JP2000229987A - Production of 2-trialkylsilyl-2,2-difluoroacetic ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently produce the subject compound useful as a reagent for introducing difluoromethylene group to an organic compound or the like in high purity and high yield by electrolytically reducing a specific trifluoroacetic esters in the presence of a specified halogenated trialkylsilane. SOLUTION: Trifluoroacetic esters of formula I (R1 is a monovalent organic group) such as methyl trifluoroacetate are electrolytically reduced in the presence of a halogenated trialkylsilane of formula II (R2 is methyl, ethyl, propyl, isopropyl or phenyl; and X is chlorine, bromine or iodine) such as trimethylsilane chloride to provide the objective 2-trialkylsilyl-2,2-difluoroacetic ester such as ethyl 2-trimethylsilyl-2,2-difluoroacetate. Preferably, the R1 is an alkyl group, a cycloalkyl group, an aryl group, an alkenyl group, an alkynyl group, a heteroaromatic group or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2-trialkylsilyl 2,2-difluoroacetic acid ester by an electrolytic reduction method. 2-trialkylsilyl 2,2
-Difluoroacetic acid ester is useful as a reaction reagent for introducing a difluoromethylene group into an organic compound or as an intermediate for producing an organic compound.

[0002]

2. Description of the Related Art In recent years, a compound having a difluoromethylene group has a particular biological activity, and therefore its synthetic method has attracted attention. Heretofore, a carbonyl group, a thiocarbonyl group or a thiocetal group is often converted to a difluoromethylene group by reacting it with DAST (dimethylaminosulfur trifluoride) or an oxidizing fluorinating agent having a similar effect. A method of dehalogenating a halodifluoromethyl group to obtain a difluoromethylene group is also well known.

As a reagent for introducing a difluoromethylene group, difluoroketene silyl acetal has often been used for the mild synthesis of difluoro-β-amino, β-hydroxyester and β-ethoxycarbonyldifluoromethyl-β-lactam. However, difluoroketene silyl acetals are unstable in the presence of moisture and zinc salts and must be prepared and used in situ in a Reformatsky reaction of halodifluoroacetates.

[0004] It has been described in the literature that when ethyl trifluoroacetate is electrolytically reduced, a Claisen condensation product is obtained as a main product and a small amount of 2-trialkylsilyl 2,2-difluoroacetate is formed (Novel Trends i).
n Electroorg., Synth., [Pap.Int.Symp.], 3rd (1998), Me
eting Date 1997,299-300. Editor: S Torii).

[0005]

Therefore, in the present invention, 2-trialkylsilyl 2,2-difluoroacetic acid ester, which is a stable and isolable compound applicable to the same reaction as difluoroketene silyl acetal, is obtained in good yield. A method of manufacturing is provided.

[0006]

Means for Solving the Problems The present inventors electrolytically reduce trifluoroacetic acid esters in the presence of a halogenated trialkylsilane under specific conditions to obtain 2-trialkylsilyl 2,2-difluoroacetic acid esters. Was found to be obtained in good yield, and the present invention was achieved.

That is, the present invention provides a compound represented by the general formula (1):

[0008]

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[0009] (wherein, R ¹ represents. A monovalent organic group) Formula _{^{(2) (R 2) 3}} SiX (2) ( wherein trifluoroacetic acid ester represented by, R ² is Each independently represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a phenyl group;
Represents chlorine, bromine or iodine. Formula (3) by electrolytic reduction in the presence of a halogenated trialkylsilane represented by

[0010]

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[0011] (wherein, TAS represents a trialkylsilyl group, R ¹ represents. The same substituents as R ¹ in formula (1)) 2-trialkylsilyl-difluoro acetic ester represented by It is a manufacturing method of.

The trifluoroacetic acid ester represented by the general formula (1) according to the present invention is not particularly limited, and the monovalent organic group represented by R ¹ is inactive under the conditions of the electrolytic reduction reaction. I just need. Such organic groups include those having 1-2 carbon atoms.
An alkyl group which may have 0 branches, an alkenyl group or an alkynyl group, a cycloalkyl group which may have a substituent having 1 to 20 carbon atoms, an aryl group which may have a substituent having 1 to 20 carbon atoms, formula _{(4) - (CH 2)} n -R 3 (4) ( wherein, R ³ is a cycloalkyl group having 1 to 10 carbon atoms, an aryl group, an alkoxyl group, thioalkoxyl group, tertiary amino group, an acyl Group, an alkoxycarbonyl group, or a heteroaromatic group, and n represents an integer of 1 or more.).

Specific examples of the trifluoroacetates represented by the general formula (1) include methyl trifluoroacetate, ethyl trifluoroacetate and n-trifluoroacetate.
Propyl, i-propyl trifluoroacetate, n-butyl trifluoroacetate, s-butyl trifluoroacetate, t-butyl trifluoroacetate, n-hexyl trifluoroacetate, cyclohexyl trifluoroacetate, phenyl trifluoroacetate, trifluorothio St-butyl acetate and S-phenyl trifluorothioacetate can be mentioned, but it goes without saying that they are not limited to these.

According to the present invention, 2 represented by the general formula (3)
-Trialkylsilyl 2,2-difluoroacetic acid esters are the corresponding 2-trialkylsilyl 2,2-difluoroacetic acid esters, each having the same substituent R ¹ as R ^{1 in} general formula (1).

The halogenated trialkylsilane used in the present invention is not particularly limited, but in the general formula (2) (R ² ) ₃ SiX (2), R ² independently represents a methyl group, an ethyl group,
Represents a propyl group, an isopropyl group or a phenyl group,
X preferably represents chlorine, bromine or iodine. Preferred examples of the halogenated trialkylsilane include trimethylsilane chloride, triethylsilane chloride, phenyldimethylsilane chloride, diphenylmethylsilane chloride, and triethylsilane bromide. Of these, trimethylsilane chloride is the most preferable because it is easily available. The solvent used in the method of the present invention may be any type as long as it is inert under the conditions of the electrolytic reduction reaction of the present invention.
For example, acetonitrile, propionitrile, phenylacetonitrile, isobutyronitrile, benzonitrile, acid amides such as dimethylformamide, dimethylacetamide, methylformamide, formamide, hexamethylphosphoric triamide, ethers such as tetrahydrofuran, 1 , 2-dimethoxyethane,
1,4-dioxane, diethyl ether, 1,2-epoxyethane and the like are used, and acetonitrile, dimethylformamide, and tetrahydrofuran are preferable, and acetonitrile is particularly preferable.

The electrolytic reduction of the present invention can be carried out by applying a conventionally known method. As the electrolytic cell used in the method of the present invention, an anode / cathode separation type cell or a single type cell can be used. In the case of the separation type cell, examples of the membrane include a well-known ion exchange membrane, for example, a Nafion (DuPont, registered trademark) membrane, and a porous membrane of an inorganic material, for example, glass or ceramic. Preferably, a separate cell is used.

The supporting electrolyte used in the method of the present invention is preferably a tetraalkylammonium salt or a lithium salt. As the alkyl group of the tetraalkylammonium salt, a C ₁ to C ₆ lower alkyl group is preferable. As the anion of the salt, a halide ion, perchlorate ion, tetrafluoroborate ion, p-toluenesulfonate ion or p-toluenesulfonate ion is preferable. Specifically, preferred supporting electrolytes used in the method of the present invention include tetraethylammonium tetrafluoroborate (Et ₄ NBF ₄ ), tetrabutylammonium tetrafluoroborate (Bu ₄ NBF ₄ ), tetraethylammonium bromide (Et ₄ NBr), Tetrabutylammonium bromide (Bu ₄ NBr), tetraethylammonium perchlorate (Bu ₄ ClO ₄ ), tetrabutylammonium perchlorate (Bu ₄ NClO ₄ ), lithium bromide (L
lithium halide such as iBr) and lithium perchlorate (LiClO ₄ ). Of these,
Particularly, tetrabutylammonium bromide and lithium perchlorate are preferred. Further, n-Bu ₄ NBr- acetonitrile, LiClO ₄ -DMF, LiClO ₄ - supporting electrolyte acetonitrile - system of the solvent can be exemplified as particularly preferable combination. The concentration of the supporting electrolyte is preferably 0.01 to 10 mol / liter.

The anode material used in the production method of the present invention is not particularly limited, and conventionally known materials can be widely used. As the anode material when using a separation type cell,
Lead, carbon and platinum are preferred.

The cathode material used in the production method of the present invention is not particularly limited, and conventionally known materials can be widely used. Preferred are lead, platinum, stainless steel, zinc, magnesium, nickel, aluminum,
And carbon.

The current density in the manufacturing method of the present invention is 1
〜1000 mA / cm ² is preferred. The amount of electricity passed by the method of the present invention is theoretically 2 F / m
Although it is ol, it does not matter even if the current is excessively supplied. Normal,
Performed at 2-40 F / mol.

The reaction temperature for carrying out the production method of the present invention is-
40 to 100 ° C., preferably −20 to 80 ° C.
° C. At a low temperature, ketene silyl acetal is likely to be formed, so that 2-trialkylsilyl 2,2-
It is not preferable because the yield of difluoroacetic acid ester is reduced.

The amount of the halogenated trialkylsilane used in the method of the present invention is 2 to 50 times, preferably about 3 to 10 times, that of trifluoromethyl ketones. Although not clear, in the method of the present invention, the halogenated trialkylsilane is not only used as a reaction reagent,
It is considered that a part thereof acts as a scavenger for the detached fluorine ions, so that 1 mol times or more of the halogenated trialkylsilane is required. Furthermore, when the amount of the halogenated trialkylsilane is less than 2 mole times,
Since the product is a by-product of Claisen condensation, the yield of the target product may decrease, which is not preferable. Although the necessary amount of the trialkylsilane halide varies depending on the amount of electricity used for electrolytic reduction, it is preferably at least 2 mol times at the most preferred amount of electricity of about 2 F / mol.

In the method of the present invention, since the product may be unstable depending on the kind of trifluoroacetates, bases such as trimethylamine are added to the catholyte after or before the completion of the reduction reaction. , Triethylamine, tripropylamine, aliphatic tertiary amines such as tributylamine, dimethylamine, diethylamine, aliphatic secondary amines such as dipropylamine, methylamine,
It is preferable to add primary amines such as ethylamine and propylamine, alicyclic amines such as cyclohexylamine, and aromatic amines such as dimethylaniline and diethylaniline.

The 2-trialkylsilyl 2,2-difluoroacetic acid ester produced by the method of the present invention can be used as an electrophilic reagent in the presence of a fluorine ion as shown in the following formula. , Benzyl chloride and the like can proceed the alkylation reaction.

[0025]

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Here, E corresponds to the electrophilic reagent,
_{PhCH (OH) -, PhCH 2} -, respectively represent PhCO-. As the F- ion, a quaternary ammonium fluoride such as tetrabutylammonium fluoride;
An alkali metal fluoride such as potassium fluoride (a co-catalyst such as copper iodide may be used) can be used as appropriate. Further, as the solvent, the above-mentioned solvent used in the method of the present invention such as THF and DMF can be used. The reaction temperature varies depending on the type of the reagent, but is about -78 to 150 ° C.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to these Examples.

[0028]

EXAMPLES Example 1 Tetrabutylammonium bromide (4.8 g, 12.0 mmol, 2.4) was placed in an H-type electrolytic cell.
) Was weighed on the anode side, the rotor was placed in the bipolar chamber, and a carbon rod was attached to the anode side, and a lead plate (10 cm ² ) was attached to the cathode side. Under an argon atmosphere, acetonitrile was added to the bipolar chamber at 35
ml, followed by ethyl trifluoroacetate (0.7
1 g, 5.0 mmol, 1.0 equiv), trimethylsilane chloride (2.5 ml, 20.0 mmol, 4.0 equiv), triethylamine (2.8 ml, 20.0 mmol)
1, 4.0 equivalents). The mixture was heated at 50 ° C. and constant current
A current of 2.0 F / mol (201 minutes) was applied at 0 mA. After the completion of the current supply, the reaction solution in the cathode chamber was distilled off under reduced pressure and concentrated. The obtained viscous liquid was extracted with hexane and concentrated. The obtained liquid was purified by distillation to obtain a target product in a yield of 47%.

Ethyl 2-trimethylsilyl 2,2-difluoroacetate ¹ H-NMR (200 MHz, CDCl ₃ ); δ 0.23
(S, 9H), 1.34 (t, 3H, J = 7.0H
z), 4.31 (q, 2H, J = 7.2 Hz) ¹⁹ F-NMR (188 MHz, CDCl ₃ );
5 (s, 2F) IR (neat) 2976, 1756, 1372, 12
76,1114Cm ^-1 Example 2 trifluoroacetic acid t- butyl instead of ethyl trifluoroacetate (0.85 g, 5.0 mmol,
1.0 equivalent), and the same treatment as in Example 1 was carried out. As a result, 2-trimethylsilyl 2,2-difluoroacetic acid t-
Butyl was obtained with a yield of 58%.

¹ H-NMR (200 MHz, CDC
l ₃ ); δ 0.22 (s, 9H), 1.52 (s, 9
H) ¹⁹ F-NMR (188 MHz, CDCl ₃ );
9 (s, 2F) IR (neat) 2984, 2964, 1760, 15
96, 1462, 1398, 1292, 1112 cm ^-1 [Example 3] n-hexyl trifluoroacetate (1.0 g, 5.0 mmol,
1.0 equivalent), and the same treatment as in Example 1 was carried out. As a result, 2-trimethylsilyl 2,2-difluoroacetic acid n-
Hexyl was obtained with a yield of 62%.

¹ H-NMR (200 MHz, CDC
l ₃ ); δ 0.23 (s, 9H), 0.89 (t, 3
H, J = 6.6 Hz), 1.30-1.41 (m, 6
H) 1.62-1.72 (m, 2H), 4.23
(T, 2H, J = 6.8 Hz) ¹⁹ F-NMR (188 MHz, CDCl ₃ );
7 (s, 2F) IR (neat) 2968, 2868, 1756, 14
70,1278,1198Cm ^-1 Example 4 where the reaction temperature was subjected to the same experiment as in Example 3 as a 0 ° C., to obtain a 2-trimethylsilyl difluoro acetate n- hexyl in 41% yield. ¹⁹ F-NM
When analyzed by R, 18% of 1-n-
Hexyl-2,2-difluoroketene trimethylsilyl acetal was formed.

REFERENCE EXAMPLE 1 The same experiment as in Example 1 was carried out by setting the amount of trimethylsilane chloride to 1.0 equivalent (0.6 ml, 5.0 mmol, and the reaction temperature to 0 ° C.).
The yield of ethyl trimethylsilyl 2,2-difluoroacetate was 5% or less, and 33% of ethyl trifluoroacetate was recovered. Analysis by ¹⁹ F-MNR revealed that 21% of 2-trifluoromethylcarbonyl 2,2-difluoroacetic acid ethyl ester was formed in the reaction product.

[0033]

According to the production method of the present invention, 2-trifluoroalkylsilyl 2,2 useful in an organic synthesis reaction is obtained from trifluoroacetates which are easily available.
-It has an effect that difluoroacetic acid ester can be produced in one step with high yield.

Claims (2)

[Claims] 1. A compound of the general formula (1) (Wherein R ¹ represents a monovalent organic group) represented by the general formula (2) (R ² ) ₃ SiX (2) (wherein R ² is each independently X represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a phenyl group;
Represents chlorine, bromine or iodine. Formula (3) by electrolytic reduction in the presence of a halogenated trialkylsilane represented by formula (3): (Wherein, TAS represents a trialkylsilyl group, R ¹ represents. The same substituents as R ¹ in formula (1)) represented by 2-
A method for producing a trialkylsilyl 2,2-difluoroacetic acid ester. 2. The monovalent organic group is an alkyl group, a cycloalkyl group, an aryl group, an alkenyl group, an alkynyl group, a heteroaromatic group or a compound of the general formula (4)-(CH ₂ ) _n -R ³ (4) (wherein, R ³ represents a cycloalkyl group, an aryl group, an alkoxyl group, a thioalkoxyl group, a tertiary amino group, an acyl group, an alkoxycarbonyl group, a heteroaromatic group, and n
Represents an integer of 1 or more. The method for producing a 2-trialkylsilyl 2,2-difluoroacetic acid ester according to claim 1, which is an organic group represented by the formula: