Next Article in Journal
Reduced Graphene Oxide-Zinc Sulfide Nanocomposite Decorated with Silver Nanoparticles for Wastewater Treatment by Adsorption, Photocatalysis and Antimicrobial Action
Next Article in Special Issue
An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones
Previous Article in Journal
Inhibition of Klf10 Attenuates Oxidative Stress-Induced Senescence of Chondrocytes via Modulating Mitophagy
Previous Article in Special Issue
Fluorescent Pyranoindole Congeners: Synthesis and Photophysical Properties of Pyrano[3,2-f], [2,3-g], [2,3-f], and [2,3-e]Indoles
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 28
Issue 3
10.3390/molecules28030923
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

Dess–Martin Periodinane-Mediated Oxidative Coupling Reaction of Isoquinoline with Benzyl Bromide

by
Chunmei Yang
1,2,†,
Guoqing Zhang
1,†,
Senling Tang
1,2,
Yang Pan
1,2,
Huawu Shao
1 and
Wei Jiao
1,*
1
Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
2
University of Chinese Academy of Sciences, Beijing 100049, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2023, 28(3), 923; https://doi.org/10.3390/molecules28030923
Submission received: 21 December 2022 / Revised: 13 January 2023 / Accepted: 15 January 2023 / Published: 17 January 2023
(This article belongs to the Special Issue Chemistry of Indoles)
Browse Figures
Review Reports Versions Notes

Abstract

:
Dess–Martin periodinane (DMP) is a broadly applicable oxidant in chemical synthesis. In this work, an efficient and convenient synthesis of N-substituted isoquinolinone derivatives mediated by DMP was achieved through the oxidative coupling reaction of functionalized isoquinoline with readily available benzyl bromide, which is a metal-free, mild, and practical method for synthesizing isoquinoline-1,3-dione or isoquinoline-1,3,4-trione derivatives in excellent yields. The H2O18-labeling experiment was performed to gain insight into the possible mechanism for this reaction.

Graphical Abstract

1. Introduction

Isoquinoline is an essential structural unit in pharmaceutical molecules and naturally occurring alkaloids [1,2,3]. In particular, isoquinolinones and their derivatives are the critical moiety of many pharmaceuticals [4,5]. As a member of the isoquinoline alkaloid family, isoquinolinones have exhibited a wide range of structural diversity and biological activity [6,7], and gliquidone is used as a commercial drug to treat diabetes (Figure 1, I) [8]. It was also found that isoquinolinones exhibit antiviral (Figure 1, II) [9], anticancer (Figure 1, III) [10], and anti-metastatic biological activities (Figure 1, IV) [11].
Various methods have been developed to synthesize isoquinolinone derivatives due to their significant pharmacological properties and diverse biological activities. Specifically, several synthetic strategies, such as organic electrochemistry [12], visible-light catalysis [13], and metal-catalyzed strategy [14], have been used to initiate these intriguing reactions and have proven highly useful. It was reported that a mild and efficient carboperfluoroalkylation reaction of alkenes led to isoquinoline-1,3-diones using perfluoroalkyl iodides or bromides (Figure 2a) [15]. The synthesis of nitro-functionalized isoquinolinedione derivatives has also been achieved by a tandem reaction (Figure 2b) [16]. In 2012, Da-you Ma et al. developed a convenient iodine-catalyzed multiple C-H bonds functionalization of isoquinolines with methylarenes to produce N-benzyl isoquinoline-1,3,4-triones (Figure 2c) [17]. There are still some limitations, although these methods have synthesized the target product, such as high temperature and heavy metal residue. In particular, the direct synthesis of isoquinoline-1,3-dione from isoquinoline as the substrate has been rarely reported [18]. Therefore, it is necessary and valuable to develop a more practical and efficient method to synthesize isoquinoline-1,3-dione.
The oxidative coupling reaction mediated by hypervalent iodine reagents (HIRs) have the advantages of mild reaction conditions, high selectivity, and environmental friendliness compared with traditional metal catalysts [19]. HIRs have become a powerful tool for new bond formation due to their excellent ability to construct C-C and carbon–heteroatom bonds [20]. In recent decades, hypervalent iodine (V) reagents have become a powerful synthetic tool in organic chemistry [21,22]. In particular, DMP has been proven an effective oxidant to construct C-N bonds [23].
In the previous study, our group disclosed a method of direct trifluoromethylation and perfluoroalkylation of isoquinoline mediated by [Bis(trifluoroacetoxy)iodo]benzene (PIFA) [24], which led us to speculate that hypervalent iodine may induce isoquinoline to undergo C-H functionalization. Herein, as part of our continuing research on the functionalization of isoquinoline caused by hypervalent iodine reagent, we first disclose a metal-free oxidative transformation of isoquinoline to provide isoquinolinone with DMP as the oxidant. Compared with the traditional synthesizing isoquinolinone, this method has the edge of easy substrate acquisition, mild reaction conditions, one step, and environmental friendliness (Figure 2d).

2. Results

Based on the above speculation, the model substrate of isoquinoline (1a) with benzyl bromide (2a) was first examined. Then, they were treated with 2.0 eq. of DMP in N-methyl-2-pyrrolidone (NMP) at room temperature. After 24 h, it was found that the desired oxidative coupling product 3aa could be obtained in 62% yield, along with a trace amount of oxylated product 4 forming (Table 1, entry 1). The structure of 3aa was confirmed by X-ray single-crystal diffraction (Figure 3). When DMP was replaced by other hypervalent iodine reagents, such as (diacetoxyiodo)benzene (PIDA), PIFA, Koser’s reagent, and iodosobenzene (PhIO), no reaction occurred, and the starting material 1a was almost recovered (Table 1, entries 2−5). When 2-iodoxybenzoic acid (IBX) was used, the desired product 3aa was obtained in 47% yield, a little lower than the yield of DMP (Table 1, entry 6). Different solvents were tested with hypervalent iodine (V) reagent DMP to enhance the yield of product 3aa. NMP was found to serve as the best reaction medium as compared to the other solvents, such as dimethylformamide (DMF), acetonitrile (MeCN), and dimethyl sulfoxide (DMSO) (Table 1, entry 7–9). In addition, the hypervalent iodine (III) reagent could successfully catalyze the reaction when the solvent was DMF, and the undesired isoquinoline-1-one 4 was formed along without the product 3aa (Table 1, entry 10).
We further studied the effects of reaction temperature, substrate equivalence ratio, and water content of the reaction system on the reaction yield. When the temperature decreased, the reaction took more time, and the yield also decreased (Table 1, entry 12). Higher temperatures also led to lower yield (Table 1, entry 13). If the temperature dropped to −10 °C, isoquinoline did not react with benzyl bromide (Table 1, entry 11). Further investigation of the amount of DMP revealed that 3.4 eq. of DMP was enough for the present reaction (Table 1, entry 15). In addition, the controlled experiments proved that the reactions must be conducted under air. Firstly, no corresponding products 3aa or 4 were detected with substrate 1a and 3.4 eq. of DMP in NMP at room temperature under N2 for 36 h (Table 1, entry 16). Conversely, the increase in the ten equivalents of H2O led to a decrease in yield (Table 1, entry 17). Hence, trace amounts of H2O in the air are sufficient for the process without additional water. Due to the results presented above, the optimal conditions for product 3aa were DMP (3.4 eq.) in NMP at room temperature under air for 36 h.
With the optimized reaction conditions in hand (Table 1, entry 15), the substrate scope was investigated. We investigated the generality of this multiple C-H bonds functionalization of isoquinoline with benzyl bromide. The substrate scope for the benzyl bromide moiety is listed in Figure 4. Benzyl bromides bearing electron-donating substituents were successfully tolerated to afford the corresponding N-substituted isoquinoline-1,3-diones in excellent yields, such as methyl (3ab, 3ac) and methoxy (3ad, 3ae) groups. As expected, 3-chloro and 3-bromo -substituted benzyl bromides were suitable substrates for this transformation, which all reacted with isoquinoline smoothly to yield corresponding isoquinoline-1,3-diones (3af, 3ag). Meanwhile, when one strong electron-withdrawing nitro group was installed in the 4-position of benzyl bromide, the desired product 3ah could be obtained in 78% yield.
Besides benzyl bromide derivatives, the optimized reaction condition was further applied to allyl bromide and 2-(bromomethyl) naphthalene. For an allyl bromide, the oxidative coupling reaction gave the desired product 3ai in 65% yield. Secondly, the oxidative coupling reaction of 2-(bromomethyl) naphthalene smoothly reacted with isoquinoline to provide the corresponding product 3aj as a white solid in 73% yield. The corresponding isoquinolinone was not detected when 1-bromopentane was stirred with isoquinoline 1a.
Encouraged by the exciting results obtained from the hypervalent iodine-catalyzed multiple C-H bonds functionalization of isoquinoline with various benzyl bromides, we then focused on the scope of isoquinoline derivatives (Figure 5). As expected, 6-methyl, 6-chloro, and 6-bromo -substituted isoquinolines were suitable substrates for this transformation, which all reacted with benzyl bromide smoothly to yield substituted N-benzyl isoquinoline-1,3-diones (3ba–3bh). Furthermore, when bromine was installed in the 7-position of isoquinoline, benzyl bromide was consumed, providing the desired isoquinoline-1,3-diones (3bi, 3bj). However, substrates were not converted when one strong electron-withdrawing nitro group was installed in isoquinoline, and the related product was not observed.
In further studies, the results revealed that the substituents in different positions and types greatly influenced the structure of the products (Figure 6). A similar phenomenon has also been reported by Xu’s group [25]. Firstly, the optimized reaction conditions were further applied to the reaction of 5-bromoisoquinoline with benzyl bromides, but the corresponding isoquinoline-1,3-diones cannot be detected, with N-benzylation product (isoquinoline-1,3,4-triones, 3ca) at around 59% yield. Similarly, 5-chloroisoquinoline exhibited a similar property, providing isoquinolinetrione at 61% yield (3cb). Secondly, when one strong electron-donating methoxy group was installed in the 5-, 6-, or 7-position of isoquinoline, no desired isoquinoline-1,3-diones were formed, whereas isoquinoline-1,3,4-triones were afforded in medium-to-excellent yields (3cc–3cg).
Many studies have proved that DMP is less likely to provide oxygen atoms in oxidation reactions [26,27,28], as the oxygen atoms in the product may come from water in the air. An H2O18-labeling experiment was carried out with 3.4 eq. of DMP in a mixed solvent consisting of NMP and H2O18 at room temperature under N2 for 36 h (Figure 7). The corresponding molecular weight (3da) was detected by ESI. The result indicates that the oxygen at the C-1 or C-3 position of the corresponding isoquinolinones stemmed from H2O.

3. Discussion

Based on the mechanistic experiments described above and previous studies [25,29,30,31,32], a plausible mechanism for this hypervalent iodine-catalyzed multiple C-H bonds functionalization is proposed in Figure 8, with the reaction of isoquinoline (1a) and benzyl bromide (2a) shown as an example. Initially, the quaternary ammonium salt A is generated from benzyl bromide reacted with isoquinoline readily. Subsequently, A is attacked by H2O, followed by the removal of one hydrobromide (HBr), affording hydroxyl intermediate B. DMP easily oxidizes the intermediate B to obtain enamide C, and DMP is reduced to iodinane INT-1. Referring to Robert H. Dodd’s research [33], when the bromide anions are present, the iodinane INT-1 reacts with the bromide source in situ to generate INT-2. The intermediate D is obtained via the bromophilic attack of C on hypervalent iodine INT-2. The key intermediate 2-benzyl-4-bromoisoquinolinone E is then formed via isomerization. Intermediate E reacts with another equivalent of hypervalent iodine INT-2 to form iodonium salt F. Bromine anion attacks the C-2 position of iodonium salt F, followed by the removal of one iodinane, to obtain G, whereafter the nucleophilic attack of H2O in the C-3 of isoquinolinone generates hydroxyl product H, which is easily oxidized by the third equivalent of DMP to obtain 3aa.
On the other hand, when methoxyl is presented or halogen-substituted at C-5 of isoquinoline, for H2O it may be easier to nucleophilic attack intermediate iodonium salt F than bromine. Therefore, F was attacked by H2O at the C-3 position to obtain I. Then, the water acts as a nucleophile and attacks the second iodonium salt I at the C-4 position to further convert to L by losing one hydrogen bromide. Finally, intermediate L is oxidized by the third equivalent of DMP to generate the final isoquinoline-1,3,4-trione compound 3ca.

4. Materials and Methods

4.1. Materials

All commercially sourced reagents were used as supplied unless otherwise stated. The 1H NMR and 13C NMR spectra were recorded on a Bruker Avance 400 spectrometer (400 MHz or 100 MHz, respectively). 1H NMR chemical shifts were reported in ppm (δ) relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl3, δ 7.26 ppm). 13C NMR chemical shifts were determined relative to the solvent: CDCl3 at δ 77.16 ppm. High-resolution mass spectroscopy data of the products were collected on a BioTOF Q instrument. Infrared (IR) spectra are obtained by the use of Spectrum One and expressed in wave number (cm−1). Visualization on TLC was achieved by UV light (254 nm). Flash chromatography was performed on silica gel 90, 200–300 mesh.

4.2. General Procedure for the Oxidative Coupling Reactions

To a solution of isoquinoline 1 (0.1 mmol) and benzyl bromide 2 (0.25 mmol) in NMP (6 mL), in a 10 mL rounded bottom flask was added DMP (0.34 mmol). The reaction was stirred at room temperature and monitored by TLC. The mixture was then allowed to stir at room temperature for 36 h. After the complete consumption of substrates (monitored by TLC), the resulting mixture was diluted with EtOAc and washed with saturated NaCl solution (×3). The organic layer was dried over Na2SO4 and concentrated under a vacuum. The crude product was purified by silica gel column chromatography using 5% EtOAc/petroleum ether as the eluent.
Please see the Supplementary Materials for all synthesized compounds’ original 1H and 13C NMR spectra. Detailed physicochemical properties of isoquinolinone derivatives:
  • 2-Benzyl-4,4-dibromoisoquinoline-1,3(2H,4H)-dione (3aa). White solid, 193 mg; mp: 116 °C; IR (KBr) cm−1 2965, 1679, 1597, 1429, 1375, 1336, 1271, 1238, 1150, 960,731, 699; 1H NMR (400 MHz, CDCl3) δ 8.14 (t, J = 7.6 Hz, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 7.4 Hz, 2H), 7.30 (dt, J = 19.2, 7.2 Hz, 3H), 5.26 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 165.0, 161.5, 140.3, 135.4, 134.6, 130.4, 130.2, 128.7, 128.3, 127.6, 120.1, 44.9; ESI-HRMS: m/z calcd for C16H11Br2NO2Na [M + Na]+: 429.90542, found 429.90537.
  • 4,4-Dibromo-2-(3-methylbenzyl)isoquinoline-1,3(2H,4H)-dione (3ab). White solid, 190 mg; mp: 95 °C; IR (KBr) cm−1 2960, 1724, 1681, 1598, 1428, 1371, 1347, 1235, 1150, 960, 748, 696; 1H NMR (400 MHz, CDCl3) δ 8.14 (ddd, J = 8.1, 7.1, 1.3 Hz, 2H), 7.74 (td, J = 7.7, 1.4 Hz, 1H), 7.53 (td, J = 7.6, 1.2 Hz, 1H), 7.28 (dd, J = 8.9, 1.9 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 5.23 (s, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3, 161.9, 140.6, 138.3, 135.7, 134.9, 130.7, 130.5, 129.6, 128.7, 128.6, 128.5, 125.9, 120.5, 51.0, 45.2, 21.5. ESI-HRMS: m/z calcd for C17H13Br2NO2Na [M + Na]+: 443.92107, found 443.92127.
  • 4,4-Dibromo-2-(4-methylbenzyl)isoquinoline-1,3(2H,4H)-dione (3ac). White solid, 201 mg; mp: 92 °C; IR (KBr) cm−1 2960, 1726, 1690, 1598, 1438, 1372, 1337, 1307, 1237, 1154, 964, 746, 692; 1H NMR (400 MHz, CDCl3) δ 8.18–8.09 (m, 2H), 7.74 (td, J = 7.7, 1.5 Hz, 1H), 7.53 (td, J = 7.6, 1.3 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 5.22 (s, 2H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.0, 161.5, 140.3, 137.3, 134.5, 132.5, 130.4, 130.1, 128.9, 128.7, 128.3, 120.2, 44.6, 20.9; ESI-HRMS: m/z calcd for C17H13Br2NO2Na [M + Na]+: 443.92107, found 443.92129.
  • 4,4-Dibromo-2-(3-methoxybenzyl)isoquinoline-1,3(2H,4H)-dione (3ad). White solid, 197 mg; mp: 75 °C; IR (KBr) cm−1 2962, 1724, 1683, 1609, 1508, 1457, 1376, 1333, 1246, 1183, 1026, 951, 748, 689; 1H NMR (400 MHz, CDCl3) δ 8.14 (td, J = 8.4, 1.3 Hz, 2H), 7.75 (td, J = 7.7, 1.5 Hz, 1H), 7.54 (td, J = 7.7, 1.2 Hz, 1H), 7.28–7.19 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.82 (dd, J = 8.1, 2.6 Hz, 1H), 5.23 (s, 2H), 3.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.0, 161.5, 159.4, 140.3, 136.9, 134.6, 130.5, 130.2, 129.3, 128.3, 120.8, 120.0, 113.8, 113.4, 54.9, 44.7; ESI-HRMS: m/z calcd for C17H13Br2NO2Na [M + Na]+: 459.91599, found 459.91580.
  • 4,4-Dibromo-2-(4-methoxybenzyl)isoquinoline-1,3(2H,4H)-dione (3ae). White solid, 211 mg; mp: 63 °C; IR (KBr) cm−1 2971, 1725, 1686, 1599, 1465, 1375, 1330, 1265, 1235, 1167, 1036, 955, 742, 712; 1H NMR (400 MHz, CDCl3) δ 8.13 (ddd, J = 7.9, 4.6, 1.2 Hz, 2H), 7.74 (td, J = 7.7, 1.4 Hz, 1H), 7.53 (td, J = 7.7, 1.2 Hz, 1H), 7.49–7.41 (m, 2H), 6.93–6.80 (m, 2H), 5.19 (s, 2H), 3.77 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.0, 161.5, 159.0, 140.2, 134.5, 130.4, 130.2, 130.1, 129.1, 128.2, 127.6, 120.2, 113.6, 113.5, 54.9, 44.4; ESI-HRMS: m/z calcd for C17H13Br2NO2Na [M + Na]+: 459.91599, found 459.91613.
  • 4,4-Dibromo-2-(3-chlorobenzyl)isoquinoline-1,3(2H,4H)-dione (3af). Yellow oil, 190 mg; mp: 85 °C; IR (KBr) cm−1 2920, 1720, 1670, 1595, 1419, 1369, 1338, 1266, 1236, 1158, 966, 748, 708; 1H NMR (400 MHz, CDCl3) δ 8.15 (td, J = 8.4, 1.3 Hz, 2H), 7.76 (td, J = 7.7, 1.4 Hz, 1H), 7.55 (td, J = 7.6, 1.2 Hz, 1H), 7.47 (q, J = 1.4 Hz, 1H), 7.37 (td, J = 4.7, 1.7 Hz, 1H), 7.32–7.16 (m, 2H), 5.22 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 165.0, 161.5, 140.3, 137.9, 135.3, 134.6, 130.4, 130.1, 129.3, 128.4, 128.3, 128.2, 125.6, 120.2, 44.9; ESI-HRMS: m/z calcd for C16H10Br2ClNO2Na [M + Na]+: 463.86645, found 463.86648.
  • 4,4-Dibromo-2-(3-bromobenzyl)isoquinoline-1,3(2H,4H)-dione (3ag). Yellow oil, 187 mg; mp: 75 °C; IR (KBr) cm−1 3074, 1727, 1671, 1595, 1436, 1376, 1336, 1272, 1234, 1153, 960, 884, 745, 708; 1H NMR (400 MHz, CDCl3) δ 8.13 (ddd, J = 10.3, 8.0, 1.3 Hz, 2H), 7.75 (td, J = 7.7, 1.4 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.54 (td, J = 7.6, 1.1 Hz, 1H), 7.44–7.36 (m, 2H), 7.18 (t, J = 7.9 Hz, 1H), 5.20 (s, 2H).13C NMR (100 MHz, CDCl3) δ 164.9, 161.4, 140.1, 137.5, 134.7, 131.5, 130.8, 130.5, 130.1, 129.8, 128.3, 127.2, 122.2, 119.9, 44.1. ESI-HRMS: m/z calcd for C16H10Br3NO2Na [M + Na]+: 507.81694, found 507.81615.
  • 4,4-Dibromo-2-(4-nitrobenzyl)isoquinoline-1,3(2H,4H)-dione (3ah). White solid, 211 mg; mp: 133 °C; IR (KBr) cm−1 3061, 1725, 1686, 1600, 1517, 1430, 1380, 1345, 1235, 954, 705; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.21–8.11 (m, 3H), 7.79 (td, J = 7.8, 1.4 Hz, 1H), 7.68–7.61 (m, 2H), 7.57 (td, J = 7.6, 1.1 Hz, 1H), 5.33 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 165.1, 161.6, 147.4, 142.4, 140.2, 135.0, 130.69, 130.3, 129.4, 128.4, 123.6, 119.7, 44.1; ESI-HRMS: m/z calcd for C16H11Br2N2O4 [M + H]+: 452.90856, found 452.90488.
  • 2-Allyl-4,4-dibromoisoquinoline-1,3(2H,4H)-dione (3ai). Colorless oil, 110 mg; mp: 63 °C; IR (KBr) cm−1 2938, 1717, 1683, 1597, 1459, 1420, 1373, 1345, 1239, 1163, 965, 753, 699; 1H NMR (400 MHz, CDCl3) δ 8.14 (ddd, J = 10.8, 8.0, 1.3 Hz, 2H), 7.75 (td, J = 7.7, 1.4 Hz, 1H), 7.54 (td, J = 7.6, 1.2 Hz, 1H), 5.91 (ddt, J = 17.3, 10.2, 5.8 Hz, 1H), 5.34 (dq, J = 17.1, 1.5 Hz, 1H), 5.24 (dq, J = 10.3, 1.3 Hz, 1H), 4.66 (dt, J = 5.9, 1.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 164.6, 161.2, 140.3, 134.5, 130.4, 130.3, 130.2, 128.2, 120.0, 118.5, 43.6; ESI-HRMS: m/z calcd for C12H10Br2NO2 [M + H]+: 357.90783, found 357.90736.
  • 4,4-Dibromo-2-(naphthalen-2-ylmethyl)isoquinoline-1,3(2H,4H)-dione (3aj). White solid, 164 mg; mp: 112 °C; IR (KBr) cm−1 3043, 1718, 1677, 1599, 1431, 1336, 1235, 1151, 975, 748, 597; 1H NMR (400 MHz, CDCl3) δ 8.15 (dt, J = 7.8, 1.7 Hz, 2H), 7.99–7.94 (m, 1H), 7.87–7.77 (m, 3H), 7.74 (td, J = 7.7, 1.4 Hz, 1H), 7.61 (dd, J = 8.5, 1.8 Hz, 1H), 7.53 (td, J = 7.7, 1.1 Hz, 1H), 7.50–7.40 (m, 2H), 5.43 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 165.1, 161.6, 140.2, 134.6, 132.9, 132.8, 132.6, 130.4, 130.1, 128.3, 128.1, 127.9, 127.7, 127.3, 126.4, 125.9, 125.8, 120.1, 45.0; ESI-HRMS: m/z calcd for C20H13Br2NO2Na [M + Na]+: 479.92107, found 479.92071.
  • 2-Benzyl-4,4-dibromo-6-methylisoquinoline-1,3(2H,4H)-dione (3ba). White solid, 193 mg; mp: 105 °C; IR (KBr) cm−1 2923, 1717, 1676, 1608, 1419, 1374, 1348, 1246, 971, 716, 699; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 1H), 7.95–7.90 (m, 1H), 7.51–7.44 (m, 2H), 7.37–7.22 (m, 4H), 5.24 (s, 2H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1, 161.5, 145.9, 140.1, 135.5, 131.5, 130.4, 128.6, 128.3, 128.3, 127.6, 117.6, 44.7, 21.6; ESI-HRMS: m/z calcd for C17H14Br2NO2 [M + H]+: 421.93913, found 421.93872.
  • 4,4-Dibromo-2-(3-bromobenzyl)-6-methylisoquinoline-1,3(2H,4H)-dione (3bb). White solid, 198 mg; mp: 115 °C; IR (KBr) cm−1 2917, 1724, 1675, 1608, 1433, 1331, 1225, 1152, 956, 685; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 7.9, 1.8 Hz, 2H), 7.34 (dd, J = 8.1, 1.6 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 5.19 (s, 2H), 2.52 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1, 161.5, 146.1, 140.1, 137.6, 131.6, 130.8, 130.4, 129.8, 128.4, 127.2, 122.3, 117.4, 44.1, 21.6; ESI-HRMS: m/z calcd for C17H12Br3NO2 Na [M + Na]+: 521.83159, found 521.83128.
  • 4,4-Dibromo-6-methyl-2-(3-methylbenzyl)isoquinoline-1,3(2H,4H)-dione (3bc). White solid, 178 mg; mp: 92 °C; IR (KBr) cm−1 2922, 1721, 1676, 1609, 1422, 1369, 1341, 1248, 1158, 971, 730, 696; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 1H), 7.93 (s, 1H), 7.38–7.16 (m, 4H), 7.08 (d, J = 7.4 Hz, 1H), 5.21 (s, 2H), 2.51 (s, 3H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1, 161.5, 145.9, 140.2, 137.9, 135.4, 131.5, 130.4, 129.2, 128.4, 128.3, 128.2, 125.6, 117.7, 44.7, 21.6, 21.1; ESI-HRMS: m/z calcd for C18H15Br2NO2Na [M + Na]+:2 457.93672, found 457.93633.
  • 2-Benzyl-4,4,6-tribromoisoquinoline-1,3(2H,4H)-dione (3bd). White solid, 218 mg; mp: 112 °C; IR (KBr) cm−1 3063, 1721, 1679, 1585, 1406, 1344, 1239, 1159, 971, 727, 693; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.4, 1.8 Hz, 1H), 7.50–7.42 (m, 2H), 7.39–7.23 (m, 3H), 5.24 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 164.4, 160.9, 141.6, 135.2, 133.9, 133.0, 129.8, 129.7, 128.7, 128.3, 127.7, 118.9, 45.0; ESI-HRMS: m/z calcd for C16H11Br3NO2 [M + H]+: 485.83399, found 485.83301.
  • 4,4,6-Tribromo-2-(3-bromobenzyl)isoquinoline-1,3(2H,4H)-dione (3be). Colorless oil, 219 mg; mp: 81 °C; IR (KBr) cm−1 2921, 1723, 1683, 1586, 1472, 1403, 1336, 1236, 1158, 969, 756, 693; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.68 (dd, J = 8.4, 1.8 Hz, 1H), 7.61 (q, J = 3.1, 2.5 Hz, 1H), 7.41 (td, J = 7.8, 1.7 Hz, 2H), 7.20 (t, J = 7.9 Hz, 1H), 5.19 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 164.5, 160.9, 141.6, 137.3, 134.0, 133.1, 131.7, 131.0, 129.9, 129.9, 127.4, 122.4, 118.8, 44.3; ESI-HRMS: m/z calcd for C16H9Br4O2Na [M + Na]+: 585.72654, found 585.76965.
  • 4,4,6-Tribromo-2-(3-methylbenzyl)isoquinoline-1,3(2H,4H)-dione (3bf). Colorless oil, 200 mg; mp: 108 °C; IR (KBr) cm−1 2922, 1720, 1682, 1586, 1405, 1339, 1234, 1161, 970, 759, 689; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.4, 1.8 Hz, 1H), 7.32–7.11 (m, 4H), 7.09 (d, J = 7.6 Hz, 1H), 5.20 (s, 2H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.5, 160.9, 141.6, 138.0, 135.1, 133.9, 133.0, 129.8, 129.7, 129.3, 128.7, 128.5, 128.2, 125.6, 119.0, 45.0, 21.1; ESI-HRMS: m/z calcd for C17H12Br3O2Na [M + Na]+: 521.83159, found 521.83128.
  • 2-Benzyl-4,4,7-tribromoisoquinoline-1,3(2H,4H)-dione (3bg). White solid, 223 mg; mp: 163 °C; IR (KBr) cm−1 2922, 1702, 1670, 1588, 1432, 1348, 1259, 1148, 961, 696; 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.85 (dd, J = 8.5, 2.1 Hz, 1H), 7.50–7.42 (m, 2H), 7.39–7.23 (m, 3H), 5.24 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 164.6, 160.5, 139.0, 137.6, 135.1, 131.8, 131.0, 128.7, 128.4, 127.8, 124.9, 121.5, 45.1; ESI-HRMS: m/z calcd for C16H10Br3NO2Na [M + Na] +: 507.81594, found 507.27163.
  • 4,4,7-Tribromo-2-(3-methylbenzyl)isoquinoline-1,3(2H,4H)-dione (3bh). Colorless oil, 199 mg; mp: 127 °C; IR (KBr) cm−1 2925, 1683, 1599, 1430, 1320, 1297, 1245, 1020, 687; 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 8.5, 2.1 Hz, 1H), 7.26 (d, J = 9.1 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 5.21 (s, 2H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.5, 160.4, 139.0, 138.0, 137.6, 135.0, 131.8, 131.0, 129.3, 128.7, 128.5, 128.2, 125.6, 124.9, 121.5, 49.5, 45.0, 21.1; ESI-HRMS: m/z calcd for C17H12Br3O2Na [M + Na]+: 521.83159, found 521.83128.
  • 2-Benzyl-4,4-dibromo-6-chloroisoquinoline-1,3(2H,4H)-dione (3bi). Yellow solid, 88 mg; mp: 88 °C; IR (KBr) cm−1 3087, 1730, 1688, 1587, 1426, 1374, 1349, 1264, 1230, 906, 733, 706; 1H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 7.6, 1.6 Hz, 1H), 7.85–7.72 (m, 2H), 7.52–7.46 (m, 2H), 7.35–7.23 (m, 4H), 5.21 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 172.4, 161.0, 156.3, 137.2, 136.1, 135.3, 135.1, 132.0, 129.2, 128.9, 128.4, 127.9, 127.22, 44.3; ESI-HRMS: m/z calcd for C16H10ClNO3Na [M + Na]+: 322.02469, found 322.02361.
  • 4,4-Dibromo-6-chloro-2-(3-methylbenzyl)isoquinoline-1,3(2H,4H)-dione (3bj). White solid, 72 mg; mp: 108 °C; IR (KBr) cm−1 2921, 1729, 1682, 1589, 1416, 1326, 1266, 1225, 1156, 1077, 976, 906, 764, 707; 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 7.7, 1.0 Hz, 1H), 7.77 (dd, J = 8.5, 7.8 Hz, 1H), 7.52–7.47 (m, 2H), 7.34–7.26 (m, 4H), 5.19 (s, 2H), 4.02 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 172.2, 161.9, 160.8, 157.0, 136.7, 135.6, 131.5, 129.1, 128.3, 127.7, 121.9, 118.9, 117.3, 56.5, 44.1; ESI-HRMS: m/z calcd for C17H14NO4 [M + H]+: 296.09228, found 296.09301.
  • 2-Benzyl-5-bromoisoquinoline-1,3,4(2H)-trione (3ca). Colorless oil, 139 mg; mp: 158 °C; IR (KBr) cm−1 2923, 1705, 1669, 157, 1427, 1361, 1237, 1163, 1025, 950, 733, 698; 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 8.9, 1.8 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.51–7.44 (m, 2H), 7.39–7.29 (m, 2H), 7.33–7.22 (m, 2H), 7.03 (dt, J = 8.8, 2.2 Hz, 1H), 5.23 (s, 2H), 3.96 (d, J = 1.8 Hz, 3H), 1.37–1.20 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 165.1, 164.3, 161.2, 142.3, 135.6, 130.6, 128.6, 128.3, 127.5, 117.2, 114.3, 112.9, 55.7, 44.7, 29.4; ESI-HRMS: m/z calcd for C17H13NO4Na [M + Na]+: 318.07423, found 318.07315.
  • 2-Benzyl-5-chloroisoquinoline-1,3,4(2H)-trione (3cb). White solid, 81 mg; mp: 193 °C; IR (KBr) cm−1 2922, 1700, 1674, 1574, 1433, 1362, 1332, 1235, 1153, 102, 753, 703; 1H NMR (400 MHz, CDCl3) δ 8.15 (dt, J = 7.8, 1.7 Hz, 2H), 7.99–7.94 (m, 1H), 7.87–7.77 (m, 3H), 7.74 (td, J = 7.7, 1.4 Hz, 1H), 7.61 (dd, J = 8.5, 1.8 Hz, 1H), 7.53 (td, J = 7.7, 1.1 Hz, 1H), 7.50–7.40 (m, 2H), 5.43 (s, 2H), 0.09 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 165.1, 161.6, 140.2, 134.6, 132.9, 132.8, 132.6, 130.4, 130.1, 128.3, 128.1, 127.9, 127.7, 127.3, 126.4, 125.9, 125.8, 120.1, 45.0; ESI-HRMS: m/z calcd for C16H10ClNO3Na [M + Na]+: 322.02469, found 322.02414.
  • 2-Benzyl-5-methoxyisoquinoline-1,3,4(2H)-trione (3cc). Yellow solid, 100 mg; mp: 183 °C; IR (KBr) cm−1 2924, 1723, 1680, 1587, 1453, 1379, 1358, 1283, 1225, 1070, 1014, 751, 699; 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 7.8, 1.1 Hz, 1H), 8.04 (dd, J = 8.1, 1.1 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.52–7.47 (m, 2H), 7.36–7.27 (m, 3H), 5.22 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 165.6, 163.2, 160.8, 141.9, 140.7, 135.3, 133.94, 132.7, 130.8, 129.3, 128.3, 128.2, 127.9, 127.5, 125.3, 120.0, 44.7; ESI-HRMS: m/z calcd for C16H10BrNO3Na [M + Na]+: 365.97418, found 365.97343.
  • 2-Benzyl-6-methoxyisoquinoline-1,3,4(2H)-trione (3cd). Colorless oil, 123 mg; mp: 135 °C; IR (KBr) cm−1 2924, 1695, 1674, 1593, 1466, 1286, 1008, 872, 757, 622; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.26 (d, J = 9.0 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H), 7.11–7.00 (m, 2H), 5.20 (s, 2H), 3.96 (s, 3H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1, 164.3, 161.2, 143.2, 137.9, 135.5, 135.7, 130.7, 129.2, 128.3, 128.2, 125.5, 117.2, 114.3, 113.0, 55.7, 44.7, 26.7; ESI-HRMS: m/z calcd for C17H13NO4Na [M + Na]+: 332.08988, found 332.09010.
  • 2-(3-Bromobenzyl)-6-methoxyisoquinoline-1,3,4(2H)-trione (3ce). White solid, 121 mg; mp: 102 °C; IR (KBr) cm−1 2967, 1723, 1677, 1604, 1499, 1432, 1336, 1372, 1288, 1245, 1152, 1026, 960, 740, 691; 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 8.8, 1.8 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.54–7.46 (m, 2H), 7.36–7.25 (m, 3H), 7.03 (dd, J = 8.8, 2.4 Hz, 1H), 5.23 (s, 2H), 3.96 (d, J = 1.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1, 164.3, 161.2, 142.3, 135.6, 130.6, 128.6, 128.3, 127.5, 117.2, 114.3, 112.9, 55.7, 44.7. ESI-HRMS: m/z calcd for C17H13NO4Na [M + Na]+: 318.07423, found 318.07493.
  • 6-Methoxy-2-(3-methylbenzyl)isoquinoline-1,3,4(2H)-trione (3cf). Colorless oil, 148 mg; mp: 112 °C; IR (KBr) cm−1 2923, 1653, 1600, 1457, 1403, 1254, 1206, 1130, 1093, 1024, 944, 766; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 11.6, 2.1 Hz, 2H), 7.36 (t, J = 6.5 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H), 7.01 (dd, J = 8.9, 2.5 Hz, 1H), 5.15 (s, 2H), 3.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.9, 164.3, 160.9, 142.1, 137.7, 131.3, 130.6, 130.5, 129.7, 127.1, 122.1, 117.1, 114.3, 112.6, 55.6, 50.7, 43.84; ESI-HRMS: m/z calcd for C17H12BrNO4Na [M + Na]+: 395.98474, found 395.98453.
  • 2-Benzyl-7-methoxyisoquinoline-1,3,4(2H)-trione (3cg). Colorless oil, 113 mg; mp: 109 °C; IR (KBr) cm−1 2925, 1708, 1675, 1603, 1497, 1429, 1376, 1341, 1280, 1244, 1115, 1026, 961, 763, 698; 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 8.0, 1.2 Hz, 1H), 7.83 (dd, J = 7.8, 1.7 Hz, 1H), 7.52–7.45 (m, 2H), 7.45–7.30 (m, 4H), 7.14 (td, J = 7.7, 1.8 Hz, 1H), 5.39 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 165.9, 141.0, 135.1, 134.5, 132.4, 130.7, 128.3, 128.2, 128.1, 127.6, 93.9, 67.0; ESI-HRMS: m/z calcd for C16H11Br2NONa [M + Na]+: 391.92855, found 391.92857.

4.3. X-ray Crystallographic Data of 3aa

The crystal of 3aa for XRD analysis was prepared (see the Supporting Information for details). CCDC 2217215 containing the supplementary crystallographic data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

5. Conclusions

In summary, we have demonstrated the first example of a direct oxidative coupling reaction of isoquinolines using inexpensive DMP. The methodology furnishes a diverse collection of synthetically valuable isoquinolinone under metal-free, easy-to-operate, and mild conditions. This method features a broad substrate scope with excellent functional group tolerance, affording structurally diverse isoquinoline-1,3-dione in high yields. Meanwhile, allyl bromide and 2-(bromomethyl) naphthalene were also suitable bromides to obtain isoquinoline-1,3-dione. Moreover, efficient access to isoquinoline-1,3,4-trione is also accomplished under the same conditions, reflecting this method’s synthetic utility. Further investigation into the biological activity of the above isoquinolinone and the synthesis of 4-bromoisoquinoline-1,3-dione is underway.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28030923/s1, 1H NMR and 13C NMR spectra of the synthesized compounds and single crystal structure and data.

Author Contributions

Conceptualization, W.J.; methodology, Y.P. and H.S.; software, G.Z. and S.T.; validation, W.J.; formal analysis, C.Y.; investigation, G.Z. and C.Y.; data curation, G.Z. and C.Y.; writing—original draft preparation, G.Z.; writing—review and editing, W.J.; funding acquisition, W.J.; project administration, W.J.; supervision, W.J. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Key Research and Development Program of Sichuan Province (No. 2022YFS0001), the National Natural Science Foundation of China (No. 21672205), and the Western Light Talent Culture Project of CAS (No. 2017XBZG_XBQNXZ_A1_006).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The details of the data supporting the report results in this research, were included in the paper and Supplementary Materials.

Conflicts of Interest

The authors declared that they have no conflict of interest in this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Sample Availability

Samples of the compounds are not available from authors.

References

  1. Li, D.; Yu, P.; Xiao, W.; Wang, Z.Z.; Zhao, L.G. Berberine: A Promising Natural Isoquinoline Alkaloid for the Development of Hypolipidemic Drugs. Curr. Top. Med. Chem. 2020, 20, 2634–2647. [Google Scholar] [CrossRef] [PubMed]
  2. Yun, D.; Yoon, S.Y.; Park, S.J.; Park, Y.J. The Anticancer Effect of Natural Plant Alkaloid Isoquinolines. Int. J. Mol. Sci. 2021, 22, 1653. [Google Scholar] [CrossRef] [PubMed]
  3. Chueh, W.H.; Lin, J.Y. Berberine, an Isoquinoline Alkaloid in Herbal Plants, Protects Pancreatic Islets and Serum Lipids in Nonobese Diabetic Mice. J. Agric. Food Chem. 2011, 59, 8021–8027. [Google Scholar] [CrossRef]
  4. Hua, R. Isoquinolone Syntheses by Annulation Protocols. Catalysts 2021, 11, 620. [Google Scholar] [CrossRef]
  5. Krane, B.D.; Shamma, M. The Isoquinolone Alkaloids. J. Nat. Prod. 1982, 45, 377–384. [Google Scholar] [CrossRef]
  6. Kumar, A.; Kumar, N.; Roy, P.; Sondhi, S.M.; Sharma, A. Synthesis of Acridine Cyclic Imide Hybrid Molecules and Their Evaluation for Anticancer Activity. Med. Chem. Res. 2015, 24, 3272–3282. [Google Scholar] [CrossRef]
  7. Braña, M.F.; Cacho, M.; García, M.A.; De Pascual Teresa, B.; Ramos, A.; Domínguez, M.T.; Pozuelo, J.M.; Abradelo, C.; Rey Stolle, M.F.; Yuste, M.; et al. New Analogues of Amonafide and Elinafide, Containing Aromatic Heterocycles: Synthesis, Antitumor Activity, Molecular Modeling, and DNA Binding Properties. J. Med. Chem. 2004, 47, 1391–1399. [Google Scholar] [CrossRef]
  8. Malaisse, W.J. Gliquidone Contributes to Improvement of Type 2 Diabetes Mellitus Management: A Review of Pharmacokinetic and Clinical Trial Data. Drugs R D 2006, 7, 331–337. [Google Scholar] [CrossRef]
  9. Jang, Y.; Han, J.; Li, X.; Shin, H.; Cho, W.J.; Kim, M. Antiviral Activity of Isoquinolone Derivatives against Influenza Viruses and Their Cytotoxicity. Pharmaceuticals 2021, 14, 650. [Google Scholar] [CrossRef]
  10. Mayer, S.C.; Banker, A.L.; Boschelli, F.; Di, L.; Johnson, M.; Kenny, C.H.; Krishnamurthy, G.; Kutterer, K.; Moy, F.; Petusky, S.; et al. Lead Identification to Generate Isoquinolinedione Inhibitors of Insulin-like Growth Factor Receptor (IGF-1R) for Potential Use in Cancer Treatment. Bioorg. Med. Chem. Lett. 2008, 18, 3641–3645. [Google Scholar] [CrossRef]
  11. Francis, S.; Croft, D.; Schüttelkopf, A.W.; Parry, C.; Pugliese, A.; Cameron, K.; Claydon, S.; Drysdale, M.; Gardner, C.; Gohlke, A.; et al. Structure-Based Design, Synthesis and Biological Evaluation of a Novel Series of Isoquinolone and Pyrazolo[4,3-c] Pyridine Inhibitors of Fascin 1 as Potential Anti-Metastatic Agents. Bioorg. Med. Chem. Lett. 2019, 29, 1023–1029. [Google Scholar] [CrossRef]
  12. Xu, J.; Yang, Z.; Hua, J.; Lin, Y.; Bian, M.; Li, Y.; Liu, C.; He, W.; Fang, Z.; Guo, K. The Continuous-Flow Electrosynthesis of 4-(Sulfonylmethyl) Isoquinoline-1,3(2H, 4H)-Diones from N -Alkyl- N -Methacryloyl Benzamides under Metal-Free and Oxidant-Free Conditions. Org. Chem. Front. 2020, 7, 3223–3228. [Google Scholar] [CrossRef]
  13. Su, Y.; Zhang, R.; Xue, W.; Liu, X.; Zhao, Y.; Wang, K.H.; Huang, D.; Huo, C.; Hu, Y. Visible-Light-Promoted Acyl Radical Cascade Reaction for Accessing Acylated Isoquinoline-1,3(2: H,4 H)-Dione Derivatives. Org. Biomol. Chem. 2020, 18, 1940–1948. [Google Scholar] [CrossRef] [PubMed]
  14. Chen, Y.; Zhang, Y.; Zhang, H.; Liu, D.; Gu, M.; Li, J.; Wu, F.; Zhu, X.; Li, J.; Nan, F. Design, Synthesis, and Biological Evaluation of Isoquinoline-1, 3, 4-Trione Derivatives as Potent. J. Med. Chem. 2006, 49, 1613–1623. [Google Scholar] [CrossRef]
  15. Tang, S.; Deng, Y.L.; Li, J.; Wang, W.X.; Ding, G.L.; Wang, M.W.; Xiao, Z.P.; Wang, Y.C.; Sheng, R.L. Synthesis of Perfluorinated Isoquinolinediones through Visible-Light-Induced Cyclization of Alkenes. J. Org. Chem. 2015, 80, 12599–12605. [Google Scholar] [CrossRef]
  16. Li, X.; Zhuang, S.; Fang, X.; Liu, P.; Sun, P. Addition of Nitrogen Dioxide to Carbon-Carbon Double Bond Followed by a Cyclization to Construct Nitromethylated Isoquinolinediones. Org. Biomol. Chem. 2017, 15, 1821–1827. [Google Scholar] [CrossRef] [PubMed]
  17. Zhu, D.; Luo, W.K.; Yang, L.; Ma, D.Y. Iodine-Catalyzed Oxidative Multiple C-H Bond Functionalization of Isoquinolines with Methylarenes: An Efficient Synthesis of Isoquinoline-1,3,4(2: H)-Triones. Org. Biomol. Chem. 2017, 15, 7112–7116. [Google Scholar] [CrossRef] [PubMed]
  18. Niu, C.; Du, D.M. Diastereoselective Construction of CF3-Containing Bispiro[Isoquinolone-Pyrrolidine-Benzothiophenone]s through 1,3-Dipolar Cycloaddition. Eur. J. Org. Chem. 2022, 2022, e202200645. [Google Scholar] [CrossRef]
  19. Yadav, J.S.; Reddy, B.V.S.; Basak, A.K.; Venkat Narsaiah, A. Recyclable 2nd Generation Ionic Liquids as Green Solvents for the Oxidation of Alcohols with Hypervalent Iodine Reagents. Tetrahedron 2004, 60, 2131–2135. [Google Scholar] [CrossRef]
  20. Zhdankin, V.V.; Muniz, K. Editorial for the Special Issue on Hypervalent Iodine Reagents. J. Org. Chem. 2017, 82, 11667–11668. [Google Scholar] [CrossRef]
  21. Zhang, G.; Wang, Y.; Xu, J.; Sun, J.; Sun, F.; Zhang, Y.; Zhang, C.; Du, Y. A New Hypervalent Iodine (Iii/v) Oxidant and Its Application to the Synthesis of 2H-Azirines. Chem. Sci. 2020, 11, 947–953. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Jalali, M.; Bissember, A.C.; Yates, B.F.; Wengryniuk, S.E.; Ariafard, A. Oxidation of Electron-Deficient Phenols Mediated by Hypervalent Iodine(V) Reagents: Fundamental Mechanistic Features Revealed by a Density Functional Theory-Based Investigation. J. Org. Chem. 2021, 86, 12237–12246. [Google Scholar] [CrossRef] [PubMed]
  23. Maity, A.; Hyun, S.M.; Wortman, A.K.; Powers, D.C. Oxidation Catalysis by an Aerobically Generated Dess-Martin Periodinane Analogue. Angew. Chem. 2018, 130, 7323–7327. [Google Scholar] [CrossRef]
  24. Pan, Y.; Li, J.; Li, Z.; Huang, F.; Ma, X.; Jiao, W.; Shao, H. An Efficient and Facile Strategy for Trifluoromethylation and Perfluoroalkylation of Isoquinolines and Heteroarenes. Chem. Commun. 2020, 56, 7813–7816. [Google Scholar] [CrossRef] [PubMed]
  25. Xu, D.; Sun, W.W.; Xie, Y.; Liu, J.K.; Liu, B.; Zhou, Y.; Wu, B. Metal-Free Regioselective Hypervalent Iodine-Mediated C-2 and C-3 Difunctionalization of N-Substituted Indoles. J. Org. Chem. 2016, 81, 11081–11094. [Google Scholar] [CrossRef]
  26. Bose, D.S.; Idrees, M. Dess-Martin Periodinane Mediated Intramolecular Cyclization of Phenolic Azomethines: A Solution-Phase Strategy toward Benzoxazoles and Benzothiazoles. Synthesis 2010, 3, 398–402. [Google Scholar] [CrossRef]
  27. Nicolaou, K.C.; Baran, P.S.; Zhong, Y.L.; Sugita, K. Iodine(V) Reagents in Organic Synthesis. Part 1. Synthesis of Polycyclic Heterocycles via Dess-Martin Periodinane-Mediated Cascade Cyclization: Generality, Scope, and Mechanism of the Reaction. J. Am. Chem. Soc. 2002, 124, 2212–2220. [Google Scholar] [CrossRef]
  28. Kupwade, R.V.; Khot, S.S.; Kulkarni, M.A.; Desai, U.V.; Wadgaonkar, P.P. Diethylamine Dess-Martin Periodinane: An Efficient Catalyst-Oxidant Combination in a Sequential, One-Pot Synthesis of Difficult to Access 2-Amino-3,5-Dicarbonitrile-6-Sulfanylpyridines at Ambient Temperature. RSC Adv. 2017, 7, 38877–38883. [Google Scholar] [CrossRef] [Green Version]
  29. Ye, Z.S.; Guo, R.N.; Cai, X.F.; Chen, M.W.; Shi, L.; Zhou, Y.G. Enantioselective Iridium-Catalyzed Hydrogenation of 1- and 3-Substituted Isoquinolinium Salts. Angew. Chem. 2013, 125, 3773–3777. [Google Scholar] [CrossRef]
  30. Jiang, X.; Yang, L.; Yang, W.; Zhu, Y.; Fang, L.; Yu, C. Controllable Synthesis of 3-Chloro- and 3,3-Dichloro-2-Oxindoles via Hypervalent Iodine-Mediated Chlorooxidation. Org. Biomol. Chem. 2019, 17, 6920–6924. [Google Scholar] [CrossRef]
  31. Sun, W.W.; Chen, N.; Wei, T.T.; You, G.J.; Yang, H.; Liu, J.K.; Wu, B. Environmentally Friendly Protocol for 2,3-Difunctionlization of Indole Derivatives. J. Org. Chem. 2020, 85, 10143–10151. [Google Scholar] [CrossRef] [PubMed]
  32. Chaudhari, S.S.; Akamanchi, K.G. A Mild, Chemoselective, Oxidative Method for Deoximation Using Dess- Martin Periodinane. Synthesis 1999, 5, 760–764. [Google Scholar] [CrossRef]
  33. Nocquet, S.; Retailleau, P.; Cariou, K.; Dodd, R.H. Iodine (III)-Mediated Umpolung of Bromide Salts for the Ethoxybromination of Enamides. Org. Lett. 2013, 15, 1842–1845. [Google Scholar] [CrossRef] [PubMed]
Molecules 28 00923 g001 550
Figure 1. Selected biologically active compounds containing the isoquinolinone structural motif.
Figure 1. Selected biologically active compounds containing the isoquinolinone structural motif.
Molecules 28 00923 g001
Molecules 28 00923 g002 550
Figure 2. Various synthetic routes for isoquinolinone derivatives.
Figure 2. Various synthetic routes for isoquinolinone derivatives.
Molecules 28 00923 g002
Molecules 28 00923 g003 550
Figure 3. X-ray crystal structure of 3aa.
Figure 3. X-ray crystal structure of 3aa.
Molecules 28 00923 g003
Molecules 28 00923 g004 550
Figure 4. Investigating benzyl bromide substrates in isoquinoline oxidation coupling reaction.
Figure 4. Investigating benzyl bromide substrates in isoquinoline oxidation coupling reaction.
Molecules 28 00923 g004
Molecules 28 00923 g005 550
Figure 5. Substrate scope for isoquinoline counterpart.
Figure 5. Substrate scope for isoquinoline counterpart.
Molecules 28 00923 g005
Molecules 28 00923 g006 550
Figure 6. Scope of the synthesis of isoquinoline-1,3,4-triones.
Figure 6. Scope of the synthesis of isoquinoline-1,3,4-triones.
Molecules 28 00923 g006
Molecules 28 00923 g007 550
Figure 7. Mechanistic studies.
Figure 7. Mechanistic studies.
Molecules 28 00923 g007
Molecules 28 00923 g008 550
Figure 8. A plausible mechanism for the oxidative coupling reaction of isoquinoline mediated by DMP.
Figure 8. A plausible mechanism for the oxidative coupling reaction of isoquinoline mediated by DMP.
Molecules 28 00923 g008
Table
Table 1. Optimization of the reaction conditions a,b.
Table 1. Optimization of the reaction conditions a,b.
Molecules 28 00923 i001
EntryOxidant (Eq.)ConditionsYield (%) of 3aa/4
1DMP (2.0)NMP, rt, air, 24 h62/trace
2PIDA (2.0)NMP, rt, air, 24 h0/0
3PIFA (2.0)NMP, rt, air, 24 h0/0
4Koser’s reagent (2.0)NMP, rt, air, 24 h0/0
5PhIO (2.0)NMP, rt, air, 24 h0/0
6IBX (2.0)NMP, rt, air, 24 h47/0
7DMP (2.0)DMF, rt, air, 24 h38/0
8DMP (2.0)MeCN, rt, air, 24 h55/0
9DMP (2.0)DMSO, rt, air, 24 h0/0
10PIDA (2.0)DMF, rt, air, 24 h0/37
11DMP (2.0)NMP, −10 °C, air, 24 hTrace/0
12DMP (2.0)NMP, 0 °C, air, 72 h39/0
13DMP (2.0)NMP, 50 °C, air, 24 h18/0
14DMP (1.0)NMP, rt, air, 24 h21/0
15DMP (3.4)NMP, rt, air, 36 h96/0
16DMP (3.4)NMP, rt, N2, 36 h0/0
17DMP (3.4)NMP, rt, air, H2O (10 eq.), 36 h54/0
a Reaction conditions: 1a (1.0 eq., 0.1 mmol) and 2a (2.5 eq., 0.25 mmol) in solvent (6.0 mL) at room temperature. b Yield was determined by NMR.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Yang, C.; Zhang, G.; Tang, S.; Pan, Y.; Shao, H.; Jiao, W. Dess–Martin Periodinane-Mediated Oxidative Coupling Reaction of Isoquinoline with Benzyl Bromide. Molecules 2023, 28, 923. https://doi.org/10.3390/molecules28030923

AMA Style

Yang C, Zhang G, Tang S, Pan Y, Shao H, Jiao W. Dess–Martin Periodinane-Mediated Oxidative Coupling Reaction of Isoquinoline with Benzyl Bromide. Molecules. 2023; 28(3):923. https://doi.org/10.3390/molecules28030923

Chicago/Turabian Style

Yang, Chunmei, Guoqing Zhang, Senling Tang, Yang Pan, Huawu Shao, and Wei Jiao. 2023. "Dess–Martin Periodinane-Mediated Oxidative Coupling Reaction of Isoquinoline with Benzyl Bromide" Molecules 28, no. 3: 923. https://doi.org/10.3390/molecules28030923

Article Metrics

Back to TopTop