Synthesis of Pyrroles and Indoles yl condensations (c.f. chapt. 3) - Pyrroles Strategy a; Paal-Knorr synth. O R' O R NH 2 R'' N R'' OH R' HO R N R'' R' R - 2 H 2 O R''=H, alkyl, aryl - 2 H 2 O OH HO CO 2 HO 2 C HO OH RNH 3 Δ O O HO 2 C CO 2 H RNH 2 N R'' OH CO 2 H HO HO 2 C - 2 H 2 O N R'' CO 2 H HO 2 C -2 CO 2 N R'' R, R' = H: O O Unstable Synthons: O OMe MeO OH HO CO 2 HO 2 C HO OH BuNH 3 X a b X X X c Not useful for indoles N R X O R H 2 N-R Would requir Nu.Ar subst.
12
Embed
Synthesis of Pyrroles and Indoles Carbonyl condensations (c.f. chapt. 3) - Pyrroles Strategy a; Paal-Knorr synth. Not useful for indoles.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
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)