A method for preparing and applying a sterically hindered oxygen heterospirocyclic compound

Abstract

This invention discloses a method for synthesizing a sterically hindered oxaspirocyclic compound, namely 4,4',6,6'-tetratert-butyl-1,1'-spirodihydrobenzofuran-7,7'-diol and its bisphosphine compounds. The method uses 3-methoxyphenol as a starting material and proceeds through seven steps: nucleophilic substitution, oxidation, bromination, Friedel-Crafts cyclization, debromination, demethylation, and alkylation; or through four (or five) steps: alkylation, nucleophilic substitution, (oxidation), Friedel-Crafts cyclization, and demethylation, to obtain the corresponding racemic oxaspirodiol, which is then esterified to obtain a sterically hindered oxaspirocyclic bisphosphonate compound. The oxaspirocyclic bisphosphine compound has the structure shown in Formula I, and its racemic form with a transition metal ligand exhibits excellent reactivity, selectivity, and stability in the hydroformylation of olefins. Simultaneously, this invention discloses the preparation of pentanal using rhodium / oxaspirocyclic bisphosphine ligands in a hydroformylation reaction with mixed C4 as a starting material.

Description

Technical Field

[0001] This invention relates to the preparation method and application of the oxaspirocyclodiol skeleton 4,4',6,6'-tetratert-butyl-1,1'-spirodihydrobenzofuran-7,7'-diol and its bisphosphonates. Background Technology

[0002] Axisymmetric organic compounds have always been a research hotspot in the field of asymmetric catalysis, and they have wide applications in biomedicine, industrial catalysis, and functional materials. Biaryl ligands such as BINOL and BINAP, which have already achieved near-successful industrialization, have found widespread use.

[0003]

[0004] In 1999, Birman et al. obtained racemic spirodihydroindole ((±)-SPINOL) through a six-step reaction starting from acetone and 3-methoxybenzaldehyde. The diastereomers formed by this diphenol and menthol chloroformate can be separated by column chromatography to obtain optically pure (R)-(+)-SPINOL and (S)-(-)-SPINOL. Similar synthetic routes and resolution methods were also reported in US20130135574A1 and CN1055003542A. Building on this, Zhou Qilin et al. of Nankai University reported a more practical resolution method in 2002. They utilized the characteristic of benzyl octinidine chloride and one of the enantiomers readily forming inclusion complexes, obtaining optically pure spirodihydroindole through simple steps of reflux, cooling, crystallization, filtration, and acidification. In 2016, Tan et al. reported the asymmetric synthesis of spinol catalyzed by chiral phosphonic acids, directly cyclizing and dehydrating 1,5-bis(5-hydroxy-2-methylphenyl)-3-pentanone to (S)-4,4'-dimethyl-7,7'-dihydroxy-1,1'-spirodihydroindene (97% yield, ee value 90%). Notably, the ligands they used were phosphonic acids with chiral spinol as the backbone. Furthermore, CN109761774A investigated a method for synthesizing racemic spinol from 1,5-bis(3-hydroxyphenyl)-3-pentanone via Friedel-Crafts cyclization, which is the first report on the synthesis of 1,1'-spirodihydroindene-7,7'-diol via cyclization at the para-hydroxyl position without the need for a stationary group.

[0005] Since its discovery by Professor Otto Roelen in 1938, the hydroformylation reaction has been widely applied in industry. The largest production and consumption process involves the hydroformylation of propylene to produce butyraldehyde, followed by condensation and hydrogenation to produce butanol (primarily used in the production of dioctyl phthalate, DOP), with domestic demand exceeding 3 million tons annually. Due to DOP's small molecular weight and high volatility, the global trend, based on environmental and health safety considerations, is towards using plasticizers with higher molecular weight, lower volatility, and greater stability. The hydroformylation of butene to produce pentanal, followed by condensation and hydrogenation to obtain 2-propylheptanol (2-PH), and the DPHP plasticizer produced from 2-PH, effectively addresses the environmental, health, and safety concerns associated with DOP. To date, countries such as the United States and the European Union have begun using DPHP to replace DOP, and this trend is starting to influence the Asian market.

[0006] The mixed C4 hydroformylation method is currently recognized as the most economical and direct route for pentanal production. The catalytic system developed by Union Carbide (now Dow Chemical) using a biphenyl bisphosphonate ligand (Biphephos) and rhodium enables the efficient hydroformylation of 2-butene in mixed C4 compounds, achieving a high N / I ratio. For example, the bisphosphonate ligands proposed in US4668651, US4769498, US4148830, CN86106770, and CN86106811 can achieve an N / I ratio of 26. Furthermore, the fourth-generation bisphosphonate-catalyzed hydroformylation process based on Biphephos has been industrialized.

[0007] In hydroformylation reactions, bidentate and multidentate phosphonite / phosphonamide ligands with biphenyl, binaphthalene, and anthracenetriol skeletons (such as Biphephos and Anthracenetriol-based triphosphite) have been widely reported and patented by large international chemical companies such as BASF, Dow Chemical, and Evonik, as well as some research groups. However, reports on spirocyclic bisphosphonite / phosphonamide ligands are very rare. In 2012, Ding et al. reported a series of spiroketal bisphosphonamide ligands that exhibited excellent conversion (90%) and anisotropic ratio (l / b = 174.4) in the hydroformylation of 1-hexene and other terminal alkenes, but the conversion in the hydroformylation of internal alkenes (such as trans-2-butene) was less than 15%. Therefore, developing novel spirocyclic bisphosphonate ligands with higher efficiency, selectivity, and stability is of great significance and has industrial application value.

[0008]

[0009] The novel preparation method for sterically barrier oxygen-spirocyclic diphenols and their bisphosphonates developed in this invention involves only four steps from starting materials to racemic O-SPINOL. This method is characterized by ease of synthesis, suitability for scale-up synthesis, absence of expensive reagents and metal catalysts, and industrial applicability. The process route is simple, yields high, avoids harsh and dangerous experimental conditions and reagents, and allows for the recycling of raw materials. Furthermore, the novel sterically barrier oxygen-spirocyclic bisphosphonates (racemic form) can be used to catalyze hydroformylation reactions using inexpensive post-ether C4 or MTO C4 as starting materials. Summary of the Invention

[0010] The purpose of this invention is to provide a method for preparing and applying sterically hindered oxygen heterospirocyclic compounds.

[0011] The embodiments of the present invention are implemented as follows: a sterically hindered oxygen-spirocyclodiol and its bisphosphonates, the structure of which is shown in general formula I:

[0012]

[0013] The structures of general formula I and its derivatives are represented as follows:

[0014]

[0015] Another objective of this invention is to provide a method for preparing and applying sterically hindered oxaspirocyclic diphenols and their bisphosphonates. The oxaspirocyclic bisphosphonates are prepared by reacting 4,4',6,6'-tetratert-butyl-1,1'-spirodihydrobenzofuran-7,7'-diphenol with a chlorophosphonate containing an aryl or cyclic aryl structure in an organic solvent and under the action of n-butyllithium or triethylamine. The oxaspirocyclic bisphosphonate ligand is one of L1-L31. Attached Figure Description

[0016] Figure 1 The intermittent olefin pilot-scale evaluation device used in the comparative embodiments of the present invention;

[0017] Figure 2 The ligand compound L4 of this invention 1 Schematic diagram of H NMR (600MHz, CDCl3);

[0018] Figure 3 The ligand compound L4 of this invention 31 Schematic diagram of PNMR (243MHz, CDCl3). Detailed Implementation

[0019] The above-described approach of the present invention will be specifically described below through embodiments. To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the present invention.

[0020] This invention discloses three synthetic routes for oxyspirocyclic compounds with large positions of oxygen. Starting from 3-methoxyphenol, the oxyspirocyclic diol is obtained after 4 to 7 steps of reaction, and then esterified with chlorophosphonates to obtain oxyspirocyclic bisphosphonates ligands.

[0021] Specifically, the synthesis method involved in this invention is described as follows:

[0022] In some embodiments, 3-methoxyphenol undergoes a nucleophilic substitution reaction with 1,3-dichloro-2-propanol to give 1,5-bis(3-methoxyphenoxy)-2-propanol (2); under the catalysis of a protic acid or Lewis acid, isobutylene undergoes proton addition to generate a tert-butyl carbocation, which further undergoes an alkylation reaction with the benzene ring on 3-methoxyphenol to give 2,4-di-tert-butyl-5-methoxyphenol (2a or 2c); 2,4-di-tert-butyl-5-methoxyphenol then undergoes a nucleophilic substitution reaction with 1,3-dichloro-2-propanol or 2,2-bis(chloromethyl)-1,3-dioxolane to give 2,4-di-tert-butyl-1,5-bis(3-methoxyphenoxy)-2-propanol (3a) or 2,4-di-tert-butyl-1,5-bis(3-methoxyphenoxy)-2-propyldioxolane (3c).

[0023] In some embodiments, the halogenating agent used in the nucleophilic substitution reaction may be any one of the following, in addition to 1,3-dichloro-2-propanol or 2,2-bis(chloromethyl)-1,3-dioxolane: 1,3-difluoro-2-propanol, 1,3-dibromo-2-propanol, 1,3-diiodo-2-propanol, epichlorohydrin; or any one of 2,2-bis(fluoromethyl)-1,3-dioxolane, 2,2-bis(bromomethyl)-1,3-dioxolane, 2,2-bis(iodomethyl)-1,3-dioxolane.

[0024] In some embodiments, the protic acid or Lewis acid used in the alkylation reaction is one or more of organic or inorganic acids. Organic acids include: formic acid, acetic acid, oxalic acid, dichloroacetic acid, trifluoroacetic acid, propionic acid, malonic acid, pyruvic acid, butyric acid, valeric acid, hexanoic acid, adipic acid, benzoic acid, p-nitrobenzoic acid, terephthalic acid, benzenesulfonic acid, fluorosulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, etc. Inorganic acids include: hydrobromic acid, hydrochloric acid, hydrofluoric acid, sulfurous acid, sulfuric acid, perchloric acid, phosphonic acid, pyrophosphate, nitric acid, nitrous acid, chromic acid, fluoroantimonysulfonic acid, fluoroantimony acid, etc. The alkylating agent is any one of tert-butane bromide, tert-butane chloroform, isobutylene, tert-butanol. The reaction temperature is 80–140°C, and the reaction solvent is any one of benzene, toluene, p-toluene, p-xylene, o-xylene, chlorobenzene, or dichlorobenzene.

[0025] In some embodiments, intermediate 2 or 3a is catalytically oxidized with chromium trioxide to obtain 1,5-bis(3-methoxyphenoxy)-acetone (3) or 2,4-di-tert-butyl-1,5-bis(3-methoxyphenoxy)-acetone (4a).

[0026] In some embodiments, the metal oxide used in the oxidation reaction is any one of chromium trioxide, chromic acid, potassium dichromate, and sodium dichromate; the acidic solution can be any one of concentrated sulfuric acid, phosphonic acid, hexafluorophosphonic acid, hypochlorous acid, chloroous acid, glacial acetic acid, and peracetic acid; the amount of metal oxide used is 0.05 to 1 equivalent; the reaction solvent is acetone or water, or a mixture thereof, with the ratio of the mixed solvent between 50:50 and 70:30; and the reaction temperature is 25 to 45°C.

[0027] In some preferred embodiments, intermediate 3 undergoes a halogenation reaction with bromine or N-bromosuccinimide to give 1,5-bis(2-bromo-3-methoxyphenoxy)-acetone (4); intermediate 4 or 4a or 3c is subjected to Friedel-Crafts cyclization in the presence of a dehydrating agent to give 4,4'-dibromo-7,7'-dimethoxy-1,1'-spirodihydrobenzofuran (5) or 4,4',6,6'-tetratert-butyl-7,7'-dimethoxy-1,1'-spirodihydrobenzofuran (5a or 4c).

[0028] In some embodiments, the amount of bromine or N-bromosuccinimide used in the halogenation reaction is 1 to 10 equivalents, the amount of pyridine is 2 to 20 equivalents, the reaction temperature is -20 to 40°C, the reaction time is 2 to 24 hours, and the reaction solvent is an organic solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, or dichloromethane.

[0029] In some embodiments, the dehydrating agent used in the Friedel-Crafts cyclization reaction is any one of polyphosphoric acid, concentrated sulfuric acid, acetic anhydride, methanesulfonic acid, benzoic acid, p-toluenesulfonic acid, and anhydrous aluminum trichloride. The reaction solvent is any one of toluene, n-heptane, dichloromethane, trichloromethane, and dichloroethane. The amount of dehydrating agent used is 10–70 equivalents, the reaction temperature is 45–135°C, and the reaction time is 2–6 hours.

[0030] In some embodiments, intermediate 4 or 4a undergoes a cyclization reaction under the action of a dehydrating agent to obtain 4,4',6,6'-tetratert-butyl-1,1'-spirodihydroindene-7,7'-diol (5) or 4,4'-dimethoxy-6,6'-ditert-butyl-1,1'-spirodihydroindene-7,7'-diol (5a).

[0031] In some embodiments, the dehydrating agent is any one of polyphosphoric acid, concentrated sulfuric acid, acetic anhydride, methanesulfonic acid, benzoic acid, p-toluenesulfonic acid, and anhydrous aluminum trichloride. The reaction solvent is any one of toluene, n-heptane, dichloromethane, trichloromethane, and dichloroethane. The amount of dehydrating agent used is 10–70 equivalents, the reaction temperature is 45–135°C, and the reaction time is 2–6 hours.

[0032] In some embodiments, intermediate 5 undergoes a debromination reaction under the action of n-butyllithium to obtain 7,7'-dimethoxy-1,1'-spirodihydrobenzofuran (6), and intermediate 6 or 5a or 4c undergoes a demethylation reaction under the action of a demethylating agent to obtain 1,1'-spirodihydrobenzofuran-7,7'-diol (7) or 4,4',6,6'-tetratert-butyl-1,1'-spirodihydrobenzofuran-7,7'-diol ((rac)-O-SPINOL). Intermediate 7 undergoes an alkylation reaction with isobutylene to obtain racemic, sterically hindered (rac)-O-SPINOL.

[0033] In some embodiments, the amount of n-butyllithium used in the debromination reaction is 2.5 to 10 equivalents, the reaction temperature is -78 to 5°C, the reaction time is 0.5 to 5 hours, and the reaction solvent is an organic solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, or methyl tert-butyl ether.

[0034] In some embodiments, the demethylating agent is any one of boron tribromide, hydrobromic acid, aluminum trichloride, pyridine hydrochloride, and sodium ethanethiol. The amount of the demethylating agent used is 2.0 to 5 equivalents, the reaction temperature is -78 to 25°C, and the reaction solvent is any one of dichloromethane, dichloroethane, and trichloroethane.

[0035] In some embodiments, (rac)-O-SPINOL reacts with n-butyllithium to obtain a lithified reaction solution; the lithified reaction solution reacts with chlorophosphonates containing aryl or cyclic aryl structures to obtain a sterically hindered heterospirocyclic bisphosphonate compound.

[0036] In some embodiments, (rac)-O-SPINOL is reacted with a mixed solution of a chlorophosphonite containing an aryl or cyclic aryl structure and an acid-binding agent to obtain a sterically hindered spirocyclic bisphosphonite compound.

[0037] In some embodiments, in the esterification reaction, the amount of n-butyllithium is 2 to 4 equivalents; the acid-binding agent is any one of triethylamine, N,N-diisopropylethylamine, and pyridine, and the amount is 5 to 20 equivalents; the reaction temperature is -78 to 80°C, the reaction time is 12 to 48 hours, and the reaction solvent is any one of toluene, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, butyl ether, cyclopentyl methyl ether, or 1,4-dioxane.

[0038] Example 1: Preparation of 2,4-di-tert-butyl-5-methoxyphenol (2)

[0039]

[0040] Add 1a (30.0 g, 241.7 mmol) to a 2 L double-necked flask, purge the reaction flask to a nitrogen atmosphere, and add 200 mL of tetrahydrofuran and concentrated sulfuric acid (3.9 g) at 25 °C. Isobutylene is continuously bubbled through the mixture at 1.5 atm, and the reaction is heated to 100 °C for 12 hours. After quenching the reaction solution with water, add 300 mL of water and extract with ethyl acetate. The resulting organic phase is dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain 54.8 g of a pale yellow solid, with a yield of 96%. 1 HNMR (400MHz, CDCl3): δ = 1.39 (s, 9H), 1.44 (s, 9H), 3.84 (s, 3H), 6.32 (s, 1H), 6.72 (s, 1H), 7.17 (s, 1H).

[0041] Example 2: Preparation of 1,5-bis(3-methoxyphenoxy)-2-propanol (2), 2,4-di-tert-butyl-1,5-bis(3-methoxyphenoxy)-2-propanol (3a) or 2,4-di-tert-butyl-1,5-bis(3-methoxyphenoxy)-2-propyldioxolane (3c)

[0042]

[0043] Add 100 g of product 1,3-dichloro-2-propanol or 2,2-bis(chloromethyl)-1,3-dioxolane, potassium carbonate, and dimethylformamide to a 5 L two-necked flask. React at 140 °C for 10 hours. Filter the reaction solution, dry it over anhydrous sodium sulfate, and then evaporate to dryness under reduced pressure to obtain product 2 (74.8 g), 3a (64.9 g), or 3c (62.8 g), with corresponding yields of 61%, 58%, and 52%, respectively. 1 H NMR (400MHz, CDCl3): δ = 3.54 (d, 1H), 3.78 (s, 6H), 4.04–4.17 (m, 4H), 4.31 (m, 1H), 6.42 (t, 2H), 6.62 (m, 2H), 6.80 (m, 2H), 7.19 (t, 2H); 3a: 1 H NMR (400MHz, CDCl3): δ = 1.37 (d, 36H), 3.28 (d, 1H), 3.81 (s, 6H), 4.03–4.18 (m, 4H), 4.27 (m, 1H), 6.49 (s, 2H), 7.27 (s, 2H); 3c: 1 H NMR (400MHz, CDCl3): δ = 1.38 (d, 36H), 3.84 (s, 6H), 3.92 (s, 4H), 4.41 (s, 4H), 6.43 (s, 2H), 7.25 (s, 2H).

[0044] Example 3: Preparation of 1,5-bis(3-methoxyphenoxy)-acetone (3) or 2,4-di-tert-butyl-1,5-bis(3-methoxyphenoxy)-acetone (4a)

[0045]

[0046] Add 2 or 3a (30.0 g), chromium trioxide (9.0 g), concentrated sulfuric acid (7.5 ml), and 200 ml of acetone to a 500 ml round-bottom flask. After stirring thoroughly, continue the reaction at room temperature for 6 hours. Filter the reaction solution, wash with water, dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure to obtain target product 3 (25.8 g) or 4a (27.3 g), with corresponding yields of 87% and 91%, respectively. 1 H NMR (400MHz, CDCl3): δ = 3.78 (s, 6H), 4.97 (s, 4H), 6.50 (t, 2H), 6.70 (m, 2H), 6.80 (m, 2H), 7.20 (t, 2H); 4a: 1H NMR (400MHz, CDCl3): δ = 1.38 (s, 18H), 1.42 (s, 18H), 3.84 (s, 6H), 4.99 (s, 4H), 6.50 (s, 2H), 7.27 (s, 2H).

[0047] Example 4: Preparation of 1,5-bis(2-bromo-3-methoxyphenoxy)-acetone (4)

[0048]

[0049] Add 20.0 g (66.2 mmol) of methyl methacrylate (MCP) to a 500 mL two-necked flask, followed by 200 mL of dichloromethane. After stirring thoroughly, add dropwise a 2.0 mol / L bromine solution in dichloromethane (40 mL, 79.4 mmol). After the addition is complete, stir the reaction mixture for 4 hours. Filter the reaction solution, dry it over anhydrous sodium sulfate, and evaporate it to dryness under reduced pressure to obtain the crude product. Rapid column chromatography yields 21.9 g of the target product, with a yield of 72%. 1 HNMR (400MHz, CDCl3): δ = 3.81 (s, 6H), 5.02 (s, 4H), 6.53 (dd, 2H), 6.77 (d, 2H), 7.52 (d, 2H).

[0050] Example 5: Preparation of 4,4',6,6'-tetratert-butyl-1,1'-spirodihydroindene-7,7'-diol (5) or 4,4'-dimethoxy-6,6'-ditert-butyl-1,1'-spirodihydroindene-7,7'-diol (5a or 4c)

[0051]

[0052] In a 500 mL round-bottom flask, 4 (20.0 g, 43.5 mmol), 4a (20.0 g, 38.0 mmol), or 3c (20.0 g, 35.0 mmol), polyphosphoric acid, and methanol were added sequentially, and the mixture was heated and stirred at 60 °C for 6 hours. After the reaction was complete, the mixture was washed with water, the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was then separated by rapid column chromatography. Recrystallization from n-hexane yielded the target product 5 (13.7 g), 5a (12.6 g), or 4c (10.1 g), with corresponding yields of 71%, 65%, and 57%, respectively. 1 HNMR (400MHz, CDCl3): δ = 3.82 (s, 6H), 4.49 (d, 2H), 4.66 (d, 2H), 6.58 (d, 2H), 7.40 (d, 2H); 5a or 4c: 1H NMR (400MHz, CDCl3): δ = 1.39 (s, 18H), 1.42 (s, 18H), 3.77 (s, 6H), 4.46 (d, 2H), 4.61 (d, 2H), 7.28 (s, 2H).

[0053] Example 6: Preparation of 7,7'-dimethoxy-1,1'-spirodihydrobenzofuran (6)

[0054]

[0055] In a dry 250 mL Schlenk flask, 5 g (5.0 g, 11.3 mmol) and 80 mL of tetrahydrofuran were added. The reaction flask was purged under a nitrogen atmosphere, and the reaction solution was cooled to -78 °C. Then, 2.5 M n-butyllithium (18.1 mL, 4.0 eq) was added dropwise. After reacting for 1 hour, the reaction was quenched by adding 6.0 mL of ethanol, washed with water, the organic phase was extracted with dichloromethane, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. Recrystallization from n-hexane gave 3.1 g of the product, with a yield of 95%. 1 H NMR (400MHz, CDCl3): δ = 3.80 (s, 6H), 4.45 (d, 2H), 4.62 (d, 2H), 6.64–6.74 (dd, 4H), 7.07 (t, 2H).

[0056] Example 7: Preparation of 1,1'-spirodihydrobenzofuran-7,7'-diol (7) or 4,4',6,6'-tetratert-butyl-1,1'-spirodihydrobenzofuran-7,7'-diol ((rac)-O-SPINOL)

[0057]

[0058] In a dry 500 mL Schlenk flask, add 6 (5.0 g, 17.6 mmol) or 5a (or 4c) (5.0 g, 9.8 mmol) and 100 mL of dichloromethane. Purge the reaction flask to a nitrogen atmosphere, cool the reaction solution to -78 °C, and then add a 2.0 mol / L solution of boron tribromide in dichloromethane dropwise. After the addition is complete, allow the reaction solution to return to room temperature and incubate overnight. Quench the reaction with water, dilute with dichloromethane and extract the organic phase, dry with anhydrous sodium sulfate, evaporate to dryness under reduced pressure, and recrystallize the crude product from n-hexane to give the target product 7 (4.2 g) or (rac)-O-SPINOL (4.3 g), with corresponding yields of 94% and 92%, respectively. 1H NMR (400MHz, DMSO): δ = 4.50 (d, 2H), 4.58 (d, 2H), 6.23-6.27 (m, 4H), 6.92 (dd, 2H), 6.78-6.80 (m, 4H), 7.06-7.09 (m, 8H); (rac)-O-SPINOL: 1 H NMR (400MHz, CDCl3): δ = 1.40 (d, 36H), 4.53 (d, 2H), 4.69 (d, 2H), 6.75 (s, 2H), 7.14 (s, 2H).

[0059] Example 8: Preparation of 4,4',6,6'-tetratert-butyl-1,1'-spirodihydrobenzofuran-7,7'-diol ((rac)-O-SPINOL)

[0060]

[0061] In a 200 mL three-necked flask, 7 (2.0 g, 7.8 mol), tert-butanol (3.7 g, 49.5 mmol), and concentrated sulfuric acid (2.4 g, 24.7 mmol) were added sequentially. After the addition was complete, the reaction flask was purged under a nitrogen atmosphere and heated to reflux for 24 hours. The solvent was evaporated to dryness under reduced pressure, 50 mL of water was added, and the organic phase was extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the residue was evaporated to dryness under reduced pressure. The residue was subjected to rapid column chromatography to obtain 3.7 g of the target product, with a yield of 98%. 1 H NMR (400MHz, CDCl3): δ = 1.42 (d, 36H), 4.54 (d, 2H), 4.71 (d, 2H), 6.76 (s, 2H), 7.15 (s, 2H).

[0062] Example 9: Preparation of 7,7'-bis[(1,1'-biphenyl-2,2'-diyl)phosphonite]-4,4',6,6'-tetratert-butyl-1,1'-spirodihydroindene (L4)

[0063]

[0064] In a dry 200 mL Schlenk flask under nitrogen protection, (rac)-O-SPINOL (2.0 g, 4.2 mmol), anhydrous triethylamine (8.8 mL, 63.0 mmol, 15.0 eq.), and anhydrous tetrahydrofuran (40 mL) were added sequentially. The mixture was then cooled to -40 °C and 1,1′-dioxyphosphine chloride (2.6 g, 10.5 mmol, 2.5 equiv.) was added dropwise to 30 mL of anhydrous tetrahydrofuran solution. After the addition was complete, the reaction mixture was reacted at room temperature for 24 hours. The reaction solution was concentrated under nitrogen atmosphere, and the crude product was separated by rapid column chromatography and recrystallized from acetonitrile to give 2.9 g of the target product, with a yield of 75%.1 HNMR (600MHz, CDCl3): δ=1.18-1.24(d,36H),4.75(d,2H),4.96(d,2H),6.91–7.23(m,10H),7.27–7.30(m,4H),7.41–7.44(m,4H); 31 P NMR (243MHz, CDCl3): δ=145.18.

[0065] It should be noted that the other L1-L31 oxaspirocyclic bisphosphonates in Formula I can be prepared simply by using different chlorophosphonate substituent derivatives.

[0066] After obtaining the target oxaspirocyclic bisphosphonate ligand, we developed a batch-type pilot-scale reaction apparatus (see attached diagram) to match this novel ligand, simulating the industrial hydroformylation reaction of mixed / etherified C4. We used two C4 feedstocks: the first was etherified C4 with the following components (w / w): isobutane (52.1%), 1-butene (16.6%), cis-2-butene (15.3%), and trans-2-butene (16.0%); the second was MTO C4 with the following components (w / w): n-butane (6.0%), 1-butene (0.7%), cis-2-butene (34.7%), and trans-2-butene (58.6%).

[0067] To ensure ligand activity and prevent aldehyde product oxidation, the above materials undergo a raw material pretreatment process. This process involves removing water, oxygen, sulfur (sulfides), chlorine (halides), and nitrogen-containing compounds (such as HCN), as well as carboxylic acids, butadiene, propylene, and alkynes that inhibit rhodium catalyst activity in the C4 feedstock. To test the reactivity of the novel sterically hindered oxygen-spirocyclic bisphosphonate ligand in post-ether / MTO C4 reactions, we compared it with other commercially available and patented ligands under nearly identical reaction conditions. The ligand Ligand 1-10 used in the following examples has the following structure:

[0068]

[0069] This comparative example uses the oxaspirocyclic bisphosphonates listed in the above examples as transition metal ligands to catalyze the hydroformylation of olefins, as detailed below:

[0070] Comparative Example 1: Under an argon atmosphere, a certain amount of Rh(acac)(CO)₂ (0.01 mmol, 2.6 mg) and a certain amount of the ligand Ligand 1-10 (0.03–0.04 mmol) were added to a 200 ml stainless steel high-pressure reactor equipped with a pressure sensor, temperature probe, online sampling port, and safety relief valve. A certain volume of toluene and the internal standard n-decane were also added. The mixture was stirred with a magnetic stirrer for 30 minutes to form a rhodium-ligand catalytic complex. Subsequently, after connecting the gas pipeline and fully purging it, a certain proportion of liquid etherified C4 was added to the reactor using a metering plunger pump with a two-position four-way valve, controlling the concentration of the rhodium catalyst in the total solution to approximately 159 ppm. The mixture was then stirred uniformly at room temperature for 5–10 minutes. After uniform stirring, a mixture of carbon monoxide and hydrogen (1:1) was introduced into the reaction apparatus until the total pressure reached 1.0 MPa. The reactor was heated to the required temperature (70℃) using a magnetic stirrer (heating the bottom of the reactor) and an electric heating mantle (heating the reactor body). Gas was continuously added during the reaction to maintain a constant total pressure of 1.0 MPa. After 2–4 hours of reaction, the reactor was connected to a -40℃ cooling mantle for cooling. Once the reactor temperature had dropped to room temperature, the online sampling port was opened to take a sample without opening the reactor. The sample was diluted with chromatographic grade ethyl acetate and the n-to-iso ratio (ratio of n-pentanal / 2-methylbutanal: 1:b) was determined by gas chromatography (GC). After opening the reactor, the gas inside the high-pressure reactor was completely released in a fume hood, and the sample was weighed. The results are shown in Table 1.

[0071] Table 1

[0072]

[0073] Comparative Example 2: Under an argon atmosphere, a certain amount of Rh(acac)(CO)₂ (0.01 mmol, 2.6 mg) and a certain amount of the ligand Ligand 1-10 (0.03–0.04 mmol) were added to a 200 ml stainless steel high-pressure reactor equipped with a pressure sensor, temperature probe, online sampling port, and safety relief valve. A certain volume of toluene and the internal standard n-decane were also added. The mixture was stirred with a magnetic stirrer for 30 minutes to form a rhodium-ligand catalytic complex. Subsequently, after connecting the gas pipeline and fully purging it, a certain proportion of liquid MTO C₄ was added to the reactor using a metering plunger pump with a two-position four-way valve, controlling the concentration of the rhodium catalyst in the total solution to approximately 159 ppm. The mixture was then stirred uniformly at room temperature for 5–10 minutes. After uniform stirring, a mixture of carbon monoxide and hydrogen (1:1) was introduced into the reaction apparatus until the total pressure reached 1.0 MPa. The reactor was heated to the required temperature (70℃) using a magnetic stirrer (heating the bottom of the reactor) and an electric heating mantle (heating the reactor body). Gas was continuously added during the reaction to maintain a constant total pressure of 1.0 MPa. After 2–4 hours of reaction, the reactor was connected to a -40℃ cooling mantle for cooling. Once the reactor temperature had dropped to room temperature, the online sampling port was opened to take a sample without opening the reactor. The sample was diluted with chromatographic grade ethyl acetate and the n-to-iso ratio (ratio of n-pentanal / 2-methylbutanal: 1:b) was determined by gas chromatography (GC). After opening the reactor, the gas inside the high-pressure reactor was completely released in a fume hood, and the sample was weighed. The results are shown in Table 2.

[0074] Table 2

[0075]

Claims

1. A method for preparing a sterically hindered oxygen heterospirocyclic compound, characterized in that: It has the following synthetic route: Synthesis Route 2 ： Synthetic route 3： PPA is polyphosphoric acid, and its R structure is as follows:

2. The method for preparing the sterically hindered oxygen heterospirocyclic compound according to claim 1, characterized in that: Intermediate (3a) was catalytically oxidized with chromium trioxide to obtain 2,4-di-tert-butyl-1,5-bis(3-methoxyphenoxy)-acetone (4a); the amount of metal oxide used was 0.05 to 1 equivalent, the reaction solvent was acetone or water, and the reaction temperature was 25 to 45 °C.

3. A catalytic complex, characterized in that: The catalytic complex comprises a transition metal Rh precursor and an oxaspirocyclic compound ligand of formula (I) as described in claim 1.

4. A method for preparing straight-chain aldehydes by hydroformylation of olefins, characterized in that: The preparation method includes reacting a carbotetraolefin with syngas in the presence of the catalytic complex described in claim 3 to obtain a straight-chain aldehyde; the method is implemented according to the following process steps and parameters; (1). In the reaction apparatus, under the protection of an inert gas, a certain proportion of racemic oxaspirocyclic bisphosphonates ligand and Rh(acac)(CO)2 are added sequentially, with the phosphine-rhodium molar ratio being about 1:1 to 5:1, and the mixture is stirred and complexed at room temperature in an organic solvent for 30 minutes. (2). Subsequently, under the protection of inert gas, a certain proportion of liquid etherified C4 or MTO C4 or cis-2-butene or trans-2-butene is added to the reactor using a plunger pump with metering function, so that the concentration of rhodium catalyst is controlled at about 50 to 200 ppm, and then stirred evenly at room temperature for 5 to 10 minutes. (3) After stirring evenly, CO and H2 are introduced into the reaction apparatus at a certain pressure. The pressure ratio of hydrogen to carbon monoxide is between 1:1 and 1:5, and the total pressure is between 0.5 MPa and 1 MPa. The reaction is stirred for 1 to 4 hours at a temperature between 40°C and 100°C. The C4 ether and MTO C4 used in the above hydroformylation reaction comprise the following components by mass percentage: 0-30% 1-butene, 0-70% trans-2-butene, 0-40% cis-2-butene, 0-30% n-butane, 0-20% isobutane, and 0-10% isobutene, wherein the total mass percentage of 1-butene, trans-2-butene, cis-2-butene, n-butane, isobutane, and isobutene is 100%.

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