Metal-Free Air Oxidation in a Convenient Cascade Approach for the Access to Isoquinoline-1,3,4(2H)-triones

Article abstract of DOI:10.3390/molecules24112177

Herein we describe a very useful application of the readily available trifunctional aromatic ketone methyl-2-(2-bromoacetyl)benzoate in reactions with primary amines. An unexpected in situ air oxidation that follows a cascade process allowed the access to

Full text of DOI:10.3390/molecules24112177

Article
Metal-Free Air Oxidation in a Convenient Cascade
Approach for the Access to
Isoquinoline-1,3,4(2H)-triones
Antonia Di Mola*, Consiglia Tedesco and Antonio Massa*
Dipartimento di Chimica e Biologia "A. Zambelli", Università degli studi di Salerno, Via Giovanni Paolo II,
84084-Fisciano, Salerno, Italy; ctedesco@unisa.it
* Correspondence:toniadimola@libero.it (A.D.M.); amassa@unisa.it (A.M.); Tel.: +39-089969565 (A.M.)
Received: 14 May 2019; Accepted: 7 June 2019; Published: 10 June 2019
Abstract: Herein we describe a very useful application of the readily available trifunctional
aromatic ketone methyl-2-(2-bromoacetyl)benzoate in reactions with primary amines. An
unexpected in situ air oxidation that follows a cascade process allowed the access to a series of
isoquinoline-1,3,4(2H)-triones, a class of heterocyclic compounds of great interest containing an
oxygen-rich heterocyclic scaffold. A modification of the original protocol, utilizing a Staudinger
reaction in the presence of trimethylphosphine, was necessary for the synthesis of Caspase
inhibitor trione with free NH group.
Keywords: heterocycles; metal-free oxidation; one-pot reactions
1. Introduction
The interest of academia and industry toward one-pot reactions has notably increased during
the last two decades because of the environmentally benign conditions deriving from the high level
of atom and step economy [1]. These transformations, which also include cascade, tandem, and
domino reactions, generally refer to a process involving two or more consecutive reactions, without
the isolation of the intermediates. The development of effective one-pot reactions is related to the
rational design of multifunctional starting materials [2]. Within this context, we have recently
investigated the reactivity as electrophiles in cascade reactions of easily accessible bifunctional
aromatic ketones like 2-acylbenzonitriles [3–5], developing a particularly convenient process for the
synthesis of highly functionalized isoindolinones [3–5], a valuable class of heterocyclic compounds
[6]. Continuing the efforts to explore the chemistry of multifunctional ketones, we were interested to
investigate the reactivity of readily available methyl 2-(2-bromoacetyl)benzoate 1 with primary
amines (Scheme 1). There are relatively few reports on the applications of methyl
2-(2-bromoacetyl)benzoate, which consist of displacement reactions with thiols for the synthesis of
anticancer agents 1,4-disubstituted phthalazines [7,8] or the preparation of Gd(III)-complexes
involving reactions with secondary amines [9]. In this project, we have focused on the possibility to
obtain in a single pot procedure 2,3-dihydroisoquinoline-1,4-diones 2 and to study the second
reactivity for instance in oxidation reactions, which can allow the access to
2,3-dihydroisoquinoline-1,3,4-triones 3 (Scheme 1).
Molecules 2019, 24, 2177; doi:10.3390/molecules24112177
www.mdpi.com/journal/molecules

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Scheme
1.
This
work
and
literature
methodologies
for
the
synthesis
of
2,3-dihydroisoquinoline-1,3,4-trione.
2,3-Dihydroisoquinoline-1,3,4-triones 3 are highly appealing for the number of biological
activities as caspase inhibitors [10–12], nerve protectors to treat various neurodegenerative diseases,
especially Alzheimer’s disease apoplexy and ischemic brain injuries [12,13]. Amino-substituted
derivatives have been found to be active as herbicides due to their efficient redox mediation of
photosystem I and their activity was found to be greater than that of the parent trione (Figure 1)
[14–17]. The semicarbazide derivative prepared from phthalonimide shows good binding affinity
toward oxytocin receptors (Ki = 1.6 nM) [18]. In addition, these compounds are particularly useful as
intermediates in the synthesis of biologically active alkaloids such as benzo[c]phenanthridine
alkaloids or nuevamine [19,20]. In contrast to their fascinating biological profiles, the methods for
synthesis of these compounds are relatively limited, usually requiring multi-step sequences
employing harsh conditions or harmful reagents with tedious purifications of the intermediates or
show a limited substrate scope (Scheme 1).

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Figure 1. 1,3,4(2H)-Isoquinolinetrione derivatives of biological interest.
One of the first synthesis approach was carried out by the oxidation of
3,4-dihydroisoquinolin-1,3-dione with RuO4 as a catalyst and NaIO4 as the stoichiometric oxidant
(Scheme 1a) [21]. Later modifications included the oxidation by SeO2 (Scheme 1a) [10],
tetraphenylporphyrin sensitized photooxygenation (Scheme 1a) [22,23] or the oxidation of
C5-substituted isoquinolin-1-one by K2Cr2O7 (Scheme 1b) [10]. Phthalimides can be transformed into
isoquinolinetriones after alkylation with chloroacetone and ring expansion in the presence of excess
of sodium methoxide to give 4-hydroxyisocarbostyrils. These intermediates in a suitable solvent in
the presence of oxygen undergo to an oxidative deacylation (Scheme 1c) [12]. Some
isoquinolinetriones can be prepared from the corresponding secondary benzamides, as shown in
Scheme 1d: The reactions of appropriate benzamides and oxalyl chloride lead to N-aroyloxamoyl
chlorides. These isolable intermediates undergo cyclization upon heating when the group X is an
activating group such as an alkoxy substituent [24]. Besides the above reactions involving the
oxidation of de-aromatized isoquinolines, isoquinoline-1,3,4-trione can also be prepared by the
Beckmann rearrangement or the azido-Schmidt reaction of ninhydrin, using hydroxylamine
hydrochloride [25] or trimethylsilyl azide [26], respectively. Recently, a more direct access to
dihydroisoquinoline-1,3,4(2H)-triones has been reported using I2/TBHP as oxidant, but it suffers
from a limited substrate scope and harsh reaction conditions (Scheme 1e) [27]. Even though
isoquinoline-1,3-diones are known compounds both as intermediates in the synthesis of
2,3-dihydroisoquinoline-1,3,4-triones and bioactive molecules [28–33], to the best of our knowlwdge,
the analogues 2,3-dihydroisoquinoline-1,4-diones 2 have never been reported in literature.
Therefore, the development of an efficient method to prepare 2,3-dihydroisoquinolines-1,4-diones
from readily available sources and investigation of their reactivity would be highly desirable.
2. Results
In order to develop a direct access to 2,3-dihydroisoquinolines-1,4-diones 2, we treated
2-(2-bromoacetyl)benzoate 1 with one equivalent of benzyl amine, used as model nucleophile, at
room temperature in dry CH3CN (Table 1). However, under the conditions reported in Entries 1 and
2 of Table 1, the unreacted starting materials were recovered. The conversion was significantly
improved in the presence of one equivalent of diisopropylethylamine (DIPEA) at 50 °C (Entry 3–5).
In this case, instead of the expected 2,3-dihydroisoquinoline-1,4-dione 2, we isolated the respective
2,3-dihydroisoquinoline-1,3,4-trione 3a in a very good 71% yield (Entry 5). The structure of the
obtained product was clearly attributed by single-crystal X-ray diffraction, MS spectrum, and
1
comparison of H-NMR spectrum with literature [27]. The X-ray molecular structure is reported in
Figure 2 (for details check Supplementary Materials).

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Figure 2. ORTEP drawing and atom numbering scheme of compound 3a. Hydrogen atoms have
been omitted for clarity. Ellipsoids are drawn at 30% probability level. CCDC 1915668 contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, Cambridge, UK).
In a control experiment performed under nitrogen atmosphere at 50 °C (Entry 6), we observed
the formation of a mixture of products, and only a tiny amount of 3a was isolated after
1
chromatography. Since H-NMR performed on the crude did not highlight the presence of 3a, its
formation was probably due to slow air oxidation during purification and isolation procedures
(Entry 6). We also tested other bases. However, either Et3N or inorganic bases like NaHCO3 and
K2CO3 were less effective, leading to decomposition products in a larger extent (Entries 7–11).
Table 1. Preliminary reaction conditions screening.
Entry Base (1 eq) T (°C) Time (h) Yield 3aa
1
2
3
-
-
r.t.
r.t.
r.t
50
50
50
50
r.t
50
50
50
3
--
--
18
18
3
18
18
18
18
3
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
NaHCO3
NaHCO3
K2CO3
K2CO3
18%b
53%
71%
10%
50%
26%
41%
40%
Dec.
4
5
6c
7
8
9
10
11
4
18
a Yields refer to chromatographically pure compounds. b 80% of 1 was recovered. c Reaction was
performed under nitrogen.
Then, under the optimized reaction conditions, we briefly analyzed the scope of the method
using a series of aliphatic and benzyl primary amines (Table 2). In all the cases, also with the highly
volatile methylamine or ethylamine, added as THF solutions, as well as in the presence of benzyl
amines substituted with both electron-withdrawing or -donating groups, we obtained the
2,3-dihydroisoquinoline-1,3,4-triones in good yields. Only in the presence of the less nucleophilic
aniline, even though after 18 h at 50 °C the starting materials disappeared, we recovered a complex
mixture of products (Entry 10).

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Table 2. Substrate scope.
Entry
1
2
3
4
5
6
7
8
R
3
(3a)
(3b)
Yield %a
71%
73%
75%
69%
69%
72%
70%
73%
72%
--
-CH2Ph
4-Cl-CH2Ph
4-MeO-CH2Ph (3c)
2-F-CH2Ph (3d)
3-NO2-CH2Ph (3e)
-CH3
-CH2CH3
-(CH2)3CH3
-CH2CH=CH2
Ph
(3f)
(3g)
(3h)
(3i)
9
10
a Yields refer to chromatographically pure compounds.
We also investigated the reaction of 1 with ammonia, used as 0.5 M solution in dioxane in order
to developed one-pot protocol in the synthesis of the 3-caspase inhibitor [12]. The reaction, as
summarized in Scheme 2A, was sluggish. The expected product was obtained only in 30% yield
together with a series of not well identified intermediates and decomposition products. To this
purpose, we modified the original protocol, reacting 1a with NaN3 and the crude derivative was
subjected to Staudinger reaction [34] in the presence of PMe3 [35]. Even though the isolation and
purification of the azide intermediate was necessary in this case, the reduction, cyclization, and air
oxidation were carried out in a single pot reaction, simply changing N2 with air at the end of the
cascade reaction and reacting for further 18 h at 50 °C. This furnished the expected 3j in a satisfying
62% yield.
Scheme 2. Synthesis of NH-unsubstitued 2,3-dihydroisoquinoline-1,3,4-trione.
On the basis of the obtained results and the control experiments, we can confidently propose
the mechanism as described in Scheme 3. In particular, we believe that the first steps of the process
involve a nucleophilic displacement of bromine and then lactamization. In this sequence of
reactions, one equivalent of hindered DIPEA is necessary to neutralize the formed HBr, while the
less-hindered Et3N could give competing nucleophilic displacement. Once formed the supposed
2,3-dihydroisoquinoline-1,4-diones intermediate 2, this is subject to in situ air auto-oxidation
probably via enol formation 5 (Scheme 4).

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Scheme 3. Proposed one-pot mechanism for the developed process.
Aerobic oxidations without the use of any reagent or metal catalyst are quite rare, but two
notable examples have been recently reported for the aerobic α-oxidation of nitrogen containing
heterocycles [36,37]. In particular, Foss et al. described an isoindolinone synthesis by selective
metal-free aerobic oxidation of isoindolines [36]. In addition, Tang et al. reported an aerobic
hydroxylation of isoquinoline-1,3-diones to 4-hydroxy-isoquinoline-1,3-diones by air oxidation via
enol formation [37]. Supported by these studies, the enol 5 may react with oxygen in the air, with a
following protonation to give hydroperoxide 6. Then, water elimination furnishes the
2,3-dihydroisoquinoline-1,3,4-triones 3.
Scheme 4. Proposed mechanism for air oxidation to afford 2,3-dihydroisoquinoline-1,3,4-triones.
3. Materials and Methods
3.1. General Information
Reactions were performed using commercially available compounds without further
purification and analytical grade solvents. All the reactions were monitored by thin layer
chromatography (TLC) on precoated silica gel plates (0.25 mm) and visualized by fluorescence
quenching at 254 nm. Flash chromatography was carried out using silica gel 60 (70–230 mesh, Merck,
Darmastdt, Germany). The NMR spectra were recorded on Bruker (Rheinstetten, Germany) 400 and
1
13
1
13
300 spectrometers (400 MHz, H, 100 MHz, C, 300 MHz, H, 75 MHz, C). Spectra were referenced
1
13
to residual CHCl3 (7.26 ppm, H, 77.00 ppm, C). The following abbreviations are used to indicate
the multiplicity in NMR spectra: s—singlet, d—doublet, t—triplet, q—quartet, dd—double doublet,
ddd—doublet of doublet of doublet, m—multiplet, bs—broad signal. Coupling constants (J) are
quoted in hertz. Yields are given for isolated products showing one spot on a TLC plate and no
impurities detectable in the NMR spectrum. FTIR spectra were recorded as thin films on KBr plates
using Bruker (Rheinstetten, Germany) VERTEX 70 spectrometer and absorption maxima are
−1
reported in wavenumber (cm ). High-resolution mass spectra (HRMS) were acquired using a
Bruker solariX XR Fourier transform ion cyclotron resonance mass spectrometer (Bruker Daltonik
GmbH, Bremen, Germany) equipped with a 7T refrigerated actively shielded superconducting
magnet. The samples were ionized in a positive ion mode using an electrospray (ESI) ionization
source. Methyl 2-(bromoacetyl)benzoate was prepared according to the literature procedure [7].
3.2. General Procedure for Isoquinoline-1,3,4(2H)-triones Synthesis
Methyl 2-(bromoacetyl)benzoate (0.24 mmol, 1 equiv.) was dissolved in dry CH3CN (2 mL) and
DIPEA (1 equiv.) was added followed by the addition of amine (1 equiv.). The mixture was
vigorously stirred under air at 50 °C overnight in a round bottomed flask with a rubber stopper and
a needle. The solvent was removed under vacuum and the crude was purified by flash column
chromatography (Hexane 90/Ethyl acetate 10) using silica gel deactivated with 1% Et3N.

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3.3. Product Characterization
2-benzylisoquinoline-1,3,4(2H)-trione (3a)[10,21,27,38]: Light yellow solid, 71% yield (45 mg). Mp. 190–
1
191 °C. Data in accordance with literature. H-NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 1.0, 7.8 Hz, 1H),
8.20 (dd, J = 7.6, 1.0 Hz, 1H), 7.88 (td, J = 1.4, 7.6 Hz, 1H), 7.81 (dt, J = 1.3, 7.6 Hz, 1H), 7.51–7.49 (m,
13
2H), 7.35–7.27 (m, 3H), 5.24 (s, 2H). C-NMR (100 MHz, CDCl3) δ 174.6, 162.0, 156.8, 136.1, 135.9,
+
134.4, 130.8, 129.8, 129.7, 129.3, 128.6, 127.7, 127.3, 44.3. HRMS (ESI): calcd. for [M + H] C16H12NO3:
266.0812, found: 266.0814.
2-(4-chlorobenzyl)isoquinoline-1,3,4(2H)-trione (3b) [27]: Light yellow solid, 73% yield (52 mg). Mp.
1
187–188 °C. Data in accordance with literature. H-NMR (300 MHz, CDCl3) δ 8.35 (d, J = 7.7 Hz, 1H), 8.22
(d, J = 7.6 Hz, 1H), 7.91 (td, J = 1.2, 7.6 Hz, 1H), 7.84 (td, J = 1.2, 7.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.28
13
(d, J = 8.4 Hz, 2H), 5.20 (s, 2H). C-NMR (75 MHz, CDCl3) δ 174.7, 162.4, 157.3, 136.7, 134.5, 134.0,
+
134.3, 131.2, 130.9, 130.8, 129.0, 128.8, 128.1, 43.6. HR-MS (ESI): calcd. for [M + H] C16H11 ClNO3:
300.0422, found: 300.0427.
2-(4-methoxybenzyl)isoquinoline-1,3,4(2H)-trione (3c) [27]: Light yellow solid, 75% yield (57 mg). Mp.
1
163–164 °C. Data in accordance with literature. H-NMR (CDCl3, 300 MHz) δ 8.33 (dd, J= 7.4 Hz, 1H),
8.17 (dd, J = 7.5 Hz, 1H), 7.91–7.82 (m, 2H), 7.47 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 5.15 (s, 2H),
13
3.76 (s, 3H). C-NMR (CDCl3, 100 MHz) δ 174.8, 162.3, 159.5, 156.8, 135.9, 134.3, 131.3, 130.6, 130.1,
+
129.7, 128.1, 127.6, 113.8, 55.1, 43.6. HR-MS (ESI): calcd. for [M + Na] C17H13NO4Na: 318.0736, found:
318.0733.
2-(2-fluorobenzyl)isoquinoline-1,3,4(2H)-trione (3d) [12]: Light yellow solid, 69% yield (47 mg). Mp.
1
186–187 °C. Data in accordance with literature. H-NMR (CDCl3, 400 MHz) δ 8.36 (dd, J = 0.8, 7.8 Hz,
1H), 8.25 (dd, J = 0.8, 7.8 Hz, 1H), 7.94–7.82 (m, 2H), 7.34–7.31 (m, 1H), 7.29–7.25 (m, 1H), 7.09–7.04
13
(m, 2H), 5.36 (s, 2H). C-NMR (CDCl3, 75 MHz) δ 174.7, 162.0 (J = 240 Hz), 161.9, 156.9, 136.3, 134.5,
130.8, 130.1 (J = 3.0 Hz), 130.0, 129.7, 129.6 (J = 9.0 Hz), 127.9, 124.1 (J = 3.0 Hz), 122.6 (J = 9.0 Hz), 115.6
+
(J = 9.0 Hz), 38.3 (J = 3.0 Hz). HR-MS (ESI): calcd. for [M + H] C16H11FNO3: 284.1707, found: 284.1710.
2-(3-nitrobenzyl)isoquinoline-1,3,4(2H)-trione (3e) [27]: Light yellow solid, 69% yield (51 mg). Mp.
1
186–187 °C. Data in accordance with literature. H-NMR (CDCl3, 400 MHz) δ 8.38 (t, J = 7.7 Hz, 2H),
8.24 (d, J = 7.6 Hz, 1H), 8.16 (J = 8.0 Hz, 1H), 7.97–7.94 (m, 1H), 7.89–7.82 (m, 2H), 7.52 (t, J = 8.0 Hz,
13
1H), 5.34 (s, 2H). C-NMR (100 MHz, CDCl3) δ 174.7, 162.3, 157.1, 148.8, 137.5, 136.4, 135.2, 135.9,
+
131.3, 130.3, 129.9, 129.8, 128.2, 124.5, 123.4, 43.8. HR-MS (ESI): calcd. for [M + H] C16H11N2O5:
311.0662, found: 311.0659.
2-Methylisoquinoline-1,3,4(2H)-trione (3f) [10,12,21,38]: Light yellow solid, 72% yield (32 mg). Mp.
1
186–187 °C. Data in accordance with literature. H-NMR (CDCl3, 300 MHz) δ 8.36 (dd, J = 1.3, 7.6 Hz,
13
1H), 8.23 (dd, J = 1.3, 7.6 Hz, 1H), 7.94–7.81 (m, 2H), 3.50 (s, 3H). C-NMR (CDCl3, 100 MHz) δ 174.5,
+
162.4, 157.3, 136.20, 134.4, 130.6, 129.8, 129.7, 127.8, 27.5. HR-MS (ESI): calcd. for [M + H] C10H8NO3:
190.0499, found: 190.0492.
2-Ethylisoquinoline-1,3,4(2H)-trione (3g) [14,21,38,39]: Light yellow solid, 70% yield (34 mg). Mp.
1
101–102 °C. Data in accordance with literature. H-NMR (CDCl3, 300 MHz) δ 8.38 (dd, J = 0.6, 5.8 Hz,
1H), 8.24 (dd, J = 0.8, 5.8 Hz, 1H), 7.94–7.83 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
13
C-NMR (CDCl3, 100 MHz) δ 174.6, 161.8, 156.7, 135.9, 134.3, 130.7, 129.9, 129.7, 127.7, 37.3, 13.1.
+
HR-MS (ESI): calcd. for [M + H] C11H10NO3: 204.0655, found: 204.0658.
2-Butylisoquinoline-1,3,4(2H)-trione (3h) [14,39]: Light yellow solid, 73% yield (40 mg). Mp. 60–61 °C.
1
Data in accordance with literature. H-NMR (CDCl3, 300 MHz) δ 8.33 (d, J = 7.9 Hz, 1H), 8.20 (d, J =
7.9 Hz, 1H), 7.98–7.82 (m, 2H), 4.11 (t, J = 7.4 Hz, 2H), 1.74–1.68 (m, 2H), 1.66–1.41 (m, 2H), 1.03 (t, J =
13
7.4 Hz, 3H). C-NMR (CDCl3, 100 MHz) δ 174.7, 162.1, 156.9, 135.9, 134.3, 130.8, 129.9, 129.7, 127.7,
+
41.0, 29.9, 20.2, 13.7. HR-MS (ESI): calcd. for [M + H] C13H14NO3: 232.0968, found: 232.0963.
2-Allylisoquinoline-1,3,4(2H)-trione (3i) [10,12]: Light yellow solid, 72% yield (37 mg). Mp. 180–181 °C.
1
Data in accordance with literature. H-NMR (CDCl3, 400 MHz) δ 8.35 (dd, J = 0.7, 7.8 Hz, 1H), 8.22

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(dd, J = 0.8, 7.7 Hz, 1H), 7.94–7.83 (m, 2H), 5.96–5.86 (m, 1H), 5.38 (d, J = 17 Hz, 1H), 5.26 (d, J = 10 Hz,
13
1H), 4.66 (d, J = 6.1 Hz, 2H). C-NMR (CDCl3, 75 MHz) δ 174.7, 162.1, 156.9, 136.3, 134.7, 134.5, 131.0,
+
130.1, 130.0, 128.1, 119.4, 43.4. HR-MS (ESI): calcd. for [M + H] C10H12NO3: 216.0655, found: 216.0657.
3.4. General Procedure for Isoquinoline-1,3,4(2H)-trione Synthesis via Staudinger Reaction
Methyl 2-(bromoacetyl)benzoate (100 mg, 0.39 mmol, 1 equiv.) and NaN3 (1.5 equiv.) were
vigorously stirred at room temperature overnight. The suspension was diluted with MTBE and solid
was filtered off. The solvent was removed under vacuum and the crude was purified by flash
column chromatography on silica gel (Hexane 95/Ethyl acetate 5). To a solution of azide 4 (84 mg,
0.38 mmol, 1 equiv.) in THF/H2O (2 mL/200 μL) under nitrogen atmosphere, trimethylphosphine
(1M in THF, 456 μL, 1.2 equiv) was added and the mixture was stirred for 4 h at room temperature.
Then, the mixture was stirred under air at 50 °C overnight utilizing a rubber stopper with a needle.
After evaporation of the solvent, the crude was taken up with dichloromethane and washed with
water. Purification by chromatography (Ethyl acetate 3/CHCl3 7) using silica gel deactivated wih 1%
Et3N gave 3j as yellow solid.
1
Methyl 2-(2-azidoacetyl)benzoate (4): Pale oil, 98% yield (84 mg). H-NMR (CDCl3, 400 MHz) δ 7.99 (d, J
= 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.56 (J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.25 (s, 2H), 3.90 (s,
13
3H). C-NMR (CDCl3, 100 MHz) δ 200.2, 166.3, 140.7, 132.9, 130.4, 130.2, 127.9, 126.3, 57.8, 52.8.
+
HR-MS (ESI): calcd. for [M + H] C10H10N3O3: 219.0644, found: 219.0638.
Isoquinoline-1,3,4(2H)-trione (3j) [12,21,38]: Yellow solid, 62% yield (41 mg). Mp. 220–221 °C. Data in
1
accordance with literature. H-NMR (DMSO-d6, 400 MHz) δ 11.98 (br, 1H), 8.14 (d, J = 7.9 Hz, 1H),
13
8.07 (d, J = 7.6 Hz, 1H), 7.95–7.88 (m, 2H). C-NMR (DMSO-d6, 75 MHz) δ 174.8, 162.7, 157.4, 136.5,
+
134.8, 131.2, 130.1, 129.7, 128.1. HR-MS (ESI): calcd. for [M + H] C9H6NO3: 176.0342, found: 176.0346.
4. Conclusions
In conclusion, we report simple and synthetically useful protocols for the preparation of
2,3-dihydroisoquinoline-1,3,4-triones
by
one-pot
cascade
reactions
of
methyl
2-bromoacetyl)benzoate with primary amines followed by in situ oxidation promoted by air,
without the use of any other reagent or catalyst. This transformation proved to be of general
applicability with respect to aliphatic or benzylic amines, while aromatic amines like aniline lead to
decomposition products. A suitable modification of the original protocol utilizing a Staudinger
reaction, allowed the synthesis of the NH-unsubstituted caspase inhibitor trione. On the basis of the
present work, other studies are in course in order to analyze the applicability of the concepts herein
developed and in particular of the metal-free air oxidation on related multifunctional substrates.
Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1, Figure 1: The X-ray
molecular structure of compound 3a and X-Ray data and NMR spectra of all the compounds.
Author Contributions: methodology and investigation, A.D.M.; X-ray structural analysis, C.T.;
writing—original draft preparation and supervision, A.M.; writing—review and editing, A.M.
Funding: This research received no external funding
Acknowledgments: This work was supported by MIUR and University of Salerno.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors
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