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Article Cite This: ACS Omega 2018, 3, 8160−8168
Copper-Catalyzed Diversity-Oriented Synthesis (DOS) of 4‑Amino‑2H‑chromen-2-imines: Application of Kemp Elimination toward O‑Heterocycles Zhiyuan Chen,*,†,‡ Cuifen Han,‡ Congbin Fan,† Gang Liu,† and Shouzhi Pu*,† †
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Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, P. R. China ‡ Key Laboratory of Functional Small Organic Molecules, Ministry of Education, and College of Chemistry & Chemical Engineering, Jiangxi Normal University, 99 Ziyang Road, Nanchang, Jiangxi 330022, P. R. China S Supporting Information *
ABSTRACT: We report herein a copper-catalyzed sequential multicomponent reaction of benzo[d]isoxazoles with terminal alkynes and sulfonyl azides, which produced divergent 4amino-2H-chromen-2-imines with excellent chemical selectivity. The reaction tolerated a broad range of functional groups, and released only N2 as the sole byproduct. The sulfonyl imino group could be removed to give biologically active free 4-amino-2H-chromenone in good yield.
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INTRODUCTION Chromenone motifs are valuable category of O-containing heterocycles that widely exist in nature, pharmaceutical agents, and synthetic intermediates.1 Among the most significant subfamilies of chromenones, the amino substitution on the pyranone ring have attracted much attention recently, due to their potent effects in medicinal applications or clinical therapeutic effects. A particular example is 3-aminochromen4-one, which has been reported to be cytotoxic active, and has the ability to inhibit cyclic AMP phosphodiesterase.2 In addition, a series of 2- or 3-amino-substituted chromones have been identified to possess antiproliferative activities, antiviral and enzymatic inhibition,3 and antirheumatic activities.4 The 4-amino-substituted chromones have been recently recognized as a useful substrate to prepare bioactive chromeno[4,3-b]pyrrol-4(1H)-one derivatives.5 To date, there are many methods including step-wise synthesis,6 pyranone ring cyclizations,7 and conjugate addition reactions,8 which have been reported to effectively construct the chromone core structures. Although these approaches have been used frequently for the synthesis of chromone family members, they are not applicable for the synthesis of 2-iminosubstituted or 2-amino-substituted chromenones. Recently, some new protocols have been successfully developed to prepare 2H-chromen-2-imines. For example, in 2011, Liu and Wang’s group reported a microwave-assisted two-step synthesis of 2-iminocoumarin-3-carboxamide derivatives.9 Later, Punniyamurthy developed a copper(I)-catalyzed one-pot synthesis of iminocoumarin aryl methyl ethers starting from ynal, phenol, and sulfonyl azide.10 Li and co-workers described a straightforward path to the 2-aryliminochromene skeleton via a cascade three-component coupling reaction of arynes, N,Sketeneacetals, and dimethylformamide (DMF).11 It should be © 2018 American Chemical Society
noted that although these protocols have been frequently utilized in the synthesis of 2- or 3-amino-substituted coumarin derivatives, less attention has been focused on 4-amino-2Hchromen-2-imines, which have found noticeable applications in medicinal sciences and biological studies.12 We were interested in developing novel domino reactions to construct combinatorial natural products like small organic molecules for the use in different biological assays.13 A tandemtype cyclization that employs the first-row transition-metals is of particular interest because this would obviate the need for toxic and expensive heavy metal species. Our access to the amination of chromenone derivatives was inspired by the Cucatalyzed regioselective Huisgen azide−alkyne cycloaddition (CuAAC) reaction of azides and terminal alkynes.14 The key to the success of CuAAC is the in situ generation of a reactive ketenimine intermediate, which could be chemo- and regioselectively transformed into various heterocyclic molecules as disclosed by the groups of Chang and Wang,15 and recently among others.16 Copper-catalyzed tandem cyclization of ketenimine intermediates with different dipole nucleophile− electrophile building blocks such as 2-hydroxylacetophenones and 2-hydroxyphenylpropiolates has so far been explored to construct 2-iminocoumarins or similar fused O-heterocycles.17 Recently, the Zhang and Yi’s group reported an expedient synthesis of 4-amino-2H-chromen-2-imines by the combination of copper-catalyzed CuAAC reaction with 2-hydroxybenzonitriles.18 The development of novel dipole nucleophile− electrophile building blocks for difunctionalization of the intermediate species can be expected, thus expanding the Received: May 30, 2018 Accepted: July 5, 2018 Published: July 23, 2018 8160
DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
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ACS Omega synthetic applications of useful cyclic molecules in stepeconomic domino reactions. Motivated by the pioneering works mentioned above, we herein present a novel Cucatalyzed three-component cycloaddition reaction of benzo[d]isoxazole 1 with the in situ generated sulfonylketenimines from Huisgen azide−alkyne adducts, to produce functionalized 4-amino-4H-chromen-2-one imines 4 in good yields with excellent chemo- and regioselectivity. Benzo[d]isoxazoles are readily available and stable substances, they have been recently employed to prepare various aza-heterocycles based on the nucleophilicity of the nitrogen atom in the molecule.19 The Kemp elimination is a wellstudied reaction in which a catalytic base abstracts a proton from the benzo[d]isoxazole ring, and thus results in ringopening to form the cyanophenol product (Scheme 1).20,21
Ever since its discovery, this protocol has been established as an important tool to develop conceptually innovative organocatalysis.22 We envisioned that this anionic cyanophenol species could react with the highly reactive ketenimine species in suitable catalytic conditions through [4 + 2] cycloaddition process, thus giving the targeted 2-aminochromenone imines in a one-pot procedure. Interestingly, to our knowledge, there are currently very few reports to prepare O-heterocycles based on Kemp elimination process.
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RESULTS AND DISCUSSION We first screened the reaction conditions in the coppercatalyzed three-component cyclization of benzo[d]isoxazole 1a with tosyl azide 2a and terminal alkyne 3a (Table 1). We supposed that the addition of base should be crucial for both of the desired Kemp elimination and triazole decomposition in this reaction. Indeed, when triethylamine (TEA) was added, the expected 4-amino-2H-chromen-2-imine 4a was identified, albeit in very low yield at room temperature (entry 1). A brief screening of the copper catalyst, including Cu(I) and Cu(II) salts, indicated that CuBr gave a slightly improved yield of 21% (entries 2−5). Typically, the undesired Huisgen adduct 4a′ (10−15%),14,23 and the remaining substrate 1a (>61%) accounted for the mass balance. The unusual slow conversion of this reaction was ascribed to the fact that the basic azaheterocycle 1a can potentially deactivate the metal catalyst via coordination. In addition, the slow Kemp elimination of 1a and the poor solubility of product 4a should be taken into account. With these considerations in mind, we next raised the
Scheme 1. Kemp Elimination Reaction and Its Application in the Synthesis of O-Containing Heterocycles
Table 1. Optimization of the Conditionsa
entry
cat. (x)
base (equiv)
solvent
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
CuI (10) CuBr (10) CuCl (10) CuCN (10) Cu(OTf)2 (10) CuBr (10) CuBr (10) CuBr (10) CuBr (10) CuBr (10) CuBr (10) CuBr (5) CuBr (10) CuBr (10) CuBr (10) CuBr (10) CuBr (10) CuBr (10) CuBr (10) CuBr (10) CuBr (10)
TEA (3) TEA (3) TEA (3) TEA (3) TEA (3) TEA (3) DIPEA (3) K2CO3 (3) Py (3) DABCO (3) TEA (2) TEA (3) TEA (3) TEA (3) TEA (3) TEA (3) TEA (3) TEA (3) TEA (3) TEA (3) TEA (3)
DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE CHCl3 THF 1,4-dioxane toluene DMF DMSO DCE/DCM (1:1) DCE/CHCl3 (1:1) DCE/DCM (1:1) (0.5 M)
T/°C, t/h 25, 25, 25, 25, 25, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80,
12 12 12 24 12 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4
yield (%) 19 21 13 5 17 74 69 10 0 5 64 43 50 0 22 22 trace 0 89 80 84b
a
Reaction conditions: benzo[d]isoxazole 1a (0.24 mmol), azide 2a (0.40 mmol), and alkyne 3a (0.20 mmol) in 2.0 mL of solvent under N2. Gas chromatography yield was estimated with naphthalene as an internal standard. Isolated yield in parentheses. bSolvent = 1.0 mL. DABCO = 1,4diazabicyclo[2.2.2]octane. 8161
DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
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ACS Omega Table 2. Substrate Scope for the Synthesis of 4a
reaction temperature to a reflux condition of 80 °C in dichloroethane (DCE). Gratifyingly, a smooth reaction was observed to proceed for 4 h, the desired product 4a was isolated in 74% yield (entry 6). A comparative result was observed when diisopropylethylamine (DIPEA) was employed (entry 7), whereas, the addition of other bases like K2CO3, pyridine, and 1,4-diazabicyclo[2.2.2]octane (DABCO) all failed to achieve any improvement, and worse yet the triazole 4a′ remained dominant in these cases (entries 8−10). The aims to reduce the loading of the copper catalyst and base gave no superior results, thus, 10 mol % of CuBr and 3.0 equiv of TEA were chosen as the optimal conditions for this threecomponent transformation (entries 11 and 12). Solvent screening indicated that modest yield was obtained in CHCl3, and no superior result was observed in 1,4-dioxane or toluene. It should be noted that complex results were observed in strong polar solvents like tetrahydrofuran (THF), DMF, and dimethyl sulfoxide (DMSO) (entries 13−18). Notably, a significant improvement in product formation was achieved when a mixture of organochlorine solvent was employed (entries 19−21). The expected product 4a could be isolated in 89% yield in 0.1 M of DCE/dichloromethane (DCM) (1:1, v/v) system (entry 19). The reaction scope for this convenient preparation of 4amino-2H-chromen-2-imines 4 was next studied as presented in Table 2. Employing benzo[d]isoxazole 1a and tosyl azide 2a as starting materials, the reactivity of various terminal alkynes 3 was evaluated. The aromatic alkynes that bear electrondonating functionalities (OMe, nBu) at the para position of the phenyl ring participated in this three-component reaction smoothly, affording the corresponding products 3b and 3d in 68 and 96% yields, respectively. The structure of compound 4d was verified unambiguously through X-ray crystallography analysis.24 The synthetically useful halo-substituents such as fluoro (4e) and bromo (4f) groups were tolerated, which indicate that the further elaborations based on these synthetic handles can be applicable. The ester moiety attached on the phenyl ring of alkyne underwent the reaction smoothly to give product 4g in moderate yield. In addition to these aryl terminal alkynes, the 3-thienyl heterocycle could also participate in this reaction, thus furnishing the bis-heterocyclic compound 4h in 71% yield. A sluggish result of aliphatic alkyne 3i with 1a and 2a was observed under the standard conditions. Fortunately, in modified reaction conditions, we found that when mixing tosyl azide 2a with oct-1-yne 3i in anhydrous DCE firstly under the catalysis of CuBr at room temperature, followed by the addition of benzo[d]isoxazole 1a and TEA, the product 4i could be successfully isolated at 80 °C in 62% yield. By utilizing this optimal procedure, the structurally strained cycloalkyl group could also be compatible, the reaction of 1a and 2a with ethynylcyclopropane afforded the expected product 4j in 65% yield. To further explore the synthetic utility of this diversityoriented method for the synthesis of more complex Oheterocyclic imines 5, we employed a variety of functionalized benzo[d]isoxazoles 1, sulfonyl azides 2, and terminal alkynes 3 in the reaction (Table 3). Substitution on the benzoid ring of benzo[d]isoxazoles 1 such as 5-methylbenzo[d]isoxazole or 5chlorobenzo[d]isoxazole reacted with TsN3 2a and 1-butyl-4ethynylbenzene 3 under the catalysis of CuBr to afford the corresponding substituted 2-amino-4H-chromen-4-one imines 5a and 5b in 83 and 79% yields, respectively (entries 1 and 2). A smooth reaction was observed in the three-component
a Reaction conditions: 1a (0.24 mmol), 2a (0.40 mmol), terminal alkyne 3 (0.20 mmol) in 2.0 mL of DCE at 80 °C. Isolated yield based on 3. bCompound 2a and alkyl alkyne 3 firstly reacted in DCE under the catalysis of CuBr for 1 h at room temperature, followed by the addition of substrate 1a and TEA, the mixture was then stirred at 80 °C for an additional 4 h.
reaction of 5-methylbenzo[d]isoxazole, 4-methoxybenzenesulfonyl azide, and 1-butyl-4-ethynylbenzene, the desired product 5c was isolated in 95% yield (entry 3). The multicomponent cyclization reaction of 5-methoxybenzo[d]isoxazole with TsN3 and 1-butyl-4-ethynylbenzene gave the targeted product 5e in 66% yield (entry 5). Interestingly, the result could be improved to 94% (5f) when 1-ethynyl-4-methoxybenzene was employed instead of 1-butyl-4-ethynylbenzene (entry 6). It seemed that the electron-rich aryl azides that bear electron-donating groups such as MeO or Me generally performed well compared to those of the electron-deficient ones (entries 1−4 vs 5−7). Indeed, when 4-bromobenzenesulfonyl azide was utilized as a nitrogen source of the ketenimine intermediate, the corresponding products 5h, 5i, and 5j were produced in yields ranging from 59 to 67% (entries 8−10). The scope of the azide counterpart also turned out to be broad, the reaction of alkyl sulfonyl azide (MsN3) with various benzo[d]isoxazoles and aryl alkynes were readily employed with high efficiency and excellent chemical selectivity (entries 11−15). Other than the 5-substituted benzo[d]isoxazoles 1, functional groups located at the other positions of the benzoid could be well tolerated in the reaction. For example, the reactions of 6-Me or 7-MeO8162
DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
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ACS Omega Table 3. Substrate Scope Studiesa
entry
R1
R2
R3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
5-Me 5-Cl 5-Me 5-Me 5-MeO 5-MeO 5-Me 5-Me 5-Me 5-Me 5-Cl H 5-Cl 5-Cl 5-Cl 6-Me 7-MeO 7-MeO
4-MeC6H4 4-MeC6H4 4-MeOC6H4 C6H5 4-ClC6H4 4-ClC6H4 4-ClC6H4 4-BrC6H4 4-BrC6H4 4-BrC6H4 Me Me Me Me Me 4-MeC6H4 4-MeC6H4 Me
nBu nBu nBu2 nBu nBu MeO nBu Me nBu F nBu Me Me H F nBu H MeO
yield (%)a 83 79 95 88 66 94 73 59 67 62 56 76 98 76 84 82 43 47
(5a) (5b) (5c) (5d) (5e) (5f) (5g) (5h) (5i) (5j) (5k) (5l) (5m) (5n) (5o) (5p) (5q) (5r)
a
Reaction conditions: benzo[d]isoxazole 1 (0.24 mmol), azide 2 (0.40 mmol), and terminal alkyne 3 (0.20 mmol) in 2.0 mL of DCE/DCM (v/v = 1:1) at 80 °C. Isolated yield of products 5 based on 3.
selectivity. As can be seen in Scheme 2, in the 5.0 mmol reaction of 1-butyl-4-ethynylbenzene 3a with benzo[d]isoxazole 1a and tosyl azide 2a, the desired product 4a could be isolated in 93% yield when 7.5 mol % of CuBr was employed as the catalyst (Scheme 2, eq 2). On the other hand, with an aim to broaden the utility of the product, the Ts group was successfully removed to afford free 4-amino-3-arylcoumarins, whose analogues showed good antiarrhythmic activity, platelet antiaggregating activity and infiltration anesthesia activities in rats.25 It was found that the treatment of compound 4a with 5 N of H2SO4 in MeOH can give free 4amino-3-arylchromen-2-one 7 in 78% yield. (Scheme 2, eq 3).
substituted benzo[d]isoxazole with TsN3 and aromatic alkynes successfully afforded the desired products 5p and 5q in moderate to good yields, respectively (entries 16−17). The 7methoxybenzo[d]isoxazole reacted with MsN3 and 1-ethynyl4-methoxybenzene smoothly to give compound 5r in 47% yield (entry 18). In addition to these results, 4-chlorobenzo[d]isoxazole 1s was found to react with TsN3 and an alkyl alkyne, hex-1-yne, to produce the desired product 5s in 67% yield (Scheme 2, eq 1). We were pleased to observe that this copper-catalyzed threecomponent cyclization reaction could be easily enlarged to gram-scale, without the loss of catalytic efficiency and chemical Scheme 2. Extended Experiments
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CONCLUSIONS
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EXPERIMENTAL SECTION
In conclusion, we have developed a copper-catalyzed multicomponent cascade cyclization reaction of benzo[d]isoxazoles with azides and terminal alkynes. The reaction proceeds through sequential azide−alkyne cycloaddition (CuAAC)/ Kemp elimination/tandem cyclization, thus providing efficient access to diversity-oriented O-heterocycles 4-amino-2Hchromenone-2-imines. The reaction tolerated a broad range of functional groups, and only released N2 as the sole byproduct. Moreover, the reaction could be easily extended to gram-scale and the afforded product could be converted into medicinally active free 4-amino-2H-chromen-2-one in good yield.
Unless otherwise noted, commercial reagents were purchased from Aldrich, Alfa Aesar, or other commercial suppliers, and were used as received. Solvents were dried and distilled according to standard procedures before use. Reactions were 8163
DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
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ACS Omega
1.38−1.26 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.6, 152.0, 151.6, 143.0, 142.1, 140.9, 132.3, 130.5, 129.3, 129.0, 128.7, 126.9, 125.0, 123.1, 116.8, 114.0, 101.4, 35.4, 33.4, 22.4, 21.5, 14.0. HRMS calcd for C26H27N2O3S (M + H)+: 447.1742, found: 447.1737. N-(4-Amino-3-(4-fluorophenyl)-2H-chromen-2-ylidene)-4methylbenzenesulfonamide (4e). Yield: 71%; white solid, mp: 301−302 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.26 (d, J = 6.0 Hz, 1H), 7.82 (d, J = 5.4 Hz, 2H), 7.70 (d, J = 6.7 Hz, 1H), 7.44−7.41 (m, 2H), 7.38−7.02 (m, 6H), 2.32 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ: 162.3 (d, 1J = 243 Hz), 159.2, 153.0, 152.0, 142.0, 141.7, 133.8, 133.7, 133.6, 129.5, 129.2, 127.3, 125.7, 124.4, 116.5, 116.3 (d, 2J = 21 Hz), 114.7 (d, 2J = 23 Hz), 99.0, 21.4. HRMS calcd for C22H18FN2O3S (M + H)+: 409.1022, found: 409.1017. N-(4-Amino-3-(4-bromophenyl)-2H-chromen-2-ylidene)4-methylbenzenesulfonamide (4f). Yield: 53%; yellow solid, mp: 284−285 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.25 (d, J = 8.0 Hz, 1H), 7.88−7.56 (m, 5H), 7.43−7.25 (m, 6H), 2.32 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.0, 152.8, 152.0, 142.1, 141.6, 133.9, 133.6, 132.4, 129.5, 128.5, 127.3, 125.7, 124.4, 121.7, 117.0, 114.7, 98.8, 21.4. HRMS calcd for C22H18BrN2O3S (M + H)+: 469.0222, found: 469.0216. Methyl-4-(4-amino-2-(tosylimino)-2H-chromen-3-yl)benzoate (4g). Yield: 40%; white solid, mp: 268−269 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.27 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.48−7.43 (m, 4H), 7.32 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.32 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 166.7, 158.8, 152.8, 152.1, 142.1, 141.6, 138.4, 133.7, 132.2, 130.3, 129.5, 129.3, 127.3, 125.7, 124.5, 117.1, 114.6, 98.9, 52.77, 21.4. HRMS calcd for C24H21N2O5S (M + H)+: 449.1171, found: 449.1166. N-(4-Amino-3-(thiophen-3-yl)-2H-chromen-2-ylidene)-4methylbenzenesulfonamide (4h). Yield: 71%; yellow solid, mp: 246−247 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.27 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.75−7.64 (m, 2H), 7.55 (d, J = 1.6 Hz, 1H), 7.72−7.66 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 4.8 Hz, 1H), 2.33 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 158.9, 153.0, 151.8, 142.0, 141.7, 133.6, 132.1, 130.3, 129.5, 127.3, 126.6, 126.4, 125.7, 124.4, 117.1, 114.5, 95.0, 21.4. HRMS calcd for C20H17N2O3S2 (M + H)+: 397.0681, found: 397.0675. N-(4-Amino-3-hexyl-2H-chromen-2-ylidene)-4-methylbenzenesulfonamide (4i). Yield: 62%; white solid, mp: 188− 189 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.15 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.47−7.29 (m, 4H), 2.49 (d, J = 8.2 Hz, 2H), 2.31 (s, 3H), 1.40−1.25 (m, 8H), 0.84 (t, J = 6.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.7, 151.9, 151.6, 141.9, 132.8, 129.4, 127.2, 125.4, 123.7, 116.9, 114.8, 98.7, 31.8, 28.9, 27.1, 24.2, 22.6, 21.4, 14.4. HRMS calcd for C22H27N2O3S (M + H)+: 399.1742, found: 399.1737. N-(4-Amino-3-cyclopropyl-2H-chromen-2-ylidene)-4methylbenzenesulfonamide(4j). Yield: 65%; white solid, mp: 242−243 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.18 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 3H), 2.32 (s, 3H), 1.32−1.30 (m, 1H), 1.00 (d, J = 7.0 Hz, 2H), 0.54 (d, J = 4.7 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ: 159.8, 154.5, 151.8, 142.0, 141.8, 132.9, 129.4, 127.2, 125.4, 123.8, 116.8, 114.75, 97.7, 21.4, 8.8, 6.6. HRMS calcd for C19H19N2O3S (M + H)+: 355.1116, found: 355.1111.
conducted using standard Schlenk techniques on a vacuum line. Analytical thin-layer chromatography (TLC) was performed using glass plates precoated with 0.25 mm 230− 400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Flash column chromatography was performed using a silica gel (60 Å pore size, 32−63 μm, standard grade). Organic solutions were concentrated on rotary evaporators at ∼20 Torr (house vacuum) at 25−35 °C. NMR spectra are recorded in parts per million (ppm) from internal standard tetramethylsilane on the δ scale. High-resolution mass spectrometry (HRMS) analysis was performed by electrospray ionization (ESI-micrOTOF). General Procedure for the Preparation of 2-Imino2H-chromen-4-amines 4 and 5. Sulfonyl azide 2 (0.30 mmol, 1.5 equiv), terminal alkyne 3 (0.20 mmol, 1.0 equiv), CuBr (0.02 mmol, 10 mol %), and benzo[d]isoxazole 1 (0.30 mmol, 1.5 equiv) were added to a solution of anhydrous solvent mixture of DCE/DCM (2.0 mL, v/v = 1:1) at room temperature under N2. Then triethylamine (0.60 mmol, 3.0 equiv) was slowly added by a syringe. The reaction was stirred at 80 °C for about 2−4 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with saturated NH4Cl solution (3.0 mL), and extracted with ethyl acetate (3.0 mL × 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatograph (EtOA/DCM = 1:20, or recrystallization) to give the desired products 4 or 5. N-(4-Amino-3-(p-tolyl)-2H-chromen-2-ylidene)-4-methylbenzenesulfonamide (4a). Yield: 89%; white solid, mp: 270− 271 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.26 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.70 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 8.9 Hz, 2H), 7.33−7.30 (m, 4H), 7.16 (d, J = 7.7 Hz, 2H), 2.38 (s, 3H), 2.32 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.3, 152.7, 152.0, 142.0, 141.7, 137.3, 133.5, 131.4, 130.0, 129.9, 129.5, 127.3, 125.6, 124.4, 116.9, 114.7, 99.9, 21.5, 21.4. HRMS calcd for C23H21N2O3S (M + H)+: 405.1273, found: 405.1267. N-(4-Amino-3-(4-methoxyphenyl)-2H-chromen-2-ylidene)-4-methylbenzenesulfonamide (4b). Yield: 68%; white solid, mp: 218−219 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.18 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 7.7 Hz, 1H), 7.38−7.33 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 3.75 (s, 3H), 2.25 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.4, 159.2, 152.9, 152.0, 142.0, 141.7, 133.4, 132.7, 129.5, 127.3, 125.6, 124.8, 124.4, 116.9, 115.0, 114.7, 99.7, 55.5, 21.4. HRMS calcd for C23H21N2O4S (M + H)+: 421.1222, found: 421.1217. N-(4-Amino-3-phenyl-2H-chromen-2-ylidene)-4-methylbenzenesulfonamide (4c). Yield: 68%; white solid, mp: 261− 262 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.31 (t, J = 9.8 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.72 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.4 Hz, 2H), 7.47−7.41 (m, 3H), 7.34−7.21 (m, 4H), 2.32 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.2, 152.7, 152.0, 142.0, 141.7, 133.6, 133.0, 131.6, 129.5, 128.2, 127.3, 125.7, 124.5, 117.0, 114.7, 100.0, 21.4. HRMS calcd for C22H19N2O3S (M + H)+: 391.1116, found: 391.1111. N-(4-Amino-3-(4-butylphenyl)-2H-chromen-2-ylidene)-4methylbenzenesulfonamide (4d). Yield: 96%; white solid, mp: 92−93 °C. 1H NMR (400 MHz, CDCl3) δ: 7.84 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.21−7.18 (m, 3H), 7.14−7.10 (m, 5H), 6.02−5.75 (br, 2H), 2.52 (t, J = 7.7 Hz, 2H), 2.34 (s, 3H), 1.56−1.52 (m, 2H), 8164
DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
Article
ACS Omega N-(4-Amino-3-(4-butylphenyl)-6-methyl-2H-chromen-2ylidene)-4-methylbenzenesulfonamide (5a). Yield: 83%; white solid, mp: 210−211 °C. 1H NMR (400 MHz, CDCl3) δ: 7.85 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 7.17− 6.96 (m, 4H), 5.90−7.76 (br, 2H), 2.49 (t, J = 7.7 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 3H), 1.54−1.50 (m, 2H), 1.35−1.30 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.7, 151.6, 150.3, 142.8, 141.9, 141.0, 135.0, 133.5, 130.5, 129.2, 128.9, 128.8, 127.0, 122.8, 116.5, 113.7, 101.4, 35.4, 33.4, 22.4, 21.4, 20.9, 14.0. HRMS calcd for C27H29N2O3S (M + H)+: 461.1899, found: 461.1893. N-(4-Amino-3-(4-butylphenyl)-6-chloro-2H-chromen-2ylidene)-4-methylbenzenesulfonamide (5b). Yield: 79%; white solid, mp: 229−230 °C. 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 8.8, 1.9 Hz, 1H), 7.22−7.20 (m, 3H), 7.12−7.01 (m, 4H), 5.92−5.74 (br, 2H), 2.44 (t, J = 7.6 Hz, 2H), 2.35 (s, 3H), 1.53−1.45 (m, 2H), 1.35−1.26 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.3, 150.5, 150.5, 143.2, 142.3, 140.5, 132.3, 130.5, 130.3, 129.3, 129.0, 128.3, 127.1, 123.1, 118.2, 115.3, 101.9, 35.3, 33.4, 22.3, 21.5, 14.0. HRMS calcd for C26H26ClN2O3S (M + H)+: 481.1353, found: 481.1347. N-(4-Amino-3-(4-butylphenyl)-6-methyl-2H-chromen-2ylidene)-4-methoxybenzenesulfonamide (5c). Yield: 95%; white solid, mp: 198−199 °C. 1H NMR (400 MHz, DMSOd6) δ: 8.11 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.35−7.30 (m, 3H), 7.17 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 2.64 (t, J = 7.7 Hz, 2H), 2.38 (s, 3H), 1.67−1.60 (m, 2H), 1.42−1.36 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 161.9, 159.2, 152.5, 150.2, 142.1, 136.5, 135.0, 134.2, 131.3, 130.2, 129.3, 124.0, 116.7, 114.3, 114.1, 99.9, 55.9, 35.3, 33.4, 22.5, 21.0, 14.3. HRMS calcd for C27H28N2O4SNa (M + Na)+: 499.1667, found: 499.1662. N-(4-Amino-3-(4-butylphenyl)-6-methyl-2H-chromen-2ylidene)benzenesulfonamide (5d). Yield: 88%; white solid, mp: 105−106 °C. 1H NMR (400 MHz, CDCl3) δ: 7.96 (d, J = 7.0 Hz, 2H), 7.54 (s, 1H), 7.42−7.37 (m, 3H), 7.27 (d, J = 9.0 Hz, 1H), 7.20−7.04 (m, 5H), 6.02−5.78 (br, 2H), 2.51 (t, J = 7.6 Hz, 2H), 2.26 (s, 3H), 1.55−1.52 (m, 2H), 1.36−1.31 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 159.8, 151.6, 150.3, 143.9, 142.9, 135.1, 133.6, 131.5, 130.5, 129.2, 128.7, 128.3, 126.9, 122.7, 116.6, 113.6, 101.5, 35.4, 33.4, 22.4, 20.9, 14.0. HRMS calcd for C26H26N2O3SNa (M + Na)+: 469.1562, found: 469.1556. N-(4-Amino-3-(4-butylphenyl)-6-methoxy-2H-chromen-2ylidene)-4-chlorobenzenesulfonamide (5e). Yield: 66%; white solid, mp: 267−268 °C. 1H NMR (400 MHz, DMSOd6) δ: 8.21 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H), 3.92 (s, 3H), 2.63 (t, J = 7.5 Hz, 2H), 1.66−1.59 (m, 2H), 1.41−1.33 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, DMSOd6) δ: 163.5, 159.5, 153.8, 153.5, 143.7, 142.1, 136.6, 131.5, 120.0, 129.3, 129.1, 125.9, 114.1, 107.7, 100.3, 98.4, 56.7, 35.3, 33.4, 22.5, 14.3. HRMS calcd for C26H26ClN2O4S (M + H)+: 497.1302, found: 497.1296. N-(4-Amino-6-methoxy-3-(4-methoxyphenyl)-2H-chromen-2-ylidene)-4-chlorobenzenesulfonamide (5f). Yield: 94%; white solid, mp: 237−238 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.19 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 8.5 Hz,
2H), 7.59 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.10− 6.95 (m, 3H), 6.83 (d, J = 2.1 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 163.4, 159.6, 159.2, 153.7, 143.7, 136.6, 132.8, 129.3, 129.1, 125.9, 124.7, 114.9, 114.0, 107.8, 100.3, 98.2, 56.6, 55.5. HRMS calcd for C23H20ClN2O5S (M + H)+: 471.0781, found: 471.0776. N-(4-Amino-3-(4-butylphenyl)-6-methyl-2H-chromen-2ylidene)-4-chlorobenzenesulfonamide (5g). Yield: 73%; white solid, mp: 219−220 °C. 1H NMR (400 MHz, DMSOd6) δ: 8.31 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.58−7.52 (m, 3H), 7.34−7.30 (m, 2H), 7.18 (d, J = 7.7 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.39 (s, 3H), 1.67−1.60 (m, 2H), 1.43−1.36 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.6, 153.2, 150.2, 143.6, 142.2, 136.6, 135.3, 134.5, 131.3, 130.0, 129.4, 129.2, 129.1, 124.1, 116.7, 114.3, 100.0, 35.3, 33.4, 22.4, 21.0, 14.3. HRMS calcd for C26H25ClN2O3SNa (M + Na)+: 503.1172, found: 503.1167. N-(4-Amino-6-methyl-3-(p-tolyl)-2H-chromen-2-ylidene)4-bromobenzenesulfonamide (5h). Yield: 59%; yellow solid, mp: 281−282 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.12 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.35−7.29 (m, 3H), 7.16 (d, J = 7.8 Hz, 2H), 2.38 (s, 6H). 13C NMR (100 MHz, DMSO-d6) δ: 159.6, 153.2, 150.2, 144.0, 137.4, 135.3, 134.5, 132.1, 131.4, 130.1, 129.8, 129.4, 125.5, 124.1, 116.7, 114.3, 100.0, 21.4, 21.0. HRMS calcd for C23H20BrN2O3S (M + H)+: 483.0378, found: 483.0373. N-(4-Amino-3-(4-butylphenyl)-6-methyl-2H-chromen-2ylidene)-4-bromobenzenesulfonamide (5i). Yield: 67%; yellow solid, mp: 221−222 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.13 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.34−7.30 (m, 3H), 7.18 (d, J = 7.8 Hz, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.39 (s, 3H), 1.66−1.62 (m, 2H), 1.42−1.36 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.6, 153.2, 150.2, 144.0, 142.2, 135.3, 134.5, 132.1, 131.3, 123.0, 129.4, 125.5, 124.1, 116.7, 114.3, 100.0, 35.3, 33.4, 22.4, 21.0, 14.3. HRMS calcd for C26H26BrN2O3S (M + H)+: 525.0848, found: 525.0842. N-(4-Amino-3-(4-fluorophenyl)-6-methyl-2H-chromen-2ylidene)-4-bromobenzenesulfonamide (5j). Yield: 62%; yellow solid, mp: 278−279 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.12 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.36−7.31 (m, 5H), 2.39 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 162.5 (d, 1J = 243 Hz), 159.5, 153.5, 150.3, 143.9, 135.3, 134.6, 133.8, 133.7, 132.1, 129.4, 124.9 (d, 2J = 23 Hz), 116.7, 116.3 (d, 2J = 21 Hz), 114.3, 100.0, 99.1, 21.0. HRMS calcd for C22H17BrFN2O3S (M + H)+: 487.0127, found: 487.0122. N-(4-Amino-3-(4-butylphenyl)-6-chloro-2H-chromen-2ylidene)methanesulfonamide (5k). Yield: 56%; white solid, mp: 210−211 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.48 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 7.7 Hz, 2H), 3.00 (s, 3H), 2.63 (t, J = 7.6 Hz, 2H), 1.67−1.59 (m, 2H), 1.41−1.36 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSOd6) δ: 159.1, 151.3, 150.7, 142.2, 132.9, 131.2, 130.0, 129.8, 129.3, 123.9, 119.4, 116.4, 100.2, 43.0, 35.3, 33.4, 22.5, 14.3. HRMS calcd for C20H22ClN2O3S (M + H)+: 405.1040, found: 405.1034. N-(4-Amino-3-(p-tolyl)-2H-chromen-2-ylidene)methanesulfonamide (5l). Yield 76%; white solid, mp: 214− 8165
DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
Article
ACS Omega 215 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.30 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 2.99 (s, 3H), 2.38 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.5, 152.3, 152.1, 137.2, 133.3, 131.4, 130.0, 125.6, 124.3, 117.4, 114.8, 99.7, 79.7, 43.0, 21.4. HRMS calcd for C17H17N2O3S (M + H)+: 329.0960, found: 329.0954. N-(4-Amino-6-chloro-3-(p-tolyl)-2H-chromen-2-ylidene)methanesulfonamide (5m). Yield: 98%; white solid, mp: 286−287 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (d, J = 2.1 Hz, 1H), 7.78−7.75 (m, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 2.99 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.1, 151.3, 150.7, 137.3, 132.9, 131.3, 130.0, 129.8, 123.9, 119.4, 116.4, 100.2, 43.0, 21.4. HRMS calcd for C17H16ClN2O3S (M + H)+: 363.0570, found: 363.0565. N-(4-Amino-6-chloro-3-phenyl-2H-chromen-2-ylidene)methanesulfonamide (5n). Yield: 76%; white solid, mp: 230− 231 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.48 (d, J = 2.1 Hz, 1H), 8.32 (s, 1H), 7.79−7.76 (m, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 2.99 (s, 3H). 13C NMR (100 MHz, DMSOd6) δ: 159.0, 151.2, 150.8, 133.0, 132.8, 131.5, 129.8, 129.4, 128.2, 123.9, 119.4, 116.4, 100.3, 79.7, 43.0. HRMS calcd for C16H14ClN2O3S (M + H)+: 349.0414, found: 349.0408. N-(4-Amino-6-chloro-3-(4-fluorophenyl)-2H-chromen-2ylidene)methanesulfonamide (5o). Yield: 84%; white solid, mp: 268−269 °C. 1H NMR (400 MHz, DMSO-d6) δ: 8.46 (s, 1H), 8.32 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.42−7.25 (m, 3H), 2.99 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 162.2 (d, 1J = 243 Hz), 159.0, 151.6, 150.8, 133.7, 133.6, 129.8, 129.1, 123.9, 119.5, 116.3 (d, 2J = 21 Hz), 99.3, 79.8, 43.0. HRMS calcd for C16H13ClFN2O3S (M + H)+: 367.0319, found: 367.0314. N-(4-Amino-3-(4-butylphenyl)-7-methyl-2H-chromen-2ylidene)-4-methylbenzenesulfonamide (5p). Yield: 82%; white solid, mp: 109−110 °C. 1H NMR (400 MHz, DMSOd6) δ: 8.14 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.33− 7.26 (m, 6H), 7.18 (d, J = 7.9 Hz, 2H), 5.75 (br, 2H), 2.65 (t, J = 7.7 Hz, 2H), 2.46 (s, 3H), 2.33 (s, 3H), 1.67−1.63 (m, 2H), 1.42−1.37 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 159.4, 152.8, 152.1, 144.4, 142.1, 141.9, 131.4, 130.1, 129.4, 129.3, 127.2, 126.8, 124.2, 116.8, 112.2, 99.4, 35.3, 33.4, 22.4, 21.5, 21.4, 14.3. HRMS calcd for C27H29N2O3S (M+H)+: 461.1893, found: 461.1899. N-(4-Amino-8-methoxy-3-phenyl-2H-chromen-2-ylidene)-4-methylbenzenesulfonamide (5q). Yield: 43%; white solid, mp: >320 °C. 1H NMR (400 MHz, DMSO-d6) δ: 7.89 (d, J = 8.0 Hz, 2H), 7.80−7.78 (m, 1H), 7.53−7.47 (m, 2H), 7.43−7.37 (m, 3H), 7.29−7.23 (m, 4H), 4.02 (s, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 158.8, 152.8, 147.9, 142.3, 141.8, 141.2, 133.1, 131.5, 129.5, 129.0, 128.2, 127.7, 125.5, 115.6, 115.4, 115.0, 100.4, 56.8, 21.4. HRMS calcd for C23H21N2O4S (M + H)+: 421.1217, found: 421.1219. N-(4-Amino-8-methoxy-3-(4-methoxyphenyl)-2H-chromen-2-ylidene)methanesulfonamide (5r). Yield: 47%; white solid, mp: 227−228 °C. 1H NMR (400 MHz, DMSO-d6) δ: 7.84−7.82 (m, J = 6.4, 2.6 Hz, 1H), 7.40 (d, J = 6.4 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 3.97 (s, 3H), 3.82 (s, 3H), 3.15 (s, 3H). 13C NMR (100 MHz, DMSOd6) δ: 159.2, 159.0, 152.8, 147.9, 142.2, 132.7, 125.4, 124.9, 115.7, 115.3, 115.2, 114.9, 99.5, 57.2, 55.6, 42.6. HRMS calcd for C18H19N2O5S (M + H)+: 375.1009, found: 375.1012.
N-(4-Amino-3-butyl-5-chloro-2H-chromen-2-ylidene)-4methylbenzenesulfonamide (5s). Yield: 67%; white solid, mp: 181−182 °C. 1H NMR (400 MHz, DMSO-d6) δ: 7.85 (d, J = 8.1 Hz, 2H), 7.62 (br, 2H), 7.58 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.36−7.32 (m, 3H), 2.33 (s, 3H), 1.40−1.31 (m, 6H), 0.90 (t, J = 6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 158.4, 153.3, 151.2, 142.1, 141.6, 132.8, 129.5, 129.5, 128.9, 127.1, 117.1, 112.2, 100.3, 28.9, 24.0, 22.4, 21.4, 14.5. HRMS calcd for C20H22ClN2O3S (M + H)+: 405.1034, found: 405.1039. Gram-Scale Synthesis of Compound 4a. Tosyl azide 2a (TsN3, 7.5 mmol, 1.5 equiv), 1-butyl-4-ethynylbenzene 3a (5 mmol, 1.0 equiv), CuBr (0.50 mmol, 10 mol %), and benzo[d]isoxazole 1a (7.5 mmol, 1.5 equiv) were added to a solution of anhydrous DCE/DCM (10 mL, v/v = 1:1) at room temperature under N2. Then TEA (15 mmol, 3.0 equiv) was slowly added by a syringe. The reaction mixture was stirred at 80 °C for about 2−4 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with saturated NH4Cl (30 mL), and extracted with ethyl acetate (30.0 mL × 3). The crude residue was purified by column chromatography (ethyl acetate/DCM, 1:20) to give the desired product 4a (2.1 g, 94% yield) as a white solid. General Procedure for the Hydrolysis of 2-Imino-2Hchromen-4-amine 4a. To a screw-capped Schlenk tube 2imino-2H-chromen-4-amine 4a (0.30 mmol, 134 mg) and MeOH (0.5 mL) were added. Then H2SO4 (0.5 mL, 50% aqueous solution) was added at room temperature. The reaction mixture was heated to 100 °C and stirred overnight under N2. Upon completion, the reaction mixture was cooled down to room temperature, concentrated under vacuum to remove the volatile component. Then quenched with solid Na2CO3 to pH = 10. The reaction was extracted with ethyl acetate (5 mL × 3). The crude residue was purified by column chromatography to give the desired product 7 as a white solid (68.5 mg, 78% yield). 4-Amino-3-(4-butylphenyl)-2H-chromen-2-one 7. Yield: 78%; white solid, mp: 154−155 °C. 1H NMR (400 MHz, CDCl3) δ: 7.58−7.50 (m, 2H), 7.32−7.22 (m, 6H), 5.21 (br, 2H), 2.60 (t, J = 8.0 Hz, 2H), 1.61−1.55 (m, 2H), 1.42−1.33 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 162.4, 153.1, 150.2, 142.8, 131.7, 130.4, 129.9, 129.3, 123.6, 121.9, 117.4, 114.4, 100.6, 35.5, 33.5, 22.5, 14.0. HRMS calcd for C19H19N NaO2 (M + Na)+: 316.1313, found: 316.1308.
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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/acsomega.8b01179. 1
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H, 13C NMR spectra and X-ray Oak Ridge thermal ellipsoid plot of 4d (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (Z.C.). *E-mail:
[email protected] (S.P.). ORCID
Zhiyuan Chen: 0000-0002-5159-7287 Congbin Fan: 0000-0003-1472-4395 8166
DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
Article
ACS Omega Notes
(8) (a) Hardman-Baldwin, A. M.; Visco, M.; Wieting, J.; Stern, C.; Kondo, S.; Mattson, A. Silanediol-catalyzed chromenone functionalization. Org. Lett. 2016, 18, 3766−3769. (b) He, L.; Zhao, L.; Wang, D.; Wang, M.-X. Catalytic Asymmetric Difunctionalization of Stable Tertiary Enamides with Salicylaldehydes: Highly Efficient, Enantioselective, and Diastereoselective Synthesis of Diverse 4-Chromanol Derivatives. Org. Lett. 2014, 16, 5972−5975. (9) Guo, D.; Chen, T.; Ye, D.; Xu, J.; Jiang, H.; Chen, K.; Wang, H.; Liu, H. Cell-Permeable Iminocoumarine-Based Fluorescent Dyes for Mitochondria. Org. Lett. 2011, 13, 2884−2887. (10) Murugavel, G.; Punniyamurthy, T. Novel copper-catalyzed multicomponent cascade synthesis of iminocoumarin aryl methyl ethers. Org. Lett. 2013, 15, 3828−3831. (11) Wen, L. R.; Man, N.; Yuan, W.; Li, M. Direct Construction of 2-Aryliminochromenes from Arynes, N,S-Keteneacetals, and DMF Quick View Other Sources. J. Org. Chem. 2016, 81, 5942. (12) Peng, W.; Świtalska, M.; Wang, L.; Mei, Z.; Edazawa, Y.; Pang, C.; El-Sayed, I. T.; Wietrzyk, J.; Inokuchi, T. Synthesis and in vitro antiproliferative activity of new 11-aminoalkylamino-substituted chromeno[2,3-b]indoles. Eur. J. Med. Chem. 2012, 58, 441−451. (13) For selective examples: (a) Zhou, H.; Chen, W.; Chen, Z. Pd/ Norbornene Collaborative Catalysis on the Divergent Preparation of Heterocyclic Sulfoximine Frameworks. Org. Lett. 2018, 20, 2590− 2594. (b) Tu, Z.; Tan, J.; Chen, Z.; Tu, T. Iridium-Catalyzed Regioand Stereoselective C-H Oxidative Reaction to (Z)-3-Arylidene-2oxindole Imides under Neutral Conditions. Adv. Synth. Catal. 2017, 359, 4294−4299. (c) Huang, J.; Huang, Y.; Wang, T.; Huang, Q.; Wang, Z.; Chen, Z. Microwave-assisted Cp*CoIII-Catalyzed C-H Activation/Double C-N Bond Formation Reactions to Thiadiazine-1oxides. Org. Lett. 2017, 19, 1128−1131. (d) Zhu, H.; Chen, Z. DDQMediated Oxidative Radical Cycloisomerization of 1,5-Diynols: Regioselective Synthesis of Benzo[b]fluorenones under Metal-Free Conditions. Org. Lett. 2016, 18, 488−491. (e) Huang, J.; Yang, Y.; Chen, Z. Rh(II)-Catalyzed Regioselective Carbenoid Insertion Reaction of Simple Indoles with N-Sulfonyltriazoles: A Rapid Access to Tryptamine Vinylogues. Adv. Synth. Catal. 2016, 358, 201−206. (f) Xiao, Q.; Zhu, H.; Li, G.; Chen, Z. Synthesis of Trifluoromethanesulfanyl Benzofulvenes via a Cascade Electrophilic Cyclization under Mild Conditions. Adv. Synth. Catal. 2014, 356, 3809− 3815. (g) Xiao, Q.; Sheng, J.; Chen, Z.; Wu, J. Generation of 4((Trifluoro- methyl)thio)-2H-benzo[e][1,2]thiazine 1,1-Dioxides via a Reaction of Trifluoromethanesulfanylamide with 2-(2-Alkynyl)benzenesulfonamide. Chem. Commun. 2013, 49, 8647−8649. (14) For selective examples on Huisgen cycloadditions: (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3157. (15) For selected examples, see: (a) Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S. K. Catalytic One-Pot Synthesis of Cyclic Amidines by Virtue of Tandem Reactions Involving Intramolecular Hydroamination under Mild Conditions. J. Am. Chem. Soc. 2006, 128, 12366−12367. (b) Yoo, E. J.; Chang, S. A New Route to Indolines by the Cu-Catalyzed Cyclization Reaction of 2-Ethynylanilines with Sulfonyl Azides. Org. Lett. 2008, 10, 1163−1166. (c) Cui, S.-L.; Wang, J.; Wang, Y. Facile Access to Pyrazolines via Domino Reaction of the Huisgen Zwitterions with Aziridines. Org. Lett. 2008, 10, 13−16. (d) Bae, I.; Han, H.; Chang, S. Highly Efficient One-Pot Synthesis of N-Sulfonylamidines by Cu-Catalyzed Three-Component Coupling of Sulfonyl Azide, Alkyne, and Amine. J. Am. Chem. Soc. 2005, 127, 2038−2039. (e) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. Copper-Catalyzed Hydrative Amide Synthesis with Terminal Alkyne, Sulfonyl Azide, and Water. J. Am. Chem. Soc. 2005, 127, 16046− 16047. (f) Cho, S. H.; Chang, S. Rate-Accelerated Nonconventional Amide Synthesis in Water: A Practical Catalytic Aldol-Surrogate Reaction. Angew. Chem., Int. Ed. 2007, 46, 1897−1900. (g) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47, 2836. (h) Yoo, E. J.; Park, S. H.; Lee, S. H.; Chang, S. A New Entry of Copper-Catalyzed Four-Component Reaction: Facile Access to α-Aryl β-Hydroxy Imidates. Org. Lett. 2009, 11, 1155−1158. (i) Husmann, R.; Na, Y.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the China Postdoctoral Science Foundation (2017M612155), and the Jiangxi Province Postdoctoral Science Foundation (2016RC37) for financial support.
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REFERENCES
(1) (a) Yu, D.; Suzuki, M.; Xie, L.; Morris-Natschke, S.; Lee, K.-H. Recent progress in the development of coumarin derivatives as potent anti-HIV agents. Med. Res. Rev. 2003, 23, 322−345. (b) Coumarins: Biology, Applications, and Mode of Action; O’Kennedy, R.; Thomas, R. D., Eds.; Wiley: Chichester, U.K., 1997. (2) Dauzonne, D.; Folléas, B.; Martinez, L.; Chabot, G. Synthesis and in vitro cytotoxicity of a series of 3-aminoflavones. Eur. J. Med. Chem. 1997, 32, 71−82. (3) (a) Hayashi, K.; Mori, J.; Saito, H.; Hayashi, T. Antiviral targets of a chromene derivative from Sargassum micracanthum in the replication of human cytomegalovirus. Biol. Pharm. Bull. 2006, 29, 1843. (b) Inaba, T.; Tanaka, K.; Takeno, R.; Nagaki, H.; Yoshida, C.; Takano, S. Synthesis and antiinflammatory activity of 7-methanesulfonylamino-6-phenoxychromones. Antiarthritic effect of the 3formylamino compound (T-614) in chronic inflammatory disease models. Chem. Pharm. Bull. 2000, 48, 131. (c) Tanaka, K.; Yamamoto, T.; Aikawa, Y.; Kizawa, K.; Muramoto, K.; Matsuno, H.; Muraguchi, A. Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice. Rheumatology 2003, 42, 1365. (4) Aikawa, Y.; Yamamoto, M.; Yamamoto, T.; Morimoto, K.; Tanaka, K. An anti-rheumatic agent T-614 inhibits NF-κB activation in LPS- and TNF-α-stimulated THP-1 cells without interfering with IκBα degradation. Inflammation Res. 2002, 51, 188−194. (5) (a) Peng, S.; Wang, L.; Huang, J.; Sun, S.; Guo, H.; Wang, J. Palladium-Catalyzed Oxidative Annulation via C-H/N-H Functionalization: Access to Substituted Pyrroles. Adv. Synth. Catal. 2013, 355, 2550−2557. (b) Hua, C.; Zhang, K.; Xin, M.; Ying, T.; Gao, J.; Jia, J.; Li, Y. High quantum yield and pH sensitive fluorescence dyes based on coumarin derivatives: fluorescence characteristics and theoretical study. RSC Adv. 2016, 6, 49221−49227. (c) Saha, M.; Pradhan, K.; Das, A. R. Facile and eco-friendly synthesis of chromeno[4,3-b]pyrrol4(1H)-one derivatives applying magnetically recoverable nano crystalline CuFe2O4 involving a domino three-component reaction in aqueous media. RSC Adv. 2016, 6, 55033−55038. (6) (a) Baskar, B.; Wittstein, K.; Sankar, M.; Khedkar, V.; Schü rmann, M.; Kumar, K. Stereoselective Cascade DoubleAnnulations Provide Diversely Ring-Fused Tetracyclic Benzopyrones. Org. Lett. 2012, 14, 5924. (b) Vedachalam, S.; Zeng, J.; Gorityala, B.; Antonio, M.; Liu, X. N-Heterocyclic Carbene-Catalyzed Intramolecular Aldehyde-Nitrile Cross Coupling: An Easy Access to 3Aminochromones. Org. Lett. 2010, 12, 352−355. (c) Robinson, C. W.; Rye, C. S.; Chessum, N. E. A.; Jones, K. A model β-sheet interaction and thermodynamic analysis of β-strand mimetics. Org. Biomol. Chem. 2015, 13, 7402−7407. (d) Wang, Q.; Zhang, Z.; Zhang, X.; Zhang, J.; Kang, Y.; Peng, J. Synthesis of 7a-phenyl-1a,7adihydro-benzopyrano[2,3-b]azirin-7-ones via photoisomerization reaction. RSC Adv. 2015, 5, 4788−4794. (7) (a) Wang, L.; Liu, X.; Dong, Z.; Fu, X.; Feng, X. Asymmetric intramolecular oxa-Michael addition of activated α,β-unsaturated ketones catalyzed by a chiral N,N′-dioxide nickel (II) complex: highly enantioselective synthesis of flavanones. Angew. Chem., Int. Ed. 2008, 47, 8670−8673. (b) Biddle, M. M.; Lin, M.; Scheidt, K. Catalytic Enantioselective Synthesis of Flavanones and Chromanones. J. Am. Chem. Soc. 2007, 129, 3830−3831. (c) Butler, J. D.; Conrad, W.; Lodewyk, M.; Fettinger, J.; Tantillo, D.; Kurth, M. Synthesis of Substituted Chromanones: An Organocatalytic Aldol/oxa-Michael Reaction. Org. Lett. 2010, 12, 3410−3413. 8167
DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
Article
ACS Omega S.; Bolm, C.; Chang, S. Copper-catalyzed one-pot synthesis of αfunctionalized imidates. Chem. Commun. 2010, 46, 5494. (j) Lu, W.; Song, W. Z.; Hong, D.; Lu, P.; Wang, Y. Copper-Catalyzed One-Pot Synthesis of 2-Alkylidene-1,2,3,4- tetrahydropyrimidines. Adv. Synth. Catal. 2009, 351, 1768. (k) Jin, H.; Xu, X.; Gao, J.; Zhong, J.; Wang, Y. Copper-Catalyzed One-Pot Synthesis of Substituted Benzimidazoles. Adv. Synth. Catal. 2010, 352, 347. (l) Song, W.; Lu, W.; Wang, J.; Lu, P.; Wang, Y. A Facile Route to γ-Nitro Imidates via FourComponent Reaction of Alkynes with Sulfonyl Azides, Alcohols, and Nitroolefins. J. Org. Chem. 2010, 75, 3481. (m) Cui, S.-L.; Wang, J.; Wang, Y. Copper-Catalyzed Multicomponent Reaction: Facile Access to Functionalized 5-Arylidene-2-imino-3-pyrrolines. Org. Lett. 2007, 9, 5023−5025. (n) Wang, J.; Wang, J.; Zhu, Y.; Lu, P.; Wang, Y. Copper-Cascade Catalysis: Synthesis of 3-Functionalized Indoles. Chem. Commun. 2011, 47, 3275−3277. (o) Wang, J.; Lu, P.; Wang, Y. Copper-catalyzed multi-component synthesis of acrylamidines and benzoimidazoles. Org. Chem. Front. 2015, 2, 1346−1351. (p) Xing, Y.; Cheng, B.; Wang, J.; Lu, P.; Wang, Y. Copper-Catalyzed ThreeComponent Synthesis of 3-Aminopyrazoles and 4-Iminopyrimidines via β-Alkynyl-N-sulfonyl Ketenimine Intermediates. Org. Lett. 2014, 16, 4814−4817. (q) Sun, L.; Zhu, Y.; Lu, P.; Wang, Y. Cu-Catalyzed 1,2-Dihydroisoquinolines Synthesis from o-Ethynyl Benzacetals and Sulfonyl Azides. Org. Lett. 2013, 15, 5894−5897. (r) Wang, J.; Wang, J.; Lu, P.; Wang, Y. Copper-Catalyzed Cascade Preparation of Dihydropyrimidin-4-ones from N-(Prop-2-yn-1-yl)amides and Azides. J. Org. Chem. 2013, 78, 8816−8820. (s) Jiang, Z.; Lu, P.; Wang, Y. Three-Component Reaction of Propargyl Amines, Sulfonyl Azides, and Alkynes: One-Pot Synthesis of Tetrasubstituted Imidazoles. Org. Lett. 2012, 14, 6266−6269. (16) (a) Shang, Y.; He, X.; Hu, J.; Wu, J.; Zhang, M.; Yu, S.; Zhang, Q. Copper-Catalyzed Efficient Multicomponent Reaction: Synthesis of Benzoxazoline-Amidine Derivatives. Adv. Synth. Catal. 2009, 351, 2709. (b) Cano, I.; Alvarez, E.; Nicasio, M. C.; Péerez, P. J. Regioselective Formation of 2,5-Disubstituted Oxazoles Via Copper(I)-Catalyzed Cycloaddition of Acyl Azides and 1-Alkynes. J. Am. Chem. Soc. 2011, 133, 191. (c) Yao, W.; Pan, L.; Zhang, Y.; Wang, G.; Wang, X.; Ma, C. Three-component assembly and divergent ringexpansion cascades of functionalized 2-iminooxetanes. Angew. Chem., Int. Ed. 2010, 49, 9210. (d) Chen, Z.; Ye, C.; Gao, L.; Wu, J. Diversity-oriented approach to 1,2-dihydroisoquinolin-3(4H)-imines via copper(I)-catalyzed reaction of (E)-2-ethynylphenylchalcone, sulfonyl azide and amine. Chem. Commun. 2011, 47, 5623−5626. (e) Shang, Y.; Ju, K.; He, X.; Hu, J.; Yu, S.; Zhang, M.; Liao, K.; Wang, L.; Zhang, P. J. Org. Chem. 2010, 75, 5743. (f) Chen, Z.; Zheng, D.; Wu, J. A Facile Route to Polysubstituted Indoles via Three-Component Reaction of 2-Ethynylaniline, Sulfonyl Azide, and Nitroolefin. Org. Lett. 2011, 13, 848−851. (g) Namitharana, K.; Pitchumani, K. Copper(I)-catalyzed [3+2] cycloaddition/ring-opening rearrangement/[4+2] cycloaddition/aromatization cascade. An unprecedented chemo- and stereoselective three-component coupling of sulfonyl azide, alkyne and N-arylidenepyridin-2-amine to pyrido[1,2-a]pyrimidin-4-imine. Adv. Synth. Catal. 2013, 355, 93. (h) Yao, B.-B.; Shen, C.; Liang, Z.-J.; Zhang, Y.-H. Copper-Catalyzed Reaction of Ketenimine and in Situ Generated Immonium Ion: Access to α,βUnsaturated Amidines. J. Org. Chem. 2014, 79, 936. (i) Li, B.-S.; Yang, B.-M.; Wang, S.-H.; Zhang, Y.-Q.; Cao, X.-P.; Tu, Y.-Q. Copper(i)catalyzed intramolecular [2 + 2] cycloaddition of 1,6-enyne-derived ketenimine: an efficient construction of strained and bridged 7substituted-3-heterobicyclo[3.1.1]heptan-6-one. Chem. Sci. 2012, 3, 1975. (j) Cheng, G.; Cui, X. Efficient Approach to 4-Sulfonamidoquinolines via Copper(I)-Catalyzed Cascade Reaction of Sulfonyl Azides with Alkynyl Imines. Org. Lett. 2013, 15, 1480. (k) Rajagopal, B.; Chen, Y.-Y.; Chen, C.-C.; Liu, X.-Y.; Wang, H.-R.; Lin, P.-C. Cu(I)-Catalyzed Synthesis of Dihydropyrimidin-4-ones toward the Preparation of β- and β3-Amino Acid Analogues. J. Org. Chem. 2014, 79, 1254. (l) Ramanathan, D.; Pitchumani, K. Copper(I)-Catalyzed One-Pot Synthesis of Highly Functionalized Pyrrolidines from Sulfonyl Azides, Alkynes, and Dimethyl 2-(phenylamino)maleate. Eur. J. Org. Chem. 2015, 2015, 463.
(17) (a) Cui, S.-L.; Lin, X.-F.; Wang, Y.-G. Novel and Efficient Synthesis of Iminocoumarins via Copper-Catalyzed Multicomponent Reaction. Org. Lett. 2006, 8, 4517. (b) Shen, Y.; Cui, S.; Wang, J.; Chen, X.; Lu, P.; Wang, Y.-G. Copper-Catalyzed Three-Component Synthesis of 2-Iminodihydrocoumarins and 2-Iminocoumarins. Adv. Synth. Catal. 2010, 352, 1139. (18) Yi, F.; Zhang, S.; Huang, Y.; Zhang, L.; Yi, W. An Efficient OnePot Protocol for the Synthesis of Polysubstituted 4-Aminoiminocoumarins and 4-Aminoquinolines by a Copper-Catalyzed Three-Component Reaction. Eur. J. Org. Chem. 2017, 102−110. (19) (a) Han, Y.; Li, X.; Sun, Z.; Zhu, X.; Li, M.; Song, X.; Liang, Y.M. Lewis acid-catalyzed [4+2] annulation between propargylic alcohols with benzo[d]isoxazoles. Adv. Synth. Catal. 2017, 359, 2735−2740. (b) Lei, X.; Gao, M.; Tang, Y. Rh(II)-Catalyzed Transannulation of N-Sulfonyl-1,2,3-Triazoles with 2,1-Benzisoxazoles or 1,2-Benzisoxazoles. Org. Lett. 2016, 18, 4990−4993. (20) (a) Kemp, D. S.; Casey, M. L. Physical organic chemistry of benzisoxazoles. II. Linearity of the Brønsted free energy relation for the base-catalyzed decomposition of benzisoxazoles. J. Am. Chem. Soc. 1973, 95, 6670−6680. (b) Casey, M. L.; Kemp, D. S.; Paul, K. G.; Cox, D. D. Physical organic chemistry of benzisoxazoles. I. Mechanism of the base-catalyzed decomposition of benzisoxazoles. J. Org. Chem. 1973, 38, 2294−2301. (21) For a radical ring-opening of benzoisoxazole: Nunes, C. M.; Pinto, S. M. V.; Reva, I.; Fausto, R. Photochemistry of 3-amino-1,2benzisoxazole: unexpected photoisomerization of an amino-spiro-2Hazirine to a 1H-diazirine. Tetrahedron Lett. 2016, 57, 5038−5041. (22) (a) Zhao, Y.; Beuchat, C.; Domoto, Y.; Gajewy, J.; Wilson, A.; Mareda, J.; Sakai, N.; Matile, S. Anion-π Catalysis. J. Am. Chem. Soc. 2014, 136, 2101−2111. (b) Röthlisberger, D.; Khersonsky, O.; Wollacott, A.; Jiang, L.; DeChancie, J.; Betker, J.; Gallaher, J.; Althoff, E.; Zanghellini, A.; Dym, O.; Albeck, S.; Houk, K. N.; Tawfik, D. S.; Baker, D. Kemp elimination catalysts by computational enzyme design. Nature 2008, 453, 190−195. (c) Hu, Y.; Houk, K. N.; Kikuchi, K.; Hotta, K.; Hilvert, D. Nonspecific medium effects versus specific group positioning in the antibody and albumin catalysis of the basepromoted ring-opening reactions of benzisoxazoles. J. Am. Chem. Soc. 2004, 126, 8197−8205. (d) Kennan, A. J.; Whitlock, H. W. HostCatalyzed Isoxazole Ring Opening: A Rationally Designed Artificial Enzyme. J. Am. Chem. Soc. 1996, 118, 3027−3028. (23) Yoo, E. J.; Ahlquist, M.; Kim, S. K.; Bae, I.; Fokin, V. V.; Sharpless, K. B.; Chang, S. Copper-Catalyzed Synthesis of N-Sulfonyl1,2,3-triazoles: Controlling Selectivity. Angew. Chem., Int. Ed. 2007, 46, 1730−1733. (24) CCDC 1586533 (4d) contain the supplementary crystallographic data for this paper. (25) Bargagna, A.; Longobardi, M.; Mariani, E.; Schenone, P.; Russo, S.; Vitagliano, S.; De Novellis, V.; Marmo, E. N,N-Disubstituted 4amino-(6-methoxy)-3-phenyl-2H-naphtho[1,2-b]pyran-2-ones with antiarrhythmic, platelet-antiaggregating and local-anesthetic activities. Farmaco, Ed. Sci. 1988, 43, 857−877.
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DOI: 10.1021/acsomega.8b01179 ACS Omega 2018, 3, 8160−8168
