CN115536573B - Method for synthesizing azabicyclo [3.1.0] hexane-2-ketone compound - Google Patents
Method for synthesizing azabicyclo [3.1.0] hexane-2-ketone compound Download PDFInfo
- Publication number
- CN115536573B CN115536573B CN202211207358.2A CN202211207358A CN115536573B CN 115536573 B CN115536573 B CN 115536573B CN 202211207358 A CN202211207358 A CN 202211207358A CN 115536573 B CN115536573 B CN 115536573B
- Authority
- CN
- China
- Prior art keywords
- azabicyclo
- hexane
- chlorophenyl
- reaction
- vinylcyclopropane
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- -1 vinylcyclopropane carboxamides Chemical class 0.000 claims abstract description 47
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000000376 reactant Substances 0.000 claims abstract description 8
- 238000001308 synthesis method Methods 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 3
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical class CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 claims description 24
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 12
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- ZQVKTHRQIXSMGY-UHFFFAOYSA-M 4-ethylbenzoate Chemical compound CCC1=CC=C(C([O-])=O)C=C1 ZQVKTHRQIXSMGY-UHFFFAOYSA-M 0.000 claims 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 230000009435 amidation Effects 0.000 abstract description 3
- 238000007112 amidation reaction Methods 0.000 abstract description 3
- 238000012216 screening Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000003960 organic solvent Substances 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 238000000605 extraction Methods 0.000 description 13
- 238000002156 mixing Methods 0.000 description 13
- 238000007865 diluting Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- RMXLHIUHKIVPAB-OWOJBTEDSA-N (e)-1,4-dibromobut-2-ene Chemical compound BrC\C=C\CBr RMXLHIUHKIVPAB-OWOJBTEDSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 238000005888 cyclopropanation reaction Methods 0.000 description 2
- 150000001942 cyclopropanes Chemical class 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- CZCUWZUDNNQIGJ-UHFFFAOYSA-N 2-benzylsulfonyl-n-phenylacetamide Chemical compound C=1C=CC=CC=1NC(=O)CS(=O)(=O)CC1=CC=CC=C1 CZCUWZUDNNQIGJ-UHFFFAOYSA-N 0.000 description 1
- ISGZCVYHHCGKCK-UHFFFAOYSA-N 2-ethenylcyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C=C ISGZCVYHHCGKCK-UHFFFAOYSA-N 0.000 description 1
- HGWUUOXXAIISDB-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2CC21 HGWUUOXXAIISDB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 125000005610 enamide group Chemical group 0.000 description 1
- 238000005837 enolization reaction Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- WWIYGBWRUXQDND-UHFFFAOYSA-N methyl 2-(4-chlorophenyl)acetate Chemical compound COC(=O)CC1=CC=C(Cl)C=C1 WWIYGBWRUXQDND-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- SEEYREPSKCQBBF-UHFFFAOYSA-N n-methylmaleimide Chemical compound CN1C(=O)C=CC1=O SEEYREPSKCQBBF-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000006265 spirocyclization reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07D209/52—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 condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a synthetic azabicyclo [3.1.0]]Method for preparing hexane-2-ketone compound, wherein the reactant is 2-vinyl cyclopropane-1-formamide compound, and the reaction condition is that O is 2 In DMF solvent with Pd (PPh under atmospheric and alkaline conditions 3 ) 2 Cl 2 As a catalyst, 3-azabicyclo [3.1.0] is prepared in one step]Hexane-2-onesA compound. The invention adopts the structure to synthesize the azabicyclo [3.1.0]]Process for obtaining conformationally constrained azabicyclo [3.1.0] s by intramolecular amidation of palladium-catalyzed vinylcyclopropane carboxamides]The hexane-2-ketone compound further enriches the synthesis methods of the compound, and provides more candidate methods for industrial screening.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing an azabicyclo [3.1.0] hexane-2-ketone compound.
Background
Azabicyclo [3.1.0] hexane-2-ones are useful organic synthons, often for the selective functionalization of a variety of bioactive molecules, and further for the post-modification of drug candidates in pharmaceutical chemistry. There are many reports of synthesis methods of azabicyclo [3.1.0] hexane-2-one compounds, and from the standpoint of synthesis strategies, these methods can be classified into the following three categories: the first is the metal-mediated alkene cyclopropanation domino reaction to build azabicyclo [3.1.0] hexane-2-ones. Such as divergent C-H insertion-cyclization cascade of literature H, V.Adc. k, E.Chatzopoulou, P.W.Davies.N-allylalkynylamide, chemistry, international editions 2015,54, 15525-15529, using strategies for in situ formation of metal carbene species in the presence of Pd, au, rh, co, ni and Ru salt catalysts to form azabicyclo [3.1.0] hexane-2-ones; the conversion of nitrobenzene from benzofuran to N-allylalkynamide catalyzed by V.Y.Kukushkin, A.Y.Dubovtsev. gold is described in N.V.Shcherbakov, D.V.Dar' in: synthesis of 3-azabicyclo [3.1.0] hexane [ J ] org.chem.2021,86,12964-12972 is prepared by cyclopropanation intermediate of gold-alpha-iminocarbene with gold as catalyst and benzofuran and N-allylamide as substrate to obtain azabicyclo [3.1.0] hexane-2-ketone.
The second is to build azabicyclo [3.1.0] hexane-2-ones by derivatization of substituted cyclopropanes. For example, copper-catalyzed (2+1) cyclization of acetophenone with maleimide in document S.Manna, A.P.Antonchick.: the direct synthesis of cyclopropane, chemistry, international edition 2015,54, 14845-14848, under the condition of metallic copper as a catalyst, uses N-methyl maleimide and acetophenone as substrates, and leads ligand exchange to generate a cyclic intermediate through keto enolization so as to directly generate cyclopropane derivatives, namely azabicyclo [3.1.0] hexane-2-ketone compounds.
The third class is the construction of azabicyclo [3.1.0] hexane-2-ones by base-induced intramolecular spiro cyclization of alkylated subunit precursors, such as the five-membered lactone prodrugs of CBI-based analogs of the literature M.Uematsu, D.M.Brody, D.L.Boger. bicubicin, tetrahedron lett.2015,56,3101-3104.
In summary, although there are a number of literature reports on the synthesis of azabicyclo [3.1.0] hexane-2-ones, it remains a challenge to carefully design and adjust the rigid structure or steric hindrance of the substrate to achieve synthesis of structurally multifunctional enamides, achieving direct C-H bond activated amidation of olefins.
Disclosure of Invention
The invention aims to provide a method for synthesizing an azabicyclo [3.1.0] hexane-2-ketone compound, which obtains the conformational limited azabicyclo [3.1.0] hexane-2-ketone compound through the intramolecular amidation of vinyl cyclopropane formamide catalyzed by a palladium catalyst, further enriches the synthesis method of the compound, and provides more candidate methods for industrial screening.
To achieve the above object, the present invention provides a synthetic azabicyclo [3.1.0]Method for preparing hexane-2-ketone compound, wherein the reactant is 2-vinyl cyclopropane-1-formamide compound, and the reaction condition is that O is 2 In DMF solvent with Pd (PPh under atmospheric and alkaline conditions 3 ) 2 Cl 2 As a catalyst, 3-azabicyclo [3.1.0] is prepared in one step]Hexane-2-one compounds;
the reaction equation in the synthesis method is as follows:
wherein R is 1 One selected from 4-chlorophenyl, 3-methoxyphenyl, phenyl, 3-chlorophenyl, 4-bromophenyl and tosyl;
R 2 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, phenyl, ethyl 4-benzoate and methoxy.
Preferably, the alkaline conditions are anhydrous K 2 CO 3 Alkaline conditions are provided.
Preferably, the reaction temperature is 40 to 60 ℃.
More preferably, the reaction temperature is 50 ℃.
Preferably, the synthetic route of the reactant 2-vinylcyclopropane-1-carboxamide compound is as follows:
wherein R is 1 One selected from 4-chlorophenyl, 3-methoxyphenyl, phenyl, 3-chlorophenyl and 4-bromophenyl;
R 2 one selected from 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, phenyl and ethyl 4-benzoate.
Preferably, the synthetic route of the reactant 2-vinylcyclopropane-1-carboxamide compound is as follows:
preferably, the synthetic route of the reactant 2-vinylcyclopropane-1-carboxamide compound is as follows:
the invention has the beneficial effects that:
(1) 2-vinylcyclopropane-1-carboxamide in Pd (PPh 3 ) 2 Under the catalysis of Cl, the catalyst is coordinated with C=C bond and amide to form palladium ring, and then the palladium ring is reduced and eliminated to finally form azabicyclo [3.1.0]Hexane-2-one compounds. The reaction process is simple to operate, the functional group compatibility is good, and the palladium catalyst is cheap and easy to obtain.
(2) The reaction step only needs one step, the experimental steps are few, the technical difficulty is low, the operation is easy, and Pd (PPh) used in the reaction 3 ) 2 Cl 2 Is a cheap and easily available chemical product, and has easily available raw materials and low cost;
(3) The reaction can achieve good catalytic effect, the reaction process is simple, the process of using multi-step reaction is avoided, and the defects of complex operation and poor functional group compatibility are avoided.
The technical scheme of the invention is further described in detail through examples.
Detailed Description
The present invention will be further described with reference to examples in which various chemicals and reagents are commercially available unless otherwise specified.
Example 1
Preparation of reactant 1- (4-chlorophenyl) -N- (p-tolyl) -2-vinylcyclopropane-1-carboxamide
Step (1): naH (4.0 g,2.0 equiv) was charged to a baked two-necked flask, and N was replaced 2 Three times, dry THF (120 mL) was added to the system, the system was cooled to 0 ℃, methyl p-chlorophenylacetate (9.2 g,1.0 equiv) was slowly added to the system, the system was returned to room temperature and stirred for 10 minutes before cooling back to 0 ℃, (E) -1, 4-dibromo-2-butene (12.8 g,1.2 equiv) was added dropwise to the system and the system was moved to a 35 ℃ sand bath for reaction, the course of which was monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, adding saturated ammonium chloride solution into the system, extracting with ethyl acetate, separating and combining organic phases; dried over anhydrous sodium sulfate, the organic solvent was removed by depressurization, and the sample was stirred on silica gel and passed through a column using petroleum ether and ethyl acetate as the eluent to give methyl 1- (4-chlorophenyl) -2-vinylcyclopropane-1-carboxylate (8.0 g, 67%).
Step (2): to a 100mL round bottom flask was added methyl 1- (4-chlorophenyl) -2-vinylcyclopropane-1-carboxylate (11 mmol,1.0 equiv), KOH (3.1 g,5.0 equiv) and absolute ethanol (30 mL), and the mixture was heated to reflux. After the reaction is completed, adding water and methylene dichloride into the system after removing ethanol under reduced pressure, discarding an organic phase, and reserving a water phase; the pH of the aqueous phase was adjusted to 3-1, extracted with methylene chloride, the organic phases were combined, and the organic solvent was removed under reduced pressure to give the title compound 1- (4-chlorophenyl) -2-vinylcyclopropane-1-carboxylic acid (2.3 g, 93%).
Step (3): 1- (4-chlorophenyl) -2-vinylcyclopropane-1-carboxylic acid (10 mmol,1.0 equiv.) is added to a 100mL round bottom flask, thionyl chloride (1.8 g,1.5 equiv.) and dichloromethane (30 mL) are stirred at room temperature for 5-10 minutes, the system is cooled to 0deg.C, triethylamine is added dropwise to the system until no white smoke is formed, p-toluidine (1.1 g,1.0 equiv.) is added, the reaction is resumed to room temperature and the reaction process is monitored by TLC. After the reaction was completed, the organic solvent was removed under reduced pressure, and silica gel was stirred, and 1- (4-chlorophenyl) -N- (p-tolyl) -2-vinylcyclopropane-1-carboxamide (2.9 g, 94%) was obtained by passing through a column using petroleum ether and ethyl acetate as the eluent.
Preparation of 1- (4-chlorophenyl) -4-methylene-3- (p-tolyl) -3-azabicyclo [3.1.0] hexane-2-one
1- (4-chlorophenyl) -N- (p-tolyl) -2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to a 10mL dry Schlenk's tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as leacheate to obtain 1- (4-chlorophenyl) -4-methylene-3- (p-tolyl) -3-azabicyclo [3.1.0]]Hexane-2-one (93 mg, 60%).
The product was a white solid, yield: 60%.
1 H NMR(400MHz,CDCl 3 )δ7.45–7.41(m,2H),7.34–7.31(m,2H),7.24(d,J=7.6Hz,2H),7.11–7.08(m,2H),4.38(d,J=1.2Hz,1H),4.16(d,J=0.8Hz,1H),2.83(q,J=4.0Hz,1H),2.37(s,3H),1.67(dd,J=8.0,4.8Hz,1H),1.54(t,J=4.0Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ173.3,146.8,138.1,133.5,133.4,132.0,130.02,130.00,128.7,127.5,86.8,33.7,25.8,23.7,21.2.
Example 2
Preparation of 3- (4- (tert-butyl) phenyl) -1- (4-chlorophenyl) -4-methylene-3-azabicyclo [3.1.0] hexane-2-one
N- (4- (tert-butyl) phenyl) -1- (4-chlorophenyl) -2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to 10mL of dried Schlemk's tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as eluent to obtain 3- (4- (tert-butyl) phenyl) -1- (4-chlorophenyl) -4-methylene-3-azabicyclo [ 3.1.0)]Hexane-2-one (81 mg, 46%).
The product was a white solid, yield: 46%.
1 H NMR(600MHz,CDCl 3 )δ7.45(t,J=7.8Hz,4H),7.33(d,J=8.4Hz,2H),7.14(d,J=8.4Hz,2H),4.40(s,1H),4.21(s,1H),2.83(dd,J=7.8,3.6Hz,1H),1.68(dd,J=7.8,4.8Hz,1H),1.55(d,J=5.4Hz,1H),1.33(s,9H).
13 C NMR(151MHz,CDCl 3 )δ173.3,151.0,146.7,133.5,133.4,131.9,130.0,128.7,127.1,126.3,87.0,34.7,33.7,31.3,25.8,23.7.
Example 3
Preparation of 1- (4-chlorophenyl) -3- (4-methoxyphenyl) -4-methylene-3-azabicyclo [3.1.0] hexane-2-one
1- (4-chlorophenyl) -N- (4-methoxyphenyl) -2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to 10mL of dried Schlemk's tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as eluent to obtain 1- (4-chlorophenyl) -3- (4-methoxyphenyl) -4-methylene-3-azabicyclo [ 3.1.0)]Hexane-2-one (96 mg, 59%)
The product was a white solid, yield: 59%.
1 H NMR(600MHz,CDCl 3 )δ7.43(d,J=8.4Hz,2H),7.32(d,J=9.0Hz,2H),7.12(d,J=9.0Hz,2H),6.95(d,J=9.0Hz,2H),4.37(d,J=0.6Hz,1H),4.14(s,1H),3.81(s,3H),2.83(dd,J=7.8,3.6Hz,1H),1.66(dd,J=7.8,4.8Hz,1H),1.53(t,J=4.2Hz,1H).
13 C NMR(151MHz,CDCl 3 )δ173.5,159.2,147.0,133.5,133.4,130.0,128.9,128.7,127.2,114.7,86.8,55.5,33.7,25.7,23.7.
Example 4
Preparation of 1- (4-chlorophenyl) -3- (3-methoxyphenyl) -4-methylene-3-azabicyclo [3.1.0] hexane-2-one
1- (4-chlorophenyl) -N- (3-methoxyphenyl) -2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to 10mL of dried Schlemk's tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as eluent to obtain 1- (4-chlorophenyl) -3- (3-methoxyphenyl) -4-methylene-3-azabicyclo [ 3.1.0)]Hexane-2-one (78 mg, 48%).
The product was a white solid, yield: 48%.
1 H NMR(600MHz,CDCl 3 )δ7.44(d,J=8.4Hz,2H),7.35(d,J=8.4Hz,1H),7.33(t,J=4.2Hz,2H),6.91(dd,J=8.4,1.8Hz,1H),6.81(d,J=7.8Hz,1H),6.77(s,1H),4.41(s,1H),4.23(s,1H),3.81(s,3H),2.84(dd,J=7.8,4.2Hz,1H),1.67(dd,J=7.8,4.8Hz,1H),1.55(t,J=4.2Hz,1H).
13 C NMR(151MHz,CDCl 3 )δ173.2,160.3,146.5,135.7,133.5,133.4,130.1,130.0,128.7,119.8,114.1,113.3,87.2,55.4,33.8,25.7,23.6.
Example 5
Preparation of 1- (4-chlorophenyl) -4-methylene-3-phenyl-3-azabicyclo [3.1.0] hexane-2-one
1- (4-chlorophenyl) -N-phenyl-2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to a 10mL dry Schlenk tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as eluent to obtain 1- (4-chlorophenyl) -4-methylene-3-phenyl-3-azabicyclo [3.1.0]]Hexane-2-one (97 mg, 66%).
The product was a white solid, yield: 66%.
1 H NMR(600MHz,DMSO)δ7.51(dd,J=13.8,8.1Hz,5H),7.43(d,J=8.4Hz,2H),7.28(d,J=7.2Hz,2H),4.41(s,1H),3.97(s,1H),3.13(dd,J=7.8,3.6Hz,1H),1.84(dd,J=7.8,4.2Hz,1H),1.67(t,J=3.9Hz,1H).
13 C NMR(151MHz,DMSO)δ173.2,147.4,135.2,134.7,132.4,130.9,129.8,128.8,128.65,128.56,86.6,33.7,26.2,23.2.
Example 6
Preparation of ethyl 4- (1- (4-chlorophenyl) -4-methylene-2-oxo-3-azabicyclo [3.1.0] hexane-2-one) benzoate
Ethyl 4- (1- (4-chlorophenyl) -2-vinylcyclopropane-1-carboxamide) benzoate (156 mg,0.5 mmol) was added to a 10mL dry Schlenk tube, anhydrous K 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and the organic phase is washed with water, saturated sodium chloride solutionA phase; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as eluent to obtain 4- (1- (4-chlorophenyl) -4-methylene-2-oxo-3-azabicyclo [ 3.1.0)]Hexane-2-one) benzoic acid ethyl ester (88 mg, 48%).
The product was a white solid, yield: 48%.
1 H NMR(600MHz,CDCl 3 )δ8.13(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),7.34(t,J=9.0Hz,4H),4.46(d,J=1.2Hz,1H),4.39(q,J=7.2Hz,2H),4.26(d,J=1.2Hz,1H),2.86(dd,J=7.8,3.6Hz,1H),1.69(dd,J=7.8,4.8Hz,1H),1.56(t,J=4.2Hz,1H),1.39(t,J=7.2Hz,3H).
13 C NMR(151MHz,CDCl 3 )δ173.0,165.8,145.9,138.8,133.6,133.1,130.7,130.1,129.9,128.8,127.4,87.5,61.2,34.0,25.7,23.5,14.3.
Example 7
Preparation of 1- (4-chlorophenyl) -N-methoxy-2-vinylcyclopropane-1-carboxamide
Acid (2.78 mmol), DCM (15 mL) and 2 drops of DMF are charged to a dry round bottom flask, then oxalyl chloride (0.529 g,1.5 equiv) is added dropwise at 0deg.C, the resulting mixture is stirred at room temperature for 3.5 hours and concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and K 2 CO 3 (0.768g,2.0equiv)、MeONH 2 HCl (0.278 g,1.2 equiv) and water (10 mL). The resulting mixture was stirred at room temperature, checked by TLC, extracted with ethyl acetate after completion of the reaction, and the organic layer was successively extracted with saturated NaHCO 3 The aqueous solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized to give the product 1- (4-chlorophenyl) -N-methoxy-2-vinylcyclopropane-1-carboxamide (0.647 g, 93%).
Preparation of 1- (4-chlorophenyl) -3-methoxy-4-methylene-3-azabicyclo [3.1.0] hexane-2-one
1- (4-chlorophenyl) -N-methoxy-2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to a 10mL dry Schlenk tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as eluent to obtain 1- (4-chlorophenyl) -3-methoxy-4-methylene-3-azabicyclo [3.1.0]]Hexane-2-one (59 mg, 47%).
The product was a white solid, yield: 47%.
1 H NMR(400MHz,CDCl 3 )δ7.37–7.28(m,4H),4.58(s,1H),4.45(s,1H),3.84(s,3H),2.61(dd,J=7.6,4.0Hz,1H),1.61(dd,J=7.6,4.8Hz,1H),1.38(t,J=4.4Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ167.9,140.1,133.7,132.8,129.9,128.8,85.1,62.6,30.3,23.6,22.1.
Example 8
Preparation of 1- (3-methoxyphenyl) -4-methylene-3-phenyl-3-azabicyclo [3.1.0] hexane-2-one
1- (4-methoxyphenyl) -N-phenyl-2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to a 10mL dry Schlenk tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and heated to 50 in an earthen bathThe reaction was carried out at C, and the progress of the reaction was monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as leacheate to obtain 1- (3-methoxyphenyl) -4-methylene-3-phenyl-3-azabicyclo [3.1.0]]Hexane-2-one (76 mg, 52%).
The product was a white solid, yield: 52%.
1 H NMR(400MHz,CDCl 3 )δ7.48–7.42(m,2H),7.37–7.33(m,1H),7.32–7.26(m,2H),7.26–7.23(m,2H),6.99–6.93(m,1H),6.91(d,J=8.4Hz,1H),4.33(d,J=0.8Hz,1H),4.14(s,1H),3.88(s,3H),2.50(q,J=4.0Hz,1H),1.83(dd,J=8.0,4.8Hz,1H),1.48(t,J=4.4Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ174.2,159.3,148.0,135.3,130.7,129.4,129.2,128.8,127.85,127.80,127.2,123.9,120.5,110.7,85.8,55.9,32.4,25.8,19.8.
Example 9
Preparation of 4-methylene-1, 3-diphenyl-3-azabicyclo [3.1.0] hexane-2-one
N, 1-diphenyl-2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to a 10mL dry Schlenk tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, mixing with petroleum ether andethyl acetate is used as eluent to pass through a column to obtain 4-methylene-1, 3-diphenyl-3-azabicyclo [3.1.0]Hexane-2-one (64 mg, 49%).
The product was a white solid, yield: 49%.
1 H NMR(600MHz,CDCl 3 )δ7.44–7.40(m,2H),7.39–7.35(m,2H),7.31–7.26(m,3H),7.24–7.21(m,1H),7.18–7.15(m,2H),4.32(d,J=1.2Hz,1H),4.10(s,1H),2.77(q,J=4.2Hz,1H),1.65(dd,J=7.8,4.8Hz,1H),1.47(t,J=4.2Hz,1H).
13 C NMR(151MHz,CDCl 3 )δ172.6,145.9,133.8,128.3,127.6,127.5,126.95,126.70,126.5,85.6,33.3,24.7,22.4.
Example 10
Preparation of 1- (3-chlorophenyl) -4-methylene-3-phenyl-3-azabicyclo [3.1.0] hexane-2-one
1- (3-chlorophenyl) -N-phenyl-2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to a 10mL dry Schlenk tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as eluent to obtain 1- (3-chlorophenyl) -4-methylene-3-phenyl-3-azabicyclo [3.1.0]]Hexane-2-one (75 mg, 51%).
The product was a white solid, yield: 51%.
1 H NMR(400MHz,CDCl 3 )δ7.43–7.37(m,2H),7.37–7.30(m,2H),7.30–7.18(m,3H),7.18–7.14(m,2H),4.34(d,J=1.2Hz,1H),4.12(d,J=1.2Hz,1H),2.79(q,J=3.9Hz,1H),1.64(dd,J=8.0,4.4Hz,1H),1.51(d,J=4.0Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ173.0,146.5,136.9,134.6,134.4,129.8,129.4,128.7,128.1,127.73,127.70,126.8,87.1,33.9,25.9,23.6.
Example 11
Preparation of 1- (4-bromophenyl) -4-methylene-3-phenyl-3-azabicyclo [3.1.0] hexane-2-one
1- (4-bromophenyl) -N-phenyl-2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to a 10mL dry Schlenk tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as eluent to obtain 1- (4-bromophenyl) -4-methylene-3-phenyl-3-azabicyclo [3.1.0]]Hexane-2-one (81 mg, 48%).
The product was a white solid, yield: 48%.
1 H NMR(600MHz,CDCl 3 )δ7.42–7.38(m,2H),7.39–7.34(m,2H),7.31–7.27(m,3H),7.16–7.13(m,2H),4.32(d,J=1.2Hz,1H),4.11(d,J=1.2Hz,1H),2.76(dd,J=7.8,4.2Hz,1H),1.60(dd,J=7.8,4.8Hz,1H),1.47(t,J=4.2Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ168.3,139.3,137.7,135.2,132.6,132.0,128.9,124.4,122.4,119.8,116.9,38.2,32.4,21.3.
Example 12
Preparation of N-phenyl-1-tosyl-2-vinylcyclopropane-1-carboxamide
Anhydrous K was added to a 100mL round bottom flask at 0deg.C 2 CO 3 (2.4 g,2.0 equiv.), DMF (40 mL) and N-phenyl-2-toluenesulfonylacetamide (8.8 mmol,1.0 equiv.) are added dropwise after stirring at this temperature for 30 minutes (E) -1, 4-dibromo-2-butene (2.26 g,1.2 equiv.), 0 ℃ The reaction was carried out under the condition that the reaction progress was monitored by TLC. Adding water into the system after the reaction is completed, extracting with dichloromethane, merging the organic phases after the extraction is completed, and washing the organic phases with water and saturated sodium chloride solution; dried over anhydrous sodium sulfate, the organic solvent was removed by depressurization, and the sample was stirred on silica gel, and the mixture was passed through a column using petroleum ether and ethyl acetate as the eluent to give N-phenyl-1-tosyl-2-vinylcyclopropane-1-carboxamide (1.3 g, 43%).
Preparation of 4-methylene-3-phenyl-1-tosyl-3-azabicyclo [3.1.0] hexane-2-one
N-phenyl-1-tosyl-2-vinylcyclopropane-1-carboxamide (156 mg,0.5 mmol), anhydrous K, was added to a 10mL dry Schlenk tube 2 CO 3 (69mg,1.0equiv),Pd(PPh 3 ) 2 Cl 2 (35 mg,5 mol%) charge O 2 Three times, anhydrous DMF (2 mL) was then added and the reaction was heated to 50deg.C in an overhead bath and monitored by TLC. After the reaction is finished, naturally cooling the system to room temperature, diluting the system with dichloromethane, then adding water, and separating an organic phase; after extraction is completed, the organic phases are combined and washed with water, saturated sodium chloride solution; drying with anhydrous sodium sulfate, removing organic solvent under reduced pressure, mixing with silica gel, and purifying with petroleum ether and ethyl acetate as leacheate to obtain 4-methylene-3-phenyl-1-tosyl-3-azabicyclo [3.1.0]]Hexane-2-one (27 mg, 16%).
The product was a white solid, yield: 16%.
1 H NMR(600MHz,CDCl 3 )δ7.99(d,J=8.4Hz,2H),7.42(t,J=7.8Hz,2H),7.36(d,J=7.8Hz,3H),7.14–7.11(m,2H),4.50(d,J=1.8Hz,1H),4.24(d,J=1.8Hz,1H),3.49(dd,J=8.6,4.8Hz,1H),2.44(s,3H),2.17(dd,J=9.0,5.4Hz,1H),1.56(d,J=4.8Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ165.9,145.2,143.0,136.0,133.6,129.6,129.5,129.2,128.6,127.5,89.9,47.9,26.5,22.3,21.7.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention and not for limiting it, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that: the technical scheme of the invention can be modified or replaced by the same, and the modified technical scheme cannot deviate from the spirit and scope of the technical scheme of the invention.
Claims (4)
1. Synthesis of azabicyclo [3.1.0]]A method for preparing hexane-2-ketone compounds is characterized in that: the reactant is 2-vinyl cyclopropane-1-formamide compound, and the reaction condition is that O is 2 In DMF solvent with Pd (PPh under atmospheric and alkaline conditions 3 ) 2 Cl 2 As a catalyst, 3-azabicyclo [3.1.0] is prepared in one step]Hexane-2-one compounds;
the reaction equation in the synthesis method is as follows:
;
wherein R is 1 One selected from 4-chlorophenyl, 3-methoxyphenyl, phenyl, 3-chlorophenyl, 4-bromophenyl and tosyl;
R 2 one selected from 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, phenyl, 4-ethyl benzoate and methoxy.
2. The method for synthesizing azabicyclo [3.1.0] hexane-2-one compound according to claim 1, wherein the 2-vinylcyclopropane-1-carboxamide compound is selected from the group consisting of 1a,1a by the synthetic route of:
;
wherein R is 1 One selected from 4-chlorophenyl, 3-methoxyphenyl, phenyl, 3-chlorophenyl and 4-bromophenyl;
R 2 one selected from 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, phenyl and 4-ethyl benzoate.
3. A method for synthesizing azabicyclo [3.1.0] hexane-2-one compounds according to claim 1, wherein the synthetic route of reactant 2-vinylcyclopropane-1-carboxamide compound is selected from 1b,1 b:
。
4. a method for synthesizing azabicyclo [3.1.0] hexane-2-one compounds according to claim 1, wherein the 2-vinylcyclopropane-1-carboxamide compound is selected from the group consisting of 1c,1c by the synthetic route:
。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211207358.2A CN115536573B (en) | 2022-09-30 | 2022-09-30 | Method for synthesizing azabicyclo [3.1.0] hexane-2-ketone compound |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211207358.2A CN115536573B (en) | 2022-09-30 | 2022-09-30 | Method for synthesizing azabicyclo [3.1.0] hexane-2-ketone compound |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115536573A CN115536573A (en) | 2022-12-30 |
CN115536573B true CN115536573B (en) | 2024-01-30 |
Family
ID=84732549
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211207358.2A Active CN115536573B (en) | 2022-09-30 | 2022-09-30 | Method for synthesizing azabicyclo [3.1.0] hexane-2-ketone compound |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115536573B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114085181A (en) * | 2022-01-18 | 2022-02-25 | 南京桦冠生物技术有限公司 | Synthesis method and application of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
-
2022
- 2022-09-30 CN CN202211207358.2A patent/CN115536573B/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114085181A (en) * | 2022-01-18 | 2022-02-25 | 南京桦冠生物技术有限公司 | Synthesis method and application of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
Non-Patent Citations (5)
Title |
---|
Kallam, Srinivasa Reddy等.A diastereoselective synthesis of boceprevir's gem-dimethyl bicyclic [3.1.0] proline intermediate from an insecticide ingredient cis-cypermethric acid.Tetrahedron.2017,第73卷(第30期),4285-4294. * |
Le-Song Wu等.Asymmetric Synthesis of γ-Lactams Containing α,β-Contiguous Stereocenters via Pd(II)-Catalyzed Cascade Methylene C(sp3)–H Alkenylation/Aza-Wacker Cyclization.Org. Lett..2021,第23卷(第6期),2048–2051. * |
Pd(II)-Catalyzed Intramolecular Amidoarylation of Alkenes with Molecular Oxygen as Sole Oxidant;Kai-Tai Yip等;Org. Lett.;第13卷(第8期);2134–2137 * |
Pd-Catalyzed enantioselective synthesis of 2-methyl-3-methyleneindoline;Chun-Hua Lu等;Chinese Chemical Letters;第32卷(第1期);405-407 * |
Sulfamate-tethered aza -Wacker approach towards analogs of Bactobolin A;Someshwar Nagamalla等;Medicinal Chemistry Research;1348–1357 * |
Also Published As
Publication number | Publication date |
---|---|
CN115536573A (en) | 2022-12-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2010511017A (en) | Ruthenium-based catalyst complexes and use of said complexes for olefin metathesis | |
CN105294536B (en) | A kind of method for preparing 3- iminoisoindolinone class compounds | |
KR20100041772A (en) | Process for the synthesis of intermediates of renin inhibitors such as aliskiren | |
WO2016082583A1 (en) | Kinetic resolution of asymmetric catalytic hydrogenation of racemic δ-hydroxy ester and application thereof | |
Nie et al. | Chiral bifunctional thiourea-catalyzed enantioselective aldol reaction of trifluoroacetaldehyde hemiacetal with aromatic ketones | |
Li et al. | An efficient enantioselective synthesis of florfenicol via a vanadium-catalyzed asymmetric epoxidation | |
Rubio-Pérez et al. | One-pot stibine modified Co2 (CO) 8 catalyzed reductive N-alkylation of primary amides with carbonyl compounds | |
Wang et al. | Palladium-catalyzed one pot 2-arylquinazoline formation via hydrogen-transfer strategy | |
CN110483582B (en) | Aza-carbene-palladium complex crystal, synthesis method thereof and application thereof in preparing amide compound | |
CN113200933B (en) | Method for synthesizing optically active benzocarboxylate compound by asymmetric addition reaction | |
CN115536573B (en) | Method for synthesizing azabicyclo [3.1.0] hexane-2-ketone compound | |
Mei et al. | KOH-catalyzed highly efficient aminohalogenation of β-nitrostyrenes with t-butyl N, N-dichlorocarbamate as nitrogen/halogen source | |
Fichtler et al. | Practical three-component synthesis of crowded arenes with donor–acceptor substitution | |
JP2009172474A (en) | Diels alder reaction catalyst and manufacturing method of asymmetric cyclized addition product | |
Yanagisawa et al. | Mannich‐Type Reaction Using Alkenyl Trichloroacetates Catalyzed by Dibutyltin Dimethoxide | |
CN109485647B (en) | Preparation method of anxiolytic drug namely palogron or palsiene clone | |
Wang et al. | Enantioselective and α‐Regioselective Allylic Amination of Morita‐Baylis‐Hillman Acetates with Simple Aromatic Amines Catalyzed by Planarly Chiral Ligand/Palladium Catalyst | |
Naderi | Investigation and Biological Application of MNPs-phenanthroline-Cu as an Efficient Catalyst in the Synthesis of Oxazoles | |
JP2000327659A (en) | Preparation of optically active pyridylalcohol | |
JP5344523B2 (en) | Catalyst capable of proceeding Strecker reaction stereoselectively, and method for stereoselectively producing an α-amino nitrile derivative using the same | |
JP6858761B2 (en) | Methods and Intermediates for Producing Benzo [B] Thiophene Compounds | |
WO2006004093A1 (en) | Process for producing optically active phenylpropylamine derivative | |
CN111410656B (en) | Preparation method of isoquinolone derivative | |
CN110028443B (en) | Preparation method of tricyclic compound drug intermediate for regulating FXR activity | |
Liu et al. | Lewis base organocatalyzed enantioselective hydrosilylation of α-keto ketimines |
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 |