JPH0586768B2 - - Google Patents

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to carbonyl compounds having a fluorine atom at the α-position or α, β carbonyl compounds having a fluorine atom at the γ-position.
-Regarding a method for producing an unsaturated carbonyl compound. The above-mentioned carbonyl compounds having a fluorine atom are known to be agricultural chemicals, pharmaceuticals, or useful intermediates for their production. Among them, fluorine-containing steroid compounds with a fluorine-substituted carbonyl structure are known to have excellent pharmacological effects such as anti-inflammatory, mineral metabolism, and sugar metabolism [Nobuo Ishikawa, Yoshiro Kobayashi, “ Fluorine Compounds - Their Chemistry and Applications, Kodansha Scientific, pp202
-232 (1979); R&D Report No. 6, “Chemistry and Industry of Fluorine Compounds”, CMC (1977), pp415-473; Enryoka, 42 , 794 (1984); Aryoka, 43 , 1073 (1985);
JP-A-60-6700; JP-A-59-139398;
See Tetrahedron Lett, 21 , 3591, 3593 (1980)]. [Prior Art] Generally, the following fluorine sources are known for producing carbonyl or α,β-unsaturated carbonyl compounds having a fluorine atom at the α- or γ-position. (1) F ₂ [See J.Org Chem, 47 , 1107 (1982)] (2) The following fluorinating agent XeF ₂ [For example, J.Chem.Soc.Chem.Comm,
1980, 759] CF ₃ OF [e.g. J.Am.Chem.Soc., 102 , 4845
(1980)] CF ₃ CF ₂ OF [See Tetrahedron Lett, 725 (1979)] FClO ₃ [For example, Chem.Ber., 102 , 1944 (1969)]
Reference] CF ₃ COOF [J.Fluorine Chem., 16 , 19 (1980)
Reference] CH ₃ COOF [Synthesis, 665?1985] Reference] ArSO ₂ NFR [J.Am.Chem.Soc., 106 , 452
(1984)] 1-Fluoro-2-pyridone [J.Org.Chem.,
48, 761 (1983)] (3) F-containing salts such as KF and AgF [for example, J.Chem.Soc.3786 (1953), J.Am
Chem Soc, 78 , 2658 (1956)] (4) Fluoroolefins such as trifluoroethylene and hexafluoropropene [Chem.Lett.
1980, 1107, 1981 , 107] [Problems to be solved by the invention] However, the method (1) using F ₂ is difficult to control due to the intense reactivity of F ₂ , and the range of use is extremely limited. , In the method (2) using a fluorinated reagent, expensive reagents are used, highly explosive or toxic reagents are used, and unstable reagents are used, so for example, extremely low temperatures are required for the reaction. It has drawbacks such as difficulty in synthesizing the fluorination reagent and low yield or selectivity of the fluorination reaction. In addition, in method (3), since F cannot replace a hydrogen atom, the carbonyl compound must be converted into a compound with a leaving group that can replace F, which limits the range of use. Furthermore, in the reaction with F, not only the desired substitution reaction but also an elimination reaction, which is a side reaction, occurs [for example, J.Fluorine Chem., 27 , 35
(1985)]. Furthermore, silver salt is expensive. Method (4) is a method for producing α-fluoro-β-ketoester and fluoromalonic acid diester using fluoroolefin as a key intermediate, but this method requires expensive raw materials and a large number of reaction steps. As described above, both methods are insufficient as industrial production methods. The present inventors conducted intensive research to overcome these drawbacks, and as a result, they discovered an excellent fluorination reaction that is completely different from conventional reactions and completed the present invention. ^[ Means for Solving the Problems] The production method of the present invention is based on ^the general ^formula :
R ¹¹ , R ¹² , and R ¹³ are an alkyl group, an aryl group,
an alkoxy group, an aryloxy group, or a halogen atom, which may have a cyclic structure with or without intervening hetero atoms in various combinations), R ¹
is a hydrogen atom, an alkyl group, an alkoxy group, or a trialkylsilyloxy group, R ² and R ³ are a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an acyl group, or an alkoxycarbonyl group, R ⁴ and R ⁵ is a hydrogen atom or an alkyl group,
n is 0 or 1. R ¹ , R ² , R ³ , R ⁴ and R ⁵ may form a cyclic structure in various combinations with or without intervening hetero atoms. ^{] An} enol compound ^represented by ^{the general} formula
Alkyl group, aryl group, alkoxy group, hydroxy group, aryloxy group, acyl group, acyloxy group, acylthio group, nitro group, cyano group, alkenyl group, alkynyl group, alkoxycarbonyl group, aryloxycarbonyl group, amide group,
It is a carbamoyl group, an alkylsulfonyl group, an arylsulfonyl group, an alkoxysulfonyl group, an aryloxysulfonyl group, an alkanesulfonyloxy group, an arenesulfonyloxy group, or a halogen atom, and X ^- is a conjugate base of Bronsted acid. R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ may have a cyclic structure in various combinations with or without intervening hetero atoms. Also, X ^- is R ⁶ , R ⁷ , R ⁸ ,
It may be bonded to R ⁹ and R ¹⁰ in various combinations with or without intervening heteroatoms. ), characterized in that it is reacted with an N-fluoropyridinium salt represented by the general formula: (wherein R ¹ , R ² , R ₃ , R ⁴ and R ⁵ have the same meanings as above). ) A fluorine-substituted carbonyl compound represented by the following formula is produced. Compounds represented by the general formula () in which M is a hydrogen atom are readily available or can be easily produced, and compounds in which M is other than a hydrogen atom are generally produced by the following method. (1) When M is SiR ¹¹ R ¹² R ¹³ . The corresponding carbonyl compound [the above general formula (), M=H] is ClSiR ¹¹ R ¹² R ¹³ in the presence of a base.
Or treatment with CF ₃ SO ₂ CSiR ¹¹ R ¹² R ¹³ [J.
Org.Chem., 34 , 2324 (1969); Synthesis,
1976, 259] (2) When M is an acyl group. The corresponding carbonyl compound as an acid anhydride or
- Method of treatment with acyloxy-1-propene etc. [Fieser & Fieser, “Reagents for
Organic Synthesis, “John Wiley and Sons,”
Inc., Vol 1, pp524-526 (1967)] (3) When M is an alkyl group or an aryl group. A method in which the corresponding carbonyl compound is treated with an orthoacid ester, etc. It is well known that the compound represented by the above general formula () in which M is a hydrogen atom is in a state of ketoenol equilibrium as shown in the following formula [HOHouse, “Modern Synthetic
Reactions”2nd., WABenjamin, Inc.
California (1972), pp. 492-497]. [Chemical formula] Examples of the enol compound represented by the general formula () include 2-trimethylsilyloxy-2-dodecene, 2-methoxy-2-dodecene, 2-trimethylsilyloxy-1-phenyl-1
-Propene, 2-trimethylsilyloxy-1,3-butadiene, 1-phenyl-3-trimethylsilyloxy-
1,3-butadiene, 2-trimethylsilyloxy-3,3-dimethyl-1-butene, 1-trimethylsilyloxy-1-cyclohexene, 1-trimethylsilyloxy-1-cyclopentene, 1-triethylsilyloxy-1-cyclohexene, 1 -dimethyl-t-butylsilyloxy-1-cyclohexene, 1-dimethylphenylsilyloxy-1-cyclohexene, 1-chlorodiphenylsilyloxy-1-cyclohexene, 1-triethoxysilyloxy-1-cyclohexene, 1- Methoxy-1-cyclohexene, 1-phenoxy-1-cyclohexene, 1-acetyloxy-1-cyclohexene, 1-propionyloxy-1-cyclohexene, 1-formyloxy-1-cyclohexene, 1-trimethylsilyloxy-1-cycloocta sen, 1-methoxy-1-cyclononene, 1-methoxy-1-cyclodecene, phenylacetone, acetylacetone, benzoylacetic acid ethyl ester, formyl acetone, acetoacetic acid methyl ester, 2-methylacetoacetic acid ethyl ester, 3-trimethylsilyloxy-2 , 3-dimethyl-2-butenoic acid methyl ester, 3-trimethylsilyloxy-3-methoxy-2
-Propenoic acid methyl ester, 2-methoxycarbonylcyclopentanone, 2-methyl-cyclopentane-1,3-dione, 2-fluoroacetylacetone, 2-chloroacetylacetone, 1-trimethylsilyloxy-1-ethoxyethene, 1-trimethylsilyl Oxy-1-methoxy-1
-octene, 1,1-bis(trimethylsilyloxy)-2-
Phenylethene, 1,1-bis(trimethylsilyloxy)-2-
(p-isobutylphenyl)ethene, 1,1-bis(trimethylsilyloxy)-2-
(p-cyclohexylphenyl)ethene, 1-trimethylsilyloxy-1-methoxy-2
-(p-chlorophenyl)ethene, 1-trimethylsilyloxy-1-methoxy-2
-(α-thienyl)ethene, 1-trimethylsilyloxy-1-ethoxy-2
-(α-furyl)ethene, 1-trimethylsilyloxy-1-methoxy-2
-(β-naphthyl)ethene, 1-trimethylsilyloxy-1-methoxy-2
-(α-N-methylpyrrolyl)ethene, oxalacetic acid diethyl ester, phenylpyruvic acid, phenylpyridic acid methyl ester, 2-phenylacetylacetic acid methyl ester, 2-phenyl-3-trimethylsilyloxy-3
-Methoxypropenoic acid ethyl ester, 2-(p-methoxyphenyl)malonic acid diethyl ester, 5,5-dimethylcyclohexane-1,3-dione, 2-trimethylsilyloxy-1,4-dihydronaphthalene, 2-allylacetoacetic acid Methyl ester, 2-formylcyclohexanone, α-acetyl-δ-lactone, 2-benzoyl-6,6-dimethylcyclohexanone, 2-acetylmalonic acid diethyl ester, 2-trimethylsilyloxy-1,3-cyclohexadiene, 6-trimethylsilyl Oxy-N,N-dimethyluracil, 6-oxouracil, 2-trimethylsilyloxy-4,5-dihydrofuran, 2-(trimethylsilyloxy)furan, 2-acetyloxy-4,5-dihydrofuran, 6-trimethylsilyloxy −2H, 3H, 4H−
Examples include pyran, [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] On the other hand, the N-fluoropyridinium salt represented by the general formula () can be prepared by reacting pyridine with F ₂ [Z.Chem., 5 , 64 (1965)], or by reacting pyridine or a pyridine derivative with F ₂ and M″X (M″ is a hydrogen atom,
It is a metal atom, an ammonium residue, a pyridinium residue, or SiR ¹¹ R ¹² R ¹³ . ) or Lewis acid (see Japanese Patent Application No. 118882/1982). Examples of the N-fluoropyridinium salt represented by the general formula () include [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [C] [Formula] [Formula] [Formula] (n is an integer) [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] The reaction of the present invention is preferably carried out in a solvent, and examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and cycloethane, ethers such as diethyl ether, tetrahydrofuran (THF), and dimethoxyethane; Hydrocarbons such as hexane, pentane, toluene, etc., acetonitrile, etc., or a mixed solvent thereof can be used. The reaction temperature can be selected from -100℃ to 150℃, but in order for the reaction to proceed efficiently, -80℃ to +100℃ is recommended.
°C is preferred. In the reaction between the enol compound represented by the above general formula () and the N-fluoropyridinium salt represented by the above general formula (), when M is an alkyl group or an aryl group, the target product in the above general formula () is In order to obtain the expressed fluorine-substituted carbonyl compound in good yield, it is preferable to subsequently perform hydrolysis. One of the advantages of the present invention is the selectivity of the reaction. As shown in Examples 18 and 19 below, when there are two or more reaction points in the same molecule, it is possible to cause a reaction to occur with only one reaction point by setting the reaction conditions. Reaction selectivity is an important point in synthesizing complex compounds with many reactive sites, and the higher the reaction selectivity, the more beneficial the reaction is. Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples. Reference Example 1 [Chemical] A solution of 10 g (0.126 mol) of pyridine in 100 ml of anhydrous acetonitrile was cooled to -40°C and diluted to 10% with nitrogen gas while stirring vigorously.
A flow rate of ml/min was introduced. The total amount of fluorine introduced was 0.18 mol. Then add 22g (0.128mol) of sodium trifluoromethanesulfonate,
Stirred at -40°C for 5 hours. Thereafter, the generated sodium fluoride was filtered off, the solvent was distilled off, and the residue was crystallized using methylene chloride to obtain 17.5 g of N-fluoropyridinium trifluoromethanesulfonate (71
%)Obtained. Recrystallization was performed using methylene chloride-acetonitrile. The physical property values are shown in Table 1. Reference example 2 [Chemical formula] 2,4,6-trimethylpyridine 0.57g
(4.67 mmol) and 0.803 g (4.67 mmol) of sodium trifluoromethanesulfonate were dissolved in 20 ml of anhydrous acetonitrile, and while cooling to -40°C and stirring vigorously, fluorine gas diluted to 10% with nitrogen gas was added at a rate of 30 ml/min. It was introduced at a flow rate. The amount of fluorine gas introduced was 8.93 mmol. After the reaction, the produced sodium fluoride was filtered off, the solvent was distilled off, and the crystallization was performed using acetonitrile-diethyl ether to obtain 1.11 N-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate.
g (82%) was obtained. The physical property values are shown in Table 1. Reference Examples 3 to 10 Perform the same operation as Reference Example 2, and obtain N shown in Table 1.
-Fluoropyridinium salts were obtained in yields of 51-87%. The physical property values are shown in Table 1. Reference Example 9 uses 2-l-menthoxypyridine [optical rotation [α] ²⁰ _D = -110.7 (C =
0.994)], N-fluoro-2-l produced using
The optical rotation of -menthoxypyridinium trifluoromethanesulfonate was [α] ²⁵ _D = -77.73 (C = 4.16, CHCl ₃ ). Reference example 11 [chemical formula] 2,4,6-trimethylpyridine 0.605g
(5 mmol) in 10 ml of anhydrous acetonitrile at -40
A mixed gas of fluorine and nitrogen (1:9) was introduced at a flow rate of 40 ml/min while stirring vigorously while cooling to .degree.
The total amount of fluorine introduced was 15 mmol. Then add 0.5ml of fluorosulfonic acid at the same temperature.
(8.7 mmol) was added and stirred for 10 minutes. After the reaction, 20 ml of diethyl ether was added for crystallization to obtain 0.665 g (56%) of N-fluoro-2,4,6-trimethylpyridinium fluorosulfonate as white crystals. The physical property values are shown in Table 1. [Table] [Table] [Table] Example 1 [Chemical formula] N-fluoropyridinium trifluoromethanesulfonate 249 mg under argon atmosphere
(1 mmol) in dry methylene chloride suspension (4 ml)
, trimethylsiloxycyclohexene 170mg
(1 mmol) was added dropwise, and the mixture was stirred at room temperature for 7 hours. Chlorobenzene was added to the reaction mixture as an internal standard, and the yield of 2-fluorocyclohexanone was 87% as determined by gas chromatography. The reaction mixture was poured into water, extracted with ether, the ether layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting crude product was purified by gas chromatography to determine the structure of 2-fluorocyclohexanone. Confirmed from spectrum. The NMR data is shown below. ¹ H−nmr (CDCl ₃ ) δ; 1.55−2.80 (m, 8H),
4.90 (d, m, J=50Hz, 1H): ¹⁹ F−nmr
( _CDCl3 ) ppm; +188.0 (d, J = 50Hz). Examples 2 to 23 In the same manner as in Example 1, an enol compound and an N-fluoropyridinium salt were reacted under the conditions shown in Table 2. The results are shown in Table 2 along with Example 1.
It was shown to. Note that the yields described in Examples 10 to 23 are isolated yields by silica gel column chromatography. Moreover, the yields of Examples 12 and 13 are the yields obtained by treating the obtained product with diazomethane, purifying it, and isolating it as a methyl ester. [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] Example 24 [Chemical] Under an argon atmosphere, N-fluoropyridinium trifluoromethane sulfonate Nato 250mg
(1.01 mmol) in dry methylene chloride suspension (4 ml)
, 1-methoxycyclohexene 113mg
(1.01 mmol) was added dropwise and heated under reflux for 0.5 hour. Thereafter, 0.05 ml of water was added to the mixture and stirred at room temperature for about 4 hours, and 2-fluorocyclohexanone was obtained in a yield of 60% (gas chromatography yield).

Claims (1)

[Claims] 1. A compound represented by the general formula [Formula], characterized in that an enol compound represented by the general formula [Formula] and an N-fluoropyridinium salt represented by the general formula [Formula] are reacted. Method for producing a substituted carbonyl compound [wherein M is a hydrogen atom, an alkyl group, an aryl group, an acyl group, or SiR ¹¹ R ¹² R ¹³ (R ¹¹ ,
R ¹² and R ¹³ are an alkyl group, an aryl group, an alkoxy group, an aryloxy group, an acyloxy group, or a halogen atom, and may form a cyclic structure in various combinations with or without intervening hetero atoms. ), R ¹ is a hydrogen atom, an alkyl group, an alkoxy group or a trialkylsilyloxy group,
R ² and R ³ are a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an acyl group, or an alkoxycarbonyl group, R ⁴ and R ⁵ are a hydrogen atom or an alkyl group, and n is 0 or 1. ^R1 , ^R2 , ^R3 ,
R ⁴ and R ⁵ may form a cyclic structure in various combinations with or without intervening hetero atoms.
R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are hydrogen atoms, alkyl groups, aryl groups, alkoxy groups, hydroxy groups,
Aryloxy group, acyl group, acyloxy group,
Acylthio group, nitro group, cyano group, alkenyl group, alkynyl group, alkoxycarbonyl group, aryloxycarbonyl group, amide group, carbamoyl group, alkylsulfonyl group, arylsulfonyl group, alkoxysulfonyl group, aryloxysulfonyl group, alkanesulfonyloxy basis,
It is an arenesulfonyloxy group or a halogen atom, and X ^- is a conjugate base of Bronsted acid.
R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ may have a cyclic structure in various combinations with or without intervening hetero atoms. Also, X ^- is R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰
may be bonded with or without intervening heteroatoms in various combinations. ].