Synthesis of aromatic heterocycles SYNTHESIS OF AROMATIC HETEROCYCLES

34 Pages·2009·1.17 MB·English

Chapter 3
Synthesis of aromatic heterocycles
SYNTHESIS OF AROMATIC HETEROCYCLES
CONSTRUCTION OF THE RING SKELETON
I. Carbonyl condensation type reactions
II. Cycloadditions
a) with 1,3-dipoles
b) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion
Carbonyl condensations
a a
X
X
b b
X
X
X X
Strategy a) - 5-membered rings
1,4 dicarbonyl
X
X X=N: NH , RNH
3 2
H H H H H H
Pyrrole R-NH
2
O O O HN OH HO N OH - 2 H2O N
±H
±H
R R R
(Paal-Knorr Synthesis s 255)
Furan
H H H H H
- H O O
O O OH O ±H O OH 2
c.f. furan
Thiophene H H LR H H LH: Lawesons reagent
S
O O S S S
S
P OMe
MeO P
S
S
Strategy a) - 6-membered rings
1,5-dicarbonyl
X=N: NH
3
X X
H
NH
H 3
O O HO N OH - 2 H2O N
H
Strategy b
5-membered rings
X X
O
H H OH H OH
EWG H EWG H EWG EWG EWG
- 2 H O
HX 2
X
O O O HO X
±H H ±H X
H H
EWG: CN, COR etc.
X: NR; O, S
Enol
O
(or phenol)
HX X
HO
6-membered rings
X X
Enamine
(or aniline)
OH
H OH OH H
- 2 H O
H H H H 2
O H
N ±H ±H HO N N
O H O NH O NH H
2
I. Carbonyl condensation type reactions
II. Cycloadditions
a) with 1,3-dipoles
b) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion
1,3-Dipolar Cycloaddition
1,3-dipol
Only 5-membered rings
b
b
a
c
a c
d e
d e
Alkene / alkyne
Ex. ozonolysis
POCl R
3
R
R N
O 3
O N N N
O O O O O O - H2O R O R
O
nitriloxide isoxazole
Cycloaddition with ortho-Quinodimethanes
O
X S
O
- SO
2
X
Electrocyclic
X X X ring opening
- 2 HX
X
Diels-Alder
X
Ring formed carbocyclic
O
O
Br O
O
NaI O
O
Δ
N Br N
Me Me
N
Me
I. Carbonyl condensation type reactions
II. Cycloadditions
a) with 1,3-dipoles
b) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion
Generation of nitrenes
Δ or hν
R N N N R N N N R N (c.f. carbene)
- N
2
azide Nitrene R C
(1,3-dipol)
R
P(OEt)
3
O Ar
R O
N S
R N
O O
H O
B
React. of nitrenes
R'-N + R C-H R C N H
Insertion 3 3
R'
R'
N
Add. to double bonds R'-N + R C=CR R R
2 2
R R
R' R'
Dominating react alkyl
Rearrangement R C N C N
nitrenes
H R H
Abstraction R'-N + R C-H R'-N-H + R C
3 3
Dimerisation 2 R'-N R'-N=N-R'
Nitrene insertion - Heterocyclic synthesis
H
H +
N
N R
R
NO N N
H 2 H
H