CN114478627A - 一种烯丙基化单膦配体及其制备方法 - Google Patents
一种烯丙基化单膦配体及其制备方法 Download PDFInfo
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- CN114478627A CN114478627A CN202210166475.2A CN202210166475A CN114478627A CN 114478627 A CN114478627 A CN 114478627A CN 202210166475 A CN202210166475 A CN 202210166475A CN 114478627 A CN114478627 A CN 114478627A
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- Prior art keywords
- boc
- acid
- phosphine
- tris
- sodium
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000005937 allylation reaction Methods 0.000 title abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000654 additive Substances 0.000 claims abstract description 7
- 230000000996 additive effect Effects 0.000 claims abstract description 7
- 229940125904 compound 1 Drugs 0.000 claims abstract description 7
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 229940125782 compound 2 Drugs 0.000 claims abstract description 5
- 239000012298 atmosphere Substances 0.000 claims abstract description 3
- -1 methyl isopropylphenyl Chemical group 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
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- UYUUAUOYLFIRJG-UHFFFAOYSA-N tris(4-methoxyphenyl)phosphane Chemical compound C1=CC(OC)=CC=C1P(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 UYUUAUOYLFIRJG-UHFFFAOYSA-N 0.000 claims description 7
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 7
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- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- QJCNLJWUIOIMMF-YUMQZZPRSA-N (2s,3s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C QJCNLJWUIOIMMF-YUMQZZPRSA-N 0.000 claims description 5
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- SZXBQTSZISFIAO-SSDOTTSWSA-N (2r)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-SSDOTTSWSA-N 0.000 claims description 4
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 claims description 4
- OJVAMHKKJGICOG-UHFFFAOYSA-N 2,5-hexanedione Chemical compound CC(=O)CCC(C)=O OJVAMHKKJGICOG-UHFFFAOYSA-N 0.000 claims description 4
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 claims description 4
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- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- QVHJQCGUWFKTSE-RXMQYKEDSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-RXMQYKEDSA-N 0.000 claims description 3
- ROVVUKFHORPDSM-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclobutane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC1(C(O)=O)CCC1 ROVVUKFHORPDSM-UHFFFAOYSA-N 0.000 claims description 3
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 claims description 2
- LRFZIPCTFBPFLX-SSDOTTSWSA-N (2s)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)C(C)(C)C LRFZIPCTFBPFLX-SSDOTTSWSA-N 0.000 claims description 2
- UAGWMIDWWYHFNL-UHFFFAOYSA-N 1,1'-biphenyl;dicyclohexylphosphane Chemical group C1=CC=CC=C1C1=CC=CC=C1.C1CCCCC1PC1CCCCC1 UAGWMIDWWYHFNL-UHFFFAOYSA-N 0.000 claims description 2
- FSVXWHPAMOPZCT-UHFFFAOYSA-N 1,1'-biphenyl;ditert-butylphosphane Chemical group CC(C)(C)PC(C)(C)C.C1=CC=CC=C1C1=CC=CC=C1 FSVXWHPAMOPZCT-UHFFFAOYSA-N 0.000 claims description 2
- XFOAHNMATJZSDJ-UHFFFAOYSA-N 1-amino-2-[(2-methylpropan-2-yl)oxycarbonyl]cyclohexane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)C1CCCCC1(N)C(O)=O XFOAHNMATJZSDJ-UHFFFAOYSA-N 0.000 claims description 2
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- CVBUKMMMRLOKQR-UHFFFAOYSA-N 1-phenylbutane-1,3-dione Chemical compound CC(=O)CC(=O)C1=CC=CC=C1 CVBUKMMMRLOKQR-UHFFFAOYSA-N 0.000 claims description 2
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 claims description 2
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- FFFIRKXTFQCCKJ-UHFFFAOYSA-N 2,4,6-trimethylbenzoic acid Chemical compound CC1=CC(C)=C(C(O)=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-N 0.000 claims description 2
- AOTQGWFNFTVXNQ-UHFFFAOYSA-N 2-(1-adamantyl)acetic acid Chemical compound C1C(C2)CC3CC2CC1(CC(=O)O)C3 AOTQGWFNFTVXNQ-UHFFFAOYSA-N 0.000 claims description 2
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- MFNXWZGIFWJHMI-UHFFFAOYSA-N 2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C)(C)C(O)=O MFNXWZGIFWJHMI-UHFFFAOYSA-N 0.000 claims description 2
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 claims description 2
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- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
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- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
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- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 claims description 2
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- 229940000635 beta-alanine Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 2
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- 229940126214 compound 3 Drugs 0.000 claims description 2
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 claims description 2
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
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- PZBBESSUKAHBHD-UHFFFAOYSA-N methyl 2-oxocyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1=O PZBBESSUKAHBHD-UHFFFAOYSA-N 0.000 claims description 2
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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
- C07F9/505—Preparation; Separation; Purification; Stabilisation
- C07F9/5054—Preparation; Separation; Purification; Stabilisation by a process in which the phosphorus atom is not involved
-
- 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
- C07F9/547—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
- C07F9/572—Five-membered rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种烯丙基化单膦配体及其制备方法,属于有机化学技术领域。以化合物1和化合物2为原料,在钌催化剂、配体、碱、添加剂以及有机溶剂存在下,在惰性氛围中60‑140℃反应,处理后制得新型烯丙基化单膦配体。本发明制备方法合成步骤简单,仅采用一步即可完成,具有原材料易得,工艺操作简单方便,高效快速,降低了生产成本及对设备的要求等优点,且产物收率高,易于实现工业化大规模生产。
Description
技术领域
本发明属于有机化学技术领域,具体涉及一种新型烯丙基化单膦配体及其制备方法。
背景技术
膦配体是过渡金属催化的交叉偶联反应中使用最广泛的一类配体,其对于提高催化剂活性、反应产率、区域选择性和对映选择性有着极为关键的促进作用。其中联苯类单膦配体因具有强大的供电性和大的空间效应,使其官能团化备受关注。目前,联苯类单膦配体已经实现了一系列官能化,包括烷基化、烯基化、芳基化、硼化等。
文献(Angew.Chem.Int.Ed.2019,58,14110)报道采用昂贵Rh作为金属催化剂,烯烃作为偶联试剂,通过C-H活化实现联芳基膦邻位烷基化反应。文献(Nat Commun.2019,10,3539)报道反应中同样引入铑催化体系,通过P(III)-螯合辅助C-H活化,使烯烃和炔烃与叔膦发生氢芳基化反应。现有技术中新型单膦配体的修饰仍然具有局限性,限制了联苯类单膦配体的发展,需要开发新型官能团化单膦配体来丰富膦配体库。
近些年来,“烯丙基”结构单元已经成为许多有价值的药物分子和生物活性天然产物中重要的结构骨架。由于烯丙基特殊的化学结构性质,将烯丙基部分并入复杂的有机骨架中可增强整体合成效用,为进一步转化提供有用的价值。
发明内容
有鉴于此,本申请提供了一种烯丙基化单膦配体及其制备方法,拓展了现有技术中单膦配体官能团化的单一类型,其制备过程简单、生产成本低、操作工艺简便、并且衍生出一类新型烯丙基化单膦配体。
为了实现本发明的上述第一个目的,本发明提供了一种新型烯丙基化单膦配体,所述烯丙基化单膦配体,具有如下结构:
其中:R1选自氢、烷基、烷氧基、三氟甲基、卤素或杂芳基;R2选自氢、烷基、烷氧基、烷巯基、三氟甲基、卤素、芳基、芳氧基或酯基;R3选自烷基、苄基;R4选自氢、烷基、烷氧基、三氟甲基或卤素。
本发明的第二个目的在于提供上述新型烯丙基化单膦配体的制备方法,所述方法合成路线如下:
包括如下步骤:
以化合物1和化合物2为原料,在钌催化剂、配体、碱、添加剂以及有机溶剂存在下,在惰性氛围中60-140℃反应,处理后得到烯丙基化单膦化合物3。
进一步地,在上述技术方案中,所述钌催化剂选自甲基异丙基苯基、三苯基膦、二甲基亚砜、乙腈、环辛二烯、五甲基环戊二烯、十二羰基或乙基环戊二烯,与钌金属盐组成的催化剂。
进一步地,在上述技术方案中,所述配体选自N-Boc-2-氨基异丁酸、N-Boc-L-苯丙氨酸、N-Ac-苯丙氨酸、N-Ac-β-丙氨酸、N-Boc-D-丙氨酸、N-Boc-甘氨酸、N-Ac-甘氨酸、Boc-D-缬氨酸、N-Boc-L-亮氨酸、N-Boc-L-异亮氨酸、N-Boc-L-叔亮氨酸、N-Ac-异亮氨酸、Boc-1-氨基环己基甲酸、(2s,3s)-2-(Boc-氨基)-3-甲基戊酸、N-Boc-1-氨基环丁烷羧酸、N-Ac-D-缬氨酸、2-氨基异丁酸、丙氨酸、甘氨酸、苯丙氨酸、缬氨酸、亮氨酸、异亮氨酸、叔亮氨酸、磷酸二苯酯、磷酸二苄酯、异戊酸、2-甲基丁酸、三甲基乙酸、三苯基乙酸、环己基乙酸、1-金刚烷乙酸、1-金刚烷甲酸、2,2-二苯基丙酸、2,4,6-三甲基苯甲酸、1,1-环丁烷二羧酸、1-苯基-1,3-丁二酮、2,5-己二酮、2,2,6,6-四甲基-3.5-庚二酮、二甲基乙酰乙酸甲酯或2-氧代环戊烷羧酸甲酯。
进一步地,在上述技术方案中,所述碱选自醋酸锂、醋酸钠、醋酸钾、醋酸铯、三氟乙酸锂、叔丁醇钠、叔丁醇钾、碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、磷酸钠、磷酸钾、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾、磷酸氢二钾、甲酸钠、乙醇钠、1-金刚烷甲酸钠或对甲苯磺酸钠。
进一步地,在上述技术方案中,所述添加剂包括三苯基膦、三(4-三氟甲基苯基)膦、三(3-三氟甲基苯基)膦、三(4-氟苯基)膦、三(3-氟苯基)膦、三(2-氟苯基)膦、三(五氟苯基)膦、三(4-甲基苯基)膦、三(3-甲基苯基)膦、三(4-甲氧基苯基)膦、三(3-甲氧基苯基)膦、三(2,4-二甲基苯基)膦、三环己基膦、二环己基膦联苯、二叔丁基膦联苯或2,2'-双-(二苯膦基)-1,1'-联萘。
进一步地,在上述技术方案中,所述有机溶剂为芳烃类溶剂、醇类溶剂、烷烃类溶剂、卤代烃类溶剂、醚类溶剂、腈类溶剂、酮类溶剂中的任意一种或多种混合。所述的有机溶剂的用量可不作具体限定,只要不影响反应进行即可。优选情况下,所述芳烃类溶剂选自苯、甲苯、二甲苯、三甲苯、卤代苯、三氟甲苯等苯类溶剂中的任意一种;所述醇类溶剂选自甲醇、乙醇、丙醇、丁醇、戊醇、乙二醇、丙二醇等醇类溶剂中的任意一种;所述烷烃类溶剂包括戊烷、己烷、庚烷、辛烷、环己烷、环庚烷、环辛烷等烷烃类溶剂中的任意一种;所述卤代烃类溶剂选自二氯甲烷、二氯乙烷、氯仿等卤代烃类溶剂中的任意一种;所述醚类溶剂包括乙醚、四氢呋喃、甲基四氢呋喃、甲基叔丁基醚、苯甲醚、乙二醇二甲醚和二氧六环等醚类溶剂中的任意一种,所述腈类溶剂包括乙腈、三甲基乙腈、异戊腈、苯甲腈等腈类溶剂中的任意一种,所述酮类溶剂包括丙酮,丁酮、戊酮等酮类溶剂中的任意一种。
进一步地,在上述技术方案中,所述化合物2、化合物1与钌催化剂摩尔比为1-10:1:0.001-1;所述添加剂、配体、碱与化合物1摩尔比为0.005-1:0.005-1:1-15:1。
与现有技术相比,本发明涉及的一种新型烯丙基化单膦配体及其简单制备方法具有如下有益效果:
(1)本发明合成步骤简单,仅采用一步即可完成,合成过程中不需要引入其他官能团或复杂的反应流程来构建C-C键,且本发明合成工艺高效,操作过程简单;
(2)本发明反应过程中所需要的原材料廉价易得,目标产物收率高,且合成过程中对工艺设备要求简单,降低了生产成本;
(3)本发明反应过程中产生的三废少,对环境污染影响小,不会对工作人员自身造成伤害,适合大规模工业化生产。
具体实施方式
下面结合具体实施案例对本发明作进一步详细说明。本实施案例在本发明技术方案的前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施案例。
为了更好地理解本发明而不是限制本发明的范围,在本申请中所用的表示用量、百分比的所有数字、以及其他数值,在所有情况下都应理解为以词语“大约”所修饰。因此,除非特别说明,否则在说明书和所附权利要求书中所列出的数字参数都是近似值,其可能会根据试图获得的理想性质的不同而加以改变。各个数字参数至少应被看作是根据所报告的有效数字和通过常规的四舍五入方法而获得的。
实施例1
本实施例新型烯丙基化单膦配体{(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯},合成路线如下:
在反应釜中加入33.8mg(0.1mmol)2-二苯基膦-联苯1a,49.6mg 2-(乙酰氧基苯基甲基)丙烯酸乙酯2a(0.2mmol),3.1mg对伞花烃二氯化钌二聚体,7.3mg 1-叔丁氧羰酰胺环己羧酸,1.8mg三(4-甲氧基苯基)膦,32.8mg磷酸钠及1.5mL正己烷,搅拌混合均匀后向反应体系中通氩气,控制反应在氩气氛围中、温度在120℃条件下反应12h后冷却至室温,硅藻土抽滤、减压蒸馏后柱层色谱分离得39.5mg产物3a,收率75%。1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.43-7.36(m,3H),7.35-7.26(m,7H),7.26-7.16(m,8H),7.10-6.97(m,4H),6.72(d,J=8.0Hz,1H),4.25-4.18(m,2H),3.80(q,J=32.0Hz,2H),1.25(t,J=16.0Hz,3H).
化学位移δ7.96,单峰,归属为苯环苄位上的一个氢;化学位移δ7.43-7.36,多重峰,归属为苯环上的三个氢;化学位移δ7.35-7.26,多重峰,归属为苯环上的七个氢;化学位移δ7.26-7.16,多重峰,归属为苯环上的八个氢;化学位移δ7.10-6.97,多重峰,归属为苯环上的四个氢;化学位移δ6.72,双重峰,归属为苯环上的一个氢;化学位移δ4.25-4.18,多重峰,归属为与双键相连亚甲基的二个氢;化学位移δ3.80,四重峰,归属为乙基上亚甲基的二个氢;化学位移δ1.25,三重峰,归属为甲基的三个氢;
13C NMR(101MHz,CDCl3)δ168.29,147.29(d,J=32.3Hz),141.30,141.22,137.91(d,J=13.1Hz),137.21(d,J=12.1Hz),136.85(d,J=13.1Hz),136.59,135.21,134.05(d,J=20.2Hz),133.83,133.62(d,J=19.2Hz),130.61,130.50(d,J=3.0Hz),129.69(d,J=6.1Hz),129.58(d,J=1.0Hz),128.72(d,J=39.4Hz),128.66,128.30,128.26(d,J=3.0Hz),128.20,127.69(d,J=26.3Hz),126.33,125.23,60.85,32.48(d,J=5.1Hz),29.74,14.17.
31P NMR(162MHz,CDCl3)δ-14.01.
HRMS(ESI+)exact mass calculated for[M+H]+(C36H32O2P):527.2140,found:527.2141.
高分辨质谱得出化合物加氢的真实相对分子质量为527.2140,实测值为527.2141。
综合上述核磁、质谱测试结果,可以确定,本实施例产品为{(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯}。
实施例2
本实施例新型烷基化单膦配体{3-(2'-(二苯基膦基)-[1,1'-联苯]-2-基)丙酸叔丁基酯},合成路线如下:
在反应釜中加入37.2mg(0.1mmol)4-氯-2-二苯基膦-联苯1b,49.6mg 2-(乙酰氧基苯基甲基)丙烯酸乙酯2a(0.2mmol),3.1mg对伞花烃二氯化钌二聚体,7.3mg1-叔丁氧羰酰胺环己羧酸,1.8mg三(4-甲氧基苯基)膦,32.8mg磷酸钠及1.5mL正己烷,搅拌混合均匀后向反应体系中通氩气,控制反应在氩气氛围中、温度在120℃条件下反应12h后冷却至室温,硅藻土抽滤、减压蒸馏后柱层色谱分离得50.4mg产物3b,收率90%。1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.40-7.27(m,9H),7.26-7.13(m,8H),7.09-6.97(m,3H),6.93(dd,J=8.0,4.0Hz,1H),6.59(d,J=12.0Hz,1H),4.27-4.14(m,2H),3.75(q,J=44.0Hz,2H),1.26(t,J=12.0Hz,3H).13C NMR(101MHz,CDCl3)δ167.94,145.96(d,J=33.3Hz),141.88,139.70(d,J=7.1Hz),138.98,137.42(d,J=12.1Hz),136.95(d,J=12.1Hz),136.80(d,J=12.1Hz),134.94,134.08(d,J=20.2Hz),133.73(d,J=12.1Hz),133.63(d,J=19.2Hz),131.69(d,J=3.0Hz),129.68(d,J=6.1Hz),129.68,129.53(d,J=1.0Hz),128.95(d,J=17.2Hz),128.56(d,J=37.3Hz),128.53(d,J=37.4Hz),128.30,127.88,126.54,125.44,60.99,32.44(d,J=5.1Hz),29.74,14.29.31P NMR(162MHz,CDCl3)δ-13.97.HRMS(ESI+)exactmass calculated for[M+H]+(C36H31Cl O2P):561.1750,found:526.1749.
实施例3
本实施例新型烷基化单膦配体(E)-2-((2'-(二苯基膦基)-4'-甲基-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,合成路线如下:
在反应釜中加入35.2mg(0.1mmol)(4-甲基-[1,1'-联苯]-2-基)二苯基膦1c,49.6mg 2-(乙酰氧基苯基甲基)丙烯酸乙酯2a(0.2mmol),3.1mg对伞花烃二氯化钌二聚体,7.3mg 1-叔丁氧羰酰胺环己羧酸,1.8mg三(4-甲氧基苯基)膦,32.8mg磷酸钠及1.5mL正己烷,搅拌混合均匀后向反应体系中通氩气,控制反应在氩气氛围中、温度在120℃条件下反应12h后冷却至室温,硅藻土抽滤、减压蒸馏后柱层色谱分离得14.1mg产物3c,收率26%。1HNMR(400MHz,CDCl3)δ7.94(s,1H),7.40-7.36(m,2H),7.33-7.16(m,15H),7.12-7.04(m,2H),7.02-6.94(m,1H),6.83(d,J=4.0Hz,1H),6.71(d,J=8.0Hz,1H),4.20(q,J=16.0Hz,2H),3.88-3.63(m,2H),2.24(s,3H),1.23(t,J=12.0Hz,3H).13C NMR(101MHz,CDCl3)δ168.33,144.48(d,J=32.3Hz),141.29(d,J=7.1Hz),141.12,137.99(d,J=13.1Hz),137.40(d,J=12.1Hz),136.91(d,J=25.3Hz),136.41(d,J=12.1Hz),135.23,134.20,134.00(d,J=20.2Hz),133.60(d,J=19.2Hz),130.71,130.66,129.83,129.60,129.54,128.62,128.28(d,J=32.3Hz),128.24(d,J=1.0Hz),128.17(d,J=3.0Hz),127.68,126.33,125.20,60.83,32.49(d,J=5.1Hz),21.30,14.28.31P NMR(162MHz,CDCl3)δ-13.90.HRMS(ESI)m/z:[M+H]+calcd for C37H34O2P 541.2296;found 541.2296.
实施例4
本实施例新型烷基化单膦配体(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-(4-甲氧基苯基)丙烯酸乙酯,合成路线如下:
在反应釜中加入35.2mg(0.1mmol)2-二苯基膦-联苯1a,55.6mg 2-(乙酰氧基(4-甲氧基苯基)甲基)丙烯酸乙酯2b(0.2mmol),3.1mg对伞花烃二氯化钌二聚体,7.3mg 1-叔丁氧羰酰胺环己羧酸,1.8mg三(4-甲氧基苯基)膦,32.8mg磷酸钠及1.5mL正己烷,搅拌混合均匀后向反应体系中通氩气,控制反应在氩气氛围中、温度在120℃条件下反应12h后冷却至室温,硅藻土抽滤、减压蒸馏后柱层色谱分离得44.5mg产物3d,收率80%。1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.44-7.16(m,15H),7.12-7.03(m,3H),6.97(t,J=16.0Hz,1H),6.81(d,J=8.0Hz,2H),6.69(d,J=4.0Hz,1H),4.19(q,J=16.0Hz,2H),3.84-3.74(m,2H),3.66(s,3H),1.24(t,J=16.0Hz,3H).13C NMR(101MHz,CDCl3)δ168.59,160.02,147.36(d,J=32.3Hz),141.31(d,J=7.1Hz),141.12,138.00(d,J=13.1Hz),137.10(d,J=12.1Hz),136.77(d,J=12.1Hz),136.51,134.13(d,J=20.2Hz),133.87,133.50(d,J=19.2Hz),131.48(d,J=2.0Hz),130.50(d,J=3.0Hz),129.69(d,J=6.1Hz),128.80(d,J=37.4Hz),128.27(d,J=7.1Hz),128.11(d,J=6.1Hz),127.81(d,J=9.1Hz),127.58,126.23,125.20,114.15,60.77,55.18,32.62(d,J=4.0Hz),29.74,14.33.31P NMR(162MHz,CDCl3)δ-13.97.HRMS(ESI)m/z:[M+H]+calcd for C37H34O3P 557.2246;found 557.2245.
实施例5
本实施例新型烷基化单膦配体(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸苄酯,合成路线如下:
在反应釜中加入35.2mg(0.1mmol)2-二苯基膦-联苯1a,62.0mg 2-(乙酰氧基(苯基)甲基)丙烯酸苄酯2c(0.2mmol),3.1mg对伞花烃二氯化钌二聚体,7.3mg 1-叔丁氧羰酰胺环己羧酸,1.8mg三(4-甲氧基苯基)膦,32.8mg磷酸钠及1.5mL正己烷,搅拌混合均匀后向反应体系中通氩气,控制反应在氩气氛围中、温度在120℃条件下反应12h后冷却至室温,硅藻土抽滤、减压蒸馏后柱层色谱分离得47.0mg产物3e,收率为47%。1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.37-7.27(m,2H),7.28-7.02(m,20H),7.02-6.86(m,5H),6.62(d,J=4.0Hz,1H),5.09(dd,J=20.0,8.0Hz,2H),3.87-3.51(m,2H).13C NMR(101MHz,CDCl3)δ168.10,147.19(d,J=32.3Hz),141.98,141.29(d,J=7.1Hz),137.78(d,J=13.1Hz),137.17(d,J=12.1Hz),136.82(d,J=12.1Hz),136.54,136.20,135.09,134.02(d,J=21.2Hz),133.64(d,J=19.2Hz),130.53(d,J=2.0Hz),130.25,129.59(d,J=1.0Hz),128.86(d,J=11.1Hz),128.57(d,J=24.2Hz),128.42(d,J=21.2Hz),128.20(d,J=4.0Hz),128.08(d,J=35.4Hz),127.97,127.54,126.28,125.31,66.58,32.48(d,J=5.1Hz),29.75.31P NMR(162MHz,CDCl3)δ-13.98.HRMS(ESI)m/z:[M+H]+calcd for C41H34O2P 589.2296;found589.2296.
实施例6
通过改变反应原料1与化合物2a反应,得到系列烯丙基化修饰的单膦配体衍生物:
以(4'-甲基-[1,1'-联苯]-2-基)二苯基膦为原料,参照实施例2方法,产物(E)-2-((2'-(二苯基膦基)-4-甲基-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,收率85%。
以(4'-(甲硫基)-[1,1'-联苯]-2-基)二苯基膦为原料,参照实施例2方法,得到产物(E)-2-((2'-(二苯基膦基)-4-(甲硫基)-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,收率60%。
以2'-(二苯基膦基)-[1,1'-联苯]-4-羧酸甲酯为原料,参照实施例2方法,得到(E)-2'-(二苯基膦基)-2-(2-(乙氧基羰基)-3-苯基烯丙基)-[1,1'-联苯]-4-羧酸甲酯,收率94%。
以(4'-苯氧基-[1,1'-联苯]-2-基)二苯基膦为原料,参照实施例2方法,得到(E)-2-((2'-(二苯基膦基)-4-苯氧基-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,收率72%。
以(2'-甲基-[1,1'-联苯]-2-基)二苯基膦为原料,参照实施例2方法,得到(E)-2-((2'-(二苯基膦基)-6-甲基-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,收率28%。
以[1,1':3',1”-三联苯]-2-基二苯基膦为原料,参照实施例2方法,得到(E)-2-((2”-(二苯基膦基)-[1,1':3',1”-三联苯]-4'-基)甲基)-3-苯基丙烯酸乙酯,收率50%。
以二苯基(3'-(三氟甲基)-[1,1'-联苯]-2-基)膦为原料,参照实施例2方法,得到(E)-2-((2'-(二苯基膦基)-5-(三氟甲基)-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,收率82%。
以(3',4'-二氟-[1,1'-联苯]-2-基)二苯基膦为原料,参照实施例2方法,得到(E)-2-((2'-(二苯基膦基)-4,5-二氟-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,收率56%。
以(5-甲氧基-[1,1'-联苯]-2-基)二苯基膦为原料,参照实施例1方法,得到(E)-2-((2'-(二苯基膦基)-5'-甲氧基-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯目标产物,目标产物收率为56%。
以二苯基(5-(三氟甲基)-[1,1'-联苯]-2-基)膦为原料,参照实施例3方法,得到(E)-2-((2'-(二苯基膦基)-5'-(三氟甲基)-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,收率67%。
以(4-氟-[1,1'-联苯]-2-基)二苯基膦为原料,参照实施例3方法,得到(E)-2-((2'-(二苯基膦基)-4'-氟-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸乙酯,收率45%。
以2-(二苯基膦基)-1-苯基-1H-吡咯为原料,参照实施例3方法,得到(E)-2-(2-(2-(二苯基膦基)-1H-吡咯-1-基)苄基)-3-苯基丙烯酸乙酯,收率77%。
实施例7
通过改变反应原料2与化合物1a反应,得到系列烯丙基化修饰的单膦配体衍生物:
以2-(乙酰氧基(4-三氟甲基苯基)甲基)丙烯酸乙酯为原料,参照实施例4方法,得到(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-(4-(三氟甲基)苯基)丙烯酸乙酯,收率45%。
以2-(乙酰氧基(4-溴苯基)甲基)丙烯酸乙酯为原料,参照实施例4方法,得到(E)-3-(4-溴苯基)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)丙烯酸乙酯,收率64%。
以2-(乙酰氧基(4-氟苯基)甲基)丙烯酸乙酯为原料,参照实施例4方法,得到(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-(4-氟苯基)丙烯酸乙酯,收率67%。
以2-(乙酰氧基(对甲苯基)甲基)丙烯酸乙酯为原料,参照实施例4方法,得到(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-(对甲苯基)丙烯酸乙酯,收率50%。
以2-(乙酰氧基(4-叔丁基苯基)甲基)丙烯酸乙酯为原料,参照实施例4方法,得到(E)-3-(4-(叔丁基)苯基)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)丙烯酸乙酯,收率74%。
以2-(乙酰氧基(2-溴苯基)甲基)丙烯酸乙酯为原料,参照实施例4方法,得到(E)-3-(2-溴苯基)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)丙烯酸乙酯,收率31%。
以2-(乙酰氧基(2-甲氧基苯基)甲基)丙烯酸乙酯为原料,参照实施例4方法,得到(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-(2-甲氧基苯基)丙烯酸乙酯,收率52%。
以2-(乙酰氧基(3-氟-4-甲氧基苯基)甲基)丙烯酸乙酯为原料,参照实施例4方法,得到(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-(3-氟-4-甲氧基苯基)丙烯酸乙酯,收率38%。
以2-(乙酰氧基(苯基)甲基)丙烯酸叔丁酯为原料,参照实施例5方法,得到(E)-2-((2'-(二苯基膦基)-[1,1'-联苯]-2-基)甲基)-3-苯基丙烯酸叔丁酯,收率78%。
从以上实施例以及测定的数据可以看出,采用本申请的方式制备新型单膦配体方法操作方便简单,所需要的原材料容易获得,降低了生产成本,且在合成过程中对设备的要求低,适合工业化生产。
以上仅是本发明的优选实施方式,应当指出的是,上述优选实施方式不应视为对本发明的限制,本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术人员来说,在不脱离本发明的精神和范围内,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (8)
3.根据权利要求2所述烯丙基化单膦配体的制备方法,其特征在于:所述钌催化剂选自甲基异丙基苯基、三苯基膦、二甲基亚砜、乙腈、环辛二烯、五甲基环戊二烯、十二羰基或乙基环戊二烯,与钌金属盐组成的催化剂。
4.根据权利要求2所述烯丙基化单膦配体的制备方法,其特征在于:所述配体选自N-Boc-2-氨基异丁酸、N-Boc-L-苯丙氨酸、N-Ac-苯丙氨酸、N-Ac-β-丙氨酸、N-Boc-D-丙氨酸、N-Boc-甘氨酸、N-Ac-甘氨酸、Boc-D-缬氨酸、N-Boc-L-亮氨酸、N-Boc-L-异亮氨酸、N-Boc-L-叔亮氨酸、N-Ac-异亮氨酸、Boc-1-氨基环己基甲酸、(2s,3s)-2-(Boc-氨基)-3-甲基戊酸、N-Boc-1-氨基环丁烷羧酸、N-Ac-D-缬氨酸、2-氨基异丁酸、丙氨酸、甘氨酸、苯丙氨酸、缬氨酸、亮氨酸、异亮氨酸、叔亮氨酸、磷酸二苯酯、磷酸二苄酯、异戊酸、2-甲基丁酸、三甲基乙酸、三苯基乙酸、环己基乙酸、1-金刚烷乙酸、1-金刚烷甲酸、2,2-二苯基丙酸、2,4,6-三甲基苯甲酸、1,1-环丁烷二羧酸、1-苯基-1,3-丁二酮、2,5-己二酮、2,2,6,6-四甲基-3.5-庚二酮、二甲基乙酰乙酸甲酯或2-氧代环戊烷羧酸甲酯。
5.根据权利要求2所述烯丙基化单膦配体的制备方法,其特征在于:所述碱选自醋酸锂、醋酸钠、醋酸钾、醋酸铯、三氟乙酸锂、叔丁醇钠、叔丁醇钾、碳酸锂、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、磷酸钠、磷酸钾、磷酸氢二钠、磷酸二氢钠、磷酸二氢钾、磷酸氢二钾、甲酸钠、乙醇钠、1-金刚烷甲酸钠或对甲苯磺酸钠。
6.根据权利要求2所述烯丙基化单膦配体的制备方法,其特征在于:所述添加剂包括三苯基膦、三(4-三氟甲基苯基)膦、三(3-三氟甲基苯基)膦、三(4-氟苯基)膦、三(3-氟苯基)膦、三(2-氟苯基)膦、三(五氟苯基)膦、三(4-甲基苯基)膦、三(3-甲基苯基)膦、三(4-甲氧基苯基)膦、三(3-甲氧基苯基)膦、三(2,4-二甲基苯基)膦、三环己基膦、二环己基膦联苯、二叔丁基膦联苯或2,2'-双-(二苯膦基)-1,1'-联萘。
7.根据权利要求2所述烯丙基化单膦配体的制备方法,其特征在于:所述有机溶剂为芳烃类溶剂、醇类溶剂、烷烃类溶剂、卤代烃类溶剂、醚类溶剂、腈类溶剂、酮类溶剂中的任意一种或多种混合。
8.根据权利要求2所述烯丙基化单膦配体的制备方法,其特征在于:所述化合物2、化合物1与钌催化剂摩尔比为1-10:1:0.001-1;所述添加剂、配体、碱与化合物1摩尔比为0.005-1:0.005-1:1-15:1。
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