CN110627823A - Method for catalyzing arylamine to generate deamination boric acid esterification or halogenation - Google Patents
Method for catalyzing arylamine to generate deamination boric acid esterification or halogenation Download PDFInfo
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- CN110627823A CN110627823A CN201910990267.2A CN201910990267A CN110627823A CN 110627823 A CN110627823 A CN 110627823A CN 201910990267 A CN201910990267 A CN 201910990267A CN 110627823 A CN110627823 A CN 110627823A
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- arylamine
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- 150000004982 aromatic amines Chemical class 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000005658 halogenation reaction Methods 0.000 title claims abstract description 19
- 230000009615 deamination Effects 0.000 title claims abstract description 18
- 238000006481 deamination reaction Methods 0.000 title claims abstract description 18
- 230000026030 halogenation Effects 0.000 title claims abstract description 18
- 230000032050 esterification Effects 0.000 title claims abstract description 15
- 238000005886 esterification reaction Methods 0.000 title claims abstract description 15
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 239000004327 boric acid Substances 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 149
- 125000000524 functional group Chemical group 0.000 claims abstract description 19
- 239000012046 mixed solvent Substances 0.000 claims abstract description 18
- 238000007306 functionalization reaction Methods 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 230000003197 catalytic effect Effects 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 110
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 claims description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 36
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 27
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 26
- -1 phenoxy, benzyloxy Chemical group 0.000 claims description 18
- 238000005286 illumination Methods 0.000 claims description 12
- 230000002209 hydrophobic effect Effects 0.000 claims description 9
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 235000009518 sodium iodide Nutrition 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 229910001415 sodium ion Inorganic materials 0.000 claims description 5
- 125000005336 allyloxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 239000011737 fluorine 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
- 238000010438 heat treatment Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 229910052751 metal Chemical group 0.000 claims description 2
- 239000002184 metal Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical group S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000002156 mixing Methods 0.000 abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 4
- 125000005264 aryl amine group Chemical group 0.000 abstract 1
- 150000002832 nitroso derivatives Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 27
- 239000012043 crude product Substances 0.000 description 26
- 239000000203 mixture Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 19
- 239000011521 glass Substances 0.000 description 17
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 16
- 239000012414 tert-butyl nitrite Substances 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- 239000003480 eluent Substances 0.000 description 14
- 239000012467 final product Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 238000002390 rotary evaporation Methods 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- 230000000171 quenching effect Effects 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 10
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000002194 synthesizing effect Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 4
- VBXDEEVJTYBRJJ-UHFFFAOYSA-N diboronic acid Chemical compound OBOBO VBXDEEVJTYBRJJ-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 2
- WVUYYXUATWMVIT-UHFFFAOYSA-N 1-bromo-4-ethoxybenzene Chemical compound CCOC1=CC=C(Br)C=C1 WVUYYXUATWMVIT-UHFFFAOYSA-N 0.000 description 2
- GWQSENYKCGJTRI-UHFFFAOYSA-N 1-chloro-4-iodobenzene Chemical compound ClC1=CC=C(I)C=C1 GWQSENYKCGJTRI-UHFFFAOYSA-N 0.000 description 2
- KGNQDBQYEBMPFZ-UHFFFAOYSA-N 1-fluoro-4-iodobenzene Chemical compound FC1=CC=C(I)C=C1 KGNQDBQYEBMPFZ-UHFFFAOYSA-N 0.000 description 2
- MPWOAZOKZVMNFK-UHFFFAOYSA-N 1-iodo-4-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=C(I)C=C1 MPWOAZOKZVMNFK-UHFFFAOYSA-N 0.000 description 2
- VFIKPDSQDNROGM-UHFFFAOYSA-N 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C1=CC(OC)=CC=C1B1OC(C)(C)C(C)(C)O1 VFIKPDSQDNROGM-UHFFFAOYSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 1
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 description 1
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical compound NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 1
- NYARTXMDWRAVIX-UHFFFAOYSA-N 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(Cl)C=C1 NYARTXMDWRAVIX-UHFFFAOYSA-N 0.000 description 1
- SBWKQMCGTSWDPE-UHFFFAOYSA-N 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(F)C=C1 SBWKQMCGTSWDPE-UHFFFAOYSA-N 0.000 description 1
- PNXWQTYSBFGIFD-UHFFFAOYSA-N 2-(4-iodophenyl)acetonitrile Chemical compound IC1=CC=C(CC#N)C=C1 PNXWQTYSBFGIFD-UHFFFAOYSA-N 0.000 description 1
- GKSSEDDAXXEPCP-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(4-methylphenyl)-1,3,2-dioxaborolane Chemical compound C1=CC(C)=CC=C1B1OC(C)(C)C(C)(C)O1 GKSSEDDAXXEPCP-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- IMPPGHMHELILKG-UHFFFAOYSA-N 4-ethoxyaniline Chemical compound CCOC1=CC=C(N)C=C1 IMPPGHMHELILKG-UHFFFAOYSA-N 0.000 description 1
- XJEVFFNOMKXBLU-UHFFFAOYSA-N 4-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=C(N)C=C1 XJEVFFNOMKXBLU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GCLYIYMYJSRXCT-UHFFFAOYSA-N C(C)#N.IC1=CC=CC=C1 Chemical compound C(C)#N.IC1=CC=CC=C1 GCLYIYMYJSRXCT-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 238000005885 boration reaction Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000011941 photocatalyst Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly discloses a method for catalyzing arylamine to generate deamination boric acid esterification or halogenation, which comprises the steps of placing arylamine and nitroso compounds in a mixed solvent, and pre-reacting at 0-5 ℃; and then adding a raw material capable of providing the functional group A and a catalytic amount of a reaction promoter, and performing deamination functionalization reaction at the temperature of 10-50 ℃ under the irradiation of light to obtain a product of modifying the functional group A at the amino position of arylamine. By means of cooperative control of the substrate, the reaction solvent, the mixing mode, the temperature, the reaction promoter and the addition amount, the invention can realize effective boric acid esterification or halogenation of arylamine, particularly electron-substituted arylamine which is difficult to effectively treat by technical schemes in the industry.
Description
Technical Field
The invention relates to a method for catalyzing arylamine to generate deamination functionalization. Belongs to the field of organic chemical synthesis.
Background
Amines are widely present in the biological world and have very important physiological and biological activities, such as proteins, nucleic acids, many hormones, antibiotics, alkaloids, etc. are complex derivatives of amines, and most drugs used clinically are also amines or derivatives of amines. The arylamine compounds are also abundant in nature and industry, and due to the characteristics of low price, high activity and the like, the arylamine compounds are used as substrates in the field of organic synthesis, and the functionalization from arylamine has practical significance.
For example, in the aryl amine borate ester functionalization reaction, a noble metal catalyst is mostly adopted in the prior art, the treatment cost is high, and the practical industrial application is difficult. In the aspect of halogenation, the Stack team 2017 reported that aniline and trichlorobromomethane or diiodomethane are used as raw materials, sodium nitrite is used as a diazotization reagent, acetic acid is used as an acid, and dichloromethane is used as a solvent to complete deamination halogenation reaction at room temperature (Dereka. Leas, Yuxiang Dong, Jonathan L.Vennerstrom, and Douglas E.Stack Org.Lett.2017,19, 2518-. And part of products can only be brominated and can not be iodinated, and the method has insufficient universality. And has no essential difference with the traditional diazonium salt reaction.
Disclosure of Invention
Aiming at the general technical defects that arylamine is deaminated by illumination to generate different functional group products in the prior art, the invention aims to provide a general method for deaminating arylamine and performing different functional groups, which aims to perform boric acid esterification and halogenation on aryl mildly by illumination by using arylamine and different functional group reagents and butanedione as an illumination reaction promoter.
A method for catalyzing arylamine to carry out deamination boric acid esterification or halogenation comprises the steps of placing arylamine with a formula 1 and a compound with a formula 2 in a mixed solvent, and carrying out pre-reaction at 0-5 ℃; then adding a raw material capable of providing a functional group A and a catalytic amount of a reaction promoter, and carrying out deamination functionalization reaction at the temperature of 10-50 ℃ under the irradiation of light to modify the functional group A at the amino position of the formula 1 to obtain a product with a structure of a formula 3;
the reaction promoter is butanedione;
the mixed solvent is a mixed solvent containing water and a hydrophobic organic solvent;
formula 1
Formula 2
Formula 3
R1-R3 are independently H, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, benzyloxy, nitro, halogen, cyano, ester group, trifluoromethyl, C1-C4 alkylthio, sulfonyl or allyloxy;
r4 is H or F;
r5 is C1-C6 alkyl or metallic sodium ion;
a isI or Br.
The invention provides a method for boric acid esterification and halogenation functionalization of arylamine by light-promoted deamination. The inventor can unexpectedly realize the high-selectivity boric acid esterification or halogenation of arylamine by the combined control of the substrate, the reaction solvent, the mixing mode, the butanedione reaction promoter and the dosage.
In the technical scheme of the invention, in order to realize the efficient boric acid esterification and halogenation of arylamine, the ortho position of the substrate in the formula 1 needs to be strictly controlled, and the mixed solvent of water and a hydrophobic organic solvent, the material mixing sequence and the pre-reaction mode need to be controlled, the butanedione is innovatively used, the addition amount of the butanedione is controlled, and the boric acid esterification and the halogenation functionalization under the condition of photo-acceleration can be realized through the cooperative control of all parameters.
The present inventors have found that at least one ortho position of the amino group of the substrate of formula 1 is H, and the other ortho position may be H or F, which surprisingly improves the yield of the product,
through further research, the invention discovers that the yield of the target product is further improved by controlling the substituent group and the substituent position of the arylamine.
Preferably, R1, R3, R4 are hydrogen.
R2 is hydrogen, alkyl of C1-C6, alkoxy of C1-C6, methylthio, nitro, trifluoromethyl, benzyloxy, allyloxy, fluorine, bromine, chlorine atom or cyano.
The research of the invention also finds that when the R2 is electron donor, for example, alkyl of C1-C6 and alkoxy of C1-C6 can show a photo-induced yield which is superior to that of the prior method. The method can overcome the defects of boric acid esterification and poor halogenation effect of the conventional electron-donating substituent group, and can realize high-efficiency functionalization of electron-donating arylamine.
The electron-donating group is, for example, a C1-C6 alkyl group or a C1-C6 alkoxy group.
The alkyl of C1-C6 is, for example, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or isopropoxy.
In the invention, R5 is C1-C6 alkyl or metallic sodium ion,
preferably, R5 is tert-butyl, tert-amyl or metal sodium ion.
The difference in the R5 group results in different suitability for different functionalization reactions, and the group can be adjusted to achieve good suitability for functionalization reactions. For example, when R5 is t-butyl, very good yields are obtained when boration, bromination or iodination is carried out.
Preferably, the order of addition of the reactants is: firstly, arylamine is added, then a mixed solvent is added, the compound of the formula 2 is dripped at the temperature of 0-5 ℃, after reaction is carried out for 10min, raw materials capable of providing functional groups A and a reaction promoter are added, and then illumination and heating reaction are carried out. The problem of low yield of electron donating arylamines can be unexpectedly solved by the feeding sequence, the substrate, the reaction system and the temperature control.
More preferably, the molar ratio of arylamine to nitrite compound of formula 2 is 1: 1.1-2. At this preferred molar ratio, removal of the amino groups is facilitated, thereby facilitating a further increase in the yield of the functionalized product. The addition of nitrite compound in an amount higher than 2 equivalents is not favorable for the next functionalization.
In the present invention, the mixed solvent needs to be a two-phase solution of the water and the hydrophobic solvent. In this way, the yield of the desired functionalized product of arylamines, in particular electron donating arylamines, can be surprisingly improved.
Preferably, in the mixed solvent, the hydrophobic organic solvent is at least one of ethyl acetate, dichloromethane and diethyl ether.
In the mixed solvent, the volume ratio of water to the hydrophobic organic solvent is 1: 0.5-1.5.
In the reaction starting solution, the concentration of arylamine is 0.05-0.5 mol/L.
The raw material capable of providing the functionalized group A is a material capable of modifying the functionalized group A at an amino position in the reaction system.
Preferably, the starting material which provides the functional group A is a pinacol ester of diboronic acidSodium iodide or carbon tetrabromide. The halogenation raw materials are inorganic salt of iodine and carbon tetrabromide. The yield of the prior art adopting the halogenated raw materials is generally not ideal, but the technical scheme of the invention can obtain high yield through the combined control of the system.
In the invention, when the raw material capable of providing the functional group A is the bis (pinacolato) diboron, the synthesized product of the formula 3 is a compound of a formula 3-A; when the raw material capable of providing the functional group A is sodium iodide or carbon tetrabromide, the product is a compound of formula 3-B (X is Br or I).
More preferably, the raw materials capable of providing the functionalized group A are calculated by the functional group A, and the molar ratio of the arylamine to the raw materials capable of providing the functionalized group A is 1: 2-4. At this preferred molar ratio, the formation of the corresponding functionalized product is facilitated, while the formation of acyl by-products is effectively suppressed. The addition of the functionalizing agent at an equivalent of more than 4 is not favorable for electron transfer of the reaction promoter.
The invention innovatively utilizes butanedione as a reaction promoter, researches the reaction, and can remarkably improve the product yield, particularly the deamination functionalization yield of electron-supplying substituent arylamine by using catalytic amount of butanedione. Researches show that the dosage of the reaction promoter has great influence on the reaction yield, the dosage is large, the selectivity of deamination functionalization is seriously influenced, and the yield of boric esterification and halogenation functionalization is reduced.
Preferably, the molar ratio of arylamine to reaction accelerator is 1: 0.05-0.2, which is a catalytic amount. At this preferred molar ratio, butanedione can perform excellently in photoelectric conversion, assisting deamination of arylamine, forming a benzene radical. The addition of butanedione at a molar equivalent of more than 0.2 leads to the formation of a large amount of acetylated by-products, which is detrimental to the formation of functionalized products.
In the invention, after the pre-reaction, the functional group raw material and the reaction promoter are added, and the temperature is raised to 15-35 ℃ for reaction.
The light is preferably white light, for example 36w white light.
The light irradiation reaction time is preferably 12 to 24 hours.
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 99: 1-1: 1.
The reaction mechanism of the invention is shown in the reaction formula 1 (taking R1/R3/R4 in the formula 1 as H, R4 as methoxy as an example):
reaction scheme 1
The beneficial technology is as follows:
1. the technical scheme of the invention provides a method for carrying out boric acid esterification and halogenation by deamination of general arylamine. The invention can realize the high-efficiency deamination and boric acid esterification or halogenation of arylamine, particularly electron-substituted arylamine which is difficult to effectively treat by the technical scheme in the industry, by the cooperative control of the substrate, the reaction solvent, the mixing mode, the temperature and the reaction promoter.
2. 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;
the technical scheme of the invention produces different functionalized products from arylamine substrates, and has high yield. (ii) a The research shows that the yield of the product can reach 80%.
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 51HNMR spectrogram.
FIG. 4 shows the product obtained in example 513CNMR spectrogram.
FIG. 5 shows the product obtained in example 101HNMR spectrogram.
FIG. 6 shows the product obtained in example 1113CNMR 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 following examples and comparative examples, unless otherwise stated, all of the illumination is referred to as white light; for example, there is a 36W white light illumination response.
In the following case, the room temperature is 15-35 ℃.
Example 1
Synthesizing, separating and purifying 4-methoxyphenylboronic acid pinacol ester: 4-Methoxyaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After the completion of the dropwise addition, stirring was further carried out for 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) and pinacol ester of diboronic acid (761.8mg, 3mmol, 3eq) were added to the reaction flask by a microinjector and the reaction was allowed to proceed with light at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 20:1 mixture to obtain the final product: the 4-methoxyphenylboronic acid pinacol ester was a white solid in 51% yield.
1H NMR(400MHz,CDCl3)δ＝7.75(d,J＝8.3Hz,2H),6.90(d,J＝8.3Hz,2H),3.83(s,3H),1.33(s,12H).13C NMR(101MHz,CDCl3)δ＝162.15,136.52,113.32,83.57,55.11,24.87.
Example 2
Synthesizing, separating and purifying 4-methylphenylboronic acid pinacol ester: 4-methylaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After the completion of the dropwise addition, stirring was further carried out for 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) and pinacol ester of diboronic acid (761.8mg, 3mmol, 3eq) were added to the reaction flask by a microinjector and the reaction was allowed to proceed with light at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 20:1 mixture to obtain the final product: pinacol ester 4-methylphenylborate was a white solid in 54% yield.
1H NMR(400MHz,CDCl3)δ＝7.70(d,J＝7.7,2H),7.19(d,J＝7.6,2H),2.36(s,3H),1.34(s,12H).13C NMR(101MHz,CDCl3)δ＝141.43,134.82,128.54,83.64,24.87,21.74.
Example 3
Synthesizing, separating and purifying 4-chlorobenzene boronic acid pinacol ester: 4-chloroaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After the completion of the dropwise addition, stirring was further carried out for 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) and pinacol ester of diboronic acid (761.8mg, 3mmol, 3eq) were added to the reaction flask by a microinjector and the reaction was allowed to proceed with light at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 50:1 mixture to obtain the final product: the 4-chlorobenzeneboronic acid pinacol ester was a white solid in 39% yield.
1H NMR(400MHz,CDCl3)δ＝7.75(d,J＝8.2,2H),7.36(d,J＝8.3,2H),1.36(s,12H).13C NMR(101MHz,CDCl3)δ＝137.54,136.83,128.02,84.03,24.87.
Example 4
Synthesizing, separating and purifying 4-fluorobenzene pinacol borate: 4-fluoroaniline (formula shown in Table 1: 1mmol, 1.0eq) was charged in a 20mL glass vial with 5mL water and 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After the completion of the dropwise addition, stirring was further carried out for 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) and pinacol ester of diboronic acid (761.8mg, 3mmol, 3eq) were added to the reaction flask by a microinjector and the reaction was allowed to proceed with light at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 50:1 mixture to obtain the final product: the 4-fluorophenylboronic acid pinacol ester was a colorless transparent liquid, and the yield was 41%.
1H NMR(400MHz,CDCl3)δ＝7.80(dd,J＝8.4,6.4,2H),7.05(t,J＝8.9,2H),1.34(s,12H).13C NMR(101MHz,CDCl3)δ＝166.35,163.86,137.03,136.95,114.96,114.76,83.92,24.87.
Example 5
Synthesizing, separating and purifying 4-methylsulfonyl iodobenzene: 4-Methanesulfonylaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, followed by addition of sodium iodide (449.7mg, 3mmol, 3eq) and light reaction at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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: 4-Methanesulfonyliodobenzene was a yellow, transparent liquid with a yield of 78%.
1H NMR(400MHz,CDCl3)δ＝7.93(d,J＝8.3,2H),7.64(d,J＝8.4,2H),3.04(s,3H).13C NMR(101MHz,CDCl3)δ＝140.15,138.68,128.79,101.65,44.47.
Example 6
4-chloro-iodobenzene synthesis, separation and purification: 4-chloroaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, followed by addition of sodium iodide (449.7mg, 3mmol, 3eq) and light reaction at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 20:1 mixture to obtain the final product: the 4-chloroiodobenzene was a yellow transparent liquid with a yield of 71%.
1H NMR(400MHz,CDCl3)δ＝7.60(d,J＝8.6,2H),7.08(d,J＝8.6,2H).13C NMR(101MHz,CDCl3)δ＝138.75,134.24,130.56,91.21.
Example 7
Synthesizing, separating and purifying 4-fluoroiodobenzene: 4-fluoroaniline (formula shown in Table 1: 1mmol, 1.0eq) was charged in a 20mL glass vial with 5mL water and 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, followed by addition of sodium iodide (449.7mg, 3mmol, 3eq) and light reaction at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 20:1 mixture to obtain the final product: the 4-fluoroiodobenzene was a pale yellow transparent liquid with a yield of 69%.
1H NMR(400MHz,CDCl3)δ＝7.56(m,2H),6.77(t,J＝8.7,2H).13C NMR(101MHz,CDCl3)δ＝163.96,161.50,139.01,138.93,117.91,117.69,86.96,86.93.
Example 8
4-iodobenzene acetonitrile synthesis and separation purification: 4-Aminophenylacetonitrile (formula shown in Table 1: 1mmol, 1.0eq) was charged into a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, followed by addition of sodium iodide (449.7mg, 3mmol, 3eq) and light reaction at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 4-iodophenylacetonitrile is a light yellow transparent liquid, and the yield is 80%.
1H NMR(400MHz,CDCl3)δ＝7.84(d,J＝8.4,2H),7.36(d,J＝8.4,2H).13C NMR(101MHz,CDCl3)δ＝138.53,133.20,118.25,111.76,100.36.
Example 9
Synthesizing, separating and purifying 4-methoxy iodobenzene: 4-Methoxyaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, followed by addition of sodium iodide (449.7mg, 3mmol, 3eq) and light reaction at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 20:1 mixture to obtain the final product: the 4-methoxyiodobenzene was a pale yellow transparent liquid with a yield of 86%.
1H NMR(400MHz,CDCl3)δ＝7.55(d,J＝9.0,2H),6.68(d,J＝9.0,2H),3.77(s,3H).13C NMR(101MHz,CDCl3)δ＝159.49,138.21,116.38,82.69,55.33。
Example 10
4-methoxy bromobenzene is synthesized, separated and purified: 4-Methoxyaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, and carbon tetrabromide (994.9mg, 3mmol, 3eq) was added thereto, followed by a reaction under illumination at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 is mixed solution of 99:1 to obtain a final product: 4-Methoxybromobenzene is a yellow transparent liquid with a yield of 78%.
1H NMR(400MHz,CDCl3)δ＝7.38(d,J＝8.8,2H),6.79(d,J＝8.8,2H),3.78(s,3H).13C NMR(101MHz,CDCl3)δ＝158.70,132.25,115.74,112.82,55.45.
Example 11
4-ethoxy bromobenzene is synthesized, separated and purified: 4-ethoxyaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, and carbon tetrabromide (994.9mg, 3mmol, 3eq) was added thereto, followed by a reaction under illumination at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 is mixed solution of 99:1 to obtain a final product: 4-ethoxybromobenzene was a colorless transparent liquid with a yield of 76%.
1H NMR(400MHz,CDCl3)δ＝7.24(d,J＝9.0,2H),6.65(d,J＝9.0,2H),3.86(q,J＝7.0,2H),1.29(t,J＝7.0,3H).13C NMR(101MHz,CDCl3)δ＝158.10,132.23,116.32,112.65,63.70,14.78.
Example 12
And (3) synthesis, separation and purification of dibromobenzene: 4-bromoaniline (formula shown in Table 1: 1mmol, 1.0eq) was added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, and carbon tetrabromide (994.9mg, 3mmol, 3eq) was added thereto, followed by a reaction under illumination at room temperature for 16 hours. After the reaction is finished, quenching the reaction solution by water, extracting the reaction solution twice by using 20mL of dichloromethane, drying the obtained organic phase by using anhydrous sodium sulfate, filtering, and carrying out reduced pressure rotary evaporation 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 is mixed solution of 99:1 to obtain a final product: the p-dibromobenzene is a colorless transparent liquid with a yield of 78%.
1H NMR(400MHz,CDCl3)δ＝7.36(s,4H).13C NMR(101MHz,CDCl3)δ＝133.16,121.08.
The substrates, products and yields of examples 1-12 are shown in Table 1:
TABLE 1
As can be seen from the data in Table 1, the technical scheme of the invention can still obtain good product yield under the condition of no noble metal catalyst, and particularly, the yield of electron-donating substituted substrates can still reach about 80%.
Comparative example 1
Compared with the example 10, the difference is mainly that no nitrite compound is added, and the specific operation is as follows:
4-methoxy bromobenzene is synthesized, separated and purified: 4-Methoxyaniline (1mmol, 1.0eq) was added to a 20mL glass vial, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 15 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask with a micro syringe, followed by addition of carbon tetrabromide (994.9mg, 3mmol, 3eq) and light reaction at room temperature for 16 hours. After the reaction is finished, the product is not obtained by processing according to the post-processing method of the invention. This comparative example illustrates that the nitrite compound has a major effect on arylamine deamination functionalization.
Comparative example 2
Compared with the example 10, the difference is mainly that the adopted solvent is single water or dichloromethane, and a mixed solvent is not adopted, and the specific operation is as follows:
4-methoxy bromobenzene is synthesized, separated and purified: 4-Methoxyaniline (1mmol, 1.0eq) was added to a 20mL glass vial, 10mL water or dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, and carbon tetrabromide (994.9mg, 3mmol, 3eq) was added thereto, followed by a reaction under illumination at room temperature for 16 hours. After the reaction is finished, the post-treatment method is adopted for treatment, and when water is used as a solvent, the yield of the product is 23%; the yield of the product is less than 10% when DCM is used as a solvent, and the yield of example 9 is as high as 78%. This comparative example shows that the yield is higher using a mixed solvent of dichloromethane and water.
Comparative example 3
Compared with the example 10, the difference is mainly that the reaction is not carried out under the illumination, and the specific operation is as follows:
4-methoxy bromobenzene is synthesized, separated and purified: 4-Methoxyaniline (1mmol, 1.0eq) was added to a 20mL glass vial, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe, and carbon tetrabromide (994.9mg, 3mmol, 3eq) was added thereto, followed by reaction for 16 hours at room temperature in the dark. After the reaction was completed, the product yield was 7% by the work-up according to the invention. Compared with example 9, the yield of the product is obviously reduced without the light treatment.
Comparative example 4
Compared with the example 10, the difference is mainly that the adding sequence of the functionalizing agent is different, and the specific operation is as follows:
4-methoxy bromobenzene is synthesized, separated and purified: 4-methoxyaniline (1mmol, 1.0eq) and carbon tetrabromide (994.9mg, 3mmol, 3eq) were added to a 20mL glass bottle, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (8.7. mu.L, 0.1mmol, 0.1eq) was added to the reaction flask by a micro syringe and the mixture was reacted with light at room temperature for 16 hours. After the reaction was completed, the product yield was 35% by the work-up according to the present invention.
Comparative example 5
Compared with the example 10, the difference is mainly that the adding equivalent weight of the butanedione (the molar ratio of the butanedione to the 4-methoxyaniline) is as follows:
4-methoxy bromobenzene is synthesized, separated and purified: 4-Methoxyaniline (1mmol, 1.0eq) was added to a 20mL glass vial, 5mL water, 5mL dichloromethane. The reaction flask was placed in an ice bath at 0 ℃ and stirred for 5 minutes, and tert-butyl nitrite (0.24mL,2mmol, 2.0eq) was slowly added dropwise to the reaction flask with a syringe. After the completion of the dropwise addition, the mixture was stirred for another 10 minutes, and butanedione (1.0 eq, 2eq, and 4eq, respectively) and carbon tetrabromide (994.9mg, 3mmol, and 3eq) were added to the reaction flask by a syringe, followed by a light reaction at room temperature for 16 hours. After the reaction is finished, the product yield is lower than 20% by carrying out the treatment according to the post-treatment method of the invention, and partial acetylation products are generated. In comparison with example 9, excessive butanedione content resulted in increased side reactions and decreased reaction yields.
Comparative example 6
Compared with example 10, the difference is that 4-methoxyaniline is replaced by an ortho-methoxy-substituted substrate (2-methoxyaniline). The product yield was found to be less than 10%. The research shows that the yield of the amino-containing group at the ortho-position is obviously reduced.
Comparative example 7
Compared with example 10, the difference is that Hantzsh ester or eosin Y disodium salt is used to replace butanedione. The study found that the yield of Hantzsh ester product was 30% while the yield of eosin Y disodium salt was less than 10%. Other photocatalysts have been found to affect the yield of the reaction.
Comparative example 8
Compared with example 10, the difference is that acetonitrile is used to replace dichloromethane, and a mixed solvent of acetonitrile and water is formed. The product yield was found to be 33%, which is much lower than in example 10. It was found that hydrophilic solvents reduce the yield of the reaction.
In conclusion, the deamination functionalization can be completed by arylamine shown in formula 1, nitrite compound shown in formula 3, pinacol ester diboron diboride or sodium iodide or carbon tetrabromide under the catalysis of butanedione and the irradiation of light. It has also been found that the combined control of the substrate, reaction solvent, mixing sequence, temperature, diacetyl and amount of these can improve the decarbamoboration and halogenation of arylamines, particularly substrates that are difficult to handle in technical solutions within the industry, for electronic substitution.
Claims (10)
1. A method for catalyzing arylamine to carry out deamination boric acid esterification or halogenation is characterized in that arylamine with a formula 1 and a compound with a formula 2 are placed in a mixed solvent and pre-reacted at 0-5 ℃; then adding a raw material capable of providing a functional group A and a catalytic amount of a reaction promoter, and carrying out deamination functionalization reaction at 10-50 ℃ under the irradiation of light to modify the functional group A at the amino position of the formula 1 to obtain a product with a structure of a formula 3;
the reaction promoter is butanedione;
the mixed solvent is a mixed solvent containing water and a hydrophobic organic solvent;
R1-R3 are independently H, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, benzyloxy, nitro, halogen, cyano, ester group, trifluoromethyl, C1-C4 alkylthio, sulfonyl or allyloxy;
r4 is H or F;
r5 is C1-C6 alkyl or metallic sodium ion;
a isI or Br.
2. The method of claim 1, wherein R1, R3, R4 are hydrogen;
r2 is hydrogen, methyl, methoxy, methylthio, nitro, trifluoromethyl, benzyloxy, allyloxy, fluorine, bromine, chlorine atom or cyano.
3. The method of claim 1, wherein R5 is t-butyl, t-amyl, or a metal sodium ion.
4. The method of claim 1, wherein the molar ratio of arylamine to compound of formula 2 is 1: 1.1-2.
5. The method of claim 1, wherein in the mixed solvent, the hydrophobic organic solvent is at least one of ethyl acetate, toluene, dichloromethane and diethyl ether;
in the mixed solvent, the volume ratio of water to the hydrophobic organic solvent is 1: 0.5-1.5.
6. The method of claim 1, wherein the reactants are added in the order of: firstly, arylamine is added, then a mixed solvent is added, the compound of the formula 2 is dripped at the temperature of 0-5 ℃, after reaction is carried out for 10min, raw materials capable of providing functional groups A and a reaction promoter are added, and then illumination and heating reaction are carried out.
7. The method of claim 1, wherein the functionalizing group a is provided from pinacol ester diboron, sodium iodide, or carbon tetrabromide.
8. The method of claim 1, wherein the functional group a is provided from a starting material that provides the functional group a, and wherein the molar ratio of the arylamine to the starting material that provides the functional group a is 1: 2-4.
9. The method of claim 1, wherein the molar ratio of arylamine to reaction promoter is 1: 0.05-0.2.
10. The method of claim 1, wherein the light is white light;
the light irradiation reaction time is preferably 12 to 24 hours.
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