Copper-catalyzed cross-dehydrogenative coupling between quinazoline-3-oxides and indoles

Abstract

A novel and simple protocol for the synthesis of 4-(indole-3-yl)quinazolines via cross-dehydrogenative coupling of quinazoline-3-oxides and indoles under an air atmosphere has been developed. A series of biheteroaryl products were obtained in moderate to good yields.

---

Introduction

The nitrogen-containing heterocycles occupy an important position in pharmaceuticals and natural products.¹ Futhermore, they exhibit remarkable biological activities, such as anticancer, antileukemic, antiviral, and antifungal properties.² The complexity and diversity of N-heterocycles have been employed broadly in the studies of advanced materials and ligands for transition metal catalysis.³ Among reported studies, quinazoline⁴ and indole⁵ derivatives are useful nitrogen-containing heterocyclic compounds, and are core structural motifs of many natural products and pharmaceuticals. Thus heterocyclic compounds bearing these two skeletons most likely possess interesting biological and physicochemical properties.⁶ For example, indoloquinazoline derivatives have been reported to be protein kinase CK2 inhibitors^6a and poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.^6b 4-(Indole-3-yl)quinazolines have been reported to be potent epidermal growth factor receptor tyrosine kinase inhibitors.^6c

Over the past decade, substantial effort has been devoted to the development of reaction conditions for the coupling between quinazoline and indole compounds.⁷ One elegant methodology relies on the nucleophilic substitution of quinazoline chlorides or their analogous with indoles. However, this method cannot be widely employed due to the need for harsh reaction conditions and/or operationally complex protocols. For instance, the substitution reaction between 2,4-dichloroquinazolines and indoles relies on 1.2 equiv. of AlCl₃ (Scheme 1a).^7a Additionally, the reaction of quinazoline with indole required Brønsted acid mediator, followed by photocatalyzed aromatization to give the corresponding 4-(indol-3-yl)-quinazoline product in 70% yield (Scheme 1b).^7d

Scheme 1 Typical strategies for the synthesis of 4-(indole-3-yl)quinazolines.

On the other hand, we have noticed that cross-dehydrogenative-coupling (CDC) reactions⁸ have emerged as an excellent alternative for the formation of C–C bonds. Furthermore, the N-oxide moiety in aza-heteroarene compounds has been recognized as a powerful and removable directing group for ortho C–H bond activation.⁹ In the past decade, pyridine N-oxides,¹⁰ pyrimidine N-oxides,¹¹ quinoline N-oxides and isoquinoline N-oxides¹² have been extensively employed as useful building block for the preparation of a diverse range of N-heterocycles. However, the C4–H functionalization of quinazoline N-oxides remains rare.¹³ Therefore, the development of a general and practical strategy for the synthesis of 4-(indole-3-yl)quinazolines via CDC reactions of quinazoline N-oxides and indoles under mild conditions, is highly desired. Recently, our group has directed its studies to that of the structural elaboration of quinazoline core, with the aim of constructing a quinazoline-based molecular library for bioactivity assays.¹⁴ Herein, we report a copper-catalyzed CDC reaction between the Csp²–H of quinazoline-3-oxide and the Csp²–H of various indoles for the synthesis of biheteroaryl structures using a mild and operationally simple procedure (Scheme 1c).

Results and discussion

We initiated our investigation on the model reaction of quinazoline-3-oxide (1a) with N-methyl-indole (2a) in order to optimize the reaction parameters (Table 1). First, the reaction was performed in the presence of 20 mol% CuCl₂ at 60 °C in toluene (Entry 1). To our delight, the desired product 3a was isolated in a moderate yield of 47%. Encouraged by this preliminary result, we then screened various solvents. The desired product was obtained in moderate or low yields when the reaction was carried out in THF, CH₃CN and DMF (Entries 2–4). Further studies showed that CH₃OH was the best solvent for this transformation, affording the desired product 3a in 77% yield (Entry 7). Incrementally reducing the catalyst loading from 20 to 5 mol%, showed that 10 mol% catalyst was the optimal amount (Entries 7–9). No transformation took place in the absence of metal catalyst in CH₃OH (Entry 10). Next, further screening of other metal salts was conducted, but no better conditions were discovered (Entries 11–15). Several copper salts were utilized to promote the reaction (Entries 16–20); however, it was found that copper(II) chloride was the most effective. No better result was obtained even at a higher or lower reaction temperature (Entries 21 and 22).

Table 1 Screening of the reaction condition^a,b

Entry	Solvent	Catalyst	T/°C	Yield^c/%
a Optimized conditions are denoted in bold.b Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst, solvent (2.0 mL), 16 h, under air.c Isolated yield.
1	Toluene	CuCl2 (20 mol%)	60	47
2	THF	CuCl2 (20 mol%)	60	57
3	CH3CN	CuCl2 (20 mol%)	60	40
4	DMF	CuCl2 (20 mol%)	60	32
5	PhCl	CuCl2 (20 mol%)	60	70
6	DCE	CuCl2 (20 mol%)	60	75
7	CH3OH	CuCl2 (20 mol%)	60	77
8	CH3OH	CuCl2 (10 mol%)	60	78
9	CH3OH	CuCl2 (5 mol%)	60	67
10	CH3OH	—	60	ND
11	CH3OH	In(OTf)3 (10 mol%)	60	Trace
12	CH3OH	FeCl2 (10 mol%)	60	37
13	CH3OH	FeCl3 (10 mol%)	60	40
14	CH3OH	CoCl2 (10 mol%)	60	20
15	CH3OH	Ni(OTf)2 (10 mol%)	60	17
16	CH3OH	Cu(OTf)2 (10 mol%)	60	73
17	CH3OH	Cu(acac)2 (10 mol%)	60	Trace
18	CH3OH	CuCl (10 mol%)	60	62
19	CH3OH	CuBr (10 mol%)	60	73
20	CH3OH	Cu(OAc)2 (10 mol%)	60	40
21	CH3OH	CuCl2 (10 mol%)	80	53
22	CH3OH	CuCl2 (10 mol%)	40	50

---

Under the optimized reaction conditions, the reaction scope was explored, and the results of which are shown in Table 2. The CDC reaction of quinazoline-3-oxides 1 and N-methylindole 2a occurred smoothly to generate the desired products 3 in good yields. When R² was an aryl group, both electron-donating and electron-withdrawing substituents on the aryl ring had a slight effect on the reaction (3aa–3ka), albeit strongly electron-withdrawing substituents, such as the nitro group, greatly retarded the reaction, forming 3ja in 61% yield. It was observed that an R² aliphatic substituent was also tolerated to give the corresponding product 3la in 72% yield. When the parent quinazoline ring (R² = H) was used, the desired product 3ma was obtained in 68% yield. Subsequently, R¹ substituents on the phenyl ring moiety of the quinazoline 3-oxide were investigated. Methyl, methoxy, trifluoromethyl, chloro and bromo functionalities were all tolerated, providing the desired products 3na–3ra in 52–84% yields.

Table 2 The reaction of quinazoline-3-oxide 1 with 1-methylindole^a

a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), CuCl₂ (10 mol%), CH₃OH (2.0 mL), 60 °C, under air.b Isolated yield.

---

Subsequently, the indole scope was examined under the optimized reaction conditions. As shown in Table 3, quinazoline-3-oxide underwent smooth coupling with a variety of substituted indoles. N-Methylindoles possessing alkyl, halide, and alkoxy substituents at the 5-position are amenable to the reaction conditions (3ab–3af), and the expected products were isolated in moderate to good yields. The coupled products were isolated in high yields for N-iPr and N-Bn substrates (3ag and 3ah). To our surprise, indole itself also proved to be a good coupling partner, providing the corresponding product (3ai) in 83% yield. Single-crystal X-ray analysis of 3ai confirmed its structure and demonstrated the high regioselectivity of the reaction (Fig. 1). In contrast, no desired coupling product was observed for 3-methylindole, which is consistent with selectivity for the C–H activation at the 3-position of the indole (this result is not shown in Table 3). When a CH₃ group is present at the 2-position of the indole, the steric hindrance arising from this substituent influences the reaction; the cross-coupling product 3aj was obtained in lower yield. However, indoles containing electron-withdrawing N-protecting groups, for example, N-tosyl-indole, were not amenable to this transformation, and none of the desired product (3ak) was isolated.

Table 3 The reaction of quinazoline-3-oxide 1a with various indoles 2^a

a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), CuCl₂ (10 mol%), CH₃OH (2.0 mL), 60 °C, under air.b Isolated yield.

---

Fig. 1 X-ray ORTEP illustration of compound 3ai.

The coupled quinazoline-3-oxides products were easily deoxygenated to give the corresponding 4-(indole-3-yl)quinazolines. For example, when 3aa was treated with PCl₃ (rt, 30 min), clean reduction occurred and 4a was obtained in 86% yield (Scheme 2).¹⁵ The combination of the described C–H/C–H cross-dehydrogenative-coupling and subsequent reduction provides an attractive and simple procedure for the synthesis of indole-functionalized quinazoline derivatives.

Scheme 2 Deoxygenation reaction.

In order to further understand the mechanism of this copper-catalyzed reaction of quinazoline-3-oxide 1 with indole 2, three control experiments were conducted (Scheme 3). The desired product was obtained in 84% yield when the reaction was conducted under oxygen atmosphere (Scheme 3a). However, only a trace amount of product 3aa was obtained when the reaction was carried out under argon, which indicates that oxygen plays a crucial role in this transformation (Scheme 3b). When 1a was replaced by 2-(p-tolyl)quinazoline, the desired product was not obtained (Scheme 3c).

Scheme 3 Control experiments.

On the basis of these observations and related reports,¹⁶ we have proposed a plausible mechanism for this reaction, as shown in Scheme 4. The CuCl₂ reacts with quinazoline-3-oxide 1a to form intermediate A via C–H activation of 1a. Next, A undergoes an insertion into the 3-position of the C–H bond of 2a to afford B. Oxidation of B to Cu(III) complex C occurs via disproportionation with a second equivalent of CuCl₂, liberating CuCl.¹⁷ C undergoes reductive elimination to give the product 3aa together with Cu(I), which is reoxidized to CuCl₂ by O₂ and HCl, to complete the cycle.

Scheme 4 Plausible mechanism.

In conclusion, a novel, simple and efficient protocol for the synthesis of 4-(indole-3-yl)quinazolines via a cross-dehydrogenative coupling of quinazoline-3-oxides and indoles under an air atmosphere has been successfully developed. A series of biheteroaryl products were obtained in moderate to good yields. The unique reactivity and selectivity observed in the CDC reaction prompted us to initiate further studies on the reaction mechanism.

Experimental section

Unless otherwise stated, all commercial reagents were used as received. All solvents were dried and distilled according to standard procedures. Flash column chromatography was performed using silica gel (60 Å pore size, 32–63 mm, standard grade). Analytical thin-layer chromatography was performed using glass plates pre-coated with 0.25 mm 230–400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin layer chromatography plates were visualized by exposure to ultraviolet light. Organic solutions were concentrated on rotary evaporators at ∼20 torr at 25–35 °C. Nuclear magnetic resonance (NMR) spectra are recorded in parts per million from internal tetramethylsilane on the δ scale. ¹H and ¹³C NMR spectra were recorded in CDCl₃ on a Bruker DRX-400 spectrometer operating at 400 MHz and 100 MHz, respectively. All chemical shift values are quoted in ppm and coupling constants quoted in Hz.

General experimental procedure for synthesis of 3

The quinazoline-3-oxide (0.2 mmol), indole (0.3 mmol), CuCl₂ (0.02 mmol) and 2.0 mL CH₃OH were mixed in a dry reaction tube. The mixture was stirred at 60 °C under air for 12–16 hours. After completion of the reaction (monitored by TLC), the mixture was concentrated in vacuum and the residue was purified by flash column chromatography on silica gel with petroleum ether–ethyl acetate as eluent to give the desired product.

4-(1-Methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3aa). Compound was obtained as a yellow solid: yield 78%; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 8.22 (d, J = 8.0 Hz, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.69 (td, J = 7.6, 1.2 Hz, 1H), 7.52–7.40 (m, 3H), 7.36–7.27 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 3.94 (s, 3H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.7, 147.1, 141.2, 140.7, 136.7, 135.5, 130.6, 130.5, 130.3, 128.7, 128.6, 128.0, 127.6, 126.5, 123.1, 122.5, 121.7, 121.0, 110.0, 102.6, 33.6, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₂₀N₃O: 366.1606, found 366.1609.

4-(1-Methyl-1H-indol-3-yl)-2-(m-tolyl)quinazoline 3-oxide (3ba). Compound was obtained as a yellow solid: yield 87%; ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 8.12–7.85 (m, 3H), 7.95 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.54–7.36 (m, 4H), 7.35–7.28 (m, 2H), 7.18 (t, J = 7.2 Hz, 1H), 3.95 (s, 3H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 156.0, 147.1, 141.2, 137.5, 136.7, 135.6, 133.3, 131.2, 130.65, 130.61, 128.8, 128.1, 127.9, 127.6, 127.4, 126.6, 123.2, 122.5, 121.6, 121.0, 110.0, 102.5, 33.6, 21.5. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₂₀N₃O: 366.1606, found 366.1607.

4-(1-Methyl-1H-indol-3-yl)-2-(o-tolyl)quinazoline 3-oxide (3ca). Compound was obtained as a yellow solid: yield 71%; ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.11–8.02 (m, 2H), 7.74 (td, J = 7.2, 1.2 Hz, 1H), 7.59–7.53 (m, 2H), 7.51–7.43 (m, 2H), 7.43–7.37 (m, 1H), 7.37–7.30 (m, 3H), 7.20 (t, J = 7.6 Hz, 1H), 3.92 (s, 3H), 2.35 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 157.8, 146.7, 140.9, 137.1, 136.8, 136.3, 134.1, 130.7, 130.2, 129.6, 128.8, 128.8, 128.3, 127.6, 126.7, 125.8, 123.2, 122.6, 121.7, 121.1, 110.1, 102.4, 33.6, 19.7. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₂₀N₃O: 366.1606, found 366.1611.

2-(4-Methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)quinazoline 3-oxide (3da). Compound was obtained as a yellow solid: yield 87%; ¹H NMR (400 MHz, CDCl₃) δ 8.46–8.37 (m, 2H), 8.28 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.70 (td, J = 7.4, 1.2 Hz, 1H), 7.51–7.41 (m, 3H), 7.33 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.05–6.98 (m, 2H), 3.96 (s, 3H), 3.89 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.5, 155.1, 147.2, 141.3, 136.7, 135.3, 132.4, 130.6, 128.6, 127.8, 127.6, 126.5, 125.7, 123.0, 122.5, 121.7, 120.9, 113.3, 110.0, 102.7, 55.4, 33.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₂₀N₃O₂: 382.1556, found 382.1555.

2-(4-Fluorophenyl)-4-(1-methyl-1H-indol-3-yl)quinazoline 3-oxide (3ea). Compound was obtained as a yellow solid: yield 83%; ¹H NMR (400 MHz, CDCl₃) δ 8.45–8.35 (m, 2H), 8.30 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.49–7.41 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.23–7.14 (m, 3H), 3.97 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.2 (d, J = 249.2 Hz), 154.5, 141.2, 136.8, 135.5, 132.8 (d, J = 8.5 Hz), 129.4 (d, J = 3.3 Hz), 128.7, 128.2, 127.5, 126.6, 123.2, 122.6, 121.6, 121.1, 114.9 (d, J = 21.6 Hz), 110.1, 102.5, 33.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₃H₁₇FN₃O: 370.1356, found 370.1381.

2-(4-Chlorophenyl)-4-(1-methyl-1H-indol-3-yl)quinazoline 3-oxide (3fa). Compound was obtained as a yellow solid: yield 82%; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J = 8.4 Hz, 2H), 8.28 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.55–7.41 (m, 5H), 7.34 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 3.95 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 154.4, 147.5, 141.2, 136.8, 136.6, 135.5, 131.9, 131.7, 130.9, 128.8, 128.3, 128.1, 127.5, 126.6, 123.2, 122.6, 121.6, 121.1, 110.1, 102.4, 33.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₃H₁₇ClN₃O: 386.1060, found 386.1075, and 388.1031, found 388.1044.

2-(3-Chlorophenyl)-4-(1-methyl-1H-indol-3-yl)quinazoline 3-oxide (3ga). Compound was obtained as a yellow solid: yield 83%; ¹H NMR (400 MHz, CDCl₃) δ 8.35 (t, J = 1.6 Hz, 1H), 8.29 (s, 1H), 8.25–8.19 (m, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.56–7.40 (m, 5H), 7.33 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 3.95 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 154.1, 147.5, 141.1, 136.8, 135.5, 135.0, 133.9, 130.9, 130.5, 130.4, 129.1, 128.9, 128.6, 128.5, 127.5, 126.6, 123.3, 122.6, 121.6, 121.1, 110.1, 102.4, 33.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₃H₁₇ClN₃O: 386.1060, found 386.1075, and 388.1031, found 388.1045.

2-(4-Bromophenyl)-4-(1-methyl-1H-indol-3-yl)quinazoline 3-oxide 3-oxide (3ha). Compound was obtained as a yellow solid: yield 76%; ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.25 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.48–7.41 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 3.96 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 154.5, 147.5, 141.2, 136.8, 135.5, 132.2, 132.1, 131.1, 130.9, 128.8, 128.4, 127.5, 126.6, 125.1, 123.2, 122.6, 121.6, 121.1, 110.1, 102.4, 33.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₃H₁₇BrN₃O: 430.0555, found 430.0557, and 432.0535, found 432.0537.

4-(1-Methyl-1H-indol-3-yl)-2-(4-(trifluoromethyl)phenyl) quinazoline 3-oxide (3ia). Compound was obtained as a yellow solid: yield 93%; ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J = 8.0 Hz, 2H), 8.31 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.99 (dd, J = 8.4, 0.4 Hz, 1H), 7.77–7.73 (m, 3H), 7.55 (td, J = 7.8, 1.2 Hz, 1H), 7.46 (t, J = 8.8 Hz, 2H), 7.34 (td, J = 7.8, 1.2 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 3.96 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 154.2, 147.6, 141.2, 136.8, 135.7, 132.0 (q, J = 32.3 Hz), 131.0, 130.7, 128.9, 128.7, 127.4, 126.7, 124.8 (q, J = 3.8 Hz), 124.0 (q, J = 207.7 Hz), 123.4, 122.7, 121.6, 121.2, 110.1, 102.3, 33.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₁₇F₃N₃O: 420.1324, found 420.1324.

4-(1-Methyl-1H-indol-3-yl)-2-(4-nitrophenyl)quinazoline 3-oxide (3ja). Compound was obtained as a yellow solid: yield 61%; ¹H NMR (400 MHz, CDCl₃) δ 8.58–8.50 (m, 2H), 8.38–8.29 (m, 3H), 8.08 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.60–7.55 (m, 1H), 7.60–7.55 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.77 (td, J = 7.8, 1.2 Hz, 1H), 7.58 (td, J = 7.8, 1.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35 (td, J = 7.6, 1.0 Hz, 1H), 7.21 (td, J = 7.6, 1.0 Hz, 1H), 3.98 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 153.3, 148.7, 141.3, 139.4, 136.8, 135.7, 131.5, 131.3, 129.01, 128.99, 127.4, 126.8, 123.4, 122.9, 122.8, 121.5, 121.3, 110.2, 102.2, 33.7. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₃H₁₇N₄O₃: 397.1301, found 397.1276.

4-(1-Methyl-1H-indol-3-yl)-2-phenylquinazoline 3-oxide (3ka). Compound was obtained as a yellow solid: yield 79%; ¹H NMR (400 MHz, CDCl₃) δ 8.37–8.22 (m, 3H), 8.07 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.1 Hz, 1H), 7.58–7.41 (m, 6H), 7.34 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 3.95 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.7, 147.1, 141.2, 136.7, 135.6, 133.4, 130.6, 130.4, 130.3, 128.8, 128.1, 127.9, 127.6, 126.6, 123.2, 122.5, 121.6, 121.0, 110.0, 102.5, 33.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₃H₁₈N₃O: 352.1450, found 352.1437.

2-Ethyl-4-(1-methyl-1H-indol-3-yl)quinazoline 3-oxide (3la). Compound was obtained as a yellow solid: yield 72%; ¹H NMR (400 MHz, CDCl₃) δ 8.22 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.51–7.41 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 3.94 (s, 3H), 3.34 (q, J = 7.2 Hz, 2H), 1.53 (t, J = 7.2 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 161.3, 145.8, 140.7, 136.7, 135.1, 130.4, 1228.2, 127.5, 126.5, 122.8, 122.5, 121.6, 120.9, 110.0, 102.5, 33.5, 26.3, 10.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₈N₃O: 304.1450, found 304.1456.

4-(1-Methyl-1H-indol-3-yl)quinazoline 3-oxide (3ma). Compound was obtained as a yellow solid: yield 68%; ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.26 (s, 1H), 8.14–7.89 (m, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 3.94 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 148.6, 141.5, 136.8, 135.4, 130.8, 128.8, 128.7, 127.2, 126.8, 123.2, 122.7, 121.5, 121.1, 110.1, 101.7, 33.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₁₇H₁₄N₃O: 276.1137, found 276.1132.

7-Methyl-4-(1-methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3na). Compound was obtained as a yellow solid: yield 71%; ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 8.22 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.45 (dd, J = 8.6, 1.8 Hz, 2H), 7.35–7.27 (m, 4H), 7.18 (t, J = 7.6 Hz, 1H), 3.95 (s, 3H), 2.56 (s, 3H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.6, 147.1, 141.6, 141.5, 140.6, 136.7, 135.5, 130.6, 130.3, 130.1, 128.5, 127.9, 127.6, 126.3, 122.4, 121.6, 121.1, 120.9, 110.0, 102.7, 33.6, 21.8, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₅H₂₂N₃O: 380.1763, found 380.1767.

6-Methoxy-4-(1-methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3oa). Compound was obtained as a yellow solid: yield 52%; ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.50–7.43 (m, 2H), 7.37–7.27 (m, 4H), 7.22–7.16 (m, 2H), 3.96 (s, 3H), 3.67 (s, 3H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 158.9, 153.6, 146.0, 140.3, 137.3, 136.7, 135.5, 130.6, 130.3, 130.1, 128.6, 127.2, 124.1, 123.2, 122.4, 121.8, 120.6, 110.1, 104.6, 102.5, 55.7, 33.6, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₅H₂₂N₃O₂: 396.1712, found 396.1737.

4-(1-Methyl-1H-indol-3-yl)-2-(p-tolyl)-7-(trifluoromethyl)quinazoline 3-oxide (3pa). Compound was obtained as a yellow solid: yield 75%; ¹H NMR (400 MHz, CDCl₃) δ 8.37–8.32 (m, 2H), 8.26 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 8.8, 1.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37–7.30 (m, 3H), 7.21 (t, J = 7.6 Hz, 1H), 3.95 (s, 3H), 2.45 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 157.0, 147.0, 141.5, 140.2, 136.9, 136.0, 132.1 (q, J = 32.9 Hz), 130.5, 129.9, 128.8, 127.7, 127.4, 126.5 (q, J = 4.2 Hz), 124.6, 123.7 (q, J = 270.9 Hz), 123.6 (q, J = 3.0 Hz), 122.9, 121.45, 121.40, 110.3, 102.2, 33.7, 21.7. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₅H₁₉F₃N₃O: 434.1480, found 434.1478.

6-Chloro-4-(1-methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3qa). Compound was obtained as a yellow solid: yield 83%; ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J = 8.8 Hz, 3H), 7.97 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.47–7.29 (m, 3H), 7.22 (t, J = 7.6 Hz, 1H), 3.96 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.9, 146.3, 141.1, 139.4, 136.8, 135.3, 134.0, 131.2, 130.3, 130.1, 131.2, 130.3, 130.1, 128.6, 127.2, 125.0, 124.0, 122.7, 121.4, 121.3, 110.1, 102.3, 33.6, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₁₉ClN₃O: 400.1217, found 400.1219, and 402.1187, found 402.1188.

6-Bromo-4-(1-methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3ra). Compound was obtained as a yellow solid: yield 84%; ¹H NMR (400 MHz, CDCl₃) δ 8.31–8.19 (m, 3H), 8.10 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 8.8, 1.6 Hz, 3H), 7.46 (d, J = 8.4 Hz, 2H), 7.37–7.28 (m, 3H), 7.23 (t, J = 7.6 Hz, 1H), 3.96 (s, 3H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 156.0, 146.3, 141.1, 139.7, 136.8, 135.3, 133.8, 130.34, 130.29, 130.1, 128.6, 128.3, 127.2, 124.4, 122.8, 122.0, 121.4, 121.3, 110.1, 102.3, 33.6, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₁₉BrN₃O: 444.0711, found 444.0706, and 446.0691, found 446.0687.

4-(1,5-Dimethyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3ab). Compound was obtained as a yellow solid: yield 76%; ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.34–7.30 (m, 3H), 7.22 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.7, 147.3, 141.2, 140.7, 135.4, 135.2, 130.5, 130.4, 130.3, 128.7, 128.6, 127.8, 126.6, 124.1, 123.2, 121.3, 109.7, 102.1, 33.6, 21.63, 21.57. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₅H₂₁N₃O: 380.1763, found 380.1762.

4-(5-Methoxy-1-methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3ac). Compound was obtained as a yellow solid: yield 69%; ¹H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 8.27–8.18 (m, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.71–7.67 (m, 1H), 7.50–7.46 (m, 1H), 7.34–7.30 (m, 3H), 6.97 (dd, J = 8.8, 2.4 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.7, 155.1, 147.1, 141.2, 140.7, 135.8, 131.9, 130.6, 130.5, 130.3, 128.8, 128.6, 128.2, 127.7, 126.6, 122.9, 112.7, 110.7, 103.6, 102.3, 55.8, 33.7, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₅H₂₁N₃O₂: 396.1712, found 396.1712.

4-(5-Fluoro-1-methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3ad). Compound was obtained as a yellow solid: yield 72%; ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.22 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.38–7.35 (m, 1H), 7.31 (d, J = 7.8 Hz, 2H), 7.15–7.01 (m, 2H), 3.94 (s, 3H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 158.5 (d, J = 235.5 Hz), 155.7, 146.7, 141.2, 140.9, 136.6, 133.4, 130.7, 130.3, 128.9, 128.6, 128.2, 128.0 (d, J = 10.4 Hz), 126.1, 123.0, 111.2, 110.9, 110.8 (d, J = 9.8 Hz), 107.0 (d, J = 24.8 Hz), 102.8, 33.8, 29.7, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₁₈FN₃O: 384.1512, found 384.1501.

4-(5-Chloro-1-methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3ae). Compound was obtained as a yellow solid: yield 78%; ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J = 8.4 Hz, 3H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.42 (s, 1H), 7.36–7.25 (m, 4H), 3.92 (s, 3H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.6, 146.5, 141.2, 140.9, 136.2, 135.2, 130.8, 130.3, 128.9, 128.6, 128.5, 128.3, 127.0, 126.0, 123.1, 123.0, 121.1, 111.0, 102.4, 33.7, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₄H₁₈ClN₃O: 400.1217, found 400.1219, and 402.1187, found 402.1188.

4-(5-Bromo-1-methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3af). Compound was obtained as a yellow solid: yield 87%; ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.57 (s, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 3H), 3.92 (s, 3H), 2.43 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.6, 146.5, 141.2, 140.9, 136.1, 135.5, 130.8, 130.3, 129.1, 128.9, 128.6, 128.3, 126.0, 125.5, 124.1, 123.1, 114.5, 111.5, 102.4, 100.0, 33.7, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₃H₁₈BrN₃O: 444.0711, found 444.0710, and 446.0691, found 446.0690.

4-(1-Isopropyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3ag). Compound was obtained as a yellow solid: yield 88%; ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.19 (d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.56–7.44 (m, 3H), 7.36–7.28 (m, 3H), 7.18 (t, J = 7.4 Hz, 1H), 4.90–4.75 (m, 1H), 2.44 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.9, 147.4, 141.3, 140.6, 135.7, 131.0, 130.61, 130.55, 130.2, 128.7, 128.6, 127.9, 127.8, 126.7, 123.2, 122.2, 121.9, 120.9, 110.3, 102.8, 48.1, 22.8, 21.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₄N₃O: 394.1919, found 394.1919.

4-(1-Benzyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3ah). Compound was obtained as a yellow solid: yield 82%; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H), 8.22 (d, J = 7.6 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.37–7.21 (m, 7H), 7.17 (t, J = 7.4 Hz, 1H), 5.45 (s, 2H), 2.42 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.8, 147.0, 141.1, 140.7, 136.3, 134.8, 130.53, 130.47, 130.3, 129.0, 128.8, 128.6, 128.1, 128.0, 127.2, 126.4, 123.2, 122.6, 121.9, 121.1, 110.6, 103.4, 51.0, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₃₀H₂₄N₃O: 442.1919, found 442.1935.

4-(1H-Indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3ai). Compound was obtained as a yellow solid: yield 83%; ¹H NMR (400 MHz, CDCl₃) δ 10.24 (s, 1H), 8.28 (d, J = 7.2 Hz, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.57–7.39 (m, 3H), 7.33 (d, J = 7.6 Hz, 2H), 7.08 (s, 3H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.5, 148.5, 141.5, 140.9, 136.1, 131.1, 131.0, 130.5, 130.4, 128.7, 128.6, 128.3, 126.6, 126.3, 123.5, 122.4, 121.4, 120.8, 112.3, 103.5, 21.6. HRMS (ESI†): m/z [M + H]⁺ calcd for C₂₃H₁₈N₃O: 352.1450, found 352.1447.

4-(2-Methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline 3-oxide (3aj). Compound was obtained as a yellow solid: yield 58%; ¹H NMR (400 MHz, CDCl₃) δ 9.55 (s, 1H), 8.31 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.7 Hz, 1H), 7.05 (s, 3H), 2.43 (s, 3H), 2.04 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 155.7, 149.4, 141.03, 140.99, 139.7, 136.1, 130.8, 130.50, 130.45, 128.7, 128.5, 127.7, 126.6, 124.2, 121.4, 120.2, 119.5, 111.7, 101.3, 21.6, 13.7. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₀N₃O: 366.1606, found 366.1602.

4-(1-Methyl-1H-indol-3-yl)-2-(p-tolyl)quinazoline (4a). Compound was obtained as an off-white solid: yield 86%; ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d, J = 8.4 Hz, 2H), 8.37 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 1H), 7.85 (td, J = 7.0, 1.2 Hz, 1H), 7.76 (s, 1H), 7.53 (td, J = 7.6, 0.8 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.42–7.31 (m, 4H), 3.94 (s, 3H), 2.46 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 163.1, 160.4, 152.1, 140.4, 137.6, 136.1, 133.0, 132.7, 129.3, 129.1, 128.6, 127.4, 126.8, 126.3, 123.0, 122.1, 121.8, 121.4, 113.4, 109.7, 33.4, 21.54. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₁₉N₃: 350.1657, found 350.1656.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from National Natural Science Foundation of China (no. 21762020 and 21362014), Jiangxi Provincial Department of Science and Technology (no. 20171BAB203006), and Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Jiangxi Normal University (no. KLFS-KF-201623) is gratefully acknowledged.

Notes and references

1. (a) A. F. Pozharskii, A. T. Soldartenkov, and A. R. Katrizky, Heterocycles in Life and Society, John Wiley & Sons, Weinheim, 2nd edn, 2011; (b) W. R. Pitt, D. M. Parry, B. G. Perry and C. R. Groom, J. Med. Chem., 2009, 52, 2952; (c) S. Bongarzone and M. L. Bolognesi, Expert Opin. Drug Discovery, 2011, 6, 251; (d) J. Polanski, A. Kurczyk, A. Bak and R. Musiol, Curr. Med. Chem., 2012, 19, 1921.
2. (a) P. Y. Chung, Z. X. Bian, H. Y. Pun, D. Chan, A. S. C. Chan, C. H. Chui and K. H. Lam, Future Med. Chem., 2015, 7, 947; (b) A. M. Mfuh and O. V. Larionov, Curr. Med. Chem., 2015, 22, 2819.
3. (a) G. Hughes and M. R. Bryce, J. Mater. Chem., 2005, 15, 94; (b) A. Kimyonok, X. Y. Wang and M. Weck, J. Macromol. Sci., Polym. Rev., 2006, 46, 47.
4. For selected reviews, see: (a) D. Connolly, D. Cusack, T. O'Sullivan and P. Guiry, Tetrahedron, 2005, 61, 10153; (b) J. Michael, Nat. Prod. Rep., 2007, 24, 223; (c) S. Mhaske and N. Argade, Tetrahedron, 2006, 62, 9787.
5. (a) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875; (b) M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608; (c) A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489.
6. (a) E. Vangrevelinghe, K. Zimmermann, J. Schoepfer, R. Portmann, D. Fabbro and P. Furet, J. Med. Chem., 2003, 46, 2656; (b) D. V. Ferraris, J. Med. Chem., 2010, 53, 4561; (c) A. Lüth and W. Löwe, Eur. J. Med. Chem., 2008, 43, 1478; (d) Y. Rao, H. Liu, L. Gao, H. Yu, J. H. Tan, T. M. Ou, S. L. Huang, L. Q. Gu, J. M. Ye and Z. S. Huang, Bioorg. Med. Chem., 2015, 23, 4719.
7. (a) S. Kumar and D. P. Sahu, J. Heterocycl. Chem., 2009, 46, 748; (b) Y. A. Azev, S. V. Shorshnev and B. V. Golomolzin, Tetrahedron Lett., 2009, 50, 2899; (c) M. Staderini, M. L. Bolognesi and J. C. Menéndez, Adv. Synth. Catal., 2015, 357, 185; (d) I. A. Utepova, M. A. Trestsova, O. N. Chupakhin, V. N. Charushin and A. A. Rempel, Green Chem., 2015, 17, 4401; (e) O. N. Chupakhin, A. V. Shchepochkin and V. N. Charushin, Green Chem., 2017, 19, 2931.
8. (a) C.-J. LI, Acc. Chem. Res., 2009, 42, 335; (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; (d) Y. Yang, J. Lan and J. You, Chem. Rev., 2017, 117, 8787; (e) W. Hu and Y. Long, Chin. J. Org. Chem., 2017, 37, 2850.
9. For recent reviews: (a) G. Yan, A. J. Borah and M. Yang, Adv. Synth. Catal., 2014, 356, 2375; (b) L. Yali, Z. Yunhui, F. Hongyan and J. Xinhua, Chin. J. Org. Chem., 2013, 33, 267; (c) W. Ma, P. Gandeepan, J. Li and L. Ackermann, Org. Chem. Front., 2017, 4, 1435.
10. (a) X. Gong, G. Song, H. Zhang and X. Li, Org. Lett., 2011, 13, 1766; (b) M. Li, X. Li, H. Chang, W. Gao and W. Wei, Org. Biomol. Chem., 2016, 14, 2421; (c) A. Lehecq, K. Rousée, C. Schneider, V. Levacher, C. Hoarau, X. Pannecoucke and S. Couve-Bonnaire, Eur. J. Org. Chem., 2017, 21, 3049.
11. (a) J. P. Leclerc and K. Fagnou, Angew. Chem., Int. Ed., 2006, 45, 7781; (b) D. J. Schipper, M. El-salfiti, C. J. Whipp and K. Fagnou, Tetrahedron, 2009, 65, 4977; (c) J. M. Keith, J. Org. Chem., 2010, 75, 2722; (d) J. M. Keith, J. Org. Chem., 2012, 77, 11313; (e) L. A. Galliamova, M. V. Varaksin, O. N. Chupakhin, P. A. Slepukhin and V. N. Charushin, Organometallics, 2015, 34, 5285; (f) A. P. Colleville, R. A. Horan, S. Olazabal and N. C. Tomkinson, Org. Process Res. Dev., 2016, 20, 1283; (g) F. Roudesly, L. F. Veiros, J. Oble and G. Poli, Org. Lett., 2018, 20, 2346.
12. (a) T. Nishida, H. Ida, Y. Kuninobu and M. Kanai, Nat. Commun., 2014, 5, 3387; (b) Y. Kuninobu, M. Nagase and M. Kanai, Angew. Chem., Int. Ed., 2015, 54, 10263; (c) X. Y. Zhang, Z. S. Qi and X. W. Li, Angew. Chem., Int. Ed., 2014, 53, 10794; (d) H. Hwang, J. Kim, J. Jeong and S. Chang, J. Am. Chem. Soc., 2014, 136, 10770; (e) Q. Xiao, J. Sheng, Q. Ding and J. Wu, Eur. J. Org. Chem., 2014, 1, 217; (f) K. Shin, S. W. Park and S. Chang, J. Am. Chem. Soc., 2015, 137, 8584; (g) X. Chen, X. Cui and Y. Wu, Org. Lett., 2016, 18, 3722; (h) D. E. Stephens, J. Lakey-Beitia, A. C. Atesin, T. A. Ateşin, G. Chavez, H. D. Arman and O. V. Larionov, ACS Catal., 2015, 5, 167; (i) B. Yao, C. L. Deng, Y. Liu, R. Y. Tang, X. G. Zhang and J. H. Li, Chem. Commun., 2015, 51, 4097; (j) N. Barsu, M. Sen, J. R. Premkumar and B. Sundararaju, Chem. Commun., 2016, 52, 1338; (k) D. Y. Li, Z. L. Huang and P. N. Liu, Org. Lett., 2018, 20, 2028.
13. (a) L. Fan, T. Wang, Y. Tian, F. Xiong, S. Wu, Q. Liang and J. Zhao, Chem. Commun., 2016, 52, 5375; (b) Q. Yang, M. Lou, Z. Yin, Z. Deng, Q. Ding and Y. Peng, Org. Biomol. Chem., 2018, 16, 8724.
14. (a) Y. Y. Peng, G. Y. S. Qiu, Q. Yang, J. J. Yuan and Z. H. Deng, Synthesis, 2012, 44, 1237; (b) G. Y. S. Qiu, P. Huang, Q. Yang, H. Lu, J. Xu, Z. Deng, M. Zhang and Y. Y. Peng, Synthesis, 2013, 45, 3131; (c) X. Chen, Q. Yang, Y. R. Zhou, Z. H. Deng, X. C. Mao and Y. Y. Peng, Synthesis, 2015, 47, 2055; (d) X. Zhao, Y. Zhou, Y. Xie, Q. Ding, Z. Deng, M. Zhang, J. Xu and Y. Y. Peng, Synthesis, 2013, 45, 3245; (e) Y. Y. Peng, P. Huang, Y. Wang, Y. R. Zhou, J. J. Yuan, Q. Yang, X. Jiang, Z. Deng and J. S. Xu, Org. Biomol. Chem., 2014, 12, 5922; (f) C. Zhang, Y. Zhou, Z. Deng, X. Chen and Y. Y. Peng, Eur. J. Org. Chem., 2015, 8, 1735; (g) X. L. Ye, Z. H. Yuan, Y. R. Zhou, Q. Yang, Y. P. Xie, Z. H. Deng and Y. Y. Peng, J. Heterocycl. Chem., 2016, 53, 1956; (h) X. L. Ye, J. J. Yuan, Y. R. Zhou, Z. H. Deng, X. C. Mao and Y. Y. Peng, Synthesis, 2016, 48, 3976; (i) M. Lou, Z. Deng, X. Mao, Y. Fu, Q. Yang and Y. Peng, Org. Biomol. Chem., 2018, 16, 1851.
15. S. H. Cho, S. J. Hwang and S. Chang, J. Am. Chem. Soc., 2008, 130, 9254.
16. (a) M. Kitahara, N. Umeda, K. Hirano, T. Satoh and M. Miura, J. Am. Chem. Soc., 2011, 133, 2160; (b) S. Fan, Z. Chen and X. Zhang, Org. Lett., 2012, 14, 4950; (c) R. Odani, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2013, 78, 11045.
17. (a) A. E. King, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc., 2009, 131, 5044; (b) A. M. Suess, M. Z. Ertem, C. J. Cramer and S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 9797; (c) J. C. Vantourout, H. N. Miras, A. Isidro-Llobet, S. Sproules and A. J. Watson, J. Am. Chem. Soc., 2017, 139, 4769.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, ¹H and ¹³C NMR spectra of compounds 3. CCDC 1813925 (compound 3ai). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ra09864f

---