CN109232529A - A kind of preparation method of compound of Rh (III) catalysis with azepine ring skeleton - Google Patents

A kind of preparation method of compound of Rh (III) catalysis with azepine ring skeleton Download PDF

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CN109232529A
CN109232529A CN201811178105.0A CN201811178105A CN109232529A CN 109232529 A CN109232529 A CN 109232529A CN 201811178105 A CN201811178105 A CN 201811178105A CN 109232529 A CN109232529 A CN 109232529A
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ring skeleton
iii
preparation
compound
azepine ring
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CN109232529B (en
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张岩
朱钢国
朱海倩
黄晨超
戚佳
戚佳一
陈泽辉
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Zhejiang Normal University CJNU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention discloses a kind of preparation methods of self assembly homing device auxiliary Rh (III) catalysis building azepine ring skeleton, under the conditions of including the following steps: existing for the rhodium catalyst and acetate, aromatic aldehyde reacts in a solvent with 2-aminopyridine, in situ to generate an effective homing device.The homing device reacts under rhodium catalysis with substituted olefine again, after the reaction was completed, obtains the compound of the azepine ring skeleton after post treatment.The preparation method is catalyzed using rhodium, is successfully realized the synthetic strategy of self assembly high-efficiency guide base.Reaction utilizes " one kettle way " to synthesize the isoindolone skeleton and isoquinoline structure of new substituted feature from simpler raw material in succinct mild catalyst system, and easy to operate, reaction condition is mild, high income, and Atom economy is high.

Description

A kind of preparation method of compound of Rh (III) catalysis with azepine ring skeleton
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of self assembly homing device auxiliary Rh (III) catalysis building The preparation method of azepine ring skeleton.
Background technique
Isoindolone (gamma-lactam) is a more common and important parent nucleus.Because α be have relatively by force complexing power N atom, therefore using the nitrogen-atoms in benzamide as guiding atom, and the research for participating in being formed gamma-lactam has more Report.
The fragrant formamide that the big seminar of Li Xing most early in 2010 attempted that N- phenyl is used to replace is as substrate, with acrylic acid Ester reaction builds isoindolone skeleton (Org.Lett., 2010,12,5430).It has been firstly generated in reaction among Heck product Body, and then Michael's addition occurs and is cyclized.If but being unfavorable for forming iso-indoles when the heterocycles such as aromatic ring furans, indoles in substrate Ketone product is mostly to have rested on oxidation Heck reactor product, and reaction condition is more harsh.Reaction equation is as follows:
2014, the above reaction is improved in Jin Quan seminar.They have used N- perfluor substituted-phenyl virtue first Amide is as substrate (Chem.Sci., 2015,6,1923), and actually the drawing of substituent group is electric on nitrogen-atoms in increase amide Sub- ability weakens the isomerization of amido bond and increases its nucleophilicity.Although substrate classification has been widened in this work, such as heterocycle Thiophene, furans, pyridine have good applicability, and reaction condition becomes more mild, but the universality of its substrate is still inadequate Extensively, and raw material is complex, and preparation process is not simple enough.
Summary of the invention
The present invention provides a kind of methods of self assembly homing device auxiliary Rh (III) catalysis building azepine ring skeleton, should Preparation method can generate an effective novel homing device in situ, and raw material is simple, and reaction condition is mild, reaction yield Height, Atom economy are high.
A kind of preparation method of self assembly homing device auxiliary Rh (III) catalysis building azepine ring skeleton, including walk as follows Rapid: under the conditions of existing for the rhodium catalyst and acetate, aromatic aldehyde reacts in a solvent with 2-aminopyridine, in situ to generate One effective homing device.The homing device reacts under rhodium catalysis with substituted olefine again, after the reaction was completed, after post treatment Obtain the compound of the azepine ring skeleton.
Shown in the structure of the aromatic aldehyde such as formula (I):
Shown in the structure of the 2-aminopyridine such as formula (II):
Shown in the structure of the substituted olefine such as formula (III):
Shown in the structure such as formula (IV) of the compound of the azepine ring skeleton:
In formula (I)~formula (IV), R is alkyl, alkoxy, hydrogen atom, halogen atom, cyano, ester group, nitro, fluoroform Base；
R ' is alkoxy acyl, alkanoyl, cyano, amide.
The reaction response formula is as follows:
Speculate the reaction mechanism are as follows:
Firstly, condensation reaction occurs for aromatic aldehyde and 2-aminopyridine, an effective novel homing device is generated in situ. It is as follows:
Then, self assembly guiding base occurs to react as follows with substituted olefine under metal rhodium (III) catalysis:
Preferably, the rhodium catalyst is [Cp*RhCl2]2(CAS:12354-85-7), dosage 2mol%, this kind High catalytic efficiency of the rhodium catalyst to the substrate in the present invention.
Preferably, the acetate is copper acetate, dosage 2eq.The acetate plays the role of oxidant, helps In the catalysis of rhodium catalyst in the reaction.
Preferably, with molar amount, aromatic aldehyde, 2-aminopyridine and substituted olefine amount ratio be 1:1.2~2:1.2~ 2。
Preferably, the R is C1~C5Alkyl, C1~C5Alkoxy, hydrogen atom, halogen atom, cyano, ester group, nitre Base, trifluoromethyl, these substituent groups can be such that reaction goes on smoothly.
Preferably, the R ' is C1~C5Alkoxy acyl, C1~C5Alkanoyl, cyano, amide, these substituent groups are equal For electron-withdrawing substituent, be conducive to the reactivity for improving the substituted olefine, facilitate Michael addition reaction into Row.
Preferably, the solvent be at least one of acetonitrile, water, methanol, ethyl alcohol, DMF, DMSO and THF, these Solvent is all polar solvent, is conducive to the fracture of c h bond in substrate, and as a further preference, the solvent is acetonitrile.
Preferably, the temperature of reaction is 80~110 DEG C, reaction temperature is excessively high, can side reaction be increased, reaction temperature It is too low, the conversion ratio of reactant can be reduced, as a further preference, the temperature of reaction is 80 DEG C.
Preferably, reaction atmosphere be one of air, nitrogen, in these atmosphere, can make reaction more preferably into Row has higher yields, and as a further preference, the atmosphere of reaction is N2Atmosphere.
In the present invention, the time of reaction can be monitored by TLC, and reaction in 4~12 hours is stirred at 80 DEG C can Occur complete.
It, can be first by aromatic aldehyde compound, 2-aminopyridine, Cu (OAc) in order to improve the yield of reaction2[Cp* RhCl2]2It is added in Schlenk bottles, vacuumize process is then carried out to it and is passed through nitrogen again, after operating three times, adds solvent And substituted olefine.
Compared with the existing technology, the beneficial effects of the present invention are embodied in: the reactions is prepared using " one kettle way ", operation letter It is single.It can self-generating high-efficiency guide group in reaction.The isoindolone skeleton and isoquinoline structure of the new substituted feature of synthesis produce Object high income, the raw material for reacting required is simple and easy to get, and reaction of atomic economy is high, and catalyst system is succinctly mild, meets greenization Requirement.
Detailed description of the invention
Fig. 1 is product made from embodiment 11HNMR spectrogram；
Fig. 2 is product made from embodiment 113CNMR spectrogram；
Fig. 3 is product made from embodiment 21HNMR spectrogram；
Fig. 4 is product made from embodiment 213CNMR spectrogram.
Specific embodiment
Embodiment 1
In the Schlenk bottle of 25mL, it is weighed into 24mg (0.2mmol) p-tolyl aldehyde (1.5eq), Cu (OAc) 2 53mg (2.0eq), 2-aminopyridine 25mg (2.0eq), [Cp*RhCl2] 2 3mg (2%).Then vacuumize process is carried out to it It is passed through nitrogen again, after operation three times, 2mL acetonitrile is added, stirs 10min, 45 μ L (2.0eq) of ethyl acrylate is added, 80 Constant temperature stirs in nitrogen atmosphere at DEG C.TLC detects end of reaction after about 5h, and a little silica gel is added, steams solvent, solidifies, solid Loading carries out pillar layer separation.Obtain product 55mg, yield 90%.Reaction equation is as follows:
Product physical property and spectral data are as follows: white solid；Fusing point: 90-92 DEG C；1H NMR(CDCl3,600MHz)δ 8.54 (d, J=12.6Hz, 1H), 8.42-8.40 (m, 1H), 7.81-7.73 (m, 2H), 7.39 (s, 1H), 7.31 (d, J= 12Hz,1H),7.07-7.04(m,1H),5.95-5.92(m,1H),4.12-4.08(m,2H),3.33(dd,J1=24Hz, J2= 5.4Hz), 2.81-2.75 (m, 1H), 2.47 (s, 3H), 1.16 (t, J=10.8Hz, 3H) ppm；13C NMR(CDCl3, 150MHz)δ170.7,167.7,151.1,147.7,145.4,143.8,138.0,129.8,129.4,124.1,123.3, 119.4,115.7,60.7,56.4,38.2,22.2,14.2ppm.
Embodiment 2
In the Schlenk bottle of 25mL, it is weighed into 21mg (0.2mmol) benzaldehyde (1.0eq), Cu (OAc)2 80mg (2.0eq), 2-aminopyridine 38mg (2.0eq), [Cp*RhCl2]24.96mg (2%).Then vacuumize process is carried out to it It is passed through nitrogen again, after operation three times, 2mL acetonitrile is added, stirs 10min, ethyl acrylate 43mL (2.0eq) is added, 80 Constant temperature stirs in nitrogen atmosphere at DEG C.TLC detects end of reaction after about 5h, and a little silica gel is added, steams solvent, solidifies, solid Loading carries out pillar layer separation.Obtain product 51mg, yield 85%.Reaction equation is as follows:
Product physical property and spectral data are as follows: white solid；Fusing point: 123-125 DEG C；1H NMR(CDCl3, 600MHz) δ 8.54 (d, J=11.4Hz, 1H), 8.42 (m, 1H), 7.92 (d, J=11.4Hz, 1H), 7.79-7.74 (m, 1H), 7.60(m,2H),7.53-7.49(m,1H),7.09-7.06(m,1H),5.98(m,1H),4.11-4.05(m,2H),3.35 (dd,J1=24 Hz, J2=5.4 Hz, 1H), 2.78 (m, 1H), 1.15 (t, J=10.8 Hz, 3H) ppm；13C NMR(CDCl3, 150 MHz)δ170.7,167.7,151.0,147.9,145.0,138.1,133.0,132.0,128.8,124.4,123.0, 119.7,115.9,60.8,56.6,38.2,14.2 ppm.。

Claims (8)

1. the preparation method that a kind of Rh (III) catalysis has the compound of azepine ring skeleton, which is characterized in that including walking as follows Rapid: under the conditions of existing for the rhodium catalyst and acetate, aromatic aldehyde reacts in a solvent with 2-aminopyridine, in-situ preparation Intermediate containing homing device；The intermediate reacts under rhodium catalysis with substituted olefine again, after the reaction was completed, after post treatment To the compound of the azepine ring skeleton；
Shown in the structure of the aromatic aldehyde such as formula (I):
Shown in the structure of the 2-aminopyridine such as formula (II):
Shown in the structure of the substituted olefine such as formula (III):
Shown in the structure such as formula (IV) of the compound with azepine ring skeleton:
In formula (I)~formula (IV), R is alkyl, alkoxy, hydrogen atom, halogen atom, cyano, alkoxy acyl, nitro or fluoroform Base；
R ' is alkoxy acyl, alkanoyl, cyano or amide.
2. the preparation side of self assembly homing device auxiliary Rh (III) catalysis building azepine ring skeleton according to claim 1 Method, which is characterized in that the rhodium catalyst is [Cp*RhCl2]2, dosage is the 2mol% of aromatic aldehyde.
3. Rh (III) catalysis according to claims 1 and 2 has the preparation method of the compound of azepine ring skeleton, special Sign is that the acetate is copper acetate, and dosage is 1.2~2.0 times of aromatic aldehyde mole.
4. Rh (III) catalysis according to claim 1 has the preparation method of the compound of azepine ring skeleton, feature exists In the R is C1~C5Alkyl, C1~C5Alkoxy, hydrogen atom, halogen atom, cyano, ester group, nitro, trifluoromethyl.
5. Rh (III) catalysis according to claim 1 has the preparation method of the compound of azepine ring skeleton, feature exists In the R ' is C1~C5Alkoxy acyl, C1~C5Alkanoyl, cyano, amide.
6. Rh (III) catalysis according to claim 1 has the preparation method of the compound of azepine ring skeleton, feature exists In the solvent is at least one of acetonitrile, water, methanol, ethyl alcohol, DMF, DMSO and THF.
7. Rh (III) catalysis according to claim 1 has the preparation method of the compound of azepine ring skeleton, feature exists In the temperature of reaction is 60~110 DEG C.
8. Rh (III) catalysis according to claim 1 has the preparation method of the compound of azepine ring skeleton, feature exists In the atmosphere of reaction is one of air, nitrogen.
CN201811178105.0A 2018-10-10 2018-10-10 Preparation method of Rh (III) catalytic compound with nitrogen heterocyclic skeleton Active CN109232529B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109608459A (en) * 2019-02-13 2019-04-12 河南师范大学 The synthetic method of nitrogen-containing heterocycle quaternary salt compounds
CN111270260A (en) * 2020-02-09 2020-06-12 浙江师范大学 Method for alkenylating ortho-position of aromatic amide compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102091638A (en) * 2009-12-10 2011-06-15 中国科学院大连化学物理研究所 Catalyst for use in preparation of piperidine and piperidine derivatives
CN102952073A (en) * 2011-08-17 2013-03-06 中国科学院大连化学物理研究所 Method for synthesizing dihydrogen phenanthridine
CN106732565A (en) * 2016-12-09 2017-05-31 西安凯立新材料股份有限公司 It is continuous to prepare 3,5 lupetidine catalyst and its preparation method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102091638A (en) * 2009-12-10 2011-06-15 中国科学院大连化学物理研究所 Catalyst for use in preparation of piperidine and piperidine derivatives
CN102952073A (en) * 2011-08-17 2013-03-06 中国科学院大连化学物理研究所 Method for synthesizing dihydrogen phenanthridine
CN106732565A (en) * 2016-12-09 2017-05-31 西安凯立新材料股份有限公司 It is continuous to prepare 3,5 lupetidine catalyst and its preparation method and application

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109608459A (en) * 2019-02-13 2019-04-12 河南师范大学 The synthetic method of nitrogen-containing heterocycle quaternary salt compounds
CN109608459B (en) * 2019-02-13 2020-06-23 河南师范大学 Synthetic method of nitrogen-containing heterocyclic quaternary salt compound
CN111270260A (en) * 2020-02-09 2020-06-12 浙江师范大学 Method for alkenylating ortho-position of aromatic amide compound
CN111270260B (en) * 2020-02-09 2021-05-25 浙江师范大学 Method for alkenylating ortho-position of aromatic amide compound

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