Bioactive 1,3-Azoles

MeHN H
H2N
N
N
Me N
S
N N Me CN N
N

O S Me N
H
MeO N
HO
O-methylhalfordinol vitamin B1 (thiamin) cimetidine

• O-Methylhalfordinol is a plant-derived alkaloid

• Vitamin B1 (thiamin) is essential for carbohydrate metabolism. Deficiency leads to
beriberi, a disease which is characterised by nerve, heart and brain abnormalities
• Cimetidine (Tagamet®, GSK) is an H2-receptor antagonist which reduces acid
secretion in the stomach and is used to treat peptic ulcers and heartburn

91
 Drugs Containing a 1,3-Azole
NO2

H N
N H
S S N
NH2 N
N N N

N
Name: Mirapex Name: Azathioprine
2008 Sales: $0.34 billion 2008 Sales: $53 million
2008 Ranking: 108 branded 2008 Ranking: 178 generic
Company: Boehringer Ingelheim Company: N/A
Disease: Parkinson's disease Disease: Kidney transplant rejection
Cl
N
S N OH
N Ph S N N NH
O O
N N
H
N
N N N O
H H
O OH
Ph
Name: Norvir Name: Cozaar
2008 Sales: $0.31billion 2008 Sales: $0.69 billion
2008 Ranking: 112 branded 2008 Ranking: 54 branded
Company: Abbott Company: Merck 92
Disease: HIV/AIDS Disease: Hypertension
 1,3-Azoles - Synthesis
The Hantzsch Synthesis (“3+2”)

Me Me H
O HO
δ+Me C6H6, heat ONH2 N
NH2
δ+
Me S Cl S Me S Me

Me Me
HO
N −H2O N

S Me S Me
43%

• The reaction is particularly important for the synthesis of thiazoles

• A thiourea can be used in place of a thioamide leading to a 2-aminothiazole

93
 1,3-Azoles - Synthesis
Cyclodehydration of α-acylaminocarbonyl compounds
H H H
H
N c-H2SO4, rt N N − H2 O N
Ph Ph Ph Ph Ph
Ph Ph Ph
O O O O H2 O O O
72%
H

• A particularly important strategy for the synthesis of oxazoles which is known as the
Robinson-Gabriel Synthesis
• The starting α-acylaminocarbonyl compounds are easily prepared

From Isocyanides
Ts Ts
H Ts H H
Me K2CO3, MeOH N C N N
Me Me
N Me
H N H N H N N
C
t-Bu t-Bu t-Bu t-Bu
Ts = O2S Me
94%

• Tosylmethylisocyanide (TOSMIC) is a readily available isocyanide

• Route can be adapted to give oxazoles and thiazoles using an acid chloride or a
94
thiocarbonyl compound
1,3-Azoles - Electrophilic Substitution
Nitration
O2N O2N
N c-HNO3, N N N2O4/BF3 N N
+
1% oleum, rt rt → 70 °C
Me O2N Me Me
N N S S S
H H
90% 59% 27%
• Imidazoles are much more reactive to nitration than thiazoles (activation helps)
• Imidazoles usually nitrate at the 4-position and thiazoles tend to react at the 5-position
• Oxazoles do not generally undergo nitration

Halogenation Br Br
N Br2, AcOH, N Na2SO3 aq., N
NaOAc, rt heat
N Br N Br N
H H H
78% 58%

• Imidazoles are brominated easily and bromination at multiple positions can occur
• Thiazole does not brominate easily but 2-alkylthiazoles brominate at the 5-position
95
1,3-Azoles - Electrophilic Substitution
Acylation
O O O

Ph Ph Ph
N PhCOCl, Et3N, N N N H2O N
MeCN, rt Ph Ph
N N N N N

Me Me Me Me O Me O
71%

• 1,3-Azoles do not undergo Friedel-Crafts acylation because complexation between the

Lewis acidic catalyst and N deactivates the ring
• Acylation can be accomplished under mild conditions via the N-acylimidazolium ylide

96
1,3-Azoles - Nucleophilic Substitution
Displacement of Halogen
N PhSNa, MeOH, rt N

S Cl S SPh
75%

• There are many examples of displacement of halogen at the 2-position

• 2-Halothiazoles react rapidly with sulfur nucleophiles, and are even more reactive than
2-halopyridines

n-Pr n-Pr
N PhNHMe, N
xylene, 155 °C Ph
n-Pr O Cl n-Pr O N
96% Me

• 2-Halo-1-alkylimidazoles and 2-halooxazoles will react with nitrogen nucleophiles

97
 1,3-Azoles - Metallation
Direct Deprotonation 1.

N n-BuLi, THF, −78 °C N N Br N

Pd(PPh3)4 N
then ZnCl2
N ZnCl 2. acid aq. N
N
H
SO2NMe2 SO2NMe2
90%

• Direct deprotonation oxazoles, thiazoles and N-alkylimidazoles occurs preferentially at

either the 2- or 5-position
• Transmetallation of the lithiated intermediate is possible

Metal-Halogen Exchange OH
Ph
Br
Ph
N 1. t-BuLi (2 equiv.) N
2. Ph2CO
N N
H H
64%
• Metallation at the 4-position can be accomplished by metal-halogen exchange
• In the case of imidazoles without substitution at the 1-position, two equivalents of base
98
are required
 1,2-Azoles - Bioactive 1,2-Azoles
CF3
O

NH
N
N
N Me
Me
O

CF3

leflunomide celecoxib SO2NH2

• Leflunomide (Arava®, Sanofi-Aventis) inhibits pyrimidine synthesis in the body and is

used for the treatment of rheumatoid arthritis and psoriatic arthritis
• Celecoxib (Celebrex®, Pfizer) is a non-steroidal anti-inflamatory (NSAID) used in the
treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and
menstrual symptoms
• Celecoxib is a COX-2 inhibitor, blocking the cyclooxygenase-2 enzyme responsible
for the production of prostaglandins. It is supposed to avoid gastrointestinal problems
associated with other NSAIDs, but side effects (heart attack, stroke) have emerged

99
 1,2-Azoles - Synthesis
Synthesis of Pyrazoles/Isoxazoles from 1,3-Dicarbonyl Compounds and Hydrazines or
Hydroxylamines (“3+2”)

Me Me OEt

H2NNH2, H2NOH.HCl
Me O N OEt N
NaOH aq., rt Me EtO H2O, heat
O NH2 OEt NH2 O
H N
H2N HO
75% 84%

• This is the most widely used route to pyrazoles and isoxazoles

• The dicarbonyl component can be a β-keto ester or a β-keto aldehyde (masked)
• When a β-keto ester is used a pyrazolone/isoxazalone is formed

100
 1,2-Azoles - Synthesis
Synthesis of Isoxazoles by Cycloaddition of Nitrile Oxides to Alkynes or Enamines
(“3+2”)
Et H Et EtO2C Et
EtO2C EtO2C
EtO2C
EtCNO C
Me
N N N
Me N Me N Me
O O
O N
70%

• Nitrile oxides react readily with alkenes and alkynes

• Addition to an alkene generates an isoxazoline unless a leaving group is present

Ph
Ph
Cl Ph
Et3N, Et2O, rt PhCCH

N N N
Ph
HO O
O Ph 76%

• Mono-alkyl/-aryl alkynes react to give 3,5-disubstituted isoxazoles but when the alkyne
possesses two substituents mixtures of 3,4- and 3,5-disubstituted isoxazoles are
usually produced
101
1,2-Azoles - Electrophilic Substitution
Nitration of Isoxazoles, Pyrazoles and Isothiazoles
O 2N
c-HNO3, Ac2O, c-H2SO4, 0
N AcOH, rt N N
N N °C N
H H
70% NO2 80%

• Pyrazoles and isothiazoles undergo straightforward nitration

• 1-Nitropyrazole is formed in good yield by treatment of pyrazole with the mild nitrating
reagent, acetyl nitrate
• 1-Nitropyrazole can be rearranged to give 4-nitropyrazole by treatment with acid at
low temperature

Me O2N Me
f-H2SO4,
N c-HNO3, N
O 0 → 70 °C O
40%

• Isoxazole nitrates in very low yield, but 3-methylisoxazole is sufficiently reactive to

undergo nitration at the 4-position
102
1,2-Azoles - Electrophilic Substitution
Halogenation of Isoxazoles, Pyrazoles and Isothiazoles
H Br Br
Br Br Br
Br2, NaOAc
N N N
N N N
H H H
• Halogenation (iodination, bromination) of pyrazole leads to the 4-halopyrazole
• Poor yields are obtained when attempting to halogenate isoxazole or isothiazole, but
bromination can be accomplished when an activating group is present as a substituent
O
Acylation
Me Ph Me
O

N N H
Cl Cl
N PhCOCl, AlCl3, N Me2NCHO, POCl3,
95 °C N 95 °C then H2O N
N N

Me Me
33%
Me Me

• Only N-substituted pyrazoles can be C-acylated directly

103
• Vilsmeier formylation produces the 4-formylpyrazole in modest yield
 1,2-Azoles - Metallation
Direct Metallation of Isoxazoles, Pyrazoles and Isothiazoles
Ph Ph
n-BuLi, MeI n-BuLi, THF,
N N N −78 °C then HO
CO22C N
Me S
N N S
88%
Ph Ph

• 1-Substituted pyrazoles and isothiazoles can be lithiated and alkylated at the 5-position

N 1. n-BuLi, THF,
H −78 °C
O
N CH2O, EtOH, heat N 2. PhNCO N
N N 3. HCl aq. N
H H
PhNH
79%
N

• It is possible to temporarily protect the 1-position of pyrazole and then perform

sequential deprotonation and alkylation/acylation at the 5-position
104
 1,2-Azoles - Metallation
Direct Metallation of 4-Bromopyrazoles
Br Br Br
n-BuLi, Et2O, CO2
N N N
Li HO2C
−78 °C N N
N
SO2Ph SO2Ph SO2Ph
65%
• At low temperature, N-sulfonyl 4-bromopyrazoles can be lithiated at 5-position without
undergoing metal-halogen exchange

Metallation of 4-Bromopyrazoles by Metal-Halogen Exchange

H OH

Br Li S
n-BuLi, THF, O S
N −78 °C N N
N N N
H 39% H
Li

• Treatment of 4-bromopyrazole with two equivalents on n-butyllithium results in

N-deprotonation and exchange of lithium for bromine
• 2,5-Dilithiopyrazole reacts with carbon electrophiles to give the 4-substituted product
105
1,2-Azoles - Side Chain Deprotonation
Deprotonation of 5-methylisothiazole and 5-methylisoxazole
3-O2NC6H4CHO, O2N

N Ac2O, piperidine N
Me
S 150 °C S
42%

• A weak base can be used to deprotonate 5-methylisothiazole and 5-methylisoxazole

• In this case above, dehydration of the initial product occurs in situ
• Surprisingly, 3-methylisothiazole does not deprotonate as easily as 5-methylisothiazole
and the same effect is found in isoxazoles
Me Me Me
n-BuLi, THF, CH2CHCH2Br
N N N
Me −78 °C O O
O Li 80%

• Metal-halogen exchange can be used to avoid deprotonation of alkyl groups

Me Br Me HO2C Me
1. n-BuLi, THF,
Br2 −78 °C

N N 2. CO2 N
Me Me Me
O O 3. HCl aq. O
106
 1,2-Azoles - Synthesis of a Drug Me

Synthesis of Celecoxib (Celebrex®, Pfizer) CF3

CF3
N
Me O N + N
F 3C
Me N
O
NH2NH2

celecoxib SO2NH2
SO2NH2
SO2NH2
• A regioisomeric mixture is formed requiring separation and disposal of the side product
Me
CF3
CF3
F3C OSO2Ph

N
N N N
HN N N
Me
Et3N, THF, EtOAc O

5 → 10 °C

SO2NH2 SO2NH2 72% SO2NH2

107
• 1,3-Dipolar cycloaddition of a nitrile imine offers a regioselective alternative route
•END