JP2011111426A - Method for producing bisimidazolidine ligand and catalyst using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To construct a more complex coordination field by using a bisimidazolidine having C2 symmetry as a ligand, and to achieve useful catalytic asymmetric synthesis. <P>SOLUTION: The bisimidazolidine ligand is represented by formula (1) (wherein, R<SP>1</SP>and R<SP>2</SP>are each one of CH<SB>3</SB>, -(CH<SB>2</SB>)<SB>4</SB>- and Ph; R<SP>3</SP>is one of H, CH<SB>3</SB>SO<SB>2</SB>, CH<SB>3</SB>C<SB>6</SB>H<SB>4</SB>SO<SB>2</SB>, C<SB>6</SB>H<SB>5</SB>SO<SB>2</SB>, CH<SB>3</SB>CO, C<SB>6</SB>H<SB>5</SB>CO, CH<SB>3</SB>, C<SB>2</SB>H<SB>5</SB>, CH<SB>2</SB>Ph and Ph; R<SP>4</SP>is one of H, CH<SB>3</SB>, Br and NO<SB>2</SB>; with the proviso that Ph is an aromatic ring). <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing a bisimidazolidine ligand and a catalyst using the same.

  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.

  At present, catalytic asymmetric synthesis is achieved by using various metal catalysts. As asymmetric ligands that realize useful catalytic asymmetric reactions, the development of optically active imidazolidine ligands described in C2 symmetric optically active bisoxazolines and the following non-patent documents has been reported.

Myung-Jong Jin et al., “Highly enantioselective Pd-catalyzed allyl lysing using new chiral ferrhosinoimidazolididine ligands”, Chem. Comm. 2006, 663-664 Geon-Jong Kim et al., “New enantioselective chiral imidazolidin ligands for Pd-catalyzed asymmetry allylation”, Tetrahedron. Lett. 2003, 1971-1974.

  However, although bisoxazoline is useful for various reactions, it has a simple coordination field in which the coordination field is a planar four-coordination because of its highly planar structure. Further, mononuclear ones are known as optically active imidazolidine ligands, and there are no reports of bisimidazolidine. There is no report of an asymmetric reaction using azomethine ylide with imidazolidine as a ligand.

  Therefore, in view of the above problems, the present invention aims to construct a more complex coordination field by using C2-symmetric bisimidazolidine as a ligand instead of a mononuclear, and more useful catalytic asymmetric synthesis. The purpose is realization.

  The inventors of the present invention have been diligently studying the above problems, and succeeded in synthesis in two stages by introducing a substituent into an optically active diamine and then reacting with an aldehyde to complete the present invention. It came.

That is, the ligand according to one aspect of the present invention is characterized by the following chemical formula (1).

(However, R ¹ and R ² are either CH ₃ , — (CH ₂ ) ₄ — or Ph, and R ³ is H, CH ₃ SO ₂ , CH ₃ C ₆ H ₄ SO ₂ , C ₆ H _5. One of SO ₂ , CH ₃ CO, C ₆ H ₅ CO, CH ₃ , C ₂ H ₅ , CH ₂ Ph, and Ph, and R ⁴ is one of CH ₃ , Br, and NO ₂ . Ph represents an aromatic ring.)

A catalyst according to another aspect of the present invention is characterized by the following chemical formula (2).

(However, R ¹ and R ² are either CH ₃ , — (CH ₂ ) ₄ — or Ph, and R ³ is H, CH ₃ SO ₂ , CH ₃ C ₆ H ₄ SO ₂ , C ₆ H _5. One of SO ₂ , CH ₃ CO, C ₆ H ₅ CO, CH ₃ , C ₂ H ₅ , CH ₂ Ph, and Ph, and R ⁴ is one of CH ₃ , Br, and NO ₂ . Ph represents an aromatic ring, and M represents a metal atom.

  As described above, according to the present invention, an efficient ligand can be synthesized in two steps. By changing the substituent of the optically active diamine, it is possible to provide a ligand having a high degree of freedom due to an electronic effect and a steric effect, and a catalytic reaction using the ligand. Moreover, the problem of a planar ligand can be overcome and a more complex coordination field can be constructed.

  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)
The ligand according to this embodiment is represented by the above chemical formula (1). A bimolecular imidazolidine skeleton having an optically active diamine as a building unit can be constructed by reacting a diamine with a pyridine having an aldehyde group at the 2nd and 6th positions. In addition, one NH on the imidazolidine ring is changed to CH ₃ SO ₂ , CH ₃ C ₆ H ₄ SO ₂ , C ₆ H ₅ SO ₂ , CH ₃ CO, C ₆ H ₅ CO, CH ₃ , C ₂ H ₅ , By substituting with CH ₂ Ph, Ph, etc., coordination ability and coordination field complexity can be changed by electronic and steric effects. Here, Ph represents an aromatic ring.

  The ligand is oily at room temperature in the air and can be stored for 1 month or longer in a cool and dark place. It is soluble in many organic solvents (acetone, tetrahydrofuran, methylene chloride, chloroform, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, dioxane, etc.), and complex formation and catalytic asymmetric reaction using these as solvents Can be used.

Moreover, the ligand which concerns on this embodiment is compoundable with the following method.

  In addition, the ligand according to this embodiment can be used as a catalyst by coordinating to a metal, and can be suitably used for Mannich-type reaction and 1,3-dipole cyclization reaction.

Moreover, as a method of coordinating the ligand according to the present embodiment to a metal, a method of reacting an equivalent amount of the ligand in an organic solvent with respect to the target metal salt is conceivable. Although it does not limit as a metal to coordinate, For example, copper, nickel, cobalt, ruthenium, rhodium, or iron can be illustrated. As a method of coordinating with a metal, a well-known method can be adopted, and although not limited, it can be coordinated by mixing a metal salt and a ligand. The metal salts include, but are not limited to, when the metal is _copper, can be used CuCl, CuOAc, the _{CuCl 2, Cu (OAc) 2} , Cu (OTf) 2 and the like.

  As described above, according to the present invention, synthesis of versatile and versatile bisimidazolidine ligands can be achieved, and a ligand having a high degree of freedom and a catalyst using the same can be provided.

  Hereinafter, specific compounds were prepared and evaluated for the ligand and catalyst according to the above embodiment. This will be specifically described below.

Example 1
As an example according to the above embodiment, bisimidazolidine was synthesized. This will be described below.

Synthesis of [(1S, 2S) -N-benzoyl-1,2-diphenylethane-1,2-diamine] (A):
First, dimethylformamide (25 ml) is placed in an eggplant flask containing activated MS4Å (2.5 g) and purged with argon. Thereafter, (1S, 2S) -1,2-diphenylethane-1,2-diamine (1 g, 5 mmol) and cesium hydroxide monohydrate (836 mg) and benzyl chloride (690 μl) were added in this order, and the mixture was stirred at 35 ° C. . After stirring for 24 hours or more, the MS is removed by filtration with filter paper, 1N aqueous sodium hydroxide solution is added, and the mixture is extracted in the order of ethyl acetate, water, and brine. The organic layer is dried with dead glass and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent 1: 1 n-hexane / ethyl acetate to ethyl acetate) to obtain the target compound (A) as a yellow oil in a yield of 46%.
(A) Equipment data:
¹ H NMR (400 MHz, CDCl ₃ ) d 3.47 (d, J = 13.5 Hz, 1H), 3.67 (d, J = 13.5 Hz, 1H), 3.76 (d, J = 7. 3 Hz, 1 H), 4.01 (d, J = 7.3 Hz, 1 H), 7.09-7.31 (m, 15 H, aromatic)
¹³ C NMR (125 MHz, CDCl ₃ ): d 51.4, 61.8, 68.8, 126.8, 126.9, 127.02, 127.003, 128.0, 128.07, 128.09 , 128.3, 140.2, 140.6, 141.2, 143.5
FT / IR 3375, 3311, 3060, 3026, 2904, 2837, 1601, 1493, 1452, 762, 696 cm ⁻¹
[Α] _D ²⁰ = −7.5 ° (c = 1.23, CHCl ₃ )
HRMS (FAB +) calcd for C ₂₁ H ₂₃ N ₂ (M ⁺ + H) 303.1186: found 303.1873.

(Experiment 2)
Synthesis of [2,6-bis ((2R, 4S, 5S) -1-benzyl-4,5-diphenylimidazolidine-2-yl) pyridine] (1-1):
Under an argon atmosphere, 2,6-pyridylaldehyde (74.3 mg, 0.55 mmol) was dissolved in anhydrous methylene chloride (10 ml), acetic acid (63 μl) and (1) were added, and the mixture was stirred at 30 ° C. for 24 hours. After adding multistory water, it extracts using chloroform. The organic layer is dried with dead glass and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (developing solvent 3: 1 n-hexane / ethyl acetate) to give yellow oily (1-1) in 99% yield.

(1-1) Device data:
¹ H NMR (400 MHz, CDCl ₃ ) d 3.66 (d, 2H), 3.83-3.87 (m, 4H), 4.40 (d, 2H), 5.02 (s, 2H), 7.00-7.37 (m, 33H, aromatic)
¹³ C NMR (100 MHz, CDCl ₃ ) d 55.24, 61.61, 69.29, 70.36, 81.94, 94.16, 115.55, 121.29, 122.21, 126.60, 127.21, 127.49, 127.67, 127.99, 128.15, 128.21, 128.30, 129.46, 136.37, 137.38, 139.95, 141.50, 161. 02, 196.3, 206.67
FT / IR 3340.1, 3028.66, 2839.67, 1739.48, 1552.42, 1454.06, 1153.22, 761.744 cm ⁻¹
[Α] _D ²⁰ = −69.5 (c = 1.00, CHCl ₃ )
_{FTMS (ESI +) calcd for C} 49 H 45 N 5 Na (M + + Na) 726.3567; found 726.3567.

As described above, a ligand represented by the following structural formula (1-1) was obtained.

(Example 2)
Further, the following structural formula (1-2) having R ³ as a tosyl group was synthesized in two steps by the same operation as in Example 1 above.

Device data (1-2):
¹ H NMR (400 MHz, CDCl ₃ ) d 2.40 (s, 6H), 3.55 (br, 2H), 4.25 (d, 2H), 4.71 (d, 2H), 5.83 ( s, 2H), 6.99-7.98 (m, 31H, aromatic)
¹³ C NMR (100 MHz, CDCl ₃ ) d 21.50, 58.94, 69.21, 71.37, 78.28, 93.94, 120.89, 124.01, 126.62, 126.90, 127.31, 127.35, 127.70, 127.96, 128.19, 128.41, 129.46, 134.14, 138.00, 139.10, 139.66, 143.67, 157. 89, 183.39
FT / IR 3672.77, 3296.71, 2923.56, 2254.38, 1598.70, 1347.03, 1160.94, 983.518 cm ⁻¹
[Α] _D ²⁰ = −28.2 (c = 1.00, CHCl ₃ )
HRMS (FAB +) calcd for C ₄₉ H ₄₆ N ₅ S ₄ O ₂ (M ⁺ + H) 832.2991: found 832.2991.

(Example 3)
Next, the ligand obtained in the examples was coordinated to a divalent copper salt to prepare a catalyst. And the effect as this catalyst was confirmed. Specifically, the copper complex using (1-1) obtained in Example 1 was adjusted and applied to catalytic asymmetric Mannich type reaction and 1,3-dipole cyclization reaction.

(Preparation of copper complex using (1-1))
Under an argon atmosphere, Cu (OTf) ₂ (3.6 mg, 0.01 mmol) and bisimidazolidine (1-1) (0.011 mmol) were dissolved in 1 ml of anhydrous methylene chloride and stirred at room temperature for 2 hours or more. After concentration under reduced pressure, recrystallization occurred.

(Confirmation of Mannich type reaction using (1-1) -Cu (OTf) ₂ complex)

  The copper complex is dissolved in 1 ml of toluene, and azomethine ylide (50.6 μl, 0.2 mmol), triethylamine (2.8 μl), and tosylimine (57.7 mg) are added at −20 ° C. After 20 hours, the reaction solution was concentrated under reduced pressure, and 62% yield (syn: anti = 84: 16) was obtained by silica gel chromatography (developing solvent 5: 1 from n-hexane / ethyl acetate 3: 1). The optical purity of the product was 97% ee for the syn isomer and 92% ee for the anti isomer. (Analysis conditions: DAICEL CHIRALCEL AD-H, flow rate = 1.0 ml / min, hexane: 2-propanol = 90: 10)

(Confirmation of 1,3-dipolar cyclization reaction using (1-1) -Cu (OTf) ₂ complex)

  The copper complex is dissolved in 1 ml of 1,4-dioxane, azomethine ylide (35.0 μl, 0.2 mmol), cesium carbonate (6.5 mg) and trans-β-nitrostyrene (32.86 mg) are added, and 20 at room temperature. Stir for hours. The reaction solution was concentrated under reduced pressure, and subjected to silica gel chromatography (developing solvent 3: 1 n-hexane / ethyl acetate) to obtain a 96% yield (endo: exo = 99: 1). The optical purity of the resulting product was The body was 99% ee. (Analysis conditions: DAICEL CHIRALCEL AS-H, flow rate = 0.7 ml / min, hexane: 2-propanol = 70: 30)

  As described above, the effect of this catalyst can be confirmed by this example, and it has been confirmed that a novel bisimidazolidine ligand having high versatility and a high degree of freedom and a catalyst using the same are obtained.

  The present invention has industrial applicability as a catalyst and a ligand therefor.

Claims (3)

Ligand represented by the following formula (1)
(However, R ¹ and R ² are either CH ₃ , — (CH ₂ ) ₄ — or Ph, and R ³ is H, CH ₃ SO ₂ , CH ₃ C ₆ H ₄ SO ₂ , C ₆ H _5. One of SO ₂ , CH ₃ CO, C ₆ H ₅ CO, CH ₃ , C ₂ H ₅ , CH ₂ Ph, and Ph, and R ⁴ is any one of H, CH ₃ , Br, and NO ₂ . Here, Ph represents an aromatic ring.) A catalyst represented by the following formula (2).
(However, R ¹ and R ² are either CH ₃ , — (CH ₂ ) ₄ — or Ph, and R ³ is H, CH ₃ SO ₂ , CH ₃ C ₆ H ₄ SO ₂ , C ₆ H _5. One of SO ₂ , CH ₃ CO, C ₆ H ₅ CO, CH ₃ , C ₂ H ₅ , CH ₂ Ph, and Ph, and R ⁴ is one of CH ₃ , Br, and NO ₂ . Ph represents an aromatic ring, and M represents a metal atom.   The catalyst according to claim 2, which is used in at least one of Mannich type reaction or 1,3-dipole cyclization reaction.