CN114805152B - Synthetic method of thioamide - Google Patents
Synthetic method of thioamide Download PDFInfo
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- CN114805152B CN114805152B CN202210487922.4A CN202210487922A CN114805152B CN 114805152 B CN114805152 B CN 114805152B CN 202210487922 A CN202210487922 A CN 202210487922A CN 114805152 B CN114805152 B CN 114805152B
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- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 220
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims abstract description 88
- 239000012535 impurity Substances 0.000 claims abstract description 48
- 229910052786 argon Inorganic materials 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 18
- -1 nitrile compound Chemical class 0.000 claims abstract description 17
- OMBRFUXPXNIUCZ-UHFFFAOYSA-N dioxidonitrogen(1+) Chemical class O=[N+]=O OMBRFUXPXNIUCZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 261
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 234
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 90
- 239000007787 solid Substances 0.000 claims description 68
- 239000012043 crude product Substances 0.000 claims description 45
- 239000003480 eluent Substances 0.000 claims description 45
- 239000000706 filtrate Substances 0.000 claims description 45
- 238000003818 flash chromatography Methods 0.000 claims description 45
- 239000003960 organic solvent Substances 0.000 claims description 45
- 239000000741 silica gel Substances 0.000 claims description 45
- 229910002027 silica gel Inorganic materials 0.000 claims description 45
- 238000001914 filtration Methods 0.000 claims description 44
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 32
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- WHGPQZJYJWIBGZ-UHFFFAOYSA-N 7-bromobicyclo[2.2.1]heptane Chemical compound C1CC2CCC1C2Br WHGPQZJYJWIBGZ-UHFFFAOYSA-N 0.000 claims description 10
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- FFWQLZFIMNTUCZ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CBr FFWQLZFIMNTUCZ-UHFFFAOYSA-N 0.000 claims description 4
- WGVYCXYGPNNUQA-UHFFFAOYSA-N 1-(bromomethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CBr WGVYCXYGPNNUQA-UHFFFAOYSA-N 0.000 claims description 4
- SNRYBGHMHAJTTM-UHFFFAOYSA-N 1-(bromomethyl)-3,5-ditert-butylbenzene Chemical compound CC(C)(C)C1=CC(CBr)=CC(C(C)(C)C)=C1 SNRYBGHMHAJTTM-UHFFFAOYSA-N 0.000 claims description 4
- SCBZBMXPJYMXRC-UHFFFAOYSA-N 1-(bromomethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CBr)=C1 SCBZBMXPJYMXRC-UHFFFAOYSA-N 0.000 claims description 4
- ZKSOJQDNSNJIQW-UHFFFAOYSA-N 1-(bromomethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CBr)=C1 ZKSOJQDNSNJIQW-UHFFFAOYSA-N 0.000 claims description 4
- FWLWTILKTABGKQ-UHFFFAOYSA-N 1-(bromomethyl)-3-methylbenzene Chemical compound CC1=CC=CC(CBr)=C1 FWLWTILKTABGKQ-UHFFFAOYSA-N 0.000 claims description 4
- IKSNDOVDVVPSMA-UHFFFAOYSA-N 1-(bromomethyl)-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(CBr)C=C1 IKSNDOVDVVPSMA-UHFFFAOYSA-N 0.000 claims description 4
- UFCSSWZQROEFBZ-UHFFFAOYSA-N 1-(bromomethyl)-4-chloro-2-fluorobenzene Chemical compound FC1=CC(Cl)=CC=C1CBr UFCSSWZQROEFBZ-UHFFFAOYSA-N 0.000 claims description 4
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 claims description 4
- DAKPIAWEPVZDNG-UHFFFAOYSA-N 1-(bromomethyl)-4-fluoro-2-methylbenzene Chemical compound CC1=CC(F)=CC=C1CBr DAKPIAWEPVZDNG-UHFFFAOYSA-N 0.000 claims description 4
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 claims description 4
- WZRKSPFYXUXINF-UHFFFAOYSA-N 1-(bromomethyl)-4-methylbenzene Chemical compound CC1=CC=C(CBr)C=C1 WZRKSPFYXUXINF-UHFFFAOYSA-N 0.000 claims description 4
- QZNQSIHCDAGZIA-UHFFFAOYSA-N 1-(bromomethyl)-4-tert-butylbenzene Chemical compound CC(C)(C)C1=CC=C(CBr)C=C1 QZNQSIHCDAGZIA-UHFFFAOYSA-N 0.000 claims description 4
- QQIOJAHQDFJQSJ-UHFFFAOYSA-N 1-bromo-4-(1-bromoethyl)benzene Chemical compound CC(Br)C1=CC=C(Br)C=C1 QQIOJAHQDFJQSJ-UHFFFAOYSA-N 0.000 claims description 4
- YLRBJYMANQKEAW-UHFFFAOYSA-N 1-bromo-4-(bromomethyl)benzene Chemical compound BrCC1=CC=C(Br)C=C1 YLRBJYMANQKEAW-UHFFFAOYSA-N 0.000 claims description 4
- VQHPRVYDKRESCL-UHFFFAOYSA-N 1-bromoadamantane Chemical compound C1C(C2)CC3CC2CC1(Br)C3 VQHPRVYDKRESCL-UHFFFAOYSA-N 0.000 claims description 4
- CRRUGYDDEMGVDY-UHFFFAOYSA-N 1-bromoethylbenzene Chemical compound CC(Br)C1=CC=CC=C1 CRRUGYDDEMGVDY-UHFFFAOYSA-N 0.000 claims description 4
- RUHJZSZTSCSTCC-UHFFFAOYSA-N 2-(bromomethyl)naphthalene Chemical compound C1=CC=CC2=CC(CBr)=CC=C21 RUHJZSZTSCSTCC-UHFFFAOYSA-N 0.000 claims description 4
- LOXORFRCPXUORP-UHFFFAOYSA-N bromo-Cycloheptane Chemical compound BrC1CCCCCC1 LOXORFRCPXUORP-UHFFFAOYSA-N 0.000 claims description 4
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 claims description 4
- VBWIZSYFQSOUFQ-UHFFFAOYSA-N cyclohexanecarbonitrile Chemical compound N#CC1CCCCC1 VBWIZSYFQSOUFQ-UHFFFAOYSA-N 0.000 claims description 4
- SVPZJHKVRMRREG-UHFFFAOYSA-N cyclopentanecarbonitrile Chemical compound N#CC1CCCC1 SVPZJHKVRMRREG-UHFFFAOYSA-N 0.000 claims description 4
- 229960000815 ezetimibe Drugs 0.000 claims description 4
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 claims description 4
- QUCXLVDIVQWYJR-UHFFFAOYSA-N 1-bromo-3,5-dimethyladamantane Chemical compound C1C(C2)CC3(C)CC1(C)CC2(Br)C3 QUCXLVDIVQWYJR-UHFFFAOYSA-N 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- OQROAIRCEOBYJA-UHFFFAOYSA-N bromodiphenylmethane Chemical compound C=1C=CC=CC=1C(Br)C1=CC=CC=C1 OQROAIRCEOBYJA-UHFFFAOYSA-N 0.000 claims description 3
- WCZAXBXVDLKQGV-UHFFFAOYSA-N n,n-dimethyl-2-(7-oxobenzo[c]fluoren-5-yl)oxyethanamine oxide Chemical compound C12=CC=CC=C2C(OCC[N+](C)([O-])C)=CC2=C1C1=CC=CC=C1C2=O WCZAXBXVDLKQGV-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 claims description 3
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 claims description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 2
- 150000003556 thioamides Chemical class 0.000 abstract description 14
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 3
- 150000001649 bromium compounds Chemical class 0.000 abstract description 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 238000005980 thioamidation reaction Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003205 fragrance Substances 0.000 abstract 1
- 239000007789 gas Substances 0.000 description 147
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 86
- 239000000047 product Substances 0.000 description 74
- 239000003153 chemical reaction reagent Substances 0.000 description 45
- 239000002994 raw material Substances 0.000 description 44
- 239000003208 petroleum Substances 0.000 description 43
- 238000007789 sealing Methods 0.000 description 43
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 42
- 229910000365 copper sulfate Inorganic materials 0.000 description 39
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- 238000001514 detection method Methods 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- 239000013078 crystal Substances 0.000 description 13
- 239000007788 liquid Substances 0.000 description 7
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241000402754 Erythranthe moschata Species 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 238000005659 Kindler reaction Methods 0.000 description 1
- 241000124033 Salix Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ZINJLDJMHCUBIP-UHFFFAOYSA-N ethametsulfuron-methyl Chemical compound CCOC1=NC(NC)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CC=2)C(=O)OC)=N1 ZINJLDJMHCUBIP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000010512 small scale reaction Methods 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000005987 sulfurization reaction Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/46—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/20—All rings being cycloaliphatic the ring system containing seven carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of synthesis of organic intermediates, and particularly relates to a method for synthesizing thioamide, which comprises the following steps: (1) Dissolving a nitronium salt in a nitrile compound or dissolving the nitronium salt and the nitrile compound in a solvent; (2) Under the protection of argon, adding bromide at the temperature of-35-90 ℃ for reaction; (3) Cooling to-35-45 ℃, and adding a vulcanizing agent for reaction; (4) After the reaction is finished, removing fixed impurities and solvent, and purifying to obtain thioamide with a structural formula
Wherein R is various substituted benzyl, linear alkyl and cycloalkyl, R 1 The method has a wide substrate range, good to excellent yields and relatively mild reaction conditions for alkyl or phenyl groups, and more importantly, the method for the first time realizes the synthesis of thioamides through a Ritter reaction-like process and the thioamidation of bromo-derivatives of drug molecules or fragrances.
Description
Technical Field
The invention belongs to the field of synthesis of organic intermediates, and particularly relates to a method for synthesizing thioamide.
Background
Thioamides are of great significance in the research of biological, material and chemical disciplines, and are widely applied to a plurality of related research fields. In the aspect of biological research, the compound containing the thioamide structural unit shows certain biological activity and medicinal value, and most importantly, in the polypeptide or the protein, the thioamide structural unit can be used as an amide isostere for detecting the biological activity, the physical property, the stability, the catalytic function, the structural change, the direct change of the physicochemical property and the like of the polypeptide or the protein; in materials research, thioamides also exhibit their unique functionality in several respects; in the aspect of chemical research, thioamides can be widely applied to natural product synthesis, functional group conversion and heterocyclic compound synthesis as catalysts or synthons. With the continuous and intensive research on thioamides, the importance of thioamides is more and more shown, and therefore, the efficient synthesis of thioamides is always one of the important directions for the research on synthetic chemistry.
However, the current synthesis methods still have some disadvantages, which are mainly shown in that: 1) Using Lawesson reagent/P 2 S 5 The amide is converted into thioamide to be applied to various small-scale reactions, and the main defects are that the organophosphorus pollution problem is caused, the Lawesson reagent is difficult to separate and the like; 2) The synthesis of thioamides by oxidation using nitriles generally allows the synthesis of only primary thioamides and is generally not applicable to aliphatic nitrile substrates; 3) By BeckmannAlthough the thioamide can be synthesized by the rearrangement reaction, oxime needs to be prepared in advance, and the synthesis steps are complex; 4) The Friedel-Crafts reaction of isothiocyanate mainly has the problem of position selectivity; 5) The Willgenodt-Kindler reaction is generally carried out at high temperature, the yield is low, and a milder and green improved method needs to be developed; 6) The oxidative coupling reaction of amines is generally only suitable for the synthesis of conjugated thioamides. Therefore, the development of new methods for synthesizing thioamides is of great scientific interest, but with certain synthetic challenges.
In view of the above technical problems, the inventors have developed a method for synthesizing thioamides, which is simple in steps and can rapidly prepare thioamides without pollution.
Disclosure of Invention
In order to solve the technical problems, the invention provides the following technical scheme: a method for synthesizing thioamide, which comprises the following steps:
(1) Dissolving a nitronium salt in a nitrile compound or dissolving the nitronium salt and the nitrile compound in a solvent;
(2) Under the protection of argon, adding bromide at the temperature of-35-90 ℃ for reaction;
(3) Cooling to-35-45 ℃, and adding a vulcanizing agent for reaction;
(4) After the reaction is finished, removing fixed impurities and solvent, and purifying to obtain thioamide with the structural formula
Wherein R is various substituted benzyl, linear alkyl and cycloalkyl, R 1 Is alkyl or phenyl.
The phenyl in the substituted benzyl is halogenated phenyl, tert-butyl phenyl, methyl phenyl or methoxyphenyl.
Preferably, the nitronium salt of step (1) is NOBF 4 、NO 2 BF 4 、NOPF 6 And NOSbF 6 The nitrile compound is one of acetonitrile, n-butyronitrile, cyclopentanenitrile, benzonitrile and cyclohexanenitrile.
Preferably, the addition amount of the nitronium salt and the nitrile compound in the step (1) is 0.6:1n/v; the addition amount of the nitronium salt, the nitrile compound and the solvent is 6:20:10n/n/v.
Preferably, the solvent in step (1) is CH 3 CN or CH 3 NO 2 。
Preferably, the bromide in step (2) is any one of benzyl bromide, 4-fluorobenzyl bromide, 2-fluorobenzyl bromide, 3-fluorobenzyl bromide, 4-chlorobenzyl bromide, 4-bromobenzyl bromide, 4-trifluoromethylbenzyl bromide, 4-methylbenzyl bromide, 2-methylbenzyl bromide, 3-methylbenzyl bromide, 4-tert-butylbenzyl bromide, 3-methoxybenzyl bromide, 2-bromomethylnaphthalene, 3,5-di-tert-butylbenzyl bromide, 4-fluoro-2-methylbenzyl bromide, 4-chloro-2-fluorobenzyl bromide, (1-bromoethyl) benzene, 1-bromo-4- (1-bromoethyl) benzene, diphenylbromomethane, tert-butyl bromide, bromocyclopentane, bromocycloheptane, 7-bromonorbornane, 1-bromoadamantane, 7-bromonorbornane, 1-bromo-3,5-dimethyladamantane, salbene bromide derivatives, and ezetimibe bromo derivatives.
Preferably, the reaction time in step (2) is 30min.
Preferably, the molar ratio of bromide to nitronium salt is 1.5.
Preferably, the sulfurizing reagent in step (3) is thioacetamide, thiourea or Na 2 S, naHS or H 2 S。
Preferably, the solid impurities in the step (4) are removed by filtering through diatomite, and ethyl acetate is used as an eluent; distilling the filtrate under reduced pressure to remove the organic solvent; the crude product was purified by flash column chromatography on silica gel.
Preferably, the thioamide comprises
The invention has the beneficial effects that: the invention discloses a synthesis method of thioamide, which uses nitronium salt to promote bromide, nitrile and a sulfurization reagent to synthesize various thioamides. The method has the advantages of bulk chemicals as raw materials, simple operation, mild reaction conditions, short reaction time, gram-scale preparation and the like, and more importantly, the method can realize thioamidation of active functional molecules.
Detailed Description
The preferred embodiments of the present invention are described below, and it should be understood that the preferred embodiments described herein are only for illustrating and explaining the present invention and are not to be construed as limiting the present invention.
Example 1
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at room temperature (20 ℃) and reacted at room temperature (20 ℃) for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for guiding H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (48.3mg, 73%, white crystals).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.39-7.32(m,5H),4.80(d,J＝5.2Hz,2H),2.57(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ201.0,136.2,129.1,128.5,128.3,50.8,34.3；MS(EI)m/z(％):165(52),132(21),105(32),91(100)；IR(KBr plate):3220,3069,2923,1551,1393,1341,1165,1071,940,694cm -1 .
example 2
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued for 30 minutes at 45 ℃. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for guiding H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (52.9 mg,80%, white crystals).
Example 3
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to-35 ℃, and a gas guide needle is used for leading H 2 S introduction reaction tubeMedium (gas needle with significant gas outflow), for 1 minute, tail gas was absorbed with aqueous copper sulfate solution and stirring was continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (49.6 mg,75%, white crystals).
Example 4
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to 0 ℃, and H is injected by using an air guide needle 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (46.3mg, 70%, white crystals).
Example 5
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. Will reactThe tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to 20 ℃, and a gas guide needle is used for guiding H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (43.0 mg,65%, white crystals).
Example 6
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then cooling to-15 deg.C, adding Na 2 S (4.0 mmol, 312.2mg) and stirring was continued at this temperature for 20 minutes. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (19.8mg, 30%, white crystals).
Example 7
Taking benzyl bromide and acetonitrile as raw materials:
10mL to be driedPutting the reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued for 30 minutes at 45 ℃. The temperature was then lowered to-15 ℃ and NaHS (4.0 mmol, 224.2mg) was added and stirring continued at this temperature for 20 minutes. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (15.9 mg,24%, white crystals).
Example 8
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. The temperature was then reduced to-15 ℃ and thiourea (4.0 mmol,304.5 mg) was added and stirring continued at this temperature for 20 minutes. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (10.0 mg,15%, white crystals).
Example 9
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. The temperature was then reduced to-15 ℃ and thioacetic amine (4.0 mmol,300.5 mg) was added and stirring continued at this temperature for 20 minutes. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (50.2mg, 76%, white crystals).
Example 10
Taking benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NOBF 4 (0.6mmol, 71.3mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃. And the reaction was continued at a temperature of 45 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for guiding H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (52.9 mg,80%, white crystals).
Example 11
Taking benzyl bromide and acetonitrile as raw materials:
the dried 10mL reaction tube and the dried reagent are put into a glove box, and NOPF is added 6 (0.6mmol, 106.2mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued for 30 minutes at 45 ℃. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for guiding H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (47.6 mg,72%, white crystals).
Example 12
Taking benzyl bromide and acetonitrile as raw materials:
the dried 10mL reaction tube and the dried reagent are put into a glove box, and the NOSbF is put into the glove box 4 (0.6 mmol, 154.1mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate is then distilled under reduced pressure to remove the organic solvent and the crude product is purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding compoundProduct (19.8mg, 30%, white crystals).
Example 13
Taking 4-fluorobenzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, 4-fluorobenzyl bromide (0.4 mmol,75.6 mg) was added slowly at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (51.3mg, 70%, white crystals).
The product detection data were as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.55(s,1H),7.31-7.28(m,2H),7.03(t,J＝8.4Hz,2H),4.77(d,J＝5.2Hz,2H),2.55(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ201.1,162.6(d,J＝246.0Hz),132.0(d,J＝3.0Hz),130.2(d,J＝8.0Hz),115.9(d,J＝21.0Hz),49.8,34.2；HRMS(ESI)m/z calculated for C 9 H 10 FNS[M+H] + 184.0591,found 184.0598.MS(EI)m/z(％):184(4),183(37),124(19),109(100),59(17)；IR(KBr plate):3224,3070,1555,1509,1227,1168,1079,827,729cm -1 .
example 14
Taking 2-fluorobenzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 2-fluorobenzyl bromide (0.4 mmol,75.6 mg) was added slowly at 90 ℃ under the protection of argon, and the reaction was continued at 90 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for guiding H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (27.5mg, 38%, yellow oily liquid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.53(s,1H),7.40(td,J＝1.6Hz,J＝7.6Hz,1H),7.34-7.28(m,1H),7.15-7.05(m,2H),4.88(d,J＝5.2Hz,2H),2.56(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ201.3,161.3(d,J＝245.0Hz),131.2(d,J＝4.0Hz),130.2(d,J＝8.0Hz),124.6(d,J＝4.0Hz),123.1(d,J＝15.0Hz),115.7(d,J＝21.0Hz),44.4(d,J＝3.0Hz),34.3；HRMS(ESI)m/z calculated for C 9 H 10 FNS[M+H] + 184.0591,found 184.0589.MS(EI)m/z(％):183(43),167(27),124(75),110(15),109(100)；IR(KBr plate):3223,3046,2929,1535,1492,1390,1336,1232,1171,1105,1075,758cm -1 .
example 15
3-fluorobenzyl bromide and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 3-fluorobenzyl bromide (0.4 mmol,75.6 mg) was slowly added at 90 ℃ under the protection of argon, and the reaction was continued at 90 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (29.3mg, 40%, yellow oily liquid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.69(s,1H),7.34-7.30(m,1H),7.10(d,J＝7.8Hz,1H),7.03-6.99(m,2H),4.82(d,J＝5.4Hz,2H),2.57(s,3H)； 13 C NMR(150MHz,CDCl 3 ):δ201.5,163.0(d,J＝244.5Hz),138.6(d,J＝6.0Hz),130.6(d,J＝7.5Hz),123.9(d,J＝3.0Hz),115.14(d,J＝34.5Hz),115.13(d,J＝6.0Hz),49.8,34.1；MS(EI)m/z(％):184(6),183(52),164(4),124(41),109(100)；IR(KBr plate):3221,3050,2929,1592,1536,1488,1450,1387,1334,1254,1170,1069,950,787,685cm -1 .
example 16
4-chlorobenzyl bromide and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, 4-chlorobenzyl bromide (0.4 mmol, 82.2mg) was added slowly at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S guideInto the reaction tube (gas needle with significant gas outflow) for 1 minute, the tail gas was absorbed with aqueous copper sulfate solution and stirring was continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (57.0 mg,71%, yellow solid).
The product detection data were as follows: 1 H NMR(600MHz,CDCl 3 ):δ7.42(s,1H),7.34-7.32(m,2H),7.27(d,J＝8.4Hz,2H),4.80(d,J＝5.4Hz,2H),2.58(s,3H)； 13 C NMR(150MHz,CDCl 3 ):δ201.4,134.7,134.2,129.8,129.2,49.8,34.3；HRMS(ESI)m/zcalculated for C 9 H 10 ClNS[M+H] + 200.0295,found 200.0293.MS(EI)m/z(％):201(16),199(40),142(8),140(28),127(33),125(100),89(26)；IR(KBr plate):3227,3065,2927,1596,1376,1336,1169,1092,927,814,695cm -1 .
example 17
4-bromobenzyl bromide and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, 4-bromobenzyl bromide (0.4mmol, 100.0mg) was slowly added at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/acetic acid)Ethyl ester) to give the corresponding product (79.6 mg,82%, white solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.52(s,1H),7.49-7.45(m,2H),7.20(d,J＝8.4Hz,2H),4.77(d,J＝5.2Hz,2H),2.57(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ201.4,135.2,132.1,130.1,122.2,49.8,34.2；HRMS(ESI)m/zcalculated for C 9 H 10 BrNS[M+H] + 243.9790,245.9770,found 243.9801,245.9779.MS(EI)m/z(％):245(85),243(81),186(25),184(30),171(94),169(100)；IR(KBr plate):3216,3044,2924,1536,1487,1383,1332,1167,1072,1012,798cm -1 .
example 18
4-trifluoromethyl benzyl bromide and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, 4-trifluoromethylbenzyl bromide (0.4 mmol,95.6 mg) was slowly added at 90 ℃ and the reaction was continued at 90 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (11.6 mg,12%, yellow solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.60(d,J＝8.0Hz,2H),7.44(d,J＝8.0Hz,2H),4.90(d,J＝5.6Hz,2H),2.59(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ201.8,140.2,130.4(q,J＝33.0Hz),128.6,125.9(q,J＝4.0Hz),124.0(d,J＝270.0Hz).49.7,34.2；HRMS(ESI)m/z calculated for C 10 H 10 F 3 NS[M+H] + 234.0559,found 234.0558.MS(EI)m/z(％):234(12),233(68),174(46),159(100),145(11)；IR(KBr plate):3222,3048,2928,1537,1387,1326,1166,1124,1067,1019,931,692cm -1 .
example 19
Taking 4-methylbenzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 4-methylbenzyl bromide (0.4mmol, 74.0 mg) was added slowly at room temperature (20 ℃ C.) under an argon blanket, and the reaction was continued at room temperature (20 ℃ C.) for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (55.3mg, 77%, yellow solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.46(s,1H),7,21(d,J＝7.8Hz,2H),7.16(d,J＝7.8Hz,2H),4.74(d,J＝5.4Hz,2H),2.55(s,3H),2.34(s,3H)； 13 C NMR(150MHz,CDCl 3 ):δ200.7,138.1,133.1,129.7,128.5,50.5,34.2,21.2；HRMS(ESI)m/z calculated for C 10 H 13 NS[M+H] + 180.0841,found 180.0839.MS(EI)m/z(％):179(31),120(19),105(100),91(17)；IR(KBr plate):3220,3049,3023,2922,1535,1385,1333,1166,1071,924,808,700cm -1 .
example 20
Taking 2-methylbenzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 2-methylbenzyl bromide (0.4mmol, 74.0 mg) was slowly added at room temperature (20 ℃) under an argon shield, and the reaction was continued at room temperature (20 ℃) for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (58.5mg, 82%, yellow solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.28-7.18(m,5H),4.76(d,J＝4.8Hz,2H),2.55(s,3H),2.33(s,3H)； 13 CNMR(100MHz,CDCl 3 ):δ200.6,137.1,134.1,130.9,129.6,128.6,126.5,49.1,34.1,19.2；HRMS(ESI)m/zcalculated for C 10 H 13 NS[M+H] + 180.0841,found 180.0850.MS(EI)m/z(％):179(83),164(9),105(100),91(18)；IR(KBr plate):3218,3021,2924,1531,1389,1331,1169,1071,924,745cm -1 .
example 21
3-methylbenzyl bromide and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 3-methylbenzyl bromide (0.4mmol, 74.0 mg) was added slowly at room temperature (20 ℃ C.) under an argon blanket, and the reaction was continued at room temperature (20 ℃ C.) for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (51.5mg, 72%, oily liquid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.44(s,1H),7.27-7.24(m,1H),7.15-7.11(m,3H),4.76(d,J＝5.2Hz,2H),2.57(s,3H),2.35(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ200.8,138.9,136.0,129.2,190.0,128.95,125.5,50.8,34.2,21.5；HRMS(ESI)m/z calculated for C 10 H 13 NS[M+H] + 180.0841,found 180.0850.MS(EI)m/z(％):179(86),146(36),120(28),105(100),91(12)；IR(KBr plate):3220,3026,2921,1534,1491,1331,1168,1072,942,693cm -1 .
example 22
Taking 4-tert-butyl benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film, and then was taken out of the glove boxAnd removing. 4-tert-butylbenzylbromide (0.4 mmol, 90.9mg) was slowly added under argon at room temperature (20 ℃) and the reaction was continued at room temperature (20 ℃) for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (74.6 mg,84%, white solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.40(d,J＝8.4H z,2H),7.27(d,J＝8.4Hz,2H),4.76(d,J＝4.8Hz,2H),2.56(s,3H),1.32(s,9H)； 13 C NMR(150MHz,CDCl 3 ):δ200.7,151.5,133.1,128.4,126.0,50.5,34.7,34.2,31.4；HRMS(ESI)m/z calculated for C 13 H 19 NS[M+H] + 222.1311,found 222.1320.MS(EI)m/z(％):221(78),162(19),147(100),132(52),117(29)；IR(KBr plate):3217,2962,1536,1388,1333,1166,1071,1019,927,690cm -1 .
example 23
3-methoxybenzyl bromide and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 3-methoxybenzyl bromide (0.4mmol, 80.4 mg) was added slowly at room temperature (20 ℃ C.) under an argon blanket and the reaction was continued for 30 minutes at room temperature (20 ℃ C.). Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is led into a reaction tube (the gas guide needle has obvious gas outflow) for 1 minute, and the tail gas is absorbed by copper sulfate aqueous solutionAnd stirred at this temperature for an additional 20 minutes. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (13.0 mg,17%, yellow oily liquid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.41(s,1H),7.30-7.27(m,1H),6.92-6.85(m,3H),4.77(d,J＝5.2Hz,2H),3.81(s,3H),2.58(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ200.9,160.0,137.6,130.1,120.6,114.1,113.6,55.4,50.7,34.2；HRMS(ESI)m/z calculated for C 10 H 13 NOS[M+H] + 196.0791,found 196.0799.MS(EI)m/z(％):195(73),162(45),136(20),122(12),121(100)；IR(KBr plate):3221,3049,2933,1601,1534,1490,1331,1292,1166,1047,785,691cm -1 .
example 24
Taking 2-bromomethylnaphthalene and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 2-bromomethylnaphthalene (0.4mmol, 88.4 mg) was added slowly at 0 ℃ under an argon blanket and the reaction was continued for 30 minutes in an ice-water bath (0 ℃). Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (56.7 mg)66%, yellow solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.85-7.81(m,3H),7.76(s,1H),7.51-7.48(m,2H),7.42(dd,J＝1.6Hz,J＝8.4Hz,1H),4.96(d,J＝5.2Hz,2H),2.59(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ201.0,133.5,133.4,133.1,128.9,127.9,127.8,127.4,126.6,126.4,126.1,50.8,34.2；HRMS(ESI)m/z calculated for C 13 H 13 NS[M+H] + 216.0841,found 216.0842.MS(EI)m/z(％):215(33),182(25),156(9),141(100),127(8)；IR(KBr plate):3360,3219,3051,2923,1531,1392,1362,1323,1167,1074,1019,818,741cm -1
example 25
Using 3,5-di-tert-butyl benzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 3,5-di-tert-butylbenzylbromide (0.4mmol, 113.3mg) was added slowly under argon at room temperature (20 ℃) and the reaction was continued for 30 minutes at room temperature (20 ℃). Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (90.9mg, 82%, white solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.47(s,1H),7.42(s,1H),7.19(d,J＝1.8Hz,2H),4.76(d,J＝4.8Hz,2H),2.57(s,3H),1.34(s,18H)； 13 C NMR(150MHz,CDCl 3 ):δ200.4,151.7,135.2,123.0,122.5,51.7,35.0,34.1,31.5；HRMS(ESI)m/z calculated for C 17 H 27 NS[M+Na] + 300.1756,found 300.1768.MS(EI)m/z(％):278(20),277(100),262(7),203(95),187(31),57(43)；IR(KBr plate):3238,3055,2964,2866,1599,1545,1390,1363,1172,1077,945,712cm -1 .
example 26
Taking 4-fluoro-2-methylbenzyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under an argon atmosphere, 4-fluoro-2-methylbenzyl bromide (0.4 mmol, 81.2mg) was slowly added at room temperature (20 ℃) and the reaction was continued at room temperature (20 ℃) for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (67.3mg, 85%, white solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.45(s,1H),7.19(dd,J＝6.0Hz,J＝8.4Hz,1H),6.90-6.83(m,2H),4.69(d,J＝4.8Hz,2H),2.52(s,3H),2.29(s,3H)； 13 C NMR(150MHz,CDCl 3 ):δ200.7,162.5(d,J＝244.5),139.5(d,J＝7.5Hz),131.1(d,J＝9.0Hz),129.8(d,J＝3.0Hz),117.5(d,J＝21.0Hz),113.0(d,J＝21.0Hz),48.2,33.9,19.3；HRMS(ESI)m/z calculated for C 10 H 12 FNS[M+H] + 198.0747,found 198.0746.MS(EI)m/z(％):198(6),197(48),138(10),123(100),122(57),109(11)；IR(KBr plate):3217,3033,2984,2925,1532,1500,1388,1329,1254,1170,1068,1005,961,699cm -1 .
example 27
4-chloro-2-fluorobenzyl bromide and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, 4-chloro-2-fluorobenzyl bromide (0.4 mmol,89.4 mg) was slowly added at 90 ℃ and the reaction was continued at 90 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (44.2mg, 51%, yellow solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.64(s,1H),7.35(t,J＝8.4Hz,1H),7.10(t,J＝7.8Hz,2H),4.84(d,J＝5.4Hz,2H),2.55(s,3H)； 13 C NMR(150MHz,CDCl 3 ):δ201.6,160.9(d,J＝247.5Hz),135.0(d,J＝10.5Hz),131.8(d,J＝4.5Hz),124.8(d,J＝3.0Hz),121.9(d,J＝15.0Hz),116.5(d,J＝24.0Hz),43.6(d,J＝1.5Hz),34.2；HRMS(ESI)m/z calculated for C 9 H 9 ClFNS[M+H] + 218.0201,found 218.0200.MS(EI)m/z(％):219(15),217(39),160(11),158(36),145(22),143(100)；IR(KBr plate):3220,3048,2932,1612,1535,1489,1336,1170,1078,931,896,687cm -1 .
example 28
Taking (1-bromoethyl) benzene and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. (1-bromoethyl) benzene (0.4 mmol,74.0 mg) was slowly added at 0 ℃ under an argon blanket, and the reaction was continued for 30 minutes in an ice-water bath (0 ℃). Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (52.9 mg,74%, yellow oily liquid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.54(s,1H),7.38-7.34(m,4H),7.32-7.28(m,1H),5.76-5.71(m,1H),2.53(s,3H),1.60(d,J＝7.2Hz,3H)； 13 C NMR(150MHz,CDCl 3 ):δ199.6,141.3,128.9,128.0,126.7,54.9,34.5,20.0；MS(EI)m/z(％):179(44),146(61),120(11),105(100),104(58),77(28)；IR(KBr plate):3219.3030,2974,1531,1453,1385,1217,1181,1091,761,698cm -1 .
example 29
1-bromo-4- (1-bromoethyl) benzene and acetonitrile are used as raw materials:
will dryThe 10mL reaction tube and the dried reagent are put into a glove box, and NO is added 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 1-bromo-4- (1-bromoethyl) benzene (0.4 mmol,105.6 mg) was added slowly at 0 ℃ under an argon blanket and the reaction was continued for 30 minutes in an ice-water bath (0 ℃). Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (81.3mg, 79%, yellow solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.79(s,1H),7.43(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),5.67-5.60(m,1H),2.49(s,3H),1.54(d,J＝6.8Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ199.9,140.3,131.8,128.3,121.6,54.3,34.2,20.3；HRMS(ESI)m/z calculated for C 10 H 12 BrNS[M+H] + 257.9947,259.9926,found 257.9946,269.9925.MS(EI)m/z(％):259(37),257(33),185(42),184(34),183(43),182(32),104(100)；IR(KBr plate):3217,3028,2975,2928,1530,1489,1455,1383,1218,1094,1073,1009,826,728cm -1 .
example 30
Diphenyl bromomethane and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, slowly adding the mixture at-35 DEG CDiphenylbromomethane (0.4 mmol, 98.9mg) and reaction was continued at-35 deg.C for 30min. Continuing to maintain the temperature, introducing H through a gas-introducing needle 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (44.5mg, 46%, white solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.80(s,1H),7.37-7.27(m,6H),7.24-7.21(m,4H),6.84(d,J＝8.0Hz,1H),2.56(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ200.4,139.9,128.9,127.9,127.8,63.1,34.3；HRMS(ESI)m/zcalculated for C 15 H 15 NS[M+Na] + 264.08171,found 264.0817.MS(EI)m/z(％):241(40),208(32),167(100),164(9),152(33)；IR(KBr plate):3219,3060,2915,1520,1376,1173,1084,1061,744,698cm -1 .
example 31
Taking tert-butyl bromide and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, t-butyl bromide (0.4 mmol,54.8 mg) was added at-35 ℃ and the reaction was continued at-35 ℃ for 30 minutes. Continuing to maintain the temperature, introducing H through a gas-conducting needle 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove elemental sulfurSolid impurities were aliquoted using ethyl acetate as eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (11.9 mg,23%, white solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.02(s,1H),2.51(s,3H),1.55(s,9H)； 13 C NMR(150MHz,CDCl 3 ):δ199.9,56.0,37.6,27.8；MS(EI)m/z(％):131(100)；IR(KBr plate):3231,3046,2966,2928,1540,1363,1140,1021,738,703cm -1 .
example 32
Taking bromocyclopentane and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Bromocyclopentane (0.4 mmol,59.6 mg) was added slowly at 45 ℃ under argon protection and the reaction was continued for 30min at 45 ℃. The temperature is adjusted to-15 ℃, and H is injected by using a gas guide needle 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (36.1mg, 63%, yellow solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.42(s,1H),4.71-4.65(m,1H),2.50(s,3H),2.13-2.08(m,2H),1.72-1.66(m,2H),1.65-1.60(m,2H),1.51-1.46(m,2H)； 13 C NMR(150MHz,CDCl 3 ):δ199.8,57.7,34.5,32.2,24.1；HRMS(ESI)m/z calculated for C 7 H 13 NS[M+Na] + 166.0661,found 166.0660.MS(EI)m/z(％):143(100),84(9),76(68),69(7),59(24)；IR(KBr plate):3225,3036,2960,2869,1536,1456.1390,1346,1143,1095,723cm -1 .
example 33
Bromo-cycloheptane and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. Bromocycloheptane (0.4mmol, 70.8mg) was slowly added at 45 ℃ under an argon blanket, and the reaction was continued at 45 ℃ for 30 minutes. The temperature is reduced to-15 ℃, and a gas guide needle is used for introducing H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (36.1mg, 63%, yellow solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.50(s,1H),4.44-4.41(m,1H),2.48(s,3H),2.03-1.99(m,2H),1.63-1.57(m.4H),1.52-1.47(m,6H)； 13 C NMR(150MHz,CDCl 3 ):δ198.4,56.9,34.5,33.6,28.0,24.2；HRMS(ESI)m/zcalculated for C 9 H 11 NS[M+H] + 172.1154,found 172.1154.MS(EI)m/z(％):171(54),138(100),112(56)；IR(KBr plate):3221,3036,2928,2855,1534,1461,1391,1368,1155,1069,715cm -1 .
example 34
Taking 7-bromonorbornane and acetonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 7-bromonorbornane (0.4mmol, 70.0 mg) was added slowly at 45 ℃ under argon protection and the reaction was continued for 30 minutes at 45 ℃. Cooling to-15 deg.C, and introducing H with air-guiding needle 2 S is introduced into the reaction tube (gas guide needle has obvious gas outflow) for 1 minute, the tail gas is absorbed by copper sulfate aqueous solution, and the stirring is continued for 20 minutes at the temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (51.9mg, 77%, white solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.33(s,1H),4.14(d,J＝7.8Hz,J＝10.8Hz,2H),2.49(s,3H),2.37(d,J＝3.6Hz,1H),2.31(s,1H),1.90-1.86(m,1H),1.54-1.44(m,2H),1.34-1.23(m,4H),1.16-1.12(m,1H)； 13 C NMR(150MHz,CDCl 3 ):δ199.2,59.4,41.6,39.8,36.2,35.9,34.4,28.1,26.5；HRMS(ESI)m/z calculated for C 9 H 15 NS[M+H] + 170.0998,found 170.0996.MS(EI)m/z(％):169(100),136(38),113(67),110(11),95(30)；IR(KBr plate):3214,3039,2956,2873,1537,1454,1370,1347,1304,1137,1096,718cm -1 .
example 35
1-bromoadamantane and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of extra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 1-bromoadamantane (0.4 mmol,86.1 mg) was added slowly at 45 ℃ under argon and the reaction was continued for 30min at 45 ℃. Cooling to-35 deg.C, and introducing H with gas-introducing needle 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (55.2mg, 66%, white solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ6.92(s,1H),2.49(s,3H),2.28(d,J＝1.6Hz,6H),2.10(s,3H),1.68(s,6H)；
13 C NMR(100MHz,CDCl 3 ):δ199.3,56.7,40.1,37.8,36.3,29.5；MS(EI)m/z(％):209(55),208(64),194(8),150(3),135(100)；IR(KBr plate):3308,2908,2895,1525,1406,1393,1090,670,639cm -1 .
example 36
Taking benzyl bromide and n-butyronitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6mmol, 79.7mg) and n-butyronitrile (2.0mmol, 138.2mg) were dissolved in 1mL of dry CH 3 NO 2 In (1). The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued at 45 ℃ for 30 minutes. Then reducing the temperature to-15 DEG CUsing a gas-guiding needle to guide H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (44.2mg, 57%, oily liquid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.41(s,1H),7.38-7.35(m,2H),7.33-7.31(m,3H),4.82(d,J＝4.8Hz,2H),2.64(t,J＝7.2Hz,2H),1.85-1.79(m,2H),0.95(t.J＝7.8Hz,3H)； 13 C NMR(150MHz,CDCl 3 ):δ205.6,136.3,129.1,128.4,128.2,50.4,49.1,22.9,13.5；HRMS(ESI)m/z calculated for C 11 H 15 NS[M+H] + 194.0998,found 194.0997.MS(EI)m/z(％):193(100),149(53),123(59),106(59)；IR(KBr plate):3226,3032,2962,2931,2872,1532,1454,1404,1167,1075,1027,738,697\cm -1 .
example 37
Taking benzyl bromide and cyclopentanenitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6mmol, 79.7mg) and cyclopentanecarbonitrile (2.0mmol, 190.3mg) in 1mL dry CH 3 NO 2 In (1). The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued for 30 minutes at 45 ℃. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for guiding H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction was completed, the reaction mixture was filtered through celite to removeElemental sulfur and other solid impurities, and ethyl acetate as eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (44.4 mg,51%, yellow solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.39-7.31(m,5H),4.84(d,J＝5.2Hz,2H),2.94-2.86(m,1H),2.00-1.93(m,4H),1.87-1.77(m,2H),1.66-1.55(m,2H)； 13 C NMR(100MHz,CDCl 3 ):δ210.2,136.5,129.1,128.4,128.2,55.3,50.3,34.2,25.9；HRMS(ESI)m/z calculated for C 13 H 17 NS[M+H] + 220.1154,found 220.1153.MS(EI)m/z(％):219(100),149(30),113(19),106(60)；IR(KBr plate):3237,3031,2955,2867,1527,1451,1402,1321,1131,1076,1028,732,696,617cm -1 .
example 38
Taking benzyl bromide and benzonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol, 79.7mg) and benzonitrile (2.0 mmol, 206.2mg) in 1mL of dry CH 3 NO 2 In (1). The reaction tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, benzyl bromide (0.4 mmol,68.4 mg) was added dropwise at 45 ℃ and the reaction was continued for 30 minutes at 45 ℃. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for guiding H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (19.4 mg,21%, yellow solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.76-7.74(m,3H),7.48-7.44(m,1H),7.41-7.35(m,7H),5.00(d,J＝5.2Hz,2H)； 13 C NMR(100MHz,CDCl 3 ):δ199.3,141.8,136.3,131.3,129.2,128.7,128.5,128.4,126.8,51.2；HRMS(ESI)m/z calculated for C 14 H 13 NS[M+H] + 220.0841,found 220.0841.MS(EI)m/z(％):227(91),149(10),121(100),106(69)；IR(KBr plate):3232,3060,3029,1519,1450,1381,1335,1066,1029,943,694cm -1 .
example 39
Taking 7-bromonorbornane and n-butyronitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6mmol, 79.7mg) and n-butyronitrile (2.0mmol, 138.2mg) were dissolved in 1mL of dry CH 3 NO 2 In (1). The reaction tube was sealed with a sealing film and removed from the glove box. 7-bromonorbornane (0.4 mmol,70.0 mg) was added at 45 ℃ under an argon blanket and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, filtering the mixture by using kieselguhr to remove solid impurities such as elemental sulfur and the like, and using ethyl acetate as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (55.3mg, 70%, white solid).
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 ):δ7.20(s,1H),4.18-4.15(m,1H),2.55(t,J＝7.8Hz,2H),2.37(d,J＝3.6Hz,1H),2.31(s,1H),1.91-1.87(m,1H),1.77-1.74(m,2H),1.53-1.46(m,2H),1.33-1.23(m,4H),1.16-1.13(m,1H),0.91(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ203.8,59.0,49.2,41.6,40.0,36.2,35.9,28.1,26.5,22.9,13.3；
example 40
Taking 7-bromonorbornane and cyclohexanecarbonitrile as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6mmol, 79.7mg) and cyclohexanecarbonitrile (2.0mmol, 218.3mg) in 1mL of dry CH 3 NO 2 In (1). The reaction tube was sealed with a sealing film and removed from the glove box. 7-bromonorbornane (0.4 mmol,70.0 mg) was added at 45 ℃ under an argon atmosphere, and the reaction was continued at 45 ℃ for 30 minutes. Then the temperature is reduced to-15 ℃, and a gas guide needle is used for leading H 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (61.7 mg,65%, white solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):7.02(s,1H),4.23-4.18(m,1H),2.45-2.33(m,3H),1.95-1.78(m,5H),1.69-1.67(m,1H),1.61-1.45(m,4H),1.33-1.14(m,8H)； 13 C NMR(100MHz,CDCl 3 ):δ208.6,58.5,55.1,41.7,40.2,36.3,36.0,33.04,32.95,28.2,26.5,26.1,25.7；
example 41
1-bromine-3,5-dimethyl adamantane and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. The reaction tube was sealed with a sealing film and removed from the glove box. 1-bromo-3,5-dimethyladamantane (0.4mmol, 97.3mg) was added slowly at 45 ℃ under argon and the reaction was continued for 30 minutes at 45 ℃. Cooling to-35 deg.C, and introducing H with air-guiding needle 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent, and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (67.9mg, 72%, yellow oily liquid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ6.99(s,1H),2.46(s,3H),2.16-2.13(m,1H),2.12(s,2H),1.90(dd,J＝12.4Hz,J＝28.4Hz,4H),1.38-1.25(m,4H),1.18-1.10(m,2H),0.83(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ199.3,58.3,50.6,45.9,42.6,38.5,37.7,32.6,30.1,30.0；HRMS(ESI)m/z calculated for C 14 H 23 NS[M+H] + 238.1624,found 238.1623.MS(EI)m/z(％):237(30),236(40),213(16),163(58),107(100)；IR(KBr plate):3253,3037,2945,2903,2862,2842,1535,1454,1393,1161,1069,1040,690cm -1 .
example 42
The salix musk bromo-derivative and acetonitrile are used as raw materials:
putting the dried 10mL reaction tube and the dried reagent into a glove box, and adding NO 2 BF 4 (0.6 mmol,79.7 mg) was dissolved in 1mL of ultra dry acetonitrile. Will reactThe tube was sealed with a sealing film and removed from the glove box. Under the protection of argon, salsa musk bromo-derivative (0.4mmol, 123.7 mg) was added at-35 ℃ and the reaction was continued for 30 minutes at-35 ℃. Continuing to maintain the temperature, introducing H through a gas-introducing needle 2 S is introduced into the reaction tube (gas guide needle has significant gas outflow) for 1 minute, the tail gas is absorbed by the aqueous copper sulfate solution and stirring is continued for 20 minutes at this temperature. After the reaction is finished, diatomite is used for filtering to remove solid impurities such as elemental sulfur and the like, and ethyl acetate is used as an eluent. The filtrate was then distilled under reduced pressure to remove the organic solvent and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give the corresponding product (61.8mg, 51%, white solid).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ7.21(d,J＝1.6Hz,1H),7.16(d,J＝1.6Hz,1H),5.81-5.74(m,1H),2.86(td,J＝2.8Hz,J＝7.2Hz,2H),2.53(s,3H),1.93(t,J＝7.2Hz,2H),1.62(d,J＝6.8Hz,3H),1.35(s,9H),1.27(s,3H),1.26(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ199.0,153.5,150.7,139.3,135.8,120.2,118.9,53.2,44.3,41.4,35.1,34.6,31.8,28.9,28.8,28.4,18.5；HRMS(ESI)m/z calculated for C 19 H 29 NS[M+H] + 304.2093,found304.2092.MS(EI)m/z(％):303(9),229(88),228(100),213(91),129(43),115(29)；IR(KBr plate):3217,2955,2864,1531,1458,1384,1103,1042,748,720cm -1 .
example 43
The method is characterized by taking ezetimibe bromo-derivative and acetonitrile as raw materials:
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 ):δ8.30(d,J＝8.0Hz,1H),8.21(d,J＝8.4Hz,0.9H),7.34-7.27(m,8H),7.22-7.17(m,4H),7.10(s,2H),7.08(s,1.8H),7.02-6.98(m,4H),6.94-6.89(m,4H),5.64(q,J＝8.0Hz,0.9H),5.54(q,J＝7.6Hz,1H),4.65(d,J＝2.0Hz,0.9H),4.63(d,J＝2.0Hz,1H),3.08-3.04(m,2H),2.48(s,3H),2.45(s,2.8H),2.30(s,3H),2.29(s,2.7H),2.24-1.76(m,8H)； 13 C NMR(100MHz,CDCl 3 ):δ200.5,200.2,169.6,169.5,167.2,167.1,163.51,163.46,161.1,161.0,160.4,157.9,150.9,135.88,135.85,135.5,135.4,134.8,134.7,133.5,129.0,128.9,128.8,128.7,127.0,122.62,122.59,118.54,118.46,116.1,115.92,115.87,115.71,115.65,60.9,60.6,60.2,60.1,58.9,58.6,34.1,32.5,32.1,25.58,25.55,21.1；HRMS(ESI)m/z calculated for C 28 H 26 F 2 N 2 O 3 S[M+Na] + 531.1524,found 531.1523.MS(EI)m/z(％):509(11),508(36),474(19),296(16),254(96),194(51),135(100)；IR(KBr plate):3302,3047,2985,2936,1743,1510,1372,1223,1045,1015,836cm -1 .
finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. The method for synthesizing thioamide is characterized by comprising the following steps of:
(1) Dissolving a nitronium salt in a nitrile compound or dissolving the nitronium salt and the nitrile compound in a solvent;
(2) Under the protection of argon, adding bromide at the temperature of-35-90 ℃ for reaction;
(3) Cooling to-35-45 ℃, and adding a vulcanizing agent for reaction;
(4) After the reaction is finished, removing solid impurities and solvent, and purifying to obtain thioamide with a structural formula
The nitronium salt in the step (1) is NOBF 4 、NO 2 BF 4 、NOPF 6 And NOSbF 6 The nitrile compound is one of acetonitrile, n-butyronitrile, cyclopentanecarbonitrile, benzonitrile and cyclohexanecarbonitrile;
the bromide in the step (2) is any one of benzyl bromide, 4-fluorobenzyl bromide, 2-fluorobenzyl bromide, 3-fluorobenzyl bromide, 4-chlorobenzyl bromide, 4-bromobenzyl bromide, 4-trifluoromethylbenzyl bromide, 4-methylbenzyl bromide, 2-methylbenzyl bromide, 3-methylbenzyl bromide, 4-tert-butylbenzyl bromide, 3-methoxybenzyl bromide, 2-bromomethylnaphthalene, 3,5-di-tert-butylbenzyl bromide, 4-fluoro-2-methylbenzyl bromide, 4-chloro-2-fluorobenzyl bromide, (1-bromoethyl) benzene, 1-bromo-4- (1-bromoethyl) benzene, diphenylbromomethane, tert-butylbromide, bromocyclopentane, bromocycloheptane, 7-bromonorbornane, 1-bromoadamantane, 7-bromonorbornane, 1-bromo-3,5-dimethyladamantane, salivabromomusk derivatives and ezetimibe bromo derivatives;
the vulcanizing agent in the step (3) is thioacetamide, thiourea and Na 2 S, naHS or H 2 S。
2. The synthesis process according to claim 1, wherein the nitronium salt and the nitrile compound of step (1) are added in an amount of 0.6:1n/v; the addition amount of the nitronium salt, the nitrile compound and the solvent is 6:20:10n/n/v.
3. The method of claim 1, wherein the solvent of step (1) is CH 3 CN or CH 3 NO 2 。
4. The method of claim 1, wherein the reaction time of step (2) is 30min.
5. The synthesis process according to claim 1, wherein the molar ratio of bromide to nitronium salt is 1.
6. The synthesis method of claim 1, wherein the solid impurities in step (4) are removed by filtration with celite, using ethyl acetate as eluent; distilling the filtrate under reduced pressure to remove the organic solvent; the crude product was purified by flash column chromatography on silica gel.
7. The method of claim 1, wherein said thioamide comprises
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