Diversity synthesis of N-substituted 2-amino-l,6-naphthyridine derivatives under microwave irradiation

Article abstract of DOI:10.1021/cc900030e

A sequential three-component reaction of 3, 5-diarylidenepiperidm-4-one, malononitrile, and amine (such as aromatic amine, cyclopropanamine, and NH ₄OAc) in acetic acid under microwave irradiation has been developed. In this one-pot reaction, a series of new N-substituted 2-amino-l, 6-naphthyridine derivatives were synthesized with excellent yields. This method has the advantages of operational simplicity and increased safety for small-scale fast synthesis of N-aryl 2-amino-l, 6-naphthyridines for biomedical screening.

Full text of DOI:10.1021/cc900030e

16
J. Comb. Chem. 2010, 12, 16–19
Article
Diversity Synthesis of N-Substituted 2-Amino-1,6-naphthyridine
Derivatives under Microwave Irradiation
Zheng-Guo Han,† Chun-Bao Miao,‡ Feng Shi,† Ning Ma,† Ge Zhang,† and
Shu-Jiang Tu*,†
School of Chemistry and Chemical Engineering, Xuzhou Normal UniVersity, Xuzhou, Jiangsu, 221116,
P.R. China, and School of Chemistry and Chemical Engineering, Jiangsu Polytechnic UniVersity,
Changzhou, Jiangsu, 213164, P.R. China
ReceiVed February 23, 2009
A sequential three-component reaction of 3,5-diarylidenepiperidin-4-one, malononitrile, and amine (such as
aromatic amine, cyclopropanamine, and NH4OAc) in acetic acid under microwave irradiation has been
developed. In this one-pot reaction, a series of new N-substituted 2-amino-1,6-naphthyridine derivatives
were synthesized with excellent yields. This method has the advantages of operational simplicity and increased
safety for small-scale fast synthesis of N-aryl 2-amino-1,6-naphthyridines for biomedical screening.
Introduction
piperidin-4-one 1, malononitrile 2, and amine 3 in acetic acid
(HOAc) (Scheme 1). It is an efficient and promising method
to construct the 2-amino-1,6-naphthyridine skeleton.
Various naphthyridine derivatives have received considerable
attention over the past years because of their wide range of
biological activities, such as antitumor, anti-inflammatory, and
antifungal properties.1-4 Compounds incorporating this motif
are useful in the treatment of hypertension, myocardial infarc-
tion, hyperlipidemia, cardiac arrhythmia, and rheumatoid
arthritis.5-8 Therefore, the synthesis of these compounds is of
great significance. A number of reports on this topic have
appeared in the literature.2-4,6 El-Subbagh et al. have reported
the synthesis of 1,6-naphthyridine derivatives through two-
component reactions between R,ꢀ-unsaturated ketones and
cyanoacetamide in BuOH catalyzed by piperidine.2 Although
the above method offered a synthetic approach to this class of
important compounds, quite surprisingly, the investigation of
N-aryl 2-amino-1,6-naphthyridines has not stimulated much
interest so far. Thus, development of an efficient and simple
method for the synthesis of N-aryl substituted 1,6-naphthyridines
is still desired.
Results and Discussion
Initially, the three-component reaction of 3,5-diben-
zylidene-1-methylpiperidin-4-one 1a (1 mmol) with equimo-
lar amounts of malononitrile 2 and aniline 3 was employed
to optimize the reaction conditions. As illustrated in Table
1, acetic acid (HOAc) was preferred as the optimal solvent
and 110 °C was chosen as the most suitable reaction
temperature (Scheme 2).
On the basis of the optimized conditions [HOAc, 110 °C,
200W (maximum power)], reactions of different substrates
1, malononitrile 2, and aniline 3a were performed, and a
series of N-substituted 2-amino-1,6-naphthyridine derivatives
Scheme 1
The diversity generating potential of multicomponent reactions
(MCRs) has been recognized, and their utility in preparing libraries
to screen for functional molecules is well appreciated.9,10 Microwave-
assisted organic synthesis has rapidly gained popularity since it
accelerates a variety of synthetic transformations,11 and have the
prominent advantages of short reaction time and high yield.12
With the aim to develop more efficient synthetic processes
and minimized byproducts, and in continuation of our recent
interest in the construction of heterocyclic scaffolds,13 we
herein describe a practical, inexpensive and rapid microwave
(MW)-promoted method for diversity synthesis of 2-amino-
1,6-naphthyridine derivatives via MCRs of 3,5-diarylidene-
Table 1. Optimization for the Synthesis of 4a
entry
solventa
temp (°C)
time (min)
yield (%)
1
2
3
4
5
6
7
8
9
HOAc
Glycol
DMF
EtOH
HOAc
HOAc
HOAc
HOAc
HOAc
100
100
100
100
90
110
120
130
140
7
7
7
7
8
5
5
4
4
92
35
22
32
89
94
92
91
88
* Towhomcorrespondenceshouldbeaddressed.E-mail:laotu2001@263.net.
Phone: 0086-516-83500065. Fax: 0086-516-83500065.
† Xuzhou Normal University.
‡ Jiangsu Polytechnic University.
a The volume of solvent is 2.0 mL.
10.1021/cc900030e CCC: $40.75  2010 American Chemical Society
Published on Web 10/23/2009

N-Substituted 2-Amino-1,6-naphthyridine Derivatives
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 17
Scheme 2
To expand the scope of aromatic amines substrates, we
used various 3,5-dibenzylidenepiperidine-4-ones and mal-
ononitrile as model substrates to examine various aromatic
amines 3 including 4-chlorobenzenamine 3b, 4-methoxy-
benzenamine 3c, 2-methoxybenzenamine 3d, p-toluidine 3e,
3-toluidine 3f, and naphthalen-1-amine 3g. In all these cases,
the reactions proceeded steadily to produce corresponding
N-aryl substituted 2-amino-1,6-naphthyridines in good to
excellent yields of 89-92% (Table 2, entries 1-32).
To further expand the scope of the present method, the
replacement of aromatic amines with, cyclopropanamine 3h,
NH4OAc 3i, and methylamine 3j were employed in the
chemistry. To our delight, under the optimized conditions
were synthesized with good yields. The results (Table 2,
entries 1-15) indicated that substrates 1 bearing both
electron-donating groups (such as alkoxy and methyl) and
electron-withdrawing groups (such as nitro or halide) can
be involved in these MCRs to afford desired products 4 with
high yields. So it is concluded that the electronic nature of
the substituents has no significant effect on this reaction.
Table 2. Synthesis of N-Aryl Substituted 1,6-Naphthyridines 4 under Microwave Irradiation
entry
4
R
R1
R2
time/min
yield/%
Mp/°C
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Methyl
Methyl
Benzyl
Benzyl
Benzyl
Benzyl
Methyl
Methyl
Methyl
Benzyl
Methyl
Methyl
Methyl
Benzyl
Methyl
C6H5 (1a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
Phenyl (3a)
4-ClC6H4 (3b)
4-ClC6H4 (3b)
4-ClC6H4 (3b)
4-ClC6H4 (3b)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
4-CH3OC6H4 (3c)
2-CH3OC6H4 (3d)
4-CH3C6H4 (3e)
4-CH3C6H4 (3e)
3-CH3C6H4 (3f)
Naphthalen (3g)
Naphthalen (3g)
5
5
5
6
6
6
8
6
6
7
7
8
7
7
9
6
6
6
6
6
8
7
6
6
9
6
6
6
6
5
8
8
94
94
96
89
92
93
92
93
94
93
89
91
90
91
92
92
91
90
90
91
91
90
91
92
90
91
92
91
92
90
90
91
229-231
244-246
253-255
268-270
244-247
243-245
233-235
232-233
243-245
249-252
259-261
251-253
197-199
229-231
240-242
220-222
247-249
230-233
238-241
217-219
225-227
227-230
176-178
238-241
232-233
229-231
218-220
230-232
228-230
215-218
209-211
204-206
4-FC6H4 (1b)
4-ClC6H4 (1c)
4-BrC6H4 (1d)
3-NO2C6H4 (1e)
4-NO2C6H4 (1f)
4-CH3C6H4 (1g)
C6H5 (1h)
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4-FC6H4 (1i)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
4-ClC6H4 (1j)
4-BrC6H4 (1k)
4-CH3C6H4 (1l)
3-NO2C6H4 (1m)
4-NO2C6H4 (1n)
4-CH3OC6H4 (1o)
C6H5 (1h)
4-ClC6H4 (1j)
3-NO2C6H4 (1e)
2-Thienyl (1p)
2-Thienyl (1q)
4-CH3C6H4 (1l)
4-ClC6H4 (1j)
4-FC6H4 (1i)
4-ClC6H4 (1c)
4-CH3OC6H4 (1r)
2-Thienyl (1p)
4-ClC6H4 (1j)
3-NO2C6H4 (1e)
2-Thienyl (1p)
3-NO2C6H4 (1e)
4-CH3C6H4 (1l)
4-CH3C6H4 (1g)
4s
4t
4u
4v
4w
4x
4y
4z
4aa
4ab
4ac
4ad
4ae
4af
Table 3. Synthesis of N-Substituted 1,6-Naphthyridines 4 under Microwave Irradiation
entry
4
R
R1
R2
time/min
yield/%
Mp/°C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
4ap
4aq
4ar
4as
4at
4au
4av
4aw
4ax
4ay
4az
Benzyl
Benzyl
Benzyl
Benzyl
Methyl
Methyl
Methyl
Methyl
Methyl
Benzyl
Benzyl
Benzyl
Benzyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
4-FC6H4 (1i)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
Cyclopropyl (3h)
H (3i)
H (3i)
H (3i)
H (3i)
H (3i)
H (3i)
H (3i)
H (3i)
Me (3j)
7
8
8
10
10
7
8
6
7
8
8
5
5
7
8
5
4
4
92
89
90
89
91
92
90
92
89
92
91
89
90
92
90
91
93
91
90
85
202-204
214-216
177-179
219-221
195-197
220-222
226-228
194-196
240-242
195-197
202-204
219-222
200-202
254-256
239-240
229-231
256-258
>300
4-BrC6H4 (1k)
4-CH3C6H4 (1l)
4-CH3OC6H4 (1o)
4-CH3OC6H4 (1r)
4-CH3C6H4 (1g)
4-BrC6H4 (1d)
4-FC6H4 (1b)
3-NO2C6H4 (1e)
2-Thienyl (1q)
4-ClC6H4 (1j)
2-Thienyl (1q)
4-NO2C6H4 (1n)
4-CH3C6H5 (1g)
4-CH3OC6H4 (1r)
4-ClC6H4 (1c)
4-FC6H4 (1b)
4-NO2C6H4 (1f)
3-NO2C6H4 (1e)
4-CH3C6H4 (1g)
4
8
220-221
230-231

18 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Han et al.
Scheme 3
described above, the reactions proceeded smoothly to afford
a sets of N-substituted 2-amino-1,6-naphthyridines in good
to excellent yields (Table 3, entries 1-20). The results
showed that the reaction is suitable not only for aromatic
amines, but also for aliphatic amines.
Encouraged by the above interesting results, we also
attempted to synthesize non-symmetric substrates 1 to further
broaden the scope of this three-component reaction. How-
ever, we have not achieved good results yet since very
complex mixtures were generated.
2-amino-1,6-naphthyridine derivatives with a new substitu-
tion pattern under microwave irradiation. In addition, the
procedure offers several advantages including operational
simplicity, and increased safety for small-scale high-speed
synthesis, which make it a useful and attractive process for
the synthesis of structure-diversity N-substituted 2-amino-
1,6-naphthyridines. Moreover, this series of N-substituted
2-amino-1,6-naphthyridine derivatives may provide a new
substitution pattern of biological active compounds for
biomedical screening.
The mechanism for the formation of N-substituted 2-amino-
1,6-naphthyridines 4 includes Michael addition, nucleophilic
addition, cyclization, and subsequently aromatization (Scheme
3), which is similar to that we reported.14
Acknowledgment. We are grateful to financial support
from the National Science Foundation of China (Nos.
20672090 and 20810102050), Natural Science Foundation
of the Jiangsu Province (No. BK2006033), Six Kinds of
Professional Elite Foundation of the Jiangsu Province (No.
06-A-039), the Qing Lan Project (No.08QLT001), and
Jiangsu Provincial Key Laboratory of Fine Petrochemical
Technology (No.KF0807).
The structures of all the synthesized compounds were
established on the basis of their spectroscopic data. The IR
spectrum of compound 4b showed strong absorptions at 3317
cm-1 due to the NH group, and at 2217 cm-1 due to the CN
1
group. The H NMR spectrum of 4b showed a singlet at δ
) 9.06 due to the NH proton and a singlet at δ 7.81 due to
the )CH proton. Moreover, the structure of 4ar was
established by X-ray crystallography (Figure 1).
Supporting Information Available. Representative ex-
perimental procedures, spectral data of compounds 4a-4az,
and crystallographic information file (CIF) of 4ar. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Conclusion
In conclusion, we have demonstrated a simple, efficient
and practical method for the synthesis of a wide range of
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Figure 1. ORTEP drawing of 4ar

N-Substituted 2-Amino-1,6-naphthyridine Derivatives
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CC900030E