CN114656369A - High allylamine compound, synthesis method and application thereof - Google Patents

High allylamine compound, synthesis method and application thereof Download PDF

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CN114656369A
CN114656369A CN202210058369.2A CN202210058369A CN114656369A CN 114656369 A CN114656369 A CN 114656369A CN 202210058369 A CN202210058369 A CN 202210058369A CN 114656369 A CN114656369 A CN 114656369A
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alkyl
cycloalkane
hydrogen
imine
heterocycloalkane
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石磊
宋冰坤
陈昱清
林爽杰
史彩哲
张丹丹
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Dalian University of Technology
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    • C07C229/00Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
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    • C07C311/21Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract

The invention provides a high allylamine compound, a synthesis method and application thereof, belonging to the field of organic chemistry. Under the conditions of room temperature and inert gas protection, and in the presence of an organic photosensitizer and an electron donor, imine reacts with 1, 3-butadiene derivatives and halogenated alkane under blue light irradiation, and the high allylamine compound is obtained with high selectivity. The method has the advantages of mild reaction conditions, short reaction steps, simple post-treatment, and high stereoselectivity and regional selection of reaction products. Meanwhile, the method can be used for derivatization of natural products and post-modification of drug molecules.

Description

High allylamine compound, synthesis method and application thereof
Technical Field
The invention belongs to the field of organic synthesis, and relates to a high allylamine compound, a synthesis method and application thereof.
Background
The homoallylamine compounds are important components for synthesizing various medicaments and natural substances with biological activity. The addition of allyl metal complexes to the carbon-nitrogen double bond of imines is one of the most efficient methods for obtaining homoallylic amines, which has promoted the rapid development of synthetic and pharmaceutical chemistry over the last decades. However, the process of preparation relying on preactivated allylhalohydrocarbons and stoichiometric amounts of metal reducing agents is cumbersome and uneconomical and results in environmental pollution and waste of resources. Therefore, the simple, economical and environment-friendly synthesis method of the high allylamine compound is developed, and the high allylamine compound is applied to the synthesis of natural substances with biological activity and has great promotion effect on synthetic chemistry and pharmaceutical chemistry.
Disclosure of Invention
The invention provides a high allylamine compound, a synthesis method and application thereof.
The technical scheme adopted by the invention is as follows:
a high allylamine compound has the following structure:
Figure BDA0003477281320000011
wherein Ar is2Is a substituted phenyl group; ar (Ar)1Is substituted phenyl or heterocyclyl;
R1selected from hydrogen, C1-C6 primary alkyl, C1-C6 secondary alkyl, C1-C6 tertiary alkyl, cycloalkane or heterocompoundA cycloalkyl group;
R2selected from hydrogen, primary alkyl groups of C1-C6, secondary alkyl groups of C1-C6, tertiary alkyl groups of C1-C6, cycloalkane or heterocycloalkyl radicals;
R3selected from hydrogen, C1-C6 primary alkyl, C1-C6 secondary alkyl, C1-C6 tertiary alkyl, cycloalkane or heterocycloalkane;
r4 is selected from hydrogen, C1-C6 primary alkyl, C1-C6 secondary alkyl, C1-C6 tertiary alkyl, cycloalkane or heterocycloalkane;
r5 is selected from hydrogen, C1-C6 primary alkyl, C1-C6 secondary alkyl, C1-C6 tertiary alkyl, cycloalkane or heterocycloalkane;
the substituent in the substituted phenyl is selected from halogen, alkyl, alkoxy, alkoxycarbonyl or amino.
The invention also provides a synthetic method of the high allylamine compound, and the synthetic route is as follows:
Figure BDA0003477281320000021
the method comprises the following steps: under the conditions of room temperature and the protection of inert gases, illumination, the presence of an organic photosensitizer and an electron donor, the halogenated alkane 1 reacts with the 1, 3-butadiene derivative 2 and the imine 3 in a solvent to obtain the homoallylamine compound 4.
The organic photosensitizer may be 4 CzIPN.
The electron donor may be diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate (HE) or triethylamine.
The molar ratio of the halogenated alkane 1, the 1, 3-butadiene 2, the imine 3, the organic photosensitizer and the HE is 2.0:2.0:1.0:0.01: 2.0;
the molar ratio of the halogenated alkane 1, the 1, 3-butadiene 2, the imine 3, the organic photosensitizer and the triethylamine is 2.0:2.0:1.0:0.01: 4.0.
the solvent is Dichloroethane (DCE).
The method of the invention can be applied to derivatization of natural substances with biological activity or post-modification of drug molecules, based on homoallylic amination of various compounds and high-yield derivatization of natural active substances (such as lithocholic acid and estrone) or drug molecules (such as indomethacin and probenecid), and has a promoting effect on the development of synthetic chemistry and pharmaceutical chemistry.
The method is applicable to imine reaction substrates with similar structures, and has the advantages of high reaction yield and high selectivity. Meanwhile, the reaction has better application in derivatization of natural active substances and post-modification of drug molecules.
Drawings
FIG. 1 is a schematic representation of the imine quenched 4CzIPN of example 16.
FIG. 2 is a schematic representation of triethylamine quenched 4CzIPN in example 16.
FIG. 3 is a schematic representation of 3-iodooxetane quenched 4CzIPN of example 16.
In the figure: i is0Fluorescence intensity without addition of a quencher; i is the fluorescence intensity after addition of the quencher.
FIG. 4 is a graph showing the change of the main species in the fluorescence quenching reaction system of example 16.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to the following specific examples.
Exploration test of reaction conditions: (taking the example of the reaction of 2a, 1, 3-butadiene and 3a to give 5 a)
Typically, compound 2a (2.0mmol), 1, 3-butadiene (2.0mmol), compound 3a (1.0mmol), 4CzIPN (0.01mmol), HE (2.0mmol) and 5mL DCE were mixed and reacted by irradiation with a 10W 450nm LED lamp at room temperature under inert gas protection for 4h, and the complete disappearance of the starting material 3a was monitored by thin layer plate (TLC) (4 h); the solvent was dried by spin-drying and column chromatography (eluent petroleum ether/ethyl acetate 20/1) gave colorless liquid 4 a.
The reaction equation is as follows:
Figure BDA0003477281320000031
TABLE 1
Numbering Reaction conditions 4a yield/%
1 none 89%
2 No PC,450nm 40%
3 No light N.R
4 Ir-1instead of 4CzPIN 88%
5 Ir-2instead of 4CzPIN 91%
6 TEA instead of HE N.R
7 DIPEA instead of HE N.R
8 DBACO instead of HE N.R
9 THF instead of DCE 57%
10 ACN instead of DCE 71%
11 DCM instead of DCE 66%
12 Under air 0
13 No PC,400nm 23%
Figure RE-GDA0003633581430000041
As shown in the table, the boundary conditions of the reaction were investigated, and it was found that the target product was obtained in different yields under all other possible reaction conditions. Finally, the optimal reaction conditions are determined as follows: under the protection of inert gas at room temperature, 4CzIPN is used as photosensitizer, HE is used as electron donor, and the mixture is irradiated by a 450nm LED lamp in trichloroethane (DCE) solvent.
Example 1:
Figure BDA0003477281320000042
4a, the experimental procedures and purification methods were carried out with reference to the search experiment. RF 0.5(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 10/1, 87% yield, product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.18–7.07(m,2H),6.81(d,J=8.7Hz,2H),6.74(s, 2H),5.55–5.43(m,1H),5.44–5.26(m,1H),4.10(dd,J=7.7,5.9Hz,1H),3.78(s, 3H),3.24(s,1H),2.72–2.45(m,2H),2.27–2.17(m,7H),2.12(s,6H),1.43(s,9H). 13C NMR(101MHz,CDCl3):δ172.43,158.45,142.08,135.80,131.37,130.52, 129.44,129.06,127.84,127.47,113.57,80.07,61.15,55.13,39.95,35.26,28.06, 28.03,20.46,18.98.HRMS-ESI(m/z)[M+H]+calculated for C27H38NO3,424.2852, found:424.2841.
Example 2:
Figure BDA0003477281320000051
by using
Figure BDA0003477281320000052
Replacement of
Figure BDA0003477281320000053
The experimental procedures and purification were carried out according to the search experiment. RF 0.5(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20:1, 65% yield, product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.24(dd,J=26.8,8.4Hz,2H),7.13(d,J=8.4Hz, 2H),6.74(dd,J=128.5,48.0Hz,2H),5.61–5.44(m,1H),5.34(d,J=7.1Hz,1H), 4.14(dt,J=399.6,7.5,5.9Hz,1H),3.25(s,1H),2.57(ddd,J=37.4,14.0,7.1Hz, 2H),2.21(d,J=8.7Hz,7H),2.10(s,6H),1.43(s,9H).13C NMR(101MHz, CDCl3):δ172.34,142.22,132.48,132.05,130.76,130.40,129.56,128.91,128.33, 128.22,126.75,80.13,61.13,40.02,35.17,28.06,27.99,20.45,19.00.HRMS-ESI (m/z)[M+H]+calculated for C26H35ClNO2,428.2356,found:428.2344.
Example 3:
Figure BDA0003477281320000054
by using
Figure BDA0003477281320000055
Replacement of
Figure BDA0003477281320000056
The experimental procedures and purification were carried out according to the search experiment. RF 0.5(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20/1% yield, the product being a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.39(d,J=8.4Hz,2H),7.08(dd,J=8.6,2.1Hz, 2H),6.74(s,2H),5.58–5.46(m,1H),5.39–5.28(m,1H),4.19–4.09(m,1H),3.25 (s,1H),2.55(dq,J=36.8,7.1Hz,2H),2.20(d,J=9.1Hz,7H),2.10(d,J=4.4Hz, 6H),1.42(s,9H).13C NMR(101MHz,CDCl3):δ172.33,142.78,141.89,132.06, 131.25,130.67,129.54,128.82,128.55,126.70,120.56,80.12,61.10,40.02,35.14, 28.04,27.97,20.43,19.01.HRMS-ESI(m/z)[M+H]+calculated for C26H35BrNO2, 474.1831,found:474.1814.
Example 4:
Figure BDA0003477281320000061
by using
Figure BDA0003477281320000062
Replacement of
Figure BDA0003477281320000063
The experimental procedure and the purification mode were performed according to the exploration experiment. RF 0.6(EA: PE 1:2), eluent: petroleum ether/ethyl acetate 20/1, 89% yield, the product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.32–7.20(m,5H),6.76(s,2H),5.74–5.44(m, 1H),5.38(dd,J=14.6,7.5Hz,1H),4.43–3.80(m,1H),3.29(s,1H),2.95–2.51 (m,2H),2.22(d,J=4.0Hz,8H),2.13(s,5H),1.44(s,9H).13C NMR(101MHz, CDCl3):δ172.43,143.72,142.18,131.52,130.43,129.45,128.91,128.22,127.28, 126.84,126.77,80.08,61.70,40.02,35.24,28.05,20.46,18.99.HRMS-ESI(m/z) [M+H]+calculated for C26H36NO2,394.2746,found:394.2737.
Example 5:
Figure BDA0003477281320000064
by using
Figure BDA0003477281320000065
Replacement of
Figure BDA0003477281320000066
The experimental steps and the purification mode are carried out according to the exploration experiment. RF 0.5(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20/1 in 76% yield as a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.19–7.12(m,2H),7.01–6.92(m,2H),6.74(s, 2H),5.50(dddd,J=15.4,7.7,4.5,1.2Hz,1H),5.38–5.29(m,1H),4.13(dd,J=7.6, 5.9Hz,1H),3.21(s,1H),2.61(td,J=7.6,6.9,4.1Hz,1H),2.55–2.47(m,1H), 2.29–2.16(m,7H),2.10(s,6H),1.42(s,9H).13C NMR(101MHz,CDCl3):δ 172.39,161.74(d,J=244.8Hz),141.92,139.43(d,J=2.0Hz),131.83,130.72, 129.51,129.02,128.29(d,J=7.9Hz),126.99,115.09,114.88,80.13,61.05,40.06, 35.20,28.05,28.0,20.46,18.96.HRMS-ESI(m/z)[M+H]+calculated for C26H35NO2, 412.2652,found:412.2640.
Example 6:
Figure BDA0003477281320000071
by using
Figure BDA0003477281320000072
Replacement of
Figure BDA0003477281320000073
The experimental procedures and purification were carried out according to the search experiment. RF 0.5(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20/1% yield, the product being a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.51(dd,J=8.0,1.3Hz,1H),7.46(dd,J=7.8,1.7 Hz,1H),7.31(td,J=7.5,1.3Hz,1H),7.10(ddd,J=7.9,7.3,1.7Hz,1H),6.77(s, 2H),5.64–5.50(m,1H),5.43–5.25(m,1H),4.71(t,J=5.8Hz,1H),3.63(s,1H), 2.64–2.48(m,1H),2.32–2.22(m,4H),2.21(d,J=2.7Hz,4H),2.17(s,6H),1.45 (s,9H).13C NMR(101MHz,CDCl3):δ172.35,143.41,142.69,132.71,132.64, 129.85,129.63,128.52,128.11,127.53,127.21,126.09,122.87,80.15,60.29,39.80, 35.13,28.04,20.36,19.17.HRMS-ESI(m/z)[M+H]+calculated for C26H35BrNO2, 472.1851,found:472.1842.
Example 7:
Figure BDA0003477281320000081
by using
Figure BDA0003477281320000082
Replacement of
Figure BDA0003477281320000083
The experimental procedures and purification were carried out according to the search experiment. RF 0.5(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20/1, 75% yield, product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.39(d,J=8.4Hz,1H),7.34(d,J=2.1Hz,1H), 7.23(dd,J=8.3,2.2Hz,1H),6.76(s,2H),5.62–5.50(m,1H),5.33–5.22(m,1H), 4.67(t,J=5.7Hz,1H),3.56(s,1H),2.53(tq,J=14.3,7.8Hz,2H),2.27–2.15(m, 7H),2.13(s,6H),1.43(s,9H).13C NMR(101MHz,CDCl3):δ172.31,142.52, 140.55,133.02,132.98,132.73,130.18,129.70,129.45,129.15,127.63,126.93, 125.72,80.22,57.85,39.50,35.09,28.06,28.02,20.37,19.12.HRMS-ESI(m/z) [M+H]+calculated for C26H34Cl2NO2,462.1967,found:462.1957.
Example 8:
Figure BDA0003477281320000084
by using
Figure BDA0003477281320000085
Replacement of
Figure BDA0003477281320000086
The experimental steps and the purification mode are carried out according to the exploration experiment. RF 0.5(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20/1, 81% yield, the product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.43(dd,J=7.7,1.4Hz,1H),7.23(td,J=7.5,1.7 Hz,1H),7.14(td,J=7.3,1.4Hz,1H),7.11–7.08(m,1H),6.76(s,2H),5.56–5.44 (m,1H),5.39–5.26(m,1H),4.46(dd,J=7.5,5.8Hz,1H),3.33(s,1H),2.61–2.45 (m,2H),2.22(s,6H),2.18(s,3H),2.15(d,J=6.5Hz,7H),1.45(d,J=8.1Hz,9H). 13C NMR(101MHz,CDCl3):δ172.41,142.58,142.52,135.16,131.56,130.29, 130.25,129.48,128.62,127.18,126.52,126.13,125.71,80.08,57.26,39.71,35.22, 28.03,28.00,20.43,19.27,18.90.HRMS-ESI(m/z)[M+H]+calculated for C27H38NO2,408.2903,found:408.2892.
Example 9:
Figure BDA0003477281320000091
by using
Figure BDA0003477281320000092
Replacement of
Figure BDA0003477281320000093
The experimental steps and the purification mode are carried out according to the exploration experiment. RF 0.5(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20/1 in 85% yield as a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.08(d,J=2.7Hz,4H),6.74(s,2H),5.56–5.43(m, 1H),5.41–5.25(m,1H),4.13(dd,J=7.6,5.9Hz,1H),3.24(s,1H),2.70–2.44(m, 1H),2.56(dtd,J=21.3,13.9,13.5,6.2Hz,2H),2.31(d,J=2.9Hz,3H),2.20(d,J= 4.7Hz,6H),2.11(d,J=2.9Hz,6H),1.43(d,J=9.2Hz,9H).13C NMR(101MHz, CDCl3):δ172.43,142.22,140.70,136.30,131.34,130.32,129.43,128.89,127.43, 126.64,80.05,61.38,40.03,35.24,28.04,21.02,20.44,19.01.HRMS-ESI(m/z) [M+H]+calculated for C27H38NO2,408.2903,found:408.2889.
Example 10:
Figure BDA0003477281320000094
by using
Figure BDA0003477281320000095
Replacement of
Figure BDA0003477281320000096
The experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20/1, 69% yield, the product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.16(dd,J=5.0,1.2Hz,1H),6.90(dd,J=5.1,3.5 Hz,1H),6.77(s,2H),6.74(d,J=3.4Hz,1H),5.60–5.42(m,2H),4.43–4.37(m, 1H),3.22(s,1H),2.75–2.54(m,2H),2.24(dd,J=6.8,2.4Hz,4H),2.21(s,3H), 2.12(s,6H),1.43(s,9H).13C NMR(101MHz,CDCl3):δ172.51,147.98,141.62, 131.98,131.04,129.52,129.47,127.08,126.64,123.92,123.77,80.20,57.28,40.47, 35.24,28.14,28.10,20.58,18.79.HRMS-ESI(m/z)[M+H]+calculated for C24H34NO2S,400.2310,found:400.2300.
Example 11:
Figure BDA0003477281320000101
by using
Figure BDA0003477281320000102
Replacement of
Figure BDA0003477281320000103
The experimental procedure and purification mode were carried out with reference to the exploratory experiment using 3-iodooxetane as the alkyl radical precursor. RF 0.4(EA: PE 1:5), eluent: petroleum ether/ethyl acetate 20/1, 71% yield, and the product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.56(dd,J=7.9,1.2Hz,1H),7.37–7.29(dd,3H), 7.22(td,J=7.5,1.2Hz,1H),7.10(td,J=7.6,1.8Hz,1H),6.20(d,2H),5.56(dt,J= 15.0,6.5Hz,1H),5.42(dt,1H),4.78(ddd,J=7.8,6.0,2.9Hz,2H),4.70(dt,J=8.5, 4.5Hz,1H),4.35(t,J=6.0Hz,2H),4.27(d,J=4.2Hz,1H),3.02(tt,J=7.6,5.9Hz, 1H),2.61(dt,J=14.4,5.6Hz,1H),2.38(m,J=11.7,6.9Hz,3H).13C NMR(101 MHz,CDCl3):δ146.30,141.05,137.70,133.10,130.91,128.69,127.81,127.55, 127.35,122.92,115.55,78.38,76.62,55.98,39.54,36.01,34.28.HRMS-ESI(m/z) [M+H]+calculated for C20H22BrINO,497.9929,found:497.9930.
Example 12: derivatization of lithocholic acid
Lithocholic acid is a secondary bile acid, also known as cholalic acid, 3 a-dihydroxy -carboxylic acid, and is present in higher vertebrate bile. The molecular structure of the bile acid contains both hydrophilic groups and hydrophobic groups, so that the spatial configuration of the bile acid has two properties of hydrophilicity and hydrophobicity, and the bile acid has strong interfacial activity. Meanwhile, lithocholic acid has more pharmacological activities, such as: inhibiting tumor growth, selectively killing breast cancer cells, and selectively inhibiting the activity of mammalian DNA polymerase.
The steps of the derivatization of lithocholic acid in the invention are as follows:
first, lithocholic acid is derivatized to an imine by reaction with an imine:
Figure RE-GDA0003633581430000111
and reacting the derived imine with 1, 3-butadiene and an alkyl halide to obtain the homoallylic amine compound derived from lithocholic acid.
Figure BDA0003477281320000112
The experimental procedures and purification were carried out according to the search experiment. RF 0.5(EA: PE 1:2), eluent: petroleum ether/ethyl acetate 20/1, 51% yield, the product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.30(dd,J=8.6,3.6Hz,4H),7.02(d,J=8.5Hz, 2H),6.30–6.23(m,2H),5.60(dt,J=15.2,5.8Hz,1H),5.38(dt,J=14.8,7.0Hz, 1H),4.29(d,J=11.0Hz,2H),3.63(dt,J=11.0,6.2Hz,1H),2.64–2.35(m,4H), 2.29(q,J=1.7Hz,3H),2.03–1.71(m,9H),1.50(dd,J=15.5,7.2Hz,3H),1.43(s, 15H),1.32–1.21(m,4H),1.21–1.03(m,5H),0.97(d,J=6.3Hz,4H),0.92(s,3H), 0.66(s,3H).13C NMR(101MHz,CDCl3):172.75,172.33,149.69,146.76,140.34, 137.56,133.15,127.09,126.40,121.65,115.79,80.32,78.08,71.85,58.46,56.51(d, J=4.3Hz),55.95,42.75,42.07,41.87,40.41,40.16,36.43,35.83,35.34,35.24, 34.55,31.37,30.94,30.53,28.22,28.10,27.17,26.39,24.19,23.35,20.81,18.29, 12.06.HRMS-ESI(m/z)[M+H]+calculated for C47H67INO5,852.4064,found: 852.4055.
Example 13: derivatization of estrone
Estrone, also known as feminone, is a white crystalline powder, soluble in ethanol and insoluble in water. Is obtained from pregnant woman urine or livestock ovary. It is the original hormone secreted by female animal ovary, has been used in clinic, is an important medical intermediate, is the intermediate of hormone ethinylestradiol for No. 1 contraceptive, and is mainly used for treating uterine hypoplasia, menstrual disorder, climacteric disturbance and the like.
The steps of the derivatization of estrone in the invention are as follows:
firstly, estrone reacts with 1, 3-diiodopropane to be derived into iodide:
Figure BDA0003477281320000121
and reacting the derived iodo product with 1, 3-butadiene and imine to obtain the homoallylic amine compound derived from estrone.
Figure BDA0003477281320000122
The experimental procedures and purification were carried out according to the search experiment. RF 0.5(EA: PE 1:4), eluent: petroleum ether/ethyl acetate 20/1, 58% yield, product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.56(dd,J=7.9,1.3Hz,1H),7.35(dd,J=7.8,1.8 Hz,1H),7.31(dd,J=8.7,3.4Hz,2H),7.22(ddd,J=10.3,7.8,2.6Hz,2H),7.09 (dd,J=7.6,1.8Hz,1H),6.71(dd,J=8.6,2.7Hz,1H),6.65(d,J=2.8Hz,1H), 6.19(d,J=8.7Hz,2H),5.62(dt,J=15.0,6.6Hz,1H),5.41(dt,J=14.9,7.7Hz, 1H),4.68(dt,J=8.7,4.3Hz,1H),4.29(d,J=4.6Hz,1H),3.93(t,J=6.4Hz,2H), 3.10–2.77(m,2H),2.70–2.58(m,1H),2.51(dd,J=18.8,8.6Hz,1H),2.40(dd,J =8.0,4.9Hz,1H),2.36–2.24(m,2H),2.19–2.08(m,3H),2.08–1.93(m,3H), 1.82–1.72(m,2H),1.67–1.38(m,8H),0.92(s,3H).13C NMR(101MHz,CDCl3): δ157.02,146.41,141.24,137.70,137.64,134.67,133.06,131.91,128.61,127.79, 127.56,126.29,125.82,122.84,115.59,114.52,112.02,78.28,77.21,67.52,56.06, 50.36,47.98,43.94,39.55,38.33,35.84,32.15,31.54,29.63,28.71,26.53,25.89, 25.75,21.55.HRMS-ESI(m/z)[M+H]+calculated for C38H44BrINO2,752.1600, found:752.1590.
Example 14: derivatization of indomethacin
Indomethacin, a white-like to yellowish crystalline powder, dissolved in acetone and insoluble in water. Is an artificially synthesized indole derivative. Indomethacin is one of the strongest PG synthetase inhibitors, has remarkable anti-inflammatory and antipyretic effects, and has obvious analgesic effect on inflammatory pain.
The steps of the derivatization of the indometacin in the invention are as follows:
indometacin is firstly derived from imine reaction and then reacts with butadiene and alpha-bromoacetic acid tert-butyl ester:
Figure BDA0003477281320000131
the experimental procedures and purification were carried out according to the search experiment. RF 0.5(EA: PE 1:2), eluent: petroleum ether/ethyl acetate 20/1, 52% yield, the product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ7.67(d,J=8.6Hz,2H),7.47(d,J=8.5Hz,2H), 7.32–7.27(m,3H),7.05(d,J=2.5Hz,3H),7.01(d,J=8.5Hz,1H),6.88(d,J= 9.1Hz,1H),6.69(dd,J=9.0,2.5Hz,1H),6.26(dd,J=8.9,2.7Hz,2H),5.60(dd,J =15.2,6.4Hz,1H),5.38(dt,J=12.9,7.7Hz,1H),4.65(tdd,J=10.9,8.2,4.4Hz, 1H),4.26(dt,J=12.1,4.5Hz,2H),3.89(s,2H),3.83(s,3H),2.55–2.48(m,1H), 2.45(s,2H),2.35(d,J=3.1Hz,4H),1.93–1.79(m,2H),1.70–1.64(m,2H),1.50 –1.23(m,3H),1.06–0.92(m,2H),0.88(dd,J=6.9,2.1Hz,5H),0.84(d,J=6.5 Hz,2H),0.73(dd,J=14.3,7.0Hz,3H).13C NMR(101MHz,CDCl3):δ172.51, 169.27,168.28,156.09,149.59,146.68,140.76,139.33,136.19,133.79,132.99, 131.19,130.81,130.47,129.14,127.09,127.07,126.74,126.62,121.50,115.82, 115.00,111.98,111.77,101.17,78.17,77.20,74.25,74.15,56.52,56.44,55.71,46.94, 42.02,41.90,40.99,40.94,34.48,34.17,31.35,31.28,30.56,28.13,26.21,23.35, 22.00,20.75,16.29,16.26,13.40.HRMS-ESI(m/z)[M+H]+calculated for C48H53ClIN2O6,915.2637,found:915.2631。
Example 15: derivatization of probenecid
Probenecid is also called carbosulfan, white crystalline powder, is dissolved in acetone and is not dissolved in water. Is a renal tubule blocking drug, inhibits the reabsorption of urate by renal tubules, promotes the excretion of uric acid, reduces the concentration of uric acid plasma, reduces the deposition of uric acid, promotes the reabsorption of uric acid sediments, and thus plays a role in resisting chronic gout.
The steps of derivatization of propane sulfonic acid in the invention are as follows:
firstly, probenecid reacts with imine to derive a new imine compound, and then reacts with butadiene and alpha-tert-butyl bromoacetate:
Figure BDA0003477281320000151
Figure BDA0003477281320000152
the experimental procedures and purification were carried out according to the search experiment. RF 0.5(EA: PE 1:2), eluent: petroleum ether/ethyl acetate ═ 20-1, yield 71%, product was a colorless liquid.
1H NMR(400MHz,CDCl3):δ8.30(d,J=8.5Hz,2H),7.94(d,J=8.5Hz,2H), 7.38(d,J=8.5Hz,2H),7.32(d,J=8.7Hz,2H),7.17(d,J=8.6Hz,2H),6.29(d,J =8.8Hz,2H),5.62(dt,J=14.8,6.0Hz,1H),5.40(dt,J=14.8,7.0Hz,1H),4.35– 4.30(m,2H),3.18–3.08(m,4H),2.63–2.38(m,2H),2.34–2.25(m,4H),1.57(dd, J=15.1,7.3Hz,4H),1.43(s,9H),0.88(t,J=7.4Hz,6H).13C NMR(101MHz, CDCl3):δ172.30,163.80,149.51,146.71,144.89,141.05,137.58,133.29,132.81, 130.74,127.33,127.15,126.27,121.57,115.81,80.31,78.17,56.54,49.92,41.87, 35.21,28.09,28.07,21.92,11.13.HRMS-ESI(m/z)[M+H]+calculated for C36H46IN2O6S,761.2121,found:761.2111.
Example 16: fluorescence quenching experiments, as shown in fig. 1, 2, 3 and 4.
In FIG. 1, the Stern-Volmer equation: f0/F=1+Kqτ0[Q],Kqτ0=964.65L/mol,τ0=5100 ns,Kq=1.89×108L/(mol*s);
In FIG. 2, the Stern-Volmer equation: f0/F=1+Kqτ0[Q],Kqτ0=107.31L/mol,τ0=5100 ns,Kq=2.1×107L/(mol*s)
In FIG. 3, the Stern-Volmer equation: f0/F=1+Kqτ0[Q],Kqτ0=0.85L/mol,τ0=5100ns, Kq=1.67×105L/(mol*s)。
FIG. 4 is a graph showing the change of the main species in the fluorescence quenching reaction system.
The emission intensity of all experiments was recorded using an Edinburgh FS920 fluorescence spectrophotometer. All 4CzIPN solutions were excited at 468nm and emission intensities were collected at 500-800 nm. In a typical experiment, 4CzIPN (10)-5M) adding a proper amount of quenching agent into the DCE solution, placing the solution into a quartz test tube with a spiral top of 4.5cm, degassing by nitrogen, and collectingEmission spectrum of the sample. The results show that imine and triethylamine have a faster quenching effect on photoexcited 4 CzIPN.
Based on the above experimental results, the reaction process is presumed to be as follows. Firstly, the reaction is started, and the activated imine is reduced into an N-alpha free radical by single-electron reduction with an excited-state photosensitizer 4CzIPN, meanwhile, an alkyl halide is reduced to generate an alkyl free radical, then, 1, 3-butadiene is immediately added to generate an allyl free radical, and then, the allyl free radical and the N-alpha free radical are subjected to cross coupling to generate a final target product of the homoallylamine.
Figure BDA0003477281320000161

Claims (8)

1. A homoallylamine compound is characterized in that the structural formula is as follows:
Figure FDA0003477281310000011
wherein Ar is2Is a substituted phenyl group; ar (Ar)1Is substituted phenyl or heterocyclyl;
R1selected from hydrogen, C1-C6 primary alkyl, C1-C6 secondary alkyl, C1-C6 tertiary alkyl, cycloalkane or heterocycloalkane;
R2selected from hydrogen, C1-C6 primary alkyl, C1-C6 secondary alkyl, C1-C6 tertiary alkyl, cycloalkane or heterocycloalkane;
R3selected from hydrogen, primary alkyl groups of C1-C6, secondary alkyl groups of C1-C6, tertiary alkyl groups of C1-C6, cycloalkane or heterocycloalkyl radicals;
r4 is selected from hydrogen, C1-C6 primary alkyl, C1-C6 secondary alkyl, C1-C6 tertiary alkyl, cycloalkane or heterocycloalkane;
r5 is selected from hydrogen, C1-C6 primary alkyl, C1-C6 secondary alkyl, C1-C6 tertiary alkyl, cycloalkane or heterocycloalkane;
the substituent in the substituted phenyl is selected from halogen, alkyl, alkoxy, alkoxycarbonyl or amino.
2. The method for synthesizing the homoallylamine compound of claim 1, wherein the synthetic route is as follows:
Figure FDA0003477281310000012
under the protection of inert gas and illumination at room temperature and in the presence of an organic photosensitizer and an electron donor, halogenated alkane reacts with 1, 3-butadiene derivative and imine in a solvent to obtain the homoallylamine compound.
3. The synthesis of claim 2, wherein the organic photosensitizer is 4 CzIPN.
4. The synthetic method of claim 2 or 3 wherein the electron donor is 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid diethyl ester HE or triethylamine.
5. The method of claim 4, wherein the molar ratio of haloalkane, 1, 3-butadiene derivative, imine, organic photosensitizer, HE is 2.0:2.0:1.0:0.01: 2.0; the molar ratio of the halogenated alkane 1, the 1, 3-butadiene derivative 2, the imine 3, the organic photosensitizer and the triethylamine is 2.0:2.0:1.0:0.01: 4.0.
6. The method of synthesis according to claim 2, 3 or 5, wherein the solvent is 1, 2-Dichloroethane (DCE).
7. The method for synthesizing the homoallylamine compound of any of claims 2 to 6, wherein the method is used for derivatization of natural active substances.
8. The use according to claim 7, wherein the natural active substances comprise lithocholic acid and estrone and the drug molecules comprise indomethacin and probenecid.
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