A method for preparing a benzo[iodo[x]pentane] reagent

Abstract

This invention belongs to the technical field of organic synthesis and discloses a method for preparing benzo[i]iodo[i]oxapentane reagent. The method involves adding periodic acid or periodate as an oxidant, along with an o-iodobenzyl alcohol compound, to an aqueous acetic acid solution. Heating causes a redox reaction, followed by recrystallization or slurrying to obtain the product, benzo[i]iodo[i]oxapentane reagent. R1 is selected from methyl or trifluoromethyl; R2 is selected from hydrogen, halogen, or methyl; R3 is selected from hydrogen or methyl; and periodate is selected from sodium periodate, potassium periodate, tetrabutylammonium potassium periodate, or lithium periodate. This invention provides a one-step, efficient method for preparing benzo[i]iodo[i]oxapentane reagent using periodic acid / salt, with simple steps and easily separable reaction products. The redox reaction equation is as follows:

Description

Technical Field

[0001] This invention belongs to the technical field of organic synthesis, and more specifically, relates to a method for preparing a benzo[i]iodo[i]oxapentane reagent. Background Technology

[0002] With the continuous development of organic synthetic chemistry, more and more researchers have realized the significant synthetic importance of developing green, environmentally friendly, and low-cost reagents. In recent years, benzo[i]iodoxopentane reagents have become increasingly popular among researchers. They possess similar chemical properties and reactivity to heavy metal oxidants such as mercury, titanium, and lead, but without the toxicity and environmental pollution problems associated with these heavy metal reagents (J. Org. Chem. 2003, 68, 2297-3008). Furthermore, they are inexpensive, readily available, have mild reaction conditions, and simple post-processing, leading to their widespread application in organic synthesis and providing new solutions to many challenging problems in organic synthesis.

[0003] Structurally, the trivalent iodine atom in benzo[i]iodoxapentylene reagent has 10 electrons, forming a trigonal bipyramidal molecule in three dimensions. The iodine atom is at the center, the substituents and two lone pairs of electrons are in planar positions, and the two heteroatom ligands are at the vertices. The bonding orbitals in benzo[i]iodoxapentylene reagent are occupied by two electrons from the unhybridized 5p orbital of the iodine atom and two electrons from the two ligands. This structure makes the chemical bonds of trivalent iodine longer, weaker, and more easily polarized than ordinary covalent bonds, resulting in high electrophilic activity of benzo[i]iodoxapentylene reagent (Chemical Bulletin, 2018, 81, 681-691). Their unique reactivity has inspired continuous exploration of new synthetic transformation methods, such as the deprotection reaction of thioacetals / ketones, alkoxymethylation, and glycosylation reactions, etc., using benzo[i]iodoxapentylene reagent.

[0004] Existing technology reports a synthetic method for benzo[i]iodoxapentane reagent (II-1) (SyntheticCommun, 2009, 39, 1065-1075), which describes the reaction of 1-chloro-1,3-dihydro-3,3-bis(trifluoromethyl)-1,2-benziodarone as a starting material in the presence of KOH and BnNMe3Cl at room temperature for 2 hours to obtain benzo[i]iodoxapentane reagent II-1. However, this method has difficulties in obtaining the starting material, has a low yield, and requires column chromatography separation, which is not conducive to large-scale synthesis. Literature (Adv. Syn. Catal. 2018, 360, 3889-3893) also uses a chlorinated derivative as a starting material, reacting at room temperature for 12 hours in the presence of silver acetate to prepare II-5, which has a high preparation cost. Considering the existing technology reports, there is a lack of literature on the preparation of benzo[i]iodoxapentane reagent (II), and a new method for preparing benzo[i]iodoxapentane reagent (II) is still needed. Summary of the Invention

[0005] To address the above-mentioned deficiencies or improvement needs of existing technologies, this invention provides a method for preparing benzo[i]iodoxapentane reagent. This method uses periodic acid or periodate as an oxidant to react with o-iodobenzyl alcohol compounds under heating conditions to undergo a redox reaction. The benzo[i]iodoxapentane reagent is obtained through simple post-processing steps. This solves the technical problems of difficulty in obtaining raw materials, numerous reaction steps, and complex post-processing in existing technologies for this type of reaction.

[0006] To achieve the above objectives, according to one aspect of the present invention, a method for preparing benzo[i]iodoxapentyl ring reagent is provided. This method involves adding periodic acid or periodate as an oxidant, along with an o-iodobenzyl alcohol compound with the structural formula shown in Formula I, to an aqueous acetic acid solution. The mixture is then heated to undergo a redox reaction. After recrystallization or slurrying, the product benzo[i]iodoxapentyl ring reagent with the structural formula shown in Formula II is obtained. The reaction equation for the redox reaction is as follows:

[0007]

[0008] Wherein, R1 is selected from methyl or trifluoromethyl; R2 is selected from hydrogen, halogen or methyl; R3 is selected from hydrogen or methyl; periodate is selected from sodium periodate, potassium periodate, potassium periodate tetra-n-butylammonium or lithium periodate.

[0009] Preferably, the o-iodobenzyl alcohol compound (I) is selected from compounds with any of the following structures:

[0010]

[0011] Preferably, the molar ratio of the o-iodobenzyl alcohol compound to the periodic acid is 1.0:(1.0-2.0), or the molar ratio of the o-iodobenzyl alcohol compound to the periodate is 1.0:(1.0-2.0).

[0012] Preferably, the periodate is sodium periodate;

[0013] The preferred molar ratio of the o-iodobenzyl alcohol compound to the sodium periodate is 1.0:1.05.

[0014] Preferably, in the aqueous acetic acid solution, the volume ratio of acetic acid to water is 1:9 to 1:1.

[0015] Preferably, in the aqueous acetic acid solution, the volume ratio of acetic acid to water is preferably 3:7.

[0016] Preferably, the oxidation reaction is carried out under the following conditions: temperature 25–140°C and time 4–12 h.

[0017] Preferably, the oxidation reaction conditions are a temperature of 110°C and a time of 4 hours.

[0018] In summary, compared with the prior art, the solutions conceived by this invention have the following main advantages:

[0019] (1) The present invention provides a method for preparing benzo[i]iodo[i]oxapentane reagent, which uses periodic acid or periodate as an oxidant to react with o-iodobenzyl alcohols under heating conditions. The present invention provides a one-step method for efficiently preparing benzo[i]iodo[i]oxapentane reagent with periodic acid or periodate. The steps are simple and the reaction products are easy to separate.

[0020] (2) This invention is applicable to a wide range of substrates and has good applicability to substrates of different types and structures. This invention relates to periodic acid or periodate, which are readily available raw materials and have good reaction performance.

[0021] (3) Compared with the prior art, which requires multiple steps such as oxidation, hydrolysis and dehydration of o-iodobenzyl alcohol compounds or harsh reactions such as the use of precious metal reagents, the present invention performs a one-step reaction of readily available periodic acid or periodate, thereby avoiding intermediate separation operations caused by multiple steps.

[0022] (4) The post-processing of the present invention does not require complex operations such as column chromatography, but only simple recrystallization or pulping to obtain the product. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0024] Unless otherwise stated, all raw materials and reagents used in this invention are commercially available. All reagents are commercial grade and used according to the received standards. 1 H and 13 C10 NMR spectra were recorded on Bruker AV 400 and Bruker AV 600. Chemical shifts (δ) are expressed in ppm, with tetramethylsilane as an internal standard. Coupling constants (J) are expressed in Hz. Scientific and technical terms and abbreviations used in this invention have the meanings commonly understood by those skilled in the art.

[0025] The method for preparing the benzo[i]iodo[i]oxapentane reagent provided by this invention includes the following steps:

[0026] Step S1: Place o-iodobenzyl alcohol compound (Ⅰ) and periodic acid / periodate in a reaction vessel and inject solvent (acetic acid aqueous solution) to obtain a mixed system of reaction raw materials.

[0027] In step S2, the reaction mixture system of step S1 is heated and stirred for 4 to 12 hours.

[0028] After the reaction in steps S3 and S2 is completed, the reaction system is cooled and then filtered directly. The filter cake is washed sequentially with water, acetonitrile, and dichloromethane to obtain part of the target product. The mother liquor is concentrated and pulped to obtain another part of the target product. The two parts of the target product are combined to obtain all the target products of the final reaction, namely benzo[i]iodo[i]oxapentane reagent (II).

[0029] The chemical formulas of the reactions involved in the specific reaction step (2) are as follows:

[0030]

[0031] Wherein, R1 is selected from methyl or trifluoromethyl; R2 is selected from hydrogen, halogen or methyl; R3 is selected from hydrogen or methyl; periodate is selected from sodium periodate, potassium periodate, potassium periodate tetra-n-butylammonium or lithium periodate.

[0032] Preferably, (I) in the above reaction formula is selected from compounds with any of the following structures:

[0033]

[0034] Sodium periodate is preferred.

[0035] Preferably, the molar ratio of the above-mentioned o-iodobenzyl alcohol compound to the above-mentioned periodic acid or periodate is 1.0:(1.0 to 2.0).

[0036] The preferred compound is sodium periodate with o-iodobenzyl alcohol, and the molar ratio of sodium periodate to periodic acid or periodate is preferably 1.0:1.05.

[0037] Preferably, the solvent is an aqueous solution of acetic acid, and the volume ratio of acetic acid to water is 1:9 to 1:1.

[0038] In an aqueous acetic acid solution, the preferred volume ratio of acetic acid to water is 3:7.

[0039] Preferably, the conditions for the above oxidation reaction are: temperature 110°C and time 4 hours.

[0040] The molecular structure of the target product obtained from the reaction based on the above scheme is as follows: II-a and / or II-b:

[0041]

[0042] As mentioned above, the structures of the products differ due to the different substituents on the o-iodobenzyl alcohol compounds (I). For example, when R1 is CF3 and there are no substituents on the aromatic ring, only one halogen or one methyl substituent, the product contains only a dimer structure, corresponding to Formula II-1, Formula II-2 and Formula II-3 below, respectively; when R1 is methyl and there are no substituents on the aromatic ring, the product contains only the structure of OAc, as shown in Formula II-5 below; when R1 is CF3 and there are two methyl substituents on the aromatic ring, the product is a mixture of a dimer structure and a structure containing OAc, as shown in Formula II-4 below.

[0043]

[0044] The following are specific examples:

[0045] Example 1:

[0046] Preparation of benzo[i]iodo[x]pentane reagent II-1

[0047]

[0048] Weigh 50 g (0.13 mol, 1.0 equiv) of o-iodobenzyl alcohol (I-1), 30.4 g (0.14 mol, 1.05 equiv) of sodium periodate, and a magnetic immersion magnet into a 500 mL reaction flask. After the addition is complete, add 208 mL of 30% AcOH-H2O (V / V) (c = 0.65 M). Place the reaction flask in a 110 °C metal bath and reflux for 4 h. After the reaction is complete, cool to room temperature. Filter the reaction system directly through a sintered glass funnel. Wash the filter cake with water, acetonitrile, and dichloromethane to obtain the target product. Remove impurities from the mother liquor by concentrating the organic solvent and slurrying to obtain the target product. Combine the results to obtain the final product, a white solid, which is product II-1 (44.9 g, 88%).

[0049] The NMR data for benzo[i]iodide-oxapentane reagent II-1 in this embodiment are as follows: 1 H NMR (600MHz, DMSO-d6) δ7.98(d,J=8.4Hz,2H,Ar-H),7.96-7.93(m,2H,Ar-H),7.77-7.74(m,2H,Ar-H),7.71(d,J=7.7Hz,2H,Ar-H); 13 C NMR (150MHz, DMSO-d6) δ133.3, 131.0, 130.8, 128.9, 128.0, 123.4, 117.2, 83.7.HRMS (ESI + ): calc.for C 18 H8F 12 I₂O₃[M+Na] +776.8263, found:776.8266.

[0050] Example 2:

[0051] Preparation of benzo[i]iodo[xapral]reagent II-2

[0052]

[0053] Weigh out 500 mg (1.30 mmol, 1.0 equiv) of o-iodobenzyl alcohol (I-2), 292.4 mg (1.37 mmol, 1.05 equiv) of sodium periodate, and a magnetic stir bar into a 10 mL reaction flask. After the addition is complete, add 2 mL of 30% AcOH-H2O (V / V) (c = 0.65 M). Place the reaction flask in a 110 °C metal bath and reflux for 4 h. After the reaction is complete, cool to room temperature. Filter the reaction system directly through a sintered glass funnel. Wash the filter cake with water, acetonitrile, and dichloromethane to obtain the target product. Remove impurities from the mother liquor by concentrating the organic solvent and slurrying to obtain the target product. Combine the results to obtain the final product, a white solid, which is product II-2 (382.8 mg, 75%).

[0054] The NMR data for benzo[i]iodide-oxypyridine reagent II-2 in this embodiment are as follows: 1 H NMR (600MHz, DMSO-d6) δ7.80 (d, J = 8.4 Hz, 2H, Ar-H), 7.76 (d, J = 8.4 Hz, 2H, Ar-H), 7.50 (s, 2H, OH), 2.50 (s, 6H, CH3). 13 CNMR (150MHz, DMSO-d6) δ141.0, 134.1, 131.2, 129.1, 127.5, 123.4, 113.4, 83.5, 20.3.HRMS (ESI + ): calc.for C 20 H 12 F 12 I2O3[M+H]+ 782.8757, found: 782.8768.

[0055] Example 3:

[0056] Preparation of benzo[i]iodo[xapral]reagent II-3

[0057]

[0058] Weigh out 300 mg (0.69 mmol, 1.0 equiv) of o-iodobenzyl alcohol (I-3), 150.1 mg (0.70 mmol, 1.05 equiv) of sodium periodate, and a magnetic stir bar into a 5 mL reaction flask. After the addition is complete, add 1.0 mL of 30% AcOH-H2O (V / V) (c = 0.65 M). Place the reaction flask in a 110 °C metal bath and stir under reflux for 4 h. After the reaction is complete, cool to room temperature. Filter the reaction system directly through a sintered glass funnel. Wash the filter cake with water, acetonitrile, and dichloromethane to obtain the target product. Recover the mother liquor. Dissolve impurities by concentrating the organic solvent and using DCM to slurry. Filter to obtain the target product. Combine the products to obtain the final product, which is a white solid, namely product II-3 (278.6 mg, 42%).

[0059] The NMR data for benzo[i]iodide-oxypyridine reagent II-3 in this embodiment are as follows: 1 H NMR (600MHz, DMSO) δ8.16 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.73 (s, 1H). 13 C NMR (150MHz, DMSO) δ136.2,133.5,130.9,130.3,124.6,123.2,117.0,83.4.HRMS (ESI + ): calc.for C 18 H6Br2F 12 I22O3[M+Na]+ 932.6474,found:932.6464..

[0060] Example 4:

[0061] Preparation of benzo[i]iodo[xapral]reagent II-4

[0062]

[0063] Benzyl alcohol (I-4) (265 mg, 0.66 mmol, 1.0 equiv), sodium periodate (149.5 mg, 0.70 mmol, 1.05 equiv), and a magnetic flux were weighed into a 5 mL reaction flask. After the addition was complete, 1.0 mL of 30% AcOH-H2O (V / V) (c = 0.65 M) was added, and the reaction flask was refluxed in a metal bath at 110 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, and ethyl acetate was added to the system. The mixture was extracted with water, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. The organic phase was transferred to a suitable beaker, dried with anhydrous sodium sulfate, and the organic solvent was evaporated to obtain a crude solid. Finally, recrystallization yielded a white solid, which was product II-4a (140.0 mg, 46%). Recrystallization further yielded a white solid, which was II-4b (56.1 mg, 21%).

[0064] The NMR data for benzo[i]iodide-oxypyridine reagent II-4a in this embodiment are as follows: 1 H NMR (600MHz, CDCl3) δ7.57(s,1H,Ar-H),7.41(s,1H,Ar-H),2.39(s,3H),2.37(s,3H),2.17(s,3H,OCOCH3). 13 C NMR (151MHz, CDCl3) δ176.7, 143.5, 140.7, 130.4, 130.3, 129.0, 126.1, 124.2, 122.3, 120.4, 112.3, 85.8, 85.6, 85.4, 20.7, 20.6, 19.9. HRMS (ESI + ): calc.for C 13 H 11 F6IO3[M+Na] + 478.9550, found: 478.9556.

[0065] The NMR data for benzo[i]iodide-oxapentane reagent II-4b in this embodiment are as follows: 1 H NMR (600MHz, CDCl3) δ7.49(s,2H),7.46(s,2H),2.41(s,6H),2.37(s,6H). 13 C NMR (150MHz, CDCl3) δ143.4, 140.7, 131.0, 129.1, 123.5 (q, J CF =285Hz), 112.5, 84.0 (m), 20.6, 19.9. 19 F NMR(565MHz, CDCl3)δ-76.27(s).HRMS(ESI + ): calc.for C 22 H 16 F 12 I₂O₃[M+Na] + 832.8889, found: 832.8883.

[0066] Example 5:

[0067] Preparation of benzo[i]iodo[x]pentane reagent II-5

[0068]

[0069] Benzyl alcohol (I-5) (500 mg, 1.91 mmol, 1.0 equiv), sodium periodate (428.4 mg, 2.00 mmol, 1.05 equiv), and a magnetic flux were weighed into a 10 mL reaction flask. After the addition was complete, 2.9 mL of 30% AcOH-H2O (V / V) (c = 0.65 M) was added, and the reaction flask was refluxed in a metal bath at 110 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, and ethyl acetate was added to the system. The mixture was extracted with water and saturated sodium bicarbonate, and then with water and saturated sodium chloride. The organic phase was transferred to a suitable beaker, dried with anhydrous sodium sulfate, and the organic solvent was evaporated to obtain a crude solid. Finally, recrystallization yielded a white solid, which was product II-5 (547.0 mg, 90%).

[0070] The NMR data for benzo[i]iodide-oxapentane reagent II-5 in this embodiment are as follows: 1 H NMR (600MHz, CDCl3) δ7.78 (dd, J=1.2, 8.4Hz, 1H, Ar-H), 7.47 (dt, J=1.8, 7.2Hz, 1H, Ar-H), 7.43 (dt, J=1.2, 7.8Hz, 1H, Ar-H), 7.16 (dd, J=1.8, 7.2Hz, 1H, Ar-H), 2.09 (s, 3H, OCOCH3), 1.51 (s, 6H, CH3).

[0071] Example 6:

[0072] Preparation of benzo[i]iodo[x]pentane reagent II-1

[0073]

[0074] Following the literature, S2 was prepared from o-iodobenzoic acid S1 (150.0 g, 0.61 mol, 1.0 equiv) (Chem. Commun., 2023, 59, 12637-12640). S2 was placed in a reaction flask, and KF (52.7 g, 0.91 mol, 1.5 equiv) and MeOH (c = 0.5 M) were added. The reaction was carried out at room temperature for 1 h. After the reaction was complete, ethyl acetate was added to the reaction system for multiple extractions. The combined organic phases were extracted sequentially with water, 1 M HCl, and saturated NaCl solution. After drying with anhydrous Na2SO4, the mixture was filtered and concentrated to obtain crude compound I-1. I-1 was placed in a reaction flask, and sodium periodate (135.8 g, 0.63 mol, 1.05 equiv) and 30% AcOH (c = 0.65 M) were added. The reaction system was then refluxed at 110 °C for 4 h. After the reaction was completed and cooled to room temperature, the reaction system was directly filtered through a sintered glass funnel. The filter cake was washed with water, acetonitrile, and dichloromethane to obtain the target product. The mother liquor was concentrated with organic solvent and pulped to remove impurities, and the target product was obtained. The final product was a white solid, namely benzo[i]iodo[i]oxapentane reagent II-1 (126.7 g, 56%, for 5 steps).

[0075] Example 7:

[0076] Preparation of benzo[i]iodo[xapral]reagent II-2

[0077]

[0078] I-2 (7.8 g, 73%, 2 steps) was prepared from p-methylaniline (150.0 g, 0.61 mol, 1.0 equiv) according to the literature (Front. Chem. 2024, 12, 1376948). I-2 (7.8 g, 20.3 mmol, 1.0 equiv) was placed in a reaction flask, and sodium periodate (4.56 g, 21.3 mol, 1.05 equiv) and 30% AcOH (c = 0.65 M) were added. The reaction system was then refluxed at 110 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction system was directly filtered through a sintered glass funnel. The filter cake was washed with water, acetonitrile, and dichloromethane to obtain the target product. The mother liquor was concentrated with organic solvent and slurryed to remove impurities, yielding the target product. The final product was a white solid, namely benzo[i]iodo[i]oxapentane] reagent II-2 (6.98 g, 88%).

[0079] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a benzo[i]iodo[x]pentane reagent, characterized in that, This method involves adding periodic acid or periodate as an oxidant, along with an o-iodobenzyl alcohol compound with the structural formula shown in Formula I, to an aqueous acetic acid solution. Heating causes a redox reaction, followed by recrystallization or slurrying to obtain the product benzo[i]iodo[i]oxapentane] reagent with the structural formula shown in Formula II. The reaction equation for the redox reaction is as follows: ； Wherein, R1 is selected from methyl or trifluoromethyl; R2 is selected from hydrogen, halogen or methyl; R3 is selected from hydrogen or methyl; periodate is selected from sodium periodate, potassium periodate, potassium periodate tetra-n-butylammonium or lithium periodate.

2. The method for preparing the benzo[i]iodo[x]pentane reagent as described in claim 1, characterized in that, The o-iodobenzyl alcohol compound (Ⅰ) is selected from compounds with any of the following structures: 。 3. The method for preparing the benzo[i]iodo[x]pentane reagent as described in claim 1, characterized in that, The molar ratio of the o-iodobenzyl alcohol compound to the periodic acid is 1.0:(1.0 ~ 2.0), or the molar ratio of the o-iodobenzyl alcohol compound to the periodate is 1.0:(1.0 ~ 2.0).

4. The method for preparing the benzo[i]iodo[x]pentane reagent as described in claim 3, characterized in that, The periodate is sodium periodate; The molar ratio of the o-iodobenzyl alcohol compound to the sodium periodate is 1.0:1.

05.

5. The method for preparing the benzo[i]iodo[i]oxapentane reagent as described in claim 1, characterized in that, In the acetic acid aqueous solution, the volume ratio of acetic acid to water is 1:9 to 1:

1.

6. The method for preparing the benzo[i]iodo[x]pentane reagent as described in claim 5, characterized in that, In the acetic acid aqueous solution, the volume ratio of acetic acid to water is 3:

7.

7. The method for preparing the benzo[i]iodo[x]pentane reagent as described in claim 1, characterized in that, The conditions for the redox reaction are: temperature 25 ~ 140℃, time 4 ~ 12 h.

8. The benzo[a]iodine as described in claim 1 A method for preparing an oxapentane reagent, characterized in that, The conditions for the redox reaction are: temperature 110℃ and time 4 h.

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