CN117865804A - Aldolization method of alkyl aromatic hydrocarbon - Google Patents
Aldolization method of alkyl aromatic hydrocarbon Download PDFInfo
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- CN117865804A CN117865804A CN202410031846.5A CN202410031846A CN117865804A CN 117865804 A CN117865804 A CN 117865804A CN 202410031846 A CN202410031846 A CN 202410031846A CN 117865804 A CN117865804 A CN 117865804A
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- hydroformylation
- reaction
- tbaci
- hydrocarbon
- alkylaromatic
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- -1 alkyl aromatic hydrocarbon Chemical class 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 238000007037 hydroformylation reaction Methods 0.000 claims abstract description 17
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 8
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000758 substrate Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 5
- 230000001678 irradiating effect Effects 0.000 claims abstract description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 239000000047 product Substances 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 10
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 7
- 229960000590 celecoxib Drugs 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- HZXXSCOUSGLRRX-UHFFFAOYSA-N cyanoboronic acid Chemical group OB(O)C#N HZXXSCOUSGLRRX-UHFFFAOYSA-N 0.000 claims description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims 9
- 150000002430 hydrocarbons Chemical class 0.000 claims 9
- 239000004215 Carbon black (E152) Substances 0.000 claims 5
- 125000004185 ester group Chemical group 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract description 2
- 150000001336 alkenes Chemical class 0.000 abstract description 2
- 150000001345 alkine derivatives Chemical class 0.000 abstract description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 abstract description 2
- 239000004327 boric acid Substances 0.000 abstract description 2
- 239000010703 silicon Substances 0.000 abstract description 2
- 229910052710 silicon Inorganic materials 0.000 abstract description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 150000003934 aromatic aldehydes Chemical class 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- VXWBQOJISHAKKM-UHFFFAOYSA-N (4-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=O)C=C1 VXWBQOJISHAKKM-UHFFFAOYSA-N 0.000 description 3
- CYGUXEZVBLMVRV-UHFFFAOYSA-N 1-bromonaphthalene-2-carbaldehyde Chemical compound C1=CC=C2C(Br)=C(C=O)C=CC2=C1 CYGUXEZVBLMVRV-UHFFFAOYSA-N 0.000 description 3
- TYNJQOJWNMZQFZ-UHFFFAOYSA-N 4-prop-2-enoxybenzaldehyde Chemical compound C=CCOC1=CC=C(C=O)C=C1 TYNJQOJWNMZQFZ-UHFFFAOYSA-N 0.000 description 3
- VWYFITBWBRVBSW-UHFFFAOYSA-N 5-chlorothiophene-2-carbaldehyde Chemical compound ClC1=CC=C(C=O)S1 VWYFITBWBRVBSW-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- QSSJZLPUHJDYKF-UHFFFAOYSA-N methyl 4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C=C1 QSSJZLPUHJDYKF-UHFFFAOYSA-N 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052684 Cerium Inorganic materials 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- DQVXWCCLFKMJTQ-UHFFFAOYSA-N (4-methylphenoxy)boronic acid Chemical compound CC1=CC=C(OB(O)O)C=C1 DQVXWCCLFKMJTQ-UHFFFAOYSA-N 0.000 description 1
- CMIMBQIBIZZZHQ-UHFFFAOYSA-N 1-bromo-2-methylnaphthalene Chemical compound C1=CC=CC2=C(Br)C(C)=CC=C21 CMIMBQIBIZZZHQ-UHFFFAOYSA-N 0.000 description 1
- LRLRAYMYEXQKID-UHFFFAOYSA-N 1-methyl-4-(trifluoromethyl)benzene Chemical compound CC1=CC=C(C(F)(F)F)C=C1 LRLRAYMYEXQKID-UHFFFAOYSA-N 0.000 description 1
- AROCNZZBLCAOPH-UHFFFAOYSA-N 1-methyl-4-prop-2-enoxybenzene Chemical compound CC1=CC=C(OCC=C)C=C1 AROCNZZBLCAOPH-UHFFFAOYSA-N 0.000 description 1
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 description 1
- JSMMZMYGEVUURX-UHFFFAOYSA-N 2-chloro-5-methylthiophene Chemical compound CC1=CC=C(Cl)S1 JSMMZMYGEVUURX-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000235648 Pichia Species 0.000 description 1
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction 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
- 238000001704 evaporation Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000013384 organic framework Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- ADZWSOLPGZMUMY-UHFFFAOYSA-M silver bromide Chemical compound [Ag]Br ADZWSOLPGZMUMY-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an hydroformylation formula of alkyl aromatic hydrocarbonIn the method, methyl arene is used as a substrate, feCl 3 ·6H 2 O is used as a photosensitizer, TBACI is used as a catalyst, and CH in an oxygen atmosphere is used at room temperature 3 And in the CN solution or the DCM solution, irradiating with a blue LED lamp, carrying out an hydroformylation reaction of alkyl aromatic hydrocarbon, and separating to obtain a benzaldehyde target product after the reaction is finished. The invention optimizes the reaction conditions under the condition of low yield of the target product of the strong electron-withdrawing substituted methyl arene hydroformylation, so that the reaction is applicable to methyl arene containing trifluoromethyl, cyano, ester, boric acid, silicon and remote alkene and alkyne.
Description
Technical Field
The invention relates to the technical field of aromatic aldehyde synthesis, in particular to an hydroformylation method of alkyl aromatic hydrocarbon.
Background
Aromatic aldehyde is an important organic framework structure and plays an irreplaceable role in the production of fine chemicals such as pesticides, fragrances, medicines and the like. It differs from aliphatic aldehydes in that two single bonds on the carbonyl group, one attached to the aryl group and one attached to the hydrogen, form an aromatic aldehyde. The aromatic aldehyde is interposed between the alcohol and the acid, and can be further oxidized to synthesize benzoic acid or reduced to synthesize benzyl alcohol. Due to its structural versatility, aromatic aldehydes are often used as synthetic modules for important molecules. Because of the importance of aromatic aldehydes, the development of efficient methods for preparing aromatic aldehydes has attracted attention from many chemists, and as early as 1966, a simple method for metal cerium oxide aryl side chains was reported by the Ludwik Syper subject group at the university of chemical technology, polish Wo Luocha Watts. Ammonium ceric nitrate is used as an oxidant, and heated in an acid solution, so that the aryl side chain can be selectively oxidized to synthesize aldehyde. Unlike most other oxidants, cerium produces only one electron change, so the reaction can be made selective, but cerium is a toxic metal reagent. The method adopted in the industry for synthesizing aromatic aldehyde is toluene halogenation and then saponification. Obviously, this process generates a significant amount of halide waste. Therefore, there is a strong need to find a green, economical and sustainable method for preparing aromatic aldehyde.
Disclosure of Invention
Therefore, the invention provides an hydroformylation method of alkyl aromatic hydrocarbon, which takes methyl aromatic hydrocarbon as a substrate and FeCl 3 ·6H 2 O is used as a photosensitizer, TBACI is used as a catalyst, and CH in an oxygen atmosphere is used at room temperature 3 In CN solution or DCM solution, irradiating with blue LED lamp, carrying out hydroformylation reaction of alkyl arene, and separating to obtain benzaldehyde target product after the reaction is completed; the reaction equation is as follows:
wherein R1 is an electron withdrawing group selected from one of trifluoromethyl, cyano, boric acid, ester and carbamoyl; or R1 is halogen and cyano, and the two substituents are substituted together.
Further, the concentration of the methyl aromatic hydrocarbon in the reaction system was 0.1M.
Further, the FeCl 3 ·6H 2 The mole percent of O in the reaction system is 10 mole/%.
Further, the mole percent of the TBACI content in the reaction system is 10 mole/%.
Further, the TBACI contains ZnCl with five times of TBACIU 2 Or five times the amount of NaCl.
Further, the irradiation reaction time of the blue LED lamp is 24 hours.
Further, the irradiation power of the blue LED lamp is 45W, and the wavelength is 465nm.
Further, the methyl arene is celecoxib.
The invention has the beneficial effects that: the invention optimizes the reaction conditions under the condition of low yield of the target product of the strong electron-withdrawing substituted methyl arene hydroformylation, so that the reaction is applicable to methyl arene containing trifluoromethyl, cyano, ester, boric acid, silicon and remote alkene and alkyne.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 shows a nuclear magnetic resonance hydrogen spectrum of methyl paraformylbenzoate according to an embodiment of the present invention 1 H NMR(DMSO,400MHz))；
FIG. 2 shows a nuclear magnetic resonance carbon spectrum of methyl paraformylbenzoate according to an embodiment of the present invention 13 C NMR(DMSO,101MHz))；
FIG. 3 shows a hydrogen nuclear magnetic resonance spectrum of 4- (trifluoromethyl) benzaldehyde provided by an embodiment of the present invention 1 H NMR(DMSO,400MHz))；
FIG. 4 shows a nuclear magnetic resonance carbon spectrum of 4- (trifluoromethyl) benzaldehyde provided by an embodiment of the present invention 13 C NMR(DMSO,101MHz))；
FIG. 5 shows a nuclear magnetic resonance fluorine spectrum of 4- (trifluoromethyl) benzaldehyde provided by an embodiment of the invention 19 F NMR(CDCl 3 ,376MHz))。
FIG. 6 shows a hydrogen nuclear magnetic resonance spectrum of (4-formylphenyl) boronic acid according to the present invention 1 H NMR(DMSO,400MHz))；
FIG. 7 shows a nuclear magnetic resonance carbon spectrum of (4-formylphenyl) boronic acid according to the present invention 13 C NMR(DMSO,101MHz))；
FIG. 8 shows a hydrogen nuclear magnetic resonance spectrum of celecoxib provided by an embodiment of the invention 1 H NMR(CDCl 3 ,400MHz))。
FIG. 9 shows a nuclear magnetic resonance carbon spectrum of celecoxib provided by an embodiment of the invention 13 CNMR(CDCl 3 ,101MHz))。
FIG. 10 shows a nuclear magnetic resonance fluorine spectrum of celecoxib provided by an embodiment of the invention 19 FNMR(CDCl 3 ,376MHz))。
FIG. 11 shows a hydrogen nuclear magnetic resonance spectrum of 1-bromo-2-naphthaldehyde provided by the embodiment of the invention 1 H NMR(CDCl 3 ,400MHz))。
FIG. 12 shows a nuclear magnetic resonance carbon spectrum of 1-bromo-2-naphthaldehyde provided by an embodiment of the present invention 13 C NMR(CDCl 3 ,101MHz))。
FIG. 13 shows a hydrogen nuclear magnetic resonance spectrum of 5-chlorothiophene-2-carbaldehyde according to the embodiment of the present invention 1 H NMR(CDCl 3 ,400MHz))。
FIG. 14 shows a nuclear magnetic resonance carbon spectrum of 5-chlorothiophene-2-carbaldehyde according to the embodiment of the present invention 13 C NMR(CDCl 3 ,101MHz))。
FIG. 15 shows a nuclear magnetic resonance hydrogen spectrum of 4- (prop-2-en-1-yloxy) benzaldehyde according to an embodiment of the present invention 1 H NMR(CDCl 3 ,400MHz))。
FIG. 16 shows a nuclear magnetic resonance carbon spectrum of 4- (prop-2-en-1-yloxy) benzaldehyde according to an embodiment of the present invention 13 C NMR(CDCl 3 ,101MHz))。
Detailed Description
The invention is further illustrated below with reference to examples.
In the early stage, research is conducted on the reaction of synthesizing aromatic aldehyde by catalyzing methyl aromatic hydrocarbon to oxidize by light-induced iron, and the application of the aromatic aldehyde to electron-rich substrates is found to be very good, but the reaction effect of electron-withdrawing toluene substrates such as para-ester, cyano and the like is very poor. Therefore, methyl p-methylbenzoate 5d is used as a model substrate, and the reaction conditions are optimized on the basis of the prior study, and are as follows: methyl p-methylbenzoate (1 equiv,0.2 mmol), feCl 3 ·6H 2 O (10 mol%) was used as a photosensitizer and irradiated with blue light LED in a solvent at 25℃in an air atmosphere for 24 hours according to the following reaction equation:
(1) The solvent for the reaction is selected, and under the condition of the same addition amount, other solvents are used for replacing DMSO, other process parameters are identical, and the reaction equation is as follows. Found in DCM and CH 3 When CN was used as a solvent, we detected the hydroformylation target product as shown in Table 1. We selected CH in view of the fact that the DCM solvent reaction process cannot guarantee a constant concentration (volatile) 3 CN was used as solvent for the next screening.
TABLE 1 screening of solvents
(2) Additional compounds are added to help activate the benzylic C-H bond. N-hydroxyphthalimide is used as a precondition of free radicals, oxygen free radicals are generated under illumination, and a benzyl C-H bond is activated through the oxygen free radicals. Although this method produces the target product, it is not effective. We therefore tried to add BrCF 2 CO 2 Et is a precondition of free radical, it is hoped that bromine free radical is generated under illumination, benzyl C-H bond is activated by bromine free radical, and bromine anion generated in the process can be combined with silver ion to realize circulation, but no target product is generated, so that it is presumed that bromine generated is not available to generate bromine free radical, and silver bromide precipitate is generated by direct combination with anion, so that the effect is lost. Then we tried to deactivate the benzyl C-H bond by means of the sulfur radical generated by cleavage of diphenyl disulfide under light on the premise of using diphenyl disulfide as radical, and then further oxidation was carried out, but the experimental results showed that this method was ineffective. In the future, tetrabutylammonium chloride (TBACI) is tried, more chlorine radicals are expected to be generated in the system, the collision opportunity with toluene is increased, more target product conversion is realized, and the result has no obvious promotion effect. As shown in table 2. The reaction equation is as follows:
TABLE 2 attempts at different radical premises
Although the previous experimental results of the various radical preconditions were not very good, some experience was given to us, such as the use of oxygen radicals and the increase of chlorine content, both with the target product. Our conjecture that these two ideas probably solve the problem of inert benzyl oxidation as quickly as possible, so we directly try to add oxygen radical preconditions. As shown in table 3, the experimental results show only a slight increase in hydrogen peroxide (both radical precondition and oxidant), potassium persulfate. We again tried to add the bromo radical precondition N-bromophthalimide, but still not so much improvement. We then tried a series of chlorine compounds. Surprisingly, when TBACI was added alone, we obtained 84% of the target product, which also verifies that increasing the chlorine content has a promoting effect on the reaction. Subsequently we performed the next optimization of TBACI as part of the reaction.
TABLE 3 attempts at different radical premises
(3) And (3) selecting the loading of TBACI. We have further screened the TBACI loading for the presence of more chlorine, which promotes the reaction. As shown in Table 4, contrary to our imagination, more TBACI had no promoting effect on the reaction, and the addition of a proper amount of TBACI had a better effect on the reaction. The reaction equation is as follows:
table 4 screening of additive loadings
(4) Subsequently, we performed control experiments under the superior conditions of the screening, as shown in Table 5, the reaction was not performed when the solvent was changed to DMSO and no light catalyst was used, and the yield was extremely decreased when air was used as an oxygen source, and the results are shown in Table 5. The reaction equation is as follows:
TABLE 5 control conditions
After screening by various conditions, we determined the preferred reaction conditions as follows: methyl arene (1 equiv,0.2 mmol), feCl 3 ·6H 2 O (10 mol%) as photosensitizer, TBACI (10 mol%) as catalyst, CH in an oxygen atmosphere at 25 DEG C 3 And in the CN solution, the benzaldehyde target product can be obtained by irradiating for 24 hours by using a blue LED.
(5) Application of the process in medicine molecules
Celecoxib is used as a substrate: celecoxib (76.3 mg,0.2 mmol), feCl were added sequentially to a 10mL Schlenk tube dried and carrying a magneton 3 ·6H 2 O (5.4 mg,10 mol%), TBACI (5.7 mg,10 mol%), then O 2 3 times of replacement, add CH 3 CN (2 mL). The reaction was monitored by TLC by stirring for 24h under irradiation of a blue LED lamp (45 w, 460 nm) at 25 ℃ and after completion of the reaction, the organic layer was concentrated under reduced pressure and the crude product was purified by wet column chromatography on silica gel (200-300 mesh) to give the product as a white solid (13.4 mg,17% yield). The reaction formula is as follows:
the foregoing detailed description of the embodiments of the present invention will be provided to those skilled in the art, and the detailed description and the examples should not be construed as limiting the invention.
The reagents used in the examples below were all of the reagent grade and purchased from reagent companies such as SigmaAldrich, alfa-Aesar, an Naiji, pichia, ledak, and moisturizing and did not require further purification unless otherwise specified. The nitrogen, argon and oxygen used in the experiment were supplied by Nanchang Hongwei gas company. TLC analysis was performed using a 0.20mm thick GF254 silica gel plate (nictita, bevanda silica gel ltd) with 254nm fluorescent indicator. TLC plates were prepared by UV lamp or with alkaline potassium permanganate reagent (KMnO 4 、K 2 CO 3 、NaOH、H 2 O) color development. The purification of general products is carried out by silica gel (200-300 meshes) rapid column chromatography, and for large-amount crude product systems which are not easy to separate, the method can be used (300-400 meshes silica gel powder is used as column chromatography stationary phase), and the crude product systems which are small in amount and not easy to separate are used<50 mg) can be isolated and purified using PTLC. The mobile phase solvent of column chromatography is n-hexane, ethyl acetate, dichloromethane, methanol, etc., and is subjected to low temperature re-evaporation before use. The solvent used for nuclear magnetic resonance measurement is CDCl provided by Beijing Inock reagent company 3 (TMS, 1 Hδ＝0；CDCl 3 ,1Hδ＝7.26, 13 Cδ=7.16) or DMSO-d6 (TMS, 1 Hδ＝0；DMSO-d6, 1 Hδ＝2.50, 13 cδ=39.2). Chemical shifts (δ) of the spectral data are reported in ppm, coupling constants (J) in Hz, and the following abbreviations are used to represent peak multiplicity: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet.
Example 1
To a 10mL Schlenk tube dried and magneton was added methyl p-methylbenzoate (0.2 mmol,1.0 equiv) followed by FeCl 3 .6H 2 O (5.4 mg,10 mol%), TBACI (5.7 mg,10 mol%), then O 2 3 times of replacement, add CH 3 CN (2 mL). Stirring for 24 hr under irradiation of 25deg.C blue LED lamp (45W, 460 nm), monitoring reaction progress by TLC, concentrating organic layer under reduced pressure, subjecting crude product to silica gel column chromatography (200-300 mesh) wet column purification to obtain methyl p-formylbenzoate (27.6 mg, yield 84%))。
Example 2
To a 10mL Schlenk tube dried and magneton was added 4- (trifluoromethyl) toluene (0.2 mmol,1.0 equiv) and FeCl in sequence 3 .6H 2 O (5.4 mg,10 mol%), TBACI (5.7 mg,10 mol%), then O 2 3 times of replacement, add CH 3 CN (2 mL). The reaction was monitored by TLC under stirring for 24h at 25℃under the irradiation of a blue LED lamp (45W, 460 nm), after the completion of the reaction, the organic layer was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (200-300 mesh) wet-process to give 4- (trifluoromethyl) benzaldehyde (28.1 mg, yield 81%).
Example 3
To a 10mL Schlenk tube dried and magneton, (4-methylphenyl) boric acid (0.2 mmol,1.0 equiv), feCl were added in sequence 3 .6H 2 O (5.4 mg,10 mol%), TBACI (5.7 mg,10 mol%), then O 2 3 times of replacement, add CH 3 CN (2 mL). Stirring for 24h at 25deg.C under blue LED lamp (45W, 460 nm), monitoring the progress of the reaction by TLC, concentrating the organic layer under reduced pressure, and subjecting the crude product to column purification by silica gel column chromatography (200-300 mesh) wet method to give (4-formylphenyl) boronic acid (18.3 mg, yield 61%).
Example 4
To a 10mL Schlenk tube dried and magneton was added 1-bromo-2-methylnaphthalene (0.2 mmol,1.0 equiv) and FeCl in this order 3 .6H 2 O (5.4 mg,10 mol%), TBACI (5.7 mg,10 mol%), then O 2 3 times of replacement, add CH 3 CN (2 mL). Stirring for 24h at 25deg.C under irradiation of blue LED lamp (45W, 460 nm), monitoring reaction progress by TLC, concentrating organic layer under reduced pressure, and subjecting crude product to silica gel column chromatography (200-300 mesh) wet column purification to obtain 1-bromo-2-naphthaldehyde (37.4 mg, yield 80%).
Example 5
To a 10mL Schlenk tube dried and magneton was added 5-chloro-2-methylthiophene (0.2 mmol,1.0 equiv), feCl in sequence 3 .6H 2 O (5.4 mg,10 mol%), TBACI (5.7 mg,10 mol%), then O 2 3 times of replacement, add CH 3 CN (2 mL). Blue LED lamp (45W, 460 nm) at 25deg.CStirring under radiation for 24h, monitoring the progress of the reaction by TLC, concentrating the organic layer under reduced pressure after the reaction is completed, and subjecting the crude product to column purification by silica gel column chromatography (200-300 mesh) wet method to give 5-chlorothiophene-2-carbaldehyde (21.6 mg, yield 74%).
Example 6
To a 10mL Schlenk tube dried and magneton was added 4- (prop-2-en-1-yloxy) toluene (0.2 mmol,1.0 equiv) and FeCl in this order 3 .6H 2 O (5.4 mg,10 mol%), TBACI (5.7 mg,10 mol%), then O 2 3 times of replacement, add CH 3 CN (2 mL). The reaction was monitored by TLC under stirring for 24h at 25℃under blue LED lamp (45W, 460 nm), after the completion of the reaction, the organic layer was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (200-300 mesh) wet-process to give 4- (prop-2-en-1-yloxy) benzaldehyde (22.1 mg, yield 70%).
Claims (8)
1. A process for hydroformylation of alkyl aromatic hydrocarbon features that methyl aromatic hydrocarbon is used as substrate and FeCl 3 ·6H 2 O is used as a photosensitizer, TBACI is used as a catalyst, and CH in an oxygen atmosphere is used at room temperature 3 In CN solution or DCM solution, irradiating with blue LED lamp, carrying out hydroformylation reaction of alkyl arene, and separating to obtain benzaldehyde target product after the reaction is completed; the reaction equation is as follows:
wherein R is 1 Is an electron withdrawing group selected from one of trifluoromethyl, cyano, boric acid group, ester group and carbamoyl; or R is 1 Is jointly substituted by two substituents of halogen and cyano.
2. The process for the hydroformylation of alkylaromatic hydrocarbons according to claim 1, wherein the concentration of said methylaromatic hydrocarbon in the reaction system is 0.1M.
3. A process for the hydroformylation of alkylaromatic hydrocarbons according to claim 2,characterized in that the FeCl 3 .6H 2 The molar percentage of O in the reaction system was 10mol/%.
4. The process for the hydroformylation of alkylaromatic hydrocarbons according to claim 2, wherein the TBACI content in the reaction system is 10mol/%.
5. The process for the hydroformylation of alkylaromatic hydrocarbons according to claim 4, wherein said TBACI is obtained by reacting a crude product of ZnCl with a five times TBACI content 2 Or five times the amount of NaCl.
6. The method for hydroformylation of alkylaromatic hydrocarbon according to claim 1, wherein the blue LED lamp irradiation reaction time is 24 hours.
7. The method for hydroformylation of alkylaromatic hydrocarbon according to claim 5, wherein the blue LED lamp has an irradiation power of 45W and a wavelength of 465nm.
8. The process for the hydroformylation of an alkylaromatic hydrocarbon according to claim 1, characterized in that the methylaromatic hydrocarbon is celecoxib.
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