JP5360722B2 - Catalyst for epoxide ring-opening reaction and process for producing homohomoallylic alcohol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a reaction method of selectively producing an internal ring-opened product (a primary homo homoallyl alcohol such as 2-phenylpent-4-en-1-ol) by a ring opening reaction of an epoxide. <P>SOLUTION: An internal ring-opened product 3 is selectively produced by subjecting styrene oxide to an ring opening reaction of an epoxide using an indium catalyst comprising two species of indium compounds [indium trichloride and indium tri(hexamethyldisilazide)] and allyl boronate as a nucleophilic agent, according to the reaction formula shown herein. <P>COPYRIGHT: (C)2011,JPO&amp;INPIT

Description

  The present invention relates to a catalyst for epoxide ring-opening reaction and a method for producing homohomoallylic alcohol by selectively ring-opening an epoxide.

Epoxides are important building blocks in organic synthesis. Selective epoxide ring-opening reaction is a key step in the synthesis of compounds with more complex structures. Epoxides undergo ring-opening reactions with various nucleophiles. Generally, nitrogen, oxygen and sulfur nucleophiles are used, and methods using these have already been established.
Although carbon nucleophiles have low reactivity, there are few reports, but the usefulness of the products is high. A typical carbon nucleophile is an allyl metal reagent (Patent Document 1). The product is an alcohol that is one carbon longer than homoallylic alcohol (generated by the reaction of a carbonyl group and an allylating reagent). Therefore, this reaction is complementary to the carbonyl allylation reaction.
In addition, there is no example which used the nonmetallic allylation reagent (allyl boron reagent used by this invention) for this epoxide ring-opening reaction.
Moreover, the indium catalyst conventionally used for the epoxide ring-opening reaction etc. was a simple indium metal salt (patent document 2).

Tetrahedron 61 (2005) 6726-6742 Tetrahedron Lett. 48 (2007) 6743-6746

  The product of the epoxide ring-opening reaction using a conventional allyl metal reagent (Patent Document 1, etc.) was a terminal ring-opening product (secondary homohomoallylic alcohol, for example, compound 4 of the chemical formula (Chemical Formula 6)). An object of this invention is to provide the reaction system which selectively produces | generates an internal ring-opening product (Primary homo homo allyl alcohol, for example, the compound 3 of Chemical formula (Formula 6)).

  The present inventors developed an indium catalyst composed of two kinds of indium compounds, and used this catalyst to carry out an epoxide ring-opening reaction using allyl boronate as a nucleophile. It has been found that a secondary homohomoallyl alcohol, for example, a compound 3) of the chemical formula (Chemical Formula 6) can be selectively produced, and the present invention has been completed.

That is, the present invention relates to an indium compound represented by InX ₃ (wherein X represents a halogen atom ) and In (N (SiR ¹² ₃ ) ₂ ) ₃ (wherein R ¹² represents an alkyl group. ). The indium catalyst for epoxide ring-opening reaction which consists of the mixture of the indium compound represented by this.

（式中、Ｒ^１は、アリール基又はアラルキル基を表し、Ｒ^２は、水素原子、アルキル基、アリール基又はアラルキル基を表す。）で表わされるエポキシドと下式

（式中、Ｒ^３は、水素原子、ハロゲン原子、アルキル基、アルコキシ基、アリールオキシ基又はアラルキロキシ基を表し、Ｒ^４、Ｒ^５及びＲ^６は、それぞれ独立して、水素原子、アルキル基又はアリール基を表し、Ｒ^７及びＲ^８は、それぞれ独立して、アルコキシ基を表し、但し、Ｒ^７及びＲ^８は、ホウ素原子と共に４〜７員環を形成してもよい。）で表わされるアリルボロネート（求核剤）とを反応させることから成る、下式

（式中、Ｒ^１〜Ｒ^６は上記と同様を表す。）で表わされるホモホモアリルアルコールの製造方法である。 The present invention also provides the following formula in the presence of this indium catalyst.

(Wherein R ¹ represents an aryl group or an aralkyl group, and R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group) and the following formula:

(Wherein R ³ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryloxy group or an aralkyloxy group, and R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, an alkyl group or Represents an aryl group, and R ⁷ and R ⁸ each independently represents an alkoxy group, provided that R ⁷ and R ⁸ may form a 4- to 7-membered ring together with a boron atom. Consisting of reacting with allylboronate (nucleophile)

(Wherein R ^{1 to} R ⁶ are the same as those described above).

The catalyst used in the present invention comprises a mixture of the following two indium compounds, preferably a mixture of the following two indium compounds in a molar ratio of 1: 2 to 2: 1.
(1) indium compound formula represented by InX _3, X represents a halogen atom. The halogen atom is Cl, Br, I or F, preferably Cl or Br.
^{_{(2) In (N (SiR}} 12 3) 2) indium compound in formula represented by _3, ^{R 12} is A alkyl group, preferably an alkyl group having 1 to 4 carbon atoms. N (Si (CH ₃ ) ₃ ) ₂ is called hexamethyldisilazide (hmds).

式中、Ｒ^１は、アリール基又はアラルキル基を表し、Ｒ^２は、特に制限は無いが、好ましくは水素原子、アルキル基、アリール基又はアラルキル基、より好ましくは水素原子を表す。アリール基は好ましくはフェニル基又はα若しくはβ−ナフチル基、より好ましくはフェニル基である。アラルキル基は好ましくはベンジル基である。 The epoxide which is one reactant of the reaction of the present invention is represented by the following formula.

In the formula, R ¹ represents an aryl group or an aralkyl group, and R ² is not particularly limited, but preferably represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, more preferably a hydrogen atom. The aryl group is preferably a phenyl group or an α or β-naphthyl group, more preferably a phenyl group. The aralkyl group is preferably a benzyl group.

式中、Ｒ^３は、特に制限は無いが、好ましくは水素原子、ハロゲン原子、アルキル基、アルコキシ基、アリールオキシ基又はアラルキロキシ基、より好ましくはアルキル基、アルコキシ基又はアリールオキシ基を表す。ハロゲン原子は、Ｃｌ、Ｂｒ、Ｉ又はＦであり、好ましくはＣｌ又はＢｒである。アルキル基は好ましくは炭素数が１〜６の直鎖アルキル基である。アルコキシ基は、好ましくは炭素数が１〜１０、より好ましくは２〜６の直鎖アルコキシ基である。アリールオキシ基は好ましくはフェノキシ基であり、アラルキロキシ基は好ましくはベンジルオキシ基である。
Ｒ^４、Ｒ^５及びＲ^６は、特に制限は無いが、好ましくは、それぞれ独立して、水素原子、アルキル基又はアリール基、より好ましくは水素原子を表す。アルキル基は好ましくは炭素数が１〜６の直鎖アルキル基である。アリール基は好ましくはフェニル基又はα若しくはβ−ナフチル基、より好ましくはフェニル基である。
Ｒ^７及びＲ^８は、それぞれ独立して、アルコキシ基であり、このアルコキシ基は分枝であってもよく、炭素数は好ましくは１〜１０、より好ましくは２〜６である。またＲ^７及びＲ^８は、ホウ素原子と共に４〜７員環、好ましくは５〜６員環を形成してもよい。Ｒ^７及びＲ^８は、好ましくはピナコール基（pin）である。 Allylboronate, which is a nucleophile for the reaction of the present invention, is represented by the following formula.

In the formula, R ³ is not particularly limited, but preferably represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryloxy group or an aralkyloxy group, more preferably an alkyl group, an alkoxy group or an aryloxy group. The halogen atom is Cl, Br, I or F, preferably Cl or Br. The alkyl group is preferably a linear alkyl group having 1 to 6 carbon atoms. The alkoxy group is preferably a linear alkoxy group having 1 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. The aryloxy group is preferably a phenoxy group, and the aralkyloxy group is preferably a benzyloxy group.
R ⁴ , R ⁵ and R ⁶ are not particularly limited, but preferably each independently represents a hydrogen atom, an alkyl group or an aryl group, more preferably a hydrogen atom. The alkyl group is preferably a linear alkyl group having 1 to 6 carbon atoms. The aryl group is preferably a phenyl group or an α or β-naphthyl group, more preferably a phenyl group.
R ⁷ and R ⁸ are each independently an alkoxy group, which may be branched, and preferably has 1 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. R ⁷ and R ⁸ may form a 4- to 7-membered ring, preferably a 5- to 6-membered ring, together with the boron atom. R ⁷ and R ⁸ are preferably a pinacol group (pin).

These are usually reacted under the following conditions.
As the reaction solvent, dichloromethane, toluene, and hexane are mainly used, and a solvent obtained by adding a small amount of methanol to dichloromethane is preferable.
The catalyst concentration is usually 0.01 to 0.5M, preferably 0.025 to 0.1M.
The molar ratio of epoxide and allyl boronate (epoxide: allyl boronate) as a reactant is usually 1: 0.9 to 1: 2, preferably 1: 1 to 1: 1.5.
The concentration of the reactant is usually 0.2 to 3M, preferably 0.5 to 2M.
The reaction temperature is generally 0 to 100 ° C., preferably room temperature to 60 ° C.
The reaction time is usually about 8 to 48 hours.

As a result, the reaction of the following formula mainly occurs to produce an internal ring-opening product (primary homohomoallylic alcohol).

This reaction is characterized in that the isomer having the structure of the following formula is not synthesized or only slightly synthesized.

The following examples illustrate the invention but are not intended to limit the invention.
Example 1
In this example, 1-phenylpent-4-en-2-ol (compound 3, internal ring-opening product (primary homohomoallylic alcohol)) was synthesized. The reaction formula is shown in the following formula (in the formula, the number represents the number of the compound. Pin represents a pinacol group).

In a reaction vessel washed and dried, indium trichloride (InCl ₃ , 2.2 mg, 5 mol%), In (hmds) ₃ (indium (III) hexamethyldisilazide, literature (H. Buerger, J. Cichon, U. Goetze, U Wannagat, HJ Wismar, J. Organomet. Chem. 1971, 33, 1.) Prepared as described, 6.0 mg, 5 mol%, methylene chloride (CH2Cl2, 100 μL, 2M) and methanol (2.0 μL, 24 mol) %) Was added. Styrene oxide (> 98% manufactured by Tokyo Chemical Industry Co., Ltd. was distilled and purified, 24 mg, 0.2 mmol) and allyl pinacol boronate (literature (WR Roush, MA Adam, AE Walts, DJ Harris, J. Am. Chem) Soc. 1986, 108, 3422.), 51 μL, 0.28 mmol) was added dropwise in that order. The mixture was heated to 40 ° C. and stirred for 20 hours. After cooling, the product was purified and 2-phenylpent-4-en-1-ol (Compound 3) was separated by preparative thin layer chromatography (PTLC; eluant: hexane / AcOEt = 7/1) (27 mg, yield 86%). 1-phenylpent-4-en-2-ol (Compound 5, rearrangement product) was obtained as a by-product (<1 mg, yield 1%). Compound 4 (terminal ring-opening product (secondary homohomoallylic alcohol)) was not detected.

The analytical value of 2-phenylpent-4-en-1-ol (compound 3) is shown:
¹ H-NMR (CDCl ₃ , 600 MHz): δ = 7.33-7.31 (m, 2H), 7.24-7.20 (m, 3H), 5.74-5.67 (m, 1H), 5.03-4.95 (m, 2H), 3.78-3.70 (m, 2H), 2.87 (q, J = 6.6 Hz, 1H), 2.49-2.35 (m, 2H), 1.50 (s, 1H) ppm. ¹³ C-NMR (CDCl ₃ , 150 MHz): δ = 141.8, 136.3, 128.6, 127.9, 126.7, 116.3, 66.8, 48.1, 36.5 ppm. IR: νmax (neat): 3347, 3063, 3027, 2923, 1641, 1601, 1493, 1452, 1026, 914, 759 and 700 cm ^-1 .
The analytical value of 1-phenylpent-4-en-2-ol (Compound 5) is shown:
¹ H-NMR (CDCl ₃ , 600 MHz): δ = 7.33-7.31 (m, 2H), 7.24-7.20 (m, 3H), 5.74-5.67 (m, 1H), 5.03-4.95 (m, 2H), 3.78-3.70 (m, 2H), 2.87 (q, J = 6.6 Hz, 1H), 2.49-2.35 (m, 2H), 1.50 (s, 1H) ppm.

本願発明の反応系においては化合物３（内部開環生成物（１級ホモホモアリルアルコール））が主生成物として合成される（entry 5〜11）。
一方、従来用いられている３価のインジウム無機塩触媒を用いた場合、エポキシドからアルデヒドへの転位反応を起こすため、目的の化合物３は得られない(entries 2 and 3)。また、本願発明の求核剤（即ち、炭素求核剤）は反応性が低いため、３価のインジウムアミド触媒を用いた場合、反応は進行しない（ルイス酸性が十分でない）(entry 4)。 Example 2
Using the same reactant as in Example 1, the reaction was carried out in the same manner as in Example 1 except that the catalyst and solvent were changed as shown in Table 1. The results are shown in the table below.

In the reaction system of the present invention, compound 3 (internal ring-opening product (primary homohomoallylic alcohol)) is synthesized as the main product (entries 5 to 11).
On the other hand, when a conventionally used trivalent indium inorganic salt catalyst is used, a rearrangement reaction from epoxide to aldehyde occurs, and thus target compound 3 cannot be obtained (entries 2 and 3). In addition, since the nucleophile (ie, carbon nucleophile) of the present invention has low reactivity, the reaction does not proceed when the trivalent indium amide catalyst is used (Lewis acidity is not sufficient) (entry 4).

Example 3
In this example, 3-methyl-2-phenylpent-4-en-1-ol (Compound 7) was synthesized. The reaction formula is shown below.

In a reaction vessel washed and dried, indium trichloride (InCl ₃ , 2.2 mg, 5 mol%), In (hmds) ₃ (6.0 mg, 5 mol%), methylene chloride (CH ₂ Cl ₂ , 100 μL, 2M) and Methanol (2.0 μL, 24 mol%) was added. Styrene oxide (> 98% manufactured by Tokyo Chemical Industry Co., Ltd. was distilled and purified, 24 mg, 0.2 mmol) and α-methylallyl pinacol boronate (ref. (RW Hoffmann, JJ Wolff, Chem. Ber. 1991, 124, 563.), 51 mg, 0.28 mmol) were added dropwise in order. The mixture was heated to 40 ° C. and stirred for 20 hours. After cooling, the product was purified and purified by preparative thin layer chromatography (PTLC; eluant: hexane / AcOEt = 7/1) to give 3-methyl-2-phenylpent-4-en-1-ol (compound 7, internal The ring-opening product (primary homohomoallylic alcohol)) was isolated (32 mg, 99% yield). Compounds 8-12 were not detected.

The analytical value of 3-methyl-2-phenylpent-4-en-1-ol (compound 7) is shown:
¹ H-NMR (CDCl ₃ , 500 MHz): δ = 7.34-7.16 (m, 10H syn / anti), 5.80-5.73 (m, 1H, syn), 5.61-5.54 (m, 1H, anti), 5.11- 5.01 (m, 2H, syn), 4.92-4.88 (m, 2H, anti), 3.91-3.72 (m, 4H, syn / anti), 2.76-2.43 (m, 4H, syn / anti), 1.02 (d, J = 6.9 Hz, 1H, anti), 0.8 (d, J = 6.9 Hz, 1H syn) ppm. ¹³ C-NMR (syn) (CDCl ₃ , 124.5 MHz): δ = 143.0, 141.1, 128.6, 128.5, 126.8 , 114.3, 66.0, 53.9, 41.2, 19.2 ppm. ¹³ C-NMR (anti) (CDCl ₃ , 125 MHz): δ = 141.6, 140.2, 129.0, 128.3, 126.7, 114.2, 64.7, 53.6, 39.4, 18.1 ppm. IR: νmax (neat): 3342, 3082, 3027, 2961, 2883, 1640, 1601, 1495, 1453, 1419, 1372, 1052, 1003, 914, 758 and 700 cm ^-1 .

Claims (6)

In the presence of indium catalyst,

(Wherein R ¹ represents an aryl group or an aralkyl group, and R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group) and the following formula:

(Wherein R ³ represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryloxy group or an aralkyloxy group, and R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, an alkyl group or Represents an aryl group, and R ⁷ and R ⁸ each independently represents an alkoxy group, provided that R ⁷ and R ⁸ may form a 4- to 7-membered ring together with a boron atom. Consisting of reacting with allylboronate (nucleophile)

(Wherein R ^{1 to} R ⁶ represent the same as above), wherein the indium catalyst is InX ₃ (wherein X represents a halogen atom ). And an In (N (SiR ¹² ₃ ) ₂ ) ₃ (wherein R ¹² represents an alkyl group). The manufacturing method of the homo homo allyl alcohol which consists of a mixture of the indium compound represented by this . 2. The method according to claim 1, wherein a molar ratio of the indium compound represented by InX ₃ and the indium compound represented by In (N (SiR ¹² ₃ ) ₂ ) ₃ is 1: 2 to 2: 1. ^{R 2,} R 4, A process according to claim 1 or 2 ^{R 5} and ^{R 6} are hydrogen atoms. The method according to any one of claims 1 to 3 , wherein R ⁷ and R ⁸ are each independently an alkoxy group having 1 to 10 carbon atoms or a pinacol group. An indium compound represented by InX ₃ (wherein X represents a halogen atom ) and In (N (SiR ¹² ₃ ) ₂ ) ₃ (wherein R ¹² represents an alkyl group). The indium catalyst for epoxide ring-opening reaction which consists of a mixture of the indium compound represented by this . The catalyst according to claim 5 , wherein a molar ratio of the indium compound represented by InX ₃ and the indium compound represented by In (N (SiR ¹² ₃ ) ₂ ) ₃ is 1: 2 to 2: 1.