JP2003311156A - Catalyst, and manufacturing method for allyl compound using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a catalyst capable of widely acting on the whole carbonyl derivatives and a manufacturing method for an allyl compound using the same. <P>SOLUTION: The catalyst arylates the carbonyl derivatives and contains a silane compound activating agent and a carbonyl group activating agent. In the manufacturing method for the allyl compound, the allyl compound is provided by reacting the carbonyl derivatives with allylsilane in the presence of a catalyst as defined in claims 1-3. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a catalyst and a method for producing an allyl compound using the same, and more particularly to a catalyst for allylating a carbonyl derivative and a method for producing an allyl compound using the same.

[0002]

Due to the versatility of homoallyl alcohol and homoallylamine as synthetic intermediates, allylation of carbonyl derivatives such as aldehydes, ketones, imines is one of the most important carbon-carbon bond forming reactions. is there.
Allylation of carbonyl derivatives can be used to achieve efficient synthesis of various pharmaceutical lead compounds, bioactive natural products.

Of the various allyl metal reagents, allylsilane and allyltin are very useful due to their mild reactivity which allows catalytically enantioselective reactions upon application.

[0004]

However, when using allyl tin, one must always consider environmental concerns due to the toxicity of tin in allyl tin. on the other hand,
Allylsilane is less toxic than allyltin and is therefore more environmentally friendly and more stable. However, the very low reactivity of allylsilane has limited its overall utility.

Therefore, the development of a highly versatile and environmentally friendly allylic carbonyl derivative has been long awaited.

Therefore, the present invention is to provide a novel catalyst which can act on a wide range of carbonyl derivatives, can be efficiently synthesized, and is environmentally friendly, and a process for producing an allyl compound using the same.

[0007]

[Means for Solving the Problems] In order to achieve the above object, the present inventors have studied combinations of various silane compound activators and metals, and as a result of diligent research on the allylation reaction, the catalyst of the present invention has been obtained. And, they have come to find a method for producing an allyl compound using the same.

The catalyst of the present invention is a catalyst for allylating a carbonyl derivative, and is characterized by containing a silane compound activator and a metal.

In a preferred embodiment of the catalyst of the present invention, the silane compound activator is a fluorine anion.

In a preferred embodiment of the catalyst of the present invention, the silane compound activator is tetrabutylammonium difluorotriphenylsilicate (TBAT), tetrabutylammonium fluoride (TBAF), tris (dimethylaminosulfer (trimethylsilyl) difluoride ( TASF) is at least one selected from the group consisting of.

In a preferred embodiment of the catalyst of the present invention, the carbonyl group activator is AgCl, CuCl, N 2.
It is characterized by being at least one selected from the group consisting of iCl ₂ , CuF, CuBr, CuI, and CuOTf.

The method for producing an allyl compound according to the present invention comprises:
~ 4 in the presence of the catalyst in the presence of a carbonyl derivative and allylsilane are obtained.

A preferred embodiment of the method for producing an allyl compound of the present invention is characterized in that the carbonyl derivative is at least one selected from the group consisting of aldehydes, ketones, imines and ketoimines.

In a preferred embodiment of the method for producing an allyl compound of the present invention, the allylsilane is at least one of allyltrimethoxysilane and allyltrimethylsilane.

A preferred embodiment of the process for producing an allyl compound of the present invention is characterized in that the reaction is carried out in the presence of an aprotic solvent.

In a preferred embodiment of the method for producing an allyl compound of the present invention, the aprotic solvent is tetrahydrofuran (THF), CH ₂ Cl ₂ , toluene, Et ₂ O, CH ₃ CN, MeOH,
It is characterized in that it is selected from the group consisting of N, N-dimethylformamide (DMF).

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The catalyst of the present invention is a catalyst for allylating a carbonyl derivative, and contains a silane compound activator and a metal. Here, the silane compound activator is a substance capable of activating a silane compound, particularly a substance capable of activating allylsilane. The term “metal” here means a substance capable of activating a carbonyl group or an allyl group of a carbonyl derivative.

The reason for using these activators together is that the reaction mechanism for activating both components, that is, activating both the silane compound and the carbonyl group, effectively activates the silane compound having low reactivity. This is because it was decided to make it.

Examples of the silane compound activator used in the catalyst of the present invention include a fluorine anion. Examples thereof include tetrabutylammonium difluorotriphenylsilicate (TBAT), tetrabutylammonium fluoride (TBAF) and tris ( Dimethylaminosulfur
At least one selected from the group consisting of (trimethylsilyl) difluoride (TASF) can be mentioned.

When used in the method for producing an allyl compound, from the viewpoints of a short reaction time and a high yield of the allyl compound,
As the silane compound activator, tetrabutylammonium difluorotriphenylsilicate (TBAT) is preferable.

Further, as the carboxyl group activator,
The carbonyl group of the carbonyl derivative is not particularly limited as long as it can activate the carbonyl group.
gCl, CuCl, NiCl ₂ , CuF, CuBr, C
at least selected from the group consisting of uI and CuOTf
One can be mentioned.

Next, a method for producing the allyl compound of the present invention will be described. In the method for producing an allyl compound of the present invention,
An allylic compound such as homoallyl alcohol or homoallylamine can be obtained by reacting a carbonyl derivative with allylsilane in the presence of the catalyst of the present invention.

The catalyst can be used in the method for producing an allyl compound by appropriately combining the catalysts of the present invention described above. The amount of the catalyst depends on various conditions such as the catalyst to be used, the substrate and the solvent, but it is 0 to 15 mol%, more preferably 1 to 10 mol.
l%. The reason for setting this range is that the reaction time can be shortened.

The carbonyl derivative is not particularly limited, but at least one selected from the group consisting of aldehyde, ketone, imine and ketoimine can be mentioned. Thus, it can be said that the present invention can provide a method for producing an allyl compound which can act regardless of the type of carbonyl derivative, has high generality and versatility, is stable, and is environmentally friendly.

In a preferred embodiment of the present invention, the allylsilane may be at least one selected from the group consisting of allyltrimethoxysilane and allyltrimethylsilane. As the allylsilane, allyltrimethoxysilane is preferable from the viewpoint that the pentacoordinated silicate can be formed more easily.

According to the method for producing an allyl compound of the present invention, the carbonyl derivative is 1 to 2 equivalents, preferably 1 to
1.5 equivalents of allylsilane in a suitable solvent
At an appropriate temperature of -50 ° C, preferably near room temperature, 0.1
An allyl compound is obtained by reacting for about 50 hours.

Examples of the solvent include aprotic solvents. As the aprotic solvent, tetrahydrofuran
(THF), CH ₂ Cl ₂ , toluene, Et ₂ O, CH ₃ CN, MeOH, N, N-
At least one selected from the group consisting of dimethylformamide (DMF) can be mentioned. From the viewpoint of easy availability, high yield, and short reaction time,
As the aprotic solvent, tetrahydrofuran (TH
F), CH ₂ Cl ₂ , N, N-dimethylformamide (DMF) and the like are preferable.

The reaction formula of one embodiment of the method for producing an allyl compound of the present invention is shown below.

[Chemical 1] However, in [Chemical formula 1], X represents O, NBn, N-aryl, N-acyl, or the like, and R ¹ and R ² represent hydrogen, allyl, alkyl, aryl, acetylene, or the like.

[0029]

EXAMPLES One example of the present invention will now be described, but the present invention is not construed as being limited to the following example. Needless to say, appropriate changes can be made without departing from the spirit of the present invention.

Example 1 In order to overcome the low reactivity of allylsilane, an attempt was made to prepare homoallyl alcohol and homoallylamine using the dual component activation reaction concept. That is, this is due to the speculation that if the catalyst activates both the allylsilane and the carbonyl substrate at the same time, a high catalytic activity will be obtained, and that the fluorine anion can activate the silylated nucleophile. It is a thing. Therefore, the combination of fluoride anion and metal was investigated and activated allylsilane and substrate respectively.

First, using tetrabutylammonium difluorotriphenylsilicate (TBAT: 10 mol%) and allyltrimethoxysilane (1.5 equivalents),
The combination was investigated with various Lewis acids for the reaction of benzaldehyde as a substrate. Et ₂ AlCl, ZrCl
Hard Lewis acids such as ₄ · 2THF and HfCl ₄ · 2THF, which did not promote no response, the immediate reaction, AgCl (60% yield), CuCl (yield 100
%: 1.5 hours).
After investigating various copper salts, fluoride anion sources, solvents, and catalysts, completely optimal reaction conditions were determined, as will be demonstrated in the Examples below. (1 mol% CuCl and
TBAT in THF, room temperature).

Here, when various aldehydes, ketones and imines are used as substrates, the catalyst of the present invention,
Using CuCl and TBAT (Ymol%), the substrate was reacted with 1.5 equivalents of allyltrimethoxysilane to obtain an allyl compound.

The experimental results are shown in Table 1.

[0034]

[Table 1] A, b, c, d and e in Table 1 are as follows. a: Refer to instruction information for experimental procedure.
b: isolated yield. c: Desilylation was done by TBAF. d: A mixture of diastereomers was used. e: 2
Using the equivalent of allylsilane, ^t BuOH (1 equivalent) was added slowly for 5 hours.

As shown in Table 1, the reaction is universal and
It has proved applicable to a wide range of aldehydes, ketones, and imines. Specifically, the reaction proceeded slowly under very mild conditions at ambient temperature, and at neutral pH, with an overall acceptable catalyst loading. (1-1
0 mol%).

Application to complex complex substrates clearly demonstrated these advantages (entry 8). The reaction was completely functional group selective and the lactone did not react. Enone 3h showed complete 1,2-selectivity (entry 16). Imines, including aliphatic imines and ketoimines,
Slowly add proton source ( ^t BuOH) (5 h),
The allyl compound was given in high yield. (Entry 17-2
0).

The details of the experiment will be described in detail below. <Method of catalytic allylation of aldehydes> CuCl (2 mg 0.02 mmol) and TBAT (11 mg, in THF (2 mL)
0.02 mmol) was stirred for 1 hour at room temperature. After cooling in an ice bath, allyltrimethoxysilane (0.5 m
L, 3.0 mmol) and benzaldehyde (0.2 mL,
2.0 mmol) was added and then the cooling bath was removed. After disappearance of the starting material by TLC, 2N HCl (1: 1) solution in MeOH was added for desilylation. In addition, H ⁺ is appropriately used in order to convert —O—SiR ₃ produced as an intermediate into —OH.

<Method of catalytic allylation of ketone> THF (2 m
L) CuCl (4 mg 0.04 mmol) and TBAT (2
A mixture of 2 mg, 0.04 mmol) was stirred for 1 hour at room temperature. After cooling in an ice bath, allyltrimethoxysilane (0.5 mL, 3.0 mmol) and aldehyde (2.0 mmo
l) was added and then the cooling bath was removed. After disappearance of the starting material by TLC, 2NHCl in MeOH (1: 1) for desilylation
The solution was added.

<Method of catalytic allylation of imine> THF
CuCl (4 mg 0.04 mmol) and TBAT in (2 mL)
A mixture of (22 mg, 0.04 mmol) was stirred for 1 hour at room temperature. After cooling in an ice bath, allyltrimethoxysilane (0.67 mL, 4.0 mmol) and imine (2.0 m
mol) was added and then the cooling bath was removed. To this mixture, ^t BuOH (0.19 mL, 2 mmol) was added slowly by syringe pump over 5 hours. The starting material is
After disappearance by TLC, saturated NaHCO ₃ solution was added to terminate the reaction.

<Method of catalytic enantioselective allylation of acetophenone> CuCl (4.5 mg) in THF (0.3 mL)
0.045 mmol), p-tolu-BINAP (30.5 mg,
0.045 mmol) and TBAT (34.3 mg, 0.045 mm)
ol) was stirred for 1 hour at room temperature. After cooling in an ice bath, allyltrimethoxysilane (76 μL, 0.
45 mmol) and acetophenone (0.3 mmol) were added. After 90 hours, add 2 NHCl (1: 1) solution in MeOH,
The aqueous layer was extracted with AcOEt. The combined organic layer was washed with saturated NaCl solution and dried over Na ₂ SO ₄ . Purification of the crude material by SiO ₂ column chromatography gave pure 4a in 65% yield. Enantiomeric excess was determined to be 61% ee by chiral HPLC analysis (DAICEL,
CHIRALCEL OJ-H, hexane / iPrOH = 20/1, TR 9.
1min (major) and 11.3min (minor). [Α] 23n = +
_{36.3 (c0.843, CHCl 3) (} ee 61%).

The product thus obtained was identified under the following conditions. NMR spectra are 500 MHz for ¹ H NMR and 125.65 for ¹³ C NMR.
470.4 MHz for MHz and ¹⁹ F NMR
Recorded on a JEOL JNM-LA500 spectrometer, operating at. TMS (= for ¹ H NMR
0) reported the downstream region. ^{For 13} C NMR, chemical shifts were reported in magnitude relative to the solvent used as an internal reference. ¹⁹ F NMR was performed with trifluoroacetic acid (= 0) as an external standard.

Optical rotation was measured on a JASCO P-1010 Polymeter. Silica gel Merick 60 (23
Column chromatography was performed on 0-400 mesh ASTM). The enantiomeric excess (ee) was determined by HPLC analysis. The HPLC analysis is performed as follows: pump (880-PU or PU-980), detector (254n
JASCO consisting of 875-UV or UV-970 measured by m), column (DAICEL CHIRALCEL OJ-H), mobile phase (hexane-2-propanol).
Performed on an HPLC system.

The product data is shown below. Product 2a
-2c, 2f, 2g, 4a-4c, 4g, 4h, 6a-6
d is a known compound and 2d, 2h will be reported elsewhere.

2,2 dimethyl-1-phenyl-5-hex
Sen-3-ol (2e):¹H-NMR (CDCl₃) δ 0.89 (s, 31
1), 0.96 (s, 3H), 1.60 (s, 1H),
2.11 (dt.J = 9.8, 14.0 Hz, 1H), 2.
43-2.48 (m, 1H), 2.56 (d, J = 1
2.8Hz, 1H), 2.83 (d, J = 12.8H
z, 1H), 3.34 (dd, J = 1.9, 10.7H)
z, 1H), 5.20 (s, 1H), 5.22 (d, J =
8.6Hz, 1H), 5.83-5.92 (m, 1H),
7.23-5.33 (m. 5H);^ThirteenC-NMR (CDCl₃) δ
21.3, 22.3, 35.4, 37.3, 43.8,
74.8, 117.2, 124.9, 126.7, 12
9.8, 135.4, 135.4; IR (ncat) 3459 cm
^-1MSm / z204 (M ⁺), 186 (M-OH), 163 (M
-C₃II_Three, 91 (Bn); HRMS Caled for C₁₄H₂₀O
(M⁺) 204.1514. Found204.1514.4
-Ethyl-1-heptene-1-ol ::¹H-NMR (CDCl₃) δ
0.88 (t, J = 7.6Hz, 3H), 0.92 (t, J
= 7.3 Hz, 3H), 1.30-1.50 (m, 6
H), 1.56 (s, 1H), 2.20 (d, J = 7.
3Hz, 1H), 5.09-5.14 (m, 2H),
5.80-5.88 (m, 1H);^ThirteenC-NMR (CDCl₃)
δ6.83, 13.7, 15.7, 30.5, 40.
0, 42.4, 73.1.117.4, 133.0; I
R (neat) 3399 cm^-1MS m / z 125 (M-OH),
101 (M-C₃H_Five); HRMS Caled for C₉H₁₇(M-OH)
125.1330. Found 125.1330.

Example 2 Next, in order to gain insight into the reaction mechanism, we used THF.
The reaction procedure was followed while observing the ¹⁹ FNMR in (Fig.
1). Reaction with TBAF in CuCl (1: 1) provided the reported CuF _· 3PPh 3 _· 2EtOH chemical ¹⁹ new believed CuF based on shift F NMR peaks (-155.7ppm). When allyltrimethylsilane (1 equivalent) was added to the mixture, the CuF peak disappeared, chemical shift and the presence of satellite (J = 112H) peak derived from the bond with Si are considered to be allylfluorodimethyloxysilane. Peak (-12
9.0 ppm) appeared. Therefore, CuOMe is generated at this stage. However, the addition of aldehyde 1a to this reaction mixture (CuOMe and allylfluorodimethoxysilane) did not give any product for at least 3 hours. On the other hand, when allyltrimethoxysilane (1 equivalent) was further added to this reaction mixture,
2a was produced. Therefore, CuOMe and allyltrimethoxysilane are needed to produce the reactive species.

In this respect, the fluoride ion acts only as an initiator to generate the copper alkoxide, and a direct entry into the catalytic cycle is the mechanism of the catalytic enantioselective aldol reaction reported by Careira. We hypothesized that copper alkoxide and allyltrimethoxysilane might be inferred from the above. However, in this system this was not true. That is, the only trace amount (<1%) of 2a (in Table 1) is CuOBu (10mo).
1%) and allyltrimethoxysilane (1.5 eq) in the presence of 1a (in Table 1). When (EtO) ₃ SiF (10 mol%) was added to this solution as an analog of allylfluorodimethyloxysilane, the reaction proceeded and 2a was obtained in 27% yield (4h). (E
Addition of PhSiF instead of tO) ₃ SiF did not give the desired product. Alkoxyl fluoride appears to be the required structure factor to accelerate the reaction. Therefore, in this reaction, the fluoride anion has an active role in the catalytic cycle as well as an initiator that produces the actual catalytic species, and CuOMe, allylmethyloxysilane, and silyl fluorides They are all essential for the immediate catalytic promotion of the reaction. In addition, fluoride is
It has been found that it has an important role in the catalytic cycle as well as an initiator for generating the active catalyst.

Example 3 A first attempt was also made to develop this reaction for the catalytic enantioselective allylation of ketones. As a catalyst, R-
Substrates 3a in Table 1 in tol-BINAP-CuCl and TBAT (15 mol% each) at 4 ° C. and room temperature in the solvent THF,
1.5 equivalents of allyltrimethoxysilane were reacted. 4 ° C
Then, in a reaction time of 90 hours, 4a (in Table 1) was obtained from 3a (in Table 1) in a yield of 65% and 61ee%. Further, at room temperature, 4a (in Table 1) was obtained from 3a (in Table 1) in a yield of 100% and 56ee% after a reaction time of 7 hours.

Although the enantioselectivity was moderate, it is the first example of a catalytic enantioselective allylation of ketones with allylsilane.

Example 4 Next, the copper salt (10 mol% +) was added at room temperature in the solvent CH ₂ Cl _2.
The effect of TBAT (10 mol%) was investigated.

An experiment was conducted in the same manner as in Example 1 except that various copper salts and a CH ₂ Cl ₂ solvent were used. The results are shown in Table 2.

[0051]

[Table 2]

As a result, CuCl, CuBr.Sme, CuI, and Cu
All CN showed good results.

Example 5 Next, a fluorine anion source at room temperature in a solvent CH ₂ Cl _{2 was} used.
The effect of (10 mol% + CuCl (10 mol%) was investigated.

Various sources of fluorine anions, and CH ₂ Cl
An experiment was conducted in the same manner as in Example 1 except that _two solvents were used. The results are shown in Table 3.

[0055]

[Table 3]

As a result, TBAT, TBAF and TASF all showed good results.

Example 6 Next, the influence of various solvents was investigated. Specifically, TBAT and CuCl (10 mol%) were used as catalysts and reacted at room temperature.

An experiment was conducted in the same manner as in Example 1 except that various solvents were used. The results are shown in Table 4.

[0059]

[Table 4]

As a result, good results were shown for all the solvents. Especially in CH ₂ Cl ₂ , THF and DMF, high yields were obtained with short reaction times.

Example 7 Next, the influence of the amount of catalyst was investigated. The test was performed as described in Example 1 except that the amount of catalyst was changed. TBAT and CuCl were used as catalysts.

The results are shown in Table 5.

[0063]

[Table 5]

As a result, when the amount of the catalyst was increased, the reaction time was shortened, the yield was increased, and good results were obtained.

[0065]

According to the catalyst of the present invention and the method for producing an allyl compound using the catalyst, a wide range of carbonyl derivatives can be exerted, and the advantageous effect of efficient synthesis can be obtained.

Further, according to the catalyst of the present invention and the method for producing an allyl compound using the same, since a silane compound having low toxicity is used, there is an advantageous effect that the allyl compound can be synthesized in harmony with the environment. Play. The present invention also enables the synthesis of various pharmaceutical lead compounds and bioactive natural products.

Further, according to the catalyst of the present invention and the method for producing an allyl compound using the catalyst, a versatile synthetic intermediate which can be converted into various compounds by modification such as oxidation and reduction of carbon-carbon double bond. Allyl compounds such as homoallyl alcohol and homoallyl amine can be provided.

[Brief description of drawings]

FIG. 1 is a diagram showing an example of a reaction mechanism for the catalyst of the present invention.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI Theme Coat (Reference) C07C 41/30 C07C 41/30 43/164 43/164 209/60 209/60 211/20 211/20 211 / 28 211/28 C07F 7/18 C07F 7/18 S // C07B 61/00 300 C07B 61/00 300 F term (reference) 4G069 AA06 BA27A BA27B BB08A BB08B BC31A BC31B BC32A BC68A BD05A BD05B BD12A BD12BHB006A BD02B BD15A 006 AC41 BA05 BA21 BA53 BB11 BB12 BB14 BB15 BB20 BB21 BB25 BC31 BC34 FC32.

Claims (9)

[Claims] 1. A catalyst for allylating a carbonyl derivative, comprising a silane compound activator and a metal. 2. The catalyst according to claim 1, wherein the silane compound activator is a fluorine anion. 3. The silane compound activator is tetrabutylammonium difluorotriphenylsilicate (TBA).
T), tetrabutylammonium fluoride (TBA
2. The catalyst according to claim 1, wherein the catalyst is at least one selected from the group consisting of F) and tris (dimethylaminosulfur (trimethylsilyl) difluoride (TASF). 4. The metal is AgCl, CuCl, NiCl
The catalyst according to any one of claims 1 to 3, wherein the catalyst is at least one selected from the group consisting of ₂ , CuF, CuBr, CuI, and CuOTf. 5. A process for producing an allyl compound, which is obtained by reacting a carbonyl derivative with allylsilane in the presence of the catalyst according to any one of claims 1 to 4. 6. The method according to claim 5, wherein the carbonyl derivative is at least one selected from the group consisting of aldehydes, ketones, imines, and ketoimines. 7. The method according to claim 5, wherein the allylsilane is at least one of allyltrimethoxysilane and allyltrimethylsilane. 8. The production method according to claim 5, wherein the reaction is carried out in the presence of an aprotic solvent. 9. The aprotic solvent is tetrahydrofuran (THF), CH ₂ Cl ₂ , toluene, Et ₂ O, CH ₃ CN, MeOH, N, N.
A process according to claim 8, characterized in that it is selected from the group consisting of dimethylformamide (DMF).