Heterocyclic Chemistry

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1 Dr. P. Wipf Page 1 of 8 10/24/2009 eterocyclic Chemistry Most Common Aromatic Scaffolds Present in Bioactive Molecules S S S S rtl, 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, Properties, Reactivity and Reactions of eterocycles eterocycles can be classified into: π-excessive π-deficient π-excessive: the -- bonds not involved, yes, in the π-system excess electron density on carbons π-deficient: decreased electron density in carbons lectron-density surface encoded with the electrostatic potential lectrophilic substitution is most difficult at C-2 or C-4 electrophilic substitution is difficult also at C-3 cf. 2 lectron-density surface encoded with the ionization potential

2 Dr. P. Wipf Page 2 of 8 10/24/ C 3 C 3 C 2 C 2 C C pk a ~42 ~35 ~25 R + 1 pk unit/alkyl decreases with number of alkyls, thus penta-me ~ pk a ~ 6 pk a ~ pk a ~ 5 2 pk a ~ pk a ~ R 2 pk a ~ 10 Pyridine: lectrophilic Substitution + δ e.g. Friedel-Crafts on pyridine has not been achieved LA 2 2 S 4 S 3, Δ x Direct C-nitration of pyridine is very difficult to effect. Pyridine can be C-nitrated with nitric acid in sulfuric acid at 25 C 10 8 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.

3 Dr. P. Wipf Page 3 of 8 10/24/2009 Pyridine: ucleophilic Substitution u u Two modes possible: 1) addition - elimination 2) elimination - addition (via heteroarynes) Addition/elimination preferably on C-2/C-4 u 4 3 B - 2 Most acidic hydrogen ( 3 ) is removed?? - Kinetic Selectivity?? Pyridine: Reactions Me Me CuC C ote! is T formed in the reaction ow would you make this? 2 Me Me Me an aminoimidazoquinoxaline (IQx) MeIQ x one of the most potent mutagens known; rev/µg/plate in the Ames test (aflatoxin !)

4 Dr. P. Wipf Page 4 of 8 10/24/ Bierer, D..; 'Connell, J. F.; Parquette, J. R.; Thompson, C. M.; Rapoport,., "Regiospecific synthesis of the aminoimidazoquinoxaline (IQx) mutagens from cooked foods." J. rg. Chem. 1992, 57, 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

5 Dr. P. Wipf Page 5 of 8 10/24/2009 Pyrrole: lectrophilic Aromatic Substitution vs I I I I I 2 (4 eq) t, 0 C 80% Ac 2, Ac, -10 C 64% : 1 2 DMF, PCl 3 rt Me 2 aq. a 2 C 3 83% C 2, t 2 Ac, rt; 62% t2 Boc BS, TF -78 to rt Boc Pyrrole: lectrophilic Aromatic Substitution Cl 3 CCCl, t 2, rt; 79% CCl 3 90% C; 77% CCl 3 2 ame, Me rt; 89% Me Pyrrole: Alkylation/Regiocontrol R R Si(iPr) 3 BuLi RX Si(iPr) 3 F- TIPS shields from deprotonation at C-2's Muchowski Tetrahedron Lett. 1983, 24, Kozikowski J. rg. Chem , schenmoser elv. Chim. Acta , Stefan Chem. Ber , 169. Muchowski J. rg. Chem , BS (2 eq) Cu( 3 ) 2 2 TBAF, TF 2 TIPS TF, -78 C 78% TIPS Ac 2, rt; 77% TIPS rt; 100%

6 Dr. P. Wipf Page 6 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: Structural and electronic properties (cont): lectron-density surface encoded with the electrostatic potential Structural and electronic properties (cont): lectron-density surface encoded with the ionization potential

7 Dr. P. Wipf Page 7 of 8 10/24/2009 Chemical properties of quinolines and isoquinolines 2-Cyanoquinoline is obtained from quinoline -oxide by treatment with cyanide/benzoyl chloride with deoxygenation and alpha-substitution. -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 KC Ph 3 P PhCCl C via C Ph Syntheses of Methoxatin Zhang, Z.; Tillekeratne, L. M. V.; udson, R. A., Synthesis of isomeric analogs of coenzyme pyrroloquinoline quinone (PQQ). Synthesis 1996, MacKenzie, A. R.; Moody, C. J.; Rees, C. W., Synthesis of the bacterial coenzyme methoxatin. Tetrahedron 1986, 42, Buchi, G.; Botkin, J..; Lee, G. C. M.; Yakushijin, K., A synthesis of methoxatin. J. Am. Chem. Soc. 1985, 107, Gainor, J. A.; Weinreb, S. M., Synthesis of the bacterial coenzyme methoxatin. J. rg. * Chem. 1982, 47, endrickson, J. B.; DeVries, J. G., A convergent total synthesis of methoxatin. J. rg. * Chem. 1982, 47, C C 2 C 2

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