Baran, Richter Essentials of Heterocyclic Chemistry-I ...

1 Heterocyclic ChemistryBaran, RichterEssentials of Heterocyclic chemistry -IOSNNHNHNHNHOONONSNNHNNHHNNHNN HNNHHNNHOONNHOHNSSSHNNNOONNNHHNNNNSSSNNN ONSNNONNNHNNSF uranpKa: : : , : ,441,3-DioxolaneOxazolepKa: : , : , , : , : 3 IsothiazolepKa: ,2,3-Oxadiazole1,2,3-TriazolepKa: ,3,4-ThiadiazolepKa: : : ,4-DioxaneMorpholinepKa: ,4-DithianeThiomorpholinePyridazinepKa: : : ,3,5-TriazinepKa: <01,3,5-TrithianeNNHNHNNHOSNHNNHNSNNNNHN NNNNNNNNNNNNNNNNNNHONNNNHSNHNI ndolizineIndolepKa: , : : [b]thiophenepKa: : : : , : : ,8-NaphthyridinepKa: : : : : ,3-DithianepKa: 31156432 NNN1,2,4-TriazinepKa: <0156432 NHTetrahydroquinolinepKa: Me tBu NH2 NHAc OMe SMe Cl Ph vinyl CN NO2 CH(OH)22-position 3-position Positions: First, SecondNMeSNNOOSSSRRNNRNSE ffects of Substitution on Pyridine Basicity:Sites of Electrophilic Substitution: Major, MinorSNHONSNNHNNNNNHNHOSNNHNNMeNSSNON kineticthermodynamicLipinski Rule of Five.

2 Christopher Lipinski (retired from Pfizer) formulated a set of criteria fulfilled in most orally available No more than five hydrogen bond No more than ten hydrogen bond A molecular weight under A LogP (partition coefficient) value under of N H, Deprotonation of C H, Deprotonation of Conjugate AcidMedicinal chemistry Glossary:ED50: Dose required to yield maximum therapeutic effect in 50% of test : Description of the relative intensity with which agonists vary in the response they produce, even with similar : A compound belonging to a series of compounds differing from each other by a repeating unit ( a CH2, a peptide residue, etc.).Intrinsic activity: The maximal stimulatory response induced by a compound relative to that of a given reference : Dose required to kill 50% of test coefficient (LogP): Log10 of the ratio of a compound's concentration in 1-octanol vs.

3 Water at equilibrium. A LogP<0 means that a compound is more soluble in water than in : The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or block) its biological response. This is not a real molecule or moiety, but rather an abstract concept that is considered the largest common denominator shared by a set of active : The dose of a drug required to produce a specific effect of given intensity as compared to a standard index: LD50/ED50 Heterocyclic Aromaticity Values: % (of PhH) -value % (of PhH) -valueOIsobenzofuran1237654pyridinetetra zolepyrazolequinolineisoquinolinepyrazin e1,2, ,2,4-TriazolepKa: , , : 'NHR'RIndoles:acid, Fischer Indole SynthesisNH2 PdII; [H]NHMeHegedus Indole SynthesisNHSRnBu3 SnHAIBNNHRMeFukuyama Indole SynthesisNHRi.

4 Baseiv. Raney-Ni, H2 SMeR'ONRG assman Indole SynthesisINHRR'R''Pd(OAc)2,baseNRR'R''La rock Indole SynthesisXNRR'XNRR'NRR'Pd0 PdIIPyrroles:RNO2R'CNCO2 XNHR'RCO2 XbaseBarton-Zard Pyrrole SynthesisOR'NH2 RXOYONHR'COYXRK norr Pyrrole SynthesisN+XO-PhNCO2 MePhCO2 MeDMADH uisgen Pyrrole SynthesisR'ROONRRR'RNH2 Paal-Knorr Pyrrole SynthesisRNH2 PdIINRNNMeO2 CMeOCO2 MeNHCO2 MeMeO2 COMeZnHOAcThiophenes:CO2 MeHSSMeO2 CCO2 MeOHi. DMAD, piperidineii. NaOMeFiesselmann Thiophene SynthesisPhOPhOi. NaOEt, S(CH2CO2Et)2ii. acidSHO2 CCO2 HPhPhHinsberg Thiophene SynthesisMeOMeOP4S10 SMeMePaal Thiophene SynthesisOxazoles and Isoxazoles:CO2 XROR'NH2 OHONOHR'RClaisen Isoxazole SynthesisROHCNR'CHOHClNOR'RFisher Oxazole SynthesisRONHR''OR'NORR''R'Robinson-Gabr iel Oxazole SynthesisCHOTosMICK2CO3 NOPhvan Leusen Oxazole SynthesisHeterocyclic ChemistryBaran, RichterEssentials of Heterocyclic chemistry -INO2RR1R2 BrMgNHR2R1R+Bartoli Indole SynthesisMeNO2 NHBatcho-Leimgruber Indole Synthesisi.

5 DMFDMAii. Pd/C, H2 RRHNXRRX = OH, NH2i. PhNHNH2 NaHSO3, ii. H+Bucherer Carbazole SynthesisRNNNRNH Graebe-Ullmann Carbazole SynthesisRBase Madelung Indole SynthesisNR1R2OR3 RNR1R3R2 OORR3 HNR1R2+HORNR3R1R2 Nenitzescu Indole SynthesisRi. (CO2Et)2, Baseii. [H], H+Reissert Indole SynthesisNO2 RNHCO2 HOR1R2 CNXSR2NH2XR1i. S8ii. Amine+Gewald Aminothiophene SynthesisNORR1R2 ONORR2R1O Cornforth RearrangementHNORCO2 HAc2 ONOROE rlenmeyer-Pl chl Azlactone Synthesisi. LAii. NaBH4 Sugasawa Indole SynthesisNH2 NHCNCl+H+ Bischler Indole SynthesisNH2 NHX+ArOX = halideINH2 RNHRC astro Indole SynthesisCuOTfHemetsberger Indole SynthesisCO2RN3H+ NHCO2 RClNRNRMeNi0 Mori-Ban Indole SynthesisOMeMeH2 NNH2 CoI2, NHEtMeMeEtPiloty Pyrrole SynthesisROBrH2NR1R2++NHRR2R1 Hantzsch Pyrrole SynthesisR'ArBoger Pyrrole Synthesis