An efficient method for the preparation of nitriles via the dehydration of aldoximes with phthalic anhydride

Article abstract of DOI:10.1002/jccs.200400093

A new and highly efficient method for the conversion of aldoximes to nitriles was established. By fusing with phthalic anhydride, aldoximes were efficiently and smoothly converted into nitriles, in high yields (over 85%) and in a short time (within 5 minutes). The mixture of phthalic anhydride, a cyclic anhydride, and aldoximes in fusing state set up an ideal transition state for a selective [3.3]-sigmatropic rearrangement of the acylated aldoximes to nitriles.

Full text of DOI:10.1002/jccs.200400093

Journal of the Chinese Chemical Society, 2004, 51, 619-627
619
An Efficient Method for the Preparation of Nitriles via the Dehydration of
Aldoximes with Phthalic Anhydride
Eng-Chi Wanga* (
), Keng-Shiang Huanga,b
(
), Hsing-Ming Chena,b
(
),
Chung-Chin Wua (
) and Gwo-Jiun Lina (
)
aFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung City 807, Taiwan, R.O.C.
bInstitute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung City 807, Taiwan, R.O.C.
A new and highly efficient method for the conversion of aldoximes to nitriles was established. By fusing
with phthalic anhydride, aldoximes were efficiently and smoothly converted into nitriles, in high yields (over
85%) and in a short time (within 5 minutes). The mixture of phthalic anhydride, a cyclic anhydride, and
aldoximes in fusing state set up an ideal transition state for a selective [3.3]-sigmatropic rearrangement of the
acylated aldoximes to nitriles.
Keywords: Aldoximes; Phthalic anhydride; Nitriles.
INTRODUCTION
Nitriles, important reagents, have been widely used by
was commonly used for this purpose,13 but it may suffer from
some limitations which were described in our previous
study.14 In order to facilitate the reaction, a thermal fusing
condition, which has never been approached in the dehydra-
tion chemistry of aldoximes, was investigated in our labora-
tory (Scheme I). This concomitant acylation and dehydration
of aldoximes, prepared from corresponding aldehydes and
hydroxylamine, with fusing phthalic anhydride is expected to
be a useful method for the preparation of nitriles.
chemists in many aspects for a long time. They can be re-
duced to furnish primary amines,1 can be hydrolyzed to give
either amides2 or carboxylic acids,3 can be attacked by orga-
nometallics to afford various ketones,4 can be reacted with
tertiary alcohols in acidic condition to undergo the Ritter re-
action to afford N-alkyl amide,5 etc. Although numerous de-
hydration methods for conversion of aldoximes to nitriles
have been developed, it is still an interesting topic to current
organic chemists. Among the strategies, much attention has
been paid to the activation of the hydroxyl group in aldoxime
as leaving group for the subsequent 1,2-elimination by base
to give nitrile.6 For the past development of methodologies
including the use of trifluoromethane sulfonic anhydride,7
trifluoroacetic anhydride,8 phosphonium anhydride,9 tri-
chloromethyl carbonochloridate,10 bis(trichloromethyl)car-
bonate,11 and 2,2¢-oxalyl-di(O-sulfobenzimide),12 it was pro-
posed to undergo decarboxylation by a 1,4-concerted elimi-
nation. Furthermore these methodologies have drawbacks of
low yield, long reaction time, and harsh reaction conditions.
In addition the reagents used in these preparations are corro-
sive, toxic, expensive or commercially unavailable, which
are disadvantages. To the best of our knowledge, all previous
reports have paid much attention to the use of acyclic anhy-
dride as dehydration agent of aldoximes. Acetic anhydride
RESULTS AND DISCUSSION
Aldoximes are prepared by a general method (using
water as solvent), but with a little modification. Increasing
the alcohol/water ratio to 1/5 to increase the solubility of al-
dehyde gave aldoximes (2a-r) in good yields. Without further
separation, the mixture of syn- or (and) anti-aldoxime was di-
rectly used for dehydration studies. In order to overcome the
drawback of low yield, or long reaction time, thus, a dehydra-
tion of aldoximes with phthalic anhydride in fusing state was
studied. It turned out to be an effective and practical method
for the preparation of nitriles in a very short reaction time, 5
minutes, and in yields of 85 to 90%. The rationale for using
cyclic anhydride was the ability of forming the acylated
aldoxime intermediate, which made it undergo efficiently a
feasible [3.3]-sigmatropic rearrangement as the reaction
* Corresponding author. E-mail: enchwa@kmu.edu.tw

620 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Wang et al.
Scheme I
O
O
O
COOH
COOH
R
NH2OH
RCHO
C
N
OH
RC
N
+
H
160-170oC, 5 min.
1
2
4
m. R=4-CH3C6H4
g. R=3-BnO-4-MeOC6H3
h. R=4-EtO-3-MeOC6H3
i. R=3,4-diEtOC6H3
j. R=2-NO2C6H4
a. R=C6H5
q. R=
n. R=4-AllylO-3-MeOC6H3
o. R=3,5-diMeO-4-HOC6H2
b. R=3-BnOC6H4
c. R=4-BnOC6H4
d. R=4-AllylOC6H4
S
r.
p.
R=
R=
e. R=4-HO-3-MeOC6H3 k. R=3-NO2C6H4
l. R=4-NO2C6H4
N
N
H
f. R=3,4-diMeOC6H3
pathway via this proposed six-membered transition state
(3a-r). Consequently it gave the nitrile (4a-r) in good yields,
and without the requirement of using an external base
(Scheme II). The results of fusing the mixtures of phthalic an-
hydride and aldoxime to give nitrile at 160-170 °C are sum-
marized in Table 1.
ammonium water, allowing easy workup, or by passing it
through a short APS silica-gel (Daiso Co.) column, (3) a short
reaction time was taken, within 5 minutes, but only a little/or
no trace of aldoxime could be detected by either GC or TLC,
(4) only a stochiometric amount of phthalic anhydride was
consumed, (5) in fusing reaction, no solvent was required, (6)
no limitation for E- and Z-aldoximes, which can be worked
without any significant difference, and (7) furthermore,
phthalic anhydride and aldoximes are thermally almost sta-
ble, and phthalic anhydride is nonhygroscopic, readily avail-
able, inexpensive and innocuous.
In conclusion an interesting aspect of the conversion of
aldoxime to nitrile using phthalic anhydride as a sole reagent
at fusing condition has been illustrated. In the case of pheno-
lic aldehydes with labile groups such as methoxymethyl,
methoxyethylmethoxy were limited to our fusing process.
But allyloxybenzaldoxime (2d) can be smoothly converted to
allyoxybenzonitrile (4d), and without causing the Claisen re-
arrangement in such a short reaction time, 5 min. Further-
more heterocyclic aldoximes such as pyrrole (2p), thiophene
(2q) and pyridine (2r), which are considered to be fragile and
oxidizable, can be converted into corresponding nitriles, 4p,
4q, and 4r by our fusing procedure. On the other hand this
solvent free reaction with innocuous reagent is significant in
this era of increased environmental concern. Furthermore our
method has the following advantages: (1) it is applicable to
aromatic, and heterocyclic aldoximes, (2) phthalic acid
formed can be readily removed as it is nearly insoluble in
cold chloroform and ethyl acetate or by washing with cold
EXPERIMENTAL
Melting points (Yanaco micro melting-point apparatus)
1
are uncorrected. H-NMR and 13C-NMR spectra were ob-
tained on a Varian Gemini-200 or Varian Unity plus 400
Spectrometer. Chemical shifts are measured in parts per mil-
lion with respect to TMS. Elemental analyses were recorded
on a Heraeus CHN-O Rapid analyzer. Mass spectra were re-
corded on a Chem/hp/middle instrument. Silica gel (70-230
mesh) for column chromatography and precoated silica gel
plates (60 F-254) for TLC were purchased from E. Merck Co.
Scheme II
O
O
O
O
C
RCH=N
O
H O
+
COOH
..
O
H
RCH=NOH
+
N
O C
C N
RC
..
O-
C
O
H
O
COOH
4
3
2
R

Preparation of Nitriles
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 621
Table 1. The Results for the Fusion of Aldoximesa (5 mmol) with Phthalic Anhydride (5 mmol) at 160-170 °C within 5
Minutes
Entry
Substrate
Product
Yield (%) Entry
Substrate
Product
Yield (%)
NO2
NO2
2a
90
2j
90
C6H5CH=NOH
4j
4a
4b
C6H5CN
CN
CH=NOH
NO2
OBn
OBn
CN
NO2
2b
2c
2d
88
2k
87
91
85
4k
CH=NOH
NO2
CN
CH=NOH
NO2
BnO
BnO
4c
4l
90
88
2l
CH=NOH
CN
CH=NOH
CH3
CN
CH3
4d
2m
4m
O
O
CH=NOH
CN
CN
CH=NOH
OMe
O
OMe
O
2e
2f
4e
85
87
2n
2o
87
90
4n
4o
OMe
HO
HO
OMe
CH=NOH
CN
CH=NOH
OH
CH=NOH
OH
OMe
OMe
MeO
4f
CH=NOH
MeO
OMe
MeO
OMe
MeO
CN
OBn
CN
CH=NOH
OBn
MeO
2g
2h
4g
95
93
2p
2q
MeO
EtO
86
85
NOH
4p
4q
CN
N
N
CH=NOH
CN
OMe
H
H
OMe
CH=NOH
4h
EtO
EtO
CN
CN
S
CN
S
CH=NOH
OEt
CH=NOH
OEt
4i
2i
EtO
86
2r
85
4r
N
CN
N
CH=NOH
a The procedure for the preparation of aldoximes is described in the Experimental section.
APS silica-gel for column chromatography was supplied
from Daiso Co. UV light (254 nm) was used to detect spots on
TLC plates after development.
room temperature for another h. Finally the reaction mixture
was concentrated in vacuo to remove ethanol, and then im-
mersed in an ice-bath to precipitate the corresponding
aldoxime, which could be recrystallized from a mixing sol-
vent, ethyl acetate and n-hexane to give aldoximes (2a-r).
Without further purification, the given aldoximes were di-
rectly used for the following dehydration studies, respec-
tively.
General procedure for the preparation of Aldoximes
(2a-r)
A solution of water (100 mL), ethanol (20 mL) and
NaOH (2 g, 50 mmol) was cooled with an ice-bath. To this
cold solution was added hydroxylamine hydrochloride (3.5 g,
50 mmol), and subsequently added dropwise with a corre-
sponding aldehyde (45 mmole) in ethanol (5 mL). The mix-
ture was stirred at 0 °C for 4 h, and then continually stirred at
Benzaldehyde oxime (2a)15
Pure 2a (5.17 g, 95%) was obtained as colorless crys-
tals, mp 35-36 °C (lit.15 34-36 °C), Rf 0.50, and 0.40 (EA/n-

622 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Wang et al.
1
hexane = 1/3), H-NMR (200 MHz, CDCl3) d 7.42 (m, 3H,
MHz, CDCl3) d 55.97, 107.60, 114.39, 122.31, 124.36,
128.30, 147.58, 150.28; EI-MS (70 eV) m/z 167 (M+, 100),
149 (27), 134 (33), 124 (58), 106 (33).
ArH), 7.61 (m, 2H, ArH), 8.23 (s, 1H, ArCH=N-OH), 8.40
(br s, 1H, ArCH=N-OH); 13C-NMR (50 MHz, CDCl3) d
127.00, 128.72, 130.03, 131.70, 150.24; EI-MS (70 eV) m/z
121 (M+, 100), 94 (35), 78 (59), 77 (62), 66 (30), 51 (51).
3,4-Dimethoxybenzaldehyde oxime (2f)19
Pure 2f (7.49 g, 92%) was obtained as colorless crys-
tals, mp 93-94 °C [lit.19 94-95 °C], Rf 0.23 and 0.18 (EA/n-
hexane = 1/3), 1H-NMR (200 MHz, CDCl3) d 3.91, 3.92 (each
s, 3H, OCH3), 6.85 (d, J = 8.4 Hz, 1H, ArH), 7.03 (dd, J = 8.4
Hz, 2.0 Hz, 1H, ArH), 7.22 (d, J = 2.0 Hz, 1H, ArH), 7.99 (br
s, 1H, ArCH=N-OH), 8.08 (s, 1H, ArCH=N-OH); 13C-NMR
(50 MHz, CDCl3) d 55.86, 55.91, 107.99, 110.76, 121.62,
124.84, 149.28, 150.13, 150.77; EI-MS (70 eV) m/z 181 (M+,
100), 163 (67), 148 (23), 138 (37), 120 (27), 92 (24), 79 (26),
77 (34), 65 (28).
m-Benzyloxybenzaldehyde oxime (2b)16
Pure 2b (9.82 g, 96%) was obtained as colorless crys-
1
tals, mp 53-54 °C, Rf 0.50 (EA/n-hexane = 1/3); H-NMR
(200 MHz, CDCl3) d 5.10 (s, 2H, ArOCH2Ph), 6.99 (m, 2H,
ArH), 7.41 (m, 5H, ArOCH2Ph), 7.53 (m, 2H, ArH), 7.96 (br
s, 1H, OH), 8.10 (s, 1H, ArCH=N-OH); 13C-NMR (50 MHz,
CDCl3) d 70.08, 112.45, 117.16, 120.29, 127.43, 127.94,
128.50, 129.75, 133.28, 136.68, 150.23, 159.02; EI-MS (70
eV) m/z 227 (M+, 4.7), 91 (100), 65 (15).
p-Benzyloxybenzaldehyde oxime (2c)17
3-Benzyloxy-4-methoxybenzaldehyde oxime (2g)20
Pure 2c (9.62 g, 94%) was obtained as colorless crys-
tals, mp 110-111 °C [lit.17 110-111.5 °C], Rf 0.50, and 0.36
(EA/n-hexane = 1/3); 1H-NMR (200 MHz, CDCl3) d 5.10 (s,
2H, ArOCH2Ph), 6.99 (d, J = 8.8 Hz, 2H, ArH), 7.52 (d, J =
8.8 Hz, 2H, ArH), 7.40 (m, 5H, ArOCH2Ph), 7.90 (br s, 1H,
OH), 8.09 (s, 1H, ArCH=N-OH); 13C-NMR (50 MHz, CDCl3)
d 70.06, 115.12, 124.86, 127.42, 128.68, 128.48, 128.61,
136.50, 149.87, 160.19; EI-MS (70 eV) m/z 227 (M+, 6), 221
(9), 92 (13), 91 (100), 65 (20).
Pure 2g (10.42 g, 90%) was obtained as colorless crys-
tals, mp 102-103 °C [lit.20 96-97 °C], Rf 0.30 and 0.20
(EA/n-hexane = 1/3), 1H-NMR (200 MHz, CDCl3) d 3.93 (s,
3H, OCH3), 5.21 (s, 2H, OCH2C6H5), 6.88 (d, J = 8.2 Hz, 1H,
ArH), 6.99 (dd, J = 8.2 Hz, 2.0 Hz, 1H, ArH), 7.26 (d, J = 2.0
Hz, 1H, ArH), 7.41 (m, 5H, OCH2C6H5), 8.09 (s, 1H,
ArCH=N-OH), 8.40 (br s, 1H, OH); 13C-NMR (50 MHz,
CDCl3) d 55.94, 70.82, 97.08, 108.53, 113.25, 121.40, 125.21,
127.16, 127.91, 128.54, 136.60, 149.81, 150.04; EI-MS (70
eV) m/z 257 (M+, 5), 105 (4), 92 (7), 91 (100), 77 (6), 65 (12).
p-Allyloxybenzaldehyde oxime (2d)
Pure 2d (7.57 g, 95%) was obtained as colorless crys-
tals, mp 88-89 °C, Rf 0.54, and 0.36 (EA/n-hexane = 1/3);
1H-NMR (200 MHz, CDCl3) d 4.57 (dt, J = 5.2 Hz, 1.4 Hz,
2H, ArOCH2CH=CH2), 5.31 (dd, Jcis-gem = 10.6 Hz, 1.4 Hz,
1H, ArOCH2CH=CH2), 5.42 (dd, Jtrans-gem = 17.2 Hz, 1.4 Hz,
1H, ArOCH2CH=CH2), 6.02 (ddd, 17.2 Hz, 10.6 Hz, 5.2 Hz,
1H, ArOCH2CH=CH2), 6.92 (d, J = 8.8 Hz, 2H, ArH), 7.50
(d, J = 8.8 Hz, 2H, ArH), 7.80 (br s, 1H, OH), 8.09 (s, 1H,
ArCH=N-OH); 13C-NMR (50 MHz, CDCl3) d 29.71, 68.82,
114.97, 117.90, 128.42, 132.81, 149.81, 159.99; EI-MS (70
eV) m/z 177 (M+, 100), 160 (12), 136 (21).
4-Ethoxy-3-methoxybenzaldehyde oxime (2h)21
Pure 2h (7.91 g, 90%) was obtained as colorless crys-
tals, mp 102-103 °C [lit.21 100 °C], Rf 0.30 and 0.20 (EA/n-
hexane = 1/3), 1H-NMR (200 MHz, CDCl3) d 1.47 (t, J = 7.0
Hz, 3H, OCH2CH3), 3.89 (s, 3H, OCH3), 4.12 (q, J = 7.0 Hz,
2H, OCH2CH3), 6.84 (d, J = 8.6 Hz, 1H, ArH), 7.01 (dd, J =
8.6 Hz, 2.0 Hz, 1H, ArH), 7.21 (d, J = 2.0 Hz, 1H, ArH), 8.08
(s, 1H, ArCH=N-OH), 8.44 (br s, 1H, OH); 13C-NMR (50
MHz, CDCl3) d 14.66, 55.88, 64.29, 108.26, 111.89, 117.30,
121.56, 124.63, 149.43, 150.10; EI-MS (70 eV) m/z 195 (M+,
100), 167 (56), 125 (22), 124 (75), 121 (15), 106 (15), 79
(23), 65 (17), 63 (16), 51 (27).
4-Hydroxy-3-methoxybenzaldehyde oxime (2e)18
Pure 2e (6.69 g, 89%) was obtained as colorless crys-
tals, mp 123-124 °C [lit.18 118.2 °C], Rf 0.15 (EA/n-hexane =
1/3); 1H-NMR (200 MHz, CDCl3) d 3.94 (s, 3H, OCH3), 5.95
(br s, 1H, ArOH), 6.93 (d, J = 8.0 Hz, 1H, ArH), 7.02 (d, J =
8.0 Hz, 1H, ArH), 7.23 (s, 1H, ArH), 7.85 (br s, 1H,
ArCH=N-OH), 8.09 (s, 1H, ArCH=N-OH); 13C-NMR (50
3,4-Diethoxybenzaldehyde oxime (2i)22
Pure 2i (8.66 g, 92%) was obtained as colorless crys-
tals, mp 99-100 °C [lit.22 98 °C], Rf 0.40 (EA/n-hexane = 1/3),
1H-NMR (200 MHz, CDCl3) d 1.47 (m, 6H, 2 ´ OCH2CH3),
4.13 (m, 4H, 2 ´ OCH2CH3), 6.84 (d, J = 8.4 Hz, 1H, ArH),
7.01 (dd, J = 8.4 Hz, 2.0 Hz, 1H, ArH), 7.21 (d, J = 2.0 Hz,

Preparation of Nitriles
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 623
1H, ArH), 8.07 (s, 1H, ArCH=N-OH), 8.77 (br s, 1H, OH);
13C-NMR (50 MHz, CDCl3) d 14.66, 64.43, 110.01, 112.47,
121.44, 124.69, 148.79, 150.07, 150.39; EI-MS (70 eV) m/z
209 (M+, 100), 181 (20), 152 (55), 135 (42), 110 (50), 79 (28),
63 (16), 52 (30), 51 (31).
4-Allyloxy-3-methoxybenzaldehyde oxime (2n)14
Pure 2m (8.3 g, 89%) was obtained as colorless crys-
1
tals, mp 68-69 °C, Rf 0.34 (EA/n-hexane = 1/3), H-NMR
(400 MHz, CDCl3) d 3.92 (s, 3H, OCH3), 4.65 (dd, J = 5.2 Hz,
1.4 Hz, 2H, OCH2CH=CH2), 5.32 (m, 1H, OCH2CH=CH2),
5.42 (m, 1H, OCH2CH=CH2), 6.08 (m, 1H, OCH2CH=CH2),
6.87 (d, J = 8.0 Hz, 1H, ArH), 7.02 (dd, J = 8.0 Hz, 2.0 Hz,
1H, ArH), 7.24 (d, J = 2.0 Hz, 1H, ArH), 8.09 (s, 1H,
CH=NOH), 10.52 (br s, 1H, OH); 13C-NMR (100 MHz,
CDCl3) d 55.88, 69.69, 108.38, 112.60, 118.25, 121.40,
125.01, 132.76, 149.57, 149.67, 150.04; EI-MS (70 eV) m/z
207 (56), 191 (32), 166 (100), 150 (48), 148 (28), 135 (14),
120 (28), 95 (38), 79 (35), 65 (31).
o-Nitrobenzaldehyde oxime (2j)23
Pure 2j (6.36 g, 85%) was obtained as colorless crys-
tals, mp 100-101 °C [lit.23 102-103 °C], Rf 0.40 (EA/n-hex-
1
ane = 1/3), H-NMR (200 MHz, CDCl3) d 7.47 (dd, J = 8.0
Hz, 1.4 Hz, 1H, ArH), 7.54 (dd, J = 8.0 Hz, 1.4 Hz, 1H, ArH),
7.91 (t, J = 8.0 Hz, 1H, ArH), 7.92 (t, J = 8.0 Hz, 1H, ArH),
8.56 (s, 1H, ArCH=N-OH), 10.52 (br s, 1H, OH); 13C-NMR
(50 MHz, CDCl3) d 124.40, 127.53, 128.49, 129.68, 133.10,
145.40, 147.54; EI-MS (70 eV) m/z 166 (M+, 12), 135 (100),
102 (27), 92 (20), 91 (40), 90 (21), 79 (30), 76 (50), 65 (59),
50 (50), 51 (31).
4-Hydroxy-3,5-dimethoxybenzaldehyde oxime (2o)26
Pure 2o (8.28 g, 88%) was obtained as colorless crys-
tals, mp 130-131 °C [lit.26 128-129 °C], Rf 0.08 (EA/n-hex-
1
ane = 1/3); H-NMR (400 MHz, CDCl3) d 3.91 (s, 6H, 2 ´
m-Nitrobenzaldehyde oxime (2k)24
OCH3), 3.93 (s, 1H, OH), 6.83 (s, 2H, ArH), 8.04 (s, 1H,
CH=NOH), 8.05 (s, 1H, CH=NOH); 13C-NMR (100 MHz,
CDCl3) d 56.44, 104.16, 123.42, 136.85, 147.32, 150.42;
EI-MS (70 eV) m/z 197 (100), 179 (19), 155 (16), 154 (55),
67 (15), 65 (14).
Pure 2k (6.43 g, 86%) was obtained as colorless crys-
tals, mp 123-124 °C [lit.24 121-122 °C], Rf 0.50 (EA/n-hex-
ane = 1/3), 1H-NMR (200 MHz, CDCl3) d 7.50 (t, J = 8.0 Hz,
1H, ArH), 7.85 (dd, J = 8.0 Hz, 1.2 Hz, 1H, ArH), 8.12 (s, 1H,
ArCH=N-OH), 8.13 (t, J = 8.0 Hz, 1H, ArH), 8.39 (d, J = 2.0
Hz, 1H, ArH), 10.69 (br s, 1H, OH); 13C-NMR (50 MHz,
CDCl3) d 121.12, 123.56, 129.47, 132.29, 134.73, 146.73,
148.33; EI-MS (70 eV) m/z 166 (M+, 100), 149 (67), 119 (69),
102 (65), 76 (69), 75 (68), 65 (71), 50 (37).
Pyrrole-2-carboxaldehyde oxime (2p)27
Pure 2p (4.22 g, 85%) was obtained as colorless crys-
tals, mp 135-136 °C [lit.27 165-166 °C], Rf 0.25 (EA/n-hex-
ane = 1/3); 1H-NMR (CDCl3, 400 MHz) d 6.27 (m, 1H), 6.52
(m, 1H), 6.98 (m, 1H), 7.21 (s, 1H), 7.30 (s, 1H), 10.14 (br s,
1H); 13C-NMR (DMSO-d6 + CDCl3, 100 MHz) d 108.84,
113.71, 120.85, 125.23, 138.05; EI-MS (70 eV) m/z 110
(100), 93 (26), 67 (73), 66 (60), 65 (29), 52 (31).
p-Nitrobenzaldehyde oxime (2l)25
Pure 2l (6.36 g, 85%) was obtained as colorless crys-
tals, mp 128-129 °C [lit.25 130-134 °C], Rf 0.5 (EA/n-hexane
= 1/3), 1H-NMR (200 MHz, CDCl3) d 7.39 (t, J = 8.8 Hz, 1H,
ArH), 7.85 (d, J = 8.8 Hz, 1H, ArH), 8.13 (d, J = 8.8 Hz, 2H,
ArH), 8.41 (s, 1H, ArCH=N-OH), 10.65 (br s, 1H, OH); 13C-
NMR (50 MHz, CDCl3) d 124.0, 127.59, 136.29, 138.73,
148.24; EI-MS (70 eV) m/z 166 (M+, 100), 136 (19), 103 (20),
102 (27), 76 (37), 75 (39), 65 (46), 50 (31).
Thiophene-2-carboxaldehyde oxime (2q)28
Pure 2q (4.98 g, 87%) was obtained as colorless crys-
tals, mp 125-126 °C [lit.28 130-133 °C], Rf 0.45 (EA/n-hex-
ane = 1/3); 1H-NMR (CDCl3, 200 MHz) d 7.05 (t, J = 4.5 Hz,
1H), 7.34 (dd, J = 5.0 Hz, 4.0 Hz, 1H), 7.49 (dd, J = 5.0 Hz,
4.0 Hz, 1H), 7.70 (s, 1H), 8.21 (br s, 1H); 13C-NMR (CDCl3,
50 MHz) d 126.23, 130.94, 131.62, 131.86, 141.18; EI-MS
(70 eV) m/z 127 (M+, 100), 109 (30), 100 (41), 84 (94), 58
(40).
p-Methylbenzaldehyde oxime (2m)25
Pure 2m (5.5 g, 91%) was obtained as colorless crystals,
mp 74-75 °C [lit.25, 70-75 °C] Rf 0.5 (EA/n-hexane = 1/3);
1H-NMR (400 MHz, CDCl3) d 2.34 (s, 3H, CH3), 7.17, 7.46
(each d, J = 8.2 Hz, 2H, ArH), 8.14 (s, 1H, CH=NOH), 9.42
(br s, 1H, CH=NOH); 13C-NMR (100 MHz, CDCl3) d 21.35
(CH3), 126.98, 129.04, 129.12, 129.45, 140.25 (CH=NOH);
EI-MS (70 eV) m/z 135 (31), 119 (45), 117 (100), 116 (64), 92
(25), 91 (40), 90 (46), 89 (29), 65 (14), 63 (86).
Pyridine-2-carboxaldehyde oxime (2r)29
Pure 2r (4.73 g, 86%) was obtained as colorless crys-
tals, mp 111-112 °C [lit.29 113.5 °C], Rf 0.18 (EA/n-hexane =
1/3); 1H-NMR (CDCl3, 200 MHz) d 7.73 (td, J = 7.7 Hz, 1.8
Hz, 1H), 7.72 (td, J = 7.7 Hz, 1.8 Hz, 1H), 7.87 (d, J = 8.0 Hz,

624 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Wang et al.
1H), 7.38 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 10.83 (br s, 1H,
OH); 13C-NMR (CDCl3, 50 MHz) d 120.92, 123.93, 136.90,
149.08, 149.84, 151.83; EI-MS (70 eV) m/z 122 (M+, 100),
121 (58), 92 (23), 79 (45), 78 (23), 77 (22), 65 (53), 52 (22),
51 (36).
5H); 13C-NMR (CDCl3, 100 MHz) d 70.19, 104.14, 115.51,
119.07, 127.39, 128.33, 128.68, 133.91, 135.63, 161.89; MS
(70 eV), m/z (relative intensity) 209 (M+, 4), 92 (9), 91 (100),
89 (2), 65 (12); HRMS calcd for C14H11NO: 209.0841.
Found: 209.0841.
General procedure for the preparation of nitriles (4a-s)
Aldoxime (10 mmol) and phthalic anhydride (1.5 g,
10.1 mmol) were mixed well in a mortar, and transferred into
a sealed tube (9 ´ 1.8 cm), which was immersed into a pre-
heated oil bath (160-170 °C). After fusing for 5 minutes, the
reaction mixture was cooled to room temperature, and perco-
lated with CH2Cl2. The combined CH2Cl2 solution was
washed with cold 5% aq. ammonia to remove phthalic acid
and phthalic anhydride. Then the solution was washed with
water and brine, and dried with MgSO4. Finally the solution
was filtered, and the filtrate was concentrated under reduced
pressure to provide the product, which showed a single spot
in TLC (n-hexane/EtOAc = 3/1).
4-Allyloxybenzonitrile (4d)14
Pure 4d was obtained as colorless crystals (1.20 g,
88%); mp 43-44 °C (EtOAc + n-hexane) [lit.14 44-45 °C]; Rf
= 0.66 (EtOAc/n-hexane = 1/3); IR nmax (CH2Cl2) cm-1:
2223.6 cm-1 (CN); 1H-NMR (CDCl3, 200 MHz) d 4.43 (dt, J =
5.2 Hz, 1.4 Hz, 2H, ArOCH2CH=CH2), 5.16 (dd, Jcis-gem
10.6 Hz, 1.4 Hz, 1H, ArOCH2CH=CH2), 5.32 (dd, Jtrans-gem
=
=
17.2 Hz, 1.4 Hz, 1H, ArOCH2CH=CH2), 5.89 (ddd, 17.2 Hz,
10.6 Hz, 5.2 Hz, 1H, ArOCH2CH=CH2), 6.95 (d, J = 8.2 Hz,
1H, ArH), 7.08 (d, J = 1.8 Hz, 1H, ArH), 7.22 (dd, J = 8.2 Hz,
1.8 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) d 56.18,
103.19, 113.73, 115.19, 119.20, 126.94, 146.61, 149.88
(CN); MS (70 eV), m/z (relative intensity), 159 (M+, 100),
144 (15), 119 (23), 75 (14), 64 (25), 63 (21), 51 (14); HRMS
calcd for C10H9NO: 159.0684. Found: 159.0687.
Benzonitrile (4a)11
Pure 4a was obtained as colorless liquid (0.93 g, 90%);
bp 95-97 °C (25 mmHg) [lit.11 35-40 °C (0.05 torr)]; Rf = 0.77
(EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2228.0 cm-1
(CN); 1H-NMR (CDCl3, 200 MHz) d 7.42-7.61 (m, 5H); 13C-
NMR (CDCl3, 50 MHz) d 111.57, 118.12, 128.49, 131.34,
132.15; MS (70 eV), m/z (relative intensity), 103 (M+, 100),
76 (39), 75 (8), 50 (11); HRMS calcd for C7H5N: 103.0422.
Found: 103.0424.
4-Hydroxy-3-methoxybenzonitrile (4e)30
Pure 4e was obtained as colorless crystals (1.27 g,
85%); mp 86-87 °C (EtOAc + n-hexane) [lit.30 85-87 °C]; Rf
= 0.24 (EtOAc/n-hexane = 1/3); IR nmax (CH2Cl2) cm-1:
2225.3 cm-1 (CN); 1H-NMR (CDCl3, 200 MHz) d 3.92 (s, 3H,
OCH3), 6.21 (br s, 1H, ArOH), 6.95 (d, J = 8.2 Hz, 1H, ArH),
7.08 (d, J = 1.8 Hz, 1H, ArH), 7.22 (dd, J = 8.2 Hz, 1.8 Hz,
1H, ArH); 13C-NMR (CDCl3, 50 MHz) d 56.18, 103.19,
113.73, 115.19, 119.20, 126.94, 146.61, 149.88 (CN); MS
(70 eV), m/z (relative intensity), 149 (M+, 100), 134 (89), 106
(82), 51 (49); HRMS calcd for C8H7NO2: 149.0477. Found:
149.0477.
3-Benzyloxybenzonitrile (4b)12
Pure 4b was obtained as colorless crystals (1.84 g,
88%); mp 38-39 °C (EtOAc + n-hexane) [lit.12 38-40 °C]; Rf
= 0.63 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2227.4
cm-1 (CN); 1H-NMR (CDCl3, 400 MHz) d 5.08 (s, 2H,
CH2C6H5), 7.12-7.26 (m, 4H), 7.35-7.41 (m, 5H); 13C-NMR
(CDCl3, 100 MHz) d 70.36, 113.26, 117.85, 118.65, 120.13,
124.76, 127.43, 128.35, 128.73, 130.36, 135.83, 158.78; MS
(70 eV), m/z (relative intensity) 209 (M+, 14), 92 (7), 91
(100), 65 (14), 51 (2); HRMS calcd for C14H11NO: 209.0841.
Found: 209.0839.
3,4-Dimethoxybenzonitrile (4f)31
Pure 4f was obtained as colorless crystals (1.84 g,
87%); mp 65-66 °C (EtOAc + n-hexane) [lit.31 66-68 °C]; Rf
= 0.37 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2226.2
1
cm-1 (CN); H-NMR (CDCl3, 400 MHz) d 3.91 (s, 3H,
OCH3), 3.94 (s, 3H, OCH3), 6.90 (d, J = 8.4 Hz, 1H, ArH-5),
7.08 (d, J = 2.0 Hz, 1H, ArH-2), 7.29 (dd, J = 8.4 Hz, 2.0 Hz,
1H, ArH-6); 13C-NMR (CDCl3, 100 MHz) d 56.09, 56.14,
103.95, 111.26, 114.00, 119.19, 126.46, 149.24, 152.90; MS
(70 eV), m/z (relative intensity): 164 (M+1, 10.36), 163 (M+,
100), 148 (41), 120 (14), 102 (8), 92 (23), 77 (20), 65 (21),
50 (8); HRMS calcd for C9H9NO2: 163.0633. Found:
163.0635.
4-Benzyloxybenzonitrile (4c)13
Pure 4c was obtained as colorless crystals (1.88 g,
90%); mp 87-88 °C (EtOAc + n-hexane) [lit.13 62 °C]; Rf =
0.65 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2221.2
cm-1 (CN); 1H-NMR (CDCl3, 400 MHz) d 5.12 (s, 2H,
CH2C6H5), 7.02, 7.59 (each d, J = 8.8 Hz, 2H), 7.34-7.43 (m,

Preparation of Nitriles
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 625
3-Benzyloxy-4-methoxybenzonitrile (4g)32
calcd for C7H4N2O2: 148.0273. Found: 148.0273.
Pure 4g was obtained as colorless crystals (1.84 g,
95%); mp 73-74 °C (EtOAc + n-hexane) [lit.32 75 °C]; Rf =
0.61 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2222.8
cm-1 (CN); 1H-NMR (CDCl3, 200 MHz) d 3.93 (s, 3H, OCH3),
5.15 (s, 2H, CH2C6H5), 6.92 (d, J = 8.3 Hz, 1H, ArH-5), 7.10 (d,
J = 2.0 Hz, 1H, ArH-2), 7.54 (m, 5H, OCH2C6H5), 8.17 (dd, J
= 8.3 Hz, 2.0 Hz, 1H, ArH-6); 13C-NMR (CDCl3, 50 MHz) d
56.10, 71.23, 103.78, 111.64, 116.52, 118.52, 126.85, 127.33,
128.29, 128.74, 135.88, 148.26, 153.57; MS (70 eV), m/z (rel-
ative intensity): 239 (M+, 15), 92 (9), 91 (100), 77 (2), 65 (13);
HRMS calcd for C15H13NO2: 239.0946. Found: 239.0945.
3-Nitrobenzonitrile (4k)36
Pure 4k was obtained as colorless crystals (1.28 g,
87%); mp 117-118 °C (EtOAc + n-hexane) [lit.36 118 °C]; Rf
= 0.50 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2235.1
cm-1 (CN); 1H-NMR (CDCl3, 400 MHz) d 7.76 (t, J = 8.0 Hz,
1H, ArH), 8.02 (dt, J = 8.0 Hz, 1.0 Hz, 1H, ArH), 8.49 (dt, J =
8.0 Hz, 1.0 Hz, 1H, ArH), 8.55 (br s 1H, ArH); 13C-NMR
(CDCl3, 50 MHz) d 114.10, 116.48, 127.18, 127.48, 130.64,
137.57, 148.20 (CN); MS (70 eV), m/z (relative intensity):
148 (M+, 100), 102 (65), 90 (30), 76 (23), 75 (48), 51 (29);
HRMS calcd for C7H4N2O2: 148.0273. Found: 148.0276.
4-Ethoxy-3-methoxybenzonitrile (4h)33
Pure 4h was obtained as colorless crystals (1.65 g,
93%); mp 103 °C [lit.33 102 °C]; Rf = 0.54 (EtOAc/n-hexane
4-Nitrobenzonitrile (4l)37
Pure 4l was obtained as colorless crystals (1.34 g,
91%); mp 148-149 °C (EtOAc + n-hexane) [lit.37 147-149
°C]; Rf = 0.58 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1:
2230.1 cm-1 (CN); 1H-NMR (CDCl3, 400 MHz) d 7.92, 8.38
(each d, J = 8.8 Hz, 2H); 13C-NMR (CDCl3, 400 MHz) d
116.74, 118.25, 124.22, 133.43, 149.98 (CN); MS (70 eV),
m/z (relative intensity), 148 (M+, 72), 118 (9), 102 (100), 90
(16), 76 (16), 75 (34), 51 (17); HRMS calcd for C7H4N2O2:
148.0273. Found: 148.0275.
1
= 1/3); IR nmax (neat) cm-1: 2221.3 cm-1 (CN); H-NMR
(CDCl3, 200 MHz) d 1.50 (t, J = 6.8 Hz, 3H, CH3CH2O), 3.89
(s, 3H, OCH3), 4.15 (q, J = 6.8 Hz, 2H, CH3CH2O), 6.88 (d, J
= 8.4 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.4 Hz,
2.0 Hz, 1H); 13C-NMR (CDCl3, 50 MHz) d 14.51, 56.15,
64.59, 103.66, 112.17, 114.22, 119.29, 126.40, 149.36, 152.32;
MS (70 eV), m/z (relative intensity): 177 (M+, 64), 149 (100),
134 (68), 106 (20), 51 (9); HRMS: calcd for C10H11NO2:
177.0790. Found: 177.0791.
4-Methylbenzonitirle (4m)38
3,4-Diethoxybenzonitrile (4i)34
Pure 4m was obtained as liquid (1.0 g, 85 %); mp 39 °C
(EtOAc + n-hexane) [lit.38 37-38 °C]; Rf = 0.66 (EtOAc/n-
hexane = 1/3); IR nmax (neat) cm-1: 2227.5 cm-1 (CN), H-
Pure 4i was obtained as colorless crystals (1.64 g, 86
%); mp 67-68 °C (EtOAc + n-hexane) [lit.34 68 °C]; Rf = 0.55
(EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2225.7 cm-1
(CN); 1H-NMR (CDCl3, 200 MHz) d 1.43-1.52 (m, 6H, 2 ´
CH2CH3), 4.04-4.19 (m, 4H, 2 ´ CH2CH3), 6.88 (d, J = 8.0
Hz, 1H, ArH), 7.08 (d, J = 2.0 Hz, 1H, ArH), 7.24 (dd, J = 8.0
Hz, 2.0 Hz, 1H, ArH); 13C-NMR (CDCl3, 50 MHz) d 14.54,
14.59, 64.64, 64.87, 103.62, 112.58, 115.81, 119.39, 126.34,
148.72, 152.70; MS (70 eV), m/z (relative intensity): 191
(M+, 45), 163 (16), 136 (9), 135 (100), 134 (7), 106 (6), 51 (6);
HRMS calcd for C11H13NO2: 191.0946. Found: 191.0945.
1
NMR (CDCl3, 400 MHz) d 2.39 (s, 3H, CH3), 7.24, 7.48 (each
d, J = 8.0 Hz, 2H, ArH); 13C-NMR (CDCl3, 100 MHz) d
21.29, 108.79, 118.65, 129.44, 131.50, 143.30 (CN); MS (70
eV), m/z (relative intensity): 117 (M+, 100), 116 (63), 90 (46),
89 (24), 63 (9); HRMS calcd for C8H7N: 117.0578. Found:
117.0579.
4-Allyloxy-3-methoxybenzonitrile (4n)39
Pure 4n was obtained as colorless crystals (1.64 g,
87%); mp 59-60 °C [lit.39 58-60 °C]; (EtOAc + n-hexane)
[lit.39; Rf = 0.49 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1:
2223.8 cm-1 (CN); 1H-NMR (CDCl3, 400 MHz) d 3.89 (s, 3H,
OCH3), 4.66 (dd, J = 5.4 Hz, 1.2 Hz, 2H), 5.33 (ddd, J = 10.7
Hz, 3.0 Hz, 1.2 Hz, 1H), 5.43 (ddd, J = 17.2 Hz, 3.0 Hz, 1.2
Hz, 1H), 6.06 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H, ArH), 7.09 (d,
J = 2.0 Hz, 1H, ArH), 7.24 (dd, J = 8.4 Hz, 2.0 Hz, 1H, ArH);
13C-NMR (CDCl3, 100 MHz) d 55.94, 69.52, 103.78, 112.72,
114.12, 118.53, 118.97, 126.01, 131.90, 149.29 (CN), 151.68;
MS (70 ev), m/z (relative intensity): 189 (M+, 100), 149 (17),
2-Nitrobenzonitrile (4j)35
Pure 4j was obtained as colorless crystals (1.33 g,
90%); mp 109-110 °C (EtOAc + n-hexane) [lit.35 111 °C], Rf
= 0.28 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2231.6
cm-1 (CN); 1H-NMR (CDCl3, 200 MHz) d: 7.83-7.88 (m, 2H),
7.93-7.95 (m, 1H), 8.33-8.38 (m, 1H); 13C-NMR (CDCl3, 50
MHz) d 108.09, 114.90, 125.54, 133.67, 134.27, 135.58,
148.85; MS (70 eV), m/z (relative intensity): 148 (M+, 99),
118 (18), 102 (100), 90 (52), 76 (45), 75 (78), 51 (29); HRMS

626 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Wang et al.
148 (94), 146 (12), 134 (15), 120 (30), 102 (16), 92 (38), 77
(33), 65 (21), 51 (7); Anal calcd for C11H11NO2: C, 69.82; H,
5.86; N, 7.40. Found: C, 69.48; H, 5.83; N, 7.31.
ACKNOWLEDGMENT
We are grateful to the National Science Council of Tai-
wan (NSC 90-2113-M-037-010) for financial support.
3,5-Dimethoxy-4-hydroxybenzonitrile (4o)40
Pure 4o was obtained as colorless crystals (1.61 g,
90%); mp 121-122 °C (EtOAc + n-hexane) [lit.40 123-124
°C]; Rf = 0.13 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1:
Received September 26, 2003.
1
2230.3 cm-1 (CN); H-NMR (CDCl3, 200 MHz) d: 3.96 (s,
6H, 2 ´ OCH3), 6.36 (s, 1H, OH), 6.87 (s, 2H); 13C-NMR
(CDCl3, 50 MHz) d 56.51 (OCH3), 102.16, 109.13, 119.24,
139.28, 147.12 (CN); MS (70 eV), m/z (relative intensity):
179 (M+, 100), 164 (57), 136 (14), 121 (13), 118 (23), 93 (7),
90 (16), 53 (6); Anal calcd for C9H9NO3: C, 60.33; H, 5.06; N,
7.82. Found: C, 60.56; H, 4.98; N, 7.71.
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2-Cyanopyrrole (4p)41
Pure 4p was obtained as colorless liquid (0.93 g, 86%);
bp 143-150 °C (20 mmHg) [lit.41 120-123 °C (15 torr)]; Rf =
0.46 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1: 2234.0
cm-1 (CN); 1H-NMR (CDCl3, 400 MHz) d 6.24 (m, 1H), 6.86
(m, 1H), 6.94 (m, 2H); 13C-NMR (CDCl3, 100 MHz) d 100.23,
109.85, 114.84, 120.19, 123.89; MS (70 eV), m/z (relative in-
tensity): 92 (M+, 100), 70 (16), 65 (29), 64 (21), 61 (18), 45
(18), 43 (80); HRMS calcd for C5H4N2: 92.0374. Found:
92.0376.
2-Cyanothiophene (4q)42
Pure 4q was obtained as colorless liquid (0.93 g, 85%),
bp 112 °C; Rf = 0.51 (EtOAc/n-hexane = 1/3); IR nmax (neat)
cm-1: 2221.7 cm-1 (CN); 1H-NMR (CDCl3, 400 MHz) d 7.14
(dd, J = 4.8 Hz, 4.0 Hz, 1H), 7.62-7.64 (m, 2H); 13C-NMR
(CDCl3, 100 MHz) d 109.53, 114.03, 127.48, 132.50 137.23;
MS (70 eV), m/z (relative intensity): 109 (M+1, 100), 82 (10),
70 (11), 58 (6), 57 (16); HRMS calcd for C5H3NS: 108.9986.
Found: 108.9989.
2-Cyanopyridine (4r)43
Pure 4r was obtained as colorless liquid (0.88 g, 85%).
Rf = 0.37 (EtOAc/n-hexane = 1/3); IR nmax (neat) cm-1:
2236.7 cm-1 (CN); 1H-NMR (CDCl3, 400 MHz) d 7.51-7.55
(m, 1H), 7.70 (dt, J = 7.6 Hz, 0.8 Hz, 1H), 7.85 (td, J = 7.8 Hz,
2.0 Hz, 1H), 8.72 (dd, J = 4.8 Hz, 0.8 Hz, 1H); 13C-NMR
(CDCl3, 100 MHz) d 117.11, 126.86, 128.48, 134.00, 136.97,
151.08; MS (70 eV), m/z (relative intensity): 104 (M+, 100),
77 (45), 51 (11), 50 (12); HRMS calcd for C6H4N2: 104.0374.
Found: 104.0376.

Preparation of Nitriles
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 627
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