JP2016160215A - METHOD FOR PRODUCING OPTICALLY ACTIVE α-THIO-β-AMINONITRILE - Google Patents

METHOD FOR PRODUCING OPTICALLY ACTIVE α-THIO-β-AMINONITRILE Download PDF

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JP2016160215A
JP2016160215A JP2015040258A JP2015040258A JP2016160215A JP 2016160215 A JP2016160215 A JP 2016160215A JP 2015040258 A JP2015040258 A JP 2015040258A JP 2015040258 A JP2015040258 A JP 2015040258A JP 2016160215 A JP2016160215 A JP 2016160215A
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group
isomer
alkyl group
optically active
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修一 中村
Shuichi Nakamura
修一 中村
近藤　健
Ken Kondo
健 近藤
奈津美 小林
Natsumi Kobayashi
奈津美 小林
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Nagoya Institute of Technology NUC
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Abstract

PROBLEM TO BE SOLVED: To provide a convenient and high enantioselective synthesis method for optically active α-thioacetonitrile using α-thioacetonitrile.SOLUTION: The present invention provides an asymmetric catalytic production method for optically active α-thio-β-amino nitrile by the following formula using optically active palladium catalyst (R1 is an alkyl group, or an aryl group; R2 is a diarylphosphinoyl group, an arenesulfonyl group, an alkylcarbonyl group or the like; R3 is a cyclic alkyl group or the like; R4 is a cyclic alkyl group or the like; silver salt used therein is acetate or the like; palladium complex therein used is pincer-type bisimidazoline-palladium complex).SELECTED DRAWING: None

Description

本発明は、光学活性なα−チオ−β−アミノニトリル類の製造方法に関するものである。   The present invention relates to a method for producing optically active α-thio-β-amino nitriles.

光学活性なα−チオアセトニトリル化合物誘導体は、様々な生理活性物質や医農薬品合成の中間体として広く用いており、ホルミル及びアシルアニオン等価体、アルキルニトリル等価体として機能し得る（非特許文献１―２）。特に、光学活性なα−チオ−β−アミノニトリル類を合成する有力な手法としては、イミン類に対するα−チオアセトニトリルの不斉求核付加反応が挙げられる。しかしながら、α−チオアセトニトリルを求核剤として用いる反応は、用いることのできる求電子剤はカルボニル化合物に限定され、非不斉反応に限定されていた（非特許文献３）。

Optically active α-thioacetonitrile compound derivatives are widely used as intermediates in the synthesis of various physiologically active substances and medical and agrochemical products, and can function as formyl and acyl anion equivalents and alkylnitrile equivalents (Non-patent Document 1). ―2). In particular, an effective method for synthesizing optically active α-thio-β-amino nitriles includes asymmetric nucleophilic addition reaction of α-thioacetonitrile to imines. However, in the reaction using α-thioacetonitrile as a nucleophile, the electrophile that can be used is limited to carbonyl compounds, and is limited to non-asymmetric reactions (Non-patent Document 3).

B. M. Trost, J. R. Granja, J. Am. Chem. Soc. 1991, 113, 1044-1046.B. M. Trost, J. R. Granja, J. Am. Chem. Soc. 1991, 113, 1044-1046. D. Nath, M. C. Skilbeck, I. Coldham, F. F. Fleming, Org. Lett. 2014, 16, 62-65.D. Nath, M. C. Skilbeck, I. Coldham, F. F. Fleming, Org. Lett. 2014, 16, 62-65. D. Morgans, Jr. G. B. Feigelson, J. Org. Chem. 1982, 47, 1131-1133D. Morgans, Jr. G. B. Feigelson, J. Org. Chem. 1982, 47, 1131-1133

この出願の発明が解決しようとする課題は、現状の技術では、α−チオアセトニトリルを用いる光学活性なα−チオアセトニトリル類の簡便かつ高エナンチオ選択的合成法がない点である。 The problem to be solved by the invention of this application is that there is no simple and highly enantioselective synthesis method of optically active α-thioacetonitriles using α-thioacetonitrile in the present state of the art.

本発明の目的は、上記点に鑑みて、適切な不斉触媒を用いて光学活性なα−チオ−β−アミノニトリル類の不斉触媒的製造方法を提供することにある。

In view of the above points, an object of the present invention is to provide an asymmetric catalytic production method of optically active α-thio-β-amino nitriles using an appropriate asymmetric catalyst.

本発明は、下記化学式（化1）で示される反応により種々のイミン類に対し光学活性パラジウム錯体存在下でα−チオアセトニトリルを反応させることにより光学活性な四置換不斉炭素を有するα−チオ−β−アミノニトリル類を製造する方法を提供することにある（請求項１）。 In the present invention, α-thio having an optically active tetrasubstituted asymmetric carbon is obtained by reacting various imines with α-thioacetonitrile in the presence of an optically active palladium complex by a reaction represented by the following chemical formula (Formula 1). An object of the present invention is to provide a method for producing -β-aminonitriles (claim 1).

前記イミン類は、次式（化２）で示される。 The imines are represented by the following formula (Formula 2).

R1は、アルキル基、アリール基を示す。R2はジアリールホスフィノイル基、ジアルキルホスフィノイル基、アレーンスルホニル基、アルキルスルホニル基、アレーンカルボニル基、アルキルカルボニル基、アルコキシカルボニル基、アリール基、アルキル基を示す。
（化１）において、R3は、環状アルキル基、鎖状アルキル基、フルオロ基、クロロ基、ブロモ基、またはアリール基を示す。R4は、環状アルキル基、鎖状アルキル基、アリール基を示す。 R 1 represents an alkyl group or an aryl group. R 2 represents a diarylphosphinoyl group, a dialkylphosphinoyl group, an arenesulfonyl group, an alkylsulfonyl group, an arenecarbonyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an aryl group, or an alkyl group.
In (Chemical Formula 1), R 3 represents a cyclic alkyl group, a chain alkyl group, a fluoro group, a chloro group, a bromo group, or an aryl group. R 4 represents a cyclic alkyl group, a chain alkyl group, or an aryl group.

また、用いる銀塩は、酢酸塩、安息香酸塩、アセチルアセトナート塩などでもよい。
用いるパラジウム錯体はピンサー型ビスイミダゾリン−パラジウム錯体である。
また、アルキルアルコール、フェノール、シリルアルコールなどの添加を行ってもよい。
以下、種々の実施例を示す。 The silver salt used may be acetate, benzoate, acetylacetonate salt or the like.
The palladium complex used is a pincer type bisimidazoline-palladium complex.
Moreover, you may perform addition of alkyl alcohol, phenol, silyl alcohol, etc.
Various examples will be described below.

発明者らは、イミンの窒素上にトルエンスルホニル基を導入し、α−チオアセトニトリルの不斉求核付加反応を求核剤として用いる触媒的不斉求核付加反応を実施検討した。
（第１実施形態）
次式（３） The inventors conducted a catalytic asymmetric nucleophilic addition reaction using an asymmetric nucleophilic addition reaction of α-thioacetonitrile as a nucleophile by introducing a toluenesulfonyl group onto the nitrogen of the imine.
(First embodiment)
The following formula (3)

（実施例１）
次式（４）の化学式で与えられる(2S,3S)-3-(toluenesulfonyl)amino-3-phenyl-2- phenylthiopropionitrileの合成について記述する。 Example 1
The synthesis of (2S, 3S) -3- (toluenesulfonyl) amino-3-phenyl-2-phenylthiopropionitrile given by the chemical formula of the following formula (4) is described.

乾燥させた試験管にピンサー型ビスイミダゾリン−パラジウム錯体（4.3 mg, 0.00394 mmol）、アセチルアセトナート銀（Ｉ）（0.8 mg, 0.00394 mmol）をテトラヒドロフラン0.5 mLに溶解させ、-30 ℃に冷却した。続いてフェニルチオアセトニトリル（15 mL, 0.116 mmol）とヘキサフルオロイソプロパノール(10 mL, 0.095 mmol)、(N-Toluenesulfonyl)imine（20.4 mg, 0.0788 mmol）を加え-30 ℃で48時間攪拌した。反応はTLC（薄層クロマトグラフィー）にて確認後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下、留去し、シリカゲルクロマトグラフィー（Benzene:CH3CN = 98:2）で精製し、目的生成物を30.5 mg(95%, 91:9 Dr, 99/89% ee)で得た。 In a dried test tube, pincer-type bisimidazoline-palladium complex (4.3 mg, 0.00394 mmol) and acetylacetonate silver (I) (0.8 mg, 0.00394 mmol) were dissolved in 0.5 mL of tetrahydrofuran and cooled to −30 ° C. Subsequently, phenylthioacetonitrile (15 mL, 0.116 mmol), hexafluoroisopropanol (10 mL, 0.095 mmol) and (N-Toluenesulfonyl) imine (20.4 mg, 0.0788 mmol) were added, and the mixture was stirred at −30 ° C. for 48 hours. The reaction was confirmed by TLC (thin layer chromatography), a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (Benzene: CH 3 CN = 98: 2) to obtain the target product as 30.5 mg (95%, 91: 9 Dr, 99/89% ee). It was.


１H NMR (300 MHz, CDCl3) δ7.59-7.50 (m, 4H), 7.44-7.32 (m, 3H), 7.26-7.11 (m, 7H),
, 5.69 (d, J = 8.1 Hz, 1H), 4.84 (m, 1H), 4.03 (d, J = 3.9 Hz, 1H), 2.34 (s, 3H);
HPLC (DAICEL CHIRALPAKID-3O, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm ) tR = 45.1 min (minor syn-isomer), 95.5 min (major syn-isomer), 105.2 min (minor anti-isomer), 182.1 min (major anti-isomer).

（実施例２−１０）
下記反応式（化５）で示すベンズアルデヒド由来のN-トルエンスルホニルイミンの代わりに窒素上の置換基を種々変更したイミン類へ種々の不斉触媒を用いた実施例の結果を表１に示す
1 H NMR (300 MHz, CDCl 3 ) δ7.59-7.50 (m, 4H), 7.44-7.32 (m, 3H), 7.26-7.11 (m, 7H),
, 5.69 (d, J = 8.1 Hz, 1H), 4.84 (m, 1H), 4.03 (d, J = 3.9 Hz, 1H), 2.34 (s, 3H);
HPLC (DAICEL CHIRALPAKID-3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 45.1 min (minor syn-isomer), 95.5 min (major syn-isomer), 105.2 min (minor anti- isomer), 182.1 min (major anti-isomer).

(Example 2-10)
Table 1 shows the results of Examples in which various asymmetric catalysts were used for imines in which substituents on nitrogen were changed in place of benzaldehyde-derived N-toluenesulfonylimine represented by the following reaction formula (Formula 5).



表１から、Rとしては、トルエンスルホニル基が最も良く、触媒はベンゾイル基及びメシチル基を導入したピンサー型ビスイミダゾリン−パラジウム触媒が最も良い。さらに、アセチルアセトナート銀の添加により反応性が向上し、また、反応温度を下げることにより、立体選択性が向上する。また、ヘキサフルオロイソプロパノールを添加することにより、立体選択性が向上する・

（実施例１1−２０）
上記のベンズアルデヒド由来のイミンの代わりに、様々なアルデヒドから誘導したイミンを用いた実施例の結果を表２に示す。 From Table 1, as toluene, the toluenesulfonyl group is the best and the pincer type bisimidazoline-palladium catalyst into which the benzoyl group and the mesityl group are introduced is the best. Furthermore, the reactivity is improved by the addition of silver acetylacetonate, and the stereoselectivity is improved by lowering the reaction temperature. In addition, stereoselectivity is improved by adding hexafluoroisopropanol.

(Example 11-20)
Table 2 shows the results of Examples in which imines derived from various aldehydes were used instead of the above benzaldehyde-derived imines.


以下、上記式で生成した化合物2ｂ、2c〜2mについて説明する。 Hereinafter, the compounds 2b and 2c to 2m generated by the above formula will be described.


（実施例３）
(Example 3)

1H NMR (300 MHz, CDCl3) δ7.65-7.53 (m, 2H), 7.45-7.30 (m, 8H), 5.40-5.27 (m, 1H), 5.27-5.13 (m, 1H), 4.22-4.13 (m, 1H), 1.46 (s, 9H);
HPLC (DAICEL CHIRALPAKIDO, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm ) tR = 10.1 min (minor major-diastereomer), 15.4 min (minor minor-diastereomer), 20.7 min (major major-diastereomer), 25.2 min (major minor-diastereomer).
 1 H NMR (300 MHz, CDCl 3 ) δ7.65-7.53 (m, 2H), 7.45-7.30 (m, 8H), 5.40-5.27 (m, 1H), 5.27-5.13 (m, 1H), 4.22- 4.13 (m, 1H), 1.46 (s, 9H);
HPLC (DAICEL CHIRALPAKID O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 10.1 min (minor major-diastereomer), 15.4 min (minor minor-diastereomer), 20.7 min (major major-diastereomer) , 25.2 min (major minor-diastereomer).


（実施例１０）
(Example 10)

1H NMR (300 MHz, CDCl3) δ 7.59-7.26 (m, 7H), 7.14-7.06 (m, 4H), 6.74 (d, J = 6.9 Hz, 2H), 5.60 (d, J = 8.1 Hz, 1H), 4.85-4.72 (m, 1H), 4.02 (d, J = 1.8 Hz, 1H), 3.75 (s, 3H), 2.35 (s, 3H);
HPLC (DAICEL CHIRALPAK ID-3O, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm) tR = 79.6 min (minor syn-isomer), 152.9 min (major syn-isomer), 171.3 min (minor anti-isomer), 229.5 min (major anti-isomer). 1 H NMR (300 MHz, CDCl 3 ) δ 7.59-7.26 (m, 7H), 7.14-7.06 (m, 4H), 6.74 (d, J = 6.9 Hz, 2H), 5.60 (d, J = 8.1 Hz, 1H), 4.85-4.72 (m, 1H), 4.02 (d, J = 1.8 Hz, 1H), 3.75 (s, 3H), 2.35 (s, 3H);
HPLC (DAICEL CHIRALPAK ID-3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 79.6 min (minor syn-isomer), 152.9 min (major syn-isomer), 171.3 min (minor anti -isomer), 229.5 min (major anti-isomer).


（実施例１１）
(Example 11)

1H NMR (300 MHz, CDCl3) δ 7.60-7.26 (m, 7H), 7.16-7.11 (m, 3H), 6.79-6.64 (m, 3H), 5.71(d, J = 8.4 Hz, 1H), 4.87-4.74 (m, 1H), 4.04 (d, J = 2.4 Hz, 1H), 3.69 (s, 3H), 2.34 (s, 3H);
HPLC (DAICEL CHIRALPAK IF-3O, Hexane:iPrOH = 70:30, 1.0 mL/min , 225 nm) tR = 30.3 min (minor syn-isomer), 34.9 min (minor anti-isomer), 36.8 min (major anti-isomer), 64.0 min (major syn-isomer).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.60-7.26 (m, 7H), 7.16-7.11 (m, 3H), 6.79-6.64 (m, 3H), 5.71 (d, J = 8.4 Hz, 1H), 4.87-4.74 (m, 1H), 4.04 (d, J = 2.4 Hz, 1H), 3.69 (s, 3H), 2.34 (s, 3H);
HPLC (DAICEL CHIRALPAK IF-3 O , Hexane: iPrOH = 70:30, 1.0 mL / min, 225 nm) tR = 30.3 min (minor syn-isomer), 34.9 min (minor anti-isomer), 36.8 min (major anti -isomer), 64.0 min (major syn-isomer).


（実施例１２）
(Example 12)

1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 6.6 Hz,2H), 7.54-7.45 (m, 2H), 7.39-7.36 (m, 7H), 7.15-7.14 (m, 4H), 6.94-6.89(m, 2H), 5.58 (d, J = 7.2 Hz, 1H), 4.90-4.76 (m, 1H), 4.06-3.92 (m, 1H), 2.36 (s, 3H);HPLC (DAICEL CHIRALPAKID-3O, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm) tR = 33.0 min (minor syn-isomer), 62.1 min (major syn-isomer), 76.2 min (minor anti-isomer), 96.0 min (major anti-isomer).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 (d, J = 6.6 Hz, 2H), 7.54-7.45 (m, 2H), 7.39-7.36 (m, 7H), 7.15-7.14 (m, 4H), 6.94-6.89 (m, 2H), 5.58 (d, J = 7.2 Hz, 1H), 4.90-4.76 (m, 1H), 4.06-3.92 (m, 1H), 2.36 (s, 3H); HPLC (DAICEL CHIRALPAKID -3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 33.0 min (minor syn-isomer), 62.1 min (major syn-isomer), 76.2 min (minor anti-isomer), 96.0 min (major anti-isomer).


（実施例１３）
(Example 13)

1H NMR (300 MHz, CDCl3) δ 7.57-7.38 (m, 7H), 7.26-7.08 (m, 6H), 5.74 (d, J = 7.8 Hz, 1H), 4.86-4.73 (m, 1H), 4.00 (d, J = 3.0 Hz, 1H), 2.37 (s, 3H);
HPLC (DAICEL CHIRALPAK ID-3O, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm) tR = 30.0 min (minor syn-isomer), 54.5 min (major syn-isomer), 72.5 min (minor anti-isomer), 88.9 min (major anti-isomer).

 1 H NMR (300 MHz, CDCl 3 ) δ 7.57-7.38 (m, 7H), 7.26-7.08 (m, 6H), 5.74 (d, J = 7.8 Hz, 1H), 4.86-4.73 (m, 1H), 4.00 (d, J = 3.0 Hz, 1H), 2.37 (s, 3H);
HPLC (DAICEL CHIRALPAK ID-3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 30.0 min (minor syn-isomer), 54.5 min (major syn-isomer), 72.5 min (minor anti -isomer), 88.9 min (major anti-isomer).


（実施例１４）
(Example 14)

1H NMR (300 MHz, CDCl3) δ 7.56-7.26 (m, 9H), 7.15-7.01 (m, 4H), 5.64 (d, J = 8.1 Hz, 1H), 4.84-4.73 (m, 1H), 3.99 (d, J = 3.0 Hz, 1H), 2.38 (s, 3H);
HPLC (DAICEL CHIRALPAKID-3O, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm) tR = 31.1 min (minor syn-isomer), 55.4 min (major syn-isomer), 77.3 min (minor anti-isomer), 88.1 min (major anti-isomer).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.56-7.26 (m, 9H), 7.15-7.01 (m, 4H), 5.64 (d, J = 8.1 Hz, 1H), 4.84-4.73 (m, 1H), 3.99 (d, J = 3.0 Hz, 1H), 2.38 (s, 3H);
HPLC (DAICEL CHIRALPAKID-3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 31.1 min (minor syn-isomer), 55.4 min (major syn-isomer), 77.3 min (minor anti- isomer), 88.1 min (major anti-isomer).


（実施例１５）
(Example 15)

1H NMR (300 MHz, CDCl3) δ 7.81-7.71 (m, 2H), 7.62-7.58 (m, 2H), 7.50-7.29 (m, 9H), 6.97 (d, J = 7.2 Hz, 2H), 5.71-5.50 (m, 2H), 4.19 -4.03 (m, 1H), 2.27 (s, 3H);HPLC (DAICEL CHIRALPAK IE-3O, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm) tR = 39.1 min (minor syn-isomer), 53.1 min (major syn-isomer), 90.6 min (minor anti-isomer), 168.3 min (major anti-isomer).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.81-7.71 (m, 2H), 7.62-7.58 (m, 2H), 7.50-7.29 (m, 9H), 6.97 (d, J = 7.2 Hz, 2H), 5.71-5.50 (m, 2H), 4.19 -4.03 (m, 1H), 2.27 (s, 3H); HPLC (DAICEL CHIRALPAK IE-3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 39.1 min (minor syn-isomer), 53.1 min (major syn-isomer), 90.6 min (minor anti-isomer), 168.3 min (major anti-isomer).


（実施例１６）
(Example 16)

1H NMR (300 MHz, CDCl3) δ 7.77-7.70 (m, 3H), 7.55-7.39 (m, 10H), 6.85(d, J = 6.9 Hz, 2H), 5.57 (d, J = 5.1 Hz, 1H), 5.05-4.94 (m, 1H) , 4.20-4.06 (m, 1H), 2.18 (s, 3H);HPLC (DAICEL CHIRALPAK IE-3O, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm) tR = 66.0 min (minor syn-isomer), 79.6 min (major syn-isomer), 99.3 min (minor anti-isomer), 115.3 min (major anti-isomer).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.77-7.70 (m, 3H), 7.55-7.39 (m, 10H), 6.85 (d, J = 6.9 Hz, 2H), 5.57 (d, J = 5.1 Hz, 1H), 5.05-4.94 (m, 1H), 4.20-4.06 (m, 1H), 2.18 (s, 3H); HPLC (DAICEL CHIRALPAK IE-3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 66.0 min (minor syn-isomer), 79.6 min (major syn-isomer), 99.3 min (minor anti-isomer), 115.3 min (major anti-isomer).


（実施例１７）
(Example 17)

1H NMR (300 MHz, CDCl3) δ 7.68-7.66 (d, J = 7.2 Hz, 2H), 7.60-7.47 (m, 2H), 7.45-7.32 (m, 3H), 7.42-7.21 (s, 2H), 6.22 (d, J = 10.5 Hz,2H), 5.39 (d, J = 9.6 Hz, 1H), 5.00-4.88 (m, 1H), 4.12 (d, J = 3.0Hz , 1H), 2.40 (s, 3H);
HPLC (DAICEL CHIRALPAK IDO, Hexane:iPrOH = 80:20, 1.0 mL/min , 225 nm ) tR = 70.2 min (minor syn-isomer), 113.2 min (major syn-isomer), 172.2 min (minor anti-isomer), 222.9 min (major anti-isomer). 1 H NMR (300 MHz, CDCl 3 ) δ 7.68-7.66 (d, J = 7.2 Hz, 2H), 7.60-7.47 (m, 2H), 7.45-7.32 (m, 3H), 7.42-7.21 (s, 2H ), 6.22 (d, J = 10.5 Hz, 2H), 5.39 (d, J = 9.6 Hz, 1H), 5.00-4.88 (m, 1H), 4.12 (d, J = 3.0Hz, 1H), 2.40 (s , 3H);
HPLC (DAICEL CHIRALPAK ID O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 70.2 min (minor syn-isomer), 113.2 min (major syn-isomer), 172.2 min (minor anti-isomer ), 222.9 min (major anti-isomer).


（実施例１８）
(Example 18)

1H NMR (300 MHz, CDCl3) δ 7.68-7.65 (m, 1H), 7.60-7.54 (m, 2H), 726-7.22 (m, 6H), 6.98-6.88 (m, 2H), 5.14 (d, J = 6.0 Hz, 1H, major), 65.36 (d, J = 4.8 Hz, 1H, minor), 5.24-4.88 (m, 1H, major), 5.07-4.77 (m, 1H, minor), 4.27 (d, J = 6.0 Hz, 1H, minor), 4.12 (d, J = 3.9 Hz, 1H, major), 2.38 (s, 3H);HPLC (DAICEL CHIRALPAK ID-3O, Hexane:iPrOH = 70:30, 1.0 mL/min , 225 nm ) tR = 29.7 min (minor syn-isomer), 46.9 min (major syn-isomer), 61.2 min (minor anti-isomer), 111.7 min (major anti-isomer).
 1 H NMR (300 MHz, CDCl 3 ) δ 7.68-7.65 (m, 1H), 7.60-7.54 (m, 2H), 726-7.22 (m, 6H), 6.98-6.88 (m, 2H), 5.14 (d , J = 6.0 Hz, 1H, major), 65.36 (d, J = 4.8 Hz, 1H, minor), 5.24-4.88 (m, 1H, major), 5.07-4.77 (m, 1H, minor), 4.27 (d , J = 6.0 Hz, 1H, minor), 4.12 (d, J = 3.9 Hz, 1H, major), 2.38 (s, 3H); HPLC (DAICEL CHIRALPAK ID-3 O , Hexane: iPrOH = 70:30, 1.0 mL / min, 225 nm) tR = 29.7 min (minor syn-isomer), 46.9 min (major syn-isomer), 61.2 min (minor anti-isomer), 111.7 min (major anti-isomer).


（実施例１９）
(Example 19)

1H NMR (300 MHz, CDCl3) δ 7.77-7.67 (m, 2H), 7.61-7.47 (m, 2H), 7.40-7.22 (m, 11H), 6.45-6.31 (m, 1H), 5.98-5.90 (m, 1H), 5.28 (d, J = 6.0 Hz, 1H, minor), 5.11 (d, J = 4.5 Hz, 1H, major), 4.59-4.43 (m, 1H, minor), 4.26-4.03 (m, 2H, major), 4.00-3.87 (m, 1H, minor), 2.36 (s ,3H, major), 2.33 (s, 3H, minor);
HPLC (DAICEL CHIRALPAK IA-3O, Hexane:iPrOH = 80:20, 1.0 mL/min, 225 nm) tR = 16.7 min (major syn-isomer), 18.5 min (minor syn-isomer), 21.0 min (minor anti-isomer), 33.6 min (major anti-isomer).

（実施例２０） 1 H NMR (300 MHz, CDCl 3 ) δ 7.77-7.67 (m, 2H), 7.61-7.47 (m, 2H), 7.40-7.22 (m, 11H), 6.45-6.31 (m, 1H), 5.98-5.90 (m, 1H), 5.28 (d, J = 6.0 Hz, 1H, minor), 5.11 (d, J = 4.5 Hz, 1H, major), 4.59-4.43 (m, 1H, minor), 4.26-4.03 (m , 2H, major), 4.00-3.87 (m, 1H, minor), 2.36 (s, 3H, major), 2.33 (s, 3H, minor);
HPLC (DAICEL CHIRALPAK IA-3 O , Hexane: iPrOH = 80:20, 1.0 mL / min, 225 nm) tR = 16.7 min (major syn-isomer), 18.5 min (minor syn-isomer), 21.0 min (minor anti -isomer), 33.6 min (major anti-isomer).

(Example 20)

実施例１で得られた生成物を出発物質として下式により光学活性β−アミノニトリルが合成できる。
乾燥させた試験管に亜鉛（13.1 mg, 0.04 mmol）、硫酸銅（31.9 mg, 0.04 mmol）とα−チオ−β−アミノニトリル（16.3 mg, 0.02 mmol）、酢酸0.4 mLを加え、5時間加熱還流した。その後、ジエチルエーテルと飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下、留去し、シリカゲルクロマトグラフィー（Hexane: AcOEt = 70:30）で精製し、目的生成物を8.5 mg(71%)で得た。 Using the product obtained in Example 1 as a starting material, an optically active β-amino nitrile can be synthesized according to the following formula.
Add zinc (13.1 mg, 0.04 mmol), copper sulfate (31.9 mg, 0.04 mmol), α-thio-β-aminonitrile (16.3 mg, 0.02 mmol), and acetic acid 0.4 mL to the dried test tube and heat for 5 hours. Refluxed. Then, diethyl ether and saturated aqueous sodium hydrogen carbonate solution were added, extracted with diethyl ether, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (Hexane: AcOEt = 70: 30) to obtain 8.5 mg (71%) of the desired product.

1H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 7.5 Hz, 2H), 7.30-7.14 (m, 7H), 5.01 (d, J = 6.0 Hz, 1H), 4.57 (d, J = 5.4Hz, 1H), 3.02-2.86 (m, 2H), 2.42 (s, 3H);
（実施例２１） 1 H NMR (300 MHz, CDCl 3 ) δ 7.68 (d, J = 7.5 Hz, 2H), 7.30-7.14 (m, 7H), 5.01 (d, J = 6.0 Hz, 1H), 4.57 (d, J = 5.4Hz, 1H), 3.02-2.86 (m, 2H), 2.42 (s, 3H);
(Example 21)

実施例１で得られた生成物を出発物質として下式により光学活性α−チオ−β−アミノアミドが合成できる。   By using the product obtained in Example 1 as a starting material, optically active α-thio-β-aminoamide can be synthesized according to the following formula.

乾燥させた試験管にα−チオ−β−アミノニトリル（16.3 mg, 0.04 mmol）、アセトアルドキシム（7.2 ml, 0.12 mmol）と塩化インジウム4水和物（0.59 mg, 0.002 mmol）、トルエン0.2 mLを加え、１８時間４０℃にて加熱した。その後、溶媒を減圧下、留去し、シリカゲルクロマトグラフィー（Hexane: AcOEt = 50:50）で精製し、目的生成物を17.0 mg(99%)で得た。1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 7.5 Hz, 2H), 7.36-7.28 (m, 6H), 7.13-7.03 (m, 7H), 6.66 (d, J = 8.7 Hz,1H), 5.88 (br, 2H), 5.10-4.92 (m, 1H), 3.81 (d, J = 4.2 Hz, 1H), 2.31 (s, 3H); In a dried test tube, α-thio-β-amino nitrile (16.3 mg, 0.04 mmol), acetaldoxime (7.2 ml, 0.12 mmol) and indium chloride tetrahydrate (0.59 mg, 0.002 mmol), toluene 0.2 mL And heated at 40 ° C. for 18 hours. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (Hexane: AcOEt = 50: 50) to obtain 17.0 mg (99%) of the desired product. 1 H NMR (300 MHz, CDCl 3 ) δ 7.54 (d, J = 7.5 Hz, 2H), 7.36-7.28 (m, 6H), 7.13-7.03 (m, 7H), 6.66 (d, J = 8.7 Hz, 1H), 5.88 (br, 2H), 5.10-4.92 (m, 1H), 3.81 (d, J = 4.2 Hz, 1H), 2.31 (s, 3H);

Claims (1)

下記化学式（化1）で示される種々のイミン類に対し光学活性パラジウム錯体存在下でα−チオアセトニトリルを反応させることによりα−チオ−β−アミノニトリル類を製造する方法。

前記イミン類は、次式（化２）で示される。

（R1は、アルキル基、アリール基を示す。R2はジアリールホスフィノイル基、ジアルキルホスフィノイル基、アレーンスルホニル基、アルキルスルホニル基、アレーンカルボニル基、アルキルカルボニル基、アルコキシカルボニル基、アリール基、アルキル基を示す。）
化学式（化１）において、R3は、環状アルキル基、鎖状アルキル基、フルオロ基、クロロ基、ブロモ基、またはアリール基を示す。R4は、環状アルキル基、鎖状アルキル基、アリール基を示す。用いる銀塩は、酢酸塩、安息香酸塩、アセチルアセトナート塩 で、
用いるパラジウム錯体はピンサー型ビスイミダゾリン−パラジウム錯体である。
また、アルキルアルコール、フェノール、シリルアルコールの添加を行ってもよい。
A method for producing α-thio-β-amino nitriles by reacting various imines represented by the following chemical formula (Chemical Formula 1) with α-thioacetonitrile in the presence of an optically active palladium complex.

The imines are represented by the following formula (Formula 2).

(R 1 represents an alkyl group or an aryl group. R 2 represents a diarylphosphinoyl group, a dialkylphosphinoyl group, an arenesulfonyl group, an alkylsulfonyl group, an arenecarbonyl group, an alkylcarbonyl group, an alkoxycarbonyl group, or an aryl group. Represents an alkyl group.)
In the chemical formula (Chemical Formula 1), R 3 represents a cyclic alkyl group, a chain alkyl group, a fluoro group, a chloro group, a bromo group, or an aryl group. R 4 represents a cyclic alkyl group, a chain alkyl group, or an aryl group. The silver salt used is acetate, benzoate, acetylacetonate salt,
The palladium complex used is a pincer type bisimidazoline-palladium complex.
Alkyl alcohol, phenol, and silyl alcohol may be added.
JP2015040258A 2015-03-02 2015-03-02 METHOD FOR PRODUCING OPTICALLY ACTIVE α-THIO-β-AMINONITRILE Pending JP2016160215A (en)

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