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PAPER I2-catalyzed cross dehydrogenative coupling: Rapid access to benzoxazinones and quinazolinones Received 00th January 20xx, Accepted 00th January 20xx

Kaili Chen,a Biao Gao,a Yanguo Shang,a Jianyao Du,a Qinlan Gu,*b Jinxin Wang*a

DOI: 10.1039/x0xx00000x

An efficient and applicable I2-catalyzed intramolecular dehydrogenative C-O/C-N coupling reaction via activating the C-H bond adjacent to the N atom has been developed to provide dozens of substituted benzoxazinones (31 examples) and quinazolinones (5 examples) in good to excellent yields (up to 98%). This one-pot methodology has significant advantages, including metal-free process, broad substrate scope, high atom economy, and simple operation. The strategy goes through a iminium intermediate followed by nucleophilic attack to provide desired products.

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Introduction Benzo-fused N-heterocycle is a ubiquitous type of drug scaffold, among which benzoxazinones and quinazolinones are of significant importance due to their wide presence in complex natural products and pharmaceutically relevant molecules with a broad spectrum of biological properties, including anti-inflammatory, anticancer, anti-diabetes, antithrombotic, anti-obesity and neuro-protective properties. For example, as shown in Figure 1, Sinitrodil is a novel organic nitrate, which showed a marked anti-ischaemic activity in rat, 1 rabbit and dog models. As a dual activator of PPAR-α and PPAR-γ, DRF-2655 has the potential to be a body-weight 2 lowering, hypolipidemic and euglycemic agent. CX-614, a positive modulator of AMPA-type glutamate receptor, possesses neuro-protective function against Alzheimer's 3 disease as well as Parkinson. In addition, Idelalisib and Raltitrexed are anticancer agents, which are used for the treatment of chronic lymphocytic leukemia and colorectal 4 cancer, respectively. Rutaecarpine, isolated from a Chinese herbal medicine Wu-Chu-Yu, was used to treat headache and 5 cholera. Consequently, the synthesis of these privileged structures has received intensive attention. The general synthetic methods toward benzoxazinone framework involve the condensation of 2-hydroxybenzamide 6a 6b,6c derivatives and paraformaldehyde or ketones, the direct imine acylation (DIA) of functionalized benzoic acids and 6d imine, and the intramolecular electrophilic addition of 26e hydroxy-N-alkenyl benzamide. In the past years, transitiona

Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang Road, Nanjing 210009, P. R. China. E-mail: [email protected]. b Senior Vocational School, China Pharmaceutical University, Nanjing 211198, P. R. China. E-mail: [email protected]. Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x

Figure 1 Biologically active molecules containing benzoxazinone and quinazolinone moiety metal catalyzed synthetic strategy has got an increasing attention.3b, 7 For instance, a copper-catalyzed intramolecular cross-dehydrogenative coupling to form C-O bonds has been achieved employing active Cu/O2 species by Modak and coworkers (Scheme 1, pathway A).8 And more recently, Fang and co-workers have developed a Pd(II)-catalyzed intramolecular oxidative Wacker-type cyclization/dearomatization of 2,3disubstituted indoles (Scheme 1, pathway B).9 As for quinazolinone skeleton, owing to their significance and potential utility, many synthetic efforts have been made, including Cu-catalyzed condensation of anthranilamide with aryl or alkyl,10a coupling/condensative cyclization,10b-d amination,10e-g oxidative annulations,10h trifluoromethylation,10i Pd-catalyzed carboxamidation,10j amidine arylation,10k carbonylation,10l Ir-catalyzed oxidative cyclization,11a radical cascade cyclization,11b dehydrogenative coupling,11c and Fecatalyzed oxidative cyclization,12a condensation/nucleophilic addition.12b Very recently, Zheng and co-workers realized the Ag-catalyzed phosphorylation/cyclization of N-Cyanamide Alkenes (Scheme 1, pathway C).13

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Journal Name Table 1 Optimization of the reaction conditions. O N OH

Cat., Oxidant. Solvent., Temp.

2a

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1a

Scheme 1 Pathways to synthesize benzoxazinones and quinazolinones Despite significant progress, due to narrow substrate scope, hard-to-obtain precursors, harsh reaction conditions, and heavy-metal pollution, the application of the methods mentioned above was severely restricted in organic and pharmaceutical synthesis. Therefore, the development of a simple, effective, economic and environment-friendly method for the preparation of benzoxazinones and quinazolinones is highly desirable. However, to the best of our knowledge, there is no report for the metal-free catalyzed one-pot synthesis of benzoxazinone and quinazolinone derivatives via intramolecular cross-dehydrogenative coupling. On the other hand, molecular iodine has emerged as an efficient catalyst in organic transformations in view of the advantage of low toxicity and cost. A variety of studies in relation to iodinecatalyzed carbon-heteroatom bonds formation have been 14 reported. Herein, we describe a novel metal-free molecular iodine-catalyzed approach to diverse substituted benzoxazinones and quinazolinones (Scheme 1, pathway D).

Entry

Catalyst (mol%)

Oxidant (equiv)

Solvent

Yieldb (%)

1

/

DTBP(3)

Toluene

trace

2

KI(20)

DTBP(3)

DCE

37

3

Bu4NI(20)

DTBP(3)

DCE

38

4

NaIO4(20)

DTBP(3)

DCE

39

5

NaI(20)

DTBP(3)

DCE

36

6

I2 (20)

DTBP(3)

DCE

45

7

I2(10)

DTBP(3)

DCE

34

8

I2 (25)

DTBP(3)

DCE

51

9

I2(30)

DTBP(3)

DCE

54

10

I2(40)

DTBP(3)

DCE

33

11

I2(30)

30% H2O2(3)

DCE

19

12

I2(30)

70% TBHP(3)

DCE

46

13

I2(30)

K2S2O8(3)

DCE

26

14

I2(30)

DTBP(3)

CH3CN

69

15

I2(30)

DTBP(3)

EA

84

16

I2(30)

DTBP(3)

CH3OH

nd

17

I2(30)

DTBP(3)

DMF

nd

18

I2(30)

DTBP(3)

THF

37

19

I2(30)

DTBP(3)

Toluene

87

20

I2(30)

DTBP(3)

H2O

nd

21

I2(30)

DTBP(2)

Toluene

77

22

I2(30)

DTBP(4)

Toluene

67

c

I2(30)

DTBP(3)

Toluene

51

24d

I2(30)

DTBP(3)

Toluene

82

23

Results and discussion

N O

a

Our study began with the reaction of N,N-dibenzyl-2hydroxybenzamide (1a) in the presence of KI and DTBP in DCE under 130℃ in the sealed tube. To our delight, the desired product (2a) was isolated in 37% yield (Table 1, entry 2). This encouraging result prompted us to investigate four other catalysts, such as Bu4NI, NaIO4, NaI and I2, among which I2 was the best catalyst that gave a 45% yield (Table 1, entries 3-6). The amount of I2 employed can be as high as 30 mol%, while further increasement in catalyst loading led to dramatic decrease in product yield (Table 1, entries 7-10). Next, the evaluation of oxidants (such as 30% H2O2, 70% TBHP , and

Reaction conditions: 1a (0.2 mmol), catalyst (mol%), oxidant, in solvent (4.0 mL), reacted at 130°C for 12 h in sealed tube. b Isolated yields. c The reaction temperature was 120 °C. d The reaction temperature was 140 °C. nd = not detected.

K2S2O8) disclosed that DTBP was the best choice with the yield of 54% (Table 1, entries 11-13). To further improve the yield of 2a, we screened different solvents. Toluene was found to be the optimum solvent, offering 2a in significantly improved yield of 87% (Table 1, entries 14-20). Encouraged by this, we then carefully evaluated the amount of oxidant and reaction temperature (Table 1, entries 21-24). Based on the above experiments, 1a (1 equiv) in the

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presence of 30 mol% I2, and 3 equiv DTBP in toluene at 130 °C for 12 h was ultimately chosen as the optimal reaction conditions (Table 1, entry 19), providing 2a in 87% yield. With the optimized conditions in hand, the generality of this reaction was subsequently probed. We first examined the stereoelectronic effect by varying substituents of the salicylic acid unit (Table 2). There was an obvious discrimination in the yield between electron-donating and electron-withdrawing groups substituted on the aromatic ring. While hydrogen and methoxy group at the para position of the phenol ring were well tolerated for this reaction, offering 2a in 87% and 2g in 89% yields, halogen groups (F, Cl, Br) and the strong electron-withdrawing group (NO2) at the para and ortho positions had a negative effect on the reaction, affording 2b-2f in moderate yields (43-49%). The location of the substiuents on salicylic acid moiety appeared to play a pivotal role in these reactions. Substrates with methoxy groups at para-, meta-, and ortho- positions showed different reactivities (o-MeO > p-MeO > m-MeO), and the highest yield of 95% was observed with o-methoxy substituted salicylamide. This reactivity profile could be attributed to the ortho effect which strengthened the nucleophilicity and propelled the process of the cyclization reaction, furnishing the corresponding product 2i. Both naphthalene substrate 1j and densely-functionalized substrate 1k were well tolerated under this reaction protocol, resulting in the formation of 2j and 2k in 84% and 67% yields, respectively. Next, the substituent effect of the amine part was explored (Table 3). The substrates bearing either electron-donating or withdrawing substituents on the benzyl ring were smoothly transformed into the desired products in great yields from 76% to Table 2 Substrate scope for the synthesis of substituted benzoxazina ones on the salicylic acid unit

O R1

N

Toluene, 12 h, 130 °C

OH 1a-1k

O

O F

N

N

2d, 46%

O

O O

N O

N O

2c, 47%

O

O

O Br

N O

2b, 49%

O

O 2a-2k

O

O

O2 N

N

R1

Cl

N

O 2a, 87%

O

I 2 (30 mol%) DTBP (3.0 equiv)

N

N O

O

O

NO2 2e, 43%

O

O N

O O 2i, 95%

O N

O

O

N

O 2j, 84%

2h, 66%

2g, 89%

2f, 45%

O 2k, 67%

a

Reaction conditions: 1 (0.2 mmol), I2 (30 mol%) and DTBP (0.6 mmol) were stirred in toluene (4 mL) at 130 °C for 12 h in the sealed tube, isolated yield.

Table 3 Substrate scope for the synthesis of substituted benzoxazina ones on the amine part

a

Reaction conditions: 1 (0.2 mmol), I2 (30 mol%) and DTBP (0.6 mmol) were stirred in toluene (4 mL) at 130 °C for 12 h in the sealed tube, isolated yield.

98%, such as p-MeO (2l, 2m), p-Me (2n, 2o) and p-Cl (2p, 2q). We then investigated the unsymmetrical amides. The preferential cyclization occurred on the MeO-substituted side when nitro group substituted on the other side of the amine part to give 2r in 67% yield. As expected, we observed that the C-O bond only formed at the benzylic position in the presence of an N-methyl moiety. N-benzyl-2-hydroxy-N-methylbenzamides bearing hydrogen (1s, 1t), ethoxy (1u), fluorine (1v), and cyano (1w) groups at the para position of the phenyl ring all proceeded smoothly to afford 2s-2w in moderate to good yields with the exception of nitro group (2x) in a slightly decreased 47% yield. In addition to aromatic benzylamines, alkylamines also tolerated well. Comparing the yields of 2y and 2z, we found that the C-H bond at the benzylic position is more liable to be functionalized. Other alkylamines like piperidine (2a’, 52%), pyrrolidine (2b’, 71%), and diethylamine (2c’, 86%) were apparently amenable to this conversion in preparatively useful yields. However, in the case of 2c’ (86%) vs 2d’ (0), no desired product 2d’ was detected, which could be attributed to the increased seric hindrance of isopropyl. To our immense gratification, two benzo[e][1,3]oxazine-4(3H)-thiones 2e’ and 2f’ were synthesized with this methodology in 62% and 70% yields.

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To further extent the scope of the reaction, we tested several substrates that replaced the 2-OH with 2-NH2 under the optimized reaction conditions (Table 4). These substrates would provide quinazolinones. Fortunately, remarkable successes have been achieved. By prolonging the reaction time from 12 h to 24 h, we obtained the desired product 4a in 88% yield. Additionally, other quinazolinone derivatives 4b-4e could be efficiently offered in medium to excellent yields (59-90%). In order to clarify the reaction mechanism, several control experiments were performed (Scheme 2). TEMPO (2,2,6,6-TetrameTable 4 Substrate scope for the synthesis of products quinazolina ones

thylpiperidine-N-oxyl) was added as a radical scavenger under the standard reaction conditions which almost ceased the reaction with a 6% isolated yield of 2a. The observed result implied that this reaction might proceed through a radical pathway. Then, the reaction was carried out in the absence of DTBP to investigate the role of I2, and only trace amount of product was detected at 12 h, indicating that I2 did not react with the substrates directly, but transformed to another intermediate with DTBP prior to reacting with salicylamide. 15 Based on the previous experimental results and reports, we proposed a plausible reaction mechanism as shown in Scheme 3. 16 Initially, the homolysis of DTBP gave tert-butoxy radicals. The tertbutoxyl radical could abstract an H atom from the amide 1a to form intermediate A. Subsequently, intermediate A went through single17 electron transfer to generate intermediate B, followed by nucleophilic attack of the phenol oxygen at the iminium carbon center to provide cyclic intermediate C. Finally, C was converted to the desired product 2a via proton elimination.

Conclusions

a

Reaction conditions: 1 (0.2 mmol), I2 (30 mol%) and DTBP (0.6 mmol) were stirred in toluene (4 mL) at 130 °C for 24 h in the sealed tube, isolated yield.

In summary, we have developed a highly practical and efficient method, for the first time, to synthesize both diversely substituted benzoxazinone and quinazolinone derivatives involving an intramolecular cross-dehydrogenative C-O/C-N coupling reaction. This one-pot protocol employs I2 as green catalyst and DTBP as oxidant avoiding the use of transition metal. It is worth noting that this metal-free transformation is characterized by environment-friendly conditions, broad substrate scope, good to excellent yields, high atom economy and simple operation. Biological activity test of benzoxazinone and quinazolinone derivatives and further expansion of the synthetic application of this strategy are ongoing in our laboratory.

Experimental section Scheme 2 Control experiments.

General All reactions were carried out in oven-dried glassware. Melting points (m.p.) were taken on an XT-4 micro melting point 1 13 19 apparatus and uncorrected. H NMR, C NMR and F NMR spectra were recorded on Bruker-300 and Bruker-500 spectrometers, and were referenced to the residual peaks of 1 CDCl3 at 7.26 ppm or DMSO-d6 at 2.50 ppm ( H NMR) and 13 CDCl3 at 77.23 ppm or DMSO-d6 at 39.52 ppm ( C NMR). Data are reported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet), coupling constant (Hz), and integration. High Resolution Mass measurement was performed on Agilent QTOF 6520 mass spectrometer with electron spray ionization (ESI) as the ion source. Flash column chromatography was carried out using commercially available 200-300 mesh under pressure.

Scheme 3 Plausible reaction mechanism

Materials

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General procedure A To a 15 mL sealed tube with a magnetic stirring bar were added 1 (0.2 mmol), I2 (30 mol%), DTBP (0.6 mmol) and toluene (4 mL). The reaction mixture was placed in an oil bath at 130 °C and vigorously stirred for 12 h. The reaction mixture was cooled to room temperature and 2 mL of brine solution and 5 mL of DCM was added to it. Aqueous portion was washed two times with DCM. The total organic portion was dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo and the residue was purified by silica gel flash column chromatography to afford the corresponding product 2. 3-benzyl-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4one (2a). Prepared from N,N-dibenzyl-2-hydroxybenzamide (63.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 24:1 v/v) furnished the product 2a as a white solid (55 mg, 87% 1 yield). H NMR (300 MHz, DMSO) δ 7.81 (dd, J = 7.7, 1.6 Hz, 1H), 7.45 (td, J = 8.2, 1.6 Hz, 1H), 7.39-7.17 (m, 9H), 7.17-7.01 (m, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.67 (s, 1H), 5.24 (d, J = 15.4 Hz, 13 1H), 4.20 (d, J = 15.4 Hz, 1H); C NMR (75 MHz, CDCl3) δ 162.22, 155.65, 136.56, 135.95, 134.38, 129.72, 128.81, 128.27, 128.05, 127.781, 127.49, 122.57, 118.70, 117.06, 87.49, 47.29; + HRMS (ESI): calcd. for C21H18NO2 (M+H ): 316.1332, found: 316.1333; mp: 104-106 ˚C. 3-benzyl-6-fluoro-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2b). Prepared from N,N-dibenzyl-5-fluoro-2hydroxybenzamide (67.0 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2b as 1 viscous liquid (33 mg, 49% yield). H NMR (300 MHz, CDCl3) δ 7.67 (dd, J = 8.1, 3 Hz, 1H), 7.31-7.28 (m, 8H), 7.23-7.21 (m, 2H), 7.04 (td, J = 9.0, 3.0, 1H), 6.79 (dd, J = 8.7, 4.2 Hz, 1H), 6.77 (s, 13 1H), 5.56 (d, J = 15.3 Hz, 1H), 3.92 (d, J = 15.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 161.38, 161.35, 158.03 (d, J = 240.1 Hz), 151.58 (d, J = 1.86 Hz), 136.24, 135.53, 129.86, 128.87, 128.02, 127.90, 127.43, 121.48 (d, J = 24.0 Hz), 119.64 (d, J = 7.7 Hz), 19 118.59 (d, J = 7.7 Hz), 114.11 (d, J = 24.6 Hz), 87.48, 47.41; F NMR (282 MHz, CDCl3) δ -118.7; HRMS (ESI): calcd. for + C21H17FNO2 (M+H ): 334.1238, found: 334.1234. 3-benzyl-6-chloro-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2c). Prepared from N,N-dibenzyl-5-chloro-2hydroxybenzamide (70.2 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2c as 1 viscous liquid (32 mg, 47% yield). H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 2.4 Hz, 1H), 7.36-7.28 (m, 9H), 7.25-7.22 (m, 2H), 6.79 (d, J = 8.7 Hz, 1H), 6.24 (s, 1H), 5.60 (d, J = 15.3 Hz, 1H), 13 3.91 (d, J = 15.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 161.12, 154.03, 136.16, 135.49, 134.28, 129.92, 128.92, 128.91, 128.05, 127.95, 127.92, 127.872, 127.40, 119.81, 118.72, 47.44; HRMS

+

(ESI): calcd. for C21H17ClNO2 (M+H ): 350.0942, found: 350.0947. 3-benzyl-6-bromo-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2d). Prepared from N,N-dibenzyl-5-bromo-2hydroxybenzamide (79.0 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2d as 1 viscous liquid (37 mg, 46% yield). H NMR (300 MHz, CDCl3) δ 8.12 (d, J = 2.4 Hz, 1H), 7.44 (dd, J =8.7, 2.4 Hz, 1H), 7.35-7.22 (m, 10H), 6.74 (d, J = 8.7 Hz, 1H), 6.24 (s, 1H), 5.59 (d, J = 15.3 13 Hz, 1H), 3.91 (d, J = 15.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 161.00, 154.52, 137.16, 136.14, 135.47, 130.89, 129.95, 128.94, 128.93, 128.07, 127.98, 127.40, 120.21, 119.10, 115.10, 87.44, + 47.45; HRMS (ESI): calcd. for C21H17BrNO2 (M+H ): 394.0437, found: 394.0443. 3-benzyl-6-nitro-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2e). Prepared from N,N-dibenzyl-2-hydroxy-5nitrobenzamide (72.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2e as a white solid 1 (31 mg, 43% yield). H NMR (300 MHz, CDCl3) δ 8.91 (d, J = 2.7 Hz, 1H), 8.24 (dd, J = 9.0, 2.7 Hz, 1H), 7.39-7.27 (m, 8H), 7.267.23 (m, 2H), 6.96 (d, J = 9.0 Hz, 1H), 6.34 (s, 1H), 5.64 (d, J = 13 15.3 Hz, 1H), 3.94 (d, J = 15.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 160.23, 160.04, 143.13, 135.65, 134.97, 130.36, 129.49, 129.18, 129.06, 128.25, 128.22, 127.31, 124.73, 118.73, 118.33, + 88.02, 47.66; HRMS (ESI): calcd. for C21H17N2O4 (M+H ): 361.1183, found: 361.1149; mp: 140-142 ˚C. 3-benzyl-8-nitro-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2f). Prepared from N,N-dibenzyl-2-hydroxy-3nitrobenzamide (72.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2f as a white solid (34 1 mg, 45% yield). H NMR (300 MHz, CDCl3) δ 8.27 (dd, J = 7.8, 1.8 Hz, 1H), 8.04 (dd, J = 8.1, 1.5 Hz, 1H), 7.35-7.28 (m, 10H), 7.14 (t, J = 8.1 Hz, 1H), 6.46 (s, 1H), 5.69 (d, J = 15.3 Hz, 1H), 13 3.99 (d, J = 15.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 160.09, 149.51, 138.41, 135.50, 134.89, 133.68, 130.18, 130.14, 129.09, 128.29, 128.27, 127.16, 121.95, 121.42, 87.63, 47.97; HRMS + (ESI): calcd. for C21H16N2O4Na (M+Na ): 383.1002, found: 383.1022; mp: 166-168 ˚C. 3-benzyl-6-methoxy-2-phenyl-2,3-dihydro-4H-benzo[e][1,3] oxazin-4-one (2g). Prepared from N,N-dibenzyl-2-hydroxy-5methoxybenzamide (69.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 24:1 v/v) furnished the product 2g as 1 colorless oily liquid (61 mg, 89% yield). H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 3 Hz, 1H), 7.22-7.32 (m, 10H), 6.94 (dd, J = 9, 3.3 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.20 (s, 1H), 5.58 (d, J = 13 15.3 Hz, 1H), 3.92 (d, J = 15.3 Hz, 1H), 3.80 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.32, 155.06, 149.66, 136.61, 136.03, 129.68, 128.84, 128.79, 128.02, 127.79, 127.51, 122.34, 118.96, 118.22, 110.33, 87.49, 55.93, 47.43; HRMS (ESI): calcd. for C22H20NO3 + (M+H ): 346.1438, found: 346.1438. 3-benzyl-7-methoxy-2-phenyl-2,3-dihydro-4H-benzo[e][1,3] oxazin-4-one (2h). Prepared from N,N-dibenzyl-2-hydroxy-4methoxybenzamide (69.4 mg, 0.20 mmol, 1.0 equiv) according

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Unless otherwise indicated, all reagents were obtained from commercial suppliers used without further purification. PE refers to petroleum ether (b.p. 60-90 °C) and EA refers to ethyl acetate, and all reaction solvents were freshly distilled prior to use.

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to the general procedure A. Column chromatography purification (PE: EA = 24:1 v/v) furnished the product 2h as a 1 white solid (46 mg, 66% yield). H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 8.7 Hz, 1H), 7.40-7.22 (m, 10H), 6.60 (dd, J = 7.2 Hz, 1.5 Hz, 1H), 6.34 (s, 1H), 6.21 (s, 1H), 5.59 (d, J = 15.3 Hz, 1H), 13 3.89 (d, J = 15.3 Hz, 1H), 3.75 (s, 3H); C NMR (75 MHz, CDCl3) δ 164.80, 162.31, 157.32, 136.76, 136.03, 129.76, 129.72, 128.84, 128.03, 127.75, 127.50, 111.66, 109.73, 101.37, 87.66, + 55.66, 47.05; HRMS (ESI): calcd. for C22H20NO3 (M+H ): 346.1438, found: 346.1436; mp: 112-114 ˚C. 3-benzyl-8-methoxy-2-phenyl-2,3-dihydro-4H-benzo[e][1,3] oxazin-4-one (2i). Prepared from N,N-dibenzyl-2-hydroxy-3methoxybenzamide (69.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 24:1 v/v) furnished the product 2i as a 1 white solid (66 mg, 95% yield). H NMR (300 MHz, CDCl3) δ 7.59 (dd, J = 7.5, 1.8 Hz, 1H), 7.39-7.23 (m, 10H), 7.01-6.92 (m, 2H), 6.32 (s, 1H), 5.66 (d, J = 15.3 Hz, 1H), 3.94 (d, J = 15.3 Hz, 13 1H), 3.80 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.06, 148.31, 145.11, 136.35, 136.05, 129.67, 128.87, 128.83, 128.02, 127.83, 127.35, 122.26, 119.54, 116.11, 87.33, 56.37, 47.52; HRMS + (ESI): calcd. for C22H20NO3 (M+H ): 346.1438, found: 346.1439; mp: 124-127 ˚C. 2-benzyl-3-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazin-1-one (2j). Prepared from N,N-dibenzyl-2-hydroxy-1naphthamide (73.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2j as colorless oily liquid 1 (61 mg, 84% yield). H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 9 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.66-7.60 (m, 1H), 7.45-7.39 (m, 3H), 7.33-7.28 (m, 8H), 7.05 (d, J = 9 Hz, 1H), 6.34 (s, 1H), 5.65 13 (d, J = 15.3 Hz, 1H), 4.09 (d, J = 15.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 162.72, 156.51, 137.09, 135.88, 135.78, 132.02, 130.24, 129.69, 128.88, 128.82, 128.73, 128.04, 127.77, 127.54, 126.38, 124.97, 117.67, 111.06, 87.11, 47.46; HRMS (ESI): calcd. + for C25H20NO2 (M+H ): 366.1489, found: 366.1494. methyl (E)-3-(3-benzyl-4-oxo-2-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)acrylate (2k). Prepared from methyl (E)3-(3-(dibenzylcarbamoyl)-4-hydroxyphenyl)acrylate (80.2 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 12:1 v/v) furnished the product 2k as colorless oily liquid (53 mg, 67% 1 yield). H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 2.1 Hz, 1H), 7.63 (d, J = 15.9 Hz, 1H), 7.51 (dd, J = 8.4, 2.1 Hz, 1H), 7.33-7.28 (m, 8H), 7.22-7.26 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.38 (d, J = 15.9 Hz, 1H), 6.27 (s, 1H), 5.62 (d, J = 15.3 Hz, 1H), 3.91 (d, J = 15.3 13 Hz, 1H), 3.79 (s, 1H); C NMR (75 MHz, CDCl3) δ 167.50, 161.63, 156.96, 143.52, 136.20, 135.63, 133.97, 130.00, 129.22, 129.00, 128.97, 128.12, 128.01, 127.42, 118.87, 117.91, 117.59, + 87.57, 51.91, 47.43; HRMS (ESI): calcd. for C25H22NO4 (M+H ): 400.1543, found: 400.1550. 3-(4-methoxybenzyl)-2-(4-methoxyphenyl)-2,3-dihydro-4Hbenzo[e][1,3]oxazin-4-one (2l). Prepared from 2-hydroxy-N,Nbis(4-methoxybenzyl)benzamide (75.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 24:1 v/v) furnished the 1 product 2l as colorless oily liquid (57 mg, 76% yield). H NMR

(300 MHz, CDCl3) δ 7.99 (dd, J = 7.8, 1.5 Hz, 1H), 7.33 (td, J = 8.1, 1.8 Hz, 1H), 7.23 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 6.82-6.79 (m, 5H), 6.17 (s, 1H), 5.47 (d, J = 15.3 Hz, 1H), 3.84 (d, J = 15.3 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 13 3H); C NMR (75 MHz, CDCl3) δ 162.23, 160.59, 159.27, 155.58, 134.31, 129.49, 128.89, 128.59, 128.17, 127.98, 122.44, 118.69, 117.032, 114.18, 114.11, 55.38, 46.62; HRMS (ESI): calcd. for + C23H22NO4 (M+H ): 376.1543, found: 376.1541. 8-methoxy-3-(4-methoxybenzyl)-2-(4-methoxyphenyl)-2,3dihydro-4H-benzo[e][1,3]oxazin-4-one (2m). Prepared from 2hydroxy-3-methoxy-N,N-bis(4-methoxybenzyl)benzamide (81.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 12:1 v/v) furnished the product 2m as a white solid (79 mg, 98% yield). 1 H NMR (300 MHz, CDCl3) δ 7.58 (dd, J = 6.9, 2.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.4 Hz 2H), 7.00-6.93 (m, 2H), 6.82 (dd, J = 8.7, 1.8 Hz, 4H), 6.25 (s, 1H), 5.52 (d, J = 15.3 Hz, 1H), 3.86 (d, J = 15.3 Hz, 1H), 3.80 (s, 3H), 3.780 (s, 3H), 3.76 (s, 13 3H); C NMR (75 MHz, CDCl3) δ 162.14, 160.66, 159.40, 148.44, 129.58, 128.88, 128.56, 128.23, 122.15, 119.71, 119.64, 116.28, 114.31, 114.20, 87.23, 56.49, 55.51, 55.47, 46.99; HRMS (ESI): + calcd. for C24H24NO5 (M+H ): 406.1649, found: 406.1648; mp: 174-176 ˚C. 3-(4-methylbenzyl)-2-(p-tolyl)-2,3-dihydro-4H-benzo[e][1,3] oxazin-4-one (2n). Prepared from 2-hydroxy-N,N-bis(4methylbenzyl)benzamide (69 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the 1 product 2n as a white solid (57 mg, 83% yield). H NMR (300 MHz, CDCl3) δ 7.99 (dd, J = 7.5, 1.2 Hz, 1H), 7.34 (td, J = 7.8, 1.5 Hz, 1H), 7.22-7.19 (m, 2H), 7.12-7.10 (m, 6H), 7.03 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.19 (s, 1H), 5.59 (d, J = 15.3 Hz, 13 1H), 3.80 (d, J = 15.3 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.24, 155.63, 137.73, 137.55, 134.34, 133.54, 133.18, 129.56, 128.27, 128.19, 127.45, 122.50, 118.81, 117.12, 87.22, 47.05, 21.36, 21.30; HRMS (ESI): calcd. for + C23H21NO2Na(M+Na ): 366.1645, found: 366.1661; mp: 105107 ˚C. 8-methoxy-3-(4-methylbenzyl)-2-(p-tolyl)-2,3-dihydro-4Hbenzo[e][1,3]oxazin-4-one (2o). Prepared from 2-hydroxy-3methoxy-N,N-bis(4-methylbenzyl)benzamide (75 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2o as a white solid (57 mg, 77% yield). 1 H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 7.16-7.09 (m, 6H), 6.98-6.91 (m, 3H), 6.27 (s, 1H), 5.61 (d, J = 15.3 Hz, 1H), 3.84 (d, J = 15.3 Hz, 1H), 3.78 (s, 3H), 2.31 (s, 3H), 13 2.29 (s, 3H); C NMR (75 MHz, CDCl3) δ 161.96, 148.35, 145.15, 139.53, 137.45, 133.33, 133.25, 129.48, 129.46, 128.07, 127.25, 122.05, 119.65, 119.52, 116.17, 87.15, 56.36, 47.24, 21.26, + 21.20; HRMS (ESI): calcd. for C24H24NO3 (M+H ): 374.1751, found: 374.1745; mp: 175-178 ˚C. 3-(4-chlorobenzyl)-2-(4-chlorophenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2p). Prepared from N,N-bis(4chlorobenzyl)-2-hydroxybenzamide (77 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the

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product 2p as colorless oily liquid (58 mg, 76% yield). H NMR (300 MHz, CDCl3) δ 7.99 (td, J = 7.8, 1.8 Hz, 1H), 7.41-7.35 (m, 1H), 7.30-7.23 (m, 6H), 7.16-7.14 (m, 2H), 7.08 (td, J = 7.5, 0.6 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.19 (s, 1H), 5.44 (d, J = 15.3 Hz, 13 1H), 3.94 (d, J = 15.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 162.21, 155.48, 135.95, 134.99, 134.74, 134.32, 133.82, 129.41, 129.16, 129.09, 128.91, 128.39, 122.95, 118.47, 117.13, 87.02, + 46.80; HRMS (ESI): calcd. for C21H16Cl2NO2 (M+H ): 384.0553, found: 384.0544. 3-(4-chlorobenzyl)-2-(4-chlorophenyl)-8-methoxy-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2q). Prepared from N,Nbis(4-chlorobenzyl)-2-hydroxy-3-methoxybenzamide (83 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 24:1 v/v) furnished the product 2q as a white solid (67 mg, 81% yield). 1 H NMR (300 MHz, CDCl3) δ 7.56 (dd, J = 7.2, 2.1 Hz, 1H), 7.287.26 (m, 6H), 7.19-7.16 (m, 2H), 7.04-6.95 (m, 2H), 6.25 (s, 1H), 5.48 (d, J = 15.3 Hz, 1H), 3.96 (d, J = 15.3 Hz, 1H), 3.82 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 162.05, 148.41, 145.04, 135.90, 134.89, 134.52, 133.86, 129.39, 129.17, 129.12, 128.79, 122.67, 119.61, 119.43, 116.43, 87.10, 56.44, 47.10; HRMS (ESI): calcd. + for C22H18Cl2NO3 (M+H ): 414.0658, found: 414.0681; mp: 157160 ˚C. 2-(4-methoxyphenyl)-3-(4-nitrobenzyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2r). Prepared from 2-hydroxy-N-(4methoxybenzyl)-N-(4-nitrobenzyl)benzamide (78.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2r as yellow viscous liquid (52 mg, 67% 1 yield). H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.6 Hz, 2H), 7.90 (dd, J = 7.8, 1.4 Hz, 1H), 7.32-7.29 (m, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 6.12 (s, 1H), 5.12 (d, J = 13 16.0 Hz, 1H), 4.14 (d, J = 16.0 Hz, 1H), 3.66 (s, 3H); C NMR (125 MHz, CDCl3) δ 162.92, 160.97, 156.14, 147.43, 144.69, 134.74, 129.05, 128.46, 128.34, 127.03, 123.82, 122.80, 118.20, 117.07, 114.23, 88.47, 55.40, 46.62; HRMS (ESI): calcd. for + C22H21N2O5 (M+H ): 391.1288, found: 391.1282. 3-methyl-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4one (2s). Prepared from N-benzyl-2-hydroxy-Nmethylbenzamide (48.2 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2s as 1 colorless oily liquid (38 mg, 79% yield). H NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 7.8, 1.5 Hz, 1H), 7.42-7.33 (m, 6H), 7.04 (td, J = 7.8, 0.9 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.24 (s, 1H), 13 3.01 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.57, 155.75, 136.10, 134.23, 129.89, 129.01, 128.02, 127.36, 122.56, 118.50, 116.87, + 89.75, 31.76; HRMS (ESI): calcd. for C15H14NO2 (M+H ): 240.1019, found: 240.1014. 7-methoxy-3-methyl-2-phenyl-2,3-dihydro-4H-benzo[e][1,3] oxazin-4-one (2t). Prepared from N-benzyl-2-hydroxy-4methoxy-N-methylbenzamide (54.2 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the 1 product 2t as colorless oily liquid (33 mg, 61% yield). H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.7 Hz, 1H), 7.39 (m, 5H), 6.58

(d, J = 8.4 Hz, 1H), 6.36 (s, 1H), 6.22 (s, 1H), 3.76 (s, 3H), 2.98 (s, 13 3H); C NMR (75 MHz, CDCl3) δ 164.57, 162.65, 157.39, 136.18, 129.85, 129.46, 128.99, 127.35, 111.52, 109.61, 101.15, 89.96, + 55.61, 31.55; HRMS (ESI): calcd. for C16H16NO3 (M+H ): 270.1125, found: 270.1126. 2-(4-ethoxyphenyl)-3-methyl-2,3-dihydro-4H-benzo[e][1,3] oxazin-4-one (2u). Prepared from N-(4-ethoxybenzyl)-2hydroxy-N-methylbenzamide (57 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the 1 product 2u as colorless oily liquid (36 mg, 63% yield). H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 7.5 Hz, 1H), 7.38-7.30 (m, 3H), 7.04 (t, J = 7.5 Hz, 1H), 6.88-6.84 (m, 3H), 6.36 (s, 1H), 6.19 (s, 1H), 4.00 (q, J = 6.9 Hz, 2H), 2.97 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H); 13 C NMR (75 MHz, CDCl3) δ 162.69, 160.13, 155.81, 134.16, 128.74, 128.44, 127.97, 122.44, 118.47, 116.86, 114.78, 89.61, + 63.64, 31.54, 14.86; HRMS (ESI): calcd. for C17H18NO3 (M+H ): 284.1281, found: 284.1283. 2-(4-fluorophenyl)-3-methyl-2,3-dihydro-4H-benzo[e][1,3] oxazin-4-one (2v). Prepared from N-(4-fluorobenzyl)-2hydroxy-N-methylbenzamide (51.8 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 12:1 v/v) furnished the 1 product 2v as colorless oily liquid (36 mg, 70% yield). H NMR (300 MHz, CDCl3) δ 7.94 (dd, J = 7.8, 1.8 Hz, 1H), 7.41-7.34 (m, 3H), 7.09-7.02 (m, 3H), 6.86 (dd, J = 8.1, 0.9 Hz, 1H), 6.23 (s, 13 1H), 3.01 (s, 3H); C NMR (75 MHz, CDCl3) δ 163.53 (d, J = 247.8 Hz), 162.50, 155.54, 134.37, 129.30 (d, J = 8.4 Hz), 129.07, 128.95, 128.07, 122.73, 116.89, 116.10 (d, J = 21.7 Hz), 19 89.10, 31.79; F NMR (282 MHz, CDCl3) δ -110.0; HRMS (ESI): + calcd. for C15H13FNO2 (M+H ): 258.0925, found: 258.0924. 4-(3-methyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-2yl)benzonitrile (2w). Prepared from N-(4-cyanobenzyl)-2hydroxy-N-methylbenzamide (53.2 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 12:1 v/v) furnished the 1 product 2w as colorless oily liquid (36 mg, 69% yield). H NMR (300 MHz, CDCl3) δ 7.92 (dd, J = 7.8, 1.5 Hz, 1H), 7.68-7.65 (m, 2H), 7.53-7.50 (m, 2H), 7.40-7.34 (m, 1H), 7.08-7.03 (m, 1H), 13 6.86 (d, J = 8.1 Hz, 1H), 6.29 (s, 1H), 3.10 (s, 3H); C NMR (75 MHz, CDCl3) δ 161.99, 155.12, 141.41, 134.60, 132.86, 128.13, 128.02, 123.05, 118.36, 118.17, 116.93, 113.79, 88.56, 32.28; + HRMS (ESI): calcd. for C16H13N2O2 (M+H ): 265.0972, found: 265.096; mp: 153-155 ˚C. 3-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2x). Prepared from 2-hydroxy-N-methyl-N-(4nitrobenzyl)benzamide (57.2 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 12:1 v/v) furnished the 1 product 2x as yellow oily liquid (27 mg, 47% yield). H NMR (300 MHz, CDCl3) δ 8.22 (dt, J = 9, 2.1 Hz, 2H), 7.93 (dd, J = 7.8, 1.5 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.38 (dddd, J = 8.1, 7.2, 1.8 Hz, 1H), 7.06 (td, J = 7.5, 0.9 Hz, 1H), 6.87 (dd, J = 8.1, 0.6 Hz, 13 1H), 6.34 (s, 1H), 3.13 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.00, 155.13, 148.83, 143.29, 134.69, 128.37, 128.23, 124.30, 123.18, 118.43, 116.99, 88.43, 32.39; HRMS (ESI): calcd. for + C15H13N2O4 (M+H ): 285.0870, found: 285.0867.

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DOI: 10.1039/C7OB02038D

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5,13a-dihydro-6H,8H-benzo[5,6][1,3]oxazino[2,3-a]isoquinolin-8-one (2y). Prepared from (3,4-dihydroisoquinolin-2(1H)yl)(2-hydroxyphenyl)methanone (50.6 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 24:1 v/v) furnished the 1 product 2y as colorless oily liquid (41 mg, 82% yield). H NMR (300 MHz, CDCl3) δ 8.06 (dd, J = 7.5, 1.5 Hz, 1H), 7.65-7.60 (m, 1H), 7.50 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H), 7.43-7.37 (m, 2H), 7.297.28 (m, 1H), 7.17 (t, J = 7.5, 1H), 7.09 (d, J = 8.1Hz, 1H), 6.30 (s, 1H), 4.54 (dt, J = 12.9, 4.5 Hz, 1H), 3.44 (ddd, J = 12.3, 11.1, 3.9 13 Hz, 1H), 3.17-3.07 (m, 1H), 2.88 (dt, J = 15.9, 3.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 163.18, 157.67, 136.28, 134.35, 130.80, 129.53, 128.78, 128.73, 128.25, 127.35, 122.92, 118.893, 116.73, 84.19, 38.40, 28.62; HRMS (ESI): calcd. for C16H14NO2 + (M+H ): 252.1019, found: 252.1018. 6,6a-dihydro-5H,12H-benzo[5,6][1,3]oxazino[3,2-a]quinolin-12-one (2z). Prepared from (3,4-dihydroquinolin-1(2H)-yl)(2hydroxyphenyl)methanone (50.6 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 24:1 v/v) furnished the 1 product 2z as colorless oily liquid (33 mg, 65% yield). H NMR (300 MHz, CDCl3) δ 8.33 (d, J = 8.4 Hz, 1H), 8.12 (dd, J =7.8, 1.5 Hz, 1H), 7.51 (dddd, J = 8.1, 7.2, 1.5 Hz, 1H), 7.32-7.28 (m, 1H), 7.22-7.16 (m, 2H), 7.11-7.03 (m, 2H), 5.64 (t, J = 5.1 Hz, 1H), 13 2.94-2.76 (m, 2H), 2.48-2.38 (m, 1H), 2.30-2.20 (m, 1H); C NMR (75 MHz, CDCl3) δ 162.17, 158.07, 135.63, 134.48, 130.04, 129.47, 127.74, 127.06, 124.21, 122.86, 122.79, 119.73, 116.27, + 86.70, 29.54, 24.63; HRMS (ESI): calcd. for C16H14NO2 (M+H ): 252.1019, found: 252.1020. 5a,6,8,9-tetrahydro-7H,11H-benzo[e]pyrido[2,1-b][1,3]oxazin-11-one (2a’). Prepared from (2-hydroxyphenyl)(piperidin-1yl)methanone (40.1 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 2a’ as colorless oily 1 liquid (21 mg, 52% yield). H NMR (300 MHz, CDCl3) δ 7.94 (dd, J = 7.5, 1.2 Hz, 1H), 7.41 (td, J = 8.1, 1.5 Hz, 1H), 7.06 (td, J = 7.8, 0.9 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 5.20 (dd, J = 9.9, 4.5 Hz, 1H), 4.50-4.44 (m, 1H), 2.77 (td , J = 12.9, 3.6 Hz, 1H), 2.25-2.20 (m, 1H), 1.95-1.89 (m, 1H), 1.85-1.77 (m, 2H), 1.59-1.43 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 163.66, 156.74, 134.23, 128.32, 122.41, 117.69, 116.20, 86.08, 41.50, 31.59, 23.70, 21.42; + HRMS (ESI): calcd. for C12H14NO2 (M+H ): 204.1019, found: 204.1027. 1,2,3,3a-tetrahydro-9H-benzo[e]pyrrolo[2,1-b][1,3]oxazin9-one (2b’). Prepared from (2-hydroxyphenyl)(pyrrolidin-1yl)methanone (38.2 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 8:1 v/v) furnished the product 2b’ as colorless oily 1 liquid (26 mg, 71% yield). H NMR (300 MHz, CDCl3) δ 7.92 (dd, J = 7.8, 1.5 Hz, 1H), 7.41 (td, J = 7.8, 1.8 Hz, 1H), 7.10 (td, J = 7.5, 0.9 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 5.49 (t, J = 5.7Hz, 1H), 3.883.79 (m, 1H), 3.65-3.57 (m, 1H), 2.48-2.38 (m, 1H), 2.30-2.17 13 (m, 1H), 2.15-2.04 (m, 1H), 2.00-1.88 (m, 1H); C NMR (75 MHz, CDCl3) δ 161.06, 157.41, 133.90, 128.06, 122.75, 119.88, 116.58, 88.60, 44.44, 32.06, 21.44; HRMS (ESI): calcd. for + C11H12NO2 (M+H ): 190.0863, found: 190.0862.

3-ethyl-2-methyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-one (2c’). Prepared from N,N-diethyl-2-hydroxybenzamide (38.6 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 12:1 v/v) furnished the product 2c’ as yellow oily liquid (33 mg, 86% 1 yield). H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 7.2 Hz, 1H), 7.447.39 (m, 1H), 7.07 (td, J = 7.5, 1.5 Hz, 1H), 6.91 (dd, J = 8.4, 1.2 Hz, 1H), 5.47 (q, J = 6.0 Hz, 1H), 3.94-3.82 (m, 1H), 3.30-3.19 (m, 13 1H), 1.57 (d, J = 6.0 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H); C NMR (75 MHz, CDCl3) δ 161.01, 155.56, 133.97, 128.30, 128.01, 122.20, 116.75, 84.50, 38.29, 19.34, 13.82; HRMS (ESI): calcd. + for C11H14NO2 (M+H ): 192.1019, found: 192.1013. 3-benzyl-2-phenyl-2,3-dihydro-4H-benzo[e][1,3]oxazine-4thione (2e’). Prepared from methyl N,N-dibenzyl-2hydroxybenzothioamide (66.6 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the 1 product 2e’ as brown oily liquid (41 mg, 62% yield). H NMR (300 MHz, CDCl3) δ 8.43 (dd, J = 8.1, 1.5 Hz, 1H), 7.36-7.29 (m, 11H), 7.06-7.00 (m, 1H), 6.80 (dd, J = 8.1, 0.6 Hz, 1H), 6.65 (d, J 13 = 15.3 Hz, 1H), 6.36 (s, 1H), 4.30 (d, J = 15.3 Hz, 1H); C NMR (75 MHz, CDCl3) δ 189.61, 150.10, 135.24, 134.83, 134.41, 132.35, 129.87, 129.08, 129.01, 128.18, 127.88, 127.31, 124.06, 122.94, 117.08, 86.34, 54.65; HRMS (ESI): calcd. for C21H18NOS + (M+H ): 332.1104, found: 332.1103. 3-benzyl-6-methoxy-2-phenyl-2,3-dihydro-4H-benzo[e][1,3] oxazine-4-thione (2f’). Prepared from N,N-dibenzyl-2-hydroxy5-methoxybenzothioamide (72.6 mg, 0.20 mmol, 1.0 equiv) according to the general procedure A. Column chromatography purification (PE: EA = 48:1 v/v) furnished the 1 product 2f’ as yellow viscous liquid (50 mg, 70% yield). H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 3 Hz, 1H), 7.35-7.27 (m, 10H), 6.91 (dd, J = 9.0, 3.3 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.61 (d, J = 15.3 Hz, 1H), 6.32 (s, 1H), 4.31 (d, J = 15.3 Hz, 1H), 3.81 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 189.50, 155.02, 144.23, 135.32, 134.99, 129.82, 128.99, 128.17, 127.86, 127.33, 124.39, 122.63, 118.22, 114.22, 86.43, 55.99, 54.85; HRMS (ESI): calcd. for + C22H20NO2S (M+H ): 362.1209, found: 362.1206. General procedure B To a 15 mL sealed tube with a magnetic stirring bar were added 3 (0.2 mmol), I2 (30 mol%), DTBP (0.6 mmol) and toluene (4 mL). The reaction mixture was placed in an oil bath at 130 °C and vigorously stirred for 24 h. The reaction mixture was cooled to room temperature and 2 mL of brine solution and 5 mL of DCM was added to it. Aqueous portion was washed two times with DCM. The total organic portion was dried over anhydrous Na2SO4. The organic phase was concentrated in vacuo and the residue was purified by silica gel flash column chromatography to afford the corresponding product 4. 3-benzyl-2-phenylquinazolin-4(3H)-one (4a). Prepared from 2-amino-N,N-dibenzylbenzamide (63.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure B. Column chromatography purification (PE: EA = 48:1 v/v) furnished the 1 product 4a as a white solid (55 mg, 88% yield). H NMR (300 MHz, CDCl3) δ 8.39-8.36 (m, 1H), 7.82-7.75 (m, 2H), 7.56-7.32

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(m, 6H), 7.23-7.18 (m, 3H), 6.94-6.91 (m, 2H), 5.27 (s, 2H); C NMR (75 MHz, CDCl3) δ 162.63, 156.55, 147.44, 136.75, 135.45, 134.73, 130.07, 128.77, 128.69, 128.17, 127.77, 127.61, 127.33, 127.28, 127.14, 121.04, 48.97; HRMS (ESI): calcd. for + C21H17N2O (M+H ): 313.1335, found: 313.1336; mp: 147-149 ℃. 3-methyl-2-phenylquinazolin-4(3H)-one (4b). Prepared from 2-amino-N-benzyl-N-methylbenzamide (48 mg, 0.20 mmol, 1.0 equiv) according to the general procedure B. Column chromatography purification (PE: EA = 12:1 v/v) furnished the 1 product 4b as a white solid (36 mg, 77% yield). H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 8.1 Hz, 1H), 7.76-7.69 (m, 2H), 7.5713 7.44 (m, 6H), 3.47 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.79, 156.21, 147.38, 135.47, 134.40, 130.17, 128.99, 127.57, 127.08, + 126.75, 120.59, 34.38; HRMS (ESI): calcd. for C15H13N2O (M+H ): 237.1022, found: 237.1014; mp: 139-141 ℃. 2-(4-methoxyphenyl)-3-methylquinazolin-4(3H)-one (4c). Prepared from 2-amino-N-(4-methoxybenzyl)-N-methylbenzamide (54 mg, 0.20 mmol, 1.0 equiv) according to the general procedure B. Column chromatography purification (PE: EA = 8:1 v/v) furnished the product 4c as a white solid (32 mg, 65% 1 yield). H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 7.8 Hz, 1H), 7.787.71 (m, 2H), 7.55-7.46 (m, 3H), 7.03 (d, J = 8.4 Hz, 2H), 3.88 (s, 13 3H), 3.53 (s, 3H); C NMR (75 MHz, CDCl3) δ 163.00, 161.01, 156.11, 147.49, 134.31, 129.87, 127.85, 127.49, 126.84, 126.71, 120.45, 114.27, 55.57, 34.55; HRMS (ESI): calcd. for C16H15N2O2 + (M+H ): 267.1128, found: 267.1128; mp: 147-149 ℃. 4-(3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)benzonitrile (4d). Prepared from 2-amino-N-(4-cyanobenzyl)-N-methylbenzamide (53 mg, 0.20 mmol, 1.0 equiv) according to the general procedure B. Column chromatography purification (PE: EA = 8:1 v/v) furnished the product 4d as a white solid (31 mg, 1 59% yield). H NMR (300 MHz, CDCl3) δ 8.35 (d, J = 7.8 Hz, 1H), 7.87-7.83 (m, 2H), 7.78 (dd , J = 7.2, 1.5 Hz, 1H), 7.74- 7.71 (m, 13 3H), 7.55 (t, J = 7.8 Hz, 1H), 3.49 (s, 3H); C NMR (75 MHz, CDCl3) δ 162.37, 154.22, 147.07, 139.52, 134.66, 132.79, 129.15, 127.69, 127.65, 126.84, 120.68, 118.02, 114.09, 34.23; + HRMS (ESI): calcd. for C16H12N3O (M+H ): 262.0975, found: 262.0971; mp: 227-230 ℃. 5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one (4e). Prepared from (2-aminophenyl)(3,4-dihydroisoquinolin-2(1H)yl)methanone (50.4 mg, 0.20 mmol, 1.0 equiv) according to the general procedure B. Column chromatography purification (PE: EA = 48:1 v/v) furnished the product 4e as a white solid 1 (45 mg, 90% yield). H NMR (300 MHz, CDCl3) δ 8.49 (dd, J = 7.5, 1.5 Hz, 1H), 8.34-8.31 (m, 1H), 7.79-7.73 (m, 2H), 7.52-7.42 (m, 3H), 7.31-7.28 (m, 1H), 4.43 (t, J = 6.3 Hz, 2H), 3.11 (t, J = 13 6.6 Hz, 2H); C NMR (75 MHz, CDCl3) δ 161.89, 149.54, 147.98, 137.23, 134.40, 131.89, 129.74, 128.19, 127.80, 127.68, 127.04, 126.70, 120.93, 39.77, 27.63; HRMS (ESI): calcd. for C16H13N2O + (M+H ): 249.1022, found: 249.1023; mp: 162-164 ℃.

Conflicts of interest There are no conflicts to declare.

This work was supported financially by the key research & development program in Jiangsu (NO. BE2015683), by the introduction program of leading scientific and technological entrepreneurship in Nanjing (NO. 2013B14007), by the innovative research project of graduate student in Jiangsu (NO. KYLX16_1170).

Notes and references 1

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