CN113527022A - 非对称多硫类化合物及其合成方法和应用 - Google Patents

非对称多硫类化合物及其合成方法和应用 Download PDF

Info

Publication number
CN113527022A
CN113527022A CN202010315986.7A CN202010315986A CN113527022A CN 113527022 A CN113527022 A CN 113527022A CN 202010315986 A CN202010315986 A CN 202010315986A CN 113527022 A CN113527022 A CN 113527022A
Authority
CN
China
Prior art keywords
formula
reaction
hours
mol
asymmetric
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202010315986.7A
Other languages
English (en)
Other versions
CN113527022B (zh
Inventor
姜雪峰
薛佳晖
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China Normal University
Original Assignee
East China Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by East China Normal University filed Critical East China Normal University
Priority to CN202010315986.7A priority Critical patent/CN113527022B/zh
Publication of CN113527022A publication Critical patent/CN113527022A/zh
Application granted granted Critical
Publication of CN113527022B publication Critical patent/CN113527022B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B45/00—Formation or introduction of functional groups containing sulfur
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
    • C07C321/18—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C07D261/16—Benzene-sulfonamido isoxazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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
    • 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)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Catalysts (AREA)

Abstract

本发明公开了一种式(1)、式(2)、式(3)和式(4)所示的非对称多硫类化合物及其合成方法，所述方法分别以式(6)、式(7)、式(8)和式(9)所示的化合物与二硫试剂(5)为反应原料，在催化剂的作用下，反应得到所述非对称多硫类化合物。本发明反应条件温和，原料廉价易得，反应操作简单、产率较高；反应底物容易制备；本发明的反应可以用于构建新型的多硫化合物。本发明还提出了所述非对称多硫类化合物在小分子药物偶联物和多肽物偶联物中的应用。

Description

非对称多硫类化合物及其合成方法和应用
技术领域
本发明属于有机化合物工艺应用技术领域，具体涉及非对称多硫类化合物及其合成方法和应用。
背景技术
非对称多硫类化合物广泛存在于天然产物，药物和生物体内，因此一直以来，对非对称多硫类化合物的合成方法都广受大家的关注。如今科学家们已经设计了多种过硫化的方法，但是现有制备方法都有一个共同的缺点，即对于每一个试剂，均需要通过特殊的步骤多步合成，合成路线长，耗费时间和试剂。虽然已经有很多关于非对称多硫类化合物合成方法的报道，但是一直以来都没有找到一个好的试剂，可以对硫硫键两侧的分子任意连接，得到新型的非对称多硫类化合物。
因此，寻找一种具有通用性的，高效、环境友好、条件温和和经济适用的过硫化方法便显得尤其重要。
发明内容
本发明克服了传统合成非对称多硫类化合物的局限性，使用两侧可以离去的双边二硫试剂，该反应具有很强的兼容性，通过对碳，硫，氮不同亲核试剂的连接，可以得到六种不同的非对称多硫类化合物。鉴于此，本发明设计了通过使用金属铜催化剂，通过有机硼酸类化合物、双边二硫试剂与有机胺或者硫醇，或者通过有机硼酸类化合物、双边二硫试剂与芳烃，或者通过有机胺、双边二硫试剂与另一分子硫醇或者有机胺，或者通过硫醇、双边二硫试剂与另一分子硫醇来制备非对称多硫类化合物的反应方法。
本发明提出了一种非对称多硫类化合物，其结构式如式(1)，(2)，(3)，(4)所示：
Figure BDA0002459564230000011
其中，Ar1选自苯基，取代苯基，杂环；
RX选自烷胺基，芳胺基，氨基酸酯，磺胺类药物，烷巯基，芳巯基，苄硫醇；
Ar2选自芳基，维生素E，杂环芳基；
R1选自烷基，氨基酸衍生物，磺胺类药物，芳基；
R2选自烷基，青霉胺；
R3选自烷基，芳基，硫苷，氨基酸，多肽。
优选地，Ar1选自苯基，氯取代、溴取代、氟取代、乙酰基取代、乙氧酰基取代、3,4-二亚甲基取代苯基，雌酚酮，苯丙氨酸酯，噻吩；
RX选自甲基、叔丁基取代苯胺基，1-甲基苄胺基，氨基酸酯，磺胺类药物，直链胺基，2-巯基嘧啶，甲氧基取代苄硫醇，2-羟基乙基、金刚烷基、叔丁基、正十二烷基、1-三乙氧硅基正丙基；
Ar2选自1，3，5-三甲氧基苯，维生素E，甲基取代、甲氧基取代、氯取代、甲氧基甲基取代吲哚，吡咯；
R1选自氰基、溴、氯、乙烯基、苯基、甲基、叔丁基取代苯基，氨基酸衍生物，磺胺类药物，十八烷基；
R2选自金刚烷、叔丁基、正丙基、1-三乙氧硅基正丙基硫醇，青霉胺；
R3选自2-巯基嘧啶，吡嗪-2-乙基、烯丙基硫醇，硫苷，半胱氨酸，多肽。
进一步地，本发明式(1)～(4)所示的非对称多硫类化合物包括：
Figure BDA0002459564230000021
Figure BDA0002459564230000031
Figure BDA0002459564230000041
Figure BDA0002459564230000051
Figure BDA0002459564230000061
本发明还提出了一种非对称多硫类化合物的制备方法，以式(5)所示的二硫试剂、式(7)所示的芳基硼酸和式(8)所示的有机胺或硫醇RXH为反应原料，在催化剂、配体的作用下，在添加或不添加碱的条件下，在有机溶剂中，反应得到如式(1)所示的非对称多硫类化合物，所述反应过程如反应式(a)所示；
Figure BDA0002459564230000071
其中，Ar1选自苯基，取代苯基，杂环；
RX选自烷胺基，芳胺基，烷巯基，芳巯基。
优选地，Ar1选自苯基，氯取代、溴取代、氟取代、乙酰基取代、乙氧酰基取代、3,4-二亚甲基取代苯基，雌酚酮，苯丙氨酸酯，噻吩；
RX选自甲基、叔丁基取代苯胺基，1-甲基苄胺基，氨基酸酯，磺胺类药物，直链胺基，2-巯基嘧啶，甲氧基取代苄硫醇，2-羟基乙基、金刚烷基、叔丁基、正十二烷基、1-三乙氧硅基正丙基硫醇。
本发明中，所述式(7)所示的芳基硼酸(有机硼酸)与式(5)所示的二硫试剂的摩尔比例为1.0:2.0-2.0:1.0；优选地，两者用量的摩尔比例为1.5:1.0。
本发明中，所述式(8)所示的有机胺或硫醇RXH与式(5)所示的化合物的摩尔比例为1.0:2.0-2.0:1.0；优选地，两者用量的摩尔比例为1.2:1.0。
本发明中，所述催化剂是CuI，CuCl，Cu(MeCN)4BF4，Cu(MeCN)4BF6等中的一种或几种；优选地，所述催化剂是Cu(MeCN)4BF6。
本发明中，所述催化剂的摩尔用量为原料式(5)所示的二硫试剂的5-10mol％；优选地，催化剂的摩尔用量为原料式(5)所示的二硫试剂的10mol％。
本发明中，所述配体是2,2’-联吡啶、4,4’-二甲基-2,2’-联吡啶、1,10-菲咯啉、4,7-二苯基-1,10-菲罗啉等中的一种或几种；优选地，为2,2’-联吡啶。
本发明中，所述配体的摩尔用量为原料式(5)所示的二硫试剂的10-20mol％；优选地，所述配体的摩尔用量为原料式(5)所示的二硫试剂的20mol％。
本发明中，优选地，不添加碱。当添加碱时，所述碱是碳酸锂，碳酸钠，碳酸钾等中的一种或几种。
本发明中，所述碱的用量为原料式(5)所示的二硫试剂的1-2当量；优选地，所述碱的用量为原料式(5)所示的二硫试剂的1当量。
本发明中，所述有机溶剂是二氯甲烷，四氢呋喃，甲苯等中的一种或几种；优选地，所述有机溶剂是二氯甲烷或甲苯。
本发明中，所述反应温度是0-40℃；优选地，为25℃。
本发明中，所述反应的时间为10-28小时；优选地，为28小时。
本发明中，所述反应在氮气氛围中进行。
本发明还提出了一种非对称多硫类化合物的制备方法，以式(5)所示的二硫试剂，式(7)所示的芳基硼酸和式(9)所示的芳烃为反应原料，在催化剂、配体的作用下，在添加或不添加碱的条件下，在有机溶剂中，反应得到如式(2)所示非对称二硫类化合物，所述反应过程如反应式(b)所示；
Figure BDA0002459564230000081
其中，Ar1选自苯基，取代苯基，杂环；
Ar2选自芳基，杂环芳基。
优选地，Ar1选自苯基，氯取代、溴取代、氟取代、乙酰基取代、乙氧酰基取代、3,4-二亚甲基取代苯基，雌酚酮，苯丙氨酸酯，噻吩；
Ar2选自1，3，5-三甲氧基苯，维生素E，甲基取代、甲氧基取代、氯取代、甲氧基甲基吲哚、吡咯。
本发明中，所述式(7)所示的芳基硼酸(有机硼酸)与式(5)所示的二硫试剂的摩尔比例为1.0:2.0-2.0:1.0；优选地，两者用量的摩尔比例为1.5:1.0。
本发明中，所述式(9)所示的芳烃与式(5)所示的二硫试剂的摩尔比例为1.0:2.0-2.0:1.0；优选地，两者用量的摩尔比例为1.2:1.0。
本发明中，所述催化剂是CuI，CuCl，Cu(MeCN)4BF4，Cu(MeCN)4BF6中的一种或几种；优选地，所述催化剂是Cu(MeCN)4BF6。
本发明中，所述催化剂的摩尔用量为原料式(5)所示的二硫试剂的5-10mol％；优选地，所述催化剂的摩尔用量为原料式(5)所示的二硫试剂的10mol％；
本发明中，所述配体是2,2’-联吡啶、4,4’-二甲基-2,2’-联吡啶、1,10-菲咯啉、4,7-二苯基-1,10-菲罗啉等中的一种或几种；优选地，所述配体是2,2’-联吡啶。
本发明中，所述配体的摩尔用量为原料式(5)所示的二硫试剂的10-20mol％；优选地，所述配体的摩尔用量为原料式(5)所示的二硫试剂的20mol％。
本发明中，优选地，不添加碱。当添加碱时，所述碱是碳酸锂，碳酸钠，碳酸钾等中的一种或几种。
本发明中，所述碱的用量为原料式(5)所示的二硫试剂的1-2当量；优选地，所述碱的用量为原料式(5)所示的二硫试剂的1当量。
本发明中，所述有机溶剂是二氯甲烷，四氢呋喃，甲苯等中的一种或几种；优选地，所述有机溶剂是二氯甲烷或甲苯。
本发明中，所述反应的温度是0-40℃；优选地，为25℃。
本发明中，所述反应的时间为10-28小时；优选地，为28小时。
本发明中，所述反应在氮气氛围中进行。
本发明还提出了一种非对称多硫类化合物的制备方法，以式(5)所示的二硫试剂，式(10)所示的有机胺R1NH2，式(8)所示的另一分子有机胺或硫醇RXH为反应原料，在催化剂和碱的作用下，在有机溶剂中，反应得到如式(3)所示的非对称多硫类化合物，所述反应过程如反应式(c)所示；
Figure BDA0002459564230000091
其中，R1选自烷基，芳基；
RX选自烷胺基，芳胺基，烷巯基，芳巯基。
优选地，R1选自氰基、溴、氯、乙烯基、苯基、甲基、叔丁基取代苯基，氨基酸衍生物，磺胺类药物，十八烷基；
RX选自甲基、叔丁基取代苯胺基，1-甲基苄胺基，氨基酸酯，磺胺类药物，直链胺基，2-巯基嘧啶，甲氧基取代苄硫醇，2-羟基乙基、金刚烷基、叔丁基、正十二烷基、1-三乙氧硅基正丙基硫醇。
本发明中，所述式(10)所示的有机胺R1NH2与起始原料式(5)所示的二硫试剂的摩尔比例为1.05-1.0：1.2-1.0；优选地，为1.05:1.0。
本发明中，所述式(8)所示的另一分子有机胺或硫醇RXH与起始原料式(5)所示的二硫试剂的摩尔比例为(1.0-1.2):1.0；优选地，为1.2:1.0。
本发明中，所述催化剂是三五氟苯基硼。
本发明中，所述催化剂的当量为式(5)所示的二硫试剂的1mol％-5mol％；优选地，所述催化剂的当量为式(5)所示的二硫试剂的2mol％。
本发明中，所述碱为碳酸锂。
本发明中，所述碱的当量为式(5)所示的二硫试剂的1-2当量；优选地，为1当量。
本发明中，所述有机溶剂是二氯甲烷，四氢呋喃，1,4-二氧六环，丙酮，乙腈等中的一种或几种；优选地，所述有机溶剂为1,4-二氧六环。
本发明中，所述反应的温度为0-25℃；优选地，为25℃。
本发明中，所述反应的时间为4-20小时；优选地，为14小时。
本发明中，所述反应在空气氛围中进行。
本发明还提出了一种非对称多硫类化合物的制备方法，以式(6)所示的二硫试剂，式(11)所示的有机硫醇R2SH，式(12)所示的另一分子硫醇R3SH为反应原料，在催化剂的作用下，在有机溶剂中，反应得到如式(4)所示的非对称多硫类化合物(四硫类化合物)，所述反应过程如反应式(d)所示；
Figure BDA0002459564230000101
其中R2选自烷基；
R3选自烷基，芳基。
优选地，R2选自金刚烷、叔丁基、正丙基、1-三乙氧硅基正丙基硫醇，青霉胺；
R3选自2-巯基嘧啶，吡嗪-2-乙基、烯丙基硫醇，硫苷，半胱氨酸，多肽。
本发明中，所述式(11)所示的有机硫醇R2SH与起始原料式(6)所示的二硫试剂的摩尔比例为1.05-1.0:1.2-1.0；优选地，为1.2:1.0。
本发明中，所述式(12)所示的另一分子硫醇R3SH与起始原料式(6)所示的二硫试剂的摩尔比例为(1.0-1.2):1.0；优选地，为1.2:1.0。
本发明中，所述催化剂是三五氟苯基硼。
本发明中，所述催化剂的当量为式(5)所示的二硫试剂的1mol％-5mol％；优选地，所述催化剂的当量为式(5)所示的二硫试剂的2mol％。
本发明中，所述有机溶剂是二氯甲烷，四氢呋喃，甲醇等中的一种或几种；优选地，所述有机溶剂为甲醇。
本发明中，所述反应的温度为-78℃-25℃；优选地，为-78℃。
本发明中，所述反应的时间为1-5；优选地，为4.5小时。
本发明中，所述反应在空气氛围中进行。
本发明中，所述反应的选择性控制受环状二硫试剂的环张力影响。
在一个具体实例中，如反应式(a)，本发明合成反应是在反应瓶A中，加入二硫试剂(5)(U mmol)，有机硼酸(7)(V mmol)，催化剂(W mmol)，配体(X mmol)，碱(Y mmol)，有机溶剂(P mL)，反应体系在25℃，空气氛围下搅拌；二硫试剂(5)消耗完，加RXH(8)(Z mmol)，搅拌4小时；反应完毕后，加硅胶旋干，经柱层析分离得到目标产物。
在另一个具体实例中，如反应式(b)，本发明合成反应是在反应瓶A中，加入二硫试剂(5)(U mmol)，有机硼酸(7)(V mmol)，催化剂(W mmol)，配体(X mmol)，碱(Y mmol)，有机溶剂(P mL)，反应体系在25℃，空气氛围下搅拌；二硫试剂(5)消耗完，加芳烃(9)(Z mmol)，搅拌4小时；反应完毕后，加硅胶旋干，经柱层析分离得到目标产物。
在另一个具体实例中，如反应式(c)，本发明合成反应是在反应瓶A中，加入二硫试剂(5)(X mmol)，有机胺(10)(Y mmol)，催化剂(Z mmol)，有机溶剂(P mL)，反应体系在25℃搅拌4小时；二硫试剂(5)消耗完，加RXH(8)(U mmol)，碱(V mmol)，搅拌10小时；反应完毕后，加硅胶旋干，经柱层析分离得到目标产物。
在另一个具体实例中，如反应式(d)，本发明合成反应是在反应瓶A中，加入二硫试剂(6)(X mmol)，有机硫醇(11)(Y mmol)，有机溶剂(P mL)，反应体系在-78℃搅0.5小时，加R3SH(12)(U mmol)，催化剂(V mmol)，搅拌4小时；反应完毕后，加硅胶旋干，经柱层析分离得到目标产物。
本发明还提出了按照本发明上述合成方法制备得到的如式(1)，(2)，(3)，(4)所示的非对称多硫类化合物。
本发明还提出了所述式(1)，(2)，(3)，(4)所示的非对称多硫类化合物在作为或制备小分子药物偶联物和多肽物偶联物中的应用。
本发明合成方法制备得到的如式(1)所示的非对称多硫类化合物的最优条件如下所示，其中反应式(a)的收率为75％及以上。
Figure BDA0002459564230000111
其中，Ar1选自苯基，氯取代、溴取代、氟取代、乙酰基取代、乙氧酰基取代、3,4-二亚甲基取代苯基，雌酚酮，苯丙氨酸酯，噻吩；
RX选自甲基、叔丁基取代苯胺基，1-甲基苄胺基，氨基酸酯，磺胺类药物，直链胺基，2-巯基嘧啶，甲氧基取代苄硫醇，2-羟基乙基、金刚烷基、叔丁基、正十二烷基、1-三乙氧硅基正丙基。
本发明合成方法制备得到的如式(2)所示的非对称多硫类化合物的最优条件如下所示，其中反应式(b)的收率为70％及以上。
Figure BDA0002459564230000121
其中，Ar1选自苯基，氯取代、溴取代、氟取代、乙酰基取代、乙氧酰基取代、3,4-二亚甲基取代苯基，雌酚酮，苯丙氨酸酯，噻吩；
Ar2选自1，3，5-三甲氧基苯，维生素E，甲基取代、甲氧基取代、氯取代、甲氧基甲基吲哚、吡咯。
本发明合成方法制备得到的如式(3)所示的非对称多硫类化合物的最优条件如下所示，其中反应式(c)的收率为88％及以上。
Figure BDA0002459564230000122
其中，R1选自氰基、溴、氯、乙烯基、苯基、甲基、叔丁基取代苯基，氨基酸衍生物，磺胺类药物，十八烷基；
RX选自金刚烷、叔丁基、正丙基、1-三乙氧硅基正丙基硫醇，青霉胺；R3选自2-巯基嘧啶，吡嗪-2-乙基、烯丙基硫醇，硫苷，半胱氨酸，多肽。
本发明合成方法制备得到的如式(3)所示的对称二杂二硫类化合物的最优条件如下所示，其中反应式(d)的收率为98％及以上。
Figure BDA0002459564230000123
其中R2选自金刚烷、叔丁基、正丙基、1-三乙氧硅基正丙基硫醇，青霉胺；
R3选自2-巯基嘧啶，吡嗪-2-乙基、烯丙基硫醇，硫苷，半胱氨酸，多肽。
本发明具有以下优点：原料廉价易得，反应底物容易制备，反应操作简单，反应高效，产率高，其中，实施例28、42、43、45、46、49、52、53产率都在80％以上，过硫化试剂制备简单、稳定、并且无刺激性气味；反应中条件较为温和。本发明双边二硫试剂与两分子硫醇或者胺，反应得到非对称二杂二硫类化合物，或者硼酸偶联后，与硫醇，胺，芳烃反应，得到多硫化合物，反应操作简单，反应条件较为温和，可以用于构建新型的多硫化合物，适合大规模工业化生产。
具体实施方式
结合以下具体实施例，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
本发明不对称二硫类化合物的合成反应，包括以下步骤：
如反应式(a)，本发明合成反应是在反应瓶中加入二硫试剂(5)，有机硼酸(7)，催化剂，配体，有机溶剂，反应体系在25℃，空气氛围下搅拌24小时；二硫试剂(5)消耗完，加RXH(8)(Z mmol)，搅拌4小时；加硅胶旋干，经柱层析分离得到目标产物。
如反应式(b)，本发明合成反应是在反应瓶中加入二硫试剂(5)，有机硼酸(7)，催化剂，配体，有机溶剂，反应体系在25℃，空气氛围下搅拌24小时；二硫试剂(5)消耗完，加芳烃(9)(Z mmol)，搅拌4小时；加硅胶旋干，经柱层析分离得到目标产物。
如反应式(c)，本发明合成反应是在反应瓶中加入二硫试剂(5)，有机胺(10)，催化剂，碱，有机溶剂，反应体系在25℃，空气氛围下搅拌4小时；二硫试剂(5)消耗完，加RXH(8)，搅拌10小时，加硅胶旋干，经柱层析分离得到目标产物。
如反应式(d)，本发明合成反应是在反应瓶中加入二硫试剂(5)，有机硫醇(11)，催化剂，有机溶剂，反应体系在-78℃，空气氛围下搅拌0.5小时；加R3SH(12)，搅拌4小时，加硅胶旋干，经柱层析分离得到目标产物。
如表1所示的不对称多硫类化合物，均为通过本发明方法合成得到的产物，尚未见有公开文献揭示这些化合物。
表1本发明的新的不对称二硫类化合物
Figure BDA0002459564230000131
Figure BDA0002459564230000141
Figure BDA0002459564230000151
Figure BDA0002459564230000161
Figure BDA0002459564230000171
Figure BDA0002459564230000181
实施例1
化合物1a的合成：
Figure BDA0002459564230000182
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时。加入4-甲苯胺(12.8mg,0.12mmol,1.2equiv)，反应8小时，除去溶剂，柱层析得到无色液体1a(17.3mg,70％)。1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.51(d,J＝7.5Hz,2H),7.32(dd,J＝10.2,4.1Hz,2H),7.26(dd,J＝7.7,5.3Hz,1H),6.95(d,J＝7.8Hz,2H),6.87(d,J＝7.8Hz,2H),2.14(s,3H).13C NMR(100MHz,DMSO-d6)δ143.42,137.82,130.26,130.06,129.94,129.63,128.15,116.76,20.65.IR(film)3340,2972,2920,1612,1508,1475,1438,1373,1226,1022,812,740,688.HRMS(EI)Calcd for C13H13NS2247.0489,found 247.0492.
实施例2
化合物1b的合成：
Figure BDA0002459564230000191
向反应管中加入4-氯苯硼酸(23.4mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时。加入4-叔丁基苯胺(17.9mg,0.12mmol,1.2equiv)，反应8小时，除去溶剂，柱层析得到无色液体1b(23.6mg,73％)。1HNMR(400MHz,CDCl3)δ7.32(d,J＝8.5Hz,2H),7.20–7.11(m,4H),6.83(d,J＝8.7Hz,2H),5.19(s,1H),1.21(s,9H).13C NMR(100MHz,CDCl3)δ145.11,141.97,136.02,134.11,132.58,129.12,126.07,116.87,34.20,31.50.IR(film)3350,2963,1608,1510,1473,1267,1234,1184,1092,1013,899,818,742,553.HRMS(EI)Calcd for C16H18ClNS2323.0569,found 323.0564.
实施例3
化合物1c的合成：
Figure BDA0002459564230000192
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时。加入2,2-二苯乙烷-1-胺(23.7mg,0.12mmol,1.2equiv)，反应8小时，除去溶剂，柱层析得到无色液体1c(25.3mg,75％)。1HNMR(400MHz,DMSO-d6)δ7.62–7.58(m,2H),7.39–7.33(m,2H),7.31–7.13(m,11H),5.34(t,J＝4.7Hz,1H),4.24(t,J＝7.8Hz,1H),3.49(dd,J＝7.7,4.8Hz,2H).13C NMR(100MHz,CDCl3)δ141.93,138.21,129.94,129.17,128.76,128.18,127.48,126.82,55.62,50.64.IR(film)3315,3059,2922,2852,1739,1579,1492,1450,1438,1066,1024,1024,1001,739,698.HRMS(EI)Calcd for C20H19NS2337.0959,found 337.0955.
实施例4
化合物1d的合成：
Figure BDA0002459564230000201
向反应管中加入4-三氟甲基苯硼酸(28.5mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时。加入3-苯基-1-丙胺(16.2mg,0.12mmol,1.2equiv)，反应8小时，除去溶剂，柱层析得到无色液体1d(23.3mg,68％)。1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.1Hz,2H),7.48(d,J＝8.2Hz,2H),7.16(d,J＝7.4Hz,2H),7.09(t,J＝6.9Hz,1H),7.02(d,J＝7.4Hz,2H),3.02(s,1H),2.86(dd,J＝12.8,6.3Hz,2H),2.51(t,J＝7.6Hz,2H),1.79–1.67(m,2H).19F NMR(282MHz,CDCl3)δ-62.41.13CNMR(100MHz,CDCl3)δ143.14,141.43,128.97(q,2JC-F＝32.7Hz),128.44,128.39,128.31,126.00,125.85(q,3JC-F＝3.8Hz),124.09(q,1JC-F＝271.9Hz),50.45,33.05,30.70.IR(film)3350,2926,2856,1602,1494,1454,1400,1323,1165,1122,1105,1080,1061,1012,830,698.HRMS(EI)Calcd for C16H16F3NS2343.0676,found343.0681.
实施例5
化合物1e的合成：
Figure BDA0002459564230000202
向反应管中加入4-溴苯硼酸(30.0mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时。加入1-苯基乙胺(14.5mg,0.12mmol,1.2equiv)，反应8小时，除去溶剂，柱层析得到无色液体1e(28.2mg,83％)。1HNMR(400MHz,CDCl3)δ7.30(q,J＝8.5Hz,4H),7.25–7.20(m,2H),7.20–7.15(m,1H),7.11(d,J＝7.4Hz,2H),4.11(q,J＝6.5Hz,1H),3.36(s,1H),1.30(d,J＝6.6Hz,3H).13C NMR(100MHz,CDCl3)δ143.24,137.26,132.06,131.05,128.57,127.65,127.04,121.25,57.95,22.68.IR(film)3317,3028,2974,2924,2868,1602,1493,1470,1452,1384,1369,1340,1307,1078,1007,812,760,698,640.HRMS(EI)Calcd for C14H14BrNS2338.9751,found338.9748.
实施例6
化合物1f的合成：
Figure BDA0002459564230000211
向反应管中加入4-溴苯硼酸(30.0mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时。加入L-色氨酸甲酯(14.5mg,0.12mmol,1.2equiv)，反应8小时，除去溶剂，柱层析得到无色液体1f(29.3mg,67％)。1HNMR(400MHz,CDCl3)δ7.96(s,1H),7.50(d,J＝7.9Hz,1H),7.28–7.22(m,3H),7.14(t,J＝7.5Hz,1H),7.09–7.03(m,3H),6.90(d,J＝1.8Hz,1H),4.00(dt,J＝7.5,5.2Hz,1H),3.63(d,J＝5.0Hz,1H),3.59(s,3H),3.21(dd,J＝14.6,5.2Hz,1H),3.03(dd,J＝14.6,7.7Hz,1H).13C NMR(100MHz,CDCl3)δ173.41,136.75,136.23,132.03,131.73,127.24,123.09,122.38,121.76,119.76,118.75,111.25,110.21,63.22,52.36,28.80.IR(film)3414,2976,2949,1734,1470,1456,1437,1340,1211,1093,1006,814,742.HRMS(EI)Calcd forC18H17BrN2O2S2435.9915,found 435.9908.
实施例7
化合物1g的合成：
Figure BDA0002459564230000212
向反应管中加入N-(叔丁氧羰基)苯丙氨酸甲酯的硼酸衍生物(48.4mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应48小时，除去溶剂，加入L-色氨酸甲酯(14.5mg,0.12mmol,1.2equiv)和甲苯(1mL)，反应8小时，除去溶剂，柱层析得到黄色液体1g(19.0mg,34％)。1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.53(d,J＝7.7Hz,1H),7.30(d,J＝7.9Hz,1H),7.15(t,J＝7.5Hz,1H),7.10–7.05(m,1H),7.01(d,J＝6.2Hz,2H),6.86(d,J＝7.2Hz,2H),6.78(s,1H),4.93(d,J＝7.4Hz,1H),4.52(s,1H),4.05(dd,J＝14.0,6.9Hz,1H),3.68(s,3H),3.65–3.61(m,3H),3.52(s,1H),3.27(dd,J＝20.1,7.0Hz,1H),3.05–2.96(m,2H),2.89(dd,J＝13.8,6.5Hz,1H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ173.30,172.30,155.21,136.43,135.71,135.54,130.16,129.87,127.12,123.23,122.25,119.59,118.78,111.35,109.93,80.40,62.23,54.46,52.42,52.33,37.94,28.78,28.34.IR(film)3416,2972,2926,1736,1697,1491,1437,1365,1213,1165,1101,1051,1016,881,742.HRMS(ESI)Calcd for C27H34N3O6S2(M+H+)560.1884,found 560.1882.
实施例8
化合物1h的合成：
Figure BDA0002459564230000221
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，除去溶剂，加入磺胺二甲嘧啶(33.4mg,0.12mmol,1.2equiv)和甲苯(1mL)，反应24小时，除去溶剂，柱层析得到浅黄色固体1h(27.6mg,66％)。1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.7Hz,2H),7.44–7.40(m,2H),7.24–7.19(m,3H),6.91(d,J＝8.8Hz,2H),6.55(s,1H),5.79(s,1H),2.29(s,6H).13C NMR(100MHz,CDCl3)δ168.36,156.27,149.40,136.72,131.55,131.25,130.61,129.23,128.52,115.53,114.97,23.64,23.62.IR(film)3343,2956,2922,1595,1552,1490,1439,1153,1084,679,584.HRMS(ESI)Calcd for C18H19N4O2S3(M+H+)419.0665,found 419.0661.
实施例9
化合物1i的合成：
Figure BDA0002459564230000231
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入2-巯基嘧啶(13.4mg,0.12mmol,1.2equiv)，反应2小时，除去溶剂，柱层析得到白色固体1i(18.9mg,75％)。1H NMR(400MHz,CDCl3)δ8.50(d,J＝4.8Hz,2H),7.58–7.54(m,2H),7.28–7.22(m,3H),7.00(t,J＝4.8Hz,1H).13C NMR(100MHz,CDCl3)δ170.25,157.86,136.08,131.24,129.08,128.68,118.17.IR(film)3190,1658,1554,1379,1168,742,686.HRMS(EI)Calcdfor C10H8N2S3251.9850,found251.9849.
实施例10
化合物1j的合成：
Figure BDA0002459564230000232
向反应管中加入4-氯苯硼酸(23.4mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入2-巯基乙醇(9.4mg,0.12mmol,1.2equiv)，反应2小时，除去溶剂，柱层析得到黄色液体1j(16.4mg,65％)。1H NMR(400MHz,CDCl3)δ7.49–7.45(m,2H),7.31–7.25(m,2H),3.84(t,J＝5.8Hz,2H),2.97(t,J＝5.8Hz,2H),1.90(s,1H).13C NMR(100MHz,CDCl3)δ134.95,134.85,131.79,129.43,59.86,41.68.IR(film)3354,2922,2872,1641,1570,1472,1387,1089,1043,1010,814.742.HRMS(EI)Calcd for C8H9ClOS3251.9504,found 251.9503.
实施例11
化合物1k的合成：
Figure BDA0002459564230000241
向反应管中加入4-乙酰苯硼酸(24.5mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应24小时，过滤，溶液中加入4-甲氧基苯甲硫醇(18.5mg,0.12mmol,1.2equiv)，反应2小时，除去溶剂，柱层析得到无色液体1k(21.2mg,63％)。1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.12(d,J＝8.6Hz,2H),6.77(d,J＝8.6Hz,2H),3.99(s,2H),3.72(s,3H),2.51(s,3H).13CNMR(100MHz,CDCl3)δ197.06,159.33,143.17,136.05,130.61,128.88,128.32,127.79,114.14,55.29,42.97,26.55.IR(film)3001,2955,1680,1585,1462,1392,1248,1086,956,820,617,588.HRMS(EI)Calcd for C16H16O2S3336.0312,found 336.0316.
实施例12
化合物1l的合成：
Figure BDA0002459564230000242
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入N-(邻苯二甲酰基)半胱氨酸甲酯(31.8mg,0.12mmol,1.2equiv)，反应6小时，除去溶剂，柱层析得到黄色液体1l(32.4mg,80％)。1H NMR(400MHz,CDCl3)δ7.79(dd,J＝5.5,3.0Hz,2H),7.67(dd,J＝5.4,3.1Hz,2H),7.50(dd,J＝7.9,1.4Hz,2H),7.28–7.18(m,3H),5.19(dd,J＝10.7,4.7Hz,1H),3.66(s,3H),3.65–3.46(m,2H).13C NMR(100MHz,CDCl3)δ168.36,167.37,136.40,134.34,131.78,130.57,129.22,128.43,123.72,53.08,51.00,36.86.IR(film)3068,1745,1713,1467,1437,1385,1240,1172,1068,914,866,788,688.HRMS(ESI)Calcd forC18H16NO4S3(M+H+)406.0236,found 406.0231.
实施例13
化合物1m的合成：
Figure BDA0002459564230000251
向反应管中加入4-乙酰苯硼酸(24.5mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应24小时，过滤，溶液中加入金刚烷硫醇(20.2mg,0.12mmol,1.2equiv)，反应6小时，除去溶剂，柱层析得到浅黄色固体1m(18.2mg,52％)。1H NMR(400MHz,CDCl3)δ7.89–7.82(m,2H),7.60–7.53(m,2H),2.52(s,3H),2.02(s,3H),1.84(d,J＝2.5Hz,6H),1.67–1.55(m,6H).13C NMR(100MHz,CDCl3)δ197.16,143.76,135.73,128.86,127.88,51.25,42.52,36.01,29.89,26.61.IR(film)2905,2848,1684,1587,1392,1259,1089,1051,883,819,617.HRMS(EI)Calcd for C18H22OS3350.0833,found 350.0835.
实施例14
化合物1o的合成：
Figure BDA0002459564230000252
向反应管中加入4-乙氧羰基苯硼酸(29.1mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应24小时，过滤，溶液中加入十二硫醇(24.2mg,0.12mmol,1.2equiv)，反应2小时，除去溶剂，柱层析得到浅黄色固体1o(24.9mg,60％)。1H NMR(400MHz,CDCl3)δ7.96–7.91(m,2H),7.58–7.54(m,2H),4.31(q,J＝7.1Hz,2H),2.85–2.71(m,2H),1.68–1.56(m,2H),1.32(t,J＝7.1Hz,3H),1.29–1.24(m,2H),1.18(s,16H),0.81(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ166.02,142.89,130.09,129.48,128.11,61.10,39.18,31.93,29.65,29.63,29.57,29.47,29.35,29.14,28.90,28.46,22.70,14.33,14.12.IR(film)2922,2853,1718,1591,1564,1487,1396,1269,1103,846,758,688.HRMS(EI)Calcd for C21H34O2S3414.1721,found 414.1723.
实施例15
化合物1p的合成：
Figure BDA0002459564230000261
向反应管中加入雌酚酮衍生的硼酸(44.7mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应48小时，过滤，溶液中加入3-(三乙氧基硅基)1-丙硫醇(28.6mg,0.12mmol,1.2equiv)，反应4小时，除去溶剂，柱层析得到浅黄色固体1p(28.6mg,34％)。1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.1Hz,1H),7.27(s,1H),7.21(s,1H),3.75(q,J＝7.0Hz,6H),2.88–2.79(m,4H),2.44(dd,J＝18.7,8.7Hz,1H),2.35(dd,J＝12.9,4.6Hz,1H),2.24(dd,J＝20.7,10.6Hz,1H),2.09(dd,J＝18.5,9.3Hz,1H),2.04–1.88(m,3H),1.84–1.73(m,2H),1.61–1.31(m,10H),1.16(t,J＝7.0Hz,9H),0.84(s,3H),0.68–0.62(m,2H).13C NMR(100MHz,CDCl3)δ140.31,137.65,133.92,130.90,127.89,126.23,58.45,50.52,47.94,44.36,41.75,38.00,35.84,31.57,29.70,29.30,26.35,25.66,22.42,21.59,18.33,13.84,9.62.IR(film)3030,2945,1741,1639,1375,1124,1072,921,866,557.HRMS(ESI)Calcd for C27H42O4S3SiNa(M+Na+)577.1907,found577.1902.
实施例16
化合物2a的合成：
Figure BDA0002459564230000262
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入1,3,5-三甲氧基苯(20.1mg,0.12mmol,1.2equiv)和B(C6F5)3(0.5mg,0.001mmol,1mol％)，反应2小时，除去溶剂，柱层析得到无色液体2a(17.3mg,56％)。1H NMR(400MHz,CDCl3)δ7.56–7.51(m,2H),7.24–7.17(m,2H),7.11(t,J＝7.3Hz,1H),6.00(s,2H),3.73(s,3H),3.65(s,6H).13C NMR(100MHz,CDCl3)δ163.11,162.28,138.80,128.98,128.37,126.56,104.57,91.02,55.94,55.39.IR(film)2940,2837,1580,1466,1410,1337,1227,1159,1088,812,740.HRMS(EI)Calcd for C15H16O3S2308.0541,found 308.0537.
实施例17
化合物2b的合成：
Figure BDA0002459564230000271
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入δ-生育酚(48.2mg,0.12mmol,1.2equiv)和B(C6F5)3(0.5mg,0.001mmol,1mol％)，反应2小时，除去溶剂，柱层析得到无色液体2b(21.1mg,37％)。1H NMR(400MHz,CDCl3)δ7.43(d,J＝6.5Hz,2H),7.29–7.20(m,3H),6.57(s,1H),5.74(s,1H),2.62–2.43(m,2H),2.07(s,3H),1.64–1.53(m,2H),1.50–1.14(m,15H),1.10(s,3H),1.09–0.94(m,6H),0.82–0.74(m,12H).13C NMR(100MHz,CDCl3)δ150.40,146.07,137.09,133.07,131.87,129.24,129.18,124.01,116.52,115.00,75.16,39.75,39.39,37.49,37.48,37.45,37.31,32.82,32.70,31.29,27.99,24.81,24.47,23.82,22.72,22.63,21.99,20.95,19.76,19.66,16.57.IR(film)2951,2924,1460,1377,1221,1151,1076,1038,744.HRMS(EI)Calcd forC33H50O2S2542.3252,found 542.3248.
实施例18
化合物2c的合成：
Figure BDA0002459564230000281
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入5-甲氧基吲哚(17.6mg,0.12mmol,1.2equiv)和B(C6F5)3(0.5mg,0.001mmol,1mol％)，反应2小时，除去溶剂，柱层析得到无色液体2c(21.8mg,76％)。1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.53–7.46(m,1H),7.26–7.21(m,1H),7.19–7.15(m,1H),7.12(d,J＝8.8Hz,1H),6.87(d,J＝2.2Hz,1H),6.77(dd,J＝8.8,2.4Hz,1H),3.62(s,1H).13C NMR(100MHz,CDCl3)δ155.22,138.77,131.05,130.65,130.17,129.19,128.91,127.45,113.94,112.40,108.08,100.93,55.63.IR(film)3416,2829,1622,1581,1436,1286,1207,1168,920,802,742,690.HRMS(EI)Calcd for C15H13NOS2 287.0439,found 287.0434.
实施例19
化合物2d的合成：
Figure BDA0002459564230000282
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入N-(甲氧基甲基)吲哚(19.3mg,0.12mmol,1.2equiv)和B(C6F5)3(0.5mg,0.001mmol,1mol％)，反应2小时，除去溶剂，柱层析得到无色液体2d(14.4mg,48％)。1H NMR(400MHz,CDCl3)δ7.56(d,J＝7.9Hz,1H),7.45(d,J＝7.7Hz,2H),7.39(d,J＝8.1Hz,1H),7.27–7.17(m,5H),7.15–7.09(m,1H),5.29(s,2H),3.11(s,3H).13C NMR(100MHz,CDCl3)δ138.23,136.82,133.47,130.33,129.51,128.88,127.57,123.35,121.46,120.09,110.43,108.13,77.65,56.05.IR(film)3053,2949,1502,1458,1335,1234,1153,1111,1086,972,743,688.HRMS(EI)Calcd forC16H15NOS2301.0595,found 301.0590.
实施例20
化合物2e的合成：
Figure BDA0002459564230000291
向反应管中加入苯硼酸(18.3mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入N-甲基吲哚(15.7mg,0.12mmol,1.2equiv)和B(C6F5)3(0.5mg,0.001mmol,1mol％)，反应2小时，除去溶剂，柱层析得到无色液体2e(13.0mg,48％)。1H NMR(400MHz,CDCl3)δ7.52(d,J＝7.9Hz,1H),7.49–7.45(m,2H),7.26–7.20(m,3H),7.20–7.15(m,2H),7.11(s,1H),7.10–7.06(m,1H),3.65(s,3H).13C NMR(100MHz,CDCl3)δ138.56,137.31,134.52,129.92,129.20,128.87,127.34,122.71,120.69,119.91,109.69,106.18,33.09.IR(film)2976,1580,1475,1458,1332,1242,1051,881,741,688.HRMS(EI)Calcd for C15H13NS2271.0489,found 271.0490.
实施例21
化合物2f的合成：
Figure BDA0002459564230000292
向反应管中加入4-氯苯硼酸(23.4mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入N-甲基-6-氯吲哚(19.8mg,0.12mmol,1.2equiv)和B(C6F5)3(0.5mg,0.001mmol,1mol％)，反应2小时，除去溶剂，柱层析得到白色固体2f(22.1mg,65％)。1HNMR(400MHz,CDCl3)δ7.39–7.36(m,2H),7.35–7.33(m,1H),7.21(d,J＝1.7Hz,1H),7.20(d,J＝1.9Hz,1H),7.18(dd,J＝4.4,1.6Hz,1H),7.07(s,1H),7.05(dd,J＝8.5,1.7Hz,1H),3.62(s,3H).13C NMR(100MHz,CDCl3)δ137.71,136.87,135.06,133.73,131.57,129.07,129.02,127.62,121.54,120.78,109.92,106.42,33.25.IR(film)2933,1606,1504,1472,1460,1418,1387,1327,1232,1090,1065,1011,974,806,642,598.HRMS(EI)Calcd for C15H11Cl2NS2338.9710,found 338.9713.
实施例22
化合物2g的合成：
Figure BDA0002459564230000301
向反应管中加入2-噻吩硼酸(19.2mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入N-甲基吲哚(15.7mg,0.12mmol,1.2equiv)和B(C6F5)3(0.5mg,0.001mmol,1mol％)，反应2小时，除去溶剂，柱层析得到无色液体2g(15.5mg,56％)。1HNMR(400MHz,CDCl3)δ7.56(d,J＝7.9Hz,1H),7.36(dd,J＝5.3,1.1Hz,1H),7.27(d,J＝8.1Hz,1H),7.24–7.19(m,1H),7.15–7.11(m,1H),7.11–7.08(m,1H),6.96(dd,J＝3.5,1.2Hz,1H),6.88(dd,J＝5.3,3.6Hz,1H),3.72(s,3H).13C NMR(100MHz,CDCl3)δ137.60,137.43,135.31,134.71,131.29,129.31,127.56,122.80,120.77,119.87,109.69,106.15,33.18.IR(film)3107,2816,1626,1504,1333,1242,1215,1144,1113,848,742,706.HRMS(EI)Calcd for C13H11NS3277.0054,found277.0059.
实施例23
化合物2h的合成：
Figure BDA0002459564230000302
向反应管中加入3,4-亚甲基苯硼酸(24.9mg,0.15mmol,1.5equiv)，5(27.6mg,0.10mmol,1equiv)，Cu(MeCN)4PF6(3.7mg,0.01mmol,10mol％)，2,2’-联吡啶(3.1mg,0.02mmol,20mol％)和重蒸二氯甲烷(1mL)，置换氮气，反应10小时，过滤，溶液中加入N-甲基吲哚(15.7mg,0.12mmol,1.2equiv)和B(C6F5)3(0.5mg,0.001mmol,1mol％)，反应2小时，除去溶剂，柱层析得到黄色液体2h(14.6mg,55％)。1HNMR(400MHz,CDCl3)δ6.93–6.89(m,1H),6.84–6.79(m,1H),6.76(s,1H),6.67–6.63(m,1H),6.29–6.24(m,1H),6.04–5.99(m,1H),5.93–5.88(m,2H),3.54(s,3H).13C NMR(100MHz,CDCl3)δ148.54,147.99,129.45,127.29,127.07,121.95,119.71,113.12,108.49,108.42,101.50,34.31.IR(film)3003,2889,1716,1475,1363,1290,1039,933,806,731,612.HRMS(ESI)Calcd for C12H12NO2S2(M+H+)266.0304,found 266.0302.
实施例24
化合物3a的合成：
Figure BDA0002459564230000311
向反应管中加入4-氰基苯胺(11.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(1.0mg，0.002mmol，2mol％)和重蒸的1，4-二氧六环(0.25mL)，室温搅拌4小时，然后加入苄胺(12.8mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到白色固体3a(20.3mg,71％)。1H NMR(400MHz,Acetone-d6)δ7.61(d,J＝8.7Hz,2H),7.33(d,J＝4.0Hz,4H),7.29(dt,J＝9.4,4.8Hz,1H),7.23(d,J＝8.8Hz,2H),4.64(t,J＝5.0Hz,1H),4.19(d,J＝5.3Hz,2H),2.10(s,1H).13C NMR(100MHz,Acetone-d6)δ151.25,138.79,133.34,128.49,128.33,127.31,119.23,116.03,102.28,54.98.IR(film)3361,2974,2926,2222,1383,1335,1093,1053,883,804,574.HRMS(EI)Calcd for C14H13N3S2287.0551,found287.0549.
实施例25
化合物3b的合成：
Figure BDA0002459564230000312
向反应管中加入4-溴苯胺(17.2mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入苄胺(12.8mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到白色固体3b(26.6mg,78％)。1H NMR(400MHz,CDCl3)δ7.25(dt,J＝11.8,4.9Hz,5H),7.19(d,J＝7.8Hz,2H),6.79(d,J＝8.5Hz,2H),4.77(s,1H),3.99(d,J＝3.3Hz,2H),3.07(s,1H).13C NMR(100MHz,CDCl3)δ145.44,138.47,132.06,128.66,128.45,127.76,117.99,113.29,55.81.IR(film)3360,3294,1585,1481,1435,1365,1276,1228,1113,1001,887,812,748,696,632,578.HRMS(EI)Calcdfor C13H13BrN2S2339.9704,found339.9709.
实施例26
化合物3c的合成：
Figure BDA0002459564230000321
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入环己胺(11.9mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到无色液体3c(21.6mg,75％)。1HNMR(400MHz,CDCl3)δ7.12(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),5.01(s,1H),2.80(s,1H),2.73–2.63(m,1H),1.79(d,J＝11.7Hz,2H),1.61(dd,J＝8.5,4.5Hz,2H),1.15–0.93(m,6H).13C NMR(100MHz,CDCl3)δ145.28,129.12,125.92,117.55,57.67,32.56,25.85,24.38.IR(film)3329,2935,2856,1774,1595,1489,1448,1276,1232,825,739.HRMS(EI)Calcd for C12H17ClN2S2288.0522,found 288.0525.
实施例27
化合物3d的合成：
Figure BDA0002459564230000322
向反应管中加入4-乙烯基苯胺(11.9mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入3,4-二甲氧基苄胺(11.9mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到白色固体3d(19.1mg,55％)。1H NMR(400MHz,CDCl3)δ7.24(dd,J＝17.5,7.4Hz,2H),6.92(dd,J＝16.7,8.3Hz,2H),6.81–6.66(m,3H),6.64–6.49(m,1H),5.54(t,J＝17.3Hz,1H),5.13–4.89(m,1H),3.93(d,J＝17.4Hz,1H),4.01–3.41(m,2H),3.80(dd,J＝16.8,7.5Hz,6H),3.01(s,1H).13C NMR(100MHz,DMSO-d6)δ148.99,148.39,147.35,136.83,131.73,129.52,127.44,120.91,116.26,112.58,111.99,111.34,55.96,55.81,54.89.IR(film)3200,3055,2835,1604,1508,1325,1269,1238,1139,1026,738.HRMS(ESI)Calcd for C17H20N2O2S2(M+H+)349.1039,found 349.1037.
实施例28
化合物3e的合成：
Figure BDA0002459564230000331
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入2,2-二苯基乙-1-胺(23.6mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到亮黄色液体3e(34.7mg,90％)。1H NMR(400MHz,CDCl3)δ7.23(t,J＝7.5Hz,4H),7.15(d,J＝6.7Hz,2H),7.09(d,J＝7.7Hz,4H),7.06(d,J＝8.6Hz,2H),6.77(d,J＝8.4Hz,2H),4.82(s,1H),4.11(t,J＝7.6Hz,1H),3.45–3.34(m,2H),2.70(s,1H).13C NMR(100MHz,CDCl3)δ144.85,141.98,129.20,128.81,128.06,126.88,126.08,117.69,56.77,51.14.IR(film)3358,3061,2924,2852,1593,1487,1275,1230,889,823,738,702.HRMS(EI)Calcd for C20H19ClN2S2386.0678,found 386.0681.
实施例29
化合物3f的合成：
Figure BDA0002459564230000332
向反应管中加入4-氨基联苯(16.9mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入二烯丙基胺(11.6mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到亮黄色液体3f(22.0mg,67％)。1H NMR(400MHz,CDCl3)δ7.50–7.40(m,4H),7.36–7.28(m,2H),7.24–7.17(m,1H),6.99–6.92(m,2H),5.87–5.64(m,2H),5.10–4.94(m,4H),4.83(s,1H),3.38–3.34(m,4H).13C NMR(100MHz,CDCl3)δ145.89,140.81,134.86,134.04,128.78,127.88,126.69,126.62,118.08,116.74,60.28.IR(film)3373,3030,2920,1714,1606,1516,1485,1361,1282,1265,1224,991,925,889,833,761,698.HRMS(EI)Calcd for C18H20N2S2328.1068,found 328.1070.
实施例30
化合物3g的合成：
Figure BDA0002459564230000341
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入色胺(19.2mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到亮黄色液体3g(25.2mg,72％)。1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.57(t,J＝7.2Hz,1H),7.33(t,J＝6.7Hz,1H),7.23–7.15(m,1H),7.10(dd,J＝14.6,7.3Hz,1H),6.94–6.83(m,3H),6.72–6.63(m,2H),4.70(s,1H),3.20(s,3H),2.99–2.84(m,3H),2.76(s,1H).13C NMR(100MHz,CDCl3)δ144.75,136.49,129.03,127.19,125.72,122.45,122.38,119.65,118.83,117.32,112.75,111.47,51.22,25.60.IR(film)3314,3061,2924,2868,1593,1487,1275,1230,889,823,739.702.HRMS(ESI)Calcd for C16H16ClN3S2(M+H+)350.0547,found 350.0546.
实施例31
化合物3h的合成：
Figure BDA0002459564230000351
向反应管中加入4-甲基苯胺(10.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入2-氨甲基吡啶(13.0mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到棕色液体3h(20.2mg,73％)。1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝4.2Hz,1H),7.72(td,J＝7.7,1.8Hz,1H),7.54(s,1H),7.33(d,J＝7.8Hz,1H),7.27–7.21(m,1H),7.00(d,J＝8.3Hz,2H),6.90(d,J＝8.4Hz,2H),5.14(t,J＝5.5Hz,1H),4.13(d,J＝5.5Hz,2H),2.18(s,3H).13C NMR(100MHz,DMSO-d6)δ159.03,149.31,144.81,137.04,129.87,129.00,122.75,122.67,116.42,56.80,20.64.IR(film)2920,2848,1714,1633,1508,1431,1361,1093,763,723.HRMS(ESI)Calcd for C13H16N3S2(M+H+)278.0780,found 278.0782.
实施例32
化合物3i的合成：
Figure BDA0002459564230000352
向反应管中加入3-氰基苯胺(11.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(1.0mg，0.002mmol，2mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌12小时，然后加入L-苯丙氨酸叔丁酯(26.5mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到无色液体3i(23.2mg,58％)。1H NMR(300MHz,CDCl3)δ7.22(ddd,J＝11.2,4.9,2.3Hz,5H),7.14–7.06(m,4H),5.37(s,1H),3.66(dt,J＝8.5,6.9Hz,1H),3.56(d,J＝8.6Hz,1H),2.89(d,J＝6.7Hz,2H),1.38(s,9H).13C NMR(100MHz,CDCl3)δ169.39,141.60,131.64,125.23,124.73,123.69,122.22,119.71,116.18,114.62,114.15,108.34,77.84,61.89,34.73,23.18.IR(film)3348,3030,2980,2229,1726,1598,1583,1495,1456,1392,1369,1269,1151,740,702.HRMS(ESI)Calcdfor C20H23N3O2S2(M+Na+)424.1124,found424.1119.
实施例33
化合物3j的合成：
Figure BDA0002459564230000361
向反应管中加入4-叔丁基苯胺(14.9mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.005mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入L-色氨酸甲酯(26.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到浅黄色固体3j(28.3mg,66％)。1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.55(d,J＝7.8Hz,1H),7.28(d,J＝8.1Hz,1H),7.12(dd,J＝8.6,2.3Hz,3H),7.06(t,J＝7.4Hz,1H),6.92(d,J＝2.1Hz,1H),6.72(d,J＝8.6Hz,2H),4.62(s,1H),3.97(dd,J＝13.2,6.4Hz,1H),3.65(s,3H),3.45(d,J＝6.4Hz,1H),3.11(ddd,J＝22.3,14.6,6.6Hz,2H),1.19(s,9H).13C NMR(100MHz,CDCl3)δ175.00,143.99,142.67,136.21,127.21,126.02,123.34,122.37,119.75,118.76,116.10,111.40,110.39,63.69,52.53,52.49,34.11,31.51,28.86.IR(film)3495,3290,2926,1728,1510,1282,1093,1053,881,827,742,643.HRMS(ESI)Calcd for C22H28N3O2S2(M+H+)430.1617,found 430.1616.
实施例34
化合物3k的合成：
Figure BDA0002459564230000362
向反应管中加入(R)-4-(2-氨基苯基)-1-(苯磺酰基)-2,3-二氢-1H-吡咯-2-羧酸叔丁酯(40.0mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌12小时，然后加入2,2-二苯基乙-1-胺(23.6mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到棕色泡沫固体3k(40.9mg,62％)。1H NMR(400MHz,CDCl3)δ7.78(d,J＝6.8Hz,2H),7.54(dd,J＝8.4,6.2Hz,1H),7.47(t,J＝7.2Hz,2H),7.17(ddd,J＝20.3,14.0,7.0Hz,8H),7.05(d,J＝6.7Hz,4H),6.81(d,J＝7.5Hz,1H),6.75(t,J＝7.2Hz,1H),6.53(s,1H),5.22(s,1H),4.21(t,J＝7.6Hz,1H),4.06(t,J＝6.9Hz,1H),3.30(s,2H),2.90–2.73(m,2H),2.69(t,J＝4.8Hz,1H),1.44(s,9H).13C NMR(100MHz,CDCl3)δ169.75,143.94,142.06,141.99,136.65,133.51,129.41,128.72,128.36,128.03,127.92,127.58,126.78,122.74,121.27,120.72,117.30,82.75,61.12,56.80,51.07,38.06,27.98.IR(film)3489,3001,1633,1446,1373,1168,1149,1089,1041,754,721.HRMS(ESI)Calcd forC35H37N3O4S3(M+H+)660.2019,found 660.2010.
实施例35
化合物3l的合成：
Figure BDA0002459564230000371
向反应管中加入色氨酸甲酯(21.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(1.0mg，0.002mmol，2mol％)和重蒸的乙腈(0.5mL)，室温搅拌12小时，然后加入十八胺(32.3mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到浅黄色固体3l(19.3mg,35％)。1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.56–7.49(m,1H),7.31–7.23(m,1H),7.12(dd,J＝13.4,6.6Hz,1H),7.05(dd,J＝13.3,6.6Hz,1H),6.99(s,1H),3.96–3.89(m,1H),3.63(d,J＝5.3Hz,3H),3.40(t,J＝5.7Hz,1H),3.23–3.01(m,2H),2.76(s,1H),2.70(s,1H),2.51(s,1H),1.38–1.30(m,2H),1.17(s,30H),0.84–0.77(m,3H).13C NMR(100MHz,CDCl3)δ175.38,136.13,127.35,123.02,122.29,119.69,118.74,111.25,110.66,64.04,52.45,50.37,31.96,29.74,29.66,29.61,29.56,29.46,29.40,29.03,26.96,22.73,14.16.IR(film)3072,3061,1512,1404,1269,742,704.HRMS(ESI)Calcd for C30H51N3O2S2(M+H+)550.3495,found 550.3498.
实施例36
化合物3m的合成：
Figure BDA0002459564230000381
向反应管中加入磺胺二甲嘧啶(27.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌24小时，然后加入十八胺(32.3mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到白色固体3m(24.4mg,40％)。1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),7.84(d,J＝8.5Hz,2H),7.05(d,J＝8.5Hz,2H),6.75(s,1H),4.88(s,1H),2.79(d,J＝5.1Hz,2H),2.25(s,6H),1.38–1.32(m,3H),1.23(s,30H),0.85(t,J＝6.0Hz,3H).13C NMR(100MHz,DMSO-d6)δ167.79,156.95,151.55,130.75,130.29,114.64,112.29,51.07,31.78,29.52,29.40,29.28,29.19,28.88,26.74,23.51,22.57,14.40.IR(film)3091,3012,1716,1688,1421,1220,1091,992,708,686.HRMS(ESI)Calcd for C30H51N5O2S3(M+H+)610.3278,found 610.3274.
实施例37
化合物3n的合成：
Figure BDA0002459564230000382
向反应管中加入色氨酸甲酯(21.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的乙腈(0.5mL)，室温搅拌12小时，然后加入L-苯丙氨酸甲酯(21.5mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到浅黄色固体3n(19.3mg,42％)。1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.52(d,J＝7.7Hz,1H),7.25(d,J＝7.7Hz,1H),7.20–7.16(m,3H),7.15–7.09(m,2H),7.07–7.02(m,2H),6.94(s,1H),3.85(dd,J＝13.6,6.5Hz,1H),3.70–3.63(m,1H),3.59(s,3H),3.57(s,3H),3.49(d,J＝6.8Hz,1H),3.38(d,J＝6.8Hz,1H),3.09(ddd,J＝21.9,14.7,6.5Hz,2H),2.84(ddd,J＝21.1,13.8,6.7Hz,2H).13C NMR(100MHz,CDCl3)δ175.25,175.01,136.58,136.13,129.27,128.43,127.41,126.87,122.99,122.16,119.55,118.76,111.24,110.62,64.78,63.80,52.47,52.39,39.28,29.14.IR(film)3055,2953,1734,1494,1456,1435,1340,1267,1203,1097,742,702.HRMS(ESI)Calcd for C22H25N3O4S2(M+H+)460.1359,found 460.1353.
实施例38
化合物3o的合成：
Figure BDA0002459564230000391
向反应管中加入色氨酸甲酯(21.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的乙腈(0.5mL)，室温搅拌12小时，然后加入L-缬氨酸甲酯(15.7mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到白色固体3o(22.2mg,54％)。1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.55(d,J＝7.8Hz,1H),7.27(d,J＝8.0Hz,1H),7.11(t,J＝7.5Hz,1H),7.05(t,J＝7.4Hz,1H),6.99(s,1H),3.95(dd,J＝13.3,6.6Hz,1H),3.63(d,J＝2.6Hz,6H),3.37(d,J＝9.3Hz,1H),3.12(ddd,J＝22.1,14.6,6.6Hz,1H),2.97(s,1H),1.77(td,J＝13.4,6.7Hz,1H),1.64(s,1H),0.78(t,J＝6.5Hz,6H).13C NMR(100MHz,CDCl3)δ175.91,175.42,136.21,127.39,123.10,122.15,119.54,118.81,111.22,110.67,70.50,63.66,52.46,52.26,32.03,29.30,18.98,18.24.IR(film)3055,1746,1467,1269,1189,1022,740,704.HRMS(ESI)Calcd for C18H25N3O4S2(M+H+)412.1359,found 412.1351.
实施例39
化合物3p的合成：
Figure BDA0002459564230000392
向反应管中加入磺胺二甲嘧啶(27.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌24小时，然后加入叔丁氧羰基-L-异亮氨酰-L-赖氨酸甲酯(44.8mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到白色固体3p(46.4mg,65％)。1H NMR(400MHz,CDCl3)δ7.89(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),6.76(d,J＝7.4Hz,1H),6.52(s,1H),6.28(s,1H),5.28(d,J＝8.9Hz,1H),4.51(dd,J＝13.0,7.8Hz,1H),4.02(t,J＝7.6Hz,1H),3.65(s,3H),3.02(brs,1H),2.83(t,J＝6.1Hz,2H),2.27(s,6H),1.84–1.68(m,2H),1.63–1.54(m,1H),1.51–1.40(m,3H),1.35(s,9H),1.29–1.17(m,2H),1.15–1.01(m,2H),0.89(d,J＝6.7Hz,3H),0.83(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ172.51,172.13,168.16,156.34,156.02,151.06,130.50,114.91,114.59,113.27,80.07,59.19,52.42,52.09,51.04,37.31,31.80,28.69,28.33,24.76,23.56,22.52,15.50,11.27.IR(film)3433,3275,2941,1741,1689,1593,1346,1244,1207,1155,1080,866.HRMS(ESI)Calcd for C30H47N7O7S3(M+H+)714.2772,found714.2764.
实施例40
化合物3q的合成：
Figure BDA0002459564230000401
向反应管中加入磺胺甲恶唑(25.3mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌24小时，然后加入叔丁氧羰基-L-苯丙氨酰基-L-亮氨酰-L-赖氨酸(62.4mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到白色固体3q(37.6mg,45％)。1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.7Hz,2H),7.19–7.10(m,5H),7.03(s,2H),6.91(d,J＝7.7Hz,2H),6.20(s,1H),6.12(d,J＝3.9Hz,1H),5.09(d,J＝7.0Hz,1H),4.55–4.41(m,2H),4.32(s,1H),3.66(s,3H),3.09(s,1H),2.95–2.65(m,4H),2.26(s,3H),1.82–1.70(m,1H),1.58–1.49(m,3H),1.46–1.34(m,3H),1.26(s,9H),1.22–1.14(m,3H),0.83–0.76(m,6H).13C NMR(100MHz,CDCl3)δ172.48,172.24,172.20,170.47,158.30,155.49,151.40,136.53,130.24,129.36,128.62,128.52,126.87,115.63,95.84,80.28,55.55,52.43,52.19,52.05,51.77,40.78,37.92,31.72,28.97,28.21,24.51,22.69,22.08,12.65.IR(film)3406,3313,3219,2976,1382,1093,1055,883,688.HRMS(ESI)Calcd for C37H53N7O9S3Na(M+Na+)858.2959,found 858.2952.
实施例41
化合物3r的合成：
Figure BDA0002459564230000411
向反应管中加入磺胺二甲嘧啶(27.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌24小时，然后加入西那卡塞(42.9mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌12小时，除去溶剂，柱层析得到黄色固体3r(51.6mg,74％)。1HNMR(400MHz,CDCl3)δ7.94(d,J＝8.1Hz,2H),7.90(d,J＝8.3Hz,1H),7.74(d,J＝8.1Hz,1H),7.64(d,J＝7.9Hz,1H),7.40(dt,J＝14.7,7.0Hz,3H),7.33–7.22(m,3H),7.10(t,J＝7.6Hz,1H),7.02(s,1H),6.82(d,J＝8.0Hz,3H),6.42(s,1H),5.34(s,1H),4.66(br,1H),2.72–2.50(m,2H),2.32–2.25(m,2H),2.22(s,6H),2.08–1.95(m,2H),1.49(br,3H).19FNMR(376MHz,CDCl3)δ-62.42.13C NMR(101MHz,CDCl3)δ168.28,156.32,150.78,142.63,138.19,133.99,131.57,131.39,130.75,130.63,130.36(q,2JCF＝31.8Hz),128.94,128.63,128.27,126.29,125.74,125.23,124.73(q,3JCF＝3.6Hz),124.48,124.25(q,1JCF＝272.5Hz),123.54,122.56(q,3JCF＝3.8Hz),114.63,63.17,52.02,32.18,29.75,28.68,23.50.IR(film)3319,3055,1593,1552,1438,1153,1074,972,868,736,671,582.HRMS(ESI)Calcd for C34H35F3N5O2S3(M+H+)698.1899,found 698.1881.
实施例42
化合物3s的合成：
Figure BDA0002459564230000421
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入1-金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3s(33.3mg,93％)。1H NMR(400MHz,CD3CN)δ7.23–7.10(m,2H),7.07–6.97(m,2H),6.61(s,1H),1.97(s,3H),1.77(d,J＝2.6Hz,6H),1.60(q,J＝12.4Hz,6H).13C NMR(100MHz,CD3CN)δ144.89,129.56,126.16,118.54,117.85,50.30,43.11,36.17,30.50.IR(film)2906,1591,1487,1228,1093,891,819,659.HRMS(EI)Calcd for C16H20ClNS3357.0446,found 357.0437.
实施例43
化合物3t的合成：
Figure BDA0002459564230000422
向反应管中加入4-溴苯胺(17.2mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入1-金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3t(39.4mg,98％)。1H NMR(400MHz,Acetone-d6)δ7.50(s,1H),7.28(d,J＝8.8Hz,2H),7.04(d,J＝8.8Hz,2H),1.93(s,3H),1.74(s,6H),1.56(q,J＝12.3Hz,6H).13C NMR(100MHz,Acetone-d6)δ145.10,131.87,118.43,112.73,49.58,42.62,35.78,29.94.IR(film)3360,2903,2849,1587,1483,1296,1273,1228,1037,1003,895,818,684.HRMS(EI)Calcd forC16H20BrNS3400.9941,found 400.9945.
实施例44
化合物3u的合成：
Figure BDA0002459564230000431
向反应管中加入4-叔丁基苯胺(14.9mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入1-金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3u(28.5mg,75％)。1HNMR(400MHz,Acetone-d6)δ7.24(s,1H),7.20–7.16(m,2H),7.03–6.98(m,2H),1.95–1.89(m,3H),1.74(d,J＝2.7Hz,6H),1.55(q,J＝12.3Hz,6H),1.16(s,9H).13C NMR(100MHz,Acetone-d6)δ143.78,142.93,125.80,116.27,49.38,42.64,35.79,33.76,30.96,29.93.IR(film)3344,2960,2903,2848,1510,1450,1296,1284,1234,1184,1039,904,825.HRMS(EI)Calcd for C20H29NS3379.1462,found 379.1464.
实施例45
化合物3v的合成：
Figure BDA0002459564230000432
向反应管中加入4-氰基苯胺(11.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌12小时，然后加入1-金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3v(28.5mg,86％)。1HNMR(400MHz,Acetone-d6)δ8.02(s,1H),7.58–7.48(m,2H),7.27–7.19(m,2H),1.94(s,3H),1.75(d,J＝2.6Hz,6H),1.56(q,J＝12.3Hz,6H).13C NMR(100MHz,Acetone-d6)δ150.02,133.42,118.94,116.70,103.48,49.84,42.56,35.70,29.91.IR(film)3361,2904,2212,1624,1448,1309,1170,1045,831,738,688.HRMS(EI)Calcd for C17H20N2S3348.0789,found348.0788.
实施例46
化合物3w的合成：
Figure BDA0002459564230000441
向反应管中加入2-苯基苯胺(11.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌12小时，然后加入1-金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3w(28.5mg,86％)。1HNMR(400MHz,Acetone-d6)δ7.50(d,J＝8.2Hz,1H),7.39–7.30(m,2H),7.29–7.18(m,4H),7.01(d,J＝7.5Hz,1H),6.89(t,J＝7.4Hz,1H),6.34(s,1H),1.90(s,3H),1.68(s,6H),1.54(q,J＝12.3Hz,6H).13C NMR(100MHz,Acetone-d6)δ141.77,138.37,131.32,130.48,129.25,128.98,128.44,127.60,121.55,116.62,49.54,42.55,35.75,29.89.IR(film)3379,2903,2848,1499,1477,1296,1261,1207,1039,896,750.HRMS(EI)Calcd forC22H25NS3399.1149,found 399.1151.
实施例47
化合物3x的合成：
Figure BDA0002459564230000442
向反应管中加入3-氟苯胺(11.1mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌12小时，然后加入1-金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到亮黄色液体3x(26.2mg,77％)。1H NMR(400MHz,Acetone-d6)δ7.61(s,1H),7.14(dd,J＝15.0,7.7Hz,1H),6.93–6.82(m,2H),6.53(ddd,J＝8.6,2.6,1.2Hz,1H),1.94(s,3H),1.75(d,J＝2.7Hz,6H),1.57(q,J＝12.3Hz,6H).19F NMR(376MHz,Acetone-d6)δ-113.77.13C NMR(100MHz,Acetone-d6)δ163.69(d,1JCF＝242.5Hz),147.94(d,3JCF＝10.2Hz),130.58(d,3JCF＝9.8Hz),112.49(d,4JCF＝2.5Hz),107.35(d,2JCF＝21.6Hz),103.21(d,2JCF＝26.0Hz),49.60,42.59,35.74,29.92.IR(film)3199,2905,1612,1487,1273,1165,1139,1001,968,765,681.HRMS(EI)Calcd forC16H20FNS3341.0742,found 341.0744.
实施例48
化合物3y的合成：
Figure BDA0002459564230000451
向反应管中加入3,5-二氟苯胺(12.9mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌12小时，然后加入1-金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到亮黄色液体3y(25.1mg,70％)。1H NMR(400MHz,Acetone-d6)δ7.85(s,1H),6.76–6.61(m,2H),6.39(ddd,J＝9.2,5.7,2.3Hz,1H),1.95(s,3H),1.76(d,J＝2.7Hz,6H),1.58(q,J＝12.4Hz,6H).19FNMR(282MHz,Acetone-d6)δ-105.54,-105.57.13C NMR(100MHz,Acetone-d6)δ163.81(dd,1JCF＝244.3,3JCF＝15.4Hz),149.25(t,3JCF＝12.7Hz),99.41(d,2JCF＝29.2Hz),95.69(t,2JCF＝26.4Hz),49.79,42.57,35.71,29.92.IR(film)3362,2904,2849,1620,1597,1485,1467,1342,1296,1139,1112,1016,993,827,671.HRMS(EI)Calcd forC16H19F2NS3359.0648,found 359.0649.
实施例49
化合物3z的合成：
Figure BDA0002459564230000452
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入4-甲苯硫醇(14.9mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到黄色固体3z(28.8mg,92％)。1H NMR(400MHz,Acetone-d6)δ7.54(s,1H),7.25(d,J＝8.2Hz,2H),7.12–7.04(m,2H),7.04–6.95(m,4H),2.18(s,3H).13C NMR(100MHz,Acetone-d6)δ145.17,139.01,134.23,130.59,130.41,129.63,126.41,118.76,20.91.IR(film)3354,2918,2852,1591,1487,1435,1276,1224,1170,1090,817,800.HRMS(EI)Calcd for C13H12ClNS3312.9820,found 312.9821.
实施例50
化合物3aa的合成：
Figure BDA0002459564230000461
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入2-溴苯硫醇(22.7mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到无色液体3aa(29.2mg,77％)。1H NMR(400MHz,Acetone-d6)δ7.68(s,1H),7.48(dd,J＝13.5,7.9Hz,2H),7.12(dd,J＝14.3,6.6Hz,2H),7.08–7.01(m,4H).13C NMR(100MHz,Acetone-d6)δ145.09,138.00,133.81,129.87,129.53,129.25,129.14,126.84,122.17,118.90.IR(film)3414,2953,2922,2851,1651,1462,1377,1080,746,543.HRMS(EI)Calcd for C12H9BrClNS3376.8769,found376.8772.
实施例51
化合物3ab的合成：
Figure BDA0002459564230000462
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入2-巯基嘧啶(13.4mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3ab(19.9mg,66％)。1HNMR(300MHz,Acetone-d6)δ8.58(d,J＝4.8Hz,2H),7.72(s,1H),7.26(t,J＝4.8Hz,1H),7.22–7.13(m,4H).13C NMR(100MHz,Acetone-d6)δ169.78,157.97,144.86,128.78,125.61,118.58,118.11.IR(film)2976,1593,1553,1487,1377,1169,1092,903,824,770742,629.HRMS(EI)Calcd for C10H8ClN3S3300.9569,found 300.9572.
实施例52
化合物3ac的合成：
Figure BDA0002459564230000471
向反应管中加入苯胺(9.3mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入正十二硫醇(24.2mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到亮黄色液体3ac(29.0mg,81％)。1H NMR(300MHz,CD3CN)δ7.30(dd,J＝8.5,7.4Hz,2H),7.16(dd,J＝8.6,1.0Hz,2H),6.96(t,J＝7.3Hz,1H),6.59(s,1H),2.81–2.62(m,2H),1.63(dt,J＝14.7,7.2Hz,2H),1.30(s,18H),0.91(t,J＝6.7Hz,3H).13C NMR(100MHz,CD3CN)δ146.11,129.80,122.05,117.20,40.03,32.26,29.96,29.87,29.77,29.69,29.36,29.35,28.64,23.01,14.01.IR(film)3352,2976,2924,2852,1598,1492,1468,1282,1229,1093,1051,885,750,690.HRMS(EI)Calcdfor C18H31NS3357.1619,found 357.1622.
实施例53
化合物3ad的合成：
Figure BDA0002459564230000472
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入N-(邻苯二甲酰)半胱氨酸(33.5mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到亮黄色液体3ad(37.5mg,80％)。1H NMR(400MHz,Acetone-d6)δ7.78(s,4H),7.58(s,1H),7.11(d,J＝8.8Hz,2H),7.06–7.02(m,2H),5.05(dd,J＝10.2,5.1Hz,1H),4.05(q,J＝7.1Hz,2H),3.51(qd,J＝14.5,7.6Hz,2H),1.05(t,J＝7.1Hz,3H).13C NMR(100MHz,Acetone-d6)δ167.57,167.15,144.40,134.86,131.59,129.05,125.72,123.51,118.04,61.94,51.36,38.07,13.49.IR(film)3329,2980,1776,1745,1715,1489,1387,1232,1094,1022,875,824,721.HRMS(EI)Calcd for C19H17ClN2O4S3468.0039,found 468.0037.
实施例54
化合物3ae的合成：
Figure BDA0002459564230000481
向反应管中加入4-氯苯胺(12.7mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入呋喃基-2-甲硫醇(13.7mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到无色液体3ae(20.3mg,67％)。1HNMR(400MHz,Acetone-d6)δ7.47(s,1H),7.39(dd,J＝1.8,0.8Hz,1H),7.20–7.14(m,2H),7.11–7.05(m,2H),6.23(dd,J＝3.2,1.9Hz,1H),6.10(dd,J＝3.2,0.6Hz,1H),3.92(s,2H).13C NMR(100MHz,Acetone-d6)δ149.74,144.78,142.97,129.03,125.58,118.00,110.64,109.28,35.92.IR(film)3354,1593,1487,1436,1274,1228,1172,1149,1091,1010,935,822738.HRMS(EI)Calcd for C11H10ClNOS3302.9613,found 302.9616.
实施例55
化合物3af的合成：
Figure BDA0002459564230000482
向反应管中加入磺胺二甲嘧啶(27.8mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌24小时，然后加入1-金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3af(37.6mg,74％)。1H NMR(400MHz,Acetone-d6)δ7.93(d,J＝8.7Hz,3H),7.21(d,J＝8.9Hz,2H),6.60(s,1H),2.16(s,6H),1.87(s,3H),1.76–1.66(m,6H),1.96(s,1H),1.49(dd,J＝28.1,11.9Hz,6H).13C NMR(100MHz,Acetone-d6)δ168.04,156.77,150.03,132.02,130.59,115.34,114.33,49.77,42.57,35.68,29.90,22.77.IR(film)3327,3267,1595,1433,1383,1153,1092,1053,883,582.HRMS(ESI)Calcd for C22H29N4O2S4(M+H+)509.1168,found509.1168.
实施例56
化合物3ag的合成：
Figure BDA0002459564230000491
向反应管中加入(R)-4-(2-氨基苯基)-1-(苯磺酰基)-2,3-二氢-1H-吡咯-2-羧酸叔丁酯(40.0mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.005mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌12小时，然后加入十二硫醇(24.2mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到棕色固体3ag(27.9mg,42％)。1HNMR(400MHz,Acetone-d6)δ7.83–7.79(m,2H),7.63(t,J＝7.3Hz,1H),7.57(t,J＝7.4Hz,2H),7.32(t,J＝6.3Hz,1H),7.14(t,J＝7.7Hz,1H),6.98(d,J＝7.6Hz,1H),6.82(t,J＝7.6Hz,1H),6.63–6.56(m,1H),6.44(s,1H),4.23(dd,J＝10.9,7.3Hz,1H),3.05(ddd,J＝16.0,11.0,1.9Hz,1H),2.78(ddd,J＝16.2,7.3,1.7Hz,1H),2.55–2.50(m,2H),1.50–1.41(m,2H),1.39(s,9H),1.15(s,18H),0.75(t,J＝6.6Hz,3H).13C NMR(100MHz,Acetone-d6)δ169.52,142.97,136.90,133.56,129.52,129.08,128.41,128.03,128.00,127.64,124.00,122.17,120.50,118.58,81.54,61.37,39.36,37.75,31.77,29.50,29.43,28.67,28.18,27.26,22.47,13.53.IR(film)2953,2924,2852,1736,1487,1446,1367,1309,1171,1092,752,721,690,605,572.HRMS(ESI)Calcd for C33H49N2O4S4(M+H+)665.2570,found 665.2551.
实施例57
化合物3ah的合成：
Figure BDA0002459564230000501
向反应管中加入甲基(叔丁氧羰基)-L-异亮氨酸-D-赖氨酸(37.3mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(1.0mg，0.002mmol，2mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入十二硫醇(24.2mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3ah(24.2mg,40％)。1H NMR(400MHz,CDCl3)δ6.35(d,J＝7.5Hz,1H),4.98(d,J＝8.3Hz,1H),4.53(td,J＝7.7,5.4Hz,1H),3.93–3.85(m,1H),3.68(s,3H),3.24(t,J＝5.1Hz,1H),2.95(dd,J＝12.5,6.6Hz,2H),2.03(s,3H),1.87–1.76(m,8H),1.72(s,1H),1.67–1.58(m,6H),1.51(dt,J＝14.2,7.2Hz,2H),1.38(s,9H),1.35–1.28(m,2H),1.27–1.17(m,2H),0.89–0.83(m,6H).IR(film)3319,2970,2910,2854,1743,1658,1520,1452,1369,1292,1246,1167,1088,1045,977,877.13C NMR(100MHz,CDCl3)δ172.55,171.39,155.76,79.99,59.33,52.43,51.97,50.27,49.85,42.66,37.13,36.09,32.15,29.87,28.56,28.34,24.79,22.51,15.53,11.43.IR(film)3319,2970,2910,2854,1743,1658,1452,1369,1292,1246,1209,1087,1045,877.HRMS(ESI)Calcd for C28H50N3O5S3(M+H+)604.2907,found 604.2902.
实施例58
化合物3aj的合成：
Figure BDA0002459564230000502
向反应管中加入色胺(16.0mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(0.5mg，0.001mmol，1mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入金刚烷硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到无色液体3aj(20.3mg,52％)。1H NMR(400MHz,Acetone-d6)δ9.89(s,1H),7.48(d,J＝7.8Hz,1H),7.24(d,J＝8.0Hz,1H),7.05(d,J＝1.8Hz,1H),6.96(t,J＝7.5Hz,1H),6.89(t,J＝7.4Hz,1H),4.42(s,1H),3.25(td,J＝7.3,5.5Hz,2H),2.94(t,J＝7.4Hz,2H),1.94–1.88(m,3H),1.73(d,J＝2.3Hz,6H),1.61–1.48(m,6H).13C NMR(100MHz,Acetone-d6)δ136.85,127.67,122.59,121.24,118.56,118.37,112.37,111.30,51.85,49.11,42.62,35.84,29.87,25.18.IR(film)3410,2903,2849,1456,1340,1298,1078,1039,740,582.HRMS(ESI)Calcd for C20H27N2S3(M+H+)391.1331,found 391.1328.
实施例59
化合物3ak的合成：
Figure BDA0002459564230000511
向反应管中加入磺胺醋酰(21.4mg，0.1mmol，1.0equiv)，3ak(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.001mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌24小时，然后加入十二硫醇(24.2mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3ak(33.0mg,69％)。1HNMR(400MHz,CDCl3)δ8.84(s,1H),7.87(d,J＝8.8Hz,2H),7.14(d,J＝8.8Hz,2H),5.99(s,1H),2.75(t,J＝7.3Hz,2H),2.00(s,3H),1.62(dt,J＝14.8,7.3Hz,2H),1.32–1.25(m,2H),1.19(s,16H),0.81(t,J＝6.8Hz,3H).13C NMR(100MHz,Acetone-d6)δ173.21,162.01,155.40,137.51,135.80,120.54,119.51,71.95,44.71,36.97,34.70,34.69,34.63,34.51,34.13,33.99,33.31,27.97,27.67,18.73.IR(film)3244,2922,2850,1697,1589,1450,1232,1151,910,736,680.HRMS(ESI)Calcd for C20H35N2O3S4(M+H+)479.1525,found 479.1517.
实施例60
化合物3al的合成：
Figure BDA0002459564230000512
向反应管中加入磺胺异恶唑(25.3mg，0.1mmol，1.0equiv)，3al(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(2.5mg，0.001mmol，5mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌24小时，然后加入1-金刚烷基硫醇(20.1mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3al(31.4mg,65％)。1HNMR(400MHz,Acetone-d6)δ9.72(s,1H),8.01(s,1H),7.84–7.55(m,2H),7.37–7.10(m,2H),6.10(s,1H),2.19(s,3H),1.93–1.90(m,3H),1.73(s,6H),1.54(dd,J＝25.4,12.1Hz,6H).13C NMR(100MHz,Acetone-d6)δ170.38,157.91,150.42,131.37,128.88,128.77,116.09,95.34,49.85,42.55,35.69,29.89,11.55.IR(film)3053,2949,1591,1275,1157,1072,1008,862,742,702,586.HRMS(ESI)Calcd for C20H26N3O3S4(M+H+)484.0852,found 484.0854.
实施例61
化合物3am的合成：
Figure BDA0002459564230000521
向反应管中加入十八胺(26.9mg，0.1mmol，1.0equiv)，5(29.0mg，0.105mmol，1.05equiv)，B(C6F5)3(1.0mg，0.002mmol，2mol％)和重蒸的1,4-二氧六环(0.25mL)，室温搅拌4小时，然后加入十二硫醇(24.2mg,0.12mmol,1.2equiv)和碳酸锂(7.4mg,0.1mmol,1.0equiv)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3am(18.7mg,35％)。1H NMR(400MHz,CDCl3)δ3.15(s,1H),2.95(dd,J＝11.5,6.6Hz,2H),2.78(t,J＝7.3Hz,2H),1.64(dt,J＝14.8,7.3Hz,2H),1.53–1.44(m,2H),1.37–1.29(m,4H),1.19(s,44H),0.81(t,J＝6.6Hz,6H).13C NMR(100MHz,CDCl3)δ50.94,39.24,31.94,29.72,29.68,29.65,29.62,29.58,29.53,29.41,29.38,29.37,29.34,29.22,29.11,28.54,26.91,22.71,14.13.IR(film)2953,2916,2847,1462,1402,1371,1296,1242,1061,1022,723,633.HRMS(EI)Calcdfor C30H63NS3533.4123,found 533.4133.
实施例62
化合物3an的合成：
Figure BDA0002459564230000531
向反应管中加入H-Ala-Phe-Lys-OMe(75.6mg,0.2mmol,1.0equiv)，5(55.2mg,0.2mmol,1.0equiv)和二氯甲烷(20mL)，然后加入B(C6F5)3(5.1mg，0.01mmol，5mol％)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3an(22.0mg,25％)。1H NMR(400MHz,CD3OD)δ7.26(d,J＝4.4Hz,4H),7.22–7.16(m,1H),4.73(dd,J＝9.2,6.4Hz,1H),4.52(dd,J＝7.0,3.9Hz,1H),3.94(q,J＝6.9Hz,1H),3.70(s,3H),3.17(dd,J＝14.0,6.4Hz,1H),2.98(ddd,J＝13.6,9.4,6.3Hz,2H),2.80(dt,J＝13.6,4.5Hz,1H),1.88–1.70(m,2H),1.53(ddd,J＝14.1,10.8,5.7Hz,2H),1.31–1.26(m,6H),1.11(d,J＝6.9Hz,3H).13C NMR(100MHz,CD3OD)δ175.95,171.99,170.90,137.21,128.88,128.04,126.28,58.37,53.62,53.29,51.66,51.41,34.74,30.56,28.92,21.33,18.51.IR(film)3325,2976,2916,1732,1649,1528,1452,1383,1290,1184,1091,1051,885,808,740.HRMS(ESI)Calcd for C19H29N4O4S2(M+H+)441.1625,found 441.1622.
实施例63
化合物3ao的合成：
Figure BDA0002459564230000532
向反应管中加入H-Ala-Phe-Trp-Lys-OMe(112.9mg,0.2mmol,1.0equiv)，5(55.2mg,0.2mmol,1.0equiv)和二氯甲烷(20mL)，然后加入B(C6F5)3(5.1mg，0.01mmol，5mol％)，室温搅拌8小时，除去溶剂，柱层析得到白色固体3ao(28.8mg,23％)。1HNMR(400MHz,CD3OD)δ7.57(t,J＝7.9Hz,2H),7.39(td,J＝7.6,1.3Hz,1H),7.33(t,J＝7.4Hz,2H),7.29(dd,J＝11.5,4.8Hz,2H),7.25–7.19(m,3H),7.13–7.10(m,2H),7.09(dd,J＝7.9,0.8Hz,1H),7.01(t,J＝7.5Hz,1H),6.96(s,1H),4.64(t,J＝6.7Hz,1H),4.52–4.45(m,2H),4.30(s,2H),3.65(dd,J＝9.4,4.5Hz,1H),3.62(s,3H),3.36(dd,J＝14.4,6.6Hz,1H),3.20(dd,J＝14.5,7.0Hz,1H),3.12(dd,J＝14.2,4.4Hz,1H),2.84(dd,J＝14.1,9.9Hz,1H),2.76–2.64(m,1H),1.78(ddd,J＝11.1,7.9,3.9Hz,1H),1.65–1.54(m,1H),1.51–1.40(m,2H),1.29(s,2H),1.00(d,J＝7.0Hz,3H).13C NMR(100MHz,CD3OD)δ176.54,172.38,172.09,171.79,139.22,138.83,136.63,129.22,128.93,128.35,127.43,126.67,123.76,121.11,118.49,118.32,111.02,109.09,61.41,55.32,54.41,51.37,51.30,50.01,36.77,30.10,27.00,26.44,22.48,18.09.IR(film)3373,2978,2887,1689,1554,1390,1333,1092,1051,883,795,739.HRMS(ESI)Calcd for C30H39N6O5S2(M+H+)627.2418,found 627.2420.
实施例64
化合物4a的合成：
Figure BDA0002459564230000541
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加金刚烷硫醇(16.8mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入2-巯基嘧啶(12.3mg,0.11mmol,1.1equiv)，B(C6F5)3(0.5mg,0.001mmol,1mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到白色固体4a(23.9mg,70％)。1H NMR(400MHz,CDCl3)δ8.60(d,J＝4.8Hz,2H),7.07(t,J＝4.8Hz,1H),2.04(s,3H),1.91–1.81(m,6H),1.68–1.57(m,6H).13CNMR(100MHz,CDCl3)δ170.35,158.00,118.29,51.06,42.79,36.00,29.95.IR(film)2904,2848,1556,1377,1296,1167,769,742.HRMS(EI)Calcd for C14H18N2S4342.0353,found342.0357.
实施例65
化合物4b的合成：
Figure BDA0002459564230000542
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加金刚烷硫醇(16.8mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入2-吡嗪基乙硫醇(15.4mg,0.11mmol,1.1equiv)，B(C6F5)3(0.5mg,0.001mmol,1mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到无色液体4b(18.5mg,50％)。1H NMR(400MHz,CDCl3)δ8.46(s,2H),8.37(s,1H),3.39–3.18(m,4H),2.04(s,3H),1.85(s,6H),1.68–1.56(m,6H).13CNMR(100MHz,CDCl3)δ155.02,145.09,144.27,142.76,51.13,42.77,37.70,36.02,34.69,29.94.IR(film)2972,1468,1377,1340,1097,1055,887,622.HRMS(ESI)Calcd forC16H23N2S4(M+H+)371.0739,found 371.0734.
实施例66
化合物4c的合成：
Figure BDA0002459564230000551
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加叔丁基硫醇(9.0mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入2-巯基嘧啶(12.3mg,0.11mmol,1.1equiv)，B(C6F5)3(0.5mg,0.001mmol,1mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到白色固体4c(17.2mg,65％)。1H NMR(400MHz,CDCl3)δ8.59(d,J＝4.8Hz,2H),7.07(t,J＝4.8Hz,1H),1.35(s,9H).13C NMR(100MHz,CDCl3)δ170.27,157.99,118.31,49.39,30.22.IR(film)2982,1641,1070,899,796,680,565.HRMS(ESI)Calcd forC8H13N2S4(M+H+)264.9956,found 264.9954.
实施例67
化合物4d的合成：
Figure BDA0002459564230000552
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加乙酰青霉胺甲酯(20.5mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入乙酰半胱氨酸甲酯(19.5mg,0.11mmol,1.1equiv)，B(C6F5)3(1.0mg,0.001mmol,2mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到白色固体4d(23.5mg,53％)。1H NMR(400MHz,CDCl3)δ6.52(dd,J＝15.2,8.0Hz,2H),4.88(dd,J＝12.4,5.3Hz,1H),4.73(d,J＝8.7Hz,1H),3.72(s,3H),3.69(s,3H),3.40(ddd,J＝42.6,14.3,5.3Hz,2H),2.01(s,3H),2.01(s,3H),1.42(s,3H),1.38(s,3H).13C NMR(100MHz,CDCl3)δ170.67,170.44,170.16,170.13,58.90,53.64,52.89,52.38,52.00,40.98,26.30,24.99,23.14,23.07.IR(film)3294,2949,1740,1645,1529,1435,1371,1215,1126,1032,982,659,584.HRMS(ESI)Calcd for C14H25N2O6S4(M+H+)445.0590,found 445.0595.
实施例68
化合物4e的合成：
Figure BDA0002459564230000561
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加金刚烷硫醇(16.8mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入乙酰半胱氨酸甲酯(19.5mg,0.11mmol,1.1equiv)，B(C6F5)3(1.0mg,0.001mmol,2mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到白色固体4e(21.2mg,52％)。1H NMR(400MHz,CDCl3)δ6.33(d,J＝7.1Hz,1H),4.89(dt,J＝7.6,5.0Hz,1H),3.72(s,3H),3.45(dd,J＝14.2,4.6Hz,1H),3.37(dd,J＝14.2,5.4Hz,1H),2.05(s,3H),2.00(s,3H),1.85(d,J＝2.3Hz,6H),1.70–1.58(m,7H).13C NMR(100MHz,CDCl3)δ170.73,169.83,52.84,51.78,51.25,42.75,41.32,35.98,29.94,23.18.IR(film)3279,2904,1745,1657,1537,1450,1371,1296,1171,1038,976,684,588.HRMS(EI)Calcd for C16H25NO3S4407.0717,found 407.0713.
实施例69
化合物4f的合成：
Figure BDA0002459564230000562
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加金刚烷硫醇(16.8mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入三肽(51.8mg,0.11mmol,1.1equiv)，B(C6F5)3(1.0mg,0.001mmol,2mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到白色固体4f(28.2mg,40％)。1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,2H),7.53(t,J＝6.6Hz,2H),7.33(t,J＝7.5Hz,2H),7.24(t,J＝7.2Hz,2H),7.07(s,1H),6.89(s,1H),5.83(dd,J＝33.6,5.8Hz,1H),4.50(s,1H),4.37(d,J＝6.0Hz,2H),4.16(t,J＝6.7Hz,1H),4.06–3.85(m,4H),3.62(s,3H),3.29(dd,J＝33.9,6.6Hz,2H),2.02(s,3H),1.84(s,6H),1.61(s,6H).13C NMR(100MHz,CDCl3)δ170.58,170.40,170.09,168.79,143.65,141.33,127.82,127.13,125.11,120.05,67.51,52.38,51.38,47.15,43.19,42.85,42.69,42.54,41.12,36.00,29.87.IR(film)3572,2972,2881,1456,1419,1379,1327,1275,1088,1045,879.HRMS(ESI)Calcd for C33H40N3O6S4(M+H+)702.1794,found702.1793.
实施例70
化合物4g的合成：
Figure BDA0002459564230000571
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加金刚烷硫醇(16.8mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入硫苷(40.0mg,0.11mmol,1.1equiv)，B(C6F5)3(1.0mg,0.001mmol,2mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到白色固体4g(33.8mg,57％)。1H NMR(400MHz,CDCl3)δ5.27–5.04(m,3H),4.73(d,J＝9.5Hz,1H),4.23(dd,J＝12.4,4.7Hz,1H),4.13(dd,J＝12.4,2.2Hz,1H),3.73(ddd,J＝9.9,4.5,2.3Hz,1H),2.06(s,3H),2.03(s,3H),1.98(s,3H),1.97(s,3H),1.95(s,3H),1.85(d,J＝2.3Hz,6H),1.69–1.59(m,6H).13C NMR(100MHz,CDCl3)δ170.64,170.17,169.32,169.19,88.22,76.29,73.89,69.70,68.05,61.99,51.14,42.75,35.99,29.93,20.79,20.77,20.68,20.67,20.57,20.56.IR(film)2906,2851,1747,1452,1365,1298,1211,1035,912,737,684,598.HRMS(ESI)Calcd for C24H34O9S4Na(M+Na+)617.0978,found 617.0970.
实施例71
化合物4h的合成：
Figure BDA0002459564230000581
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加3-三乙氧基硅丙硫醇(23.8mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入2-巯基乙醇(8.6mg,0.11mmol,1.1equiv)，B(C6F5)3(0.5mg,0.001mmol,1mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到无色液体4h(16.2mg,43％)。1HNMR(400MHz,CDCl3)δ3.91(t,J＝5.8Hz,2H),3.76(q,J＝7.0Hz,6H),3.05(t,J＝5.8Hz,2H),2.92(t,J＝7.2Hz,2H),1.84(dt,J＝15.6,7.7Hz,2H),1.17(t,J＝7.0Hz,9H),0.73–0.66(m,2H).13C NMR(100MHz,CDCl3)δ60.17,58.50,42.23,41.96,22.67,18.32,9.60.IR(film)3379,2980,1637,1089,1047,879,682,669.IR(film)3523,2980,1637,1089,1047,879,721,682,669.HRMS(ESI)Calcd for C11H26O4S4SiNa(M+H+)401.0375,found 401.0373.
实施例72
化合物4i的合成：
Figure BDA0002459564230000582
-78℃下，向6(24.0mg,0.12mmol,1.2equiv)的甲醇(1mL)溶液中滴加正丙硫醇(7.6mg,0.1mmol)的甲醇(1mL)溶液，反应0.5小时，除去甲醇，加入烯丙基硫醇(8.1mg,0.11mmol,1.1equiv)，B(C6F5)3(1.0mg,0.001mmol,2mol％)和二氯甲烷(1mL)，反应四小时，除去溶剂，柱层析得到白色固体4i(10.2mg,48％)。1H NMR(400MHz,CDCl3)δ5.83(ddt,J＝17.2,9.9,7.3Hz,1H),5.18(dd,J＝21.3,5.5Hz,2H),3.52(d,J＝7.3Hz,2H),2.86(t,J＝7.2Hz,2H),1.80–1.66(m,2H),0.96(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ132.57,119.50,42.11,41.41,22.38,13.10.IR(film)3082,2961,2928,2871,1634,1454,1377,1288,1074,1034,984,918,858,781,719,578.HRMS(EI)Calcd for C6H12S4211.9822,found211.9824.
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。

Claims (19)

1.一种非对称多硫类化合物，其特征在于，其结构式如式(1)，(2)，(3)，(4)所示：
Figure FDA0002459564220000011
其中，Ar1选自苯基，取代苯基，杂环；
RX选自烷胺基，芳胺基，氨基酸酯，磺胺类药物，烷巯基，芳巯基，苄硫醇；
Ar2选自芳基，维生素E，杂环芳基；
R1选自烷基，氨基酸衍生物，磺胺类药物，芳基；
R2选自烷基，青霉胺；
R3选自烷基，芳基，硫苷，氨基酸，多肽。
2.如权利要求1所述的非对称多硫类化合物，其特征在于，所述Ar1选自苯基，氯取代、溴取代、氟取代、乙酰基取代、乙氧酰基取代、3,4-二亚甲基取代苯基，雌酚酮，苯丙氨酸酯，噻吩；RX选自甲基、叔丁基取代苯胺基，1-甲基苄胺基，氨基酸酯，磺胺类药物，直链胺基，2-巯基嘧啶，甲氧基取代苄硫醇，2-羟基乙基、金刚烷基、叔丁基、正十二烷基、1-三乙氧硅基正丙基；Ar2选自1，3，5-三甲氧基苯，维生素E，甲基取代、甲氧基取代、氯取代、甲氧基甲基吲哚、吡咯；R1选自氰基、溴、氯、乙烯基、苯基、甲基、叔丁基取代苯基，氨基酸衍生物，磺胺类药物，十八烷基；R2选自金刚烷、叔丁基、正丙基、1-三乙氧硅基正丙基硫醇，青霉胺；R3选自2-巯基嘧啶，吡嗪-2-乙基、烯丙基硫醇，硫苷，半胱氨酸，多肽。
3.如权利要求1或2所述的非对称多硫类化合物，其特征在于，所述不对称二硫类化合物包括：
Figure FDA0002459564220000012
Figure FDA0002459564220000021
Figure FDA0002459564220000031
Figure FDA0002459564220000041
Figure FDA0002459564220000051
Figure FDA0002459564220000061
4.一种非对称多硫类化合物的合成方法，其特征在于，以式(5)所示的二硫试剂、式(7)所示的芳基硼酸和式(8)所示的有机胺或硫醇为反应原料，在催化剂、配体的作用下，在有机溶剂中，反应得到如式(1)所示非对称多硫类化合物，所述反应过程如反应式(a)所示；
Figure FDA0002459564220000062
其中，Ar1选自苯基，氯取代、溴取代、氟取代、乙酰基取代、乙氧酰基取代、3,4-二亚甲基取代苯基，雌酚酮，苯丙氨酸酯，噻吩；
RX选自甲基、叔丁基取代苯胺基，1-甲基苄胺基，氨基酸酯，磺胺类药物，直链胺基，2-巯基嘧啶，甲氧基取代苄硫醇，2-羟基乙基、金刚烷基、叔丁基、正十二烷基、1-三乙氧硅基正丙基。
5.一种非对称多硫类化合物的合成方法，其特征在于，以式(5)所示的二硫试剂，式(7)所示的芳基硼酸和式(9)所示的芳烃反应原料，在催化剂、配体的作用下，在有机溶剂中，反应得到如式(2)所示非对称二硫类化合物，所述反应过程如反应式(b)所示；
Figure FDA0002459564220000063
其中，Ar1选自苯基，氯取代、溴取代、氟取代、乙酰基取代、乙氧酰基取代、3,4-二亚甲基取代苯基，雌酚酮，苯丙氨酸酯，噻吩；
Ar2选自1，3，5-三甲氧基苯，维生素E，甲基取代、甲氧基取代、氯取代、甲氧基甲基吲哚、吡咯。
6.一种非对称多硫类化合物的合成方法，其特征在于，以式(5)所示的二硫试剂，式(10)所示的有机胺R1NH2，式(8)所示的另一分子有机胺或硫醇RXH为反应原料，在催化剂和碱的作用下，在有机溶剂中，反应得到如式(3)所示非对称多硫类化合物，所述反应过程如反应式(c)所示；
Figure FDA0002459564220000071
其中，R1选自氰基、溴、氯、乙烯基、苯基、甲基、叔丁基取代苯基，氨基酸衍生物，磺胺类药物，十八烷基；
RX选自甲基、叔丁基取代苯胺基，1-甲基苄胺基，氨基酸酯，磺胺类药物，直链胺基，2-巯基嘧啶，甲氧基取代苄硫醇，2-羟基乙基、金刚烷基、叔丁基、正十二烷基、1-三乙氧硅基正丙基。
7.一种非对称多硫类化合物的合成方法，其特征在于，以式(6)所示的二硫试剂，式(11)所示的硫醇R2SH，式(12)所示的另一分子硫醇R3SH为反应原料，在催化剂的作用下，在有机溶剂中，反应得到如式(4)所示非对称多硫类化合物，所述反应过程如反应式(d)所示；
Figure FDA0002459564220000072
其中R2选自金刚烷、叔丁基、正丙基、1-三乙氧硅基正丙基硫醇，青霉胺；
R3选自2-巯基嘧啶，吡嗪-2-乙基、烯丙基硫醇，硫苷，半胱氨酸，多肽。
8.如权利要求4所述的合成方法，其特征在于，所述式(7)所示的芳基硼酸与式(5)所示的二硫试剂的摩尔比例为1.0:2.0-2.0:1.0；所述式(8)所示的有机胺或硫醇RXH与式(5)所示的化合物的摩尔比例为1.0:2.0-2.0:1.0。
9.如权利要求4所述的合成方法，其特征在于，所述催化剂是CuI，CuCl，Cu(MeCN)4BF4，Cu(MeCN)4BF6中的一种或几种；和/或，所述催化剂的摩尔用量为式(5)所示的化合物的5-10mol％；和/或，所述配体是2,2’-联吡啶、4,4’-二甲基-2,2’-联吡啶、1,10-菲咯啉、4,7-二苯基-1,10-菲罗啉中的一种或几种；和/或，所述配体的摩尔用量为式(5)所示的化合物的10-20mol％。
10.如权利要求4所述的合成方法，其特征在于，当添加碱时，所述碱是碳酸锂，碳酸钠，碳酸钾中的一种或几种，所述碱的用量为式(5)所示的二硫试剂的1-2当量；和/或，所述有机溶剂是二氯甲烷，四氢呋喃，甲苯中的一种或几种；和/或，所述反应在0-40℃下进行；和/或，所述反应的时间为10-28小时。
11.如权利要求5所述的合成方法，其特征在于，所述式(7)所示的芳基硼酸与式(5)所示的二硫试剂的摩尔比例为1.0:2.0-2.0:1.0；所述式(9)所示的芳烃与式(5)所示的二硫试剂的摩尔比例为1.0:2.0-2.0:1.0。
12.如权利要求5所述的合成方法，其特征在于，所述催化剂是CuI，CuCl，Cu(MeCN)4BF4，Cu(MeCN)4BF6中的一种或几种；和/或，所述催化剂的摩尔用量为式(5)所示的二硫试剂的10-20mol％；和/或，所述配体是2,2’-联吡啶、4,4’-二甲基-2,2’-联吡啶、1,10-菲咯啉、4,7-二苯基-1,10-菲罗啉中的一种或几种；和/或，所述配体的摩尔用量为式(5)所示的二硫试剂的10mol％-20mol％。
13.如权利要求5所述的合成方法，其特征在于，当添加碱时，所述碱是碳酸锂，碳酸钠，碳酸钾中的一种或几种，所述碱的用量为式(5)所示的二硫试剂的1-2当量；所述有机溶剂是二氯甲烷，四氢呋喃，甲苯中的一种或几种；和/或，所述反应在0-40℃下进行；和/或，所述反应的时间为10-28小时。
14.如权利要求6所述的合成方法，其特征在于，所述式(10)所示的有机胺R1NH2与起始原料式(5)所示的二硫试剂的摩尔比例为1.05-1.0：1.2-1.0；所述式(8)所示的另一分子有机胺或硫醇RXH与起始原料式(5)所示的二硫试剂的摩尔比例为(1.0-1.2):1.0。
15.如权利要求6所述的合成方法，其特征在于，所述催化剂是三五氟苯基硼；和/或，所述催化剂的当量为式(5)所示的二硫试剂的1mol％-5mol％；和/或，所述碱是碳酸锂；和/或，所述碱的当量为式(5)所示的二硫试剂的1-2当量。
16.如权利要求6所述的合成方法，其特征在于，所述有机溶剂是二氯甲烷，四氢呋喃，1,4-二氧六环，丙酮，乙腈中的一种或几种；和/或，所述反应在0-25℃下进行；和/或，所述反应的时间为4-20小时。
17.如权利要求7所述的合成方法，其特征在于，所述式(11)所示的有机硫醇R2SH与式(6)所示的二硫试剂的摩尔比例为1.05-1.0:1.2-1.0；所述式(12)所示的另一分子硫醇R3SH与式(6)所示的二硫试剂的摩尔比例为(1.0-1.2):1.0。
18.如权利要求7所述的合成方法，其特征在于，所述催化剂是三五氟苯基硼；所述催化剂的当量为式(5)所示的二硫试剂的1mol％-5mol％；和/或，所述有机溶剂是二氯甲烷，四氢呋喃，甲醇的一种或几种；和/或，所述反应在-78℃-25℃下进行；和/或，所述反应的时间为1-5。
19.如权利要求1～3之任一项所述的非对称多硫类化合物在作为或制备小分子药物偶联物和多肽物偶联物中的应用。
CN202010315986.7A 2020-04-21 2020-04-21 非对称多硫类化合物及其合成方法和应用 Active CN113527022B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010315986.7A CN113527022B (zh) 2020-04-21 2020-04-21 非对称多硫类化合物及其合成方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010315986.7A CN113527022B (zh) 2020-04-21 2020-04-21 非对称多硫类化合物及其合成方法和应用

Publications (2)

Publication Number Publication Date
CN113527022A true CN113527022A (zh) 2021-10-22
CN113527022B CN113527022B (zh) 2022-12-06

Family

ID=78123776

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010315986.7A Active CN113527022B (zh) 2020-04-21 2020-04-21 非对称多硫类化合物及其合成方法和应用

Country Status (1)

Country Link
CN (1) CN113527022B (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104387303A (zh) * 2014-10-31 2015-03-04 华东师范大学 芳基-芳基、芳基-烷基、烷基-烷基不对称过硫化合物及其合成方法
CN106278965A (zh) * 2016-08-09 2017-01-04 华东师范大学 芳基‑烷基不对称过硫类化合物及其合成方法和应用
CN110117238A (zh) * 2018-02-07 2019-08-13 华东师范大学 过硫醇醚类化合物及其合成方法和应用
CN110117240A (zh) * 2018-02-07 2019-08-13 华东师范大学 二硫胺类化合物及其合成方法和应用
CN110117239A (zh) * 2018-02-07 2019-08-13 华东师范大学 不对称三硫类化合物及其合成方法和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104387303A (zh) * 2014-10-31 2015-03-04 华东师范大学 芳基-芳基、芳基-烷基、烷基-烷基不对称过硫化合物及其合成方法
CN106278965A (zh) * 2016-08-09 2017-01-04 华东师范大学 芳基‑烷基不对称过硫类化合物及其合成方法和应用
CN110117238A (zh) * 2018-02-07 2019-08-13 华东师范大学 过硫醇醚类化合物及其合成方法和应用
CN110117240A (zh) * 2018-02-07 2019-08-13 华东师范大学 二硫胺类化合物及其合成方法和应用
CN110117239A (zh) * 2018-02-07 2019-08-13 华东师范大学 不对称三硫类化合物及其合成方法和应用

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DOAA ALI 等: "Unsymmetrical Organotrisulfide Formation via Low-Temperature Disulfanyl Anion Transfer to an Organothiosulfonate", 《J. ORG. CHEM.》 *
ELOISA HELENA A. ANDRADE 等: "Volatile constituents from Adenocalymma alliaceum Miers and Petiveria alliaceaL.,two medicinal herbs of the Amazon", 《FLAVOUR FRAGR.J》 *
PRAVEEN RAMARAJU 等: "Synthesis and antimicrobial activities of structurally novel S,S-bis(heterosubstituted)disulfides", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
WEIGUO WANG 等: "Cu-Catalyzed Electrophilic Disulfur Transfer: Synthesis of Unsymmetrical Disulfides", 《ORG. LETT.》 *
XIAO XIAO 等: "Polysulfurating reagent design for unsymmetrical polysulfide construction", 《NATURE COMMUNICATIONS》 *

Also Published As

Publication number Publication date
CN113527022B (zh) 2022-12-06

Similar Documents

Publication Publication Date Title
US6362351B2 (en) Catalyst and method for amide formation
CN113527022B (zh) 非对称多硫类化合物及其合成方法和应用
CN111620896B (zh) 8-氨基喹啉衍生物为双齿配体的四配位n,n-螯合二芳基硼酸酯化合物的制备方法
CN116535280A (zh) 一种炔基硫醚类化合物的合成方法
WO2016197580A1 (zh) α-烷基支链取代的α-氨基酸衍生物的合成方法
CN110105337A (zh) 一种喹啉类三芳基胺及其制备方法
CN112479898B (zh) 一种二价锰催化的芳胺邻位烯化反应方法
CN114773136A (zh) 一种合成芳胺的方法
CN110981790B (zh) 一种1,4-二氢吡啶类衍生物及其合成方法
CN113234099B (zh) 一种烷基硼酸酯类化合物的光化学合成方法
CN111377838B (zh) 一种大位阻烷基-烷基砜类化合物及其合成方法和应用
CN114634431A (zh) 一种含硫醚和砜基取代的烯烃类化合物的合成方法
CN114262356A (zh) 一种修饰蛋白质色氨酸残基的方法
CN112480034B (zh) 一种新型硒氰基试剂及其制备方法与应用
CN113845491A (zh) 苯并吩噻嗪衍生物及制备方法
EP1699768A2 (en) Multifunctional amine capture agents
CN110540516A (zh) 一种1-磺酰甲基-3,4-二氢萘的制备方法
CN111116461A (zh) 一种钯催化邻甲苯吡啶酰胺γ-C-(sp3)H硫/硒醚类化合物的合成方法
CN114702417B (zh) 一种偕二氟丙二烯类化合物β位进行亲核取代制备二氟乙烯类硫化物的合成方法
CN111606785B (zh) 一种光介导铜催化制备芳基内炔烃类化合物的方法
CN115448918B (zh) 一种邻菲罗啉类配体及其在铜催化芳基卤代物偶联反应中的应用
CN109796372B (zh) 一种制备多取代烯基脒的方法
CN113527178A (zh) 对称二杂二硫类化合物及其合成方法和应用
Li et al. Odorless, catalyst-free synthesis of diaryl sulfides using K2S as sulfur source
WO2007105622A1 (ja) 複素環式化合物の製造方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant