CN114213206A - α-氘代烯醛的制备方法 - Google Patents
α-氘代烯醛的制备方法 Download PDFInfo
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- CN114213206A CN114213206A CN202111655750.9A CN202111655750A CN114213206A CN 114213206 A CN114213206 A CN 114213206A CN 202111655750 A CN202111655750 A CN 202111655750A CN 114213206 A CN114213206 A CN 114213206A
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Images
Classifications
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及一种α‑氘代烯醛的制备方法，以α,β‑烯醛为原料，在氘水、亲核试剂和有机催化剂作用下，经历可逆迈克尔加成机理，得到α‑氘代烯醛化合物。本方法具有高选择性，不会产生其它位置氘代的副产物。本发明制备的α‑氘代烯醛化合物具有很大的应用价值，可以进一步进行广泛的转化，制备单(多)氘代的烯烃及衍生物、烯酸、共轭烯醛以及烯炔等化合物，在药物合成中具有重要意义。
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种α-氘代烯醛的制备方法。
背景技术
氘(D)代化合物是一类重要的高附加值化学品，不仅广泛应用于核磁共振波谱分析领域，而且在揭示有机反应机理、改善材料性能和探究药物代谢等方面也有着重要的应用。药物研发中，氘标记的作用日渐凸显，成为一种理想的药物修饰方法，特别是FDA在2017年正式批准了第一例氘代药物(Deutetrabenazine)，可以有效地治疗亨丁顿舞蹈症，掀起了氘代药物研究的热潮。现有技术制备氘代化合物的方法之一是以含有氘的化合物为起始原料，经过一步或多步合成得到含氘的产物，此方法的缺点是氘代分子的种类不多，而且多步合成可能导致最终产物氘代率降低，所以这种方法很多时候是有很大的局限性。另外现有技术中另一种广泛用于制备氘代化合物的方法是HDE(氢/氘交换法)，此方法可以通过对特定的C-H活化，以氘代溶剂或者D2为氘源与分子中氢进行交换，从而可以对药物分子作后期修饰引入氘。经典HDE主要通过酸/碱或过渡金属催化促进氢与氘的交换，但是此方法可能会导致多个位置发生非选择性氘代以及官能团的耐受性差。
α,β-烯醛(RHC＝CHCHO)是一种重要的有机官能团，不仅可以作为迈克尔受体，也广泛存在于多种天然产物、生物活性分子和药物中。烯醛通过脱碳反应是制备烯烃的一种常用方法，而烯烃在化学合成中则是一种重要的合成子。目前，对于烯烃的氘代研究主要集中于未活化烯烃、苯乙烯和缺电子烯烃，但他们都会存在多个位置氘代或者应用范围窄的问题，而通过氘代烯醛制备端位高选择性氘代的烯烃将是一个不错的选择。然而，对于α,β-烯醛的α位选择性氘代目前尚未报道，尽管Chi课题组(ACS Catal.,2020,10,5475-5482)报道了一种有效的卡宾催化的烯醛选择性α,γ-氘化，但得到的产物是羧酸而不是醛。因此，发展利用简单易得的氘源和简便的操作制备α位氘代的α,β-烯醛新方法具有重要意义。
发明内容
本发明的主要目的就是针对以上存在的问题，提供一种α-氘代烯醛的制备方法，以α,β-烯醛为原料，在氘水、亲核试剂和有机催化剂作用下发生可逆迈克尔加成，得到α-氘代烯醛化合物，其中，原料和氘源易于获取，反应操作简单，具有很好的原子经济性。
为了实现上述目的，本发明采用的制备α-氘代烯醛的方法的技术方案如下：
所述的方法包括：将α,β-烯醛、亲核试剂、有机催化剂和氘水混合在溶剂中，升温至50～80℃，搅拌，反应得到α-氘代烯醛；
所述的α,β-烯醛的化学结构式如下：
其中，R为取代或者未取代的芳基或芳杂环，取代指基团上的一个或多个氢原子被取代基取代，取代基独立的选自卤素、硝基、醛基、酯基、烷基醚、三氟甲基、三氟甲氧基或二甲氨基中的一种或几种；芳杂环选自O、或N中的一种或两种；
所述的亲核试剂的化学结构式选自如下一种：
其中，R1、R2为苯磺酰基、对甲基苯磺酰基、-COOMe、-COOEt、-COMe、-COPh中的一种或两种；R3、R4、R5为卤素、硝基、氨基、醚、或烷基中的一种或多种；
所述的α-氘代烯醛的化学结构式如下：
上述技术方案可以表示如下：
较佳地，芳杂环为吲哚、呋喃、吡咯、咪唑、恶唑、三氮唑或二茂铁。
较佳地，所述的溶剂为DCM(二氯甲烷)、DMSO(二甲基亚砜)、DMF(N,N-二甲基甲酰胺)、甲苯、四氢呋喃、二氧六环等，优选DCM和甲苯，更优选DCM。
较佳地，所述的亲核试剂为双(苯磺酰基)甲烷、氟代双(苯磺酰基)甲烷、苯酚、对三氟甲基苯酚、2-吲哚酮、2-氟丙二酸二乙酯、乙酰乙酸乙酯、4-羟基香豆素等，优选双(苯磺酰基)甲烷和氟代双(苯磺酰基)甲烷，更优选双(苯磺酰基)甲烷。
较佳地，所述反应的温度为50～80℃，优选50℃；所述反应的时间为24～96小时，优选24～48小时，更优选24小时。
本发明的制备α-氘代烯醛方法：1)α位高选择性引入氘，不会产生芳环氘代和β位氘代的产物；2)所用的氘水是最便宜的氘源，易于获得；3)反应条件温和，不需要氮气保护，温度只需50℃或者80℃；4)官能团兼容性强，底物范围广；5)产物可以合成单氘代、双氘代和三氘代烯烃类化合物，可以进行广泛的官能团转化。
附图说明
图1a～1c分别为化合物5a的1H NMR、13C NMR、2H NMR核磁谱图。
具体实施方式
为了能够更清楚地理解本发明的技术内容，特举以下实施例详细说明。
本发明以α,β-烯醛为原料，在氘水、亲核试剂和有机催化剂作用下，发生可逆迈克尔加成，得到α-氘代烯醛化合物。实现了第一例α,β-烯醛的α位选择性氘代，并且解决了单氘代、双氘代和三氘代烯烃类化合物的合成问题。
本发明涉及的原料或者为现有可市购产品，或者可根据现有方法制备。
实施例一
α-氘代烯醛的制备
将α,β-烯醛1(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和DCM(1mL)中，升温至50℃剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代烯醛产品5。
不同反应底物α,β-烯醛1和双(苯磺酰基)甲烷2b以得到的对应产物α-氘代烯醛产品5如下：
上述收率为分离收率，不同的底物，反应完成的时间为24～96小时。
上述产物数据表征如下：
按照标准投料量，1a(0.2mmol)，收率94％。
1H NMR(400MHz,CDCl3):δ9.78(s,1H),8.31–8.29(m,2H),7.74–7.72(m,2H),7.53(s,1H),6.81(dd,J＝16.1,7.4Hz,0.05H).13C NMR(151MHz,CDCl3):δ192.9,149.0,148.8,139.9,131.5(t,J＝24.9Hz),129.1,124.4.2H NMR(77MHz,CHCl3):δ6.87(s,1D).HRMS(EI-TOF):m/z caled for C9H6DNO3[(M)+]:178.0489,found:178.0492.
1H NMR(400MHz,CDCl3):δ9.77(s,1H),8.42(s,1H),8.30(d,J＝8.2Hz,1H),7.90(d,J＝8.2Hz,1H),7.65(t,J＝8.0Hz,1H),7.53(s,1H),6.82(dd,J＝16.0,7.6Hz,0.03H).13C NMR(151MHz,CDCl3):δ192.9,149.0,148.8,135.7,133.6,130.82–130.29(m),130.3,125.4,123.1.HRMS(EI-TOF):m/z caled for C9H6DNO3[(M)+]:178.0489,found:178.0492.
1H NMR(400MHz,CDCl3):δ9.78(s,1H),8.11(dd,J＝8.1,0.9Hz,1H),8.04–8.03(m,1H),7.74–7.66(m,2H),7.63–7.59(m,1H),6.64(dd,J＝15.8,7.7Hz,0.01H).13C NMR(151MHz,CDCl3):δ193.2,148.1,147.2,133.9,132.4(t,J＝24.8Hz),131.2,130.0,129.1,125.3.HRMS(EI-TOF):m/z caled for C9H6DNO3[(M)+]:178.0489,found:178.0487.
1H NMR(400MHz,CDCl3):δ9.74(s,1H),7.80(s,1H),7.75(d,J＝7.8Hz,1H),7.69(d,J＝7.8Hz,1H),7.57(t,J＝7.8Hz,1H),7.52–7.47(m,1H),6.77(dd,J＝16.0,7.5Hz,0.01H).13C NMR(151MHz,CDCl3):δ193.2,150.3,134.8,131.8(q,J＝32.8Hz),131.2,129.7,129.6(t,J＝24.9Hz),127.7(q,J＝3.4Hz),125.3(q,J＝3.7Hz),122.0(q,J＝272.5Hz).19F NMR(565MHz,CDCl3):δ-62.95.HRMS(EI-TOF):m/z caled for C10H6DF3O[(M)+]:201.0512,found:201.0510.
1H NMR(400MHz,CDCl3):δ9.76(s,1H),7.72–7.66(m,4H),7.52–7.49(m,1H),6.78(dd,J＝16.0,7.6Hz,0.03H).13C NMR(151MHz,CDCl3):δ193.2,150.2,137.3,132.7(q,J＝32.9Hz),130.2(t,J＝24.9Hz),128.6,126.1(d,J＝4.0Hz),122.8(t,J＝273.0Hz).19F NMR(565MHz,CDCl3):δ-62.99.HRMS(EI-TOF):m/z caled for C10H6DF3O[(M)+]:201.0512,found:201.0509.
1H NMR(400MHz,CDCl3):δ9.70(s,1H),7.64(s,1H),7.58(t,J＝7.5Hz,1H),7.42(dd,J＝14.1,6.8Hz,1H),7.20(t,J＝7.5Hz,1H),7.16–7.09(m,1H),6.78(dd,J＝16.1,7.7Hz,0.01H).13C NMR(151MHz,CDCl3):δ193.8,161.2(d,J＝254.8Hz),144.7(d,J＝3.6Hz),132.9(d,J＝8.9Hz),130.44–130.07(m),128.9,124.7(d,J＝3.6Hz),122.1(d,J＝11.4Hz),116.4(d,J＝22.0Hz).19F NMR(565MHz,CDCl3):δ-114.27.HRMS(EI-TOF):m/zcaled for C9H6DFO[(M)+]:151.0544,found:151.0547.
1H NMR(400MHz,CDCl3)：δ9.69(s,1H),7.60–7.53(m,2H),7.43(d,J＝1.9Hz,1H),7.12(t,J＝8.6Hz,2H),6.65(dd,J＝16.0,7.7Hz,0.02H).13C NMR(101MHz,CDCl3):δ193.5,164.4(d,J＝254.2Hz),151.2,130.4(dd,J＝21.0,6.0Hz),128.2(t,J＝25.6Hz),116.5,116.3.19F NMR(565MHz,CDCl3):δ-107.8.HRMS(EI-TOF):caled for C9H6DFO[(M)+]:151.0544,found:151.0546.
1H NMR(400MHz,CDCl3):δ9.77(s,1H),7.94(s,1H),7.67(d,J＝7.5Hz,1H),7.47(d,J＝7.5Hz,1H),7.40–7.31(m,2H),6.71(dd,J＝16.0,7.7Hz,0.08H).13C NMR(151MHz,CDCl3):δ193.7,148.0,135.2,132.1,132.0,130.56–130.11(m),130.4,127.9,127.4.HRMS(EI-TOF):m/z caled for C9H6DClO[(M)+]:167.0248,found:167.0246.
1H NMR(400MHz,CDCl3):δ9.71(s,1H),7.51(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,3H),6.69(dd,J＝16.0,7.8Hz,0.03H).13C NMR(151MHz,CDCl3):δ193.4,151.0,137.3,132.5,129.6,129.5,128.7(t,J＝24.5Hz).HRMS(EI-TOF):m/z caled for C9H6DClO[(M)+]:167.0248,found:167.0251.
1H NMR(400MHz,CDCl3):δ9.78(s,1H),7.93–7.88(m,1H),7.66(dd,J＝7.8,1.9Hz,2H),7.38(t,J＝7.3Hz,1H),7.31–7.27(m,1H),6.68(dd,J＝15.8,7.7Hz,0.03H).13C NMR(151MHz,CDCl3):δ193.5,150.5,133.8,133.7,132.1,130.5(t,J＝24.0Hz),128.0(d,J＝13.4Hz),125.7.HRMS(EI-TOF):m/z caled for C9H6DBrO[(M)+]:210.9743,found:210.9748.
1H NMR(400MHz,CDCl3):δ9.71(s,1H),7.57(d,J＝8.4Hz,2H),7.43(d,J＝8.6Hz,2H),7.41(s,1H),6.70(dd,J＝15.9,7.6Hz,0.03H).13C NMR(101MHz,CDCl3):δ193.4,151.0,132.9,132.4,129.8,128.8(t,J＝24.4Hz),125.7.HRMS(EI-TOF):m/z caled forC9H6DBrO[(M)+]:210.9743,found:210.9746.
1H NMR(400MHz,CDCl3):δ9.74(s,1H),7.63(d,J＝8.7Hz,2H),7.48(s,1H),7.30(d,J＝8.4Hz,2H),6.72(dd,J＝16.0,7.6Hz,0.03H).13C NMR(151MHz,CDCl3):δ193.4,151.1,150.6,132.5,130.0,129.8,129.0(t,J＝24.3Hz),121.3,121.2.2H NMR(77MHz,CHCl3):δ6.76(s,1D).19F NMR(565MHz,CDCl3):δ-57.72.HRMS(EI-TOF):m/z caled forC10H6DF3O2[(M)+]:217.0461,found:217.0458.
1H NMR(400MHz,CDCl3):δ10.08(s,1H),9.76(s,1H),8.07(s,1H),7.98–7.94(m,1H),7.84(d,J＝7.8Hz,1H),7.65(d,J＝7.7Hz,1H),7.56–7.52(m,1H),6.81(dd,J＝16.0,7.5Hz,0.06H).13C NMR(151MHz,CDCl3):δ193.3,191.4,150.5,137.1,135.0,133.7,132.1,129.9,130.20–129.52(m),129.3.2H NMR(77MHz,CHCl3):δ6.86(s,1D).HRMS(EI-TOF):m/zcaled for C10H7DO2[(M)+]:161.0587,found:161.0590.
1H NMR(400MHz,CDCl3):δ9.74(s,1H),8.09(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),7.50(s,1H),6.78(dd,J＝16.0,7.7Hz,0.04H),3.94(s,3H).13C NMR(151MHz,CDCl3):δ193.3,166.3,150.8,138.1,132.2,130.3,130.0(t,J＝24.2Hz),128.3,52.4.2H NMR(77MHz,CHCl3):δ6.83(s,1D).HRMS(EI-TOF):m/z caled for C11H9DO3[(M)+]:191.0693,found:191.0695.
1H NMR(400MHz,CDCl3):δ9.71(s,1H),7.57(dd,J＝6.7,2.9Hz,2H),7.49–7.46(m,1H),7.46–7.40(m,3H),6.72(dd,J＝16.0,7.7Hz,0.02H).13C NMR(101MHz,CDCl3):δ193.8,152.7,134.0,131.3,129.1,128.5,128.3(t,J＝24.6Hz).2H NMR(77MHz,CHCl3):δ6.79(s,1D).HRMS(EI-TOF):m/z caled for C9H7DO[(M)+]:133.0638,found:133.0640.
1H NMR(400MHz,CDCl3):δ9.71(s,1H),7.76(s,1H),7.58(d,J＝7.5Hz,1H),7.35–7.29(m,1H),7.23(d,J＝7.4Hz,2H),6.66(dd,J＝15.8,7.7Hz,0.06H),2.47(s,3H).13C NMR(151MHz,CDCl3):δ194.0,150.3,138.0,132.8,131.1(d,J＝2.9Hz),129.59–129.14(m),126.9,126.6,19.8.HRMS(EI-TOF):m/z caled for C10H9DO[(M)+]:147.0794,found:147.0796.
1H NMR(400MHz,CDCl3):δ9.69(s,1H),7.45(s,1H),7.37(d,J＝4.5Hz,2H),7.33(t,J＝5.7Hz,1H),7.26(d,J＝7.5Hz,1H),6.71(dd,J＝16.0,7.7Hz,0.04H),2.39(s,3H).13C NMR(151MHz,CDCl3):δ193.9,153.1,138.9,134.0,132.2,129.2,129.0,128.2(t,J＝24.2Hz),125.8,21.3.HRMS(EI-TOF):m/z caled for C10H9DO[(M)+]:147.0794,found:147.0796.
1H NMR(400MHz,CDCl3):δ9.68(s,1H),7.46(d,J＝8.1Hz,2H),7.45(d,J＝2.6Hz,1H),7.24(d,J＝8.1Hz,2H),6.68(dd,J＝15.9,7.7Hz,0.02H),2.40(s,3H).13C NMR(101MHz,CDCl3):δ193.8,152.9,142.0,131.3,129.9,128.6,127.5(t,J＝24.3Hz),21.6.HRMS(EI-TOF):m/z caled for C10H9DO[(M)+]:147.0794,found:147.0792.
1H NMR(400MHz,CDCl3):δ9.68(s,1H),7.83(s,1H),7.54(d,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.00(t,J＝7.6Hz,1H),6.95(d,J＝7.6Hz,1H),6.79(dd,J＝16.0,7.9Hz,0.06H),3.91(s,3H).13C NMR(151MHz,CDCl3):δ194.6,158.3,148.2,132.7,129.09–128.66(m),128.9,123.0,120.9,111.3,55.6.HRMS(EI-TOF):m/z caled for C10H9DO2[(M)+]:163.0744,found:163.0746.
1H NMR(400MHz,CDCl3):δ9.66(s,1H),7.53(d,J＝8.7Hz,2H),7.42(s,1H),6.95(d,J＝8.7Hz,2H),6.61(dd,J＝15.9,7.8Hz,0.02H),3.86(s,3H).13C NMR(151MHz,CDCl3):δ193.8,162.2,152.7,130.4,126.8,126.2(t,J＝24.5Hz),114.6,55.5.2H NMR(77MHz,CHCl3):δ6.67(s,1D).HRMS(EI-TOF):m/z caled for C10H9DO2[(M)+]:163.0744,found:163.0742.
1H NMR(400MHz,CDCl3):δ9.59(s,1H),7.49–7.43(m,2H),7.37(s,1H),6.71–6.67(m,2H),6.54(dd,J＝15.6,7.9Hz,0.02H),3.05(s,6H).13C NMR(151MHz,CDCl3):δ193.8,153.8,152.4,130.5,123.5(t,J＝24.2Hz),121.7,111.7,40.1.HRMS(EI-TOF):m/z caledfor C11H12DNO[(M)+]:176.1060,found:176.1063.
1H NMR(400MHz,CDCl3):δ9.67(s,1H),7.42(s,1H),7.17(d,J＝8.3Hz,1H),7.08(s,1H),6.91(d,J＝8.3Hz,1H),6.62(dd,J＝15.8,7.7Hz,0.03H),3.94(d,J＝3.7Hz,6H).13C NMR(101MHz,CDCl3):δ193.6,152.8,152.0,149.4,127.0,126.70–126.14(m),123.5,111.1,109.8,56.1,56.9.HRMS(EI-TOF):m/z caled for C11H11DO3[(M)+]:193.0849,found:193.0847.
1H NMR(400MHz,CDCl3):δ9.70(s,1H),7.43(s,1H),7.17(dd,J＝8.1,1.8Hz,1H),7.14(d,J＝1.8Hz,1H),7.10(d,J＝8.1Hz,1H),6.67(dd,J＝15.9,7.6Hz,0.09H),3.88(s,3H),2.33(s,3H).13C NMR(151MHz,CDCl3):δ193.5,168.7,151.8,151.6,142.2,132.9,128.73–128.27(m),123.5,121.9,111.4,56.0,20.6.2H NMR(77MHz,CHCl3):δ6.72(s,1D).HRMS(EI-TOF):m/z caled for C12H11DO4[(M)+]:221.0798,found:221.0800.
1H NMR(400MHz,CDCl3):δ9.84(s,1H),8.31(s,1H),8.18(d,J＝8.4Hz,1H),7.96-7.89(m,2H),7.80(d,J＝8.4Hz,1H),7.64-7.50(m,3H),6.83(dd,J＝15.6,7.7Hz,0.02H).13C NMR(151MHz,CDCl3):δ193.7,149.3,133.8,131.7,131.2,131.0,130.6(t,J＝24.6Hz),129.0,127.3,126.5,125.8,125.5,122.8.HRMS(EI-TOF):m/z caled for C13H9DO[(M)+]:183.0794,found:183.0791.
1H NMR(400MHz,CDCl3):δ9.41(s,1H),7.35-7.28(m,3H),7.21(s,1H),7.03(d,J＝7.3Hz,2H),6.95(s,1H),6.83(d,J＝3.8Hz,1H),6.40(dd,J＝15.5,7.9Hz,0.15H),6.34–6.29(m,1H),5.25(s,2H).13C NMR(151MHz,CDCl3):δ193.1,139.6,137.0,129.1,129.0,128.6,128.0,126.2,124.10–123.66(m),114.6,110.7,50.9.2H NMR(77MHz,CHCl3):δ6.46(s,1D).HRMS(EI-TOF):m/z caled for C14H12DNO[(M)+]:212.1060,found:212.1057.
1H NMR(400MHz,CDCl3):δ9.60(s,1H),7.62(s,1H),7.41-7.36(m,3H),7.33(s,1H),7.23(s,1H),7.22–7.16(m,2H),6.77(dd,J＝15.6,8.0Hz,0.08H),5.14(s,2H).13C NMR(101MHz,CDCl3):δ193.7,144.1,139.2,138.5,135.1,129.2,128.8,127.5,126.7(t,J＝27.9Hz),122.7,51.3.HRMS(EI-TOF):m/z caled for C13H11DN2O[(M)+]:213.1012,found:213.1015.
1H NMR(400MHz,CDCl3):δ9.77(s,1H),7.85–7.82(m,2H),7.52–7.47(m,3H),7.37(s,1H),6.90(s,1H),6.87(s,0.05H).13C NMR(151MHz,CDCl3):δ192.2,165.8,163.2,133.2,130.5,130.2,129.1,128.50–126.95(m),126.8,105.1.HRMS(EI-TOF):m/z caledfor C12H8DNO2[(M)+]:200.0696,found:200.0694.
1H NMR(400MHz,CDCl3):δ9.65(s,1H),7.71(s,1H),7.47(s,1H),7.39–7.26(m,5H),6.77(dd,J＝15.9,7.7Hz,0.02H),5.57(s,2H).13C NMR(151MHz,CDCl3):δ193.2,143.8,140.0,133.9,129.72–129.38(m),129.4,129.2,128.2,123.6,54.5.HRMS(EI-TOF):m/z caled for C12H10DN3O[(M)+]:214.0965,found:214.0963.
1H NMR(400MHz,CDCl3):δ9.60(s,1H),7.94–7.88(m,1H),7.64(s,1H),7.49(s,1H),7.36–7.19(m,6H),7.19–7.14(m,2H),6.76(dd,J＝15.6,7.9Hz,0.01H),5.35(s,2H).13C NMR(151MHz,CDCl3):δ194.1,146.2,137.9,135.8,133.4,129.1,128.3,127.1,126.1,124.3(t,J＝23.9Hz),123.6,122.1,120.6,112.9,110.7,50.7.HRMS(EI-TOF):m/z caledfor C18H14DNO[(M)+]:262.1216,found:262.1220.
1H NMR(400MHz,CDCl3):δ9.55(s,1H),7.41(s,1H),6.34(dd,J＝15.6,8.0Hz,0.02H),4.53(dd,J＝12.1,1.6Hz,4H),4.16(s,5H).13C NMR(151MHz,CDCl3):δ193.2,155.1,126.1(t,J＝24.2Hz),77.8,71.9,70.0,69.2.HRMS(EI-TOF):m/z caled forC13H11DFeO[(M)+]:241.0301,found:241.0303
1H NMR(400MHz,CDCl3):δ9.75(s,2H),7.64(s,4H),7.49(s,2H),6.81–6.76(m,0,02H).13C NMR(151MHz,CDCl3):δ193.4,150.8,136.5,130.12–129.33(m),129.1.HRMS(EI-TOF):m/z caled for C12H8D2O2[(M)+]:188.0806,found:188.0804.
本发明的反应底物可常规市购也可根据常规方法制备，比如：
将芳基溴(碘)化物(1mmol)、丙烯醛二乙缩醛(3mmol)、K2CO3(1.5mmol)、Bu4N+·OAc(2mmol),KCl(1mmol)和Pd(OAc)2(3mol％)悬于DMF(4mL)中，在N2保护下90℃下反应，TLC监测，反应完后，冷却至室温，再缓慢加入2N HCl(10mL)，室温搅拌30分钟，加入乙酸乙酯，反应液再用水洗三遍，饱和食盐水洗一遍，无水硫酸钠干燥，旋干，硅胶粉柱层析，得到肉桂醛产物。
1H NMR(400MHz,CDCl3):δ9.66(d,J＝7.5Hz,1H),7.63–7.56(m,4H),7.42(d,J＝16.0Hz,1H),6.68(dd,J＝16.0,7.5Hz,1H).13C NMR(151MHz,CDCl3):δ193.2,150.3,137.3,132.7(q,J＝32.9Hz),130.5,128.6,126.2(q,J＝3.8Hz),122.8(t,J＝272.4Hz).19F NMR(565MHz,CDCl3):δ-62.99.
1H NMR(400MHz,CDCl3):δ9.72(d,J＝7.6Hz,1H),7.66(d,J＝16.1Hz,1H),7.59(t,J＝7.3Hz,1H),7.48–7.38(m,1H),7.21(t,J＝7.4Hz,1H),7.14(t,J＝9.4Hz,1H),6.79(dd,J＝16.1,7.6Hz,1H).13C NMR(151MHz,CDCl3):δ193.9,161.2(d,J＝254.8Hz),144.9(d,J＝3.6Hz),132.9(d,J＝8.9Hz),130.5(d,J＝5.3Hz),128.8,124.7(d,J＝3.7Hz),122.1(d,J＝11.4Hz),116.3(d,J＝21.8Hz),19F NMR(565MHz,CDCl3):δ-114.25.
1H NMR(400MHz,CDCl3):δ9.76(d,J＝7.7Hz,1H),7.94(d,J＝16.0Hz,1H),7.67(d,J＝7.3Hz,1H),7.46(d,J＝7.5Hz,1H),7.39–7.38(m,2H),6.71(dd,J＝16.0,7.7Hz,1H).13CNMR(151MHz,CDCl3):δ193.6,148.0,135.2,132.1,132.0,130.5,130.4,127.9,127.3.
1H NMR(400MHz,CDCl3):δ9.72(d,J＝7.6Hz,1H),7.61(d,J＝8.6Hz,2H),7.47(d,J＝16.0Hz,1H),7.28(d,J＝8.6Hz,2H),6.70(dd,J＝16.0,7.6Hz,1H).13C NMR(151MHz,CDCl3):δ193.4,151.1,150.8,132.6,130.0,129.3,121.3,121.2.19F NMR(565MHz,CDCl3):δ-57.75.
1H NMR(400MHz,CDCl3):δ10.08(s,1H),9.76(d,J＝7.6Hz,1H),8.08(s,1H),7.96(d,J＝7.6Hz,1H),7.85(d,J＝7.7Hz,1H),7.64(t,J＝7.7Hz,1H),7.56(d,J＝16.0Hz,1H),6.81(dd,J＝16.0,7.6Hz,1H).13C NMR(151MHz,CDCl3):δ193.2(d,J＝3.4Hz),191.4(d,J＝1.9Hz),150.6(d,J＝2.4Hz),137.1,135.0,133.7,132.0,130.0,129.9,129.3.
1H NMR(400MHz,CDCl3):δ9.74(d,J＝7.6Hz,1H),8.09(d,J＝8.1Hz,2H),7.63(d,J＝8.1Hz,2H),7.50(d,J＝16.0Hz,1H),6.78(dd,J＝16.0,7.6Hz,1H),3.94(s,3H).13C NMR(151MHz,CDCl3):δ193.4,166.3,150.9,138.1,132.2,130.4,130.3,128.3,52.4.
1H NMR(400MHz,CDCl3):δ9.72(d,J＝7.5Hz,1H),7.77(d,J＝15.8Hz,1H),7.59(d,J＝7.1Hz,1H),7.32(d,J＝6.9Hz,1H),7.24(d,J＝6.1Hz,2H),6.66(dd,J＝15.8,7.5Hz,1H),2.48(s,3H).13C NMR(151MHz,CDCl3):δ193.9,150.3,137.9,132.8,131.1,131.0,129.6,126.8,126.6,19.7.
1H NMR(400MHz,CDCl3):δ9.60(d,J＝7.7Hz,1H),7.35(d,J＝15.9Hz,1H),7.28(s,2H),7.23–7.15(m,2H),6.61(dd,J＝15.9,7.7Hz,1H),2.30(s,3H).13C NMR(151MHz,CDCl3):δ193.8,153.1,138.9,134.0,132.2,129.2,129.0,128.4,125.8,21.1.
1H NMR(400MHz,CDCl3):δ9.86(d,J＝7.7Hz,1H),8.34(d,J＝15.7Hz,1H),8.19(d,J＝8.4Hz,1H),7.94(dd,J＝18.0,8.1Hz,2H),7.83(d,J＝7.2Hz,1H),7.66–7.49(m,3H),6.85(dd,J＝15.7,7.7Hz,1H).13C NMR(151MHz,CDCl3):δ193.7,149.3,133.8,131.6,131.2,131.0,130.9,129.0,127.3,126.4,125.7,125.5,122.8.
1H NMR(400MHz,CDCl3):δ9.74(d,J＝7.6Hz,2H),7.64(s,4H),7.49(d,J＝16.0Hz,2H),6.77(dd,J＝16.0,7.6Hz,2H).13C NMR(151MHz,CDCl3):δ193.4,150.9,136.6,129.8,129.1.
将起始原料A(1.0g,5.13mmol)悬于THF(20mL)中，0℃下缓慢加入BH3.THF(1mol/L,7.25mL)溶液，继续搅拌30分钟，再缓慢升至室温搅拌3小时，反应完后，加入H2O(5mL)，再缓慢加入1N HCl(5mL)，反应液再用乙酸乙酯(15mL)提取三遍，提取液再用H2O(10mL)，饱和碳酸氢钠溶液(10mL)和饱和食盐水(10mL)各洗一遍，无水硫酸钠干燥，旋干，得到中间体B，直接用于下一步反应。
将中间体B(5.13mmol)悬于DMSO(10mL)和乙腈(15mL)中，再缓慢加入IBX(3.59g,12.83mmol)和催化剂IV(259.6mg,1.03mmol)，室温反应，TLC监测，反应完后，加入H2O(20mL)，再加入乙酸乙酯(80mL)稀释，反应液再用H2O(20mL)洗四遍，饱和食盐水(20mL)洗一遍，无水硫酸钠干燥，旋干，硅胶粉柱层析，得到肉桂醛1b(569mg，总收率：63％)。
1H NMR(400MHz,CDCl3):δ9.77(d,J＝7.4Hz,1H),8.42(s,1H),8.29(d,J＝8.0Hz,1H),7.89(d,J＝7.6Hz,1H),7.65(t,J＝7.6Hz,1H),7.54(d,J＝16.0Hz,1H),6.82(dd,J＝16.0,7.4Hz,1H).13C NMR(151MHz,CDCl3):δ192.8,149.1,148.8,135.7,133.6,130.9,130.3,125.4,123.1.
合成方法同1b，1H NMR(400MHz,CDCl3):δ9.64(d,J＝7.7Hz,1H),7.40(d,J＝15.8Hz,1H),7.15(dd,J＝8.3,1.8Hz,1H),7.07(d,J＝1.8Hz,1H),6.89(d,J＝8.3Hz,1H),6.60(dd,J＝15.8,8.3Hz,1H),3.92(s,3H),3.91(s,3H).13C NMR(151MHz,CDCl3):δ193.6,152.9,152.0,149.4,127.1,126.7,123.5,111.1,109.9,56.1,55.9.
在0℃和N2保护条件下，将NaH(800mg,20mmol)悬于DMF(20mL)中，搅拌条件下加入起始原料C(950mg,10mmol)，搅拌20分钟，再加入BnBr(2.38mL，20mmol)，缓慢升至室温搅拌3小时。0℃下缓慢加入H2O(10mL)，反应液再用DCM(80mL)稀释，反应液用H2O(20mL)洗四遍，饱和食盐水(20mL)洗一遍，提取液用无水硫酸钠干燥，旋干，硅胶粉柱层析，得到中间体D(1.73g，收率：94％)。
在0℃和N2保护条件下，将中间体D(1.73g,9.35mmol)悬于THF(30mL)中，再向反应液中缓慢加入E(6.02g,14mmol)、NaH(1.87g,46.75mmol)和18-crown-6(200mg)，反应液再缓慢升至室温，搅拌过夜。缓慢加入1N HCl(80mL)，搅拌30分钟，再用氨水中和，反应液用DCM(40mL)萃取四次，提取液用饱和食盐水(30mL)洗一遍，无水硫酸钠干燥，旋干，硅胶粉柱层析，得到肉桂醛1y(723mg，收率：34％)。
1H NMR(400MHz,CDCl3):δ9.42(d,J＝7.9Hz,1H),7.37–7.28(m,3H),7.22(d,J＝15.5Hz,1H),7.03(d,J＝7.3Hz,2H),6.96(s,1H),6.84(d,J＝3.8Hz,1H),6.41(dd,J＝15.5,7.9Hz,1H),6.35–6.31(m,1H),5.26(s,2H).13C NMR(151MHz,CDCl3):δ193.1,139.7,136.9,129.1,129.0,128.5,128.0,126.1,124.1,114.6,110.7,50.9.HRMS(ESI-TOF):m/zcaled for C14H14NO[(M+H)]+:212.1075,found:212.1076.
本发明的α-氘代烯醛产物可以进行广泛的官能团转化，合成其它重要的结构，比如：
把一个干净的、烘箱干燥的螺旋盖反应管，放入搅拌子，装入
分子筛(150mg)、5c(89mg，0.5mmol，氘代率99％)、Pd(OAc)2(9mg，8mol％)。通过注射器将环己烷(2ml)添加到该混合物中。把螺帽拧紧，并将反应管置于140℃的预热油浴中。将反应混合物剧烈搅拌6小时。将反应混合物冷却至室温并通过硅藻土过滤，用EtOAc(20mL)清洗反应管和残留物。滤液浓缩并通过柱层析纯化，得到标题化合物8c，为黄色油(37mg，49％产率)，D1和D2的氘代率分别为94％和4％。
1H NMR(400MHz,CDCl3):δ7.93(d,J＝8.2Hz,1H),7.66–7.54(m,2H),7.45–7.38(m,1H),7.22–7.13(m,1H),5.74(dd,J＝17.3,6.2Hz,0.06H),5.48(dd,J＝10.9,5.9Hz,0.96H).13C NMR(151MHz,CDCl3):δ147.9,133.4,133.1,132.4,128.5,128.4,124.4,118.7(t,J＝24.0Hz).2H NMR(77MHz,CHCl3):δ5.80(d,J＝2.6Hz,1D),5.54(d,J＝1.2Hz,0.04D).HRMS(EI-TOF):m/z caled for C8H6D1NO2[(M)+]:150.0540,found:150.0536.
将9(2.38g，5.6mmol)、NaH(747mg，18.7mmol)和18-冠-6(88mg)在0℃氮气下添加到搅拌下的5t(603mg，3.7mmol，氘代率98％)的THF(30mL)溶液中。将反应缓慢升温至室温并搅拌过夜，然后缓慢添加1N HCl(15mL)以使反应停止，将混合物搅拌30分钟，并用氨水中和，然后用DCM(3×30mL)萃取。用饱和盐水(20mL)洗涤合并的有机溶液，在Na2SO4上干燥并减压浓缩。粗产物通过柱层析纯化，得到黄色固体的标题化合物10(476mg，68％产率)，氘代率为98％。
1H NMR(400MHz,CDCl3):δ9.59(d,J＝8.0Hz,1H),7.46(d,J＝8.8Hz,2H),7.29–7.21(m,1H),6.97(s,1H),6.91(d,J＝8.8Hz,2.02H),6.23(dd,J＝15.2,8.0Hz,1H),3.84(s,3H).13C NMR(151MHz,CDCl3):δ193.7,161.0,152.7,142.2,130.6,129.2,128.4,123.8(t,J＝23.6Hz),114.4,55.4.HRMS(ESI-TOF):calculated for C12H12DO2[(M+H)]+:190.0978,found:190.0979.
按照制备化合物5的一般步骤，在氘化反应中使用10(37.8mg，0.2mmol，氘代率98％)为底物，在50℃下剧烈搅拌96h，得到化合物11为黄色固体(25mg，产率66％)，α和γ位置的氘代率都为98％。
1H NMR(400MHz,CDCl3):δ9.59(s,1H),7.45(d,J＝8.8Hz,2H),7.24(s,1H),6.96(s,1H),6.91(d,J＝8.8Hz,2.02H),6.23(dd,J＝15.2,8.0Hz,0.02H),3.84(s,3H).13C NMR(151MHz,CDCl3):δ193.6,160.9,152.5,142.2,130.55–130.08(m),129.1,128.4,124.05–123.63(m),114.4,55.4.2H NMR(77MHz,CHCl3):δ6.94(s,1D),6.28(s,1D).HRMS(ESI-TOF):m/z caled for C12H11D2O2[(M+H)]+:191.1041,found:191.1040.
将12(930mg，5mmol，氘代率98％)和13(2.13g，7mmol)在甲苯(40mL)中的混合物在80℃下的N2氛围中剧烈搅拌17h。然后在减压下浓缩反应，并通过柱层析纯化，得到标题化合物14为棕色固体(606mg，57％产率)，氘代率为98％。
1H NMR(400MHz,CDCl3):δ9.71(d,J＝7.6Hz,1H),7.58(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2.02H),6.72–6.68(m,1H).13C NMR(151MHz,CDCl3):δ193.4,150.8(t,J＝23.6Hz),132.9,132.4,129.8,128.9,125.7.HRMS(ESI-TOF):calculated for C9H7DBrO[(M+H)]+:211.9821,found:211.9824.
按照制备化合物5的一般步骤，氘化反应中使用14(42.4mg，0.2mmol，氘代率98％)为底物，在50℃下剧烈搅拌反应混合物96h。得到15为黄色固体(40.5mg，95％产率)，α和β位置的氘代率都为98％。
1H NMR(400MHz,CDCl3):δ9.71(s,1H),7.58(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2.02H),6.70(dd,J＝8.4,2.8Hz,0.02H).13C NMR(151MHz,CDCl3):δ193.4,150.7(t,J＝23.4Hz),132.8,132.4,129.8,128.95–128.50(m),125.7.2H NMR(77MHz,CHCl3):δ7.46(s,1D),6.75(s,1D).HRMS(ESI-TOF):m/z caled for C9H6D2BrO[(M+H)]+:212.9884,found:212.9883.
将15(106mg，0.5mmol％)、氮杂环卡宾催化剂23(27.9mg，10mol％)和KOAc(49.07mg，0.5mmol)溶解在D2O(2mL)和DCM(0.5mL)的混合物中。然后在60℃下剧烈搅拌反应混合物12小时。得到产物16为黄色固体(33mg，31％产率)，2位和3位的氘代率都为98％，1位的氘代率为99％。
1H NMR(400MHz,CDCl3):δ9.7(s,0.00H),7.58(d,J＝8.4Hz,2H),7.44(d,J＝8.4Hz,2.02H),6.70(s,0.02H).13C NMR(101MHz,CDCl3):δ193.2(t,J＝26.6Hz),150.7(t,J＝23.5Hz),132.8,132.4,129.8,128.86–128.37(m),125.7.2H NMR(77MHz,CHCl3):δ9.75(s,1.03D),7.46(s,1D),6.74(s,1D).HRMS(ESI-TOF):m/z caled for C9H5D3BrO[(M+H)]+:213.9947,found:213.9944.
0℃，N2保护下，将17(74mg，0.33mmol)滴加至NaH(13.2mg，0.33mmol)在干燥THF(3mL)的搅拌溶液中，将混合物搅拌1h，然后滴加15(63.6mg，0.3mmol)在THF(2mL)中的溶液。将反应缓慢升温至室温，并搅拌直至完成。用饱和NH4Cl(5mL)终止反应，并用EtOAc(3x5mL)萃取水相。用饱和盐水(5mL)洗涤合并的有机溶液，用Na2SO4干燥并减压浓缩。粗产物通过柱层析纯化，得到产物18，为淡黄色固体(55.5mg，产率65％)，4位氘代率为97％，5位氘代率为98％。
1H NMR(400MHz,CDCl3):δ7.47(d,J＝8.8Hz,2H),7.41(d,J＝15.6Hz,1H),7.31(d,J＝8.8Hz,2H),6.85(s,0.02H),6.82(d,J＝6.8Hz,0.03H),6.00(d,J＝15.2Hz,1H),4.23(q,J＝7.2Hz,2H),1.31(t,J＝7.2Hz,3H).13C NMR(151MHz,CDCl3):δ166.9,144.0,138.73–138.22(m),134.9,132.0,128.5,126.76–126.32(m),123.0,121.9,60.4,14.3.2H NMR(77MHz,CHCl3):δ6.87(s,2D),two deuterium peaks are overlapped.HRMS(ESI-TOF):m/z caled for C13H12D2BrO2[(M+H)]+:283.0303,found:283.0301.
在0℃的氮气保护下，将n-BuLi(0.16mL，0.39mmol，2.5M的己烷溶液)逐滴添加到19(129mg，0.36mmol)在THF(2mL)的搅拌溶液中。将反应缓慢升温至室温，并搅拌30min，得到深红色溶液。然后在室温下逐滴添加5a(53.4mg，0.3mmo)的THF(1.0mL)溶液，并搅拌过夜。然后将石油醚(5ml)添加到反应混合物中并搅拌1h。反应通过硅藻土过滤，减压浓缩。粗产物通过柱层析纯化，得到标题化合物20，为淡黄色油(25.3mg，48％产率)，氘代率为93％。
1H NMR(400MHz,CDCl3):δ8.18(d,J＝8.8Hz,2H),7.52(d,J＝8.8Hz,2H),6.93(dd,J＝15.6,10.8Hz,0.07H),6.64–6.45(m,2H),5.48(d,J＝17.2Hz,1H),5.35(d,J＝10.0Hz,1H).13C NMR(151MHz,CDCl3):δ146.8,143.7,136.3,133.99–133.53(m),130.3,126.8,124.1,120.9.2H NMR(77MHz,CHCl3):δ6.98(s,1D).HRMS(EI-TOF):m/z caled forC10H8DNO2[(M)+]:176.0696,found:176.0697.
在0℃的氮气保护下，向5a(178mg，1mmol)和CBr4(664mg，2mmol)在无水DCM(10mL)中的搅拌溶液中加入Ph3P(3.05g，4mmol)，20分钟加完。反应混合物变为棕色，在0℃下继续搅拌2h。向反应混合物中添加H2O(5mL)，并用DCM(3x10mL)萃取反应混合物，合并有机层，用饱和盐水(10mL)洗涤，用Na2SO4干燥并减压浓缩。粗产物通过柱层析纯化，得到化合物(E)-1-(4,4-二溴丁基-1,3-二烯-1-基)-4-硝基苯，为淡黄色固体(315mg，95％产率)。
在室温下，向(E)-1-(4,4-二溴丁基-1,3-二烯-1-基)-4-硝基苯(315mg，0.95mmol)在无水CH3CN(4mL)中的搅拌溶液中逐滴添加DBU(578mg，3.8mmol))。将反应混合物搅拌16h，在减压下去除溶剂。通过柱层析纯化粗产物，得到目标化合物21，为淡黄色油状物(72.7mg，44％产率)，氘代率为94％。
1H NMR(400MHz,CDCl3):δ8.21(d,J＝8.8Hz,2H),7.53(d,J＝8.8Hz,2H),7.07(s,1H),6.30(dd,J＝16.0,2.4Hz,0.06H),3.21(s,1H).13C NMR(151MHz,CDCl3):δ147.7,142.0,140.4,126.9,124.2,111.91–111.47(m),82.0,81.9.2H NMR(77MHz,CHCl3):δ6.34(s,1D).HRMS(EI-TOF):m/z caled for C10H6DNO2[(M)+]:174.0540,found:174.0542.
实施例二
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和甲苯(1mL)中，升温至50℃剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：89％，收率：62％。
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和THF(1mL)中，升温至50℃剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：28％，收率：61％。
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和DMF(1mL)中，升温至50℃剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：58％，收率：28％。
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.02mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和DCM(1mL)中，升温至50℃剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：69％，收率：98％。
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.06mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和DCM(1mL)中，升温至50℃剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：87％，收率：92％。
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(0.25mL)和DCM(1mL)中，升温至50℃剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：90％，收率：86％。
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和DCM(1mL)中，升温至50℃剧烈搅拌6小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：54％，收率：94％。
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和DCM(1mL)中，升温至50℃剧烈搅拌12小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：79％，收率：95％。
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(0.5mL)和DCM(1mL)中，升温至50℃剧烈搅拌48小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：99％，收率：82％。
将4-硝基肉桂醛1a(0.2mmol)和催化剂3(0.04mmol)溶于D2O(0.5mL)和DCM(1mL)中，升温至50℃剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：10％，收率：95％。(此例不加辅助物2)
将4-硝基肉桂醛1a(0.2mmol)、双(苯磺酰基)甲烷2b(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(20eq)和DCM(1mL)中，室温剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：80％，收率：84％。
将4-硝基肉桂醛1a(0.2mmol)、氟代双(苯磺酰基)甲烷2a(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(20eq)和DCM(1mL)中，室温剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：81％，收率：89％。
将4-硝基肉桂醛1a(0.2mmol)、2-氟丙二酸二乙酯2c(0.04mmol)、和催化剂3(0.04mmol)溶于D2O(20eq)和DCM(1mL)中，室温剧烈搅拌24小时，冷却至室温，再用DCM(5mL×3)提取，提取液合并，提取液合并，硫酸钠干燥，减压下浓缩，残余物用硅胶粉过柱得到α-氘代4-硝基肉桂醛产品5a。氘代率：6％，收率：82％。
本发明利用α,β-烯醛和双(苯磺酰基)甲烷或者氟代双(苯磺酰基)甲烷的反应，可以在短时间内成功合成α-氘代烯醛产物，方法的选择性好，条件温和，结果令人十分满意。所有的产品都通过一系列的核磁共振技术进行结构表征，给出图1为代表性例子，且5a的氘代率通过1HNMR和2HNMR分析确认。
本发明使用α,β-烯醛和双(苯磺酰基)甲烷或者氟代双(苯磺酰基)甲烷的反应，在有机催化剂的催化下发生可逆迈克尔加成反应，具有很好的区域选择性，不会产生其它位置氘代的副产物。该方案操作十分简便，只需要在有机催化剂作用下，不需要氮气保护，50℃搅拌24-96小时即可；原料便宜易得，官能团耐受性好，产物可以进行广泛的官能团转化，得到多种重要的结构。本发明为α-氘代烯醛的合成提供了一种优秀方案，对药物合成发展具有重大意义。
在此说明书中，本发明已参照其特定的实施例作了描述。但是，很显然仍可以作出各种修改和变换而不背离本发明的精神和范围。因此，说明书和附图应被认为是说明性的而非限制性的。
Claims (5)
1.一种制备α-氘代烯醛的方法，其特征在于，所述的方法包括：将α,β-烯醛、亲核试剂、有机催化剂和氘水混合在溶剂中，升温至50～80℃，搅拌，反应得到α-氘代烯醛；
所述的α,β-烯醛的化学结构式如下：
其中，R为取代或者未取代的芳基或芳杂环，取代指基团上的一个或多个氢原子被取代基取代，取代基独立的选自卤素、硝基、醛基、酯基、烷基醚、三氟甲基、三氟甲氧基或二甲氨基中的一种或几种；芳杂环选自O、或N中的一种或两种；
所述的亲核试剂的化学结构式选自如下一种：
其中，R1、R2为苯磺酰基、对甲基苯磺酰基、-COOMe、-COOEt、-COMe、-COPh中的一种或两种；R3、R4、R5为卤素、硝基、氨基、醚、或烷基中的一种或多种；
所述的α-氘代烯醛的化学结构式如下：
2.根据权利要求1所述的制备α-氘代烯醛的方法，其特征在于，芳杂环为吲哚、呋喃、吡咯、咪唑、恶唑、三氮唑或二茂铁。
3.根据权利要求1所述的制备α-氘代烯醛的方法，其特征在于，所述的溶剂为二氯甲烷、二甲基亚砜、N,N-二甲基甲酰胺、甲苯、四氢呋喃或二氧六环中的一种或多种。
4.根据权利要求1所述的制备α-氘代烯醛的方法，其特征在于，所述的亲核试剂为双(苯磺酰基)甲烷、氟代双(苯磺酰基)甲烷、苯酚、对三氟甲基苯酚、2-吲哚酮、2-氟丙二酸二乙酯、乙酰乙酸乙酯或4-羟基香豆素。
5.根据权利要求1所述的制备α-氘代烯醛的方法，其特征在于，反应时间为24～96小时。
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