CN114478337B - 一种轴手性含硫双芳基衍生物及其合成方法 - Google Patents
一种轴手性含硫双芳基衍生物及其合成方法 Download PDFInfo
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- CN114478337B CN114478337B CN202210114499.3A CN202210114499A CN114478337B CN 114478337 B CN114478337 B CN 114478337B CN 202210114499 A CN202210114499 A CN 202210114499A CN 114478337 B CN114478337 B CN 114478337B
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- 229910052717 sulfur Inorganic materials 0.000 title claims abstract description 74
- 239000011593 sulfur Substances 0.000 title claims abstract description 74
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title claims abstract description 68
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 title claims abstract description 67
- 238000001308 synthesis method Methods 0.000 title claims abstract description 51
- -1 diaryl phenol Chemical compound 0.000 claims abstract description 54
- 239000003054 catalyst Substances 0.000 claims abstract description 53
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 44
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 claims description 123
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 claims description 41
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 16
- 229910052786 argon Inorganic materials 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N deuterated methanol Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-LIDOUZCJSA-N ethanol-d6 Chemical compound [2H]OC([2H])([2H])C([2H])([2H])[2H] LFQSCWFLJHTTHZ-LIDOUZCJSA-N 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 3
- 125000005841 biaryl group Chemical class 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 30
- 239000000758 substrate Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 3
- 231100000956 nontoxicity Toxicity 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 81
- 238000005481 NMR spectroscopy Methods 0.000 description 73
- 230000014759 maintenance of location Effects 0.000 description 70
- 238000004896 high resolution mass spectrometry Methods 0.000 description 40
- 239000007787 solid Substances 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- 238000004128 high performance liquid chromatography Methods 0.000 description 36
- 239000000203 mixture Substances 0.000 description 36
- 239000000741 silica gel Substances 0.000 description 36
- 229910002027 silica gel Inorganic materials 0.000 description 36
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
- 238000000926 separation method Methods 0.000 description 35
- 239000011734 sodium Substances 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 150000001875 compounds Chemical class 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 125000005000 thioaryl group Chemical group 0.000 description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
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- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 3
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Classifications
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
- B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/41—Y being a hydrogen or an acyclic carbon atom
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
- C07C323/49—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4294—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using S nucleophiles, e.g. thiols
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
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Abstract
本发明公开了一种轴手性含硫双芳基衍生物及其合成方法,属于有机化学合成技术领域,上述轴手性含硫双芳基衍生物的结构式为式(I),其合成方法为:将式(II)所示双芳基苯酚与式(III)所示硫芳基试剂在式(IV)所示3,3′‑二取代二联萘衍生硒化物催化剂的存在下发生反应,获得式(I)所示轴手性含硫双芳基衍生物。本发明式(I)所示轴手性含硫双芳基衍生物具有高对映体过量(ee)值,其合成方法反应条件温和、可重复性好、所使用原料便宜易制且基本无毒、底物适用范围广、经济性好。
Description
技术领域
本发明属于有机化学合成技术领域,具体涉及一种轴手性含硫双芳基衍生物及其合成方法。
背景技术
手性有机硫化合物广泛存在于具有生物活性的天然产物和药物中,也被用作手性催化剂和配体。鉴于这些化合物的重要性,对映体选择性合成方法的开发是非常有必要的。其中,烯烃的催化不对称亲电磺基化是制备手性有机硫化合物的最直接和有效的策略之一,近来引起了越来越多的关注。
轴向手性组分,特别是轴向手性双芳基,广泛存在于生物活性分子中,并被用作手性催化剂和配体的骨架,进而广泛应用于不对称转化反应。已报道的形成轴向手性二芳基的各种合成方法。然而,这一策略目前只研究了数量有限的催化方法,Hayashi课题组开创性的利用偶联合成了双芳基轴手性化合物(J.Am.Chem.Soc.1995,117,9101-9102),随后Akiyama及其同事还开发了一种新的手性磷酸催化对映选择性方法,用于双酚的溴化,作为构建多取代二芳基化合物的一种手段(J.Am.Chem.Soc.2013,135,3964-3970)。
发明内容
本发明的目的在于提供一种高ee值的R构型的轴手性含硫双芳基衍生物,其合成方法反应条件温和、可重复性好、所使用原料便宜易制且基本无毒、底物适用范围广、经济性好。
本发明为实现上述目的所采取的技术方案的结构式为:
一种式(I)所示轴手性含硫双芳基衍生物,
式中,X选自Ar、Ar1或Ar2;R0选自/> 或X;R、R1、R2各自独立地选自H、取代或未被取代的烷基、取代或未被取代的烯基、取代或未被取代的芳基、酰胺基、磺酰胺基、取代或未被取代的烷氧基、取代或未被取代的苄基、苄氧基、卤素、多取代烷基卤素、芳硫基、硝基或氰基;R3选自H、取代或未被取代的烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的苄基。
优先地,Ar为Ar1为/>Ar2为/>
本发明式(I)所示轴手性含硫双芳基衍生物是具有高对映体过量(ee)值。
本发明还提供了一种式(I)轴手性含硫双芳基衍生物的合成方法,将式(II)所示双芳基苯酚与式(III)所示硫芳基试剂在催化剂的存在下发生反应,获得式(I)所示轴手性含硫双芳基衍生物;
式(II)中,R0选自/> 或X;R、R1、R2各自独立地选自H、取代或未被取代的烷基、取代或未被取代的烯基、取代或未被取代的芳基、酰胺基、磺酰胺基、取代或未被取代的烷氧基、取代或未被取代的苄基、苄氧基、卤素、多取代烷基卤素、芳硫基、硝基或氰基;R3选自H、取代或未被取代的烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的苄基;X选自Ar、Ar1或Ar2;式(III)中,X选自Ar、Ar1或Ar2。
本发明式(I)所示轴手性含硫双芳基衍生物的合成方法以易制的双芳基苯酚和硫芳基试剂为原料,在催化剂和对氯苯磺酸的作用下,于低温下,氩气氛围中进行反应一段时间后,将体系升至一定温度,继续反应一段时间,制得轴手性含硫双芳基衍生物。本发明合成方法的反应机理如下:底物在手性催化剂和非手性磺酸的作用下,首次经过不对称催化,其中一种构象的反应速率远大于另一种构象,故得到手性的单芳基的双苯基轴手性化合物,劣势S构型的手性单芳基的双苯基轴手性化合物在该反应体系中会经过快速的动力学拆分步骤,反应生成非手性的双芳基双苯基化合物,进步一步提升优势构型产物的比例,最终得到高ee值的R构型产物。
优先地,式(II)所示双芳基苯酚与式(III)所示硫芳基试剂的摩尔比为1:1.0-1.8。
更优先地,式(II)所示双芳基苯酚与式(III)所示硫芳基试剂的摩尔比为1:1.2-1.5。
优先地,催化剂为式(IV)所示3,3′-二取代二联萘衍生硒化物催化剂,
更优先地,式(IV)所示3,3′-二取代二联萘衍生硒化物催化剂和式(II)所示双芳基苯酚的摩尔比为0.05-0.12:1。更进一步优先地,(IV)所示3,3′-二取代二联萘衍生硒化物催化剂和式(II)所示双芳基苯酚的摩尔比为0.08-0.1:1。
优先地,合成方法为:将式(II)所示双芳基苯酚与式(III)所示硫芳基试剂在催化剂、酸和溶剂的存在下发生反应,获得式(I)所示轴手性含硫双芳基衍生物。
优先地,酸为对氯苯磺酸。更优先地,酸与式(II)所示双芳基苯酚的摩尔比为0.05-0.12:1。更进一步优先地,酸与式(II)所示双芳基苯酚的摩尔比为0.08-0.1:1。
优先地,溶剂选自氘代氯仿、氘代二甲亚砜、氘代甲醇、氘代乙醇或氘代二氯甲烷。更优先地,溶剂与式(II)所示双芳基苯酚的用量比为2-50mL:1mmol。更进一步优先地,溶剂与式(II)所示双芳基苯酚的用量比为5-20mL:1mmol。
本发明还提供了一种式(IV)所示3,3′-二取代二联萘衍生硒化物催化剂。
本发明还提供了式(IV)所示3,3′-二取代二联萘衍生硒化物催化剂在制备式(I)轴向手性含硫双芳基衍生物中的用途。
与现有技术相比,本发明具有如下有益效果:本发明方法通过双芳基苯酚的亲电亚砜基化,首次实现了轴向手性含硫双芳基衍生物的对映选择性合成,得到高ee值的R构型产物;本发明方法采用一种首次合成的新型3,3′-二取代二联萘衍生硒化物催化剂和非手性磺酸共催化体系;本发明方法采用廉价易制双芳基苯酚底物,反应过程避免了复杂的底物合成;本发明方法底物具有多样性,可以合成多种不同取代基的轴手性含硫双芳基衍生物。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。以下提供的实施例可作为本技术领域普通技术人员进行进一步改进的指南,并不以任何方式构成对本发明的限制。
于一实施方式中,轴手性含硫双芳基衍生物的合成方法为:将式(II)所示双芳基苯酚、式(III)所示硫芳基试剂、催化剂、酸和溶剂在-80至-40℃下搅拌反应12-48小时,然后在-30至-10℃下搅拌反应2-12小时,获得式(I)所示轴手性含硫双芳基衍生物。
于一实施方式中,轴手性含硫双芳基衍生物如式(V)所示,
式中,R1选自烷基、烯基、芳基、取代芳基、酰胺、烷氧基、苄氧基、卤素、多取代烷基卤素、硝基或氰基。
于一实施方式中,轴手性含硫双芳基衍生物的对映体过量大于75%。
于一实施方式中,轴手性含硫双芳基衍生物包括如下化合物1-化合物35(Ar=2,6-diMe-4-OMe-C6H2):
于一实施方式中,轴手性含硫双芳基衍生物的合成方法为:将式(II)所示双芳基苯酚、式(III)所示硫芳基试剂、催化剂、酸和溶剂在-80至-40℃下搅拌反应12-48小时,然后在-30至-10℃下搅拌反应2-12小时,获得式(I)所示轴手性含硫双芳基衍生物。
下述实施例中所用双芳基苯酚的合成方法为:通过溴苯或溴萘与2,6-二甲氧基苯硼酸反应,再脱去甲氧基制得。氩气条件下,向溴苯的乙二醇二甲醚溶液和乙醇的混合溶液中加入2,6-二甲氧基苯硼酸和碳酸钠,向其中加入四(三苯基磷)钯和水加热回流搅拌12h,反应完全后冷却至室温,用乙酸乙酯萃取,有机相用水和饱和食盐水分别洗涤后,经干燥、减压蒸馏、柱色谱提纯即得甲氧基保护的双芳基苯酚;室温下甲氧基保护的双芳基苯酚溶于超干的二氯甲烷,将体系降至-78℃,向其中滴加三溴化硼,体系缓慢升至室温,室温下搅拌反应2h。反应完全后冰浴条件下用水小心的淬灭反应,利用乙酸乙酯萃取,有机相用水和饱和食盐水分别洗涤后,经干燥、减压蒸馏、柱色谱提纯即得双芳基苯酚。
下述实施例中,化合物的氢核磁共振谱(1H NMR、13C NMR和19F NMR)由BrukerAVANCE III HD 400测定,溶剂为氘代氯仿,氘代甲醇,氘代二甲基亚砜,氘代二氯甲烷。化学位移(δ)以ppm为单位引用,以四甲基硅烷作为内标,多重性:s=单重态,d=双重态,t=三重态,q=四重态,m=多重态。高分辨率质谱分析(HRMS)数据是通过ESI技术和傅里叶变换离子回旋加速器(SolariX 7.0T)的Q-TOF质谱测得。采用Daicel Chiralpak IE、DaicelChiralpak IA、Daicel Chiralpak IC、Daicel Chiralpak IF、Chiralcel OD-H通过高效液相色谱(HPLC)分析测定产品的对映体过量(ee)。
下述实施例中,实验方法,如无特殊说明,均为常规方法。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1:
2,6-二甲基,4-甲氧基-硫芳基试剂的合成方法
将干燥的5mL正己烷加入到装有氢化钠(15mmol)的圆底烧瓶中,摇晃并静置15-20分钟后,吸走上清液并重复三次,之后用氩气吹干剩余的正己烷。接下来将装有氢化钠的圆底烧瓶置于氩气下保护并加入干燥的四氢呋喃(40mL),同时于室温下将邻磺酰苯酰亚胺(15mmol)溶于干燥的四氢呋喃(24mL)中并缓慢滴加入装有氢化钠的圆底烧瓶中,于室温下继续反应18小时后,将体系在0摄氏度下浓缩后,并将体系用油泵抽干,真空度为10mmHg左右,即可制备得到邻磺酰苯酰亚胺的钠盐,为白色固体;
将邻磺酰苯酰亚胺的钠盐溶于干燥的二氯甲烷(30mL)中,惰性气氛及0摄氏度下缓慢加入2,6-二甲基-4-甲氧基苯次磺酰氯(15mmol)的二氯甲烷溶液(15mL)并在该温度下反应2小时,之后于室温下进行反应3小时,分别用丙酮和苯溶解过滤,用苯和正己烷结晶,用油泵抽干,真空度为10mmHg左右,制备得到2,6-二甲基,4-甲氧基-硫芳基试剂,为白色固体,两步总产率为50%。1H NMR(400MHz,CDCl3)δ8.08(dt,J=7.3,0.9Hz,1H),7.93–7.73(m,3H),6.68(s,2H),3.78(s,3H),2.81(s,6H);13C NMR(101MHz,CDCl3)δ162.17,159.85,147.97,138.21,135.28,134.43,127.50,125.75,122.63,121.38,114.15,55.35,23.00;HRMS(ESI)m/zcalcd.for C16H15NNaO4S2(M+Na)+:372.0335,found:372.0332.
(IV)所示3,3′-二取代二联萘衍生硒化物催化剂的合成方法
将4.0mmol三氯化磷溶解于超干DCM(16.0mL)中。将体系溶液冷却至0℃,并向其中逐滴滴加20.0mmol Et3N。10分钟后,将反应体系缓慢升至室温,并加入4.0mmol二仲丁胺,继续搅拌反应5小时。在室温条件下再加入4.0mmol IV-0搅拌反应12h,然后加入12.0mmol硒粉,搅拌反应2h。反应完成后用硅藻土过滤,并在真空下浓缩。粗产物通过硅胶(50:1EtOAc:石油醚)纯化,得到白色固体化合物,即(IV)所示3,3′-二取代二联萘衍生硒化物催化剂,产率为81%。1H NMR(400MHz,Chloroform-d)δ7.85–7.70(m,2H),7.50–7.34(m,3H),7.30(d,J=4.8Hz,1H),7.24(d,J=8.7Hz,1H),7.17–7.01(m,3H),4.45–4.05(m,4H),3.47(dq,J=21.5,6.9Hz,2H),2.31–1.99(m,1H),1.81–1.61(m,1H),1.60–1.50(m,6H),1.48–1.23(m,5H),1.07–0.83(m,6H),0.66(dt,J=23.2,7.4Hz,3H);13C NMR(101MHz,Chloroform-d)δ150.62,149.74,149.71,141.09,141.03,138.83,138.75,132.58,131.64,131.63,127.43,127.41,127.27,127.25,127.15,126.93,125.88,125.84,124.33,124.05,123.84,123.60,123.57,109.63,109.46,109.09,108.89,64.86,64.80,64.59,64.49,55.00,29.68,29.56,28.70,28.36,19.60,19.38,18.69,18.40,15.00,14.85,14.82,12.17,12.14,11.80,11.75;HRMS(ESI)m/z calcd.for C32H38NNaO4PSe(M+Na)+:634.1596,found:634.1587.[α]D 20=-380.6(c=1.0,CHCl3).
一种轴手性含硫双芳基衍生物(化合物1)的合成方法
将0.1mmol 2'-甲基-[1,1'-联苯]-2,6-二醇、0.15mmol 2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物1,收率为79%。
化合物1的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.48–7.28(m,3H),7.24(m,1H),6.84(d,J=8.6Hz,1H),6.68(s,2H),6.47(d,J=8.6Hz,1H),5.95(s,1H),4.69(s,1H),3.78(s,3H),2.45(s,6H),2.14(s,3H);13C NMR(101MHz,Chloroform-d)δ159.74,152.90,151.97,144.36,139.06,131.21,131.10,130.87,130.60,129.45,127.01,123.32,114.73,114.26,113.02,108.53,55.29,22.47,19.62;HRMS(ESI)m/z calcd.for C22H22NaO3S(M+Na)+:389.1182,found:389.1181;separation of enantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=88:12,1mL/min,minor retention time:5.49min,majorretention time:4.90min,er=4:96;[α]D 20=-28.0(c=1.0,CHCl3).
实施例2:
一种轴手性含硫双芳基衍生物(化合物2)的合成方法
将0.1mmol 2'-异丙基-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物2,收率为72%。
化合物2的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.62–7.40(m,2H),7.33(td,J=7.3,1.7Hz,1H),7.20(dd,J=7.6,1.4Hz,1H),6.86(d,J=8.6Hz,1H),6.69(s,2H),6.48(d,J=8.6Hz,1H),5.95(s,1H),4.64(s,1H),3.79(s,3H),2.73(p,J=6.9Hz,1H),2.46(s,3H),1.14(dd,J=9.7,6.9Hz,6H);13C NMR(101MHz,Chloroform-d)δ159.73,153.18,152.25,149.83,144.34,131.27,130.92,129.95,129.15,127.05,126.74,123.51,114.66,114.26,112.95,108.45,55.31,30.50,24.14,23.96,22.45;HRMS(ESI)m/z calcd.for C24H26NaO3S(M+Na)+:417.1495,found:417.1494;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=90:10,1mL/min,minor retention time:5.58min,majorretention time:6.20min,er=5.5:94.5;[α]D 20=-11.4(c=1.0,CHCl3).
实施例3:
一种轴手性含硫双芳基衍生物(化合物3)的合成方法
将0.1mmol 2'-氯-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物3,收率为74%。
化合物3的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.66–7.52(m,1H),7.49–7.32(m,3H),6.95(d,J=8.6Hz,1H),6.68(s,2H),6.48(d,J=8.6Hz,1H),3.78(s,3H),2.46(s,6H);13C NMR(101MHz,Chloroform-d)δ159.73,153.31,152.73,144.20,135.59,132.74,132.24,131.16,130.47,130.38,127.64,123.60,114.31,113.29,113.01,108.88,55.31,22.53;HRMS(ESI)m/z calcd.for C21H19ClNaO3S(M+Na)+:409.0636,found:409.0637;separationof enantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=92:8,1mL/min,minor retention time:7.55min,major retention time:6.94min,er=2.5:97.5;[α]D 20=-27.0(c=1.0,CHCl3).
实施例4:
一种轴手性含硫双芳基衍生物(化合物4)的合成方法
将0.1mmol 2'-氯-5'-甲基-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物4,收率为70%。
化合物4的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.45(d,J=8.2Hz,1H),7.23–7.12(m,2H),6.93(d,J=8.6Hz,1H),6.68(s,2H),6.48(d,J=8.6Hz,1H),6.17(s,1H),4.69(s,1H),3.78(s,3H),2.46(s,6H),2.38(s,3H);13C NMR(101MHz,Chloroform-d)δ159.73,153.23,152.61,144.25,137.77,133.13,132.44,132.04,131.28,130.57,130.23,123.56,114.30,113.36,113.01,108.81,55.31,22.54,21.01;HRMS(ESI)m/z calcd.for C22H21ClNaO3S(M+Na)+:423.0792,found:423.0788;separation of enantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=88:12,1mL/min,minor retention time:6.60min,majorretention time:5.33min,er=5:95;[α]D 20=-9.0(c=1.0,CHCl3).
实施例5:
一种轴手性含硫双芳基衍生物(化合物5)的合成方法
将0.1mmol 2'-氯-5'-甲氧基-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物5,收率为68%。
化合物5的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.46(d,J=8.8Hz,1H),6.97–6.91(m,2H),6.88(d,J=3.0Hz,1H),6.68(s,2H),6.48(d,J=8.6Hz,1H),6.19(s,1H),4.77(s,1H),3.81(s,3H),3.78(s,3H),2.46(s,6H);13C NMR(101MHz,Chloroform-d)δ159.76,158.89,153.17,152.55,144.27,132.11,131.78,131.19,126.70,123.50,117.54,116.34,114.32,113.34,113.12,108.88,55.77,55.31,22.53;HRMS(ESI)m/z calcd.for C22H21ClNaO4S(M+Na)+:439.0741,found:439.0737;separation of enantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=88:12,1mL/min,minor retention time:14.62min,majorretention time:8.22min,er=4.5:95.5;[α]D 20=-9.6(c=1.0,CHCl3).
实施例6:
一种轴手性含硫双芳基衍生物(化合物6)的合成方法
将0.1mmol 2'-氯-5'-氟-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物6,收率为79%。
化合物6的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.62–7.39(m,1H),7.10(m,2H),6.97(d,J=8.6Hz,1H),6.68(s,2H),6.46(d,J=8.6Hz,1H),6.28(s,1H),4.81(s,1H),3.78(s,3H),2.46(s,6H);13CNMR(101MHz,Chloroform-d)δ161.46(d,J=248.4Hz),159.78,153.25,152.79,144.14,133.33(d,J=8.4Hz),132.75,131.47(d,J=8.5Hz),130.43(d,J=3.3Hz),123.53,119.67(d,J=22.7Hz),117.22(d,J=22.7Hz),114.37,113.19,112.59(d,J=1.4Hz),109.05,55.32,22.52;19F NMR(376MHz,Methanol-d4)δ-118.92;HRMS(ESI)m/zcalcd.for C21H18ClFNaO3S(M+Na)+:427.0541,found:427.0539;separation ofenantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=95:5,1mL/min,minor retention time:13.00min,major retention time:11.70min,er=4:96;[α]D 20=-7.6(c=1.0,CHCl3).
实施例7:
一种轴手性含硫双芳基衍生物(化合物7)的合成方法
将0.1mmol 2',4'-二氯-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物7,收率为72%。
化合物7的结构式为:
1H NMR(400MHz,Methylene Chloride-d2)δ7.58(d,J=2.1Hz,1H),7.39(dd,J=8.2,2.1Hz,1H),7.29(d,J=8.2Hz,1H),6.94(d,J=8.6Hz,1H),6.69(s,2H),6.44(d,J=8.6Hz,1H),6.27(s,1H),5.03(s,1H),3.77(s,3H),2.45(s,6H);13C NMR(101MHz,MethyleneChloride-d2)δ160.34,154.00,153.41,144.64,136.62,135.58,134.08,132.89,130.92,130.39,128.20,123.96,114.70,113.65,112.87,109.25,55.72,22.66.HRMS(ESI)m/zcalcd.for C21H18Cl2NaO3S(M+Na)+:443.0246,found:443.0243;separation ofenantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=91:9,1mL/min,minor retention time:5.55min,major retention time:5.00min,er=4:96;[α]D 20=-18.6(c=1.0,CHCl3).
实施例8:
一种轴手性含硫双芳基衍生物(化合物8)的合成方法
将0.1mmol 2'-溴-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物8,收率为79%。
化合物8的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.76(dd,J=8.0,1.2Hz,1H),7.46(td,J=7.5,1.2Hz,1H),7.33(ddd,J=15.3,7.6,1.8Hz,2H),6.96(d,J=8.6Hz,1H),6.68(s,2H),6.48(d,J=8.6Hz,1H),6.18(s,1H),4.64(s,1H),3.78(s,3H),2.46(s,6H);13C NMR(101MHz,Chloroform-d)δ159.76,153.15,152.59,144.19,133.70,133.35,132.75,132.27,130.57,128.31,125.92,123.61,115.21,114.33,113.05,108.88,55.32,22.58;HRMS(ESI)m/zcalcd.for C21H19BrNaO3S(M+Na)+:453.0130,found:453.0126;separation ofenantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=85:15,1mL/min,minor retention time:5.44min,major retention time:4.91min,er=4.5:95.5;[α]D 20=-30.4(c=1.0,CHCl3).
实施例9:
一种轴手性含硫双芳基衍生物(化合物9)的合成方法
将0.1mmol 2'-((苄氧基)甲基)-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物9,收率为74%。
化合物9的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.60(dd,J=5.6,3.5Hz,1H),7.46(dd,J=5.7,3.3Hz,2H),7.38–7.16(m,6H),6.80(d,J=8.6Hz,1H),6.69(s,2H),6.51(d,J=8.6Hz,1H),6.08(s,1H),5.40(s,1H),4.44(d,J=2.3Hz,2H),4.32(q,J=10.7Hz,2H),3.79(s,3H),2.44(s,6H);13CNMR(101MHz,Chloroform-d)δ159.81,153.35,151.90,144.56,138.04,137.51,131.68,130.55,130.45,129.41,129.35,128.56,128.17,127.97,123.06,115.28,114.26,114.06,109.86,73.32,71.03,55.30,22.47;HRMS(ESI)m/z calcd.for C29H28NaO4S(M+Na)+:495.1601,found:495.1599;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=91:9,1mL/min,minor retention time:10.99min,major retention time:11.95min,er=6:94;[α]D 20=-28.8(c=1.0,CHCl3).
实施例10:
一种轴手性含硫双芳基衍生物(化合物10)的合成方法
将0.1mmol 2'-(甲氧基甲基)-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物10,收率为66%。
化合物10的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.58(dd,J=5.6,3.5Hz,1H),7.47(dd,J=5.6,3.4Hz,2H),7.29(dd,J=5.6,3.4Hz,1H),6.80(d,J=8.6Hz,1H),6.70(s,2H),6.51(d,J=8.6Hz,1H),6.14(s,1H),5.53(s,1H),4.49–4.13(m,2H),3.80(s,3H),3.31(s,3H),2.46(s,6H);13C NMR(101MHz,Chloroform-d)δ159.82,153.38,151.93,144.57,137.82,131.75,130.45,130.30,129.40,129.38,123.08,115.40,114.26,114.25,109.97,73.52,58.73,55.32,22.46;HRMS(ESI)m/z calcd.for C23H24NaO4S(M+Na)+:419.1288,found:419.1283;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=92:8,1mL/min,minor retention time:11.40min,major retention time:12.53min,er=6:94;[α]D 20=-55.6(c=1.0,CHCl3).
实施例11:
一种轴手性含硫双芳基衍生物(化合物11)的合成方法
将0.1mmol 2'-((苄氧基)甲基)-5'-氯-[1,1'-联苯]-2,6-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物11,收率为67%。
化合物11的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.53(d,J=8.3Hz,1H),7.42(dd,J=8.2,2.2Hz,1H),7.35–7.17(m,6H),6.87(d,J=8.6Hz,2H),6.69(s,2H),6.51(d,J=8.6Hz,1H),6.17(s,1H),5.45(s,1H),4.44(m 2H),4.34–4.20(m,2H),3.79(s,3H),2.44(s,6H);13C NMR(101MHz,Chloroform-d)δ159.85,153.50,152.11,144.39,137.33,136.43,134.76,133.87,131.59,131.42,129.29,128.60,128.15,128.06,123.08,114.34,114.21,113.99,110.20,73.35,70.31,55.32,22.50;HRMS(ESI)m/z calcd.for C29H27ClNaO4S(M+Na)+:529.1211,found:529.1212;separation of enantiomers by HPLC,Column OD-H,30℃,n-hexane:i-PrOH=90:10,1mL/min,minor retention time:9.35min,majorretention time:12.93min,er=6.5:93.5;[α]D 20=-27.0(c=1.0,CHCl3).
实施例12:
一种轴手性含硫双芳基衍生物(化合物12)的合成方法
将0.1mmol N-(2',6'-二羟基-[1,1'-联苯]-2-基)乙酰胺、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌40小时。通过硅胶纯化粗混合物,得到白色固体,即化合物12,收率为67%。
化合物12的结构式为:
1H NMR(400MHz,D4-MeOD)δ7.70–7.65(m,1H),7.37(ddd,J=8.2,6.5,2.5Hz,1H),7.32–7.25(m,2H),6.76(s,2H),6.42(d,J=8.6Hz,1H),6.35(d,J=8.6Hz,1H),3.79(s,3H),2.42(s,6H),1.96(s,3H);13C NMR(126MHz,D4-MeOD)δ172.40,161.48,155.14,153.46,146.18,137.71,133.57,130.02,129.27,126.93,126.55,124.22,116.58,115.36,115.14,109.68,55.77,23.50,22.49;HRMS(APCI)m/z calcd.for C23H24NO4S(M+H)+:410.1421,found:410.1420;separation of enantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=65:35,1mL/min,minor retention time:6.24min,major retentiontime:6.73min,er=12:88;[α]D 20=-57.6(c=1.0,CHCl3).
实施例13:
2,4,6-三甲基-硫芳基试剂的合成方法
将干燥的5mL正己烷加入到装有氢化钠(15mmol)的圆底烧瓶中,摇晃并静置15-20分钟后,吸走上清液并重复三次,之后用氩气吹干剩余的正己烷。接下来将装有氢化钠的圆底烧瓶置于氩气下保护并加入干燥的四氢呋喃(40mL),同时于室温下将邻磺酰苯酰亚胺(15mmol)溶于干燥的四氢呋喃(24mL)中并缓慢滴加入装有氢化钠的圆底烧瓶中,于室温下继续反应18小时后,将体系在0摄氏度下浓缩后,并将体系用油泵抽干,真空度为10mmHg左右,即可制备得到邻磺酰苯酰亚胺的钠盐,为白色固体。
将邻磺酰苯酰亚胺的钠盐溶于干燥的二氯甲烷(30mL)中,惰性气氛及0摄氏度下缓慢加入2,4,6-三甲基苯次磺酰氯(15mmol)的二氯甲烷溶液(15mL)并在该温度下反应2小时,之后于室温下进行反应3小时,分别用丙酮和苯溶解过滤,用苯和正己烷结晶,用油泵抽干,真空度为10mmHg左右,制备得到N-硫2,6-二甲基-4-甲氧基苯邻磺酰苯酰亚胺,为白色固体,两步总产率为15%。Data for 3b:1H NMR(400MHz,CDCl3)δ8.08(dd,J=6.9,1.3Hz,1H),7.93–7.67(m,3H),6.97(s,2H),2.78(s,6H),2.27(s,3H);13C NMR(101MHz,CDCl3)δ159.73,145.32,142.52,138.17,135.30,134.45,129.71,127.91,127.44,125.75,121.38,22.49,21.39;HRMS(ESI)m/z calcd.for C16H15NNaO3S2(M+Na)+:356.0386,found:356.0385.
一种轴手性含硫双芳基衍生物(化合物13)的合成方法
将0.1mmol 2'-氯-[1,1'-联苯]-2,6-二醇、0.15mmol 2-(均三硫代)苯并[d]异噻唑-3(2H)-一个1,1-二氧化物和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于1mL氘代氯仿在-60℃下搅拌40小时,然后升温至-10度搅拌反应5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物13,收率为89%。
化合物13为:
1H NMR(400MHz,CDCl3)δ7.63–7.51(m,1H),7.47–7.31(m,3H),6.98(d,J=8.6Hz,1H),6.94(s,2H),6.48(d,J=8.7Hz,1H),6.23(s,1H),4.76(s,1H),2.43(s,6H),2.27(s,3H);13CNMR(101MHz,CDCl3)δ153.47,152.97,142.25,138.78,135.60,132.75,132.68,131.19,130.45,130.36,129.74,129.25,127.62,113.29,112.57,108.91,22.10,21.11;HRMS(ESI)m/z calcd.for C21H19ClNaO2S(M+Na)+:393.0686,found:393.0684;separationof enantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=92:8,1mL/min,minor retention time:5.66min,major retention time:5.32min,er=10:90;[α]D 20=-52.4(c=1.0,CHCl3).
实施例14:
一种轴手性含硫双芳基衍生物(化合物14)的合成方法
将0.1mmol 2-(萘-1-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物14,收率为84%。
化合物14的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.96(dd,J=13.5,8.2Hz,2H),7.71–7.39(m,5H),6.91(d,J=8.6Hz,1H),6.72(s,2H),6.56(d,J=8.6Hz,1H),5.92(s,1H),4.68(s,1H),3.80(s,3H),2.50(s,6H);13C NMR(101MHz,Chloroform-d)δ159.82,153.48,152.46,144.54,134.36,132.29,130.99,129.82,129.36,128.80,128.74,127.16,126.78,126.07,125.39,123.12,114.30,113.45,113.38,108.74,55.31,22.52;HRMS(ESI)m/z calcd.forC25H22NaO3S(M+Na)+:425.1182,found:425.1185;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=88:12,1mL/min,minor retention time:9.03min,major retention time:10.06min,er=5:95;[α]D 20=-64.2(c=1.0,CHCl3).
实施例15:
一种轴手性含硫双芳基衍生物(化合物15)的合成方法
将0.1mmol 5-(2,6-二羟基苯基)-1-萘腈、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌35小时。通过硅胶纯化粗混合物,得到白色固体,即化合物15,收率为82%。
化合物15的结构式为:
1H NMR(400MHz,Chloroform-d)δ8.46–8.32(m,1H),7.97(dd,J=7.1,1.2Hz,1H),7.84(m,2H),7.65(dd,J=7.1,1.2Hz,1H),7.51(dd,J=8.6,7.1Hz,1H),7.01(d,J=8.6Hz,1H),6.70(s,2H),6.56(d,J=8.6Hz,1H),6.10(s,1H),4.67(s,1H),3.80(s,3H),2.48(s,6H);13C NMR(101MHz,DMSO-d6)δ159.35,154.13,152.31,144.47,134.20,132.94,132.03,131.81,130.49,128.89,127.02,125.28,123.65,122.46,117.98,114.41,114.14,114.01,108.99,108.13,55.10,21.80;HRMS(ESI)m/z calcd.for C26H21NNaO3S(M+Na)+:450.1134,found:450.1135;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=75:25,1mL/min,minor retention time:7.10min,major retentiontime:7.93min,er=4.5:95.5;[α]D 20=-79.2(c=0.5,CHCl3).
实施例16:
一种轴手性含硫双芳基衍生物(化合物16)的合成方法
将0.1mmol 2-(5-硝基萘-1-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-60℃下搅拌36小时。通过硅胶纯化粗混合物,得到白色固体,即化合物16,收率为65%。
化合物16的结构式为:
1H NMR(400MHz,Chloroform-d)δ8.64(dt,J=8.8,1.1Hz,1H),8.23(dd,J=7.6,1.2Hz,1H),7.98–7.75(m,2H),7.65(dd,J=7.1,1.1Hz,1H),7.52(dd,J=8.5,7.6Hz,1H),7.02(d,J=8.7Hz,1H),6.71(s,2H),6.56(d,J=8.6Hz,1H),6.11(s,1H),4.68(s,1H),3.80(s,3H),2.49(s,6H);13C NMR(101MHz,DMSO-d6)δ159.33,154.08,152.25,146.90,144.45,133.83,133.26,132.21,130.32,129.21,126.97,124.46,124.42,123.13,122.41,121.36,114.66,114.16,113.98,108.10,55.06,21.76;HRMS(ESI)m/z calcd.for C25H21NNaO5S(M+Na)+:470.1033,found:470.1032;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=90:10,1mL/min,minor retention time:19.65min,major retention time:24.20min,er=3.5:96.5;[α]D 20=-118.4(c=0.5,CHCl3).
实施例17:
一种轴手性含硫双芳基衍生物(化合物17)的合成方法
将0.1mmol N-(5-(2,6-二羟基苯基)萘-1-基)-4-甲苯磺酰胺,实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-60℃下搅拌40小时。通过硅胶纯化粗混合物,得到白色固体,即化合物17,收率为90%。
化合物17的结构式为:
1H NMR(400MHz,CDCl3)δ8.06(dt,J=8.5,1.2Hz,1H),7.73–7.62(m,2H),7.58–7.39(m,3H),7.34–7.23(m,2H),7.21(d,J=8.2Hz,2H),7.01(s,1H),6.91(d,J=8.6Hz,1H),6.71(s,2H),6.53(d,J=8.6Hz,1H),5.99(s,1H),4.74(s,1H),3.79(s,3H),2.48(s,6H),2.38(s,3H);13C NMR(101MHz,CDCl3)δ159.86,153.50,152.47,144.48,144.10,136.47,133.22,132.14,131.29,130.40,129.83,129.80,129.65,127.59,126.77,126.44,124.87,123.70,123.63,123.08,114.33,113.53,113.26,108.91,55.32,22.51,21.69;HRMS(APCI)m/z calcd.for C32H30NO5S2(M+H)+:572.1560,found:572.1559;separation ofenantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=60:40,1mL/min,minor retention time:15.38min,major retention time:20.02min,er=7.5:92.5;[α]D 20=-45.8(c=1.0,CHCl3).
实施例18:
一种轴手性含硫双芳基衍生物(化合物18)的合成方法
将0.1mmol N-(4-(2,6-二羟基苯基)萘-1-基)-4-甲苯磺酰胺,实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-60℃下搅拌24小时。然后升温至-20度搅拌反应5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物18,收率为59%。
化合物18的结构式为:
1H NMR(400MHz,CDCl3)δ8.03–7.83(m,1H),7.77–7.67(m,2H),7.54(dd,J=8.3,1.5Hz,1H),7.49–7.39(m,3H),7.37(d,J=7.7Hz,1H),7.21(d,J=8.0Hz,3H),6.90(d,J=8.6Hz,1H),6.71(s,2H),6.53(d,J=8.6Hz,1H),5.99(s,1H),4.77(s,1H),3.79(s,3H),2.48(s,6H),2.37(s,3H);13C NMR(101MHz,CDCl3)δ159.85,153.55,152.52,144.47,144.22,136.68,133.10,132.92,131.33,129.89,129.24,129.01,127.80,127.52,127.42,127.35,126.14,123.10,122.10,121.46,114.33,113.50,112.92,108.91,55.32,22.51,21.68;HRMS(APCI)m/z calcd.for C32H30NO5S2(M+H)+:572.1560,found:572.1553;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=60:40,1mL/min,minor retention time:14.84min,major retention time:18.16min,er=4.5:95.5;[α]D 20=-46.0(c=1.0,CHCl3).
实施例19:
一种轴手性含硫双芳基衍生物(化合物19)的合成方法
将0.1mmol 2-(4-苯基萘-1-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物19,收率为75%。
化合物19的结构式为:
1H NMR(400MHz,Chloroform-d)δ8.12–7.84(m,1H),7.75–7.62(m,1H),7.59–7.42(m,9H),6.95(d,J=8.6Hz,1H),6.72(s,2H),6.58(d,J=8.7Hz,1H),6.01(s,1H),4.76(s,1H),3.81(s,3H),2.51(s,6H);13C NMR(101MHz,Chloroform-d)δ159.85,153.66,152.61,144.53,142.02,140.46,132.64,132.59,131.20,130.21,128.89,128.52,128.28,127.70,127.13,126.99,126.84,125.69,123.17,114.33,113.49,113.43,108.81,55.33,22.56;HRMS(ESI)m/z calcd.for C31H26NaO3S(M+Na)+:501.1495,found:501.1497;separation ofenantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=88:12,1mL/min,minor retention time:9.37min,major retention time:10.55min,er=4:96;[α]D 20=-68.0(c=1.0,CHCl3).
实施例20:
一种轴手性含硫双芳基衍生物(化合物20)的合成方法
将0.1mmol 2-(4-溴代萘-1-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌40小时。通过硅胶纯化粗混合物,得到白色固体,即化合物20,收率为89%。
化合物20的结构式为:/>
1H NMR(400MHz,Chloroform-d)δ8.35(d,J=8.5Hz,1H),7.92(d,J=7.6Hz,1H),7.66(ddd,J=8.4,6.6,1.5Hz,1H),7.58(dd,J=8.6,1.5Hz,1H),7.52(ddd,J=8.3,6.6,1.2Hz,1H),7.36(d,J=7.5Hz,1H),6.96(d,J=8.6Hz,1H),6.71(s,2H),6.55(d,J=8.6Hz,1H),6.01(s,1H),4.62(s,1H),3.80(s,3H),2.49(s,6H);13C NMR(101MHz,Chloroform-d)δ159.88,153.56,152.68,144.42,133.50,132.86,131.74,130.20,129.56,129.27,128.16,128.04,127.89,126.04,124.72,123.15,114.37,113.46,112.74,108.92,55.34,22.55;HRMS(ESI)m/z calcd.for C25H21BrNaO3S(M+Na)+:503.0287,found:503.0283;separationof enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=88:12,1mL/min,minor retention time:8.74min,major retention time:10.13min,er=7.5:92.5;[α]D 20=-72.2(c=1.0,CHCl3).
实施例21:
一种轴手性含硫双芳基衍生物(化合物21)的合成方法
将0.1mmol 2-(8-甲基萘-1-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物21,收率为62%。
化合物21的结构式为:
1H NMR(400MHz,Chloroform-d)δ8.05–7.92(m,1H),7.81(d,J=8.1Hz,1H),7.62–7.51(m,1H),7.40(ddd,J=7.8,4.8,3.4Hz,2H),7.27(m,1H),6.87(d,J=8.6Hz,1H),6.70(s,2H),6.49(d,J=8.6Hz,1H),5.78(s,1H),4.55(s,1H),3.80(s,3H),2.47(s,6H),2.16(s,3H);13CNMR(101MHz,Chloroform-d)δ159.85,153.20,152.10,144.55,135.83,135.20,131.98,131.56,131.38,130.58,130.44,128.17,127.80,126.27,125.54,122.91,118.52,114.29,113.20,108.32,55.32,22.72,22.54;HRMS(ESI)m/z calcd.for C26H24NaO3S(M+Na)+:439.1338,found:439.1338;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=90:10,1mL/min,minor retention time:10.91min,majorretention time:12.01min,er=10:90;[α]D 20=-126.8(c=0.5,CHCl3).
实施例22:
一种轴手性含硫双芳基衍生物(化合物22)的合成方法
将0.1mmol 2-(4-氟萘-1-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物22,收率为69%。
化合物22的结构式为:
1H NMR(400MHz,Chloroform-d)δ8.21(dt,J=8.3,1.0Hz,1H),7.65–7.49(m,3H),7.45(dd,J=7.8,5.4Hz,1H),7.33–7.19(m,1H),6.94(d,J=8.6Hz,1H),6.71(s,2H),6.55(d,J=8.6Hz,1H),5.97(s,1H),4.65(s,1H),3.80(s,3H),2.49(s,6H);13C NMR(101MHz,Chloroform-d)δ159.73,159.46(d,J=254.6Hz),153.59,152.65,144.33,133.66(d,J=5.1Hz),131.33,129.19(d,J=8.5Hz),127.93,126.94(d,J=2.1Hz),125.39(d,J=2.7Hz),124.68(d,J=4.6Hz),124.54(d,J=16.3Hz),123.01,121.20(d,J=5.3Hz),114.22,113.30,112.60,109.72(d,J=20.1Hz),108.67,55.20,22.41;19F NMR(376MHz,Chloroform-d)δ-120.77;HRMS(ESI)m/z calcd.for C25H21FNaO3S(M+Na)+:443.1088,found:443.1087;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=88:12,1mL/min,minor retention time:7.56min,major retentiontime:8.64min,er=3.5:96.5;[α]D 20=-94.0(c=1.0,CHCl3).
实施例23:
一种轴手性含硫双芳基衍生物(化合物23)的合成方法
将0.1mmol 4-(2,6-二羟基苯基)-1-萘腈、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌40小时。通过硅胶纯化粗混合物,得到白色固体,即化合物23,收率为80%。
化合物23的结构式为:
Mp:246.1~251.0℃.1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.51(s,1H),8.18(t,J=8.1Hz,2H),7.79(ddd,J=8.2,6.7,1.4Hz,1H),7.67–7.55(m,2H),7.49(d,J=7.4Hz,1H),6.84(s,2H),6.54–6.17(m,2H),3.77(s,3H),2.39(s,6H);13C NMR(101MHz,DMSO-d6)δ159.33,153.88,152.04,144.41,139.43,132.91,132.20,131.96,128.58,128.44,127.39,127.01,124.43,122.45,117.99,114.21,114.16,113.99,108.15,108.04,55.07,21.76;HRMS(ESI)m/zcalcd.for C26H21NNaO3S(M+Na)+:450.1134,found:450.1136;separation ofenantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=80:20,1mL/min,minor retention time:6.95min,major retention time:8.16min,er=4:96;[α]D 20=-100.8(c=0.5,CHCl3).
实施例24:
一种轴手性含硫双芳基衍生物(化合物24)的合成方法
将0.1mmol 2-(荧蒽-3-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物24,收率为50%。
化合物24的结构式为:
1H NMR(400MHz,Chloroform-d)δ8.05(d,J=7.0Hz,1H),8.02–7.88(m,3H),7.72–7.52(m,3H),7.41(m,2H),6.93(m,1H),6.72(s,2H),6.57(m,1H),6.02(s,1H),4.83(s,1H),3.80(s,3H),2.51(s,6H);13C NMR(101MHz,Chloroform-d)δ159.87,153.62,152.59,144.55,139.78,139.07,138.48,137.74,133.33,131.27,131.04,129.47,129.03,128.86,128.25,127.98,125.19,123.10,121.94,121.83,120.95,120.42,114.34,113.51,112.64,108.84,55.34,22.56;HRMS(ESI)m/z calcd.for C31H24NaO3S(M+Na)+:499.1338,found:499.1339;separation of enantiomers by HPLC,Column OD-H,30℃,n-hexane:i-PrOH=75:25,1mL/min,minor retention time:16.54min,major retentiontime:10.85min,er=4:96;[α]D 20=-110.0(c=0.5,CHCl3).
实施例25:
一种轴手性含硫双芳基衍生物(化合物25)的合成方法
将0.1mmol 2-(9-苄基-9H-咔唑-4-基)苯-1,3-二醇,0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-60℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物25,收率为90%。
化合物25的结构式为:
1H NMR(400MHz,CDCl3)δ7.57(dd,J=8.3,7.1Hz,1H),7.49(m,1H),7.42–7.38(m,2H),7.35–7.24(m,4H),7.21(dt,J=6.3,1.1Hz,3H),7.04(ddd,J=8.0,5.7,2.5Hz,1H),6.95(d,J=8.6Hz,1H),6.73(s,2H),6.62(d,J=8.7Hz,1H),5.94(s,1H),5.57(s,2H),4.92(s,1H),3.81(s,3H),2.52(s,6H);13C NMR(101MHz,CDCl3)δ159.85,153.21,152.12,144.68,141.64,141.06,136.97,130.84,129.02,127.79,126.71,126.65,126.54,125.01,123.08,122.23,122.13,122.01,121.99,119.89,114.30,114.15,113.68,109.96,108.97,108.81,55.33,46.91,22.58;HRMS(APCI)m/z calcd.for C34H30NO3S(M+H)+:532.1941,found:532.1934;separation of enantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=65:35,1mL/min,minor retention time:9.78min,major retentiontime:11.86min,er=11:89;[α]D 20=-42.2(c=1.0,CHCl3).
实施例26:
一种轴手性含硫双芳基衍生物(化合物26)的合成方法
将0.1mmol 2-(二苯并[b,d]呋喃-1-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物26,收率为79%。
化合物26的结构式为:
Mp:>340.0℃.1H NMR(400MHz,Chloroform-d)δ7.67(d,J=8.2Hz,1H),7.63–7.53
(m,2H),7.50–7.38(m,1H),7.33(d,J=7.3Hz,1H),7.20–7.10(m,2H),7.04(d,J=8.6Hz,1H),6.72(s,2H),6.60(d,J=8.6Hz,1H),6.08(s,1H),4.92(s,1H),3.80(s,3H),2.51(s,6H);13CNMR(101MHz,Chloroform-d)δ159.86,156.89,156.45,153.36,152.50,144.42,131.87,127.93,127.70,125.84,125.39,124.02,123.51,123.07,123.05,122.01,114.38,113.51,112.95,112.38,111.64,108.95,55.32,22.57;HRMS(ESI)m/z calcd.forC27H22NaO4S(M+Na)+:465.1131,found:465.1128;separation of enantiomers by HPLC,Column OD-H,30℃,n-hexane:i-PrOH=88:12,1mL/min,minor retentiontime:10.69min,major retention time:12.37min,er=5:95;[α]D 20=-147.4(c=1.0,CHCl3).
实施例27:
一种轴手性含硫双芳基衍生物(化合物27)的合成方法
将0.1mmol 2-(菲-9-基)苯-1,3-二醇、0.15mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-70℃下搅拌24小时,然后升温至-20℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物27,收率为53%。
化合物27的结构式为:
1H NMR(400MHz,Chloroform-d)δ8.78(dd,J=14.3,8.3Hz,2H),7.92(dd,J=7.8,1.4Hz,1H),7.84(s,1H),7.78–7.69(m,2H),7.68–7.62(m,2H),7.57(m,1H),6.93(d,J=8.6Hz,1H),6.72(s,2H),6.59(d,J=8.6Hz,1H),5.96(s,1H),4.80(s,1H),3.81(s,3H),2.51(s,6H);13CNMR(101MHz,Chloroform-d)δ159.87,153.66,152.63,144.60,131.55,131.28,131.05,131.01,130.73,130.58,129.09,127.79,127.69,127.56,127.45,127.24,126.27,123.30,123.09,122.88,114.33,113.53,113.39,108.83,55.34,22.56;HRMS(ESI)m/z calcd.for C29H24NaO3S(M+Na)+:475.1338,found:475.1337;separation ofenantiomers by HPLC,Column IF,30℃,n-hexane:i-PrOH=82:18,1mL/min,minor retention time:12.02min,major retention time:12.94min,er=4:96;[α]D 20=-50.4(c=1.0,CHCl3).
实施例28:
一种轴手性含硫双芳基衍生物(化合物28)的合成方法
将0.1mmol 2-(萘-1-基)苯-1,3-二醇、0.15mmol实施例13得2,4,6-三甲基-硫芳基试剂和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-60℃下搅拌24小时,然后升温至-10℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物28,收率为70%。
化合物28的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.96(ddt,J=13.7,8.1,1.0Hz,2H),7.70–7.32(m,5H),7.04–6.88(m,3H),6.56(d,J=8.6Hz,1H),5.96(s,1H),4.72(s,1H),2.47(s,6H),2.30(s,3H);13C NMR(101MHz,Chloroform-d)δ153.69,152.76,142.57,138.85,134.35,132.29,131.55,129.80,129.72,129.34,128.88,128.85,128.74,127.14,126.77,126.07,125.40,113.38,112.94,108.78,22.11,21.15;HRMS(ESI)m/z calcd.for C25H22NaO2S(M+Na)+:409.1233,found:409.1231;separation of enantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=94:6,1mL/min,minor retention time:7.01min,major retention time:6.67min,er=11.5:88.5;[α]D 20=-52.4(c=1.0,CHCl3).
实施例29:
一种轴手性含硫双芳基衍生物(化合物29)的合成方法
将0.1mmol 2-(萘-1-基)苯-1,3-二醇、0.15mmol 2,6-二甲基-硫芳基试剂(N-硫2,6-二甲基苯邻磺酰苯酰亚胺)和0.01mmol实施例1得催化剂,以及0.01mmol 4-氯苯磺酸溶于0.5mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-60℃下搅拌24小时,然后升温至-10℃搅拌5小时。通过硅胶纯化粗混合物,得到白色固体,即化合物29,收率为83%。
化合物29的结构式为:
1H NMR(400MHz,CDCl3)δ8.11–7.90(m,2H),7.75–7.37(m,5H),7.16(q,J=5.4Hz,3H),6.96(d,J=8.6Hz,1H),6.56(d,J=8.6Hz,1H),5.94(s,1H),4.73(s,1H),2.51(s,6H);13CNMR(101MHz,CDCl3)δ153.82,152.85,142.72,134.36,132.40,132.28,131.76,129.84,129.35,128.84,128.80,128.76,127.17,126.79,126.08,125.37,113.42,112.55,108.84,22.23;HRMS(ESI)m/z calcd.for C24H20NaO2S(M+Na)+:395.1076,found:395.1077;separation of enantiomers by HPLC,Column IE,30℃,n-hexane:i-PrOH=92:8,1mL/min,minor retention time:8.47min,major retention time:10.50min,er=11:89;[α]D 20=-84.2(c=1.0,CHCl3).
实施例30:
一种轴手性含硫双芳基衍生物(化合物30)的合成方法
将0.1mmol 2',3'-二甲基-[1,1':4',1”-三苯基]-2,2”,6,6”-四醇、0.3mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.02mmol实施例1得催化剂,以及0.02mmol 4-氯苯磺酸溶于1.0mL氘代氯仿:氘代二氯甲烷(v:v=1:1),在-60℃下搅拌36小时,三乙胺淬灭反应。通过硅胶纯化粗混合物,得到白色固体,即化合物30,收率为28%。
化合物30的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.28(s,2H),6.94(d,J=8.6Hz,2H),6.71(s,4H),6.53(d,J=8.6Hz,2H),6.20(s,2H),5.03(s,2H),3.81(s,6H),2.49(s,12H),2.15(s,6H);13C NMR(101MHz,Chloroform-d)δ159.78,153.42,152.22,144.23,139.19,132.00,131.52,129.35,123.50,115.08,114.34,112.76,108.93,55.33,22.54,17.16;HRMS(ESI)m/z calcd.for C38H38NaO6S2(M+Na)+:677.2002,found:677.1995;separation ofenantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=94:6,1mL/min,minor retention time:12.41min,major retention time:9.95min,er=2.5:97.5;[α]D 20=-37.6(c=1.0,CHCl3).
实施例31:
一种轴手性含硫双芳基衍生物(化合物31)的合成方法
将0.1mmol 2,2'-(萘-1,4-二酰基)双(苯-1,3-二醇)、0.3mmol实施例1得2,6-二甲基,4-甲氧基-硫芳基试剂和0.02mmol实施例1得催化剂,以及0.02mmol 4-氯苯磺酸溶于1.0mL氘代氯仿,在-70℃下搅拌36小时,三乙胺淬灭反应。通过硅胶纯化粗混合物,得到白色固体,即化合物31,收率为58%。
化合物31的结构式为:
Mp:145.1~147.7℃.1H NMR(400MHz,Chloroform-d)δ7.67(dd,J=6.4,3.3Hz,2H),7.64(s,2H),7.51(dd,J=6.5,3.2Hz,2H),7.00(d,J=8.6Hz,2H),6.71(s,4H),6.59(d,J=8.6Hz,2H),6.17(s,2H),4.96(s,2H),3.80(s,6H),2.51(s,12H);13C NMR(101MHz,Chloroform-d)δ159.86,153.99,152.80,144.35,133.10,131.97,130.86,129.35,127.64,126.16,123.34,114.38,113.17,113.11,109.17,55.34,22.59;HRMS(ESI)m/z calcd.forC40H36NaO6S2(M+Na)+:699.1846,found:699.1843;separation of enantiomers by HPLC,Column IE,30℃,n-hexane:i-PrOH=85:15,1mL/min,minor retention time:19.18min,major retention time:20.63min,er=0.5:99.5;[α]D 20=-84.5(c=0.4,CHCl3).
实施例32:
一种轴手性含硫双芳基衍生物(化合物32)的合成方法
在干燥的反应管中,氩气条件下,将0.05mmol实施例1得化合物1(92%ee)和0.125mmol3-氯过氧苯甲酸溶于超干二氯甲烷(0.5mL),室温下搅拌反应4小时,通过硅胶纯化粗混合物,得到白色固体,即化合物32,收率为99%。
化合物32的结构式为:
1H NMR(400MHz,Chloroform-d)δ9.70(s,1H),7.47–7.31(m,3H),7.24–7.13(m,2H),6.66(s,2H),6.56(d,J=8.9Hz,1H),5.30(s,1H),3.83(s,3H),2.64(s,6H),2.16(s,3H);13CNMR(101MHz,Chloroform-d)δ162.19,158.13,154.66,142.60,138.98,131.20,130.98,130.01,129.65,129.53,129.06,127.03,117.70,116.64,116.43,108.57,55.48,23.04,19.62;HRMS(ESI)m/z calcd.for C22H22NaO5S(M+Na)+:421.1080,found:421.1079;separation of enantiomers by HPLC,Column IC,30℃,n-hexane:i-PrOH=70:30,1mL/min,minor retention time:11.90min,major retention time:9.23min,er=4:96;[α]D 20=-35.4(c=1.0,CHCl3).
实施例33:
一种轴手性含硫双芳基衍生物(化合物33)的合成方法
在干燥的反应管中,氩气条件下,将0.05mmol实施例1得化合物1(92%ee)和0.05mmol NBS在-40℃下溶于超干二氯甲烷(0.5mL),氩气条件下搅拌反应8h,通过硅胶纯化粗混合物,得到白色固体,即化合物33,收率为83%。
化合物33的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.46–7.28(m,3H),7.24–7.19(m,1H),6.89(s,1H),6.73(s,2H),5.77(s,1H),5.25(s,1H),3.82(s,3H),2.46(s,6H),2.15(s,3H);13C NMR(101MHz,Chloroform-d)δ160.11,151.16,148.90,144.76,138.53,131.02,130.93,130.89,130.71,129.43,126.79,121.90,115.87,115.79,114.44,101.33,55.34,22.41,19.66;HRMS(ESI)m/z calcd.for C22H21BrNaO3S(M+Na)+:467.0287,found:467.0286;separation of enantiomers by HPLC,Column IA,30℃,n-hexane:i-PrOH=75:25,1mL/min,minor retention time:6.03min,major retention time:5.27min,er=5:95;[α]D 20=-261.0(c=1.0,CHCl3).
实施例34:
一种轴手性含硫双芳基衍生物(化合物34)的合成方法
在干燥的反应管中,氩气条件下,将0.045mmol实施例1得化合物1(92%ee)、0.045mmol3-氯过氧苯甲酸和0.225mmol NaHCO3在-20℃的超干二氯甲烷(0.5mL)中搅拌反应18小时,通过硅胶纯化粗混合物,得到白色固体,即化合物34,收率为97%。
化合物34的结构式为:
1H NMR(400MHz,Chloroform-d)δ10.89(s,1H),7.36(m,3H),7.25(m,1H),6.63(s,2H),6.48(s,2H),5.03(s,1H),3.83(s,3H),2.60(s,6H),2.18(s,3H);13C NMR(101MHz,Chloroform-d)δ162.44,157.31,155.72,142.69,138.87,131.20,131.12,131.08,130.02,129.41,126.97,125.22,117.37,115.49,112.39,107.73,55.47,19.86,19.61.HRMS(ESI)m/z calcd.for C22H23O4S(M+H)+:383.1312,found:383.1312;separation of enantiomersby HPLC,Column IC,30℃,n-hexane:i-PrOH=70:30,1mL/min,minorretention time:33.06min,major retention time:13.59min,er=4.5:95.5;[α]D 20=280.4(c=1.0,CHCl3).
实施例35:
一种轴手性含硫双芳基衍生物(化合物35)的合成方法
在干燥的反应管中,氩气条件下,将0.041mmol实施例1得化合物1(92%ee)、0.049mmol2-(苯硫基)苯并[d]异噻唑-3(2H)-酮1,1-二氧化物和0.004mmol对氯苯磺酸,在室温下溶于超干二氯甲烷(0.5mL),氩气条件下搅拌反应1.5h,通过硅胶纯化粗混合物,得到白色固体,即化合物35,收率为74%。
化合物35的结构式为:
1H NMR(400MHz,Chloroform-d)δ7.37–7.28(m,3H),7.26–7.18(m,3H),7.17–7.10(m,1H),7.06–6.95(m,3H),6.69(s,2H),6.34(s,1H),5.94(s,1H),3.79(s,3H),2.44(s,6H),2.15(s,3H);13C NMR(101MHz,Chloroform-d)δ159.99,153.99,153.86,144.67,138.22,136.47,136.10,131.58,130.77,130.64,129.26,129.01,126.61,126.48,126.15,122.08,115.35,115.31,114.40,108.57,55.31,22.40,19.72;HRMS(ESI)m/z calcd.forC28H26NaO3S2(M+Na)+:497.1216,found:497.1210;separation of enantiomers by HPLC,Column ID,30℃,n-hexane:i-PrOH=90:10,1mL/min,minor retention time:14.68min,major retention time:11.34min,er=4:96;[α]D 20=-10.2(c=1.0,CHCl3).
本发明的操作步骤中的常规操作为本领域技术人员所熟知,在此不进行赘述。
以上所述的实施例对本发明的技术方案进行了详细说明,应理解的是以上所述仅为本发明的具体实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改、补充或类似方式替代等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种式(I)所示轴手性含硫双芳基衍生物的合成方法,将式(II)所示双芳基苯酚与式(III)所示硫芳基试剂在催化剂、酸和溶剂的存在下发生反应,获得式(I)所示轴手性含硫双芳基衍生物;
(I);/>(II);/>(III);
R0选自、/>、/>、/>、或/>;
R、R1、R2各自独立地选自H、取代或未被取代的烷基、取代或未被取代的烯基、取代或未被取代的芳基、酰胺基、磺酰胺基、取代或未被取代的烷氧基、取代或未被取代的苄基、苄氧基、卤素、芳硫基、硝基或氰基;
R3选自H、取代或未被取代的烷基、取代或未被取代的烯基、取代或未被取代的芳基、取代或未被取代的苄基;
X选自Ar、Ar1或Ar2;Ar为,Ar1为/>,Ar2为/>;
所述催化剂为式(IV)所示3,3ʹ-二取代二联萘衍生硒化物催化剂,
(IV);
所述酸为对氯苯磺酸。
2.根据权利要求1所述的一种式(I)所述轴手性含硫双芳基衍生物的合成方法,其特征在于,所述R0为,R1、R2各自独立地选自H、取代或未被取代的烷基、取代或未被取代的烯基、取代或未被取代的芳基、酰胺基、磺酰胺基、取代或未被取代的烷氧基、取代或未被取代的苄基、苄氧基、卤素、芳硫基、硝基或氰基,R1、R2不同时为H。
3.根据权利要求1所述的一种式(I)所述轴手性含硫双芳基衍生物的合成方法,其特征在于,所述式(II)所示双芳基苯酚与式(III)所示硫芳基试剂的摩尔比为1:1.0-1.8。
4.根据权利要求1所述的一种式(I)所述轴手性含硫双芳基衍生物的合成方法,其特征在于,所述式(IV)所示3,3ʹ-二取代二联萘衍生硒化物催化剂和式(II)所示双芳基苯酚的摩尔比为0.05-0.12:1。
5.根据权利要求1所述的一种式(I)所述轴手性含硫双芳基衍生物的合成方法,其特征在于,所述溶剂选自氘代氯仿、氘代二甲亚砜、氘代甲醇、氘代乙醇或氘代二氯甲烷。
6.根据权利要求1所述的一种式(I)所述轴手性含硫双芳基衍生物的合成方法,其特征在于,所述轴手性含硫双芳基衍生物的对映体过量大于75%。
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