PYRROLES

N H N H N NH

Pyrrole (kap 13)

Indole (kap 17)

Indolizine (kap 25)

Isoindole (kap 19)

Reaction with electrophiles - Protonation

H N H H least stable H N H H H H N H N H H H pKA -3.8 N H H H N H H H N H H H

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

Protonated pyrroles iminium ions Reactive intermediates in many react.

H N H H

H N H H

H N H H

Reaction with electrophiles - E-fil Ar. Subst.

E N H N H E H N H E H N H E H -H N H E

React. i 2-pos - Best stabilized intermed.

H

Nitration Sulfonation Halogenation FC-acylation (FC-alkylation)

H H H N Si -H N Si E

H N H N H

H H

Decomposition

React. under strongly acidic conditions

Nu N H H H

N Si

N Si

Steric hindrance in 2-pos.

Iminium ion

E N H

E H N H

E H N H -H

E N H

React. in 3-pos - Best stabilized intermed.

Reaction with electrophiles - E-fil Ar. Subst.

-Halogenation
X "X " N H X N H X
+

X
N R

R=H: Unstable X R=EWG (i.e. Boc): More stable

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

Br2 N H EWG ex. -CO2Me deactivating m-directing N H EWG

Steric hindrance in 2/5-pos.

X "X " N R 1) LDA 2) "X+ " N R N R N R

+

Mechanisms may be complex

Haloindoles (esp. 2-halo-) unstable

X

Reaction with electrophiles - E-fil Ar. Subst.

-Acylation
N H N Met Met: i.e. Tl Ac2O or AcCl Ac2O 200 oC N N O N O N H O major prod. O N O not formed N H minor prod.

Ac2O BF3 N PhO2S O Weak L.A. Weak E+ N O S O Ph EWG Deactivating Lewis acid requir.

AcCl AlCl3 N SO2Ph Strong L.A. Strong E+

O Ac2O N H Base Ac2O N N O 140 oC N O

H+/H2O or OH-

O H N H O O N H H N H

N H

Reaction with electrophiles - E-fil Ar. Subst.

-Alkylation
RX, Lewis acid N R F.C.-alkyl.

Low reactivity, unselective, polymerization etc

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

Reaction with electrophiles - Condensation with aldehydes / ketones

H , RCHO N H R=H, alkyl N H
+

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
+

EWG EWG R Me H N H EWG R N H N Me H EWG R

N H R

Reductive trapping sometimes possible

With electron rich arylaldehydes

O N H NMe2 N H N N H N

O N H

Indoles
N H N H N H N H N H

R'

H+, RCR'O N H

Somewhat more stable

N H

Application in Porphyrine Synthesis

N

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

Hemoglobine Myoglobine Cytochromes

Copper Phtalocyanin Blue synthetic dye

Application in Porphyrine Synthesis

N NH N HN

React. under acidic conditions

OH N H H H+ N H

H , CH2O N H R=H, alkyl

OH2 - H2O

N H

Polymer

React. under alkaline conditions

K2CO3(aq) N H N O N H OH H+ N H OH HO N H N H HCl (0.15M) HO N NH N Porphyrin HN Chloranil NH N H H N N H HN OH BF3 N H N H N H OH

No highly reactive iminium salts

Porphyrinogen

Reaction with electrophiles - Condensation with Imines / Iminum Ions

Aldehyde / Ketone Nu O Protonated Aldehyde / Ketone Nu H OH Imine Nu N R H Iminium ion Nu NH R

Nu O

Nu OH

Nu N R

Nu NH R

Pyrrole punstable in acidic media

H H H N H H N H H H H N H Iminium ion HCl 6M, 0oC, 30 sec POLYMER H N H H N H H HN -H N H H HN Enamine H N H H HN Iminium ions

Reaction with electrophiles - Condensation with Imines / Iminum Ions

Mannich react.
CH2O, R2NH, H+
N CH2O, R2NH, H+ R R R N R

R N N H R iminium ion gen. in situ N H HR N R N

N H

acidic cond. -H Neutral cond. 0 oC

-H

N H

N H AcOH N N R R

N H

MeX N H

Nu N N H soft Nu (malonate etc.) N H Nu

CH2O, R2NH

Vilsmeier react. (Vilsmeier-Haack): Formylation

1) POCl3, DMF 2) H+/H2O N H N H O
Cl

Generation of Vilsmeier reagent E-fil Ar. subst. Hydrolysis of iminium salt

O N Cl P O Cl Cl N Cl Cl N N H

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

Reaction with nucleophiles

Electron rich ring - not very reactive towards Nu
O2N Nu N H NO2 N H Nu O2N

Indole: React. In benzene ring prefered

Reaction with base and further react. with E-files

Base N H pKa 17.5 N N N
N H pKa 44

N H pKa 16.2

R H R-X Base N H N Met R-X N R-X N R N R H H+

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)

C-metallation and further react.

X

Li E

E N R

t-BuLi
X=Br

TMS-Cl BuLi N R RCOX R-X RR'CO O N R R N OH R N R R R R N R Li Bu3SnCl

N R

SiMe3 Stille N R SnBu3 NBS N R N R N R N R MgX Br

N R

N R

t-BuLi X=H
N R Li E N R E

MgX2 B(OMe)3, H3O+ ZnX2

Simple routes to 2- or 3-subst. indoles

Suzuki
N R 1) RLi 2) E+ E N R

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)

The less aromatic furane reacts

EWG: Less interact. Between Lone pair on N and diene

Vinylpyrrole as diene
O N SO2Ph O O N H PhO2S O O O N PhO2S O O O

Pyrrole as dienophile (2 component)

A few intramolek. ex.
H N N N N N N N H N N H H - N2 N - H2 N N

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

Indole as dienophile (2 component)

EWG
O N N 1,3-dipole ON N

EWG H+/H2O

NO2

N H Formally reverse ecetron demand DA, might be step wise mechanism

N MgBr

Reaction with carbenes / carbenoids

R' R'' N R N R R' R'' Rearrangements
N H N H Cl Cl -HCl N Cl

Indoles: No cyclopropanes isolated from carben(oid) react.

Pyrrole / Indole Carboxylic Acids

O O E N R E O O -CO2 N E R E: H, halogen

Ring synthesis

N R

CO2R1

N R

Also decarboxylation of indole carboxylic acids

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

N H detectable minor taut.

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

Nu No Nu subst in pyrrole ring

Synthesis of Pyrroles and Indoles

Carbonyl condensations (c.f. chapt. 3) - Pyrroles
a b X c X X X

Strategy a; Paal-Knorr synth.

O R R' O HO R N R'' OH R' R N R'' R' R, R' = H: O

Unstable HO HO2C HO OH CO2 OH BuNH3

- 2 H2O

Synthons: MeO O OMe

NH2R'' R''=H, alkyl, aryl

HO HO2C HO

OH CO2 OH RNH3 - 2 H2O O HO2C O CO2H

RNH2

HO HO2C

N R''

OH CO2H

- 2 H2O HO2C

N CO2H -2 CO2 R''

N R''

Not useful for indoles

O N R X R H2N-R Would require Nu.Ar subst.

Strategy b; Knorr synth.

X

X b c X X

Neccesary for easy enolization RO2C O R2 R3 O RO2C O R2

Can be removed; hydrol., decarbox. H OH RO2C R3 R2 R4 N H HO R5 Alkyl, aryl

Base

R3

RO2C - 2 H2O R2

R3 N R4 R5

HN R4 R5

HN R4 R5

R2, R3 H

May be H

If R2=CO2R Can be removed; hydrol., decarbox.

Strategy a and b combined; Hantzsch synth.

a/b X X

R, R4: alkyl, aryl Cl R': H, alkyl, aryl R

CO2R3 O NH2 O R4 R' R N R'

CO2R3 R4 May be removed; hydrol, decarbox.

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

R4 OH - H2O N R4 R' imin

CO2R3 R N R' R4 - H2O

H H CO2R3 R HO N R' R4

X b X X

Strategy c
X

R, R2: H, alkyl, aryl R2 R O O HN CO2R3 R' glycine der.

R2 O R - H2O HO N R' CO2R3 R

R2 O N R' CO2R3 Base R

R2 O N R' CO2R3 R

OH H N CO R - H2O 2 3 R'

R2

R2 R N R' CO2R3

taut. R2 R O Base N Ts CO2R3 R R2

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

Carbonyl condensations (c.f. chapt. 3) - Indoles Strategy b -Reissert synth.

O CH3 NO2 Base CH2 NO2 EtO O OEt O CO2Et NO2 H2 / cat. O CO2Et NH2
N

a N b C N

-H2O

N H

CO2Et

- Modified Reissert synth.; Leimbruger-Batcho

N O O

CH3 NO2 p 358 NO2

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

Carbonyl condensations (c.f. chapt. 3) - Indoles Strategy a -Bischler synth.

1) BrCH2CH(OEt)2 2) (CF3CO)2O NH2 EtO OEt N Tf - H2O N Tf
N

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

SMe N H R H2 / cat. N H R - H2O

MeS H OH N R H

Cycloadditions with 1,3-dipoles (c.f. chapt. 3)

a
alkene / alkyne X X 1,3-dipole

b c d e a d

b c e

Reaction with isocyanide

EWG N C R isocyanate Base 'R N C EWG 'R H H H R N R=Ts (TsMIC) R=Benzotriazolyl (BetMIC) R=-CO2R EWG= NO2, COR MIC: methyl isocyanate Bet: N N N

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

Reaction with mesoionic oxido-oxazoliums

R H N O O R2 R3 R4 O R N H R2 R4 - CO2 O R3 R N H R2 R4

R3

H O N R4 R3 - H2O HO O

R3

N-acylaminoacid

N HR 4 O O

R3

H N O O

R4

Mesoionic: Zwitter ion no uncharged res. form

N H

O Not mesoionic

N H

Reaction with nitrenes

R N N N R N N N or h - N2 R N

H N R N R

azid (1,3-dipol)

Nitren

CHO N3

MeNO2 Base N3

NO2

NO2 N H NO2

Synthesis from aminoalkynes

I I R Base HN Ts R EWG N Ts I H H H EWG I Base R H H R I H N H EWG taut R I N H EWG

N EWG Ts

JOC 2003, 7853

R HN 'R R: alkyl, alkenyl cat. Pd(II) or Cu(II) R N R'

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

R HN 'R R: H, Ph, THP

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 TMS PdX base - HX N R' TMS Pd red, elim Pd(0)

R N R' TMS

NH R'

Miscellaneous indol syntheses Fischer indol synthesis

R' + NHNH2 O R - H2O R' R N N H hydrazone H+ H R' R R' R N N H H H enamin H R' H+ R N NH3 H N N H HH R' R NH H H R' R

N N H H iminium R'

NH2

R' + Br H2NN R

cat. Pd base

N H May also be cat. by Lewis acids

- NH4+

H R' R N NH2 H

H R' NH2

R NH2

Synthesis from pyrroles

protected aldehyde O N Ts XMg O O HO N Ts O O H+ HO N Ts E-fil. Ar. subst HO N Ts - 2 H2O N Ts H O OH

Miscellaneous indol syntheses Bartoli synthesis

H N O O XMg N O O N MgX O XMg O N MgX N MgX H+ N H -H2O O H XMg OMgX N H

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

CO2H NH2 N H Tryptophan Essential amino acid

HO

NH2

H N

N H Serotonin Neurotransmitter

N H Sumatriptan, Imigran Drug against Migraine serotonin reseptor antagonist

S O2

N
O HN N H Melatonin Hormone

MeO

OR N H

Halucinogens from Psilocybe sopper R=H: Psilocin R=PO3H: Psilocybin

in vivo
CO2H N H Auxine Plant growth hormone

Serotoninagonists, not broken down in the body strong, continuos nerve impulse

Psilocybe semilanceata (Spiss fleinsopp) Psilocybe Mexicana

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

Reserpine from Rauwolfia sp. Reduce blood pressure

Vinca alkaloids from Vinca rosea Anticancer comp. HO N N N H MeO2C MeO H

Vinca rosea (Catharantus roseus) From Madagaskar Perivinkle

OCOMe

N O

N X=H, R'=Me, R= H Ergotamin, Anervanel Drug against migraine

CO2Me N OH R R=-Me: Vinblastin, Oncovin R=-CHO: Vinkristin, Velbe