CN108059579B - Borane reagent combined solution containing stabilizer, preparation method and application thereof - Google Patents
Borane reagent combined solution containing stabilizer, preparation method and application thereof Download PDFInfo
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- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 239000003381 stabilizer Substances 0.000 title claims abstract description 69
- 229910000085 borane Inorganic materials 0.000 title claims abstract description 40
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 145
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims abstract description 82
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000012279 sodium borohydride Substances 0.000 claims description 35
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 35
- 238000006722 reduction reaction Methods 0.000 claims description 24
- MCYCSIKSZLARBD-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MCYCSIKSZLARBD-UHFFFAOYSA-N 0.000 claims description 9
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 9
- 239000012448 Lithium borohydride Substances 0.000 claims description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 9
- 229910052700 potassium Inorganic materials 0.000 claims description 9
- 239000011591 potassium Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 230000005587 bubbling Effects 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000010926 purge Methods 0.000 claims description 4
- 230000009467 reduction Effects 0.000 abstract description 18
- 239000000243 solution Substances 0.000 description 107
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 7
- 238000013112 stability test Methods 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- -1 Amine boranes Chemical class 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005661 deetherification reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000002560 nitrile group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GVPVKKWXJXESIC-UHFFFAOYSA-N 1-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC(Cl)=C(N)C(C(F)(F)F)=C1 GVPVKKWXJXESIC-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 238000005750 Corey-Bakshi-Shibata reduction reaction Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- BDOLXPFAFMNDOK-UHFFFAOYSA-N oxazaborolidine Chemical compound B1CCON1 BDOLXPFAFMNDOK-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- 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 Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
Abstract
The invention provides a borane reagent combination solution containing a stabilizer, wherein the borane reagent combination solution comprises a borane dimethyl sulfide complex, tetrahydrofuran and the stabilizer, the concentration of the borane dimethyl sulfide complex in the tetrahydrofuran is 1-10 mol/L, and the molar ratio of the borane dimethyl sulfide complex to the stabilizer is 100: 1-1000: 1. The combined solution has higher concentration and better thermal stability, can more efficiently utilize a reaction container, saves a tetrahydrofuran reagent and reduces the cost; when the method is applied to Corey asymmetric reduction, the enantioselectivity of the reaction is better, and the enantiomeric excess value (% ee) of the product is higher.
Description
Technical Field
The invention relates to a combined solution, in particular to a borane reagent combined solution containing a stabilizer, a preparation method and application thereof.
Background
Diborane (B)2H6) Is a toxic, pyrophoric gas, very susceptible to hydrolysis and oxidation. It must be handled with extreme care and must be transported and stored at temperatures below-20 ℃. To reduce the risk of using diborane, Boranes (BH) are frequently used3) With complexes of electron donating molecules such as tetrahydrofuran, thioethers, amines and phosphines, in particular for the reduction of functional groups and hydroboration reactions with alkenes and alkynes. Functional groups reduced by these borane complexes include aldehyde, ketone, lactone, epoxide, ester, amide, oxime, imine and nitrile groups.
The most common commercial source of borane is a solution of borane tetrahydrofuran complex (BTHF) in Tetrahydrofuran (THF), which is commercially available and is typically at a concentration of 1 mole/liter. However, borane tetrahydrofuran complexes are susceptible to thermal decomposition due to ether cleavage of the tetrahydrofuran ring. The inventor researches and discovers that the concentration of a 1 mol/L borane-tetrahydrofuran complex solution is reduced by 18 percent after 15 days at the temperature of 25 ℃, and the concentration of the 1 mol/L borane-tetrahydrofuran complex solution is reduced by 24 percent after 15 days at the temperature of 35 ℃, so that the poor thermal stability greatly influences the transportation, storage and application of the product.
When the low-concentration Borane Tetrahydrofuran (BTHF) complex solution participates in organic reaction, more reaction space is occupied due to the low concentration and large using amount of borane, and the waste of capacity is caused; the tetrahydrofuran solvent has larger dosage and higher cost; the enantioselectivity of the reaction when applied to Corey asymmetric reduction is poor, and referring to US6218585, when a solution of a borane tetrahydrofuran complex stabilized with sodium borohydride is used in Me-CBS catalyzed reduction of acetophenone, only 80% to 95% ee values are obtained in the reduction.
Amine boranes are often not sufficiently reactive to reduce a particular functional group, and such complexing agents are sometimes difficult to remove from the reaction mixture, making purification of the product difficult and limiting their commercial use.
On the other hand, sulfide boranes such as borane dimethyl sulfide complex (BDMS) are present in high concentrations, for example up to 10 mol/l. Borane dimethyl sulfide complexes are also suitable for Corey asymmetric reduction, for example, when applied to the reduction of 3 ', 5' -bis (trifluoromethyl) acetophenone, good reduction results are obtained (J.AM. CHEM. SOC.2003,125, 2129-2135). However, the borane dimethylsulfide complex with high concentration is highly flammable, reacts violently when meeting water, and is very easy to emit flammable gas which can be spontaneously combusted, so that the storage, transportation and use of the borane dimethylsulfide complex are greatly risky.
The tetrahydrofuran solution of borane dimethyl sulfide complex with the concentration of 1.5-5 mol/L is higher than that of the commercial tetrahydrofuran solution of borane dimethyl sulfide complex, and the reaction efficiency is higher when the tetrahydrofuran solution is used for reducing 3 ', 5' -bis (trifluoromethyl) acetophenone. However, the inventor researches and finds that the concentration of 2 mol/L borane dimethyl sulfide complex in tetrahydrofuran solution is reduced by 3.3% after 28 days at the temperature of 35 ℃, and proves that the stability of the borane dimethyl sulfide complex in tetrahydrofuran solution is not good enough.
Referring to US3634277, the storage stability of solutions of known borane tetrahydrofuran complexes at different concentrations can be improved by adding small amounts of hydride sources, such as sodium borohydride, potassium borohydride, lithium borohydride.
However, since the effect of adding a stabilizer such as borohydride to a tetrahydrofuran solution of borane dimethylsulfide complex is not reported, the effect of stability and reduction performance, for example, enantioselectivity in asymmetric reduction reaction, of a tetrahydrofuran solution of borane dimethylsulfide complex containing borohydride is not obvious.
Disclosure of Invention
The inventor researches to find that the borane dimethyl sulfide complex can also react with tetrahydrofuran to cause ether cleavage of tetrahydrofuran ring, and the tetrahydrofuran solution of the borane dimethyl sulfide complex is also easy to be decomposed by heat. In order to overcome the defects in the prior art, the invention provides a safe, stable and efficient borane reagent combination solution. In order to realize the purpose of the invention, the technical scheme of the invention is as follows:
the invention provides a borane reagent combination solution containing a stabilizer, wherein the borane reagent combination solution comprises a borane dimethyl sulfide complex, tetrahydrofuran and a stabilizer, the concentration of the borane dimethyl sulfide complex in the tetrahydrofuran is 1-10 mol/L, the molar ratio of the borane dimethyl sulfide complex to the stabilizer is 100: 1-1000: 1, and the stabilizer is selected from one or the combination of sodium borohydride, lithium borohydride and potassium borohydride.
In a preferred embodiment of the present invention, the concentration of the borane dimethyl sulfide complex in tetrahydrofuran is 1.5 to 5 mol/l.
In a preferred embodiment of the present invention, the molar ratio of the borane dimethyl sulfide complex to the stabilizer is 200:1 to 500: 1.
In a preferred embodiment of the present invention, wherein the stabilizer is sodium borohydride.
The invention provides a preparation method of a borane reagent combination solution containing a stabilizer, wherein the preparation method comprises the following steps:
(1) purging a glass reaction flask by using nitrogen, simultaneously filling a proper amount of dimethyl sulfide, controlling the temperature of the reaction flask to be 0 ℃, bubbling 0.5 equivalent of diborane into the reaction flask for several hours, controlling the temperature to be 0-5 ℃ in the bubbling and introducing process, and continuously stirring and reacting for 10-20 minutes after the diborane is introduced to prepare a borane dimethyl sulfide complex;
(2) adopting tetrahydrofuran to dilute the borane dimethyl sulfide complex obtained in the step (1) to 1-10 mol/L to prepare a tetrahydrofuran solution of the borane dimethyl sulfide complex;
(3) and (3) adding a stabilizer into the tetrahydrofuran solution of the borane dimethyl sulfide complex obtained in the step (2) to prepare a borane reagent combined solution, wherein the molar ratio of the borane dimethyl sulfide complex to the stabilizer is 100: 1-1000: 1, and the stabilizer is selected from one or a combination of sodium borohydride, lithium borohydride and potassium borohydride.
In a preferred embodiment of the present invention, in the step (2), the concentration of the borane dimethyl sulfide complex in the tetrahydrofuran solution is 1.5-5 mol/l.
In a preferred embodiment of the present invention, in the step (3), the molar ratio of the borane dimethyl sulfide complex to the stabilizer is 200:1 to 500: 1.
The invention also provides application of the borane reagent combination solution containing the stabilizer in Corey asymmetric reduction reaction, wherein when the combination solution is used for reducing 3 ', 5' -bis (trifluoromethyl) acetophenone, the enantioselectivity of the reaction is good, the product yield is up to 93%, and the% ee value is up to more than 99%.
The present invention is to add borohydride as a stabilizer to a tetrahydrofuran solution of borane dimethyl sulfide complex to increase the stability of the combined solution. Thus, the stability of the borane reagent combination solutions containing stabilizers of the present invention has been investigated under different conditions. For example, fig. 1 compares the stability data of 2 mol/l tetrahydrofuran solution of borane dimethylsulfide complex at 35 ℃ in the presence of different kinds of stabilizers, and it can be seen from the figure that the stability of tetrahydrofuran solution of borane dimethylsulfide complex is significantly improved in the presence of stabilizers (sodium borohydride, potassium borohydride, lithium borohydride); FIG. 2 compares the stability data of a 2 mol/l solution of borane dimethylsulfide complex in tetrahydrofuran with a 2 mol/l solution of borane tetrahydrofuran complex in tetrahydrofuran at 35 ℃ in the presence of a stabilizer (sodium borohydride), and it can be seen that the solution of borane dimethylsulfide complex in tetrahydrofuran is more stable than the solution of borane tetrahydrofuran complex in tetrahydrofuran also containing a stabilizer; FIG. 3 compares the stability data of 2 mol/L tetrahydrofuran solution of borane dimethylsulfide complex at 35 ℃ in the presence of different molar ratios of sodium borohydride, demonstrating that the composition of the present invention is stable when the molar ratio of borane dimethylsulfide complex to stabilizer is in the range of 100:1 to 1000: 1; FIG. 4 compares the stability data of tetrahydrofuran solutions of borane dimethyl sulfide complex at different concentrations in the presence of a stabilizer at 35 ℃ to demonstrate that the tetrahydrofuran solutions of borane dimethyl sulfide complex at different concentrations are stable in the presence of a stabilizer; figure 5 shows stability data for 2 moles/liter solution of borane dimethylsulfide complex in tetrahydrofuran in the presence of a stabilizer at 2-8 c, indicating that the composition of the present invention is stable in the presence of a stabilizer for a long period of time.
The borane reagent combination solution provided by the invention has numerous advantages, for example, 1) the borane reagent combination solution can be stored at low temperature for at least one year, referring to example 6, and the stable borane reagent can not cause the increase of the pressure in a steel cylinder due to gas generation in the storage process, so that the safety risk of storage is effectively reduced compared with the thioether borane with high concentration; 2) the product can not deteriorate after being transported at high temperature for a long time (refer to example 3), refrigeration transportation is not needed, the transportation cost can be reduced, repeated detection is not needed after transportation or before use, resources are saved, and waste is reduced; 3) compared with the common tetrahydrofuran solution of borane tetrahydrofuran complex with 1 mol/L, the combined solution has higher concentration and better thermal stability, can more efficiently utilize a reaction vessel, saves tetrahydrofuran reagent and reduces the cost; 4) the enantioselectivity of the reaction was better when the reaction was carried out in the Corey asymmetric reduction reaction, as shown in the experimental results of examples 7-10, and as shown in Table 5, the yield of the product obtained by using borane dimethylsulfide complex as a reducing agent was comparable to that of borane tetrahydrofuran complex, while the enantiomeric excess (% ee) was higher.
The borane reagent combination solutions of the present invention may be stable for at least 28 days at 35 ℃ or for at least one year at 2-8 ℃. The composite solution of the present invention can be used for a variety of organic transformations. Examples are the reduction of functional groups including aldehyde, ketone, lactone, epoxide, ester, amide, oxime, imine and nitrile groups by such borane complexes.
Corey-Bakshi-Shibata reduction (i.e., Corey asymmetric reduction) (e.j.corey, r.k.bakshi, s.shibata, j.am.chem.soc.1987,109,5551-5553) refers to the enantioselective reduction of ketones using borane and a chiral oxazaborolidine catalyst to give the corresponding chiral alcohols. Due to their high enantioselectivity, predictability and high yield, this reduction reaction can compete effectively with enzymes and transition metal catalyzed hydrogenation reactions. The reduction reaction has high reduction efficiency and simple operation, thus being very suitable for industrial production. The borane reagent combination solution of the present invention is also suitable for such reduction reactions, and compared to the use of a borane tetrahydrofuran complex solution stabilized with sodium borohydride as a reducing agent, the combination solution of the present invention can achieve higher enantiomeric excess values in the reduction, even without reducing the enantioselectivity of the reaction in the presence of sodium borohydride.
The method can prepare the stable tetrahydrofuran solution of borane dimethyl sulfide complex, and can be widely applied to Corey asymmetric reduction to selectively reduce prochiral ketone to obtain corresponding chiral alcohol. Borohydride is added to the tetrahydrofuran solution of borane dimethyl sulfide complex in the combined solution of the present invention as a stabilizer to increase the stability of the combined solution. The boron reagent combination solution containing the stabilizer disclosed by the invention can be applied to Corey asymmetric reduction.
The invention provides a borane reagent combination solution containing a stabilizer, which is a high-efficiency borane reagent with good stability, safety and reactivity and has great commercial application value.
Drawings
FIG. 1 compares the stability data of 2 mol/l solutions of borane dimethyl sulfide complex in tetrahydrofuran at 35 ℃ in the presence of different types of stabilizers
FIG. 2 compares the stability data of a 2 mole/liter solution of borane dimethyl sulfide complex in tetrahydrofuran with a 2 mole/liter solution of borane tetrahydrofuran complex in tetrahydrofuran at 35 ℃ in the presence of a stabilizer
FIG. 3 shows the stability of a 2 mole/liter tetrahydrofuran solution of borane dimethyl sulfide complex with different molar ratios of stabilizer to borane dimethyl sulfide complex at 35 ℃;
FIG. 4 shows the stability of tetrahydrofuran solutions of borane dimethylsulfide complexes at different concentrations in the presence of a stabilizer at 35 ℃;
FIG. 5 shows the stability of a 2 mol/l solution of borane dimethylsulfide complex in tetrahydrofuran at 2-8 ℃ in the presence of a stabilizer.
Detailed Description
The following examples illustrate the invention without limiting it. According to Brown, h.c.; kramer, g.w.; levy, a.b.; borane concentrations were determined by acid titration of borane as described in Midland, M.M.in Organic Synthesis via Borans, John Wiley and Sons, Inc., New York 1973, p.241-244.
The instrument for measuring the enantiomeric excess value (% ee) of the invention is a high performance liquid chromatograph, and a chromatographic column comprises: CHIRALCEL OD-H (0.46cm I.D. 25cm L5 μm), the mobile phase was n-hexane and isopropanol.
EXAMPLE 1 preparation of borane dimethylsulfide Complex (BDMS)
Purging a glass reaction flask by using nitrogen, simultaneously filling 660 g of dimethyl sulfide, reducing the temperature in the reaction flask to 0 ℃, bubbling 138 g of diborane into the reaction flask for 1 hour, controlling the temperature to be 0-5 ℃ in the bubbling introduction process, and continuing stirring for reacting for 15 minutes after the diborane is introduced. The density of borane dimethyl sulfide complex obtained by the reaction was detected to be 0.80 g/ml, and the concentration of borane (i.e., borane dimethyl sulfide complex) was detected to be 10.08 mol/l (M).
EXAMPLE 2 preparation of borane tetrahydrofuran Complex (BTHF)
Purging a glass reaction bottle by using nitrogen, simultaneously filling 353.8 g of tetrahydrofuran, reducing the temperature in the reaction bottle to 0 ℃, bubbling diborane (11.8 g) into the reaction bottle for 0.5 hour, controlling the temperature to be 0-5 ℃ in the bubbling process, and continuing stirring for reacting for 15 minutes after the diborane is completely pumped. The density of the reacted solution was determined to be 0.87 g/ml and the borane (i.e., borane-tetrahydrofuran complex) concentration was 2 mol/l.
And adding sodium borohydride into the prepared borane tetrahydrofuran complex solution to ensure that the final concentration of the sodium borohydride in the solution is 0.005M, namely the molar ratio of the sodium borohydride to the borane tetrahydrofuran complex is 1: 400. After the addition of sodium borohydride was completed, the solution was stirred for 1 hour to dissolve the sodium borohydride, resulting in a solution a. And finally, placing the solution added with the sodium borohydride in a constant-temperature (35 ℃) stability test box for stability study.
Example 3 effect of stabilizer species (sodium, potassium and lithium borohydride) on the stability of tetrahydrofuran solutions of borane dimethyl sulfide complex and comparison of the stability of tetrahydrofuran solutions of borane tetrahydrofuran complex and borane dimethyl sulfide complex under the same conditions
Tetrahydrofuran is used as a solvent, borane dimethyl sulfide complex obtained in the embodiment 1 is diluted to about 2 mol/L, then the diluted solution is divided into four equal parts, and sodium borohydride, potassium borohydride and lithium borohydride are respectively added into three parts of the solution, so that the final concentration of three stabilizers in the solution is 0.005M, namely the molar ratio of the borane dimethyl sulfide complex to the sodium borohydride is 400: 1. After adding sodium borohydride and lithium borohydride, stirring the solution for 1 hour to dissolve the stabilizer to obtain solutions B and C; after addition of potassium borohydride, the solution was stirred for 24 hours to dissolve the stabilizer to obtain solution D. Finally, the tetrahydrofuran solutions of borane dimethyl sulfide complex (solution E) with and without the addition of the stabilizer are both placed in a constant-temperature (35 ℃) stability test box for stability study. The experimental results are shown in table 1 and fig. 1 and 2, and it can be seen that the tetrahydrofuran solution of borane dimethylsulfide complex is more stable in the presence of the stabilizer and more stable than the tetrahydrofuran solution of borane tetrahydrofuran complex under the same conditions.
TABLE 1 Effect of stabilizer classes (sodium, potassium and lithium borohydride) on the stability of tetrahydrofuran solutions of borane dimethyl sulfide complexes
And comparison of the stability of the tetrahydrofuran solution of borane tetrahydrofuran complex with the tetrahydrofuran solution of borane dimethyl sulfide complex under the same conditions
Example 4 Effect of stabilizer (sodium borohydride) concentration on the stability of tetrahydrofuran solution of borane dimethyl sulfide complex
The borane dimethyl sulfide complex obtained in example 1 was diluted to 2 mol/l with tetrahydrofuran as a solvent, and then the solution was divided into four equal parts, sodium borohydride as a stabilizer was added thereto so that the final concentrations of the sodium borohydride in the solution were 0.002M (solution F), 0.005M (solution B), 0.01M (solution G) and 0.02M (solution H), respectively, in the molar ratios of the borane dimethyl sulfide complex to the sodium borohydride of 1000:1, 400:1, 200:1 and 100:1, respectively, and when the sodium borohydride was added to the solution in the molar ratio of 100:1, stirring was required for a longer time to dissolve the sodium borohydride, and the solutions to which the sodium borohydride was added were all placed in a stability test box at a constant temperature (35 ℃) for stability study. The experimental results are shown in table 2 and fig. 3, and it can be seen that the molar ratio of borane dimethyl sulfide complex to stabilizer is 100: 1-1000: 1, the combined solution of the present invention is stable.
TABLE 2 Effect of stabilizer (sodium borohydride) concentration on the stability of tetrahydrofuran solution of borane dimethyl sulfide complex
Example 5 Effect of stabilizers on the stability of tetrahydrofuran solutions of different concentrations of borane dimethyl sulfide Complex
The borane dimethyl sulfide complex obtained in example 1 was diluted to 1.5 mol/l (solution I), 2 mol/l (solution B) and 5 mol/l (solution J), respectively, with tetrahydrofuran as a solvent, and then sodium borohydride was added as a stabilizer at a molar ratio of borane dimethyl sulfide complex to stabilizer of 400:1, and the solutions to which sodium borohydride was added were all placed in a stability test chamber at a constant temperature (35 ℃) for stability studies. The results of the experiments are shown in table 3 and fig. 4, and it can be seen that tetrahydrofuran solutions of borane dimethylsulfide complexes at different concentrations are stable in the presence of the stabilizer.
TABLE 3 stability test results of tetrahydrofuran solutions of borane-dimethylsulfide complex at different concentrations at 35 deg.C
EXAMPLE 6 stability Change of borane dimethyl sulfide Complex in tetrahydrofuran solution at 2-8 deg.C
Tetrahydrofuran is used as a solvent, borane dimethyl sulfide complex obtained in the embodiment 1 is diluted to 2 mol/L, then sodium borohydride is added as a stabilizer according to the molar ratio of the borane dimethyl sulfide complex to the stabilizer of 400:1, and the solution added with the sodium borohydride is placed in a low-temperature (2-8 ℃) stability test box for stability study. The experimental results are shown in table 4 and fig. 5, and it can be seen that the composition solution of the present invention is stable at 2 to 8 c for a long time in the presence of a stabilizer.
TABLE 4 stability Change of tetrahydrofuran solution of borane dimethylsulfide Complex at 2-8 deg.C
Examples 7-10 Performance Studies of different kinds of borane reagents as reducing agents for the asymmetric reduction of 3 ', 5' -bis (trifluoromethyl) acetophenone
3 ', 5' -bis (N-bis) is prepared by a syringe pump for 2 hours at 0-5 DEG C(trifluoromethyl) acetophenone (3.1 ml in 17 ml THF, i.e. 17 mmol) was added separately to a mixed solution of 5 ml of 2M (i.e. 10 mmol) of the different borane reagents and 0.85 ml (5 mol% relative to 3 ', 5' -bis (trifluoromethyl) acetophenone) 1M (R) -MeCBS in toluene. After 3 ', 5' -bis (trifluoromethyl) acetophenone was added, stirring was carried out for 30 minutes, and then hydrochloric acid (1M, 4.2 ml) was added dropwise to the reaction solution to quench the reaction. The organic phase of the reaction solution was extracted with 20 ml of methyl t-butyl ether, and the organic layer was washed with water and saturated brine, and then with anhydrous Na2SO4Drying, and finally evaporating the organic phase to obtain the product. (S) -1- [3, 5-bis (trimethyl) phenyl obtained by chiral HPLC detection]The enantiomeric excess (% ee) of ethanol is shown in Table 5. When BTHF is used as a reducing agent to selectively reduce 3 ', 5' -bis (trifluoromethyl) acetophenone, the obtained product has low% ee value, and the addition of sodium borohydride has great influence on the% ee value of the product; when 3 ', 5' -bis (trifluoromethyl) acetophenone was selectively reduced using BDMS as the reducing agent, the% ee was high and the presence of sodium borohydride did not reduce the% ee of the reaction.
TABLE 5 reduction results for different borane reagents
Claims (8)
1. The borane reagent combination solution containing the stabilizing agent comprises borane dimethyl sulfide complex, tetrahydrofuran and the stabilizing agent, wherein the concentration of the borane dimethyl sulfide complex in the tetrahydrofuran is 1-10 mol/L, the molar ratio of the borane dimethyl sulfide complex to the stabilizing agent is 100: 1-1000: 1, and the stabilizing agent is selected from one or the combination of sodium borohydride, lithium borohydride and potassium borohydride.
2. The stabilizer-containing borane reagent combination solution according to claim 1, wherein the concentration of borane dimethylsulfide complex in tetrahydrofuran is between 1.5 and 5 mol/l.
3. The stabilizer-containing borane reagent combination solution according to claim 1, wherein the molar ratio of borane dimethylsulfide complex to stabilizer is from 200:1 to 500: 1.
4. The stabilizer-containing borane reagent combination solution according to claim 1, wherein the stabilizer is sodium borohydride.
5. A method of preparing a borane reagent combination solution with stabilizers according to claim 1, wherein the method comprises the steps of:
(1) purging a glass reaction flask by using nitrogen, simultaneously filling a proper amount of dimethyl sulfide, controlling the temperature of the reaction flask to be 0 ℃, bubbling 0.5 equivalent of diborane into the reaction flask for several hours, controlling the temperature to be 0-5 ℃ in the bubbling and introducing process, and continuously stirring and reacting for 10-20 minutes after the diborane is introduced to prepare a borane dimethyl sulfide complex;
(2) adopting tetrahydrofuran to dilute the borane dimethyl sulfide complex obtained in the step (1) to 1-10 mol/L to prepare a tetrahydrofuran solution of the borane dimethyl sulfide complex;
(3) adding a stabilizer into the tetrahydrofuran solution of borane dimethyl sulfide complex obtained in the step (2) to prepare the borane reagent combination solution.
6. The method according to claim 5, wherein the concentration of the borane dimethyl sulfide complex in the tetrahydrofuran solution in the step (2) is 1.5 to 5 mol/l.
7. The method according to claim 5, wherein in the step (3), the molar ratio of the borane dimethyl sulfide complex to the stabilizer is 200:1 to 500: 1.
8. Use of a borane reagent combination solution containing a stabilizer according to claim 1 in a Corey asymmetric reduction reaction, wherein the combination solution has good enantioselectivity, a product yield of up to 93%, and an ee value of up to 99% or more when reducing 3 ', 5' -bis (trifluoromethyl) acetophenone.
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