reaction with electrophiles - protonation
TRANSCRIPT
PYRROLES
NH
NH
Pyrrole (kap 13)
Indole(kap 17)
N
Indolizine(kap 25)
NH
Isoindole(kap 19)
Reaction with electrophiles - Protonation
NH
N NHH H
least stable
H
H
H
HH N
H
HH N
H
HH
NH
HH
NH
HH
most stable
pKA -3.8
NH
H
pKA -3.5 NH
H H
NH
H H
most stableH
NH
HH N
H
HH N
H
HH
NH
HH N
H
HH
Protonated pyrroles ≈ iminium ionsReactive intermediates in many react.
Reaction with electrophiles - E-fil Ar. Subst.
NH
ENH
EH N
H
EH N
H
EH
- HNH
E
React. i 2-pos - Best stabilized intermed.
NSi
ENSi
NSi
HH
HH
- HNSi
E
Steric hindrance in 2-pos.
•Nitration•Sulfonation•Halogenation•FC-acylation•(FC-alkylation)
NH
NH
E H
NH
E HE
- H
React. in 3-pos - Best stabilized intermed.
NH
E
NH
HNH
HH
Decomposition
React. under strongly acidic conditions
NH
HH
Nu Iminium ion
Reaction with electrophiles - E-fil Ar. Subst.-Halogenation
NR
"X+"NR
X
Mechanisms may be complex
NR
1) LDA2) "X+"
NR
X
NH
"X+"NH
XX
X X
NBoc
(NBS)NBoc
BrBr
NN
O Br
BrO
AIBNNBoc
Br
N OOBr
NSi
NBS (1 equiv.) NSi
Br
Steric hindrance in 2/5-pos.
NBS (1 equiv.) NSi
BrBr
NH
EWG
ex. -CO2Medeactivatingm-directing
Br2
NH
EWG
Br
N XR=H: UnstableR=EWG (i.e. Boc): More stable
R
Haloindoles (esp. 2-halo-) unstable
Reaction with electrophiles - E-fil Ar. Subst.-Acylation
NSO OPhEWG
Deactivating
Lewis acid requir.
AcClAlCl3
N
OAc2OBF3
NPhO2S
O
Strong L.A.Strong E+
Weak L.A.Weak E+
SO2Ph
NH
Ac2ONH200 oC O
major prod.
NH
minor prod.
O
NO
not formed
NO
NN
O
NMet
Met: i.e. TlAc2Oor AcCl
H+/H2Oor OH-
NH
Ac2O140 oC N
O
O
NH
O
Base
NAc2O
N
O
NH O
HNH H
O
NH
O
Reaction with electrophiles - E-fil Ar. Subst.
-Alkylation
NR
RX, Lewis acid
F.C.-alkyl.
Low reactivity, unselective, polymerization etc
-HNR
NR
MeMeI110 oC
Scatole
Me-I
NR
Me Me
NR
MeH
Me
NR
Me
Me
Plancher rearrangement
NR
Me Me
Me
NR
X Lewisacid
NR Plancher
rearrangementNR
Reaction with electrophiles - Condensation with aldehydes / ketones
NH
H+, RCHONHR=H, alkyl H
OHR
H±H+
NH R H
OH2- H2O N
H RH Polymer
red.
NH R
Reductive trapping sometimes possible
With electron rich arylaldehydes
NH
NMe2O
NH
N
NH
N
NH
NH
NH
NH
ONH
NH
Indoles
2:1 adducts
NH
R
EWGH+, MeCHO
NH H
Me
EWG
RNH
R
EWG
NH
R
EWG
MeNH
EWG
R
NH
H+, RCR'ONH
RR'
Somewhat more stable
Application in Porphyrine Synthesis
NHNNH
N
NNN
NMet
NNN
NMg
O
CO2MeH
H
HO
O
Chlorophyll A
NNN
NFe
CO2H
CO2H
Heme
•Hemoglobine•Myoglobine•Cytochromes
NNN
NCu
Copper PhtalocyaninBlue synthetic dye
Vit. B12
Application in Porphyrine Synthesis
NH N
H H
OH
NH
OH2NH
H+, CH2O
R=H, alkyl
±H+
- H2OPolymer
React. under acidic conditions
NH
K2CO3(aq)
NO
N HOH
±H+
NH
OH
React. under alkaline conditions
No highly reactive iminium salts
NH
OHHO
NH
HCl (0.15M)
NH
NH
NH
NH
OHHO
BF3N
HNNHN
NH
HNNHHN
Porphyrinogen
Chloranil
Porphyrin
NHNNH
N
Reaction with electrophiles - Condensation with Imines / Iminum Ions
OH
OHNu
Nu
ONu
OHNu
Aldehyde / KetoneProtonatedAldehyde / Ketone
NH
NHNu
Nu
NNu
NHNu
R
R R
R
Imine Iminium ion
NH
HNH
Iminium ionH
NH
HH
HH N
HNH HNH
H
H- NH HNH
Enamine
H
NH HNH
Iminium ions
HH
POLYMERHCl 6M, 0oC, 30 sec
Pyrrole punstable in acidic media
Reaction with electrophiles - Condensation with Imines / Iminum IonsMannich react.
CH2O, R2NH, H+
NR
RNH iminium ion gen. in situ
NH
HNR
RH-
NH
N RR N
H
CH2O, R2NH, H+
NR
R
H-NH
NR
R
acidic cond.
N CH2O, R2NH NNR
R
Neutral cond. 0 oC
AcOH
Vilsmeier react. (Vilsmeier-Haack): Formylation
NH
DMF, POCl3NH
O
NOP
O
ClClCl N
OPO
ClCl
Cl
NCl
ClNH
NH
HNCl-H
NH
NCl
NH
N
Cl
H+/H2ONHO
NH
1) POCl3, DMF2) H+/H2O
NH O
Generation of Vilsmeier reagentE-fil Ar. subst.Hydrolysis of iminium salt
NH
N MeXN
N
HN
Nu
Hsoft Nu(malonate etc.)
NH
Nu
Reaction with nucleophilesElectron rich ring - not very reactive towards Nu
NH
NO2
O2NNu
NH
Nu
O2N
Indole: React. In benzene ring prefered
Reaction with base and further react. with E-files
NH
BaseN N N
pKa 17.5
NH
pKa 44NH
pKa 16.2
N-alkylation favoured by:-Ionic N-Met bond (Li)-High solvating power of solvent (DMF, DMSO etc., crown ethers, PTC)
NH
BaseNMet R-X
R-X
R-X
NR
NRH
±H+
NH
R
N
RH ±H+
NH
R
C-metallation and further react.
NR
BuLiNR
Li
TMS-Cl NR
SiMe3
Bu3SnClNR
SnBu3
MgX2
NR
MgXB(OMe)3, H3O+
NR
B(OH)2Suzuki
Stille
NBS
NR
Br
ZnX2
NR
ZnXNegishi
R-X
NR
R
RCOX
RR'CO
NR R R
OHNR
O
R
NR
BrBuLi
NR
LiE
NR
E
NR
X t-BuLi
t-BuLiX=H
X=BrNR
LiE
NR
E
NR
Li ENR
E
Simple routes to 2- or 3-subst. indoles
NR
NR
ENR
E
E-fil Ar Subst1) RLi2) E+
NR
Pd(OAc)2N
H PdOAc
R
OAc
NR
PdOAcEWG
NR
EWG
Heck
+ Pd(0)
Cu(II)
Electrophilic Palladation
Radical Reactions
NR
R=H
Decomposition ("Tar")
R≠HBu3SnHAIBN N
RSnBu3
(PhCO2)2
NR
OCOPh
+ 2,6-disubst
NR
(PhCO2)2NR
OCOPh
NOTs
X
Bu3SnHAIBN
NX
X=H NSnBu3
NX=Br
Cyclo Additions
NH
+NH
low yield
HN
The less aromatic furane reacts
NEWG
EWGR
(or alkene)
N-EWG
R
EWGPyrrole as diene (4π component)
Vinylpyrrole as diene
NSO2Ph
OO
O
NPhO2S
H OO
ON
PhO2SO
O
O
Pyrrole as dienophile (2π component)
EWG: Less interact. Between Lone pair on N and “diene”
NNN
N N NNN N N
H
H
H
H - N2N N- H2
A few intramolek. ex.
Cyclo AdditionsIndole as diene (4π component)
Vinylindole as diene
Indole as dienophile (2π component)
NR
No examples
NEWG
generaldienophile
NEWG
NEWGH
Also
NEWG
N
O nN
O n
N NO2 NNO
1,3-dipole
N
NO
NMgBr
EWG
H+/H2O
NH
EWG
Formally reverse ecetron demand DA,might be step wise mechanism
Reaction with carbenes / carbenoids
NR
R'R''
NR
R'R'' Rearrangements
NH
N
ClCl
H N
Cl
-HCl
Indoles: No cyclopropanes isolated from carben(oid) react.
Pyrrole / Indole Carboxylic Acids
NR
CO2R1Ringsynthesis
NR O
O ENR O
OE-CO2
NR
E
E: H, halogen
Also decarboxylation of indole carboxylic acids
Oxypyrroles
NH
OH NH
ONH
O
Major tautomer
NH
O NH
O
NB! sp3 C NB! sp3 C
Oxyindoles
NH N
Hdetectableminor taut.
OH O
Inoxyl
NH
OH NH
Onot detectable
NH
O
Inoxyl
BaseNH
O
NH
O
- e
2 2NH
O2
NH
O
NH
O
H H NH
OHN
OIndigo
NH
OH
NH
O
NH
O
NH
O H
RO N
H
O
RO
O OH
O O
Aminopyrroles-Amino (not iminoform) - unstable
Aminoindoles
NH
NH2 N NH2 N NH23-Amino - unstable
Azaindoles (Pyrrolopyridines)
NH
N
4-azaindole
NH
N
5-azaindole
NH
N
6-azaindole
NH
N
7-azaindole
5-membered ring≈ pyrrol (less electron rich)6-membered ring≈pyridine (more electron rich)
NH
N
pyrrolo[2,3-b]pyridine
largest ring
N
NH1
23 4
5
ab
cdef
NH
N E NH
NE
NH
N
E- HNH
NX
XNu
No Nu substin pyrrole ring
Nu
Nu-subst if X α or γ to N
Synthesis of Pyrroles and IndolesCarbonyl 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
CO2HO2CHO OH
RNH3
ΔOO
HO2C CO2H
RNH2
NR''
OHCO2H
HOHO2C - 2 H2O N
R''CO2HHO2C -2 CO2 N
R''
R, R' = H: OO Unstable
Synthons:
O OMeMeO OHHOCO2HO2C
HO OH
BuNH3
X
a
bX
X
X
c
Not useful for indoles
NR
X
OR
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
R4R2R5
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/bX
ORCl
CO2R3
O R4
NR'
R R4
CO2R3
NH2R'
OHR4
CO2R3
HNR'
CO2R3
NR'
R4
imin
taut.CO2R3
HNR'
R4
enamin- HCl- H2O O
RN
R4
CO2R3
R'imin
taut.
OR
HNR4
CO2R3
R'enamin
N
CO2R3
R4R'
RHO
HH
- H2O
ORClR, R4: alkyl, aryl
R': H, alkyl, arylCO2R3
O R4 NR'
R R4
CO2R3
May be removed;hydrol, decarbox.NH2
R'
X
a
bX
X
X
c
Strategy cX
a
bX
X
X
c
R2
RO
O
R, R2: H, alkyl, aryl
HNR'
CO2R3
glycine der.
R2
R OHO N
R'- H2O
R2
R ONR'CO2R3 CO2R3
Base
R2
R ONR' CO2R3
N
R2OH
CO2R3
H
R'R - H2O N
R'CO2R3R
R2
R2
O
HNTs
CO2R3
R2
R ONTs CO2R3
Base
R2
R ONTs CO2R3
N
R2OH
CO2R3
H
TsR - H2O N
R2
CO2R3
H
TsR
BaseHN
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
OCO2Et
H2 / cat.
NH2
OCO2Et
-H2O NH
CO2Et
N O
O
- Modified Reissert synth.; Leimbruger-BatchoCH3
NO2p 358 NO2
X
X: NO2, NMe2
TiCl3NH
-Madelung synth.
CH2Br
NO2
PPh3CH2PPh3
NO2
Br 1) Zn /H+
2) RCOCl CH2PPh3
NH
BrO
R
BaseNH
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
- H2O NTf
-Gassman synth.
NH2t-BuOCl
NH
Cl
OR
SNH
S
OR
ClBase
NH
S
OR
ON
SCH3R
H
H
Base
NH
MeS HOHR- H2ON
HR
SMeH2 / cat.
NH
R
Cycloadditions with 1,3-dipoles (c.f. chapt. 3)a
bc
d e d e
cb
a
X X
alkene / alkyne1,3-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:N
NN
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
O O- CO2 N
H
R R2
R4R3
O
HN R4
O
R3O
N R4
O
R3H
- 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
NO2Δ
N
NO2
NH
NO2
N+H R NH
RR 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
REWG
EWGBaseH
NTs
I
R EWG N
I
R EWG
tautHH
HH H
H
NH
I
EWGR
JOC 2003, 7853R
HN'R
R: alkyl, alkenyl
cat. Pd(II) or Cu(II)
NR'
R R
HN'R
Metn+
NR'H
RMet
(n-1)+
- Metn+NR'
R
H tautHH
H
H NR'
R
R
HN'R
R: H, Ph, THP
NR'
Spont.1) PBr32) R'NH2 RR
OH
R
NHR'
cat. Pd(II)
NR'
PdX
RH+
NR'
R
I
NHR'
Pd(0)PdX
NHR'
R TMS
NHR'
R
PdXTMS
N Pd
RTMS
R'
base- HX red, elim
Pd(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
RHR'
R' R' R' R' R'H
NH2NH2
RR'H
NH
RNH2
H R'H+
NH
RNH3
H R'
- NH4+N
HR
R'
Br H2NNR
R'+
cat. Pdbase
May also be cat. by Lewis acids
Synthesis from pyrroles
NTsO
XMg OO
NTsHO
OO
H+
NTsHO
OHprotected
aldehyde
E-fil. Ar. subst
NHO
OH
Ts- 2 H2O N
Ts
Miscellaneous indol syntheses
Bartoli synthesis
NO
O XMgNO
O
MgX
NO XMg
N OMgX
O
NMgX
N
HOMgXH
H XMg
NOMgXH
MgX-H2O
H+
NH
Fürstner synthesisO
ClNO2
Ar-SnBu3
(Pd not required)
ArO
NO2
1) H2 / cat2) HCO2H, Ac2O
ArO
NH O
TiCl3, Zn
McMurry couplingNH
Ar
Pd-cat. couplings
NH
R
R'Br cat. Pd, baseNH
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
TryptophanEssential amino acid
NH
NH2
SerotoninNeurotransmitter
HO
NH
CO2H
Auxine Plant growth hormonePsilocybe 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
OO
OMe
OMeOMe
OMe
Reserpinefrom Rauwolfia sp.Reduce blood pressure
NH
NHR'O
R Secale 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
NO N
O
HO
O
NNH
O
N
NH
NO N
O
HO
O
Rauwolfia serpentinaIndia, Thailand etc
Vinca rosea (Catharantus roseus)From MadagaskarPerivinkle
NH
NHO
MeO2CMeO N
R
NH OCOMe
CO2MeOH
R=-Me: Vinblastin, Oncovin®R=-CHO: Vinkristin, Velbe®
Vinca alkaloidsfrom Vinca roseaAnticancer comp.