9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disclaimer: Indole: This lecture will only cover methodology for the construction of the indole and pyrrole 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 tar 1. Batcho-Leimgruber Indole Synthesis – Biosynthesis of tryptophan 2. Reissert Indole Synthesis CO H 3. Hegedus Indole Synthesis 15 2 3 serine 4. Fukuyama Indole Synthesis glucose Steps NH Steps N 5. Sugasawa Indole Synthesis 2 H 6. Bischler Indole Synthesis anthranilate 7. Gassman Indole Synthesis tryptophan 8. Fischer Indole Synthesis 9. Japp-Klingemann Indole Synthesis Reactivity: 10. Buchwald Indole Synthesis C–4 C–3 11. Bucherer Carbazole Synthesis C–5 C–2 12. Japp-Maitland Carbazole Synthesis C–6 N 13. Larock Indole Synthesis C–7 H 14. Bartoli Indole Synthesis 15. Castro Indole Synthesis – Isoelectronic with naphthalene (slightly lower stabilization energy) 16. Hemetsberger Indole Synthesis – Indole has a higher stabilization energy than benzene 17. Mori-Ban Indole Synthesis – Very weakly basic: pKa of protonated indole: –2.4 18. Graebe-Ullmann Carbazole Synthesis – Protonation occurs at C–3 preferentially 19. Madelung Indole Synthesis – Easily oxidized (atmospheric oxygen) – very electron rich 20. Nenitzescu Indole Synthesis – Less prone to oxidation of EWG's on the ring – less electron rich 21. Piloty Pyrrole Synthesis – Electrophilic attack occurs at C–3 (site of most electron density) 13 22. Barton-Zard Pyrrole Synthesis – C–3 is 10 times more reactive to electrophilic attack than benzene 23. Huisgen Pyrrole Synthesis – C–2 is the second most reactive site on the molecule, but most easily 24. Trofimov Pyrrole Synthesis functionalized by directed lithiation 25. 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 indole 27. Paal-Knorr Pyrrole Synthesis – Nucleophilic substitution at benzylic carbons enhanced 28. Zav'Yalov Pyrrole Synthesis – Regiospecific functionalization of the carbocycle is difficult without 29. Wolff Rearrangement pre-functionalization of the ring (i.e. halogenation) Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting O X + + + N X N O H H H2N O NH2 N O H NH 1a 2 N N Ring 1b N H H O H Contracton 9c 1c N X H NH2 9b 11 12 13 N 1d H 10 N 1 X H 9a NH2 N O 9 H + 2 R O + N H N N H H N 8c H 8 N 3 H Y X 8b + 7 3a 8a NH X N 6 5 4 2 H N 3b H S X + 3c N NHCl H O N 3d N N H R N H X H H + NHOH N Y + H N + H NH2 NHNH2 O R NH2 X Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disconnection 1a: Disconnection 1a: R OCOR Batcho-Leimgruber Indole Synthesis: O NO OMe 2 NO2 Me N OMe 1 Me N 2 Me [H] R R R NO NO N 2 NH 2 H R 6 R R O OH – Typical [H] = H , Pd/C; hydrazine, Raney Ni 3 2 NO2 NH2 NO2 – Other side products from reductive cyclization include N–O – Yields: 50's – 90's 5 4 Variants: Me CN CH NO R 3 2 NO NO2 2 NO 2 NO2 [H] – 1: Reduction, then acid R R – 2: Reduction, then acid NO N 2 H – 3: Oxidation, then reduction, then acid R 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: 40's – 90's Reissert Indole Synthesis: Me Base CO2Et [H] CO2Me O (CO2Et)2 NO N NO2 2 H Sundberg, R.J. Indoles. Sundberg, R.J. Indoles; Reissert, A. Ber. 1897, 30, 1030 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disconnection 1b: Disconnection 1d: Palladium Synthesis: Hegedus Indole Synthesis: II R' Pd , then [H] or Me R N NH2 PdII, Cu(OAc) , R II R'M N 2 H Pd 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: 40's – 90's – 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 NO N 2 H N NH Ts N R H R R Disconnection 1–Misc.: R NO N 2 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 H Sundberg, 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. 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disconnection 2: Disconnection 3b: Pyrrone Diels-Alder: Gassman Indole Synthesis: 1. t-BuOCl SMe 2. R'' O R S R R'' Raney-Ni R R'' NH O O N N N N 3. base H H R' 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: O Sugasawa Indole Synthesis: OH N O BCl3 CN CN NaBH4 R + Ac Li2PdCl4 R ZnCl2, AlCl3 NH2 Cl NH2 NaOMe N H or TiCl4 H acid O- O N • Z N – Requires very strong Lewis Acids so many functionalities are not stable H N R H – Choice of second Lewis acid depends on substitution pattern O Bischler Indole Synthesis: OH OMe N NH 2 O R Ar + Ar N – Quite mild, if the O-vinyl derivatives can be synthesized X H o – Not very general: requires HBr (1 eq) and 200+ C – 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 + NaHSO + acid 3 R' R NHNH NHNH2 R H2O 2 acid N N H H X=OH, NH Mechanism? 2 – 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'' + R OR'' D N2 N CH2R' H Buchwald Modification: Disconnection 3–Misc.: R' NH Larock Indole Synthesis: Br 1. Pd//BINAP N (Larock, R.C. J. Org. Chem. 1998, 63, 7652) + R R' R 2. TsOH N H R'' I R' Pharmaceutical Applications of the Fischer Indole Synthesis: + Pd(OAc)2 R' NH O Base N O N Me R R'' R N O S Me N OBn HN Me N – Base additives vary by reaction S O H O – High functional group tolerance O Imitrex® – Bulkier R group placed at C–2 of the indole MK-677 Glaxo NH •MsOH Merck 2 e.g. Heterocycles, 2000, 53, 665 T, 1997, 53, 10983 Sundberg, 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(TMS) 3. RCOCl N NO2 R' R'' N 2 H R 2 eq H 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 NH 2 N CHO CHO H RO C N RO2C N 2 TBDMSTf HO Disconnection 4: N N H H Hemetsberger Indole Synthesis: O CO2R D CO2R Disconnection 7: N CO R N 2 3 N H O – Formed by condensation of aromatic aldehyde with a-azoester with TsOH NaOEt, under very carefully controlled conditions to prevent N loss 2 N N – Yields = 30's – 90's H H R R – Unknown mechanism – not a nitrene insertion reaction OH Bartoli, G. Tetrahedron Lett. 1989, 30, 2129; Castro, C.E. J Org. Chem. 1966, 31, 4071 Sundberg, R.J. Indoles. 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting Disconnection 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 = 70's – 90's – 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 o N taut.