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 PDF

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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
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azabicyclo
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chlorophenyl
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vinylcyclopropane
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张贵生
李晶亚
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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

Method for synthesizing azabicyclo [3.1.0] hexane-2-ketone compound
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:
。
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