CN109180554A - A kind of method of methylation reaction - Google Patents
A kind of method of methylation reaction Download PDFInfo
- Publication number
- CN109180554A CN109180554A CN201811224832.6A CN201811224832A CN109180554A CN 109180554 A CN109180554 A CN 109180554A CN 201811224832 A CN201811224832 A CN 201811224832A CN 109180554 A CN109180554 A CN 109180554A
- Authority
- CN
- China
- Prior art keywords
- reaction
- mmol
- methylation
- cdcl
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/02—Preparation of carboxylic acid esters by interreacting ester groups, i.e. transesterification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及一种甲基化反应的方法。其特征在于，包括：反应底物在有机溶剂中，三氟乙酸甲酯作为甲基化试剂，在碱的存在下进行反应，得到相应的甲基化产物。本发明开辟一种新的甲基化方法，该方法廉价，操作简便，反应条件温和，底物适用范围广，避免使用硫酸二甲酯、碘甲烷等剧毒性甲基化试剂，能得到较高产率的甲基化产物。The present invention relates to a method for methylation reaction. It is characterized in that: the reaction substrate is in an organic solvent, and methyl trifluoroacetate is used as a methylation reagent, and the reaction is carried out in the presence of a base to obtain a corresponding methylation product. The present invention develops a new methylation method, which is cheap, easy to operate, mild in reaction conditions, and widely applicable to substrates, avoids the use of highly toxic methylating reagents such as dimethyl sulfate and methyl iodide, and can obtain relatively High yields of methylated products.
Description
Technical field
The invention belongs to organic synthesis field, in particular to a kind of method of methylation reaction.
Background technique
Methylation reaction is not only related with bioprocess, but also has in synthesis chemistry to the functionalization of bioactive molecule
There is important role.Traditional methylating reagent has iodomethane, dimethyl suflfate, p-methyl benzenesulfonic acid methyl esters and diazomethane,
Although these methylating reagents are efficiently, usually very unstable, dangerous or hypertoxic.Therefore, as environmentally protective reagent,
Dimethyl carbonate is widely used in methylation reaction.But dimethyl carbonate has variable chemical reactivity (Sen, S.;
Patil, S.; Argyropoulos, D. S. Green Chem.2015, 17,1077-1087.), become depending mainly on temperature
Change.Dimethyl carbonate is reacted by alkylolysis nucleophilic displacement of fluorine mechanism as methylating reagent at high temperature (120 DEG C or more)；But
It is reacted by bimolecular acylolysis nucleophilic mechanism as methoxy acylating reagent when compared with low temperature (about 90 DEG C).And due to carbonic acid two
Low (Glasnov, the T. N. of methyl esters reactivity; Holbrey, J. D.; Kappe, C. O.; Seddon, K. R.;
Yan, T. Green Chem.2012, 14, 3071-3076.), when use, generally also needs to carry out under the harsh conditions such as high pressure,
Or just occur in the presence of special catalyst, the more expensive even severe toxicity of used catalyst.In recent years, although CO2,
CH3OH and HCO2H is also by as N- methylating reagent, but these reagents lack generality, have the shortcomings that substrate narrow application range
(Li, Y.; Sorribes, I.; Vient, C.; Junge, K.; Beller, M.Chem. Eur. J. 2015,21, 16759-16763).Therefore, finding has less toxic, efficient, cheap, wide application range of substrates methylation method still aobvious
It obtains particularly significant.
Summary of the invention
The purpose of the present invention is to propose to a kind of new methylation method, technical problem to be solved is to overcome existing first
The disadvantages of methylating reagent toxicity used is high in base method, reactivity is low or substrate narrow application range.
In order to achieve the above object, the present invention provides a kind of methods of methylation reaction characterized by comprising anti-
Answer substrate in organic solvent, trifluoro-acetate is reacted in the presence of base as methylating reagent, is obtained corresponding
Methylate.
Preferably, the reaction substrate structure are as follows:
Wherein R is selected from H, halogen, alkoxy, any one in nitro and alkyl;
The methylate structure are as follows:
Wherein R is selected from H, halogen, alkoxy, any one in nitro and alkyl.
Preferably, the organic solvent is n,N-Dimethylformamide or dimethyl sulfoxide.
Preferably, the alkali is sodium hydride, potassium tert-butoxide or sodium methoxide.
Preferably, the reaction temperature and pressure are normal temperature and pressure, and the reaction time is 4-10 h.
Preferably, the molar ratio of the alkali and reaction substrate is 3-6:1.
Preferably, the molar ratio of the trifluoro-acetate and reaction substrate is 4-8:1.
Compared with prior art, the beneficial effects of the present invention are:
The present invention opens a kind of new methylation method, at low cost, easy to operate, wide application range of substrates, reaction condition temperature
With react at normal temperatures and pressures, the methylate of higher yields can be obtained.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate this hair
It is bright rather than limit the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, art technology
Personnel can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Fixed range.
Embodiment 1
The preparation of 1- methyl -4- nitroindoline
By 4- nitroindoline (100 mg, 0.62 mmol), DMF(4 mL), NaH(60% is dispersed in mineral oil, 74 mg,
1.85 mmol, 3eq.) it sequentially adds in reaction flask, stirring at normal temperature after five minutes, after NaH is evenly dispersed, is delayed into reaction flask
Slow injection trifluoro-acetate (0.25 mL, 2.48mmol, 4 eq.), after reacting 4 hours, TLC contact plate, raw material point disappears
It loses, i.e. fully reacting, stops stirring.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, is associated with
Machine phase, the dry organic phase of anhydrous magnesium sulfate, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains yellow solid 1-
Methyl -4- nitroindoline (106 mg, yield 98%).1H NMR (400 MHz, CDCl3) δ8.17 (dd, J = 8.0,
0.6 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 13.9, 5.7 Hz, 2H), 7.25
(dd, J = 3.1, 0.7 Hz, 1H), 3.91 (s, 3H).13C NMR (100 MHz, CDCl3) δ140.45,
138.86, 133.21, 122.59, 120.36, 117.40, 115.99, 101.79, 33.34.
Embodiment 2
The preparation of 1- methyl-5-nitro indoles
By 5- nitroindoline (100 mg, 0.62 mmol), DMF(4 mL), NaH(60% is dispersed in mineral oil, 74 mg,
1.85 mmol, 3eq.) it sequentially adds in reaction flask, stirring at normal temperature after five minutes, after NaH is evenly dispersed, is delayed into reaction flask
Slow injection trifluoro-acetate (0.25 mL, 2.48 mmol, 4 eq.), after reacting 4 hours, TLC contact plate, raw material point disappears
It loses, i.e. fully reacting, stops stirring.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, is associated with
Machine phase, the dry organic phase of anhydrous magnesium sulfate, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains yellow solid 1-
Methyl-5-nitro indoles (101 mg, yield 93%).1H NMR (400 MHz, CDCl3) δ8.57 (d, J = 1.9 Hz,
1H), 8.11 (dd, J = 9.1, 2.1 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.22 (d, J =
3.2 Hz, 1H), 6.67 (d, J = 3.2 Hz, 1H), 3.87 (s, 3H).13C NMR (100 MHz, CDCl3) δ
141.54, 139.44, 132.09, 127.62, 118.11, 117.18, 109.10, 103.82, 33.29.
Embodiment 3
The preparation of 1- methyl -4- bromo indole
By 4- bromo indole (100 mg, 0.51 mmol), DMF(4 mL), and potassium tert-butoxide (17 2mg, 1.53 mmol, 3
Eq. it) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.20 mL, 2.0 mmol, 4 eq.), after reacting 4 hours, TLC contact plate, raw material point disappears, i.e., instead
Stirring should be stopped completely.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, nothing
Water magnesium sulfate dries organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains greenish liquid 1- methyl-
4- bromo indole (100 mg, yield 93%).1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 7.6, 0.6 Hz,
1H), 7.30 (d, J = 8.2 Hz, 1H), 7.16–7.10 (m, 2H), 6.60 (dd, J = 3.1, 0.8 Hz,
1H), 3.79 (s, 3H).13C NMR (100 MHz, CDCl3) δ 137.02, 129.35, 129.14, 122.37,
122.24, 114.86, 108.42, 101.37, 33.21.
Embodiment 4
The preparation of 1- methyl -5- bromo indole
By 5- bromo indole (100 mg, 0.51 mmol), DMSO(4 mL), CH3ONa(81 mg, 1.5 mmol, 3 eq.) according to
In secondary addition reaction flask, stirring at normal temperature after five minutes, after NaH is evenly dispersed, trifluoro-acetate is slowly injected into reaction flask
(0.20 mL, 2 mmol, 4 eq.), after reacting 4 hours, TLC contact plate, raw material point disappears, i.e. fully reacting stops stirring
It mixes.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, anhydrous magnesium sulfate is dry
Organic phase is filtered to remove magnesium sulfate, and solvent is evaporated off, and column Chromatographic purification obtains greenish liquid 1- methyl -5- bromo indole (95
Mg, yield 89%).1H NMR (400 MHz, CDCl3) δ7.77 (d, J = 1.8 Hz, 1H), 7.32 (dd, J =
8.7, 1.9 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 3.1 Hz, 1H), 6.45
(dd, J = 3.1, 0.6 Hz, 1H), 3.80 (s, 3H).13C NMR (100 MHz, CDCl3) δ135.37,
130.12, 129.95, 124.31, 123.29, 112.67, 110.64, 100.54, 32.99.
Embodiment 5
The preparation of 1- methyl indol
By indoles (100 mg, 0.85 mmol), DMF(4 mL), potassium tert-butoxide (287mg, 2.55mmol, 3eq.) successively adds
Enter in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, trifluoroacetic acid first is slowly injected into reaction flask
Ester (0.35 mL, 3.4mmol, 4 eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, and stops stirring.Use acetic acid
Ethyl ester and distilled water are extracted twice, then are washed with saturation NaCl solution, and organic phase, the dry organic phase of anhydrous magnesium sulfate, mistake are merged
Magnesium sulfate is filtered out, solvent is evaporated off, column Chromatographic purification obtains weak yellow liquid 1- methyl indol (98 mg, yield 88%).1H
NMR (400 MHz, CDCl3): δ 7.66 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H),
7.26 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H),
6.52 (s, 1H), 3.83 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 136.69, 128.78,
128.47, 121.48, 120.86, 119.26, 109.17, 100.89, 32.82.
Embodiment 6
The preparation of 1,4- dimethyl indole
By 4- methyl indol (100 mg, 0.76 mmol), DMF(4 mL), potassium tert-butoxide (258 mg, 2.28mmol, 3
Eq. it) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.3 mL, 3.0mmol, 4 eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, that is, reacts
Completely, stop stirring.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, it is anhydrous
Magnesium sulfate dries organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains light yellow liquid Isosorbide-5-Nitrae-dimethyl
Indoles (53 mg, yield 48%).1H NMR (400 MHz, CDCl3) δ7.31–7.24 (m, 2H), 7.14 (d, J =
3.1 Hz, 1H), 7.07–7.03 (m, 1H), 6.63 (d, J = 3.1 Hz, 1H), 3.86 (s, 3H), 2.70
(s, 3H).13C NMR (100 MHz, CDCl3) δ135.22, 128.86, 128.81, 128.46, 123.16,
120.54, 108.90, 100.33, 32.83, 21.45.
Embodiment 7
The preparation of 1,5- dimethyl indole
By 5- methyl indol (100 mg, 0.76 mmol), DMF(4 mL), and potassium tert-butoxide (512 mg, 4.56 mmol, 6
Eq. it) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.6 mL, 6.0mmol, 8 eq.), after reacting 4 hours, TLC contact plate, raw material point disappears, that is, reacts
Completely, stop stirring.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, it is anhydrous
Magnesium sulfate dries organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains green liquid 1,5- dimethyl Yin
Diindyl (76 mg, yield 69%).1H NMR (400 MHz, CDCl3) δ 7.55–7.52 (m, 1H), 7.31 (d, J =
8.3 Hz, 1H), 7.17 (dd, J = 8.3, 1.5 Hz, 1H), 7.09 (d, J = 3.1 Hz, 1H), 6.51
(dd, J = 3.1, 0.7 Hz, 1H), 3.83 (s, 3H), 2.57 (s, 3H).13C NMR (100 MHz, CDCl3)
δ135.22, 128.86, 128.81, 128.46, 123.16, 120.54, 108.90, 100.33, 32.83,
21.45.
Embodiment 8
The preparation of 1- methyl -5- methoxy-Indole
By 5- methoxy-Indole (100 mg, 0.68 mmol), DMF(4 mL), and potassium tert-butoxide (457 mg, 4.1 mmol, 6
Eq. it) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.55 mL, 5.4 mmol, 8eq.), after reacting 4 hours, TLC contact plate, raw material point disappears, that is, reacts
Completely, stop stirring.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, it is anhydrous
Magnesium sulfate dries organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains light yellow solid 1- methyl -5-
Methoxy-Indole (53 mg, yield 49%).1H NMR (400 MHz, CDCl3) δ7.24 (d, J = 8.8 Hz, 1H),
7.12 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 2.9 Hz, 1H), 6.91 (dd, J = 8.9, 2.4
Hz, 1H), 6.42 (d, J = 2.6 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H).13C NMR (100
MHz, CDCl3) δ154.01, 132.15, 129.30, 128.79, 111.87, 109.89, 102.55, 100.39,
55.92, 32.98.
Embodiment 9
The preparation of 1- methyl -4- methoxy-Indole
By 4- methoxy-Indole (100 mg, 0.68 mmol), DMF(4 mL), and potassium tert-butoxide (457 mg, 4.1 mmol, 6
Eq. it) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.55 mL, 5.4 mmol, 8 eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, i.e., instead
Stirring should be stopped completely.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, nothing
Water magnesium sulfate dries organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains white solid 1- methyl -4-
Methoxy-Indole (97 mg, yield 89%).1H NMR (400 MHz, CDCl3) δ7.21 (t, J = 8.0 Hz, 1H),
7.04–6.98 (m, 2H), 6.65 (d, J = 3.1 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 4.02
(s, 3H), 3.81 (s, 3H).13C NMR (100 MHz, CDCl3) δ153.42, 138.21, 127.27,
122.32, 119.00, 102.71, 99.22, 98.20, 55.34, 33.06.
Embodiment 10
The preparation of 1- methyl carbazole
By carbazole (100 mg, 0.60mmol), DMF(4 mL), potassium tert-butoxide (201 mg, 1.8 mmol, 3 eq.) is successively
It is added in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, trifluoroacetic acid is slowly injected into reaction flask
Methyl esters (0.29 mL, 2.4mmol, 4 eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, i.e. fully reacting stops
Only stir.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, anhydrous magnesium sulfate
Dry organic phase, is filtered to remove magnesium sulfate, is evaporated off solvent, column Chromatographic purification obtain white solid 1- methyl carbazole (108 mg,
Yield 99%).1H NMR (400 MHz, CDCl3) δ8.27 (d, J = 7.7 Hz, 2H), 7.68–7.60 (m, 2H),
7.49 (d, J = 8.2 Hz, 2H), 7.43 (dd, J = 7.1, 3.8 Hz, 2H), 3.87 (s, 3H).13C NMR
(100 MHz, CDCl3) δ141.14, 125.83, 122.93, 120.46, 119.00, 108.60, 29.05.
Embodiment 11
The preparation of 1- tolimidazole
By benzimidazole (100 mg, 0.85 mmol), DMF(4 mL), CH3ONa(137 mg, 2.5 mmol, 3 eq.) according to
In secondary addition reaction flask, stirring at normal temperature after five minutes, after NaH is evenly dispersed, trifluoro-acetate is slowly injected into reaction flask
(0.34 mL, 3.4 mmol, 4eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, i.e. fully reacting stops stirring
It mixes.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, anhydrous magnesium sulfate is dry
Organic phase is filtered to remove magnesium sulfate, and solvent is evaporated off, and obtains brown liquid 1- tolimidazole (81 with column Chromatographic purification
Mg, yield 72%).1H NMR (400 MHz, CDCl3) δ7.83–7.78 (m, 2H), 7.36 (dd, J = 6.6, 2.0
Hz, 1H), 7.33–7.25 (m, 2H), 3.78 (s, 3H).13C NMR (100 MHz, CDCl3) δ143.63,
143.52, 134.51, 122.92, 122.08, 120.17, 109.37, 30.96.
Embodiment 12
The preparation of 1- naphthyl methyl ether
Will how phenol (100 mg, 0.69 mmol), DMSO(4 mL), CH3ONa(112mg, 2.1 mmol, 3 eq.) it sequentially adds
In reaction flask, stirring at normal temperature after five minutes, to CH3After ONa is evenly dispersed, trifluoro-acetate is slowly injected into reaction flask
(0.28 mL, 2.76 mmol, 4 eq.), after reacting 10 hours, after, TLC contact plate, raw material point disappears, i.e. fully reacting stops
Only stir.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, anhydrous magnesium sulfate
Dry organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains colourless liquid 1- naphthyl methyl ether, and (94 mg are produced
Rate 86%).1H NMR (400 MHz, CDCl3) δ8.37–8.30 (m, 1H), 7.89–7.83 (m, 1H), 7.60–
7.52 (m, 2H), 7.51–7.41 (m, 2H), 6.87 (dd, J = 7.4, 0.8 Hz, 1H), 4.05 (s,
3H).13C NMR (100 MHz, CDCl3) δ155.49, 134.52, 127.49, 126.43, 125.90, 125.66,
125.22, 122.02, 120.27, 103.82, 55.52.
Embodiment 13
The preparation of para-bromoanisole
By p bromophenol (100 mg, 0.58mmol), DMF(4 mL), potassium tert-butoxide (195mg, 1.74 mmol, 3eq.) according to
In secondary addition reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, trifluoro second is slowly injected into reaction flask
Sour methyl esters (0.23 mL, 2.32 mmol, 4 eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, that is, has reacted
Entirely, stop stirring.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, anhydrous sulphur
The dry organic phase of sour magnesium, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains colourless liquid para-bromoanisole (90
Mg, yield 83%).1H NMR (400 MHz, CDCl3) δ7.43–7.37 (m, 2H), 6.84–6.78 (m, 2H),
3.80 (s, 3H).13C NMR (100 MHz, CDCl3) δ158.71, 132.23, 115.74, 112.81, 55.43.
Embodiment 14
Preparation to tert-butyl benzene methyl ether
By p-tert-butylphenol (100 mg, 0.67mmol), DMF(4 mL), potassium tert-butoxide (224mg, 2.0 mmol,
It 3eq.) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.27 mL, 2.68 mmol, 4 eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, i.e.,
Fully reacting stops stirring.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase,
Anhydrous magnesium sulfate dries organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains colourless liquid to tertiary fourth
Base methyl phenyl ethers anisole (95 mg, yield 87%).1H NMR (400 MHz, CDCl3) δ7.37 (t, J = 5.9 Hz, 2H),
6.91 (t, J = 5.9 Hz, 2H), 3.84 (s, 3H), 1.36 (s, 9H).13C NMR (100 MHz, CDCl3)
δ157.34, 143.34, 126.22, 113.38, 55.22, 34.07, 31.56.
Embodiment 15
Preparation to bromophenyl sulfide
Will be to bromo thiophenol (100 mg, 0.53 mmol), DMF(4 mL), potassium tert-butoxide (178 mg, 1.6 mmol,
It 3eq.) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.21mL, 2.1mmol, 4 eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, that is, reacts
Completely, stop stirring.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, it is anhydrous
Magnesium sulfate dries organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains colourless liquid to bromophenyl sulfide
(72 mg, yield 67%).1H NMR (400 MHz, CDCl3) δ7.45–7.39 (m, 2H), 7.17–7.10 (m, 2H),
2.48 (s, 3H).13C NMR (100 MHz, CDCl3) δ137.76, 131.80, 128.15, 118.63, 15.94.
Embodiment 16
Preparation to tert-butyl benzene methyl sulfide
Will be to tert .- butylthiophenol (100 mg, 0.60 mmol), DMF(4 mL), potassium tert-butoxide (202 mg, 1.8 mmol,
It 3eq.) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.24 mL, 2.4 mmol, 4 eq.), after reacting 10 hours, TLC contact plate, raw material point disappears, i.e., instead
Stirring should be stopped completely.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, nothing
Water magnesium sulfate dries organic phase, is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains colourless liquid to tert-butyl benzene
Methyl sulfide (88 mg, yield 81%).1H NMR (400 MHz, CDCl3) δ7.41–7.36 (m, 2H), 7.31–7.26
(m, 2H), 2.53 (s, 3H), 1.37 (s, 9H).13C NMR (100 MHz, CDCl3) δ148.36, 134.90,
126.92, 125.91, 34.41, 31.36, 16.31.
Embodiment 17
The preparation of p-tert-butyl benzoic acid methyl esters
By p-tert-butyl benzoic acid (100 mg, 0.56 mmol), DMF(4 mL), potassium tert-butoxide (189 mg, 1.7 mmol,
It 3eq.) sequentially adds in reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, is slowly injected into reaction flask
Trifluoro-acetate (0.23mL, 2.2mmol, 4 eq.), after reacting 4 hours, TLC contact plate, raw material point disappears, and stops stirring
It mixes.It is extracted twice with ethyl acetate and distilled water, then is washed with saturation NaCl solution, merge organic phase, anhydrous magnesium sulfate is dry
Organic phase is filtered to remove magnesium sulfate, and solvent is evaporated off, and column Chromatographic purification obtains colourless liquid p-tert-butyl benzoic acid methyl esters (63
Mg, yield 58%).1H NMR (400 MHz, CDCl3) δ7.99 (d, J = 8.5 Hz, 2H), 7.47 (d, J =
8.5 Hz, 2H), 3.92 (s, 3H), 1.36 (s, 9H).13C NMR (100 MHz, CDCl3) δ167.16,
156.54, 129.43, 127.38, 125.32, 51.93, 35.07, 31.11.
Embodiment 18
The preparation of methyl phenylpropionate
By benzenpropanoic acid (100 mg, 0.67 mmol), DMF(4 mL), potassium tert-butoxide (224 mg, 2.0 mmol, 3eq.) according to
In secondary addition reaction flask, stirring at normal temperature after five minutes, after potassium tert-butoxide is evenly dispersed, trifluoro second is slowly injected into reaction flask
Sour methyl esters (0.27mL, 2.7mmol, 4 eq.), after reacting 4 hours, TLC contact plate, raw material point disappears, and stops stirring.Use second
Acetoacetic ester and distilled water are extracted twice, then are washed with saturation NaCl solution, merging organic phase, the dry organic phase of anhydrous magnesium sulfate,
It is filtered to remove magnesium sulfate, solvent is evaporated off, column Chromatographic purification obtains colourless liquid methyl phenylpropionate (80 mg, yield 73%).1H
NMR (400 MHz, CDCl3) δ7.30 (d, J = 7.0 Hz, 2H), 7.22 (d, J = 7.8 Hz, 3H),
3.70 (s, 3H), 2.98 (t, J = 7.8 Hz, 2H), 2.66 (t, J = 7.9 Hz, 2H).13C NMR (100
MHz, CDCl3) δ173.32, 140.54, 128.52, 128.29, 126.29, 51.58, 35.71, 30.97。
Claims (7)
1. a kind of method of methylation reaction, it is characterised in that: in organic solvent, trifluoro-acetate is as first for reaction substrate
Base reagent, is reacted in the presence of base, obtains corresponding methylate.
2. a kind of method of methylation reaction according to claim 1, which is characterized in that the reaction substrate structure
Are as follows:
Wherein R is selected from H, halogen, alkoxy, any one in nitro and alkyl;
The methylate structure are as follows:
Wherein R is selected from H, halogen, alkoxy, any one in nitro and alkyl.
3. a kind of method of methylation reaction according to claim 1, which is characterized in that the organic solvent is N, N-
Dimethylformamide or dimethyl sulfoxide.
4. a kind of method of methylation reaction according to claim 1, which is characterized in that the alkali is sodium hydride, uncle
Butanol potassium or sodium methoxide.
5. a kind of method of methylation reaction according to claim 1, which is characterized in that the reaction temperature and pressure
For normal temperature and pressure, the reaction time is 4-10 h.
6. a kind of method of methylation reaction according to claim 1, which is characterized in that the alkali and reaction substrate
Molar ratio is 3-6:1.
7. a kind of method of methylation reaction according to claim 1, which is characterized in that the trifluoro-acetate with
The molar ratio of reaction substrate is 4-8:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811224832.6A CN109180554B (en) | 2018-10-19 | 2018-10-19 | A kind of method of methylation reaction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811224832.6A CN109180554B (en) | 2018-10-19 | 2018-10-19 | A kind of method of methylation reaction |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109180554A true CN109180554A (en) | 2019-01-11 |
| CN109180554B CN109180554B (en) | 2022-04-29 |
Family
ID=64946371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811224832.6A Active CN109180554B (en) | 2018-10-19 | 2018-10-19 | A kind of method of methylation reaction |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109180554B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110272323A (en) * | 2019-07-05 | 2019-09-24 | 广东石油化工学院 | A kind of microwave assisted synthesizing method of ethylation reaction |
| CN112409149A (en) * | 2020-10-28 | 2021-02-26 | 利安隆(天津)新材料科技有限公司 | Preparation method of benzophenone ultraviolet absorbent |
| CN113563167A (en) * | 2021-07-16 | 2021-10-29 | 南通华祥医药科技有限公司 | Preparation method of 2-methyl-1-tetralone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746315A (en) * | 2011-12-23 | 2012-10-24 | 浙江大学 | Preparation method and use of 10-<11>C-methoxycamptothecin |
| WO2017222950A1 (en) * | 2016-06-23 | 2017-12-28 | Merck Sharp & Dohme Corp. | 3-heterocyclyl substituted 5-trifluoromethyl oxadiazoles as histone deacetylase 6 (hdac6) inhibitors |
-
2018
- 2018-10-19 CN CN201811224832.6A patent/CN109180554B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746315A (en) * | 2011-12-23 | 2012-10-24 | 浙江大学 | Preparation method and use of 10-<11>C-methoxycamptothecin |
| WO2017222950A1 (en) * | 2016-06-23 | 2017-12-28 | Merck Sharp & Dohme Corp. | 3-heterocyclyl substituted 5-trifluoromethyl oxadiazoles as histone deacetylase 6 (hdac6) inhibitors |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110272323A (en) * | 2019-07-05 | 2019-09-24 | 广东石油化工学院 | A kind of microwave assisted synthesizing method of ethylation reaction |
| CN112409149A (en) * | 2020-10-28 | 2021-02-26 | 利安隆(天津)新材料科技有限公司 | Preparation method of benzophenone ultraviolet absorbent |
| CN112409149B (en) * | 2020-10-28 | 2022-07-22 | 天津利安隆新材料股份有限公司 | Preparation method of benzophenone ultraviolet absorbent |
| CN113563167A (en) * | 2021-07-16 | 2021-10-29 | 南通华祥医药科技有限公司 | Preparation method of 2-methyl-1-tetralone |
| CN113563167B (en) * | 2021-07-16 | 2023-09-08 | 南通华祥医药科技有限公司 | Preparation method of 2-methyl-1-tetralone |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109180554B (en) | 2022-04-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109180554A (en) | A kind of method of methylation reaction | |
| JP5441395B2 (en) | Improved catalytic synthesis of diaryl ethers | |
| Tommasi et al. | Utilisation of 1, 3-dialkylimidazolium-2-carboxylates as CO2-carriers in the presence of Na+ and K+: application in the synthesis of carboxylates, monomethylcarbonate anions and halogen-free ionic liquids | |
| JP7339677B2 (en) | Fluorosulfonyl-containing compounds, intermediates, methods of preparation and uses thereof | |
| JP2013522213A (en) | Production of methionine or selenomethionine from homoserine via lactone intermediate | |
| CN109761943A (en) | A kind of synthetic method of C-3-position alkyl substituted coumarin derivative | |
| CN107098834A (en) | A kind of preparation method of aromatic sulfinic acids class compound | |
| WO2020103529A1 (en) | Condensation reaction of trimethylbenzoyl halide and diphenylphosphine oxide and preparation for organic phosphine compound | |
| CN110452141A (en) | A method of without transition metal-catalyzed synthesis of diaryl thio-ether type compounds | |
| CN111995638B (en) | Synthesis method of 3-sulfur-1-glycal compounds | |
| CN105348048A (en) | Method for preparing aryl trifluoroethoxyl ether | |
| US20130331585A1 (en) | Cyclopropyl pida boronate | |
| US8722916B2 (en) | Cyclopropyl MIDA boronate | |
| CN109293491A (en) | A kind of method of aryl diazonium salt de-acyl group on diazonium | |
| CN113336781A (en) | Preparation method of clitorium | |
| CN101374799B (en) | Process for preparing substituted biphenyls | |
| KR20100021321A (en) | Process for the preparation of n-phenyl-2-pyrimidine-amine derivatives | |
| CN110183380B (en) | Synthesis method and application of 4-hydroxy-1, 8-naphthalimide derivative | |
| CN105037081B (en) | A kind of trifluoromethylation method of xenyl olefin(e) compound | |
| AU727050B2 (en) | Process for preparing 1-alkyl-4- (2-chloro-3-alkoxy- 4-alkylsulfonylbenzoyl) -5-hydroxypyrazole and related compounds | |
| CN106632213B (en) | A kind of synthetic method of dibenzopyrans coupling compound | |
| Bauerová et al. | Substituent effects on the base-catalysed hydrolysis of phenyl esters of ortho-substituted benzoic acids | |
| WO2006109570A1 (en) | Method for producing 2-isopropenyl-5-methyl-4-hexen-1-yl 3-methyl-2-butenoate | |
| EP1505054A1 (en) | Process for producing 4-phenyl-4-oxo-2-butenoic ester derivative | |
| JP2005314322A (en) | Method for producing catechol derivative and its precursor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |