Synthesis method of chiral 3, 3-disubstituted isoindolinone compound through rhodium catalysis

A technology for isoindolinone and compounds, which is applied in the field of synthesis of chiral 3,3-disubstituted isoindolinone compounds, can solve the problems that the cyclization reaction has not yet been realized, and achieve a wide range of substrates, The effect of mild reaction conditions and simple operation

Pending Publication Date: 2021-12-03
SHAANXI NORMAL UNIV
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  • Abstract
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AI Technical Summary

Problems solved by technology

However, the enantioselective [4+1] cyclization involving enynes has not yet been realized

Method used

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  • Synthesis method of chiral 3, 3-disubstituted isoindolinone compound through rhodium catalysis
  • Synthesis method of chiral 3, 3-disubstituted isoindolinone compound through rhodium catalysis
  • Synthesis method of chiral 3, 3-disubstituted isoindolinone compound through rhodium catalysis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Add 15.1mg (0.1mmol) N-methoxybenzamide, 5.0mg (0.004mmol) chiral rhodium catalyst A, 35.0mg (0.24mmol) silver difluoride to the test tube, cool to -15°C, add 2 mL of 3-pentanol, 18.0 mg (0.15 mmol) (4-methylpent-3-en-1-ynyl) cyclopropane, and 200 μL of 1.0 mol / L acetic acid in 3-pentanol solution, stirred at 10 ° C React for 72 hours. After the reaction is over, add 1.0 mL of ethylenediamine to quench, and spin dry to obtain the crude product. The crude product is quickly passed through the column with silica gel (petroleum ether:ethyl acetate=10:1~5:1) to obtain the following structural formula: Yellow oily liquid 18.8mg, its yield is 70%, its ee value is 90% according to HPLC analysis.

[0022]

[0023] The structural characterization data of the resulting product are: 1 H NMR (600MHz, CDCl 3 )δ7.84(d, J=7.8Hz,1H),7.53(td,J=7.8,1.2Hz,1H),7.46(td,J=7.2,0.6Hz,1H),7.25(d,J=7.2 Hz,1H),6.61(d,J=16.2Hz,1H),5.70(d,J=15.6Hz,1H),5.05(s,1H),5.04(s,1H),4.05(s,3H), 1.82(s...

Embodiment 2

[0025] In this example, the N-methoxybenzamide in Example 1 is replaced with equimolar N-methoxy-4-methylbenzamide, and the other steps are the same as in Example 1 to obtain a colorless The oily liquid was 24.5 mg, the yield was 86%, and the ee value was 95% according to HPLC analysis.

[0026]

[0027] The structural characterization data of the resulting product are: 1 H NMR (600MHz, CDCl 3 )δ7.72(d, J=7.8Hz, 1H), 7.26(d, J=8.4Hz, 1H), 7.02(s, 1H), 6.62(d, J=16.2Hz, 1H), 5.69(d, J=15.6Hz,1H),5.06(s,1H),5.05(s,1H),4.03(s,3H),2.44(s,3H),1.83(s,3H),1.57–1.53(m,1H ),0.73–0.68(m,1H),0.60–0.56(m,1H),0.49–0.45(m,1H),-0.02–-0.05(m,1H); 13 C NMR (150MHz, CDCl 3 )δ164.6, 144.0, 142.5, 141.1, 135.5, 129.6, 127.4, 127.0, 123.64, 123.59, 118.1; [α] D 20 =+52.8 (c=0.1, CHCl 3 ).

Embodiment 3

[0029] In this example, the N-methoxybenzamide in Example 1 is replaced with equimolar N-methoxy-4-tert-butylbenzamide, and the other steps are the same as in Example 1 to obtain the following structural formula: The color oily liquid was 28.4 mg, the yield was 87%, and the ee value was 95% according to HPLC analysis.

[0030]

[0031] The structural characterization data of the resulting product are: 1 H NMR (600MHz, CDCl 3)δ7.76(d, J=8.4Hz, 1H), 7.49(dd, J=7.8, 1.8Hz, 1H), 7.20(d, J=1.2Hz, 1H), 6.63(d, J=15.6Hz, 1H), 5.71(d, J=16.2Hz, 1H), 5.06(s, 1H), 5.05(s, 1H), 4.03(s, 3H), 1.84(s, 3H), 1.60–1.56(m, 1H ),1.34(s,9H),0.73–0.68(m,1H),0.57–0.53(m,1H),0.49–0.44(m,1H),-0.05–0.09(m,1H); 13 CNMR (150MHz, CDCl 3 )δ164.6, 155.8, 143.5, 141.1, 135.5, 127.4, 127.0, 125.9, 123.4, 119.9, 118.1, 70.2, 65.0, 35.3, 31.3, 18.5, 15.8, 2.4, 0.4; HRMS (ESI-TOF) (m / z) :C 21 h 27 NNaO 2 ,([M+Na] + ), theoretical value 348.1934, measured value 348.1935; [α] D 20 =-8.4 (c=0.1, CHCl...

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Abstract

The invention discloses a synthesis method of a chiral 3, 3-disubstituted isoindolinone skeleton, a chiral cyclopentadienyl rhodium catalyst easy to prepare is adopted as a catalyst to realize cascade reactions of C-H bond activation, eneyne migration and insertion, 1, 4-rhodium migration, nucleophilic cyclization and the like of an N-methoxybenzamide compound and a 1, 3-eneyne compound, and the 3, 3-disubstituted chiral isoindolinone skeleton compound can be constructed with high yield and high enantioselectivity under mild conditions. The method is easy to operate, low in catalyst dosage, mild in reaction condition and wide in substrate application range, overcomes the defects that traditional synthesis of the compounds needs to be carried out in multiple steps, initial raw materials are difficult to prepare, the substrate application range is limited and the like, and has a good development prospect.

Description

technical field [0001] The invention relates to a synthesis method of chiral 3,3-disubstituted isoindolinone compounds. Background technique [0002] 3,3-Disubstituted chiral isoindolinone skeletons have been widely used in the fields of medicine, biology, and synthetic chemistry. Exploring effective methods for synthesizing indole skeletons has become a very important research field. 3,3-Disubstituted chiral isoindolinones have attracted extensive attention from organic synthesis workers because of their unique biological and pharmaceutical activities. In the existing literature, the construction of disubstituted chiral isoindolinone skeletons is mainly achieved through the enantioselective functionalization of the 3-position of isoindolinones, but this strategy inevitably leads to difficulties in the synthesis of substrates. Disadvantages such as low atom and step economy, and unsatisfactory diversity and complexity of products. It is worth looking forward to the develop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/46C07D209/64C07D495/04B01J31/22
CPCC07D209/46C07D209/64C07D495/04B01J31/2295C07B2200/07B01J2531/822B01J2531/0266
Inventor 郑光范孙佳琼田荣李兴伟哈迪
Owner SHAANXI NORMAL UNIV
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