JP2005120041A - METHOD OF PURIFYING BIS-pi-ALLYLPALLADIUM COMPLEX AND METHOD FOR SYNTHESIZING ASYMMETRIC ALLYLAMINE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for synthesizing an asymmetric allylamine from an imine in high yield and in high asymmetry yield. <P>SOLUTION: The method for synthesizing an asymmetric allylamine represented by formula (6) (wherein R<SB>1</SB>is selected from the group consisting of o-, m- and p-substituted aromatics, naphthyl, an alkenyl, an alkyl, furyl, thiophenyl and a pyridine group; and R<SB>2</SB>is selected from the group consisting of benzyl, an aromatic ring substituted benzyl, allyl, and methyl) comprises reacting an imine represented by formula (5) with an allyltributylstannane in the presence of a bis-π-allylpalladium complex represented by chemical formula (2a) as a catalyst. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for purifying a bis-π-allyl palladium complex and a method for synthesizing an asymmetric allylamine.

  Since homoallylic alcohols and amines are useful synthetic intermediates, allylation of carbonyl compounds such as aldehydes, ketones, and their derivatives is one of the most important reactions that form C—C bonds. . Many methods have been studied, but research continues in search of more effective new methods. Of the various allyl metal reagents, allyl stannane and allyl silane are very useful. This is due to its mild reactivity and is enhanced by catalytic activity and can be applied to catalytic enantioselective reactions.

  Imine activation methods using Lewis or Bronsted acids have been similarly studied. However, these acids coordinate strongly with the amine product and cause catalyst deactivation. Further, it has been reported that a fluoride anion or an alkoxide similarly activates a C—Si bond of alkylsilane by coordinating to a silicon atom. Recently, chiral sulfoxides have been used for the allylation of N-acylhydrazones as neutral coordination organocatalysts (NCOs). Reactions with aldehydes have also been studied, but there is little to do with asymmetric allylation of imines.

The present inventors have reported an asymmetric allylation catalyzed reaction of imine using allyltributylstannane in the presence of a chiral π-allyl palladium complex (see, for example, Non-Patent Document 1). However, the yield and asymmetric yield of the obtained asymmetric allylamine are not sufficient, and further improvement is demanded, and the catalyst for that purpose is not obtained.
Catalytic Asymmetric Allylation of Imines via Chiral Bis-π-allylpalladium Complexes (H. Nakamura, et al., American Chemical Society (1998))

  An object of this invention is to provide the method of obtaining the compound used as a suitable catalyst for asymmetric allylation of imine. Another object of the present invention is to provide a method for synthesizing an asymmetric allylamine from an imine with high yield and asymmetric yield.

前記混合物をアセトン中、ｎ−Ｂｕ₄ＮＣｌの存在下でＰｄ（ＯＣＯＣＦ₃）₂と反応させて、下記化学式（２ａ）で表わされる化合物と化学式（２ｂ）で表わされる化合物との混合物を得る工程、

前記化合物（２ａ）と（２ｂ）との混合物を、ＣＨ₂Ｃｌ₂／ヘキサン中で２回、結晶化する工程、
結晶化後の前記化合物（２ａ）と（２ｂ）との混合物を、プロピオニトリル中で３回再結晶化する工程、および
ろ過により前記化学式（２ａ）で表わされる化合物を単離する工程を具備することを特徴とする。 A method for purifying a bis-π-allyl palladium complex according to one embodiment of the present invention includes:
A step of obtaining a 1: 1 mixture of E-form and Z-form of exoethylidene norpinane represented by the following chemical formula (7) from (1S)-(−)-β-pinene;

Reacting the mixture with Pd (OCOCF ₃ ) _{2 in} the presence of n-Bu ₄ NCl in acetone to obtain a mixture of a compound represented by the following chemical formula (2a) and a compound represented by the chemical formula (2b) ,

Crystallizing the mixture of the compounds (2a) and (2b) twice in CH ₂ Cl ₂ / hexane;
A step of recrystallizing the mixture of the compounds (2a) and (2b) after crystallization in propionitrile three times, and a step of isolating the compound represented by the chemical formula (2a) by filtration. It is characterized by doing.

A method for synthesizing an asymmetric allylamine according to one embodiment of the present invention includes imine and allyltributylstannane represented by the following general formula (5) as bis-π-allyl palladium represented by the following chemical formula (2a) as a catalyst. The reaction is carried out in a solvent containing water in the presence of the complex.

(Wherein R ₁ is selected from the group consisting of ortho, meta, para-substituted aromatic, naphthyl, alkenyl, alkyl, furyl, thiophenyl, and pyridine groups; R ₂ is benzyl, aromatic ring-substituted benzyl; Selected from the group consisting of, allyl, and methyl.)
A method for synthesizing an asymmetric allylamine according to another embodiment of the present invention comprises imine and allyltrimethylstannane represented by the following general formula (5) as a catalyst and bis-π-allyl represented by the following chemical formula (2a). The reaction is carried out in a solvent containing water in the presence of a palladium complex.

(Wherein R ₁ is selected from the group consisting of ortho, meta, para-substituted aromatic, naphthyl, alkenyl, alkyl, furyl, thiophenyl, and pyridine groups; R ₂ is benzyl, aromatic ring-substituted benzyl; Selected from the group consisting of, allyl, and methyl.)

  According to the aspect of the present invention, a method for obtaining a compound that becomes a suitable catalyst for asymmetric allylation of imine is provided. Moreover, according to this invention, the method of synthesize | combining asymmetric allylamine from imine with a high yield and asymmetric yield is provided.

  Hereinafter, embodiments of the present invention will be described in detail.

(Purification of bis-π-allyl palladium complex)
In the method for purifying a bis-π-allylpalladium complex according to an embodiment of the present invention, first, E form of exoethylidene norpinane represented by the following chemical formula (7) from (1S)-(−)-β-pinene. And a 1: 1 mixture of isomers and Z form.

(1R)-(+)-norpinone was obtained by ozonolysis of the exo double bond of (1S)-(−)-β-pinene by a conventional method. For the ozonization, for example, the method described in Brown, HC; Weissman, SA; Perumal, PT; Dhokte, UPJOrg. Chem. 1990, 55, 1217 can be employed. The yield of (1R)-(+)-norpinone was 75%, [α] _D ²² +39.4 (C = 1, MeOH). Subsequently, Wittig reaction was performed with ethyltriphenylphosphonium bromide and BuOK to obtain exoethylidene norpinane represented by the following chemical formula (7). The reaction here is based on, for example, the technique described in Trost, BM; Strege, PE; Weber, L .; Fullerton, TJ; Dietsche, TJJ Am. Chem. Soc. 1978, 100, 3407. it can. The yield was 83%, and this product was a 1: 1 mixture of E-form and Z-form.

Subsequently, a mixture of a compound represented by the following chemical formula (2a) and a compound represented by the following chemical formula (2b) was obtained from the exoethylidene norpinane represented by the general formula (7). For this reaction, for example, a method described in Trost, BM; Metzner, PJJ Am. Chem. Soc. 1980, 102, 3572 can be employed.

A solution was prepared by dissolving 5 g (15.04 mmol) of Pd (OCOCF ₃ ) ₂ in 125 mL of dry acetone, and this was placed in a round bottom two-necked flask. In an argon atmosphere, exoethylidene norpinane (2.26 g, 15.05 mmol) represented by the chemical formula (7) was added thereto to prepare a mixture, and the mixture was stirred at room temperature for 1 hour while monitoring the reaction by TLC. Meanwhile, Bu ₄ NCl (4.56 g, 16.55 mmol) was dissolved in 30 mL of acetone, and the resulting solution was added to the above reaction mixture and stirred for 1 hour.

As a result, a clear orange-brown solution was obtained, which was filtered through a plug made of Celite to remove Pd-black. The filtrate was concentrated to give a dark amber oil which was purified by silica gel column chromatography. Hexane / EtOAc was used as the extractant, and 6.92 g of a semi-solid product was obtained. This product was shown by ¹ H NMR to be a mixture of compound (2a): compound (2b) = 1.3: 1.

When the product was dissolved in a small amount of CH ₂ Cl ₂ and 30 mL of hexane was added, crystals were formed. The crystallized solid was filtered through a sintered funnel, washed with hexane and sucked dry. As a result, compound (2a): compound (2b) = 4.8: 1, and 3.2 g of yellow powder was obtained.

Further purification is performed according to the flow chart as shown in FIGS. In order to recover the catalyst, the filtrates after recrystallization (F1-F3) were combined and concentrated as shown in FIG. 2 to obtain a yellow solid foam. As a result of column chromatography using benzene as an extractant, the first trace fraction was Compound (2b), which was 0.45 g, [α] _D ²² +44.5 (c = 0.4, CHCl ₃ ). . The subsequent fraction was a mixture of compounds (2a) and (2b). The filtrates F4 and F5 were combined and concentrated to give a yellow powder (1 g).

When recrystallization was performed three times in succession in propionitrile, compound (2a): compound (2b) = 100: 1 (0.452 g) was obtained. [Α] _D ²² -17.2 (c = 0.4, CHCl ₃ ). As a result of recrystallization in propionitrile three more times, (2a) :( 2b) was 400: 1 (0.215 g) or more, and [α] _D ²² -19.8 (c = 0.0). 4, CHCl ₃ ).

^The analysis results by ¹ H NMR and ¹³ C NMR are shown below.

(2a): ¹ H NMR of (2b) ≧ 400: 1
Compound 2a
(CDCl ₃ ) δ 3.84-3.80 (m, 1H), 3.78-3.68 (m, 1H), 2.7-2.64 (m, 1H), 2.55 (brt, J = 5.5Hz, 1H), 2.44-2.33 (m, 1H), 2.08-2.03 (m, 1H), 1.77-1.74 (m, 2H), 1.34 (s, 3H), 1.13 (d, J = 6.5Hz, 3H), 0.91 (s, 3H).
¹³ C NMR: (CDCl ₃ ) δ 136.0, 72.2, 71.0, 40.5, 39.9, 37.8, 33.8, 29.9, 26.1, 21.7, 13.9.
IR (KBr) 2982, 2951, 2912, 2870, 1499, 1466, 1448, 1429, 1367, 1265, 1219, 1101, 1051, 1032, 974, 860, 758 cm ^-1
Compound (2b)
¹ H NMR: (CDCl ₃ ) δ 4.47-4.41 (m, 1H), 4.33-4.22 (m, 1H), 2.67-2.52 (m, 1H), 2.36-2.3 (m, 1H), 2.2-2.13 (m , 1H), 2.08-2.02 (m, 1H), 1.87-1.74 (m, 2H), 1.29 (s, 3H), 1.03 (d, J = 6.8Hz, 3H), 0.71 (s, 3H).
¹³ C NMR: (CDCl ₃ ) δ 132.5, 72.7, 70.8, 46.5, 39.9, 38.0, 34.4, 29.9, 26.0, 21.7, 16.2
IR (KBr) 2980, 2918, 2872, 2833, 1468, 1454, 1429, 1369, 1265, 1221, 1099, 1042, 968, 920, 762 cm ^-1
(Synthesis of asymmetric allylamine)
In the method for synthesizing an asymmetric allylamine according to an embodiment of the present invention, the compound (2a) obtained as described above is reacted with allyltributylstannane as shown in the following reaction formula (1). Asymmetric amination of the imine represented by the general formula (5) is performed.

(Wherein R ₁ is selected from the group consisting of ortho, meta, para-substituted aromatic, naphthyl, alkenyl, alkyl, furyl, thiophenyl, and pyridine groups; R ₂ is benzyl, aromatic ring-substituted benzyl; Selected from the group consisting of, allyl, and methyl.)
Allyltrimethylstannane can be used in place of allyltributylstannane. In addition, the allyl group in these may be substituted with at least one substituent selected from the group consisting of allyl, 2-methylallyl, crotyl, prenyl, 2-methoxycarbonyl-allyl and the like.

  As shown in the reaction formula (1), in the method for synthesizing an asymmetric allylamine according to the embodiment of the present invention, water must be present in the solvent. This was confirmed by the following experiment.

First, allylation of imine represented by the following chemical formula (8a) was performed in a tetrahydrofuran (THF) solvent containing 5 mol% of the compound (2a) under anhydrous conditions at 0 ° C.

The reaction conditions are as follows. A solution of imine 8a (0.5 mmol) in dry THF (1.25 mL: commercially available anhydrous THF) was added to allyl SnBu ₃ (0.5 mmol) and the mixture was cooled to 0 ° C. Compound (2a) (5 mol%) was added, and the reaction mixture was stirred for a predetermined time while monitoring by GC-MS. The kind of allyltributylstannane, the solvent, and the reaction temperature were changed as shown in Table 1 below, and an asymmetric allylation reaction was performed to synthesize an asymmetric allylamine represented by the chemical formula (9a). The reaction time, product yield, and asymmetric yield (% ee) are shown in Table 1 below together with the reaction conditions.

  In Experiments 1 and 2, the reaction was carried out under standard conditions, but there was no reproducibility and asymmetric selectivity was low. In addition, catalyst degradation was observed under these anhydrous conditions.

  It can be seen that by adding 1 equivalent of water to the solvent (Experiment 3), the yield and asymmetric selectivity are improved. More importantly, in the presence of water, the asymmetry yield and yield data are consistent and reproducible results are obtained. As shown in Experiment 4, when the amount of allyltributylstannane used was increased to 1.25 equivalents, the reaction time was shortened, and higher yield and enantioselectivity were obtained.

  When the order of addition was changed by adding the catalyst first and then adding stannane (Experiment 5), a longer reaction time was required, and the asymmetric selectivity slightly decreased. You can see from the comparison. Excess water (5 equivalents, Experiment 6) or less than 1 equivalent of water (0.5 equivalents, Experiment 7) results in inferior results compared to Experiment 4. At −20 ° C. (experiment 8), the reaction takes longer to complete and the yield decreases. Similar results were obtained at room temperature (Experiment 9). When compound (2b) is used as a catalyst (experiment 10), imine 8a cannot be completely consumed even after 168 hours have elapsed, and the yield of the product is low. Moreover, the asymmetric selectivity is incomplete. Although catalyst 2b gives similar enantiomers, it is necessary to separate 2b from 2a.

  Based on the above results, in the method for synthesizing an asymmetric allylamine according to the embodiment of the present invention, it is defined that the reaction is performed in a solvent containing water. In addition, if content of the water in a solvent was in the range of 0.7-4.0 equivalent, the effect similar to the case of 1 equivalent was able to be acquired. Moreover, when it was made to react not only at 0 degreeC but in the temperature within the range of -10-10 degreeC, both the yield and the asymmetric yield became tolerance.

Next, the influence was investigated using additives other than water. In dry THF at 0 ° C., imine represented by the following chemical formula (10a) was reacted with allylbutylstannane in the presence of 5 mol% of compound (2a) and additives. By this asymmetric allylation reaction, an asymmetric allylamine represented by the following chemical formula (11a) is obtained.

The reaction time, product yield, and asymmetric yield (% ee) are summarized in Table 2 below along with the reaction conditions.

As shown in Table 2, the best results for both yield and asymmetric yield are obtained when 1 equivalent of water is added. Comparable results were obtained when using molecular sieves and methanol. TBAF (tetrabutylammonium fluoride), i-PrOH (isopropanol), and KOAc (potassium acetate) have slightly low asymmetric selectivity, and KOAc has a low yield. Na ₂ CO ₃ is not suitable because it takes a long time to complete the reaction, and the yield and asymmetric selectivity are low. AcOH (acetic acid) has a long reaction time and a low yield, but an asymmetric yield comparable to that of water is obtained.

  From the above results, it was confirmed that the best results were obtained when a solvent containing 1 equivalent of water was used.

  Using various imines, asymmetric allylation was performed by the method according to the embodiment of the present invention to synthesize asymmetric allylamines. The general method is as follows. The imine (0.5 mmol) was housed in a Wheaton microreactor (5 mL capacity) and the reactor was maintained in an Ar atmosphere. Dry THF (1.25 mL), defoamed water (9 μL, 0.5 mmol, 1 eq), and allyltributylstannane (194 μL, 0.625 mmol, 1.25 eq) were added sequentially. The mixture was cooled to 0 ° C. and chiral palladium chloride complex 2a (14.56 mg, 0.025 mmol, 5 mol%) was added in an argon atmosphere. The reaction mixture was replaced with argon and stirred at 0 ° C. for a predetermined time. The progress of the reaction was monitored by GC-MS or TLC.

After the reaction was complete, the opaque reaction mixture was quenched in 1N HCl (2.5 mL). CH ₃ CN (1 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. CH ₃ CN was added to increase the solubility of the stannane byproduct. Then, extraction was performed twice using 3 mL of hexane, and the hexane layer was removed. The aqueous layer was basified with 10% aqueous NaOH (1.25 mL) and the resulting solution was stirred for 5 minutes. The solution was extracted twice with 5 mL of EtOAc, dried over Na ₂ SO ₄ and concentrated. Purification by silica gel column chromatography (hexane / EtOAc = 5: 1) gave homoallylamine. Asymmetric yield (% ee) was determined by HPLC.

The reaction time, yield, and asymmetric yield are shown below along with the imine and product used. Furthermore, the analysis result of each obtained asymmetric allylamine is summarized below.

Compound (13a): N-benzyl-1-phenyl-3-butenylamine colorless oil; [α] _D ²³ = + 51.2 (c 1.45, CHCl ₃ )
IR (neat) 3327, 3062, 3026, 3003,2976, 2925, 2837, 1639, 1493, 1454, 1120, 1117, 1070, 1028, 995, 916, 758, 735, 700 cm-1
¹ H NMR (CDCl ₃ ) δ 7.40-7.19 (m, 10H), 5.71 (dd, J = 17.0, 10.1, 7.0Hz, 1H), 5.07 (m, 1H), 5.04 (m, 1H), 3,69 (dd, J = 7.6, 6.5Hz, 1H), 3.52 (d, J = 13.5 z, 2H), 3.67 (d, J = 13.5Hz, 2H), 2.49-2.33 (m, 2H)
¹³ C NMR (CDCl ₃ ) δ 143.7, 140.5, 135.4, 128.4, 128.3, 127.3, 127.0, 126.8, 117.5, 61.6, 51.4, 43.0
Analysis of C ₁₇ H ₁₉ N (237.15) Calculated: C, 86.02; H, 8.08; N, 5.90
Analytical value: C, 85.91; H, 8.27; N, 5.78.
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 40/60, flow rate = 0.8 mL / min, UV detection at 254 nm t _R = 16.38 min (main enantiomer), t _R = 18.48 min (sub enantiomer).

Compound (13b): N-benzyl-1- (4-methoxyphenyl) -3-butenylamine colorless oil; [α] _D ²² = + 56.1 (c 0.745, CHCl ₃ )
IR (neat) 3327, 3063, 3026, 2999, 2931, 2907, 2833, 1638, 1611, 1512, 1456, 1246, 1175, 1036, 995, 915, 735, 698 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.34-7.19 (m. 7H), 6.89 (ddd, J = 8.4Hz, 3.4Hz, 2.2Hz, 2H), 5.69 (ddt, J = 16.4Hz, 10.0Hz, 6.9Hz, 1H), 5.06 (ddt, J = 16.4Hz, 2Hz, 2Hz, 1H), 5.03 (ddt, 10.0Hz, 2Hz, 2Hz, 1H), 3.81 (s, 3H), 3.66 (d, J = 12.8Hz, 1H ), 3.64 (t, J = 6.4Hz, 1H), 3.50 (d, J = 12.8Hz, 1H), 2.39 (ddt, J = 6.9, 6.5, 2.0Hz, 2H)
¹³ C NMR (CDCl ₃ ) δ 158.6, 140.7, 135.8, 135.6, 128.3, 128.1, 126.8, 117.4, 113.7, 60.9, 55.2, 51.3, 43.1
Analysis of C ₁₈ H ₂₁ N (267.16) Calculated: C, 80.82; H, 7.92; N, 5.24
Analytical value: C, 80.67; H, 7.96; N, 5.22.
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 40/60, flow rate = 0.8 mL / min, detected at 254 nm
t _R = 18.02 min (enantiomer), t _R = 21.5 min (sub-enantiomer).

Compound (13c): N-benzyl-1- (4-methylphenyl) -3-butenylamine colorless oil; [α] _D ²² = + 50.4 (c 1.0, CHCl ₃ )
IR (neat) 3325, 3061, 3025, 2977, 2921, 1638, 1603, 1513, 1495, 1454, 1350, 1304, 1176, 1029, 995, 916, 816, 735 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.28-7.13 (m, 7H), 7.09 (d, J = 8Hz, 2H), 5.6 (ddt, J = 17.1Hz, 10.3Hz, 7.1Hz, 1H), 5.02 (ddt, J = 17.1Hz, 2Hz, 2Hz, 1H), 4.97 (ddt, J = 10.3Hz, 2Hz, 2Hz, 1H), 3.61-3.59 (m, 1H), 3.6 (d, J = 13.4Hz, 1H), 3.45 (d, J = 13.4Hz, 1H), 2.34-2.32 (m, 2H), 2.3 (s, 3H), 1.66 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 140.7, 136.5, 135.5, 129.0, 128.2, 128.0, 127.2, 126.7, 117.4, 61.2, 51.3, 43.1, 21.0
MS (EI) m / z (relative intensity) 210 [M ⁺ -allyl] (5.7), 132 (0.7), 118 (1.2), 105 (2.9), 91 (100)
Analysis of C ₁₈ H ₂₁ N (251.37) Calculated: C, 86.00; H, 8.42; N, 5.57
Measurement: C, 85.82; H, 8.66; N, 5.52
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 40/60, flow rate = 0.8 mL / min, detected by UV at 254 nm
t _R = 22.82 min (major enantiomer), t _R = 27.20 min (minor enantiomer).

Compound (13d): N-benzyl-1- (2-methoxyphenyl) -3-butenylamine colorless oil; [α] _D ²² = + 37.2 (c 1.0, CHCl ₃ )
IR (neat) 3330, 3063, 3027, 3001, 2935, 2835, 1638, 1600, 1586, 1489, 1437, 1363, 1281, 1239, 1173, 1095, 1050, 1029, 996, 914, 754 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.38-7.35 (m, 1H), 7.26-7.16 (m, 6H), 6.95-6.83 (m, 2H), 5.72 (ddt, J = 16.1Hz, 10.2Hz, 6.7Hz, 1H), 5.03-4.93 (m, 2H), 4.07-4.03 (m, 1H), 3.77 (s, 3H), 3.65 (d, J = 13Hz, 1H), 3.51 (d, J = 13Hz, 1H), 2.5-2.34 (m, 2H), 1.8 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ ¹³ C NMR (CDCl ₃ ) δ 157.2, 140.7, 136.0, 131.2, 128.0, 127.9, 127.7, 127.4, 127.1, 126.5, 120.4, 116.6, 110.3, 55.8, 55.0, 51.4, 40.7
MS (EI) m / z (relative intensity) 226 [M ⁺ -allyl] (15.8), 209 (6.7), 197 (3.1), 194 (4.9), 134 (3.8), 121 (17.6), 91 (100 )
Analysis of C ₁₈ H ₂₁ NO (267.37) Calculated: C, 80.86; H, 7.91; N, 5.23
Measurement: C, 80.81; H, 8.11; N, 5.28
The asymmetric yield was determined using a CHIRALCEL OD column by changing to trifluoroacetylamide ([α] _D ²² = + 31.0 (c2.8, CHCl ₃ )) Hexane / i-PrOH = 100 / 1. Flow rate = 0.7 mL / min, detected with UV at 254 nm
t _R = 9.04 min (major enantiomer), t _R = 10.43 min (minor enantiomer).

Compound (13e): N-benzyl-1- (3,4-dimethoxyphenyl) -3-butenylamine colorless oil; [α] _D ²³ = + 38.6 (c 1.75, CHCl ₃ )
IR (neat) 3325, 3062, 2998, 2932, 2833, 1638, 1593, 1514, 1463, 1417, 1358, 1262, 1233, 1139, 1029, 916, 856, 808, 747 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.32-7.19 (m, 5H), 6.95-6.81 (m, 3H), 5.72 (ddt, J = 16.2Hz, 10.2Hz, 7.2Hz, 1H), 5.06 (ddt, J = 16.2Hz, 2Hz, 2Hz, 1H), 5.03 (ddt, J = 10.2Hz, 2Hz, 2Hz, 1H), 3.9 (s, 3H), 3.88 (s, 3H), 3.69 (d, J = 13.2Hz, 1H ), 3.63-3.59 (m, 1H), 3.54 (d, J = 13.2Hz, 1H), 2.41-2.34 (m, 2H), 1.81 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 149.0, 147.9, 140.6, 136.3, 135.5, 128.3, 128.1, 126.8, 119.5, 117.5, 110.8, 109.9, 61.2, 55.8, 51.3, 43.2
MS (EI) m / z (relative intensity) 256 [M ⁺ -allyl] (14.8), 239 (5), 214 (9.4), 151 (20.8), 91 (100)
Analysis of C ₁₉ H ₂₃ NO ₂ (297.39) Calculated: C, 76.73; H, 7.79; N, 4.71
Measurement: C, 76.68; H, 8.06; N, 4.72
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO4 aq = 30/70, flow rate = 0.8 mL / min, detected by UV at 254 nm
t _R = 28.57 min (major enantiomer), t _R = 32.58 min (minor enantiomer).

As shown in Table 3, in (Entry Nos. 1 to 5), most of the imine reacted in a short time, and the target asymmetric allylamine was obtained with high yield and excellent asymmetric yield. For example, N-benzylidenebenzylamine (compound 12a) gives compound (13a) with an asymmetric yield of 85% by reaction for 48 hours. Compounds (12b) and (12e) give compounds (13b) and (13e) in asymmetric yields of 85% and 70%, respectively, but it takes a long time to complete the reaction. Compound (12c) having a methyl group at the para position gives compound (13c) in high yield and 90% asymmetric yield. It is presumed that ortho-chelating groups such as methoxy groups give rigidity to the moving state during chelation and a high asymmetric yield is obtained. The compound (12d), which is an imine having a methoxy group at the ortho position, gives the compound (13d) with a very high asymmetric yield of 88%, but it is remarkable between 12d and 12b (paramethoxy-substituted product). No difference is confirmed.

Compound (15): N-benzyl-1-cyclohexyl-3-butenylamine colorless oil; [α] _D ²¹ = −5.4 (c 0.5, CHCl ₃ )
IR (neat) 3329, 3063, 3026, 3001, 2924, 2851, 1638, 1495, 1450, 1120, 995, 733, 698cm ^-1
1 H NMR (CDCl ₃ ) δ 7.39-7.19 (m, 5H), 5.78 (dddd, J = 18.0, 10.5, 8.0, 7.0Hz, 1H), 5.08 (m, 1H), 5.06 (m, 1H), 3.75 (bs, 2H), 2.41 (ddd, J = 8.0, 5.0, 5.0Hz, 1H), 2.35-2.02 (m, 2H), 1.83-0.95 (m, 11H)
¹³ C NMR (CDCl ₃ ) δ 141.1, 136.7, 128.2, 128.1, 126.7, 116.8, 61.3, 51.9, 40.6, 35.3, 29.4, 28.9, 26.8, 26.7
The asymmetric yield was determined using a CHIRALCEL OD column, changed to trifluoroacetylamide of [α] _D ²² = −7.8 (c 0.6, CHCl ₃ ) Hexane / i-PrOH = 800/1 , Flow rate = 0.6mL / min, detected with 254nm UV
t _R = 26.04 min (minor enantiomer), t _R = 30.41 min (main enantiomer).

Compound (17): N-benzyl-1-phenyl-1,5-hexadien-3-ylamine colorless oil; [α] _D ²³ = + 77.2 (c 1.0, CHCl ₃ )
IR (neat) 3319, 3081, 3061, 3026, 3001, 2976, 2924, 2837, 1639, 1599, 1493, 1452, 1109, 1072, 1028, 995, 968, 914, 748, 694 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.43-7.20 (m, 10H), 6.51 (d, J = 15.7Hz, 1H), 6.09 (dd, J = 15.7, 7.5Hz, 1H), 5.79 (ddt, J = 17.0 , 10.0, 6.5Hz, 1H), 5.12 (ddt, J = 17.0, 2.0, 1.5Hz, 1H), 5.09 (ddt, J = 10.0, 2.0, 1.5Hz, 1H), 3.89 (d, J = 13.5Hz, 1H), 3.70 (d, J = 13.5Hz, 1H), 3.30 (dt, J = 7.5, 6.5Hz, 1H), 2.47-2.25 (m, 2H)
¹³ C NMR (CDCl ₃ ) δ 140.5, 137.0, 135.0, 132.5, 131.3, 128.5, 128.4, 128.1, 127.4, 126.8, 126.3, 117.6, 59.5
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 60/40, flow rate = 0.6 mL / min, detected by UV at 254 nm
t _R = 10.03 min (major enantiomer), t _R = 12.17 min (minor enantiomer).

When obtaining homoallylamine (compound 15) from N-cyclohexylidenebenzylamine (compound 14), the present inventors have confirmed that the asymmetric yield is only 40% even after 111 hours of reaction. Yes. However, as shown in entry 6 of Table 4 above, the method according to the embodiment of the present invention made it possible to obtain 50% ee of the compound (15) in 74 hours of reaction. Also, as shown in entry 7, compound (16) also gives compound (17) with a high yield and an excellent asymmetric yield of 69%.

Compound (19a): N-benzyl-1- (2-furfuryl) -3-butenylamine colorless oil; [α] _D ²² = + 55.9 (c 1.0, CHCl ₃ )
IR (neat) 3330, 3063, 3028, 2978, 2914, 2837, 1640, 1604, 1512, 1495, 1455, 1346, 1248, 1176, 1148, 1108, 1073, 1028, 918, 884, 807, 734 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.31-7.13 (m, 6H), 6.25 (dd, J = 3.2Hz, 2Hz, 1H), 6.11 (d, J = 3.2Hz, 1H), 5.68 (ddt, J = 17.1 Hz, 10.2Hz, 6.6Hz, 1H), 5.05 (ddt, J = 17.1Hz, 2.2Hz, 2Hz, 1H), 5.03 (ddt, J = 10.2Hz, 2.2Hz, 2Hz, 1H), 3.72-3.70 (m , 1H), 3.69 (d, J = 13.2Hz, 1H), 3.54 (d, J = 13.2Hz, 1H), 2.4 (dd, J = 6.6Hz, 1.3Hz, 2H), 1.65 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 156.0, 141.4, 140.1, 134.8, 128.2, 128.0, 126.7, 117.5, 109.7, 106.5, 54.7, 50.93, 39.2
MS (EI) m / z (relative intensity) 186 [M ⁺ -allyl] (33.9), 131 (1.5), 95 (1.8), 91 (100)
Analysis of C ₁₅ H ₁₇ NO (227.3) Calculated: C, 79.26; H, 7.53; N, 6.16
Analytical value: C, 79.11; H, 7.84; N, 6.15.
The asymmetric yield was determined using a CHIRALCEL OD column by changing to [trifluoro] amide of [α] _D ²² = + 54.7 (c 1.0, CHCl ₃ ) hexane / i-PrOH = 500/1, Flow rate = 0.5mL / min, detected at 254nm UV
t _R = 22.18 min (major enantiomer), t _R = 25.2 min (minor enantiomer).

Compound (19b): N-benzyl-1- (2-thiophenyl) -3-butenylamine colorless oil; [α] _D ²² = + 24.5 (c 1.0, CHCl ₃ )
IR (neat) 3325, 3064, 3027, 2977, 2910, 2835, 1639, 1603, 1495, 1454, 1434, 1368, 1225, 1168, 1029, 995, 917, 850, 735 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.27-7.14 (m, 6H), 6.9-6.84 (m, 2H), 5.69 (ddt, J = 16.1Hz, 10.0Hz, 6.9Hz, 1H), 5.05 (ddt, J = 16.1Hz, 2.1Hz, 2Hz, 1H), 5.0 (ddt, J = 10.0Hz, 2.1Hz, 2Hz, 1H), 3.92 (t, J = 6.7Hz, 1H), 3.74 (d, J = 13.2Hz, 1H ), 3.55 (d, J = 13.2Hz, 1H), 2.44-2.34 (m, 2H), 1.73 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 149.2, 140.2, 134.8, 128.3, 128.2, 126.9, 126.3, 124.2, 123.9, 117.9, 57.0
MS (EI) m / z (relative intensity) 202 [M ⁺ -allyl] (18.9), 111 (2), 106 (1.3), 97 (7.9), 91 (100)
Analysis of C ₁₅ H ₁₇ NS (243.37) Calculated: C, 74.03; H, 7.04; N, 5.75; S, 13.17
Analytical value: C, 73.96; H, 7.32; N, 5.66; S, 13.18.
The asymmetric yield was changed to trifluoroacetylamide of [α] _D ²² = + 43.4 (c 1.0, CHCl ₃ ) and determined using a CHIRALCEL OD column Hexane / i-PrOH = 500/1 Flow rate = 0.5 mL / min, detected with 254 nm UV
t _R = 27.55 min (major enantiomer), t _R = 30.59 min (minor enantiomer).

From the results in Table 5 (entries 8 and 9), the heterocyclic imines (compounds 18a and 18b) react well to give compound 19a (67% ee) and compound 19b (53% ee), respectively. Understand. In all cases, the asymmetric yield was moderate, but the yield was high, and polymerization often occurring during the catalytic reaction using a Lewis acid was not confirmed.

Compound (11a): N- (4-methoxybenzyl) -1-phenyl-3-butenylamine colorless oil; [α] _D ²³ = + 49.1 (c 1.0, CHCl ₃ )
IR (neat) 3350, 3063, 3026, 3001, 2976, 2931, 2908, 2833, 1639, 1612, 1512, 1454, 1250, 1200, 1175, 1105, 1070, 1038, 995, 916, 756, 702 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.39-7.22 (m, 5H), 7.17 (ddd, J = 8.5Hz, 2.7Hz, 2.4Hz, 2H), 6.84 (ddd, J = 8.5Hz, 2.7Hz, 2.4Hz, 2H), 5.70 (dddd, J = 17.0 Hz, 10.0Hz, 8Hz, 7Hz, 1H), 5.06 (dddd, J = 17.0Hz, 2Hz, 2Hz, 2Hz, 1H), 5.03 (dddd, J = 10.0Hz, 2Hz , 2Hz, 1Hz, 1H), 3.79 (S, 3H), 3.68 (dd, J = 7.5Hz, 6.4Hz, 1H), 3.6 (d, J = 13.0Hz, 1H), 3.46 (d, J = 13.0Hz , 1H), 2.49-2.31 (m, 2H)
¹³ C NMR (CDCl ₃ ) δ 158.5, 143.8, 135.5, 132,7 129.2, 128.3, 127.3, 127.0, 117.5, 113.7, 61.5, 55.2, 50.8, 43.0
Analysis of C ₁₈ H ₂₁ NO (267.36) Calculated: C, 80.86; H, 7.92; N, 5.24
Analytical value: C, 80.67; H, 7.96; N, 5.22.
The asymmetric yield was determined by changing [α] _D ²² = + 75.0 (c 1.75, CHCl ₃ ) to trifluoroacetylamide and using a CHIRALCEL OD column. Hexane / i-PrOH = 100/1 , Flow rate = 0.6 mL / min, detected with 254 nm UV
t _R = 17.02 min (major enantiomer), t _R = 20.19 min (minor enantiomer).

Compound (11b):
N- (4-methoxybenzyl) -1- (4-methoxyphenyl) -3-butenylamine colorless oil; [α] _D ²² = + 48.3 (c 1.0, CHCl ₃ )
IR (neat) 3325, 3072, 2998, 2932, 2907, 2834, 2059, 1638, 1611, 1585, 1512, 1463, 1351, 1301, 1245, 1174, 1106, 1036, 997, 917, 831, 781, 756 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.26 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6Hz, 2H), 5.7 (ddt, J = 16.2Hz, 10.1Hz, 6.5Hz, 1H), 5.07-4.9 (m, 2H), 3.8 (s, 3H), 3.78 (s, 3H), 3.63-3.61 (m, 1H), 3.58 (d, J = 13Hz, 1H), 3.44 (d, J = 13Hz, 1H), 2.38-2.33 (m, 2H), 1.69 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 158.5, 135.7, 135.6, 132.7, 129.2, 128.2, 117.3, 113.6, 60.7, 55.2, 55.1, 50.6, 43.1
MS (EI) m / z (relative intensity) 256 [M ⁺ -allyl] (9.4), 160 (6), 122 (8.8), 121 (100), 91 (6.7), 77 (2.9)
Analysis of C ₁₉ H ₂₃ NO ₂ (297.39) Calculated: C, 76.73; H, 7.79; N, 4.71
Analytical value: C, 76.6; H, 7.98; N, 4.68.
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 35/65, flow rate = 0.8 mL / min, detected by UV at 254 nm
t _R = 31.9 min (major enantiomer), t _R = 36.22 min (minor enantiomer).

Compound (11c):
N- (4-methoxybenzyl) -1- (4-methylphenyl) -3-butenylamine colorless oil; [α] _D ²² = + 48.5 (c 1.0, CHCl ₃ )
IR (neat) 3325, 3002, 2910, 2833, 1638, 1612, 1584, 1512, 1463, 1349, 1301, 1247, 1173, 1105, 1037, 996, 917, 817, 781, 757 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.32 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8 Hz, 4H), 6.92 (d, J = 8.5 Hz, 2H), 5.78 (ddt, J = 16Hz, 10.2Hz, 6.8Hz, 1H), 5.07-5.15 (m, 2H), 3.85 (s, 3H), 3.72-3.7 (m, 1H), 3.69 (d, J = 13Hz, 1H), 3.53 (d , J = 13Hz, 1H), 2.47-2.45 (m, 2H), 2.42 (s, 3H), 1.73 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 158.4, 140.7, 136.4, 135.6, 132.7, 129.2, 129.0, 127.1, 117.4, 113.6, 61.0, 55.1, 50.6, 43.1, 21.0
MS (EI) m / z (relative intensity) 240 [M ⁺ -allyl] (13.3), 160 (4.9), 121 (100), 119 (4.9), 91 (12.4), 77 (5.3)
Analysis of C ₁₉ H ₂₃ NO (281.39) Calculated: C, 81.10; H, 8.24; N, 4.97
Analytical value: C, 81.02; H, 8.47; N, 4.97
Asymmetric yield determined by using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 35/65, flow rate = 0.8 mL / min, detected by UV at 254 nm
t _R = 41.41 min (major enantiomer), t _R = 46.64 min (minor enantiomer).

Compound (11d):
N- (4-methoxybenzyl) -1- (4-nitrophenyl) -3-butenylamine pale yellow oil; [α] _D ²² = + 26.9 (c 1.0, CHCl ₃ )
IR (neat) 3331, 3075, 3001, 2933, 2835, 1639, 1609, 1515, 1463, 1346, 1301, 1247, 1176, 1108, 1035, 1013, 996, 920, 856, 825, 753 cm ^-1
1 H NMR (CDCl ₃ ) δ 8.14 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6Hz, 2H), 5.62 (ddt, J = 16.4Hz, 10.1Hz, 6.4Hz, 1H), 5.52-4.96 (m, 2H), 3.74-3.73 (m, 1H), 3.72 (s, 3H), 3.52 (d, J = 13Hz, 1 H), 3.38 (d, J = 13Hz, 1H), 2.37-2.21 (m, 2H), 1.7 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 158.6, 151.8, 147.0, 134.2, 131.9, 129.1, 128.0, 123.6, 118.5, 113.7, 60.9, 55.2, 50.9, 42.8
MS (EI) m / z (relative intensity) 271 [M ⁺ -allyl] (2), 186 (14.6), 150 (4.3), 121 (44.6), 91 (100), 81 (10.2), 77 (11.8 )
Analysis of C ₁₈ H ₂₀ N ₂ O ₃ (312.37) Calculated: C, 69.21; H, 6.45; N, 8.96
Analytical value: C, 68.98; H, 6.73; N, 8.8
The asymmetric yield was determined by changing the trifluoroacetylamide of [α] _D ²² = + 30.6 (c 1.5, CHCl ₃ ) and using a CHIRALCEL OD column Hexane / i-PrOH = 50/1 , Flow rate = 0.8 mL / min, detected with 254 UV
t _R = 27.43 min (minor enantiomer), t _R = 29.75 min (main enantiomer).

Compound (11e): N- (2-methoxybenzyl) -1-phenyl-3-butenylamine colorless oil; [α] _D ²² = + 51.6 (c 1.0, CHCl ₃ )
IR (neat) 3343, 3062, 3026, 3001, 2934, 2835, 1638, 1601, 1588, 1492, 1463, 1358, 1288, 1241, 1175, 1117, 1048, 1029, 955, 916, 836, 754, 702 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.34-7.18 (m, 6H), 7.1-7.05 (m, 1H), 6.89-6.82 (m, 2H), 5.66 (ddt, J = 16.8Hz, 10.1Hz, 6.8Hz, 1H), 5.07 (ddt, J = 16.8Hz, 2.2Hz, 2Hz, 1H), 5.02 (ddt, J = 10.1Hz, 2.2Hz, 2Hz, 1H), 3.8 (s, 3H), 3.72 (d, J = 13.4Hz, 1H), 3.63-3.6 (m, 1H), 3.58 (d, J = 13.4Hz, 1H), 2.39-2.35 (m, 2H), 2.12-1.91 (brs, 1H)
13C NMR (CDCl ₃ ) δ 157.6, 143.8, 135.5, 129.8, 128.2, 128.1, 128.0, 127.3, 126.8, 120.1, 117.3, 110.0, 60.9, 54.9, 47.1, 43.1
MS (EI) m / z (relative intensity) 226 [M ⁺ -allyl] (11.9), 160 (3.9), 122 (9.2), 121 (100), 105 (2.3), 94 (3.1), 93 (37.6 ), 91 (7.2), 79 (1.3), 77 (1)
Analysis of C ₁₈ H ₂₁ NO (267.37) Calculated: C, 80.86; H, 7.91; N, 5.23
Analytical value: C, 80.83; H, 8.18; N, 5.2
Asymmetric yield determined by using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 50/50, flow rate = 0.8mL / min, detected by UV at 254nm
t _R = 10.03 min (deputy enantiomer), t _R = 12.66 min (main enantiomer).

Table 6 summarizes the results for imines having a chelate methoxy substituent on either the aryl group of the aldehyde moiety or the benzyl group of the imino nitrogen. As shown in entries 10-12, compounds (10a), (10b), and (10c) having a paramethoxybenzyl group were homoallylamine in asymmetric yields of 90%, 85%, and 86%, respectively. (11a), (11b), and (11c) are obtained. Compound (10d) having a nitro group at the para position of the aldehyde moiety gives compound (11d) with a high yield of 94%, but the asymmetric yield is not sufficient (entry 13). Furthermore, as shown in entry 14, compound (11e) is obtained from compound (10e) having a ltomethoxybenzyl group with an asymmetric yield of 89%.

Compound (21a): N-benzyl-1- (2-naphthyl) -3-butenylamine colorless oil; [α] _D ²¹ = + 64.0 (c 1.5, CHCl ₃ )
IR (neat) 3327, 3059, 3026, 2976, 2909, 2833, 1638, 1495, 1454, 1124, 870, 819, 746, 698 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.80-7.65 (m, 4H), 7.49-7.30 (m, 3H), 7.27-7.10 (m, 5H), 5.65 (dddd, J = 16.5, 10.0, 6.8, 6.5, 1H ), 5.00 (m. 1H), 4.95 (m, 1H), 3.78 (t, J = 6.5Hz, 1H), 3.62 (d, J = 12.7Hz, 1H), 3.47 (d, J = 12.7Hz. 1H ), 2.48-2.34 (m, 2H)
¹³ C NMR (CDCl ₃ ) δ 141.2, 14.5, 135.3, 133.4, 132.9, 128.3, 128.2, 128.1, 127.8, 127.6, 126.8, 126.2, 125.9
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 40/60, flow rate = 0.8mL / min, detected by UV at 254nm
t _R = 58.3 min (major enantiomer), t _R = 67.45 min (minor enantiomer).

Compound (21b):
N- (4-methoxybenzyl) -1- (2-naphthyl) -3-butenylamine colorless oil; [α] _D ²² = + 54.3 (c 1.0, CHCl ₃ )
IR (neat) 3330, 3076, 3026, 2978, 2911, 2833, 1640, 1602, 1492, 1454, 1415, 1357, 1115, 1070, 1027, 994, 759 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.95-7.86 (m, 4H), 7.63-7.51 (m, 3H), 7.26 (d, J = 8.6Hz, 2H), 6.94 (d, J = 8.6Hz, 2H), 5.85 (ddt, J = 16.4Hz, 10.2Hz, 6.9Hz, 1H), 5.2-5.1 (m, 2H), 3.95-3.91 (m, 1H), 3.87 (s, 3H), 3.74 (d, J = 13Hz , 1H), 3.5 (d, J = 13Hz, 1H), 2.62-2.52 (m, 2H), 1.87 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 158.4, 141.1, 135.3, 133.3, 132.7, 132.5, 129.1, 128.0, 127.6, 126.1, 125.8, 125.3, 125.2, 117.5, 113.6, 61.4, 55.0, 50.6, 42.8
MS (EI) m / z (relative intensity) 276 [M ⁺ -allyl] (7.7), 160 (6.6), 122 (8.7), 121 (100), 91 (4.8), 77 (2.4)
Analysis of C ₂₂ H ₂₃ NO (317.43) Calculated: C, 83.24; H, 7.3; N, 4.41
Analytical value: C, 83.19; H, 7.49; N, 4.58
Asymmetric yield determined by CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 50/50, flow rate = 0.7mL / min, detected by UV at 254nm
t _R = 38.16 min (major enantiomer), t _R = 42.87 min (minor enantiomer).

As shown in Table 7, N-2-naphthylidenebenzylamine (compound 20a) gives compound 21a with a high asymmetric yield of 91% (entry 15). However, as shown in entry 16, in the case of compound (20b) having a para-methoxybenzyl group, the asymmetric yield is relatively low.

無色の油状；［α］_D ²³＝＋２４．８（ｃ １．０，ＣＨＣｌ₃）
ＩＲ(neat) 3329, 3077, 3026, 3003, 2977, 2910, 2833, 1640, 1602, 1542, 1492, 1454, 1357, 1307, 1235, 1199, 1069, 1027, 994, 917, 758 cm^-1
1Ｈ ＮＭＲ(CDCl₃) δ 7.35-7.23(m, 5H), 5.86-5.73(m, 1H), 5.73-5.7(m, 1H), 5.14-5.03(m, 4H), 3.72(dd, J=6.2Hz, 1.2Hz, 1H), 3.11-3.02(m, 2H), 2.44-2.39(m, 2H), 1.71(brs, 1H)
¹³Ｃ ＮＭＲ(CDCl₃) δ 143.4, 136.4, 135.2, 128.5, 126.9, 126.7, 117.3, 115.4, 61.4, 49.7, 42.8
ＭＳ （ＥＩ） ｍ／ｚ （相対強度） 188 [M⁺+1] (0.9), 146 [M⁺-allyl] (16.1), 129 (14.9), 119 (2.6), 104 (4.8), 91 (100), 77 (2.1)
Ｃ₁₃Ｈ₁₇Ｎ（１８７．２８）
計算値：Ｃ，８３．３７；Ｈ，９．１４；Ｎ，７．４７
分析値：Ｃ，８３．０７；Ｈ，９．３５；Ｎ，７．４
不斉収率は、［α］_D ²²＝＋９３．２（ｃ １．０，ＣＨＣｌ₃）のトリフルオロアセチルアミドに変化させ、ＣＨＩＲＡＬＣＥＬ ＯＤカラムを用いて決定
ヘキサン／ｉ−ＰｒＯＨ＝３００／１，流量=0.6mL/min，２５４ｎｍのUVで検出
t_R=16.17min（主エナンチオマー），t_R=17.85min（副エナンチオマー）。 Compound (23a): N-allyl-1-phenyl-3-butenylamine

Colorless oil; [α] _D ²³ = + 24.8 (c 1.0, CHCl ₃ )
IR (neat) 3329, 3077, 3026, 3003, 2977, 2910, 2833, 1640, 1602, 1542, 1492, 1454, 1357, 1307, 1235, 1199, 1069, 1027, 994, 917, 758 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.35-7.23 (m, 5H), 5.86-5.73 (m, 1H), 5.73-5.7 (m, 1H), 5.14-5.03 (m, 4H), 3.72 (dd, J = 6.2Hz, 1.2Hz, 1H), 3.11-3.02 (m, 2H), 2.44-2.39 (m, 2H), 1.71 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 143.4, 136.4, 135.2, 128.5, 126.9, 126.7, 117.3, 115.4, 61.4, 49.7, 42.8
MS (EI) m / z (relative intensity) 188 [M ⁺ +1] (0.9), 146 [M ⁺ -allyl] (16.1), 129 (14.9), 119 (2.6), 104 (4.8), 91 ( 100), 77 (2.1)
C ₁₃ H ₁₇ N (187.28)
Calculated value: C, 83.37; H, 9.14; N, 7.47
Analytical value: C, 83.07; H, 9.35; N, 7.4
The asymmetric yield was changed to trifluoroacetylamide of [α] _D ²² = + 93.2 (c 1.0, CHCl ₃ ) and determined using a CHIRALCEL OD column Hexane / i-PrOH = 300/1 Flow rate = 0.6mL / min, detected at 254nm UV
t _R = 16.17 min (major enantiomer), t _R = 17.85 min (minor enantiomer).

The imines in which substituents other than the benzyl group were bonded to the imino nitrogen were examined, and the results are summarized in Table 8 above. As shown in entry 17, N-allylimine (compound 22a) gives allylated homoallylamine (compound 23a) in high yield and asymmetric yield of 78%. It can be seen from entry 18 that the reaction of compound (22b) is very slow and when the imine is completely consumed, the yield of product 23b is less than 10% even after 144 hours. The reason for such a slow reaction will be described later.

Compound (25): N-methyl-1- (3-pyridyl) -3-butenylamine yellow liquid; [α] _D ²² = + 43.1 (c 1.66, CHCl ₃ )
IR (neat) 3324, 3082, 2979, 2936, 1666, 1640, 1578, 1476, 1428, 1098, 1027, 996, 734 cm ^-1
1 H NMR (CDCl ₃ ) δ 8.45-8.41 (m, 2H), 7.62-7.58 (m, 1H), 7.23-7.2 (m, 1H), 5.69-5.59 (m, 1H), 5.08-5.01 (m, 2H), 3.64-3.60 (m, 1H), 3.51 (t, J = 6.8Hz, 1H), 2.47-2.4 (m, 2H), 2.2 (s, 3H)
¹³ C NMR (CDCl ₃ ) δ 149.2, 148.5, 138.6, 134.7, 134.3, 123.5, 118.3, 62.1, 42.4, 34.7
MS (EI) m / z (relative intensity) 163 [M ⁺ + H] (3.5), 161 [M ⁺ -H] (6.3), 121 [M ⁺ -allyl] (100), 119 (9.6), 94 (92), 80 (18.7), 78 (9.4)
Analysis of C ₁₀ H ₁₄ N ₂ (162.23) Calculated: C, 74.04; H, 8.69; N, 17.27
Analytical value: C, 74.24; H, 8.85; N, 16.94.
The asymmetric yield was changed to trifluoroacetylamide of [α] _D ²² = + 90.5 (c 0.5, CHCl ₃ ) and determined using a CHIRALCEL OD column. Hexane / i-PrOH = 10/1, Flow rate = 0.7mL / min, detected with 254nm UV
t _R = 24.13 min (minor enantiomer), t _R = 32.58 min (main enantiomer).

Compound (27):
N-benzyl-1- (3,4,5-trimethoxyphenyl) -3-butenylamine colorless thick liquid; [α] _D ²² = + 15.3 (c 1.0, CHCl ₃ )
IR (neat) 3325, 3062, 2997, 2936, 2835, 1638, 1590, 1505, 1462, 1419, 1325, 1233, 1183, 1128, 1009, 917, 831, 739 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.34-7.21 (m, 5H), 6.6 (s, 2H), 5.73 (ddt, J = 16.6Hz, 10.0Hz, 6.9Hz, 1H), 5.13-5.05 (m, 2H) , 3.87 (s, 6H), 3.85 (s, 3H), 3.71 (d, J = 13.2Hz, 1H), 3.63-3.59 (m, 1H), 3.56 (d, J = 13.2Hz, 1H), 2.45- 2.31 (m, 2H), 1.81 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 153.2, 140.5, 139.6, 136.6, 135.4, 128.3, 128.1, 126.8, 117.7, 103.8, 61.8, 60.8, 56.0, 51.4, 43
MS (EI) m / z (relative intensity) 286 [M ⁺ -allyl] (14.9), 254 (8.4), 238 (23.2), 209 (6.1), 195 (6.9), 181 (13.8), 169 (4 ), 125 (1.2), 91 (100)
Analysis of C ₂₀ H ₂₅ NO ₃ (327.42) Calculated: C, 73.36; H, 7.69; N, 4.27
Analytical value: C, 73.12; H, 7.89; N, 4.57
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 30/70, flow rate = 0.8 mL / min, detected by UV at 254 nm
t _R = 31.15 min (major enantiomer), t _R = 34.64 min (minor enantiomer).

As shown in Table 9, N-3-pyridylidenemethylamine (Compound 24) requires a longer reaction time and the asymmetric yield of Compound (25) is moderate. Compound 26 having three methoxy groups gives compound (27) with an asymmetric yield as insufficient as 34%.

Compound (9a): N-benzyl-1-piperonyl-3-butenylamine colorless oil; [α] _D ²² = + 59.1 (c 1.0, CHCl ₃ )
IR (neat) 3327, 3063, 3026, 2976, 2894, 1638, 1607, 1468, 1439, 1376, 1243, 1183, 1100, 1040, 996, 865, 736 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.32-7.21 (m, 5H), 6.91 (s, 1H), 6.77 (s, 2H), 5.95 (s, 2H), 5.69 (ddt, J = 17.0Hz, 10.2Hz, 7.2Hz, 1H), 5.09 (ddt, J = 17.0Hz, 2.2Hz, 2Hz, 1H), 5.03 (ddt, J = 10.2Hz, 2.2Hz, 2Hz, 1H), 3.66 (d, J = 13.2Hz, 1H ), 3.6 (t, J = 6.8Hz, 1H), 3.51 (d, J = 13.2Hz, 1H), 2.38-2.28 (m, 2H), 1.7 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 147.8, 146.4, 140.5, 137.8, 135.3, 128.3, 128.0, 126.8, 120.5, 117.5, 107.9, 107.2, 100.8, 61.3, 51.3, 43.2
MS (EI) m / z (relative intensity) 240 [M ⁺ -allyl] (100), 148 (3.9), 117 (2.5), 91 (81), 65 (5.7)
Analysis of C ₁₈ H ₁₉ NO ₂ (281.35) Calculated: C, 76.84; H, 6.8; N, 4.97
Analytical value: C, 76.52; H, 6.68; N, 5.21
Asymmetric yield determined by CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 40/60, flow rate = 0.8mL / min, detected by UV at 254nm
t _R = 18.4 min (major enantiomer), t _R = 22.2 min (minor enantiomer).

Compound (9b):
N- (4-methoxybenzyl) -1-piperonyl-3-butenylamine colorless oil; [α] _D ²² = + 54.9 (c 1.0, CHCl ₃ )
IR (neat) 3327, 3072, 2902, 2834, 1638, 1611, 1584, 1512, 1376, 1300, 1244, 1177, 1101, 1038, 997, 814, 759 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.26 (d, J = 8.4 Hz, 2H), 7.0 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.85 (s, 2H), 6.04 (s, 2H), 5.78 (ddt, J = 16.1Hz, 10.1Hz, 6.6Hz, 1H), 5.1 (ddt, J = 16.1Hz, 2.1Hz, 2Hz, 1H), 5.12 (ddt, J = 10.1Hz, 2.1Hz, 2Hz, 1H), 3.87 (s, 3H), 3.71-3.7 (m, 1H), 3.67 (d, J = 13Hz, 1H), 3.55 (d, J = 13Hz, 1H), 2.46-2.42 (m, 2H ), 1.77 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 158.4, 147.7, 146.4, 137.8, 135.4, 132.6, 129.2, 120.5, 117.4, 113.6, 107.8, 107.2, 100.8, 61.1, 55.2, 50.6, 43.1
MS (EI) m / z (relative intensity) 270 [M ⁺ -allyl] (8.4), 160 (5.4), 122 (9.8), 121 (100), 91 (7.4), 77 (2.8)
Analysis of C ₁₉ H ₂₁ NO ₃ (311.38) Calculated: C, 73.28; H, 6.79; N, 4.49
Analytical value: C, 73.07; H, 6.9; N, 4.78
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 35/65, flow rate = 0.8 mL / min, detected by UV at 254 nm
t _R = 34.37 min (major enantiomer), t _R = 38.25 min (minor enantiomer).

Compound (9c):
N- (2-methoxybenzyl) -1-piperonyl-3-butenylamine colorless oil; [α] _D ²² = + 57.8 (c 1.0, CHCl ₃ )
IR (neat) 3341, 3073, 3001, 2902, 2834, 1638, 1601, 1588, 1490, 1376, 1326, 1289, 1180, 1098, 996, 868, 755 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.18-7.12 (m, 1H), 7.03-7.0 (m, 1H), 6.85-6.76 (m, 3H), 6.69 (s, 2H), 5.87 (s, 2H), 5.6 (ddt, J = 16.4Hz, 10.2Hz, 6.6Hz, 1H), 5.0 (ddt, J = 16.4Hz, 2.1Hz, 2Hz, 1H), 4.96 (ddt, J = 10.2Hz, 2.1Hz, 2Hz, 1H) , 3.75 (s, 3H), 3.65 (d, J = 13.4Hz, 1H), 3.48-3.46 (m, 1H), 3.42 (d, J = 13.4Hz, 1H), 2.3-2.17 (m, 2H), 1.95 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 157.5, 147.0, 146.2, 137.9, 135.5, 129.8, 128.2, 128.0, 120.5, 120.1, 117.2, 110.0, 107.7, 107.3, 100.6, 60.7, 54.9, 46.9, 43.2
MS (EI) m / z (relative intensity) 270 [M ⁺ -allyl] (10.5), 160 (5.9), 148 (1.4), 122 (8.9), 121 (100), 93 (23), 91 (3.5 )
Analysis of C ₁₉ H ₂₁ NO ₃ (311.38) Calculated: C, 73.28; H, 6.79; N, 4.49
Analytical value: C, 73.1; H, 7.01; N, 4.4
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 50/50, flow rate = 0.7mL / min, detected by UV at 254nm
t _R = 13.3 min (minor enantiomer), t _R = 17.11 min (main enantiomer).

Compound (9d): N-benzyl-1-chloropiperonyl-3-butenylamine colorless oil; [α] _D ²² = + 48.0 (c 1.0, CHCl ₃ )
IR (neat) 3330, 3075, 3027, 2977, 2896, 1639, 1603, 1502, 1475, 1408, 1391, 1375, 1269, 1237, 1159, 1110, 1038, 996, 935, 841, 796, 734 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.92-7.21 (m, 5H), 7.2 (s, 1H), 6.77 (s, 1H), 5.94-5.92 (m, 2H), 5.74 (ddt, J = 16.8Hz, 10.2 Hz, 6.8Hz, 1H), 5.07-5.0 (m, 2H), 4.15 (dd, J = 4.8Hz, 3.8Hz, 1H), 3.62 (d, J = 13.2Hz, 1H), 3.5 (d, J = 13.2Hz, 1H), 2.43-2.35 (m, 1H), 2.23-2.13 (m, 1H), 1.66 (brs, 1H)
13C NMR (CDCl ₃ ) δ 147.1, 146.7, 140.3, 134.9, 134.2, 128.2, 128.0, 126.8, 124.9, 117.8, 109.5, 107.4, 101.5, 57.1, 51.4, 41.4
MS (EI) m / z (relative intensity) 274 [M ⁺ -allyl] (7.5), 169 (2), 115 (2.2), 91 (100)
Analysis of C ₁₈ H ₁₈ ClNO ₂ (315.8) Calculated: C, 68.46; H, 5.75; N, 4.43; Cl, 11.23
Analytical value: C, 68.4; H, 5.85; N, 4.46; Cl, 11.11.
Asymmetric yield determined by CHIRALCEL OD-R column
CH3CN / 1M NaClO ₄ aq = 60/40, flow rate = 0.6mL / min, detected by UV at 254nm
t _R = 17.13 min (major enantiomer), t _R = 19.3 min (minor enantiomer).

Compound (9e): N-benzyl-1-bromobromoperonyl-3-butenylamine colorless oil; [α] _D ²² = + 40.2 (c 1.0, CHCl ₃ )
IR (neat) 3330, 3074, 3027, 2976, 2896, 1638, 1604, 1500, 1473, 1406, 1388, 1373, 1234, 1158, 1038, 996, 981, 837, 735 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.38-7.31 (m, 5H), 7.3 (s, 1H), 7.03 (s, 1H), 6.02-6.01 (m, 2H), 5.81 (ddt, J = 16.8Hz, 10.2 Hz, 6.7Hz, 1H), 5.16-5.09 (m, 2H), 4.19 (dd, J = 4.6Hz, 3.9Hz, 1H), 3.70 (d, J = 13.2Hz, 1H), 3.58 (d, J = 13.2Hz, 1H), 2.52-2.43 (m, 1H), 2.29-2.18 (m, 1H), 1.76 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 147.7, 147.0, 140.3, 135.7, 134.9, 128.2, 128.0, 126.8, 117.8, 113.9, 112.4, 107.8, 101.5, 59.6, 51.4, 41.5
MS (EI) m / z (relative intensity) 318 [M ⁺ -allyl] (1.8), 238 (2.9), 214 (2.1), 148 (2), 107 (2.2), 91 (100)
Analysis of C ₁₈ H ₁₈ BrNO ₂ (360.25) Calculated: C, 60.01; H, 5.04; N, 3.89; Br, 22.18
Analytical value: C, 59.71; H, 5.17; N, 3.98; Br, 22.48.
Asymmetric yield determined using CHIRALCEL OD-R column
CH ₃ CN / 1M NaClO ₄ aq = 60/40, flow rate = 0.6 mL / min, detected by UV at 254 nm
t _R = 21.97 min (major enantiomer), t _R = 24.92 min (minor enantiomer).

Compound (9f): N-diphenylmethylene-1-piperonyl-3-butenylamine colorless oil; [α] _D ²² = + 53.5 (c 1.58, CHCl ₃ )
IR (neat) 3325, 3063, 3027, 2978, 2887, 2775, 1639, 1600, 1547, 1504, 1487, 1445, 1377, 1324, 1246, 1184, 1098, 1075, 1042, 941, 912, 864, 762 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.32-7.13 (m, 10H), 6.81 (d, J = 2Hz, 1H), 6.74 (d, J = 8Hz, 1H), 6.64 (dd, J = 8Hz, 2Hz, 1H ), 5.92 (s, 2H), 5.6 (ddt, J = 16.8Hz, 10.1Hz, 6.8Hz, 1H), 5.05 (ddt, J = 16.8Hz, 2Hz, 2Hz, 1H), 4.97 (ddt, J = 10.1 Hz, 2Hz, 2Hz, 1H), 4.59 (s, 1H), 3.46 (t, 6.5Hz, 1H), 2.38-2.34 (m, 2H), 2.0-1.94 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 147.7, 146.4, 144.5, 143.3, 137.8, 135.4, 128.4, 128.2, 127.7, 127.3, 126.9, 126.6, 120.5, 117.3, 107.9, 107.2, 100.8, 63.0, 58.9, 43.0
MS (EI) m / z (relative strength) 316 [M ⁺ -allyl] (8.6), 167 (100), 165 (17.3), 148 (1.8), 122 (3), 115 (4.2), 76 (5.7 )
Analysis of C ₂₄ H ₂₃ NO ₂ (357.45) Calculated: C, 80.64; H, 6.48; N, 3.92
Analytical value: C, 80.52; H, 6.51; N, 3.8
The asymmetric yield was determined using a CHIRALCEL OD column, changing to [trifluoro] amide of [α] _D ²² = + 78.2 (c 1.0, CHCl ₃ ) Hexane / i-PrOH = 50/1 , Flow rate = 0.8mL / min, detected with UV at 254nm
t _R = 14.44 min (major enantiomer), t _R = 18.95 min (minor enantiomer).

  The inventors focused on the compound (9a) obtained by allylation of the compound (8a) shown in Table 10. Complete reduction of the double bond in this amine (compound 9a) and elimination of the benzyl protecting group gives (R) -α-propylpiperonylamine. This chiral butylamine is an important substance for the synthesis of human leukocyte elastase antagonist L-694,458. Only a few examples of the synthesis of such amines have been reported so far. As shown in entry 21, allylation of compound (8a) gives compound (9a) in a high yield of 76%, asymmetric yield of 90% (21). This compound can be readily converted to (R) -α-propylpiperonylamine by double bond hydrogenation and benzyl deprotection.

Table 10 also shows the results of allylation of arylimines having other substituents at the allyl moiety and arylimines having other substituents bonded to the benzyl group. Compound (8b) having a para-methoxybenzyl group and compound (8c) having an ortho-methoxybenzyl group give compounds (9b) and (9c), respectively, with an asymmetric yield of 89%, as described above. They are equivalent (entries 22, 23). As shown in entries 24 and 25, the introduction of Cl or Br at the ortho position of the aryl group does not change the effect. When bulky substituents such as diphenylmethylene are introduced into the imino nitrogen, there is little improvement. Compound (8f) gives compound (9f) with a low yield of 30% and an asymmetric yield of 83% (entry 26).

The [α] _D value employed here is the same as that of Nakamura, M .; Hirai, A .; Nakamura, E .; J. et al. Am. Chem. Soc. 1996, 118, 8489. Or Meyers. A. I. Dickman, D .; A. Boes, M .; Tetrahedron 1987, 43, 5095.

Compound (29): ¹ H NMR of (S) -2-allylpiperidine hydrochloride (D ₂ O + CH ₃ NO ₂ internal standard) δ 5.877-5.73 (m, 1H), 5.26-5.2 (m, 2H), 3.39- 3.35 (m, 1H), 3.17-3.13 (m, 1H), 3.06-2.87 (m, 1H), 2.52-2.29 (m, 2H), 2.00-1.43 (m, 6H)
¹³ C NMR (CDCl ₃ ) δ 135.5, 117.2, 56.0, 47.0, 41.9, 32.6, 26.2, 24.8
The asymmetric yield was determined by changing [α] _D ²¹ = −0.43 (c, 0.9, CH ₂ Cl ₂ ), pale yellow N-tosylamide and using a CHIRALCEL OD column. PrOH = 50/1, flow rate = 1.0 mL / min, detected by UV at 254 nm
t _R = 9.91min (deputy enantiomer), t _R = 11.12min (main enantiomer)
The placement was determined by comparison with the reported optical rotation.

Compound (30): (R) -2-allylpiperidine
^{In 1} H NMR and ¹³ C NMR, the asymmetric yield was changed to [α] _D ²³ = + 4.1 (c, 0.995, CH ₂ Cl ₂ ), pale yellow N-tosylamide, as described above. Determined using a CHIRALCEL OD column Hexane / i-PrOH = 50/1, flow rate = 1.0 mL / min, detected with UV at 254 nm
t _R = 9.92 min (main enantiomer, t _R = 11.42 min (minor enantiomer).

Compound (32): (R) -1-allyl-1,2,3,4-tetrahydroisoquinoline yellow oil; [α] _D ²² = + 6.2 (c 0.61, THF)
The determination of the arrangement was made by comparison with the reported optical rotation IR (neat) 3072, 3018, 2920, 2833, 2803, 2728, 1638, 1492, 1454, 1430, 1315, 1132, 997, 914, 741 cm ^-1
1 H NMR (CDCl ₃ ) δ 7.17-7.07 (m, 4H), 5.85-5.79 (m, 1H), 5.2-5.12 (m, 2H), 4.05 (dd, J = 9.0Hz, 3.5Hz, 1H), 3.26-3.2 (m, 1H), 3.01-2.93 (m, 1H), 2.83-2.63 (m, 3H), 2.55-2.48 (m, 1H), 1.81 (brs, 1H)
¹³ C NMR (CDCl ₃ ) δ 138. 7, 135.8, 129.1, 126.4, 125.5, 117.8, 55.3, 41.2, 29.8
MS (EI) m / z (relative intensity) 173 [M ⁺ ] (0.3), 172 [M ⁺ -H] (1.9), 132 [M ⁺ -allyl] (100), 117 (6.9), 105 (5.1 ), 91 (1.2), 77 (3.5).

Compound (33): (S) -1-allyl-1,2,3,4-tetrahydroisoquinoline yellow oil; [α] _D ²² = −16.1 (c 0.61, THF)
IR, ¹ H NMR, ¹³ C NMR and MS data were the same as described above.

  Table 11 shows the allylation of cis cyclic imines (compounds 28 and 31) as entries 27 and 28. It has been proved that a compound that is a cis-cyclic imine is a substance that hardly undergoes asymmetric allylation by the method according to the embodiment of the present invention. The reason for the significant difference between trans-imine and cis-imine is explained in detail below.

The mechanism of allylation is represented by the following scheme.

  As already reported, bis-π-allyl palladium complex 4 is a reactive intermediate, the allyl ligand acts as a mobile group, and other non-mobile allyl groups are allylated. Determine the three-dimensional control. Thus, transmetallation between catalyst 2a and allyltributylstannane yields tributylstannyl chloride and bis-π-allyl palladium complex 4. Complex 4 reacts with imine 5 and π-allyl palladium amine 35 is obtained via complex 34.

  An important step for chiral introduction is the step in which imine 5 coordinates to bis-π-allyl palladium chloride 4 to give compound 34, and subsequent allylation proceeds in a 6-membered chain transition state. Compound 35 is obtained. Subsequent transmetallation of allyltributylstannane to palladium yields the corresponding stannyl homoallylamine 36 and recycle 4 to complete the catalytic cycle.

  The product, homoallylamine 6, is obtained by hydrolysis of compound 36. The role of water in this reaction is to form pentacoordinate allylstannane. That is, water coordinates to tetravalent stannane to promote C-Sn bond cleavage and enhances the transmetallation step in providing regenerated product 4 and stannyl homoallylamine 36. In addition, even if the sulfonylimine (compound 22b) shown in the above-mentioned entry 18 is consumed by reaction, it cannot produce | generate an amine with sufficient yield. This is presumably due to stabilization and reduction of the nucleophilicity of the nitrogen atom by the electron-withdrawing tosyl group of the intermediate corresponding to compound 35. This intermediate yields the product amine and regenerated product 4 by transmetallation with allyltributylstannane. Therefore, the catalyst cycle must be closed.

Trans-imine and cis-imine transition state models are shown in the scheme below.

  A) and b) in the scheme are models for trans-imine and cis-imine, respectively.

In the case of trans-imine, as shown in a), the front of the palladium catalyst η ³ -10-methylpinene group is crowded by the methyl group at the C-10 position, and the imine approaches from the rear with less interference. To do. The nitrogen atom of imine coordinates to a palladium atom, and a C—C bond is formed through a transition state of a chair type 6-membered ring. In the case of Compound 38, a large steric repulsive force exists between the R group of the imine and the C-7 methylene group. Thus, the reaction proceeds via the transition state model 37 and preferentially yields (R) -homoallylamine.

  On the other hand, in the case of cis-imine shown in b), since the hydrogen atom (H) is small, there is no large repulsive force between the hydrogen atom of the imine and the C-7 methylene group. Thus, a cyclic cis-imine that does not have an α-substituent on the nitrogen does not interact sterically vigorously with any allylating agent of the activated complex. For these reasons, the energy difference between the transition state models 39 and 40 is small and a satisfactory asymmetric yield cannot be obtained.

  Allylamine can be synthesized in high yield and asymmetric yield by asymmetric allylation of trans-imine by the method according to the embodiment of the present invention.

  The method concerning embodiment of this invention can be used suitably for the synthesis | combination of asymmetric allylamine which is an important substance as a pharmaceutical intermediate.

The flowchart explaining the purification method concerning embodiment of this invention. The flowchart explaining the purification method concerning embodiment of this invention.

Claims (12)

A step of obtaining a 1: 1 mixture of E-form and Z-form of exoethylidene norpinane represented by the following chemical formula (7) from (1S)-(−)-β-pinene;

Reacting the mixture with Pd (OCOCF ₃ ) _{2 in} the presence of n-Bu ₄ NCl in acetone to obtain a mixture of a compound represented by the following chemical formula (2a) and a compound represented by the chemical formula (2b) ,

Crystallizing the mixture of the compounds (2a) and (2b) twice in CH ₂ Cl ₂ / hexane;
A step of recrystallizing the mixture of the compounds (2a) and (2b) after crystallization in propionitrile three times, and a step of isolating the compound represented by the chemical formula (2a) by filtration. A method for purifying a bis-π-allyl palladium complex. A method for synthesizing an asymmetric allylamine represented by the following general formula (6),
Reacting an imine represented by the following general formula (5) with allyltributylstannane in a solvent containing water in the presence of a bis-π-allyl palladium complex represented by the following chemical formula (2a) as a catalyst. A characteristic synthesis method.

(Wherein R ₁ is selected from the group consisting of ortho, meta, para-substituted aromatic, naphthyl, alkenyl, alkyl, furyl, thiophenyl, and pyridine groups; R ₂ is benzyl, aromatic ring-substituted benzyl; Selected from the group consisting of, allyl, and methyl.)   The method for synthesizing an asymmetric allylamine according to claim 2, wherein the allyltributylstannane is used at a ratio of 1.25 equivalents.   The allyl group in the allyltributylstannane is substituted with at least one substituent selected from the group consisting of allyl, 2-methylallyl, crotyl, prenyl, and 2-methoxycarbonyl-allyl. Item 4. A method for synthesizing an asymmetric allylamine according to Item 2 or 3. A method for synthesizing an asymmetric allylamine represented by the following general formula (6),
Reacting an imine represented by the following general formula (5) with allyltrimethylstannane in a solvent containing water in the presence of a bis-π-allyl palladium complex represented by the following chemical formula (2a) as a catalyst. A characteristic synthesis method.

(Wherein R ₁ is selected from the group consisting of ortho, meta, para-substituted aromatic, naphthyl, alkenyl, alkyl, furyl, thiophenyl, and pyridine groups; R ₂ is benzyl, aromatic ring-substituted benzyl; Selected from the group consisting of, allyl, and methyl.)   The method for synthesizing an asymmetric allylamine according to claim 5, wherein the allyltributylstannane is used at a ratio of 1.25 equivalents.   The allyl group in the allyltrimethylstannane is substituted with at least one substituent selected from the group consisting of allyl, 2-methylallyl, crotyl, prenyl, and 2-methoxycarbonyl-allyl. Item 7. A method for synthesizing an asymmetric allylamine according to Item 5 or 6.   The method for synthesizing an asymmetric allylamine according to any one of claims 2 to 7, wherein the solvent is tetrahydrofuran containing 0.7 to 4.0 equivalents of water.   The method for synthesizing an asymmetric allylamine according to any one of claims 2 to 8, wherein the solvent is tetrahydrofuran containing 1 equivalent of water.   The method for synthesizing an asymmetric allylamine according to any one of claims 2 to 9, wherein the reaction is performed at -10 to 10 ° C.   The method for synthesizing an asymmetric allylamine according to any one of claims 2 to 10, wherein the reaction is carried out at 0 ° C. The R ₁ in the general formula (5) is a group represented by the following chemical formula (Ra), and R ₂ is a group represented by the following chemical formula (Rb). A method for synthesizing an asymmetric allylamine according to Item.

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