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

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. This journal is © The Royal Society of Chemistry.

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, quinazoline[4] and indole[5] 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[6] and poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.[6] 4-(Indole-3-yl)quinazolines have been reported to be potent epidermal growth factor receptor tyrosine kinase inhibitors.[6]

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).[7] 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).[7]

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) reactions[8] 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-oxides[12] 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).

Screening of the reaction conditiona,b

Entry	Solvent	Catalyst	T/°C	Yieldc/%
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

Optimized conditions are denoted in bold.

Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst, solvent (2.0 mL), 16 h, under air.

Isolated yield.

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.

The reaction of quinazoline-3-oxide 1 with 1-methylindolea

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

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.

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

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

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 Avia 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.