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Home , Pyrrole

PYRROLES

NH N N N H H Pyrrole Indolizine (kap 13) (kap 17) (kap 25) (kap 19)

Reaction with - Protonation

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

H H H H H H H H H N N H H N pKA -3.5 N N H H H most stable Protonated pyrroles ≈ iminium ions H

Reactive intermediates in many react. H H H N H N H N H H H H

H H N H N H H H Reaction with electrophiles - E-fil Ar. Subst. •Nitration •Sulfonation E E E E •Halogenation N N H N H N H N E H H H H - H H •FC-acylation React. i 2-pos - Best stabilized intermed. •(FC-alkylation)

H H E H H H H Decomposition E N N H N N N N H Si Si Si Si H React. under strongly acidic conditions - H Steric hindrance in 2-pos. Nu H Iminium ion N H H

E H E H E E N N N N H H H - H H React. in 3-pos - Best stabilized intermed. Reaction with electrophiles - E-fil Ar. Subst. -Halogenation

X X R=H: Unstable X O Br "X+" N R=EWG (i.e. Boc): More stable N O N O X R N X N N O H H Br Br (NBS) Br N AIBN N Br N Br Boc Boc Boc Br Br Br Br NBS (1 equiv.) NBS (1 equiv.) N N N Br2 Si Si Si N EWG N EWG H H ex. -CO Me Steric hindrance in 2/5-pos. 2 deactivating m-directing

X "X+" Mechanisms may be complex N N R R Haloindoles (esp. 2-halo-) unstable 1) LDA 2) "X+" X N N R R Reaction with electrophiles - E-fil Ar. Subst. -Acylation O Ac O 2 N N 200 oC N N H H O H O major prod. minor prod. not formed N N N Met O O Met: i.e. Tl Ac2O AcCl BF AlCl3 Ac2O 3 or AcCl N N N N O O S O O PhO2S SO2Ph EWG Ph Weak L.A. Deactivating Strong L.A. Weak E+ Strong E+ Lewis acid requir.

O O + O H /H2O - Ac2O or OH O H N 140 oC N N H H N N H N O H O H H Base

Ac2O N N O Reaction with electrophiles - E-fil Ar. Subst.

-Alkylation

RX, Lewis acid Low reactivity, N unselective, R F.C.-alkyl. etc

Me Me Me Me Me Me Me MeI Me-I Me Me o Me N 110 C N N H N N N -H R R R R R R Scatole Plancher rearrangement

X Lewis acid N N Plancher N R R rearrangement R Reaction with electrophiles - Condensation with /

OH + H+, RCHO R ±H H OH2 H Polymer N N H N - H O N H R=H, alkyl H H R H 2 H R

red. 2:1 adducts EWG Reductive trapping EWG N sometimes possible EWG EWG R EWG H R + N H , MeCHO Me H R R R N N R N N H H H H Me H

With electron rich arylaldehydes

N O N NMe2 N N N H H H O R N R' H N N + N N H N H H , RCR'O H H H N N H H Somewhat more stable Application in Porphyrine Synthesis

N N H O N N Mg N N Met N NH HN N H O N N CO2Me A H O Vit. B12

N •Hemoglobine N Fe N •Myoglobine N CO2H •Cytochromes

CO2H

N N Cu N N

Copper Phtalocyanin Blue synthetic dye Application in Porphyrine Synthesis N NH HN N React. under acidic conditions

OH H+, CH O ±H+ 2 OH Polymer N 2 N H N - H O N H R=H, alkyl H H 2 H

React. under alkaline conditions

+ K2CO3(aq) O ±H OH OH HO OH N N N H N N H H H No highly reactive iminium salts N H HCl (0.15M)

HO OH N N N H Chloranil H BF3 NH HN NH HN H N N N N N H H H

Porphyrin Reaction with electrophiles - Condensation with / Iminum Ions

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

Nu Nu Nu Nu N NH O OH R R

Pyrrole punstable in acidic media

H H H H N H H H H N N N N H N H H H H H HN -H H HN H HN H Iminium ion Enamine Iminium ions

H HCl 6M, 0oC, 30 sec N H H POLYMER Reaction with electrophiles - Condensation with Imines / Iminum Ions + Mannich react. CH2O, R2NH, H R CH O, R NH, H+ R 2 2 N N R R R N R N acidic cond. N R H R H H N N -H N N R N R H H -H H iminium ion gen. in situ Neutral cond. AcOH 0 oC Nu N CH O, R NH MeX 2 2 N N N Nu R N N N N N H H H R H soft Nu (malonate etc.)

Vilsmeier react. (Vilsmeier-Haack): Formylation Generation of Vilsmeier reagent E-fil Ar. subst. Hydrolysis of iminium salt 1) POCl3, DMF + 2) H /H2O O O N N P O P O Cl Cl Cl H H O N Cl N N N Cl Cl Cl H Cl O + H /H2O H DMF, POCl3 N N N N N N N H H N N O H H Cl -H Cl H H Cl Reaction with Electron rich ring - not very reactive towards Nu

O2N O2N Nu N NO2 N Nu Indole: React. In ring prefered H H

Reaction with base and further react. with E-files

Base N N N N N N H H H pKa 16.2 pKa 17.5 pKa 44

R R H ±H+ R-X N N H + Base R-X R ±H N N N H N R H Met R-X H N-alkylation favoured by: N R -Ionic N-Met bond (Li) -High solvating power of (DMF, DMSO etc., crown ethers, PTC) C-metallation and further react. Li E E X t-BuLi N N N SiMe3 X=Br R R TMS-Cl N R Stille t-BuLi R X=H Bu3SnCl SnBu NBS E BuLi N 3 Li E Br N Li R N N N N MgX2 R R R R R MgX B(OMe)3, N H O+ Simple routes to 2- or 3-subst. indoles RCOX 3 R Suzuki R-X ZnX 2 N B(OH)2 1) RLi N RR'CO R E-fil Ar Subst 2) E+ R Negishi E O R N ZnX E N N N OH R R R R N R N R R R R

Br Li E Electrophilic Palladation BuLi E OAc N N N EWG H PdOAc R R R PdOAc Pd(OAc)2 EWG N N N Heck N R R R R

+ Pd(0)

Cu(II) Radical Reactions

Bu SnH SnBu 3 N 3 AIBN R≠H R

N (PhCO2)2 R

OCOPh R=H N R Decomposition ("Tar") + 2,6-disubst

OCOPh Bu SnH SnBu (PhCO2)2 3 3 AIBN N N N OTs X=H R R N N X X

X=Br N Cyclo Additions N Pyrrole as (4π component) EWG N-EWG H EWG N R EWG + R (or ) N N H H low yield EWG: Less interact. Between Lone pair on N The less aromatic furane reacts and “diene” Vinylpyrrole as diene

O O O O N N H O N O O PhO S PhO S SO2Ph 2 O 2 O

Pyrrole as dienophile (2π component)

A few intramolek. ex. H H N N N N N N N N N - N N - H N N H 2 H 2 Cyclo Additions

Indole as diene (4π component)

N No examples R Vinylindole as diene

Also

N general N H N N EWG dienophile EWG EWG EWG

N N O n O n

Indole as dienophile (2π component) EWG EWG O N O H+/H O N 2 NO N N 2 N N N MgBr H Formally reverse ecetron demand DA, 1,3-dipole might be step wise mechanism Reaction with / carbenoids

R' R' Cl R'' Rearrangements Cl R'' Cl N N N R R N -HCl N H H Indoles: No cyclopropanes isolated from carben(oid) react.

Pyrrole / Indole Carboxylic Acids

E O E O E Ring N CO2R1 N N -CO N synthesis R R O R O 2 R E: H,

Also of indole carboxylic acids Oxypyrroles

OH O O N O N OH N O H H H Major N N N H H H

O H O

N O N O O O H H N N H R H R NB! sp3 C NB! sp3 C

H O O O O Oxyindoles OH O

OH N N O N N H H H H not detectable detectable Inoxyl minor taut.

O O O O O O 2 Base 2 2 HN

N N - e N N H H N N H H H H H H O Inoxyl Indigo O

N H Aminopyrroles

-Amino (not iminoform) - unstable

Aminoindoles

3-Amino - unstable N NH2 N NH2 N NH2 H Azaindoles (Pyrrolopyridines)

f N a N N N e 3 4 N b d c 2 5 N N N N N N N H H H H H H 1 4-azaindole 5-azaindole 6-azaindole 7-azaindole pyrrolo[2,3-b]

5-membered ring≈ pyrrol (less electron rich) largest ring 6-membered ring≈pyridine (more electron rich)

E N Nu N X N E H Nu-subst Nu if X or to N N α γ X N N H N No Nu subst - H H in pyrrole ring N E H Synthesis of Pyrroles and Indoles

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

Strategy a; Paal-Knorr synth. X

HO OH R, R' = H: Unstable O O O O R N R' R N R' R R' - 2 H O R'' 2 R'' Synthons: HO OH

NH2R'' HO2C CO2 MeO OMe BuNH R''=H, alkyl, aryl O HO OH 3

HO OH RNH2 Δ HO OH HO2C CO2 O O - 2 H O - 2 H O -2 CO2 2 HO2C N CO2H 2 HO2C N CO2H N HO OH HO2C CO2H R'' R'' R'' RNH3

Not useful for indoles

O R Would require N X Nu.Ar subst. R H2N-R a X Strategy b; Knorr synth. b X X c Can be removed; Neccesary for hydrol., decarbox. easy enolization X Alkyl, aryl H OH RO2C R3 RO C R O RO C R3 O RO C 2 3 Base 2 2 R3 R2 R4 O HN R4 O HN R4 - 2 H2O R2 R4 R2 R2 HO N H N R5 R5 R5 R5 May be H R2, R3 ≠H If R2=CO2R Can be removed; hydrol., decarbox. Strategy a and b combined; Hantzsch synth. a/b CO R CO2R3 R, R : alkyl, aryl Cl 2 3 X 4 May be removed; X R': H, alkyl, aryl R R R N R4 hydrol, decarbox. O NH2 O 4 R' R'

Cl R CO2R3 CO2R3 CO R CO2R3 CO2R3 O CO2R3 2 3 taut. taut. R4 R4 R4 R R N R HN R4 NH R HN OH - H O 4 - HCl O N O HN 2 O 4 2 R' R' R' R' R' R' imin enamin imin enamin

H CO R CO2R3 H 2 3 R R R N R4 - H2O HO N 4 R' R' a X Strategy c b X X c

X

R, R2: H, alkyl, aryl R2 R R R 2 2 R2 R2 2 OH O O Base O R O R R R H R N R N CO2R3 O HO N - H2O N N CO R - H2O CO R CO R CO R R' 2 3 R' HN CO2R3 R' 2 3 R' 2 3 R' 2 3 R' der. taut.

R R 2 R2 2 R2 R2 R2 OH H O Base O H H Base H O R R R N R N N CO R - H O CO R R N CO2R3 N Ts 2 3 2 2 3 Ts CO2R3 Ts CO2R3 Ts HN CO2R3 Ts Carbonyl condensations (c.f. chapt. 3) - Indoles a N Strategy b b -Reissert synth. N C N O O CH O O CH3 Base 2 EtO OEt H2 / cat. CO2Et CO2Et CO2Et NO NO NH -H O N NO2 2 2 2 2 H - Modified Reissert synth.; Leimbruger-Batcho

O CH3 X N TiCl3 O NO p 358 N 2 NO2 H -Madelung synth. X: NO2, NMe2

1) Zn /H+ Br CH2Br CH2PPh3 CH2PPh3 Br PPh3 2) RCOCl Base O R N NO2 NO2 N H R H Carbonyl condensations (c.f. chapt. 3) - Indoles a N Strategy a b -Bischler synth. N C N

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

-Gassman synth. Base O O O R R H SCH3 t-BuOCl Cl S Base R R N S NH2 N S O H H Cl N N H H

SMe MeS H H / cat. R 2 R OH N N - H2O N R H H H with 1,3-dipoles (c.f. chapt. 3) b b a c alkene / a c

X X 1,3-dipole d e d e

Reaction with

EWG MIC: methyl isocyanate 'R EWG R=Ts (TsMIC) Base 'R R=Benzotriazolyl (BetMIC) N C H H Bet: N R H R=-CO2R N isocyanate R N N N C EWG= NO2, COR R Alt. I; van Leusen synth. R: Ts or Bet (Good leaving groups) EWG: -COR

COR COR R' COR 'R COR 'R 'R taut. H H H H H H N N N N Ar Ar H

Alt. II; Barton Zard synth. R: -CO2R EWG: -NO2 R' 'R NO2 'R NO2 taut. 'R H H H H H RO2C RO2C N N RO2C N RO2C N H H Reaction with mesoionic oxido-oxazoliums

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

H N H O R4 H Mesoionic: R N R N R 3 4 R3 R4 Zwitter ion - 3 - H2O HO O O O no uncharged N O N O O O res. form H H N-acylaminoacid Not mesoionic

Reaction with nitrenes

Δ or hν H R N N N R N N N R N H + N - N N R azid 2 Nitren R (1,3-dipol)

MeNO CHO 2 NO2 NO2 Base Δ NO2 N N N N 3 3 H Synthesis from aminoalkynes

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

JOC 2003, 7853 Metn+ cat. Pd(II) (n-1)+ R H H H taut or Cu(II) R R Met R N H N H N HN N R n+ R HN R' - Met R' R' 'R R' 'R H R: alkyl, alkenyl

OH 1) PBr3 2) R'NH R R 2 Spont. R HN N 'R R' R: H, Ph, THP

R PdX cat. Pd(II) H+ R R NH N N R' R' R' R R TMS R R I PdX TMS TMS Pd(0) base PdX Pd TMS NH NH NH - HX N red, elim N R' R' R' R' Pd(0) R' Miscellaneous indol syntheses

Fischer indol synthesis R' R' H R' R' H H R' + R R' R + O R H R R R NHNH2 - H2O NH N N N N N N N N NH 2 H H H H H H H H H hydrazone iminium enamin R' cat. Pd base R' H H H R' + R' + R' R R R H R Br H NN 2 R + NH - NH NH3 NH2 2 N 4 N N NH2 H H H May also be cat. by Lewis acids Synthesis from pyrroles

protected H aldehyde O O OH O O + XMg O H N N N N - 2 H O N HO HO E-fil. HO 2 O Ts Ts Ts Ar. subst Ts Ts Miscellaneous indol syntheses Bartoli synthesis H XMg O H XMg OMgX O O O XMg O N N N N N N H O O MgX MgX MgX

+ H OMgX N N H -H O H 2 MgX Fürstner synthesis O Ar Ar 1) H2 / cat Ar Cl Ar-SnBu3 O 2) HCO2H, Ac2O O TiCl3, Zn

NO2 NO2 N O N H H (Pd not required) McMurry coupling

Pd-cat. couplings R' Br Br R' cat. Pd, base R' cat. Pd, base + R N I H N R N R 2 Hartvig-Buchwald H Heck ? H Bioactive Indoles CO2H NH2 N H Tryptophan Essential amino acid H N S N HO NH2 O2 N N H O MeO HN H Sumatriptan, Imigran ® Serotonin Drug against Migraine N Neurotransmitter serotonin reseptor antagonist H Melatonin Hormone

Halucinogens from Psilocybe sopper N OR R=H: Psilocin in vivo R=PO3H: Psilocybin N CO2H H Serotoninagonists, not broken down in the body strong, continuos nerve impulse N H Auxine Psilocybe semilanceata Plant growth hormone (Spiss fleinsopp) Psilocybe Mexicana Bioactive Indoles Rauwolfia serpentina India, Thailand etc Secale alkaloids and derivatives R OMe from Claviceps purpurea (meldrøye) O R' OMe N N H H O X=H, R'=Me, R=OH: Lysergic acid OMe X=H, R'=Me, R=NEt2: LSD MeO N H O H H X OMe MeO C N X=H, R'=Me, R=-NHCH(Et)CH2OH: Metylergometrin, 2 H Reserpine Uterus contractions, drug used after birth from Rauwolfia sp. HO Reduce blood pressure O N X=Br, R'=Me, R= N N O H Bromokriptin, Parlodel® O Prolactine inhibitor O NH X=H, R'=Allyl, R= N Vinca alkaloids Kabergolin, Dostinexl® from Vinca rosea Prolactine inhibitor N Anticancer comp. HO HO N Vinca rosea (Catharantus roseus) O N From Madagaskar X=H, R'=Me, R= N N O N Perivinkle H N Ergotamin, Anervanel® O H H OCOMe Drug against migraine MeO C 2 N CO2Me MeO R OH R=-Me: Vinblastin, Oncovin® R=-CHO: Vinkristin, Velbe®