Next Article in Journal
Dispersion of Carbon Nanotubes with “Green” Detergents
Next Article in Special Issue
Asymmetric Synthesis of Tetrahydroisoquinoline Derivatives through 1,3-Dipolar Cycloaddition of C,N-Cyclic Azomethine Imines with Allyl Alkyl Ketones
Previous Article in Journal
The Effects of CO2 Additional on Flame Characteristics in the CH4/N2/O2 Counterflow Diffusion Flame
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 26
Issue 10
10.3390/molecules26102907
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Structural Identification between Phthalazine-1,4-Diones and N-Aminophthalimides via Vilsmeier Reaction: Nitrogen Cyclization and Tautomerization Study

by
Cheng-Yen Chung
1,2,
Ching-Chun Tseng
1,2,
Sin-Min Li
3,
Shuo-En Tsai
1,2,
Hui-Yi Lin
1,* and
Fung Fuh Wong
1,*
1
School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan
2
The Ph.D. Program for Biotech Pharmaceutical Industry and School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan
3
Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(10), 2907; https://doi.org/10.3390/molecules26102907
Submission received: 25 April 2021 / Revised: 10 May 2021 / Accepted: 10 May 2021 / Published: 13 May 2021
(This article belongs to the Special Issue Cycloaddition Reactions and Their Stereochemistry)
Browse Figures
Versions Notes

Abstract

:
N-Aminophthalimides and phthalazine 1,4-diones were synthesized from isobenzofuran-1,3-dione, isoindoline-1,3-dione, furo [3,4-b] pyrazine-5,7-dione, or 1H-pyrrolo [3,4-c] pyridine-1,3-dione with monohydrate hydrazine to carry out the 5-exo or 6-endo nitrogen cyclization under the different reaction conditions. Based on the control experimental results, 6-endo thermodynamic hydrohydrazination and kinetical 5-exo cyclization reactions were individually selective formation. Subsequently, Vilsmeier amidination derivatization was successfully developed to probe the structural divergence between N-aminophthalimide 2 and phthalazine 1,4-dione 3. On the other hand, the best tautomerization of N-aminophthalimide to diazinone was also determined under acetic acid mediated solution.

Graphical Abstract

1. Introduction

Nitrogen-containing heterocyclic compounds are widely applied to the biologically active pharmaceuticals, agrochemicals, and functional materials and become more and more important [1,2,3,4,5]. Especially, heterocycle derivatives containing bridgehead amine and hydrazine [6,7] such as N-aminophthalimides [8] and phthalazine 1,4-diones [9] have received considerable attention. Therefore, the development of new efficient methods to synthesize N-heterocycles with structural diversity is one major interest of modern synthetic organic chemists [10,11,12].
Heterocycles containing phthalazine 1,4-dione moiety have been reported to possess different pharmacological properties including anti-inflammatory, cardiotonic vasorelaxant, anticonvulsant [13], antihypertensive [14], antibacterial [15], anti-cancer [16], and carbonic anhydrase enzyme activity [17]. On the other hand, phthalimide group was conceived as a nitrogen source [18], for the direct introduction of masked amino function via the classical Gabriel protocol [19,20] as well as for the protection of amino groups [21,22,23]. N-aminophthalimides can be considered as phthalazine 1,4-dione tautomeric pairs. The structural arrangement of hydrazine derivatives is the mainly associated with the interconversion of imine−enamine [24,25]. Herein, we selectively synthesize N-aminophthalimide and phthalazine 1,4-dione derivatives in via the thermodynamic-kinetic control conditions. They will provide as the precursors for constructing the pharmacological heterocyclic compounds (PDE5 inhibitors) [26,27] or the chemiluminescent luminol derivatives [28]. Owing to the structural divergence between N-aminophthalimides 2 and phthalazine-1,4-diones 3, we explored the Vilsmeier amidination derivatization to identify them in this work [29,30,31,32,33]. Furthermore, we successfully developed the prototrophic tautomeric interconversion from N-aminophthalimides to phthalazine 1,4-diones under Brønsted–Lowry acidic condition [29,30,31,32,33,34,35].

2. Results and Discussion

Initially, isobenzofuran-1,3-diones (1a–c), isoindoline-1,3-dione (1d), furo [3,4-b] pyrazine-5,7-dione (1e), and 1H-pyrrolo[3,4-c] pyridine-1,3-dione (1f) [34,35,36] were purchased or prepared as the starting materials. Reacting compounds 1a–f with monohydrate hydrazine in ethanol solution at low (at 0 °C or –20 °C) or room temperature led directly to the 5-exo cyclization N-aminophthalimide products 2a–f (81–94%) without the accumulation of hydrohydrazination products 3a–f (Table 1). On the other hand, the 6-exo cyclization of distal nitrogen instead of proximal one was exclusively observed at reflux for ~4 h, and the corresponding 6-endo phthalazine 1,4-dione products 3a–f were formed (83–91%, Table 1). Fortunately, compounds 2a–f and 3a–f can be selectively prepared via kinetic and thermodynamic control reaction with hydrazine hydrate. From the fundamental perspective, these symmetric molecules of N-aminophthalimide products 2a–f provide themselves for investigation of tautomeric conversion controlling processes as well as convenient platforms for the structural identity.
Additionally, phthalazine 1,4-diones 3a–f were used as the reference standards. Although compounds 2 and 3 were tautomeric pairs, they significantly possessed the different polarity, such as, Rf = 0.33 for N-aminophthalimide 2a and Rf = 0.41 for phthalazine 1,4-dione 3a (EA/MeOH = 9/1). All of the 2a–f and 3a–f compounds were fully characterized by spectroscopic methods. For example, compound 2a presented peaks at 3447 and 3482 cm−1 for stretching of the –NH2 group and at 1020 cm−1 for stretching of the N–N group in FT-IR spectrum. For compound 3a, its IR absorption peaks were at 3461 cm−1 for stretching of the –NH–NH– group and at 1051 cm−1 for stretching of the N–N group. In 1H-NMR, compounds 2 and 3 presented similar chemical shift and coupling constants, resulting in difficult structural identification of each other. For example, the 1H-NMR spectra of compounds 2a and 3a were similar as shown in Figure 1. This observation drove us to develop a novel identification method.
On the other hand, N-aminophthalimides 2c and 2e reveal the existence of intramolecular hydrogen bonding phenomenon between carbonyl and amino group in 1H-NMR spectra. This phenomenon leads to the different chemical shift values between Ha and Ha’ in an aromatic ring (Figure 1). However, compounds 3a–f were favorable for the free base form in DMSO-d6 solvent. For example, the 1H-NMR spectrum of compound 3e was presented in Figure 1. Furthermore, Compound 2c was dissolved in DMSO-d6 and heated at ~100 °C by NMR technique. The sample was monitored in 0, 10, 20, 30, and 60 min, the timed programming result was shown in Figure 2, we found that the intramolecular hydrogen bonding phenomenon was very clearly stable.
Vilsmeier amidination methodology was essentially examined for the applicable protected utilization of primary amines. The usual method was directly treating primary amines with dimethylformamide (DMF) and coupling agents including POCl3, P2O5, PCl5, (COCl)2, PyBOP, SOCl2, acyl chlorides, trifluoroacetic anhydride (TFAA), or sulfonyl chloride to give the corresponding amidine products [37,38,39]. To further probe the structural divergence, pyrazolopyridopyridazine diones 2f and N-aminopyrazolopyrrolopyridine-6,8-diones 3f were selected as model cases for the further control experiments [28]. At first, we employed Vilsmeier reagent (halomethyleniminium salt) [29,30,31,32,33] to compounds 2f and 3f (Scheme 1). The reactions were individually monitored by TLC method. When compound 2f was completely consumed for 4 h at 65 °C, the corresponding acquired amidination product 4 was formed and obtained in 89% yield without producing chlorinated compound 5. The structure of compound 4 was fully characterized by spectroscopic methods and single-crystal X-ray diffraction study. Based on 1H NMR spectroscopic characterization, compound 4 possesses singlet signal of pyridine ring proton Ha around 9.03 ppm, and significant amidinyl moiety signals of iminium proton Hb around 7.70 ppm and two peaks of NMe2 around 2.97 and 3.02 ppm (Figure 3). These results showed the free primary amine group of compound 2f was successfully converted into the amidinyl substituent. On the other hand, chlorination of compound 3f was accomplished without amidination product 4 formation by Vilsmeier reagent at reflux for 4 h, affording the corresponding product 5 with down-field proton signal Hc of pyridine ring around 9.68 ppm in good yield (80%, Scheme 1 and Figure 3) [27]. Based on the above derivatization study, Vilsmeier reaction was conceived as the significant derivatization agent to identify isomers between 2f and 3f.
For further investigation into the reactivity of Vilsmeier amidination derivatization, Vilsmeier reaction was carried out using different substrates including N-aminophthalimides 2a–e at 50 °C for 0.5 h. Various substituted reactants 2a–e were demonstrated to perform the reactions smoothly, regardless of whether electron-donating or electron-withdrawing substituents, and the corresponding amidination products 6−10 were afforded in 74−88% yields (Table 2). All products 6–10 were fully characterized by spectroscopic methods, and they actually presented singlet peak for the significant amidinyl moiety signals of iminium proton H and two peaks of NMe2 in 1H-NMR. Subsequently, a series of phthalazine 1,4-diones 3a–e were treated with Vilsmeier reagent (POCl3/DMF) at 65 °C or 80 °C for 2–4 h. The chlorination happened smoothly to afford the desired products 11–15 in high yields (82−90%, Table 2), except for 3d (31%). Owing to the electron-rich property of nitrogen atoms on the aromatic motif of compound 3d, the complicated aromatic substitution and polylization were proceeded. All chlorinated products 11–15 were also fully characterized by spectroscopic methods, and two peaks for the significant dione moieties were converted into –N = 13C–Cl singlet signal at δ 153–157 ppm in 13C-NMR spectrum. Therefore, Vilsmeier reagent (POCl3/DMF) was used as the derivatization reagent for the different reactive phenomenon to distinguish N-aminophthalimides 2 and phthalazine-1,4-diones 3.
To explore the interconversion reactivity of the tautomerization, the solvent scope was first examined by using 7-aminopyrazolopyrrolopyridine-6,8-dione 2f. Compound 2f was screened and refluxed in the various solvents including CH2Cl2, THF, EtOH, MeCN, toluene, dioxane, and DMSO for 24 h. However, the reactions in CH2Cl2, EtOH, toluene recovered the starting material 2f without conversion happening (Table 3 entries 1–3). The use of polar THF, MeCN, dioxane, and DMSO led to lower interconversion ratios of 2f/3f from 93/7 to 88/12 (Table 3, entries 4–7). Subsequently, Brønsted–Lowry acids including acetic acid (AcOH), methanesulfonic acid (TsOH), methanesulfonic chloride (TsCl), and trifluoroacetic acid (TFA) were studied for the interconversion reaction at reflux for 4 h (Entries 8–11, Table 3). Several experimental observations are worthy to discuss: we firstly found that the conversion ratios were improved under acidic condition (Entries 8–11, Table 3). Secondly, under the strong acid such as trifluoroacetic acid (pKa = 0.30), p-toluenesulfonic acid (TsOH, pKa = −1.9), and methanesulfonic chloride (TsCl), the low conversion ratio and decomposed products were observed (Entries 8–10, Table 3).
For further investigations, the timed programming of the thermodynamic conversion of compound 2f was carried out under acetic acid (AcOH) solution and shown in Figure 4. The reaction mixture was sampled at 1.5, 2.3, 3.5, and 5 h and detected by the 1H-NMR spectroscopic method. This result showed that compound 2f was gradually converted to the thermodynamic stable product 3f (Figure 4). Finally, transformation reaction was equilibrated at reflux for more than 5 h, and the conversion ratio was obtained proximately 6/94 (2f/3f, Entry 11 of Table 4 and Figure 4). Based on the above experimental result, acetic acid was conceived as the best acidic solvent with 6/94 conversion ratio. Fortunately, 2f can be successfully and smoothly transformed to more thermodynamically stable product 3f by refluxing in acidic medium [40,41]. To further demonstrate the reliable of conversion procedure, N-aminophthalimides 2a–e were also used as starting materials at reflux for 8–9 h. Fortunately, compounds 2a–e can be smoothly transformed to give the corresponding thermodynamically pyrazolopyridopyridazine diones 3a–e under acetic acid solvent, with the ratio of 2a–e/3a–e from 6/94 to 1/99 (Table 4).

3. Experimental Section

3.1. General Procedure

All reagents were purchased commercially. All reactions were carried out under argon or nitrogen atmosphere and monitored by TLC. Flash column chromatography was carried out on silica gel (230–400 mesh). Analytical thin-layer chromatography (TLC) was performed using pre-coated plates (silica gel 60 F-254) purchased from Merck Inc. Flash column chromatography purification was carried out by gradient elution using n-hexane in ethyl acetate (EtOAc) unless otherwise stated. 1H NMR spectra were recorded at 400 or 500 MHz and 13C NMR spectra were recorded at 100 or 125 MHz, respectively, in CDCl3, DMSO-d6, or D2O solvent. The standard abbreviations s, d, t, q, and m refer to the singlet, doublet, triplet, quartet, and multiplet, respectively. Coupling constant (J), whenever discernible, has been reported in Hz. Infrared spectra (IR) were recorded in neat solutions or solids; and mass spectra were recorded using electron impact or electrospray ionization techniques. The reported wavenumbers are referenced to the polystyrene 1601 cm−1 absorption. ESI-MS analyses were performed on an Applied Biosystems API 300 mass spectrometer. High-resolution mass spectra were obtained from a JEOL JMS-HX110 mass spectrometer.

3.2. Standard Procedure for Synthesis of N-Aminophthalimides 2a–f

Standard procedure for synthesis of N-aminophthalimides 2a–f. The reliable procedure involved the treatment of isobenzofuran-1,3-diones (1a–c), isoindoline-1,3-dione (1d), furo[3,4-b] pyrazine-5,7-dione (1e), or 1H-pyrrolo[3,4-c] pyridine-1,3-dione (1f, 1.0 equiv.) with monohydrate hydrazine (~5.0 equiv.) in EtOH/H2O (2.0 mL/2.0 mL) at 0 °C or –20 °C to room temperature within 4 h. When the reaction was completed, the reaction mixture was added water (10 mL) for precipitation. The precipitate was filtered, washed with cold water (10 mL) and n-hexane/EA (1/2, 15 mL) to give the corresponding crude N-aminophthalimides 2a–f. The crude desired products 2a–f were recrystallized in acetone/THF (1/4) solution to obtain the pure N-aminophthalimides 2a–f in 81–94% yields. The low solubility of the compounds 2a–f made the 13C-NMR characterization of quaternary and carbonyl carbons of these substrates unclear [28].
N-Aminophthalimide (2a) [42]: White solid; 92% yield; mp 202–205 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.83 (dd, J = 5.8, 3.4 Hz, 2H, ArH), 8.05 (dd, J = 5.8, 3.4 Hz, 2H, ArH); 13C NMR (DMSO-d6, 100 MHz): δ 123.28 (2 × C), 130.53 (2 × C), 134.81 (2 × C), 167.36 (2 × C); FT-IR (KBr): 3482, 3341, 3262, 3093, 1778, 1719, 1605, 1468, 1409, 1291, 1197, 1091, 1075, 1020, 918, 800, 718, 526 cm−1; EIMS m/z: 162 (M+, 100), 105 (12), 104 (74), 77 (12), 76 (26), 50 (11); HRMS (EI) m/z: [M]+ Calcd for C8H6N2O2: 162.0429; Found: 162.0425.
N-Amino-4,5-difluoropthalimide (2b): white solid; 92% yield; mp 288–290 °C; 1H NMR (D2O, 500 MHz): δ 7.40 (t, J = 9.38 Hz, 2H, ArH); 13C NMR (D2O, 125 MHz): δ 116.43 (dd, J = 12.98, 6.09 Hz, 2 × C), 134.91 (2 × C), 148.62 (d, J = 14.79 Hz), 150.61 (d, J = 14.78 Hz), 175.06 (2 × C). FT-IR (KBr): 3358, 3290, 3072, 2593, 1658, 1597, 1495, 1372, 1182, 1094, 1029, 910, 788, 743 cm−1; EIMS m/z: 198 (M+, 100), 141 (24), 140 (83), 113 (14), 112 (33); HRMS (EI) m/z: [M]+ Calcd for C8H4F2N2O2: 198.0241; Found: 198.0233.
N-Amino-4,5-dichlorophthalimide (2c): White solid; 81% yield; mp 302–305 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.72 (s, 1H, ArH), 7.84 (s, 1H, ArH); 13C NMR (DMSO-d6, 100 MHz) δ 130.36, 131.12, 132.08, 132.25, 132.57, 141.90, 164.74, 169.22; FT-IR (KBr): 3466, 3321, 3220, 3027, 2646, 1653, 1619, 1521, 1393, 1356, 1308, 1106, 1022, 930, 809, 782, 613 cm−1; EIMS m/z: 232 (M+ + 2, 64), 230 (M+, 100), 174 (46), 173 (12), 172 (72), 146 (13), 144 (19), 109 (19), 74 (17); HRMS m/z: [M]+calcd for C8H4Cl2N2O2: 229.9650; found: 229.9653.
N-Amino-2,3-pyrazinedicarboxylicphthalimide (2d) [42]: Brown solid; 82% yield; mp 220–222 °C; 1H NMR (D2O, 400 MHz) δ 8.59 (s, 2H, ArH); 13C NMR (D2O, 100 MHz) δ 143.28 (2 × C), 149.18 (2 × C), 172.29 (2 × C); FT-IR (KBr): 3430, 3282, 3164, 2936, 2750, 2636, 1679, 1621, 1353, 1161, 1107, 975, 825 cm−1. EIMS m/z: 164 (M+, 36), 150 (25), 124 (40), 106 (76), 80 (100), 79 (30), 78 (56), 53 (69), 52 (95), 51 (52). HRMS m/z: [M]+calcd for C6H4N4O2: 164.0334; found: 164.0338.
Naphthalene-2,3-dicarboxylic hydrazide (2e): Yellow solid; 94% yield; mp 298–300 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.51–7.56 (m, 2H, ArH), 7.92–7.96 (m, 2H, ArH), 8.11 (s, 1H, ArH), 8.16 (s, 1H, ArH); 13C NMR (DMSO-d6, 100 MHz) δ 127.12, 127.52, 128.32, 128.48, 128.68, 128.87, 132.17, 132.32, 133.31, 137.68, 168.21, 171.85; FT-IR (KBr): 3466, 3429, 3304, 3190, 3054, 2653, 1673, 1636, 1606, 1390, 1339, 1177, 1140, 1099, 964, 809, 758, 481 cm−1; EIMS m/z: 213 (14), 212 (M+, 100), 155 (10), 154 (45), 127 (14), 126 (39); HRMS m/z: [M]+calcd for C12H8N2O2: 212.0586; found: 212.0578.
7-Amino-1,3-diphenylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2f) [28]: White solid; 83% yield; mp 217–219 °C; 1H NMR (DMSO-d6, 400 MHz) δ 4.55 (br, 2H, NH2), 7.42 (t, J = 7.46 Hz, 1H, ArH), 7.49–7.55 (m, 3H, ArH), 7.60–7.65 (m, 4H, ArH), 8.25 (d, J = 8.08 Hz, 2H, ArH), 8.82 (s, 1H, ArH).

3.3. Standard Procedure for Synthesis of Phthalazine 1,4-Diones 3a–f

The reliable procedure involved the treatment of isobenzofuran-1,3-diones (1a–c), isoindoline-1,3-dione (1d), furo[3,4-b] pyrazine-5,7-dione (1e), or 1H-pyrrolo[3,4-c] pyridine-1,3-dione (1f, 1.0 equiv.) with monohydrate hydrazine (~40 equiv.) in EtOH solution (2.0 mL) at room temperature or in neat at reflux for 4 h. When the reaction was completed, the reaction mixture was added water (10 mL) for precipitation. The precipitation was filtered, washed with cold water (10 mL) and n-hexane/EA (1/2, 15 mL) to give the corresponding crude phthalazine 1,4-diones 3a–f. The crude desired products 3a–f were recrystallized in acetone/THF (1/4) solution to obtain the pure phthalazine 1,4-diones 3a–f in 83–91% yields. The low solubility of the compounds 3a–f made the 13C-NMR characterization of quaternary and carbonyl carbons of these substrates unclear [28].
2,3-Dihydro-phthalazine-1,4-dione (3a) [43]: White solid; 89% yield; mp 227–229 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.82 (dd, J = 5.93, 3.30 Hz, 2H, ArH), 8.06 (dd, J = 5.89, 3.28 Hz, 2H, ArH); 13C NMR (DMSO-d6, 100 MHz) δ 125.78 (2 × C), 128.68 (2 × C), 132.35 (2 × C), 156.41 (2 × C); FT-IR (KBr): 3461, 3207, 2715, 1773, 1749, 1609, 1468, 1386, 1309, 1051, 715 cm−1.
6,7-Fluoroo-2,3-dihydrophthalazine-1,4-dione (3b): White solid; 85% yield; mp 220–222 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.99 (t, J = 9.11 Hz, 2H, ArH); 13C NMR (DMSO-d6, 100 MHz) δ 114.38 (2 × C), 126.58 (2 × C), 151.48 (d, J = 16.11 Hz), 154.02 (d, J = 16.10 Hz), 154.61 (2 × C); FT-IR (KBr): 3490, 3180, 3070, 2610, 1660, 1590, 1511, 1460, 1354, 1303, 1189, 1067, 899, 804, 565 cm−1; EIMS m/z: 199 (13), 198 (M+, 100), 141 (23), 140 (75), 113 (17), 112 (30), 63 (13); HRMS m/z: [M]+calcd for C8H4F2N2O2: 198.0241; found: 198.0234.
6,7-Dichloro-2,3-dihydrophthalazine-1,4-dione (3c): White solid; 87% yield; mp 237–239 °C; 1H NMR (DMSO-d6, 400 MHz) δ 8.15 (s, 2H, ArH); 13C NMR (DMSO-d6, 100 MHz) δ 128.16 (2 × C), 129.64 (2 × C), 134.98 (2 × C), 156.12 (2 × C); FT-IR (KBr): 3314, 3193, 2984, 2926, 2879, 1666, 1565, 1467, 1450, 1373, 1075, 822 cm−1; EIMS m/z: 232 (M+ + 2, 64), 231 (M+ + 1, 17) 230 (M+, 100), 174 (46), 173 (12), 172 (72), 146 (13), 144 (19), 109 (19), 74 (17); HRMS m/z: [M]+calcd for C8H4Cl2N2O2: 229.9650; found:229.9643.
7-Dihydropyrazino[2,3-d] pyridazine-5,8-dione (3d) [44]: Brown solid; 83% yield; mp 325–327 °C; 1H NMR (D2O, 500 MHz) δ 8.82 (s, 2H, ArH); 13C NMR (D2O, 125 MHz) δ 145.14 (2 × C), 146.29 (2 × C), 169.64 (2 × C). FT-IR (KBr): 3343, 3204, 1661, 1632, 1543, 1314, 1293, 1100 cm−1; EIMS m/z: 164 (M+, 1), 150 (26) 140 (16), 106 (77), 80 (100), 78 (46), 52 (2).
2,3-Dihydrobenzo[g]phthalazine-1,4-dione (3e): White solid; 91% yield; mp 301–303 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.71(dd, J = 6.29, 3.27 Hz, 2H, ArH), 8.25 (dd, J = 6.28, 3.28 Hz, 2H, ArH), 8.72 (s, 2H, ArH); 13C NMR (DMSO-d6, 100 MHz) δ 125.13 (2 × C), 126.69 (2 × C), 128.84 (2 × C), 129.66 (2 × C), 134.54 (2 × C), 156.22 (2 × C); FT-IR (KBr): 3416, 1663, 1626, 1501, 1467, 1440, 1366, 1072, 815 cm−1; EIMS m/z: 213 (14), 212 (M+, 100), 155 (12), 154 (43), 237 (17), 126 (44); HRMS m/z: [M]+calcd for C12H8N2O2: 212.0586; found: 212.0588.
1,3-Diphenyl-7,8-dihydro-3H-pyrazolo [4’,3’:5,6] pyrido[3,4-d] pyridazine-6,9-dione(3f) [28]: white solid; 84% yield; mp 292–295 °C; 1H NMR (DMSO-d6, 600 MHz) δ 7.43–7.47 (m, 4H, ArH), 7.60–7.64 (m, 4H, ArH), 8.20 (d, J = 7.88 Hz, 2H, ArH), 9.43 (s, 1H, ArH).

3.4. Standard Procedure for Preparation of Amidination Products 4 and 6–10 from N-Aminophthalimides 2a–f with Vilsmeier Reagent (POCl3/DMF)

The reliable procedure that involved N-aminophthalimides 2a–f (1.0 equiv..) was individually treated with ~3.0 equivalent amount of POCl3 in N, N-dimethylformamide solution (DMF, 2.0 mL) at 50 °C or 65 °C for 0.5–4 h. When the reaction was completed, the reaction mixture was added to saturate sodium bicarbonate (15 mL) and extracted with dichloromethane (15 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residues were purified by column chromatography on silica gel to give the corresponding amidination products 4 in 89% yield and 6–10 in 74–88% yields [37,38,39].
N’-(6,8-Dioxo-1,3-diphenyl-6,8-dihydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridin-7(3H)-yl)-N,N-dimethylformimidamide (4): Brown solid; 89% yield; mp 225–227 °C; 1H NMR (CDCl3, 400 MHz) δ 2.97 (s, 3H, NMe), 3.02 (s, 3H, NMe), 7.37 (t, J = 7.36 Hz, 1H, ArH), 7.48–7.50 (m, 3H, ArH), 7.54 (t, J = 7.74 Hz, 2H, ArH), 7.70 (s, 1H, ArH), 7.87 (d, J = 4.40 Hz, 2H, ArH), 8.24 (d, J = 8.00 Hz, 2H, ArH), 9.03 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz) δ 33.83, 41.06, 108.85, 119.70, 122.21 (2 × C), 127.20, 127.90 (2 × C), 129.14 (2 × C), 129.37, 129.82 (2 × C), 131.52, 133.65, 138.40, 143.04, 146.08, 153.77, 161.77, 163.79, 165.45; FT-IR (KBr): 3064, 2923, 2852, 1714, 1626, 1500, 1413, 846 cm−1; EIMS m/z: 411 (25), 410 (M+, 100), 341 (29), 340 (87), 339 (52), 268 (14), 77 (31); HRMS calcd. For C23H18N6O2: 410.1491; found: 410.1482.
N’-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N,N-dimethyliminoformamide hydrochloride (6): Yellow solid; 88% yield; mp 177–179 °C; 1H NMR (CDCl3, 400 MHz) δ 3.02 (s, 6H, N(CH3)2), 7.66 (dd, J = 5.37, 3.03, 2H, ArH), 7.75 (s, 1H), 7.79 (dd, J = 5.42, 3.09, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 34.84, 41.10, 123.01 (2 × C), 123.58 (2 × C), 130.77 (2 × C), 133.77 (2 × C), 161.52, 166.38 (2 × C); FT-IR (KBr): 3446, 2933, 1699, 1620, 1321, 1138, 706 cm−1; EIMS m/z: 218 (12), 217 (M+, 100), 148 (19), 130 (27), 105 (17), 104 (22), 90 (11), 76 (29), 71 (41), 70 (21); HRMS m/z: [M]+calcd for C11H11N3O2: 217.0851; found: 217.0842.
N’-(1,3-Dioxo-5,6-difluoro-2H-isoindolin-2-yl)-N,N-dimethylformimidamide (7): Light yellow solid; 74% yield; mp 183–185 °C; 1H NMR (CDCl3, 400 MHz) δ 2.88 (s, 3H, NMe), 2.96 (s, 3H, NMe), 7.69 (t, J = 8.96 Hz, 2H, ArH), 8.04 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 31.83, 36.98, 119.75 (dd, J = 13.4, 7.63 Hz, 2 × C), 129.46 (t, J = 4.77 Hz, 2 × C), 150.11 (d, J = 14.45 Hz), 152.68 (d, J =14.31 Hz), 163.68, 168.39 (2 × C); FT-IR (KBr): 3048, 2919, 1695, 1620, 1450, 1355, 1148, 818 cm−1; EIMS m/z: 254 (13), 253 (M+, 100), 166 (20), 141 (25), 140 (40), 139 (16), 126 (22), 125 (12), 113 (13), 112 (52), 111 (20), 109 (16), 97 (23), 95 (17), 85 (16), 83 (21), 81 (17); HRMS m/z: [M]+calcd for C11H9F2N3O2: 253.0663; found: 253.0657.
N’-(1,3-Dioxo-5,6-dichloro-2H-isoindolin-2-yl)-N,N-dimethylformimidamide (8): Light orange solid; 85% yield; mp 192–194 °C; 1H NMR (CDCl3, 400 MHz) δ 3.04 (s, 6H, N(CH3)2), 7.74 (s, 1H), 7.87 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 34.80, 41.07, 125.09 (2 × C), 129.90 (2 × C), 138.54 (2 × C), 161.35, 164.42 (2 × C). FT-IR (KBr): 3092, 3024, 2926. 1773, 1705, 1624, 1345, 1145, 774 cm−1; EIMS m/z: 287 (M+ + 2, 61), 286 (M+ +1, 12), 285 (M+, 100), 198 (13), 175 (12), 174 (14), 173 (22), 172 (20), 146 (16), 144 (24), 109 (11), 71 (98), 70 (36), 69 (10); HRMS m/z: [M]+calcd for C11H9Cl2N3O2: 285.0072; found: 285.0064.
N’-(1,3-Dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)-N,N-dimethylformimidamide (9): Light yellow solid; 88% yield, mp 219–221 °C; 1H NMR (CDCl3, 400 MHz) δ 3.03 (s, 3H, NMe), 3.05 (s, 3H, NMe), 7.81 (s, 1H), 8.84 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 34.83, 41.18, 146.17 (2 × C), 148.52 (2 × C), 161.28, 162.31 (2 × C); FT-IR (KBr): 1654, 1289, 1545, 1293, 1104, 825 cm−1; EIMS m/z: 220 (12), 219 (M+, 56), 193 (10), 179 (13), 178 (13), 169 (12), 168 (12), 167 (14), 165 (11), 155 (11), 152 (11), 151 (26), 150 (14), 149 (23), 147 (11), 141 (12), 139 (15), 137 (13), 135 (11), 127 (12), 125 (21), 123 (19), 121 (11), 119 (11), 115 (14), 113 (14), 112 (14), 111 (36), 110 (11), 109 (27), 107 (15), 106 (16), 105 (16), 99 (17), 98 (13), 97 (52), 96 (16), 95 (36), 93 (12), 91 (27); HRMS m/z: [M]+calcd for C9H9N5O2: 219.0756; found: 219.0748.
N’-(1,3-Dioxo-5,6-dihydro-2H-benzo[f]isoindol-2-yl)-N,N-dimethylformimidamide (10): Light yellow solid; 77% yield; mp 199–201 °C; 1H NMR (CDCl3, 400 MHz) δ 3.05 (s, 3H, NMe), 3.07 (s, 3H, NMe), 7.64–7.69 (m, 2H, ArH), 7.84 (s, 1H), 7.99–8.02 (m, 2H, ArH), 8.28 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 34.89, 41.10, 124.33 (2 × C), 126.68 (2 × C), 128.99 (2 × C), 130.20 (2 × C), 135.45 (2 × C), 161.23, 166.00 (2 × C) cm−1; FT-IR (KBr): 2918, 2807, 1757, 1693, 1621, 1521, 1425, 1411, 1321, 1154, 1118, 1004, 900, 754, 479 cm−1; EIMS m/z: 268 (19), 267 (M+, 100), 225 (13), 210 (10), 198 (26), 197 (49), 180 (28), 155 (64), 154 (24), 153 (20), 152 (13), 140 (21), 127 (26), 126 (74), 71 (17), 57 (11); HRMS m/z: [M]+calcd for C15H13N3O2: 267.1008; found: 267.1015.

3.5. Standard Procedure for Preparation of Chlorination Products 5, and 11–15 from Phthalazine 1,4-Diones 3a–f with Vilsmeier Reagent (POCl3/DMF)

The reliable procedure that involved phthalazine 1,4-diones 3a–f (1.0 equiv.) was individually treated with ~3.0 equivalent amount of POCl3 in N, N-dimethylformamide solution (DMF, 2.0 mL) at 65 °C or 80 °C for 2–4 h. When the reaction was completed, the reaction mixture was added to saturate sodium bicarbonate (15 mL) and extracted with dichloromethane (15 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residues were purified by column chromatography on silica gel to give the corresponding chlorinated products 5 in 80% yield and 11–15 in 31–90% yields [29].
6,9-Dichloro-1,3-diphenyl-3H-pyrazolo[4’,3’:5,6]pyrido[3,4-d]pyridazine (5): Light yellow solid; 80% yield; mp 196–197 °C; 1H NMR (CDCl3, 500 MHz) δ 7.46 (t, J = 7.43 Hz, 1H, ArH), 7.49–7.51 (m, 3H, ArH), 7.57–7.60 (m, 4H, ArH), 8.17 (dd, J = 8.60, 1.09 Hz, 2H, ArH), 9.68 (s, 1H, ArH); 13C NMR (CDCl3, 125 MHz) δ 103.92, 118.46, 123.39 (2 × C), 127.91, 127.95 (2 × C), 128.19, 129.13, 129.33 (2 × C), 130.01 (2 × C), 135.22, 137.87, 147.79, 149.88, 151.00, 152.05, 153.49; FT-IR (KBr): 3064, 2923, 2846, 1571, 1501, 1413, 1243, 1119, 863 cm−1; EIMS m/z: 395 (12), 394 (17), 393 (M+ + 2, 65), 392 (36), 391 (M+, 99), 390 (20), 356 (20), 321 (35), 320 (60), 288 (14), 263 (12), 244 (33), 218 (17), 91 (19), 77 (100); HRMS calcd. For C20H11Cl2N5: 391.0392; found: 391.0397.
1,4-Dichlorophthalazine (11): Yellow solid; 90% yield; mp 162–164 °C; 1H NMR (CDCl3, 400 MHz) δ 7.74–7.76 (m, 2H, ArH), 7.85–7.7.87 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 125.86 (2 × C), 127.21 (2 × C), 134.49 (2 × C), 155.03 (2 × C); IR (KBr): 3157, 3000, 2896, 2875, 1671, 1346, 1289, 1157, 993, 775, 664 cm−1; EIMS m/z: 202 (M+ + 4, 10), 200 (M+ + 2, 63), 198 (M+, 100), 182 (25), 180 (77), 172 (17), 170 (26), 151 (17), 135 (20), 128 (14), 125 (11), 123 (29), 102 (17), 101 (11), 99 (20), 90 (11). HRMS calcd. For C8H4Cl2N2: 197.9752; found: 197.9746.
1,4-Dichloro-2,3-difluorophthalazine (12): White solid; 82% yield; mp 75–76 °C; 1H NMR (CDCl3, 400 MHz) δ 8.09 (t, J = 8.34 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 113.97 (dd, J = 14.25, 7.66 Hz, 2 × C), 125.19 (t, J = 5.23 Hz, 2 × C), 153.50 (d, J = 16.46 Hz), 153.68 153.50 (2 × C), 156.15 (d, J = 16.39 Hz); IR (KBr): 3143, 3068, 2836, 2782, 2718, 2611, 1625, 1571, 1539, 1511, 1389, 1218, 1161, 1104, 893, 814 cm−1; EIMS m/z: 238 (M+ + 4, 11), 236 (M+ + 2, 78), 234 (M+, 100), 234 (30), 218 (12), 216 (36), 208 (24), 206 (38), 171 (27), 164 (30), 159 (18), 138 (11), 136 (16), 124 (10), 88 (15), 75 (11); HRMS calcd. For C8H2Cl2F2N2: 233.9563; found: 233.9568.
1,4,6,7-Tetrachlorophthalazine (13): Light orange solid; 84% yield; mp 135–136 °C; 1H NMR (CDCl3, 400 MHz) δ 8.40 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 126.07 (2 × C), 127.39 (2 × C), 140.2 (2 × C), 153.45 (2 × C); IR (KBr): 3094, 1596, 1535, 1453, 1501, 1380, 1268, 1242, 1130, 1035, 702, 663 cm−1; EIMS m/z: 270 (M+ + 2, 26), 270 (M+ + 2, 16), 268 (M+, 100), 266 (77), 240 (19), 238 (14), 205 (14), 203 (14), 196 (13), 84 (10); HRMS calcd. For C8H2Cl4N2: 265.8972; found: 265.8979.
6,7-Dichloropyrazino[2,3-d] pyridazine (14) [28]: Black solid; 31% yield; mp 204–206 °C; 1H NMR (CDCl3, 400 MHz) δ 9.14 (s, 1H, ArH), 9.17 (s, 1H, ArH) [28].
1,4-Dichlorobenzo[g]phthalazine (15): Gray solid; 85% yield; mp 212–214 °C; 1H NMR (CDCl3, 400 MHz) δ 7.78–7.81 (m, 2H, ArH), 8.18–8.21 (m, 2H, ArH), 8.82 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 123.23 (2 × C), 126.83 (2 × C), 129.22 (2 × C), 129.79 (2 × C), 135.46 (2 × C), 155.39 (2 × C); IR (KBr): 2961, 2932, 2857, 1739,1725, 1461, 1282, 1264, 1121, 1075, 739 cm−1; EIMS m/z: 250 (M+ + 2, 59), 249 (M+ + 1, 11), 248 (M+, 100), 178 (31), 152 (19), 151 (14), 150 (18); HRMS calcd. For C23H18N6O2: 247.9908; found: 247.9906.

4. Conclusions

N-aminophthalimides 2 and phthalazine 1,4-diones 3 were successfully and selectively synthesized from isobenzo-furan-1,3-diones (1a–c), isoindoline-1,3-dione (1d), furo[3,4-b] pyrazine-5,7-dione (1e), and 1H-pyrrolo[3,4-c] pyridine-1,3-dione (1f) with monohydrate hydrazine under the different reaction condition. The structural divergence between N-aminophthalimides 2f and phthalazine 1,4-diones 3f was effectively identified via Vilsmeier reaction methodology. Furthermore, the thermodynamically transformation from N-aminophthalimides 2a–f to phthalazine 1,4-diones 3a–f was successfully found, which provides the good conversion ratio from 6/94 to 1/99 of 2a–f /3a–f under acetic acid mediated solution.

Supplementary Materials

The following are available online, copies of 1H and 13C-NMR spectra of compounds 2a–2e, 3a–3e, and 4–15, Table S1: Crystal data and structure refinement for N’-(6,8-dioxo6,8-dihydropyrazolopyrrolo-pyridine-yl)-N,N-dimethylformimidamide 4 (CCDC No. 1954819).

Author Contributions

F.F.W. conceived and designed the experiments; C.-Y.C., C.-C.T., S.-M.L. and S.-E.T. performed the experiments; C.-Y.C., C.-C.T. and S.-M.L. analyzed the data; F.F.W., H.-Y.L., contributed reagents/materials/analysis tools; F.F.W., C.-Y.C., C.-C.T. and S.-E.T. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the China Medical University (CMU109-ASIA-08 and CMU109-MF-86) and the Ministry of Science and Technology of Taiwan (MOST 109-2113-M-039-003).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the article and the Supplementary Materials.

Acknowledgments

We are grateful to the China Medical University (CMU109-ASIA-08 and CMU109-MF-86) and the Ministry of Science and Technology of Taiwan (MOST 109-2113-M-039-003) for financial support.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

References

  1. Franklin, E.C. Heterocyclic Nitrogen Compounds. I. Pentacyclic Compounds. Chem. Rev. 1935, 16, 305–361. [Google Scholar] [CrossRef]
  2. Bergstrom, F.W. Heterocyclic Nitrogen Compounds. Part IIA. Hexacyclic Compounds: Pyridine, Quinoline, and Isoquinoline. Chem. Rev. 1944, 35, 77–277. [Google Scholar] [CrossRef]
  3. Lichtenthaler, F.W. Unsaturated O- and N-Heterocycles from Carbohydrate Feedstocks. Acc. Chem. Res. 2002, 35, 728–737. [Google Scholar] [CrossRef]
  4. Litvinov, V.P. Multicomponent Cascade Hetero-cyclisation as a Promising Route to Targeted Synthesis of Poly-functional Pyridines. Russ. Chem. Rev. 2003, 72, 69–85. [Google Scholar] [CrossRef]
  5. Guo, Q.-X.; Xu, Y. Syntheses of Heterocyclic Compounds under Micro-wave Irradiation. Heterocycles 2004, 63, 903–974. [Google Scholar] [CrossRef]
  6. Turk, C.; Svete, J.; Stanovnik, B.; Golič, L.; Golič-Grdadolnik, S.; Golobič, A.; Selič, L. Regioselective 1,3-Dipolar Cycloadditions of (1Z)-1-(Arylmethylidene)-5,5-Dimethyl-3-Oxopyrazolidin-1-Ium-2-Ide Azomethine Imines to Acetylenic Dipolarophiles. Helv. Chim. Acta 2001, 84, 146–156. [Google Scholar] [CrossRef]
  7. Clark, M.P.; Laughlin, S.K.; Laufer-sweiler, M.J.; Bookland, R.G.; Brugel, T.A.; Golebiowski, A.; Sabat, M.P.; Townes, J.A.; VanRens, J.C.; Djung, J.F.; et al. Develop-ment of Orally Bioavailable Bicyclic Pyrazolones as Inhibitors of Tumor Necrosis Factor-α Production. J. Med. Chem. 2004, 47, 2724–2727. [Google Scholar] [CrossRef]
  8. Küçükgüzel, Ş.G.; Rollas, S.; Küçükgüzel, I.; Kiraz, M. Synthesis and Antimycobacterial Activity of Some Coupling Products from 4-Aminobenzoic Acid Hydrazones. Eur. J. Med. Chem. 1999, 34, 1093–1100. [Google Scholar] [CrossRef]
  9. Türkeş, C.; Arslan, M.; Demir, Y.; Çoçaj, L.; Rifati Nixha, A.; Bey-demir, Ş. Synthesis, Biological Evaluation and in Silico Studies of Novel N-Substituted Phthalazine Sulfonamide Compounds as Po-tent Carbonic Anhydrase and Acetylcholinesterase Inhibitors. Bioorg. Chem. 2019, 89, 103004–103020. [Google Scholar] [CrossRef]
  10. Padwa, A.; Waterson, A.G. Synthesis of Nitrogen Heterocycles Using the Intramolecular Pummerer Reaction. Curr. Org. Chem. 2000, 4, 175–203. [Google Scholar] [CrossRef]
  11. Orru, R.V.A.; De Greef, M. Recent Advances in Solution-Phase Multicomponent Methodology for the Synthesis of Heterocyclic Compounds. Synthesis 2003, 1471–1499. [Google Scholar] [CrossRef]
  12. Kirsch, G.; Hesse, S.; Comel, A. Synthesis of Five- and Six-Membered Heterocycles through Palladium-Catalyzed Reactions. Curr. Org. Synth. 2004, 1, 47–63. [Google Scholar] [CrossRef]
  13. Dogruer, D.S.; Kupeli, E.; Yesilada, E.; Sahin, M.F. Synthesis of New 2-[1(2H)-Phthalazinon-2-yl]Acetamide and 3-[1(2H)-Phthalazinon-2-yl]Propanamide Derivatives as Antinociceptive and Anti-Inflammatory Agents. Arch. Pharm. 2004, 337, 303–310. [Google Scholar] [CrossRef] [PubMed]
  14. Demirayak, S.; Karaburun, A.C.; Beis, R. Some Pyrrole Substituted Aryl Pyridazinone and Phthalazinone Derivatives and Their Anti-hypertensive Activities. Eur. J. Med. Chem. 2004, 39, 1089–1095. [Google Scholar] [CrossRef] [PubMed]
  15. EL-Sakka, S.; Soliman, A.; Imam, A. Synthesis, Antimicrobial Ac-tivity and Electron Impact of Mass Spectra of Phthalazine-1,4-dione Derivatives. Afinidad 2009, 66, 540. [Google Scholar]
  16. Curtin, N. PARP Inhibitors for Anticancer Therapy. Biochem. Soc. Trans. 2014, 42, 82–88. [Google Scholar] [CrossRef]
  17. Berber, N.; Arslan, M.; Bilen, Ç.; Sackes, Z.; Gençer, N.; Arslan, O. Synthesis and Evaluation of New Phthalazine Substituted β-Lactam Derivatives as Carbonic Anhydrase Inhibitors. Bioorg. Khim. 2015, 41, 468–474. [Google Scholar]
  18. Li, J.; Chan, P.W.H.; Che, C.-M. Aryl Iodide Mediated Aziridina-tion of Alkenes. Org. Lett. 2005, 7, 5801–5804. [Google Scholar] [CrossRef]
  19. Gabriel, S. Ueber Eine Darstellungsweise Primärer Amine Aus Den Entsprechenden Halogenverbindungen. Berichte der Dtsch. Chem. Gesellschaft 1887, 20, 2224–2236. [Google Scholar] [CrossRef] [Green Version]
  20. Gibson, M.S.; Brad-shaw, R.W. The Gabriel Synthesis of Primary Amines. Angew. Chem. Int. Ed. Engl. 1968, 7, 919–930. [Google Scholar] [CrossRef]
  21. Kunz, H. Book Review: Protective Groups in Organic Synthesis. 2nd Edition. Edited by T. W. Greene and P. G. M. Wuts. Angew. Chem. Int. Ed. Engl. 1992, 31, 658–659. [Google Scholar] [CrossRef]
  22. Theodoridis, G. Nitrogen Protecting Groups: Recent Develop-ments and New Applications. Tetrahedron 2000, 56, 2339–2358. [Google Scholar] [CrossRef]
  23. Jarowicki, K.; Kocieński, P. Protecting Groups. J. Chem. Soc. Perkin Trans. 1 1999, 1589–1616. [Google Scholar] [CrossRef]
  24. Smith, M.B.; March, J. (Eds.) March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed.; John Wiley & Sons: Hoboken, NJ, USA, 2007. [Google Scholar]
  25. Antonov, L. (Ed.) Tautomerism: Methods and Theories, 1st ed.; Wiley-VCH: Weinheim, Germany, 2013. [Google Scholar]
  26. Yu, G.; Macor, J.E.; Chung, H.J.; Humora, M.; Katipally, K.; Wang, Y.; Kim, S. Fused Pyridopyridazine Inhibitors of cGMP Phosphodiesterase. U.S. Patent 6,316,438, 13 November 2001. [Google Scholar]
  27. Yu, G.; Mason, H.; Wu, X.; Wang, J.; Chong, S.; Beyer, B.; Henwood, A.; Pongrac, R.; Seliger, L.; He, B.; et al. Substituted Pyrazolopyridopyridazines as Orally Bioavailable Potent and Selective PDE5 Inhibitors:  Potential Agents for Treatment of Erectile Dysfunction. J. Med. Chem. 2003, 46, 457–460. [Google Scholar] [CrossRef] [PubMed]
  28. Tseng, C.-C.; Chung, C.-Y.; Tsai, S.-E.; Takayama, H.; Uramaru, N.; Lin, C.-Y.; Wong, F.F. Selective Synthesis and Photoluminescence Study of Pyrazolopyridopyridazine Diones and N-Aminopyrazolopyrrolopyridine Diones. Molecules 2020, 25, 2409. [Google Scholar] [CrossRef] [PubMed]
  29. Tsai, S.-E.; Chiang, K.-H.; Tseng, C.-C.; Chen, N.-W.; Chern, C.-Y.; Wong, F.F. Facile One-Pot Synthesis of Methyl 1-Aryl-1H-1,2,4-Triazole-3-Carboxylates from Nitrilimines with Vilsmeier Reagent. Eur. J. Org. Chem. 2019, 2019, 1754–1762. [Google Scholar] [CrossRef]
  30. Lu, S.-H.; Liu, P.-L.; Wong, F.F. Vilsmeier Reagent-Mediated Synthesis of 6-[(Formyloxy)Methyl]-Pyrazolopyrimidines via a One-Pot Multiple Tandem Reaction. RSC Adv. 2015, 5, 47098–47107. [Google Scholar] [CrossRef]
  31. Huang, J.-J.; Lu, S.-H.; Chung, Y.H.; Wong, F.F. Vilsmeier–Haack Reagent-Promoted Formyloxylation of α-Chloro-N-Arylacetamides by Formamide. RSC Adv. 2015, 5, 35934–35939. [Google Scholar] [CrossRef]
  32. Chang, C.-H.; Tsai, H.J.; Huang, Y.-Y.; Lin, H.-Y.; Wang, L.-Y.; Wu, T.-S.; Wong, F.F. Selective Synthesis of Pyrazolo[3,4-d]Pyrimidine, N-(1H-Pyrazol-5-yl)Formamide, or N-(1H-Pyrazol-5-yl)Formamidine Derivatives from N-1-Substituted-5-Aminopyrazoles with New Vilsmeier-Type Reagents. Tetrahedron 2013, 69, 1378–1386. [Google Scholar] [CrossRef]
  33. Huang, Y.-Y.; Kaneko, K.; Takayama, H.; Kimura, M.; Wong, F.F. New Investigation of Vilsmeier-Type Reaction Using Pyrazolones with Various Amides. Tetrahedron Lett. 2011, 52, 3786–3792. [Google Scholar] [CrossRef]
  34. Mundy, B.P.; Ellerd, M.G.; Favaloro, F.G. (Eds.) Name Reactions and Reagents in Organic Synthesis, 2nd ed.; John Wiley & Sons: Hoboken, NJ, USA, 2005. [Google Scholar]
  35. Liu, J.; Yang, X.; Zuo, Z.; Nan, J.; Wang, Y.; Luan, X. Catalytic Enantioselective Tautomerization of Metastable Enamines. Org. Lett. 2018, 20, 244–247. [Google Scholar] [CrossRef]
  36. Tseng, C.-C.; Yen, W.-P.; Tsai, S.-E.; Hu, Y.-T.; Takayama, H.; Kuo, Y.-H.; Fuh Wong, F. ZnCl2-Catalyzed Aza-Diels-Alder Reaction for the Synthesis of 1H-Pyrazolo[3,4-b]pyridine-4,5-dicarboxylate Derivatives. Eur. J. Org. Chem. 2018, 13, 1567–1571. [Google Scholar] [CrossRef]
  37. Vincent, S.; Stkphane Mons, S.; Lebeau, L.; Mioskowski, C. N,N-Dibenzyl Formamidine as a New Protective Group for Primary Amines. Tetrahedron Lett. 1997, 38, 7527–7530. [Google Scholar] [CrossRef]
  38. Wong, F.F.; Huang, Y.-Y. Novel Vilsmeier-type Methylenation for Synthesis of Dipyrazolylmethane Derivatives using Formamide or N-methylformamide. Tetrahedron 2011, 67, 3863–3867. [Google Scholar] [CrossRef]
  39. Huang, Y.-Y.; Wang, L.-Y.; Chang, C.-H.; Kuo, Y.-H.; Kaneko, M.; Takayama, K.; Kimura, H.; Juang, S.-H.; Wong, F.F. One-Pot Synthesis and Antiproliferative Evaluation of Pyrazolo[3,4-d]pyrimidine Deriv-atives. Tetrahedron 2012, 68, 9658–9664. [Google Scholar] [CrossRef]
  40. Flitsch, W.; Krämer, U.; Zimmerman, H. Cyclische Verbindungen mit Heterobrückenatomen, V. Zur Chemie der 1-Amino-pyrrole. Chem. Ber. 1969, 102, 3268–3276. [Google Scholar] [CrossRef]
  41. Dey, S.K.; Lightner, D.A. 1,1’-Bipyrroles: Synthesis and Stereochemistry. J. Org. Chem. 2007, 72, 9395–9397. [Google Scholar] [CrossRef] [Green Version]
  42. Kumar, S.; Kumar, A.; Kumar, N.; Roy, P.; Sondhi, S.M. Grinding and Microwave-assisted Synthesis of Heterocyclic Molecules in High Yields and Their Biological Evaluation. J. Heterocyclic. Chem. 2015, 53, 1761–1770. [Google Scholar] [CrossRef]
  43. Prime, M.E.; Courtney, S.M.; Brookfield, F.A.; Marston, R.W.; Walker, V.; Justin Warne, J.; Andrew, E.; Boyd, A.E.; Kairies, N.A.; von der Saal, W.; et al. Phthalazinone Pyrazoles as Potent, Selective, and Orally Bioavailable Inhibitors of Aurora-A Kinase. J. Med. Chem. 2011, 54, 312–319. [Google Scholar] [CrossRef] [PubMed]
  44. Cee, V.J.; Deak, H.L.; Du, B.; Geuns-Meyer, S.D.; Hodous, B.L.; Nguyen, H.N.; Olivieri, P.R.; Patel, V.F.; Romero, K.; Schenkel, L. Aurora Kinase Modulators and Method of Use. Patent WO 2007/0872760A1, 2 August 2007. [Google Scholar]
Molecules 26 02907 g001 550
Figure 1. 1H NMR spectra of N-aminophthalimides 2a, 2c and 2e and phthalazines 1,4-dione 3a and 3e.
Figure 1. 1H NMR spectra of N-aminophthalimides 2a, 2c and 2e and phthalazines 1,4-dione 3a and 3e.
Molecules 26 02907 g001
Molecules 26 02907 g002 550
Figure 2. The timed programming result of N-aminophthalimides 2c of 1H NMR spectra (a) 0 min, (b) 10 min, (c) 20 min, (d) 30 min, (e) 60 min.
Figure 2. The timed programming result of N-aminophthalimides 2c of 1H NMR spectra (a) 0 min, (b) 10 min, (c) 20 min, (d) 30 min, (e) 60 min.
Molecules 26 02907 g002
Molecules 26 02907 sch001 550
Scheme 1. The results of 7-aminopyrazolopyrrolopyridine-6,8-dione 2f and pyrazolopyridopyridazine dione 3f treated with Vilsmeier reagent.
Scheme 1. The results of 7-aminopyrazolopyrrolopyridine-6,8-dione 2f and pyrazolopyridopyridazine dione 3f treated with Vilsmeier reagent.
Molecules 26 02907 sch001
Molecules 26 02907 g003 550
Figure 3. 1H NMR spectra of 7-amidination product 4 and dichloropyridazine 5.
Figure 3. 1H NMR spectra of 7-amidination product 4 and dichloropyridazine 5.
Molecules 26 02907 g003
Molecules 26 02907 g004 550
Figure 4. (a) 1H NMR spectrum of the beginning of the reaction (1H NMR of compound 2f). (b–d) Reaction at reflux for 1.5, 2.3, and 3.5 h (1H NMR of compounds 2f and 3f; the ratios of 2f/3f = ~72/28, 48/52, and 36/64). (e) Reaction at reflux for 5 h (1H NMR of compounds 3f; the ratios of 2f/3f = ~6/94).
Figure 4. (a) 1H NMR spectrum of the beginning of the reaction (1H NMR of compound 2f). (b–d) Reaction at reflux for 1.5, 2.3, and 3.5 h (1H NMR of compounds 2f and 3f; the ratios of 2f/3f = ~72/28, 48/52, and 36/64). (e) Reaction at reflux for 5 h (1H NMR of compounds 3f; the ratios of 2f/3f = ~6/94).
Molecules 26 02907 g004
Table
Table 1. The thermodynamic-kinetic control synthesis of N-aminophthalimides 2a–f and phthalazine 1,4-diones 3a–f.
Table 1. The thermodynamic-kinetic control synthesis of N-aminophthalimides 2a–f and phthalazine 1,4-diones 3a–f.
Molecules 26 02907 i001
Molecules 26 02907 i002 Molecules 26 02907 i003 Molecules 26 02907 i004
Molecules 26 02907 i005 Molecules 26 02907 i006 Molecules 26 02907 i007
Molecules 26 02907 i008 Molecules 26 02907 i009 Molecules 26 02907 i010
Molecules 26 02907 i011 Molecules 26 02907 i012 Molecules 26 02907 i013
Molecules 26 02907 i014 Molecules 26 02907 i015 Molecules 26 02907 i016
Molecules 26 02907 i017 Molecules 26 02907 i018 Molecules 26 02907 i019
a The reaction condition at –20 °C within 4h. b The reaction condition at 0 °C within 4h. c Compound 2f and 3f were provided and prepared from our previous work [28].
Table
Table 2. Derivatization results of N-aminophthalimides 2a–e and phthalazine 1,4-diones 3a–e with Vilsmeier reagent.
Table 2. Derivatization results of N-aminophthalimides 2a–e and phthalazine 1,4-diones 3a–e with Vilsmeier reagent.
Molecules 26 02907 i020
Molecules 26 02907 i021
Molecules 26 02907 i022
Molecules 26 02907 i023
Table
Table 3. Derivatization results of N-aminophthalimides 2a–e and phthalazine 1,4-diones 3a–e with Vilsmeier reagent.
Table 3. Derivatization results of N-aminophthalimides 2a–e and phthalazine 1,4-diones 3a–e with Vilsmeier reagent.
Molecules 26 02907 i024
EntryS.M.SolventReaction Time (h)ProductRatio of 2f/3f a
12fCH2Cl2243fnon-conversion
22fToluene243fnon-conversion
32fEtOH243fnon-conversion
42fTHF243f88/12
52fCH3CN243f93/7
62fDioxane243f91/9
72fDMSO243f89/11
82fTsOH
(pKa = –1.9)		43f61/39
92fTsCl43f56/44
102fTFA
(pKa = 0.30)		43f54/46
112fAcOH
(pKa = 4.76)		43f6/94
a The ratio was identified by 1H-NMR.
Table
Table 4. The conversion results between N-aminophthalimide 2a–e and pyrazolopyridopyridazine dione 3a–e.
Table 4. The conversion results between N-aminophthalimide 2a–e and pyrazolopyridopyridazine dione 3a–e.
Molecules 26 02907 i025
EntryS.M.Reaction Time (h)Product2a–e/3a–e a
1 Molecules 26 02907 i0268 Molecules 26 02907 i0271/99
2 Molecules 26 02907 i0289 Molecules 26 02907 i0293/97
3 Molecules 26 02907 i03010 Molecules 26 02907 i0316/94
4 Molecules 26 02907 i03211 Molecules 26 02907 i0335/95
5 Molecules 26 02907 i0343 Molecules 26 02907 i0354/96
a The ratio of 2/3 was determined by crude 1H-NMR.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Chung, C.-Y.; Tseng, C.-C.; Li, S.-M.; Tsai, S.-E.; Lin, H.-Y.; Wong, F.F. Structural Identification between Phthalazine-1,4-Diones and N-Aminophthalimides via Vilsmeier Reaction: Nitrogen Cyclization and Tautomerization Study. Molecules 2021, 26, 2907. https://doi.org/10.3390/molecules26102907

AMA Style

Chung C-Y, Tseng C-C, Li S-M, Tsai S-E, Lin H-Y, Wong FF. Structural Identification between Phthalazine-1,4-Diones and N-Aminophthalimides via Vilsmeier Reaction: Nitrogen Cyclization and Tautomerization Study. Molecules. 2021; 26(10):2907. https://doi.org/10.3390/molecules26102907

Chicago/Turabian Style

Chung, Cheng-Yen, Ching-Chun Tseng, Sin-Min Li, Shuo-En Tsai, Hui-Yi Lin, and Fung Fuh Wong. 2021. "Structural Identification between Phthalazine-1,4-Diones and N-Aminophthalimides via Vilsmeier Reaction: Nitrogen Cyclization and Tautomerization Study" Molecules 26, no. 10: 2907. https://doi.org/10.3390/molecules26102907

Article Metrics

Back to TopTop