JP6548214B2 - Catalyst having an aminosalicylaldimine ligand coordinated to metal and method for producing iodocyclic compound using the same - Google Patents

Description

  The present invention relates to a catalyst in which an aminosalicylaldimine ligand is coordinated to a metal and a method for producing an iodocyclic compound using the same.

  The iodocyclization is capable of various chemical transformations from its product and is an important reaction used for the synthesis of complex compounds such as natural products. In particular, development of a catalytic asymmetric reaction attracts attention because a novel quaternary asymmetric carbon can be constructed by cyclization. In recent years, catalytic asymmetric iodocyclization has been achieved by Jacobsen (Non-Patent Document 1), Johnston (Non-Patent Document 2), Gao (Non-Patent Document 3) and the like.

Dobish, M. C. Johnston, J. et al. N. J. Am. Chem. Soc. 2012, 134, 6068 Veitch, G. E. : Jacobsen, E. N. Angew. Chem. Int. Ed. 2010, 49, 7332 Ning, Z. : Jin, R. : Ding, J. : Gao, L. SYNLETT. 2009, 14, 2291

  However, in any of the documents described above, the substrate used for the reaction is limited to the carboxylic acid compound, and development of a reaction system for obtaining an iodo cyclized product using another substrate is desired.

  Therefore, in view of the above problems, the present invention aims to provide an asymmetric iodocyclization reaction for a wider range of substrates.

  The inventors of the present invention conducted intensive studies on the above-mentioned problems and found that the enantiomeric reaction is carried out by reacting unsaturated amide with N-iodosuccinimide in the presence of a catalyst in which an aminosalicylaldimine ligand is coordinated to a metal. It discovered that the iodo-cyclization thing could be obtained selectively, and came to complete this invention.

That is, the catalyst according to one means of the present invention is a catalyst in which a metal or a metal salt is coordinated to a ligand represented by the following formula (1).

In the ligand represented by the above formula (1), R ¹ and R ^{2 each} have hydrogen, an alkyl group, a phenyl group (which may have a substituent) or a naphthyl group (which has a substituent) R ¹ and R ² may combine to form a ring. R ¹ and R ² may be the same or different. R ³ and R ⁴ are hydrogen, fluorine, chlorine, bromine, iodine, a nitro group, an alkyl group, an alkynyl group, an alkoxy group or a phenyl group (which may have a substituent).

Moreover, the method for producing an iodocyclic compound according to another means of the present invention is characterized in that the unsaturated compound is prepared in the presence of a catalyst in which a metal or a metal salt is coordinated to a ligand represented by the following formula (1). By reacting an amide with N-iodosuccinimide, an iodocyclic compound represented by the following formula (2) is produced.
Here, R ¹ and R ^{2 each} represent hydrogen, an alkyl group, a phenyl group (which may have a substituent) or a naphthyl group (which may have a substituent), and R ¹ and R ² may be combined to form a ring. R ¹ and R ² may be the same or different. R ³ and R ⁴ are hydrogen, fluorine, chlorine, bromine, iodine, a nitro group, an alkyl group, an alkynyl group, an alkoxy group or a phenyl group (which may have a substituent).

Here, R ^{1 is} hydrogen, an alkyl group, a phenyl group (which may have a substituent) or a naphthyl group (which may have a substituent), and R ² is a hydrogen, an alkyl group , A phenyl group (which may have a substituent), a carbonyl group and a sulfonyl group.

  As described above, according to the present invention, it is possible to provide a novel metal catalyst, and to use this to make it possible to enantioselectively provide an asymmetric iodocyclization reaction and an iodocyclic compound obtained thereby, and to obtain an optical activity obtained It is possible to expand the iodine form of It is also possible to obtain very high yields according to the invention.

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

(Embodiment 1)
The catalyst according to the present embodiment is obtained by coordinating a ligand represented by the following chemical formula (1) to a metal or metal salt.

In the ligand according to this embodiment, R ¹ and R ² may employ various ones as a substituent of diamine. For example, hydrogen, an alkyl group, a phenyl group (which may have a substituent) or a naphthyl group (which may have a substituent) is desirable, and R ¹ and R ² are bonded together. It may form a ring. R ¹ and R ² may be the same or different.

In addition, in the ligand according to the present embodiment, R ³ and R ⁴ are not limited as long as they are substituents that can be introduced into the aromatic ring, and various ones can be adopted. For example, hydrogen, fluorine, chlorine, bromine, iodine, a nitro group, an alkyl group, an alkoxy group or a phenyl group (which may have a substituent) can be exemplified.

As a metal which coordinates a ligand, it is not necessarily limited to this as long as it can coordinate, for example, copper, nickel, zinc, cobalt, ruthenium, rhodium or iron can be illustrated. Moreover, as a method of coordinating a ligand to a metal, a known method can be adopted, and it is possible to coordinate by mixing a metal salt and a ligand, without limitation. The metal salt is not limited, but when the metal is copper, Cu (OAc) ₂ , Cu (OTf) ₂ , CuCl ₂ or the like can be used.

Furthermore, the catalyst according to this embodiment can be used to carry out an asymmetric iodocyclization reaction using an unsaturated amide. Specifically, in the presence of the catalyst according to the present embodiment, as in the reaction represented by the following formula (3), the unsaturated amide and N-iodosuccinimide are reacted to make the iodocyclic compound enantioselectively It can be synthesized.

Here, R ^{1 is} hydrogen, an alkyl group, a phenyl group (which may have a substituent) or a naphthyl group (which may have a substituent), and R ² is a hydrogen, an alkyl group , A phenyl group (which may have a substituent), a carbonyl group and a sulfonyl group.

(Production of catalyst)

First, to obtain a mono-DAB-modified diamine represented by the following formula (5) by causing 1,3 dimethyl-5-acetyl-barbituric acid (DAB) to act on a diamine represented by the following formula (4) Can.

Next, a mono-DAB-modified diamine represented by (5) is reacted with 1,2-bisbromomethylbenzene having a substituent R ³ in the presence of diisopropylethylamine (DIPEA) to give the following formula (6) The diamine which introduce | transduced the DAB group and tertiary amine site | part which are shown can be obtained.

Next, a diamine having a tertiary amine moiety represented by the following formula (7) can be obtained by removing the DAB group in the presence of 2-aminoethanol with respect to the diamine represented by (6).

  And the ligand shown by the said Formula (1) can be obtained by making a salicylaldehyde act on diamine shown by following formula (7) in anhydrous sodium sulfate presence.

  Furthermore, a catalyst can be obtained by causing a metal or a metal salt to act on the ligand represented by the above formula (1).

  As described above, this embodiment can provide a catalyst that gives high asymmetric yield over a wide range of substrates in halocyclization reaction, and an optically active iodocyclization product thereby.

  Hereinafter, the catalyst of the above embodiment was actually prepared, and the effect was confirmed. It will be described below.

(Example)
In this example, a catalyst in which a ligand represented by the following formula (1-1) was coordinated to a metal salt was prepared, and the catalyst was used for a halocyclization reaction.

(Catalyst synthesis)
First, synthesis of the following formula (7-1) was performed according to the following reaction formula (8).

  First, (1R, 2R) -1, 2-diphenylethane-1, 2-diamine (1.06 g, 5.0 mmol) and 1,3-dimethyl-5-acetyl-barbituric acid (DAB) (991 mg, 5 mmol) It is dissolved in anhydrous THF solution (15 ml), stirred at 20 ° C. for 48 hours under argon atmosphere and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent 1: 1 n-hexane / ethyl acetate) to obtain a white solid mono-DAB-ized diamine in 98% yield.

  Next, the mono-DAB-formed diamine obtained above (98 mg, 0.25 mmol) is dissolved in anhydrous DMF (3 ml), diisopropylethylamine (DIPEA) (94 μl, 0.55 mmol) and o-xylenedibromide (72.6 mg, 0) .275 mmol) are added and stirred at 40.degree. C. for 48 hours under an argon atmosphere, distilled water (10 ml) is added, and then ethyl acetate and saturated brine are sequentially extracted. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent 3: 1 n-hexane / ethyl acetate) to obtain a diamine in which 81% yield was introduced as a yellow solid DAB group and tertiary amine moiety. .

  Next, the diamine (196 mg, 0.396 mmol) introduced with the DAB group and the tertiary amine moiety obtained above and 2-aminoethanol (238 μl, 3.96 mmol) are dissolved in absolute ethanol (3 ml), and the atmosphere is under argon. Stir at 50 ° C. for 24 h and concentrate under reduced pressure. The resulting residue is purified by silica gel chromatography (developing solvent 1: 1 n-hexane / ethyl acetate) to obtain 99% of diamine having a tertiary amine moiety in the form of a yellow oil represented by the above formula (12). Obtained at a rate.

Device data of (7-1):
¹ H NMR (400 MHz, CDCl ₃ ) δ 2.10 (br-s, 2 H), 4.00-4.09 (m, 5 H), 4.55 (d, J = 8.3 Hz, 1 H), 7. 07-7.24 (m, 14 H, aromatic);
¹³ C NMR (100 MHz, CDCl ₃ ) δ 16.5, 55.1, 56.0, 56.8, 63.2, 73.0, 122.2, 126.5, 126.8, 127.1, 127 .7, 127.8, 127.9, 129.8, 136.1, 139.7, 142.9;
FT / IR (solid) 3374, 3230, 3057, 3035, 2935, 2890, 2792, 1600, 1490, 1452, 1359, 1322, 1218, 1180, 1078, 1027, 873, 744, 700, 626 cm- ¹ ;
[Α] _D = + 25.7 ° (c = 0.74, CHCl ₃ );
HRMS (FAB +) calcd for C ₂₂ H ₂₃ N ₂ (M ⁺ + H) 315.1861: found 315.1870.

  Next, the diamine (7-1) (518.8 mg) and 3,5-dibromosalicylic aldehyde (419.9 mg) obtained above are dissolved in dichloromethane (10 mL) according to the following formula (9), and anhydrous sodium sulfate Add (9.0 mg), stir at room temperature under argon atmosphere for 12 hours, and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent 4: 1 n-hexane / ethyl acetate) to give 2,4-dibromo-6-((E)-((E) represented by the above formula (1-1)) ((1R, 2R) -2- (isoindolin-2-yl) -1,2-diphenylethyl) imino) methyl) phenol (860.6 mg) was obtained in a yield of 99%.

Device data of (1-1):
¹ H NMR (400 MHz, CDCl ₃ ) δ 3.98 (d, J = 11.00 Hz, 2 H), 4.07 (d, J = 11.00 Hz, 2 H), 4.30 (d, J = 7.02 Hz , 1H), 4.97 (d, J = 7.02 Hz, 1 H), 7.09-7. 19 (m, 14 H), 7. 29 (s, 1 H), 7. 69 (s, 1 H), 8.31 (s, 1 H)
¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.1, 158.2, 139.2, 139.2, 137.0, 133.0, 123.0, 129.5, 128.2, 127.9, 127 .9, 127.5, 127.5, 126.7, 122.2, 120.1, 112.3, 109.4, 76.2, 74.6, 57.5;
FT / IR (solid) 3352, 3031, 2787, 1631, 1451, 1168, 1049, 747, 705 cm- ¹
[Α] _D = + 53.16 ° (c = 0.1, CHCl ₃ );
_{HRMS (FAB +) calcd for C} 29 H 23 Br 2 N 2 O (M-H) -: 573.0183, found 573.0180.

Next, using 6.3 mg of this obtained ligand (1-1), a complex was obtained by coordinating 2.0 mg of copper acetate (II) monohydrate in methylene chloride thereto.

The asymmetric iodocyclization reaction was carried out at -78 ° C for 18 hours in the presence of the complex catalyst described above and 34.3 mg of 5-phenyl-N-tosylhex-5-amide and 24.7 mg of N-iodosuccinamide. As a result, 46.0 mg of iodo-cyclized compound (2-1) shown below could be obtained, and the yield was 98% (93% ee).

Device data of (2-1)
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 7.76 Hz, 2 H), 7.38-7.27 (m, 7 H), 3.50 (s, 2 H), 2.47 -2.33 (m, 4 H), 2.42 (s, 3 H), 1. 80 (m, 1 H), 1. 59 (m, 1 H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 143.4, 138.7, 129.3, 129.1, 128.7, 127.7 (2C), 125.1, 87.5, 31. 5, 28.3, 21.5, 16.1, 15.3;
FT / IR (solid) 3023, 2960, 1600, 1318, 1157, 758 cm ⁻¹ ;
[Α] _D = + 47.88 ° (c = 0.1, CHCl ₃ , 93% ee);
HRMS (FAB +) calcd for C ₁₉ H ₂₀ INO ₃ NaS (M + Na) ⁺ : 492.0101, found 492.0095.

When 5- (p-tolyl) -N-tosylhex-5-amide is used as a substrate, 48.3 mg of the following compound (2-2) can be obtained, and the yield is 99% (94% ee) Met.

Device data of (2-2)
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 7.56 Hz, 2 H), 7.30 (d, J = 8.48 Hz, 2 H), 7. 15 (m, 4 H), 3. 47 (s, 2 H), 2.50-2.29 (m, 4 H), 2.43 (s, 3 H), 2. 34 (s, 3 H), 1.80-1. 78 (m, 1 H) , 1.60-1.50 (m, 1 H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 143.3, 138.7, 138.6, 135.7, 129.7, 129.3, 127.6, 125.0, 87.5, 31 .3, 28.2, 21.5, 21.0, 16.3, 15.3;
FT / IR (solid) 1601, 1319, 1158, 819 cm ⁻¹
[Α] _D = + 58.55 ° (c = 0.1, CHCl ₃ , 94% ee);
_{HRMS (FAB +) calcd for C} 20 H 23 INO 3 S (M + H) + 484.0438: found 484.0427.

When the reaction is carried out using 5-cyclohexyl-N-tosylhex-5-amide as a substrate, 47.5 mg of the following compound (2-3) can be obtained, and the yield is 99% (91% ee) The

Device data of (2-3)
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (d, J = 8.38 Hz, 2 H), 7.28 (d, J = 8.38 Hz, 2 H), 3.45 (m, 2 H), 57-2.45 (m, 2H), 2.41 (s, 3H), 1.98-1.50 (m, 10H), 1.28-0.98 (m, 5H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.4, 143.0, 138.9, 129.1, 127.3, 88.6, 45.8, 29.2, 27.3, 26.5, 26 .2, 26.1, 26.1, 25.8, 21.5, 16.0, 12.5;
FT / IR (solid) 2927, 1584, 1361, 1159, 808, 576 cm ⁻¹ ;
[Α] _D = -30.81 ° (c = 0.1, CHCl ₃ , 91% ee);
HRMS (FAB +) calcd for C ₁₉ H ₂₇ INO ₃ S (M + H) ⁺ 476.0751: found 476.0737.

As described above, the utility of the catalyst according to the present invention can be confirmed by this example, and it has been confirmed that a wide range of iodo-cyclized compounds can be synthesized with high optical purity.

The present invention is useful for the development and production of medicines and agrochemicals and has industrial applicability because it can supply iodocyclized products with very high optical purity.

Claims (2)

A complex catalyst formed by coordinating a ligand represented by the following formula (1) to a copper salt , which is used to carry out an asymmetric iodocyclization reaction using an unsaturated amide.

Here, R ¹ and R ^{2 each} represent hydrogen, an alkyl group, a phenyl group (which may have a substituent) or a naphthyl group (which may have a substituent), and R ¹ and R ² may be combined to form a ring. R ¹ and R ² may be the same or different. R ³ and R ⁴ are hydrogen, fluorine, chlorine, bromine, iodine, a nitro group, an alkyl group, an alkynyl group, an alkoxy group or a phenyl group (which may have a substituent). An iodo ring represented by the following formula (2) by reacting an unsaturated amide with N-iodosuccinimide in the presence of a complex catalyst formed by coordinating a ligand represented by the following formula (1) to a copper salt Method of producing

Here, R ¹ and R ^{2 each} represent hydrogen, an alkyl group, a phenyl group (which may have a substituent) or a naphthyl group (which may have a substituent), and R ¹ and R ² may be combined to form a ring. R ¹ and R ² may be the same or different. R ³ and R ⁴ are hydrogen, fluorine, chlorine, bromine, iodine, a nitro group, an alkyl group, an alkynyl group, an alkoxy group or a phenyl group (which may have a substituent).

Here, R ^{1 is} hydrogen, an alkyl group, a phenyl group (which may have a substituent) or a naphthyl group (which may have a substituent), and R ² is a hydrogen, an alkyl group , A phenyl group (which may have a substituent), a carbonyl group and a sulfonyl group.