Preparation method of alkenyl side chain-containing polysubstituted furan compound

Abstract

The invention belongs to the technical field of synthesis of fine chemicals, and discloses a preparation method of a polysubstituted furan compound containing an alkenyl side chain, which comprises the following step: by taking unsaturated aldehyde and a carbonyl compound as raw materials, carrying out one-pot reaction in an organic solvent in the presence of an acid catalyst and an auxiliary agent to obtain a polysubstituted furan product containing the alkenyl side chain. According to the invention, reaction raw materials and a corresponding synthesis mechanism are optimized, unsaturated aldehyde and a carbonyl compound are subjected to a one-pot reaction under the action of an acid catalyst and an auxiliary agent to efficiently synthesize the polysubstituted furan compound containing the alkenyl side chain, and the polysubstituted furan compound containing the alkenyl side chain has the advantages of low cost and easiness in obtaining; a series of complex synthesis steps and conditions such as pre-activation, transition metal catalytic coupling and anhydrous and anaerobic operation are avoided, and the method has the advantages of simple steps, high operability and the like.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical synthesis technology, and more specifically, relates to a method for preparing a polysubstituted furan compound containing an alkenyl side chain. Background Technology

[0002] Polysubstituted furans are an important class of heterocyclic structural units, widely found in numerous bioactive natural products, drug molecules, organic optoelectronic materials, and functional materials. In particular, furan derivatives with alkenyl side chains can undergo further cyclization, addition, and polymerization reactions, providing great flexibility for constructing more complex molecular structures and possessing significant application value in medicinal chemistry and materials science (Bioorg. Med. Chem. Lett. 2013, 23, 3262-3266).

[0003]

[0004] Traditional synthetic methods for constructing furan derivatives with alkenyl side chains, such as the Paal-Knorr and Feist-Benary methods, often suffer from cumbersome procedures, demanding reaction conditions (e.g., high temperature, anhydrous and oxygen-free environments), the use of expensive catalysts (e.g., palladium or rhodium catalysts), a narrow substrate range, and poor selectivity at the C2 or C3 sites for multi-substituted furan derivatives, especially those with specific alkenyl substitutions, resulting in yields mostly between 30% and 50%. In reported cases, the introduction of furan cycloalkenyl groups requires a Pd(OAc)2-catalyzed coupling reaction at 140°C under N2 atmosphere, with a yield of only 30% (Org. Lett. 2008, 10, 1159–1162). This limits the rapid preparation and industrial production of these compounds. Therefore, developing a new synthetic method that is simple to operate, operates under mild conditions, uses readily available raw materials, exhibits good selectivity, and yields high yields is of significant scientific and industrial application value. Summary of the Invention

[0005] To address the aforementioned deficiencies or improvement needs of existing technologies, the present invention aims to provide a method for preparing polysubstituted furan compounds containing alkenyl side chains. This method optimizes the reaction participants and corresponding synthetic mechanisms, enabling the efficient one-pot reaction of unsaturated aldehydes and carbonyl compounds with acid catalysts and auxiliaries to synthesize polysubstituted furan compounds containing alkenyl side chains. Compared to traditional methods using palladium or rhodium-catalyzed coupling reactions to synthesize alkenyl furans, this method offers advantages in terms of the availability and cost-effectiveness of the raw materials and reagents used. It also avoids a series of complex synthetic steps and conditions, such as pre-activation, transition metal catalytic coupling, and anhydrous and oxygen-free operations, resulting in a simpler and more operable process.

[0006] To achieve the above objectives, according to one aspect of the present invention, a method for preparing a polysubstituted furan compound containing an alkenyl side chain is provided, characterized in that the method uses unsaturated aldehydes and carbonyl compounds as raw materials, and obtains the polysubstituted furan product containing an alkenyl side chain by one-pot reaction in an organic solvent under the presence of an acid catalyst and an auxiliary agent.

[0007] As a further preferred embodiment of the present invention, the synthetic route is as follows:

[0008] Among them, R 1 It is aryl; R 2 It is H or any one of C1 to C10 alkyl or aryl; R 3 It is any one of C1 to C10 alkyl or aryl; R 4 It can be either an ester group or an amide group.

[0009] As a further preferred embodiment of the present invention, the unsaturated aldehyde is obtained by self-condensation of aliphatic aldehydes with more than C2 carbon atoms, or by cross-condensation of hydroxyl aldehydes with more than C2 carbon atoms. Preferably, the unsaturated aldehyde is obtained by aryl acetaldehyde through self-condensation or cross-condensation with other C2 or higher aliphatic aldehydes or hydroxyl aldehydes.

[0010] As a further preferred embodiment of the present invention, the carbonyl compound is a β-keto ester or a β-keto amide.

[0011] As a further preferred embodiment of the present invention, the auxiliary agent is a halogenated reagent, which is any one of liquid bromine, elemental iodine, N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), dibromohydantoin (DBDMH), bromochlorohydantoin (BCDMH), and carbon tetrabromoide (CBr4).

[0012] As a further preferred embodiment of the present invention, the acid catalyst is at least one selected from boron tribromide (BBr3), boron trichloride diethyl ether complex (BF3·Et2O), aluminum chloride (AlCl3), zinc chloride (ZnCl2), ferric chloride (FeCl3), zirconium tetrachloride (ZrCl4), p-toluenesulfonic acid (PTSA), and aluminum trifluoromethanesulfonate (Al(OTf)3).

[0013] As a further preferred embodiment of the present invention, the organic solvent is any one of dichloromethane (DCM), 1,2-dichloroethane (DCE), acetonitrile (MeCN), tetrahydrofuran (THF), ethanol (EtOH), ethyl acetate (EtOAc), and toluene (PhMe).

[0014] As a further preferred embodiment of the present invention, the molar ratio of the unsaturated aldehyde to the carbonyl compound is 1:2 to 2:1; The molar ratio of the unsaturated aldehyde to the auxiliary agent is 1:1 to 1:2; The molar ratio of the unsaturated aldehyde to the acid catalyst is 20:1 to 5:1.

[0015] As a further preferred embodiment of the present invention, the one-pot reaction is carried out by stirring at a temperature of 25–100 °C for 1–12 hours.

[0016] Compared with the prior art, the present invention uses unsaturated aldehydes (also known as aldol condensates) and carbonyl compounds as raw materials and utilizes the synergistic effect of auxiliaries and acid catalysts to achieve one-pot cyclization of unsaturated aldehydes and carbonyl compounds, and efficiently constructs polysubstituted furan rings with alkenyl groups (in the one-pot reaction, a series of reactions such as condensation, rearrangement and aromatization will occur, thereby forming polysubstituted furan products with alkenyl side chains).

[0017] The core of this invention lies in using unsaturated aldehydes as substrates and activating them with auxiliaries (such as halogenated reagents), achieving a polarity reversal process in an in-situ reaction system. Preferably, the molar ratio of the unsaturated aldehyde to the carbonyl compound in the reaction system is controlled at 1:2 to 2:1, ensuring that the reaction rates are matched even when there are significant differences in the reactivity of the two substrates. Preferably, the molar ratio of the unsaturated aldehyde to the auxiliary in the reaction system is controlled at 1:1 to 1:2 to ensure that the unsaturated aldehyde is fully activated by the auxiliary.

[0018] Compared with traditional furan synthesis methods, this invention does not require high temperature, does not require controlled anhydrous and oxygen-free conditions, and does not require the use of precious metal catalysts such as palladium or rhodium. It has the advantages of simple route, mild reaction conditions, wide substrate applicability, high reaction selectivity, good yield, low cost, simple post-processing, and great industrial application value. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0020] In the examples described below, the separation of alkenyl-containing polysubstituted furan compounds from the system after the reaction was performed using post-treatment method A (i.e., general method A), as follows: After the reaction was complete, saturated sodium thiosulfate solution was added to the reaction solution to quench excess auxiliaries, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (using petroleum ether / ethyl acetate as eluent) or recrystallization to obtain the target furan compound.

[0021] The following are specific embodiments (the reaction conditions for all embodiments in this invention are under normal pressure and atmospheric atmosphere, and there is no need to control the anhydrous and oxygen-free conditions): Example 1: Preparation of ethyl 2-methyl-5-phenyl-4-vinylfuran-3-carboxylate

[0022] In a 20 mL round-bottom flask equipped with a magnetic stirrer, 2-phenyl-2-butenal (147 mg, 1.0 mmol) and ethyl acetoacetate (130 mg, 1.0 mmol) were dissolved in 5 mL of tetrahydrofuran (THF). Then, N-bromosuccinimide (NBS, 180 mg, 1.0 mmol) and zinc chloride (ZnCl2, 3.4 mg, 0.025 mmol) were added. The reaction mixture was stirred at 40 °C for 4 hours. After the reaction was complete as monitored by TLC, it was post-processed according to general method A. The product was purified by column chromatography (petroleum ether:ethyl acetate, v / v 20:1) to give 180 mg (70% yield) of the pale yellow liquid target product, ethyl 2-methyl-5-phenyl-4-vinylfuran-3-carboxylate. 1H NMR (400 MHz, CDCl3) δ [ppm] 7.74–7.66 (m,2H), 7.37 (tq, J = 3.5, 1.1 Hz, 2H), 7.32–7.28 (m, 1H), 6.86 (dd, J = 17.8,11.4 Hz, 1H), 5.53 (dd, J = 17.8, 1.9 Hz, 1H), 5.35 (dd, J = 11.4, 1.9 Hz,1H), 4.32 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13 HRMS (ESI) m / z calcd for C 16 H 17 O3⁺ [M+H]⁺: 257.1172, found: 257.1178. Comparative Example 1: Comparison of reported methods for preparing ethyl 2-methyl-5-phenyl-4-vinylfuran-3-carboxylate ( Eur. J. Org. Chem. 2014, 2014 , 7095–7098)

[0023] In this comparative case, researchers synthesized vinyl-containing furan products using a self-made alkynyl-containing substrate in the presence of the noble metal catalyst AgBF4, with a yield of only 36%.

[0024] In contrast, Example 1 of this invention uses commercially available reagents as substrates and does not employ any precious metal catalysts. It achieves a 70% reaction yield of the same compound under mild conditions, demonstrating a significant advantage over Comparative Example 1. Therefore, this invention avoids the use of precious metal catalysts such as palladium and rhodium, provides mild reaction conditions, does not require anhydrous or oxygen-free environments, and is highly operable.

[0025] Example 2: Preparation of ethyl 2-methyl-5-phenyl-4-vinylfuran-3-carboxylic acid

[0026] In a 20 mL round-bottom flask equipped with a magnetic stirrer, 2-phenyl-2-butenal (147 mg, 1.0 mmol) and ethyl acetoacetate (130 mg, 1.0 mmol) were added and dissolved in 5 mL acetonitrile (MeCN). Then, dibromohydantoin (DBDMH, 158 mg, 0.55 mmol) and aluminum chloride (AlCl3, 6.7 mg, 0.05 mmol) were added. The reaction mixture was stirred at 60 °C for 5 hours. After the reaction was completed by TLC monitoring, it was post-processed according to general method A. The product was purified by column chromatography (petroleum ether:ethyl acetate, v / v 20:1) to give 138 mg (54% yield) of the pale yellow liquid target product, ethyl 2-methyl-5-phenyl-4-vinylfuran-3-carboxylate. 1 H NMR (400 MHz, CDCl3) δ [ppm] 7.74–7.66 (m, 2H),7.37 (tq, J = 3.5, 1.1 Hz, 2H), 7.32–7.28 (m, 1H), 6.86 (dd, J = 17.8, 11.4Hz, 1H), 5.53 (dd, J = 17.8, 1.9 Hz, 1H), 5.35 (dd, J = 11.4, 1.9 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13 HRMS (ESI) m / z calcd for C 16 H 17 O3⁺ [M+H]⁺: 257.1172, found: 257.1178. Example 3: Preparation of ethyl 2-methyl-5-phenyl-4-vinylfuran-3-carboxylate

[0027] In a 20 mL round-bottom flask equipped with a magnetic stirrer, 147 mg (1.0 mmol) of 2-phenyl-2-butenal and 130 mg (1.0 mmol) of ethyl acetoacetate were added to 5 mL of ethyl acetate (EtOAc). Liquid bromine (Br2, 56 μL, 1.1 mmol) and aluminum chloride (AlCl3, 6.7 mg, 0.05 mmol) were then added. The reaction mixture was stirred at 60 °C for 5 hours. After the reaction was complete as monitored by TLC, it was post-processed according to general method A. The product was purified by column chromatography (petroleum ether:ethyl acetate, v / v 20:1) to give 151 mg (59% yield) of the pale yellow liquid target product, ethyl 2-methyl-5-phenyl-4-vinylfuran-3-carboxylate. 1 H NMR (400 MHz, CDCl3) δ [ppm] 7.74–7.66 (m, 2H), 7.37 (tq,J = 3.5, 1.1 Hz, 2H), 7.32–7.28 (m, 1H), 6.86 (dd, J = 17.8, 11.4 Hz, 1H),5.53 (dd, J = 17.8, 1.9 Hz, 1H), 5.35 (dd, J = 11.4, 1.9 Hz, 1H), 4.32 (q, J= 7.1 Hz, 2H), 2.60 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13 HRMS (ESI) m / z calcd for C 16 H 17 O3⁺ [M+H]⁺: 257.1172, found: 257.1178. Example 4: Preparation of (E)-2-methyl-4-(3-methylbutenyl)-5-phenylfuran-3-carboxylic acid ethyl ester

[0028] In a 20 mL round-bottom flask equipped with a magnetic stirrer, cocaine (190 mg, 1.0 mmol) and ethyl acetoacetate (130 mg, 1.0 mmol) were dissolved in 5 mL acetonitrile (MeCN). Liquid bromine (Br2, 56 μL, 1.1 mmol) and aluminum chloride (AlCl3, 6.7 mg, 0.05 mmol) were then added. The reaction mixture was stirred at 80 °C for 5 hours. After the reaction was complete as monitored by TLC, post-processing was performed according to general method A. The product was purified by column chromatography (petroleum ether:ethyl acetate, v / v 50:1) to give 224 mg (75% yield) of the pale yellow liquid target product, ethyl (E)-2-methyl-4-(3-methylbutenyl)-5-phenylfuran-3-carboxylate. The resulting product contains an alkenyl side chain and can be used as an intermediate to further construct naphthofuran compounds with ester substituents. These compounds could serve as a favorable scaffold structure for Mcl-1 protein inhibitors and have potential application value in drug screening. WO2013149124 ). 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.0 Hz, 2H), 7.34(t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 6.45 (dd, J = 16.2, 1.5 Hz, 1H), 5.86 (dd, J = 16.2, 6.8 Hz, 1H), 4.31 (t, J = 7.1 Hz, 2H), 2.59 (s, 3H), 2.41(dtd, J = 13.5, 6.8, 1.4 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H), 1.04 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 164.58, 158.36, 147.26, 142.24, 131.07, 128.28,127.44, 126.55, 119.77, 117.28, 114.67, 60.07, 31.78, 21.93, 14.36, 14.29.HRMS (ESI) m / z calcd for C 19 H 23O3⁺ [M+H]⁺: 299.1642, found: 299.1643. Example 5: Preparation of (E)-2-methyl-4-(3-methylbutenyl)-N,5-diphenylfuran-3-carboxamide

[0029] In a 20 mL round-bottom flask equipped with a magnetic stirrer, cocaine (190 mg, 1.0 mmol) and acetoacetanilide (180 mg, 1.0 mmol) were added and dissolved in 5 mL acetonitrile (MeCN). Liquid bromine (Br2, 56 μL, 1.1 mmol) and aluminum chloride (AlCl3, 6.7 mg, 0.05 mmol) were then added. The reaction mixture was stirred at 60 °C for 4 hours. After the reaction was complete as monitored by TLC, post-treatment was performed according to general method A. The product was purified by column chromatography (petroleum ether:ethyl acetate, v / v 20:1) to give 200 mg (58%) of the pale yellow liquid target product (E)-2-methyl-4-(3-methylbutenyl)-N,5-diphenylfuran-3-carboxamide. The resulting product contains an alkenyl side chain and can be used as an intermediate to further construct naphthofuran compounds with amide groups. These compounds can serve as a favorable scaffold structure for Mcl-1 protein inhibitors and have potential application value in drug screening. WO2013149124 ). 1 H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.67 (d, J = 7.2Hz, 2H), 7.47–7.35 (m, 4H), 7.30 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 8.1 Hz, 2H), 6.49–6.40 (m, 1H), 6.06 (dd, J = 16.2, 6.8 Hz, 1H), 2.64 (s, 3H), 2.59–2.48 (m,1H), 1.09 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.38, 150.11,147.65, 146.16, 135.38, 133.82, 130.70, 129.57, 128.46, 127.54, 126.10,119.70, 117.29, 31.96, 22.14, 13.80. HRMS (ESI) m / z calcd for C 23 H 24 NO2⁺ [M+H]⁺: 346.1802, found: 346.1799. The above examples are merely illustrative; the reaction substrates and specific reaction parameters can be adjusted according to actual needs (e.g., unsaturated aldehydes and carbonyl compounds). , In the middle, R 1 It can be aryl, R 2 It can be any of H or alkyl (with C1 to C10 carbon atoms) or aryl, R 3 It can be any of alkyl (with C1 to C10 carbon atoms) or aryl, R 4 (It can be either an ester group or an amide group); for example, depending on the specific unsaturated aldehyde, a halogenated reagent matching the reactivity of that unsaturated aldehyde can be selected as an auxiliary agent to achieve the best results. Furthermore, depending on the substrate's reactivity, the molar ratio of the unsaturated aldehyde to the acid catalyst in the reaction system, the one-pot stirring reaction temperature, and the reaction time can all be adjusted according to the actual situation to ensure the optimal yield of the target product (for example, the molar ratio of the unsaturated aldehyde to the acid catalyst in the reaction system can be adjusted from 20:1 to 5:1, the one-pot reaction temperature can be adjusted from 25–100 ℃, and the reaction time can be adjusted from 1–12 hours).

[0030] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the preparation of a polysubstituted furan compound containing alkenyl side chains, characterized in that, The method is to obtain a polysubstituted furan product containing an alkenyl side chain by one-pot reaction in an organic solvent under the condition of an acid catalyst and an auxiliary agent, taking unsaturated aldehyde and carbonyl compound as raw materials.

2. The preparation method according to claim 1, characterized in that, The synthetic route is as follows: wherein R is an aryl group; and 1 is an aryl group; and R 2 is any one of H or C1to C10alkyl or aryl; R 3 is any one of Crto C10alkyl or aryl; R 4 is any one of an ester group or an amide group.

3. The preparation method according to claim 1, characterized in that, The unsaturated aldehyde is obtained by self-condensation of C2 or more aliphatic aldehyde, or by aldol cross condensation between C2 or more aliphatic aldehydes; Preferably, the unsaturated aldehyde is obtained by self-condensation or aldol cross condensation of aryl acetaldehyde with other C2 or more aliphatic aldehydes.

4. The preparation method according to claim 1, characterized in that, The carbonyl compound is a β-keto ester or a β-keto amide.

5. The method of claim 1, wherein the step of forming the first and second layers is performed by a method selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. The auxiliary agent is a halogenating agent, and the halogenating agent is any one of liquid bromine, elemental iodine, N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), dibromohydantoin (DBDMH), bromochlorohydantoin (BCDMH), and carbon tetrabromide (CBr4).

6. The preparation method according to claim 1, characterized in that, The acid catalyst is at least one of boron tribromide (BBr3), boron trichloride diethyl ether complex (BF3·Et2O), aluminum chloride (AlCl3), zinc chloride (ZnCl2), iron chloride (FeCl3), zirconium tetrachloride (ZrCl4), p-toluenesulfonic acid (PTSA), and aluminum trifluoromethanesulfonate (Al(OTf)3).

7. The preparation method according to claim 1, characterized in that, The organic solvent is any one of dichloromethane (DCM), 1,2-dichloroethane (DCE), acetonitrile (MeCN), tetrahydrofuran (THF), ethanol (EtOH), ethyl acetate (EtOAc), and toluene (PhMe).

8. The method of claim 1, wherein the step of forming the first and second layers is performed by a method selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. The molar ratio of the unsaturated aldehyde to the carbonyl compound is 1:2 to 2:

1. The molar ratio of the unsaturated aldehyde to the auxiliary agent is 1:1 to 1:

2. The molar ratio of the unsaturated aldehyde to the acid catalyst is 20:1 to 5:

1.

9. The method of claim 1, wherein the step of forming the first and second layers is performed by a method selected from the group consisting of: sputtering, evaporation, and chemical vapor deposition. The one-pot reaction is stirred at a temperature of 25-100 ℃ for 1-12 hours.

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