WO2022178692A1 - 一种在碱金属氢化物作用下制备2-碘代芳醚的方法 - Google Patents
一种在碱金属氢化物作用下制备2-碘代芳醚的方法 Download PDFInfo
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- alkali metal
- metal hydride
- phenol
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- 229910000102 alkali metal hydride Inorganic materials 0.000 title claims abstract description 25
- 150000008046 alkali metal hydrides Chemical class 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000009471 action Effects 0.000 title claims abstract description 13
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 150000008378 aryl ethers Chemical class 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 47
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 18
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 18
- 239000012312 sodium hydride Substances 0.000 claims description 18
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 4
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 3
- 150000002989 phenols Chemical class 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 abstract description 7
- 238000010168 coupling process Methods 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 abstract description 3
- 150000003624 transition metals Chemical class 0.000 abstract description 3
- 230000008878 coupling Effects 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000011109 contamination Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- -1 aryl alkyne Chemical class 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/04—Formation or introduction of functional groups containing oxygen of ether, acetal or ketal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
Definitions
- the invention belongs to the technical field of organic synthesis, and in particular relates to the generation of an aryl alkyne intermediate from an o-iodo halide under the action of an alkali metal hydride, and then a coupling reaction with a phenol to generate a 2-iodo aryl ether.
- a method for preparing 2-iodoaryl ether under the action of alkali metal hydride comprising the following steps: in the presence of alkali metal hydride, 1,2-diiodoarene is reacted with phenol to obtain 2- iodo aryl ether; preferably, alkali metal hydride and phenol are added to the solvent, then 1,2-diiodo aromatic hydrocarbon is added, and the reaction is carried out at 0-100° C. to obtain a 2-iodo aryl ether product.
- the alkali metal hydrides are sodium hydride, potassium hydride and lithium hydride, preferably sodium hydride and potassium hydride, more preferably sodium hydride.
- the reaction temperature is 0-100°C, preferably 10-50°C, more preferably room temperature; the reaction time is 0.2-10 hours, preferably 0.5-2 hours.
- the chemical structural formula of the 1,2-diiodoarenes is as follows: .
- the chemical structural formula of the phenol is Ar 2 OH.
- Ar 1 is a group such as benzene, naphthalene
- Ar 2 is a group such as benzene, naphthalene, pyridine, quinoline, pyrimidine, thiophene
- M is sodium, potassium, lithium.
- the present invention has the following advantages for preparing 2-iodoaryl ether: 1) the coupling process does not need to add a transition metal catalyst, which will not cause metal pollution to the product; 2) the method of the present invention can be carried out at room temperature, and the functional groups are compatible It has high performance and solves the problem that the existing metal-catalyzed coupling into aryl ether needs to be carried out at a higher temperature; 3) The reaction is simple, the reagents are cheap, and the required cost is very small; 4) Products that are difficult to prepare by other methods can be prepared , such as products containing iodine on both sides of the aromatic ring.
- Fig. 1 is the hydrogen nuclear magnetic spectrum of the product iodoaryl ether 3aa.
- the coupling reaction of the phenol and the iodide of the present invention does not need to add any catalyst, the operation is simple, the by-product of the reaction is only sodium iodide, and no toxic substances are produced; the preparation of the 2-iodoaryl ether in the present invention requires only one step of mild reaction. Can be obtained without over-coupling products, outperforming all existing methods.
- the technical scheme of the present invention is as follows: the alkali metal hydride is suspended in the solvent, then phenol is added, then 1,2-diiodoarene is added, the reaction is carried out at room temperature for 0.2 to 10 hours, the reaction is terminated by adding water, extracted with a solvent, and evaporated to dryness , and purified by column chromatography to obtain the product 2-iodoaryl ether.
- the raw materials involved in the present invention are all commercially available products, and the specific operation method and testing method are all in the prior art; the reaction of the present invention does not require inert gas, and the reaction bottle is charged in a conventional environment, and the reaction is completed after the charging is completed; the specific operation and purification are conventional techniques.
- the ester was extracted three times, and the organic layers were combined, dried over sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain the product, iodoaryl ether 3ae , in a yield of 91%.
- the above-mentioned embodiments verify that the products of the embodiments of the present invention are matched with the design through nuclear magnetic test and mass spectrometry test;
- the 2-iodo aryl ether can be obtained by stirring at room temperature for a period of time, which is obviously superior to the existing method in terms of synthesis efficiency and cost.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种在碱金属氢化物作用下制备2-碘代芳醚的方法,将碱金属氢化物和酚加入溶剂中,然后加入1,2-二碘芳烃,0~100℃下进行反应,得到2-碘代芳醚产物。本发明偶联过程不需要添加过渡金属催化剂,不会对产物造成金属污染;本发明的方法可以在室温进行,官能团兼容性高,解决了现有金属催化的偶联成芳醚反应需要在较高温度进行的问题。
Description
本发明属于有机合成技术领域,具体涉及由邻碘卤化物在碱金属氢化物作用下产生芳炔中间体,然后和酚偶联反应,生成2-碘代芳醚。
2-碘代芳醚是非常有用的有机合成砌块,可用于多种含氧杂环的合成,还可以把碘进行多样的转化,制备邻位取代的芳醚衍生物。现有技术中,碳-碳或碳-杂原子键形成反应需要金属催化剂或强碱作为促进剂;或者采用复杂的前体,比如以化合物1为前体,在碳酸铯存在下,反应12小时得到碘代芳醚。
现有技术采用贵金属催化剂催化单卤素取代芳烃与酚的反应,未见采用双卤素取代芳烃与酚反应的报道。
本发明提供一种室温下一步反应合成2-碘代芳醚的方法;这是首次使用邻碘卤化物在碱金属氢化物作用下吸收另一分子邻碘卤化物的卤素原子成为2-碘代芳醚产物。本发明是一种碱金属氢化物促进的苯酚和邻碘卤化物的偶联反应,这类转化快速、简捷而且温和,不需要过渡金属催化,没有过度偶联的副产物,是一种快速构建各种2-碘代芳醚的新颖方法。
本发明实现以上提及的合成2-碘代芳醚的技术手段是把碱金属氢化物、酚和1,2-二碘芳烃混合在溶剂中,无需其他试剂,搅拌反应得到产物。具体技术方案如下:一种在碱金属氢化物作用下制备2-碘代芳醚的方法,包括以下步骤,在碱金属氢化物存在下,1,2-二碘芳烃与酚反应,得到2-碘代芳醚;优选的,将碱金属氢化物和酚加入溶剂中,然后加入1,2-二碘芳烃,0~100℃下进行反应,得到2-碘代芳醚产物。
本发明中,所述酚为苯酚、取代的苯酚或者杂环苯酚。
本发明中,所述碱金属氢化物为氢化钠、氢化钾和氢化锂,优选氢化钠和氢化钾,更优选氢化钠。
本发明中,所述溶剂为DMF(
N,N-二甲基甲酰胺)、DMA(
N,N-二甲基乙酰胺)、THF(四氢呋喃)、2-MeTHF (2-甲基四氢呋喃)、DME(乙二醇二甲醚)、MTBE(甲基叔丁基醚)、乙醚、DMSO、NMP(
N-甲基吡咯烷酮)、甲苯中的一种或几种,优选DMA和THF,更优选DMA和THF的混合物。
本发明中,所述酚、1,2-二碘芳烃和碱金属氢化物的摩尔比为1
:(0.1~10)
:(1.2~10);优选为1
:(0.5~5)
:(1.5~5);更优选为1
:(1~3)
:(2~4);最优选为1
:1.5
:3。
上述技术方案中,所述反应的温度为0~100 ℃,优选10~50℃,更优选室温;所述反应的时间为0.2~10小时,优选0.5~2小时。
本发明中,所述苯酚的化学结构式为Ar
2OH。
本发明中,Ar
1为苯、萘等基团;Ar
2为苯、萘、吡啶、喹啉、嘧啶、噻吩等基团;M为钠、钾、锂。
本发明用来制备2-碘代芳醚有以下几点优势:1)偶联过程不需要添加过渡金属催化剂,不会对产物造成金属污染;2)本发明的方法可以在室温进行,官能团兼容性高,解决了现有金属催化的偶联成芳醚反应需要在较高温度进行的问题;3)反应简单,试剂便宜,所需的花费很小;4)可以制备其它方法不易制备的产物,比如两边芳环都含有碘的产物。
图1为产物碘代芳醚3aa的氢核磁谱图。
本发明的酚和碘代物的偶联反应,无需添加任何催化剂,操作简单,反应的副产物只有碘化钠,无毒害物质产生;本发明制备2-碘代芳醚,仅需一步温和反应即可得到,无过度偶联产物,优于已有的所有方法。
本发明的技术方案如下:将碱金属氢化物悬浮于溶剂中,再加入酚,然后加入1,2-二碘芳烃,室温下进行反应0.2~10小时,加水终止反应,用溶剂萃取,蒸干,柱层析纯化,得到产物2-碘代芳醚。
本发明涉及的原料都是市售产品,具体操作方法以及测试方法都为现有技术;本发明的反应无需惰性气体,常规环境往反应瓶内加料,加料完成后盖盖反应即可;具体操作与提纯为常规技术。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2a (36
mg, 0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温反应2小时,再加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3aa,收率99%,氢核磁谱图见图1,LR-MS (ESI): m/z 322.1 [M+H]
+。
用氢化钾等摩尔量替换上述氢化钠,其余不变,得到产物碘代芳醚
3aa,收率39%。
用氢化锂等摩尔量替换上述氢化钠,其余不变,无法得到产物碘代芳醚
3aa。
用氢化钙等摩尔量替换上述氢化钠,其余不变,无法得到产物碘代芳醚
3aa。
将上述室温替换为冰水浴,其余不变,得到产物碘代芳醚
3aa,收率51%。
将上述氢化钠用量替换为2eq,其余不变,得到产物碘代芳醚
3aa,收率81%。
将上述室温反应2小时替换为室温反应1小时,其余不变,得到产物碘代芳醚
3aa,收率96%。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2a (28
mg, 0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温进行反应1小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3ba,收率35%。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2b (42
mg, 0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温进行反应0.5小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3ab,收率97%。
1H NMR
(400 MHz, CDCl
3) δ: 8.22 (d,
J =
7.8 Hz, 2H), 7.92 (d,
J = 7.5 Hz, 1H), 7.43 (t,
J = 7.5 Hz, 1H),
7.09 (d,
J = 7.5 Hz, 1H), 7.03 (t,
J = 7.2 Hz, 1H), 6.96 (d,
J
= 7.8 Hz, 2H). LR-MS (ESI): m/z 342.1 [M+H]
+。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2c (28
mg, 0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温进行反应0.5小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3ac,收率98%。
1H NMR
(400 MHz, CDCl
3) δ 7.87 (dd,
J =
7.8, 1.5 Hz, 1H), 7.42-7.32 (m, 2H), 7.32-7.26 (m, 1H), 7.18-7.07 (m, 1H),
7.02-6.94 (m, 2H), 6.94-6.83 (m, 2H). LR-MS (ESI): m/z 297.1 [M+H]
+。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2d (37
mg, 0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温进行反应1小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3ad,收率89%。
1H NMR
(400 MHz, CDCl
3) δ:7.84 (dd,
J =
7.8, 1.5 Hz, 1H), 7.24 (ddd,
J = 8.8, 5.7, 1.5 Hz, 1H), 7.02-6.92 (m,
2H), 6.92-6.86 (m, 2H), 6.81 (td,
J = 7.7, 1.4 Hz, 1H), 6.76 (dd,
J =
8.2, 1.3 Hz, 1H), 3.81 (s, 3H). LR-MS (ESI): m/z 327.2 [M+H]
+。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2e (38
mg, 0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温进行反应1小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3ae,收率91%。
1H NMR (400 MHz, CDCl
3) δ 8.31 (d,
J = 8.5 Hz, 1H), 7.89 (t,
J = 7.1
Hz, 1H), 7.82 (dd,
J = 17.9, 8.5 Hz, 2H), 7.64 (t,
J = 7.6 Hz,
1H), 7.52 (t,
J = 7.4 Hz, 1H), 7.23 (d,
J = 8.1 Hz, 1H), 7.11 (d,
J = 8.7 Hz, 1H), 6.87 (t,
J = 7.4 Hz, 1H), 6.71 (d,
J =
8.1 Hz, 1H). LR-MS (ESI): m/z 424.7 [M+H]
+。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2f(34mg,
0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温进行反应1小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3af,收率85%。
1H NMR
(400 MHz, CDCl
3) δ:7.85 (d,
J
= 7.6 Hz, 1H), 7.19-7.04 (m, 4H), 6.74 (dd,
J = 15.2, 7.7 Hz, 1H), 6.30
(d,
J = 8.1 Hz, 1H), 2.13 (s, 6H). LR-MS (ESI): m/z 325.1 [M+H]
+。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2g (38
mg, 0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温进行反应0.5小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3ag,收率96%。
1H NMR
(400 MHz, CDCl
3) δ: 7.88 (dd,
J
= 7.9, 1.5 Hz, 1H), 7.36-7.30 (m, 1H), 7.26 (dd,
J = 9.2, 7.1 Hz,
1H), 7.08 (ddd,
J = 8.0, 1.9, 0.8 Hz, 1H), 7.01-6.89 (m, 3H), 6.85 (ddd,
J = 8.3, 2.4, 0.8 Hz, 1H). LR-MS (ESI): m/z 331.0 [M+H]
+。
将氢化钠 (60% in oil, 72 mg, 1.8 mmol, 6 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2h (86
mg, 0.3 mmol, 1 eq.) 在DMA (0.4 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (297
mg, 0.9 mmol, 3 eq.) 在THF (0.6 mL) 中的溶液,室温进行反应1小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3ah,收率89%.
1H NMR (400 MHz, CDCl
3) δ 7.90 (t,
J = 7.4 Hz, 4H), 7.66 (d,
J = 7.7
Hz, 2H), 7.47 (d,
J = 8.4 Hz, 2H), 7.41 (dd,
J = 15.2, 7.6 Hz,
2H), 7.33 (t,
J = 7.5 Hz, 2H), 7.13 (d,
J = 9.0 Hz, 2H), 7.04 (t,
J = 7.6 Hz, 2H), 6.70 (t,
J = 6.9 Hz, 4H). LR-MS (ESI): m/z 690.8
[M+H]
+。
将氢化钠 (60% in oil, 36 mg, 0.9 mmol, 3 eq.) 悬浮于THF (1 mL) 中,常规搅拌下加入酚
2k(43mg,
0.3 mmol, 1 eq.) 在DMA (0.3 mL) 中的溶液,加完后室温搅拌10分钟,然后加入
1a (148
mg, 0.45 mmol, 1.5 eq.) 在THF (0.2 mL) 中的溶液,室温进行反应1小时,加水淬灭,用乙酸乙酯萃取三次,合并有机层,用硫酸钠干燥,蒸干,柱层析纯化,得到产物碘代芳醚
3aj,收率85%。
1H NMR
(400 MHz, CDCl
3) δ 8.25–8.16 (m, 1H), 7.89 (ddd,
J = 9.4, 7.4, 2.6 Hz,
2H), 7.63 (d,
J=8.3 Hz, 1H), 7.58–7.45
(m, 2H), 7.41–7.32 (m, 1H), 7.28–7.20 (m, 1H), 6.91–6.76
(m, 3H). LR-MS (ESI): m/z 347.2 [M+H]
+。
上述实施例通过核磁测试、质谱测试验证本发明实施例的产物与设计匹配;与现有技术相比,本发明只需要从商品化的1,2-二碘芳烃和酚在碱金属氢化物作用下室温搅拌一段时间就可以得到2-碘代芳醚,从合成效率和成本上来看,明显优于已有方法。
Claims (10)
- 一种在碱金属氢化物作用下制备2-碘代芳醚的方法,其特征在于,包括以下步骤,在碱金属氢化物存在下,1,2-二碘芳烃与酚反应,得到2-碘代芳醚。
- 根据权利要求1所述在碱金属氢化物作用下制备2-碘代芳醚的方法,其特征在于,将碱金属氢化物和酚加入溶剂中,然后加入1,2-二碘芳烃,进行反应,得到2-碘代芳醚产物。
- 根据权利要求2所述在碱金属氢化物作用下制备2-碘代芳醚的方法,其特征在于,所述溶剂为DMF、DMA、THF、2-MeTHF、DME、MTBE、乙醚、DMSO、NMP、甲苯中的一种或几种。
- 根据权利要求1所述在碱金属氢化物作用下制备2-碘代芳醚的方法,其特征在于,所述碱金属氢化物为氢化钠、氢化钾或氢化锂。
- 根据权利要求1所述在碱金属氢化物作用下制备2-碘代芳醚的方法,其特征在于,所述酚为苯酚、取代的苯酚或者杂环苯酚。
- 根据权利要求1所述在碱金属氢化物作用下制备2-碘代芳醚的方法,其特征在于,所述酚、1,2-二碘芳烃和碱金属氢化物的摩尔比为1 :(0.1~10) :(1.2~10)。
- 根据权利要求1所述在碱金属氢化物作用下制备2-碘代芳醚的方法,其特征在于,所述反应的温度为0~100 ℃;所述反应的时间为0.2~10小时。
- 根据权利要求1所述在碱金属氢化物作用下制备2-碘代芳醚的方法制备的2-碘代芳醚。
- 碱金属氢化物在以1,2-二碘芳烃、酚为原料制备2-碘代芳醚中的应用。
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