Photoredox-Cocatalyzed Tandem Oxidative Cyclization of α

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CO2/Photoredox Cocatalyzed Tandem Oxidative Cyclization of #Bromo Ketones and Amines to Construct Substituted Oxazoles Xiaowei Zhang, Yonghui He, Jing Li, Rui Wang, Lijun Gu, and Ganpeng Li J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 22 May 2019 Downloaded from http://pubs.acs.org on May 22, 2019

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The Journal of Organic Chemistry

CO2/Photoredox Cocatalyzed Tandem Oxidative Cyclization of α-Bromo Ketones and Amines to Construct Substituted Oxazoles Xiaowei Zhang, ‡a Yonghui He, ‡b Jing Li, b Rui Wang, a Lijun Gu, *b,c and Ganpeng Li *b School of Chemistry and Environment, Yunnan Minzu University Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, Yunnan, 650500, China; c Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, China a

b

Supporting Information Placeholder O Ar

O Br

+

R

NH2

Ar

R DBN

N

CO2 as a mediator eosin Y catalyzed photoredox reactions 19 examples ABSTRACT: CO2/photoredox cocatalyzed tandem oxidative cyclization of α-bromo ketones and amines for the preparation of substituted oxazoles has been achieved. The avoidance of using both transition-metal catalysts and peroxides make this method more sustainable and renewable.

Substituted oxazoles are widely found in various molecules with biological activities. They are of significance to the community of pharmaceutical discovery.1 Of biologically active natural products that contain oxazole moieties, the diazonamide and phorboxazole families in particular, display remarkable antineoplastic properties.2 Moreover, substituted oxazoles have found industrial application as scintillator and laser dyes.3 Subsequently, many new methods have been applied to prepare oxazoles.4,5 Although a variety of highly efficient methods have been reported to synthesize the substituted oxazoles, the exploration for more methods is in continuous demand. In particular, the development of new synthetic methods toward substituted oxazoles, aiming at affording greater levels of molecular complexity and improved functional group compatibility in a convergent and atomeconomical fashion from cheap starting chemicals under mild conditions is a primary research endeavors which is sought by many in modern chemical science. Metal-free-catalyzed reactions, which are often used to satisfy the above criteria, are among the most magnetic synthetic methods. A good number of interests in synthetic community is focusing on the visible light photoredox catalysis recently, largely because of the readiness of reactions conditions, sustainability, environmental friendliness, etc..4,6 Compare to thermal reactions,

photoredox reactions are effected under mild conditions without radical initiators or stoichiometric reagents. Moreover, some organic dyes, such as eosin Y, have recently emerged as superior alternatives to the transition metal photoredox catalysts, which have much lower costs7. Driven by visible light, some novel discoveries have been reported effected in the presence of the eosin Y.4a On the basis of our previous experience with eosin Y catalyzed photoredox reactions,8 we rationalized that eosin Y can act as a promoter for the synthesis of oxazole derivatives irradiated by visible light in the presence of CO2. Herein, we would like to report our efforts on the transformations promoted by visible light of α-bromo ketones and amines towards the synthesis of substituted oxazoles induced by eosin Y under a CO2 atmosphere.9 Mechanistically,10 we envisaged eosin Y would undergo a single-electron transfer (SET) with α-amino carbonyl compound A to furnish the amine radical cation and [eosin Y]• ━ (Scheme 1). After deprotonation, radical cation [A]•+ will form radical B. At the same time, the catalyst radical anion [eosin Y]•━ will reduce intermediate II, to give the corresponding radical III and [eosin Y]. With the aid of DMSO and intermediate III, the radical B will generate an alkyl carbonate C. Decomposition of the alkyl carbonate C would produce an imine intermediate D.

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Intermediate E would be obtained via the enolization of D.5a Then F would be obtained via the intramolecular nucleophilic addition of E. As a result, G would collapse into the product 3aa via an oxidative dehydrogenation reaction. To assess the reaction platform, we started our studies by examining the CO2/photoredox co-catalyzed tandem oxidative cyclization of α-bromo ketones and benzylamines to prepare substituted oxazoles. We were pleased to find that, under optimized conditions, 2,5-diphenyloxazole 3aa was afforded in 76% yield (Table 1, The reactions in control clearly indicated that CO2 and light are all needed for reactivity (entry 2-4). Decreasing the amount of 1,5-diazabicyclo [4.3.0]non-5-ene (DBN) from 2.5 to 1.8 equiv reduced the yield to 64% (entry 5). It turned out that eosin Y was much better than other photoredox catalysts (See entries 6-8). Subsequently, an examination of the reaction solvent revealed that dimethyl sulfoxide (DMSO) was the optimal reaction medium for this transformation (entries 9-11), presumably with DMSO acting as an oxidant. Other bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2,6-lutidine and Et3N were less efficient than DBN (entries 12-14). We found that the presence of H2O had a negative influence on the reaction (entry 15). It was presumed that the presence of water disfavored the generation of intermediate II. That the by-product of the reaction is H2O is another plausible reason. Using (benzylamino)1-phenylethanone (A) as the starting material, the desired target 3aa was afforded in 86% yield under standard reaction conditions (entry 16). Unfortunately, no product 3aa was obtained in Ar atmosphere (entry 17). The scalability of the reaction could be showcased by the facile preparation of 0.73 g of product 3aa (entry 18).

Scheme 1. Proposed Mechanism for CO2/photoredox Catalyzed Tandem Oxidative Cyclization of α-bromo Ketones and Amines. N

+

N

N

CO2

O Br

+ Ph

O

NH2

SET

N

N

A

MeSMe + DBN Ph GC-MS analysis

O III OH

O

O

A

Ph

O

+

[A]

-H+

NH

-H

Ph N D

Ph NH B

Ph

Ph

C

O

Ph

SET

dehydrogenation cycle

Ph NH

H2O + CO2

DMSO

[eosin Y] *

G

O

OH

[eosin Y]

HO+

1a

Br

Entry

Ph

2a

DMSO (2 mL), DBN (2.5 equv) CO2, 20 h, r.t.

Variation from the “ standard reaction conditions”

Ph O N Ph

3aa

Yiel d (%)b

1

none

76

2

without DBN

0

3

in Ar atmosphere

0

4

in the darkness

5

DBN (1.8 equiv)

6

fac-Ir(ppy)3 as catalyst

trace

7

Ru(bpy)3(PF6)2 as catalyst

trace

8

Rose Bengal as catalyst

8

9

MeCN as solvent for 30 h

0

10

DMF as solvent for 30 h

0

11

THF as solvent for 30 h

0

12

DBU as the base

19

13

2,6-lutidine as the base

23

14

Et3N

14

15

0.1 mL H2O was added

7

trace 64

16c

(benzylamino)-1-phenylethanone (0.3 mmol) as the starting material

86

17d

(benzylamino)-1-phenylethanone (0.3 mmol) as the starting material

0

18e

Ph

[eosin Y]

Ph

OH

NH

Ph

HBr

2a

1a

+

O

"standard reaction conditions" NH2 eosin Y (3 mol%), 20W blue LED

large-scale reaction

55

II

I

Ph

O

N

N

Ph

O

O

N

II

H+

O

Page 2 of 7

H+

Ph

NH

Ph

HO N

Ph

F

E

photoredox cycle

3aa

Table 1. Optimization of the Reaction Conditions a

a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), eosin Y (3 mol%), DMSO (2.0 mL), DBN (2.5 equiv), room temperature, 20 W blue LED light (λmax = 450 nm) in CO2 atmosphere for 20 h. b Isolated yield. c Reaction conditions: standard reaction conditions. d Reaction conditions: standard reaction conditions, without CO2, in Ar atmosphere. e Reaction conditions: 1a (1.19 g, 6.0 mmol), 2a (0.64 g, 6.0 mmol), eosin Y (0.117 g, 0.18 mmol), DMSO (8.0 mL), DBN (1.86 g, 15 mmol), room temperature, 20 W blue LED light (λmax = 450 nm) in CO2 atmosphere for 22 h. With the conditions optimized, we next explored the reaction scope. A series of ketones 1 were investigated as shown in Table 2. The data indicate that reactions of 2-bromoketones 1 with electron-abundant groups (methyl, methoxy) and electrondeficient groups (halogen, cyano) on the benzene ring proceeded well with yields from moderate to good (See Table 2, entries 1-5). In addition, the substitution patterns of the arene ring (para, and ortho position) did not influence the efficiency obviously (See Table 2, entries 3 and 4). Interestingly, the polysubstituted substrate 1g gave the desired target 3ag with a good yield. We also performed the transformation of 2a with 1h bearing a heterocycle moiety and obtained the substituted oxazole 3ah in 64% yield (See Table 2, entry 7). Furthermore, unsaturated αbromoketones also gave the corresponding products in 51% yield (See Table 2, entry 8). Unfortunately, aliphatic 1-bromopropan-2-

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The Journal of Organic Chemistry

one did not work under these reaction conditions (See Table 2, entry 9). Interestingly, reaction of 2-bromo-1-phenylpropan-1-one 1k with benzylamine 2a could give the desired product 4-methyl2,5-diphenyloxazole 3ak in 75% yield (See Table 2, entry 10).

Table 2. Scope of Substrate 1a

Br + Ph

R

NH2

Entry

DMSO (2 mL), DBN CO2, 20 h, r.t.

2a

1

Substrates 1

R

O

Ph

N 3

Products 3

Yield (%)b

O Br

1

Ph

O

77

N

1b

3ab OMe

O Br

2

Ph

MeO Br

O

71

N

1c

3ac

O

Br Br

3

Ph

1d

O N

70 3ad

O

F Br

4

F

Ph

1e

O N

53 3ae

CN

O Br

5

Ph

NC

O N

1f

66 3af

OMe

O MeO

6

Br Ph

MeO

O N

1g

OMe

Br Br

S

S Ph

1h

Br

Br

Ph

Ph

64

O N

O

8

69

3ag

O

7

3ah

Ph

O N

3ai

51

1i

O Br

9 1j

Ph

10

O

Br

Ph

Ph N

Ph 3ak

75

1k a

20W blue LED eosin Y (3 mol%)

O

O

O N

3aj

0

Reaction conditions: 1 (0.3 mmol), 2a (0.3 mmol), eosin Y (3 mol%), DMSO (2.0 mL), DBN (2.5 equiv), room temperature, 20 W blue LED light (λmax = 450 nm) in CO2 atmosphere for 20 h. b Isolated yield. Next, we investigated the general applicability of this visiblelight promoted tandem oxidative cyclization reaction with respect to an array of amines 2. The substituents at the phenyl ring of benzylamines had no obvious influence on the efficiency of this reaction, and the expected oxazole products were produced in yields from moderate to good. It was discovered that the halosubstituted benzylamine gave good yield for these transformations (Table 3, entries 2, 3 and 5). The heteroaryl amine was subsequently used in this reaction, affording the desired product in good yield (Table 3, entry 4). It is noteworthy that alkyl-, alkenyl-, alkynyl-substituted amines were also tolerated in this reaction (Table 3, entries 6-8). For example, prop-2-yn-1-amine furnished the products in moderate yield (Table 3, entry 8). Some control experiments were performed to explore the mechanistic details of this reaction. It has been reported that 2bromo-1-phenylethanones can be oxidized to 2-oxo-2phenylacetaldehydes, which might react with benzylamines to synthetize benzoxazoles. To explore this possibility, we checked the possibilities of the aldehyde formations by the reactions in Tables 1-3. No aldehydes were found, which suggested that the transformation does not proceed via a aldehyde intermediate. When the transformation of 1a with 2a was conducted in the presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl, a radical-capturing agent), the reaction was then totally quenched. These results implied that a radical pathway may have been presented in this transformation. The reaction failed to show any activity in the absence of CO2 which clearly suggested the unique role of CO2 in this reaction. Moreover, the yield of desired product dropped significantly without photocatalyst in the reaction and/or under dark conditions. It was noteworthy that there were no reduced products from CO2 such as CO HCO2H, or HCO2− were found either by gas-phase GC analysis (Confer the Supporting Information). To find the oxidant in facto and to determine the reduced product in this reaction, dibutyl sulfoxide was selected as solvent in place of DMSO. The corresponding product 3aa was thus obtained in 61% yield. The GC-MS analysis of the reaction mixture clearly revealed the evidence of the solvent being the oxidant in facto and generating the expected dibutyl sulfide. To explore the detailed mechanistic information of the catalyst with substrates, a series of experiments were performed (seen in the Supporting Information). Our first attempt at assessing the oxidative quenching ability of the DBN-CO2 adduct to [eosin Y] catalyst showed no quenching effect. In contrast, the addition of 2-(benzylamino)-1-phenylethanone to the excited [eosin Y] catalyst resulted in a strongly enhanced quenching effect. These results implied that a reductive quenching of [eosin Y]* by 2(benzylamino)-1-phenylethanone was involved in the mechanism.

Table 3. Scope of Substrates 2a

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O Br +

Ph

NH2

R

1a

Entry

Substrates 2

MeO

3

associated with deprotonation of radical cation [A]•+ forming radical H demands a much higher energy barrier of 5.4 kcal/mol (Scheme 2). On the basis of these observations, a proposed mechanistic pathway has been obtained (Scheme 1).

Yield (%)b

Scheme 2. Alternative Reaction Pathway

R

O

Ph

N

DMSO (2 mL), DBN CO2, 20 h, r.t.

2

Products 3 NH2

1

20W blue LED eosin Y (3 mol%)

Page 4 of 7

O

Ph

O

O

MeO N

2b

79

[A]

-H+

Ph

3ba

O

NH2

2

Cl

Cl 3ca

NH2

3

F

70

N

2d

3da

S

Ph

O

NH2

4

Ph

O F

S

2e

73

N

5

Cl

NH2

O F

F

N

2f

Ph

60

3fa

NH2

O

2g

6

Ph

49

N 3ga

NH2

7

2h

O

Ph

44

N 3ha

8

NH2 2i

O N

Ph

III

Ph NH I O

O OH

N

In summary, we have afforded a novel CO2/photoredox cocatalyzed tandem oxidative cyclization of α-bromo ketones and amines for the synthesis of substituted oxazoles. Notably, this methodology has been achieved without using metal salts and tolerated various functional groups such as halide, ether, alkenyl, nitrile, alkynyl, and so on. This method is characterization of the mild reaction conditions and operational simplicity.

EXPERIMENTAL SECTION

3ea Cl

NH H

DMSO Ph

J

68

N

2c

Ph

Ph

O

Ph

Ph

56

3ia a Reaction conditions: 1a (0.3 mmol), 2 (0.3 mmol), eosin Y (3 mol%), DMSO (2.0 mL), DBN (2.5 equiv), room temperature, 20 W blue LED light (λmax = 450 nm) in CO2 atmosphere for 20 h. b Isolated yield. To understand CO2/eosin Y cocatalyzed tandem oxidative cyclization of α-bromo ketones and amines, we carried out a DFT study using the package Gaussian 16 with the theory level of M06-2X / 6-31G(d) // M06-2X / 6-311++G(d, p) / SMD11. Unsurprisingly, a amine radical cation [A]•+ is formed by a SET from α-amino carbonyl compound A to the excited state [Eosin Y*], which is an energetically downhill process. The amine radical cation [A]•+ readily undergoes almost barrierless basemediated deprotonation to afford the radical B at -19 kcal/mol. With the aid of DMSO and intermediate III, the radical B would yield an alkyl carbonate C in a highly exothermic reaction (ΔG = -61.9 kcal/mol). Then imine D would be formed by the decompose of C at -82.9 kcal/mol. Thus the energy demand of the formation of [A]•+ is easily compensated from the radical B to the dehydrogenation product D. The alternative reaction pathway

Material and Methods. Reagents and solvents were purchased and used without further treatments. IR spectra were recorded on an EQUINOX-55 spectrometer with a KBr matrix. 1H NMR and 13C NMR spectra were recorded on an Bruker-400 spectrometer with TMS as an internal standard. Chemical shift values (δ) are given in ppm. Coupling constants (J) were measured in Hz. High resolution mass spectrometer (HRMS) spectra were obtained from a Bruker micrOTOF-Q II analyzer. 200-300 mesh silica gel was used for column chromatography. Photocatalytic reactor (HY-CL016) was obtained from Shenzhen Hongye Photoelectric Technology, Co. Ltd (China). Typical experimental procedure for the synthesis of compounds 3. To a Schlenk tube were added 2-bromoketones 1 (0.3 mmol), amines 2 (0.3 mmol), DBN (0.75 mmol), eosin Y (3 mol%), DMSO (2.0 mL). Then the tube was filled with CO2, and stirred at room temperature with the irradiation of a 20 W blue LED at ir = 450nm ± 10 nm (at a distance of approximately 10 cm so that the reaction mixture did not heat up during the course of the reaction) for about 16 h-20 h. Upon the completion of the reaction, the mixture was diluted in 50 mL ethyl acetate, washed with a saturated solution of brine (2 × 10 mL), 1 M HCl (1 × 8 mL), a saturated solution of brine (10 mL), dried (Na2SO4) and concentrated in vacuum, and the resulting residue was purified with silica gel column chromatography (eluent: hexane/ethyl acetate) to furnish the products 3. Experimental procedure for large-scale reaction for the synthesis of compounds 3aa. To a Schlenk tube were added 2bromoketones 1a (1.19 g, 6.0 mmol), amines 2a (0.64 g, 6.0 mmol), eosin Y (0.117 g, 0.18 mmol), DMSO (8.0 mL), DBN (1.86 g, 15 mmol). Then the tube was filled with CO2, and stirred at room temperature with the irradiation of a 20 W blue LED at ir = 450nm ± 10 nm (at a distance of approximately 10 cm so that the reaction mixture did not heat up during the course of the reaction) for 22 h. Upon the completion of the reaction, the mixture was diluted in 150 mL ethyl acetate, washed with a saturated solution of brine (2 × 30 mL), 1 M HCl (2 × 20 mL), a saturated solution of brine (20 mL), dried (Na2SO4) and concentrated in vacuum, and the resulting residue was purified with silica gel column chromatography (eluent: hexane/ethyl acetate = 50:1) to furnish the products 3aa (0.73g, 55% yield).

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The Journal of Organic Chemistry

Characterization Data for the Products. 2,5-Diphenyloxazole (3aa): Purified by column chromatography (petroleum ether/ethyl acetate = 50:1), 50 mg, 76% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.13 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.2 Hz, 2H), 7.49-7.42 (m, 6H), 7.36 (t, J = 7.6 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 161.0, 151.1, 130.2, 128.8, 128.7, 128.3, 127.9, 127.3, 126.1, 124.1, 123.3; IR (neat cm-1) 3063, 1602, 1566, 1485, 1129, 947; LRMS (EI 70 ev) m/z: 221 (M+); HRMS m/z (ESI) calcd for C15H12NO (M+H)+ 222.0913, found 222.0921. 2-Phenyl-5-(p-tolyl)oxazole (3ab): Purified by column chromatography (petroleum ether/ethyl acetate = 50:1), 54 mg, 77% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.00 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.39-7.34 (m, 3H), 7.29 (s, 1H), 7.15 (d, J = 9.2 Hz, 2H), 2.28 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ: 160.7, 151.4, 138.4, 130.1, 129.5, 129.1, 128.7, 126.1, 125.2, 124.0, 122.7, 21.3; IR (neat cm-1) 3403, 2927, 1611, 1543, 1445, 1304, 953, 726; LRMS (EI 70 ev) m/z: 235 (M+); HRMS m/z (ESI) calcd for C16H14NO (M+H)+ 236.1070, found 236.1072. 5-(4-Methoxyphenyl)-2-phenyloxazole (3ac): Purified by column chromatography (petroleum ether/ethyl acetate = 30:1), 53 mg, 71% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.00 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.39-7.33 (m, 3H), 7.21 (s, 1H), 6.86 (d, J = 8.8 Hz, 2H), 3.72 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ: 160.4, 159.6, 151.1, 130.0, 128.6, 127.4, 126.0, 125.6, 121.8, 120.7, 114.2, 55.2; IR (neat cm-1) 3387, 2912, 1567, 1421, 1238, 823; LRMS (EI 70 ev) m/z: 251 (M+); HRMS m/z (ESI) calcd for C16H14NO2 (M+H)+ 252.1019, found 252.1027. 5-(2-Bromophenyl)-2-phenyloxazole (3ad): Purified by column chromatography (petroleum ether/ethyl acetate = 40:1), 63 mg, 70% yield, known compound,[4e] pale yellow solid; 1H NMR (400 MHz, CDCl3) δ: 8.017.99 (m, 2H), 7.84 (s, 1H), 7.72 (dd, J = 2.0 Hz, J = 1.6 Hz, 1H), 7.57 (dd, J = 0.8 Hz, J = 1.2 Hz, 1H), 7.37-7.34 (m, 3H), 7.30-7.26 (m, 1H), 7.07-7.03 (ddd, J = 2.0 Hz, J = 1.2 Hz, J = 1.6 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 160.9, 148.6, 134.0, 130.4, 129.1, 128.7, 128.6, 128.3, 128.0, 127.4, 127.0, 126.3, 119.7; LRMS (EI 70 ev) m/z: 299 (M+); HRMS m/z (ESI) calcd for C15H11BrNO (M+H)+ 300.0019, found 300.0034. 5-(4-Fluorophenyl)-2-phenyloxazole (3ae): Purified by column chromatography (petroleum ether/ethyl acetate = 40:1), 38 mg, 53% yield, [4e] 1 known compound, white solid; H NMR (400 MHz, CDCl3) δ: 7.98 (dd, 1J = 2.4 Hz, 2J = 1.6 Hz, 2H), 7.58 (dd, 1J = 5.2 Hz, 2J = 5.2 Hz, 2H), 7.37-7.33 (m, 3H), 7.26 (s, 1H), 7.03 (t, J = 8.8 Hz, 2H); 13C{H} NMR (100 MHz, CDCl3) δ: 163.8 (d, J = 225.1 Hz), 161.0, 150.3, 130.3, 128.7, 127.2, 126.1 (d, J = 15.3 Hz), 124.3, 124.2, 123.0 (d, J = 1.2 Hz), 116.1 (d, J = 22.0 Hz); IR (neat cm-1) 3433, 1619, 1449, 1127, 813; LRMS (EI 70 ev) m/z: 239 (M+); HRMS m/z (ESI) calcd for C15H11FNO (M+H)+ 240.0819, found 240.0829. 4-(2-Phenyloxazol-5-yl)benzonitrile (3af): Purified by column chromatography (petroleum ether/ethyl acetate = 30:1), 49 mg, 66% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.12 (dd, J = 3.6 Hz, J = 2.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.58 (s, 1H), 7.49 (t, J = 3.6 Hz, 3H); 13C{H} NMR (100 MHz, CDCl3) δ: 162.3, 149.2, 132.7, 131.8, 130.9, 128.8, 126.7, 126.4, 126.2, 124.2, 118.5, 111.4; IR (neat cm-1) 3380, 2221, 1601, 1414, 910; LRMS (EI 70 ev) m/z: 246 (M+); HRMS m/z (ESI) calcd for C16H11N2O (M+H)+ 247.0866, found 247.0877. 5-(3,4-Dimethoxyphenyl)-2-phenyloxazole (3ag): Purified by column chromatography (petroleum ether/ethyl acetate = 20:1), 58 mg, 69% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.0 Hz, 2H), 7.50-7.44 (m, 3H), 7.33-7.19 (m, 2H), 7.18 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ: 160.5, 151.2, 149.3, 149.2, 130.1, 128.7, 127.4, 126.0, 122.1, 120.9, 117.1, 111.3, 107.2, 55.95, 55.91; IR (neat cm-1) 3423, 2931, 1606, 1448, 1119, 937, 705; LRMS (EI 70 ev) m/z: 281 (M+); HRMS m/z (ESI) calcd for C17H16NO3 (M+H)+ 282.1125, found 282.1117. 5-(5-Bromothiophen-2-yl)-2-phenyloxazole (3ah): Purified by column chromatography (petroleum ether/ethyl acetate = 50:1), 58 mg, 64% yield, new compound, yellow solid; 1H NMR (400 MHz, CDCl3) δ: 7.98 (dd, J = 4.4 Hz, J = 2.4 Hz, 2H), 7.39 (dd, J = 1.2 Hz, J = 2.0 Hz, 3H), 7.17 (s, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 159.7, 144.5, 129.6, 129.5, 127.8, 126.8, 125.8, 125.2, 123.2, 122.3, 111.7; IR (neat cm-1) 3369, 1620, 1469, 1340, 729; LRMS (EI 70 ev) m/z: 306 (M+); HRMS m/z (ESI) calcd for C13H9BrNOS (M+H)+ 305.9583, found 305.9594. (E)-2-Phenyl-5-styryloxazole (3ai): Purified by column chromatography (petroleum ether/ethyl acetate = 50:1), 38 mg, 51% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.12 (d, J = 8.0 Hz, 2H), 7.52-7.46 (m, 5H), 7.40 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 6.8 Hz, 2H), 6.96 (d, J = 16.4 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 161.0, 150.3, 136.3, 130.4, 129.4, 128.7, 128.2, 127.2, 126.5, 126.4, 126.3, 113.0; IR (neat cm-1) 3393, 1603, 1463, 1336, 1139, 710; LRMS (EI 70 ev) m/z: 247 (M+); HRMS m/z (ESI) calcd for C17H14NO (M+H)+ 248.1070, found 248.1074. 4-Methyl-2,5-diphenyloxazole (3ak): Purified by column chromatography (petroleum ether/ethyl acetate = 50:1), 53 mg, 75% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.10 (dd, J = 2.0 Hz, J = 1.6 Hz,

2H), 7.70 (d, J = 7.2 Hz, 2H), 7.47-7.43 (m, 5H), 7.35 (t, J = 7.6 Hz, 1H), 2.51 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ: 159.2, 145.3, 133.3, 130.1, 129.0, 128.7, 128.7, 128.4, 127.5, 127.3, 126.1, 125.2, 13.4; IR (neat cm-1) 3413, 2931, 1604, 1511, 1454, 869; LRMS (EI 70 ev) m/z: 235 (M+); HRMS m/z (ESI) calcd for C16H14NO (M+H)+ 236.1070, found 236.1081. 2-(4-Methoxyphenyl)-5-phenyloxazole (3ba): Purified by column chromatography (petroleum ether/ethyl acetate = 30:1), 59 mg, 79% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.04 (d, J = 9.2 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.44-7.39 (m, 3H), 7.31 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 9.2 Hz, 2H), 3.85 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ: 161.2, 161.1, 150.6, 128.8, 128.1, 128.0, 127.8, 123.9, 123.1, 120.1, 114.1, 55.3; IR (neat cm-1) 3393, 2934, 1607, 1486, 1134, 723; LRMS (EI 70 ev) m/z: 251 (M+); HRMS m/z (ESI) calcd for C16H14NO2 (M+H)+ 252.1019, found 252.1027. 2-(4-Chlorophenyl)-5-phenyloxazole (3ca): Purified by column chromatography (petroleum ether/ethyl acetate = 40:1), 52 mg, 68% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.06 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 7.2 Hz, 2H), 7.48-7.44 (m, 5H), 7.39 (t, J = 7.2 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 160.2, 151.3, 136.4, 129.1, 128.8, 127.8, 127.6, 127.5, 126.9, 124.6, 123.6; IR (neat cm-1) 3429, 1602, 1554, 1433, 1341, 836; LRMS (EI 70 ev) m/z: 255 (M+); HRMS m/z (ESI) calcd for C15H11ClNO (M+H)+ 256.0524, found 256.0532. 2-(4-Fluorophenyl)-5-phenyloxazole (3da): Purified by column chromatography (petroleum ether/ethyl acetate = 40:1), 50 mg, 70% yield, known compound,[4e] white solid; 1H NMR (400 MHz, CDCl3) δ: 8.11 (dd, J = 6.8 Hz, J = 5.2 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.49-7.42 (m, 3H), 7.36 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 8.0 Hz, 2H); 13C{H} NMR (100 MHz, CDCl3) δ: 165.2 (d, J = 249.5 Hz), 160.2, 151.2, 129.0, 128.9, 128.4 (d, J = 2.2 Hz), 128.3, 128.2, 127.8, 124.1, 123.7 (d, J = 2.9 Hz), 116.0 (d, J = 22.0 Hz); IR (neat cm-1) 3411, 3033, 1612, 1476, 1273, 903; LRMS (EI 70 ev) m/z: 239 (M+); HRMS m/z (ESI) calcd for C15H11FNO (M+H)+ 240.0819, found 240.0819. 5-Phenyl-2-(thiophen-2-yl)oxazole (3ea): Purified by column chromatography (petroleum ether/ethyl acetate = 50:1), 50 mg, 73% yield, [4e] 1 known compound, light yellow solid; H NMR (400 MHz, CDCl3) δ: 7.74 (d, J = 4.0 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.45-7.43 (m, 3H), 7.39 (s, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 157.3, 150.7, 129.9, 128.8, 128.4, 128.2, 127.9, 127.6, 127.5, 124.0, 123.2; IR (neat cm-1) 3403, 3021, 1601, 1424, 1203, 876; LRMS (EI 70 ev) m/z: 227 (M+); HRMS m/z (ESI) calcd for C13H10NOS (M+H)+ 228.0478, found 228.0483. 5-Phenyl-2-(4-fluoro-3-chlorophenyl)oxazole (3fa): Purified by column chromatography (petroleum ether/ethyl acetate = 30:1), 49 mg, 60% yield, new compound, white solid; 1H NMR (400 MHz, CDCl3) δ: 7.89 (d, J = 8.0 Hz, 1H), 7.90-7.87 (dt, J = 2.4 Hz, J = 1.6 Hz, 1H), 7.62 (d, J = 7.2 Hz, 2H), 7.457.40 (m, 3H), 7.36 (t, J = 7.6 Hz, 1H), 7.16 (td, J = 2.4 Hz, J = 2.4 Hz, J = 2.4 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 164.0, 161.6, 159.83, 159.80, 151.5, 130.48, 130.40, 129.3, 129.2, 128.8, 128.5, 127.6, 124.1, 123.4, 121.88, 121.85, 117.2, 117.0, 113.2, 112.9; IR (neat cm-1) 3411, 1575, 1412, 1128, 916, 709; LRMS (EI 70 ev) m/z: 273 (M+); HRMS m/z (ESI) calcd for C15H10ClFNO (M+H)+ 274.0429, found 274.0439. 5-Phenyl-2-propyloxazole (3ga): Purified by column chromatography (petroleum ether/ethyl acetate = 40:1), 27 mg, 49% yield, known compound,[4e] yellow oil; 1H NMR (500 MHz, CDCl3) δ: 7.65 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 2.84 (t, J = 7.5 Hz, 2H), 1.89 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H); 13C{H} NMR (100 MHz, CDCl3) δ: 164.5, 150.8, 128.8, 128.2, 128.0, 123.9, 121.6, 30.1, 21.5, 13.6; IR (neat cm-1) 3455, 2927, 1559, 1451, 1239, 774; LRMS (EI 70 ev) m/z: 187 (M+); HRMS m/z (ESI) calcd for C12H14NO (M+H)+ 188.1070, found 188.1061. 5-Phenyl-2-vinyloxazole (3ha): Purified by column chromatography (petroleum ether/ethyl acetate = 30:1), 23 mg, 44% yield, known compound,[4e] yellow oil; 1H NMR (500 MHz, CDCl3) δ: 7.67 (d, J = 7.2 Hz, 2H), 7.44-7.40 (m, 2H), 7.36 (s, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.67 (dd, J = 11.2 Hz, J = 11.2 Hz, 1H), 6.27 (dd, J = 1.2 Hz, J = 0.8 Hz, 1H), 5.67 (dd, J = 0.8 Hz, J = 0.8 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 160.4, 150.8, 131.2, 128.8, 128.5, 127.7, 124.1, 123.3, 121.5; IR (neat cm-1) 3093, 1631, 1557, 1443, 992, 761; LRMS (EI 70 ev) m/z: 171 (M+); HRMS m/z (ESI) calcd for C11H10NO (M+H)+ 172.0757, found 172.0747. 2-Ethynyl-5-phenyloxazole (3ia): Purified by column chromatography (petroleum ether/ethyl acetate = 30:1), 28 mg, 56% yield, new compound, yellow solid; 1H NMR (400 MHz, CDCl3) δ: 7.58 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.29-7.25 (m, 1H), 7.17 (s, 1H), 3.24 (s, 1H); 13C{H} NMR (100 MHz, CDCl3) δ: 156.9, 152.3, 129.1, 128.9, 128.4, 125.3, 122.8, 80.4, 71.5; IR (neat cm-1) 3312, 2209, 1571, 1422, 1129, 720; LRMS (EI 70 ev) m/z: 169 (M+); HRMS m/z (ESI) calcd for C11H8NO (M+H)+ 170.0600, found 170.0593.

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Emission quenching and gas chromatography analysis experimental; Density functional calculation procedures; 1H and 13C NMR spectra of all the products (PDF)

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected];. * E-mail: [email protected].

Author Contributions ‡These authors contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We are grateful for the financial support from the National Natural Science Foundation of China (21662045) and the Applied Basic Research Project of Yunnan (2016FB019, 2016FB149); the Opening Foundation of the Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University (2018GDGP0103); Scientific Research Fund Project of Education Department of Hunan Province (17C1385).

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