An efficient and chemoselective synthesis of 1,6-naphthyridines and pyrano[3,2-c]pyridines under microwave irradiation

Article abstract of DOI:10.1055/s-0028-1088052

A series of 1,6-naphthyridines and pyrano[3,2-c]pyridines were selectively synthesized via microwave-assisted reactions controlled by the nature of the solvent. This has resulted in an efficient and promising synthetic method for constructing the 1,6-naph

Full text of DOI:10.1055/s-0028-1088052

PAPER
1639
An Efficient and Chemoselective Synthesis of 1,6-Naphthyridines and
Pyrano[3,2-c]pyridines under Microwave Irradiation
C
hemoselective
h
S
ynthesis
o
e
f
1,6-Napht
n
hyridines an
g
-
-
c
]pyridi
G
nes uo Han, Shu-Jiang Tu,* Bo Jiang, Shu Yan, Xiao-Hong Zhang, Shan-Shan Wu, Wen-Juan Hao,
Xu-Dong Cao, Feng Shi, Ge Zhang, Ning Ma
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou, Jiangsu 221116, P. R. of China
Fax +86(516)83500065; E-mail: laotu2001@263.net
Received 6 December 2008; revised 14 January 2009
piperidine as catalyst2,3 and (b) the use of piperidone via
multiple steps to obtain the target compounds.5 However,
these methods suffer from time-consuming and complex
synthetic paths. Thus, the development of a simple and
rapid method for the synthesis of these heterocyclic com-
pounds is strongly desired.
Abstract: A series of 1,6-naphthyridines and pyrano[3,2-c]py-
ridines were selectively synthesized via microwave-assisted reac-
tions controlled by the nature of the solvent. This has resulted in an
efficient and promising synthetic method for constructing the 1,6-
naphthyridine and pyrano[3,2-c]pyridine skeletons.
Key words: solvent-dependent chemoselectivity, 1,6-naphthy-
ridines, pyrano[3,2-c]pyridines
In the context of our interest in the design and develop-
ment of useful tactics and strategies for the synthesis of
heterocyclic compounds,9 we were pleased to find that
1,6-naphthyridine and pyrano[3,2-c]pyridine derivatives
can be efficiently synthesized via microwave-assisted
chemoselective reactions controlled by the nature of the
solvent (Scheme 1). To the best of our knowledge, the sol-
vent-dependent chemoselective synthesis of 1,6-naphthy-
ridines and pyrano[3,2-c]pyridines has been seldom
investigated.
Chemoselectivity is a key issue to be controlled in organic
synthesis. In particular, chemoselectivity is synthetically
useful because it gives one of several products selectively
from the same substrate without the need to separate the
products from a product mixture. It continues to be devel-
oped as organic synthesis strives for ever-increasing lev-
els of efficiency. As a result, many studies have focused
on the chemoselectivity of reactions.1 In recent years,
many reports have dealt with the control of chemoselec-
tivity of reactions with metal catalysts,1a–e while solvent-
dependent chemoselective reactions have been researched
in relatively few papers.1g–i Despite these achievements,
the development of highly solvent-dependent chemose-
lective reactions is still of current interest.
Choosing an appropriate solvent is of crucial importance
not only for successful microwave-promoted syntheses
but also for the effective control of chemoselective reac-
tions. In order to choose the optimum solvent, the micro-
wave-assisted reaction of equimolar amounts of chalcone
1b (R1 = 4-Tol, R2 = Me) and malononitrile (2) in the pres-
ence of ammonium acetate was examined at 110 °C, using
acetic acid, ethanol, ethylene glycol, water or N,N-di-
methylformamide as solvent. All the reactions were car-
ried out under microwave irradiation (initial power: 150
W, maximum power: 200 W). The results of the screening
of these solvents are presented in Table 1 (entries 1–5).
When ethylene glycol, water or ethanol was selected as
the solvent, compound 3b was obtained as the main prod-
uct and only a small quantity of 4b was formed. In con-
trast, when acetic acid was used as the solvent, 4b was
obtained in 92% yield (entry 4). Moreover, only the prod-
uct 3b was obtained in N,N-dimethylformamide (entry 5).
Various naphthyridine and pyrano[3,2-c]pyridine deriva-
tives have received considerable attention over the past
years because of their wide range of biological activities,
including antitumor, anti-inflammatory and antifungal
properties.2–4 Furthermore, compounds incorporating
naphthyridine are useful in the treatment of hypertension,
myocardial infarction, hyperlipidemia, cardiac arrhyth-
mia and rheumatoid arthritis.5–8 Therefore, a number of
reports for the synthesis of these molecules have been
published, such as (a) the reaction of dibenzylidene-4-pi-
peridones with cyanoacetamide (or malononitrile) using
R1
O
R1
R1
R1
O
NH2
CN
CN
CN
N
NH2
CN
NH4OAc
DMF
NH4OAc
AcOH
+
N
N
R2
N
R2
R2
R1
R1
3
1
2
4
Scheme 1
SYNTHESIS 2009, No. 10, pp 1639–1646
x
x.
x
x
.
2
0
0
9
Advanced online publication: 20.04.2009
DOI: 10.1055/s-0028-1088052; Art ID: F28408SS
© Georg Thieme Verlag Stuttgart · New York

1640
Z.-G. Han et al.
PAPER
clizes to ultimately afford compound 4. In N,N-dimethyl-
formamide, however, the intermediate of the addition is
the enol 8, which cyclizes to yield compound 3. The sug-
gested pathways for the formation of compounds 4 and 3
are illustrated in Scheme 2 and Scheme 3, respectively.
Table 1 Optimization of Chemoselectivity Conditions in the Syn-
thesis of Compounds 3b and 4b
Entry
Solventa
Solvent Ratio Yieldb (%)
4b
3b
78
65
45
1
1
2
EtOH
6
4
Furthermore, a study on the effect of the acidity of the re-
action solution was conducted with the same substrate 1b
(see Table 1, entries 6–12). Increasing the proportion of
N,N-dimethylformamide in the mixed solvent acetic acid–
N,N-dimethylformamide to a ratio of 1:1 and 1:2 resulted
in a higher yield of product 3b, to 6% and 55%, respec-
tively (entries 8 and 9). When the volume/volume ratio of
the mixed solvent was increased to 1:3, compound 3b was
obtained as the main product (entry 10). Moreover, when
chalcone 1b was reacted with an equimolar amount of ma-
lononitrile (2) and excess ammonium acetate in the mixed
solvent formic acid–N,N-dimethylformamide (1:3), the
yield of product 3b was 74%, while the yield of product
4b was 13% (entry 12). However, when the formic acid of
the mixed solvent was replaced with trifluoroacetic acid,
only product 4b was obtained (entry 11). These results in-
dicate that the acidity of the solvent has obvious effects on
the formation of products 3b and 4b.
HOCH2CH2OH
H2O
3
2
4
AcOH
92
0
5
DMF
91
2
6
AcOH–DMF
AcOH–DMF
AcOH–DMF
AcOH–DMF
AcOH–DMF
TFA–DMF
HCO2H–DMF
3:1
2:1
1:1
1:2
1:3
1:3
1:3
87
84
80
34
4
7
3
8
6
9
55
84
0
10
11
12
56
13
74
a Volume of solvent = 2.0 mL.
b Isolated yields.
In a further study, the microwave-assisted reaction of
equimolar amounts of chalcone 1b and malononitrile (2)
was carried out in N,N-dimethylformamide without am-
monium acetate, which resulted in 3b in good yield.
Therefore, ammonium acetate plays an unessential role in
the synthesis of the pyrano[3,2-c]pyridines.
It is worth noting that the reaction could therefore be con-
trolled to exclusively yield 4b or 3b by varying the reac-
tion medium (Scheme 1).
The effect of temperature on the reaction using the same
reagents, in N,N-dimethylformamide and in acetic acid, at
temperatures ranging from 80 to 140 °C, in increments of
10 °C, was investigated. The results are summarized in
Table 2. The yield of product 4b was increased and the re-
action time was shortened when the temperature was in-
creased from 80 to 110 °C (entries 1–4); however, further
Thus, the question is, why is there selective formation of
product 4 in acetic acid and selective formation of product
3 in N,N-dimethylformamide? The chemoselectivity of
the reaction could be attributed to the acidity of the reac-
tion solution. In acetic acid, the reactive position of inter-
mediate 5 is the ketone carbonyl, which is attacked by an
NH2 group to form the intermediate product 6, which cy-
R1
NC
CN
R1
O
O
CN
NH
R1
R1
R1
R1
NH4OAc
HOAc
CN
N
CN
R2
CN
N
N
R2
R2
1
2
5
6
R1
R1
N
R1
H
N
H
NH2
R1
NH
N
NH2
CN
CN
N
R2
N
R2
CN
R2
CN
R1
R1
7
–2H
R1
NH2
CN
N
N
R2
R1
4
Scheme 2
Synthesis 2009, No. 10, 1639–1646 © Thieme Stuttgart · New York

PAPER
Chemoselective Synthesis of 1,6-Naphthyridines and Pyrano[3,2-c]pyridines
1641
R1
N
R1
N
O
–
CN
N–
N
O
O
R1
R1
DMF
–
CN
R2
N
R2
CN
CN
R1
R2
2
8
9
R1
1
R1
N
R1
N
O
NH2
CN
O
NH
CN
R2
R2
R1
R1
3
Scheme 3
Table 3 Synthesis of Compounds 3 and 4 under Microwave Irradi-
ation (continued)
temperature increase from 120 to 140 °C failed to im-
prove the yield of product 4b (entries 5–7). Therefore,
110 °C was chosen as the most suitable temperature for
the synthesis of 4b. In addition, we found that the most
suitable temperature for the synthesis of 3b is 120 °C
(Table 2, entry 5).
Entry Product R1
R2
Time Yielda Mp
(min) (%)
(°C)
8
9
4h
4i
3-O2NC6H4
2-thienyl
Ph
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
4
5
5
5
8
6
8
5
6
7
7
7
7
7
6
7
7
8
9
9
90
89
93
90
92
94
89
90
93
93
95
91
92
93
90
94
93
90
89
90
220–221
219–222
296–298
202–203
234–235
287–288
233–234
200–202
200–202
215–217
238–240
225–227
238–240
245–246
226–228
243–245
235–237
225–227
234–236
242–244
Table 2 Temperature Optimization in the Synthesis of Compounds
3b and 4b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4j
Entry
Temp (°C) Time (min)
Yielda (%)
4k
4l
3-O2NC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
Ph
4bb
3bc
14
11
9
4bb
3bc
86
89
90
91
93
90
86
1
2
3
4
5
6
7
80
90
13
10
8
83
85
89
92
90
88
85
4m
4n
4o
3a
3b
3c
3d
3e
3f
100
110
120
130
140
6
7
6
6
4-Tol
5
5
4-ClC6H4
3-O2NC6H4
4-O2NC6H4
4-BrC6H4
Ph
5
5
a Isolated yield.
b Microwave irradiation in AcOH.
c Microwave irradiation in DMF.
3g
3h
3i
Table 3 Synthesis of Compounds 3 and 4 under Microwave
Irradiation
4-ClC6H4
4-FC6H4
3-O2NC6H4
4-O2NC6H4
4-BrC6H4
Entry Product R1
R2
Time Yielda Mp
(min) (%)
(°C)
3j
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
Ph
Me
Me
Me
Me
Me
Me
Me
4
6
8
5
4
6
4
91
92
90
92
93
90
91
251–252
254–256
239–240
229–231
256–258
231–233
>300
3k
3l
4-Tol
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
4-O2NC6H4
a Isolated yield.
Under these optimized chemoselectivity conditions, a se-
ries of 1,6-naphthyridines 4 and pyrano[3,2-c]pyridines 3
were selectively synthesized via the reaction of chalcones
1, malononitrile (2) and ammonium acetate in an appro-
priate solvent under microwave irradiation. The results,
4g
Synthesis 2009, No. 10, 1639–1646 © Thieme Stuttgart · New York

1642
Z.-G. Han et al.
PAPER
summarized in Table 3, show that this protocol could be
applied not only to chalcones with either an electron-
withdrawing group (such as a nitro or a halide group) or
an electron-donating group (such as an alkoxy group, en-
tries 3 and 12), but also to chalcones with a heterocyclic
group (such as the 2-thienyl group, entry 9). Therefore, we
concluded that the electronic nature of the chalcone sub-
stituents has no significant effect on this reaction.
Additionally, to demonstrate the purely nonthermal mi-
crowave effects, the same temperature was applied under
classical heating conditions to the synthesis of some ex-
amples of compounds 3 and 4. The results for six com-
pounds are listed in Table 4. A comparison with the data
in Table 3 for the corresponding compounds indicates that
the reaction was efficiently promoted by microwave irra-
diation, and the reaction time was strikingly shortened
from hours required under traditional heating conditions
to minutes; the yields were also obviously increased under
the microwave irradiation conditions.
Figure 1 ORTEP diagram of compound 4i
products by varying the reaction medium. In light of its
operational simplicity, simple purification procedure and
good yields, this protocol is superior to the existing meth-
ods.
Table 4 Synthesis of Some Examples of Compounds 3 and 4 Using
Conventional Heating
Entry
Product
4b
Time (h)
Yielda (%)
All microwave-assisted reactions were performed in a monomodal
Emrys™ Creator from Personal Chemistry, Uppsala, Sweden.
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were recorded on an FT-IR Tensor 27 spectrom-
eter using KBr pellets. 1H NMR spectra were measured on a Bruker
DPX 400 MHz spectrometer using TMS as internal standard and
DMSO-d6 as solvent. HRMS (ESI) data were determined using a
micrOTOF-Q II HPLC/MS instrument (Bruker). X-ray crystallo-
graphic analysis was performed with a Siemens SMART CCD and
a Siemens P4 diffractometer.
1
6
6
5
5
4
5
71
81
80
84
81
83
2
3b
3
4f
4
3f
5
4g
6
3e
Chalcones 1; General Procedure
a Isolated yields.
In a 50-mL reaction vial, a mixture of the 4-piperidone (10 mmol),
the appropriate aldehyde (20 mmol), 10% NaOH (1 mL) and 95%
EtOH (30 mL) was stirred at r.t. for 0.5–2 h. The separated solid was
collected by filtration.
The structures of all the synthesized compounds were es-
tablished on the basis of their spectroscopic data. The IR
spectrum of compound 4b showed strong absorptions at
3330 and 3214 cm–1 due to the NH2 group, and at 2219
cm–1 due to the CN group. The 1H NMR spectrum of 4b
showed a broad singlet at d = 6.71 due to the NH2 protons
and a singlet at d = 7.92 due to the =CH proton. In the IR
spectrum of compound 3b, the appearance of absorption
peaks at 3389, 3295 and 2178 cm–1 due to the NH2 group
and the CN triple bond, and the disappearance of the band
at 1685–1710 cm–1 due to the C=O group of the starting
chalcone, confirmed the formation of product. The ap-
pearance of a broad singlet at d = 6.76 due to the NH2 pro-
tons and a singlet at d = 6.87 due to the =CH proton in the
1H NMR spectrum provided further confirmation. More-
over, the structure of 4i was also established by X-ray
crystallography (Figure 1).10
1,6-Naphthyridines 4; General Procedure Using Microwave
Irradiation
In a 10-mL reaction vial, the 3,5-dibenzylidene-4-piperidone 1 (1
mmol), malononitrile (2; 1 mmol), NH4OAc (6 mmol) and AcOH
(2 mL) were mixed, and then the vial was capped. The mixture was
irradiated at 200 W (initial power: 150 W, maximum power: 200 W)
at 110 °C for the time given in Table 3. Upon completion of the re-
action (monitored by TLC), the mixture was cooled to r.t. and then
poured into H2O (70 mL); filtration gave the crude product, which
was further purified by recrystallization (95% EtOH) to give pure
product.
2-Amino-8-benzylidene-5,6,7,8-tetrahydro-6-methyl-4-phenyl-
1,6-naphthyridine-3-carbonitrile (4a)
IR (KBr): 3355, 3212, 2214, 1621, 1556, 1446, 1424, 1370, 1262,
1120, 923, 893, 770, 719, 698 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.97 (s, 1 H, =CH), 7.54–7.44
(m, 5 H, ArH), 7.40–7.37 (m, 5 H, ArH), 6.74 (s, 2 H, NH2), 3.57 (s,
2 H, CH2), 3.13 (s, 2 H, CH2), 2.21 (s, 3 H, CH3).
In summary, we have demonstrated an efficient and prac-
tical method for the synthesis of a wide range of 1,6-naph-
thyridines and pyrano[3,2-c]pyridines under mild
HRMS (ESI): m/z [M + H]+ calcd for C23H21N4: 353.1766; found:
conditions. Most distinctively, we have shown that the re- 353.1788.
action could be controlled to exclusively yield specific
Synthesis 2009, No. 10, 1639–1646 © Thieme Stuttgart · New York

PAPER
Chemoselective Synthesis of 1,6-Naphthyridines and Pyrano[3,2-c]pyridines
1643
2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(4-methylben-
zylidene)-4-(4-methylphenyl)-1,6-naphthyridine-3-carbonitrile
(4b)
2-Amino-8-(4-bromobenzylidene)-4-(4-bromophenyl)-5,6,7,8-
tetrahydro-6-methyl-1,6-naphthyridine-3-carbonitrile (4f)
IR (KBr): 3366, 3206, 2210, 1614, 1569, 1543, 1488, 1453, 1429,
1358, 1259, 1192, 1114, 1069, 1009, 891, 842, 818, 782, 738 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.89 (s, 1 H, =CH), 7.75 (d,
J = 8.4 Hz, 2 H, ArH), 7.64 (d, J = 8.4 Hz, 2 H, ArH), 7.37–7.32 (m,
4 H, ArH), 6.82 (s, 2 H, NH2), 3.53 (s, 2 H, CH2), 3.12 (s, 2 H, CH2),
2.22 (s, 3 H, CH3).
IR (KBr): 3330, 3214, 2219, 1626, 1555, 1513, 1449, 1426, 1362,
1265, 1125, 923, 907, 810, 737, 703 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.92 (s, 1 H, =CH), 7.34 (d,
J = 8.0 Hz, 2 H, ArH), 7.27–7.24 (m, 6 H, ArH), 6.71 (s, 2 H, NH2),
3.55 (s, 2 H, CH2), 3.12 (s, 2 H, CH2), 2.39 (s, 3 H, CH3), 2.34 (s, 3
H, CH3), 2.20 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 160.45, 157.94, 139.12,
138.20, 132.51, 131.59, 130.18, 129.79, 129.51, 129.34, 129.27,
129.22, 128.08, 127.62, 126.80, 116.06, 91.57, 54.43, 54.08, 44.79,
20.92.
HRMS (ESI): m/z [M + H]+ calcd for C23H19Br2N4: 508.9976;
found: 508.9964.
2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(4-nitrobenzylidene)-
4-(4-nitrophenyl)-1,6-naphthyridine-3-carbonitrile (4g)
IR (KBr): 3374, 3302, 2210, 1623, 1595, 1558, 1501, 1488, 1451,
1429, 1343, 1266, 1109, 1013, 925, 861, 850, 817, 785, 724 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.39 (d, J = 8.4 Hz, 2 H, ArH),
8.28 (d, J = 8.8 Hz, 2 H, ArH), 8.03 (s, 1 H, =CH), 7.74 (d, J = 8.8
Hz, 2 H, ArH), 7.66 (d, J = 8.4 Hz, 2 H, ArH), 6.95 (s, 2 H, NH2),
3.60 (s, 2 H, CH2), 3.15 (s, 2 H, CH2), 2.23 (s, 3 H, CH3).
HRMS (ESI): m/z [M + H]+ calcd for C25H25N4: 381.2079; found:
381.2093.
2-Amino-5,6,7,8-tetrahydro-8-(4-methoxybenzylidene)-4-(4-
methoxyphenyl)-6-methyl-1,6-naphthyridine-3-carbonitrile
(4c)
IR (KBr): 3356, 3226, 2214, 1632, 1605, 1552, 1510, 1460, 1428,
HRMS (ESI): m/z [M + H]+ calcd for C23H19N6O4: 443.1468; found:
443.1491.
1361, 1262, 1175, 1126, 1027, 927, 901, 838, 787, 744 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.90 (s, 1 H, =CH), 7.33 (d,
J = 8.8 Hz, 4 H, ArH), 7.08 (d, J = 8.4 Hz, 2 H, ArH), 7.02 (d,
J = 8.8 Hz, 2 H, ArH), 6.67 (s, 2 H, NH2), 3.83 (s, 3 H, OCH3), 3.80
(s, 3 H, OCH3), 3.56 (s, 2 H, CH2), 3.15 (s, 2 H, CH2), 2.22 (s, 3 H,
CH3).
2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(3-nitrobenzylidene)-
4-(3-nitrophenyl)-1,6-naphthyridine-3-carbonitrile (4h)
IR (KBr): 3379, 3284, 2212, 1625, 1556, 1526, 1449, 1352, 1264,
1097, 916, 859, 822, 808, 743, 717, 701 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 159.64, 158.90, 157.97,
152.64, 152.41, 131.12, 130.72, 129.72, 128.55, 127.96, 127.29,
117.60, 116.92, 114.13, 114.04, 88.95, 56.02, 55.66, 55.18, 54.78,
45.26.
HRMS (ESI): m/z [M + H]+ calcd for C25H25N4O2: 413.1978; found:
413.2001.
1H NMR (400 MHz, DMSO-d6): d = 8.39 (d, J = 8.0 Hz, 1 H, ArH),
8.29 (s, 1 H, ArH), 8.20 (d, J = 8.4 Hz, 1 H, ArH), 8.15 (s, 1 H,
ArH), 8.03 (s, 1 H, =CH), 7.92–7.84 (m, 3 H, ArH), 7.75 (t, J = 8.4
Hz, 1 H, ArH), 6.90 (s, 2 H, NH2), 3.61 (s, 2 H, CH2), 3.22–3.14 (m,
2 H, CH2), 2.23 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 157.85, 151.94, 150.56,
147.95, 147.87, 137.52, 136.60, 135.70, 135.09, 134.90, 130.58,
130.17, 126.02, 124.07, 123.71, 123.23, 122.33, 117.10, 116.25,
89.60, 54.78, 54.23, 44.99.
2-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-
tetrahydro-6-methyl-1,6-naphthyridine-3-carbonitrile (4d)
IR (KBr): 3288, 3159, 2210, 1624, 1571, 1555, 1493, 1453, 1422,
1368, 1274, 1260, 1183, 1129, 1089, 1010, 917, 901, 847, 834, 818,
739 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C23H19N6O4: 443.1468; found:
443.1460.
1H NMR (400 MHz, DMSO-d6): d = 7.91 (s, 1 H, =CH), 7.61 (d,
J = 8.4 Hz, 2 H, ArH), 7.50 (d, J = 8.4 Hz, 2 H, ArH), 7.44–7.39 (m,
4 H, ArH), 6.80 (s, 2 H, NH2), 3.54 (s, 2 H, CH2), 3.13 (s, 2 H, CH2),
2.22 (s, 3 H, CH3).
2-Amino-6-benzyl-5,6,7,8-tetrahydro-4-(2-thienyl)-8-(2-thien-
ylmethylene)-1,6-naphthyridine-3-carbonitrile (4i)
IR (KBr): 3275, 3201, 2207, 1621, 1556, 1454, 1412, 1352, 1267,
1215, 1088, 1067, 935, 855, 750, 716 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 158.36, 152.46, 134.44,
133.73, 133.25, 133.10, 131.59, 131.44, 130.25, 129.89, 129.09,
128.84, 115.95, 112.72, 110.85, 90.17, 52.55, 51.79, 42.37, 30.69.
HRMS (ESI): m/z [M + H]+ calcd for C23H19Cl2N4: 421.0987;
found: 421.1007.
1H NMR (400 MHz, DMSO-d6): d = 8.07 (s, 1 H, =CH), 7.80 (d,
J = 5.2 Hz, 1 H, ArH), 7.73 (d, J = 5.2 Hz, 1 H, ArH), 7.29–7.25 (m,
5 H, ArH), 7.23 (m, 2 H, ArH), 7.21–7.16 (m, 2 H, ArH), 6.81 (s, 2
H, NH2), 3.70 (s, 2 H, CH2), 3.63 (s, 2 H, CH2), 3.33 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 158.24, 153.04, 145.23,
138.97, 137.55, 134.08, 130.68, 129.57, 129.41, 129.27, 128.94,
128.80, 128.15, 128.11, 127.62, 127.13, 121.38, 118.33, 116.61,
89.28, 60.67, 53.13, 52.20.
2-Amino-8-(4-fluorobenzylidene)-4-(4-fluorophenyl)-5,6,7,8-
tetrahydro-6-methyl-1,6-naphthyridine-3-carbonitrile (4e)
IR (KBr): 3273, 3146, 2215, 1625, 1602, 1558, 1505, 1452, 1423,
1362, 1265, 1224, 1160, 1105, 1012, 917, 848, 829, 798, 736 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.92 (s, 1 H, =CH), 7.47–7.41
(m, 4 H, ArH), 7.38 (t, J = 8.8 Hz, 2 H, ArH), 7.28 (t, J = 8.8 Hz, 2
H, ArH), 6.76 (s, 2 H, NH2), 3.54 (s, 2 H, CH2), 3.13 (s, 2 H, CH2),
2.22 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 162.36 (1JC,F = 245 Hz),
161.48 (1JC,F = 245 Hz), 157.88, 152.30, 151.83, 132.51, 132.45,
131.66, 131.58, 130.65, 130.57, 127.10, 117.68, 116.56, 115.85,
115.65, 115.44, 89.32, 55.24, 54.58, 45.17.
HRMS (ESI): m/z [M + H]+ calcd for C25H21N4S2: 441.1207; found:
441.1192.
2-Amino-6-benzyl-8-benzylidene-5,6,7,8-tetrahydro-4-phenyl-
1,6-naphthyridine-3-carbonitrile (4j)
IR (KBr): 3329, 3208, 2223, 1655, 1571, 1533, 1473, 1367, 1331,
1232, 1154, 1100, 932, 892, 766, 736, 698 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.79 (s, 1 H, =CH), 7.49–7.48
(m, 3 H, ArH), 7.39–7.31 (m, 8 H, ArH), 7.18 (m, 1 H, ArH), 7.16
(s, 2 H, NH2), 7.12–7.10 (m, 3 H, ArH), 3.64 (s, 2 H, CH2), 3.50 (s,
2 H, CH2), 3.18 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 161.21, 160.43, 155.01,
137.38, 135.24, 134.38, 130.64, 129.55, 129.41, 128.82, 128.66,
HRMS (ESI): m/z [M + H]+ calcd for C23H19F2N4: 389.1578; found:
389.1586.
Synthesis 2009, No. 10, 1639–1646 © Thieme Stuttgart · New York

1644
Z.-G. Han et al.
PAPER
128.53, 128.34, 128.05, 128.00, 127.55, 127.03, 115.89, 113.99,
112.72, 88.31, 59.81, 51.67.
HRMS (ESI): m/z [M + H]+ calcd for C29H23Br2N4: 585.0284;
found: 585.0296.
HRMS (ESI): m/z [M + H]+ calcd for C29H25N4: 429.2074; found:
429.2106.
2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(4-nitrobenzylidene)-4-
(4-nitrophenyl)-1,6-naphthyridine-3-carbonitrile (4o)
IR (KBr): 3343, 3217, 2211, 1594, 1556, 1513, 1455, 1429, 1342,
1260, 1108, 1014, 894, 851, 750, 703 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.33 (d, J = 8.8 Hz, 2 H, ArH),
8.20 (d, J = 8.8 Hz, 2 H, ArH), 8.02 (s, 1 H, =CH), 7.67 (d, J = 8.8
Hz, 2 H, ArH), 7.56 (d, J = 8.8 Hz, 2 H, ArH), 7.20–7.11 (m, 5 H,
ArH), 6.99 (s, 2 H, NH2), 3.71 (s, 2 H, CH2), 3.52 (s, 2 H, CH2), 3.28
(s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 157.90, 152.30, 151.25,
147.79, 146.15, 142.71, 141.64, 137.43, 135.55, 130.44, 129.96,
128.80, 128.04, 127.02, 126.78, 123.75, 123.57, 117.30, 116.08,
89.46, 59.77, 52.22, 51.78.
2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(3-nitrobenzylidene)-4-
(3-nitrophenyl)-1,6-naphthyridine-3-carbonitrile (4k)
IR (KBr): 3365, 3204, 2212, 1616, 1556, 1528, 1455, 1350, 1264,
1101, 1028, 935, 809, 764, 741, 700 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.31 (s, 1 H, ArH), 8.25 (s, 2
H, NH2), 8.14 (m, 1 H, ArH), 8.02 (s, 1 H, =CH), 7.84 (d, J = 7.6
Hz, 1 H, ArH), 7.72–7.64 (m, 3 H, ArH), 7.14 (s, 7 H, ArH), 3.81
(s, 2 H, CH2), 3.56 (s, 2 H, CH2), 3.38 (d, J = 7.2 Hz, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 157.92, 152.39, 150.78,
147.82, 147.73, 137.45, 137.33, 136.54, 135.62, 134.51, 130.47,
130.03, 128.87, 127.93, 126.97, 126.57, 123.94, 123.53, 123.12,
122.25, 117.39, 116.24, 89.70, 59.76, 52.09, 51.60.
HRMS (ESI): m/z [M + H]+ calcd for C29H23N6O4: 519.1781; found:
519.1767.
HRMS (ESI): m/z [M + H]+ calcd for C29H23N6O4: 519.1781; found:
519.1794.
Pyrano[3,2-c]pyridines 3; General Procedure Using Microwave
Irradiation
2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(4-methoxyben-
zylidene)-4-(4-methoxyphenyl)-1,6-naphthyridine-3-carboni-
trile (4l)
In a 10-mL reaction vial, the 3,5-dibenzylidene-4-piperidone 1 (1
mmol), malononitrile (2; 1 mmol), NH4OAc (6 mmol) and DMF (2
mL) were mixed, and then the vial was capped. The mixture was ir-
radiated at 200 W (initial power: 150 W, maximum power: 200 W)
at 120 °C for the time given in Table 3. Upon completion of the re-
action (monitored by TLC), the mixture was worked up using the
procedure given above for the 1,6-naphthyridines 4.
IR (KBr): 3378, 3235, 2208, 1640, 1608, 1548, 1501, 1459, 1363,
1297, 1255, 1178, 1029, 908, 830, 757, 736, 700 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.90 (s, 1 H, =CH), 7.29–7.18
(m, 7 H, ArH), 7.16–7.14 (m, 2 H, ArH), 7.03–6.99 (m, 2 H, ArH),
6.96–6.93 (m, 2 H, ArH), 6.63 (s, 2 H, NH2), 3.81 (s, 3 H, CH3), 3.78
(s, 3 H, CH3), 3.68 (s, 2 H, CH2), 3.52 (s, 2 H, CH2), 3.30 (s, 2 H,
CH2).
13C NMR (100 MHz, DMSO-d6): d = 159.54, 158.83, 158.03,
153.11, 152.61, 137.76, 131.04, 130.37, 129.67, 128.78, 128.49,
128.37, 128.03, 127.20, 126.97, 117.29, 116.93, 114.05, 113.92,
89.04, 60.44, 55.17, 53.17, 52.35.
2-Amino-8-benzylidene-5,6,7,8-tetrahydro-6-methyl-4-phenyl-
4H-pyrano[3,2-c]pyridine-3-carbonitrile (3a)
IR (KBr): 3338, 3284, 2189, 1640, 1619, 1594, 1489, 1453, 1415,
1399, 1326, 1272, 1218, 1171, 1110, 1050, 917, 904, 878, 766, 756,
699 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.43–7.35 (m, 4 H, ArH),
7.31–7.22 (m, 6 H, ArH), 6.93 (s, 1 H, =CH), 6.84 (s, 2 H, NH2),
4.06 (s, 1 H, CH), 3.48 (d, J = 14.4 Hz, 1 H, CH2), 3.28 (d, J = 14.4
Hz, 1 H, CH2), 3.00 (d, J = 16.0 Hz, 1 H, CH2), 2.57 (d, J = 16.0 Hz,
1 H, CH2), 2.15 (s, 3 H, CH3).
HRMS (ESI): m/z [M + H]+ calcd for C31H29N4O2: 489.2291; found:
489.2269.
2-Amino-6-benzyl-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-
5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile (4m)
IR (KBr): 3298, 3213, 2221, 1636, 1562, 1529, 1493, 1474, 1365,
1246, 1225, 1092, 1013, 904, 827, 762, 700 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 159.79, 143.49, 139.15,
135.93, 128.96, 128.69, 128.49, 127.60, 127.46, 127.14, 121.43,
120.44, 113.23, 112.71, 55.86, 54.56, 54.08, 44.50, 41.07.
1H NMR (400 MHz, DMSO-d6): d = 7.75 (s, 1 H, =CH), 7.57 (d,
J = 8.4 Hz, 2 H, ArH), 7.44–7.39 (m, 5 H, ArH), 7.31 (d, J = 8.8 Hz,
2 H, ArH), 7.19–7.17 (m, 4 H, ArH and NH2), 7.12–7.10 (m, 2 H,
ArH), 3.60 (s, 2 H, CH2), 3.51 (s, 2 H, CH2), 3.19 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 160.35, 157.71, 137.34,
134.32, 134.06, 133.15, 132.97, 131.25, 129.68, 129.43, 128.85,
128.80, 128.56, 128.03, 127.85, 127.06, 119.58, 115.75, 112.72,
100.94, 59.58, 51.50, 51.32.
HRMS (ESI): m/z [M + H]+ calcd for C23H22N3O: 356.1758; found:
356.1756.
2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(4-methylben-
zylidene)-4-(4-methylphenyl)-4H-pyrano[3,2-c]pyridine-3-car-
bonitrile (3b)
IR (KBr): 3389, 3295, 2178, 1644, 1604, 1511, 1461, 1448, 1416,
1395, 1323, 1269, 1205, 1171, 1101, 1055, 911, 812 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.22 (d, J = 8.0 Hz, 2 H, ArH),
7.17–7.13 (m, 4 H, ArH), 7.09 (d, J = 8.0 Hz, 2 H, ArH), 6.87 (s, 1
H, =CH), 6.76 (s, 2 H, NH2), 3.99 (s, 1 H, CH), 3.46 (d, J = 14.8 Hz,
1 H, CH2), 3.28 (d, J = 17.2 Hz, 1 H, CH2), 2.96 (d, J = 16.4 Hz, 1
H, CH2), 2.53 (d, J = 17.6 Hz, 1 H, CH2), 2.31 (s, 3 H, CH3), 2.29
(s, 3 H, CH3), 2.14 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 159.72, 140.55, 139.08,
136.53, 136.21, 133.09, 129.23, 129.09, 128.92, 127.50, 126.80,
121.28, 120.48, 112.93, 55.99, 54.56, 54.17, 44.52, 40.70, 20.79,
20.65.
HRMS (ESI): m/z [M + H]+ calcd for C29H23Cl2N4: 497.1295;
found: 497.1286.
2-Amino-6-benzyl-8-(4-bromobenzylidene)-4-(4-bromophe-
nyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile (4n)
IR (KBr): 3304, 3197, 2222, 1639, 1604, 1566, 1531, 1510, 1474,
1364, 1235, 1160, 1105, 1014, 903, 834, 792, 759, 700 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.71–7.67 (m, 3 H, ArH and
=CH), 7.57 (d, J = 8.4 Hz, 2 H, ArH), 7.34 (d, J = 8.4 Hz, 2 H,
ArH), 7.30–7.20 (m, 4 H, ArH), 7.19–7.18 (m, 3 H, ArH and NH2),
7.12–7.10 (m, 2 H, ArH), 3.61 (s, 2 H, CH2), 3.51 (s, 2 H, CH2), 3.22
(s, 2 H, CH2).
HRMS (ESI): m/z [M + H]+ calcd for C25H26N3O: 384.2071; found:
384.2089.
Synthesis 2009, No. 10, 1639–1646 © Thieme Stuttgart · New York

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Chemoselective Synthesis of 1,6-Naphthyridines and Pyrano[3,2-c]pyridines
1645
2-Amino-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-
tetrahydro-6-methyl-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(3c)
IR (KBr): 3365, 3289, 2180, 1645, 1605, 1489, 1461, 1449, 1413,
1393, 1321, 1267, 1207, 1169, 1092, 1056, 1014, 986, 911, 817,
737, 697 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.48–7.43 (m, 4 H, ArH), 7.26
(m, 4 H, ArH), 6.92 (s, 2 H, NH2), 6.89 (s, 1 H, =CH), 4.12 (s, 1 H,
CH), 3.46 (d, J = 13.6 Hz, 1 H, CH2), 3.28 (d, J = 14.8 Hz, 1 H,
CH2), 3.00 (d, J = 16.0 Hz, 1 H, CH2), 2.55 (d, J = 16.0 Hz, 1 H,
CH2), 2.16 (s, 3 H, CH3).
2-Amino-6-benzyl-8-benzylidene-5,6,7,8-tetrahydro-4-phenyl-
4H-pyrano[3,2-c]pyridine-3-carbonitrile (3g)
IR (KBr): 3299, 3259, 2189, 1639, 1618, 1592, 1491, 1453, 1400,
1374, 1349, 1269, 1218, 1169, 1100, 1075, 1042, 919, 878, 746,
696 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.37–7.32 (m, 4 H, ArH),
7.29–7.25 (m, 2 H, ArH), 7.23–7.19 (m, 4 H, ArH), 7.18–7.16 (m,
3 H, ArH), 7.09–7.07 (m, 2 H, ArH), 6.95 (s, 1 H, =CH), 6.86 (s, 2
H, NH2), 4.01 (s, 1 H, CH), 3.63 (d, J = 14.4 Hz, 1 H, CH2), 3.45
(m, 3 H, CH2), 3.07 (d, J = 16.0 Hz, 1 H, CH2), 2.69 (d, J = 16.0 Hz,
1 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 159.79, 142.43, 139.23,
134.78, 131.76, 131.72, 130.71, 129.47, 128.70, 128.51, 128.13,
120.36, 120.19, 113.25, 55.54, 54.39, 53.92, 44.40, 40.39.
HRMS (ESI): m/z [M + H]+ calcd for C23H20Cl2N3O: 424.0978;
found: 424.0989.
13C NMR (100 MHz, DMSO-d6): d = 159.79, 151.99, 150.42,
143.48, 139.47, 137.74, 135.89, 128.87, 128.64, 128.38, 128.00,
127.56, 127.10, 126.91, 121.83, 120.39, 112.87, 108.59, 59.89,
56.05, 52.26, 51.69, 41.07.
HRMS (ESI): m/z [M + H]+ calcd for C29H26N3O: 432.2071; found:
432.2081.
2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(3-nitrobenzylidene)-
4-(3-nitrophenyl)-4H-pyrano[3,2-c]pyridine-3-carbonitrile (3d)
IR (KBr): 3359, 3267, 2190, 1639, 1596, 1522, 1456, 1416, 1348,
1266, 1174, 1116, 1052, 984, 899, 818, 738, 714, 682 cm–1.
2-Amino-6-benzyl-8-(4-chlorobenzylidene)-4-(4-chlorophenyl)-
5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(3h)
IR (KBr): 3329, 3279, 2192, 1649, 1598, 1489, 1411, 1395, 1375,
1325, 1265, 1214, 1169, 1091, 1049, 1013, 917, 884, 826, 753, 700
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.43–7.39 (m, 4 H, ArH),
7.23–7.17 (m, 7 H, ArH), 7.07–7.06 (m, 2 H, ArH), 6.92 (s, 1 H,
=CH), 6.90 (s, 2 H, NH2), 4.07 (s, 1 H, CH), 3.61 (d, J = 14.8 Hz, 1
H, CH2), 3.46–3.42 (m, 3 H, CH2), 3.06 (d, J = 16.8 Hz, 1 H, CH2),
2.66 (d, J = 16.0 Hz, 1 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 159.78, 142.45, 139.46,
137.69, 134.73, 131.70, 130.62, 129.45, 128.66, 128.60, 128.42,
127.99, 127.74, 126.94, 120.79, 120.19, 112.86, 112.72, 59.65,
55.60, 51.81, 51.61, 40.30.
1H NMR (400 MHz, DMSO-d6): d = 8.19–8.14 (m, 2 H, ArH), 8.09
(s, 1 H, ArH), 8.06 (s, 1 H, ArH), 7.75–7.69 (m, 4 H, ArH), 7.05 (s,
3 H, NH2 and =CH), 4.41 (s, 1 H, CH), 3.53 (d, J = 14.0 Hz, 1 H,
CH2), 3.28 (d, J = 14.8 Hz, 1 H, CH2), 3.09 (d, J = 16.4 Hz, 1 H,
CH2), 2.59 (d, J = 16.0 Hz, 1 H, CH2), 2.17 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 159.98, 148.06, 147.94,
145.66, 139.42, 137.45, 135.14, 134.46, 130.48, 130.09, 129.62,
123.37, 122.41, 122.04, 121. 84, 119.98, 119.84, 113.67, 55.07,
54.14, 53.60, 44.25, 40.48.
HRMS (ESI): m/z [M + H]+ calcd for C23H20N5O5: 446.1459; found:
446.1459.
2-Amino-5,6,7,8-tetrahydro-6-methyl-8-(4-nitrobenzylidene)-
4-(4-nitrophenyl)-4H-pyrano[3,2-c]pyridine-3-carbonitrile (3e)
IR (KBr): 3365, 3293, 2182, 1642, 1593, 1521, 1458, 1418, 1392,
1340, 1273, 1172, 1097, 1055, 907, 868, 809, 716 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.26 (d, J = 8.0 Hz, 4 H, ArH),
7.54 (d, J = 8.8 Hz, 4 H, ArH), 7.06 (s, 2 H, NH2), 7.03 (s, 1 H,
=CH), 4.36 (s, 1 H, CH), 3.53 (d, J = 14.4 Hz, 1 H, CH2), 3.48–3.43
(m, 1 H, CH2), 3.08 (d, J = 16.4 Hz, 1 H, CH2), 2.56 (d, J = 16.4 Hz,
1 H, CH2), 2.17 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 159.91, 150.84, 146.75,
145.93, 142.74, 139.46, 130.70, 130.09, 128.98, 124.10, 123.70,
120.07, 119.95, 114.32, 56.01, 54.75, 54.25, 53.81, 44.30, 40.69.
HRMS (ESI): m/z [M + H]+ calcd for C23H20N5O5: 446.1459; found:
446.1472.
HRMS (ESI): m/z [M + H]+ calcd for C29H24Cl2N3O: 500.1291;
found: 500.1301.
2-Amino-6-benzyl-8-(4-fluorobenzylidene)-4-(4-fluorophenyl)-
5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(3i)
IR (KBr): 3334, 3298, 2197, 1650, 1602, 1507, 1417, 1398, 1375,
1267, 1225, 1157, 1091, 916, 831, 780, 756, 697 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.25–7.20 (m, 4 H, ArH),
7.19–7.14 (m, 7 H, ArH), 7.08–7.06 (m, 2 H, ArH), 6.92 (s, 1 H,
=CH), 6.83 (s, 2 H, NH2), 4.05 (s, 1 H, CH), 3.59 (d, J = 14.0 Hz, 1
H, CH2), 3.45 (s, 2 H, CH2), 3.40 (d, J = 14.4 Hz, 1 H, CH2), 3.05
(d, J = 16.0 Hz, 1 H, CH2), 2.65 (d, J = 16.0 Hz, 1 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 161.15 (1JC,F = 257 Hz),
161.00 (1JC,F = 256 Hz), 153.76, 146.37, 139.63, 139.37, 137.69,
132.32, 132.28, 130.89 (3JC,F = 8 Hz), 129.44 (3JC,F = 8 Hz), 128.62,
127.99, 126.94, 120.86, 120.32, 115.40 (2JC,F = 21 Hz), 115.31
(2JC,F = 21 Hz), 112.66, 59.75, 55.84, 51.98, 51.57.
2-Amino-8-(4-bromobenzylidene)-4-(4-bromophenyl)-5,6,7,8-
tetrahydro-6-methyl-4H-pyrano[3,2-c]pyridine-3-carbonitrile
(3f)
IR (KBr): 3364, 3283, 2181, 1644, 1590, 1486, 1459, 1409, 1391,
HRMS (ESI): m/z [M + H]+ calcd for C29H24F2N3O: 468.1882;
found: 468.1873.
1321, 1267, 1169, 1104, 1074, 1010, 910, 895, 828, 814, 734 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.61–7.56 (m, 4 H, ArH),
7.23–7.18 (m, 4 H, ArH), 6.89 (s, 2 H, NH2), 6.87 (s, 1 H, =CH),
4.11 (s, 1 H, CH), 3.46 (d, J = 14.0 Hz, 1 H, CH2), 3.26 (d, J = 14.0
Hz, 1 H, CH2), 3.00 (d, J = 16.4 Hz, 1 H, CH2), 2.53 (d, J = 16.4 Hz,
1 H, CH2), 2.16 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 159.72, 142.77, 139.18,
135.05, 131.55, 131.36, 130.93, 129.78, 128.11, 120.35, 120.30,
120.18, 120.11, 113.16, 55.39, 54.32, 53.85, 44.33, 40.40.
2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(3-nitrobenzylidene)-4-
(3-nitrophenyl)-4H-pyrano[3,2-c]pyridine-3-carbonitrile (3j)
IR (KBr): 3337, 3293, 2184, 1647, 1596, 1522, 1465, 1399, 1351,
1263, 1218, 1159, 1085, 914, 815, 739, 695, 685 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.17–8.16 (m, 1 H, ArH),
8.12–8.10 (m, 1 H, ArH), 8.03 (s, 2 H, NH2), 7.70–7.65 (m, 4 H,
ArH), 7.12–7.11 (m, 3 H, ArH), 7.07 (s, 1 H, =CH), 7.06–7.04 (m,
4 H, ArH), 4.35 (s, 1 H, CH), 3.66 (d, J = 14.4 Hz, 1 H, CH2), 3.54
HRMS (ESI): m/z [M + H]+ calcd for C23H20Br2N3O: 511.9968;
found: 511.9979.
Synthesis 2009, No. 10, 1639–1646 © Thieme Stuttgart · New York

1646
Z.-G. Han et al.
PAPER
(d, J = 15.2 Hz, 1 H, CH2), 3.49–3.34 (m, 2 H, CH2), 3.13 (d,
J = 16.4 Hz, 1 H, CH2), 2.69 (d, J = 16.0 Hz, 1 H, CH2).
tion of Jiangsu Province (No. BK2006033) and the Six Kinds of
Professional Elite Foundation of Jiangsu Province (No. 06-A-039).
13C NMR (100 MHz, DMSO-d6): d = 159.78, 142.45, 139.46,
137.69, 134.73, 131.70, 131.09, 130.62, 129.45, 128.66, 128.60,
128.42, 127.99, 127.74, 126.93, 124.02, 120.79, 118.67, 114.22,
112.87, 59.65, 56.01, 55.60, 51.89, 51.81, 51.62, 40.29.
HRMS (ESI): m/z [M + H]+ calcd for C29H24N5O5: 522.1772; found:
522.1761.
References
(1) (a) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1797. (b) Seo, J.; Chui, H. M. P.; Heeg, M. J.;
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(c) Organ, M. G.; Arvanitis, E. A.; Dixon, C. E.; Cooper, J.
T. J. Am. Chem. Soc. 2002, 124, 1288. (d) Davies, H. M. L.;
Panaro, S. A. Tetrahedron 2000, 56, 4871. (e) Lebel, H.;
Paquet, V. Org. Lett. 2002, 4, 1671. (f) Hunter, R.; Hinz,
W.; Richards, P. Tetrahedron Lett. 1999, 40, 3643. (g) Tu,
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Org. Biomol. Chem. 2007, 5, 355. (h) Wang, J.; Mason, R.;
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(2) El-Subbagh, H. I.; Abu-Zaid, S. M.; Mahran, M. A.; Badria,
F. A.; Al-Obaid, A. M. J. Med. Chem. 2000, 43, 2915.
(3) Hammam, A. G.; Sharaf, M. A.; Abdel-Hafez, N. A. Indian
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(4) Gangjee, A.; Zeng, Y.; McGuire, J. J.; Kisliuk, R. L. J. Med.
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(5) El-Kashef, H. S.; Geies, A. A.; Kamal, E. l.-DeanAM.;
Abdel-Hafez, A. A. J. Chem. Technol. Biotechnol. 1993, 57,
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(6) Haglid, F. Ark. Kemi 1967, 26, 489.
(7) Skotnicki, J. S., (American Home Products Corporation,
New York, N.Y.), US Patent 4902685, 1990.
(8) Blagg, J.; Fray, M. J.; Lewis, M. L.; Mathias, J. P.; Stefaniak,
M. H.; Stobie, A. (Pfizer Ltd, UK; Pfizer, USA), PCT Int.
Appl. WO 2003076427, 2003.
(9) (a) Tu, S.; Jia, R.; Jiang, B.; Zhang, J.; Zhang, Y.; Yao, C.;
Ji, S. Tetrahedron 2007, 63, 381. (b) Tu, S.; Zhang, J.; Jia,
R.; Zhang, Y.; Jiang, B.; Shi, F. Synthesis 2007, 558.
(10) The single-crystal growth was carried out in ethanol at room
temperature. X-ray crystallographic analysis was performed
with a Siemens SMART CCD and a Siemens P4
diffractometer (graphite monochromator, MoKa radiation,
l = 0.71073 Å). Crystal data for 4i: empirical formula =
C25H20N4S2, formula weight = 440.57, crystal dimensions =
0.13 × 0.12 × 0.03 mm, monoclinic, space group P2(1)/n,
a = 11.0619(12) Å, b = 11.2598(13) Å, c = 17.5329(19) Å,
a = 90, b = 93.6620(10), g = 90, m = 0.265 mm–1,
V = 2179.3(4) Å3, Z = 4, Dc = 1.343 g/cm3, F(000) = 920,
S = 0.808, R1 = 0.0665, wR2 = 0.0863.
2-Amino-6-benzyl-5,6,7,8-tetrahydro-8-(4-nitrobenzylidene)-4-
(4-nitrophenyl)-4H-pyrano[3,2-c]pyridine-3-carbonitrile (3k)
IR (KBr): 3329, 3301, 2200, 1650, 1591, 1517, 1421, 1398, 1340,
1269, 1218, 1168, 1108, 920, 895, 859, 811, 748, 700 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.24–8.19 (m, 4 H, ArH),
7.51–7.48 (m, 4 H, ArH), 7.15 (s, 1 H, =CH), 7.14–7.13 (m, 2 H,
ArH), 7.08–7.06 (m, 3 H, ArH), 7.05 (s, 2 H, NH2), 4.31 (s, 1 H,
CH), 3.69 (d, J = 14.8 Hz, 1 H, CH2), 3.53 (d, J = 14.8 Hz, 1 H,
CH2), 3.48 (s, 2 H, CH2), 3.13 (d, J = 16.4 Hz, 1 H, CH2), 2.66 (d,
J = 15.6 Hz, 1 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 159.90, 150.89, 146.73,
145.92, 142.73, 139.70, 137.52, 133.95, 130.34, 130.01, 128.97,
128.57, 127.98, 126.95, 124.03, 123.60, 120.54, 119.90, 113.88,
59.42, 54.85, 51.58, 40.59.
HRMS (ESI): m/z [M + H]+ calcd for C29H24N5O5: 522.1772; found:
522.1774.
2-Amino-6-benzyl-8-(4-bromobenzylidene)-4-(4-bromophe-
nyl)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine-3-carboni-
trile (3l)
IR (KBr): 3326, 3293, 2196, 1644, 1594, 1485, 1407, 1392, 1373,
1322, 1267, 1170, 1098, 1071, 1010, 917, 887, 815, 749, 696 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.51–7.48 (m, 4 H, ArH),
7.14–7.12 (m, 5 H, ArH), 7.10 (m, 2 H, ArH), 7.02–7.00 (m, 2 H,
ArH), 6.86 (s, 2 H, NH2), 6.84 (s, 1 H, =CH), 3.99 (s, 1 H, CH), 3.56
(d, J = 14.4 Hz, 1 H, CH2), 3.40–3.36 (m, 3 H, CH2), 3.00 (d,
J = 16.0 Hz, 1 H, CH2), 2.60 (d, J = 16.0 Hz, 1 H, CH2).
13C NMR (100 MHz, DMSO-d6): d = 159.77, 142.87, 139.46,
137.69, 135.06, 131.59, 131.58, 131.34, 130.92, 129.83, 128.60,
128.01, 127.77, 126.93, 120.85, 120.32, 120.23, 112.84, 59.62,
55.48, 51.75, 51.67, 40.36.
HRMS (ESI): m/z [M + H]+ calcd for C29H24Br2N3O: 588.0281;
found: 588.0272.
Acknowledgment
We are grateful for financial support from the National Science
Foundation of China (No. 20672090), the Natural Science Founda-
Synthesis 2009, No. 10, 1639–1646 © Thieme Stuttgart · New York