Manual de Síntesis de Indoles

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
CO2H
3. Hegedus Indole Synthesis 15 3 serine
4. Fukuyama Indole Synthesis glucose
Steps NH2 Steps N
5. Sugasawa Indole Synthesis 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)
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. 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

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 O

Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996

9/1/04

Disconnection 1a: Disconnection 1a:
R OCOR
Batcho-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: 50's – 90's
5
4
Variants:

Me CN

R CH3NO2
NO2 NO2
NO2 NO2
[H] – 1: Reduction, then acid
R R
– 2: Reduction, then acid
NO2 N
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 CO2Et
Base
[H] CO2Me
(CO2Et)2 O N
NO2 NO2
H

Sundberg, R.J. Indoles. Sundberg, R.J. Indoles; Reissert, A. Ber. 1897, 30, 1030

9/1/04

Disconnection 1b: Disconnection 1d:

Palladium Synthesis: Hegedus Indole Synthesis:
R' PdII, then [H]
or
Me
R NH2 N
R R'M 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: 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
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
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

Disconnection 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:
O
Sugasawa 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
O
Bischler 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

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, 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

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 = 30's – 90's R H
OH R
– Unknown mechanism – not a nitrene insertion reaction

Bartoli, G. Tetrahedron Lett. 1989, 30, 2129; Castro, C.E. J Org. Chem. 1966, 31, 4071 Sundberg, R.J. Indoles.

9/1/04

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
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 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

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
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 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

Disconnection 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–3

From 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 EWG's 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 pyrrole

Katritzky, A.R. Handbook of Heterocyclic Chemistry. Pergamon. San Diego, 2000 Mass, G. Science of Synthesis. Thieme. New York: 2001

9/1/04

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

9/1/04

Disconnection 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
H

Mass, G. Science of Synthesis. Thieme. New York: 2001

9/1/04

Disconnection 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 NR
2-Aminopyrroles:
Disconnection 7:
R''
R' R R'
N R'''NC Knorr Pyrrole Synthesis: O
NHR''' COR''
R' O R'
R''
D N +
R R''
R'''
R NH2 N
O R''' R H
From Cyclopropenes:
R' Trofimov Pyrrole Synthesis:
Ar hn
+ R' N Ar
R
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

Disconnection 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 compound
Formal 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
Bn
Stepwise:
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
Zav'Yalov 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
R


9/1/04


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 N
Disconnection 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, DDQ
McMurray 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 H


9/1/04


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

Disconnection 14:
Disconnection 17:
R'
RNH2 EtNO2 SmCl3 R' R' 1. BuLi
NR R
R' Me R'' R'' O R'NH2
O R' 2. O
N
R Br N R''
R R R'

Disconnection 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 N
Titanium: 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 AlEt2Cl
Zirconium:
NR N
Li Cp2(Me)ZrCl Ph Ph R
Ph N Ph
TMS Ph
NTMS
Cp2Zr CO N
H


9/1/04

Selected 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 H

Strychnine: 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 Variant

Syntheses were only included if they synthesized the indole or pyrrole

9/1/04

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
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
N
Mitosene: 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 Synthesis

Syntheses were only included if they synthesized the indole or pyrrole

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