JP2014172821A - Optically active thiochroman derivative and method for producing the same - Google Patents
Optically active thiochroman derivative and method for producing the same Download PDFInfo
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- WPWNEKFMGCWNPR-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromene Chemical class C1=CC=C2CCCSC2=C1 WPWNEKFMGCWNPR-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- KSDMMCFWQWBVBW-UHFFFAOYSA-N 2-sulfanylbenzaldehyde Chemical compound SC1=CC=CC=C1C=O KSDMMCFWQWBVBW-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000003446 ligand Substances 0.000 description 8
- 238000006842 Henry reaction Methods 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 6
- 238000006957 Michael reaction Methods 0.000 description 4
- 238000011914 asymmetric synthesis Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229920001222 biopolymer Polymers 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JKQUXSHVQGBODD-VOTSOKGWSA-N 1-(4-Methoxyphenyl)-2-nitroethylene Chemical compound COC1=CC=C(\C=C\[N+]([O-])=O)C=C1 JKQUXSHVQGBODD-VOTSOKGWSA-N 0.000 description 1
- HABXLWPUIWFTNM-AATRIKPKSA-N 1-nitro-4-[(e)-2-nitroethenyl]benzene Chemical compound [O-][N+](=O)\C=C\C1=CC=C([N+]([O-])=O)C=C1 HABXLWPUIWFTNM-AATRIKPKSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- ISDGWTZFJKFKMO-UHFFFAOYSA-N 2-phenyl-1,3-dioxane-4,6-dione Chemical compound O1C(=O)CC(=O)OC1C1=CC=CC=C1 ISDGWTZFJKFKMO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- VHGFUYBCCFYXTH-UHFFFAOYSA-N [Ni+2].[O-][N+]([O-])=C.[O-][N+]([O-])=C Chemical compound [Ni+2].[O-][N+]([O-])=C.[O-][N+]([O-])=C VHGFUYBCCFYXTH-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 description 1
- AIYYMMQIMJOTBM-UHFFFAOYSA-L nickel(ii) acetate Chemical compound [Ni+2].CC([O-])=O.CC([O-])=O AIYYMMQIMJOTBM-UHFFFAOYSA-L 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PIAOLBVUVDXHHL-VOTSOKGWSA-N β-nitrostyrene Chemical compound [O-][N+](=O)\C=C\C1=CC=CC=C1 PIAOLBVUVDXHHL-VOTSOKGWSA-N 0.000 description 1
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- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明は、光学活性チオクロマン誘導体及びその製造方法に関する。 The present invention relates to an optically active thiochroman derivative and a method for producing the same.
光学活性なアミノ酸や糖を基本構成単位とする生体高分子は、高度な不斉空間を構築しており、この生体高分子を受容体とする医薬品も光学活性を有している必要がある。このような光学活性な物質を合成する方法は不斉合成法と呼ばれており、不斉合成法の中でも少量の不斉源から理論上無限の光学活性体を合成することが可能な触媒的不斉合成法は極めて有用、重要なものとなっている。 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.
現在、光学活性チオクロマン誘導体は有機触媒を用いることにより触媒的不斉合成が達成されており、例えば、従来の技術として、有機触媒を用いたチオサリチルアルデヒドの反応において、α,β−不飽和オキサゾリジノンを用いる例が下記文献1に、ベンジリデンマロネートを用いる例が下記文献2に、ニトロアルケンを用いる例が下記文献3に記載されている。 At present, optically active thiochroman derivatives have been achieved by catalytic asymmetric synthesis using an organic catalyst. For example, as a conventional technique, in the reaction of thiosalicylaldehyde using an organic catalyst, α, β-unsaturated oxazolidinone is used. The following document 1 describes an example using benzylidene, an example using benzylidene malonate in the following document 2, and an example using nitroalkene in the following document 3.
しかしながら、上記文献に記載のいずれにおいても、金属触媒を用いた例は無く、新規ジアステレオマーを合成する反応系の開発が望まれる。 However, in any of the documents described above, there is no example using a metal catalyst, and development of a reaction system for synthesizing a novel diastereomer is desired.
そこで、本発明は、上記課題を鑑み、下記式で示される反応のように、金属触媒による、チオサリチルアルデヒドとニトロアルケンのタンデムMichael/Henry反応により得られるチオクロマン誘導体合成を提供することを目的とする。
本発明者らは、上記課題について鋭意検討を行なっていたところ、下記式で示される反応のように、金属にイミダゾリン‐アミノフェノール配位子を配位させた触媒の存在下で、チオサリチルアルデヒドとニトロアルケンを反応させることで、Michael/Henry反応を行わせ、式(2)で示されるチオクロマン誘導体を得ることができる点を発見し、本発明を完成させるに至った。
即ち、本発明の一手段に係るチオクロマン誘導体を製造する方法は、下記式(1)で示される触媒の存在下で、チオサリチルアルデヒドとニトロアルケンを反応させることである。
なおこの結果、下記式(2)で示されるチオクロマン誘導体を得ることができる。
以上、本発明により、金属触媒による、チオサリチルアルデヒドとニトロアルケンのMichael/Henry反応およびそれにより得られるチオクロマン誘導体を提供することが可能となる。また、本発明によると下記式(2)で示されるチオクロマンを高化学収率、高ジアステレオ選択的、高エナンチオ選択的に得ることができる。
以下、本発明の実施形態について図面を参照しつつ説明する。ただし、本発明は多くの異なる態様で実施することが可能であり、以下に示す実施形態に限定されるものではない。 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.
(実施形態1)
本実施形態に係るインドール誘導体の製造方法は、下記式(1)で示される触媒の存在下で、チオサリチルアルデヒドとニトロアルケンを反応させる。
In the method for producing an indole derivative according to this embodiment, thiosalicylaldehyde and nitroalkene are reacted in the presence of a catalyst represented by the following formula (1).
本実施形態において用いられる触媒における配位子は、その構成中に窒素で架橋されたイミダゾリン骨格とフェニル骨格とを有しているため、反応場が広い。またフェノール環にニトロ基を有するため活性が高い。 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.
また、配位子を配位させる金属としては、配位させることができる限りにおいてこれに限定されるわけではないが、例えばニッケル、コバルト、または銅を例示することができる。また配位子を金属に配位させる方法としては、周知の方法を採用することができ、限定されるわけではないが、金属塩と配位子を混合することで配位させることができる。金属塩としては、限定されるわけではないが、金属がニッケルである場合、Ni(OAc)2、Ni(acac)2、Ni(OTf)2等を用いることができる。 Moreover, as a metal which coordinates a ligand, as long as it can coordinate, it is not necessarily limited to this, For example, nickel, cobalt, or copper 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 salt is not limited, but when the metal is nickel, Ni (OAc) 2 , Ni (acac) 2 , Ni (OTf) 2 or the like can be used.
本実施形態に係る触媒は、チオサリチルアルデヒドとニトロアルケンを用いたMichael/Henry反応を行うために用いることができる。具体的には、本実施形態に係る触媒の存在下で、下記式で示される反応のように、チオサリチルアルデヒドとニトロアルケンを反応させてチオクロマン誘導体を合成することができる。
ここでR1およびR2は、おのおの独立して、H、Me、Et、tBu、ハロゲン、アルコキシ、又はニトロ基である。R1およびR2は、いずれ位置に複数結合していてもよい。 Here, R 1 and R 2 are each independently H, Me, Et, tBu, halogen, alkoxy, or nitro group. A plurality of R 1 and R 2 may be bonded at any position.
上記反応は、トルエン中において行なうことが好ましい。 The above reaction is preferably performed in toluene.
上記反応において、反応基質として用いられるチオサリチルアルデヒドは下記式(3)で示される。ここにおいてR1は限定されるわけではないが、例えばH、Me、tBu、ハロゲン、アルコキシ基を用いることができる。なお、上記反応において、用いるチオサリチルアルデヒドの量は、ニトロアルケンを1モルとした場合、1モル以上2モル以下の範囲にあることが好ましく、より好ましくは1.2モル以上1.5モル以下の範囲内である。また、チオサリチルアルデヒドはスローアディションすることが望ましい。
上記反応において、反応基質として用いられるニトロアルケンは下記式(4)で示される。ここにおいてR2は限定されるわけではないが、例えばH、Me、tBu、ハロゲン、アルコキシ、ニトロ基を用いることができる。
この結果、本実施形態に係る方法によると、下記式(2)で示すチオクロマン誘導体を得ることができる。
ここでR1およびR2は、おのおの独立して、H、Me、Et、tBu、ハロゲン、アルコキシ、又はニトロ基である。R1およびR2は、いずれ位置に複数結合していてもよい。) Here, R 1 and R 2 are each independently H, Me, Et, tBu, halogen, alkoxy, or nitro group. A plurality of R 1 and R 2 may be bonded at any position. )
なおここで本実施形態に関わる触媒を用いた反応の機構について説明しておく。
イミダゾリン−アミノフェノール−ニッケル触媒の作用により、ニトロアルケンが活性化され、チオサリチルアルデヒドがMichael反応を起こす。この反応により生成したニッケルニトロナートがアルデヒドとHenry反応を起こし、生成物に至るとともに、触媒が再生する。
Under the action of an imidazoline-aminophenol-nickel catalyst, the nitroalkene is activated and the thiosalicylaldehyde undergoes a Michael reaction. Nickel nitronate produced by this reaction causes a Henry reaction with the aldehyde to reach the product, and the catalyst is regenerated.
(配位子の合成)
また本実施形態に係る配位子及び触媒は、合成できる限りにおいて限定されるわけではないが、例えば特開2011−6363号公報に記載の技術を用いて合成することができる。
(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 can be synthesized, for example, using the technique described in JP2011-6363A.
そしてこの配位子を12.8mg用い、これを酢酸ニッケル(II)に配位させることで触媒として不斉Michael/Henry反応を行なった。 Then, 12.8 mg of this ligand was used, and this was coordinated with nickel (II) acetate to carry out an asymmetric Michael / Henry reaction as a catalyst.
(実施例1)
本実施例は、上記触媒の存在下、無水トルエン1mLに溶解した(E)−(2−ニトロビニル)ベンゼン22.5mgを−40℃に保ち、2−メルカプトベンズアルデヒドのトルエン溶液(0.045M)5mL(1.5当量)を15時間かけてスローアディションすることで行った。この結果、下記に示す化合物(2−1)を47mg得ることができた。また、(2−1)の化学収率は>99%、ジアステレオ比は>99/1、エナンチオ過剰率は95%eeであった。
In this example, 22.5 mg of (E)-(2-nitrovinyl) benzene dissolved in 1 mL of anhydrous toluene in the presence of the above catalyst was kept at −40 ° C., and toluene solution of 2-mercaptobenzaldehyde (0.045 M) 5 mL (1.5 equivalents) was slow-added over 15 hours. As a result, 47 mg of the compound (2-1) shown below was obtained. The chemical yield of (2-1) was> 99%, the diastereo ratio was> 99/1, and the enantiomeric excess was 95% ee.
1H NMR (500MHz,Acetone−d6)δ 7.59−7.61(m,2H),7.48−7.50(m,1H),7.39−7.42(m,2H),7.33−7.37(m,1H),7.30(dt,1H,J=7.8,1.5 Hz),7.20(dt,1H,J=7.5,1.2 Hz),7.15(dd,1H,J=8.1,0.9Hz),5.70(dd,1H,J=11.5,2.9Hz),5.40−5.46(m,2H),5.31(d,1H,J=11.8Hz);
13C NMR(100MHz,Acetone−d6)δ 137.7,134.6,133.5,132.0,129.9,129.7,129.3,129.2,125.7,125.4,90.2,70.6,41.4;
Enantiomeric excess was determined by HPLC with a Chiralkap AD−H column (85:15 Hexane:2−Propanol,0.7mL/min,254nm); minor enantiomer tr=14.6min, major enantiomer tr=21.8min;95%ee
1 H NMR (500 MHz, Acetone-d 6 ) δ 7.59-7.61 (m, 2H), 7.48-7.50 (m, 1H), 7.39-7.42 (m, 2H) , 7.33-7.37 (m, 1H), 7.30 (dt, 1H, J = 7.8, 1.5 Hz), 7.20 (dt, 1H, J = 7.5, 1. 2 Hz), 7.15 (dd, 1H, J = 8.1, 0.9 Hz), 5.70 (dd, 1H, J = 11.5, 2.9 Hz), 5.40-5.46 ( m, 2H), 5.31 (d, 1H, J = 11.8 Hz);
13 C NMR (100 MHz, Acetone-d 6 ) δ 137.7, 134.6, 133.5, 132.0, 129.9, 129.7, 129.3, 129.2, 125.7, 125. 4,90.2,70.6,41.4;
Enantiomeric excess was determined by HPLC with a Chiralkap AD-H column (85:15 Hexane: 2-Propanol, 0.7mL / min, 254nm); minor enantiomer t r = 14.6min, major enantiomer t r = 21.8min; 95% ee
(実施例2)
本実施例は、上記触媒の存在下、無水トルエン1mLに溶解した(E)−1−メトキシ−4−(2-ニトロビニル)ベンゼン26.8mgを−40℃に保ち、2−メルカプトベンズアルデヒドのトルエン溶液(0.045M)5mL(1.5当量)を15時間かけてスローアディションすることで行った。この結果、下記に示す化合物(2−2)を48mg得ることができた。また、(2−2)の化学収率は>99%、ジアステレオ比は96/4、エナンチオ過剰率は84%eeであった。
In this example, 26.8 mg of (E) -1-methoxy-4- (2-nitrovinyl) benzene dissolved in 1 mL of anhydrous toluene in the presence of the above catalyst was kept at −40 ° C., and a toluene solution of 2-mercaptobenzaldehyde was used. (0.045M) 5 mL (1.5 equivalents) was slow-added over 15 hours. As a result, 48 mg of the following compound (2-2) was obtained. Further, the chemical yield of (2-2) was> 99%, the diastereo ratio was 96/4, and the enantiomeric excess was 84% ee.
1H NMR (Acetone−d6,500MHz)δ 7.50−7.53(m,2H),7.47(dd,1H,J=7.8,1.5Hz),7.29(dt,1H,J=7.5,1.4 Hz),7.19(dt,1H,J=7.5,1.2 Hz),7.14 (dd,1H,J=8.0,1.2 Hz),6.93−6.96(m,2H),5.62(dd,1H,J=11.5,2.9 Hz),5.37−5.44(m,2H),5.25(d,1H,J=11.8Hz),3.79(s,3H);
13C NMR(Acetone−d6,500MHz)δ 160.7,134.5,133.9,132.1,130.5,129.9,129.2,125.6,125.4,115.0,90.4,70.8,55.5,40.9;
Enantiomeric excess was determined by HPLC with a Chiralpak AD−H column (85:15 Hexane:2−Propanol,0.7 mL/min,254nm); minor enantiomer tr=22.5min,major enantiomer tr=35.4min;84% ee
1 H NMR (acetone-d 6 , 500 MHz) δ 7.50-7.53 (m, 2H), 7.47 (dd, 1H, J = 7.8, 1.5 Hz), 7.29 (dt, 1H, J = 7.5, 1.4 Hz), 7.19 (dt, 1H, J = 7.5, 1.2 Hz), 7.14 (dd, 1H, J = 8.0, 1. 2 Hz), 6.93-6.96 (m, 2H), 5.62 (dd, 1H, J = 11.5, 2.9 Hz), 5.37-5.44 (m, 2H), 5.25 (d, 1H, J = 11.8 Hz), 3.79 (s, 3H);
13 C NMR (Acetone-d 6 , 500 MHz) δ 160.7, 134.5, 133.9, 132.1, 130.5, 129.9, 129.2, 125.6, 125.4, 115. 0, 90.4, 70.8, 55.5, 40.9;
Enantiomeric excess was determined by HPLC with a Chiralpak AD-H column (85:15 Hexane: 2-Propanol, 0.7 mL / min, 254nm); minor enantiomer t r = 22.5min, major enantiomer t r = 35.4min 84% ee
(実施例3)
本実施例は、上記触媒の存在下、無水トルエン1mLに溶解した(E)−1−ニトロ−4−(2−ニトロビニル)ベンゼン29.1mgを−40℃に保ち、2−メルカプトベンズアルデヒドのトルエン溶液(0.045M)5mL(1.5当量)を15時間かけてスローアディションすることで行った。この結果、下記に示す化合物(2−3)を49mg得ることができた。また、(2−2)の化学収率は98%、ジアステレオ比は>99/1、エナンチオ過剰率は91%eeであった。
In this example, 29.1 mg of (E) -1-nitro-4- (2-nitrovinyl) benzene dissolved in 1 mL of anhydrous toluene in the presence of the above catalyst was kept at −40 ° C., and a toluene solution of 2-mercaptobenzaldehyde was used. (0.045M) 5 mL (1.5 equivalents) was slow-added over 15 hours. As a result, 49 mg of the following compound (2-3) could be obtained. The chemical yield of (2-2) was 98%, the diastereo ratio was> 99/1, and the enantiomeric excess was 91% ee.
1H NMR(Acetone−d6,500 MHz)δ 8.27−8.30(m,2H),7.93−7.95(m,2H),7.50−7.52(m,1H),7.32(dt,1H,J=7.5,1.4Hz),7.23(dt,1H,J=7.5,1.2Hz),7.17−7.18(m,1H),5.80−5.83(m,1H),5.60(d,1H,J=5.2Hz),5.45−5.49(m,2H);
13C NMR(Acetone−d6,125MHz)δ 148.8,145.5,134.4,132.7,132.3,130.7,130.2,126.0,125.3,124.8,89.5,70.6,40.6;
Enantiomeric excess was determined by HPLC with a Chiralcel OD−H column(80:20 Hexane:2−Propanol,0.7mL/min,254nm); major enantiomer tr=37.3min,minor enantiomer tr=49.3min;91%ee
1 H NMR (acetone-d 6 , 500 MHz) δ 8.27-8.30 (m, 2H), 7.93-7.95 (m, 2H), 7.50-7.52 (m, 1H ), 7.32 (dt, 1H, J = 7.5, 1.4 Hz), 7.23 (dt, 1H, J = 7.5, 1.2 Hz), 7.17-7.18 (m, 1H), 5.80-5.83 (m, 1H), 5.60 (d, 1H, J = 5.2 Hz), 5.45-5.49 (m, 2H);
13 C NMR (Acetone-d 6 , 125 MHz) δ 148.8, 145.5, 134.4, 132.7, 132.3, 130.7, 130.2, 126.0, 125.3, 124. 8, 89.5, 70.6, 40.6;
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (80:20 Hexane: 2-Propanol, 0.7mL / min, 254nm); major enantiomer t r = 37.3min, minor enantiomer t r = 49.3min; 91% ee
以上の通り、本実施例によると、イミダゾリン−アミノフェノール−ニッケル触媒の存在下、チオサリチルアルデヒドとニトロアルケンを用いたジアステレオおよびエナンチオ選択的Michael/Henry反応を実現できた。 As described above, according to this example, diastereo- and enantioselective Michael / Henry reactions using thiosalicylaldehyde and nitroalkene could be realized in the presence of an imidazoline-aminophenol-nickel catalyst.
本発明は、チオクロマン誘導体を非常に高い光学純度で供給できることから、医薬・農薬の開発と生産に有用であり、産業上の利用可能性がある。
Since the thiochroman 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.
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CN105924425A (en) * | 2016-04-29 | 2016-09-07 | 浙江师范大学 | Preparation method of dihydrothiochroman derivative |
CN111606924A (en) * | 2020-06-03 | 2020-09-01 | 成都大学 | Chiral thiopyranoindolophenylthiolsulfone derivatives and preparation method thereof |
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---|
JPN6016033945; Dodda, R. et al.: 'Synthesis of 2,3,4-Trisubstituted Thiochromanes using an Organocatalytic Enantioselective Tandem Mic' Advanced Synthesis & Catalysis 350(4), 2008, pp. 537-541 * |
JPN6016033947; O'Connor, C. J. et al.: 'Facile Synthesis of 3-Nitro-2-substituted Thiophenes' Journal of Organic Chemistry 75(8), 2010, pp. 2534-2538 * |
JPN6016033949; Liansuo Zu et al.: 'Cascade Michael-Aldol Reactions Promoted by Hydrogen Bonding Mediated Catalysis' J. Am. Chem. Soc 129(5), 2007, pp. 1036-1037 * |
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CN105924425A (en) * | 2016-04-29 | 2016-09-07 | 浙江师范大学 | Preparation method of dihydrothiochroman derivative |
CN111606924A (en) * | 2020-06-03 | 2020-09-01 | 成都大学 | Chiral thiopyranoindolophenylthiolsulfone derivatives and preparation method thereof |
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