JPH0967312A - Asymmetric cyclopropane formation reaction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optically active cyclopropane compound by using a specific optically active cobalt complex as a catalyst and subjecting ad olefin compound and a diazo-acetic ester compound to an asymmetric cyclopropane formation reaction, useful as an intermediate for a medicine, an agrochemical, etc. SOLUTION: (B) A compound of formula II [Z<1> to Z<4> are each H, a halogen, a 1-4C alkyl, phenyl (substituted with a halogen, a 1-4C alkyl, etc.) and (C) a compound of the formula N2 CHCOOZ<5> (Z<5> is a 1-8C alkyl) are subjected to asymmetric cyclopropane formation reaction in the presence of (A) a complex compound of formula I [R<1> to R<4> are each H, a halogen, a 1-4C alkyl, phenyl (substituted with a halogen, a 1-4C alkyl, etc.; Y<1> to Y<4> are each as shown for R<1> to R<4> , naphthyl (substituted with a halogen, a 1-4C alkyl, etc.), an anthracene group (substituted with a halogen, a 1-4C alkyl, etc.), etc.; X is an anion pair] as a catalyst to give the objective compound of formula III (* is asymmetric carbon atom).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active cyclopropane compound, which is an important intermediate for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art Optically active cyclopropane compounds are important intermediates for various physiologically active substances such as pharmaceuticals and agricultural chemicals, and particularly as a synthetic intermediate for pyrethroid insecticides and β-lactam antibiotics. well known. As a method for directly synthesizing such an optically active cyclopropane compound from a prochiral olefin, an asymmetric cyclopropanation reaction using an optically active transition metal complex as a catalyst is known.

For example, Synlett 638 (1993) describes an asymmetric cyclopropanation reaction using a copper complex by J. Am. Chem. S.
oc. 113, 1423 (1991), J. Am. Chem. Soc. 116, 222 describes an asymmetric cyclopropanation reaction using a rhodium complex.
3 (1994) reported asymmetric cyclopropanation reactions using ruthenium complexes, which are all excellent methods.

Further, J. Am. Chem. Soc. 100, 3443 (1978)
Reported an asymmetric cyclopropanation reaction using a cobalt complex.

[0005]

However, the transition metal complex used in the above-mentioned asymmetric cyclopropanation reaction is still under various improvements, and it is more excellent in view of catalyst performance and economical efficiency. The present situation is that active research and development of optically active transition metal complex catalysts is being actively conducted. Also, J. A
m. Chem. Soc. 100, 3443 (1978) optically active salen (2
Compound produced by condensation reaction of one molecule of salicylaldehyde derivative and one molecule of ethylenediamine derivative) Asymmetric yield of asymmetric cyclopropanation reaction by cobalt complex is 5
% Ee or less, which is not practical at all.

[0006]

Means for Solving the Problems The present inventor has completed the present invention as a result of extensive studies on the asymmetric cyclopropanation reaction. That is, in the present invention, an optically active salen cobalt complex is used as a catalyst when an optically active cyclopropane compound is produced by reacting an olefin compound with a diazoacetic acid ester compound to carry out a catalytic asymmetric cyclopropanation reaction. And a method for producing an optically active cyclopropane compound.

Further, in more detail, the formula (1)

[0008]

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[Wherein Z¹, Z², Z^ThreeAnd Z^FourAre each
Independently, hydrogen atom, halogen atom, C₁~ C_FourAlkyl
Group, phenyl group (the phenyl group is a halogen atom, C₁
~ C_FourAlkyl group, C₁~ C_FourAlkoxy group, cyano group or
May be substituted with a nitro group. ), Naphthyl group
(The naphthyl group is a halogen atom, C₁~ C_FourAlkyl
Group, C ₁~ C_FourSet with an alkoxy group, cyano group or nitro group
It may be replaced. ), C₁~ C_FourAlkoxy group, C₂
~ C_FiveAlkylcarbonyloxy group, C₂~ C_FiveAlkano
Il group, C₂~ C_FiveAlkoxycarbonyl group, nitro group or
Means a cyano group. ] Olefin compounds represented by
Thing and formula (2)

[0010]

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[In the formula, Z ⁵ means a C ₁ -C ₈ alkyl group. ] By the asymmetric cyclopropanation reaction with a diazoacetic acid ester compound represented by the formula (3)

[0012]

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[In the formula, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are the same as defined above. The absolute configuration of the carbon atom indicated by * means R or S. ] When producing an optically active cyclopropane compound represented by the formula (4)

[0014]

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[In the formula, R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a C ₁ -C ₄ alkyl group, a phenyl group (the phenyl group is a halogen atom, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, cyano group or nitro group may be substituted), and any two of them together form a C ₄ -C ₈ ring. May be. Y ¹ ,
Y ² , Y ³ and Y ⁴ are each independently a hydrogen atom, C ₁ to
C ₄ alkyl group, phenyl group (the phenyl group includes a halogen atom, a C _{1 to} C ₄ alkyl group, a C _{1 to} C ₄ alkoxy group,
It may be substituted with a cyano group or a nitro group. ), A naphthyl group (the naphthyl group may be substituted with a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a cyano group or a nitro group), an anthracene group (the anthracene group). Is a halogen atom, a C ₁ -C ₄ alkyl group,
It may be substituted with a C ₁ -C ₄ alkoxy group, a cyano group or a nitro group. ), And any two of them may together form a C _{4 to} C ₈ ring, or may form a condensed ring such as a naphthyl ring.

[0016] X ^- is meant an anion pair which may form salts. ] It is related with the manufacturing method of the optically active cyclopropane compound characterized by using the optically active cobalt complex compound represented by these.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The substituents of the formulas (1) to (4) will be described below. As the halogen atom, fluorine,
Examples thereof include chlorine, bromine and iodine atoms. The C ₁ -C ₄ alkyl group, a methyl group, an ethyl group, n- propyl group, i
-Propyl group, n-butyl group, i-butyl group, sec-
Examples thereof include a butyl group.

Examples of the C ₁ -C ₄ alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group and a sec-butoxy group. The C ₂ -C ₅ alkylcarbonyloxy group, a methyl carbonyloxy group, ethyl carbonyloxy group, n- propyl carbonyloxy group, i
-Propylcarbonyloxy group, n-butylcarbonyloxy group, i-butylcarbonyloxy group, sec-butylcarbonyloxy group and the like.

The C ₂ -C ₅ alkanoyl group includes an acyl group, an ethylcarbonyl group, an n-propylcarbonyl group,
i-propylcarbonyl group, n-butylcarbonyl group,
Examples thereof include i-butylcarbonyl group and sec-butylcarbonyl group. Examples of the C _{2 to} C ₅ alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group,
Examples thereof include an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group and a sec-butoxycarbonyl group.

As the C ₁ -C ₈ alkyl group, a methyl group,
Ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, pentyl group,
Hexyl group, heptyl group, octyl group and the like can be mentioned.
X ^- is ^{the, OH -, F -, Br} -, I -, CH 3 CO 2 -, PF 6 -, ClO 4
^{_{-, BF 4 -, CO 3}} 2-, SO 4 2-, PO 4 3- , and the like. Of the present invention,
As the optically active cobalt complex compound of the formula (4),

[0021]

[Chemical 12]

And the like, and their enantiomers. Next, a specific method of the asymmetric cyclopropanation reaction will be described. In the reaction, the optically active cobalt complex compound of the formula (4) is used as a catalyst in the absence of a solvent or in the presence of a suitable solvent, and the olefin compound of the formula (1) is reacted with the diazoacetic acid ester compound of the formula (2). It is a thing.

The amount of the olefin of the formula (1) used is
1-10 with respect to the diazoacetic acid ester compound of formula (2)
The molar ratio is preferably 1 to 5 mol times. The amount of the optically active cobalt complex of the formula (4) to be used is usually 0.1 mol% to 5 with respect to the diazoacetic acid ester compound of the formula (2).
Mol% range. The reaction solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane and carbon tetrachloride, tetrahydrofuran, diethyl ether, t-butyl methyl ether, dimethoxyethane and the like. Ethers, methanol, ethanol, 1-propanol, 2-
Alcohols such as propanol, 1-butanol, 2-butanol, isobutanol and cyclohexanol, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, chlorobenzene and o-dichlorobenzene, n
-Hexane, cyclohexane, n-octane, n-decane and other aliphatic hydrocarbons, methyl acetate, ethyl acetate, butyl acetate and other esters, acetonitrile, butyronitrile and other nitriles, N, N-dimethylformamide,
Examples thereof include amides such as N, N-dimethylacetamide and N-methylpyrrolidone, and ureas such as 1,3-dimethylimidazolidinone and tetramethylurea.

These can be used alone or in combination. The reaction temperature is usually in the range of -50 ° C to 50 ° C, preferably -25 ° C to 25 ° C. After completion of the reaction, the target optically active cyclopropane compound can be isolated by concentrating an organic solvent or the like under reduced pressure and separating by silica gel chromatography or distillation.

The optical purity of the obtained optically active cyclopropane compound can be analyzed as it is or after converting it into a derivative by an optically active chromatography column or optical rotation.

[0026]

The present invention will be described in more detail with reference to the following examples.
The present invention is not limited to these. Example 1

[0027]

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Salen cobalt (II) complex 2 synthesized from Schiff Base 1 and cobalt acetate 2.0 mg (4.2 μm)
mol) in 0.5 ml of dichloromethane, 17 μl of iodine in dichloromethane (0.12 M, 2.1 μm)
ol) was added and stirred for 2 hours to synthesize optically active salen cobalt (III) complex 3 . Add styrene 49 to this solution.
μl (0.42 mmol) and 8.5 μl (0.50 M, 4.2 μmol) of a dichloromethane solution of methanol were added and stirred for 10 minutes. Furthermore, 150 μl of a dichloromethane solution of diazoacetic acid t-butyl ester (0.57 M,
85 μmol) was added to the above mixture and stirred for 24 hours at room temperature.

After the reaction, the mixture was concentrated, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1/0 to 9/1) and t-butyl 4 -phenylcyclopropane-1-carboxylate 4 17.1 mg
(Yield 69%, trans / cis = 96/4) was obtained. Furthermore, only the trans form was purified by preparative TLC (silica gel, hexane / diisopropyl ether = 4/1),
The asymmetric yield was calculated by reducing the ester moiety to the corresponding alcohol with LiAlH ₄ .

Asymmetric yield: 74% ee. Absolute coordination: (1R,
2S) [DAICEL CHIRALCEL OJ, hexane / isopropanol = 9/1].

[0031]

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Examples 2 to 3 As in Example 1, the following table shows the results of asymmetric cyclopropanation reaction of various olefin compounds using the optically active cobalt complex 3 . ────────────────────────────── Example olefin yield cis: trans asymmetric yield Compound %% ee ──── ────────────────────────── 2 4-chlorostyrene 67 94: 6 71 3 2 naphthylethylene 66 88:12 70 ──────── ──────────────────────── Example 4 to 6 As in Example 1, styrene was used as an optically active cobalt complex 5 to 7 as a catalyst. The following table shows the results of the asymmetric cyclopropanation reaction using the same.

─────────────────────────────────── Example Catalyst yield cis: trans asymmetric yield Absolute configuration %% ee─────────────────────────────────── 4 5 73 94: 6 69 (1S, 2S) 5 6 76 98: 2 73 (1S, 2S) 6 7 76 95: 5 75 (1S, 2S) ───────────────────────── ───────────

[0034]

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[0035]

According to the method of the present invention, the optically active cyclopropane compound of formula (3), which is an important intermediate useful for the synthesis of physiologically active substances such as pharmaceuticals and agricultural chemicals, can be easily obtained in a high yield. It can be manufactured.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07C 201/12 C07C 201/12 205/05 205/05 253/30 253/30 255/31 255 / 31 C07F 15/06 9450-4H C07F 15/06 // C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (4)

[Claims] 1. A formula (1):[Wherein, Z¹, Z², Z^ThreeAnd Z^FourEach independently, water
Elementary atom, halogen atom, C₁~ C_FourAlkyl group, phenyl
Group (the phenyl group is a halogen atom, C₁~ C_FourAlkyl
Group, C₁~ C_FourSet with an alkoxy group, cyano group or nitro group
It may be replaced. ), A naphthyl group (the naphthyl group
Is a halogen atom, C₁~ C_FourAlkyl group, C ₁~ C_FourAl
It may be substituted with a coroxy group, a cyano group or a nitro group.
Yes. ), C₁~ C_FourAlkoxy group, C₂~ C_FiveAlkyl cal
Bonyloxy group, C₂~ C_FiveAlkanoyl group, C₂~ C_FiveA
Means lucoxycarbonyl group, nitro group or cyano group
You. ] And an olefin compound represented by the formula (2):[Wherein, Z^FiveIs C₁~ C₈It means an alkyl group. ]
Asymmetric CycloProp with Diazoacetic Acid Ester Compound
By the panning reaction, the compound represented by the formula (3):[Wherein, Z¹, Z², Z^Three, Z^FourAnd Z^FiveIs the same as above. *
The absolute configuration of the carbon atom indicated by means R or S. ]
To produce an optically active cyclopropane compound
In this case, equation (4)[Wherein, R¹, R², R^ThreeAnd R^FourEach independently water
Elementary atom, C₁~ C_FourAlkyl group, phenyl group (the phenyl
The group is a halogen atom, C₁~ C_FourAlkyl group, C₁~ C_FourA
Even if it is substituted with a lucoxy group, a cyano group or a nitro group
Good. ), And any two of them together are C
_Four~ C₈May be formed. Y¹, Y², Y^ThreeAnd Y
^FourAre each independently a hydrogen atom, C₁~ C_FourAlkyl
Group, phenyl group (the phenyl group is a halogen atom, C₁
~ C_FourAlkyl group, C₁~ C_FourAlkoxy group, cyano group or
May be substituted with a nitro group. ), Naphthyl group
(The naphthyl group is a halogen atom, C₁~ C_FourAlkyl
Group, C₁~ C_FourSet with an alkoxy group, cyano group or nitro group
It may be replaced. ), An anthracene group (the anthracene
The sen group is a halogen atom, C₁~ C_FourAlkyl group, C₁~
C_FourSubstituted with an alkoxy group, cyano group or nitro group
May be. ), And any two together
C_Four~ C₈Ring may be formed, and a condensed ring such as a naphthyl ring may be formed.
A ring may be formed. X^-Is an anion capable of forming a salt
Means pair. ] Optically active cobalt complexation represented by
Optically active cyclopropene characterized by using a compound
Method of producing a compound. 2. An optically active cobalt complex compound of the formula (4) has the formula (5) and (5 ′): The method according to claim 1, wherein 3. An optically active cobalt complex compound of the formula (4) has the formulas (6) and (6 ′): The method according to claim 1, wherein 4. An optically active cobalt complex compound of the formula (4) has the formula (7) and (7 ′): The method according to claim 1, wherein