CN108997183A - 一种二氟甲基化试剂及其制备方法与应用 - Google Patents

一种二氟甲基化试剂及其制备方法与应用 Download PDF

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CN108997183A
CN108997183A CN201811022609.3A CN201811022609A CN108997183A CN 108997183 A CN108997183 A CN 108997183A CN 201811022609 A CN201811022609 A CN 201811022609A CN 108997183 A CN108997183 A CN 108997183A
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刘国凯
陆声乐
李鑫
秦文兵
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Abstract

本发明属于化学制备技术领域，具体涉及一种二氟甲基化试剂及其制备与应用。针对目前亲电二氟甲基化试剂稳定性较差这个关键问题，通过创新设计，解决试剂稳定性问题。合成得到了室温下稳定保存的亲电二氟甲基化试剂；可满足不同类型底物的二氟甲基官能化，发展多种二氟甲基化新方法和新反应。而且试剂为固体，使用操作简便，可操作性高。

Description

一种二氟甲基化试剂及其制备方法与应用
技术领域
本发明属于化学制备技术领域，具体涉及一种二氟甲基化试剂及其制备方法与应用。
背景技术
二氟甲基作为一种重要的氟烷基，由于氟的高电负性，导致其中的质子具有较强的酸性，从而使其很 容易形成分子内或分子间氢键。在有机分子中引入二氟甲基，往往带来特殊的物理、化学和生物学特性的 变化。二氟甲基的这些特性和优点，使其广泛应用于医药、农药、先进功能材料和生命科学等领域。
例如参考文献：
a)、Smart,B.E.Chem.Rev.1996,96,1555g)T.Furuya,C.Kuttruff,T.Ritter,Curr.Opin. Drug Discovery Dev.2008,11,803；
b)、M.Bassetto,S.Ferla,F.Pertusati,Future Med.Chem.2015,7,527；
c)、New Fluorinated Carbons:Fundamentals and Applications(Eds.:O.V.Boltalina,T.Nakajima), Elsevier,Amsterdam,2016；
d)、K.Müller,C.Faeh,F.Diederich,Science 2007,317,1881；e)J.Hu,W.Zhang,F.Wang, Chem.Commun.2009,7465。
尤其是在药物分子的设计、发现和发展中占有重要的地位。二氟甲基化合物广泛应用于药物发展中， 二氟甲基(CF2H)是羟基(OH)、巯基(SH)等基团的生物电子等排体。
例如参考文献：
a)、G.K.S.Prakash,M.Mandal,S.Schweizer,N.A.Petasis,G.A.Olah,J.Org.Chem.2002, 67,3718-3723；
b)、F.Narjes,K.F.Koehler,U.K℃h,B.Gerlach,S.Colarusso,C.Steink_hler,M.Brunetti, S.Altamura,R.De Francesco,V.G.Matassa,Bioorg.Med.Chem.Lett.2002,12,701-704.。
另外，作为影响药物的药理活性和与靶点亲和力的重要因素，药物分子与靶蛋白之间的氢键作用占有 重要地位。而作为氢键供体，二氟甲基(CF2H)相比于羟基(OH)和氨基(NH)等具有更好的亲脂性，可以 改善药物分子的脂溶性、膜透性、生物利用度及其他药代动力学特性等。
例如参考文献：
a)、Y.Li,J.Hu,Angew.Chem.Int.Ed.2005,44,5882-5886；b)G.K.S.Prakash,C.Weber, S.Chacko,G.A.Olah,Org.Lett.2007,9,1863-1866。
发展稳定高效的二氟甲基试剂及相应的二氟甲基化方法，向药物分子中选择性地引入二氟甲基,有助 于研究药物结构与性质的相互关系,发现新的具有特殊性质的先导化合物，进而加快新药开发。所以，二 氟甲基的引入，在药物设计和新药创制中占有非常重要的地位。因此，研发高效稳定的亲电二氟甲基新试 剂，及其相应的温和条件下的二氟甲基化新方法与新反应的发展，具有很高的应用价值和广阔的前景，以 及较高学术意义。含有二氟甲基的药物如图1所示。
然而，作为向有机分子中引入二氟甲基，尤其是在药物分子的全合成后期阶段区域、立体和选择性的 直接引入二氟甲基的一种最重要的策略和途径，非官能化直接的亲电型二氟甲基试剂的开发及其应用的发 展遇到了很大的困难，迄今为止，稳定有效的亲电二氟甲基试剂及相应二氟甲基化方法的研究成果鲜有报 道，过去20年中仅有Prakash等人发展的二氟甲基硫鎓盐和N，N-二甲基保护的亚砜亚胺，例如参考文献：
a)、G.K.S.Prakash,C.Weber,S.Chacko,G.A.Olah,Org.Lett.2007,9,1863-1866.
b)、G.K.S.Prakash,Z.Zhang,F.Wang,C.Ni,G.A.Olah,J.Fluorine Chem.2011,132, 792-798.
以及胡金波等人发展的N-对甲苯磺酰保护的二氟甲基亚砜亚胺试剂，例如参考文献：
a)、W.Zhang,F.Wang,J.Hu,Org.Lett.2009,11,2109-2112.)
以及最近沈其龙等发展的硫叶立德型亲电二氟甲基试剂，例如参考文献：
a)、J.Zhu,Y.Liu,and Q.Shen,Angew.Chem.Int.Ed.2016,55,9050-9054.，
b)、沈其龙，朱建生，刘亚飞，CN107235878A，
然而，二氟甲基硫鎓盐由于其试剂稳定性，反应活性等方面存在的问题，主要用于N、P、S、O等杂原 子亲核剂的二氟甲基化反应，效率不高且底物类型和官能团兼容性受限，对于重要的C亲核剂的二氟甲基 化效能较低，其应用受到极大限制。而且该试剂为粘稠状半固体，可操作性差，使用不便。N-甲基保护亚 砜亚胺试剂，底物适用性亦比较局限，当使用苯硫酚钠和醇为底物时，收率非常低，对于重要的C-亲核剂 的二氟甲基化其效率较低。
CN107235878A公开了一系列硫叶立德型亲电二氟甲基化试剂、其制备方法与应用，但用于醇的二氟甲 基醚化需要2.0当量的底物，否则收率小于50％，而对于重要的C-亲核剂时，也仅得到中等收率的目标产 物，且底物适应性亦有限。
发明内容
针对目前亲电二氟甲基化试剂稳定性较差这个关键问题，本发明通过创新设计，合成得到了室温下稳 定保存的亲电二氟甲基化试剂，解决试剂稳定性问题。发展具有不同电子效应和空间结构的一系列亲电二 氟甲基化试剂，可满足不同类型底物的二氟甲基官能化，发展多种二氟甲基化新方法和新反应，而且试剂 为固体，使用操作简便，可操作性高。
本发明基于二芳基二氟甲基硫鎓盐型试剂，通过试剂分子内电子效应和空间效应的精密设计和调整， 尤其是通过试剂分子内弱键如氢键的设计来实现试剂的自稳定。
具体地，本发明通过以下技术方案来实现：
一种二氟甲基化试剂，其特征在于，具有下式(I)、(II)、(III)结构的化合物或其盐，
其中R1为在邻位、间位、或对位单取代或多取代的氢、卤素、硝基、氰基、多氟烷基、C1-20的烷基、C1-20的烷氧基或C1-20的烷硫基中的一种或几种；R2为在邻位、间位、或对位单取代或多取代的C1-20的烷氧基、C1-20的烷硫基、C3-12的环烷氧基或C3-12的环烷硫基中的一种或几种；R2中的O或S与CF2H中的H形成分子内氢键。
前述试剂实现本发明的主要原理为：
1.本发明二氟甲基化试剂的成功，关键在于分子内氢键的设计，以及芳香环上的取代基的电子效应 和空间效应的调整。通过在苯环上引入氢键受体基团(环)烷氧(硫)基，与试剂中二氟甲基中的氢之间 形成分子内氢键，对试剂的稳定及反应活性的调控具有重要作用。氢键受体通过氢键对亲电的二氟甲基的 电子反馈，降低了硫鎓盐的正电部位的电正性，以此来达到稳定试剂的目的，得到室温下稳定的试剂，可 以调节试剂的反应活性，使其对各种底物，尤其是重要的C-亲核剂具有较高的反应活性和效率。
2.苯环上不同位置引入具有不同空间效应和电子效应(包括给电子效应和吸电子效应)的取代基。 其作用有二，一是进一步改善试剂的稳定性，其二，基于软硬酸碱理论，对氟化剂的结构进行进一步的优 化，可对试剂的反应活性进行精细调整，以满足不同类型底物的二氟甲基官能化，发展多种二氟甲基化新 方法和新反应。
作为本发明的一种优选方案，
所述R1中，所述的氢为氕、氘或氚；
和/或，所述R1中，所述的卤素为氟、氯、溴或碘；
和/或，所述R1中，所述的C1-20的烷基为C1-6的烷基；
和/或，所述R1中，所述的C1-20的烷氧基为C1-6的烷氧基；
和/或，所述R1中，所述的C1-20的烷硫基为C1-6的烷硫基；
和/或，所述R2中，所述的C1-20的烷氧基为C1-6的烷氧基；
和/或，所述R2中，所述的C1-20的烷硫基为C1-6的烷硫基；
和/或，所述R2中，所述的C3-12的环烷氧基为C3-6的环烷氧基；
和/或，所述R2中，所述的C3-12的环烷硫基为C3-6的环烷硫基；
和/或，所述二氟甲基化试剂的二氟甲基上的氢为氕、氘或氚。
作为本发明的另一种优选方案，所述二氟甲基化试剂其盐为硫鎓盐，所述硫鎓盐的抗阴离子为四氟 合硼酸根或六氟磷酸根或三氟甲磺酸根或氟、氯、溴、碘或磷酸根，具体为下式(Ia)、(IIa)、(IIIa)：
进一步优选的，抗阴离子为四氟合硼酸根或六氟磷酸根。
另一优选的，所述硫鎓盐为二氟甲基化试剂与氟、氯、溴、碘或磷酸根之阴离子形成的化合物。
通过对硫鎓盐的抗阴离子的改变来调整试剂的稳定性和反应活性。不同的抗阴离子亲核性和碱性不同， 与二氟甲基形成弱键的能力和强弱不同。
作为本发明的另一种优选方案，所述的二氟甲基化试剂具体选自：
本发明进一步提供了所述二氟甲基化试剂的制备方法，包括以下合成路线：
其中R1和R2如上所述。反应在三氟甲磺酸酐的作用下进行，所选溶剂为乙醚、正己烷、环己烷、二氯 甲烷、氯仿、甲苯或四氢呋喃等中的一种或几种；反应温度为-80℃至室温(优选-50℃至室温，更优选-30℃ 至室温，最优选为-10℃至室温)；所述盐的水溶液为四氟硼酸钠和/或六氟硼酸钾和/或六氟磷酸钾和/或氯 化钠和/或氟化钾和/或碘化钾和/或磷酸钠的水溶液，优选四氟硼酸钠和/或六氟硼酸钾。
具体的制备方法包括：将“二氟甲基芳基亚砜或二氟甲基杂环亚砜”(如二氟甲基芳基亚砜，用量为 0.8-1.2当量，优选1.0当量)和取代基为R2的苯(如烷氧基苯，用量为1.0-1.5当量，优选1.1当量) 溶于干燥的乙醚中，在搅拌和氮气保护下于-20℃-25℃(优选-10℃-15℃，更优选-5℃-5℃，最优选0℃) 滴加三氟甲磺酸酐；反应完成后(TLC监控)，停止搅拌，静置，将上层乙醚相倾出，再加入乙醚继续搅拌， 然后静置，倾出乙醚相，此操作重复2次以上(优选2-3次)；析出固体，过滤，滤得固体用乙醚洗涤， 干燥得三氟甲磺酸硫鎓盐，具体为S-(二氟甲基)二芳基三氟甲磺酸根硫鎓盐，此盐溶于有机溶剂中，加 入盐的水溶液(优选1M的四氟硼酸钠水溶液或者饱和六氟硼酸钾水溶液)剧烈搅拌(优选10分钟)，静置，有机相分离出来，此过程重复2次以上(优选2-3次)，有机相用无水硫酸钠干燥，过滤，减压蒸去 溶剂，产物用二氯甲烷和正己烷结晶(产物若为半固体或者液体，用硅胶柱层析分离纯化)，制得相应的 硫鎓盐。
本发明的试剂具有广泛的二氟甲基化应用价值，可发展不同类型的二氟甲基化新方法和新反应。
通过大量的实验发现，本发明试剂适合不同类型底物的二氟甲基化能力，如C、O、S、N、P或Se等亲 核剂的二氟甲基化反应，尤其是重要的C亲核剂的二氟甲基化反应。
具体地，一种化合物进行二氟甲基化的制备方法，制备方法包括以下路线，其中1为前述的二氟甲基 化试剂：
反应所用的碱为NaH、KH、LiH、CaH2、NaOH、KOH、LiOH、CsOH、Na2CO3、K2CO3、Cs2CO3、K3PO4、Na3PO4等，优选NaH和/或LiOH。
所用溶剂为四氢呋喃、二氯甲烷、1,2-二氯乙烷、乙腈、苯、甲苯、二甲苯、氯苯、氟苯、溴苯等， 优选氟苯和/或氯苯和/或甲苯。反应温度为-80℃至100℃，优选-30℃至50℃，再优选为-10℃至35℃，更 优选为0℃至25℃，最优选为0℃。反应时间为10分钟至12小时，优选10分钟至6小时，再优选10分钟 至4.5小时，更优选10分钟至3小时，最优选为20分钟。
所述化合物进行二氟甲基化后得到如下二氟甲基化化合物：
反应方法如下：
底物2或5(例如，优选β-酮酸酯或丙二酸酯类，1.0当量)溶于溶剂中(优选氟苯最好)，反应温 度为-80℃至100℃(优选-30℃至50℃，再优选为-10℃至35℃，更优选为0℃至25℃，最优选为 0℃)，加入碱(优选NaH和/或LiOH，2.2当量)，搅拌10分钟至12小时(优选10分钟至6小时，再 优选10分钟至4.5小时，更优选10分钟至3小时，最优选为20分钟)，自然升至18-30℃，加入本发明 前述的二氟甲基化试剂1，于室温下搅拌反应10分钟至3小时(优选10分钟至1.5小时，再优选10分钟 至45分钟，更优选10分钟至30分钟，最优选为20分钟)，饱和氯化铵水溶液淬灭，乙酸乙酯萃取2次 以上(优选3次)，合并萃取相，水和盐水洗涤各一次，有机相用无水硫酸钠干燥，过滤，减压蒸去溶剂， 粗品用硅胶柱层析纯化，得纯品二氟甲基官能化产物3或6。
在现有技术中，如：羰基化合物α位的二氟甲基化：在羰基的α位进行二氟甲基化，目前仍是一个重 大挑战。使用本发明设计的稳定的新型亲电二氟甲基试剂，发展在羰基化合物的α位引入二氟甲基的方法 和策略，包括羰基α位碳的不对称二氟甲基化，为在有机化合物和药物分子的羰基α位碳上高效便捷的引 入二氟甲基提供解决方案。
上述反应制得的二氟甲基化的化合物3aa作为底物，还可以通过进一步转化制得下述二氟甲基官能化 化合物：
化合物7、8具有抗肿瘤、降血糖的生物活性；
化合物9具有抗感染、镇痛的生物活性。
附图说明
图1为一些含有二氟甲基的药物；
图2为本发明的二氟甲基化试剂原理示意图；
图3为本发明的二氟甲基化试剂1a的单晶衍射图谱；
图4为本发明二氟甲基化试剂应用于羰基化合物的亲电子C-选择性二氟甲基化的反应路线示意图，其 中，羰基化合物的亲电选择性碳-二氟甲基化(另外说明除外):2(β-酮酸酯)或者5(丙二酸酯)(1.0当 量)，碱(2.2当量)，1(1.2当量)，氟苯，室温，20分钟。产物3和6的收率及碳/氧比率由氟谱定量。
图5为本发明试剂应用于羰基化合物的亲电子C-选择性二氟甲基化的反应结果示意图，[a]LiOH用 作碱，[b]NaH用作碱，Me＝甲基，Et＝乙基，i-Pr＝异丙基，Bn＝苄基，Ph＝苯基。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。
总实施例A二氟甲基化试剂的制备,通式如下：
其中R1为在邻位、间位、或对位单取代或多取代的氢、卤素、硝基、氰基、多氟烷基、C1-20的烷基、C1-20的烷氧基或C1-20的烷硫基中的一种或几种；R2为在邻位、间位、或对位单取代或多取代的C1-20的烷氧基、C1-20的烷硫基、C3-12的环烷氧基或C3-12的环烷硫基中的一种或几种。
制备方法：取一经烘箱干燥的50mL Schlenk瓶，加入“二氟甲基芳基亚砜或二氟甲基杂环亚砜” RS(O)CF2H(10mmol)、取代基为R2的苯(11mmol)及磁力搅拌子；抽换氩气三次后，在氮气保护下加入经干 燥的乙醚(20mL)，充分搅拌均匀；将此反应液冷却至0℃，向其中缓慢滴加三氟甲磺酸酐(10mmol)，滴 加完毕后静置2分钟，移走上层乙醚相；加入10mL干燥的乙醚后剧烈搅拌5分钟，移走上层乙醚相；重 复上述步骤3次，固体析出；过滤，滤饼用干燥的乙醚(10mL)洗三次，得近白色粉末状三氟甲磺酸硫鎓盐； 将此盐溶于30mL二氯甲烷后倒入分液漏斗，加入50mL 1M的四氟硼酸钠溶液后剧烈摇晃5分钟，分液， 弃去水相。重复4次后，有机相经无水硫酸钠滤饼干燥，30℃下减压蒸去溶剂，产物用二氯甲烷和正己烷 重结晶，得相应的硫鎓盐。采用饱和六氟磷酸钾溶液替代上述四氟硼酸钠溶液，可得六氟磷酸根硫鎓盐。
以下实施例根据前述方法调整母核的取代基，得到以下具体实施例。
实施例1按照前述通式方法，制备得到下式化合物：
收率86％,产物为白色结晶性粉末,熔点95.5-96.5℃。1H NMR(400MHz,CDCl3)δ8.10(t,J＝54.6 Hz,1H),7.72-7.64(m,5H),6.37(s,2H),3.99(s,6H),3.96(s,3H)；13CNMR(101MHz,CDCl3) δ170.4,163.0,134.7,131.5,129.9,120.9,119.3(t,J＝298.0Hz),93.1,81.2,57.5,56.9； 19F NMR(376MHz,CDCl3)δ-97.7(dd,J＝233.6,54.2Hz,1F),-98.4(dd,J＝235.0,56.2Hz, 1F),-153.8(s,1F),-153.9(s,3F)；MS(ESI):m/z 327(C16H17O3F2S+).HRMS(ESI):calcd.for C16H17O3F2S+:327.0861；Found:327.0849.
实施例2按照前述通式方法，制备得到下式化合物：
收率82％，产物为白色结晶性粉末，熔点104-105℃。1H NMR(400MHz,CDCl3)δ7.87(dd,J＝56.2, 54.1Hz,1H),7.72-7.66(m,5H),6.35(s,2H),3.97(s,6H),3.95(s,3H)；13CNMR(101MHz, CDCl3)δ170.5,163.0,134.8,131.6,126.6,120.7,119.2(t,J＝296.5Hz),93.1,80.6,57.4, 56.8；19F NMR(376MHz,CDCl3)δ-73.6(d,J＝711.1Hz,6F),-97.0(dd,J＝233.5,53.9Hz, 1F),-98.0(dd,J＝233.5,53.9Hz,1F)；MS(ESI):m/z 327(C16H17O3F2S+)；HRMS(ESI):calcd. for C16H17O3F2S+:327.0861；Found:327.0851.
实施例3按照前述通式方法，制备得到下式化合物：
收率66％，产物为白色结晶性粉末，熔点109.5-110.5℃。1H NMR(400MHz,CDCl3)δ7.92(t,J＝ 54.9Hz,1H),7.74-7.62(m,5H),6.31(s,2H),4.28-4.16(m,6H),1.40(t,J＝7.0Hz,3H),1.31 (t,J＝7.0Hz,6H)；13C NMR(101MHz,CDCl3)δ169.7,162.3,134.4,131.4,129.2,121.0,119.3 (t,J＝298.0Hz),93.8,80.2,66.6,65.5,14.4,13.9；19F NMR(376MHz,CDCl3)δ-96.1(d,J ＝52.6Hz),-153.86,-153.91；MS(ESI):m/z 369(C19H23O3F2S+)；HRMS(ESI):calcd.for C19H23O3F2S+: 369.1331；Found:369.1323.
实施例4按照前述通式方法，制备得到下式化合物：
收率60％，产物为白色固体，熔点76.3-77.3℃。1H NMR(400MHz,CDCl3)δ7.84(dd,J＝55.6, 54.3Hz,1H),7.73-7.58(m,5H),6.24(s,2H),4.78-4.40(m,3H),1.35(d,J＝6.0Hz,6H),1.29 (d,J＝6.1Hz,6H),1.23(d,J＝6.1Hz,6H)；13C NMR(101MHz,CDCl3)δ168.7,161.6,134.2, 131.4,128.6,121.4,119.3(t,J＝298.9Hz),94.7,80.8,74.1,72.1,21.81,21.78,21.35,21.32； 19F NMR(376MHz,CDCl3)δ-95.5(dd,J＝225.6,56.4Hz),-96.4(dd,J＝225.6,56.40Hz),-153.9, -154.0；MS(ESI):m/z 411(C22H29O3F2S+)；HRMS(ESI):calcd.for C22H29O3F2S+:411.1793；Found: 411.1796.
实施例5按照前述通式方法，制备得到下式化合物：
收率40％产物为粘稠油状物。1H NMR(400MHz,CDCl3)δ7.59(t,J＝55.0Hz,1H),7.54-7.39 (m,5H),6.10(s,2H),4.91-4.85(m,3H),1.82-1.35(m,27H)；13C NMR(101MHz,CDCl3)δ168.5, 161.5,134.1,128.3,121.0,119.1(t,J＝299.0Hz),95.2,83.1,81.4,79.6,32.6,32.4,32.2, 23.9,23.71,23.67；19F NMR(376MHz,CDCl3)δ-94.5(dd,J＝222.4,54.2Hz),-95.3(dd,J＝ 222.4,54.2Hz),-153.98,-154.03；MS(ESI):m/z 489(C17H19O3F2S+)；HRMS(ESI):calcd.for C28H35O3F2S+:489.2270；Found:489.2262.
实施例6按照前述通式方法，制备得到下式化合物：
收率84％，产物为白色结晶性粉末，熔点119-120℃。1H NMR(400MHz,CDCl3)δ7.81(t,J＝54.3 Hz,1H),7.65(td,J＝9.2,1.4Hz,1H),7.23(dd,J＝8.1,1.2Hz,1H),7.18(d,J＝8.4Hz, 1H),7.15(t,J＝8.0Hz,1H),6.37(s,2H),4.02(s,3H),3.96(s,3H),3.93(s,6H)；13C NMR (101MHz,CDCl3)δ170.2,163.2,158.4,136.3,129.7,122.9,119.5(t,J＝302.0Hz),113.0, 108.1,93.0,79.6,57.2,57.1,56.8；19F NMR(376MHz,CDCl3)δ-95.4(dd,J＝214.3,56.4Hz, 1F),-98.8(dd,J＝214.3,56.4Hz,1F),-153.56(s),-153.62(s)；MS(ESI):m/z 357(C17H19O4F2S+)； HRMS(ESI):calcd.for C17H19O4F2S+:357.0967；Found:357.0959.
实施例7按照前述通式方法，制备得到下式化合物：
收率82％，产物为白色结晶性粉末，熔点94.8-95.8℃。1H NMR(400MHz,CDCl3)δ8.11(t,J＝54.7 Hz,1H),7.53(t,J＝8.2Hz,1H),7.24-7.16(m,3H),6.38(s,2H),3.98(s,6H),3.94(s,3H), 3.83(s,3H)；13C NMR(101MHz,CDCl3)δ170.4,163.0,161.3,132.3,121.9,121.8,121.0,119.3 (t,J＝296.9Hz),114.4,93.1,81.4,57.5,56.9,56.0；19F NMR(376MHz,CDCl3)δ-96.8(dd, J＝233.1,56.4Hz,1F),-97.5(dd,J＝233.1,56.4Hz,1F),-152.78(s),-152.84(s)；MS(ESI): m/z 357(C17H19O4F2S+)；HRMS(ESI):calcd.forC17H19O4F2S+:357.0967；Found:357.0962.
实施例8按照前述通式方法，制备得到下式化合物：
收率82％，产物为白色结晶性粉末，熔点125-126℃。1H NMR(400MHz,CDCl3)δ8.11(t,J＝54.6 Hz,1H),7.83(dd,J＝8.1,0.7Hz,1H),7.74(d,J＝8.1Hz,1H),7.69(s,1H),7.60(t,J＝ 8.1Hz,1H),6.38(s,2H),3.99(s,6H),3.96(s,3H)；13C NMR(101MHz,CDCl3)δ170.8,163.1, 137.8,133.1,131.9,128.6,124.5,122.7,119.5(t,J＝299.0Hz),93.2,80.1,57.6,56.9；19F NMR(376MHz,CDCl3)δ-97.8--99.4(m),-153.4(s),-153.5(s)；MS(ESI):m/z 357(C17H19O4F2S+)； HRMS(ESI):calcd.for C17H19O4F2S+:357.0967；Found:357.0953.
实施例9按照前述通式方法，制备得到下式化合物：
收率70％，产物为浅棕色固体，熔点77.5-78.5℃。1H NMR(400MHz,CDCl3)δ8.15(dd,J＝55.8, 54.2Hz,1H),7.41(dd,J＝8.6,2.1Hz,1H),7.31(d,J＝2.1Hz,1H),7.09(d,J＝8.6Hz,1H), 6.32(s,2H),4.01(s,6H),3.91(s,3H),3.90(s,3H),3.89(s,3H)；13C NMR(101MHz,CDCl3) δ189.8,162.6,155.1,151.1,126.5,118.7(dd,J＝296.9,293.9Hz),112.8,112.3,110.5,92.9, 84.2,57.4,56.7,56.5,56.5；19F NMR(376MHz,CDCl3)δ-99.5(dd,J＝236.9,56.4Hz,1F), -100.6(dd,J＝236.9,56.4Hz,1F),-153.01(s),-153.07(s)；MS(ESI):m/z 387(C18H21O5F2S+)； HRMS(ESI):calcd.for C18H21O5F2S+:387.1072；Found:387.1066.
实施例10按照前述通式方法，制备得到下式化合物：
收率73％，产物为白色结晶性粉末，熔点136.9-137.9℃。1H NMR(400MHz,CDCl3)δ8.25(t,J＝ 54.6Hz,1H),7.88(d,J＝7.1Hz,1H),7.55(t,J＝6.3Hz,1H),7.47-7.40(m,2H),6.32(s, 2H),3.99(s,6H),3.89(s,3H),2.58(s,3H)；13C NMR(101MHz,CDCl3)δ169.9,162.6,141.5, 134.9,132.8,131.4,129.3,120.7,118.9(t,J＝295.9Hz),93.0,82.8,57.4,56.8,19.9；19F NMR(376MHz,CDCl3)δ-97.8--99.4(m),-153.4(s),-153.5(s)；MS(ESI):m/z 341(C17H19O3F2S+)； HRMS(ESI):calcd.for C17H19O3F2S+:341.1018；Found:341.1025.
实施例11按照前述通式方法，制备得到下式化合物：
收率75％，产物为白色结晶性粉末，熔点86.9-87.9℃。1H NMR(400MHz,CDCl3)δ8.06(dd,J＝ 55.9,54.1Hz,1H),7.62(d,J＝8.3Hz,2H),7.46(d,J＝8.3Hz,2H),6.36(s,2H),4.01(s, 6H),3.96(s,3H),2.43(s,3H)；13C NMR(101MHz,CDCl3)δ170.2,162.9,146.5,132.2,130.2, 119.1(t,J＝341.4Hz),117.2,93.0,82.0,57.5,56.8,21.6；19F NMR(376MHz,CDCl3)δ-97.9 (dd,J＝236.9,56.4Hz,1F),-98.8(dd,J＝236.9,56.4Hz,1F),-153.45(s),-153.51(s)；MS (ESI):m/z 341(C17H19O3F2S+)；HRMS(ESI):calcd.forC17H19O3F2S+:341.1018；Found:341.1012.
实施例12按照前述通式方法，制备得到下式化合物：
收率82％，产物为白色结晶性粉末，熔点144.5-145.5℃。1H NMR(400MHz,CDCl3)δ8.31(t,J＝ 55.0Hz,1H),7.70(s,1H),7.38(d,J＝7.9Hz,1H),7.30(d,J＝7.9Hz,1H),6.34(s,2H), 4.03(s,6H),3.94(s,3H),2.55(s,3H),2.39(s,3H)；13C NMR(101MHz,CDCl3)δ169.8,162.6, 139.9,138.4,136.0,132.5,131.4,120.3,118.9(t,J＝295.9Hz),93.0,83.3,57.4,56.8,20.9, 19.4.
19F NMR(376MHz,CDCl3)δ-98.6(dd,J＝236.9,56.4Hz,1F),-99.4(dd,J＝236.9,56.4 Hz,1F),-153.28(s),-153.33(s)；MS(ESI):m/z 355(C18H21O3F2S+)；HRMS(ESI):calcd.for C18H21O3F2S+:355.1174；Found:355.1169.
实施例13按照前述通式方法，制备得到下式化合物：
制备温度为-20℃，收率22％，产物为白色结晶性粉末，熔点96.7-97.7℃。1H NMR(400MHz,CDCl3) δ8.16(t,J＝54.4Hz,1H),7.78-7.73(m,1H),7.71-7.67(m,1H),7.50(t,J＝7.9Hz,1H), 7.38(t,J＝9.0Hz,1H),6.37(s,2H),4.00(s,6H),3.96(s,3H)；13C NMR(101MHz,CDCl3)δ 170.7,163.2,160.9(d,J＝257.6Hz),137.4(d,J＝8.1Hz),131.4,127.4,119.5(t,J＝300.0 Hz),117.7(d,J＝20.2Hz),108.4(d,J＝16.2Hz),93.2,79.3,57.5,56.8；19F NMR(376MHz, CDCl3)δ-96.2(d,J＝56.4Hz,2F),-107.7(s,1F),-153.1(s)；MS(ESI):m/z 345(C16H16O3F3S+)； HRMS(ESI):calcd.for C16H16O3F3S+:345.0767；Found:345.0767.
实施例14按照前述通式方法，制备得到下式化合物：
制备温度为-20℃，收率38％，产物为无色粘稠油状物。1H NMR(400MHz,CDCl3)δ8.07(t,J＝54.6 Hz,1H),7.71-7.65(m,1H),7.52(d,J＝8.0Hz,1H),7.39(td,J＝8.2,2.1Hz,1H),7.34(dt, J＝7.7,1.8Hz,1H),6.36(s,2H),3.95(s,6H),3.92(s,3H)；13C NMR(101MHz,CDCl3)δ170.8, 163.1,163.0(d,J＝256.2Hz),133.4(d,J＝8.1Hz),125.9(d,J＝3.3Hz),122.4,122.2(d, J＝52.2Hz),119.5(t,J＝271.1Hz),116.6,93.2,80.1,57.5,56.8；19F NMR(376MHz,CDCl3) δ-96.8(d,J＝54.4Hz,2F),-106.2(m,1F),-152.5(s),-152.6(s)；MS(ESI):m/z 345 (C16H16O3F3S+)；HRMS(ESI):calcd.for C16H16O3F3S+:345.0767；Found:345.0767.
实施例15按照前述通式方法，制备得到下式化合物：
制备温度为-20℃，收率19％，产物为白色结晶性粉末，熔点113.5-114.5℃。1HNMR(400MHz,CDCl3) δ8.12(dd,J＝55.8,54.2Hz,1H),7.66-7.64(m,3H),7.55(s,1H),6.38(s,2H),3.98(s,6H), 3.96(s,3H)；13C NMR(101MHz,CDCl3)δ170.8,163.1,137.0,134.8,132.9,129.1,128.2,122.6, 119.5(t,J＝299.0Hz),93.2,80.1,57.5,56.9；19F NMR(376MHz,CDCl3)δ-96.6(d,J＝52.6 Hz,2F),-153.13(s),-153.19(s)；MS(ESI):m/z 361(C16H16O3ClF2S+)；HRMS(ESI):calcd.for C16H16O3ClF2S+:361.0471；Found:361.0468.
实施例16按照前述通式方法，制备得到下式化合物：
制备温度为-20℃，收率41％，产物为白色结晶性粉末，熔点114.9-115.9℃。1HNMR(400MHz,CDCl3) δ8.11(t,J＝54.6Hz,1H),7.83(dd,J＝8.1,0.7Hz,1H),7.74(d,J＝8.1Hz,1H),7.69(s, 1H),7.60(t,J＝8.1Hz,1H),6.38(s,2H),3.99(s,6H),3.96(s,3H)；13C NMR(101MHz,CDCl3) δ170.8,163.1,137.8,133.1,131.9,128.6,124.5,122.7,119.5(t,J＝299.0Hz),93.2,80.1, 57.6,56.9；19F NMR(376MHz,CDCl3)δ-96.5(d,J＝56.4Hz),-153.05(s),-153.10(s)；MS(ESI): m/z 405(C16H16O3BrF2S+)；HRMS(ESI):calcd.for C16H16O3BrF2S+:404.9966；Found:404.9963.
实施例17按照前述通式方法，制备得到下式化合物：
制备温度为-20℃，收率55％，产物为白色结晶性粉末，熔点115.9-116.9℃。1HNMR(400MHz,CDCl3) δ8.12(t,J＝54.9Hz,1H),7.77(d,J＝8.8Hz,2H),7.63(d,J＝8.8Hz,2H),6.35(s,2H), 3.98(s,6H),3.94(s,3H)；13C NMR(101MHz,CDCl3)δ170.6,163.0,134.7,131.5,130.2,120.0, 119.1(t,J＝298.0Hz),93.1,80.9,57.5,56.8；19F NMR(376MHz,CDCl3)δ-97.6(dd,J＝233.1, 56.4Hz,1F),-98.3(dd,J＝233.1,56.4Hz,1F),-152.9(s),-153.0(s)；MS(ESI):m/z 405 (C16H16O3BrF2S+)；HRMS(ESI):calcd.forC16H16O3BrF2S+:404.9966；Found:404.9952.
实施例18按照前述通式方法，制备得到下式化合物：
收率73％，产物为白色结晶性粉末，熔点115.9-116.9℃。1H NMR(400MHz,CDCl3)δ8.34(d,J＝ 1.1Hz,1H),8.23(t,J＝55.4Hz,1H),8.07(d,J＝8.9Hz,1H),8.02(d,J＝8.0Hz,1H),7.86 (d,J＝8.1Hz,1H),7.67-7.57(m,3H),6.35(s,2H),3.99(s,6H),3.93(s,3H)；13C NMR(101 MHz,CDCl3)δ170.3,163.0,135.3,133.1,132.7,132.0,130.3,129.2,128.6,128.1,123.5,119.0 (t,J＝298.0Hz),117.6,93.1,82.1,57.5,56.8；19F NMR(376MHz,CDCl3)δ-97.9(dd,J＝233.1, 52.6Hz,1F),-98.7(dd,J＝233.1,52.6Hz,1F),-152.89(s),-152.94(s)；MS(ESI):m/z 377 (C20H19O3F2S+)；HRMS(ESI):calcd.forC20H19O3F2S+:377.1018；Found:377.1014.
实施例19按照前述通式方法，制备得到下式化合物：
收率75％，产物为白色结晶性粉末，熔点104-105℃。1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.08 (d,J＝8.9Hz,1H),8.01(t,J＝55.9Hz,1H),8.01(d,J＝7.7Hz,1H),7.88(d,J＝7.5Hz, 1H),7.67-7.60(m,3H),6.34(s,2H),3.98(s,6H),3.94(s,3H)；13C NMR(101MHz,CDCl3)δ 170.4,163.0,135.3,133.1,132.5,132.1,130.4,129.2,128.7,128.1,123.1,117.4(t,J＝296.9 Hz),116.0,93.1,81.6,57.4,56.7；19F NMR(376MHz,CDCl3)δ-73.3(d,J＝714.4Hz,6F),-97.7 (dd,J＝233.1,56.4Hz,1F),-98.3(dd,J＝233.1,56.4Hz,1F)；MS(ESI):m/z 377(C17H19O3F2S+)； HRMS(ESI):calcd.for C20H19O3F2S+:377.1018；Found:377.1013.
实施例20按照前述通式方法，制备得到下式化合物：
收率70％，产物为白色结晶性粉末，熔点117-118℃。1H NMR(400MHz,CDCl3)δ8.08(d,J＝4.8 Hz,1H),8.03(d,J＝3.7Hz,1H),7.95(dd,J＝55.9,54.5Hz,1H),7.28(dd,J＝4.8,3.7Hz, 1H),6.34(s,2H),4.07(s,6H),3.93(s,3H)；13C NMR(101MHz,CDCl3)δ170.4,162.6,142.8, 140.9,129.0,118.8(t,J＝230.0Hz),114.7,92.8,84.5,57.4,56.9；19FNMR(376MHz,CDCl3) δ-97.5(dd,J＝243.4,57.7Hz,1F),-100.9(dd,J＝243.4,57.7Hz,1F),-152.9(s),-153.0 (s)；MS(ESI):m/z 333(C14H15O3F2S2+)；HRMS(ESI):calcd.forC14H15O3F2S2+:333.0425；Found: 333.0419.
实施例21按照前述通式方法，制备得到下式化合物：
收率84％，产物为白色结晶性粉末，熔点116.1-117.1℃。1H NMR(500MHz,CDCl3)δ7.74-7.70(m, 3H),7.68-7.65(m,2H),6.37(s,2H),4.00(s,6H),3.97(s,3H)；13C NMR(126MHz,CDCl3)δ 170.4,163.0,134.7,131.5,129.9,120.9,119.0(tt,J＝294.8,39.1Hz),93.0,81.2,57.5,56.9； 19F NMR(376MHz,CDCl3)δ-97.6(dt,J＝223.1,7.5Hz),-98.3(dt,J＝223.1,7.5Hz),-153.5, -153.6.MS(ESI):m/z 328(C16H162HO3F2S+:)；HRMS(ESI):calcd.for C16H162HO3F2S+:328.0924； Found:328.0913.
实施例22按照前述通式方法，制备得到下式化合物：
收率81％，产物为白色结晶性粉末，熔点97-98℃。1H NMR(400MHz,CDCl3)δ7.73-7.62(m,5H), 7.34(s,2H),3.96(s,6H),3.94(s,3H)；13C NMR(126MHz,CDCl3)δ170.5,163.0,134.8,131.6, 129.6,120.7,93.1,80.7,57.4,56.7；19F NMR(376MHz,CDCl3)δ-73.6(d,J＝711.1Hz),-97.9 (d,J＝233.9Hz),-98.8(d,J＝233.9Hz).MS(ESI):m/z 328(C16H162HO3F2S+:)；HRMS(ESI):calcd. for C16H162HO3F2S+:328.0924；Found:328.0917.
总实施例B，二氟甲基化试剂的应用：
羰基化合物(β-酮酸酯和丙二酸酯等)选择性碳-二氟甲基化，如下通式所示的β-酮酸酯2和丙二酸 酯5的二氟甲基化方法：
方法一：取一经烘箱干燥的25mL Schlenk管，加入底物(0.2毫摩尔，β-酮酸酯或丙二酸酯类，1.0 当量)溶于2.0mL氟苯中，冷至0℃加入LiOH(0.44毫摩尔，2.2当量)，在此温度下搅拌20分钟，自然 升至室温，加入二氟甲基化试剂1，于室温下搅拌反应20分钟，饱和氯化铵水溶液淬灭，乙酸乙酯萃取3 次，合并萃取相，水和盐水洗涤各一次，有机相用无水硫酸钠干燥，过滤，减压蒸去溶剂，粗品用硅胶柱 层析纯化，得纯二氟甲基官能化产物。
以下实施例根据前述方法调整母核的取代基，得到以下具体实施例。
实施例23按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
甲基-2-(二氟甲基)-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-2-(difluoromethyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate(3aa).
氟谱测得C/O比为97:3，分离收率87％，产物为无色透明液体。1H NMR(400MHz,CDCl3)δ8.04(dd, J＝8.0,1.4Hz,1H),7.53(td,J＝8.0,1.4Hz,1H),7.33(t,J＝7.6Hz,1H),7.26(d,J＝7.6 Hz,1H),6.60(t,J＝55.2Hz,1H),3.75(s,3H),3.32(ddd,J＝17.0,11.5,5.0Hz,1H),3.04 (dt,J＝17.0,4.5Hz,1H),2.66(dt,J＝14.0,4.5Hz,1H),2.46(ddd,J＝14.0,11.5,5.0Hz, 1H).19F NMR(376MHz,CDCl3)δ-127.8(dd,J＝283.3,55.3Hz,1H),-132.3(dd,J＝283.4,55.7 Hz,1H).MS(ESI):m/z 277.1(C13H12F2O3Na+).
实施例24按照前述通式方法，二氟化甲基试剂选用1b，制备得到下式化合物：
甲基-2-(二氟甲基)-5-甲氧基-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-2-(difluoromethyl)-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3ab).
氟谱测得C/O比为97:3，分离收率78％，产物为无色透明液体。1H NMR(400MHz,CDCl3)δ7.58(dd, J＝8.0,1.1Hz,1H),7.22(t,J＝8.0Hz,1H),6.98(dd,J＝8.0,1.1Hz,1H),6.50(t,J＝55.3 Hz,1H),3.80(s,3H),3.65(s,3H),3.07(ddd,J＝18.0,5.7,3.6Hz,1H),2.93(ddd,J＝18.0, 11.2,5.5Hz,1H),2.61(ddd,J＝14.0,5.5,3.6Hz,1H),2.30(ddd,J＝14.0,11.2,5.5Hz,1H). 19F NMR(376MHz,CDCl3)δ-128.0(dd,J＝283.4,55.0Hz,1H),-132.4(dd,J＝283.2,55.2Hz, 1H).13C NMR(101MHz,CDCl3)δ190.3(d,J＝5.8Hz),166.7(d,J＝7.9Hz),156.7,132.7,132.0, 127.2,119.6,115.7(dd,J＝247.5,247.5Hz),115.1,60.5(t,J＝21.4Hz),55.7,53.2,22.5 (t,J＝3.8Hz),18.8.MS(ESI):m/z 307.1(C14H14F2O4Na+),HRMS(ESI):calcd.for C14H15F2O4+: 285.0933；Found:285.0923.
实施例25按照前述通式方法，二氟化甲基试剂选用1c，制备得到下式化合物：
甲基-2-(二氟甲基)-6-甲氧基-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-2-(difluoromethyl)-6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3ac).
氟谱测得C/O比为96:4，分离收率80％，产物为浅黄色液体。1H NMR(400MHz,CDCl3)δ8.00(d,J ＝8.8Hz,1H),6.83(dd,J＝8.8,2.5Hz,1H),6.68(d,J＝2.5Hz,1H),6.61(t,J＝55.4Hz, 1H),3.86(s,3H),3.74(s,3H),3.31(ddd,J＝17.0,11.5,5.0Hz,1H),2.98(dt,J＝17.0,4.5 Hz,1H),2.62(dt,J＝13.9,4.5Hz,1H),2.43(ddd,J＝13.9,11.5,5.1Hz,1H).19F NMR(376 MHz,CDCl3)δ-128.0(dd,J＝282.7,55.7Hz,1H),-132.6(dd,J＝282.7,55.8Hz,1H).MS(ESI): m/z 307.1(C14H14F2O4Na+).
实施例26按照前述通式方法，二氟化甲基试剂选用1d，制备得到下式化合物：
甲基-2-(二氟甲基)-7-甲氧基-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-2-(difluoromethyl)-7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3ad).
氟谱测得C/O比为92:8，分离收率77％，产物为浅黄色液体。1H NMR(400MHz,CDCl3)δ7.42(d,J ＝2.8Hz,1H),7.09(d,J＝8.5Hz,1H),7.03(dd,J＝8.5,2.8Hz,1H),6.51(t,J＝55.3Hz, 1H),3.75(s,3H),3.67(s,3H),3.15(ddd,J＝16.8,11.5,5.0Hz,1H),2.89(dt,J＝17.0,4.5 Hz,1H),2.56(dt,J＝13.9,4.5Hz,1H),2.35(ddd,J＝13.8,11.5,5.2Hz,1H).19F NMR(376 MHz,CDCl3)δ-127.8(ddd,J＝283.3,55.0,23.5Hz,1H),-132.2(ddd,J＝283.3,55.6,23.5 Hz,1H).13C NMR(101MHz,CDCl3)δ190.0(d,J＝5.8Hz),166.8(d,J＝8.8Hz),158.5,136.2, 131.8,130.1,123.2,115.8(t,J＝246.8Hz),109.8,60.7(t,J＝21.5Hz),55.5,53.2,24.2, 23.4(t,J＝3.8Hz).MS(ESI):m/z 307.1(C14H13F2O4Na+),HRMS(ESI):calcd.for C14H15F2O4+: 285.0933；Found:285.0923.
实施例27按照前述通式方法，二氟化甲基试剂选用1e，制备得到下式化合物：
甲基-2-(二氟甲基)-6,7-二甲氧基-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-2-(difluoromethyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3ae).
氟谱测得C/O比为93:7，分离收率85％，产物为白色固体，熔点86-88℃。1H NMR(400MHz,CDCl3) δ7.46(s,1H),6.64(s,1H),6.60(t,J＝55.4Hz,1H),3.92(s,3H),3.88(s,3H),3.73(s, 3H),3.26(ddd,J＝17.0,11.0,5.0Hz,1H),2.92(dt,J＝17.0,4.5Hz,1H),2.61(dt,J＝14.0, 4.5Hz,1H),2.42(ddd,J＝14.0,11.0,5.0Hz,1H).19F NMR(376MHz,CDCl3)δ-128.1(dd,J ＝283.2,55.3Hz,1H),-132.7(dd,J＝282.5,55.6Hz,1H).13C NMR(101MHz,CDCl3)δ188.5 (d,J＝6.4Hz),167.0(d,J＝9.0Hz),154.7,148.3,138.9,124.1,116.0(t,J＝246.4Hz),110.1, 109.1,60.2(t,J＝21.5Hz),56.2,56.0,53.1,24.8,23.2(t,J＝3.8Hz).MS(ESI):m/z 337.1 (C15H16F2O5Na+),HRMS(ESI):calcd.for C15H17F2O5+:315.1039；Found:315.1027.
实施例28按照前述通式方法，二氟化甲基试剂选用1f，制备得到下式化合物：
甲基-2-(二氟甲基)-5,7-二甲基-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-2-(difluoromethyl)-5,7-dimethyl-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3af).
氟谱测得C/O比为91:9，分离收率70％，产物为白色固体，熔点87-89℃。1H NMR(400MHz,CDCl3) δ7.73(d,J＝2.0Hz,1H),7.23(d,J＝2.0Hz,1H),6.59(t,J＝55.3Hz,1H),3.73(s,3H), 3.07(ddd,J＝17.0,11.0,5.0Hz,1H),2.94(ddd,J＝17.0,5.4,3.5Hz,1H),2.69(ddd,J＝ 14.0,5.0,3.5Hz,1H),2.39(ddd,J＝14.0,11.0,5.6Hz,1H),2.33(s,3H),2.27(s,3H).19F NMR(376MHz,CDCl3)δ-128.1(dd,J＝282.9,55.1Hz,1H),-132.7(dd,J＝282.7,55.7Hz,1H). 13C NMR(101MHz,CDCl3)δ190.5(d,J＝6.1Hz),166.6(d,J＝8.4Hz),139.0,137.1,136.5, 136.1,131.0,126.0,115.9(dd,J＝247.5,246.4Hz),60.3(t,J＝21.4Hz),53.2,22.4(t,J ＝3.5Hz),22.0,20.8,19.1.MS(ESI):m/z 305.1(C15H16F2O3Na+),HRMS(ESI):calcd.for C15H17F2O3+: 283.1140；Found:283.1131.
实施例29按照前述通式方法，二氟化甲基试剂选用1g，制备得到下式化合物：
甲基-6-溴-2-(二氟甲基)-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-6-bromo-2-(difluoromethyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3ag).
氟谱测得C/O比为96:4，分离收率83％，产物为白色固体，熔点45-47℃。1H NMR(400MHz,CDCl3) δ7.90-7.45(m,3),6.58(t,J＝55.2Hz,1H),3.75(s,3H),3.30(ddd,J＝17.0,11.5,5.0 Hz,1H),3.00(dt,J＝17.0,4.0Hz,1H),2.65(ddd,J＝14.0,5.0,4.0Hz,1H),2.44(ddd,J ＝14.0,11.5,5.0Hz,1H).19F NMR(376MHz,CDCl3)δ-127.3(dd,J＝284.2,55.4Hz,1H),-131.7 (dd,J＝284.3,56.0Hz,1H).13C NMR(101MHz,CDCl3)δ189.2(d,J＝6.1Hz),166.5(d,J＝ 9.0Hz),145.1,131.9,130.6,130.4,130.1,129.8,115.6(t,J＝246.9Hz),60.7(t,J＝21.6 Hz),53.3,24.8,23.0(t,J＝3.8Hz).MS(ESI):m/z 354.9(C13H11BrF2O3Na+),HRMS(ESI):calcd. for C13H12BrF2O3+:332.9932；Found:332.9923.
实施例30按照前述通式方法，二氟化甲基试剂选用1h，制备得到下式化合物：
甲基-2-(二氟甲基)-6-氟-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-2-(difluoromethyl)-6-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3ah).
氟谱测得C/O比为92:8，分离收率86％，产物为浅黄色液体。1H NMR(400MHz,CDCl3)δ8.07(dd, J＝9.0,5.9Hz,1H),7.02(td,J＝8.5,2.5Hz,1H),6.94(dd,J＝9.0,2.5Hz,1H),6.60(t, J＝55.2Hz,1H),3.76(s,3H),3.33(ddd,J＝17.0,11.5,5.1Hz,1H),3.02(dt,J＝17.0,4.5 Hz,1H),2.65(dt,J＝14.0,4.5Hz,1H),2.46(ddd,J＝14.0,11.5,5.1Hz,1H).19F NMR(376 MHz,CDCl3)δ-102.8(s,1H),-127.86(dd,J＝283.5,55.0Hz,1H),-132.3(dd,J＝283.4,55.0 Hz,1H).13C NMR(101MHz,CDCl3)δ188.5(d,J＝5.9Hz),166.7(d,J＝8.9Hz),166.4(d,J ＝257.9Hz),146.8(d,J＝9.5Hz),131.6(d,J＝10.2Hz),127.7(d,J＝2.4Hz),115.7(t,J ＝246.7Hz),115.3(d,J＝21.6Hz),115.0(d,J＝22.3Hz),60.7(t,J＝21.8Hz),53.3,25.2, 23.0(t,J＝3.9Hz).MS(ESI):m/z 295.1(C13H11F3O3Na+),HRMS(ESI):calcd.for C13H12F3O3+: 273.0733；Found:273.0723.
实施例31按照前述通式方法，二氟化甲基试剂选用1i，制备得到下式化合物：
甲基-2-(二氟甲基)-7-氟-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-2-(difluoromethyl)-7-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3ai).
氟谱测得C/O比为93:7，分离收率85％，产物为浅黄色液体。1H NMR(500MHz,CDCl3)δ8.29-7.17 (m,3H),6.60(t,J＝55.2Hz,1H),3.78(s,3H),3.28(ddd,J＝17.0,11.5,5.0Hz,1H),3.04 (dt,J＝17.0,4.5Hz,1H),2.69(dt,J＝14.0,4.5Hz,1H),2.47(ddd,J＝14.0,11.5,5.0Hz, 1H).19F NMR(376MHz,CDCl3)δ-102.8(s,1H),-127.9(dd,J＝283.0,54.8Hz,1H),-132.3(dd, J＝284.2,54.9Hz,1H).13C NMR(126MHz,CDCl3)δ189.2(dd,J＝6.0,2.1Hz),166.5(d,J ＝8.6Hz),161.6(d,J＝247.2Hz),139.3(d,J＝3.1Hz),132.4(dd,J＝6.4,2.6Hz),130.9 (d,J＝7.2Hz),122.1(d,J＝22.2Hz),115.6(t,J＝247.0Hz),114.0(d,J＝22.3Hz),60.6 (t,J＝21.7Hz),53.4,24.4,23.3(t,J＝3.8Hz).MS(ESI):m/z 295.1(C13H11F3O3Na+),HRMS (ESI):calcd.for C13H12F3O3+:273.0733；Found:273.0725.
实施例32按照前述通式方法，二氟化甲基试剂选用1j，制备得到下式化合物：
甲基-7-氯-2-(二氟甲基)-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Methyl-7-chloro-2-(difluoromethyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3aj).
氟谱测得C/O比为93:7，分离收率78％，产物为浅黄色固体，熔点63-65℃。1H NMR(400MHz,CDCl3) δ7.99(d,J＝2.3Hz,1H),7.48(dd,J＝8.3,2.3Hz,1H),7.22(d,J＝8.2Hz,1H),6.57(t, J＝55.2Hz,1H),3.75(s,3H),3.26(ddd,J＝16.9,11.5,5.0Hz,1H),3.01(dt,J＝17.4,4.6 Hz,1H),2.66(dt,J＝14.0,4.5Hz,1H),2.44(ddd,J＝14.1,11.5,5.1Hz,1H).19F NMR(376 MHz,CDCl3)δ-127.7(dd,J＝284.1,56.3Hz,1H),-132.1(dd,J＝284.1,55.2Hz,1H).13C NMR (126MHz,CDCl3)δ189.0(d,J＝6.0Hz),166.5(d,J＝8.8Hz),141.7,134.5,133.3,132.2, 130.5,127.8,115.5(t,J＝247.0Hz),60.7(d,J＝21.8Hz),53.4,24.5,23.0(t,J＝3.8Hz). MS(ESI):m/z 311.0(C13H11ClF2O3Na+),HRMS(ESI):calcd.forC13H12ClF2O3+:289.0438；Found: 289.0431.
实施例33按照前述通式方法，二氟化甲基试剂选用1k，制备得到下式化合物：
乙基-2-(二氟甲基)-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Ethyl-2-(difluoromethyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate(3ak).
氟谱测得C/O比为96:4，分离收率84％，产物为无色透明液体。1H NMR(400MHz,CDCl3)δ8.05(dd, J＝7.6,1.5Hz,1H),7.54(td,J＝7.5,1.5Hz,1H),7.34(t,J＝7.6Hz,1H),7.28(d,J＝7.5 Hz,1H),6.62(t,J＝55.3Hz,1H),4.32-4.15(m,2H),3.35(ddd,J＝16.9,11.5,5.0Hz,1H), 3.05(dt,J＝17.3,4.6Hz,1H),2.68(dt,J＝13.9,4.7Hz,1H),2.47(ddd,J＝14.0,11.5,5.2 Hz,1H),1.23(t,J＝7.1Hz,3H).19F NMR(376MHz,CDCl3)δ-127.9(dd,J＝282.7,55.3Hz, 1H),-132.4(dd,J＝283.3,55.2Hz,1H).13C NMR(101MHz,CDCl3)δ190.1(d,J＝6.3Hz),166.3 (d,J＝8.8Hz),143.5,134.5,131.1(d,J＝2.3Hz),128.9,128.2,127.0,115.9(t,J＝246.6 Hz),62.5,60.8(t,J＝21.4Hz),25.0,23.1(t,J＝3.8Hz),13.9.MS(ESI):m/z 291.0 (C14H14F2O3Na+),HRMS(ESI):calcd.for C14H15F2O3+:269.0984；Found:269.0974.
实施例34按照前述通式方法，二氟化甲基试剂选用1l，制备得到下式化合物：
烯丙基-2-(二氟甲基)-1-氧代-1,2,3,4-四氢化萘-2-羧酸酯
Allyl-2-(difluoromethyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate(3al).
氟谱测得C/O比为97:3，分离收率82％，产物为浅红色油状液体。1H NMR(400MHz,CDCl3)δ8.06(dd, J＝7.9,1.4Hz,1H),7.55(td,J＝7.5,1.5Hz,1H),7.35(t,J＝7.6Hz,1H),7.28(d,J＝7.7 Hz,1H),6.64(t,J＝55.2Hz,1H),5.84(ddt,J＝17.2,10.8,5.5Hz,1H),5.31-5.14(m,2H), 4.70-4.63(m,2H),3.35(ddd,J＝16.8,11.5,4.9Hz,1H),3.06(dt,J＝17.3,4.6Hz,1H),2.70 (dt,J＝14.0,4.6Hz,1H),2.49(ddd,J＝14.0,11.5,5.2Hz,1H).19F NMR(376MHz,CDCl3)δ -127.3(dd,J＝283.4,55.1Hz,1H),-131.6(dd,J＝283.4,55.4Hz,1H).13C NMR(126MHz,CDCl3) δ190.0(d,J＝5.9Hz),166.0(d,J＝9.0Hz),143.5,134.5,131.1(d,J＝2.3Hz),130.8,128.9, 128.2,127.0,118.9,115.8(t,J＝246.7Hz),66.6,60.9(t,J＝21.4Hz),25.0,23.1(t,J＝ 3.8Hz).MS(ESI):m/z 303.1(C15H14F2O3Na+),HRMS(ESI):Calcd.for C15H15F2O3+:281.0984；Found: 281.0973.
实施例35按照前述通式方法，二氟化甲基试剂选用1m，制备得到下式化合物：
甲基-3-(二氟甲基)-4-氧代色满-3-羧酸酯
Methyl-3-(difluoromethyl)-4-ox℃hroman-3-carboxylate(3am).
氟谱测得C/O比为97:3，分离收率86％，产物为浅黄色液体。1H NMR(400MHz,CDCl3)δ7.95(dd, J＝7.9,1.8Hz,1H),7.56(ddd,J＝8.7,7.2,1.8Hz,1H),7.09(td,J＝7.7,7.3,1.0Hz,1H), 7.04(dd,J＝8.4,1.0Hz,1H),6.59(t,J＝54.3Hz,1H),5.06(d,J＝12.0Hz,1H),4.75(d, J＝12.0Hz,1H),3.83(s,3H).19F NMR(376MHz,CDCl3)δ-127.2(dd,J＝287.5,54.5Hz,1H), -130.4(dd,J＝287.5,54.5Hz,1H).13C NMR(101MHz,CDCl3)δ183.9(d,J＝5.7Hz),164.7 (d,J＝8.2Hz),161.3,137.2,127.9,122.2,119.6(d,J＝2.5Hz),118.2,113.9(4,J＝248.5 Hz),66.3(d,J＝9.9Hz),60.1(t,J＝20.7Hz),53.7.MS(ESI):m/z 279.0(C12H10F2O4Na+),HRMS (ESI):Calcd.for C12H11F2O4+:257.0620；Found:257.0620.
实施例36按照前述通式方法，二氟化甲基试剂选用1n，制备得到下式化合物：
甲基-3-(二氟甲基)-4-氧代硫代色-3-羧酸酯
Methyl-3-(difluoromethyl)-4-oxothi℃hroman-3-carboxylate(3an).
氟谱测得C/O比为97:3，分离收率53％，产物为浅黄色固体，熔点89-91℃。1H NMR(400MHz,CDCl3) δ8.15(dd,J＝8.1,1.6Hz,1H),7.41(ddd,J＝8.4,7.2,1.5Hz,1H),7.22(ddd,J＝15.1, 7.9,1.5Hz,2H),6.52(dd,J＝55.5,54.1Hz,1H),3.78(s,1H),3.68(d,J＝13.7Hz,1H),3.54 (d,J＝13.7Hz,1H).19F NMR(376MHz,CDCl3)δ-126.4(dd,J＝283.5,54.1Hz,1H),-130.5 (dd,J＝283.6,55.6Hz,1H).13C NMR(101MHz,CDCl3)δ187.1(d,J＝4.5Hz),165.2(d,J＝ 6.9Hz),140.9,134.0,130.4,129.6,127.5,125.5,113.8(t,J＝250.5Hz),60.7(t,J＝20.3 Hz),53.6,27.7(t,J＝4.0Hz).MS(ESI):m/z 295.0(C12H10F2O3SNa+),HRMS(ESI):calcd.for C12H11F2O3S+:273.0392；Found:273.0381.
实施例37按照前述通式方法，二氟化甲基试剂选用1o，制备得到下式化合物：
甲基-6-(二氟甲基)-5-氧代-6,7,8,9-四氢-5H-苯并[7]轮烯-6-羧酸酯
Methyl-6-(difluoromethyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carboxylate (3c).
氟谱测得C/O比为96:4，分离收率84％，产物为无色透明液体。1H NMR(400MHz,CDCl3)δ7.38(dd, J＝7.5,1.5Hz,1H),7.33(td,J＝7.5,1.5Hz,1H),7.21(d,J＝7.5Hz,1H),7.08(d,J＝7.5 Hz,1H),6.33(t,J＝55.2Hz,1H),3.58(s,3H),3.22–1.76(m,6H).19FNMR(376MHz,CDCl3) δ-127.2(d,J＝46.5Hz,1H),-127.3(d,J＝47.3Hz,1H).MS(ESI):m/z291.1(C14H14F2O3Na+).
方法二：取一经烘箱干燥的25mL Schlenk管，加入底物(0.2毫摩尔，β-酮酸酯或丙二酸酯类，1.0 当量)溶于2.0mL氟苯中，冷至0℃加入NaH(0.44毫摩尔，2.2当量)，在此温度下搅拌20分钟，自然 升至室温，加入二氟甲基化试剂1，于室温下搅拌反应20分钟，饱和氯化铵水溶液淬灭，乙酸乙酯萃取3 次，合并萃取相，水和盐水洗涤各一次，有机相用无水硫酸钠干燥，过滤，减压蒸去溶剂，粗品用硅胶柱 层析纯化，得纯二氟甲基官能化产物。
以下实施例根据前述方法调整母核的取代基，得到以下具体实施例。
实施例38按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
甲基-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Methyl-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3ba).
氟谱测得C/O比为91:9，分离收率80％，产物为黄色液体。1H NMR(400Hz,CDCl3)δ7.78(d,J＝ 7.7Hz,1H),7.67(t,J＝7.4Hz,1H),7.56(d,J＝7.7Hz,1H),7.42(t,J＝7.5Hz,1H),6.60 (t,J＝55.2Hz,1H),3.79(s,3H),3.72(d,J＝17.6Hz,1H),3.56(d,J＝17.6Hz,1H).19F NMR(376MHz,CDCl3)δ-126.5(dd,J＝287.5,54.9Hz,1H),-129.8(dd,J＝287.5,54.9Hz,1H). MS(ESI):m/z 263.1(C12H10F2O3Na+).
实施例39按照前述通式方法，二氟化甲基试剂选用1b，制备得到下式化合物：
甲基-2-(二氟甲基)-6-甲基-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Methyl-2-(difluoromethyl)-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bb).
氟谱测得C/O比为93:7，分离收率65％，产物为白色固体，熔点65-67℃。1H NMR(400MHz,CDCl3) δ7.60-7.40(m,3H),6.58(t,J＝55.2Hz,1H),3.78(s,3H),3.66(d,J＝17.4Hz,1H),3.50 (d,J＝17.4Hz,1H),2.41(s,3H).19F NMR(376MHz,CDCl3)δ-126.6(dd,J＝287.5,55.1Hz, 1H),-129.9(dd,J＝287.8,55.1Hz,1H).MS(ESI):m/z 277.1(C13H12F2O3Na+).
实施例40按照前述通式方法，二氟化甲基试剂选用1c，制备得到下式化合物：
2-(二氟甲基)-6-甲氧基-1-氧代-2,3-二氢-1H-茚-2-羧酸甲酯
Methyl-2-(difluoromethyl)-6-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bc).
氟谱测得C/O比为93:7，分离收率58％，产物为白色固体，熔点77-79℃。1H NMR(400MHz,CDCl3) δ7.37(d,J＝8.4Hz,1H),7.19(dd,J＝8.4,2.6Hz,1H),7.10(d,J＝2.6Hz,1H),6.51(t, J＝55.2Hz,1H),3.76(s,3H),3.71(s,3H),3.55(d,J＝17.1Hz,1H),3.40(d,J＝17.1Hz, 1H).19F NMR(376MHz,CDCl3)δ-126.5(dd,J＝285.0,55.3Hz,1H),-123.0(dd,J＝287.6,55.4 Hz,1H).MS(ESI):m/z 293.0(C13H12F2O4Na+).
实施例41按照前述通式方法，二氟化甲基试剂选用1d，制备得到下式化合物：
甲基-2-(二氟甲基)-6-(甲硫基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Methyl-2-(difluoromethyl)-6-(methylthio)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bd).
氟谱测得C/O比为91:9，分离收率63％，产物为浅黄色固体，熔点57-59℃。1H NMR(400MHz,CDCl3) δ7.67-7.30(m,3H),6.51(t,J＝55.2Hz,1H),3.71(s,3H),3.58(d,J＝17.6Hz,1H),3.42 (d,J＝17.6Hz,1H),2.43(s,3H).19F NMR(376MHz,CDCl3)δ-126.5(dd,J＝287.5,55.1Hz, 1H),-129.8(dd,J＝287.8,55.4Hz,1H).13C NMR(101MHz,CDCl3)δ195.2(d,J＝6.6Hz),166.3 (d,J＝12.2Hz),150.8,140.0,134.8,134.8,126.5,121.2,115.3(dd,J＝247.5,241.1Hz),64.9 (dd,J＝24.2,20.9Hz),53.4,29.5(t,J＝2.7Hz),15.6.MS(ESI):m/z 309.0(C13H12F2O3SNa+). HRMS(ESI):calcd.for C13H13F2O3S+:287.0548；found:287.0538.
实施例42按照前述通式方法，二氟化甲基试剂选用1e，制备得到下式化合物：
甲基-2-(二氟甲基)-5,6-二甲氧基-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Methyl-2-(difluoromethyl)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3be).
氟谱测得C/O比为91:9，分离收率58％，产物为白色固体，熔点104-106℃。1H NMR(400MHz,CDCl3) δ7.16(s,1H),6.96(s,1H),6.58(t,J＝55.3Hz,1H),4.00(s,3H),3.91(s,3H),3.79(s, 3H),3.61(d,J＝17.3Hz,1H),3.45(d,J＝17.3Hz,1H).19F NMR(376MHz,CDCl3)δ-126.7 (dd,J＝286.7,55.5Hz,1H),-130.2(dd,J＝286.8,55.5Hz,1H).MS(ESI):m/z 323.1 (C14H14F2O5Na+).
实施例43按照前述通式方法，二氟化甲基试剂选用1f，制备得到下式化合物：
甲基-4-溴-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Methyl-4-bromo-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bf).
氟谱测得C/O比为90:10，分离收率60％，产物为黄色液体。1H NMR(400MHz,CDCl3)δ7.85(d,J ＝6.8Hz,1H),7.74(d,J＝7.7Hz,1H),7.34(t,J＝7.8Hz,1H),6.59(t,J＝55.0Hz,1H), 3.81(s,3H),3.66(d,J＝18.0Hz,1H),3.48(d,J＝18.0Hz,1H).19F NMR(376MHz,CDCl3)δ -126.3(dd,J＝288.6,55.0Hz,1H),-129.6(dd,J＝288.8,55.0Hz,1H).MS(ESI):m/z 341.0 (C12H9BrF2O3Na+).
实施例44按照前述通式方法，二氟化甲基试剂选用1g，制备得到下式化合物：
甲基-6-溴-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Methyl-6-bromo-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bg).
氟谱测得C/O比为92:8，分离收率72％，产物为浅黄色液体。1H NMR(400MHz,CDCl3)δ7.82(d,J ＝2.0Hz,1H),7.70(dd,J＝8.2,2.0Hz,1H),7.38(d,J＝8.2Hz,1H),6.50(t,J＝55.1Hz, 1H),3.72(s,3H),3.59(d,J＝17.8Hz,1H),3.42(d,J＝17.8Hz,1H).19FNMR(376MHz,CDCl3) δ-126.3(dd,J＝288.1,51.3Hz,1H),-129.5(dd,J＝289.2,54.0Hz,1H).13C NMR(101MHz, CDCl3)δ194.4(d,J＝7.0Hz),166.0(d,J＝11.9Hz),152.4,138.9,135.8,128.1,128.0,122.3, 115.2(dd,J＝247.9,241.3Hz),65.0(dd,J＝24.1,21.2Hz),53.6,29.7(t,J＝2.7Hz).MS (ESI):m/z 340.9(C12H9BrF2O3Na+).HRMS(ESI):calcd.forC12H9BrF2O3Na+:340.9595；found: 340.9587.
实施例45按照前述通式方法，二氟化甲基试剂选用1h，制备得到下式化合物：
甲基-5-氯-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Methyl-5-chloro-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bh).
氟谱测得C/O比为90:10，分离收率57％，产物为浅黄色固体，熔点87-89℃。1H NMR(400MHz,CDCl3) δ7.63(d,J＝8.2Hz,1H),7.49(s,1H),7.33(d,J＝8.2Hz,1H),6.51(t,J＝55.1Hz,1H), 3.72(s,3H),3.63(d,J＝17.6Hz,1H),3.46(d,J＝17.6Hz,1H).19F NMR(376MHz,CDCl3)δ -126.5(dd,J＝289.2,57.4Hz,1H),-129.6(dd,J＝289.2,57.4Hz,1H).MS(ESI):m/z 297.0 (C12H9ClF2O3Na+).
实施例46按照前述通式方法，二氟化甲基试剂选用1i，制备得到下式化合物：
甲基-5,7-二氯-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Methyl-5,7-dichloro-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bi).
氟谱测得C/O比为92:8，分离收率56％，产物为白色固体，熔点67-69℃。1H NMR(400MHz,CDCl3) δ7.46(s,1H),7.39(s,1H),6.57(t,J＝55.1Hz,2H),3.81(s,3H),3.67(d,J＝18.0Hz, 1H),3.49(d,J＝18.0Hz,1H).19F NMR(376MHz,CDCl3)δ-127.0(dd,J＝288.5,55.5Hz,1H), -129.4(dd,J＝288.8,55.5Hz,1H).13C NMR(101MHz,CDCl3)δ191.4(d,J＝6.7Hz),165.8 (d,J＝11.7Hz),156.8,142.8,134.2,130.1,128.9,125.2,115.1(dd,J＝247.7,241.6Hz),65.3 (dd,J＝23.9,21.3Hz),53.7,29.0(t,J＝2.9Hz).MS(ESI):m/z341.0(C12H8Cl2F2O3Na+).HRMS (ESI):calcd.for C12H9Cl2F2O3Na+:330.9711；found:330.9698.
实施例47按照前述通式方法，二氟化甲基试剂选用1j，制备得到下式化合物：
乙基-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Ethyl-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bj).
氟谱测得C/O比为94:6，分离收率82％，产物为黄色液体。1H NMR(400MHz,CDCl3)δ7.86–7.39(m, 4H),6.60(t,J＝55.3Hz,1H),4.25(q,J＝8.0Hz,2H),3.72(d,J＝17.6Hz,1H),3.55(d, J＝17.6Hz,1H),1.28(t,J＝8.0Hz,3H).19F NMR(376MHz,CDCl3)δ-126.7(dd,J＝287.5, 55.2Hz,1H),-129.7(dd,J＝287.5,55.2Hz,1H).MS(ESI):m/z 277.1(C13H12F2O3Na+).
实施例48按照前述通式方法，二氟化甲基试剂选用1k，制备得到下式化合物：
异丙基-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Isopropyl-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bk).
氟谱测得C/O比为94:6，分离收率67％，产物为浅黄色液体。1H NMR(400MHz,CDCl3)δ7.77(d,J ＝7.7Hz,1H),7.67(t,J＝7.5Hz,1H),7.56(d,J＝7.7Hz,1H),7.41(t,J＝7.5Hz,1H),6.58 (t,J＝55.4Hz,1H),5.09(p,J＝6.3Hz,1H),3.71(d,J＝17.5Hz,1H),3.53(d,J＝17.5Hz, 1H),1.25(dd,J＝10.6,6.3Hz,6H).19F NMR(376MHz,CDCl3)δ-126.9(dd,J＝287.5,55.5 Hz,1H),-129.6(dd,J＝287.5,55.5Hz,1H).MS(ESI):m/z 291.1(C14H14F2O3Na+).
实施例49按照前述通式方法，二氟化甲基试剂选用1l，制备得到下式化合物：
苄基-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Benzyl-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bl).
氟谱测得C/O比为92:8，分离收率63％，产物为无色透明液体。1H NMR(400MHz,CDCl3)δ7.97– 7.07(m,9H),6.55(t,J＝55.2Hz,1H),5.35–4.94(m,2H),3.66(d,J＝17.5Hz,1H),3.49(d, J＝17.5Hz,1H).19F NMR(376MHz,CDCl3)δ-126.4(dd,J＝288.0,55.1Hz,1H),-129.6(dd, J＝287.9,55.7Hz,1H).MS(ESI):m/z 339.1(C18H14F2O3Na+).
实施例50按照前述通式方法，二氟化甲基试剂选用1m，制备得到下式化合物：
烯丙基-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
Allyl-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate(3bm).
氟谱测得C/O比为90:10，分离收率62％，产物为浅黄色液体。1H NMR(400MHz,CDCl3)δ7.95–7.37 (m,4H),6.64(t,J＝55.2Hz,1H),5.88(ddt,J＝17.2,10.9,5.5Hz,1H),5.42–5.20(m,2H), 4.71(d,J＝5.6Hz,2H),3.76(d,J＝17.6Hz,1H),3.59(d,J＝17.6Hz,1H).19F NMR(376MHz, CDCl3)δ-126.5(dd,J＝287.7,55.0Hz,1H),-129.7(dd,J＝287.8,55.0Hz,1H).MS(ESI): m/z 289.1(C14H12F2O3Na+).
实施例51按照前述通式方法，二氟化甲基试剂选用1n，制备得到下式化合物：
(1r，3r，5r，7r)金刚烷-2-基-2-(二氟甲基)-1-氧代-2,3-二氢-1H-茚-2-羧酸酯
(1r,3r,5r,7r)-Adamantan-2-yl-2-(difluoromethyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3bn).
氟谱测得C/O比为92:8，分离收率69％，产物为黄色液体。1H NMR(400MHz,CDCl3)δ7.99–7.34(m, 4H),6.56(t,J＝55.4Hz,1H),3.68(d,J＝17.5Hz,1H),3.51(d,J＝17.4Hz,1H),2.18(s, 3H),2.10(s,6H),1.65(s,6H).19F NMR(376MHz,CDCl3)δ-127.2(dd,J＝289.6,55.2Hz,1H), -129.3(dd,J＝286.6,55.4Hz,1H).13C NMR(101MHz,CDCl3)δ196.3(d,J＝7.5Hz),164.4 (d,J＝11.5Hz),154.0,135.9,134.3,127.9,126.4,125.1,115.7(dd,J＝246.7,240.9Hz),83.9, 65.6(dd,J＝22.6,21.3Hz),41.0,36.0,30.9,29.9(d,J＝2.7Hz).MS(ESI):m/z 383.1 (C21H22F2O3Na+).HRMS(ESI):calcd.for C21H23F2O3+:361.1610；found:361.1602.
实施例52按照前述通式方法，二氟化甲基试剂选用1o，制备得到下式化合物：
苄基-1-(二氟甲基)-2-氧代环戊烷羧酸酯
Benzyl-1-(difluoromethyl)-2-ox℃yclopentanecarboxylate(3d).
氟谱测得C/O比为95:5，分离收率56％，产物为无色透明液体。1H NMR(400MHz,CDCl3)δ8.11-6.97 (m,5H),6.40(t,J＝55.3Hz,1H),5.23(s,2H),2.88–1.94(m,6H).19FNMR(376MHz,CDCl3) δ-127.1(dd,J＝288.2,55.1Hz,1H),-128.4(dd,J＝288.3,55.5Hz,1H).MS(ESI):m/z 291.1 (C14H14F2O3Na+).
实施例53按照前述通式方法，二氟化甲基试剂选用1p，制备得到下式化合物：
苄基-1-(二氟甲基)-2-氧代环庚烷羧酸酯
Benzyl-1-(difluoromethyl)-2-ox℃ycloheptanecarboxylate(3e).
氟谱测得C/O比大于99:1，分离收率85％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.56-7.21 (m,5H),6.44(t,J＝55.0Hz,1H),5.50-5.02(m,2H),2.66-2.40(m,2H),2.35-2.20(m,2H), 2.03-1.46(m,6H).19F NMR(376MHz,CDCl3)δ-128.6(dd,J＝284.8,54.7Hz,1H),-130.3(dd, J＝285.0,55.4Hz,1H).13C NMR(101MHz,CDCl3)δ204.8(d,J＝5.0Hz),167.0(d,J＝8.1 Hz),134.8,128.7,128.6,128.1,115.6(dd,J＝247.9,245.0Hz),67.9,67.0(t,J＝20.0Hz), 42.4,30.4,25.8,25.6(t,J＝3.0Hz),25.1(d,J＝2.8Hz).MS(ESI):m/z 319.1(C16H18F2O3Na+). HRMS(ESI):calcd.for C16H19F2O3+:297.1297；found:297.1286.
实施例54按照前述通式方法，二氟化甲基试剂选用1q，制备得到下式化合物：
苄基-1-(二氟甲基)-2-氧代环辛烷基羧酸酯
Benzyl-1-(difluoromethyl)-2-ox℃yclo℃tanecarboxylate(3f).
氟谱测得C/O比为98:2，分离收率68％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.88-7.24 (m,5H),6.42(t,J＝54.5Hz,1H),5.50-4.84(m,2H),2.88-2.17(m,4H),2.13-1.02(m,8H).19F NMR(376MHz,CDCl3)δ-128.1(d,J＝55.1Hz,1H).13C NMR(101MHz,CDCl3)δ208.2,166.6 (d,J＝4.0Hz),134.7,128.7,128.6,128.2,115.9(t,J＝247.3Hz),68.0,66.1(t,J＝19.5 Hz),39.4,28.4,26.2,25.9,24.8,24.0.MS(ESI):m/z 333.1(C17H20F2O3Na+).HRMS(ESI):calcd. for C17H21F2O3+:311.1453；found:311.1443.
实施例55按照前述通式方法，二氟化甲基试剂选用1r，制备得到下式化合物：
2-苯甲酰基-3,3-二氟-2-甲基丙酸甲酯
Methyl-2-benzoyl-3,3-difluoro-2-methylpropanoate(3g).
氟谱测得C/O比为96:4，分离收率60％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.83(dd, J＝8.5,1.2Hz,2H),7.57(tt,J＝6.9,1.2Hz,1H),7.45(t,J＝7.8Hz,2H),6.48(t,J＝54.0, 1H),3.75(s,3H),1.70(s,3H).19F NMR(376MHz,CDCl3)δ-127.3(dd,J＝281.9,54.6Hz,1H), -130.3(dd,J＝281.9,55.6Hz,1H).13C NMR(101MHz,CDCl3)δ193.2(d,J＝6.0Hz),168.8 (d,J＝6.1Hz),134.7,133.6,128.8,128.6,115.2(dd,J＝250.2,243.8Hz),61.7(t,J＝21.1 Hz),53.4,14.0(dd,J＝5.5,3.3Hz).MS(ESI):m/z265.0(C12H12F2O3Na+).HRMS(ESI):calcd. for C12H13F2O3+:243.0827；found:243.0826.
实施例56按照前述通式方法，二氟化甲基试剂选用1s，制备得到下式化合物：
乙基-2-(4-溴苄基)-2-(二氟甲基)-3-氧代丁酸酯
Ethyl-2-(4-bromobenzyl)-2-(difluoromethyl)-3-oxobutanoate(3h).
氟谱测得C/O比为97:3，分离收率60％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.42(d, J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),6.06(t,J＝54.3Hz,1H),4.50-4.04(m,2H),3.29 (d,J＝5.4Hz,2H),2.28(s,3H),1.26(t,J＝7.1Hz,3H).19F NMR(376MHz,CDCl3)δ-125.4 (dd,J＝283.5,54.0Hz,1H),-128.2(dd,J＝283.7,54.2Hz,1H).13C NMR(101MHz,CDCl3)δ 199.0,167.3(d,J＝8.6Hz),133.4,131.8,131.7,121.6,114.6(dd,J＝252.5,242.4Hz),67.1 (dd,J＝21.2,18.8Hz),62.3,35.4(dd,J＝3.9,2.6Hz),29.4(d,J＝3.9Hz),13.9.MS(ESI): m/z 366.0(C14H15BrF2O3Na+).HRMS(ESI):calcd.forC14H16BrF2O3+:349.0245；found:349.0240.
实施例57按照前述通式方法，二氟化甲基试剂选用1t，制备得到下式化合物：
乙基-2-苄基-2-(二氟甲基)-3-氧代丁酸酯
Ethyl-2-benzyl-2-(difluoromethyl)-3-oxobutanoate(3i).
氟谱测得C/O比为98:2，分离收率70％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.28-7.00 (m,5H),5.96(t,J＝54.3Hz,1H),4.29-4.01(m,2H),3.25(s,2H),2.20(s,3H),1.15(t,J ＝7.1Hz,3H).19F NMR(376MHz,CDCl3)δ-126.2(dd,J＝282.6,54.8Hz,1H),-128.6(dd,J ＝282.5,55.0Hz,1H).13C NMR(101MHz,CDCl3)δ199.4,167.6(d,J＝8.2Hz),134.3,130.0, 128.6,127.5,115.3(dd,J＝247.8,246.1Hz),67.1(dd,J＝21.5,18.5Hz),62.1,36.2(dd,J ＝4.2,2.7Hz),29.5(d,J＝3.9Hz),13.8.MS(ESI):m/z 293.0(C14H16F2O3Na+).HRMS(ESI):calcd. for C14H17F2O3+:271.1140；found:271.1134.
实施例58按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
乙基-2-(二氟甲基)-3-氧代-2-(噻吩-3-基甲基)丁酸酯
Ethyl-2-(difluoromethyl)-3-oxo-2-(thiophen-3-ylmethyl)butanoate(3j).
氟谱测得C/O比为99:1，分离收率61％，产物为浅黄色油状液体。1H NMR(400MHz,CDCl3)δ7.24 (dd,J＝5.0,3.0Hz,1H),7.03(d,J＝3.0Hz,1H),6.86(d,J＝5.0Hz,1H),6.07(t,J＝54.5 Hz,1H),4.40-4.11(m,2H),3.36(s,2H),2.25(s,3H),1.25(t,J＝7.1Hz,3H).19F NMR(376 MHz,CDCl3)δ-125.7(dd,J＝283.2,54.3Hz,1H),-128.4(dd,J＝283.2,54.3Hz,1H).13C NMR (101MHz,CDCl3)δ199.5,167.5(d,J＝7.7Hz),134.2,129.0,125.9,124.2,115.4(dd,J＝252.5, 242.4Hz),67.0(dd,J＝20.9,18.6Hz),62.3,30.5(t,J＝3.7Hz),29.3(d,J＝3.6Hz),13.9. MS(ESI):m/z 299.1(C12H14F2O3SNa+).HRMS(ESI):calcd.for C12H15F2O3+:277.0882；found: 277.0884.
实施例59按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
乙基-2-(二氟甲基)-2-(4-甲基苄基)-3-氧代丁酸酯
Ethyl-2-(difluoromethyl)-2-(4-methylbenzyl)-3-oxobutanoate(3k).
氟谱测得C/O比为97:3，分离收率60％，产物为浅黄色油状液体。1H NMR(400MHz,CDCl3)δ7.10 (d,J＝7.9Hz,2H),7.03(d,J＝7.9Hz,2H),6.05(t,J＝54.3Hz,1H),4.51-4.12(m,2H),3.32 (s,2H),2.33(s,3H),2.29(s,3H),1.27(t,J＝7.1Hz,3H).19F NMR(376MHz,CDCl3)δ-126.5 (dd,J＝282.3,54.1Hz,1H),-128.7(dd,J＝282.5,54.1Hz,1H).13C NMR(101MHz,CDCl3)δ 199.5,167.6(d,J＝8.3Hz),137.1,131.0,129.8,129.2,114.7(t,J＝246.4Hz),67.1(dd,J ＝21.6,18.4Hz),62.1,35.9-35.8(m),29.4(d,J＝3.9Hz),21.0,13.8.MS(ESI):m/z 307.10 (C15H18F2O3Na+).HRMS(ESI):calcd.for C15H19F2O3+:285.1297；found:282.1292.
实施例60按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
苄基-2-(二氟甲基)-2-甲基-3-氧代丁酸酯
Benzyl-2-(difluoromethyl)-2-methyl-3-oxobutanoate(3l).
氟谱测得C/O比为97:3，分离收率60％，产物为无色透明液体。1H NMR(400MHz,CDCl3)δ7.71-7.12 (m,5H),6.39(t,J＝55.1Hz,1H),5.24(s,2H),2.18(s,3H),1.56(s,3H).19F NMR(376MHz, CDCl3)δ-127.1(dd,J＝285.5,55.2Hz,1H),-129.7(dd,J＝285.7,54.8Hz,1H).13C NMR(101 MHz,CDCl3)δ200.1(d,J＝5.4Hz),167.3(d,J＝7.5Hz),134.6,128.7,128.3,114.5(t,J ＝247.0Hz),68.0,63.8(t,J＝21.3Hz),26.9,12.4.MS(ESI):m/z279.1(C13H14F2O3Na+).HRMS (ESI):calcd.for C13H15F2O3+:257.0984；found:257.0979.
实施例61按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
3-(二氟甲基)-2-氧代-1-苯基二氢吲哚-3-羧酸甲酯
Methyl-3-(difluoromethyl)-2-oxo-1-phenylindoline-3-carboxylate(3m).
氟谱测得C/O比为96:4，分离收率72％，产物为浅黄色固体，熔点109-111℃。1HNMR(400MHz,CDCl3) δ7.70-7.30(m,7H),7.18(t,J＝7.6Hz,1H),6.85(d,J＝7.9Hz,1H),6.63(t,J＝54.8Hz, 1H),3.82(s,3H).19F NMR(376MHz,CDCl3)δ-127.8(dd,J＝55.1,10.9Hz,2H).13C NMR(101 MHz,CDCl3)δ167.4(dd,J＝6.1,3.3Hz),165.3(dd,J＝6.6,3.8Hz),145.1,133.5,130.3, 129.8,128.8,126.7,126.0,123.8,121.3,114.0(t,J＝252.2Hz),110.2,62.7(t,J＝23.1Hz), 53.7.MS(ESI):m/z 340.0(C17H13F2NO3Na+).HRMS(ESI):calcd.for C17H14F2NO3+:318.0936；found: 318.0930.
实施例62按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
3-(二氟甲基)-5-甲氧基-2-氧代-1-苯基二氢吲哚-3-甲酸甲酯
Methyl-3-(difluoromethyl)-5-methoxy-2-oxo-1-phenylindoline-3-carboxylate(3n).
氟谱测得C/O比为92:8，分离收率72％，产物为蓝色固体，熔点115-117℃。1H NMR(400MHz,CDCl3) δ7.59–7.36(m,5H),7.08(d,J＝2.5Hz,1H),6.88(dd,J＝8.7,2.5Hz,1H),6.78(d,J ＝8.7Hz,1H),6.62(t,J＝54.7Hz,1H),3.82(s,3H),3.81(s,3H).19F NMR(376MHz,CDCl3) δ-128.0(d,J＝54.1Hz,2H).13C NMR(101MHz,CDCl3)δ167.1(t,J＝5.0Hz),165.3(t,J ＝5.2Hz),156.6,138.5,133.8,129.8,128.6,126.4,122.3,115.1,114.7(t,J＝246.5Hz),112.7, 110.7,63.1(t,J＝23.3Hz),55.9,53.7.MS(ESI):m/z370.1(C18H15F2NO3Na+).HRMS(ESI):calcd. for C18H16F2NO3+:348.1042；found:348.1033.
实施例63按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
3-(二氟甲基)-4-甲基-2-氧代-1-苯基二氢吲哚-3-甲酸甲酯
Methyl-3-(difluoromethyl)-4-methyl-2-oxo-1-phenylindoline-3-carboxylate(3o).
氟谱测得C/O比为95:5，分离收率73％，产物为白色固体，熔点94-96℃。1H NMR(400MHz,CDCl3) δ7.56(t,J＝7.5Hz,2H),7.47(t,J＝7.5Hz,1H),7.42(d,J＝8.0Hz,2H),7.26(td,J＝ 7.9,1.6Hz,1H),7.02(d,J＝8.0Hz,1H),6.68(t,J＝52.0Hz,1H),6.68(d,J＝7.9Hz,1H), 3.86(s,3H),2.37(s,3H).19F NMR(376MHz,CDCl3)δ-122.5(dd,J＝282.7,55.1Hz,1H),-128.9 (dd,J＝282.7,54.5Hz,1H).13C NMR(101MHz,CDCl3)δ167.7(d,J＝8.5Hz),165.5(d,J＝ 10.0Hz),145.6,137.0,133.5,129.9,129.7,128.7,126.8,126.2,119.8,115.4(dd,J＝252.0, 242.6Hz),107.7,63.4(dd,J＝24.0,22.5Hz),53.4,19.3(d,J＝8.5Hz).MS(ESI):m/z 354.1 (C18H15F2NO3Na+).HRMS(ESI):calcd.for C18H16F2NO3+:332.1093；found:332.1086.
实施例64按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
甲基-3-(二氟甲基)-1-甲基-2-氧代-1,2,3,4-四氢喹啉-3-羧酸酯
Methyl-3-(difluoromethyl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate(3p).
氟谱测得C/O比大于99:1，分离收率83％，产物为白色固体，熔点119-121℃。1HNMR(400MHz,CDCl3) δ7.27(d,J＝7.2Hz,1H),7.09(t,J＝7.5Hz,2H),6.99(d,J＝8.2Hz,1H),6.63(t,J＝ 55.3Hz,1H),3.64(s,3H),3.47-3.27(m,5H).19F NMR(376MHz,CDCl3)δ-127.6(dd,J＝281.6, 55.4Hz),-131.9(dd,J＝281.4,56.1Hz,1H).13C NMR(101MHz,CDCl3)δ166.0(d,J＝7.8Hz), 163.5(d,J＝8.3Hz),138.2,128.6,127.9,124.0,122.7,115.0(dd,J＝249.8,244.4Hz),114.9, 57.1(dd,J＝23.6,21.5Hz),53.4,30.3,26.3(t,J＝4.0Hz).MS(ESI):m/z 292.1(C13H13F2NO3Na+). HRMS(ESI):calcd.for C13H14F2NO3+:270.0936；found:270.0929.
实施例65按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
甲基-1-苄基-3-(二氟甲基)-2-氧代-1,2,3,4-四氢喹啉-3-羧酸酯
Methyl-1-benzyl-3-(difluoromethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate(3q).
氟谱测得C/O比大于99:1，分离收率95％，产物为白色固体，熔点89-91℃。1H NMR(400MHz,CDCl3) δ7.32(dq,J＝23.5,7.2Hz,6H),7.17(t,J＝7.7Hz,1H),7.07(t,J＝7.3Hz,1H),6.92(d, J＝8.1Hz,1H),6.71(t,J＝55.2Hz,1H),5.55(d,J＝16.2Hz,1H),4.89(d,J＝16.2Hz,1H), 3.73(s,3H),3.57-3.27(m,2H).19F NMR(376MHz,CDCl3)δ-127.3(dd,J＝282.0,55.1Hz,1H), -131.2(dd,J＝281.7,55.6Hz,1H).13C NMR(101MHz,CDCl3)δ166.0(d,J＝7.3Hz),163.9 (d,J＝7.9Hz),137.8,136.4,128.8,128.8,128.0,127.4,126.3,124.1,122.7,115.7,114.7(dd, J＝250.0,244.8Hz),57.4(dd,J＝23.2,21.5Hz),53.4,47.2,26.7(t,J＝4.2Hz).MS(ESI): m/z 368.1(C19H17F2NO3Na+).HRMS(ESI):calcd.for C19H18F2NO3+:346.1249；found:346.1242.
实施例66按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
2-(二氟甲基)-2-苯基丙二酸二乙酯
Diethyl-2-(difluoromethyl)-2-phenylmalonate(6a).
氟谱测得C/O比大于99:1，分离收率88％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.82-7.30 (m,5H),6.55(t,J＝54.9Hz,1H),4.35(qd,J＝7.1,2.1Hz,4H),1.31(t,J＝7.1Hz,6H). 19F NMR(376MHz,CDCl3)δ-124.1(d,J＝55.1Hz,2H).MS(ESI):m/z 309.1(C14H16F2O4Na+).
实施例67按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
二乙基-2-(4-氯苯基)-2-(二氟甲基)丙二酸酯
Diethyl-2-(4-chlorophenyl)-2-(difluoromethyl)malonate(6b).
氟谱测得C/O比大于99:1，分离收率80％，产物为浅黄色油状液体。1H NMR(400MHz,CDCl3)δ7.39 (d,J＝8.8Hz,2H),7.30(d,J＝8.7Hz,2H),6.55(t,J＝54.9Hz,1H),4.37(qd,J＝7.1,2.3 Hz,4H),1.32(t,J＝7.2Hz,6H).19F NMR(376MHz,CDCl3)δ-124.1(d,J＝55.0Hz,2H).13C NMR(101MHz,CDCl3)δ165.7(t,J＝4.6Hz),134.9,131.0,128.7,128.4,113.8(t,J＝248.2 Hz),66.9(t,J＝21.5Hz),62.9,13.9.MS(ESI):m/z 343.0(C14H15ClF2O4Na+).HRMS(ESI):calcd. for C14H16ClF2O4+:321.0700；found:321.0695.
实施例68按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
二乙基-2-(二氟甲基)-2-(4-氟苯基)丙二酸酯
Diethyl-2-(difluoromethyl)-2-(4-fluorophenyl)malonate(6c).
氟谱测得C/O比大于99:1，分离收率74％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.32 (dd,J＝8.7,5.1Hz,2H),7.08(t,J＝8.7Hz,2H),6.52(t,J＝55.0Hz,1H),4.35(qd,J＝ 7.2,2.4Hz,4H),1.30(t,J＝7.1Hz,6H).19F NMR(376MHz,CDCl3)δ-113.6(s,1H),-124.2 (d,J＝55.0Hz,2H).13C NMR(101MHz,CDCl3)δ165.9(t,J＝4.6Hz),162.8(d,J＝248.6Hz), 131.4(d,J＝8.3Hz),126.0(d,J＝2.6Hz),115.2(d,J＝21.6Hz),113.9(t,J＝247.9Hz), 66.8(t,J＝21.5Hz),62.8,13.9.MS(ESI):m/z 327.1(C14H15F3O4Na+).HRMS(ESI):calcd.for C14H16F3O4+:305.1001；found:305.1001.
实施例69按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
2-(二氟甲基)-2-(4-氟苯基)丙二酸二乙酯
Diethyl-2-(2,4-dichlorophenyl)-2-(difluoromethyl)malonate(6d).
氟谱测得C/O比大于99:1，分离收率82％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.36 (d,J＝2.2Hz,1H),7.32(d,J＝8.6Hz,1H),7.21(dd,J＝8.7,2.2Hz,1H),6.74(t,J＝54.7 Hz,1H),4.26(qq,J＝10.8,7.1Hz,4H),1.22(t,J＝7.2Hz,6H).19F NMR(376MHz,CDCl3)δ -123.4(d,J＝54.6Hz,2H).13C NMR(101MHz,CDCl3)δ165.1(t,J＝3.8Hz),135.4,135.0, 132.9,130.7,128.6,127.1,113.5(t,J＝249.4Hz),67.0(t,J＝21.6Hz),63.1,13.8.MS(ESI): m/z 376.9(C14H14Cl2F2O4Na+).HRMS(ESI):calcd.forC14H15Cl2F2O4+:355.0310；found:355.0306.
实施例70按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
2-(二氟甲基)-2-(4-甲氧基苯基)丙二酸二乙酯
Diethyl-2-(difluoromethyl)-2-(4-methoxyphenyl)malonate(6e).
氟谱测得C/O比大于99:1，分离收率91％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.28 (d,J＝8.9Hz,2H),6.94(d,J＝9.0Hz,2H),6.54(t,J＝55.1Hz,1H),4.36(qd,J＝7.1,2.0 Hz,4H),3.83(s,3H),1.32(t,J＝7.1Hz,6H).19F NMR(376MHz,CDCl3)δ-124.2(d,J＝55.2 Hz,2H).13C NMR(101MHz,CDCl3)δ166.3(t,J＝4.5Hz),159.7,130.6,122.2,114.2(t,J＝ 247.8Hz),113.7,66.7(t,J＝21.6Hz),62.6,55.2,13.9.MS(ESI):m/z 339.1(C15H18F2O5Na+). HRMS(ESI):calcd.for C15H19F2O5+:317.1195；found:317.1186.
实施例71按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
2-苄基-2-(二氟甲基)丙二酸二乙酯
Diethyl-2-benzyl-2-(difluoromethyl)malonate(6f).
氟谱测得C/O比大于99:1，分离收率91％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.43-7.19 (m,5H),6.08(t,J＝54.2Hz,1H),4.99-3.98(m,4H),3.46(s,2H),1.27(t,J＝7.2Hz,6H). 19F NMR(376MHz,CDCl3)δ-127.5(d,J＝54.2Hz,2H).MS(ESI):m/z323.0(C15H18F2O4Na+).
实施例72按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
2-(二氟甲基)-2-(4-硝基苄基)丙二酸二乙酯
Diethyl-2-(difluoromethyl)-2-(4-nitrobenzyl)malonate(6g).
氟谱测得C/O比大于99:1，分离收率72％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ8.13 (d,J＝9.0Hz,2H),7.45(d,J＝9.0Hz,2H),6.20(t,J＝54.3Hz,1H),4.77-3.87(m,4H),3.53 (s,2H),1.25(t,J＝7.1Hz,6H).19F NMR(376MHz,CDCl3)δ-125.7(d,J＝54.3Hz,2H).13C NMR(101MHz,CDCl3)δ165.9(t,J＝4.1Hz),147.2,142.6,131.5,123.3,114.4(t,J＝248.4 Hz),62.6,62.6(t,J＝20.9Hz),34.3(t,J＝2.8Hz),13.9.MS(ESI):m/z368.1(C15H17F2NO6Na+). HRMS(ESI):calcd.for C15H18F2NO6+:346.1097；found:346.1091.
实施例73按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
2-(二氟甲基)-2-(2-硝基苄基)丙二酸二乙酯
Diethyl-2-(difluoromethyl)-2-(2-nitrobenzyl)malonate(6h).
氟谱测得C/O比大于99:1，分离收率72％，产物为浅黄色油状液体。1H NMR(400MHz,CDCl3)δ7.92 (d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.53(t,J＝7.6Hz,1H),7.42(t,J＝7.7Hz, 1H),6.26(t,J＝54.4Hz,1H),4.30-4.06(m,4H),3.86(s,2H),1.18(t,J＝7.2Hz,6H).19F NMR(376MHz,CDCl3)δ-126.4(d,J＝54.6Hz,2H).13C NMR(101MHz,CDCl3)δ165.9(t,J＝ 4.0Hz),150.4,133.8,132.6,130.3,128.4,124.9,114.5(t,J＝248.9Hz),62.6,62.3(t,J＝ 20.5Hz),29.5(t,J＝3.5Hz),13.7.MS(ESI):m/z 368.1(C15H17F2NO6Na+).HRMS(ESI):calcd. for C15H18F2NO6+:346.1097；found:346.1088.
实施例74按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
1,1-二甲基-2-(二氟甲基)-2-(4-甲氧基苄基)丙二酸酯
Dimethyl-2-(difluoromethyl)-2-(4-methoxybenzyl)malonate(6i).
氟谱测得C/O比大于99:1，分离收率94％，产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.08 (d,J＝8.5Hz,2H),6.81(d,J＝8.5Hz,2H),6.02(t,J＝54.2Hz,1H),3.77(s,9H),3.38(s, 2H).19F NMR(376MHz,CDCl3)δ-127.7(d,J＝54.4Hz,2H).13C NMR(101MHz,CDCl3)δ166.9 (t,J＝3.3Hz),159.0,131.1,125.8,114.4(t,J＝247.9Hz),113.9,62.5(t,J＝20.4Hz),55.2, 53.0,35.5(t,J＝3.2Hz).MS(ESI):m/z 325.1(C14H16F2O5Na+).HRMS(ESI):calcd.for C14H17F2O5+: 303.1039；found:303.1033.
实施例75按照前述通式方法，二氟化甲基试剂选用1a，制备得到下式化合物：
2-(二氟甲基)-2-((5-(乙氧羰基)呋喃-3-基)甲基)丙二酸二乙酯
Diethyl-2-(difluoromethyl)-2-((5-(ethoxycarbonyl)furan-3-yl)methyl)malonate(6j).
氟谱测得C/O比大于99:1，分离收率80％，产物为浅黄色油状液体。1H NMR(400MHz,CDCl3)δ7.04 (d,J＝3.4Hz,1H),6.27(d,J＝3.3Hz,1H),6.23(t,J＝54.3Hz,1H),4.28(dq,J＝9.7,7.2 Hz,6H),3.50(s,2H),1.32(t,J＝7.1Hz,3H),1.25(t,J＝7.1Hz,6H).19F NMR(376MHz,CDCl3) δ-127.3(d,J＝54.3Hz,2H).13C NMR(101MHz,CDCl3)δ165.6(t,J＝3.9Hz),158.4,153.6, 144.2,118.7,114.3(t,J＝248.3Hz),111.3,62.7,61.0(t,J＝202.5Hz),60.8,28.1(t,J＝ 3.5Hz),14.3,13.8.MS(ESI):m/z 385.1(C16H20F2O7Na+).HRMS(ESI):calcd.for C16H21F2O7+: 363.1250；found:363.1239.
实施例76化合物3aa的合成反应条件的优化
[a]反应条件(除非另有说明)：2aa(0.1mmol)，碱，1(1.2mmol，1.2当量)，溶剂(如氟苯，1.0mL)， 室温，20分钟。收率和3aa/4aa的比率由氟谱定量。[b]反应温度为0℃。[c]括号中给出的是分离产物 的收率。
实施例77 2-(二氟甲基)-2-(羟基甲基)-1,2,3,4-四氢萘-1-醇
2-(Difluoromethyl)-2-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ol(7)的制备
氮气保护下，将3aa(46.3mg,0.18mmol,in 1mL THF)缓慢滴加到0℃下氢化锂铝和无水四氢呋喃 (THF)的混合液中，保持此温度下反应1小时。小心滴加乙酸乙酯淬灭过量的氢化锂铝，然后加入10％盐 酸溶液。搅拌20分钟后，用乙酸乙酯萃取(20mL x3)。合并有机相，水洗，饱和氯化钠洗涤，无水硫酸钠 干燥，减压旋干。柱层析(300-400目硅胶，正己烷：乙酸乙酯＝5：1)分离纯化得两个非对映异构体7(30.0 mg,72％,dr＝5:1)。
其中，极性较小的化合物为白色固体，熔点111.1-112.1℃。1H NMR(400MHz,CDCl3):δ7.54(d, J＝7.2Hz,1H),7.29-7.22(m,2H),7.13(d,J＝7.2Hz,1H),6.18(t,J＝56.4Hz,1H),4.97 (s,1H),3.83(t,J＝12Hz,2H),2.86-2.72(m,2H),1.94-1.87(m,1H),1.77-1.70(m,1H),1.94-1.70 (br,2H).13C NMR(CDCl3,101MHz)δ137.2,135.7,128.4,127.9,127.3,126.8,118.1(t,J＝242.6 Hz),70.7(t,J＝4.7Hz),63.3(t,J＝4.4Hz),45.7,25.1,21.5(t,J＝4.0Hz).19F NMR(376 MHz,CDCl3):δ-133.5(dd,J＝227.5,56.4Hz),-134.9(dd,J＝227.5,56.4Hz).MS(ESI):m/z 229(M+H+)；HRMS calcd for(C12H14F2O2+H+):229.1035,Found:229.1038.
极性较大的化合物为白色固体，熔点111.1-112.1℃。1H NMR(400MHz,CDCl3):δ7.39(d,J＝7.0 Hz,1H),7.29-7.23(m,2H),7.17(d,J＝7.0Hz,1H),6.12(t,J＝56.0Hz,1H),4.73(s,1H), 3.79(d,J＝12.4,1H),3.65(d,J＝12.4,1H),2.96-2.81(m,2H),2.04-1.98(m,1H),1.88-1.83 (m,1H),2.05-1.83(br,2H).13C NMR(101MHz,CDCl3)δ136.2,135.6,129.0,128.9,128.4,126.8, 120.3(dd,J＝243.4Hz,2.4Hz),69.7(dd,J＝2.9Hz,2.5Hz),62.2(t,J＝3.6Hz),45.7(t, J＝16.7Hz),24.7,20.4(dd,J＝3.6Hz,2.0Hz).19FNMR(376MHz,CDCl3):δ-129.0(dd,J＝ 228.6,55.3Hz),-133.4(dd,J＝228.6,55.3Hz).MS(ESI):m/z 251(M+Na+)；HRMS(ESI):calcd for (C12H14F2O2+Na+):251.0854,Found:251.0849.
实施例78甲基-2-(二氟甲基)-1,2,3,4-四氢萘-2-羧酸酯
Methyl-2-(Difluoromethyl)-1,2,3,4-tetrahydronaphthalene-2-carboxylate(8)的制备
将3aa(30毫克,0.12毫摩尔)溶于1.0mL三氟乙酸中，三乙基硅烷0.1mL(0.63毫摩尔)在0℃ 下滴加如上述溶液，反应混合物在0℃下搅拌反应2小时；升至室温搅拌过夜；再冷至0℃，用碳酸氢钠水 溶液淬灭，乙酸乙酯萃取3次，有机相用水和盐水洗，无水硫酸钠干燥，过滤，浓缩，粗品通过硅胶柱层 析纯化(正己烷/乙酸乙酯＝100:1)得21.2毫克化合物8，75％收率，无色液体。
1H NMR(400MHz,CDCl3):δ7.17-7.14(m,3H),7.08-7.06(m,3H),6.00(t,J＝44.8Hz,1H), 3.70(s,3H),3.28(d,J＝13.2Hz,1H),3.01(d,J＝13.2Hz,1H),2.88-2.75(m,2H),2.30-2.45 (m,1H),1.97-1.91(m,1H).13C NMR(101MHz,CDCl3)δ171.8,134.9,133.4,129.2,128.6,126.3, 126.2,117.6(t,JC-F＝196.8Hz),52.8,51.0(t,JC-F＝15.5Hz),29.3(t,JC-F＝3.0Hz),25.9, 25.6(dd,JC-F＝2.1Hz,1.4Hz).19F NMR(376MHz,CDCl3):δ-127.8(dd,J＝227.8,55.0Hz), -132.3(dd,J＝227.8,55.0Hz).MS(ESI):m/z 241(M+H+)；HRMS(ESI)calcd for(C13H14F2O2+H +):241.1035,Found:241.1032.
实施例79 3a-(二氟甲基)-2,3a，4,5-四氢-3H-苯并[g]吲唑-3-酮
3a-(difluoromethyl)-2,3a,4,5-tetrahydro-3H-benzo[g]indazol-3-one(9)的制备
将水合肼(0.6mmol)加入到3aa(51.0mg,0.2mmol)的乙醇(5mL)溶液中，加热回流15分钟。减 压蒸去溶剂后加入乙酸乙酯溶解，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，减压旋干。粗产 物经柱层析(300-400目硅胶，正己烷：乙酸乙酯＝2：1)分离纯化，得到产物9(35.0mg,75％)，为白色 固体，熔点189-191℃。1H NMR(500MHz,DMSO-d6)δ11.78(s,1H),7.72(dd,J＝7.6,1.4Hz,1H), 7.41(td,J＝7.5,1.4Hz,1H),7.32(t,J＝8.2Hz,2H),6.41(t,J＝54.0Hz,1H),3.14(ddd, J＝18.4,12.8,5.8Hz,1H),2.94(dd,J＝17.9,6.4Hz,1H),2.43(dd,J＝13.9,5.1Hz,1H), 2.08-1.97(m,1H).19F NMR(376MHz,DMSO-d6)δ-125.44(qd,J＝284.5,53.7Hz).13C NMR(126 MHz,DMSO-d6)δ174.13(d,J＝4.7Hz),155.29(d,J＝3.8Hz),138.70,130.77,129.70,127.79, 127.26,123.77,115.47(dd,J＝248.3,245.9Hz),53.00(t,J＝20.5Hz),25.14(t,J＝4.9Hz), 25.10.MS(ESI):m/z273.1(C12H11F2N2O+).HRMS(ESI):calcd.for C12H11F2N2O+:273.0828；found:273.0834.
前述实施例部分参考文献(注：此处的参考文献为实施例及产物表征中的参考文献)
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[4](a)X.Xie，G.Cai，D.Ma，Org.Lett.2005，7，4693-4695；(b)M.A.Aramendía，V.Borau， C.Jiménez，J.M.Marinas，J.R.Ruiz，F.J.Urbano，Tetrahedron Lett.2002，2847-2849；(c)D. L.Musso et al.J.Med.Chem.2003，46，399-408.(d)R.A.Ward etal.J.Med.Chem.2012，55， 3285-3306.
[5]G.-k.Liu,X.Wang,X.Lu,X.-Hua.Xu,E.Tokunaga,N.Shibata,ChemistryOpen,2012,1, 227-231.
[6]Chinese Academy Of Sciences Shanghai Organic Chemistry Institute；Q.-L.Shen,J.-Sh.Zhu, Y.-F.Liu-CN107235878,2017,A.
[7]K.Manuel,C.Tanja,B.michael,H.Paul,G.Bernhard,Kappe,C.Oliver,GreenChenmistry, 2018,20,108-112.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未 背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含 在本发明的保护范围之内。

Claims (10)

1.一种二氟甲基化试剂，其特征在于，具有下式(I)、(II)、(III)结构的化合物或其盐，
其中R1为在邻位、间位、或对位单取代或多取代的氢、卤素、硝基、氰基、多氟烷基、C1-20的烷基、C1-20的烷氧基或C1-20的烷硫基中的一种或几种；R2为在邻位、间位、或对位单取代或多取代的C1-20的烷氧基、C1-20的烷硫基、C3-12的环烷氧基或C3-12的环烷硫基中的一种或几种；
所述R2中的O或S与CF2H中的H形成分子内氢键。
2.根据权利要求1所述的二氟甲基化试剂，其特征在于，所述二氟甲基化试剂其盐为硫鎓盐，所述硫鎓盐的抗阴离子为四氟合硼酸根或六氟磷酸根或三氟甲磺酸根或氟、氯、溴、碘或磷酸根，具体为下式(Ia)、(IIa)、(IIIa)：
3.根据权利要求1所述的二氟甲基化试剂，其特征在于，所述二氟甲基化试剂具体选自：
4.一种根据权利要求1-3任一项所述的二氟甲基化试剂的制备方法，其特征在于，包括以下合成路线：
反应在三氟甲磺酸酐的作用下进行，所选溶剂为乙醚、正己烷、环己烷、二氯甲烷、氯仿、甲苯或四氢呋喃中的一种或几种；反应温度为-80℃至室温；所述盐的水溶液为四氟硼酸钠和/或六氟硼酸钾和/或六氟磷酸钾和/或氯化钠和/或氟化钾和/或碘化钾和/或磷酸钠的水溶液。
5.根据权利要求4所述的二氟甲基化试剂的制备方法，其特征在于，包括：将“二氟甲基芳基亚砜或二氟甲基杂环亚砜”和取代基为R2的苯溶于干燥的乙醚中，在搅拌和氮气保护下于-20℃-25℃滴加三氟甲磺酸酐；反应完成后，停止搅拌，静置，将上层乙醚相倾出，再加入乙醚继续搅拌，然后静置，倾出乙醚相，此操作重复2次以上；析出固体，过滤，滤得固体用乙醚洗涤，干燥得三氟甲磺酸硫鎓盐，此盐溶于有机溶剂中，用盐的水溶液进行离子交换，制得相应的硫鎓盐。
6.一种化合物进行二氟甲基化的制备方法，其特征在于，制备方法包括以下路线，其中1为权利要求1-3任一项所述的二氟甲基化试剂：
所述碱为NaH、KH、LiH、CaH2、NaOH、KOH、LiOH、CsOH、Na2CO3、K2CO3、Cs2CO3、K3PO4或Na3PO4中的一种或几种的组合；
所述溶剂为四氢呋喃、二氯甲烷、1,2-二氯乙烷、乙腈、苯、甲苯、二甲苯、氯苯、氟苯、或溴苯中的一种或几种的组合；
反应温度为-80℃至100℃。
7.根据权利要求6所述的化合物进行二氟甲基化的制备方法，其特征在于，所述化合物为C、O、S、N、P或Se亲核剂。
8.根据权利要求6所述的化合物进行二氟甲基化的制备方法，其特征在于，所述制备方法为将底物2或5溶于溶剂中，冷至-80℃-100℃，加入碱，搅拌10分钟-12小时，自然升至18-30℃，加入前述的二氟甲基化试剂1，于此温度下搅拌反应10分钟-3小时，饱和氯化铵水溶液淬灭，乙酸乙酯萃取2次以上，合并萃取相，水和盐水洗涤，有机相用无水硫酸钠干燥，过滤，减压蒸去溶剂，粗品用硅胶柱层析纯化，得纯品二氟甲基官能化产物3或6。
9.根据权利要求6或8所述的化合物进行二氟甲基化的制备方法，其特征在于，所述的化合物进行二氟甲基化后为以下任一化合物中的一种：
10.一种二氟甲基化的化合物，其特征在于，使用了如权利要求9中所述的化合物3aa作为底物制得，具体如下：
所述化合物7、8具有抗肿瘤、降血糖的生物活性；
所述化合物9具有抗感染、镇痛的生物活性。
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