Heterocyclic Chemistry Π-Excessive Π-Deficient

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

Most Common Aromatic Scaffolds Present in Bioactive Molecules

H N S N N H N N

N N S N N N O N N N N H H

O O O H H H N HN N N N N N O N N H H O

O O O N N N N O N N S N

H O N H O N N O O O HN NH S N O N H H O 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 N excess electron density on carbons H

π-deficient: Electron-density decreased electron density in carbons surface encoded with N the electrostatic potential

N N N N

0.16 0.05 Electrophilic substitution is most difficult at C-2 or C-4 electrophilic substitution is difficult also at C-3 N 0.14 -0.54 cf.

NO2

Electron-density surface encoded with the ionization potential Dr. P. Wipf Page 2 of 8 10/24/2009 O

CH3 CH3 CH2 CH2 CH CH N N N H2 H2 H

pKa 11 8 5 ~42 ~35 ~25

R + 1 pK unit/alkyl N decreases with number of alkyls, thus penta-Me ~ 8.5

+ + NH2 H NH2 H NH3

N pKa ~ 6 N pKa ~ 0-1 N H H

NO2 NO2

N NH2

pKa ~ 5 pKa ~ 2-3

H+

pK ~ 6 N NH2 a N NH2 N NH2 H H

NH pKa ~ 10 R NH2

Pyridine: Electrophilic Substitution

H E+ E

N N

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

H LA N E H

Br Br Br Br2 H SO •SO , Δ N 2 4 3 x N 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. Dr. P. Wipf Page 3 of 8 10/24/2009 Pyridine: Nucleophilic Substitution

Nu H Two modes possible: N N Nu 1) addition - elimination 2) elimination - addition (via heteroarynes)

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

H Nu N

H4 H3 B-

N H2 N N N

3 Most acidic hydrogen (H ) is removed ?? - Kinetic Selectivity??

Pyridine: Reactions

Br MeO OMe

N N

CN CuCN N

NH2

NH2 - NH2 N N

Note! Br is NOT formed in the reaction - NH2 N N N

How would you make this?

MeIQx NH2 N N Me N Me one of the most potent mutagens known; N 100 000 rev/µg/plate in the Ames test Me (aflatoxin 10 000!) an aminoimidazoquinoxaline (IQx) Dr. P. Wipf Page 4 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 5 of 8 10/24/2009 Pyrrole: Electrophilic Aromatic Substitution

E E H H E E E vs N H N H N H N N H H H H H

I I NO2 I2 (4 eq) AcONO2, + I EtOH, 0 °C AcOH, -10 °C N I N N NO2 N H 80% H 64% H 4 : 1 H

DMF, POCl3 aq. Na2CO3 H H N rt N 83% N H H NMe2 H O

CH2O, Et2NH NBS, THF Br N AcOH, rt; 62% N N -78 to rt N Br H H NEt2 Boc Boc

Pyrrole: Electrophilic Aromatic Substitution

O2N Cl3CCOCl, 90% HNO3 CCl3 CCl3 N Et2O, rt; 79% N -50 °C; 77% H H O N H O

NaOMe, MeOH rt; 89% O2N OMe N H O

Pyrrole: Alkylation/Regiocontrol

R R

BuLi F- N N N RX Si(iPr)3 Si(iPr)3 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 NO2 NO2 NBS (2 eq) Cu(NO3)2 TBAF, THF

THF, -78 °C Ac2O, rt; 77% rt; 100% N 78% N N N TIPS TIPS TIPS H Dr. P. WipfReactions of Quinolines & Isoquinolines Page 6 of 8 10/24/2009 • 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:

1.37 1.38 -0.15 0 -0.11 -0.36 -0.55 0.5 -0.18 -0.36 0.36 1.42 -0.05 1.36 0.66 -0.12 -0.01 0.34 -0.11 N -0.54 -0.41 N -0.63 -0.17 0.24 1.36 1.32 1.42 1.37

• 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 Dr. P. Wipf Page 7 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

MCPBA KCN

N Ph3P N PhCOCl N CN O

via N CN 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 CO2H

O N CO2H O Dr. P. Wipf Page 8 of 8 10/24/2009