Efficient transformation of aldoximes to nitriles using 2-chloro-1-methylpyridinium iodide under mild conditions

Article abstract of DOI:10.1081/SCC-120034158

Various (aliphatic, aromatic, and heterocyclic aromatic) types of aldoximes were converted into the corresponding nitriles in good to excellent yields using 2-chloro-1-methylpyridinium iodide (CMPI) as a dehydrating agent under mild conditions.

Full text of DOI:10.1081/SCC-120034158

w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 10, pp. 1775–1782, 2004
Efficient Transformation of Aldoximes
to Nitriles Using 2-Chloro-
1
-methylpyridinium Iodide
Under Mild Conditions
*
Kieseung Lee, Sang-Bae Han, Eun-Mi Yoo,
Soon-Ryang Chung, Haibum Oh, and
Sungwan Hong
Department of Chemistry, Woosuk University, Chonbuk, South Korea
ABSTRACT
Various (aliphatic, aromatic, and heterocyclic aromatic) types of aldox-
imes were converted into the corresponding nitriles in good to excellent
yields using 2-chloro-1-methylpyridinium iodide (CMPI) as a dehydrat-
ing agent under mild conditions.
Key Words: Dehydration; Aldoxime; Nitrile; Primary amide; 2-Chloro-
1
-methylpyridinium iodide.
*
Correspondence: Kieseung Lee, Department of Chemistry, Woosuk University,
Chonbuk 565-701, South Korea; Fax: 82-63-290-1501; E-mail: kslee@woosuk.ac.kr.
1
775
DOI: 10.1081/SCC-120034158
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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1
776
Lee et al.
INTRODUCTION
[1]
Nitriles are important intermediates in organic synthesis, especially in the
synthesis of various heterocyclic compounds and biologically important mole-
[
cules. While a wide variety of synthetic approaches to nitriles from diverse
2]
[1a,3]
chemical sources have been developed,
nitrile synthesis from aldoxime
using various dehydrating agents has been one of the classical routes. Numerous
[4a]
reagents, e.g., Burgess reagent,
[4b]
[4c]
PPh /CCl ,
3
alkyl cyanoformates,
4
[
4d]
[4e]
[4f]
di-2-pyridyl sulfite, InCl3,
[4g]
AlI3,
TiCl (OTf),
dichlorocarbene/reverse micelle,
[
4h]
[4i]
[4j]
cytochrome p450,
[RuCl (p-cymene)] ,
2
etc. have been
3
2
developed. Many reagents, however, may have some limitations such as low
yields, use of strong acids/or bases or oxidants, harsh reaction conditions,
use of expensive or less readily available reagents, tedious workup procedure,
or limited substrate scope. Therefore there is still a need to develop mild and
general dehydrating reagent for this transformation.
2
-Chloro-1-methylpyridinium iodide (CMPI) was initially introduced as
[5]
an efficient condensing reagent for the synthesis of carboxylic esters, and
has extensively been studied as a powerful reagent for many useful transform-
ations. However, to the best of our knowledge, CMPI has not been previously
utilized for the synthesis of nitriles from aldoximes. We herein wish to report
the first application of CMPI to the effective generation of nitriles from aldox-
imes under mild conditions (Sch. 1).
Various aldoximes were tested following the protocol described in Sch. 1,
and the results were summarized in Table 1. To obtain the basic information
regarding the optimum reaction conditions, anthracene oxime 1a reacted first
with CMPI (1.1 equiv) in CH Cl for ca. 10 min, then with Et N (2.2 equiv) at
2
2
3
room temperature under Ar. As the reaction proceeded, the color of the reac-
tion mixture was gradually changed from yellow to reddish brown and the
reaction was confirmed to be complete in 2 hr by TLC-analysis without any
significant side reactions. Upon completion of reaction, the reaction mixture
was quenched with aqueous HCl (5%) to remove the by-product (1-methyl-
2
-pyridone), and the crude product obtained was subjected to flash column
chromatography on SiO2 to provide the pure nitrile 2a in 94% yield
entry 1). Attempts to utilize (i-Pr) NEt as base or THF as reaction medium
(
2
were found to be equally effective, however, with less amount of CMPI or
Scheme 1.

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Transformation of Aldoximes to Nitriles
1777
Table 1. Results of attempted reaction of aldoximes with CMPI
CMPI
(equiv) (equiv) (hr) (%)
Et N Time Yield
3
a
Entry
1
R55
b
(1a)
1.10
1.05
2.20
2.10
2.0 94
c
2
(1b)
1.0 91
c
d
3
4
(1c)
2.20
1.05
4.40
2.10
2.0 92
1.5 88
e
(1d)
c
5
6
(1e)
1.10
1.10
2.20
2.20
2.0 81
2.0 93
f
(1f)
c
7
(1g)
1.00
2.00
1.0 91
g
h
h
8
9
(1h)
1.05
1.05
2.10
2.10
1.0 86
1.0 88
g
(1i)
(continued)

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Lee et al.
Table 1. Continued.
Entry
R55
CMPI
Et
equiv) (equiv) (hr) (%)
3
N
Time Yield
a
(
c
1
0
(1j)
1.00
1.00
2.00
2.00
1.5 90
1.5 90
c
1
1
(1k)
a
2
Isolated yields by flash column chromatography (SiO ).
b
Mixture (ca. 7 : 93) of E- and Z-isomer.
Predominantly E-isomer.
c
d
3
CH CN was used as solvent.
e
Mixture (ca. 60 : 40) of E- and Z-isomer.
Mixture (ca. 55 : 45) of E- and Z-isomer.
f
g
h
Predominantly Z-isomer.
Saturated brine instead of HCl (5%) was used for the quenching step.
base the reaction was confirmed to be incomplete. Other aromatic aldoximes
1b, 1c) have shown the similar reactivity with CMPI under the similar con-
(
ditions to afford the corresponding nitriles in excellent yields (entries 2 and 3).
With promising results in hand, we next tested other types of aldoximes to
examine the generality of this reaction. Several aliphatic (entries 4–7) and
heterocyclic aromatic (entries 8–11) aldoximes were found to exhibit the
same reaction patterns under the similar reaction conditions, and the desired
nitriles were obtained in 81–93% yields, respectively.
It has been known that many dehydrating reagents reported to be efficient
for the generation of nitriles from aldoximes are also able to transform primary
[
4a,b,f]
amides to nitriles.
Therefore, it is highly desirable to check whether
CMPI could react with primary amides or not. CMPI was turned out to
be inactive at all with both aliphatic and aromatic primary amides under the
a
similar reaction conditions, which renders another advantage of CMPI as a
selective dehydrating agent.
In summary, we have found that CMPI is a mild and practical reagent for
the effective conversion of aldoximes into nitriles. Considering commercial
a
When primary amide such as m-nitrobenzamide or 5-phenylvalerylamide was reacted
with CMPI (1.05 equiv) and Et N (2.10 equiv) in CH Cl at rt for 4 hr under Ar, no
reaction occurred.
3
2
2

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Transformation of Aldoximes to Nitriles
1779
availability and cheap cost of CMPI, mild reaction conditions, good to excel-
lent yields, wide scope of applicability, and furthermore excellent selectivity
differentiating primary amide from aldoxime, this dehydration protocol
should be the method of choice in the synthesis of nitriles from various
aldoximes.
EXPERIMENTAL
All reactions were carried out in oven-dried glassware under an argon
atmosphere. Melting points were taken on an electrothermal melting-point
apparatus and were not corrected. IR-spectra were obtained on a Jasco
1
FT-IR/410 using KBr or as CH Cl solution. H-NMR (400 MHz) spectra
2
2
were obtained in CDCl on Jeol JNM-EX400 FT NMR spectrometer, and
3
chemical shifts (d) were reported in ppm downfield from tetramethylsilane.
Flash column chromatography was carried out on silica gel (Merck, 230–
400 mesh) and solvents were reported as V/V ratio mixtures. CH Cl was
2 2
distilled from calcium hydride. 2-Chloro-1-methylpyridinium iodide was pur-
chased from Aldrich Chemical Co. and used directly without further purifi-
cation. The aldoximes were purchased from Aldrich Chem. Co., or
synthesized from their corresponding aldehydes according to the literature
[
7]
procedures. All other chemicals were purchased from commercial sources
and used as received unless otherwise stated.
General Procedure for the Dehydration of Aldoxime to Nitrile
To a solution of anthracene oxime 1a (127.0 mg, 0.574 mmol) in CH Cl
2
2
(10 mL) was added CMPI (161.0 mg, 1.10 equiv) in one portion and the result-
ing mixture was stirred vigorously for ca. 10 min at room temperature under
Ar. Et N (176.0 mL, 2.20 mmol) was then added by syringe and stirring was
3
continued for an additional 2 hr. During this time, the color of the reaction
mixture was changed slowly from yellow to reddish brown. The reaction
was quenched with aqueous HCl (5%, 10 mL), and the organic layer was sep-
arated. The aqueous layer was extracted with CH Cl (5 mL Â 2), and the
2
2
combined organic layers were washed with saturated brine, dried over
MgSO , filtered, and concentrated. Purification of the crude product by flash
4
column chromatography on SiO2 (hexane/CH Cl , 2/1) provided 2a
2
2
[8a]
(
119.0 mg, 94%) as a yellow solid: mp 172–1748C (lit.
173–1748C); Rf
2
.53 (hexane/EtOAc, 3/1); IR (KBr) 2213 cm (CN); H-NMR (CDCl ),
1
1
0
3
d 7.59 (t, 2H, J ¼ 7.6 Hz), 7.72 (t, 2H, J ¼ 7.6 Hz), 8.08 (d, 2H,
J ¼ 7.9 Hz), 8.42 (d, 2H, J ¼ 8.5 Hz), 8.67 (s, 1H).

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1
780
Lee et al.
b. Yield 91%; an off-while solid; mp 115–1168C (lit. 114–1158C); Rf
[8b]
2
2
1
1
0
7
8
.43 (hexane/EtOAc, 1/2), IR (KBr) 2237 cm (CN); H-NMR (CDCl ), d
3
.75 (t, 1H, J ¼ 7.9 Hz), 8.01 (d, 1H, J ¼ 7.9 Hz), 8.49 (d, 1H, J ¼ 7.9 Hz),
.55 (bs, 1H).
[
8c]
2
c. Yield 92%; an off-while solid; mp 223–2258C (lit. 2228C); R 0.40
f
2
hexane/EtOAc, 2/1), IR (KBr) 2232 cm (CN); H-NMR (CDCl ), d 7.80
s, 4H).
2
1
1
(
(
3
[8d]
d. Yield 88%; yellow liquid;
Rf 0.48 (hexane/EtOAc, 3/1), IR
2
1
1
(
CH Cl ) 2220 cm (CN); H-NMR (CDCl ), d 5.88 (d, 1H, J ¼ 16.6 Hz),
2
2
3
7
.38–7.46 (m, 6H).
[8e]
2
e. Yield 81%; colorless liquid;
2
Rf 0.58 (hexane/EtOAc, 6/1), IR
1
1
(
CH Cl ) 2248 cm (CN); H-NMR (CDCl ), d 0.88 (t, 3H, J ¼ 6.6 Hz),
2
2
3
1
.28–1.29 (m, 10H), 1.41–1.46 (m, 2H), 1.58–1.69 (m, 2H), 2.34 (t, 2H,
J ¼ 7.1 Hz).
[4a]
2
f. Yield 93%; colorless liquid;
2
R 0.59 (hexane/CH Cl , 1/3), IR
f 2 2
1
1
(
CH Cl ) 2249 cm (CN); H-NMR (CDCl ), d 1.43 (d, 3H, J ¼ 6.8 Hz),
2
2
3
2
.52 (dd, 1H, J ¼ 16.7 Hz, J ¼ 7.6 Hz), 2.59 (dd, 1H, J ¼ 16.7 Hz,
1
2
1
J ¼ 6.8 Hz), 3.11–3.16 (m, 1H), 7.20–7.25 (m, 3H), 7.32–7.35 (m, 2H).
2
[8f]
2
g. Yield 91%; an off-while solid; mp 88–908C (lit. 918C); R 0.51
f
2
1
1
hexane/EtOAc, 1/2); IR (KBr) 2245 cm (CN); H-NMR (CDCl ), d 3.63
(
(
3
s, 2H), 4.10 (d, 2H, J ¼ 5.9 Hz), 5.96 (br s, 1H), 7.24–7.26 (m, 2H), 7.31–
7
.40 (m, 3H).
[
8g]
2h. Yield 86%; an off-while solid; mp 78–798C (lit.
798C); R 0.50
f
2
1
1
(CN); H-NMR (CDCl ), d
(
hexane/EtOAc, 1/1), IR (KBr) 2242 cm
3
7
.55 (d, 2H, J ¼ 5.6 Hz), 8.83 (d, 2H, J ¼ 5.6 Hz).
[8h]
i. Yield 88%; yellow liquid;
2
242 cm
R 0.47 (hexane/EtOAc, 2/1), IR (KBr)
f
2
1
1
2
(CN); H-NMR (CDCl ), d 7.64 (dd, 1H, J ¼ 7.8 Hz,
3
1
J ¼ 4.7 Hz), 7.72 (d, 1H, J ¼ 7.8 Hz), 7.88 (td, 1H, J ¼ 7.8 Hz,
2
1
J ¼ 2.0 Hz), 8.74 (d, 1H, J ¼ 4.7 Hz).
2
[8i]
2
j. Yield 90%; yellow solid; mp 60–628C (lit.
59–628C); R 0.44
f
21
1
(CN); H-NMR (CDCl ), d
(
hexane/EtOAc, 2/1); IR (KBr) 2240 cm
3
7
.28 (d, 1H, J ¼ 3.9 Hz), 7.37 (d, 1H, J ¼ 3.9 Hz).
[
8j]
2
k. Yield 91%; yellow solid; mp 45–468C (lit. 458C); R 0.42 (hexane/
f
2
EtOAc, 4/1); IR (KBr) 2224 cm (CN); H-NMR (CDCl ), d 7.58 (d, 1H,
1
1
3
J ¼ 4.4 Hz), 7.90 (s, 1H, J ¼ 4.4 Hz).
ACKNOWLEDGMENTS
This work was financially supported through the Academic Research
Fund of Woosuk University.

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Received in Japan December 11, 2003

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