γ PYRIDINES 4 β 5 3 β α α Synthesis of Pyridines 6 N 2 1 From 1,5-dicarbonyl and ammonia (c.f. chapt. 3)

1,5-dicarbonyl H H NH3 X=N: NH3 X X N - 2 H2O N O O HO H OH From 1,3-dicarbonyl and enamine (c.f. chapt. 3)

H OH OH H H H H O H2N ±H O O ±H X X O NH NH2

From 2 equivs. 1,3-dicarbonyl , aldehyde and ammonia - Hantzsch Synthesis

O O H O O O C H H O ox O N X X H N O O -3 H2O NH3 Dihydropyridine Symmetri Various syntheses from other heterocycles γ 4 PYRIDINES β 5 3 β α α 6 N 2 1

Reaction with electrophiles - react. on N: •Protonation

•Nitration E Nu E-Nu + •Sulfonation N N N E

•Amination Mild, not acidic N N electrophile N •Halogenation F OTf O2N BF4 O S O O •Alkylation

•Acylation N N

Ac2O ROH N N AcO DMAP O Reaction with electrophiles - react. on C: Electrophilic Aromatic Substitution

Electron defficient / Poor nucleophiles Difficult Electrophiles may react at N

•Nitration Not: •Sulfonation React. in 3-pos. •FC alkylation •Halogenation } •FC acylation

N N N N N Nitration

R=H N BF4 NO2 NO KNO3 / H2SO4 NO BF 2 o N 2 4 N 24 h, 300 C N 6% H R N R R=Cl NO2

Cl N Cl

Bakke:

Na O O O S NO O OH 2 N N OSO2H H N O O O N N H OSO H N 2 NO2 H NO2 NO3 Pyridinium kation activated for Nu-attack - HOSO2H

NO2 4 N H [1,5]-sigmatropic rearrang. 3 5 5 68% 2 1 1 H Sulfonation Possible intermediates

conc. H2SO4 SO3H cat. HgSO4 N o 220 C N 70% Hg-SO4H SO3H N N N N HgSO4 - HgO

Halogenation

X2 Br2 / conc. H2SO4 X POX3 X=Br; 66% PdCl2 or Cl2 / AlCl3 X=Cl; 33% N O N X N H N

Via: N

Cl Pd Cl

N Reaction with Nucleophiles

a) X=H Nu Nu + X b) X=Good leaving group N X N X N Nu a) X=H, Substitution with “hydride” transfer

Nu: NaNH2 - amination - Chichibabin reaction Nu: BuLi, PhLi etc - alkylation / arylation Attack in the 2-pos (not 4-pos) Nu: NaOH - “hydroxylation” - NB! High temp }

b) X=LG, Displacement of good leaving group

X: Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR X Nu X Nu Nu Nu N N X N Nu N N

t t Br NaNH2, Bu OK NaNH2, Bu OK Via Pyridyne Br R2NH R2NH Nu N N N N

NR2 NR2 + N N Metallation and Reactions with Electrophiles

D MeONa / MeOD D o Termodynamic N 165 C N D N N 1 : 9 : 12

K BuLi / ButOK Bu-Li + Kinetic N N low temp N K N

Ortho directing subst.

Cl Cl Cl LDA Li E E N N N

Metal - Halogen Exchange

Br 1) BuLi 2) E Br 1) BuLi 2) E E - 90 oC - 78 oC - 78 oC - r.t. N E N Br N Br Direct Reactions with Electrophiles: Additions, Substitutions

Some examples (c.f. react. with ArLi)

HO R

R' O N O SnR3 1) N DMF R SnX R R' N 3 + 2) H /H2O

O Li SiR 1) ArCN Ar 3 R3SiX N + 2) H /H2O N N

ZnX2 Br ZnX I2 N

N I

N Pd-Catalyzed Coupling reactions a) On metallated pyridines

Ar-X Met Ar cat. "Pd" Met = -SnR3; Stille coupling Met= -B(OR)2; Suzuki N N Met= -ZnX; Negishi b) On halopyridines

Ar-Met X Ar Reactivity cat. "Pd" Met = -SnR3; Stille coupling Met= -B(OR)2; Suzuki X N N Met= -ZnX; Negishi X R R N X X N N cat. Pd, CuX, R3N Sonogashira coupling N N X=I>X=Br/OTf>X=Cl R R X cat. Pd, Base Heck coupling N N

R RR'NH, N Br cat. "Pd", Base R' Hartvig - Buchwald N N Radical Reactions a) Reactions with C-radicals: Minisci React.

Nucleophilic radical AgNO3 / (NH4)2S2O8 R-CO2H R R Alkyl radical R ox. CO2 N N H N R H H O t H2SO4, Bu OOH, FeSO4 O Reactivity: Pyridinum cation > neutral pyridine H R 2-pos. > 4-pos. > >3-position R R=Alkyl, Aryl, -NR2 Acyl radical (aldehyd / formamid)

b) Generation of / Reaction on pyridylradicals

Intramolecuar cyclisations

X Bu3SnH, AIBN Br Bu3SnH, AIBN N N N N Reductions

Ph(Me)SiH2 Na, NH3 (l) cat. Cp2TiMe2 N N N Si H H Ph Me H2, Pt AcOH

N H

Photochemistry

hν (254 mn)

H H

N N

t1/2 = 2 min Oxy-, Thio- and Aminopyridines

Structure - Tautomerism

2-Pyridone 3-Hydroxtpyridine 4-Pyridone OH O HO

HO N O N N N N H H

O

O N H N H

H N N HN N HN N 2 H H

XH X X=O: one / hydroxy ? ? X=NR: imino / amino HX N X N X=S: thione (6-membered rings) / N N H H thiol (5 membered) Reactions on Pyridones - With Electrophiles

E o/p-directing E OH OH OH OH

N N E N N E H

OH N-protonation as pyridine N H

E E

N O N O N O H H H

H H N OH N O N O o/p-directing H H O-protonation as amides Reactions on Pyridones - Deprotonation - O or N-substitution Ambident anion

Me3SiNHSiMe3 Base (HMDS) R-X SiMe N O N O N O N O Δ N O 3 N O H H R pKa≈11 R-X

and / or N O N O R R

Reactions on Pyridones - Replacement of Oxygen

O Cl P O Cl Cl O Cl P N O N O Cl N P N Cl Cl O Cl H H Cl H Cl B Triflate

(CF3SO2)2O Base Pd-cat. couplings etc N O N OSO2CF3 H Thiopyridones

O Base O Cl R O R'MgX N S 'R R N S R H ketone Useful synthetic intermedites

O R' R' O NHProt N S + Prot Prot NHProt H2N N R O O H R Peptide

O OH N S n

heat O N S O n N S H H Lactone O n O Aminopyridines NH2

N NH2 H N NH2 H H H H H N NH2 N NH2

N NH2 H N pKa 7.2 H pKa 9.1

NH2 NH NH H 2 H 3 N N N H H pKa 6.6 pKa -1.5

O

H2O N H F NH2 N2 NaNO2, acid HF

N N N HBr Br2 Br

N Alkyl- and Vinylpyridines

N CH Base 2 E Nu-H

N CH3 N CH2E N N N Nu

N CH2

Quartenary Pyridinium Salts

Add of: -hydrides N N N -dithionite R R R -organometallics

Nu -stab. carbanions H Nu etc. etc. Nu and / or N H N Ph PhMgBr H Ph R R Cleav. of R R: -SiMe But CuI Ox. 2 -SO2R N N N -CO2R R R O O NH2 H H O O N NH2 NH2 O + Sub-H + Sub + H O P O N 2 N O Co-enz. HO OH O P O + + O NAD NAD NADH O N N HO N NH2 HO N

Hydride add. to NAD+, SubH2 oxidized Nicotine amide: Vit. B3 Adenine: Vit. B4

Isoniazide N N CO2H Antituberculosis drug [ox] O N N HN NH2 Nicotine Nicotinic acid Mn2+ /O N N Active acyl radical O O formed in vivo H H O H O

NH2 NH2 N N

NADH co-enzyme Inactive der. of co-enz in enzyme involved in cell wall component synth Pyridine N-oxides

HO OH + OH + H O + PPh3 + POPh N N 2 N 3 N N OH O O (or peracid etc)

N N

O O

N N N N N 2.22D

Neg. charge i α,γ pos. N N N 4.25D O O O More activated for electrophilic

N N and nucleophilic attack O O H E E

E N N Electrophilic Ar. subst O O N H O E NO2 KNO3 / H2SO4 N N o N N 24 h, 300 C N 6% OH O H c.f. Electrophilic Ar. subst on pyridine / puridinium cation

NO2 H NO2 H NO2 fum. HNO3 conc. H SO 2 4 66% o N 100 C N N N O O O O Rearrangements

Ac O 2 H hydrolysis N N OAc N OAc -AcOH N OAc N O O OAc OAc H

Ac2O N CH3 H N N C OAc O O H2 O O N OAc O