Synthesis of Quinazolines via an Iron-Catalyzed Oxidative Amination

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Synthesis of Quinazolines via an Ironcatalyzed Oxidative Amination of N-H Ketimines Cheng-yi Chen, Fengxian He, Guangrong Tang, Huiqing Yuan, Ning Li, Jinmin Wang, and Roger Faessler J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02943 • Publication Date (Web): 17 Jan 2018 Downloaded from http://pubs.acs.org on January 17, 2018

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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 Supporting Information Placeholder

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 2-alkylamino N-H ketimine species. The FeCl2-catalyzed C(sp3)-H oxidation of the alkyl group employing tertBuOOH followed by intramolecular C-N bond formation and aromatization afforded a wide variety of 2,4-disubstituted quinazolines in good to excellent yields.

Among 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 the drug discovery and development. Evidently, a large number of drugs has been developed based on this pharmacophore (Figure 1).2 For example, a quinazoline-containing drug, gefitinib, is an inhibitor of the protein kinase of epidermal growth factor receptor (EGFR) which was marketed as an anti-cancer 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 relaxer5 and an antimetabolite drug, raltitrexed,6 also contains a quinazoline moiety. Last, quinazolines bearing 4-aromatic groups have been identified as potent PI3K deltaselective inhibitors, potentially new oncology drugs.7

Figure 1. Quinazolines as medicinal agents. The importance of quinazolines as medicinal agents has consequently inspired development of variable synthetic methods towards this class of compounds.8 Many conventional synthetic methods for the construction of quinazoline

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based pre-activated substrates or multistep transformations have been reported.9 Transition metalcatalyzed transformations are now serving as powerful tools to synthesize these useful compounds.10 On the other hand, an increasing demand for clean, fast, efficient and selective processes, especially the 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, the ironcatalyzed reactions in organic synthesis have gained strong momentum in recent years.11 The applications of iron-catalysis in heterocycles synthesis have also been highlighted.12 Herein, we report a facile synthesis of quinazolines via an iron-catalyzed C(sp3)-H oxidation using tertBuOOH as the terminal oxidant followed by intramolecular amination and aromatization.13 We have reported that addition of Grignard or organolithium reagents to readily available orthoalkylamino benzonitriles (1) forms orthoalkylaminoaryl N-H ketimines (2, Scheme 1).14 We envisioned that subsequent C(sp3)-H oxidation on the α-proton of aminoalkyl group would form imine or iminium species (4). Facile ringclosure with nucleophilic attack of the imine N-H group would then form the dihydroquinolines (5a and 5b). Aromatization via oxidation9b would ultimately lead to the formation of quinazoline (3). Scheme 1. Synthetic strategy for quinazoline via C(sp3)-H oxidation and ring-closure

Hence, a combination of iron salt and oxidizer was screened as shown in Table 1. In entries1-3, combination of FeCl2 as catalyst 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 tertBuOOH 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, 7) to give quinazoline. It was also noted that 1.3 eq 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 tertBuOOH are less effective than FeCl2. We then chose conditions shown in entry 5 for the oxidative amination and applied them to the synthesis of a wide variety of quinazolines from orthoalkyamino ketimines. Table 1. Screening of iron-catalysts and oxidizers for the construction of quinazoline

a

Addition of phenylmagnesium bromide to nitrile 6 afforded ketimine 7 readily. Ketimine 7 was isolated and used to explore the oxidative amination for the preparation of quinazolines.

Reaction conditions: 6, (2 mmol), catalyst (20 mol %), oxidizer (1.3 equiv.), DMSO (5 mL) under air for 18 h. b 30% aq. H2O2 (2.6 equiv.) was used. c5.0~6.0M t-BuOOH in decane was used. d70% aq. t-BuOOH (2.6 equiv.) was

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used. eAll the yields were based on HPLC analysis against the standard of 8. f 1.0 g scale, isolated yield.

We first explored the generality of the identified conditions in the synthesis of quinazolines from ketimines 9 bearing N-methyl group. As shown in Scheme 2, the C(sp3)-H oxidation 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 cyclopropyl group can be introduced to the molecule to give quinazolines (10a-e) in 5281% 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

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 2methylaminobenzonitrile, the benzyl species, in general, afforded comparable yields of quinazolines. Steric bulky groups such as mesityl and ortho-methoxynathyl group were introduced in quinazoline core to afford 15i and 15j16 in 61% and 55% yield, respectively. Scheme 3. Synthesis of 2-phenyl-4-substituted quinazolines from 2-benzylaminobenzonitriles (13)a

Scheme 2. Synthesis of 4-substituted quinazolines from 2-methylaminobenzonitrilea

a

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. b15i was prepared at 45oC. o

a

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. o

The success of quinzoline synthesis from methylaminonitrile 6 was next extended to the 2benyzlamino substrates (13) to afford 2-phenyl-4substituted quinazolines (15a-j). We anticipated these substrates would allow for more efficient

The methodology of C(sp3)-H oxidation followed by ring-closure was next applied to other nitriles bearing 2-alkylamino groups besides methyl and benzyl. As shown in Scheme 4, nitrile bearing ethylamino group afforded the desired 2methylqunazoline (17a) in 86% yield. Extension to para-substituted benzyl groups led to quinazolines (17b-d) in good yields (84-85%). Compared to 15g, substrates containing groups such as chlorine and methyl at ortho-position 3



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seemed to decrease the efficiency of the process with lower yields obtained (17e-f). Using this protocol, heterocycles such as pyridine, furan, and thiophene can be readily installed at 2position of the quinazoline to afford products (17g-i) in 80-82% yields. Scheme 4. Synthesis of 2,4-disubstituted quinazolines from 2-alkylaminobenzonitrilesa

a

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.

o

In conclusion, we have developed an efficient synthetic method for the synthesis of quinazolines based on iron-catalyzed 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 complementary to the other methods reported in the literature. The oxidation of N-alkyl group in this protocol employs inexpensive and non-toxic 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 application of the iron-catalysis in the heterocycle syntheses. Experiment Section General Information. Preparation of imines was carried out under nitrogen. Commercially availa-

ble 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 SIMM (Shanghai Institute of Materia Medica, Chinese Academy of Sciences). 4,5-Dimethoxy-2-(methylamino)benzonitrile (11):17 The reaction was run according to the literature procedure using 4,5-dimethoxy-2-aminobenzonitrile (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 pale yellow solid. mp: 135.8-137.4 oC. 1 H 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); 13 C 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((arylmethylene)amino) benzonitriles. The 2((arylmethylene)amino) benzonitrile 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 oC for 24-72 h until 2-aminobenzonitrile was consumed. Then NaBH4 (1.5 equiv.) was added in portions at 0-5 o C and the mixture was stirred at 0-5 oC 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/n-heptane=1/20) to afford 2((arylmethylene)amino)benzonitriles. 2-(Benzylamino)benzonitrile (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-(benzylamino)benzonitrile (6.2 g, 70% yield) as white solid. 1H NMR (400 MHz, CDCl3): δ 7.44-7.40 (m, 1H), 7.40-7.27 (m, 6H), 4


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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 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-Bromobenzyl)amino)benzonitrile (16, R=4-p-Ph): The reaction was run according to the general method using 2-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-((4bromobenzyl)amino)benzonitrile (8.1 g, 67% yield) as off-white solid. mp: 118.2-121.4 oC. 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-Methoxybenzyl)amino)benzonitrile (16, R=p-MeOPh):20 The reaction was run according to the general method using 2-aminobenzonitrile (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-((4methoxybenzyl)amino) benzonitrile (4.1 g, 68% yield) as white solid. 1H NMR (400 MHz, CDCl3): δ 7.42 (dd, J = 7.7, 1.3 Hz, 1H), 7.397.33 (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-(Trifluoromethyl) benzyl)amino) benzonitrile (16, R=p-CF3Ph): The reaction was run according to the general method using 2aminobenzonitrile (5.0 g, 42.3 mmol), 4(trifluoromethyl)benzaldehyde (8.8 g, 50.8 mmol) and NaBH4 (2.4 g, 63.5 mmol) in absolute methanol (150 mL) to afford 2-((4(trifluoromethyl)benzyl)amino)benzonitrile (7.6 g, 65% yield) as off-white solid. mp: 108.0-110.3 o 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); 13 C 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-Tolyl)amino)benzonitrile (16, R=otolyl):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 2-((2methylbenzyl)amino)benzonitrile (5.7 g, 61% yield) as 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-Chlorobenzyl)amino)benzonitrile (16, R=o-ClPh): The reaction was run according to the general method using 2-aminobenzonitrile (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-((2chlorobenzyl)amino)benzonitrile (4.2 g, 68% yield) as white solid. mp: 117.1-119.0 oC. 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-((Pyridin-2’-ylmethyl)amino)benzonitrile (16, R=2-pyridinyl): The reaction was run according 5


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to the general method using 2-aminobenzonitrile (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-((pyridin-2ylmethyl)amino)benzonitrile (7.3 g, 83% yield) as pale yellow solid. mp: 63.0-63.6 oC. 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-((Furan-2’-ylmethyl)amino)benzonitrile (16, R=2-furanyl):21 The reaction was run according to the general method using 2-aminobenzonitrile (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-((furan-2ylmethyl)amino)benzonitrile (7.2 g, 73% yield) as 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-((Thiophen-2’-ylmethyl)amino)benzonitrile (16, R=2-thiophenyl): The reaction was run according to the general method using 2aminobenzonitrile (5.0 g, 42.3 mmol), thiophene2-carbaldehyde (5.7 g, 50.8 mmol) and NaBH4 (2.4 g, 63.5 mmol) in absolute methanol (150 mL) to afford 2-((thiophen-2-ylmethyl)amino) benzonitrile (5.0 g, 55% yield) as white solid. mp: 53.6-55.5 oC. 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

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eqiuv.) at 10 oC (for Grignard reagent) or -50 oC (for organolithium reagent) under nitrogen. After addition, the reaction was stirred for 3h at 30 oC (for Grignard reagent) or 10 oC (for organolithium reagent). This reaction mixture was poured into brine and extracted with MTBE. The organic layer was dried over Na2SO4 and concentrated in 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 oC. The resulted mixture was stirred at 25 oC (unless specified otherwise) until the imine was consumed completely. The reaction was poured into water, and then extracted with EtOAc. After concentration in vacuum, the crude product was purified through flash chromatography (EtOAc/nheptane = 1/20-1/10). 4-Phenylquinazoline (8):22 The reaction was run according to the general procedure using 2(methylamino)benzonitrile (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 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(methylamino)benzonitrile (1.00 g, 7.57 mmol), methylmagnesium bromide (25.0 mL, 1M 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 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(methylamino)benzonitrile (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, 5.06.0 M in decane) in DMSO (18 mL) to afford 46


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ethylquinazoline (0.62 g, 52% yield) as yellow oil. 1H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 8.14-8.08 (m, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.887.81 (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-(methylamino)benzonitrile (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 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-(methylamino)benzonitrile (1.00 g, 7.57 mmol), cyclopropylmagnesium bromide (25.0 mL, 1.0 M in THF), FeCl2 (0.19 g, 1.53 mmol) and tBuOOH (2.0 mL, 5.0-6.0 M in decane) in DMSO (18 mL) to afford 4-cyclopropylquinazoline (0.81 g, 63% yield) as yellow solid. mp: 62.8-65.2 oC. 1 H 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); 13 C 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(methylamino)benzonitrile (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, 5.06.0 M in decane) in DMSO (18 mL) to afford 4n-butylquinazoline (0.82 g, 58% yield) as yellow oil. 1H 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), 3.313.17 (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-Fluorophenyl)quinazoline (10f): The reaction was run according to the general procedure

using 2-(methylamino)benzonitrile (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-(3-fluorophenyl) quinazoline (1.21 g, 71% yield) as yellow solid. mp: 57.3-58.0 oC. 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-Fluorophenyl)quinazoline (10g):25 The reaction was run according to the general procedure using 2-(methylamino)benzonitrile (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-(4-fluorophenyl) quinazoline (1.19 g, 70% yield) as 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-Methoxyphenyl)quinazoline (10h):26 The reaction was run according to the general procedure using 2-(methylamino)benzonitrile (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-(4methoxyphenyl)quinazoline (1.20 g, 67% yield) as 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-(2-Tolyl)quinazoline (10i):27 The reaction was run according to the general procedure using 2(methylamino)benzonitrile (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-tolyl)quinazoline (1.42 g, 85% 7



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yield) as 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(methylamino)benzonitrile (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 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-(methylamino) benzonitrile (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 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-(benzylamino)benzonitrile (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-2phenylquinazoline (0.99 g, 83% yield) as 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-(benzylamino) benzonitrile (1.00 g, 4.80

mmol), n-butylmagnesium bromide (15.8 mL, 1.0 M in THF), FeCl2 (122 mg, 0.96 mmol) and tBuOOH (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-phenyl quinazoline (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-2phenylquinazoline (0.74 g, 63% yield) as offwhite solid. 1H NMR (400 MHz, CDCl3): δ 8.608.58 (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-tolyl)quinazoline (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-(otolyl)quinazoline (1.05 g, 74% yield) as 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-benzylamino benzonitrile (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-(4-fluorophenyl)-2-phenylquinazoline (1.00 g, 69% yield) as 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 8


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general procedure using 2-(benzylamino) benzonitrile (1.02 g, 4.90 mmol), 4-methoxyphenyl 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-(4-methoxy-phenyl)-2-phenylquinazoline (1.01 g, 67% yield) as 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), 7.627.44 (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 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 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 pale yellow solid. mp: 120.6-127.0 oC (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 oC to afford 4-mesityl-2phenylquinazoline (0.95 g, 61% yield) as yellow solid. mp: 112.9-116.1 oC. 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-phenyl quinazoline (15j):31 The reaction was run according to the general procedure using 2benzylaminobenzonitrile (1.00 g, 4.80 mmol), 2methoxynaphthalen-1-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-(2methoxynaphthalen-1-yl)-2-phenylquinazoline (0.95 g, 55% yield) as 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 tBuOOH (1.8 mL, 5-6 M in decane) in DMSO (18 mL) to afford 2-methyl-4-phenylquinazoline (1.29 g, 86% yield) as 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), 7.607.45 (m, 4H), 2.95 (s, 3H). 2-(p-Bromophenyl)-4-phenylquinazoline (17b):32 The reaction was run according to the general procedure using 2-(4’-bromobenzyl)aminobenzonitrile (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(4’-bromophenyl)-4-phenyl quinazoline (1.07 g, 85% yield) as 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 9


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general procedure using 2-(4-methoxybenzyl) aminobenzonitrile (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-(4-methoxyphenyl)-4-phenylquinazoline (1.32 g, 85% yield) as off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.67-8.64 (m, 2H), 8.138.10 (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-(trifluoromethyl)phenyl) quinazoline (17d):28 The reaction was run according to the general procedure using 2-(4trifluoromethylbenzyl)amino)benzonitrile (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-(4trifluoromethylphenyl)quinazoline (1.06 g, 84% yield) as 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). 4-Phenyl-2-(o-tolyl)quinazoline (17e):28 The reaction was run according to the general procedure using 2-(2-methylbenzyl)aminobenzonitrile (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-(otolyl)quinazoline (0.87 g, 65% yield) as 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-(2-chlorobenzyl) aminobenzonitrile (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-(2-chlorophenyl)-4-phenyl quinazoline (0.90 g, 70% yield) as yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.24-8.15 (m, 2H), 7.987.84 (m, 4H), 7.68-7.51 (m, 5H), 7.45-7.36 (m, 2H).

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4-Phenyl-2-(pyridin-2’-yl)quinazoline (17g):32 The reaction was run according to the general procedure using 2-(pyridin-2-yl)methylamino) 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 4phenyl-2-(pyridin-2-yl)quinazoline (1.11 g, 82% yield) as 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-(Furan-2’-yl)-4-phenylquinazoline (17h):33 The reaction was run according to the general procedure using 2-((furan-2-ylmethyl)amino) benzonitrile (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(furan-2-yl)-4-phenylquinazoline (1.10 g, 80% yield) as 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-(thiophen-2’-yl)quinazoline (17i):34 The reaction was run according to the general procedure using 2-(thiophen-2-yl) methylaminobenzonitrile (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 4phenyl-2-(thiophen-2-yl)quinazoline (1.10 g, 82% yield) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 3.6 Hz, 1H), 8.08 (d, J = 8.4Hz, 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). ASSOCIATED CONTENT Supporting Information The supporting inforamtion is available free of charge via the Internet at http://pubs.acs.org. Copies of 1H and 13C NMR spectra of new compounds. Corresponding Author *E-Mail: [email protected]

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Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We would like to acknowledge Mrs. Huawei Ma and Mrs. Jingjing Shi at Porton (Shanghai) R&D Center for analytical supports. We also acknowledge Mr. Peter J. Yao of Janssen R&D at Cilag AG for helpful discussions during the preparation of this manuscript. REFERENCES (1) (a) Khan, I.; Ibrar, A.; Ahmed, W.; Saeed, A. Eur. J. Med. Chem. 2015, 90, 124. (b) Alam, M. J.; Alam, O.; Naim, M. J.; Alam, P. Int. J. Adv. Res. 2015, 3, 1656. (c) Wang D.; Gao, F. Chem. Cent. J. 2013, 7, 1. (2) For a review on quinazoline marketed drugs, see: Selvam, T. P.; Kumar P. V. Res. in Pharm. 2011, 1, 1. (3) (a) Lu, J.; Zhan, X.; Chen, L.; Zhang, L.; Mao, S. J. Chem. Eng. Data 2014, 59, 2665. (b) Zhang, Y.; Tortorella, M. D.; Liao, J.; Qin, X.; Chen, T.; Luo, J.; Guan, J.; Talley, J. J.; Tu, Z. ACS Med. Chem. Lett. 2015, 6, 1086. (c) Duncton, M. A.; Estiarte, J. M. A.; Johnson, R. J.; Cox, M.; O'Mahony, D. J. R.; Edwards, W. T.; Kelly, M. G. J. Org. Chem. 2009, 74, 6354. (d) Zeng, Q.; Wang, J.; Cheng, Z.; Chen, K.; Johnström, P.; Varnäs, K.; Li, D. Y.; Yang, Z. F.; Zhang, X. J. Med. Chem. 2015, 58, 8200. (4) Minkovsky, N., Berezov, A. Curr. Opin. Investig. Drugs 2008, 9, 1336. (5) Amer, M. S.; Browder, H. P. Proc. Soc. Exp. Biol. Med. 1971, 136, 750. (6) Gunasekara, N. S.; Faulds, D. Drugs 1998, 55, 423. (7) Hoegenauer, K.; Soldermann, N.; Stauffer, F.; Furet, P.; Graveleau, N.; Smith, A. B.; Hebach, C.; Hollingworth, G. J.; Lewis, I.; Gutmann, S.; Rummel, G.; Knapp, M.; Wolf, R. M.; Blanz, J.; Feifel, R.; Burkhart, C.; Zécri, F. ACS Med. Chem. Lett. 2016, 7, 762. (8) (a) Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal, J.; Saeed, A. Bioorg. Med. Chem. 2016, 24, 2361. (b) Kikelj, D. Product class 13: quinazolines. Sci. Synth. 2004, 16, 573. (9) For recent examples, see: (a) Mani Ramanathan, M.; Liu, S.-T. J. Org. Chem. 2017, 82, 8290 and references cited therein. (b) Zhang, Z.-H.; Zhang, X.-N.; Mo, L.-P.; Li, Y.-X.; Ma, F.-P. Green Chem. 2012, 14, 1502. (c) Yao, S.; Zhou, K.; Wang, J.; Cao, H.; Yu, L.; Wu, J.; Qiu, P.; Xu, Q. Green Chem. 2017, 19, 2945.

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Synthesis of Quinazolines via an Iron-Catalyzed Oxidative Amination

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