CN109575060B - Synthesis of spiro bisboron catalyst and application of spiro bisboron catalyst in hydrogenation reaction - Google Patents

Abstract

The invention relates to the synthesis of a class of chiral spirocyclic diene compounds with C ₂ symmetry, and a series of chiral spirocyclic double boron catalysts are prepared by reacting them with borohydride compounds. These spirocyclic double boron catalysts show high activity and enantioselectivity in the asymmetric hydrogenation of quinoline compounds, and belong to the technical field of application. The invention mainly solves the problems of using precious metal catalysts and poor functional group tolerance in the previous method for asymmetric hydrogenation of quinoline, and realizes the reaction of non-metal catalyzed asymmetric hydrogenation of quinoline. The reaction has a wide range of substrates and strong functional group tolerance. . The invention will be applied in drug research and chemical production.

Description

Synthesis of Spiroring Double Boron Catalyst and Its Application in Hydrogenation

technical field

The invention relates to the synthesis of a new class of spirocyclic diene compounds with C ₂ symmetry, and a spirocyclic double boron catalyst is prepared in situ through a hydroboration reaction. The spirocyclic double boron catalyst is used in the asymmetric hydrogenation reaction of quinoline. It exhibits high activity and enantioselectivity, and belongs to the field of organic chemistry synthesis methodology research and application technology.

Background technique

In 2006, Professor DW Stephan of the University of Toronto found that B(C ₆ F ₅ ) ₃ and a large sterically hindered base (tri-tert-butylphosphine) could not form a classic Lewis acid-base adduct, but instead formed an acid-base pair in the form of an acid-base pair. Existing, such acid-base pairs can achieve hydrogen activation at room temperature and can reduce some unsaturated compounds. Based on this, some chiral boron catalysts have been synthesized and applied in asymmetric hydrogenation of various substrates (as shown in the figure below). However, this field is still in its infancy, the reported chiral boron catalysts are still very limited, and the asymmetric hydrogenation of many heterocyclic compounds has not yet been solved. Therefore, the development of new and efficient chiral catalysts is an important research in this field. content.

SUMMARY OF THE INVENTION

The content of the present invention includes: 1. Preparation of a new type of chiral spiro diene compound; 2. Preparation of spirocyclic double boron catalyst through hydroboration reaction of spirocyclic diene compound and identification of its structure; 3. Spirocyclic double boron catalyst Application in the asymmetric hydrogenation of quinoline.

1. The chiral spiro diene compound of the present invention has the following structural formula (the absolute configuration of the spiro skeleton is (R) or (S)):

The characteristics of this kind of chiral spiro dienes are that the molecule has a spiro[4.4]-nonane skeleton, and the R group in the structural formula is an aryl or an alkyl group. Its synthesis method is as follows:

First step: racemic spiro[4.4]-1,6-nonanedione (rac-1) (reference for its preparation: Synth. Commun. 1999, 29, 3829.) and (R)-phenethylamine Under the catalysis of iodine, oxalyl hydrazide was refluxed overnight to obtain a pair of diastereomeric bishydrazone compound intermediates, and the single configuration (R)-bishydrazone can be isolated by recrystallization twice in ethanol The compound, the intermediate bihydrazone compound was hydrolyzed in the iodine-potassium iodide system to obtain the optically pure product (R)-spiro[4.4]-1,6-nonanedione ((R)-1). The molar ratio of racemic spiro[4.4]-1,6-nonanedione (rac-1) and (R)-phenethylamino oxalyl hydrazide is 1:1, and the elemental iodine is the catalytic amount.

The second step: at -78 ℃ temperature, with bis(trimethylsilyl) potassium amide as base, (R)-spiro[4.4]-1,6-nonanedione ((R)-1) and 2 -[N-N-bis(trifluoromethanesulfonyl)amino]pyridine was reacted in tetrahydrofuran for 40 minutes to produce enol trifluoromethanesulfonate compound 2. wherein (R)-spiro[4.4]-1,6-nonanedione ((R)-1), 2-[N-bis(trifluoromethanesulfonyl)amino]pyridine and bis(trimethylsilyl) ) in a molar ratio of 1:3:3.

The third step: Toluene and ethanol are mixed in a volume ratio of 3:1 as a mixed solvent, and under the condition of heating and refluxing, the trifluoromethanesulfonic acid enol ester compound (2) is mixed with aromatic compounds in the presence of tetrakis(triphenylphosphine) palladium and a base. The Suzuki coupling reaction occurs with the base or alkylboronic acid reagent, and the chiral spirocyclic diene compound (3) of the present invention is obtained after the reaction for 5 hours. The molar ratio of the trifluoromethanesulfonic acid enol ester compound (2) and the boronic acid reagent is 1:4, and the amount of tetrakis(triphenylphosphine)palladium is 10 mol%. The molecular formula of the above boronic acid reagent is RB(OH) ₂ , and R is an aryl group or an alkyl group.

2. Preparation and structure identification of chiral spirocyclic double boron catalyst:

In the glove box, the chiral spiro diene compound, HB(C ₆ F ₅ ) ₂ and solvent toluene were added to the reaction flask, stirred at the specified temperature for 15 minutes, and then returned to room temperature to prepare the chiral spiro biboron catalyst . Then add isoquinoline or pyridine (L) to react with the prepared chiral spirocyclic diboron catalyst, stir at room temperature for 30 minutes, remove the solvent, recrystallize, separate and purify to obtain the adduct of the chiral spirocyclic diboron catalyst and L. The molar ratio of the chiral spiro diene compound, HB(C ₆ F ₅ ) ₂ and L (isoquinoline or pyridine) was 1:2:4. The structure of the adduct was confirmed by X-ray single crystal diffraction, and then the structure of the prepared chiral spirocyclic double boron catalyst was determined. Wherein, HB(C ₆ F ₅ ) ₂ can be replaced by other fluorine-containing aryl borohydride compounds.

3. Asymmetric hydrogenation of quinoline catalyzed by chiral spirocyclic double boron catalysts:

The chiral spiro-ring double boron catalyst of the present invention can be applied to the asymmetric hydrogenation of quinoline compounds to obtain 2-position substituted tetrahydroquinoline compounds with high conversion number and extremely high enantioselectivity.

The advantages of the present invention are:

1. The boron catalyst replaces the transition metal catalyst, which saves the cost and solves the problem of heavy metal residues in drug synthesis.

2. The consumption of the spirocyclic double boron catalyst of the present invention is low, and can be scaled up to a gram-level experiment, and the reaction conditions are mild.

3. The developed asymmetric hydrogenation can obtain 2-substituted tetrahydroquinolines with high reactivity and extremely high enantioselectivity, with a wide range of substrates and strong functional group compatibility.

Specific implementation method

The following implementation examples will better illustrate the present invention, but it should be emphasized that the present invention is by no means limited to the contents represented by these implementation examples. The following examples illustrate different aspects of the invention. The data presented include specific operating and reaction conditions and products. The purity of the product was identified by NMR.

Example 1: Synthesis of Chiral Spirodiene Compound 3a

The first step: the resolution of spiro[4.4]-1,6-nonanedione

(R)-Phenethylamino oxalyl hydrazide (4.15g, 2eq) was added to a 250mL dry round bottom flask, followed by 1.52g racemic spiro[4.4]-1,6-nonanedione and a small pellet Iodine element, 120 mL of anhydrous dichloromethane was added under argon protection, a water separator and a reflux condenser were installed, and the mixture was heated and refluxed overnight. After the reaction, the system was cooled to room temperature, the insoluble solid was removed by diatomaceous earth filtration, the dichloromethane was removed by rotary evaporation under reduced pressure to obtain a yellow solid crude product, and 3.5g of white powdery solid bishydrazone compound intermediate was obtained by recrystallization and purification in absolute ethanol. , the yield is 66%.

2.0 g of the bishydrazone compound intermediate was added to a 500 mL eggplant-shaped flask, and recrystallized twice with absolute ethanol to obtain 600 mg of a single-configuration bishydrazone compound with a yield of 60%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.71 (s, 2H), 8.25 (d, J=8.3 Hz, 2H), 7.39-7.22 (m, 8H), 7.22-7.12 (m, 2H), 5.17- 4.98(m, 2H), 2.57-2.39(m, 4H), 2.36-2.26(m, 2H), 2.24-2.12(m, 2H), 1.91-1.71(m, 4H), 1.59(d, J=6.8 Hz, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 172.8, 158.7, 155.1, 142.1, 128.7, 127.6, 126.2, 57.8, 49.6, 37.4, 28.0, 21.6, 21.5.

2.0g of the single-configuration bishydrazone compound was added to a 250mL round-bottomed flask, potassium iodide (800mg) and iodine element (200mg) were added successively, acetone (80mL) and water (20mL) were added as mixed solvents, and the reaction solution was heated Reflux for 40 minutes with TLC monitoring. After the reaction was completed, saturated sodium thiosulfate solution was added dropwise with stirring to quench the iodine, the reaction solution changed from brown to colorless, the acetone was removed by rotary evaporation under reduced pressure, the residue was extracted three times with dichloromethane, and the combined organic phases were saturated with Wash with sodium chloride solution, dry with anhydrous sodium sulfate, spin off the solvent, and the crude product is subjected to silica gel column chromatography to obtain a white solid product (R)-spiro[4.4]-1,6-nonanedione ((R)-1) (385 mg), 67% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.42-2.13 (m, 8H), 1.93-1.77 (m, 4H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 217.0, 64.5, 38.6, 34.4, 19.9.

Step 2: Synthesis of Compound 2

Under argon, the (R)-spiro[4.4]-1,6-nonanedione ((R)-1) (400 mg) and 2-[N,n-bis(trifluoromethanesulfonyl) Amino]pyridine (2.4eq, 2.3g) was added to a dry 100mL Schlenk reaction flask, pumped for 3 times, and 30mL of anhydrous tetrahydrofuran was added. The system was cooled to -78°C, and bis(trimethylsilyl)potassium amide (3eq) was added dropwise to the reaction system under argon protection. After the dropwise addition, the reaction was incubated for 40 minutes, and the reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution, the reaction solution was extracted three times with ethyl acetate (3×20 mL), the combined organic phases were washed with 5% sodium hydroxide solution and saturated sodium chloride solution in turn, and anhydrous carbonic acid Potassium was dried, the desiccant was removed by suction filtration, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain a yellow liquid product enol trifluoromethanesulfonate compound (2) (915 mg) with a yield of 83%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.80 (t, J=2.5 Hz, 2H), 2.52-2.38 (m, 4H), 2.37-2.29 (m, 2H), 2.04-1.97 (m, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 148.5, 123.4, 120.2, 117.4, 117.0, 113.8, 58.3, 33.3, 26.2.

Step 3: Synthesis of Chiral Spirodienes

Under the protection of argon, a 100mL three-necked flask was added with trifluoromethanesulfonic acid enol ester compound (2) (500mg), phenylboronic acid (4eq, 585mg) and tetrakis(triphenylphosphine)palladium (10mol%), respectively, and the Degassed for 3 times, degassed toluene-ethanol mixture (3:1, 30 mL) and sodium carbonate solution (15 mL) were added, the system was refrigerated and degassed with liquid nitrogen three times, returned to room temperature, and heated to reflux at 80°C for 5 hours. The progress of the reaction was monitored by TLC. After the conversion was complete, the system was cooled to room temperature, saturated ammonium chloride solution was added, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate, the organic phase was washed twice with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the solvent was removed by rotary evaporation, and the crude product was subjected to n-hexane column chromatography to obtain 327 mg of white powdery solid 3a, with a yield of 55%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51-7.49 (m, 4H), 7.23-7.14 (m, 6H), 6.20 (t, J=2.6 Hz, 2H), 2.51-2.42 (m, 4H), 2.28 -2.20 (m, 2H), 2.08-2.02 (m, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 148.1, 136.6, 128.4, 128.1, 126.7, 64.4, 37.5, 30.2.

Example 2: Synthesis and identification of spirocyclic double boron catalyst 4a

In the glove box, 3a (13.6 mg, 0.05 mmol), HB(C ₆ F ₅ ) ₂ (34.6 mg, 0.1 mmol) and toluene (1.0 mL) were sequentially added to the reaction flask, and the reaction was carried out at 25° C. for 15 minutes. Then, isoquinoline (25.8 mg, 0.2 mmol) and toluene (0.5 mL) were added, and the reaction was continued for 30 minutes at 25°C. After the completion of the reaction, toluene was distilled off under reduced pressure to obtain a white powdery solid. The internal standard CH ₂ Br ₂ was added, and the nuclear magnetic yield was determined to be 95% by ¹ H NMR. The crude product was recrystallized from dichloromethane and n-hexane to give the product 4a·2L. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.74 (s, 2H), 8.04 (d, J=6.8 Hz, 2H), 7.83 (t, J=7.5 Hz, 2H), 7.74 (d, J= 8.1Hz, 2H), 7.62(t, J=7.4Hz, 2H), 7.59-7.30(m, 8H), 7.16(t, J=7.1Hz, 2H), 6.87(br, 2H), 6.69(br, 2H), 2.92(t, J=9.6Hz, 2H), 2.32-2.18(m, 2H), 2.14(d, J=9.0Hz, 2H), 1.80-1.54(m, 4H), 0.86(dd, J = 19.2, 11.5 Hz, 2H); ¹³ C NMR (101 MHz, CD ₂ Cl ₂ ) δ 149.6, 137.0, 136.0, 134.6, 131.8, 129.9, 129.8, 129.0, 127.8, 127.2, 127.0, 126.0, 125.8, 122.7, 61.4, 53.1, 34.5, 33.5, 27.4.

Example 3: Synthesis of (R)-2-methyl-1,2,3,4-tetrahydroquinoline (P1)

In a nitrogen-filled glove box, the chiral spiro diene compound 3a (3.4 mg, 0.0125 mmol, 5 mol %) and HB(C ₆ F ₅ ) ₂ (8.65 mg, 0.025 mmol, 10 mol %) were added to a 10 mL small test tube 2 mL of trifluorotoluene was added to dissolve it, and the reaction was carried out at 25°C for 15 minutes. The system was cooled to room temperature, then 2-methylquinoline S1 (35.8 mg, 0.25 mmol) and 3 mL of trifluorotoluene were added, then the test tube was transferred to the autoclave, after replacing the hydrogen three times, and finally filled with hydrogen to 50 bar, - 20°C reaction for 24h. After the reaction, hydrogen was released, the solvent was removed by rotary evaporation, and the residue was separated and purified by silica gel column chromatography to obtain the hydrogenated product P1, a colorless oily liquid, the yield was 97%, and the enantioselectivity was 90% ee. ¹ H NMR (400MHz, CDCl ₃ )δ7.00-6.95(m, 2H), 6.68-6.59(m, 1H), 6.51(d, J=6.9Hz, 1H), 3.72(br, 1H), 3.50- 3.30(m, 1H), 2.87-2.81(m, 1H), 2.80-2.70(m, 1H), 2.01-1.87(m, 1H), 1.69-1.54(m, 1H), 1.24(d, J=6.2 Hz, 3H); ¹³ CNMR (101 MHz, CDCl ₃ ) δ 144.9, 129.4, 126.8, 121.2, 117.1, 114.1, 47.2, 30.2, 26.7, 22.7.

Claims (8)

1. A preparation method of a chiral spiro diboron catalyst comprises the following steps:

in a glove box, a chiral spirocyclic diene compound and HBAr^F ₂And adding solvent toluene into the reaction bottle, and stirring at a specified temperatureAfter 15 minutes, the temperature is restored to room temperature, and the chiral spiro diboron catalyst is prepared; adding L to react with the prepared chiral spiro diboron catalyst, stirring at room temperature for 30 minutes, removing the solvent, recrystallizing, separating and purifying to obtain an adduct of the chiral spiro diboron catalyst and L; chiral spirocyclic diene Compound, HBAr^F ₂And L in a molar ratio of 1:2: 4; the chiral spirocyclic diene compound has the following structural formula:

wherein, the R group is aryl or alkyl;

the structural formula of the adduct of the chiral spiro diboron catalyst and L is as follows:

wherein R is aryl or alkyl, Ar is^FIs fluorine-containing aryl, and L is isoquinoline or pyridine.

2. The process according to claim 1, wherein the chiral spirocyclic diene compound is prepared by:

the first step is as follows: racemic spiro [4.4] -1, 6-nonanedione and (R) -phenethylamino oxalyl hydrazine are refluxed overnight under the catalysis of iodine to obtain a pair of diastereoisomer dihydrazone compound intermediates, the (R) -dihydrazone compound with single configuration is obtained by recrystallization twice in ethanol and separation, the (R) -dihydrazone compound is hydrolyzed in an iodine-potassium iodide system to obtain an optical pure product (R) -spiro [4.4] -1, 6-nonanedione ((R) -1),

wherein the molar ratio of the racemic spiro [4.4] -1, 6-nonanedione to (R) -phenethylamino oxalyl hydrazine is 1: 1;

the second step is that: reacting the (R) -spiro [4.4] -1, 6-nonanedione ((R) -1) and 2- [ N-N-bis (trifluoromethanesulfonyl) amino ] pyridine in tetrahydrofuran at-78 ℃ for 40 minutes using potassium bis (trimethylsilyl) amide as a base to give an enol trifluoromethanesulfonate compound (2),

wherein the molar ratio of the optically pure product (R) -spiro [4.4] -1, 6-nonanedione ((R) -1), 2- [ N-N-bis (trifluoromethanesulfonyl) amino ] pyridine and bis (trimethylsilyl) amino potassium is 1:3: 3;

the third step: toluene and ethanol are mixed according to the volume ratio of 3:1 to be used as a mixed solvent, under the condition of heating reflux, the triflate enol ester compound (2) and an aryl or alkyl boric acid reagent generate Suzuki coupling reaction in the presence of tetrakis (triphenylphosphine) palladium and alkali, and the chiral spirocyclic diene compound (3) is obtained after 5 hours of reaction,

wherein the molar ratio of said alkenyl triflate compound (2) to said aryl or alkyl boronic acid reagent is 1:4, said tetrakis (triphenylphosphine) palladium is present in an amount of 10 mol%, and said aryl or alkyl boronic acid reagent has the formula RB (OH)₂And R is aryl or alkyl.

3. The method of claim 2, wherein: the absolute configuration of the chiral spirodiene compound is (R) or (S).

4. The method of claim 2, wherein: the aryl is phenyl, 4-fluorophenyl, 3-phenyl or 4-phenyl.

5. Use of a chiral spirocyclic bisboron catalyst according to any one of claims 1 to 4 for catalyzing asymmetric hydrogenation of quinoline to give 2-substituted tetrahydroquinoline compounds, characterized in that: the structural formula of the quinoline is as follows:

wherein, R is¹,R²Are all alkyl, aryl, styryl, alkynyl, conjugated dienyl or conjugated alkenylalkynyl.

6. The use according to claim 5, wherein the chiral spirocyclic diene compound of claim 1 and the HBAr of claim 1 are added sequentially to a reaction flask under nitrogen atmosphere^F ₂And trifluorotoluene, stirring for 15 minutes at the specified temperature, cooling to room temperature, adding 2-substituted quinoline, transferring to a high-pressure kettle, sealing, replacing with hydrogen for three times, filling to reaction pressure, reacting at-20 ℃, discharging residual hydrogen in the kettle carefully after reacting for 24 hours, heating the reaction system to room temperature, reducing pressure to remove the solvent, and performing column chromatography separation to obtain a 2-substituted tetrahydroquinoline product.

7. Use according to claim 6, characterized in that: the dosage of the trifluorotoluene is 1.0-2.0mL for each millimole of 2-substituted quinoline.

8. Use according to claim 6, characterized in that: the reaction pressure of hydrogen is 2-5 MPa.