WO2024011415A1 - 一种邻碘苯基化合物的制备方法 - Google Patents

一种邻碘苯基化合物的制备方法 Download PDF

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WO2024011415A1
WO2024011415A1 PCT/CN2022/105231 CN2022105231W WO2024011415A1 WO 2024011415 A1 WO2024011415 A1 WO 2024011415A1 CN 2022105231 W CN2022105231 W CN 2022105231W WO 2024011415 A1 WO2024011415 A1 WO 2024011415A1
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minor
compound
iodophenyl
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mmol
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PCT/CN2022/105231
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French (fr)
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张士磊
姜远锐
祝文静
胡延维
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苏州大学
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    • C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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Definitions

  • the invention belongs to organic synthesis technology, and specifically relates to a preparation method of o-iodophenyl compounds.
  • the present invention introduces a new method that uses o-diiodobenzene as a precursor and does not require metal catalysts, expensive special ligands, high temperature, high pressure and other conditions to efficiently construct C-N bonds.
  • the present invention adopts the following technical solution: a method for preparing o-iodophenyl compounds, using iodobenzene compounds and amide compounds as raw materials, in the presence of sodium hydride, potassium hydride or n-butyllithium and solvents, reacting to obtain o-iodophenyl compounds compound.
  • the reaction temperature is room temperature to 50°C.
  • the solvent is one or more of tetrahydrofuran, dimethylacetamide, 1,4-dioxane, and ethylene glycol dimethyl ether.
  • the molar ratio of iodobenzene compound, amide compound, sodium hydride or potassium hydride is (2 ⁇ 3):1:(2 ⁇ 3); the molar ratio of iodobenzene compound, amide compound and n-butyllithium is ( 2 ⁇ 3):1: (1.5 ⁇ 2.5).
  • the iodobenzene compound has the following chemical structure: .
  • Amide compounds have the following chemical structures: .
  • the o-iodophenyl compound has the following chemical structure: .
  • G 1 and G 2 independently select an alkyl group, an aryl group, or a heterocyclic group
  • R is hydrogen, an alkyl group, an aryl group, or a heterocyclic group
  • X is an iodine, bromine, chlorine, or triflate group; preferably,
  • the aryl group contains one or more benzene rings, with or without substituents;
  • the alkyl group is a straight alkyl group, a cycloalkyl group, or a branched alkyl group.
  • the invention discloses a new C-N coupling method of great significance. This method does not require metal catalysts, high temperature, high pressure, mild conditions, and can obtain unique o-iodophenyl products. Since iodine atoms are important in organic synthesis transformations, Universal functional groups facilitate the derivatization of products, so they are of great significance.
  • Figure 1 is a schematic diagram of some raw materials and preparation of the present invention.
  • Figure 2 is a schematic diagram of some raw materials and preparation of the present invention.
  • Figure 3 is a schematic diagram of some raw materials and preparation of the present invention.
  • Figure 4 is a schematic diagram of the reaction results of N-benzylbenzamide and o-diiodobenzene under different conditions of the present invention.
  • Figure 5 shows the aromatic amide substrate topology
  • Figure 6 is a diagram showing the aliphatic amide topography.
  • Figure 7 shows the topography of primary amine compounds protected by Boc or Cbz.
  • Figure 8 shows the topology of aromatic amine substrates.
  • Figure 9 is a diagram showing the o-iodobenzene compound.
  • Figure 10 is a schematic diagram of the enlarged experiment.
  • the present invention discloses a new non-metal catalyzed C-N coupling method. It conducts substrate expansion and a certain scale of scale-up experiments, proving that this method does not require metal catalysts, high temperature and high pressure, and the conditions are mild and can be convenient and fast. It can efficiently construct C-N bonds and obtain unique o-iodo arylation products, which has very high practical value and has industrial prospects for large-scale preparation. Afterwards, the obtained product was further derivatized as a synthetic intermediate, and a variety of compounds of important value were prepared, proving that it also has very high application value. Therefore, the new method developed in this paper is of great significance.
  • Agilent 400 MHz ( 1 H NMR) and Bruker 400 MHz ( 1 H NMR and 13 C NMR) nuclear magnetic instruments (Suzhou University Analysis and Testing Center provides testing services, 1 H NMR spectrum reference TMS (0.00 ppm) and 13 C NMR spectrum reference CDCl 3 Solvent center peak (77.10 ppm) for calibration, chemical shift in ppm, NMR data report includes: chemical shift, peak type, hydrogen number peak area integration, coupling constant, etc.); Agilent LC-MS liquid mass spectrometry Instrument (Public Experimental Instrument Platform of School of Pharmacy, Suzhou University); Type 85-1 Magnetic Stirrer (Zhengzhou Ketai); DF-101S Collecting Constant Temperature Heating Magnetic Stirrer (Zhengzhou Ketai); Rotary Evaporator (EYELA); BSA224S analytical balance (Sartorius); glass instrument (Xinwei); ZF-7 type 254 nm or 365 nm portable UV detection lamp (Shanghai Guanghao); 200-300 mesh fast
  • the substrates involved in the present invention are commercially available or can be synthesized according to the following methods.
  • the specific preparation operations and testing methods are conventional techniques.
  • the generated crude acid chloride was redissolved in methylene chloride (20 mL, 0.5 M), and methylamine hydrochloride or ethylamine hydrochloride (15 mmol, 1.5 equiv) and triethylamine (30 mmol) were dissolved in an ice-water bath. , 3.0 equiv) were added dropwise to the reaction mixture, and stirred at room temperature overnight. Water was added to the reacted solution, and extracted with ethyl acetate (3 x 100 mL). The obtained organic phase was dried over anhydrous Na2SO4 , filtered, and distilled under reduced pressure.
  • the crude product is separated and purified by pre-adsorption on silica gel and flash column chromatography (usually using a mixture of petroleum ether and ethyl acetate as the eluent) to obtain pure product 1an with a yield of 82%.
  • the corresponding diiodobenzene derivative 2m or 2o was purified by flash column chromatography (petroleum ether as eluent). Dissolve 3-phenyl-1-propyne (6.0 mmol, 1.2 equiv) in THF (5 mL, 1.0 M) at room temperature, and add ethylmagnesium bromide (5.5 mL, 1.0 M in THF, 1.1 equiv) , the reaction mixture was stirred at 50 °C for 1 h. Remove the heating instrument, slowly add 4-bromobenzaldehyde (5.0 mmol, 1.0 equiv) dissolved in a small amount of THF into the above reaction solution, and stir at room temperature for 3 h.
  • the structure of the aromatic amide compound can be determined from the product; NaH (1.5 mmol, 2.5 equiv) , compound 1 (0.6 mmol, 1.0 equiv) dissolved in THF (2.0 mL), 2a (1.5 mmol, 2.5 equiv) dissolved in THF (0.4 mL), reaction at room temperature (except for two substrates), where: b 40 °C reaction , c 50 °C reaction; the reaction time is shown in Figure 5.
  • Figure 6 expands the aliphatic amide. Whether it is an alkenyl, alkynyl or alkyl group, the product ( 3ae-3an ) can be produced in medium yield.
  • the structure of the aliphatic amide compound can be determined from the product; NaH (1.5 mmol, 2.5 equiv), compound 1 (0.6 mmol, 1.0 equiv) dissolved in THF (2.0 mL), 2a (1.5 mmol, 2.5 equiv) dissolved in THF (0.4 mL), reaction at room temperature (except three substrates) , where: b 40 °C reaction; the reaction time is shown in Figure 6.
  • Figure 7 expands a series of compounds after primary amines are protected by Boc or Cbz. There is little difference in the reaction conditions of primary amines protected by Boc or Cbz.
  • amide compound 1 can be determined from the product; NaH (1.5 mmol, 2.5 equiv), compound 1 (0.6 mmol, 1.0 equiv) dissolved in THF (2.0 mL), 2a (1.5 mmol, 2.5 equiv) dissolved in THF (0.4 mL), reaction at 40°C (except three substrates), including: b reaction at 50°C, c reaction at room temperature; the reaction time is shown in Figure 7.
  • Figure 8 expands the types of aromatic amine substrates, including Boc or Cbz protected monosubstituted aromatic amines ( 3ca1-3cg ), polysubstituted aromatic amines ( 3ch-3cl ), heterocyclic aromatic amines ( 3cam-3cp ) and bis Aromatic amine compounds ( 3cq-3cs ) at the reaction site can have very high yields, and even pyridones, piperidinamines and urea compounds also have good yields ( 3ct-3cw ), Figure 8 In , the structure of the aromatic amine compound can be determined from the product; NaH (1.5 mmol, 2.5 equiv), compound 1 (0.6 mmol, 1.0 equiv) dissolved in THF (2.0 mL), 2a (1.5 mmol, 2.5 equiv) dissolved in THF ( 0.4 mL), reaction at 40°C (except five substrates), including: b reaction at 50°C, d reaction at room temperature, changes in the amount of raw materials for three
  • Figure 9 expands on o-iodobenzene compounds.
  • Diiodobenzene with a symmetrical structure can have good yields ( 3da-3df ), regardless of whether the ortho position is methyl, methoxy, phenyl or styrene group. There is a good yield, and the production of isomers is not detected, and the regional selectivity is excellent ( 3dg-3dk ).
  • O-iodoaromatic amine compound 3ca1 (409 mg, 1.0 mmol, 2.0 equiv) and sulfur 8e (16 mg, 0.5 mmol, 1.0 equiv) were dissolved in 10 mL with 1,4-dioxane (1.5 mL, 0.33 M) solution in two reaction bottles. Subsequently, Cu(OAc) 2 (20 mg, 0.1 mmol, 20 mol%), KF (58.1 mg, 1.0 mmol, 2.0 equiv), Et 3 N (0.3 mL) were added, and the reaction mixture was heated at 110 °C under nitrogen protection. Stir for 12 h.
  • reaction solution was filtered through diatomaceous earth, diluted with ethyl acetate (5.0 mL), added with water (10 mL), and extracted with ethyl acetate (3 x 5.0 mL).
  • the organic layers were combined and dried over anhydrous Na 2 SO 4 , filtered, evaporated to dryness, and purified by flash column chromatography to obtain pure compound 9j (60 mg) with a yield of 38%.
  • the NMR data of the o-iodophenyl compound of the present invention are as follows.
  • the reaction of the present invention does not require a metal catalyst, o-diiodobenzene is commercially available, is cheap, and has stable chemical properties; the reaction conditions are mild, requiring neither low temperature nor high temperature, and the reagents used are cheap and easy to obtain, making it a very practical C-N coupling aromatic.

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Abstract

本发明公开了一种邻碘苯基化合物的制备方法，以碘苯化合物、酰胺化合物为原料，在氢化钠或者正丁基锂、溶剂存在下，反应得到邻碘苯基化合物。随着有机化学深入生活的方方面面，无论是在药物合成工艺研发还是其他工业制造方面探寻绿色环保、方便快捷、原子利用率高的合成方法都是至关重要的。含有C-N键的化合物不仅广泛存在于自然界，在生物医药领域同样扮演着不可替代的作用。本发明介绍了一种以邻二碘苯为前体，不需要金属催化剂和及其昂贵特殊的配体以及高温、高压等条件，高效构建C-N键的新方法。

Description

一种邻碘苯基化合物的制备方法 技术领域
本发明属于有机合成技术，具体涉及一种邻碘苯基化合物的制备方法。
 背景技术
含有酰胺以及胺类的结构是有机化学、材料化学等学科中及其重要的合成中间体或者目标产物，在药物合成领域和功能材料制造领域广泛应用，扮演着不可或缺的作用。一般来说，酰胺以及胺类化合物的C-N偶联芳基化反应是在金属催化下完成的。但是近些年来，常用的一些金属催化剂价格水涨船高，使得药物研发与制造成本大大增加，且使用金属催化剂后的金属残留问题也比较突出，这对药物合成工艺的研究是一个巨大的考验；且所用的重金属以及配体也会对环境造成严重污染，这是必须考虑的问题。
 技术问题
现有上市的药物中，含有C-N键的药物分子不计其数。因此，发展一种高效、便捷、经济、环保的C-N偶联方法具有重大的意义。本发明介绍了一种以邻二碘苯为前体，不需要金属催化剂和及其昂贵特殊的配体以及高温、高压等条件，高效构建C-N键的新方法。
 技术解决方案
本发明采用如下技术方案：一种邻碘苯基化合物的制备方法，以碘苯化合物、酰胺化合物为原料，在氢化钠、氢化钾或者正丁基锂，溶剂存在下，反应得到邻碘苯基化合物。优选的，反应的温度为室温～50℃。
本发明中，溶剂为四氢呋喃、二甲基乙酰胺、1,4-二氧六环、乙二醇二甲醚中的一种或几种。
本发明中，碘苯化合物、酰胺化合物、氢化钠或者氢化钾的摩尔比为（2～3）∶1∶（2～3）；碘苯化合物、酰胺化合物、正丁基锂的摩尔比为（2～3）∶1∶（1.5～2.5）。
本发明中，碘苯化合物为如下化学结构： 。
酰胺化合物为如下化学结构： 。
邻碘苯基化合物为如下化学结构： 。
G 1、G 2独立的选择烷基或者芳基、杂环基，R为氢、烷基或者芳基、杂环基，X为碘、溴、氯或者三氟甲磺酸基；优选的，芳基含有一个或者多个苯环，含有或者不含有取代基；烷基为直连烷基或者环烷基、支链烷基。
有益效果
本发明公开了一种具有重要意义的C-N偶联新方法，此方法无需金属催化剂，无需高温、高压，条件温和，并能得到独特的邻碘苯基产物，由于碘原子在有机合成转化中是万能官能团，便于产物的衍生化，所以具有重要意义。
 附图说明
图1为本发明部分原料及制备示意图。
图2为本发明部分原料及制备示意图。
图3为本发明部分原料及制备示意图。
图4为本发明N-苄基苯甲酰胺与邻二碘苯在不同条件下的反应结果示意图。
图5为芳香酰胺底物拓展示意图。
图6为脂肪族酰胺拓展示意图。
图7为被Boc或者Cbz保护后的伯胺化合物拓展示意图。
图8为芳胺底物拓展示意图。
图9为邻碘苯化合物拓展示意图。
图10为放大实验示意图。
 本发明的实施方式
本发明公开了一种非金属催化进行C-N偶联的的新方法，进行了底物拓展以及一定规模的放大实验，证明了此方法无需金属催化剂，无需高温、高压，条件温和，可以方便快捷的高效构建C-N键，并能得到独特的邻碘芳基化产物，具有非常高的实用价值，并且有大规模制备的工业前景。之后，将得到的产物作为合成中间体进一步衍生化，制备了多种多样具有重要价值的化合物，证明了其同样具有非常高的应用价值。因此，本论文发展的新方法具有重要的意义。
安捷伦400 MHz ( 1H NMR)和布鲁克400 MHz ( 1H NMR和 13C NMR)核磁仪器（苏州大学分析测试中心提供测试服务， 1H NMR谱参考TMS (0.00 ppm)及 13C NMR谱参考CDCl 3溶剂中心峰(77.10 ppm)进行定标，化学位移以ppm为单位，核磁数据报告包括：化学位移，峰型，氢个数峰面积积分，偶合常数等。）；安捷伦LC-MS液质联用仪（苏州大学药学院公共实验仪器平台）；85-1型磁力搅拌器（郑州科泰）；DF-101S集热式恒温加热磁力搅拌器（郑州科泰）；旋转蒸发仪(EYELA)；BSA224S分析天平(Sartorius)；玻璃仪器（欣维尔）；ZF-7型254 nm或365 nm手提式紫外检测灯（上海光豪）；200-300目快速柱层析硅胶（青岛海洋化工）；含有TMS内标的CDCl 3或 d6-DMSO（百灵威）；常用显色剂（碘缸、KMnO 4、磷钼酸以及2,4-二硝基苯肼）；其余试剂及溶剂（均为市售分析纯或化学纯）。
本发明涉及的底物可市购，也可以根据以下方法合成，具体制备操作以及测试方法都为常规技术。
合成例：图1、图2、图3为部分原料及制备示意。底物合成的一般步骤( 1c-1n, 1p-1ae):将苯甲酸衍生物(10 mmol, 1.0 equiv)溶解在二氯甲烷(20 mL, 0.5 M)溶液中，加入1滴DMF和草酰氯(15 mmol, 1.5 equiv)；将反应混合物搅拌成为均相溶液后，在减压蒸馏下除去溶剂。生成的粗酰氯被重新溶解在二氯甲烷(20 mL, 0.5 M)中，在冰水浴下将甲胺盐酸盐或乙胺盐酸盐(15 mmol, 1.5 equiv)和三乙胺(30 mmol, 3.0 equiv)依次滴加到反应混合物中，室温搅拌过夜。将水加入反应后的溶液中，用乙酸乙酯(3 x 100 mL)萃取。得到的有机相用无水Na 2SO 4干燥、过滤、减压蒸馏。用乙酸乙酯与石油醚对混合物进行打浆或者快速柱层析纯化，得到纯产品( 1c-1n, 1p-1ae)，产率80-99%。将溴代芳酰胺 1k (10 mmol, 1.0 equiv)，PdCl 2(dppf) (0.3 mmol, 3 mol%)，KOAc (30 mmol, 3.0 equiv)和联硼酸频那醇酯(15 mmol, 1.5 equiv)的混合物溶解在1,4-二氧六烷中，在80 ℃下搅拌过夜。待反应冷却至室温后，用水稀释，乙酸乙酯萃取。得到的有机相用水和饱和NaCl洗涤，无水Na 2SO 4干燥、过滤、减压蒸馏。用乙酸乙酯、石油醚为洗脱剂，快速柱层析对粗产物进行分离纯化，得到纯产品 1o，产率92%。底物合成的一般步骤( 1af-1am):在圆底烧瓶中，依次加入羧酸(10 mmol, 1.0 equiv)、EDCI (15 mmol, 1.5 equiv)、DMAP (5 mmol, 0.5 equiv)、DCM (20 mL)，混合物搅拌20 min。随后，在上述混合液中加入乙胺盐酸盐(10 mmol, 1.0 equiv)和三乙胺(20 mmol, 2.0 equiv)。将反应液在室温下搅拌12 h，用1 N HCl溶液淬灭反应，分离有机相，用饱和NaHCO 3溶液洗涤有机相，无水Na 2SO 4干燥、过滤、减压蒸馏。快速柱层析对粗产物进行分离纯化(通常用石油醚和乙酸乙酯的混合物作为洗脱剂)，得到纯产品 1af-1am，产率80-99%。将苯丙炔酸 (11 mmol, 1.1 equiv)溶解在DCM (20 mL, 0.5 M)溶液中,加入DMAP (1.0 mmol, 0.1 equiv)和DCC (11 mmol, 1.1 equiv) ，然后搅拌约10 min。随后,在0 ℃下将溶于DCM (10 mL, 1.0 M)的苄胺(10 mmol, 1.0 equiv)滴入混合液中，所得混合物在室温下搅拌16 h。通过减压蒸馏除去一部分溶剂，将粗混合物溶液通过硅藻土过滤，用乙醚洗脱。通过在硅胶上预吸附，快速柱层析对粗产物进行分离纯化(通常用石油醚和乙酸乙酯的混合物作为洗脱剂)，得到纯产品 1an，产率82%。底物合成的一般步骤( 1ba1, 1bb1, 1bc-1bw, 1ca1, 1cb- 1co1, 1cp- 1cs):将胺类化合物(10 mmol, 1.0 equiv)溶解在乙醇(20 mL, 0.5 M)溶液中（制备 1cm时使用叔丁醇, 1cd, 1cg, 1ck使用甲醇），加入(Boc) 2O (12 mmol, 1.2 equiv) (制备 1cq-1cs时为2.4 equiv)。在30-100 ℃（根据溶剂选择）下将反应，TLC测反应进度。反应完成后，将溶剂减压除去，用乙酸乙酯与石油醚对混合物进行打浆，或者快速柱层析对粗产物进行分离纯化（通常用石油醚和乙酸乙酯的混合物作为洗脱剂），得到纯产品( 1ba1, 1bb1, 1bc-1bw, 1ca1, 1cb- 1co1, 1cp- 1cs)，产率70-99%。将肼基甲酸叔丁酯(10 mmol, 1.0 equiv)和对甲基苯甲醛(10 mmol, 1.0 equiv)溶解在EtOH (0.25 M)溶液中,在80 ℃下搅拌回流6 h。反应完成后，通过减压蒸馏除去溶剂，将粗产品重结晶，得到纯产品 1baa，产率94%。将四氢吡咯(10 mmol, 1.0 equiv)和间氯苯异氰酸酯(10 mmol, 1.0 equiv)溶解在DCM (0.25 M)溶液中,在室温下搅拌1 h。反应完成后，通过减压蒸馏除去溶剂，将粗产品重结晶，得到纯产品 1cw，产率93%。邻碘苯酚(10 mmol, 1.0 equiv)溶解在DCM (0.33 M)的溶液中，在-78 ℃下将无水DIPEA (12.5 mmol, 1.25 equiv)和三氟甲磺酸酐(12.5 mmol, 1.25 equiv)依次滴加到反应液中。10 min后，移开冷却装置，反应混合物逐渐恢复至室温反应。1-2 h后，加入水淬灭反应，用乙酸乙酯萃取，之后合并有机相并用饱和NaCl洗涤，无水Na 2SO 4干燥、过滤、减压蒸馏。快速柱层析对粗产物进行分离纯化（石油醚作为洗脱剂），得到纯产品 2d，产率89%。在水(15 mL)和甲苯(15 mL)的混合物中加入氢氧化钠(3.05 g, 76.2 mmol, 3.8 equiv)，然后依次加入四丁基溴化铵(0.65 g, 2.0 mmol, 2.0 equiv)、2-羟基苯并咪唑( 2.68 g, 20.0 mmol, 1.0 equiv)和苄溴(8.20 g, 48.0 mol, 2.4 equiv)。60 ℃下反应12 h后，冷却至室温，用分液漏斗直接分离有机层，用水洗涤3次，饱和食盐水洗涤1次，无水Na 2SO 4干燥，过滤，减压去除溶剂后，快速柱层析（石油醚:乙酸乙酯= 10:1）进行纯化,得到化合物 10a (5.53 g)，产率88%；将DCM (20 mL)、乙酸(17.6 mL)、质量分数为20 %的硫酸水溶液(10.6 mL)加入100 mL两口瓶中，依次将化合物 10a (5.53 g, 17.6 mmol, 1.0 equiv)、碘酸(1.55 g, 8.8 mmol, 0.5 equiv)、I 2 (4.52 g, 17.6 mmol, 1.0 equiv)加入两口瓶中，60 ℃回流搅拌反应12 h，待反应体系温度降至室温，边搅拌边将反应液倒入水中，用DCM萃取两遍(3 x 30 mL)，随后分离有机相并用水将有机相洗至中性，无水Na 2SO 4干燥，过滤，减压浓缩，将粗产物固体用石油醚重结晶，得到白色固体化合物 2g,收率63%。在N 2保护条件下，依次将HIO 4 (8.0 mmol, 0.4 equiv)，I 2 (16.0 mmol, 0.8 equiv)加入MeOH (30 mL, 0.66 M)溶液中搅拌溶解，随后将邻二甲氧基苯(20 mmol, 1.0 equiv)加入混合液中，并将混合液移至70 ℃条件下搅拌21 h。待反应完成后，将反应体系冷却至室温，加入适量饱和NaHSO 3溶液还原过量的碘单质，处理后的反应液变为白色混悬液，减压抽滤，收集滤饼，烘箱55 ℃干燥，得到白色固体产品 2i，产率86%。在氮气保护下，将相应的炔醇(10 mmol, 1.0 equiv)溶解在无水的DMF (10 mL, 1.0 M)中，室温下依次加入K 2CO 3 (1.93 g, 14 mmol, 1.4 equiv)、四丁基溴化铵(483 mg, 1.5 mmol, 0.15 equiv)和CuI (96 mg, 0.5 mmol, 0.05 equiv)。混合物搅拌15 min后，加入3-氯-2-甲基丙烯(1.36 g, 15 mmol, 1.5 equiv)，继续将反应混合物搅拌24 h。待反应完成后，将反应液倒入水(20 mL)中，用乙酸乙酯(3 x 30 mL)萃取，合并有机相后再用水(3 x 30 mL)反萃洗掉DMF。有机相用饱和NaCl水溶液洗涤一次，无水Na 2SO 4干燥、过滤、减压蒸馏。粗产品经快速柱层析(石油醚:乙酸乙酯=10:1)纯化，得到相应的纯产品 10c或 10d，产率均为80%，为淡黄色油状液体；将 10c或 10d (8 mmol, 1.0 equiv)溶解在CH 3NO 3 (115 mL, 0.07 M)中，在室温下加入I 2 (3.66 g, 14.4 mmol, 1.8 equiv)并搅拌2 h。TLC检测反应完全后，加入NaHSO 3水溶液还原过量的碘，随后用乙酸乙酯(3 x 50 mL)萃取，合并有机相并用饱和NaCl水溶液洗涤一次，无水Na 2SO 4干燥、过滤、减压蒸馏。粗产品在室温下无需纯化直接加入DCM (160 mL, 0.05 M)溶液，然后加入DDQ (3.63 g, 16 mmol, 2.0 equiv)。TLC检测反应完全后，先过滤除去固体残渣，滤液加入硅胶拌样。经快速柱层析（石油醚作为洗脱剂）纯化得到相应二碘苯衍生物 2m or 2o。在室温下，将3-苯-1-丙炔(6.0 mmol, 1.2 equiv)溶解在THF (5 mL, 1.0 M)中，加入乙基溴化镁(5.5 mL, 1.0 M in THF, 1.1 equiv)，反应混合物在50 ℃下搅拌1 h。撤去加热仪器，将溶解在少量THF中的4-溴苯甲醛(5.0 mmol, 1.0 equiv)缓慢滴加到上述反应液中，室温下搅拌3 h。反应完成后加入饱和NH 4Cl溶液淬灭反应，用乙酸乙酯(2 x 40 mL)萃取。常规处理后，用快速柱层析法对粗产品进行纯化，得到纯的1-(4-溴苯基)-4-苯基-2-炔-1-醇 10e，收率为80%；在室温下，将化合物 10e (4.0 mmol, 1.0 equiv)溶解在CH 3NO 3 (60 mL, 0.07 M)溶液中，加入I 2 (2.03 g, 8.0 mmol, 2.0 equiv)并搅拌2 h。TLC检测反应完全后，加入适量NaHSO 3水溶液还原过量的碘，随后用乙酸乙酯(3 x 30 mL)萃取，合并有机相并用饱和NaCl水溶液洗涤一次，无水Na 2SO 4干燥、过滤、减压蒸馏。粗产品在室温下无需纯化直接加入DCM (80 mL, 0.05 M)溶液，然后加入DDQ (2.72 g, 12 mmol, 3.0 equiv)。TLC检测反应完全后，先过滤除去固体残渣，滤液加入硅胶拌样。经快速柱层析（石油醚作为洗脱剂）纯化得到相应二碘苯衍生物 2n，收率为63%，黄色固体化合物。
实施例：胺类化合物与邻碘苯化合物的通用的反应步骤：将溶解在THF (2.0 mL) 溶液中的化合物 1 (0.6 mmol, 1.0 equiv)加入氢化钠 (60% in oil, 60 mg, 1.5 mmol, 2.5 equiv)中，室温下常规搅拌2min，然后加入溶解在THF (0.4 mL) 溶液中的化合物 2 (1.5 mmol, 2.5 equiv)，特定温度下反应1-15 h；然后将反应液加入水(5.0 mL)中，用乙酸乙酯(3×3.0 mL)萃取，合并有机层，用无水Na 2SO 4干燥，过滤，蒸干，快速柱层析纯化，得到产物邻碘苯基化合物 3，产率20-98%。
N-苄基苯甲酰胺1a与邻二碘苯2a在NaH作用下制备3a的反应参见图4，标准反应条件为将氢化钠 (60% in oil, 60 mg, 1.5 mmol, 2.5 equiv) 称量至反应瓶中，常规磁力搅拌下加入溶解在THF (2.0 mL) 溶液中的化合物 1a (127 mg, 0.6 mmol, 1 equiv)，室温下搅拌2 min；然后加入溶解在THF (0.4 mL) 溶液中的化合物 2a (496 mg, 196 µL, 1.5 mmol, 2.5 equiv)，室温反应1小时；再将反应液加入水(5.0 mL)中，用乙酸乙酯(3 x 3.0 mL)萃取，合并有机层，用无水Na 2SO 4干燥，过滤，蒸干，快速柱层析纯化，得到2-碘芳基化产物 3a，产率90%。单因素更换条件，取得不同产物收率，为分离收率。
在上述标准反应条件下进行底物拓展，参见图5、图6、图7、图8、图9。图5对芳香酰胺进行了底物拓展，无论是具有强吸电子基的三氟甲基、三氟甲氧基，给电子基的甲氧基，还是乙烯基、卤素等基团，都能得到非常高的产率( 3b-3aa)，芳杂环酰胺( 3ab-3ad)也能有不错的收率，图5中，从产物可确定芳香酰胺化合物的结构；NaH (1.5 mmol, 2.5 equiv) 、化合物 1 (0.6 mmol, 1.0 equiv) 溶于THF (2.0 mL) 、 2a (1.5 mmol, 2.5 equiv) 溶于THF (0.4 mL) ，室温反应（除了两个底物），其中： b 40 ℃反应， c 50 ℃反应；反应时间见图5。图6对脂肪族酰胺进行了拓展，无论是烯基、炔基还是烷基都能有中等产率的产物( 3ae-3an) ，图6中，从产物可确定脂肪族酰胺化合物的结构；NaH (1.5 mmol, 2.5 equiv) 、化合物 1 (0.6 mmol, 1.0 equiv) 溶于THF (2.0 mL) 、 2a (1.5 mmol, 2.5 equiv) 溶于THF (0.4 mL) ，室温反应（除了三个底物），其中： b 40 ℃反应；反应时间见图6。图7对伯胺被Boc或者Cbz保护后的一系列化合物进行拓展，无论是Boc还是Cbz保护下的伯胺反应情况差别不大，各种类型的脂肪胺都能有中等偏上的收率( 3ba1-3bz)；抗感染药物利奈唑胺在经过Boc保护后反应可以给出82%的收率( 3bw)，Boc保护的肼类化合物也能有30%的产率( 3baa) ，图7中，从产物可确定酰胺化合物1的结构；NaH (1.5 mmol, 2.5 equiv) 、化合物 1 (0.6 mmol, 1.0 equiv) 溶于THF (2.0 mL) 、 2a (1.5 mmol, 2.5 equiv) 溶于THF (0.4 mL) ，40℃反应（除了三个底物），其中： b 50 ℃反应， c 室温反应；反应时间见图7。图8对芳胺类型的底物进行了拓展，Boc或Cbz保护的单取代芳香胺( 3ca1-3cg)、多取代芳香胺( 3ch-3cl)、杂环类芳胺( 3cam-3cp)以及双反应位点的芳胺类化合物( 3cq-3cs)都能有非常高的产率，甚至吡啶酮类、哌啶胺类以及脲类化合物也都有不错的产率( 3ct-3cw)，图8中，从产物可确定芳胺化合物的结构；NaH (1.5 mmol, 2.5 equiv) 、化合物 1 (0.6 mmol, 1.0 equiv) 溶于THF (2.0 mL) 、 2a (1.5 mmol, 2.5 equiv) 溶于THF (0.4 mL) ，40℃反应（除了五个底物），其中： b 50 ℃反应， d 室温反应，有三个底物的原料用量变化， c 2a (5.0 equiv)、NaH (5.0 equiv)；反应时间见图8。图9对邻碘苯化合物进行了拓展，具有对称结构的二碘苯都能有不错的收率( 3da-3df)，无论邻位是甲基、甲氧基、苯基还是苯乙烯基都能有不错的产率，并且没有检测到异构体的产生，区域选择性优秀( 3dg-3dk) ，图9中，从产物可确定芳胺化合物以及邻碘苯化合物的结构；除了特别指出的条件变化外，按NaH (1.5 mmol, 2.5 equiv) 、化合物 1 (0.6 mmol, 1.0 equiv) 溶于THF (2.0 mL) 、 2a (1.5 mmol, 2.5 equiv) 溶于THF (0.4 mL) ，40℃反应；其中： b 2 (1.5 equiv), 45 ℃， c 60℃反应， d 50℃反应， e 室温反应， f 1H NMR， g X = Br；反应时间见图9。
放大实验。选取了几个典型的底物进行了1 g以及5 g规模的放大实验，参见图10，反应操作如上标准条件，反应过程在完全的可控范围内，并且反应后NaH残留很少或根本没有残留，这对后处理时的安全性是非常友好的；无论是1 g规模还是5 g规模，反应的产率上下浮动不超过5%。这说明本发明的反应具有优秀的工业应用前景，可以满足大规模制备的内在条件。
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拓展实验。将邻碘芳胺化合物 3ca1 (409 mg, 1.0 mmol, 2.0 equiv)和硫磺 8e (16 mg, 0.5 mmol, 1.0 equiv)用1,4二氧六环(1.5 mL, 0.33 M)溶液溶解于10 mL两口反应瓶中。随后，加入Cu(OAc) 2 (20 mg, 0.1 mmol, 20 mol%), KF (58.1 mg, 1.0 mmol, 2.0 equiv), Et 3N (0.3 mL)，在氮气保护下，反应混合物在110 ℃下搅拌12 h。将反应液用硅藻土过滤后加入乙酸乙酯(5.0 mL)稀释，加入水(10 mL)，用乙酸乙酯(3 x 5.0 mL)萃取，合并有机层，用无水Na 2SO 4干燥，过滤，蒸干，快速柱层析纯化，得到纯化合物 9j (60 mg)，产率38%。
本发明产物邻碘苯基化合物的核磁数据如下。
N-benzyl-N-(2-iodophenyl)benzamide (3a): 1H NMR (400 MHz, CDCl 3) δ 7.77 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.3 Hz, 2H), 7.28 (s, 5H), 7.20 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.83 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 5.82 (d, J = 14.2 Hz, 1H), 4.27 (d, J = 14.2 Hz, 1H). 13C NMR (101 MHz, CDCl 3) δ 170.46, 144.55, 140.15, 136.85, 135.95, 132.16, 129.75, 129.61, 129.17, 128.64, 128.46, 128.31, 127.68, 127.61, 100.06, 52.45. LR-MS (ESI): m/z 414.0 [M+H] +。
N-(2-iodophenyl)-N-methylbenzamide (3b): 1H NMR (400 MHz, CDCl 3) δ 7.79 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.3 Hz, 2H), 7.20 (t, J = 7.2 Hz, 2H), 7.15 (t, J = 7.2 Hz, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 3.38 (s, 3H). 13C NMR (101 MHz, CDCl 3) δ 170.79, 146.99, 140.16, 135.72, 130.19, 129.82, 129.37, 129.08, 128.36, 127.65, 99.10, 37.58. LR-MS (ESI): m/z 337.9 [M+H] +。
N-(2-iodophenyl)-N,4-dimethylbenzamide (3c): 1H NMR (400 MHz, CDCl 3) δ 7.80 (d, J = 7.4 Hz, 1H), 7.30 – 7.16 (m, 3H), 7.09 (d, J = 7.2 Hz, 1H), 6.98 – 6.85 (m, 3H), 3.36 (s, 3H), 2.23 (s, 3H). 13C NMR (101 MHz, CDCl 3) δ 170.75, 147.17, 140.08, 139.94, 132.72, 130.07, 129.36, 128.93, 128.49, 128.27, 99.09, 37.64, 21.35. LR-MS (ESI): m/z 352.0 [M+H] +。
N-(2-iodophenyl)-N-methyl-4-pentylbenzamide (3d) 1H NMR (400 MHz, CDCl 3) δ 7.80 (d, J = 7.2 Hz, 1H), 7.30 – 7.15 (m, 3H), 7.07 (d, J = 7.2 Hz, 1H), 6.99 – 6.85 (m, 3H), 3.36 (s, 3H), 2.48 (t, J = 8.8 Hz, 2H), 1.50 (m, 2H), 1.28 – 1.13 (m, 4H), 0.83 (t, J = 6.1 Hz, 3H). 13C NMR (101 MHz, CDCl 3) δ 170.84, 147.24, 144.92, 140.09, 132.91, 130.13, 129.33, 128.91, 128.47, 127.65, 99.09, 37.64, 35.64, 31.31, 30.61, 22.45, 14.01. LR-MS (ESI): m/z 408.1 [M+H] +。
4-( Tert-butyl)-N-(2-iodophenyl)-N-methylbenzamide (3e): 1H NMR (400 MHz, CDCl 3) δ 7.82 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.24 – 7.13 (m, 3H), 7.08 (d, J = 7.7 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 3.36 (s, 3H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl 3) δ 170.76, 153.14, 147.32, 140.16, 132.63, 130.16, 129.43, 128.99, 128.38, 124.61, 99.12, 37.78, 34.73, 31.13. LR-MS (ESI): m/z 394.0 [M+H] +。
N-(2-iodophenyl)-N-methyl-4-vinylbenzamide (3f): 1H NMR (400 MHz, CDCl 3) δ 7.79 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.18 (m, 3H), 7.10 (d, J = 7.5 Hz, 1H), 6.89 (t, J = 7.9 Hz, 1H), 6.58 (m, 1H), 5.68 (d, J = 17.7 Hz, 1H), 5.22 (d, J = 10.8 Hz, 1H), 3.36 (s, 3H). 13C NMR (101 MHz, CDCl 3) δ 170.49, 147.06, 140.24, 138.90, 136.14, 134.92, 130.14, 129.49, 129.13, 128.85, 125.49, 115.28, 99.12, 77.42, 77.10, 76.78, 37.71. LR-MS (ESI): m/z 364.0 [M+H] +。
Tert-butyl benzyl(2-iodophenyl)carbamate (3ba1): 1H NMR (400 MHz, CDCl 3) δ 7.87 (minor)/ 7.84 (major) (br d, J = 7.6 Hz 1H), 7.34–7.12 (br m, 6 H), 6.99–6.71 (br m, 2 H), 5.27 (major)/5.16 (minor) (br d, J = 14.8 Hz), 4.14 (minor)/4.10 (major) (br d, J = 14.8 Hz), 1.55 (minor)/1.37 (major) (br s, 9 H). 13C NMR (101 MHz, CDCl 3) δ 154.37, 154.24 (minor), 144.25 (minor), 144.19, 139.84 (minor), 139.43, 138.07 (minor), 137.80, 130.67 (minor), 130.31, 129.14, 129.05 (minor), 128.70, 128.59, 128.41, 127.46, 100.33, 81.16 (minor), 80.43, 54.08 (minor), 52.72, 28.57 (minor), 28.34. LR-MS (ESI): m/z 432.0 [M+Na] +。
Benzyl benzyl(2-iodophenyl)carbamate (3ba2): 1H NMR (400 MHz, CDCl 3) δ 7.88 (minor)/ 7.86 (major) (br d, J = 8.0 Hz 1H), 7.42–7.12 (br m, 11 H), 6.99–6.85 (br m, 1 H), 6.76 (br d, J = 7.8 Hz, 1H), 5.33 (br d, J = 14.7 Hz, 1H), 5.28 – 5.07 (br m, 2H), 4.25–4.10 (br m, 1H). 13C NMR (101 MHz, CDCl 3) δ 155.26, 143.31, 139.88 (minor), 139.61, 137.16 (minor), 137.08, 136.48, 136.40 (minor), 130.58 (minor), 130.32, 129.34 (minor), 129.19, 129.04 (minor), 128.88 (minor), 128.77, 128.60 (minor), 128.52 (minor), 128.43, 128.27, 127.73, 127.66, 127.60 (minor), 127.46, 100.13, 99.80 (minor), 67.83 (minor), 67.48, 53.82 (minor), 53.54. LR-MS (ESI): m/z 444.0 [M+H] +。
Tert-butyl (furan-2-ylmethyl)(2-iodophenyl)carbamate (3bb1): 1H NMR (400 MHz, CDCl 3) δ 7.87 (minor)/ 7.84 (major) (br d, J = 7.6 Hz 1H), 7.35 (br s, 1H), 7.31–7.19 (br m, 1H), 7.11–6.85 (br m, 2H), 6.30 (minor)/ 6.26 (major) (br s, 1H), 6.13 (br s, 1H),5.12 (major)/5.02 (minor) (br d, J = 15.6 Hz), 4.26 (major)/4.22 (minor) (br d, J = 16.0 Hz), 1.55 (minor)/1.36 (major) (br s, 9 H). 13C NMR (101 MHz, CDCl 3) δ 153.93, 151.39 (major), 150.98, 144.36 (major), 143.91, 142.20, 142.08 (major), 139.59 (major), 139.25, 130.47 (major), 129.98, 129.18 (major), 128.84, 128.77, 110.35, 109.12, 108.49 (major), 100.31, 81.16 (major), 80.59, 46.68 (major), 45.13, 28.51 (major), 28.30. LR-MS (ESI): m/z 422.0 [M+Na] +。
Benzyl (furan-2-ylmethyl)(2-iodophenyl)carbamate (3bb2): 1H NMR (400 MHz, CDCl 3) δ 7.88 (minor)/ 7.85 (major) (br d, J = 8.0 Hz 1H), 7.48 – 7.32 (br m, 2H), 7.32 – 7.14 (br m, 5H), 7.06 – 6.89 (br m, 2H), 6.28 – 6.24 (br m, 1H), 6.15 (major)/ 6.05 (minor) (br d, J = 2.8 Hz 1H), 5.34 – 5.07 (br m, 3H), 4.34 – 4.25 (br m, 1H). 13C NMR (101 MHz, CDCl 3) δ 154.94, 154.74 (minor), 150.58 (minor), 150.39, 143.76 (minor), 143.13, 142.44, 142.32 (minor), 139.71 (minor), 139.48, 136.45, 130.39 (minor), 130.05, 129.53 (minor), 129.38, 129.25 (minor), 129.01, 128.53 (minor), 128.30, 128.17 (minor), 127.77, 127.54, 110.42, 109.50, 109.03 (minor), 100.15, 99.88 (minor), 67.87 (minor), 67.57, 46.44 (minor), 45.97. LR-MS (ESI): m/z 434.0 [M+H] +。
Tert-butyl (4-fluorobenzyl)(2-iodophenyl)carbamate (3bc): 1H NMR (400 MHz, CDCl 3) δ 7.89 (minor)/ 7.85 (major) (br d, J = 7.6 Hz 1H), 7.24 – 7.14 (br m, 3H), 7.02 – 6.88 (br m, 3H), 6.73 (br d, J = 7.7 Hz, 1H), 5.17 (major)/ 5.09 (minor) (br d, J = 14.8 Hz 1H), 4.13 (br d, J = 14.8 Hz 1H), 1.55 (minor)/1.37 (major) (br s, 9 H). 13C NMR (101 MHz, CDCl 3) δ 163.50, 161.06, 154.28, 143.99, 139.88 (minor), 139.50, 133.57 (minor), 130.87 (d, J = 7.9 Hz, 130.91, 130.83), 130.57, 130.19, 129.07 (minor), 128.72 (d, J = 12.2 Hz, 128.78, 128.66), 115.22 (d, J = 21.3 Hz, 115.33, 115.12), 100.32, 81.25 (minor), 80.53, 53.31 (minor), 51.98, 28.55 (minor), 28.30. 19F NMR (377 MHz, CDCl 3) δ -114.9, -115.0. LR-MS (ESI): m/z 450.0 [M+Na] +。
Tert-butyl (4-chlorobenzyl)(2-iodophenyl)carbamate (3bd): 1H NMR (400 MHz, CDCl 3) δ 7.89 (minor)/ 7.85 (major) (br d, J = 7.6 Hz 1H),  7.30 – 7.14 (br m, 5H), 6.94 (br t, J = 7.3 Hz, 1H), 6.74 (br d, J = 7.6 Hz, 1H), 5.18 (major)/ 5.09 (minor) (br d, J = 14.8 Hz 1H), 4.13 (br d, J = 14.8 Hz 1H), 1.54 (minor)/1.36 (major) (br s, 9 H). 13C NMR (101 MHz, CDCl 3) δ 154.28, 153.99 (minor), 144.38 (minor), 144.00, 139.89 (minor), 139.52, 136.45 (minor), 136.29, 133.32, 130.53, 130.13, 129.83 (minor), 129.10 (minor), 128.83, 128.70, 128.56, 100.24, 81.32 (minor), 80.60, 53.41 (minor), 52.10, 28.53 (minor), 28.28. LR-MS (ESI): m/z 466.0 [M+Na] +。
Tert-butyl (4-bromobenzyl)(2-iodophenyl)carbamate (3be): 1H NMR (400 MHz, CDCl 3) δ 7.88 (minor)/ 7.84 (major) (br d, J = 7.6 Hz 1H), 7.46 – 7.30 (br m, 2H), 7.24 – 7.07 (br m, 3H), 6.94 (br t, J = 6.3 Hz, 1H), 6.75 (br d, J = 7.1 Hz, 1H), 5.17 (major)/ 5.08 (minor) (br d, J = 14.8 Hz 1H), 4.08 (br d, J = 14.8 Hz 1H), 1.54 (minor)/1.36 (major) (br s, 9 H). 13C NMR (101 MHz, CDCl 3) δ 154.24, 153.93 (minor), 144.10 (minor), 143.95, 139.87 (minor), 139.50, 136.95 (minor), 136.77, 131.49, 130.84, 130.49 (minor), 130.09, 129.11 (minor), 128.82, 128.70, 121.45, 100.21, 81.28 (minor), 80.58, 53.41 (minor), 52.13, 28.52 (minor), 28.26. LR-MS (ESI): m/z 509.9 [M+Na] +。
Tert-butyl (2-iodophenyl)(4-(trifluoromethyl)benzyl)carbamate (3bf): 1H NMR (400 MHz, CDCl 3) δ 7.90 (minor)/ 7.86 (major) (br d, J = 7.7 Hz 1H), 7.55 (br d, J = 7.7 Hz, 2H), 7.38 (br d, J = 8.0 Hz, 2H), 7.19 (br t, J = 7.6 Hz, 1H), 6.96 (br t, J = 7.3 Hz, 1H), 6.78 (br d, J = 7.6 Hz, 1H), 5.27 (major)/ 5.18 (minor) (br d, J = 14.8 Hz 1H), 4.23 (minor)/ 4.18 (major) (br d, J = 14.8 Hz 1H), 1.54 (minor)/1.37 (major) (br s, 9 H). 13C NMR (101 MHz, CDCl 3) δ 154.37, 153.97 (minor), 144.51 (minor), 144.13, 142.10 (minor), 141.87, 140.02 (minor), 139.66, 130.41 (minor), 130.25 (minor), 130.03, 129.93 (minor), 129.61 (minor), 129.28, 128.97, 128.83, 128.57 (minor), 128.35 (minor), 125.70, 125.42 (q, J = 3.7 Hz, 125.47, 125.43, 125.40, 125.36), 124.24 (q, J = 273.5 Hz, 128.30, 125.60, 122.89, 120.19), 100.15, 81.53 (minor), 80.83, 53.80 (minor), 52.51, 28.50 (minor), 28.29. 19F NMR (377 MHz, CDCl 3) δ -62.4. LR-MS (ESI): m/z 500.0 [M+Na] +。
Tert-butyl (2-iodophenyl) (4-methoxybenzyl)carbamate (3bg): 1H NMR (400 MHz, CDCl 3) δ 7.88 (minor)/ 7.84 (major) (br d, J = 7.2 Hz 1H), 7.23 – 7.10 (br m, 3H), 6.98 – 6.86 (br m, 1H), 6.80 (br d, J = 8.2 Hz, 2H), 6.72 (br d, J = 7.6 Hz, 1H), 5.19 (major)/ 5.10 (minor) (br d, J = 14.8 Hz 1H), 4.06 (br d, J = 14.8 Hz 1H), 3.79 (br s, 3H), 1.57 (minor)/1.36 (major) (br s, 9H). 13C NMR (101 MHz, CDCl 3) δ 159.00, 154.27, 144.44 (minor), 144.10, 139.75 (minor), 139.35, 130.77 (minor), 130.47, 130.38, 130.07 (minor), 129.94, 129.88 (minor), 128.97 (minor), 128.62, 128.53, 113.71, 100.40, 81.03 (minor), 80.28, 55.26, 53.34 (minor), 52.01, 28.60 (minor), 28.32. LR-MS (ESI): m/z 462.0 [M+Na] +。
Tert-butyl ([1,1'-biphenyl]-4-ylmethyl) (2-iodophenyl)carbamate (3bh): 1H NMR (400 MHz, CDCl 3) δ 7.89 (minor)/ 7.86 (major) (br d, J = 8.0 Hz 1H), 7.59 (br d, J = 7.5 Hz, 2H), 7.52 (br d, J = 7.8 Hz, 2H), 7.43 (br t, J = 7.5 Hz, 2H), 7.37 – 7.29 (br m, 3H), 7.23 – 7.13 (br m, 1H), 7.02 – 6.90 (br m, 1H), 6.81 (br d, J = 7.6 Hz, 1H), 5.30 (major)/ 5.20 (minor) (br d, J = 14.8 Hz 1H), 4.18 (minor)/ 4.14 (major) (br d, J = 14.8 Hz 1H), 1.57 (minor)/1.38 (major) (br s, 9H). 13C NMR (101 MHz, CDCl 3) δ 154.36, 154.23 (minor), 144.60 (minor), 144.25, 140.85, 140.27, 139.84 (minor), 139.45, 137.06 (minor), 136.86, 130.66 (minor), 130.32, 129.51, 129.07 (minor), 128.81, 128.74, 128.64, 127.31, 127.09, 127.07, 100.32, 81.17 (minor), 80.46, 53.77 (minor), 52.45, 28.58 (minor), 28.34. LR-MS (ESI): m/z 508.0 [M+Na] +。
Tert-butyl (4-(tert-butyl)benzyl)(2-iodophenyl)carbamate (3bi): 1H NMR (400 MHz, CDCl 3) δ 7.85 (br d, J = 7.4 Hz 1H), 7.30 (br d, J = 6.9 Hz, 2H), 7.23 – 7.11 (br m, 3H), 7.01 – 6.88 (br m, 1H), 6.79 (br d, J = 6.9 Hz, 1H), 5.24 (major)/ 5.14 (minor) (br d, J = 14.8 Hz 1H), 4.05 (br d, J = 14.8 Hz 1H), 1.56 (minor)/1.37 (major) (br s, 9H), 1.31 (br s, 9H). 13C NMR (101 MHz, CDCl 3) δ 154.32, 150.42 (minor), 150.30, 144.71 (minor), 144.40, 139.79 (minor), 139.37, 134.98 (minor), 134.78, 130.73 (minor), 130.37, 129.00 (minor), 128.70, 128.64, 128.57, 128.34 (minor), 128.19, 125.28, 100.36, 81.05 (minor), 80.29, 53.69 (minor), 52.40, 34.55 (minor), 31.45, 28.58 (minor), 28.35. LR-MS (ESI): m/z 488.1 [M+Na] +。
Tert-butyl (2-chlorobenzyl)(2-iodophenyl)carbamate (3bj): 1H NMR (400 MHz, CDCl 3) δ 7.87 (minor)/ 7.83 (major) (br d, J = 8.0 Hz 1H), 7.46 – 7.35 (br m, 1H), 7.35 – 7.26 (br m, 1H), 7.24 – 7.10 (br m, 3H), 7.01 – 6.88 (br m, 1H), 6.83 (br d, J = 7.6 Hz, 1H), 5.27 (major)/ 5.22 (minor) (br d, J = 15.2 Hz 1H), 4.50 (major)/ 4.46 (minor) (br d, J = 15.2 Hz 1H), 1.53 (minor)/1.38 (major) (br s, 9H). 13C NMR (101 MHz, CDCl 3) δ 154.24, 154.18 (minor), 143.94, 139.84 (minor), 139.40, 135.11, 134.16, 131.00, 130.33 (minor), 129.97, 129.57 (minor), 129.49, 129.46, 128.78, 128.65, 126.87, 126.73 (minor), 100.20, 80.62, 80.48 (minor), 51.25 (minor), 49.77, 28.47 (minor), 28.32. LR-MS (ESI): m/z 466.0 [M+Na] +。
Tert-butyl (2-iodophenyl)(2,4,6-trimethylbenzyl)carbamate (3bk): 1H NMR (400 MHz, CDCl 3) δ 7.82 (minor)/ 7.79 (major) (br d, J = 7.6 Hz 1H), 6.99 (br t, J = 7.1 Hz, 1H), 6.87 (br t, J = 7.2 Hz, 1H), 6.71 (br s, 2H), 6.29 (br d, J = 7.6 Hz, 1H), 5.24 (major)/ 5.12 (minor) (br d, J = 14.4 Hz 1H), 4.47 (minor)/4.42 (major) (br d, J = 14.4 Hz 1H), 2.21 (minor)/2.02 (major) (br s, 9H), 1.60 (minor)/1.36 (major) (br s, 9H). 13C NMR (101 MHz, CDCl 3) δ 153.99 (minor), 153.85, 142.60, 139.33 (minor), 138.94, 138.42, 138.20 (minor), 137.06, 130.96, 130.20, 128.93, 128.63, 128.26, 100.72, 80.93 (minor), 80.05, 45.87 (minor), 44.39, 28.59 (minor), 28.31, 20.98, 19.63. LR-MS (ESI): m/z 474.0 [M+Na] +。
Tert-butyl (2-iodophenyl)(naphthalen-1-ylmethyl)carbamate (3bl): 1H NMR (400 MHz, CDCl 3) δ 8.26 (major)/ 8.12 (minor) (br d, J = 7.6 Hz 1H), 7.89 – 7.71 (br m, 3H), 7.57 – 7.45 (br m, 2H), 7.36 – 7.18 (br m, 1H), 7.12 – 6.75 (m, 3H), 6.60 (minor)/6.32 (major) (br d, J = 7.2 Hz, 1H), 5.78 (major)/ 5.67 (minor) (br d, J = 14.8 Hz 1H), 4.72 (minor)/4.68 (major) (br d, J = 14.8 Hz 1H), 1.62 (minor)/1.39 (major) (br s, 9H). 13C NMR (101 MHz, CDCl 3) δ 154.09, 143.69 (minor), 143.20, 139.70 (minor), 139.25, 133.80, 133.06, 132.24, 130.87 (minor), 130.54, 129.03 (minor), 128.76 (minor), 128.63, 128.60, 128.51, 128.47, 128.29, 127.33 (minor), 126.41, 126.16 (minor), 125.78, 125.06, 124.50, 123.76 (minor), 100.16 (minor), 99.97, 81.37 (minor), 80.47, 51.20 (minor), 49.82, 28.63 (minor), 28.33. LR-MS (ESI): m/z 482.0 [M+Na] +。
Benzyl (2,2-diethoxyethyl)(2-iodophenyl)carbamate (3bz): 1H NMR (400 MHz, CDCl 3) δ 7.91 – 7.82 (m, 1H), 7.46 – 7.14 (m, 7H), 6.99 (ddd, J = 8.9, 6.5, 2.6 Hz, 1H), 5.32 – 5.03 (m, 2H), 4.87 – 4.65 (m, 1H), 4.16 – 4.00 (m, 1H), 3.73 – 3.38 (m, 4H), 3.33 – 3.16 (m, 1H), 1.21 – 1.09 (m, 6H). 13C NMR (101 MHz, CDCl 3) δ 155.10, 154.94 (minor), 144.62 (minor), 144.29, 139.58 (minor), 139.29, 136.42, 136.36 (minor), 130.89 (minor), 130.56, 129.22 (minor), 129.05, 128.99 (minor), 128.80, 128.49 (minor), 128.42 (minor), 128.24, 128.18 (minor), 127.70, 127.44 (minor), 127.38, 126.55 (minor), 100.80 – 99.29 (m, 100.60, 100.05, 99.82, 99.48), 67.75 (minor), 67.36, 62.27, 61.83, 52.07 (minor), 51.97, 15.26 (d, J = 9.6 Hz, 15.31, 15.21), 15.21 (d, J = 8.3 Hz, 15.25, 15.17) (minor). LR-MS (ESI): m/z 492.0 [M+Na] +。
Tert-butyl (2-iodophenyl)(p-tolyl)carbamate (3ca1): 1H NMR (400 MHz, CDCl 3) δ 7.89 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.26 (d, J = 6.7 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 2.29 (s, 3H), 1.45 (s, 9H). 13C NMR (101 MHz, CDCl 3) δ 152.84, 145.16, 139.80, 139.26, 134.71, 130.09, 129.27, 129.12, 128.65, 124.98, 100.68, 81.30, 77.42, 77.10, 76.78, 28.29, 20.92. LR-MS (ESI): m/z 432.0 [M+Na] +。
Benzyl (2-iodophenyl)(p-tolyl)carbamate (3ca2): 1H NMR (400 MHz, CDCl 3) δ 7.90 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 – 7.20 (m, 9H), 7.12 – 7.07 (m, 2H), 7.00 (td, J = 8.0, 1.6 Hz, 1H), 5.22 (d, J = 4.3 Hz, 2H), 2.30 (s, 3H). 13C NMR (101 MHz, CDCl 3) δ 153.86, 144.50, 139.95, 138.88, 136.16, 135.31, 130.01, 129.37, 129.27, 129.01, 128.31, 127.88, 127.81, 124.97, 100.33, 67.72, 20.90. LR-MS (ESI): m/z 444.0 [M+H] +。
Tert-butyl (4-fluorophenyl)(2-iodophenyl)carbamate (3cb): 1H NMR (400 MHz, CDCl 3) δ 7.90 (dd, J = 7.9, 1.4 Hz, 1H), 7.36 (td, J = 7.7, 1.4 Hz, 1H), 7.33 – 7.28 (m, 2H), 7.27 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.03 – 6.93 (m, 3H), 1.45 (s, 9H). 13C NMR (101 MHz, CDCl 3) δ 160.00 (d, J = 244.9 Hz, 161.22, 158.78), 152.82, 144.88, 139.98, 137.76, 130.09, 129.40, 128.93, 126.86, 115.28 (d, J = 22.5 Hz, 115.40, 115.17), 100.51, 81.68, 28.26. 19F NMR (377 MHz, CDCl 3) δ -117.3. LR-MS (ESI): m/z 436.0 [M+Na] +。
Tert-butyl (2-iodophenyl)(4-iodophenyl)carbamate (3cc): 1H NMR (400 MHz, CDCl 3) δ 7.90 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.1 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.12 – 6.95 (m, 3H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl 3) δ 152.38, 144.38, 141.53, 139.98, 137.49, 130.15, 129.46, 129.10, 126.41, 100.60, 88.88, 81.92, 28.23. LR-MS (ESI): m/z 543.9 [M+Na] +。
Tert-butyl (2-iodophenyl)(4-nitrophenyl)carbamate (3cd): 1H NMR (400 MHz, CDCl 3) δ 8.12 (d, J = 8.7 Hz, 2H), 7.95 (d, J = 7.8 Hz, 1H), 7.48 – 7.35 (m, 3H), 7.27 (d, J = 7.3 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl 3) δ 151.99, 147.29, 143.47, 143.40, 140.26, 130.15, 129.84, 129.78, 124.26, 122.75, 100.37, 82.93, 28.09. LR-MS (ESI): m/z 463.0 [M+Na] +。
Tert-butyl (2-bromophenyl)(2-iodophenyl)carbamate (3cf): 1H NMR (400 MHz, CDCl 3) δ 7.90 (d, J = 5.0 Hz, 1H), 7.64 (t, J = 6.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 – 7.18 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 1.48 (s, 9H). 13C NMR (101 MHz, CDCl 3) δ 151.79 / 151.77, 145.55 / 145.41, 142.21 / 141.98, 140.05 / 139.79, 133.70 / 133.35, 129.80, 129.45 / 129.34, 129.15, 128.75, 128.62 / 128.53, 128.45 / 128.40, 123.43 / 123.22, 99.98 / 99.84, 81.70 / 81.65, 28.26. LR-MS (ESI): m/z 495.9 [M+Na] +。
Tert-butyl (2-(tert-butyl)phenyl)(2-iodophenyl)carbamate (3cg): 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 6.7 Hz, 1H), 7.32 – 7.06 (m, 4H), 7.04 – 6.75 (m, 2H), 1.54 – 1.38 (m, 18H). 13C NMR (101 MHz, CDCl 3) δ 153.77, 146.94, 146.16, 141.12, 140.69, 132.10, 129.21, 128.78 (minor), 128.42, 127.69, 126.80, 126.62, 126.54, 126.39 (minor), 98.08, 81.92 (minor), 81.30, 36.51 (minor), 35.93, 32.01 (minor), 31.70, 28.40. LR-MS (ESI): m/z 474.1 [M+Na] +。
本发明的反应无需金属催化剂，邻二碘苯有市售，价格便宜、化学性质稳定；反应条件温和，既不需要低温也不需要高温，所用试剂廉价易得，是非常实用的C-N偶联芳基化的新方法。因此，发展这样一种无金属催化的酰胺以及Boc (Cbz)保护的胺类化合物的C-N偶联芳基化反应意义非常重大。

Claims (10)

  1. 一种邻碘苯基化合物的制备方法，其特征在于，以碘苯化合物、酰胺化合物为原料，在氢化钠、氢化钾或者正丁基锂，溶剂存在下，反应得到邻碘苯基化合物。
  2. 根据权利要求1所述邻碘苯基化合物的制备方法，其特征在于，氢化钠存在下，反应的温度为室温～50℃。
  3. 根据权利要求1所述邻碘苯基化合物的制备方法，其特征在于，正丁基锂存在下，反应的温度为-80℃～-70℃。
  4. 根据权利要求1所述邻碘苯基化合物的制备方法，其特征在于，溶剂为四氢呋喃、二甲基乙酰胺、1,4-二氧六环、乙二醇二甲醚中的一种或几种。
  5. 根据权利要求1所述邻碘苯基化合物的制备方法，其特征在于，碘苯化合物、酰胺化合物、氢化钠或者氢化钾的摩尔比为（2～3）∶1∶（2～3）；碘苯化合物、酰胺化合物、正丁基锂的摩尔比为（2～3）∶1∶（1.5～2.5）。
  6. 根据权利要求1所述邻碘苯基化合物的制备方法，其特征在于，碘苯化合物为如下化学结构：
    酰胺化合物为如下化学结构：
    邻碘苯基化合物为如下化学结构：
    其中，G 1、G 2独立的选择烷基或者芳基、杂环基，R为氢、烷基或者芳基、杂环基，X为碘、溴、氯或者三氟甲磺酸基。
  7. 根据权利要求6所述邻碘苯基化合物的制备方法，其特征在于，芳基含有一个或者多个苯环，含有或者不含有取代基；烷基为直连烷基或者环烷基、支链烷基。
  8. 根据权利要求1所述邻碘苯基化合物的制备方法，其特征在于，反应的时间为1～15小时。
  9. 根据权利要求1所述邻碘苯基化合物的制备方法制备的邻碘苯基化合物。
  10. 氢化钠在以碘苯化合物、酰胺化合物为原料制备邻碘苯基化合物中的应用。
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