A novel procedure for the synthesis of benzo[b][1,8]naphthyridine-3- carboxylate derivatives from Morita-Baylis-Hillman adduct acetates

Article abstract of DOI:10.1055/s-0029-1216853

A novel procedure has been designed for the preparation of benzo[b][1,8]naphthyridine-3-carboxylate derivatives from the reaction of Morita-Baylis-Hillman adduct acetates with primary amines, ammonium acetate or benzenesulfonamides. The approach, which in

Full text of DOI:10.1055/s-0029-1216853

PAPER
2333
A Novel Procedure for the Synthesis of Benzo[b][1,8]naphthyridine-
3-carboxylate Derivatives from Morita–Baylis–Hillman Adduct Acetates
S
ynthesisof Benzo[
b
][1
e
,8]naphthyr
i
idine-
3
h
-carboxylate
u
D
erivativesi Zhong, Fuliang Lin, Ren’er Chen, Weike Su*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Fax +86(571)88871087; E-mail: pharmlab@zjut.edu.cn
Received 2 March 2009; revised 8 April 2009
conditions has been one of the underlying principles of
chemical research.7 During our ongoing studies toward
the exploitation of MBH adduct acetates in heterocyclic
chemistry, we have reported that several oxygen- and
Abstract: A novel procedure has been designed for the preparation
of benzo[b][1,8]naphthyridine-3-carboxylate derivatives from the
reaction of Morita–Baylis–Hillman adduct acetates with primary
amines, ammonium acetate or benzenesulfonamides. The approach,
which involves readily available starting materials and mild reac- nitrogen-fused heterocycles, including polyhydro-
tion conditions, gives excellent yields after a convenient workup
chromenes, polyhydroquinolines and 1,2,4-triazole deriv-
procedure.
atives, could be readily synthesized from MBH adducts
Key words: benzo[b][1,8]naphthyridine-3-carboxylate, Morita–
Baylis–Hillman adduct acetates, primary amines, ammonium ace-
tate, benzenesulfonamides
under solvent-free conditions with good to excellent
yields.8 Moreover, very recently, the direct conversion of
acetanilides into 2-chloro-3-formyl quinolines 2 in good
isolated yields, has been successfully achieved.9 It oc-
curred to us that it would be useful to directly convert
MBH adduct acetates such as 3 (derived from 2-chloro-3-
formyl quinolines) into the desired title compounds by
treatment under environmentally benign and clean condi-
tions.
Quinoline and its annelated derivatives1 are well known to
both synthetic and biological chemists. They are impor-
tant structural units present in many biologically impor-
tant molecules that show a broad range of biological
activities.2,3
Herein, we wish to report a simple methodology for con-
structing the target compounds under environmentally
friendly conditions.
To our knowledge, only one preparative method has been
reported in the literature (Scheme 1).3 This approach uses
methyl 3-(2-chloroquinolin-3-yl)acrylate as substrate in
combination with methylamine in acetonitrile and is fol-
lowed by reaction with the Vilsmeier reagent. The method
finally afforded methyl benzo[b][1,8]naphthyridine-3-
carboxylate (1) in only 42% yield. However, this ap-
proach has several drawbacks, including harsh reaction
conditions, low reaction efficiency, and requires the use of
hazardous and toxic reagents. In addition, the preparation
of 1,2-dihydrobenzo[b][1,8]naphthyridines has not so far
been documented. Thus, the development of simple and
efficient methods for selectively constructing such hetero-
cycles employing ‘green’ reaction conditions remains
highly desirable.
OAc
CHO
CO2Me
(1) MBH reaction
(2) acetylation
N
Cl
N
Cl
2
3
4 steps
TsNH2
?
CO2Me
CO2Me
(1) MeNH2
(2) POCl3, DMF
42%
N
Cl
N
N
1
Scheme 1
The Morita–Baylis–Hillman (MBH) reaction is a well
known coupling reaction of aldehydes and activated alk-
enes, which takes place in the presence of a tertiary base
and affords a highly functionalized product. The versatil-
ity of the reaction has led to an exponential increase in the
synthetic utility of this approach over the last decade,4 and
increasing numbers of research groups have initiated
work on different facets of this reaction.5,6
At the onset of the research, we examined the MBH reac-
tion between 2-chloro-3-formyl quinolines 2 and activat-
ed alkenes at room temperature, in the presence of
DABCO as a base, under solvent-free conditions. The
MBH adducts were then transformed into the acetates 3
via acetylation with acetyl chloride (Scheme 2). The re-
sults, illustrated in Table 1, show that the substituent
group played a minimal role in governing the reactivity of
the substrates.
To access structurally complex and diverse molecules
through simple starting substrates under mild reaction
Generally, the MBH reaction proceeded well and afforded
the desired products 3a–f in moderate overall yields
(Table 1).
SYNTHESIS 2009, No. 14, pp 2333–2340
x
x.
x
x
.
2
0
0
9
Advanced online publication: 29.05.2009
DOI: 10.1055/s-0029-1216853; Art ID: F05109SS
© Georg Thieme Verlag Stuttgart · New York

2334
W. Zhong et al.
PAPER
Table 2 Synthesis of Methyl Benzo[b][1,8]naphthyridine-3-car-
boxylate (1) under Different Reaction Conditionsa
R2
OAc
Cl
R1
R2
R1
CHO
(1)
Entry
Solvent
Base (1.1
equiv)
Temp
(°C)
Time Yield
(%)b
(2)
AcCl
N
N
Cl
(h)
2
3
1
2
3
4
DMF
K2CO3
Et3N
120
5
80
Scheme 2
DMF
120
5
45
95% EtOH
95% EtOH
K2CO3
Et3N
reflux
reflux
30
30
18
Table 1 Synthesis of MBH Adduct Acetates 3 under Solvent-Free
Conditionsa
20
Entry
R1
H
R2
Product
3a
Yield (%)b
a Reaction conditions: 3a (1 equiv), TsNH2 (1 equiv), K2CO3 (1.1
equiv), DMF, 120 °C, 5 h.
1
2
3
4
5
6
CO2Me
CO2Et
CO2(n-Bu)
CN
72
71
72
70
73
72
b Isolated yield based on 3a.
H
3b
Interestingly, when an excess of tosylamide (2.5 equiv)
was used under the same conditions, the unexpected prod-
uct 5a was exclusively obtained in 85% yield (Scheme 4).
H
3c
H
3d
Me
Cl
CO2Me
CO2Me
3e
We presumed that the formation of product 5a might pro-
ceed through a two-step successive reaction: SN2¢ substi-
tution cyclization of the tosylamide with the MBH adduct
acetate 3a, followed by a 1,4-addition process. Enlight-
ened by the research and in order to confirm our hypothe-
sis, the reaction was carried out as shown in Scheme 5.
Cyclization of compound 3a with tosylamide (1.0 equiv)
yielded the intermediate compound 4p, which was then
treated with p-chlorobenzenesulfonamide (1.5 equiv) and
stirred for four hours. The progress of the reaction was
monitored by TLC. Gratifyingly, the desired product 5b
was successfully isolated in good yield (83%).
3f
a Reaction conditions: (1) 2 (1 equiv), alkene (2 equiv), DABCO (1.2
equiv), r.t., 2 d; (2) AcCl (9.6 equiv), Et3N (9.6 equiv), CH2Cl2, r.t.,
30 min.
b Isolated total yield based on 2.
In light of the successful formation of the MBH adduct
acetates 3, we intended to test the one-pot construction of
methyl benzo[b][1,8]naphthyridine-3-carboxylate (1),
from the MBH adduct acetate 3a and tosylamide
(Scheme 3).10 The reaction conditions were optimized and
the results are summarized in Table 2. When an equimolar
amount of substrate 3a was mixed with tosylamide and
1.1 equivalents of potassium carbonate in N,N-dimethyl-
formamide at 120 °C for five hours, the target compound
1 was successfully synthesized in 80% isolated yield.
Encouraged by these results, we further investigated the
formation of 1,2-dihydrobenzo[b][1,8]naphthyridine-3-
carboxylates 4 from MBH adduct acetates 3 and either
primary amines or ammonium acetate.
Preliminary experiments were carried out using com-
pound 3a and aniline (Scheme 6) as typical substrates.
The reaction was performed in acetone at room tempera-
ture for 10 hours without any catalyst or additive. Unfor-
tunately, the desired product 4a was obtained in only 45%
yield (Table 3, entry 1). In order to optimize the reaction
conditions, various factors including bases, solvents, reac-
tion temperature and time were investigated and the re-
sults are summarized in Table 3. In the presence of either
OAc
CO2Me
CO2Me
TsNH2 (1.0 equiv)
N
N
N
Cl
3a
1
Scheme 3
NHTs
OAc
Cl
TsNH2 (2.5 equiv)
K2CO3 (1.1 equiv)
CO2Me
CO2Me
DMF, 120 °C, 5 h
85%
N
N
N
3a
5a
Scheme 4
p-ClC6H4SO2NH
CO2Me
OAc
Cl
p-ClC6H4SO2NH2
(1.5 equiv)
CO2Me
CO2Me
TsNH2 (1.0 equiv)
DMF, 120 °C, 4 h
83% from 3a
K2CO3 (1.1 equiv), DMF
90 °C, 15 min
N
N
N
N
N
5b
Ts
3a
4p
Scheme 5
Synthesis 2009, No. 14, 2333–2340 © Thieme Stuttgart · New York

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Synthesis of Benzo[b][1,8]naphthyridine-3-carboxylate Derivatives
2335
OAc
Cl
Table 4 Synthesis of 1,2-Dihydrobenzo[b][1,8]naphthyridine-3-
carboxylates 4 from MBH Adduct Acetates 3a
R1
R2
R1
R2
R3NH2
base
Entry R1
R2
R3
Time Product Yield
(%)b
N
N
N
(h)
R3
3
4
1
2
H
H
H
H
CO2Me
CO2Et
Ph
Ph
4
4a
4b
4c
4d
4e
4f
88
3a: R1 = H, R2 = CO2Me
4a: R1 = H, R2 = CO2Me, R3 = Ph
4
89
Scheme 6
3
CO2(n-Bu) Ph
4
89
triethylamine or potassium carbonate, the required reac-
tion time could be significantly reduced and higher yields
were observed (Table 3, entries 3 and 5). When the reac-
tion was carried out at elevated temperature, compound
4a was formed in good yield within a shorter reaction
time, however, the formation of some unknown byprod-
ucts were also observed (Table 3, entry 7). After screen-
ing a variety of reaction media, 95% ethanol was
determined to be the best solvent for generation of the de-
sired product (Table 3, entries 4 and 5). It is worthwhile
mentioning that the workup procedure was very conve-
nient; the product could be isolated by simple filtration
without further purification when this reaction was per-
formed at room temperature using 95% ethanol as a sol-
vent and triethylamine as a base.
4
CN
Ph
4
76
5
Me CO2Me
Ph
4
88
6
Cl
H
H
H
H
H
H
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
4
87
7
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3,4-F2C6H3
benzyl
cyclohexyl
n-Bu
3
4g
4h
4i
87
8
3
90
9
6
84
10
11
12
13
14
15
16
5
4j
85
2
4k
4l
90
3
89
3
4m
4n
4o
4p
88
Table 3 Synthesis of Methyl 1-Phenyl-1,2-dihydroben-
zo[b][1,8]naphthyridine-3-carboxylate (4a) under Different Reaction
Conditionsa
t-Bu
3
87
H
5
86
Ts
10
20 (89)c
Entry
Solvent
Base
Temp
(°C)
Time Yield (%)b
(h)
a Reaction conditions: 3 (1 equiv), R3NH2 (1.1 equiv), Et3N (1.5
equiv), r.t., 95% EtOH (5 mL).
b Isolated yield based on MBH adduct acetates 3.
c Isolated yield when carried out with K2CO3 in DMF at 90 °C for 15
min.
1
2
acetone
acetone
acetone
95% EtOH
95% EtOH
EtOH
–
r.t.
reflux
r.t.
r.t.
r.t.
r.t.
90
10
5
45
–
55
3
Et3N
Et3N
K2CO3
Et3N
K2CO3
K2CO3
Et3N
Et3N
Et3N
5
75 (81)c
88 (85)c
87 (85)c
81
4
4
reaction times and gave lower yields than those of primary
amines with electron-donating groups. The presence of
electron-withdrawing or electron-donating groups in sub-
strate 3 did not appear to exert much influence on either
the rate or efficiency of the reaction (Table 4, entries 5 and
6). On the other hand, the presence of a nitrile in substrate
3 gave a lower yield than those of the esters (Table 4, en-
try 4).
5
4
6
4
7
DMF
0.2
4
84
8
DMF
r.t.
r.t.
r.t.
r.t.
79
9
CHCl3
4
64
According to the above results, a possible mechanism for
the formation of compounds 1, 4 and 5 from MBH adduct
acetates 3 can be illustrated as shown in Scheme 7.10
10
11
CH2Cl2
DMSO
4
57
4
76
In summary, we have developed a novel and efficient
strategy for the synthesis of various target compounds
from MBH adducts and either primary amines, ammoni-
um acetate or benzenesulfonamides under environmental-
ly friendly and clean conditions. The merits of the present
process are the simple experimental procedure, high se-
lectivity and high to excellent yields.
a Reaction conditions: 3a (1 equiv), amine (1 equiv), base (1.1 equiv).
b Isolated yield based on 3a.
c Isolated yield when the reaction was carried out at reflux for 1 h.
With the optimal conditions established, a series of prima-
ry amines, ammonium acetate and tosylamide were react-
ed with MBH adduct acetates in order to assess the scope
of this method (Table 4).
Melting points were determined using a Büchi B-540 capillary
melting point apparatus and are uncorrected. IR spectra were re-
corded on a Nicolet Avatar-370 instrument. 1H and 13C NMR spec-
tra were recorded on Varian (400 MHz) instruments using TMS as
As shown in Table 4, the reaction was compatible with a
variety of primary amines. It can be seen that the primary
amines with electron-withdrawing groups required longer
Synthesis 2009, No. 14, 2333–2340 © Thieme Stuttgart · New York

2336
W. Zhong et al.
PAPER
OAc
R1
R2
+ R3NH2
R1
R2
R1
R2
– AcOH
3 = Ts
– HCl
••
NHR3
N
Cl
N
Cl
N
N
••
3
R3
4
R2 = CO Me,
R1 = H
R
2
O
NHR3
O
NHR3 OH
OMe
+
1,4-addition
OMe
OMe
R3NH2
– TsH
N
N
N
N
N
N
R3 = Ts, 4-ClC6H4SO2
Ts
5b
4p
Ts
air oxidation
– TsH
NHR3
CO2Me
CO2Me
N
N
1
N
N
5
Scheme 7
an internal standard. Mass spectra were measured with a Finnigan
Trace DSQ instrument. High-resolution mass spectral (HRMS)
analyses were measured on an APEX (Bruker) mass III spectrome-
ter using ESI (electrospray ionization) techniques. All spectroscop-
ic data for the products were identical to data from authentic
samples. Starting materials and solvents were purchased from com-
mon commercial sources and were used without additional purifica-
tion. Silica-gel for chromatography was purchased from Qingdao
Haiyang Chemical Co., Ltd. (200–300 mesh). Petroleum ether (PE),
where used, had a boiling range 60–90 °C.
MS (ESI): m/z (%) = 320 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C16H14ClNO4: 319.0611; found:
319.0617.
Ethyl 2-[Acetoxy(2-chloroquinolin-3-yl)methyl]acrylate (3b)
Viscous oil; Rf = 0.50 (hexanes–EtOAc, 4:1).
IR (neat): 2982, 1750, 1720, 1566, 1490, 1370, 1224, 1051, 1024
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.24 (t, J = 8.0 Hz, 3 H, CH2CH3),
2.17 (s, 3 H, CH3), 4.19 (q, J = 8.0 Hz, 2 H, CH2CH3), 5.79 (s, 1 H,
CH2), 6.58 (s, 1 H, CH2), 7.13 (s, 1 H, CH), 7.58 (t, J = 8.0 Hz, 1 H,
ArH), 7.76 (t, J = 8.0 Hz, 1 H, ArH), 7.83 (d, J = 8.0 Hz, 1 H, ArH),
8.03 (d, J = 8.0 Hz, 1 H, ArH), 8.14 (s, 1 H, ArH).
Synthesis of MBH Adduct Acetates (3); General Procedure
A mixture of 2-chloro-3-formyl quinoline (2; 10 mmol) and either
acrylate or acrylonitrile (20 mmol) and DABCO (1.2 mmol) was
kept at r.t. for 2 d under solvent-free conditions. The progress of the
reaction was monitored by TLC. After completion of the reaction,
the mixture was extracted with EtOAc (2 × 20 mL) and the com-
bined organic layer was dried over anhydrous Na2SO4 and concen-
trated in vacuo. The desired product was obtained by flash column
chromatography on silica gel (PE–EtOAc, 4:1) to give a white solid
2¢.
13C NMR (100 MHz, CDCl3): d = 13.9, 20.8, 61.2, 70.0, 126.8,
127.3, 127.7, 128.1, 128.3, 129.9, 130.9, 137.4, 137.8, 147.3, 149.7,
164.5, 169.0.
MS (ESI): m/z (%) = 334 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C17H16ClNO4: 333.0768; found:
333.0762.
AcCl (9.6 mmol) at 0 °C was slowly added to a solution of 2¢ (8
mmol) and Et3N (9.6 mmol) in CH2Cl2 and stirred at r.t. for 30 min.
After completion of the reaction, as indicated by TLC, H2O (30 mL)
was added and the reaction mixture was extracted with EtOAc (2 ×
20 mL). The organic phase was collected, dried over anhydrous
Na2SO4, and evaporated under reduced pressure to give a crude
product, which was purified by flash chromatography on silica gel
(PE–EtOAc, 5:1) to give a white solid 3.
Butyl 2-[Acetoxy(2-chloroquinolin-3-yl)methyl]acrylate (3c)
Viscous oil; Rf = 0.50 (hexanes–EtOAc, 4:1).
IR (neat): 2960, 1751, 1720, 1566, 1490, 1370, 1223, 1051, 1024
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.84 [t, J = 8.0 Hz, 3 H,
(CH2)3CH3], 1.23–1.28 (m, 2 H, CH2), 1.53–1.59 (m, 2 H, CH2),
2.17 (s, 3 H, CH3), 4.13 (t, J = 8.0 Hz, 2 H, CH2), 5.80 (s, 1 H, CH2),
6.59 (s, 1 H, CH2), 7.13 (s, 1 H, CH), 7.58 (t, J = 8.0 Hz, 1 H, ArH),
7.75 (t, J = 8.0 Hz, 1 H, ArH), 7.83 (d, J = 8.0 Hz, 1 H, ArH), 8.03
(d, J = 8.0 Hz, 1 H, ArH), 8.14 (s, 1 H, ArH).
Methyl 2-[Acetoxy(2-chloroquinolin-3-yl)methyl]acrylate (3a)
White solid; mp 81.3–83.2 °C; Rf = 0.50 (hexanes–EtOAc, 4:1).
IR (KBr): 3078, 2950, 1746, 1708, 1632, 1567, 1402, 1299, 1230,
1048, 750 cm–1.
13C NMR (100 MHz, CDCl3): d = 13.5, 18.9, 20.7, 30.0, 65.1, 70.0,
126.7, 127.3, 127.6, 128.1, 128.3, 129.8, 130.9, 137.4, 137.8, 147.3,
149.7, 164.6, 168.9.
1H NMR (400 MHz, CDCl3): d = 2.18 (s, 3 H, CH3), 3.75 (s, 3 H,
OCH3), 5.82 (s, 1 H, CH2), 6.59 (s, 1 H, CH2), 7.12 (s, 1 H, CH),
7.58 (t, J = 8.0 Hz, 1 H, ArH), 7.75 (t, J = 8.0 Hz, 1 H, ArH), 7.83
(d, J = 8.0 Hz, 1 H, ArH), 8.03 (d, J = 8.0 Hz, 1 H, ArH), 8.14 (s,
1 H, ArH).
MS (ESI): m/z (%) = 362 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C19H20ClNO4: 361.1081; found:
361.1083.
13C NMR (100 MHz, CDCl3): d = 20.7, 52.2, 69.9, 126.7, 127.3,
127.6, 128.2, 128.4, 129.7, 130.9, 137.3, 137.5, 147.3, 149.7, 164.9,
168.9.
1-(2-Chloroquinolin-3-yl)-2-cyanoallyl Acetate (3d)
White solid; mp 88.4–89.6 °C; Rf = 0.55 (hexanes–EtOAc, 4:1).
IR (KBr): 2230, 1749, 1617, 1399, 1208, 1035 cm–1.
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Synthesis of Benzo[b][1,8]naphthyridine-3-carboxylate Derivatives
2337
1H NMR (400 MHz, CDCl3): d = 2.26 (s, 3 H, CH3), 6.22 (s, 1 H,
CH2), 6.26 (s, 1 H, CH2), 6.80 (s, 1 H, CH), 7.62 (t, J = 8.0 Hz, 1 H,
ArH), 7.79 (t, J = 8.0 Hz, 1 H, ArH), 7.91 (d, J = 8.0 Hz, 1 H, ArH),
8.04 (d, J = 8.0 Hz, 1 H, ArH), 8.40 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 52.7, 119.5, 123.0, 127.3 (2 ×
CH), 128.2 (2 × CH), 130.3, 132.7, 140.0, 140.9, 151.9, 155.2,
165.2.
MS (ESI): m/z (%) = 239 (100) [M+ + 1].
13C NMR (100 MHz, CDCl3): d = 20.7, 71.1, 115.5, 120.8, 126.8,
127.7, 127.9, 128.3, 131.4, 132.0, 134.6, 137.1, 147.5, 148.0, 168.7.
HRMS: m/z [M+] calcd for C14H10N2O2: 238.0742; found:
238.0739.
MS (ESI): m/z (%) = 287 (100) [M+ + 1].
Preparation of 1,2-Dihydrobenzo[b][1,8]naphthyridine-3-car-
boxylate (4); General Procedure
HRMS: m/z [M+] calcd for C15H11ClN2O2: 286.0509; found:
286.0518.
To a solution of MBH adduct acetate 3 (1 mmol) in 95% EtOH (5
mL), was added either ammonium acetate (1.1 mmol) or primary
amine (1.1 mmol) and Et3N (1.5 mmol). The mixture was stirred
vigorously at r.t. for 4 h, and the progress of the reaction was mon-
itored by TLC. After completion of the reaction, the reaction was
cooled to 0 °C and the desired product 4 was obtained by simple fil-
tration without further purification.
Methyl 2-[Acetoxy(2-chloro-6-methylquinolin-3-yl)meth-
yl]acrylate (3e)
White solid; mp 115.7–116.6 °C; Rf = 0.50 (hexanes–EtOAc, 4:1).
IR (KBr): 2952, 1739, 1710, 1630, 1496, 1401, 1236, 1051, 821
cm–1.
1H NMR (400 MHz, CDCl3): d = 2.17 (s, 3 H, CH3), 2.53 (s, 3 H,
CH3), 3.74 (s, 3 H, OCH3), 5.80 (s, 1 H, CH2), 6.58 (s, 1 H, CH2),
7.09 (s, 1 H, CH), 7.58 (d, J = 8.0 Hz, 1 H, ArH), 7.60 (s, 1 H, ArH),
7.92 (d, J = 8.0 Hz, 1 H, ArH), 8.04 (s, 1 H, ArH).
Methyl 1-Phenyl-1,2-dihydrobenzo[b][1,8]naphthyridine-3-
carboxylate (4a)
Yellow solid; mp 228.0–230.5 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
13C NMR (100 MHz, CDCl3): d = 20.8, 21.5, 52.2, 70.0, 126.6,
126.8, 127.9, 128.4, 129.6, 133.2, 136.8, 137.4, 137.6, 145.9, 148.8,
165.0, 169.0.
IR (KBr): 3145, 1718, 1652, 1615, 1494, 1441, 1384, 1232, 1183,
753 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.83 (s, 3 H, OCH3), 4.91 (s, 2 H,
CH2), 7.17 (t, J = 8.0 Hz, 1 H, ArH), 7.24–7.27 (m, 1 H, ArH),
7.41–7.49 (m, 6 H, ArH), 7.53 (d, J = 8.0 Hz, 2 H, ArH), 7.66 (s,
1 H, ArH).
MS (ESI): m/z (%) = 334 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C17H16ClNO4: 333.0768; found:
333.0771.
13C NMR (100 MHz, CDCl3): d = 50.9, 52.0, 118.0, 123.2, 124.4,
125.4 (2 × CH), 125.5, 127.0, 127.3, 127.6, 128.9 (2 × CH), 130.4,
133.6, 136.3, 144.1, 148.6, 153.5, 165.1.
Methyl 2-[Acetoxy(2,6-dichloroquinolin-3-yl)methyl]acrylate
(3f)
White solid; mp 135.8–136.6 °C; Rf = 0.50 (hexanes–EtOAc, 4:1).
MS (ESI): m/z (%) = 317 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C20H16N2O2: 316.1212; found:
316.1218.
IR (KBr): 3120, 1739, 1711, 1630, 1439, 1401, 1236, 1183, 1051
cm–1.
1H NMR (400 MHz, CDCl3): d = 2.18 (s, 3 H, CH3), 3.75 (s, 3 H,
OCH3), 5.82 (s, 1 H, CH2), 6.59 (s, 1 H, CH2), 7.08 (s, 1 H, CH),
7.69 (d, J = 8.0 Hz, 1 H, ArH), 7.83 (s, 1 H, ArH), 7.97 (d, J = 8.0
Hz, 1 H, ArH), 8.06 (s, 1 H, ArH).
Ethyl 1-Phenyl-1,2-dihydrobenzo[b][1,8]naphthyridine-3-car-
boxylate (4b)
Yellow solid; mp 134.3–135.9 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
IR (KBr): 3228, 1715, 1617, 1400, 1229, 1176 cm–1.
13C NMR (100 MHz, CDCl3): d = 21.0, 52.5, 70.1, 126.7, 127.8,
128.9, 130.1, 131.2, 132.1, 133.5, 136.6, 137.5, 145.9, 150.3, 165.1,
169.1.
1H NMR (400 MHz, CDCl3): d = 1.34 (t, J = 8.0 Hz, 3 H, CH2CH3),
4.28 (q, J = 8.0 Hz, 2 H, CH2CH3), 4.89 (s, 2 H, CH2), 7.16 (t,
J = 8.0 Hz, 1 H, ArH), 7.25–7.27 (m, 1 H, ArH), 7.39–7.47 (m, 6 H,
ArH), 7.52 (d, J = 8.0 Hz, 2 H, ArH), 7.65 (s, 1 H, ArH).
MS (ESI): m/z (%) = 354 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C16H13Cl2NO4: 353.0222; found:
353.0227.
13C NMR (100 MHz, CDCl3): d = 14.2, 50.9, 61.0, 118.0, 123.1,
124.4, 125.4 (2 × CH), 125.8 (2 × CH), 126.9, 127.5, 128.8 (2 × C),
130.3, 133.3, 136.2, 144.1, 148.5, 153.5, 164.6.
Preparation of Methyl Benzo[b][1,8]naphthyridine-3-carboxy-
late (1); Typical Procedure
MS (ESI): m/z (%) = 331 (100) [M+ + 1].
A stirred solution of MBH adduct acetate 3a (319 mg, 1 mmol),
TsNH2 (172 mg, 1 mmol), and K2CO3 (152 mg, 1.1 mmol) in DMF
(5 mL) was mixed at 120 °C for 5 h. After completion of the reac-
tion, as indicated by TLC, H2O (10 mL) was added and the reaction
mixture was extracted with EtOAc (3 × 10 mL). The organic phase
was collected, dried over anhydrous Na2SO4, and evaporated under
reduced pressure to give the crude product 1, which was purified by
flash chromatography on silica gel (PE–EtOAc, 4:1) to give 1 as a
pale solid.
HRMS: m/z [M+] calcd for C21H18N2O2: 330.1368; found:
330.1364.
Butyl 1-Phenyl-1,2-dihydrobenzo[b][1,8]naphthyridine-3-car-
boxylate (4c)
Yellow solid; mp 118.9–120.8 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
IR (KBr): 3132, 1714, 1651, 1614, 1496, 1399, 1239 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.97 [t, J = 8.0 Hz, 3 H,
(CH2)3CH3], 1.39–1.48 (m, 2 H, CH2), 1.66–1.73 (m, 2 H, CH2),
4.23 (t, J = 8.0 Hz, 2 H, CH2), 4.90 (s, 2 H, CH2), 7.16 (t, J = 8.0 Hz,
1 H, ArH), 7.23–7.27 (m, 1 H, ArH), 7.39–7.46 (m, 6 H, ArH), 7.50
(s, 1 H, ArH), 7.52 (d, J = 8.0 Hz, 1 H, ArH), 7.66 (s, 1 H, ArH).
Yield: 190 mg (80%); yellowish solid; mp 256.8–258.1 °C;
Rf = 0.40 (hexanes–EtOAc, 2:1).
IR (KBr): 3132, 1705, 1618, 1400, 1338, 1256, 1159, 1090 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.07 (s, 3 H, OCH3), 7.68 (t,
J = 8.0 Hz, 1 H, ArH), 7.94 (t, J = 8.0 Hz, 1 H, ArH), 8.11 (d,
J = 8.0 Hz, 1 H, ArH), 8.44 (d, J = 8.0 Hz, 1 H, ArH), 8.99 (s, 1 H,
ArH), 9.11 (s, 1 H, ArH), 9.80 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 13.9, 19.4, 30.9, 51.1, 65.1, 118.3,
123.4, 124.6, 125.6 (3 × CH), 126.1, 127.2, 127.8, 129.1 (2 × CH),
130.5, 133.5, 136.4, 144.3, 148.8, 153.7, 164.9.
MS (ESI): m/z (%) = 359 (100) [M+ + 1].
Synthesis 2009, No. 14, 2333–2340 © Thieme Stuttgart · New York

2338
W. Zhong et al.
PAPER
Methyl 1-(4-Methoxyphenyl)-1,2-dihydrobenzo[b][1,8]naph-
thyridine-3-carboxylate (4h)
HRMS: m/z [M+] calcd for C23H22N2O2: 358.1681; found:
358.1679.
Yellow solid; mp 208.5–209.9 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
1-Phenyl-1,2-dihydrobenzo[b][1,8]naphthyridine-3-carboni-
trile (4d)
Yellow solid; mp 179.8–182.1 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
IR (KBr): 3139, 3007, 1715, 1651, 1613, 1509, 1443, 1381, 1239,
1180 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H, OCH3), 3.85 (s, 3 H,
OCH3), 4.86 (s, 2 H, CH2), 6.96–6.99 (m, 2 H, ArH), 7.13 (t, J = 8.0
Hz, 1 H, ArH), 7.32–7.44 (m, 4 H, ArH), 7.49 (d, J = 8.0 Hz, 2 H,
ArH), 7.60 (s, 1 H, ArH).
IR (KBr): 3143, 2201, 1641, 1618, 1493, 1400, 753 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.81 (s, 2 H, CH2), 7.20–7.29 (m,
3 H, ArH), 7.37–7.47 (m, 6 H, ArH), 7.55 (d, J = 8.0 Hz, 1 H, ArH),
7.64 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 51.6, 52.0, 55.4, 114.3 (2 × CH),
117.7, 122.9, 124.2, 125.2, 126.9, 127.0 (2 × CH), 127.6, 130.3,
133.8, 136.2, 137.0, 148.8, 153.8, 157.3, 165.1.
13C NMR (100 MHz, CDCl3): d = 29.6, 51.6, 106.7, 116.8, 123.7,
124.2, 125.2 (2 × CH), 125.9, 127.2, 127.8, 129.0 (2 × CH), 131.0,
136.3, 138.6, 143.2, 148.6, 152.5.
MS (ESI): m/z (%) = 347 (100) [M+ + 1].
MS (ESI): m/z (%) = 284 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C21H18N2O3: 346.1317; found:
346.1310.
HRMS: m/z [M+] calcd for C19H13N3: 283.1109; found: 283.1114.
Methyl 7-Methyl-1-phenyl-1,2-dihydrobenzo[b][1,8]naphthyri-
dine-3-carboxylate (4e)
Yellow solid; mp 224.4–225.2 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
Methyl 1-(4-Chlorophenyl)-1,2-dihydrobenzo[b][1,8]naph-
thyridine-3-carboxylate (4i)
Yellow solid; mp 177.0–178.8 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
IR (KBr): 3147, 1715, 1650, 1494, 1400, 1236, 1186, 823 cm–1.
IR (KBr): 3133, 1718, 1706, 1651, 1615, 1494, 1399, 1239 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.40 (s, 3 H, CH3), 3.83 (s, 3 H,
OCH3), 4.89 (s, 2 H, CH2), 7.25–7.32 (m, 3 H, ArH), 7.44–7.52 (m,
6 H, ArH), 7.61 (s, 1 H, ArH).
1H NMR (400 MHz, DMSO-d6): d = 3.76 (s, 3 H, OCH3), 4.80 (s,
2 H, CH2), 7.21 (t, J = 8.0 Hz, 1 H, ArH), 7.28 (d, J = 8.0 Hz, 1 H,
ArH), 7.43–7.50 (m, 5 H, ArH), 7.59 (s, 1 H, ArH), 7.64 (d, J = 8.0
Hz, 1 H, ArH), 8.05 (s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 21.1, 44.8, 52.1, 118.0, 124.2,
125.2 (2 × CH), 125.4, 125.5, 126.4, 126.9, 129.2 (2 × CH), 132.6,
133.0, 133.6, 136.1, 142.3, 143.8, 152.8, 165.0.
13C NMR (100 MHz, DMSO-d6): d = 50.4, 52.0, 117.6, 123.2,
124.2, 125.3, 126.0, 127.4 (2 × CH), 127.9, 128.6 (2 × CH), 129.2,
130.4, 132.7, 136.5, 142.7, 147.7, 152.8, 164.3.
MS (ESI): m/z (%) = 331 (100) [M+ + 1].
MS (ESI): m/z (%) = 351 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C21H18N2O2: 330.1368; found:
330.1365.
HRMS: m/z [M+] calcd for C20H15ClN2O2: 350.0822; found:
350.0816.
Methyl 7-Chloro-1-phenyl-1,2-dihydrobenzo[b][1,8]naphthyri-
dine-3-carboxylate (4f)
Yellow solid; mp 241.4–245.0 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
Methyl 1-(3,4-Difluorophenyl)-1,2-dihydrobenzo[b][1,8]naph-
thyridine-3-carboxylate (4j)
Yellow solid; mp 186.5–186.9 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
IR (KBr): 3131, 1719, 1652, 1616, 1497, 1399, 1077 cm–1.
IR (KBr): 3128, 1707, 1650, 1613, 1516, 1480, 1398, 1218, 1174
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.77 (s, 3 H, OCH3), 4.84 (s,
2 H, CH2), 7.23 (d, J = 8.0 Hz, 1 H, ArH), 7.26–7.29 (m, 1 H, ArH),
7.39 (d, J = 2.4 Hz, 1 H, ArH), 7.41–7.46 (m, 4 H, ArH), 7.57 (s,
1 H, ArH), 7.72 (d, J = 2.0 Hz, 1 H, ArH), 8.00 (s, 1 H, ArH).
1H NMR (400 MHz, DMSO-d6): d = 3.77 (s, 3 H, OCH3), 4.80 (s,
2 H, CH2), 7.22 (t, J = 8.0 Hz, 1 H, ArH), 7.29–7.33 (m, 2 H, ArH),
7.44–7.53 (m, 2 H, ArH), 7.59–7.66 (m, 3 H, ArH), 8.06 (s, 1 H,
ArH).
13C NMR (100 MHz, CDCl3): d = 51.2, 52.2, 118.7, 124.9, 125.5 (3
× CH), 125.9, 126.2 (2 × CH), 128.3, 129.1 (2 × CH), 130.9, 133.1,
135.2, 143.7, 146.8, 153.6, 164.9.
13C NMR (100 MHz, DMSO-d6): d = 50.6, 51.9, 115.4, 115.6,
117.1, 117.3, 117.5, 122.7, 123.2, 124.2, 125.2, 126.0, 127.9, 130.5,
132.7, 136.5, 140.6, 147.6, 152.8, 164.3.
MS (ESI): m/z (%) = 351 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C20H15ClN2O2: 350.0822; found:
350.0824.
MS (ESI): m/z (%) = 353 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C20H14F2N2O2: 352.1023; found:
352.1026.
Methyl 1-p-Tolyl-1,2-dihydrobenzo[b][1,8]naphthyridine-3-
carboxylate (4g)
Yellow solid; mp 210.0–211.7 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
Methyl 1-Benzyl-1,2-dihydrobenzo[b][1,8]naphthyridine-3-
carboxylate (4k)
Yellow solid; mp 177.0–179.0 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
IR (KBr): 3136, 1717, 1652, 1610, 1489, 1442, 1399, 1232, 1178
cm–1.
IR (KBr): 3126, 3023, 1703, 1650, 1614, 1393, 1244, 1217, 1080
cm–1.
1H NMR (400 MHz, CDCl3): d = 2.39 (s, 3 H, CH3), 3.81 (s, 3 H,
OCH3), 4.87 (s, 2 H, CH2), 7.14 (t, J = 8.0 Hz, 1 H, ArH), 7.23 (d,
J = 8.0 Hz, 2 H, ArH), 7.32 (d, J = 8.0 Hz, 2 H, ArH), 7.38–7.51 (m,
4 H, ArH), 7.61 (s, 1 H, ArH).
1H NMR (400 MHz, CDCl3): d = 3.77 (s, 3 H, OCH3), 4.46 (s, 2 H,
CH2), 4.97 (s, 2 H, CH2), 7.13 (t, J = 8.0 Hz, 1 H, ArH), 7.24–7.33
(m, 3 H, ArH), 7.39–7.47 (m, 6 H, ArH), 7.50 (d, J = 8.0 Hz, 1 H,
ArH).
13C NMR (100 MHz, CDCl3): d = 21.1, 51.2, 52.0, 117.9, 123.0,
124.3, 125.3 (2 × CH), 125.4, 126.9, 127.6, 129.5 (2 × CH), 130.3,
133.7, 135.1, 136.2, 141.5, 148.7, 153.6, 165.1.
13C NMR (100 MHz, CDCl3): d = 48.5, 50.4, 52.0, 116.8, 122.4,
123.8, 124.7, 126.3, 127.2, 127.7, 128.4 (2 × CH), 128.5 (2 × CH),
130.4, 133.8, 136.1, 137.4, 149.4, 153.7, 165.2.
MS (ESI): m/z (%) = 331 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C21H18N2O2: 330.1368; found:
330.1369.
MS (ESI): m/z (%) = 331 (100) [M+ + 1].
Synthesis 2009, No. 14, 2333–2340 © Thieme Stuttgart · New York

PAPER
Synthesis of Benzo[b][1,8]naphthyridine-3-carboxylate Derivatives
2339
HRMS: m/z [M+] calcd for C21H18N2O2: 330.1368; found:
330.1373.
13C NMR (100 MHz, DMSO-d6): d = 42.7, 51.9, 116.1, 121.9,
123.6, 124.5, 125.2, 128.1, 130.4, 132.9, 135.8, 148.9, 154.7, 164.7.
MS (ESI): m/z (%) = 241 (100) [M+ + 1].
Methyl 1-Cyclohexyl-1,2-dihydrobenzo[b][1,8]naphthyridine-
3-carboxylate (4l)
Yellow solid; mp 182.1–184.3 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
HRMS: m/z [M+] calcd for C14H12N2O2: 240.0899; found:
240.0897.
IR (KBr): 3132, 2929, 2852, 1719, 1657, 1616, 1492, 1400, 1231
cm–1.
Methyl 1-Tosyl-1,2-dihydrobenzo[b][1,8]naphthyridine-3-car-
boxylate (4p)
White solid; mp 208.3–209.0 °C; Rf = 0.45 (hexanes–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 1.50–1.62 (m, 5 H, CH2), 1.71–
1.88 (m, 5 H, CH2), 3.82 (s, 3 H, OCH3), 4.48 (s, 2 H, CH2), 4.94–
4.95 (m, 1 H, CH), 7.08 (t, J = 8.0 Hz, 1 H, ArH), 7.34 (s, 1 H,
ArH), 7.40–7.44 (m, 3 H, ArH), 7.52 (d, J = 8.0 Hz, 1 H, ArH).
IR (KBr): 3133, 1705, 1618, 1399, 1338, 1255, 1159, 1089 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.40 (s, 3 H, CH3), 3.88 (s, 3 H,
OCH3), 5.03 (s, 2 H, CH2), 7.30–7.38 (m, 3 H, ArH), 7.48 (s, 1 H,
ArH), 7.58–7.63 (m, 2 H, ArH), 7.76–7.81 (m, 2 H, ArH), 8.18 (d,
J = 8.0 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 25.9 (3 × CH2), 28.6 (2 × CH2),
42.8, 51.9, 52.6, 117.6, 122.0, 123.4, 124.9, 126.2, 127.5, 130.1,
133.8, 135.6, 149.5, 153.6, 165.5.
13C NMR (100 MHz, CDCl3): d = 21.6, 45.5, 52.3, 118.7, 125.5,
125.6, 126.7, 127.7, 127.8, 128.9 (2 × CH), 129.1 (2 × CH), 130.8,
132.8, 136.4, 137.1, 144.1, 146.8, 148.5, 164.6.
MS (ESI): m/z (%) = 323 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C20H22N2O2: 322.1681; found:
322.1680.
MS (ESI): m/z (%) = 395 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C21H18N2O4S: 394.0987; found:
394.0986.
Methyl 1-Butyl-1,2-dihydrobenzo[b][1,8]naphthayridine-3-car-
boxylate (4m)
Yellow solid; mp 112.9–114.5 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
Methyl 4-(4-Methylphenylsulfonamido)benzo[b][1,8]naph-
thyridine-3-carboxylate (5a)
IR (KBr): 3137, 2957, 2926, 1719, 1651, 1614, 1510, 1400, 1235,
1175 cm–1.
A stirred solution of 3a (319 mg, 1 mmol), TsNH2 (430 mg, 2.5
mmol), and K2CO3 (152 mg, 1.1 mmol) in DMF (5 mL) was heated
at 120 °C for 5 h. After completion of the reaction, as indicated by
TLC, H2O (10 mL) was added and the reaction mixture was extract-
ed with EtOAc (3 × 10 mL). The organic phase was collected, dried
over anhydrous Na2SO4, and evaporated under reduced pressure to
give the crude product 5a, which was purified by flash chromatog-
raphy on silica gel (PE–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 0.99 [t, J = 8.0 Hz, 3 H,
(CH2)3CH3], 1.39–1.45 (m, 2 H, CH2), 1.63–1.70 (m, 2 H, CH2),
3.66 (t, J = 8.0 Hz, 2 H, CH2), 3.82 (s, 3 H, OCH3), 4.56 (s, 2 H,
CH2), 7.08 (t, J = 8.0 Hz, 1 H, ArH), 7.36 (s, 1 H, ArH), 7.40–7.44
(m, 3 H, ArH), 7.51 (d, J = 8.0 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 14.0, 20.2, 27.9, 47.2, 49.0, 52.0,
117.1, 122.0, 123.5, 124.6, 126.2, 127.7, 130.3, 134.1, 135.7, 149.7,
153.8, 165.4.
Yield: 346 mg (85%); yellow solid; mp 271.5–273.4 °C; Rf = 0.30
(hexanes–EtOAc, 2:1).
MS (ESI): m/z (%) = 297 (100) [M+ + 1].
IR (KBr): 3414, 3133, 1726, 1619, 1508, 1401, 1261, 1081 cm–1.
HRMS: m/z [M+] calcd for C18H20N2O2: 296.1525; found:
296.1519.
1H NMR (400 MHz, DMSO-d6): d = 2.43 (s, 3 H, CH3), 3.93 (s, 3 H,
OCH3), 7.43–7.46 (m, 3 H, ArH), 7.78 (d, J = 8.0 Hz, 1 H, ArH),
7.88–7.92 (m, 3 H, ArH), 8.53 (d, J = 8.0 Hz, 1 H, ArH), 9.31 (s,
1 H, ArH), 9.75 (s, 1 H, ArH), 13.49 (s, 1 H, NH).
Methyl 1-tert-Butyl-1,2-dihydrobenzo[b][1,8]naphthyridine-3-
carboxylate (4n)
Yellow solid; mp 127.4–130.5 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
13C NMR (100 MHz, DMSO-d6): d = 20.9, 52.4, 111.1, 118.2,
119.4, 119.5, 123.8, 125.6 (2 × CH), 127.8, 129.4 (2 × CH), 135.2,
139.9, 141.1, 141.4, 142.0, 151.2, 155.5, 160.2, 164.4.
IR (KBr): 3136, 2956, 1693, 1615, 1436, 1397, 1249, 720 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.61 (s, 9 H, t-Bu), 3.76 (s,
3 H, OCH3), 4.45 (s, 2 H, CH2), 7.16–7.19 (m, 1 H, ArH), 7.42 (s,
1 H, ArH), 7.47 (d, J = 3.2 Hz, 2 H, ArH), 7.57 (d, J = 8.0 Hz, 1 H,
ArH), 7.81 (s, 1 H, ArH).
MS (ESI): m/z (%) = 406 (100) [M+ – 1).
HRMS: m/z [M+] calcd for C21H17N3O4S: 407.0940; found:
407.0937.
13C NMR (100 MHz, DMSO-d6): d = 27.5 (3 × CH3), 43.9, 51.8,
56.9, 119.5, 122.5, 122.9, 125.9, 126.5, 127.6, 130.0, 133.2, 135.1,
147.4, 154.4, 164.7.
Methyl 4-(4-Chlorophenylsulfonamido)benzo[b][1,8]naph-
thyridine-3-carboxylate (5b)
A stirred solution of 3a (319 mg, 1 mmol), TsNH2 (172 mg, 1
mmol), and K2CO3 (152 mg, 1.1 mmol) in DMF (5 mL) was heated
at 90 °C for 15 min. p-Chlorobenzenesulfonamide (287 mg, 1.5
mmol) was added and the reaction was stirred at 120 °C for 4 h. Af-
ter completion of the reaction, as indicated by TLC, H2O (10 mL)
was added and the reaction mixture was extracted with EtOAc
(3 × 10 mL). The organic phase was collected, dried over anhydrous
Na2SO4, and evaporated under reduced pressure to give the crude
product 5b, which was purified by flash chromatography on silica
gel (PE–EtOAc, 2: 1).
MS (ESI): m/z (%) = 297 (100) [M+ + 1].
HRMS: m/z [M+] calcd for C18H20N2O2: 296.1525; found:
296.1520.
Methyl 1,2-Dihydrobenzo[b][1,8]naphthyridine-3-carboxylate
(4o)
Yellow solid; mp 186.2–188.1 °C; Rf = 0.60 (hexanes–EtOAc, 4:1).
IR (KBr): 3142, 1709, 1651, 1615, 1437, 1398, 1242, 754 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.75 (s, 3 H, OCH3), 4.46 (s,
2 H, CH2), 7.08 (t, J = 8.0 Hz, 1 H, ArH), 7.16 (s, 1 H, NH), 7.32 (d,
J = 8.0 Hz, 1 H, ArH), 7.39–7.44 (m, 2 H, ArH), 7.52 (d, J = 8.0 Hz,
1 H, ArH), 7.79 (s, 1 H, ArH).
Yield: 354 mg (83%); yellow solid; mp 272.0–273.6 °C; Rf = 0.30
(hexanes–EtOAc, 2:1).
IR (KBr): 3427, 3170, 1724, 1619, 1508, 1400, 1259, 1080 cm–1.
Synthesis 2009, No. 14, 2333–2340 © Thieme Stuttgart · New York

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W. Zhong et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 4.01 (s, 3 H, OCH3), 7.40 (t,
J = 8.0 Hz, 1 H, ArH), 7.52–7.57 (m, 3 H, ArH), 7.77 (t, J = 8.0 Hz,
1 H, ArH), 8.05–8.09 (m, 2 H, ArH), 8.68 (d, J = 8.0 Hz, 1 H, ArH),
9.27 (s, 1 H, ArH), 9.84 (s, 1 H, ArH).
(3) Nithyadevi, V.; Rajendran, S. P. J. Heterocycl. Chem. 2006,
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2003, 103, 811. (c) Shi, Y.; Shi, M. Eur. J. Org. Chem.
2007, 2905. (d) Masson, G.; Housseman, C.; Zhu, J. Angew.
Chem. Int. Ed. 2007, 46, 4614. (e) Lee, K. Y.; Gowrisankar,
S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1481.
(5) (a) Shi, M.; Liu, X. G. Org. Lett. 2008, 10, 1043.
(b) Basavaiah, D.; Roy, S. Org. Lett. 2008, 10, 1819.
(c) Zhou, A.; Hanson, P. R. Org. Lett. 2008, 10, 2951.
(d) Krishna, P. R.; Reddy, P. S. J. Comb. Chem. 2008, 10,
426. (e) Mandal, S. K.; Paira, M.; Roy, S. C. J. Org. Chem.
2008, 73, 3823. (f) Jiang, Y. Q.; Shi, Y. L.; Shi, M. J. Am.
Chem. Soc. 2008, 130, 7202. (g) Yadav, J. S.; Reddy, B. V.
S.; Mandal, S. S.; Singh, A. P.; Basak, A. K. Synthesis 2008,
1943. (h) Garre, S.; Parker, E.; Ni, B.; Headley, A. D. Org.
Biomol. Chem. 2008, 6, 3041. (i) Abermil, N.; Masson, G.;
Zhu, J. J. Am. Chem. Soc. 2008, 130, 12596.
(6) (a) Kim, J. M.; Kim, K. H.; Kim, T. H.; Kim, J. N.
Tetrahedron Lett. 2008, 49, 3248. (b) Lee, H. S.; Kim, S.
H.; Gowrisankar, S.; Kim, J. N. Tetrahedron 2008, 64,
7183. (c) Lu, A.; Xu, X.; Gao, P.; Zhou, Z.; Song, H.; Tang,
C. Tetrahedron: Asymmetry 2008, 19, 1886. (d) Nag, S.;
Mishra, A.; Batra, S. Tetrahedron 2008, 64, 10162.
(e) Kim, J. M.; Kim, S. H.; Kim, S. H.; Kim, J. N. Bull.
Korean Chem. Soc. 2008, 29, 1583.
(7) (a) Chen, J.; Su, W.; Hua, H.; Liu, M.; Jin, C. Green Chem.
2007, 9, 972. (b) Chen, J.; Hua, H.; Jin, C.; Zhang, X.; Xie,
Y.; Su, W. Green Chem. 2006, 8, 330.
(8) (a) Zhong, W.; Zhao, Y.; Su, W. Tetrahedron 2008, 64,
5491. (b) Zhong, W.; Lin, F.; Chen, R.; Su, W. Synthesis
2008, 2561. (c) Zhong, W.; Zhao, Y.; Guo, B.; Wu, P.; Su,
W. Synth. Commun. 2008, 38, 3291.
(9) (a) Ali, M. M.; Tasneem Rajanna, K. C.; Sai-Prakash, P. K.
Synlett 2001, 251. (b) Su, W.; Zhuang, Y.; Wu, D.; Zhong,
W. Org. Prep. Proced. Int. 2007, 39, 195. (c) Su, W.; Li, Z.;
Zhao, L. Org. Prep. Proced. Int. 2007, 39, 495; Method for
the preparation of 2-chloro-3-formyl quinolines 2: the
reaction was carried out using bis(trichloromethyl)carbonate
BTC/DMF instead of the DMF/POCl3 system..
(10) (a) Chung, Y. M.; Lee, H. J.; Hwang, S. S.; Kim, J. N. Bull.
Korean Chem. Soc. 2001, 22, 799. (b) Chung, Y. M.; Kim,
J. N.; Im, Y. J. Tetrahedron Lett. 2002, 43, 6209.
13C NMR (100 MHz, CDCl3): d = 52.6, 112.2, 117.4, 119.9, 120.5,
124.0, 127.7 (2 × CH), 128.9 (2 × CH), 129.1, 135.2, 137.9, 139.7,
141.8, 142.6, 151.0, 155.8, 161.2, 165.0.
MS (ESI): m/z (%) = 426 (100) [M+ – 1].
HRMS: m/z [M+] calcd for C20H14ClN3O4S: 427.0394; found:
427.0388.
Acknowledgment
We thank the National Key Technology R&D Program [No:
2007BAI34B01], the National Natural Science Foundation of
China [20676123 and 20876147], and the Zhejiang Province Pro-
ject of Sciences and Technology [No: 2006C11018] for financial
support.
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Synthesis 2009, No. 14, 2333–2340 © Thieme Stuttgart · New York