第18-3 六元杂环化合物

[H] N [H] = Na/EtOH, H2/Pt N H
六氢吡啶，哌啶 (piperidine)
3、Synthesis of pyridine ring system

韩奇（Hantzsch A）合成法
R'' CHO + R O NH3 O R R N H R O C OR' R'' R'OOC COOR'
PhLi N N Li Ph 110oC 8h N Ph
（3）Oxidation
oxidation of side chain oxidation
H3C N
oxidation of pyridine ring
oxidation of nitrogen atom
CH 3 N
HNO 3 N
COOH
N
Explain:
2-,6-position
H N Nu H Nu N H Nu N H Nu N H N Nu H NU N H Nu N N H Nu H NU
Nu 3-,5-position
-
N
4-position
N
H
H N
H Nu N N
Nu
Nu
N
H NU N H NU
a、Leaving-group-replaced nucleophilic substitutions
O R'O C
1,4-二氢吡啶 (1,4-dihydropyridine)
NO 2
EtOOC H 3C N H
COOE t CH 3
尼群地平(nitrendipine)
Review: the synthesis of pyrrole derivatives
R O O R + R'NH2 H+ R
N N NH 2 NH 2
（3）Oxidation reactions

Oxidation occurs on benzene ring.
KMnO 4 N H+
N COOH COOH
KMnO 4 N H+
COOH N COOH
（4）Reduction reactions

Reduction maily occurs on pyridine ring.
N Cl
CH3OH,
N
OCH 3
Br Br N
NH3, H2O 160oC
NH 2 Br N
b、Hydrogen-replaced nucleophilic substitutions
NaNH 2 N Ph N(CH 3)2 N NH - Na + H2O N NH 2
齐齐巴宾反应（Chichibabin reaction）
The activity of electrophilic substitutions :
>
N H O
>
S
>
>
N
The electrophilic substitutions of pyridine mainly occur on 3-,5-positions.
Explain:
2-,6-position
N
+ H
E H
+
N
H E H E N N N
+
H E H E
E+
N
3-,5-position
N
E
H
E
H
E
H
E
4-position
N N + N
H
H N
H E N N
+
E
E
H E
N +
H E N
Examples:
Cl 2, AlCl3 100oC Br 2, Cat. 300oC
N N
Cl
Br
N
浓 H2SO4 HgSO4,220oC 浓 H2SO4,浓HNO3 300oC, 1d
+
Ph
O +
OR' Ph O
NH4OAc
Summary:
structure electrophilic substitution
pyridine
chemical properties
nucleophic substitution
oxidation
reduction
home
synthesis
Hantzsch method
. .
. .
第十八章 杂环化合物 Chap 18 Heterocyclic Compounds
N ..
. .
任课教师: 石 枫
所属单位:化学化工学院
1
2
N N CH 3
尼古丁(nicotine)
COOH N
烟酸 (nicotinic acid)
§18-3 六元杂环化合物
(Six-membered heterocyclic compoundddition R R'' R
O C OR' R
-H2O
O H2N
R'' COOR' 1)H2O R 2) -CO2 R N R
Improvement of Hantzsch method：
Ar CHO CH3 R + O NH4OAc O Ar CH3 MWI R H2O R N R
O O
HO H3CO
H3CO N OCH3
N
奎宁 (quinine)
黄连素 (berberine )
二、喹啉和异喹啉 (quinoline and isoquinoline)
1、Structure
. . . . . . .
N
.
.
. .
.
..
.
. . .
.
.
.
. . N .
quinoline
isoquinoline
N CH 3
HNO 3
COOH N

Pyridine ring is more stable than benzene ring in acidic oxidant.
N KMnO 4 H
H2O2 N HOAc N O
+
N
COOH
吡啶-N-氧化物 (pyridine-N-oxide)
Application： Change the position of electrophilic substitution in pyridine to 4-position.
一、吡啶 (pyridine) 1、Structure of pyridine
. . . . . .
.
sp
2
. p . . sp2
. . N
sp2
N ..
N
2、Chemical properties of pyridine
electrophilic substitution nucleophic substitution pyridine ring pyridine oxidation reduction reaction with electrophic reagents
Review:
Cl
Cl NH 2
NH 2
NO 2 2
NO 2 NO
2
NH 3 NH
NO
3
NO NO 2 2
NO NO 22
OCH OCH 3 3 Cl Cl
Cl Cl Cl Cl CH CH 3ONa 3ONa
CH CH 3OH 3OH
NO NO 2 2 Cl
NO NO 2 2 OCH
CH3ONa
[H] N [H] N NH [H] = Sn/HCl, Na/EtOH, 2 mol H2/Pt N H
end
Exercise:
2. Synthesizing
Ph
Analysis: CH 3
CH 3
end
N
Ph
CH 3 CH 3 CHO CH 3 Ph
Ph
N
Ph
Ph
O
+ O NH4OAc
CH 3 ROOC Ph N
ROOC COOR CH 2 Ph Ph
CH 3 CHO H2C O
COOR H3C
COOR
N N
SO3H
NO 2
Examples:
Br 2, HOAc
N NH 2
Br N NH 2
20oC
Br2, Cat
N
Comparison ：
Br N
300 C
o
Br
Br2/H2O
Br NH 2 NH 2 Br
（2） Reactions with nucleophilic reagents
i） The activity of pyridine on nucleophilic substitutions is higher than benzene. ii） The nucleophilic substitutions of pyridine mainly occur on 2-,6- and 4positions.
S. Tu et al., Tetrahedron, 2007, 63, 381-388.
Ar CHO CH3 Ar' + O NH4OAc O O Ar MWI DMF Ar' N O
茚-1,3-二酮
茚并吡啶
(indene-1,3-dione)