CN112500270B - 一种合成α,α-二氟酮类化合物的方法 - Google Patents

一种合成α,α-二氟酮类化合物的方法 Download PDF

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CN112500270B
CN112500270B CN202011402001.0A CN202011402001A CN112500270B CN 112500270 B CN112500270 B CN 112500270B CN 202011402001 A CN202011402001 A CN 202011402001A CN 112500270 B CN112500270 B CN 112500270B
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李金山
王治明
吴海建
奚文学
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Abstract

本发明公开了一种合成α,α‑二氟酮类化合物的方法，包括：在催化剂(氟代醇、Lewis酸、

Description

一种合成α,α-二氟酮类化合物的方法
技术领域
本发明属于有机合成领域，具体涉及一种合成α,α-二氟酮类化合物的方法。
背景技术
α,α-二氟酮类化合物因其独特的物理化学性质和生物活性，被广泛应用于医药化学中。该类化合物常被作为酶抑制剂(式1)。同时，α,α-二氟酮类化合物是合成多种含氟复杂化合物的重要砌块。由于两个氟原子强烈的诱导效应，α,α-二氟烯醇类化合物无法直接与亲电试剂(C(sp3))反应得到α,α-二氟酮类化合物。因此，含氟烯醇类化合物与亲电试剂的直接亲核取代反应存在一定的挑战性。
Figure BDA0002817260390000011
目前，合成α,α-二氟酮类化合物主要依赖于亲电的氟化试剂、预官能团化的脱氧氟化试剂、以及氧化氟化试剂。在过去的三十年中，仅有两次报道α,α-二氟烯醇硅醚经SN1或者SN2的烷基化反应得到α,α-二氟酮类化合物，而且需要当量的金属试剂来促进反应。2015年，Altman课题组报道了首例钯催化的脱羧烷基化反应，原位生成α,α-二氟酮类化合物，该反应底物适用范围广，但是底物α,α-二氟酯不易获得，需由伯醇、溴代二氟乙酸乙酯及醛经多步反应制得，同时参与到反应的催化剂钯属于贵金属，价格相对较高。因此，开发一种原料易得且无金属参与的方法合成α,α- 二氟酮类化合物显得尤为重要。
醇类化合物广泛存在于药物、天然产物中。由于醇类化合物的广泛存在性，将羟基转化成CF3O,CF3S,CF3,HCF2等含氟的基团能够明显改善化合物的物理化学性质以及生物活性，因此，利用醇类化合物构建含氟化合物具有重要的价值。但是由于C-OH键具有较高的活化能(85-91kcal mol-1)，要想通过断C-OH键来实现这些反应具有一定的挑战性。目前，三氟甲氧基化、三氟硫甲基化、三氟甲基化反应都是通过特殊的氟化试剂来实现的，或者预先将底物的羟基转化成易离去基团。2019年，肖吉昌教授课题组报道了利用R3P/ICH2CH2I体系实现脱羟基二氟甲基化反应，但是R3P/ICH2CH2I是需要当量的。因此，醇的直接催化脱羟基氟烷基化还有待开发。
要实现醇与α,α-二氟烯醇类化合物的直接取代问题，关键问题是找到一种高效的催化剂来活化羟基。而六氟异丙醇(HFIP)是一种具有酸性质子、亲核性弱的极性溶剂，其已被证实能够在温和条件下，通过氢键网络作用来代替Lewis酸、
Figure BDA0002817260390000022
酸实现各类反应。因此，我们利用HFIP 的氢键网络作用来同时活化醇羟基和烯醇硅醚，实现了HFIP催化下的醇与α,α-二氟烯醇硅醚的脱羟基氟烷基化反应，合成了一系列α,α-二氟酮类化合物。
发明内容
本发明提供了一种合成α,α-二氟酮类化合物的方法，该方法原料易得且无金属参与，反应条件温和，且反应收率高。
一种合成α,α-二氟酮类化合物的方法，包括：
在催化剂的作用下，醇类化合物与二氟烯醇硅醚类化合物在有机溶剂中进行反应，反应结束后经过后处理得到所述的α,α-二氟酮类化合物；
反应式如下：
Figure BDA0002817260390000021
其中，R1、R2、R3独立地选自氢、C1～C4烷基、取代或者未取代的芳基、取代或者未取代的乙烯基或者炔基，该芳基上的取代基选自卤素、羟基、C1～C4烷氧基，所述乙烯基上的取代基为苯基或则萘基；
R4选自取代或者未取代的芳基，该芳基上的取代基选自卤素、C1～C4烷氧基。
作为优选，R1、R2、R3独立地选自氢、甲基、取代或者未取代的苯基、苯乙烯基或者乙炔基，该苯基上的取代基选自氟、氯、甲氧基；
R4选自取代或者未取代的苯基，该苯基上的取代基选自氟、氯、甲氧基。
作为优选，所述的催化剂为
Figure BDA0002817260390000031
酸、Lewis酸或者氟代醇。
作为进一步的优选，所述的
Figure BDA0002817260390000032
酸可以为常见的有机酸或者无机酸，选自乙酸、苯甲酸、对甲基苯磺酸、三氟醋酸、三氟甲磺酸、乳酸、草酸、丙烯酸、硫酸、盐酸、高氯酸、磷酸、硝酸、硼酸或氢氟酸；
所述的Lewis酸选自金属三氟甲磺酸盐及其水合物、金属高氯酸盐及其水合物、六氟合锑酸盐、六氟合磷酸盐、金属硝酸盐、金属磷酸盐、金属硫酸盐、金属氟化物、金属氯化物或者金属溴化物；
所述的氟代醇六氟异丙醇(HFIP)、三氟乙醇(TFE)、六氟-2-甲基异丙醇(HFMIP)、六氟-2-苯基异丙醇(HFPIP)或四氟丁二醇(TFBD)。
作为优选，所述的有机溶剂为二氯甲烷、三氯甲烷、四氯甲烷、乙腈或甲苯。
作为优选，反应温度为室温，反应时间为2～12h。
作为优选，醇类化合物、二氟烯醇硅醚类化合物和催化剂的摩尔比为 1.0:0.05～0.15:1.0～1.1。
作为优选，所述的后处理包括：反应结束后，减压除去溶剂，浓缩物经柱层析分离纯化得到α,α-二氟酮类化合物。
作为优选，所述的α,α-二氟酮类化合物的为以下具体化合物：
Figure BDA0002817260390000041
同现有技术相比，本发明的有益效果在于：
本发明采用了氟代醇、Lewis酸或
Figure BDA0002817260390000042
酸作为催化剂，反应条件温和，反应效率高，原料价廉易得，具有重要的应用意义。
具体实施方式
实施例1～19
在史莱克管中依次加入醇1(1.0mmol)、二氟烯醇硅醚2(1.05mmol, 1.05equiv)、溶剂(3.0mL)、催化剂(0.1mmol,10.5μL)，室温下反应，TLC点板监测反应，约2-12h反应完毕。反应结束后，减压除去溶剂，浓缩物经柱层析分离纯化得到产物3，反应条件和反应结果如下：
Figure DEST_PATH_IMAGE001
实施例20～61
在史莱克管中依次加入醇(1.0mmol)、二氟烯醇硅醚2(1.05mmol, 1.05equiv)、二氯甲烷(3.0mL)、HFIP(0.1mmol,10.5μL)，室温下反应， TLC点板监测反应，监测反应完毕。反应结束后，减压除去溶剂，浓缩物经柱层析分离纯化得到产物，结果如下：
Figure 100002_DEST_PATH_IMAGE002
实施例中部分产物的表征数据如下：
Figure BDA0002817260390000071
2,2-difluoro-3-(4-methoxyphenyl)-1-phenylpropan-1-one(4):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物4(白色固体,114.6mg,83％收率).M.p.:146–147℃；1H NMR(400MHz,CDCl3) δ8.04(d,J＝7.5Hz,2H),7.65–7.54(m,1H),7.51–7.41(m,2H),7.22(d,J ＝8.6Hz,2H),6.88–6.81(m,2H),3.79(s,3H),3.47(t,J＝17.7Hz,2H)；19F NMR(376MHz,CDCl3)δ–98.93(t,J＝17.7Hz,2F)；13C NMR(100MHz, CDCl3)δ189.6(t,J＝31.1Hz),159.1,134.2,132.2(t,J＝2.5Hz),131.9, 130.1(t,J＝3.3Hz),128.6,123.1(t,J＝3.9Hz),118.3(t,J＝254.2Hz),113.8, 55.2,39.3(t,J＝23.3Hz)；HRMS(ESI)m/z:[M+Na]+计算值 C16H14F2O2Na 299.0860；测量值：299.0853.
Figure BDA0002817260390000072
3-(ferrocenylmethyl)-2,2-difluoro-1-phenylpropan-1-one(5):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(100/1to 50/1,v/v)得到化合物5(orange yellowsolid,108.2mg,61％收率).M.p.:89–90℃；1H NMR (400MHz,CDCl3)δ7.99(d,J＝7.5Hz,2H),7.72–7.52(m,1H),7.45(t,J＝ 7.8Hz,2H),4.20(s,2H),4.13(s,5H),4.13–4.09(m,2H),3.30(t,J＝17.2 Hz,2H)；19F NMR(376MHz,CDCl3)δ–98.68(t,J＝16.8Hz,2F)；13C NMR(100MHz,CDCl3)δ189.9(t,J＝30.9Hz),134.1,132.2(t,J＝2.3Hz),130.1 (t,J＝3.3Hz),128.5,117.7(t,J＝254.5Hz),70.3,68.8,68.3,35.4(t,J＝24.0 Hz)；HRMS(ESI)m/z:[M+Na]+计算值C19H16F2FeO2Na 377.0416；测量值：377.0412.
Figure BDA0002817260390000073
2,2-difluoro-3-(4-hydroxyphenyl)-1-phenylpropan-1-one(6):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(20/1,v/v)得到化合物6(pale yellow solid,85.2mg,65％收率).M.p.:65–66℃；1H NMR(400MHz, CDCl3)δ8.02(d,J＝7.6Hz,2H),7.61(t,J＝7.4Hz,1H),7.46(t,J＝7.8Hz, 2H),7.15(d,J＝8.4Hz,2H),6.84–6.74(m,2H),5.21(s,1H),3.45(t,J＝ 17.6Hz,2H)；19F NMR(376MHz,CDCl3)δ–98.92(t,J＝17.2Hz,2F)；13C NMR(100MHz,CDCl3)δ189.8(t,J＝31.1Hz),155.1,134.2,132.2(t,J＝ 2.5Hz),132.1,130.1(t,J＝3.3Hz),128.6,123.2(t,J＝3.8Hz),118.4(t,J＝ 254.4Hz),115.3,39.4(t,J＝23.5Hz)；HRMS(ESI)m/z:[M+Na]+计算值 C15H12F2O2Na 285.0703；测量值：285.0708.
Figure BDA0002817260390000081
2,2-difluoro-3-(4-hydroxy-3-methoxyphenyl)-1-phenylpropan-1-one (7):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(20/1,v/v)得到化合物7(白色固体,90.6mg,62％收率).M.p.:98–99℃；1H NMR(400MHz, CDCl3)δ8.02(d,J＝7.5Hz,2H),7.61(t,J＝7.4Hz,1H),7.46(t,J＝7.8Hz, 2H),6.90–6.81(m,1H),6.77(d,J＝6.0Hz,2H),5.57(s,1H),3.85(s,3H), 3.44(t,J＝17.6Hz,2H)；19F NMR(376MHz,CDCl3)δ–98.81(t,J＝17.4Hz, 2F)；13C NMR(100MHz,CDCl3)δ189.7(t,J＝30.9Hz),146.3,145.2,134.2, 132.3(t,J＝2.3Hz),130.0(t,J＝3.3Hz),128.6,123.9,122.7(t,J＝3.9Hz), 118.4(t,J＝254.4Hz),114.3,113.2,55.9,39.9(t,J＝23.4Hz)；HRMS(ESI) m/z:[M+Na]+计算值C16H14F2O3Na 315.0809；测量值：315.0806.
Figure BDA0002817260390000082
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-phenylpropan-1-one(8):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(20/1,v/v)得到化合物8(白色固体,132.9mg,71％收率).M.p.:119–120℃；1H NMR (400MHz,CDCl3)δ7.92(d,J＝7.8Hz,2H),7.57(t,J＝7.4Hz,1H),7.42(t, J＝7.8Hz,2H),7.02(s,2H),5.15(s,1H),3.43(t,J＝17.4Hz,2H),1.38(s, 18H)；19F NMR(376MHz,CDCl3)δ–99.03(t,J＝18.5Hz,2F)；13C NMR(100MHz,CDCl3)δ190.4(t,J＝30.4Hz),153.3,135.9,133.9,132.7(d,J＝ 2.1Hz),130.0(t,J＝3.4Hz),128.5,127.4,121.5(t,J＝4.0Hz),118.7(t,J＝ 254.2Hz),40.6(t,J＝23.4Hz),34.2,30.2；HRMS(ESI)m/z:[M+Na]+计算值C23H28F2O2Na 397.1955；测量值：397.1959.
Figure BDA0002817260390000091
2,2-difluoro-1,3-diphenylbutan-1-one(9):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物9(pale yellow liquid,111.8 mg,86％收率).1HNMR(400MHz,CDCl3)δ7.90(d,J＝7.5Hz,2H),7.56 (t,J＝7.1Hz,1H),7.40(t,J＝7.4Hz,2H),7.26(s,5H),3.87–3.47(m,1H), 1.48(d,J＝7.0Hz,3H)；19F NMR(376MHz,CDCl3)δ–104.77(dd,J＝272.6, 15.6Hz,1F),–106.18(dd,J＝272.3,16.4Hz,1F)；13C NMR(100MHz,CDCl3)δ190.3(t,J＝30.3Hz),137.3(d,J＝3.9Hz),133.9,132.9,129.9(t,J ＝3.4Hz),129.1,128.5,128.4,127.7,119.5(t,J＝257.4Hz),43.9(t,J＝22.1 Hz),14.3(t,J＝4.6Hz)；HRMS(ESI)m/z:[M+Na]+计算值C16H14F2ONa 283.0910；测量值：283.0918.
Figure BDA0002817260390000092
2,2-difluoro-1-phenyl-3-(p-tolyl)butan-1-one(10):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物10(pale yellow liquid,122.1mg,89％收率).1H NMR(400MHz,CDCl3)δ7.94(d,J＝7.7 Hz,2H),7.59(t,J＝7.4Hz,1H),7.44(t,J＝7.7Hz,2H),7.17(d,J＝7.7Hz, 2H),7.10(d,J＝7.9Hz,2H),3.84–3.55(m,1H),2.31(s,3H),1.49(d,J＝ 7.1Hz,3H)；19F NMR(376MHz,CDCl3)δ–104.92(dd,J＝271.8,15.2Hz,1F),–106.28(dd,J＝271.8,16.5Hz,1F)；13C NMR(100MHz,CDCl3) δ190.3(t,J＝30.2Hz),137.4,134.2(d,J＝4.4Hz),133.9,132.9,129.9(t,J＝ 3.4Hz),129.1,129.0,128.5,119.5(t,J＝257.2Hz),43.5(t,J＝22.1Hz),21.0, 14.3(t,J＝4.6Hz)；HRMS(ESI)m/z:[M+Na]+计算值C17H16F2ONa 297.1067；测量值：297.1063.
Figure BDA0002817260390000101
3-(4-chlorophenyl)-2,2-difluoro-1-phenylbutan-1-one(11):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物11(pale yellow liquid,120.8mg,82％收率).1H NMR(400MHz,CDCl3)δ7.95(d,J ＝7.8Hz,2H),7.59(t,J＝7.4Hz,1H),7.43(t,J＝7.8Hz,2H),7.29–7.18(m, 4H),3.87–3.54(m,1H),1.46(d,J＝7.2Hz,3H)；19F NMR(376MHz,CDCl3) δ–104.86(dd,J＝276.7,15.3Hz,1F),–105.76(dd,J＝277.0,15.8Hz,1F)；13C NMR(100MHz,CDCl3)δ189.73(t,J＝30.4Hz),135.9(t,J＝2.8Hz), 134.13(s),133.56(s),132.63(t,J＝2.0Hz),130.47(s),129.87(t,J＝3.5Hz), 128.58(d,J＝3.7Hz),119.20(t,J＝257.8Hz),43.17(t,J＝22.2Hz),14.34(t, J＝4.7Hz)；HRMS(ESI)m/z:[M+Na]+计算值C16H13ClF2ONa 294.0623；测量值：294.0629.
Figure BDA0002817260390000102
3-(4-bromophenyl)-2,2-difluoro-1-phenylbutan-1-one(12):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物12 (yellow liquid,132.2mg,78％收率).1H NMR(400MHz,CDCl3)δ7.98(d,J ＝7.9Hz,2H),7.61(t,J＝7.4Hz,1H),7.51–7.34(m,4H),7.19(d,J＝8.3 Hz,2H),3.94–3.56(m,1H),1.48(d,J＝7.2Hz,3H)；19F NMR(376MHz, CDCl3)δ–104.83(dd,J＝281.1,18.9Hz,1F),–105.62(dd,J＝277.6,16.2Hz,1F)；13C NMR(100MHz,CDCl3)δ189.6(t,J＝30.4Hz),136.4(t,J＝2.9Hz), 134.1,132.6(t,J＝2.0Hz),131.5,130.8,129.8(t,J＝3.5Hz),128.6,121.7, 119.1(t,J＝257.8Hz),43.2(t,J＝22.2Hz),14.3(t,J＝4.7Hz)；HRMS(ESI) m/z:[M+Na]+计算值C16H13BrF2ONa338.0118；测量值：338.0111.
Figure BDA0002817260390000103
3-cyclopropyl-2,2-difluoro-1,3-diphenylpropan-1-one(13):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物13 (yellow liquid,124.5mg,87％收率).1H NMR(400MHz,CDCl3)δ8.00(d,J ＝7.7Hz,2H),7.60(t,J＝7.4Hz,1H),7.46(t,J＝7.8Hz,2H),7.39–7.27(m, 5H),2.79(ddd,J＝18.9,12.6,10.5Hz,1H),1.49–1.33(m,1H),0.76–0.57 (m,1H),0.51(ddd,J＝14.0,9.0,5.4Hz,1H),0.30(dq,J＝10.1,5.1Hz,1H), 0.14–0.01(m,1H)；19F NMR(376MHz,CDCl3)δ–100.46(dd,J＝266.4,14.4 Hz,1F),–106.61(dd,J＝266.5,21.5Hz,1F)；13C NMR(100MHz,CDCl3) δ190.9(t,J＝29.0Hz),136.4(d,J＝2.9Hz),133.9,133.3,129.8(t,J＝3.7 Hz),129.6,128.6,128.3,127.6,119.6(t,J＝257.7Hz),54.8(t,J＝21.3Hz), 10.5(dd,J＝6.8,3.7Hz),7.1,3.4；HRMS(ESI)m/z:[M+Na]+计算值 C18H16F2ONa 309.1067；测量值：309.1073.
Figure BDA0002817260390000111
2,2-difluoro-1-phenyl-2-(1,2,3,4-tetrahydronaphthalen-1-yl)ethanone(14):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物14(yellowliquid,105.9mg,74％收率).1H NMR(400MHz,CDCl3) δ8.00(d,J＝7.7Hz,2H),7.60(t,J＝7.4Hz,1H),7.46(t,J＝7.8Hz,2H), 7.39–7.27(m,5H),2.79(ddd,J＝18.9,12.6,10.5Hz,1H),1.49–1.33(m, 1H),0.76–0.57(m,1H),0.51(ddd,J＝14.0,9.0,5.4Hz,1H),0.30(dq,J＝ 10.1,5.1Hz,1H),0.14–0.01(m,1H)；19F NMR(376MHz,CDCl3)δ–96.68 (dd,J＝271.9,15.1Hz,1F),–103.63(dd,J＝271.9,21.1Hz,1F)；13C NMR (100MHz,CDCl3)δ190.9(t,J＝29.0Hz),136.4(d,J＝2.9Hz),133.9,133.3, 129.8(t,J＝3.7Hz),129.6,128.6,128.3,127.6,119.6(t,J＝257.7Hz),54.8 (t,J＝21.3Hz),10.5(dd,J＝6.8,3.7Hz),7.1,3.4；HRMS(ESI)m/z:[M+ Na]+计算值C18H16F2ONa 309.1067；测量值：309.1075.
Figure BDA0002817260390000121
2,2-difluoro-1,3,3-triphenylpropan-1-one(15):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物15(白色固体,154.7 mg,96％收率).M.p.:82–83℃；1H NMR(400MHz,CDCl3)δ8.04–7.83(m, 2H),7.67–7.52(m,1H),7.48–7.37(m,6H),7.34–7.22(m,6H),5.03(t,J＝ 18.1Hz,1H)；19F NMR(376MHz,CDCl3)δ–100.00(d,J＝17.8Hz,2F)；13C NMR(100MHz,CDCl3)δ189.9(t,J＝30.1Hz),136.3(t,J＝2.1Hz),134.0,132.8(t,J＝2.2Hz),129.8(t,J＝3.4Hz),129.7,128.6,127.5,118.9(t,J＝ 259.1Hz),54.9(t,J＝21.4Hz)；HRMS(ESI)m/z:[M+Na]+计算值 C21H16F2ONa 345.1067；测量值：309.1060.
Figure BDA0002817260390000122
2,2-difluoro-3,3-bis(4-fluorophenyl)-1-phenylpropan-1-one(16):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物16 (白色固体,119.8mg,67％收率).M.p.:46–47℃；1H NMR(400MHz, CDCl3)δ7.94(d,J＝7.9Hz,2H),7.62(t,J＝7.4Hz,1H),7.46(t,J＝7.8Hz, 2H),7.35(dd,J＝8.1,5.5Hz,4H),7.00(t,J＝8.7Hz,4H),5.02(t,J＝17.8 Hz,1H)；19F NMR(376MHz,CDCl3)δ–100.32(d,J＝19.7Hz,2F),–112.65 ––116.65(m,2F)；13C NMR(100MHz,CDCl3)δ189.5(t,J＝30.2Hz),163.4, 160.9,134.2,132.6(t,J＝2.1Hz),131.9(d,J＝2.5Hz),131.2,131.2,130.9, 129.8(t,J＝3.3Hz),128.6,118.6(t,J＝259.4Hz),115.7,115.5,53.2(t,J＝ 21.8Hz)；HRMS(ESI)m/z:[M+Na]+计算值C21H14F4ONa 381.0878；测量值：381.0872.
Figure BDA0002817260390000131
3-(4-bromophenyl)-2,2-difluoro-1,3-diphenylpropan-1-one(18):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物18 (白色固体,140.4mg,70％收率).M.p.:80–81℃；1H NMR(400MHz, CDCl3)δ7.94(d,J＝7.5Hz,2H),7.61(t,J＝7.4Hz,1H),7.49–7.40(m,4H), 7.36(d,J＝7.2Hz,2H),7.33–7.26(m,5H),4.99(t,J＝17.9Hz,1H)；19F NMR(376MHz,CDCl3)δ–99.40(dd,J＝286.5,19.5Hz,1F),–100.42(dd,J ＝286.7,19.3Hz,1F)；13C NMR(100MHz,CDCl3)δ189.5(t,J＝30.2Hz), 135.8(t,J＝2.1Hz),135.5(dd,J＝2.7,1.4Hz),134.2,132.6(t,J＝2.1Hz), 131.7,131.3,129.9(t,J＝3.3Hz),129.6,128.7,128.6,127.7,121.7,118.7(t, J＝259.5Hz),54.2(t,J＝21.6Hz)；HRMS(ESI)m/z:[M+Na]+计算值 C21H15BrF2ONa 400.0274；测量值：400.0268.
Figure BDA0002817260390000132
2,2-difluoro-1,3-diphenyl-3-(4-(trifluoromethyl)phenyl)propan-1-one(19):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物19(白色固体,169.8mg,87％收率).M.p.:63–64℃；1H NMR(400 MHz,CDCl3)δ7.95(d,J＝7.5Hz,2H),7.62(t,J＝7.4Hz,1H),7.55(q,J＝ 8.6Hz,4H),7.51–7.42(m,2H),7.33(ddd,J＝14.4,10.6,6.9Hz,5H),5.10 (t,J＝17.8Hz,1H)；19F NMR(376MHz,CDCl3)δ–62.65(s,3F),–99.59(qd, J＝288.3,19.8Hz,2F)；13C NMR(100MHz,CDCl3)δ189.3(t,J＝30.4Hz), 140.6(d,J＝2.9Hz),135.5(d,J＝4.1Hz),134.3,132.5(t,J＝2.2Hz),130.0, 129.9(t,J＝3.1Hz),129.6,128.8,128.7,127.9,127.4,127.3,127.1(d,J＝1.0 Hz),125.5(q,J＝3.7Hz),118.7(t,J＝260.6Hz),54.5(t,J＝21.7Hz)； HRMS(ESI)m/z:[M+Na]+计算值C22H15F5ONa390.1043；测量值： 390.1051.
Figure BDA0002817260390000141
methyl 4-(2,2-difluoro-3-oxo-1,3-diphenylpropyl)benzoate(20):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物20 (白色固体,119.6mg,63％收率).M.p.:101–102℃；1H NMR(400MHz, CDCl3)δ8.14–7.80(m,4H),7.60(dd,J＝10.7,4.2Hz,1H),7.49(d,J＝7.3 Hz,2H),7.44(t,J＝7.8Hz,2H),7.38(d,J＝7.2Hz,2H),7.33–7.25(m,3H), 5.10(t,J＝17.4Hz,1H),3.88(s,3H)；19F NMR(376MHz,CDCl3)δ–99.13(dd,J＝286.1,17.1Hz,1F),–100.09(dd,J＝286.2,17.0Hz,1F)；13C NMR (100MHz,CDCl3)δ189.4(t,J＝30.3Hz),166.7,141.6(d,J＝2.6Hz),135.6 (d,J＝2.8Hz),134.2,132.5(t,J＝2.0Hz),129.8(t,J＝3.5Hz),129.8,129.7 (d,J＝4.6Hz),129.3,128.7,128.6,127.8,118.7(t,J＝259.6Hz),54.7(t,J＝ 21.6Hz),52.1；HRMS(ESI)m/z:[M+Na]+计算值C23H18F2O3Na 403.1122；测量值：403.1128.
Figure BDA0002817260390000142
2,2-difluoro-3-(3-(hydroxymethyl)phenyl)-1,3-diphenylpropan-1-one(21):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(3/1,v/v)得到化合物21(白色固体,149.8mg,85％收率).M.p.:83–84℃；1H NMR(400 MHz,CDCl3)δ7.97(d,J＝7.8Hz,2H),7.60(t,J＝7.4Hz,1H),7.48–7.39 (m,6H),7.36–7.23(m,5H),5.07(t,J＝18.1Hz,1H),4.61(s,2H),2.32(brs, 1H)；19F NMR(376MHz,CDCl3)δ–99.85(d,J＝16.4Hz,2F)；13C NMR(100MHz,CDCl3)δ189.8(t,J＝30.2Hz),140.1,136.2(t,J＝1.9Hz),135.6 (d,J＝2.0Hz),134.0,132.7(t,J＝1.9Hz),129.8(t,J＝1.6Hz),129.6,128.5, 127.5,127.1,118.8(t,J＝259.1Hz),64.7,54.6(t,J＝21.5Hz)；HRMS(ESI) m/z:[M+Na]+计算值C22H18F2O2Na375.1173；测量值：375.1180.
Figure BDA0002817260390000151
2,2-difluoro-1-phenyl-2-(9H-xanthen-9-yl)ethanone(22):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(30/1,v/v)得到化合物22(pale yellowsolid,129.5mg,77％收率).M.p.:62–63℃；1H NMR(400MHz, CDCl3)δ7.68(d,J＝7.6Hz,2H),7.51(t,J＝7.4Hz,1H),7.36–7.27(m,6H), 7.16(d,J＝7.9Hz,2H),7.06(td,J＝7.5,1.0Hz,2H),4.97(t,J＝14.3Hz, 1H)；19F NMR(376MHz,CDCl3)δ–103.17(d,J＝13.9Hz,2F)；13C NMR(100MHz,CDCl3)δ191.0(t,J＝29.6Hz),153.5,133.9,133.2(t,J＝1.7Hz), 130.6,129.8(t,J＝3.7Hz),129.5,128.3,123.3,118.1(t,J＝260.5Hz),116.8, 116.3(t,J＝3.1Hz),44.4(t,J＝23.8Hz)；HRMS(ESI)m/z:[M+Na]+计算值C21H14F2O2Na 359.0860；测量值：359.0852.
Figure BDA0002817260390000152
2-(9H-fluoren-9-yl)-2,2-difluoro-1-phenylethanone(23):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物23(白色固体,134.5mg,84％收率).M.p.:83–84℃；1H NMR(400MHz,CDCl3)δ7.99 (d,J＝7.8Hz,2H),7.78(d,J＝7.6Hz,2H),7.66–7.53(m,3H),7.43(q,J＝ 7.7Hz,4H),7.30(t,J＝7.5Hz,2H),4.98(t,J＝14.7Hz,1H)；19F NMR(376 MHz,CDCl3)δ–98.15(d,J＝15.5Hz,2F)；13C NMR(100MHz,CDCl3)δ189.1(t,J＝31.1Hz),142.3,138.9(t,J＝3.7Hz),134.1,132.6(t,J＝2.6 Hz),130.1(t,J＝3.4Hz),128.5(d,J＝4.9Hz),127.2,126.2,120.0,119.4(t,J ＝258.4Hz),51.3(t,J＝23.5Hz)；HRMS(ESI)m/z:[M+Na]+计算值 C21H14F2ONa 343.0910；测量值：343.0913.
Figure BDA0002817260390000161
2-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-2,2-difluoro-1-phenylethanone(24):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1, v/v)得到化合物24(白色固体,146.3mg,84％收率).M.p.:142–143℃；1H NMR(400MHz,CDCl3)δ7.80(d,J＝7.8Hz,2H),7.56(t,J＝7.4Hz,1H), 7.39(t,J＝7.8Hz,2H),7.16(dd,J＝14.8,7.4Hz,6H),7.09–7.01(m,2H), 5.01(t,J＝18.1Hz,1H),3.75–3.52(m,2H),3.05–2.75(m,2H)；19F NMR(376MHz,CDCl3)δ–96.05(d,J＝18.7Hz,2F)；13C NMR(100MHz,CDCl3) δ190.9(t,J＝25.6Hz),141.9,133.8,133.4,133.2,131.8,130.8,129.7(t,J＝ 3.5Hz),128.4,128.3,125.9,119.6(d,J＝260.5Hz),58.5(t,J＝23.1Hz), 33.1(t,J＝2.7Hz)；HRMS(ESI)m/z:[M+Na]+计算值C23H18F2ONa 371.1223；测量值：371.1216.
Figure BDA0002817260390000162
2,2-difluoro-1-phenyl-2-(9-phenyl-9H-fluoren-9-yl)ethanone(25):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物 25(白色固体,77.2mg,39％收率).M.p.:136–137℃；1H NMR(400MHz, CDCl3)δ7.58(d,J＝7.8Hz,4H),7.45(t,J＝6.9Hz,4H),7.38–7.30(m,3H), 7.28–7.19(m,5H),7.14(t,J＝7.9Hz,2H)；19F NMR(376MHz,CDCl3) δ–96.41(s,2F)；13C NMR(100MHz,CDCl3)δ188.2(t,J＝30.0Hz),144.3(t, J＝3.1Hz),141.5,138.8,133.9(t,J＝1.8Hz),132.9,129.3(t,J＝3.7Hz), 128.7,128.4,127.7(dd,J＝6.5,3.0Hz),127.4,127.3,120.3(t,J＝265.7Hz), 120.0,63.8(t,J＝22.0Hz)；HRMS(ESI)m/z:[M+Na]+计算值 C27H18F2ONa 419.1223；测量值：419.1228.
Figure BDA0002817260390000171
3-(benzo[b]thiophen-2-yl)-2,2-difluoro-1-phenylbutan-1-one(26):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物 26(白色固体,77.2mg,61％收率).M.p.:84–85℃；1H NMR(400MHz, CDCl3)δ8.02(d,J＝7.5Hz,2H),7.78(dd,J＝8.0,0.9Hz,1H),7.70(dd,J＝ 6.7,1.9Hz,1H),7.60(t,J＝7.4Hz,1H),7.45(t,J＝7.8Hz,2H),7.35–7.26 (m,2H),7.21(s,1H),4.46–3.67(m,1H),1.61(d,J＝7.1Hz,3H)；19F NMR(376MHz,CDCl3)δ–104.25(dd,J＝279.2,13.9Hz,1F),–105.47(dd,J＝ 279.4,15.8Hz,1F)；13C NMR(100MHz,CDCl3)δ189.5(t,J＝30.4Hz), 140.6(dd,J＝4.7,1.4Hz),139.6,139.3,134.2,132.6(t,J＝2.1Hz),129.9(t, J＝3.4Hz),128.6,124.2(d,J＝3.1Hz),123.7,123.4,122.1,119.9(t,J＝ 258.9Hz),40.0(t,J＝23.4Hz),15.5(t,J＝4.6Hz)；HRMS(ESI)m/z:[M+ Na]+计算值C18H14F2OSNa 339.0631；测量值：339.0638.
Figure BDA0002817260390000172
(E)-2,2-difluoro-1,3,5-triphenylpent-4-en-1-one(27):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物27(白色固体, 148.1mg,85％收率).M.p.:88–89℃；1H NMR(400MHz,CDCl3)δ7.97(d, J＝6.1Hz,2H),7.65–7.53(m,1H),7.45(t,J＝7.1Hz,2H),7.42–7.27(m, 9H),7.25–7.22(m,1H),6.55(s,2H),4.49(t,J＝16.2Hz,1H)；19F NMR (376MHz,CDCl3)δ–102.53(dd,J＝275.3,16.9Hz,1F),–103.38(dd,J＝275.3,16.7Hz,1F)；13C NMR(100MHz,CDCl3)δ189.9(t,J＝29.8Hz), 136.5,135.4,135.3,134.0,132.9,129.8(d,J＝3.4Hz),129.6,128.6(t,J＝7.6 Hz),127.9,126.5,123.6(t,J＝3.9Hz),118.7(t,J＝258.9Hz),53.3(t,J＝ 22.0Hz)；HRMS(ESI)m/z:[M+Na]+计算值C23H18F2ONa 371.1223；测量值：371.1218.
Figure BDA0002817260390000181
(E)-2,2-difluoro-1-phenyl-3,5-di-p-tolylpent-4-en-1-one(28):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物28(白色固体,172.8mg,92％收率).M.p.:96–97℃；1H NMR(400MHz,CDCl3) δ7.95(d,J＝7.9Hz,2H),7.57(t,J＝7.4Hz,1H),7.42(t,J＝7.8Hz,2H), 7.31–7.19(m,4H),7.12(d,J＝7.9Hz,2H),7.08(d,J＝7.9Hz,2H),6.58– 6.33(m,2H),4.60–4.10(m,1H),2.30(s,6H)；19F NMR(376MHz,CDCl3) δ–103.19(d,J＝16.2Hz,2F)；13C NMR(100MHz,CDCl3)δ190.1(t,J＝ 29.7Hz),137.8,137.6,135.0,134.0,133.9,133.0,132.5,129.9(t,J＝3.4Hz), 129.5,129.4,129.3,128.6,126.5,122.7(t,J＝4.2Hz),118.8(t,J＝258.6Hz), 53.1(t,J＝22.0Hz),21.2(d,J＝10.7Hz)；HRMS(ESI)m/z:[M+Na]+计算值C25H22F2ONa 399.1536；测量值：399.1540.
Figure BDA0002817260390000182
(E)-2,2-difluoro-3,5-bis(4-methoxyphenyl)-1-phenylpent-4-en-1-one(29):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(30/1,v/v)得到化合物29(白色固体,181.7mg,89％收率).M.p.:104–105℃；1H NMR (400MHz,CDCl3)δ7.98(d,J＝7.6Hz,2H),7.64–7.56(m,1H),7.46(t,J＝ 7.8Hz,2H),7.34–7.27(m,4H),6.91–6.81(m,4H),6.43(dt,J＝15.8,11.9 Hz,2H),4.50–4.31(m,1H),3.79(s,3H),3.79(s,3H)；19F NMR(376MHz,CDCl3)δ–102.78(dd,J＝271.5,14.8Hz,1F),–103.91(dd,J＝269.9,13.3Hz, 1F)；13C NMR(100MHz,CDCl3)δ190.1(t,J＝29.6Hz),159.2(d,J＝24.9 Hz),134.4,133.9,133.0(d,J＝1.6Hz),130.6,129.8(t,J＝3.3Hz),129.3, 129.2,128.5,127.6,121.4(t,J＝4.6Hz),118.7(t,J＝258.5Hz),114.0,113.8, 55.1(d,J＝5.7Hz),52.6(t,J＝22.1Hz)；HRMS(ESI)m/z:[M+Na]+计算值C25H22F2O3Na 431.1435；测量值：431.1429.
Figure BDA0002817260390000191
(E)-2,2-difluoro-3,5-bis(4-fluorophenyl)-1-phenylpent-4-en-1-one(30):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物 30(白色固体,153.7mg,80％收率).M.p.:71–72℃；1H NMR(400MHz, CDCl3)δ7.98(d,J＝7.6Hz,2H),7.62(t,J＝7.4Hz,1H),7.47(t,J＝7.8Hz, 2H),7.39–7.28(m,4H),7.08–6.94(m,4H),6.44(dt,J＝15.8,11.9Hz,2H), 4.48(td,J＝16.1,7.8Hz,1H)；19F NMR(376MHz,CDCl3)δ–102.46(dd,J＝ 277.7,17.8Hz,1F),–103.44(dd,J＝278.3,17.7Hz,1F),–113.67(dd,J＝ 12.3,8.1Hz,1F),–114.17(dd,J＝12.4,8.0Hz,1F)；13C NMR(100MHz, CDCl3)δ189.6(t,J＝29.9Hz),163.7(d,J＝15.6Hz),161.2(d,J＝15.1Hz), 134.2(d,J＝2.9Hz),132.7(t,J＝1.9Hz),132.5(d,J＝3.3Hz),131.2,131.2, 129.8(t,J＝3.4Hz),128.7,128.1,128.0,123.1(d,J＝1.8Hz),118.5(t,J＝ 259.4Hz),115.7,115.6,115.5,115.4,52.4(t,J＝22.2Hz)；HRMS(ESI) m/z:[M+Na]+计算值C23H16F4ONa 407.1035；测量值：431.1429.
Figure BDA0002817260390000192
(E)-2,2-difluoro-3,5-di(naphthalen-2-yl)-1-phenylpent-4-en-1-one(33):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物 33(白色固体,118.6mg,53％收率).M.p.:123–124℃；1H NMR(400MHz, CDCl3)δ8.01(d,J＝7.7Hz,2H),7.92–7.74(m,7H),7.69(s,1H),7.60(td,J ＝6.5,1.5Hz,3H),7.52–7.39(m,6H),6.87–6.61(m,2H),4.74(td,J＝16.3, 6.8Hz,1H)；19F NMR(376MHz,CDCl3)δ–96.03(d,J＝21.1Hz,2F)；13C NMR(100MHz,CDCl3)δ189.8(t,J＝29.8Hz),135.5,134.1,133.9,133.4,133.3,133.1,132.9(d,J＝3.6Hz),129.9(t,J＝3.4Hz),128.9,128.6,128.4, 128.2,128.0,128.0,127.6(d,J＝1.6Hz),127.2,126.6,126.3,126.2(d,J＝2.1Hz),126.0,124.0(t,J＝4.2Hz),123.5,118.8(t,J＝259.2Hz),53.4(t,J＝ 21.9Hz)；HRMS(ESI)m/z:[M+Na]+计算值C31H22F2ONa 471.1536；测量值：471.1529.
Figure BDA0002817260390000201
mixture of 2,2-difluoro-1,3-diphenylpent-4-en-1-one(34)and (E)-2,2-difluoro-1,5-diphenylpent-4-en-1-one(34’)(1.3:1):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)give mixture of compounds 34 and 34’(pale yellowliquid,113.2mg,83％收率,1.3:1).HRMS(ESI)m/z: [M+Na]+计算值C17H14F2ONa 295.0910；测量值：295.0903.
1H NMRof34(400MHz,CDCl3)δ7.90(d,J＝7.5Hz,2H),7.53(dd,J＝ 10.7,4.2Hz,1H),7.39(t,J＝7.8Hz,2H),7.27–7.17(m,5H),6.16(dddd,J ＝12.8,8.2,7.5,1.6Hz,1H),5.26(d,J＝10.3Hz,1H),5.17(d,J＝17.1Hz, 1H),4.27(td,J＝16.4,8.3Hz,1H)；19FNMRof34(376MHz,CDCl3) δ–102.77(dd,J＝274.7,16.9Hz,1F),–103.63(dd,J＝274.7,16.0Hz,1F)；1H NMRof34’(400MHz,CDCl3)δ8.07(d,J＝7.5Hz,2H),7.61–7.56(m, 1H),7.44(t,J＝7.8Hz,2H),7.31(d,J＝7.5Hz,2H),7.27–7.23(m,2H), 6.53(d,J＝15.9Hz,1H),6.16(dddd,J＝12.8,8.2,7.5,1.6Hz,2H),3.08(td, J＝17.1,7.3Hz,2H)；19F NMRof34’(376MHz,CDCl3)δ–98.84(t,J＝17.1 Hz,2F)；13C NMRof34 and34’(100MHz,CDCl3)δ189.8(t,J＝29.7Hz), 189.2(t,J＝31.2Hz),136.6,136.2,135.1(d,J＝2.7Hz),134.3,134.0,132.9, 132.4(t,J＝4.4Hz),132.0(t,J＝2.6Hz),130.2(t,J＝3.2Hz),129.8(t,J＝3.4Hz),129.6,128.7,128.6,128.5,127.8,127.7,126.3,120.5,118.8(t,J＝ 5.3Hz),118.7(t,J＝254.2Hz),118.6(t,J＝258.7Hz),53.9(t,J＝21.8Hz), 37.8(t,J＝23.6Hz).
Figure BDA0002817260390000202
2,2-difluoro-1,5,5-triphenylpent-4-en-1-one(35):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物35(pale yellow liquid,141.1mg,81％收率).1H NMR(400MHz,CDCl3)δ8.03(d,J＝7.5 Hz,2H),7.60(t,J＝7.4Hz,1H),7.44(t,J＝7.7Hz,2H),7.39–7.29(m,3H), 7.24(d,J＝5.8Hz,5H),7.14(d,J＝6.4Hz,2H),6.26–6.05(m,1H),3.17– 2.94(m,2H)；19F NMR(376MHz,CDCl3)δ–98.89––99.41(m,2F)；13C NMR(100MHz,CDCl3)δ189.1(t,J＝30.6Hz),147.0,141.7,139.0,134.3, 131.8(t,J＝2.2Hz),130.1(t,J＝3.2Hz),129.6,128.6,128.4,128.2,127.6, 127.4,127.3,118.9(t,J＝254.2Hz),117.4(t,J＝5.0Hz),35.1(t,J＝23.3Hz)； HRMS(ESI)m/z:[M+Na]+计算值C23H18F2ONa 371.1223；测量值： 371.1231.
Figure BDA0002817260390000211
(E)-2,2-difluoro-1,5-diphenylhex-4-en-1-one(36):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物36(pale yellow liquid,116.6mg,78％收率).1H NMR(400MHz,CDCl3)δ8.04(d,J＝7.6 Hz,2H),7.55(t,J＝7.4Hz,1H),7.42(t,J＝7.8Hz,2H),7.30–7.26(m,2H), 7.23(t,J＝7.3Hz,2H),7.17(dd,J＝6.1,3.6Hz,1H),5.71(td,J＝7.4,1.2Hz, 1H),3.07(td,J＝17.3,7.4Hz,2H),1.98(s,3H)；19F NMR(376MHz,CDCl3) δ–98.84(t,J＝17.1Hz,2F)；13C NMR(100MHz,CDCl3)δ189.4(t,J＝31.2 Hz),143.2,140.7,134.3,130.1(t,J＝3.3Hz),128.7,128.2,127.2,125.9, 119.2(t,J＝254.3Hz),116.5(t,J＝5.3Hz),33.9(t,J＝23.4Hz),16.3； HRMS(ESI)m/z:[M+Na]+计算值C18H16F2ONa 309.1067；测量值： 309.1073.
Figure BDA0002817260390000212
3-(4-chlorophenyl)-3-(3,3-dimethylcyclopent-1-en-1-yl)-2,2-difluoro-1-phenylpropan-1-one(37):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物37(白色固体,155.2mg,83％收率).M.p.: 51–52℃；1H NMR(400MHz,CDCl3)δ7.96(d,J＝7.6Hz,2H),7.62(t,J＝ 7.4Hz,1H),7.47(t,J＝7.8Hz,2H),7.29(t,J＝3.3Hz,3H),5.43(s,1H), 4.33(dd,J＝22.6,12.6Hz,1H),2.25(t,J＝7.1Hz,2H),1.82–1.49(m,3H), 1.00(s,3H),0.96(s,3H)；19F NMR(376MHz,CDCl3)δ–97.45(dd,J＝278.5, 13.7Hz,1F),–105.91(dd,J＝278.7,24.1Hz,1F)；13C NMR(100MHz, CDCl3)δ190.0(dd,J＝30.7,29.0Hz),140.4(d,J＝2.0Hz),135.1(d,J＝5.3 Hz),133.9,133.7,133.1(t,J＝2.0Hz),133.0(d,J＝2.9Hz),131.4,129.7(t,J ＝3.3Hz),128.6,128.5,118.5(dd,J＝262.1,256.3Hz),50.3(t,J＝21.8Hz), 45.5,38.6,34.4,28.1,27.9；HRMS(ESI)m/z:[M+Na]+计算值 C22H21ClF2ONa 397.1147；测量值：397.1156.
Figure BDA0002817260390000221
mixture of (E)-2-(2-benzylidene-1,2,3,4-tetrahydronaphthalen-1-yl)-2,2-difluoro-1-ph enylethanone(38)and 3-(3,4-dihydronaphthalen-2-yl)-2,2-difluoro-1,3-diphenylpropan-1-one (38’)(1:1):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v) give mixture of compounds 38and 38’(pale yellow liquid,174.1mg,93％收率,1:1).HRMS(ESI)m/z:[M+Na]+计算值C25H20F2ONa 397.1380；测量值：397.1373.
1H NMRof38and38’(400MHz,CDCl3)δ8.02(dd,J＝15.0,7.8Hz,4H), 7.63(t,J＝7.4Hz,2H),7.53–7.43(m,6H),7.38–7.31(m,4H),7.30(d,J＝ 7.5Hz,2H),7.25(d,J＝2.3Hz,1H),7.21(t,J＝7.4Hz,3H),7.16–7.11(m, 2H),7.11–7.05(m,3H),7.01–6.96(m,1H),6.56(s,1H),6.38(s,1H),4.58 –4.28(m,2H),3.24–3.02(m,1H),2.92–2.76(m,3H),2.73(t,J＝8.1Hz, 2H),2.26(t,J＝8.1Hz,2H)；19F NMRof38 and38’(376MHz,CDCl3) δ–97.15(dd,J＝115.7,15.9Hz,1F),–97.87(dd,J＝91.3,16.0Hz,1F), –102.63(dd,J＝179.9,23.2Hz,1F),–103.35(dd,J＝155.2,23.2Hz,1F)；13C NMRof38 and38’(100MHz,CDCl3)δ190.8(t,J＝28.6Hz),190.0(t,J＝29.8 Hz),138.6,136.8,135.7(d,J＝5.1Hz),134.5,134.5(d,J＝3.1Hz),134.0, 133.9,133.8,133.6(d,J＝1.8Hz),133.2,133.1,133.0,130.7,130.6(d,J＝ 3.2Hz),130.5(d,J＝2.5Hz),130.1,129.9–129.7(m),128.9,128.7,128.6, 128.4,128.1,127.9(d,J＝4.4Hz),127.2(d,J＝3.0Hz),126.8,126.4,126.3, 126.0,119.6(dd,J＝261.8,260.1Hz),118.9(dd,J＝261.2,257.3Hz),55.6(t, J＝21.3Hz),53.0(t,J＝22.0Hz),29.2,28.0,27.1,24.1(d,J＝1.6Hz).
Figure BDA0002817260390000231
2-(cyclohex-2-en-1-yl)-2,2-difluoro-1-phenylethanone(39):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物39(pale yellow liquid,75.6mg,64％收率).1H NMR(400MHz,CDCl3)δ8.10(d,J＝ 7.6Hz,2H),7.63(t,J＝7.4Hz,1H),7.49(t,J＝7.8Hz,2H),5.96(ddd,J＝ 10.0,6.5,3.3Hz,1H),5.68(dd,J＝10.3,1.8Hz,1H),3.26–2.90(m,1H), 2.11–1.96(m,2H),1.94–1.75(m,2H),1.68–1.43(m,2H)；19FNMR(376 MHz,CDCl3)δ–105.60(dd,J＝275.5,15.3Hz,1F),–107.78(dd,J＝275.5,16.6Hz,1F)；13C NMR(100MHz,CDCl3)δ189.9(t,J＝30.4Hz),134.1, 132.8(t,J＝2.0Hz),131.8,130.1(t,J＝3.6Hz),128.7,121.4(t,J＝5.2Hz), 119.8(t,J＝255.8Hz),40.0(dd,J＝22.7,20.9Hz),24.6,21.8(t,J＝4.1Hz), 20.8；HRMS(ESI)m/z:[M+Na]+计算值C14H14F2ONa 259.0910；测量值： 259.0916.
Figure BDA0002817260390000232
2,2-difluoro-1,3-diphenylpent-4-yn-1-one(40):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物40(pale yellow liquid, 70.3mg,52％收率).1H NMR(400MHz,CDCl3)δ8.02(d,J＝7.9Hz,2H), 7.62(t,J＝7.4Hz,1H),7.52(d,J＝6.6Hz,2H),7.47(t,J＝7.8Hz,2H),7.42 –7.33(m,3H),4.74(dd,J＝17.7,11.0Hz,1H),2.41(d,J＝2.1Hz,1H)；19F NMR(376MHz,CDCl3)δ–101.17(dd,J＝274.9,13.6Hz,1F),–104.76(dd, J＝275.0,21.4Hz,1F)；13C NMR(100MHz,CDCl3)δ189.0(t,J＝29.8Hz),134.2,132.4(t,J＝2.2Hz),131.7(d,J＝1.8Hz),130.0,129.9(d,J＝3.5Hz), 128.5(d,J＝4.2Hz),128.4,116.7(dd,J＝263.4,260.3Hz),78.1(dd,J＝8.8, 2.4Hz),74.3,42.5(dd,J＝27.0,23.0Hz)；HRMS(ESI)m/z:[M+Na]+计算值C17H12F2ONa 293.0754；测量值：293.0759.
Figure BDA0002817260390000241
2,2-difluoro-1,3-diphenylpent-4-yn-1-one(41):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(40/1,v/v)得到化合物41(yellow liquid, 157.6mg,91％收率).1HNMR(400MHz,CDCl3)δ8.15–7.95(m,2H),7.61 (dd,J＝15.0,7.4Hz,3H),7.47(t,J＝7.7Hz,2H),7.40(ddd,J＝6.4,5.7,2.9 Hz,5H),7.34–7.26(m,3H),4.92(ddd,J＝18.2,10.4,4.2Hz,1H)；19F NMR (376MHz,CDCl3)δ–100.50(dd,J＝267.7,11.7Hz,1F),–105.72(dd,J＝267.8,20.0Hz,1F)；13C NMR(100MHz,CDCl3)δ189.6(dd,J＝30.2,28.6 Hz),134.2,133.1,132.9(t,J＝1.7Hz),132.4(d,J＝1.9Hz),131.7,130.1, 130.0(dd,J＝3.9,3.2Hz),122.4,116.9(dd,J＝263.3,259.9Hz),86.2,83.4 (dd,J＝9.4,2.2Hz),43.6(dd,J＝27.4,23.1Hz)；HRMS(ESI)m/z:[M+ Na]+计算值C23H16F2ONa 369.1067；测量值：369.1060.
Figure BDA0002817260390000242
2,2-difluoro-1-phenyl-3-(4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)propan-1-one(42):The crudeproducts were purified by column chromatography with dichloromethane/methanol(10/1to 5/1,v/v)得到化合物42(白色固体, 137.9mg,65％收率).M.p.:87–88℃；1H NMR(400MHz,DMSO-d6)δ8.00 (d,J＝7.7Hz,2H),7.75(t,J＝7.4Hz,1H),7.60(t,J＝7.8Hz,2H),7.19(d,J ＝8.4Hz,2H),6.99(d,J＝8.6Hz,2H),5.33(d,J＝4.8Hz,1H),5.11(d,J＝4.5Hz,1H),5.04(d,J＝5.2Hz,1H),4.85(d,J＝7.3Hz,1H),4.59(t,J＝5.7 Hz,1H),3.75–3.66(m,1H),3.51(ddd,J＝24.5,18.0,12.3Hz,3H),3.37– 3.14(m,4H)；19F NMR(376MHz,DMSO-d6)δ–98.31(t,J＝20.4Hz,2F)；13C NMR(100MHz,DMSO-d6)δ189.7(t,J＝29.9Hz),157.3,135.2,132.1, 131.9,130.0,129.5,129.0,124.5(t,J＝3.1Hz),118.8(t,J＝252.8Hz),116.4, 100.7,77.4,77.0,73.6,70.1,65.4,63.1,61.0；HRMS(ESI)m/z:[M+Na]+计算值C21H22F2O7Na 447.1231；测量值：447.1237.
Figure BDA0002817260390000251
isopropyl 2-(4-(1-(4-chlorophenyl)-2,2-difluoro-3-oxo-3-phenylpropyl)phenoxy)-2-
methylpropanoate(43):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(20/1,v/v)得到化合物43(colourless liquid,150.3mg,60％收率).1H NMR(400MHz,CDCl3)δ7.89(d,J＝7.9Hz,2H),7.59(t,J＝7.4Hz, 1H),7.43(t,J＝7.8Hz,2H),7.34–7.23(m,4H),7.19(d,J＝8.4Hz,2H), 6.75(d,J＝8.7Hz,2H),5.04(dt,J＝12.5,6.3Hz,1H),4.93(t,J＝17.8Hz, 1H),1.56(s,6H),1.16(d,J＝6.3Hz,6H)；19F NMR(376MHz,CDCl3) δ–99.45(dd,J＝281.1,17.0Hz,1F),–101.50(dd,J＝281.6,18.8Hz,1F)；13C NMR(100MHz,CDCl3)δ189.8(t,J＝30.1Hz),173.5,155.1,135.1(d,J＝ 3.9Hz),134.1,133.5,132.8,130.9,130.4,129.7(t,J＝3.3Hz),128.8(d,J＝ 4.6Hz),128.7,128.6,118.7,118.6(t,J＝265.5Hz),79.1,68.9,53.5(t,J＝ 21.7Hz),25.4,21.5；HRMS(ESI)m/z:[M+Na]+计算值C28H27ClF2O4Na523.1464；测量值：523.1456.
Figure BDA0002817260390000261
3,3-bis(4-chlorophenyl)-2,2-difluoro-1-phenylbutan-1-one(44):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯(50/1,v/v)得到化合物44 (yellow liquid,149.7mg,74％收率).1H NMR(400MHz,DMSO-d6)δ7.69(t, J＝5.9Hz,2H),7.64(d,J＝7.4Hz,1H),7.45(t,J＝7.9Hz,2H),7.39–7.32 (m,4H),7.25(d,J＝8.6Hz,4H),1.96(s,3H)；19FNMR(376MHz,DMSO-d6) δ–97.56(s,2F)；13C NMR(100MHz,DMSO-d6)δ189.4(t,J＝30.9Hz),141.0,134.6,133.3(t,J＝2.1Hz),132.4,130.9,129.7(t,J＝3.6Hz),129.0, 128.4,53.4(t,J＝20.3Hz),24.5；HRMS(ESI)m/z:[M+Na]+计算值 C26H16Cl2F2ONa 427.0444；测量值：427.0453.
Figure BDA0002817260390000262
(E)-3-(benzo[d][1,3]dioxol-5-yl)-2,2-difluoro-6,6-dimethyl-1-phenylhept-4-en-1-one(45):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯 (40/1,v/v)得到化合物45(yellow liquid,182.4mg,98％收率).1H NMR (400MHz,CDCl3)δ7.97(d,J＝7.8Hz,2H),7.61(t,J＝7.4Hz,1H),7.47(t, J＝7.8Hz,2H),6.85(s,1H),6.75(s,2H),5.94(d,J＝1.2Hz,2H),5.70– 5.42(m,2H),4.31–3.80(m,1H),0.93(s,9H)；19F NMR(376MHz,CDCl3) δ–102.41(dd,J＝264.8,12.7Hz,1F),–106.41(dd,J＝264.8,18.8Hz,1F)；13C NMR(100MHz,CDCl3)δ190.3(t,J＝29.1Hz),147.8,147.7,147.1, 133.9,133.3,129.8(t,J＝3.6Hz),129.4(d,J＝3.3Hz),128.6,123.0,118.8(t, J＝258.4Hz),118.5(dd,J＝5.8,2.3Hz),109.7,108.2,101.1,53.0(t,J＝21.9 Hz),333,29.1；HRMS(ESI)m/z:[M+Na]+计算值C22H22F2O3Na 395.1435；测量值：395.1442.
Figure BDA0002817260390000271
2,2-difluoro-2-((5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-1- phenylethanone(46):粗产物用柱层析纯化，淋洗剂为石油醚/乙酸乙酯 (40/1,v/v)得到化合物46(yellow liquid,95.8mg,66％收率,dr＝2:1 determined by 19F NMR).1H NMR(400MHz,CDCl3)δ8.09(d,J＝7.8Hz, 2H),7.63(t,J＝7.4Hz,1H),7.50(t,J＝7.8Hz,2H),5.72(dd,J＝28.3,2.8 Hz,1H),4.68(dd,J＝15.1,9.7Hz,2H),3.38–2.99(m,1H),2.49–2.03(m, 2H),2.03–1.87(m,1H),1.87–1.79(m,3H),1.76(s,1H),1.67(d,J＝14.8 Hz,3H),1.59–1.51(m,1H)；19F NMR(376MHz,CDCl3)δ–94.73(dd,J＝ 268.6,15.4Hz,2F),–99.28––107.39(m,2F)；13C NMR(100MHz,CDCl3) δ190.4(t,J＝29.9Hz),189.6(t,J＝32.9Hz),148.8(d,J＝9.2Hz),134.1(d, J＝4.5Hz),132.9(d,J＝2.2Hz),132.8(dd,J＝2.6,1.0Hz),130.0(dd,J＝ 7.1,3.8Hz),129.2(dd,J＝2.9,1.8Hz),128.7(d,J＝3.2Hz),128.1,127.8(d, J＝2.4Hz),127.4,120.7(dd,J＝259.1,256.0Hz),120.2(t,J＝257.2Hz), 109.3,109.0,44.6(dd,J＝21.8,20.7Hz),43.0(dd,J＝22.1,20.0Hz),40.7,35.7(d,J＝2.1Hz),30.7,30.3,28.6(t,J＝4.9Hz),27.8(dd,J＝5.2,2.1Hz), 24.1(d,J＝3.9Hz),23.1(dd,J＝3.6,0.9Hz),20.6,20.5；HRMS(ESI) m/z:[M+Na]+计算值C18H20F2ONa313.1380；测量值：313.1386.

Claims (8)

1.一种合成α,α-二氟酮类化合物的方法，其特征在于，包括：
在催化剂的作用下，醇类化合物与二氟烯醇硅醚类化合物在有机溶剂中进行反应，反应结束后经过后处理得到所述的α,α-二氟酮类化合物；
反应式如下：
Figure DEST_PATH_IMAGE002
其中，R1、R2独立地选自氢、C1~C4烷基、取代或者未取代的芳基、取代或者未取代的乙烯基或者炔基，该芳基上的取代基选自卤素、羟基、C1~C4烷氧基，所述乙烯基上的取代基为苯基或者萘基；
R3为氢；
R4选自取代或者未取代的芳基，该芳基上的取代基选自卤素、C1~C4烷氧基；
所述的催化剂为氟代醇。
2.根据权利要求1所述的合成α,α-二氟酮类化合物的方法，其特征在于，R1、R2独立地选自氢、甲基、取代或者未取代的苯基、苯乙烯基或者乙炔基，该苯基上的取代基选自氟、氯、甲氧基；
R3为氢；
R4选自取代或者未取代的苯基，该苯基上的取代基选自氟、氯、甲氧基。
3.根据权利要求1所述的合成α,α-二氟酮类化合物的方法，其特征在于，所述的氟代醇选自六氟异丙醇、三氟乙醇、六氟-2-甲基异丙醇、六氟-2-苯基异丙醇或四氟丁二醇。
4.根据权利要求1所述的合成α,α-二氟酮类化合物的方法，其特征在于，所述的有机溶剂为二氯甲烷、三氯甲烷、四氯甲烷、乙腈或甲苯。
5.根据权利要求1所述的合成α,α-二氟酮类化合物的方法，其特征在于，反应温度为室温，反应时间为2~12 h。
6.根据权利要求1所述的合成α,α-二氟酮类化合物的方法，其特征在于，醇类化合物、二氟烯醇硅醚类化合物和催化剂的摩尔比为1.0:0.05~0.15:1.0~1.1。
7.根据权利要求1所述的合成α,α-二氟酮类化合物的方法，其特征在于，所述的后处理包括：反应结束后，减压除去溶剂，浓缩物经柱层析分离纯化得到α,α-二氟酮类化合物。
8.根据权利要求1所述的合成α,α-二氟酮类化合物的方法，其特征在于，所述的α,α-二氟酮类化合物的为以下具体化合物：
Figure DEST_PATH_IMAGE004
。
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