Preparation method of benzoiodo-oxalane reagent

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a preparation method of a benzoiodo-oxalane reagent. The method comprises the following steps: by taking periodate or periodate as an oxidant, adding the periodate or periodate and an o-iodobenzyl alcohol compound into an acetic acid aqueous solution together, heating to generate an oxidation-reduction reaction, and recrystallizing or pulping to obtain a product benzo-iodo-oxalane reagent; 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. The benzoiodo-oxalane reagent is efficiently prepared through a periodate / salt one-step method, the steps are simple, and reaction products are easy to separate. Reaction equation of oxidation-reduction reaction as follows: # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field related to organic synthesis, and more specifically, relates to a method for preparing a benziodooxolane reagent. Background Art

[0002] With the continuous development of organic synthesis chemistry, more and more researchers realize that developing some green and environmentally friendly, low-cost reagents has great synthetic significance. In recent years, benziodooxolane reagents are increasingly favored by researchers, and they have chemical properties and reactivity similar to heavy metal oxidants such as mercury, titanium and lead, but do not have the toxicity and environmental pollution problems (J.Org.Chem.2003,68,2297-3008) that these heavy metal reagents bring, and have the characteristics of low price, easy availability, mild reaction conditions, and simple post-processing, and are widely used in organic synthesis, providing new ideas for solving many problems in organic synthesis.

[0003] Structurally, the trivalent iodine atom of the benziodine oxaline reagent has 10 electrons, which is a triangular bipyramidal molecule from a three-dimensional space, with the iodine atom at the center, the substituent and two pairs of lone pairs of electrons in a plane position, and the ligands of two heteroatoms at the vertices. The bonding orbital in the benziodine oxaline reagent is occupied by two electrons of the non-hybridized 5p orbital of the iodine atom and two electrons of the two ligands, and this structure makes the chemical bond of the trivalent iodine longer, weaker and more easily polarized than ordinary covalent bonds, causing the benziodine oxaline reagent to have a higher electrophilic activity (Chemical Bulletin, 2018, 81, 681-691). Their unique reactivity inspires people to continuously explore new synthetic transformation methods, such as using benziodine oxaline reagents to achieve the deprotection reaction of acetal / ketone, alkoxymethylenation reaction, glycosylation reaction, etc.

[0004] Prior art reports a synthesis method of a benziodine oxolane reagent (II-1) (Synthetic Commun, 2009, 39, 1065-1075) reported that 1-chloro-1,3-dihydro-3,3-bis (trifluoromethyl) -1,2-benzyl iodine ketone was used as a raw material, and in the presence of KOH and BnNMe3Cl, the room temperature reaction was 2h to obtain the benziodine oxolane reagent II-1. However, this method has difficulty in obtaining raw materials, low yield, and column chromatography separation is required, which is not conducive to large-scale synthesis. Literature (Adv. Syn. Catal. 2018, 360, 3889-3893) also uses chloro as a raw material, in the presence of silver acetate, room temperature reaction 12h to prepare II-5, and the preparation cost is relatively high. Combined with the report of the prior art, the literature for preparing benziodine oxolane reagent (II) is actually lacking, and a new method for preparing benziodine oxolane reagent (II) is still needed. Summary of the invention

[0005] In view of the above defects or improvement needs of the prior art, the present invention provides a method for preparing a benziodooxolane reagent, which uses periodic acid or periodate as an oxidant to undergo a redox reaction with an o-iodobenzyl alcohol compound under heating conditions, and obtains the benziodooxolane reagent through a simple post-treatment step, thereby solving the technical problems of the prior art in this type of reaction, such as difficulty in obtaining raw materials, numerous reaction steps and complex post-treatment.

[0006] To achieve the above object, according to one aspect of the present invention, a method for preparing a benziodooxolane reagent is provided, wherein periodic acid or periodate is used as an oxidant, and is added together with an o-iodobenzyl alcohol compound of the structural formula shown in Formula I to an aqueous acetic acid solution, heated to cause a redox reaction, and after recrystallization or pulping, a product benziodooxolane reagent of the structural formula shown in Formula II is obtained; the reaction equation of 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; and periodate is selected from sodium periodate, potassium periodate, potassium tetra-n-butylammonium periodate or lithium periodate.

[0009] Preferably, the o-iodobenzyl alcohol compound (I) is selected from compounds having 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 preferably sodium periodate;

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

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

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

[0016] Preferably, the oxidation reaction is carried out at a temperature of 25 to 140° C. and a time of 4 to 12 hours.

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

[0018] In general, compared with the prior art, the above technical solution conceived by the present invention has the following beneficial effects:

[0019] (1) The present invention provides a method for preparing a benzoiodine oxolane reagent, which uses periodic acid or periodate as an oxidant to undergo a redox reaction with an o-iodobenzyl alcohol chemical under heating conditions. The present invention uses periodic acid or periodate as an oxidant to efficiently prepare a benzoiodine oxolane reagent in a one-step method, the steps are simple, and the reaction product is easy to separate.

[0020] (2) The present invention is applicable to a wide range of substrates and has good applicability to substrates of different types and structures. The periodic acid or periodate raw material involved in the present invention is easy to obtain and has a good effect in participating in the reaction.

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

[0022] (4) The post-treatment of the present invention does not require complicated operations such as column chromatography, and only requires simple recrystallization or beating to obtain the product. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

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

[0025] The preparation method of the benziodooxolane reagent provided by the present invention comprises the following steps:

[0026] Step S1, placing an o-iodobenzyl alcohol compound (I) and periodic acid / periodate in a reaction container, injecting a solvent (acetic acid aqueous solution) to obtain a reaction raw material mixed system.

[0027] Step S2: the reaction raw material mixture system of step S1 is heated and stirred for reaction for 4 to 12 hours.

[0028] Step S3, after the reaction of step S2 is completed, the reaction system is cooled and directly filtered, and the filter cake is washed with water, acetonitrile and dichloromethane in sequence to obtain part of the target product, and the mother liquor is concentrated and pulped to further obtain part of the target product, and the two parts of the target product are combined to obtain all the target products of the final reaction, i.e., the benzoiodine oxolane reagent (II);

[0029] The specific reaction chemical formula involved in the reaction step (2) is 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; and periodate is selected from sodium periodate, potassium periodate, potassium tetra-n-butylammonium periodate or lithium periodate.

[0032] Preferably, (I) in the above reaction formula is selected from compounds of 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:(1.0-2.0).

[0036] The sodium periodate o-iodobenzyl alcohol compound is preferred, and the molar ratio of the sodium periodate to the above-mentioned 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 the acetic acid aqueous solution, the volume ratio of acetic acid to water is preferably 3:7.

[0039] Preferably, in the above oxidation reaction conditions, the temperature is 110° C. and the time is 4 hours.

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

[0041]

[0042] As mentioned above, due to the different substituents on the o-iodobenzyl alcohol compound (I), the structure of the product is different. For example, when R1 is CF3, and there is no substituent on the aromatic ring, and there is only one halogen or one methyl substituent, the generated product contains only a dimer structure, corresponding to the following formula II-1, II-2 and II-3 respectively; when R1 is methyl, and there is no substituent on the aromatic ring, the generated product contains only an OAc structure, which is the following formula II-5; when R1 is CF3, and there are two methyl substituents on the aromatic ring, the generated product is a mixture of a dimer structure and an OAc structure, which is the following formula II-4.

[0043]

[0044] The following are specific embodiments:

[0045] Embodiment 1:

[0046] Preparation of benzoiodine oxolane reagent II-1,

[0047]

[0048] Weigh o-iodobenzyl alcohol (I-1) (50 g, 0.13 mol, 1.0 equiv), sodium periodate (30.4 g, 0.14 mol, 1.05 equiv), and a magnetic particle in a 500 mL reaction bottle. After the addition, add 208 mL of 30% AcOH-H2O (V / V) (c = 0.65 M), and place the reaction bottle in a 110°C metal bath and reflux and stir for 4 h. After the reaction is completed, cool to room temperature, and the reaction system is directly filtered through a sand core funnel. The filter cake is washed with water, acetonitrile, and dichloromethane to obtain the target product. The mother liquor is concentrated by organic solvent and pulped to remove impurities to obtain the target product. The final product is combined to obtain a white solid, namely, the product II-1 (44.9 g, 88%).

[0049] The NMR data of the benziodooxolane reagent II-1 in this example 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] Embodiment 2:

[0051] Preparation of benzoiodine oxolane reagent II-2,

[0052]

[0053] Weigh o-iodobenzyl alcohol (I-2) (500 mg, 1.30 mmol, 1.0 equiv), sodium periodate (292.4 mg, 1.37 mmol, 1.05 equiv), and a magnetic particle in a 10 mL reaction bottle. After the addition, add 2 mL of 30% AcOH-H2O (V / V) (c = 0.65 M), and place the reaction bottle in a 110 ° C metal bath and reflux and stir for 4 hours. After the reaction is completed, cool to room temperature, and the reaction system is directly filtered through a sand core funnel. The filter cake is washed with water, acetonitrile, and dichloromethane to obtain the target product. The mother liquor is concentrated by organic solvent and pulped to remove impurities to obtain the target product. The final product is combined to obtain a white solid, that is, the product II-2 (382.8 mg, 75%).

[0054] The NMR data of the benziodooxolane reagent II-2 in this example are as follows: 1 H NMR (600MHz, DMSO-d6) δ7.80 (d, J = 8.4Hz, 2H, Ar-H), 7.76 (d, J = 8.4Hz, 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] Embodiment 3:

[0056] Preparation of benzoiodine oxolane reagent II-3,

[0057]

[0058] Weigh o-iodobenzyl alcohol (I-3) (300 mg, 0.69 mmol, 1.0 equiv), sodium periodate (150.1 mg 0.70 mmol, 1.05 equiv), and a magnetic particle in a 5 mL reaction bottle. After the addition, add 1.0 mL of 30% AcOH-H2O (V / V) (c = 0.65 M), and place the reaction bottle in a 110 ° C metal bath and reflux and stir for 4 h. After the reaction is completed, cool to room temperature, and the reaction system is directly filtered through a sand core funnel. The filter cake is washed with water, acetonitrile, and dichloromethane to obtain the target product. The mother liquor is recovered, and the impurities are dissolved by concentrating the organic solvent and beating with DCM. The target product is filtered and combined to obtain the final product, which is a white solid, that is, the product II-3 (278.6 mg, 42%).

[0059] The NMR data of the benziodooxolane reagent II-3 in this example 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] Embodiment 4:

[0061] Preparation of benzoiodine oxolane reagent II-4,

[0062]

[0063] Weigh 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 particle in a 5 mL reaction bottle. After the addition, add 1.0 mL of 30% AcOH-H2O (V / V) (c=0.65 M), and place the reaction bottle in a 110°C metal bath and reflux with stirring for 4 h. After the reaction is completed, cool to room temperature, add ethyl acetate to the system, extract with water, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, transfer the organic phase to a suitable beaker, add anhydrous sodium sulfate to dry, and spin dry the organic solvent to obtain a solid crude product. Finally, a white solid is obtained by recrystallization, which is the product II-4a (140.0 mg, 46%). Recrystallization gives a white solid, which is II-4b (56.1 mg, 21%).

[0064] The NMR data of the benziodooxolane reagent II-4a in this example 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 of the benziodooxolane reagent II-4b in this example 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] Embodiment 5:

[0067] Preparation of benzoiodine oxolane reagent II-5,

[0068]

[0069] Weigh 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 particle in a 10 mL reaction bottle. After the addition, add 2.9 mL of 30% AcOH-H2O (V / V) (c=0.65 M), and place the reaction bottle in a 110°C metal bath and reflux with stirring for 4 h. After the reaction is completed, cool to room temperature, add ethyl acetate to the system, extract with water, saturated sodium bicarbonate, water, and saturated sodium chloride, transfer the organic phase to a suitable beaker, add anhydrous sodium sulfate to dry, and spin dry the organic solvent to obtain a solid crude product. Finally, a white solid is obtained by recrystallization, which is the product II-5 (547.0 mg, 90%).

[0070] The NMR data of the benziodooxolane reagent II-5 in this example 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] Embodiment 6:

[0072] Preparation of benzoiodine oxolane reagent II-1,

[0073]

[0074] According to 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, KF (52.7 g, 0.91 mol, 1.5 equiv) was added, MeOH (c = 0.5 M) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, ethyl acetate was added to the reaction system for multiple extraction operations. The organic phases were combined and extracted with water, 1 M HCl, and saturated NaCl solution in sequence, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product of compound I-1. I-1 was placed in a reaction flask, sodium periodate (135.8 g, 0.63 mol, 1.05 equiv) was added, 30% AcOH (c = 0.65 M) was added, and the reaction system was transferred to 110°C for reflux reaction for 4 h. After the reaction is completed, the reaction mixture is cooled to room temperature, and the reaction system is directly filtered through a sand core funnel. The filter cake is washed with water, acetonitrile, and dichloromethane to obtain the target product. The mother liquor is concentrated by organic solvent and pulped to remove impurities to obtain the target product. The final product is combined to obtain a white solid, namely, benzoiodine oxolane reagent II-1 (126.7 g, 56%, for 5 steps).

[0075] Embodiment 7:

[0076] Preparation of benzoiodine oxolane reagent II-2,

[0077]

[0078] According to the literature, I-2 (7.8 g, 73%, 2 steps) was prepared by p-methylaniline (150.0 g, 0.61 mol, 1.0 equiv) (Front. Chem. 2024, 12, 1376948). I-2 (7.8 g, 20.3 mmol, 1.0 equiv) was taken into a reaction bottle, sodium periodate (4.56 g, 21.3 mol, 1.05 equiv) was added, 30% AcOH (c = 0.65 M) was added, and the reaction system was transferred to 110 ° C for reflux reaction for 4 h. After the reaction was completed, it was cooled to room temperature, and the reaction system was directly filtered through a sand core funnel, and the filter cake was washed with water, acetonitrile, and dichloromethane to obtain the target product. The mother liquor was concentrated by organic solvent, pulped to remove impurities, and the target product was obtained. The final product was combined to obtain a white solid, that is, the benzoiodine oxolane reagent II-2 (6.98 g, 88%).

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

Claims

1. A method for preparing a benziodooxolane reagent, characterized in that: The method is to add periodic acid or periodate as an oxidant and an o-iodobenzyl alcohol compound with a structural formula as shown in Formula I into an acetic acid aqueous solution, heat to cause an oxidation-reduction reaction, and obtain a product benzoiodooxolane reagent with a structural formula as shown in Formula II after recrystallization or pulping; the reaction equation of the oxidation-reduction 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; and periodate is selected from sodium periodate, potassium periodate, potassium tetra-n-butylammonium periodate or lithium periodate.

2. The method for preparing the benziodooxolane reagent according to claim 1, wherein The o-iodobenzyl alcohol compound (I) is selected from the following compounds of any structure:

3. The method for preparing the benziodooxolane reagent according to claim 1, wherein 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 benziodooxolane reagent according to claim 3, wherein: The periodate is preferably sodium periodate; The molar ratio of the o-iodobenzyl alcohol compound to the sodium periodate is preferably 1.0:1.

05.

5. The method for preparing the benziodooxolane reagent according to claim 1, wherein: 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 benziodooxolane reagent according to claim 5, characterized in that: In the acetic acid aqueous solution, the volume ratio of acetic acid to water is preferably 3:

7.

7. The method for preparing the benziodooxolane reagent according to claim 1, wherein: The oxidation reaction conditions include a temperature of 25 to 140° C. and a reaction time of 4 to 12 hours.

8. Benzoiodine as claimed in claim 1 The method for preparing an oxolane reagent is characterized in that: Among the conditions for the oxidation reaction, the preferred temperature is 110° C. and the time is 4 h.

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