New method for the synthesis of nitriles from o-arylaldoximes with ZrCl4

Article abstract of DOI:10.1081/SCC-120015406

Nitriles were readily synthesized from the corresponding O-phenyl- or O-(p-cyanophenyl)-aldoximes with ZrCl₄ in nitromethane or in benzene.

Full text of DOI:10.1081/SCC-120015406

This article was downloaded by: [Kungliga Tekniska Hogskola]
On: 08 October 2014, At: 13:46
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
NEW METHOD FOR THE SYNTHESIS OF NITRILES FROM
O-ARYLALDOXIMES WITH ZrCl
Chiho Tsuji , Etsuko Miyazawa , Takeshi Sakamoto & Yasuo Kikugawa
4
a
a
a
b
a
Faculty of Pharmaceutical Sciences , Josai University , 1-1 Keyakidai, Sakado, Saitama,
50-0295, Japan
3
b
Faculty of Pharmaceutical Sciences , Josai University , 1-1 Keyakidai, Sakado, Saitama,
50-0295, Japan
3
Published online: 23 Aug 2006.
To cite this article: Chiho Tsuji , Etsuko Miyazawa , Takeshi Sakamoto & Yasuo Kikugawa (2002) NEW METHOD FOR THE
SYNTHESIS OF NITRILES FROM O-ARYLALDOXIMES WITH ZrCl , Synthetic Communications: An International Journal for Rapid
4
Communication of Synthetic Organic Chemistry, 32:24, 3871-3879, DOI: 10.1081/SCC-120015406
To link to this article: http://dx.doi.org/10.1081/SCC-120015406
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONS
Vol. 32, No. 24, pp. 3871–3879, 2002
NEW METHOD FOR THE SYNTHESIS OF
NITRILES FROM O-ARYLALDOXIMES
WITH ZrCl4
Chiho Tsuji, Etsuko Miyazawa, Takeshi Sakamoto,
and Yasuo Kikugawa*
Faculty of Pharmaceutical Sciences, Josai University,
1-1 Keyakidai, Sakado, Saitama 350-0295, Japan
ABSTRACT
Nitriles were readily synthesized from the corresponding O-
phenyl- or O-( p-cyanophenyl)-aldoximes with ZrCl in nitro-
methane or in benzene.
4
Key Words: O-Aryloxime; Nitrile; ZrCl4
Nitriles are versatile synthetic intermediates, and, as such, are import-
ant targets in synthetic organic chemistry. For example, several methods
have been reported for the transformation of oximes to the corresponding
[1]
nitriles.
We now report a new synthesis of nitriles from O-arylaldoximes (1)
catalyzed by ZrCl . During the course of our investigations on the chemistry
4
of O-aryloximes, we have found that ZrCl -mediated decomposition of
4
O-arylketoximes in benzene leads to intramolecular migration of the imino
*
Corresponding author. E-mail: kikugawa@josai.ac.jp
871
3
DOI: 10.1081/SCC-120015406
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
872
TSUJI ET AL.
Scheme 1.
group from the oxygen to the ortho position of the aryl group to afford the
[
2]
rearranged products 2 without promoting the Beckmann rearrangement. In
an extension of this work, we now have investigated the reaction of 1 with
ZrCl in benzene. The reaction proceeds via a Beckmann fragmentation to
4
give the corresponding nitriles (3) and phenol (4a) in high yield (Scheme 1).
Both aliphatic and aromatic nitriles carrying electron-donating or
electron-withdrawing substituents are readily prepared. Several solvents
were investigated, including benzene, chlorobenzene, CH Cl , and
2
2
nitromethane. Of these, nitromethane and benzene proved to be the solvents
of choice due to the short reaction time and high yield achieved with these.
For example p-methoxybenzaldehyde O-( p-cyanophenyl)oxime (1e) was
converted with ZrCl4 to p-methoxybenzonitrile (3e) in refluxing nitro-
methane for 2min in 93% yield (see Experimental). In contrast, in
dimethoxyethane 1e reacted with ZrCl to give 3e in only 6% yield and 1e
4
was recovered in 85% yield. Next, we investigated the production of 3i using
different Lewis acids (AlCl , BF ꢀOEt and SnCl ). The results are presented
3
3
2
4
in Table 1.
We found that use of ZrCl affords the best results. AlCl is too strong
4
3
Lewis acid as compared with ZrCl and the color of the reaction mixture
4
turned to brown to black and tarry compounds were obtained. SnCl works
4

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NITRILES FROM O-ARYLALDOXIMES CATALYZED BY ZrCl4
Table 1. Synthesis of 3i from 1i Using Lewis Acid
3873
Yield (%)
Lewis Acid
(Equiv.)
Temp.
ꢁ
Time
(h)
Entry
1
Solvent
CH NO
( C)
3i
4b
a
AlCl (2)
3
Refl.
70
Refl.
Refl.
60
Refl.
Refl.
Refl.
0.2—
0.5
4
8
1
0.5
0.5
9
88
67
3
3
3
2
2
3
4
5
6
7
8
AlCl
3
(2)
ꢀOEt
CH
CH
NO
NO
2
2
59
12—
66
68
86
6260
19
BF
3
2
(4)
BF ꢀOEt (5)
Benzene
CH NO
Benzene
96
68
90
3
2
ZrCl
ZrCl
4
4
(2)
(5)
3
2
SnCl (2)
4
CH NO
3
2
SnCl (5)
4
Benzene
30
a
Several spots on TLC.
well in nitromethane, but does not in benzene. Use of BF ꢀOEt requires
3
2
prolonged reaction time along with recovery of starting compound. Two
molar equivalents of ZrCl were adequate to obtain a high yield of 3i. A
4
plausible reaction mechanism involves an initial coordination of ZrCl with
4
the phenoxy oxygen that assists in the elimination of the phenol to produce
the nitriles. As expected from this mechanism, the yield of 3 increases when
electron-withdrawing p-cyanophenyl derivatives are employed (Table 2,
Entries 4, 5 and 8, 9). The results are presented in Table 2.
Recently, it was reported that, after several other approaches
had failed, 3-cyano-4-benzopyrone (5) could be synthesized from the
corresponding O-methyloxime (6a) in 63% yield by an acid-promoted elim-
[3]
ination of MeOH. Using the procedure reported here, the corresponding
O-( p-cyanophenyl)oxime (6b) undergoes a Beckmann fragmentation under
the conditions we detailed above to afford 5 in higher yield (83%). On the
other hand, under the similar conditions (8 h reflux in benzene) the corre-
sponding methoxime 6a undergoes a Beckmann rearrangement to afford the
corresponding 3-formamido derivative (7) in 65% yield, along with recov-
ered starting compound (22%) (Fig. 1).
In summary, ZrCl -mediated decomposition of O-arylaldoximes leads
4
to formation of the corresponding nitriles in high yield.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
874
TSUJI ET AL.
Table 2. Synthesis of 3 from 1 in Nitromethane or in
Benzene Using ZrCl (2Equiv.)
4
Reaction
Time
(min)
3 Yield
(%)
Entry
1
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
286
10
297
5
293
292
60
10
2
89
a
82
b
c
g
h
i
94
71
0 6
a
a
8
1
0
j
298
a
In benzene.
b
Obtained as p-hydroxybenzonitrile.
Equiv. of ZrCl were used.
c
3
4
Figure 1.
EXPERIMENTAL
All melting points were determined with a Yanagimoto hot-stage melt-
1
ing point apparatus and are uncorrected. H NMR spectra were measured at
70 MHz on a JEOL JNM-EX270 spectrometer with tetramethylsilane
Me Si) as an internal reference and CDCl as the solvent, unless otherwise
2
(
4
3
1
noted. H NMR spectral data are reported in parts per million (ꢀ) relative, to
Me Si. IR spectra were recorded on a JASCO IR 810 spectrophotometer.
4
Mass spectra were obtained with a JEOL JMX-DX 300 spectrometer with a
direct inlet system at 70 eV. Elemental analyses were performed in the
Microanalytical Laboratory of this University.
3-Formylchromone was purchased from Aldrich. All reagents and
other aldehydes were purchased from Tokyo Kasei Kogyo Co. and used

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NITRILES FROM O-ARYLALDOXIMES CATALYZED BY ZrCl4
3875
without further purification. Compound 6a and N-phenoxy- and N-( p-
[
cyanophenoxy)-amines were prepared by the published procedures.
3–5]
Synthesis of p-Methoxybenzaldehyde
O-( p-Cyanophenyl)oxime (1e), Typical Procedure
To a stirred solution of acetonitrile (8 mL) and H O (4 mL) containing
2
anisaldehyde (300 mg, 2.20 mmol) was added N-( p-cyanophenoxy)amine
(
(
(
355 mg, 2.64 mmol). After stirring the reaction mixture for 10 min, H O
2
10 mL) was added and the aqueous layer was extracted with EtOAc
20 mL ꢂ 2). The combined organic layers were washed with brine (20 mL),
dried (Na SO ), and concentrated. The residue was recrystallized from ben-
2
4
zene/hexane to afford the pure 1e (234 mg) as white crystals. The filtrate was
concentrated and the residue was chromatographed on a column of silica gel
(
30 g) using benzene/hexane (5 : 1) as eluent to afford 1e (289 mg, total yield,
94%). Physical and analytical data are presented in Tables 3 and 4.
Synthesis of p-Methoxybenzonitrile (3e), Typical Procedure
To a stirred solution of nitromethane (4 mL) containing 1e (100 mg,
.396 mmol) was added ZrCl (185 mg, 0.792mmol). After refluxing the reac-
0
tion mixture for 2min, H O (10 mL) was added with cooling and the aqueous
4
2
layer was extracted with EtOAc (25 mL ꢂ 2). The combined organic layers
were washed with brine (25 mL), dried (Na SO ), and concentrated. The
2
4
residue was chromatographed on a column of silica gel (10 g). Elution with
benzene/EtOAc (20 : 1) afforded initially 3e (49 mg, 93%) as white crystals;
ꢁ
[6]
m.p. 56–58 C (lit. m.p. 58–59 C). Further elution with the same solvent
ꢁ
ꢁ
[7]
mixture afforded p-cyanophenol (43 mg, 91%); m.p. 110–112 C (lit. m.p.
ꢁ
1
12.0–112.4 C). Physical data for 3 are listed in Table 5.
Synthesis of 4-Oxo-4H-1-benzopyran-3-carbonitrile (5)
A mixture of 6b (200 mg, 0.689 mmol), ZrCl (321 mg, 1.38 mmol) and
4
nitromethane (50 mL) was refluxed for 5 h. After evaporation of the solvent
in vacuo, H O (50 mL) was added to the residue and the aqueous layer was
2
extracted with EtOAc (50 mL ꢂ 2). The combined organic layers were
washed with brine (50 mL), dried (Na SO ), and concentrated. The residue
2
4
was chromatographed on a column of silica gel (35 g). Elution with
benzene/EtOAc (30 : 1) first afforded 5 (98 mg, 83%) as white crystals;

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
876
TSUJI ET AL.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NITRILES FROM O-ARYLALDOXIMES CATALYZED BY ZrCl4
3877

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3
878
TSUJI ET AL.
Table 5. Physical Constants for Nitriles (3)
M.P.
ꢁ
Lit. M.P.
ꢁ
Compd.
( C)
( C)
[
8]
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
42–43
111–113
89–90
55.5–57.5
56–58
43–44
[
9]
110–112
[
[
[
10]
94–95
58–59
58–59
6]
6]
[
7]
107–109
62–64
112.0–112.4
[
6]
65–66
—
—
a
Oil
Oil
Oil
a
a
j
—
a
The products were characterized by com-
parison of their spectral data with those of
commercially available samples.
ꢁ
[3]
m.p. 177–180 C (benzene) (lit. m.p. 177–179 C). Further elution with the
ꢁ
same solvent mixture afforded p-cyanophenol (71 mg, 86.5%); m.p.
111–112 C (lit. m.p. 112.0–112.4 C).
[7]
ꢁ ꢁ
Synthesis of 3-Formamido-4-oxo-4H-1-benzopyran (7)
A mixture of 6a (200 mg, 0.984 mmol), ZrCl (1.146 g, 4.92mmol) and
benzene (10 mL) was refluxed for 8 h. After evaporation of the solvent in
4
vacuo, H O (50 mL) was added to the residue and the aqueous layer was
2
extracted with EtOAc (50 mL ꢂ 2). The combined organic layers were
washed with brine (50 mL), dried (Na SO ), and concentrated. The residue
4
2
was chromatographed on a column of silica gel (25 g). Elution with
ꢁ
[3]
hexane/EtOAc (2: 1) first afforded 6a (44 mg, 22%); m.p. 71–73 C (lit.
ꢁ
m.p. 75–77 C). Further elution with the same solvent mixture afforded 7
ꢁ
(
ꢁ
123 mg, 65%) as white crystals; m.p. 202–205 C (EtOAc). IR (KBr):
ꢃ1
1
¼ 3200, 1660, 1620, 1470 cm ; H NMR (DMSO-d ): ꢀ ¼ 7.55 (t, 1H,
6
J ¼ 7.6 Hz, ArH), 7.70 (d, 1H, J ¼ 8.0 Hz, ArH), 7.85 (t, 1H, J ¼ 7.8 Hz,
ArH), 8.08 (br s, 1H, NH), 8.12(dd, 1H, J ¼ 8.1, 1.7 Hz, ArH), 8.69 (s,
þ
1
H, ArH), 11.42(s, 1H, CHO); MS (EI): m/z (%) ¼ 189 (M , 100). Anal.
Calcd. for C H NO : C, 63.49; H, 3.73; N, 7.40. Found: C, 63.41; H, 3.84;
7
1
0
3
N, 7.36.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NITRILES FROM O-ARYLALDOXIMES CATALYZED BY ZrCl4
3879
REFERENCES
1
. Friedrich, K.; Wallenfels, K. In The Chemistry of the Cyano Group;
Rappoport, H., Ed.; Interscience Publishers: New York, 1970;
pp 67–122; Kikugawa, Y.; Fu, L.H.; Sakamoto, T. Synth. Commun.
1993, 23, 1061; Tamami, B.; Kiasat, A.R. Synth. Commun. 2000, 30,
235; Jose, B.; Sulatha, M.S.; Pillai, P.M.; Prathapan, S. Synth.
Commun. 2000, 30, 1509; Miller, C.P.; Kaufman, D.H. Synlett 2000,
169.
1
2
3
. Kikugawa, Y.; Tsuji, C.; Miyazawa, E.; Sakamoto, T. Tetrahedron
Lett. 2001, 42, 2337.
. Hsung, R.P.; Zificsak, C.A.; Wei, L.-L.; Zehnder, L.R.; Park, F.;
Kim, M.; Tran, T.-T.T. J. Org. Chem. 1999, 64, 8736.
. Cadogan, J.I.G.; Rowley, A.G. Synth. Commun. 1977, 7, 365.
. Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. Org. Prep. Proced. Int.
4
5
1
997, 29, 594.
. Sakamoto, T.; Mori, H.; Takizawa, M.; Kikugawa, Y. Synthesis
991, 750.
. Wheland, G.W.; Brownell, R.M.; Mayo, E.C. J. Am. Chem. Soc. 1948,
0, 2492.
6
7
1
7
8
. Norris, J.F.; Klemka, A.J. J. Am. Chem. Soc. 1940, 62, 1432.
. Bunnett, J.F.; Levitt, A. J. Am. Chem. Soc. 1948, 70, 2778.
9
0. Knudsen, R.D.; Morrice, A.G.; Snyder, H.R. J. Org. Chem. 1975, 40,
1
2878.
Received in Japan October 25, 2001

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©
2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.