CN113461590B - Method for constructing 1-substituted cyclopropane compound by virtue of phosphine-catalyzed C-H activated amination reaction of cyclopropane - Google Patents

Method for constructing 1-substituted cyclopropane compound by virtue of phosphine-catalyzed C-H activated amination reaction of cyclopropane Download PDF

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CN113461590B
CN113461590B CN202110662816.0A CN202110662816A CN113461590B CN 113461590 B CN113461590 B CN 113461590B CN 202110662816 A CN202110662816 A CN 202110662816A CN 113461590 B CN113461590 B CN 113461590B
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叶智识
刘奎
成少杰
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Dalian University of Technology
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Abstract

The invention discloses a method for constructing a 1-substituted cyclopropylamine compound by a phosphine-catalyzed C-H activated amination reaction of cyclopropane. The corresponding cyclopropylamine compound is obtained by using an organic phosphine catalyst and cyclopropane and amide or an N-heterocyclic aromatic compound as reaction substrates, and the yield of the corresponding cyclopropylamine compound can reach 99 percent at most. The method has the advantages of no transition metal, excellent regioselectivity, simple, convenient, practical and feasible operation, high yield, environmental friendliness, commercial availability of the catalyst, mild reaction conditions and potential practical application value.

Description

Method for constructing 1-substituted cyclopropane compound by virtue of phosphine-catalyzed C-H activated amination reaction of cyclopropane
Technical Field
The invention belongs to the field of synthesis of cyclopropylamine compounds, and particularly relates to a method for constructing a 1-substituted cyclopropylamine compound by catalyzing a C-H activated amination reaction of cyclopropane with organic phosphine.
Background
The core skeleton of cyclopropylamine is widely found in natural products and biologically active drugs. (reference one (a) t.t.talle, j.med.chem.2016,59,8712.). For example, BMS-929075 is an inhibitor of the replication enzyme of hepatitis C virus NS 5B. (reference II (a) K. -S.Yeung, B.R.Beno, K.Parcella, J.A.Bender, K.A.Grant-Young, A.Nickel, P.Gunaga, P.Anjanappa, R.O.Bora, K.Selvakumar, K.Rigat, Y. -K.Wang, M.Liu, J.Lemm, K.Mosure, S.Sheriff, C.Wan, M.Witter, K.Kish, U.Hanumowda, X.ZHuo, Y. -Z.Shu, D.Parker, R.Haskell, A.Ng, Q.Gao, E.Colston, J.Raybon, D.M.Grasela, K.Santone, M.Gao, N.Anweill, S.Guitar, S.W.J.S.J.J.S.J.S.J.S.J.S.J.S.J.S.J.S.S.S.J.S.S.S.J.S.S.S.J.S.S.S.S.S.J.S.S.S.J.S.S.S.J.S.S.J.S.S.J.S.S.J.J.S.S.S.S.S.S.J.S.S.J.J.S.J.S.S.S.S. 60,4369.S.S.S.S.J.S.J.J.S.S.S.S.S.S.J.S.S.J.J.S.J.S.S.S.S.S.S.J.S.S.S.S.S.S.S.S.J.S.J.J.S.S.S.J.S.S.J.J.J.J.S.S.S.S.S.J.S.S.S.S.J.S.S.S.J.J.J.J.S.S.J.S.S.S.S.S.S.S.J.J.J.J.S.S.S.S.J.S.S.S.S.S.S.J.J.J.J.J.J.J.J.S.S.S.S.S.S.S.J.S.S.S.S.S.S.S.S.J.S.S.S.S.S.S.S.J.S.S.S.S.J.J.S.J.S.S.S.J.J.S.J.J.J.S.S.S.S.S.J.J.S.S.S.S.S.S.S.S.S.S.S.S.S.J.J.J.J.J.J.J.J.J.J.J.S.T.T.T.S.T.S.S.S.J.S.S.J.S.S.J.S.S.S.S.S.J.J.S.S.J.J.S.T.T.T.T.T.T.T.T.T.S.T.T.T.T.T.T.. Precolibacin B as an effective genotoxin can be used for inducing the double-strand break of DNA. (ref. iii: a) z.r.li, y.li, j.y.lai, j.tang, b.wang, l.lu, g.zhu, x.wu, y.xu, p.y.qian, chembichem.2015, 16,1715.). Therefore, the development of efficient methods for synthesizing the cyclopropylamine compounds and improving the technical level of related industries has important scientific value and application prospect.
Synthetic methods for preparing 1-substituted cyclopropylamine compounds have been reported, with the classical synthetic method involving a Kulinkovich-de Meijere reaction between an alkyl Grignard reagent and a nitrile or amide. (reference IV: (a) V.Chaplinki, A.de Meijere, Angew.Chem., int.Ed.1996,35,413; Angew.Chem.1996,108,491.(b) P.Bertus, J.Szymnoak, chem.Commun.2001,1792.(c) A.Wolan, Y.Six, tetrahedron.2010,66,15.(d) A.de Meijere, V.Chaplinski, H.Winsel, M.Kordes, B.Stecker, V.Zizova, A.I.Savnko, R.Boese, F.Scheul, chem.J.2010, 16,13862.(e) P.Bertus, C.Menava, C.Tang, J.56. enzymott. 10,777. org.L.38g.). The cyclopropane-1-carbonyl azide undergoes Curtius rearrangement. (reference five (a) n.b.m.arts, a.j.h.klundr, b.zwanenburg, tetrahedron.1978,34,1271.(B) t.n.wheeler, j.a.ray, synth.commu.1988, 1,141.(c) m.ohno, h.tanaka, m.komatsu, y.ohshiro, syntett1991, 919.(d) a.b.charette, B.
Figure BDA0003116047230000011
J.Am.Chem.Soc.1995,117,12721.(e)B.Jiang,Zhang, w.xiong, chem.commu.2003, 536.(f) f.gnad, o.reiser, chem.rev.2003,103, 1603.). Olefin and nitrogen substituted metal carbene generation [2+1 ]]Cyclopropanation. (reference six (a) v.k.agarwal, j.de vicenet, r.v.bonnert, org.lett.2001,3,2785.(b) j.barluenga, f.aznar, i.guti é rrez, s.garci-Granda, M.A.
Figure BDA0003116047230000012
Org.Lett.2002,4,4273.(c)G.Bégis,D.E.Cladingboel,W.B.Motherwell,Chem.Commun.2003,2656.(d)B.Moreau,A.B.Charette,J.Am.Chem.Soc.2005,127,18014.(e)L.Jerome,T.D.Sheppard,A.E.Aliev,W.B.Motherwell,Tetrahedron Lett.2009,50,3709.(f)V.N.G.Lindsay,W.Lin,A.B.Charette,J.Am.Chem.Soc.2009,131,16383.(g)S.Ishikawa,T.D.Sheppard,J.M.D’Oyley,A.Kamimura,W.B.Motherwell,Angew.Chem.,Int.Ed.2013,52,10060；Angew.Chem.2013,125,10244.(h)S.Chanthamath,D.T.Nguyen,K.Shibatomi,S.Iwasa,Org.Lett.2013,15,772.(i)P.Cyr,A.
Figure BDA0003116047230000021
S.m.bronner, org.lett.2016,18,6448.(j) c.zhu, j.li, p.chen, w.wu, y.ren, h.jiang, org.lett.2016,18,1470.). Although these methods are very reliable, there are disadvantages such as severe reaction conditions, use of an excessive amount of metal catalyst, use of a highly active organometallic reagent, and limitation in the range of application of the substrate. Therefore, the development of a new synthetic strategy for 1-substituted cyclopropylamines, which is highly efficient and more versatile, is a very valuable and challenging research direction in chemical research.
Disclosure of Invention
The invention aims to provide a method for synthesizing 1-substituted cyclopropylamine compounds with high regioselectivity by catalyzing the C-H activated amination reaction of cyclopropane with phosphine.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a method for constructing 1-substituted cyclopropylamine compounds by phosphine-catalyzed C-H activated amination reaction of cyclopropane takes organic phosphine as a catalyst, cyclopropane 1 and amide or N-heterocyclic aromatic compound 2 as reaction substrates, and the corresponding cyclopropylamine compounds are obtained by reaction, so that amination of the cyclopropane C-H bond is realized, and the reaction formula and conditions of the method are as follows:
Figure BDA0003116047230000022
r is unsubstituted or substituted alkyl, or unsubstituted alkoxy, or unsubstituted or substituted phenyl, or unsubstituted naphthyl, thiophene or furan; when substituted, the substituents are selected from methyl, methoxy, nitro, cyano, trifluoromethyl, dipropylaminosulfonyl, halogen, and the halogen is selected from fluorine, chlorine, bromine;
the amide or N-heterocyclic aromatic compound 2 is unsubstituted or substituted indole, pyrrole, imidazole, uracil, pyridine, pyrimidine or phthalimide, when substituted, the substituent is selected from acyl, aldehyde group, carbomethoxy, methyl, alkoxy, hydroxyl, nitro, cyano, trifluoromethyl and halogen, and the halogen is selected from fluorine, chlorine, bromine and iodine.
Based on the technical scheme, preferably, the alkyl in R is C1-C35 alkyl, and the alkoxy is C1-C2 alkoxy.
Based on the above technical scheme, the alkoxy in the amide or the N-heterocyclic aromatic compound 2 is preferably C1-C7 alkoxy.
Based on the above technical scheme, preferably, the substituted aryl is aryl containing 1-2 substituents.
Based on the above technical scheme, preferably, the substituted indole is an indole containing 1 to 2 substituents, the substituted pyrrole is a pyrrole containing 1 substituent, the substituted imidazole is an imidazole containing 1 substituent, the substituted uracil is a uracil containing 1 substituent, the substituted pyridine is a pyridine containing 1 to 2 substituents, and the substituted pyrimidine is a pyrimidine containing 1 substituent.
Based on the above technical scheme, preferably, when the amide or the N-heterocyclic aromatic compound 2 is substituted indole, the reaction formula and conditions of the method are as follows:
Figure BDA0003116047230000031
in the formula: r is as defined above, R1、R2Selected from acyl, aldehyde group, carbomethoxy, halogen, methyl, alkoxy, nitro, cyano and trifluoromethyl; preferably, R1Is nitro, acetyl, aldehyde group, carbomethoxy or methyl; r2Is halogen, methyl, alkoxy of C1-C7, carbomethoxy, nitro, cyano or trifluoromethyl.
When the amide or N-heterocyclic aromatic compound 2 is phthalimide, the reaction formula and conditions of the process are as follows:
Figure BDA0003116047230000032
in the formula: r is as described above;
when the amide or N-heterocyclic aromatic compound 2 is a uracil compound, the reaction formula and conditions of the method are as follows:
Figure BDA0003116047230000033
in the formula: r is as described above, preferably R is methyl; r3Selected from hydrogen, iodine, trifluoromethyl, preferably, R3Is iodine or trifluoromethyl.
Based on the above technical scheme, the amide or N-heterocyclic aromatic compound 2 is preferably 2-nitropyrrole, or imidazole-4-methyl formate, or 2-hydroxy-5-acetylpyridine, or 4-hydroxypyrimidine.
Based on the above technical solution, preferably, the amination reaction includes the following steps:
under the nitrogen atmosphere, adding an organic phosphine catalyst and an organic solvent into cyclopropane 1 and amide or N-heterocyclic aromatic compound 2 substrate, and reacting to obtain the cyclopropylamine compound.
Based on the technical scheme, preferably, after the reaction is completed, the reaction solution is cooled to room temperature, water is added for quenching reaction, then Dichloromethane (DCM) is used for extraction, the solvent is removed under reduced pressure, and the pure product is obtained through column chromatography separation.
Based on the above technical scheme, preferably, in the amination reaction, the organic solvent used is selected from one of benzene, toluene, o-xylene, dichloromethane, dichloroethane, chloroform, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, diethyl ether, acetonitrile and N, N-dimethylformamide, wherein the activity of acetonitrile and N, N-dimethylformamide is poor, and the activity and regioselectivity of 1, 4-dioxane and dichloromethane are good.
Based on the above technical scheme, preferably, the organic phosphine catalyst is selected from triphenylphosphine (Ph)3P), tricyclohexylphosphorus (Cy)3P), tri-tert-butylphosphine (f)tBu3P), tri-n-butylphosphine (nBu3P), diphenylcyclohexylphosphine (CyPh)2P), tris (4-methoxyphenyl) phosphine ((4-OMePh)3P)。
Based on the technical scheme, preferably, the organic phosphine catalyst is diphenyl cyclohexyl phosphine or tricyclohexyl phosphorus.
Based on the above technical scheme, preferably, the reaction feeding: the molar ratio of the organic phosphine catalyst, the substrate 1 and the substrate 2 is 0.05-0.3:1.0-1.5:1.0, and preferably 0.2:1.5: 1.0.
Based on the above technical scheme, the concentration of the substrate 2 is preferably 0.05-0.2mmol/mL, preferably 0.1 mmol/mL.
Based on the technical scheme, the reaction temperature is preferably between room temperature and 100 ℃, and preferably between 50 and 100 ℃; the reaction time is 12-24 h.
Advantageous effects
1. The reaction activity and the regioselectivity are high;
2. the reaction operation is simple and practical;
3. the reaction condition is mild.
The method has the advantages of no transition metal, excellent regioselectivity, simple, convenient, practical and feasible operation, high yield (up to 99%), environment friendliness, commercial availability of the catalyst, mild reaction conditions and potential practical application value.
Detailed Description
The present invention is described in detail below by way of examples, but is not limited to the following examples in which the organophosphine catalysts are commercially available and do not require any treatment, the cyclopropane 1 substrate references used in the following examples synthesize [ (a) org.biomol.chem.2018,16,9461.(b) org.lett.2019,21,6795.(c) angelw.chem.int.ed.2021, 60,685.(d) org.lett.2019,21,1283.(e) RSC adv.2015,5,12807.(f) ACS med.chem.lett.2017,8,762.], the substituted 3-nitroindole substrate references used in the following examples synthesize [ (a) tetrahedron.2000,56,10133.(b) angelw.chem.int.ed.2018, 57,2134.], and all of the examples are commercially available and do not require any treatment with phthalimide, pyrrolidine, uracil, and uracil.
Example 1
Optimization of reaction conditions
Under nitrogen atmosphere, putting an organic phosphine catalyst (20.0 mmol% or 30.0 mmol%), a cyclopropane substrate 1a (0.15mmol) and a 3-nitroindole substrate 2a (0.1mmol) into a reaction bottle, dissolving the organic phosphine catalyst, the 3-nitroindole substrate and the 3-nitroindole substrate by using a solvent for reaction, putting the reaction bottle into an oil bath at room temperature or 50 ℃, reacting for 12 hours, cooling the reaction liquid to room temperature, adding 10mL of water to quench the reaction, extracting DCM (20mL) for three times, combining organic layers, removing the solvent under reduced pressure, and carrying out column chromatography separation to obtain a pure product, wherein the reaction formula is as follows:
Figure BDA0003116047230000051
TABLE 1 optimization of the alkylation reaction conditions for cyclopropanea
Figure BDA0003116047230000052
Example 2
The cyclopropane substrate 1 and the 3-nitroindole substrate 2a are subjected to amination reaction to synthesize the cyclopropylamine compound 3
Under the nitrogen atmosphere, putting diphenylcyclohexylphosphine (20.0 mmol), a cyclopropane substrate 1(0.15mmol) and a 3-nitroindole substrate 2a (0.1mmol) into a reaction bottle, dissolving the diphenylcyclohexylphosphine, the 3-nitroindole substrate and the 1, 4-dioxane (1.0mL) used as a solvent for reaction, then putting the reaction bottle into a 50 ℃ oil bath, reacting for 24 hours, cooling the reaction liquid to room temperature, adding 10mL of water to quench the reaction, extracting DCM (20mL) for three times, combining organic layers, removing the solvent under reduced pressure, and carrying out column chromatography separation to obtain a pure product, wherein the type of R in the cyclopropane substrate is changed to obtain different cyclopropylamine compounds 3, and the reaction formula is as follows:
Figure BDA0003116047230000061
Conditions:1(0.15mmol),2a(0.10mmol),CyPh2P(20.0mol％),1,4-dioxane(1.0mL),50℃,24h.
the yield was isolated.
Example 3
The cyclopropane substrate 1a and the indole substrate 2 are subjected to amination reaction to synthesize the cyclopropylamine compound 3
Under nitrogen atmosphere, putting diphenylcyclohexylphosphine or tricyclohexylphosphine (20.0 mmol), cyclopropane substrate 1a (0.15mmol or 0.25mmol) and indole substrate 2(0.1mmol) into a reaction bottle, dissolving the diphenylcyclohexylphosphine or tricyclohexylphosphine with a solvent 1, 4-dioxane (1.0mL) used for reaction, putting the reaction bottle into an oil bath at 50 ℃, reacting for 24 hours, cooling the reaction liquid to room temperature, adding 10mL of water to quench the reaction, extracting DCM (20mL) for three times, combining organic layers, removing the solvent under reduced pressure, and carrying out column chromatography separation to obtain a pure product, wherein the type of R in the indole substrate is changed to obtain different cyclopropylamine compounds 3, and the reaction formula is as follows:
Figure BDA0003116047230000081
conditions (except forb，cUnless otherwise stated, 1a (0.15mmol),2(0.10mmol), CyPh2P(20.0mol％),1,4-dioxane(1.0mL),50℃,24h.
bConditions:1a(0.25mmol).
cConditions:Cy3P(20.0mol％).
The yield was isolated.
Example 4
Performing amination reaction on cyclopropane substrate 1a and N-heterocyclic aromatic compound 2 to synthesize cyclopropylamine compound 3
Under nitrogen atmosphere, adding diphenylcyclohexylphosphine or tricyclohexylphosphorus (20.0 mmol), a cyclopropane 1a substrate (0.15mmol) and an N-heterocyclic aromatic compound 2(0.1mmol) into a reaction bottle, dissolving the diphenylcyclohexylphosphine or tricyclohexylphosphorus with a solvent 1, 4-dioxane (1.0mL) used for reaction, putting the reaction bottle into an oil bath at 50 ℃, reacting for 24 hours, cooling the reaction liquid to room temperature, adding 10mL of water to quench the reaction, extracting DCM (20mL) for three times, combining organic layers, removing the solvent under reduced pressure, and carrying out column chromatography separation to obtain a pure product, wherein different N-heterocyclic aromatic compounds are used as substrates to obtain different cyclopropylamine compounds 3, and the reaction formula is as follows:
Figure BDA0003116047230000091
conditions (except forbUnless otherwise stated, 1a (0.15mmol),2(0.10mmol), CyPh2P(20.0mol％),1,4-dioxane(1.0mL),50℃,24h.
bConditions:Cy3P(20.0mol％).
The yield was isolated.
Example 5
The cyclopropane substrate 1 and phthalimide 2 a' are subjected to amination reaction to synthesize the cyclopropylamine compound 3
Under the nitrogen atmosphere, adding diphenylcyclohexylphosphine or tricyclohexylphosphorus (20.0 mmol), a cyclopropane substrate 1(0.15mmol) and phthalimide 2 a' (0.1mmol) into a reaction bottle, dissolving the diphenylcyclohexylphosphine or tricyclohexylphosphorus (20.0 mmol) by using a solvent 1, 4-dioxane (1.0mL) used for reaction, then putting the reaction bottle into an oil bath at 50 ℃, reacting for 12 hours, cooling the reaction liquid to room temperature, adding 10mL of water for quenching reaction, extracting DCM (20mL) for three times, combining organic layers, removing the solvent under reduced pressure, and carrying out column chromatography separation to obtain a pure product, wherein the type of R in the cyclopropane substrate is changed to obtain different cyclopropylamine compounds 3, and the reaction formula is as follows:
Figure BDA0003116047230000101
conditions (except forbUnless otherwise stated, 1(0.15mmol),2 a' (0.10mmol), CyPh2P(20.0mol％),1,4-dioxane(1.0mL),50℃,12h.
bConditions:Cy3P(20.0mol％).
The yield was isolated.
Example 6
The cyclopropane substrate 1 and the N-heterocyclic aromatic compound 2 are subjected to amination reaction to synthesize the cyclopropylamine compound 3
Under nitrogen atmosphere, adding diphenylcyclohexylphosphine or tricyclohexylphosphorus (20.0 mmol), a cyclopropane substrate 1(0.15mmol) and an N-heterocyclic aromatic compound 2(0.1mmol) into a reaction bottle, dissolving the diphenylcyclohexylphosphine or tricyclohexylphosphorus with a solvent 1, 4-dioxane (1.0mL) used for reaction, putting the reaction bottle into an oil bath at 50 ℃, reacting for 24 hours, cooling the reaction liquid to room temperature, adding 10mL of water to quench the reaction, extracting DCM (20mL) for three times, combining organic layers, removing the solvent under reduced pressure, performing column chromatography separation to obtain a pure product, changing the type of R in the cyclopropane substrate, and obtaining different cyclopropylamine compounds 3 by taking different N-heterocyclic aromatic compounds as substrates according to the following reaction formula:
Figure BDA0003116047230000111
Figure BDA0003116047230000121
conditions (except forbUnless otherwise specified 1(0.15mmol),2(0.10mmol), CyPh2P(20.0mol％),1,4-dioxane(1.0mL),50℃,24h.
bConditions:Cy3P(20.0mol％).
The yield was isolated.
(E)-4-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3aa):the reaction was conducted at 0.1mmol
Figure BDA0003116047230000122
17.7.HRMS(EI)m/zCalculated for C15H13N2O3[M-H]-269.0932found 269.0935.
(E)-4-methyl-1-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)pent-1-en-3-one(3ba):the reaction was conducted at
Figure BDA0003116047230000123
6H).13C NMR(100MHz,CDCl3)δ202.2,146.2,135.7,130.8,129.7,125.5,125.2,124.9,121.4,121.0,111.9,40.5,40.0,18.1,17.6.HRMS(EI)m/z Calculated for C17H18N2NaO3[M+Na]+321.1210,found 321.1210.
(E)-1-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)pent-1-en-3-one(3ca):the reaction was conducted at 0.1mmol
Figure BDA0003116047230000124
121.0,111.9,40.3,35.2,17.6,7.9.HRMS(EI)m/z Calculated for C16H16N2NaO3[M+Na]+307.1053,found307.1058.
(E)-1-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)-5-phenylpent-1-en-3-one(3da):the reaction was conducted at
Figure BDA0003116047230000131
CDCl3)δ197.8,146.4,140.9,135.6,130.8,129.7,128.6,128.5,127.0,126.3,125.3,124.9,121.4,121.0,111.9,43.3,40.3,29.9,17.6.HRMS(EI)m/z Calculated for C22H20N2NaO3[M+Na]+383.1366,found 383.1365.
Methyl(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)acrylate(3ea):the reaction was conducted at 0.1 mmol
Figure BDA0003116047230000132
17.4.HRMS(EI)m/z Calculated for C15H14N2NaO4[M+Na]+309.0846 found 309.0844.
Ethyl(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)acrylate(3fa):the reaction was conducted at 0.1 mmol
Figure BDA0003116047230000133
121.4,121.0,120.0,111.9,60.9,40.3,17.4,14.3.HRMS(EI)m/z Calculated for C16H16N2NaO4[M+Na]+323.1002,found 323.1002.
(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)-1-phenylprop-2-en-1-one(3ga):the reaction was conducted at
Figure BDA0003116047230000134
123.3,121.4,121.0,112.0,41.0,17.8.HRMS(EI)m/z Calculated for C20H16N2NaO3[M+Na]+355.1053,found 355.1053.
(E)-1-(4-fluorophenyl)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)prop-2-en-1-one(3ha):the reaction was
Figure BDA0003116047230000135
JC-F＝254.0Hz),148.8,135.7,133.5(d,JC-F＝3.0Hz),131.2(d,JC-F＝9.0Hz),130.8,129.8,125.4,125.0,122.8,121.4,121.0,116.0(d,JC-F＝22.0Hz),112.0,41.0,17.9.19F NMR(376MHz,CDCl3)δ-104.51.HRMS(EI)m/z Calculated for C20H14FN2O3[M-H]-349.0994,found 349.0993.
(E)-1-(4-chlorophenyl)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)prop-2-en-1-one(3ia):the reaction was
Figure BDA0003116047230000141
139.9,135.7,135.5,130.8,130.0,129.8,129.2,125.4,125.0,122.8,121.5,121.0,111.9,41.0,18.0.HRMS(EI)m/z Calculated for C20H15ClN2NaO3[M+Na]+389.0663,found 389.0663.
(E)-1-(4-bromophenyl)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)prop-2-en-1-one(3ja):the reaction was
Figure BDA0003116047230000142
125.4,125.0,122.8,121.5,121.0,111.9,41.1,18.0.HRMS(EI)m/z Calculated for C20H14BrN2O3[M-H]-409.0193,found 409.0193.
(E)-1-(4-methoxyphenyl)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)prop-2-en-1-one(3ka):the reaction was
Figure BDA0003116047230000143
CDCl3)δ187.1,163.9,147.6,135.8,130.9,130.9,130.1,129.7,125.3,124.9,123.1,121.4,121.0,114.0,112.1,55.6,41.0,17.7.HRMS(EI)m/z Calculated for C21H18N2NaO4[M+Na]+385.1159,found 385.1150.
(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)-1-(p-tolyl)prop-2-en-1-one(3la):the reaction was conducted at
Figure BDA0003116047230000144
130.9,129.8,129.5,128.7,125.3,124.9,123.3,121.4,121.0,112.0,41.0,21.8,17.8.HRMS(EI)m/z Calculated for C21H18N2NaO3[M+Na]+369.1210,found 369.1211.
(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)-1-(m-tolyl)prop-2-en-1-one(3ma):the reaction was conducted
Figure BDA0003116047230000145
138.7,137.3,135.8,134.2,130.8,129.8,129.0,128.7,125.7,125.3,124.9,123.6,121.4,121.0,112.0,41.0,21.5,17.8.HRMS(EI)m/z Calculated for C21H18N2NaO3[M+Na]+369.1210,found 369.1209.
(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)-1-(o-tolyl)prop-2-en-1-one(3na):the reaction was conducted at
Figure BDA0003116047230000151
135.7,131.7,131.3,130.8,129.8,128.4,127.5,125.8,125.3,124.9,121.5,121.0,111.9,40.7,20.6,17.8.HRMS(EI)m/z Calculated for C21H18N2NaO3[M+Na]+369.1210,found 369.1204.
(E)-1-(furan-2-yl)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)prop-2-en-1-one(3oa):the reaction was
Figure BDA0003116047230000152
135.8,130.9,129.8,125.3,124.9,122.7,121.4,121.0,118.5,112.8,112.0,41.0,17.9.HRMS(EI)m/zCalculated for C18H14N2NaO4[M+Na]+345.0846,found 345.0848.
(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)-1-(thiophen-2-yl)prop-2-en-1-one(3pa):the reaction was
Figure BDA0003116047230000153
144.5,135.8,134.8,132.5,130.8,129.8,128.5,125.4,125.0,123.1,121.4,121.0,112.0,40.9,17.9.HRMS(EI)m/z Calculated for C18H14N2NaO3S[M+Na]+361.0617,found 361.0623.
(E)-1-(naphthalen-1-yl)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)prop-2-en-1-one(3qa):the reaction was
Figure BDA0003116047230000154
193.0,149.0,136.1,135.7,133.9,132.6,130.8,130.3,129.8,128.7,127.9,127.8,127.8,126.7,125.5,125.3,124.9,124.6,121.5,121.0,111.9,40.8,17.8.HRMS(EI)m/z Calculated for C24H19N2O3[M+H]+383.1390,found 383.1388.
(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(3ra):the
Figure BDA0003116047230000155
J＝15.1Hz,1H),1.87–1.81(m,2H),1.80–1.73(m,2H).13C NMR(100MHz,CDCl3)δ187.9,150.0,140.0,135.7,134.6(q,JC-F＝33.0Hz),130.7,130.0,128.9,125.9(q,JC-F＝4.0Hz),125.5,125.1,123.7(q,JC-F＝272.0Hz),122.9,121.6,121.0,111.9,41.1,18.1.19F NMR(376MHz,CDCl3)δ-63.19.HRMS(EI)m/zCalculated for C21H14F3N2O3[M-H]-399.0962,found 399.0970.
(E)-3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)-1-(4-nitrophenyl)prop-2-en-1-one(3sa):the reaction was
Figure BDA0003116047230000161
141.9,135.7,130.6,130.0,129.5,125.5,125.1,124.1,122.6,121.6,121.1,111.8,41.1 18.3.HRMS(EI)m/zCalculated for C20H15N3NaO5[M+Na]+400.0904,found 400.0908.
(E)-4-(3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)acryloyl)benzonitrile(3ta):the reaction was conducted at 0.1
Figure BDA0003116047230000162
125.5,125.1,122.4,121.6,121.0,118.0,116.5,111.8,41.1,18.2.HRMS(EI)m/z Calculated for C21H15N3NaO3[M+Na]+380.1006,found 380.1009.
(E)-4-(1-(6-fluoro-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ab):the reaction was conducted at 0.1
Figure BDA0003116047230000163
11.0Hz),131.0(d,JC-F＝3.0Hz),129.9,127.8,122.9(d,JC-F＝9.0Hz),117.4,113.9(d,JC-F＝23.0Hz),98.9(d,JC-F＝26.0Hz),40.3,28.7,17.6.19F NMR(376MHz,CDCl3)δ-114.84.HRMS(EI)m/z Calculated forC15H12FN2O3[M-H]-287.0837,found 287.0845.
(E)-4-(1-(5-chloro-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ac):the reaction was conducted at 0.1
Figure BDA0003116047230000164
125.0,121.4,119.2,114.4,40.4,27.1,17.3.HRMS(EI)m/z Calculated for C15H12ClN2O3[M-H]-303.0542,found 303.0549.
(E)-4-(1-(6-chloro-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ad):the reaction was conducted at
Figure BDA0003116047230000171
119.5,111.8,40.3,28.7,17.7.HRMS(EI)m/z Calculated for C15H12ClN2O3[M-H]-303.0542,found 303.0543.
(E)-4-(1-(5-bromo-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ae):the reaction was conducted at
Figure BDA0003116047230000172
121.9,117.4,114.7,40.4,27.1,17.3.HRMS(EI)m/z Calculated for C15H12BrN2O3[M-H]-347.0037,found347.0042.
(E)-4-(1-(5-methyl-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3af):the reaction was conducted at
Figure BDA0003116047230000173
129.4,127.7,126.9,121.2,121.0,111.5,40.3,28.8,21.8,17.6.HRMS(EI)m/z Calculated for C16H15N2O3[M-H]-283.1088 found 283.1080.
(E)-4-(1-(6-methyl-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ag):the reaction was conducted at
Figure BDA0003116047230000174
130.3,129.8,127.7,126.6,121.0,118.9,111.6,40.1,28.7,22.0,17.7.HRMS(EI)m/z Calculated for C16H16N2NaO3[M+Na]+307.1053,found 307.1052.
(E)-4-(1-(5-methoxy-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ah):the reaction was conducted at
Figure BDA0003116047230000175
146.9,130.6,130.5,129.4,127.7,121.9,115.9,112.8,102.4,56.1,40.3,28.7,17.6.HRMS(EI)m/z Calculatedfor C16H16N2NaO4[M+Na]+323.1002 found 323.1003.
(E)-4-(1-(7-methoxy-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ai):the reaction was conducted at
Figure BDA0003116047230000181
126.7,125.7,125.5,123.4,113.3,106.4,56.0,43.4,28.6.HRMS(EI)m/z Calculated for C16H15N2O4[M-H]-299.1037 found 299.1038.
(E)-4-(1-(5-(benzyloxy)-3-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3aj):the reaction was conducted
Figure BDA0003116047230000182
196.5,157.2,146.8,136.9,130.7,130.6,129.5,128.8,128.23,127.9,127.7,121.8,116.4,112.9,103.8,70.8,40.3,28.7,17.6.HRMS(EI)m/z Calculated for C22H20N2NaO4[M+Na]+399.1315 found 399.1317.
(E)-3-nitro-1-(1-(3-oxobut-1-en-1-yl)cyclopropyl)-1H-indole-5-carbonitrile(3ak):the reaction was
Figure BDA0003116047230000183
128.2,127.8,126.8,120.8,119.1,113.0,108.7,40.5,28.7,17.7.HRMS(EI)m/z Calculated for C16H13N3NaO3[M+Na]+318.0849 found 318.0853.
(E)-3-nitro-1-(1-(3-oxobut-1-en-1-yl)cyclopropyl)-1H-indol-4-yl acetate(3al):the reaction was conducted at
Figure BDA0003116047230000184
130.4,128.1,127.2,125.0,124.8,117.4,115.6,52.1,41.1,27.3,17.9.HRMS(EI)m/z Calculated for C17H17N2O5[M+H]+329.1132 found 329.1133.
(E)-4-(1-(3,5-dinitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3am):the reaction was conducted at 0.1
Figure BDA0003116047230000185
128.3,121.3,120.5,117.5,114.2,41.6,27.5,18.0.HRMS Calculated for C15H13N3NaO5[M+Na]+338.0747found 338.0745.
(E)-4-(1-(3,6-dinitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3an):the reaction was conducted at 0.1
Figure BDA0003116047230000191
135.6,129.9,128.3,126.0,121.9,120.0,109.6,41.5,27.4,18.0.HRMS(EI)m/z Calculated for C15H13N3NaO5[M+Na]+338.0747 found 338.0748.
(E)-4-(1-(3-acetyl-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ao):the reaction was conducted at 0.1 mmol
Figure BDA0003116047230000192
CDCl3)δ196.9,193.4,148.0,137.3,135.0,127.6,126.5,124.1,123.4,123.14,118.4,111.1,39.8,28.8,27.9,17.7.HRMS(EI)m/z Calculated for C17H17NNaO2[M+Na]+290.1151 found290.1155.
Methyl(E)-1-(1-(3-oxobut-1-en-1-yl)cyclopropyl)-1H-indole-3-carboxylate(3ap):the reaction was
Figure BDA0003116047230000193
(m,2H),1.61–1.55(m,2H).13C NMR(100MHz,CDCl3)δ196.9,165.4,148.1,137.0,134.7,127.5,126.8,123.6,122.7,122.3,111.3,108.6,51.4,39.7,28.8,17.6.HRMS(EI)m/z Calculated for C17H17NNaO3[M+Na]+306.1101 found 306.1104.
(E)-1-(1-(3-oxobut-1-en-1-yl)cyclopropyl)-1H-indole-3-carbaldehyde(3aq):the reaction was conducted at
Figure BDA0003116047230000194
MHz,CDCl3)δ196.8,184.9,147.6,138.6,137.7,127.6,125.5,124.8,123.7,122.7,119.3,111.3,39.9,28.8,17.6.HRMS(EI)m/z Calculated for C16H15NNaO2[M+Na]+276.0995 found 276.0998.
(E)-4-(1-(5-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3ar):the reaction was conducted at 0.1 mmol
Figure BDA0003116047230000195
2H),1.67–1.60(m,2H).13C NMR(100MHz,CDCl3)δ196.8,148.3,142.6,139.6,131.4,128.2,127.5,118.6,118.1,110.6,105.2,39.6,28.6,17.8.HRMS(APCI)m/z Calculated for C15H15N2O3[M+H]+271.1077 found271.1078.
(E)-4-(1-(6-nitro-1H-indol-1-yl)cyclopropyl)but-3-en-2-one(3as):the reaction was conducted at 0.1 mmol
Figure BDA0003116047230000201
2H),1.67–1.63(m,2H).13C NMR(100MHz,CDCl3)δ196.9,148.8,143.7,135.3,134.0,133.7,127.8,121.5,116.0,107.4,103.7,39.4,28.1,17.7.HRMS(APCI)m/z Calculated for C15H15N2O3[M+H]+271.1077 found 271.1077.
(E)-4-(1-(2-nitro-1H-pyrrol-1-yl)cyclopropyl)but-3-en-2-one(3au):the reaction was conducted at 0.1 mmol
Figure BDA0003116047230000202
148.3,127.4,122.8,122.7,106.3,43.0,28.8,17.5.HRMS(EI)m/z Calculated for C11H12N2NaO3[M+Na]+243.0740,found 243.0738.
Methyl(E)-1-(1-(3-oxobut-1-en-1-yl)cyclopropyl)-1H-imidazole-5-carboxylate(3av):the reaction was
Figure BDA0003116047230000203
CDCl3)δ196.4,163.1,147.8,139.1,134.2,127.2,126.5,52.0,40.0,29.0,17.2.HRMS(EI)m/z Calculated for C12H15N2O3[M+H]+235.1077,found 235.1077.
(E)-5-iodo-1-(1-(3-oxobut-1-en-1-yl)cyclopropyl)pyrimidine-2,4(1H,3H)-dione(3aw):the reaction was
Figure BDA0003116047230000204
for C11H10IN2O3[M-H]-344.9742 found 344.9741.
(E)-1-(1-(3-oxobut-1-en-1-yl)cyclopropyl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione(3ax):the
Figure BDA0003116047230000205
31.0Hz),42.5,27.2,18.2.19F NMR(376MHz,(CD3)2SO)δ-61.45.HRMS(EI)m/z Calculated for C12H11F3N2NaO3[M+Na]+311.0614,found 311.0610.
(E)-5-acetyl-1-(1-(3-oxobut-1-en-1-yl)cyclopropyl)pyridin-2(1H)-one(3ay):the reaction was conducted at
Figure BDA0003116047230000211
18.4.HRMS(APCI)m/z Calculated for C14H16NO3[M+H]+246.1125 found 246.1131.
(E)-3-(1-(3-oxobut-1-en-1-yl)cyclopropyl)pyrimidin-4(3H)-one(3az):the reaction was conducted at 0.1
Figure BDA0003116047230000212
28.0,17.6.HRMS(APCI)m/z Calculated for C11H13N2O3[M+H]+205.0972 found 205.0973.
(E)-2-(1-(3-oxobut-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3aa′):the reaction was conducted at 0.1
Figure BDA0003116047230000213
[M+Na]+278.0788 found 278.0789.
(E)-2-(1-(3-oxopent-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ca′):the reaction was conducted at 0.1
Figure BDA0003116047230000214
m/z Calculated for C16H15NNaO3[M+Na]+292.0944 found 292.0943.
(E)-2-(1-(3-oxo-5-phenylpent-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3da′):the reaction was
Figure BDA0003116047230000215
17.1.HRMS(EI)m/z Calculated for C22H19NNaO3[M+Na]+368.1257 found 368.1256.
Methyl(E)-3-(1-(1,3-dioxoisoindolin-2-yl)cyclopropyl)acrylate(3ea′):the reaction was conducted at 0.1
Figure BDA0003116047230000221
[M+Na]+294.0737 found 294.0734.
Ethyl(E)-3-(1-(1,3-dioxoisoindolin-2-yl)cyclopropyl)acrylate(3fa′):the reaction was conducted at 0.1 mmol
Figure BDA0003116047230000222
(E)-2-(1-(3-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ga′):the reaction was
Figure BDA0003116047230000223
Hz),131.6,131.2(d,JC-F＝10.0Hz),123.9,121.8,115.8(d,JC-F＝21.0Hz),33.2,17.5.19F NMR(376MHz,CDCl3)δ-105.67.HRMS(EI)m/z Calculated for C20H14FNNaO3[M+Na]+358.0850 found 258.0848.
(E)-2-(1-(3-(4-chlorophenyl)-3-oxoprop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ha′):the reaction
Figure BDA0003116047230000224
130.1,129.0,123.9,121.8,33.2,17.6.HRMS(EI)m/z Calculated for C20H14ClNNaO3[M+Na]+374.0554 found 374.0554.
(E)-2-(1-(3-(4-bromophenyl)-3-oxoprop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ia′):the reaction was
Figure BDA0003116047230000225
[M+Na]+418.0049 found 418.0049.
(E)-2-(1-(3-oxo-3-(p-tolyl)prop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ja′):the reaction was
Figure BDA0003116047230000231
forC21H17NNaO3[M+Na]+354.1101 found 354.1100.
(E)-2-(1-(3-oxo-3-(m-tolyl)prop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ka′):the reaction was
Figure BDA0003116047230000232
(EI)m/z Calculated for C21H17NNaO3[M+Na]+354.1101 found 354.1097.
(E)-2-(1-(3-oxo-3-(o-tolyl)prop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3la′):the reaction was
Figure BDA0003116047230000233
Calculated for C21H17NNaO3[M+Na]+354.1101 found 354.1101.
(E)-2-(1-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ma′):the reaction
Figure BDA0003116047230000234
C21H17NNaO4[M+Na]+370.1050 found 370.1052.
(E)-2-(1-(3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3na′):the
Figure BDA0003116047230000235
(q,JC-F＝271.0Hz),122.0,33.2,17.8.19F NMR(376MHz,CDCl3)δ-63.07.HRMS(EI)m/z Calculated for C21H14F3NNaO3[M+Na]+408.0818 found 408.0817.
(E)-4-(3-(1-(1,3-dioxoisoindolin-2-yl)cyclopropyl)acryloyl)benzonitrile(3oa′):the reaction was conducted at
Figure BDA0003116047230000241
m/z Calculated forC21H14N2NaO3[M+Na]+365.0897 found 365.0899.
(E)-2-(1-(3-(4-nitrophenyl)-3-oxoprop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3pa′):the reaction was
Figure BDA0003116047230000242
385.0791.
(E)-2-(1-(3-(furan-2-yl)-3-oxoprop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3qa′):the reaction was
Figure BDA0003116047230000243
found 330.0736.
(E)-2-(1-(3-oxo-3-(thiophen-2-yl)prop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ra′):the reaction was
Figure BDA0003116047230000244
found 346.0513.
(E)-2-(1-(3-(naphthalen-1-yl)-3-oxoprop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3sa′):he reaction was
Figure BDA0003116047230000245
Calculated for C24H17NNaO3[M+Na]+390.1101 found 390.1098.
(E)-2-(1-(3-oxo-3-phenylprop-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ta′):the reaction was conducted
Figure BDA0003116047230000251
(R,E)-6-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-bis((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthene-17-yl)-1-(1-(3-nitro-1H-indol-1-yl)cyclopr-opyl)hept-1-en-3-one
Figure BDA0003116047230000252
8H),1.60–1.36(m,8H),1.36–1.13(m,7H),1.13–0.99(m,3H),0.93–0.91(m,4H),0.90–0.87(m,18H),0.81(d,J＝6.4Hz,3H),0.59(s,3H),0.08–0.04(m,12H).13C NMR(100MHz,CDCl3)δ199.3,145.6,135.7,130.8,129.7,127.0,125.3,124.9,121.4,121.0,111.9,72.9,72.7,55.6,55.0,44.1,43.9,43.0,40.4,40.1,39.1,39.0,38.2,38.0,35.4,35.3,34.3,31.1,30.0,28.7,27.5,26.6,26.2,23.8,21.4,18.8,18.5,18.5,17.5,12.3,-2.7,-3.2,-4.4.HRMS(EI)m/z Calculated for C49H78N2NaO5Si2[M+Na]+853.5341,found 853.5334.
(R,E)-6-((3R,5R,6S,8S,9S,10R,13R,14S,17R)-3,6-bis((tert-butyldimethylsilyl)oxy)-10,13-dim-ethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-(1-(3-nitro-1H-indol-1-yl)cyclop-ropyl)hept-1-en-3-one(3va):the reaction was conducted at 0.1 mmol scale,CyPh2P asthecatalyst,82.8 mg,96％yield,unknown compound,
Figure BDA0003116047230000253
(m,12H).13C NMR(100MHz,CDCl3)δ199.3,145.7,135.7,130.8,129.7,127.0,125.3,124.9,121.4,121.0,111.9,73.1,68.8,56.2,56.0,49.7,43.0,40.4,40.1,39.7,39.0,36.1,36.1,35.6,35.4,35.0,31.2,29.9,28.2,26.2,26.1,24.3,23.7,20.9,18.6,18.6,18.3,17.6,12.2,-4.3,-4.5,-4.6,-4.6.HRMS(EI)m/z Calculated for C49H78N2NaO5Si2[M+Na]+853.5341,found 853.5342.
(E)-4-(3-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)acryloyl)-N,N-dipropylbenzenesulfonamide(3wa):the reaction was conducted at 0.1 mmol scale,CyPh2P asthecatalyst,31.8 mg,64％yield,unknown compound,
Figure BDA0003116047230000254
(100MHz,CDCl3)δ187.7,150.1,144.4,140.0,135.7,130.7,129.9,129.1,127.5,125.5,125.1,122.8,121.5,121.0,111.9,50.2,41.1,22.2,18.1,11.3.HRMS(EI)m/z Calculated for C26H29N3NaO5S[M+Na]+518.1720,found 518.1717.
(E)-4-(4-isobutylphenyl)-1-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)pent-1-en-3-one(3xa):the reaction was
Figure BDA0003116047230000261
2H),6.51(d,J＝15.3Hz,1H),5.36(d,J＝15.3Hz,1H),3.55(q,J＝6.9Hz,1H),2.41(d,J＝7.2Hz,2H),1.88–1.75(m,1H),1.70–1.63(m,2H),1.62–1.55(m,2H),1.29(d,J＝7.0Hz,3H),0.88(d,J＝6.6Hz,6H).13CNMR(100MHz,CDCl3)δ198.3,145.9,140.8,136.9,135.7,130.6,129.7,129.6,127.7,126.0,125.1,124.7,121.2,120.9,111.9,51.9,45.2,40.5,30.3,22.5,17.5,17.4,17.1.HRMS(EI)m/z Calculated for C26H28N2NaO3[M+Na]+439.1992,found 439.1994.
(E)-4-(5-methoxynaphthalen-1-yl)-1-(1-(3-nitro-1H-indol-1-yl)cyclopropyl)pent-1-en-3-one(3ya):thereaction was conducted at 0.1 mmol scale,CyPh2P asthecatalyst,24.1 mg,55％yield,unknown compound,
Figure BDA0003116047230000262
6.9Hz,1H),1.69–1.57(m,2H),1.55–1.49(m,2H),1.37(d,J＝6.9Hz,3H).13C NMR(100MHz,CDCl3)δ198.1,158.0,145.8,135.5,134.8,133.8,130.5,129.6,129.4,129.2,127.7,126.7,126.4,126.1,125.0,124.6,121.0,120.7,119.3,111.7,105.8,55.6,52.2,40.5,17.5,17.3,17.1.HRMS(EI)m/z Calculated forC27H24N2NaO4[M+Na]+463.1628,found 463.1626.
2-(1-((R,E)-6-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-bis((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-oxohept-1-en-1-yl)cyclopro-pyl)is-oindoline-1,3-dione(3ua′):the reaction was conducted at 0.1 mmol scale,Cy3P asthecatalyst,76.3 mg,94％yield,unknown
Figure BDA0003116047230000263
0.93–0.85(m,25H),0.61(s,3H),0.09–0.02(m,12H).13C NMR(100MHz,CDCl3)δ199.5,167.9,146.9,134.6,131.6,126.4,123.8,72.9,72.7,55.7,55.0,44.2,43.9,43.0,40.1,39.0,38.2,38.0,37.5,35.4,35.3,34.3,32.5,31.1,30.1,28.7,27.5,26.6,26.2,23.8,21.4,18.9,18.5,18.5,17.0,12.3,-2.7,-3.2,-4.4.HRMS(EI)m/zCalculated for C49H77NNaO5Si2[M+Na]+838.5232,found 838.5224.
2-(1-((R,E)-6-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-bis((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phena-nthren-17-yl)-3-oxohept-1-en-1-yl)cyclopro-pyl)is-oindoline-1,3-dione(3va′):the reaction was conducted at 0.1 mmol scale,Cy3P asthecatalyst,68.0 mg,83％yield,unknown
Figure BDA0003116047230000271
(m,12H).13C NMR(100MHz,CDCl3)δ199.5,167.9,147.0,134.6,131.6,126.4,123.8,73.1,68.8,56.3,56.0,49.7,43.0,40.1,39.8,37.5,36.1,36.1,35.6,35.8,35.0,32.5,31.2,30.0,28.2,26.2,26.1,24.4,23.7,20.9,18.7,18.6,18.3,17.0,12.2,-4.3,-4.5,-4.6,-4.6.HRMS(EI)m/z Calculated for C49H77NNaO5Si2[M+Na]+838.5232,found 838.5224.
(E)-4-(3-(1-(1,3-dioxoisoindolin-2-yl)cyclopropyl)acryloyl)-N,N-dipropylbenzenesulfonamide(3wa′):the reaction was conducted at 0.1 mmol scale,CyPh2P asthecatalyst,35.7 mg,74％yield,unknown compound,
Figure BDA0003116047230000272
123.9,121.7,50.1,33.2,22.1,17.8,11.3.HRMS(EI)m/z Calculated for C26H28N2NaO5S[M+Na]+503.1611,found 503.1607.
(E)-2-(1-(4-(4-isobutylphenyl)-3-oxopent-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3xa′):the reaction
Figure BDA0003116047230000273
6.9Hz,1H),2.44–2.36(m,2H),1.85–1.73(m,1H),1.52–1.37(m,4H),1.35(d,J＝7.0Hz,3H),0.90–0.85(m,6H).13C NMR(100MHz,CDCl3)δ198.7,167.8,147.6,140.5,137.8,134.6,131.5,129.7,127.8,124.8,123.7,50.9,45.2,32.62,30.3,22.6,18.1,17.1,17.0.HRMS(EI)m/z Calculated for C26H27NNaO3[M+Na]+424.1883,found 424.1882.
(E)-2-(1-(4-(5-methoxynaphthalen-1-yl)-3-oxopent-1-en-1-yl)cyclopropyl)isoindoline-1,3-dione(3ya′):thereaction was conducted at 0.1 mmol scale,Cy3P asthecatalyst,28.3 mg,67％yield,unknown compound,white
Figure BDA0003116047230000274
134.5,133.7,131.3,129.3,129.2,127.6,126.6,124.7,123.6,119.1,105.7,55.5,51.3,32.7,18.1,17.1,17.0.HRMS(EI)m/z Calculated for C27H23NNaO4[M+Na]+448.1519,found 448.1523.
(Z)-4-cyclopropyl-3-(3-nitro-1H-indol-1-yl)but-3-en-2-one(4aa):unknown compound,colorless oil,Rf＝
Figure BDA0003116047230000281

Claims (10)

1. A method for constructing a 1-substituted cyclopropylamine compound by a phosphine-catalyzed C-H activated amination reaction of cyclopropane is characterized in that the cyclopropylamine compound is obtained by reacting cyclopropane 1 and an amide or an N-heterocyclic aromatic compound 2 as substrates with organic phosphine as a catalyst;
the reaction route is as follows:
formula I
Figure FDA0003587151810000011
In the formula:
r is unsubstituted or substituted alkyl, or is alkoxy, or is unsubstituted or substituted phenyl, or is naphthyl, thiophene or furan; when substituted, the substituents are selected from methyl, methoxy, nitro, cyano, trifluoromethyl, dipropylaminosulfonyl, halogen;
the amide or N-heterocyclic aromatic compound 2 is unsubstituted or substituted indole, pyrrole, imidazole, uracil, pyridine, pyrimidine or phthalimide, and when substituted, the substituent is selected from acyl, aldehyde, carbomethoxy, halogen, methyl, alkoxy, hydroxyl, nitro, cyano, trifluoromethyl.
2. The method of claim 1, wherein: the alkyl in R is C1-C35, and the alkoxy is C1-C2.
3. The method of claim 1, wherein: the substituted indole is indole containing 1-2 substituents, the substituted pyrrole is pyrrole containing 1 substituent, the substituted imidazole is imidazole containing 1 substituent, the substituted uracil is uracil containing 1 substituent, the substituted pyridine is pyridine containing 1-2 substituents, and the substituted pyrimidine is pyrimidine containing 1 substituent.
4. The method of claim 1, wherein: the method comprises the following steps:
under the nitrogen atmosphere, adding an organic phosphine catalyst and an organic solvent into cyclopropane 1 and an amide or N-heterocyclic aromatic compound 2 substrate, and reacting to obtain the cyclopropylamine compound.
5. The method of claim 1, wherein: the reaction temperature is between room temperature and 100 ℃, and the reaction time is between 12 and 24 hours.
6. The method of claim 4, wherein: the concentration of the amide or the N-heterocyclic aromatic compound 2 is 0.05 to 0.2 mmol/mL.
7. The method of claim 1, wherein: the mol ratio of the organic phosphine catalyst, the cyclopropane 1 and the amide or the N-heterocyclic aromatic compound 2 is 0.05-0.3:1.0-1.5: 1.0.
8. The method of claim 4, wherein: the organic solvent is one of benzene, toluene, o-xylene, dichloromethane, dichloroethane, chloroform, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, diethyl ether, acetonitrile and N, N-dimethylformamide.
9. The method of claim 1, wherein: the organic phosphine catalyst is selected from tricyclohexylphosphine, triphenylphosphine, tri-tert-butylphosphine, tri-n-butylphosphine, diphenylcyclohexylphosphine and tri (4-methoxyphenyl) phosphine.
10. The process of claim 1, wherein after the reaction is completed, the reaction mixture is cooled to room temperature and quenched with water.
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