This document summarizes a refresher course on chemistry that included a presentation on the ultrasound assisted one-pot synthesis of imidazole derivatives. Key points include: - Imidazoles and benzimidazoles are important structures in drug chemistry, with examples like omeprazole cited. - Literature methods for synthesis include using acids, metal chlorides, and other reagents. - The presented method uses diethyl bromophosphate under ultrasonic irradiation to efficiently synthesize imidazole derivatives from benzil or benzoin, an aldehyde, and ammonium acetate in 30 minutes with yields of 90-98%. - Optimization of reaction conditions like molar ratios,

1. Welcome
to
Refresher Course in Chemistry-2015
organized by
Dept. of Chemistry,
Shivaji University,
Kolhapur

2. Ultrasound assisted one pot synthesis of imidazole derivatives
using diethyl bromophosphate as an oxidant
Ultrasonics Sonochemistry 19, (2012), 94–96
Dr. Deepak R. Nagargoje,
M. P. A S C College,
Panvel

3. Introduction
 Imidazoles and benzimidazoles are priviled structure in heterocyclic and
drug chemistry
 Omeprazole, proton pump inhibitor
 Flumazenil, benzodiazepine antagonist
 A platelet coagulation drug, trifenagrel
H3CO
N
H
N
S
N
CH3
OCH3
OCH3
O
Omeprazole
N
H
N
O
N
N
N
N O
O
O
F
Flumazenil
Trifenagrel

4. Literature Methods
 Acetic acid
 Acidic Al2O3
 HY/ Silicagel
 Sodium bisulphite
 ZrCl4
 NiCl2.2H2O
 Iodine
 Yb(OTf)3
 KH2PO4
 ILs

5. Ultrasonics/Sonochemistry – An introduction
Ultrasound is defined as sound of a frequency beyond that to
which the human ear can respond. (20 KHz to 10000 KHz)

6.  Ultrasound irradiation offers an alternative energy source for organic
reactions which are ordinarily accomplished by heating
 Ultrasound-assisted reactions proceed by the formation, growth and
collapse of acoustic bubbles in the reaction medium
 These directly help in shortening the time span of reactions and increasing the
yield of products

7. The reaction scheme
Reaction conditions: a. Reaction of benzil, benzaldehyde and ammonium acetate (1:1:3) in
presence of DEP (1 mol) under ultrasonic waves (45 KHz).
b. Yields based on GC analysis after 30 min.
O
O
OR
O
OH
+
H
O
R + NH4OAc
DEP
)))))), rt
N
H
N
R
( 90-98 %)

8. General Procedure of the reaction
To benzil/benzoin (1 mmol), aldehyde (1mmol) and ammonium acetate (3 mmol)
which were dissolved in acetonitrile were added (1 mmol) diethyl bromophosphate.
This reaction mixture was then irradiated under ultrasonication at room
temperature. The progress of the reaction was monitored using TLC. After
completion of the reaction, the solvent was evaporated. The reaction mixture was
quenched in water and neutralized by aqueous sodium bicarbonate solution. The
mixture was extracted with ethyl acetate (3–10 ml) eluted over silica gel using
ether–ethyl acetate as eluting solvent.
Compound (3a): IR (KBr): v 3450, 3050, 1600, 1580 cm-1;
1H NMR (200 MHz, CDCl3): d 7.15–8.00 (m, 15H, Ph), 9.20 (s, br, NH);
EI-MS: m/z, 297 (M+).

9. Optimization of molar ratios of reactants and oxidant
Reaction conditions: Reaction of benzil, benzaldehyde and ammonium acetate (1:1:3)
under ultrasonic waves (45 KHz).
b Isolated Yields
Sr.
No.
Molar ratio
substrate
Oxidant
(mol)
Time
(min.)
Yield (%) b
a 1:1:3 0.25 30 61
b 1:1:3 0.50 30 79
c 1:1:3 1.0 30 97

10. Screening of solvent effect on model
reaction
Sr. No. Solvent Time
(min.)
Yield (%) b
1 Ethanol 30 60
2 Methanol 30 58
3 DCM 30 85
4 DMF 30 63
5 THF 30 86
6 Acetonitrile 30 97
Reaction conditions: Reaction of benzil, benzaldehyde and ammonium acetate (1:1:3)
under ultrasonic waves (45 KHz).
b Yields based on GC analysis

11. Effect of ultrasonic frequency
0
10
20
30
40
50
60
70
80
90
100
35 45 60

12. Optimal reaction conditions
Substrate: 1mol aldehyde ,1 mol benzil/benzoin, 3mmol amm. acetate
 solvent: Acetonitrile
 catalyst: 1 mol diethyl bromophosphate (DEP)
 Ultrasonic frequency: 45KHz
 Reaction temperature: Room Temp.

13. Scope and limitations of substituted Benzaldehydes
ent
ry
Aryl aldehyde Reaction Time Yield (%) M. P.
(O C)
Benzil Benzoin Benzil Benzoin
1 Benzaldehyde 40 50 95 93 275-276
195-196
262-264
230-232
232-234
215-217
232
270
191
201
2 O-chlorobenzaldehyde 35 45 96 91
3 p-chlorobenzaldehyde 30 50 95 94
4 P- Toluilaldehyde 45 65 92 90
5 P-methoxybenzaldehyde 35 70 98 94
6 O, p- dimethoxy
benzaldehyde
30 50 93 94
7 P-nitrobenzaldehyde 40 80 96 93
8 P-hydroxy benzaldehyde 45 60 98 97
9 P-fluorobenzaldehyde 25 35 97 95
10 Furfuraldehyde 45 50 94 91

14. Mechanism of the reaction
OH
Ph
NH4OAc
NH3 + AcOH
OH
Ph
H+
NH3
NH2
Ph
HO
H
NH2
Ph
O
H
H
H
NH2
Ph
H2N
H
OPh
OPh
N
NO
O
Ph
H
H
Ph
Ph
H
H
H
H
N
NPh
Ph
Ph
H
N
H
NPh
Ph
Ph
OPh
OHPh
H2N
NO
O
Ph
HPh
Ph
H
H
H
H
N
NPh
Ph
Ph
H
air oxidation
H+
H+
NH3
-2H2O
-2H2O

15. Conclusions
 A simple and practical method was developed using diethyl bromophosphate under
ultrasound irradiation
 The method offers several advantages viz. simple experimental process, easy work up
and improved yields

16. Acknowledgement
 Coordinator, RC in Chemistry
 Prof. Charansingh H. Gill
 Council of Scientific & Industrial Research (CSIR), New Delhi
 National Chemical Laboratory (NCL), Pune
 Dr. Babasaheb Ambedkar Marathwada University, Aurangabad

18. Thank you…