Dr. P. Wipf
Page 1 of 8
Heterocyclic Chemistry
Most Common Aromatic Scaffolds Present in Bioactive Molecules
H
N
N
H
N
N
S
S
N
N
N
N
O
N
N
N
H
N
O
N
H
N
O
H
N
HN
O
N
H
N
S
H
N
HN
O
N
O
H
N
N
O
N
N
O
H
N
N
H
O
O
N
H
N
O
N
H
N
N
O
N
N
O
N
S
O
O
O
O
NH
N
H
N
Ertl, P.; Jelfs, S.; Muehlbacher, J.; Schuffenhauer, A.; Selzer, P., "Quest for the rings. In silico exploration of ring universe to identify novel bioactive heteroaromatic scaffolds." J.
Med. Chem. 2006, 49, 4568-4573.
Properties, Reactivity and Reactions of Heterocycles
• Heterocycles can be classified
into:
π-excessive
π-deficient
π-excessive:
the -NH- bonds not involved, N yes, in the π-system
excess electron density on carbons
N
H
π-deficient:
decreased electron density in carbons
N
N
N
Electron-density
surface encoded with
the electrostatic
potential
N
0.16
N
-0.54
0.05
0.14
Electrophilic substitution is most difficult at C-2 or C-4
electrophilic substitution is difficult also at C-3
cf.
NO2
Electron-density surface
encoded with the ionization
potential
N
10/24/2009
Dr. P. Wipf
Page 2 of 8
O
pKa
CH3 CH3
N
H2
N
H2
N
H
11
8
5
CH2 CH2
~42
CH CH
~35
~25
+ 1 pK unit/alkyl
R
N
decreases with number of alkyls, thus penta-Me ~ 8.5
NH2
H+
pKa ~ 6
N
NH3
H+
NH2
pKa ~ 0-1
N
H
N
H
NO2
NO2
N
NH2
pKa ~ 2-3
pKa ~ 5
H+
NH
R
pKa ~ 6
NH2
N
N
H
NH2
N
H
NH2
pKa ~ 10
NH2
Pyridine: Electrophilic Substitution
H
E
E+
N
N
e.g. Friedel-Crafts on pyridine has not been achieved
δ
N
N
LA
H
H
E
Br
Br2
N
H2SO4•SO3, Δx
N
Br
Br
N
Direct C-nitration of pyridine is very difficult to effect. Pyridine can be C-nitrated with nitric acid in
sulfuric acid at 25 °C 108 times more slowly as compared with benzene. Thus, the C-nitration of pyridine
has been effected only under extremely drastic conditions; i.e. treatment of pyridine with an alkali metal nitrate in
fuming sulfuric acid at 300 °C is reported to afford 3-nitropyridine in 14% yield.
10/24/2009
Dr. P. Wipf
Pyridine: Nucleophilic Substitution
Nu
H
Nu
N
N
Page 3 of 8
Two modes possible:
1) addition - elimination
2) elimination - addition (via heteroarynes)
Addition/elimination preferably on C-2/C-4
H
Nu
N
H4
H3
N
B-
H2
N
Most acidic hydrogen (H3) is removed
N
N
?? - Kinetic Selectivity??
Pyridine: Reactions
Br
OMe
MeO
N
N
CN
CuCN
N
NH2
NH2
- NH2
N
N
Note!
Br
- NH2
N
is NOT formed in the reaction
N
N
How would you make this?
N
Me
NH2
N
N
MeIQx
Me
N
Me
an aminoimidazoquinoxaline (IQx)
one of the most potent mutagens known;
100 000 rev/µg/plate in the Ames test
(aflatoxin 10 000!)
10/24/2009
Dr. P. Wipf
Page 4 of 8
- Bierer,
D. E.; O'Connell, J. F.; Parquette, J. R.; Thompson, C. M.; Rapoport, H., "Regiospecific
synthesis of the aminoimidazoquinoxaline (IQx) mutagens from cooked foods." J. Org. Chem.
1992, 57, 1390-1405.
• The regioselective synthesis of 6 MeIQx was accomplished with this general
strategy
• The key step involves the dehydrobrominative photocyclization (in 25-90% yield) of
imidazolylpyrazinylethylenes - a previously unexplored transformation
10/24/2009
Dr. P. Wipf
Page 5 of 8
Pyrrole: Electrophilic Aromatic Substitution
E
E
E
N
H
N
H
H
I
I
I
I2 (4 eq)
NO2
N
H
N
H
NO2
H
N
H
83%
NMe2
N
H
4 : 1
aq. Na2CO3
H
rt
+
CH2O, Et2NH
N
H
N
H
N
H
H
AcOH, -10 °C
64%
N
H
DMF, POCl3
N
H
vs
AcONO2,
EtOH, 0 °C
80%
I
N
H
N
H
H
H
H
E
E
O
NBS, THF
N
H
AcOH, rt; 62%
N
Boc
NEt2
Br
-78 to rt
Br
N
Boc
Pyrrole: Electrophilic Aromatic Substitution
Cl3CCOCl,
N
H
CCl3
N
H
Et2O, rt; 79%
O
O2N
90% HNO3
CCl3
-50 °C; 77%
N
H
O
NaOMe, MeOH
rt; 89%
O2N
OMe
N
H
O
Pyrrole: Alkylation/Regiocontrol
R
N
Si(iPr)3
BuLi
RX
R
F-
N
Si(iPr)3
N
H
TIPS shields from deprotonation at C-2's
Muchowski Tetrahedron Lett. 1983, 24, 3455.
Kozikowski J. Org. Chem. 1984 49, 3239.
Eschenmoser Helv. Chim. Acta 1987 70, 1115.
Stefan Chem. Ber. 1989 122, 169.
Muchowski J. Org. Chem. 1990 55, 6317.
Br
Br
N
TIPS
NBS (2 eq)
THF, -78 °C
78%
Cu(NO3)2
N
TIPS
Ac2O, rt; 77%
NO2
N
TIPS
NO2
TBAF, THF
rt; 100%
N
H
10/24/2009
Dr. P. WipfReactions of Quinolines & Isoquinolines Page 6 of 8
• Structural and electronic properties:
• Quinoline is a π-deficient heterocycle, related to pyridine but with a slightly lower pKa = 4.9
(pyridine has a pKa = 5.2). The pKa of isoquinoline is 5.1.
• The following electrostatic charges and bond distances were calculated at the DFT/BLY3P/
6-31G* level:
1.38
1.37
-0.15
-0.18
-0.11
0
-0.36
-0.36
0.66
-0.01
-0.41
1.42
0.5
-0.55
0.36
-0.05
-0.12
0.34
-0.11
N
-0.17
-0.63
1.36
N -0.54
0.24
1.36
1.37
1.32
1.42
• Structural and electronic properties (cont):
Electron-density surface encoded with
the electrostatic potential
• Structural and electronic properties (cont):
Electron-density surface encoded with the
ionization potential
10/24/2009
Dr. P. Wipf
Page 7 of 8
• Chemical properties of quinolines and isoquinolines
• 2-Cyanoquinoline is obtained from quinoline N-oxide by treatment with cyanide/benzoyl
chloride with deoxygenation and alpha-substitution. O-Acylation is the first step; this is
followed by addition of cyanide to the 1-benzyloxy quinolinium ion to give the 1,2dihydroquinoline, which eliminates benzoic acid
MCPBA
N
KCN
N
Ph3P
PhCOCl
N
CN
O
via
CN
N
O
Ph
O
Syntheses of Methoxatin
*
*
Zhang, Z.; Tillekeratne, L. M. V.; Hudson, R. A., “Synthesis of isomeric analogs of coenzyme
pyrroloquinoline quinone (PQQ).” Synthesis 1996, 377-382.
MacKenzie, A. R.; Moody, C. J.; Rees, C. W., “Synthesis of the bacterial coenzyme
methoxatin.” Tetrahedron 1986, 42, 3259-3268.
Buchi, G.; Botkin, J. H.; Lee, G. C. M.; Yakushijin, K., “A synthesis of methoxatin.” J. Am.
Chem. Soc. 1985, 107, 5555-5556.
Gainor, J. A.; Weinreb, S. M., “Synthesis of the bacterial coenzyme methoxatin.” J. Org.
Chem. 1982, 47, 2833-2837.
Hendrickson, J. B.; DeVries, J. G., “A convergent total synthesis of methoxatin.” J. Org.
Chem. 1982, 47, 1148-1150.
HO2C
NH
O
CO2H
N
O
CO2H
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Dr. P. Wipf
Page 8 of 8
10/24/2009