Electrosynthesis of Quinazolines and Quinazolinones via an Anodic Direct Oxidation C(sp3)-H Amination/C-N Cleavage of Tertiary Amine in Aqueous Medium.

An electrochemical synthesis for quinazolines and quinazolinones was developed via a C(sp3)-H amination/C-N cleavage by virtue of the anodic oxidation. The reaction can be carried out in aqueous media under mild conditions to afford the desired products with high yields. The reaction mechanism was proposed after detailed investigation.

Introduction

Nitrogen-containing heterocycles are privileged compounds in natural products and pharmaceutical chemistry.[1] In particular, quinazolines and quinazolinones are heterocyclic compounds containing two nitrogen atoms, such as lapatinib, prazosin, iressa, erlotinib, rutaecarpine, and luotonin E (Figure ), which features broad-spectrum biological activities and pharmacological effects.[2]

Figure 1

Structures of selected bioactive quinazolines and quinazolinones.

Recently, there have been a number of well-established methods to prepare quinazolines[3] and quinazolinones.[4] However, most of these methods usually involve either metal catalysts[5] or chemical oxidants.[6] The use of stoichiometric oxidants leads to unnecessary waste and low atomic economy. On the other hand, the addition of metal catalysts increases the difficulty of post-treatment. Therefore, it is desirable to develop a simple, efficient, and green way to synthesize quinazolines and quinazolinones.

Organic electrochemistry represents an environmentally benign and sustainable method with electrons as reagents,[7a−7g] and recently some good examples about electrosynthesis provide the possibility of constructing N-heterocycles without the need for chemical oxidants.[7h−7j] Electrochemical preparation provides the possibility of constructing C–N bonds to synthesize quinazolines and quinazolinones without the addition of metallic and chemical oxidants. As our ongoing research on the C(sp3)-H functionalization in electrochemistry,[8] we herein report an electrosynthesis of quinazolines and quinazolinones via an anodic direct oxidation from readily available amines as a C source in the absence of metal and chemical oxidants. To the best of our knowledge, this should be one of the most efficient, simple, and green approaches for the construction of quinazolines and quinazolinones.

Results and Discussion

Initially, the model reaction of 2-aminobenzophenone (1a) with TMEDA (2a) was electrolyzed in an undivided cell at a constant current density of 5 mA/cm2, while NH4PF6 was used as the electrolyte in the solvent of DMA. The desired product was obtained with a yield of 72% (entry 1, Table ). Inspired by this result, the solvent was first investigated. After screening the various solvent, DMSO was turned to be a good kind of solvent (entries 1–3, Table ). With the addition of water to this DMSO, it was found that this co-solvent could afford an excellent yield. Then, the ratio of DMSO to water was examined and DMSO/H2O (5:1) was determined to be the best solvent for this reaction, perhaps due to the solubility increase of the electrolyte in the presence of water (entry 4, Table ). On the other hand, 2a was necessary for this reaction, and no target product was obtained in the absence of 2a (entry 5, Table ). Afterward, various electrolytes were examined. The experimental results showed that almost all of the ammonium salts could act as both the N source and the supporting electrolyte except for NH4HCO3(entries 6–8, Table ). Increasing or decreasing the current density resulted in the decrease of the product yield (entries 9 and 10, Table ). Further screening of the electrode materials showed that the couple electrode of Pt/Pt was the optimal choice (entries 11–13, Table ). As for the reaction temperature, either beyond or below 80 °C decreased the reaction yield (entries 14 and 15, Table ). A relatively lower yield was obtained when the reaction was conducted under a nitrogen or an oxygen atmosphere (entries 16 and 17, Table ). Without galvanization, the reaction did not work (entry 18, Table ). After detailed investigation, the optimal electrolytic conditions were described as entry 4 of Table .

Table 1

Optimization of Reaction Conditionsa

entry	electrolyte	solvent	anode/cathode	J (mA/cm2)	yield (%)b
1	NH4PF6	DMA	Pt/Pt	5	72%
2	NH4PF6	CH3CN	Pt/Pt	5	86%
3	NH4PF6	DMSO	Pt/Pt	5	95%
4	NH4PF6	DMSO/H2O	Pt/Pt	5	98%
5c	NH4PF6	DMSO/H2O	Pt/Pt	5	nd
6	NH4HCO3	DMSO/H2O	Pt/Pt	5	trace
7	NH4BF4	DMSO/H2O	Pt/Pt	5	91%
8	NH4Cl	DMSO/H2O	Pt/Pt	5	85%
9	NH4PF6	DMSO/H2O	Pt/Pt	3	73%
10	NH4PF6	DMSO/H2O	Pt/Pt	10	90%
11	NH4PF6	DMSO/H2O	C/Pt	5	92%
12	NH4PF6	DMSO/H2O	Pt/C	5	90%
13	NH4PF6	DMSO/H2O	C/C	5	67%
14d	NH4PF6	DMSO/H2O	Pt/Pt	5	92%
15e	NH4PF6	DMSO/H2O	Pt/Pt	5	94%
16f	NH4PF6	DMSO/H2O	Pt/Pt	5	96%
17g	NH4PF6	DMSO/H2O	Pt/Pt	5	97%
18	NH4PF6	DMSO/H2O	Pt/Pt	0	nd

Reaction conditions: 1a (0.3 mmol), 2a (TMEDA, 0.6 mmol), electrolyte both acting as supporting salts and a N source (0.6 mmol), DMSO/H2O = 5:1 (3 mL); the electrolysis was conducted in an undivided cell in an oil bath (T = 80 °C).

Yield of the isolated products.

No 2a.

T = 70 °C.

T = 90 °C.

Under O2.

Under N2. nd = not detected.

With the optimal electrolytic conditions in hand, various amines 2b–2i were employed as the carbon source for the synthesis of 4-phenylquinazoline and 2-methyl-4-phenylquinazoline (Table ). When various tertiary amines such as 1-methylpiperazine (2b), 4-methylmorpholine (2c), and N,N-dimethylaniline (2d) were used instead of TMEDA, all the reactions gave the desired product 3a. Moreover, 2d gave a yield higher than those of 2b and 2c. In addition, using secondary amines such as N-methylcyclohexylamine (2e), N,N′-dimethylethylenediamine (2f), N-methylaniline (2g), and N-methylbenzylamine (2h) as the carbon source, the reactions also produced 3a in moderate to good yields. It was noted that 2f afforded a yield higher than those of 2e, 2g, and 2h. These results clearly showed that the reactivity of tertiary amines was greater than that of secondary amines. Delightfully, when trimethylamine (2i) was employed, 2-methyl-substituted quinazoline (3a′) can be obtained with 85% yield.

Table 2

Substrate Scope of Various Aminesa

Reaction conditions: 1a (0.3 mmol), 2b–2i (0.6 mmol), NH4PF6 (0.6 mmol), DMSO/H2O = 5:1 (3 mL); the electrolysis was conducted in an undivided cell in an oil bath (80 °C) for 10–16 h.

Isolated yields.

Subsequently, we investigated the substrate scope of o-carbonyl-substituted anilines under the standard conditions (Table ). When R1 was an aromatic substituent, substrates (1a–1h) gave the desired products (3a–3h) with excellent yields, regardless of the electron-withdrawing (F, Cl, or Br) or electron-donating (Me, OMe) groups on the phenyl ring. Then, the methyl group was used to illustrate the effect of steric hindrance on the reaction. When the methyl group was located at the ortho-position of this phenyl ring, the corresponding target product can be obtained in 85% yield (3e). Comparing it with the meta-substituted 3f (94%) and para-substituted 3g (97%), this indicated that steric hindrance had a negative influence on the reaction support by Table . When R1 was alkyl substituents, substrates (1i–1o) can be performed smoothly to give the desired products (3i–3o) in 50–88% yields. This implied that aromatic substitution favored the reaction, perhaps due to the assistance from the aromatic ring to the stability of the reaction intermediate. To our delight, when 2-aminobenzaldehyde derivatives were used as substrates under the standard conditions, the corresponding products (3p–3r) can be obtained with moderate to good yields. For multisubstituted substrate 1s, the product 3s was obtained in 91% isolated yield. Finally, when Cl, Br, and NO2 groups were introduced into the 5-position of 2-aminobenzophenone, the desired products (3t–3v) were obtained in excellent yields except 1v. As for the nitro-substitution in 1v, maybe the nitro group interfered in the reaction. It should be noted that the carbon–halogen bond of the substrate survived the reaction, providing additional processing for further derivation. Additionally, the electrolytic reaction of 1a with 2a could be performed on a gram scale to afford the desired product with an excellent yield. On the other hand, the desired product 3a could be further derived into quinazoline derivatives 3a″ (Scheme ).

Table 3

Substrate Scope of o-Carbonyl Anilinesa

Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), NH4PF6 (0.6 mmol), DMSO/H2O = 5:1 (3 mL); the electrolysis was conducted in an undivided cell in an oil bath (80 °C) for 8–9 h.

Scheme 1

Gram-Scale Experiments and Product Transformation

We next make use of this developed method to synthesize quinazolinones. Initially, the model reaction of 2-amino-N-phenylbenzamide (4a) with TMEDA (2a) was electrolyzed in an undivided cell at a constant current density of 10 mA/cm2 and 80 °C, while Bu4NPF6 was used as the electrolyte in the solvent of DMSO/H2O (5:1). The desired product was obtained with a yield of 54% (see entry 1, Supporting Information, Table S1). Inspired by this result, the electrolyte was first investigated. Afterward, the various electrolytes were examined. Bu4NClO4 was determined to be the best electrolyte for this reaction (see entries 1–3, Supporting Information, Table S1). Increasing or decreasing the current density resulted in the decrease of the product yield (see entries 4 and 5, Supporting Information, Table S1). Without galvanization, the reaction did not work (see entry 6, Supporting Information, Table S1). After detailed investigation, the optimal electrolytic conditions were described as entry 2 of Supporting Information, Table S1.

Subsequently, we investigated the substrate scope of 2-aminobenzamide under the standard conditions (Table ). Gratifyingly, the reaction of 2-amino-N-phenylbenzamide (4a) with TMEDA (2a) under the standard conditions gave the desired 3-phenylquinazolin- 4(3H)-one (5a) in 62% isolated yield. Similarly, 2-amino-N-alkylbenzamides (4b–4e) also afforded products (5b–5e) in moderate yields (24–76%). Moreover, 2-amino-N-benzylbenzamide (4f) and 2-amino-N-allylbenzamide (4g) gave the desired product 5f with an 84% yield and 5g with a 66% yield. Benzyl and allyl groups are very compatible under the standard conditions. However, none of the desired product 5h was formed when 2-aminobenzamide (4h) was used as a substrate.

Table 4

Substrate Scope of 2-Aminobenzamidea

Reactions: 4 (0.3 mmol), 2a (TMEDA, 0.6 mmol), Bu4NClO4 (0.6 mmol), DMSO/H2O = 5:1 (3 mL); the electrolysis was conducted in an undivided cell in an oil bath (80 °C) for 10–12 h.

To understand the reaction mechanism, a series of control experiments were performed (Scheme ). When the radical scavengers 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT) were added, the reaction was not inhibited (Scheme a,b). We obtained the product with 97 and 88% yields, respectively. This implied that the reaction might undergo a non-radical process. Replacing 1a with 6 under the standard conditions (Scheme c), 7 was detected. Moreover, by heating 1a with formaldehyde (concentration of 40% in water) at 80 °C, the desired product 3a was obtained in 59% isolated yield (Scheme d), indicating that the HCHO intermediate may be generated in the reaction. Meanwhile, the 15N-labeled experiment was also performed, and [ can be obtained in a yield of 85%, which showed that the quinazoline nitrogen atom was derived from NH4Cl rather than TMEDA (Scheme e). When (2-nitrophenyl)(phenyl) methanone (8) was employed, the desired product (3a) was not obtained. Perhaps the nitro group interfered in the reaction (Scheme f).

Scheme 2

Control Experiments and a 15N Labeling Experiment

Based on the above experimental results and previous reports,[9,10,14] a plausible mechanism was proposed for the formation of the quinazoline (Scheme ). TMEDA loses two electrons and one proton at the anode, affording iminium A. Then, A is hydrolyzed to generate B. Subsequently, B condenses with 1a to give intermediate C. On the other hand, the NH3 generated from the cathode conducts the nucleophilic attack to intermediate C, affording intermediate D. Finally, 3a is obtained via a tandem condensation-oxidation process from D.

Scheme 3

Proposed Possible Reaction Mechanism

Conclusions

In conclusion, we developed an anodic direct electrochemical oxidation method for the synthesis of quinazolines and quinazolinones. The reaction features metal-free and chemical oxidant-free, broad substrate scope, water tolerance, and scalability. More importantly, this electrosynthesis reaction provides a way for the conversion of inorganic ammonium salts to organic compounds. This is a facile and green approach for the construction of quinazolines and quinazolinones under mild conditions.

Experimental Section

General Information

All products were characterized by 1H NMR and 13C NMR, using TMS as an internal reference (1H NMR, 400 MHz; 13C NMR, 100 MHz). HRMS (ESI) data were recorded on a Q-TOF Premier. The instrument for electrolysis is a DC-regulated power supply (HY3005M, made in China). The anode electrode and cathode electrode are both Pt (1.0 × 1.0 cm2). These electrodes are commercially available from GaossUnion, China. Commercial reagents and solvents were used without purification unless otherwise indicated.

Preparation of Substrates

Substrates 1a–1d, 1i, 1j, 1p–1t, 1v, 2, and 4h are commercially available. Other substrates 1 and 4 were prepared using previously reported literature procedures.[11,12,14]

Procedure for the Electrosynthesis of Quinazolines

An undivided cell was equipped with a magnetic stirrer, a platinum plate (1.0 × 1.0 cm2) electrode as the working electrode, and a counter electrode. The substrate o-carbonyl-substituted anilines 1 (0.3 mmol), amines 2 (0.6 mmol), and electrolyte NH4PF6 (97.8 mg, 0.6 mmol) were added to the solvent DMSO/H2O = 5:1 (3 mL). The electrolysis was performed (J = 5 mA/cm2, I = 5 mA) in an undivided cell in an oil bath (80 °C). After the reaction was completed, the reaction system was allowed to attain room temperature and extracted with ethyl acetate (3 × 20 mL), and then the organic layer was washed with brine (2 × 10 mL) and dried with anhydrous Na2SO4. Subsequently, the solvent was removed under reduced pressure and the remaining crude product was purified by column chromatography over silica gel (PE/EtOAc = 5:1) to afford the corresponding products (procedure A).

Procedure for the Electrosynthesis of Quinazolinones

An undivided cell was equipped with a magnetic stirrer, a platinum plate (1.0 × 1.0 cm2) electrode as the working electrode, and a counter electrode. The substrate 2-aminobenzamide 3 (0.3 mmol), amines 2 (0.6 mmol), and electrolyte Bu4NClO4 (205.1 mg, 0.6 mmol) were added to the solvent DMSO/H2O = 5:1 (3 mL). The electrolysis was electrolyzed (J = 10 mA/cm2, I = 10 mA) in an undivided cell in an oil bath (80 °C). After the reaction was completed, the reaction system was allowed to attain room temperature and extracted with ethyl acetate (3 × 20 mL), and then the organic layer was washed with brine (2 × 10 mL) and dried with anhydrous Na2SO4. Subsequently, the solvent was removed under reduced pressure and the remaining crude product was purified by column chromatography over silica gel (PE/EtOAc = 3:1) to afford the corresponding products (procedure B).

Gram-scale Synthesis of 3a

An undivided cell was equipped with a magnetic stirrer, a platinum plate (1.5 × 1.5 cm2) electrode as the working electrode, and a counter electrode. The substrate (2-aminophenyl) (phenyl)methanone 1a (1.18 g, 6 mmol), TMEDA 2a (1.39 g, 12 mmol), and electrolyte NH4PF6 (1.95 g, 12 mmol) were added to the co-solvent DMSO/H2O (5:1) (60 mL). The electrolysis was performed (J = 5 mA/cm2, I = 12 mA) in an undivided cell in an oil bath (80 °C). After the reaction was completed, the reaction system was allowed to attain room temperature and extracted with ethyl acetate, and then the organic layer was washed with brine and dried with anhydrous Na2SO4. Subsequently, the solvent was removed under reduced pressure and the remaining crude product was purified by column chromatography over silica gel (PE/EtOAc = 5:1) to afford the corresponding products (1.12 g, 91% yield).

15N Labeling Experiment

[15N] Ammonium chloride (15N, 99%) was purchased from Shanghai Aladdin Biochemical Technology Inc., without further purification. An undivided cell was equipped with a magnetic stirrer, a platinum plate (1.0 × 1.0 cm2) electrode as the working electrode, and a counter electrode. The substrate (2-aminophenyl) (phenyl)methanone 1a (0.3 mmol), TMEDA 2 (0.6 mmol), and electrolyte 15NH4Cl (32.7 mg, 0.6 mmol) were added to the solvent DMSO/H2O = 5:1 (3 mL). The electrolysis was conducted in an undivided cell in an oil bath (80 °C). After the reaction was completed, the reaction system was allowed to attain room temperature and extracted with ethyl acetate (3 × 20 mL), and then the organic layer was washed with brine (2 × 10 mL) and dried with anhydrous Na2SO4. Subsequently, the solvent was removed under reduced pressure and the remaining crude product was purified by column chromatography over silica gel (PE/EtOAc = 5:1) to afford the corresponding products. [ (52.8 mg, 85% yield) (procedure C).

4-Phenylquinazoline (3a)[14]

Compound 3a was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 98% yield, (60.6 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.38 (s, 1 H), 8.14–8.10 (m, 2 H), 7.93–7.89 (m, 1 H), 7.90–7.75 (m, 2 H), 7.62–7.56 (m, 4 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.5, 154.8, 151.2, 137.2, 133.8, 130.2, 130.0, 129.0, 128.8, 127.9, 127.2, 123.3.

2-Methyl-4-phenylquinazoline (3a′)[13]

Compound 3a′ was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a yellow oil: 85% yield, (56.1 mg). 1H NMR (400 MHz, CDCl3): δ(ppm) 8.03(t, J = 9.7 Hz, 2 H), 7.88–7.84 (m, 1 H), 7.76–7.72 (m, 2 H), 7.59–7.50 (m, 4 H), 2.95, (s, 3.H). 13C NMR (100 MHz, CDCl3): δ (ppm) 168.7, 164.0, 151.5, 137.4, 133.8, 130.0, 128.7, 128.3, 127.2, 126.9, 121.2, 26.7.

2-(1-Azido-3-(trimethylsilyl)propan-2-yl)-4-phenylquinazoline (3a″) procedure for the electrosynthesis of 2-(1-azido-3-(trimethylsilyl) propan-2-yl)-4-phenylquinazoline (3a″) in air: a solution of 3a (1 equiv, 0.5 mmol), TFA (trifluoroacetic acid, 0.6 mmol, 68 mg), allyltrimethylsilane (2.5 mmol), and trimethylsilylazide (TMSN3, 2.0 mmol, 230 mg) in AcOH (0.5 mL) was cooled to 0 °C. Then, a solution of iodobenzene diacetate (DIB, 1.0 mmol, 322 mg) in 1.7 mL of AcOH and 1.0 mL of DCM was added dropwise very carefully through a constant pressure funnel. After 1.0 h, the cooling bath was removed and the mixture was stirred at room temperature for 0.5 h. Afterward, the reaction was quenched with saturated K2CO3 solution and extracted with dichloromethane, washed with brine, and dried over anhydrous Na2SO4. The organic extract was concentrated under reduced pressure and the remaining crude product was purified by column chromatography over silica gel (PE/EtOAc = 20:1) to give the product as a light yellow oil: 60% yield, (108.3 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.08 (dd, J1 = 8.4 Hz, J2 = 3.9 Hz, 2 H), 7.87 (t, J = 7.7 Hz,1 H), 7.80–7.76 (m, 2 H), 7.61–7.53 (m, 4 H), 4.00 (dd, J1 = 11.5 Hz, J2 = 8.7 Hz, 1 H), 3.66–3.54 (m, 2 H), 1.35 (dd, J1 = 14.6 Hz, J2 = 9.6 Hz, 1 H), 1.07 (dd, J1 = 14.7 Hz, J2 = 5.2 Hz, 1 H), −0.12 (s, 9 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.7, 167.5, 151.5, 137.5, 133.7, 130.1, 130.0, 128.8, 128.6, 127.2, 127.1, 121.7, 57.8, 45.8, 20.6, −1.0. HRMS calcd. [C20H23N5Si + H]+: 362.1795, found: 362.1791.

4-(4-Fluorophenyl) Quinazoline (3b)[14]

Compound 3b was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 98% yield, (65.9 mg). 1H NMR (400 MHz, CDCl3): δ(ppm) 9.37 (s 1 H), 8.13(dd, J1 = 13.2 Hz, J2 = 8.4 Hz, 2 H), 7.95–7.91 (m, 1 H), 7.83–7.78 (m, 2 H), 7.66–7.61 (m, 1 H), 7.31–7.25 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ (ppm) 167.3, 164.1 (d, JC–F = 249.3 Hz), 154.7, 151.3, 133.9, 133.3 (d, JC–F = 3.4 Hz), 132.1 (d, JC–F = 8.6 Hz), 129.1, 128.0, 126.9, 123.2, 115.9 (d, JC–F = 21.8 Hz).

4-(4-Chlorophenyl) Quinazoline (3c)[14]

Compound 3c was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 97% yield, (69.8 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.35 (s, 1 H), 8.12–8.05 (m, 2 H), 7.93–7.89 (m, 1 H), 7.74–7.71 (m, 2 H), 7.63–7.59 (m, 1 H), 7.56–7.52 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.2, 154.7, 151.3, 136.6, 135.6, 133.9, 131.4, 129.2, 129.0. 128.0, 126.8, 123.0.

4-(4-Bromophenyl) Quinazoline (3d)[14]

Compound 3d was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 95% yield, (80.9 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.36 (s, 1 H), 8.12–8.05 (m, 2 H), 7.93–7.90 (m, 1 H), 7.72–7.70 (m, 2 H), 7.67–7.59 (m, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.3, 154.7, 151.3, 136.1, 134.0, 132.0, 131.6, 129.2, 128.1, 126.7, 124.9, 123.0.

4-o-Tolylquinazoline (3e)[6a]

Compound 3e was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a yellow oil: 85% yield, (56.1 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.38 (s, 1 H), 8.10 (d, J = 8.5 Hz, 1 H), 7.91–7.86 (m, 1 H), 7.68–7.65 (m, 1 H), 7.55–7.51 (m, 1 H), 7.43–7.39 (m, 1 H), 7.36–7.34 (m, 1 H), 7.33–7.29 (m, 1 H), 2.11 (s, 1 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 170.0, 154.7, 150.1, 136.5, 136.2, 134.0, 130.7, 129.4, 129.3, 128.8., 127.8, 127.2, 125.8, 124.2, 19.8.

4-m-Tolylquinazoline (3f)[14]

Compound 3f was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a yellow oil: 94% yield, (62.0 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.35 (s, 1 H), 8.12–8.07 (m, 2 H), 7.90–7.85 (m, 1 H), 7.59–7.52 (m, 3 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.37–7.34 (m, 1 H), 2.45 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.6, 154.7, 151.1, 138.6, 137.1, 133.7, 130.9, 130.5, 128.9, 128.5, 127.7, 127.2, 127.2, 123.2, 21.5.

4-(p-Tolyl) Quinazoline (3g)[14]

Compound 3g was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 97% yield, (64.0 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.34 (s, 1 H), 8.13–8.11 (m, 1 H), 8.07 (d, J = 8.4 Hz, 1 H),7.88–7.84 (m, 1 H), 7.66 (d, J = 6.4 Hz, 2 H), 7.58–7.54 (m, 1 H), 7.35 (d, J = 7.8 Hz, 2 H), 2.44 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.4, 154.7, 151.1, 140.4, 134.3, 133.6, 130.0, 129.4, 128.9, 127.6, 127.2, 123.2, 21.5.

4-(3-Methoxyphenyl) Quinazoline (3h)[15]

Compound 3h was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a yellow solid: 95% yield, (67.2 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.35 (s, 1 H),8.14–8.07 (m, 2 H), 7.90–7.86 (m, 1 H), 7.60–7.55 (m, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.32–7.19 (m, 2 H), 7.10–7.07 (m, 1 H), 3.86 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.3, 159.8, 154.6, 151.1, 138.4, 133.8, 129.7, 128.9, 127.8, 127.2, 123.2, 122.5, 116.0, 115.1, 55.5.

6-Bromo-4-methylquinazoline (3i)

Compound 3i was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 66% yield, (43.9 mg). mp 118–121 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 9.16 (s, 1 H), 8.22 (d, J = 2.0 Hz, 1 H), 7.92 (d, J = 3.7 Hz, 1 H), 7.88 (d, J = 8.9 Hz, 1 H), 2.91 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.5, 154.9, 148.4, 137.2, 131.0, 127.5, 125.6, 121.4, 21.5. HRMS calcd. [C9H7Br1N2 + H]+: 222.9865, found: 222.9868.

4-Methylquinazoline (3j)[3a]

Compound 3j was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a yellow oil: 62% yield, (26.8 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.12 (s, 1 H), 8.05–8.03 (m, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.85–7.81 (m, 1 H), 7.61–7.57 (m, 1 H), 2.90 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.3, 154.6, 149.6, 133.7, 129.0, 127.6, 125.0, 124.5, 21.8.

4-Ethylquinazoline (3k)[3a]

Compound 3k was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow oil: 50% yield, (23.7 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.20 (s, 1 H), 8.11 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 7.88–7.83 (m, 1 H), 7.63–7.59 (m, 1 H), 3.30 (q, J = 7.5 Hz, 2 H), 1.44 (t, J = 7.5 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 172.5, 154.8, 149.9, 133.6, 129.3, 127.6, 124.6., 123.8, 27.8, 12.8.

4-Propylquinazoline (3l)[3a]

Compound 3l was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a yellow oil: 76% yield, (39.2 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.18 (s, 1 H),8.10 (d, J = 8.4 Hz 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.86–7.82 (m, 1 H), 7.62–7.58 (m, 1 H), 3.22 (t, J = 7.7 Hz, 2 H), 1.94–1.85 (m, 2 H), 1.04 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 171.6, 154.6, 149.9, 133.6, 129.2, 127.6, 124.8, 124.1, 36.6, 22.4, 14.3.

4-Butylquinazoline (3m)[14]

Compound 3m was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a yellow oil: 52% yield, (29.1 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.20 (s, 1 H), 8.14–8.11 (m, 1 H), 8.03 (d, J = 8.5 Hz, 1 H), 7.89–7.84 (m, 1 H), 7.64–7.60 (m, 1 H), 3.27 (t, J = 7.9 Hz, 2 H), 1.90–1.81 (m, 2 H), 1.53–1.44 (m, 2 H), 0.98 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 172.0, 154.7, 150.0, 133.6, 129.3, 127.6, 124.9, 124.1, 34.5, 31.3, 23.0, 14.0.

4-Isopropylquinazoline (3n)[14]

Compound 3n was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a yellow oil: 66% yield, (34.1 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.23 (s, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.86–7.82 (m, 1 H), 7.62–7.58 (m, 1 H), 3.98–3.90 (m, 1 H), 1.41 (d, J = 6.8 Hz, 6 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 175.9, 154.8, 150.1, 133.4, 129.4, 127.5, 124.3, 123.2, 31.0, 21.8.

4-Cyclopropylquinazoline (3o)[5a]

Compound 3o was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 88% yield, (44.9 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.06 (s, 1 H), 8.27 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.85–7.81 (m, 1 H), 7.62–7.58 (m, 1 H), 2.77–2.70 (m, 1 H), 1.41–1.37 (m, 2 H), 1.24–1.20 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 172.5, 154.8, 149.5, 133.4, 129.1, 127.3, 124.5, 124.5, 12.9, 12.4.

6-Chloroquinazoline (3p)[14]

Compound 3p was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 43% yield, (21.2 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.35 (d, J = 6.2 Hz, 2 H), 8.01 (d, J = 9.0 Hz, 1 H), 7.93 (d, J = 2.1 Hz, 1 H), 7.86 (dd, J1 = 9.0 Hz, J2 = 2.3 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.4, 155.6, 148.7, 135.4, 133.8, 130.4, 126.0, 125.7.

6-Bromoquinazoline: (3q)

Compound 3q was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 64% yield, (39.9 mg). mp 136–138 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 9.31 (d, J = 4.4 Hz, 2 H), 8.06 (d, J = 2.0 Hz, 1 H), 7.95 (d, J1 = 9.0 Hz, 1 H), 7.90 (d, J = 9.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.2, 155.6, 148.7, 137.8, 130.3, 129.3, 126.0, 121.7. HRMS calcd. [C8H5Br2N2 + H]+: 208.9709, found: 208.9711.

6,8-Dibromoquinazoline: (3r)

Compound 3r was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 72% yield, (61.8 mg). mp 165–167 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 9.43 (s, 1 H), 9.30 (s, 1 H), 8.29 (d, J = 2.0 Hz, 1 H), 8.05 (d, J = 2.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.8, 156.3, 146.5, 140.4, 129.0, 126.7, 125.0, 121.4. HRMS calcd. [C8H4Br2N2 + H]+: 286.8814, found: 286.8815.

6-Chloro-4-(2-chlorophenyl) Quinazoline: (3s)[5a]

Compound 3s was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 91% yield, (74.8 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.39 (s, 1 H), 8.05 (d, J = 9.0 Hz, 1 H) 7.81 (d, J = 9.0 Hz, 1 H) 7.60 (d, J = 2.3 Hz, 1 H), 7.56–7.54 (m, 1 H), 7.50–7.40 (m, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 166.4, 154.9, 149.1, 135.4, 135.1, 133.8, 132.7, 131.1, 130.9, 130.7, 130.2, 127.2, 125.6, 124.4.

6-Chloro-4-phenylquinazoline: (3t)[14]

Compound 3t was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 93% yield, (66.9 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.34 (s, 1 H), 8.07 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 9.0 Hz, 1 H), 7.85 (d, J = 9.0 Hz, 1 H), 7.75–7.72 (m, 2 H), 7.57–7.55 (m, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.6, 154.8, 149.6, 136.5, 134.7, 133.5, 130.7, 130.4, 129.9, 128.9, 125.8, 123.7.

6-Bromo-4-phenylquinazoline (3u)[14]

Compound 3u was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give the product as a light yellow solid: 92% yield, (78.4 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.37 (s, 1 H), 8.25 (d, J = 1.8 Hz, 1 H), 7.99–7.93 (m, 2 H), 7.76–7.72 (m, 2 H), 7.61–7.54 (m, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.6, 155.0, 149.9, 137.3, 136.6, 130.8, 130.5, 129.9, 129.2, 128.9, 124.2, 121.7.

3-Phenylquinazolin-4(3H)-one (5a)[14]

Compound 5a was prepared according to general working procedure B and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow solid: 62% yield, (41.3 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.37 (d, J = 8.1 Hz, 1 H), 8.13 (s, 1 H), 7.83–7.76 (m, 2 H), 7.58–7.47 (m, 4 H), 7.44–7.41 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.9, 148.0, 146.2, 137.6, 134.7, 129.8, 129.3, 127.8, 127.7, 127.3, 127.1, 122.5.

3-Butylquinazolin-4(3H)-one (5b)[14]

Compound 5b was prepared according to general working procedure B and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow solid: 76% yield, (46.1 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.30 (d, J = 7.1 Hz, 1 H), 8.02 (s, 1 H), 7.76–7.68 (m, 2 H), 7.51–7.45 (m, 1 H), 3.99 (t, J = 7.4 Hz, 2 H), 1.81–1.73 (m, 2 H), 1.45–1.35 (m, 2 H), 0.96 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 161.2, 148.2, 146.7, 134.3, 127.5, 127.4, 126.8, 122.3, 46.9, 31.5, 20.0, 13.8.

3-Isopropylquinazolin-4(3H)-one (5c)[14]

Compound 5c was prepared according to general working procedure B and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow solid: 52% yield, (29.3 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.30 (d, J = 8.1 Hz, 1 H), 8.11 (s, 1 H), 7.75–7.67 (m, 2 H), 7.50–7.46 (m, 1 H), 5.18 (m, 1 H), 1.48 (d, J = 6.9 Hz, 6 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.7, 147.7, 143.7, 134.2, 127.4, 127.3, 127.0, 122.1, 46.1, 22.1.

3-Cyclohexylquinazolin-4(3H)-one (5d)[16]

Compound 5d was prepared according to general working procedure B and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow solid: 62% yield, (42.4 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.29 (d, J = 8.1 Hz, 1 H), 8.11 (s, 1 H), 7.74–7.66(m, 2 H), 7.49–7.45(m, 1 H), 4.84–4.76(m, 1 H), 2.00–1.90(m, 4 H), 1.68–1.44(m, 4 H), 1.30–1.18(m, 2 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.8, 146.6, 143.0, 133.2, 126.3, 126.2, 126.0, 121.0, 52.5, 31.7, 25.0, 24.4.

3-tert-Butylquinazolin-4(3H)-one (5e)[14]

Compound 5e was prepared according to general working procedure B and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow solid: 24% yield, (14.5 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.29 (s, 1 H), 8.27–8.25 (m, 1 H), 7.72–7.62 (m, 2 H), 7.46–7.42 (m, 1 H), 1.73 (s, 9 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 162.1, 147.4, 144.1, 134.0, 127.0, 126.8, 126.8, 123.2, 60.8, 28.8.

3-Benzylquinazolin-4(3H)-one (5f)[14]

Compound 5f was prepared according to general working procedure B and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow solid: 84% yield, (59.4 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.32–8.30 (, 1 H), 8.10 (s, 1 H), 7.75–7.67 (m, 2 H), 7.50–7.46 (m, 1 H), 7.34–7.26 (m, 5 H), 5.18 (s, 2 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.1, 147.1, 145.4, 134.8, 133.4, 128.1, 130.7, 127.4, 127.1, 126.5, 126.4, 125.9, 121.2, 48.7.

3-Allylquinazolin-4(3H)-one (5g)[17]

Compound 5g was prepared according to general working procedure B and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow solid: 66% yield, (36.8 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.31 (d, J = 8.0 Hz, 1 H), 8.03 (s, 1 H), 7.78–7.70 (m, 2 H), 7.52–7.48 (m, 1 H), 6.03–5.94 (m, 1 H), 5.32–5.22 (m, 2 H), 4.64–4.62, (m, 2 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.9, 148.1, 146.4, 134.4, 131.9, 127.5, 127.5, 126.9, 122.2, 119.1, 48.5.

[3-15N]-4-Phenylquinazoline ([)[14]

Compound []3a was prepared according to general working procedure C and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow solid: 85% yield, (52.8 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 9.35 (d, J = 14.8 Hz, 1 H), 8.10–8.07 (m, 2 H), 8.89–8.85 (m, 1 H), 7.77–7.72 (m, 2 H), 7.58–7.52 (m, 4 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.4, 154.7(d, J = 4.3 Hz), 151.1 (d, J = 3.0 Hz), 137.1 (d, J = 7.2 Hz), 133.7, 130.1, 130.0 (d, J = 1.1 Hz), 128.9, 128.7, 127.8, 127.1, 123.2. HRMS calcd. [C14H10N15N + H]+: 208.0892 , found: 208.0891.

1,1′-(2,6-Dimethylpyridine-3,5-diyl) Diethanone (7)[18]

Compound 7 was prepared according to general working procedure A and purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give the product as a light yellow oil: 53% yield, (30.4 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.21 (s, 1 H), 2.73 (s, 6 H), 2.59 (s, 6 H). 13C NMR (100 MHz, CDCl3) δ (ppm) 199.3, 160.4, 137.9, 130.2, 29.4, 25.1.