Chapter 3

Synthesis of aromatic heterocycles

SYNTHESIS OF AROMATIC HETEROCYCLESCONSTRUCTION OF THE RING SKELETON

I. Carbonyl condensation type reactionsII. Cycloadditions

a) with 1,3-dipolesb) with ortho-quinodimethanes (DA type react.)

III. Nitrene insertion

Carbonyl condensations

X

a

bX

X

X

a

b

X

X

Strategy a) - 5-membered rings

XX

1,4 dicarbonyl

X=N: NH3, RNH2

OO

HH LR

SS

HHc.f. furan

S

PS

MeO SPSS

OMe

LH: Lawesons reagent

Pyrrole

Furan

Thiophene

(Paal-Knorr Synthesis s 255)

OO

HH

±HHNO

HH

OHR

±H NR

HH

OHHO - 2 H2O NR

R-NH2

OO

HH

OOH

H

±H O

H

OHO

H- H2O

Strategy a) - 6-membered rings

X X

1,5-dicarbonyl

X=N: NH3

HO O

NH3

NHHO OH

H

- 2 H2O N

X X

Strategy b

5-membered rings

6-membered ringsX X

Enol(or phenol)

Enamine(or aniline)

O

EWGH

H

O

EWG HHX

O

EWG: CN, COR etc.X: NR; O, S

O

EWGH OH

XH±H ±H

X

H OHEWG

HOHH

- 2 H2O

X

EWG

HOHX

O

X

NHHO

HOH

- 2 H2O

NO

OH

H

N ±HNH

HOH

O

H

NH2

OH

O

H

H

H±H

1,3-Dipolar Cycloaddition

Only 5-membered rings

OO

O O OO

Ex. ozonolysis

ab

c

d e d e

cb

a

Alkene / alkyne

1,3-dipol

NO

nitriloxide

NO O

POCl3R3N- H2O

R

RN

O

R

R

isoxazole

I. Carbonyl condensation type reactionsII. Cycloadditions

a) with 1,3-dipolesb) with ortho-quinodimethanes (DA type react.)

III. Nitrene insertion

Cycloaddition with ortho-Quinodimethanes

NMe

Br

BrNaIΔ N

Me

O

O

O

NMe

OO

O

Electrocyclicring opening

X

X- 2 HX

- SO2

SOO

Diels-Alder

X

X X X

X

Ring formed carbocyclic

Generation of nitrenes

R N N N R N N N R N

R C

R

RN

OS

Ar

H O O

azide(1,3-dipol)

R NO

O

Δ or hν

Nitrene

(c.f. carbene)- N2

B

P(OEt)3

I. Carbonyl condensation type reactionsII. Cycloadditions

a) with 1,3-dipolesb) with ortho-quinodimethanes (DA type react.)

III. Nitrene insertion

Insertion R'-N + R3C-H R3C NR'

H

Add. to double bonds R'-N + R2C=CR2N

R R

R RR'

Rearrangement C NH

R'R C N

H

R'

RDominating react alkyl nitrenes

Abstraction R'-N + R3C-H R'-N-H + R3C

Dimerisation 2 R'-N R'-N=N-R'

React. of nitrenes

H NO2 H N NH

Nitrene insertion - Heterocyclic synthesis

N+H R NH

R

Chapter 5

Pyridines: reactions and synthesis

Chapter 4

Typical reactivity of pyridines, quinolines and isoquinolines

PyridineN

QuinolineN

Isoquinoline

N

Pyridine

N1

2

34

5

6 α

β

γ

α

β

Synthesis - Carbonyl condensations

X X

1,5-dicarbonyl

X=N: NH3

Strategy a - Chapt 3

X X

Strategy b - Chapt 3

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

X X

C

O

OH

O

OH

O

NH

-3 H2O

H OO

Dihydropyridine

ox

N

OO

SymmetriNH3

(- H2)

Pyridine - Reactivity

Reaction with electrophiles - react. on N:•Protonation•Nitration•Sulfonation•Amination•Halogenation•Alkylation•Acylation

N

E

N

E

Mild, not acidicelectrophile

NuE-Nu +

N

NF OTf

NNO2

NS OOO

BF4

N

N

DMAP

N

N

O

Ac2O

AcO

ROH

Reaction with electrophiles - react. on C - E-fil Ar subst

•Nitration•Sulfonation•Halogenation

NOT:•FC Alkylation•FC Acylation

N N N N N

in the 3/5 pos

Difficult:•Electron defficient ring (poor Nu)•Electrophiles may react at N

N

conc. H2SO4cat. HgSO4

N

SO3H

70%220 oC

N NHgSO4

N

Hg-SO4H

N

SO3H

- HgO

Sulfonation

Possible intermed.

N

Br2 / conc. H2SO4or Cl2 / AlCl3

N

X

X=Br; 66%X=Cl; 33%

X2PdCl2

N XNH

O

POX3

PdCl

Cl

NN

Via:(See reactivity of pyridones)

Nitration

Halogenation

N

KNO3 / H2SO4

24 h, 300 oC NH

N

NO2

6%

N RR

NNO2

R=H

R=Cl

N ClCl

NO2

NO2 BF4

BF4

Nitration - Bakke (NTNU, http://www.chem.ntnu.no/organisk/ansatte/Bakke/jb.html)

NN

ON

O

O

O

O NNO2

Pyridinium cationactivated for Nu-attack

SO

O OH

NOSO2HH

NO2N H

OSO2H

NO2H

N

NO2

68%

NO3

Na

- HOSO2H

H

123

4

5 H5

1

[1,5]-sigmatropic rearrangement

OH

OH

More electrophil C than neutral carbonyl

Reaction with nucleophiles

N N N N N

a) X=H, Substitution with “hydride” transfer

Nu: NaNH2 - amination - Chichibabin reaction

Nu: BuLi, PhLi etc - alkylation / arylation

Nu: NaOH - “hydroxylation” - NB! High temp} Attack in the 2-pos (not 4-pos)

a) X=Hb) X=Good leaving group

b) X=LG, Displacement of good leaving group

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

N X

NuN Nu N

NuN

X Nu

N

X Nu

X Nu XNu

X

Nu

X

NuNu

+ X

SNAr

•SNAr •SN1: Via diazonuim salts and arylic cation•Benzyne•SRN1: Involves radicals•VNS: Vicarious nucl. Subst.

N

Br NaNH2, ButOKR2NH

N N

NaNH2, ButOKR2NH Br Nu

N

NR2

N

NR2+

HH

BB

NN

Br

BHMore difficult to generate

Metallation and reactions with electrophiles

Direct metallation

Direct metallation with ortho directing group (ODG)

Metal halogen exchange

N

Cl

LDA

N

ClLi E

N

ClE

N Bu-Li

N Br

Br 1) BuLi

- 78 oC

2) E

- 78 oC - r.t. N Br

E1) BuLi2) E

- 90 oCN E

Br

N

BuLi / ButOKlow temp N K

Kinetic

N

K

N

K

E

NE

Mixt of isom.

Metallation and reactions with electrophiles

N

Li

R R'

O1)

2) H+/H2O

N

HO RR'

DMFN

O

1) ArCN

2) H+/H2O N

O

Ar

Br

N

I2

N

I

R3SnX

R3SiX

ZnX2

N

SnR3

N

SiR3

N

ZnX

Pd-Catalyzed Coupling reactions

a) On metallated pyridines

N

Met Ar-Xcat. "Pd"

N

Ar Met = -SnR3; Stille couplingMet= -B(OR)2; SuzukiMet= -ZnX; Negishi

b) On halopyridines

N

X Ar-Metcat. "Pd"

N

Ar Met = -SnR3; Stille couplingMet= -B(OR)2; SuzukiMet= -ZnX; Negishi

N

XR

cat. Pd, CuX, R3N

N

RSonogashira coupling

N

X cat. Pd, Base

N

Heck coupling

R R

N

RR'NH, cat. "Pd", Base

NHartvig - Buchwald

Br NR

R'

N X N

X

N

X

Reactivity

X=IX=Br / OTfX=Cl

Pd(0)

Ar'-Met

Ar-Pd-Ar'

Met-X

Oxidativeaddition

transmetallation

reductiveelimination

Ar-X

Ar-Pd-X+II+II

Ar-Ar'

Polarity in couplings

ArX + Ar’Met or Ar’X + ArMet??

ca. electrophile

ca. nucleophlile

Substituted pyridines - Structure and reactivity•Oxy-, Thio- and Aminopyridines•Alkyl- and Vinylpyridines•Quartenary Pyridinium Salts•Pyridine N-oxides

Oxy-, Thio- and Aminopyridines - Structure; Tautomery

NHO NH

ON

HO

N NH

OH O

NH

O

NH

O

2-Pyridone 3-Hydroxypyridine(c.f. phenol)

4-Pyridone

NH

S

N

HS

Thio:

NH

S

NH2N NH

HNNH

HN N

H2N

Amino

N

NH2

Oxypyridines - Reactivity

Reaction with electrophiles

N

OH

H

E o/p-directing

NH

OH

N

EOH

N

OH

N

OH

E E

N-protonation as pyridine

NH

O

N OHo/p-directing

NH

O

E

NH

O

E

NH

O H NH

O H

O-protonation as amides

NH

O

pKa≈11

BaseN O N O

R-X

Ambident anion

N O N O RR

and / or

NH

O

Me3SiNHSiMe3(HMDS)

Δ N O SiMe3R-X

N OR

Replacement of Oxygen

N OH

(CF3SO2)2OBase

N OSO2CF3

Pd-cat. couplings etc

Triflate

Deprotonation - O or N substitution

c.f. silyl enol ethers

N O

P

O

ClCl

Cl

H

NH

OP

O

ClCl

NH

Cl

O P

O

ClCl

N Cl

Cl

B

Thiopyridines - Reactivity

N S

H

Cl

O

R Base

N S

O

R

Useful synthetic intermedites

R'MgXR'

O

R

ketone

N S

O

R

NHProt + H2NProt

R'

ONH

O

R

NHProtR'

Prot

O

Peptide

N S

OOHn

NH

S

OO

heat

n

N SH

O n

O

Lactone

Aminopyridines - Reactivity

N NH2

H

N NH2H

NH

NH2

pKa 7.2

HN

H

NH

NH

pKa 9.1

HNH2

NH2

NH2

NH

NH2

N

NH2

HpKa 6.6

HN

NH3

HpKa -1.5

Aminopyridines - Reactivity

Alkylpyridines - Reactivity

Vinylpyridines - Reactivity

N

NH2NaNO2, acid

N

N2

HBrBr2

NH

O

N

Br

N

F

H2O

HF

c.f. enolate anionR

CH3O O

R

CH2 O

R

CH2

N CH3

Base N CH2

N CH2

E

N CH2E

Basec.f. Michael type add.

N N

Nu-H

N

Nu

R

O

R

O

Nu

Quartenary pyridinium salts

NR

NR

NR

Nu

NR

Nu

Hand / or

NR

H Nu

R-X

X

N

Add of: -hydrides -dithionite -organometallics -stab. carbanions etc. etc.

Hard Nu Soft NuBig R

NR

PhMgBrCuI

NR

H PhCleav. of ROx.

N

PhR: -SiMe2But -SO2R -CO2R

Co-enz.NAD+

N

O

NH2+ Sub-H2

NAD+

N

O

NH2

NADH

H H

+ Sub + H

Hydride add. to NAD+, SubH2 oxidizedNicotine amide: Vit. B3Adenine: Vit. B4

N

ONH2

O

OHHO

OPOP

OO

O OO

ON

HOHO

N

NN

NH2

N

N

Nicotine

[ox]N

CO2H

Nicotinic acid

Pyridine N-oxides

N

HO OH

(or peracid etc)

NOH

+ OH N

O

+ H2O

O

OO

H

Cl mCPBA

N

O

+ PPh3N

+ O=PPh3

NN

OO

Pyridine N-oxides

N N N N N2.22D

4.25DNO

NO

NO

Neg. charge i α,γ pos.

NO

NO

More activated for electrophilic and nucleophilic attack

Pyridine N-oxidesElectrophilic Ar. subst

N

O

E N

O

E

N

O

H E

N

OH

N

O

E

c.f. Electrophilic Ar. subst on pyridine / pyridinium cation(difficult reactions)

H

B

+ resonanse forms

N

KNO3 / H2SO4

24 h, 300 oC NH

N

NO2

6%

N

O

conc. HNO3conc. H2SO4

160 oC N

O

NO2

48%N

O

H NO2

+ resonanse forms

Pyridine N-oxidesRearrangements etc.

N

O

N

OAcNOAc

HOAc N OAc

hydrolysis

NH

O

Ac2O

OAc -AcOH

N

O

CH3 N

OAc

CH2

H NO O N

O

O

Ac2O

OAc