劉 輝, 張曉梅

(1.中國科學(xué)院 成都有機化學(xué)研究所,四川 成都 610041；2.西華大學(xué) 化學(xué)系, 四川 成都 610039；3.中國科學(xué)院大學(xué), 北京 100049)

異噁唑類衍生物具有多種生物活性,異噁唑也常作為關(guān)鍵的活性結(jié)構(gòu)片段廣泛存在于農(nóng)藥、醫(yī)藥和生物活性分子中[1-3]。近年來研究也表明,在分子結(jié)構(gòu)中引入異噁唑骨架有助于提高化合物生物活性,降低其毒性和改善藥代動力學(xué)的特點[4]。如Chart 1所示,氯苯西林(Cloxacillin)、雙氯西林(Dicloxacillin)、苯甲異噁唑青霉素(Oxacillin)及氟氯西林(Flucloxacillin)等被廣泛用于治療青霉素耐藥型金黃色葡萄球菌所導(dǎo)致的感染[5-8]。鵝膏氨酸(Ibotenic acid)是日本科學(xué)家在1964年從毒蠅鵝膏菌中提取出來的天然產(chǎn)物,具有很強的神經(jīng)毒性,常被用作腦損傷劑[9-10]?；诋悋f唑在藥物中的重要作用,化學(xué)家們已經(jīng)開發(fā)了多種可行的合成異噁唑類化合物的方法。例如1,3-雙羰基化合物與羥胺反應(yīng)[11-12],α-炔酮(醛)與羥胺反應(yīng)[13-14],鹵代α,β-不飽和羰基化合物[15]與羥胺反應(yīng)等。雖然已有多種方法可用于構(gòu)建該類化合物,但仍存在一些缺點：使用1,3-雙羰基化合物合成時會涉及到選擇性；α-炔酮(醛)、鹵代α,β-不飽和羰基化合物等原料穩(wěn)定性差且產(chǎn)率低,不利于反應(yīng)放大。

Chart 1

對苯醌及其衍生物具有較高的化學(xué)活性,由于含有α,β-不飽和羰基結(jié)構(gòu),可與多種親核試劑發(fā)生1,2-或1,4-加成反應(yīng),加成產(chǎn)物很容易進一步芳構(gòu)化形成芳基化產(chǎn)物。近年來,本課題組在對苯醌及其衍生物參與的反應(yīng)研究中取得了一定進展[16-19]。為了進一步研究對苯醌及其衍生物的反應(yīng),本文實現(xiàn)了在酸催化下對苯醌單亞胺與5-氨基異噁唑的加成反應(yīng),并以中等到良好的產(chǎn)率構(gòu)建一系列新穎的4-芳基-5氨基異噁唑類衍生物。

1 實驗部分

1.1 儀器與試劑

Büchi B-545型熔點儀；Bruker Avance-300 MHz型核磁共振儀(TMS為內(nèi)標(biāo))；Bruker FT-MS/BioTOF Q型質(zhì)譜儀。

所用試劑均為分析純。

1.2 化合物3a～3n的合成(以3a為例)

向干燥反應(yīng)管中依次加入5-氨基異噁唑(1a)19 mg(0.1 mmol)、2,5-二氯取代的對苯醌單亞胺(2a)50 mg(1.5 mmol)和聯(lián)萘酚磷酸酯(PA)3.5 mg(0.01 mmol),氯仿為溶劑,于0 ℃下反應(yīng)12 h(TLC檢測)。反應(yīng)結(jié)束后,直接經(jīng)硅膠柱層析純化得到白色固體3a40 mg,收率75%。

用類似的方法合成化合物3b～3n。

N-(2,5-dichloro-3-(5-(ethylamino)-3-phenylisoxazol-4-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3a)：white solid, m.p.187.7～189.3 ℃, 75% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.73(s, 2H), 7.48(d,J=8.3 Hz, 2H), 7.42～7.25(m, 4H), 7.21(d,J=8.1 Hz, 2H), 7.19～7.12(m, 2H), 6.93(t,J=5.8 Hz, 1H), 3.04(ddd,J=12.9 Hz, 8.9 Hz, 5.6 Hz, 2H), 2.30(s, 3H), 1.05(t,J=7.2 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 167.23, 161.71, 152.63, 143.40, 137.44, 132.85, 130.24, 129.74, 129.68, 129.25, 128.83, 127.01, 126.76, 125.99, 119.55, 119.01, 83.36, 37.16, 21.28, 15.64; HR-MS(ESI)m/z: Calcd for C24H21Cl2N3O4SH+{[M+H]+}518.0703(35Cl), 520.0673(35Cl37Cl), found 518.0684(35Cl), 520.0670(35Cl37Cl)。

N-(2,5-dichloro-3-(3-(3-chlorophenyl)-5-(ethylamino)isoxazol-4-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3b): white solid, m.p.166.3～168.4 ℃, 67% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.85(s, 1H), 9.73(s, 1H), 7.52～7.41(m, 3H), 7.37(t,J=7.9 Hz, 1H), 7.28(s, 1H), 7.23(t,J=1.9 Hz, 1H), 7.19(d,J=8.0 Hz, 2H), 7.10～7.01(m, 2H), 3.17～2.97(m, 2H), 2.30(s, 3H), 1.05(t,J=7.1 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 167.13, 160.10, 152.37, 142.90, 137.31, 133.16, 132.54, 132.05, 130.50, 129.33, 129.17, 126.62, 126.11, 125.75, 124.97, 118.82, 118.78, 82.90, 36.83, 20.94, 15.28; HR-MS(ESI)m/z: Calcd for C24H20Cl3N3O4SH+{[M+H]+}552.0313(35Cl), 556.0254(35Cl37Cl2), found 552.0311(35Cl), 556.0286(35Cl37Cl2)。

N-(2,5-dichloro-3-(3-(4-chlorophenyl)-5-(ethylamino)isoxazol-4-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3c): white solid, m.p.204.4～206.8 ℃, 75% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.75(s, 2H), 7.49(d,J=7.8 Hz, 2H), 7.41(d,J=8.2 Hz, 2H), 7.31(s, 1H), 7.21(d,J=8.0 Hz, 2H), 7.16(d,J=8.1 Hz, 2H), 6.99(t,J=5.7 Hz, 1H), 3.13～2.99(m, 2H), 2.31(s, 3H), 1.05(t,J=7.2 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 167.05, 160.36, 152.32, 142.91, 137.34, 134.04, 132.31, 129.37, 129.15, 128.97, 128.70, 128.11, 126.72, 125.74, 118.88, 82.85, 36.85, 20.96, 15.33; HR-MS(ESI)m/z: Calcd for C24H20Cl3N3O4SH+{[M+H]+}552.0313(35Cl), 556.0254(35Cl37Cl2), found 552.0292(35Cl), 556.0240(35Cl37Cl2)。

N-(3-(3-(4-bromophenyl)-5-(ethylamino)isoxazol-4-yl)-2,5-dichloro-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3d): white solid, m.p.197.3～199.5 ℃, 57% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.75(s, 2H), 7.54(d,J=8.5 Hz, 2H), 7.48(d,J=8.0 Hz, 2H), 7.31(s, 1H), 7.21(d,J=7.9 Hz, 2H), 7.09(d,J=8.5 Hz, 2H), 6.99(t,J=5.8 Hz, 1H), 3.14～2.97(m, 2H), 2.31(s, 3H), 1.04(t,J=7.1 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ 167.04, 160.40, 152.27, 142.87, 137.35, 132.26, 131.55, 129.32, 129.06, 128.33, 126.67, 125.74, 122.71, 118.86, 82.84, 36.82, 20.93, 15.28; HR-MS(ESI)m/z: Calcd for C24H20BrCl2N3O4SH+{[M+H]+}595.9808(35Cl), 599.9749(37Cl), found 595.9788(35Cl), 599.9744(37Cl)。

N-(2,5-dichloro-3-(5-(ethylamino)-3-(4-fluorophenyl)isoxazol-4-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3e): white solid, m.p.216.5～216.9 ℃, 79% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.79(s, 1H), 9.72(s, 1H), 7.49(d,J=7.9 Hz, 2H), 7.30(s, 1H), 7.22(d,J=9.1 Hz, 2H), 7.18(d,J=6.6 Hz, 4H), 6.96(t,J=5.8 Hz, 1H), 3.13～2.98(m, 2H), 2.30(s, 3H), 1.05(t,J=7.2 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 166.96, 162.56(J=244.5 Hz), 160.45, 152.35, 142.87, 137.29, 132.38, 129.36, 129.11, 128.54(J=8.25 Hz), 126.71, 126.58, 125.67, 118.96, 118.81, 115.56(J=21.75 Hz), 82.79, 36.82, 20.91, 15.32; HR-MS(ESI)m/z: Calcd for C24H20Cl2FN3O4SH+{[M+H]+}536.0608(35Cl), 538.0579(35Cl37Cl), found 536.0572(35Cl), 538.0555(35Cl37Cl)。

N-(2,5-dichloro-3-(5-(ethylamino)-3-(4-methoxyphenyl)isoxazol-4-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3f): white solid, m.p.210.1～211.8 ℃, 78% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.74(s, 1H), 9.72(s, 1H), 7.50(d,J=8.3 Hz, 2H), 7.30(s, 1H), 7.21(d,J=8.0 Hz, 2H), 7.11(d,J=8.8 Hz, 2H), 6.92～6.80(m, 3H), 3.76(s, 3H), 3.04(dq,J=10.7, 6.9 Hz, 2H), 2.30(s, 3H), 1.04(t,J=7.1 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 166.83, 160.85, 159.94, 152.42, 142.89, 137.34, 132.58, 129.39, 129.04, 127.77, 126.72, 125.63, 122.40, 119.37, 118.66, 113.91, 82.64, 55.15, 36.82, 20.96, 15.36; HR-MS(ESI)m/z: Calcd for C25H23Cl2N3O5SH+{[M+H]+}548.0808(35Cl), 550.0779(35Cl37Cl), found 548.0817(35Cl), 550.0802(35Cl37Cl)。

N-(2,5-dichloro-3-(5-(ethylamino)-3-(furan-2-yl)isoxazol-4-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3g): white solid, m.p.215.2～217.4 ℃, 73% yield;1H NMR(300 MHz, Acetone-d6)δ: 8.73(s, 1H), 8.41(s, 1H), 7.64(d,J=7.6 Hz, 3H), 7.54(d,J=1.8 Hz, 1H), 7.31(d,J=8.0 Hz, 2H), 6.45(dd,J=3.4 Hz, 1.8 Hz, 1H), 6.37～6.28(m, 1H), 6.01(d,J=3.4 Hz, 1H), 3.31～3.19(m, 2H), 2.36(s, 3H), 1.15(t,J=7.2 Hz, 3H);13C NMR(75 MHz, Acetone-d6)δ: 168.17, 154.70, 153.05, 145.45, 144.54, 144.38, 138.26, 132.25, 130.43, 129.15, 128.13, 127.45, 120.12, 119.05, 112.08, 110.61, 82.44, 38.33, 21.47, 15.81; HR-MS(ESI)m/z: Calcd for C22H19Cl2N3O5SK+{[M+K]+}546.0054(35Cl), 548.0025(35Cl37Cl), found 546.0059(35Cl), 548.0023(35Cl37Cl)。

N-(2,5-dichloro-3-(5-(ethylamino)-3-(thiophen-2-yl)isoxazol-4-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3h): white solid, m.p.220.2～221.4 ℃, 88% yield;1H NMR(300 MHz, Acetone-d6)δ: 8.79(s, 1H), 8.41(s, 1H), 7.66(s, 1H), 7.63(d,J=8.4 Hz, 2H), 7.49(dd,J=5.1 Hz, 1.2 Hz, 1H), 7.27(d,J=8.0 Hz, 2H), 7.00(dd,J=5.1 Hz, 3.6 Hz, 1H), 6.75(dd,J=3.6 Hz, 1.2 Hz, 1H), 6.35(t,J=5.7 Hz, 1H), 3.38～3.12(m, 2H), 2.34(s, 3H), 1.15(t,J=7.2 Hz, 3H);13C NMR(75 MHz, Acetone-d6)δ: 168.50, 157.54, 153.34, 144.53, 138.19, 132.51, 131.94, 130.42, 129.45, 128.21, 128.12, 127.87, 127.58, 127.00, 120.20, 118.96, 82.94, 38.27, 21.49, 15.82; HR-MS(ESI)m/z: Calcd for C22H19Cl2N3O4S2Na+{[M+Na]+}546.0086(35Cl), 548.0057(35Cl37Cl), found 546.0078(35Cl), 548.0053(35Cl37Cl)。

N-(3-(3-(tert-butyl)-5-(ethylamino)isoxazol-4-yl)-2,5-dichloro-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3i): white solid, m.p.89.1～92.4 ℃, 74% yield;1H NMR(300 MHz, Acetone-d6)δ: 8.40(s, 1H), 8.35(s, 1H), 7.63(d,J=8.3 Hz, 2H), 7.61(s, 1H), 7.32(d,J=8.0 Hz, 2H), 5.87(t,J=5.9 Hz, 1H), 3.27～3.06(m, 2H), 2.39(s, 3H), 1.09(t,J=7.2 Hz, 3H), 0.99(s, 9H);13C NMR(75 MHz, Acetone-d6)δ: 170.22, 168.25, 153.21, 144.54, 138.14, 132.58, 130.47, 129.14, 128.18, 127.43, 120.67, 119.82, 82.51, 38.13, 33.55, 29.13, 21.48, 15.90; HR-MS(ESI)m/z: Calcd for C22H25Cl2N3O4SNa+{[M+Na]+}520.0835(35Cl), 522.0806(35Cl37Cl), found 520.0818(35Cl), 522.0788(35Cl37Cl)。

N-(2,5-dichloro-4-hydroxy-3-(5-(methylamino)-3-phenylisoxazol-4-yl)phenyl)-4-methylbenzenesulfonamide(3j): white solid, m.p.193.0～195.4 ℃, 86% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.74(s, 2H), 7.47(d,J=7.9 Hz, 2H), 7.42～7.28(m, 3H), 7.27(s, 1H), 7.21(d,J=8.2 Hz, 2H), 7.17(dt,J=6.9 Hz, 1.5 Hz, 2H), 6.87(q,J=4.9 Hz, 1H), 2.66(d,J=4.8 Hz, 3H), 2.30(s, 3H);13C NMR(75 MHz, DMSO-d6)δ: 167.52, 161.34, 152.41, 143.00, 137.24, 132.68, 130.07, 129.46, 129.31, 129.07, 128.53, 126.71, 126.46, 125.67, 119.22, 118.75, 82.75, 28.43, 21.02; HR-MS(ESI)m/z: Calcd for C23H19Cl2N3O4SH+{[M+H]+}504.0546(35Cl), 506.0517(35Cl37Cl), found 504.0549(35Cl), 506.0539(35Cl37Cl)。

N-(2,5-dichloro-4-hydroxy-3-(5-(isopropylamino)-3-phenylisoxazol-4-yl)phenyl)-4-methylbenzenesulfonamide(3k): white solid, m.p.193.1～195.4 ℃, 55% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.71(s, 2H), 7.48(d,J=8.3 Hz, 2H), 7.42～7.28(m, 3H), 7.28(s, 1H), 7.20(d,J=8.1 Hz, 2H), 7.18～7.11(m, 2H), 6.78(d,J=8.4 Hz, 1H), 3.59(dt,J=14.1 Hz, 6.9 Hz, 1H), 2.29(s, 3H), 1.08(dd,J=6.5 Hz, 4.4 Hz, 6H);13C NMR(75 MHz, DMSO-d6)δ: 166.55, 161.33, 152.47, 142.91, 137.40, 132.62, 130.14, 129.45, 129.27, 129.14, 128.50, 126.73, 126.51, 125.66, 119.26, 118.63, 83.06, 44.44, 23.21, 23.05, 21.03; HR-MS(ESI)m/z: Calcd for C25H23Cl2N3O4SH+{[M+H]+}532.0859(35Cl), 534.0830(35Cl37Cl), found 532.0870(35Cl), 534.0841(35Cl37Cl)。

N-(3-(5-(butylamino)-3-phenylisoxazol-4-yl)-2,5-dichloro-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3l): white solid, m.p.176.8～178.5 ℃, 60% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.74(s, 2H), 7.48(d,J=8.3 Hz, 2H), 7.42～7.28(m, 3H), 7.27(s, 1H), 7.20(d,J=8.2 Hz, 2H), 7.17(dd,J=8.2 Hz, 1.4 Hz, 2H), 6.98(t,J=6.0 Hz, 1H), 3.01(qd,J=7.4 Hz,2.3 Hz, 2H), 2.30(s, 3H), 1.40(p,J=7.2 Hz, 2H), 1.29～1.14(m, 2H), 0.83(t,J=7.3 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 166.99, 161.30, 152.41, 142.89, 137.36, 132.65, 130.11, 129.39, 129.22, 129.04, 128.47, 126.67, 126.46, 125.64, 119.26, 118.65, 82.62, 41.64, 31.75, 20.98, 19.29, 13.58; HR-MS(ESI)m/z: Calcd for C26H25Cl2N3O4SH+{[M+H]+}546.1016(35Cl), 548.0986(35Cl37Cl), found 546.0996(35Cl), 548.0974(35Cl37Cl)。

N-(2,5-dibromo-3-(5-(ethylamino)-3-phenylisoxazol-4-yl)-4-hydroxyphenyl)-4-methylbenzenesulfonamide(3m): white solid, m.p.189.3～193.8 ℃, 82% yield;1H NMR(300 MHz, Acetone-d6)δ: 8.70(s, 1H), 8.17(s, 1H), 7.75(s, 1H), 7.58(d,J=7.9 Hz, 2H), 7.44～7.36(m, 1H), 7.36～7.28(m, 4H), 7.24(d,J=8.0 Hz, 2H), 6.35～6.23(m, 1H), 3.37～3.20(m, 2H), 2.36(s, 3H), 1.18(t,J=7.2 Hz, 3H);13C NMR(75 MHz, Acetone-d6)δ: 168.38, 162.21, 154.14, 144.48, 138.21, 132.49, 131.27, 130.39, 130.11, 129.31, 128.09, 127.65, 126.27, 121.26, 109.54, 85.86, 38.25, 21.48, 15.91; HR-MS(ESI)m/z: Calcd for C24H21Br2N3O4SH+{[M+H]+}605.9692(79Br), 607.9672(79Br81Br), 609.9651(81Br), found 605.9682(79Br), 607.9682(79Br81Br), 609.9648(81Br)。

N-(3-(5-(ethylamino)-3-phenylisoxazol-4-yl)-4-hydroxy-2,5-dimethylphenyl)-4-methylbenzenesulfonamide(3n): white solid, m.p.204.4～205.7 ℃, 99% yield;1H NMR(300 MHz, DMSO-d6)δ: 9.11(s, 1H), 8.24(s, 1H), 7.43～7.33(m, 3H), 7.33～7.27(m, 2H), 7.24(dd,J=8.3 Hz, 1.7 Hz, 2H), 7.15(d,J=8.0 Hz, 2H), 6.79(s, 1H), 6.56(t,J=5.9 Hz, 1H), 3.02(dq,J=13.4 Hz, 6.7 Hz, 2H), 2.29(s, 3H), 2.06(s, 3H), 1.35(s, 3H), 1.03(t,J=7.1 Hz, 3H);13C NMR(75 MHz, DMSO-d6)δ: 166.92, 161.31, 153.76, 142.41, 137.60, 134.80, 130.84, 130.55, 129.24, 129.08, 128.35, 126.59, 126.54, 125.67, 121.51, 117.13, 84.21, 36.87, 20.93, 16.44, 15.54, 14.65; HR-MS(ESI)m/z: Calcd for C26H27N3O4SH+{[M+H]+}478.1795, found 478.1799。

2 結(jié)果與討論

2.1 反應(yīng)條件優(yōu)化

以3-苯基-5-氨基異噁唑1a和2,5-二氯取代的對苯醌單亞胺2a為反應(yīng)的模板底物,對反應(yīng)條件進行了篩選,實驗結(jié)果見表1。首先,考察了不同的酸對反應(yīng)的催化作用(Table 1, Entries 1～4),其中聯(lián)萘酚磷酸酯(PA)作催化劑時能以較好的產(chǎn)率得到目標(biāo)產(chǎn)物。接著為進一步提高反應(yīng)的產(chǎn)率,開展了對反應(yīng)溶劑的篩選。當(dāng)使用其他氯代溶劑時,反應(yīng)的產(chǎn)率均出現(xiàn)了不同程度的降低(Table 1, Entries 5～7)；在甲叔醚或氯苯中,反應(yīng)產(chǎn)率出現(xiàn)了大幅降低(Table 1, Entries 8, 10)；而在四氫呋喃和乙腈中反應(yīng)不能發(fā)生。因此,仍以氯仿為最優(yōu)溶劑。最后,在最優(yōu)催化劑和溶劑下對反應(yīng)溫度進行了考察(Table 1, Entries 13～14)。結(jié)果表明,降低反應(yīng)溫度對反應(yīng)速率減慢,產(chǎn)率也出現(xiàn)一定程度降低。綜上,以氯仿作溶劑,在PA(10 mmol/mmol)催化下,0 ℃反應(yīng)為最優(yōu)條件。

表1 5-氨基異噁唑與對苯醌單亞胺反應(yīng)條件的優(yōu)化

2.2 底物普適性研究

在最優(yōu)條件下,對反應(yīng)的底物進行了普適性研究,實驗結(jié)果見Scheme 1 所示。由結(jié)果表明,異噁唑C3位苯環(huán)取代基無論是給電子還是吸電子基都對反應(yīng)均具有很好的普適性(3a～3f)；異噁唑C3位為其他芳雜環(huán)或是烷烴取代基對該反應(yīng)依然有較好的適應(yīng)性(3g～3i)；異噁唑C5位氨基的不同保護基對該反應(yīng)同樣具有很好的適應(yīng)性(3j～3l)；對于對苯醌單亞胺上不同取代基考察發(fā)現(xiàn),當(dāng)使用給電子取代基時反應(yīng)可以以定量的產(chǎn)率得到目標(biāo)產(chǎn)物3n。

Scheme 1

報道了在溫和的條件下5-氨基異噁唑和取代對苯醌單亞胺發(fā)生的加成反應(yīng),可以以中等到優(yōu)秀的產(chǎn)率(55%～99% yield)構(gòu)建一系列新穎的異噁唑C4位芳基化產(chǎn)物。反應(yīng)對不同取代基的底物均具有很好的普適性。