CN110885343A - 一种薄荷基双碳、磷手性叔膦衍生物、其制备方法及应用 - Google Patents
一种薄荷基双碳、磷手性叔膦衍生物、其制备方法及应用 Download PDFInfo
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- CN110885343A CN110885343A CN201911266797.9A CN201911266797A CN110885343A CN 110885343 A CN110885343 A CN 110885343A CN 201911266797 A CN201911266797 A CN 201911266797A CN 110885343 A CN110885343 A CN 110885343A
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title abstract description 35
- 229910052698 phosphorus Inorganic materials 0.000 title abstract description 31
- 239000011574 phosphorus Substances 0.000 title abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 235000006679 Mentha X verticillata Nutrition 0.000 title description 6
- 235000002899 Mentha suaveolens Nutrition 0.000 title description 6
- 235000001636 Mentha x rotundifolia Nutrition 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 12
- 230000001588 bifunctional effect Effects 0.000 claims abstract description 8
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 239000007858 starting material Substances 0.000 claims description 23
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 8
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 claims description 7
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 claims description 6
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- KGKAYWMGPDWLQZ-UHFFFAOYSA-N 1,2-bis(bromomethyl)benzene Chemical compound BrCC1=CC=CC=C1CBr KGKAYWMGPDWLQZ-UHFFFAOYSA-N 0.000 claims description 4
- OXHOPZLBSSTTBU-UHFFFAOYSA-N 1,3-bis(bromomethyl)benzene Chemical compound BrCC1=CC=CC(CBr)=C1 OXHOPZLBSSTTBU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- GRJWOKACBGZOKT-UHFFFAOYSA-N 1,3-bis(chloromethyl)benzene Chemical compound ClCC1=CC=CC(CCl)=C1 GRJWOKACBGZOKT-UHFFFAOYSA-N 0.000 claims description 3
- RBZMSGOBSOCYHR-UHFFFAOYSA-N 1,4-bis(bromomethyl)benzene Chemical compound BrCC1=CC=C(CBr)C=C1 RBZMSGOBSOCYHR-UHFFFAOYSA-N 0.000 claims description 3
- IWQNFYRJSVJWQA-UHFFFAOYSA-N 2,6-bis(chloromethyl)pyridine Chemical compound ClCC1=CC=CC(CCl)=N1 IWQNFYRJSVJWQA-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 claims description 3
- ATWLRNODAYAMQS-UHFFFAOYSA-N 1,1-dibromopropane Chemical compound CCC(Br)Br ATWLRNODAYAMQS-UHFFFAOYSA-N 0.000 claims description 2
- BXXWFOGWXLJPPA-UHFFFAOYSA-N 2,3-dibromobutane Chemical compound CC(Br)C(C)Br BXXWFOGWXLJPPA-UHFFFAOYSA-N 0.000 claims description 2
- VCJZTATVUDMNLU-UHFFFAOYSA-N dibromomethylbenzene Chemical compound BrC(Br)C1=CC=CC=C1 VCJZTATVUDMNLU-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- RKTIAZVXWYFNJG-UHFFFAOYSA-N 3,4-dichloro-2-methylpyridine Chemical compound CC1=NC=CC(Cl)=C1Cl RKTIAZVXWYFNJG-UHFFFAOYSA-N 0.000 claims 1
- -1 phosphine compound Chemical group 0.000 abstract description 23
- 229910000073 phosphorus hydride Inorganic materials 0.000 abstract description 18
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 14
- 125000004437 phosphorous atom Chemical group 0.000 abstract description 14
- 238000006555 catalytic reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical group P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- LBVWYGNGGJURHQ-UHFFFAOYSA-N dicarbon Chemical compound [C-]#[C+] LBVWYGNGGJURHQ-UHFFFAOYSA-N 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- 239000003999 initiator Substances 0.000 abstract description 2
- 150000003018 phosphorus compounds Chemical class 0.000 abstract description 2
- 230000006340 racemization Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 116
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
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- 238000004983 proton decoupled 13C NMR spectroscopy Methods 0.000 description 18
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 17
- GYURZOHWLNEPNR-UHFFFAOYSA-N C1(CC(C(CC1)C(C)C)P(C1=CC=CC=C1)=O)C Chemical compound C1(CC(C(CC1)C(C)C)P(C1=CC=CC=C1)=O)C GYURZOHWLNEPNR-UHFFFAOYSA-N 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- JXBAVRIYDKLCOE-UHFFFAOYSA-N [C].[P] Chemical class [C].[P] JXBAVRIYDKLCOE-UHFFFAOYSA-N 0.000 description 2
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- 229940126214 compound 3 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 229910052751 metal Inorganic materials 0.000 description 2
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 150000003009 phosphonic acids Chemical class 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5329—Polyphosphine oxides or thioxides
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- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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Abstract
本公开属于复合多手性磷化合物合成技术领域,具体涉及一种薄荷基双碳、磷手性叔膦衍生物、其制备方法及应用。复合多手性的叔膦化合物由于具有多个种类的手性中心,在不对称催化反应中具有广泛的应用,但目前本领域对于复合多手性叔膦化合物的开发还存在含磷产物结构不稳定及反应条件苛刻等缺陷。本公开提供了一系列含薄荷基双碳、磷手性叔膦衍生物,以手性仲膦氧化物作为起始物,通过双官能团试剂对其进行烃基化反应,实现双手性双膦化合物的合成。本公开提供的制备方法反应条件温和,避免了磷原子的消旋问题,显著降低反应的经济成本,具有良好的推广意义。
Description
技术领域
本公开属于复合多手性磷化合物合成技术领域,具体涉及一种薄荷基双碳、磷手性叔膦衍生物、其制备方法及应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本公开的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
不对称合成是获取手性物质的重要方法,在化工、医药、农药、材料等领域,发挥着重要作用。利用手性催化剂催化的不对称反应,具有良好手性放大效应,因此得到了广泛的应用。其中,手性叔膦化合物由于具有良好的供电子能力、可控的空间和电子性能,常作为配体被广泛应用于不对称催化反应中。作为配体使用的手性叔膦化合物,多为两个膦组分通过某种碳骨架相连并保持一定距离的双齿配体,在催化过程中,通过和过渡金属形成结构比较稳定的螯合物,是一种复合的多手性叔膦化合物,并在过渡金属原子周围形成不对称环境,产生不对称诱导和催化的效果。
复合多手性的叔膦化合物,因为含有多个种类的手性中心,通过其协同作用,可望提供卓越的不对称环境,有效提高不对称催化反应的对映选择性,因而在不对称合成领域,具有广阔的应用前景。但目前合成领域对于复合多手性叔膦化合物的开发还存在一定的技术缺陷。例如,将两个手性膦组分连接的方式,多通过碳磷键,但是,在碳磷键形成的过程中,磷原子手性往往会丢失,并且往往因为目标产物分子中含有不止一个手性磷原子,其手性丢失的效果会放大,导致产物中形成多个非对映异构体,严重影响其不对称催化的效果。
为了克服该弊端,本领域目前采用的方法,第一,使用磷原子构型稳定的手性膦前体,在上述连接过程中,磷原子手性能完整保留。但是这种手性膦前体获取不易,往往需要多步反应或繁琐的拆分过程;第二,通过极端的反应条件,完成手性磷组分的连接,这需要配合使用难以获得的高活性试剂。例如最常见的方法,在零下78度的低温下,使用丁基锂脱氢,然后进行磷原子的烷基化反应。
发明人认为,上述方法中,不论是使用构型稳定的前体化合物或采用极端实验条件都会显著增大反应的成本,导致研究成果无法被放大。
目前,复合多手性的叔膦化合物,无论其种类还是应用,研究报道的都很少。已经报道的该类化合物,都是通过多步化学反应,同时,还必须经过化学拆分过程,其合成方法繁琐,效率低下,并且往往涉及使用低温条件、活泼金属试剂,实际操作难度大。
发明内容
本公开采用发明人前期开发的手性仲膦氧化物作为起始物,使用氢氧化钾做碱,在水-甲苯体系的相转移条件下,使用双官能团试剂对其进行烃基化反应,在分子里引入两个手性磷组分,获得了一系列含薄荷基双碳、磷手性叔膦衍生物。本公开采用的前体化合物含有薄荷基团、并且磷原子构型稳定,本公开方法制备的复合多手性磷化合物,不仅具有磷手性中心,还含有手性的薄荷基,属于复合多手性的双膦配体,并且,其中各手性中心,还可以在一定程度上进行调控。
另外,本公开提供的合成方法中,因为手性烃基的存在,手性磷原子的构型得以稳定,使后续的烷基化反应可以在温和的条件下进行。该方法避免了使用苛刻的活泼金属试剂和超低温、无水无氧的反应条件,并且避免了该类化合物合成中困扰最大的手性磷原子的消旋问题,高效高选择性地获得目标化合物,可以有效的降低反应成本,提高安全性和推广意义。
基于上述研究结果,本公开提供以下技术方案:
本公开第一方面,提供一种化合物,或所述化合物的异构体或溶剂化物,所述化合物具有下式3或式2所示的结构:
其中,R1=Ph、pPhC6H4、oMeC6H4、pMeOC6H4、pMeC6H4;
R2=Ph、pPhC6H4、oMeC6H4、pMeOC6H4、pMeC6H4。
Men为(L)-(-)-menthyl,(L)-(-)-薄荷基,G选自1,2-CH2C6H4CH2、 1,3-CH2C6H4CH2、1,4-CH2C6H4CH2、2,6-CH2PyCH2、(CH2)n,其中n=1、3或4。
优选的,所述式2化合物具体结构及编号如下:
优选的,所述式3化合物具体结构及编号如下:
本公开第二方面,提供式3所述化合物的制备方法,所述制备方法流程如下式所示:
优选的,所述制备方法步骤如下:
将起始化合物加入碱、及水-甲苯体系中,通过引入双官能团试剂对起始化合物进行烃基化反应。
进一步优选的,所述起始化合物结构如下式1所示:
其中,R1=Ph、pPhC6H4、oMeC6H4、pMeOC6H4、pMeC6H4。
在一些具体的实施例中,所述起始化合物的编号及取代基对应关系如下:
起始化合物RP-1a中,R1=Ph(RP);
起始化合物SP-1a'中,R1=Ph(SP);
起始化合物RP-1b中,R1=pPhC6H4(RP);
起始化合物SP-1b'中,R1=pPhC6H4(SP);
起始化合物RP-1c中,R1=oMeC6H4(RP);
起始化合物RP-1d中,R1=pMeOC6H4(RP);
起始化合物SP-1d'中,R1=pMeOC6H4(SP);
起始化合物RP-1e中,R1=pMeC6H4(RP);
起始化合物SP-1e'中,R1=pMeC6H4(SP)。
优选的,所述双官能团试剂包括:四正丁基溴化铵、二溴甲基苯、二氯甲基吡啶、二碘甲烷、二溴丙烷及二溴丁烷。
更为优选的,所述双官能团试剂包括:四正丁基溴化铵、1,2-二溴甲基苯、1,4-二溴甲基苯、2,6-二氯甲基吡啶、二碘甲烷、1,3-二溴丙烷、1,4-二溴丁烷及1,3-二溴甲基苯。
本公开第三方面,提供式2所示化合物的制备方法:将化合物RP-1a与四正丁基溴化铵加入二氯甲烷溶液中,加入1,3-二氯甲基苯及碱溶液后在室温下混合反应。
本公开第四方面,提供第一方面所述化合物作为催化剂或中间体的应用。
与现有技术相比,本公开的有益效果是:
1、本公开首次提供了一系列双碳、磷手性叔膦衍生物,属于结构新颖的含有碳磷手性的叔膦化合物,可望在不对称合成领域发挥重要作用,用于获取多种手性药物或其中间体。
2、与本公开化合物结构具有一定类似程度的其他化合物,比如其他取代的碳磷手性的叔膦,其合成方法,涉及了使用手性拆分试剂预先与外消旋的中间体原料结合,经多步重结晶分离后,再通过反应将拆分试剂除去,相比之下,本公开提供的方法避免了这一过程,因此合成效率更高。
3、本公开提供的双碳、磷手性叔膦衍生物,连接两个手性磷组分的,可以为种类结构多样碳骨架,可以方便地调整控制两个手性磷组分的距离角度和位置,有利于获得可在不同不对称催化领域中应用的多手性叔膦化合物催化剂。
4、本公开提供的叔膦化合物,因为含有体积比较大的薄荷基团,具有更加优良的不对称诱导效果,同时,手性的薄荷基及环系结构,有助于磷原子构型在应用和修饰转化过程中的稳定。
5、本公开提供的方法,可以适用于在同一分子中,引入两个取代基不同或构型不同的磷组分,该类化合物尚未见于报道,对丰富该类化合物的结构种类,获得不同应用目的的化合物,具有重要意义。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本公开提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本公开所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本公开的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
术语解释部分:
斜体的R和S表示手性原子或其他手性位点的构型,其附带的大写非斜体下标,“P”表示的手性磷原子(phosphorus);例如,“RP”表示磷原子的R构型化合物,“SP”表示磷原子的S构型化合物。
正如背景技术所介绍的,现有技术中复合多手性磷化合物的合成还存在手性磷化合物结构不稳定、反应条件苛刻等缺陷。本公开提供了一系列含薄荷基双碳、磷手性叔膦衍生物及其制备方法,反应条件温和,磷原子结构构型稳定。
为了使得本领域技术人员能够更加清楚地了解本公开的技术方案,以下将结合具体的实施例与对比例详细说明本公开的技术方案。
实施例1所述式1化合物结构及制备
除上述碳磷手性的双叔膦化合物外,本公开还提供了该类化合物的合成方法。下面结合实施例,对本公开作进一步的说明,但本公开的保护范围并不局限于实施例中所涉及溶剂种类、用量、及其他数据表示的范围。
1、制备方法
本实施例中,以(RP,RP)-(1,3-苯基双亚甲基)双(-)-薄荷基苯基氧膦3b的制备为例对本公开的制备方法进行说明:
反应可在空气条件下进行。将苯基薄荷基氧膦RP-1a(50mg,0.190mmol)和四正丁基溴化铵(6mg,0.019mmol,10%mol)溶解于二氯甲烷中(0.2mL),然后向溶液中加入1,3-二溴甲基苯(0.014ml,0.095mmol)。将氢氧化钾的水溶液 (50%,0.5mL)加入后,混合物在室温下搅拌10小时,使用薄层层析监控反应 (silica gel,petroleum ether/ethyl acetate=1/1as eluent,Rf=0.3).反应完成后,混合物用二氯甲烷萃取三次,每次10毫升,合并的萃取液水洗三次,每次5毫升使用无水硫酸镁干燥,减压移除溶剂后,残留物用薄层层析提纯(silica gel, petroleum ether/ethyl acetate=1/1)得到3b.
2、化合物结构及结构确证信息
化合物1(RP,RP-3a)、(RP,RP)-(1,2-苯基双亚甲基)双(-)-薄荷基苯基氧膦,3a.
纯化合物3a由RP-1a和1,2-二溴甲基苯制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=1/5as eluent),为白色固体(34mg,52%,>99:1dr,dr值根据1H-NMR谱估算);(c=0.18,CH2Cl2);m.p.290.8–292.7℃;31P NMR(162MHz,CDCl3)δ=41.88(s);1H NMR(400MHz,CDCl3)δ=7.55–7.47 (m,4H),7.38–7.29(m,6H),6.53(dd,J=5.1,3.7Hz,2H),6.26–6.17(m,2H),4.73 (t,J=15.0Hz,2H),2.74(dd,J=14.8,6.4Hz,2H),2.26(d,J=9.9Hz,2H),2.15–2.06 (m,2H),2.00–1.88(m,2H),1.87–1.73(m,6H),1.58–1.44(m,4H),1.13–0.99 (m,10H),0.78(d,J=6.8Hz,6H),0.28(d,J=6.8Hz,6H);13C{1H}NMR(101MHz, CDCl3)δ=134.4(d,J=87.6Hz),132.5–132.3(m),131.0(s),130.7–130.4(m), 127.9(s),127.9(s),127.8(s),125.4(s),43.3(s),40.2(d,J=65.9Hz),35.3(s),34.5 (s),34.2(s),33.6(s),33.5(s),33.4(s),33.4(s),28.0(s),24.6(s),24.6(s),24.6(s), 22.9(s),21.5(s),15.2(s).HRMS(ESI+)Calcd.for C40H57O2P2[M+H+]:631.3834, Found:631.3830.
化合物2(RP,RP-3b)、(RP,RP)-(1,3-苯基双亚甲基)双(-)-薄荷基苯基氧膦,3b.
纯化合3b见实施例,为白色固体(39mg, 62%,>99:1dr,dr值根据1H-NMR谱估算); (c=0.19,CH2Cl2).m.p.209.9–213.2℃.31PNMR(162MHz,CDCl3)δ= 40.06(s);1H NMR(400MHz,CDCl3)δ=7.50–7.41(m,4H),7.35(d,J=6.3,2H), 7.33–7.27(m,4H),6.91(s,1H),6.71(dd,J=27.7,7.3,3H),3.40(t,J=15.6,2H), 2.93(dd,J=14.1,7.8,2H),2.13–1.99(m,5H),1.92(s,2H),1.72(s,7H),1.41–1.24(m,4H),0.95(t,J=8.2,9H),0.76(d,J=6.6,6H),0.35(d,J=6.6,6H);13C{1H}NMR(101MHz,CDCl3)δ=134.18(s),133.29(s),132.26(s),131.56(d,J=9.7),130.68 (s),130.57(s),130.48(s),127.98(s),127.87(s),127.58(s),43.41(s),41.06(s), 40.40(s),35.82(s),35.44(s),35.22(s),34.25(s),33.29(s),33.16(s),28.12(s), 24.70(s),24.58(s),22.61(s),21.42(s),15.17(s).HRMS(ESI+)Calcd.for C40H57O2P2[M+H+]:631.3834,Found:631.3858.
化合物3(RP,RP-3c)、(RP,RP)-(1,4-苯基双亚甲基)双(-)-薄荷基苯基氧膦,3c.
纯化合物3c由RP-1a和1,4-二溴甲基苯制备,通过重结晶(petroleum ether-dichloromethane),为白色固体 (37mg,62%,>99:1dr,dr值根据1H-NMR谱估算);m.p.310.5–312.2℃;31P NMR(162MHz,CDCl3)δ=39.84(s);1H NMR(400MHz,CDCl3)δ=7.43(t, J=7.6Hz,4H),7.36(d,J=7.2Hz,2H),7.32–7.27(m,4H),6.72(s,4H),3.37(t, J=15.2Hz,2H),2.93(dd,J=14.4,7.2Hz,2H),2.06–1.91(m,8H),1.74–1.63(m,6H),1.42–1.31(m,4H),0.97–0.92(m,8H),0.76(d,J=6.8Hz,6H),0.29(d,J=6.8 Hz,6H);13C{1H}NMR(101MHz,CDCl3)δ=134.2(s),133.3(s),130.8(s), 130.5(s),130.4(s),130.4(s),130.4–129.3(m),127.9(s),127.9(s),127.8(s),43.3 (s),40.8(s),40.1(s),36.1(s),35.5(s),35.3(s),34.2(s),33.3(s),33.2(s),28.1(s), 24.7(s),24.6(s),22.6(s),21.4(s),15.1(s).HRMS(ESI+)Calcd.for C40H57O2P2 [M+H+]:631.3834,Found:631.3819.
化合物4(RP,RP-3d)、(RP,RP)-(2,6-吡啶基双亚甲基)双(-)-薄荷基苯基氧膦,3d.
纯化合物3d由RP-1a和2,6-二氯甲基吡啶制备, 通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=1/5as eluent),为白色固体(42mg,71%,>99:1dr,dr值根据1H-NMR谱估算).(c=0.10,CH2Cl2).m.p.203.4–207.6℃.31P NMR(162MHz, CDCl3)δ=41.29(s);1H NMR(400MHz,CDCl3)δ=7.51–7.45(m,4H),7.41– 7.35(m,2H),7.33–7.24(m,4H),7.17(t,J=7.8Hz,1H),6.88(d,J=7.8Hz,2H), 3.44(dd,J=16.4,14.4Hz,2H),3.32(dd,J=14.0,10.0Hz,2H),2.14–2.01(m,6H), 1.78–1.64(m,6H),1.46–1.25(m,4H),1.09–0.98(m,3H),0.96(d,J=6.4Hz, 7H),0.78(d,J=6.8Hz,6H),0.37(d,J=6.8Hz,6H);13C{1H}NMR(100MHz, CDCl3)δ=152.6(s),152.5(s),136.1(s),133.5(d,J=89.2Hz),130.8(s),130.7(s), 130.6(s),127.8(d,J=11.1Hz),122.4(s),43.3(d,J=2.5Hz),40.6(d,J=66.4Hz), 38.7(d,J=58.2Hz),35.3(s),34.3(s),33.2(d,J=13.3Hz),28.1(s),24.7(d,J=12.3 Hz),22.7(s),21.5(s),15.3(s).IR(KBr)ν/cm-1:2929,1438,1193,745,540.HRMS (ESI+)Calcd.for C39H56NO2P2[M+H+]:632.3786.Found:632.3781.
化合物5(RP,RP-3e)、(RP,RP)-亚甲基双(-)-薄荷基苯基氧膦,3e.
纯化合物3e由RP-1a和二碘甲烷制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate==1/3as eluent),为白色固体(25mg,57%,>99:1dr,dr值根据1H-NMR谱估算).m.p. 151.3–153.4℃.31P NMR(162MHz,CDCl3)δ=41.32(s).1H NMR(400MHz, CDCl3)δ=7.78–7.66(m,4H),7.57–7.41(m,6H),2.27–2.10(m,2H),1.97– 1.86(m,2H),1.80–1.69(m,8H),1.65(d,J=12.4Hz,6H),1.34(s,2H),1.22–1.11 (m,2H),1.05–1.94(m,4H),0.90(d,J=6.4Hz,6H),0.85(d,J=6.8Hz,4H),0.42(d, J=6.8Hz,4H);13C{1H}NMR(101MHz,CDCl3)δ=135.8(d,J=91.1Hz),131.0(d, J=2.6Hz),130.0(d,J=8.8Hz),128.3(d,J=11.1Hz),43.4(d,J=3.1),41.5(s),40.8 (s),35.6(s),34.3(s),33.2(d,J=13.6Hz),28.3(s),24.6(d,J=12.3Hz),22.6(s),21.5 (s),15.3(s),15.1(s),14.6(s),1.0(s).HRMS(ESI+)Calcd for C33H51O2P2[M+H+]: 541.3364,Found:541.3363.
化合物6(RP,RP-3f)、(RP,RP)-(1,3-亚丙基)双(-)-薄荷基苯基氧膦,3f.
纯化合物3f由RP-1a和1,3-二溴丙烷制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=1/3 as eluent),为白色固体(26mg,56%,>99:1dr,dr值根据1H-NMR谱估算). (c=0.12,CH2Cl2).m.p.203.3–204.8℃.31P NMR(162MHz,CDCl3) δ=40.43(s);1H NMR(400MHz,CDCl3)δ=7.55–7.50(m,4H),7.42–7.36(m, 2H),7.35–7.31(m,4H)2.15–1.96(m,7H),1.91–1.75(m,4H),1.75–1.56(m, 5H),1.48–1.34(m,2H),1.34–1.16(m,4H),1.02–0.96(m,2H),0.91(d,J=6.0Hz, 7H),0.81(d,J=6.8Hz,6H),0.27(d,J=6.8Hz,6H);13C{1H}NMR(101MHz, CDCl3)δ=134.3(s),133.5(s),131.1(s),130.9(s),130.8(s),130.6(s),130.5(s), 128.7(s),128.6(s),128.4(s),128.3(s)128.2(s),43.4(d,J=13.1Hz),41.5(s), 40.9(s),35.4(s),34.4(s),34.3(s),33.4(s),28.5(s),28.4(s),27.9(s),27.8(s),25.0 (s),24.8(s),24.7(s),24.6(s),22.8(s),22.7(s),21.8(s),21.7(s),15.3(s),15.2(s), 15.1(s)14.7(s).HRMS(ESI+)Calcd.for C35H55O2P2[M+H+]:569.3677,Found: 569.3676.
化合物7(RP,RP-3g)、(RP,RP)-(1,4-亚丁基)双(-)-薄荷基苯基氧膦,3g.
纯化合物3g由RP-1a和1,4-二溴丁烷制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate= 1/3as eluent),为白色固体(30mg,60%,>99:1dr,dr值根据1H-NMR谱估算).m.p. 192.4–196.3℃.31P NMR(162MHz,CDCl3)δ=43.10(s);1H NMR(400MHz, CDCl3)δ=7.64–7.57(m,4H),7.47–7.39(m,6H),2.08–1.98(m,4H),1.93– 1.76(m,4H),1.73–1.54(m,10H),1.31(s,2H),1.22–1.11(m,4H),1.03–0.94(m, 3H),0.91(d,J=6.4Hz,6H),0.81(d,J=6.8Hz,6H),0.31(d,J=6.8Hz,6H);13C{1H} NMR(101MHz,CDCl3)δ=134.3(d,J=87.0Hz),130.9(d,J=2.0Hz),130.4(d, J=8.1Hz),128.3(d,J=11.1Hz),43.2(d,J=3.4Hz),40.9(d,J=66.5Hz),35.3(s), 34.2(s),33.2(d,J=12.9Hz),28.2(d,J=2.8Hz),27.5(d,J=65.9Hz),24.6(d,J=11.9 Hz),22.8(s),22.6(s),21.5(s),15.1(s).HRMS(ESI+)Calcd.for C36H57O2P2 [M+H+]:583.3834,Found:583.3837.
化合物8(SP,SP-3h)、(SP,SP)-(1,3-苯基双亚甲基)双(-)-薄荷基苯基氧膦,3h.
纯化合物3a由SP-1a’和1,3-二溴甲基苯制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate= 1/5as eluent),为白色固体(41mg,70%,>99:1dr,dr值根据1H-NMR谱估算). m.p.181.0–184.4℃;31P NMR(162MHz,CDCl3)δ=42.47(s);1H NMR(400 MHz,CDCl3)δ=7.57(dd,J=9.3,7.7,3H),7.44(dd,J=7.1,6.0,2H),7.41–7.38(m, 2H),7.14(s,1H),6.91(t,J=3.2,2H),3.45(t,J=14.4,2H),3.21(dd,J=14.5,10.3,2H), 2.67–2.55(m,2H),2.05–1.94(m,2H),1.84(d,J=9.2,2H),1.66(d,J=9.3,4H), 1.35–1.17(m,4H),1.09–1.02(m,2H),0.98–0.91(m,2H),0.86(d,J=6.4,6H), 0.82(d,J=6.7,6H),0.77(d,J=6.9,6H);13C{1H}NMR(101MHz,CDCl3)δ=132.23(d,J=5.2),131.76(d,J=6.9),131.13(s),131.05(s),130.92(s),128.16(s),128.05(s),127.94(s),43.39(s),41.44(s),40.79(s),36.60(s),36.40(s),36.00(s),34.28(s),33.17(s),33.03(s),28.38(s),24.75(s),24.62(s),22.63(s),21.46(s),15.77(s);HRMS(ESI+)Calcd.for C40H57O2P2[M+H+]:631.3834,Found:631.3849.
化合物9(SP,SP-3i)、(SP,SP)-(1,2-苯基双亚甲基)双(-)-薄荷基苯基氧膦,3i.
纯化合物3i由SP-1a’和1,2-二溴甲基苯制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate= 1/5as eluent),为白色固体(43mg,72%,>99:1dr,dr值根据1H-NMR谱估算).m.p.199.5–201.2℃;31P NMR(162MHz,CDCl3)δ=43.09 (s);1H NMR(400MHz,CDCl3)δ=7.58(t,J=8.4,4H),7.39(dd,J=15.3,6.6,6H), 6.59(s,2H),6.40(s,2H),4.55(t,J=14.7,2H),3.22(dd,J=14.7,7.0,2H),2.60(s, 2H),2.18–2.09(m,2H),1.91(s,2H),1.73(d,J=11.2,4H),1.39(s,4H),1.16–1.06 (m,3H),0.96(d,J=6.4,6H),0.85(dd,J=24.8,6.4,15H);13C{1H}NMR(101MHz,cdcl3)δ=132.61(s),131.89(s),131.25–130.87(m),128.16–127.83(m),125.67 (s),43.60(s),42.49(s),41.84(s),36.57(s),35.67(s),35.08(s),34.44(s),33.50– 33.27(m),28.59(s),24.83(d,J=12.9),22.57(s),21.50(s),15.88(s);HRMS(ESI+) Calcd.forC40H57O2P2[M+H+]:631.3834,Found:631.3849.
化合物10(RP,RP-3j)、(RP,RP)-亚甲基双(-)-薄荷基对联苯基氧膦,3j.
纯化合物3j由RP-薄荷基4-联苯基氧膦RP-1b和二碘甲烷制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=1/5as eluent),为白色固体(34mg, 66%,>99:1dr,dr值根据1H-NMR谱估算).m.p.96.8–99.1℃;31P NMR(162 MHz,CDCl3)δ=41.16(s);1H NMR(400MHz,CDCl3)δ=7.81–7.74(m,4H), 7.72–7.67(m,4H),7.63(d,J=7.2,4H),7.47(t,J=7.4,4H),7.40(d,J=7.3,2H),2.29 –2.19(m,2H),1.96(dd,J=20.1,8.9,2H),1.76(s,5H),1.70(s,3H),1.67(s,3H), 1.33(s,2H),1.15(dd,J=12.0,6.6,2H),1.10–0.96(m,3H),0.91(d,J=6.3,6H),0.87 (d,J=6.8,6H),0.47(d,J=6.7,6H);13C{1H}NMR(101MHz,CDCl3)δ=143.79– 143.76(m),143.74(s),139.97(s),134.82(s),133.95–133.90(m),130.62(s), 130.53(s),128.89(s),128.00(s),127.18(s),127.06(s),126.94(s),43.54–43.50(m), 43.48–43.44(m),41.60(s),40.91(s),35.73(s),34.35(s),33.27(s),33.13(s),28.37 (s),24.67(s),24.55(s),22.57(s),21.56(s),15.23(s),14.55(s);HRMS(ESI+)Calcd. for C45H59O2P2[M+H+]:693.3990,Found:693.4005.
化合物11(SP,SP-3k)、(SP,SP)-亚甲基双(-)-薄荷基苯基氧膦,3k.
纯化合物3k由SP-1b’和二碘甲烷制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=1/5 as eluent),为白色固体(33mg,65%,>99:1dr,dr值根据1H-NMR谱估算).m.p.121.3–123.6℃;31P NMR(162MHz,CDCl3)δ=42.74 (s);1H NMR(400MHz,CDCl3)δ=7.74(dt,J=8.1,6.9,8H),7.68–7.61(m,4H), 7.47(t,J=7.4,4H),7.43–7.37(m,2H),2.57–2.48(m,1H),1.99(t,J=10.6,1H), 1.84(s,3H),1.81(s,2H),1.78(s,2H),1.72(d,J=2.9,7H),1.34(s,4H),1.26(s,1H), 0.84(dt,J=17.5,8.3,20H);13C{1H}NMR(101MHz,CDCl3)δ=143.94(s),139.95 (s),132.86(s),131.97–131.93(m),131.06–131.03(m),131.01(s),130.92(s), 128.91(s),128.03(s),127.20(s),127.10(s),126.98(s),109.99(s),43.48(s),42.32 (s),41.64(s),36.28(s),34.32(s),33.26(s),33.13(s),28.60(s),24.73(s),24.60(s), 22.54(s),21.50(s),16.88(s),16.21(s),15.64(s);HRMS(ESI+)Calcd.for C45H59O2P2[M+H+]:693.3990,Found:693.4001.
化合物12(RP,RP-3l)、(RP,RP)-1,3亚丙基双(-)-薄荷基邻甲苯基氧膦,3l.
纯化合物3l由薄荷基邻甲基苯基RP-1c和1,3-二溴丙烷制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=2/1as eluent),为白色固体(33mg,61%,>99:1dr,dr值根据1H-NMR谱估算).m.p.70.6–78.6℃;31P NMR(162MHz,CDCl3)δ=47.95(s);1H NMR(400MHz,CDCl3)δ=7.60–7.46(m,3H),7.28(s,2H),7.12(dd,J=16.4, 9.4,3H),2.49(s,6H),2.25(d,J=7.4,2H),2.09(dd,J=15.0,7.6,3H),2.01(s,3H), 1.70(s,15H),1.55(s,2H),1.25(s,2H),0.89(d,J=6.2,6H),0.82(d,J=6.7,6H),0.32 (dd,J=12.7,5.6,6H);13C{1H}NMR(101MHz,CDCl3)δ=140.16(s),140.08(s), 132.25(s),132.16(s),131.79(s),131.62(s),131.52(s),130.95(s),130.87(s),125.62(s),125.51(s),43.10(d,J=3.4),40.94(s),40.29(s),35.27(s),34.21(s),33.38(s),33.25(s),29.68(s),28.11(d,J=2.7),27.51(s),27.45–27.37(m),24.59(s),24.47(s),22.56(s),21.51(s),14.94(s),14.59(d,J=3.1),1.00(s);HRMS(ESI+)Calcd.forC37H59O2P2[M+H+]:597.3990,Found:597.4001.
化合物13(RP,RP-3m)、(RP,RP)-亚丙基双(-)-薄荷基对甲氧基苯基氧膦,3m,.
纯化合物3m,由RP-1d和1,3-二溴丙烷制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=1/5as eluent),为白色固体(35mg,66%,>99:1dr,dr值根据1H-NMR谱估算).m.p.180.5–185.4℃;31P NMR(162MHz,CDCl3)δ=44.10(s);1H NMR (400MHz,CDCl3)δ=7.43(t,J=9.3,4H),6.90–6.78(m,4H),3.83(s,6H),2.05(dt, J=22.1,7.4,5H),1.88(s,1H),1.82–1.76(m,3H),1.69(d,J=11.1,4H),1.62(s,1H), 1.41(s,2H),1.25(s,4H),1.19(d,J=6.5,2H),0.96(s,2H),0.90(d,J=6.3,7H),0.82 (d,J=6.8,5H),0.33(d,J=6.7,6H);13C{1H}NMR(101MHz,CDCl3)δ=161.49(s), 132.29(s),132.19(s),125.09–125.00(m),124.17–124.05(m),113.89(s),113.77 (s),55.12(s),43.21(s),43.18(s),41.48(s),40.81(s),35.27(s),34.22(s),33.26(s), 33.13(s),29.66(s),28.46–28.37(m),28.32–28.27(m),28.12(s),27.79–27.71 (m),27.66–27.59(m),24.61(s),24.49(s),22.52(s),21.52(s),15.10(s),14.47–14.38(m);HRMS(ESI+)Calcd.for C37H59O4P2[M+H+]:629.3889,Found: 629.3908.
化合物14(SP,SP-3n)、(SP,SP)-(1,2-苯基双亚甲基)双(-)-薄荷基苯基氧膦,3n.
纯化合物3n由SP-1d’和1,3-二溴丙烷制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate= 1/5as eluent),为白色固体(31mg,52%,>99:1dr,dr值根据1H-NMR谱估算).m.p. 223.0–224.7℃;31P NMR(162MHz,CDCl3)δ=45.44(s);1H NMR(400MHz, CDCl3)δ=7.49(t,J=9.1,4H),6.90(d,J=7.3,3H),3.84(s,6H),2.62–2.50(m,2H), 2.24(dd,J=14.5,7.3,2H),2.05(dd,J=13.9,7.2,2H),1.94(d,J=12.5,2H),1.71(s, 6H),1.64(d,J=13.1,4H),1.25(s,4H),1.14–0.98(m,4H),0.85–0.80(m,12H), 0.76(d,J=6.8,6H);13C{1H}NMR(101MHz,cdcl3)δ=161.77(s),132.79(s), 132.69(s),122.49(s),121.57(s),113.97(s),113.85(s),55.19(s),43.31(s),42.09(s), 41.43(s),36.15(s),34.27(s),33.19(s),33.05(s),29.32–29.27(m),29.23–29.16 (m),28.69–28.63(m),28.56–28.50(m),28.38(s),24.69(s),24.56(s),22.61(s), 21.43(s),15.73(s);HRMS(ESI+)Calcd.for C37H59O4P2[M+H+]:629.3889,Found:629.3904.
化合物15(RP,RP-3o)、(RP,RP)-1,4-亚丁基双(-)-薄荷基苯基氧膦,3o.
纯化合物3o由RP-薄荷基对甲基苯基RP-1e和 1,4-二溴丁烷制备,通过薄层色谱纯化(silica gel, petroleum ether/ethyl acetate=1/5aseluent),为白色固体(35mg,65%,>99:1dr,dr 值根据1H-NMR谱估算).m.p.206.1–208.5℃;31P NMR(162MHz,CDCl3)δ= 42.90(s);1H NMR(400MHz,CDCl3)δ=7.55–7.45(m,4H),7.22(d,J=7.4,4H), 2.38(s,6H),2.11–2.06(m,2H),1.97(d,J=12.0,3H),1.86(s,1H),1.78(s,1H),1.70 (d,J=11.5,4H),1.61(s,4H),1.30(s,2H),1.22–1.14(m,3H),0.99(d,J=10.8,2H), 0.90(d,J=5.7,6H),0.82(d,J=6.4,6H),0.36(d,J=6.7,6H);13C{1H}NMR(101 MHz,CDCl3)δ=141.29(d,J=2.7),131.01(s),130.46(d,J=8.8),130.11(s),129.16 (d,J=11.3),43.26(d,J=3.3),41.25(s),40.58(s),35.33(d,J=2.2),34.54(s),34.41(s), 34.23(s),33.72(s),33.59(s),33.28(s),33.15(s),32.79(s),28.17(d,J=2.7),27.20 (s),26.54(s),24.64(s),24.52(s),22.61(s),22.49(s),21.54(s),20.19(d,J=3.6), 15.19(s),5.64(s);HRMS(ESI+)Calcd.for C37H58O2P2Na[M+Na+]:619.3810,Found:619.3817.
化合物16(SP,SP-3p)、(SP,SP)-(1,2-苯基双亚甲基)双(-)-薄荷基苯基氧膦,3p.
纯化合物3p由薄荷基对甲苯基SP-1e’和1,4- 二溴丁烷制备,通过薄层色谱纯化(silica gel, petroleum ether/ethyl acetate=1/5aseluent),为白色固体(37mg,66%,>99:1dr,dr 值根据1H-NMR谱估算).m.p.80.3–84.6℃;31P NMR(162MHz,CDCl3)δ= 45.15(s);1H NMR(400MHz,CDCl3)δ=7.49(dd,J=9.6,8.4,5H),7.31–7.19(m, 5H),2.63–2.51(m,2H),2.41(d,J=9.8,6H),2.16(s,1H),2.11–1.99(m,2H),1.91 –1.81(m,3H),1.74–1.58(m,9H),1.37(dd,J=31.7,26.9,4H),1.14–0.99(m,5H), 0.88–0.80(m,14H),0.77(q,J=5.5,7H);13C{1H}NMR(101MHz,CDCl3)δ= 141.45(s),130.93(d,J=8.5),130.52(s),129.11(d,J=11.1),128.67(s),127.96(s), 43.30(d,J=2.9),41.69(s),41.16(s),36.22(s),34.30(s),33.16(d,J=13.3),29.68(s), 28.72(s),28.29(d,J=26.2),28.19–27.82(m),24.68(d,J=12.6),23.12–22.58(m), 22.57(s),21.45(d,J=11.7),15.70(s),15.17(s),1.00(s);HRMS(ESI+)Calcd.for C37H58O2P2[M+Na+]:619.3810,Found:619.3790.
化合物18(RP,RP-3q)、(RP,RP)-1-薄荷基苯基氧膦亚甲基-3-薄荷基对联苯基亚甲基) 苯,3q.
纯化合物3q由RP-1b和RP-2a制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=1/5as eluent),为白色固体(105mg, 79%,>99:1dr,dr值根据1H-NMR谱估算).m.p.111.1–114.8℃;31P NMR(162 MHz,CDCl3)δ=40.51(s),39.97(s);1H NMR(400MHz,CDCl3)δ=7.57(dd, J=14.3,10.8,7H),7.45–7.41(m,2H),7.37(d,J=7.1,3H),7.22(d,J=5.5,2H),6.91 (s,1H),6.82–6.75(m,2H),6.59(s,1H),3.42(d,J=18.9,2H),3.00(s,1H),2.88(s, 1H),2.03(s,3H),1.92(s,2H),1.72(s,7H),1.36(s,3H),0.95(d,J=4.1,9H),0.77 (dd,J=13.8,6.7,8H),0.41(d,J=6.6,3H),0.31(d,J=6.6,3H);13C{1H}NMR(101 MHz,CDCl3)δ=143.23(s),139.95(s),132.29(s),131.58(s),131.20(s),131.11(s), 130.67(s),130.43(s),130.35(s),128.85(s),127.90(s),127.76–127.62(m),127.09 (s),126.66(s),126.54(s),59.24–59.15(m),43.42(s),41.30–41.18(m),40.90(s), 40.64–40.55(m),40.36–40.19(m),36.02(s),35.76–35.65(m),35.51(s),35.36 (s),35.19–35.05(m),34.24(s),33.27(s),33.15(s),29.68(s),28.20(s),28.14– 28.10(m),24.67(s),24.32(s),19.81–19.75(m),15.32(s),15.18(s),13.76(s); HRMS(ESI+)Calcd.for C46H60O2P2Na[M+Na+]:729.3966,Found:729.3996.
化合物19(RP,SP-3r)、(RP)-1-薄荷基苯基氧膦亚甲基-(SP)-3-薄荷基苯基亚甲基) 苯,3r.
纯化合物3r由SP-1a’和RP-2a制备,通过薄层色谱纯化(silica gel,petroleum ether/ethyl acetate=1/5 as eluent),为白色固体(96mg,81%,>99:1dr,dr值根据1H-NMR谱估算).m.p. 199.5–201.2℃;31P NMR(162MHz,CDCl3)δ=42.42(s),40.25(s);1H NMR (400MHz,CDCl3)δ=7.61–7.54(m,2H),7.50–7.42(m,3H),7.41–7.34(m,3H), 7.31(t,J=6.0,2H),6.89–6.79(m,3H),6.70(d,J=7.0,1H),3.26(ddt,J=24.2,14.6, 12.3,3H),2.94(dd,J=14.4,7.2,1H),2.60–2.50(m,1H),2.09–1.95(m,5H),1.92 (d,J=10.2,1H),1.81(d,J=9.5,1H),1.70(dd,J=27.4,12.7,5H),1.40–1.28(m,3H), 1.20(s,1H),1.06–0.91(m,7H),0.85(dd,J=19.2,6.6,6H),0.76(dd,J=9.2,7.0,6H), 0.30(d,J=6.7,3H);13C{1H}NMR(101MHz,CDCl3)δ=137.01(s),134.17(s),133.28(s),132.51(s),132.43(s),130.87(d,J=2.8),130.35(d,J=8.2),130.06(d, J=4.8),128.28(s),128.09(s),127.98(s),126.45(d,J=2.5),46.03(s),43.33(d, J=3.6),40.71(s),40.05(s),36.58(s),35.98(s),35.24(s),34.18(s),33.35(s),33.21(s),28.10(s),24.64(s),24.52(s),22.64(s),21.45(s),15.45(s),15.13(s);HRMS (ESI+)Calcd.for C40H57O2P2[M+H+]:631.3834,Found:631.3848.
实施例2(RP)-1-薄荷基苯基氧膦甲基-3-氯甲基苯的制备RP-2a
反应在空气条件下进行.RP-1a(300mg,1.136mmol) 和四正丁基溴化铵(36mg,0.1136mmol,10%mol)在二氯甲烷(1.2mL)的溶液中,加入1,3-二氯甲基苯(0.33ml,2.27mmol)。氢氧化钾水溶液(50%,3mL)加入后,反应混合物在室温下搅拌7小时,同时用薄层层析监控反应(2a,Rf=0.7;3a,Rf=0.3,petroleum ether/ethyl acetate=1/1).反应完成后, 混合物用二氯甲烷萃取三次,每次10毫升,合并的萃取液水洗三次,每次5毫升,使用无水硫酸镁干燥,减压移除溶剂后,残留物用薄层层析提纯(silica gel,petroleum ether/ethyl acetate=1/1)得到纯的白色固体2a(300毫克,66%).m.p.154.1–163.8℃;31P NMR(162MHz,CDCl3)δ=39.88(s);1H NMR(400MHz, CDCl3)δ=7.50(dd,J=9.4,8.0,2H),7.41–7.30(m,3H),7.13–7.05(m,2H),6.98 –6.89(m,2H),4.39(q,J=11.5,2H),3.51(dd,J=16.9,14.4,1H),3.01(dd,J=14.2, 7.5,1H),2.12(d,J=4.1,1H),2.00(dd,J=11.9,6.3,2H),1.78(d,J=28.6,4H),1.46 (dd,J=20.6,8.5,2H),0.98(d,J=5.7,4H),0.77(d,J=6.8,3H),0.30(d,J=6.7,3H);13C{1H}NMR(101MHz,CDCl3)δ=137.01(s),134.17(s),133.28(s),132.51(s), 132.43(s),130.87(d,J=2.8),130.35(d,J=8.2),130.06(d,J=4.8),128.28(s),128.09 (s),127.98(s),26.45(d,J=2.5),46.03(s),43.33(d,J=3.6),40.71(s),40.05(s),36.58 (s),35.98(s),35.24(s),34.18(s),33.34(s),33.21(s),28.10(s),24.58(d,J=11.9), 22.64(s),21.45(s),15.45(s),15.13(s);HRMS(ESI+)Calcd.for C24H33ClOP [M+H+]:403.1958,Found:403.1955.
实施例3
手性双膦配体的合成:(RP,RP)-1,3-双(薄荷基苯基膦甲基)取代苯双硼烷络合物,所述化合物公开于文献Nonepimerizing Alkylation of H-P Species toStereospecifically Generate P-Stereogenic Phosphine Oxides:A Shortcut toBidentate Tertiary Phosphine Ligands中。
氮气保护下,化合物RP,RP-3b(124毫克,0.2毫摩尔)溶于甲苯(2毫升),室温下滴加草酰氯(0.025毫升,0.3毫摩尔)。反应混合物在室温下搅拌30分钟后,冷却至-65℃,加入硼氢化钠-氯化锌在四氢呋喃中的溶液(0.2毫升,含有0.4 毫摩尔的硼氢化钠),缓慢升至室温,继续搅拌12小时,加入稀盐酸(0.2N,5 毫升),水层用乙醚萃取三次,每次20毫升,合并的有机相用无水硫酸镁干燥,减压移除溶剂后,残留物薄层层析纯化,得到(RP,RP)-1,3-双(薄荷基苯基膦甲基) 取代苯双硼烷络合物,为白色固体,重90毫克,产率72%,dr值为97:3,熔点66.1 –68.2℃;31P NMR(162MHz,CDCl3)δ=25.52(broad s);1H NMR(400MHz, CDCl3)δ7.47(t,J=8.4Hz,4H),7.43–7.36(m,2H),7.35–7.28(m,4H),6.65(t,J =8.0Hz,2H),6.47(dd,J=7.6,1.6Hz,2H),3.34(dd,J=13.6,7.2Hz,2H),3.18(t,J =14.0Hz,2H),2.41–2.29(m,2H),2.24–2.10(m,2H),1.82–1.55(m,7H), 1.42–1.22(m,5H),1.18–1.02(m.3H),0.96(d,J=6.8Hz,7H),0.92–0.81(m, 11H),0.73(d,J=6.4Hz,7H).13C NMR(101MHz,CDCl3)δ133.1(d,J=7.6Hz), 132.5(dd,J=5.1,2.4Hz),131.9(t,J=7.6Hz),130.7(s),128.3(s),128.2(s),128.0 (s),127.5(s),127.2(s),44.5(s),37.0(s),36.9(s),36.7(s),34.7(s),34.4(s),34.3(s), 33.4(d,J=10.5Hz),28.7(d,J=2.7Hz),25.1(d,J=11.2Hz),22.4(s),21.4(s), 15.8(s).HRMS(ESI+)Calcd.for C40H57P2[M-BH3+H+]:599.3935,Found: 599.3940.
以上所述仅为本公开的优选实施例而已,并不用于限制本公开,对于本领域的技术人员来说,本公开可以有各种更改和变化。凡在本公开的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本公开的保护范围之内。
Claims (9)
5.如权利要求4所述化合物的制备方法,其特征在于,所述制备方法步骤如下:
将起始化合物加入碱性、及水-甲苯体系中,通过引入双官能团试剂对起始化合物进行烃基化反应。
6.如权利要求5所述所述化合物的制备方法,其特征在于,所述起始化合物结构如下式1所示:
其中,R1=Ph、pPhC6H4、oMeC6H4、pMeOC6H4、pMeC6H4。
在一些具体的实施例中,所述起始化合物的编号及取代基对应关系如下:
起始化合物RP-1a中,R1=Ph(RP);
起始化合物SP-1a'中,R1=Ph(SP);
起始化合物RP-1b中,R1=pPhC6H4(RP);
起始化合物SP-1b'中,R1=pPhC6H4(SP);
起始化合物RP-1c中,R1=oMeC6H4(RP);
起始化合物RP-1d中,R1=pMeOC6H4(RP);
起始化合物SP-1d'中,R1=pMeOC6H4(SP);
起始化合物RP-1e中,R1=pMeC6H4(RP);
起始化合物SP-1e'中,R1=pMeC6H4(SP)。
7.如权利要求5所述所述化合物的制备方法,其特征在于所述双官能团试剂包括:四正丁基溴化铵、二溴甲基苯、二氯甲基吡啶、二碘甲烷、二溴丙烷及二溴丁烷;
更为优选的,所述双官能团试剂包括:四正丁基溴化铵、1,2-二溴甲基苯、1,4-二溴甲基苯、2,6-二氯甲基吡啶、二碘甲烷、1,3-二溴丙烷、1,4-二溴丁烷及1,3-二溴甲基苯。
8.式2所示化合物的制备方法,其特征在于,所述制备方法包括以下步骤:将化合物RP-1a与四正丁基溴化铵加入二氯甲烷溶液中,加入1,3-二氯甲基苯及碱溶液后在室温下混合反应。
9.所述式2或式3化合物作为催化剂或中间体的应用。
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