Oxidative Halocyclization of N-Allylarylamides with KX/Oxone System: Green Synthesis of 5-Halomethyl-2-Oxazolines

Xinming Liu Lu Li Licheng Jin Jincan Zhao Yuanzhao Hua Mincan Wang Lantao Liu

Citation:  Liu Xinming, Li Lu, Jin Licheng, Zhao Jincan, Hua Yuanzhao, Wang Mincan, Liu Lantao. Oxidative Halocyclization of N-Allylarylamides with KX/Oxone System: Green Synthesis of 5-Halomethyl-2-Oxazolines[J]. Chinese Journal of Organic Chemistry, 2020, 40(12): 4298-4304. doi: 10.6023/cjoc202005087 shu

KX/Oxone体系实现的N-烯丙基芳酰胺的氧化卤环化反应:5-卤甲基-2-噁唑啉的绿色合成

    通讯作者: 赵金灿, jczhao@hbu.edu.cn
    刘澜涛, liult05@iccas.ac.cn
  • 基金项目:

    中西部高校综合提升工程 521000981026

    河南省科技创新人才 2018JQ0011

    国家自然科学基金(No.21572126)、河南省科技创新人才(No.2018JQ0011)、河北省自然科学基金(No.B2019201415)和中西部高校综合提升工程(No.521000981026)资助项目

    国家自然科学基金 21572126

    河北省自然科学基金 B2019201415

摘要: 以廉价的卤化钾为卤源,Oxone为氧化剂,一系列烯丙胺在温和的条件下经过卤环化反应以较好的产率得到5-卤甲基-2-噁唑啉.该方法的优势在于应用了便宜的卤源,没有有机副产物的产生,具有成本低廉和环保友好的特点.5-卤甲基-2-噁唑啉还可以通过不同的亲核取代反应得到许多有用的衍生物.

English

  • 2-Oxazolines as a class of prominent compounds, are important building blocks of natural products, biologically active compounds and pharmaceuticals, and have also been widely utilized as key structures, protective groups, [1] chiral ligands, [2-3] chiral auxiliaries[4-8] and catalyst[9-17] in organic synthesis or materials science. Great efforts have been devoted to their efficient synthesis, and up to now, significant methods have been developed by using carboxylic acids, carboxylic esters, nitriles, aldehydes, olefins and β-hydrox- yamides as starting materials.[18-20]

    5-Halomethyl-2-oxazolines with a halomethyl group are more attractive for their versatile reactivities. Several efficient methods for their synthesis have been developed during the past decades. Particularly, the methods based on the halocyclization reaction of cheap and readily available N-allylamides attracted more and more attentions.[21-28] While several elegant asymmetric versions with organic halogenating reagents have been realized under mild reaction conditions (Eq. 1a).[29-33] Much attention has been paid for the development of different oxidant promoter/halo- genating reagent systems, such as PIDA/TMSX (Eq. 1b), [24] CuBr2, [27] and Selectfluor/Pyr·(HF)x/Et3N·3HF systems, [34] for the transformation. Wang et al.[26] reported the iodine- promoted regioselective cyclization of N-allylamides with sulfonyl hydrazides for the synthesis of 5-methyl-arylthio- oxazolines via sulfenylation reactions (Eq. 1c). Very recently, Waldvogel et al.[35] achieved a hypervalent iodoarene-mediated fluorocyclization of N-allylcarboxamide to 5-fluoromethyl-2-oxazoline by using electric current as the only oxidant, and Et3N·5HF as fluorinating agents (Eq. 1d). Despite of the great progress, some of them suffered from the use of expensive organic halogenating agents or organic terminal oxidants, special equipment, and especially, the generation of hazardous organic byproducts, or heavy metal residues. The transition-metal-free systems using inorganic oxidant promoter/halogenating reagents are highly desirable.

    (1a)

    (1b)

    (1c)

    (1d)

    (1e)

    Considering to the multifaceted advantages including low-cost, stability, non-toxicity, and air/moisture-insensi- tiveness, oxone has been widely used as inorganic oxidant for halides to generate halogenating agents.[36] Meanwhile KX is a kind of cheap and ideal halogenating reagent source. Thus, KX/oxone system is an ideal environmentally friendly protocol for organic reactions with inorganic K2SO4 as the byproduct.[37-40] Herein, the green synthesis of 5-halomethyl-2-oxazolines via oxidative halocyclization of allylamides with KX/oxone is reported (Eq. 1e).

    Inspired by recent progress, an intramolecular iodooxygenation reaction was proposed using N-allyl carboxamide 1a as the model substrate and KI as halogen source. With the success of reaction, the conditions including the amount of oxone and KI, reaction time and temperature were optimized. It is indicated that 5 equiv. of KI and 2 equiv. of oxone to 1a are enough for the conversion. 4 h is best for this reaction (Table 1, Entries 5~8), and 0 ℃ promised best conversion (Table 1, Entries 9~11). It was interesting to find that when the ratio of H2O to CH3CN increased from 0.5:1 to 1:1 (Table 1, Entries 11~12), the yield reached nearly 90%, which decreased with further increasing of water ratio of 1:0.5. The dependence of the conversion on the water indicated that the solubility of the media toward both inorganic salt of KI and the organic reagents should be well-balanced.[41-44]

    Table 1

    Table 1.  Reaction optimization studies
    下载: 导出CSV
    Entry KI/ equiv. Oxone/ equiv. CH3CN/ mL H2O/ mL Temp/℃ Time/h Yielda/%
    1 2.5 1 1 0.5 25 6 21.9
    2 5.0 2 1 0.5 25 6 29.6
    3 7.5 3 1 0.5 25 6 29.3
    4 10.0 4 1 0.5 25 6 30.8
    5 5.0 2 1 0.5 25 2 45.8
    6 5.0 2 1 0.5 25 4 51.7
    7 5.0 2 1 0.5 25 6 29.8
    8 5.0 2 1 0.5 25 8 23.1
    9 5.0 2 1 0.5 -20 4 36.3
    10 5.0 2 1 0.5 0 4 80.9
    11 5.0 2 1 0.5 50 4 48.9
    12 5.0 2 1 1.0 0 4 88.0
    13 5.0 2 0.5 1.0 0 4 56.8
    a Isolated yield.

    On the optimized conditions, carboxamide substrates 1b~1w were then subjected to the same reaction to test the scope of the reaction (Eq. 2). Seen from the results, 5-iodomethyl-2-aryloxazolines could be obtained in good to excellent yields. All substrates 2b~2t with either electron-donating or electron-withdrawing groups on aromatic rings could be cyclized in 66.5%~98.8% yields. The yields of regents with electron-donating substituents including Me, MeO, tBu, Ph were higher than those with electron-withdrawing substituents including F and NO2. Moreover, the regents with 2- and 4-position occupied gave higher yields than those with 3-position substituted. Especially, substrate 1t bearing 4-phenyl group worked very well in the current reaction system, and generated the corresponding 2-([1, 1'-biphenyl]-4-yl)-5-(iodomethyl)-4, 5-di- hydrooxazoline (2t) with up to 98.8% yield. Oxazoline structures bearing heterocycles have been used as important functional groups in antibiotic, antidiabetic and antihypertensive agents. To this end, structurally diversified heterocyclic oxazoline compounds were also prepared using the same method. As shown in Eq. 2, the thiophene- and pyridine-containing oxazoline products 2u and 2v could also be obtained in 84.6% and 55.8% yields, respectively. Furthermore, the current protocol was also employed to the synthesis of bis(oxazoline) compound 2w in 58.1% yield.

    (2)

    Reaction conditions: substrate (0.5 mmol), KI (5.0 mmol), oxone (2 mmol), CH3CN (1 mL), H2O (1 mL), 0 ℃, 4 h. 10 mmol of KI and 4 mmol of oxone were used for the preparation of 2w. Isolated yield.

    To demonstrate the scalability of the protocol, a gram-scale synthesis of 2d was also carried out. Cyclization of N-allyl-4-methyl benzamide 1d on 1.0 g scale afforded the desired 2, 5-disubstituted oxazoline 2d in 90.6% yield (Eq. 3).

    (3)

    To test the synthetic utility of current reaction, functional group transformations of 2d were also pursued, and the C—I bond in 2d provided an easy access to other functional groups (Scheme 1). For example, iodine group in 2d was replaced by different nucleophiles, such as azide (3a) and benzenethiol (3b) under mild conditions.

    Scheme 1

    Scheme 1.  Derivatization of oxazoline 2d

    To demonstrate the universality of the protocol, some less active KX reagents such as KCl, KBr were tested with N-allyl-4-methyl benzamide 1d as the substrate, the corresponding 5-bromo- and 5-chloro-methyl-2-oxazolines 4a and 4b were obtained in 81.3% and 55.8% isolated yields respectively under the similar experimental conditions (Scheme 2).

    Scheme 2

    Scheme 2.  Synthesis of 5-chloro- and 5-bromo-methyl-2-aryl- 4, 5-dihydrooxazolines

    Based on the results and previous literature reports, [36, 45] a preliminary reaction pathway is put forward (Scheme 3). Firstly, the hypoiodous acid is generated in situ from the reaction of oxone with KI.[36] Afterwards, N-allylbenzamide forms an intermediate (iodonium ion herein) which is then intramolecular nucleophilic attacked by oxygen atom. A five-membered ring is formed and halooxygenation products are provided.

    Scheme 3

    Scheme 3.  Plausible mechanism for intramolecular halooxygenation reaction

    In summary, a practical method for preparation of 5-halomethyloxazolines with oxone as the reaction promoter and KX (X=I, Br and Cl) as the halogen sources was reported. 5-Halomethyl-2-oxazoline products could be achieved in good to excellent yields. The method has the following advanced features: (ⅰ) all the starting materials such as acid and acyl chloride are cheap and commercial available; (ⅱ) the reaction is operationally simple, without requirement of strict anhydrous or inert reaction conditions only inorganic byproducts K2SO4 are generated from the reaction; (ⅲ) the reaction scope is universal and tolerate for both electron withdrawing groups and electron-donating groups. What's more, the 5-chloro and 5-bromo products can also be achieved effectively. It is reasonable to believe that the current method will have widespread application in organic and medicinal chemistry.

    Reagents were used as received without further purification unless otherwise indicated. Reactions were monitored with thin layer chromatography using silica gel GF254 plates. Organic solutions were concentrated in vacuo with a rotavapor. Flash column chromatography was performed using silica gel (200~300 meshes). Petroleum ether used has a boiling point range of 60~90 ℃. Melting points were measured on a digital melting point apparatus without correction of the thermometer. Nuclear magnetic resonance spectra were recorded at ambient temperature (unless otherwise stated) at 400 MHz (100 MHz for 13C NMR) in CDCl3. Chemical shifts were reported in δ using TMS as internal standard. High resolution mass spectrometry (HRMS) analyses were carried out on an Accurate-Mass Q-TOF. Substrates used were prepared by coupling of carboxylic acids or acyl chloride and allylamine described by Borhan et al.[30]

    In a 10 mL long neck tube, N-allylcarboxamides (0.5 mmol), oxone (1.0 mmol), KX (2.5 mmol), H2O (1 mL) and CH3CN (1 mL) were added. The reaction mixture was then stirred at 0 ℃ for 4 h. Ethyl acetate (10 mL) was then added, and the mixture was washed with aqueous Na2S2O3. The combined organic layer was dried (Na2SO4) and concentrated to give crude residue, which was purified by flash column chromatography to give the corresponding products.

    5-(Iodomethyl)-2-phenyl-4, 5-dihydrooxazole (2a): Obtained as an oil in 88.0% yield (126.3 mg) after flash chromatography (silica gel, petroleum ether/ethyl acetate, V:V=5:1). 1H NMR (400 MHz, CDCl3) δ: 7.94~7.91 (m, 2H), 7.51~7.44 (m, 1H), 7.42~7.37 (m, 2H), 4.81~4.75 (m, 1H), 4.19~4.11 (m, 1H), 3.82~3.75 (m, 1H), 3.40~3.26 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 163.4, 131.4, 128.3, 128.1, 127.4, 78.2, 60.7, 7.7. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(o-tolyl)-4, 5-dihydrooxazole (2b): Obtained as an oil in 93.3% yield (140.5 mg) after flash chromatography (silica gel, petroleum ether/ethyl acetate, V:V=4:1). 1H NMR (400 MHz, CDCl3) δ: 7.81 (d, J=8.0 Hz, 1H), 7.36~7.31 (m, 1H), 7.24~7.20 (m, 2H), 4.73~4.70 (m, 1H), 4.22~4.14 (m, 1H), 3.85~3.80 (m, 1H), 3.35~3.32 (m, 2H), 2.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.8, 138.8, 131.2, 130.7, 129.8, 126.7, 125.5, 77.3, 61.0, 21.9, 8.1. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(m-tolyl)-4, 5-dihydrooxazole (2c): Obtained as an oil in 83.3% yield (125.4 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=4:1). 1H NMR (400 MHz, CDCl3) δ: 7.77 (s, 1H), 7.73 (t, J=3.6 Hz, 1H), 7.33~7.28 (m, 2H), 4.83~4.77 (m, 1H), 4.18 (dd, J=15.2, 9.6 Hz, 1H), 3.80 (dd, J=15.2, 6.8 Hz, 1H), 3.39 (dd, J=10.4, 4.8 Hz, 1H), 3.32 (dd, J=10.4, 3.2 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.4, 137.9, 132.1, 128.6, 128.1, 127.1, 125.1, 78.0, 60.5, 21.1, 7.7. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(p-tolyl)-4, 5-dihydrooxazole (2d): Obtained as a white solid in 93.4% yield (140.6 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=4:1); m.p. 94~96 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.82 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 4.82~4.78 (m, 1H), 4.17 (dd, J=15.2, 9.6 Hz, 1H), 3.80 (dd, J=14.8, 6.4 Hz, 1H), 3.38 (dd, J=10.4, 5.2 Hz, 1H), 3.31 (dd, J=10.0, 7.2 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.4, 141.7, 128.9, 128.0, 124.5, 78.0, 60.5, 21.4, 7.8. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(2-methoxyphenyl)-4, 5-dihydrooxazole (2e): Obtained as an oil in 91.2% yield (144.6 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 7.80 (dd, J=8.0, 1.6 Hz, 1H), 7.46~7.42 (m, 1H), 7.01~6.97 (m, 2H), 4.78~4.73 (m, 1H), 4.24 (dd, J=15.2, 9.6 Hz, 1H), 3.93 (s, 3H), 3.88 (dd, J=14.4, 6.8 Hz, 1H), 3.38 (dd, J=10.4, 5.2 Hz, 1H), 3.31 (dd, J=10.0, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 161.6, 158.4, 132.4, 131.0, 120.0, 116.2, 111.4, 76.9, 61.2, 55.8, 7.7. HRMS-ESI calcd for C11H12INO2 [M+H]+ 317.9991, found 317.9981.

    5-(Iodomethyl)-2-(3-methoxyphenyl)-4, 5-dihydrooxazole (2f): Obtained as an oil in 80.2% yield (127.2 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 7.44 (d, J=2.4 Hz, 1H), 7.38~7.37 (m, 1H), 7.23 (t, J=8.0 Hz, 1H), 6.95~6.92 (m, 1H), 4.73~4.66 (m, 1H), 4.07 (dd, J=15.2, 9.2 Hz, 1H), 3.74 (s, 3H), 3.70 (dd, J=15.2, 6.8 Hz, 1H), 3.27 (dd, J=10.4, 5.2 Hz, 1H), 3.21 (dd, J=10.4, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 163.2, 159.3, 129.3, 128.4, 120.4, 118.0, 112.4, 78.1, 60.5, 55.2, 7.7. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(4-methoxyphenyl)-4, 5-dihydrooxazole (2g): Obtained as a white solid in 80.2% yield (151.4 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 104~106 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 4.81~4.74 (m, 1H), 4.15 (dd, J=15.2, 9.6 Hz, 1H), 3.83 (s, 3H), 3.77 (dd, J=15.2, 6.8 Hz, 1H), 3.36 (dd, J=10.4, 5.2 Hz, 1H), 3.30 (dd, J=10.0, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 163.3, 162.1, 129.8, 119.6, 113.6, 78.1, 60.4, 55.2, 7.7. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(2-fluorophenyl)-4, 5-dihydrooxazole (2h): Obtained as an oil in 66.5% yield (101.4 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 7.89~7.84 (m, 1H), 7.49~7.43 (m, 1H), 7.23~7.13 (m, 2H), 4.83~4.77 (m, 1H), 4.22 (dd, J=15.2, 9.6 Hz, 1H), 3.86 (dd, J=15.6, 6.8 Hz, 1H) 3.41~3.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 161.0 (d, J=256.8 Hz), 159.9 (d, J=5.7 Hz), 132.9 (d, J=8.7 Hz), 130.8 (d, J=1.4 Hz), 123.9 (d, J=3.8 Hz), 116.5 (d, J=21.7 Hz), 115.6 (d, J=10.3 Hz), 77.5, 60.9, 7.5; 19F NMR (376 MHz, CDCl3) δ: -109.4. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(4-fluorophenyl)-4, 5-dihydrooxazole (2i): Obtained as a white solid in 88.6% yield (135.2 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 112~113 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.94~7.90 (m, 2H), 7.08(t, J=8.8 Hz, 2H), 4.81~4.77 (m, 1H), 4.15 (dd, J=15.2, 9.6 Hz, 1H), 3.77 (dd, J=15.2, 6.8 Hz, 1H), 3.36 (dd, J=10.4, 5.2 Hz, 1H), 3.31 (dd, J=10.0, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 164.7 (d, J=250.5 Hz), 162.5, 130.4 (d, J=89.0 Hz), 123.6 (d, J=3.1 Hz), 115.5 (d, J=21.9 Hz), 78.4, 60.7, 69.5, 7.6; 19F NMR (376 MHz, CDCl3) δ: -107.8. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(2-nitrophenyl)-4, 5-dihydrooxazole (2j): Obtained as an oil in 81.3% yield (135.0 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 7.86 (dd, J=8.0, 1.6 Hz, 1 H), 7.83 (dd, J=8.0, 1.6 Hz, 1H), 7.67~7.62 (m, 2H), 4.88~4.84 (m, 1H), 4.20 (dd, J=15.2, 9.6 Hz, 1H), 3.86 (dd, J=15.2, 6.4 Hz, 1H), 3.38 (dd, J=10.4, 5.2 Hz, 1H), 3.33 (dd, J=10.4, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 160.7, 148.8, 132.5, 131.5, 131.0, 123.8, 122.7, 79.2, 60.8, 6.9. HRMS-ESI calcd for C11H12INO2 [M+H]+ 332.9736, found 332.9729.

    5-(Iodomethyl)-2-(3-nitrophenyl)-4, 5-dihydrooxazole (2k): Obtained as a white solid in 73.0% yield (121.2 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 85~88 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.77 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 4.90~4.83 (m, 1H), 4.24 (dd, J=15.6, 9.6 Hz, 1H), 3.86 (dd, J=15.6, 9.6 Hz, 1H), 3.43~3.29 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 161.4, 148.0, 133.8, 129.5, 129.1, 125.9, 123.1, 78.6, 60.8, 7.56. HRMS-ESI calcd for C11H12INO2 [M+H]+ 332.9736, found 332.9724.

    5-(Iodomethyl)-2-(4-nitrophenyl)-4, 5-dihydrooxazole (2l): Obtained as a white solid in 80.4% yield (133.5 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 124~125 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.27 (dd, J=8.8, 1.6 Hz, 2H), 8.10 (dd, J=8.8, 2.0 Hz, 2H), 4.89~4.81 (m, 1H), 4.23 (dd, J=15.6, 9.6 Hz, 1H), 3.85 (dd, J=15.6, 6.8 Hz, 1H), 3.42~3.34 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 161.7, 149.5, 133.2, 129.2, 123.6, 78.7, 61.1, 7.4. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(3-bromophenyl)-4, 5-dihydrooxazole (2m): Obtained as an oil in 81.4% yield (149.0 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 8.07 (t, J=4.0 Hz, 1H), 7.86~7.84 (m, 1H), 7.61~7.58 (m, 1H), 7.30~7.26 (m, 1H), 4.83~4.76 (m, 1H), 4.17 (dd, J=15.2, 9.2 Hz, 1H), 3.79 (dd, J=15.2, 6.8 Hz, 1H), 3.36 (dd, J=10.4, 4.8 Hz, 1H), 3.33 (dd, J=10.0, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.1, 134.4, 131.1, 129.9, 129.3, 126.7, 122.3, 78.4, 60.7, 7.5. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(4-bromophenyl)-4, 5-dihydrooxazole (2n): Obtained as a white solid in 90.9% yield (166.3 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 115~117 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.78 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 4.82~4.75 (m, 1H), 4.15 (dd, J=15.2, 9.6 Hz, 1H), 3.77 (dd, J=15.2, 6.8 Hz, 1H), 3.36 (dd, J=10.4, 5.2 Hz, 1H), 3.31 (dd, J=10.0, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.6, 131.6, 129.6, 126.3, 126.2, 78.4, 60.8, 7.6. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(4-(tert-butyl)phenyl)-4, 5-dihydrooxa-zole (2o): Obtained as a white solid in 94.8% yield (162.7 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). m.p. 104~106 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.86 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 4.88~4.74 (m, 1H), 4.17 (dd, J=15.2, 9.2 Hz, 1H), 3.80 (dd, J=15.2, 6.4 Hz, 1H), 3.38 (dd, J=10.4, 4.8 Hz, 1H), 3.31 (dd, J=10.0, 7.2 Hz, 1H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 163.3, 154.8, 127.9, 125.2, 124.5, 78.0, 60.6, 34.8, 31.0, 7.8. Spectral data are in good agreement with literature values.[24-45]

    N-Allyl-4-ethylbenzamide (1p): Obtained as an oil, 1H NMR (400 MHz, CDCl3) δ: 7.72 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.58 (s, 1H), 5.70~5.95 (m, 1H), 5.30~5.10 (m, 2H), 4.13~4.00 (m, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 167.4, 148.0, 134.2, 131.7, 127.9, 127.0, 116.3, 42.3, 28.6, 15.2. HRMS-ESI calcd for C12H14INO [M+H]+ 190.1232, found 190.1225.

    5-(Iodomethyl)-2-(4-ethylphenyl)-4, 5-dihydrooxazole (2p): Obtained as an white solid in 83.7% yield (131.9 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 104~106 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.84 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 4.83~4.73 (m, 1H), 4.15 (dd, J=15.2, 9.6 Hz, 1H), 3.78 (dd, J=15.2, 6.4 Hz, 1H), 3.37 (dd, J=10.4, 4.8 Hz, 1H), 3.30 (dd, J=10.0, 7.2 Hz, 1H), 2.68 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.5, 148.1, 128.2, 127.9, 124.8, 78.1, 60.7, 28.8, 15.3, 7.8. HRMS-ESI calcd for C12H14INO [M+H]+ 316.0198, found 316.0190.

    5-(Iodomethyl)-2-(4-chlorophenyl)-4, 5-dihydrooxazole (2q): Obtained as an oil in 86.3% yield (138.7 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 7.85 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 4.83~4.76 (m, 1H), 4.16 (dd, J=15.2, 9.6 Hz, 1H), 3.78 (dd, J=15.6, 6.8 Hz, 1H), 3.36 (dd, J=10.4, 4.8 Hz, 1H), 3.31 (dd, J=10.0, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.6, 137.7, 129.5, 128.7, 125.8, 78.4, 60.7, 7.6. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(3, 5-dimethylphenyl)-4, 5-dihydrooxa-zole (2r): Obtained as an oil in 84.6% yield (133.3 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 7.55 (s, 2H), 7.11 (s, 1H), 4.80~75 (m, 1H), 4.15 (dd, J=15.2, 9.6 Hz, 1H), 3.78 (dd, J=15.2, 6.8 Hz, 1H), 3.37 (dd, J=10.4, 4.8 Hz, 1H), 3.31 (dd, J=10.0, 7.2 Hz, 1H), 2.34 (s, 6H); 13C NMR (100MHz, CDCl3) δ: 163.8, 138.0, 133.2, 127.1, 125.9, 78.1, 60.6, 21.1, 7.8. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(2, 4, 6-trimethylphenyl)-4, 5-dihydroox-azole (2s): Obtained as an oil in 94.5% yield (155.5 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 104~106 ℃; 1H NMR (400 MHz, CDCl3) δ: 6.86 (s, 2H), 4.81~4.76 (m, 1H), 4.20 (dd, J=15.2, 9.6 Hz, 1H), 3.85 (dd, J=15.2, 7.2 Hz, 1H), 3.41 (dd, J=10.4, 5.2 Hz, 1H), 3.32 (dd, J=10.0, 7.2 Hz, 1H), 2.31 (s, 6H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.8, 139.3, 136.9, 128.2, 125.4, 77.9, 60.7, 21.1, 19.8, 7.5. HRMS-ESI calcd for C13H16INO [M+H]+ 330.0355, found 330.0350.

    5-(Iodomethyl)-2-(1, 1'-biphenyl)-4, 5-dihydrooxazole (2t): Obtained as a white solid in 98.8 % yield (179.4 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). m.p. 107~109 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.01 (d, J=8.4 Hz, 2H), 7.67~7.62 (m, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.39 (t, J=7.2 Hz, 1H), 4.88~4.81 (m, 1H), 4.21 (dd, J=15.2, 9.6 Hz, 1H), 3.84 (dd, J=15.2, 6.4 Hz, 1H), 3.41 (dd, J=10.4, 4.8 Hz, 1H), 3.35 (dd, J=10.0, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 163.4, 144.2, 140.1, 128.9, 128.6, 127.9, 127.2, 127.0, 126.2, 60.8, 7.7. HRMS-ESI calcd for C16H14INO [M+H]+ 364.0198, found 364.0197.

    5-(Iodomethyl)-2-(thiophen-2-yl)-4, 5-dihydrooxazole (2u): Obtained as a white solid in 84.6% yield (123.6 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 100~102 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, J=3.6 Hz, 1H), 7.47 (dd, J=5.2, 1.2 Hz, 1H), 7.09 (dd, J=4.8, 4.0 Hz, 1H), 4.84~4.80 (m, 1H), 4.17 (dd, J=15.2, 9.6 Hz, 1H), 3.79 (dd, J=15.2, 6.4 Hz, 1H), 3.39 (dd, J=10.4, 4.8 Hz, 1H), 3.31 (dd, J=10.0, 7.2 Hz, 1H); 13C NMR (100MHz, CDCl3) δ: 159.0, 130.3, 129.9, 129.8, 127.4, 78.5, 60.6, 7.4. Spectral data are in good agreement with literature values.[24-45]

    5-(Iodomethyl)-2-(pyridine-4-yl)-4, 5-dihydrooxazole (2v): Obtained as a white solid in 55.8% yield (80.4 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 103~104 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.73 (d, J=6.0 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 4.89~4.80 (m, 1H), 4.22 (dd, J=15.7, 9.6 Hz, 1H), 3.84 (dd, J=15.7, 6.8 Hz, 1H), 3.42~3.32 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 161.7, 150.2, 134.6, 121.7, 78.4, 60.8, 7.3. Spectral data are in good agreement with literature values.[24-45]

    1, 4-Bis(5-(iodomethyl)-4, 5-dihydrooxazol-2-yl)benzene (2w): Obtained as a white solid in 58.1% yield (144.1 mg) after flash chromatography (Silica gel, petroleum ether/ ethyl acetate, V:V=3:1). m.p. 189~191 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.98 (s, 4H), 4.86~4.81 (m, 2H), 4.21 (dd, J=15.2, 9.6 Hz, 2H), 3.83 (dd, J=15.7, 6.8 H, 2Hz), 3.40 (dd, J=10.4, 4.8 Hz, 2H), 3.34 (dd, J=10.0, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 162.8, 130.1, 128.2, 78.4, 60.8, 7.5. HRMS-ESI calcd for C14H14I2N2O2, 496.9223 [M+H]+ found 496.9197.

    5-(Azidomethyl)-2-(p-tolyl)-4, 5-dihydrooxazole (3a): Obtained as an oil in 93.2% yield (100.8 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 7.83 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.88~4.83 (m, 1H), 4.11 (dd, J=14.8, 10.0 Hz, 1H), 3.78 (dd, J=14.8, 10.0 Hz, 1H), 3.38~3.46 (m, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.7, 141.9, 129.0, 128.1, 124.4, 78.0, 57.6, 53.9, 21.5. HRMS-ESI calcd for C11H12N4O [M+H]+ 217.1089, found 217.1081.

    5-(((4-Methoxyphenyl)thio)methyl)-2-(p-tolyl)-4, 5-dihydrooxazole (3b): Obtained as an oil in 84.6% yield (132.6 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). 1H NMR (400 MHz, CDCl3) δ: 7.74 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.18 (d, J=7.7 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.80~4.73 (m, 1H), 4.12 (dd, J=15.2, 9.6 Hz, 1H), 3.84 (dd, J=15.2, 6.8 Hz, 1H), 3.79 (s, 3H), 3.20 (dd, J=13.7, 5.5 Hz, 1H), 2.96 (dd, J=13.7, 7.2 Hz, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.8, 159.4, 141.7, 134.1, 129.0, 128.1, 125.0, 124.8, 114.7, 78.3, 59.5, 55.3, 40.3, 21.5. HRMS-ESI calcd for C18H19NO2S [M+H]+ 314.1215, found 314.1207.

    5-(Bromomethyl)-2-(p-tolyl)-4, 5-dihydrooxazole (4a): Obtained as a white solid in 73.1% yield (103.3 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=4:1). m.p. 86~88 ℃; 1H NMR (400 MHz, CDCl3 ) δ: 7.82 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 4.97~4.86 (m, 1H), 4.18 (dd, J=15.2, 9.6 Hz, 1H), 3.90 (dd, J=15.2, 6.8 Hz, 1H), 3.55 (dd, J=10.8, 5.2 Hz, 1H), 3.49 (dd, J=10.8, 6.4 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.7, 141.9, 129.1, 128.1, 124.5, 77.8, 59.3, 33.7, 21.6. Spectral data are in good agreement with literature values.[24-45]

    5-(Chloromethyl)-2-(p-tolyl)-4, 5-dihydrooxazole (4b): Obtained as a white solid in 58.1% yield (117.0 mg) after flash chromatography (Silica gel, petroleum ether/ethyl acetate, V:V=3:1). m.p. 65~67 ℃; 1H NMR (400 MHz, Chloroform-d) δ: 7.95 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 5.64~5.57 (m, 1H), 4.13~4.04 (m, 2H), 3.87 (dd, J=12.0, 4.4 Hz, 1H), 3.80 (dd, J=12.0, 4.0 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 165.3, 144.4, 129.9, 129.2, 126.3, 74.6, 70.0, 43.5, 21.7. Spectral data are similar with literature values.[24-45]

    Supporting Information  NMR and HRMS spectra of new compounds 1e, 2e, 1j, 2j, 1k, 2k, 1p, 2p, 1s, 2s, 1t, 2t, 1w, 2w, 3a and 3b. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.


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  • Scheme 1  Derivatization of oxazoline 2d

    Scheme 2  Synthesis of 5-chloro- and 5-bromo-methyl-2-aryl- 4, 5-dihydrooxazolines

    Scheme 3  Plausible mechanism for intramolecular halooxygenation reaction

    Table 1.  Reaction optimization studies

    Entry KI/ equiv. Oxone/ equiv. CH3CN/ mL H2O/ mL Temp/℃ Time/h Yielda/%
    1 2.5 1 1 0.5 25 6 21.9
    2 5.0 2 1 0.5 25 6 29.6
    3 7.5 3 1 0.5 25 6 29.3
    4 10.0 4 1 0.5 25 6 30.8
    5 5.0 2 1 0.5 25 2 45.8
    6 5.0 2 1 0.5 25 4 51.7
    7 5.0 2 1 0.5 25 6 29.8
    8 5.0 2 1 0.5 25 8 23.1
    9 5.0 2 1 0.5 -20 4 36.3
    10 5.0 2 1 0.5 0 4 80.9
    11 5.0 2 1 0.5 50 4 48.9
    12 5.0 2 1 1.0 0 4 88.0
    13 5.0 2 0.5 1.0 0 4 56.8
    a Isolated yield.
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  • 发布日期:  2020-12-25
  • 收稿日期:  2020-05-29
  • 修回日期:  2020-07-02
  • 网络出版日期:  2020-07-22
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