CN110028390B - 烷基二氟甲基醚类化合物的合成方法 - Google Patents
烷基二氟甲基醚类化合物的合成方法 Download PDFInfo
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- CN110028390B CN110028390B CN201910453848.2A CN201910453848A CN110028390B CN 110028390 B CN110028390 B CN 110028390B CN 201910453848 A CN201910453848 A CN 201910453848A CN 110028390 B CN110028390 B CN 110028390B
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- -1 alkyl difluoromethyl ether compounds Chemical class 0.000 title claims abstract description 58
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 63
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 36
- 238000006266 etherification reaction Methods 0.000 claims abstract description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 109
- 238000006243 chemical reaction Methods 0.000 claims description 79
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000003480 eluent Substances 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 10
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
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- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
技术领域
本发明涉及一种烷基二氟甲基醚类化合物的合成方法。
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【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 FluorinatedCarbons: Fundamentals and Applications(Eds.:O.V.Boltalina,T.Nakajima),Elsevier,Amsterdam,2016;d)K. Müller,C.Faeh,F.Diederich,Science2007,317,1881;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的应用于药物发展中。二氟甲基(CF2H)是羟基(OH)、巯基(SH)等基团的生物电子等排体【1】【(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.Koch,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【2】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】。
所以二氟甲基砌块的引入可以赋予化合物特殊的物理、化学及生物特性,往往可以有效提高化合物的生物活性和靶点特异性,这使得它在创新药物设计中有非常重要的作用。所以向有机小分子引入二氟甲基基团,是进行药物结构修饰、改造,获得潜在药物分子的重要方法和途径。尤其是二氟甲氧基砌块(OCF2H)常常出现在药物分子中,如酶抑制剂/激动剂、抗艾滋药物、抗菌药及麻醉剂等【3-4】(图1)。
二氟甲氧基(OCF2H)的强吸电子特性可以减少药物分子的电子密度,从而减少药物分子被体内细胞色素P450 酶氧化代谢的可能性,延长了药物的半衰期[3d]。另外,OCF2H基团中的质子作为氢键给体,可以提高药物分子与靶点的亲和力和选择性,从而提高药物的药理活性和特异性[1c]。美国FDA于2011年批准的新分子实体罗氟司特 (Roflumilast)(图1),用于治疗严重COPD患者支气管炎相关咳嗽和黏液过多的症状,该活性分子中就含有关键的二氟甲基芳基醚结构[3h]。其他如加雷沙星,利奥地平,泮托拉唑(图1)等同样含有关键的二氟甲基芳基醚结构。 GRN-529(图1),作为一个很有潜力和前景的在研新药,用于儿童自闭症和孤独症的治疗,其结构中也含有关键的二氟甲基醚砌块。
发展稳定高效的二氟甲基试剂及相应二氟甲基化方法,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,及其相应的温和的条件下的二氟甲基化新方法与新反应的发展,具有很高应用价值和广阔的前景,以及较高学术意义。
二氟甲基醚类化合物,作为新药设计合成中的关键合成子和中间体,在天然产,唯一物中从未有发现过的途径是通过人工合成。但是,由于环境友好、稳定高效的二氟甲基试剂的缺乏,目前二氟甲基醚类化合物的有效合成方法不多,尽管报道了一些方法,但是由于氟化试剂及其氟化方法本身固有的缺陷,大多都存在效率不高,产率较低、普适性差、浪费较大、污染比严重等诸多问题。如氟利昂22气体(HCF2Cl),使用量大,效率低下,破坏臭氧层(ODS),环境危害性大。所以,发展便捷高效、环境友好的绿色合成方法显得尤为重要,具有较高的学术意义和应用价值。
目前,二氟甲基醚类化合物合成主要使用各种二氟卡宾前体如ClCF2H[5],CF3H[6],TMSCF2Br[7],TMSCF2Cl[8], ClCF2SO2Ph[9],ClCF2COPh[10],n-Bu3N+(CF2H)Cl-[11],BrCF2P(O)(OEt)2[12],FSO2CF2CO2H[13],HCF2OTf[14],等原位产生二氟卡宾,对酚类和脂肪醇类底物进行O-二氟甲基化反应获得二氟甲基醚类化合物(图2)。但大部分方法存在诸如效率低下、收率低、底物普适性及官能团兼容性差、试剂使用需大大过量、浪费严重和环境危害性大等问题。迄今为止,最常用的是使用Freon22气体(HCF2Cl)和Freon23(CF3H),但Freon气体对大气臭氧层有破坏作用(ODS),而且反应活性一般,需要大大过量的Freon气体,效果一般,收率较低。
而且,目前已有的方法绝大部分是用于(硫)酚的O-二氟甲基化制备芳基二氟甲基(硫)醚类化合物。而由脂肪醇的O-二氟甲基化反应制备烷基二氟甲基(硫)醚方法仍非常缺乏。
2016年,沈其龙小组使用二氟甲基硫叶立德作为二氟甲基试剂,对烷基醇进行了二氟甲基醚化,但该方法的一个重要缺陷,需要至少2当量的底物醇。机理研究表明反应是通过醇对二氟甲基硫叶立德的直接亲核进攻途径,而非二氟卡宾机制(图3a)【15】。2017年,胡金波教授等使用Me3SiCF2Br作为二氟卡宾前体试剂,实现了对烷基醇进行了二氟甲基醚化(图3b)【16】。Mykhailiuk使用FSO2CF2COOH,报道了一种铜催化脂肪醇的二氟甲基醚化【图3c,J.Org.Chem.2016,81,5803-5813.】
尽管一些二氟卡宾前体可用于合成二氟甲基醚化合物,但大部分方法存在诸如效率低下、收率低、底物普适性及官能团兼容性差、试剂使用需大大过量、浪费严重和环境危害性大等问题。而且主要用于酚类底物的二氟甲基醚化,对于脂肪醇类化合物的二氟甲基醚化目前为止鲜有方法报道。
参考文献如下:
【1】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.Koch,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;c)J.A. Erickson,J.I.McLoughlin,J.Org.Chem.1995,60,1626-1631;d)Y.Zafrani,D.Yeffet,G.Sod-Moriah,A.Berliner,D.Amir,D.Marciano,E.Gershonov,S.Saphier,J.Med.Chem.2017,60,797.
【2】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.
【3】a)S.S.Patel,K.L.Goa,Drugs1995,50,742;b)Takahata,M.;Mitsuyama,J.;Yamashiro,Y.;Yonezawa, M.;Araki,H.;Todo,Y.;Minami,S.;Watanabe,Y.;Narita,H.Antimicrob.Agents Chemother.1999,43,1077 -1084;c)Ohmine,T.;Katsube,T.;Tsuzaki,Y.;Kazui,M.;Kobayashi,N.;Komai,T.;Hagihara,M.; Nishigaki,T.;Iwamoto,A.;Kimura,T.;Kashiwase,H.;Yamashita,M.Bioorg.Med.Chem.Lett.2002,12, 739-742;d)N.Chauret,D.Guay,C.Li,S.Day,J.Silva,M.blouin,Y.Ducharme,J.A.Yergey,D.A.Nicoli-Griffith,Bioorg.Med.Chem.Lett.2002,12,2149-2152;e)P.Jeschke,E.Baston,F.R.Leroux, Mini-Rev.Med.Chem.2007,7,1027,and references therein;f)Zheng,S.;Kaur,G.;Wang,H.;Li,M.; Macnaughtan,M.;Yang,X.;Reid,S.;Prestegard,J.;Wang,B.;Ke,H.J.Med.Chem.2008,51,7673;g) B.Manteau,S.Pazenok,J.-P.Vors,F.R.Leroux,J.Fluorine Chem.2010,131,140,andreferences therein; h)J.Wang,M.Sanchez-Rosello,J.L.Acena,C.del Pozo,A.E.Sorochinsky,S.Fustero,V.A.Soloshonok, H.Liu,Chem.Rev.2014,114,2432.
【4】a)D.McKerrecher,K.G.Pike,M.J.Waring,PCT Int.Appl.WO 2007007042 A1,2007;b)Bender, J.A.;Ding,M.;Gentles,R.G.;Hewawasam,P.U.S.Patent ApplicationPublication U.S.2007/270405 A1, 2007;c)Bjoere,A.;Bostroem,J.;Davidsson,O.;Emtenaes,H.;Gran,U.;Iliefski,T.;Kajanus,J.; Olsson,R.;Sandberg,L.;Strandlund,G.;Sundell,J.;Yuan,Z.-Q.PCT Int.Appl.WO/2008/008022,2008; d)Schoenafinger,K.;Keil,S.;Urmann,M.;Matter,H.;Glien,M.;Wendler,W.PCTInt.Appl.WO/2009/080223,2009;e)T.J.Hoffman,S.Sulzer-Mosse,PCT Int.Appl.WO 2016/071239 A1,2016.
【5】a)B.Langlois,J Fluorine Chem.1988,41,247-261;b)D.L. S.Brahms,W.P.Dailey,Chem.Rev.1996,96,1585–1632;c)“Chlorodifluoromethane”:D.J.Burton,W.Qiu,A. Jończyk,A.Kowalkowska ine-EROS Encyclopedia of Reagents for OrganicSynthesis(Ed.:R.A.Paquette), Wiley,2010,DOI:10.1002/047084289X.rc090.pub2.
【6】Charles S.Thomoson and Willian R.Dolbier,Jr.,J.Org.Chem.2013,78,8904-8908.
【7】a)L.Li,F.Wang,C.Ni,J.Hu,Angew.Chem.Int.Ed.2013,52,12390-12394;b)Q.Xie,C. Ni,R.Zhang,L.Li,J.Rong,and J.Hu,Angew.Chem.Int.Ed.2017,56,3206-3210.
【8】a)F.Wang,W.Zhang,J.Zhu,H.Li,K.-W.Huang,J.Hu,Chem. Commun.2011,47,2411–2413;b)J.Hu,F.Wang,W.Zhang,2009,CN101538193A.
【9】a)J.Zheng,Y.Li,L.Zhang,J.Hu,G.J.Meuzelaar,H.-J.Federsel,Chem.Commun.2007, 5149–5151;b)F.Wang,L.Zhang,J.Zheng,J.Hu,J.FluorineChem.2011,132,521–528.
【10】L.Zhang,J.Zheng,J.Hu,J.Org.Chem.2006,71,9845–9848.
【11】F.Wang,W.Huang,J.Hu,Chin.J.Chem.2011,29,2717–2721.
【12】Y.Zafrani,G.Sod-Moriah,Y.Segall,Tetrahedron 2009,65,278–5283.
【13】a)Q.-Y.Chen,S.-W.Wu,J.Fluorine Chem.1989,44,433;b)K.Levchenko,O.P.Datsenko, O.Serhiichuk,A.Tolmachev,V.O.Iaroshenko,P.K.Mykhailiuk,J.Org.Chem.2016,81,5803-5813.
【14】P.S.Fier,J.F.Hartwig,Angew.Chem.Int.Ed.2013,52,2092–2095.
【15】J.Zhu,Y.Liu,Q.Shen,Angew.Chem.Int.Ed.2016,55,9050-9054.
【16】G.Liu;X.Wang,;X.Xu;X.Lu;E.Tokunaga;J.Tsuzuki and N.Shibata;Org.Lett.2013,15(5), 1044-1047.
发明内容
基于现有技术存在的上述缺陷,本发明提供一种烷基二氟甲基醚类化合物的合成方法,其便捷高效、条件温和、普适性良好,具有能在目标分子全合成的后期阶段很方便的构建二氟甲氧基结构(OCF2H)的优点,且合成方法绿色环保。
本发明提供的一种烷基二氟甲基醚类化合物的合成方法,包括脂肪醇的二氟甲基醚化反应和硫醇的二氟甲基醚化反应:所述脂肪醇的二氟甲基醚化反应所使用的试剂为
所述硫醇的二氟甲基醚化反应所使用的试剂为
作为本发明进一步的改进:所述脂肪醇的二氟甲基醚化反应通用步骤:
在反应瓶中依次加入磁力搅拌子、醇2、试剂1a、三水合醋酸钠、四丁基四氟硼酸铵、二溴甲烷和水,室温下搅拌至反应结束。
作为本发明进一步的改进:反应条件具体包括:
二氟甲基试剂的使用量为原料醇的1至10当量;
活化剂为选自KF、KHF2、NaOH、KOH、LiOH、CsOH、Na2CO3、NaHCO3、K2CO3、Cs2CO3、NaOAc、或NaOAc·3H2O中的一种或几种的组合,其用量为原料醇的1至10当量;
添加剂为Bu4NBF4、Bu4NBr、Bu4NF、Bu4NOTf、Bu4NI的一种或几种的组合,其使用量为原料醇的1%至300%摩尔量;
有机溶剂为选自1,1-二氯乙烷、1,2-二氯乙烷、二氯甲烷、氯仿、二溴甲烷、甲苯、氯苯或氟苯中的一种或两种以上的混合;
反应温度为-20℃至80℃;
反应时间为24小时至48小时。
作为本发明进一步的改进:反应条件具体包括:
二氟甲基试剂的使用量为原料醇的2至3当量;
活化剂为NaOAc、或NaOAc·3H2O,其用量为原料醇的5当量;
添加剂为选自Bu4NBF4、Bu4NBr、Bu4NF、Bu4NOTf、Bu4NI中的一种或几种的组合,用量为原料醇的20%摩尔量;
有机溶剂为二溴甲烷;
反应温度为10℃至30℃。
作为本发明进一步的改进:反应结束后,加入二氯甲烷稀释,经无水硫酸钠干燥,过滤,减压旋干后柱层析分离纯化,得二氟甲基烷基醚;
所述柱层析分离纯化中洗脱剂为正己烷或正己烷与乙酸乙酯的混合物。
作为本发明进一步的改进:所述硫醇的二氟甲基醚化反应通用步骤:
在硫醇4的乙腈溶液中,加入氢氧化钾溶液,室温反应30分钟,一次性加入试剂1b,反应30分钟后,加入饱和氯化铵溶液淬灭。
作为本发明进一步的改进:反应条件具体包括:
二氟甲基试剂的使用量为原料硫醇的1至5当量;
碱为NaOH、KOH、LiOH、CsOH、NaH、KH、CaH2的一种,其用量为原料硫醇的1至10当量;
碱为水溶液,其所用浓度为0.5摩尔/升至10摩尔/升;
有机溶剂为选自乙腈、四氢呋喃、二氯甲烷、氯仿、甲苯、氯苯、氟苯,N,N-二甲基甲酰胺中的一种或两种以上的混合;
反应温度为-20℃至80℃;
反应时间为10分钟至5小时。
作为本发明进一步的改进:反应条件具体包括:
二氟甲基试剂的使用量为原料硫醇的1至1.5当量;
碱为KOH,其用量为原料硫醇的2.2至2.5当量;
碱为水溶液,其所用浓度为1摩尔/升摩尔量;
有机溶剂为乙腈或氟苯;
反应温度为10℃至30℃;
反应时间为30分钟。
作为本发明进一步的改进:加入试剂1b,反应30分钟后,加入饱和氯化铵溶液淬灭,乙酸乙酯:10mL×3萃取,合并有机相,无水硫酸钠干燥,过滤,减压旋干,柱层析分离纯化,得二氟甲基烷基硫醚5。
作为本发明进一步的改进:柱层析分离纯化中洗脱剂为正己烷。
上述当量指的是原料醇的摩尔倍数。
本发明提供的一种烷基二氟甲基醚类化合物的合成方法,使用亲电二氟甲基试剂,其为室温空气条件下以固体存在的稳定非官能化亲电型二氟甲基试剂,相比较于以前的二氟卡宾前体试剂,其优点是易于保存和操作、绿色、且环保。本发明即基于该试剂,得到二氟甲基醚类化合物的合成方法,实现对各种酚类和烷基醇类的O-二氟甲基化,其为一种反应条件温和、操作简便、高效合成二氟甲基醚类化合物的方法。该方法在药物合成及新药创制中具有重要用途,可用于生物活性分子、先导化合物及候选药物分子的设计合成,以及对现有药物进行合成新工艺的开发。
附图说明
图1是:现有技术中的含有关键二氟甲氧基结构的药物。
图2是:现有技术中的酚和醇的二氟甲基醚化反应策略。
图3是:现有技术中的烷基二氟甲基醚类化合物的合成方法。
图4是:本发明提供的一种的烷基二氟甲基醚类化合物的合成方法。
图5是:本发明提供的一种烷基二氟甲基硫醚化合物的合成方法。
图6是:实施例1的脂肪醇的二氟甲基醚化反应产物及相应产率,其中括号内为氟谱收率。
图7是:实施例2的硫醇的二氟甲基硫醚化反应产物及相应产率。
具体实施方式
以下通过具体实施例对本发明提供的一种烷基二氟甲基醚类化合物的合成方法做进一步更详细的说明:
注:下述当量指的是原料醇的摩尔倍数。
试验1
1.脂肪醇的二氟甲基醚化反应通用实验步骤:
在2mL的反应瓶中依次加入磁力搅拌子、醇2(0.2mmol,醇的1.0当量)、试剂1a(0.6mmol,醇的3.0 当量)、三水合醋酸钠(1.0mmol,醇的5.0当量)、四丁基四氟硼酸铵(0.04mmol,醇的20%摩尔量)、0.2mL二溴甲烷以及0.2mL水,室温下剧烈搅拌24或48小时。反应结束后,加入二氯甲烷稀释,经无水硫酸钠干燥,过滤,减压旋干后柱层析分离纯化,得二氟甲基烷基醚3,其中柱层析中硅胶的粒度为:300-400目。
产物1:
((Difluoromethoxy)methyl)benzene(3a):
反应48小时,洗脱剂为正己烷,收率65%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ 7.42-7.34(m,5H),6.31(t,J=74.4Hz,1H),4.90(s,2H);19F NMR(376MHz,CDCl3) δ-84.8(d,J=74.3Hz,2F);MS(EI):m/z158(M+).
产物2:
1-((Difluoromethoxy)methyl)-4-methylbenzene(3b):
反应24小时,洗脱剂为正己烷,收率78%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.27(d,J=7.8Hz,2H),7.20(d,J=7.8Hz,2H),6.29(t,J=74.6Hz,1H), 4.87(s,2H),2.37(s,3H);19F NMR(376MHz,CDCl3)δ-84.6(d,J=74.6Hz,2F);MS(EI):m/z172(M+).
产物3:
1-((Difluoromethoxy)methyl)-4-iodobenzene(3c):
反应48小时,洗脱剂为正己烷,收率70%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.71(d,J=8.2Hz,2H),7.10(d,J=8.2Hz,2H),6.30(t,J=74.0Hz,1H), 4.83(s,2H);19F NMR(376MHz,CDCl3)δ-84.9(d,J=73.9Hz,2F);MS(EI):m/z284(M+).
产物4:
2-(4-((Difluoromethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3d):
反应48小时,洗脱剂为正己烷,收率57%,产物为无色油状液体。1H NMR(400MHz, CDCl3)δ7.83(d,J=7.9Hz,2H),7.37(d,J=7.9Hz,2H),6.31(t,J= 74.4Hz,1H),4.91(s,2H),1.35(s,12H);19F NMR(376MHz,CDCl3)δ-84.8 (d,J=74.3Hz,2F);MS(EI):m/z284(M+).
产物5:
Methyl4-((difluoromethoxy)methyl)benzoate(3e):
反应48小时,洗脱剂为正己烷,收率63%,产物为无色油状液体。1H NMR(400MHz, CDCl3)δ8.05(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),6.34(t,J=74.0 Hz,1H),4.95(s,2H),3.92(s,3H);19F NMR(376MHz,CDCl3)δ-85.0(d,J=73.8Hz,2F);MS(EI):m/z 216(M+).
产物6:
1-((Difluoromethoxy)methyl)-4-ethynylbenzene(3f):
反应24小时,洗脱剂为正己烷,收率60%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.50(d,J=8.2Hz,2H),7.32(d,J=8.2Hz,2H),6.31(t,J=74.0Hz,1H), 4.89(s,2H),3.10(s,1H);13C NMR(101MHz,CDCl3)δ136.2,132.5,127.8,122.3,113.3(t,J=262.7 Hz),83.3,77.8,64.8(t,J=6.3Hz);19F NMR(376MHz,CDCl3)δ-84.9(d,J=74.0Hz,2F);MS(EI): m/z182(M+);HRMS(APCI):calcd.for C11H13F2O2 +([M+H+CH3OH]+):215.0878;found:215.0879.
产物7:
1-((Difluoromethoxy)methyl)-4-nitrobenzene(3g):
反应48小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例50:1),收率50%,产物为白色固体。熔点:38-39℃;1H NMR(400MHz,CDCl3)δ8.24(d,J=8.6Hz,2H),7.53 (d,J=8.6Hz,2H),6.38(t,J=73.4Hz,1H),5.00(s,2H);19F NMR(376MHz,CDCl3)δ-85.3(d,J= 73.3Hz,2F);MS(EI):m/z203(M+).
产物8:
5-((Difluoromethoxy)methyl)benzo[d][1,3]dioxole(3h):
反应24小时,洗脱剂为正己烷,收率84%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ6.86-6.79(m,3H),6.27(t,J=74.5Hz,1H),5.97(s,2H),4.79(s,2H);13C NMR(101MHz,CDCl3)δ148.0,147.8,129.0,122.0,115.9(t,J=261.6Hz),108.8,108.3,101.2,65.5 (t,J=6.1Hz);19F NMR(376MHz,CDCl3)δ-84.6(d,J=74.4Hz,2F);MS(EI):m/z202(M+);HRMS(ESI): calcd.for C9H9F2O3 +:203.0514;found:203.0515.
产物9:
1-Chloro-2-(2-(difluoromethoxy)ethyl)benzene(3i):
反应48小时,洗脱剂为正己烷,收率90%,产物为无色油状液体。The product was purified by silica gel column chromatography(Hexane)in90%yield as colorless oil;1H NMR (400MHz,CDCl3)δ7.38-7.17(m,4H),6.18(t,J=74.7Hz,1H),4.08(t,J=7.0Hz,2H),3.10(t,J =7.0Hz,2H);13C NMR(101MHz,CDCl3)δ135.2,134.3,131.4,129.7,128.4,127.0,116.2(t,J=258.3 Hz),62.4(t,J=5.5Hz),33.7;19FNMR(376MHz,CDCl3)δ-84.6(d,J=74.6Hz,2F);MS(EI):m/z206 (M+);HRMS(APCI):calcd.for C8H8Cl+([M-HCF2O]+):139.0309;found:139.0309.
产物10
(2-(Difluoromethoxy)ethyl)benzene(3j):
反应24小时,洗脱剂为正己烷,收率78%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.34-7.31(m,2H),7.27-7.23(m,3H),6.19(t,J=74.7Hz,1H),4.07(t,J=7.1Hz,2H),2.97(t,J=7.1Hz,2H);13C NMR(101MHz,CDCl3)δ137.6,129.0,128.7,126.8,116.1(t, J=261.4Hz),64.1(t,J=5.4Hz),35.8;19F NMR(376MHz,CDCl3)δ-84.7(d,J=74.6Hz,2F);MS(EI): m/z172(M+).
产物11
1-(2-(Difluoromethoxy)ethyl)-4-methoxybenzene(3k):
反应24小时,洗脱剂为正己烷,收率91%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.15(d,J=8.5Hz,2H),6.86(d,J=8.5Hz,2H),6.19(t,J=74.9Hz, 1H),4.02(t,J=7.1Hz,2H),3.80(s,3H),2.90(t,J=7.1Hz,2H);19F NMR(376MHz,CDCl3)δ-84.6 (d,J=74.8Hz,2F);MS(EI):m/z202(M+).
产物12
4-(2-(Difluoromethoxy)ethyl)phenol(3l):
反应24小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例20:1),收率62%,产物为白色半固体。1H NMR(400MHz,CDCl3)δ7.09(d,J=8.4Hz,2H),6.79(d,J= 8.4Hz,2H),6.18(t,J=74.9Hz,1H),4.01(t,J=7.1Hz,2H),2.89(t,J=7.1Hz,2H);13C NMR(101 MHz,CDCl3)δ154.5,130.2,129.7,116.2(t,J=261.2Hz),115.6,64.5(t,J=5.3Hz),34.9;19F NMR (376MHz,CDCl3)δ-84.5(d,J=74.9Hz,2F);MS(EI):m/z120([M-HCF2OH]+);HRMS(APCI):calcd.for C8H9O+([M-HCF2O]+):121.0648;found:121.0649.
产物13
(3-(Difluoromethoxy)propyl)benzene(3m):
反应24小时,洗脱剂为正己烷,收率78%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.33-7.28(m,2H),7.23-7.19(m,3H),6.22(t,J=75.1Hz,1H),3.86(t,J =6.4Hz,2H),2.73(t,J=7.5Hz,2H),1.98(quint,J=7.0Hz,2H);13C NMR(101MHz,CDCl3)δ141.2, 128.6,126.2,116.3(t,J=260.7Hz),62.9(t,J=5.3Hz),32.0,30.9;19F NMR(376MHz,CDCl3)δ-83.8 (d,J=75.0Hz,2F);MS(EI):m/z186(M+).
产物14
Benzyl(R)-(1-(difluoromethoxy)-3-phenylpropan-2-yl)carbamate(3n):
反应48小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例10:1),收率61%,产物为白色固体。熔点:68-69℃;1H NMR(400MHz,CD3CN)δ7.39-7.22(m,10H),6.38(t, J=75.7Hz,1H),5.77(d,J=8.4Hz,1H),5.02(d,J=12.7Hz,1H),4.98(d, J=12.7Hz,1H),4.09-4.00(m,1H),3.89(dd,J=10.1,4.6Hz,1H),3.82(dd,J=10.1,4.6Hz,1H), 2.90(dd,J=13.8,5.6Hz,1H),2.75(dd,J=13.8,9.1Hz,1H),2.23(s,1H);13C NMR(101MHz,CD3CN) δ155.9,138.1,129.3,128.5,128.4,127.8,127.5,126.5,117.4,116.9(t,J=258.2Hz),65.7,63.9 (t,J=3.4Hz),52.0,36.8;19F NMR(376MHz,CD3CN)δ-84.6(d,J=74.3Hz,2F);MS(ESI):m/z336.1 (M+H+);HRMS(ESI):calcd.for C18H20F2NO3 +:336.1406;found:336.1394.
产物15
(E)-(3-(difluoromethoxy)prop-1-en-1-yl)benzene(3o):
反应48小时,洗脱剂为正己烷,收率73%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.40(d,J=7.3Hz,2H),7.34(t,J=7.1Hz,2H),7.30(t,J=7.0Hz,1H), 6.67(d,J=15.9Hz,1H),6.29(t,J=74.6Hz,1H),6.27(dt,J=15.9,6.3Hz,1H),4.53(t,J=6.3 Hz,1H);19F NMR(376MHz,CDCl3)δ-84.5(d,J=74.6Hz,2F);MS(EI):m/z184(M+).
产物16
(5-(Difluoromethoxy)pent-1-yn-1-yl)benzene(3p):
反应48小时,洗脱剂为正己烷,收率80%,产物为无色油状液体。1H NMR(400MHz, CDCl3)δ7.43-7.39(m,2H),7.31-7.28(m,3H),6.23(t,J=75.0Hz,1H), 4.02(t,J=6.2Hz,2H),2.55(t,J=7.0Hz,2H),1.95(quint,J=6.5Hz,2H);19F NMR(376MHz,CDCl3) δ-84.4(d,J=74.9Hz,2F);MS(EI):m/z210(M+).
产物17
1-(2-(Difluoromethoxy)ethyl)naphthalene(3q):
反应48小时,洗脱剂为正己烷,收率78%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ8.03(d,J=8.4Hz,1H),7.89(d,J=7.8Hz,1H),7.78(d,J=7.9Hz,1H), 7.58-7.49(m,2H),7.45-7.39(m,2H),6.23(t,J=74.7Hz,1H),4.20(t,J=7.4Hz,2H),3.45(t,J=7.4Hz,2H);19F NMR(376MHz,CDCl3)δ-84.5(d,J=74.6Hz,2F);MS(EI):m/z 222(M+).
产物18
1-((Difluoromethoxy)methyl)naphthalene(3r):
反应48小时,洗脱剂为正己烷,收率85%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ 8.11(d,J=8.4Hz,1H),7.93(t,J=7.9Hz,2H),7.64-7.55(m,3H),7.52-7.48(m, 1H),6.40(t,J=74.4Hz,1H),5.40(s,2H);19F NMR(376MHz,CDCl3)δ-84.7(d,J =74.4Hz,2F);MS(EI):m/z208(M+).
产物19
3-(2-(Difluoromethoxy)ethyl)-1H-indole(3s):
反应24小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例20:1),收率88%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ8.01(br,1H),7.62(d,J=7.8Hz,1H),7.37(d, J=8.1Hz,1H),7.22(t,J=7.1Hz,1H),7.15(t,J=7.8Hz,1H),7.08(s,1H), 6.23(t,J=75.1Hz,1H),4.14(t,J=7.1Hz,2H),3.14(t,J=7.1Hz,2H);19F NMR(376MHz,CDCl3) δ-84.2(d,J=75.0Hz,2F);MS(EI):m/z211(M+).
产物20
3-(2-(Difluoromethoxy)ethyl)thiophene(3t):
反应24小时,洗脱剂为正己烷,收率81%,产物为无色油状液体。1HNMR(400MHz,CDCl3)δ 7.29(dd,J=4.8,3.0Hz,1H),7.03(d,J=3.0Hz,1H),6.99(d,J=4.8Hz,1H), 6.18(t,J=74.7Hz,1H),4.04(t,J=6.9Hz,2H),2.97(t,J=6.9Hz,2H);19FNMR(376MHz,CDCl3) δ-84.7(d,J=74.5,2.0Hz,2F);MS(EI):m/z178(M+).
产物21
2-((Difluoromethoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxine(3u):
反应48小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例200:1),收率60%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ6.92-6.85(m,4H),6.29(t,J=73.7Hz, 1H),4.42-4.37(m,1H),4.40(dd,J=11.5,2.2Hz,1H),4.14-4.03(m,3H);19F NMR(376MHz,CDCl3)δ -85.5(d,J=73.6Hz,2F);MS(EI):m/z216(M+).
产物22
1-(Difluoromethoxy)decane(3v):
反应24小时,洗脱剂为正己烷,收率91%,产物为无色油状液体。1HNMR(400MHz,CDCl3)δ6.18 (t,J=75.3Hz,1H),3.83(t,J=6.6Hz,2H),1.63(quint,J=7.0Hz,2H),1.38-1.27 (m,14H),0.88(t,J=6.5Hz,3H);19F NMR(376MHz,CDCl3)δ-84.2(d,J=75.2Hz,2F);MS(EI):m/z 140([M-HCF2OH]+).
产物23
1-(Difluoromethoxy)octadecane(3w):
反应24小时,洗脱剂为正己烷,收率95%,产物为白色半固体。1HNMR(400MHz,CDCl3)δ6.18 (t,J=75.3Hz,1H),3.83(t,J=6.6Hz,2H),1.63(quint,J=6.6Hz,2H),1.36-1.25 (m,30H),0.88(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3)δ116.3(t,J=260.4Hz),63.9(t,J= 5.3Hz),32.1,29.9,29.83,29.81,29.73,29.68,29.5,29.4,29.3,25.9,22.9,14.3;19F NMR(376MHz, CDCl3)δ-84.3(d,J=75.3Hz,2F);MS(EI):m/z252([M-HCF2OH]+);HRMS(EI):calcd.for C18H36 +([M-HCF2OH]+): 252.2812;found:252.2811.
产物24
1-Bromo-11-(difluoromethoxy)undecane(3x):
反应24小时,洗脱剂为正己烷,收率98%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ 6.18(t,J=75.3Hz,1H),3.82(t,J=6.6Hz,2H),3.40(t,J=6.9Hz,2H),1.85 (quint,J=7.2Hz,2H),1.63(quint,J=7.0Hz,2H),1.43-1.28(m,14H);19F NMR(376MHz,CDCl3)δ -84.2(d,J=75.2Hz,2F);MS(EI):m/z232([M-HCF2OH]+).
产物25
2-(Difluoromethoxy)tridecane(3aa):
反应48小时,洗脱剂为正己烷,收率75%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ6.20(t, J=75.8Hz,1H),4.24-4.17(m,1H),1.62-1.55(m,1H),1.50-1.41(m,1H),1.33-1.25(m,21H), 0.88(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3)δ116.6(t,J=258.5Hz),72.9(t,J=3.5Hz),37.0, 32.1,29.81,29.78,29.74,29.70,29.59,29.52,25.4,22.9,21.3,14.3;19F NMR(376MHz,CDCl3)δ-80.5 (dd,J=161.3,75.9Hz,1F),-81.1(dd,J=161.3,75.9Hz,1F);MS(EI):m/z182([M-HCF2OH]+).
产物26
1-(Difluoromethoxy)-1,2,3,4-tetrahydronaphthalene(3ab):
反应48小时,洗脱剂为正己烷,收率70%,产物为无色油状液体。1HNMR(400MHz,CDCl3)δ 7.39-7.36(m,1H),7.26-7.21(m,2H),7.15-7.12(m,1H),6.37(dd,J=75.4,74.4Hz, 1H),5.32-5.30(m,1H),2.88(dt,J=16.7,5.2Hz,1H),2.79-2.71(m,1H),2.17-2.10 (m,1H),2.08-1.97(m,2H),1.86-1.78(m,1H);19F NMR(376MHz,CDCl3)δ-80.1(dd,J=160.0,75.5Hz, 1F),-81.5(dd,J=160.0,75.5Hz,1F);MS(EI):m/z198(M+).
产物27
1-(Difluoromethoxy)-2,3-dihydro-1H-indene(3ac):
反应48小时,洗脱剂为正己烷,收率77%,产物为无色油状液体。1HNMR(400MHz,CDCl3)δ7.43 (t,J=7.2Hz,1H),7.34-7.24(m,3H),6.35(t,J=74.6Hz,1H),5.69(dd,J=6.9, 4.7Hz,1H),3.12(ddd,J=16.0,8.5,5.4Hz,1H),2.87(ddd,J=16.1,8.3,6.0Hz, 1H),2.49(ddd,J=20.8,7.6,6.3Hz,1H),2.26-2.17(m,1H);13C NMR(101MHz,CDCl3)δ144.0,140.7, 129.2,126.9,125.4,125.0,116.2(t,J=261.1Hz),78.7(t,J=4.9Hz),33.5,30.1;19F NMR(376MHz, CDCl3)δ-80.9(dd,J=160.0,74.9Hz,1F),-81.5(dd,J=160.0,74.9Hz,1F);MS(EI):m/z184(M+); HRMS(ESI):calcd.for C10H11F2O+:185.0773;found:185.0775.
产物28
(Difluoromethoxy)cyclododecane(3ad):
反应48小时,洗脱剂为正己烷,收率93%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ6.21(t,J=75.9Hz,1H),4.27(tt,J=7.2,4.5Hz,1H),1.78-1.69(m,2H), 1.59-1.51(m,2H),1.48-1.33(m,18H);19F NMR(376MHz,CDCl3)δ-80.5(d,J=75.8 Hz,2F);MS(EI):m/z166([M-HCF2OH]+).
产物29
(3-(Difluoromethoxy)-3-methylbutyl)benzene(3ae):
反应48小时,洗脱剂为正己烷,收率38%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.31-7.27(m,2H),7.22-7.17(m,3H),6.33(t,J=76.8Hz,1H),2.57-2.71(m,2H),1.94-1.85(m,2H), 1.42(s,6H);19F NMR(376MHz,CDCl3)δ-76.8(d,J=76.7Hz,2F);MS(EI):m/z214(M+),146([M-OCF2H2]+). (3S,5S,8R,9S,10S,13S,14S)-3-(difluoromethoxy)-10,13-dimethylhexadecahydro-17H-
产物30
cyclopenta[a]phenanthren-17-one(3af):
反应48小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例6:1),收率71%,产物为白色固体。熔点:91-92℃;1H NMR(400MHz,CDCl3)δ6.21(t,J=75.8Hz, 1H),4.07-3.98(m,1H),2.42(dd,J=19.2,8.8Hz,1H),2.10-2.00(m,1H), 1.95-1.72(m,6H),1.66-1.42(m,6H),1.36-1.22(m,4H),1.19-1.10(m,1H), 1.03-0.96(m,2H),0.85(s,3H),0.84(s,3H),0.69(td,J=11.3,3.6Hz,1H);19F NMR(376MHz,CDCl3) δ-80.3(dd,J=161.2,75.7Hz,1F),-80.8(dd,J=161.2,75.7Hz,1F);13C NMR(101MHz,CDCl3)δ116.4(t,J=258.7Hz),75.1(t,J=3.6Hz),54.4,51.5,47.9,44.8,36.8,35.9,35.6,35.4,35.1, 31.6,30.9,28.8,28.4,21.8,20.5,13.9,12.3;MS(ESI):m/z341.4(M+H+);HRMS(ESI):calcd.for C20H31F2O2 +: 341.2287;found:341.2284.
产物31
1-((3S,8S,9S,10R,13S,14S,17S)-3-(difluoromethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15, 16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one(3ag)
反应48小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例30:1),收率60%,产物为白色固体。熔点:127-128℃;1H NMR(400MHz,CDCl3)δ6.21(t,J=75.6 Hz,1H),5.37(d,J=5.0Hz,1H),3.99-3.91(m,1H),2.52(m,1H),2.42-2.33 (m,2H),2.20-2.15(m,1H),2.11(s,3H),2.05-1.97(m,2H),1.90-1.84(m, 2H),1.71-1.56(m,5H),1.52-1.39(m,4H),1.27-0.94(m,3H),1.00(s,3H),0.62(s,3H);19F NMR(376 MHz,CDCl3)δ-80.7(d,J=75.6Hz,2F);13C NMR(101MHz,CDCl3)δ209.6,139.8,122.5,116.3(t,J=259.2Hz),75.3(t,J=3.6Hz),63.8,57.0,50.0,44.1,39.6,38.9,37.1,36.6,31.9,31.9,31.6, 29.1,24.6,22.9,21.1,19.4,13.3;MS(ESI):m/z367.2(M+H+);HRMS(ESI):calcd.for C22H33F2O2 +:367.2443; found:367.2432.
产物32
2-(10-(Difluoromethoxy)decyl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione(3ah):
反应24小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例10:1),收率62%,产物为棕黄色油状液体。1H NMR(400MHz,CDCl3)δ6.15(t,J=75.4Hz,1H),3.96(s,6H),3.79(t, J=6.6Hz,2H),2.42(t,J=6.8Hz,2H),1.98(s,3H),1.60(quint,J=6.7Hz,2H), 1.35-1.25(m,14H);19F NMR(376MHz,CDCl3)δ-84.2(d,J=75.3Hz,2F);MS(EI): m/z388(M+).
产物33
N-(4-((difluoromethoxy)methyl)phenyl)acetamide(3ba)
反应48小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例3:1),收率34%,产物为白色固体。熔点:115-116℃;1H NMR(400MHz,CDCl3)δ7.59(br,1H),7.51(d,J =8.4Hz,2H),7.29(d,J=8.4Hz,2H),6.28(t,J=74.5Hz,1H),4.83(s, 2H),2.16(s,3H);13C NMR(101MHz,CDCl3)δ188.7,138.2,131.3,129.0,120.1,116.1(t,J=261.9 Hz),65.2(t,J=5.9Hz),24.7;19F NMR(376MHz,CDCl3)δ-84.6(d,J=74.4Hz,2F);MS(ESI):m/z 216.2(M+H+);HRMS(ESI):calcd.for C10H12F2NO2 +:216.0831;found:216.0825.
产物34
1-((Difluoromethoxy)methyl)-2-methoxybenzene(3bb):
反应24小时,洗脱剂为正己烷,收率74%,产物为无色油状液体。1HNMR(400MHz,CDCl3)δ7.39 (d,J=8.3Hz,1H),7.33(t,J=7.6Hz,1H),6.98(t,J=7.5Hz,1H),6.91(d,J=8.2Hz,1H),6.33(t,J=75.1Hz,1H),4.95(s,2H),3.86(s,3H);19F NMR(376MHz,CDCl3) δ-84.3(d,J=75.0Hz,2F);MS(EI):m/z188(M+).
产物35:
1-Bromo-4-((difluoromethoxy)methyl)benzene(3bc):
反应24小时,洗脱剂为正己烷,收率69%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.51(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),6.31(t,J=74.1Hz,1H), 4.85(s,2H);19F NMR(376MHz,CDCl3)δ-84.9(d,J=73.9Hz,2F);MS(EI):m/z236(M+),238(M+).
产物36:
1,4-Dichloro-2-((difluoromethoxy)methyl)benzene(3bd)
反应24小时,洗脱剂为正己烷,收率42%,产物为无色油状液体。1HNMR(400MHz,CDCl3)δ 7.48(d,J=2.4Hz,1H),7.29(d,J=8.5Hz,1H),7.25(dd,J=8.5,2.4Hz,1H),6.38 (t,J=73.6Hz,1H),4.97(s,2H);19F NMR(376MHz,CDCl3)δ-85.3(d,J=73.5Hz, 2F);MS(EI):m/z226(M+),228(M+).
产物37:
4-((Difluoromethoxy)methyl)benzaldehyde(3be)
反应48小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例50:1),收率40%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ10.0(s,1H),7.90(d,J=8.1Hz,2H), 7.53(d,J=8.1Hz,2H),6.36(t,J=73.7Hz,1H),4.98(s,2H);13C NMR(101MHz,CDCl3)δ191.9, 142.3,136.4,130.1,128.0,115.9(t,J=263.3Hz),64.4(t,J=6.4Hz);19FNMR(376MHz,CDCl3)δ-85.1(d,J=73.9Hz,2F);MS(EI):m/z186(M+);HRMS(APCI):calcd.forC9H9F2O2 +:187.0565;found:187.0565.
产物38
9-((Difluoromethoxy)methyl)anthracene(3bf):
反应48小时,洗脱剂为正己烷,收率54%,产物为浅黄色固体。熔点:111-112℃;1HNMR(400 MHz,CDCl3)δ8.53(s,1H),8.35(d,J=8.9Hz,2H),8.04(d,J=8.4Hz,2H),7.61 (t,J=7.8Hz,2H),7.51(t,J=7.8Hz,2H),6.39(t,J=74.3Hz,1H),5.93(s,2H);13C NMR(101MHz,CDCl3)δ131.5,131.2,129.7,129.3,127.0,125.3,125.1,123.7,116.3(t,J=262.9 Hz),57.6(t,J=6.6Hz);19F NMR(376MHz,CDCl3)δ-85.2(d,J=74.2Hz,2F);MS(EI):m/z258(M+); HRMS(ESI):calcd.for C16H13F2O+:259.0929;found:259.0935.
产物39:
4-((Difluoromethoxy)methyl)pyrene(3bg):
反应48小时,洗脱剂为正己烷,收率38%,产物为白色固体。熔点:76-77℃;1H NMR(400 MHz,CDCl3)δ8.29(d,J=9.2Hz,1H),8.23-8.15(m,4H),8.10-8.01(m,4H),6.43 (t,J=74.3Hz,1H),5.61(s,2H);13C NMR(101MHz,CDCl3)δ132.0,131.3,130.8, 129.6,128.5,128.09,128.06,127.5,127.4,126.3,125.71,125.67,125.0,124.75,124.71,122.8,116.3 (t,J=262.4Hz),64.0(t,J=6.4Hz);19F NMR(376MHz,CDCl3)δ-85.0(d,J=74.3Hz,2F);MS(EI): m/z282(M+);HRMS(ESI):calcd.for C18H13F2O+:283.0929;found:283.0935.
产物40:
(8R,9S,10S,13S,14S)-10-((difluoromethoxy)methyl)-13-methyl-1,6,7,8,9,10,11,12,13,14,15,16-dode cahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione(3bh):
反应48小时,洗脱剂为正己烷与乙酸乙酯混合溶剂(比例4:1),收率32%,产物为浅棕色固体。熔点:141-142℃;1H NMR(400MHz,CDCl3)δ6.20(t,J=73.7Hz,1H),6.90 (s,1H),4.19(d,J=9.8Hz,1H),4.07(d,J=9.8Hz,1H),2.60-2.30(m,6H), 2.13-1.93(m,3H),1.88-1.77(m,4H),1.62-1.42(m,2H),1.29-1.09(m,4H),0.90 (s,3H);19F NMR(376MHz,CDCl3)δ-86.1(dd,J=156.9,73.6Hz,1F),-86.7(dd,J=156.9,73.6Hz, 1F);13C NMR(101MHz,CDCl3)δ199.2,164.9,127.0,115.6(t,J=263.6Hz),65.2(t,J=5.8Hz),54.1, 51.3,47.6,41.7,35.8,35.7,34.5,33.2,33.0,31.7,31.0,21.7,21.0,13.9;MS(ESI):m/z353.2(M+H+); HRMS(ESI):calcd.for C20H27F2O3 +:353.1923;found:353.1910.
产物41:
(3-(Difluoromethoxy)prop-1-yn-1-yl)benzene(3bi):
反应48小时,洗脱剂为正己烷,收率30%,产物为无色油状液体。1H NMR(400MHz,CDCl3) δ7.46(dd,J=7.8,1.4Hz,2H),7.38-7.31(m,3H),6.37(t,J=74.1Hz,1H), 4.73(s,2H);19F NMR(376MHz,CDCl3)δ-85.7(d,J=74.0Hz,2F);MS(EI):m/z182(M+).
试验2
2、硫醇的二氟甲基醚化反应通用步骤:
在硫醇4(0.2mmol,醇的1.0当量)的乙腈(0.2mL)溶液中,加入1.0mol/L的氢氧化钾溶液(0.48mmol, 醇的2.4当量)。室温反应30分钟,一次性加入试剂1b(0.24mmol,醇的1.2当量)。反应30分钟后,加入饱和氯化铵溶液淬灭,乙酸乙酯(10mL×3)萃取。合并有机相,无水硫酸钠干燥,过滤,减压旋干,柱层析分离纯化,得二氟甲基烷基硫醚5。
产物1:
(Difluoromethyl)(phenethyl)sulfane(5a):
洗脱剂为正己烷,收率50%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.35-7.32 (m,2H),7.28-7.22(m,3H),6.78(t,J=56.3Hz,1H),3.09-3.05(m,2H),3.01-2.97 (m,2H);19F NMR(376MHz,CDCl3)δ-92.7(d,J=56.2Hz,2F);MS(EI):m/z188(M+).
产物2:
(3-Bromobenzyl)(difluoromethyl)sulfane(5b):
洗脱剂为正己烷,收率50%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.51(t, J=2.0Hz,1H),7.42(d,J=7.8Hz,1H),7.28(d,J=7.8Hz,1H),7.21(t,J =7.8Hz,1H),6.75(t,J=56.2Hz,1H),3.98(s,2H);13C NMR(101MHz,CDCl3)δ138.9,132.0,130.9, 130.4,127.6,122.8,120.1(t,J=274.8Hz),31.1(t,J=3.8Hz);19FNMR(376MHz,CDCl3)δ-94.7(d, J=56.1Hz,2F);MS(EI):m/z252(M+),254(M+);HRMS(EI):calcd.for C8H7 79BrF2S+:251.9414;found:251.9415.
产物4:
(Difluoromethyl)(4-methoxybenzyl)sulfane(5c):
洗脱剂为正己烷,收率57%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.27(d, J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),6.73(t,J=56.6Hz,1H),3.99(s, 2H),3.81(s,3H);19F NMR(376MHz,CDCl3)δ-95.0(d,J=56.6Hz,2F);MS(EI):m/z204(M+)。
产物5:
(Difluoromethyl)(trityl)sulfane(5d):
洗脱剂为正己烷,收率46%,产物为白色固体。熔点:96-97℃;1H NMR(400MHz,CDCl3)δ7.45-7.26 (m,15H),6.05(t,J=55.8Hz,1H);13C NMR(126MHz,CDCl3)δ143.7,129.7,128.3,127.6,123.3(t, J=269.0Hz),68.7(t,J=2.2Hz);19F NMR(376MHz,CDCl3)δ-94.1(d,J=55.8Hz,2F);MS(EI):m/z 243(M+);HRMS(APCI):calcd.for C19H15 +([M-SCF2H]+):243.1168;found:243.1168.
产物6:
(Difluoromethyl)(1-phenylethyl)sulfane(5e):
洗脱剂为正己烷,收率38%,产物为无色油状液体。1H NMR(400MHz,CDCl3)δ7.39-7.32(m, 4H),7.30-7.26(m,1H),6.55(dd,J=59.0,55.4Hz,1H),4.41(q,J=7.1Hz,1H), 1.69(d,J=7.1Hz,3H);19F NMR(376MHz,CDCl3)δ-93.0(dd,J=250.3,59.0Hz, 1F),-96.6(dd,J=250.3,59.0Hz,1F);MS(EI):m/z188(M+).
实施例1
脂肪醇的二氟甲基醚化反应通用步骤:
在反应瓶中依次加入磁力搅拌子、醇2、试剂1a、三水合醋酸钠、四丁基四氟硼酸铵、二溴甲烷和水,室温下搅拌至反应结束,反应结束后,加入二氯甲烷稀释,经无水硫酸钠干燥,过滤,减压旋干后柱层析分离纯化,得二氟甲基烷基醚;柱层析分离纯化中洗脱剂为正己烷或正己烷与乙酸乙酯的混合物。
反应条件具体包括:
二氟甲基试剂的使用量为1至10当量;
活化剂为选自KF、KHF2、NaOH、KOH、LiOH、CsOH、Na2CO3、NaHCO3、K2CO3、Cs2CO3、NaOAc、或NaOAc·3H2O的一种或几种的组合,其用量为1至10当量;
添加剂为Bu4NBF4、Bu4NBr、Bu4NF、Bu4NOTf、Bu4NI的一种或几种的组合,其使用量为1%至300%摩尔量;
有机溶剂为1,1-二氯乙烷、1,2-二氯乙烷、二氯甲烷、氯仿、二溴甲烷、甲苯、氯苯、氟苯中的两种或两种以上的混合;
反应温度为-20℃至80℃;
反应时间为24小时至48小时。
实施例2
本实施例基本同实施例1,唯有不同之处在于:
反应条件具体包括:
二氟甲基试剂的使用量为2至3当量;
活化剂为NaOAc、或NaOAc·3H2O,其用量为5当量;
添加剂为选自Bu4NBF4、Bu4NBr、Bu4NF、Bu4NOTf、Bu4NI的一种或几种的组合,20%摩尔量;
有机溶剂为二溴甲烷;
反应温度为室温25℃。
实施例3
硫醇的二氟甲基醚化反应通用步骤:
在硫醇4的乙腈溶液中,加入氢氧化钾溶液,室温反应30分钟,一次性加入试剂1b,反应30分钟后,加入饱和氯化铵溶液淬灭,乙酸乙酯:10mL×3萃取,合并有机相,无水硫酸钠干燥,过滤,减压旋干,柱层析分离纯化,得二氟甲基烷基硫醚5。
柱层析分离纯化中洗脱剂为正己烷。
反应条件具体包括:
二氟甲基试剂的使用量为1至5当量;
碱为选自NaOH、KOH、LiOH、CsOH、NaH、KH、CaH2中的一种,其用量为1至10当量;
碱为水溶液,其所用浓度为0.5摩尔/升至10摩尔/升;
有机溶剂为乙腈、四氢呋喃、二氯甲烷、氯仿、甲苯、氯苯、氟苯或N,N-二甲基甲酰胺中的两种或两种以上的混合;
反应温度为-20℃至80℃;
反应时间为10分钟或5小时。
实施例4
本实施例基本同实施例3,唯有不同之处在于:反应条件具体包括:
二氟甲基试剂的使用量为1至1.5当量;
碱为KOH,其用量为2.2至2.5当量;
碱为水溶液,其所用浓度为1摩尔/升摩尔量;
有机溶剂为乙腈或氟苯;
反应温度为室温25℃;
反应时间为30分钟。
应当理解,这些实施例的用途仅用于说明本发明而非意欲限制本发明的保护范围。此外,也应理解,在阅读了本发明的技术内容之后,本领域技术人员可以对本发明作各种改动、修改和/或变型,所有的这些等价形式同样落于本申请所附权利要求书所限定的保护范围之内。
由技术常识可知,本发明可以通过其它的不脱离其精神实质或必要特征的实施方案来实现。因此,上述公开的实施方案,就各方面而言,都只是举例说明,并不是仅有的。所有在本发明范围内或在等同于本发明的范围内的改变均被本发明包含。
Claims (4)
1.烷基二氟甲基醚类化合物的合成方法,其特征在于,包括烷基醇的二氟甲基醚化反应, 所述烷基醇的二氟甲基醚化反应通用步骤为
在反应瓶中依次加入磁力搅拌子、醇2、二氟甲基试剂1a、活化剂、添加剂、有机溶剂和水,反应温度为-20℃至80℃;反应时间为24小时至48小时;
所述二氟甲基试剂1a的使用量为醇2的1至10当量;
所述活化剂为KF、KHF2 、NaOH、KOH、LiOH、CsOH、Na2CO3 、NaHCO3 、K2CO3 、Cs2CO3 、NaOAc、或NaOAc·3H2O中的一种或几种的组合,其用量为原料醇2的1至10当量;
所述添加剂为Bu4NBF4、Bu4NBr、Bu4NF、Bu4NOTf、Bu4NI的一种或几种的组合,其使用量为醇2的1%至300%摩尔量;
所述有机溶剂为选自1,1-二氯乙烷、1,2-二氯乙烷、二氯甲烷、氯仿、二溴甲烷、甲苯、氯苯或氟苯中的一种或两种以上的混合。
2.根据权利要求1所述的烷基二氟甲基醚类化合物的合成方法,其特征在于:反应条件具体包括:
所述二氟甲基试剂1a的使用量为醇2的2至3当量;
所述活化剂为NaOAc或NaOAc·3H2O,其用量为醇2的5当量;
所述添加剂为Bu4NBF4 、Bu4NBr、Bu4NF、Bu4NOTf、Bu4NI中的一种或几种的组合,用量为醇2的20%摩尔量;
所述有机溶剂为二溴甲烷;
所述反应温度为10℃至30℃。
4.根据权利要求1所述的烷基二氟甲基醚类化合物的合成方法,其特征在于:反应结束后,加入二氯甲烷稀释,经无水硫酸钠干燥,过滤,减压旋干后柱层析分离纯化,得二氟甲基烷基醚;
所述柱层析分离纯化中洗脱剂为正己烷或正己烷与乙酸乙酯的混合物。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1671657A (zh) * | 2002-06-28 | 2005-09-21 | 罗狄亚化学公司 | 氢氟亚甲基磺酰基团衍生物的合成方法 |
WO2015051141A1 (en) * | 2013-10-04 | 2015-04-09 | E. I. Du Pont De Nemours And Company | Methods for preparation of fluorinated sulfur-containing compounds |
CN107235878A (zh) * | 2016-03-28 | 2017-10-10 | 中国科学院上海有机化学研究所 | 二氟甲基化试剂、其制备方法与应用 |
CN108997183A (zh) * | 2018-09-03 | 2018-12-14 | 深圳大学 | 一种二氟甲基化试剂及其制备方法与应用 |
-
2019
- 2019-05-28 CN CN201910453848.2A patent/CN110028390B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1671657A (zh) * | 2002-06-28 | 2005-09-21 | 罗狄亚化学公司 | 氢氟亚甲基磺酰基团衍生物的合成方法 |
WO2015051141A1 (en) * | 2013-10-04 | 2015-04-09 | E. I. Du Pont De Nemours And Company | Methods for preparation of fluorinated sulfur-containing compounds |
CN107235878A (zh) * | 2016-03-28 | 2017-10-10 | 中国科学院上海有机化学研究所 | 二氟甲基化试剂、其制备方法与应用 |
CN108997183A (zh) * | 2018-09-03 | 2018-12-14 | 深圳大学 | 一种二氟甲基化试剂及其制备方法与应用 |
Non-Patent Citations (7)
Title |
---|
Air- and Light-Stable S‑(Difluoromethyl)sulfonium Salts: C‑Selective Electrophilic Difluoromethylation of β‑Ketoesters and Malonates;Sheng-Le Lu等;《Org. Lett.》;20181012;第6925-6929页 * |
Difluoromethylation and gem-difluorocyclopropenation with difluorocarbene generated by decarboxylation;Xiao-Yun Deng等;《ChemComm》;20151231;第51卷;第8805-8808页 * |
Direct Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide;Jiansheng Zhu等;《Communications》;20161231;第9050–9054页 * |
Efficient Difluoromethylation of sp3 Carbon Nucleophiles by Bromodifluoromethylation Reagents with Organic Bases;Guokai Liu等;《CHEMISTRY OPEN》;20121231;第227-231页 * |
N-Tosyl-S-difluoromethyl-S-phenylsulfoximine: A New Difluoromethylation Reagent for S-, N-, and C-Nucleophiles;Wei Zhang等;《ORGANIC LETTERS》;20091231;第11卷(第10期);Supporting information第S3页、第2110页Scheme 2、第2111页Table 1 * |
Radical Difluoromethylation of Thiols with (Difluoromethyl)triphenylphosphonium Bromide;Niklas B.Heine等;《ORGANIC LETTERS》;20170720;第4150-4153页 * |
Selective O-difluoromethylation of 1,3-diones using S-(difluoromethyl) sulfonium salt;Guo-Kai Liu等;《Chinese Chemical Letters》;20190323;第1515-1518页 * |
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