Acylation Reactions

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Cite This: J. Org. Chem. 2018, 83, 3354−3360

Palladium-Catalyzed Sequential Heteroarylation/Acylation Reactions of Iodobenzenes: Synthesis of Functionalized Benzo[d]oxazoles Pingshun Zhang,† Shanfei Pan,† Wanzhi Chen,*,† Miaochang Liu,‡ and Huayue Wu*,‡ †

Department of Chemistry, Zhejiang University, Yuquan Campus, Hangzhou 310027, China College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, China

‡

S Supporting Information *

ABSTRACT: We report an efficient palladium-catalyzed approach to the synthesis of benzoxazole derivatives via sequential heteroarylation/acylation reaction of iodobenzenes. Three readily available starting materials, iodobenzenes, anhydrides, and benzoxazoles, were smoothly coupled to form new C−C bonds at the ortho and ipso positions of the iodobenzenes to afford 2-heteroaryl-3-acylbenzene derivatives in good yields.

B

generate 2-arylated benzoxazoles in good yields by using an appropriate palladium catalyst. These approaches are quite practical but limited to readily available electrophiles. The palladium-catalyzed Catellani reaction allows dual functionalization of aryl halides at both the ortho and ipso sites in one pot.12 Through this protocol, ortho C−H arylation, alkylation, acylation, and amination and ipso C−I alkenylation, alkynylation, cyanation, borylation have been realized in recent years.12,13 The reaction proceeds via a Pd-catalyzed norbornene-mediated activation of the ortho C−H position and subsequent cross-coupling at the ipso position.12,14 Direct C−H activation and functionalization of benzoxazoles have been recently reported.15 Palladium-catalyzed tandem ortho alkylation/C−H functionalization reactions between aryl iodides and N-bromoalkylindoles,16 3-(bromoalkyl)thiophenes, or furans17 have also been reported to give polycyclic heterocycles. We envisioned that this strategy could be applied to the 2-arylation of benzoxazoles in which benzoxazoles act as the nucleophilic partner, and an additional functional group could be simultaneously introduced at the ipso site. Herein, we report palladium-catalyzed three-component reactions of iodoarenes, aromatic anhydrides, and benzoxazoles. A number of 2-arylated benzoxazoles were obtained in good yields. Initially, we chose 2-iodotoluene (1a), benzoic anhydride (2a), and benzoxazole (3a) as the starting materials and used the typical conditions previously reported for acylation/ cyanation of iodobenzene.14,18 The results are summarized in Table 1. Reaction did not occur in the presence of palladium chloride (10 mol %), TFP (20 mol %), norbornene (NBE, 2 equiv), and Cs2CO3 (3 equiv) at 100 °C in 1,4-dioxane (Table

enzoxazole derivatives are an important class of heterocyclic compounds found in many natural and functional products such as UK-1, MUK-1, DMUK-1, AJI9561,1 estrogen receptor ligand,2 A33853, and Tetraacetyl A33853,3 which show antimicrobial, antibacterial, and antitumor activities (Figure 1). 2-Arylbenzoxazoles are important structural units

Figure 1. Important molecules featuring benzoxazole core structure.

for the construction of functional materials, agrochemicals, and pharmaceutically active compounds.4 Benzoxazoles are typically prepared from the condensation of 2-aminophenols and carboxylates.5 Recently, the C−H arylation of benzoxazoles with aryl electrophiles has been reported, and the reaction offers an efficient protocol for the derivatization of readily available benzoxazoles. In the presence of oxidants, compounds such as aryl halides,6 acyl chlorides,7 and aryltrimethylammonium triflates8 or arylboronates,9 arylsilanes,10 and polyfluorinated arenes11 were able to couple with benzoxazoles to © 2018 American Chemical Society

Received: December 4, 2017 Published: February 20, 2018 3354

DOI: 10.1021/acs.joc.7b03055 J. Org. Chem. 2018, 83, 3354−3360

Note

The Journal of Organic Chemistry Table 2. Scope of Acid Anhydridesa

Table 1. Optimization of the Catalysts and the Reaction Conditionsa

entry

[Pd]

ligand

base

solvent

1

PdCl2

TFPb

Cs2CO3

2

PdCl2

TFP

Cs2CO3

3

PdCl2

TFP

K2CO3

4

PdCl2

TFP

Na2CO3

5 6 7 8 9

PdCl2 PdCl2 PdCl2

TFP TFP TFP TFP TFP

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

1,4dioxane 1,4dioxane 1,4dioxane 1,4dioxane toluene DME CH3CN CH3CN CH3CN

TFP TFP

K2CO3 K2CO3

CH3CN CH3CN

10 11

Pd2(dba)3· CHCl3 Pd(OAc)2 [Pd(C3H5) Cl]2

additive

yield (%) 0

CuBr

58

CuBr

83

CuBr

trace

CuBr CuBr CuBr CuBr CuBr

53 35 93 0 trace

CuBr CuBr

trace trace

a

Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), 3a (0.6 mmol), catalyst (0.03 mmol), TFP (0.06 mmol), NBE (0.6 mmol), base (0.9 mmol), CuBr (0.3 mmol), solvent (3.0 mL), 100 °C, 16 h in a sealed tube under N2. bTFP is tri(2-furyl)phosphine.

1, entry 1). To our delight, the same reaction did proceed smoothly when 1 equiv of CuBr was added, and target product 4a was isolated in 58% yield (entry 2). When Cs2CO3 was replaced by K2CO3, the yield of 4a sharply increased to 83% (entry 3). Other bases such as Na2CO3 did not work well, and only a trace amount of 4a was obtained (entry 4). After further screening of several common solvents, we identified CH3CN as the most effective solvent, and the yield could be further increased to 93% (entries 5−7). The reaction resulted in a lower yield when other solvents such as toluene and DME were chosen. Further experiments showed that without PdCl2 the reaction did not proceed, and other palladium catalysts such as Pd2(dba)3·CHCl3, Pd(OAc)2, and [Pd(C3H5)Cl]2 were not effective for this three-component reaction (entries 8−11). Under the optimized reaction conditions described above, we next examined the scope of the acid anhydride substrates. Various acid anhydrides bearing either electron-withdrawing or electron-donating functional groups such as methyl, methoxyl, and fluoride reacted smoothly with iodobenzene and benzoxazoles and afforded the corresponding products 4a−m in good yields (Table 2). Generally, electron-rich aromatic acid anhydrides were good reaction partners, and target products 4a and 4d could be obtained in greater than 90% yields. The reactions of acid anhydrides containing strong electronwithdrawing groups gave somewhat lower yields. When 2naphthoic anhydride was used, 4g was obtained in 58% yield, illustrating that steric hindrance has little influence on the reaction. Unfortunately, we found that aliphatic acid anhydrides were not active in the three-component reaction. The substrate scope of the reaction was further extended to a range of iodobenzenes and heterocyclic compounds, and the results are shown in Tables 3 and 4, respectively. In general, all of the reactions occurred smoothly and gave the desired

a

Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), 3a (0.6 mmol), PdCl2 (0.03 mmol), TFP (0.06 mmol), NBE (0.6 mmol), K2CO3 (0.9 mmol), CuBr (0.3 mmol), acetonitrile (3.0 mL), 100 °C, 16 h in a sealed tube under N2.

products in moderate yields. The reactions of iodobenzenes bearing alkyl and alkoxyl groups afforded the corresponding products in good yields. However, iodobenzenes bearing fluoro and chloro substituents were much less active. When 1iodonaphthalene was used, 5a was obtained in 85% yield. These results illustrated that strong electron-donating groups have a significant influence on the reaction. 2,4-Difluoroiodobenzene was also tolerated and afforded corresponding product 5e in moderate yield. To examine the compatibility of benzo[d]oxazoles, a few substituted benzo[d]oxazoles were subjected to the optimized reaction conditions. The results are given in Table 3. Benzo[d]oxazoles with electron-donating and electron-withdrawing groups were all compatible with the reaction conditions. The desired products were obtained in moderate yields. Under the same conditions, thiazoles could also participate in the reaction and gave 2-arylated thiazole derivatives. When benzo[d]thiazole and 4-methylthiazole were used, 6h and 6i were obtained in 58% and 24% yields, respectively. However, when 5-tert-butylbenzo[d]oxazole was used, 6g was only obtained in 45% yield, illustrating that steric 3355


Note

The Journal of Organic Chemistry Table 3. Scope of Iodobenzenes and Heterocyclesa

Table 4. Reactions of 6-Nitrobenzo[d]oxazolea

a

Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), 3a (0.6 mmol), PdCl2 (0.03 mmol), TFP (0.06 mmol), NBE (0.6 mmol), K2CO3 (0.9 mmol), CuBr (0.3 mmol), acetonitrile (3.0 mL), 100 °C, 16 h in sealed tube under N2.

compound 7c′ were grown by slow diffusion of its hexane solution, and its structure was determined by X-ray diffraction analysis and is shown in the Supporting Information. However, when 4-nitrobenzoic anhydride and 2-iodophenol were used, the normal three-component coupling product was not obtained, but 7g and 7f were obtained in 46% and 65% yields, respectively. Acylation at the ortho position did not occur. Obviously, anhydrides with strong electron-withdrawing groups disfavored the acylation process. A plausible mechanism of the three-component reaction was proposed on the basis of the literature reports and is depicted in Figure 2.12−14 The first step involves oxidative addition of the iodobenzene on to Pd(0) to produce intermediate I. Insertion of a molecule of norbornene into the C−Pd bond of I would form intermediate II. Subsequent C−H activation and elimination of HI leads to palladacycle III. Further oxidative addition of acid anhydride to III was proposed to form Pd(IV) species IV. Reductive elimination of intermediate IV leads to ortho-acylated intermediate V. Decarbopalladation with expulsion of norbornene would give intermediate VI. Reductive elimination would release the final product. Because nitrocontaining benzoxazole is more acidic, the oxidative addition of the C−H bond would form Pd(IV) species IV′. In this case, products 7′ were obtained.

a

Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), 3a (0.6 mmol), PdCl2 (0.03 mmol), TFP (0.06 mmol), NBE (0.6 mmol), K2CO3 (0.9 mmol), CuBr (0.3 mmol), acetonitrile (3.0 mL), 100 °C, 16 h in a sealed tube under N2.

hindrance has a significant influence on the reaction. Other heterocyclic compounds such as benzofuran, benzothiophene, and benzoimidazole were also tested. Unfortunately, no desired coupling products were obtained. In the case of 6-nitrobenzo[d]oxazole, the reaction with 2iodotoluene and benzoic anhydride under the standard conditions afforded two products, 7a and 7a′, in 45% and 30% yields, respectively (Table 4). 1H NMR and mass spectral analyses showed that 7a is the normal three-component coupling product, and 7a′ contains a bicyclo[2.2.1]heptane moiety. Similarly, the reactions of 2,4-dimethyliodobenzene, 2,4-fluoroiodobenzene, 2-isopropyliodobenzene, and 1-iodonaphthalene with 6-nitrobenzo[d]oxazole under the optimized reaction conditions also gave mixtures of two products. It seemed that in the case of electron-deficient benzoxazoles the elimination of norbornene is more difficult. The ratios of the two products depend on the reactants. Single crystals of

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CONCLUSION In summary, we have described a palladium-catalyzed sequential ortho acylation/ipso heteroarylation of iodobenzenes 3356


Note

The Journal of Organic Chemistry

CDCl3): δ 7.60−7.66 (m, 1H), 7.50−7.54 (m, 3H), 7.43−7.49 (m, 2H), 7.36−7.41 (m, 1H), 7.22−7.28 (m, 2H), 7.10−7.17 (m, 2H), 2.58 (s, 3H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.2, 161.3, 150.4, 141.4, 141.2, 139.3, 137.9, 137.1, 133.4, 133.1, 130.1, 129.9, 127.9, 127.1, 126.9, 126.7, 125.1, 124.3, 120.1, 110.5, 21.2, 20.6. HRMS (EI-TOF): m/z calcd for C22H17NO2 327.1259, found 327.1258. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(3,5-dimethylphenyl)methanone (4d). Light yellow oil. Yield: 96.2 mg, 94%. 1H NMR (400 MHz, CDCl3): δ 7.60−7.66 (m, 1H), 7.49−7.53 (m, 2H), 7.45− 7.48 (m, 1H), 7.36−7.41 (m, 1H), 7.29 (s, 2H), 7.22−7.27 (m, 2H), 6.97 (s, 1H), 2.56 (s, 3H), 2.21 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 197.3, 161.4, 150.4, 141.5, 141.3, 139.3, 137.7, 137.1, 134.3, 133.0, 130.0, 127.4, 127.1, 126.8, 125.0, 124.2, 120.1, 110.5, 21.1, 20.6. HRMS (EI-TOF): m/z calcd for C23H19NO2 341.1416, found 341.1417. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(p-tolyl)methanone (4e). Light yellow solid. Mp: 83−85 °C. Yield: 78.5 mg, 80%. 1H NMR (400 MHz, CDCl3): δ 7.58−7.66 (m, 3H), 7.48−7.51 (m, 2H), 7.42− 7.46 (m, 1H), 7.35−7.41 (m, 1H), 7.21−7.27 (m, 2H), 7.07 (d, J = 8.0 Hz, 2H), 2.58 (s, 3H), 2.26 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.6, 161.4, 150.4, 143.6, 139.4, 134.5, 132.9, 130.1, 129.7, 128.8, 127.6, 126.9, 126.5, 125.8, 125.1, 124.3, 121.5, 120.2, 111.5, 110.5, 21.6, 20.7. HRMS (EI-TOF): m/z calcd for C22H17NO 2 327.1259, found 327.1257. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(mesityl)methanone (4f). White solid. Mp: 189−191 °C. Yield: 67.1 mg, 63%. 1H NMR (400 MHz, CDCl3): δ 7.71−7.76 (m, 1H), 7.49−7.54 (m, 2H), 7.44− 7.48 (m, 2H), 7.29−7.34 (m, 2H), 6.70 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H), 2.13 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 199.8, 162.0, 150.8, 141.6, 140.0, 139.1, 136.1, 135.3, 134.4, 130.5, 128.5, 128.3, 127.6, 124.9, 124.2, 120.1, 110.6, 29.7, 21.1, 20.0, 19.7. HRMS (EITOF): m/z calcd for C24H21NO2 355.1572, found 355.1574. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(naphthalen-2-yl)methanone (4g). Light yellow oil. Yield: 63.2 mg, 58%. 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.89 (dd, J = 1.6, 8.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.42−7.58 (m, 6H), 7.28−7.34 (m, 1H), 7.14−7.19 (m, 2H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.9, 161.4, 150.4, 141.4, 141.3, 139.6, 135.3, 134.5, 133.2, 132.1, 131.9, 130.1, 129.5, 128.4, 128.2, 127.7, 127.0, 126.8, 126.6, 125.1, 124.8, 124.3, 120.1, 110.5, 20.8. HRMS (EI-TOF): m/z calcd for C25H17NO2 363.1259, found 363.1263. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(2-methoxyphenyl)methanone (4h). Light yellow solid. Mp: 110−111 °C. Yield: 57.6 mg, 56%. 1H NMR (400 MHz, CDCl3): δ 7.52−7.58 (m, 1H), 7.39− 7.48 (m, 3H), 7.31−7.36 (m, 1H), 7.26 (dd, J = 1.6, 7.6 Hz, 1H), 7.17−7.21 (m, 2H), 7.06−7.13 (m, 1H), 6.65 (dt, J = 0.4, 7.2 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 3.57 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 195.9, 161.6, 158.1, 150.5, 142.3, 141.5, 138.8, 133.1, 132.9, 131.1, 130.1, 127.5, 127.3, 126.6, 124.8, 124.1, 120.0, 119.9, 111.3, 110.6, 55.7, 20.1. HRMS (EI-TOF): m/z calcd for C22H 17NO3 343.1208, found 343.1207. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(3-fluorophenyl)methanone (4i). Light yellow oil. Yield: 51.7 mg, 52%. 1H NMR (400 MHz, CDCl3): δ 7.61−7.65 (m, 1H), 7.53−7.57 (m, 2H), 7.46−7.50 (m, 1H), 7.37−7.44 (m, 3H), 7.25−7.28 (m, 2H), 7.18−7.23 (m, 1H), 7.00−7.06 (m, 1H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 195.6 (d, JC−F = 2.3 Hz), 162.4 (d, JC−F = 246.5 Hz), 161.0, 150.3, 141.3, 140.5, 139.5, 139.2 (d, JC−F = 6.3), 133.5, 130.3, 129.8 (d, JC−F = 7.4 Hz), 127.0, 126.5, 125.3, 125.2 (d, JC−F = 2.8), 124.4, 120.2, 119.6 (d, JC−F = 21.5 Hz), 115.8 (d, JC−F = 22,2 Hz), 110.5, 20.7. HRMS (EITOF): m/z calcd for C21H 14FNO2 331.1009, found 331.1011. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(4-fluorophenyl)methanone (4j). Light yellow oil. Yield: 47.8 mg, 48%. 1H NMR (400 MHz, CDCl3): δ 7.61−7.68 (m, 2H), 7.53−7.59 (m, 1H), 7.47 (d, J = 4.8 Hz, 2H), 7.39 (t, J = 4.4 Hz, 1H), 7.29−7.34 (m, 1H), 7.19−7.24 (m, 2H), 6.86 (t, J = 8.8 Hz, 2H), 2.53 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 195.5, 165.4 (d, JC−F = 253.4 Hz), 161.1, 150.3, 141.1 (d, JC−F = 44.4 Hz), 139.4, 133.5 (d, JC−F = 3.0 Hz), 133.2, 132.0 (d, JC−F = 9.6 Hz), 130.3, 126.8, 126.4, 125.3, 124.5, 120.2, 115.3 (d, JC−F =

Figure 2. Plausible mechanism.

using readily available anhydrides and benzoxazoles as the coupling reagents. The reaction proceeds via a palladiumcatalyzed/norbornene-mediated regioselective ortho C−H activation/acylation and subsequent oxidative coupling at the C−I position. A number of 2-heteroaryl-3-acylbenzene derivatives were obtained in good yields in a one-pot manner.

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EXPERIMENTAL SECTION

All chemicals were of reagent grade quality obtained from commercial sources and used as received. Benzoic anhydrides 219 and benzoxazoles 320 were prepared according to the literature. General Procedure for Synthesis of 4−7. A 15 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar was charged with aryl iodide 1a (65.4 mg, 0.3 mmol, 1.0 equiv), benzoxazole 3a (71.4 mg, 0.6 mmol, 2.0 equiv), anhydride 2a (203.5 mg, 0.9 mmol, 3.0 equiv), PdCl2 (5.4 mg, 0.03 mmol, 10 mol %), TFP (13.9 mg, 0.06 mmol, 20 mol %), K2CO3 (124.4 mg, 0.9 mmol, 3.0 equiv), CuBr (43.0 mg, 0.3 mmol, 1.0 equiv), norbornene (56.5 mg, 0.6 mmol, 2.0 equiv), and acetonitrile (3.0 mL). The resulting suspension was stirred at room temperature for 5 min under N2 and then heated to 100 °C for 16 h. Upon completion of the reaction as monitored by TLC, the reaction was allowed to cool to room temperature, diluted with ethyl acetate (10 mL) and water (15 mL), and extracted with ethyl acetate (15 mL × 3). The organic phase was collected and washed with brine, dried over Na2SO4, and then filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel using petroleum ether/ethyl acetate (10/1) as eluent to give the corresponding products 4−7. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(phenyl)methanone (4a). Light yellow oil. Yield: 87.4 mg, 93%. 1H NMR (400 MHz, CDCl3): δ 7.66−7.70 (m, 2H), 7.59−7.64 (m, 1H), 7.53 (d, J = 4.8 Hz, 2H), 7.46−7.49 (m, 1H), 7.31−7.40 (m, 2H), 7.21−7.28 (m, 4H), 2.59 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.0, 161.2, 150.3, 141.4, 141.1, 139.3, 137.1, 133.2, 132.7, 130.2, 129.4, 128.1, 127.0, 126.5, 125.1, 124.3, 121.5, 120.1, 111.5, 110.5, 20.7. HRMS (EI-TOF): m/z calcd for C21H15NO2 313.1103, found 313.1108. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(o-tolyl)methanone (4b). Light yellow oil. Yield: 82.4 mg, 84%. 1H NMR (400 MHz, CDCl3): δ 7.59−7.64 (m, 1H), 7.49−7.54 (m, 3H), 7.36−7.41 (m, 1H), 7.23−7.29 (m, 2H), 7.19 (dd, J = 1.2, 7.6 Hz, 1H), 7.08 (dt, J = 1.6, 7.6 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 2.49 (s, 3H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 198.6, 161.4, 150.4, 142.1, 141.3, 139.2, 138.5, 137.2, 133.5, 130.9, 130.3, 130.1, 127.7, 127.0, 125.0, 124.9, 124.3, 120.1, 110.5, 20.7, 20.3. HRMS (EI-TOF): m/z calcd for C22H17NO2 327.1259, found 327.1262. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(m-tolyl)methanone (4c). Light yellow oil. Yield: 70.7 mg, 72%. 1H NMR (400 MHz, 3357


Note


11.8, 260 Hz), 156.1, 150.4, 143.9 (dd, JC−F = 1.2, 8 Hz), 141.2, 136.1, 133.5, 129.3, 128.5, 125.6, 124.6, 120.4, 112.7 (dd, JC−F = 3.6, 22.8 Hz), 111.8 (dd, JC−F = 4.1, 13.5 Hz), 110.6, 106.8 (t, JC−F = 25.3 Hz). HRMS (EI-TOF): m/z calcd for C20H 11F2NO2 335.0758, found 335.0757. (2-(Benzo[d]oxazol-2-yl)-3-fluorophenyl)(phenyl)methanone (5f). Light yellow solid. Mp: 90−92 °C. Yield: 50.4 mg, 53%. 1H NMR (400 MHz, CDCl3): δ 7.71−7.76 (m, 2H), 7.60−7.67 (m, 2H), 7.36− 7.49 (m, 4H), 7.28−7.33 (m, 2H), 7.24−7.27 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 195.2 (d, JC−F = 2.5 Hz), 160.7 (d, JC−F = 256.8 Hz), 156.9 (d, JC−F = 3.4 Hz), 150.5, 142.4, 141.3, 136.7, 133.1, 132.5 (d, JC−F = 8.9 Hz), 129.4, 128.4, 125.6, 124.9 (d, JC−F = 3.5 Hz), 124.5, 120.5, 118.6 (d, JC−F = 21.8 Hz), 115.2 (d, JC−F = 13.5 Hz), 110.6. HRMS (EI-TOF): m/z calcd for C20H12FNO2 317.0852, found 317.0851. ( 2- ( 5 - M e t h y lb e n zo [d ] ox a zo l- 2 - y l) - 1 , 3- p h e n yl e n e )b i s (phenylmethanone) (5g). Light brown solid. Mp: 165−167 °C. Yield: 52.6 mg, 42%. 1H NMR (400 MHz, CDCl3): δ 7.71−7.77 (m, 7H), 7.34−7.38 (m, 2H), 7.25−7.28 (m, 4H), 7.17 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.90 (dd, J = 1.2, 8.4 Hz, 1H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.2, 159.1, 148.6, 141.3, 140.8, 136.7, 134.1, 133.1, 130.6, 130.6, 130.2, 129.4, 128.5, 128.3, 126.5, 125.2, 120.1, 109.6, 21.3. HRMS (EI-TOF): m/z calcd for C28H 19NO3 417.1365, found 417.1363. (2-(Benzo[d]oxazol-2-yl)-3-isopropylphenyl)(phenyl)methanone (5h). White solid.Mp: 100−101 °C. Yield: 40.9 mg, 40%. 1H NMR (400 MHz, CDCl3): δ 7.65−7.71 (m, 3H), 7.58−7.64 (m, 2H), 7.48 (dd, J = 1.2, 7.6 Hz, 1H), 7.40−7.44 (m, 1H), 7.34−7.40 (m, 1H), 7.24−7.30 (m, 4H), 3.33 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 197.0, 161.3, 150.5, 150.1, 141.4, 140.8, 137.0, 132.6, 130.4, 129.7, 128.5, 128.0, 127.1, 126.2, 125.8, 125.0, 124.3, 121.5, 120.2, 111.5, 110.6, 30.3, 24.0. HRMS (EI-TOF): m/z calcd for C23H19NO 2 341.1416, found 341.1420. (3-Chloro-2-(5-methylbenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (5i). Light yellow oil. Yield: 36.4 mg, 35%. 1H NMR (400 MHz, CDCl3): δ 7.72−7.74 (m, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.57− 7.59 (m, 2H), 7.37−7.42 (m, 2H), 7.28−7.32 (m, 3H), 7.10 (d, J = 8 Hz, 1H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 195.5, 158.8, 148.8, 142.6, 141.3, 136.4, 135.2, 134.3, 133.1, 132.4, 131.3, 129.6, 128.2, 127.7, 126.9, 126.7, 120.2, 110.0, 21.4. HRMS (EI-TOF): m/z calcd for C21H14ClNO2 347.0713, found 347.0711. (3,4-Dimethyl-2-(5-methylbenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (6a). Light yellow oil. Yield: 74.7 mg, 73%. 1H NMR (400 MHz, CDCl3): δ 7.64−7.67 (m, 3H), 7.39−7.40 (m, 3H), 7.31−7.33 (m, 1H), 7.22−7.27 (m, 3H), 7.05 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.8, 162.0, 148.7, 141.6, 141.0, 138.6, 137.9, 137.3, 134.0, 132.5, 131.3, 129.6, 128.0, 127.6, 127.1, 126.1, 120.0, 109.9, 21.4, 20.8, 16.9. HRMS (EI-TOF): m/z calcd for C23H19NO2 341.1416, found 341.1415. (3,5-Dimethyl-2-(5-methylbenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (6b). Light yellow solid. Mp: 99−101 °C. Yield: 71.6 mg, 70%. 1H NMR (400 MHz, CDCl3): δ 7.65−7.70 (m, 2H), 7.38 (s, 1H), 7.31−7.36 (m, 2H), 7.19−7.28 (m, 4H), 7.03 (dd, J = 1.2, 8.4 Hz, 1H), 2.57 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.3, 161.5, 148.5, 141.6, 141.2, 140.5, 139.1, 137.2, 134.0, 133.8, 132.6, 129.4, 128.0, 127.5, 126.0, 123.7, 119.9, 109.7, 31.0, 21.4, 21.4, 20.7. HRMS (EI-TOF): m/z calcd for C23H 19NO2 341.1416, found 341.1420. (2-(5-Chlorobenzo[d]oxazol-2-yl)-3-methylphenyl)(phenyl)methanone (6c). Light brown oil. Yield: 43.7 mg, 42%. 1H NMR (400 MHz, CDCl3): δ 7.66−7.71 (m, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.51− 7.55 (m, 2H), 7.46−7.50 (m, 1H), 7.36−7.42 (m, 1H), 7.25−7.32 (m, 3H), 7.22 (dd, J = 2, 8.8 Hz, 1H), 2.57 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.8, 162.7, 148.9, 142.5, 141.0, 139.4, 137.0, 133.3, 132.9, 130.4, 129.8, 129.5, 128.2, 127.2, 126.1, 125.4, 120.1, 111.3, 20.7. HRMS (EI-TOF): m/z calcd for C21H 14ClNO2 347.0713, found 347.0712. (3-Methyl-2-(6-methylbenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (6d). Light yellow solid. Mp: 78−79 °C. Yield: 53.0 mg, 54%. 1H NMR (400 MHz, CDCl3): δ 7.67−7.71 (m, 2H), 7.50−7.54

21.8 Hz), 110.5, 29.7, 20.7. HRMS (EI-TOF): m/z calcd for C21H14FNO2 331.1009, found 331.1012. (2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)(2-fluorophenyl)methanone (4k). Light yellow oil. Yield: 44.7 mg, 45%. 1H NMR (400 MHz, CDCl3): δ 7.60−7.66 (m, 1H), 7.51−7.58 (m, 3H), 7.40−7.47 (m, 2H), 7.19−7.29 (m, 3H), 6.95 (td, J = 0.8, 7.6 Hz, 1H), 6.82−6.89 (m, 1H), 2.53 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 193.6, 161.1, 160.6 (d, JC−F = 254.7 Hz), 150.4, 141.6, 141.4, 139.3, 133.8, 133.6 (d, JC−F = 8.9 Hz), 131.0 (d, JC−F = 1.4 Hz), 130.4, 127.0, 126.4, 126.3 (d, JC−F = 11.3 Hz), 125.1, 124.3, 123.7 (d, JC−F = 3.6 Hz), 120.1, 116.1 (d, JC−F = 21.7 Hz), 110.6, 20.3. HRMS (EI-TOF): m/z calcd for C21H 14FNO2: 331.1009, found 331.1010. (3-Methyl-2-(5-methylbenzo[d]oxazol-2-yl)phenyl)(p-tolyl)methanone (4l). Light yellow solid. Mp: 94−95 °C. Yield: 51.2 mg, 50%. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.4 Hz, 2H), 7.46− 7.51 (m, 2H), 7.40−7.44 (m, 2H), 7.23−7.26 (m, 1H), 7.03−7.10 (m, 3H), 2.57 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.6, 161.4, 148.6, 143.6, 141.7, 141.3, 139.3, 134.5, 134.0, 132.9, 130.0, 129.8, 128.9, 126.8, 126.6, 126.2, 120.0, 109.9, 21.6, 21.4, 20.7. HRMS (EI-TOF): m/z calcd for C23H19NO2 341.1416, found 341.1420. 1-(2-(Benzo[d]oxazol-2-yl)-3-methylphenyl)ethan-1-one (4m). Orange yellow solid. Mp: 59−61 °C. Yield: 37.6 mg, 56%. 1H NMR (400 MHz, CDCl3): δ 7.79−7.81 (m, 1H), 7.66 (dd, J = 1.6, 6.8 Hz, 1H), 7.58−7.60 (m, 1H), 7.49−7.55 (m, 2H), 7.38−7.40 (m, 2H), 2.42 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 200.1, 162.2, 150.7, 141.6, 140.4, 140.0, 133.8, 130.5, 126.4, 126.3, 125.2, 124.5, 120.3, 110.8, 28.5, 20.0. HRMS (EI-TOF): m/z calcd for C16H13NO2 251.0946, found 251.0943. (1-(Benzo[d]oxazol-2-yl)naphthalen-2-yl)(phenyl)methanone (5a). Light yellow solid. Mp: 134−136 °C. Yield: 89.0 mg, 85%. 1H NMR (400 MHz, CDCl3): δ 8.46−8.65 (m, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.83−7.89 (m, 1H), 7.48−7.64 (m, 6H), 7.23−7.29 (m, 1H), 7.12−7.20 (m, 3H), 7.05−7.12 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 197.3, 160.5, 150.4, 141.5, 139.3, 137.0, 134.3, 132.7, 131.4, 130.9, 129.3, 128.5, 128.5, 128.1, 127.9, 126.5, 125.4, 125.3, 124.6, 124.3, 121.5, 120.3, 111.5, 110.6. HRMS (EI-TOF): m/z calcd for C24H15NO2 349.1103, found 349.1101. (2-(Benzo[d]oxazol-2-yl)-3,4-dimethylphenyl)(phenyl)methanone (5b). White solid. Mp: 87−89 °C. Yield: 81.4 mg, 83%. 1H NMR (400 MHz, CDCl3): δ 7.61−7.66 (m, 3H), 7.39−7.42 (m, 3H), 7.32−7.34 (m, 1H), 7.22−7.26 (m, 4H), 2.44 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.8, 161.9, 150.4, 141.4, 141.1, 138.6, 137.9, 137.2, 132.4, 131.4, 129.5, 128.0, 127.4, 127.2, 125.0, 124.2, 120.1, 110.6, 20.8, 16.9. HRMS (EI-TOF): m/z calcd for C22H 17NO2 327.1259, found 327.1257. (3-Methoxy-2-(5-methylbenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (5c). Brown oil. Yield: 84.4 mg, 82%. 1H NMR (400 MHz, CDCl3): δ 7.67−7.69 (m, 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.24 (t, J = 8.0 Hz, 5H), 7.04 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.2, 159.2, 158.4, 148.7, 142.2, 141.6, 136.9, 133.9, 132.7, 131.9, 129.4, 128.1, 126.1, 121.4, 120.0, 116.5, 113.7, 109.8, 56.4, 21.4. HRMS (EI-TOF): m/z calcd for C22H17NO 3 343.1208, found 343.1205. (2-(Benzo[d]oxazol-2-yl)-3,5-dimethylphenyl)(phenyl)methanone (5d). Light yellow solid. Mp: 80−82 °C. Yield: 75.6 mg, 77%. 1H NMR (400 MHz, CDCl3): δ 7.65−7.70 (m, 2H), 7.57−7.62 (m, 1H), 7.30−7.36 (m, 3H), 7.29 (s, 1H), 7.25−7.27 (m, 1H), 7.21−7.25 (m, 3H), 2.58 (s, 3H), 2.45 (s, 3H),. 13C NMR (100 MHz, CDCl3): δ 197.3, 161.4, 150.2, 141.4, 141.2, 140.7, 139.1, 137.2, 133.9, 132.5, 129.3, 128.0, 127.6, 124.9, 124.2, 123.6, 120.0, 110.4, 21.4, 20.7. HRMS (EI-TOF): m/z calcd for C22H17NO2 327.1259, found 327.1259. (2-(Benzo[d]oxazol-2-yl)-3,5-difluorophenyl)(phenyl)methanone (5e). Light yellow solid. Mp = 105−106 °C (53% yield). mp: 105−106 °C. Yield: 53.3 mg, 53%. 1H NMR (400 MHz, CDCl3): δ 7.61−7.68 (m, 2H), 7.52−7.58 (m, 1H), 7.28−7.37 (m, 2H), 7.21−7.28 (m, 2H), 7.16−7.20 (m, 2H), 7.06−7.14 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 193.9, 163.9 (dd, JC−F = 12.3, 256.3 Hz), 161.4 (dd, JC−F = 3358


Note


(3,5-Dimethyl-2-(6-nitrobenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (7b). Light yellow oil. Yield: 49.1 mg, 44%. 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 2.0 Hz, 1H), 8.22 (dd, J = 1.6, 8.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 3H), 7.40−7.44 (m, 1H), 7.38 (s, 1H), 7.30−7.34 (m, 3 H), 2.59 (s, 3H), 2.47 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.8, 166.4, 156.6, 149.4, 146.6, 145.1, 141.7, 141.3, 139.6, 136.9, 134.2, 133.0, 129.5, 128.3, 128.0, 122.5, 120.5, 120.0, 107.1, 21.5, 20.7. HRMS (EI-TOF): m/z calcd for C22H16N2O4 372.1110, found 372.1108. 2-(3-(2,4-Dimethylphenyl)bicyclo[2.2.1]heptan-2-yl)-6nitrobenzo[d]oxazole (7b′). Light yellow oil. Yield: 53.2 mg, 49%. 1H NMR (400 MHz, CDCl3): δ 8.05−8.12 (m, 2H), 7.54 (d, J = 8.8 Hz,1H), 7.08 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 3.67 (d, J = 9.6 Hz, 1H), 3.44 (d, J = 9.6 Hz, 1H), 2.64−2.83 (m, 3H), 2.32 (s, 3H), 2.00 (s, 3H), 1.75−1.86 (m, 2H), 1.67 (d, J = 10.0 Hz, 1H), 1.52 (dd, J = 2.0, 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 172.6, 149.2, 146.1, 144.4, 136.1, 136.0, 135.4, 130.5, 126.1, 125.8, 119.9, 119.1, 106.3, 49.4, 49.2, 41.7, 41.1, 37.8, 31.2, 29.1, 20.6, 20.2. HRMS (EI-TOF): m/z calcd for C22H22N2O3 362.1630, found 362.1630. (3,5-Difluoro-2-(6-nitrobenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (7c). Light yellow solid. Mp: 152−154 °C. Yield: 61.6 mg, 54%. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 2.0 Hz, 1H), 8.24 (dd, J = 2.4, 8.8 Hz, 1H), 7.72−7.78 (m, 3H), 7.49−7.52 (m, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.18−7.25 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ 193.3, 164.5 (dd, J = 12.7, 258.4 Hz), 161.7 (dd, J = 11.9, 261.4 Hz), 160.9 (d, J = 29.0 Hz), 149.6, 146.1, 145.5, 144.3 (d, J = 7.6 Hz), 135.8, 133.9, 129.5, 128.7, 120.8, 120.5, 113.1 (dd, J = 3.6, 23.1 Hz), 107.4, 107.0 (t, J = 25.2 Hz), 29.7. HRMS (EI-TOF): m/z calcd for C20H10F2N2O4 380.0609, found 380.0611. 2-(3-(2,4-Difluorophenyl)bicyclo[2.2.1]heptan-2-yl)-6-nitrobenzo[d]oxazole (7c′). Colorless solid. Mp: 148−149 °C. Yield: 44.4 mg, 40%. 1H NMR (400 MHz, CDCl3): δ 8.12−8.18 (m, 2H), 7.58 (dd, J = 1.2, 8.4 Hz, 1H), 7.11−7.21 (m, 1H), 6.45−6.59 (m, 2H), 3.68 (d, J = 9.6 Hz, 1H), 3.61 (d, J = 9.6 Hz, 1H), 2.86 (s, 1H), 2.64 (s, 1H), 2.60 (d, J = 10.4 Hz, 1H), 1.83 (dd, J = 2.8, 10.8 Hz, 2H), 1.68 (d, J = 10.4 Hz, 1H), 1.52−1.58 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 172.1, 161.3 (dd, J = 12.0, 246.0 Hz,), 160.4 (dd, J = 11.7, 246.5 Hz), 149.2, 146.0, 144.7, 128.3 (d, J = 5.6 Hz), 128.2 (d, J = 5.6 Hz), 124.2 (dd, J = 3.8, 14.8 Hz), 120.2, 119.3, 110.6 (dd, J = 3.5, 20.7 Hz), 106.4, 102.9 (t, J = 25.8 Hz), 49.0, 44.9, 41.6, 40.6, 37.5, 30.7, 28.8. HRMS (EI-TOF): m/z calcd for C20H16F2N2O3 370.1129, found 370.1130. (3-Isopropyl-2-(6-nitrobenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (7d). Light yellow oil. Yield: 34.8 mg, 30%. 1H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 2.0 Hz, 1H), 8.26 (dd, J = 2.4, 8.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.69−7.74 (m, 3H), 7.66 (t, J = 7.6 Hz, 1H), 7.52 (dd, J = 1.2, 8.8 Hz, 1H), 7.43−7.49 (m, 1H), 7.33− 7.37 (m, 2H), 3.18−3.28 (m, 2H), 1.31 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 196.5, 166.5, 150.4, 149.7, 146.6, 145.2, 140.6, 136.8, 133.1, 131.1, 129.8, 129.0, 128.3, 127.7, 125.3, 120.5, 120.2, 107.4, 30.6, 24.0. HRMS (EI-TOF): m/z calcd for C23H18N2O4 386.1267, found 386.1271. 2-(3-(2-Isopropylphenyl)bicyclo[2.2.1]heptan-2-yl)-6-nitrobenzo[d]oxazole (7d′). Orange yellow oil. Yield: 73.3 mg, 65%. 1H NMR (400 MHz, CDCl3): δ 8.09 (dd, J = 2.4, 8.8 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.21−7.23 (m, 1H), 6.92−6.95 (m, 1H), 6.84−6.87 (m, 2H), 3.71 (d, J = 9.2 Hz, 1H), 3.55 (d, J = 9.6 Hz, 1H), 3.28−3.25 (m, 1H), 2.77−2.82 (m, 2H), 2.71 (s, 1H), 1.81−1.84 (m, 2H), 1.70 (d, J = 10.4 Hz, 1H), 1.53−1.55 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 172.3, 149.2, 146.5, 146.1, 144.5, 137.4, 126.5, 126.1, 125.2, 124.4, 120.0, 119.0, 106.2, 49.8, 48.5, 41.6, 41.4, 37.9, 31.2, 29.3, 29.1, 25.3, 22.2. HRMS (EI-TOF): m/z calcd for C23H24N2O3 376.1787, found 376.1792. (1-(6-Nitrobenzo[d]oxazol-2-yl)naphthalen-2-yl)(phenyl)methanone (7e). Light yellow solid. Mp: 173−174 °C. Yield: 68.6 mg, 58%. 1H NMR (400 MHz, CDCl3): δ 8.51−8.54 (m, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.27 (dd, J = 2.0, 8.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.03−8.06 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.70−7.76 (m, 5H), 7.41 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H). 13C NMR (100 MHz,

(m, 2H), 7.44−7.50 (m, 2H), 7.33−7.39 (m, 1H), 7.24−7.30 (m, 2H), 7.18 (s, 1H), 7.06 (dd, J = 0.8, 8.0 Hz, 1H), 2.59 (s, 3H), 2.42 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 197.0, 160.6, 150.6, 141.1, 139.3, 139.2, 137.1, 135.5, 133.1, 132.6, 130.0, 129.5, 128.1, 126.9, 126.6, 125.6, 119.5, 110.6, 21.7, 20.7. HRMS (EI-TOF): m/z calcd for C22H17NO2 327.1259, found 327.1260. (3-Methyl-2-(5-methylbenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (6e). Light yellow oil. Yield: 51.0 mg, 52%. 1H NMR (400 MHz, CDCl3): δ 7.66−7.70 (m, 2H), 7.50−7.54 (m, 2H), 7.44−7.49 (m, 1H), 7.40 (s, 1H), 7.33−7.38 (m, 1H), 7.22−7.29 (m, 3H), 7.06 (dd, J = 1.2, 8.4 Hz, 1H), 2.59 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.0, 161.3, 148.5, 141.6, 141.1, 139.3, 137.1, 134.1, 133.1, 132.7, 130.1, 129.5, 128.1, 126.9, 126.7, 126.2, 120.0, 109.8, 21.4, 20.7. HRMS (EI-TOF): m/z calcd for C22H17NO2 327.1259, found 327.1259. (2-(5-Chlorobenzo[d]oxazol-2-yl)-3,5-dimethylphenyl)(phenyl)methanone (6f). Light yellow oil. Yield: 53.1 mg, 49%. 1H NMR (400 MHz, CDCl3): δ 7.65−7.70 (m, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.33− 7.40 (m, 2H), 7.23−7.30 (m, 4H), 7.20 (dd, J = 2.0, 8.4 Hz, 1H), 2.56 (s, 3H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.1, 162.9, 148.8, 142.5, 141.2, 141.0, 139.2, 137.1, 134.0, 132.8, 129.7, 129.4, 128.1, 127.7, 126.1, 125.3, 123.1, 120.0, 111.2, 21.4, 20.7. HRMS (EITOF): m/z calcd for C22H16ClNO 2 361.0870, found 361.0869. (2-(5-tert-Butylbenzo[d]oxazol-2-yl)-3-methylphenyl)(phenyl)methanone (6g). White solid. Mp: 84−86 °C. Yield: 49.8 mg, 45%. 1 H NMR (400 MHz, CDCl3): δ 7.68−7.74 (m, 2H), 7.65 (d, J = 1.2 Hz, 1H), 7.49−7.54 (m, 2H), 7.43−7.47 (m, 1H), 7.35−7.41 (m, 1H), 7.24−7.32 (m, 4H), 2.59 (s, 3H), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 207.0, 197.0, 161.3, 148.4, 147.8, 141.3, 141.0, 139.4, 137.1, 133.1, 132.6, 129.9, 129.6, 128.1, 126.9, 126.8, 122.9, 116.6, 109.6, 34.9, 31.7, 30.9, 20.7. HRMS (EI-TOF): m/z calcd for C25H23NO2 369.1729, found 369.1728. (2-(Benzo[d]thiazol-2-yl)-3-methylphenyl)(phenyl)methanone (6h). Light yellow solid. Mp: 82−84 °C. Yield: 57.3 mg, 58%. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.0 Hz, 1H), 7.78 (dd, J = 0.8, 8.0 Hz, 1H), 7.66−7.72 (m, 2H), 7.46−7.50 (m, 2H), 7.36−7.43 (m, 3H), 7.24−7.35 (m, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 197.3, 165.2, 152.9, 140.7, 138.2, 137.4, 136.2, 132.8, 132.8, 129.9, 129.3, 128.0, 126.6, 126.0, 125.2, 123.4, 121.3, 31.6, 22.7, 20.5, 14.1. HRMS (EI-TOF): m/z calcd for C21H15NOS 329.0874, found 329.0874. (3-Methyl-2-(4-methylthiazol-2-yl)phenyl)(phenyl)methanone (6i). Light brown solid. Mp: 59−60 °C. Yield: 21.1 mg, 24%. 1H NMR (400 MHz, CDCl3): δ 7.61−7.67 (m, 2H), 7.40−7.47 (m, 3H), 7.35− 7.40 (m, 1H), 7.27−7.34 (m, 2H), 6.77 (d, J = 0.8 Hz, 1H), 2.41 (s, 3H), 2.28 (d, J = 1.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 197.8, 163.4, 152.7, 140.9, 137.8, 137.5, 132.6, 132.5, 132.3, 129.7, 129.0, 128.0, 126.4, 115.2, 20.6, 16.8. HRMS (EI-TOF): m/z calcd for C18H15NOS 293.0874, found 293.0878. (3-Methyl-2-(6-nitrobenzo[d]oxazol-2-yl)phenyl)(phenyl)methanone (7a). Light yellow oil. Yield: 32.2 mg, 30%. 1H NMR (400 MHz, CDCl3): δ 8.31−8.35 (m, 1H), 8.24 (dd, J = 2.0, 8.8 Hz, 1H), 7.72−7.76 (m, 3H), 7.58−7.59 (m, 2H), 7.50−7.52 (m, 1H), 7.42− 7.46 (m, 1H), 7.32−7.36 (m, 2H), 2.60 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.5, 166.2, 156.6, 149.5, 146.5, 145.2, 141.1, 139.8, 136.8, 133.5, 133.1, 130.9, 130.2, 129.7, 128.3, 127.5, 125.6, 120.5, 120.1, 107.2, 20.7. HRMS (EI-TOF): m/z calcd for C21H14N 2O4 358.0954, found 358.0954. 6-Nitro-2-(3-(o-tolyl)bicyclo[2.2.1]heptan-2-yl)benzo[d]oxazole (7a′). Light yellow solid. Mp: 91−93 °C. Yield: 47.0 mg, 45%. 1H NMR (400 MHz, CDCl3): δ 8.07 (dd, J = 2.0, 8.8 Hz, 1H), 8.05 (d, J = 5.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.74 (t, J = 7.6 Hz, 1H), 3.69 (dd, J = 1.2, 9.6 Hz, 1H), 3.48 (d, J = 9.6 Hz, 1H), 2.71−2.81 (m, 3H), 2.37 (s, 3H), 1.80−1.84 (m, 2H), 1.67−1.70 (m, 1H), 1.53 (dd, J = 2.0, 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 172.4, 149.2, 146.0, 144.5, 139.2, 136.2, 129.7, 126.1, 125.9, 125.5, 120.0, 119.0, 106.3, 49.6, 49.1, 41.6, 41.2, 37.8, 31.2, 29.1, 20.3. HRMS (EI-TOF): m/z calcd for C21H20N2O3 348.1474, found 348.1477. 3359



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CDCl3): δ 196.7, 165.4, 149.5, 146.5, 145.4, 139.8, 136.8, 134.3, 133.2, 132.3, 130.8, 129.5, 128.9, 128.7, 128.4, 128.2, 126.0, 125.3, 123.2, 120.7, 120.3, 107.3. HRMS (EI-TOF): m/z calcd for C24H14N2O4 394.0954, found 394.0956. 2-(3-(Naphthalen-1-yl)bicyclo[2.2.1]heptan-2-yl)-6-nitrobenzo[d]oxazole (7e′). Colorless solid. Mp: 147−148 °C. Yield: 34.6 mg, 30%. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 2.4, 8.8 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.43−7.57 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H), 7.30−7.36 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 4.11 (d, J = 9.6 Hz, 1H), 3.90 (dd, J = 0.8, 9.6 Hz, 1H), 2.93 (s, 1H), 2.78−2.87 (m, 2H), 1.83−1.96 (m, 2H), 1.75 (d, J = 10.0 Hz, 1H), 1.66 (d, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 172.3, 148.7, 145.8, 144.3, 136.9, 133.2, 131.5, 128.4, 126.8, 125.4, 125.3, 124.9, 124.0, 123.6, 119.8, 118.8, 106.0, 50.0, 48.9, 42.4, 41.1, 37.6, 30.9, 29.4. HRMS (EI-TOF): m/z calcd for C24H20N2O3 384.1474, found 384.1473. 2-(3-(Benzo[d]oxazol-2-yl)bicyclo[2.2.1]heptan-2-yl)phenylbenzoate (7f). Light yellow oil. Yield: 79.8 mg, 65%. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 7.2 Hz, 2H), 7.67−7.72 (m, 1H), 7.61 (t, J = 7.6 Hz, 2H), 7.50−7.53 (m, 1H), 7.37 (dd, J = 2.0, 7.6 Hz, 1H), 7.20−7.24 (m, 1H), 7.10−7.15 (m, 2H), 6.93−7.02 (m, 2H), 6.88 (dd, J = 1.6, 7.6 Hz, 1H), 3.60 (d, J = 9.6 Hz, 1H), 3.43 (d, J = 9.2 Hz, 1H), 2.76 (br. s, 1H), 2.72 (br. s, 1H), 2.68 (d, J = 10.4 Hz, 1H), 1.75 (d, J = 8.0 Hz, 2H), 1.61 (d, J = 10.0 Hz, 1H), 1.43 (dd, J = 2.0, 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 167.3, 164.8, 150.2, 148.7, 140.9, 133.7, 133.4, 130.4, 129.9, 128.8, 127.4, 127.0, 125.4, 124.1, 123.6, 121.6, 119.3, 109.9, 49.2, 46.7, 42.1, 40.5, 37.2, 30.6, 29.2. HRMS (EI-TOF): m/z calcd for C27H23NO3 409.1678, found 409.1688. 2-(3-(o-Tolyl)bicyclo[2.2.1]heptan-2-yl)benzo[d]oxazole (7g). Colorless solid. Mp: 67−69 °C. Yield: 41.8 mg, 46%. 1H NMR (400 MHz, CDCl3): δ 7.44−7.50 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.05− 7.16 (m, 3H), 6.88 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 3.66 (d, J = 8.8 Hz, 1H), 3.43 (d, J = 9.6 Hz, 1H), 2.75−2.82 (m, 2H), 2.69 (s, 1H), 2.37 (s, 3H), 1.75−1.85 (m, 2H), 1.65 (d, J = 10.4 Hz, 1H), 1.52 (dd, J = 1.6, 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 167.3, 150.2, 140.6, 139.8, 136.3, 129.5, 126.0, 125.8, 125.3, 123.9, 123.5, 119.2, 109.6, 49.4, 49.0, 41.8, 41.2, 37.7, 31.2, 29.2, 20.4. HRMS (EI-TOF): m/z calcd for C21H21NO 303.1623, found 303.1626.

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REFERENCES

(1) Kumar, D.; Jacob, M. R.; Reynolds, M. B.; Kerwin, S. M. Bioorg. Med. Chem. 2002, 10, 3997. (2) Malamas, M. S.; Manas, E. S.; McDevitt, R. E.; Gunawan, I.; Xu, Z.; Collini, M. D.; Miller, C. P.; Dinh, T.; Henderson, R. A.; Keith, J. J. C.; Harris, H. J. Med. Chem. 2004, 47, 5021. (3) Tipparaju, S. K.; Joyasawal, S.; Pieroni, M.; Kaiser, M.; Brun, R.; Kozikowski, A. P. J. Med. Chem. 2008, 51, 7344. (4) (a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995. (b) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60, 8991. (c) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389. (5) Fortenberry, C.; Nammalwar, B.; Bunce, R. A. Org. Prep. Proced. Int. 2013, 45, 57. (6) (a) Shibahara, F.; Yamaguchi, E.; Murai, T. Chem. Commun. 2010, 46, 2471. (b) Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi, J. I.; Itami, K. I. Chem. - Eur. J. 2011, 17, 10113. (c) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 3674. (7) Wang, L.; Ren, X.; Yu, J.; Jiang, Y.; Cheng, J. J. Org. Chem. 2013, 78, 12076. (8) Zhu, F.; Tao, J.; Wang, Z. Org. Lett. 2015, 17, 4926. (9) (a) Yang, F.; Xu, Z.; Wang, Z.; Yu, Z.; Wang, R. Chem. - Eur. J. 2011, 17, 6321. (b) Ranjit, S.; Liu, X. Chem. - Eur. J. 2011, 17, 1105. (10) (a) Han, W.; Mayer, P.; Ofial, A. R. Chem. - Eur. J. 2011, 17, 6904. (b) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202. (11) Yu, D.; Lu, L.; Shen, Q. Org. Lett. 2013, 15, 940. (12) (a) Della Ca’, N.; Fontana, M.; Motti, E.; Catellani, M. Acc. Chem. Res. 2016, 49, 1389. (b) Ye, J.; Lautens, M. Nat. Chem. 2015, 7, 863. (13) (a) Li, R.; Dong, G. Angew. Chem., Int. Ed. 2018, 57, 1697. (b) Whyte, A.; Olson, M.; Lautens, M. Org. Lett. 2018, 20, 345 and references cited therein. (14) Maestri, G.; Motti, E.; Della Ca’, N.; Malacria, M.; Derat, E.; Catellani, M. J. Am. Chem. Soc. 2011, 133, 8574. (15) (a) Gao, W.; Li, W.; Zeng, C.; Tian, H.; Hu, L.; Little, R. D. J. Org. Chem. 2014, 79, 9613. (b) Lei, C.; Jin, X.; Zhou, J. Angew. Chem., Int. Ed. 2015, 54, 13397. (c) Pal, P.; Giri, A. K.; Singh, H.; Ghosh, S. C.; Panda, A. B. Chem. - Asian J. 2014, 9, 2392. (16) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. (17) Martins, A.; Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 4827. (18) (a) Pan, S.; Wu, F.; Yu, R.; Chen, W. J. Org. Chem. 2016, 81, 1558. (b) Pan, S.; Ma, X.; Zhong, D.; Chen, W.; Liu, M.; Wu, H. Adv. Synth. Catal. 2015, 357, 3052. (19) Phakhodee, W.; Duangkamol, C.; Wangngae, S.; Pattarawarapan, M. Tetrahedron Lett. 2016, 57, 325. (20) Fortenberry, C.; Nammalwar, B.; Bunce, R. A. Org. Prep. Proced. Int. 2013, 45, 57.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03055. 1

H NMR and 13C NMR spectra for new products (PDF) Crystallographic data for 7c′ (CIF)

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Note

AUTHOR INFORMATION

Corresponding Authors

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

Wanzhi Chen: 0000-0002-7076-1521 Huayue Wu: 0000-0003-3431-561X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

The National Natural Science Foundation of China (21572203 and 21472140) and Zhejiang Provincial Natural Science Foundation (LZ16B020001) are acknowledged for the financial support. 3360


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