CN117447441A - 一种二氟甲基试剂及其制备方法和应用 - Google Patents
一种二氟甲基试剂及其制备方法和应用 Download PDFInfo
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- CN117447441A CN117447441A CN202311390875.2A CN202311390875A CN117447441A CN 117447441 A CN117447441 A CN 117447441A CN 202311390875 A CN202311390875 A CN 202311390875A CN 117447441 A CN117447441 A CN 117447441A
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- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 91
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical group 0.000 claims abstract description 3
- -1 sodium tetrafluoroborate Chemical compound 0.000 claims description 77
- 238000006243 chemical reaction Methods 0.000 claims description 65
- MWQBVQXZJXZJHN-UHFFFAOYSA-N difluoromethylsulfinyl(difluoro)methane Chemical compound FC(F)S(=O)C(F)F MWQBVQXZJXZJHN-UHFFFAOYSA-N 0.000 claims description 27
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 20
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 238000005349 anion exchange Methods 0.000 claims description 9
- 150000001336 alkenes Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- WRAQQYDMVSCOTE-UHFFFAOYSA-N phenyl prop-2-enoate Chemical compound C=CC(=O)OC1=CC=CC=C1 WRAQQYDMVSCOTE-UHFFFAOYSA-N 0.000 claims description 6
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- HGVOJSYCQGSZLB-UHFFFAOYSA-N 3,5-diethyl-2,6-dimethyl-1,4-dihydropyridine Chemical compound CCC1=C(C)NC(C)=C(CC)C1 HGVOJSYCQGSZLB-UHFFFAOYSA-N 0.000 claims description 5
- ONQBUHWENXKHHP-UHFFFAOYSA-N 2-phenyl-3,4-dihydro-1h-isoquinoline Chemical compound C1CC2=CC=CC=C2CN1C1=CC=CC=C1 ONQBUHWENXKHHP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
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- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 6
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- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 5
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- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- PYVZXJWQADAHLT-UHFFFAOYSA-N [bromo(difluoro)methyl] diethyl phosphate Chemical compound P(=O)(OC(F)(F)Br)(OCC)OCC PYVZXJWQADAHLT-UHFFFAOYSA-N 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
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- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
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- 239000000575 pesticide Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
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- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
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- 229910052760 oxygen Inorganic materials 0.000 description 2
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- 239000002994 raw material Substances 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- GVIJJXMXTUZIOD-UHFFFAOYSA-N thianthrene Chemical group C1=CC=C2SC3=CC=CC=C3SC2=C1 GVIJJXMXTUZIOD-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OVVURKRTLZQGJM-UHFFFAOYSA-N 1-iodo-2-[2-(trifluoromethylsulfanyloxy)propan-2-yl]benzene Chemical compound CC(C)(OSC(F)(F)F)c1ccccc1I OVVURKRTLZQGJM-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- KHNBLWUKKFEWGC-UHFFFAOYSA-N BrC1=C(C=CC=C1)S(=O)C(F)F Chemical compound BrC1=C(C=CC=C1)S(=O)C(F)F KHNBLWUKKFEWGC-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229910020808 NaBF Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- PHMXCRFNZWZIIP-UHFFFAOYSA-N dibenzothiophene sulfane Chemical class S.C1=CC=C2C3=CC=CC=C3SC2=C1 PHMXCRFNZWZIIP-UHFFFAOYSA-N 0.000 description 1
- KLJYQOSMCTZTGU-UHFFFAOYSA-N difluoromethanethiol Chemical class FC(F)S KLJYQOSMCTZTGU-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
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- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YSSXSOYCVGPPIL-UHFFFAOYSA-N n-(difluoromethyl-oxo-phenyl-$l^{6}-sulfanylidene)benzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(C(F)F)=NS(=O)(=O)C1=CC=CC=C1 YSSXSOYCVGPPIL-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000005555 sulfoximide group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229950005792 tenoate Drugs 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/06—Six-membered rings
- C07D327/08—[b,e]-condensed with two six-membered carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种二氟甲基试剂及其制备方法和应用,涉及二氟甲基试剂的设计发明和化合物制备技术领域。所述的二氟甲基试剂具有以下结构通式:其中,X为BF4,OTf或PF6;R为烷氧基、卤素、NO2、CN或CF3。该试剂为一类骨架新颖、可稳定保存的应用广谱的二氟甲基试剂,使用操作便利,可高效的进行各种二氟甲基转化反应。
Description
技术领域
本发明涉及二氟甲基试剂的设计发明和化合物制备技术领域,尤其涉及一种二氟甲基试剂及其制备方法和应用。
背景技术
有机小分子引入氟原子后往往表现出独特的物理、化学与生物特性,因此含氟功能分子在医药、农药、材料等领域中得到了广泛应用,尤其是在药物发展中起着重要作用。含氟药物已经成为现在新药研究中的一个热点领域,目前,生物活性分子和先导化合物的氟修饰改造已然成为了新药设计与研制的常规策略。
二氟烷基是一个重要的结构基元,常见于医药、农药和功能材料中,尤其是在药物的设计和发现中占有重要地位,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;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。因此,发展性能稳定、实用高效的二氟甲基试剂及其相应绿色高效的二氟甲基反应,可以向生物活性分子和药物分子中选择性地引入二氟甲基砌块,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或候选药物分子,进而加快新药研制。因此,二氟甲基试剂的研制及其二氟甲基新反应新方法新策略的发展,在过去20年一直是有机氟化学和药物化学中的一个重要研究方向和热点领域之一。
向有机分子、尤其是在药物分子的全合成后期阶段选择性的直接引入二氟甲基的一种最重要策略和途径,使用亲电二氟甲基试剂可以经由亲电、二氟卡宾以及二氟甲基自由基三种方式实现目标分子的合成,在有机氟化学和药物设计与创制研究中具有非常重要的作用和地位。然而,由于亲电二氟甲基试剂天然的缺陷,亲电型二氟甲基试剂的发展及其应用研究较为落后,报道的试剂寥寥无几。这主要由于试剂+CF2H中的质子酸性强,+CF2H中心的高电正性,以及试剂相对较硬的性质,致使这些试剂往往对光、热、碱等较敏感,试剂稳定性差,或合成复杂困难,或反应活性和效率低下,因此适用的反应类型少,应用局限性大。目前,仅有少数几个试剂报道,包括硫鎓盐型(Prakash试剂Org.Lett.2007,9,1863【1】和Liu试剂Org.Lett.2018,20,6925【2】),亚砜亚胺型(Hu试剂,Org.Lett.2009,11,2109【3】),[7]硫叶立德型(Shen试剂,Angew.Chem.I nt.Ed.2016,55,9050【4】)。但这些试剂也都存在稳定性差,反应活性低或应用范围受限都等问题。综上所述,目前在研制的几个亲电二氟甲基试剂均存在诸如不稳定,合成复杂,或反应活性和效率低,或反应类型受限,或应用范围窄,原子经济低等问题。因此,合成便利、稳定高效、普适性高、应用范围广泛的多用途通用亲电二氟甲基试剂的研制是一个迫切需要解决的重要课题。
发明内容
为解决上述技术问题,本发明的目的是通过以下技术方案实现的。
本发明的二氟甲基试剂,具有以下结构式:
其中,X为BF4,OTf,PF6等,R为烷氧基,卤素,NO2,CN或CF3等。
上述二氟甲基试剂的制备方法:采用1-((二氟甲基)亚砜基)-2-苯氧基苯或其类似物在三氟甲磺酸酐作用下进行环化,再与相应的阴离子交换得到二氟甲基试剂。
进一步的,所述的二氟甲基试剂为式1a或式1b的化合物:
优选的,采用1-((二氟甲基)亚砜基)-2-苯氧基苯,在三氟甲磺酸酐作用下进行环化,再与四氟硼酸盐溶液进行阴离子交换得到式1a的亲电的二氟甲基试剂S-(二氟甲基)吩噁噻四氟硼酸盐。具体的,将1-((二氟甲基)亚砜基)-2-苯氧基苯(1.0当量),加入乙醚,在0℃情况下,逐滴加入三氟甲磺酸酐(1当量),反应完全后除去乙醚,加入二氯甲烷溶解反应物,再用四氟硼酸钠(1M)进行负离子交换,最后减压蒸馏二氯甲烷相至粘稠,在-10℃情况下逐滴加入乙醚,重结晶得到产物S-(二氟甲基)吩噁噻四氟硼酸盐。
进一步的,所述的1-((二氟甲基)亚砜基)-2-苯氧基苯由1-((二氟甲基)亚砜基)-2-溴苯与苯酚偶联合成。具体的,将1-((二氟甲基)亚砜基)-2-溴苯(1.0当量),加入苯酚(2.0当量),碘化亚铜(1.0当量)和正丁基咪唑(1.0当量),放入手套箱中,加入甲苯,密闭,取出,在150℃下反应,完成反应后,用二氯甲烷萃取反应液,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-((二氟甲基)亚砜基)-2-苯氧基苯。
优选的,采用1-(2-((二氟甲基)亚砜基)苯氧基)-3,5-二甲氧基苯,在三氟甲磺酸酐作用下进行环化,再与四氟硼酸盐溶液进行阴离子交换得到式1b的亲电的二氟甲基试剂10-(二氟甲基)-1,3-二甲氧基-10H-吩恶烷-10-四氟硼酸硫鎓盐。具体的,将1-(2-((二氟甲基)亚砜基)苯氧基)-3,5-二甲氧基苯(1.0当量),加入乙醚,在0℃情况下,逐滴加入三氟甲磺酸酐(1当量),反应完全后除去乙醚,加入二氯甲烷溶解反应物,再用四氟硼酸钠(1M)进行负离子交换,最后减压蒸馏二氯甲烷相至粘稠,在-10℃情况下逐滴加入乙醚,重结晶得到产物S-(二氟甲基)吩噁噻四氟硼酸盐。
进一步的,所述的1-(2-((二氟甲基)亚砜基)苯氧基)-3,5-二甲氧基苯由1-((二氟甲基)亚砜基)-2-溴苯与2,4-二甲氧基苯酚偶联合成。具体的,将1-((二氟甲基)亚砜基)-2-溴苯(1.0当量),加入2,4-二甲氧基苯酚(2.0当量),碘化亚铜(1.0当量)和正丁基咪唑(1.0当量),放入手套箱中,加入甲苯,密闭,取出,在150℃下反应,完成反应后,用二氯甲烷萃取反应液,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-(2-((二氟甲基)亚砜基)苯氧基)-3,5-二甲氧基苯。
优选的,所述的1-((二氟甲基)亚砜基)-2-溴苯由2-溴-二氟甲基苯硫醚与间氯过氧苯甲酸反应合成。具体的,将2-溴-二氟甲基苯硫醚(1.0当量),加入二氯甲烷,在零度条件下,缓慢加入间氯过氧苯甲酸(1.0当量),反应过夜,完成反应后,用饱和碳酸钠水溶液与反应液萃取,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-((二氟甲基)亚砜基)-2-溴苯。
优选的,其特征在于,2-溴-二氟甲基苯硫醚由2-溴苯硫酚与溴二氟甲基磷酸二乙酯反应合成。具体的,将2-溴苯硫酚(1.0当量),再加入纯净水和乙腈,加入搅拌子后,在零度情况下加入氢氧化钠(3.0当量),再逐滴加入溴二氟甲基磷酸二乙酯(2.0当量),反应过夜,完成反应后,用石油醚与反应液萃取,收集石油醚,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到2-溴-二氟甲基苯硫醚。
需要指出的是,相比较与以前的试剂,本发明设计的该试剂的原子经济性可藉由精细化学品吩噁噻的再利用获得很高的提升。吩噁噻广泛应用于医药工业和材料科学等领域;而且,它们可以作为重要的原料直接用于烷基、芳基自由基试剂等试剂的合成。
一种上述二氟甲基试剂的应用,用于烯烃的氢/二氟甲基双官能化反应,合成具有以下式3结构的化合物:
其中,R1为H;R2为H,烷基或芳基等;EWG为酯,酮,砜或其他吸电子基团。
具体的,以2,6-二甲基-3,5-二乙酯基-1,4-二氢吡啶为供氢体,采用丙烯酸苯酯或非活化烯烃类与所述二氟甲基试剂合成式3结构的化合物。
进一步的,上述二氟甲基试剂的应用可合成以下化合物:
本发明另一种上述二氟甲基试剂的应用,用于四氢异喹啉C(sp3)-H的二氟甲基官能化反应,合成具有以下式5结构的化合物:
其中,R1为H,吸电子或给电子取代基;R2为H,吸电子或给电子取代基。
具体的,采用2-苯基-1,2,3,4-四氢异喹啉或其衍生物类与所述二氟甲基试剂合成具有式5结构的化合物。
进一步的,上述二氟甲基试剂的应用可合成以下化合物:
本发明设计和制备了一种应用广谱的稳定亲电二氟甲基试剂,即“(二氟甲基)吩噁噻锍盐”,该试剂合成简便,原料易得,可大量合成;试剂新能稳定,为可稳定保存的固体,使用方便;试剂具有高效和多样的反应活性,可经二氟甲基自由基(·CF2H),二氟甲基正离子(+CF2H)和二氟卡宾(:CF2)三种途径进行各种二氟甲基转化反应。
该试剂为一类骨架新颖、可稳定保存的应用广谱的二氟甲基试剂,使用操作便利,可高效的进行各种二氟甲基转化反应。为向有机分子,生物活性分子及药物中便利的引入二氟甲基砌块提供一种功能强大二氟甲基试剂平台。在医药,农药和功能材料等领域具有广泛的应用前景。
附图说明
为了更清楚地说明本发明实施例技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明介绍的亲电二氟甲基试剂的设计。
图2为本发明亲电二氟甲基试剂1a的合成反应式。
图3为本发明亲电二氟甲基试剂1a的合成路线。
图4为本发明亲电二氟甲基试剂1b的合成路线。
具体实施方式
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
应当理解,当在本说明书和所附权利要求书中使用时,术语“包括”和“包含”指示所描述特征、整体、步骤、操作、元素和/或组件的存在,但并不排除一个或多个其它特征、整体、步骤、操作、元素、组件和/或其集合的存在或添加。
一、试剂的设计
针对亲电二氟甲基试剂热力学稳定性不足的天然缺陷,在分析以往失败经验的基础上,从试剂热力学稳定的维度考量,在分子水平上进行试剂设计,研制热力学稳定的亲电二氟甲基试剂。如图1A所示,早在2007年,国际著名有机氟化学家Prakash教授小组试图合成二苯并噻吩硫鎓盐型二氟甲基试剂,但高度不稳定,原位即分解成二苯并噻吩和三氟甲磺酸酯,无法获得预想的二氟甲基试剂,仅在-80℃下检测到少量硫鎓盐的19F NMR信号。基于此失败方案,我们分析研究可能由于二苯并五元噻吩环三个共平面环相对较高的环张力使S-CF2H键具有较低的解离焓,热力学上极度不稳定,导致试剂快速分解。因此,我们设想通过扩环至六元环,使用吩噁噻或者噻蒽骨架,如图1B所示。由此,一、吩噁噻或者噻蒽的六元杂环环张力相对较小,热力学上相对稳定;二、芳环上的富裕的π电子可以通过p-π,d-π作用分散锍盐的正电荷,最大程度上起到稳定试剂的效应;三、对位上的氧或硫原子上富裕的外层电子可与锍盐中心的缺电子S相互作用,进一步使锍盐的正电荷离域而降低分子的能量,从而提高试剂的热力学稳定性(根据X-ray单晶衍射测定的结果,O与S两者之间的距离为小于O和S的泛德华半径之和/>证实两个原子之间作用力的存在)。
二、试剂的合成
如图2所示的亲电二氟甲基试剂的合成反应式,我们从由邻溴苯二氟甲基亚砜与苯酚偶联合成邻苯氧基苯基二氟甲基亚砜,其在三氟甲磺酸酐(Tf2O)作用下进行环化成S-(二氟甲基)吩噁噻三氟甲磺酸盐,与四氟硼酸钠溶液(NaBF4)进行阴离子交换得到目标的亲电二氟甲基试剂S-(二氟甲基)吩噁噻四氟硼酸盐。所得试剂为稳定的结晶性粉末,其结构经X-ray单晶衍射研究得到确证。
本发明的亲电二氟甲基试剂S-(二氟甲基)吩噁噻四氟硼酸盐的具体合成路线如图3所示。具体实施过程如下。
第一步:取一干燥的500mL圆底烧瓶,加入2-溴苯硫酚(5.7克,30.0毫摩尔,1.0当量),再加入100mL纯净水和100mL乙腈,加入适当大小搅拌子后,在零度情况下加入氢氧化钠(3.6克,90.0毫摩尔,3.0当量),10分钟后,再逐滴加入溴二氟甲基磷酸二乙酯(16.0克,60.0毫摩尔,2.0当量),反应过夜,完成反应后,用100mL石油醚与反应液萃取两次,收集石油醚,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到2-溴-二氟甲基苯硫醚。
产物的谱图数据表征:
按照上述方法,制备得到下式化合物:
2-溴-二氟甲基苯硫醚(2-bromophenyl)(difluoromethyl)sulfane
白色液体;Rf=0.8(石油醚);6.57克,92%的分离收率;1H-NMR(CDCl3):6.87(t,1H,JH-F=57.50Hz),7.20-7.26(m,1H),7.28-7.34(m,1H),7.60-7.68(m,2H).13C-NMR(CDCl3):120.6(t,J=277Hz),128.50,128.52,129.3,131.2,134.0,136.619F-NMR(CDCl3):-92.65(d,J=57.50Hz).
第二步:取一干燥的250mL圆底烧瓶,加入2-溴-二氟甲基苯硫醚(7.17克,30.0毫摩尔,1.0当量),再加入100mL二氯甲烷,在零度条件下,缓慢加入间氯过氧苯甲酸(5.2克,30.0毫摩尔,1.0当量),反应过夜,完成反应后,用100mL的饱和碳酸钠水溶液与反应液萃取两次,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-((二氟甲基)亚砜基)-2-溴苯。
按照上述方法,制备得到下式化合物:
1-((二氟甲基)亚砜基)-2-溴苯
1-((difluoromethyl)sulfinyl)-2-phenoxybenzen
白色固体;Rf=0.4(石油醚:乙酸乙酯=10:1);6.71克,88%的分离收率;1H NMR(400MHz,CDCl3)NMR(400MHz,=7.9,1.6Hz,1H),7.72-7.62(m,2H),7.52(dd,J=7.6,1.6Hz,1H),6.36(s,1H).19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl9,1.6
第三步:取一干燥的100mL反应瓶,加入1-((二氟甲基)亚砜基)-2-溴苯(7.6克,30.0毫摩尔,1.0当量),再加入苯酚(5.6克,60.0毫摩尔,2.0当量),碘化亚铜(5.7克,30.0毫摩尔,1.0当量)和正丁基咪唑(3.7克,30.0毫摩尔,1.0当量),放入手套箱中,加入30毫升甲苯,密闭,取出,在150℃下反应12小时,完成反应后,用二氯甲烷50mL萃取反应液两次,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-((二氟甲基)亚砜基)-2-苯氧基苯。
按照上述方法,制备得到下式化合物:
1-((二氟甲基)亚砜基)-2-苯氧基苯
1-((difluoromethyl)sulfinyl)-2-phenoxybenzen
淡黄色液体;Rf=0.3(石油醚:乙酸乙酯=10:1);6.67克,83%的分离收率;1HNMR(500MHz,CDCl3)NMR(500MHz,CDCl乙酸乙酯=10:1);6.67克,83%的分离收率;毫摩尔,2.0当量),碘化亚铜(5.7克,30.0毫摩尔,1.0当量)和正丁基咪唑(3.7克,30.0毫摩尔,1.0当量),放入手套箱中,加入30毫升甲苯,密闭,取出,在150℃下反应12小时,完成反应后,用二氯甲烷50mL萃取反应液两次,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-((t.z,1H).13C NMR(151MHz,CDCl3)NMR(151MHz,CDCl乙酸乙酯=10:1);6.67克,83%的分离收率;毫摩尔,2.0当量),碘化亚铜(5.7克,30.0毫摩尔,1.0当量)和正丁基咪唑(3.7克,30.0毫摩尔,1.0当量),放19F NMR(471MHz,CDCl3)NMR(471MHz,CDCl乙酸乙酯=10:1);6.67克,83%的分离收率;毫摩尔,2.0当量),碘化亚铜(5.7克,30.0毫摩尔,1.0当量)和正丁基咪唑(3.7克,3269.0403,found 269.0440.
第四步:取一干燥的250mL圆底反应瓶,加入1-((二氟甲基)亚砜基)-2-苯氧基苯(24.1克,90.0毫摩尔,1.0当量),再加入90mL乙醚,在0℃情况下,逐滴加入三氟甲磺酸酐(25.6克,90.0毫摩尔,1当量),15分钟后,通过薄层色谱硅胶确认反应完全,反应完全后除去乙醚,加入100mL二氯甲烷溶解反应物,再用100mL四氟硼酸钠(1M)进行负离子交换4次,最后减压蒸馏二氯甲烷相至粘稠,在-10℃情况下逐滴加入乙醚,重结晶得到产物S-(二氟甲基)吩噁噻四氟硼酸盐。
按照上述方法,制备得到下式化合物:
S-(二氟甲基)吩噁噻四氟硼酸盐
Difluoromethyl Phenoxathiinium Tetrafluoroborate
浅棕色固体;25.25克,84%的重结晶收率;1H NMR(500MHz,CDCl3)NMR(500MHz,CDClxathiinium Tetrafluoroborate乙醚,加入100mL二氯甲烷溶解反应物,再用100mL四氟硼6(m,4H),7.56-7.34(t,1H).19F NMR(471MHz,CDCl3)NMR(471MHz,CDClxathiiniumTetrafluoroborate乙醚,加入10013C NMR(101MHz,CDCl3)NMR(101MHz,CDClxathiiniumTetrafluoroborate乙醚,加入100mL二氯甲烷溶解反应物,再用100mL四氟硼6(m,4H),7.56-7.34(t,1H).手套箱中,加入30毫升甲OS+251.0337,found 251.0335.Meltingpoint:97-99℃.
本发明的亲电二氟甲基试剂10-(二氟甲基)-1,3-二甲氧基-10H-吩恶烷-10-四氟硼酸硫鎓盐的具体合成路线如图4所示。具体实施过程如下。
第一步:取一干燥的100mL反应瓶,加入1-((二氟甲基)亚砜基)-2-溴苯(7.6克,30.0毫摩尔,1.0当量),再加入2,4-二甲氧基苯酚(5.6克,60.0毫摩尔,2.0当量),碘化亚铜(5.7克,30.0毫摩尔,1.0当量)和正丁基咪唑(3.7克,30.0毫摩尔,1.0当量),放入手套箱中,加入30毫升甲苯,密闭,取出,在150℃下反应12小时,完成反应后,用二氯甲烷50mL萃取反应液两次,收集二氯甲烷相,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-(2-((二氟甲基)亚砜基)苯氧基)-3,5-二甲氧基苯。
按照上述方法,制备得到下式化合物:
1-(2-((二氟甲基)亚砜基)苯氧基)-3,5-二甲氧基苯
1-(2-((difluoromethyl)sulfinyl)phenoxy)-3,5-dimethoxybenzene
淡黄色液体;Rf=0.3(石油醚:乙酸乙酯=10:1);6.67克,73%的分离收率;1HNMR(400MHz,CDCl3)NMR(400MHzJ=7.8,1.7Hz,1H),7.48(ddd,J=8.6,7.5,1.7Hz,1H),7.32(td,J=7.6,1.0Hz,1H),6.95(dd,J=8.3,1.0Hz,1H),6.40(t,J=55.1,0.9Hz,1H),6.31(t,J=2.3Hz,1H),6.20(d,J=2.3Hz,2H),3.74(s,6H).19F NMR(377MHz,CDCl3)NMR(377--135.97(m).13C NMR(101MHz,CDCl3)δ161.88,161.43,156.65,155.49,154.53,133.79,126.75,124.28,123.15(t,J=295.1Hz),117.38,110.70,98.19,96.61,55.56,55.41.HRMS(ESI):m/z[M+H]+calcd for C15H15F2O4S+329.0659,found 329.0452.
第二步:取一干燥的250mL圆底反应瓶,加入1-(2-((二氟甲基)亚砜基)苯氧基)-3,5-二甲氧基苯(24.1克,90.0毫摩尔,1.0当量),再加入90mL乙醚,在0℃情况下,逐滴加入三氟甲磺酸酐(25.6克,90.0毫摩尔,1当量),15分钟后,通过薄层色谱硅胶确认反应完全,反应完全后除去乙醚,加入100mL二氯甲烷溶解反应物,再用100mL四氟硼酸钠(1M)进行负离子交换4次,最后减压蒸馏二氯甲烷相至粘稠,在-10℃情况下逐滴加入乙醚,重结晶得到产物10-(二氟甲基)-1,3-二甲氧基-10H-吩恶烷-10-四氟硼酸硫鎓盐。
按照上述方法,制备得到下式化合物:
10-(二氟甲基)-1,3-二甲氧基-10H-吩恶烷-10-四氟硼酸硫鎓盐
10-(difluoromethyl)-1,3-dimethoxy-10H-phenoxathiin-10-iumTetrafluoroborate
淡黄色固体;27.15克,76%的重结晶收率;1H NMR(500MHz,CDCl3)NMR(500M,J=8.1,1.5Hz,1H),7.88(ddd,J=8.7,7.4,1.6Hz,1H),7.58(ddd,J=8.4,7.5,1.2Hz,1H),7.54(d,J=1.2Hz,1H),7.42(t,J=54.5,4.0Hz,1H),6.66(d,J=2.2Hz,1H),6.56(d,J=2.2Hz,1H),4.09(s,3H),3.99(s,3H).19F NMR(377MHz,CDCl3)NMR(377MHz,CDClHz,1H),6.56(d,J=2.2Hz,13C NMR(101MHz,CDCl3)δ168.35,160.87,154.99,152.23,139.15,137.64,133.59,127.34,119.89,114.29(t,J=297.8Hz),97.06,96.45,57.74,56.64.HRMS(ESI):m/z[M-BF4]+calcd for C15H13F2O3S+311.0548,found 311.0362.Meltingpoint:95-100℃.
三、试剂的应用
(1)烯烃的氢/二氟甲基双官能化
实施过程:
反应条件和参数优化过程:以丙烯酸苯酯为模板底物,试剂1为二氟甲基试剂,2,6-二甲基-3,5-二乙酯基-1,4-二氢吡啶为供氢体,反应用2,6-二甲基-3,5-二乙酯基-1,4-二氢吡啶用量为模板底物的1.5当量、2.0当量、2.5当量,优选2.5当量;反应用二氟甲基试剂用量1当量、1.5当量、2.0当量,优选2.0当量二氟甲基试剂,反应使用溶剂MeCN、EA、DCM、THF,优选反应使用溶剂为MeCN;反应时间4小时、8小时、12小时,优选反应时间12小时;所用的光照波长为350nm至550nm之间,优选波长为450nm的蓝光;反应温度为-30℃至80℃,优选0℃至50℃,优选为室温条件。反应完成后(TLC监控),停止光照和搅拌,减压蒸馏除去溶剂,粗品用硅胶柱层析纯化,得纯品氢/二氟甲基化的丙烯酸苯酯(3a)。
取一干燥的10mL Sch lenk管,加入底物X(例如,丙烯酸苯酯或活化缺电子烯烃类,0.2毫摩尔,1.0当量)、二氟甲基试剂1(137.6毫克,0.4毫摩尔,2.0当量)、2,6-二甲基-3,5-二乙酯基-1,4-二氢吡啶(142.1毫克,0.5毫摩尔,2.5当量),反应管放置于手套箱中,随后加入2毫升乙腈作溶剂,封闭取出,反应液在12瓦LED蓝光照射下搅拌反应12小时,反应完成后,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到氢/二氟甲基化的丙烯酸苯酯3a。
烯烃的氢/二氟甲基双官能化最优条件实施过程:
其中,R1为H;R2为H,烷基,芳基等;EWG为酯,酮,砜或其他吸电子基团。
参照以上最优条件实施过程,获得以下烯烃的氢/二氟甲基双官能化产物:
产物的谱图数据表征如下。
按照前述通式方法,制备得到下式化合物:
4,4-二氟丁酸苯酯
Phenyl 4,4-difluorobutanoate
白色液体;Rf=0.3(石油醚/乙酸乙酯=20:1);43.5毫克,88%的分离收率;1HNMR(400MHz,CDCl3)NMR(400MHz,CDCl酸乙酯=20:1,7.26-7.21(m,1H),7.09(dq,J=6.9,1.0Hz,2H),6.01(tt,J=56.5,4.1Hz,1H),2.78(t,J=7.4Hz,2H),2.29(ttd,J=17.5,7.4,4.1Hz,2H).
19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl酸乙酯=2
按照前述通式方法,制备得到下式化合物:
4,4-二氟丁酸4-乙基苯酯
4-ethylphenyl 4,4-difluorobutanoate
无色透明液体;Rf=0.3(石油醚/乙酸乙酯=20:1);36.5毫克,80%的分离收率;1H NMR(400MHz,CDCl3)NMR(400MHz,CDCl/乙酸乙酯=20:1);36.57.21(m,1H),7.09(dq,J=6.9,1.0Hz,2H),6.01(tt,J=56.5,4.1Hz,1H),2.78(t,J=7.Hz,2H),2.33-2.21(m,2H),1.23(t,J=7.6Hz,3H).13C NMR(151MHz,CDCl3)NMR(151MHz,CDCl/乙酸乙酯=20:1);36.57.21(m,1H),7.09(dq,J=6.9,1.0Hz,2H),6.01(tt,J=56.5,4.1Hz,1H),2.78(t,J=7.19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl/乙6.5,17.4Hz).
HRMS(ESI):m/z[M+Na]+calcd for C12H14F2O2Na+250.9951,found 251.0856.
按照前述通式方法,制备得到下式化合物:
4-((6-((4,4-二氟丁酰)氧基)己基)氧基)苯甲酸对甲氧基苯酯
4-methoxyphenyl 4-((6-((4,4-difluorobutanoyl)oxy)hexyl)oxy)benzoate
白色固体;Rf=0.3(石油醚/乙酸乙酯=10:1);81.8毫克,87%的分离收率;1HNMR(400MHz,CDCl3)NMR(400MHz,CDCl酸乙酯=10:1);81.8毫克,87%的分离收率;y)hexyl)oxy)benzoate251.0856.,2H),6.01(tt,J=56.5,4.1Hz,1H),2.78(t,J=7.Hz,2H),2.33-2.21(m,2H),1.23(t,J=7.6Hz,3H).for2.17(dddt,J=20.5,13.1,7.4,3.7Hz,2H),1.83(dt,J=8.1,6.5Hz,2H),1.69(p,J=6.8Hz,2H),1.58-1.39(m,4H).13C NMR(151MHz,CDCl3)NMR(151MHz,CDCl酸乙酯=10:1);81.8毫克,87%的分离收率;y)hexyl)oxy)benzoate251.0856.,2H),6.01(tt,J=56.5,4.1Hz 68.05,64.87,55.64,29.74,29.35(t,J=22.3Hz),29.01,28.52,26.84(t,J=6.0Hz),25.71.19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl酸乙酯=10:1);81.8毫克HRMS(ESI):m/z[M+Na]+calcd for C24H28F2O6Na+473.0843,found 473.1751.
按照前述通式方法,制备得到下式化合物:
2-([1,1'-联苯]-2-氧基)4,4-二氟丁酸乙酯
2-([1,1'-biphenyl]-2-yloxy)ethyl 4,4-difluorobutanoate
白色固体;Rf=0.3(石油醚/乙酸乙酯=20:1);58.9毫克,92%的分离收率;1HNMR(400MHz,CDCl3)NMR(400MHz,CDCl酸乙酯=20:1);58.9毫克,92%的分离收率;tenoate.0843,found473.13H),7.09-7.04(m,1H),6.97(d,J=8.1Hz,1H),5.85(tt,J=56.6,4.2Hz,1H),4.37-4.34(m,2H),4.16-4.13(m,2H),2.42(t,J=7.5Hz,2H),2.07(dddd,J=17.4,10.0,7.5,3.7Hz,2H).13C NMR(101MHz,CDCl3)NMR(101MHz,CDCl酸乙酯=20:1);58.9毫131.14,129.57,128.65,127.93,126.97,121.84,118.23-114.26(m),113.29,66.53,63.00,29.23(t,J=22.2Hz),26.67(t,J=6.0Hz).19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl酸乙酯=20:1);58.9毫131.14,129.57,128.65,127.93,126.97,121.84,118.23-11,found 343.1118.
按照前述通式方法,制备得到下式化合物:
4,4-二氟丁酸十四烷基酯
Tetradecyl 4,4-difluorobutanoate
白色固体;Rf=0.3(石油醚/乙酸乙酯=20:1);57.0毫克,89%的分离收率;1HNMR(400MHz,CDCl3)NMR(400MHz,CDCl酸乙酯=20:1);57.0毫克,89%的分离收率;.57,128.65,127.93,126.97,121.84,118.23-11,found 343.1118.66.53,63.00,29.23(t,J=22.2Hz),26.67(t,J=6.0Hz).2H),413C NMR(126MHz,CDCl3)NMR(126MHz,CDCl酸乙酯=20:1);57.0毫克,89%的分离收率;.57,12.69,29.67,29.65,29.64,29.57,29.54,29.51,29.36,29.23,29.19,28.56,26.85(t,J=6.0Hz),25.88,22.69,14.12.19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl酸乙酯=20:1);57.0毫克,89%的分离收率;.57,12.69,29.67,29.65,29.64,29.57,2343.1516,found343.2420.
按照前述通式方法,制备得到下式化合物:
4,4-二氟-2-甲基丁酸苯酯
Phenyl 4,4-difluoro-2-methylbutanoate
无色透明液体;Rf=0.3(石油醚/乙酸乙酯=20:1);23.5毫克,55%的分离收率;1H NMR(400MHz,CDCl3)NMR(400MHz,CDCl/乙酸乙酯=20:1);23.5 89%的分离收率;.57,12.69,29.67,29.65,29.2H),6.00(tt,J=56.5,4.5Hz,1H),2.97(h,J=7.2Hz,1H),2.49-2.36(m,1H),2.10-1.98(m,1H),1.42(d,J=7.2Hz,3H).13C NMR(151MHz,CDCl3)NMR(151MHz,CDCl/乙酸乙酯=20:1);23.5 89%的分离收率;.57,12.69,29.67,29.65,29.2H),6.00(tt,J=56.5(t,J=5.4Hz),17.66.19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl/乙酸乙酯=20:1);23.5 89%的分离收率;.57,12.69,29.67,29.65,29.2H),6.00(tt,J=56.5(t
按照前述通式方法,制备得到下式化合物:
2-(二氟甲基)丁二酸二乙酯
Diethyl 2-(difluoromethyl)succinate
无色透明液体;Rf=0.3(石油醚/乙酸乙酯=10:1);25.5毫克,57%的分离收率;1H NMR(400MHz,CDCl3)NMR(400MHz,CDCl/乙酸乙酯=10:1);25.5 89%的分离收率;.57,12.69,29.67,29.65,29.2H),6.00(tt,J=56.5(t,J=5.4Hz),17.66.J=7.2Hz,1H),2.49-2.36(m,1H),2.10-1.98(m,1H),1.44.4Hz,1H),1.28(q,J=7.3Hz,6H).13C NMR(151MHz,CDCl3)NMR(151MHz,CDCl/乙酸乙酯=10:1);25.5 89%的分离收率;.57,12.69,29.67,29.65,29.2H),6.00(tt,J=56.5(t,J=5.419F NMR(471MHz,CDCl3)NMR(471MHz,CDCl/乙酸乙酯=10:1);25.5 89%的分离收率;.57,12.69,for C9H14F2O4Na+246.9849,found247.0754.
按照前述通式方法,制备得到下式化合物:
4,4-二氟-2-(萘-1-基)丁酸乙酯
ethyl 4,4-difluoro-2-(naphthalen-1-yl)butanoate
白色固体;Rf=0.3(石油醚/乙酸乙酯=20:1);23.4毫克,42%的分离收率;1HNMR(400MHz,CDCl3)NMR(400MHz,CDCl酸Hz,1H),7.89(d,J=8.0Hz,1H),7.81(d,J=7.8Hz,1H),7.60-7.56(m,1H),7.52(t,J=7.5Hz,1H),7.48-7.40(m,2H),5.82(tt,J=56.6,4.6Hz,1H),4.70-4.55(m,1H),3.67(s,3H),2.87(dtdd,J=19.2,13.6,8.8,4.6Hz,1H),2.47-2.28(m,1H).13C NMR(151MHz,CDCl3)NMR(151MHz,CDCl酸Hz,1H),7.89(d,J=8.0Hz,1H),7.81(d,J=7.8Hz,1H),7.60-7.56(m,1H),7.52(t,J=7.5Hz,1H),7.48-7.40(m,2H),5.82(tt,J=56.19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl酸Hz,1H),7.89(:m/z[M+Na]+calcd for C15H14F2O2Na+286.9951,found 287.0852.
按照前述通式方法,制备得到下式化合物:
((3,3-二氟丙基)磺酰基)苯((3,3-difluoropropyl)sulfonyl)benzene
白色固体;Rf=0.3(石油醚/乙酸乙酯=3:1);41.8毫克,95%的分离收率;1H NMR(400MHz,CDCl3)NMR(400M.85(m,2H),7.70(t,J=7.5Hz,1H),7.61(t,J=7.7Hz,2H),6.00(tt,J=56.0,3.9Hz,1H),3.31-3.21(m,2H),2.31(dtt,J=20.8,11.8,4.2Hz,2H).19F NMR(377MHz,CDCl3)NMR(377MHz,CDCl2H),7.70(t,J
按照前述通式方法,制备得到下式化合物:
4,4-二氟-1-苯基-1-丁酮
4,4-difluoro-1-phenylbutan-1-one
无色透明液体;Rf=0.3(石油醚/乙酸乙酯=20:1);27.7毫克,77%的分离收率;1H NMR(400MHz,CDCl3)NMR(400MHz,CDCl/乙酸乙酯=20:1);27.7毫克,77%的分离收率;,7.61(t,J=7.7Hz,2H),6.00(tt,J=56.0,3.9Hz,1H),3.31-3.=7.2Hz,2H),2.31(ttd,J=18.0,7.2,4.2Hz,2H).19F NMR(377MHz,CDCl3)乙酯=20:1);27.7毫克,77%的分离收率;,7.61(
(2)四氢异喹啉C(sp3)-H的二氟甲基官能化
实施过程:
反应条件和参数优化过程:
以2-苯基-1,2,3,4-四氢异喹啉4aa为模板底物,试剂1为二氟甲基试剂,反应条件:是否使用光催化剂Ir[(ppy)2dtbpy]PF6、Ir(ppy)3,优选使用光催化剂Ir[(ppy)2dtbpy]PF6;反应所用碱为NaHCO3、Na2CO3、K2CO3,优选NaHCO3;反应用溶剂MeCN、EA、DCM、THF,优选MeCN;所用的光照波长为350nm至550nm之间,优选波长为450nm的蓝光;反应温度为-30℃至80℃,优选0℃至50℃,优选为室温条件;反应时间过夜,反应完成后(TLC监控),停止光照和搅拌,减压蒸馏除去溶剂,粗品用硅胶柱层析纯化,得纯品1-(二氟甲基)-2-苯基-1,2,3,4-四氢异喹啉。
取一干燥的10mL Schlenk管,加入底物4(例如,2-苯基-1,2,3,4-四氢异喹啉或其衍生物类,0.2毫摩尔,1.0当量)、二氟甲基试剂1(137.6毫克,0.4毫摩尔,2.0当量)、Ir[(ppy)2dtbpy]PF6(2.0毫克,0.004毫摩尔,2%当量),NaHCO3(48.2毫克,0.6毫摩尔,3.0当量),反应管放置于手套箱中,随后加入2毫升乙腈作溶剂,封闭取出,反应液在12瓦LED蓝光照射下搅拌反应过夜,反应完成后,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-(二氟甲基)-2-苯基-1,2,3,4-四氢异喹啉。
四氢异喹啉C(sp3)-H的二氟甲基官能化最优条件实施过程:
R1为H,吸电子或给电子取代基;R2为H,吸电子或给电子取代基。
参照以上最优条件实施过程,获得以下四氢异喹啉C(sp3)-H的二氟甲基官能化产物:
各产物数据表征如下。
按照前述通式方法,制备得到下式化合物:
1-(二氟甲基)-2-苯基-1,2,3,4-四氢异喹啉
1-(difluoromethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);47.1毫克,91%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);47.1毫克,91%的分离收率;oquinolineLED蓝光照射下搅拌反应过夜,反应完成后,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-(过夜,反应完成后(TLC监控),停止光照和搅拌,减压蒸馏除去溶剂,粗品用硅胶柱层析纯化,得纯品1-(,7.2,4.2(td,J=7.2,3.6Hz,1H),3.54-3.41(m,1H),2.99(ddd,J=15.2,7.0,5.1Hz,2H).13C NMR(101MHz,CDCl3)101MHz,CDCl(石油醚/乙酸乙酯=50:1);47.1毫克,91%的分离收率;oquinolineLED蓝光照射下搅拌反应过夜,反应完成后,减压蒸馏除去溶剂J=250.9Hz),114.09,61.17(t,J=23.6Hz),43.53,27.80.19F NMR(377MHz,CDCl3)377MHz,CDCl.53,27.80.7HRMS(ESI):m/z[M+H]+calcd for C16H16F2N+260.1206,found 260.1244.
按照前述通式方法,制备得到下式化合物:
1-(二氟甲基)-2-(对甲苯基)-1,2,3,4-四氢异喹啉
1-(difluoromethyl)-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);40.9毫克,75%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);40.9毫克,75%的分离收率;oisoquinoline蓝光照射下搅拌反应过夜,反应完成后,减压蒸馏除去溶剂,粗品经硅胶柱层析纯化得到1-(过夜,反应完成后(TLC监控),停止光照和搅拌,减压蒸馏除去溶剂,粗品用硅胶柱层析纯化,得纯品1-(,7.2,4.2(td,J=7.2,3.6Hz,1H),3.54-3.41Hz,1H),3.84(d,J=2.1Hz,3H),3.73(dt,J=11.7,5.8Hz,1H),3.50(ddd,J=12.1,7.3,5.5Hz,1H),3.02(td,J=5.7,5.2,3.2Hz,2H).13C NMR(101MHz,CDCl3)101MHz,CDCl(石油醚/乙酸乙酯=50:1);40.9毫克,75%的分离收率;oisoquinoline蓝光照射下搅拌反应过夜,反应完成后,减压蒸馏除去溶剂J=249.5Hz),114.68,61.35(t,J=23.3Hz),43.77,27.67,20.31.19F NMR(377MHz,CDCl3)377MHz,CDCl.77,27.67,HRMS(ESI):m/z[M+H]+calcd for SC17H18F2N+274.1363,found 274.1399.
按照前述通式方法,制备得到下式化合物:
1-(二氟甲基)-2-(4-异丙基苯基)-1,2,3,4-四氢异喹啉
1-(difluoromethyl)-2-(4-isopropylphenyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);50.5毫克,76%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);50.5毫克,76%的分离收率;oisoquinoline蓝光照射下搅拌反应过夜,反应完成后,减压蒸馏除去溶剂,粗品经硅胶6.94(d,J=8.4Hz,2H),6.01(d,J=3.2Hz,1H),4.96(ddd,J=17.4,9.2,3.2Hz,1H),3.73(ddd,J=11.8,6.8,5.0Hz,1H),3.50(ddd,J=12.2,7.4,5.2Hz,1H),3.08-2.94(m,2H),2.89(p,J=6.9Hz,1H),1.26(d,J=6.9Hz,6H).13C NMR(101MHz,CDCl3)101MHz,CDCl(石油醚/乙酸乙酯=50:1);50.5毫克,76%的分离收率;oisoquinoline蓝光照射下搅拌反应过夜,反应完成后,减压蒸馏除去溶剂J=252.1Hz),114.37,61.38(t,J=23.2Hz),43.74,33.13,27.78,24.21.19F NMR(377MHz,CDCl3)377MHz,CDCl.74,33.13,HRMS(ESI):m/z[M+H]+calcd for C19H22F2N+302.1676,found302.1712.
按照前述通式方法,制备得到下式化合物:
1-(二氟甲基)-2-(3,4-二甲基苯基)-1,2,3,4-四氢异喹啉
1-(difluoromethyl)-2-(3,4-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);44.8毫克,78%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);44.8毫克,78%的分离收率;e-tetrahydroisoquinoline,反应完成后,减压蒸馏除去溶剂,粗Hz,1H),6.70(dd,J=8.3,2.8Hz,1H),5.96(td,J=56.4,3.2Hz,1H),4.91(ddd,J=17.7,9.2,3.2Hz,1H),3.67(ddd,J=12.0,7.0,4.9Hz,1H),3.47(ddd,J=12.0,6.8,5.1Hz,1H),3.04-2.88(m,2H),2.25(s,3H),2.18(s,3H).13C NMR(101MHz,CDCl3)101MHz,CDCldd,J=8.3,2.8Hz,1H),5.96(td,J=56.4,3.2Hz,1H),4.91(ddd,J=17.7,9.2,3.2J=248.6Hz),112.13,61.27(t,J=23.2Hz),43.71,27.71,20.41,18.68.19F NMR(377MHz,CDCl3)377MHz,CDCl.71,27.71,
按照前述通式方法,制备得到下式化合物:
1-(二氟甲基)-2-(4-氟苯基)-1,2,3,4-四氢异喹啉
1-(difluoromethyl)-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);48.8毫克,88%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);48.8毫克,88%的分离收率;trahydroisoquinoline 1H),4.91(ddd,J=17.7,9.2,3.2Hz,1H),3.67(ddd,J=12.0,7.0,4.9Hz,1H),3.47(ddd,J=12.0,6.8,5.1Hz,1H),3.04-2.88(m,1H),2.99(ddd,J=15.2,7.0,5.1Hz,2H).13C NMR(101MHz,CDCl3)101MHz,CDCl(石油醚/乙酸乙酯=50:1);48.8毫克,88%的分离收率;trahydroisoquinoline 1H),4.91(ddd,JJ=241.4Hz),115.88(t,J=23.5Hz),61.76(t,J=23.2Hz),44.32,27.46.19F NMR(377MHz,CDCl3)δ-116.09--124.25(m),-125.92(dq,J=8.4,4.3Hz).HRMS(ESI):m/z[M+H]+calcd for C16H15F3N+278.1112,found 278.1149.
按照前述通式方法,制备得到下式化合物:
2-(4-溴苯基)-1-(二氟甲基)-1,2,3,4-四氢异喹啉
2-(4-bromophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);57.5毫克,85%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);57.5毫克,85%的分离收率;rahydroisoquinolinee 1H),4.91(ddd,J=17.7,9.2,3.2Hz,1H),3.67(ddd,J=12.0,7.0,4.9Hz,1H),3.47Hz,1H),3.71(dt,J=11.6,5.7Hz,1H),3.46(ddd,J=12.2,7.3,5.6Hz,1H),3.02(td,J=5.9,2.7Hz,2H).13C NMR(101MHz,CDCl3)101MHz,CDCl(石油醚/乙酸乙酯=50:1);57.5毫克,85%的分离收率;rahydroisoquinolinee 1H),4.91J=245.6Hz),115.62,110.72,61.19(t,J=26.4Hz),43.69,27.71.19F NMR(377MHz,CDCl3)377MHz,CDCl.69,27.71.7HRMS(ESI):m/z[M+Na]+calcd for C17H15BrF2Na+359.0224,found359.0220.
按照前述通式方法,制备得到下式化合物:
2-(4-氯苯基)-1-(二氟甲基)-1,2,3,4-四氢异喹啉
2-(4-chlorophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);48.1毫克,82%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);48.1毫克,82%的分离收率;rahydroisoquinolinee 1H),4.91(ddd,J=17.7,9.2,3.2Hz,1H),3.67(ddd,J=12.(dt,J=11.3,5.5Hz,1H),3.54(dt,J=11.8,6.8Hz,1H),3.08(t,J=6.2Hz,2H).13C NMR(101MHz,CDCl3)101MHz,CDCl(石油醚/乙酸乙酯=50:1);48.1毫克,82%的分离收率;rahydroisoquinolinee 1H),4.91(ddd,JJ=254.4Hz),115.26,61.30(t,J=23.5Hz),43.80,27.72.19F NMR(377MHz,CDCl3)377MHz,CDCl.80,27.72.0HRMS(ESI):m/z[M+H]+calcd for C16H15ClF2N+294.0816,found294.0854.
按照前述通式方法,制备得到下式化合物:
1-(二氟甲基)-2-(4-(三氟甲基)苯基)-1,2,3,4-四氢异喹啉
1-(difluoromethyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);51.0毫克,78%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);51.0毫克,78%的分离收率;-1,2,3,4-tetrahydroisoqu,4.91(ddd,J=17.7,9.2,3.2Hz,1H),3.67(ddd,J=12.(dt,J=11.3,5.5Hz,1H),3.54(dt,J=11.8,6.8Hz,1H),3.08(t,J=6.2Hz,2H).13C NMR(101MHz,CDCl3)101MHz,CDCl(石油醚/乙酸乙酯=50:1);51.0毫克,78%的分离收率;-1,2,3,4-tetrahydroisoqu,4.91(ddd,J=J=64.2,32.1Hz),115.74(t,J=246.1Hz),112.67,60.86(t,J=23.8Hz),43.57,27.91.19F NMR(377MHz,CDCl3)377MHz,CDCl.57,27.91.6(t,1.0HRMS(ESI):m/z[M+H]+calcd for C17H15F5N+328.1080,found 328.1117.
按照前述通式方法,制备得到下式化合物:
1-(二氟甲基)-6-甲氧基-2-苯基-1,2,3,4-四氢异喹啉
1-(difluoromethyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);39.3毫克,68%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);39.3毫克,68%的分离收率;-1,2,3,4-tetrahydroisoqu,4.91(ddd,J=17.7,9.2,3.2Hz,1H),3.67(ddd,J=12.),6.75(d,J=2.7Hz,1H),5.94(td,J=56.4,3.4Hz,1H),4.90(ddd,J=17.3,8.9,3.4Hz,1H),3.81(s,3H),3.69(dt,J=11.8,5.8Hz,1H),3.46(dt,J=12.2,6.3Hz,1H),2.99J=12.),6.7513CNMR(101MHz,CDCl3)δ101MHz,CDCl17.3,8.9,3.4.85,129.41,118.67,116.80(t,J=252.3,250.3Hz),115.21,114.08,113.35,112.20,60.64(t,J=23.6Hz),55.29,43.42,28.10.19FNMR(377MHz,CDCl3)377MHz,CDCl.29,43.42,HRMS(ESI):m/z[M+H]+calcd for C17H18F2NO+290.1312,found290.1348.
按照前述通式方法,制备得到下式化合物:
2-([1,1'-联苯]-4-基)-1-(二氟甲基)-1,2,3,4-四氢异喹啉
2-([1,1'-biphenyl]-4-yl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);52.3毫克,81%的分离收率;1HNMR(400MHz,CDCl3)1H NMR(400MHz,Chloroform-d)δ7.55(td,J=5.8,3.1Hz,4H),7.40(t,J=7.7Hz,2H),7.28(ddd,J=12.3,5.3,2.2Hz,3H),7.25-7.18(m,2H),7.05-6.98(m,2H),5.99(td,J=56.2,3.4Hz,1H),5.00(ddd,J=16.6,9.3,3.4Hz,1H),3.75(dt,J=11.6,5.7Hz,1H),3.52(ddd,J=12.2,7.4,5.5Hz,1H),3.08-2.94(m,2H).13C NMR(101MHz,CDCl3)101MHz,CDClHz,Chloroform-d)δ7.55(td,J=5.8,3.1Hz,4H),7.40(t,J=7.7Hz,2H),7.28(ddd,J=12.3,5.3,J=249.5Hz),114.17,61.16(t,J=23.6Hz),43.62,27.89.19F NMR(377MHz,CDCl3)377MHz,CDCl.62,27.89.6HRMS(ESI):m/z[M+H]+calcd for C22H20F2N+336.1519,found 336.1555.
按照前述通式方法,制备得到下式化合物:
1-(二氟甲基)-2-(3-甲氧基苯基)-1,2,3,4-四氢异喹啉
1-(difluoromethyl)-2-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);43.9毫克,76%的分离收率;1HNMR(400MHz,CDCl3)400MHz,CDCl(石油醚/乙酸乙酯=50:1);43.9毫克,76%的分离收率;etrahydroisoquinoli7.40(t,J=7.7Hz,2H),7.28(ddd,J=12.3,5.3,2.2Hz,3H),7.25-7.18(m,2.97(td,J=56.3,3.3Hz,1H),4.95(ddd,J=17.3,9.1,3.3Hz,1H),3.81(d,J=2.1Hz,3H),3.70(dt,J=11.7,5.8Hz,1H),3.47(ddd,J=12.1,7.3,5.5Hz,1H),2.99(td,J=5.7,5.2,3.2Hz,2H).13C NMR(101MHz,CDCl3)101MHz,CDCl(石油醚/乙酸乙酯=50130.12,128.75,128.49,128.25,128.1Z9,126.37,115.99(t,J=243.8Hz),106.91,103.18,100.89,61.19(t,J=23.5Hz),55.27,43.59,27.87,27.86.19F NMR(377MHz,CDCl3)377MHz,CDCl.27,43.59,HRMS(ESI):m/z[M+H]+calcd for C17H18F2NO+290.1312,found290.1348.
按照前述通式方法,制备得到下式化合物:
2-(3-氯苯基)-1-(二氟甲基)-1,2,3,4-四氢异喹啉
2-(3-chlorophenyl)-1-(difluoromethyl)-1,2,3,4-tetrahydroisoquinoline
淡黄色固体;Rf=0.3(石油醚/乙酸乙酯=50:1);47.5毫克,81%的分离收率;1HNMR(400MHz,CDCl3)400MHz,C.26(m,2H),7.23(s,1H),7.21-7.16(m,2H),6.91(q,J=3.2,2.8Hz,1H),6.81(td,J=8.5,7.9,2.2Hz,2H),5.94(td,J=56.1,3.6Hz,1H),4.92(ddd,J=15.7,9.6,3.6Hz,1H),3.69(dt,J=11.5,5.7Hz,1H),3.44(dt,J=12.2,6.3Hz,1H),3.06-2.94(m,2H).13C NMR(101MHz,CDCl3)101MHz,CDCl(m,2H),7.23(s,1H),7.21-7.16(m,2H),6.91(q,J=3.2,2.8Hz,1H),6.81J=244.8Hz),113.80,111.87,61.08(t,J=23.6Hz),43.60,27.79.19F NMR(377MHz,CDCl3)377MHz,CDCl.60,27.79.8HRMS(ESI):m/z[M+H]+calcd for C16H14ClF2N+294.0816,found 294.0853.
参考文献:
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以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到各种等效的修改或替换,这些修改或替换都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以权利要求的保护范围为准。
Claims (8)
1.一种二氟甲基试剂,其特征在于,具有以下结构通式:
其中,X为BF4,OTf或PF6;R为烷氧基,卤素,NO2,CN或CF3。
2.根据权利要求1所述的二氟甲基试剂,其特征在于,为式1a或式1b的化合物:
3.如权利要求1所述的二氟甲基试剂的制备方法,其特征在于,采用1-((二氟甲基)
亚砜基)-2-苯氧基苯或其类似物在三氟甲磺酸酐作用下进行环化,再进行相应的阴离子交换得到二氟甲基试剂。
4.如权利要求2所述的二氟甲基试剂的制备方法,其特征在于,采用1-((二氟甲基)亚砜基)-2-苯氧基苯或1-((二氟甲基)亚砜基)-2-苯氧基-3,5-二甲氧基苯,在三氟甲磺酸酐作用下进行环化,再与四氟硼酸钠溶液进行阴离子交换得到亲电的二氟甲基试剂。
5.如权利要求1所述二氟甲基试剂的应用,其特征在于,用于烯烃的氢/二氟甲基双官能化反应,合成具有以下式3结构的化合物:
其中,R1为H;R2为H,烷基或芳基;EWG为酯,酮,砜或其他吸电子基团。
6.根据权利要求5所述的应用,其特征在于,以2,6-二甲基-3,5-二乙酯基-1,4-二氢吡啶为供氢体,采用丙烯酸苯酯或非活化烯烃类与所述二氟甲基试剂合成式3结构的化合物。
7.如权利要求1所述二氟甲基试剂的应用,其特征在于,用于四氢异喹啉C(sp3)-H的二氟甲基官能化反应,合成具有以下式5结构的化合物:
其中,R1为H,吸电子或给电子取代基;R2为H,吸电子或给电子取代基。
8.根据权利要求7所述的应用,其特征在于,采用2-苯基-1,2,3,4-四氢异喹啉或其衍生物类与所述二氟甲基试剂合成具有式5结构的化合物。
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