Heterocyclic Chemistry

N NH N

HN

N

S

S N N

N NH

N N

N NH

N O

NH

OHN HN

NH

O

O

HN

NN

HN

N

O

O

O N

O ON

N

ON

S

N

N

N

S NH

NHN

HN

O

ONH

O

HN O

N

NH

OO O

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.

Most Common Aromatic Scaffolds Present in Bioactive Molecules

Properties, Reactivity and Reactions of Heterocycles• Heterocycles can be classified into:π-excessiveπ-deficient

NH

π-excessive:the -NH- bonds not involved, N yes, in the π-systemexcess electron density on carbons

π-deficient:decreased electron density in carbons

N

Electron-density surface encoded with the electrostatic potential

N N N N

N

0.16

-0.54

0.050.14

Electrophilic substitution is most difficult at C-2 or C-4electrophilic substitution is difficult also at C-3

cf.NO2

Electron-density surface encoded with the ionization potential

Dr. P. Wipf Page 1 of 8 10/24/2009

NH2

NH2

O

NH

pKa 11 8 5

CH3 CH3 CH2 CH2 CH CH

~42 ~35 ~25

NR + 1 pK unit/alkyl

decreases with number of alkyls, thus penta-Me ~ 8.5

N

NH2

pKa ~ 6

H+

pKa ~ 0-1

H+

NH

NH2

N

NO2

pKa ~ 5

NO2

NH2

pKa ~ 2-3

N NH2 pKa ~ 6

H+

NH

NH2 NH

NH2

NH

R NH2pKa ~ 10

NH

NH3

Pyridine: Electrophilic Substitution

N

E+

N

HE

e.g. Friedel-Crafts on pyridine has not been achieved

N

LAH

δ

NHE

N N

BrBr2H2SO4•SO3, Δx N

BrBr

Direct C-nitration of pyridine is very difficult to effect. Pyridine can be C-nitrated with nitric acid insulfuric acid at 25 °C 108 times more slowly as compared with benzene. Thus, the C-nitration of pyridinehas been effected only under extremely drastic conditions; i.e. treatment of pyridine with an alkali metal nitrate infuming sulfuric acid at 300 °C is reported to afford 3-nitropyridine in 14% yield.

Dr. P. Wipf Page 2 of 8 10/24/2009

Pyridine: Nucleophilic Substitution

N NHNu

NuTwo modes possible:1) addition - elimination2) elimination - addition (via heteroarynes)

Addition/elimination preferably on C-2/C-4

N

HNu

N

H4

H3

H2

B-

N N N

Most acidic hydrogen (H3) is removed ?? - Kinetic Selectivity??

Pyridine: Reactions

N

Br

N

OMe

CuCN

N

CN

N

NH2- NH2

- NH2

N

Br

N

N

NH2

Nis NOT formed in the reactionNote!

MeO

How would you make this?

MeIQx

one of the most potent mutagens known;100 000 rev/µg/plate in the Ames test (aflatoxin 10 000!)

N

NMe

Me

NN

Me

NH2

an aminoimidazoquinoxaline (IQx)

Dr. P. Wipf Page 3 of 8 10/24/2009

- 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

Dr. P. Wipf Page 4 of 8 10/24/2009

NH

I2 (4 eq)

EtOH, 0 °C80%N

HI

II

I

AcONO2,

AcOH, -10 °C64% N

HNO2

+

NH

NO2

4 : 1

Pyrrole: Electrophilic Aromatic Substitution

NH

EH N

H

EH N

H

EH

vsNH

EH

NH

EH

NH

DMF, POCl3

rt NH

H

NMe2

aq. Na2CO3

83% NH

H

O

NH

CH2O, Et2NH

AcOH, rt; 62% NH NEt2

NBoc

NBS, THF

-78 to rt NBoc

BrBr

Pyrrole: Electrophilic Aromatic Substitution

NH

Cl3CCOCl,

Et2O, rt; 79% NH O

CCl390% HNO3

-50 °C; 77% NH O

CCl3

O2N

NH O

OMe

O2N

NaOMe, MeOHrt; 89%

Pyrrole: Alkylation/Regiocontrol

NSi(iPr)3

BuLiRX

F-NSi(iPr)3

R

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.

NH

R

NTIPS

NBS (2 eq)

THF, -78 °C78%N

TIPS

BrBr Cu(NO3)2

Ac2O, rt; 77% NTIPS

NO2 TBAF, THF

rt; 100%NH

NO2

Dr. P. Wipf Page 5 of 8 10/24/2009

Reactions of Quinolines & Isoquinolines• 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:

NN

-0.63

0.34

-0.36

0-0.11

0.66

-0.41-0.01

-0.18-0.15

1.321.37

1.42

1.37

-0.54

0.24

0.36-0.55

0.5

-0.12

-0.17-0.11

-0.05

-0.36

1.421.36

1.36

1.38

Electron-density surface encoded with the electrostatic potential

• Structural and electronic properties (cont):

• Structural and electronic properties (cont):

Electron-density surface encoded with the ionization potential

Dr. P. Wipf Page 6 of 8 10/24/2009

• 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 1,2-dihydroquinoline, which eliminates benzoic acid

N

MCPBA

Ph3P N

O

KCN

PhCOCl N CN

via N CNO

O

Ph

Syntheses of MethoxatinZhang, 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.

*

*

N CO2H

NHHO2C

CO2H

OO

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