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N H N H N NH
most stable
H N H H H N H H pKA -3.5
H H N H most stable H N H H
H H N H
H N H H
H N H H
H N H H
H N H N H
H H
Decomposition
N Si
N Si
E N H
E H N H
E H N H -H
E N H
X
N R
Br O O N Boc
Br
Br
Br N Si NBS (1 equiv.) N Si NBS (1 equiv.) Br N Si Br
N Boc
N Br AIBN
N O Br (NBS) Br N Br Boc
Ac2O BF3 N PhO2S O Weak L.A. Weak E+ N O S O Ph EWG Deactivating Lewis acid requir.
H+/H2O or OH-
O H N H O O N H H N H
N H
Me MeI N R 110 C
o
Me-I N R Scatole
Me
Me
Me Me N H R -H
Me N R Me
Me N R
Me Me
N R Plancher rearrangement
X Lewis acid N R N R
Plancher rearrangement
N R
OH R H H
H+ N H
OH2 RH - H2O
N H
H R red.
Polymer
2:1 adducts
EWG R H , MeCHO N H R N H
+
O N H
Indoles
N H N H N H N H N H
R'
H+, RCR'O N H
N H
N NH N HN
N N Met N N
N Mg N N
O Chlorophyll A
O H CO2Me H O
Vit. B12
N N Fe N N CO2H Heme CO2H
N N Cu N N
OH2 - H2O
N H
Polymer
Porphyrinogen
Nu O
Nu OH
Nu N R
Nu NH R
-H
N H
N H AcOH N N R R
N H
MeX N H
CH2O, R2NH
O P Cl O Cl
O DMF, POCl3 N H N H
O N H
H+/H2O
H N Cl N H N N Cl H N -H N Cl H
N H pKa 16.2
R N H H+ N H R
N-alkylation favoured by: -Ionic N-Met bond (Li) -High solvating power of solvent (DMF, DMSO etc., crown ethers, PTC)
Li E
E N R
t-BuLi
X=Br
N R
N R
t-BuLi X=H
N R Li E N R E
B(OH)2
E-fil Ar Subst
ZnX
Negishi
E N R
Br BuLi N R N R
Li E N R
Electrophilic Palladation
OAc H PdOAc Pd(OAc)2 N R N R N R EWG PdOAc EWG Heck + Pd(0) Cu(II) N R
Radical Reactions
Bu3SnH AIBN (PhCO2)2 R=H Decomposition ("Tar") N OCOPh R + 2,6-disubst SnBu3
RH N R
N R
OCOPh (PhCO2)2 N R N R
N OTs X
Bu3SnH AIBN N X
X=H
SnBu3
X=Br
Cyclo Additions
Pyrrole as diene (4 component)
H N N H low yield N H +
N EWG R EWG
N-EWG EWG R
(or alkene)
Vinylpyrrole as diene
O N SO2Ph O O N H PhO2S O O O N PhO2S O O O
Cyclo Additions
Indole as diene (4 component)
N R
No examples
Vinylindole as diene
Also N EWG general dienophile N H EWG N EWG N EWG
N O n
N O n
EWG H+/H2O
NO2
N MgBr
Ring synthesis
N R
CO2R1
N R
Oxypyrroles
N O H Major tautomer N H OH N H O
OH N H N H
O N H
O H
N O H NB! sp3 C N O H NB! sp3 C
O N H O R
N H
O R
H O O
Oxyindoles
OH O N H Inoxyl
N OH H not detectable
N H
O 2 N H Inoxyl Base 2 N H
O 2 -e N H
OO N H HN H H
O HN N H O Indigo
O N H
Aminopyrroles
-Amino (not iminoform) - unstable
Aminoindoles
N H NH2 N NH2 N NH2
3-Amino - unstable
Azaindoles (Pyrrolopyridines)
N N H 4-azaindole N N N H 5-azaindole N H 6-azaindole N H 7-azaindole N
N N H
e d
f Na b c
pyrrolo[2,3-b]pyridine
2 N 5 H 1
5-membered ring pyrrol (less electron rich) 6-membered ringpyridine (more electron rich)
largest ring
Nu
N N H -H E N N H E N H
Nu-subst if X or to N
X N N H X
- 2 H2O
HO HO2C HO
RNH2
HO HO2C
N R''
OH CO2H
- 2 H2O HO2C
N R''
X b c X X
Base
R3
RO2C - 2 H2O R2
R3 N R4 R5
HN R4 R5
HN R4 R5
R2, R3 H
May be H
Cl CO2R3 NH2 R' O R4 HN R' CO2R3 CO2R3 R taut. O CO2R3 HN R4 R' enamin R - HCl O CO2R3 R4 N R' imin taut. R CO2R3 R4 O HN R' enamin
H H CO2R3 R HO N R' R4
X b X X
Strategy c
X
R2 O N R' CO2R3 R
OH H N CO R - H2O 2 3 R'
R2
R2 R N R' CO2R3
R2 O HN CO2R3 Ts
R2 O N Ts CO2R3 R
OH H N CO R - H O 2 3 2 Ts
R2 H R H N CO R 2 3 Ts Base H R N
R2 CO2R3
a N b C N
-H2O
N H
CO2Et
TiCl3 N H
-Madelung synth.
CH2Br NO2 PPh3 CH2PPh3 Br NO2 1) Zn /H+ 2) RCOCl
X: NO2, NMe2
CH2PPh3 Br Base O N H R
N H
a N b C N
-Gassman synth.
O R NH2 O R N H S Cl Base N H S Base O R H SCH3 R O N H
t-BuOCl
N H
Cl
MeS H OH N R H
b c d e a d
b c e
Alt. I; van Leusen synth. R: Ts or Bet (Good leaving groups) EWG: -COR COR 'R H H H Ar N COR 'R H H Ar N H R' COR N taut. 'R N H
Alt. II; Barton Zard synth. R: -CO2R EWG: -NO2 NO2 'R H H RO2C H N 'R H RO2C NO2 H N H RO2C R' N taut. 'R N H
COR
RO2C
R3
H O N R4 R3 - H2O HO O
R3
N-acylaminoacid
N HR 4 O O
R3
H N O O
R4
N H
O Not mesoionic
N H
H N R N R
azid (1,3-dipol)
Nitren
CHO N3
MeNO2 Base N3
NO2
NO2 N H NO2
N EWG Ts
Metn+ R HN 'R
(n-1)+
Met R
H N H - Metn+ H R'
H R
H taut N H R'
R N R'
OH 1) PBr3 2) R'NH2
Spont.
R N R'
R NH R'
cat. Pd(II)
PdX N R' R
H+ N R'
I NH R'
Pd(0)
PdX NH R'
TMS
R N R' TMS
NH R'
N N H H iminium R'
NH2
R' + Br H2NN R
cat. Pd base
- NH4+
H R' R N NH2 H
H R' NH2
R NH2
OMgX N H MgX
Frstner synthesis
O Cl NO2 (Pd not required) Ar-SnBu3 Ar O NO2 1) H2 / cat 2) HCO2H, Ac2O Ar O N H TiCl3, Zn O McMurry coupling N H Ar
Pd-cat. couplings
Br I + H2N R' cat. Pd, base Br N H R' R' R cat. Pd, base Heck ? N H R
R Hartvig-Buchwald
Bioactive Indoles
HO
NH2
H N
N H Serotonin Neurotransmitter
S O2
N
O HN N H Melatonin Hormone
MeO
OR N H
in vivo
CO2H N H Auxine Plant growth hormone
Serotoninagonists, not broken down in the body strong, continuos nerve impulse
Bioactive Indoles
Rauwolfia serpentina India, Thailand etc
OMe OMe O O OMe OMe N H X R O N R' H Secale alkaloids and derivatives from Claviceps purpurea (meldrye) X=H, R'=Me, R=OH: Lysergic acid X=H, R'=Me, R=NEt 2: LSD X=H, R'=Me, R=-NHCH(Et)CH2OH: Metylergometrin, Uterus contractions, drug used after birth HO O N X=Br, R'=Me, R= N N O H Bromokriptin, Parlodel O Prolactine inhibitor O NH X=H, R'=Allyl, R= N Kabergolin, Dostinexl N Prolactine inhibitor HO O N O
N MeO N H H H MeO2C
N O