The Construction of C–N, C–O, and C(sp2)–C(sp3) Bonds from

Jun 5, 2018 - Selvakumar(21a,d) and Shen(21f) developed C(sp2)–C(sp3) cross coupling ... para to benzoxazolyl group could undertake SNAr conversion...
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Article Cite This: J. Org. Chem. 2018, 83, 6363−6372

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The Construction of C−N, C−O, and C(sp2)−C(sp3) Bonds from Fluorine-Substituted 2‑Aryl Benzazoles for Direct Synthesis of N‑, O‑, C‑Functionalized 2-Aryl Benzazole Derivatives Quan Zhou, Xi Hong, He-Zhen Cui, Shuang Huang, Ying Yi, and Xiu-Feng Hou* Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China

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S Supporting Information *

ABSTRACT: Herein, a general and practical route to 2-(2aminophenyl)- and 2-(2-alkoxyphenyl)-substituted benzazoles by nucleophilic aromatic substitution (SNAr) is described. Upon treatment with Cs2CO3, the formation of C−N, C−O bonds occur between fluorine-substituted 2-aryl benzazoles and a diverse range of nitrogen, oxygen nucleophiles to provide the targets in good to excellent yields. Commercially available nucleophiles and high atom economy are notable features of the protocol. Meanwhile, the construction of C(sp2)−C(sp3) bond was also furnished in the presence of palladium catalyst.

1. INTRODUCTION 2-Aryl benzazoles, an important structural motif for medicinal chemistry, have been applied for the therapeutical agents for Alzheimer’s disease1 and have potential applications in fluorescent materials or light-activated catalysts.2 [11C]-2-(4(Methylamino)phenyl)-6-hydroxybenzothiazol (PIB)3 was the most extensively studied positron emission tomography radiolabeled imaging agent for Alzheimer’s disease β-amyloid plaques. Furthermore, 2-(2-aminophenyl)-benzoxazoles derivatives are special bidenated ligands for anion/cation fluorescence chemosensors as well as solid-state luminescent dyes.4 Up to now, extensive reports mainly focused on transition metal catalyzed ortho C−H activation and functionalization, for example, arylation,5 acylation,6 hydroxylation,7 fluorination,8 olefination.9 The construction of C−N/C−O bond for benzoxazoles is rare. Chang10 reported an efficient Ir(III)/ Ag(I) catalytic system for C−H activation and amination of 2aryl benzoxazole with sulfonyl azides. Yao11 provided a copper catalyzed formation of 2-(2-aminophenyl)-benzoxazoles, which utilized diiodosubstituted N-phenyl benzamide as substrates. Sequentially, similar halogen substituted N-phenyl benzamide was also disclosed by Han12 (Scheme 1). However, these protocols require loading high amounts of metal catalysts and/ or multihalogen substituted starting material. We speculated that the formation of C−N bond for benzazoles may be furnished via SNAr strategy. First, an abnormal product B always accompanies with the aerobic oxidative cyclization for A in our previous studies (Scheme 1),13 which is probably associated with intramolecular nucleophilic attack from phenol anion to fluorine atom at the aldehyde ring. Second, benzimidazole-activated phenyl moieties SNAr reaction was found in several special cases.14 Considering the importance of N-, O-, C-functionalized 2aryl benzazoles, we reported a practical and high atom economy © 2018 American Chemical Society

Scheme 1. Transformations Involving 2-Aryl Benzazoles C− N Construction

protocol to obtain 2-(2-aminophenyl)-benzazoles and 2-(2alkoxyphenyl)-benzazoles by nucleophilic aromatic substitution of fluorine-substituted 2-aryl benzazoles. Meanwhile, two C(sp3)-functional 2-aryl benzazole derivatives were also afforded in the presence of palladium (Scheme 1). Received: March 5, 2018 Published: June 5, 2018 6363

DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372

Article

The Journal of Organic Chemistry Table 2. Scope of Nitrogen Nucleophilesa

2. RESULTS AND DISCUSSION Initially, as the imidazole was frequently found as fragment of organic light emitting diodes15 and artificial pharmaceuticals,16 we attempted to anchor it on benzoxazole fragment. However, the reported protocol is not quite efficient enough to synthesize the target molecules.11 We took a primary test between 1a and imidazole (Table 1, entry 1). To our delight, 3a was obtained in Table 1. Optimization of Reaction Conditionsa

entry

substrate

base

solvent (temp.)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13

1a 1b 1c 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a

Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 Cs2CO3 NaOH TEA Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

DMF (120) DMF (120) DMF (120) DMF (120) DMF (120) DMF (120) DMF (120) DMSO (120) Toluene (120) 1,4-Dioxane (100) THF (60) CH3CN (80) MeOH (60)

95 N.R. N.R. 70c 60d N.R. N.R. 60 N.R. 21 N.R. 71 N.R.

a

a

Standard condition: 1a (0.5 mmol), NuH (0.75 mmol, 1.5 equiv), solvent (3 mL), Cs2CO3 (1 mmol, 2.0 equiv). b10 mmol scale. c0.3 mmol.

95% isolated yield. Then bromo-, chloro-substituted substrates were tested to scrutinize element effect.17 (see Table 1, entries 2−3). Examination showed that chloro-, bromo-substituted 2aryl benzoxazoles (1b, 1c) did not convert into 3a with the imidazole. This observation is important with respect to the conversion mechanism, which is consistent with a typical nucleophilic aromatic substitution (SNAr) where the leaving ability of halogen commonly bear a clear trend (F ≫ Cl > Br).18 Further optimization studies showed that Cs2CO3 is crucial for this reaction, while other bases, like K2CO3, NaOH or triethylamine (TEA), would result in significant decrease in reaction efficiency and conversion. Different solvents were also evaluated (Table 1, entries 8−13), MeOH, toluene, 1,4dioxane, THF did not give satisfactory yields, which might be due to their poor solubility of Cs2CO3 and/or imidazole, polar aprotic solvent, CH3CN, DMSO, comparatively, could also express moderate conversion, however not better than DMF. With the encouraging result of the reaction, the scope of nitrogen nucleophiles was explored (Table 2). First, we tested benzo[d]imidazole, 1,2,4-triazole, pyrazole and halogen substituted pyrazole derivatives, luckily all forging the desired products albeit with quantitative isolated yields under optimal condition. Notable, halogen substituted azoles were well tolerated (3e, 86%; 3f, 83%). To further test the facility of this reaction, a gram-scale reaction of 3a was conducted. Pleasingly, no apparent yield decrease was observed; worthy to note, no gel chromatography was necessary for the gram-scale purification, only by simple extraction and crystallization, which would result in good purity. Then the anilines with electronwithdrawing groups or electron-donating groups were tested.

However, all of them (2a, 2b, 2c) did not totally convert into the corresponding products under standard condition. Attempts to make modifications, such as changing other aprotic solvent (DMSO), bases (NaH, K2CO3 or NaOH), have all proven ineffectual. After all, we turned our attention to alkyl amine. To our delight, not only primary (3h, 3i), but also secondary amine (3j) present to be good nucleophiles. However, diisopropylamine (2d) with large steric hindrance was proved not feasible to undertake the SNAr reaction, which was inconsistent with the previous reports.19 Furthermore, cycloalkyl amine could fuse with 1a albeit with moderate to excellent isolated yields, for example pyrrolidine (3k, 80%), piperidine (3l, 86%), morpholine (3m, 91%), azetidine (3n, 43%). After the C−N bond construction with first and second amines, we focused our attention to C−O bond construction as shown in Table 3. Initially, various kinds of oxygen nucleophiles were checked with the 1a under the standard condition, for example, alkyl alcohol, phenol and acid. To our surprised, phenols with steric bulky group at para or ortho position are both good nucleophilics (4ap, 91%; 4ao, 89%), while phenols with halogen at para, meta or ortho position have distinct difference: the para, meta iodo-substitued phenols could be smoothly converted into the desired products (4bp, 91%; 4bm, 81%), however, the conversion of ortho-iodophenol (2e) was not observed. Furthmore, considering the heterocyclic aromatic rings in term of medical chemistry, we tried to fuse the pyridine or quinoline into the 2-aryl benzoxazoles. Under the optimized condition, pyridin-4-ol, pyridin-3-ol and quinolin-6-ol were successfully converted into the desire products in good yields (4cp, 61%; 4cm, 70%; 4d, 69%,); unfortunately, pyridin-2-ol (2f), quinolin-8-ol (2g) were demonstrated not available

Standard condition: substrate (0.5 mmol), imidazole (0.75 mmol, 1.5 equiv), solvent (3 mL), base (1 mmol, 2.0 equiv), 12 h. bIsolated yield. c 24 h. d3 h.

6364

DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372

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The Journal of Organic Chemistry Table 3. Scope of Oxygen Nucleophilesa

Scheme 2. Construction of C(sp2)−C(sp3) Bond Catalyzed by Palladium

frequently used SNAr C−C bond construction, C(sp2)− C(sp),20 C(sp2)−C(sp3)21 formation have been reported as protocols to access various substrates. Selvakumar21a,d and Shen21f developed C(sp2)−C(sp3) cross coupling methodologies under strong base (NaH, NaHMDS). So, we followed these methods; however, no desired product was forged. We rationalized that additional transition metal would stabilize in situ generated carbon anion by the metal−carbon interaction, which might facilitate the conversion.22 Actually, the 5 mol % Pd(PPh3)4 addition into reaction (5a, 52%) could achieve moderate yield. Comparable experiment showed that bromide substrate (1b) instead of fluoride substrate could not have any trace of desired product, which indicated the SNAr effect assisted C−C bond formation. In the same way, the para fluoride substrate could also take use of the strategy en route to the desired C(sp2)−C(sp3) cross coupling product. Furthermore, taking into account the fact that aryl terminal alkyne proton owns higher pKa value than methyl 2-cyanoacetate C(sp3)−H bond, it would more likely undertake deprotonation under the basic situation and trap by the palladium precursor, However, some tries have proven ineffectual (see the SI for details). Interestingly, the C(sp3)−H chemical shift of orthosubstituted product 5a (7.00 ppm) moved to lower field compared to that of para-substituted product 5b (4.83 ppm). This is similarly observed in our previous study.9 Such significant difference is likely due to shielding field and hydrogen bonding resulted from benzoxazole ring. After exploring the scope of O-, N- C-nucleophiles, we turned our attention on the scope of 2-aryl benzazoles (Table 4). First, we evaluate whether fluorine atom located meta, para to benzoxazolyl group could undertake SNAr conversion. As expectation, para substrate (1d) worked well (3o, 90%; 3p, 84%), the desired SNAr products had the similar good yield with 1a, while meta substrate (1e) was exclusively not reactive and owned good starting material recycle, which is coincident with other electron-withdrawing groups directed SNAr reaction.17 Furthermore, two kinds of important benzoxazoles derivatives, benzo[d]thiazole (1f), benzo[d]imidazole (1g), were also screened, which demonstrated their feasibility of utilizing this strategy for easy access to N-, O-derivatives at ortho and para position (3q, 90%; 4t, 78%; 3r, 85%). Lastly, we designed and screened two special substrates to evaluate the electronic effect on the benzoxazole fragment (1h, 1i), which demonstrated that neither electron-withdrawing nor electrondonating group on benzo[d]oxazole ring would affect the SNAr efficiency of this reaction, both smoothly converted into substituted products (3s, 94%; 3t, 90%; 3u, 94%). Interesting, 3u was generated and fused with two imidazole molecules, one imidazole molecule was fused the standard C−F bond, while another is, determined by 19F NMR spectra, the C−F bond

a

Standard condition: 1a (0.5 mmol), 2 (0.75 mmol, 1.5 equiv), solvent (3 mL), Cs2CO3 (1 mmol, 2.0 equiv). b2 (0.25 mmol).

nucleophiles. Moreover, phenols containing late-stage functionalization functional groups were also tested, for example, aldehyde- and acetyl-containing phenols, which could bear good tolerance to this condition and afforded the corresponding products in excellent yields (4e, 93%; 4f, 78%). However, their positional isomers, 2-hydroxybenzaldehyde (2h) and 1-(2hydroxyphenyl)ethan-1-one (2i) failed to convert into the desired products. The failed reactions (2e−2i) were possibly due to the presence of the intramolecular hydrogen bond between the hydroxyl and adjacent electron-withdrawing groups. When hydroquinone worked as nucleophile, double C−O bonds were formed en route to a symmetric molecule with good yield (4g, 86%). In addition, different benzyl alcohols (BnOHs) worked well, too. The BnOHs could range from heteroaromatic rings (4h, 90%; 4i, 95%) to benzyl ring with substitution at ortho-(4l, 65%), meta-(4m, 76%), para-(4n, 75%; 4o, 79%; 4p, 77%). The halogen atoms affiliated on the nucleophile are well tolerated under such conversion and useful for future transformation. Steric bulky alcohols have a slight negative effect on this reaction, which could be observed by the comparison between 4j (81%) and 4k (78%). More significant steric effect could be learned from 4q (45%) and 4r (93%), which was derived from large steric tetra-butyl alcohol and nhexanol. Lastly, we tried to take usage of benzyl acid as the oxygen nucleophile. However, neither benzoate sodium nor benzoic acid (2j) could work as the oxygen nucleophile for SNAr transformation. After the C−O, C−N bond construction, we addressed on C−C bond construction (Scheme 2). As the most two 6365

DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372

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The Journal of Organic Chemistry Table 4. Scope of 2-Aryl Benzazolesa

delocalization and stabilization of the bielectronic species in zwitterionic intermediate. (Scheme 3, D, benzOxa-Nu).18,24

3. CONCLUSIONS In summary, benzazolyl groups were discovered to facilitate SNAr reaction for C−O, C−N construction upon simple deprotonation of N- or O-nucleophiles. Available nucleophiles could range from azoles (benzo[d]imidazole, imidazole, triazole, pyrazole derivatives), alkyl amines (primary and secondary amines), alcohols to phenols. The facile protocol presents good functional group tolerance for the nucleophiles, especially to acetyl, aldehyde, halogen, which provides a versatile platform for further transformation. Moreover, C(sp2)−C(sp3) bond was also constructed in the presence of palladium catalyst. Worthy to note, the new benzoazolesimidazole backbones could be used as bidentate ligands in coordination chemistry, an avenue that we will pursue in future work. 4. EXPERIMENTAL SECTION All commercially available compounds were purchased and used without purification. Reaction temperatures are reported as the temperature of the bath surrounding the reaction bottle unless otherwise stated. Toluene, xylene (mixture of o, m, p-xylene), N,Ndimethyl formaldehyde (DMF), ethanol, were purchased and used without purification. Dry THF and dry DMF were purchased and used under Schlenk line. Analytical thin layer chromatography was performed on GF 254 plates. Flash Chromatography was performed on silica gel (200−300 mesh) by standard technical eluting with solvents as indicated. 1H and 13 C NMR were recorded at 295 K in CDCl3 or DMSO-d6; The residual solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm; DMSO-d6: δH = 2.50 ppm, δC = 39.52 ppm). For 19F NMR, chemical shifts refer to an external calibration using CFCl3 (δ = 0.00 ppm). Data for 1H NMR are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, dd = double doublet, m = multiplet), coupling constants (J) in Hz and integration. Mass spectrometric data were obtained using ESI (electrospray ionization, Q-Tof, positive ion) mode. Melting points (mp) of the reported values are tested in capillary auxiliary. Infrared spectra were recorded on a Nicolet 8700 Fourier Transform Infrared Spectrometer (FT-IR), and were reported in wave numbers (cm−1). Substrates (1b,13 1c,13 1d,13 1e13 1g,13 1i,9 1j,25 1k23) were synthesized according to reported references. 1a was synthesized according to the according procedures13 on 10 mmol scale. Into a 50 mL round-bottom flask were added 5-methyl-2amino phenol (2.463g, 20 mmol) and 2-fluorobenzaldehyde (2.482g, 20 mmol), xylene (30 mL; mixture of o, m, p-xylene), the mixture was allowed into preheated 120 °C oil-bath, stirred for half an hour, then 1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide (0.5 mmol, 136 mg) and NaOH (2 mmol, 80 mg) were added into the reaction bottle, continued to stir for 12 h under oxygen gas. After reaction, the mixture was diluted with ethyl acetate, filtrated, the solution was concentrated under vacuum, and the residue was applied on silica gel column chromatography (PE/EA: 50/1), which afforded the corresponding oxidative cyclization product 1a as light yellow solid (3.5 g, 77%). Characterization Data of Newly Synthesized Substrates. 2(2-Fluorophenyl)benzo[d]thiazole (1f).26 Title compound was synthesized by the same protocol for 1a on 10 mmol scale, which afforded yellow solid 1.7 g (74%); mp 67.4−67.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.46 (td, J = 7.7, 1.7 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.57−7.52 (m, 1H), 7.47 (ddt, J = 18.3, 15.2, 4.8 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.30−7.20 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 161.2, 160.6 (d, J = 253.5 Hz), 152.5, 135.8 (d, J = 8.0 Hz), 132.2 (d, J = 8.6 Hz), 129.8, 126.4, 125.4, 124.8, 124.7, 123.4, 121.5, 116.6, 116.3; 19F NMR (376 MHz, CDCl3) δ

a Standard condition: 1 (0.5 mmol), NuH (0.75 mmol, 1.5 equiv), solvent (3 mL), Cs2CO3 (1 mmol, 2.0 equiv), 12 h. b10 mmol scale. c 1i (0.2 mmol), NuH (0.6 mmol, 3 equiv), Cs2CO3 (0.8 mmol, 4 equiv).

ortho to oxygen atom of benzoxazole fragment (see Supporting Information). After all, we want to shed some light on the reaction mechanism. First, 2-(2-fluorophenyl)-4-methyl-oxazoline (1j) was tested (Scheme 3, A); however, no conversion was Scheme 3. Mechanism Studies and Proposal

observed, which demonstrated the importance of benzazoles for this SNAr conversion. Second 2-(2-fluorophenyl)pyridine,23 was synthesized and addressed whether undertake the SNAr reaction with nucleophiles. Various nucleophiles were tested (Scheme 3, B); however, we failed to observe more than trace amounts of the desired substituted products. Compared to benzazoles, pyridinyl- owns sole electron-withdrawing nitrogen in the aromatic ring. We wondered whether one more nitrogen atom on the aromatic ring could furnish this conversion. Luckily, 2-(2-fluorophenyl)pyrimidine (1l) could give 20% conversion under the optimized condition (Scheme 3, C). Above all, we speculated the excellent SNAr mainly benefit from the conjugation system and extra heteroatom (X) of 2-aryl benzazoles, which may provide enough space for electron 6366

DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372

Article

The Journal of Organic Chemistry −111.84 (tt, J = 11.1, 7.2 Hz); IR (neat/cm−1) 3061, 1620, 1581, 1504, 1453, 1437, 1312, 1280, 1203, 1101, 796, 966, 765, 729, 694, 653, 544, 457; HRMS (ESI) calcd for C13H9FNS+ [M + H+] 230.0434 , found 230.0432. Worthy to note, no benzo[b,f ][1,4]thiazepine was isolated from this reaction. 5-(tert-Butyl)-2-(2-fluorophenyl)benzo[d]oxazole (1h). Into a 50 mL round-bottom flask were added 4-tert-butyl-2-amino-phenol (10 mmol, 2.69 g) and 2-fluorobenzaldehyde (10 mmol, 1.24 g), xylene (15 mL; mixture of o, m, p-xylene), the mixture were lowered into preheated 120 °C oil-bath, stirred for half an hour, monitored by TLC, when the aldehyde point was disappeared, then 1-butyl-3-methyl-1Himidazol-3-ium iodide (1 mmol, 266 mg, 10% equiv) and K2CO3 (2 mmol, 276 mg, 20% equiv) were added into the reaction bottle, continued to stir for 12 h under oxygen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure to remove the versatile solution, the residue was applied on silica gel chromatography (PE/EA: 100/1), which afforded the desired product 1h as light yellow oil (1.5 g, 57% yield)]. Rf = 0.8 (PE/EA = 10:1); mp 29.5−30.3 °C; 1H NMR (500 MHz, CDCl3) δ 8.27−8.21 (m, 1H), 7.89 (t, J = 2.5 Hz, 1H), 7.53 (dt, J = 6.7, 5.1 Hz, 2H), 7.47 (dd, J = 8.6, 1.9 Hz, 1H), 7.37−7.30 (m, 1H), 7.28 (d, J = 8.7 Hz, 1H), 1.42 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 160.8 (d, J = 258.8 Hz), 159.5, 159.5, 148.5, 148.3, 141.7, 132.9 (d, J = 8.6 Hz), 130.4 (d, J = 1.3 Hz), 124.5 (d, J = 3.8 Hz), 123.3, 117.1 (d, J = 21.5 Hz), 116.9, 115.7 (d, J = 10.4 Hz), 109.8, 35.0, 31.8; 19F NMR (471 MHz, CDCl3) δ −110.19 (d, J = 6.1 Hz); IR (neat/cm−1) 3077, 2962, 2907, 2869, 1623, 1613, 1588, 1546, 1482, 1460, 1341, 1274, 1223, 1203, 1111, 1024, 874, 829, 803, 777, 749, 704, 659; HRMS (ESI) calcd for C17H17FNO [M + H+] 270.1289, found 270.1291. 2-(2-Fluorophenyl)pyrimidine (1l). A suspension of 2-bromopyrimidine (1 mmol, 157 mg, 1.0 equiv) and (2-fluorophenyl)boronic acid (1.1 mmol, 154 mg, 1.1 equiv), Pd(PPh3)4 (0.05 mmol, 57 mg, 5 mol %), Na2CO3 (2 mmol, 210 mg, 2.0 equiv), EtOH (3 mL), deionic water (3 mL), N,N-dimethylacetamide (5 mL) was stirred at 120 °C under nitrogen in a sealed Shlenck tube for 18 h. After finished, the mixture was extracted with ethyl acetate (5 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified through Silica gel chromatography (PE/EA = 10/1), which afforded the desired product 1l in colorless oil (150 mg, 86%); 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.9 Hz, 2H), 7.99 (td, J = 7.8, 1.7 Hz, 1H), 7.44−7.31 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −115.53 to −115.68 (m); 13C NMR (101 MHz, CDCl3) δ 163.3, 161.0 (d, J = 255.0 Hz), 157.2 (2), 131.8 (2), 126.3(d, J = 9.4 Hz), 124.1, 116.8 (d, J = 22.5 Hz); IR (neat/cm−1) 3045, 2968, 1620, 1588, 1572, 1498, 1456, 1424, 1248, 1232, 1216, 1120, 1037, 838, 819, 768, 637; HRMS (ESI) calcd for C10H8FN2 [M + H+] 175.0666, found 175.0665. General Protocol for the Construction of C−N Bond. General Procedure I. Into a glass tube were added substrate 1a (0.5 mmol, 112 mg), Cs2CO3 (326 mg, 1 mmol, 2.0 equiv), nitrogen nucleophiles (0.75 mmol), DMF (3 mL), sealed by rubber stopper. The glass tube was stirred under preheated 120 °C oil bath for 12 h. After finished, the reaction solution was diluted by NH4Cl solution (20 mL), extracted by ethyl acetate (EA) (3 × 10 mL), combined the organic phase, washed by brine (2 × 10 mL), dried by anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was applied on silica gel chromatography. General Procedure II. According to procedure I, the residue was set overnight at ∼10 °C, until no more solid grew out. Then the supernatant was decanted, the precipitate was washed three times with PE/EA (10/1) mixture, and the resulting product was dried under vacuum. 2-(2-(1H-Imidazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3a). According to the general procedure II, which afforded 3a in a yellow solid (131 mg, 95%); while 10 mmol scale forge 3a abeit with 92% yield. Rf = 0.3 (PE/EA = 1:1) or = 0.1 (DCM/MeOH = 50:1); mp 51.7−53.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.52 (t, J = 6.4 Hz, 2H), 7.40 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.08 (s, 1H), 7. 03 (d, J = 8.3

Hz, 1H), 6.95 (s, 1H), 2.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.2, 149.0, 141.6, 137.9, 136.2, 134.7, 132.0, 131.4, 129.5, 129.1, 128.0, 126.9, 124.3, 120.8, 120.2, 110.2, 21.5; IR (neat/cm−1) 3109, 2962, 2923, 2853, 1601, 1585, 1504, 1267, 1203, 1111, 1066, 1034, 803, 774, 662, 598; HRMS (ESI) calcd for C17H14N3O [M + H+] 276.1131, found 276.1151. 2-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3b). According to the general procedure II, which afforded 3b in yellow solid (156 mg, 96%); Rf = 0.2 (DCM/MeOH = 50:1); mp 134.3−137.4 °C;1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 7.3, 2.1 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.72−7.63 (m, 2H), 7.54 (dd, J = 7.2, 1.8 Hz, 1H), 7.37 (s, 1H), 7.26 (td, J = 8.1, 1.2 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 2.37 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.0, 148.8, 143.7, 143.5, 141.5, 135.2, 134.6, 134.5, 132.2, 131.6, 129.5, 129.1, 126.9, 125.2, 123.6, 122.5, 120.3, 120.2, 109.98, 109.95, 21.4; IR (neat/cm−1) 3106, 3051, 2955, 2923, 1617, 1604, 1578, 1556, 1504, 1488, 1456, 1309, 1293, 1235, 1194, 1040, 813, 790, 777, 742, 704; HRMS (ESI) calcd for C21H16N3O [M + H+] 326.1288, found 326.1297. 2-(2-(1H-1,2,4-Triazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3c). According to the general procedure I, which afforded 3c in white solid (123 mg, 89%); Rf = 0.45 (DCM/MeOH= 50:1); mp 117.1− 118.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.30 (dd, J = 5.9, 3.4 Hz, 1H), 8.11 (s, 1H), 7.71−7.61 (m, 2H), 7.58 (dd, J = 5.8, 3.3 Hz, 1H), 7.47 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.7, 152.3, 148.9, 144.9, 141.7, 135.7, 134.7, 131.9, 131.1, 130.0, 128.0, 127.0, 124.1, 120.4, 110.1, 21.5; IR (neat/cm−1) 3132, 2917, 2850, 1510, 1453,1283, 1203, 1139, 1069, 1035, 979, 960, 867, 808, 772, 751, 697; HRMS (ESI) calcd for C16H13N4O [M + H+] 277.1084, found 277.1083. 2-(2-(1H-Pyrazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3d). According to the general procedure I, which afforded 3d in colorless oil (124 mg, 90%); Rf = 0.1 (DCM/MeOH = 50:1); 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.6 Hz, 1H), 7.68−7.48 (m, 6H), 7.21 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.38 (s, 1H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.2, 149.1, 141.8, 141.1, 139.6, 134.3, 131.8, 131.4, 130.9, 128.4, 127.0, 126.6, 123.5, 120.2, 110.1, 107.0, 21.5; IR (neat/cm−1) 3109, 3067, 2920, 2859, 1591, 1521, 1485, 1399, 1335, 1261, 1200, 1111, 1037, 941, 832, 803, 762, 621, 598; HRMS (ESI) calcd for C17H14N3O [M + H+] 276.1131, found 276.1150. 2-(2-(4-Bromo-1H-pyrazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3e). According to the general procedure I, which afforded 3e in yellow solid (152 mg, 86%); Rf = 0.75 (DCM/MeOH= 50:1); mp 103.9−105.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 7.5, 1.4 Hz, 1H), 7.67 (s, 1H), 7.64−7.59 (m, 2H), 7.59−7.50 (m, 3H), 7.27 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.5, 149.0, 141.7, 141.4, 138.8, 134.4, 131.7, 131.3, 131.0, 129.0, 127.0, 126.7, 123.5, 120.2, 110.0, 94.7, 21.4; IR (neat/cm−1) 3128, 3045, 2965, 2927, 2856, 1601, 1562, 1498, 1457, 1389, 1335, 1194, 1037, 960, 803, 768, 704, 611; HRMS (ESI) calcd for C17H13N3BrO [M + H+] 354.0237, found 354.0241. 2-(2-(4-Chloro-1H-pyrazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3f). According to the general procedure I, which afforded 3f in white solid (128 mg, 83%); Rf = 0.85 (DCM/MeOH = 50:1); white solid; mp 189.8−191.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.29 (dd, J = 5.8, 3.4 Hz, 1H), 8.22 (s, 1H), 7.76−7.65 (m, 2H), 7.63− 7.55 (m, 1H), 7.46 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.3, 148.8, 141.8, 137.7, 136.9, 136.6, 134.9, 132.0, 131.2, 131.1, 130.5, 127.8, 127.2, 124.0, 120.6, 110.1, 21.5; IR (neat/cm−1) 3112, 2920, 1537, 1507, 1498, 1483, 1405, 1320, 1280, 1197, 1043, 1002, 819, 805, 766, 754, 704, 598; HRMS (ESI) calcd for C17H13ClN3O [M + H+] 310.0742, found 310.0740. 5-Methyl-2-(2-(4-phenyl-1H-imidazol-1-yl)phenyl)benzo[d]oxazole (3g). According to the general procedure I, which afforded 3g in white solid (145 mg, 80%); Rf = 0.6 (DCM/MeOH= 50:1); mp 81.6−82.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 6.8, 1.3 Hz, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.65 (s, 1H), 7.58 (m, 2H), 7.44 (d, 6367

DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372

Article

The Journal of Organic Chemistry

601; HRMS (ESI) calcd for C19H21N2O [M + H+] 293.1648, found 293.1664. 5-Methyl-2-(2-morpholinophenyl)benzo[d]oxazole (3m). According to the general procedure I, which afforded 3m in yellow oil (133 mg, 91%); Rf = 0.2 (PE/EA = 10:1); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.46 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.12 (m, 2H), 3.88 (s, 4H), 3.04 (s, 4H), 2.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 163.2, 152.0, 148.8, 142.3, 134.4, 132.33, 132.32, 126.3, 122.4, 120.5, 120.1, 118.9, 109.9, 67.0(2), 52.6(2), 21.5; IR (neat/cm−1) 2956, 2920, 2891, 2863, 2818, 1604, 1572,1549, 1489, 1450, 1380, 1338, 1300, 1268, 1223, 1197, 1117, 1037, 935, 925, 800, 762, 710, 601; HRMS (ESI) calcd for C18H19N2O2 [M + H+] 295.1441, found 295.1450. 2-(2-(Azetidin-1-yl)phenyl)-5-methylbenzo[d]oxazole (3n). According to the general procedure I on 0.3 mmol scale, with azetidine hydrochloride (93.5 mg, 1 mmol, 3.3 equiv) as nucleophilic, Cs2CO3 (652 mg,2 mmol, 6.6 equiv) as base, which afforded 3n in white solid (35 mg, 43%). mp 58.1−59.1 °C; Rf = 0.3 (PE/EA = 10:1); 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.37 (t, J = 7.0 Hz, 1H), 7.14 (dd, J = 8.2, 0.8 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 3.86 (t, J = 7.4 Hz, 4H), 2.48 (s, 3H), 2.35−2.21 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 162.7, 151.5, 148.7, 142.4, 134.1, 131.6, 131.4, 125.8, 119.8, 117.8, 114.0, 112.3, 109.8, 54.2(2), 21.6, 16.7; IR (neat/cm−1) 3064, 2997, 2972, 2920, 2863, 1607, 1578, 1549, 1482, 1437, 1351, 1309, 1261, 1197, 1165, 1031, 925, 832, 803, 755, 710, 608; HRMS (ESI) calcd for C17H17N2O [M + H+] 265.1335, found 265.1333. 2-(4-(1H-Imidazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3o). The reaction was conducted as general procedure II, after finished, deionic water (10 mL) was added, then numerous white power precipitate out, than ethyl acetate was used to remove nonconsumed starting material, filtrated, the white solid was washed by PE/EA (1/1; v/v), which afforded 3o in white solid (124 mg, 90%); Rf = 0.05 (DCM/MeOH = 50:1); mp 254.1−255.4 °C; 1H NMR (400 MHz, MeOD) δ 8.36−8.27 (m, 2H), 8.21 (s, 1H), 7.77−7.68 (m, 2H), 7.62 (s, 1H), 7.54−7.48 (m, 2H), 7.25−7.18 (m, 2H), 2.49 (s, 3H); 13C NMR (101 MHz, MeOD) δ 161.6, 148.4, 141.0, 138.9, 134.9, 134.5, 129.1, 128.5(2), 126.2, 125.3, 120.6, 118.7, 117.5 (2), 109.5, 20.1; IR (neat/cm−1) 3087, 2989, 1605, 1542, 1504, 1474, 1452, 1433, 1344, 1308, 1295, 1258, 1187, 1062, 880, 845, 821, 796, 758, 738, 694, 630, 527; HRMS (ESI) calcd for C17H14N3O [M + H+] 276.1131, found 276.1150. 2-(4-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3p). Similar procedure as 3o, addition of large amount deionic water as well as filtration and washed with PE/EA (1/1; v/v, 20 mL), dried under reduced pressure, which afforded 3p in white solid (136 mg, 84%); Rf = 0.1 (DCM/MeOH = 50:1); mp 213.5− 224.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.48−8.41 (m, 2H), 8.20 (s, 1H), 7.94−7.87 (m, 1H), 7.72−7.66 (m, 2H), 7.66−7.60 (m, 1H), 7.59 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.42−7.35 (m, 2H), 7.20 (dd, J = 8.3, 1.1 Hz, 1H), 2.51 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.0, 149.2, 144.4, 142.4, 142.0, 138.9, 134.9 (2), 133.4, 129.4 (2), 126.9, 126.8, 124.2, 124.0, 123.3, 121.0, 120.2, 110.6, 110.2, 21.7; IR (neat/cm−1) 3087, 3055, 3019, 2917, 2862, 1605, 1496, 1476, 1453, 1298, 1280, 1234, 1202, 1063, 842, 807, 779, 735, 696, 578, 526, 427; HRMS (ESI) calcd for C21H16N3O [M + H+] 326.1288, found 326.1298. 2-(2-(1H-Imidazol-1-yl)phenyl)benzo[d]thiazole (3q). According to the general procedure II, which afforded 3q in yellow-brown crystal (124 mg, 90%); Rf = 0.1 (DCM/MeOH = 50:1); mp 85.7−88.1 °C; 1 H NMR (400 MHz, CDCl3) δ 8.23 (dd, J = 6.6, 1.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.76 (dd, J = 7.5, 0.5 Hz, 1H), 7.65−7.53 (m, 3H), 7.46 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 7.41−7.31 (m, 2H), 7.18 (s, 1H), 7.01 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 163.1, 152.8, 137.9, 136.2, 135.6, 131.21, 131.16, 130.8, 130.1, 129.5, 128.0, 126.4, 125.7, 123.6, 121.6, 121.1; IR (neat/cm−1) 3112, 3071, 3061, 2968, 2930, 2846, 1504, 1453, 1428, 1319, 1300, 1287, 1245, 1101, 1043, 970, 957, 909, 765, 749, 736, 662, 624, 544, 464; HRMS (ESI) calcd for C16H12N3S [M + H+] 278.0746, found 278.0768.

J = 8.4 Hz, 2H), 7.39−7.31 (m, 3H), 7.26−7.18 (m, 2H), 7.06 (d, J = 8.3 Hz, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.1, 148.9, 142.3, 141.5, 138.2, 138.1, 135.9, 134.6, 134.0, 131.9, 131.3, 129.1, 128.6, 128.0, 126.9, 125.0, 124.0, 120.3, 120.2, 116.6, 116.5, 110.2, 21.4; IR (neat/cm−1) 3119, 3100, 2917, 1601, 1578, 1556, 1501, 1456, 1338, 1264, 1197, 1123, 1069, 1024, 931, 877, 803, 755, 707; HRMS (ESI) calcd for C23H18N3O [M + H+] 352.1444, found 352.1455. 2-(5-Methylbenzo[d]oxazol-2-yl)-N-propylaniline (3h). According to the general procedure I, which afforded 3h in slight yellow liquid (80 mg, 60%); Rf = 0.85 (PE/EA = 10:1); 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.08 (dd, J = 7.9, 1.1 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.71 (t, J = 7.4 Hz, 1H), 3.33 (dd, J = 12.3, 6.8 Hz, 2H), 2.48 (s, 3H), 1.83 (Sept, J = 7.2 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.6, 148.7, 147.5, 142.2, 134.0, 132.7, 129.1, 125.7, 119.4, 114.9, 111.0, 109.6, 108.2, 45.0, 22.6, 21.6, 12.0; IR (neat/cm−1) 3304, 2962, 2927, 2869, 1607, 1588, 1546, 1530, 1440, 1335, 1319, 1264, 1197, 1165, 1030, 800, 749, 701, 592; HRMS (ESI) calcd for C17H19N2O [M + H+] 267.1492, found 267.1503. N-Benzyl-2-(5-methylbenzo[d]oxazol-2-yl)aniline (3i). According to the general procedure I, which afforded 3i in colorless crystal (115 mg, 73%); Rf = 0.8 (PE/EA = 10:1); mp 77.1−80.4 °C;1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.12 (dd, J = 7.9, 1.4 Hz, 1H), 7.48 (s, 1H), 7.43 (dd, J = 7.8, 3.7 Hz, 3H), 7.36 (t, J = 7.5 Hz, 2H), 7.31−7.26 (m, 2H), 7.14 (dd, J = 8.2, 0.9 Hz, 1H), 6.77−6.68 (m, 2H), 4.64 (d, J = 5.8 Hz, 2H), 2.48 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 163.5, 148.3, 147.5, 142.0, 139.4, 134.2, 132.7, 129.0, 128.8 (2), 127.1, 127.0 (2), 125.8, 119.4, 115.5, 111.6, 109.7, 108.7, 47.2, 21.6; IR (neat/ cm−1) 3304, 3055, 3026, 2968, 2920, 2853, 1623, 1610, 1597, 1527, 1447, 1335, 1261, 1200, 1095, 1030, 925, 800, 736, 697, 464; HRMS (ESI) calcd for C21H19N2O [M + H+] 315.1492, found 315.1501. N-Butyl-N-methyl-2-(5-methylbenzo[d]oxazol-2-yl)aniline (3j). According to the general procedure I, which afforded 3j in light yellow oil (94 mg, 64%); Rf = 0.55 (PE/EA = 10:1); 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 3.00−2.90 (m, 2H), 2.80 (s, 3H), 2.49 (s, 3H), 1.55−1.46 (m, 2H), 1.14 (q, J = 7.4 Hz, 2H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.3, 152.5, 149.0, 142.4, 134.2, 132.6, 131.8, 126.0, 120.3, 120.0, 119.1, 118.9, 110.0, 56.1, 40.4, 29.3, 21.6, 20.6, 13.9; IR (neat/cm−1) 2959, 2930, 2866, 2802, 1604, 1482, 1457, 1264, 1194, 1034, 797, 755, 605; HRMS (ESI) calcd for C19H23N2O [M + H+] 295.180, found 295.1821. 5-Methyl-2-(2-(pyrrolidin-1-yl)phenyl)benzo[d]oxazole (3k). According to the general procedure I, which afforded 3k in yellow oil (111 mg, 80%); Rf = 0.6 (PE/EA = 10:1); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 3.16 (d, J = 5.5 Hz, 4H), 2.49 (s, 3H), 1.87 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 164.6, 148.9, 148.8, 142.5, 134.2, 132.7, 131.6, 125.7, 119.9, 116.8, 114.4, 113.5, 110.0, 51.0 (2), 25.9 (2), 21.5; IR (neat/cm−1) 2965, 2917, 2869, 1604, 1572, 1485, 1450, 1354, 1261, 1191, 1024, 800, 752, 601; HRMS (ESI) calcd for C18H19N2O [M + H+] 279.1492, found 279.1507. 5-Methyl-2-(2-(piperidin-1-yl)phenyl)benzo[d]oxazole (3l). According to the general procedure I, which afforded 3l in yellow oil (125 mg, 86%); Rf = 0.2 (PE/EA = 10:1); 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 3.03−2.88 (m, 4H), 2.50 (s, 4H), 1.71 (d, J = 4.6 Hz, 4H), 1.56 (d, J = 5.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 164.1, 153.3, 149.0, 142.3, 134.1, 132.3, 132.1, 126.0, 121.4, 120.2, 120.0, 118.9, 53.6 (2), 26.1 (2), 24.2, 21.5; IR (neat/ cm−1) 2936, 2853, 2795, 2744, 2706, 2674, 1597, 1572, 1485, 1450, 1386, 1267, 11232, 1200, 1127, 1104, 1034, 925, 829, 803, 761, 710, 6368

DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372

Article

The Journal of Organic Chemistry 2-(4-(1H-Imidazol-1-yl)phenyl)-1-butyl-1H-benzo[d]imidazole (3r). According to the general procedure II, which afforded 3r in colorless crystal needles (134 mg, 85%); Rf = 0.2 (DCM/MeOH = 50:1); mp 67.3−70.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.84 (m, 3H), 7.56 (d, J = 8.0 Hz, 2H), 7.43 (m, 1H), 7.37 (s, 1H), 7.32 (m, 2H), 7.25 (s, 1H), 4.26 (t, J = 7.5 Hz, 2H), 1.88−1.77 (m, 2H), 1.30 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 152.3, 143.2, 138.3, 135.8, 135.5, 131.05 (2), 131.99, 129.96, 123.1, 122.7, 121.4(2), 120.2, 118.0, 110.3, 44.8, 32.0, 20.1, 13.7; IR (neat/cm−1) 3359, 3301, 3119, 3100, 2962, 2875, 1681, 1614, 1543, 1495, 1469, 1425, 1399, 1309, 1261, 1117, 1069, 963, 842, 771, 749, 665, 531; HRMS (ESI) calcd for C20H21N4 [M + H+] 317.1761, found 317.1769. 2-(2-(1H-Imidazol-1-yl)phenyl)-5-(tert-butyl)benzo[d]oxazole (3s). According to the general procedure II on 10 mmol scale, which afforded 3s in slight yellow solid (3g, 94%); Rf = 0.2 (DCM/MeOH = 50:1); mp 49.6−52.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 7.2, 2.1 Hz, 1H), 7.74−7.68 (m, 2H), 7.67−7.59 (m, 2H), 7.46 (dd, J = 7.2, 2.1 Hz, 1H), 7.40 (dd, J = 8.6, 1.8 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.21 (s, 1H), 7.06 (s, 1H), 1.37 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 160.2, 148.9, 148.6, 141.5, 137.9, 136.2, 132.0, 131.5, 129.4, 129.2, 128.2, 124.6, 123.8, 121.1, 117.1, 110.1, 35.1, 31.9 (3); IR (neat/cm−1) 3135, 3119, 2962, 2866, 1588, 1546, 1504, 1488, 1463, 1353, 1364, 1338, 1277, 1242, 1203, 1072, 1069, 1037, 816, 771, 707, 669; HRMS (ESI) calcd for C20H20N3O [M + H+] 318.1601, found 318.1607. 5-(tert-Butyl)-2-(2-morpholinophenyl)benzo[d]oxazole (3t). According to the general procedure I, which afforded 3t in slight yellow liquid (151 mg, 91%); Rf = 0.4 (PE/EA = 10:1); 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 8.1, 1.6 Hz, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.47(dd, 7.8, 1.2 Hz, 1H), 7.43 (dd, J = 7.8, 1.9 Hz, 1H), 7.15−7.10 (m, 2H), 3.97−3.83 (m, 4H), 3.07−3.02 (m, 4H), 1.43 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.3, 152.0, 148.5, 148.0, 142.0, 132.3, 132.2, 122.9, 122.4, 120.5, 118.8, 116.6, 109.6, 67.1, 52.6, 35.0, 31.9; IR (neat/cm−1) 3068, 2968, 2907, 2863, 2818, 1601, 1578, 1546, 1482, 1453, 1271, 1229, 1117, 1037, 931, 925, 774, 717, 659; HRMS (ESI) calcd for C21H25N2O2 [M + H+] 337.1911, found 337.1919. 2-(2-(1H-Imidazol-1-yl)phenyl)-5-fluoro-7-(1H-imidazol-1-yl)benzo[d]oxazole (3u). Into a glass tube were added 5, 7-difluoro-2-(2fluorophenyl)benzo[d]oxazole (50 mg, 0.2 mmol), imidazole (20 mg, 0.6 mmol, 3 equiv), Cs2CO3 (254 mg, 0.8 mmol, 4.0 equiv), DMF (3 mL). The mixture was stirred under 120 °C for 12 h. Then the reaction solution was diluted by saturated NH4Cl aq., extracted by ethyl acetate (3 × 10 mL). The organic phase was collected, washed with brine (5 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure to appear precipitation, and light yellow precipitation increased with the extension of the setting time (∼10 °C). Then the supernatant was decanted, the precipitate was washed three times with PE/EA (5 mL × 2, 10/1, v/v), which afforded the desired product in yellow solid (62 mg, 90% crystallized yield); Rf = 0.05 (DCM/MeOH = 50:1); mp 223.5−225.1 °C; 1H NMR (400 MHz, DMSO) δ 8.33 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.87−7.78 (m, 2H), 7.75 (t, J = 7.6 Hz, 1H), 7.69 (dd, J = 8.1, 2.2 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.16 (s, 1H), 7.09 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 162.7, 160.1 (d, J = 243.8 Hz), 144.1 (d, J = 14.2 Hz), 138.4, 137.9, 136.5, 136.5, 133.2, 131.9, 130.9, 130.3, 129.6, 128.4, 123.2, 122.1 (d, J = 12.2 Hz), 121.0, 118.4, 105.9 (d, J = 29.7 Hz), 105.3 (d, J = 25.6 Hz); 19F NMR (376 MHz, CDCl3) δ −114.0 (dd, J = 9.7, 7.8 Hz); IR (neat/ cm−1) 3141, 3106, 3039, 1642, 1601, 1514, 1434, 1239, 1210, 1149, 1130, 1075, 1027, 995, 835, 765, 653; HRMS (ESI) calcd for C19H13FN5O [M + H+] 346.1099, found 346.1094 2-(2-(1H-Imidazol-1-yl)phenyl)pyrimidine (3v). According to the general procedure I, which afforded 3v in colorless oil (22 mg, 20%). Rf = 0.2 (PE/EA = 1:1); 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.9 Hz, 2H), 7.97−7.89 (m, 1H), 7.46 (s, 1H), 7.44−7.39 (m, 1H), 7.18 (t, J = 4.9 Hz, 1H), 7.04 (s, 1H), 6.93 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 164.8, 157.2 (2), 137.9, 136.0, 135.3, 131.5, 130.6, 128.9, 128.8, 126.9, 120.8, 119.3; IR (neat/cm−1) 2965, 2933, 2862,

1617, 1607, 1575, 1485, 1421, 1267, 1194, 1069; HRMS (ESI) calcd for C13H11N4 [M + H+] 223.0978, found 223.0977. General Protocol for the Construction of C−O Bond. Into a glass tube were added fluoride 2-aryl benzazoles (0.5 mmol), oxygen nucleophiles (0.75 mmol), Cs2CO3 (326 mg, 1 mmol), DMF (3 mL), the mixture was stirred under 120 °C oil bath, after 12 h, the reaction solution was diluted by saturated NH4Cl solution, extracted with ethyl acetate (10 × 3 mL), combined the organic phase, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was applied on silica gel chromatography, which afforded the corresponding the desired product. 2-(2-(4-(tert-Butyl)phenoxy)phenyl)-5-methylbenzo[d]oxazole (4ap). White solid (162 mg, 91%); Rf = 0.8 (PE/EA = 10:1); mp 85.9− 87.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.47−7.39 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.03 (dd, J = 8.6, 2.7 Hz, 3H), 2.47 (s, 3H), 1.32 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 161.6, 156.4, 154.7, 149.2, 146.6, 142.2, 134.2, 132.5, 131.5, 126.7(2), 126.2, 123.3, 120.1, 119.9, 119.1, 118.8(2), 110.1, 34.4, 31.6(3), 21.6; IR (neat/ cm−1) 2959, 2946, 2923, 2859, 1543, 1508, 1444, 1226, 1104, 1024, 829, 800, 707, 598, 547; HRMS (ESI) calcd for C24H24NO2 [M + H+] 358.1802, found 358.1818. 2-(2-(2-(tert-Butyl)phenoxy)phenyl)-5-methylbenzo[d]oxazole (4ao). White solid (142 mg, 89%); Rf = 0.65 (PE/EA = 30:1); mp 143.3−145.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 7.9, 1.7 Hz, 1H), 7.57 (s, 1H), 7.47−7.40 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H), 7.26−7.20 (m, 1H), 7.18−7.05 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 6.85 (dd, J = 7.9, 1.3 Hz, 1H), 2.48 (s, 3H), 1.50 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 162.0, 156.3, 155.6, 149.4, 142.1, 141.2, 134.2, 132.6, 131.6, 127.5, 127.3, 126.2, 123.6, 123.0, 120.02, 119.96, 119.4, 110.1, 34.9, 30.3(3), 21.6; IR (neat/cm−1) 3077, 2994, 2959, 2914, 2869, 1543, 1572, 1492, 1466, 1440, 1335, 1261, 1226, 1197, 1114, 1085, 1027, 883, 803, 749, 704, 604; HRMS (ESI) calcd for C24H24INO2 [M + H+] 358.1802, found 358.1797. 2-(2-(4-Iodophenoxy)phenyl)-5-methylbenzo[d]oxazole (4bp). White solid (194 mg, 91%); Rf = 0.6 (PE/EA = 10:1); mp 161.7− 163.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.9 Hz, 2H), 7.54 (s, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.8, 157.7, 154.6, 148.9, 141.9, 138.6 (2), 134.3, 132.6, 131.4, 126.3, 124.5, 121.1, 120.4, 120.1(2), 119.9, 110.0, 86.0, 21.5; IR (neat/cm−1) 3051, 3023, 2955, 2923, 2859, 1604, 1575, 1482, 1440, 1248, 1200, 1165, 1037, 1005, 829, 803, 768, 707, 601, 496, 467; HRMS (ESI) calcd for C20H15INO2 [M + H+] 428.0142, found 428.0157. 2-(2-(3-Iodophenoxy)phenyl)-5-methylbenzo[d]oxazole (4bm). Colorless oil (179 mg, 84%); mp 63.5−65.5 °C;Rf = 0.53 (PE/EA = 30:1); 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 7.8, 1.2 Hz, 1H), 7.55 (s, 1H), 7.53−7.46 (m, 1H), 7.44−7.35 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.05−6.97 (m, 2H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.9, 158.2, 154.8, 149.1, 142.1, 134.4, 132.8, 132.4, 131.6, 131.1, 127.6, 126.4, 124.6, 121.2, 120.2, 120.0, 117.8, 110.1, 94.3, 21.6; IR (neat/cm−1) 3087, 3023, 2920, 2862, 1607, 1578, 1485, 1466, 1264, 1245, 1037, 893, 803, 742; HRMS (ESI) calcd for C20H15INO2 [M + H+] 428.0142, found 428.0135. 5-Methyl-2-(2-(pyridin-4-yloxy)phenyl)benzo[d]oxazole (4cp). Yellow solid (92 mg, 61%), after simple slowing evaporating, it will grow into yellow crystals. Rf = 0.15 (DCM/MeOH = 50:1); mp 86.1− 89.4 °C; 1H NMR (400 MHz, CDCl3) δ 8.32 (m, 1H), 7.65 (m, 2H), 7.45 (s, 2H), 7.35 (d, J = 6.6 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 6.7 Hz, 2H), 2.42 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 179.3, 159.0, 148.8, 141.6, 141.5, 140.8(2), 135.0, 132.5, 131.3, 130.1, 128.1, 127.4, 124.0, 120.5, 118.4(2), 110.2, 21.5; IR (neat/cm−1) 3369, 3266, 3055, 3074, 3055, 3032, 1555, 1572, 1495, 1412, 1348, 1191, 1037, 854, 784, 710; 531; HRMS (ESI) calcd for C19H15N2O2 [M + H+] 303.1128, found 303.1134. 5-Methyl-2-(2-(pyridin-3-yloxy)phenyl)benzo[d]oxazole (4cm). White solid (105 mg, 70%). Rf = 0.1 (DCM/MeOH = 50:1); mp 6369

DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372

Article

The Journal of Organic Chemistry 108.5−109.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.6 Hz, 1H), 8.32 (dd, J = 4.6, 1.3 Hz, 1H), 8.28 (dd, J = 7.9, 1.6 Hz, 1H), 7.54−7.47 (m, 2H), 7.37−7.31 (m, 2H), 7.31−7.27 (m, 1H), 7.25− 7.22 (m, 1H), 7.13−7.07 (m, 2H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.7, 154.5, 154.4, 149.1, 144. 4, 142.1, 141.1, 134.5, 132.9, 131.7, 126.6, 125.4, 125.1, 124.8, 124.2, 121.4, 120.3, 110.1, 21.6; IR (neat/cm−1) 3042, 2930, 2869, 1607, 1575, 1553, 1492, 1476, 1437, 1280, 1235, 1203, 1114, 1046, 1040, 928, 864, 809, 797, 777, 704, 601, 582; HRMS (ESI) calcd for C19H15N2O2 [M + H+] 303.1128, found 303.1125. 5-Methyl-2-(2-(quinolin-6-yloxy)phenyl)benzo[d]oxazole (4d). White solid (121 mg, 69%); Rf = 0.2 (DCM/MeOH = 50:1); mp 91.1−92.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.83−8.75 (m, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.53−7.46 (m, 2H), 7.37−7.25 (m, 3H), 7.17 (d, J = 6.6 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 2.41 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.8, 156.0,, 154.6, 149.04, 148.95, 145.1, 141.9, 135.3, 134.3, 132.8, 131.6, 131.4, 129.1, 126.4, 124.8, 123.2, 121.8, 121.5, 120.2, 120.1, 112.2, 110.0, 21.5; IR (neat/cm−1) 3071, 3035, 2920, 2856, 1629, 1585, 1543, 1501, 1453, 1325, 1232, 1197, 1155, 1030, 915, 838, 787, 755, 701, 624; HRMS (ESI) calcd for C23H17N2O2 [M + H+] 353.1285, found 353.1294. 3-(2-(5-Methylbenzo[d]oxazol-2-yl)phenoxy)benzaldehyde (4e). Yellow solid (153 mg, 93%); Rf = 0.35 (PE/EA= 10:1); mp 71.6− 74.3 °C; 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.29 (dd, J = 7.8, 1.3 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.55−7.45 (m, 4H), 7.35 (m, 3H), 7.14−7.10 (m, 2H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 191.7, 160.7, 158.7, 154.3, 149.0, 142.0, 138.1, 134.4, 132.9, 131.6, 130.5, 126.5, 125.0, 124.8, 124.3, 121.7, 120.2 117.7, 110.0, 21.4; IR (neat/cm−1) 3051, 2917, 2853, 2741, 1703, 1597, 1578, 1482, 1440, 1386, 1261, 1216, 1200, 1043, 797, 701; HRMS (ESI) calcd for C21H16NO3 [M + H+] 330.1125, found 330.1134. 1-(4-(2-(5-Methylbenzo[d]oxazol-2-yl)phenoxy)phenyl)ethan-1one (4f). Yellow solid (133 mg, 78%); Rf = 0.3 (PE/EA= 10/1); eluent = PE/EA 50:1−10:1; mp 159.1−160.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 7.8, 1.2 Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 2.53 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 196.8, 162.3, 160.6, 153.6, 149.0, 142.0, 134.4, 132.9, 132.0, 131.6, 130.7(2), 126.5, 125.5, 122.7, 120.7, 120.2, 116.9 (2), 110.0, 26.5, 21.6; IR (neat/cm−1) 3069, 3045, 2959, 2927, 2850, 1668, 1601, 1578, 1488, 1444, 1364, 1283, 1258, 1165, 1040, 960, 829, 797, 768, 701, 598; HRMS (ESI) calcd for C22H18NO3 [M + H+] 344.1281, found 344.1289. 1,4-Bis(2-(5-methylbenzo[d]oxazol-2-yl)phenoxy)benzene (4g). White solid (112.7 mg, 86%); Rf = 0.05 (PE/EA = 10:1) mp 226.1−227.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.8 Hz, 2H), 7.61 (s, 2H), 7.46 (dd, J = 12.8, 7.8 Hz, 4H), 7.29 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.10 (s, 4H), 7.01 (d, J = 8.3 Hz, 2H), 2.51 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 161.3(2), 156.2(2), 153.0(2), 149.1(2), 142.1(2), 134.3(2), 132.6(2), 131.5(2), 126.3(2), 123.6(2), 120.5(4), 120.2(2), 119.8(2), 119.1(2), 110.1(2), 21.6(2); IR (neat/cm−1) 3035, 2930, 2862, 1607, 1549, 1504, 1485, 1248, 1191, 1034, 797, 765; HRMS (ESI) calcd for C34H25N2O4 [M + H+] 525.1809, found 525.1826. 2-(2-(Furan-2-ylmethoxy)phenyl)-5-methylbenzo[d]oxazole (4h). White solid (137 mg, 90%); Rf = 0.25 (PE/EA = 10:1); mp 57.0−59.4 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.52−7.38 (m, 3H), 7.21−7.10 (m, 3H), 6.48 (s, 1H), 6.37 (s, 1H), 5.20(s, 2H), 2.48 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.9, 157.2, 150.3, 149.0, 142.9, 142.2, 134.1, 132.5, 131.5, 126.1, 121.9, 120.0, 117.9, 115.4, 110.6, 110.0 (2), 64.3, 21.5; IR (neat/cm−1) 3039, 2955, 2920, 1677, 1649, 1610, 1553, 1498, 1460, 1296, 1248, 1200, 1171, 1143, 1056, 1040, 995, 912, 890, 742, 704, 601; HRMS (ESI) calcd for C19H16NO3 [M + H+] 306.1125, found 306.1128. 5-Methyl-2-(2-(thiophen-2-ylmethoxy)phenyl)benzo[d]oxazole (4i). Yellow solid (152 mg, 95%); Rf = 0.25 (PE/EA = 10:1); mp 96.3−97.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 8.0, 1.5 Hz, 1H), 7.61 (s, 1H), 7.48−7.43 (m, 2H), 7.31 (dd, J = 5.0, 1.0 Hz,

1H), 7.21−7.07 (m, 4H), 6.99 (dd, J = 5.0, 3.6 Hz, 1H), 5.41 (s, 2H), 2.49 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.0, 157.0, 149.1, 142.2, 139.2, 134.1, 132.5, 131.5, 126.7, 126.5, 126.11, 126.07, 121.8, 120.0, 117.9, 115.2, 110.0, 66.9, 21.6; IR (neat/cm−1) 3083, 2923, 2898, 1607, 1581, 1556, 1498, 1485, 1440, 1290, 1264, 1200, 1168, 1053, 1030, 800, 752, 701, 601, 476; HRMS (ESI) calcd for C19H16NO2S [M + H+] 322.0896, found 322.0900. 5-Methyl-2-(2-(1-(naphthalen-1-yl)ethoxy)phenyl)benzo[d]oxazole (4j). White solid (149 mg, 78%); Rf = 0.6 (PE/EA = 10:1); mp 75.8−78.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.5 Hz, 1H), 7.87−7.81 (m, 3H), 7.77−7.62 (m, 2H), 7.62−7.45 (m, 3H), 7.35−7.27 (m, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.12−6.94 (m, 2H), 5.64 (q, J = 6.2 Hz, 1H), 2.56 (s, 3H), 1.83 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 162.7, 156.9, 149.3, 142.3, 140.5, 134.2, 133.4, 133.1, 132.4, 131.6, 128.6, 128.1, 127.8, 126.3, 126.1, 126.0, 124.8, 123.9, 121.2, 120.0, 118.0, 116.0, 110.0, 77.9, 24.4, 21.7; IR (neat/ cm−1) 3035, 2984, 2971, 2917, 2898, 1607, 1549, 1492, 1482, 1453, 1437, 1261,1072, 1027, 813, 742, 697, 598; HRMS (ESI) calcd for C26H22NO2 [M + H+] 380.1645, found 380.1638. 5-Methyl-2-(2-(naphthalen-1-ylmethoxy)phenyl)benzo[d]oxazole (4k). White solid (147 mg, 81%); Rf = 0.55 (PE/EA= 10:1); mp 146.4−147.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.7 Hz, 1H), 8.09 (s, 1H), 7.92−7.83 (m, 3H), 7.64 (d, J = 11.8 Hz, 2H), 7.47 (m, 4H), 7.17 (t, J = 8.3 Hz, 2H), 7.13 (t, J = 7.9 Hz, 1H), 5.46 (s, 2H), 2.54 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.2, 157.5, 149.1, 142.4, 134.4, 134.3, 133.5, 133.1, 132.7, 131.6, 128.3, 128.1, 127.9, 126.3, 126.2, 126.1, 125.8, 124.8, 121.4, 120.1, 117.4, 114.2, 110.0, 71.0, 21.7; IR (neat/cm−1) 3045, 2917, 2856, 1604, 1585, 1549, 1498, 1485, 1437, 1399, 1290, 1271, 1258, 1242, 1203, 1171, 1127, 1034, 922, 742, 697, 601, 486; HRMS (ESI) calcd for C25H20NO2 [M + H+] 366.148, found 366.1489. 5-Methyl-2-(2-((2-methylbenzyl)oxy)phenyl)benzo[d]oxazole (4l). Colorless needle crystals (106 mg, 65%); Rf = 0.6 (PE/EA= 10:1); mp 71.1−74.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 7.50 (dd, J = 14.8, 7.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.30−7.28 (m, 1H), 7.22 (m, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 5.28 (s, 2H), 2.52 (s, 3H), 2.43(s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.2, 157.6, 149.1, 142.2, 135.9, 134.8, 134.2, 132.7, 131.6, 130.2, 128.0, 127.9, 126.1(2), 121.3, 120.0, 117.3, 114.0, 109.9, 69.4, 21.6, 19.0; IR (neat/cm−1) 3061, 3029, 2920, 2843, 1604, 1578, 1537, 1488, 1453, 1312, 1271, 1248, 1197, 1120, 1040, 1030, 793, 755, 701, 595; HRMS (ESI) calcd for C22H20NO2 [M + H+] 330.1489, found 330.1487. 2-(2-((3-Chlorobenzyl)oxy)phenyl)-5-methylbenzo[d]oxazole (4m). White solid (132 mg, 76%); Rf = 0.5 (PE/EA = 10:1); mp 106.2−107.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 7.6 Hz, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.49−7.43 (m, 1H), 7.39 (s, 1H), 7.30 (s, 2H), 7.18 (d, J = 8.2 Hz, 1H), 7.16− 7.10 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 5.23 (s, 2H), 2.51 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.9, 157.1, 149.0, 142.3, 139.0, 134.7, 134.3, 132.7, 131.5, 129.7, 127.9, 127.1, 126.2, 124.6, 121.5, 120.1, 117.1, 113.7, 110.0, 69.8, 21.7; IR (neat/cm−1) 3051, 2971, 2927, 2866, 1604, 1585, 1549, 1498, 1434, 1373, 1290, 1258, 1200, 1168, 1101, 1059, 1027, 816, 793, 777, 745, 697, 678, 604; HRMS (ESI) calcd for C21H17ClNO2 [M + H+] 350.0942, found 350.0952. 2-(2-((4-Methoxybenzyl)oxy)phenyl)-5-methylbenzo[d]oxazole (4n). White solid (129 mg, 75%); Rf = 0.5 (PE/EA = 10:1); mp 109.3−111.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.15−7.10 (m, 2H), 6.91 (d, J = 7.5 Hz, 2H), 5.25 (s, 2H), 3.81 (s, 3H), 2.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.2, 159.3, 157.5, 149.0, 142.2, 134.2, 132.6, 131.5, 128.9, 128.6 (2), 126.1, 121.2, 120.0, 117.4, 114.4, 113.9 (2), 109.9, 70.8, 55.4, 21.6; IR (neat/cm−1) 3058, 2997, 2962, 2927, 2834, 1617, 1607, 1581, 1549, 1517, 1495, 1444, 1306, 1264, 1251, 1191, 1030, 822, 797, 749, 701, 595, 512; HRMS (ESI) calcd for C22H20NO3 [M + H+] 346.1438, found 346.1424. 5-Methyl-2-(2-((4-methylbenzyl)oxy)phenyl)benzo[d]oxazole (4o). White solid (130 mg, 79%); Rf = 0.7 (PE/EA= 10:1); mp 126.7− 128.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.6 Hz, 1H), 6370

DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372

Article

The Journal of Organic Chemistry

NMR (400 MHz, CDCl3) δ 8.32.(dd, J = 7.1, 1.9 Hz, 1H), 7.75 (dd, J = 7.2, 1.4 Hz, 1H), 7.65−7.56 (m, 2H), 7.54 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.98 (s, 1H,, CN−CH−COOMe), 3.82 (s, 3H,, CN−CH−COOMe), 2.49 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.7, 160.9, 148.1, 141.7, 134.7, 131.6, 130.3, 130.0, 129.8, 129.5, 127.0, 125.6, 120.2, 116.1, 110.0, 53.8, 40.8, 21.4; IR (neat/ cm−1) 2965, 2917, 2882, 2853, 1764, 1546, 1498, 1431, 1258, 1200, 1191, 1143, 1046, 992, 816, 784, 736, 704, 598; HRMS (ESI) calcd for C18H15N2O3 [M + H+] 307.1077, found 307.1086. Methyl 2-cyano-2-(4-(5-methylbenzo[d]oxazol-2-yl)phenyl)acetate (5b). Similar procedure as for 5a was conducted on 0.5 mmol scale, which afforded the 5b in white solid (49 mg, 32%); Rf = 0.1 (PE/EA = 10:1); mp 103.5−106.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (t, J = 9.5 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.56 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.83 (s, 1H, CN−CH−COOMe), 3.84 (s, 3H, CN−CH−COOMe), 2.49 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 165.1, 162.0, 149.2, 142.3, 134.9, 132.7, 128.7 (2), 128.59, 128.55 (2), 126.9, 120.3, 115.2, 110.2, 54.3, 43.6, 21.7; IR (neat/cm−1) 3055, 3016, 2965, 2930, 1754, 1501, 1440, 1418, 1300, 1258, 1239, 1059, 806, 704, 598; HRMS (ESI) calcd for C18H15N2O3 [M + H+] 307.1077, found 307.1085.

7.60 (s, 1H), 7.46 (d, J = 7.3 Hz, 4H), 7.19 (d, J = 8.2 Hz, 2H), 7.16− 7.08 (m, 3H), 5.27 (s, 2H), 2.50 (s, 3H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.3, 157.6, 149.1, 142.3, 137.5, 134.2, 133.9, 132.6, 131.6, 129.3(2), 127.0 (2), 126.1, 121.2, 120.1, 117.3, 114.3, 110.0, 70.9, 21.7, 21.3; IR (neat/cm−1) 3045, 2917, 2859, 1604, 1578, 1553, 1504, 1444, 1383, 1293, 1267, 1261, 1200, 1175, 1059, 1030; HRMS (ESI) calcd for C22H20NO2 [M + H+] 330.1489, found 330.1487. 2-(2-((4-Bromobenzyl)oxy)phenyl)-5-methylbenzo[d]oxazole (4p). Light yellow solid (151 mg, 78%); Rf = 0.6 (PE/EA = 10:1); mp 124.7−125.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.47 (dd, J = 15.0, 7.8 Hz, 4H), 7.44 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 5.20 (s, 2H), 2.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.9, 157.1, 148.9, 142.2, 135.9, 134.3, 132.6, 131.6 (2), 131.5, 128.6 (2), 126.2, 121.7, 121.5, 120.0, 117.2, 114.0, 109.9, 70.0, 21.6; IR (neat/cm−1) 3048, 3035, 2923, 2853, 1607, 1585, 1549, 1501, 1492, 1444, 1408, 1376, 1296, 1274, 1264, 1200, 1162, 1127, 1040, 1008, 835, 819, 806, 765, 752, 697, 601; HRMS (ESI) calcd for C21H17BrNO2 [M + H+] 394.0437 (100.0%), 396.0417 (97.3%), found 394.0433 (100%), 396.0412 (97%). 2-(2-(tert-Butoxy)phenyl)-5-methylbenzo[d]oxazole (4q). Yellow solid (63.3 mg, 45%); Rf = 0.1 (PE/EA = 10:1); mp 156.2−158.4 °C; 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 2.49 (s, 3H), 1.34 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 155.1, 149.1, 142.1, 134.3, 131.8, 131.4, 126.2, 124.9, 123.6, 123.3, 120.1, 110.0, 81.2, 29.0 (3), 21.7; IR (neat/cm−1) 3051, 2981, 2927, 2866, 1588, 1447, 1367,1335, 1303, 1165, 1117, 1062, 1030, 893, 809, 787, 601, 537; HRMS (ESI) calcd for C18H20NO2 [M + H+] 282.1489, found 282.1461. 2-(2-(Hexyloxy)phenyl)-5-methylbenzo[d]oxazole (4r). Light yellow liquid (143 mg, 93%); Rf = 0.8 (PE/EA= 10:1); 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.19 (t, J = 6.7 Hz, 2H), 7.05 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1H), 4.42 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H), 1.90−1.78 (m, 2H), 1.55−1.45 (m, 2H), 1.39 (m, 4H), 0.94 (t, J = 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.9, 160.4, 149.9, 138.1, 135.4, 133.3, 129.1, 127.9, 126.3, 124.9, 124.6, 120.6, 120.5, 66.7, 31.7, 28.8, 26.0, 22.8, 20.8, 14.2; IR (neat/cm−1) 3026, 2955, 2933, 2856, 1645, 1604, 1492, 1450, 1309, 1283, 1258, 1200, 1162, 1095, 854, 819, 790, 681; HRMS (ESI) calcd for C20H24NO2 [M + H+] 310.1808, found 310.1802. 2-(2-(Quinolin-6-yloxy)phenyl)benzo[d]thiazole (4s). Light yellow crystals (138 mg, 78%); Rf = 0.3 (DCM/MeOH= 50:1); mp 67.3− 70.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.66 (dd, J = 7.9, 1.6 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.63 (dd, J = 9.2, 2.7 Hz, 1H), 7.52−7.45 (m, 2H), 7.37 (dd, J = 8.2, 0.9 Hz, 1H), 7.35 (t, J = 4.2H, 1H), 7.34 (dd, J = 6.9, 1.0 Hz, 1H), 7.28 (d, J = 2.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 162.2, 154.7, 154.1, 152.3, 149.5, 145.5, 136.1, 135.3, 132.0, 131.8, 130.1, 129.1, 126.2, 125.7, 125.2, 124.9, 123.1, 123.0, 121.8, 121.4, 120.5, 112.9; IR (neat/cm−1) 3055, 2962, 2927, 2850, 1523, 1498, 1447, 1437, 1383, 1322, 1219, 1197, 1157, 1117, 963, 918; 829, 758; HRMS (ESI) calcd for C22H15N2OS [M + H+] 355.0900, found 355.0897. General Protocol for Construction of C−C Bond. Methyl 2cyano-2-(2-(5-methylbenzo[d]oxazol-2-yl)phenyl)acetate (5a). Into a 25 mL dried Schlenk tube were added 1a (227 mg, 0.5 mmol), Cs2CO3 (326 mg, 1 mmol), Pd(PPh3)4 (28 mg, 0.025 mmol) under N2 atmosphere, sealed by rubber, methyl 2-cyanoacetate (100 mg, 1 mmol) and DMF (3 mL) were added sequentially via syringe, and the rubber was changed to glass topper and sealed. The mixture was heated and stirred in 120 °C oil bath for 12 h. After finished, the reaction mixture was quenched by saturated NH4Cl solution, extracted by ethyl acetate (3 × 10 mL). The organic phase was combined, washed by brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue was applied on silica gel chromatography, afforded the desired product in yellow solid (80 mg, 52%). Yellow crystals were obtained by slow evaporation in open-air vessel at room temperature. Rf = 0.35 (PE/EA = 10:1); mp 114.2−118.1 °C;1H

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00587. 1 H, 13C and 19F NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xiu-Feng Hou: 0000-0001-7513-4650 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support by the National Science Foundation of China (Grant Nos. 20971026, 21271047) and ShanXi Science and Technology Department, China (Project No. MH2014-07) is gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.joc.8b00587 J. Org. Chem. 2018, 83, 6363−6372