JPS61257933A - Production of stereoselective alcohol from ketone - Google Patents

Abstract

PURPOSE:To obtain an equatorial alcohol useful mainly as drugs, agricultural chemicals, etc., in the field of so-called fine chemistry, by treating a specific reagent with a ketone and reacting the reaction product with a carbon nucleating agent at <=0 deg.C. CONSTITUTION:A compound shown by the formula I (R' is alkyl or halogen; R'' is alkyl or H) as a reagent is treated with a ketone. Then, the reaction product is reacted with a carbon nucleating agent, preferably an organolithium compound, and/or a Grignard reagent, at <=0 deg.C to give the titled compound. Cyclohexane or 4-tertiary butylcyclohexane is used as the ketone. Preferably the reaction is carried out in the presence of an organic solvent at the reaction temperature of -78 deg.C.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention is directed to reacting a ketone with a reactant having the following general formula (where R' is an alkyl group or a halogen, and R# is an alkyl group or hydrogen). and then act with a carbon nucleophile mainly an alkylating agent at a temperature below 0°C.
-Regarding a method for producing a characteristic stereoselective alcohol.

The present invention is a method for selectively producing efuato-11 alcohol by carrying out such a reaction, and is a method useful mainly in the so-called fine chemistry fields such as pharmaceuticals and agricultural chemicals.

[Conventional technology]

The alkylation reaction of ketones has been studied for a long time and is one of the fundamental reactions in organic synthesis.

Recently, from cyclohexanone to axialalal = r -A
Considerable efforts have been made to develop stereoselective alkylating agents to obtain equa-tor 11-alcohols (equa-tor
No good method has been established for the selective synthesis of ial alcohols.

[Defined means of solving problems]

Therefore, the inventors used methylaluminum bis(2,6-di-tert-butyl-4-methyl-phenoxide), which is a sterically bulky organoaluminum compound, as a reactant.
(2,6-di-tart-buthl-4-met
Focusing on hylphenoxide (hereinafter abbreviated as MAD), various studies were conducted on stereoselective alkylation reactions of ketones using this reactant.

An example of the method of the present invention will be described below.

1 (99:1) 2 (However, Me is a methyl group. molar ratio l:2) ft. Prepared by reacting for 1 hour at xi in toluene.

In the above formula, treatment of 4-tertiary + 1-butyl-cyclohexanone with 3 equivalents of MAD in toluene followed by treatment with an ethereal solution of methyl l]thium (MeLi) at -78°C gives a yield of 84%. A mixture of isomers of methyl carbinol was obtained, of which 99% was found to be efuato-11 alcohol (abbreviated as eq) and 1.1% was axial alcohol (abbreviated as AX).

It has been reported that when MeLi is used alone, the ratio of ax2 to eqx is 79=21. (McDonalds 1 Tei, Elle,
Still, Double 21, Sea, This Yarnal, Kasabuzaame 11 Kan, Chemical, Society ni uec>onald, T, L,; 5till.

W, C, J, Am, Chem, Soc, 1975
,9755280) ,Eh. On the other hand, the effectiveness of MAD is clear from the results of detailed studies using various reactants under similar conditions.

That is, the reaction of 4-tert-butyl-cyclohexanone with MeLi in the presence of various organoaluminum reactants produces ax2 and eql as shown below, and the production ratio is changed by Me snow Azoph (ph is phenyl group) [ 72
:28, dimethyl aluminum 2,4.6-dimethyl phenoxide
m 2 , 4 , 6-trimethylpheno
69:31 for 襦ide), 5:9 for dimethyl aluminum
The production rate is 5.

As a result of testing the quantitative relationship between t7tMAD, MeLi and M
Even when AD was used in an amount of 3 equivalents or more, no significant improvement in yield was observed.

When MAD and MeLi each have 2 equivalents, ax:aq=1:99, but the yield is 59%, and when both reactants have 1 equivalent, a
Although x:eq=2:98, the yield was low at 31%.

Although 4-tasha+7-butyl-cyclohexanone was used as the raw material in the above explanation, it is not limited thereto, and any ketone may be used.

Further, the reactant is not limited to MAD, and in the above formula, Re may be an alkyl group or a halogen, R'' may be an alkyl group, and hydrogen may be used.

Carbon nucleophile: UMeLi and Guineal reagents are specifically mentioned here, but any carbon nucleophile may be used as a carbon nucleophile.

It is not preferable to react the ketone and MeLi first and then react with MAD, and Example 2
．． NIL4, Example 3. MeL at low temperature as shown in Appendix 5
Reaction of a mixture of i and MAD with a ketone t! MeLi is simply added, which is not preferable.

[Examples and effects of the invention]

Examples will be described below, but the invention is not limited thereto.

Example 1 1.322 f (6 mmol) of 2.
6-di-tert-butyl-4-methylphenol was added to the solution, and 3 seeds dissolved in 2 mol of hexane were added to the solution.
mol of trimethylaluminum was added. After that, stir at room temperature for 1 hour.

The mixture was cooled to -78°C, 1541'f (1 mmol) of 4-tertiary II-butylcyclohexanone was added, and then 3 mmol of MeLi in 1.54 mol of ether solution was added at -78°C. friend.

The solution was then kept at that temperature for 2 hours. The reaction solution was poured into 1 normal hydrochloric acid solution, and the organic layer was washed with salt water and concentrated. After that, extract with ether and sift the mixture of concentrates 1 and 2 into 1 sieve.
The product was purified by chromatography using a column packed with 1 gel, and 14311P was obtained with a t0 yield of 84%. Analysis by gas and chromatography showed that the ratio was 1:2=99:1.

Example 2 The following reactions were carried out under the conditions shown in Table 1.

The reaction conditions are the same as in Example 1.

(ax) (eq) l (Comparative Example 2-1) 2-1) None -79:2
12 (# 2-2) I DAD 81
5:953 (Example 1) #MA
D84 1:994 (Comparative Example 2-3) 2-3) + MA
D” 78 84:165 (12-4) EtMg
Br No9548:526 (Example 2-1)
I MAD 91 1:997 (Comparative Example 2
5) BuMgBr None 58 56:448 (
Example 2-2) I MAD 67
1:999 (Comparative Example 2-6) AllylMgB
r None 86 48:5210 (Example 2-3)
I MAD 90 9:91 solution.

(b) ------Used as an ether solution Example 3゜ The following reaction was carried out under the same conditions as in Example 1.

No. Carbon nucleophile (b) kW,'-JR rate 19
Specific acid (aX/eq) 1 (Comparative example a-1) No MeLi -92:
82 (Comparative Example 3-2) #DAD
80 58:425 (Comparative Example 3-3) MeLi+
MAD (&' 81 91: 9 but d)...
...The reaction was carried out at -95°C for 3 hours.

Example 4゜ The following reaction was carried out under the same conditions as in Example 1.

Table 3 1 (Comparative Example 4-1) MeLi No go
83:172 (14-2) #DAD
77 48:523 (Example 4-1) #
MAD 69 9:91 (e'4 (Comparative Example 4-
3) BuMgBr None 86 79:21
5 (Example 4-2) # MAD 75
1:996 (Comparative Example 4-4) AllylMg
Br None 95 56:447 (Example 4-3)
I MAD 72 24 near 6 however e)
...The reaction was carried out at -95°C for 3 hours.

Example 5゜ The following reaction was carried out under the same conditions as in Example 1.

,,,,,people 4. ,,＋ 箕' ＞p Qing
°−゛\1 procedure? Contents of the amendment (spontaneous) 1. In the second line of page 4 of the specification, [-buthl J] was corrected to ``-butyl J.

2. On page 5, line 15 of the specification, it says “Muc[)onald J”.
[)Corrected by onald J.

3. On page 6, line 4 of the detailed letter It says "to the generation ratio" Corrected "The generation ratio is."

4. On page 8, line 14 of the detailed letter It says "l honinami" Corrected to "after concentration."

Claims (6)

[Claims] (1) Reactant having the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R' is an alkyl group or halogen, R' is an alkyl group or hydrogen) is reacted with a ketone, and then a carbon nucleophile 1. A method for producing a stereoselective alcohol, which comprises reacting at a temperature of 0°C or lower. (2) Claim 1 in which the ketone is cyclohexanone or 4-tert-butyl-cyclohexanone
The method described in section. (3) The method according to claim 1 or 2, wherein the reactant is represented by a numerical formula, chemical formula, table, etc. (provided that R'' is a methyl group or a tertiary-butyl group). (4) Claims 1 to 3, wherein the carbon nucleophile is an organolithium compound and/or a Grignard reagent.
The method described in any one of the preceding paragraphs. (5) The method according to any one of claims 1 to 4, which is carried out in the presence of an organic solvent. (6) The method according to any one of claims 1 to 5, wherein the reaction is carried out at -78°C.