JP2013147460A - OPTICALLY ACTIVE γ-DICYANONITRO COMPOUND AND METHOD FOR PRODUCING THE SAME - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an optically active γ-dicyanonitro compound and to provide a method for producing the compound.SOLUTION: There is provided a nitrile compound expressed by formula (3) (Rand Rare each independently an alkyl, acyl or aromatic group) and obtained by reacting a nitroalkene with malononitrile in the presence of a pincer palladium complex having a bisimidazolidine skeleton.

Description

  The present invention relates to an optically active γ-dicyanonitro compound and a method for producing the same, and more specifically to a method for producing an optically active γ-dicyanonitro compound using a malononitrile conjugate addition to a nitroalkene.

  A biopolymer having an optically active amino acid or sugar as a basic structural unit constructs a highly asymmetric space, and a drug using the biopolymer as a receptor needs to have optical activity. Such a method for synthesizing an optically active substance is called an asymmetric synthesis method. Among the asymmetric synthesis methods, a catalytically capable of synthesizing a theoretically infinite optically active substance from a small amount of an asymmetric source. Asymmetric synthesis methods are extremely useful and important.

  The 1,4-addition reaction of nitroalkene has high synthetic usefulness of the product, is an easy synthesis step to nitroalkane and the like, and many reports including catalytic asymmetric synthesis have been made. Examples of 1,4-addition reaction of nitroalkene and malononitrile reported here are described in Non-Patent Documents 1 and 2 below.

Okino, T; Hoashi, Y; Furukawa, T; Xu, X; Takemoto, Y, J. et al. Am. Chem. Soc, 2005, 127, 119 Srihari, G; Marthanda, M .; M, Synthetic Communications. 2009, 39, 896

  However, there have been no reports of obtaining products with high enantioselectivity in the 1,4-addition reaction of nitroalkene and malononitrile, and the development of an efficient catalytic asymmetric synthesis method is desired.

  In view of the above problems, an object of the present invention is to provide a 1,4-addition reaction between a nitroalkene and malononitrile using a metal catalyst and synthesis of a nitrile compound obtained thereby.

The inventors of the present invention have been diligently examining the above problems, and asymmetric 1,4-addition reaction proceeds by reacting nitroalkene with malononitrile in the presence of a pincer palladium complex having a bisimidazolidine skeleton. The inventors have discovered that a nitrile compound represented by the following formula can be obtained, and have completed the present invention.

That is, in the method for producing an optically active γ-dicyanonitro compound according to one means of the present invention, nitrostyrene and malononitrile are reacted in the presence of a catalyst represented by the following formula (1) or (2).

As a result, an optically active γ-dicyanonitro compound represented by the following formula (3) can be obtained.

In the above formula, R ¹ and R ² are each independently an alkyl group, an acyl group or an aromatic group.

  As described above, according to the present invention, an optically active γ-dicyanonitro compound obtained by conjugate addition of malononitrile to a nitroalkene and a production method thereof can be provided.

  Embodiments of the present invention will be described below with reference to the drawings. However, the present invention can be implemented in many different modes and is not limited to the embodiments shown below.

(Embodiment 1)
In the method for producing a nitrile compound according to this embodiment, a nitroalkene and malononitrile are reacted in the presence of a catalyst represented by the following formula (1) or (2).

  The pincer complex used in this embodiment not only exhibits catalytic activity with a cation complex represented by the following formula (2), but also has high catalytic activity even in a neutral complex represented by the following formula (1) that is an intermediate. Is expressed.

The catalyst according to this embodiment can be used to perform a 1,4-addition reaction between a nitroalkene and malononitrile. Specifically, an optically active γ-dicyanonitro compound can be synthesized by reacting a nitroalkene and malononitrile in the presence of the catalyst according to the present embodiment, as in the reaction represented by the following formula.

Although not limited here, R ¹ and R ² can each independently be an alkyl group, an acyl group, or an aromatic group. In the case of an alkyl group, examples thereof include, but are not limited to, for example, a methyl group, an ethyl group, or a benzyl group. be able to. Moreover, although it is not necessarily limited in the case of aromatic, for example, a phenyl group, a pyridine, indole, or pyrrole can be mentioned.

  Although the solvent is not limited, the reaction is particularly preferably carried out in tetrahydrofuran.

In the above reaction, a nitroalkene used as a reaction substrate is represented by the following formula (4). In the above reaction, when the amount of nitroalkene used is 1 mol, the amount of malononitrile is preferably about 1.5 mol.

In the above reaction, malononitrile is represented by the following formula (5).

As a result, according to the method according to the present embodiment, a nitrile compound represented by the following formula (3) can be obtained.

(Catalyst synthesis)
In the present embodiment, the synthesis of the catalyst is not limited as long as it can be synthesized. It can be constructed by reacting with Specifically, the complex according to this embodiment can be synthesized by the following method.

In the above formula, M represents Pd, R ¹ and R ² represent Ph, R ³ represents Bn, R ⁴ represents t-Bu, and X represents Cl or OTf.

  As described above, the metal catalyst according to this embodiment can provide the 1,4-addition reaction using nitroalkene and malononitrile and the nitrile compound obtained thereby, and the reaction substrate can be expanded. Moreover, according to the present invention, the target compound can be obtained with high chemical yield and high optical purity.

  Here, the optically active γ-dicyanonitro compound and the production method thereof according to the above embodiment were actually created and the effects were confirmed. This will be specifically described below.

The asymmetric 1,4-addition reaction was performed as a catalyst using 0.0089 g of the complex represented by the following formula (1) obtained by the above embodiment or 0.0101 g of the complex represented by the following formula (2). . A specific example will be described below.

Example 1
The present Example was performed by dissolving in 1 ml of anhydrous tetrahydrofuran and reacting 29.8 mg of tatrans-β-nitrostyrene and 19.81 mg of malononitrile in the presence of the catalyst (1) at 0 ° C. for 48 hours. As a result, 0.035 g of the compound (3-1) shown below could be obtained. The yield of (3-1) was 82%, and the enantiomeric excess was 80% ee.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.50-7.46 (m, 3H), 7.39-7.34 (m, 2H), 5.02-4.96 (q, 1H), 4. 95-4.89 (q, 1H), 4.44 (d, 1H), 4.11-4.05 (m, 1H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 131.8, 130.3, 129.9, 127.7, 110.5, 110.4, 74.9, 43.6, 27.5;
Enantiomerically excused was determined by HPLC with a chiralcel AD-Hcolumn (8: 2 hexane: 2-propanol, 1.0 mL / min, 254 nm)

_{minor enantiomer t r = 9.9 min,} major enantiomer t r = 11.2 min, 80% ee)

IR (neat) 2258, 1554 cm ⁻¹

(Example 2)
In this example, 31.04 mg of (E) -1-cyclohexyl-2-nitroethene, 19.81 mg of malononitrile, and 16.80 mg of sodium bicarbonate dissolved in 1 ml of anhydrous tetrahydrofuran were added at 0 ° C. in the presence of the catalyst (1), The reaction was performed for 48 hours. As a result, 0.036 g of the following compound (3-2) could be obtained. The yield of (3-2) was 82%, and the enantiomeric excess was 87% ee.

¹ H NMR (500 MHz, CDCl ₃ ) δ 4.71-4.66 (dd, 1H), 4.61-4.55 (dd, 1H), 4.24 (d, 1H), 2.78-2 .71 (m, 1H), 1.91-1.77 (m, 5H), 1.77-1.71 (m, 1H), 1.40-1.11 (m, 4H), 1.10 -1.00 (m, 1H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 111.1, 111.0, 73.5, 43.3, 38.8, 30.8, 28.8, 25.9, 25.8, 25.6, 24.2;
Enantiomerically excess was determined by HPLC with a chiralcel AD-H column (97: 3 hexane: 2-propanol, 1.0 mL / min, 220 nm)

_{major enantiomer t r = 35.5 min,} minor enantiomer t r = 42.5 min, 87% ee

IR (neat) 2258, 1554 cm ⁻¹

(Example 3)
In this example, 31.04 mg of (E) -1-cyclohexyl-2-nitroethene and 19.81 mg of malononitrile dissolved in 1 ml of anhydrous tetrahydrofuran were reacted at 0 ° C. for 48 hours in the presence of the catalyst (2). It was. As a result, 0.035 g of the following compound (3-2) could be obtained. The yield of (3-2) was 80%, and the enantiomeric excess was 88% ee.

  As described above, according to this example, it was confirmed that a useful catalyst capable of performing an asymmetric 1,4-addition reaction could be realized.

Since the optically active γ-dicyanonitro compound can be supplied with high optical purity, the present invention is useful for the development and production of medicines and has industrial applicability.

Claims (2)

A method for producing an optically active γ-dicyanonitro compound represented by the following formula (3) using a catalyst represented by the following formula (1) or the following formula (2).
(Here, R ¹ and R ² are each independently an alkyl group, an acyl group, or an aromatic group.) An optically active γ-dicyanonitro compound represented by the following formula (3).
(Here, R ¹ and R ² are each independently an alkyl group, an acyl group, or an aromatic group.)