Lecture 3

Functional groups
transformation
Part 2
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J. Chem. Ed. 2010, 87, 1348

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
Atorvastatin is placed among other suggested prescribed oral statin drugs, is sold under the brand
name Lipitor. It is known to inhibit cardiovascular sickness by decreasing levels of low density lipoprotein
(LDL) cholesterol level in blood.
 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
Eluxadoline, originally developed by Janssen and currently marketed by Allergan (formerly
Actavis), was approved in May 2015 by the FDA for the treatment of diarrhea-predominant irritable bowel
syndrome (IBS-D).
 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
Celecoxib is a selective COX-II inhibitor established by P zer company and sold under the brand
name of Celebrex®.
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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is used on the treatment of migraine attacks.
 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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treatment of certain kinds of malaria (chloroquine-sensitive malaria).
•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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RSC Adv., 2020, 10, 44247–44311

Ozenoxacin is a novel, nonfluorinated quinolone antibiotic discovered by Toyama Chemical Co.
Ltd. and developed by Maruho Co. Ltd
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