CN113277935B - Far-end halogenated alkyl ketone using HX as halogen source and synthesis method thereof - Google Patents

Far-end halogenated alkyl ketone using HX as halogen source and synthesis method thereof Download PDF

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CN113277935B
CN113277935B CN202110516201.7A CN202110516201A CN113277935B CN 113277935 B CN113277935 B CN 113277935B CN 202110516201 A CN202110516201 A CN 202110516201A CN 113277935 B CN113277935 B CN 113277935B
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郭丽娜
段新华
刘帅
白铭
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Xian Jiaotong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/53—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of hydroperoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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    • C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption

Abstract

A far-end halogenated alkyl ketone using HX as a halogen source and a synthesis method thereof are disclosed, wherein naphthenic base peroxyalcohol and a copper acetate catalyst are added under the nitrogen atmosphere, HCl, HBr and HI solution are added as halogen, and stirring is carried out at normal temperature; after the reaction is finished, adding enough water to extract a reaction solvent N-methylpyrrolidone, washing with saturated saline solution, finally drying an organic phase with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and removing the solvent; carrying out column chromatography on the organic phase to obtain a target product; the method takes industrial bulk raw materials of HCl, HBr and HI solution as halogen sources to realize free radical halogenation of C-C bond cracking, and obtains the far-end halogenated alkyl ketone compound with higher yield. The byproduct of the reaction is water, thereby reducing the environmental pollution and greatly improving the industrial production benefit.

Description

Far-end halogenated alkyl ketone using HX as halogen source and synthesis method thereof
Technical Field
The invention belongs to the technical field of fine chemical engineering, and relates to a synthesis method of far-end halogenated alkyl ketone by taking HX (X ═ Cl, Br and I) as a halogen source.
Background
Alkyl halides containing functional groups are important components of many biological and pharmaceutical molecules and have wide application in nucleophilic Substitution (SN), cross-coupling and other reactions. Through conversion, alkyl chains can be introduced into molecules, and complex molecules can be rapidly assembled. On the other hand, functionalized alkyl moieties are widely found in many natural products, drugs and biologically active compounds; and the construction of remotely functionalized alkyl halides is relatively difficult and challenging.
Halogenation utilizing free radicals to effect cleavage of the C-C bond has become an effective strategy for obtaining remote haloalkyl ketones. The current common approach in the field is to use a variety of organic halogenating agents including N-chlorosuccinimide (NCS), tert-butyl hypochlorite (t-BuOCl), N-bromosuccinimide (NBS), Tetrabutylammonium (TBAX) and CX 4 And the like, ring opening of cycloalkanols is used for the synthesis of distal haloalkyl ketones. However, the method has certain limitations, such as poor atom economy, poor functional group tolerance, waste post-treatment in mass production, and the like.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a far-end halogenated alkyl ketone taking HX as a halogen source and a synthesis method thereof, and solves the problems of low atom economy, high price, poor reaction activity and large amount of by-products discharged by products of the traditional halogenated reagent. Simultaneously, non-strained macrocyclic ring-opening halogenation can be realized.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the method comprises the following steps of (1) using HX as a halogen source, using HCl, HBr and HI solution as the halogen source, and realizing free radical halogenation of C-C bond cracking, wherein the molecular formula of the compound is as follows:
Figure GDA0003649951830000021
r is aryl or alkyl.
The method for synthesizing the far-end halogenated alkyl ketone by taking HX as the halogen source comprises the following steps:
(A) drying a reaction tube with a branch tube, adding a stirrer, adding cycloalkyl peroxyalcohol and a copper acetate catalyst in a nitrogen atmosphere, backfilling with nitrogen, adding an HCl solution, an HBr solution or an HI solution into the reaction tube, adding a reaction solvent N-methylpyrrolidone, keeping the concentration range of reactants between 0.1M and 0.2M, stirring for 1 to 2 hours at normal temperature, and finishing the reaction;
(B) after the reaction is finished, adding sufficient water to extract a reaction solvent N-methyl pyrrolidone, washing with saturated saline solution, finally drying an organic phase with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and removing the solvent;
(C) and carrying out column chromatography on the organic phase to obtain a target product.
The mol ratio of the naphthenic base peroxyalcohol to the copper acetate to the HCl/HBr/HI is 1 (0.05-0.1) to 1.5-2.
The column chromatography conditions are as follows: silica gel with 200-300 meshes is used, the mass ratio of the silica gel to a substance to be purified is (50-100):1, an eluent is a mixed solution of petroleum ether and ethyl acetate, and the petroleum ether: the volume ratio of the ethyl acetate is (60-30) to 1.
The cycloalkyl peroxyalcohol comprises (1-hydroperoxycyclopentyl) benzene, (1-hydroperoxy-2-methylcyclohexyl) benzene or 1-hydroperoxy-1-phenylcyclododecane.
The nitrogen backfilling is carried out at least three times.
The mass concentration of the HCl solution is 36 percent; the mass concentration of HBr solution is 40%; the HI solution has a mass concentration of 57%.
The advantages and the characteristics of the invention are that:
1. the chloro, bromo and iodo are achieved simultaneously using HCl, HBr, and HI solutions as the halogenating agents.
2. The raw materials are cheap and easy to obtain, the catalyst copper acetate is cheap, the reaction condition is mild, and the application range is wide.
3. The byproduct of the reaction is water, so that the environment pollution is small and the green and environment-friendly concept is compounded; the economic benefit of industrial production is greatly improved.
Drawings
FIG. 1 shows the nuclear magnetic hydrogen spectrum of 5-chlorophenylpentanone.
FIG. 2 is a nuclear magnetic carbon spectrum of 5-chlorophenylpentanone.
FIG. 3 is a nuclear magnetic hydrogen spectrum of 5-chloro-1-phenylhex-1-one.
FIG. 4 is a nuclear magnetic carbon spectrum of 5-chloro-1-phenylhex-1-one.
FIG. 5 is a nuclear magnetic hydrogen spectrum of 12-bromo-1-phenyldodecyl-1-one.
FIG. 6 is a nuclear magnetic carbon spectrum of 12-bromo-1-phenyldodecyl-1-one.
FIG. 7 shows the nuclear magnetic hydrogen spectrum of 5-bromovalerone.
FIG. 8 is a nuclear magnetic carbon spectrum of 5-bromovalerone.
FIG. 9 shows the nuclear magnetic hydrogen spectrum of 5-iodobenzene pentanone.
FIG. 10 is a nuclear magnetic carbon spectrum of 5-iodobenzene pentanone.
FIG. 11 is a substrate universality extension of the reaction of the present invention.
FIG. 12 shows the use of the products of the invention in the synthesis of pharmaceuticals and natural products.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example one
The method for preparing 5-chlorophenylpentanone in the embodiment specifically comprises the following steps:
a Schlenk reaction flask was charged with (1-hydroperoxycyclopentyl) benzene (38.4mg,0.2mmol), aqueous HCl (36%) solution (33. mu.L, 0.4mmol), copper acetate (1.8mg, 0.01mmol), nitrogen-filled 3 times, and N-methylpyrrolidinone (1mL) was added. Reacting for 1 hour at room temperature; after the reaction is finished, extracting with water (10mL), washing with saturated saline solution (10mL), drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using 200-mesh silica gel, the mass ratio of the silica gel to the to-be-purified product is 50: 1, the eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate in the mixed solution is 60:1) to obtain white solid 5-chlorophenyl pentanone (35.4mg, 90%), wherein the nuclear magnetic spectrum and the high-resolution mass spectrum of the product are proved to obtain a pure product.
The reaction equation is as follows:
Figure GDA0003649951830000041
the product structure is as follows:
Figure GDA0003649951830000051
referring to fig. 1 and 2, the hydrogen and carbon spectra data of the product are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝7.1Hz,2H),7.56(t,J＝ 7.4Hz,1H),7.46(t,J＝7.6Hz,2H),3.58(t,J＝6.2Hz,2H),3.02(t,J＝ 6.8Hz,2H),1.98–1.82(m,4H). 13 C NMR(100MHz,CDCl 3 )δ199.6, 136.9,133.1,128.7,128.0,44.8,37.6,32.1,21.5.
example two
This example, for the preparation of 5-chloro-1-phenylhex-1-one, specifically includes the following steps:
a Schlenk flask was charged with (1-hydroperoxy-2-methylcyclohexyl) benzene (38.4mg,0.2mmol), aqueous HCl (38%) (33. mu.L, 0.4mmol), copper acetate (1.8mg, 0.01mmol), nitrogen-filled 3 times, and N-methylpyrrolidinone (1mL) was added. Reacting for 1h at room temperature; after the reaction is finished, extracting with water (10mL), washing with saturated saline (10mL), drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using 300-mesh silica gel, the mass ratio of the silica gel to the substance to be purified is 100:1, the eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate in the mixed solution is 60:1) to obtain a white solid 5-chloro-1-phenylhex-1-one (33.6mg, 80%), wherein the nuclear magnetic spectrum and the high resolution mass spectrum of the product and the infrared spectrum of the product both prove that a pure product is obtained.
The reaction equation is as follows:
Figure GDA0003649951830000061
the product structure is as follows:
Figure GDA0003649951830000062
referring to fig. 3 and 4, the hydrogen and carbon spectra and high resolution mass spectra data of the product are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝7.1Hz,2H),7.56(t,J＝ 7.4Hz,1H),7.47(t,J＝7.5Hz,2H),4.14–4.02(m,1H),3.01(td,J＝ 7.1,2.0Hz,2H),2.03–1.72(m,4H),1.53(d,J＝6.6Hz,3H). 13 C NMR (100MHz,CDCl 3 )δ199.8,136.9,133.1,128.6,128.0,58.5,39.7,37.8, 25.3,21.3.HRMS(ESI)calcd for C 12 H 16 ClO[M+H] + 211.0884,found 211.0881.
EXAMPLE III
The preparation method of the 12-bromo-1-phenyldodecyl-1-ketone comprises the following steps: 1-hydroperoxy-1-phenylcyclododecane (55.2mg,0.2mmol), aqueous HBr (40%) (55. mu.L, 0.4mmol), copper acetate (1.8mg, 0.01mmol) and nitrogen were charged 3 times in a Schlenk reaction flask and N-methylpyrrolidinone (1mL) was added. Reacting for 1h at room temperature; after the reaction is finished, extracting with water (10mL), washing with saturated saline (10mL), drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using 250-mesh silica gel, the mass ratio of the silica gel to the substance to be purified is 80:1, the eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate in the mixed solution is 60:1) to obtain a white solid 12-bromo-1-phenyldodecyl-1-ketone (48mg, 71%), wherein the nuclear magnetic spectrum and the high-resolution mass spectrum of the product both prove that the pure product is obtained.
The reaction equation is as follows:
Figure GDA0003649951830000071
the product structure is as follows:
Figure GDA0003649951830000072
referring to fig. 5 and 6, the hydrogen and carbon spectra data of the product are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝7.1Hz,2H),7.59–7.52 (m,1H),7.45(t,J＝7.5Hz,2H),3.40(t,J＝6.9Hz,2H),2.96(t,J＝7.4 Hz,2H),1.89–1.80(m,2H),1.78–1.69(m,2H),1.45–1.26(m,14H). 13 C NMR(100MHz,CDCl 3 )δ200.6,137.1,132.9,128.6,128.1,38.6, 34.1,32.8,29.5,29.5,29.4,29.4,29.4,28.8,28.2,24.4.
example four
An example is the preparation of 5-bromovalerone, comprising in particular the following steps: a Schlenk reaction flask was charged with (1-hydroperoxycyclopentyl) benzene (1.78g,10mmol), aqueous HBr (40%) solution (2.8mL,20mmol), cupric acetate (90mg, 0.5mmol), nitrogen-filled 3 times, and N-methylpyrrolidinone (50mL) was added. Reacting for 12 hours at room temperature; after the reaction is finished, extracting with water (200 mL), washing with saturated saline (100mL), drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using 300-mesh silica gel, the mass ratio of the silica gel to the to-be-purified product is 60:1, the eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate in the mixed solution is 60:1) to obtain white solid 5-bromobenzophenone (1.92g, 80%), wherein the nuclear magnetic spectrum and the high resolution mass spectrum of the product both prove that the pure product is obtained.
The reaction equation is as follows:
Figure GDA0003649951830000081
the structure of the product is as follows:
Figure GDA0003649951830000082
referring to fig. 7 and 8, the hydrogen and carbon spectra data of the product are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝7.2Hz,2H),7.57(t,J＝ 7.4Hz,1H),7.46(t,J＝7.6Hz,2H),3.45(t,J＝6.4Hz,2H),3.02(t,J＝ 6.8Hz,2H),2.02–1.82(m,5H). 13 C NMR(100MHz,CDCl 3 )δ199.6, 136.8,133.1,128.7,128.0,37.4,33.4,32.2,22.8.
EXAMPLE five
An example is the preparation of 5-iodobenzene pentanone, comprising in particular the following steps: a Schlenk reaction flask was charged with (1-hydroperoxycyclopentyl) benzene (38.4mg,0.2mmol), HI (57%) in water (55. mu.L, 0.4mmol), copper acetate (1.8mg, 0.01mmol), nitrogen-filled 3 times, and N-methylpyrrolidinone (1mL) was added. Reacting for 1h at room temperature; after the reaction is finished, extracting with water (10mL), washing with saturated saline (10mL), drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying the product by column chromatography (using 200-mesh silica gel, the mass ratio of the silica gel to the substance to be purified is 70:1, the eluent is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate in the mixed solution is 60:1) to obtain white solid 5-iodobenzene pentanone (46mg, 80%), wherein the nuclear magnetic spectrum and the high-resolution mass spectrum of the product both prove that the pure product is obtained.
The reaction equation is as follows:
Figure GDA0003649951830000091
the product structure is as follows:
Figure GDA0003649951830000092
referring to fig. 9 and 10, the hydrogen and carbon spectra data of the product are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝7.1Hz,2H),7.56(t,J＝ 7.4Hz,1H),7.46(t,J＝7.6Hz,2H),3.22(t,J＝6.7Hz,2H),3.00(t,J＝ 6.9Hz,2H),1.83–1.94(m,4H). 13 C NMR(100MHz,CDCl 3 )δ200.5, 137.0,133.0,128.6,128.1,45.1,38.5,32.6,29.2,28.8,26.7,24.2.
general applicability of the reaction
The substrate universality of this ring-opening chlorination reaction was evaluated. The various cyclopentyl peroxy alcohols can be obtained in moderate to good yields in this C-C bond cleavage/halogenation reaction. The effect of substituents on the aromatic ring on yield was not apparent. 1-thienyl substituted substrates were also suitable (2g,3g,4g) with yields between 53% and 68%. In addition, alkyl substituted cycloalkyl peroxyalcohols also give the desired product (2c,3c,4c) in yields between 54% and 73%. It is noteworthy that, in addition to cyclopentyl peroxyalcohol, 6-, 7-, and 12-membered ring peroxyalcohols gave the corresponding products (d-f) in yields ranging from 41% to 78%. The 1, 2-disubstituted cycloalkylperoxyalcohols have good regioselectivity, giving the expected secondary chlorides 2h, 2i in yields between 49-80%, as shown in FIG. 11.
Use of reaction products
The reaction product of the invention can carry out alkyl chain modification on various bioactive molecules and natural product molecules, and shows great potential of modification of medical molecules and pesticide molecules. For example, ketoalkylation modification can be carried out on a mental drug Fluoxetine hydrochloride (Fluoxetine hydrochloride) for treating depression and loxoprofen drugs with significant analgesic, anti-inflammatory and antipyretic functions; the product of the invention can also carry out ketone alkylation modification on the estrone steroid hormone; ketones can also be converted into alcohols to prepare a series of halogenated alkyl alcohol compounds, which show great application potential and value, as shown in fig. 12.

Claims (6)

1. The method for synthesizing the far-end halogenated alkyl ketone by taking HX as a halogen source is characterized by comprising the following steps of:
(A) drying a reaction tube with a branch tube, adding a stirrer, adding cycloalkyl peroxyalcohol and a copper acetate catalyst in a nitrogen atmosphere, backfilling with nitrogen, adding an HCl solution, an HBr solution or an HI solution into the reaction tube, adding a reaction solvent N-methylpyrrolidone, keeping the concentration range of reactants between 0.1M and 0.2M, stirring for 1 to 2 hours at normal temperature, and finishing the reaction;
(B) after the reaction is finished, adding sufficient water to extract a reaction solvent N-methyl pyrrolidone, washing with saturated saline solution, finally drying an organic phase with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and removing the solvent;
(C) and carrying out column chromatography on the organic phase to obtain a target product.
2. The method for synthesizing a remote haloalkyl ketone with HX as the halogen source as recited in claim 1, wherein the molar ratio of cycloalkyl peroxyalcohol, copper acetate, HCl/HBr/HI is 1 (0.05-0.1) to (1.5-2).
3. The method for synthesizing a remote haloalkyl ketone with HX as halogen source as claimed in claim 1, wherein the column chromatography conditions are as follows: silica gel with 200-300 meshes is used, the mass ratio of the silica gel to a substance to be purified is (50-100):1, an eluent is a mixed solution of petroleum ether and ethyl acetate, and the petroleum ether: the volume ratio of the ethyl acetate is (60-30) to 1.
4. The method for synthesizing a remote haloalkyl ketone with HX as a halogen source as recited in claim 1, wherein said cycloalkyl peroxyalcohol comprises (1-hydroperoxycyclopentyl) benzene, (1-hydroperoxy-2-methylcyclohexyl) benzene or 1-hydroperoxy-1-phenylcyclododecane.
5. The method for synthesizing a remote haloalkyl ketone with HX as a halogen source as recited in claim 1 wherein the nitrogen backfill is at least three times.
6. The method for synthesizing a remote haloalkyl ketone with HX as halogen source as recited in claim 1 wherein the HCl solution has a mass concentration of 36%; the mass concentration of HBr solution is 40%; the HI solution has a mass concentration of 57%.
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