Process for the co-catalysis of the intramolecular ring closure of cis-epoxides with diarylboronic acids and tetrabutylammonium halides

Abstract

The application discloses a method for co-catalyzing intramolecular ring closure of cis-epoxide by diarylboronic acid and tetrabutylammonium halide, and belongs to the technical field of organic synthesis. The diarylboronic acid and the tetrabutylammonium halide are used as catalysts, and intramolecular ring closure reaction of cis-4-hydroxymethyl-1,2-cyclopentene oxide is carried out in an organic solvent to synthesize bicyclic alcohol; the cis-substrate is activated by the diarylboronic acid, the tetrabutylammonium halide is used as a transient nucleophile to make the epoxide open, the oxygen in the substrate intramolecularly attacks, and then the halide ion is removed, so that the product of intramolecular ring closure is obtained; the reaction shows good functional group tolerance. The application has the characteristics of low catalyst consumption (one thousandth), simple operation, high yield, environmental friendliness and mild reaction conditions, and has potential practical application value.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a method for efficiently catalyzing the ring closure of cis-4-hydroxymethyl-1,2-cyclopentene oxide to synthesize bicyclic alcohol by using a homogeneous system of diarylboronic acid and tetrabutylammonium halide. BACKGROUND

[0002] The application of multifunctional small molecules in constructing structurally diverse small molecule libraries has been widely concerned. Functionalized cyclopentane has great potential in rapidly constructing molecules with various scaffolds and pharmacophores. For example, the functionalization of multiple hydroxyl groups on cyclopentane can obtain mimics of natural monosaccharides ((a) Meutermans, W.; Le, G. T.; Becker, B. ChemMedChem 2006, 1, 1164-1194. (b) Thanh, G. L.; 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.; McKeveney, D.; Muldoon, C.; Pearson, A.; Rajaratnam, P.; Ryan, S.; Tometzki, G.; Verquin, G.; Waanders, J.; West, M.; Wilcox, N.; Wimmer, N.; Yau, A.; Zuegg, J.; Meutermans, W.; Versatile, A. J. Org. Chem. 2010, 75, 197-203.). The oxygen-containing bicyclic alcohol structural motif exists in drug intermediates and natural products ((a) Abell, A. D.; Blunt, J. W. Foulds, G. J.; Munro, M. H. G. J. Chem. Soc., Perkin Trans. 1997, 1, 1647-1654. (b) Hans, G.; Dag, K.; Boeckman, R. K.; Maw, G. N. Org. Synth. 1993, 71, 48.). Therefore, a strategy for conveniently and rapidly synthesizing cyclopentane-containing substituted bicyclic alcohols from simple and readily available starting materials has important scientific value and application prospect, and it is of great significance to develop a reaction efficient, simple operation and high stereoselectivity catalytic ring closure of cis-4-hydroxymethyl-1,2-cyclopentene oxide to synthesize cyclopentane-containing substituted bicyclic alcohols. SUMMARY

[0003] The purpose of this invention is to provide a method for the efficient catalytic cyclization synthesis of bicyclic alcohols using a homogeneous system of diarylboronic acid and tetrabutylammonium halide, catalyzing the cyclization of cis-4-hydroxymethyl-1,2-cyclopentene oxide.

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

[0005] A method for catalytic cyclization of cis-4-hydroxymethyl-1,2-cyclopentene oxide to bicyclic alcohols is disclosed, using diarylboronic acid (Ar₂BOH) and tetrabutylammonium halide as catalysts. The bicyclic alcohol is synthesized via an intramolecular cyclization reaction of cis-4-hydroxymethyl-1,2-cyclopentene oxide (epoxide substrate) in an organic solvent. The cis substrate is activated by diarylboronic acid, and tetrabutylammonium halide acts as a transient nucleophile to open the epoxide ring. Oxygen in the substrate undergoes intramolecular nucleophilic attack, followed by the departure of the halide ion, thus yielding the intramolecularly cyclized product. The reaction formula is as follows:

[0006]

[0007] In the formula:

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

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

[0010] Based on the above technical solutions, preferably, the electron-withdrawing or electron-donating groups include methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, cyano, phenyl, tolyl, halophenyl, and halogen.

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

[0012] Based on the above technical solutions, preferably, the diarylboronic acid is p-fluorodiphenylboronic acid.

[0013] Based on the above technical solutions, the preferred reaction temperature is 40-80℃ and the reaction time is 1-10h.

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

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

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

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

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

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

[0020] 1. The present application uses p-fluorodiphenyl boronic acid and tetrabutylammonium chloride to catalyze the reaction, and high-reactivity bicyclic alcohol can be obtained.

[0021] 2. The catalyst of the present application is easy to obtain, and the reaction operation is simple and practical, and can be carried out on a gram scale.

[0022] 3. The reaction condition of the present application is mild, the treatment steps after reaction are less, and the operation is simple. DETAILED DESCRIPTION

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

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

[0025] The synthetic starting materials (1-cyclopent-3-enyl)methanol S1a, S1c, S1e, S1h, S1m and S1n in the following examples refer to the literature as follows: (S1a, S1c, S1e and S1h: Wu, Y. J.; He, H.; Bertekap, R.; Westphal, R.; Lelas, S.; Newton, A.; Wallace, T.; Taber, M.; Davis, C; Macor, J. E.; Bronson, J. Bioorg. Med. Chem. 2013, 21, 2217-2228.; Gui, Q. W.; Wang, J. J.; Ng, S.; Dancevic, A.; Wright, T. B.; Evans, P. A. Chem. Commun., 2019, 55, 12368-12371.; Oliveira, J. M. D.; Angnes, R. A.; Khan, I. U.; Polo, E. C. P.; Heerdt, G.; Servilha, B. M.; Silva, V. H. M. D.; Braga, A. A. C; Correia, C. R. D. Chem-Eur. J. 2018, 24, 11738-11747. Chen, M.; Li, Y. g; Guan, Z.-H. Org. Lett. 2023, 25, 25715-2576.).

[0026]

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

[0028]

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

[0030] To a reaction flask under nitrogen atmosphere was added methyl 2-(p-tolyl)acetate (3.284 g, 20.0 mmol) and N,N-dimethylformamide (10 mL), the reaction flask was moved into an ice water bath at 0 °C, sodium hydride (60% oil dispersion, 2.400 g, 60.0 mmol) was added to the reaction flask, the resulting suspension was stirred at 0 °C for 30 minutes, then allyl bromide (6.049 g, 50.0 mmol) was added, the reaction mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated sodium chloride (5.0 mL), extracted with ethyl acetate (60 mL x 3); the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was column chromatographed on silica gel using petroleum ether / ethyl acetate as eluent (50 / 1) to give the allyl alkylated intermediate.

[0031] To the allyl alkylated intermediate (3.117 g, 12.1 mmol) in dichloromethane (25 mL) was added phenylmethylenebis(tricyclohexylphosphine)dichlororuthenium (Grubbs 1st catalyst) (0.199 g, 0.24 mmol), the resulting suspension was heated at 50 °C under reflux for 12 hours. After cooling to room temperature, the volatiles were removed in vacuo. The residue was column chromatographed on silica gel using petroleum ether / ethyl acetate as eluent (20 / 1) to give the 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 was added lithium aluminum hydride (0.276 g, 7.3 mmol), and the suspension was stirred at 0 °C for 2 hours, the reaction was quenched with saturated sodium sulfate, then extracted with ethyl acetate (40 mL x 3); the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel using petroleum ether / ethyl acetate (20 / 1) as eluent to give the desired S1b (1.135 g, 30%).

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

[0034] The characterization data for the above Part (1-cyclopent-3-enyl)methanols compounds are as follows:

[0035]

[0036] The synthetic route for the cis 4-hydroxymethyl-1,2-cyclopentene oxides 1a-1n is as follows:

[0037]

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

[0039] The above olefin S1a (3.210 g, 18.4 mmol) was added to dichloromethane (20 mL) and 3-chloroperoxybenzoic acid (6.358 g, 36.8 mmol) was added at 0°C, then the resulting suspension was stirred at room temperature for 12 hours; the reaction was quenched with saturated sodium thiosulfate, then with saturated sodium bicarbonate, this process was repeated twice, all the remaining 3-chloroperoxybenzoic acid was washed out (when the wet starch 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 column chromatographed on silica gel, first using petroleum ether / ethyl acetate (10 / 1) as eluent, then using petroleum ether / ethyl acetate (5 / 1) as eluent, to give the desired epoxide 1a.

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

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

[0042]

[0043]

[0044] Examples 1-15

[0045] Optimization of the epoxide ring opening reaction conditions

[0046] Under an atmosphere, to the reaction bottle containing 0.2 mmol of cis 4-hydroxymethyl-1,2-cyclopentene oxide substrate 1a, p-fluorobenzene boronic 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, the reaction was stirred at 40°C for 2 hours, then the reaction was stopped, the solvent was removed under reduced pressure, and the pure product was separated by column chromatography, the reaction formula was as follows:

[0047]

[0048] The yield was the conversion rate, and the type of catalyst, the type of organic solvent, the amount of catalyst were changed during the reaction process, which was shown in Table 1 in detail.

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

[0050]

[0051]

[0052] Examples 16-30

[0053] Synthesis of bicyclic alcohols by cis 4-hydroxymethyl-1,2-cyclopentene oxide ring closure

[0054] To a solution of 0.5 mmol of cis 4-hydroxymethyl-1,2-cyclopentene oxide substrate la-lo in ethyl acetate (2.0 mL) was added p-fluorobenzenboronic acid catalyst 2a (0.1 mol% of substrate), tetrabutylammonium chloride (0.2 mol% of substrate) at 60 °C under an atmosphere of nitrogen and stirred for 6 hours. The reaction was then stopped and the solvent removed under reduced pressure. The pure product was isolated by column chromatography. The reaction conditions and parameters varied with the substrate and are shown in the scheme below:

[0055]

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

[0057]

[0058]

Claims

1. A method for catalytic ring closure of cis 4-hydroxymethyl- 1,2- cyclopentene oxide to synthesize bicyclic diols, characterized in that, The bicyclic alcohol is synthesized by intramolecular cyclization reaction of cis-4-hydroxymethyl-1,2-cyclopentene oxide in an organic solvent with diarylboronic acid and tetrabutylammonium halide as catalysts; the reaction formula is as follows: In the formula, R is C1-C 10 alkyl, phenyl, phenyl with a substituent, which is methyl, methoxy, tert-butyl or halogen; Ar is Ph, 4-FC6H4, 4-CF3C6H4 or 3,4,5-triFC6H2; X is halogen.

2. The method of claim 1, wherein, The organic solvent includes chloroform, dichloromethane, dichloroethane, toluene, trifluorotoluene, acetonitrile, ethyl acetate, tetrahydrofuran and 1,4-dioxane.

3. The method of claim 1, wherein, The diarylboronic acid is p-fluorodiphenylboronic acid.

4. The method of claim 1, wherein, The reaction temperature is 40-80 o C, and the reaction time is 1-10 h.

5. The method of claim 1, wherein, The method comprises the following steps: (1) adding diarylboronic acid, tetrabutylammonium halide and organic solvent into a cis-4-hydroxymethyl-1,2-cyclopentene oxide substrate to obtain a reaction solution; (2) Heat the reaction solution at 40-80°C o The reaction was stirred at C for 1-10 h to obtain the cyclized product. The solvent was then removed under reduced pressure, and the pure bicyclic alcohol product was obtained by column chromatography.

6. The method of claim 5, wherein, The molar ratio of diarylboronic acid, tetrabutylammonium halide and the substrate is 0.001-0.01:0.002-0.02:

1.

7. The method of claim 5, wherein, The concentration of the substrate in the reaction solution is 0.1-10 mmol / mL.

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