Lecture 3

Functional groups
transformation
Part 2
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Synthesis of
aromatic
heterocycles
SYNTHESIS OF AROMATIC HETEROCYCLES
CONSTRUCTION OF THE RING SKELETON

I. Carbonyl condensation type reactions

II. Cycloadditions
a) with 1,3-dipoles
b) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion

Carbonyl condensations
a a
X
X
b X b
X

X X
Strategy a) - 5-membered rings

1,4 dicarbonyl
X
X X=N: NH3, RNH2

H H H H H H
Pyrrole R-NH2

OO O HN OH N - 2 H2O N
±H HO OH
±H R R R

(Paal-Knorr Synthesis s 255)

Furan H H H H
H
- H2O O
OO ±H O OH
OH O

c.f. furan
Thiophene H H LR H H LH: Lawesons reagent

S S S S
OO S
P P OMe
MeO
S
S
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Strategy a) - 6-membered rings

1,5-dicarbonyl

X=N: NH3
X X

H
H NH3
- 2 H2O
OO HO NH OH N
Strategy b
5-membered rings X X

O
H H OH H OH
EWG H EWG H EWG EWG EWG
- 2 H2O
HX
X HO X
O O O
±H H ±H X
H H

EWG: CN, COR etc.

X: NR; O, S
Enol
(or phenol) O

HX X
HO

6-membered rings
X X
Enamine
(or aniline)
OH
H OH OH H
H H H H - 2 H2O
O H
N ±H N N
±H HO H
O H O NH O NH2
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I. Carbonyl condensation type reactions
II. Cycloadditions
a) with 1,3-dipoles
b) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion

1,3-Dipolar Cycloaddition

1,3-dipol
Only 5-membered rings b
a b
c
a c

d e d e

Alkene / alkyne

Ex. ozonolysis R
POCl3
R3N R
O O N N N
O O O O - H2O O
O O O R R

nitriloxide isoxazole
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Cycloaddition with ortho-Quinodimethanes

O
X S
O

- SO2
X
Electrocyclic
X X X ring opening
- 2 HX
X

Diels-Alder

Ring formed carbocyclic

Br O O
O
NaI O
N Δ N O
Br
Me Me N
Me
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I. Carbonyl condensation type reactions
II. Cycloadditions
a) with 1,3-dipoles
b) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion

Generation of nitrenes

Δ or hn
RNNN R N NN R N (c.f. carbene)
- N2
azide Nitrene R C
(1,3-dipol)
R
P(OEt)3

O Ar
R O
N S
R N
O O
H O

B
React. of nitrenes

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

R'

R'
R N
Add. to double bonds R'-N + R2C=CR2 R
R R

R' R'
RCN C N Dominating react alkyl
Rearrangement nitrenes
H R H

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

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

Nitrene insertion - Heterocyclic synthesis

H
H + N R N
R

H NO2 H N N
H
Typical reactivity of pyridines,
quinolines and isoquinolines

N
N N
Pyridine Quinoline Isoquinoline

Pyridines: reactions and synthesis

Pyridine
g
4
b 5 3 b
a 6 2 a
N
1

Synthesis - Carbonyl condensations

1,5-dicarbonyl

X=N: NH3
X X X X

Strategy a - Chapt 3 Strategy b - Chapt 3

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

C O
O H O O O
H H ox
X X O O
-3 H2O (- H2)
N N
O O H
NH3 Dihydropyridine Symmetri
Pyridine - Reactivity

Reaction with electrophiles - react. on N:

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

E
•Amination
Mild, not acidic
•Halogenation electrophile
N N N

•Alkylation F
OTf
NO2 BF4 O S O
O

•Acylation

N N

Ac2O ROH

N N
AcO
DMAP O
Reaction with electrophiles - react. on C - E-fil Ar subst
Difficult:
•Electron defficient ring (poor Nu)
•Electrophiles may react at N

N N N N N
•Nitration
•Sulfonation in the 3/5 pos
•Halogenation

Sulfonation
conc. H2SO4
NOT: cat. HgSO4
SO3H

N 220 oC
•FC Alkylation N 70%

•FC Acylation Possible intermed.

Hg-SO4H SO3H

N N N - HgO N
HgSO4
Halogenation
X2 Br2 / conc. H2SO4
POX3 PdCl2 X
or Cl2 / AlCl3
N O
H N X N N
(See reactivity of pyridones) X=Br; 66%
Via:
X=Cl; 33%
Cl
N Pd N
Cl

Nitration

NO2
KNO3 / H2SO4
24 h, 300 oC N N
N
H 6%

N BF4
R=H
NO2
NO2 BF4

R N R

R=Cl NO2

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

Na O
O O S NO2
O OH
N N OSO2H H
O O O N N H OSO2H
N
NO2 N
NO2 H
NO3
- HOSO2H
Pyridinium cation
activated for Nu-attack [1,5]-sigmatropic
rearrangement
NO2

N 68%

H H 4
O O
3 H
5
2 5
More electrophil C
1
1
than neutral carbonyl H
Reaction with nucleophiles

N N N N N

SNAr
X X X
X Nu Nu
Nu Nu Nu

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

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 X N Nu N N N

a) X=H
b) X=Good leaving group
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•SNAr
•SN1: Via diazonuim salts and arylic cation
•Benzyne
•SRN1: Involves radicals
•VNS: Vicarious nucl. Subst.

B
B

Br NaNH2,ButOK NaNH2, ButOK H

H R2NH R2NH Br Nu

N N N

NR2
NR2
+
N N

Br
More difficult
N to generate
N H B
Metallation and reactions with electrophiles
K
Direct metallation
N
E
BuLi / ButOK Bu-Li
E N
low temp
N N K N
K
Kinetic Mixt of isom.

Direct metallation with ortho directing group (ODG)

Cl Cl Cl
Li E
LDA E

N N N

Metal halogen exchange

1) BuLi
Br Br E
2) E 1) BuLi 2) E

N E - 90 oC - 78 oC - 78 oC - r.t.
N Br N Br
Metallation and reactions with electrophiles

HO R
R' O
N
SnR3 1) O N
R R' DMF
N R3SnX
2) H+/H 2O

O
Li
SiR3 1) ArCN Ar
R3SiX
N 2) H+/H2O N
N
ZnX2
Br
ZnX
I2
N

N
I

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

Oxy-, Thio- and Aminopyridines - Structure; Tautomery

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

HO
HO N O N O N S N
H H H
N
HS
4-Pyridone
OH O O N
S

N N N
H H
N
H

Amino
NH2
H2N

H2N N HN N HN N N N
H H
Oxypyridines - Reactivity

Reaction 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

N OH H H
N O N O
o/p-directing H H
O-protonation as amides
Deprotonation - O or N substitution
Ambident anion
Me3SiNHSiMe3
Base (HMDS) R-X
N O N O N O N O Δ N O SiMe3 N O
H H R
pKa≈11
R-X
c.f. silyl enol ethers

and / or
N O N OR
R

Replacement of Oxygen
O Cl
O
P Cl O
Cl Cl P
N O Cl N O Cl N P N Cl
O Cl
H Cl H
H Cl

B
Triflate
(CF3SO2)2O
Base Pd-cat. couplings etc
N O N OSO2CF3
H
Thiopyridines - Reactivity
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 Prot Prot NHProt
N S + H2N N
H
R O O R

Peptide

O
OH
N S
n

heat O

N S n
O
N S H
H Lactone
O
n
O
Aminopyridines - Reactivity
NH2

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

N NH2 N
H H
pKa 7.2 pKa 9.1

NH2 NH2 NH3

H H
N N N
H H
pKa 6.6 pKa -1.5
Aminopyridines - Reactivity
O

H2O N
H
NH2 N2 F
NaNO2, acid HF

N N N
HBr
Br2 Br

Alkylpyridines - Reactivity N

N CH2 E
Base

N CH3 N CH2E
Vinylpyridines - Reactivity
N CH2
Nu-H Nu
c.f. enolate anion
R R N N N
R
Base
O CH3 O CH2 O CH2 c.f. Michael type add.
R R Nu

O O
Quartenary pyridinium salts

R-X Add of: -hydrides

N N N N -dithionite
R R R -organometallics
X -stab. carbanions
Nu
etc. etc.
H Nu

Hard Nu Nu
Soft Nu
N H
and / or
N Big R
R R

H Ph Ph
PhMgBr Cleav. of R
CuI Ox. R: -SiMe2But
-SO2R
-CO2R
N N N
R R