TBHP-Mediated Oxidative Coupling of Amino-Based

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I2/TBHP-mediated Oxidative Coupling of Amino-Based Bisnucleophiles and Isocyanides: Access to 2-Aminobenzoxazinones, 2Aminobenzoxazines and 2-Aminoquinazolines under Metal-free Conditions Hong-Xia Wang, Tian-Qi Wei, Pei Xu, Shun-Yi Wang, and Shun-Jun Ji J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02395 • Publication Date (Web): 11 Oct 2018 Downloaded from http://pubs.acs.org on October 11, 2018

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The Journal of Organic Chemistry

I2/TBHP-mediated Oxidative Coupling of Amino-Based Bisnucleophiles and Isocyanides: Access to 2-Aminobenzoxazinones, 2-Aminobenzoxazines and 2Aminoquinazolines under Metal-free Conditions Hong-Xia Wang,a Tian-Qi Wei,b Pei Xu,b Shun-Yi Wang,b,* and Shun-Jun Jib,* aSchool bKey

of chemistry, biology and materials engineering, Suzhou Univeristy of science and technology.

Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical

Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, P. R. China; E-mail: [email protected]; [email protected] *CORRESPONDING AUTHOR FAX: 86-512-65880307. O

O OH

R1 or R1

NH2 C N R

or

2

TBHP (2 equiv) 50 oC, 12 h

R2

N

R1 N

NH2

N H

N

I2 (10 mol %) +

NH2

O

R1

N H

R2

ABSTRACT. An I2/tert-Butyl hydroperoxide (TBHP)-mediated oxidative coupling reaction of isocyanides with amino-based bisnucleophiles is described for the synthesis of 2-aminobenzoxazinones, 2-aminobenzoxazines and 2-aminoquinozolines in moderate to excellent yields. Furthermore, this method provide a simple and practical method to construct potential functionalized biologically active molecules.

KEYWORDS: I2, TBHP, Oxidative Coupling, Isocyanide, Metal-Free ACS Paragon Plus Environment

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INTRODUCTION 2-aminobenzoxazinones, 2-aminobenzoxazines and 2-aminoquinozolines are privileged heterocyclic scaffolds in bioactive compounds and natural products.1 For example, compound I acts as an inhibitor of C1r.2 Compound II shows good antiviral activity against HSV-1 protease.3 Etifoxine III is used for the treatment of anxiety neurosis.4 Compound IV demonstrates nanomolar activity against protein kinase (MAPK) p38 (Figure 1).5

O

O O

Cl

N

O N H

I Inhibitor of C1r Serine Protease

H N

O N III Etifoxine

N H

II Inhibitor of HSV-1 Protease

O

Cl

N

Cbz-Ala-HN

I

O

N N H

N

N

N H IV Potent p38 Inhibitors

Figure 1. Biologically active 2-aminobenzoxazinones, 2-aminobenzoxazines and 2aminoquinozolines Consequently, intensive efforts have been made for their preparation.1-6 Especially the synthesis of 2aminobenzoxazinones have been developed fast during the past decades. However, the methods for their synthesis mainly located on the Pd(II)-catalyzed reactions (Scheme 1). Houlden’s group realized a Pd(II)-catalyzed carbonylative method through C-H activation and CO insertion of N-arylureas (Scheme 1, A).7 Similarly, Wu’s group reported a carbonylative synthesis of 2 –aminobenzoxazoles via in situ formation of N-arylureas by the reaction of isocyanates and 2-bromoanilines (Scheme 1, B).8 In 2013, Orru et al reported an oxidative reaction of 2-aminobenzoic acids and isocyanides using Pd(II)-catalyst to give 2-aminobenzoxazinones. The procedure is easy to handle and toxic CO is not required (Scheme ACS Paragon Plus Environment

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1, C).9 Although the reported methods have made a great step forward in the production of these scaffolds, they suffer from the use of transition metals, which limits their applications in medicinal chemistry. In order to provide a more environmentally friendly strategy, the development of a metal-free approach is still highly desirable. Isocyanides are usually used in the construction of nitrogen-containing compounds as vital and meritorious C1 building blocks.10 Iodine and compounds of iodine-mediated oxidative coupling reactions are very important for they are more green and less expensive than those transition-metalmediated oxidative coupling reactions.11 An procedure of using isocyanides and amines to developed carbodiimides through I2/CHP-mediated cross-coupling reaction, has been reported in our previous work.12 The carbonimidic diiodine intermediate was assumed to be an active species in the formation of carbodiimides. Inspired by our previous work, we herein describe a metal-free I2/TBHP mediated oxidative coupling reaction of 2-aminobenzoic acid and isocyanides producing various 2 ‑ aminobenzoxazinones (Scheme 1, D). Previous work

A NHCONR R

Pd(OAc)2 (3 mol %) BuPAd2 (6 mo l%)

Br R1

+

O

TsOH (1 equiv), CO (1 atm) CH2Cl2, 3-5 h, 18 oC

2 3

B

O

[(MeCN)2Pd(OTs)2] (5 mol %) benzoquinone (2 equiv)

H

R2 NCO

N

NHR2

N

Wu's work

O Pd(OAc)2 (5 mol %)

OH

R1

O

R1

O C

NR R O

[Mo(CO)6] (1.5 equiv) K3PO4/toluene,120 oC

NH2

Houlden's work 2 3

NH2

+

C N R2

1,4-dioxane,75 oC,4 h 4A MS,O2 (1 atm)

O

R1

N H

N

R2

Orru's work

This work O

O D

R1

OH + NH2

I2 (10 mol %) C N R2

TBHP (2 equiv) 50 oC, 12 h

O

R1 N

N H

R2

Scheme 1. Routes toward 2- Aminobenzoxazinones. ACS Paragon Plus Environment

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RESULTS AND DISCUSSION We investigated the reaction of 2-aminobenzoic acid 1a and tert-butyl isocyanide 2a, in the presence of 0.2 equiv. of iodine and 2 equiv. of TBHP, using 1,4-dioxane as solvent at 110 °C for 4 h. To our delight, the desired product 2-(tert-butylamino)-4H-benzo[d][1,3]oxazin-4-one 3a was obtained in 53% GC-yield (Table 1, entry 1). In the absence of the catalyst, no expected product was observed (Table 1, entry 2). The yield of 3a decreased when we used different iodine sources like NIS and Bu4NI (Table 1, entries 3, 4 and 6). We also evaluated other halide-source catalyst such as Bu4NBr, which could not promote this reaction (Table 1, Entry 5). Further examinations of other kinds of oxidants, such as CHP, TBHP, O2, TBPB, and K2S2O8 was operated and TBHP proved to be the most efficient oxidant (Table 1, entries 1, 7-11). Various solvents, including THF, MeCN, MTBE, DCE), DMF, toluene and DME were screened subsequently, which indicated that MTBE was the best solvent (Table 1, entries 12–18). 3a was obtained in 72% yield by GC, when the reaction was carried out for 12 h. (Table 1, entry 19). The yield of 3a was increased by decreasing the reaction temperature to 50 oC (Table 1, entry 20). Further examination of the amount of I2, showed that 10 mol % I2 gave 3a in 83% GC yield (Table 1, entry 21). Therefore, optimum reaction conditions was 10 mol % of I2 and 2 equiv. of oxidant TBHP in MTBE at 50 °C for 12 h.

Table 1. Optimization of the reaction conditions a O OH

+

C N

NH2 1a

entry 1 2 3 4 5 6

catalyst (mol%) I2 (20) -Bu4NI (20) NISd (20) Bu4NBr (20) NaI (20)

catalyst oxidant solvent, 110 oC

2a

oxidant (equiv.) TBHPc (2) TBHP (2) TBHP (2) TBHP (2) TBHP (2) TBHP (2)

O O N 3a

N H

solvent 1,4-Dioxane 1,4-Dioxane 1,4-Dioxane 1,4-Dioxane 1,4-Dioxane 1,4-Dioxane

yieldb (%) 53 0 28 32 0 26

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7 I2 (20) -1,4-Dioxane 0 e 8 I2 (20) CHP (2) 1,4-Dioxane 42 f 9 I2 (20) TBPB (2) 1,4-Dioxane 13 10 I2 (20) O2 1,4-Dioxane 0 11 I2 (20) K2S2O8 (2) 1,4-Dioxane 0 12 I2 (20) TBHP (2) THFg 23 13 I2 (20) TBHP (2) MeCN 18 14 I2 (20) TBHP (2) MTBEh 56 i 15 I2 (20) TBHP (2) DCE 46 16 I2 (20) TBHP (2) DMFj 0 17 I2 (20) TBHP (2) Toluene 27 18 I2 (20) TBHP (2) DMEk 29 l 19 I2 (20) TBHP (2) MTBE 72 l,m 20 I2 (20) TBHP (2) MTBE 75 21 l,m I2 (10) TBHP (2) MTBE 83 l,m 22 I2 (5) TBHP (2) MTBE 67 aReaction conditions: 1a (0.5 mmol), 2a (1.2 equiv., 0.6 mmol), oxidant and catalyst in solvent (3mL) at 110 oC for 4 h, under air. bYields were determined by GC analysis using biphenyl as an internal standard. cTBHP(70% in H2O). d NIS = N-iodosuccinimide. eCHP = cumene hydroperoxide. fTBPB = tert-butylperoxybenzoate. gTHF = tetrahydrofuran. hMTBE = methyl tert-butyl ether. iDCE = 1, 2dichloroethane. jDMF = N,N-dimethylformamide. kDME = 1,2-dimethoxyethane. lReaction time 12 h. mThe system was carried out at 50 oC. With this optimized protocol, we tested various substituted anthranilic acids. Results are shown in Table 2. o-Aminobenzoic acid 1a reacted with 2a to give the desired product 3a in 70% yield. Noteworthily, 2-aminobenzoic acids bearing electron-donating groups led to the corresponding products 3b-3g in 27-85% yields. When halogen-substituted 2-aminobenzoic acids 1h-1i were subjected to the reactions, the desired 2-aminobenzoxazinones 3h–3i were observed in good yields (63–70 %). Unfortunately, the reaction of 2-amino-3-nitrobenzoic acid 1j with 2a was messy due to the presence of the NO2 group.


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Table 2 Aerobic oxidative coupling of various 2-aminobenzoic acids with 2aa O OH

R1 1

+

NH2

C N 2a

3 O

O

O

3a, 70%

O N H

N

N H

3c, 53%

O

N H

N

N H

N

O MeO

O

O

O O N H

N 3g, 57%

N H

3f, 27%

O F

O N

3e, 85%

3d, 45%

N H

N

3b, 81%

O

N H

N

O

N

O

R1

MTBE (3 mL) 50 oC, 12h

O

MeO

O

I2 (10 mol%) TBHP (2 equiv)

O Cl

O N

N H

3h, 63%

O N

N H

3i, 70%

O O N NO2

N H

3j, messy aReaction

conditions: compound 1 (0.5 mmol), 2a (1.2 equiv, 0.6 mmol), I2 (10 mol %), TBHP (70% in H2O) (2 equiv) in MTBE (3 mL) at 50 oC for 12 h. Isolated yields. Next, the scope of isocyanides was investigated (Table 3). Tertiary aliphatic isocyanides (2b and 2c) and secondary aliphatic isocyanides (2d and 2e) gave the desired products 3k-3n in moderate yields (41-58%). Unfortunately, primary aliphatic isocyanide 2f didn’t give the desired product 3o. It is worth noting that aromatic isocyanides 3,5–dimethylphenylisocyanide 2g and 2,6–dimethylphenylisocyanide ACS Paragon Plus Environment

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2h could afford 3p and 3q in 60% and 45% yields, respectively, while Orru’s method could not reach the same level for these isocyanides.9

Table 3 Aerobic oxidative coupling of 2-aminobenzoic acid with diverse isocyanidesa O

O OH

R1

+

C N R

NH2 1

2

O

2

I2 (10 mol%) TBHP (2 equiv) MTBE (3 mL) 50 oC,12 h

O O

NH R2

N 3 O

O N H

N

3k, 41% O

O N H

N

3l, 58% O

N H

3n, 48%

N

N H

N

3m, 55% O

O

O N

O

R1

O N H

3o, trace

N

N H

3p, 60%

O O N

N H

3q, 45%

aReaction

conditions: compound 1 (0.5 mmol), 2 (1.2 equiv, 0.6 mmol), I2 (10 mol %), TBHP (70% in H2O) (2 equiv) in MTBE (3mL) at 50 oC for 12 h. Isolated yields. Illustrating the importance of our procedure, we applied it to the late-stage modification of the bioactive compound (Table 4). When we performed the reaction of galactose derivative 2h with 1b under optimzed conditions, the desired product 3r was obtained in 68% isolated yield, providing a novel synthesis protocol for the construction of potential pharmaceutically and biologically active compounds.


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Table 4 Late-stage functionalization of biologically active molecule.a O OH

I2 (10 mol%) TBHP (2 equiv)

CN +

O

NH2

MTBE (3 mL) 50 oC,12 h

R 1b

2h

O

O O

N

R N H

3r, 68% O O

R=

O

O O

O

D-alpha-Galactose derivative

aReaction

condition: compound 1b (0.21 mmol), 2 (1.2 equiv, 0.25 mmol), I2 (10 mol %), TBHP (70% in H2O) (2 equiv) in MTBE (3mL) at 50 oC for 12 h. Isolated yields. Additionally, under the optimal conditions, we investigated other amine-based bisnucleophiles, such as (2-aminophenyl)methanol 1k and 2-(aminomethyl)aniline 1l. Results are listed in Table 5. Reaction of (2-aminophenyl)methanol 1k with tert-butyl isocyanide 2a furnished the desired product 4 in 54% yield. When 2-(aminomethyl)aniline 1l was treated with various isocyanides under analogous reaction conditions, diverse substituted 2-aminoquinozolines 5a-f were obtained in up to 83% yields (Table 5). Unfortunately, primary aliphatic isocyanide ethyl 2-isocyanoacetate 2i could not afford the desired product 5d. It is evident that the products have undergone an additional oxidation to aromatize.


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Table 5 Aerobic oxidative coupling of other bisnucleophiles with isocyanidesa

OH

(1)

+

I2 (10 mol %) TBHP (2 equiv)

C N

MTBE (3 mL) 50 oC,12 h

NH2 1k

O

2a

N H

N 4, 54%

I2 (10 mol %) NH2

(2)

NH2

+

TBHP (2 equiv)

C N R2

1,4-dioxane (3 mL)

N

50 oC, 4 h

2

1l

N N H 5a, 83%

N H 5b, 70%

N H

N

O

N

N H 5c, 68%

Cl

N

N H 5e, 40%

O

5d, 0%

R2

N

N

N

N H

5

N

N

N

N

N N

N H

5f, 40%

aReaction

conditions: (1) compound 1k (0.5 mmol), 2a (1.2 equiv, 0.6 mmol), I2 (10 mol %), TBHP (70% in H2O) (2 equiv) in MTBE (3mL) at 50 oC for 12 h; (2) compound 1l (0.5 mmol), 2 (1.2 equiv, 0.6 mmol), I2 (10 mol %), TBHP (70% in H2O) (2 equiv) in 1,4-dioxane (3mL) at 50 oC for 4 h. Isolated yields. Based on the results above, a plausible mechanismfor this reaction is depicted in scheme 2. The 1,1addition of iodine to isocyanide 2 gives intermediate I.12,13 Then, Intermediate I reacts with 2aminobenzoic acid 1, resulting in intermediate II through dehydrohalogenation. HI is oxidized by TBHP giving iodine and then complete the cycle. Subsequently, second dehydrohalogenation of II occus, leading to the formation of carbodiimide III (path a) or IV (path b). And then isomerization of IV or intramolecular cyclization of III frunishes 3. ACS Paragon Plus Environment

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H 2O OH

I2 C N R2

O

2

OH

TBHP

TBHP I N

HI I

R2

I

HI

path b

O

R1

O

O

O

N H IV

N

R

2

OH

R1

b R2 N

NH a

OH

R1

NH2 1

I II path a

O O

O

R1 N 3

N H

R2

OH

R1 N III

C

N R2

Scheme 2. Proposed mechanism CONCLUSION In conclusion, a new and practical I2-TBHP-catalysed oxidative coupling reaction of isocyanides with active N-H, O-H bonds has been developed. This protocol provides a novel, general, reliable, straightforward and atom efficient approach leading to 2-aminobenzoxazinones 3, 2-aminobenzoxazines 4 and 2-aminoquinozolines 5 under metal-free conditions. Furthermore, the utility of this approach can be applied to late-stage modification of pharmaceutically and biologically active molecules. EXPERIMENTAL SECTION General Experimental Information. All the solvents for routine isolation of products and chromatography were reagent grade. Flash chromatography was performed using silica gel (200-300 mesh) with the indicated solvents. Melting points were recorded on an electrothermal digital melting point apparatus and were uncorrected. IR spectra were recorded on a spectrophotometer using KBr optics. 1H NMR and 13C NMR spectra were recorded on a 400 MHz (1H NMR) and 100 MHz (13C NMR) spectrometer using CDCl or DMSO-d6 3 as solvent and TMS as internal standard. The 1H NMR data are reported as the chemical shift in parts per million, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant in hertz, and number of protons. High resolution mass spectra were obtained using a high resolution ESI-TOF mass spectrometer.


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General Procedure for the construction of 3 To a mixture of 2-aminobenzoic acids, (2-aminophenyl)methanol or 2-(aminomethyl)aniline (0.5 mmol), I2 (0.05 mmol), tert-Butyl hydroperoxide (TBHP, 70% in H2O) (1 mmol) and isocyanide (0.6 mmol) were added in 3 mL MTBE or 1,4-dioxane to test tube. The test tube was closed. The reaction mixture was stirred at 50 oC. When the reactions were completed(checked by TLC), they were cooled to room temperature, washed with 10 % Na2S2O3 Solution(3*15 mL) and extracted with Ethyl acetate(3*15 mL). The combined organic layers were dried over Na2SO4. Removal of solvent followed by flash column chromatographic purification afforded products using petroleum and Ethyl acetate. 2-(tert-butylamino)-4H-benzo[d][1,3]oxazin-4-one 3a. Light pink solid, m. p.: 132-133 oC. IR (neat, ν cm-1) 3298, 2972, 1739. 1H NMR (400 MHz, Chloroform-d) : δ 8.01 (d, J = 7.3 Hz, 1H), 7.67 – 7.52 (m, 1H), 7.26 (d, J = 8.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.97 (s, 1H), 1.49 (s, 9H) ppm. 13C NMR (100 MHz, Chloroform-d): δ 160.4, 152.2, 150.5, 136.6, 128.6, 124.6, 123.5, 113.4, 52.0, 28.9 ppm. HRMS (ESI) m/z: calcd for C12H15N2O2+ (M+H+): 219.1134, found: 219.1129. 2-(tert-butylamino)-8-methyl-4H-benzo[d][1,3]oxazin-4-one 3b. White solid, m. p.: 154-155 oC. IR (neat, ν cm-1): 3278, 2963, 1731. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.96 (s, 1H), 2.43 (s, 3H), 1.51 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 160.9, 151.01, 149.0, 136.9, 133.0, 126.1, 122.9, 113.1, 51.9, 28.6, 17.4 ppm. HRMS (ESI) m/z: calcd for C13H17N2O2+: (M+H) +: 233.1290, found: 233.1297. 2-(tert-butylamino)-6-methyl-4H-benzo[d][1,3]oxazin-4-one 3c. Light yellow solid, m.p.:166-166 oC. IR (neat, ν cm-1): 3296, 2978, 1736. 1H NMR (400 MHz, Chloroform-d) δ 7.81 (s, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.81 (s, 1H), 2.37 (s, 3H), 1.48 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 160.5, 151.8, 148.3, 138.0, 133.4, 128.1, 124.5, 113.1, 52.0, 29.0, 20.9 ppm. HRMS (ESI) m/z: calcd for C13H17N2O2+: (M+H) +: 233.1290, found: 233.1300. 2-(tert-butylamino)-5-methyl-4H-benzo[d][1,3]oxazin-4-one 3d. Light red solid, m.p.: 132-133 oC. IR (neat, ν cm-1): 3294, 2972,1732. 1H NMR (400 MHz, Chloroform-d) δ 7.44 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 4.87 (s, 1H), 2.70 (s, 3H), 1.47 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 159.6, 152.2, 152.0, 142.8, 135.6, 126.1, 122.7, 112.2, 51.9, 29.0, 22.8 ppm. HRMS (ESI) m/z: calcd for C13H17N2O2+: (M+H) +: 233.1290, found: 233.1290. 2-(tert-butylamino)-6,8-dimethyl-4H-benzo[d][1,3]oxazin-4-one 3e. Pale yellow solid, m. p.: 168-170 oC. IR (neat, ν cm-1): 3293, 2969, 1730. 1H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 4.80 (s, 1H), 2.39 (s, 3H), 2.32 (s, 3H), 1.49 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 161.0, 150.7, 146.8, 138.5, 132.8, 132.6, 125.5, 112.9, 51.8, 28.6, 20.9, 17.3 ppm. HRMS (ESI) m/z: calcd for C14H19N2O2+: (M+H) +: 247.1447, found: 247.1443. 2-(tert-butylamino)-6-methoxy-4H-benzo[d][1,3]oxazin-4-one 3f. Light yellow solid, m. p.: 128-130 oC. IR (neat, ν cm-1): 3296, 2977, 1736. 1H NMR (400 MHz, Chloroform-d) δ 7.41 (d, J = 2.7 Hz, 1H), 7.26 – 7.19 (m, 2H), 4.77 (s, 1H), 3.84 (s, 3H), 1.47 (s, 9H) ppm. 13C NMR (100 MHz, Chloroform-d) δ 160.5, 155.9, 151.2, 144.9, 126.6, 126.1, 113.5, 108.4, 55.9, 51.9, 29.0 ppm. HRMS (ESI) m/z: calcd for C13H17N2O3+(M+H+): 249.1239, found: 249.1238. 2-(tert-butylamino)-7-methoxy-4H-benzo[d][1,3]oxazin-4-one 3g. Pale yellow solid, m. p.: 168-170 oC. IR (neat, ν cm-1): 3287, 2958, 1714. 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 8.7 Hz, 1H), 6.84 – 6.48 (m, 2H), 4.98 (s, 1H), 3.88 (s, 3H), 1.48 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 166.6, 159.9, 153.0, 152.9, 130.3, 113.2, 106.4, 106.0, 55.7, 52.0, 28.9 ppm. HRMS (ESI) m/z: calcd for C13H17N2O3+ (M+H+): 249.1239, found: 249.1243. 2-(tert-butylamino)-6-fluoro-4H-benzo[d][1,3]oxazin-4-one 3h. Light orange solid, m.p.: 124-125 oC. IR (neat, ν cm-1): 3296, 1736. 1H NMR (400 MHz, Chloroform-d) δ 7.66 (dd, J = 8.0, 2.9 Hz, 1H), 7.34 (td, J = 8.5, 3.0 Hz, 1H), 7.25 (dd, J = 8.7, 4.4 Hz, 1H), 4.89 (s, 1H), 1.48 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 159.6(JC-F, 3.4 Hz), 158.5(JC-F, 242 Hz) 151.7, 147.1(JC-F, 1.3 Hz), 126.6(JC-F, 7.4 Hz), 124.9(JC-F, 23.6 Hz), 114.0(JC-F, 8.6 Hz), 113.4(JC-F, 23.6 Hz), 52.1, 28.9 ppm. HRMS (ESI): m/z: calcd for C12H14N2O2F+: (M+H)+: 237.1039, found: 237.1042. 2-(tert-butylamino)-6-chloro-4H-benzo[d][1,3]oxazin-4-one 3i. Light purple solid, m.p.: 154-155 oC. IR (neat, ν cm-1): 3290, 1748. 1H NMR (400 MHz, Chloroform-d) δ 7.96 (d, J = 2.5 Hz, 1H), 7.53 (dt, J = 9.0, 2.4 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 4.99 (s, 1H), 1.48 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 159.3, 149.1, 136.8, 128.6, 127.7, 126.3, 114.4, 52.3, 28.9 ppm. HRMS (ESI) m/z: calcd for C12H14N2O2Cl+: (M+H)+: 253.0714, found: 253.0744. 2-(tert-pentylamino)-4H-benzo[d][1,3]oxazin-4-one 3k. Light orange solid, m. p.: 68-69 oC. IR (neat, ν cm-1): 3305, 1739. 1H NMR (400 MHz, Chloroform-d) δ 8.01 (dd, J = 7.9, 1.6 Hz, 1H), 7.60 (ddt, J = 8.5, 7.0, 1.4 Hz, 1H), 7.31 – 7.22 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.85 (s, 1H), 1.85 (q, J = 7.5 Hz, 2H), 1.43 (s, 4H), 0.91 (t, J = 7.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 160.3, 152.2, 150.5, 136.6, 128.7, 124.6, 123.5, 113.4, 54.8, 33.0, 26.5, 8.4 ppm. HRMS (ESI) m/z: calcd for C13H17N2O2+(M+H+): 233.1290, found: 233.1293. 2-(((3s,5s,7s)-adamantan-1-yl)amino)-4H-benzo[d][1,3]oxazin-4-one 3l. Light pink solid, m. p.: 242-242oC. IR (neat, ν cm-1): 3275, 1736. 1H NMR (400 MHz, Chloroform-d) δ 8.01 (dd, J = 7.9, 1.5 Hz, 1H), 7.73 – 7.49 (m, 1H), 7.36 – 7.19 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.74 (s, 1H), 2.34 – 2.04 (m, 9H), 1.72 (d, J = 3.0 Hz, 7H). 13C NMR (100 MHz, CDCl3) δ 160.3, 150.6, 136.6, 128.7, 124.6, 123.5, 113.5, 52.6, 41.7, 36.4, 29.61 ppm. HRMS (ESI) m/z: calcd for C18H21N2O2+(M+H+): 297.1603, found: 297.1608.


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2-(isopropylamino)-4H-benzo[d][1,3]oxazin-4-one 3m. Yellow solid, m. p.: 195-196 oC. IR (neat, ν cm-1): 3298, 1737. 1H NMR (400 MHz, Chloroform-d) δ 8.02 (dd, J = 7.9, 1.6 Hz, 1H), 7.67 – 7.35 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.95 (s, 1H), 4.14 (q, J = 6.6 Hz, 1H), 1.29 (d, J = 6.5 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 160.2, 153.2, 150.7, 136.8, 128.8, 124.3, 123.6, 113.3, 43.8, 22.8 ppm. HRMS (ESI) m/z: calcd for C11H13N2O2+ (M+H+): 205.0977, found: 205.0974. 2-(cyclohexylamino)-4H-benzo[d][1,3]oxazin-4-one 3n. Pale yellow solid, m. p.: 186-188 oC. IR (neat, ν cm-1): 3290, 1737. 1H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.37 – 6.94 (m, 2H), 4.85 (s, 1H), 3.82 (d, J = 10.0 Hz, 1H), 2.07 (dd, J = 12.0, 4.6 Hz, 2H), 1.70 (ddt, J = 43.3, 13.4, 4.4 Hz, 3H), 1.44 (q, J = 12.0 Hz, 2H), 1.34 – 1.14 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 160.2, 153.2, 150.8, 136.8, 128.9, 124.3, 123.6, 113.3, 50.3, 33.1, 25.6, 24.8 ppm. HRMS (ESI) m/z: calcd for C14H17N2O2+ (M+H+): 245.1290, found: 245.1291. 2-((3,5-dimethylphenyl)amino)-4H-benzo[d][1,3]oxazin-4-one 3p. White solid, m. p.: 195-196 oC. IR (neat, ν cm-1): 3289, 1731. 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.96 (d, J = 6.9 Hz, 1H), 7.82 – 7.70 (m, 1H), 7.48 – 7.32 (m, 3H), 7.28 (t, J = 7.5 Hz, 1H), 6.72 (s, 1H), 2.28 (s, 6H). 13C NMR (100 MHz, DMSO)δ 159.2, 150.6, 149.5, 137.9, 137.7, 136.8, 128.1, 124.7, 124.6, 124.2, 117.3, 113.8, 21.2 ppm. HRMS (ESI) m/z: calcd for C16H15N2O2+ (M+H+): 267.1134, found: 267.1138. 2-((2,6-dimethylphenyl)amino)-8-methyl-4H-benzo[d][1,3]oxazin-4-one 3q. White solid, m.p.: 153-154 oC. IR (neat, ν cm-1): 3258, 1735. 1H NMR (400 MHz, Chloroform-d) δ 7.90 (dd, J = 8.0, 1.5 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.21 – 7.01 (m, 4H), 6.44 (s, 1H), 2.32 (s, 6H), 2.25 (s, 3H).13C NMR (100 MHz, CDCl3) δ 160.6, 151.2, 148.8, 137.3, 135.9, 133.4, 133.2, 128.4, 127.6, 126.4, 123.6, 113.3, 18.7, 17.1 ppm. HRMS (ESI) m/z: calcd for C17H17N2O2+ (M+H+): 281.1290, found: 281.1298. ((3aR,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methyl 4-((8-methyl-4-oxo-4Hbenzo[d][1,3]oxazin-2-yl)aminobenzoate 3r. White solid, m. p.: 119-121 oC. IR (neat, ν cm-1): 3282, 2987, 1738, 1649. 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.97 (d, J = 1.5 Hz, 4H), 7.84 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 – 7.63 (m, 1H), 7.24 (t, J = 7.6 Hz, 1H), 5.49 (d, J = 4.9 Hz, 1H), 4.66 (dd, J = 7.9, 2.4 Hz, 1H), 4.49 – 4.31 (m, 3H), 4.27 (dd, J = 11.3, 7.6 Hz, 1H), 4.11 (ddd, J = 7.0, 4.7, 1.8 Hz, 1H), 2.62 – 2.41 (m, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 1.30 (d, J = 11.0 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 166.0, 160.3, 148.4, 147.5, 141.8, 137.6, 133.8, 131.0, 126.3, 124.7, 118.2, 113.9, 109.7, 108.8, 96.4, 71.2, 70.7, 70.5, 66.2, 63.8, 26.1, 26.0, 25.0, 24.5, 17.5. HRMS (ESI) m/z: calcd for C28H31N2O9+ (M+H+): 539.2030, found: 539.2026. N-(tert-butyl)-4H-benzo[d][1,3]oxazin-2-amine 4. Brown solid, m. p.: 71 -73 oC. IR (neat, ν cm-1): 3263, 2924. 1H NMR (400 MHz, DMSO-d6) δ 7.18 – 7.08 (m, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.90 – 6.76 (m, 2H), 6.57 (s, 1H), 5.03 (s, 2H), 1.35 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 154.8, 143.0, 129.0, 123.6, 122.1, 121.5, 121.2, 67.2, 51.2, 29.6 ppm. HRMS (ESI) m/z: calcd for C12H17N2O+(M+H+): 205.1341, found: 205.1349. N-(tert-butyl)quinazolin-2-amine 5a. Yellow solid, m. p.: 82-83 oC. IR (neat, ν cm-1):3302, 2961, 1620, 1594, 753. 1H NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 7.83 – 7.46 (m, 3H), 7.23 – 7.08 (m, 1H), 5.32 (s, 1H), 1.53 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 161.5, 159.2, 152.1, 133.9, 127.5, 126.0, 122.4, 119.9, 51.2, 29.0 ppm. HRMS (ESI) m/z: calcd for C12H16N3+ (M+H+): 202.1344, found: 202.1350. N-((3s,5s,7s)-adamantan-1-yl)quinazolin-2-amine 5b. Pale yellow solid, m. p.: 108-109 oC. IR (neat, ν cm-1): 3291, 2905, 1622, 1593, 755. 1H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1H, -CH=N), 7.67 – 7.57 (m, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.17 (ddd, J = 9.2, 5.5, 2.0 Hz, 1H), 2.21 (d, J = 2.5 Hz, 6H), 2.13 (s, 3H), 1.84 – 1.65 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 161.4, 159.2, 152.1, 133.9, 127.5, 125.9, 122.3, 120.0, 51.7, 41.8, 36.7, 29.8 ppm. HRMS (ESI) m/z: calcd for C18H22N3+ (M+H+): 280.1814, found: 280.1817. N-cyclohexylquinazolin-2-amine 5c. White solid, m. p.: 108-109 oC. IR (neat, ν cm-1): 3270, 2926, 1619, 1591, 752. 1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 8.06 – 7.42 (m, 3H), 7.38 – 6.94 (m, 1H), 5.31 (s, 1H), 4.01 (dtd, J = 10.2, 6.6, 4.1 Hz, 1H), 2.14 – 2.08 (m, 2H), 1.76 (dt, J = 13.2, 4.0 Hz, 2H), 1.66 (dt, J = 13.2, 4.0 Hz, 1H), 1.46 (td, J = 14.5, 13.5, 7.6 Hz, 2H), 1.27 (q, J = 11.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.1, 159.2, 152.4, 134.2, 127.6, 125.6, 122.4, 120.2, 49.7, 33.4, 25.9, 25.0 ppm. HRMS (ESI) m/z: calcd for C14H18N3+ (M+H+): 228.1501, found: 228.1510. N-(4-chlorophenyl)quinazolin-2-amine 5e. Brown solid, m. p.: 152-153 oC. IR (neat, ν cm-1): 3256, 2993, 1620, 1600, 1589, 762. 1H NMR (400 MHz, Chloroform-d) δ 9.09 (s, 1H), 7.88 – 7.68 (m, 5H), 7.47 (s, 1H), 7.39 – 7.29 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 162.0, 156.7, 151.5, 138.4, 134.7, 129.0, 127.6, 127.4, 126.5, 124.2, 121.1, 120.3 ppm. HRMS (ESI) m/z: calcd for C14H11ClN3+ (M+H+): 256.0642, found: 256.0642. N-(2,6-dimethylphenyl)quinazolin-2-amine 5f. Brown solid, m. p.: 170-170 oC. IR (neat, ν cm-1): 3234, 1618, 1601, 1589, 762. 1H NMR (400 MHz, Chloroform-d) δ 9.03 (s, 1H), 7.77 – 7.63 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.30 – 7.23 (m, 1H), 7.16 (s, 3H), 6.87 (s, 1H), 2.28 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 162.6, 152.3, 136.5, 135.8, 134.4, 128.4, 127.6, 127.0, 125.9, 123.2, 122.3, 120.6, 18.9 ppm. HRMS (ESI) m/z: calcd for C16H16N3+ (M+H+): 250.1344, found: 250.1351.

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Supporting Information Available. The copies of 1H and 13C NMR spectra of the products. This material is available free of charge via the Internet at http://pubs.acs.org. ACKNOWLEDGMENT We gratefully acknowledge the National Natural Science Foundation of China (21772137, 21672157), the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 16KJA150002), the Ph.D. Programs Foundation of PAPD, the project of scientific and technologic infrastructure of Suzhou (SZS201708), and Soochow University for financial support.

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The Journal of Organic Chemistry (7) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagné, M. R.; Lloyd-Jones, G. C.; BookerMilburn, K. I. Room-Temperature Palladium-Catalyzed C-H Activation: ortho-Carbonylation of Aniline Derivatives. Angew. Chem. Int. Ed. 2009, 48, 1830. (8) Wu, X.-F.; Sharif, M.; Shoaib, K.; Neumann, H.; Pews-Davtyan, A.; Langer, P.; Beller, M. A Convenient PalladiumCatalyzed Carbonylative Synthesis of 2-Aminbenzoxazinones from 2-Bromoanilines and Isocyanates. Chem. A Eur. J. 2013, 19, 6230. (9) Vlaar, T.; Orru, R. V. A.; Maes, B. U. W.; Ruijter, E. Palladium-Catalyzed Synthesis of 2-Aminobenzoxazinones by Aerobic Oxidative Coupling of Anthranilic Acids and Isocyanides. J. Org. Chem. 2013, 78, 10469. (10) Qiu, G.; Ding, Q.; Wu, J. Recent advances in isocyanide insertion chemistry. Chem. Soc. Rev. 2013, 42, 5257. (11) (a) Yusubov, M. S.; Zhdankin, V. V. Iodine catalysis: A green alternative to transition metals in organic chemistry and technology. Resource-Efficient Tech. 2015, 1, 49; (b) Liu, D.; Lei, A. Iodine-Catalyzed Oxidative Coupling Reactions Utilizing C-H and X-H as Nucleophiles. Chem. Asian J. 2015, 10, 806; (c) Iaroshenko, V. O.; Dudkin, S.; Sosnovskikh, V. Y.; Villinger, A.; Langer, P. Recyclization in the Series of Spiro[indole-3,5 ′ -pyrimido[4,5b]quinoline]-2,2′,4′-triones Prepared by a Three-Component Reaction of Isatins with (Thio)barbituric Acids and Electron-Rich Anilines. Synthesis. 2013, 7, 971; (d) Zhu, Y.-P.; Jia, F.-C.; Liu, M.-C.; Wu, L.-M.; Cai, Q.; Gao, Y.; Wu, A.-X. I2–CF3SO3H Synergistic Promoted sp3 C–H Bond Diarylation of Aromatic Ketones. Org. Lett. 2012, 14, 5378; (e) Cai, Z.-J.; Wang, S.-Y.; Ji, S.-J. I2/TBHP-Catalyzed Chemoselective Amination of Indoles. Org. Lett. 2013, 15, 5226; (f) Zhang, X.; Wang, M.; Li, P.; Wang, L. n-Bu4NI/TBHP-catalyzed direct amination of allylic and benzylic C(sp3)–H with anilines under metal-free conditions. Chem. Commun. 2014, 50, 8006; (g) Zhang, J.; Zhu, D.; Yu, C.; Wan, C.; Wang, Z. A Simple and Efficient Approach to the Synthesis of 2-Phenylquinazolines via sp3 C−H Functionalization. Org. Lett. 2010, 12, 2841. (12) Zhu, T.-H.; Wang, S.-Y.; Tao, Y.-Q.; Ji, S.-J. Synthesis of Carbodiimides by I2/CHP-Mediated Cross-Coupling Reaction of Isocyanides with Amines under Metal-Free Conditions. Org. Lett. 2015, 17, 1974. (13) (a) Jung, F.; Delvare, C.; Boucherot, D.; Hamon, A. Cephalosporins with C-7-isocyanide dihalides : useful synthons for the introduction of amino heterocycles at C-7-new routes to the synthesis of amino imidazoles. Tetrahedron Letters. 1989, 30, 2375; (b) Mirza, B. An efficient metal-free synthesis of 2-amino-substituted-4(3H)-quinazolinones. Tetrahedron Letters. 2016, 57, 146; (c) Kaim, El. L.; Grimaud, L.; Patil, P. Three-Component Strategy toward 5-


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TBHP-Mediated Oxidative Coupling of Amino-Based

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