JP2012092066A - Pyrrole and indole derivative and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a Friedel-Crafts/protonation reaction using a trisubstituted nitroalkene, and to provide pyrrole and indole derivatives obtained thereby.SOLUTION: Using a metal catalyst prepared by using a ligand represented by formula (1), pyrrole and indole derivatives are composed. In the formula: X is bromine, fluorine, a nitro group, or a sulphonyl group; Ph is a phenyl group; Ts is a tosyl group; and Ph and Ts may have substituents.

Description

  The present invention relates to pyrrole and indole derivatives and a method for producing 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.

  Currently, optically active pyrrole and indole derivatives have achieved catalytic asymmetric synthesis by using various metal catalysts. For example, as a conventional technique, an example of using a copper catalyst in the reaction of pyrrole or indole with a nitroalkene. Are described in the following document 1, and examples using a zinc catalyst are described in the following documents 2 and 3.

Yokoyama N. Arai T .; , Chem. Commun, 2009, 3285. Trost B.E. M.M. Muller C .; , J .; Am. Chem. Soc. , 2008, 130, 2438. Liu H. Lu S .; -F. Xu J .; Du D .; -M. , Chem. Asian. J. et al. 2008, 3, 1111.

However, in any of the documents described above, pyrrole or indole Friedel-Crafts using a trisubstituted nitroalkene represented by the following formula (4) (R ⁴ is not hydrogen as shown in the following formula (4)): There is no example in which the reaction is applied to catalytic asymmetric synthesis, and development of a reaction system using a metal catalyst is desired in order to expand the reaction substrate.

In view of the above problems, the present invention provides a Friedel-Crafts / protonation reaction using a metal-catalyzed trisubstituted nitroalkene (R ⁴ is not hydrogen) and a pyrrole and indole derivative synthesis obtained thereby. With the goal.

The inventors of the present invention have been diligently examining the above-mentioned problem. In the presence of a catalyst in which an imidazoline ligand is coordinated to a metal, pyrrole or indole and a 3-substituted nitroalkene (R ⁴ is not hydrogen). Discovered that the Friedel-Crafts reaction and the asymmetric protonation reaction can be carried out simultaneously to produce a pyrrole derivative represented by the following formula (5) and an indole derivative represented by the following formula (6). As a result, the present invention has been completed.

That is, the method for producing a pyrrole derivative and an indole derivative according to one means of the present invention comprises pyrrole or indole and a 3-substituted nitro in the presence of a catalyst prepared using a ligand represented by the following formula (1). React the alkene.

  (Here, X is bromine, fluorine, nitro group, sulfonyl group, Ph is phenyl group, Ts is tosyl group. Ph and Ts may have a substituent.)

(Wherein R ¹ and R ² are hydrogen or an alkyl group, R ³ is hydrogen, an alkyl group, an aryl group, a carbonyl group, R ⁴ is an alkyl group or an aryl group, provided that R ⁴ is Not hydrogen.)

(Wherein R ³ is hydrogen, an alkyl group, an aryl group, a carbonyl group, R ⁴ is an alkyl group or an aryl group, provided that R ⁴ is not hydrogen, and R ⁵ is hydrogen, bromine, Chlorine, fluorine, alkyl group, alkoxy group, carbonyl group, nitro group, which may have a plurality.)

As described above, according to the present invention, it is possible to provide a Friedel-Crafts / protonation reaction using a trisubstituted nitroalkene (R ⁴ is not hydrogen) and a pyrrole and indole derivative obtained by using a metal catalyst, The reaction substrate can be enlarged. In addition, according to the present invention, the target compound can be obtained with a high optical purity with a very high chemical yield.

  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 pyrrole and indole derivatives according to this embodiment, pyrrole or indole is reacted with a 3-substituted nitroalkene in the presence of a catalyst prepared using a ligand represented by the following formula (1).

(Here, X is bromine, fluorine, nitro group, sulfonyl group, Ph is phenyl group, Ts is tosyl group. Ph and Ts may have a substituent.)

  Since the ligand in the catalyst used in the present embodiment has an imidazoline skeleton and a phenyl skeleton bridged with nitrogen in its structure, the reaction field is wide. Moreover, since it has a nitro group in the phenol ring, its activity is high.

Moreover, as long as it can coordinate, the metal which coordinates a ligand is not necessarily limited to this, For example, copper, nickel, cobalt, ruthenium, rhodium, or iron can be illustrated. Moreover, as a method of coordinating a ligand to 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, it is possible to use _{CuOTf, CuCl, CuOAc,} the _{CuCl 2, Cu (OAc) 2} , Cu (OTf) 2 and the like.

The catalyst according to the present embodiment can be used for performing Friedel-Crafts / protonation reaction using a tri-substituted nitroalkene. Specifically, in the presence of the catalyst according to the present embodiment, a pyrrole or indole is reacted with a 3-substituted nitroalkene as in the reaction represented by the following formula to convert a polysubstituted pyrrole derivative and an indole derivative into an optically active substance. Can be synthesized as

  The reaction is preferably carried out in toluene, but benzene, dichloromethane, tetrahydrofuran, dimethyl sulfoxide can be used.

In the above reaction, a nitroalkene used as a reaction substrate is represented by the following formula (4). Here, R ⁴ and R ⁵ are not limited, but R ³ can be, for example, an aryl group or a carbonyl group, and R ⁴ can be, for example, an alkyl group or an aryl group. In the above reaction, in the case of pyrrole, the amount of nitroalkene used is preferably in the range of 0.5 mol to 1 mol, more preferably 0.5 mol to 0 mol, with 1 mol of pyrrole. Within 6 mol or less. In the case of indole, when the indole is 1 mol, it is preferably in the range of 1.5 mol or more and 2.5 mol or less, more preferably in the range of 1.9 mol or more and 2.1 mol or less.

As a result, according to the method according to the present embodiment, a pyrrole derivative represented by the following formula (2) and an indole derivative represented by the following formula (3) can be obtained. These are not limited as long as they can be synthesized, but for the synthesis method, for example, “Ballini R .; Gabrielli S .; Palmieri A .; Petrini Marino., Tetrahedron, 2008, 64, 5435.”, “Bartoli G Bosco M; Giuli S .; Giuliami A .; Lucarelli L .; Mercantoni E .; Sambri L .; Torregiani E., J. Org. Chem., 2005, 70, 1941. "and" Sur. R .; Alkovati A. H. N., Synthetic Communications., 2010, 40, 320. ".

(Wherein R ¹ and R ² are hydrogen or an alkyl group, R ³ is hydrogen, an alkyl group, an aryl group, a carbonyl group, R ⁴ is an alkyl group or an aryl group, provided that R ⁴ is Not hydrogen.)

(Wherein R ³ is hydrogen, an alkyl group, an aryl group, a carbonyl group, R ⁴ is an alkyl group or an aryl group, provided that R ⁴ is not hydrogen, and R ⁵ is hydrogen, bromine, Chlorine, fluorine, alkyl group, alkoxy group, carbonyl group, nitro group, which may have a plurality.)

  Here, the reaction mechanism when pyrrole according to this embodiment is used as a starting material will be described.

Nitroalkene is activated by the action of imidazoline-aminophenol-copper catalyst, and pyrrole or indole causes Friedel-Crafts reaction. The copper nitronate produced by this reaction is captured by protons, the catalyst is regenerated, and the reaction proceeds. In the case of pyrrole, it reacts at the 2-position next to the nitrogen atom of the pyrrole ring, while in the case of indole, it reacts at the 3-position to give the target compound.

(Synthesis of ligand)
In addition, the ligand and the catalyst according to this embodiment are not limited as long as they can be synthesized, but for example, “Yokoyama N .; Arai T .; Yanagisawa A., Chem. Eur. J., 2008, 2052. "and" Yokoyama N .; Arai T., Chem. Commun, 2009, 3285. "

As described above, according to the present embodiment, it is possible to provide a Friedel-Crafts / protonation reaction using a trisubstituted nitroalkene (R ⁴ is not hydrogen) and a pyrrole and indole derivative obtained thereby by a metal catalyst. The reaction substrate can be enlarged. In addition, according to the present invention, the target compound can be obtained with a high optical purity with a very high chemical yield.

Hereinafter, in order to confirm the effect of the invention according to the above embodiment, a catalyst was actually created and the effect was confirmed. This is specifically shown below.
First, see "Yokoyama N .; Arai T .; Yanagisawa A., Chem. Eur. J., 2008, 2052." and "Yokoyama N .; Arai T., Chem. Commun, 2009, 3285." Then, a ligand was synthesized, 0.0120 g of this ligand was used, and an asymmetric Friedel-Crafts / protonation reaction was performed as a catalyst by coordinating copper (I) trifluoromethanesulfonate. .

Example 1
In this example, 28 mg of (E) -tert-butylethyl 3-nitrobut-2-enoate dissolved in 0.375 ml of anhydrous toluene and 0.020 ml of pyrrole were reacted in the presence of the above catalyst at 0 ° C. for 98 hours. It was. The catalyst is a catalyst obtained by removing trifluoromethanesulfonic acid from a ligand-copper complex with 0.003 g of potassium carbonate. In addition, the potassium carbonate used for acid removal is filtered and removed from the reaction system. As a result, 0.035 g of the compound (2-1) shown below could be obtained. The yield of (2-1) was 93% (major: minor = 87/13), and the enantiomeric excess was 84% ee. As for the relative arrangement of the main product of the compound, it was confirmed by single crystal X-ray crystal structure analysis that the t-butoxycarbonyl group and the nitro group had an anti-steric structure. The various data of the following compound (2-1) and the ORTEP diagram of single crystal X-ray crystal structure analysis are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.65 (br, 1H), 6.74 (m, 1H), 6.12 (m, 1H), 6.07 (m, 1H), 4.99-4 .96 (m, 1H) 4.15 (d, 1H), 1.60 (d, 3H), 1.46 (s, 9H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 168.9, 122. 8, 118.9, 108.9, 108.7, 85.4, 83.3, 49.9, 27.9, 17.5; Enantiomeric excess was determined by HPLC with a chiralcel AD-H + OD-H column ( 95: 5 hexane: 2-propanol , 0.8 mL / min, 254 nm); minor enantiomer t r = 21.3 min, _{major enantiomer t r = 22.6 min,} 84% ee); IR (neat) 3411, 2981, 1722,1553, 1369,1152 cm -1
(Syn addt: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.68 (br, 1H), 6.77 (m, 1H), 6.15 (m, 1H), 6.10 (m, 1H), 4 .99-4.96 (m, 1H), 4.12 (d, 1H), 1.41 (d, 3H), 1.41 (s, 9H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 169 8, 122.5, 118.9, 109.1, 109.9, 85.4, 83.1, 49.9, 27.8, 17.8; Enantiomerically excerced was determined by HPLC with a chiralcel AD-. H + OD-H column (95: 5 hexane: 2-propanol, 0.8 mL / min, 254 nm); minor enantiomer _{t r = 20.0 min, major enantiomer} t r = 33.5 min, 84% ee))

(Example 2)
In this example, the reaction was performed at a reaction temperature of 23 ° C. for 60 hours under the same conditions as in Example 1. As a result, 0.018 g of the following compound (2-2) could be obtained. The yield of (2-1) was 52% (major body: minor body = 80/20), and the enantiomeric excess was 87% ee for the major body and 67% ee for the minor body.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.87 (br, 1H), 7.22-7.35 (m, 5H), 6.64 (m, 1H), 6.12-6.10 (m , 2H), 5.18-5.15 (m, 1H), 4.55 (d, 1H), 1.43 (d, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 137.9, 129 .3,128.6,128.0,127.8,118.0,108.7,106.2,86.9,49.3,18.9; Enantiomerically excess was determined by HPLC with a chiralcel AD-. H column (97: 3 hexane: 2-propanol, 1.0 mL / min, 254 nm); major enantiomer t r = 22.7 m _{in, minor enantiomer t r = 24.8} min, 87% ee; IR (neat) 3426, 2923, 1547, 1359 cm -1
(Minor product: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.89 (br, 1H), 7.22-7.35 (m, 5H), 6.68 (m, 1H), 6.15 (m , 1H), 6.12 (m, 1H), 5.18-5.15 (m, 1H), 4.46 (d, 1H), 1.66 (d, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 137.9, 129.5, 129.1, 128.4, 127.9, 118.0, 109.0, 107.0, 86.9, 49.8, 19.1; Enantiomeric excess was determined by HPLC with a chiralcel AD-H column (97: 3 hexane: 2-propanol, 1.0 mL / min, 254 nm); _{enantiomer t r = 26.8 min, major} enantiomer t r = 29.7 min, 67% ee)

(Example 3)
In this example, 25 mg of trans-β-methyl-β-nitrostyrene dissolved in 0.750 ml of anhydrous toluene and 0.031 ml of pyrrole were reacted in the presence of the above catalyst at 23 ° C. for 16 hours. As a result, 0.036 g of the compound (2-3) shown below could be obtained. The yield of (2-3) was 92% (major body: minor body = 67/33).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.52 (br, 1H), 7.35-7.22 (m, 5H), 5.97 (m, 1H), 5.77 (m, 1H), 5.20-5.10 (m, 1H), 4.49 (d, 1H), 2.55-2.45 (m, 2H), 1.40 (d, 3H), 1.20-1. 10 (m, 3H);
(Minor product: ¹ H NMR (500 MHz, CDCl ₃ ) 7.57 (br, 1H), 7.35-7.22 (m, 5H), 5.76 (m, 1H), 5.75 (m, 2H), 5.20-5.10 (m, 1H), 4.40 (d, 1H), 2.55-2.45 (m, 2H), 1.65 (d, 3H), 1.20. -1.10 (m, 3H)

Example 4
In this example, 28 mg of (E) -tert-butylethyl 3-nitrobut-2-enoate dissolved in 0.184 ml of anhydrous toluene and 17 mg of indole dissolved in 0.184 ml of anhydrous toluene were added at 10 ° C., 92 It was performed by reacting for hours. The catalyst is a catalyst obtained by removing trifluoromethanesulfonic acid from a ligand-copper complex with 0.003 g of potassium carbonate. In addition, the potassium carbonate used for acid removal is filtered and removed from the reaction system. As a result, 0.042 g of the compound (2-4) shown below could be obtained. The yield of (2-4) was 94% (major body: minor body = 90/10), and the enantiomeric excess was 87% ee for the major body and 62% ee for the minor body.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.16 (br, 1H), 7.69 (d, 2H), 7.35 (d, 2H), 7.23-7.13 (m, 3H), 5.20-5.25 (m, 1H), 4.41 (d, 1H), 1.70 (d, 3H) 1.41 (s, 9H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 169 6, 136.1, 126.2, 123.5, 122.6, 120.1, 119.0, 111.5, 108.8, 85.0, 82.6, 48.7, 28.0 , 18.0; Enantiomerically excess was determined by HPLC with a chiralcel OJ-H column (90:10 hexane: 2-propanol, 1.0 mL / min, 254 nm) ;, m _{jor enantiomer t r = 27.3 min,} minor enantiomer t r = 31.7 min, 87% ee); IR (neat) 3412, 2979, 1721,1550, 1367,1151 cm -1
(Syn product: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.20 (br, 1H), 7.69 (d, 2H), 7.40 (d, 2H), 7.23-7.13 (m , 3H), 5.20-5.25 (m, 1H), 4.38 (d, 1H), 1.40 (d, 3H) 1.37 (s, 9H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 169.6, 136.4, 125.9, 123.5, 122.8, 120.3, 119.1, 111.7, 108.8, 83.7, 82.4, 48.3 , 27.9, 18.5; Enantiomerically excess was determined by HPLC with a chiralcel OJ-H column (90:10 hexane: 2-propanol, 1.0 mL / mi) n, 254 nm); minor enantiomer t r = 15.7 min, major enantiomer t r = 24.2 min, 62% ee))

(Example 5)
In this example, the reaction was performed at a reaction temperature of 23 ° C. for 46 hours under the same conditions as in Example 4 above. As a result, 0.047 g of the following compound (2-5) was obtained. The yield of (2-5) was 96% (major body: minor body = 90/10), and the enantiomeric excess was 87% ee for the major body and 65% for the minor body.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.14 (br, 1H), 7.18-7.13 (m, 3H), 6.84 (dd, 1H), 5.24-5.19 (m , 1H), 4.37 (d, 1H), 3.87 (s, 1H), 1.72 (d, 3H) 1.42 (s, 9H); Enantiomerically excess was determined by HPLC with a Chiralcel AD- H + OD-H column (90:10 hexane: 2-propanol, 0.8 mL / min, 254 nm); major enantiomer t r = 30.7 min, minor enantiomer t r = 43.1 min, 87% ee)
(Minor product: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.21 (br, 1H), 7.18-7.13 (m, 3H), 6.89 (dd, 1H), 5.24-5 .19 (m, 1H), 4.33 (d, 1H), 3.87 (s, 1H), 1.41 (d, 3H) 1.39 (s, 9H); Enantiomerically excess was determined by HPLC with a Chiralcel AD-H + OD- H column (90:10 hexane: 2-propanol, 0.8 mL / min, 254 nm); minor enantiomer t r = 38.9 min, major enantiomer t r = 44.8 min, 65 % Ee)

(Example 6)
In this example, the reaction was carried out at the reaction temperature of 23 ° C. for 40 hours under the same conditions as in Example 4. As a result, 0.029 g of the following compound (2-6) could be obtained. The yield of (2-6) was 51% (major body: minor body = 91/9), and the enantiomeric excess was 87% ee for the major body.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.21 (br, 1H), 7.86 (s, 1H), 7.27-7.24 (d, 1H), 7.19-7.17 (m , 2H), 5.26-5.20 (m, 1H), 4.30 (d, 1H), 1.72 (d, 3H) 1.42 (s, 9H); Enantiomeric excess was determined by HPLC with a Chiralcel OD-H + OD- H column (90:10 hexane: 2-propanol, 1.0 mL / min, 254 nm) ;, major enantiomer t r = 18.2 min, minor enantiomer t r = 21.87 min, 87% ee)
(Minor product: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.21 (br, 1H), 7.85 (s, 1H), 7.27-7.24 (d, 1H), 7.19-7 .17 (m, 2H), 5.26-5.20 (m, 1H), 4.30 (d, 1H), 1.40 (d, 3H) 1.38 (s, 9H)

  As described above, according to this example, it was found that a pyrrole or indole derivative having a continuous asymmetric center can be synthesized with high optical purity using a catalytic amount of a copper complex.

  Since the pyrrole derivative and the indole derivative can be supplied with very high optical purity, the present invention is useful for the development and production of pharmaceuticals and agricultural chemicals and has industrial applicability.

Claims (2)

The method to synthesize | combine the pyrrole derivative shown by following formula (2) using the metal catalyst prepared using the ligand shown by following formula (1).
(Here, X is bromine, fluorine, nitro group, or sulfonyl group, Ph is a phenyl group, and Ts is a tosyl group. Ph and Ts may have a substituent.)
(Wherein R ¹ and R ² are hydrogen or an alkyl group, R ³ is hydrogen, an alkyl group, an aryl group, a carbonyl group, R ⁴ is an alkyl group or an aryl group, provided that R ⁴ is Not hydrogen.) A method of synthesizing an indole derivative represented by the following formula (3) using a metal catalyst prepared using a ligand represented by the following formula (1).
(Here, X is bromine, fluorine, nitro group, sulfonyl group, Ph is phenyl group, Ts is tosyl group. Ph and Ts may have a substituent.)
(Wherein R ³ is hydrogen, an alkyl group, an aryl group, a carbonyl group, R ⁴ is an alkyl group or an aryl group, provided that R ⁴ is not hydrogen, and R ⁵ is hydrogen, bromine, Chlorine, fluorine, alkyl group, alkoxy group, carbonyl group, nitro group, which may have a plurality.)