Simple and highly efficient procedure for conversion of aldoximes to nitriles using N-(p-Toluenesulfonyl) imidazole

Article abstract of DOI:10.1080/00397910903261395

A facile and efficient method for dehydration of aldoximes into nitriles using N-(p-toluenesulfonyl) imidazole (TsIm) is described. In this method, aldoximes were refluxed with TsIm in the presence of 1,8-diazabicyclo-[5.4.0] undec-7-ene (DBU) in dimethylformamide (DMF) to afford the corresponding nitriles in good yields. This methodology is highly efficient for various structurally diverse aldoximes including aromatic, heteroaromatic, and aliphatic oximes. A plausible mechanism for the conversion of aldoxime into nitriles using TsIm/DBU is explained. Copyright Taylor & Francis Group, LLC.

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Simple and Highly Efficient Procedure
for Conversion of Aldoximes to Nitriles
Using N-(p-Toluenesulfonyl) Imidazole
Mohammad Navid Soltani Rad a , Ali Khalafi-Nezhad b , Somayeh
Behrouz b , Zohreh Amini a & Marzieh Behrouz b
a Department of Chemistry, Faculty of Basic Sciences, Shiraz
University of Technology, Shiraz, Iran
b Department of Chemistry, College of Sciences, Shiraz University,
Shiraz, Iran
Published online: 26 Jul 2010.
To cite this article: Mohammad Navid Soltani Rad , Ali Khalafi-Nezhad , Somayeh Behrouz ,
Zohreh Amini & Marzieh Behrouz (2010) Simple and Highly Efficient Procedure for Conversion
of Aldoximes to Nitriles Using N-(p-Toluenesulfonyl) Imidazole, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:16, 2429-2440,
DOI: 10.1080/00397910903261395
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Synthetic Communications1, 40: 2429–2440, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903261395
SIMPLE AND HIGHLY EFFICIENT PROCEDURE FOR
CONVERSION OF ALDOXIMES TO NITRILES USING
N-(p-TOLUENESULFONYL) IMIDAZOLE
Mohammad Navid Soltani Rad,1 Ali Khalafi-Nezhad,2
Somayeh Behrouz,2 Zohreh Amini,1 and Marzieh Behrouz2
1Department of Chemistry, Faculty of Basic Sciences,
Shiraz University of Technology, Shiraz, Iran
2Department of Chemistry, College of Sciences, Shiraz University,
Shiraz, Iran
A facile and efficient method for dehydration of aldoximes into nitriles using N-
(p-toluenesulfonyl) imidazole (TsIm) is described. In this method, aldoximes were refluxed
with TsIm in the presence of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) in dimethylfor-
mamide (DMF) to afford the corresponding nitriles in good yields. This methodology is
highly efficient for various structurally diverse aldoximes including aromatic, heteroaro-
matic, and aliphatic oximes. A plausible mechanism for the conversion of aldoxime into
nitriles using TsIm/DBU is explained.
Keywords: Aldoximes; DBU; dehydration; DMF; nitriles; TsIm
INTRODUCTION
Nitriles[1] are valuable intermediates in organic synthesis because they are appro-
priate precursors for the introduction of various functional groups as well as the syn-
thesis of N-heterocycles.[2] Numerous general methods have been established for the
introduction of nitrile groups to various organic functional groups.[1] The most com-
mon routes to access aliphatic and aromatic nitriles involve nucleophilic substitution
of alkyl halides with inorganic cyanides,[3] dehydration of amides,[1b,c] one pot-
conversion of aldehydes to nitriles with various reagents,[4] oxidative conversion of
primary alcohols and amines,[5] and Rosenmund[6] and Sandmeyer reactions.[7] The
conversion of oximes[1] and O-substituted aldoximes[8] into nitriles is a well-known
procedure for preparation of both aliphatic and aromatic nitriles. Numerous reagents
and various conditions have been developed for the preparation of nitriles by
dehydration of aldoximes. For example, [RuCl2(p-cymene)]2=molecular sieves,[9]
SeO2,[10] triethyl-amine=SO2,[11] PPh3=CCl4,[12] 1,10-dicarbonyl-imidazole,[13] acetic
Received July 18, 2009.
Address correspondence to Mohammad Navid Soltani Rad, Department of Chemistry, Faculty of
Basic Sciences, Shiraz University of Technology, Shiraz 71555-313, Iran. E-mail: soltani@sutech.ac.ir;
nsoltanirad@gmail.com or Ali Khalafi-Nezhad, Department of Chemistry, College of Sciences, Shiraz
University, Shiraz 71454, Iran. E-mail: khalafi@chem.susc.ac.ir
2429

2430
M. N. S. RAD ET AL.
Scheme 1. Conversion of aldoximes to nitriles using TsIm.
anhydride,[14] Vilsmeier reagent,[15] Burgess reagent,[16] cyanuric chloride,[17] ZnO=
CH3COCl,[18] cytochrome P-450,[19] di-2-pyridylsulfite,[20] 2-chloro-1-methyl pyridi-
nium iodide,[21] AlI3,[22] TiCl3(OTf),[23] 1-chlorosulfinyl-4-dimethylaminopyridinium
chloride,[24] chloro-sulfonyl isocyanate,[25] AlCl3 ꢀ 6H2O=KI,[26] chlorosulfonic acid,[27]
and S,S-dimethyl dithiocarbonate[28] have been employed for this transformation.
Arenesulfonyl chlorides[29a] and methane sulfonyl chloride[29b] have also been used
as dehydrating agents for this conversion. Although a large number of methods
have been developed, they suffer from several disadvantages, such as poor yields, long
reaction times, use of expensive or less readily available reagents, harsh reaction
conditions, tedious workup, and limited substrate scope. Hence, there is still a need
to develop practical and convenient methods for the conversion of aldoximes into
nitriles.
Recently, we reported that N-(p-toluenesulfonyl) imidazole (TsIm) is a highly
efficient, cheap, neutral, and stable reagent for various organic transformations
including one-pot conversion of alcohols to alkyl azides,[30a] alcohols to nitriles,[30b]
esterification of alcohols,[30c] and N-alkylation of nucleobases.[30d] In continuation of
our interest in the application of TsIm in organic synthesis, we hereby report that
aromatic and aliphatic aldoximes can be efficiently converted into their correspond-
ing nitriles using TsIm in the presence of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU)
in refluxing dimethylformamide (DMF; Scheme 1).
RESULTS AND DISCUSSION
The first step of this synthetic approach was optimization of the reaction con-
ditions. Initially, the effect of various solvents on the conversion of 4-chlorobenzaldehyde
oxime into 4-chlorobenzonitrile in the presence of freshly prepared TsIm[30a] (1.2 equiv)
was studied as a model reaction. The results are depicted in Table 1. As the data in Table 1
indicate, DMF (entry 2) was the most efficient solvent; hence, it was our solvent of
choice. Anhydrous DMF, dimethylsulfoxide (DMSO), and hexamethylphosphoramide
(HMPA) (Table 1, entries 1, 3, and 6) also afforded good yields of the corresponding
nitrile but took longer for completion.
The choice of the base for activation of the aldoximes to react with TsIm and
subsequent conversion into nitriles had great significance. In this case, we evaluated
the potency of several organic and inorganic bases on the model reaction (Table 2).
In the absence of a base, no reaction was achieved even after 72 h. DBU (Table 2,
entry 4) proved to be the most efficient base for conversion of 4-chlorobenzaldehyde

CONVERSION OF ALDOXIMES TO NITRILES USING TsIm
2431
Table 1. Effect of various solvents on the conversion of
4-chloro benzaldehyde oxime into 4-chlorobenzonitrile
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMFa
DMF
1
0.25
0.5
12
88
96
DMSO
THF
MeCN
91
20
6
65
HMPA
H2O
Acetone=H2Od
Toluene
1.5
30
89
NRc
15
24
30
Trace
aAnhydrous DMF.
bIsolated yield.
cNo reaction.
d1:1 ratio.
oxime into the corresponding nitrile. Other bases such as Cs2CO3, K2CO3, and NaH
(Table 2, entries 6, 7, and 9) afforded lesser yields of nitrile.
The optimized amount of TsIm was 1.2–1.5 equiv. per equivalent of oxime. We
also investigated the other TsIm analogs (Table 3). As the data in Table 3 indicate, a
short reaction time and good yield of nitrile were obtained with TsIm (Table 3, entry
3) in comparison with other sulfonyl analogs. Replacing the tolyl in TsIm with
methyl, trifluoromethyl, and phenyl (Table 3, entries 1, 2, and 4) caused no improve-
ment in the reaction efficiency. Furthermore, other azole analogs of TsIm were not
as efficient as imidazole (Table 3, entries 5 and 6). N-Tosyl phthalimide (Table 3,
entry 7) was inactive for the conversion of 4-chlorobenzaldehyde oxime into its
nitrile even after refluxing for 48 h.
Table 2. Effect of various bases on the conversion of 4-chloro
benzaldehyde oxime into 4-chlorobenzonitrile
Entry
Base
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
None
DABCO
DMAP
DBU
72
5
0
45
18
96
15
91
90
20
92
21
0.25
24
0.5
2
MgO
Cs2CO3
K2CO3
TEA
5
0.5
NaH
aIsolated yield.

2432
M. N. S. RAD ET AL.
Table 3. Comparison of TsIm reactivity with analogs on the conversion of
4-chlorobenzaldehyde oxime into 4-chlorobenzonitrile
Entry
Reagent
Time (h)
Yielda (%)
1
2
3
4
1
1
90
91
96
82
0.25
1
5
6
12
12
68
63
7
48
NRb
aIsolated yield.
bNo reaction.
The comparative dehydrating reagents under the same conditions were tested
for conversion of 4-chlorobenzaldehyde oxime into 4-chlorobenzonitrile. The
attained results are depicted in Table 4.
As data in Table 4 indicate, TsIm (Table 4, entry 5) and Ac2O (Table 4, entry 3)
demonstrated the best results; however, the reaction with TsIm was conducted in less
Table 4. Comparison of various dehydrating reagents with TsIm on the
conversion of 4-chloro benzaldehyde oxime into 4-chlorobenzonitrile
Entry
Dehydrating reagent
Time (h)
Yielda (%)
1
2
3
4
5
TsCl
MsCl
Ac2O
AcBr
TsIm
6
6
68
55
94
78
96
1
1
0.25
aIsolated yield.

CONVERSION OF ALDOXIMES TO NITRILES USING TsIm
2433
reaction time. It is assumed that the greater efficiency of TsIm and Ac2O than the
other dehydrating reagents in Table 4 is attributable to the potential role of their cor-
responding counterion, because their separated counterions (OAcꢁ and imidazolide)
have an apparent basic property that facilitates the 1,2-elimination. TsIm has several
advantages with respect to all dehydrating agents used in Table 4, as these reagents
are hygroscopic, corrosive, fuming, and toxic and=or create difficulty in handling;
however, TsIm is nonhygroscopic, cheap, less toxic, and stable and can be easily pre-
pared via a simple reaction.[30a] Thus, the TsIm is efficient enough to be considered
as a suitable alternative for the other dehydrating agents.
The generality and versatility of this method was examined by application to a
set of structurally diverse aldoximes (Table 5). As the results in Table 4 indicate, this
method is suitable for all oximes.
Both aromatic and aliphatic aldoximes were successfully converted into the
corresponding nitriles in good yields. The capability of the method was confirmed
with respect to aromatic (Table 5, entries 1–12, 17–19), heteroaromatic (Table 5,
entries 13–16), aliphatic (Table 5, entries 24, 25), vinylic (Table 5, entry 23), and
other aldoximes containing N-heterocycles (Table 5, entries 20, 21). Using this
method, excellent results were obtained for aryl aldoximes with different substituted
groups. Moreover, this methodology is highly chemoselective in the presence of
various functional groups. Thiophene and pyrrole are also stable under the reaction
conditions. By this procedure, both (E)- and (Z)-isomers of oximes can be converted
into nitriles, and in most cases, the oximes used in this research were mixtures of (Z)-
and (E)-isomers.
The TsIm=DBU-mediated conversion of aldoximes to nitriles is supposed to
proceed by the reaction pathway shown in Scheme 2. We suggest that the prelimi-
nary acid–base reaction of DBU with oxime (1) affords DBU–oxime adduct 2.
The adduct 2 reacts with TsIm to provide O-tosyl-aldoxime 3 as the main intermedi-
ate. The generation of intermediate 3 was evidently endorsed through the course of
the reaction by thin-layer chromatography (TLC) of in situ–generated 3 with auth-
entic samples. Moreover, intermediate 3 was easily separated at an early stage of the
reaction using column chromatography. The separated intermediate 3 was character-
ized by 1H NMR,13C NMR, and infrared (IR) spectroscopy methods. Two pathways
(A and B) were postulated for conversion of 3 to nitrile 4. In pathway A, the conver-
sion proceeds by 1,2-elimination of 3, whereas in pathway B, the conversion is
achieved by 1,4-elimination in a concerted process. The reasons for suggesting a
plausible mechanism comes from the facts that (i) in the absence of base, no nitrile
is produced in a trace amount (Table 2) and (ii) 1 equiv. of DBU is enough for
the reaction to proceed. Using extra amounts of DBU has negligible effects on the
completion of the reaction. It is also assumed that released imidazole residue can
regenerate DBU from protonated DBU. Finally, (iii) the thermal condition also
facilitates the concerted-type process.
To understand whether a single mechanism (pathway A or B) or both are
achieved in our reaction, we first synthesized and isolated 4-chlorobenzaldehyde
O-tosyl oxime via reaction of 4-chlorobenzaldehyde oxime with TsCl in the presence
of triethylamine (TEA) at room temperature in anhydrous DCM. Subsequently, the
pure 4-chlorobenzaldehyde O-tosyl oxime was divided into equal amounts in two
separate double-necked, round-bottom flasks, each equipped with a condenser.

2434
M. N. S. RAD ET AL.
Table 5. Dehydration of aldoximes into nitriles using TsIm=DBU in refluxing DMF
Entry
R-CNa
(n cmꢁ1 b
)
Time (min)
Yieldc (%)
Ref.
1
2
2231
2233
20
15
91
96
18, 22, 32, 34
12, 18, 22, 32, 34
3
4
2220
2223
15
20
93
91
12, 18, 34
12, 18
5
6
2230
2228
30
30
89
87
12, 18, 32, 33, 34
12, 18, 33
7
8
2237
2224
2219
2232
2226
35
20
20
25
25
86
95
92
94
90
12
18, 20, 32, 33, 34
9
33
18, 32, 34
18
10
11
12
13
14
2214
2230
2233
20
25
25
93
91
89
34
32
18, 32, 34
15
2225
25
90
18, 32, 34
16
17
2202
2217
25
30
87
91
–
–
18
2221
50
81
–
(Continued )

CONVERSION OF ALDOXIMES TO NITRILES USING TsIm
2435
Table 5. Continued
Entry
19
R-CNa
(n cmꢁ1 b
)
Time (min)
50
Yieldc (%)
83
Ref.
–
2223
2215
20
21
90
90
84
87
–
–
2222
22
23
2205
2214
40
35
85
88
22, 30b
18, 20, 33, 34
24
25
2227
2232
35
35
86
86
18
18
aAll products were characterized by 1H and 13C NMR, IR, CHN, and MS analysis.
bIR signal of nitrile in wavenumbers (cmꢁ1).
cIsolated yield.
In the first flask, a solution of 4-chlorobenzaldehyde O-tosyl oxime in DMF was
refluxed for 2 h. After this time, no progress in the reaction was observed, as
indicated by TLC. After workup and separation via column chromatography,
4-chlorobenzonitrile was attained only in 30% yield. In the second flask, which
contained the same equivalent of 4-chlorobenzaldehyde O-tosyl oxime in DMF in
the presence of DBU, the reaction finished after 20 min, and 4-chlorobenzonitrile
was attained in 90% yield (Scheme 3).
Scheme 2. A plausible mechanism for conversion of aldoximes into nitriles using TsIm. Path (A): 1,2-
elimination; Path (B): 1,4-elimination.

2436
M. N. S. RAD ET AL.
Scheme 3. The study for indicating reaction pathways A and B in the absence or presence of DBU.
These experiments have revealed that both mechanisms happen simul-
taneously. However, the base has an undeniable role in progress and termination
of the reaction, and thus we can conclude that the reaction is mostly achieved via
1,2-elemination.
In conclusion, we have described TsIm as an efficient, stable, neutral, and
cheap reagent for high-yield conversions of aldoximes to nitriles. The significant
features of this method include short reaction time, good yields of product, simple
experimental procedure, generality, and versatility.
EXPERIMENTAL
General Information
All chemicals were prepared from Fluka or Merck chemical companies except
TsIm, which was freshly prepared using the explained methods.[30a] Solvents were
purified and dried by reported methods[35] and stored over 0.3-nm molecular sieves.
The progress of the reaction was followed with TLC using silica-gel SILG=UV 254
plates. Silica gel 60, 0.063–0.200 mm (70–230 mesh ASTM), was used for column
chromatography. IR spectra were run on a Shimadzu Fourier transform (FT)–IR
8300 spectrophotometer. 1H NMR (250 MHz) and 13C NMR (62.5 MHz) were
run on a Bruker Avance DPX-250 FT-NMR spectrometer. Chemical shifts (d) are
¨
reported in parts per million, and coupling constants (J) are in hertz. Mass spectra
(MS) were recorded on a Shimadzu GC MS-QP 1000 EX apparatus. Microanalyses
were performed on a Perkin-Elmer 240-B microanalyzer. Melting points (mp) were
recorded on a Buchi 510 apparatus in open capillary tubes and are uncorrected.
¨
General Procedure for Dehydration of Aldoximes into Nitriles
A mixture of aldoxime (0.01 mol),[31] freshly prepared TsIm[30a] (0.012 mol),
and DBU (0.01 mol) in DMF (15 mL) was added to a double-necked, round-bottom
flask (100 mL) equipped with a condenser. The mixture was refluxed, and in most
cases, darkening occurred. Reflux was continued until TLC monitoring indicated
no further improvement in the conversion (Table 4). After that, the reaction mixture
was dissolved in CH2Cl2 (150 mL) and subsequently washed with water
(3 ꢂ 150 mL). The organic layer was dried (Na2SO4) and evaporated. The crude
product was purified by column chromatography on silica gel, eluting with a mixture
of n-hexane and EtOAc.

CONVERSION OF ALDOXIMES TO NITRILES USING TsIm
2437
1
All products were characterized by H NMR, 13C NMR, IR, CHN, and MS
analysis. Selected spectral data for entries 20 and 21 are given.
Selected Spectral Data
2-(2-(1,3-Dioxoisoindolin-2-yl)ethoxy)benzonitrile (Table 4, Entry
1
20). White solid; Rf (EtOAc=n-hexane) (1:1) 0.48; mp 148.1 ꢃC; H NMR (CDCl3,
250 MHz) dppm: 4.03 (t, J ¼ 5.9 Hz, 2H), 4.22 (t, J ¼ 5.9 Hz, 2H), 6.88–6.91 (m,
2H), 7.36–7.42 (m, 2H), 7.58–7.63(m, 2H), 7.68–7.73 (m, 2H); 13C NMR (CDCl3,
62.5 MHz) dppm: 36.52, 65.19, 102.29, 112.29, 115.88, 121.31, 123.34, 131.86,
133.59, 133.76, 134.11, 159.66, 167.89; IR (KBr) ((cmꢁ1): 2215 (CN); MS (EI) [m=
z (%)]: 292.08 (52). Anal. calc. for C17H12N2O3: C, 69.86; H, 4.14; N, 9.58%. Found:
C, 69.82; H, 4.17; N, 9.63%.
2-(5-(2-Methyl-4-nitro-1H-imidazol-1-yl)pentyloxy)benzonitrile (Table 4,
1
Entry 21). Bright yellow oil; Rf (EtOAc) 0.45; H NMR (CDCl3, 250 MHz) dppm
:
0.75 (m, 2H), 1.05 (m, 4H), 1.59 (s, 3H), 3.20 (complex, 4H), 6.16–6.19 (m, 2H),
6.67–6.68 (m, 2H), 7.13 (s, 1H); 13C NMR (CDCl3, 62.5 MHz) dppm: 12.42, 22.37,
27.68, 29.28, 46.51, 68.12, 100.81, 111.99, 116.02, 120.23, 132.97, 134.15, 144.42,
145.57, 159.94, 161.84; IR (liquid film) n (cmꢁ1): 2222 (CN); MS (EI) [m=z (%)]:
314.1 (48). Anal. calc. for C16H18N4O3: C, 61.13; H, 5.77; N, 17.82%. Found: C,
61.15; H, 5.81; N, 17.79%.
ACKNOWLEDGMENT
We thank the Shiraz University of Technology and Shiraz University Research
Councils for partial support of this work.
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M. N. S. RAD ET AL.
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