Safe cyano(nitro)methylating reagent - Michael addition of cyano-aci-nitroacetate leading to δ-functionalized α-nitronitriles

Article abstract of DOI:10.1016/j.tet.2014.07.013

A practical, convenient, and safe cyano(nitro)methylation method was developed, in which cyano-aci-nitroacetate served as a synthetic equivalent of anionic nitroacetonitrile. A control of the single/double Michael additions was achieved, which enabled the synthesis of unsymmetrical double Michael adducts. Moreover, the Michael adducts can be used as precursors of pyridine and naphthyridine frameworks.

Full text of DOI:10.1016/j.tet.2014.07.013

Tetrahedron 70 (2014) 6522e6528
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Safe cyano(nitro)methylating reagentdMichael addition
of cyano-aci-nitroacetate leading to d-functionalized a-nitronitriles
,
,b,
Haruyasu Asahrara a b, Kyo Muto a, Nagatoshi Nishiwaki a
*
a School of Environmental Science and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
b Research Center for Material Science and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical, convenient, and safe cyano(nitro)methylation method was developed, in which cyano-aci-
nitroacetate served as a synthetic equivalent of anionic nitroacetonitrile. A control of the single/double
Michael additions was achieved, which enabled the synthesis of unsymmetrical double Michael adducts.
Moreover, the Michael adducts can be used as precursors of pyridine and naphthyridine frameworks.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 13 June 2014
Received in revised form 2 July 2014
Accepted 3 July 2014
Available online 8 July 2014
Keywords:
Nitroacetonitrile
Michael addition
Pyridine
[1,8]-Naphthyridine
Polyfunctionalized compound
1. Introduction
Nitroacetonitrile (NAN), a methylene connected with a nitro and
a cyano functionalities, is used as a cyano(nitro)methylation agent,
which serves as a building block for the synthesis of versatile pol-
yfunctionalized compounds.1,2 Indeed, several reactions of NAN
have been reported, such as Knoevenagel condensation with a ke-
tone/aldehyde, addition reactions to polar multiple bonds, and
Michael addition.1e3 In spite of the great potential of NAN, it has not
been widely used in organic syntheses because of its low thermo-
dynamic stability and preparative methods for synthesizing this
reagent suffer from somewhat troublesome manipulations and
poor yield performance.4 Semenov overcame these drawbacks by
using a two phase system, by which NAN is prepared in good yield.5
However, Thomas recently alerted on the explosive property of the
NAN.6 In this context, the development of a safe alternative cya-
no(nitro)methylation agent is required.
Scheme 1. Generation of cyano-aci-nitroacetate 3 derived from nitroisoxazolone 1.
Meanwhile, we have reported that the pyridinium salt of
nitroisoxazolone 1 undergoes the ring opening reaction quantita-
tively under mild conditions upon treatment with pyrrolidine (2A)
to give dianionic cyano-aci-nitroacetate 3, which possesses three
different functional groups on the same carbon atom (Scheme 1).7
The dianion 3 is thermally stable and is very soluble in common
organic solvents, such as benzene, chloroform, and ethanol. Since
the dianion 3 is regarded as the masked framework of NAN, the
above-mentioned features enabled its use as the easily treatable
synthetic equivalent of the anionic form of NAN accompanied by
decarboxylation. Indeed, the dianion 3 reacts with ketones and
aldehydes to afford polyfunctionalized nitriles, such as glutaroni-
triles,7a
nitrile.7b Herein we provide a new synthetic protocol for
tionalized -nitronitriles 5 and 6 by a Michael addition reaction of
cyano-aci-nitroacetate 3 to functionalized alkenes 4. Additionally,
a
-nitro-
a,
b
-unsaturated nitriles,7a and
a
-nitro-d-keto
d-func-
a
* Corresponding author. Tel.: þ81 887 57 2517; fax: þ81 887 57 2520; e-mail
address: nishiwaki.nagatoshi@kochi-tech.ac.jp (N. Nishiwaki).
http://dx.doi.org/10.1016/j.tet.2014.07.013
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

H. Asahrara et al. / Tetrahedron 70 (2014) 6522e6528
6523
we also demonstrate a single step conversion of the Michael adduct
to a pyridine and a naphthyridine frameworks using the poly-
functionality of the Michael adducts.
any detectable double adducts 6bbeff (Table 2, entries 1e5). These
results suggested the substituent at the -position of Michael ac-
ceptors suppressed the second Michael addition reaction. It can be
attributed to the bulkiness of the counter cation, which presents
nearby the single adduct intermediate 50 (Scheme 3). On the other
hand, the reaction of 3 with methyl acrylate 4g, which has no
b
2. Results and discussion
Initially, the reaction of dianion 3 with 3-buten-2-one (4a) was
chosen as a model reaction, and N-methylpyrrolidine (2B) was used
as a base instead of 2A to avoid the undesired Michael addition
reaction of the amine to 4a (Scheme 2). When the dianion 3 was
subjected to reaction with equimolar 4a in acetonitrile at 30 ꢀC for
2 h, both single and double Michael adducts 5a8 and 6aa9 were
obtained in 35 and 38% yields, respectively (Table 1, entry 1). In
order to control the single/double Michael additions, the solvent,
reaction time, and temperature were investigated (Table 1). Al-
though the reaction proceeded efficiently in either nonpolar ben-
zene or polar ethanol, the ratio of 5a/6aa was not affected by the
polarity of the solvent (entries 2 and 3). Chloroform was found to be
somewhat effective for the predominant single addition; however,
all attempts for complete synthesis of the single Michael adduct 5a
failed (entries 5e8). To our great surprise, the single Michael adduct
5a was obtained as a sole product when 2A was used as a base
(entry 9). This suppression of the second Michael addition is
probably due to the competitive Michael addition of 2A, and the
adduct releases 4a gradually under equilibrium, which keeps the
concentration of 4a low in the reaction mixture (Scheme 2).10 On
the other hand, double adduct 6aa was exclusively obtained in 94%
yield by using 5 equiv of 4a. Consequently, the control of the single/
double Michael addition was successfully achieved.
substituent at the b-position, gave the double adduct 6gg in 9%
yield besides the single adduct 5g (49%) (entry 6). As expected, the
double adduct 6gg was afforded in 82% yield as a sole product upon
treatment of 3 with 5 equiv of 4g (entry 7). In the case of the
dibenzylideneacetone 4h, functionalized cyclohexanone 6hh11 was
obtained in 84% yield (entry 8).
As mentioned above, double Michael adduct 6bb was not
detected even under the severe conditions; employing the excess
amounts of 4b, higher temperature (>150 ꢀC), and longer reaction
time (48 h). Contrary to this, double adduct 6bb was obtained
quantitatively, when a mixture of isolated single adduct 5b and the
excess amounts of 4b was left standing without solvent at ambient
temperature for 24 h even in the absence of an amine (Scheme 4,
right). This is probably because the congestion around the active
methine group is relieved by the removal of the counter cation
through acidification (Scheme 3). This interesting result encour-
aged us to investigate the synthesis of an unsymmetrical double
Michael adducts. Indeed, desired unsymmetric double Michael
adducts 6ab were obtained in high yield (Scheme 4, left).
Both the single and double Michael adducts are useful synthetic
precursors due to their polyfunctionality. Forexample, single adduct
5a, which has both an acidic hydrogen and an appropriate func-
tionality, can be used as a substrate for the pseudo-intramolecular
Scheme 2. A plausible mechanism of reaction of 4a and 3 using pyrrolidine 2A as a base.
Table 1
Optimization of the reaction conditions for Michael addition of cyano-aci-nitroacetate 3 to 3-buten-2-one (4a)
Entry
Amine
Solv.
Temp/ꢀC
Time/h
Yield/%a,b
Total
Ratio
5a
6aa
5a:6aa
1
2
3
4
5
6
7
8
2B
2B
2B
2B
2B
2B
2B
2B
2A
2B
MeCN
PhH
30
30
30
30
30
30
0
60
30
50
2
2
2
2
0.5
6
2
2
2
73
100
93
100
56
100
39
100
100
94
35
40
40
56
38
57
19
61
>99
d
38
60
52
44
18
43
20
39
d
48:52
40:60
44:56
56:44
68:32
57:43
49:51
61:39
100:0
0:100
EtOH
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
9
10c
2
94
a
Determined by 1H NMR.
Based on 4a.
5 equiv of 4a were used.
b
c
To explore the scope and limitations of the Michael addition
process.12 Indeed, 63% of 2-amino-3-nitropyridine 712 was formed
when a mixture of keto nitrile 5a and 2 equiv of benzylamine in
acetonitrile was heated in a sealed tube at 120 ꢀC for 12 h (Scheme
5).13 The reaction proceeds in a similar manner to the dihydropyr-
idine synthesis, reported previously.12 The ammonium salt,
reaction of 3, various Michael acceptors were employed. The cyclic
enone 4b, the aromatic enones 4c, and 4d, methyl crotonate 4e, and
nitrostyrene 4f underwent Michael additions to afford the corre-
sponding single adducts 5bef in high to excellent yields without

6524
H. Asahrara et al. / Tetrahedron 70 (2014) 6522e6528
Table 2
Reaction of cyano-aci-nitroacetate 3 to Michael acceptors 4beh
Entry
1
Substrates 4
Equiv
1.0
Temp/ꢀC
60
Time/h
4
Products 5
Yield/%a,b
>99% dr¼1:1
2
3
4
1.0
1.0
5.0
60
40
80
20
20
24
87% dr¼5:1
78% dr¼1.7:1
61% dr¼1.5:1
5
1.0
50
12
75%f dr¼1.3:1
6
7
1.0
5.0
50
60
24
24
49% (6gg, 9%)
82% (5g, 0%)
8
1.0
80
24
81%g
aIsolated yield. The diastereomers were not separable, and this represents the total yield.
bThe diastereomeric ratio was determined by 1H NMR of the crude product.
cTol: 4-MeC6H4.
dPy: 2-Pyridyl.
eEthanol was used as a solvent.
fThe yield was determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard without isolation of 5f because of its instability.
gIsolated yield for cis isomer after purified by recrystallization.
Scheme 3. Steric hindrance of the Michael acceptor preventing the second addition.

H. Asahrara et al. / Tetrahedron 70 (2014) 6522e6528
6525
Scheme 4. Reaction of single adduct 5b to Michael acceptors 4a,b.
Scheme 5. Synthesis of vicinally functionalized pyridine 7 from single adduct 5a via pseudo-intramolecular process.
immediately formed upon treatment of the single adduct 5a with an
amine, liberates the amine under equilibrium. In this stage, the
amine is in close proximity to the cyano group of 5a (intimate pair),
and attacks the cyano group to construct a six-membered ring as
a result of the tandem cyclization. The subsequent dehydration and
air oxidation gives 2-amino-3-nitropyridine 7.13
Additionally, the double Michael adduct 6aa provided 2,7-
dimethyl-[1,8]-naphthyridine (8a)14 in 61% yields upon heating
with 5 equiv of ammonium acetate in acetonitrile at 120 ꢀC for 12 h. A
plausible mechanism is also depicted in Scheme 6. The reaction be-
tween the two carbonyl groups with ammonium acetate gives the
intermediate enamine 9, an intramolecular double cyclization fol-
lowed by aromatization to give the product 8a. To enhance the utility
of thismethod, we alsoexaminedthe synthesis of [1,8]-naphthyridine
from the pyridinium salt of isoxazolone 1 and Michael acceptor 4a
without purification of the double Michael adduct (Scheme 7). After
normal workup of Michael addition reaction, the residue was heated
with 5 equivofNH4OAc to afford [1,8]-naphthyridine8ain 45%overall
yield. This method was also applicable to benzoyl ethene 4i
(R1¼R2¼H, EWG¼PhCO) leading to 2,7-diphenylnaphthyridine 8i14
directly with 56% yield. The [1,8]-naphthyridine skeleton is widely
found in a biologically active substances16 and used as a ligand for
many metal complexes.17 This reaction is highly useful because the
naphthyridine skeleton is constructed in a single step, which was not
easily achieved by conventional methods.18,19 Additionally, this
method is multi-component reaction, which also fits the idea of
highly efficient green synthesis methodology.20
Scheme 6. A concise construction of [1,8]-naphthridine 8 via double cyclization/aro-
matization procedure from diketone 6aa.
6ab was demonstrated through the reaction of isolated single ad-
duct 5b with Michael acceptor 4a without solvent. As one of the
applications of the single Michael adduct 5a, polyfunctionalized
pyridine 7 was easily prepared in good yield via a pseudo-
intramolecular process. Additionally, the concise, double Michael
addition reaction, followed by intramolecular double cyclization
reaction upon treatment with ammonium acetate was successfully
achieved to afford [1,8]-naphthyridine 8.
3. Conclusions
4. Experimental section
In conclusion, we have demonstrated cyano-aci-nitroacetate 3
derived from nitroisoxazolone 1 can be regarded as a practically
usable and safe cyano(nitro)methylation agent, which reacts with
Michael acceptors 4 to afford both single/double adducts 5 and 6. In
addition, the synthesis of an unsymmetrical double Michael adduct
4.1. Typical procedure for Michael addition reaction of cyano-
aci-nitroacetate with Michael acceptor 4
To a solution of pyridinium salt 1 (0.25 mmol) in chloroform
(2 mL), amine 2B (0.5 mmol) was added and the resultant mixture

6526
H. Asahrara et al. / Tetrahedron 70 (2014) 6522e6528
Scheme 7. Synthesis of [1,8]-naphthridine 8 from the pyridinium salt of nitroisoxazolone 1.
was stirred several minutes until the salt was completely dissolved.
And then Michael acceptor 4 was added. After stirring of the so-
lution for 4 h at 30 ꢀC, 1 M HCl solution (1.5 mL) was added, and
extracted with chloroform (2ꢁ5 mL). The combined organic layer
was dried over MgSO4, filtered, and concentrated under reduced
pressure. The yield and diastereomer ratio of the product were
determined by 1H NMR integration of the crude product using
1,1,2,2-tetrachloroethane as an internal standard. Further purifica-
tion was achieved by flash column chromatography on silica gel
(hexane/EtOAc¼95/5). All products were isolated in almost pure
form but not stable to the elemental analysis.
J¼7.8 Hz, 1H), 8.67e8.69 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 38.4
(CH2), 43.6 (CH), 80.6 (CH), 111.3 (C), 122.0 (CH), 127.8 (CH), 128.1
(CH), 129.0 (CH), 129.4 (CH), 135.4 (C), 137.1 (CH), 149.1 (CH), 152.3
(C), 197.7 (C); IR (neat) 1691, 1571, 1396 cmꢂ1. HRMS (CI, Magnetic
field) m/z calcd for C16H14N3O3: 296.1035 (MþH)þ, found 296.1033.
4.1.4. Methyl 4-cyano-3-methyl-4-nitrobutanoate (5e). (28.5 mg,
61%); (1.5:1 diastereomer mixture), yellow oil. Major isomer: 1H
NMR (400 MHz, CDCl3)
d
1.19 (d, J¼6.8 Hz, 3H), 2.48e2.56 (m, 2H),
3.09e3.16 (m, 1H), 3.73 (s, 3H), 5.84 (d, J¼4.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d 15.4 (CH3), 33.6 (CH), 36.6 (CH2), 52.4 (CH3),
80.2 (CH), 110.5 (C), 171.1 (C); Minor isomer: 1H NMR (400 MHz,
4.1.1. 3-(Cyanonitromethyl)cyclohexan-1-one
>99%); (1:1 diastereomer mixture), yellow oil. Diastereomer A: 1H
NMR (400 MHz, CDCl3) 1.80e1.64 (m, 2H), 2.10e1.91 (m, 1H),
(5b). (46.0
mg,
CDCl3)
d
1.25 (d, J¼6.9 Hz, 3H), 2.54e2.66 (m, 2H), 2.97e3.02 (m,
1H), 3.72 (s, 3H), 5.59 (d, J¼5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
d 16.1 (CH3), 34.2 (CH), 36.1 (CH2), 52.3 (CH3), 80.2 (CH), 111.3 (C),
2.21e2.17 (m, 1H), 2.51e2.20 (m, 4H), 2.98e2.80 (m, 1H), 5.36 (d,
171.0 (C); IR (neat) 1730, 1580, 1337 cmꢂ1. HRMS (CI, Magnetic field)
m/z calcd for C7H11N2O4: 187.0719 (MþH)þ, found 187.0722.
J¼5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 23.6 (CH2), 26.2 (CH2),
40.5 (CH2), 40.9 (CH), 42.2 (CH2), 80.4 (CH), 110.4 (C), 206.1 (C);
Diastereomer B: 1H NMR (400 MHz, CDCl3)
d
1.80e1.64 (m, 2H),
4.1.5. 2,4-Dinitro-3-phenylbutanenitrile (5f). (NMR yield, 75%);
2.10e1.91 (m, 1H), 2.21e2.17 (m, 1H), 2.51e2.20 (m, 4H), 2.98e2.80
(1.3:1 diastereomer mixture), yellow oil. Major isomer: 1H NMR
(m, 1H), 5.27 (d, J¼5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
23.8
(400 MHz, CDCl3)
5.01e5.05 (m, 1H), 5.96 (d, J¼5.6 Hz, 1H), 7.25e7.31 (m, 2H),
7.40e7.44 (m, 3H); 13C NMR (100 MHz, CDCl3)
44.8 (CH), 74.6
(CH2), 78.3 (CH), 109.9 (C), 128.0 (CH), 129.9 (CH), 130.3 (C), 130.4
(CH). Minor isomer: 1H NMR (400 MHz, CDCl3)
4.48e4.51 (m, 1H),
d 4.56e4.62 (m, 1H), 4.86e5.00 (m, 1H),
(CH2), 27.4 (CH2), 40.4 (CH2), 40.9 (CH), 43.3 (CH2), 80.3 (CH), 110.5
(C), 206.1 (C); IR (neat) 1715, 1568, 1350 cmꢂ1. HRMS (CI, Magnetic
field) m/z calcd for C8H11N2O3: 183.0770 (MþH)þ, found 183.0770.
d
d
4.1.2. 3-Cyanonitromethyl-1,3-bis(4-methylphenyl)-1-propanone
4.86e5.00 (m, 1H), 5.01e5.05 (m, 1H), 5.76 (d, J¼5.6 Hz, 1H),
(5c). (70.8 mg, 87%); (5:1 diastereomer mixture), white solid, mp
7.25e7.31 (m, 2H), 7.40e7.44 (m, 3H); 13C NMR (100 MHz, CDCl3)
126e127 ꢀC. Major isomer: 1H NMR (400 MHz, CDCl3)
d
2.34 (s, 3H),
d 45.3 (CH), 74.4 (CH2), 78.1 (CH), 110.3 (C), 127.7 (CH), 130.0 (CH),
2.43 (s, 3H), 3.57e3.68 (m, 2H), 4.40e4.45 (m, 1H), 6.20 (d, J¼5.2 Hz
130.3 (CH), 130.8 (C). Satisfactory analytical data were not given
because of the instability of 5f.
1H), 7.17e7.19 (m, 2H), 7.22e7.30 (m, 4H), 7.83e7.87 (m, 2H); 13C
NMR (100 MHz, CDCl3)
d 21.1 (CH3), 21.7 (CH3), 40.1 (CH), 42.3
(CH2), 80.3 (CH), 110.9 (C), 128.0 (CH), 128.2 (CH), 129.5 (CH), 130.1
(CH), 131.8 (C), 133.3 (C), 139.2 (C), 145.2 (C), 195.7 (C); Minor iso-
4.1.6. Methyl 4-cyano-4-nitro-butanoate (5g). (21.2 mg, 49%);
brown oil. 1H NMR (400 MHz, CDCl3)
d 2.54e2.71 (m, 4H), 3.73 (s,
mer: 1H NMR (400 MHz, CDCl3)
d
2.33 (s, 3H), 2.42 (s, 3H),
3H), 5.59 (t, J¼7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 27.6 (CH2),
3.57e3.70 (m, 2H), 4.40e4.45 (m, 1H), 5.75 (d, J¼5.2 Hz 1H),
28.9 (CH2), 52.5 (CH3), 74.8 (CH), 111.7 (C), 171.4 (C); IR (neat) 1738,
1601, 1370 cmꢂ1. HRMS (CI, Magnetic field) m/z calcd for C6H9N2O4:
173.0562 (MþH)þ, found 173.0563.
7.19e7.22 (m, 2H), 7.24e7.30 (m, 4H), 7.83e7.85 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 21.1 (CH3), 21.7 (CH3), 38.9 (CH), 43.3 (CH2), 80.2
(CH), 111.3 (C), 127.8 (CH), 128.2 (CH), 129.6 (CH), 130.0 (CH), 132.2
(C), 133.6 (C), 139.1 (C), 144.9 (C), 195.6 (C); IR (KBr) 1684, 1572,
1410 cmꢂ1. HRMS (CI, Magnetic field) m/z calcd for C19H19N2O3:
323.1396 (MþH)þ, found 323.1394.
4.1.7. 5-Cyano-5-nitro-nonane-2,8-dione (6aa). (53.3 mg, 94%);
white solid, mp 77e78 ꢀC (from hexane/chloroform). 1H NMR
(400 MHz, CDCl3)
4H), 2.71e2.81 (m, 2H); 13C NMR (100 MHz, CDCl3)
32.4 (CH2), 38.1 (CH2), 88.9 (C), 113.8 (C), 204.1 (C); IR (KBr) 1703,
d
2.18 (s, 6H), 2.36e2.47 (m, 2H), 2.48e2.61 (m,
d
30.0 (CH3),
4.1.3. 3-Cyanonitromethyl-1-(2-pyridyl)-3-phenyl-1-propanone
(5d). (57.5 mg, 78%); (1.7:1 diastereomer mixture), yellow oil (The
isolated product was easily decomposed by heating over 60 ꢀC).
1560, 1370 cmꢂ1
. HRMS (CI, Magnetic field) m/z calcd for
C
10H15N2O4: 227.1032 (MþH)þ, found 227.1033.
Major isomer: 1H NMR (400 MHz, CDCl3)
d
3.88 (dd, J¼9.2, 19.1 Hz,
1H), 4.07 (dd, J¼5.0, 19.1 Hz, 1H), 4.44 (ddd, J¼5.0, 5.7, 9.2 Hz 1H),
6.10 (d, J¼5.7 Hz, 1H), 7.33e7.40 (m, 5H), 7.51e7.53 (m, 1H),
7.82e7.85 (m, 1H), 8.02 (d, J¼7.8 Hz, 1H), 8.67e8.69 (m, 1H); 13C
4.1.8. Dimethyl 4-cyano-4-nitro-heptanedioate (6gg). (53.0 mg,
82%); yellow solid, mp 33e34 ꢀC. 1H NMR (400 MHz, CDCl3)
d
2.39e2.54 (m, 4H), 2.61e2.71 (m, 4H), 3.72 (s, 6H); 13C NMR
NMR (100 MHz, CDCl3)
d
39.5 (CH2), 42.8 (CH), 80.4 (CH), 110.8 (C),
(100 MHz, CDCl3) d 29.2 (CH2), 33.7 (CH2), 52.5 (CH3), 88.5 (C), 113.3
122.0 (CH), 128.0 (CH), 128.2 (CH), 129.2 (CH), 129.2 (CH), 134.9 (C),
(C), 170.8 (C); IR (KBr) 1738, 1568, 1381 cmꢂ1. HRMS (CI, Magnetic
137.2 (CH), 149.2 (CH), 152.2 (C), 198.4 (C); Minor isomer: 1H NMR
field) m/z calcd for C10H15N2O6: 259.0930 (MþH)þ, found 259.0931.
(400 MHz, CDCl3)
18.6 Hz, 1H), 4.44 (ddd, J¼5.5, 6.7, 8.0 Hz 1H), 5.70 (d, J¼5.5 Hz, 1H),
7.33e7.40 (m, 5H), 7.51e7.53 (m, 1H), 7.82e7.85 (m, 1H), 7.98 (d,
d
3.88 (dd, J¼6.7, 18.6 Hz, 1H), 4.18 (dd, J¼8.0,
4.1.9. cis-4-Cyano-4-nitro-3,5-diphenylcyclohexanone (6hh). After
workup, 13:1 of cis:trans mixture was obtained and cis isomer was

H. Asahrara et al. / Tetrahedron 70 (2014) 6522e6528
6527
isolated by recrystallization from hexane/chloroform (64.9 mg,
81%); brown solid, mp 177e178 ꢀC. 1H NMR (400 MHz, CDCl3)
2.89
stirred several minutes until the salt was completely dissolved. And
then Michael acceptor 4 (1.3 mmol) was added. After stirring of the
solution for 4 h at 30 ꢀC, 1 M HCl solution (1.5 mL) was added, and
extracted with chloroform (2ꢁ5 mL). The combined organic layer
were dried over MgSO4, filtered, and evaporated to give double
Michael adduct 6, which was used for the next step without puri-
fication. The solution of 6 in acetonitrile (3 mL), ammonium acetate
(1.25 mmol) was added. The mixture was stirred at 120 ꢀC in
a sealed tube for 12 h. After removal of the solvent, the residue was
treated with column chromatography on silica gel to afford [1,8]-
naphthyridine 8a14 (17.8 mg, 45%, eluted with hexane/EtOAc¼80/
20) and 8i15 (39.5 mg, 56%, eluted with hexane/EtOAc¼80/20), re-
spectively. The product 8i was identified by comparison of NMR
spectra to those reported in the literature.
d
(dd, J¼4.0, 15.6 Hz, 2H), 3.32 (dd, J¼14.5, 15.6 Hz, 2H), 4.08 (dd,
J¼4.0, 14.5 Hz, 2H), 7.33e7.37 (m, 2H), 7.38e7.40 (m, 8H); 13C NMR
(100 MHz, CDCl3)
d 43.7 (CH2), 50.5 (CH), 97.5 (C), 111.5 (C), 128.1
(CH), 129.6 (CH), 130.0 (CH), 133.4 (C), 202.3 (C); IR (KBr) 1717, 1563,
1361 cmꢂ1. HRMS (CI, Magnetic field) m/z calcd for C19H17N2O3:
321.1239 (MþH)þ, found 321.1240.
4.2. Typical procedure for Michael addition reaction of single
adduct 5b with 4a,b
To
a single adduct 5b (0.25 mmol), Michael acceptor 4
(0.3 mmol) was added. The resulting mixture was stirred for 24 h at
60 ꢀC, and unreacted Michael acceptor was evaporated under vacuo
to afford pure double adduct 6. Further purification was performed
by recrystallization from hexane/chloroform.
Acknowledgements
The authors would like to thank Prof. Dr. S. Minakata (De-
partment of Applied Chemistry, Graduate School of Engineering,
Osaka University) for the HRMS analysis.
4.2.1. 3-(1-Cyano-1-nitro-4-oxopentyl)-cyclohexanone(6ab). (53.1 mg,
84%); (1:1 diastereomer mixture), white solid, mp 124e125 ꢀC. Di-
astereomer A: 1H NMR (400 MHz, CDCl3)
d
1.60e1.77 (m, 2H), 2.17 (s,
3H), 2.14e2.78 (m, 11H); 13C NMR (100 MHz, CDCl3)
d
23.8 (CH2), 26.4
Supplementary data
(CH2), 30.0 (CH3), 30.3 (CH2), 38.1 (CH2), 40.4 (CH2), 42.5 (CH2), 45.6
(CH), 93.8 (C), 112.8 (C), 204.2 (C), 206.0 (C); Diastereomer B: 1H NMR
1H and 13C NMR spectra of products 5beg, 6aa, 6ab, 6bb, 6hh,
and 6gg, and crystallographic data of 6aa. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.07.013.
(400 MHz, CDCl3)
d
1.60e1.77 (m, 2H), 2.15 (s, 3H), 2.14e2.78 (m, 11H);
23.5 (CH2), 26.5 (CH2), 30.0 (CH3), 30.3
13C NMR (100 MHz, CDCl3)
d
(CH2), 38.0 (CH2), 40.5 (CH2), 42.3 (CH2), 45.5 (CH), 93.9 (C), 112.6 (C),
204.0 (C), 206.1 (C); IR (KBr) 1713, 1562, 1355 cmꢂ1. HRMS (CI, Mag-
netic field) m/z calcd for C19H15Cl2NO: 343.0531 (MþH)þ, found
343.0534.
References and notes
1. For a review, see: Kislyi, V. V.; Samet, A. V.; Semenov, V. V. Curr. Org. Chem. 2001,
5, 553e570.
4.2.2. Cyanonitro-di-(3-oxochclohexyl)methane (6bb). (70.1 mg,
>99%); pale yellow solid, mp 145e146 ꢀC. 1H NMR (400 MHz,
2. For recent examples, see: (a) Amantini, D.; Fringuelli, F.; Piermatti, O.; Pizzo, F.;
Vaccaro, L. Green Chem. 2001, 3, 229e232; (b) Liu, S.; Haller, M. A.; Ma, H.;
Dalton, L. R.; Jang, S.-H.; Jen, A. K.-Y. Adv. Mater. 2003, 15, 603e607; (c) Vali-
zadeh, H.; Fringuelli, F.; Girotti, R.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Org. Lett.
2006, 8, 5741e5744.
3. (a) Ried, W.; Kohler, E.; Konigstein, F. J. Justus Liebigs Ann. Chem. 1956, 598,
145e158; (b) Valizadeh, H. Synth. Commun. 2005, 35, 785e790; (c) Fringuelli, F.;
Lanari, D.; Pizzo, F.; Vaccaro, L. Eur. J. Org. Chem. 2008, 23, 3928e3932; (d)
Tamaddon, F.; Tayefi, M.; Hosseini, E.; Zare, E. J. Mol. Catal. A Chem. 2013, 366,
36e42.
CDCl3)
2.15e2.38 (m, 7H), 2.44e2.65 (m, 3H), 2.68e2.78 (m, 3H); 13C NMR
(100 MHz, CDCl3) 23.7 (CH2), 23.8 (CH2), 26.1 (CH2), 27.0 (CH2),
d 1.45e1.61 (m, 1H), 1.62e1.83 (m, 3H), 1.84e1.95 (m, 1H),
d
40.6 (CH), 40.7 (CH), 41.1 (CH2), 41.9 (CH2), 42.3 (CH2), 42.5 (CH2),
97.2 (C), 112.9 (C), 205.6 (C), 205.7 (C); IR (KBr) 1715, 1562,
1348 cmꢂ1. HRMS (CI, Magnetic field) m/z calcd for C14H19N2O4:
279.1345 (MþH)þ, found 279.1344.
4. Grivas, J. C.; Taurins, A. Can. J. Chem. 1959, 37, 1266e1267.
5. Kislyi, V. P.; Laikhter, A. L.; Ugrak, B. I.; Semenov, V. V. Russ. Chem. Bull. 1994, 43,
70e74.
4.3. Procedure for the synthesis of 2-amino-3-nitropyridine 7
6. Thomas, C. J. Chem. Eng. News 2009, 87, 4e5.
7. (a) Nishiwaki, N.; Nogami, T.; Tanaka, C.; Nakashima, F.; Inoue, Y.; Asaka, N.;
Tohda, Y.; Ariga, M. J. Org. Chem. 1999, 64, 2160e2162; (b) Nishiwaki, N.; No-
gami, T.; Ariga, M. Heterocycles 2008, 75, 675e681.
8. Nishiwaki, N.; Hirao, S.; Sawayama, J.; Saigo, K.; Kobiro, K. Chem. Commun. 2011,
4938e4940.
To a solution of single adduct 5b (0.25 mmol) in acetonitrile
(3 mL), benzylamine (0.5 mmol) was added, and heated at 120 ꢀC in
a sealed tube for 12 h. After removal of the solvent, the residue was
treated with column chromatography on silica gel to afford 2-
amino-3-nitropyridine 7 (38.2 mg, 63%, eluted with dichloro-
methane). The product 7 was identified by comparison of spectral
data with authentic sample.
9. The structure of 6aa was determined based on the X-ray crystallography.
Crystallographic data for the structure reported in this paper have been de-
posited with the Cambridge Crystallographic Data Center as supplementary
publication no. CCDC-992171. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 1223
336 033; e-mail: deposit@ccdc.cam.ac.uk).
10. Michael adduct between pyrrolidine 2a with 4a was detected by 1H NMR
spectrum, see Supplementary data.
4.4. Synthesis of [1,8]-naphthyridine 8 from double Michael
adduct 6
11. It is reported that cis isomer is thermodynamically stable and predominantly
formed in the case of two substituents at the 1-position of 2,5-
diphenylcyclohexan-4-one were different. Indeed, the cis structure was as-
signed by the comparison of 1H NMR spectra between 6hh and a reported
analogue. For reference, see: Rowland, A. T.; Filla, S. A.; Coutlangus, M. L.;
Winemiller, M. D.; Chamberlin, M. J.; Czulada, G.; Johnson, S. D. J. Org. Chem.
1998, 63, 4359e4365.
To a solution of double adduct 6aa (0.20 mmol) in acetonitrile
(3 mL), ammonium acetate (1.0 mmol) was added, and heated at
120 ꢀC in a sealed tube for 12 h. After removal of the solvent, the
residue was treated with column chromatography on silica gel to
afford [1,8]-naphthyridine 8a14 (19.4 mg, 61%, eluted with hexane/
EtOAc¼80/20). The product 8a was identified by comparison of
NMR spectra to those reported in the literature.
12. (a) Nishiwaki, N.; Kakutani, K.; Tamura, M.; Ariga, M. Chem. Lett. 2009, 38,
680e681; (b) Nishiwaki, N. Heterocycles 2013, 87, 967e990.
13. For recent examples of 2-amino-3-nitropyridine derivatives as key in-
termediate for the synthesis of bioactive compound, see: (a) Chen, G.; Liu, Z.;
Zhang, Y.; Shan, X.; Jiang, L.; Zhao, Y.; He, W.; Feng, Z.; Yang, S.; Liang, G. ACS
Med. Chem. Lett. 2013, 4, 69e74; (b) Wang, Y.; Xu, Z.-L.; Ai, J.; Peng, X.; Lin, J.-P.;
Ji, Y.-C.; Geng, M.-Y.; Long, Y.-Q. Org. Biomol. Chem. 2013, 11, 1545e1562; (c)
Roethle, P. A.; McFadden, R. M.; Yang, H.; Hrvatin, P.; Hui, H.; Graupe, M.;
Gallagher, B.; Chao, J.; Hesselgesser, J.; Duatschek, P.; Zheng, J.; Lu, B.; Tumas, D.
B.; Perry, J.; Halcomb, R. L. J. Med. Chem. 2013, 56, 7324e7333 Pyridine de-
rivative 7 is commercially available.
4.5. Synthesis of [1,8]-naphthyridine 8 from pyridinium salt 1
To a solution of pyridinium salt 1 (0.25 mmol) in chloroform
(2 mL), amine (0.5 mmol) was added and the resultant mixture was

6528
H. Asahrara et al. / Tetrahedron 70 (2014) 6522e6528
14. (a) Allen, C. F. H. Chem. Rev. 1950, 47, 275e305; (b) Paudler, W. W. J. Heterocycl.
Chem. 1967, 4, 284e289; (c) Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Russ.
Chem. Rev. 2000, 69, 201e220; (d) Brown, D. J.; Ellman, J. A.; Taylor, E. C. The
Naphthyridines in the Chemistry of Heterocyclic Compounds; Wiley: Hoboken, NJ,
2008, Vol. 63.
18. The major synthetic approach to prepare the [1,8]-naphthyridine system in-
volves condensation of 2-aminopyridines with carbonyl compounds
€
€
(Friedlander reaction). For a recent review of Friedlander reaction, see: Marco-
Contelles, J.; Perez-Mayoral, M. E.; Samadi, A.; Carreiras, M. C.; Soriano, E. Chem.
Rev. 2009, 109, 2652e2671.
15. (a) Dietrich-Buchecker, C. O.; Marnot, P. A.; Sauvage, J. P. Tetrahedron Lett. 1982,
23, 5291e5294; (b) Ehlers, P.; Petrosyan, A.; Ghochikyan, T. V.; Saghyan, A. S.;
Neubauer, A.; Lochbrunner, S.; Langer, P. Synlett 2013, 359e362.
16. For selected reviews, see: (a) Encyclopedia of the Alkaloids; Glasby, J. S., Ed.;
Plenum: New York, NY, 1975; (b) Stanforth, S. P. In Comprehensive Heterocyclic
Chemistry II; Ramsden, C. A., Ed.; Pergamon: Tarrytown, USA, 1996; Vol. 7,
Chapter 7, 15. For recent examples, see: (c) Virek, K.; Maun, J.; Anu, T. S.; Alka,
M.; Vinod, S.; Pratibha, S.; Pramod, K. S.; Raghuveer, I.; Burman, C. Eur. J. Med.
Chem. 2009, 44, 3356e3362; (d) Kumar, M. R.; Laxminarayana, E.; Ramesh, D.;
Sreenivasulu, B.; Chary, M. T. Int. J. Chem. Sci. 2010, 8, 2025e2036.
19. Examples for the synthesis of pharmaceuticals containing [1,8]-naphthyridines
system, see: (a) Lesher, G. Y.; Froelich, E. J.; Gruett, M. D.; Bailey, J. H.; Brundage,
R. P. J. Med. Chem. 1962, 5, 1063e1065; (b) Ferrarini, P. L.; Mori, C.; Badawneh,
M.; Calderone, V.; Calzolari, L.; Loffredo, T.; Martinotti, E.; Saccomanni, G. Eur. J.
Med. Chem. 1998, 33, 383e397; (c) Iaroshenko, V. O.; Knepper, I.; Zahid, M.;
Kuzora, R.; Dudkin, S.; Villinger, A.; Langer, P. Org. Biomol. Chem. 2012, 10,
2955e2959.
20. Examples for the synthesis of [1,8]-naphthyridines via multicomponent strat-
€
egies, see: (a) Schramm, O. G.; Oeser, T.; Muller, T. J. J. J. Org. Chem. 2006, 71,
3494e3500; (b) Goswami, S. V.; Thorat, P. B.; Khade, B. C.; Bhusare, S. R. Chem.
Biol. Interface 2012, 2, 228e233; (c) Siddiqui, I. R.; Rai, P.; Rahila; Srivastava, A.;
Srivastava, A.; Srivastava, A. New J. Chem. 2013, 37, 3798e3804; (d) Fu, L.; Lin,
W.; Hu, M.-H.; Liu, X.-C.; Huang, Z.-B.; Shi, D.-O. ACS Comb. Sci. 2014, 16,
238e243.
17. For recent examples, see: (a) Ismayilov, R. H.; Wang, W.-Z.; Lee, G.-H.; Yeh, C.-Y.;
ꢀ
Hua, S.-A.; Song, Y.; Rohmer, M.-M.; Benard, M.; Peng, S.-M. Angew. Chem., Int.
Ed. 2011, 50, 2045e2048; (b) Liu, X.; Pan, S.; Wu, J.; Wang, Y.; Chen, W. Or-
ganometallics 2013, 32, 209e217; (c) Jin, S.; Wang, D. Synth. React. Inorg. Met.-
Org. Chem. 2013, 43, 562e574.