Structural identification between phthalazine-1,4-diones and n-aminophthalimides via vilsmeier reaction: Nitrogen cyclization and tautomerization study

Article abstract of DOI:10.3390/molecules26102907

N-aminophthalimides and phthalazine 1,4-diones were synthesized from isobenzofuran1,3-dione, isoindoline-1,3-dione, furo [3,4-b] pyrazine-5,7-dione, or 1H-pyrrolo [3,4-c] pyridine-1,3dione 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.

Full text of DOI:10.3390/molecules26102907

molecules
Article
Structural Identification between Phthalazine-1,4-Diones and
N-Aminophthalimides via Vilsmeier Reaction: Nitrogen
Cyclization and Tautomerization Study
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;
u109308001@cmu.edu.tw (C.-Y.C.); u106308201@cmu.edu.tw (C.-C.T.); u100003044@cmu.edu.tw (S.-E.T.)
The Ph.D. Program for Biotech Pharmaceutical Industry and School of Pharmacy, China Medical University,
No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan
Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Rd.,
Taichung 40402, Taiwan; u102003483@cmu.edu.tw
2
3
*
Correspondence: hylin@mail.cmu.edu.tw (H.-Y.L.); wongfungfuh@yahoo.com.tw or
ffwong@mail.cmu.edu.tw (F.F.W.); Tel.: +886-422-053-366 (ext. 5112) (H.-Y.L.);
+886-422-053-366 (ext. 5603) (F.F.W.); Fax: +886-422-078-083 (H.-Y.L. & F.F.W.)
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 struc-
tural 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.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: 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
Keywords: vilsmeier reagent; phthalazine-1,4-diones; N-aminophthalimide; hydrazine
1. Introduction
Academic Editor: Fangrui Zhong
Nitrogen-containing heterocyclic compounds are widely applied to the biologically
active pharmaceuticals, agrochemicals, and functional materials and become more and
Received: 25 April 2021
Accepted: 10 May 2021
Published: 13 May 2021
more important [
1–
5]. Especially, heterocycle derivatives containing bridgehead amine
and hydrazine [
6
,7
] such as N-aminophthalimides [ ] and phthalazine 1,4-diones [ ] have
8
9
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 [10–12].
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
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iations.
classical Gabriel protocol [19,20] as well as for the protection of amino groups [21–23].
N-aminophthalimides can be considered as phthalazine 1,4-dione tautomeric pairs. The
structural arrangement of hydrazine derivatives is the mainly associated with the intercon-
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
version 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].
Molecules 2021, 26, 2907. https://doi.org/10.3390/molecules26102907
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 2907
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Owing to the structural divergence between N-aminophthalimides
diones
work [29
2
and phthalazine-1,4-
3
, we explored the Vilsmeier amidination derivatization to identify them in this
33]. Furthermore, we successfully developed the prototrophic tautomeric inter-
–
conversion from N-aminophthalimides to phthalazine 1,4-diones under Brønsted–Lowry
acidic condition [29–35].
2. Results and Discussion
Initially, isobenzofuran-1,3-diones (1a
5,7-dione (1e), and 1H-pyrrolo[3,4-c] pyridine-1,3-dione (1f) [34
prepared as the starting materials. Reacting compounds 1a 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 (81–94%) without the accumulation
of hydrohydrazination products 3a (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 were formed (83–91%,
Table 1). Fortunately, compounds 2a and 3a 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 provide
–c), isoindoline-1,3-dione (1d), furo [3,4-b] pyrazine-
–
36] were purchased or
–f
◦
◦
–
f
–
f
–
f
–
f
–f
–
f
themselves for investigation of tautomeric conversion controlling processes as well as
convenient platforms for the structural identity.
Additionally, phthalazine 1,4-diones 3a
though compounds and were tautomeric pairs, they significantly possessed the differ-
ent 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 and 3a compounds were fully character-
–f were used as the reference standards. Al-
2
3
–f
–f
ized 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
resulting in difficult structural identification of each other. For example, the H-NMR
spectra of compounds 2a and 3a were similar as shown in Figure 1. This observation drove
us to develop a novel identification method.
2
and
3
presented similar chemical shift and coupling constants,
1
On the other hand, N-aminophthalimides 2c and 2e reveal the existence of intramolec-
1
ular hydrogen bonding phenomenon between carbonyl and amino group in H-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.

Molecules 2021, 26, 2907
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Table 1. The thermodynamic-kinetic control synthesis of N-aminophthalimides 2a–f and phthalazine 1,4-diones 3a–f.
◦
a
b
c
The reaction condition at –20 C within 4h. The reaction condition at 0 ◦C within 4h. Compound 2f and 3f were provided and prepared
from our previous work [28].

Molecules 2021, 26, 2907
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1
Figure 1. H NMR spectra of N-aminophthalimides 2a, 2c and 2e and phthalazines 1,4-dione 3a and 3e.
Figure 2. The timed programming result of N-aminophthalimides 2c of 1H NMR spectra (
(d) 30 min, (e) 60 min.
a) 0 min, (b) 10 min, (c) 20 min,
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 [37–39]. 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

Molecules 2021, 26, 2907
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employed Vilsmeier reagent (halomethyleniminium salt) [29
–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
. The structure of compound
single-crystal X-ray diffraction study. Based on 1H NMR spectroscopic characterization,
compound possesses singlet signal of pyridine ring proton Ha around 9.03 ppm, and
4
was formed and obtained in 89% yield without producing chlorinated compound
5
4
was fully characterized by spectroscopic methods and
4
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
product
4
5
formation by Vilsmeier reagent at reflux for 4 h, affording the corresponding
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.
Scheme 1. The results of 7-aminopyrazolopyrrolopyridine-6,8-dione 2f and pyrazolopyridopyri-
dazine dione 3f treated with Vilsmeier reagent.
1
Figure 3. H NMR spectra of 7-amidination product 4 and dichloropyridazine 5.
For further investigation into the reactivity of Vilsmeier amidination derivatization,
Vilsmeier reaction was carried out using different substrates including N-aminophthalimides
2a–e –e were demonstrated to perform
at 50 ◦C for 0.5 h. Various substituted reactants 2a

Molecules 2021, 26, 2907
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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 10 were fully characterized by spectroscopic methods, and
6
–
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
The chlorination happened smoothly to afford the desired products 11
(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 con-
verted into –N = 13C–Cl singlet signal at 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 and phthalazine-1,4-diones 3.
–e
were treated with Vilsmeier reagent (POCl3/DMF) at 65 ◦C or 80 ◦C for 2–4 h.
–
15 in high yields
−
–
δ
2
Table 2. Derivatization results of N-aminophthalimides 2a–e and phthalazine 1,4-diones 3a–e with Vilsmeier reagent.

Molecules 2021, 26, 2907
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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 =
conversion ratio and decomposed products were observed (Entries 8–10, Table 3).
−
1.9), and methanesulfonic chloride (TsCl), the low
Table 3. Derivatization results of N-aminophthalimides 2a–e and phthalazine 1,4-diones 3a–e with
Vilsmeier reagent.
Entry
S.M.
Solvent
Reaction Time (h)
Product
Ratio of 2f/3f a
1
2
3
4
5
6
7
2f
2f
2f
2f
2f
2f
2f
CH2Cl2
Toluene
EtOH
24
24
24
24
24
24
24
3f
3f
3f
3f
3f
3f
3f
non-conversion
non-conversion
non-conversion
88/12
THF
CH3CN
Dioxane
DMSO
TsOH
(pKa = –1.9)
TsCl
TFA
(pKa = 0.30)
AcOH
93/7
91/9
89/11
8
9
2f
2f
2f
4
4
4
3f
3f
3f
61/39
56/44
54/46
10
11
2f
4
3f
6/94
(pKa = 4.76)
a
The ratio was identified by 1H-NMR.
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
procedure, N-aminophthalimides 2a
h. Fortunately, compounds 2a can be smoothly transformed to give the corresponding
,
41]. To further demonstrate the reliable of conversion
–
e
were also used as starting materials at reflux for 8–9
–
e
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).

Molecules 2021, 26, 2907
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Figure 4.
Reaction at reflux for 1.5, 2.3, and 3.5 h (1H NMR of compounds 2f and 3f; the ratios of 2f
(a b–d)
) 1H NMR spectrum of the beginning of the reaction (1H NMR of compound 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).
Table 4. The conversion results between N-aminophthalimide 2a–e and pyrazolopyridopyridazine
dione 3a–e.
Entry
S.M.
Reaction Time (h)
Product
2a–e/3a–e a
1
8
1/99
2
3
9
3/97
6/94
10
4
5
11
3
5/95
4/96
a
The ratio of 2/3 was determined by crude 1H-NMR.

Molecules 2021, 26, 2907
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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
1
in ethyl acetate (EtOAc) unless otherwise stated. H 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
cedure involved the treatment of isobenzofuran-1,3-diones (1a ), 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
–f. The reliable pro-
–
c
(
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): 116.43 (dd, J =
7.40 (t, J = 9.38 Hz, 2H, ArH); 13C NMR (D2O, 125 MHz):
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
δ
δ
×
×
×
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.
◦
1
N-Amino-4,5-dichlorophthalimide (2c): White solid; 81% yield; mp 302–305 C; H NMR
(DMSO-d6, 400 MHz)
7.72 (s, 1H, ArH), 7.84 (s, 1H, ArH); 13C NMR (DMSO-d6, 100 MHz)
δ
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
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),
(2
×
C), 149.18 (2
×
C), 172.29 (2
×

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80 (100), 79 (30), 78 (56), 53 (69), 52 (95), 51 (52). HRMS m/z: [M]+calcd for C6H4N4O2:
164.0334; found: 164.0338.
◦
1
Naphthalene-2,3-dicarboxylic hydrazide (2e): Yellow solid; 94% yield; mp 298–300 C; H
NMR (DMSO-d6, 400 MHz) 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)
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,
δ
δ
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) 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)
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
δ
δ
×
×
×
×
.
◦
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)
C), 151.48 (d, J = 16.11 Hz), 154.02 (d, J = 16.10 Hz), 154.61 (2
δ
114.38 (2
×
C), 126.58 (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) 128.16
8.15 (s, 2H, ArH); 13C NMR (DMSO-d6, 100 MHz)
(2 C), 129.64 (2 C), 134.98 (2 C), 156.12 (2 C); FT-IR (KBr): 3314, 3193, 2984, 2926,
δ
δ
×
×
×
×
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) 8.82 (s, 2H, ArH); 13C NMR (D2O, 125 MHz)
δ 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)
2H, ArH), 8.72 (s, 2H, ArH); 13C NMR (DMSO-d6, 100 MHz)
C), 128.84 (2 C), 129.66 (2 C), 134.54 (2 C), 156.22 (2
δ
7.71(dd, J = 6.29, 3.27 Hz, 2H, ArH), 8.25 (dd, J = 6.28, 3.28 Hz,
125.13 (2 C), 126.69 (2
C); FT-IR (KBr): 3416, 1663,
δ
×
×
×
×
×
×

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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 con-
centrated under reduced pressure. The residues were purified by column chromatography
on silica gel to give the corresponding amidination products
74–88% yields [37–39].
4 in 89% yield and 6–10 in
N’-(6,8-Dioxo-1,3-diphenyl-6,8-dihydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridin-7(3H)-yl)-N,N-dime-
◦
4
): Brown solid; 89% yield; mp 225–227 C; 1H NMR (CDCl3, 400 MHz)
thylformimidamide (
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)
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,
δ
δ
×
×
×
×
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 (
low solid; 88% yield; mp 177–179 ◦C; 1H NMR (CDCl3, 400 MHz)
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) 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
6): Yel-
δ
δ
×
×
×
×
×
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 (
solid; 74% yield; mp 183–185 ◦C; 1H NMR (CDCl3, 400 MHz)
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)
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,
7): Light yellow
δ
δ
×
×
×
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 (
solid; 85% yield; mp 192–194 ◦C; 1H NMR (CDCl3, 400 MHz)
3.04 (s, 6H, N(CH3)2), 7.74
(s, 1H), 7.87 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
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,
8): Light orange
δ
δ
×
×
×
×
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 (
yellow solid; 88% yield, mp 219–221 ◦C; 1H NMR (CDCl3, 400 MHz)
3.03 (s, 3H, NMe),
3.05 (s, 3H, NMe), 7.81 (s, 1H), 8.84 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
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
9): Light
δ
δ
×
×
×

Molecules 2021, 26, 2907
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(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)
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,
δ
×
×
×
×
×
×
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 con-
centrated under reduced pressure. The residues were purified by column chromatography
on silica gel to give the corresponding chlorinated products
31–90% yields [29].
5
in 80% yield and 11
–15 in
6,9-Dichloro-1,3-diphenyl-3H-pyrazolo[4’,3’:5,6]pyrido[3,4-d]pyridazine (
80% yield; mp 196–197 ◦C; 1H NMR (CDCl3, 500 MHz)
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)
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,
5): Light yellow solid;
δ
δ
×
×
×
×
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 δ
7.74–7.76 (m, 2H, ArH), 7.85–7.7.87 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
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
1,4-Dichloro-2,3-difluorophthalazine (12): White solid; 82% yield; mp 75–76 C; H NMR
(CDCl3, 400 MHz) 113.97
8.09 (t, J = 8.34 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
(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
δ
δ
×
×
×
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)
(2 C), 140.2 (2
1242, 1130, 1035, 702, 663 cm−1; EIMS m/z: 270 (M+ + 2, 26), 270 (M+ + 2, 16), 268 (M+, 100),
δ
8.40 (s, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
δ
126.07 (2
×
C), 127.39
×
×
C), 153.45 (2
×
C); IR (KBr): 3094, 1596, 1535, 1453, 1501, 1380, 1268,

Molecules 2021, 26, 2907
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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)
7.78–7.81 (m, 2H, ArH), 8.18–8.21 (m, 2H, ArH), 8.82 (s, 2H, ArH); 13C NMR
(CDCl3, 100 MHz) 123.23 (2 C), 126.83 (2 C), 129.22 (2 C), 129.79 (2 C), 135.46
(2 C), 155.39 (2
δ
δ
×
×
×
×
×
×
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 15, Table S1: Crystal data and structure refinement for N’-(6,8-
dioxo6,8-dihydropyrazolopyrrolo-pyridine-yl)-N,N-dimethylformimidamide (CCDC No. 1954819).
–
,
–
4–
4
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.
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