Development of a safely handleable synthetic equivalent of cyanonitrile oxide by 1,3-dipolar cycloaddition of nitroacetonitrile

Article abstract of DOI:10.1039/c9cc03875b

Dianionic cyano-aci-nitroacetate affords 3-cyanoisoxazol(in)es upon heating with a range of dipolarophiles in the presence of hydrochloric acid. In this reaction, nitroacetonitrile is formed as an intermediate active species, which serves as a synthetic e

Full text of DOI:10.1039/c9cc03875b

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DOI: 10.1039/C9CC03875B
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Development of safely handleable synthetic equivalent of
cyanonitrile oxide –1,3-dipolar cycloaddition of
nitroacetonitrile–
Received 00th January 20xx,
Accepted 00th January 20xx
Nagatoshi Nishiwaki,*a,b Yuta Kumegawa,a Kento Iwai,a and Soichi Yokoyamaa,b
DOI: 10.1039/x0xx00000x
Abstract.
Dianionic
cyano-aci-nitroacetate
affords
3- of cyanonitrile oxide 1, based on which we envisaged that nitrile
cyanoisoxazol(in)es upon heating with a range of dipolarophiles oxide 1 should be generated upon protonation of dianion 5
in the presence of hydrochloric acid. In this reaction, accompanied by decarboxylation and dehydration.
nitroacetonitrile is formed as an intermediate active species,
which serves as a synthetic equivalent to cyanonitrile oxide that
can participate in a 1,3-dipolar cycloaddition reaction.
NOH
CCl3
SOCl2
Cl
NH2OH
The 1,3-dipolar cycloaddition of cyanonitrile oxide
1
O
NOH
(cyanofulminate or cyanogen N-oxide) is a useful preparative
method for the synthesis of 3-cyanoisoxazol(in)es, which is
superior to other methods such as direct substitution by a
cyanide,1 chemical conversion of other functional groups,2 and
ring construction3,4 because the five-membered ring can be
formed in a single step. In addition, the products are readily
transformed into polyfunctionalized compounds upon cleavage
of the N-O bond. On the other hand, nitrile oxide 1 is too unstable
to be isolated, although its generation can be confirmed using
N
C
_
+
 or base
Cl
N C C N O
NOH
2
1
N
O
N
C
N
C
+
N
NH4Ce(NO3)4

C
_
1
N
O
NO2
spectroscopy.5
Vacuum
pyrolysis6
or
base-induced
are
3
4
dehydrochlorination7,8 of chloro(cyano)formoxime
2
_
O
common methods used to generate nitrile oxide 1. In addition,
the pyrolysis of dicyanofuroxan 39 and treating nitroacetonitrile
4 with ammonium cerium(III) nitrate10 are also effective
approaches used to prepare 1 (Scheme 1). However, preparation
of precursors 2 and 3 suffers from some drawbacks such as low
yield, troublesome manipulations, and toxicity.11,12 In addition,
nitroacetonitrile 4 should be handled as an explosive material
(see ESI).3,13 Hence, the development of a safe and concise for
generating cyanonitrile oxide 1 is highly desired.
M+
_
O
+
H+
_
N
+
N C C N O
N C
_
M+
O
O
CO2, H2O
1
5a, K+ 5b
+
N
H
M+:
Me
Scheme 1 Generation methods of cyanonitrile oxide 1.
Meanwhile, we have studied the application of dianionic cyano-
aci-nitroacetate 514 as a cyano(nitro)methylating agent in organic
synthesis leading to the synthesis of functionalized heterocyclic
systems.3,15 The structure of 5 can be regarded as a masked form
Although it is possible to isolate dianion 5, decarboxylation
gradually occurs.14 Thus, 5 was generated in situ via a ring
opening reaction of pyridinium salt 6 upon treatment with N-
methylpyrrolidine. A solution of 6 and ethynylbenzene 7a in
acetonitrile showed no change even when heated at 100 °C for 1
d in a sealed tube (Table 1, entry 1). On the other hand, a trace
amount of 3-cyano-5-phenylisoxazole (8a)16 was obtained when
the reaction was conducted under the same conditions in the
presence of acetic acid (entry 2). The addition of a stronger acid
a. School of Environmental Science and Engineering, Kochi University of
Technology,, Tosayamada, Kami, Kochi 782-8502, Japan.
b. Research Center for Material Science and Engineering, Kochi University of
Technology, Tosayamada, Kami, Kochi 782-8502, Japan.
Electronic Supplementary Information (ESI) available: [experimental methods,
monitoring experiments using 1H NMR, DSC measurement, copies of 1H and 13C
NMR spectra]. See DOI: 10.1039/x0xx00000x
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such as p-toluenesulfonic acid and hydrochloric acid, was found
Table 2 Optimization of the reaction conditions.
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DOI: 10.1039/C9CC03875B
to be effective (entries 3 and 4).
O
N
Ph
(5 equiv.)
7a
CN
_
C
O
K+
(3 equiv.)
HCl
+
O
_
O
_
N
Table 1 Assessment of the acid used in the cycloaddition reaction.
N
K+
Ph
O
in a sealed tube
5b
8a
Ph
7a
(1 equiv.)
O
N
N
Me
+
_
Entry
Solv.
Temp./°C
100
Time/h
Yield/%
Acid
(3 equiv.)
CN
O
1
2
3
4
5
6
MeCN
24
24
24
3
78
90
0
_
N
(2 equiv.)
+
N
H
5a
MeCN/H2O (1/4)
100
N
O
MeCN
100 °C, 1 d
Ph
MeCN
60 °C, 0.5 h
O
O
MeCN/H2O (1/4)
MeCN/H2O (1/4)
MeCN/H2O (1/4)
MeCN/H2O (1/4)
70
6
8a
100
0
in a sealed tube
100
6
43
96
100
12
entry
Acid
—
Yield/%
1
2
3
4
0
5
AcOH
p-TsOH•H2O
HCl
The reaction conditions were optimized using dipotassium salt
5b (Table 2). A mixed solvent consisting of acetonitrile and
water was suitable because it can dissolve both 5b and 7a (entries
1 and 2). However, no reaction occurred at lower temperature,
which was presumably due to the low reactivity of
nitroacetonitrile 4 when compared with conventional 1,3-dipoles
such as nitrile oxide and nitrone (entries 2 and 3). Prolonging the
reaction time was found to be effective in the reaction with
cycloadduct 8a obtained in high yield after heating for 12 h
(entries 4–6).‡
15
27
To obtain further insight into this reaction, each step was
monitored using 1H NMR spectroscopy with deuterated
acetonitrile used as the solvent (see ESI). Cation exchange of 6
occurred after addition of 1 equivalent of N-methylpyrrolidine,
and the ring opening reaction occurred leading to dianion 5a
when another 1 equivalent of N-methylpyrrolidine was added. A
new singlet signal appeared at 5.8 ppm when hydrochloric acid
was added to the solution of 5a, in which nitroacetonitrile 4 or
its anionic form 9a was formed as a result of the decarboxylation
reaction, and either of these were considered to be the actual
species in the cycloaddition reaction. Indeed, formation of
cycloadduct 8a was confirmed after heating of this solution in
the presence of 7a.
Subsequently, the more stable dipotassium salt 5b was employed
from the viewpoint of its storage for a long period of time.
Although 5a was more soluble in organic solvents, the reaction
mixture was somewhat complicated because of the presence of
pyridinium, pyrrolidinium, and ammonium chlorides, among
which the last salt is formed during the acid-catalysed hydrolysis
of acetonitrile. Thus, 5b was concluded to be more suitable for
use as a reagent in organic synthesis.
CN
R1
O
N
R1
N
7 (5 equiv.)
HCl
(3 equiv.)
_
C
O
8
O
K+
+
+
O
_
_
or
N
K+
MeCN/H2O (1/4)
100 °C, 12 h
or
O
R4
CN
R3
R2
R4
5b
R3
R2
in a sealed tube
N
O
10 (5 equiv.)
11
CN
CN
Ph
Ph
X = CF3
Me
8b (quant.)
8c (52%)
8d (55%)
N
N
OMe
O
O
X
Monopotassium salt 9b,14 derived from 5b, did not afford any
cycloadduct 8a upon heating with ethynylbenzene 7a. However,
the formation of 8a was confirmed when the same reaction was
conducted in the presence of hydrochloric acid (Scheme 2).
These results indicate that nitroacetonitrile 4 serves as a 1,3-
dipole during the cycloaddition reaction.
11e (65%)
CN
CN
OMe
HO
HO
N
N
O
O
10h
OMe
O
O
O
O
O
11i
OH
10i
11g (quant.)
from 10f
10f
from 10h 75%
from 10i 95%
Scheme 3 Synthesis of 3-cyanoisoxazol(in)es 8 and 11.
Ph
7a
CN
N
(5 equiv.)
Under the optimized conditions dipolarophiles 7 and 10 were
subjected to the cycloaddition reaction (Scheme 3). Electron-
deficient alkyne 7b underwent the cycloaddition reaction to
afford 8b16 in quantitative yield. On the contrary, alkenes 7c and
7d, which possess an electron-donating group furnished their
corresponding cycloadducts 8c and 8d in moderate yields. Since
a considerable amounts of acetophenone derivatives were
K+
C
HCl (3 equiv.)
N
+
O
_
_
O
Ph
N
MeCN
100 °C, 1 d
in a sealed tube
O
9b
8a (61%)
Scheme 2 The cycloaddition reaction using monopotassium salt 9b under acidic
conditions.
2 | J. Name., 2012, 00, 1-3
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‡ Typical procedure: In a screw capped test tube, dipotassium salt
formed during these reactions, competitive hydration was
considered to suppress the cycloaddition. trans-Stilbene 10e was
also usable as a dipolarophile leading to diphenylisoxazoline
11e. Electron-deficient acrylates 10f and 10h also undergo the
cycloaddition reaction efficiently, however, the ester
functionality did not tolerate the reaction conditions, affording
carboxylic acids 11g and 11i, respectively. Conversely, it was
possible to use carboxylic acid 10i as a substrate without
protection in this reaction, which afforded 11i in high yield.
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5b (41.2 mg, 0.2 mmol) was dissolved into a mixed solvent of
DOI: 10.1039/C9CC03875B
MeCN/H2O (v/v = 1/1, 2 mL). After adding 1-ethynyl-4-
trifluoromethylbenzene 7b (144 L, 1mmol) and 1 M HCl (3 mL,
3 mmol), the resultant mixture was heated at 100 °C for 12 h in a
sealed tube. The solvent was removed under reduced pressure, and
MeCN (10 mL) was added to the residue. After filtration to remove
the insoluble material, the filtrate was concentrated to afford 3-
cyano-5-(4-trifluoromethylphenyl)isoxazole 8b (239 mg, 1 mmol,
quant.) as a pale yellow solid. Mp 92–95 °C. 1H NMR (400 MHz,
DMSO-d6)  8.04 (s, 1H), 8.05 (d, J = 8.2 Hz, 2H), 8.23 (d, J = 8.2
8.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6 )  105.0 (CH), 110.2
(C), 123.7 (C, q, J = 271 Hz), 126.4 (CH, d, J = 3.5 Hz), 126.9
(CH), 128.7 (C), 131.3 (C, q, J = 32.1 Hz), 140.3 (C), 170.3 (C);
IR (ATR / cm-1) 2261, 1570, 1400, 1319; HRMS (ESI/TOF) calcd.
for (M+H+) C11H6F3N2O: 239.0427, found: 239.0428.
H+
O
O
O
N
N
H
_
C
C
HCl
O
1
S. U. Dighe, S. Mukhopadhyay, S. Kolle, S. Kanojiya and S.
Batra, Angew. Chem. Int. Ed., 2015, 54, 10926; P. A. Wade
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Wade, J. Org. Chem., 1978, 43, 2020.
O
_
+
+
O
H+
_
O
_
N
H
N
O
CO2
5
12
2
Recent reports: N. A. Bumagin, A. V. Kletskov, S. K.
Petkevich, I. A. Kolesnik, A. S. Lyakhov, L. S. Ivashkevich,
A. V. Baranovsky, P. V. Kurman and V. I. Potkin,
Tetrahedron, 2018, 74, 3578; A. Nordqvist, G. O'Mahony, M.
Friden-Saxin, M. Fredenwall, A. Hogner, K. L. Granberg, A.
Aagaard, S. Baeckstroem, A. Gunnarsson, T. Kaminski, Y.
Xue, A. Dellsen, E. Hansson, P. Hansson, I. Ivarsson, U.
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Natte, R. V. Jagadeesh, M. Sharif, H. Neumann and M.
Beller, Org. Biomol. Chem., 2016, 14, 3356.
N
C
H
NC
H+
+
O
_
N
8a
HO
N
HO
Ph
O
Ph
7a
4
H2O
N
_
C
+
N C C N O
+
O
_
N
HO
1
4
3
4
K. Iwai, H. Asahara and N. Nishiwaki, J. Org. Chem., 2017,
82, 5409.
M. Tamura, T. Nishimura, N. Nishiwaki and M. Ariga,
Heterocycles, 2004, 63, 1659; N. Nishiwaki, T. Nogami, T.
Kawamura, N. Asaka, Y. Tohda and M. Ariga, J. Org. Chem.,
1999, 64, 6476; K. Gewald, P. Bellmann and H. J. Jaensch,
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Tetrahedron, 1985, 41, 727.
Scheme 4 A plausible mechanism for our 1,3-dipolar cycloaddition reaction.
This reaction was considered to proceed as shown in Scheme 4.
Protonation of dianion 5 affords 12, which immediately
undergoes decarboxylation to give nitroacetonitrile 4. The aci-
nitro form of 4 serves as a 1,3-dipole and reacts with the
dipolarophile to construct a five-membered ring. Subsequent
dehydration yields the final product. On the basis of this
mechanism, the amount of acid necessary for this reaction is 2
equivalents. However, 3 equivalents of hydrochloric acid is
necessary for an efficient reaction, which is presumably because
the acid is also consumed by forming a salt with ammonia
formed during the hydrolysis of acetonitrile.
To conclude, 3-cyanoisoxazol(in)es 8 and 11 were synthesized
via the cycloaddition of nitroacetonitrile 4. While
nitroacetonitrile 4 is an explosive material, dianion 5 is thermally
stable and can be stored for a long period of time without any
special care.3,13 Hence, dianion 5 serves as a safe handleable
synthetic equivalent of cyanonitrile oxide 1, which can be used
as a novel tool in organic synthesis.
5
6
7
8
9
10 T. Sugiyama, Appl. Organometal. Chem., 1995, 9, 399.
11 H. Mohler, Protar, 1941, 7, 57.
12 C. He and J. M. Shreeve, Angew. Chem. Int. Ed., 2016, 55,
772; L. L. Fershtat, M. A. Epishina, A. S. Kulikov, I. V.
Ovchinnikov, I. V. Ananyev and N. Nina, Tetrahedron, 2015,
71, 6764; T. M. Mel'nikova, T. S. Novikova, L. I.
Khmel'nitskii and A. B. Sheremetev, Mendeleev Commun.,
2001, 30.
Conflicts of interest
13 C. J. Thomas, Chem. Eng. News, 2009, 87 (32), 4.
14 N. Nishiwaki, Y. Takada, Y. Inoue, Y. Tohda and M. Ariga,
J. Heterocycl. Chem., 1995, 32, 473.
There are no conflicts to declare.
15 N. Nishiwaki, Curr. Med. Chem., 2017, 24, 3728; H.
Asahara, K. Muto and N. Nishiwaki, Tetrahedron, 2014, 70,
Notes and references
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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6522; N. Nishiwaki, T. Nogami, T. Kawamura, N. Asaka, Y.
Tohda and M. Ariga, J. Org. Chem., 1999, 64, 6476; N.
Nishiwaki, T. Nogami, C. Tanaka, F. Nakashima, Y. Inoue,
N. Asaka, Y. Tohda and M. Ariga, J. Org. Chem., 1999, 64,
2160.
View Article Online
DOI: 10.1039/C9CC03875B
16 N. A. Bumagin, A. V. Kletskov, S. K. Petkevich, I. A.
Kolesnik, A. S. Lyakhov, L. S. Ivashkevich, A. V.
Baranovsky, P. V. Kurman and V. I. Potkin, Chem.
Heterocycl. Compd., 2014, 49, 1515.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC03875B
O
N
N
N
_
C
C
H+
C
Ph
O
+
O
+
_
_
_
N
N
N
Ph
O
HO
O
O
CO2, H2O
Cyano-aci-nitroacetate serves as a safely handleable precursor of nitroacetonitrile to
undergo the 1,3-dipolar cycloaddition leading to 3-cyanoisoxazol(in)es.