Organic chemistry ( Ullman coupling reaction with mechanism and miconazole and sylfamerazine synthesis and use)

1. ULLMAN COUPLING & SYNTHESIS OF
MICONAZOLE, SULFAMERAZINE
PRENTED BY
SUDIN SUNDAR PRADHAN
M.PHARM 1ST YEAR
PHARMACEUTICAL CHEMISTRY
BHARAT TECHNOLOGY

2. ULLMAN COUPLING REACTION
The reaction involves the condensation of aryl halides in the presence of finely divided copper
or copper bronze at an elevated temperature (100-350 C) to yield diaryl derivatives. Thus,
iodobenzene in nitrobenzene when heated in the presence of copper powder gives diphenyl in
80% yield. Alternatively, the reactants may be heated in a sealed tube.
Introduction
2 I + 2Cu + 2CuI
C6H5NO2
∆
2

3. ULLMAN COUPLING REACTION
The mechanism for the Ullmann reaction is not known with certainty but there are two proposed
popular mechanisms
1. Free radical mechanism.
2. Ionic mechanism.
Mechanism
1. Free radical mechanism.
According to free radical mechanism, the copper generates an aryl radical by a single electron transfer (SET)
from copper metal to the alkyl halide. Two aryl radicals then react to form the final biaryl products.
3

4. ULLMAN COUPLING REACTION
2. Ionic mechanism.
According to the ionic mechanism, an aryl copper intermediate is formed. This mechanism begins with the
oxidative addition of the copper to the aryl halide followed by a single electron transfer to form an
organocuprate reagent .This organocuprate performs another oxidative addition on an aryl halide forms biaryl
copper halide complex which after reductive elimination results in the final biaryl product.
4

5. ULLMAN COUPLING REACTION
Application
Synthesis Of Biaryls and polyaryls
H
O
O
C
I
H
O
O
C C
O
O
H
C
u
P-iodobenzoic acid 4,4` Diphenic acid
Synthesis of Diarylamines
COOH
Cl H2N
OCH3
COOH OCH3
N
K2CO3.Cu
Reflux
H
+
O-Chlorobenzoic Acid
Anisidine
p-Methoxyphenyl anthranlic acid
5

6. SYNTHESIS OF MICONAZOLE
6
Cl
Cl
H
C
H2
C N
N
O
CH2
Cl
Cl
Take 2-bromo-1-(2,4-dichlorophenyl)ethanone 1 and 1-H imidazole 2 to
form compound 3
Then 3 was react with NaBH4 for reduction of ketone to form 4.
Then the 4 was react with 1-(bromomethyl)-2,4-dichlorobenzene to form
MICONAZOLE 5,
METHOD

7. SYNTHESIS OF MICONAZOLE
7
Cl
Cl
H
C
H2
C N
N
O
CH2
Cl
Cl
Miconazole
1
2
3
4
5

8. SYNTHESIS OF MICONAZOLE
8
Orally Effective broad-spectrum antifungal drug
• Vulvovaginal candidiasis(yeast infection).
• Effective against dermatomycoses in animal models.
• Suppository used to treating vaginal yeast infections (Candida).
• It works by stopping the growth of yeast that caused by fungus.
USE

9. SYNTHESIS OF SULFAMERAZINE
OEt
O
O
H2N
NH2
NH HN
N
H2N
N
N
H2N
Cl
N
N
H2N
SO2Cl
NHAc
S
HN
N
N
O
O
NH2
+
POCl3
OH
H2/Pd-C
9
USES OF SULFAMERAZINE:
It is used as an antibacterial agent.
It can be used to treat:
1. Bronchitis
2. Prostatitis
3. urinary tract infections.
SIDE EFFECTS OF SULFAMERAZINE:
1. Nausea
2. Vomiting
3. Diarrhea
4. hypersensitivity reactions.
5. Hematologic effects such as anemia.

10. SYNTHESIS OF SULFAMERAZINE
OEt
O
O
H2N
NH2
NH HN
N
H2N
O
N
N
H2N
Cl
N
N
H2N
SO2Cl
NHAc
S
HN
N
N
O
O
NH2
+
POCl3
OH
H2/Pd-C
10
3-Oxobutyric acid ethyl ester Guanidine

11. 11