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

  • Dong-Mei Chen , Jia-Yan Liu , Ming Wei , Bing-Wei Wang , Ruo-Han Chu and Dong-Sheng Chen EMAIL logo
Published/Copyright: April 3, 2019
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 25 Issue 1

Abstract

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.

Keywords: in-situ reduction; nitro compounds; indazolo [5,4-b][1,6]naphthyridine; indazolo[6,7-b][1,6]naphthyridine

Introduction

Naphthyridines are an important class of heterocycles due to their inherent biological activities [1, 2, 3, 4, 5]. Substituted indazoles are also pharmaceutically important [6]. Previously, we introduced a three-component reaction of 1H-indol-6-amine, aromatic aldehyde and cyclic 1,3-dicarbonyl compound under catalyst-free conditions [7, 8, 9]. Compared with amino compounds, nitro derivatives are more stable, easier to obtain, and they can be easily reduced to the amines [10, 11]. The reduction is often accomplished with the use of iron [Fe(0)]. This reagent is one of the most abundant, nontoxic, inexpensive and environmentally friendly transition metals [12, 13, 14]. In view of the importance of the previously detailed structures, in this report we describe synthesis of indazolo[5,4-b] [1,6]naphthyridine and indazolo[6,7-b][1,6]naphthyridine derivatives starting from 5-nitro-1H-indazole or 6-nitro-1H-indazole using Fe(0) as a reducing agent via a one-pot multicomponent protocol [15, 16, 17].

Results and discussion

Initially, 4-chlorobenzaldehyde (1a), tert-butyl 2,4-dioxopiperidine-1-carboxylate (2) and 6-nitro-1H-indazole (3) were allowed to react to optimize the reaction conditions (Scheme 1). When the reaction was performed 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 and 1 mL of acetic acid using ethanol as solvent. Ethanol was the optimal solvent in comparison to tetrahydrofuran, methanol, dioxane and toluene. With the optimized reaction conditions in hand, other aromatic aldehydes 1b-j were applied in this synthesis to furnish products 4a-j in good yields (Scheme 1). It was found that under the optimized conditions the treatment of 5-nitro-1H-indazole (5), instead of the isomer 3, with 1 and 2 furnished the expected products 6 (Scheme 2). The structures of all products were characterized by IR, NMR and HRMS spectral methods.

Scheme 1 Synthesis of indazolo[6,7-b][1,6]naphthyridine derivatives 4a-4j.
Scheme 1

Synthesis of indazolo[6,7-b][1,6]naphthyridine derivatives 4a-4j.

Scheme 2 Synthesis of indazolo[5,4-b][1,6]naphthyridine derivatives 6a-6j.
Scheme 2

Synthesis of indazolo[5,4-b][1,6]naphthyridine derivatives 6a-6j.

A possible mechanism is shown in Scheme 3 using substrate 3 as an example. First, the nitro compound 3 is reduced to 6-aminoindazole A. At the same time, the Knoevenagel product B is generated by the reaction of substrates 1 and 2. Then, 6-aminoindazole A undergoes reaction with the intermediate product B to obtain the intermediate C. Then, intramolecular cyclization of C generates the intermediate product D which is the final precursor to the observed product 4.

Scheme 3 The proposed mechanism.
Scheme 3

The proposed mechanism.

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 form nitro compounds by in situ reduction and cyclization reaction in Fe/H2O medium.

Experimental

Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded on a Tensor 27 spectrometer in KBr pellets. 1H NMR (400 MHz) and 13C NMR (125 MHz) spectra were obtained in DMSO-d6 with Me4Si as internal standard using Bruker-400 and Bruker-500 spectrometers. ESI-HRMS analyses were carried out using a Bruker-micro-TOF-Q-MS analyzer.

General procedure for the synthesis of 4 and 6

A dry 25-mL round-bottom flask was charged with aromatic aldehyde 1 (1 mmol), tert-butyl 2,4-dioxopiperidine-1-carboxylate 2 (1.0 mmol), 6-nitro-1H-indazole 3 or 5-nitro-1H-indazole 5 (1.0 mmol), powdered iron (3 mmol), EtOH (5 mL), H2O (1 mL), and AcOH (1 mL). The mixture was stirred at 80°C for 8-10 h until TLC analysis revealed that the reaction was completed and then treated with brine (10 mL). The mixture was extracted with EtOAc (3 × 15 mL). The organic layers were combined and washed thoroughly with brine, dried with Na2SO4, and filtered through Celite. Following 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-chlorophenyl)-10-oxo-7,8,10,11-tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carboxylate (4a)

Yield 88%; white powder; mp 240-241°C; IR: ν 3427, 3316, 2936, 1741, 1626, 1606, 1533, 1494, 1398, 1213, 1159, 1047, 949, 851, 774, 703 cm-1; 1H NMR: δH 12.90 (s, 1H, NH), 9.80 (s, 1H, NH), 7.94 (s, 1H, ArH), 7.53 (d, J = 8.4 Hz, 1H, ArH), 7.40 (d, J = 8.0 Hz, 2H, ArH), 7.23 (d, J = 8.0 Hz, 2H, ArH), 6.85 (d, J = 8.4 Hz, 1H, ArH), 5.56 (s, 1H, CH), 4.01-3.98 (m, 1H, CH2), 3.50-3.44 (m, 1H, CH2), 2.82-2.78 (m, 1H, CH2), 2.66-2.62 (m, 1H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR: δC 164.1, 152.5, 148.6, 145.8, 138.5, 134.1, 134.0, 130.6, 129.3, 127.8, 119.9, 119.6, 111.3, 104.7, 100.0, 80.9, 42.1, 35.8, 27.7, 26.3. HRMS. Calcd for C24H22N4O3Cl, [M - H]-: m/z 449.1386. Found: m/z 449.1384.

tert-Butyl 11-(4-bromophenyl)-10-oxo-7,8,10,11-tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carboxylate (4b)

Yield 90%; white powder; mp: 242-243°C; IR: n 3310, 3061, 1735, 1633, 1599, 1536, 1494, 1387, 1285, 1154, 1061, 947, 830, 775, 702 cm-1; 1H NMR: δH 12.89 (s, 1H, NH), 9.79 (s, 1H, NH), 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, 120.4, 120.1, 119.6, 111.8, 105.2, 100.5, 81.4, 42.6, 36.4, 28.3, 26.9. HRMS. Calcd for C24H22N4O3Br, [M - H]-: m/z 493.0881. Found: m/z 493.0885.

tert-Butyl 11-(4-fluorophenyl)-10-oxo-7,8,10,11-tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carboxylate (4c)

Yield 81%; white powder; mp 243-244°C; IR: n 3471, 3307, 2980, 1738, 1670, 1535, 1503, 1461, 1369, 1248, 1141, 1050, 946, 850, 743, 710 cm-1; 1H NMR: δH 12.88 (s, 1H, NH), 9.76 (s, 1H, NH), 7.93 (s, 1H, ArH), 7.52 (d, J = 8.0 Hz, 1H, ArH), 7.41-7.37 (m, 2H, ArH), 6.99-6.95 (m, 2H, ArH), 6.82 (d, J = 8.4 Hz, 1H, ArH), 5.54 (s, 1H, CH), 4.01-3.95 (m, 1H, CH2), 3.48-3.40 (m, 1H, CH2), 2.81-2.72 (m, 1H, CH2), 2.66-2.59 (m, 1H, CH2), 1.41 (s, 9H, 3CH3); 13C NMR: δC 164.6, 161.1(d, JF-C = 192.4 Hz), 153.0, 149.0, 143.6, 139.1, 134.6, 134.4, 129.7 (d, JF-C = 6.3 Hz), 120.4, 120.0, 115.0 (d, JF-C = 16.7 Hz), 111.8, 105.6, 100.8, 81.3, 42.6, 36.1, 28.2, 26.9. HRMS. Calcd for C24H22N4O3F, [M - H]-: m/z 433.1681. Found: m/z 433.1680.

tert-Butyl 11-(4-nitrophenyl)-10-oxo-7,8,10,11-tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carboxylate (4d)

Yield 84%; yellow powder; mp 235-236°C; IR: n 3310, 3217, 2977, 1737, 1665, 1638, 1540, 1509, 1393, 1214, 1138, 1049, 943, 852, 781, 710 cm-1; 1H NMR: δH 12.97 (s, 1H, NH), 9.90 (s, 1H, NH), 8.07 (d, J = 8.8 Hz, 2H, ArH), 7.95 (s, 1H, ArH), 7.64 (d, J = 8.4 Hz, 2H, ArH), 7.57 (d, J = 8.4 Hz, 1H, ArH), 6.88 (d, J = 8.8 Hz, 1H, ArH), 5.72 (s, 1H, CH), 4.01-3.96 (m, 1H, CH2), 3.53-3.42 (m, 1H, CH2), 2.85-2.76 (m, 1H, CH2), 2.70-2.62 (m, 1H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR: dC 164.5, 154.5, 152.9, 149.5, 146.3, 139.1, 134.8, 134.6, 129.2, 123.8, 120.54, 120.46, 111.9, 104.3, 99.9, 81.4, 42.5, 37.1, 28.2, 26.9. HRMS. Calcd for C24H22N5O5, [M - H]-: m/z 460.1626. Found: m/z 460.1635.

tert-Butyl 11-(3-chlorophenyl)-10-oxo-7,8,10,11-tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carboxylate (4e)

Yield 84%; white powder; mp: 227-228°C; IR: n 3450, 3291, 2977, 1738, 1667, 1626, 1536, 1496, 1446, 1369, 1212, 1138, 1048, 949, 850, 776, 731 cm-1; 1H NMR: dH 12.93 (s, 1H, NH), 9.83 (s, 1H, NH), 7.94 (s, 1H, ArH), 7.56-7.52 (m, 2H, ArH), 7.27 (d, J = 7.6 Hz, 1H, ArH), 7.22-7.18 (m, 1H, ArH), 7.14-7.11 (m, 1H, ArH), 6.86 (d, J = 8.8 Hz, 1H, ArH), 5.55 (s, 1H, CH), 4.02-3.97 (m, 1H, CH2), 3.51-3.44 (m, 1H, CH2), 2.83-2.76 (m, 1H, CH2), 2.70-2.64 (m, 1H, CH2), 1.43 (s, 9H, 3CH3); 13C NMR: dC 164.6, 152.9, 149.6, 149.2, 139.0, 134.7, 134.5, 133.0, 130.4, 127.8, 126.7, 126.5, 120.4, 120.2, 111.8, 105.0, 100.3, 81.4, 42.6, 36.7, 28.3, 26.8. HRMS. Calcd for C24H22N4O3Cl, [M - H]-: m/z 449.1386. Found: m/z 449.1404.

tert-Butyl 11-(3-bromophenyl)-10-oxo-7,8,10,11-tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carboxylate (4f)

Yield 83%; white powder; mp: 229-230°C; IR: n 3450, 3279, 2972, 1745, 1625, 1537, 1498, 1467, 1367, 1216, 1158, 1049, 945, 815, 775, 712 cm-1; 1H NMR: dH 12.94 (s, 1H, NH), 9.83 (s, 1H, NH), 7.94 (s, 1H, ArH), 7.66 (s, 1H, ArH), 7.54 (d, J = 8.4 Hz, 1H, ArH), 7.32-7.25 (m, 2H, ArH), 7.17-7.12 (m, 1H, ArH), 6.86 (d, J = 8.4 Hz, 1H, ArH), 5.54 (s, 1H, CH), 4.02-3.90 (m, 1H, CH2), 3.51-3.43 (m, 1H, CH2), 2.83-2.76 (m, 1H, CH2), 2.70-2.65 (m, 1H, CH2), 1.43 (s, 9H, 3CH3); 13C NMR: dC 164.5, 152.9, 149.9, 149.2, 139.0, 134.7, 134.5, 130.8, 130.7, 129.4, 127.1, 121.8, 120.4, 120.2, 111.8, 105.0, 100.4, 81.4, 42.6, 36.8, 28.3, 26.8. HRMS. Calcd for C24H22N4O3Br, [M - H]-: m/z 493.0881. Found: m/z 493.0893.

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)

Yield 89%; white powder; mp: 250-251°C; IR: n 3301, 2978, 1737, 1630, 1601, 1540, 1496, 1392, 1285, 1215, 1155, 1049, 975, 871, 774, 701 cm-1; 1H NMR: dH 12.94 (s, 1H, NH), 9.86 (s, 1H, NH), 7.96 (s, 1H, ArH), 7.71 (d, J = 8.4 Hz, 1H, ArH), 7.56 (d, J = 8.8 Hz, 1H, ArH), 7.44 (d, J = 8.4 Hz, 1H, ArH), 7.25 (dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 6.86 (d, J = 8.4 Hz, 1H, ArH), 5.55 (s, 1H, CH), 4.01-3.95 (m, 1H, CH2), 3.54-3.45 (m, 1H, CH2), 2.82-2.74 (m, 1H, CH2), 2.70-2.63 (m, 1H, CH2), 1.43 (s, 9H, 3CH3); 13C NMR: dC 164.5, 152.9, 149.3, 148.1, 139.0, 134.7, 134.5, 130.9, 130.8, 129.9, 129.1, 128.4, 120.4, 111.8, 104.5, 100.0, 81.4, 42.6, 36.4, 28.2, 26.8. HRMS. Calcd for C24H21N4O3Cl2, [M - H]-: m/z 483.0996. Found: m/z 483.0994.

tert-Butyl 11-(2-chlorophenyl)-10-oxo-7,8,10,11-tetrahydro-1H-indazolo [6,7-b][1,6]naphthyridine-9(6H)-carboxylate (4h)

Yield 86%; white powder; mp: 280-281°C; IR: n 3414, 3319, 3101, 2974, 1745, 1627, 1531, 1494, 1469, 1398, 1321, 1210, 1141, 1048, 943, 872, 782, 704 cm-1; 1H NMR: dH 11.97 (s, 1H, NH), 9.89 (s, 1H, NH), 7.90 (s, 1H, ArH), 7.86 (d, J = 7.6 Hz, 1H, ArH), 7.50 (d, J = 8.4 Hz, 1H, ArH), 7.24-7.19 (m, 2H, ArH), 7.13-7.09 (m, 1H, ArH), 6.77 (d, J = 8.4 Hz, 1H, ArH), 5.80 (s, 1H, CH), 4.01-3.96 (m, 1H, CH2), 3.45-3.37 (m, 1H, CH2), 2.80-2.71 (m, 1H, CH2), 2.59-2.48 (m, 1H, CH2), 1.40 (s, 9H, 3CH3); 13C NMR: dC 164.3, 152.8, 149.7, 142.2, 139.4, 135.3, 134.9, 133.6, 132.8, 130.5, 128.5, 127.0, 120.44, 120.37, 111.7, 103.4, 98.1, 81.3, 42.6, 38.1, 28.3, 26.9. HRMS. Calcd for C24H22N4O3Cl, [M - H]-: m/z 449.1386. Found: m/z 449.1386.

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 89%; white powder; mp > 300°C; IR: n 3203, 3079, 2975, 1699, 1651, 1604, 1545, 1504, 1453, 1388, 1324, 1216, 1156, 970, 850, 767, 710 cm-1; 1H NMR: dH 13.08 (s, 1H, NH), 9.88 (s, 1H, NH), 7.97 (s, 1H, ArH), 7.54 (d, J = 8.4 Hz, 1H, ArH), 7.17-7.15 (m, 1H, ArH), 6.97 (d, J = 3.2 Hz, 1H, ArH), 6.83-6.78 (m, 2H, ArH), 5.94 (s, 1H, CH), 4.08-4.03 (m, 1H, CH2), 3.49-3.41 (m, 1H, CH2), 2.86-2.76 (m, 1H, CH2), 2.67-2.62 (m, 1H, CH2), 1.44 (s, 9H, 3CH3); 13C NMR: dC 164.6, 153.0, 151.5, 148.9, 139.0,134.5, 134.3, 126.8, 124.3, 123.8, 120.4, 120.1, 111.7, 105.2, 100.4, 81.4, 42.6, 32.0, 28.3, 26.9. HRMS. Calcd for C22H21N4O3S, [M - H]-: m/z 421.1340. Found: m/z 421.1331.

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)-carboxylate (4j)

Yield 87%; white powder; mp 247-248°C; IR: n 3296, 3224, 2971, 1710, 1673, 1625, 1538, 1503, 1443, 1327, 1287, 1166, 1049, 946, 811, 776, 703 cm-1; 1H NMR: dH 12.86 (s, 1H, NH), 9.74 (s, 1H, NH), 7.93 (s, 1H, ArH), 7.51 (d, J = 8.4 Hz, 1H, ArH), 6.98 (s, 1H, ArH), 6.89-6.78 (m, 2H, ArH), 6.70 (d, J = 7.2 Hz, 1H, ArH), 5.88 (d, J = 7.2 Hz, 2H, CH2), 5.46 (s, 1H, CH), 4.01-3.98 (m, 1H, CH2), 3.50-3.44 (m, 1H, CH2), 2.81-2.78 (m, 1H, CH2), 2.67-2.63 (m, 1H, CH2), 1.43 (s, 9H, 3CH3); 13C NMR: dC 164.6, 153.0, 148.7, 147.3, 145.9, 141.7, 139.1, 134.5, 134.3, 120.9, 120.3, 119.8, 111.8, 108.7, 108.2, 106.0, 101.1, 101.0, 81.3,42.6, 36.5, 28.3, 26.9. HRMS. Calcd for C25H23N4O5, [M - H]-: m/z 459.1674. Found: m/z 459.1667.

tert-Butyl 11-(4-chlorophenyl)-10-oxo-7,8,10,11-tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-carboxylate (6a)

Yield 87%; white powder; mp 221-222°C; IR: n 3297, 3079, 2977, 2933, 2885, 1719, 1681, 1605, 1543, 1492, 1401, 1369, 1331, 1253, 1213, 1142, 1092, 1049, 949, 846, 805, 775, 703 cm-1; 1H NMR: dH 13.01 (s, 1H, NH), 9.67 (s, 1H, NH), 8.01 (s, 1H, ArH), 7.37-7.34 (m, 3H, ArH), 7.23 (d, J = 8.4 Hz, 2H, ArH), 7.07 (d, J = 8.4 Hz, 1H, ArH), 5.52 (s, 1H, CH), 4.02-3.96 (m, 1H, CH2), 3.60-3.50 (m, 1H, CH2), 2.82-2.75 (m, 1H, CH2), 2.64-2.59 (m, 1H, CH2), 1.41 (s, 9H, 3CH3); 13C NMR: dC 164.7, 153.1, 148.9, 147.2, 137.9, 132.1, 130.9, 130.0, 129.3, 128.4, 122.1, 117.2, 114.3, 110.0, 99.1, 81.3, 42.6, 39.0, 28.3, 27.0. HRMS. Calcd for C24H22N4O3Cl, [M - H]-: m/z 449.1386. Found: m/z 449.1384.

tert-Butyl 11-(4-bromophenyl)-10-oxo-7,8,10,11-tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-carboxylate (6b)

Yield 90%; white powder; mp 223-225°C; IR: n 3296, 3077, 2977, 2933, 2885, 1719, 1680, 1605, 1543, 1492, 1401, 1369, 1331, 1254, 1212, 1142, 1049, 949, 845, 804, 775, 738, 714 cm-1; 1H NMR: dH 12.97 (s, 1H, NH), 9.63 (s, 1H, NH), 7.98 (s, 1H, ArH), 7.35-7.32 (m, 3H, ArH), 7.28 (d, J = 8.4 Hz, 2H, ArH), 7.05 (d, J = 8.8 Hz, 1H, ArH), 5.49 (s, 1H, CH), 4.00-3.95 (m, 1H, CH2), 3.46-3.39 (m, 1H, CH2), 2.80-2.74 (m, 1H, CH2), 2.62-2.58 (m, 1H, CH2), 1.39 (s, 9H, 3CH3); 13C NMR: dC 164.7, 153.1, 148.9, 147.7, 137.9, 132.1, 131.3, 130.4, 129.3, 122.1, 119.4, 117.2, 114.2, 110.0, 99.1, 81.3, 42.6, 39.1, 28.3, 27.0. HRMS. Calcd for C24H22N4O3Br [M - H]-: m/z 493.0881. Found: m/z 493.0873.

tert-Butyl 11-(3-chlorophenyl)-10-oxo-7,8,10,11-tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-carboxylate (6c)

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; 1H NMR: dH 13.02 (s, 1H, NH), 9.68 (s, 1H, NH), 8.06 (s, 1H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.30 (d, J = 7.6 Hz, 1H, ArH), 7.23-7.19 (m, 1H, ArH), 7.13-7.07 (m, 2H, ArH), 5.55 (s, 1H, CH), 4.01-3.98 (m, 1H, CH2), 3.49-3.44 (m, 1H, CH2), 2.81-2.78 (m, 1H, CH2), 2.68-2.63 (m, 1H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR: dC 164.7, 153.0, 150.7, 149.1, 137.9, 133.2, 132.2, 130.3, 129.3, 127.8, 126.9, 126.3, 122.1, 117.2, 114.0, 110.1, 99.0, 81.3, 42.6, 39.3, 28.3, 26.9. HRMS. Calcd for C24H22N4O3, [M - H]-: m/z 449.1386. Found: m/z 449.1387.

tert-Butyl 11-(3-bromophenyl)-10-oxo-7,8,10,11-tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-carboxylate (6d)

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, 711 cm-1; 1H NMR: dH 13.01 (s, 1H, NH), 9.67 (s, 1H, NH), 8.05 (s, 1H, ArH), 7.51-7.50 (m, 1H, ArH), 7.38-7.33 (m, 2H, ArH), 7.25 (d, J = 8.0 Hz, 1H, ArH), 7.17-7.13 (m, 1H, ArH), 7.09 (d, J = 8.8 Hz, 1H, ArH), 5.54 (s, 1H, CH), 4.02-3.97 (m, 1H, CH2), 3.50-3.46 (m, 1H, CH2), 2.82-2.78 (m, 1H, CH2), 2.68-2.64 (m, 1H, CH2), 1.42 (s, 9H, 3CH3) ; 13C NMR: dC 164.7, 153.0, 150.9, 149.1, 137.9, 132.2, 130.69, 130.67, 129.3, 129.2, 127.3, 122.1, 121.9, 117.2, 114.0, 110.1, 99.0, 81.3, 42.6, 39.3, 28.3, 26.9. HRMS. Calcd for C24H22N4O3Br, [M - H]-: m/z 493.0881. Found: m/z 493.0876.

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 89%; white powder; mp 256-257°C; IR: n 3297, 3080, 2978, 2934, 2886, 1720, 1680, 1606, 1544, 1493, 1467, 1401, 1370, 1329, 1253, 1213, 1143, 1049, 1031, 947, 889, 840, 805, 776, 700 cm-1; 1H NMR: dH 13.02 (s, 1H, NH), 9.69 (s, 1H, NH), 8.07 (s, 1H, ArH), 7.60 (d, J = 2.0 Hz, 1H, ArH), 7.43 (d, J = 8.4 Hz, 1H, ArH), 7.38 (d, J = 8.4 Hz, 1H, ArH), 7.29 (dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 7.09 (d, J = 8.4 Hz, 1H, ArH), 5.58 (s, 1H, CH), 4.02-3.96 (m, 1H, CH2), 3.52-3.45 (m, 1H, CH2), 2.82-2.76 (m, 1H, CH2), 2.68-2.62 (m, 1H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR: dC 164.7, 153.0, 149.20, 149.17, 137.9, 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-(2-chlorophenyl)-10-oxo-7,8,10,11-tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-carboxylate (6f)

Yield 85%; white powder; mp 226-227°C; IR: n 3270, 3076, 2972, 2935, 2888, 1719, 1622, 1601, 1543, 1491, 1388, 1336, 1251, 1211, 1142, 1049, 943, 894, 851, 807, 779, 759, 742, 705 cm-1; 1H NMR: dH 13.03 (s, 1H, NH), 9.70 (s, 1H, NH), 7.95 (s, 1H, ArH), 7.41 (d, J = 7.2 Hz, 1H, ArH), 7.36 (d, J = 8.8 Hz, 1H, ArH), 7.29 (d, J = 7.6 Hz, 1H, ArH), 7.18-7.15 (m, 1H, ArH), 7.10-7.06 (m, 2H, ArH), 5.89 (s, 1H, CH), 4.00-3.97 (m, 1H, CH2), 3.46-3.44 (m, 1H, CH2), 2.81-2.77 (m, 1H, CH2), 2.64-2.60 (m, 1H, CH2), 1.41 (s, 9H, 3CH3); 13C NMR: dC 164.4, 152.8, 149.1, 145.8, 137.8, 132.0, 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-(2-bromophenyl)-10-oxo-7,8,10,11-tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-carboxylate (6g)

Yield 83%; white powder; mp 225-227°C; IR: n 3317, 3070, 2969, 2934, 2886, 1720, 1623, 1602, 1542, 1490, 1474, 1398, 1369, 1331, 1250, 1210, 1141, 1048, 942, 892, 851, 808, 781, 738, 710 cm-1; 1H NMR: dH 13.01 (s, 1H, NH), 9.68 (s, 1H, NH), 8.04 (s, 1H, ArH), 7.46 (d, J = 7.6 Hz, 1H, ArH), 7.39-7.35 (m, 2H, ArH), 7.22-7.19 (m, 1H, ArH), 7.07 (d, J = 8.8 Hz, 1H, ArH), 7.02-6.98 (m, 1H, ArH), 5.86 (s, 1H, CH), 4.01-3.95 (m, 1H, CH2), 3.48-3.41 (m, 1H, CH2), 2.81-2.76 (m, 1H, CH2), 2.65-2.59 (m, 1H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR: dC 164.4, 152.7, 149.0, 147.6, 137.8, 132.7, 132.3, 132.2, 129.5, 128.5, 128.3, 122.3, 122.1, 117.4, 114.1, 110.2, 99.4, 81.2, 42.6, 39.5, 28.3, 27.0. HRMS. Calcd for C24H22N4O3Br, [M - H]-: m/z 493.0881. Found: m/z 493.0876.

tert-Butyl 11-(3-methoxyphenyl)-10-oxo-7,8,10,11-tetrahydro-3H-indazolo [5,4-b][1,6]naphthyridine-9(6H)-carboxylate (6h)

Yield 86%; white powder; mp 281-283°C; IR: n 3303, 3078, 2972, 2888, 1717, 1679, 1606, 1543, 1492, 1476, 1399, 1369, 1335, 1262, 1148, 1049, 949, 843, 807, 769, 735, 710 cm-1; 1H 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, 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.

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, 1250, 1211, 1143, 1052, 949, 934, 850, 817, 779, 731 cm-1; 1H 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, 1158, 1049, 947, 845, 808, 783, 759, 709 cm-1; 1H NMR: dH 12.96 (s, 1H, NH), 9.61 (s, 1H, NH), 8.02 (s, 1H, ArH), 7.36-7.32 (m, 3H, ArH), 7.19-7.15 (m, 2H, ArH), 7.08-7.02 (m, 2H, ArH), 5.51 (s, 1H, CH), 4.03-3.99 (m, 1H, CH2), 3.48-3.41 (m, 1H, CH2), 2.83-2.73 (m, 1H, CH2), 2.66-2.61 (m, 1H, CH2), 1.42 (s, 9H, 3CH3); 13C NMR: dC 164.7, 153.1, 148.8, 148.4, 137.9, 132.2, 129.2, 128.4, 128.1, 126.3, 122.2, 117.1, 114.9, 109.7, 99.4, 81.2, 42.6, 39.5, 28.3, 27.0. HRMS. Calcd for C24H23N4O3, [M - H]-: m/z 415.1776. Found: m/z 415.1769.

Acknowledgements

We are grateful to the Natural Science Foundation for Colleges and Universities of Jiangsu Province (18KJB150024), Science Research and Development Foundation of Nanjing Medical University (2017NJMU227), Science Research and Development Foundation of the Kangda College of Nanjing Medical University (KD201822NYDKJ03, KD2017KYJJYB003, KD2017KYJJYB004) and a Qing Lan Project for financial support.

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Received: 2018-10-08
Accepted: 2018-11-16
Published Online: 2019-04-03

© 2019 Dong-Mei Chen et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 Public License.

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https://doi.org/10.1515/hc-2019-0006
Keywords for this article
in-situ reduction; nitro compounds; indazolo [5,4-b][1,6]naphthyridine; indazolo[6,7-b][1,6]naphthyridine
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