Pseudo-intramolecular cyclization of α-nitro-δ-keto nitrile leading to 2-amino-3-nitro-1,4-dihydropyridines

Article abstract of DOI:10.1246/cl.2009.680

A novel concept-the pseudo-intramolecular process-is applied to the synthesis of multiply functionalized heterocyclic compounds. Acidic α-nitro-δ-keto nitrile easily forms an ammonium salt upon treatment with an amine. When the amine is liberated under eq

Full text of DOI:10.1246/cl.2009.680

680
Chemistry Letters Vol.38, No.7 (2009)
Pseudo-intramolecular Cyclization of ꢀ-Nitro-ꢁ-keto Nitrile Leading
to 2-Amino-3-nitro-1,4-dihydropyridines
Nagatoshi Nishiwaki,ꢀ1 Kengo Kakutani,2 Mina Tamura,2 and Masahiro Ariga2
1Anan National College of Technology, 265 Aoki, Minobayashi, Anan 774-0017
2Osaka Kyoiku University, 4-698-1 Asahigaoka, Kashiwara, Osaka 582-8582
(Received April 6, 2009; CL-090341; E-mail: nishiwaki@anan-nct.ac.jp)
A novel concept—the pseudo-intramolecular process—is
ꢀ-nitro-ꢁ-keto nitrile 72 as a substrate for the present purpose
and utilized it in the synthesis of vicinally functionalized hetero-
cyclic compounds.
applied to the synthesis of multiply functionalized heterocyclic
compounds. Acidic ꢀ-nitro-ꢁ-keto nitrile easily forms an ammo-
nium salt upon treatment with an amine. When the amine is li-
berated under equilibrium, an intimate pair, namely, a nucleo-
philic amine and an electrophilic keto nitrile are located close
to each other, is formed; thus the amine efficiently attacks a cy-
ano group of keto nitrile. As a result of subsequent cyclization,
1,4-dihydropyridines containing an amino and a nitro group at
the vicinal positions as a partial structure are afforded.
Keto nitrile 7 was easily transformed to ammonium salt 8a3
upon treatment with propylamine (3a); this was confirmed by
1H NMR and IR spectra. Immediately after 3a was added to a so-
lution of keto nitrile 7 in acetonitrile-d3, in the 1H NMR spectrum,
the singlet signal at 6.29 ppm assigned to an acidic ꢀ-proton im-
mediately disappeared and the signals for a propyl group shifted
to the downfield, indicating quantitative formation of ammonium
salt 8a. The absorption of a cyano group in the IR spectrum of 8a
was observed to be as strong as that of a carbonyl group; however,
no cyano group absorption could be observed in the spectrum of
starting keto nitrile 7. The strong absorption of a cyano group is a
typical feature of the ꢀ-cyanonitronate framework.4
Acyl groups of ꢂ-keto esters 1 and 2 are efficiently transfer-
red to afford malonic acid amide esters 4 upon reaction with
amines 3 (Scheme 1).1 This transacylation proceeds via a pseu-
do-intramolecular process. The introduction of an aryl or a nitro
group increases the acidity of an ꢀ-hydrogen, and thus, ammo-
nium salt 5 is formed immediately after the addition of amine
3. Salt 5 releases an amine under equilibrium to give an intimate
pair 6, in which a nucleophilic amine and an electrophilic keto
ester are located close to each other. The spatial proximity of
the reactants enhances the reactivity, and consequently, the reac-
tion proceeds without any detectable by-product. Although the
present reaction appears to proceed via an intramolecular proc-
ess, it actually proceeds via an intermolecular process; this has
been confirmed by NMR study and by carrying out reactions
using amino alcohol in diluted conditions.1
Indeed, 3-nitro-2-propylamino-1,4-dihydropyridine (9a)5
was isolated in 71% yield when an acetonitrile solution of 8a
was heated under reflux (Table 1, Run 1). Although the transacy-
lation gave no by-product (Scheme 1), several kinds of uniden-
tified products were formed in this reaction. This is presumably
due to side reactions caused by multiple functionalities of keto
nitrile 7. The structure of dihydropyridine 9a was determined
1
on the basis of spectral and analytical data.5 In the H NMR,
the singlet signal at 7.51 ppm and the triplet one at 12.12 ppm
were exchangeable with D2O; the former signal disappeared im-
mediately and the latter one disappeared gradually. The different
exchange rates indicate the presence of intramolecular hydrogen
bonding between an amino and a nitro group. Furthermore, two
gem-methyl groups were equivalently observed despite cyclic
The pseudo-intramolecular process is considered to be a
novel method for synthesizing polyfunctionalized compounds.
In this process, it is crucial that suitable substrates, those contain-
ing both an acidic hydrogen and functionalities such as carbonyl
and cyano groups, are available; molecular design for these sub-
strates is not very difficult. From this viewpoint, we focused on
Table 1. Synthesis of dihydropyridines 9
O
O
_
N+
R1R2NH 3
O
NO2
H
R2
MeCN
reflux 40 h
O
O
O
N
R1
C
N
N
H
9
O
O
PrNH2 3a
7
EtO
OEt
CHCl3
EtO
NHPr
X
H
4a
rt, 1 d
quant.
Run
R1
R2
Yield/%
X = 2,4-dinitrophenyl 1
NO2
2
1
2
3
4
5
Et–CH2
Pr–CH2
Me2CH
Me3C
Ph
Et–CH2
H
H
H
H
H
a
71
65
0
0
0
b
c
d
e
f
_
O
O
X
O
O
O
O
6
Et–CH2
0
EtO
PrNH2
OEt
EtO
H
OEt
H
7
8
9
10
11
i-Pr–CH2
t-Bu–CH2
c-Hex–CH2
Ph–CH2
(MeO)2CH–CH2
H
H
H
H
H
g
h
i
j
k
63
48
59
80
74
X
+
NH2Pr
5
intimate pair 6
Scheme 1. Transacylation using ꢀ-substituted ꢂ-keto esters 1
and 2.
Copyright ꢀ 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.7 (2009)
681
concept is applicable to the syntheses of various polyfunctional-
ized compounds.
_
O
NO2
N+
_
O
H
C
References and Notes
C
N
1
a) N. Nishiwaki, J. Synth. Org. Chem. Jpn. 2009, 67, 349. b) Y.
Nakaike, N. Taba, S. Itoh, Y. Tobe, N. Nishiwaki, M. Ariga, Bull.
Chem. Soc. Jpn. 2007, 80, 2413. c) N. Nishiwaki, D. Nishida, T.
Ohnishi, F. Hidaka, S. Shimizu, M. Tamura, K. Hori, Y. Tohda,
M. Ariga, J. Org. Chem. 2003, 68, 8650.
H
O
O
PrNH2
N
+
PrNH2
3a
8a
7
NO2
H
2
Keto nitrile 7 is easily prepared from nitroisoxazolone in one pot, in
which intermediate cyano-aci-nitroacetate reacts with only acetone
leading to ꢂ,ꢂ-dimethyl-ꢁ-keto nitrile. Experimental details are
shown in the following literature. a) N. Nishiwaki, T. Nogami,
M. Ariga, Heterocycles 2008, 75, 675. b) N. Nishiwaki, T. Nogami,
C. Tanaka, F. Nakashima, Y. Inoue, N. Asaka, Y. Tohda, M. Ariga,
J. Org. Chem. 1999, 64, 2160.
C
N
O
PrNH2
intimate pair 10
H
NO2
H
H
H
NO2
H
Pr
3
To a solution of keto nitrile 7 (92 mg, 0.5 mmol) in acetonitrile
(10 mL), propylamine (3a) (41 mL, 0.5 mmol) was added. After stir-
ring at room temperature for 10 min., the solvent was evaporated to
afford propylammonium salt 8a (122 mg, 0.5 mmol, quant.). Pale
brown oil. IR (neat/cmꢁ1): 3200–2900 (br), 2198 (strong), 1711,
1341, 1228, 733; 1H NMR (400 MHz, CDCl3): ꢁ 0.99 (t, J ¼ 7:4
Hz, 3H), 1.26 (s, 6H), 1.71 (dt, J ¼ 7:5, 7.4 Hz, 2H), 2.10 (s,
3H), 2.97 (s, 2H), 3.00 (t, J ¼ 7:5 Hz, 2H), 7.2–8.2 (br, 4H);
13C NMR (100 MHz, CDCl3): ꢁ 9.0 (CH3), 19.3 (CH2), 24.2
(CH3), 29.0 (CH3), 32.3 (CH2), 39.6 (CH2), 48.6 (CH2), 103.6
(C), 116.1 (C), 206.0 (C).
_
H
HO
O
+
Pr
N
N
N
N
H H
H
O
N+
_
O
- H2O
H
N
N
H
9a
Pr
Scheme 2. A plausible mechanism.
4
5
N. Nishiwaki, Y. Takada, Y. Inoue, Y. Tohda, M. Ariga, J. Hetero-
cycl. Chem. 1995, 32, 473.
structure, which suggests the dihydropyridine ring is closely flat
or undergoes a facile ring flipping on the NMR time scale.
A plausible mechanism for the present pseudo-intramolecu-
lar reaction is illustrated in Scheme 2. When salt 8a is heated, the
amine is removed under equilibrium giving an intimate pair 10.
The liberated amine attacks an immediate cyano group, and then
the cyano group attacks an acyl group to form a six-membered
ring. Subsequent dehydration and proton transfer lead to the for-
mation of dihydropyridine 9a.
Butylamine (3b) reacted in a similar manner with keto nitrile
7 (Table 1, Run 2), however, bulkier amines such as isopropyl-
amine (3c), tert-butylamine (3d), aniline (3e), and dipropyl-
amine (3f) did not cause cyclizations (Runs 3–6).6 The high sen-
sitivity to steric hindrance is due to the congestion around the re-
action site of intimate pair 10. Hence, the insertion of a methyl-
ene group as a spacer between the bulky group and the amino
function facilitated the cyclization to afford dihydropyridines
9g–9k,12 respectively (Runs 7–11).
To a solution of keto nitrile 7 (92 mg, 0.5 mmol) in acetonitrile
(10 mL), propylamine (3a) (41 mL, 0.5 mmol) was added, and heat-
ed under reflux for 40 h. After removal of the solvent, the residue
was treated with column chromatography on silica gel to afford di-
hydropyridine 9a (eluted with ethyl acetate, 80 mg, 0.35 mmol,
71%). Pale yellow needles (from ethyl acetate). Mp 202–204 ꢂC.
IR (Nujol/cmꢁ1): 1720, 1626, 1535, 1333; 1H NMR (400 MHz,
CDCl3): ꢁ 1.01 (t, J ¼ 7:2 Hz, 3H), 1.48 (s, 6H), 1.72 (tq, J ¼
7:2, 7.2 Hz, 2H), 1.83 (s, 3H), 3.36 (dt, J ¼ 7:2, 5.2 Hz, 2H), 4.47
(s, 1H), 7.51 (s, 1H), 12.14 (t, J ¼ 5:2 Hz, 1H); 13C NMR (100
MHz, CDCl3): ꢁ 11.4 (CH3), 18.4 (CH3), 22.0 (CH2), 27.0
(CH3), 36.0 (C), 43.5 (CH2), 113.7 (C), 114.4 (CH), 124.7 (C),
152.5 (C); MS (FAB) m=z; 226 (½M þ 1ꢃþ100). Anal. Calcd for
C
11H19N3O2: C, 58.64; H, 8.50; N, 18.65%. Found: C, 58.49; H,
8.51; N, 18.59%.
Formations of ammonium salts 8b–8f were confirmed by 1H NMR.
M. R. Bryce, Adv. Mater. 1999, 11, 11.
6
7
8
a) M. R. Bryce, J. Mater. Chem. 2000, 10, 589. b) M. S. Wong,
C. Bosshard, F. Pan, P. Gunter, Adv. Mater. 1996, 8, 677. c) W.
¨
The frameworks containing both donor and acceptor moie-
ties are often found as partial structures of functional materials
such as molecular electronic devices,7 chromophores for dyes,8
and nonlinear optics.7,8 Although 1,4-dihydropyridines contain-
ing an amino and a nitro group can also be used in insecticides9
and central nervous system potassium channel modulators,10 this
framework is synthesized by a single procedure only, in which
nitroketene aminals (1,1-diamino-2-nitroethenes) are used as
building blocks,11 however, a drawback of this method is that
it is difficult to modify an amino moiety. In contrast, in our meth-
od, an amino group can be easily modified by changing amine 3.
Hence the present reaction will supplement the conventional one.
As mentioned thus far, multiply functionalized 1,4-dihydro-
pyridines are prepared via pseudo-intramolecular process. This
Schuddeboom, B. Krijnen, J. W. Verhoeven, E. G. J. Staring,
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9
10 K. Urbahns, S. Goldmann, H.-G. Heine, B. Junge, R. Schohe-Loop,
H. Sommemeyer, T. Glaser, R. Wittka, J. de Vry, Ger. Offen. DE
4,430,095, 1996; Chem. Abstr. 1998, 129, 69590.
11 a) V. J. Ram, N. Agarwal, A. Sharon, P. R. Maulik, Tetrahedron
Lett. 2002, 43, 307. b) R. Troschutz, A. Luckel, H. Mertens, Arch.
¨
¨
Pharm. 1993, 326, 335. c) T. Tokumitsu, Bull. Chem. Soc. Jpn.
1990, 63, 1921.
12 Supporting Information is available electronically on the CSJ-Jour-
nal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Published on the web (Advance View) May 30, 2009; doi:10.1246/cl.2009.680