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Jan 17, 2018 - erlotinib3c,d and afatinib4 were approved for the treatment of cancer with different ... Figure 1. Quinazolines as medicinal agents. No...
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Synthesis of Quinazolines via an Iron-Catalyzed Oxidative Amination of N−H Ketimines Cheng-yi Chen,*,† Fengxian He,*,‡ Guangrong Tang,‡ Huiqing Yuan,‡ Ning Li,‡ Jinmin Wang,‡ and Roger Faessler† †

Janssen R&D, Pharmaceutical Development and Manufacturing Sciences, Small Molecule API Switzerland, Cilag AG, Hochstrasse 201, 8205 Schaffhausen, Switzerland ‡ Porton (Shanghai) R&D Center, 1299 Ziyue Road, Zizhu Science Park, Minhang District, Shanghai 200241, China S Supporting Information *

ABSTRACT: An efficient synthesis of quinazolines based on an iron-catalyzed C(sp3)-H oxidation and intramolecular C−N bond formation using tert-BuOOH as the terminal oxidant is described. The reaction of readily available 2-alkylamino benzonitriles with various organometallic reagents led to 2alkylamino N−H ketimine species. The FeCl2-catalyzed C(sp3)-H oxidation of the alkyl group employing tert-BuOOH followed by intramolecular C−N bond formation and aromatization afforded a wide variety of 2,4-disubstituted quinazolines in good to excellent yields.

mong six-membered benzoheterocycles, quinazolines and quinazolinones represent a ubiquitous class of compounds displaying a broad range of biological activities.1 Structural diversities and biological activities render this class of compounds attractive targets for drug discovery and development. Evidently, a large number of drugs have been developed based on this pharmacophore (Figure 1).2 For example, the quinazoline-containing drug gefitinib is an inhibitor of the protein kinase of epidermal growth factor receptor (EGFR), which was marketed as an anticancer drug.3a,b In 2013, erlotinib3c,d and afatinib4 were approved for the treatment of cancer with different mechanisms of action. A structural simple quinazoline such as quazodine is a muscle relaxer,5 and the

A

antimetabolite drug raltiterxed6 also contains a quinazoline moiety. Last, quinazolines bearing 4-aromatic groups have been identified as potent PI3K delta-selective inhibitors and potentially as new oncology drugs.7 The importance of quinazolines as medicinal agents has consequently inspired the development of various synthetic methods toward this class of compounds.8 Many conventional synthetic methods for the construction of quinazoline-based preactivated substrates or multistep transformations have been reported.9 Transition metal-catalyzed transformations now serve as powerful tools for synthesizing these useful compounds.10 On the other hand, an increasing demand for clean, fast, efficient, and selective processes, especially ones that are viable for large-scale synthesis, has prompted utilization of readily available, less toxic, and inexpensive metal catalysts. Iron is the second most abundant metal on earth, and a variety of iron salts as well as complexes are commercially available. As a consequence of these characters, iron-catalyzed reactions in organic synthesis have gained strong momentum in recent years.11 The applications of iron-catalysis in heterocycle synthesis have also been highlighted.12 Herein, we report the facile synthesis of quinazolines via an iron-catalyzed C(sp3)-H oxidation using tert-BuOOH as the terminal oxidant followed by intramolecular amination and aromatization.13 We have reported that addition of Grignard or organolithium reagents to readily available ortho-alkylamino benzonitriles (1) forms orthoalkylaminoaryl N−H ketimines (2, Scheme 1).14 We envisioned that subsequent C(sp3)-H oxidation on the α-proton of the aminoalkyl group would form imine or iminium species (4). Facile ring-closure with nucleophilic attack of the imine N−H group would then form the dihydroquinolines (5a and 5b).

Figure 1. Quinazolines as medicinal agents.

Received: November 20, 2017 Published: January 17, 2018

© 2018 American Chemical Society

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conditions shown in entry 5 for the oxidative amination and applied them to the synthesis of a wide variety of quinazolines from ortho-alkyamino ketimines. We first explored the generality of the identified conditions in the synthesis of quinazolines from ketimines 9 bearing an Nmethyl group. As shown in Scheme 2, the C(sp3)-H oxidation Scheme 2. Synthesis of 4-Substituted Quinazolines from 2Methylaminobenzonitrilea

Aromatization via oxidation9b would ultimately lead to the formation of quinazoline (3). Addition of phenylmagnesium bromide to nitrile 6 readily afforded ketimine 7, which was isolated and used to explore the oxidative amination for the preparation of quinazolines. Hence, a combination of iron salt and oxidizer was screened as shown in Table 1. In entries 1−3, the combination of FeCl2 as catalyst Table 1. Screening of Iron Catalysts and Oxidizers for the Construction of Quinazoline

entrya 1 2 3 4 5 6 7 8 9 10

catalyst FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 FeCl2 Fe(OAc)2

oxidizer H2O2b

30% aq MnO2 K2S2O8 BPO t-BuOOHc t-BuOOH

70% aq t-BuOOHd t-BuOOH t-BuOOH

temp (°C)

yielde (%)

25 50 50 50 25 25 25 25 25 25

15 49 46 ND 84 (79f) 0 0 76 75 66

All reactions were run in DMSO (20 g/g substrate) at 25 °C for 18 h, and products were isolated in gram quantity after SiO2 column chromatography.

a

of the methyl C−H followed by ring closure afforded a wide variety of 4-substituted quinazolines (8, 10a−j, 12) in modest to good yields under milder conditions. A wide variety of alkyl groups including a cyclopropyl group can be introduced to the molecule to give quinazolines (10a−e) in 52−81% yields. Additionally, different aromatic group with ortho, meta, and para substituents can be installed in good yields (10f−i, 70− 85%). The reaction sequence can also tolerate a bulky mesityl group (10j). Furthermore, quazodine (12, 4-ethyl-6,7-dimethoxy quinazoline), a muscle relaxer drug, was easily prepared in 72% yield.15 The success of quinzoline synthesis from methylaminonitrile 6 was next extended to the 2-benyzlamino substrates (13) to afford 2-phenyl-4-substituted quinazolines (15a−j). We anticipated these substrates would allow for more efficient transformation due to the facile formation of more stable iminium species (4, R = Ph), especially with steric bulky groups. As shown in Scheme 3, a wide variety of organometallic reagents can be readily added to nitrile 13. Subsequent oxidation ring closure afforded compounds 15a−j in 55−83% yields. As compared to 2-methylaminobenzonitrile, the benzyl species in general afforded comparable yields of quinazolines. Steric bulky groups such as mesityl and ortho-methoxynathyl groups were introduced into the quinazoline core to afford 15i and 15j16 in 61 and 55% yields, respectively. The methodology of C(sp3)-H oxidation followed by ring closure was next applied to other nitriles bearing 2-alkylamino

a Reaction conditions: 6, (2 mmol), catalyst (20 mol %), oxidizer (1.3 equiv), DMSO (5 mL) under air for 18 h. bUsing 30% aq H2O2 (2.6 equiv). cUsing 5.0−6.0 M t-BuOOH in decane. dUsing 70% aq tBuOOH (2.6 equiv). eAll the yields were based on HPLC analysis against the standard of 8. fUsing 1.0 g scale; isolated yield.

with oxidizers such as H2O2, MnO2, and K2S2O8 in DMSO all gave the desired quinazoline albeit in low yield. Benzoyl peroxide (BPO) is ineffective for this reaction without forming any desired product. We were delighted to find that anhydrous tert-BuOOH in decane served as a very effective oxidizer for the oxidative amination with the formation of quinazoline 8 in 79% isolated yield (Table 1, entry 5). The oxidation did not occur in the absence of Fe-catalyst or tert-BuOOH (entries 6 and 7) to give quinazoline. It was also noted that 1.3 equiv of oxidant is sufficient to drive the reaction to completion, presumably due to the air oxidation of the intermediates.9c Aqueous tertBuOOH is also feasible to facilitate this reaction but with lower efficiency (entry 8) due to the partial hydrolysis of imine to ketone. Catalysts such as FeCl3 and Fe(OAc)2 in combination with tert-BuOOH are less effective than FeCl2. We then chose 2396

DOI: 10.1021/acs.joc.7b02943 J. Org. Chem. 2018, 83, 2395−2401

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yields obtained (17e and f). Using this protocol, heterocycles such as pyridine, furan, and thiophene can be readily installed at the 2-position of the quinazoline to afford products (17g−i) in 80−82% yields. In conclusion, we have developed an efficient synthetic method for the synthesis of quinazolines based on ironcatalyzed C(sp3)-H oxidation using tert-BuOOH as the terminal oxidant. The N−H ketimine precursors were readily prepared from ortho-alkylamino benzonitriles and organometallic reagents. The simplicity and high efficiency of this protocol offers complementarity to the other methods reported in the literature. The oxidation of the N-alkyl group in this protocol employs inexpensive and nontoxic iron salts without using privileged ligands. The method demonstrated here provided an expedited synthesis of a wide variety of quinazolines. We hope this work will prompt others to explore the application of iron catalysis in heterocycle syntheses.

Scheme 3. Synthesis of 2-Phenyl-4-substituted Quinazolines from 2-Benzylaminobenzonitriles (13)a

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EXPERIMENT SECTION

General Information. Preparation of imines was carried out under nitrogen. Commercially available reagents were used as received. Flash chromatography was carried out with Sunasiachem silica gel (200−300 mesh). 1H NMR and 13C NMR spectra were recorded on a Varian 400 NMR spectrometer with chemical shifts reported in ppm relative to Me4Si for 1H NMR and CDCl3 for 13C NMR. High-resolution mass spectra were obtained using the Waters Q-Tof Ultima global instrument at the mass spectrometry facility of the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences. 4,5-Dimethoxy-2-methylaminobenzonitrile (11).17 The reaction was run according to the literature procedure using 4,5-dimethoxy-2amino-benzonitrile (2.0 g, 11.2 mmol), dimethyl oxalate (2.0 g, 16.8 mmol), and t-BuOK (1.6 g, 14.0 mmol) in DMA (25 mL) to afford 11 (0.93 g, 43% yield) as a pale yellow solid. Mp: 135.8−137.4 °C. 1H NMR (400 MHz, CDCl3): δ 6.84 (s, 1H), 6.19 (s, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 2.93 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 155.1, 148.2, 140.9, 118.6, 114.6, 94.9, 85.6, 56.8, 56.0, 30.8. HRMS (ESI) calcd for C10H13N2O2 [M + H]+: 193.0977, found: 193.0967. General Procedure for the Preparation of 2-Arylmethylaminobenzonitriles. 2-Arylmethyleneaminobenzonitrile was prepared according to the following procedure.18 Under nitrogen, a mixture of 2-aminobenzonitrile (1.0 equiv) and arylaldehyde (1.2 equiv) in absolute methanol was heated at 45−50 °C for 24−72 h until 2aminobenzonitrile was consumed. Then, NaBH4 (1.5 equiv) was added in portions at 0−5 °C, and the mixture was stirred at 0−5 °C for 2 h. The reaction was quenched with water and extracted with EtOAc. After concentration of the organic solution in vacuum, the crude product was purified through flash chromatography (EtOAc/nheptane = 1:20) to afford 2-arylmethylaminobenzonitriles. 2-Benzylaminobenzonitrile (13).19 The reaction was run according to the general method using 2-aminobenzonitrile (5.0 g, 42.3 mmol), benzaldehyde (5.4 g, 50.8 mmol), and NaBH4 (2.4 g, 63.5 mmol) in absolute methanol (150 mL) to afford 2-benzylaminobenzonitrile (6.2 g, 70% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.44− 7.40 (m, 1H), 7.40−7.27 (m, 6H), 6.70 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 5.03 (br, 1H), 4.44 (d, J = 5.6 Hz, 2H). 2-Benzylamino-4-chlorobenzonitrile (13, X = Cl). The reaction was run according to the general method using 2-amino-4chlorobenzonitrile (2.0 g, 13.1 mmol), benzaldehyde (1.7 g, 15.7 mmol), and NaBH4 (0.75 g, 19.7 mmol) in absolute methanol (50 mL) to afford 2-benzylamino-4-chlorobenzonitrile (1.66 g, 52% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.5 Hz, 1H), 7.40−7.15 (m, 5H), 6.71 (t, J = 7.4 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 5.07 (brs, 1H), 4.43 (d, J = 5.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 149.9, 140.1, 134.9, 134.5, 132.9, 130.3, 128.0, 127.3, 125.2, 117.9, 117.4, 111.1, 96.3, 47.1. HRMS (ESI) calcd for C14H11ClN2Na [M + Na]+: 265.0508, found: 265.0503. 2-p-Bromobenzylaminobenzonitrile (16, R = 4-p-Ph). The reaction was run according to the general method using 2-

All reactions were run in DMSO (20 g/g substrate) at 25 °C for 18 h, and products were isolated in gram quantity after SiO2 column chromatography. bCompound 15i was prepared at 45 °C.

a

groups besides methyl and benzyl. As shown in Scheme 4, a nitrile-bearing ethylamino group afforded the desired 2methylqunazoline (17a) in 86% yield. Extension to parasubstituted benzyl groups led to quinazolines (17b−d) in good yields (84−85%). Compared to 15g, substrate-containing groups such as chlorine and methyl at the ortho position seemed to decrease the efficiency of the process with lower Scheme 4. Synthesis of 2,4-Disubstituted Quinazolines from 2-Alkylaminobenzonitrilesa

All reactions were run in DMSO (20 g/g substrate) at 25 °C for 18 h, and compounds were isolated in gram quantity after SiO2 column chromatography.

a

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yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 3H), 6.73 (dd, J = 20.7, 8.1 Hz, 2H), 6.34 (s, 1H), 6.26 (s, 1H), 4.95 (brs, 1H), 4.41 (s, 2H). 2-2′-Thiophenylmethylaminobenzonitrile (16, R = 2-thiophenyl). The reaction was run according to the general method using 2aminobenzonitrile (5.0 g, 42.3 mmol), 2-thiophenecarboxaldehyde (5.7 g, 50.8 mmol), and NaBH4 (2.4 g, 63.5 mmol) in absolute methanol (150 mL) to afford 2-2′-thiophenylmethylamino) benzonitrile (5.0 g, 55% yield) as a white solid. Mp: 53.6−55.5 °C. 1H NMR (400 MHz, CDCl3): δ 7.40 (ddd, J = 17.4, 8.3, 1.5 Hz, 2H), 7.24 (dd, J = 5.1, 1.2 Hz, 1H), 7.05−7.01 (m, 1H), 6.98 (dd, J = 5.0, 3.5 Hz, 1H), 6.77−6.68 (m, 2H), 5.01 (brs, 1H), 4.61 (d, J = 5.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 149.7, 141.2, 134.4, 132.9, 127.2, 125.6, 125.2, 117.8, 117.4, 111.2, 96.4, 42.8. HRMS (ESI) calcd for C12H10N2SNa [M + Na]+: 237.0462, found: 237.0458. General Procedure for the Preparation of Quinazolines. To a cooled solution of corresponding 2-alkylaminobenzonitrile (1.0 equiv) in THF was added the corresponding Grignard reagent (3.3 equiv) or organolithium reagent (3.3 equiv) at 10 °C (for Grignard reagent) or −50 °C (for organolithium reagent) under nitrogen. After addition, the reaction was stirred for 3 h at 30 °C (for Grignard reagent) or 10 °C (for organolithium reagent). This reaction mixture was poured into brine and extracted with MTBE. The organic layer was dried over Na2SO4 and concentrated in a vacuum to afford the corresponding N− H ketamine, which is directly used in the preparation of quinazolines. To the mixture of N−H ketimine and FeCl2 (0.2 equiv) in DMSO was added t-BuOOH (1.3 equiv, 5−6 M in decane) dropwise at 25 °C. The resulted mixture was stirred at 25 °C (unless otherwise specified) until the imine was completely consumed. The reaction was poured into water and then extracted with EtOAc. After concentration in vacuum, the crude product was purified through flash chromatography (EtOAc/n-heptane = 1:20−1:10). 4-Phenylquinazoline (8).22 The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.01 g, 7.64 mmol), phenylmagnesium bromide (25 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-phenylquinazoline (1.25 g, 79% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.38 (s, 1H), 8.13 (dd, J = 12.1, 4.4 Hz, 2H), 7.92 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.82−7.72 (m, 2H), 7.62−7.57 (m, 1H), 7.55 (dd, J = 6.7, 3.6 Hz, 3H). 4-Methylquinazoline (10a).23 The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), methylmagnesium bromide (25.0 mL, 1 M in THF), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5.0−6.0 M in decane) in DMSO (18 mL) to afford 4-methylquinazoline (0.59 g, 54% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 9.16 (s, 1H), 8.08 (dd, J = 8.4, 0.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.87 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.70−7.56 (m, 1H), 2.95 (s, 3H). 4-Ethylquinazoline (10b).24 The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), ethyllithium (19.0 mL, 1.3 M in Et2O), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5.0−6.0 M in decane) in DMSO (18 mL) to afford 4-ethylquinazoline (0.62 g, 52% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 8.14−8.08 (m, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.88−7.81 (m, 1H), 7.65−7.57 (m, 1H), 3.29 (m, 2H), 1.45 (dd, J = 9.5, 5.6 Hz, 3H). 4-Isopropylquinazoline (10c).25 The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), isopropylmagnesium bromide (25.0 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5.0−6.0 M in decane) in DMSO (18 mL) to afford 4-isopropylquinazoline (1.05 g, 81% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 8.17 (dd, J = 8.4, 0.5 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.86 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.62 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 3.93 (dt, J = 13.6, 6.8 Hz, 1H), 1.43 (d, J = 6.8 Hz, 6H). 4-Cyclopropylquinazoline (10d). The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), cyclopropylmagnesium bromide (25.0 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol) and t-BuOOH (2.0 mL, 5.0−6.0 M in decane) in DMSO (18 mL) to afford 4-cyclopropylquinazoline

aminobenzonitrile (5.0 g, 42.3 mmol), 4-bromobenzaldehyde (9.4 g, 50.8 mmol), and NaBH4 (2.4 g, 63.5 mmol) in absolute methanol (150 mL) to afford 2-p-bromobenzylaminobenzonitrile (8.1 g, 67% yield) as an off-white solid. Mp: 118.2−121.4 °C. 1H NMR (400 MHz, CDCl3): δ 7.53−7.44 (m, 2H), 7.42 (dd, J = 7.8, 1.5 Hz, 1H), 7.36− 7.29 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.76−6.65 (m, 1H), 6.56 (d, J = 8.5 Hz, 1H), 5.06 (brs, 1H), 4.41 (d, J = 5.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 149.9, 137.0, 134.4, 132.9, 132.1, 128.8, 121.5, 117.9, 117.3, 111.1, 96.2, 46.9. HRMS (ESI) calcd for C14H11BrN2Na [M + Na]+: 309.0003, 310.9983, found: 308.9988, 310.9979. 2-p-Methoxybenzylaminobenzonitrile (16, R = p-MeOPh).20 The reaction was run according to the general method using 2aminobenzonitrile (3.0 g, 25.4 mmol), 4-methoxybenzaldehyde (4.2 g, 30.5 mmol), and NaBH4 (1.4 g, 38.1 mmol) in absolute methanol (100 mL) to afford 2-p-methoxybenzylaminobenzonitrile (4.1 g, 68% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.42 (dd, J = 7.7, 1.3 Hz, 1H), 7.39−7.33 (m, 1H), 7.30−7.22 (m, 2H), 6.94−6.85 (m, 2H), 6.74−6.61 (m, 2H), 4.95 (brs, 1H), 4.37 (d, J = 5.4 Hz, 2H), 3.83 (s, 3H). 2-p-(Trifluoromethylbenzylaminobenzonitrile (16, R = p-CF3Ph). The reaction was run according to the general method using 2aminobenzonitrile (5.0 g, 42.3 mmol), 4-trifluoromethylbenzaldehyde (8.8 g, 50.8 mmol), and NaBH4 (2.4 g, 63.5 mmol) in absolute methanol (150 mL) to afford 2-p-trifluoromethylbenzylaminobenzonitrile (7.6 g, 65% yield) as an off-white solid. Mp: 108.0−110.3 °C. 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 8.1 Hz, 2H), 7.52−7.38 (m, 3H), 7.33 (t, J = 7.9 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H), 5.13 (brs, 1H), 4.52 (d, J = 5.8 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 149.8, 142.1(q, J = 1.2 Hz), 134.5, 133.0, 130.5 (q, J = 32.5 Hz), 127.3, 126.0 (q, J = 3.8 Hz), 124.2 (d, J = 272.0 Hz), 117.9, 117.5, 111.1, 96.4, 47.1. HRMS (ESI) calcd for C15H12F3N2 [M + H]+: 277.0953, found: 277.0949. 2-o-Tolylaminobenzonitrile (16, R = o-tolyl).20 The reaction was run according to the general method using 2-aminobenzonitrile (5.0 g, 42.3 mmol), 2-methylbenzaldehyde (6.1 g, 50.8 mmol), and NaBH4 (2.4 g, 63.5 mmol) in absolute methanol (150 mL) to afford 2otolylaminobenzonitrile (5.7 g, 61% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.46−7.32 (m, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.25−7.14 (m, 3H), 6.75−6.59 (m, 2H), 4.79 (brs, 1H), 4.36 (d, J = 5.3 Hz, 2H), 2.37 (s, 3H). 2-o-Chlorobenzylaminobenzonitrile (16, R = o-ClPh). The reaction was run according to the general method using 2aminobenzonitrile (3.0 g, 25.4 mmol), 2-chlorobenzaldehyde (4.3 g, 30.5 mmol), and NaBH4 (1.4 g, 38.1 mmol) in absolute methanol (100 mL) to afford 2-o-chlorobenzylaminobenzonitrile (4.2 g, 68% yield) as a white solid. Mp: 117.1−119.0 °C. 1H NMR (400 MHz, CDCl3): δ 7.48−7.36 (m, 2H), 7.36−7.28 (m, 2H), 7.28−7.17 (m, 2H), 6.75−6.63 (m, 1H), 6.56 (d, J = 8.5 Hz, 1H), 5.09 (brs, 1H), 4.54 (d, J = 6.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 149.9, 135.1, 134.4, 133.3, 132.9, 129.9, 129.0, 128.6, 127.2, 117.9, 117.2, 111.1, 96.2, 45.2. HRMS (ESI) calcd for C14H11ClN2Na [M + Na]+: 265.0508, found: 265.0503. 2-2′-Pyridinylmethylaminobenzonitrile (16, R = 2-pyridinyl). The reaction was run according to the general method using 2aminobenzonitrile (5.0 g, 42.3 mmol), picolinaldehyde (5.4 g, 50.8 mmol), and NaBH4 (2.4 g, 63.5 mmol) in absolute methanol (150 mL) to afford 2-2′-pyridinylmethylaminobenzonitrile (7.3 g, 83% yield) as a pale yellow solid. Mp: 63.0−63.6 °C. 1H NMR (400 MHz, CDCl3): δ 8.61 (dd, J = 4.9, 0.7 Hz, 1H), 7.67 (td, J = 7.8, 1.6 Hz, 1H), 7.43 (dd, J = 7.8, 0.5 Hz, 1H), 7.38−7.28 (m, 2H), 7.22 (dd, J = 7.5, 4.9 Hz, 1H), 6.70 (t, J = 7.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 5.77 (brs, 1H), 4.55 (d, J = 5.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 156.9, 150.0, 149.6, 136.9, 134.4, 133.0, 122.6, 121.4, 118.0, 117.0, 111.3, 96.3, 48.6. HRMS (ESI) calcd for C13H12N3 [M + H]+: 210.1031, found: 210.1025. 2-2′-Furanylmethylaminobenzonitrile (16, R = 2-furanyl).21 The reaction was run according to the general method using 2aminobenzonitrile (5.9 g, 50.0 mmol), furfural (5.8 g, 60.0 mmol), and NaBH4 (2.8 g, 75.0 mmol) in absolute methanol (150 mL) to afford 2-2′-furanylmethylaminobenzonitrile (7.2 g, 73% yield) as a 2398

DOI: 10.1021/acs.joc.7b02943 J. Org. Chem. 2018, 83, 2395−2401

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The Journal of Organic Chemistry (0.81 g, 63% yield) as a yellow solid. Mp: 62.8−65.2 °C. 1H NMR (400 MHz, CDCl3): δ 9.09 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.91−7.84 (m, 1H), 7.68−7.60 (m, 1H), 2.85−2.70 (m, 1H), 1.45−1.37 (m, 2H), 1.29−1.20 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 172.4, 154.7, 149.4, 133.3, 129.0, 127.2, 124.4, 124.4, 12.8, 12.3. HRMS (ESI) calcd for C11H11N2 [M + H]+: 171.0922, found:171.0915. 4-n-Butylquinazoline (10e).25 The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), n-butyllithium (16.0 mL, 1.6 M in hexane), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5.0−6.0 M in decane) in DMSO (18 mL) to afford 4-n-butylquinazoline (0.82 g, 58% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 9.18 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.88−7.80 (m, 1H), 7.60 (t, J = 7.6 Hz, 1H), 3.31−3.17 (m, 2H), 1.84 (dt, J = 12.9, 7.8 Hz, 2H), 1.53−1.40 (m, 2H), 0.96 (dt, J = 7.2, 5.8 Hz, 3H). 4-m-Fluorophenylquinazoline (10f). The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), 3-fluorophenylmagnesium bromide (25.0 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5.0− 6.0 M in decane) in DMSO (18 mL) to afford 4-m-fluorophenylquinazoline (1.21 g, 71% yield) as a yellow solid. Mp: 57.3−58.0 °C. 1H NMR (400 MHz, CDCl3): δ 9.39 (s, 1H), 8.13 (t, J = 8.7 Hz, 2H), 8.02−7.90 (m, 1H), 7.71−7.60 (m, 1H), 7.60−7.47 (m, 3H), 7.32− 7.26 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 167.0 (d, J = 2.3 Hz), 162.7 (d, J = 247.6 Hz), 154.5, 151.1, 139.1 (d, J = 7.5 Hz), 133.9, 130.3 (d, J = 8.2 Hz), 129.0, 128.0, 126.7, 125.7 (d, J = 3.1 Hz), 122.9, 117.1 (d, J = 7.4 Hz), 116.9 (d, J = 9.1 Hz). HRMS (ESI) calcd for C14H9FN2 [M + H]+: 225.0828, found: 225.0816. 4-p-Fluorophenylquinazoline (10g).25 The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), 4-fluorophenylmagnesium bromide (25.0 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5.0− 6.0 M in decane) in DMSO (18 mL) to afford 4-p-fluorophenylquinazoline (1.19 g, 70% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.37 (s, 1H), 8.12 (dd, J = 11.9, 4.3 Hz, 2H), 7.98− 7.90 (m, 1H), 7.86−7.75 (m, 2H), 7.65 (dd, J = 11.8, 4.5 Hz, 1H), 7.32−7.26 (m, 2H). 4-p-Methoxyphenylquinazoline (10h).26 The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), 4-methoxyphenylmagnesium bromide (25.0 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5.0−6.0 M in decane) in DMSO (18 mL) to afford 4-pmethoxyphenylquinazoline (1.20 g, 67% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.34 (s, 1H), 8.18 (dd, J = 8.4, 0.7 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.91 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.82−7.74 (m, 2H), 7.61 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.16−7.98 (m, 2H), 3.90 (s, 3H). 4-o-Tolylquinazoline (10i).27 The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), o-tolylmagnesium bromide (25.0 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5.0−6.0 M in decane) in DMSO (18 mL) to afford 4-o-tolylquinazoline (1.42 g, 85% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 9.40 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.91 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.69 (ddd, J = 8.4, 1.3, 0.6 Hz, 1H), 7.56 (ddd, J = 8.2, 6.9, 1.1 Hz, 1H), 7.47−7.40 (m, 1H), 7.40−7.30 (m, 3H), 2.14 (s, 3H). 4-Mesitylquinazoline (10j). The reaction was run according to the general procedure using 2-methylaminobenzonitrile (1.00 g, 7.57 mmol), mesitylmagnesium bromide (25.0 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol), and t-BuOOH (2.0 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-mesitylquinazoline (0.82 g, 43% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.41 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.90 (dd, J = 6.4, 2.0 Hz, 1H), 7.52 (ddd, J = 7.5, 4.2, 0.8 Hz, 2H), 6.98 (s, 2H), 2.36 (s, 3H), 1.88 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 170.7, 155.3, 150.4, 138.6, 135.6, 134.1, 133.3, 128.9, 128.5, 128.0, 126.6, 124.6, 21.3, 19.8. HRMS (ESI) calcd for C17H17N2 [M + H]+: 249.1392, found: 249.1380. 4-Ethyl-6,7-dimethoxyquinazoline (12).15 The reaction was run according to the general procedure using 4,5-dimethoxy-2-methyl-

aminobenzonitrile (0.93 g, 4.84 mmol), ethylmagnesium bromide (16.0 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-ethyl-6,7dimethoxyquinazoline (0.75 g, 72% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.05 (s, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 4.04 (d, J = 2.9 Hz, 6H), 3.21 (q, J = 7.5 Hz, 2H), 1.45 (t, J = 7.5 Hz, 3H). 4-Isopropyl-2-phenylquinazoline (15a).28 The reaction was run according to the general procedure using 2-benzylaminobenzonitrile (1.00 g, 4.80 mmol), isopropylmagnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-isopropyl-2-phenylquinazoline (0.99 g, 83% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.70−8.67 (m, 2H), 8.15−8.07 (m, 2H), 7.85−7.81 (m, 1H), 7.62− 7.41 (m, 4H), 3.98−3.91(q, 1H), δ 1.52 (d, J = 6.8 Hz, 6H). 4-n-Butyl-2-phenylquinazoline (15b).28 The reaction was run according to the general procedure using 2-benzylaminobenzonitrile (1.00 g, 4.80 mmol), n-butylmagnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol) and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-butyl-2-phenylquinazoline (0.88 g, 69% yield) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.71−8.59 (m, 2H), 8.16−8.03 (m, 2H), 7.87−7.81 (m, 1H), 7.62− 7.45 (m, 4H), 3.34 (t, J = 7.4 Hz, 2H), 2.03−1.90 (m, 2H), 1.55 (q, J = 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). 4-Cyclopropyl-2-phenylquinazoline (15c).28 The reaction was run according to the general procedure using 2-benzylaminobenzonitrile (1.00 g, 4.80 mmol), cyclopropylmagnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-cyclopropyl-2-phenylquinazoline (0.74 g, 63% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.60−8.58 (m, 2H), 8.30 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.89−7.81 (m, 1H), 7.62−7.54 (m, 1H), 7.54−7.43 (m, 3H), 2.81 (dq, J = 8.4, 4.6 Hz, 1H), 1.57−1.53 (m, 2H), 1.29− 1.24 (m, 2H). 2-Phenyl-4-o-tolylquinazoline (15d).29 The reaction was run according to the general procedure using 2-benzylaminobenzonitrile (1.00 g, 4.80 mmol), o-tolylmagnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 2-phenyl-4-o-tolylquinazoline (1.05 g, 74% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.71−8.60 (m, 2H), 8.16 (d, J = 8.4 Hz, 1H), 7.88 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.57−7.33 (m, 8H), 2.24 (s, 3H). 4-p-Fluorophenyl-2-phenylquinazoline (15e).28 The reaction was run according to the general procedure using 2-benzylaminobenzonitrile (1.02 g, 4.90 mmol), (4-fluorophenyl)magnesium bromide (16.2 mL, 1.0 M in THF), FeCl2 (124 mg, 0.98 mmol), and t-BuOOH (1.3 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-p-fluorophenyl2-phenylquinazoline (1.00 g, 69% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J = 6.5 Hz, 2H), 8.17−8.09 (m, 2H), 7.93−7.88 (m, 3H), 7.59−7.51 (m, 4H), 7.32−7.28 (m, 2H). 4-p-Methoxyphenyl-2-phenylquinazoline (15f).30 The reaction was run according to the general procedure using 2-benzylaminobenzonitrile (1.02 g, 4.90 mmol), 4-methoxyphenylmagnesium bromide (16.2 mL, 1.0 M in THF), FeCl2 (124 mg, 0.98 mmol), and t-BuOOH (1.3 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-p-methoxyphenyl-2-phenylquinazoline (1.01 g, 67% yield) as a brown solid. 1H NMR (400 MHz, CDCl3): δ 8.69 (dd, J = 8.0, 1.6 Hz, 2H), 8.18−8.13 (m, 2H), 7.96−7.83 (m, 3H), 7.62−7.44 (m, 4H), 7.12 (m, 2H), 3.93 (s, 3H). 2,4-Diphenylquinazoline (15g).28 The reaction was run according to the general procedure using 2-benzylaminobenzonitrile (1.00 g, 4.80 mmol), phenylmagnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 2,4-diphenylquinazoline (1.03 g, 75% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.72−8.69 (m, 2H), 8.18−8.12 (m, 2H), 7.91−7.87 (m, 3H), 7.62−7.50 (m, 7H). 7-Chloro-2,4-diphenylquinazoline (15h). The reaction was run according to the general procedure using 2-benzylamino-4-chlorobenzonitrile (0.83 g, 3.42 mmol), phenylmagnesium bromide (11.3 2399

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4-Phenyl-2-o-tolylquinazoline (17e).28 The reaction was run according to the general procedure using 2-(o-tolylaminobenzonitrile (1.00 g, 4.50 mmol), phenylmagnesium bromide (14.8 mL, 1.0 M in THF), FeCl2 (114 mg, 0.90 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-phenyl-2-o-tolylquinazoline (0.87 g, 65% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.18−8.16 (m, 2H), 8.01−7.95 (m, 1H), 7.94−7.90 (m, 1H), 7.88−7.85 (m, 2H), 7.62−7.57 (m, 4H), 7.37−7.32 (m, 3H), 2.67 (s, 3H). 2-o-Chlorophenyl-4-phenylquinazoline (17f).28 The reaction was run according to the general procedure using 2-o-chlorobenzylaminobenzonitrile (1.00 g, 4.12 mmol), phenylmagnesium bromide (13.6 mL, 1.0 M in THF), FeCl2 (104 mg, 0.82 mmol), and t-BuOOH (1.1 mL, 5−6 M in decane) in DMSO (18 mL) to afford 2-o-chlorophenyl4-phenylquinazoline (0.90 g, 70% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.24−8.15 (m, 2H), 7.98−7.84 (m, 4H), 7.68− 7.51 (m, 5H), 7.45−7.36 (m, 2H). 4-Phenyl-2-2′-pyridinylquinazoline (17g).32 The reaction was run according to the general procedure using 2-2′-pyridinylmethylamino)benzonitrile (1.00 g, 4.78 mmol), phenylmagnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-phenyl-2-2′pyridinylquinazoline (1.11 g, 82% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.94 (d, J = 4.4 Hz, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.01−7.83 (m, 4H), 7.66−7.56 (m, 4H), 7.47−7.37 (m, 1H). 2-2′-Furanyl-4-phenylquinazoline (17h).33 The reaction was run according to the general procedure using 2-2′-furanylmethylaminobenzonitrile (1.00 g, 5.05 mmol), phenylmagnesium bromide (16.6 mL, 1.0 M in THF), FeCl2 (127 mg, 1.01 mmol), and t-BuOOH (1.3 mL, 5−6 M in decane) in DMSO (18 mL) to afford 2-2′-furanyl-4phenylquinazoline (1.10 g, 80% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 19.8 Hz, 3H), 7.70 (s, 1H), 7.65−7.47 (m, 5H), 6.61 (s, 1H). 4-Phenyl-2-2′-thiophenylquinazoline (17i).34 The reaction was run according to the general procedure using 2-2′-thiophenylmethylaminobenzonitrile (1.00 g, 4.67 mmol), phenylmagnesium bromide (15.5 mL, 1.0 M in THF), FeCl2 (118 mg, 0.93 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-phenyl-22′-thiophenylquinazoline (1.10 g, 82% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 3.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.93−7.81 (m, 3H), 7.65−7.55 (m, 3H), 7.53−7.49 (m, 2H), 7.23−7.14 (m, 1H).

mL, 1.0 M in THF), FeCl2 (87 mg, 0.68 mmol), and t-BuOOH (0.9 mL, 5−6 M in decane) in DMSO (18 mL) to afford 7-chloro-2,4diphenylquinazoline (0.79 g, 73% yield) as a pale yellow solid. Mp: 120.6−127.0 °C (decomp.). 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.15 (t, J = 7.4 Hz, 2H), 7.90 (dd, J = 13.6, 5.8 Hz, 3H), 7.68−7.53 (m, 4H), 7.47 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 168.5, 158.9, 151.9, 140.1, 137.4, 134.6, 133.7, 130.4, 130.2, 130.0, 129.7, 129.2, 128.7, 128.6, 127.4, 127.0, 126.7, 121.8. HRMS (ESI) calcd for C20H14ClN2 [M + H]+: 317.0846, found: 317.0839. 4-Mesityl-2-phenylquinazoline (15i). The reaction was run according to the general procedure using 2-benzylaminobenzonitrile (1.00 g, 4.80 mmol), mesitylmagnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) at 45 °C to afford 4-mesityl-2phenylquinazoline (0.95 g, 61% yield) as a yellow solid. Mp: 112.9− 116.1 °C. 1H NMR (400 MHz, CDCl3): δ 8.77−8.67 (m, 2H), 8.19 (dd, J = 8.5, 0.6 Hz, 1H), 7.89 (ddd, J = 8.4, 4.1, 1.2 Hz, 1H), 7.60− 7.51 (m, 4H), 7.51−7.44 (m, 1H), 7.07 (s, 2H), 2.43 (s, 3H), 2.00 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 170.5, 160.9, 151.2, 138.5, 138.4, 135.8, 133.9, 133.8, 130.5, 129.1, 128.81, 128.6, 128.5, 127.2, 126.4, 123.0, 21.3, 20.0. HRMS (ESI) calcd for C23H21N2 [M + H]+: 325.1705, found: 325.1701. 4-o-Methoxynaphthalen-1′-yl-2-phenylquinazoline (15j).31 The reaction was run according to the general procedure using 2benzylaminobenzonitrile (1.00 g, 4.80 mmol), 2-methoxynaphthalen1-yl magnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol), and t-BuOOH (1.2 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-o-methoxynaphthalen-1′-yl-2-phenylquinazoline (0.95 g, 55% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.67− 8.59 (m, 2H), 8.17 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.86 (ddd, J = 9.9, 9.4, 4.7 Hz, 2H), 7.52−7.41 (m, 5H), 7.36 (dd, J = 16.0, 8.0 Hz, 2H), 7.29 (dd, J = 8.1, 7.0 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 3.78 (s, 3H). 2-Methyl-4-phenylquinazoline (17a).22 The reaction was run according to the general procedure using 2-ethylaminobenzonitrile (1.00 g, 6.84 mmol), phenylmagnesium bromide (22.6 mL, 1.0 M in THF), FeCl2 (173 mg, 1.37 mmol), and t-BuOOH (1.8 mL, 5−6 M in decane) in DMSO (18 mL) to afford 2-methyl-4-phenylquinazoline (1.29 g, 86% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.10−7.95 (m, 2H), 7.85 (t, J = 7.6 Hz, 1H), 7.74 (dt, J = 5.6, 1.9 Hz, 2H), 7.60−7.45 (m, 4H), 2.95 (s, 3H). 2-p-Bromophenyl-4-phenylquinazoline (17b).32 The reaction was run according to the general procedure using 2-p-bromobenzylaminobenzonitrile (1.00 g, 3.48 mmol), phenylmagnesium bromide (11.5 mL, 1.0 M in THF), FeCl2 (88 mg, 0.70 mmol), and t-BuOOH (1.0 mL, 5−6 M in decane) in DMSO (18 mL) to afford 2-p-bromophenyl4-phenyl quinazoline (1.07 g, 85% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.59−8.57 (m, 2H), 8.15−8.12 (m, 2H), 7.90− 7.87 (m, 3H), 7.68−7.63 (m, 2H), 7.61 (dd, J = 6.4, 2.5 Hz, 3H), 7.59−7.54 (m, 1H). 2-p-Methoxyphenyl-4-phenylquinazoline (17c).28 The reaction was run according to the general procedure using 2-p-methoxybenzylaminobenzonitrile (1.20 g, 5.04 mmol), phenylmagnesium bromide (16.5 mL, 1.0 M in THF), FeCl2 (127 mg, 1.00 mmol), and t-BuOOH (1.3 mL, 5−6 M in decane) in DMSO (18 mL) to afford 2-pmethoxyphenyl-4-phenylquinazoline (1.32 g, 85% yield) as an offwhite solid. 1H NMR (400 MHz, CDCl3): δ 8.67−8.64 (m, 2H), 8.13−8.10 (m, 2H), 7.89−7.85 (m, 3H), 7.65−7.58 (m, 3H), 7.56− 7.42 (m, 1H), 7.06−7.04 (m, 2H), 3.91 (s, 3H). 4-Phenyl-2-p-trifluoromethylphenylquinazoline (17d).28 The reaction was run according to the general procedure using 2-ptrifluoromethylbenzylaminobenzonitrile (1.00 g, 3.62 mmol), phenylmagnesium bromide (12.0 mL, 1.0 M in THF), FeCl2 (92 mg, 0.72 mmol), and t-BuOOH (0.9 mL, 5−6 M in decane) in DMSO (18 mL) to afford 4-phenyl-2-p-trifluoromethylphenylquinazoline (1.06 g, 84% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.83 (d, J = 8.4 Hz, 2H), 8.20−8.16 (m, 2H), 7.94−7.89 (m, 3H), 7.77 (d, J = 8.4 Hz, 2H), 7.64−7.59 (m, 4H).

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ASSOCIATED CONTENT

S Supporting Information *

The supporting inforamtion is available free of charge via the Internet at . The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.joc.7b02943. Copies of 1H and 13C NMR spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Cheng-yi Chen: 0000-0001-7666-3087 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge Mrs. Huawei Ma and Mrs. Jingjing Shi at Porton (Shanghai) R&D Center for analytical support. We also 2400

DOI: 10.1021/acs.joc.7b02943 J. Org. Chem. 2018, 83, 2395−2401

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(19) Likhar, P. R.; Arundhathi, R.; Kantam, M. L.; Prathima, P. S. Eur. J. Org. Chem. 2009, 31, 5383. (20) Hikawa, H.; Koike, T.; Izumi, K.; Kikkawa, S.; Azumaya, I. Adv. Synth. Catal. 2016, 358, 784. (21) Gangaram, S.; Adimulam, C. S.; Akula, R. K.; Kengiri, R.; Pamulaparthy, S. R.; Madabhushi, S.; Banda, N. Chem. Lett. 2013, 42, 1522. (22) Yan, Y.; Wang, Z. Chem. Commun. 2011, 47, 9513. (23) Zhao, D.; Zhu, M.-x.; Wang, Y.; Shen, Q.; Li, J.-X. Org. Biomol. Chem. 2013, 11, 6246. (24) Akazome, M.; Yamamoto, J.; Kondo, T.; Watanabe, Y. J. Organomet. Chem. 1995, 494, 229. (25) Yan, Y.; Xu, Y.; Niu, B.; Xie, H.; Liu, Y. J. Org. Chem. 2015, 80, 5581. (26) Unsinn, A.; Wunderlich, S.; Knochel, P. Adv. Synth. Catal. 2013, 355, 989. (27) Kita, Y.; Higashida, K.; Yamaji, K.; Iimuro, A.; Mashima, K. Chem. Commun. 2015, 51, 4380. (28) Zhang, J.; Yu, Y.; Wang, S.; Wan, C.; Wang, Z. Chem. Commun. 2010, 46, 5244. (29) Shrestha, B.; Thapa, S.; Gurung, S. K.; Pike, R. A. S.; Giri, R. J. Org. Chem. 2016, 81, 787. (30) Han, B.; Wang, C.; Han, R.-f.; Yu, W.; Duan, X.-y.; Fang, R.; Yang, X-l Chem. Commun. 2011, 47, 7818. (31) McCarthy, M.; Goddard, R.; Guiry, P. Tetrahedron: Asymmetry 1999, 10, 2797. (32) Karnakar, K.; Kumar, A. V.; Murthy, S. N.; Ramesh, K.; Nageswar, Y. V. D. Tetrahedron Lett. 2012, 53, 4613. (33) Lin, J.-P.; Zhang, F.-H.; Long, Y.-Q. Org. Lett. 2014, 16, 2822. (34) Derabli, C.; Boulcina, R.; Kirsch, G.; Carboni, B.; Debache, A. Tetrahedron Lett. 2014, 55, 200.

acknowledge Mr. Peter J. Yao of Janssen R&D at Cilag AG for helpful discussions during the preparation of this manuscript.

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DOI: 10.1021/acs.joc.7b02943 J. Org. Chem. 2018, 83, 2395−2401