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

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.

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.

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.

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.

Footnotes

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.

Figures and Table

Figure 1. Selected biologically active compounds containing the isoquinolinone structural motif.

Figure 2. Various synthetic routes for isoquinolinone derivatives.

Figure 3. X-ray crystal structure of 3aa.

Figure 4. Investigating benzyl bromide substrates in isoquinoline oxidation coupling reaction.

Figure 5. Substrate scope for isoquinoline counterpart.

Figure 6. Scope of the synthesis of isoquinoline-1,3,4-triones.

Figure 7. Mechanistic studies.

Figure 8. A plausible mechanism for the oxidative coupling reaction of isoquinoline mediated by DMP.

Table 1

Optimization of the reaction conditions ^a,b.

[Image omitted. Please see PDF.]
Entry	Oxidant (Eq.)	Conditions	Yield (%) of 3aa/4
1	DMP (2.0)	NMP, rt, air, 24 h	62/trace
2	PIDA (2.0)	NMP, rt, air, 24 h	0/0
3	PIFA (2.0)	NMP, rt, air, 24 h	0/0
4	Koser’s reagent (2.0)	NMP, rt, air, 24 h	0/0
5	PhIO (2.0)	NMP, rt, air, 24 h	0/0
6	IBX (2.0)	NMP, rt, air, 24 h	47/0
7	DMP (2.0)	DMF, rt, air, 24 h	38/0
8	DMP (2.0)	MeCN, rt, air, 24 h	55/0
9	DMP (2.0)	DMSO, rt, air, 24 h	0/0
10	PIDA (2.0)	DMF, rt, air, 24 h	0/37
11	DMP (2.0)	NMP, −10 °C, air, 24 h	Trace/0
12	DMP (2.0)	NMP, 0 °C, air, 72 h	39/0
13	DMP (2.0)	NMP, 50 °C, air, 24 h	18/0
14	DMP (1.0)	NMP, rt, air, 24 h	21/0
15	DMP (3.4)	NMP, rt, air, 36 h	96/0
16	DMP (3.4)	NMP, rt, N2, 36 h	0/0
17	DMP (3.4)	NMP, rt, air, H2O (10 eq.), 36 h	54/0

^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.

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.

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, pp. 2634-2647. [DOI: https://dx.doi.org/10.2174/1568026620666200908165913] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32901585]

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. [DOI: https://dx.doi.org/10.3390/ijms22041653] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33562110]

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, pp. 8021-8027. [DOI: https://dx.doi.org/10.1021/jf201627w]

4. Hua, R. Isoquinolone Syntheses by Annulation Protocols. Catalysts; 2021; 11, 620. [DOI: https://dx.doi.org/10.3390/catal11050620]

5. Krane, B.D.; Shamma, M. The Isoquinolone Alkaloids. J. Nat. Prod.; 1982; 45, pp. 377-384. [DOI: https://dx.doi.org/10.1021/np50022a001]

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, pp. 3272-3282. [DOI: https://dx.doi.org/10.1007/s00044-015-1380-2]

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, pp. 1391-1399. [DOI: https://dx.doi.org/10.1021/jm0308850]

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, pp. 331-337. [DOI: https://dx.doi.org/10.2165/00126839-200607060-00002]

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. [DOI: https://dx.doi.org/10.3390/ph14070650]

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, pp. 3641-3645. [DOI: https://dx.doi.org/10.1016/j.bmcl.2008.04.044]

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, pp. 1023-1029. [DOI: https://dx.doi.org/10.1016/j.bmcl.2019.01.035]

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, pp. 3223-3228. [DOI: https://dx.doi.org/10.1039/D0QO00909A]

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, pp. 1940-1948. [DOI: https://dx.doi.org/10.1039/D0OB00086H] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32101246]

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, pp. 1613-1623. [DOI: https://dx.doi.org/10.1021/jm050896o]

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, pp. 12599-12605. [DOI: https://dx.doi.org/10.1021/acs.joc.5b01803]

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, pp. 1821-1827. [DOI: https://dx.doi.org/10.1039/C6OB02797K] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28155962]

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, pp. 7112-7116. [DOI: https://dx.doi.org/10.1039/C7OB01539A] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28825437]

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. [DOI: https://dx.doi.org/10.1002/ejoc.202200645]

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, pp. 2131-2135. [DOI: https://dx.doi.org/10.1016/j.tet.2003.12.056]

20. Zhdankin, V.V.; Muniz, K. Editorial for the Special Issue on Hypervalent Iodine Reagents. J. Org. Chem.; 2017; 82, pp. 11667-11668. [DOI: https://dx.doi.org/10.1021/acs.joc.7b02531]

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, pp. 947-953. [DOI: https://dx.doi.org/10.1039/C9SC05536C] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34084348]

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, pp. 12237-12246. [DOI: https://dx.doi.org/10.1021/acs.joc.1c01545] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34410728]

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, pp. 7323-7327. [DOI: https://dx.doi.org/10.1002/ange.201804159]

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, pp. 7813-7816. [DOI: https://dx.doi.org/10.1039/D0CC00963F] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32602495]

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, pp. 11081-11094. [DOI: https://dx.doi.org/10.1021/acs.joc.6b02078]

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, pp. 398-402. [DOI: https://dx.doi.org/10.1055/s-0029-1217136]

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, pp. 2212-2220. [DOI: https://dx.doi.org/10.1021/ja012124x]

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, pp. 38877-38883. [DOI: https://dx.doi.org/10.1039/C7RA07738F]

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, pp. 3773-3777. [DOI: https://dx.doi.org/10.1002/ange.201208300]

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, pp. 6920-6924. [DOI: https://dx.doi.org/10.1039/C9OB01173K]

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, pp. 10143-10151. [DOI: https://dx.doi.org/10.1021/acs.joc.0c01484] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32654483]

32. Chaudhari, S.S.; Akamanchi, K.G. A Mild, Chemoselective, Oxidative Method for Deoximation Using Dess- Martin Periodinane. Synthesis; 1999; 5, pp. 760-764. [DOI: https://dx.doi.org/10.1055/s-1999-3476]

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, pp. 1842-1845. [DOI: https://dx.doi.org/10.1021/ol400453b] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23540374]