Synthesis of indazolo[5,4-b][1,6]naphthyridine and indazolo[6,7-b][1,6]naphthyridine derivatives

Article abstract of DOI:10.1515/hc-2019-0006

A simple method for the synthesis of the title compounds by an efficient in-situ reduction and cyclization reactions of aromatic aldehydes, tert-butyl 2,4-dioxopiperidine-1-carboxylate and 5-nitro-1H-indazole or 6-nitro-1H-indazole was developed.

Full text of DOI:10.1515/hc-2019-0006

Heterocycl. Commun. 2019; 25: 15–21
Research Article
Open Access
DSoyngn-Mtehi Cehseni,sJiao-YafniLniud, MainzgoWelio, B[i5ng,-4We-ibW]a[n1g,,R6uo]-nHaanpChhutahndyDronidg-Sihneeng aChnend*
indazolo[6,7-b][1,6]naphthyridine derivatives
https://doi.org/10.1515/hc-2019-0006
Results and discussion
Received October 08, 2018; accepted November 16, 2018.
Abstract: A simple method for the synthesis of the title
Initially,
4-chlorobenzaldehyde
(1a),
tert-butyl
compounds by an efficient in-situ reduction and cyc-
lization reactions of aromatic aldehydes, tert-butyl
2,4-dioxopiperidine-1-carboxylate and 5-nitro-1H-indazole
or 6-nitro-1H-indazole was developed.
2,4-dioxopiperidine-1-carboxylate (2) and 6-nitro-1H-in-
dazole (3) were allowed to react to optimize the reaction
conditions (Scheme 1). When the reaction was perfor-
med in the presence of two equivalents of Fe(0), water(1
mL) and acetic acid (1 mL) in ethanol at 80°C, we were
pleased to obtain the expected product 4a in 58% yield.
Then, the reaction was tested in ethanol under different
ratios of 3 and Fe(0). With three equivalents of Fe(0), the
yield was increased to 88%. The effects of the amounts
of water and acetic acid were also evaluated. The best
results were obtained in the presence of 1 mL of water
Keywords: in-situ reduction, nitro compounds, indazolo
[5,4-b][1,6]naphthyridine, indazolo[6,7-b][1,6]naphthy-
ridine
Introduction
Naphthyridines are an important class of heterocycles due and 1 mL of acetic acid using ethanol as solvent. Ethanol
to their inherent biological activities [1-5]. Substitu- was the optimal solvent in comparison to tetrahydrofu-
ted indazoles are also pharmaceutically important [6]. ran, methanol, dioxane and toluene. With the optimized
Previously, we introduced
a three-component reac- reaction conditions in hand, other aromatic aldehydes
tion of 1H-indol-6-amine, aromatic aldehyde and cyclic 1b-j were applied in this synthesis to furnish products
1,3-dicarbonyl compound under catalyst-free conditions 4a-j in good yields (Scheme 1). It was found that under
[7-9]. Compared with amino compounds, nitro derivatives the optimized conditions the treatment of 5-nitro-1H-in-
are more stable, easier to obtain, and they can be easily dazole (5), instead of the isomer 3, with 1 and 2 furnished
reduced to the amines [10, 11]. The reduction is often the expected products 6 (Scheme 2). The structures of all
accomplished with the use of iron [Fe(0)]. This reagent products were characterized by IR, NMR and HRMS spec-
is one of the most abundant, nontoxic, inexpensive and tral methods.
environmentally friendly transition metals [12-14]. In view
A possible mechanism is shown in Scheme 3 using
of the importance of the previously detailed structures, substrate 3 as an example. First, the nitro compound 3
in this report we describe synthesis of indazolo[5,4-b] is reduced to 6-aminoindazole A. At the same time, the
[1,6]naphthyridine and indazolo[6,7-b][1,6]naphthyridine Knoevenagel product B is generated by the reaction of
derivatives starting from 5-nitro-1H-indazole or 6-nitro- substrates 1 and 2. Then, 6-aminoindazole A undergoes
1H-indazole using Fe(0) as a reducing agent via a one-pot reaction with the intermediate product B to obtain the
multicomponent protocol [15-17].
intermediate C. Then, intramolecular cyclization of C
generates the intermediate product D which is the final
precursor to the observed product 4.
* Corresponding author: Dong-Sheng Chen, Kangda College of
Nanjing Medical University, Lianyungang 222000, Jiangsu, People’s
Republic of China, e-mail: dschen@njmu.edu.cn
Dong-Mei Chen, Jia-Yan Liu, Ming Wei, Bing-Wei Wang and Ruo-Han
Chu, Kangda College of Nanjing Medical University, Lianyungang
222000, Jiangsu, People’s Republic of China
Conclusion
A simple and efficient method was developed for the
synthesis of indazolo[5,4-b][1,6]naphthyridine and
indazolo[6,7-b][1,6]naphthyridine derivatives directly
Open Access. © 2019 Dong-Mei Chen et al., published by De Gruyter.ꢀ
Attribution alone 4.0 License.
ꢀThis work is licensed under the Creative Commons
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D.-S. Chen et al.: Indazolo[5,4-b][1,6]naphthyridines and indazolo[6,7-b][1,6]naphthyridines
N
N
NH
r
A
NH
O
O
O
O
e
F H
2O
/
N
O
N
O
+
-
Et H Ac H
O
O
+
ArCHO
80oC
N
N
H
O2
O
1
2
3
4
=
4a: Ar = 4-ClC6H4
4d: Ar = 4-NO2C6H4
4 : Ar = 3,4-Cl2C6H3 4 : Ar piperonyl
g
j
4b: Ar = 4-BrC6H4 4e: Ar = 3-ClC6H4
4h: Ar = 2-ClC6H4
4i: Ar = thiophen-2-yl
=
4c: Ar 4-FC6H4
4f: Ar = 3-BrC6H4
Scheme 1ꢂSynthesis of indazolo[6,7-b][1,6]naphthyridine derivatives 4a-4j.
N
NH
O
O
N
HN
r
A
Fe/H2O
O
O
EtOH-AcOH
80 oC
N
O
+
N
O
+
ArCHO
O2N
O
N
H
1
2
5
6
6a: Ar = 4-ClC6H4
6b: Ar = 4-BrC6H4
6c: Ar = 3-ClC6H4
6d: Ar = 3-BrC6H4
6e: Ar =
6g: Ar = 2-BrC6H4
h: Ar = 3-OCH C H
6 4
6j: Ar = Ph
3,4-Cl2C6H3
6f: Ar = 2-ClC6H4
6
3
6i: Ar =3,5-(OCH3)2C6H3
Scheme 2ꢂSynthesis of indazolo[5,4-b][1,6]naphthyridine derivatives 6a-6j.
Fe/H2O
N
N
N
H2N
EtOH-AcOH
N
H
O2N
H
A
3
Michael addition
O
O
O
O
-
H
2O
Ar
N
O
+
Ar
Ar
H
N
O
O
N
B
2
1
-
t B
OC
N
N
NH
Ar
Ar
NH
O
O
N
O
NH
-
H
2O
Nucleophilic
addition
-
-
-
t BOC
t B
OC
t B
OC
N
N
N
H
D
N
H
4
NH2
O
H
O
C
Scheme 3ꢂThe proposed mechanism.
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D.-S. Chen et al.: Indazolo[5,4-b][1,6]naphthyridines and indazolo[6,7-b][1,6]naphthyridinesꢁ
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form nitro compounds by in situ reduction and cyclization 775, 702 cm-1; 1H NMR: δH 12.89 (s, 1H, NH), 9.79 (s, 1H, NH),
reaction in Fe/H2O medium.
7.93 (s, 1H, ArH), 7.53 (d, J = 8.4 Hz, 1H, ArH), 7.37-7.33 (m,
4H, ArH), 6.84 (d, J = 8.0 Hz, 1H, ArH), 5.54 (s, 1H, CH),
4.01-3.98 (m, 1H, CH2), 3.51-3.43 (m, 1H, CH2), 2.82-2.75 (m,
1H, CH2), 2.66-2.62 (m, 1H, CH2), 1.43 (s, 9H, 3CH3); 13C NMR:
δC 164.6, 153.0, 149.1, 146.7, 139.0, 134.6, 134.5, 131.3, 130.3,
Experimental
Melting points were determined in open capillaries and 120.4, 120.1, 119.6, 111.8, 105.2, 100.5, 81.4, 42.6, 36.4, 28.3,
are uncorrected. IR spectra were recorded on a Tensor 27 26.9. HRMS. Calcd for C24H22N4O3Br, [M - H]-: m/z 493.0881.
spectrometer in KBr pellets. H NMR (400 MHz) and 13C Found: m/z 493.0885.
1
NMR (125 MHz) spectra were obtained in DMSO-d6 with
Me4Si as internal standard using Bruker-400 and Bruker- tert-Butyl 11-(4-fluorophenyl)-10-oxo-7,8,10,11-
tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-
500 spectrometers. ESI-HRMS analyses were carried out
using a Bruker-micro-TOF-Q-MS analyzer.
carboxylate (4c)
General procedure for the synthesis of 4 and 6
Yield 81%; white powder; mp 243-244°C; IR: n 3471, 3307,
2980, 1738, 1670, 1535, 1503, 1461, 1369, 1248, 1141, 1050,
A dry 25-mL round-bottom flask was charged with aromatic 946, 850, 743, 710 cm-1; 1H NMR: δH 12.88 (s, 1H, NH), 9.76 (s,
aldehyde 1 (1 mmol), tert-butyl 2,4-dioxopiperidine-1-carbo- 1H, NH), 7.93 (s, 1H, ArH), 7.52 (d, J = 8.0 Hz, 1H, ArH), 7.41-
xylate 2 (1.0 mmol), 6-nitro-1H-indazole 3 or 5-nitro-1H-in- 7.37 (m, 2H, ArH), 6.99-6.95 (m, 2H, ArH), 6.82 (d, J = 8.4 Hz,
dazole 5 (1.0 mmol), powdered iron (3 mmol), EtOH (5 mL), 1H, ArH), 5.54 (s, 1H, CH), 4.01-3.95 (m, 1H, CH2), 3.48-3.40
H2O (1 mL), and AcOH (1 mL). The mixture was stirred at (m, 1H, CH2), 2.81-2.72 (m, 1H, CH2), 2.66-2.59 (m, 1H, CH2),
80°C for 8-10 h until TLC analysis revealed that the reaction 1.41 (s, 9H, 3CH3); 13C NMR: δC 164.6, 161.1(d, JF-C = 192.4 Hz),
was completed and then treated with brine (10 mL). The 153.0, 149.0, 143.6, 139.1, 134.6, 134.4, 129.7 (d, JF-C = 6.3 Hz),
mixture was extracted with EtOAc (3 × 15 mL). The organic 120.4, 120.0, 115.0 (d, JF-C = 16.7 Hz), 111.8, 105.6, 100.8, 81.3,
layers were combined and washed thoroughly with brine, 42.6, 36.1, 28.2, 26.9. HRMS. Calcd for C24H22N4O3F, [M - H]-:
dried with Na2SO4, and filtered through Celite. Following m/z 433.1681. Found: m/z 433.1680.
removal of the solvent in vacuo, the residue was purified
by crystallization from DMF to give the pure product 4 or 6. tert-Butyl 11-(4-nitrophenyl)-10-oxo-7,8,10,11-tetra-
hydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-
carboxylate (4d)
tert-Butyl 11-(4-chlorophenyl)-10-oxo-7,8,10,11-tetrahy-
dro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carbo-
xylate (4a)
Yield 84%; yellow powder; mp 235-236°C; IR: n 3310,
3217, 2977, 1737, 1665, 1638, 1540, 1509, 1393, 1214, 1138,
Yield 88%; white powder; mp 240-241°C; IR: ν 3427, 3316, 1049, 943, 852, 781, 710 cm-1; 1H NMR: δH 12.97 (s, 1H, NH),
2936, 1741, 1626, 1606, 1533, 1494, 1398, 1213, 1159, 1047, 949, 9.90 (s, 1H, NH), 8.07 (d, J = 8.8 Hz, 2H, ArH), 7.95 (s, 1H,
851, 774, 703 cm-1; 1H NMR: δH 12.90 (s, 1H, NH), 9.80 (s, 1H, ArH), 7.64 (d, J = 8.4 Hz, 2H, ArH), 7.57 (d, J = 8.4 Hz, 1H,
NH), 7.94 (s, 1H, ArH), 7.53 (d, J = 8.4 Hz, 1H, ArH), 7.40 (d, ArH), 6.88 (d, J = 8.8 Hz, 1H, ArH), 5.72 (s, 1H, CH), 4.01-
J = 8.0 Hz, 2H, ArH), 7.23 (d, J = 8.0 Hz, 2H, ArH), 6.85 (d, J 3.96 (m, 1H, CH2), 3.53-3.42 (m, 1H, CH2), 2.85-2.76 (m, 1H,
= 8.4 Hz, 1H, ArH), 5.56 (s, 1H, CH), 4.01-3.98 (m, 1H, CH2), CH2), 2.70-2.62 (m, 1H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR:
3.50-3.44 (m, 1H, CH2), 2.82-2.78 (m, 1H, CH2), 2.66-2.62 (m, dC 164.5, 154.5, 152.9, 149.5, 146.3, 139.1, 134.8, 134.6, 129.2,
1H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR: δC 164.1, 152.5, 148.6, 123.8, 120.54, 120.46, 111.9, 104.3, 99.9, 81.4, 42.5, 37.1, 28.2,
145.8, 138.5, 134.1, 134.0, 130.6, 129.3, 127.8, 119.9, 119.6, 111.3, 26.9. HRMS. Calcd for C24H22N5O5, [M - H]-: m/z 460.1626.
104.7, 100.0, 80.9, 42.1, 35.8, 27.7, 26.3. HRMS. Calcd for Found: m/z 460.1635.
C24H22N4O3Cl, [M - H]-: m/z 449.1386. Found: m/z 449.1384.
tert-Butyl 11-(3-chlorophenyl)-10-oxo-7,8,10,11-tetra-
hydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-
tert-Butyl 11-(4-bromophenyl)-10-oxo-7,8,10,11-tetrahy-
dro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carbo-
xylate (4b)
carboxylate (4e)
Yield 84%; white powder; mp: 227-228°C; IR: n 3450, 3291,
Yield 90%; white powder; mp: 242-243°C; IR: n 3310, 3061, 2977, 1738, 1667, 1626, 1536, 1496, 1446, 1369, 1212, 1138,
1735, 1633, 1599, 1536, 1494, 1387, 1285, 1154, 1061, 947, 830, 1048, 949, 850, 776, 731 cm-1; 1H NMR: dH 12.93 (s, 1H, NH),
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D.-S. Chen et al.: Indazolo[5,4-b][1,6]naphthyridines and indazolo[6,7-b][1,6]naphthyridines
9.83 (s, 1H, NH), 7.94 (s, 1H, ArH), 7.56-7.52 (m, 2H, ArH), 1H, NH), 9.89 (s, 1H, NH), 7.90 (s, 1H, ArH), 7.86 (d, J = 7.6
7.27 (d, J = 7.6 Hz, 1H, ArH), 7.22-7.18 (m, 1H, ArH), 7.14-7.11 Hz, 1H, ArH), 7.50 (d, J = 8.4 Hz, 1H, ArH), 7.24-7.19 (m, 2H,
(m, 1H, ArH), 6.86 (d, J = 8.8 Hz, 1H, ArH), 5.55 (s, 1H, CH), ArH), 7.13-7.09 (m, 1H, ArH), 6.77 (d, J = 8.4 Hz, 1H, ArH),
4.02-3.97 (m, 1H, CH2), 3.51-3.44 (m, 1H, CH2), 2.83-2.76 (m, 5.80 (s, 1H, CH), 4.01-3.96 (m, 1H, CH2), 3.45-3.37 (m, 1H,
1H, CH2), 2.70-2.64 (m, 1H, CH2), 1.43 (s, 9H, 3CH3); 13C NMR: CH2), 2.80-2.71 (m, 1H, CH2), 2.59-2.48 (m, 1H, CH2), 1.40 (s,
dC 164.6, 152.9, 149.6, 149.2, 139.0, 134.7, 134.5, 133.0, 130.4, 9H, 3CH3); 13C NMR: dC 164.3, 152.8, 149.7, 142.2, 139.4, 135.3,
127.8, 126.7, 126.5, 120.4, 120.2, 111.8, 105.0, 100.3, 81.4, 42.6, 134.9, 133.6, 132.8, 130.5, 128.5, 127.0, 120.44, 120.37, 111.7,
36.7, 28.3, 26.8. HRMS. Calcd for C24H22N4O3Cl, [M - H]-: m/z 103.4, 98.1, 81.3, 42.6, 38.1, 28.3, 26.9. HRMS. Calcd for
449.1386. Found: m/z 449.1404.
C24H22N4O3Cl, [M - H]-: m/z 449.1386. Found: m/z 449.1386.
tert-Butyl 11-(3-bromophenyl)-10-oxo-7,8,10,11-
tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-
carboxylate (4f)
tert-Butyl 10-oxo-11-(thiophen-2-yl)-7,8,10,11-
tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-
carboxylate (4i)
Yield 83%; white powder; mp: 229-230°C; IR: n 3450, 3279, Yield 89%; white powder; mp > 300°C; IR: n 3203, 3079,
2972, 1745, 1625, 1537, 1498, 1467, 1367, 1216, 1158, 1049, 945, 2975, 1699, 1651, 1604, 1545, 1504, 1453, 1388, 1324, 1216,
1
815, 775, 712 cm-1; 1H NMR: dH 12.94 (s, 1H, NH), 9.83 (s, 1H, 1156, 970, 850, 767, 710 cm-1; H NMR: dH 13.08 (s, 1H, NH),
NH), 7.94 (s, 1H, ArH), 7.66 (s, 1H, ArH), 7.54 (d, J = 8.4 Hz, 9.88 (s, 1H, NH), 7.97 (s, 1H, ArH), 7.54 (d, J = 8.4 Hz, 1H,
1H, ArH), 7.32-7.25 (m, 2H, ArH), 7.17-7.12 (m, 1H, ArH), 6.86 ArH), 7.17-7.15 (m, 1H, ArH), 6.97 (d, J = 3.2 Hz, 1H, ArH), 6.83-
(d, J = 8.4 Hz, 1H, ArH), 5.54 (s, 1H, CH), 4.02-3.90 (m, 1H, 6.78 (m, 2H, ArH), 5.94 (s, 1H, CH), 4.08-4.03 (m, 1H, CH2),
CH2), 3.51-3.43 (m, 1H, CH2), 2.83-2.76 (m, 1H, CH2), 2.70-2.65 3.49-3.41 (m, 1H, CH2), 2.86-2.76 (m, 1H, CH2), 2.67-2.62 (m,
(m, 1H, CH2), 1.43 (s, 9H, 3CH3); 13C NMR: dC 164.5, 152.9, 1H, CH2), 1.44 (s, 9H, 3CH3); 13C NMR: dC 164.6, 153.0, 151.5,
149.9, 149.2, 139.0, 134.7, 134.5, 130.8, 130.7, 129.4, 127.1, 148.9, 139.0,134.5, 134.3, 126.8, 124.3, 123.8, 120.4, 120.1,
121.8, 120.4, 120.2, 111.8, 105.0, 100.4, 81.4, 42.6, 36.8, 28.3, 111.7, 105.2, 100.4, 81.4, 42.6, 32.0, 28.3, 26.9. HRMS. Calcd
26.8. HRMS. Calcd for C24H22N4O3Br, [M - H]-: m/z 493.0881. for C22H21N4O3S, [M - H]-: m/z 421.1340. Found: m/z 421.1331.
Found: m/z 493.0893.
tert-Butyl 11-(benzo[d][1,3]dioxol-5-yl)-10-oxo-7,8,10,11-
tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-
tert-Butyl 11-(3,4-dichlorophenyl)-10-oxo-7,8,10,11-
tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-
carboxylate (4g)
carboxylate (4j)
Yield 87%; white powder; mp 247-248°C; IR: n 3296, 3224,
Yield 89%; white powder; mp: 250-251°C; IR: n 3301, 2978, 2971, 1710, 1673, 1625, 1538, 1503, 1443, 1327, 1287, 1166,
1737, 1630, 1601, 1540, 1496, 1392, 1285, 1215, 1155, 1049, 1049, 946, 811, 776, 703 cm-1; 1H NMR: dH 12.86 (s, 1H, NH),
975, 871, 774, 701 cm-1; 1H NMR: dH 12.94 (s, 1H, NH), 9.86 (s, 9.74 (s, 1H, NH), 7.93 (s, 1H, ArH), 7.51 (d, J = 8.4 Hz, 1H,
1H, NH), 7.96 (s, 1H, ArH), 7.71 (d, J = 8.4 Hz, 1H, ArH), 7.56 ArH), 6.98 (s, 1H, ArH), 6.89-6.78 (m, 2H, ArH), 6.70 (d, J =
(d, J = 8.8 Hz, 1H, ArH), 7.44 (d, J = 8.4 Hz, 1H, ArH), 7.25 7.2 Hz, 1H, ArH), 5.88 (d, J = 7.2 Hz, 2H, CH2), 5.46 (s, 1H, CH),
(dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 6.86 (d, J = 8.4 Hz, 1H, 4.01-3.98 (m, 1H, CH2), 3.50-3.44 (m, 1H, CH2), 2.81-2.78 (m,
ArH), 5.55 (s, 1H, CH), 4.01-3.95 (m, 1H, CH2), 3.54-3.45 (m, 1H, CH2), 2.67-2.63 (m, 1H, CH2), 1.43 (s, 9H, 3CH3); 13C NMR:
1H, CH2), 2.82-2.74 (m, 1H, CH2), 2.70-2.63 (m, 1H, CH2), 1.43 dC 164.6, 153.0, 148.7, 147.3, 145.9, 141.7, 139.1, 134.5, 134.3,
(s, 9H, 3CH3); 13C NMR: dC 164.5, 152.9, 149.3, 148.1, 139.0, 120.9, 120.3, 119.8, 111.8, 108.7, 108.2, 106.0, 101.1, 101.0,
134.7, 134.5, 130.9, 130.8, 129.9, 129.1, 128.4, 120.4, 111.8, 81.3,42.6, 36.5, 28.3, 26.9. HRMS. Calcd for C25H23N4O5, [M -
104.5, 100.0, 81.4, 42.6, 36.4, 28.2, 26.8. HRMS. Calcd for H]-: m/z 459.1674. Found: m/z 459.1667.
C24H21N4O3Cl2, [M - H]-: m/z 483.0996. Found: m/z 483.0994.
tert-Butyl 11-(4-chlorophenyl)-10-oxo-7,8,10,11-
tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-
tert-Butyl 11-(2-chlorophenyl)-10-oxo-7,8,10,11-
tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-
carboxylate (4h)
carboxylate (6a)
Yield 87%; white powder; mp 221-222°C; IR: n 3297, 3079,
Yield 86%; white powder; mp: 280-281°C; IR: n 3414, 3319, 2977, 2933, 2885, 1719, 1681, 1605, 1543, 1492, 1401, 1369,
3101, 2974, 1745, 1627, 1531, 1494, 1469, 1398, 1321, 1210, 1331, 1253, 1213, 1142, 1092, 1049, 949, 846, 805, 775, 703
1
1
1141, 1048, 943, 872, 782, 704 cm-1; H NMR: dH 11.97 (s, cm-1; H NMR: dH 13.01 (s, 1H, NH), 9.67 (s, 1H, NH), 8.01
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D.-S. Chen et al.: Indazolo[5,4-b][1,6]naphthyridines and indazolo[6,7-b][1,6]naphthyridinesꢁ
ꢁ19
(s, 1H, ArH), 7.37-7.34 (m, 3H, ArH), 7.23 (d, J = 8.4 Hz, 2H, (s, 1H, ArH), 7.51-7.50 (m, 1H, ArH), 7.38-7.33 (m, 2H, ArH),
ArH), 7.07 (d, J = 8.4 Hz, 1H, ArH), 5.52 (s, 1H, CH), 4.02- 7.25 (d, J = 8.0 Hz, 1H, ArH), 7.17-7.13 (m, 1H, ArH), 7.09
3.96 (m, 1H, CH2), 3.60-3.50 (m, 1H, CH2), 2.82-2.75 (m, 1H, (d, J = 8.8 Hz, 1H, ArH), 5.54 (s, 1H, CH), 4.02-3.97 (m, 1H,
CH2), 2.64-2.59 (m, 1H, CH2), 1.41 (s, 9H, 3CH3); 13C NMR: CH2), 3.50-3.46 (m, 1H, CH2), 2.82-2.78 (m, 1H, CH2), 2.68-
dC 164.7, 153.1, 148.9, 147.2, 137.9, 132.1, 130.9, 130.0, 129.3, 2.64 (m, 1H, CH2), 1.42 (s, 9H, 3CH3) ; 13C NMR: dC 164.7,
128.4, 122.1, 117.2, 114.3, 110.0, 99.1, 81.3, 42.6, 39.0, 28.3, 153.0, 150.9, 149.1, 137.9, 132.2, 130.69, 130.67, 129.3, 129.2,
27.0. HRMS. Calcd for C24H22N4O3Cl, [M - H]-: m/z 449.1386. 127.3, 122.1, 121.9, 117.2, 114.0, 110.1, 99.0, 81.3, 42.6, 39.3,
Found: m/z 449.1384.
28.3, 26.9. HRMS. Calcd for C24H22N4O3Br, [M - H]-: m/z
493.0881. Found: m/z 493.0876.
tert-Butyl 11-(4-bromophenyl)-10-oxo-7,8,10,11-
tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-
carboxylate (6b)
tert-Butyl 11-(3,4-dichlorophenyl)-10-oxo-7,8,10,11-
tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-
carboxylate (6e)
Yield 90%; white powder; mp 223-225°C; IR: n 3296, 3077,
2977, 2933, 2885, 1719, 1680, 1605, 1543, 1492, 1401, 1369, Yield 89%; white powder; mp 256-257°C; IR: n 3297, 3080,
1331, 1254, 1212, 1142, 1049, 949, 845, 804, 775, 738, 714 cm-1; 2978, 2934, 2886, 1720, 1680, 1606, 1544, 1493, 1467, 1401,
1H NMR: dH 12.97 (s, 1H, NH), 9.63 (s, 1H, NH), 7.98 (s, 1H, 1370, 1329, 1253, 1213, 1143, 1049, 1031, 947, 889, 840, 805,
ArH), 7.35-7.32 (m, 3H, ArH), 7.28 (d, J = 8.4 Hz, 2H, ArH), 776, 700 cm-1; 1H NMR: dH 13.02 (s, 1H, NH), 9.69 (s, 1H, NH),
7.05 (d, J = 8.8 Hz, 1H, ArH), 5.49 (s, 1H, CH), 4.00-3.95 (m, 8.07 (s, 1H, ArH), 7.60 (d, J = 2.0 Hz, 1H, ArH), 7.43 (d, J =
1H, CH2), 3.46-3.39 (m, 1H, CH2), 2.80-2.74 (m, 1H, CH2), 8.4 Hz, 1H, ArH), 7.38 (d, J = 8.4 Hz, 1H, ArH), 7.29 (dd,
2.62-2.58 (m, 1H, CH2), 1.39 (s, 9H, 3CH3); 13C NMR: dC 164.7, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 7.09 (d, J = 8.4 Hz, 1H,
153.1, 148.9, 147.7, 137.9, 132.1, 131.3, 130.4, 129.3, 122.1, 119.4, ArH), 5.58 (s, 1H, CH), 4.02-3.96 (m, 1H, CH2), 3.52-3.45 (m,
117.2, 114.2, 110.0, 99.1, 81.3, 42.6, 39.1, 28.3, 27.0. HRMS. 1H, CH2), 2.82-2.76 (m, 1H, CH2), 2.68-2.62 (m, 1H, CH2), 1.42
Calcd for C24H22N4O3Br [M - H]-: m/z 493.0881. Found: m/z (s, 9H, 3CH3); 13C NMR: dC 164.7, 153.0, 149.20, 149.17, 137.9,
493.0873.
132.1, 131.0, 130.7, 129.9, 129.3, 128.9, 128.6, 122.0, 117.2, 113.6,
110.3, 98.7, 81.3, 42.6, 38.9, 28.3, 26.9. HRMS. Calcd for
C24H21N4O3Cl2, [M - H]-: m/z 483.0996. Found: m/z 483.0992.
tert-Butyl 11-(3-chlorophenyl)-10-oxo-7,8,10,11-
tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-
carboxylate (6c)
tert-Butyl 11-(2-chlorophenyl)-10-oxo-7,8,10,11-
tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-
carboxylate (6f)
Yield 86%; white powder; mp 287-288°C; IR: n 3278, 3085,
2978, 2934, 2886, 1720, 1682, 1609, 1546, 1492, 1402, 1370,
1329, 1251, 1212, 1140, 1049, 947, 894, 841, 808, 777, 732 cm-1; Yield 85%; white powder; mp 226-227°C; IR: n 3270, 3076,
1H NMR: dH 13.02 (s, 1H, NH), 9.68 (s, 1H, NH), 8.06 (s, 1H, 2972, 2935, 2888, 1719, 1622, 1601, 1543, 1491, 1388, 1336, 1251,
ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.30 (d, J = 7.6 Hz, 1H, 1211, 1142, 1049, 943, 894, 851, 807, 779, 759, 742, 705 cm-1; 1H
ArH), 7.23-7.19 (m, 1H, ArH), 7.13-7.07 (m, 2H, ArH), 5.55 (s, NMR: dH 13.03 (s, 1H, NH), 9.70 (s, 1H, NH), 7.95 (s, 1H, ArH),
1H, CH), 4.01-3.98 (m, 1H, CH2), 3.49-3.44 (m, 1H, CH2), 2.81- 7.41 (d, J = 7.2 Hz, 1H, ArH), 7.36 (d, J = 8.8 Hz, 1H, ArH), 7.29
2.78 (m, 1H, CH2), 2.68-2.63 (m, 1H, CH2), 1.42 (s, 9H, 3CH3); (d, J = 7.6 Hz, 1H, ArH), 7.18-7.15 (m, 1H, ArH), 7.10-7.06 (m, 2H,
13C NMR: dC 164.7, 153.0, 150.7, 149.1, 137.9, 133.2, 132.2, 130.3, ArH), 5.89 (s, 1H, CH), 4.00-3.97 (m, 1H, CH2), 3.46-3.44 (m,
129.3, 127.8, 126.9, 126.3, 122.1, 117.2, 114.0, 110.1, 99.0, 81.3, 1H, CH2), 2.81-2.77 (m, 1H, CH2), 2.64-2.60 (m, 1H, CH2), 1.41 (s,
42.6, 39.3, 28.3, 26.9. HRMS. Calcd for C24H22N4O3, [M - H]-: 9H, 3CH3); 13C NMR: dC 164.4, 152.8, 149.1, 145.8, 137.8, 132.0,
m/z 449.1386. Found: m/z 449.1387.
131.9, 131.4, 129.6, 129.4, 128.1, 127.9, 122.3, 117.4, 113.9, 110.2,
99.0, 81.2, 42.6, 37.4, 28.3, 27.0. HRMS. Calcd for C24H22N4O3Cl,
[M - H]-: m/z 449.1386. Found: m/z 449.1391.
tert-Butyl 11-(3-bromophenyl)-10-oxo-7,8,10,11-tetrahy-
dro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-carbo-
xylate (6d)
tert-Butyl 11-(2-bromophenyl)-10-oxo-7,8,10,11-
tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-
carboxylate (6g)
Yield 84%; white powder; mp 285-286°C; IR: n 3291, 3085,
2977, 2934, 2886, 1721, 1681, 1609, 1545, 1494, 1401, 1369,
1328, 1251, 1211, 1159, 1139, 1049, 947, 892, 840, 808, 776, Yield 83%; white powder; mp 225-227°C; IR: n 3317, 3070,
711 cm-1; 1H NMR: dH 13.01 (s, 1H, NH), 9.67 (s, 1H, NH), 8.05 2969, 2934, 2886, 1720, 1623, 1602, 1542, 1490, 1474, 1398,
Unauthenticated
Download Date | 4/10/19 3:24 PM

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20ꢁ
D.-S. Chen et al.: Indazolo[5,4-b][1,6]naphthyridines and indazolo[6,7-b][1,6]naphthyridines
1
1369, 1331, 1250, 1210, 1141, 1048, 942, 892, 851, 808, 781, 1158, 1049, 947, 845, 808, 783, 759, 709 cm-1; H NMR: dH
738, 710 cm-1; 1H NMR: dH 13.01 (s, 1H, NH), 9.68 (s, 1H, NH), 12.96 (s, 1H, NH), 9.61 (s, 1H, NH), 8.02 (s, 1H, ArH), 7.36-
8.04 (s, 1H, ArH), 7.46 (d, J = 7.6 Hz, 1H, ArH), 7.39-7.35 (m, 2H, 7.32 (m, 3H, ArH), 7.19-7.15 (m, 2H, ArH), 7.08-7.02 (m, 2H,
ArH), 7.22-7.19 (m, 1H, ArH), 7.07 (d, J = 8.8 Hz, 1H, ArH), 7.02- ArH), 5.51 (s, 1H, CH), 4.03-3.99 (m, 1H, CH2), 3.48-3.41 (m,
6.98 (m, 1H, ArH), 5.86 (s, 1H, CH), 4.01-3.95 (m, 1H, CH2), 1H, CH2), 2.83-2.73 (m, 1H, CH2), 2.66-2.61 (m, 1H, CH2), 1.42
3.48-3.41 (m, 1H, CH2), 2.81-2.76 (m, 1H, CH2), 2.65-2.59 (m, 1H, (s, 9H, 3CH3); 13C NMR: dC 164.7, 153.1, 148.8, 148.4, 137.9,
CH2), 1.42 (s, 9H, 3CH3); 13C NMR: dC 164.4, 152.7, 149.0, 147.6, 132.2, 129.2, 128.4, 128.1, 126.3, 122.2, 117.1, 114.9, 109.7, 99.4,
137.8, 132.7, 132.3, 132.2, 129.5, 128.5, 128.3, 122.3, 122.1, 117.4, 81.2, 42.6, 39.5, 28.3, 27.0. HRMS. Calcd for C24H23N4O3,
114.1, 110.2, 99.4, 81.2, 42.6, 39.5, 28.3, 27.0. HRMS. Calcd for [M - H]-: m/z 415.1776. Found: m/z 415.1769.
C24H22N4O3Br, [M - H]-: m/z 493.0881. Found: m/z 493.0876.
Acknowledgements: We are grateful to the Natural Science
tert-Butyl 11-(3-methoxyphenyl)-10-oxo-7,8,10,11-
tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-
carboxylate (6h)
FoundationforCollegesandUniversitiesofJiangsuProvince
(18KJB150024), Science Research and Development Found-
ation of Nanjing Medical University (2017NJMU227), Science
Research and Development Foundation of the Kangda
Yield 86%; white powder; mp 281-283°C; IR: n 3303, 3078, College of Nanjing Medical University (KD201822NYDKJ03,
2972, 2888, 1717, 1679, 1606, 1543, 1492, 1476, 1399, 1369, KD2017KYJJYB003, KD2017KYJJYB004) and a Qing Lan
1335, 1262, 1148, 1049, 949, 843, 807, 769, 735, 710 cm-1; H Project for financial support.
1
NMR: dH 11.76 (s, 1H, NH), 9.94 (s, 1H, NH), 7.94 (s, 1H, ArH),
7.86 (dd, J = 8.0 Hz, J’ = 1.2 Hz, 1H, ArH), 7.53 (d, J = 8.4 Hz,
1H, ArH), 7.43-7.42 (m, 1H, ArH), 7.31-7.28 (m, 1H, ArH), 7.08-
7.04 (m, 1H, ArH), 6.79 (d, J = 8.8 Hz, 1H, ArH), 5.82 (s, 1H,
References
CH), 4.04-3.98 (m, 1H, CH2), 3.67 (s, 3H, CH3O), 3.48-3.41 (m,
1H, CH2), 2.83-2.76 (m, 1H, CH2), 2.62-2.56 (m, 1H, CH2), 1.41
(s, 9H, 3CH3); 13C NMR: dC 164.7, 159.5, 153.1, 149.8, 148.8,
137.9, 132.3, 129.4, 129.3, 122.2, 120.6, 117.1, 114.8, 114.5, 111.0,
109.7, 99.3, 81.2, 55.3, 42.6, 39.4, 28.3, 27.0. HRMS. Calcd
for C25H25N4O4, [M - H]-: m/z 445.1881. Found: m/z 445.1877.
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tert-Butyl 11-(3,5-dimethoxyphenyl)-10-oxo-7,8,10,11-
tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-
carboxylate (6i)
Yield 87%; white powder; mp 284-286°C; IR: n 3307, 3082,
2976, 2887, 1792, 1660, 1610, 1546, 1497, 1464, 1398, 1368,
1
1250, 1211, 1143, 1052, 949, 934, 850, 817, 779, 731 cm-1; H
NMR: dH 12.97 (s, 1H, NH), 9.59 (s, 1H, NH), 8.11 (s, 1H, ArH),
7.34 (d, J = 8.8 Hz, 1H, ArH), 7.06 (d, J = 8.4 Hz, 1H, ArH),
6.49-6.48 (m, 2H, ArH), 6.22 (s, 1H, ArH), 5.45 (s, 1H, CH),
4.03-4.00 (m, 1H, CH2), 3.65 (s, 6H, 2CH3O), 3.50-3.43 (m,
1H, CH2), 2.82-2.77 (m, 1H, CH2), 2.67-2.62 (m, 1H, CH2), 1.43
(s, 9H, 3CH3); 13C NMR: dC 164.8, 160.6, 153.1, 150.6, 148.8,
137.9, 132.4, 129.3, 122.2, 117.2, 114.8, 109.7, 106.8, 99.3, 97.4,
81.3, 55.4, 42.7, 39.4, 28.2, 27.0. HRMS. Calcd for C26H27N4O5,
[M - H]-: m/z 475.1987. Found: m/z 475.1990.
tert-Butyl 10-oxo-11-phenyl-7,8,10,11-tetrahydro-3H-
indazolo [5,4-b][1,6]naphthyridine-9(6H)-carboxylate (6j)
Yield 85%; white powder; mp 292-294°C; IR: n 3296, 3080,
2974, 2889, 1719, 1604, 1543, 1493, 1400, 1370, 1254, 1212,
Unauthenticated
Download Date | 4/10/19 3:24 PM

D.-S. Chen et al.: Indazolo[5,4-b][1,6]naphthyridines and indazolo[6,7-b][1,6]naphthyridinesꢁ
ꢁ21
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Unauthenticated
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