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Home , Fischer indole synthesis, Indole, Knorr pyrrole synthesis, Pyrrole

9/1/04 Richter and 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 , indole-3-acetic (plant growth hormone), Partial List of Transforms Discussed: (), natural products, drugs – Isolated industrially from 1. Batcho-Leimgruber Indole Synthesis – of tryptophan 2. Reissert Indole Synthesis CO H 3. Hegedus Indole Synthesis 15 2 3 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. 9. Japp-Klingemann Indole Synthesis Reactivity:

10. Buchwald Indole Synthesis C–4 C–3 11. Bucherer 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 (slightly lower stabilization energy) 16. Hemetsberger Indole Synthesis – Indole has a higher stabilization energy than 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 ) 22. Barton-Zard Pyrrole Synthesis – C–3 is 1013 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. – 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 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. . 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

– Typical [H] = H , Pd/C; , Raney Ni O 3 OH 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 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 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 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 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 N – Requires very strong Lewis so many functionalities are not stable H H – Choice of second Lewis acid depends on substitution pattern R 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 – 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 + 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 – Tolerates a wide range of substitution – Product regioselectivity affected by choice of acid, , 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 OBn HN N N – Base additives vary by reaction S Me O O H – High functional group tolerance Imitrex® O – 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 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 on the can affect the yield Photochemical: More Palladium: hn R o N taut. N X Pd ; 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 applicable

Sundberg, R.J. Indoles; Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 17, 1803. Sundberg, R.J. Indoles; Graebe, C.; Ullmann, F. Ann. 1896, 291, 16 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Disconnection 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 = 40's – 90's – Works best when matched

Variant 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 matched

Disconnection 9b: Disconnection 12:

Base/Acid Catalyzed closure: Nenitzescu Synthesis: R' O Acid or O H R' HO D R 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 is tolerated, but R' is best as an EWG McMurray Type Closures: – Used in the synthesis of LY311727 (Lilly)

O CO2NH2 O TiCl3 P MeO N O Zn N OMe Ar Ar N Bn

Sundberg, R.J. Indoles. Sundberg, R.J. Indoles; Ninetzescu, C.D. Bull. Soc. Chim. Romania. 1929, 11, 37; J. Org. Chem. 1996, 61, 9055 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Disconnection 13: Pyrrole:

Wolff Rearrrangement: Nature: – Very abundant in nature O CO2H – Found in , natural products, drugs N2 – Isolated industrially from coal tar and/or bone oil hn

N N Reactivity: H C–3

From : C–2 CHO N H hn O Ph N+ Ph – Protonation occurs at C–2 preferentially N N – Easily oxidized (atmospheric oxygen) – very electron rich O- Ph H – Quickly colorizes upon exposure to air – Less prone to oxidation of EWG's on the ring – less electron rich – Decomposition and 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 pyrrole

Katritzky, A.R. Handbook of Heterocyclic Chemistry. Pergamon. San Diego, 2000 Mass, G. Science of Synthesis. Thieme. New York: 2001 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Ring Expansion N N H H N N H H 18 N 17 1 N H 16 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 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Disconnection 1: Disconnection 3:

Palladium with : Piloty Synthesis: Me Me H2NNH2 PdCl2 Et OH N O O CoI2, D Et N N H R H – Mechanism? – Exists mainly in the tautomeric form Disconnection 4: Palladium with : Thermal Cyclization: Pd/C CO2Et D CO2Et TEA, N N N3 N Cbz MeOH Cbz H

Carbene Insertion: Disconnection 2: O NHR''' R' CN 1. TMSCLiN R Ph 2 CN NaOEt Ph R R'' + R'' R' 2. MnO2 N Ts NC CO2Et N R''' H Disconnection 5: Disconnection 3: Rhodium: Ph Ph Ph HO Ph Ph H , CO NH4OAc Ph 2 + Ph NH2 [Rh], PPh N Ph O O Ph AcOH N 3 H Ph H

Mass, G. Science of Synthesis. Thieme. New York: 2001 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Disconnection 5 Continued: Disconnection 6:

Iron: Barton-Zard Pyrrole Synthesis: R Ph LG Ph R base R' + CN CO2R'' Fe2(CO)9 R' CO2R'' Me N R NPh MeLi; tBuBr N Me H – Original Barton-Zard used NO2 as the LG.

Niobium: Bis-/Bis-: Ph Ph Ph Ph Ph OMe Ph Ph KOtBu NbCl3 Ph O + EtO2C N CN + CN RHN O O Ph N NR O OMe Nb Ph Extrusion (Huisgen Pyrrole Synthesis): - CO2Me Ph O X Ph MeO2C Me ONb Ph DMAD Me Ph N+ N N Ph N Ph R R – X is usually S or NR 2-Aminopyrroles: Disconnection 7: R'' R' R R' N R'''NC Knorr Pyrrole Synthesis: NHR''' O COR'' R' O R' D N R'' + R'' R R''' R NH2 N O R''' R H From Cyclopropenes:

R' Trofimov Pyrrole Synthesis: Ar hn + R' N R Ar Cl or D N R NOH Base N H

Mass, 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 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Disconnection 7 Continued: Disconnection 8:

Hantzsch Pyrrole Synthesis: Paal-Knorr Pyrrole Synthesis:

R'' O O R'' + RNH + R'' 2 R' R'' Br R' R R' N H2N R N O R R H – Can access the diketone in-situ by reduction of the bis-cyano compound Formal 3+2: – Can access via reduction of the g-nitro

Bn R Palladium: R N D + PdCl2, Cu(OAc)2; N NO2 Bn AgBF , PPh , BnNH N 4 3 2 Bn Stepwise: OAc R O 1. Base Pd(PPh3)4 R + I 2. Acid N O O BnNH2 R NNMe Bn 2 3. H2, Ni N R H Zav'Yalov Pyrrole Synthesis: Ugi Approach: R NC O Ph R R' Ph O R R' Ac2O R' HO2C CN O HO2C NH2 O O N + NH R'' NC R'' TEA N NH3Cl O NMe2 R R'' CO2H Ac RCHO HN Ph NC

MeO N CH2N2 CONCy R

Mass, 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 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Disconnection 9: Disconnection 11:

Wolff Rearrangement/Photolytic: O NHR'' N2 EtO2C Cu(acac)2 + R' N2 R R' H CO2Et hn CO H N 2 R R'' N N O H OMe N Bt 1. BuLi; Br Ph OMe Ph N OMe acid hn CN OMe + N 2. BuLi; N N3 N Bn Ph NPh NHPh N H Ph Ph Ph O-

Reductive Ring Contractions: CO2Et Disconnection 12: Ar N Cl Zn Allenes: HOAc 1. PPh3 CO2Me N CO2Et MeO C N 2 H Ph 2. DDQ • CO2Me + OMe Ph TsN 3. NaOMe MeO CO2Me N Zn H N CO2Me Rhodium: R'' MeO2C N HOAc N R' MeO2C H R' R R'' Rh2(CO)12 CN CO Et + 2 CO2Et O O N Disconnection 10: R H Cobalt: Base Catalyzed: 1. Co2(CO)6 R R 2. BF3•OEt2 R Ph Ph CO Me KOtBu R 2 OH 3. N ( )n N Cl N H H MeO2C N ( ) Me n LDA, DDQ McMurray Type Coupling: n=2 n=1 R' R R Bn TiCl MeO C Ph 3 R' 2 R'' NH O R R R'' N Zn H N N O H MeO2C H

Mass, 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 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Disconnection 13: Disconnection 16:

Ph RCHO PhNC R'' X H CN CO2Me O Y DBU MeO2C + O- R'NH2 R''CO2H N+ R Ph O CN CO2Me CO2Me R' N N X Y R'' H R R'

Disconnection 14: Disconnection 17: R' RNH2 EtNO 2 SmCl3 R' R' 1. BuLi NR R R' Me R'' R'' O R'NH O 2. 2 R' N O R Br N R'' R R R' Disconnection 15: Disconnection 18: Palladium: From Cyclopropanes: Ph Ph Ph PdCl2 Ph + N(TMS) Ph MeO2C 2 hn TMSCN or NiCl2 N CO2Me NC H N N Titanium: Ph R'

R R' Ti(OiPr)4 R'' NR''' R From Cyclobutanes: R R' Ti(OiPr)2 2 iPrMgCl CO R'' PhS R' N SPh BzO R''' SPh AlEt Cl Zirconium: 2 NR N Li Ph Ph R Ph N Cp2(Me)ZrCl Ph TMS NTMS Ph Cp2Zr CO N H

Mass, 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 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Selected Syntheses: Selected Syntheses:

Strychnine: Woodward (Classics I) Isochrysohermidin: Boger (Classics II) N OH CO2Me MeO NMe H MeO N H H O O MeO C O H O 2 N HO Me

O CO Me OMe MeO2C 2 OMe PPA N MeO NH OMe MeO N Disconnection 9 MeO NHNH2 OMe N MeO H CO2Me CO2Me Fischer Indole Synthesis MeO C CO Me 2 2 MeO2C N CO2Me N N H

Strychnine: Overman (Classics I) Aspidophytine: Corey (Classics II)

N N

H O O N MeO H H N O MeO Me H H O

N N

NO2 Fe, AcOH silica gel HO N NH2 H H MeO N H MeO NO2 H MeO C MeO2C 2 OMe OMe Disconnection 1a OH OH Batcho-Leimgruber Indole Synthesis Variant

Syntheses were only included if they synthesized the indole or pyrrole 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Selected 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 OH MeO2C NH MeO N OAc MeH O CO2Me THPO OTHP nBu3SnH S CO2Bn CO2Bn AIBN MsO N O O H N CO Bn CO Bn MsO 2 O O 2 H F Fukuyama Indole Synthesis F CONHPh N Mitosene: Rebek (J. Org. Chem. 1984, 49, 5164) N Ac2O O OCONH2 CONHPh HO2C O H N 2 Huisgen Pyrrole Synthesis OMe N

O NH2 EtO OEt

OEt F - F O CO2Me O H2N OEt N MeO2C O MeO2C DMAD MeO2C + N N O Paal-Knorr Pyrrole Synthesis CONHPh CONHPh OAc OAc Huisgen Pyrrole Synthesis

Syntheses were only included if they synthesized the indole or pyrrole 9/1/04 Richter Indole and Pyrrole Synthesis: " " Group Meeting

Selected Syntheses: Selected Syntheses:

Axert®: Janssen (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004) ®: Syntex (Muchowski, Adv. Med. Chem. 1992, 1, 109) – 1st Generation strategies utilize pyrrole syntheses – Process synthesis uses starting from pyrrole N NH2 S O O O N N H H CO2H

CO2Me N I CO2Me S Pd(OAc)2 CO2Me O N CO2Me O O S Br N Bu4NBr O CO2Me O HO CO2Me TEA N N N O CF H H 3 Disconnection 8a HO Hantzsch Pyrrole Synthesis Hapalindole G: Fukuyama (J. Am. Chem. Soc. 1994, 116, 3125) Cl

H H NC MeO H O OMe AcOH N OH HO N H2N H Paal-Knorr Pyrrole Synthesis Cl Cl O S H 1. Me OMe O O H Li H

2. HgCl2, HClO4 N NHAlloc Disconnection 1a Alloc

Syntheses were only included if they synthesized the indole or pyrrole