Diborane / arylborate pair [1.1.1] propellane ring-opening reaction for the preparation of gem-diboryl cyclobutene / arylboron cyclobutane dimers

Abstract

Provided herein are two methods for the preparation of gem-diboryl cyclobutenes: one is through the ring opening of [1.1.1]propellane by diborane compounds to prepare gem-diboryl cyclobutene, and the other is through the ring opening of [1.1.1]propellane by aryl boronate to prepare aryl boryl cyclobutane dimer. Gem-diboryl cyclobutene and aryl boryl cyclobutane dimer are key compounds, which can be easily converted to other cyclobutane compounds due to the presence of boron group. The reaction conditions of the present method are mild and the operation is simple. Since the starting material [1.1.1]propellane is easy to obtain and can be prepared on a gram scale, the conversion rate of the present method can also be scaled up to a gram scale. The resulting gem-diboryl cyclobutene can be further derivatized into many other highly substituted cyclobutane compounds.

Description

Technical Field

[0001] This invention relates generally to the fields of organic synthesis and organoboron chemistry. More specifically, this invention discloses a method for synthesizing gem-diboronylcyclobutene and boronylcyclobutene dimers via a catalyst-free reaction of [1.1.1]spiroalkyl (TCP). Background Technology

[0002] [1.1.1] Propellane (TCP) possesses significant theoretical research value and synthetic implications due to its unique structure and holophilic reactivity. The antitetrahedral geometry of the bridgehead carbon atoms makes its molecule distinctly different from traditional bonding methods, exhibiting high bond strain. To date, extensive theoretical and experimental research has been conducted to elucidate the inherent properties of the central bond. After numerous discussions, chemists have generally accepted the hypothesis that a charge-transfer bond forms between the two bridgehead carbon atoms. Although this theory is primarily based on theoretical calculations, its predictions perfectly match experimental observations.

[0003] The charge-transfer bond hypothesis posits that the bonding electrons between the two bridgehead carbon atoms are delocalized from the central cage through a resonance structure, pointing outwards to avoid Pauli repulsion with the six winged carbon-carbon bonding electrons (see...). Figure 1 A). Based on this theory, it can be expected that the two bridgehead carbon atoms are prone to donating electrons, thereby promoting nucleophilic reactions. However, research over the past thirty years has mainly focused on the 1,3-bifunctionalization of TCP, which proceeds via anionic (electrophilic) or radical pathways, in which TCP undergoes an electronic structure change, transforming into charge-separated (ionic) or diradical reactions. In contrast, the more direct nucleophilic reactions that typically follow a cationic mechanism to generate methylenecyclobutane (MCB) have been rarely studied (see [link to relevant documentation]). Figure 1 B).

[0004] Three methods for generating MCBs via TCP ring-opening using protons, transition metals, and free carbene as initiators have been explored. Figure 1C, Pathway AC). The first protonation scheme (Pathway A) dates back to the initial synthesis of TCP in 1982. Wiberg and Walker reported that acetic acid could ring-open TCP, but did not provide yield data. More recently, Jiang et al. reported tris(pentafluorophenyl)boron-catalyzed protonation and amination reactions of TCP. Hong and his team established a cascade reaction based on TCP protonation products. Transition metal-catalyzed TCP ring-opening reactions (Pathway B) were initially studied by Wiberg and Waddell using rhodium (I), palladium (II), iridium (I), and platinum (O / II), but they encountered problems with selectivity control due to the formation of mixtures of monomers, dimers, and even trimers of MCBs. Until recently, controllable TCP ring-opening reactions involving carbene compounds were achieved using nickel, copper, and silver catalysts. Finally, free carbenes generated from high-valent iodine and diazo compounds (Pathway C) were shown to be effective for TCP ring-opening reactions.

[0005] Given the inherent nucleophilicity of TCP, there has been considerable interest in developing novel reactions based on the MCB backbone. However, several challenges remain to be addressed, such as controlling highly reactive cationic intermediates to prevent oligomerization by side reactions, and designing reactions to synthesize high-value-added MCBs. Therefore, this invention aims to meet these needs. Summary of the Invention

[0006] To address the aforementioned technical deficiencies, this invention provides a method for preparing boron-based cyclobutene of formula (I) and its derivatives of formula (II). This method comprises a chemical reaction of [1.1.1]spiroalkyl with diborane. (one) (two)

[0007] In one embodiment, diborane is dicatechin diborane.

[0008] In another embodiment, the above reaction is carried out in an aprotic polar solvent selected from dimethylformamide, acetonitrile, or tetrahydrofuran.

[0009] The present invention also provides a method for preparing boron-based cyclobutene, comprising chemically reacting [1.1.1]spiroalkyl with an arylboronic ester.

[0010] In one embodiment, the arylboronic ester is pinacol phenylboronic ester, catechol phenylboronic ester, or a catechol boronic ester derivative.

[0011] In another embodiment, the above method further includes increasing the molar equivalent of the [1.1.1] propeller alkane to dimerize the boron-based cyclobutene into a boron-based cyclobutene dimer having the following formula. Attached Figure Description

[0012] The embodiments of the present invention will now be described in more detail with reference to the accompanying drawings, wherein:

[0013] Figure 1 The open-loop response of TCP is outlined.

[0014] Figure 2 This demonstrates the use of B2(OR)4 to optimize the conditions for TCP open-loop reactions.

[0015] Figure 3 The derivatization of compound 3 is demonstrated.

[0016] Figure 4 The optimization of aryl catechol borate esters and their substrate range are demonstrated.

[0017] Figure 5A and Figure 5B It demonstrates the exploration of the reaction mechanism. Figure 5A It demonstrates an exploration of reaction kinetics; and Figure 5B The comparison of Lewis acidity using the Gutmann-Beckett method is shown.

[0018] Figures 6A to 6C The mechanism analysis based on density functional theory calculations is presented. Figure 6A This demonstrates the principle of selectivity of boron source for ring-opening mechanism; Figure 6B The energy profile calculations for R-Bpin and R-Bcat are shown; Figure 6C This demonstrates the inverse selectivity between catB-Bcat and PhBcat. Detailed Implementation

[0019] The following description of the preparation of compounds such as gemiborylcyclobutene / arylborylcyclobutane dimers and / or methods is merely a preferred example. Those skilled in the art will understand that modifications, including additions and / or substitutions, can be made without departing from the scope and spirit of the invention. Specific details may be omitted to avoid misunderstanding of the invention; however, the invention is intended to enable those skilled in the art to implement the contents described herein without requiring extensive experimentation.

[0020] This invention proposes a ring-opening reaction of [1.1.1] propeller alkane (TCP) using borate esters. This ring-opening reaction has the following significant characteristics: (i) no catalyst required; (ii) high reactivity; (iii) MCB borate esters can serve as multifunctional structural units; (iv) different selectivities can be achieved by using different boron sources; and (v) the mechanism behind the above selectivity is elucidated.

[0021] The method for preparing gem-diboronylcyclobutene provided by this invention is summarized by the following equations. Gem-diboronylcyclobutene 2 is obtained by reacting [1.1.1] propellerane (TCP) with diborane 1. The above-mentioned diboronylcyclobutene can also be converted into derivative 3 through ligand exchange.

[0022] In addition, the present invention also provides a method for preparing boron-based cyclobutane dimer 5 and derivative 6, as shown in the following formula.

[0023] When dicatechol diboron (B2cat2) is used as a reactant, high yields of gem-diboroncyclobutane 3 and a small amount of dimer 3′ (yield 1%) are obtained. Figure 2 This reaction is characterized by the absence of a catalyst and its rapid reaction rate. Further studies have shown that only B2cat2 is effective in this reaction, while other analogues, such as diboronol diboron (2b) and diboronic acid (2c), are completely ineffective.

[0024] To minimize dimerization, the reaction conditions were systematically evaluated, and the optimal conditions were determined: dimethylformamide as the solvent, excess dicatechol diboron (1.5 equivalents), and a reaction temperature of -20°C to room temperature. The specific procedures were as follows: Under nitrogen protection, dicatechol diboron 2 (48 mmol, 1.5 equivalents) and anhydrous dimethylformamide (60 mL) were added to a 250 mL round-bottom flask dried in an oven. Then, compound 1 (32 mmol, 1.0 equivalents) was added at -20°C. The reaction mixture was heated to room temperature and stirred for 12 hours. Then, pinacol (160 mmol, 5.0 equivalents) and triethylamine (160 mmol, 5.0 equivalents) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with H2O and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 25:1) to give compound 3 as a white solid (6.18 g, 60% yield). Notably, the reaction can be scaled up to gram scale (6.18 g, 60% yield), highlighting its practicality.

[0025] Compound 3 possesses a cyclobutane skeleton, which is widely found in pharmaceuticals and natural products. Its synthesis has attracted considerable research over the past decade due to the diverse and readily achievable derivatization pathways available for geminiborates. Therefore, compound 3 is a valuable core structure for the preparation of various cyclobutane derivatives. It is well known that geminiborates can be deboronized with bases to generate α-boron carbanion intermediates, which can subsequently undergo nucleophilic attack reactions. These reactivity has been shown to be effective for the derivatization of compound 3, achievable through a variety of nucleophilic substitution reactions (…). Figure 3 When halides are used as electrophiles, monosubstitution of two borate esters can be achieved, yielding the corresponding substituted borate ester compounds 4a-i. Using ketones or aldehydes as electrophiles, o-hydroxyborates 4j-o can be obtained in moderate to excellent yields. Notably, compounds 4n and 4o, derived from ketones, contain two adjacent quaternary carbon centers, possessing significant synthetic value and practical application potential. When esters are used as electrophiles, binucleophilic substitution reactions occur via enol salt intermediates. Various carbonylation and protonation / alkylation / halogenation products 5a-p are obtained in excellent yields, indicating the potential of this method to customize desired substitution patterns on cyclobutane skeletons. Furthermore, the insertion of a methylene group into one of the CB bonds generates o-diborate 6, and the C=C bond can be hydrogenated without affecting the CB bond to generate 7. Many of the above products can undergo further derivatization reactions. For example, compound 5j, after reduction and I2-induced cyclization, yields compound 8, a bioisosteric meta-substituted benzene with enhanced water solubility. In conclusion, this highlights the versatility and practical application value of compound 3 in synthetic chemistry.

[0026] The preparation methods of compounds 4a, 4b, 4d, 4f, and 4i are described in detail below. Following the equations below, in a glove box, compound 3 (192 mg, 0.6 mmol, 2.0 equivalent), compound S5 (0.3 mmol, 1.0 equivalent), and anhydrous tetrahydrofuran (1.5 mL) were added to a pre-dried 4 mL vial, followed by sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent). The vial was sealed, removed from the glove box, and heated at 50 °C for 12 hours. The resulting suspension was cooled to room temperature and diluted with tetrahydrofuran (1.5 mL). Subsequently, aqueous sodium hydroxide solution (0.3 mL, 3 M) and aqueous hydrogen peroxide solution (0.3 mL, 30%) were added dropwise using a syringe. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the mixture was extracted with ethyl acetate (5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain the target product 4.

[0027] In one embodiment, compound 4a (1-benzyl-3-methylenecyclobutanol) is prepared from the following compounds.

[0028] The preparation method of compound 4a is as follows: using compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), chloromethylbenzene (38.0 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent) and tetrahydrofuran (1.5 mL) as raw materials, hydrogen peroxide (0.3 mL, 30%) and sodium hydroxide (0.3 mL, 3.0 M) were added to obtain a colorless oily substance with a yield of 77% (40.0 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1).

[0029] In some embodiments, compound 4b (1-(4-fluorobenzyl)-3-methylenecyclobut-1-ol) is prepared as follows.

[0030] Compound 4b was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), 1-(chloromethyl)-4-fluorobenzene (43.4 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL) to give a colorless oil in 70% yield (40.4 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1). Hydrogen peroxide (0.3 mL, 30%) and sodium hydroxide (0.3 mL, 3.0 M) were then added.

[0031] In some embodiments, compound 4d (3-methylene-1-(3-phenylpropyl)cyclobut-1-ol) is prepared from the following compounds.

[0032] Compound 4d was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), (3-bromopropyl)benzene (59.7 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL) to give a colorless oil in 90% yield (54.6 mg, eluent: petroleum ether / ethyl acetate = 10:1). Hydrogen peroxide (0.3 mL, 30%) and sodium hydroxide (0.3 mL, 3.0 M) were then added.

[0033] In some embodiments, compound 4f (1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methylenecyclobut-1-ol) is prepared from the following compound.

[0034] Compound 4f was prepared by mixing compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), (3-bromopropoxy)(tert-butyl)dimethylsilane (76.0 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent) and tetrahydrofuran (1.5 mL), followed by the addition of hydrogen peroxide (0.3 mL, 30%) and sodium hydroxide (0.3 mL, 3.0 M), in 81% yield (62.5 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1).

[0035] In one embodiment, compound 4i(1-((4R)-4-((3R,8R,9S,10S,13R,14S,17R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)pentyl)-3-methylenecyclobut-1-ol) is prepared from the following compound.

[0036] Compound 4i was prepared by reacting a mixture of 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), (((3R,8R,9S,10S,13R,14S,17R)-17-((R)-5-bromopentan-2-yl)-10,13-dimethyl-hexadecylhydro-1H-cyclopenta[a]phenanthrene-3-yl)oxy)(tert-butyl)dimethylsilane (161.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL) with hydrogen peroxide (0.3 mL, 30%) and sodium hydroxide (0.3 mL, 3.0 M) in 93% yield (151.5 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1).

[0037] Following the equations for preparing 4c, 4e, 4g, and 4h, compound 3 (192 mg, 0.6 mmol, 2.0 equivalent), S5 (0.3 mmol, 1.0 equivalent), and anhydrous tetrahydrofuran (1.5 mL) were added to an oven-dried 4 mL vial in a glove box, followed by sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent). The vial was sealed, removed from the glove box, and heated at 50 °C for 12 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (5 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography to obtain the target product 4.

[0038] In one embodiment, compound 4c (4,4,5,5-tetramethyl-2-(1-(3-methylbut-2-en-1-yl)-3-methylenecyclobutyl)-1,3,2-dioxoborane) is prepared from the following compounds.

[0039] Compound 4c was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), 1-chloro-3-methylbut-2-ene (31.4 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL) as a colorless oil in 71% yield (60.5 mg, eluent: petroleum ether / ethyl acetate = 80:1).

[0040] In some embodiments, compound 4e (2-(1-hexyl-3-methylenecyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane) is prepared from the following compounds.

[0041] Compound 4e was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), 1-bromohexane (49.5 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL) as a colorless oil in 75% yield (66.4 mg, eluent: petroleum ether / ethyl acetate = 60:1).

[0042] In some embodiments, compound 4g (1-(5-fluoropentyl)-3-methylenecyclobut-1-ol) is prepared from the following compound.

[0043] Compound 4 g was prepared by reacting a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), 1-bromo-5-fluoropentane (50.7 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL) with hydrogen peroxide (0.3 mL, 30%) and sodium hydroxide (0.3 mL, 3.0 M) as a colorless oil in 66% yield (34.1 mg, eluent: petroleum ether / ethyl acetate = 10:1 to 6:1).

[0044] In one embodiment, compound 4h (2-(1-(3,7-dimethyloct-6-en-1-yl)-3-methylenecyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane) was prepared from the following compounds.

[0045] Compound 4h was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), 8-bromo-2,6-dimethyloct-2-ene (65.7 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL) as a colorless oil in 87% yield (87.0 mg, eluent: petroleum ether / ethyl acetate = 60:1).

[0046] To prepare compound 4j-4m, in a glove box, compound 3 (144 mg, 0.45 mmol, 1.5 equivalents), compound S6 (0.3 mmol, 1.0 equivalents), and anhydrous tetrahydrofuran (1.5 mL) were added to a pre-dried 4 mL vial, followed by sodium tert-butoxide (86.5 mg, 0.9 mmol, 3.0 equivalents). The vial was sealed, removed from the glove box, and heated at 50 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography to obtain the target product 4.

[0047] In one embodiment, compound 4j ((3-methylene-1-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)cyclobutyl)(phenyl)methanol) is prepared using the following compounds.

[0048] Compound 4j was prepared from a mixture of compound 3 (144.0 mg, 0.45 mmol, 1.5 equivalents), benzaldehyde (31.8 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (86.5 mg, 0.9 mmol, 3.0 equivalents), and tetrahydrofuran (1.5 mL) as a yellow oil in 58% yield (52.0 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1).

[0049] In some embodiments, compound 4k ((4-methoxyphenyl)(3-methylene-1-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)cyclobutyl)methanol) is prepared from the following compounds.

[0050] Compound 4k was prepared from a mixture of compound 3 (144.0 mg, 0.45 mmol, 1.5 equivalents), 4-methoxybenzaldehyde (40.8 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (86.5 mg, 0.9 mmol, 3.0 equivalents), and tetrahydrofuran (1.5 mL) as a yellow oil in 53% yield (52.1 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 6:1).

[0051] In some embodiments, compound 4l ((3-methylene-1-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)cyclobutyl)(naphthalene-2-yl)methanol) is prepared from the following compound.

[0052] Compound 4 was prepared from a mixture of compound 3 (144.0 mg, 0.45 mmol, 1.5 equivalents), 2-naphthaldehyde (46.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (86.5 mg, 0.9 mmol, 3.0 equivalents), and tetrahydrofuran (1.5 mL) as a colorless oil in 53% yield (55.6 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 6:1).

[0053] In some embodiments, compound 4m ((3-methylene-1-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)cyclobutyl)(thiophene-2-yl)methanol) is prepared from the following compound.

[0054] Compound 4m was prepared as a yellow oil in the form of a mixture of compound 3 (144.0 mg, 0.45 mmol, 1.5 equivalents), thiophene-2-carboxaldehyde (33.6 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (86.5 mg, 0.9 mmol, 3.0 equivalents), and tetrahydrofuran (1.5 mL), in a yield of 43% (39.5 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1).

[0055] To prepare compounds 4n and 4o, in a glove box, compound 3 (144 mg, 0.45 mmol, 1.5 equivalents), compound S7 (0.3 mmol, 1.0 equivalents), and anhydrous tetrahydrofuran (1.5 mL) were added to a pre-dried 4 mL vial, followed by sodium tert-butoxide (86.5 mg, 0.9 mmol, 3.0 equivalents). The vial was sealed, removed from the glove box, and heated at 50 °C for 4 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel rapid column chromatography to obtain the target product 4.

[0056] In one embodiment, compound 4n ((3-methylene-1-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)cyclobutyl)diphenylethanol) is prepared from the following compound.

[0057] Compound 4n was prepared from a mixture of compound 3 (144.0 mg, 0.45 mmol, 1.5 equivalents), benzophenone (54.7 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (86.5 mg, 0.9 mmol, 3.0 equivalents), and tetrahydrofuran (1.5 mL) as a white solid in 69% yield (78.0 mg, eluent: petroleum ether / ethyl acetate = 20:1).

[0058] In some embodiments, compound 4o (1-(hydroxy(4-methoxyphenyl)(phenyl)methyl)-3-methylenecyclobut-1-ol) is prepared from the following compounds.

[0059] Compound 4o was prepared by mixing compound 3 (144.0 mg, 0.45 mmol, 1.5 equivalents), (4-methoxyphenyl)(phenyl) methyl ketone (63.7 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (86.5 mg, 0.9 mmol, 3.0 equivalents), and tetrahydrofuran (1.5 mL), followed by the addition of hydrogen peroxide (0.3 mL, 30%) and sodium hydroxide (0.3 mL, 3.0 M), in 89% yield (79.0 mg, eluent: petroleum ether / ethyl acetate = 10:1 to 4:1).

[0060] To prepare compounds 5a-5p, in a glove box, compound 3 (192 mg, 0.6 mmol, 2.0 equivalent), compound S8 (0.3 mmol, 1.0 equivalent), and anhydrous tetrahydrofuran (1.5 mL) were added to a pre-dried 4 mL vial, followed by sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent). The vial was sealed, removed from the glove box, and heated at 60 °C for 12 hours. Then, under argon protection, an electrophilic reagent was added to the reaction mixture, and the mixture was heated at 60 °C for 2 hours. The resulting suspension was cooled to room temperature and diluted with THF (1.5 mL). Subsequently, aqueous solutions of sodium hydroxide (0.3 mL, 3 M) and hydrogen peroxide (0.3 mL, 30%) were added dropwise using a syringe. The reaction mixture was stirred at room temperature for 30 minutes. The reactants were extracted with ethyl acetate (5 mL x 3). The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel rapid column chromatography to obtain the target product 5.

[0061] In one embodiment, compound 5a ((3-methylenecyclobutyl)(phenyl) methyl ketone) is prepared from the following compounds.

[0062] Compound 5a was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL), and then water (0.1 mL) was added to give a colorless oil in 87% yield (45.1 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0063] In some embodiments, compound 5b ((3-methylenecyclobutyl-1-d)(phenyl)methyl ketone) is prepared from the following compounds.

[0064] Compound 5b was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL), followed by the addition of heavy water (0.1 mL) to give a colorless oil in 93% yield (48.4 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0065] In some embodiments, compound 5c ((3-methylenecyclobutyl)(p-tolyl) methyl ketone) is prepared from the following compounds.

[0066] Compound 5c was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl 4-methylbenzoate (45.1 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL). Water (0.1 mL) was added to give a colorless oily substance in 97% yield (54.0 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0067] In some embodiments, compound 5d ((4-methoxyphenyl)(3-methylenecyclobutyl) ketone) is prepared from the following compounds.

[0068] Compound 5d was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl 4-methoxybenzoate (49.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL). Water (0.1 mL) was added to give a colorless oil in 92% yield (55.8 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0069] In some embodiments, compound 5e ((4-fluorophenyl)(3-methylenecyclobutyl) ketone) is prepared from the following compounds.

[0070] Compound 5e was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), methyl 4-fluorobenzoate (46.2 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL). Water (0.1 mL) was added to give a colorless oil in 81% yield (46.5 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0071] In some embodiments, compound 5f ((3-chlorophenyl)(3-methylenecyclobutyl) ketone) is prepared from the following compounds.

[0072] Compound 5f was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl 3-chlorobenzoate (51.2 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL). Water (0.1 mL) was added to give a colorless oil in 52% yield (32.5 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0073] In some embodiments, 5g of compound ((1-methyl-1H-indol-5-yl)(3-methylenecyclobutyl) ketone) is prepared from the following compound.

[0074] Compound 5 g was prepared by reacting a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), methyl 1-methyl-1H-indole-5-carboxylic acid (56.8 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL), followed by the addition of water (0.1 mL). The result was a white solid with a yield of 64% (43.3 mg, eluent: petroleum ether / ethyl acetate = 15:1 to 10:1).

[0075] In some embodiments, compound 5h (5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-(3-methylenecyclobutyl)pent-1-one) is prepared from the following compound.

[0076] Compound 5h was prepared from a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl 5-(2,5-dimethylphenoxy)-2,2-dimethylvalerate (79.3 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL). Water (0.1 mL) was added to give a colorless oily substance in 99% yield (89.1 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0077] In some embodiments, compound 5i (1-(1-benzyl-3-methylenecyclobutyl)-2,2-dimethylprop-1-one) is prepared from the following compounds.

[0078] Compound 5i was prepared by adding a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl neopentanoate (34.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), tetrahydrofuran (1.5 mL), and brominated benzene (102.6 mg, 0.6 mmol, 2.0 equivalents) to give a colorless oily substance in 95% yield (69.3 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0079] In some embodiments, compound 5j ((1-benzyl-3-methylenecyclobutyl)(phenyl) methyl ketone) is prepared from the following compounds.

[0080] Compound 5j was prepared by adding a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL) to brominated benzene (102.6 mg, 0.6 mmol, 2.0 equivalents) to give a yellow oily substance in 96% yield (75.8 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0081] In some embodiments, compound 5k ((1-(4-fluorobenzyl)-3-methylenecyclobutyl)(phenyl) methyl ketone) is prepared from the following compounds.

[0082] Compound 5k was prepared by adding a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL) to 1-(chloromethyl)-4-fluorobenzene (86.7 mg, 0.6 mmol, 2.0 equivalents) to give a colorless oil in 83% yield (69.6 mg, eluent: petroleum ether / ethyl acetate = 60:1).

[0083] In some embodiments, compound 5l ((1-(3-methylbut-2-en-1-yl)-3-methylenecyclobutyl(phenyl) ketone) is prepared from the following compounds.

[0084] Compound 5l was prepared by adding a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL) to 1-chloro-3-methylbut-2-ene (62.7 mg, 0.6 mmol, 2.0 equivalent) to give a colorless oil in 83% yield (59.9 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0085] In some embodiments, compound 5m ((1-(but-2-yn-1-yl)-3-methylenecyclobutyl)(phenyl) methyl ketone) is prepared from the following compounds.

[0086] Compound 5m was prepared by adding a mixture of compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL) to 1-bromobut-2-yne (79.8 mg, 0.6 mmol, 2.0 equivalent) to give a colorless oily substance in 97% yield (65.2 mg, eluent: petroleum ether / ethyl acetate = 40:1).

[0087] In some embodiments, compound 5n ((1-hexyl-3-methylenecyclobutyl)(phenyl) methyl ketone) is prepared from the following compounds.

[0088] Compound 5n was prepared by adding compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL) to 1-bromohexane (99.0 mg, 0.6 mmol, 2.0 equivalent) to give a colorless oil in 63% yield (59.4 mg, eluent: petroleum ether / ethyl acetate = 60:1).

[0089] In some embodiments, compound 5o ((1-fluoro-3-methylenecyclobutyl)(phenyl) methyl ketone) is prepared from the following compounds.

[0090] Compound 5o was prepared by mixing compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalent), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalent), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalent), and tetrahydrofuran (1.5 mL), followed by the addition of N-fluorobis(benzenesulfonyl)imide (189.2 mg, 0.6 mmol, 2.0 equivalent) to give a colorless oil in 80% yield (45.4 mg, eluent: petroleum ether / ethyl acetate = 60:1).

[0091] In some embodiments, compound 5p ((1-chloro-3-methylenecyclobutyl)(phenyl) methyl ketone) is prepared from the following compounds.

[0092] Compound 5p was prepared by mixing compound 3 (192.0 mg, 0.6 mmol, 2.0 equivalents), methyl benzoate (40.9 mg, 0.3 mmol, 1.0 equivalents), sodium tert-butoxide (115.3 mg, 1.2 mmol, 4.0 equivalents), and tetrahydrofuran (1.5 mL), followed by the addition of N-chlorosuccinimide (80.1 mg, 0.6 mmol, 2.0 equivalents) to give a colorless oil in 50% yield (31.0 mg, eluent: petroleum ether / ethyl acetate = 60:1).

[0093] Following the equation for the preparation of compound 6 (4,4,5,5-tetramethyl-2-(3-methylene-1-((4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)methyl)cyclobutyl)-1,3,2-dioxoborane), compound 3 (64.0 mg, 0.2 mmol, 1.0 equivalent), dibromomethane (55.6 mg, 0.32 mmol, 1.6 equivalent), and tetrahydrofuran (2 mL) were added to an oven-dried 10 mL vial equipped with a magnetic stirrer, and the reaction was carried out under nitrogen protection. The mixture was cooled to -78 °C, and n-butyllithium (2.5 M, 0.12 mL, 0.3 mmol, 1.5 equivalent) was carefully added to the solution, and the mixture was stirred for 10 min. The reaction mixture was then warmed to room temperature and stirred for 12 h. After the reaction was complete, the crude reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude reaction mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1) to give compound 6 as a colorless oil (34.6 mg, yield 52%).

[0094] Following the equation for the preparation of compound 7 (2,2'-(3-methylcyclobutane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxoborane)), compound 3 (96.0 mg, 0.3 mmol, 1.0 equivalent), palladium catalyst on carbon (10 mg), and ethyl acetate (2 mL) were added to a 10 mL bottle dried in an oven and equipped with a magnetic stirrer. The reaction was stirred under hydrogen balloon pressure for 12 hours. After the reaction was completed, the crude product was filtered and concentrated to give compound 7 as a white solid (96 mg, 99% yield).

[0095] Following the equation for the preparation of compound 8 (4-benzyl-1-(iodomethyl)-3-phenyl-2-oxabicyclo[2.1.1]hexane), compound 5j (131.2 mg, 0.5 mmol, 1.0 equivalent) was added to a methanol solution (3 mL) of sodium borohydride (28.4 mg, 0.75 mmol, 1.5 equivalent) at 0 °C. The resulting solution was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain a crude intermediate. This crude product did not require further purification and was used directly in the next reaction.

[0096] The crude product (0.5 mmol) was added at 0 °C to a solution of sodium bicarbonate (84 mg, 1.0 mmol, 2.0 equivalent), iodine (254 mg, 1.0 mmol, 2.0 equivalent) in methyl tert-butyl ether (3 mL), and water (2 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the crude product was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1 to 15:1) to give compound 8 as a pale yellow oil (149.9 mg, 77% yield).

[0097] The reaction of dicatechol diboron (B2cat2) to TCP has inspired further investigation into the reactivity of related borate esters. Therefore, the reactivity of dialkyl phenylboronic acid esters was investigated, revealing that they were similar to those of diboron esters (2), with only catechol phenylboronate (PhBCat) successfully inducing ring-opening of TCP. Figure 4 (Entries 1 and 2). However, unlike B2cat2, which has high selectivity for monomer (3), PhBcat shows a significant difference in selectivity between monomer (10a) and dimer (9a), with a ratio close to 1:1. Figure 4(Entry 1). This unexpected result prompted further investigation of the dimer (9a) by increasing the stoichiometric amount of TCP, resulting in a dimer yield as high as 93% (Entry 3). Notably, it was sometimes found that when the reaction was exposed to air, the monomeric product could be captured by oxygen oxidation, thus generating compound 10a in moderate yields (Entry 4).

[0098] Under optimized condition A, a series of dimer products (9a-k) were obtained in moderate to excellent yields. Figure 4 These dimers are characterized by their two adjacent cyclobutanes, continuous quaternary carbon centers, and outwardly extending alkenyl groups. These features may facilitate further derivatization reactions; for example, compound 9a can be cyclized to form a fused-ring compound (11). Under conditions B, the corresponding arylcyclobutanols (compounds 10a-d) were synthesized in moderate yields.

[0099] To prepare compounds 9a-9k, under nitrogen protection, arylcatechol borate (0.3 mmol, 1.0 equivalent) and anhydrous dimethylacetamide (1.5 mL) were added to an oven-dried 4 mL vial, followed by compound 1 (0.75 mmol, 2.5 equivalent). The mixture was stirred at room temperature for 2 hours. Then, pinacol (1.5 mmol, 5.0 equivalent) and triethylamine (1.5 mmol, 5.0 equivalent) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (5 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in tetrahydrofuran (3 mL), and hydrogen peroxide (30%, 2.0 equivalent) and sodium hydroxide (3.0 M, 2.0 equivalent) were added at room temperature, and the mixture was stirred for 1 hour. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by silica gel column chromatography to obtain the target product.

[0100] In one embodiment, compound 9a (3,3'-dimethylene-1'-phenyl-[1,1'-bi(cyclobutane)]-1-ol) is prepared from the following compounds.

[0101] Compound 9a was prepared by adding a mixture of compound S4a (58.5 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%). The result was a colorless oil in 72% yield (48.7 mg, eluent: petroleum ether / ethyl acetate = 15:1).

[0102] In some embodiments, compound 9b (3,3'-dimethylene-1'-(p-tolyl)-[1,1'-bi(cyclobutane)]-1-ol) is prepared from the following compounds.

[0103] The preparation method of compound 9b is as follows: First, compound S4b (63.0 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent) and dimethylacetamide (1.5 mL) were mixed, and then pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M) and hydrogen peroxide (0.3 mL, 30%) were added, and finally a colorless oily substance was obtained with a yield of 59% (42.7 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1).

[0104] In one embodiment, compound 9c (1'-(4-methoxyphenyl)-3,3'-dimethyl-[1,1'-bi(cyclobutane)]-1-ol) is prepared using the following compound.

[0105] Compound 9c was prepared by adding a mixture of compound S4c (67.8 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%), as a colorless oil in 75% yield (57.6 mg, eluent: petroleum ether / ethyl acetate = 20:1).

[0106] In some embodiments, compound 9d (3,3'-dimethylene-1'-(4-(methylthio)phenyl)-[1,1'-bi(cyclobutane)]-1-ol) is prepared from the following compounds.

[0107] Compound 9d was prepared by adding a mixture of compound S4d (72.6 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%). The result was a colorless oil in 64% yield (52.3 mg, eluent: petroleum ether / ethyl acetate = 15:1).

[0108] In some embodiments, compound 9e (1'-(4-fluorophenyl)-3,3'-methylene-[1,1'-bi(cyclobutane)]-1-ol) is prepared from the following compounds.

[0109] Compound 9e was prepared by adding a mixture of compound S4e (64.2 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%), as a colorless oil in 84% yield (61.7 mg, eluent: petroleum ether / ethyl acetate = 20:1).

[0110] In some embodiments, compound 9f (1'-(4-chlorophenyl)-3,3'-methylene-[1,1'-bi(cyclobutane)]-1-ol) is prepared from the following compounds.

[0111] Compound 9f was prepared by adding a mixture of compound S4f (69.1 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%). The result was a colorless oil in 79% yield (62.1 mg, eluent: petroleum ether / ethyl acetate = 20:1).

[0112] In some embodiments, 9g of compound (methyl 4-(1'-hydroxy-3,3'-dimethyl-[1,1'-bi(cyclobutane)]-1-yl)benzoate) is prepared from the following compound.

[0113] Compound 9 g was prepared by mixing S4 g (76.2 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%), as a colorless oil in 65% yield (57.6 mg, eluent: petroleum ether / ethyl acetate = 15:1 to 10:1).

[0114] In one embodiment, compound 9h (3,3'-dimethylene-1'-(m-tolyl)-[1,1'-bi(cyclobutane)]-1-ol) was prepared using the following compound.

[0115] Compound 9h was prepared by adding a mixture of compound S4h (63.0 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%). It was a colorless oil in 87% yield (62.5 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 15:1).

[0116] In one embodiment, compound 9i (1'-(furan-2-yl)-3,3'-dimethyl-[1,1'-bi(cyclobutane)]-1-ol) can be prepared by the following compounds.

[0117] Compound 9i was prepared by adding a mixture of compound S4i (55.8 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%). The result was a colorless oil in 43% yield (28.1 mg, eluent: petroleum ether / ethyl acetate = 20:1).

[0118] In some embodiments, compound 9j (3,3'-dimethylene-1'-(thiophen-2-yl)-[1,1'-bi(cyclobutane)]-1-ol) is prepared from the following compounds.

[0119] Compound 9j was prepared by adding a mixture of compound S4j (60.6 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%). The result was a colorless oily substance in 61% yield (42.7 mg, eluent: petroleum ether / ethyl acetate = 20:1).

[0120] In some embodiments, compound 9k (3,3'-dimethylene-1'-(naphthyl-2-yl)-[1,1'-bi(cyclobutane)]-1-ol) is prepared from the following compounds.

[0121] Compound 9k was prepared by adding a mixture of compound S4k (73.8 mg, 0.3 mmol, 1.0 equivalent), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalent), and dimethylacetamide (1.5 mL), followed by the addition of pinacol (177.3 mg, 1.5 mmol, 5.0 equivalent), triethylamine (151.8 mg, 1.5 mmol, 5.0 equivalent), sodium hydroxide (0.3 mL, 3.0 M), and hydrogen peroxide (0.3 mL, 30%). The result was a pale yellow oil in 74% yield (61.0 mg, eluent: petroleum ether / ethyl acetate = 20:1).

[0122] Following the equations for the preparation of compounds 10a-10d, arylcatechol borate (0.3 mmol, 1.0 equivalent) and anhydrous dimethylformamide (1.5 mL) were added to an oven-dried 10 mL vial under atmospheric conditions. Compound 1 (0.54 mmol, 1.8 equivalent) was then added at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 4 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (5 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by silica gel column chromatography to obtain the target product.

[0123] In one embodiment, compound 10a (3-methylene-1-phenylcyclobut-1-ol) is prepared from the following compound.

[0124] Compound 10a was prepared from a mixture of compound S4a (58.8 mg, 0.3 mmol, 1.0 equivalent), compound 1 (964 μL, 0.54 mmol, 1.8 equivalent), and dimethylformamide (1.5 mL) as a colorless oil in 42% yield (20.0 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 10:1).

[0125] In some embodiments, compound 10b (1-(4-methoxyphenyl)-3-methylenecyclobut-1-ol) is prepared from the following compounds.

[0126] Compound 10b was prepared from a mixture of compound S4c (67.8 mg, 0.3 mmol, 1.0 equivalent), compound 1 (953 μL, 0.54 mmol, 1.8 equivalent), and dimethylformamide (1.5 mL) as a colorless oil in 54% yield (30.9 mg, eluent: petroleum ether / ethyl acetate = 20:1 to 8:1).

[0127] In some embodiments, compound 10c (1-(4-chlorophenyl)-3-methylenecyclobut-1-ol) is prepared from the following compounds.

[0128] Compound 10c was prepared from a mixture of compound S4f (69.1 mg, 0.3 mmol, 1.0 equivalent), compound 1 (953 μL, 0.54 mmol, 1.8 equivalent), and dimethylformamide (1.5 mL) as a colorless oil in 55% yield (32.1 mg, eluent: petroleum ether / ethyl acetate = 10:1).

[0129] In some embodiments, compound 10d (methyl 4-(1-hydroxy-3-methylenecyclobutyl)benzoate) is prepared from the following compounds.

[0130] Compound 10d was prepared from a mixture of compound S4g (76.2mg, 0.3mmol, 1.0 equivalent), compound 1 (953μL, 0.54mmol, 1.8 equivalent), and dimethylformamide (1.5mL) as a colorless oil in 43% yield (28.4mg, eluent: petroleum ether / ethyl acetate = 10:1 to 8:1).

[0131] Following the equation for the preparation of fused cyclic compound 11 (4-(iodomethyl)-3'-methylene-1-phenyl-3-oxaspiro[bicyclo[2.1.1]hexane-2,1'-cyclobutane]), compound 1 (1.6 mL, 0.75 mmol, 2.5 equivalents), catechol phenylboronic acid ester (PhBCat) (64.2 mg, 0.3 mmol, 1.0 equivalents), and dimethyl ether (1.5 mL) were used instead of dimethylacetamide, followed by the addition of sodium hydroxide (0.3 mL, 3.0 M) and hydrogen peroxide (0.3 mL, 30%). The residue was purified by rapid column chromatography to give compound 9a.

[0132] Compound 9a was added to a solution of sodium bicarbonate (50.4 mg, 0.6 mmol, 2.0 equivalent), iodine (152.4 mg, 0.6 mmol, 2.0 equivalent) in methyl tert-butyl ether (3 mL), and water (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the crude product was diluted with water, extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60:1) to give compound 11 as a white solid (62.7 mg, 59% yield).

[0133] Regarding the unique reactivity and selectivity of [1.1.1]spiroalkyl to catechol borate ester (RBcat), the reaction mechanism is elucidated below. Initially, the reaction proceeds rapidly after the reactants are mixed ( Figure 5A Therefore, obtaining the kinetic curves is quite challenging. Considering the ring-opening mode of methylenecyclobutane formation, an acid-promoted ring-opening mechanism seems to be a suitable and readily acceptable explanation. Figure 1 C). This implies that the Lewis acidity of different diboronate esters may be the reason for their differences in reactivity. To verify this hypothesis, we compared the Lewis acidity of different diboronate esters using the Gutmann-Beckett method (C). Figure 5B By comparing the 31P of different diboronates relative to triethylphosphine oxide, the unique reactivity and selectivity exhibited by [1.1.1]spiroalkyl to catechol borate (RBcat) are elucidated below. Initially, the reaction proceeds rapidly after the reactants are mixed ( Figure 5A Therefore, obtaining the kinetic curves is quite challenging. Considering the ring-opening mode of MCB formation, an acid-promoted ring-opening mechanism seems to be a suitable and readily acceptable explanation. Figure 1 C). This implies that the Lewis acidity of different diboronate esters may be the reason for their differences in reactivity. To verify this hypothesis, we compared the Lewis acidity of different diboronate esters using the Gutmann-Beckett method (C). Figure 5B By comparing the 31p nuclear magnetic resonance chemical shifts of different diboron esters relative to triethylphosphine oxide, it has been clearly demonstrated that the Lewis acidity of dicatechin diboron (2a) is significantly stronger than that of other diboron esters (2b-d). This observation is consistent with previous experimental results (such as...). Figure 2 The results (shown) show a high degree of agreement and support the reliability of the Lewis acid-initiated ring-opening mechanism. A similar trend can also be observed from dialkyl phenylborate esters, indicating that catechol phenylborate esters have stronger Lewis acidity than other borate esters.

[0134] To gain a deeper understanding of the reaction mechanism, particularly the reactivity and selectivity, density functional theory calculations were performed. Based on previous research, the proposed mechanism involves a Lewis acid-promoted ring-opening transition state (TS1), generating a charge-separated intermediate (Int), which subsequently migrates via TS2 to form the monomer c / d ( Figure 6A In fact, the related dimer product e / f also undergoes the same mechanism cycle, but it starts with monomer c / d.

[0135] First, comparing the reaction energy barriers of the first step of the reaction between compound 1 and dicatechin diboron and dipinol diboron, the results show that the reaction energy barrier of compound 1 with dicatechin diboron via the transition state TS1a is 23.8 kcal / mol, while the reaction energy barrier with dipinol diboron via the transition state TS1a-Bpin is 39.7 kcal / mol. Figure 6B These results indicate that compound 1 exhibits high reactivity with dicatechin diboron but low reactivity with dipinane diboron, which is consistent with... Figure 2 The experimental results shown are consistent. Similar energy barriers were also observed in catechol phenylboronic acid ester (TS1b 25.2 kcal / mol) and pinacol phenylboronic acid ester (TS1b-Bpin 38.7 kcal / mol). Figure 6B The significant energy barrier differences are primarily attributed to the varying Lewis acidity of the different boron esters. Boron, with its stronger Lewis acidity, possesses highly exposed and electron-withdrawing empty p orbitals, making it more readily interact with the electron pairs in the [1.1.1]spiroalkyl central bond. Subsequently, Inta and Intb are formed and stabilized by the donation of electrons from the π electrons in the newly formed C=C π bond to the empty p orbitals of the carbocation. Finally, the relevant products are generated via a 1,2-migration process (TS2), which has a slightly higher energy than TS1, indicating that the migration transition state TS2 is the rate-determining step of the reaction.

[0136] To investigate the selectivity between monomers and dimers (c vs. e and d vs. f), the relative energies of TS2 were analyzed. The energy of TS2a (24.2 kcal / mol) was slightly lower than that of TS2c (24.4 kcal / mol), indicating a slight predominance in monomer formation (c > e). Conversely, the energy of TS2b (26.6 kcal / mol) was slightly higher than that of TS2d (26.2 kcal / mol), indicating a slight predominance in dimer formation (f > d). The observed opposite trends are consistent with the experimental results above. Although the differences are small, the observed trends are clear considering that this paper discusses differences between differences.

[0137] To understand the observed opposite trends, the 1,2-migrating transition state structure (TS2) was carefully studied. In TS2a, the process involves the breaking of the BB bond, while in TS2c, it involves the breaking of the BC bond. Since the BB bond is generally weaker than the BC bond, TS2a is more favorable. Comparing the transition states TS2b and TS2d, both involve the breaking of the BC bond. However, TS2b involves the breaking of the BC (sp2) bond, while TS2d involves the breaking of the BC (sp3) bond. The results indicate that the latter is more favorable even considering the large volume of the migrating alkyl group.

[0138] In summary, a simple and efficient method was developed to prepare borocyclobutane via the ring-opening reaction of [1.1.1]spiroline using catechol borate esters. This reaction requires no catalyst, is fast, and easily scaled up, making it industrially viable. The method has a wide substrate range, including diboron biscatechol and arylcatechol borate esters, yielding versatile borocyclobutanes. These cyclobutane derivatives can be easily converted into various other derivatives, which are of significant importance in medicinal chemistry and natural product synthesis. Experimental and theoretical calculations show that the key factor influencing this reaction is the Lewis acidity of the borate ester; even subtle differences in BC bond strength can significantly affect the reaction selectivity.

[0139] Currently, various methods exist for synthesizing cyclobutene derivatives, including ring-expansion reactions of cyclopropane, ring-condensation reactions of five / six-membered rings, and [2+2] cycloaddition reactions of unsaturated precursors catalyzed by photocatalysts, Lewis acids, or transition metal catalysts. All existing methods require catalysts or complex reaction strategies. The method of this invention is very simple, requires no catalyst, and can provide a core intermediate, a gemdiboryl or arylborylcyclobutane dimer, which can be easily converted into a variety of other cyclobutene derivatives.

[0140] The terms “approximately,” “substantially,” “essentially,” and “approximately” as used herein are used to describe and explain minute variations. When used in conjunction with an event or situation, the term can refer to a situation where the event or situation occurred precisely or approximately. The term “approximately” as used herein with respect to a given value or range typically refers to a range within ±10%, ±5%, ±1%, or ±0.5% of that given value or range. This range can be expressed herein as from one endpoint to another, or between two endpoints. Unless otherwise stated, all ranges disclosed in this disclosure include endpoints. When referring to the same numerical value or characteristic, the term can refer to a value within ±10%, ±5%, ±1%, or ±0.5% of that average.

[0141] The above description of the present invention is for illustrative and descriptive purposes only. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Those skilled in the art will understand that various modifications and variations can be made.

[0142] These embodiments were chosen and described in order to best explain the principles of the invention and its practical application, thereby enabling those skilled in the art to understand the invention and its various embodiments and modifications suitable for particular purposes.

[0143] Other definitions of the selected terms used herein can be found within the specific embodiments of the invention and apply throughout. Unless otherwise defined, all other technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

Claims

1. A method for preparing boron-based cyclobutene of formula (I) and its derivatives of formula (II), characterized in that, The method includes a chemical reaction of [1.1.1]spiroline with diborane: (one) (two).

2. The method according to claim 1, characterized in that, The diborane is dicatechin diborane.

3. The method according to claim 1, characterized in that, The reaction is carried out in an aprotic polar solvent selected from dimethylformamide, acetonitrile, or tetrahydrofuran.

4. A method for preparing arylboranecyclobutene, characterized in that, The method includes chemically reacting [1.1.1]spiroalkyl with arylboronic acid ester.

5. The method according to claim 4, characterized in that, The boron ester is pinacol phenylboronic acid ester, catechol phenylboronic acid ester, or a derivative of catechol phenylboronic acid ester.

6. The method according to claim 5, characterized in that, It also includes increasing the molar equivalent of the [1.1.1] propeller alkane to dimerize the boron-based cyclobutene into a boron-based cyclobutene dimer having the following formula (iii): (three).

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