186
N. D. Kokare, D. B. Shinde
of N-hydroxy-2-phenylbenzimidazole (1) by coupling of
o-nitroaniline with benzyl bromide using sodium hydride
as base, followed by benzyl deprotection using 10% Pd/C.
Compound 1 was treated with diethyl chlorophosphate and
triethylamine in dichloromethane to afford reagent 2
(Scheme 1).
literature procedure [23–26] these compounds were iso-
lated in 82, 85, 87, and 82% yields in 1 h reaction time.
Compounds with electron-withdrawing substituents, for
example 4-nitrobenzonitrile (4i), were also isolated in very
good yield (91%) in 45 min reaction time, while a litera-
ture procedure [23–26] reports 87% yield in 35 h reaction
time.
As a test reaction the single-step conversion of 4-bro-
mobenzaldehyde to 4-bromobenzonitrile (4e) was
examined using hydroxylamine hydrochloride and reagent
2 and various reaction conditions. Although variation of
solvents, base, equivalents of reagents, and temperature
were tried, the required compound was isolated in very
poor yields (18% yield, reaction conditions: 4-bromo-
benzaldehyde (10 mmol), reagent 2 (14 mmol), 1,4-
dioxane solvent (15 cm3) and 100°C). Hence, a two step
strategy was applied, in which first 4-bromobenzaldoxime
was synthesized and then converted to 4-bromobenzonitrile
(4e) under various reaction conditions. Using optimized
reaction conditions (10 mmol aldoxime, 12 mmol 2,
22 mmol triethylamine, acetonitrile, room temperature),
compound 4e was isolated in 98% yield. This method was
applied for a range of aromatic aldoximes for conversion to
the corresponding nitrile compounds, resulting in excellent
yields (Scheme 2, Table 1). The method was equally
effective for electron-donating and electron-withdrawing
substituents. Reagent 2 was superior to previously reported
methods in terms of yields and reaction times [23–26].
Compounds 4a, 4b, 4c, and 4h were isolated in 98, 97, 94,
and 95% yields in 45 min reaction time while using a
Using similar reaction conditions, a,b-unsaturated and
aliphatic nitriles were also synthesized. The results are
summarized in Table 2. Yields obtained were in the range
76–94%. All synthesized compounds were purified with
column chromatography and characterized with MS and 1H
NMR. Melting points were compared with the reported
literature values.
The probable reaction pathway for conversion of
aldoxime to nitrile using reagent 2 is shown in Scheme 2. It
includes reaction of the aldoxime with reagent 2 to form
intermediate 3, which consequently decomposes to afford
the nitrile compound and diethylphosphoric acid.
In conclusion, reagent 2 was found to be a versatile
reagent for efficient and simple conversion of aldoximes to
the corresponding nitriles in good to excellent yields.
Because reagent 2 can be easily prepared from inexpensive
and commercially available starting materials, the method
could also be useful for large-scale applications.
Experimental
Melting points were determined in capillary tubes. 1H
NMR spectra were recorded with a 400 MHz Varian–
Gemini spectrometer. Mass spectra were recorded with a
Micromass–Quattro-II mass spectrometer (Waters). HPLC
was performed using a Zorbax SB-C18 reversed-phase
column (0.46 9 25 cm2) and a Shimadzu instrument
equipped with an automatic injector and UV-PDA detector.
Detection was carried out at 215 nm. The isocratic mobile
phase was 0.05% TFA–acetonitrile (1:1, v/v). The products
were eluted at a flow rate of 1 cm3 min-1. Flash column
N
N
N
N
a
O
OH
O
P
OEt
EtO
1
2
(a) (EtO)2P(O)Cl, (Et)3N, dichloromethane, 30 min, 0 °C.
Scheme 1
Scheme 2
N
N
O
P
O
H
N
N
H
OH
O
P
+
+
N
N
O
OEt
R
R
EtO
OEt
OH
EtO
2
3
1
O
O
H
O
P
N
+
P
OEt
R
CN
OEt
HO
R
EtO
OEt
3
4a - 4j
123
Kokare, Nagnnath D.
