Richter
Indole and Pyrrole Synthesis: "
Disclaimer:
This lecture will only cover methodology for the construction of the indole and
pyrrole ring systems, rather than functionalionalization of pre-existing heterocycles,
which would be the topic of another series of lectures.
Partial List of Transforms Discussed:
1. Batcho-Leimgruber Indole Synthesis
2. Reissert Indole Synthesis
3. Hegedus Indole Synthesis
4. Fukuyama Indole Synthesis
5. Sugasawa Indole Synthesis
6. Bischler Indole Synthesis
7. Gassman Indole Synthesis
8. Fischer Indole Synthesis
9. Japp-Klingemann Indole Synthesis
10. Buchwald Indole Synthesis
11. Bucherer Carbazole Synthesis
12. Japp-Maitland Carbazole Synthesis
13. Larock Indole Synthesis
14. Bartoli Indole Synthesis
15. Castro Indole Synthesis
16. Hemetsberger Indole Synthesis
17. Mori-Ban Indole Synthesis
18. Graebe-Ullmann Carbazole Synthesis
19. Madelung Indole Synthesis
20. Nenitzescu Indole Synthesis
21. Piloty Pyrrole Synthesis
22. Barton-Zard Pyrrole Synthesis
23. Huisgen Pyrrole Synthesis
24. Trofimov Pyrrole Synthesis
25. Knorr Pyrrole Synthesis
26. Hantzsch Pyrrole Synthesis
27. Paal-Knorr Pyrrole Synthesis
28. Zav'Yalov Pyrrole Synthesis
29. Wolff Rearrangement
"
9/1/04
Group Meeting
Indole:
Nature:
– The most abundant heterocycle in nature
– Found in tryptophan, indole-3-acetic acid (plant growth hormone),
serotonin (neurotransmitter), natural products, drugs
– Isolated industrially from coal tar
– Biosynthesis of tryptophan
CO2H
15
glucose
Steps
3
Steps
NH2
anthranilate
serine
N
H
tryptophan
Reactivity:
C–4
C–3
C–7
N
H
C–5
C–2
C–6
– Isoelectronic with naphthalene (slightly lower stabilization energy)
– Indole has a higher stabilization energy than benzene
– Very weakly basic: pKa of protonated indole: –2.4
– Protonation occurs at C–3 preferentially
– Easily oxidized (atmospheric oxygen) – very electron rich
– Less prone to oxidation of EWG's on the ring – less electron rich
– Electrophilic attack occurs at C–3 (site of most electron density)
– C–3 is 1013 times more reactive to electrophilic attack than benzene
– C–2 is the second most reactive site on the molecule, but most easily
functionalized by directed lithiation
– pKa of N–H is 16.7 (20.9 DMSO)
– N–1 is the most nucleophilic site on indole
– Nucleophilic substitution at benzylic carbons enhanced
– Regiospecific functionalization of the carbocycle is difficult without
pre-functionalization of the ring (i.e. halogenation)
Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996
Richter
Indole and Pyrrole Synthesis: "
O
+
+
X
+
N
H
N
H
O
X
H2N
NH2
O
N
H
O
N
H
O
N
H
N
H
9c
N
H
NH2
1a
Ring
Contracton
1b
1c
X
NH2
9b
12
11
9a
N
H
13
10
N
H
X
N
H
NH2
9
O
2
+
N
H
X
1d
1
R+O
N
H
9/1/04
Group Meeting
"
8c
8
Y
+
3a
7
8a
6
5
X
3b
S
+
3c
N
H
N
H
R
N
H
NHCl O
3d
N
H
+
NHOH
N
H
N
H
R
Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996
+
Y
NH2 X
X
NH2
4
N
H
N
H
N
H
3
N
H
8b
N
H
N
H
+
NH2
NHNH2
O
X
Richter
Indole and Pyrrole Synthesis: "
Disconnection 1a:
9/1/04
Group Meeting
"
Disconnection 1a:
R
Batcho-Leimgruber Indole Synthesis:
O
NO2
OMe
Me
Me
R
N
OMe
Me
NO2
N
R
NO2
1
[H]
2
R
N
H
NO2
NH
OCOR
– Typical [H] = H2, Pd/C; hydrazine, Raney Ni
– Other side products from reductive cyclization include N–O
– Yields: 50's – 90's
R
6
R
R
O
NH2
NO2
5
Variants:
OH
NO2
3
4
CN
Me
CH3NO2
R
NO2
NO2
R
[H]
R
NO2
HNO3
R
NO2
– If R = carbonyl, use KF / 18-c-6 / i-PrOH for the Henry reaction
– Use classic Henry conditions otherwise
–Typical [H] = Fe, Fe/SiO2
– Yields: 40's – 90's
N
H
– 1: Reduction, then acid
– 2: Reduction, then acid
– 3: Oxidation, then reduction, then acid
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
Ru(PPh3)2Cl2
– 4: Reduction of nitro and cyano (one or two steps), then acid
– 5: Wacker oxidation, reduction, then acid
– 6: Ozonolysis, reduction, then acid
Reissert Indole Synthesis:
Me
NO2
Sundberg, R.J. Indoles.
NO2
NO2
CO2Et
Base
(CO2Et)2
[H]
O
NO2
Sundberg, R.J. Indoles; Reissert, A. Ber. 1897, 30, 1030
CO2Me
N
H
Richter
Indole and Pyrrole Synthesis: "
Disconnection 1b:
Disconnection 1d:
Palladium Synthesis:
Hegedus Indole Synthesis:
PdII, then [H]
or
R'
R
R
PdII
Me
N
H
PdII,
Cu(OAc)2,
benzoquinone
– Applied to the total synthesis of rac-aurantioclavine by Hegedus
R
N
H
NHX
NH2
N
H
R'M
PdII
9/1/04
Group Meeting
"
(Hegedus, L.S. J. Org. Chem. 1987, 52, 3319)
H+
R
Br
H
N
I
N
H
– X can be either H, Ac, Ms, TFA
– The intermediate organopalladium can be intercepted
– Yields: 40's – 90's
N
H
N
H
– Applied to the total synthesis of arcyriacyanin A by Steglich
(Steglich, W. Chem. Eur. J. 1997, 3, 70)
Disconnection 1c:
Br
R
O
H
N
O
R
N
H
NO2
R
R
R
NO2
R
N
H
N
H
Disconnection 1–Misc.:
Fukuyama Indole Synthesis:
– Reductive cyclization mediated by (EtO)3P or PdCl2/PPh3/SnCl2 and CO
– Migratory aptitudes unknown
– Unknown mechanism – does not involve a nitrene
nBu3SnH
S
N
H
Sundberg, R.J. Indoles.
NH
N
Ts
R
R
AIBN
N
H
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.
Richter
Indole and Pyrrole Synthesis: "
Disconnection 2:
Disconnection 3b:
Pyrrone Diels-Alder:
Gassman Indole Synthesis:
O
S
N
H
N
H
R'
– Little regiocontrol observed in most reactions
– pyrrole-quinodimethanes are not stable and therefore not amenable for
Diels-Alders directly
R'' Raney-Ni
R
O
NH
O
SMe
1. t-BuOCl
2.
R''
R
9/1/04
Group Meeting
"
R
N
3. base
R''
N
R'
R'
– Good regiocontrol observed with ortho or para substitution
– ortho/para methoxy substituents failed completely
Disconnection 3c:
Disconnection 3a:
O
Sugasawa Indole Synthesis:
CN
+
NH2
BCl3
ZnCl2, AlCl3
or TiCl4
Cl
CN
NH2
N
NaBH4
NaOMe
NH2
N
H
X
R
R
N
O-
•
Z
R
N
H
O
acid
O
OH
OMe
R
Ar
Ar
+
Li2PdCl4
H
N
O
O
Ac
– Requires very strong Lewis Acids so many functionalities are not stable
– Choice of second Lewis acid depends on substitution pattern
Bischler Indole Synthesis:
OH
N
H
– Quite mild, if the O-vinyl derivatives can be synthesized
– 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.
N
H
Richter
Indole and Pyrrole Synthesis: "
Disconnection 3d:
Disconnection 3d:
Fischer Indole Synthesis:
Bucherer Carbazole Synthesis:
X
R'
O
+
R'
R
NHNH2
NaHSO3
+
acid
R
H2O
9/1/04
Group Meeting
"
NHNH2
N
H
Mechanism?
– Common acids: HCl, H2SO4, PPA, BF3/AcOH, ZnCl2, FeCl3, AlCl3,
CoCl2, NiCl2, TsOH
– Regioselectivity not great with unsymmetrical ketones
– Tolerates a wide range of substitution
– Product regioselectivity affected by choice of acid, solvent, temperature
acid
N
H
X=OH, NH2
Japp-Maitland Condensation:
0.5 eq
Japp-Klingemann Modification:
OH
R'
O
+
N2
O
R
+
acid
OR''
N
Disconnection 3–Misc.:
NH
R'
R
R'
Larock Indole Synthesis:
1. Pd//BINAP
R
2. TsOH
N
H
O
N
OBn
O
NH2•MsOH
O
Pd(OAc)2
+
N Me
S
HN
R
R''
R'
R'
NH
O
MK-677
Merck
T, 1997, 53, 10983
(Larock, R.C. J. Org. Chem. 1998, 63, 7652)
I
Pharmaceutical Applications of the Fischer Indole Synthesis:
N
S O
O
N
H
N
H
CH2R'
+
HCl
CO2R''
D
Buchwald Modification:
Br
NHNH2
R''
Base
N
R
Me
Me
N
H
Imitrex®
Glaxo
e.g. Heterocycles, 2000, 53, 665
Sundberg, R.J. Indoles; Buchwald S.L. J. Am. Chem. Soc. 1998, 120, 6621
– Base additives vary by reaction
– High functional group tolerance
– Bulkier R group placed at C–2 of the indole
Bucherer, H.T. J. Prakt. Chem. 1908, 77, 403; Japp, F.R. ; Maitland, W.J. J. Chem. Soc. 1903, 83, 273
Richter
Indole and Pyrrole Synthesis: "
Disconnection 3–Misc.:
Disconnection 5:
Bartoli Indole Synthesis:
Stepwise:
R''
+
R'
NO2
R'
R
R''
R
One pot:
1. 2.2 BuLi
– Mechanism?
– Only works well with 2-substituted nitrobenzenes
R
N
H
2. RCO2Me
NHX
X = TMS, Boc
Castro Indole Synthesis:
Disconnection 6:
R
+
R
N
H
3. RCOCl
N(TMS)2
N
H
2 eq
I
1. Zn
2. CuCN, LiCl
Br
BrMg
9/1/04
Group Meeting
"
CuOTf
R
NH2
N
H
RO2C
N
CHO
TBDMSTf
HO
RO2C
N
CHO
Disconnection 4:
Hemetsberger Indole Synthesis:
CO2R
N3
N
H
N
H
O
CO2R
D
Disconnection 7:
N
CO2R
N
H
– Formed by condensation of aromatic aldehyde with a-azoester with
NaOEt, under very carefully controlled conditions to prevent N2 loss
– Yields = 30's – 90's
– Unknown mechanism – not a nitrene insertion reaction
Bartoli, G. Tetrahedron Lett. 1989, 30, 2129; Castro, C.E. J Org. Chem. 1966, 31, 4071
O
TsOH
R
Sundberg, R.J. Indoles.
N
H
OH
N
H
R
Richter
Indole and Pyrrole Synthesis: "
Disconnection 8a:
9/1/04
Group Meeting
"
Disconnection 8b:
Heck Approach:
More Palladium:
X
R
R
X
Pdo
CO2R
CO2R
Pd(OAc)2
N
R'
N
R'
N
R'
– Yields = 70's – 90's
– Choice of base and protecting group on the nitrogen can affect the yield
N
R'
– Works best with an EWG on the olefin
Photochemical:
More Palladium:
hn
R
X
Pdo;
N
H
RZnCl
N
H
– Can intercept the intermediate organopalladium species
– Any organozinc reagent can be used to transmetallate.
N
H
Disconnection 8c:
Acid Catalyzed Cyclization:
O
R
Mori-Ban Indole Synthesis:
R
(Ph3P)4Ni
N
Me
N
Me
X = TFA,
alkyl,
solfonyl
LA
N
X
N
X
Cl
N
H
taut.
– LA commonly ZnCl2
– Can also use ketals with BF3 or TiCl4
Disconnection 8–Misc.:
– Requires stoichiometric nickel
– Yields only about 50%.
Graebe-Ullmann Carbazole Synthesis:
N
N
N
Ph
D
N
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
Richter
Indole and Pyrrole Synthesis: "
Disconnection 9a:
Disconnection 10:
Madelung Synthesis:
Diels-Alder:
R
R
N
H
EDG
EDG
3 BuLi
EWG
N
H
O
N
H
– Yields = 40's – 90's
N
H
EWG
– Works best when matched
Disconnection 11:
Variant of Madelung:
X
N
H
Base
Diels-Alder:
N
H
O
EWG
EWG
– Where X is a phosphorous, nitrogen, silicon, or oxygen to stabilize
a negative charge
– If X is phosphorous, then it is an intramolecular Wittig.
N
H
N
H
EDG
EDG
– Works best when matched
Disconnection 9b:
Disconnection 12:
Base/Acid Catalyzed closure:
Nenitzescu Synthesis:
O
N
Ar
R
Base
N
Ar
H
R'
D
R''
O
N
H
HO
R'
N
R''
R
– Mechanism?
– Substitution on the quinone ring is acceptable and predictable
– Substitution on the enamine is tolerated, but R' is best as an EWG
– Used in the synthesis of LY311727 (Lilly)
Disconnection 9c:
McMurray Type Closures:
O
TiCl3
O
N
Ar
R'
O
Acid or
R
Sundberg, R.J. Indoles.
9/1/04
Group Meeting
"
O
Zn
N
Ar
MeO
CO2NH2
P
OMe
N
Bn
Sundberg, R.J. Indoles; Ninetzescu, C.D. Bull. Soc. Chim. Romania. 1929, 11, 37; J. Org. Chem. 1996, 61, 9055
Richter
Indole and Pyrrole Synthesis: "
"
Disconnection 13:
Pyrrole:
Wolff Rearrrangement:
Nature:
– Very abundant in nature
– Found in porphyrins, natural products, drugs
– Isolated industrially from coal tar and/or bone oil
O
N2
CO2H
hn
N
H
N
9/1/04
Group Meeting
Reactivity:
C–3
From Quinolines:
C–2
CHO
hn
N+
O-
Ph
O
N
Ph
Ph
N
H
Katritzky, A.R. Handbook of Heterocyclic Chemistry. Pergamon. San Diego, 2000
N
H
– Protonation occurs at C–2 preferentially
– Easily oxidized (atmospheric oxygen) – very electron rich
– 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
Mass, G. Science of Synthesis. Thieme. New York: 2001
Richter
Indole and Pyrrole Synthesis: "
Ring
Expansion
N
H
"
N
H
N
H
N
H
N
H
18
17
16
1
N
H
2
15
3
14
N
H
N
H
4
N
H
13
5
12
N
H
N
H
6
11
10
9
8
7
N
H
N
H
N
H
N
H
Ring
Contraction
N
H
N
H
9/1/04
Group Meeting
Richter
Indole and Pyrrole Synthesis: "
9/1/04
Group Meeting
"
Disconnection 1:
Disconnection 3:
Palladium with Alkenes:
Piloty Synthesis:
Me
PdCl2
Et
OH
O
N
Me
H2NNH2
CoI2, D
O
Et
N
H
R
N
H
– Mechanism?
– Exists mainly in the tautomeric form
Disconnection 4:
Palladium with Alkynes:
Thermal Cyclization:
Pd/C
TEA,
MeOH
N
Cbz
CO2Et
N
Cbz
D
N3
CO2Et
N
H
Carbene Insertion:
Disconnection 2:
Ph
CN
+
Ts
O
CN
NaOEt
Ph
R
R'
1. TMSCLiN2
R
R''
R''
2. MnO2
R'
CO2Et
NC
NHR'''
N
R'''
N
H
Disconnection 5:
Disconnection 3:
Rhodium:
Ph
HO
Ph
NH4OAc
Ph
AcOH
+
Ph
O
Ph
Ph
Ph
O
Ph
Mass, G. Science of Synthesis. Thieme. New York: 2001
H2, CO
Ph
N
H
NH2
[Rh], PPh3
Ph
N
H
Richter
Indole and Pyrrole Synthesis: "
Disconnection 5 Continued:
Disconnection 6:
Iron:
Barton-Zard Pyrrole Synthesis:
Ph
Fe2(CO)9
NPh
R
base
+ CN
R'
R'
CO2R''
CO2R''
N
R
Me
MeLi; tBuBr
N
H
Me
– Original Barton-Zard used NO2 as the LG.
Bis-Nucleophile/Bis-Electrophile:
Niobium:
Ph
OMe
Ph
Ph
LG
R
Ph
9/1/04
Group Meeting
"
NbCl3
+
NR O
Ph
Ph
RHN
OMe
Ph
Ph
+ EtO2C
O
N
KOtBu
CN
Ph
O
O
CN
Ph
N
Ph
Nb
Extrusion (Huisgen Pyrrole Synthesis):
Ph
Me
Me
N
R
Ph
Ph
R
R'''NC
D
R''
Ph
R'
NHR'''
N
R
Knorr Pyrrole Synthesis: O
R'
From Cyclopropenes:
R'
Ar
N
COR''
O
R'
+
R
+ R'
Ph
N
Disconnection 7:
R''
Cl
DMAD
CO2Me
MeO2C
– X is usually S or NR
2-Aminopyrroles:
N
X
N+
N
R
R'
-O
Ph
ONb
NH2
R''
O
R'''
R
R'''
N
H
Trofimov Pyrrole Synthesis:
hn
R
or D
Ar
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
Richter
Indole and Pyrrole Synthesis: "
Disconnection 7 Continued:
Disconnection 8:
Hantzsch Pyrrole Synthesis:
Paal-Knorr Pyrrole Synthesis:
+
Br
R
O
R''
R''
O
H2N
+
RNH2
R'
R
R''
R'
R''
R'
O
N
H
R
9/1/04
Group Meeting
"
N
R
– Can access the diketone in-situ by reduction of the bis-cyano compound
– Can access via reduction of the g-nitro ketone
Formal 3+2:
Bn
R
R
N
Palladium:
D
PdCl2, Cu(OAc)2;
+
N
Bn
NO2
N
Bn
AgBF4, PPh3, BnNH2
Stepwise:
R
+
R
I
OAc
1. Base
2. Acid
O
R
O
NNMe2
R
N
Bn
BnNH2
O
3. H2, Ni
Pd(PPh3)4
N
H
Zav'Yalov Pyrrole Synthesis:
R
Ugi Approach:
NC
Ph
CN
HO2C
O
NC
R'
R
Ph
R'
O
NH3Cl
O
O
N
O
R
NMe2
HO2C
O
NH2
TEA
R''
CO2H
HN
RCHO
Ph
NC
MeO
CH2N2
N
R
R'
NH
+
R''
R
Ac2O
CONCy
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
R''
N
Ac
Richter
Indole and Pyrrole Synthesis: "
Disconnection 9:
Disconnection 11:
Wolff Rearrangement/Photolytic:
O
hn
R
CO2H
hn
N
CN
N
Bn
N
H
N3
O-
CO2Et
Reductive Ring Contractions:
N
Zn
Cl
N
CO2Et
MeO
CO2Me
MeO2C
N
N
HOAc
1. BuLi; Br
OMe
2. BuLi; Ph
NPh
N
H
R
Ph
Bt
OMe
OMe
Ph
Ph
TsN
CO2Me
3. NaOMe
Zn
CO2Me
acid
NHPh
Ph
1. PPh3
2. DDQ
Ph
CO2Me +
•
OMe
HOAc MeO C
2
N
R''
Disconnection 12:
Allenes:
MeO2C
R'
CO2Et
OMe
N
N+
H
R'
EtO2C
Cu(acac)2
N
H
O
N
N2
NHR''
+
N2
Ar
9/1/04
Group Meeting
"
Rhodium:
CN
R''
R'
N
H
CO2Et
+
R
Disconnection 10:
Rh2(CO)12
R''
O
Ph
N
H
O
R'
CO2Et
R
N
H
Cobalt:
Base Catalyzed:
R
R
N
KOtBu
Ph
R
OH
N
H
Cl
1. Co2(CO)6
2. BF3•OEt2
3.
MeO2C
( )n
H
N
R
Ph
Me
McMurray Type Coupling:
R'
R''
O
O
LDA, DDQ
n=2
R
NH
CO2Me
N ( )n
R
TiCl3
Zn
R'
R''
n=1
Bn
N
H
MeO2C
Ph
R
N
H
R
MeO2C
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
N
Ph
Richter
Indole and Pyrrole Synthesis: "
Disconnection 13:
H
Ph
Disconnection 16:
CN
CO2Me
CN
CO2Me
+
O
9/1/04
Group Meeting
"
Ph
RCHO
PhNC
R'NH2
R''CO2H
MeO2C
DBU
CO2Me
N
H
R''
R'
Y
X
X
O
Y
O-
N+
R
R''
R
N
R'
Disconnection 14:
R'
RNH2
EtNO2
R'
SmCl3
Disconnection 17:
R'
R'
1. BuLi
NR
O
Me
R'
R''
R''
2. O
N
R
Br
R
O
R
R'NH2
N
R'
R
Disconnection 15:
Disconnection 18:
Palladium:
Ph
Ph
+
TMSCN
From Cyclopropanes:
Ph
PdCl2
Ph
Ph
N(TMS)2
or NiCl2
NC
CO2Me
N
H
hn
N
Ph
Titanium:
R
R'
Ti(OiPr)4
2 iPrMgCl
R
Ti(OiPr)2
R''
NR'''
R'
R''
N
R'''
PhS
BzO
NR
Ph
Cp2(Me)ZrCl
Ph
TMS
Cp2Zr
Ph
Ph
NTMS
CO
SPh
SPh
Zirconium:
Li
N
N
R'
From Cyclobutanes:
R
CO
R'
MeO2C
AlEt2Cl
N
R
Ph
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
R''
Richter
Indole and Pyrrole Synthesis: "
Selected Syntheses:
Selected Syntheses:
Strychnine: Woodward (Classics I)
Isochrysohermidin: Boger (Classics II)
OH
CO2Me
N
MeO
H
N
H
O
NMe
MeO
O
H
MeO2C
N
HO Me
HO
O
OMe
OMe
O
CO2Me
MeO2C
N
PPA
OMe
N
H
OMe
NHNH2
9/1/04
Group Meeting
"
Fischer Indole Synthesis
MeO
MeO
MeO
N
Disconnection 9
MeO
CO2Me
CO2Me
CO2Me
MeO2C
MeO2C
N N
Strychnine: Overman (Classics I)
NH
N
H
CO2Me
Aspidophytine: Corey (Classics II)
N
N
H
N
O
H
MeO
HO
O
N
Me H
N
N
NO2
HO
NH2
O
MeO
H
N
H
H
MeO2C
H
MeO2C
OH
Disconnection 1a
MeO
OH
Syntheses were only included if they synthesized the indole or pyrrole
NO2
Fe, AcOH
silica gel
MeO
OMe
OMe
Batcho-Leimgruber Indole Synthesis Variant
N
H
Richter
Indole and Pyrrole Synthesis: "
9/1/04
Group Meeting
"
Selected Syntheses:
Selected Syntheses:
Vinblastine: Fukuyama (Classics II)
OH
N
Lipitor®: Pfizer (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004)
-O
OH
2C
OH
H
N
N
H
MeO2C
MeO
F
OH
N
Me H
NH
OAc
CO2Me
O
OTHP
THPO
nBu3SnH
S
MsO
N
H
N
H
CO2Bn
AIBN
CO2Bn
O
N
H
MsO
CO2Bn
CO2Bn
O
O
F
Fukuyama Indole Synthesis
CONHPh
F
N
Mitosene: Rebek (J. Org. Chem. 1984, 49, 5164)
O
N
OCONH2
H2N
O
HO2C
Ac2O
CONHPh
O
Huisgen Pyrrole Synthesis
OMe
N
O
NH2
EtO
OEt
OMeO2C
O
DMAD
MeO2C
MeO2C
N+
CO2Me
O
O
N
OAc
F
OAc
Huisgen Pyrrole Synthesis
Syntheses were only included if they synthesized the indole or pyrrole
CONHPh
H2N
OEt
F
OEt
Paal-Knorr Pyrrole Synthesis
N
CONHPh
Richter
Indole and Pyrrole Synthesis: "
9/1/04
Group Meeting
"
Selected Syntheses:
Selected Syntheses:
Axert®: Janssen (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004)
Ketorolac®: Syntex (Muchowski, Adv. Med. Chem. 1992, 1, 109)
– 1st Generation strategies utilize pyrrole syntheses
– Process synthesis uses annulation starting from pyrrole
N
O
NH2
S
O
O
N
N
H
H
CO2H
CO2Me
N
O
I
S
O
N
Bu4NBr
TEA
N
O
CO2Me
Pd(OAc)2
CF3
O
O
HO
N
H
Disconnection 8a
Br
CO2Me
N
H
CO2Me
O
CO2Me
S
CO2Me
N
HO
Hantzsch Pyrrole Synthesis
Hapalindole G: Fukuyama (J. Am. Chem. Soc. 1994, 116, 3125)
Cl
H
H
NC
H
MeO
H2N
N
H
O
1. Me
H
O
S
H
OMe
Li
O
H
2. HgCl2, HClO4
NHAlloc
Disconnection 1a
OMe
AcOH
N
OH
HO
Paal-Knorr Pyrrole Synthesis
Cl
Cl
O
N
Alloc
Syntheses were only included if they synthesized the indole or pyrrole