CN110669021B - 一种3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯以及类似物的合成方法 - Google Patents

一种3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯以及类似物的合成方法 Download PDF

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CN110669021B
CN110669021B CN201911040826.XA CN201911040826A CN110669021B CN 110669021 B CN110669021 B CN 110669021B CN 201911040826 A CN201911040826 A CN 201911040826A CN 110669021 B CN110669021 B CN 110669021B
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李洪基
杨诗超
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Huaibei Normal University
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Abstract

本发明公开了一种3‑芳基‑4,5‑二氢异噁唑‑5‑基甲基对甲苯磺酸酯以及类似物的合成方法，属于有机化学技术领域。采用铁(II)催化Koser高价碘试剂(HIRs)促进I‑O键裂解，促进不饱和肟基自由基环化，得到异恶唑啉骨架产物3‑苯基‑4,5‑二氢异噁唑‑5‑基磺酸酯。磺酸酯基团作为离去基团，可以进一步转化为多种系列类似物。该方法为合成3‑芳基‑4,5‑二氢异噁唑‑5‑基甲基磺酸酯系列提供了一种简便、廉价、高效的途径。

Description

一种3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯以及类似物的 合成方法
技术领域
本发明涉及异噁唑杂环的合成方法，具体涉及一种3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯以及类似物的合成方法，属于有机化学中技术领域。
背景技术
异噁唑啉类化合物，尤其是3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯以及类似物，作为手性配体广泛应用于生物天然产物、农药和医药、以及不对称催化等领域。过去几年，在异噁唑啉的合成方面进行了大量的研究，包括过渡金属催化和无金属策略。对于含有非活性C＝C的肟类化合物，由于其具有形成异恶唑啉的可能性更为引发关注。但大多数环化反应都受到羟基的配位能力、对氧(空气)的敏感性以及金属催化剂用量大或需额外添加剂的严重限制。此外，环化产物的后期转化极为重要，但在大多数情况下不易完成。
在过去的几十年里，高价碘试剂因其制备简单、适用性强和合成用途广泛等优点，被广泛应用于复杂有机分子的合成。传统上，HIRs可以作为反应底物、氧化剂或促进剂等。多数反应主要依赖于HIRs与过渡金属催化剂结合。铁催化由于其经济性和低毒性，也取得了一定的进展。如Kuninobu报道了第一个Fe(CO)3促进了PhI(OAc)2(PIDA)中I-O键的裂解，产生了引发后续烯烃自由基加成的高价碘自由基。
然而采用廉价金属铁与高价碘结合用来合成异噁唑啉尚未得到充分研究，因此，探索在环境友好条件下采用高效构建结构多样3-苯基-4,5-二氢异噁唑-5-基甲基磺酸酯以及类似物的方法仍然是非常必要的。
发明内容
为了克服上述缺陷，本发明采用铁(II)催化Koser高价碘试剂(HIRs)促进I-O键裂解，促进不饱和肟基自由基环化，得到异恶唑啉骨架产物3-苯基-4,5-二氢异噁唑-5-基磺酸酯。磺酸酯基团作为离去基团，可以进一步转化为多种系列类似物。该方法为合成3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯系列提供了一种简便、廉价、高效的途径。
一种3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯的合成方法，包括如下操作：以不饱和肟1和高碘试剂2为原料，在铁催化剂存在下，反应得到3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯3，反应方程式如下：
Figure BDA0002252775630000021
其中，其中，Ar为苯基、取代苯基、萘基；取代苯基中，取代为C1-C4烷基，C1-C4烷氧基或卤素中的一种多两种；R为甲基、取代苯基、萘基；取代苯基中，取代为二甲基、硝基或卤素。
进一步地，在上述技术方案中，所述铁催化剂选自Fe(acac)2、FeCl2、FeBr2、FeSO4、Fe(acac)3、Fe(OAc)3、FeCl3等，优选Fe(acac)2。
进一步地，在上述技术方案中，所述有机溶剂选自THF、CH3OH、CH3CN、CH2Cl2、CHCl3、ClCH2CH2Cl、甲苯等。优选反应溶剂为THF、CH2Cl2、ClCH2CH2Cl或甲苯。
进一步地，在上述技术方案中，所述不饱和肟1和高碘试剂2为原料，在铁催化剂摩尔比为1:1-1.5:0.03-0.05。
进一步地，在上述技术方案中，反应可在空气中，也可在惰性氛围下进行，例如氮气氛围中。
进一步地，在上述技术方案中，反应温度选自0℃至30℃，优选室温反应。
为了拓展本发明的应用范围，采用上述方法制备的二氢异噁唑3经过与不同的亲核试剂反应，分别得到磺酸酯被PhO－、PhS－、NCS－、Br－、I－、N3 －等负离子取代后多种类型衍生产物4-9，丰富了产物种类，增加了该方法的实用性。
其中，磺酸酯被PhO－取代时，亲核试剂为PhONa、PhOLi或PhOK；磺酸酯被PhS－取代时，亲核试剂为PhSNa、PhSLi或PhSK；磺酸酯被NCS－取代时，亲核试剂为NaSCN或KSCN；磺酸酯被Br－取代时，亲核试剂为NaBr、LiBr或KBr；磺酸酯被I－取代时，亲核试剂为NaI、LiI或KI。上述亲核取代时，反应条件优选在丙酮溶剂中，60-90℃反应，直至原料反应完全。
磺酸酯被N3 －取代时，亲核试剂为NaN3，溶剂优选DMF或DMSO，在80-100℃反应，直至原料反应完全。
采用反应方程式表示如下：
Figure BDA0002252775630000041
为了进一步探索反应原理，做了如下对比性实验，反应结果采用方程式直观表示如下：
Figure BDA0002252775630000042
根据上述结果，TEMPO实验表明自由基的环化参与催化循环。模型反应，在氧气气氛下进行，表明氧气不影响自由基环化。此外，在H2O中反应，得到比例为3:4的3a/11混合物，证明TsO-被H2O亲核取代。
以1a和2a反应生成3a为例，推测反应可能机理为：
Figure BDA0002252775630000051
发明有益效果：
与以前使用PIDA饱和碳氢键氧化相比,本发明发展了利用铁催化剂，从Koser的HIRs在室温下形成高度活跃磺酰氧自由基是肟自由基能够得以关环的关键点，关环后得到3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯。
其中，产物分子中的磺酸酯作为很好的离去基，与不同的亲核试剂，如N3 －、Br－、I－、SCN－、OPh－、SPh－等负离子进行亲核取代衍生，从而形成系列类似物。
具体实施方式
实施例1
反应条件的优化
将(E)-1-苯基丁-3-烯-1-肟(1a,32.2mg,0.2mmol)、铁催化剂(5mol％)、有机溶剂(1.0mL)和[羟基(对甲苯磺酰氧)碘]苯(2a,98.1mg,0.25mmol)依次加入10mL反应管中。将反应管置于室温下搅拌，然后用TLC对反应管中的混合物进行检测。反应结束后，加入蒸馏水(10mL)，有机溶剂萃取。合并有机层，无水硫酸钠干燥，减压浓缩得到粗产物，用闪蒸色谱法(硅胶、石油醚/乙酸乙酯＝3:1～9:1)纯化，得到产物3a。
Figure BDA0002252775630000061
Figure BDA0002252775630000062
在反应条件筛选过程中，考察了不加催化剂(标号1)，以及不同的铁催化剂对反应的影响(标号2-8)、不同反应溶剂对反应的影响(标号9-15)、溶剂的含水与否、以及不同的反应时间以及是否氮气保护等影响(标号16-19)。最终确定了Fe(acac)2为最佳催化剂，二氯甲烷为为最佳溶剂。
实施例2：
将(E)-1-苯基丁-3-烯-1-肟(1a,32.2mg,0.2mmol)、Fe(acac)2(2.5mg,5mol％)、DCM(1.0mL)和[羟基(对甲苯磺酰氧)碘]苯(2a,98.1mg,0.25mmol)依次加入10mL反应管中。将反应管置于室温下搅拌6h，然后用TLC对反应管中的混合物进行检测。反应结束后，加入蒸馏水(10mL)，二氯甲烷(DCM,3×10mL)萃取。将有机层合并，无水硫酸钠干燥，减压浓缩得到粗产物，用闪蒸色谱法(硅胶、石油醚/乙酸乙酯＝3:1～9:1)纯化，得到53.7mg产物3a，白色固体，收率81％。
Figure BDA0002252775630000071
(3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl 4-methylbenzenesulfonate(3a):White solid；53.7mg,81％yield；1H NMR(600MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.63–7.61(m,2H),7.44–7.38(m,3H),7.34(d,J＝7.8Hz,2H),4.96–4.91(m,1H),4.17–4.10(m,2H),3.44(dd,J＝16.8,10.8Hz,1H),3.24(dd,J＝16.8,7.2Hz,1H),2.44(s,3H).13C NMR(150MHz,CDCl3)δ156.2,145.2,132.4,130.4,129.9,128.8,128.7,128.0,126.7,77.4,69.2,37.3,21.6.HRMS(ESI)([M+H]+)Calcd.For[C17H18NO4S]+:332.0951,Found:332.0949.
实施例3：
根据实施例2反应条件，仅改变底物1结构，得到反应产物3b-3s，具体结果如下：
Figure BDA0002252775630000072
(3-(p-Tolyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3b):White solid；53.9mg,78％yield；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.50(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),7.20(d,J＝8.0Hz,2H),4.94–4.87(m,1H),4.16–4.08(m,2H),3.42(dd,J＝17.2,10.8Hz,1H),3.21(dd,J＝16.8,6.8Hz,1H),2.44(s,3H),2.38(s,3H).13C NMR(101MHz,CDCl3)δ156.2,145.2,140.7,132.5,129.9,129.4,128.0,126.7,126.0,77.2,69.2,37.4,21.6,21.4.HRMS(ESI)([M+H]+)Calcd.For[C18H20NO4S]+:346.1108,Found:346.1108.
Figure BDA0002252775630000081
(3-(4-Ethylphenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3c):White solid；53.9mg,75％yield；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),4.95–4.88(m,1H),4.16–4.08(m,2H),3.42(dd,J＝16.8,10.4Hz,1H),3.22(dd,J＝16.8,6.8Hz,1H),2.67(q,J＝7.6Hz,2H),2.44(s,3H),1.25(t,J＝7.6Hz,3H).13C NMR(100MHz,CDCl3)δ156.2,147.0,145.2,132.4,129.9,128.3,128.0,126.8,126.2,77.2,69.2,37.4,28.8,21.6,15.3.HRMS(ESI)([M+H]+)Calcd.For[C19H22NO4S]+:360.1264,Found:360.1264.
Figure BDA0002252775630000082
(3-(4-Isopropylphenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3d):White solid；57.5mg,77％yield；1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.4Hz,2H),7.54(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),7.27–7.25(m,2H),4.94–4.87(m,1H),4.15–4.07(m,2H),3.42(dd,J＝16.8,10.4Hz,1H),3.22(dd,J＝16.8,6.8Hz,1H),2.98–2.88(m,1H),2.43(s,3H),1.26(d,J＝6.8Hz,6H).13CNMR(100MHz,CDCl3)δ156.1,151.6,145.1,132.5,129.9,128.0,126.8,126.3,77.2,69.2,37.4,34.0,23.7,21.6.HRMS(ESI)([M+H]+)Calcd.For[C20H24NO4S]+:374.1421,Found:374.1422.
Figure BDA0002252775630000091
(3-(4-(tert-Butyl)phenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3e):White solid；56.6mg,73％yield；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,2H),4.95–4.88(m,1H),4.15–4.07(m,2H),3.43(dd,J＝17.2,10.8Hz,1H),3.23(dd,J＝17.2,6.8Hz,1H),2.44(s,3H),1.33(s,9H).13C NMR(100MHz,CDCl3)δ156.1,153.9,145.1,132.5,129.9,128.0,126.6,126.0,125.7,77.2,69.2,37.5,34.9,31.1,21.6.HRMS(ESI)([M+H]+)Calcd.For[C21H26NO4S]+:388.1577,Found:388.1578.
Figure BDA0002252775630000092
(3-(4-Methoxyphenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3f):White solid；54.9mg,76％yield；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,2H),6.91(d,J＝8.8Hz,2H),4.93–4.86(m,1H),4.18–4.07(m,2H),3.84(s,3H),3.42(dd,J＝16.8,10.8Hz,1H),3.22(dd,J＝16.8,6.8Hz,1H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ161.3,155.8,145.2,130.0,128.3,128.0,121.4,114.2,77.1,69.2,55.4,37.6,21.7.HRMS(ESI)([M+H]+)Calcd.For[C18H20NO5S]+:362.1057,Found:362.1058.
Figure BDA0002252775630000101
(3-(4-Chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3g):White solid；64.4mg,88％yield；1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.0Hz,2H),7.55(d,J＝8.8Hz,2H),7.38–7.33(m,4H),4.98–4.91(m,1H),4.17–4.11(,2H),3.41(dd,J＝16.8,10.8Hz,1H),3.22(dd,J＝16.8,6.8Hz,1H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ155.3,145.2,136.4,132.5,129.9,129.0,128.0,127.9,127.4,77.7,69.1,37.1,21.6.HRMS(ESI)([M+H]+)Calcd.For[C17H17ClNO4S]+:366.0561,Found:366.0561.
Figure BDA0002252775630000102
(3-(4-Bromophenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3h):White solid；70.6mg,86％yield；1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.0Hz,2H),7.53–7.32(m,4H),7.33(d,J＝8.0Hz,2H),4.97–4.90(m,1H),4.19–4.08(m,2H),3.41(dd,J＝17.2,11.2Hz,1H),3.21(dd,J＝17.2,7.2Hz,1H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ155.4,145.2,132.4,131.9,129.9,128.1,127.9,127.8,124.6,77.8,69.1,36.9,21.6.HRMS(ESI)([M+H]+)Calcd.For[C17H17BrNO4S]+:410.0056,Found:410.0056.
Figure BDA0002252775630000111
(3-(m-Tolyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3i):White solid；51.1mg,74％yield；1H NMR(600MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.45(s,1H),7.40(d,J＝7.2Hz,1H),7.34(d,J＝7.8Hz,2H),7.29(t,J＝7.8Hz,1H),7.23(d,J＝7.8Hz,1H),4.94–4.90(m,1H),4.18–4.07(m,2H),3.43(dd,J＝17.4,10.8Hz,1H),3.24(dd,J＝16.8,6.6Hz,1H),2.44(s,3H),2.37(s,3H).13C NMR(150MHz,CDCl3)δ156.3,145.2,138.5,132.4,131.2,129.9,128.7,128.6,127.3,123.9,77.3,69.2,37.4,21.6,21.3.HRMS(ESI)([M+H]+)Calcd.For[C18H20NO4S]+:346.1108,Found:346.1109.
Figure BDA0002252775630000112
(3-(3-Methoxyphenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3j):White solid；52.0mg,72％yield；1H NMR(600MHz,CDCl3)δ7.78(d,J＝7.8Hz,2H),7.34(d,J＝8.4Hz,2H),7.30(t,J＝8.4Hz,1H),7.21–7.20(m,1H),7.13(d,J＝7.8Hz,1H),6.98–6.96(m,1H),4.95–4.90(m,1H),4.19–4.10(m,2H),3.82(s,3H),3.42(dd,J＝16.8,10.8Hz,1H),3.21(dd,J＝16.8,6.6Hz,1H),2.44(s,3H).13C NMR(150MHz,CDCl3)δ159.7,156.2,145.2,132.4,130.0,129.9,129.7,127.9,119.4,116.7,111.4,77.5,69.2,55.3,37.3,21.6.HRMS(ESI)([M+H]+)Calcd.For[C18H20NO5S]+:362.1057,Found:362.1057.
Figure BDA0002252775630000121
(3-(3-Chlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3k):White solid；59.3mg,81％yield；1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.0Hz,2H),7.58(s,1H),7.48(d,J＝7.2Hz,1H),7.39–7.31(m,4H),4.98–4.92(m,1H),4.20–4.11(m,2H),3.40(dd,J＝16.8,10.8Hz,1H),3.19(dd,J＝16.8,6.8Hz,1H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ155.1,145.2,134.6,132.3,130.5,130.2,129.9,129.8,127.8,126.6,124.7,77.8,69.2,36.7,21.5.HRMS(ESI)([M+H]+)Calcd.For[C17H17ClNO4S]+:366.0561,Found:366.0561.
Figure BDA0002252775630000122
(3-(3-Bromophenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3l):White solid；68.1mg,83％yield；1H NMR(600MHz,CDCl3)δ7.77(d,J＝8.4Hz,2H),7.74(s,1H),7.53(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,2H),7.26(t,J＝7.2Hz,1H),4.97–4.92m,1H),4.19–4.10(m,2H),3.42–3.37(m,1H),3.21–3.17(m,1H),2.44(s,3H).13C NMR(150MHz,CDCl3)δ155.1,145.2,133.2,132.3,130.8,130.2,129.9,129.6,127.9,125.2,122.8,77.8,69.1,36.8,21.6.HRMS(ESI)([M+H]+)Calcd.For[C17H17ClNO4S]+:410.0056,Found:410.0057.
Figure BDA0002252775630000131
(3-(2-Methoxyphenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3m)White solid；31.8mg,44％yield；δ1H NMR(600MHz,CDCl3)δ7.78(d,J＝8.4Hz,2H),7.65–7.63(m,1H),7.38–7.36(m,1H),7.32(d,J＝8.4Hz,2H),6.96–6.91(m,2H),4.88–4.83(m,1H),4.14–4.06(m,2H),3.83(s,3H),3.54(dd,J＝17.4,10.8Hz,1H),3.32(dd,J＝18.0,6.6Hz,1H),2.42(s,3H).13C NMR(150MHz,CDCl3)δ157.4,155.7,145.0,132.4,131.5,129.8,129.3,127.8,120.7,117.9,111.3,77.2,69.5,55.4,39.8,21.5.HRMS(ESI)([M+H]+)Calcd.For[C18H20NO5S]+:362.1057,Found:362.1057.
Figure BDA0002252775630000132
(3-(3,4-Dichlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3n):White solid；71.2mg,89％yield；1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.0Hz,2H),7.67(s,1H),7.49–7.46(m,2H),7.34(d,J＝8.0Hz,2H),5.00–4.93(m,1H),4.21–4.10(m,2H),3.40(dd,J＝16.8,11.2Hz,1H),3.20(dd,J＝16.8,6.8Hz,1H),2.45(s,3H).13C NMR(100MHz,CDCl3)δ154.5,145.3,134.5,133.1,132.4,130.8,130.0,128.8,128.4,127.9,125.8,78.1,69.0,36.8,21.6.HRMS(ESI)([M+H]+)Calcd.For[C17H16Cl2NO4S]+:400.0172,Found:400.0173.
Figure BDA0002252775630000141
(3-(3,4-Dimethylphenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3o):White solid；51.0mg,71％yield；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.4Hz,2H),7.41(s,1H),7.35–7.31(m,3H),7.15(d,J＝7.6Hz,1H),4.93–4.86(m,1H),4.18–4.14(m,2H),3.42(dd,J＝16.8,10.8Hz,1H),3.21(dd,J＝16.8,6.4Hz,1H),2.44(s,3H),2.28(d,J＝2.8Hz,6H).13C NMR(100MHz,CDCl3)δ156.3,145.1,139.4,137.0,132.5,129.9,128.0,127.8,126.3,124.3,77.2,69.3,37.5,21.6,19.7,19.6.HRMS(ESI)([M+H]+)Calcd.For[C19H22NO4S]+:360.1264,Found:360.1262.
Figure BDA0002252775630000142
(3-(3,5-Dichlorophenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3p):White solid；69.6mg,87％yield；1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.0Hz,2H),7.47–7.46(m,2H),7.39–7.34(m,3H),5.00–4.94(m,1H),4.20–4.11(m,2H),3.38(dd,J＝16.8,11.2Hz,1H),3.18(dd,J＝16.8,6.8Hz,1H),2.45(s,3H).13C NMR(100MHz,CDCl3)δ154.3,145.3,135.4,132.4,131.7,130.0,129.9,127.9,125.0,78.2,69.0,36.5,21.6.HRMS(ESI)([M+H]+)Calcd.For[C17H16Cl2NO4S]+:400.0172,Found:400.0172.
Figure BDA0002252775630000151
(3-(3,5-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3q):White solid；54.8mg,70％yield；1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.0Hz,2H),7.34(d,J＝8.0Hz,2H),6.75–6.74(m,2H),6.50(s,1H),4.95–4.88(m,1H),4.19–4.06(m,2H),3.40(dd,J＝16.8,10.8Hz,1H),3.17(dd,J＝16.8,6.4Hz,1H),2.44(s,3H).13C NMR(100MHz,CDCl3)δ160.8,156.2,145.2,132.4,130.5,129.9,127.9,104.7,102.5,77.5,69.2,55.4,37.2,21.6.HRMS(ESI)([M+H]+)Calcd.For[C19H22NO6S]+:392.1162,Found:392.1160.
Figure BDA0002252775630000152
(3-(Naphthalen-2-yl)-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3r):White solid；55.7mg,73％yield；1H NMR(400MHz,CDCl3)δ7.90–7.77(m,7H),7.54–7.49(m,2H),7.30(d,J＝8.0Hz,2H),5.00–4.93(m,1H),4.23–4.11(m,2H),3.53(dd,J＝16.8,10.8Hz,1H),3.34(dd,J＝16.8,6.8Hz,1H),2.39(s,3H).13C NMR(100MHz,CDCl3)δ156.3,145.2,134.0,132.8,132.4,129.9,128.5,128.4,127.9,127.8,127.2,127.1,126.7,126.3,123.4,77.6,69.2,37.2,21.6.HRMS(ESI)([M+H]+)Calcd.For[C21H20NO4S]+:382.1108,Found:382.1108.
Figure BDA0002252775630000161
(5-Methyl-3-phenyl-4,5-dihydroisoxazol-5-yl)methyl
4-methylbenzenesulfonate(3s):White solid；46.3mg,67％yield；1H NMR(600MHz,CDCl3)δ7.78–7.77(m,2H),7.60–7.58(m,2H),7.41–7.37(m,3H),7.32(d,J＝7.8Hz,2H),4.01(d,J＝2.4Hz,2H),3.38(d,J＝16.8Hz,1H),3.05(d,J＝16.8Hz,1H),2.43(s,3H),1.48(s,3H).13C NMR(150MHz,CDCl3)δ156.4,145.2,132.4,130.2,129.9,129.2,128.7,128.0,126.6,84.4,72.2,43.0,22.9,21.6.HRMS(ESI)([M+H]+)Calcd.For[C18H20NO4S]+:346.1108,Found:346.1109.
实施例4：
根据实施例2反应条件，仅改变高价碘试剂2结构，得到反应产物3t-3z，具体结果如下：
Figure BDA0002252775630000162
(3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl benzenesulfonate(3t):Whitesolid；52.0mg,82％yield；1H NMR(400MHz,CDCl3)δ7.92–7.90(m,2H),7.68–7.60(m,3H),7.55(t,J＝8.0Hz,2H),7.42–7.37(m,3H),4.98–4.91(m,1H),4.22–4.11(m,2H),3.45(dd,J＝16.8,10.8Hz,1H),3.25(dd,J＝16.8,6.8Hz,1H).13C NMR(100MHz,CDCl3)δ156.2,134.1,130.4,129.3,128.7,127.9,126.7,77.4,69.4,37.2.HRMS(ESI)([M+H]+)Calcd.For[C16H16NO4S]+:318.0795,Found:318.0794.
Figure BDA0002252775630000171
(3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl 4-chlorobenzenesulfonate(3u):White solid；59.6mg,85％yield；1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.4Hz,2H),7.62–7.60(m,2H),7.51(d,J＝8.8Hz,2H),7.43–7.38(m,3H),4.98–4.91(m,1H),4.20–4.15(m,2H),3.46(dd,J＝16.8,10.8Hz,1H),3.24(dd,J＝17.2,6.8Hz,1H).13C NMR(100MHz,CDCl3)δ156.2140.8,134.0,130.5,129.7,129.3,128.8,126.7,69.7,37.1.HRMS(ESI)([M+H]+)Calcd.For[C16H15ClNO4S]+:352.0405,Found:352.0405.
Figure BDA0002252775630000172
(3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl 3-nitrobenzenesulfonate(3v):White solid；65.2mg,90％yield；1H NMR(400MHz,CDCl3)δ8.74–8.72(m,1H),8.51–8.48(m,1H),8.24–8.22(m,1H),7.78(t,J＝8.0Hz,1H),7.59–7.57(m,2H),7.45–7.37(m,3H),4.98–4.92(m,1H),4.36–4.28(m,2H),3.48(dd,J＝16.8,10.8Hz,1H),3.25(dd,J＝16.8,6.8Hz,1H).13C NMR(100MHz,CDCl3)δ156.2,148.2,137.8,133.4,130.8,130.5,128.8,128.5,128.4,126.7,123.3,70.6,36.9.HRMS(ESI)([M+H]+)Calcd.For[C16H15N2O6S]+:363.0645,Found:363.0645.
Figure BDA0002252775630000181
(3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl
2,4-dimethylbenzenesulfonate(3w):White solid；54.5mg,79％yield；1H NMR(600MHz,CDCl3)δ7.84(d,J＝8.4Hz,1H),7.62–7.60(m,2H),7.43–7.38(m,3H),7.15(s,1H),7.12(d,J＝7.8Hz,1H),4.95–4.90(m,1H),4.13–4.06(m,2H),3.44(dd,J＝16.8,10.8Hz,1H),3.24(dd,J＝16.8,7.2Hz,1H),2.59(s,3H),2.37(s,3H).13C NMR(100MHz,CDCl3)δ156.2,145.0,138.4,133.4,130.7,130.3,130.1,128.8,128.7,126.7,126.6,77.5,69.2,37.1,21.3,20.1.HRMS(ESI)([M+H]+)Calcd.For[C18H20NO4S]+:346.1108,Found:346.1109.
Figure BDA0002252775630000182
(3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl
2,5-dimethylbenzenesulfonate(3x):White solid；55.2mg,80％yield；1H NMR(600MHz,CDCl3)δ7.78(s,1H),7.63–7.61(m,2H),7.43–7.38(m,3H),7.32(d,J＝7.8Hz,1H),7.23(d,J＝7.8Hz,1H),4.97–4.92(m,1H),4.15–4.07(m,2H),3.45(dd,J＝16.8,10.8Hz,1H),3.26(dd,J＝16.8,6.6Hz,1H),2.58(s,3H),2.37(s,3H).13C NMR(100MHz,CDCl3)δ156.2,136.2,135.4,134.7,133.4,132.6,130.4,130.3,128.8,128.7,126.7,77.5,69.2,37.2,20.7,19.7.HRMS(ESI)([M+H]+)Calcd.For[C18H20NO4S]+:346.1108,Found:346.1109.
Figure BDA0002252775630000191
(3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl naphthalene-2-sulfonate(3y):White solid；55.0mg,75％yield；1H NMR(400MHz,CDCl3)δ8.48(s,1H),7.99–7.91(m,3H),7.86–7.84(m,1H),7.70–7.61(m,2H),7.58–7.56(m,2H),7.42–7.34(m,3H),4.98–4.91(m,1H),4.25–4.14(m,2H),3.43(dd,J＝16.8,10.8Hz,1H),3.24(dd,J＝17.2,6.8Hz,1H).13C NMR(100MHz,CDCl3)δ156.2,135.4,132.2,131.9,130.4,129.9,129.8,129.5,129.3,128.7,128.0,127.9,126.7,122.4,77.4,69.5,37.2.HRMS(ESI)([M+H]+)Calcd.For[C20H18NO4S]+:368.0951,Found:368.0952.
Figure BDA0002252775630000192
(3-Phenyl-4,5-dihydroisoxazol-5-yl)methyl methanesulfonate(3z):Whitesolid；33.7mg,66％yield；1H NMR(600MHz,CDCl3)δ7.67–7.65(m,2H),7.45–7.39(m,3H),5.03–4.98(m,1H),4.40–4.32(m,2H),3.49(dd,J＝16.8,10.8Hz,1H),3.28(dd,J＝17.4,7.2Hz,1H),3.07(s,3H).13C NMR(150MHz,CDCl3)δ156.5,130.4,128.8,128.7,126.7,77.7,69.4,37.6,36.8.HRMS(ESI)([M+H]+)Calcd.For[C11H14NO4S]+:256.0638,Found:256.0638.
实施例5：
取10mL反应管，加入3a(66.3mg,0.2mmol)、NaOPh(46.4mg,0.4mmol)和丙酮(1.0mL)。将反应管置于80℃条件下反应6h，用薄层色谱法检测。反应结束后，加入蒸馏水(10mL)，用二氯甲烷(DCM,3×10mL)萃取。合并有机层，无水硫酸钠干燥，减压浓缩得到粗品，用闪蒸色谱法(硅胶、石油醚/乙酸乙酯＝3:1至9:1)纯化，得到4a，白色固体(38.5mg,76％收率)。
Figure BDA0002252775630000201
(Phenoxymethyl)-3-phenyl-4,5-dihydroisoxazole(4a):White solid；38.5mg,76％yield；1H NMR(600MHz,CDCl3)δ7.70–7.69(m,2H),7.41–7.40(m,3H),7.28(t,J＝7.2Hz,2H),6.96(t,J＝7.2Hz,1H),6.91(d,J＝8.4Hz,2H),5.13–5.08(m,1H),4.17(dd,J＝9.6,4.8Hz,1H),4.04(dd,J＝10.2,6.0Hz,1H),3.50(dd,J＝16.8,10.8Hz,1H),3.38(dd,J＝16.8,7.2Hz,1H).13C NMR(150MHz,CDCl3)δ158.4,156.4,130.2,129.5,129.3,128.7,126.7,121.3,114.6,78.7,68.4,37.6.HRMS(ESI)([M+H]+)Calcd.For[C16H16NO2]+:254.1176,Found:254.1174.
实施例6：
取10mL反应管，加入3a(66.3mg,0.2mmol)，NaSPh(52.9mg,0.4mmol)，加入丙酮(1.0mL)。将反应管置于80℃条件下反应6h，薄层色谱法检测。反应结束后，加入蒸馏水(10mL)，用二氯甲烷(DCM,3×10mL)萃取。合并有机层，无水硫酸钠干燥，减压浓缩得到粗品，用闪蒸色谱法(硅胶、石油醚/乙酸乙酯＝3:1至9:1)纯化，得到产物5a,为白色固体(47.9mg，收率89％)。
Figure BDA0002252775630000211
Phenyl-5-((phenylthio)methyl)-4,5-dihydroisoxazole(5a):White solid；47.9mg,89％yield；1H NMR(600MHz,CDCl3)δ7.66–7.64(m,2H),7.42–7.39(m,5H),7.32–7.29(m,2H),7.24–7.22(m,1H),4.89–4.84(m,1H),3.45–3.35(m,2H),3.26(dd,J＝16.8,6.6Hz,1H),2.98(dd,J＝13.8,9.0Hz,1H).13C NMR(150MHz,CDCl3)δ156.2,134.7,130.1,130.0,129.3,129.1,128.7,126.8,126.7,79.5,39.5,37.7.HRMS(ESI)([M+H]+)Calcd.For[C16H16NOS]+:270.0947,Found:270.0946.
实施例7：
取10mL反应管，加入3a(66.3mg,0.2mmol)，KSCN(38.9mg,0.4mmol)，加入丙酮(1.0mL)。将反应管置于80℃条件下反应8h，薄层色谱法检测。反应结束后，加入蒸馏水(10mL)，用二氯甲烷(DCM,3×10mL)萃取。合并有机层，无水硫酸钠干燥，减压浓缩得到粗品，用闪蒸色谱法(硅胶、石油醚/乙酸乙酯＝3:1至9:1)纯化，得到产物6a,为白色固体(37.5mg，收率86％)。
Figure BDA0002252775630000212
Phenyl-5-(thiocyanatomethyl)-4,5-dihydroisoxazole(6a):White solid；37.5mg,86％yield；1H NMR(600MHz,CDCl3)δ7.68–7.66(m,2H),7.46–7.41(m,3H),5.10–5.05(m,1H),3.64–3.60(m,1H),3.32–3.24(m,2H),3.17(dd,J＝13.8,6.6Hz,1H).13C NMR(150MHz,CDCl3)δ156.4,130.6,128.8,128.6,126.8,111.5,78.7,39.4,37.0.HRMS(ESI)([M+H]+)Calcd.For[C11H11N2OS]+:219.0587,Found:219.0586.
实施例8：
取10mL反应管，加入3a(66.3mg,0.2mmol)，NaBr(41.2mg,0.4mmol)，加入丙酮(1.0mL)。将反应管置于80℃条件下反应8h，薄层色谱法检测。反应结束后，加入蒸馏水(10mL)，用二氯甲烷(DCM,3×10mL)萃取。合并有机层，无水硫酸钠干燥，减压浓缩得到粗品，用闪蒸色谱法(硅胶、石油醚/乙酸乙酯＝3:1至9:1)纯化，得到产物7a,为白色固体(38.4mg，收率80％)。
Figure BDA0002252775630000221
5-(Bromomethyl)-3-phenyl-4,5-dihydroisoxazole(7a):White solid；38.4mg,80％yield；1H NMR(600MHz,CDCl3)δ7.69–7.65(m,2H),7.44–7.39(m,3H),5.02–4.97(m,1H),3.57(dd,J＝10.8,4.2Hz,1H),3.51(dd,J＝16.8,10.2Hz,1H),3.41(dd,J＝10.2,8.4Hz,1H),3.32(dd,J＝17.4,6.6Hz,1H).13C NMR(150MHz,CDCl3)δ156.0,130.3,129.0,128.7,126.7,79.6,39.5,33.1.HRMS(ESI)([M+H]+)Calcd.For[C10H11BrNO]+:240.0019,Found:240.0018.
实施例9：
取10mL反应管，加入3a(66.3mg,0.2mmol)，NaI(60.0mg,0.4mmol)，加入丙酮(1.0mL)。将反应管置于80℃条件下反应10h，薄层色谱法检测。反应结束后，加入蒸馏水(10mL)，用二氯甲烷(DCM,3×10mL)萃取。合并有机层，无水硫酸钠干燥，减压浓缩得到粗品，用闪蒸色谱法(硅胶、石油醚/乙酸乙酯＝3:1至9:1)纯化，得到产物8a,为白色固体(54.5mg，收率95％)。
Figure BDA0002252775630000231
(Iodomethyl)-3-phenyl-4,5-dihydroisoxazole(8a):White solid；54.5mg,95％yield；1H NMR(600MHz,CDCl3)δ7.69–7.65(m,2H),7.44–7.39(m,3H),4.95–4.90(m,1H),3.52(dd,J＝17.4,10.8Hz,1H),3.42(dd,J＝10.2,4.2Hz,1H),3.25–3.21(m,2H).13CNMR(150MHz,CDCl3)δ155.8,130.3,129.0,128.7,126.7,80.4,41.0,7.5.HRMS(ESI)([M+H]+)Calcd.For[C10H11INO]+:287.9880,Found:287.9879.
实施例10：
取10mL反应管，加入3a(66.3mg,0.2mmol)，NaN3(26.0mg,0.3mmol)，加入DMF(1.0mL)。将反应管置于80℃条件下反应10h，薄层色谱法检测。反应结束后，加入蒸馏水(10mL)，用二氯甲烷(DCM,3×10mL)萃取。合并有机层，无水硫酸钠干燥，减压浓缩得到粗品，用闪蒸色谱法(硅胶、石油醚/乙酸乙酯＝3:1至9:1)纯化，得到产物9a,为白色固体(36.0mg，收率89％)。
Figure BDA0002252775630000232
5-(Azidomethyl)-3-phenyl-4,5-dihydroisoxazole(9a):White solid；36.0mg,89％yield；1H NMR(600MHz,CDCl3)δ7.68–7.67(m,2H),7.42–7.41(m,3H),4.94–4.90(m,1H),3.54–3.43(m,3H),3.22(dd,J＝16.8,6.6Hz,1H).13C NMR(150MHz,CDCl3)δ156.4,130.3,129.1,128.7,126.7,79.1,53.5,37.8.HRMS(ESI)([M+H]+)Calcd.For[C10H11N4O]+:203.0927,Found:203.0928.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (7)

1.一种3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯3的合成方法，其特征在于，包括如下操作：以不饱和肟1和高碘试剂2为原料，在铁催化剂存在下，反应得到3-芳基-4,5-二氢异噁唑-5-基甲基磺酸酯3，反应方程式如下：
Figure FDA0002947817030000011
其中，Ar为苯基、取代苯基、萘基；取代苯基中，取代为C1-C4烷基、C1-C4烷氧基或卤素中的一种或两种；R为甲基、取代苯基、萘基；取代苯基中，取代为二甲基、硝基或卤素；所述铁催化剂选自Fe(acac)2、FeCl2、FeBr2、FeSO4、Fe(acac)3、Fe(OAc)3或FeCl3；反应在有机溶剂中进行，所述有机溶剂选自THF、CH3OH、CH3CN、CH2Cl2、CHCl3、ClCH2CH2Cl或甲苯。
2.根据权利要求1所述的合成方法，其特征在于：所述铁催化剂选自Fe(acac)2。
3.根据权利要求1所述的合成方法，其特征在于：所述有机溶剂选自THF、CH2Cl2、ClCH2CH2Cl或甲苯。
4.根据权利要求1所述的合成方法，其特征在于：所述不饱和肟1和高碘试剂2为原料，与铁催化剂摩尔比为1:1-1.5:0.03-0.05。
5.根据权利要求1所述的合成方法，其特征在于：反应在空气或惰性氛围下进行。
6.根据权利要求1所述的合成方法，其特征在于：反应温度选自0℃至30℃。
7.根据权利要求6所述的合成方法，其特征在于：反应温度选自室温。
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