CN108586424B - Benzylation synthesis method of phenol compounds - Google Patents
Benzylation synthesis method of phenol compounds Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
Abstract
The invention provides a benzylation synthesis method of a p-phenol framework structure by means of the characteristic that hexafluoroisopropanol has strong hydrogen bond donor capacity and cation species stabilizing capacity. The invention discloses a benzylation synthesis method of phenol compounds, which utilizes phenol and amino formaldehyde compounds to carry out serial Friedel-crafts alkylation/dehydration/hydrogen migration/cyclization dearomatization/aromatization reaction in hexafluoroisopropanol at room temperature, thereby synthesizing a target product in a green and high-efficiency manner. Compared with the existing known synthesis strategies such as Friedel-crafts reaction and the like, the synthesis method of the invention does not need to synthesize an occupying group or a halogen active site on a phenol skeleton in advance, has high regioselectivity of a benzylation product, simplifies reaction test steps and improves atom economy.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a benzylation synthesis method of a phenol compound.
Background
The phenol compounds are abundant in variety and widely exist in artificially synthesized molecules such as natural products, medicines, chemical raw materials and the like. The phenol compound has a plurality of active chemical reaction sites, can carry out halogenation, hydrogenation, oxidation and alkylation (such as classical Friedel-crafts reaction) substitution reaction, and the phenolic hydroxyl functional group can carry out carboxylation, esterification, etherification and other reactions. Due to wide sources and active chemical properties, phenol compounds are often used as raw materials and structural units for constructing molecules with complex structures, and further, efficient control of regioselectivity and chemoselectivity on a phenol skeleton in related reactions is always one of research hotspots.
Direct C (sp) to the phenol skeleton2) The method has good economical efficiency because the functionalized group does not need to be introduced in advance, and the economical efficiency comprises atom economical efficiencyAnd step economics. However, this carbon-hydrogen functionalization strategy also has problems, such as better nucleophilicity of the phenolic hydroxyl group than the carbon on the phenyl ring of phenol, and a small difference in nucleophilicity between the ortho and para positions of phenol. Therefore, how to realize high-selectivity carbon-hydrogen functionalization on a phenol skeleton is very important for development and application expansion of a functionalization strategy of the phenol compound.
In 2014, Liu and Zhang group firstly utilized phenol and gold carbene intermediate addition reaction to finally obtain the product (J.Am.chem.Soc.2014,136: 6904-6907). However, this method is expensive using a noble transition metal catalyst, etc., and it is very difficult to remove the metal catalyst from the final product.
In 2016, Liu and Zhang groups synthesized 18: 1 chemoselectivity products using boron as a catalyst by direct carbon-hydrogen bond functionalization of the phenol backbone, but also by ortho-selectivity of the product produced (Angew. chem. int. Ed.2016,55,14807). The reaction utilizes hydrogen bonds formed by H on the hydroxyl group of phenol and F on the benzene ring of the catalyst, and realizes high regioselectivity of phenol through 'oriented' carbon-hydrogen bond functionalization.
However, the above synthesis method requires an additional directing group for coordination guidance with the boron catalyst, and the directing group diazo needs to be removed after the reaction is completed, resulting in poor atom economy of the synthesis strategy. In addition, the synthesis method needs to add precious metals or strong Lewis acids, has high cost and heavy pollution, needs to prepare carbene groups in advance, and has complex operation and lower yield. In order to overcome the problems in the benzylation of phenolic compounds, further improvements in the economics, selectivity and efficiency of the reaction are needed.
Disclosure of Invention
The invention aims to provide a benzylation synthesis method of phenol compounds. The method has the advantages of simple and practical operation, good yield, green and economical reaction and environmental friendliness.
The synthesis method provided by the invention comprises the following steps:
reacting a phenolic compound A and an amino formaldehyde compound B in hexafluoroisopropanol to prepare a reaction intermediate spiro compound, and adding a reducing agent into a reaction system to obtain a benzylation product of the phenolic compound.
Separating the spiro compound as the intermediate, adding reductant and opening ring in organic solvent to obtain the benzylated phenol compound.
The benzylation product of the phenol compound is any one of compounds shown in a formula I:
wherein
In formula I, the dotted line represents an optional single bond;
R1any one of hydrogen, diethylamine and tetrahydropyrrole;
R2is selected from any one of chlorine, bromine, methyl, trifluoromethyl, methoxyl, borate and p-acetyl phenyl.
The phenolic compound A is a compound shown as a formula II;
the amino formaldehyde compound B is any one of compounds shown in a formula III:
wherein
In the formulas II and III, the dotted line represents an optional single bond;
R1any one of hydrogen, diethylamine and tetrahydropyrrole;
R2is selected from any one of chlorine, bromine, methyl, trifluoromethyl, methoxyl, borate and p-acetyl phenyl.
The molar ratio of compound A to compound B was 1.3: 1.
The above-mentioned reducing agentIs mixture of Hans ester and S-binaphthol phosphate, NaBH4Any one of them.
The molar ratio of the mixture of hanster and S-binaphthol phosphate is 26: 1.
The organic solvent is any one of tetrahydrofuran, dichloromethane and methanol.
The invention provides a benzylation synthesis method of phenol compounds, which comprises the following steps:
adding the compound A and the compound B into hexafluoroisopropanol according to a certain proportion, reacting at 25 ℃, and obtaining an intermediate spiro compound after the reaction is finished;
adding NaBH into the reaction system4Stirring and reacting at 25 ℃, concentrating and purifying after the reaction is finished, and obtaining a benzylation product of the phenol compound;
wherein the intermediate spiro compound is isolated and NaBH is added4Reducing agent, reacting in methanol at 25 deg.c, concentrating and purifying to obtain benzylated phenol compound product.
Separating the intermediate spiro compound, and then reacting the intermediate spiro compound with NaBH serving as a reducing agent4The ring-opening reaction is carried out according to the molar ratio of 1: 2.
The invention provides a benzylation synthesis method of a p-phenol framework structure by means of the characteristic that hexafluoroisopropanol has strong hydrogen bond donor capacity and cation species stabilizing capacity. And the hexafluoroisopropanol aggregates two molecules through hydrogen bonds to form a double-activation model, then a nucleophilic addition product is generated, and then the benzyl alcohol immediately carries out dehydration and dearomatization reactions to obtain the dearomatized o-QM. And recovering aromatizing by using the o-QM formed in situ to drive methylene carbon to initiate [1,5] -hydrogen migration so as to obtain an aromatic intermediate, forming imine positive ions with higher electrophilicity, carrying out electrophilic addition reaction with a benzene ring to remove aromatizing of the aromatic ring so as to form a dearomatized spiro structure, and reducing by using sodium borohydride to obtain a re-aromatized benzylated product at the ortho position of the phenol.
The invention discloses a benzylation synthesis method of phenol compounds, which utilizes phenol and amino formaldehyde compounds to carry out serial Friedel-crafts alkylation/dehydration/hydrogen migration/cyclization dearomatization/aromatization reaction in hexafluoroisopropanol at room temperature, thereby synthesizing a target product in a green and high-efficiency manner. Compared with the existing known synthesis strategies such as Friedel-crafts reaction and the like, the synthesis method of the invention does not need to synthesize an occupying group or a halogen active site on a phenol skeleton in advance, has high regioselectivity of a benzylation product, simplifies reaction test steps and improves atom economy. The reaction can be carried out at room temperature, the reaction condition is mild, a metal or proton catalyst is not needed, and the operation is convenient; the reaction activity is high, and the raw material conversion is complete; the final product is convenient to separate and is environment-friendly.
Detailed Description
The foregoing aspects of the present invention are further illustrated by the specific embodiments provided in the following examples, which should not be construed as limiting the scope of the above-described subject matter of the present invention to the following examples by those skilled in the art; all the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials, instruments and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Weighing Compound A1(sesamol) 0.26mmol and Compound B10.2mmol of (2-pyrrolidinobenzaldehyde) was put in a 25m L high-pressure tube, and 2m L of hexafluoroisopropanol HFIP was added thereto, followed by stirring at room temperature for 12 hours.
Spotting on a thin layer chromatography plate, Compound B1After disappearance, NaBH is added into the reaction system4(0.4mmol) is stirred at room temperature for half an hour, added with water to quench and extracted by ethyl acetate to reactAnd (4) liquid.
Washing the water phase with ethyl acetate for 3 times, combining the two extracts, adding anhydrous sodium sulfate, drying, distilling under reduced pressure, concentrating, and concentrating to obtain white solid after passing through silica gel column chromatography.
And detecting and analyzing the separated product, wherein the obtained product is the target product, and the yield is 80%.
Example 2
Compound B was spotted on a thin layer chromatography plate according to the reaction formula and reaction conditions of example 11After disappearance, the intermediate spiro compound is isolated.
And 4 groups of parallel test groups are set, 0.2mmol of the intermediate is added into a reaction bottle, 0.4mmol of different reducing agents and 2m L of solvents are respectively added, the reaction is carried out for 10min at room temperature, and the reduction product is subjected to rotary evaporation concentration and purification and separation on a silica gel column.
And (4) detecting and analyzing the separated product, wherein the yield of the target product is different according to the difference of the reducing agent and the solvent.
TABLE 1 yield of reduction reaction of intermediates
Note: the yield is the isolated yield; the ratio of the amounts of the reducing agents Hantzsch ester to (+/-) -PA in group 3 was 26: 1.
In the following examples 3 to 9, the starting compound A and compound B were reacted in a molar ratio of 1.3:1 according to the procedure of example 1.
Example 3
Raw materials: sesamol, 2-pyrrolidinobenzaldehyde
The chemical formula is as follows: c18H19NO3
Precise molecular weight: 341.1576
Molecular weight:
structural formula (xvi):
yield: 80 percent of
1H nuclear magnetic resonance (500MHz, CDCl)3)10.94(s,1H),7.32(d,J＝7.5Hz,1H),7.18(t,J＝6.4Hz,2H),7.08(t,J＝7.0Hz,1H),6.72(s,1H),6.39(s,1H),5.80(s,2H),3.81(s,2H),3.17(s,4H),2.06(s,4H)；13C NMR(126MHz,CDCl3)150.3,146.9,146.3,140.4,137.4,130.7,127.6,125.9,120.2,119.3,108.7,100.7,99.1,54.1,33.8,23.8.；13C nuclear magnetic resonance (126MHz, CDCl)3)150.3,146.9,146.3,140.4,137.4,130.7,127.6,125.9,120.2,119.3,108.7,100.7,99.1,54.1,33.8, 23.8; high resolution mass spectrometry (ESI) calcd. for C18H19NO3[M+H]+341.1576, the actual value is 341.1580.
Example 4
Raw materials: 2-diethylaminophenol, 2-pyrrolidinobenzaldehyde
The product is as follows: the chemical formula is as follows: c21H26N2O
Precise molecular weight: 325.2123
Molecular weight:
structural formula (xvi):
yield: 78 percent of
1H nuclear magnetic resonance (500MHz, CDCl)3)10.88(s,1H),7.33(d,J＝7.5Hz,1H),7.21–7.09(m,2H),7.06(dd,J＝7.5,4.6Hz,2H),6.18(s,1H),6.15(d,J＝8.4Hz,1H),3.80(s,2H),3.26(q,J＝7.0Hz,4H),3.19(s,4H),2.07(s,4H),1.10(t,J＝7.0Hz,6H)；13C nuclear magnetic resonance (126MHz, CDCl)3)156.3,148.3,146.1,137.9,130.9,130.3,127.2,125.8,119.8,115.2,103.8,100.1,53.8,44.3,33.3,23.8,12.7 high resolution Mass Spectrometry (ESI): calcd. for C21H26N2O[M+H]+325.2123, the actual value is 32.2126.
Example 5
Raw materials: 2-pyrrolidinophenol, 2-pyrrolidinobenzaldehyde
The product is as follows: the chemical formula is as follows: c21H26N2O
Precise molecular weight: 323.2123
Molecular weight:
structural formula (xvi):
yield: 70 percent of
1H nuclear magnetic resonance (500MHz, CDCl)3)10.90(s,1H),7.33(d,J＝7.4Hz,1H),7.20–7.10(m,2H),7.10–7.01(m,2H),6.08(s,1H),6.05(d,J＝8.2Hz,1H),3.82(s,2H),3.19(s,8H),2.07(s,4H),1.92(s,4H)；13C nuclear magnetic resonance 156.2,148.5,146.0,137.9,130.9,130.2,127.2,125.8,119.8,115.4,103.7,100.1,53.9,47.7,33.3,25.5,23.8 high resolution Mass Spectrometry (ESI): calcd. for C21H26N2O[M+H]+323.2123, the actual value is 323.2121.
Example 6
Raw materials: sesamol, 4-bromo-2-pyrrolidinobenzaldehyde
The product is as follows: the chemical formula is as follows: c18H18BrNO3
Precise molecular weight: 376.0548
Molecular weight:
structural formula (xvi):
yield: 78 percent of
1H nuclear magnetic resonance (500MHz, CDCl)3)10.37(s,1H),7.30(s,1H),7.19(dd,J＝18.0,8.1Hz,2H),6.67(s,1H),6.39(s,1H),5.82(s,2H),3.75(s,2H),3.16(s,4H),2.06(s,4H)；13C nuclear magnetic resonance (126MHz, CDCl)3)150.1,147.8,147.1,140.6,136.2,132.1,128.9,123.7,120.7,118.6,108.6,100.8,99.1,54.0,33.2,23.8 high resolution Mass Spectrometry (ESI): calcd. for C18H18BrNO3[M+H]+376.0548, the actual value is 376.0539.
Example 7
Raw materials: sesamol, 4-trifluoromethyl-2-pyrrolidinebenzaldehyde
The product is as follows: the chemical formula is as follows: c19H18F3NO3
Precise molecular weight: 366.1317
Molecular weight:
structural formula (xvi):
yield: 66 percent
1H nuclear magnetic resonance (500MHz, CDCl)3)10.34(s,1H),7.42(s,2H),7.34(d,J＝7.8Hz,1H),6.70(s,1H),6.39(s,1H),5.83(s,2H),3.86(s,2H),3.21(s,4H),2.10(s,4H)；13C nuclear magnetic resonance (126MHz, CDCl)3)150.2,147.2,146.9,141.1,140.7,131.2,130.3,130.0(q, J: 32.7Hz),125.0,122.8,122.6-122.5 (m),118.1,117.2-117.1 (m),108.6,100.9,99.2,54.0,33.5,23.8, high resolution Mass Spectrometry (ESI): calcd. for C19H18F3NO3[M+H]+366.1317, the actual value is 366.1321.
Example 8
Raw materials: sesamol, 4-borate ester group-2-pyrrolidine benzaldehyde
The product is as follows: the chemical formula is as follows: c24H30BNO5
Precise molecular weight: 424.229
Molecular weight:
structural formula (xvi):
yield: 62 percent of
1H nuclear magnetic resonance (500MHz, CDCl)3)11.00(s,1H),7.64(s,1H),7.54(d,J＝7.4Hz,1H),7.34(d,J＝7.4Hz,1H),6.71(s,1H),6.37(s,1H),5.80(s,2H),3.82(s,2H),3.21(s,4H),2.07(s,4H),1.31(s,12H)；13C nuclear magnetic resonance (126MHz, CDCl3)150.3,146.9,145.6,140.7,140.4,132.5,130.2,126.4,118.9,108.7,100.7,99.1,83.8,54.0,33.9,24.8,23.8 high resolution Mass Spectrometry (ESI): calcd. for C24H30BNO5[M+H]+424.2295, the actual value is 424.2304.
Example 9
Raw materials: sesamol, 4-p-phenylacetyl-2-pyrrolidinebenzaldehyde
The product is as follows: the chemical formula is as follows: c26H25NO4
Precise molecular weight: 416.1862
Molecular weight:
structural formula (xvi):
yield: 68 percent of
1H nuclear magnetic resonance (500MHz, CDCl)3)10.72(s,1H),8.00(d,J＝7.7Hz,2H),7.59(d,J＝7.7Hz,2H),7.42(d,J＝7.0Hz,2H),7.34(d,J＝7.8Hz,1H),6.74(s,1H),6.41(s,1H),5.82(s,2H),3.86(s,2H),3.25(s,4H),2.62(s,3H),2.11(s,4H)；13C nuclear magnetic resonance (126MHz, CDCl)3)197.70,150.28,147.06,146.85,145.35,140.55,139.49,137.30,135.92,131.36,128.95,127.11,124.80,119.12,118.86,108.69,100.81,99.17,54.06,33.48,26.68, 23.85; high resolution Mass Spectrometry (ESI) calcd for C26H25NO4[M+H]+416.1862, the actual value is 416.1866.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (7)
1. A benzylation synthesis method of phenol compounds is characterized in that:
reacting a phenolic compound A with an amino formaldehyde compound B in hexafluoroisopropanol to prepare a reaction intermediate spiro compound, and adding a reducing agent into a reaction system to obtain a benzylation product of the phenolic compound;
the benzylation product of the phenol compound is any one of compounds shown in a formula I:
the phenolic compound A is a compound shown as a formula II;
the amino formaldehyde compound B is any one of compounds shown in a formula III:
in formulas I to III:
the dotted line represents an optional single bond;
R1any one of hydrogen, diethylamine and tetrahydropyrrole;
R2any one of chlorine, bromine, methyl, trifluoromethyl, methoxyl, borate and p-acetyl phenyl;
the reducing agent is a mixture of Hans ester and S-binaphthol phosphate and NaBH4Any one of them.
2. The method of synthesis according to claim 1, characterized in that: separating the spiro compound as the reaction intermediate, adding a reducing agent, and opening the ring in an organic solvent to obtain the benzylation product of the phenol compound.
3. The method of synthesis according to any one of claims 1-2, characterized in that: the molar ratio of the compound A to the compound B is 1.3: 1.
4. The method of synthesis according to claim 1, characterized in that: the molar ratio of the mixture of hanster and S-binaphthol phosphate is 26: 1.
5. The method of synthesis according to claim 2, characterized in that: the organic solvent is any one of tetrahydrofuran, dichloromethane and methanol.
6. The method of synthesis according to claim 5, characterized in that: the method comprises the following steps:
adding the compound A and the compound B into hexafluoroisopropanol according to a certain proportion, reacting at 25 ℃, and obtaining an intermediate spiro compound after the reaction is finished;
adding NaBH into the reaction system4Stirring and reacting at 25 ℃, concentrating and purifying after the reaction is finished, and obtaining a benzylation product of the phenol compound;
wherein the intermediate spiro compound is isolated and NaBH is added4Reducing agent, reacting in methanol at 25 deg.c, concentrating and purifying to obtain benzylated phenol compound product.
7. The method of synthesis according to claim 6, characterized in that: separating the intermediate spiro compound, and then reacting the intermediate spiro compound with NaBH serving as a reducing agent4The ring-opening reaction is carried out according to the molar ratio of 1: 2.
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| Title |
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| Construction of the tetrahydroquinoline spiro skeleton via cascade [1,5]-hydride transfer-involved C(sp3)–H functionalization on water;Shuai Zhu等;《Green Chemistry》;20171224;第19卷;全文 * |
| Organocatalytic Asymmetric Synthesis of 1,1-Diarylethanes by Transfer Hydrogenation;Zhaobin Wang;《JACS》;20141208;第137卷;第383-389页 * |
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