An Efficient and Practical Synthesis of Benzoxazoles from Acyl Chlorides and 2-Aminophenols Catalyzed by Lewis Acid In(OTf)3 under Solvent-Free Reaction Conditions

FULL PAPER

* E-mail: [email protected]; Tel.: 0086-0561-3802069; Fax: 0086-0561-3090518 Received January 15, 2010; revised March 28, 2010; accepted April 19, 2010. Project supported by the National Natural Science Foundation of China (No. 20972057) and the Key Project of Science and Technology of De-

partment of Education, Anhui Province, China (No. ZD2007005-1). † Dedicated to the 60th Anniversary of Shanghai Institute of Organic Chemistry, Chinses Academy of Sciences.

Chin. J. Chem. 2010, 28, 1697—1703 © 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1697

An Efficient and Practical Synthesis of Benzoxazoles from Acyl Chlorides and 2-Aminophenols Catalyzed by Lewis Acid

In(OTf)3 under Solvent-Free Reaction Conditions†

Wang, Boa(王波) Zhang, Yichenga(张义成) Li, Pinhuaa(李品华) Wang, Lei*,a,b(王磊)

a Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, China b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,

Chinese Academy of Sciences, Shanghai 200032, China

Benzoxazole derivatives have been prepared through the reaction of substituted 2-aminophenols and acyl chlo-rides in the presence of catalytic amount of In(OTf)3 under solvent-free reaction conditions in good to excellent yields. The method is simple, convenient, environmental-friendly, efficient and practical.

Keywords benzoxazoles, 2-aminophenols, acyl chlorides, heterocycles, Lewis acid, In(OTf)3, solvent-free

Introduction

Five-membered aromatic heterocyclic rings contain-ing a C＝N bond, such as benzoxazoles, benzothiazoles, and benzimidazoles, are important structural units in natural products, and in synthetic pharmaceutical and agrochemical compounds.1 These compounds have re-ceived a considerable amount of attention for their bio-logical and therapeutic activities.2-5 Recently, a survey showed that only 5% of all reactions achieved in the process research groups of three major pharmaceutical companies involve construction of a heteroaromatic rings.6 Therefore, the development of new methods for the synthesis of nitrogen-containing heterocycles is still a focus of intense and continuing interest in the organic chemistry, as well as in pharmaceutical and agrochemi-cal chemistry.

The benzoxazoles scaffold (Eq. 1) is found in a vari-ety of biologically active compounds7 and pharmaceu-tical agent,8 which have received an extensively atten-tion in diverse areas of biology and chemistry.9-12 The reported typical synthetic routes for the synthesis of benzoxazoles involve the direct condensation of 2-aminophenols with carboxylic acid derivatives,13 and the copper-catalyzed intramolecular ortho arylation of o-haloanilides or intermolecular domino annulations of o-aryl halides with acylamides.14 These methods gener-ally required the presence of strong acid or additives at high reaction temperature. To our knowledge, there are several other reported methods for the direct synthesis of benzoxazoles from 2-aminophenols and acyl chlo-

rides.15-17 However, the methods suffer from the draw-backs for the preparation of benzoxazoles, such as the yields sometimes quite poor18 or in some cases the rather harsh reaction conditions involved. To develop milder, convenient and practical approach for the con-version of 2-aminophenols and acyl chloride into the corresponding benzoxazoles is desirable.

The utility of indium(III) salts as Lewis acids in or-ganic synthesis has received a great deal of interest due to their relatively low toxicity, stability in air and water, recyclability, operational simplicity, strong tolerance to oxygen and nitrogen-containing substrates and func-tional groups.19 Their potential as Lewis acid catalysts for fundamental reactions, such as the Diels-Alder,20 Friedel-Crafts,21 Mukaiyama aldol,22 and Sa-kurai-Hosomi allylation reactions,23 has been exten-sively investigated. As a part of our program aiming to develop selective and environmental friendly methods for the preparation of heterocycles, herein, we wish to report an In(OTf)3-catalyzed efficient, simple and prac-tical procedure for the direct synthesis of substituted

Wang et al.FULL PAPER

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benzoxazoles through the reaction of acyl chlorides and 2-aminophenols under solvent-free reaction conditions (Eq. 1).

Results and discussion

In our preliminarily investigation on the model reac-tion of 2-aminophenol and benzoyl chloride, it was found that the reaction could be finished under very simple reaction conditions in the presence of catalytic amount of In(OTf)3 (5 mol%) in the absence of any solvent and additive, which gives the desire benzoxa-zole product in good yield. The effect of solvent, cata-lyst, reaction temperature and time on the reaction was systematically investigated and the results were summa-rized in Table 1. As can be seen from Table 1, the sol-vents play an important role in the model reaction. It was found that dioxane is the best one among the sol-vents tested, and the reaction proceeded smoothly in dioxane and gave the desired product in 73% yield,

while DMF afforded the product only in 15% yield. Use of CH3NO2, 1,2-dichloroethane, p-xylene, toluene, CH3CN, C2H5OH and DMSO as solvents led to slower reactions (Table 1, Entries 1—9). To our delight, 93% of model product was isolated when the model reaction was carried out in the absence of any solvent at 110 ℃

for 15 h (Table 1, Entry 10). In the absence of any solvent, among a variety of

catalyst species tested, In(OTf)3 was found to be the most effective one. InCl, InBr3, InCl3, In(OAc)3, and InCl2 were used instead of In(OTf)3 as catalyst, but their efficiencies were lower than that of In(OTf)3, especially using InCl3, In(OAc)3, and InCl2 as catalysts for the model reaction (Table 1, Entries 10—15). With respect to the catalyst loading, when 1 mol%—3 mol% of In(OTf)3 was used, the reaction did not go to completion, but a higher loading (5 mol%—10 mol%) of the catalyst gave a satisfactory results (Table 1, Entries 10, and 18—20). During the course of our further optimization of the reaction conditions, the reactions were gen-

Table 1 Optimization of the reaction conditionsa

Entry Catalyst/mol% Solvent/(Temp./℃) Yieldb/%

1 In(OTf)3 (5) 1,2-Dichloroethane/80 62

2 In(OTf)3 (5) DMSO/110 24

3 In(OTf)3 (5) Toluene/110 59

4 In(OTf)3 (5) CH3CN/80 46

5 In(OTf)3 (5) DMF/110 15

6 In(OTf)3 (5) Dioxane/100 73

7 In(OTf)3 (5) CH3NO2/100 66

8 In(OTf)3 (5) p-Xylene/110 60

9 In(OTf)3 (5) C2H5OH/78 44

10 In(OTf)3 (5) Solvent-free/110 93

11 InBr3 (5) Solvent-free/110 65

12 InCl3 (5) Solvent-free/110 47

13 InCl2 (5) Solvent-free/110 21

14 InCl (5) Solvent-free/110 83

15 In(OAc)3 (5) Solvent-free/110 32






21c In(OTf)3 (5) Solvent-free/110 93

22d In(OTf)3 (5) Solvent-free/110 83

23e In(OTf)3 (5) Solvent-free/110 74 a Reaction conditions: 2-aminophenol (0.5 mmol), benzoyl chloride (0.55 mmol), stirred in solvent (1.5 mL) or neat at the temperature indicated in Table 1 for 15 h. b Isolated yield. c Reaction was conducted for 18 h. d Reaction was conducted for 12 h. e Reaction was con-ducted for 9 h.

An Efficient and Practical Synthesis of Benzoxazoles from Acyl Chlorides and 2-Aminophenols

Chin. J. Chem. 2010, 28, 1697—1703 © 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.cjc.wiley-vch.de 1699

erally complete in a matter of hours, but the time, as expected, was inversely proportional to the temperature. A reaction temperature of 110 ℃ for 15 h was found to be optimal.

At a relative low temperature (90, 70 ℃) in the ab-sence of solvent, 67% and 41% yields were isolated, respectively (Table 1, Entries 16 and 17). Meanwhile, experimental data indicated that the reaction was not completed when reaction time was less than 15 h. However, no increase in yield was observed when the reaction time was prolonged (Table 1, Entries 21—23). The optimized reaction conditions for the reaction were found to be In(OTf)3 (5 mol%) under solvent-free reac-tion conditions at 110 for ℃ 15 h.

Having established the optimized reaction conditions, we turned our attention to explore the scope of this pro-tocol. The results are listed in Table 2. As shown in Ta-ble 2, in the most cases, 2-aminophenol reacted with a wide variety of substituted benzoyl chlorides completely and afforded the corresponding benzoxazoles in good to excellent yields (Table 2, Entries 1—6). Substituted

benzoyl chlorides containing electron-donating or elec-tron-withdrawing groups on the benzene rings reacted with 2-aminophenol smoothly under optimal reaction conditions to give the desired products. Furthermore, sterically demanding ortho substituents hampered the reaction and the corresponding products were obtained in 78% and 73% yields, respectively (Table 2, Entries 4 and 5). To our delight, cinnamoyl chloride was also successfully reacted with benzoyl chloride to give the desired product in good yield (Table 2, Entry 7). Meanwhile, substituted 2-aminophenols with elec-tron-donating or middle and weak electron-withdrawing groups on the benzene rings reacted with benzoyl chlo-rides to generate the corresponding products in high yields (Table 2, Entries 8—15). It is important to note that substituted 2-aminophenols with a strong elec-tron-withdrawing group, such as nitro group on the benzene ring, showed lower reactivity than those of ones with electron-donating groups and middle or weak elec-tron-withdrawing groups (Table 2, Entry 16).

Table 2 Synthesis of benzoxazoles from 2-aminophenols and acyl chloridesa

Entry 2-Aminophenol Acyl chloride Yieldb/%

1

93

2

90

3

95

4

78

5

73

6

96



Continued

Entry 2-Aminophenol Acyl chloride Yieldb/%

7

81

8

83

9

90

10

93

11

92

12

87

13

89

14

82

15

91

16

55

a Reaction conditions: 2-aminophenol (0.5 mmol), acyl chloride (0.55 mmol), In(OTf)3 (2.8 mg, 5 mmol%) was stirred at 110 ℃ for 15 h under solvent-free reaction conditions. b Isolated yield.

A possible mechanism of In(OTf)3-catalyzed reac-tion of 2-aminophenol with acyl chloride for the synthe-sis of benzoxazole is shown in Scheme 1. The catalyst In(OTf)3 would presumably first coordinate with hy-droxyl group in 2-aminophenol owing to stronger oxy-philic of In(OTf)3. Meanwhile, monoacylated 2-aminophenol, A was formed through the reaction of amino group with acyl chloride under the present reaction con-ditions. Then, hydroxyl group in B attacked the carbonyl group to accomplish intermolecular addition/cyclization and generated intermediate product C, which followed by dehydration to form the desired benzoxazole product

D. Further investigation on the mechanism is under way in our laboratory.

Conclusion

In conclusion, we have developed an In(OTf)3-catalyzed efficient and practical protocol for the synthesis of benzoxazoles by using various 2-aminophenols and acyl chlorides as the substrates without any solvent. The re-actions were performed smoothly to generate the corre-sponding products in high yields under safe experimen-tal conditions, and the procedure is simple and conven-



ient. This method offers one of the important motifs for synthesis of benzoxazoles, as natural products, biologi-cally active compounds and pharmaceutical agents.

Scheme 1

Experimental

Physical measurements and materials

All 1H NMR and 13C NMR spectra were recorded on 400 MHz Bruker FT-NMR spectrometers. All chemical shifts are given as δ value with reference to tetramethyl-silane (TMS) as an internal standard. Products were pu-rified by flash chromatography on 230—400 mesh silica gel, SiO2.

The chemicals and solvents were purchased from commercial suppliers either from Aldrich, Fluka (USA or Shanghai Chemical Company, China), and they were used without purification prior to use.

General procedure for the synthesis of benzoxazoles

2-Aminophenol (0.5 mmol) and acyl chloride (0.55 mmol) were placed in a sealed vessel containing In(OTf)3 (2.8 mg, 5 mol%). The reaction mixture was heated to 110 for 1℃ 5 h with stirring under a nitrogen atmosphere. After cooling, the reaction mixture was treated by a diluted solution of NaOH (1.0 mol•L－1). The solution was extracted with ethyl acetate (3×5.0 mL) and the organic layer was dried over Na2SO4. Then, the organic solution was concentrated with a rotary evaporator, and the residue was purified by column chromatography on silica gel using cyclohexane/ethyl acetate (V∶V, 9∶1) as eluent to provide the desired benzoxazole product.

2-Phenylbenzoxazole11 M.p. 103— 104 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.27— 8.26 (m, 2H), 7.79—7.76 (m, 1H), 7.58—7.55 (m, 1H), 7.52—7.50 (m, 3H), 7.35—7.33 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ: 162.99, 150.72, 142.06, 131.45, 128.85, 127.58, 127.13, 125.05, 124.53, 119.97, 110.53.

2-(4-Methylphenyl)benzoxazole10 M.p. 115 —

116.5 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.14 (d, J＝8.10 Hz, 2 H), 7.78—7.73 (m, 2 H), 7.59—7.54 (m, 4 H), 7.36—7.31 (m, 4 H), 2.43 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ: 163.27, 150.65, 142.13, 142.03, 129.62, 127.56, 124.84, 124.45, 124.36, 119.80, 110.46, 21.62.

2-(4-Chlorophenyl)benzoxazole11 M.p. 149.5—151 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.20—8.17 (m, 2H), 7.79—7.75 (m, 1H), 7.60—7.55 (m, 1H), 7.51—7.48 (m, 2H), 7.38—7.34 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 162.05, 150.74, 141.99, 137.75, 129.26, 128.83, 125.65, 125.33, 124.73, 120.07, 110.61.

2-(2,4-Dichlorophenyl)benzoxazole24 M.p. 118—119 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.12 (d, J＝8.55 Hz, 1H), 7.86—7.82 (m, 1H), 7.63—7.59 (m, 2H), 7.43—7.37 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ: 160.07, 150.52, 141.59, 137.53, 134.24, 132.52, 131.29, 127.42, 125.78, 124.80, 124.75, 120.55, 110.76.

2-(2-Chlorophenyl)benzoxazole25 M.p. 70 — 72 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.15 (dd, J＝1.96, 5.53 Hz, 1H), 7.88—7.83 (m, 1H), 7.64—7.60 (m, 1H), 7.59—7.54 (m, 1H), 7.47—7.36 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ: 160.93, 150.56, 141.67, 133.46, 131.87, 131.79, 131.36, 126.89, 126.24, 125.54, 124.62, 120.48, 110.71.

2-(3-Chlorophenyl)benzoxazole24 m.p. 131.5 —

132.5 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.17 (br, s, 1H), 8.07—8.04 (m, 1H), 7.72—7.68 (m, 1H), 7.53—7.49 (m, 1H), 7.43—7.35 (m, 2H), 7.31—7.27 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ: 161.61, 150.75, 141.89, 135.05, 131.45, 130.20, 128.84, 127.59, 125.61, 125.51, 124.79, 120.20, 110.68.

(E)-2-Styrylbenzoxazole11 M.p. 82—84 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.76 (d, J＝16.39 Hz, 1H), 7.72—7.69 (m, 1H), 7.57—7.54 (m, 2H), 7.52—7.47 (m, 1H), 7.41—7.34 (m, 3H), 7.33—7.28 (m, 2H), 7.05 (d, J＝16.37 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 162.67, 150.30, 142.10, 139.34, 135.03, 129.65, 128.85, 127.45, 125.09, 124.40, 119.77, 113.83, 110.21.

2-(4-Methylphenyl)-5-chlorobenzoxazole26 M.p. 135—137 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.10 (d, J＝8.29 Hz, 2H), 7.70 (br, s, 1H), 7.46 (d, J＝8.69 Hz, 1H), 7.33—7.27 (m, 3H), 2.43 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 164.58, 149.23, 143.31, 142.2, 129.89, 129.68, 127.69, 125.05, 123.88, 119.75, 111.13, 21.64.

2-(4-Methylphenyl)-5-methylbenzoxazole26 M.p. 135.5—137 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.14—8.12 (m, 2H), 7.54—7.53 (m, 1H), 7.44 (d, J＝8.33 Hz, 1H), 7.34—7.31 (m, 2H), 7.16—7.13 (m, 1H), 2.48 (s, 3H), 2.44 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 163.36, 148.90, 142.35, 141.86, 134.25, 129.58, 127.50, 125.94, 124.55, 119.74, 109.81, 21.60, 21.49.

2-(4-Chlorophenyl)-5-methylbenzoxazole27 M.p. 145—147 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.14 (d, J＝7.82 Hz, 2H), 7.52 (s, 1H), 7.46 (d, J＝7.66 Hz, 2H), 7.42 (d, J＝7.66 Hz, 1H), 7.14 (d, J＝8.32 Hz, 1H),



2.47 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 162.07, 148.96, 142.14, 137.55, 134.55, 129.17, 128.73, 126.44, 125.77, 119.94, 109.92, 21.47.

2-(4-Methylphenyl)-5-t-butylbenzoxazole M.p. 111—112 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.13 (t, J＝1.70 Hz, 1H), 8.11 (t, J＝1.70 Hz, 1H), 7.79 (br, s, 1H), 7.46—7.44 (m, 1H), 7.38—7.36 (m, 1H), 7.28 (d, J＝7.81 Hz, 2H), 2.39 (s, 3H), 1.39 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ: 163.33, 148.63, 147.90, 142.02, 141.72, 129.51, 127.40, 124.52, 122.48, 116.30, 109.52, 34.84, 31.71, 21.52. Anal. calcd for C18H19NO: C 81.47, H 7.22, N 5.28; found C 81.72, H 7.09, N 5.41.

2-Phenyl-5-chlorobenzoxazole28 M.p. 102.5—104 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.21—8.19 (m, 2H), 7.71 (d, J＝1.95 Hz, 1H), 7.52—7.44 (m, 4H), 7.29 (q, J＝1.97, 6.58 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 164.27, 149.26, 143.19, 131.83, 129.96, 128.90, 127.68, 126.62, 125.27, 119.91, 111.21.

2-Phenyl-5-methylbenzoxazole29 M.p. 104—105 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.19—8.17 (m, 2H), 7.50 (br, s, 1H), 7.45—7.44 (m, 3H), 7.37 (d, J＝8.25 Hz, 1H), 7.08 (d, J＝8.30 Hz, 1H), 2.42 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 162.97, 148.89, 142.21, 134.23, 131.22, 128.73, 127.43, 127.23, 126.10, 119.81, 109.81, 21.41.

2-Phenyl-5-t-butylbenzoxazole M.p. 82—83 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.24—8.22 (m, 2H), 7.81 (q, J＝0.48, 1.46 Hz, 1H), 7.49—7.37 (m, 5H), 1.39 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ: 163.04, 148.69, 147.99, 141.95, 131.22, 128.76, 127.41, 127.27, 122.73, 116.43, 109.61, 34.83, 31.69. Anal. calcd for C17H17NO: C 81.24, H 6.82, N 5.57; found C 81.39, H 6.91, N 5.72.

2-(3-Chlorophenyl)-5-chlorobenzoxazole30 M.p. 152.5—154 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.22 (t, J＝1.68 Hz, 1H), 8.12—8.10 (m, 1H), 7.74 (d, J＝2.18 Hz, 1H), 7.53—7.44 (m, 3 H), 7.34 (dd, J＝2.21, 1.85 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 162.92, 149.34, 143.02, 135.16, 131.87, 130.32, 130.28, 128.37, 127.72, 125.82, 125.76, 120.17, 111.40.

2-(4-Methylphenyl)-6-nitrobenzoxazole30 M.p. 160.5—162 ℃; 1H NMR (CDCl3, 400 MHz) δ: 8.38 (br, s, 1 H), 8.27—8.23 (m, 1H), 8.09 (d, J＝8.11 Hz, 2H), 7.76—7.74 (m, 1H), 7.32 (d, J＝7.73 Hz, 2H), 2.44 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ: 167.51, 149.63, 147.41, 144.77, 143.68, 129.78, 128.06, 122.97, 120.63, 119.37, 106.93, 21.67.

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(E1001149 Ding, W.)

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