CN110551035A - 一种铱催化酮的不对称还原胺化方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 150000002576 ketones Chemical class 0.000 title claims abstract description 23
- 238000006268 reductive amination reaction Methods 0.000 title claims abstract description 23
- 150000001412 amines Chemical class 0.000 claims abstract description 29
- 239000003446 ligand Substances 0.000 claims abstract description 22
- KDPSKENBCWJPHJ-UHFFFAOYSA-N P.NP(O)O Chemical compound P.NP(O)O KDPSKENBCWJPHJ-UHFFFAOYSA-N 0.000 claims abstract description 19
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 6
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000011065 in-situ storage Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 239000000758 substrate Substances 0.000 claims description 23
- 125000000524 functional group Chemical group 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- -1 methyl titanate Chemical compound 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- BXMJNGVLZAWGJH-UHFFFAOYSA-N [Ir].C1CCC=CC=CC1 Chemical compound [Ir].C1CCC=CC=CC1 BXMJNGVLZAWGJH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical group CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- WVQBLGZPHOPPFO-UHFFFAOYSA-N 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(1-methoxypropan-2-yl)acetamide Chemical compound CCC1=CC=CC(C)=C1N(C(C)COC)C(=O)CCl WVQBLGZPHOPPFO-UHFFFAOYSA-N 0.000 abstract description 3
- JJVKJJNCIILLRP-UHFFFAOYSA-N 2-ethyl-6-methylaniline Chemical compound CCC1=CC=CC(C)=C1N JJVKJJNCIILLRP-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 239000000575 pesticide Substances 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 35
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- XXPOATHRRKDYBT-UHFFFAOYSA-N 2,6-dimethyl-n-(1-phenylethyl)aniline Chemical compound C=1C=CC=CC=1C(C)NC1=C(C)C=CC=C1C XXPOATHRRKDYBT-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000004296 chiral HPLC Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 150000002466 imines Chemical class 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 4
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- CUZLJOLBIRPEFB-UHFFFAOYSA-N 1-methoxypropan-2-one Chemical compound COCC(C)=O CUZLJOLBIRPEFB-UHFFFAOYSA-N 0.000 description 2
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000012159 carrier gas Substances 0.000 description 2
- 238000005356 chiral GC Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- ARKIFHPFTHVKDT-UHFFFAOYSA-N 1-(3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=CC([N+]([O-])=O)=C1 ARKIFHPFTHVKDT-UHFFFAOYSA-N 0.000 description 1
- CCLHADURFVJYCL-UHFFFAOYSA-N 2,6-dimethyl-N-(1-phenylpropyl)aniline Chemical compound CCC(Nc1c(C)cccc1C)c1ccccc1 CCLHADURFVJYCL-UHFFFAOYSA-N 0.000 description 1
- YXWIRQHVEQIJOV-NSHDSACASA-N 2-ethyl-n-[(2s)-1-methoxypropan-2-yl]-6-methylaniline Chemical group CCC1=CC=CC(C)=C1N[C@@H](C)COC YXWIRQHVEQIJOV-NSHDSACASA-N 0.000 description 1
- YQYGPGKTNQNXMH-UHFFFAOYSA-N 4-nitroacetophenone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C=C1 YQYGPGKTNQNXMH-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- QYJCGOLBBQDWFE-UHFFFAOYSA-N n-(1-methoxypropan-2-yl)-2,6-dimethylaniline Chemical group COCC(C)NC1=C(C)C=CC=C1C QYJCGOLBBQDWFE-UHFFFAOYSA-N 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
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Abstract
本发明公开了一种铱催化酮的不对称还原胺化方法,该方法以手性二茂铁骨架膦‑亚磷酰胺配体与金属铱前驱体反应原位制备配合物为催化剂,催化酮与胺直接不对称还原胺化制备手性胺。本发明配体制备简单,催化剂用量低,操作简便,且可实现连续操作,适于大规模制备手性胺,产物的对映体过量值达80%以上,可满足作为农药中间体的要求。本发明对于精异丙甲草胺中间体的合成时2‑乙基‑6‑甲基苯胺/催化剂(S/C)为500000具有较好的结果,达到95%收率,81%对映选择性,具有很好的工业实用性。
Description
技术领域
本发明属于有机合成领域,具体涉及一种铱催化酮的不对称还原胺化方法。
背景技术
手性胺化合物是重要的有机合成中间体,可用于制备具有生物活性的各种天然及非天然化合物。近年来,合成手性胺的主要方法包括亚胺、烯胺的不对称氢化和不对称还原胺化。其中不对称还原胺化是一种绿色、环保、高效的合成手性胺类化合物的方法。它是在手性催化剂及其他助剂的帮助下,使酮类化合物与胺源直接反应生成手性胺类化合物。此反应省略了不对称氢化中制备亚胺或烯胺中间体的步骤,提高了手性胺的产率和反应的原子经济性。
1999年,Hans-Peter Jalett(Jalett H.P.,Spindler F.,HanreichR.G.US5886225[P],1999)等利用二茂铁双膦配体成功催化不对称氢化亚胺合成手性异丙甲草胺后,尝试以2-甲氧基丙酮与2-乙基-6-甲基苯胺反应,使用Ir-XyliPhos催化得到手性异丙甲草胺,取得了99%的产率和76%的对映选择性。这是真正意义上的不对称还原胺化反应的首次成功。但是由于底物酮会被还原成相应的醇,底物胺或者手性胺产物会与过渡金属络合,从而抑制了催化剂的催化活性;由于其催化剂用量是亚胺不对称还原的催化剂用量的100倍,因此工业化生产还是采用亚胺不对称还原的方法。但是他们的研究结果为手性胺的合成开创了新的反应思路。
2003年,Yongxiang CHi(Y.X.Chi,Y.G.Zhou,X.M.Zhang J.Org.Chem.2003,68,4120-4122)报道了以4-甲氧基苯胺为胺源与芳香酮进行直接不对称还原胺化反应,在Ir-(S,S)-f-Binaphine催化下可以得到手性α-芳基胺产物,其产物产率大于93%,对映选择性最高达到96%,然而该催化体系对脂肪酮并不适用。
因此,发展高活性、高立体选择性、底物适用广不对称还原胺化的催化剂,具有十分重要的意义。
发明内容
本发明的目的是提供一种铱催化酮的不对称还原胺化方法。
为实现上述目的,本发明的技术方案如下:
一种铱催化酮的不对称还原胺化方法,该方法采用手性催化剂Ir-L,酮与胺直接不对称还原胺化制备手性胺;所述手性催化剂Ir-L由铱-环辛二烯络合物和手性二茂铁骨架膦-亚磷酰胺配体在溶剂中原位配位生成。
一种铱催化酮的不对称还原胺化方法,该方法具体为:
在氮气保护下,将铱-环辛二烯络合物与手性二茂铁骨架膦-亚磷酰胺配体溶于溶剂,室温下搅拌10分钟,加入溶于溶剂的底物胺、酮及添加剂,将其置于高压反应釜中,氢气置换3次,然后通入氢气至20-100bar,20-100℃下反应1-24小时,慢慢释放氢气,除去溶剂后用硅胶柱分离得到产物手性胺。
所述溶剂为二氯甲烷、1,2-二氯乙烷或甲苯;
所述添加剂为钛酸异丙酯、钛酸乙酯或钛酸甲酯;
所述的底物胺为:R3NH2,其中R3为H,C1~C10烷基,C3~C12环烷基,C6-C30内的含或不含N、S、O、P等官能团的芳香基团。
为实现上述目的,本发明的技术方案如下:
本发明所涉及的酮和制得的手性胺具有以下结构:
式中:
R1为C1~C10烷基如CH3、CH3CH2等,C3~C12环烷基如环戊基、环己基等,或含有N、S、O、P中一种或二种以上官能团的C1~C10烷基如甲氧甲基、乙氧甲基等,或含有N、S、O、P中一种或二种以上官能团的C3~C10环烷基如2-四氢呋喃基、4-四氢呋喃基等;或芳基等C6-C30内的含或不含N、S、O、P等官能团的芳香基团如苯基、4-甲氧基苯基等;或酯基如COOCH3、COOCH2CH3等
R2为H,C1-C40内的烷基或芳基;
R3为H,C1~C10烷基如CH3、CH3CH2等,C3~C12环烷基如环戊基、环己基等,或芳基等C6-C30内的含或不含N、S、O、P等官能团的芳香基团如苯基、4-甲氧基苯基、2-乙基-6-甲基苯基、2,6-二甲基苯基等。
本发明所涉及的手性二茂铁骨架膦-亚磷酰胺配体具有以下结构:
式中:R1、R2为H;烷基和环烷基等C1~C40内的含或不含N、S、O、P等官能团的脂肪基团;苄基等C7-C60在内的含或不含N、S、O、P等官能团的芳香基团与脂肪基的组合基团;芳基等C6-C60内的含或不含N、S、O、P等官能团的芳香基团。
Ar为C6-C60内的含或不含N、S、O、P等官能团的芳香基团。
X基团为:手性或非手性的含或不含N、S、O、P等官能团的脂肪基团;含或不含N、S、O、P等官能团的芳香基团;手性或非手性的含或不含N、S、O、P等官能团的联苯、联萘或四氢联萘类芳香基团。
所述铱-环辛二烯络合物为:[Ir(COD)Cl]2、Ir(COD)2BF4或Ir(COD)2BARF。
所述反应体系中所述铱浓度为0.0001-0.01mol/l,所述配体与铱的摩尔比为1-5:1。
所述胺底物和催化剂的摩尔比为100-500000:1,
所述胺底物和酮的摩尔比为:0.5-1.5:1,胺底物和添加剂的的摩尔比为1:1~5。
本发明的有益效果是:与其它合成手性胺方法相比,本方法用于还原胺化的手性二茂铁骨架膦-亚磷酰胺配体合成简单、价格低廉、适宜公斤级生产,而且铱/手性二茂铁骨架膦-亚磷酰胺体系催化活性高、对映选择性高,产物的对映体过量值(ee值)达80%以上,还原胺化反应操作简单、条件温和、原子经济性高,适合工业化生产,并且本发明对于精异丙甲草胺中间体的合成时2-乙基-6-甲基苯胺/催化剂(S/C)为500000具有较好的结果,达到95%收率,81%对映选择性,具有很好的工业实用性。
具体实施方式
下面的实施例将对本发明予以进一步的说明,但并不因此而限制本发明。核磁共振是通过Bruker核磁共振仪测定,高效液相色谱(HPLC)是通过Agilent1100系列高效液相色谱测定。GC分析条件如下色谱柱:β-DEX,进样口温度:250度,检测器温度:250度,柱温:90℃。
实施例1
氮气保护下,将[Ir(COD)Cl]2(0.0025mmol,0.5mol%),手性二茂铁骨架膦-亚磷酰胺配体(如上式所示)(0.0055mmol,1.1mol%)溶于甲苯(1.0mL),室温下搅拌10分钟,加入底物2,6-二甲基苯胺(0.5mmol)及苯乙酮(0.6mol)的甲苯(1.0mL)溶液及0.2ml钛酸异丙酯,将其置于高压反应釜中,氢气置换3次,然后通入氢气至50个大气压,50℃下反应12小时。慢慢释放氢气,除去溶剂后用硅胶柱分离得到产物。
对产物进行检测分析,NMR和HPLC数据如下所示:
98%yield.83%ee was determined by chiral HPLC(chiralcel OJ-H,n-hexane/i-PrOH=90/10,1.0mL/min,254nm,40℃):tR(major)=4.9min,tR(minor)=5.4min.[α]D 25=-158(c=1.42in CHCl3).1H NMR(400MHz,CDCl3):δ=1.54(d,J=6.8Hz,3H),2.19(s,6H),3.22(br,1H),4.34(q,J=6.8Hz,1H),6.81(t,J=7.2Hz,1H),6.97(d,J=7.2Hz,2H),7.25-7.27(m,1H),7.31-7.32(m,4H);13C NMR(100MHz,CDCl3):δ=19.1,22.9,57.0,121.8,121.9,126.3,126.4,127.1,127.2,128.6,128.7,129.0,129.1,129.6,145.2,145.5。
经检测,产物为:2,6-二甲基-N-(1-苯基乙基)苯胺。
实施例2
将实施例1中的反应条件二茂铁骨架膦-亚磷酰胺配体改为B,其余同实施例1,反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,收率98%,对映选择性为80%ee。
二茂铁骨架膦-亚磷酰胺配体B结构如下:
实施例3
将实施例1中的反应条件二茂铁骨架膦-亚磷酰胺配体改为C,其余同实施例1,反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,收率98%,对映选择性为75%ee。
二茂铁骨架膦-亚磷酰胺配体C结构如下:
实施例4
将实施例1中的反应条件二茂铁骨架膦-亚磷酰胺配体改为D,其余同实施例1,反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,收率98%,对映选择性为77%ee。
二茂铁骨架膦-亚磷酰胺配体D结构如下:
实施例5
将实施例1中的反应条件H2压力改为100个大气压,其余同实施例1,反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,收率98%,对映选择性为84%ee。
实施例6
将实施例1中的反应条件H2压力改为20个大气压,其余同实施例1,反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,收率90%,对映选择性为84%ee。
实施例7
将实施例1中的反应条件温度改为20℃,其余同实施例1,反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,收率90%,对映选择性为84%ee。
实施例8
将实施例1中的反应条件温度改为100℃,其余同实施例1,反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,收率98%,对映选择性为83%ee。
实施例9
将实施例1中的底物与催化剂比例改为S/C=1000,[Ir(COD)Cl]2(0.00025mmol,0.05mol%),手性膦-亚膦酰胺配体(0.00055mmol,0.11mol%),反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,对映选择性为84%ee。
实施例10
将实施例1中的底物与催化剂比例改为S/C=10000,[Ir(COD)Cl]2(0.000025mmol,0.005mol%),手性膦-亚膦酰胺配体(0.000055mmol,0.011mol%),反应条件H2压力为80个大气压,反应温度为90℃,反应时间为36小时,其余同实施例1,反应得产物,经检测,产物为2,6-二甲基-N-(1-苯基乙基)苯胺,对映选择性为83%ee。
实施例11
将实施例1中的底物改为对硝基苯乙酮,其余同实施例1,反应得产物。
对产物进行检测分析,NMR和HPLC数据如下所示:
99%yield.88%ee was determined by chiral HPLC(chiralpak AD-H,n-hexane/i-PrOH=99/1,1.0mL/min,254nm,40℃):tR(major)=5.4min,tR(minor)=7.5min.[α]D 25=-233(c=1.90in CHCl3).1H NMR(400MHz,CDCl3):δ=1.57(d,J=6.8Hz,3H),2.16(s,6H),3.13(br,1H),4.40(q,J=6.8Hz,1H),6.81(t,J=7.2Hz,1H),6.96(d,J=7.2Hz,2H),7.45(d,J=8.8Hz,2H),8.15(d,J=8.8Hz,2H);13C NMR(100MHz,CDCl3):δ=19.0,22.9,56.5,122.1,123.6,127.1,129.1,129.3,144.4,146.9,152.9。
经检测,产物为:2,6-二甲基-N-(1-(4-硝基苯基)亚乙基苯胺。
实施例12
将实施例1中的底物改为3-硝基苯乙酮,其余同实施例1,反应得产物
对产物进行检测分析,NMR和HPLC数据如下所示:
98%yield.86%ee was determined by chiral HPLC(chiralpak AD-H,n-hexane/i-PrOH=99/1,1.0mL/min,254nm,40℃):tR(minor)=10.3min,tR(major)=10.9min.[α]D 25=-141(c=1.88in CHCl3).1H NMR(400MHz,CDCl3):δ=1.58(d,J=6.8Hz,3H),2.19(s,6H),3.20(br,1H),4.43(q,J=6.8Hz,1H),6.82(t,J=7.6Hz,1H),6.97(d,J=7.6Hz,2H),7.45(t,J=7.6Hz,1H),7.62(d,J=7.6Hz,1H),8.10(d,J=7.6Hz,1H),8.24(s,1H);13C NMR(100MHz,CDCl3):δ=19.0,23.0,56.3,121.0,122.0,122.2,129.1,129.3,129.4,132.7,144.3,147.5,148.3。
经检测,产物为:2,6-二甲基-N-(1-(3-硝基苯基)亚乙基苯胺。
实施例13
将实施例1中的底物改为丁酮,其余同实施例1,反应得产物。
对产物进行检测分析,NMR和GC数据如下所示:
94%yield.86%ee was determined by chiral GC(chiralβ-DEX 120 column(0.25mm x 30m),column temp.:90℃,carrier gas:N2):tR(major)=20.1min,tR(minor)=20.8min.[α]D 25=-41(c=0.96in CHCl3).1HNMR(400MHz,CDCl3):δ=0.98(t,J=7.2Hz,3H),1.07(d,J=6.4Hz,3H),1.37-1.44(m,1H),1.58-1.64(m,1H),2.28(s,6H),2.84(br,1H),3.21(q,J=6.8Hz,1H),6.80(t,J=7.2Hz,1H),6.99(d,J=7.2Hz,2H);13C NMR(100MHz,CDCl3):δ=7.1,15.3,17.1,27.2,50.1,117.4,125.1,141.5。
经检测,产物为:N-异丁基-2,6-二甲基苯胺。
实施例14
将实施例1中的底物改为甲氧基丙酮,其余同实施例1,反应得产物。
对产物进行检测分析,NMR和GC数据如下所示:
95%yield.85%ee was determined by chiral GC(chiralβ-DEX 120 column,column temp.:85℃,carrier gas:N2):tR(major)=69.8min,tR(minor)=71.4min.[α]D 25=9.5(c=1.31in CHCl3).1HNMR(400MHz,CDCl3):δ=1.20(d,J=6.0Hz,3H),2.30(s,6H),3.35-3.80(m,7H),6.82(t,J=7.2Hz,1H),6.99(d,J=7.2Hz,2H);13C NMR(100MHz,CDCl3):δ=18.6,18.7,52.4,59.0,76.3,121.5,128.8,129.4,145.0。
经检测,产物为N-(1-甲氧基-2-丙基)-2,6-二甲基苯胺。
实施例15
将实施例1中的底物改为丙酮甲酯,其余同实施例1,反应得产物
对产物进行检测分析,NMR和HPLC数据如下所示:
96%yield.84%ee was determined by chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH=99/1,1.0mL/min,254nm,40℃):tR(minor)=6.9min,tR(major)=7.7min.[α]D 25=-16(c=1.33in CHCl3).1HNMR(400MHz,CDCl3):δ=1.38(d,J=7.2Hz,3H),2.31(s,6H),3.68(s,3H),4.00(q,J=7.2Hz,1H),6.81(t,J=7.6Hz,1H),6.97(d,J=7.6Hz,2H)。
经检测,产物为2-(2,6-二甲基苯基氨基)丙酸甲酯。
实施例16
将实施例1中的底物改为苯丙酮,其余同实施例1,反应得产物。
对产物进行检测分析,NMR和HPLC数据如下所示:
97%yield.82%ee was determined by chiral HPLC(chiralcel OJ-H,n-hexane/i-PrOH=90/10,1.0mL/min,254nm,40℃):tR(major)=4.4min,tR(minor)=4.8min.[α]D 25=-116(c=1.79in CHCl3).1HNMR(400MHz,CDCl3):δ=0.91(d,J=7.2Hz,3H),1.87-1.92(m,1H),2.02-2.05(m,1H),2.18(s,6H),3.30(br,1H),4.07(m,1H),6.78(t,J=7.2Hz,1H),6.94(d,J=7.2Hz,2H),7.20-7.31(m,5H);13CNMR(100MHz,CDCl3):δ=11.3,19.1,29.8,63.5,121.4,126.3,126.8,127.0,128.4,128.9,129.1,143.9,145.0。
经检测,产物为2,6-二甲基-N-(1-苯基丙基)苯胺。
实施例17
氮气保护下,将[Ir(COD)Cl]2(0.000125mmol,0.0001mol%),手性二茂铁骨架膦-亚磷酰胺配体(0.000275mmol,0.00022mol%)溶于甲苯(10mL),室温下搅拌10分钟,加入底物2-乙基-6-甲基苯胺(0.125mol)及甲氧基丙酮(0.15mol)及钛酸异丙酯(0.1375mol)的甲苯(50mL)溶液,将其置于高压反应釜中,氢气置换3次,然后通入氢气至80个大气压,100℃反应12小时。慢慢释放氢气,除去溶剂后用硅胶柱分离得到产物。
对产物进行检测分析,NMR和HPLC数据如下所示:
95%yield.81%ee was determined by chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH=99/1,1.0mL/min,254nm,40℃):tR(minor)=4.4min,tR(major)=4.8min.[α]D 25=8.8(c=1.0in CHCl3).1HNMR(400MHz,CDCl3):δ=1.18(d,J=5.6Hz,3H),1.23(t,J=7.6Hz,3H),2.29(s,3H),2.65(q,J=7.6Hz,2H),3.34-3.38(m,6H),6.87(t,J=7.6Hz,1H),7.00(dd,J=7.6,15.2Hz,2H)。
经检测,产物为(S)-2-乙基-N-(1-甲氧基-2-丙基)-6-甲基苯胺。
Claims (8)
1.一种铱催化酮的不对称还原胺化方法,其特征在于:该方法采用手性催化剂Ir-L,酮与胺直接不对称还原胺化制备手性胺;所述手性催化剂Ir-L由铱-环辛二烯络合物和手性二茂铁骨架膦-亚磷酰胺配体在溶剂中原位配位生成。
2.根据权利要求1所述的一种铱催化酮的不对称还原胺化方法,其特征在于该方法具体为:
在氮气保护下,将铱-环辛二烯络合物与手性二茂铁骨架膦-亚磷酰胺配体L溶于溶剂,室温下搅拌10分钟,加入溶于溶剂的底物胺、酮及添加剂,将其置于高压反应釜中,氢气置换3次,然后通入氢气至20-100bar,20-100℃下反应1-24小时,慢慢释放氢气,除去溶剂后用硅胶柱分离得到产物手性胺。
所述溶剂为二氯甲烷、1,2-二氯乙烷或甲苯;
所述添加剂为钛酸异丙酯、钛酸乙酯或钛酸甲酯;
所述的底物胺为:R3NH2,其中R3为H,C1~C10烷基,C3~C12环烷基,C6-C30内的含或不含N、S、O、P等官能团的芳香基团。
3.根据权利要求1或2所述的一种铱催化酮的不对称还原胺化方法,其特征在于;所述的酮和制得的手性胺分别具有以下结构:
式中:
R1为C1~C10烷基,C3~C12环烷基,或含有N、S、O、P中一种或二种以上官能团的C1~C10烷基,或含有N、S、O、P中一种或二种以上官能团的C3~C10环烷基;或C6-C30内的含或不含N、S、O、P官能团的芳香基团;
或酯基;
R2为H,C1-C40内的烷基或芳基;
R3为H,C1~C10烷基,C3~C12环烷基,C6-C30内的含或不含N、S、O、P等官能团的芳香基团。
4.根据权利要求1或2所述的一种铱催化酮的不对称还原胺化方法,其特征在于:所述手性二茂铁骨架膦-亚磷酰胺配体L的结构通式如下:
式中:R1、R2为C1~C40内的含或不含N、S、O、P官能团的脂肪基团;或C7-C60在内的含或不含N、S、O、P官能团的芳香基团与脂肪基的组合基团;或C6-C60内的含或不含N、S、O、P官能团的芳香基团。
Ar为C6-C60内的含或不含N、S、O、P官能团的芳香基团;
X基团为:手性或非手性的含或不含N、S、O、P官能团的脂肪基团;含或不含N、S、O、P官能团的芳香基团;手性或非手性的含或不含N、S、O、P官能团的联苯、联萘或四氢联萘类芳香基团。
5.根据权利要求1或2所述的一种铱催化酮的不对称还原胺化方法,其特征在于:所述铱-环辛二烯络合物为:[Ir(COD)Cl]2、Ir(COD)2BF4或Ir(COD)2BARF。
6.根据权利要求2所述的一种铱催化酮的不对称还原胺化方法,其特征在于:所述反应体系中所述铱浓度为0.0001-0.01mol/L,所述配体与铱的摩尔比为1-5:1。
7.根据权利要求2所述的一种铱催化酮的不对称还原胺化方法,其特征在于:所述胺底物和手性催化剂Ir-L的摩尔比为100-500000:1。
8.根据权利要求2所述的一种铱催化酮的不对称还原胺化方法,其特征在于:所述述胺底物和酮的摩尔比为:0.5-1.5:1,胺底物和添加剂的的摩尔比为1:1~5。
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CN114733576A (zh) * | 2022-05-13 | 2022-07-12 | 江苏医药职业学院 | 一种手性二茂铁磺酸催化剂及其制备方法与应用 |
CN115417777A (zh) * | 2022-08-02 | 2022-12-02 | 西安近代化学研究所 | 一种(s)-2-乙基-n-(1-甲氧基-2-丙基)-6-甲基苯胺的制备方法 |
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