see synth of pyridines, diazines)