Application of cyano-aci-nitroacetate to organic syntheses. 1. Facile synthesis of pentanedinitrile-2,4-dinitronates

Full text of DOI:10.1021/jo9818879

2160
J . Org. Chem. 1999, 64, 2160-2162
Sch em e 1
Ap p lica tion of Cya n o-a ci-Nitr oa ceta te to
Or ga n ic Syn th eses. 1. F a cile Syn th esis of
P en ta n ed in itr ile-2,4-d in itr on a tes
Nagatoshi Nishiwaki, Tomoko Nogami, Chitose Tanaka,
Fuminori Nakashima, Yoji Inoue, Noriko Asaka,†
Yasuo Tohda,‡ and Masahiro Ariga*
Department of Chemistry, Center for Instrumental Analysis,
and Division of Natural Science, Osaka Kyoiku University,
Asahigaoka 4-698-1, Kashiwara, Osaka 582-8582, J apan
Received September 16, 1998
In tr od u ction
Ta ble 1
Pentanedinitrile (glutaronitrile) and its derivatives are
widely used as functional materials including biologically
active compounds1 and employed as excellent precursors
for azaheterocycles,2 polymers, and so on.3 Hence, novel
functionalization of pentanedinitrile and development of
facile preparative methods for their preparation are
highly demanding subjects.
Pentanedinitrile-2,4-dinitronate 14 has been investi-
gated for its antitumor activity. 2-Aryl (or alkyl) pen-
tanedinitrile-2,4-dinitronates are prepared through two-
step reactions from nitroacetonitrile. The condensation
of nitroacetonitrile with aldehydes in the presence of
thionyl chloride gives R-nitroacrylonitriles 2. The suc-
ceeding treatment of 2 with amine leads to dinitronates
1. It is known that the condensation of nitroacetonitrile
with triethyl orthoformate in the presence of thionyl
chloride also gives 4-nitropentanedinitrile-2-nitronate.5
These procedures are, however, somewhat troublesome
and are not able to afford 3,3-disubstituted dinitronates.
Meanwhile, we have been paid attention to 4-nitroisox-
azolin-5(2H)-ones that show multifunctionalities. Readily
available pyridinium salt 36,7 reacts with electrophiles
giving N-methyl derivative 4a and N-acetyl 4b (Scheme
1). The former is effectively converted to functionalized
nitrile oxide8 and polysubstituted pyrroles.9 The latter
behaves as the mild acylating agent.10 Furthermore,
* To whom correspondence should be addressed. Tel: 81-729-78-
3398. Fax: 81-729-78-3399. E-mail: ariga@cc.osaka-kyoiku.ac.jp.
† Center for Instrumental Analysis.
‡ Division of Natural Science.
(1) For example: (a) Wustermann, S.; Siebert, J . SOFW J . 1997,
123, 398. (b) Anderson, F. A. J . Am. Coll. Toxicol. 1996, 15, 140.
(2) For example: (a) DiCosimo, R.; Fallon, R. D.; Gavagan, J . E.;
Herkes, F. E. PCT Int. Appl. WO 9744318 A1 971127; Chem. Abstr.
1998, 128, 89231. (b) Diker, K.; El Biach, K.; Doe de Maindreville, M.;
Levy, J . J . Nat. Prod. 1997, 60, 791. (c) Heveling, J . Chem. Ind. 1996,
68, 265.
(3) For example: (a) Lee, J .-Y.; Song, Y.-W.; Shim, M.-J .; Kim, S.-
W. Mater. Chem. Phys. 1997, 50, 256. (b) Maddern, P.; Khalifa, S. PCT
Int. Appl. WO 9709033 A1 970313; Chem. Abstr. 1997, 126, 268320.
(c) Minagawa, M.; Yoshida, W.; Kurita, S.; Takada, S.; Yoshii, F.
Macromolecules 1997, 30, 1782.
(4) (a) Mechkov, Ts.; Demireva, Z. Z. Chem. 1989, 29, 291. (b)
Mechkov, Ts.; Demireva, Z. Z. Chem. 1985, 25, 169. (c) Mechkov, Ts.;
Demireva, Z. Z. Chem. 1985, 25, 62. (d) Mechkov, Ts.; Demireva, Z.
Zh. Org. Khim. 1985, 21, 1884; Chem. Abstr. 1986, 105, 97124.
(5) Reidlinger, G. H.; J unek, H. Synthesis 1991, 835.
(6) Nishiwaki, N.; Takada, Y.; Inoue, Y.; Tohda, Y.; Ariga, M. J .
Heterocycl. Chem. 1995, 32, 473.
(7) Ariga, M.; Tohda, Y.; Nakashima, H.; Tani, K.; Mori, Y.;
Matsumura, E. Bull. Chem. Soc. J pn. 1991, 64, 3544.
(8) Nishiwaki, N.; Uehara, T. Asaka, N.; Tohda, Y.; Ariga, M.;
Kanemasa, S. Tetrahedron Lett. 1998, 39, 4851.
deprotonation at the 3-position of 3 followed by N-O
fission quantitatively occurs to afford cyano-aci-nitro-
acetate 5 under basic conditions at room temperature.6
The estimated electrophilic susceptibility11 of cyano-
aci-nitroacetates 5 indicating multidentate nucleophilic-
ity is shown in Scheme 1. However, 5 has not been used
for organic syntheses because of the difficulty of synthe-
sizing and treating 5. By our method, 5 could be easily
prepared with various types of countercations. Among
them, dipyrrolidinium, dimorpholininium, and bis(DBU-
(9) (a) Ariga, M.; Nishiwaki, N.; Miwa, Y.; Tani, K.; Tohda, Y.
Heterocycles 1997, 44, 81. (b) Higashida, S.; Nakashima, H.; Tohda,
Y.; Tani, K.; Nishiwaki, N.; Ariga, M. Heterocycles 1992, 34, 1511.
(10) Nishiwaki, N.; Takada, Y.; Tani, K.; Tohda, Y.; Ariga, M. Chem.
Express 1992, 7, 845.
(11) The electrophilic susceptibilities were estimated by the MOPAC
(PM3) molecular orbital calculation using the CAChe system.
10.1021/jo9818879 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/13/1999

Notes
J . Org. Chem., Vol. 64, No. 6, 1999 2161
Ta ble 2
Sch em e 2
gradual decomposition was observed. In consideration of
the known reaction,4 the interconversion between 1 and
2 becomes possible.
H+) salts were soluble into organic solvents such as
benzene, CHCl3, methanol, ethanol, acetonitrile, and so
on,6 in contrast with metallic salts (M ) Na, K, Ba/2).
This improved solubility enabled us to investigate the
application of cyano-aci-nitroacetate 5 to organic syn-
theses. We initially focused the synthesis of pentanedini-
trile-2,4-dinitronates 1 by using this trifunctionalized
methane as a building block.
In summary, a facile preparative method for pentane-
dinitrile-2,4-dinitronates 1 was provided. The present
reaction does not require any particular reagent such as
thionyl chloride and troublesome experimental manipu-
lations. Furthermore, this reaction is conducted at room
temperature in one pot. Multifunctionality of dinitronates
1 suggested that 1 can become a building block for
various types of compounds. Results of chemical trans-
formations using dinitronates 1 will be reported in due
course.
Resu lts a n d Discu ssion
Dipyrrolidinium cyano-aci-nitroacetate 5a (M+ ) pyr-
rolidinium) was generated in situ, and the following
reaction was carried out in the same pot. When 5a was
reacted with acetone in benzene, white solid was pre-
Exp er im en ta l Section
cipitated. The empirical formula of the solid was C15H26
-
Syn t h eses of Dip yr r olid in iu m P en t a n ed in it r ile-2,4-
d in itr on a tes. To a suspension of pyridinium salt (3, 418 mg,
2.0 mmol) in benzene (6.0 mL) was added pyrrolidine (0.35 mL,
4.2 mmol), and the mixture was stirred at room temperature
for 0.5 h. To the resultant solution was added ketone or aldehyde
(1.0 mmol). After the solution was stirred at room temperature
for 2 h, hexane (15 mL) was added, and the resulting solution
was allowed to stand overnight. The upper solution was decanted
off. Washing the residual oil with hot benzene (20 mL × 3)
followed by evaporation afforded almost pure dipyrrolidinium
pentanedinitrile-2,4-dinitronate 1 as an oil. When the oil was
solidified, purification by recrystallization with ethanol was
performed. In the cases of 1g and 1h , the obtained products were
oils whose NMR charts show no other signals; however, further
purification giving satisfactory analytical data could not be
achieved.
N6O4. This result suggested that acetone reacted with two
molecules of 5a accompanied by elimination of two carbon
dioxides and a water, and the dianionic property was
retained. The signal of methyl groups shifted to higher
field in the 1H NMR, and the signal of an sp3 carbon
appeared at 35.0 ppm in place of carbonyl one in the 13C
NMR. Strong absorptions were observed at 2191 and
1614 cm-1 in the IR spectrum. On the basis of these
analytical and spectral data, the product was determined
as dipyrrolidinium 3,3-dimethylpentanedinitrile-2,4-dini-
tronate (1a ). This structure was confirmed by X-ray
crystallography.
A plausible mechanism is as follows. Knoevenagel-type
condensation of cyano-aci-nitroacetate 5 with acetone
proceeds to give R-nitroacrylonitrile 2. Nucleophilic at-
tack of another dianion 5 to 2 followed by decarboxylation
gives pentanedinitrile-2,4-dinitronate 1. Reactions of
cyano-aci-nitroacetate 5a with other aliphatic ketones
similarly furnished corresponding 3,3-disubstituted dini-
tronates 1a -e in good yields (Table 1). Acetophenone,
however, caused no change even though the reaction
mixture was heated. Employment of benzaldehyde and
p-methoxybenzaldehyde instead of ketones afforded 3-ar-
yl derivatives 1g,h . The reaction mixture using p-
nitrobenzaldehyde showed a singlet signal at 5.60 ppm
Dip yr r olid in iu m 3,3-d im eth ylp en ta n ed in itr ile-2,4-d in i-
tr on a te (1a ): colorless plates; mp 170-171 °C dec; IR (Nujol)
1
2191, 1614, 1333, 1225 cm-1; H NMR (DMSO-d6, 400 MHz) δ
1.34 (s, 6H), 1.7-1.9 (m, 8H), 3.0-3.2 (m, 8H), 8.8-9.2 (br, 4H);
13C NMR (DMSO-d6, 100 MHz) δ 119.6 (s), 99.5 (s), 44.1 (t), 35.0
(s), 24.0 (q), 23.2 (t). Anal. Calcd for C15H26N6O4: C, 50.84; H,
7.39; N, 23.71. Found: C, 50.85; H, 7.44; N, 23.52.
Dip yr r olid in iu m 3-eth yl-3-m eth ylp en ta n ed in itr ile-2,4-
d in itr on a tes (1b): colorless plates; mp 163-166 °C dec; IR
(Nujol) 2191, 1612, 1342, 1223 cm-1 1H NMR (DMSO-d6, 400
;
MHz) δ 0.74 (t, J ) 7.4 Hz, 3H), 1.29 (s, 3H), 1.8-1.9 (m, 10H),
3.0-3.1 (m, 8H), 8.8-9.2 (br, 4H); 13C NMR (DMSO-d6, 100
MHz) δ 121.4 (s), 100.1 (s), 45.6 (t), 40.2 (s), 29.0 (t), 24.7 (t),
21.3 (q), 9.6 (q). Anal. Calcd for C16H28N6O4: C, 52.16; H, 7.66;
N, 22.81. Found: C, 51.79; H, 7.63; N, 22.76.
1
in the H NMR and gave a chart having pattern similar
to that of 1h in the IR. Considerable formation of 1i
occurred, but an analytical sample could not be prepared
because of concomitance of unidentified byproduct. 3-Alkyl
dinitronates 1j-k were also obtained in excellent yields.
The retrocondensation of the obtained nitronates 1
easily occurred under acidic conditions to yield R-ni-
troacrylonitriles 2 (Table 2). Acrylonitriles 2g,h bearing
an aromatic ring were relatively stable. On the other
hand, 2a was unstable. Although pure 2a was isolated,
Dip yr r olid in iu m 3,3-d ieth ylp en ta n ed in itr ile-2,4-d in itr -
on a tes (1c): colorless plates; mp 160-164 °C dec; IR (Nujol)
1
2195, 1637, 1325, 1236 cm-1; H NMR (DMSO-d6, 400 MHz) δ
0.68 (t, J ) 7.4 Hz, 6H), 1.8-1.9 (m, 12H), 3.05-3.15 (m, 8H),
8.8-9.2 (br, 4H); 13C NMR (DMSO-d6, 100 MHz) δ 119.8 (s), 96.9
(s), 43.5 (t), 41.7 (s), 22.6 (t), 21.0 (t), 7.1 (q). Anal. Calcd for
C17H30N6O4: C, 53.39; H, 7.91; N, 21.97. Found: C, 53.14; H,
8.04; N, 22.23.
Dip yr r olid in iu m 3,3-tetr a m eth ylen ep en ta n ed in itr ile-
2,4-d in itr on a tes (1d ): pale yellow plates; mp 138-142 °C dec;

2162 J . Org. Chem., Vol. 64, No. 6, 1999
Notes
IR (Nujol) 2191, 1612, 1236 cm-1; 1H NMR (DMSO-d6, 400 MHz)
δ 1.5-1.65 (m, 4H), 1.7-1.9 (m, 8H), 2.0-2.1 (m, 4H), 3.0-3.2
(m, 8H), 5.7-6.2 (br, 4H); 13C NMR (DMSO-d6, 100 MHz) δ 120.6
(s), 99.5 (s), 47.7 (s), 45.1 (t), 35.7 (t), 24.7 (t), 23.8 (t). Anal.
Calcd for C17H28N6O4‚1/2H2O: C, 52.43; H, 7.51; N, 21.58.
Found: C, 52.69; H, 7.62; N, 21.94.
3.25-3.35 (m, 8H), 8.5-9.4 (br, 4H); 13C NMR (DMSO-d6, 100
MHz) δ 120.2 (s), 94.1 (s), 45.2 (d), 44.6 (t), 36.7 (s), 27.8 (q),
23.6 (t). Anal. Calcd for C17H30N6O4 : C, 53.39; H, 7.91; N, 21.97.
Found: C, 53.22; H, 7.98; N, 21.80.
Retr ocon d en sa tion of Din itr on a te 1. A solution of dini-
tronate (1, 1.0 mmol) in 1 M HCl (20 mL) was extracted with
CHCl3 (20 mL × 3). The organic layer was dried over MgSO4
and concentrated to afford acrylonitrile derivative 2 that was
pure enough for following analyses.
Dip yr r olid in iu m 3,3-p en ta m eth ylen ep en ta n ed in itr ile-
2,4-d in itr on a tes (1e): pale yellow plates; mp 134-140 °C dec;
IR (Nujol) 2193, 1614, 1329, 1219 cm-1 1H NMR (CDCl3, 400
;
MHz) δ 1.4-1.5 (m, 2H), 1.55-1.65 (m, 4H), 1.95-2.05 (m, 8H),
2.05-2.1 (m, 4H), 3.25-3.35 (m, 8H), 8.0-8.3 (br, 4H); 13C NMR
(CDCl3, 100 MHz) δ 119.2 (s), 103.8 (s), 45.1 (t), 40.8 (s), 31.1
(t), 25.7 (t), 24.5 (t), 22.6 (t). Anal. Calcd for C18H30N6O4‚1/2H2O:
C, 53.58; H, 7.74; N, 20.83. Found: C, 53.64; H, 7.86; N, 20.86.
Dip yr r olid in iu m 3-p h en ylp en t a n ed in it r ile-2,4-d in it r -
on a tes (1g): reddish brown oil; IR (neat) 2193, 1623, 1319, 1227
3-Meth yl-2-n itr o-2-bu ten en itr ile (2a ): white solid; mp 88-
93 °C dec; IR (Nujol) 2239, 1618, 1576, 1342 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 2.40 (s, 3H), 2.50 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 166.1 (s), 110.7 (s), 26.3 (q), 22.9 (q). When 2a was
standed, hydrolysis gradually proceeded. Thus, satisfactory
analytical data were not obtained.
2-Nitr o-3-p h en yl-2-p r op en en itr ile (2g): yellowish brown
cm-1 1H NMR (DMSO-d6, 400 MHz) δ 1.7-1.9 (m, 8H), 3.0-
;
solid; mp 103-104 °C; IR (Nujol) 2235, 1622, 1591, 1342 cm-1
;
3.2 (m, 8H), 5.38 (s, 1H), 7.1-7.2 (m, 3H), 7.2-7.4 (m, 2H), 7.9-
8.7 (br, 4H); 13C NMR (DMSO-d6, 100 MHz) δ 139.9 (s), 126.8
(d), 126.2 (d), 124.9 (d), 118.6 (s), 93.6 (s), 43.6 (t), 42.3 (d), 22.5
(t).
1H NMR (CDCl3, 400 MHz) δ 7.6-7.9 (m, 3H), 8.0-8.2 (m, 2H),
8.75 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 148.6 (d), 135.6 (d),
132.2 (d), 129.9 (d), 127.3 (s), 123.2 (s), 111.0 (s). Anal. Calcd
for C9H6N2O2: C, 62.07; H, 3.47; N, 16.09. Found: C, 62.40; H,
3.40; N, 15.84.
Dip yr r olid in iu m 3-(4-m eth oxyp h en yl)p en ta n ed in itr ile-
2,4-d in itr on a tes (1h ): yellowish brown oil; IR (neat) 2193, 1610,
3-(4-Meth oxyp h en yl)-2-n itr o-2-p r op en en itr ile (2h ): red
plates; mp 104-105 °C (lit.12 97-98 °C); IR (Nujol) 2231, 1591,
1560, 1319 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.97 (s, 3H), 7.11
(d, J ) 9.0 Hz, 2H), 8.08 (d, J ) 9.0 Hz, 2H), 8.65 (s, 1H); 13C
NMR (CDCl3, 100 MHz) δ 165.9 (s), 148.1 (d), 135.3 (d), 120.5
(s), 119.9 (s), 115.7 (d), 111.8 (s), 56.0 (q). Anal. Calcd for
C10H8N2O3: C, 58.82; H, 3.95; N, 13.72. Found: C, 58.87; H,
3.89; N, 13.87. The structure of 2h was confirmed by X-ray
analysis.
1
1321, 1248 cm-1; H NMR (DMSO-d6, 400 MHz) δ 1.7-1.9 (m,
8H), 3.0-3.2 (m, 8H), 3.72 (s, 3H), 5.29 (s, 1H), 4.9-6.9 (br, 4H),
6.83 (d, J ) 8.6 Hz, 2H), 7.06 (d, J ) 8.6 Hz, 2H); 13C NMR
(DMSO-d6, 100 MHz) δ 159.4 (s), 134.7 (s), 130.4 (d), 121.6 (s),
115.1 (d), 96.8 (s), 56.7 (q), 46.6 (t), 44.5 (d), 25.5 (t).
Dipyr r olidin iu m 3-eth ylpen tan edin itr ile-2,4-din itr on ates
(1j): colorless plates; mp 150-152 °C dec; IR (Nujol) 2189, 1605,
1
1292, 1230 cm-1; H NMR (DMSO-d6, 400 MHz) δ 0.85 (t, J )
7.3 Hz, 3H), 1.45-1.6 (m, 2H), 1.75-1.95 (m, 8H), 3.0-3.2 (m,
8H), 3.84 (t, J ) 7.8 Hz, 1H), 4.6-6.4 (br, 4H); 13C NMR (DMSO-
d6, 100 MHz) δ 120.6 (s), 96.7 (s), 46.1 (t), 40.3 (d), 25.2 (t), 24.7
(t), 13.5 (q). Anal. Calcd for C15H26N6O4‚1/2H2O: C, 49.58; H, 7.49;
N, 23.13. Found: C, 49.95; H, 7.44; N, 23.12.
Su p p or tin g In for m a tion Ava ila ble: X-ray data of 1a and
2h . This material is available free of charge via the Internet
at http://pubs.acs.org.
Dip yr r olid in iu m 3-ter t-bu tylp en ta n ed in itr ile-2,4-d in i-
tr on a tes (1k ): colorless plates; mp 157-159 °C dec; IR (Nujol)
J O9818879
1
2187, 1624, 1300, 1225 cm-1; H NMR (DMSO-d6, 400 MHz) δ
0.95 (s, 9H), 1.8-1.9 (m, 8H), 3.05-3.15 (m, 8H), 4.47 (s, 1H),
(12) Brillon, D.; Sauve´, G. J . Org. Chem. 1992, 57, 1838.