Chinese Chemical Letters 27 (2016) 261–264

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Chinese Chemical Letters

journal homepage: www.elsevier.com/locate/cclet

Original article

Synthesis of novel benzo[b]pyrimido[40 ,50 :5,4]thieno[2,3-

e][1,6]naphthyridine-8-ones via Pictet–Spengler cyclization
Dao-Lin Wang *[1_TD$IF], Xiao-Ce Shi, Yong-Yang Wang, Jian Ma
College of Chemistry and Chemical Engineering, Liaoning Key Laboratory of Synthesis and Application of Functional Compound, Bohai University, Jinzhou
121003, China

A R T I C L E I N F O A B S T R A C T

Article history: An efficient method for the synthesis of novel benzo[b]pyrimido[40 ,50 :5,4]thieno[2,3e][5_TD$IF]-[1,6]naphthyr-
Received 17 August 2015 idine-8-one derivatives via Pictet–Spengler cyclization is reported. The reaction of 4-(3-aminopyr-
Received in revised form 20 September 2015 imido[4,5-d]thieno-2-yl)quinoline-2-ones, which could be obtained from Thorpe–Ziegler isomerization
Accepted 29 September 2015
of 4-bromomethylquinoline-2-ones and 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine,
Available online 26 October 2015
with aromatic aldehydes in the presence of BF3OEt2 gives pyrimidothieno[1,6]naphthyridines in good
yields.
Keywords:
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
4-Bromomethylquinoline-2-one
5-Cyano-6-thioxopyrimidine
Published by Elsevier B.V. All rights reserved.
Pyrimido[40 ,50 :5,4]thieno[2,3-
e][1,6]naphthyridine
Thorpe–Ziegler reaction
Pictet–Spengler reaction

1. Introduction account of the pharmaceutical interest in these compounds, the

1,6-Naphthyridine derivatives, nitrogen heterocycles contain-
ing two pyridine rings, are widely distributed in nature [1], and
they are considered to be ‘‘privileged structures’’ in drug discovery.
In particular, functionalized [1,6]naphthyridines and their benzo/
hetero-fused analogues have displayed a wide range of physiolog-
ical activities, such as anticancer [2], anti HIV-1 [3], antimicrobial
[4] and cytotoxic activities [5]. Consequently, various methods
havebeen reported for the synthesis of these compounds including
multi component reactions [6], metal-catalyzed reactions [7],
cycloaddition reactions [8] and other approaches [9].
The Pictet–Spengler reaction [10] has become one of the most
prominent strategies for carbon–carbon bond formation in
synthetic organic chemistry with excellent functional group
tolerance, regio- and stereo-selectivity. From this perspective,
the modified Pictet–Spengler reactions are attained considerable
important for the synthesis of various products and novel
heterocycles of biological interest [11].
In addition, pyrimidine derivatives and pyrimidine-fused
compounds are of interest in medicinal chemistry and chemical
biology due to their wide range of biological activities [12]. On
* Corresponding author.
E-mail address: wangdaolin@sina.com (D.-L. Wang).
development of highthroughput methodologies for the synthesis
of novel pyrimidine-fused heterocyclic scaffolds is in continuous
expansion [13].
In our previous studies [14] we reported the synthesis of fused
nitrogen-containing ring systems. As part of our program to
develop new methods for the construction of important hetero-
cycles using Pictet–Spengler reaction, herein, a convenient
approach for the synthesis of novel benzo[b]pyrimi-
do[40 ,50 :5,4]thieno[2,3-e][1,6]naphthyridine derivatives from
readily accessible 4-bromomethyl quinoline-2-one [15] using
Pictet–Spengler reactions a key step is described (Scheme 1).
2. Experimental
2.1. Preparation of 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline-
2-ones (3)
To a solution of 4-bromomethylquinoline-2-one 1 (20.0 mmol)
in DMF (25 mL) was added 5-cyano-1,6-dihydro-4-methyl-2-
phenyl-6-thioxopyrimidine 2 [16] (6.81 g, 30.0 mmol) and anhy-
drous potassium carbonate (5.52 g, 40.0 mmol). The mixture was
heated at 80 8C for 5 h. After cooling to room temperature, water
(50 mL) was added and stirred for 20 min. The solid was filtered
and recrystallized from HOAc to give 3.

http://dx.doi.org/10.1016/j.cclet.2015.10.008
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
[(Schem_1)TD$FIG]
262 D.-L. Wang et al. / Chinese Chemical Letters 27 (2016) 261–264
O O
Me
Br Me
CN N NH 2
N
R Me
Ph N S 2
H
S N
N O
Me R R
1 3
a R = Me, b R = OMe
Scheme 1. Syntheses of benzo[b]pyrimido[40 ,50 :5,4]thieno[2,3-e][1,6]naphthyridine-8-ones.
3a: 82%. Mp > 300 8C. IR (KBr, cm1): n 3403, 3373 (NH2), 1686
5O). 1H NMR (400 MHz, CF3CO2D): d 2.51 (s, 3H), 3.01 (s, 3H),
(C5
4.27 (s, 3H), 7.67–7.70 (m, 3H), 7.77–7.81 (m, 2H), 7.97–7.99 (m,
2H), 8.25–8.30 (m, 2H). 13C NMR (100 MHz, CF3CO2D): d 16.8, 18.9,
32.3, 115.9, 116.7, 121.3, 123.7, 124.0, 125.8, 127.7, 128.1, 128.3,
129.5, 129.6, 134.9, 136.2, 137.2, 138.7, 139.8, 144.3, 154.7, 160.5.
Anal. Calcd. for C24H20N4OS: C 69.88, H 4.98, N 13.58, S 7.35.
Found: C 69.97, H 5.14, N 13.73, S 7.46.
3b: 86%. Mp > 300 8C. IR (KBr, cm1): n 3441, 3445 (NH2), 1682
5O). 1H NMR (400 MHz, CF3CO2D): d 3.32 (s, 3H), 3.90 (s, 3H),
(C5
4.28 (s, 3H), 7.33 (s, 1H), 7.68–7.78 (m, 5H), 8.08–8.09 (m, 1H),
8.29–8.31 (m, 2H). 13C NMR (100 MHz, CF3CO2D): d 16.8, 32.5, 55.2,
107.9, 116.7, 118.6, 123.0, 123.7, 124.1, 127.7, 128.1, 128.3, 129.5,
129.6, 132.9, 135.0, 138.7, 143.6, 154.7, 158.6, 159.7. Anal. Calcd.
for C24H20N4O2S: C 67.27, H 4.70, N 13.07, S 7.48. Found: C 67.38, H
4.85, N 13.15, S 7.59.
2.2. Preparation of benzo[b]pyrimido[40 ,50 :5,4]thieno[2,3e][1,6]-
naphthyridine-8-one derivatives
A mixture of 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline-
2-one 3 (1.0 mmol), aromatic aldehyde 4 (1.0 mmol) and BF3OEt2
(14.2 mg, 0.1 mmol) in DMF (15 mL) was heated for 4–12 h at
100 8C. After the completion of the reaction judged by TLC analysis,
the reaction mixture was cooled to room temperature. Water
(30 mL) was added and the mixture was stirred for 30 min. The
solid was filtered and recrystallized from DMF to afford the
corresponding products (5a–k)1[1_TD$IF].
1
Physical and spectral (IR, NMR, Anal.) data:
5a: Mp > 300 8C. IR (KBr, cm1): n 1670 (C5 5O). 1H NMR (400 MHz, CF3CO2D): d
2.69 (s, 3H), 3.38 (s, 3H), 3.75 (s, 3H), 7.44–7.45 (m, 1H), 7.56–7.58 (m, 7H), 7.71–
7.72 (m, 2H), 8.59 (s, 1H), 8.67–8.69 (m, 2H). 13C NMR (100 MHz, CF3CO2D): d 21.2,
23.1, 30.4, 115.1, 116.8, 117.4, 121.5, 123.2, 127.4, 127.7, 128.0, 128.6, 128.8, 128.9,
131.2, 132.4, 132.9, 137.0, 137.9, 138.2, 143.2, 150.7, 159.9, 160.8, 162.4, 166.2,
170.6. Anal. Calcd. for C31H22N2OS: C 74.68, H 4.45, N 11.24, S 6.43. Found: C 74.79,
H 4.54, N 11.37, S 6.58.
5b: Mp > 300 8C. IR (KBr, cm1): n 1674 (C5 5O). 1H NMR (400 MHz, CF3CO2D): d
2.51 (s, 3H), 2.66 (s, 3H), 3.43 (s, 3H), 3.77 (s, 3H), 7.36–7.38 (m, 2H), 7.44–7.46 (m,
1H), 7.58–7.64 (m, 6H), 8.62 (s, 1H), 8.69 (m, 2H). 13C NMR (100 MHz, CF3CO2D): d
19.1, 19.5, 30.9, 39.1, 112.2, 113.2, 114.9, 116.0, 116.8, 117.4, 118.7, 127.1, 127.4,
128.5, 129.0, 129.6, 129.8, 131.4, 131.9, 135.9, 137.2, 137.8, 138.5, 140.9, 143.9,
144.1, 157.3, 159.6. Anal. Calcd. for C32H24N4OS: C 74.98, H 4.72, N 10.93, S 6.26.
Found: C 75.14, H 4.86, N 11.08, S 6.42.
5c: Mp > 300 8C. IR (KBr, cm1): n 1681 (C5 5O). 1H NMR (400 MHz, CF3CO2D): d
2.39 (s, 3H), 3.00 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 6.99–7.03 (m, 2H), 7.21–7.25 (m,
1H), 7.37–7.39 (m, 1H), 7.47–7.50 (m, 1H), 7.54–7.58 (m, 4H), 8.21 (s, 1H), 8.60–8.61
(m, 2H). 13C NMR (100 MHz, CF3CO2D): d 20.8, 23.8, 29.6, 55.4, 112.4, 114.5, 117.2,
118.5, 118.7, 122.1, 124.2, 125.2, 127.4, 128.5, 128.6, 128.8, 129.7, 130.6, 132.0,
132.5, 136.5, 137.4, 138.2, 141.5, 142.8, 159.8, 160.2, 161.1, 163.7, 167.3. Anal.
Calcd. for C32H24N4O2S: C 72.71, H 4.58, N 10.60, S 6.07. Found: C 72.86, H 4.69, N
10.73, S 6.19.
5d: Mp > 300 8C. IR (KBr, cm1): n 1684 (C5 5O). 1H NMR (400 MHz, CF3COOD): d
2.67 (s, 3H), 3.34 (s, 3H), 4.09 (s, 3H), 7. 18–7.22 (m, 4H), 7.47–7.49 (m, 1H), 7.63–
7.69 (m, 3H), 7.74–7.82 (m, 4H). 13C NMR (100 MHz, CF3COOD): d 19.2, 30.8, 39.1,
112.2, 113.2, 115.0, 116.0, 116.5, 116.7, 117.0, 121.1, 126.4, 126.5, 127.9, 128.3,
128.6, 129.7, 129.8, 135.3, 135.4, 136.4, 136.5, 137.0, 137.9, 140.8, 156.5,161.6.
Anal. Calcd. for C31H21ClN4OS: C 69.85, H 3.97, N 10.51, S 6.02. Found: C 69.98, H
4.15, N 10.67, S 6.11.
R'
Me
N N
Me
R'CHO (4)
BF 3·OEt 2 S N
N N
Ph
Ph 5
3. Results and discussion
In this letter, we have presented a new and efficient method
for the synthesis of benzo[b]pyrimido[40 ,50 :5,4]thieno[2,3-
e][1,6]naphthyridine-8-ones can be readily synthesized from
4-bromomethylquinoline-2-ones and 5-cyano-1,6-dihydro-4-
methyl-2-phenyl-6-thioxopyrimidine, by using a Thorpe–Zieg-
ler isomerization and Pictet–Spengler reaction (Scheme 1).
In this study, the key intermediate amine 4-(3-aminopyri-
mido[4,5-d]thieno-2-yl)quinoline-2-ones 3 was obtained by the
5e: Mp > 300 8C. IR (KBr, cm1): n 1689 (C5 5O). 1H NMR (400 MHz, CF3COOD): d
2.72 (s, 3H), 3.22 (s, 3H), 3.33 (s, 3H), 7.21–7.29 (m, 1H), 7.28–7.29 (m, 2H), 7.64–
7.65 (m, 1H), 7.72–7.86 (m, 5H), 8.19–8.21 (m, 1H), 8.41–8.44 (m, 1H), 8.71 (s, 1H).
13
C NMR (100 MHz, CF3CO2D): d 30.8, 33.3, 39.0, 112.2, 115.1, 115.4, 116.0, 116.5 (d,
J = 23.5 Hz), 116.6, 117.1, 120.7 (d, J = 8.2 Hz), 126.5, 126.8, 127.8, 128.6, 129.7,
129.9, 130.7, 130.8, 135.4, 135.7, 136.6, 137.2, 141.4, 145.8 (d, J = 2.5 Hz), 156.6 (d,
J = 243.4 Hz), 160.0. Anal. Calcd. for C31H21FN4OS: C 72.08, H 4.10, N 10.85, S 6.21.
Found: C 72.27, H 4.27, N 10.96, S 6.37.
5f: Mp > 300 8C. IR (KBr, cm1): n 1672 (C5 5O). 1H NMR (400 MHz, CF3CO2D): d
4.06 (s, 3H), 4.13 (s, 3H), 4.27 (s, 3H), 7.28–7.31 (m, 2H), 7.82–7.86 (m, 5H), 7.92–
7.96 (m, 3H), 8.45–8.44 (m, 3H). 13C NMR (100 MHz, CF3CO2D): d 31.2, 55.1, 55.6,
110.4, 112.2, 113.3, 114.4, 115.0, 116.1, 117.3, 117.6, 120.2, 122.8, 127.2, 127.8,
128.8, 129.8, 131.0, 134.4, 135.7, 141.9, 144.3, 156.8, 157.0, 160.2, 160.9, 161.4.
Anal. Calcd. for C31H22N4O2S: C 72.35, H 4.31, N 10.89, S 6.23. Found: C 72.53, H 4.50,
N 10.95, S 6.39.
5g: Mp > 300 8C. IR (KBr, cm1): n 1678 (C5 5O). 1H NMR (400 MHz, CF3CO2D3): d
3.53 (s, 3H), 3.65 (s, 3H), 4.28 (s, 3H), 4.51 (s, 3H), 7.87–7.92 (m, 3H), 8.03–8.05 (m,
4H), 8.15–8.21 (m, 2H), 8.70–8.74 (m, 3H). 13C NMR (100 MHz, CF3CO2D): d 31.1,
33.4, 39.0, 55.4, 110.3, 113.2, 117.3, 117.4, 118.5, 119.5, 121.9, 123.6, 126.1, 127.5,
128.0, 128.6, 128.9, 129.3, 129.4, 129.7, 133.0, 134.7, 135.8, 142.6, 143.3, 157.0,
157.2, 159.7. Anal. Calcd. for C32H24N4O2S: C 72.71, H 4.58, N 10.60, S 6.07. Found: C
72.86, H 4.74, N 10.72, S 6.15.
5h: Mp > 300 8C. IR (KBr, cm1): n 1685 (C5 5O). 1H NMR (400 MHz, CF3CO2D): d
3.29 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 4.15 (s, 3H), 7.25–7.27 (m, 1H), 7.38–7.40 (m,
3H), 7.64–7.67 (m, 2H), 7.75–7.78 (m, 1H), 7.83–7.85 (m, 1H), 7.91–7.94 (m, 1H),
8.25–8.27 (m, 2H), 8.50–8.52 (m, 1H). 13C NMR (100 MHz, CF3CO2D): d 31.9, 32.2,
54.9, 55.0, 108.7, 114.4, 117.6, 118.5, 122.0, 122.2, 123.3, 124.1, 124.8, 127.8, 128.2,
128.5, 129.4, 129.5, 130.6, 132.6, 132.8, 134.8, 144.1, 144.2, 154.4, 158.4, 159.2,
160.1. Anal. Calcd. for C32H24N4O3S: C 70.57, H 4.44, N 10.29, S 5.89. Found: C 70.70,
H 4.62, N 10.41, S 5.94.
5i: Mp > 300 8C. IR (KBr, cm1): n 1688 (C5 5O). 1H NMR (400 MHz, CF3CO2D): d
2.19 (s, 3H), 3.33 (s, 3H), 4.10 (s, 3H), 4.15 (s, 3H), 7.04–7.07 (m, 2H), 7.15–7.18 (m,
2H), 7.64–7.73 (m, 4H), 7.91–7.92 (m, 1H), 8.19–8.22 (m, 1H), 8.25–8.27 (m, 1H),
8.39–8.41 (m, 1H). 13C NMR (100 MHz, CF3CO2D): d 31.5, 33.0, 39.5, 55.9, 110.7,
112.6, 113.6, 115.4, 116.4, 117.7, 118.1, 120.8, 122.8, 127.5, 128.1, 128.8, 128.9,
129.1, 130.1, 130.9, 134.6, 135.9, 138.3, 141.3, 141.6, 157.1, 157.2, 162.8. Anal.
Calcd. for C32H24N4O3S: C 70.57, H 4.44, N 10.29, S 5.89. Found: C 70.68, H 4.56, N
10.43, S 5.97.
5j: Mp > 300 8C. IR (KBr, cm1): n 1683 (C5 5O). 1H NMR (400 MHz, CF3CO2D): d
3.34 (s, 3H), 4.10 (s, 3H), 4.16 (s, 3H), 6.61–6.63 (m, 1H), 6.69–6.72 (m, 1H), 7.28–
7.30 (m, 1H), 7.65–7.74 (m, 4H), 7.91–7.92 (m, 1H), 8.20–8.23 (m, 2H), 8.27–8.30 (m,
1H), 8.42–8.44 (m, 1H). 13C NMR (100 MHz, CF3CO2D): d 34.0, 55.0, 55.5, 107.6,
110.4, 115.0, 115.2, 117.2 (d, J = 23.2 Hz), 117.9, 118.2, 121.1 (d, J = 8.4 Hz), 121.5,
126.3, 127.9, 128.0, 128.6, 129.5, 129.7, 130.7, 130.8, 133.8, 135.3, 140.3, 147.0 (d,
J = 2.3 Hz), 156.4, 156.6 (d, J = 243.1 Hz), 160.1. Anal. Calcd. for C31H21FN4O2S: C
69.91, H 3.97, N 10.52, S 6.02. Found: C 70.15, H 4.16, N 10.68, S 6.13.
5k: Mp > 300 8C. IR (KBr, cm1): n 1692 (C5 5O). 1H NMR (400 MHz, CF3CO2D): d
3.39 (s, 3H), 4.10 (s, 3H), 4.16 (s, 3H), 6.57–7.65 (m, 5H), 7.75–7.77 (m, 1H), 7.89–
7.90 (m, 1H), 8.09–8.12 (m, 2H), 8.21–8.27 (m, 3H). 13C NMR (100 MHz, CF3CO2D): d
31.4, 52.5, 55.4, 107.8, 112.1, 112.2, 113.2, 115.0, 116.1, 116.7, 118.7, 119.4, 121.7,
123.8, 127.5, 128.0, 129.5, 133.5, 134.6, 137.5, 141.3, 147.2, 148.1, 154.1, 156.7,
158.7, 159.6. Anal. Calcd. for C31H21NO4S: C 66.54, H 3.78, N 12.51, S 5.73. Found: C
66.68, H 3.89, N 12.73, S 5.87.
[(Schem_2)TD$FIG] D.-L. Wang et al. / Chinese Chemical Letters 27 (2016) 261–264 263

Scheme 2. A proposed mechanism for the formation of 5.

condensation of 4-bromomethylquinoline-2-ones 1 with 5-cyano- (15 mol%) did not improve the yield of the product (entry 12).
1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 2 via a Among the various conditions employed, the reaction in DMF at
Thorpe–Ziegler isomerization [17] in good yield. Its structure 100 8C in the presence of 10 mol% BF3OEt2 catalyst was found to
was determined from the spectral data as well as elemental give the best results (Table 1, entry 1).
analysis. Under the optimized conditions, a wide range of aromatic
To examine the Pictet–Spengler reaction of 4-(3-aminopyr- aldehydes 4 underwent this one-pot condensation with of
imido[4,5-d]thieno-2-yl)quinoline-2-ones 3 with various alde- 4-(3-amino pyrimido[4,5-d]thieno-2-yl)quinoline-2-ones 3 to
hydes 4, we chose 4-(3-aminopyrimido[4,5-d]thieno-2-yl)-6- give the corresponding benzo[b]pyrimido[40 ,50 :5,4]thieno[2,3-
methylquinoline-2-one (3a) and benzaldehyde (4a) as model e][1,6]naphthyridine-8-ones 5.
substrates to optimize the reaction conditions (Scheme 2). The Encouraged by the above results, we investigated the scope of
results are summarized in Table 1. this reaction using various aromatic aldehydes (Table 2). A variety
We have examined the influence of catalysts and solvents in the of electron-rich (entries 2, 3 and 7–9) and electron-deficient
reaction. When the reaction of 3a and 4a was carried out in DMF at aromatic aldehydes (entries 4, 5, 10 and 11) are effectively
100 8C for 4 h in the presence of BF3OEt2 (10 mol%) the targeted transformed to the corresponding naphthyridines in the presence
compound benzo[b]pyrimido [40 ,50 :5,4]thieno [2,3-e][1,6]- of BF3OEt2 in good yields (70%–85%).
naphthyridine-8-one 5a was obtained in 78% yield (Table 1, entry On the other hand, aliphatic aldehydes and ketones failed to the
1). However, when H2SO4 (10 mol%) was employed as a catalyst, Pictet–Spengler cyclization and this may be attributed to the
the desired product 5a was obtained in 53% yield at 100 8C for 4 h relatively poor electrophilicity of the imines derived from aliphatic
in DMF (entry 2). When the same reaction was carried out in the aldehydes and ketones.
presence of p-TsOH (10 mol%) for 8 h, 63% yield of the product was All the products were characterized by IR, 1H NMR, 13C NMR and
obtained (entry 3). The yield of the product was slightly increased elemental analysis. And all the data are consistent with the
when the reaction was carried out in the presence of TFA (10 mol%) proposed structures.
for 6 h in refluxing toluene, but did not exceed than that of BF3OEt2 A proposed mechanism of the process is summarized
(10 mol%) (entry 4). To improve the yield, different solvents and in Scheme 2. The present synthetic sequence was initiated by
reaction temperature were evaluated. The results revealed that
DMF provided much better results than toluene, THF, DMSO and
CH3CN (entries 5–10). We then varied the amount of catalyst Table 2
Synthesis of benzo[b]pyrimido[40 ,50 :5,4]thieno[2,3-e][1,6]naphthyridine-8-ones 5.
loading. A yield of 69% of the product was obtained when the
O O R'
reaction was carried out with 5 mol% BF3OEt2 for 4 h in refluxing
toluene (entry 11). Increasing the amount of catalyst loading Me Me
N NH2 N N
Me Me
[TD$INLE] R'CHO (4)
Table 1 S N
N BF 3·OEt 2 S
Optimization of reaction conditions on the synthesis of benzo[b]pyrimi-
do[40 ,50 :5,4]thieno[2,3-e][1,6]naphthyridine-8-one 5aa. N N
R R Ph
Ph
Entry Catalyst/(mol%) Solvent Temp (8C) Time (h) Yield (%) 3 a R = Me, b R = OMe 5
1 BF3OEt2 (10) DMF 100 4 78
Entry Products R R0 Time (h)a Yield (%)b
2 H2SO4 (10) DMF 100 4 53
3 p-TsOH (10) DMF 100 8 63 1 5a Me C6H5 4 78
4 TFA (10) Tolueneb 110 6 72 2 5b Me 4-MeC6H4 4 75
5 BF3OEt2 (10) Tolueneb 100 7 76 3 5c Me 3-MeOC6H4 5 82
6 BF3OEt2 (10) THF 70 14 62 4 5d Me 4-ClC6H4 7 72
7 BF3OEt2 (10) DMSO 100 6 65 5 5e Me 4-FC6H4 9 70
8 BF3OEt2 (10) CH3CN 80 16 57 6 5f OMe C6H5 5 75
9 BF3OEt2 (10) DMF 120 3 75 7 5g OMe 4-MeC6H4 5 74
10 BF3OEt2 (10) DMF 80 9 62 8 5h OMe 3-MeOC6H4 4 85
11 BF3OEt2 (5) DMF 100 7 69 9 5i OMe 4-MeOC6H4 4 83
12 BF3OEt2 (15) DMF 100 4 72 10 5j OMe 4-FC6H4 7 72
a 11 5k OMe 4-NO2C6H4 12 70
Reaction conditions: 3a (1.0 mmol), benzaldehyde (4a, 1.0 mmol), solvent
a
(15 mL). Reaction progress monitored by TLC.
b b
Solvent (40 mL). Isolated yield.
264 D.-L. Wang et al. / Chinese Chemical Letters 27 (2016) 261–264
an S-alkylation of 4-bromomethylquinoline-2-ones 1 with
5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 2
giving rise to the thioethers A. An intramolecular carbanion
addition across the nitrile occurred via a Thorpe–Ziegler
isomerization reaction, resulting in the formation of 4-(3-
aminopyrimido[4,5-d]thieno-2-yl)quinoline-2-ones 3. Next, sub-
strates 3 underwent a cationic p-cyclization with aldehydes as
one-carbon electrophiles in imine intermediates B under Pictet–
Spengler cyclization conditions, which resulted in the closure at
the C3 position of quinoline-2-ones to give pentacyclic benzo[b]-
pyrimido[40 ,50 :5,4]thieno[2,3-e][1,6]naphthyridine-8-ones ring
system 5.
4. Conclusion
In summary, we have developed an efficient method for the
synthesis of pharmacologically important, functionalized 1,6-
naphthyridine derivatives in two steps. The synthetic approach
involves a Thorpe–Ziegler isomerization of 4-bromomethylquino-
line-2-ones followed by a Pictet–Spengler cyclization of the
corresponding 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline-
2-ones with aromatic aldehydes in the presence of BF3OEt2. This
method has the advantages of using utilizes easily accessible
starting materials, mild reaction conditions, straightforward
product isolation and good yields.
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