CN112159389A - Preparation method of difluoro-ketone carbonyl substituted nitrile compound - Google Patents
Preparation method of difluoro-ketone carbonyl substituted nitrile compound Download PDFInfo
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- CN112159389A CN112159389A CN202011182396.8A CN202011182396A CN112159389A CN 112159389 A CN112159389 A CN 112159389A CN 202011182396 A CN202011182396 A CN 202011182396A CN 112159389 A CN112159389 A CN 112159389A
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- -1 nitrile compound Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003999 initiator Substances 0.000 claims abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 230000035484 reaction time Effects 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000605 extraction Methods 0.000 claims description 10
- YIVJZNGAASQVEM-UHFFFAOYSA-N Lauroyl peroxide Chemical compound CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC YIVJZNGAASQVEM-UHFFFAOYSA-N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002560 nitrile group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- IYRWEQXVUNLMAY-UHFFFAOYSA-N carbonyl fluoride Chemical compound FC(F)=O IYRWEQXVUNLMAY-UHFFFAOYSA-N 0.000 claims 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 230000001766 physiological effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000575 pesticide Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 239000007788 liquid Substances 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000007789 sealing Methods 0.000 description 12
- 238000002390 rotary evaporation Methods 0.000 description 10
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000004293 19F NMR spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- RXBQTZHAUYILQJ-UHFFFAOYSA-N 2,2-difluoro-2-iodo-1-phenylethanone Chemical compound FC(F)(I)C(=O)C1=CC=CC=C1 RXBQTZHAUYILQJ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZNTJVJSUNSUMPP-UHFFFAOYSA-N 1-ethyl-4-ethynylbenzene Chemical group CCC1=CC=C(C#C)C=C1 ZNTJVJSUNSUMPP-UHFFFAOYSA-N 0.000 description 1
- CMRABZVFNFBKQC-UHFFFAOYSA-N 2,2-difluoro-1-(4-fluorophenyl)-2-iodoethanone Chemical compound FC(C(=O)C1=CC=C(C=C1)F)(I)F CMRABZVFNFBKQC-UHFFFAOYSA-N 0.000 description 1
- KSZVOXHGCKKOLL-UHFFFAOYSA-N 4-Ethynyltoluene Chemical group CC1=CC=C(C#C)C=C1 KSZVOXHGCKKOLL-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of difluoro ketone carbonyl substituted nitrile compounds, which comprises the following steps: mixing a compound represented by the formula (1) with a catalyst, a ligand, a radical initiator and a solvent, and reacting the mixture in the presence of N2Reacting with a compound shown as a formula (2) and a compound shown as a formula (3) under protection until the reaction is complete, extracting and separating the obtained reaction liquid to obtain a compound shown as a formula (4), namely a difluoro ketone carbonyl substituted nitrile compound, which is shown as the following formula:
wherein: r1Is phenyl, substituted phenyl or heterocycle, R2Is phenyl, cyclohexenyl, substituted phenyl or heterocycle. Compared with the prior art, the method has the advantages of high efficiency, short reaction time, high yield and the like, has better industrial production prospect, and the prepared difluoro ketone carbonyl substituted nitrile compound has good physiological activity and better application potential in the fields of medicines and pesticides.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of a difluoro ketone carbonyl substituted nitrile compound.
Background
After the fluorine atom or the fluorine-containing group is introduced into the organic compound molecule, the physical property, the chemical property and the physiological property (such as lipophilicity, metabolic stability, binding capacity with target protein, cell membrane penetrability and bioavailability) of the organic compound are obviously improved compared with the parent molecule. It is well known that cyano groups are readily converted to other functional groups and have wide utility in the field of synthetic methodology. Therefore, the use of low toxicity cyanide-containing compounds to accomplish the cyanated difluorination of alkynes has attracted the attention of chemists.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for preparing the difluoroketone carbonyl substituted nitrile compound, which has the advantages of high efficiency, short reaction time, high yield, better industrial production prospect, good physiological activity and better application potential in the fields of medicines and pesticides.
The purpose of the invention can be realized by the following technical scheme:
a method for preparing difluoro ketone carbonyl substituted nitrile compounds comprises the following steps: mixing a compound represented by the formula (1) with a catalyst, a ligand, a radical initiator and a solvent, and reacting the mixture in the presence of N2Reacting with a compound shown as a formula (2) and a compound shown as a formula (3) under protection until the reaction is complete, extracting and separating the obtained reaction liquid to obtain a compound shown as a formula (4), namely a difluoro ketone carbonyl substituted nitrile compound shown as the following formula:
wherein: r1Is phenyl, substituted phenyl or heterocycle, R2Is phenyl, cyclohexenyl, substituted phenyl or heterocycle.
Further, when R is1When the substituted phenyl is substituted, the substituent in the substituted phenyl is selected from one or more of phenyl, hydrogen, fluorine, bromine, chlorine, C1-C4 alkyl, nitro, methoxy or trifluoromethyl.
Further, when R is2When the substituent is substituted phenyl, the substituent is selected from any one or more of hydrogen, fluorine, bromine, chlorine, nitro, methoxy, C1-C4 alkyl, trifluoromethyl, benzyl, ester group, nitrile group or phenyl.
Further, the catalyst comprises Cu (CH)3CN)4PF6。
Further, the ligand comprises 2,2':6', 2' -Terpyrdine (alpha, alpha-Terpyridine).
Further, the radical initiator includes Lauroyl Peroxide (LPO); the solvent comprises CH3OH。
Further, the molar ratio of the compound of formula (1), the compound of formula (2), the compound of formula (3), the catalyst, the ligand and the radical initiator is 0.3:0.45:0.6:0.03:0.06: 0.75.
Further, the reaction temperature is 65-70 ℃, preferably 70 ℃ and the reaction time is 4-6h, preferably 5 h.
Further, the extraction is carried out by adopting an extraction liquid, the extraction liquid comprises ethyl acetate and water in a volume ratio of (0.8-1):1, the volume ratio of the extraction liquid to the reaction liquid is 1: (1-1.5), and the extraction times are 3-4 times.
Further, the separation is carried out in a chromatographic column by using an eluent, wherein the eluent is n-hexane and ethyl acetate with the volume ratio of (30-500) to 1, preferably (30-50) to 1, and the elution time is 2-5 h.
Compared with the prior art, the preparation method has the advantages of short reaction time, lower reaction temperature, high yield and the like, and has better industrial production prospect: the difluoro ketone carbonyl substituted nitrile compound prepared by the invention has a brand new structure, has good physiological activity and can be used as a universal building block for various organic synthesis reactions.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
This example synthesized (E) -4, 4-difluoro-5-oxo-2, 5-diphenylpent-2-enenitrile
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; 2, 2-difluoro-2-iodo-1-phenylethane-1-one (0.0846g, 0.3mmol), phenylacetylene (0.0460g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, which were weighed in advance, were charged into the above 10mL standard reaction tube with a liquid charger under nitrogen protection; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, firstly decompressing and carrying out rotary distillation to remove the methanol, after the rotary distillation, using petroleum ether: column chromatography with methanol (60-20):1 eluent gave 70.5mg (83% yield) of pale yellow oily liquid.
1H NMR(500MHz,CDCl3):7.83(d,J＝10.0Hz,2H),7.61(t,J＝7.5Hz, 1H),7.45–7.39(m,3H),7.35-7.29(m,4H),6.89(t,J＝12.5Hz,1H).
13C NMR(125MHz,CDCl3):186.27(t,2'JC-F＝30.0Hz),135.41(t,2JC-F＝ 26.9Hz),134.81,131.04,130.60,130.43,129.80(t,3'JC-F＝3.1Hz),128.77,128.70, 126.67,124.57(t,3JC-F＝7.5Hz),117.47,113.91(t,1JC-F＝251.3Hz).
19F NMR(376MHz,CDCl3):-90.76(d,J＝15.0Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]＝for C17H11F2NO:306.0701,found: 306.0702.
Example 2
This example synthesized (E) -4, 4-difluoro-5- (4-methoxyphenyl) -5-oxo-2-phenylpent-2-enenitrile
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; under the protection of nitrogen, 2-difluoro-2-iodo-1- (4-methoxyphenyl) ethan-1-one (0.0936g, 0.3mmol), phenylacetylene (0.0460g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, which were weighed in advance, were added to the above 10mL standard reaction tube with a liquid charger; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain a pale yellow oily liquid, 63.9mg, and yield was 68%.
1H NMR(500MHz,CDCl3):7.85(d,J＝10.0Hz,2H),7.41-7.37(m,1H), 7.35–7.32(m,4H),6.91-6.85(m,3H),3.87(s,3H).
13C NMR(125MHz,CDCl3):184.73(t,2'JC-F＝29.4Hz),164.87,135.71(t, 2JC-F＝26.9Hz),132.49(t,3'JC-F＝2.5Hz),130.53,130.47,128.76,128.63,124.19 (t,3JC-F＝7.5Hz),123.82,117.60,114.19(t,1JC-F＝251.3Hz),114.12,55.64.
19F NMR(376MHz,CDCl3):-90.84(d,J＝15.0Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]＝for C18H13F2NO2:336.0807,found: 336.0809.
Example 3
This example synthesized (E) -4, 4-difluoro-5- (4-fluorophenyl) -5-oxo-2-phenylpent-2-enenitrile
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; 2, 2-difluoro-1- (4-fluorophenyl) -2-iodoethan-1-one (0.0900g, 0.3mmol), phenylacetylene (0.0460g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, previously weighed, were added to the above 10mL standard reaction tube with a liquid charger under nitrogen protection; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain a pale yellow oily liquid (64.2 mg, yield 71%).
(E)-4,4-difluoro-5-(4-fluorophenyl)-5-oxo-2-phenylpent-2-enenitrile, purified by flash column chromatography on silica gel(PE/EA＝30/1),light yellow oily liquid,64.2mg,71％yield.
1H NMR(500MHz,CDCl3):7.88(dd,J＝5.0Hz,2H),7.41(t,J＝7.5Hz, 1H),7.35–7.30(m,4H),7.11(t,J＝7.5Hz,2H),6.88(t,J＝12.5Hz,1H).
13C NMR(125MHz,CDCl3):184.84(t,2'JC-F＝30.0Hz),167.64,165.58, 135.06(t,2JC-F＝26.9Hz),132.78(dt,J＝10.0Hz,3.1Hz),130.63,130.43, 128.72,127.43,124.74(t,3JC-F＝8.1Hz),117.39,116.16(d,1'JC-F＝21.3Hz), 113.94(t,1JC-F＝250.6Hz).
19F NMR(376MHz,CDCl3):-90.62(d,J＝11.3Hz,2F),-100.85(m,1F).
HRMS(ESI-TOF)calculated[M+Na]＝for C17H10F3NO:324.0607,found: 324.0608.
Example 4
This example synthesized (E) -4, 4-difluoro-5-oxo-2-phenyl-5- (thiophen-2-yl) pent-2-enenitrile
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; under the protection of nitrogen, 2-difluoro-2-iodo-1- (thiophen-2-yl) ethan-1-one (0.0864g, 0.3mmol), phenylacetylene (0.0460g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol were weighed in advance, and added to the above 10mL standard reaction tube with a liquid charger; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain a pale yellow oily liquid (71.2 mg, yield 82%).
1H NMR(500MHz,CDCl3):7.84(s,1H),7.79(d,J＝5.0Hz,1H),7.42– 7.34(m,5H),7.35(t,J＝5.0Hz,1H),6.83(t,J＝12.5Hz,1H).
13C NMR(125MHz,CDCl3):179.73(t,2'JC-F＝30.6Hz),137.28,137.19, 135.94(t,3'JC-F＝4.4Hz),134.85(t,2JC-F＝26.3Hz),130.57,130.46,128.88, 128.76(t,4'JC-F＝2.5Hz),128.69,124.91(t,3JC-F＝7.5Hz),117.47,113.69(t,1JC-F＝251.3Hz).
19F NMR(376MHz,CDCl3):-92.22(d,J＝15.0Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]＝for C15H9F2NOS:312.0265,found: 312.0267.
Example 5
This example synthesized (E) -4, 4-difluoro-5-oxo-5-phenyl-2- (p-tolyl) pent-2-enenitrile
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; 2, 2-difluoro-2-iodo-1-phenylethane-1-one (0.0846g, 0.3mmol), p-tolylacetylene (0.0523g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, weighed in advance, were added to the above 10mL standard reaction tube with a liquid charger under nitrogen protection; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain 58.0mg of a pale yellow oily liquid with a yield of 65%.
1H NMR(500MHz,CDCl3):7.84(d,J＝5.0Hz,2H),7.61(t,J＝7.5Hz, 1H),7.43(t,J＝7.5Hz,2H),7.21(d,J＝5.0Hz,2H),7.13(d,J＝10.0Hz,2H), 6.84(t,J＝12.5Hz,1H),2.35(s,3H).
13C NMR(125MHz,CDCl3):186.32(t,2'JC-F＝29.4Hz),141.09,134.74, 134.59(t,2JC-F＝26.9Hz),131.13,129.79(t,3'JC-F＝2.5Hz),129.36,128.77, 128.73,127.58 124.67(t,3JC-F＝8.1Hz),117.63,113.95(t,1JC-F＝250.0Hz), 21.38.
19F NMR(376MHz,CDCl3):-90.73(d,J＝11.3Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]＝for C18H13F2NO:320.0857,found: 320.0861.
Example 6
This example synthesized (E) -2- (4-ethylphenyl) -4, 4-difluoro-5-oxo-5-phenylpent-2-enenitrile
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; 2, 2-difluoro-2-iodo-1-phenylethane-1-one (0.0846g, 0.3mmol), p-ethylphenylacetylene (0.0586g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, weighed in advance, were added to the above 10mL standard reaction tube with a liquid charger under nitrogen protection; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain 68.2mg of a pale yellow oily liquid with a yield of 73%.
1H NMR(500MHz,CDCl3):7.81(d,J＝5.0Hz,2H),7.60(t,J＝7.5Hz, 1H),7.42(t,J＝7.5Hz,2H),7.22(d,J＝5.0Hz,2H),7.15(d,J＝5.0Hz,2H), 6.84(t,J＝12.5Hz,1H),2.64(q,J＝8.3Hz,2H),1.23(t,J＝7.5Hz,3H).
13C NMR(125MHz,CDCl3):186.30(t,2'JC-F＝29.4Hz),147.34,134.70, 134.62(t,2JC-F＝26.9Hz),131.16,129.71(t,3'JC-F＝2.5Hz),128.88,128.70, 128.19,127.75,124.67(t,3JC-F＝8.1Hz),117.63,113.89(t,1JC-F＝250.0Hz), 28.70,15.25.
19F NMR(376MHz,CDCl3):-90.56(d,J＝11.3Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]＝for C19H15F2NO:334.1014,found: 334.1016。
Claims (10)
1. A method for preparing difluoro ketone carbonyl substituted nitrile compounds is characterized by comprising the following steps: mixing a compound represented by the formula (1) with a catalyst, a ligand, a radical initiator and a solvent, and reacting the mixture in the presence of N2Reacting with a compound shown as a formula (2) and a compound shown as a formula (3) under protection until the reaction is complete, extracting and separating the obtained reaction liquid to obtain a compound shown as a formula (4), namely a difluoro ketone carbonyl substituted nitrile compound, which is shown as the following formula:
wherein: r1Is phenyl, substituted phenyl or heterocycle, R2Is phenyl, cyclohexenyl, substituted phenyl or heterocycle.
2. The method of claim 1, wherein R is the number of carbon atoms in the nitrile group1When the substituted phenyl is substituted, the substituent in the substituted phenyl is selected from one or more of phenyl, hydrogen, fluorine, bromine, chlorine, C1-C4 alkyl, nitro, methoxy or trifluoromethyl.
3. The method of claim 1, wherein R is the number of carbon atoms in the nitrile group2When substituted phenyl, the substituent is selected from hydrogen, fluorine, bromine,any one or more of chlorine, nitryl, methoxyl, C1-C4 alkyl, trifluoromethyl, benzyl, ester group, nitrile group or phenyl.
4. The method of claim 1, wherein the catalyst comprises Cu (CH)3CN)4PF6。
5. The method as claimed in claim 1, wherein the ligand is 2,2':6',2 "-Terpyrdine.
6. The method of claim 1, wherein the radical initiator comprises lauroyl peroxide; the solvent comprises CH3OH。
7. The method for preparing difluoroketone carbonyl-substituted nitrile compounds as claimed in claim 1, wherein the molar ratio of the compound of formula (1), the compound of formula (2), the compound of formula (3), the catalyst, the ligand and the radical initiator is 0.3:0.45:0.6:0.03:0.06: 0.75.
8. The method for preparing difluoroketone carbonyl-substituted nitrile compounds as claimed in claim 1, wherein the reaction temperature is 65-70 ℃ and the reaction time is 4-6 h.
9. The method according to claim 1, wherein the extraction is performed by using an extraction solution, the extraction solution comprises ethyl acetate and water in a volume ratio of (0.8-1):1, the volume ratio of the extraction solution to the reaction solution is 1: (1-1.5), and the extraction times are 3-4 times.
10. The method for preparing difluoro-ketone carbonyl-substituted nitrile compound as claimed in claim 1, wherein the separation is performed by using an eluent for separation and purification in a chromatographic column, wherein the eluent comprises n-hexane and ethyl acetate in a volume ratio of (30-500):1, and the elution time is 2-5 h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06179646A (en) * | 1992-12-15 | 1994-06-28 | Tokuyama Soda Co Ltd | Cyanoketone derivative |
| US20180118648A1 (en) * | 2015-03-24 | 2018-05-03 | Okinawa Institute Of Science And Technology School Corporation | 5-substituted-5-hydroxy-5-aryl-3-oxo-pentanoate derivatives and their enantiopure forms |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06179646A (en) * | 1992-12-15 | 1994-06-28 | Tokuyama Soda Co Ltd | Cyanoketone derivative |
| US20180118648A1 (en) * | 2015-03-24 | 2018-05-03 | Okinawa Institute Of Science And Technology School Corporation | 5-substituted-5-hydroxy-5-aryl-3-oxo-pentanoate derivatives and their enantiopure forms |
Non-Patent Citations (2)
| Title |
|---|
| MUHAMMAD ISRAR 等: "Copper(I)-Catalyzed Cyanoperfluoroalkylation of Alkynes", 《ORGANIC LETTERS》 * |
| YU-TAO HE等: "Synthesis of β‑Difluoroalkylated Acrylonitriles in the Presence of Copper Powder", 《ORGANIC LETTERS》 * |
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