synthesis of pyrroles and indoles carbonyl condensations (c.f. chapt. 3) - pyrroles strategy a;...
TRANSCRIPT
Synthesis of Pyrroles and Indoles
Carbonyl condensations (c.f. chapt. 3) - Pyrroles
Strategy a; Paal-Knorr synth.
OR'
OR
NH2R''
NR''
OHR'
HOR N
R''R'R
- 2 H2O
R''=H, alkyl, aryl
- 2 H2OOHHO
CO2HO2C
HO OH
RNH3
ΔOO
HO2C CO2H
RNH2
NR''
OHCO2H
HOHO2C - 2 H2O N
R''CO2HHO2C
-2 CO2 NR''
R, R' = H: OOUnstable
Synthons:
O OMeMeO OHHO
CO2HO2C
HO OH
BuNH3
X
a
b
X
X
X
c
Not useful for indoles
NR
X
O
R
H2N-R
Would requireNu.Ar subst.
Strategy b; Knorr synth.
OR3
HNR5
RO2C
O R2R4
Base
R2, R3 ≠H
RO2C
O R2
OR3
HNR5
R4
Neccesary for easy enolization
NR5
R2HO
RO2CR4
OHH
H
R3
- 2 H2O N
RO2C R3
R4R2
R5
Can be removed;hydrol., decarbox.
If R2=CO2RCan be removed;hydrol., decarbox.
May be H
Alkyl,aryl
Strategy a and b combined; Hantzsch synth.
X
a/b
X
OR
Cl
CO2R3
O R4
NR'
R R4
CO2R3
NH2R'
OHR4
CO2R3
HNR'
CO2R3
NR'
R4
imin
taut.CO2R3
HNR'
R4
enamin
- HCl- H2O O
R
N
R4
CO2R3
R'imin
taut.
O
R
HN
R4
CO2R3
R'enamin
N
CO2R3
R4
R'
RHO
HH
- H2O
OR
ClR, R4: alkyl, arylR': H, alkyl, aryl
CO2R3
O R4NR'
R R4
CO2R3
May be removed;hydrol, decarbox.NH2
R'
X
a
b
X
X
X
c
Strategy cX
a
b
X
X
X
c
R2
RO
O
R, R2: H, alkyl, aryl
HNR'
CO2R3
glycine der.
R2
R O
HO NR'
- H2O
R2
RO
NR'CO2R3 CO2R3
Base
R2
RO
NR' CO2R3
N
R2OH
CO2R3
H
R'R - H2O N
R'
CO2R3R
R2
R2
O
HNTs
CO2R3
R2
R O
NTs CO2R3
Base
R2
RO
NTs CO2R3
N
R2OH
CO2R3
H
TsR
- H2O N
R2
CO2R3
H
Ts
RBaseH
N
R2
CO2R3RH
taut.
Carbonyl condensations (c.f. chapt. 3) - Indoles
Strategy b -Reissert synth.
N
Na
NC
b
CH3
NO2
Base CH2
NO2
O O
OEtEtO
NO2
O
CO2EtH2 / cat.
NH2
O
CO2Et-H2O N
H
CO2Et
NO
O
- Modified Reissert synth.; Leimbruger-Batcho
CH3
NO2p 358 NO2
X
X: NO2, NMe2
TiCl3
NH
-Madelung synth.
CH2Br
NO2
PPh3CH2PPh3
NO2
Br1) Zn /H+
2) RCOClCH2PPh3
NH
Br
O
R
Base
NH
R
Carbonyl condensations (c.f. chapt. 3) - Indoles
Strategy a -Bischler synth.
N
Na
NC
b
NH2
1) BrCH2CH(OEt)22) (CF3CO)2O
NTf
OEtEtO
- H2ONTf
-Gassman synth.
NH2
t-BuOClNH
Cl
O
RS
NH
S
O
R
Cl
Base
NH
S
O
R
ON
SCH3
R
H
H
Base
NH
MeS HOHR- H2ON
H
R
SMe
H2 / cat.
NH
R
Cycloadditions with 1,3-dipoles (c.f. chapt. 3)a
bc
d e d e
c
b
a
X X
alkene / alkyne
1,3-dipole
N CR isocyanate
Base
N CR
EWG
'R
N
EWG
R
'RH
HH
R=Ts (TsMIC)R=Benzotriazolyl (BetMIC)R=-CO2R
EWG= NO2, COR
MIC: methyl isocyanate
Bet:
NN
N
Reaction with isocyanide
Alt. I; van Leusen synth.
R: Ts or Bet (Good leaving groups)EWG: -COR
N
COR
Ar
'RH
HH
N
COR
Ar
'RH
HN
R'H
COR taut.
NH
'R COR
Alt. II; Barton Zard synth.
R: -CO2REWG: -NO2
N
NO2
H
'RH
RO2CH
N
NO2'RH
RO2CH
N
R'H taut.
NH
'R
RO2CRO2C
Reaction with mesoionic oxido-oxazoliums
R R2
O
HN R4
O
R3
NH
R R2
R3 R4
OO
- CO2 NH
R R2
R4R3
O
HN
R4
O
R3O
N R4
O
R3
H
- H2O
HNO
HO OR3
R4
N-acylaminoacid
Mesoionic:Zwitter ion - no unchargedres. form
NH
O NH
O
Not mesoionic
Reaction with nitrenes
N3
CHO MeNO2Base
N3
NO2 Δ
N
NO2
NH
NO2
N+H R NH
R
R N N N R N N N R N
azid(1,3-dipol)
- N2
Δ or hν
Nitren
Synthesis from aminoalkynes
R
HNTs
I I
BaseNTs
I
R
EWG
EWGBaseH
NTs
I
R EWG N
I
R EWG
tautH
HH
HH
H
NH
I
EWGR
JOC 2003, 7853
R
HN'R
R: alkyl, alkenyl
cat. Pd(II) or Cu(II)
NR'
R R
HN'R
Metn+
N
R'HR
Met(n-1)+
- Metn+NR'
R
H tautH
H
H
H NR'
R
R
HN'R
R: H, Ph, THP
NR'
Spont.1) PBr32) R'NH2 RR
OH
N
N NH
N
OH
TCB
N
N NH
N
O
R
NHR'
cat. Pd(II)
NR'
PdX
RH+
NR'
R
I
NHR'
Pd(0)PdX
NHR'
R TMS
NHR'
R
PdX
TMS
NPd
RTMS
R'
base
- HX red, elimPd(0)
NR'
TMS
R
Miscellaneous indol syntheses
Fischer indol synthesis
NH
NRNHNH2
OR+
- H2O H+
NH
NR
H
H
iminiumhydrazone
NH
NR
Henamin
HNH
NR
H HNH NH2
RH
R'
R' R' R' R' R'H
NH2NH2
RR'H
NH
RNH2
H R'H+
NH
RNH3
H R'
- NH4+
NH
R
R'
Br H2NNR
R'
+
cat. Pdbase
May also be cat. by Lewis acids
Synthesis from pyrroles
NTsO
XMg O
O
NTsHO
OO
H+
NTsHO
OH
protected aldehyde
E-fil. Ar. subst
NHO
OH
Ts- 2 H2O N
Ts
Miscellaneous indol syntheses
Bartoli synthesis
N
O
O XMgN
O
O
MgX
NO XMg
NO
MgX
O
NMgX
N
H
OMgXH
H XMg
N
OMgXH
MgX-H2O
H+
NH
Fürstner synthesisO
Cl
NO2
Ar-SnBu3
(Pd not required)
Ar
O
NO2
1) H2 / cat2) HCO2H, Ac2O
Ar
O
NH
O
TiCl3, Zn
McMurry coupling
NH
Ar
Pd-cat. couplings
NH
R
R'Brcat. Pd, base
NH
R'
R
Heck ?
Br
I H2N R
R' cat. Pd, base
Hartvig-Buchwald
+
Bioactive Indoles
NH
N
Sumatriptan, Imigran Drug against Migraineserotonin reseptor antagonist
SO2
HN
®NH
HN
MelatoninHormone
MeOO
NH
CO2H
NH2
Tryptophan
Essential amino acid
NH
NH2
SerotoninNeurotransmitter
HO
NH
CO2H
Auxine Plant growth hormone
Psilocybe Mexicana
Psilocybe semilanceata(Spiss fleinsopp)
OR
NH
NHalucinogens from Psilocybe sopper
R=H: PsilocinR=PO3H: Psilocybin
Serotoninagonists, not broken down in the bodystrong, continuos nerve impulse
in vivo
Bioactive Indoles
NHMeO
N
H
H
HMeO2C
O
OOMe
OMe
OMe
OMe
Reserpinefrom Rauwolfia sp.Reduce blood pressure
NH
NH
R'O
RSecale alkaloids and derivativesfrom Claviceps purpurea (meldrøye)
X=H, R'=Me, R=OH: Lysergic acidX=H, R'=Me, R=NEt2: LSD
X=H, R'=Me, R=-NHCH(Et)CH2OH: Metylergometrin, Uterus contractions, drug used after birth
X=Br, R'=Me, R=Bromokriptin, Parlodel®Prolactine inhibitor
X=H, R'=Allyl, R=Kabergolin, Dostinexl ®Prolactine inhibitor
X=H, R'=Me, R=Ergotamin, Anervanel ®Drug against migraine
X
NH
N
O N
O
HO
O
NNH
O
N
NH
N
O N
O
HO
O
Rauwolfia serpentinaIndia, Thailand etc
Vinca rosea (Catharantus roseus)From MadagaskarPerivinkle
NH
N
HO
MeO2CMeO
NR
N
H OCOMe
CO2MeOH
R=-Me: Vinblastin, Oncovin®R=-CHO: Vinkristin, Velbe ®
Vinca alkaloidsfrom Vinca roseaAnticancer comp.