A transition metal catalyzed method for the preparation of o-iodophenyl acetylenides

Abstract

The application discloses a transition metal-free method for preparing o-iodophenyl acetylide, which uses o-dihalobenzene and terminal alkyne as raw materials, and reacts to obtain o-iodophenyl acetylide in the presence of alkali metal hydride; preferably, the reaction is carried out in a solvent. Specifically, the alkali metal hydride is added into the solvent, then the terminal alkyne compound is added, stirred for 5 min, and then the o-dihalobenzene is added, and the reaction is carried out at 0-60 DEG C to obtain the alkylation product o-iodophenyl acetylide. The method is simple in operation, mild in reaction condition, and can be easily scaled up, and does not need any metal additive or anhydrous condition.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing o-iodophenylacetylenide via a transition metal-free Sonogashira reaction. Background Technology

[0002] The coupling of aryl or vinyl halides with terminal alkynes catalyzed by palladium and copper or other transition metals, commonly known as the Sonogashira cross-coupling reaction, is one of the most important and widely used C(sp2)-C(sp) bond formation reactions in organic synthesis. It is frequently used in the synthesis of natural products, bioactive molecules, heterocyclic compounds, dendritic polymers, conjugated polymers, or nanostructures. Currently, commonly used synthetic methods include: 1. Using aryl or vinyl halides and terminal alkynes as starting materials, coupling is catalyzed by transition metals such as palladium and copper to obtain the corresponding C(sp2)-C(sp) coupled products. However, this method suffers from problems such as high metal costs, complex preparation processes for some ligands, and environmental pollution. 2. Without transition metal catalysis, using Cs2CO3 / Et3N as a base, PPh3 is used to catalyze the Sonogashira coupling of heterocyclic aryl halides with terminal alkynes to obtain the corresponding products. However, this method often requires high reaction temperatures or microwave assistance to achieve good reaction results, limiting its further large-scale application. Summary of the Invention

[0003] This invention discloses a novel method for generating alkynylated products similar to the Sonogashira coupling reaction from ortho-dihalobenzenes and terminal alkynes under the action of alkali metal hydrides, activated by a 60% NaH dispersion in commercially available mineral oil. The method of this invention is carried out under simple and mild reaction conditions and can be easily scaled up without the need for any metal additives or strictly anhydrous conditions.

[0004] The technical solution adopted in this invention is as follows:

[0005] A method for preparing o-iodophenylacetylenide without transition metal catalysis involves reacting o-dihalobenzene and terminal alkyne as raw materials in the presence of alkali metal hydrides to obtain o-iodophenylacetylenide.

[0006] In this invention, the alkali metal hydride is one or more of NaH, KH, CaH2, and LiH, preferably NaH and KH, and more preferably NaH.

[0007] In this invention, the reaction is carried out in a solvent, which is one or more of THF, DMA, DMF, 1,4-dioxane, toluene, and DME, preferably THF, DMF, and DMA, and more preferably THF.

[0008] In this invention, the reaction temperature is 0 ℃~60 ℃, preferably 10 ℃~40 ℃, and most preferably room temperature.

[0009] In this invention, the molar ratio of terminal alkyne, ortho-dihalobenzene, and alkali metal hydride is 1:(1-3):(1-4), preferably 1:(2-2.5):(3-4), for example 1:2.5:3.

[0010] In this invention, the terminal alkyne is an alkane with an alkynyl group at the end; or the chemical structural formula of the terminal alkyne is as follows:

[0011] .

[0012] Ar represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted aromatic heterocycle. R represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted aromatic heterocycle. 1 It is selected from one of alkyl, halogen, alkoxy, and aryl; alkyl is methyl, ethyl, tert-butyl, etc.; halogen is fluorine, chlorine, bromine, etc.; alkoxy is methoxy, ethoxy, etc.; aryl is phenyl, benzyl, etc.

[0013] In this invention, the chemical structural formula of the ortho-dihalobenzene is as follows:

[0014] .

[0015] R 2 The component is selected from alkyl and alkoxy groups, preferably, the alkyl group has 1 to 10 carbon atoms and the alkoxy group has 1 to 10 carbon atoms; X is selected from chlorine, bromine, iodine and OTf; preferably X is iodine.

[0016] The chemical structural formula of the product, an o-iodophenylacetylene compound, is as follows:

[0017] Among them, Ar and R 1 Derived from terminal alkynes; R 2 Derived from ortho-dihalobenzene.

[0018] As one possible implementation, the reaction can be represented as follows:

[0019]

[0020] Preferably, the added alkali metal compound is NaH, the solvent is THF, the reaction temperature is room temperature, and the reaction time is 12–18 h.

[0021] This invention develops a novel method using o-dihalobenzenes and aryl-terminated alkynes as raw materials. Under the action of NaH, the highly reactive and nucleophilic properties of NaH facilitate C-C bond coupling, yielding the alkynylated product from the coupling reaction at room temperature. This method requires no addition of transition metals or ligands, exhibits mild reaction conditions, and produces a product that is easily further transformed, thus possessing significant application value.

[0022] The beneficial effects of the method for preparing o-iodophenylacetylene products provided by this invention are as follows:

[0023] 1) No transition metal catalysis, low cost, simple operation, less pollution, and environmentally friendly.

[0024] 2) The reaction conditions are mild and the safety factor is high.

[0025] 3) The aromatic ring in the product is substituted with iodine at the ortho position, which allows for a wide range of functional group transformations. Detailed Implementation

[0026] To better understand the technical content of this invention, the following embodiments are provided for detailed explanation.

[0027] The present invention provides a method for obtaining alkynylated products by a Sonogashira-like coupling reaction. Using o-dihalobenzene and terminal alkyne as raw materials, a Sonogashira-like coupling reaction occurs in the presence of an alkali metal hydride to obtain the alkynylated product. Specifically, the alkali metal hydride is added to a solvent, followed by the addition of a terminal alkyne compound. The mixture is stirred for 1–10 min, then o-dihalobenzene is added dropwise. After the addition is complete, the mixture is stirred at 0–60 °C, preferably room temperature, for 5–30 h, preferably 12–18 h, to obtain the o-iodophenyl acetylated product.

[0028] The preparation method provided by this invention involves reacting an aryl-terminated alkyne with o-diiodobenzene in the presence of NaH, thereby achieving C / C bond coupling through this novel benzyne generation mechanism, yielding an alkyne-modified product similar to the Sonogashira coupling reaction. This method is free of transition metals and ligands, uses mild reaction conditions, and utilizes inexpensive and readily available raw materials. The synthetic steps are simple, providing a new route for constructing C(sp2)-C(sp) bonds, and possesses significant application prospects and value, especially for the synthesis of complex drug molecules and material molecules, making it an excellent choice.

[0029] The raw materials involved in the various embodiments of this invention are either commercially available products or can be prepared using existing methods. The specific preparation operations and characterization tests of this invention are conventional techniques.

[0030] Example 1 Preparation of o-iodophenyl ynylated products

[0031] At room temperature, NaH (60 wt% in oil, 1.8 mmol, 3.0 equiv) was weighed into a round-bottom flask, and 2 mL of anhydrous THF was added and stirred to form a suspension. The substrate aryl-terminated alkyne 4 (0.6 mmol, 1.0 equiv) was dissolved in anhydrous THF (2.0 mL) and added dropwise to the above suspension under N2 protection, completing the addition in 1 minute. The mixture was stirred for 5 min, and then o-diiodobenzene 2 (1.5 mmol, 2.5 equiv) was added dropwise, completing the addition in 1 minute. The reaction was then stirred at room temperature. After the reaction was completed, the reaction solution was cooled to room temperature, added to water (10 mL), and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The product 5, an o-iodophenyl ethynylated product, was then purified by rapid column chromatography.

[0032] The different reaction substrates (terminal alkyne 4 and o-diiodobenzene 2) and the corresponding o-iodoaryl alkyne products 5 are shown below:

[0033]

[0034] The above yields are separation yields, and the recorded times are reaction times, which are 12 to 17 hours.

[0035] The above product data are characterized as follows:

[0036] 1-iodo-2-(phenylethynyl)benzene (5a). Yellow oil, yield 96%. 1 H NMR(400 MHz, CDCl3) δ 7.88 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 3.7 Hz, 2H), 7.54(d, J = 7.5 Hz, 1H), 7.42 – 7.30 (m, 4H), 7.02 (t, J = 7.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 138.81, 132.47, 131.70, 129.84, 129.42, 128.72, 128.45,127.89, 123.00, 101.26, 93.14, 91.71. LR-MS (ESI): m / z 304.9 [M+H]+.

[0037] 1-((4-fluorophenyl)ethynyl)-2-iodobenzene (5b). Yellow solid, yield83%. Mp. 39 – 41 °C, 1 H NMR (400 MHz, CD Cl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.59(dd, J = 10.8, 3.4 Hz, 2H), 7.53 (dd, J = 7.7, 1.3 Hz, 1H), 7.33 (td, J =7.6, 1.1 Hz, 1H), 7.07 (t, J = 8.7 Hz, 2H), 7.02 (td, J = 7.8, 1.6 Hz, 1H). 13 CNMR (101 MHz, CD Cl3) δ 162.78 (d, J = 250.4 Hz), 138.79, 133.59 (d, J = 8.0Hz), 132.39, 129.63, 129.48, 127.90, 119.08, 115.77 (d, J = 22.2 Hz), 101.17,92.03, 91.41. 19 F NMR (377 MHz, CDCl3) δ -110.16 (d, J = 3.7 Hz). LR-MS (ESI):m / z 322.9 [M+H]+.

[0038] 1-((4-chlorophenyl)ethynyl)-2-iodobenzene (5c). White solid, yield88%. Mp. 88 – 93 °C, 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.9 Hz, 1H), 7.53(d, J = 8.0 Hz, 3H), 7.34 (t, J = 7.4 Hz, 3H), 7.03 (t, J = 7.6 Hz, 1H). 13 CNMR (101 MHz, CDCl3) δ 138.85, 134.78, 132.88, 132.49, 129.64, 129.52,128.83, 127.93, 121.49, 101.20, 92.61, 91.94. LR-MS (ESI): m / z 339.9 [M+H]+.

[0039] chloro-2-((2-iodophenyl)ethynyl)benzene (5d). Yellow solid, yield89%. Mp. 42 – 44 °C, 1 H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 8.0, 1.0 Hz, 1H),7.67 – 7.61 (m, 1H), 7.57 (dd, J = 7.7, 1.6 Hz, 1H), 7.45 – 7.41 (m, 1H),7.37 – 7.30 (m, 1H), 7.30 – 7.21 (m, 2H), 7.02 (td, J = 7.9, 1.7 Hz, 1H). 13 CNMR (101 MHz, CDCl3) δ 138.84, 136.00, 133.56, 132.99, 129.75, 129.65,129.55, 129.41, 127.85, 126.52, 122.92, 100.73, 96.22, 89.78. LR-MS (ESI): m / z 339.9 [M+H]+.

[0040] 1-((3-chlorophenyl)ethynyl)-2-iodobenzene (5e). White solid, yield94%. Mp. 46 – 51 °C, 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.9 Hz, 1H), 7.59(s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.32 (dt, J =16.0, 7.9 Hz, 3H), 7.04 (t, J = 7.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 138.87,134.31, 132.60, 131.47, 129.81, 129.78, 129.69, 129.36, 128.96, 127.94,124.71, 101.25, 92.76, 91.54. LR-MS (ESI): m / z 339.9 [M+H]+.

[0041] 1-((4-bromophenyl)ethynyl)-2-iodobenzene (5f). White solid, yield82%. Mp. 82 – 87 °C, 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.56 –7.48 (m, 3H), 7.45 (d, J = 8.3 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.03 (t, J= 7.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 138.89, 133.10, 132.52, 131.78,129.70, 129.54, 127.96, 123.05, 121.98, 101.19, 92.78, 92.00. LR-MS (ESI): m / z 383.0 [M+H]+.

[0042] 1-((3-bromophenyl)ethynyl)-2-iodobenzene (5g). Yellow solid, yield81%. Mp. 58 – 62 °C, 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 1.0 Hz, 1H),7.75 (t, J = 1.7 Hz, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 2H), 7.49 (ddd, J = 8.1,2.0, 1.0 Hz, 1H), 7.34 (td, J = 7.6, 1.2 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H),7.03 (td, J = 7.8, 1.7 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 138.87, 134.31,132.61, 131.83, 130.25, 129.90, 129.79, 129.34, 127.94, 125.00, 122.29,101.25, 92.87, 91.40. LR-MS (ESI): m / z 383.0 [M+H]+.

[0043] 1-iodo-2-(p-tolylethynyl)benzene (5h). Yellow solid, yield 95%. Mp.74 – 82 °C, 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.9 Hz, 1H), 7.51 (t, J =9.0 Hz, 3H), 7.32 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 7.00 (t, J =7.5 Hz, 1H), 2.38 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 138.91, 138.76, 132.35,131.59, 130.03, 129.22, 127.85, 119.91, 101.23, 93.41, 91.15, 21.64. LR-MS(ESI): m / z 318.9 [M+H]+.

[0044] 1-iodo-2-(m-tolylethynyl)benzene (5i). Yellow oil, yield 98%. 1 H NMR(400 MHz, CDCl3) δ 7.88 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.41(d, J = 9.6 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.28 (s, 1H), 7.18 (d, J = 7.5Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 2.37 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ138.79, 138.15, 132.46, 132.21, 129.95, 129.65, 129.35, 128.81, 128.36,127.88, 122.79, 101.26, 93.36, 91.37, 21.33. LR-MS (ESI): m / z 318.9 [M+H]+.

[0045] 4-((2-iodophenyl)ethynyl)benzonitrile (5j). Yellow solid, yield 38%.Mp. 88 – 94 °C, 1 H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 8.0, 0.9 Hz, 1H), 7.70– 7.62 (m, 4H), 7.54 (dd, J = 7.7, 1.6 Hz, 1H), 7.36 (td, J = 7.6, 1.1 Hz,1H), 7.07 (td, J = 7.8, 1.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 138.99, 132.80,132.16, 130.30, 128.86, 128.05, 127.91, 118.55, 111.93, 101.31, 95.78, 91.14.LR-MS (ESI): m / z 329.9 [M+H]+.

[0046] 1-iodo-2-((4-methoxyphenyl)ethynyl)benzene (5k). Yellow solid, yield92%. Mp. 92 – 97 °C, 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.9 Hz, 1H), 7.57 –7.46 (m, 3H), 7.32 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.90 (d, J= 8.3 Hz, 2H), 3.84 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.01, 138.74, 133.18,132.21, 130.14, 129.07, 127.85, 115.08, 114.13, 101.13, 93.31, 90.58, 55.39.LR-MS (ESI): m / z 334.0 [M+H]+.

[0047] 1-iodo-2-((2-methoxyphenyl)ethynyl)benzene (5l). Yellow oil, yield75%. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.9 Hz, 1H), 7.62 – 7.54 (m, 2H),7.33 (td, J = 7.3, 2.6 Hz, 2H), 7.04 – 6.88 (m, 3H), 3.93 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 160.15, 138.74, 133.69, 132.60, 130.19(2C), 129.21, 127.76,120.55, 112.23, 110.89, 100.97, 95.47, 89.72, 55.92. LR-MS (ESI): m / z 334.0[M+H]+.

[0048] 1-iodo-2-((3-methoxyphenyl)ethynyl)benzene (5m). Yellow oil, yield84%. 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 7.7, 1.3Hz, 1H), 7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.23 – 7.19 (m,1H), 7.13 (s, 1H), 7.02 (td, J = 7.8, 1.6 Hz, 1H), 6.95 – 6.91 (m, 1H), 3.84(s, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.44, 138.82, 132.51, 129.78, 129.54,129.48, 127.90, 124.29, 123.98, 116.52, 115.29, 101.26, 93.04, 91.51, 55.40.LR-MS (ESI): m / z 334.0 [M+H]+.

[0049] 1-iodo-2-((4-phenoxyphenyl)ethynyl)benzene (5n). Yellow oil, yield33%. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.7 Hz,2H), 7.53 (d, J = 7.7 Hz, 1H), 7.36 (dt, J = 15.2, 8.0 Hz, 3H), 7.17 (t, J =7.4 Hz, 1H), 7.07 (d, J = 8.3 Hz, 2H), 7.01 (t, J = 7.2 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 158.02, 156.40, 138.78, 133.33, 132.33, 129.97, 129.91, 129.29,127.89, 123.99, 119.54, 118.45, 117.47, 101.20, 92.81, 91.18. LR-MS (ESI): m / z 397.0 [M+H]+.

[0050] 1-((4-(benzyloxy)phenyl)ethynyl)-2-iodobenzene (5o). Yellow solid,yield 37%. Mp. 53 – 59 °C, 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 1.0 Hz,1H), 7.58 – 7.54 (m, 2H), 7.52 (dd, J = 7.7, 1.6 Hz, 1H), 7.41 (ddd, J =23.1, 11.9, 4.4 Hz, 5H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 6.98 (d, J = 8.9 Hz,3H), 5.10 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.19, 138.75, 136.61, 133.21,132.24, 130.13, 129.10, 128.71, 128.18, 127.86, 127.54, 115.37, 115.05,101.15, 93.26, 90.68, 70.12. LR-MS (ESI): m / z 411.0 [M+H]+.

[0051] 1-((4-(tert-butyl)phenyl)ethynyl)-2-iodobenzene (5p). Yellow solid,yield 88%. Mp. 58 – 64 °C, 1 H NMR (400 MHz, DMSO- d6 ) δ 7.87 (d, J = 7.9 Hz,1H), 7.53 (t, J = 6.6 Hz, 3H), 7.39 (d, J = 8.2 Hz, 2H), 7.32 (t, J = 7.5 Hz,1H), 7.00 (t, J = 7.6 Hz, 1H), 1.34 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 152.06,138.78, 132.40, 131.45, 130.08, 129.24, 127.86, 125.48, 119.98, 101.29,93.39, 91.15, 34.92, 31.25. LR-MS (ESI): m / z 361.0 [M+H]+.

[0052] 1-iodo-2-((4-isopropylphenyl)ethynyl)benzene (5q). Yellow oil, yield79%. 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 1.0 Hz, 1H), 7.53 (dd, J =8.2, 5.0 Hz, 3H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H),7.00 (td, J = 7.9, 1.7 Hz, 1H), 2.93 (hept, J = 6.9 Hz, 1H), 1.27 (d, J = 6.9Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 149.83, 138.78, 132.39, 131.72, 130.08,129.23, 127.86, 126.62, 120.30, 101.26, 93.44, 91.08, 34.22, 23.87. LR-MS(ESI): m / z 347.0 [M+H]+.

[0053] 4-((2-iodophenyl)ethynyl)-1,1'-biphenyl (5r). Yellow solid, yield63%. Mp. 75 – 87 °C, 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.9 Hz, 1H), 7.67(d, J = 8.1 Hz, 2H), 7.61 (d, J = 5.5 Hz, 4H), 7.55 (d, J = 7.3 Hz, 1H), 7.46(t, J = 7.5 Hz, 2H), 7.40 – 7.31 (m, 2H), 7.02 (t, J = 7.3 Hz, 1H). 13 C NMR(101 MHz, CDCl3) δ 141.46, 140.39, 138.83, 132.48, 132.13, 129.88, 129.44,128.96, 127.91, 127.78, 127.15, 127.12, 121.88, 101.29, 93.09, 92.42. LR-MS(ESI): m / z 381.0 [M+H]+.

[0054] 1-iodo-2-((4-(trifluoromethyl)phenyl)ethynyl)benzene (5s). Yellowoil, yield 80%. 1 H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 8.0, 0.9 Hz, 1H), 7.70(d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.55 (dd, J = 7.7, 1.6 Hz,1H), 7.35 (td, J = 7.6, 1.1 Hz, 1H), 7.05 (td, J = 7.8, 1.6 Hz, 1H). 13 C NMR(101 MHz, CDCl3) δ 138.94, 132.71, 131.91, 130.33 (d, J = 33.3 Hz), 130.00,129.18, 128.00, 126.81, 125.39 (q, J = 3.0 Hz), 122.63, 101.31, 93.89,91.51. 19F NMR (377 MHz, CDCl3) δ -62.80. LR-MS (ESI): m / z 372.9 [M+H]+.

[0055] 1-iodo-2-((4-(trifluoromethoxy)phenyl)ethynyl)benzene (5t). Yellowoil, yield 89%. 1 H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.0, 1.0 Hz, 1H), 7.66– 7.60 (m, 2H), 7.53 (dd, J = 7.7, 1.6 Hz, 1H), 7.34 (td, J = 7.6, 1.1 Hz,1H), 7.22 (d, J = 8.0 Hz, 2H), 7.03 (td, J = 7.8, 1.6 Hz, 1H). 13 C NMR (101MHz, CDCl3) δ 149.24, 138.89, 133.22, 132.55, 129.74, 129.45, 127.96, 121.80,121.75, 121.01, 101.22, 92.46, 91.58. 19 F NMR (377 MHz, CDCl3) δ -57.75. LR-MS(ESI): m / z 388.9 [M+H]+.

[0056] 1,2-difluoro-4-((2-iodophenyl)ethynyl)benzene (5u). Yellow solid,yield 72%. Mp. 45 – 51 °C, 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 1.0 Hz,1H), 7.51 (dd, J = 7.7, 1.6 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.34 (dd, J = 8.1,6.9 Hz, 2H), 7.16 (dd, J = 18.5, 8.3 Hz, 1H), 7.03 (td, J = 7.7, 1.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 151.73 (dd, J = 75.7, 12.1 Hz), 149.24, (dd, J =71.7, 12.1 Hz), 138.89, 132.54, 129.83, 129.22, 128.35 (q, J = 10.1 Hz),127.97, 120.57 (d, J = 19.2 Hz), 119.85 (q, J = 4.0 Hz), 117.66 (d, J = 18.2Hz), 101.17, 92.10, 90.82. 19 F NMR (377 MHz, CDCl3) δ -135.14 – -135.32 (m), -136.90 – -137.09 (m). LR-MS (ESI): m / z 340.9 [M+H]+.

[0057] 2-((2-iodophenyl)ethynyl)-1,3,5-trimethylbenzene (5v). Yellow oil,yield 41%. 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 0.8 Hz, 1H), 7.55 (dd,J = 7.7, 1.5 Hz, 1H), 7.33 (td, J = 7.6, 1.1 Hz, 1H), 7.00 (td, J = 7.8, 1.6Hz, 1H), 6.91 (s, 2H), 2.55 (s, 6H), 2.31 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ140.79, 138.86, 138.38, 132.81, 130.82, 129.03, 127.84, 127.78, 119.65,100.15, 98.70, 91.46, 21.54, 21.47. LR-MS (ESI): m / z 347.0 [M+H]+.

[0058] 1-((2-iodophenyl)ethynyl)naphthalene (5w). Yellow oil, yield 84%. 1 HNMR (400 MHz, DMSO- d6) δ 8.65 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H),7.90 – 7.81 (m, 3H), 7.64 (dd, J = 19.7, 7.8 Hz, 2H), 7.55 (t, J = 7.4 Hz,1H), 7.48 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.6 Hz,1H). 13 C NMR (101 MHz, CDCl3) δ 138.87, 133.35, 133.28, 132.87, 130.86, 130.10,129.48, 129.20, 128.31, 127.93, 126.94, 126.69, 126.57, 125.33, 120.63,100.86, 96.12, 91.44. LR-MS (ESI): m / z 354.9 [M+H]+.

[0059] 9-((2-iodophenyl)ethynyl)phenanthrene (5x). Yellow solid, yield 57%.Mp. 111 – 114 °C, 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 9.2 Hz, 1H), 8.70 (d,J = 8.9 Hz, 1H), 8.66 (d, J = 8.2 Hz, 1H), 8.17 (s, 1H), 7.95 (d, J = 8.0 Hz,1H), 7.90 (d, J = 7.8 Hz, 1H), 7.76 – 7.65 (m, 4H), 7.62 (t, J = 7.3 Hz, 1H),7.39 (t, J = 7.6 Hz, 1H), 7.05 (dd, J = 11.3, 4.0 Hz, 1H). 13C NMR (101 MHz,CDCl3) δ 138.90, 132.97, 132.41, 131.24, 131.11, 130.48, 130.17, 130.07,129.55, 128.71, 127.96, 127.69, 127.47, 127.21, 127.16, 127.04, 122.79,122.71, 119.43, 100.87, 95.71, 91.60. LR-MS (ESI): m / z 405.0 [M+H]+.

[0060] 2-((2-iodophenyl)ethynyl)thiophene (5y). Yellow solid, yield 92%. Mp.39 – 44 °C, 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 8.0, 1.0 Hz, 1H), 7.52 (dd,J = 7.8, 1.6 Hz, 1H), 7.38 (dd, J = 3.6, 1.1 Hz, 1H), 7.33 (ddd, J = 8.8,6.4, 1.1 Hz, 2H), 7.08 – 6.99 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 138.75,132.32, 132.25, 129.50, 127.93, 127.85, 127.24, 122.84, 100.77, 95.22, 86.45.LR-MS (ESI): m / z 310.9 [M+H]+.

[0061] 1,4-bis((2-iodophenyl)ethynyl)benzene (5z). White solid, yield 41%.Mp. 142 – 146 °C, 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 2H), 7.60 (s,4H), 7.54 (dd, J = 7.7, 1.4 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.03 (td, J =7.8, 1.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 138.87, 132.56, 131.64, 129.67,129.58, 127.95, 123.19, 101.28, 93.68, 92.75. LR-MS (ESI): m / z 530.9 [M+H]+.

[0062] 1-iodo-4,5-dimethyl-2-(m-tolylethynyl)benzene (5aa). Yellow solid,yield 56%. Mp. 65 – 71 °C, 1 H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.39 (d, J =11.5 Hz, 2H), 7.30 (s, 1H), 7.27 – 7.22 (m, 1H), 7.15 (d, J = 7.7 Hz, 1H),2.36 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 139.41,138.96, 138.03, 136.67, 133.34, 132.10, 129.33, 128.67, 128.26, 127.07,123.02, 97.38, 92.16, 91.41, 21.28, 19.33, 19.26. LR-MS (ESI): m / z 347.0 [M+H]+.

[0063] 1-iodo-4,5-dimethoxy-2-(p-tolylethynyl)benzene (5ab). Yellow solid,yield 53%. Mp. 100 – 109 °C, 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.1 Hz,2H), 7.25 (s, 1H), 7.16 (d, J = 7.9 Hz, 2H), 7.02 (s, 1H), 3.88 (s, 6H), 2.37(s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.61, 149.04, 138.61, 131.42, 129.19,122.27, 121.06, 120.10, 114.61, 91.71, 91.21, 90.31, 56.24, 56.06, 21.60. LR-MS (ESI): m / z 379.0 [M+H]+.

[0064] Example 2

[0065]

[0066] Standard reaction: At room temperature, NaH (60 wt% in oil, 1.8 mmol, 3.0 equiv) was weighed into a round-bottom flask, and 2 mL of anhydrous THF was added and stirred to form a suspension. Substrate 4a (0.6 mmol, 1.0 equiv) was dissolved in anhydrous THF (2.0 mL) and added dropwise to the above suspension under N2 protection, completing the addition in 1 minute. The mixture was stirred for 5 min, and then o-diiodobenzene 2a (1.5 mmol, 2.5 equiv) was added dropwise, completing the addition in 1 minute. The mixture was then stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, added to water (10 mL), and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The product was then purified by rapid column chromatography to obtain o-iodophenyl ethynylated product 5 in 96% yield.

[0067] The factors were varied based on the standard reaction, and the results are shown in Table 1.

[0068]

[0069] This invention involves reacting aryl-terminated alkynes with o-diiodobenzene in the presence of NaH, achieving C-C bond coupling through this novel benzyne generation mechanism, yielding an alkyneated product similar to the Sonogashira coupling reaction. This method is free of transition metals and ligands, features mild reaction conditions, uses inexpensive and readily available starting materials, exhibits good functional group tolerance, has simple synthetic steps, and allows for extensive functional group transformations of the product, resulting in a variety of important structures. This invention provides a new pathway for constructing C(sp2)-C(sp) bonds, and has significant implications and value for future drug synthesis development.

[0070] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing o-iodophenylacetylene without transition metal catalysis, characterized in that, Using o-dihalobenzene and terminal alkyne as raw materials, o-iodophenylacetylenide is obtained by reaction in the presence of an alkali metal hydride; the alkali metal hydride is NaH; the reaction is carried out in a solvent; the solvent is THF; The chemical structural formula of the terminal alkyne is as follows: ； Ar represents phenyl or naphthyl; R represents... 1 Selected from one of alkyl, halogen, and alkoxy groups; The chemical structural formula of the ortho-dihalobenzene is as follows: ； R 2 Selected from alkyl and alkoxy groups; X is iodine; The reaction temperature is 10℃~40℃.

2. The method for preparing o-iodophenylacetylene oxide without transition metal catalysis according to claim 1, characterized in that, The molar ratio of terminal alkyne, ortho-dihalobenzene, and alkali metal hydride is 1:(1-3):(1-4).

3. The method for preparing o-iodophenylacetylene oxide without transition metal catalysis according to claim 1, characterized in that, The reaction time is 5 to 30 hours.

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