Metal-free oxidative functionalization of C(sp³)–H of ketones and alcohols for the synthesis of isoquinolinonediones

Abstract

A metal-free alkyl radical induced addition/cyclization reaction of acrylamide has been developed. The process involved C(sp³)–H bond cleavage, alkylation of the double bond, and intramolecular cyclization, which provides a new method for the synthesis of 4-substituted isoquinoline-1,3(2H,4H)-dione derivatives. In addition, the product can be easily transformed into tetrahydrofuro[2,3-c]isoquinolin-5(2H)-one derivatives in moderate yield.

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Introduction

In recent years, direct C–C bond construction via selective C(sp³)–H bond functionalization has been proved to be an extremely important research topic because it can shorten synthetic steps, alleviate waste, and improve atom economy for the preparation of functionalized products.¹ Among which, great progress has been made on C(sp³)–H bond functionalization adjacent to heteroatoms, which can generate new bonds as well as embed new functional groups such as alcohol, ether, amide, and so on.² Transition-metal-catalyzed or metal-free functionalization of C(sp³)–H bonds followed by cross-coupling, cross-dehydrogenative-coupling (CDC), has been well developed by Li and other groups.³ However, the reaction proceeding via functionalization of C(sp³)–H bonds and radical addition is a more challenging task and not well studied until now, especially via metal-free conditions. For instance, in 2013, Duan group reported a metal-free oxidative hydroxyalkylarylation of activated alkenes by direct C(sp³)–H functionalization of alcohols for the synthesis of oxindoles.⁴ Later, a metal-free oxidative spirocyclization of hydroxymethylacrylamide with 1,3-dicarbonyl compounds for the construction of spirooxindoles has been discovered by the same group.⁵ In 2015, Han et al. reported a metal-free oxidative functionalization of C(sp³)–H bond adjacent to oxygen and radical addition to olefins, successively.⁶ At the same time, a cascade construction of C–C bonds by activation of inert C(sp³)–H bonds of cyclohexane has been developed by Zhu group.⁷

The isoquinolinedione skeletons are important building blocks, which have been found in plant alkaloids, natural products and pharmaceuticals.⁸ The introduction of new functional groups into such a structural motif may offer a good opportunity to discover more intriguing new bioactive molecules. Recently, our group and others successfully realized the synthesis of isoquinolinedione via a radical process, and benzoyl, alkyl, fluoroalkyl, perfluoroalkyl, trifluoromethyl, and methoxycarbonyl groups have been easily incorporated into the skeletons (Scheme 1a).⁹ However, more diversified functional groups were needed to enrich the platform and library of active isoquinolinedione molecules. In 2015, Pan and coworkers discovered a hydroxyalkylation-initiated radical cyclization of N-allylbenzamide for direct construction of isoquinolinone.^6a However, the reported conditions were not suitable for the synthesis of isoquinolinedione from alcohols. Herein, we disclose a new method to prepare isoquinolinedione derivatives, involving C(sp³)–H bond cleavage of ketones, alcohols and ethers, alkylation of the double bond, and intramolecular cyclization (Scheme 1b).

Scheme 1 Radical-induced cyclization reaction for the synthesis of isoquinolinedione.

Results and discussion

Our hypothesis began with the reaction of N-methacryloyl-N-methylbenzamide 1a and acetone under various conditions, and the results are summarized in Table 1. Using 10% CH₃SO₃H as catalyst, 3 equiv. TBHP (5–6 M in decane) as oxidant, acetone as solvent, a 64% target product 3a was slightly obtained (Table 1, entry 1). 20% CH₃SO₃H as the catalyst gave a little lower yield. A worse result was observed using TsOH·H₂O as the catalyst. When 70% W TBHP (in water) was used as the oxidant, a poor yield was obtained (entry 4). Decreasing the oxidant loading to 2 equivalents, only a little product was detected (entry 5). No better result was achieved by using other acid catalysts such as PhCOOH and HOAc (entries 6 and 7). It should be noted that no product was detected in the absence of acid (entry 8). It is worth mentioning that 5 mmol of 1a also performed well, and a 58% yield of 3a was obtained, thus proving the effectiveness of our protocol (entry 9).

Table 1 Optimization of reaction conditions for 3a^a

Entry	Catalyst (%)	Oxidant	Yield^b
a Reaction conditions: 1a (0.3 mmol), TBHP (5–6 M in decane), and solvent (3.0 mL), 12 h.b Isolated yield.c N.R. = no reaction.d 5 mmol 1a was used in 5 mL acetone, 24 h.
1	10% CH3SO3H	3.0 equiv. TBHP (5–6 M in decane)	64%
2	20% CH3SO3H	3.0 equiv. TBHP (5–6 M in decane)	56%
3	10% TsOH·H2O	3.0 equiv. TBHP (5–6 M in decane)	45%
4	10% CH3SO3H	3.0 equiv. TBHP (70% W in water)	30%
5	10% CH3SO3H	2.0 equiv. TBHP (5–6 M in decane)	<5%
6	10% PhCOOH	3.0 equiv. TBHP (5–6 M in decane)	N.R.^c
7	10% HOAc	3.0 equiv. TBHP (5–6 M in decane)	50%
8	—	3.0 equiv. TBHP (5–6 M in decane)	N.R.
9^d	10% CH3SO3H	3.0 equiv. TBHP (5–6 M in decane)	58%

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With the optimized conditions in hand (Table 1, entry 1), we next set out to explore the substrate scope and the limitations of the C(sp³)–H bond cleavage, radical addition/cyclization reactions (Scheme 2). Firstly, other ketones such as butan-2-one and pentan-3-one were tolerated in the standard conditions, giving moderate yields of the products 3b and 3c. Then, the effect of various substitution patterns on the aryl moiety was investigated including fluoro, chloro, bromo, methoxyl, trifluoromethyl and methyl substituents, and the corresponding products were obtained in moderate to good yields. When the substituent methyl was substituted in the meta position, a single product was observed, and the product 3j can be separated in 61%. An ortho-substituted N-methacryloyl-N-methylbenzamide with methyl group was also tried, and the desired product 3k was obtained in moderate yield. It was found that N-protecting groups, such as ethyl, isopropyl, n-propyl, n-butyl and phenyl, could be used as effective substituent groups for this transformation, and moderate to good yields were observed (3l–3p). To our delight, acetophenone was also tolerated in this transformation, and a 25% yield of 3q was obtained. In addition, cyclic ketone such as cyclohexanone can deliver the target product 3r in 32% yield.

Scheme 2 Scope of acid-catalyzed cascade radical addition/cyclization.

Then, we turn our attentions to alcohols, and under metal-free conditions the alcohols can easily undergo C(sp³)–H bond cleavage, radical addition/cyclization reactions to give hydroxymethylacrylamide in moderate yields. A series of alcohols such as ethanol, propan-2-ol, butan-1-ol and ethane-1,2-diol can be transformed into 4-substituted isoquinoline-1,3(2H,4H)-dione derivatives (Scheme 3).

Scheme 3 Hydroxymethylation of N-methacryloyl-N-methylbenzamide.

When dioxane was used as solvent in this system, an ether-substituted isoquinoline-1,3(2H,4H)-dione 5a was synthesized using dicumyl peroxide (DCP) as the oxidant (Scheme 4). However, tetrahydrofuran (THF) failed in similar reaction conditions.

Scheme 4 Synthesis of ether-substituted isoquinoline-1,3(2H,4H)-dione.

To give insight into the mechanism of this transformation, inhibition experiment and kinetic experiment were conducted (Scheme 5). When 2.0 equiv. of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added into the reaction, the desired transformation was found to be completely inhibited, which shows that radical intermediates are involved in this transformation. In addition, the mixture of acetone and [D]-acetone was used as radical precursor to investigate the intermolecular competing kinetic isotope effect (KIE) experiment. The yield was 56% with a ratio of 1.1 : 1 (k_H : k_D), which meant that the cleavage of the C(sp³)–H bond was not the rate-determining steps in this transformation.

Scheme 5 Mechanism experiments.

On the basis of the above results and previous reports,¹⁰ a possible mechanism was proposed in Scheme 6. In the presence of a strong acid and TBHP, acetone can be easily transformed into ketone radical I. Then, radical I went through an intermolecular radical addition with acrylamides 1a to generate the intermediate II, following an intramolecular radical cyclization to give the intermediate III, which underwent oxidative dehydrogenation to afford the product 3a.

Scheme 6 Proposed mechanism.

Finally, the product 4a can be easily transformed into tetrahydrofuro[2,3-c]isoquinolin-5(2H)-one derivative 6a under reductive conditions. Reductive of 4a mediated by 1 equiv. of LiAlH₄ was found to proceed smoothly at ambient temperature, affording the product 6a in 60% yield (Scheme 7).

Scheme 7 Preparation of tetrahydrofuro[2,3-c]isoquinolin-5(2H)-one 5a.

Conclusions

In conclusion, we developed a metal-free cyclization reaction proceeding through cascade C(sp³)–H bond cleavage, alkylation of the double bond, and intramolecular cyclization. This alkyl radical-initiated radical cyclization reaction shows excellent functional group tolerance using ketones, alcohols and ethers as the precursor of radicals. This reaction provides a new method for the synthesis of 4-substituted isoquinoline-1,3(2H,4H)-dione derivatives with moderate to good yields. In addition, the product can be easily transformed into tetrahydrofuro[2,3-c]isoquinolin-5(2H)-one derivatives under reductive conditions.

Experimental

General remarks

Column chromatography was carried out on silica gel. Unless noted ¹H NMR spectra were recorded on 400 MHz in CDCl₃, ¹³C NMR spectra were recorded on 100 MHz in CDCl₃. IR spectra were recorded on an FT-IR spectrometer and only major peaks are reported in cm⁻¹. Melting points were determined on a microscopic apparatus and were uncorrected. All new products were further characterized by HRMS (high resolution mass spectra), high resolution mass spectrometry (HRMS) spectra was obtained on a Thermo Scientific LTQ Orbitrap XL instrument equipped with an ESI source; copies of their ¹H NMR and ¹³C NMR spectra are provided.

The procedure for the synthesis of product 3

An oven-dried Schlenk tube (10 mL) was equipped with a magnetic stir bar, N-methacryloyl-N-methylbenzamide (1, 0.3 mmol), 10% CH₃SO₃H (0.03 mmol, 2.0 μL), 3.0 equiv. TBHP (5–6 M in decane), acetone (3.0 mL). The reaction mixture was then stirred for 12 h at 60 °C. After the reaction, 6 mL water was added to quench the reaction, and the resulting mixture was extracted twice with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated. Purification of the crude product by flash column chromatography afforded the product 3 (petroleum ether/ethyl acetate as eluent (4 : 1)).

The procedure for the synthesis of product 4

An oven-dried Schlenk tube (10 mL) was equipped with a magnetic stir bar, N-methacryloyl-N-methylbenzamide (1, 0.3 mmol), 3.0 equiv. TBHP (5–6 M in decane), alcohol (3.0 mL). The reaction mixture was then stirred for 12 h at 60 °C. After the reaction, 6 mL water was added to quench the reaction, and the resulting mixture was extracted twice with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated. Purification of the crude product by flash column chromatography afforded the product 4 (petroleum ether/ethyl acetate as eluent (2 : 1)).

3a, m.p. = 63–64 °C, 2,4-dimethyl-4-(3-oxobutyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.25–8.27 (m, 1H), 7.63–7.68 (m, 1H), 7.42–7.48 (m, 2H), 3.39 (s, 3H), 2.47–2.54 (m, 1H), 2.17–2.25 (m, 2H), 1.99 (s, 3H), 1.84–1.91 (m, 1H), 1.64 (s, 3H); ¹³C NMR (100 MHz): 206.8, 176.1, 164.2, 142.8, 134.2, 128.9, 127.6, 125.1, 124.8, 46.8, 39.1, 35.8, 29.8, 29.4, 27.2, 26.4; IR (cm⁻¹): 2964, 1714, 1668, 1467, 1418, 1362, 1303, 1062, 768, 702; HRMS (ESI) m/z calcd for C₁₅H₁₈NO₃⁺ (M + H)⁺ 260.12812, found 260.12820.

3b, oil, 2,4-dimethyl-4-(3-oxopentyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.25–8.27 (m, 1H), 7.63–7.67 (m, 1H), 7.42–7.47 (m, 2H), 3.39 (s, 3H), 2.47–2.54 (m, 1H), 2.11–2.30 (m, 4H), 1.81–1.89 (m, 1H), 1.64 (s, 3H), 0.95 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz): 209.5, 176.2, 164.2, 142.8, 134.2, 128.9, 127.6, 125.2, 124.8, 46.9, 37.8, 35.9, 29.4, 27.2, 7.6; IR (cm⁻¹): 2976, 2939, 1714, 1668, 1466, 1417, 1363, 1301, 1112, 1051, 768, 702; HRMS (ESI) m/z calcd for C₁₆H₂₀NO₃⁺ (M + H)⁺ 274.14377, found 274.14398.

3c, m.p. = 70–72 °C, 2,4-dimethyl-4-(2-methyl-3-oxopentyl)-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.22–8.24 (m, 1H), 7.59–7.63 (m, 1H), 7.41–7.45 (m, 1H), 7.34–7.36 (m, 1H), 3.39 (s, 3H), 2.59–2.65 (m, 1H), 2.13–2.22 (m, 2H), 1.67–1.73 (m, 2H), 1.62 (s, 3H), 0.93 (d, J = 8.0 Hz, 3H), 0.70 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz): 213.4, 176.4, 164.2, 142.6, 133.9, 128.7, 127.5, 126.5, 124.6, 47.2, 45.1, 42.9, 34.6, 29.1, 27.2, 18.9, 7.4; IR (cm⁻¹): 2973, 2937, 1713, 1669, 1459, 1417, 1363, 1303, 767, 702; HRMS (ESI) m/z calcd for C₁₇H₂₂NO₃⁺ (M + H)⁺: 288.15942, found 288.15945.

3d, m.p. = 85–86 °C, 2,4,6-trimethyl-4-(3-oxobutyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.13–8.15 (d, J = 8.0 Hz, 1H), 7.25–7.30 (m, 1H), 7.21 (s, 1H), 3.38 (s, 3H), 2.45–2.49 (m, 1H), 2.44 (s, 3H), 2.14–2.26 (m, 2H), 2.00 (s, 3H), 1.84–1.94 (m, 1H), 1.63 (s, 3H); ¹³C NMR (100 MHz): 206.9, 176.2, 164.2, 145.2, 142.7, 128.9, 128.6, 125.5, 122.2, 46.6, 39.1, 35.8, 29.8, 29.3, 27.0, 21.9; IR (cm⁻¹): 2933, 1714, 1668, 1613, 1456, 1427, 1358, 1302, 1061, 779, 703; HRMS (ESI) m/z calcd for C₁₆H₂₀NO₃⁺ (M + H)⁺: 274.14377, found 274.14401.

3e, m.p. = 117–118 °C, 6-methoxy-2,4-dimethyl-4-(3-oxobutyl)-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.20–8.22 (m, 1H), 6.96–6.98 (m, 1H), 6.85–6.86 (m, 1H), 3.90 (s, 3H), 3.37 (s, 3H), 2.47–2.53 (m, 1H), 2.18–2.21 (m, 2H), 2.00 (s, 3H), 1.87–1.94 (m, 1H), 1.63 (s, 3H); ¹³C NMR (100 MHz): 206.9, 176.2, 164.3, 163.8, 145.0, 131.2, 117.7, 113.6, 110.0, 55.5, 47.0, 39.1, 35.8, 29.8, 29.5, 27.0; IR (cm⁻¹): 2974, 2941, 1711, 1668, 1607, 1359, 1249, 1168, 1063, 1033, 875, 777, 700; HRMS (ESI) m/z calcd for C₁₆H₂₀NO₄⁺ (M + H)⁺: 290.13868, found 290.13867.

3f, m.p. = 94–96 °C, 6-chloro-2,4-dimethyl-4-(3-oxobutyl)-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.19–8.22 (m, 1H), 7.41–7.45 (m, 1H), 7.40 (s, 1H), 3.38 (s, 3H), 2.47–2.52 (m, 1H), 2.14–2.19 (m, 2H), 2.02 (s, 3H), 1.90–1.93 (m, 1H), 1.64 (s, 3H); ¹³C NMR (100 MHz): 206.5, 175.4, 163.4, 144.6, 140.9, 130.6, 128.3, 125.4, 123.3, 46.8, 38.9, 35.9, 29.8, 29.7, 29.0, 27.3, 26.4; IR (cm⁻¹): 2971, 1714, 1669, 1597, 1427, 1356, 1305, 1061, 851, 777, 697; HRMS (ESI) m/z calcd for C₁₅H₁₇ClNO₃⁺ (M + H)⁺: 294.08915, found 294.08911.

3g, m.p. = 146–147 °C, 2,4-dimethyl-4-(3-oxobutyl)-6-(trifluoro-methyl)-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.39–8.41 (m, 1H), 7.70–7.72 (m, 1H), 7.67 (s, 1H), 3.40 (s, 3H), 2.46–2.51 (m, 1H), 2.13–2.21 (m, 2H), 2.01 (s, 3H), 1.90–1.93 (m, 1H), 1.67 (s, 3H); ¹³C NMR (100 MHz): 206.3, 175.2, 163.1, 143.7, 135.9, 135.6, 129.9, 124.5, 124.4, 122.3, 122.2, 121.9, 46.9, 38.9, 36.0, 29.8, 28.7, 27.4; IR (cm⁻¹): 2980, 1715, 1669, 1338, 1303, 1173, 1130, 1078, 702; HRMS (ESI) m/z calcd for C₁₆H₁₇F₃NO₃⁺ (M + H)⁺: 328.11550, found 328.11551.

3h, m.p. = 105–106 °C, 6-fluoro-2,4-dimethyl-4-(3-oxobutyl)-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.29–8.31 (m, 1H), 7.09–7.19 (m, 2H), 3.38 (s, 3H), 2.47–2.53 (m, 1H), 2.17–2.19 (m, 2H), 2.02 (s, 3H), 1.89–1.91 (m, 1H), 1.64 (s, 3H); ¹³C NMR (100 MHz): 206.5, 175.6, 167.7, 165.2, 163.2, 145.9, 132.1, 131.9, 121.2, 115.7, 115.5, 112.2, 111.9, 47.0, 38.9, 35.8, 29.8, 29.1, 27.2, 26.3; IR (cm⁻¹): 2977, 1714, 1669, 1358, 1304, 1061, 778, 696; HRMS (ESI) m/z calcd for C₁₅H₁₇FNO₃⁺ (M + H)⁺: 278.11870, found 278.11868.

3i, m.p. = 84–86 °C, 6-bromo-2,4-dimethyl-4-(3-oxobutyl)-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.11–8.13 (m, 1H), 7.59–7.61 (m, 1H), 7.57 (s, 1H), 3.38 (s, 3H), 2.46–2.52 (m, 1H), 2.17–2.20 (m, 2H), 2.03 (s, 3H), 1.90–1.93 (m, 1H), 1.64 (s, 3H); ¹³C NMR (100 MHz): 206.5, 175.3, 163.5, 144.6, 131.2, 130.6, 129.6, 128.4, 123.7, 46.8, 38.9, 35.9, 29.8, 29.0, 27.3; IR (cm⁻¹): 2980, 2933, 1715, 1667, 1592, 1426, 1355, 1318, 1299, 1062, 778, 697; HRMS (ESI) m/z calcd for C₁₅H₁₇BrNO₃⁺ (M + H)⁺: 338.03863, found 338.03879.

3j, m.p. = 74–76 °C, 2,4,7-trimethyl-4-(3-oxobutyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.06 (s, 1H), 7.45–7.47 (m, 1H), 7.28–7.32 (m, 1H), 3.38 (s, 3H), 2.45–2.48 (m, 1H), 2.43 (s, 3H), 2.12–2.24 (m, 2H), 1.99 (s, 3H), 1.83–1.90 (m, 1H), 1.61 (s, 3H); ¹³C NMR (100 MHz): 206.9, 176.3, 164.4, 139.8, 137.5, 135.3, 128.9, 125.1, 124.6, 46.5, 39.1, 35.7, 29.8, 29.4, 27.1, 20.9; IR (cm⁻¹): 2972, 2933, 1714, 1668, 1433, 1357, 1304, 1165, 1060, 831, 787; HRMS (ESI) m/z calcd for C₁₆H₂₀NO₃⁺ (M + H)⁺: 274.14377, found 274.14383.

3k, m.p. = 65–66 °C, 2,4,8-trimethyl-4-(3-oxobutyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 7.47–7.51 (m, 1H), 7.24–7.31 (m, 2H), 3.36 (s, 3H), 2.79 (s, 3H), 2.47–2.52 (m, 1H), 2.18–2.24 (m, 2H), 2.01 (s, 3H), 1.88–1.93 (m, 1H), 1.63 (s, 3H); ¹³C NMR (100 MHz): 207.0, 175.8, 164.7, 144.0, 142.6, 133.0, 131.5, 123.3, 123.2, 46.8, 39.2, 35.9, 29.9, 29.7, 27.2, 22.9; IR (cm⁻¹): 2971, 2931, 1712, 1667, 1595, 1433, 1358, 1316, 1288, 1064, 793, 705; HRMS (ESI) m/z calcd for C₁₆H₂₀NO₃⁺ (M + H)⁺: 274.14377, found 274.14389.

3l, oil, 2-ethyl-4-methyl-4-(3-oxobutyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.25–8.27 (m, 1H), 7.63–7.67 (m, 1H), 7.41–7.48 (m, 2H), 4.05–4.10 (m, 2H), 2.48–2.54 (m, 1H), 2.15–2.25 (m, 2H), 1.90 (s, 3H), 1.83–1.87 (m, 1H), 1.63 (s, 3H), 1.24 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz): 206.8, 175.6, 163.6, 142.8, 134.1, 128.9, 127.5, 125.1, 125.0, 46.6, 39.0, 35.6, 29.8, 29.3, 13.2; IR (cm⁻¹): 2976, 2932, 1713, 1665, 1605, 1453, 1356, 1252, 1161, 1082, 891, 766, 703; HRMS (ESI) m/z calcd for C₁₆H₂₀NO₃⁺ (M + H)⁺: 274.14377, found 274.14386.

3m, oil, 2-isopropyl-4-methyl-4-(3-oxobutyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.22–8.25 (m, 1H), 7.60–7.64 (m, 1H), 7.38–7.46 (m, 2H), 5.17–5.24 (m, 1H), 2.44–2.50 (m, 1H), 2.20–2.25 (m, 2H), 2.01 (s, 3H), 1.88–1.94 (m, 1H), 1.61 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H); ¹³C NMR (100 MHz): 206.8, 176.1, 164.2, 142.6, 133.9, 129.0, 127.5, 125.6, 124.9, 47.0, 45.6, 39.0, 35.5, 29.1, 26.4, 19.7; IR (cm⁻¹): 2973, 2935, 1713, 1665, 1355, 1254, 1164, 1087, 766, 703; HRMS (ESI) m/z calcd for C₁₇H₂₂NO₃⁺ (M + H)⁺: 288.15942, found 288.15948.

3n, m.p. = 51–53 °C, 4-methyl-4-(3-oxobutyl)-2-propyl-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.25–8.27 (m, 1H), 7.63–7.67 (m, 1H), 7.41–7.48 (m, 2H), 3.96–4.00 (m, 2H), 2.48–2.55 (m, 1H), 2.18–2.25 (m, 2H), 2.00 (s, 3H), 1.82–1.91 (m, 1H), 1.61–1.69 (m, 2H), 1.60 (s, 3H), 0.97 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz): 206.8, 175.8, 163.9, 142.7, 134.2, 128.9, 127.5, 125.1, 46.7, 41.9, 39.0, 35.5, 29.8, 29.5, 26.4, 21.2, 11.4; IR (cm⁻¹): 2967, 2933, 1712, 1668, 1358, 1235, 1088, 768, 705; HRMS (ESI) m/z calcd for C₁₇H₂₂NO₃⁺ (M + H)⁺: 288.15942, found 288.15936.

3o, oil, 2-butyl-4-methyl-4-(3-oxobutyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.25–8.27 (m, 1H), 7.63–7.67 (m, 1H), 7.41–7.48 (m, 2H), 3.99–4.03 (m, 2H), 2.48–2.54 (m, 1H), 2.18–2.25 (m, 2H), 2.00 (s, 3H), 184–1.91 (m, 1H), 1.63 (s, 3H), 1.57–1.61 (m, 2H), 1.37–1.42 (m, 2H), 0.97 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz): 206.8, 175.7, 163.8, 142.7, 134.1, 128.9, 127.5, 125.1, 124.9, 46.7, 40.3, 39.1, 35.6, 29.8, 29.5, 20.2, 13.7; IR (cm⁻¹): 2961, 2935, 1714, 1668, 1359, 1112, 1094, 769, 704; HRMS (ESI) m/z calcd for C₁₈H₂₄NO₃⁺ (M + H)⁺: 302.17507, found 302.17508.

3p, m.p. = 110–112 °C, 4-methyl-4-(3-oxobutyl)-2-phenyl-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.26–8.28 (m, 1H), 7.67–7.71 (m, 1H), 7.41–7.50 (m, 5H), 7.17–7.19 (m, 2H), 2.49–2.51 (m, 1H), 2.31–2.37 (m, 2H), 2.03–2.12 (m, 1H), 2.01 (s, 3H), 1.72 (s, 3H); ¹³C NMR (100 MHz): 206.8, 175.9, 164.0, 142.9, 135.3, 134.5, 129.3, 129.2, 128.6, 128.3, 127.7, 125.2, 124.9, 47.3, 39.1, 35.6, 29.8, 29.3; IR (cm⁻¹): 2980, 1715, 1669, 1431, 1338, 1303, 1173, 1078, 702; HRMS (ESI) m/z calcd for C₂₀H₂₀NO₃⁺ (M + H)⁺: 322.14377, found 322.14374.

3q, oil, 2,4-dimethyl-4-(3-oxo-3-phenylpropyl)isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.28–8.30 (m, 1H), 7.76–7.78 (m, 2H), 7.65–7.69 (m, 1H), 7.38–7.54 (m, 5H), 3.43 (s, 3H), 2.68–2.78 (m, 2H), 2.36–2.46 (m, 2H), 1.69 (s, 3H); ¹³C NMR (100 MHz): 198.4, 176.2, 164.3, 142.8, 133.1, 129.0, 128.5, 127.9, 127.6, 125.1, 124.8, 47.1, 36.1, 34.1, 29.8, 27.2; IR (cm⁻¹): 3066, 2954, 1710, 1669, 1602, 1417, 1362, 1299, 1057, 763; HRMS (ESI) m/z calcd for C₂₀H₂₀NO₃⁺ (M + H)⁺: 322.14377, found 322.14377.

3r, oil, dr = 1 : 1, 2,4-dimethyl-4-((2-oxocyclohexyl)methyl)-isoquinoline-1,3(2H,4H)-dione, isomor (low polarity), ¹H NMR (400 MHz): 8.24–8.26 (m, 1H), 7.60–7.64 (m, 1H), 7.41–7.45 (m, 2H), 3.38 (s, 3H), 2.77–2.82 (m, 1H), 2.25–2.28 (m, 1H), 2.02–2.08 (m, 2H), 1.91–1.96 (m, 2H), 1.74–1.78 (m, 2H), 1.62 (s, 3H), 1.40–1.45 (m, 1H), 1.26–1.36 (m, 2H); ¹³C NMR (100 MHz): 210.9, 176.4, 164.2, 142.9, 133.9, 128.8, 127.4, 125.7, 124.5, 47.5, 46.4, 40.2, 34.6, 30.1, 27.6, 27.2, 25.1; isomor (high polarity), ¹H NMR (400 MHz): 8.25–8.27 (m, 1H), 7.62–7.66 (m, 1H), 7.42–7.46 (m, 2H), 3.38 (s, 3H), 2.96–3.00 (m, 1H), 2.34–2.39 (m, 1H), 2.09–2.17 (m, 2H), 1.85–1.89 (m, 1H), 1.66–1.73 (m, 2H), 1.61 (s, 3H), 1.43–1.57 (m, 3H), 1.29–1.34 (m, 1H); ¹³C NMR (100 MHz): 211.9, 176.1, 164.3, 143.6, 133.7, 128.9, 127.3, 125.4, 124.7, 47.5, 46.4, 41.2, 35.2, 29.5, 27.7, 27.1, 24.2; IR (cm⁻¹): 2936, 2863, 1710, 1667, 1470, 1419, 1363, 1301, 1096; HRMS (ESI) m/z calcd for C₁₈H₂₂NO₃⁺ (M + H)⁺: 300.15942, found 300.15942.

4a, m.p. = 115–117 °C, 4-(2-hydroxy-2-methylpropyl)-2,4-dimethyl-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.26–8.28 (m, 1H), 7.59–7.61 (m, 1H), 7.41–7.47 (m, 2H), 3.37 (s, 3H), 2.76–2.80 (m, 1H), 2.25–2.28 (m, 1H), 1.59 (s, 3H), 1.12 (s, 3H), 0.56 (s, 3H); ¹³C NMR (100 MHz): 177.4, 164.3, 143.7, 133.2, 128.9, 127.3, 126.2, 124.7, 70.6, 54.1, 45.2, 32.9, 32.4, 29.3, 27.2; IR (cm⁻¹): 3497, 2971, 1710, 1665, 1468, 1419, 1368, 1319, 1057, 776, 761, 703; HRMS (ESI) m/z calcd for C₁₅H₂₀NO₃⁺ (M + H)⁺: 262.14377, found 262.14383.

4b, m.p. = 86–88 °C, 4-(2-hydroxypropyl)-2,4-dimethyl-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.23–8.25 (m, 1H), 7.62–7.66 (m, 1H), 7.41–7.49 (m, 2H), 3.69–3.74 (m, 1H), 3.39 (s, 3H), 2.35–2.39 (m, 1H), 2.11–2.17 (m, 1H), 1.65 (s, 3H), 1.03 (d, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz): 177.0, 164.3, 144.1, 133.8, 133.6, 128.9, 127.3, 127.2, 125.6, 125.3, 124.3, 65.6, 51.5, 46.2, 29.3, 27.2, 24.3; IR (cm⁻¹): 3501, 2970, 2930, 1712, 1661, 1468, 1418, 1365, 1308, 1095, 770, 703; HRMS (ESI) m/z calcd for C₁₄H₁₈NO₃⁺ (M + H)⁺: 248.12867, found 248.12871.

4c, dr = 2 : 1, oil, 4-(2-hydroxypentyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.22–8.27 (m, 1H), 7.61–7.65 (m, 1H), 7.47–7.49 (m, 0.7H), 7.41–7.44 (m, 0.9H), 7.35–7.37 (m, 0.4H), 3.53 (s, 0.7H, OH), 3.39 (s, 2.0H), 3.35 (s, 1.0H), 2.56–2.62 (m, 0.4H), 2.34–2.38 (m, 0.7H), 2.06–2.12 (m, 1H), 1.75 (s, 1.0H), 1.66 (s, 2H), 1.60 (s, 1H), 0.80–0.85 (m, 3H); ¹³C NMR (100 MHz): 177.6, 177.0, 164.4, 144.3, 143.0, 133.7, 133.6, 128.9, 127.2, 125.6, 125.2, 124.3, 69.1, 68.8, 50.4, 49.2, 45.4, 40.4, 40.3, 29.7, 28.9, 27.2, 18.6, 18.5, 13.8; IR (cm⁻¹): 3508, 2968, 2873, 1713, 1665, 1462, 1418, 1365, 1304, 1102, 1055, 769, 702; HRMS (ESI) m/z calcd for C₁₆H₂₂NO₃⁺ (M + H)⁺: 276.15942, found 276.15948.

4d, dr = 6 : 5, oil, 4-(2,3-dihydroxypropyl)-2,4-dimethyl-isoquinoline-1,3(2H,4H)-dione, ¹H NMR (400 MHz): 8.21–8.25 (m, 1H), 7.63–7.67 (m, 1H), 7.48–7.50 (m, 0.6H), 7.42–7.46 (m, 1H), 7.37–7.38 (m, 0.5H), 3.54 (s, 0.6H), 3.37 (s, 2.2H), 3.32 (s, 1.6H), 3.17 (s, 0.7H), 3.08 (s, 0.5H), 2.48–2.64 (m, 2H), 2.35–2.42 (m, 1H), 2.13–2.18 (m, 0.8H), 1.64 (s, 1.7H), 1.61 (s, 1.5H); ¹³C NMR (100 MHz): 177.4, 177.2, 164.5, 164.3, 142.7, 133.9, 133.8, 129.0, 128.9, 127.4, 125.6, 125.3, 125.1, 124.2, 69.4, 69.2, 66.6, 66.2, 46.0, 45.2, 44.9, 44.8, 30.5, 29.9, 27.3; IR (cm⁻¹): 3473, 2935, 1707, 1657, 1461, 1421, 1308, 1106, 1055, 767, 735, 702; HRMS (ESI) m/z calcd for C₁₄H₁₈NO₄⁺ (M + H)⁺: 264.12303, found 264.12311.

5a, m.p. = 72–74 °C 4-((1,4-dioxan-2-yl)methyl)-2,4-dimethyl-isoquinoline-1,3(2H,4H)-dione, dr = 1 : 1, ¹H NMR (400 MHz): 8.23–8.30 (m, 1H), 7.63–7.66 (m, 1H), 7.37–7.63 (m, 2H), 3.31–3.41 (m, 2H), 3.23–3.28 (m, 4.5H), 3.06–3.19 (m, 2.5H), 2.81–2.87 (m, 0.5H), 2.50–2.57 (m, 0.5H), 2.27–2.33 (m, 0.5H), 2.06–2.12 (m, 0.5H), 1.80–1.84 (m, 0.5H), 1.63–1.65 (m, 3H), 1.29–1.34 (m, 0.5H); ¹³C NMR (100 MHz): 176.5, 176.3, 164.4, 160.8, 143.4, 142.4, 133.6, 128.8, 127.4, 127.3, 125.6, 125.3, 125.2, 124.5, 70.4, 66.3, 66.0, 45.8, 44.6, 44.2, 43.9, 29.7, 29.4, 27.2, 27.1; IR (cm⁻¹): 2957, 2856, 1714, 1667, 1470, 1419, 1363, 1303, 1121, 1062, 769, 702.

Acknowledgements

We thank the National Science Foundation of China NSF 21402066, Natural Science Foundation of Jiangsu Province (BK20140139) and the Fundamental Research Funds for the Central Universities (JUSRP11419) for financial support. Financial support from MOE&SAFEA for the 111 project (B13025) is also gratefully acknowledged.

Notes and references

1. For selected reviews on C–H bond functionalization, see: (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (b) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780; (c) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111, 1293.
2. For selected recent examples of C(sp³)–H bond activation adjacent to heteroatoms, see: (a) X.-F. Xia, X.-Z. Shu, K.-G. Ji, Y.-F. Yang, A. Shaukat, X.-Y. Liu and Y.-M. Liang, J. Org. Chem., 2010, 75, 2893; (b) D. Liu, C. Liu, H. Li and A. Lei, Chem. Commun., 2014, 50, 3623; (c) J. C. Zhao, H. Fang, W. Zhou, J. L. Han and Y. Pan, J. Org. Chem., 2014, 79, 3847; (d) Z. J. Li, F. H. Fan, J. Yang and Z. Q. Liu, Org. Lett., 2014, 16, 3396; (e) W. T. Wei, M. B. Zhou, J. H. Fan, W. Liu, R. J. Song, Y. Liu, M. Hu, P. Xie and J. H. Li, Angew. Chem., Int. Ed., 2013, 52, 3638; (f) S. R. Guo, Y. Q. Yuan and J. N. Xiang, Org. Lett., 2013, 15, 4654; (g) D. Liu, C. Liu, H. Li and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 4453; (h) R.-Y. Tang, Y.-X. Xie, Y.-L. Xie, J.-N. Xiang and J.-H. Li, Chem. Commun., 2011, 47, 12867; (i) L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu and X. Wan, Chem.–Eur. J., 2011, 17, 4085; (j) N. Y. P. Kumar, R. Jeyachandran and L. Ackermann, J. Org. Chem., 2013, 78, 4145; (k) B. Du, B. Jin and P. Sun, Org. Lett., 2014, 16, 3032; (l) Q. Xia and W. Chen, J. Org. Chem., 2012, 77, 9366.
3. (a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (b) C.-J. Li, Chem. Rev., 2005, 105, 3095; (c) S. R. Chemler and P. H. Fuller, Chem. Soc. Rev., 2007, 36, 1153; (d) S.-I. Murahashi and D. Zhang, Chem. Soc. Rev., 2008, 37, 1490.
4. Y. Meng, L. N. Guo, H. Wang and X. H. Duan, Chem. Commun., 2013, 49, 7540.
5. H. Wang, L. N. Guo and X. H. Duan, Org. Lett., 2013, 15, 5254.
6. (a) W. Zhou, S. Ni, H. Mei, J. Han and Y. Pan, Org. Lett., 2015, 17, 2724; (b) W. Zhou, P. Qian, J. Zhao, H. Fang, J. Han and Y. Pan, Org. Lett., 2015, 17, 1160.
7. (a) H. Zhang, C. Pan, N. Jin, Z. Gu, H. Hua and C. Zhu, Chem. Commun., 2015, 51, 1320; (b) H. Zhang, Z. Gu, P. Xu, H. Hu, Y. Cheng and C. Zhu, Chem. Commun., 2016, 52, 477.
8. (a) M. Komoda, H. Kakuta, H. Takahashi, Y. Fujimoto, S. Kadoya, K. Kato and Y. Hashimoto, Bioorg. Med. Chem., 2001, 9, 121; (b) Y.-L. Chen, J. Tang, M. J. Kesler, Y. Y. Sham, R. Vince, R. J. Geraghty and Z. Wang, Bioorg. Med. Chem., 2012, 20, 467; (c) S. C. Mayer, A. L. Banker, F. Boschelli, L. Di, M. Johnson, C. H. Kenny, G. Krishnamurthy, K. Kutterer, F. Moy, S. Petusky, M. Ravi, D. Tkach, H. R. Tsou and W. Xu, Bioorg. Med. Chem. Lett., 2008, 18, 3641; (d) M. Billamboz, F. Bailly, C. Lion, N. Touati, H. Vezin, C. Calmels, M. L. Andréola, F. Christ, Z. Debyser and P. Cotelle, J. Med. Chem., 2011, 54, 1812; (e) M. Billamboz, F. Bailly, M. L. Barreca, L. De Luca, J. F. Mouscadet, C. Calmels, M. L. Andréola, M. Witvrouw, F. Christ, Z. Debyser and P. Cotelle, J. Med. Chem., 2008, 51, 7717; (f) S. K. V. Vernekar, Z. Liu, E. Nagy, L. Miller, K. A. Kirby, D. J. Wilson, J. Kankanala, S. T. Sarafianos, M. A. Parniak and Z. Wang, J. Med. Chem., 2015, 58, 651.
9. (a) X.-F. Xia, S.-L. Zhu, C. Chen, H. Wang and Y.-M. Liang, J. Org. Chem., 2016, 81, 1277; (b) L. Zheng, C. Yang, Z. Xu, F. Gao and W. Xia, J. Org. Chem., 2015, 80, 5730; (c) S. Tang, Y.-L. Deng, J. Li, W.-X. Wang, G.-L. Ding, M.-W. Wang, Z.-P. Xiao, Y.-C. Wang and R.-L. Sheng, J. Org. Chem., 2015, 80, 12599; (d) Y. Tang, M. Zhang, X. Li, X. Xu and X. Du, Chin. J. Org. Chem., 2015, 35, 875; (e) S. Tang, Y.-L. Deng, J. Li, W.-X. Wang, Y.-C. Wang, Z.-Z. Li, L. Yuan, S.-L. Chen and R.-L. Sheng, Chem. Commun., 2016, 52, 4470.
10. (a) X.-Q. Chu, H. Meng, Y. Zi, X.-P. Xu and S.-J. Ji, Chem.–Eur. J., 2014, 20, 17198; (b) B. Schweitzer-Chaput, J. Demaerel, H. Engler and M. Klussmann, Angew. Chem., Int. Ed., 2014, 53, 8737; (c) X.-F. Xia, S.-L. Zhu, M. Zeng, Z. Gu, H. Wang and W. Li, Tetrahedron, 2015, 71, 6099.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra12657j

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