CN112321398A - Method for synthesizing alpha-fluorinated ketone by hydrazonating aliphatic chain monoketone - Google Patents
Method for synthesizing alpha-fluorinated ketone by hydrazonating aliphatic chain monoketone Download PDFInfo
- Publication number
- CN112321398A CN112321398A CN202011229918.5A CN202011229918A CN112321398A CN 112321398 A CN112321398 A CN 112321398A CN 202011229918 A CN202011229918 A CN 202011229918A CN 112321398 A CN112321398 A CN 112321398A
- Authority
- CN
- China
- Prior art keywords
- group
- reaction
- formula
- phenyl
- hydrazone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000002576 ketones Chemical class 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 20
- 125000001931 aliphatic group Chemical group 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 88
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 150000007857 hydrazones Chemical class 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000004122 cyclic group Chemical group 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003003 spiro group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000007810 chemical reaction solvent Substances 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 22
- 229920001971 elastomer Polymers 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- 238000007789 sealing Methods 0.000 description 17
- 238000003756 stirring Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 13
- 239000003480 eluent Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012467 final product Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 238000004293 19F NMR spectroscopy Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 230000006978 adaptation Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- -1 solubility Chemical class 0.000 description 4
- YOMBUJAFGMOIGS-UHFFFAOYSA-N 2-fluoro-1-phenylethanone Chemical class FCC(=O)C1=CC=CC=C1 YOMBUJAFGMOIGS-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- PATCUTBZBAERHM-UHFFFAOYSA-N 1-(4-bromophenyl)-2-fluoroethanone Chemical compound FCC(=O)C1=CC=C(Br)C=C1 PATCUTBZBAERHM-UHFFFAOYSA-N 0.000 description 2
- MBNBAODMHRPUKN-UHFFFAOYSA-N 2-fluoro-1-phenylbutan-1-one Chemical compound CCC(F)C(=O)C1=CC=CC=C1 MBNBAODMHRPUKN-UHFFFAOYSA-N 0.000 description 2
- RPMYYOMYKLOZNP-UHFFFAOYSA-N 2-fluoro-1-phenylpentan-1-one Chemical compound CCCC(F)C(=O)C1=CC=CC=C1 RPMYYOMYKLOZNP-UHFFFAOYSA-N 0.000 description 2
- UUDYBRGMAFZKMY-UHFFFAOYSA-N 2-fluoro-2,3-dihydroinden-1-one Chemical compound C1=CC=C2C(=O)C(F)CC2=C1 UUDYBRGMAFZKMY-UHFFFAOYSA-N 0.000 description 2
- LUGDFJYIDIDZRJ-UHFFFAOYSA-N 2-fluoro-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC=C2C(=O)C(F)CCC2=C1 LUGDFJYIDIDZRJ-UHFFFAOYSA-N 0.000 description 2
- HVDDEUVUHXFXEU-UHFFFAOYSA-N 3-fluoro-4-phenylbutan-2-one Chemical compound CC(=O)C(F)CC1=CC=CC=C1 HVDDEUVUHXFXEU-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005597 hydrazone group Chemical group 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- RVNDVQQSDJGOKA-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-fluoropropan-1-one Chemical compound CC(F)C(=O)C1=CC=C(Cl)C=C1 RVNDVQQSDJGOKA-UHFFFAOYSA-N 0.000 description 1
- AAUVTDFCHAFEND-UHFFFAOYSA-N 1-fluoro-1-(4-methoxyphenyl)propan-2-one Chemical compound COC1=CC=C(C(F)C(C)=O)C=C1 AAUVTDFCHAFEND-UHFFFAOYSA-N 0.000 description 1
- UZHUCKRPDJKLDZ-UHFFFAOYSA-N 1-fluoro-4-phenylbutan-2-one Chemical compound FCC(=O)CCC1=CC=CC=C1 UZHUCKRPDJKLDZ-UHFFFAOYSA-N 0.000 description 1
- RWELYCYPEFUDEH-UHFFFAOYSA-N 2-fluoro-1-phenylpropan-1-one Chemical compound CC(F)C(=O)C1=CC=CC=C1 RWELYCYPEFUDEH-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LSEZGKDGUYTMFT-UHFFFAOYSA-N COBr(C)(C#N)[N+]([O-])=S Chemical compound COBr(C)(C#N)[N+]([O-])=S LSEZGKDGUYTMFT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- MUMHLNVTWIKASW-UHFFFAOYSA-N benzyl hypofluorite Chemical compound FOCC1=CC=CC=C1 MUMHLNVTWIKASW-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical class BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- 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
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/80—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于有机合成技术领域，提供了一种通过腙化脂肪链单酮合成α‑氟化酮的方法，脂肪链单酮和水合肼反应得到腙，然后在加热条件下，和式2化合物反应完成脱腙氟化。氟化产物在药物中的应用广泛，反应条件温和，过程简单。The invention belongs to the technical field of organic synthesis, and provides a method for synthesizing α-fluorinated ketone by hydrazone-forming aliphatic chain monoketone. Complete dehydrazone fluorination. Fluorinated products are widely used in pharmaceuticals, the reaction conditions are mild, and the process is simple.
Description
Technical Field
The invention relates to a method for synthesizing alpha-fluorinated ketone from hydrazone fatty chain monoketone. Belongs to the field of organic chemical synthesis.
Background
The Van der Waals radius of fluorine atoms is closest to that of hydrogen atoms, and the bond energy of C-F bonds is far greater than that of C-H bonds, so that the organic fluorine compounds have pseudo-effect and blocking effect when participating in metabolic process in organisms. The strong electronegativity of fluorine affects the dipole moment and acid-base property of the compound, among others. Since fluorine is a hydrophobic atom, a fluorine-containing group has hydrophobicity. Therefore, in organic and pharmaceutical chemistry, after fluorine atoms are substituted for hydrogen and introduced into organic compounds, the pharmaceutical activity and biological activity of the original compounds, such as solubility, metabolic and oxidative stability, lipophilicity and the like, can be greatly changed.
Because the carbon-fluorine bond is strong, the carbon-fluorine bond can resist the metabolic chemical environment in vivo and improve the drug-induced level. Thus, the construction of C-F bonds is of great importance, whereas alpha-fluorinated ketones are an important component of organofluoro compounds. At present, a large number of methods for synthesizing alpha-fluorinated ketone starting from different substrates are reported. In 1996, the Marko Zupan research team reported neutralization of NFTh (1-fluoro-4-hydroxy-1, 4-diazabicyclo [2.2.2 ] with ketones as substrates in acetonitrile solvents]Octane bis (tetrafluoroborate) salt) was heated under reflux to achieve synthesis of alpha-fluorination of ketones (Stavber, n.; zupan, m., Tetrahedron Letters 1996,37(20), 3591-. In the year of 2008, it was,
helge Hoff group prepared by nucleophilic fluorination using para-substituted bromoacetophenone as substrate and TBAHF2Reaction of (tetra-n-butylammonium difluoride) in tetrahydrofuran solvent synthesized p-substituted α -fluoroacetophenones (fullseth, e.; Thvedt, t.h.k.;
M.F.; hoff, b.h., Tetrahedron 2008,64(30-31), 7318-. In 2011, the Mart1n-Matute research group published an article on the synthesis of highly regioselective alpha-fluorinated ketones by isomerization of allyl alcohol and electrophilic fluorination (Matute, B., Chem Commun (Camb)2011,47(29), 8331-3.).
However, the reaction for synthesizing α -fluorinated ketone using hydrazone as a substrate has not been reported so far, and needs to be complemented in the field of organic reactions.
Disclosure of Invention
Aiming at the technical blank of synthesizing alpha-fluorinated ketone by hydrazonating fatty chain monoketone in the prior art, the invention aims to provide a method for further performing alpha-fluorination by hydrazonating fatty chain monoketone with hydrazine hydrate.
A method for synthesizing alpha-fluorinated ketone from hydrazone with a hydrazone structure formula 1 and a compound with a structure formula 2 is used for carrying out a dehydrohydrazone fluorination reaction at a temperature of 50-100 ℃ to obtain an alpha-fluorinated ketone product with a formula 3;
R1is C1～C20The alkyl group, the five-membered or six-membered heterocyclic aryl group, the phenyl group, or the condensed ring aryl group formed by the condensation of two or more aromatic rings in the heterocyclic aryl group and the phenyl group; the alkyl, the heterocyclic aryl, the phenyl and the condensed ring aryl are allowed to have substituents;
said R2、R3Is alone H, C1～C6The alkyl group, the five-membered or six-membered heterocyclic aryl group, the phenyl group, or the condensed ring aryl group formed by the condensation of two or more aromatic rings in the heterocyclic aryl group and the phenyl group; the alkyl, the heterocyclic aryl, the phenyl and the condensed ring aryl are allowed to have substituents;
or, said R2、R3Form a cyclic group through ring closure; or R2、R3Any one of the groups and R1Cyclized to form a cyclic group; the cyclic group is five-membered or six-membered cycloalkyl, cycloalkenyl, aromatic group, or atoms or bonds shared by any two or more than two of the cycloalkyl, cycloalkenyl and aromatic group, so as to form a condensed ring, spiro or bridged ring; heteroatoms are allowed in the ring structure of the cyclic group, and substituents are allowed on the ring of the cyclic group.
At present, no technical report for directly carrying out alpha-fluorination on hydrazone and synchronously converting the hydrazone into the ketone exists in the industry, and in order to fill up the technical blank, the inventor of the invention surprisingly discovers that the hydrazone with the structure of formula 1 and the compound with the structure of formula 2 have specific adaptation effect after intensive research, can unexpectedly realize the alpha-fluorination and ketonization of the hydrazone, and can obtain the alpha-fluorinated ketone in one step; moreover, it has been found that further combination of the reaction temperature and the solvent control contributes to further improvement of the yield of the α -fluorinated ketone and the selectivity of the fluorination.
In the present invention, in order to successfully achieve specific adaptation to the compound of formula 2, the α -position of the hydrazone needs to contain C-H, and in addition, the hydrazone needs to be C ═ NNH2。
In the invention, R is1May be alkyl, for example may be straight or branched chain alkyl; preferred straight chain alkyl groups are C1-C6 alkyl groups; when the alkyl group is a branched alkyl group, the carbon at the center of the branched chain is preferably directly bonded to the unsaturated carbon of the hydrazone, and more preferably, R is1The carbon to which the hydrazone is attached is an alkyl group of a tertiary carbon, for example, a tert-butyl group.
In the present invention, the aromatic group is, for example, a heterocyclic aryl group, a phenyl group or a condensed ring aryl group. The heterocyclic aryl group is, for example, a five-membered or six-membered heterocyclic aryl group, and the heteroatom is, for example, N, O, S, P. In the present invention, the aromatic ring of the heterocyclic aryl group, the phenyl group or the condensed ring aryl group may have no substituent or may have a substituent. When substituted, the preferred substituent is C1～C6Alkyl of (C)1～C6Alkoxy, phenyl, benzyloxy, nitro, halogen, cyano, ester, trifluoromethyl, C1～C4Alkylthio or sulfonyl group of (a).
In the invention, R is2、R3Is alone H, C1～C6The alkyl group, the five-membered or six-membered heterocyclic aryl group, the phenyl group, or the condensed ring aryl group formed by condensing two or more aromatic rings in the heterocyclic aryl group and the phenyl group. The alkyl, the heterocyclic aryl, the phenyl and the condensed ring aryl do not contain a substituent or are allowed to have a substituent on an aromatic ring. When substituted, the preferred substituent is C1～C6Alkyl of (C)1～C6Alkoxy, phenyl, benzyloxy, nitro, halogen, cyano, ester, trifluoromethyl, C1～C4Alkylthio or sulfonyl group of (a).
In addition, the method can be used for producing a composite materialSaid R is2、R3May be mutually cyclized to form a cyclic group (cyclic group A); or R2、R3And R is1Ring-closure to form a cyclic group (cyclic group B); the cyclic group is a five-membered or six-membered saturated cycloalkyl, cycloalkenyl or aromatic group, or any two or more than two of the cycloalkyl, cycloalkenyl or aromatic group share atoms or bonds to form a condensed ring, a spiro ring or a bridged ring; the cyclic group allows the presence of a heteroatom, and the ring of the cyclic group allows the substitution. When substituted, the preferred substituent is C1～C6Alkyl of (C)1～C6Alkoxy, phenyl, benzyloxy, nitro, halogen, cyano, ester, trifluoromethyl, C1～C4Alkylthio or sulfonyl group of (a).
Preferably, R is2Is H.
Preferably, R3Is H or C1～C6Alkyl groups of (a); or, said R1、R3The ring closure forms a cyclic group. The cyclic group is preferably a five-or six-membered ring group, which is allowed to be fused with other heterocyclic aryl or phenyl groups.
More preferably, the hydrazone is represented by a structural formula 1-a or 1-b;
said R4～R7Independently of hydrogen, C1～C6Alkyl of (C)1～C6Alkoxy, phenyl, benzyloxy, nitro, halogen, cyano, ester, trifluoromethyl, C1～C4Alkylthio or sulfonyl of (a);
said R2Is H;
said R3Is hydrogen or C1～C6Alkyl groups of (a); further preferably H, methyl or propyl;
and n is an integer of 1 or 2.
In the present invention, when the hydrazone is represented by the formula 1-a, the corresponding product is represented by the formula 3-a
When the hydrazone is represented by the formula 1-b, the corresponding product is represented by the formula 3-b
Preferably, R4Is hydrogen, methyl, methoxy, methylthio, nitro, trifluoromethyl, benzyloxy, fluorine, bromine, chlorine atom or cyano.
Preferably, R5Is hydrogen, cyano, methoxy, methylthio, nitro, bromine or chlorine atom;
preferably, R6Is hydrogen, cyano, ester or trifluoromethyl;
preferably, R7Is hydrogen, alkyl, cycloalkyl or heterocycloalkyl.
In the invention, the hydrazone can be obtained by the existing means, and is preferably obtained by the hydrazonation reaction of the ketone shown in the formula 4 and hydrazine hydrate;
for example, the ketone of formula 4 and hydrazine hydrate are reacted at reflux in an alcohol solvent.
In the invention, on the basis of the specific adaptation of the hydrazone and the compound shown in the formula 2, the molar ratio, the reaction solvent and the reaction temperature of the hydrazone and the compound shown in the formula 2 are further controlled, which is favorable for further improving the synergy of the hydrazone and the compound shown in the formula 2 and is favorable for unexpectedly further improving the yield and the fluorination selectivity of the product.
Preferably, the molar ratio of hydrazone to the compound of formula 2 is 1: 1-10; preferably 1: 1-5; more preferably 1:1.5 to 2.5.
Preferably, the solvent of the reaction is acetonitrile. It was found that, for the synthesis system of the present invention, with the preferred solvent, it is possible to unexpectedly achieve an adaptive synergy between hydrazone and the compound of formula 2, which contributes to the successful realization of the synthesis of α -fluorinated ketones from hydrazone.
Preferably, the concentration of the compound shown in the formula 2 in the reaction initial solution is 0.05-0.4 mol/L; preferably 0.1-0.4 mol/L; more preferably 0.15 to 0.25 mol/L. In this preferred range, the yield of the product is significantly increased.
Preferably, the reaction temperature is 60-80 ℃; further preferably 65 to 75 ℃.
The process of the invention can be centrally controlled by means of chromatography. Preferably, the reaction time is 6-24 h; further preferably 6 to 18 hours.
Preferably, unlike conventional fluorination of ketones, the present invention can omit the base, and the omission of such necessary techniques can unexpectedly improve the production efficiency.
After the reaction is finished, extracting by a hydrophobic solvent, concentrating and extracting to obtain an organic phase, and purifying by chromatography to obtain the compound.
According to the technical scheme, after the reaction is finished, extracting reaction mixed liquid by dichloromethane, and carrying out reduced pressure rotary evaporation to obtain a crude product; and separating and purifying the crude product by a chromatographic column to obtain the final product. The eluent used by the chromatographic column is petroleum ether, the product with larger polarity is mixed eluent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 50: 1-1: 1.
The beneficial technology is as follows:
the technical scheme of the invention realizes the synthesis of alpha-fluorinated ketone from hydrazone fatty chain monoketone for the first time, and fills the gap in the prior art;
the invention innovatively discovers that the hydrazone with the special structure and the special compound shown as the formula 2 have specific adaptation, can realize alpha-fluorination and synchronous ketonization of the hydrazone, and can realize the aim of directly preparing the alpha-fluorone from the hydrazone for the first time in the industry.
The research of the invention also finds that on the basis of the specific adaptation of the hydrazone with the special structure and the special compound shown in the formula 2, the synergistic control of the proportion of the hydrazone with the special structure and the reaction solvent and the temperature is further matched, which is beneficial to further improving the preparation effect and improving the yield and the selectivity.
The technical scheme of the invention adopts a one-pot reaction, has mild process conditions, short flow, simple steps and wide substrate applicability, and meets the requirements of industrial production;
drawings
FIG. 1 shows the product obtained in example 11HNMR spectrogram.
FIG. 2 shows the product obtained in example 113CNMR spectrogram.
FIG. 3 shows the product obtained in example 119FNMR spectrogram.
FIG. 4 shows the product obtained in example 21HNMR spectrogram.
FIG. 5 shows the product obtained in example 213CNMR spectrogram.
FIG. 6 shows the product obtained in example 219FNMR spectrogram.
FIG. 7 shows the product obtained in example 31HNMR spectrogram.
FIG. 8 shows the product obtained in example 313CNMR spectrogram.
FIG. 9 shows the product obtained in example 319FNMR spectrogram.
The specific implementation mode is as follows:
the following examples are intended to illustrate the present invention, but not to further limit the scope of the claims.
The corresponding hydrazones can be prepared in analogy to the following procedure, as shown in the examples below:
a100 mL round-bottom flask equipped with a magnetic stirrer was charged with ketone of formula 4 (20mmol, 1eq) and 20mL of methanol, followed by hydrazine hydrate (60mmol, 3eq), sealed with a rubber stopper, and reacted for 3h in an oil bath at 80 ℃. The progress of the reaction was monitored by Thin Layer Chromatography (TLC) and, after completion of the reaction, cooled to room temperature. The reaction solution was extracted 3 times with 25mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary-evaporated under reduced pressure to give a crude product. The crude product can be used directly for the next step of synthesis or used for the next step of reaction after purification by silica gel chromatography.
Example 1
3-fluoro-4-phenyl-2-butanone is synthesized, separated and purified: respectively adding 4-phenyl-2-butylhydrazone (formula shown in Table 1: 0.5mmol, 1.0eq) and the compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, and sealing with a rubber stopper; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: the 3-fluoro-4-phenyl-2-butanone is colorless liquid, and the yield is 51 percent; no 1-fluoro-4-phenyl-2-butanone product is produced, and good selectivity is shown.
1H NMR(400MHz,CDCl3)δ：7.33-7.21(m,5H),4.93(ddd,J＝49.9,7.5,3.8Hz,1H),3.24-2.98(m,2H),2.13(d,J＝5.2Hz,3H).13C NMR(100MHz,CDCl3)δ：208.0(d,J＝26.2Hz),135.3,129.5,128.6,127.1,95.9(d,J＝188.1Hz),38.1(d,J＝20.5Hz),26.4.19F NMR(376MHz,CDCl3)δ：-188.1.
Example 2
2-fluoro-1-phenyl-1-acetone synthesis, separation and purification: respectively adding 1-phenyl-1-propylhydrazone (formula shown in Table 1: 0.5mmol, 1.0eq) and compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, and sealing with a rubber stopper; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: 2-fluoro-1-phenyl-1-propanone was a pale yellow liquid with a yield of 81%.
1H NMR(400MHz,CDCl3)δ：7.98(d,J＝7.8Hz,2H),7.60(t,J＝7.4Hz,1H),7.49(t,J＝7.6Hz,2H),5.71(dq,J＝48.6,6.8Hz,1H),1.66(dd,J＝24,6.8Hz,3H).13C NMR(100MHz,CDCl3)δ：196.9(d,J＝19.5Hz),134.0,133.7,128.9(d,J＝3.7Hz),128.7,90.2(d,J＝180.7Hz),18.3(d,J＝22.2Hz).19F NMR(376MHz,CDCl3)δ：-181.3.
Example 3
2-fluoro-1-phenyl-1-butanone is synthesized, separated and purified: respectively adding 1-phenyl-1-butylhydrazone (formula shown in Table 1: 0.5mmol, 1.0eq) and the compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, and sealing with a rubber stopper; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: 2-fluoro-1-phenyl-1-butanone was a colorless liquid with a yield of 75%.
1H NMR(400MHz,CDCl3)δ：7.96(d,J＝7.4Hz,2H),7.60(t,J＝7.4Hz,1H),7.49(t,J＝7.7Hz,2H),5.51(ddd,J＝49.3,7.6,4.5Hz,1H),2.12-1.92(m,2H),1.09(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ：196.8(d,J＝19.6Hz),134.4,133.7,128.8(d,J＝15.2Hz),128.7,94.8(d,J＝184.8Hz),26.1(d,J＝22.2Hz),9.0(d,J＝4.5Hz).19F NMR(376MHz,CDCl3)δ：-190.8.
Example 4
Synthesis, separation and purification of 2-fluoro-1-phenyl-1-pentanone: respectively adding 1-phenyl-1-pentahydrazone (formula shown in Table 1: 0.5mmol, 1.0eq) and a compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, and sealing with a rubber stopper; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: 2-fluoro-1-phenyl-1-pentanone was a colorless liquid with a yield of 71%.
1H NMR(400MHz,CDCl3)δ：7.96(d,J＝7.7Hz,2H),7.60(t,J＝7.4Hz,1H),7.49(t,J＝7.7Hz,2H),5.64-5.49(m,1H),2.04-1.88(m,2H),1.61-1.56(m,2H),0.99(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ：197.0(d,J＝19.6Hz),134.4,133.7,128.8(d,J＝3.8Hz),128.7,93.7(d,J＝183.9Hz),34.7(d,J＝21.3Hz),18.1(d,J＝3.4Hz),13.6.19F NMR(376MHz,CDCl3)δ：-189.7.
Example 5
Synthesizing, separating and purifying 2-fluoro-acetophenone: adding phenylhydrazone (formula shown in table 1: 0.5mmol, 1.0eq) and compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, respectively, and sealing with a rubber stopper; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: the 2-fluoro-acetophenone was a colorless liquid with a yield of 70%.
1H NMR(400MHz,CDCl3)δ：7.90(d,J＝7.5Hz,2H),7.63(t,J＝7.4Hz,1H),7.50(t,J＝7.7Hz,2H),5.53(d,J＝46.9Hz,2H).13C NMR(100MHz,CDCl3)δ：193.5(d,J＝15.5Hz),134.1,133.8,128.9,127.9(d,J＝2.6Hz),83.6(d,J＝183.8Hz,).19F NMR(376MHz,CDCl3)δ：-230.6.
Example 6
Synthesizing, separating and purifying 1-fluoro-1-p-methoxyphenyl-2-acetone: respectively adding 1-p-methoxyphenyl-2-propylhydrazone (formula shown in Table 1: 0.5mmol, 1.0eq) and the compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, and sealing with a rubber stopper; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: 1-fluoro-1-p-methoxyphenyl-2-propanone is a brown liquid with a yield of 45%.
1H NMR(400MHz,CDCl3)δ：7.31(d,J＝8.3Hz,2H),6.93(d,J＝8.5Hz,2H),5.63(d,J＝48.5Hz,1H),3.81(s,3H),2.22(d,J＝3.6Hz,3H).13C NMR(100MHz,CDCl3)δ：204.6(d,J＝26.3Hz),160.6,127.9(d,J＝6.1Hz),126.0(d,J＝21.2Hz),114.4,95.6(d,J＝187.9Hz),55.3,25.3.19F NMR(376MHz,CDCl3)δ：-178.1(d,J＝2.7Hz).
Example 7
2-fluoro-1-p-chlorophenyl-1-acetone synthesis, separation and purification: adding 1-p-chlorophenyl-1-propylhydrazone (0.5mmol, 1.0eq) and the compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, respectively, and sealing with a rubber stopper; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: the 2-fluoro-1-p-chlorophenyl-1-propanone was a pale yellow liquid with a yield of 65%.
1H NMR(400MHz,CDCl3)δ：7.94(d,J＝8.5Hz,2H),7.47(d,J＝8.4Hz,2H),5.63(dq,J＝48.4,6.7Hz,1H),1.66(dd,J＝24.1,6.8Hz,3H).13C NMR(100MHz,CDCl3)δ：18.2(d,J＝20.7Hz),90.6(d,J＝179.1Hz),129.1,130.5(d,J＝5.1Hz),132.3,140.3,195.9(d,J＝20.6Hz).19F NMR(376MHz,CDCl3)δ：-180.5.
Example 8
Synthesizing, separating and purifying 2-fluoro-1-tetralone: respectively adding 1-tetrahydronaphthalene hydrazone (0.5mmol, 1.0eq) and a compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, and sealing with a rubber plug; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: the 2-fluoro-1-tetralone was a pale yellow liquid with a yield of 58%.
1H NMR(400MHz,CDCl3)δ：8.06(d,J＝7.8Hz,1H),7.52(t,J＝7.1Hz,1H),7.35(t,J＝7.5Hz,1H),7.27(d,J＝6.8Hz,1H),5.14(ddd,J＝47.9,12.7,5.1Hz,1H),3.13(dd,J＝9.0,3.8Hz,2H),2.61-2.53(m,1H),2.41-2.29(m,1H).13C NMR(CDCl3,100MHz)δ：192.8(d,J＝15.1Hz),142.6,133.7,130.8,128.2,127.3，126.7,90.9(d,J＝190.4Hz),29.6(d,J＝20.1Hz),26.5(d,J＝11.5Hz).19F NMR(376MHz,CDCl3)δ：-190.4.
Example 9
Synthesizing, separating and purifying 2-fluoro-1-indanone: respectively adding 1-indene hydrazone (0.5mmol, 1.0eq) and the compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask with a magnetic stirrer, and sealing with a rubber plug; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: 2-fluoro-1-indanone is a white solid with a yield of 45%.
1H NMR(400MHz,CDCl3)δ：7.80(d,J＝7.7Hz,1H),7.67(td,J＝7.6,1.2Hz,1H),7.50–7.39(m,2H),5.28(ddd,J＝51.0,7.8,4.4Hz,1H),3.67–3.59(m,J＝16.8,7.4Hz,1H),3.32–3.15(m,1H).13C NMR(101MHz,CDCl3)δ：199.98(d,J＝14.7Hz),149.67(d,J＝5.6Hz),136.40,133.92,128.48,126.84,124.80,90.51(d,J＝189.0Hz),33.46(d,J＝21.0Hz).19F NMR(376MHz,CDCl3)δ：-194.03.
Example 10
Synthesizing, separating and purifying 2-fluoro-p-bromoacetophenone: adding p-bromophenylglyoxaline (0.5mmol, 1.0eq) and a compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask with a magnetic stirrer, and sealing with a rubber plug; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was extracted twice with 20mL of dichloromethane, the organic phases were combined and washed with saturated brine, and then the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a crude product with a small amount of solvent. The crude product is then separated on a silica gel column, and the eluent is petroleum ether: ethyl acetate 9:1 mixture to obtain the final product: the 2-fluoro-p-bromoacetophenone was a white solid in 60% yield.
1H NMR(400MHz,CDCl3)δ：7.81–7.72(m,2H),7.66–7.59(m,2H),5.47(d,J＝46.9Hz,2H).13C NMR(100MHz,CDCl3)δ：192.73(d,J＝16.1Hz),132.46,132.31,129.49,129.46,82.57(d,J＝184.8.Hz).19F NMR(376MHz,CDCl3)δ：-229.71.
The substrates, products and yields of examples 1-10 are shown in Table 1:
TABLE 1
Example 11
Compared with the example 1, the difference is mainly that the adding equivalent of the compound shown in the formula 2 (the molar ratio of the compound shown in the formula 2 to the hydrazone) is different, and the specific operation is as follows:
adding 4-phenyl-2-butylhydrazone (0.5mmol, 1.0eq) into a 25ml round bottom flask with a magnetic stirrer, adding 1eq, 5eq and 10eq of the compound of formula 2 respectively, and sealing with a rubber plug; acetonitrile (5ml) is added by a syringe as a reaction solvent, and the reaction bottle is placed in an oil bath kettle at 70 ℃ for heating and stirring reaction for 16h, wherein the yield is 20%, 33% and 28% respectively. The experimental results show that the yield of the compound of formula 2 added by 2eq is optimal.
Example 12
The difference compared to example 1 is the starting concentration of the compound of formula 2, which is specifically performed as follows:
4-phenyl-2-butanone (0.5mmol, 1.0eq), a compound of formula 2 (1mmol,2.0eq), was added to a 25ml round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile 2.5ml or 10ml is respectively added as a reaction solvent by a syringe, and the reaction bottle is placed in an oil bath kettle at 70 ℃ to be heated and stirred for reaction for 16 hours, wherein the yield is respectively 44% and 29%. The experimental results show that the yield of increasing or decreasing the starting concentration of the compound of formula 2 is lower than in example 1.
Comparative example 1
The difference compared to example 1 is mainly the addition of a base. The specific operation is as follows:
adding 4-phenyl-2-butylhydrazone (0.5mmol, 1.0eq), a compound of formula 2 (1mmol,2.0eq), lithium acetate (0.5mml, 1.0eq), sodium bicarbonate (0.5mml, 1.0eq) and triethylamine (0.5mml, 1.0eq) as bases into a 25ml round bottom flask equipped with a magnetic stirrer, and sealing with a rubber plug; acetonitrile (5ml) is added by a syringe as a reaction solvent, the reaction bottle is placed in an oil bath kettle at 70 ℃ to be heated and stirred for reaction for 16 hours, the yield is 21 percent and 18 percent respectively, and 10 percent of experiment results show that the reaction yield is reduced after alkali is added into a reaction system.
Comparative example 2
Compared with the example 1, the difference is mainly that the reaction temperature is changed, and the specific operation is as follows:
respectively adding 4-phenyl-2-butylhydrazone (0.5mmol, 1.0eq) and the compound of formula 2 (1mmol,2.0eq) into a 25ml round-bottom flask equipped with a magnetic stirrer, and sealing with a rubber plug; acetonitrile (5ml) was then added as a reaction solvent using a syringe, and the reaction flask was placed in a Dewar flask at 0 ℃ for reaction for 16 hours. The experimental results show that the target product is not obtained at this temperature.
Comparative example 3
The only difference compared to example 1 is that the following reagents were used instead of the compound of formula 2, the procedure was as follows:
adding 4-phenyl-2-butylhydrazone (0.5mmol, 1.0eq) into a 25ml round bottom flask equipped with a magnetic stirrer, adding DAST (diethylaminosulfur trifluoride, 1mmol,2.0eq), NSFI (N-fluorodiphenylsulfonimide, 1mmol,2.0eq), NFPY (1-fluoropyridine tetrafluoroborate, 1mmol,2.0eq), TBAF (tetrabutylammonium fluoride, 1mmol,2.0eq) instead of the compound of formula 2, and sealing with a rubber plug; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. The experimental results show that the target product is not obtained.
Comparative example 4
Compared with the example 2, the difference is mainly the difference of the types of hydrazone, and the specific operation is as follows:
respectively adding 1-phenyl-1-propylphenylhydrazone (0.5mmol, 1.0eq) synthesized by using 1-phenyl-1-acetone and phenylhydrazine and a compound (1mmol,2.0eq) of a formula 2 into a 25ml round-bottom flask provided with a magnetic stirrer, and sealing the flask by using a rubber plug; acetonitrile (5ml) was then added as a reaction solvent by syringe, and the reaction flask was placed in an oil bath at 70 ℃ and heated with stirring for 16 hours. The experimental result shows that the phenylhydrazone used as the reaction raw material cannot obtain the target product.
Comparative example 5
Compared with the example 2, the difference lies in changing the reaction solvent, the concrete operation is as follows:
a 25ml round bottom flask equipped with a magnetic stirrer was charged with phenylhydrazone (0.5mmol, 1.0eq), a compound of formula 2 (1mmol,2.0eq), and sealed with a rubber stopper; then, ethyl acetate (5ml), dichloromethane (5ml) and tetrahydrofuran (5ml) are respectively added into the reaction flask by a syringe to serve as reaction solvents, the reaction flask is placed in an oil bath kettle at 70 ℃ to be heated and stirred for reaction for 16 hours, the yield is 5%, and the experimental results of 0% and 6% show that the yield is far lower than that of example 2 after the reaction solvents are changed.
Comparative example 6
Compared with the example 2, the difference is that the reaction substrate hydrazone is changed into ketone, and the specific operation is as follows:
adding propiophenone (0.5mmol, 1.0eq), the compound of formula 2 (1mmol,2.0eq) to a 25ml round bottom flask equipped with a magnetic stirrer, and sealing with a rubber stopper; acetonitrile (5ml) is added into the mixture by a syringe as a reaction solvent, and the reaction bottle is placed in an oil bath kettle at 70 ℃ to be heated and stirred for reaction for 16 hours, wherein the yield is 7 percent. The experimental results show that the yield of the direct reaction of the ketone with the compound of formula 2 is much lower than in example 2.
Comparative example 7
Compared with the example 2, the difference lies in changing the reaction temperature, and the specific operation is as follows:
adding propiophenone (0.5mmol, 1.0eq), the compound of formula 2 (1mmol,2.0eq) to a 25ml round bottom flask equipped with a magnetic stirrer, and sealing with a rubber stopper; acetonitrile (5ml) was then added as a reaction solvent by a syringe, and the reaction flask was placed in an oil bath at 140 ℃ and heated with stirring for reaction for 16 hours, giving a yield of 43%. The experimental results show that the temperature conditions of example 2 favor the reaction.
Comparative example 8
Compared with the example 1, the difference is that the reaction substrate hydrazone is changed into ketone, and hydrazine hydrate is added, and the specific operation is as follows:
4-phenyl-2-butanone (0.5mmol, 1.0eq), a compound of formula 2 (1mmol,2.0eq), was added to a 25ml round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; adding catalytic amount of hydrazine hydrate (10 mol%) and equivalent hydrazine hydrate (0.5mmol, 1.0eq), adding acetonitrile (5ml) as reaction solvent by a syringe, placing the reaction bottle in an oil bath kettle at 70 ℃, heating and stirring for reaction for 16h, wherein the yield is 8% and 6% respectively. The experimental results show that the yield of one-pot reaction of ketone, hydrazine hydrate and the compound of formula 2 is much lower than in example 1.
Claims (10)
1. The method for synthesizing alpha-fluorinated ketone from hydrazone of a formula 1 structural formula and a compound of a formula 2 structural formula is characterized in that a hydrazone removing fluorination reaction is carried out at a temperature of 50-100 ℃ to obtain an alpha-fluorinated ketone product of a formula 3;
R1is C1～C20The alkyl group, the five-membered or six-membered heterocyclic aryl group, the phenyl group, or the condensed ring aryl group formed by the condensation of two or more aromatic rings in the heterocyclic aryl group and the phenyl group; the alkyl, the heterocyclic aryl, the phenyl and the condensed ring aryl are allowed to have substituents;
said R2、R3Is alone H, C1～C6The alkyl group, the five-membered or six-membered heterocyclic aryl group, the phenyl group, or the condensed ring aryl group formed by the condensation of two or more aromatic rings in the heterocyclic aryl group and the phenyl group; the alkyl, the heterocyclic aryl, the phenyl and the condensed ring aryl are allowed to have substituents;
or, said R2、R3Form a cyclic group through ring closure; or R2、R3Any one of the groups and R1Cyclized to form a cyclic group; the cyclic group is five-membered or six-membered cycloalkyl, cycloalkenyl, aromatic group, or any of cycloalkyl, cycloalkenyl and aromatic groupTwo or more rings share atoms or bonds, thereby forming a fused, spiro, or bridged ring; heteroatoms are allowed in the ring structure of the cyclic group, and substituents are allowed on the ring of the cyclic group.
2. The method for synthesizing an α -fluorinated ketone from a hydrazonated aliphatic chain monoketone according to claim 1, wherein the alkyl group, the heterocyclic aryl group, the phenyl group, the condensed ring aryl group, and the cyclic group have a substituent allowed to be C1～C6Alkyl of (C)1～C6Alkoxy, phenyl, benzyloxy, nitro, halogen, cyano, ester, trifluoromethyl, C1～C4Alkylthio or sulfonyl group of (a).
3. The method of synthesizing an α -fluorinated ketone from a hydrazonated aliphatic chain monoketone according to claim 1, wherein R is1Is alkyl in which the carbon linked to the hydrazone is a tertiary carbon, or is a heterocyclic aryl, phenyl or fused-ring aryl;
said R2Is H, R3Is H or C1～C6Alkyl groups of (a);
or R1、R3And the ring is combined with heterocyclic aryl or phenyl selectively.
4. The method of synthesizing an α -fluorinated ketone from a hydrazonated aliphatic chain monoketone according to claim 1, wherein the hydrazone is represented by formula 1-a or formula 1-b;
said R4Independently of hydrogen, C1～C6Alkyl of (C)1～C6Alkoxy, phenyl, benzyloxy, nitro, halogen, cyano, ester, trifluoromethyl, C1～C4Alkylthio or sulfonyl of (a);
said R2Is H;
said R3Is hydrogen or C1～C6Alkyl groups of (a);
and n is an integer of 1 or 2.
5. The method for synthesizing alpha-fluorinated ketone from hydrazonated aliphatic chain monoketone according to any one of claims 1 to 4, wherein the hydrazone is obtained by hydrazonation reaction of the ketone of formula 4 with hydrazine hydrate;
6. the method of synthesizing an α -fluorinated ketone from a hydrazonated aliphatic chain monoketone according to claim 1, wherein the molar ratio of hydrazone to compound of formula 2 is 1: 1-10; preferably 1: 1-5; more preferably 1:1.5 to 2.5.
7. The method of synthesizing an α -fluorinated ketone from a hydrazonated aliphatic chain monoketone according to claim 1, wherein the solvent of the reaction is acetonitrile.
8. The method according to claim 1, wherein the concentration of the compound of formula 2 in the reaction starting solution is 0.05 to 0.4 mol/L; preferably 0.1-0.4 mol/L; more preferably 0.15 to 0.25 mol/L.
9. The method of claim 1, wherein the reaction temperature is 60 to 80 ℃; further preferably 65 to 75 ℃.
10. The process according to claim 1, wherein the reaction time is from 6 to 24 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011229918.5A CN112321398B (en) | 2020-11-06 | 2020-11-06 | Method for synthesizing alpha-fluorinated ketone by hydrazonating aliphatic chain monoketone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011229918.5A CN112321398B (en) | 2020-11-06 | 2020-11-06 | Method for synthesizing alpha-fluorinated ketone by hydrazonating aliphatic chain monoketone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112321398A true CN112321398A (en) | 2021-02-05 |
| CN112321398B CN112321398B (en) | 2021-11-23 |
Family
ID=74316336
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011229918.5A Expired - Fee Related CN112321398B (en) | 2020-11-06 | 2020-11-06 | Method for synthesizing alpha-fluorinated ketone by hydrazonating aliphatic chain monoketone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112321398B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150315136A1 (en) * | 2014-04-02 | 2015-11-05 | Daikin Industries, Ltd. | Method for producing fluorinated organic compound and fluorinating reagent |
| CN108299137A (en) * | 2018-04-09 | 2018-07-20 | 中南大学 | A kind of isatin hydrazone compounds selective fluorination method |
| US20190152779A1 (en) * | 2013-10-02 | 2019-05-23 | Daikin Industries, Ltd. | Fluorinating agent |
-
2020
- 2020-11-06 CN CN202011229918.5A patent/CN112321398B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190152779A1 (en) * | 2013-10-02 | 2019-05-23 | Daikin Industries, Ltd. | Fluorinating agent |
| US20150315136A1 (en) * | 2014-04-02 | 2015-11-05 | Daikin Industries, Ltd. | Method for producing fluorinated organic compound and fluorinating reagent |
| CN108299137A (en) * | 2018-04-09 | 2018-07-20 | 中南大学 | A kind of isatin hydrazone compounds selective fluorination method |
Non-Patent Citations (2)
| Title |
|---|
| JUN DENG 等: "Practical Access to Difluoromethyl Ketones via Straightforward Decarboxylative Difluorination of b-Ketoacids", 《ADV. SYNTH. CATAL.》 * |
| THOMAS MAGAUER 等: "Experimental Studies on the Selective β‑C−H Halogenation of Enones", 《J. ORG. CHEM.》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112321398B (en) | 2021-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109293468B (en) | A kind of method for synthesizing cis-alkene by decarboxylation coupling reaction of iridium-catalyzed NHP ester and terminal aryl alkyne | |
| CN113372184B (en) | Method for synthesizing C-N axis chiral phenanthridinone compound based on chiral transfer strategy | |
| CN113121462A (en) | Preparation method of 5-trifluoromethyl substituted 1,2, 3-triazole compound | |
| CN110357842B (en) | A kind of fluoroalkyl substituted furan compound and its preparation method | |
| US20090270639A1 (en) | Process for production of (±)-3a,6,6,9a- tetramethyldecahydronaphtho[2,1-b]furan-2(1h)-one | |
| CN112321398B (en) | Method for synthesizing alpha-fluorinated ketone by hydrazonating aliphatic chain monoketone | |
| CN109134306B (en) | A kind of alkyl ketone amide and its oxime amide compound and its preparation and application | |
| US20070155994A1 (en) | Optical resolver and method of optically resolving alcohol with the same | |
| WO2003093221A1 (en) | Preparation of d-(-) -1-substituted phenyl-2-dichloro-acetoamino-3fluoro-1-propanol from l type substituted phenyl serine ester | |
| JP5909238B2 (en) | Diastereoselective preparation of bicyclo [2.2.2] octan-2-one compounds | |
| CN108947995B (en) | A kind of preparation method of polysubstituted oxadiazine derivatives | |
| CN112500419A (en) | Epoxy fused 2-methylene pyrrolidine compound and preparation method thereof | |
| JP4540197B2 (en) | (E) Process for producing 3-methyl-2-cyclopentadecenone | |
| RU2838750C2 (en) | Two-step synthesis of seleksipag using nature-saving green technologies | |
| CN110590717B (en) | Polysubstituted ketene imine and synthetic method thereof | |
| CN115260192B (en) | A kind of nitrogen-containing condensed ring compound and its synthesis method | |
| CN116903434A (en) | Copper-catalyzed method for preparing difluoromethyl olefin by hydrodefluorination of trifluoromethyl olefin | |
| CN1660806A (en) | The synthetic method of 2-trifluoromethylindole | |
| WO2002051798A1 (en) | PROCESS FOR PRODUCING β-KETONITRILE COMPOUND | |
| CN120349283A (en) | Method for preparing difluoro quinoxalinone derivative by photocatalysis of iodine-containing phosphonium salt | |
| JP2024509536A (en) | Method for preparing alkyl 4-oxotetrahydrofuran-2-carboxylate | |
| CN115536500A (en) | Preparation method of 2, 2-diaryl vinyl alkyl ether | |
| CN116375603A (en) | Method for synthesizing benzocyclobutene derivative | |
| JP2005097158A (en) | Method for producing fluorine-containing organic compound | |
| CN118530110A (en) | A geminal difluorobicyclo[2.1.1]hexanecarboxylic acid compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20211123 |