JP2004189655A - Method for fluorinating with microwave - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for progressing the fluorination reaction of a substrate safely and efficiently within a short time under gentle conditions. <P>SOLUTION: The substrate and a fluorinating agent such as an HF-base complex are reacted in the presence of, optionally, a reactant under irradiation with microwaves and/or electromagnetic radiations near microwaves. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

【００２５】
実施例１３
実施例１に於いて１０ｍｌのＰＦＡ製反応容器を用いて、３−フェニルプロピルメチルスルホネート（１ｍｍｏｌ）とＥｔ_３Ｎ−３ＨＦ（１．２ｍｍｏｌ）を入れて、マイクロ波を２分間照射した以外は実同様にして行った。生成物として１−Ｆｌｕｏｒｏ−３−ｐｈｅｎｉｒｕｐｒｏｐａｎｅが収率８０％で得られた。
【００２６】
比較例１３
実施例１３に於いて、３−フェニルプロピルメチルスルホネート（１ｍｍｏｌ）とＥｔ_３Ｎ−３ＨＦ（１０ｍｍｏｌ）を、アセトニトリル溶媒（１ｍｌ）中、８０℃で１００時間反応を行い、生成物の収率を調べた。１−Ｆｌｕｏｒｏ−３−ｐｈｅｎｉｒｕｐｒｏｐａｎｅの収率は其々次の通りであった。
１０時間後の収率 １２％ ２０時間後の収率 ２０％
３８時間後の収率 ４４％ ５４時間後の収率 ７４％
７９時間後の収率 ８０％ １００時間後の収率 ８０％
【００２７】
【発明の効果】
上記の詳細な説明、及び実施例による具体的な例示によって明らかな様に、本発明によればトリエチルアミン−３ＨＦの様に安定で、実用上、腐食性の無いＨＦ−塩基錯体を用いて、種々の基質、若しくは種々のフッ素化反応、例えば、α位、β位、またはγ位の置換基によって活性化された水素原子を有する化合物、シリルエーテル化合物、或いは官能基として、不飽和基、水酸基、ハロゲノ基、アミノ基、またはジアゾニウム基を有する化合物、若しくはヘテロ原子を持つ事のある３員環以上の多員環化合物等の種々の基質に対する開環フッ素化、不飽和化合物のハロフルオロ化、或いはフルオロスルフェニル化、ハロゲン−フッ素交換、脱ジアゾフッ素化、１，３−ジチオランやヒドラゾン類のｇｅｍ−ジフッ素化、或いはシリルエーテル類の脱保護反応等を、熱反応の場合に比べて穏やかな条件下に短時間で効率的に進行させる事が出来る
。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a fluorination method, in particular, to a fluorinating agent comprising HF-base and a substrate, under irradiation of microwaves (microwaves and / or electromagnetic waves in the vicinity of microwaves, indicating electromagnetic waves in the range of 0.3 to 300 GHz), or The present invention relates to a method for fluorinating a substrate in the presence of a reactant as required.
[0002]
[Prior art]
Fluorine-containing compounds have attracted attention in various fields, including the pharmaceutical and electronic materials fields, because the unique properties derived from fluorine atoms lead to the development of useful functions. There is no. For this reason, various methods for effectively introducing a fluorine atom into a substrate have been studied. Well-known fluorination techniques include a direct fluorination method using fluorine gas (for example, see Patent Document 1), and halogen-fluorine exchange using a compound having a halogen atom with an alkali metal salt of fluorine such as HF or KF. performing, a method using a so-called halogen exchange method (e.g., see non-Patent Document 1), a method using a base such as hydrogen fluoride and pyridine or triethylamine, hypervalent iodine, for example, IF _5, etc., SF _4, DAST Or a method using a specific fluorinating agent such as a fluoroalkylamine such as a Yarovenko reagent, an electrolytic fluorination method, and the like (for example, see Non-Patent Document 2).
[0003]
The conventional fluorination method using fluorine gas, SF ₄ , or DAST has a serious problem in terms of reaction safety (for example, see Non-Patent Document 2), so fluorine atoms can be easily and safely introduced. A possible nucleophilic fluorinating agent, for example, HF-bases, can be distilled when the number of HF molecules coordinating to the base is changed, there is no danger of corrosion, and a glass container can be used. Some documents are often used at the stage and their applications are detailed (for example, see Non-Patent Documents 3 and 4). For example, halogen-fluorine exchange on a halogen-containing compound activated by a carbonyl group at the α-position, halogen-fluorine exchange of trichloropyrimidines, fluorination of sugar by halogen-fluorine exchange of sugar triflate, ring opening of oxirane compound Synthesis of fluoroethanols by fluorination (fluorohydrination), halofluorination of unsaturated compounds, or synthesis of fluorobenzene by fluorosulfenylation or dediazofluorination, gem-difluorination of 1,3-dithiolane and hydrazones Or a deprotection reaction of silyl ethers.
[0004]
However, HF-bases can increase the safety so that HF is not easily released, but also have the disadvantages that nucleophilic fluorine anions are hardly released and the reactivity is low. there were. Therefore, severe conditions are required to improve the reaction results, and it is often difficult to advance a desired reaction. In addition, from an industrial viewpoint, there is room for completing the reaction at a lower temperature and in a shorter time and improving energy costs.
[0005]
[Patent Document 1]
JP-A-53-1827 [Non-Patent Document 1]
Synthetic Organic Chemistry, vol. 47, published by the Society of Synthetic Organic Chemistry, 1999, p. 258
[Non-patent document 2]
Chemistry of Organic Fluorine Compounds II, Monograph, American Chem. Society, 1995, p. 187
[Non-Patent Document 3]
Journal fur practische Chemie Chemiker-Zeitung, 338 (1996) p. 99-113
[Non-patent document 4]
G. FIG. A. Olah, Synthetic Fluorine Chemistry chapter 8, 1992 John Wiley.
[0006]
[Problems to be solved by the invention]
An object of the present invention is to provide, for example, a compound having a hydrogen atom activated by a substituent at the α-position, β-position, or γ-position, a silyl ether compound, or a functional group such as an unsaturated group, a hydroxyl group, a halogeno group, or an amino group. Reaction for various substrates such as a compound having a group, diazo group, triazeno group, or isocyano group, or a compound having three or more membered rings which may have a hetero atom, that is, halogen-fluorine of halogen compounds Exchange, halofluorination of unsaturated groups such as olefins and alkynes, or fluorosulfenylation, nitrofluorination, fluorination of hydroxyl groups of alcohols and saccharides, dediazofluorination of amino groups, diazo groups, triazeno groups, or isocyano groups Conversion of the functional group to fluorine, ring-opening fluorination of cyclic compounds, 1,3-dithiolane and Using an HF-base complex which is easy to handle in gem-difluorination of razone, etc., gem-trifluorination, oxidative fluorination, reductive fluorination of orthothioesters and deprotection of silyl ethers To provide a method for allowing the fluorination reaction to proceed more efficiently and in a shorter time than the thermal reaction.
[0007]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the present inventors have attempted to promote a fluorination reaction by microwaves, which has hardly been applied to the fluorination reaction. As a result, it was found that even if HF-bases having no corrosive property, such as triethylamine-3HF, and having a low reactivity were used, fluorination could be efficiently performed under mild conditions in a short time and efficiently. The present invention has been reached.
[0008]
That is, the present invention relates to a method for fluorinating a substrate under irradiation of microwaves and / or electromagnetic waves near microwaves in the presence of a substrate and a fluorinating agent or, if necessary, a reactant. A compound having a hydrogen atom activated by a substituent at the α-position, β-position or γ-position, a silyl ether compound, or a functional group, wherein the agent is a complex compound comprising HF and a base. Fluorinating a substrate such as a compound having a saturated group, a hydroxyl group, a halogeno group, an amino group, a diazo group, a triazeno group, or an isocyano group, or a three- or more-membered ring compound having a hetero atom (1) ) To (6).
(1) A method of fluorinating a substrate under irradiation of microwaves and / or electromagnetic waves near microwaves in the presence of a substrate and a fluorinating agent or, if necessary, a reactant.
(2) The method according to (1), wherein the fluorinating agent is a complex compound comprising HF and a base.
(3) When the substrate is a compound having a hydrogen atom activated by a substituent at the α-position, β-position or γ-position, a silyl ether compound, or a functional group, the substrate may be an unsaturated group, a hydroxyl group, a halogeno group, an amino group, The method according to (1) or (2), which is a compound having a diazo group, a triazeno group, or an isocyano group, or a three- or more-membered multi-membered ring compound having a hetero atom.
(4) The method according to (1) to (3), wherein the substrate may contain a saccharide, a cyclopropane ring, an oxirane ring, an aziridine ring, an azirine ring, or a 1,3-dithiane ring.
(5) The method according to (1) to (4), wherein the fluorinating agent is a trialkylamine-HF complex.
(6) The method according to (1) to (4), wherein the fluorinating agent is a triethylamine-3HF complex.
[0009]
BEST MODE FOR CARRYING OUT THE INVENTION
The substrate used in the present invention may be a compound having a hydrogen atom activated by a substituent at the α-position, β-position or γ-position, a silyl ether compound, or a functional group such as an unsaturated group, a hydroxyl group, a halogeno group, or an amino group. And a compound having a diazo group, a triazeno group, or an isocyano group, or a three- or more-membered ring compound having a hetero atom.
These substrates include, for example, halogen-fluorine exchange of halogen compounds, halofluorination of unsaturated groups such as olefins and alkynes, or fluorosulfenylation, nitrofluorination, fluorination of hydroxyl groups of alcohols and saccharides, amino groups, Conversion of the functional group to fluorine typified by dediazofluorination of a diazo group, triazeno group or isocyano group, ring-opening fluorination of cyclic compounds, gem-difluorine such as 1,3-dithiolane or hydrazone It is a compound capable of causing a gem-trifluorination, oxidative fluorination, reductive fluorination reaction of orthothioesters, a deprotection reaction of silyl ethers, or the like.
[0010]
Specifically, cyclopropane, cyclobutane, cyclopentane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclodecene, cyclododecene, butene, 2,3-dimethylbutene, methylenecyclohexene, 5α-cholest-2-ene, ethylene oxide, Propylene oxide, oxetane, oxolane, cyclohexene oxide, cyclooctene oxide, cyclodecene oxide, cyclododecene oxide, alkyloxirane, styrene oxide, norbornene oxide, aziridine, azirine, thiirane, azetidine, azolidine, thiazolidine, 1,3-dithiane, etc. Cyclic compounds that may have heteroatoms, aromatic compounds and aromatic diazones that have increased nucleophilicity due to having an electron-withdrawing group Salts, heterocyclic compounds, for example, indanone, cyclopentanone, γ-butyrolactone, mevalonolactone, bromoacetone, benzenesulfonic acid, naphthalenesulfonic acid, thiobenzoic acid, methyl thiobenzoate, acrylic acid, methyl acrylate, methacrylic acid Acids, methyl methacrylate and trichloropyrimidine. Further, there are alcohols, saccharides, glycosides, monosaccharide anhydrides, oligosaccharides and polysaccharides having a hydroxyl group as a functional group, such as allyl alcohol, allyl veratrol, citronellal, α-D-glucopyranose, β-D -Fructofuranose, α-D-xylo-hexopyranose-4-ulose, β-D-glucopinaluronic acid and the like. Other examples include propylene, butene, tolan, acetylenes, and cage-like hydrocarbons such as fullerenes having an unsaturated bond. These may have a plurality of other functional groups.
The other functional groups include, for example, primary, secondary, and tertiary single or plural hydroxyl groups, thiol groups, formyl groups, carbonyl groups, carbonyloxy groups, alkyloxycarbonyl groups, cyano groups, sulfonyl groups, Alkyl sulfonyl group, sulfenyl group, thiocarbonyl group, nitro group, amino group, diazo group, etc., but not limited to organic compounds, inorganic compounds or materials having the functional groups introduced on the surface of polymer, or the like. It is also applicable to organic-inorganic hybrid materials. Of course, the invention is not limited only to these specific examples.
[0011]
The fluorinating agent is generally usable as a fluorinating reagent, and any fluorinated compound having no risk of thermal runaway can be used. Preferred is a pyridine-HF complex, a melamine-HF complex, an alkyl HF-bases such as amine-HF complexes. Among them, triethylamine-3HF, which is a triethylamine-nHF complex (n is usually an integer), is particularly preferable because it can be distilled, has no corrosive property, and can be easily handled such that a glass container can be used.
In addition to the fluorinating agent, a reactant can be co-present for the purpose of accelerating the reaction. For example, in gem-difluorination of 1,3-dithiane or the like, NBS, DBH, sulfur chloride or the like is used, and in halofluorination of olefin or alkyne or fluorosulfenylation, a sulfuryl compound is used together with an HF-base.
[0012]
The reaction can be performed in a batch system, a semi-batch system, or a continuous system. For example, a microwave is applied to a normal batch reactor to shield the microwave from leaking and causing trouble. Just good. For this purpose, a microwave oven is suitable, and a commercially available oven for chemical synthesis can also be used. The frequency of the microwave used for irradiation may be in the range of 0.3 to 300 GHz, and usually 1 to 30 GHz is preferable. However, it is preferable to use a millimeter wave of 30 to 300 GHz or an electromagnetic wave in a range of 0.3 to less than 1 GHz. Can also be. Irradiation can be appropriately selected such as a method of continuously or intermittently controlling the temperature.
In most cases, the irradiation time is shorter than that of the thermal reaction, and the reaction is preferably performed in 0.1 to 60 minutes. Particularly preferred irradiation times are from 1 minute to 30 minutes. However, long-time microwave irradiation can be performed if necessary.
The reaction temperature can be carried out within a stable range of the substrate, the fluorinating agent, and the reaction product. Usually, the temperature is preferably in the range of about room temperature of about 25 ° C. to 300 ° C. Similarly, the temperature can be controlled in the temperature range from room temperature to 200 ° C.
[0013]
The amount of the fluorinated compound to be used is preferably 1 mol or more per 1 mol of the functional group to be used as the substrate, but the reaction may be carried out in excess or stoichiometrically insufficient.
It is not necessary to use a solvent for the progress of the fluorination reaction, but a solvent may be used for sufficiently stirring and preventing a rise in temperature. Preferred solvents are aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, aromatic halogenated hydrocarbons, nitriles, ethers, etc., which are inert to the substrate, fluorine compounds and products. Can be selected from
After the microwave irradiation is completed, it goes without saying that the reaction product may be separated by performing post-treatment, extraction, distillation, filtration, and the like in the same manner as in a normal thermal reaction.
[0014]
【Example】
Hereinafter, the present invention will be specifically described with reference to Examples, Reference Examples, and Comparative Examples, but the present invention is not limited to these Examples.
The fluorination reaction was carried out in a microwave oven (width, depth 55 cm, height 70 cm, output 1 KW, frequency 2.46 GHz) in a microwave oven capable of continuous and uniform irradiation by a pyramid-type distributor, with 5 ml of reflux condenser equipped. A reactor made of a fluororesin (PFA) was installed.
[0015]
Example 1
Cyclohexene oxide (1 mmol: 0.1 g) as a substrate and triethylamine-3HF (0.6 mmol: 0.1 g) as a fluorinating agent were added, and microwaves were irradiated for 2 minutes without stirring. After the completion of the microwave irradiation, the mixture was cooled to room temperature, the reaction product was poured into 15 ml of water, and extracted three times with 15 ml of diethyl ether. The extract was neutralized with an aqueous solution of sodium bicarbonate, dried by adding an appropriate amount of anhydrous potassium carbonate. After removing the solvent under reduced pressure, the residue was purified by column chromatography (Hexane: Et ₂ O = 1: 1). As a product, trans-2-fluorocyclohexanol was obtained in a yield of 71% (purity of 98% or more).
[0016]
Comparative Example 1
Example 1 was carried out in the same manner as in Example 1 except that microwave irradiation was not performed and the reaction temperature was 115 ° C for 4 hours. The yield of the product, trans-2-Fluorocyclohexanol, was 61%.
[0017]
Example 2
Using the same apparatus as in Example 1, cyclododecene oxide (1 mmol: 0.17 g, isomer ratio = 31: 69) and Et ₃ N-3HF (0.6 mmol: 0.1 g) were added, and micro The procedure was performed in the same manner as in Example 1 except that the waves were irradiated for 10 minutes. 2-Fluorocyclododecanol was obtained as a product in a yield of 76%.
[0018]
Comparative Example 2
Example 2 was carried out in the same manner as in Example 2, except that the reaction was carried out at 155 ° C for 4 hours without irradiation with microwaves. The yield of the product, 2-Fluorocyclododecanol, was 54%.
[0019]
Example 3
Using the same apparatus as in Example 1, cyclooctene oxide (1 mmol) and Et ₃ N-3HF (1 mmol) were added, and irradiation was performed for 10 minutes with microwaves. Trans-2-Fluorocyclotanol was obtained as a product in a yield of 68%.
[0020]
Comparative Example 3
Example 3 was carried out in the same manner as in Example 3, except that the reaction was carried out at 155 ° C for 4 hours without irradiation with microwaves. The yield of the product, trans-2-Fluorocyclotanol, was 54%.
[0021]
Example 4
Put cyclododecane-1,4,8-triene monoxide (1 mmol) and _Et 3 N-3HF the (1 mmol) as a substrate, except that microwave irradiation for 2 minutes was performed in the same manner as in Example 1. 2-Fluorocyclodecane-6,10-diene-1-ol was obtained as a product in a yield of 78%.
[0022]
Comparative Example 4
Example 4 was carried out in the same manner as in Example 4 except that the reaction was carried out at 155 ° C for 4 hours without microwave irradiation. The yield of the product, 2-Fluorocyclododecane-6,10-diene-1-ol, was 51%.
[0023]
Example 5-12 and Comparative Example 5-12
Table 1 summarizes and describes comparative examples of a fluorination reaction under microwave irradiation (Example) and a thermal reaction.
[0024]
[Table 1]

[0025]
Example 13
Using PFA-made reaction vessel of 10ml In Example 1, 3-phenylpropyl put methylsulfonate (1 mmol) and _{Et 3 N-3HF (1.2mmol)} , except that microwave irradiation for 2 minutes real The same was done. 1-Fluoro-3-phenirurupropane was obtained as a product in a yield of 80%.
[0026]
Comparative Example 13
In Example 13, 3-phenylpropyl methyl sulfonate and (1mmol) _Et 3 N-3HF a (10 mmol), acetonitrile in a solvent (1 ml), subjected to 100 hours at 80 ° C., examine the yield of the product Was. The yields of 1-Fluoro-3-phenipropane were as follows.
Yield after 10 hours 12% Yield after 20 hours 20%
Yield after 38 hours 44% Yield after 54 hours 74%
Yield after 79 hours 80% Yield after 100 hours 80%
[0027]
【The invention's effect】
As is clear from the above detailed description and specific examples by examples, according to the present invention, various kinds of HF-base complexes which are stable and practically non-corrosive like triethylamine-3HF can be used. A substrate, or various fluorination reactions, for example, a compound having a hydrogen atom activated by a substituent at the α-position, β-position, or γ-position, a silyl ether compound, or as a functional group, an unsaturated group, a hydroxyl group, Ring-opening fluorination to various substrates such as compounds having a halogeno group, an amino group, or a diazonium group, or a three-membered or more multi-membered ring compound which may have a heteroatom, halofluorination of an unsaturated compound, or fluoro Sulfenylation, halogen-fluorine exchange, dediazofluorination, gem-difluorination of 1,3-dithiolane and hydrazones, or silyl ethere The deprotection reaction of classes, a short time efficiently proceed is to it can under mild conditions as compared with the case of the thermal reaction.

Claims (6)

A method of fluorinating a substrate under irradiation of microwaves and / or electromagnetic waves in the vicinity of microwaves in the presence of a substrate and a fluorinating agent or, if necessary, a reactant. The method according to claim 1, wherein the fluorinating agent is a complex compound comprising HF and a base. When the substrate is a compound having a hydrogen atom activated by a substituent at the α-position, the β-position or the γ-position, a silyl ether compound, or a functional group, the substrate may be an unsaturated group, a hydroxyl group, a halogeno group, an amino group, a diazo group, 3. The method according to claim 1, wherein the compound is a compound having a triazeno group or an isocyano group, or a multi-membered ring compound having three or more ring members which may have a hetero atom. The method according to any one of claims 1 to 3, wherein the substrate may contain a saccharide, a cyclopropane ring, an oxirane ring, an aziridine ring, an azirine ring, or a 1,3-dithiane ring. 5. The method according to claim 1, wherein the fluorinating agent is a trialkylamine-HF complex. 5. The method according to claim 1, wherein the fluorinating agent is a triethylamine-3HF complex.