9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisclaimer: Indole:This lecture will only cover methodology for the construction of the indole andpyrrole ring systems, rather than functionalionalization of pre-existing heterocycles, Nature:which would be the topic of another series of lectures. – The most abundant heterocycle in nature – Found in tryptophan, indole-3-acetic acid (plant growth hormone),Partial List of Transforms Discussed: serotonin (neurotransmitter), natural products, drugs – Isolated industrially from coal tar1. Batcho-Leimgruber Indole Synthesis – Biosynthesis of tryptophan2. Reissert Indole Synthesis CO2H3. Hegedus Indole Synthesis 15 3 serine4. Fukuyama Indole Synthesis glucose Steps NH2 Steps N5. Sugasawa Indole Synthesis H6. Bischler Indole Synthesis anthranilate7. Gassman Indole Synthesis tryptophan8. Fischer Indole Synthesis9. Japp-Klingemann Indole Synthesis Reactivity:10. Buchwald Indole Synthesis C–4 C–311. Bucherer Carbazole Synthesis C–5 C–212. Japp-Maitland Carbazole Synthesis C–6 N13. Larock Indole Synthesis C–7 H14. Bartoli Indole Synthesis15. Castro Indole Synthesis – Isoelectronic with naphthalene (slightly lower stabilization energy)16. Hemetsberger Indole Synthesis – Indole has a higher stabilization energy than benzene17. Mori-Ban Indole Synthesis – Very weakly basic: pKa of protonated indole: –2.418. Graebe-Ullmann Carbazole Synthesis – Protonation occurs at C–3 preferentially19. Madelung Indole Synthesis – Easily oxidized (atmospheric oxygen) – very electron rich20. Nenitzescu Indole Synthesis – Less prone to oxidation of EWGs on the ring – less electron rich21. Piloty Pyrrole Synthesis – Electrophilic attack occurs at C–3 (site of most electron density)22. Barton-Zard Pyrrole Synthesis – C–3 is 1013 times more reactive to electrophilic attack than benzene23. Huisgen Pyrrole Synthesis – C–2 is the second most reactive site on the molecule, but most easily24. Trofimov Pyrrole Synthesis functionalized by directed lithiation25. Knorr Pyrrole Synthesis – pKa of N–H is 16.7 (20.9 DMSO)26. Hantzsch Pyrrole Synthesis – N–1 is the most nucleophilic site on indole27. Paal-Knorr Pyrrole Synthesis – Nucleophilic substitution at benzylic carbons enhanced28. ZavYalov Pyrrole Synthesis – Regiospecific functionalization of the carbocycle is difficult without29. Wolff Rearrangement pre-functionalization of the ring (i.e. halogenation) Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996
9/1/04Richter Indole and Pyrrole Synthesis: " " Group Meeting O X + + + N X N O H H H2N O NH2 N O H NH2 1a 1b N N Ring N H H O H Contracton 9c 1c N X H NH2 9b 11 12 13 N 1d H 10 X N 1 H 9a NH2 N O 9 H 2 R+O + N H N N 8c H H N 8 H N 3 H Y X 8b + 7 3a 8a NH2 X N 6 5 4 H N 3b H S X + N 3c NHCl O H N 3d N N H R N H X H H + NHOH N Y + H N + H NH2 NHNH2 R NH2 X OSundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 1a: Disconnection 1a: R OCORBatcho-Leimgruber Indole Synthesis: O NO2 NO2 OMe Me 1 N OMe 2 Me N Me [H]R R R NO2 NO2 N 6 NH H R R R – Typical [H] = H2, Pd/C; hydrazine, Raney Ni O 3 OH NO2 NH2 NO2 – Other side products from reductive cyclization include N–O – Yields: 50s – 90s 5 4Variants: Me CNR CH3NO2 NO2 NO2 NO2 NO2 [H] – 1: Reduction, then acid R R – 2: Reduction, then acid NO2 N H – 3: Oxidation, then reduction, then acidR HNO3 Can oxidize the alcohol and not the aniline with Ru(PPh3)2Cl2 Can convert the nitro-alcohol into indole with Pd/C or Rh/C and NO2 Ru(PPh3)2Cl2 – 4: Reduction of nitro and cyano (one or two steps), then acid – If R = carbonyl, use KF / 18-c-6 / i-PrOH for the Henry reaction – 5: Wacker oxidation, reduction, then acid – Use classic Henry conditions otherwise – 6: Ozonolysis, reduction, then acid –Typical [H] = Fe, Fe/SiO2 – Yields: 40s – 90s Reissert Indole Synthesis: Me CO2Et Base [H] CO2Me (CO2Et)2 O N NO2 NO2 HSundberg, R.J. Indoles. Sundberg, R.J. Indoles; Reissert, A. Ber. 1897, 30, 1030
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 1b: Disconnection 1d:Palladium Synthesis: Hegedus Indole Synthesis: R PdII, then [H] or Me R NH2 N R RM N PdII, Cu(OAc)2, H PdII H benzoquinone PdII R – Applied to the total synthesis of rac-aurantioclavine by Hegedus NHX N (Hegedus, L.S. J. Org. Chem. 1987, 52, 3319) H H+ H R Br I N N H N H – X can be either H, Ac, Ms, TFA N H – The intermediate organopalladium can be intercepted – Yields: 40s – 90s – Applied to the total synthesis of arcyriacyanin A by Steglich (Steglich, W. Chem. Eur. J. 1997, 3, 70)Disconnection 1c: H N Br O R O R NO2 N H N NH Ts N R H R R Disconnection 1–Misc.: R NO2 N H Fukuyama Indole Synthesis: – Reductive cyclization mediated by (EtO)3P or PdCl2/PPh3/SnCl2 and CO nBu3SnH – Migratory aptitudes unknown S R – Unknown mechanism – does not involve a nitrene AIBN N N R H HSundberg, R.J. Indoles. Hegedus, L.S. J. Am. Chem. Soc. 1976, 98, 2674; ibid 1978, 100, 5800; e.g. Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 2: Disconnection 3b:Pyrrone Diels-Alder: Gassman Indole Synthesis: 1. t-BuOCl SMe O 2. R R S O R R Raney-Ni R R NH O N N N N R 3. base H H R R – Little regiocontrol observed in most reactions – Good regiocontrol observed with ortho or para substitution – pyrrole-quinodimethanes are not stable and therefore not amenable for – ortho/para methoxy substituents failed completely Diels-Alders directly Disconnection 3c:Disconnection 3a: OSugasawa Indole Synthesis: OH O BCl3 N CN CN NaBH4 R + Ac Li2PdCl4 R NH2 Cl ZnCl2, AlCl3 NH2 N H NaOMe or TiCl4 H acid O- O N • Z N N – Requires very strong Lewis Acids so many functionalities are not stable H H R – Choice of second Lewis acid depends on substitution pattern OBischler Indole Synthesis: OH OMe N NH2 O R Ar Ar + – Quite mild, if the O-vinyl derivatives can be synthesized N X H – Not very general: requires HBr (1 eq) and 200+ oC – Mechanism?Sundberg, R.J. Indoles. Gassman, P.G. J. Am. Chem. Soc. 1974, 96, 5495; Sundberg, R.J. Indoles.
9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disconnection 3d: Disconnection 3d: Fischer Indole Synthesis: Bucherer Carbazole Synthesis: X R O + NaHSO3 + acid R R NHNH2 R H2O NHNH2 acid N N H H X=OH, NH2 Mechanism? – Common acids: HCl, H2SO4, PPA, BF3/AcOH, ZnCl2, FeCl3, AlCl3, CoCl2, NiCl2, TsOH Japp-Maitland Condensation: – Regioselectivity not great with unsymmetrical ketones – Tolerates a wide range of substitution – Product regioselectivity affected by choice of acid, solvent, temperature 0.5 eq Japp-Klingemann Modification: OH HCl N R NHNH2 H O O + acid CO2R N2 + R OR D N CH2R H Buchwald Modification: Disconnection 3–Misc.: R Br NH Larock Indole Synthesis: N 1. Pd//BINAP + (Larock, R.C. J. Org. Chem. 1998, 63, 7652) R R 2. TsOH R N H R R I Pharmaceutical Applications of the Fischer Indole Synthesis: + Pd(OAc)2 R NH Base N O O N Me R R R N O S Me N OBn HN Me N – Base additives vary by reaction S O O H – High functional group tolerance O Imitrex® MK-677 Glaxo – Bulkier R group placed at C–2 of the indole NH2•MsOH Merck e.g. Heterocycles, 2000, 53, 665 T, 1997, 53, 10983Sundberg, R.J. Indoles; Buchwald S.L. J. Am. Chem. Soc. 1998, 120, 6621 Bucherer, H.T. J. Prakt. Chem. 1908, 77, 403; Japp, F.R. ; Maitland, W.J. J. Chem. Soc. 1903, 83, 273
9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disconnection 3–Misc.: Disconnection 5: Bartoli Indole Synthesis: Stepwise: R 1. Zn BrMg Br 2. CuCN, LiCl + R R N NO2 R R N N(TMS)2 3. RCOCl H R H 2 eq R One pot: 1. 2.2 BuLi – Mechanism? R – Only works well with 2-substituted nitrobenzenes N NHX 2. RCO2Me H Castro Indole Synthesis: X = TMS, Boc I R Disconnection 6: + CuOTf R NH2 N CHO CHO RO2C N H RO2C N TBDMSTf HO Disconnection 4: N N H H Hemetsberger Indole Synthesis: O CO2R D CO2R Disconnection 7: N CO2R N3 N O H – Formed by condensation of aromatic aldehyde with a-azoester with TsOH NaOEt, under very carefully controlled conditions to prevent N2 loss N N H – Yields = 30s – 90s R H OH R – Unknown mechanism – not a nitrene insertion reactionBartoli, G. Tetrahedron Lett. 1989, 30, 2129; Castro, C.E. J Org. Chem. 1966, 31, 4071 Sundberg, R.J. Indoles.
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 8a: Disconnection 8b:Heck Approach: More Palladium: R CO2R X X CO2R R Pdo Pd(OAc)2 N N N N R R R R – Yields = 70s – 90s – Works best with an EWG on the olefin – Choice of base and protecting group on the nitrogen can affect the yield Photochemical:More Palladium: hn R N taut. N X Pdo; H H N RZnCl N H H Disconnection 8c: – Can intercept the intermediate organopalladium species Acid Catalyzed Cyclization: – Any organozinc reagent can be used to transmetallate. R O R LA X = TFA,Mori-Ban Indole Synthesis: alkyl, N N solfonyl Cl X X (Ph3P)4Ni – LA commonly ZnCl2 N N – Can also use ketals with BF3 or TiCl4 Me Me Disconnection 8–Misc.: – Requires stoichiometric nickel – Yields only about 50%. Graebe-Ullmann Carbazole Synthesis: N N D N N Ph H – Mechanism? – Generally problematic and not widely applicableSundberg, R.J. Indoles; Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 17, 1803. Sundberg, R.J. Indoles; Graebe, C.; Ullmann, F. Ann. 1896, 291, 16
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 9a: Disconnection 10:Madelung Synthesis: Diels-Alder: R EDG EDG R 3 BuLi EWG N O N H N EWG N H H H – Yields = 40s – 90s – Works best when matchedVariant of Madelung: Disconnection 11: X Base Diels-Alder: N O N H H EWG EWG N – Where X is a phosphorous, nitrogen, silicon, or oxygen to stabilize H N EDG H a negative charge EDG – If X is phosphorous, then it is an intramolecular Wittig. – Works best when matchedDisconnection 9b: Disconnection 12:Base/Acid Catalyzed closure: Nenitzescu Synthesis: R O Acid or O H R HO R D R N R Base N R Ar O N R N Ar H R – Mechanism?Disconnection 9c: – Substitution on the quinone ring is acceptable and predictable – Substitution on the enamine is tolerated, but R is best as an EWGMcMurray Type Closures: – Used in the synthesis of LY311727 (Lilly) O CO2NH2 O TiCl3 P MeO N O Zn N OMe Ar Ar N BnSundberg, R.J. Indoles. Sundberg, R.J. Indoles; Ninetzescu, C.D. Bull. Soc. Chim. Romania. 1929, 11, 37; J. Org. Chem. 1996, 61, 9055
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 13: Pyrrole:Wolff Rearrrangement: Nature: – Very abundant in nature O CO2H – Found in porphyrins, natural products, drugs N2 – Isolated industrially from coal tar and/or bone oil hn N N Reactivity: H C–3From Quinolines: C–2 CHO N H hn O Ph – Protonation occurs at C–2 preferentially N+ Ph N N – Easily oxidized (atmospheric oxygen) – very electron rich - Ph H O – Quickly colorizes upon exposure to air – Less prone to oxidation of EWGs on the ring – less electron rich – Decomposition and polymerization rapid with acid – Electrophilic attack occurs at C–2 (site of most electron density) – C–3 is the second most reactive site on the molecule – pKa of N–H is 23 (DMSO) – N–1 is the most nucleophilic site on pyrroleKatritzky, A.R. Handbook of Heterocyclic Chemistry. Pergamon. San Diego, 2000 Mass, G. Science of Synthesis. Thieme. New York: 2001
9/1/04Richter Indole and Pyrrole Synthesis: " " Group Meeting Ring Expansion N N H H N N H H N 17 18 1 16 N H H 2 15 3 N 14 N H H 4 N 13 H 5 12 N N H 11 6 H 10 7 9 8 N N H H N N H Ring H N Contraction N H H
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 1: Disconnection 3:Palladium with Alkenes: Piloty Synthesis: Me H2NNH2 Me PdCl2 Et N O OH O CoI2, D Et N N H R H – Mechanism? – Exists mainly in the tautomeric form Disconnection 4:Palladium with Alkynes: Thermal Cyclization: Pd/C CO2Et D CO2Et TEA, N N3 N N MeOH Cbz H Cbz Carbene Insertion:Disconnection 2: O NHR R CN 1. TMSCLiN2 R Ph CN Ph NaOEt R R R + 2. MnO2 R N Ts NC CO2Et N R H Disconnection 5:Disconnection 3: Rhodium: Ph Ph HO Ph Ph NH4OAc Ph H2, CO Ph + Ph NH2 N Ph O O Ph AcOH N [Rh], PPh3 Ph H HMass, G. Science of Synthesis. Thieme. New York: 2001
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 5 Continued: Disconnection 6:Iron: Barton-Zard Pyrrole Synthesis: R Ph LG Ph R base R Fe2(CO)9 + CN CO2R CO2R R Me N MeLi; tBuBr R NPh N Me H – Original Barton-Zard used NO2 as the LG.Niobium: Bis-Nucleophile/Bis-Electrophile: Ph Ph Ph Ph Ph OMe Ph NbCl3 Ph KOtBu Ph O + EtO2C N CN CN + Ph RHN O O N NR O OMe Nb Ph Extrusion (Huisgen Pyrrole Synthesis): -O CO2Me Ph X MeO2C Ph Me Me ONb Ph DMAD Ph N+ N N Ph N Ph R R – X is usually S or NR2-Aminopyrroles: Disconnection 7: R R R R N RNC Knorr Pyrrole Synthesis: O NHR COR R O R R D N + R R R R NH2 N O R R HFrom Cyclopropenes: R Trofimov Pyrrole Synthesis: Ar hn + R N Ar R Cl or D N R NOH Base N HMass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 7 Continued: Disconnection 8:Hantzsch Pyrrole Synthesis: Paal-Knorr Pyrrole Synthesis: R O O R + RNH2 + R R Br R R N R H2N R O R N R R H – Can access the diketone in-situ by reduction of the bis-cyano compoundFormal 3+2: – Can access via reduction of the g-nitro ketone Bn R Palladium: N R D + PdCl2, Cu(OAc)2; NO2 N Bn N AgBF4, PPh3, BnNH2 BnStepwise: OAc R O 1. Base Pd(PPh3)4 I 2. Acid R + O O BnNH2 N R NNMe2 Bn 3. H2, Ni R N H ZavYalov Pyrrole Synthesis:Ugi Approach: R NC O Ph R R Ph O R HO2C CN R Ac2O R O HO2C NH2 O O N + NH R NH3Cl NC NMe2 R TEA N O R CO2H Ac R RCHO HN Ph NC MeO N CH2N2 CONCy RMass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 9: Disconnection 11:Wolff Rearrangement/Photolytic: O NHR N2 EtO2C Cu(acac)2 + R N2 R R H CO2Et hn CO2H N R R N N O H OMe Bt N Ph Ph 1. BuLi; Br OMe OMe acid hn CN N OMe N 2. BuLi; Ph N+ N3 N Bn NPh Ph NHPh Ph N H Ph O-Reductive Ring Contractions: CO2Et Disconnection 12: Ar N Cl Zn Allenes: HOAc N 1. PPh3 CO2Me N CO2Et MeO2C H Ph 2. DDQ • CO2Me + OMe Ph MeO CO2Me TsN 3. NaOMe N Zn H N CO2Me Rhodium: MeO2C N HOAc MeO C N R R 2 H R R R Rh2(CO)12 CN CO2Et + CO2Et O O NDisconnection 10: R H Cobalt:Base Catalyzed: 1. Co2(CO)6 R 2. BF3•OEt2 R R Ph Ph CO2Me KOtBu R OH 3. H N ( )n N Cl N H MeO2C N ( )n Me LDA, DDQMcMurray Type Coupling: n=2 n=1 R R R Bn TiCl3 R MeO2C Ph R NH O N R R Zn R H N MeO2C N O H HMass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingDisconnection 13: Disconnection 16: Ph RCHO PhNC R X H CN CO2Me O Y + DBU MeO2C RCO2H O- Ph O CO2Me RNH2 N+ R CN CO2Me R N N X Y R R H RDisconnection 14: Disconnection 17: R RNH2 EtNO2 SmCl3 R R 1. BuLi NR R R Me R R O RNH2 O R 2. O N R Br N R R R RDisconnection 15: Disconnection 18:Palladium: Ph From Cyclopropanes: Ph Ph PdCl2 Ph + Ph MeO2C N(TMS)2 TMSCN or NiCl2 CO2Me hn NC N H N Ph NTitanium: R R R Ti(OiPr)4 R NR R From Cyclobutanes: R R Ti(OiPr)2 2 iPrMgCl CO R PhS R N SPh R BzO SPh AlEt2ClZirconium: NR N Li Cp2(Me)ZrCl Ph Ph RPh N Ph TMS Ph NTMS Cp2Zr CO N HMass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingSelected Syntheses: Selected Syntheses:Strychnine: Woodward (Classics I) Isochrysohermidin: Boger (Classics II) N OH CO2Me MeO NMe H MeO N O H H O MeO2C O HO N HO Me O CO2Me OMe MeO2C OMe PPA N MeO NH OMe MeO N Disconnection 9 NHNH2 OMe N MeO MeO H CO2Me CO2Me Fischer Indole Synthesis MeO2C CO2Me MeO2C N CO2Me N N HStrychnine: Overman (Classics I) Aspidophytine: Corey (Classics II) N N H O O N MeO H H N O MeO Me H HO N N NO2 Fe, AcOH HO silica gel N NH2 H H H MeO NO2 MeO N H MeO2C MeO2C OMe OMe Disconnection 1a OH OH Batcho-Leimgruber Indole Synthesis VariantSyntheses were only included if they synthesized the indole or pyrrole
9/1/04Richter Indole and Pyrrole Synthesis: " " Group MeetingSelected Syntheses: Selected Syntheses:Vinblastine: Fukuyama (Classics II) Lipitor®: Pfizer (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004) OH OH N - O2C OH H N F H N N H MeO2C OH NH MeO N OAc Me H O CO2Me THPO OTHP nBu3SnH S CO2Bn CO2Bn AIBN MsO N O O H MsO N CO2Bn CO2Bn H O O F Fukuyama Indole Synthesis F CONHPh NMitosene: Rebek (J. Org. Chem. 1984, 49, 5164) N Ac2O O OCONH2 CONHPh HO2C O H2N Huisgen Pyrrole Synthesis OMe N O NH2 EtO OEt OEt F - F O CO2Me O H2N OEt N MeO2C MeO2C O MeO2C DMAD N+ N O Paal-Knorr Pyrrole Synthesis CONHPh CONHPh OAc OAc Huisgen Pyrrole SynthesisSyntheses were only included if they synthesized the indole or pyrrole