1II. Special TopicsPossible Topics:• heterocyclic chemistry• pericyclic chemistry [Woodward-Hoffmann Rules]• medicinal chemistry• organometallic chemistry• combinatorial chemistry• microwave chemistryII-A. HETEROCYCLIC CHEMISTRYDr. P. WipfChem 23204/9/20072Dr. P. WipfChem 23204/9/20073Dr. P. WipfChem 23204/9/20074Dr. P. WipfChem 23204/9/20075Dr. P. WipfChem 23204/9/20076Dr. P. WipfChem 23204/9/20077Dr. P. WipfChem 23204/9/20078Dr. P. WipfChem 23204/9/20079Dr. P. WipfChem 23204/9/200710Dr. P. WipfChem 23204/9/200711Dr. P. WipfChem 23204/9/200712Dr. P. WipfChem 23204/9/200713Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J., "Asymmetricsynthesis of active pharmaceutical ingredients." Chem. Rev. 2006, 106,2734-2793.Dr. P. WipfChem 23204/9/200714Dr. P. WipfChem 23204/9/200715The Heterocyclic Chemistry of Azaindoles• Structural and electronic properties:• Azaindoles, or more correctly pyrrolopyridines, are π-deficient heterocycles, related topyridine & pyrrole but with a broader variation of pKa’s:• These different pKa’s illustrate the push-pull interactions between the two parent rings; for5- and 6-azaindoles, this is reminiscent of 4-aminopyridine (pKa 9.1), and for 4- and 7-azaindoles, 2-aminopyridine (pKa 7.2) could be used as a comparison.• The azaindole skeleton is only present in nature as fused polycyclic derivatives, such asthe variolins.4-azaindole1H-pyrrolo[3,2-b]pyridinepKa = 6.945-azaindole1H-pyrrolo[3,2-c]pyridinepKa = 8.266-azaindole1H-pyrrolo[2,3-c]pyridinepKa = 7.957-azaindole1H-pyrrolo[2,3-b]pyridinepKa = 4.59Dr. P. WipfChem 23204/9/200716• The following electrostatic charges and bond distances were calculated at theDFT/BLY3P/6-31G* level:• Structural and electronic properties (cont):• Structural and electronic properties (cont):Electron-density surface encodedwith the electrostatic potential4 56 7Dr. P. WipfChem 23204/9/200717• Structural and electronic properties (cont):Electron-density surface encoded with theionization potential4 56 7• Structural and electronic properties (cont):• HOMO and LUMO as calculated at the DFT/BLY3P/6-31G* level:4 56 7Dr. P. WipfChem 23204/9/200718• Structural and electronic properties (cont):• The electrophilic frontier density measures the susceptibility of the substrate to attack by an electrophile. Itreveals reactive sites based on the electron distribution of a set of active orbitals near the HOMO. It is especiallyuseful for large molecules where several orbitals may have energies nearly equal to the HOMO [K. Fukui, et. al., J.Chem. Phys., 11, 1433-1442 (1953)]. The susceptibility to an electrophilic attack is generated by a MOPAC/PM3wavefunction for the chemical sample, at a geometry determined by performing an optimize geometry calculationin MOPAC using PM3 parameters.• Structural and electronic properties (cont):• The nucleophilic frontier density measures the susceptibility of the substrate to attack by anucleophile. It reveals reactive sites based on the electron distribution of a set of active orbitals nearthe LUMO. It is especially useful for large molecules where several orbitals may have energies nearlyequal to the LUMO.Dr. P. WipfChem 23204/9/200719• Chemical properties of azaindoles• Reactions with electrophilic reagents take place with substitution at C-3 or by addition to thepyridine nitrogen. All azaindoles are much more stable to acid than indoles, no doubt due to thediversion of protonation to the pyridine nitrogen, but the reactivity toward electrophilic attack at C-3 isonly slightly lower than in indoles. Alkylation under neutral conditions results in quaternization of thepyridine nitrogen, and alkylation with sodium salts allows N-1 alkylation. Acylation under mildconditions also occurs at N-1. For 7-azaindole, electrophilic substitution can be summarized asfollows:• Chemical properties of azaindoles• Nucleophilic displacement of halogen alpha- and gamma- to the pyridine nitrogen canbe carried our under vigorous conditions or long reaction times. Reaction of 4-chloro-7-azaindole with a secondary amine results in normal substitution of the halogen butreaction with primary amines gives 5-azaindole rearrangement products by the sequenceshown below:Dr. P. WipfChem 23204/9/200720• Chemical properties of azaindoles• The reactivity of 4-chloro-1-methyl-5-azaindole toward nucleophilic substitution ofchlorine by piperidine can be compared with that of some related systems: it issignificantly less reactive than the most closely related bicyclic systems, probably due toincreased electron density in the six-membered ring resulting from donation from N-1(J. Org. Chem. 1982, 47, 1500; Bull. Soc. Chim. Fr. 1973, 10, 511).Relative rates for nucleophilic displacement with piperidine in MeO(CH2)2OH at 100°C:• Metalations of azaindolesTetrahedron 1997, 53, 3637Dr. P. WipfChem 23204/9/200721• Metalations of azaindolesL'Heureux, A.; Thibault, C.; Ruel, R. "Synthesis of functionalized 7-azaindoles via directed ortho-metalations." Tetrahedron Letters2004, 45, 2317-2319.Dr. P. WipfChem 23204/9/200722Syntheses of AzaindolesThe earliest synthesis of this heterocycle dates back to 1943(Chem. Ber. 1943, 76, 128). To date, the most commonsynthetic approaches include the Madelung-typecyclization, a Reissert-type procedure, the Leimgruber-Batcho reaction, a Lorenz-type cyclization, and Pd-catalyzed reactions starting from iodoaminopyridines.Dr. P. WipfChem 23204/9/200723Trejo, A.; Arzeno, H.; Browner, M.; Chanda, S.; Cheng, S.; Comer, D.D.; Dalrymple, S. A.; Dunten, P.; Lafargue, J.; Lovejoy, B.; Freire-Moar, J.; Lim, J.; McIntosh, J.; Miller, J.; Papp, E.; Reuter, D.;Roberts, R.; Sanpablo, F.; Saunders, J.; Song, K.; Villasenor, A.;Warren, S. D.; Welch, M.; Weller, P.; Whiteley, P. E.; Zeng, L.;Goldstein, D. M. "Design and synthesis of 4-azaindoles asinhibitors of P38 MAP kinase." Journal of Medicinal Chemistry2003, 46, 4702-4713.Dr. P. WipfChem 23204/9/200724Dr. P. WipfChem 23204/9/200725Use of the Bartoli reaction: Zhang, Z.; Yang, Z.; Meanwell,N. A.; Kadow, J. F.; Wang, T., "A General Method for the Preparationof 4- and 6-Azaindoles." J. Org. Chem. 2002, 67, 2345-2347. Largersubstituents ortho to the nitro group produced higher yields, and ahalogen atom at the alpha- or 4-position of the pyridine is also highlybeneficial for this reaction:4- and 6-azaindoles wereprepared, but this protocol shouldalso work for 5- and 7-azaindolesfrom the
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