CN113979916B - Synthetic method of polyhalogenated aza spiro hexadienone compound - Google Patents

Synthetic method of polyhalogenated aza spiro hexadienone compound Download PDF

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CN113979916B
CN113979916B CN202111518399.9A CN202111518399A CN113979916B CN 113979916 B CN113979916 B CN 113979916B CN 202111518399 A CN202111518399 A CN 202111518399A CN 113979916 B CN113979916 B CN 113979916B
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CN113979916A (en
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吴礼军
龙芳
彭传冲
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Changsha Commerce & Tourism College
Central South University of Forestry and Technology
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Changsha Commerce & Tourism College
Central South University of Forestry and Technology
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract

The application discloses a synthetic approach of polyhalogenated aza-spiro-hexadienone compounds, which provides a simple metal-free catalytic strategy, and synthesizes polyhalogenated aza-spiro-hexadienone compounds through the serial spiro-cyclization of free radical-mediated N-benzyl acrylamide compounds and polyhalogenated alkane compounds, wherein the polyhalogenated alkane compounds are synthesized by breaking C (sp 3 ) The H bond generates a polyhaloalkyl radical.

Description

Synthetic method of polyhalogenated aza spiro hexadienone compound
Technical Field
The application belongs to the technical field of organic synthesis methodologies, and particularly relates to a method for synthesizing a polyhalogenated aza-spiro hexadienone compound.
Background
The organic molecular structure containing halogen is an important structural unit, widely existing in natural products, pesticides and bioactive molecules, and is also a common synthetic intermediate in organic synthesis. Among them, polyhalogenated compounds, particularly compounds having di-or trichloromethyl groups, are widely present in natural products and exhibit a wide range of biological activities, including anti-tumor, anti-inflammatory properties, and the like. Accordingly, chemical researchers have made considerable efforts to develop new methods of constructing polyhalogenated backbone molecules. Since the Kharasch group reported the atom transfer radical addition reaction of bromotrichloromethane as a source of polyhalogenated radicals with unsaturated hydrocarbons (j.am. Chem. Soc.1945, 67, 1626-1627.), radical mediated reaction of olefins has become one of the most effective methods for rapidly constructing a variety of polyhalogenated compounds. Generally, these methods can be divided into two categories according to the manner in which polyhaloalkyl radicals are generated, as follows: (a) Methods of synthesizing polyhalogenated molecules have generally focused on the free radical mediated reaction of olefins with polyhalogenated alkanes by using photocatalysts, thermocatalysts, organometallic reagents and/or highly toxic organic initiators (typically AIBN and Bu 3 SnH) to make carbon-cleavage of halogen bond; (b) By selective cleavage of C (sp 3 ) An H bond, a polyhaloalkyl (e.g. CH 2 Cl 2 And CHCl 3 ) Conversion to polyhaloalkyl radicals to initiate a radical tandem cyclization reaction of olefins (org.lett.2018, 20, 212-215; org.chem.front.2014,1, 1289-1294; RSC adv.2014,4, 64855-64859; org.biomol.chem.2018, 16, 5752-5755; org.chem.front.2019,6, 512-516; chem.commun.2021, 57, 3684-3687; j.org.chem.2015, 80, 2621-2626; org.lett.2014, 16, 4698-4701.). Despite the remarkable progress in this field, these processes require harsh conditions, expensive metal catalysts (usually Ir or Ru) or excessive amounts of peroxides (e.g. DCP and LPO). Thus, a straightforward strategy for constructing polyhalogenated compounds is highly desirable and necessary.
N-benzyl acrylamides have proven to be good free radical acceptors, and various aza spirohexenones (org.lett.2016, 18, 1048-1051.; org.biomol.chem.2018, 16, 2406-2410.; j.org.chem.2011, 76, 9278-9293.; org.lett.2014, 16, 3188-3191.; org.lett.2014, 16, 5914-5917; chem.commun.2016, 52, 3709-3712.; tetrahedron letters.2017, 58, 2127-2130.; org.biomol.chem.2020, 18, 8376-8380.; org.biomol.2021, 19-7602) have been developed as a strategy for the preparation of aza spirocyclic alkyls, especially as a source of N-alkyl halides. However, most of these methods are limited because of the expensive metal catalysts or oxidants required for the reaction. Furthermore, these methods of forming alkyl radicals from alkyl halides only break through carbon-halogen bonds, not carbon-hydrogen bonds. To the best of our knowledge, from readily available polyhaloalkanes (e.g. CH 2 Cl 2 And CHCl 3 ) By selective cleavage of C (sp 3 ) The generation of polyhaloalkyl radicals by the H bond to initiate the spirocyclisation of olefins has not been reported. We therefore report a simple metal-free catalytic strategy for the free radical mediated N-benzyl propeneSynthesis of polyhaloazaspirocyclic hexadienones by tandem spirocyclization of amides with polyhaloalkanes by cleavage of C (sp 3 ) The H bond generates a polyhaloalkyl radical.
Disclosure of Invention
The application aims to enrich the synthetic route of polyhalogenated aza-spiro-hexadienone compounds in the prior art, provides a simple metal-free catalytic strategy, synthesizes polyhalogenated aza-spiro-hexadienone compounds through the serial spiro-cyclization of free radical-mediated N-benzyl acrylamide compounds and polyhalogenated alkane compounds, wherein the polyhalogenated alkane compounds are synthesized by breaking C (sp 3 ) The H bond generates a polyhaloalkyl radical.
The application provides a method for synthesizing polyhalogenated aza-spirohexadienone compounds, which comprises the following steps:
sequentially adding an N-benzyl acrylamide compound shown in a formula 1, a polyhaloalkyl compound shown in a formula 2, aromatic tetrafluoroboric acid diazonium salt and alkali into a reactor, then replacing the reactor with inert atmosphere, stirring and reacting at room temperature, and after the reaction is completed, performing post-treatment to obtain a polyhalogenated aza-spirocyclic hexadienone compound shown in a formula 3; the reaction formula is as follows:
wherein R represents OR 'and R' is selected from C 1-12 Alkyl, C 6-20 aryl-C 1-12 Alkyl, tri (C) 1-12 Alkyl) silicon-based, C 1-12 An acyl group; preferably C 1-6 Alkyl, C 6-20 aryl-C 1-6 Alkyl, tri (C) 1-6 Alkyl) silicon-based, C 1-6 An acyl group; further preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, benzyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, formyl, acetyl, pivaloyl; most preferred are benzyl, methyl, t-butyldimethylsilyl, pivaloyl.
R 1 Selected from C 1-12 Alkyl, C 6-20 aryl-C 1-12 Alkyl, C 3-8 Cycloalkyl; preferably C 1-8 Alkyl, C 6-20 aryl-C 1-6 Alkyl, C 3-6 Cycloalkyl; further preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; most preferred are ethyl, n-octyl, benzyl, phenethyl, isopropyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl.
R 2 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 An alkoxy group; preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, tert-butoxy; most preferred are hydrogen, chlorine, bromine, methoxy.
R 3 、R 4 Selected from hydrogen, C 1-6 An alkyl group; preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl; most preferred are hydrogen and methyl.
R 5 Selected from hydrogen, C 1-6 Alkyl, C 1-6 A haloalkyl group; preferably hydrogen, methyl, ethyl, n-propyl, monochloromethyl, dichloromethyl, trichloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromomethyl; most preferred are hydrogen, monochloromethyl, dichloromethyl.
X 1 ，X 2 Represents halogen, independently of one another selected from fluorine, chlorine, bromine, iodine; preferably X 1 ，X 2 Independently of one another, chlorine or bromine.
The synthesis method according to the present application, wherein the aromatic diazonium tetrafluoroborate is a substituted or unsubstituted diazonium phenyltetrafluoroborate, preferably a diazonium phenyltetrafluoroborate, a diazonium methoxy-substituted phenyltetrafluoroborate, a diazonium halogen-substituted phenyltetrafluoroborate, a diazonium methyl-substituted phenyltetrafluoroborate, a diazonium nitro-substituted phenyltetrafluoroborate; most preferred are phenyl diazonium tetrafluoroborate, 4-methoxyphenyl diazonium tetrafluoroborate, 4-nitrophenyl diazonium tetrafluoroborate.
According to the synthesis method, the alkali is inorganic alkali, and the inorganic alkali is selected from one or a mixture of more of sodium carbonate, potassium phosphate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide; preferably any one of sodium carbonate, potassium phosphate, cesium carbonate and sodium bicarbonate; most preferred is sodium carbonate.
According to the synthesis method, an organic solvent is not used, and the molar ratio of the N-benzyl acrylamide compound shown in the formula 1 to the polyhalogenated alkane compound shown in the formula 2 to the aromatic tetrafluoroboric acid diazonium salt to the alkali is 1: (10-1000): (1-5); preferably 1:20-100:1-3:1-3; further preferably 1:50:2:2.
According to the synthesis method of the present application, the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably an argon atmosphere.
According to the aforementioned synthesis method of the present application, the reaction time of the stirring reaction is 4 to 48 hours, preferably 8 to 24 hours, more preferably 12 to 16 hours.
According to the synthesis method, the post-treatment operation is as follows: after the reaction is completed, the reaction solution is filtered, the solvent is removed by reduced pressure distillation, and then the polyhalogenated aza spirocyclic hexadienone compound shown in the formula 3 is obtained by silica gel column chromatography separation.
The method of the application has the following beneficial effects:
(1) The application reports the synthesis strategy of synthesizing polyhalogenated aza-spirocyclic hexadienone compound by the serial spiro cyclization of the free radical-mediated N-benzyl acrylamide compound and polyhalogenated alkane compound for the first time, and the reaction mechanism control experiment shows that the polyhalogenated alkane compound in the application has the advantages of high stability and high stability 3 ) The H bond generates polyhaloalkyl radicals, and this synthetic strategy is not reported in the prior art.
(2) The synthesis method of the application does not need to use expensive metal catalysts or oxidizing agents, does not need to use additional organic solvents, can smoothly carry out series free radical addition and intramolecular cyclization/dearomatization reaction under the conditions of aromatic tetrafluoroboric acid diazonium salt and alkali, forms various chemical bonds and spiro structures through one-step reaction, has mild and simple reaction conditions, can be carried out at room temperature, and is simple and convenient to operate.
(3) The synthesis method has wide application range of reaction substrates, and the separation yield of target products is up to 91%.
Detailed Description
The present application will be described in further detail with reference to specific examples. In the following, the N-benzyl acrylamide-type compound (1) used was prepared by a known method (see the background reference), and the polyhalogenated alkane-type compound (2) was obtained commercially by conventional methods without further purification.
Examples 1-15 reaction conditions screening and amplification experiments
The N-benzyl acrylamide compound shown in the formula 1a and methylene dichloride are used as template substrates, and the optimal reaction conditions are screened, and the results are shown in the table 1. The reaction formula is as follows:
examples Reaction variable yield(％) b
1 Without any means for 88
2 Without addition of 4-MeOC 6 H 4 N 2 BF 4 0
3 No Na is added 2 CO 3 0
4 K 2 CO 3 Instead of Na 2 CO 3 56
5 K 3 PO 4 Instead of Na 2 CO 3 62
6 Cs 2 CO 3 Instead of Na 2 CO 3 55
7 NaHCO 3 Instead of Na 2 CO 3 52
8 KOH replaces Na 2 CO 3 23
9 NEt 3 Instead of Na 2 CO 3 5
10 4-MeOC 6 H 4 N 2 BF 4 (1 equivalent) 70
11 4-MeOC 6 H 4 N 2 BF 4 (3 equivalent) 87
12 The reaction temperature is 50 DEG C 85
13 C 6 H 5 N 2 BF 4 Instead of 4-MeOC 6 H 4 N 2 BF 4 81
14 4-NO 2 C 6 H 5 N 2 -BF 4 Instead of 4-MeOC 6 H 4 N 2 BF 4 72
15 c Without any means for 82
a Reaction conditions: 1a (0.2 mmol), 2a (10 mmol), 4-MeOC 6 H 4 N 2 BF 4 (2 equiv) and Na 2 CO 3 (2 equiv), room temperature and argon protection for 16h.
b The yield was isolated.
c 1a (1 mmol), 2a (50 mmol), for 24h.
Wherein example 1 reaction conditions and operation are as follows:
n-benzyl acrylamide compound (0.2 mmol) shown in formula 1a, dichloromethane (10 mmol,50.0 eq.) and 4-MeOC were added to a Schlenk tube reactor 6 H 4 N 2 BF 4 (0.4 mmol,2.0 eq.) Na 2 CO 3 (0.4 mmol,2.0 eq.). The reaction was then stirred at room temperature under argon (latm) for 16h, and the reaction was stopped by TLC/GC-MS detection of complete consumption of the starting material. After the reaction was completed, the reaction solution was filtered, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (eluting solvent was petroleum ether/ethyl acetate, V/v=3:1) to give polyhalogenated aza-spirocyclic hexadienone compound represented by formula 3aa, 58.1mg,88%. Yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.91(d，J＝10.4Hz，2H)，6.47-6.44(m，2H)，6.13-6.10(m，1H)，3.51(d，J＝10.8Hz，1H)，3.32(d，J＝10.8Hz，1H)，2.73(dd，J＝4.4Hz，J＝15.2Hz，1H)，2.30(dd，J＝6.4Hz，J＝15.2Hz，1H)，1.42(s，9H)，1.31(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.5，175.3，147.7，147.3，131.9，131.1，68.9，54.8，52.1，49.9，48.5，47.6，27.5，17.4；HRMS m/z(ESI)calcd for C 16 H 22 Cl 2 NO 2 ([M+H] + )330.1022，found 330.1034。
as can be seen from Table 1, without the addition of 4-MeOC 6 H 4 N 2 BF 4 And/or Na 2 CO 3 The reaction is not carried out under the conditions of (a), which indicates that the use of an aromatic diazonium tetrafluoroborate and a base has a critical influence on the performance of the reaction. Na (Na) 2 CO 3 Is the best base species and the replacement of the remaining base species does not allow for higher yields. 4-MeOC 6 H 4 N 2 BF 4 The optimum amount of the compound of formula 1a to be fed is 2 molar equivalents. The reaction temperature increased to 50 ℃ resulted in a decrease in the yield of the desired product. Other aromatic groups fourDiazonium fluoroborate salts such as C 6 H 4 N 2 BF 4 And 4-NO 2 C 6 H 4 N 2 BF 4 The reaction can be well promoted, but the reaction effect is inferior to that of 4-MeOC 6 H 4 N 2 BF 4 . Example 15 the target product can still be obtained in good yields with 5-fold amplification of the reaction process, which suggests that the synthesis process of the present application is suitable for scale-up production.
In order to investigate the substrate adaptability of this synthesis strategy, a series of desired polyhalogenated azaspirocyclic hexadienones of formula 3 were prepared by varying only the substrate types under the process conditions of example 1, based on the optimum process conditions (example 1), with the following results:
the results show that the N-benzyl acrylamide compound (1) and the polyhaloalkyl compound (2) with different substituents have good adaptability to the optimal process conditions, and the synthetic strategy reaction substrate has wide application range.
Structural characterization of the product:
3ba: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.94-6.88(m，2H)，6.48-6.44(m，2H)，6.15(dd，J＝4.8Hz，J＝6.4Hz，1H)，3.49(d，J＝10.4Hz，1H)，3.34-3.30(m，2H)，3.25(d，J＝10.4Hz，1H)，2.77(dd，J＝4.4Hz，J＝15.2Hz，1H)，2.33(dd，J＝6.4Hz，J＝15.6Hz，1H)，1.57(q，J＝7.2Hz，2H)，1.36(s，3H)，0.95(t，J＝7.2Hz，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.4，175.1，147.5，147.1，131.9，131.1，68.8，51.7，51.7，48.5，48.5，44.6，20.5，17.8，11.3；HRMSm/z(ESI)calcd for C 15 H 20 Cl 2 NO 2 ([M+H] + )316.0866，found 316.0878.。
3ca: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.93-6.87(m，2H)，6.47-6.43(m，2H)，6.15(dd，J＝4.4Hz，J＝6.4Hz，1H)，3.48(d，J＝10.4Hz，1H)，3.34(dd，J＝6.0Hz，J＝8.0Hz，2H)，3.24(d，J＝10.8Hz，1H)，2.76(dd，J＝4.8Hz，J＝15.6Hz，1H)，2.33(dd，J＝6.4Hz，J＝15.6Hz，1H)，1.53(t，J＝7.2Hz，2H)，1.35(s，3H)，1.30-1.27(m，10H)，0.88(t，J＝6.8Hz，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.4，175.0，147.4，147.2，131.9，131.1，68.8，51.7，51.7，48.5，48.5，43.0，31.7，29.1，29.1，27.1，26.8，22.6，17.7，14.1；HRMS m/z(ESI)calcd for C 20 H 30 Cl 2 NO 2 ([M+H] + )386.1648，found 386.1657.。
3da: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：7.39-7.33(m，3H)，7.25-7.23(m，2H)，6.84-6.78(m，2H)，6.42-6.37(m，2H)，6.18(dd，J＝4.4Hz，J＝6.4Hz，1H)，4.51(dd，J＝14.4Hz，J＝31.6Hz，2H)，3.32(d，J＝10.8Hz，1H)，3.09(d，J＝10.4Hz，1H)，2.77(dd，J＝4.4Hz，J＝15.6Hz，1H)，2.35(dd，J＝6.8Hz，J＝15.6Hz，1H)，1.35(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.4，175.1，147.3，147.0，135.2，131.9，131.1，129.1，128.4，128.3，68.7，51.6，51.0，48.4，48.3，47.1，17.7；HRMS m/z(ESI)calcd for C 19 H 20 Cl 2 NO 2 ([M+H] + )364.0866，found 364.0876.。
3ea: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：7.34-7.31(m，2H)，7.25-7.22(m，3H)，6.72(dd，J＝3.2Hz，J＝10.4Hz，1H)，6.60(dd，J＝3.2Hz，J＝10.4Hz，1H)，6.39-6.31(m，2H)，6.07(dd，J＝4.8Hz，J＝6.4Hz，1H)，3.73-3.62(m，2H)，3.28(d，J＝10.4Hz，1H)，3.03(d，J＝10.4Hz，1H)，2.94-2.89(m，2H)，2.66(dd，J＝4.8Hz，J＝15.2Hz，1H)，2.23(dd，J＝6.4Hz，J＝15.6Hz，1H)，1.20(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.4，175.2，147.5，147.1，137.7，131.8，130.8，128.8，128.7，127.0，68.8，52.0，51.5，48.5，48.3，43.7，33.5，17.7；HRMS m/z(ESI)calcd for C 20 H 22 Cl 2 NO 2 ([M+H] + )378.1022，found 378.1025.。
3fa: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.93-6.86(m，2H)，6.48-6.43(m，2H)，6.15(dd，J＝4.8Hz，J＝6.4Hz，1H)，4.45-4.38(m，1H)，3.41(d，J＝10.4Hz，1H)，3.23(d，J＝10.4Hz，1H)，2.77(dd，J＝4.8Hz，J＝15.2Hz，1H)，2.32(dd，J＝6.4Hz，J＝15.2Hz，1H)，1.33(s，3H)，1.17(dd，J＝5.6Hz，J＝6.4Hz，6H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.4，174.3，147.4，147.2，131.9，131.2，68.8，51.8，48.4，46.8，43.1，31.6，19.6，17.5，14.1；HRMS m/z(ESI)calcd for C 15 H 20 Cl 2 NO 2 ([M+H] + )316.0866，found 316.0867.。
3ga: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.91-6.84(m，2H)，6.47-6.43(m，2H)，6.13(dd，J＝4.8Hz，J＝6.4Hz，1H)，3.44(d，J＝10.4Hz，1H)，3.21(d，J＝10.4Hz，1H)，2.77-2.68(m，2H)，2.30(dd，J＝6.4Hz，J＝15.2Hz，1H)，1.33(s，3H)，0.88-0.77(m，3H)，0.70-0.66(m，1H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.4，176.0，147.3，147.0，131.9，131.2，68.8，52.0，52.0，48.5，48.3，25.7，17.7，5.5，5.2；HRMS m/z(ESI)calcd for C 15 H 18 Cl 2 NO 2 ([M+H] + )314.0709，found 314.0731.。
3ha: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.94-6.86(m，2H)，6.48-6.43(m，2H)，6.15(dd，J＝4.8Hz，J＝6.0Hz，1H)，4.57-4.49(m，1H)，3.44(d，J＝10.8Hz，1H)，3.24(d，J＝10.4Hz，1H)，2.77(dd，J＝4.8Hz，J＝15.2Hz，1H)，2.31(dd，J＝6.4Hz，J＝15.2Hz，1H)，1.92-1.88(m，2H)，1.70-1.62(m，4H)，1.50-1.45(m，2H)，1.33(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.5，174.8，147.4，147.3，131.9，131.2，68.9，52.8，51.8，48.5，48.4，47.8，28.8，28.6，24.2，24.2，17.6；HRMS m/z(ESI)calcd for C 17 H 22 Cl 2 NO 2 ([M+H] + )342.1022，found 342.1024.。
3ia: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.93-6.86(m，2H)，6.47-6.43(m，2H)，6.15(dd，J＝4.8Hz，J＝6.0Hz，1H)，4.01-3.96(m，1H)，3.43(d，J＝10.4Hz，1H)，3.24(d，J＝10.8Hz，1H)，2.77(dd，J＝4.8Hz，J＝15.2Hz，1H)，2.31(dd，J＝6.4Hz，J＝15.2Hz，1H)，1.84-1.68(m，5H)，1.43-1.35(m，3H)，1.33(s，3H)，1.29-1.22(m，1H)，1.13-1.06(m，1H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.5，174.4，147.5，147.3，131.9，131.2，68.9，51.8，51.0，48.5，48.4，47.8，30.0，30.0，25.2，25.2，17.6；HRMS m/z(ESI)calcd for C 18 H 24 Cl 2 NO 2 ([M+H] + )356.1179，found 356.1172.。
3ja (d.r. =1.3:1): yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.91-6.86(m，1H)，6.67(s，1H)，6.45-6.42(m，1H)，6.11(dd，J＝4.8Hz，J＝6.4Hz，0.56H)，6.07(dd，J＝4.8Hz，J＝6.0Hz，0.44H)，3.52-3.47(m，1H)，3.30(dd，J＝10.4Hz，J＝16.8Hz，1H)，2.75-2.68(m，1H)，2.34-2.25(m，1H)，1.97(s，3H)，1.43(s，4H)，1.42(s，5H)，1.31(s，1.67H)，1.28(s，1.33H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ185.2，175.6，175.5，147.7，147.4，142.6，142.3，138.6，137.9，131.4，130.7，69.1，69.0，54.7，54.7，52.1，52.0，50.1，50.0，48.7，48.5，47.5，47.5，27.5，17.5，16.4，16.3；HRMS m/z(ESI)calcd for C 17 H 24 Cl 2 NO 2 ([M+H] + )344.1179，found 344.1179.。
3ka (d.r. =1:1): yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.97-6.91(m，1H)，6.47(s，0.5H)，6.45(s，0.5H)，6.14(dd，J＝4.8Hz，J＝6.4Hz，0.5H)，6.06(dd，J＝4.8Hz，J＝6.0Hz，0.5H)，5.72(t，J＝2.4Hz，1H)，3.72(s，3H)，3.55(d，J＝10.4Hz，0.5H)，3.51(d，J＝10.4Hz，0.5H)，3.40(d，J＝10.4Hz，0.5H)，3.30(d，J＝10.4Hz，0.5H)，2.78(dd，J＝4.8Hz，J＝15.6Hz，0.5H)，2.69(dd，J＝4.4Hz，J＝15.6Hz，0.5H)，2.37(dd，J＝5.6Hz，J＝15.6Hz，0.5H)，2.26(dd，J＝6.4Hz，J＝15.6Hz，0.5H)，1.44(s，4.5H)，1.43(s，4.5H)，1.36(s，1.5H)，1.25(s，1.5H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ179.8，179.7，175.7，175.3，153.0，152.8，148.5，148.2，130.7，130.1，113.5，113.2，69.1，68.9，55.1，55.1，54.8，54.7，52.3，51.8，50.9，50.8，49.0，48.5，48.3，48.3，27.6，27.5，17.7，17.2；HRMS m/z(ESI)calcd for C 17 H 24 Cl 2 NO 3 ([M+H] + )360.1128，found 360.1120.。
3la (d.r. > 20:1): yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：7.06(d，J＝2.8Hz，1H)，6.94(dd，J＝2.8Hz，J＝10.4Hz，1H)，6.54(d，J＝10.0Hz，1H)，6.12(dd，J＝4.0Hz，J＝7.2Hz，1H)，3.56(d，J＝10.8Hz，1H)，3.35(d，J＝10.4Hz，1H)，2.75(dd，J＝4.0Hz，J＝15.2Hz，1H)，2.29(dd，J＝7.2Hz，J＝15.2Hz，1H)，1.43(s，9H)，1.33(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ177.6，174.8，147.9，143.2，135.5，130.0，68.8，55.0，52.5，50.1，49.7，48.3，27.5，17.4；HRMS m/z(ESI)calcd for C 16 H 21 Cl 3 NO 2 ([M+H] + )364.0632，found 364.0628.。
3ma (d.r. > 20:1): yellow oily liquid; 1 HNMR(400MHz，CDCl 3 )δ：7.33(d，J＝2.8Hz，1H)，6.95(dd，J＝2.8Hz，J＝10.0Hz，1H)，6.54(d，J＝10.0Hz，1H)，6.11(dd，J＝4.0Hz，J＝7.2Hz，1H)，3.56(d，J＝10.4Hz，1H)，3.35(d，J＝10.4Hz，1H)，2.75(dd，J＝4.0Hz，J＝15.6Hz，1H)，2.30(dd，J＝7.2Hz，J＝15.6Hz，1H)，1.43(s，9H)，1.33(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ177.5，174.8，147.8，147.7，129.5，127.3，68.8，55.0，52.5，51.1，49.5，48.3，27.5，17.4；HRMS m/z(ESI)calcd for C 16 H 21 BrCl 2 NO 2 ([M+H] + )408.0127，found 408.0138.。
3na (d.r. > 20:1): yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.85(d，J＝10.4Hz，1H)，6.53(d，J＝1.6Hz，1H)，6.47(dd，J＝2.0Hz，J＝10.4Hz，1H)，6.13(dd，J＝3.6Hz，J＝6.0Hz，1H)，3.71(d，J＝10.8Hz，1H)，3.64(d，J＝11.2Hz，1H)，2.78(dd，J＝3.6Hz，J＝15.2Hz，1H)，2.47(dd，J＝6.4Hz，J＝15.2Hz，1H)，1.46(s，9H)，1.23(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ183.0，173.8，155.7，147.0，131.3，130.9，68.5，55.2，53.5，51.8，51.4，49.6，27.4，16.2；HRMS m/z(ESI)calcd for C 16 H 21 Cl 3 NO 2 ([M+H]+)364.0632，found 364.0637.。
3oa: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.91-6.85(m，2H)，6.47-6.42(m，2H)，6.14(q，J＝4.4Hz，1H)，3.63(d，J＝10.0Hz，1H)，3.32(d，J＝10.4Hz，1H)，2.97(dd，J＝4.4Hz，J＝9.6Hz，1H)，2.47-2.39(m，1H)，1.88-1.81(m，1H)，1.43(s，9H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.9，172.3，149.1，146.5，132.1，131.1，71.1，54.9，51.5，48.7，45.8，40.6，27.7；HRMS m/z(ESI)calcd for C 15 H 20 Cl 2 NO 2 ([M+H] + )316.0866，found 316.0878.。
3ob (d.r. =1:1): yellow oily liquid; 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ6.92-6.75(m，2H)，6.39-6.32(m，2H)，4.70-4.64(m，0.5H)，3.86-3.80(m，0.5H)，3.70-3.62(m，1H)，3.58-3.47(m，2H)，3.25(d，J＝10.4Hz，0.5H)，3.19(d，J＝10.0Hz，0.5H)，3.00(dd，J＝4.4Hz，J＝10.0Hz，0.5H)，2.92(dd，J＝2.0Hz，J＝10.8Hz，0.5H)，2.12-1.88(m，2H)，1.37(s，4.5H)，1.36(s，4.5H)； 13 C NMR(100MHz，CDCl 3 )δ：185.1，184.9，173.2，172.4，150.4，149.1，147.0，146.9，132.2，131.4，131.0，131.0，59.4，57.7，51.6，51.3，48.8，48.5，48.1，47.8，46.3，45.7，32.8，32.2，27.7，27.6；HRMS m/z(ESI)calcd for C 16 H 22 Cl 2 NO 2 ([M+H] + )330.1022，found 330.1037.。
3oc: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.86(dd，J＝3.2Hz，J＝10.0Hz，1H)，6.75(dd，J＝3.2Hz，J＝10.0Hz，1H)，6.38-6.35(m，2H)，3.95(dd，J＝12.0Hz，J＝29.6Hz，2H)，3.59(d，J＝10.0Hz，1H)，3.24(d，J＝10.0Hz，1H)，3.04(t，J＝4.0Hz，1H)，2.73(dd，J＝5.2Hz，J＝15.2Hz，1H)，1.89(dd，J＝3.6Hz，J＝15.2Hz，1H)，1.37(s，9H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ185.1，171.8，149.7，146.4，131.8，131.7，90.2，55.1，54.9，51.4，49.3，46.9，40.7，27.7；HRMS m/z (ESI)calcd for C 16 H 21 Cl 3 NO 2 ([M+H] + )364.0632，found 364.0632.。
3ad: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：7.02(dd，J＝3.2Hz，J＝10.4Hz，1H)，6.93(dd，J＝3.2Hz，J＝10.4Hz，1H)，6.46-6.41(m，2H)，3.66-3.57(m，2H)，3.18(d，J＝10.4Hz，1H)，2.95(d，J＝16.4Hz，1H)，1.56(s，3H)，1.42(s，9H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.8，174.6，148.3，148.0，131.6，130.7，96.7，56.8，55.0，54.9，50.7，48.1，27.4，16.2；HRMS m/z(ESI)calcd for C 16 H 21 Cl 3 NO 2 ([M+H] + )364.0632，found 364.0640.。
3oe: yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.91(dd，J＝3.2Hz，J＝13.6Hz，2H)，6.46(d，J＝10.0Hz，2H)，6.02(dd，J＝4.8Hz，J＝6.4Hz，1H)，3.50(d，J＝10.4Hz，1H)，3.33(d，J＝10.8Hz，1H)，3.11(dd，J＝4.8Hz，J＝15.6Hz，1H)，2.66(dd，J＝6.0Hz，J＝16.0Hz，1H)，1.43(s，9H)，1.34(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.5，175.1，147.6，147.5，131.8，131.3，54.8，53.4，50.5，49.8，47.6，37.8，27.6，17.0；HRMS m/z(ESI)calcd for C 16 H 22 Br 2 NO 2 ([M+H] + )418.0012，found 418.0021.。
3oe': yellow oily liquid; 1 H NMR(400MHz，CDCl 3 )δ：6.96(dd，J＝3.2Hz，J＝10.4Hz，1H)，6.87(dd，J＝3.2Hz，J＝10.0Hz，1H)，6.46-6.40(m，2H)，3.55-3.49(m，1H)，3.41(dd，J＝10.4Hz，J＝16.8Hz，2H)，3.32-3.25(m，1H)，2.30-2.22(m，1H)，1.90-1.82(m，1H)，1.42(s，9H)，1.13(s，3H)； 13 C{ 1 H}NMR(100MHz，CDCl 3 )δ184.7，175.4，148.1，147.9，131.3，131.2，54.6，53.4，49.8，47.6，38.1，27.6，27.3，16.8；HRMS m/z(ESI)calcd for C 16 H 23 BrNO 2 ([M+H] + )340.0907，found 340.0931.。
reaction mechanism control test one:
in order to investigate the influence of the benzene ring of the N-benzyl acrylamide compound (1) on the substituent (R), the inventors further carried out the reaction under the optimal process conditions of example 1 by using the N-benzyl acrylamide compound (1) in which R is methoxy, tert-butyldimethylsilyloxy, pivaloyl, hydrogen or fluorine as a raw material, and the results are as follows:
the above results indicate that the oxygen in the structural unit of cyclohexadienone formed by dearomatization in the synthetic strategy of the present application is derived from an oxygen-containing R group.
Reaction mechanism control test two:
under the optimal process conditions of example 1, the addition of free radical inhibitors, including TEMPO, BHT and hydroquinone, was not possible, indicating that the reaction process of the present application is a free radical mechanism.
Reaction mechanism control test three:
4-NO 2 C 6 H 4 N 2 BF 4 And deuterated chloroform under the optimal process conditions of the present application, 4-deuterated methoxybenzene was generated by GC-MS analysis, which indicates that the synthetic strategy of the present application underwent aryl radical generation, and also indicates that polyhaloalkane compounds of the present application were synthesized by cleavage of C (sp 3 ) The H bond generates a polyhaloalkyl radical.
According to the reaction mechanism control test described above in combination with the prior art document, the possible reaction mechanism of the present application is as follows:
the above-described embodiments are merely preferred embodiments of the present application and are not intended to be exhaustive of the possible implementations of the present application. Any obvious modifications thereof, without departing from the principles and spirit of the present application, should be considered to be within the scope of the appended claims.

Claims (7)

1. The synthesis method of the polyhalogenated aza-spiro hexadienone compound is characterized by comprising the following steps:
sequentially adding the components shown in the formula 1 into the reactorNBenzyl acrylamide compound, polyhaloalkyl compound shown in formula 2, aromatic tetrafluoroboric acid diazonium salt and alkali, then replacing the reactor with inert atmosphere, stirring and reacting at room temperature, and completely reactingPost-treatment is carried out to obtain the polyhalogenated aza-spiro hexadienone compound shown in the formula 3; the reaction formula is as follows:
；
wherein R represents OR 'and R' is selected from C 1-12 Alkyl, C 6-20 aryl-C 1-12 Alkyl, tri (C) 1-12 Alkyl) silicon-based, C 1-12 An acyl group;
R 1 selected from C 1-12 Alkyl, C 6-20 aryl-C 1-12 Alkyl, C 3-8 Cycloalkyl;
R 2 selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 An alkoxy group;
R 3 、R 4 selected from hydrogen, C 1-6 An alkyl group;
R 5 selected from hydrogen, C 1-6 Alkyl, C 1-6 A haloalkyl group;
X 1 ,X 2 represents halogen;
wherein the alkali is selected from one or a mixture of sodium carbonate, potassium phosphate, cesium carbonate and sodium bicarbonate;
the aromatic tetrafluoroboric acid diazonium salt is selected from phenyl tetrafluoroboric acid diazonium salt, 4-methoxy phenyl tetrafluoroboric acid diazonium salt and 4-nitrophenyl tetrafluoroboric acid diazonium salt.
2. The method of claim 1, wherein R' is selected from C 1-6 Alkyl, C 6-20 aryl-C 1-6 Alkyl, tri (C) 1-6 Alkyl) silicon-based, C 1-6 An acyl group; r is R 1 Selected from C 1-8 Alkyl, C 6-20 aryl-C 1-6 Alkyl, C 3-6 Cycloalkyl; r is R 2 Selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, tert-butoxy; r is R 3 、R 4 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl; r is R 5 Selected from hydrogen, methylEthyl, n-propyl, monochloromethyl, dichloromethyl, trichloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromomethyl; x is X 1 ,X 2 Independently of each other selected from fluorine, chlorine, bromine, iodine.
3. The synthetic method according to claim 2, wherein R' is selected from benzyl, methyl, t-butyldimethylsilyl, pivaloyl; r is R 1 Selected from ethyl, n-octyl, benzyl, phenethyl, isopropyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl; r is R 2 Selected from hydrogen, chlorine, bromine, methoxy; r is R 3 、R 4 Selected from hydrogen, methyl; r is R 5 Selected from hydrogen, monochloromethyl, dichloromethyl; x is X 1 ,X 2 Independently of one another, chlorine or bromine.
4. The method of claim 1, wherein the base is selected from the group consisting of sodium carbonate.
5. A synthetic method according to any one of claims 1 to 3, wherein the method does not use an organic solvent, and wherein the compound represented by formula 1NThe feeding mole ratio of the benzyl acrylamide compound, the polyhaloalkyl compound shown in the formula 2, the aromatic tetrafluoroboric acid diazonium salt and the alkali is 1 (10-1000): 1-5.
6. A synthetic method according to any one of claims 1 to 3 wherein the inert atmosphere is a nitrogen atmosphere or an argon atmosphere.
7. The synthesis method according to any one of claims 1 to 3, wherein the reaction time of the stirring reaction is 4 to 48 hours.
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