CN103044473A - Method for preparing cyclopropylboric acid - Google Patents
Method for preparing cyclopropylboric acid Download PDFInfo
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- CN103044473A CN103044473A CN201210558088XA CN201210558088A CN103044473A CN 103044473 A CN103044473 A CN 103044473A CN 201210558088X A CN201210558088X A CN 201210558088XA CN 201210558088 A CN201210558088 A CN 201210558088A CN 103044473 A CN103044473 A CN 103044473A
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- cyclopropyl
- cyclopropylboronic acid
- pinacol borate
- magnesium
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Abstract
The invention discloses a method for preparing cyclopropylboric acid. The method comprises the following steps: reacting cyclopropyl bromide with magnesium reagents to generate cyclopropylmagnesium bromide which then reacts with 1-substituent boronic acid pinacol ester to prepare cyclopropylboric acid. The raw materials for the method are easy to obtain, the operation is easy, the method is safe and environment-friendly, the cost is low, and the yield is high. The innovation includes that hazardous materials such as lithium metal and diethyl ether in the literature are avoided; and cyclopropylmagnesium bromide and 1-substituent boronic acid pinacol ester are taken as the raw material to synthesize cyclopropylboric acid with a high yield under the room temperature condition, therefore the raw material risk is small, the reaction conditions are mild, the yield is high, and the environment is not polluted.
Description
Technical field
The present invention relates to the chemical synthesis technical field, be specifically related to a kind of method for preparing cyclopropylboronic acid.
Background technology
The synthetic method of at present known cyclopropylboronic acid is to adopt ether to make solvent substantially, and cyclopropyl lithium and boronation reagent are synthetic.This method has some defectives: this method needs low-temp reaction, and the preparation of raw material cyclopropyl lithium needs metallic lithium and solvent ether, belongs to hazardous chemical, buying, transportation, storage and use and have a lot of potential safety hazards.
Summary of the invention
The objective of the invention is to overcome above-mentioned not enough problem, a kind of method for preparing cyclopropylboronic acid is provided, generate cyclopropyl bromination magnesium with Cyclopropyl Bromide and magnesium grignard reaction, the method for preparing again cyclopropylboronic acid with the reaction of 1-substituting group pinacol borate, this method raw material is easy to get, easy and simple to handle, safety and environmental protection, cost are lower, and yield is higher.
The technical scheme that the present invention adopts for achieving the above object is:
A kind of method for preparing cyclopropylboronic acid is characterized in that, with cyclopropyl bromination magnesium and the reaction of 1-substituting group pinacol borate, preparation cyclopropylboronic acid again is hydrolyzed.
Described cyclopropyl bromination magnesium and the reaction of 1-substituting group pinacol borate are with cyclopropyl bromination magnesium tetrahydrofuran solution, the control room temperature splashes in the 1-substituting group pinacol borate that is mixed with organic solvent, after reaction finishes, add the 5-15% aqueous hydrochloric acid and transfer pH value to 1～3, add oxygenant and stirred 2～10 hours, ethyl acetate extraction merges organic layer and adds 40～50 ℃ of washings of water management temperature, with the normal heptane making beating, obtain product after the organic layer underpressure distillation.
The mol ratio of described cyclopropyl bromination magnesium, 1-substituting group pinacol borate is 1.2:1.5.
Described 1-substituting group pinacol borate is isopropoxy pinacol borate or methoxyl group pinacol borate.
The oxygenant that adds during described hydrolysis is potassium periodate, potassium permanganate or ceric ammonium nitrate.
Described cyclopropyl bromination magnesium is fabricated material, adopting Cyclopropyl Bromide, magnesium, tetrahydrofuran (THF) is solvent, adding first tetrahydrofuran (THF), magnesium and a small amount of Cyclopropyl Bromide is warming up to 40～60 ℃ and causes, control again this interval temperature after the initiation, splash into Cyclopropyl Bromide and carry out grignard reaction, drip Bi Baowen 1～5 hour, and obtained the cyclopropyl bromination magnesium tetrahydrofuran solution of 0.9～1mol/kg.
Described a small amount of Cyclopropyl Bromide is total amount 1/10th to 1/5th.
Described organic solvent is tetrahydrofuran (THF).
The mol ratio of described preparation cyclopropyl bromination magnesium raw material tetrahydrofuran (THF), magnesium, Cyclopropyl Bromide is 10 ~ 12:1 ~ 1.2:1.
Reaction mechanism of the present invention is as follows:
R is alkyl in the formula, preferred isopropoxy, methyl.
Novelty of the present invention has been to avoid document to use hazardous substance metallic lithium and the ether of usefulness, is raw material but adopt cyclopropyl bromination magnesium and 1-substituting group pinacol borate, and high yield synthesizes cyclopropylboronic acid at ambient temperature, and purification efficiency is 55%～60%.Raw material danger is little, and reaction conditions is gentle, and yield is higher, and is free from environmental pollution.
The present invention utilizes homemade cyclopropyl bromination magnesium and 1-substituting group pinacol borate to react at ambient temperature, and the generation cyclopropylboronic acid that is hydrolyzed under acidic conditions, yield are 90～95%.This method is simple, safety and environmental protection, and cost is lower, and the yield of preparation cyclopropylboronic acid is high.
Embodiment
Below in conjunction with specific embodiment the present invention is described in further detail, but the present invention is not limited to specific embodiment.
Embodiment 1
A kind of method for preparing cyclopropylboronic acid, boronation are with the isopropoxy pinacol borate, and the hydrolysis oxidation agent is take potassium permanganate as example:
The preparation of the first step raw material cyclopropyl bromination magnesium:
In a 500ml four-hole bottle that mechanical stirring, thermometer, prolong be housed, add 9.16 g(0.382mol under the nitrogen protection) magnesium, 340mL tetrahydrofuran (THF), 2.0g Cyclopropyl Bromide (0.016 mol).Be warming up to 50 ℃, the insulation initiation reaction, 40～60 ℃ of droppings of rear control still temperature to be triggered 40g Cyclopropyl Bromide (0.331mol) drips and finishes insulation reaction 2 hours, analyzes Grignard reagent cyclopropyl bromination magnesium density 0.95mol/kg, 347.0g, yield 95%.
The preparation of second step cyclopropylboronic acid:
In the 1L four-hole bottle that mechanical stirring, thermometer, prolong are housed, add 67.46g(0.363mol under the nitrogen protection) the isopropoxy pinacol borate; 150ml (1.85mol) tetrahydrofuran (THF); the control room temperature drips the first step Grignard reagent 347.0g(0.330mol); drip and finish insulation 1～5 hour; after the gas phase monitoring reaction is complete; the control room temperature drips 10% aqueous hydrochloric acid accent still liquid pH value 1～3; then add potassium permanganate 5.2g(0.032mol) stirred 2～10 hours, the TLC monitoring reaction finishes.Tell organic layer with 40～50 ℃ of hot washes twice, tell organic layer control still temperature＜40 ℃ of vacuum-0.095Mpa distillations, add the making beating of 60ml heptane after distillation finishes, filter vacuum-0.095Mpa, 30～40 ℃ of oven dry of temperature, obtain product 16.42g, yield 57.9%, purity 98.5%.
Embodiment 2
A kind of method for preparing cyclopropylboronic acid, boronation are with the isopropoxy pinacol borate, and the hydrolysis oxidation agent is take potassium periodate as example:
The preparation of the first step raw material cyclopropyl bromination magnesium:
Identical with embodiment 1 the first step:
The preparation of second step cyclopropylboronic acid:
In the 1L four-hole bottle that mechanical stirring, thermometer, prolong are housed, add 67.46g(0.363mol under the nitrogen protection) the isopropoxy pinacol borate; 150ml (1.85mol) tetrahydrofuran (THF); the control room temperature drips the first step Grignard reagent 347.0g(0.330mol); drip and finish insulation 1～5 hour; after the gas phase monitoring reaction is complete; the control room temperature drips 10% aqueous hydrochloric acid accent still liquid pH value 1～3; then add potassium periodate 6.84g(0.032mol) stirred 2～10 hours, the TLC monitoring reaction finishes.Tell organic layer with 40～50 ℃ of hot washes twice, tell organic layer control still temperature＜40 ℃ of vacuum-0.095Mpa distillations, add the making beating of 60ml heptane after distillation finishes, filter vacuum-0.095Mpa, 30～40 ℃ of oven dry of temperature, obtain product 16.15g, yield 56.9%, purity 98.8%.
Embodiment 3
A kind of method for preparing cyclopropylboronic acid, boronation are with the isopropoxy pinacol borate, and the hydrolysis oxidation agent is take ceric ammonium nitrate as example:
The preparation of the first step raw material cyclopropyl bromination magnesium:
Identical with embodiment 1 the first step:
The preparation of second step cyclopropylboronic acid:
In the 1L four-hole bottle that mechanical stirring, thermometer, prolong are housed, add 67.46g(0.363mol under the nitrogen protection) the isopropoxy pinacol borate; 150ml (1.85mol) tetrahydrofuran (THF); the control room temperature drips the first step Grignard reagent 347.0g(0.330mol); drip and finish insulation 1～5 hour; after the gas phase monitoring reaction is complete; the control room temperature drips 10% aqueous hydrochloric acid accent still liquid pH value 1～3; then add ceric ammonium nitrate 17.54g(0.032mol) stirred 2～10 hours, the TLC monitoring reaction finishes.Tell organic layer with 40～50 ℃ of hot washes twice, tell organic layer control still temperature＜40 ℃ of vacuum-0.095Mpa distillations, add the making beating of 60ml heptane after distillation finishes, filter vacuum-0.095Mpa, 30～40 ℃ of oven dry of temperature, obtain product 16.60g, yield 58.5%, purity 98.1%.
Embodiment 4
A kind of method for preparing cyclopropylboronic acid, boronation with methoxyl group pinacol borate, hydrolysis oxidation agent take potassium permanganate as example:
The preparation of the first step raw material cyclopropyl bromination magnesium:
Identical with embodiment 1 the first step:
The preparation of second step cyclopropylboronic acid:
In the 1L four-hole bottle that mechanical stirring, thermometer, prolong are housed, add 57.35g(0.363mol under the nitrogen protection) the methoxyl group pinacol borate; 140ml (1.72mol) tetrahydrofuran (THF); the control room temperature drips the first step Grignard reagent 347.0g(0.330mol); drip and finish insulation 1～5 hour; after the gas phase monitoring reaction is complete; the control room temperature drips 10% aqueous hydrochloric acid accent still liquid pH value 1～3; then add potassium permanganate 5.2g(0.032mol) stirred 2～10 hours, the TLC monitoring reaction finishes.Tell organic layer with 40～50 ℃ of hot washes twice, tell organic layer control still temperature＜40 ℃ of vacuum-0.095Mpa distillations, add the making beating of 60ml heptane after distillation finishes, filter vacuum-0.095Mpa, 30～40 ℃ of oven dry of temperature, obtain product 15.78g, yield 55.6 %, purity 99.0%.
Embodiment 5
A kind of method for preparing cyclopropylboronic acid, boronation with methoxyl group pinacol borate, hydrolysis oxidation agent take potassium periodate as example:
The preparation of the first step raw material cyclopropyl bromination magnesium:
Identical with embodiment 1 the first step:
The preparation of second step cyclopropylboronic acid:
In the 1L four-hole bottle that mechanical stirring, thermometer, prolong are housed, add 57.35g(0.363mol under the nitrogen protection) the methoxyl group pinacol borate; 140ml (1.72mol) tetrahydrofuran (THF); the control room temperature drips the first step Grignard reagent 347.0g(0.330mol); drip and finish insulation 1～5 hour; after the gas phase monitoring reaction is complete; the control room temperature drips 10% aqueous hydrochloric acid accent still liquid pH value 1～3; then add potassium periodate 6.84g(0.032mol) stirred 2～10 hours, the TLC monitoring reaction finishes.Tell organic layer with 40～50 ℃ of hot washes twice, tell organic layer control still temperature＜40 ℃ of vacuum-0.095Mpa distillations, add the making beating of 60ml heptane after distillation finishes, filter vacuum-0.095Mpa, 30～40 ℃ of oven dry of temperature, obtain product 16.05g, yield 56.7 %, purity 98.0%.
Embodiment 6
A kind of method for preparing cyclopropylboronic acid, boronation with methoxyl group pinacol borate, hydrolysis oxidation agent take ceric ammonium nitrate as example:
The preparation of the first step raw material cyclopropyl bromination magnesium:
Identical with embodiment 1 the first step:
The preparation of second step cyclopropylboronic acid:
In the 1L four-hole bottle that mechanical stirring, thermometer, prolong are housed, add 57.35g(0.363mol under the nitrogen protection) the methoxyl group pinacol borate; 140ml (1.72mol) tetrahydrofuran (THF); the control room temperature drips the first step Grignard reagent 347.0g(0.330mol); drip and finish insulation 1～5 hour; after the gas phase monitoring reaction is complete; the control room temperature drips 10% aqueous hydrochloric acid accent still liquid pH value 1～3; then add ceric ammonium nitrate 17.54g(0.032mol) stirred 2～10 hours, the TLC monitoring reaction finishes.Tell organic layer with 40～50 ℃ of hot washes twice, tell organic layer control still temperature＜40 ℃ of vacuum-0.095Mpa distillations, add the making beating of 60ml heptane after distillation finishes, filter vacuum-0.095Mpa, 30～40 ℃ of oven dry of temperature, obtain product 15.82g, yield 55.9 %, purity 98.2%.
The above; only be the better embodiment of the present invention; but protection scope of the present invention is not limited to this; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses; be equal to replacement or change according to technical scheme of the present invention and inventive concept thereof, all should be encompassed within protection scope of the present invention.
Claims (9)
1. a method for preparing cyclopropylboronic acid is characterized in that, with cyclopropyl bromination magnesium and the reaction of 1-substituting group pinacol borate, preparation cyclopropylboronic acid again is hydrolyzed.
2. the method for preparing cyclopropylboronic acid according to claim 1, it is characterized in that the reaction of described cyclopropyl bromination magnesium and 1-substituting group pinacol borate is with cyclopropyl bromination magnesium tetrahydrofuran solution, the control room temperature splashes in the 1-substituting group pinacol borate that is mixed with organic solvent, after reaction finishes, add the 5-15% aqueous hydrochloric acid and transfer pH value to 1～3, adding oxygenant stirred 2～10 hours, ethyl acetate extraction, merge organic layer and add 40～50 ℃ of washings of water management temperature, with the normal heptane making beating, obtain product after the organic layer underpressure distillation.
3. the method for preparing cyclopropylboronic acid according to claim 2 is characterized in that the mol ratio of described cyclopropyl bromination magnesium, 1-substituting group pinacol borate is 1.2:1.5.
4. the method for preparing cyclopropylboronic acid according to claim 1 is characterized in that described 1-substituting group pinacol borate is isopropoxy pinacol borate or methoxyl group pinacol borate.
5. the method for preparing cyclopropylboronic acid according to claim 2, the oxygenant that adds when it is characterized in that described hydrolysis is potassium periodate, potassium permanganate or ceric ammonium nitrate.
6. the method for preparing cyclopropylboronic acid according to claim 1, it is characterized in that described cyclopropyl bromination magnesium is fabricated material, adopting Cyclopropyl Bromide, magnesium, tetrahydrofuran (THF) is solvent, adding first tetrahydrofuran (THF), magnesium and a small amount of Cyclopropyl Bromide is warming up to 40～60 ℃ and causes, control again this interval temperature after the initiation, splash into Cyclopropyl Bromide and carry out grignard reaction, dripped Bi Baowen 1～5 hour, obtain the cyclopropyl bromination magnesium tetrahydrofuran solution of 0.9～1mol/kg.
7. the method for preparing cyclopropylboronic acid according to claim 6 is characterized in that described a small amount of Cyclopropyl Bromide is total amount 1/10th to 1/5th.
8. the method for preparing cyclopropylboronic acid according to claim 1 is characterized in that described organic solvent is tetrahydrofuran (THF).
9. the method for preparing cyclopropylboronic acid according to claim 6 is characterized in that the mol ratio of described preparation cyclopropyl bromination magnesium raw material tetrahydrofuran (THF), magnesium, Cyclopropyl Bromide is 10 ~ 12:1 ~ 1.2:1.
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| CN201210558088.XA CN103044473B (en) | 2012-12-20 | 2012-12-20 | Method for preparing cyclopropylboric acid |
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| CN201210558088.XA CN103044473B (en) | 2012-12-20 | 2012-12-20 | Method for preparing cyclopropylboric acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001249A (en) * | 2015-06-12 | 2015-10-28 | 沧州普瑞东方科技有限公司 | Method for preparing cyclopropyl boronic acid |
| CN108948057A (en) * | 2018-10-27 | 2018-12-07 | 阜新孚隆宝医药科技有限公司 | The method for preparing cyclopropylboronic acid based on Cabbeen insertion |
| CN109305983A (en) * | 2018-12-23 | 2019-02-05 | 沧州普瑞东方科技有限公司 | A kind of synthetic method of cyclopropylboronic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1255123A (en) * | 1997-04-09 | 2000-05-31 | 联邦科学和工业研究组织 | Process for covalently coupling organic compounds utilizing diboron derivatives |
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2012
- 2012-12-20 CN CN201210558088.XA patent/CN103044473B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1255123A (en) * | 1997-04-09 | 2000-05-31 | 联邦科学和工业研究组织 | Process for covalently coupling organic compounds utilizing diboron derivatives |
Non-Patent Citations (3)
| Title |
|---|
| DEBRA J. WALLACE ET AL.: "Cyclopropylboronic acid: synthesis and Suzuki cross-coupling reactions", 《TETRAHEDRON LETTERS》 * |
| JACOB W. CLARY ET AL.: "Hydride as a Leaving Group in the Reaction of Pinacolborane with Halides under Ambient Grignard and Barbier Conditions. One-Pot Synthesis of Alkyl, Aryl, Heteroaryl, Vinyl, and Allyl Pinacolboronic Esters", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| REINHARD W. HOFFMANN ET AL.: "Amination of Grignard Reagents with Retention of Configuration", 《ORGANIC LETTERS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001249A (en) * | 2015-06-12 | 2015-10-28 | 沧州普瑞东方科技有限公司 | Method for preparing cyclopropyl boronic acid |
| CN108948057A (en) * | 2018-10-27 | 2018-12-07 | 阜新孚隆宝医药科技有限公司 | The method for preparing cyclopropylboronic acid based on Cabbeen insertion |
| CN109305983A (en) * | 2018-12-23 | 2019-02-05 | 沧州普瑞东方科技有限公司 | A kind of synthetic method of cyclopropylboronic acid |
| CN109305983B (en) * | 2018-12-23 | 2021-01-05 | 沧州普瑞东方科技有限公司 | Synthesis method of cyclopropylboronic acid |
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| CN103044473B (en) | 2015-07-15 |
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