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Richter
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 Synthesis2. Reissert Indole Synthesis3. Hegedus Indole Synthesis4. Fukuyama Indole Synthesis5. Sugasawa Indole Synthesis6. Bischler Indole Synthesis7. Gassman Indole Synthesis8. Fischer Indole Synthesis9. Japp-Klingemann Indole Synthesis10. Buchwald Indole Synthesis11. Bucherer Carbazole Synthesis12. Japp-Maitland Carbazole Synthesis13. Larock Indole Synthesis14. Bartoli Indole Synthesis15. Castro Indole Synthesis16. Hemetsberger Indole Synthesis17. Mori-Ban Indole Synthesis18. Graebe-Ullmann Carbazole Synthesis19. Madelung Indole Synthesis20. Nenitzescu Indole Synthesis21. Piloty Pyrrole Synthesis22. Barton-Zard Pyrrole Synthesis23. Huisgen Pyrrole Synthesis24. Trofimov Pyrrole Synthesis25. Knorr Pyrrole Synthesis26. Hantzsch Pyrrole Synthesis27. Paal-Knorr Pyrrole Synthesis28. Zav'Yalov Pyrrole Synthesis29. Wolff Rearrangement
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
Reactivity:
– 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)
glucose15
Steps
CO2H
NH2
anthranilate
3
Steps NH
serine
tryptophan
NH
C–3C–4
C–6C–2
C–5
C–7
9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996
NH
Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996
1
2
3
4567
8
9
1011 12 N
H
NH
NH
NHN
HNH
NH
NH
NH
NH
NH
NH
NH2
X
NH2
NH2
NH2
NH2
Y
X
O
S
NHCl
NHOH
X
NHNH2 ONH2NH2
Y
X
NH
X
NH
X
NH
R+O
NH O
X
NH
X
O
NH O
O
NH
NH
NH
NH
X
H2N
O
O
NH
R
R
+ + +
+
+
+
+
++
1a 1b
1c
1d
3a
3b
3c3d
8a
8b
8c
9a
9b
9c
13
RingContracton
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Disconnection 1a:
Batcho-Leimgruber Indole Synthesis:
– Typical [H] = H2, Pd/C; hydrazine, Raney Ni – Other side products from reductive cyclization include N–O – Yields: 50's – 90's
Variants:
– 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
NO2
MeR
NMe
MeOMe
OMe
NH NO2
RN
RNH
[H]
NO2
MeR
NO2
RNO2
RNH
[H]
CH3NO2
RNO2
HNO3
Disconnection 1a:
– 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:
R
ONH2
R
ONO2
OCOR
NO2
R
OHNO2
CN
NO2NO2
R
NO2
1 2
3
45
6
Sundberg, R.J. Indoles. Sundberg, R.J. Indoles; Reissert, A. Ber. 1897, 30, 1030
NO2
Me Base
(CO2Et)2
CO2Et
ONO2
[H]NH
CO2Me
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Sundberg, R.J. Indoles.
Disconnection 1b:
Palladium Synthesis:
– X can be either H, Ac, Ms, TFA – The intermediate organopalladium can be intercepted – Yields: 40's – 90's
Disconnection 1c:
– Reductive cyclization mediated by (EtO)3P or PdCl2/PPh3/SnCl2 and CO – Migratory aptitudes unknown – Unknown mechanism – does not involve a nitrene
Disconnection 1d:
Hegedus Indole Synthesis:
– Applied to the total synthesis of rac-aurantioclavine by Hegedus (Hegedus, L.S. J. Org. Chem. 1987, 52, 3319)
– Applied to the total synthesis of arcyriacyanin A by Steglich (Steglich, W. Chem. Eur. J. 1997, 3, 70)
Disconnection 1–Misc.:
Fukuyama Indole Synthesis:
NHX
PdII
NH
R
R
PdII NH
R
R'
NH
R
R'M
H+
NO2
R
NO2
R
R
NH
R
NH
R
R
NH2
PdII, then [H] or
PdII, Cu(OAc)2,benzoquinone
NH
Me
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.
NH
HN
NH
Br I
NTs
Br
NH
NH
HN
O O
NH
R
SnBu3SnH
AIBN NH
R
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Sundberg, R.J. Indoles.
Disconnection 2:
Pyrrone Diels-Alder:
– Little regiocontrol observed in most reactions – pyrrole-quinodimethanes are not stable and therefore not amenable for Diels-Alders directly
Disconnection 3a:
Sugasawa Indole Synthesis:
– Requires very strong Lewis Acids so many functionalities are not stable – Choice of second Lewis acid depends on substitution pattern
Bischler Indole Synthesis:
– Not very general: requires HBr (1 eq) and 200+ oC – Mechanism?
Disconnection 3b:
Gassman Indole Synthesis:
– Good regiocontrol observed with ortho or para substitution – ortho/para methoxy substituents failed completely
Disconnection 3c:
– Quite mild, if the O-vinyl derivatives can be synthesized
Gassman, P.G. J. Am. Chem. Soc. 1974, 96, 5495; Sundberg, R.J. Indoles.
NH
O
O
NH
NH2
CN
Cl+
BCl3
ZnCl2, AlCl3or TiCl4
NH2
CN NaBH4
NaOMe NH
NH2
+X
Ar
O
NH
Ar
NHR
R'
1. t-BuOCl2.
3. base
S R''O R
N
SMe
R''
R'
Raney-Ni RN
R''
R'
NAc
OH
NR
O-
NR
OH
•
H
Z
O
O
O
OMe
NH
O
Li2PdCl4
NH
RR
acid
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Sundberg, R.J. Indoles; Buchwald S.L. J. Am. Chem. Soc. 1998, 120, 6621
Disconnection 3d:
Fischer Indole Synthesis:
– 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
Japp-Klingemann Modification:
Buchwald Modification:
Pharmaceutical Applications of the Fischer Indole Synthesis:
Disconnection 3d:
Bucherer Carbazole Synthesis:
Japp-Maitland Condensation:
Disconnection 3–Misc.:
Larock Indole Synthesis: (Larock, R.C. J. Org. Chem. 1998, 63, 7652)
– 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
NHNH2 R
OR'
+ acid
NH
R'
RH2O
N2+ R
O+ acid
NH
R'
CO2R''D
CH2R'OR''
O
Br
R
NNH
R'+
1. Pd//BINAP
2. TsOH NH
R'
R
N
N
SO
O
O
OBnO
NH2•MsOHMK-677Merck
T, 1997, 53, 10983
NH
NMe
MeS
O
HN
O
MeImitrex®Glaxo
e.g. Heterocycles, 2000, 53, 665
X
NHNH2
+ NaHSO3
acid NH
Mechanism?
OH NHNH2
0.5 eq
HCl NH
NH
I
R
+R'
R''
Pd(OAc)2
Base NR
R''
R'
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
X=OH, NH2
Bartoli, G. Tetrahedron Lett. 1989, 30, 2129; Castro, C.E. J Org. Chem. 1966, 31, 4071
Disconnection 3–Misc.:
Bartoli Indole Synthesis:
– Mechanism? – Only works well with 2-substituted nitrobenzenes
Castro Indole Synthesis:
Disconnection 4:
Hemetsberger Indole Synthesis:
– 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
Disconnection 5:
Stepwise:
One pot:
Disconnection 6:
Disconnection 7:
NO2R
BrMg
R' R''+
NH
R''
R'
R
NH2
I+
R
NH
RCuOTf
CO2R
N3
CO2RN
NH
CO2RD
N(TMS)2
Br1. Zn2. CuCN, LiCl
3. RCOCl NH
R
NHX
1. 2.2 BuLi
2. RCO2Me NH
R
X = TMS, Boc
N
NH
CHORO2C
Sundberg, R.J. Indoles.
O
HO
N
NH
CHORO2C
TBDMSTf
OH
NHR
O
TsOHNH
R
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
2 eq
Disconnection 8a:
Heck Approach:
– Yields = 70's – 90's – Choice of base and protecting group on the nitrogen can affect the yield
More Palladium:
– Can intercept the intermediate organopalladium species – Any organozinc reagent can be used to transmetallate.
Mori-Ban Indole Synthesis:
– Requires stoichiometric nickel – Yields only about 50%.
Disconnection 8b:
More Palladium:
– Works best with an EWG on the olefin
Photochemical:
Disconnection 8c:
Acid Catalyzed Cyclization:
– LA commonly ZnCl2 – Can also use ketals with BF3 or TiCl4
Disconnection 8–Misc.:
Graebe-Ullmann Carbazole Synthesis:
– Mechanism? – Generally problematic and not widely applicable
NH
X
NH
Sundberg, R.J. Indoles; Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 17, 1803.
NR'
XR Pdo
NR'
R
Pdo;
RZnCl
R
NMe
Cl
NMe
(Ph3P)4Ni
NR'
X CO2R
NR'
CO2R
Pd(OAc)2
NH
NH
hn
taut.
NX
NX
LAO R
RX = TFA, alkyl, solfonyl
NPh
NN
D
NH
Sundberg, R.J. Indoles; Graebe, C.; Ullmann, F. Ann. 1896, 291, 16
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Disconnection 9a:
Madelung Synthesis:
– Yields = 40's – 90's
Variant of Madelung:
– Where X is a phosphorous, nitrogen, silicon, or oxygen to stabilize a negative charge – If X is phosphorous, then it is an intramolecular Wittig.
Disconnection 9b:
Base/Acid Catalyzed closure:
Disconnection 9c:
McMurray Type Closures:
Disconnection 10:
Diels-Alder:
– Works best when matched
Disconnection 11:
Diels-Alder:
– Works best when matched
Disconnection 12:
Nenitzescu Synthesis:
– 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)
Sundberg, R.J. Indoles.
NAr N
Ar
Acid or
Base
Sundberg, R.J. Indoles; Ninetzescu, C.D. Bull. Soc. Chim. Romania. 1929, 11, 37; J. Org. Chem. 1996, 61, 9055
R
NH O
3 BuLiNH
X
NH O
BaseNH
O
RR
NAr N
Ar
TiCl3
Zn
O
O
NH
NH
EDG
EWGEWG
EDG
NH
NH
EWG
EDG
EWG
EDG
O
O NH
R''R
H R'D
NR''
HOR'
R'
NBn
CO2NH2P
MeO
O
OMe
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
R
Disconnection 13:
Wolff Rearrrangement:
From Quinolines:
Katritzky, A.R. Handbook of Heterocyclic Chemistry. Pergamon. San Diego, 2000
N
ON2 hn
NO
Ph
NH
CO2H
N+
O-Ph
hn
NH
CHO
Ph
Pyrrole:
Nature: – Very abundant in nature – Found in porphyrins, natural products, drugs – Isolated industrially from coal tar and/or bone oil
Reactivity:
– 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
NH
C–3
C–2
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Mass, G. Science of Synthesis. Thieme. New York: 2001
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
RingContraction
RingExpansion
12
3
4
5
67
891011
12
13
14
15
1617 18
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Mass, G. Science of Synthesis. Thieme. New York: 2001
Disconnection 1:
Palladium with Alkenes:
– Exists mainly in the tautomeric form
Palladium with Alkynes:
Disconnection 2:
Disconnection 3:
Disconnection 3:
Piloty Synthesis:
– Mechanism?
Disconnection 4:
Thermal Cyclization:
Carbene Insertion:
Disconnection 5:
Rhodium:
N OR
PdCl2
NH
OH
NCbz
NCbz
Pd/C
TEA, MeOH
Ts NC
Ph
CO2Et
CN+ NaOEt
NH
CNPh
Ph
Ph
O O Ph
PhHO+
NH4OAc
AcOH NH
PhPh
PhPh
O
H2NNH2
CoI2, D NH
MeMe
EtEt
N3
CO2EtNH
CO2EtD
R'
O
R
NHR'''
R''1. TMSCLiN2
2. MnO2 NR'''
R'R
R''
PhNH2
H2, CO
[Rh], PPh3 NH
Ph
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
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
Disconnection 5 Continued:
Iron:
Niobium:
2-Aminopyrroles:
From Cyclopropenes:
Disconnection 6:
Barton-Zard Pyrrole Synthesis:
– Original Barton-Zard used NO2 as the LG.
Bis-Nucleophile/Bis-Electrophile:
Extrusion (Huisgen Pyrrole Synthesis):
– X is usually S or NR
Disconnection 7:
Knorr Pyrrole Synthesis:
Trofimov Pyrrole Synthesis:
NPh
Ph
NH
Ph
MeMe
Fe2(CO)9
MeLi; tBuBr
NR
Ph
NbCl3RHN O
PhOMe
Ph
NbO
Ph
OMe
NR
ONbPh
Me
NR
PhMe
PhPh
R''
R'N
R R'''NC
D NR
NHR'''
R''R'
Ar
ClN
RR'+
hn
or D NR
Ar
R'
RR'
LGCN CO2R''
+
+base
NR
CO2R''
RR'
Ph
OO
Ph
EtO2C NPh
CN+ KOtBu
NPh
CN
PhPh
N+
XPh
-ODMAD
NPh
MeO2CCO2Me
R NH2
R' O
O R'''
R''
O
+
NH
R'''
COR''R'
R
NOH NH
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Base
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
Disconnection 7 Continued:
Hantzsch Pyrrole Synthesis:
Formal 3+2:
Stepwise:
Ugi Approach:
Disconnection 8:
Paal-Knorr Pyrrole Synthesis:
– Can access the diketone in-situ by reduction of the bis-cyano compound – Can access via reduction of the g-nitro ketone
Palladium:
Zav'Yalov Pyrrole Synthesis:
+
+
+
R
OBr
H2N R
R''
NH
R'
R''
R
NBn
NO2
R D
NBn
R
R NNMe2
R IO
O 1. Base2. Acid
3. H2, Ni NHR
R
O
Ph
NH3Cl
HO2C CN
NC
RCHO
NO
NC O Ph
RO
HN
NMeO
NCPh
RCONCy
CH2N2
R'
OR''
O
RNH2+
NRR'
R''
PdCl2, Cu(OAc)2;
AgBF4, PPh3, BnNH2 NBn
O
OAc Pd(PPh3)4
BnNH2 NBn
R'R
O
NMe2
NH2HO2C
R''+
R'R
O
NH
CO2HR''
Ac2O
TEA NAc
R'R
R''
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
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
Disconnection 9:
Wolff Rearrangement/Photolytic:
Reductive Ring Contractions:
Disconnection 10:
Base Catalyzed:
McMurray Type Coupling:
Disconnection 11:
Disconnection 12:
Allenes:
Rhodium:
Cobalt:
N
N2
O NH
CO2H
N+
O-N3
hn
hn
NH
CN
N
N ClAr
CO2Et NHMeO2C
CO2Et
Zn
HOAc
NN
CO2Me
MeO2C
MeOZn
HOAc NHMeO2C
OMe
CO2Me
N
R
ClKOtBu
NH
R
R
O
R'
NHR''
O
TiCl3
Zn NH
R'R''
R
R
O
R'
NHR''
H CO2Et
N2+ Cu(acac)2
NR''
R'EtO2C
R
• CO2MeTsN
Ph1. PPh32. DDQ
3. NaOMe NH
Ph
CO2Me
CN CO2EtR
O
R'R''
O
+
+ Rh2(CO)12
NH
CO2Et
R''R'
R
PhOH
R1. Co2(CO)62. BF3•OEt2
3.( )n
HNMeO2C
Me
PhN
R
( )n
CO2Me
LDA, DDQ
n=1n=2
NH
RPh
MeO2CNH
R
BnMeO2C
1. BuLi;
2. BuLi;NBn
NN Br OMe
OMe
Ph NPh NPh
Ph
PhNHPh
Ph
Ph
OMeOMe
Btacid
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
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
Disconnection 13:
Disconnection 14:
Disconnection 15:
Palladium:
Titanium:
Zirconium:
Disconnection 16:
Disconnection 17:
Disconnection 18:
From Cyclopropanes:
From Cyclobutanes:
Ph O
H CO2MeCN
CO2MeCN+ DBU
NH
CO2Me
PhMeO2C
RNH2
OR'
EtNO2 SmCl3
R'NR
R'
NR
MeR'
R'
Ph Ph
TMSCN
PdCl2
or NiCl2+
NH
N(TMS)2
PhPh
NC
R R'Ti(OiPr)4
2 iPrMgClTi(OiPr)2
R
R'
R'' NR'''
CONR'''
R''
R'R
LiNPh
TMSCp2(Me)ZrCl
Cp2ZrNTMS
Ph Ph
CO NH
PhPh
RCHO
R'NH2 R''CO2H
PhNC
YXN+
OR''O-
RR' N
R'
R
XY
R''
R''1. BuLi
2.
R
OBr
R'' O
R
R'NH2
NR'
R
R''
CO2MeN
Phhn
NR'
MeO2C
Ph
NR
BzO SPh
PhS
AlEt2Cl
NR
SPh
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Selected Syntheses:
Strychnine: Woodward (Classics I)
Strychnine: Overman (Classics I)
N
O
N
OH
H
H
H
NHNH2
OOMe
OMe
PPA
NH
OMe
OMe
Fischer Indole Synthesis
N
O
N
OH
H
H
H
NHMeO2C
N
H
OH
MeO2C
N
H
OH
NH2HO
Disconnection 1a
Selected Syntheses:
Isochrysohermidin: Boger (Classics II)
Aspidophytine: Corey (Classics II)
NMe
NMe
O
O
MeO
MeO
OH
MeO2C
CO2Me
HO
N N
NN
MeOMeO
CO2MeCO2Me
MeO2C
MeO2C
NH
NH
CO2Me
CO2Me
MeO
MeO
MeO2C
CO2Me
Disconnection 9
NMe
N
H
O O
MeO
MeO
MeOOMe
NO2
NO2 Fe, AcOHsilica gel
NHMeO
OMeBatcho-Leimgruber Indole Synthesis Variant
Syntheses were only included if they synthesized the indole or pyrrole
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Selected Syntheses:
Vinblastine: Fukuyama (Classics II)
Mitosene: Rebek (J. Org. Chem. 1984, 49, 5164)
Selected Syntheses:
Lipitor®: Pfizer (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004)
MsO NH
THPO
S
CO2Bn
CO2Bn
nBu3SnH
AIBNNHMsO CO2Bn
CO2Bn
OTHP
NH
N
NMe
N
CO2Me
OHOAc
H
HMeOMeO2C
OH
H
Fukuyama Indole Synthesis
N
NHO
-O2COH
OHF
N
OHO2C
F
OO
CONHPh
Ac2O
N
F
OO
CONHPh
Huisgen Pyrrole Synthesis
CONHPhO
OF
N
F
OEtEtO
CONHPh
H2N OEt
OEt
Paal-Knorr Pyrrole Synthesis
N
OCONH2
OMe
NH2O
OH2N
O
N+
O-
OAc
MeO2C DMADN
CO2Me
OAc
MeO2CMeO2C
Huisgen Pyrrole Synthesis
Syntheses were only included if they synthesized the indole or pyrrole
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Selected Syntheses:
Axert®: Janssen (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004)
Hapalindole G: Fukuyama (J. Am. Chem. Soc. 1994, 116, 3125)
Disconnection 8a
NH
SN
OO
NH2
SN
OOI
N
O CF3
CO2Me
Pd(OAc)2
Bu4NBrTEA N
H
SN
OO
CO2Me
Syntheses were only included if they synthesized the indole or pyrrole
NH
NCHH
H
Cl
H
Cl
O
S
LiOMeMe
O
1.
2. HgCl2, HClO4NAlloc
H
H
Cl
O
NHAlloc Disconnection 1a
Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "
Selected Syntheses:
Ketorolac®: Syntex (Muchowski, Adv. Med. Chem. 1992, 1, 109) – 1st Generation strategies utilize pyrrole syntheses – Process synthesis uses annulation starting from pyrrole
O
NCO2HH
NH
CO2Me
CO2MeHO
OBr
NCO2Me
CO2Me
HO
Hantzsch Pyrrole Synthesis
OMeO OMe
H2NOH
AcOHN
HO
Paal-Knorr Pyrrole Synthesis
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