CN105859783A - 一种新型手性膦配体以及包含该配体的金属催化剂、其制备方法与应用 - Google Patents
一种新型手性膦配体以及包含该配体的金属催化剂、其制备方法与应用 Download PDFInfo
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- CN105859783A CN105859783A CN201610244753.6A CN201610244753A CN105859783A CN 105859783 A CN105859783 A CN 105859783A CN 201610244753 A CN201610244753 A CN 201610244753A CN 105859783 A CN105859783 A CN 105859783A
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- Prior art keywords
- transition metal
- aryl
- preparation
- beta
- chiral phosphine
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 239000003446 ligand Substances 0.000 title claims abstract description 42
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000003054 catalyst Substances 0.000 title claims abstract description 16
- 229910052751 metal Inorganic materials 0.000 title abstract description 6
- 239000002184 metal Substances 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 27
- 150000003624 transition metals Chemical group 0.000 claims abstract description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- -1 aryl amide Chemical class 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 229910052703 rhodium Inorganic materials 0.000 claims description 7
- 230000004044 response Effects 0.000 claims description 6
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 238000006471 dimerization reaction Methods 0.000 claims description 3
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- 239000011261 inert gas Substances 0.000 claims description 2
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- 229910052759 nickel Inorganic materials 0.000 claims description 2
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
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- 230000006340 racemization Effects 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- 239000010948 rhodium Substances 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 229910052760 oxygen Inorganic materials 0.000 description 23
- 239000001301 oxygen Substances 0.000 description 21
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
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- 238000000034 method Methods 0.000 description 11
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
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- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 7
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
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- 0 CP1c(c(OCc2ccccc2)ccc2)c2OC1[C@](*c1ccc2)Pc1c2OCc1ccccc1 Chemical compound CP1c(c(OCc2ccccc2)ccc2)c2OC1[C@](*c1ccc2)Pc1c2OCc1ccccc1 0.000 description 3
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- 239000003513 alkali Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 2
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
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- QKZWXPLBVCKXNQ-UHFFFAOYSA-N (2-methoxyphenyl)-[2-[(2-methoxyphenyl)-phenylphosphanyl]ethyl]-phenylphosphane Chemical compound COC1=CC=CC=C1P(C=1C=CC=CC=1)CCP(C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-UHFFFAOYSA-N 0.000 description 1
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- 230000007935 neutral effect Effects 0.000 description 1
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- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001843 polymethylhydrosiloxane Polymers 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供一种新型手性膦配体以及包含该配体的金属催化剂、其制备方法与应用,新型手性膦配体具有如下结构式:
Description
技术领域
本发明涉及不对称催化剂技术领域,具体涉及一种新型手性膦配体以及包含该配体的金属催化剂、其制备方法与应用。
背景技术
近些年来,采用氢气为还原剂,通过过渡金属催化的不对称氢化技术高效合成多种手性化合物取得了长足的进展,尤其是对于脱氢氨基酸、酮、亚胺、潜手性烯烃等底物,诸多优良的催化体系被相继开发出来,此外,许多高效的不对称氢化技术被成功的应用到工业化生产中。在过渡金属催化的不对称氢化反应中,配体的特性直接影响了反应的活性和选择性,手性膦配体的发展在不对称氢化反应中起着举足轻重的作用,设计和开发新型的手性膦配体是发展高效的不对称氢化技术的核心。经过多年的发展,化学家们开发出许多优秀的手性膦配体,诸如Knowles开发的双膦配体DIPAMP,Noyori发展的BINAP,Burk设计并开发的DuPhos及BPE,以及Imamoto小组所设计的P-手性双膦配体BisP,等等。
然而,尽管不对称催化氢化取得了如上的进步和发展,高效的不对称催化氢化的底物适用范围仍然十分有限,我们仍需开发新型、高效的催化剂以催化氢化更多实用性强的底物,从而更为方便地合成多种功能性的手性化合物。例如,含有手性β-芳基酰胺结构的天然产物,诸多表现出重要的生理活性。然而,目前许多药物活性分子也具有这个不可缺少的重要手性结构单元。
制备该手性β-芳基酰胺结构的方法主要有拆分消旋化合物、用手性试剂或辅助基团诱导、不对称催化。拆分消旋化合物要消耗50%的原料,用手性试剂或辅助基团诱导要消耗手性源,与它们相比,不对称催化方法利用催化量的手性催化剂,从而表现出明显的高效性和经济性。不对称氢化是现有不对称催化方法中效率最高、实用性最强的方法之一。尽管用不对称氢化合成此类手性β-芳基酰胺的方法已有所研究,但现有方法仍然存在许多缺点,包括底物合成困难、效率不够高效等等。
综上所述,本领域急需实用性更强、效率更高的手性催化剂,以便用于不对称氢化方法来高效合成手性β-芳基酰胺。
发明内容
本发明的目的是提供一种新型手性膦配体以及包含该配体的金属催化剂、其制备方法与应用,由新型手性膦配体与过渡金属络合,制成不对称催化氢化反应的金属催化剂,用来合成手性β-芳基酰胺,具有很强的经济实用性,而且产品纯度高、配体承载量(s/c)高。
为了实现上述目的,本发明采用的技术方案如下:
一种新型手性膦配体,包括具有如下化学结构式的双齿膦配体化合物、其对映体、消旋体或非对映异构体:
式中,R1独立选自氢、C1~C10烷基、C1~C4烷氧基、C3~C15环烷基、卤素或C6~C15芳基;
Ra独立选自氢、C2~C10烷基环烷基、C6~C10芳基、C6~C15芳基-CH2、C5~C15杂环芳基-CH2、C6~C30的芳基苄基取代基。
根据以上方案,所述双齿膦配体化合物为化学结构式为 的化合物、其对映体、消旋体或非对映异构体
根据以上方案,所述双齿膦配体化合物是具有如下化学结构式的化合物、其对映体、消旋体或非对映异构体:
一种新型手性膦配体制备方法,包括以下步骤:
在有机溶剂中,酚和亲电试剂Ra-X(B)反应生成然后二聚偶联生成双膦氧化合物再经还原得到产品(E),反应路线如下所示:
一种过渡金属络合物、其对映体、消旋体或非对映异构体,由所述的新型手性膦配体与过渡金属合成,所述过渡金属选自Rh、Ru、Ni、Ir、Pd、Cu、Pt、Co或Au。
根据以上方案,所述过渡金属为Rh。
根据以上方案,所述过渡金属络合物是具有如下任意化学结构式的化合物或它们的对映体、消旋体或非对映异构体:
一种过渡金属络合物的制备方法:在惰性气体气氛下,在10~25℃,将1.0当量的过渡金属前体与1.0-1.3当量的所述新型手性膦配体在四氢呋喃溶剂中反应0.1-0.5小时。
一种催化氢化合成β-芳基酰胺的制备方法,以所述过渡金属络合物作为催化剂,在有机溶剂和氢气气氛中,对β-芳基烯酰胺进行还原反应,从而得到β-芳基酰胺。
根据以上方案,所述β-芳基酰胺的一种构型的手性β-芳基酰胺的ee值>90%。
根据以上方案,所述β-芳基酰胺的一种构型的手性β-芳基酰胺的ee值>94%。
根据以上方案,所述β-芳基烯酰胺和过渡金属络合物的摩尔比为20~1000,所述还原反应时,氢气压力为15~750psi,反应温度为20~100℃,反应时间为4-24小时。
根据以上方案,所述还原反应时,氢气压力为30~500psi,反应温度为20~80℃,反应时间为12-24小时。
所述新型手性膦配体制备时,A和B在有机溶剂中,在碱的存在下进行亲核取代反应。A和B的比例为1:~4,优选1:2.2-3;所述的碱选自氟化钾、碳酸钾、碳酸钠、磷酸钾、氟化铯或碳酸铯,优选碳酸钾。所述的反应温度为0-50℃,优选20-40℃;反应时间为4-24小时,优选4-8小时;反应溶剂选自二甲基甲酰胺、四氢呋喃、二氧六环或二甲基亚砜或它们的混合溶剂,优选二甲基甲酰胺。
所述新型手性膦配体制备时,C在有机溶剂中,在有碱存在下去质子化,并在金属氧化剂存在下二聚偶联得到D。所述碱选自:正丁基鋰、仲丁基鋰、叔丁基鋰、二异丙基胺鋰、二异丙基胺氯化镁氯化锂络合物;优选二异丙基胺鋰。所述金属氧化剂选自:氯化铜(II)、氯化铁(III)、特戊酸铜(II)、异丁酸铜(II);优选氯化铜(II)。
所述新型手性膦配体制备时,D在有机溶剂中,在还原剂存在下还原得到E。还原剂选自:三氯硅烷/三乙胺、二异丙基乙基胺、三正丁胺或聚甲氧基氢硅烷/四异丙氧基钛;优选三氯硅烷/三乙胺或聚甲氧基氢硅烷/四异丙氧基钛。所述溶剂选自:甲苯、苯、四氢呋喃、二氧六环;优选四氢呋喃。
所述新型手性膦配体制备时,反应温度为20-100℃,优选60-80℃;反应时间为4-24小时,优选12-16小时。
基团定义:
本发明中,“C1~C10烷基”表示直链或支链的含有至多10个碳原子的饱和脂族烃基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、叔己基、庚基、异庚基、辛基及异辛基。类似地,“C1~C4烷氧基”表示通过氧原子连接的如上述所定义的烷基,如甲氧基、乙氧基、丙氧基、丁氧基等。
本发明中,卤素包括F、Cl、Br或I。
本发明中,“芳基”表示具有芳香环结构的性质的取代基,例如C6-C15的芳基,本发明可用的芳基包括但不限于:苯基、萘基、蒽基等等。在本发明中,芳基包括未取代的或取代的芳基,其中取代是指基团上的一个或多个氢原子被选自下组的取代基取代:C1~C4烷基、C3~C10环烷基、卤素、羟基、羧基、醛基、酰基、胺基、-NR2R3,其中R2和R3各自为H或C1-C4烷基。代表性的芳基包括带有给电子和/或吸电子取代基的芳基,如对甲苯基、对甲氧基苯基、五氟苯基等。类似地,“芳基苄基”表示芳基和甲基相连的取代基,如苄基、二苯基苄基。
类似地,“杂环芳基”表示含有一个或多个选自N、O或S的杂原子的芳基。在具体的实施方式中,本发明中的“杂芳基”含有5-15个碳原子且具有至少一个含有1-3个独立选自O、N或S的杂原子的5-8元杂环。
本发明的有益效果是:
1)本发明的手性膦配体制成的过渡金属络合物可以用作不对称催化氢化反应的催化剂;
2)本发明的过渡金属催化剂能催化氢化高效地合成一系列高光学纯度(ee值>94%)的手性β-芳基酰胺,具有很强的经济实用性;
3.本发明催化氢化合成手性β-芳基酰胺的配体承载量(s/c)可达到1000,远高于现有技术。
具体实施方式
下面结合实施例对本发明的技术方案进行说明。
实施例1:
本发明提供一种新型手性膦配体及其制备方法,包括如下合成步骤:
1)(S)-3-叔丁基-4-羟基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(a)的制备:
根据现有技术,按照如下合成路线合成化合物a:
2)(S)-4-苄氧基-3-叔丁基--2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(b)的制备:
向反应瓶中依次加入化合物(S)-3-叔丁基-4-羟基-2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(a,1.13g,5mmol,1.0当量)、碳酸钾(3.5g,25mmol,5当量),N,N-二甲基甲酰胺(20mL),室温下向上述体系中滴加溴化苄(1.8mL,15mmol),反应体系在室温下反应4小时,向上述反应体系加入水(50mL)及二氯甲烷(30mL),分液后有机相依次用水和饱和食盐水洗涤(50mL);无水硫酸钠干燥后,浓缩。粗产物经硅胶柱层析(石油醚/乙酸乙酯=2:1),得到目标产物(S)-4-苄氧基-3-叔丁基--2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(b,1.55g,98%产率):
b:31P NMR(162MHz,CDCl3)δ63.93;1H NMR(400MHz,CDCl3)δ7.43(d,J=7.3Hz,2H),7.40–7.22(m,4H),6.56–6.44(m,2H),5.15(q,J=12.1Hz,2H),4.50(dd,J=13.9,2.4Hz,1H),4.38(dd,J=13.9,10.5Hz,1H),1.21(d,J=16.4Hz,9H);13C NMR(101MHz,CDCl3)δ166.79(d,J=16.8Hz),160.37,136.50,135.98,128.57,128.04,127.38,106.66(d,J=5.3Hz),104.68(d,J=5.6Hz),103.16(d,J=91Hz),70.62(s),66.23(d,J=59Hz),33.68(d,J=74Hz),24.68;
3)(2R,2'R,3S,3'S)-4,4'-二(苄氧基)-3,3'-二叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭-3,3'-二氧(c)的制备:
在氮气保护下,将(S)-4-苄氧基-3-叔丁基--2,3-二氢苯并[d][1,3]氧,磷-戊轭-3-氧(b,1.27g,4.0mmol,1.0当量)和四氢呋喃(20mL)加入50mL的Schlenk管中,丙酮/干冰浴冷却至-78℃,5分钟内缓慢滴加二异丙基胺鋰(2.4mL,2.0M的四氢呋喃/正庚烷/乙苯溶液,4.8mmol,1.2当量);-78℃搅拌1小时后,一次性加入无水氯化铜(II)(1.62g,12mmol,3当量);继续在-78℃搅拌1小时后,升至室温再搅拌1小时;向反应液中加入10%NH4OH溶液(40mL),水层用二氯甲烷(20mL×2)萃取,合并的有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥后,浓缩,硅胶柱层析纯化(石油醚:乙酸乙酯=1:2),得到白色固体(2R,2'R,3S,3'S)-4,4'-二(苄氧基)-3,3'-二叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭-3,3'-二氧(c,1.01g,80%产率):
c:31P NMR(162MHz,CDCl3)δ62.05;1H NMR(400MHz,CDCl3)δ7.51–7.18(m,12H),6.49(dd,J=8.1,3.7Hz,2H),6.18(dd,J=8.3,2.5Hz,2H),5.24–5.20(m,2H),5.14(q,J=11.8Hz,4H),1.21(d,J=16.3Hz,18H);13C NMR(126MHz,CDCl3)δ166.09(s),160.23(s),136.14(d,J=18.5Hz),128.47,127.94,127.29,106.62,104.66,72.65(d,J=55.4Hz),70.51,34.15(d,J=73.1Hz),24.25(s).
4)(2R,2'R,3R,3'R)-4,4'-二(苄氧基)-3,3'-二-叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭(1)的制备:
室温,氮气保护下,向15mL的(2R,2'R,3S,3'S)-4,4'-二(苄氧基)-3,3'-二叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭-3,3'-二氧(c,946mg,1.5mmol)的四氢呋喃溶液中加入聚甲基氢硅氧烷(PMHS,2.0g)和异丙氧基钛(1.7g,1.2mmol,4当量);反应混合物回流搅拌至反应体系颜色变为棕黑色,回流24小时后,真空泵减压去除大部分THF溶剂;向残留物中小心加入脱气的30%氢氧化钠溶液(15mL),同时有大量气泡产生;60℃搅拌0.5小时后,室温下,向混合体系中加入脱气的乙醚(30mL),分离得到有机相;有机相用脱气的水(15mL)洗涤,经硫酸钠干燥后,浓缩,无水无氧中性氧化铝柱层析(石油醚/乙醚=3:1)得到白色固体粉末状的目标配体(2R,2'R,3R,3'R)-4,4'-二(苄氧基)-3,3'-二-叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭(1,718mg,80%产率):
1:31P NMR(162MHz,CDCl3)δ-5.98;1H NMR(400MHz,CDCl3)δ7.35(ddd,J=25.7,19.9,7.1Hz,9H),7.15(t,J=8.1Hz,3H),6.54(d,J=8.1Hz,2H),6.49(d,J=8.2Hz,2H),5.11(s,4H),4.94(s,2H),1.05–0.92(m,18H);13C NMR(101MHz,CDCl3)δ164.87,160.82(t,J=6.2Hz),137.07,132.14,128.47,127.73,127.15,110.18,105.13,104.41,86.48(d,J=10.0Hz),70.20,32.40(t,J=10.1Hz),27.58(t,J=7.3Hz)。
本发明还提供一种过渡金属络合物{(降冰片二烯)[(2R,2'R,3R,3'R)-4,4'-二(苄氧基)-3,3'-二-叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭}四氟硼酸铑(Rh(nbd)(1)BF4)及其制备方法,包含如下合成步骤:
氮气保护下,将双(降冰片二烯)铑(I)四氟硼酸盐(37.4mg,0.10mmol,1当量)溶于四氢呋喃(0.1mL)中,0℃搅拌下,加入配体(2R,2'R,3R,3'R)-4,4'-二(苄氧基)-3,3'-二-叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭(1,65.8mg,0.11mmol,1.1当量)的THF(0.5mL)溶液;反应体系在室温搅拌0.5小时后,真空泵减压浓缩去除大部分溶剂;加入脱气的乙醚(10mL),搅拌10分钟后,氮气保护下过滤得到红色固体状目标化合物{(降冰片二烯)[(2R,2'R,3R,3'R)-4,4'-二(苄氧基)-3,3'-二-叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭}四氟硼酸铑(75mg,85%产率):
Rh(nbd)(1)BF4:31P NMR(162MHz,CDCl3)δ78.29(2J RhP=157Hz);1H NMR(400MHz,CDCl3)δ7.52–7.32(m,12H),6.76(d,J=5.2Hz,2H),6.61(d,J=8.2Hz,2H),5.68(s,4H),5.19(dt,J=15.1,7.7Hz,6H),3.76(s,2H),1.52(s,2H),0.93(d,J=15.5Hz,18H)。
所述催化剂(Rh(nbd)(1)BF4的完整合成反应式为:
实施例2:
本发明提供一种过渡金属络合物{(环辛二烯)[(2R,2'R,3R,3'R)-4,4'-二(苄氧基)-3,3'-二-叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭}四氟硼酸铑(Rh(cod)(1)BF4)及其制备方法,包含如下合成步骤::
氮气保护下,将双(环辛二烯)铑(I)四氟硼酸盐(40.6mg,0.10mmol,1当量)溶于四氢呋喃(0.1mL)中,0℃搅拌下,加入配体(2R,2'R,3R,3'R)-4,4'-二(苄氧基)-3,3'-二-叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭(1,65.8mg,0.11mmol,1.1当量)的THF(0.5mL)溶液;反应体系在室温搅拌0.5小时后,真空泵减压浓缩去除大部分溶剂;加入脱气的乙醚(10mL),搅拌10分钟后,氮气保护下过滤得到红色固体状目标化合物{(环辛二烯)[(2R,2'R,3R,3'R)-4,4'-二(苄氧基)-3,3'-二-叔丁基-2,2',3,3'-四氢-2,2'-二苯并[d][1,3]氧,磷-戊轭}四氟硼酸铑(75mg,85%产率),反应式为:
Rh(cod)(1)BF4:31P NMR(162MHz,CDCl3)δ85.61(s),85.14(2J RhP=152Hz);1H NMR(400MHz,CDCl3)δ7.55–7.25(m,12H),6.70(d,J=4.4Hz,2H),6.59(d,J=8.4Hz,2H),5.88(s,2H),5.35(d,J=15.5Hz,2H),5.15(s,2H),5.07(q,J=10.2Hz,4H),2.27(s,2H),2.04(d,J=17.9Hz,2H),1.95(s,2H),1.76(d,J=7.5Hz,2H),1.08(d,J=15.6Hz,18H)。
实施例3:
本发明提供一种(E)-β-芳基烯酰胺的制备方法:
1)化合物(E)-N-(2-苯丙基-1-烯)乙酰胺(13a)的制备:
向500mL反应瓶中依次加入2-苯基丙醛(d,26.8g,200mmol),醋酸钠(20g,240mmol),盐酸羟铵(17g,240mmol),乙醇(300mL),水(60mL),将上述反应体系在室温下搅拌4小时,浓缩除去有机溶剂,随后向浓缩残留物中加入二氯甲烷(200mL)和水(200mL),分液除去水相,有机相依次用水和饱和食盐水洗涤(50mL);无水硫酸钠干燥后,浓缩,所得粗产物2-苯基丙醛肟(e)不经分离直接进行下一步反应;
向50mL三口烧瓶中依次加入乙酸(10mL),乙酸酐(8.7mL),铁粉(5.0g),在氮气保护下,将上述反应体系加热至130℃反应5小时,将体系温度降至60℃,随后向上述混合物中滴加粗品2-苯基丙醛肟(e,4.5g,30mmol)的六甲基磷酰酰胺(20mL)溶液,将所得反应体系在60℃下继续反应12小时,冷却至室温后加入乙酸乙酯(100mL),过滤,滤液水(100mL x 2)和饱和食盐水洗涤(50mL);无水硫酸钠干燥后,浓缩,所得粗产物经硅胶柱层析(石油醚/乙酸乙酯=4:1)得到目标产物(E)-N-(2-苯丙基-1-烯)乙酰胺(13a,3.2g,18mmol,60%):
13a:白色固体;1H NMR(500MHz,DMSO)δ9.48(d,J=10.3Hz,1H),7.35(d,J=7.6Hz,2H),7.30(t,J=7.4Hz,2H),7.21–7.02(m,2H),3.31(s,3H),2.02(s,3H);13C NMR(126MHz,DMSO)δ168.28,141.79,128.85,126.57,125.24,120.83,116.39,23.10,14.74。
其合成化学式为:
2)以制备的化合物13a为氢化底物,手性双膦配体(1-12)及双(降冰片二烯)铑(I)四氟硼酸盐{Rh(nbd)2BF4}为催化剂,催化剂承载量(s/c=40)下制备光学活性的手性β-芳基酰胺(S)-14a:
氮气氛围下,在手套箱中将13a(7mg,40μmol),手性双膦配体(1-12,1.1μmol)和Rh(nbd)2BF4(0.37mg,1μmol),2mL无水二氯甲烷加入氢化瓶;将氢化瓶转移到高压反应釜,封闭反应釜后,置换氢气三次,充入氢气至750psi,50℃反应20小时后,冷却至室温;放空氢气,打开反应釜,反应粗产物溶液经微孔滤膜过滤去除金属离子,异丙醇稀释后,直接用手性AD-H柱高效液相测定转化率和产物(S)-N-(2-苯丙基)-乙酰胺[(S)-14a]的ee值如下表:
Entry | Ligand | S/Rh | L/Rh | Solvent | T(℃) | t(h) | Yield(%) | ee(%) | Config |
1 | 1 | 40 | 1.1 | DCM | 50 | 20 | 99 | 83 | S |
2 | 2 | 40 | 1.1 | DCM | 50 | 20 | 99 | 47 | S |
3 | 3 | 40 | 1.1 | DCM | 50 | 20 | 99 | 74 | S |
4 | 4 | 40 | 1.1 | DCM | 50 | 20 | 99 | 60 | S |
5 | 5 | 40 | 1.1 | DCM | 50 | 20 | 99 | 70 | S |
6 | 6 | 40 | 1.1 | DCM | 50 | 20 | 99 | 60 | S |
7 | 7 | 40 | 1.1 | DCM | 50 | 20 | 99 | 20 | S |
8 | 8 | 40 | 1.1 | DCM | 50 | 20 | 99 | 83 | S |
9 | 9 | 40 | 1.1 | DCM | 50 | 20 | 99 | 80 | S |
10 | 10 | 40 | 1.1 | DCM | 50 | 20 | 0 | - | - |
11 | 11 | 40 | 1.1 | DCM | 50 | 20 | 99 | 81 | S |
12 | 12 | 40 | 1.1 | DCM | 50 | 20 | 99 | 74 | S |
其化学反应式为:
实例4:
本发明提供一种以实施例3制备的化合物13a为氢化底物,手性金属铑的络合物为催化剂,配体承载量(s/c=50or1000)下制备光学活性的手性β-芳基酰胺(R)-14a的制备方法:
氮气氛围下,在手套箱中将13a(8.8mg,50μmol),Rh(nbd)(1)BF4(0.102mg,0.1μmol)或者Rh(cod)(1)BF4(0.102mg,0.1μmol),2mL无水二氯甲烷加入氢化瓶;将氢化瓶转移到高压反应釜,封闭反应釜后,置换氢气三次,充入氢气至750psi,50℃反应20小时后,冷却至室温;放空氢气,打开反应釜,反应粗产物溶液经微孔滤膜过滤去除金属离子,异丙醇稀释后,直接用手性AD-H柱高效液相测定转化率和产物(S)-N-(2-苯丙基)-乙酰胺[(S)-14a]的ee值:
Entry | Catalyst | S/C | Solvent | T(℃) | t(h) | Yield(%) | ee(%) | Config |
1 | Rh(nbd)(1)BF4 | 50 | DCM | rt | 20 | 99 | 88 | S |
2 | Rh(nbd)(1)BF4 | 50 | DCM | 0 | 24 | 99 | 90 | S |
3 | Rh(cod)(1)BF4 | 50 | DCM | 0 | 24 | 99 | 92 | S |
4 | Rh(cod)(1)BF4 | 50 | MeOH | 0 | 24 | 99 | 92 | S |
5 | Rh(cod)(1)BF4 | 50 | iPrOH | 0 | 24 | 99 | 94 | S |
6 | Rh(cod)(1)BF4 | 50 | EtOAc | 0 | 24 | 99 | 92 | S |
7 | Rh(cod)(1)BF4 | 50 | Toluene | 0 | 24 | 99 | 92 | S |
8 | Rh(cod)(1)BF4 | 1000 | DCM | 50 | 36 | 60 | 90 | S |
9 | Rh(cod)(1)BF4 | 1000 | MeOH | 50 | 36 | 85 | 91 | S |
10 | Rh(cod)(1)BF4 | 1000 | iPrOH | 50 | 36 | 99 | 92 | S |
11 | Rh(cod)(1)BF4 | 1000 | EtOAc | 50 | 36 | 80 | 91 | S |
12 | Rh(cod)(1)BF4 | 1000 | Toluene | 50 | 36 | 40 | 92 | S |
其化学反应式为:
以上实施例仅用以说明而非限制本发明的技术方案,尽管上述实施例对本发明进行了详细说明,本领域的相关技术人员应当理解:可以对本发明进行修改或者同等替换,但不脱离本发明精神和范围的任何修改和局部替换均应涵盖在本发明的权利要求范围内。
Claims (13)
1.一种新型手性膦配体,其特征在于,包括具有如下化学结构式的双齿膦配体化合物、其对映体、消旋体或非对映异构体:
式中,R1独立选自氢、C1~C10烷基、C1~C4烷氧基、C3~C15环烷基、卤素或C6~C15芳基;
Ra独立选自氢、C2~C10烷基环烷基、C6~C10芳基、C6~C15芳基-CH2、C5~C15杂环芳基-CH2、C6~C30的芳基苄基取代基。
2.根据权利要求1所述的新型手性膦配体,其特征在于,所述双齿膦配体化合物为化学结构式为的化合物、其对映体、消旋体或非对映异构体。
3.根据权利要求1所述的新型手性膦配体,其特征在于,所述双齿膦配体化合物是具有如下化学结构式的化合物、其对映体、消旋体或非对映异构体:
。
4.一种新型手性膦配体制备方法,其特征在于,包括以下步骤:
在有机溶剂中,酚和亲电试剂Ra-X反应生成然后二聚偶联生成双膦氧化合物再经还原得到产品。
5.一种过渡金属络合物、其对映体、消旋体或非对映异构体,其特征在于,由所述的新型手性膦配体与过渡金属合成,所述过渡金属为Rh、Ru、Ni、Ir、Pd、Cu、Pt、Co或Au。
6.根据权利要求5所述的过渡金属络合物、其对映体、消旋体或非对映异构体,其特征在于,所述过渡金属为Rh。
7.根据权利要求5所述的过渡金属络合物、其对映体、消旋体或非对映异构体,其特征在于,所述过渡金属络合物是具有如下任意化学结构式的化合物 或其对映体、消旋体或非对映异构体:
。
8.一种过渡金属络合物的制备方法,其特征在于,在惰性气体气氛下,在10~25℃,将1.0当量的过渡金属前体与1.0-1.3当量的所述新型手性膦配体在四氢呋喃溶剂中反应0.1-0.5小时。
9.一种催化氢化合成β-芳基酰胺的制备方法,其特征在于,以所述过渡金属络合物作为催化剂,在有机溶剂和氢气气氛中,对β-芳基烯酰胺进行还原反应,从而得到β-芳基酰胺。
10.根据权利要求9所述的催化氢化合成β-芳基酰胺的制备方法,其特征在于,所述β-芳基酰胺的一种构型的手性β-芳基酰胺的ee值>90%。
11.根据权利要求9所述的催化氢化合成β-芳基酰胺的制备方法,其特征在于,所述β-芳基酰胺的一种构型的手性β-芳基酰胺的ee值>94%。
12.根据权利要求9所述的催化氢化合成β-芳基酰胺的制备方法,其特征在于,所述β-芳基烯酰胺和过渡金属络合物的摩尔比为20~1000,所述还原反应时,氢气压力为15~750psi,反应温度为20~100℃,反应时间为4-24小时。
13.根据权利要求9所述的催化氢化合成β-芳基酰胺的制备方法,其特征在于,所述还原反应时,氢气压力为30~500psi,反应温度为20~80℃,反应时间为12-24小时。
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CN107445999A (zh) * | 2017-08-15 | 2017-12-08 | 中国科学院上海有机化学研究所 | 金属络合物、制备方法和应用及其中间体 |
CN107445999B (zh) * | 2017-08-15 | 2020-11-13 | 中国科学院上海有机化学研究所 | 金属络合物、制备方法和应用及其中间体 |
JP2022512691A (ja) * | 2018-10-10 | 2022-02-07 | 中国科学院上海有机化学研究所 | 金属錯体、中間体、その製造方法および使用 |
WO2020073962A1 (zh) * | 2018-10-10 | 2020-04-16 | 中国科学院上海有机化学研究所 | 一种金属配合物、中间体、其制备方法及应用 |
CN111018918A (zh) * | 2018-10-10 | 2020-04-17 | 中国科学院上海有机化学研究所 | 一种金属配合物、中间体、其制备方法及应用 |
JP7411650B2 (ja) | 2018-10-10 | 2024-01-11 | 中国科学院上海有机化学研究所 | 金属錯体、中間体、その製造方法および使用 |
CN111018918B (zh) * | 2018-10-10 | 2022-10-04 | 中国科学院上海有机化学研究所 | 一种金属配合物、中间体、其制备方法及应用 |
CN111410611A (zh) * | 2020-04-09 | 2020-07-14 | 宁波赜军医药科技有限公司 | 一种(r)-1-(1-萘基)-2乙胺的制备方法 |
WO2021227641A1 (zh) * | 2020-05-11 | 2021-11-18 | 浙江医药股份有限公司新昌制药厂 | 一种手性4-芳基-β-氨基酸衍生物的制备方法 |
CN113636950B (zh) * | 2020-05-11 | 2023-01-17 | 浙江医药股份有限公司新昌制药厂 | 一种手性4-芳基-β-氨基酸衍生物的制备方法 |
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CN114805674A (zh) * | 2021-01-27 | 2022-07-29 | 中国科学院上海有机化学研究所 | 聚合膦配体、包含其的过渡金属络合物、其制备和应用 |
CN114805674B (zh) * | 2021-01-27 | 2023-08-11 | 中国科学院上海有机化学研究所 | 聚合膦配体、包含其的过渡金属络合物、其制备和应用 |
CN115819461A (zh) * | 2022-11-02 | 2023-03-21 | 黄河三角洲京博化工研究院有限公司 | 一种新双齿膦配体及其制备方法 |
CN115819461B (zh) * | 2022-11-02 | 2024-06-07 | 黄河三角洲京博化工研究院有限公司 | 一种双齿膦配体及其制备方法 |
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