Method for intramolecular cyclization of cis-epoxide under co-catalysis of diarylboronic acid and tetrabutylammonium halide

Abstract

The invention discloses a method for co-catalyzing intramolecular cyclization of cis-epoxide by diarylboronic acid and tetrabutylammonium halide, and belongs to the technical field of organic synthesis. According to the method, diarylboronic acid and tetrabutyl ammonium halide are used as catalysts, and the bicyclol is synthesized through intramolecular ring closing reaction of cis-4-hydroxymethyl-1, 2-cyclopentene oxide in an organic solvent; according to the method, a cis-substrate is activated by diarylboronic acid, tetrabutylammonium halide is used as an instantaneous nucleophilic reagent to enable epoxy to be subjected to ring opening, oxygen in the substrate is subjected to intramolecular nucleophilic attack, and then halide ions are removed, so that an intramolecular ring closing product is obtained, and the reaction shows good functional group tolerance. The method has the characteristics of low catalyst dosage (one thousandth), simplicity and convenience in operation, high yield, environment friendliness and mild reaction conditions, and has potential practical application value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing bicyclic alcohol by ring-closing cis-4-hydroxymethyl-1,2-cyclopentene oxide using a homogeneous system of diarylboric acid and tetrabutylammonium halide to efficiently catalyze the synthesis. Background Art

[0002] The application of multifunctional small molecules in constructing structurally diverse small molecule libraries has always attracted widespread attention. Functionalized cyclopentane has great potential in rapidly constructing molecules with various scaffolds and pharmacophores. For example, by functionalizing multiple hydroxyl groups on cyclopentane, mimics of natural monosaccharides can be obtained ((a) Meutermans, W.; Le, GT; Becker, B. Chem Med Chem 2006, 1, 1164-1194. (b) Thanh, GL; Abbenante, G.; Adamson, G.; Becker, B.; Clark, C.; Condie, G.; Falzun, T.; Grathwohl, M.; Gupta, P.; Hanson, M.; Huynh, N.; Katavic, P.; Kuipers, K.; Lam, A.; Liu, L.; Mann, M.; Mason, J.; M cKeveney,D.;Muldoon,C.;Pearson,A.;Rajaratnam,P.;Ryan,S.;Tometzki,G.;Verquin,G.;Waanders,J.;Wes t, M.; Wilcox, N.; Wimmer, N.; Yau, A.; Zuegg, J.; Meutermans, W.; Versatile, AJ Org. Chem. 2010, 75, 197-203.). The oxygen-containing bicyclic alcohol structural motif exists in drug intermediates and natural products ((a) Abell, AD; Blunt, JW Foulds, GJ; Munro, MHG; J. Chem. Soc., Perkin Trans. 1997, 1, 1647-1654. (b) Hans, G.; Dag, K.; Boeckman, RK; Maw, GN; Org. Synth. 1993, 71, 48.). It can be seen that the strategy of synthesizing cyclopentane-containing substituted bicyclic alcohols conveniently and quickly from simple and readily available raw materials has important scientific value and application prospects. It is of great significance to study and develop a highly efficient, simple to operate and highly stereoselective catalytic cycloclosure of cis-4-hydroxymethyl-1,2-cyclopentene oxide to synthesize cyclopentane-containing substituted bicyclic alcohols. Summary of the invention

[0003] The invention aims to provide a method for synthesizing bicyclic alcohol by ring-closing cis-4-hydroxymethyl-1,2-cyclopentene oxide using a homogeneous system of diarylboronic acid and tetrabutylammonium halide for high efficiency catalysis.

[0004] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0005] A method for catalyzing the ring-closure of cis-4-hydroxymethyl-1,2-cyclopentene oxide to synthesize bicyclic alcohols, wherein diarylboronic acid (Ar2BOH) and tetrabutylammonium halide are used as catalysts, and cis-4-hydroxymethyl-1,2-cyclopentene oxide (epoxy substrate) is subjected to an intramolecular ring-closure reaction in an organic solvent to synthesize bicyclic alcohols; the cis substrate is activated by diarylboronic acid, and tetrabutylammonium halide is used as an instantaneous nucleophilic reagent to open the epoxy ring, and the oxygen in the substrate undergoes an intramolecular nucleophilic attack, followed by the leaving of halide ions, thereby obtaining an intramolecular ring-closure product; the reaction formula is as follows:

[0006]

[0007] Where:

[0008] R is a C1-C10 alkyl group, a phenyl group, a phenyl group containing a substituent, or an aryl group containing a substituent, wherein the substituent is at least one of an electron-withdrawing group and an electron-donating group;

[0009] Ar is Ph, 4-FC6H4, 4-CF3C6H4 or 3,4,5-triFC6H2.

[0010] Based on the above technical scheme, preferably, the electron withdrawing group or the electron donating group includes methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, cyano, phenyl, tolyl, halogenated phenyl and halogen.

[0011] Based on the above technical scheme, preferably, the organic solvent includes chloroform, dichloromethane, dichloroethane, toluene, trifluorotoluene, acetonitrile, ethyl acetate, tetrahydrofuran and 1,4-dioxane.

[0012] Based on the above technical solution, preferably, the diarylboric acid is p-fluorodiphenylboric acid.

[0013] Based on the above technical solution, preferably, the reaction temperature is 40-80°C and the reaction time is 1-10h.

[0014] Based on the above technical solution, preferably, the method comprises the following steps:

[0015] (1) adding diarylboric acid, tetrabutylammonium halide and an organic solvent to a cis-4-hydroxymethyl-1,2-cyclopentene oxide substrate to obtain a reaction solution;

[0016] (2) The reaction solution is stirred at 40-80° C. for 1-10 h to obtain a ring-closed product, and then the solvent is removed under reduced pressure and separated by column chromatography to obtain a pure bicyclic alcohol product.

[0017] Based on the above technical scheme, preferably, the molar ratio of diarylboric acid, tetrabutylammonium halide and substrate is 0.001-0.01:0.002-0.02:1.

[0018] Based on the above technical solution, preferably, the concentration of the substrate in the reaction solution is 0.1-10 mmol / mL, preferably 0.2 mmol / mL.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. The present invention uses p-fluorodiphenylboric acid and tetrabutylammonium chloride as catalysts to obtain highly reactive bicyclic alcohols;

[0021] 2. The catalyst of the present invention is easy to source, the reaction operation is simple and practical, and gram-scale experiments can be carried out;

[0022] 3. The reaction conditions of the present invention are mild, the post-reaction processing steps are few, and the operation is simple. DETAILED DESCRIPTION

[0023] The present invention is described in detail below by examples, but the present invention is not limited to the following examples.

[0024] The boric acid catalysts 2a-2b used in the following examples were synthesized according to the literature method (2a-2b: Wang, G.; Garrett, G.; Taylor, MS Org. Lett. 2018, 20, 5375-5379.; Arkhipenko, S.; Sabatini, MT; Batsanov, AS; Karaluka, V.; Sheppard, TD; Rzepa, HS; Whiting, A. Chem. Sci. 2018, 9, 1058-1072.); catalyst 2c is a commercially available raw material.

[0025] References for the synthesis of raw materials (1-cyclopent-3-enyl)methanol S1a, S1c, S1e, S1h, S1m and S1n in the following examples are as follows: (S1a, S1c, S1e and S1h: Wu, YJ; He, H.; Bertekap, R.; Westphal, R.; Lelas, S.; Newton, A.; Wallace, T.; Taber, M.; Davis, C.; Macor, JE; Bronson, J. Bioorg. Med. Chem. 2013, 21, 2217-2228.; Gui, QW; Wang, JJ; Ng, S.; Dancevi c, A.; Wright, TB; Evans, PAChem. Commun., 2019, 55, 12368-12371.; Oliveira, JMD; Angnes, RA; Khan, IU; Polo, ECP; Heerdt, G.; Servilha, BM ;Silva, VHMD;Braga,AAC;Correia,CRDChem-Eur.J.2018,24,11738-11747.Chen,M.;Li,Yg;Guan,Z.-H.Org.Lett.2023,25,25715-2576.).

[0026]

[0027] The synthetic routes of (1-cyclopent-3-enyl)methanol S1b, S1d, S1f, S1g, S1i, S1j, S1k, S1l and S1o are as follows:

[0028]

[0029] (1-Cyclopent-3-enyl)methanol S1b is prepared by the following steps:

[0030] Under nitrogen atmosphere, 2-(p-toluene)acetic acid methyl ester (3.284g, 20.0mmol) and N,N-dimethylformamide (10mL) were added to the reaction bottle, the reaction bottle was moved into a 0℃ ice-water bath, sodium hydride (60% oil dispersion, 2.400g, 60.0mmol) was added to the reaction bottle, the resulting suspension was stirred at 0℃ for 30 minutes, then allyl bromide (6.049g, 50.0mmol) was added, and the reaction mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated sodium chloride (5.0mL), extracted with ethyl acetate (60mL×3); the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel, using petroleum ether / ethyl acetate as eluent (50 / 1) to obtain the allylic alkylation intermediate.

[0031] To the allyl alkylation intermediate (3.117 g, 12.1 mmol) was added phenylmethylenebis(tricyclohexylphosphine)ruthenium dichloride (Grubbs first generation catalyst) (0.199 g, 0.24 mmol) in dichloromethane (25 mL), and the resulting suspension was heated at 50° C. for 12 hours under reflux. After cooling to room temperature, volatiles were removed in vacuo. The residue was subjected to column chromatography with silica gel using petroleum ether / ethyl acetate as eluent (20 / 1) to obtain a cyclopentene derivative.

[0032] To a solution of the above cyclopentene derivative (1.570 g, 7.3 mmol) in tetrahydrofuran (5.0 mL) at 0°C, lithium aluminum hydride (0.276 g, 7.3 mmol) was added, and the suspension was stirred at 0°C for 2 hours, quenched with saturated sodium sulfate, and then extracted with ethyl acetate (40 mL×3); the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using petroleum ether / ethyl acetate (20 / 1) as eluent to obtain the desired S1b (1.135 g, 30%).

[0033] The same method as above was used to synthesize S1d, S1f, S1i, S1j, S1k, S1l and S1o; for the synthesis of S1g, lithium diisopropylamide (LDA) was used instead of sodium hydride.

[0034] The characterization data of some of the above (1-cyclopent-3-enyl)methanol compounds are as follows:

[0035]

[0036] The synthetic routes of cis-4-hydroxymethyl-1,2-cyclopentene oxide 1a-1n are as follows:

[0037]

[0038] Cis-4-hydroxymethyl-1,2-cyclopentene oxide 1a is prepared by the following steps:

[0039] The above olefin S1a (3.210 g, 18.4 mmol) was added to dichloromethane (20 ml), 3-chloroperoxybenzoic acid (6.358 g, 36.8 mmol) was added at 0°C, and the resulting suspension was stirred at room temperature for 12 hours; the reaction was quenched with saturated sodium thiosulfate and then quenched with saturated sodium bicarbonate, and the process was repeated twice, and all the remaining 3-chloroperoxybenzoic acid was washed away (when the wet starch potassium iodide paper did not change color, it meant that the 3-chloroperoxybenzoic acid was completely consumed). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel, first using petroleum ether / ethyl acetate (10 / 1) as eluent, and then using petroleum ether / ethyl acetate (5 / 1) as eluent to obtain the desired epoxide 1a.

[0040] The same method as above was used to synthesize 1b-1o.

[0041] The characterization data of some of the above cis-4-hydroxymethyl-1,2-cyclopentene oxide 1a are as follows:

[0042]

[0043]

[0044] Examples 1-15

[0045] Optimization of Epoxy Ring-Opening Reaction Conditions

[0046] Under atmospheric atmosphere, p-fluorodiphenylboric acid catalyst (1 mol% or 0.1 mol% of the substrate amount), tetrabutylammonium chloride (2 mol% or 0.2 mol% of the substrate amount) and ethyl acetate (1.0 mL) were added to a reaction bottle containing 0.2 mmol of cis-4-hydroxymethyl-1,2-cyclopentene oxide substrate 1a, and the mixture was stirred at 40° C. for 2 hours. The reaction was then stopped, the solvent was removed under reduced pressure, and the pure product was separated by column chromatography. The reaction formula is as follows:

[0047]

[0048] The yield is the conversion rate. The type of catalyst, the type of organic solvent, and the amount of catalyst used in the reaction process are changed. See Table 1 for details.

[0049] Table 1. Optimization of ring-closure conditions for cis-4-hydroxymethyl-1,2-cyclopentene oxide a

[0050]

[0051]

[0052] Embodiment 16-30

[0053] Synthesis of Bicyclic Alcohols from the Ring Closure of cis-4-Hydroxymethyl-1,2-Cyclopentene Oxide

[0054] Under atmospheric atmosphere, 0.5 mmol of cis-4-hydroxymethyl-1,2-cyclopentene oxide substrate 1a-1o was charged with p-fluorodiphenylboronic acid catalyst 2a (0.1 mol% of substrate amount), tetrabutylammonium chloride (0.2 mol% of substrate amount) and ethyl acetate (2.0 mL), and stirred at 60°C for 6 hours. Then the reaction was stopped, the solvent was removed under reduced pressure, and the pure product was separated by column chromatography. The specific reaction conditions and parameters were shown in the reaction formula when the type of reaction substrate was changed. The reaction formula is as follows:

[0055]

[0056] The characterization data of some bicyclic alcohols 3 obtained in the above examples are as follows:

[0057]

[0058]

Claims

1. A method for catalyzing the ring closure of cis-4-hydroxymethyl-1,2-cyclopentene oxide to synthesize bicyclic alcohols, characterized in that: Using diarylboric acid and tetrabutylammonium halide as catalysts, cis-4-hydroxymethyl-1,2-cyclopentene oxide is subjected to an intramolecular ring-closing reaction in an organic solvent to synthesize bicyclic alcohols; the reaction formula is as follows: Where: R is C1-C 10 An alkyl group, a phenyl group, a phenyl group having a substituent, or an aryl group having a substituent, wherein the substituent is at least one of an electron-withdrawing group and an electron-donating group; Ar is Ph, 4-FC6H4, 4-CF3C6H4 or 3,4,5-triFC6H2.

2. The method according to claim 1, characterized in that: The electron withdrawing group or the electron donating group includes methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, cyano, phenyl, tolyl, halophenyl and halogen.

3. The method according to claim 1, characterized in that The organic solvent includes chloroform, dichloromethane, dichloroethane, toluene, trifluorotoluene, acetonitrile, ethyl acetate, tetrahydrofuran and 1,4-dioxane.

4. The method according to claim 1, characterized in that: The diarylboronic acid is p-fluorodiphenylboric acid.

5. The method according to claim 1, characterized in that The reaction temperature is 40-80°C and the reaction time is 1-10h.

6. The method according to claim 1, characterized in that The method comprises the following steps: (1) adding diarylboric acid, tetrabutylammonium halide and an organic solvent to a cis-4-hydroxymethyl-1,2-cyclopentene oxide substrate to obtain a reaction solution; (2) The reaction solution is stirred at 40-80° C. for 1-10 h to obtain a ring-closed product, and then the solvent is removed under reduced pressure and separated by column chromatography to obtain a pure bicyclic alcohol product.

7. The method according to claim 1, characterized in that The molar ratio of diarylboric acid, tetrabutylammonium halide and substrate is 0.001-0.01:0.002-0.02:

1.

8. The method according to claim 1, characterized in that The concentration of the substrate in the reaction solution is 0.1-10 mmol / mL.

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