Alpha, beta-unsubstituted 1, 4-ketoaldehyde compound as well as preparation method and application of alpha, beta-unsubstituted 1, 4-ketoaldehyde compound through metal-free photocatalytic aqueous solution acetaldehyde alpha-position selective single alkylation reaction

Abstract

The invention provides an alpha, beta unsubstituted 1, 4-ketoaldehyde compound and a metal-free photocatalytic aqueous solution acetaldehyde alpha-position selective single alkylation reaction preparation method and application thereof, a photosensitizer and alpha bromine / chloro aryl ethyl ketone are mixed in an organic solvent, then TEEDA, nBu4NI and an acetaldehyde aqueous solution are sequentially added, white light irradiation stirring reaction, separation and purification are performed, and the alpha, beta unsubstituted 1, 4-ketoaldehyde compound is obtained. Compared with the prior art, the method has the advantages that by improving the light source, the reaction can be amplified to the gram scale level, the yield of the corresponding alpha and beta unsubstituted 1, 4-ketoaldehyde product is not obviously reduced, and a basis is provided for the industrialization process of the reaction. The reaction disclosed by the invention has the characteristics of wide substrate range, high functional group tolerance, simplicity in operation, mild reaction conditions and the like. Moreover, the product disclosed by the invention can be subjected to reductive amination with cyclic secondary amine to obtain a series of gamma-aminoketones with biological activity, which shows that the reaction has potential synthesis application value in the field of pharmaceuticals.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a preparation method and application of an α, β unsubstituted 1,4-ketoaldehyde compound and a metal-free photocatalytic aqueous solution acetaldehyde α-position selective single alkylation reaction. Background Art

[0002] Acetaldehyde is the simplest carbonyl compound that can be enolized, but its high reactivity has hindered its application as an important C2 fragment source in organic synthesis, especially the selective single functionalization reaction at the α position of acetaldehyde. According to current literature reports, the selective single functionalization reaction of acetaldehyde at the α position mainly relies on the organic small molecule catalytic mode, which generates chiral enamine intermediates through condensation and dehydration of chiral amine catalysts and acetaldehyde molecules.

[0003] The synthesis of α,β-unsubstituted 1,4-ketoaldehyde compounds reported in the literature requires the use of transition metal catalysts and substrates that are much more expensive than aqueous acetaldehyde. Moreover, these substrates are often not commercially available, and the reaction operation is also cumbersome and complicated. Figure 1Chemistry, Chemistry and ReviewsMondal,K.andMondal,B.Pan,SCOrganocatalytic Redox Isomerizationof Electron-Deficient Allylic Alcohols:Synthesis of1,4-Ketoaldehydes.J.Org.Chem.2016,81,4835-4840. Song, D. Xia, P.-J. Wang, J. Xiang, H.-Y., Yang, H. Visible-Light-Promoted Synthesis of 1,4-Dicarbonyl Compounds via Conjugate Addition of Aroyl Chlorides.Chem.AsianJ.2018,13,271-274 Liu, D. and Yang, K. and Fang, D. and Li, S.-J. and Lan, Y. and Chen, Y. Formyl Radical Generation fromα-Chloro N-Methoxyphthalimides EnablesSelective Aldehyde Synthesis.Angew.Chem.Int.Ed.2023,62,e202213686.Introduction(a)García-Santos,WH,Mateus-Ruiz,JB,Cordero-Vargas,A.Visible-LightPhotocatalytic Preparation of 1,4-Ketoaldehydes and 1,4-Diketones fromα-Bromoketones and Alkyl Enol Ethers.Org.Lett.2019,21,4092-4096.(b)García-Santos,WH; -Hernández, J.; Farfán-Paredes, M.; Castro-Cruz, HM; Macías-Ruvalcaba, NA; Farfán, N.; Cordero-Vargas, A. Method E is disclosed from Li, R.; Dong, Y.; Khan, SN; Zaman, MK; Zhou, J.; Miao, P.; Hu, L.; Sun, Z. Decarboxylative oxidation-enabled consecutive CC bondcleavage. Nat. Commun. 2022, 13, 7061. Method F is disclosed in Gómez-Gil, S.; Rubio-Presa, R.; Hernández-Ruiz, R.; Suárez-Pantiga, S.; Pedrosa, MR; Sanz, R. Synthesis of 1,4-ketoaldehydes and 1,4-diketones by Mo-catalyzed oxidative cleavage ofcyclobutane-1,2-diols. Org. Biomol. Chem. 2023, 21, 4185-4190.

[0004] Therefore, providing a low-cost method for preparing α,β-unsubstituted 1,4-ketoaldehyde compounds without using metals is beneficial to industrial production and subsequent conversion into drug molecules. Summary of the invention

[0005] The purpose of the present invention is to provide an α,β unsubstituted 1,4-ketoaldehyde compound and a preparation method thereof for a metal-free photocatalytic aqueous solution acetaldehyde α-position selective single alkylation reaction, wherein aqueous solution acetaldehyde and α-bromo / chloroaryl ethyl ketone are irradiated by a white LED and acted on by photosensitizers 4CzIPN and TEEDA to prepare an α,β unsubstituted 1,4-ketoaldehyde compound. The preparation method is simple and the raw materials are cheap and readily available.

[0006] Another object of the present invention is to provide the use of α,β unsubstituted 1,4-ketoaldehyde compounds for organic synthesis.

[0007] The specific technical solutions of the present invention are as follows:

[0008] The present invention provides a method for preparing a metal-free photocatalytic aqueous solution acetaldehyde α-position selective single alkylation reaction, the preparation method comprising:

[0009] Mix the photosensitizer and α-bromo / chloroaryl ethyl ketone in an organic solvent, then add TEEDA, nBu 4 NI and acetaldehyde aqueous solution are reacted by stirring under white light irradiation, and then separated and purified to obtain α, β unsubstituted 1,4-ketoaldehyde compounds.

[0010] The photosensitizer, α-bromo / chloro aryl ethyl ketone, TEEDA, nBu 4 The molar ratio of NI to acetaldehyde in the acetaldehyde aqueous solution is: 0.01:2:1.8:0-1.4:20;

[0011] The α-bromo / chloro aryl acetone is α-bromoacetophenone, nBu 4 NI dosage is 0;

[0012] The α-bromo / chloro aryl acetophenone is α-chloro acetophenone, and the photosensitizer, α-chloro acetophenone, TEEDA, nBu 4 The molar ratio of NI to acetaldehyde in the acetaldehyde aqueous solution is: 0.01:2:1.8:1.4:20;

[0013] The structural formula of the α-bromo / chloroaryl acetone is: R 1 for or X=Br or Cl; R is any one or more of halogen, H, alkyl, alkoxy or aryl; preferably, R is H, F, Br, -CH 3 、-C(CH 3 ) 3 、-OCH 3 One or several;

[0014] The dosage ratio of the α-bromo / chloroaryl ethyl ketone and the organic solvent is 0.20-0.25 mol / L;

[0015] The mass concentration of the acetaldehyde aqueous solution is 30-50%, preferably 40%;

[0016] The photosensitizer is 4CzIPN, i.e. 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile;

[0017] The TEEDA is N,N,N',N'-tetraethylethylenediamine;

[0018] The nBu 4 NI is tetra-n-butylammonium iodide;

[0019] The organic solvent is chloroform;

[0020] The white light irradiation stirring reaction refers to the white LED irradiation of 2×3W under room temperature stirring conditions, and the irradiation reaction time is 28-35min;

[0021] Separation and purification: Separate the two phases of the reaction mixture using a separatory funnel, extract the aqueous phase with dichloromethane (20 mL x 3). 2 SO 4 Dry, filter and concentrate in vacuo; the mixture is purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents to give the product.

[0022] The present invention provides an α,β unsubstituted 1,4-ketoaldehyde compound prepared by a metal-free photocatalytic aqueous solution acetaldehyde α-selective single alkylation reaction, wherein the α,β unsubstituted 1,4-ketoaldehyde compound has a structural formula of R 1 for or R is any one or more of halogen, H, alkyl, alkoxy or aryl; preferably, R is H, F, Br, -CH 3 、-C(CH 3 ) 3 、-OCH 3 One or several.

[0023] The invention provides an application of an α,β unsubstituted 1,4-ketoaldehyde compound for organic synthesis, including being used for synthesizing haloperidol, ebastine or pentabromopseudilin.

[0024] The existing technology for synthesizing α,β-unsubstituted 1,4-ketoaldehyde compounds requires the use of transition metal catalysts and substrates that are much more expensive than aqueous acetaldehyde. These substrates are often not commercially available, and the reaction operation is also cumbersome and complicated. As a type of aqueous solution compound that can be produced industrially, aqueous acetaldehyde is cheap, easy to obtain, and very safe to handle; α-bromo / chloroaryl ethyl ketone is also a type of commercial, cheap and easy to obtain reagent. Through a metal-free photocatalytic free radical strategy, these two cheap compounds, aqueous acetaldehyde and α-bromo / chloroaryl ethyl ketone, are converted into high-value-added α,β-unsubstituted 1,4-ketoaldehyde products, and through some simple synthetic reactions, aqueous acetaldehyde is transformed from a bulk commodity to a high-value active drug molecule.

[0025] Compared with the prior art, the present invention develops a metal-free photocatalytic free radical strategy to convert two types of cheap compounds, aqueous solution acetaldehyde and α-bromo / chloroaryl acetone, into high-value-added α, β-unsubstituted 1,4-ketoaldehyde products, and through some simple synthetic reactions, the aqueous solution acetaldehyde is transformed from a bulk commodity to a high-value active drug molecule. It is particularly worth mentioning that through the improvement of the light source, this type of metal-free photocatalytic aqueous solution acetaldehyde and α-bromoacetophenone α-selective single alkylation reaction of acetaldehyde can be scaled up to the gram scale level, and the corresponding α, β-unsubstituted 1,4-ketoaldehyde product yield is not significantly reduced, which provides a basis for the industrialization process of the reaction. The reaction of the present invention has the characteristics of a wide substrate range, high functional group tolerance, simple operation, mild reaction conditions, etc., and the gram-scale scale-up experiment shows no significant reduction in the reaction yield. In addition, by directly using industrially cheap acetaldehyde aqueous solution as the C2 synthon, the efficiently prepared α,β-unsubstituted 1,4-ketoaldehyde product can undergo reductive amination with cyclic secondary amines under metal-free catalysis to obtain a series of biologically active γ-amino ketones, demonstrating that this reaction has potential synthetic application value in the field of pharmaceutical chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a reported method for synthesizing α,β-unsubstituted 1,4-ketoaldehyde compounds;

[0027] Figure 2 The present invention provides a method for preparing α,β unsubstituted 1,4-ketoaldehyde compounds by a metal-free photocatalytic aqueous solution acetaldehyde α-position selective single alkylation reaction;

[0028] Figure 3 The present invention provides a synthesis of some representative α,β unsubstituted 1,4-ketoaldehyde compounds;

[0029] Figure 4 It is the synthetic application of the representative α,β unsubstituted 1,4-ketoaldehyde compound of the present invention;

[0030] Figure 5 The mechanism of the α,β-unsubstituted 1,4-ketoaldehyde product 2a of the present invention;

[0031] Figure 6 The product 2a of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0032] Figure 7 The product 2a of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0033] Figure 8 The product 2a of the present invention 19F NMR (376 MHz, CDCl 3 );

[0034] Fig. 9 Product 2b of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0035] Fig.10 Product 2b of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0036] Fig.11 The product 2c of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0037] Fig.12 The product 2c of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0038] Fig.13 The 2d product of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0039] Fig.14 The 2d product of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0040] Fig.15 The product 2e of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0041] Fig.16 The product 2e of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0042] Fig.17 The 2f product of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0043] Fig.18 The 2f product of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0044] Fig.19 2g product of the present invention1 H NMR (400 MHz, CDCl 3 );

[0045] Fig. 20 2g product of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0046] Fig.21 2g product of the present invention 19 F NMR (376 MHz, CDCl 3 );

[0047] Fig. 22 The 2h product of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0048] Fig.23 The 2h product of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0049] Fig.24 The 2i product of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0050] Fig.25 The 2i product of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0051] Fig.26 The product of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0052] Fig. 27 The product of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0053] Fig.28 Haloperidol 1 H NMR (400 MHz, CDCl 3 );

[0054] Fig.29 Haloperidol 13 C NMR (100 MHz, CDCl 3 );

[0055] Fig.30 Haloperidol 19 F NMR (376 MHz, CDCl 3 );

[0056] Fig.31 For the present invention ebastine 1 H NMR (400 MHz, CDCl 3 );

[0057] Fig.32 For the present invention ebastine 13 C NMR (100 MHz, CDCl 3 );

[0058] Fig.33 Product 6 of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0059] Fig.34 Product 6 of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0060] Fig.35 Product 7 of the present invention 1 H NMR (400 MHz, CDCl 3 );

[0061] Fig.36 Product 7 of the present invention 13 C NMR (100 MHz, CDCl 3 );

[0062] Fig.37 The present invention is pentabromopseudilin 1 H NMR (400 MHz, DMSO-d 6 );

[0063] Fig.38 The present invention is pentabromopseudilin 13 C NMR (100 MHz, DMSO-d 6 ). DETAILED DESCRIPTION

[0064] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0065] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0066] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0067] Example 1

[0068] The present invention provides a method for preparing an α, β unsubstituted 1,4-ketoaldehyde compound prepared by a metal-free photocatalytic aqueous solution acetaldehyde α-position selective single alkylation reaction, using α-bromoacetophenone as a raw material, and the preparation method is as follows:

[0069] A magnetic particle was added to a clean 10 mL reaction tube, and the photosensitizer 4CzIPN (8.0 mg, 0.5 mol%) and α-bromoacetophenone (2.0 mmol, 1.0 equiv.) were weighed and dissolved in 9 mL of chloroform. TEEDA (310.2 mg, 1.8 mmol) and acetaldehyde aqueous solution (2.20 g, containing 20.0 mmol, 40 wt%) were added to the system in sequence and stirred at room temperature. The reaction was monitored by TLC plate under white LED irradiation (2×3 W). After about 30 minutes, the reaction was completed. The two phases of the reaction mixture were separated by a separatory funnel, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated in vacuo. The mixture was purified by silica gel column chromatography (eluent: ethyl acetate and petroleum ether) to give products 2a-2j in 45-68% yield, such as Figure 3 shown.

[0070] The preparation process is as follows:

[0071]

[0072] The product is 4-(4-fluorophenyl)-4-oxobutyraldehyde (2a), and the structural formula is: The preparation method is:

[0073] According to the experimental steps of Example 1 above, The reaction was carried out on a 2.0 mmol scale and column chromatography (eluent = PE / EA, 100:0 to 10:1) gave a yellow oily product. Figure 3 The product 2a (241.3 mg, 67% yield) was characterized as follows:

[0074] 1 H NMR (400 MHz, CDCl 3 )δ9.91(s,1H),8.04-8.00(m,2H),7.17-7.12(m,2H),3.30(t,J=6.0Hz,2H),2.94(t,J=6.4Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ200.5,196.1,165.7(d,J=253.3Hz),132.7(d,J=3.9Hz),130.6(d,J=9.6Hz),115.6(d,J=21.5Hz),37.4,30.7. 19 F NMR (376 MHz, CDCl 3 )δ-104.84.IR(KBr):ν=3070,2908,2830,2723,1724,1683,1600,1232,1159,836cm -1 .HRMS:m / z(ESI)calculated for(C 10 H 10 FO 2 )[M+H] + :181.0660,found:181.0667.

[0075] The product is 4-(4-bromophenyl)-4-oxobutyraldehyde (2b), with the structural formula The preparation method is:

[0076] According to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 10:1) gave a yellow solid product 2b (302.9 mg, 63% yield), melting point = 58-59° C. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 )δ9.89(s,1H),7.86-7.83(m,2H),7.63-7.59(m,2H),3.28(t,J=6.4Hz,2H),2.94(t,J=6.8Hz,2H). 13 C NMR (100 MHz, CDCl 3)δ200.3,196.7,135.0,131.8,129.5,128.3,37.4,30.8.IR(KBr):ν=3094,2915,2828,2730,1710,1679,1582,1409,992,821,713cm -1 .HRMS:m / z(ESI)calculated for(C 10 H 10 79 B O 2 )[M+H] + :240.9859,found:240.9864; m / z(ESI)calculated for(C 10 H 10 81 B O 2 )[M+H] + :242.9839,found:242.9844.

[0077] The product is 4-oxo-4-phenylbutyraldehyde (2c), with the structural formula The preparation method is:

[0078] According to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 10:1) gave a yellow oily product 2c (202.9 mg, 63% yield). The product was characterized as follows:

[0079] 1 H NMR (400 MHz, CDCl 3 )δ9.90(s,1H),8.00-7.97(m,2H),7.60-7.55(m,1H),7.49-7.45(m,2H),3.32(t,J=6.0Hz,2H),2.93(t,J=6.4Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ200.6,197.7,136.2,133.1,128.5,127.9,37.4,30.8.IR(KBr):ν=3058,2913,2823,2720,1715,1686,1600,1242,762,692cm -1 .HRMS:m / z(ESI)calculated for(C 10 H 11 O 2 )[M+H] +:163.0754,found:163.0760.

[0080] The product is 4-(4-(tert-butyl)phenyl)-4-oxobutyraldehyde (2d), with the structural formula The preparation method is:

[0081] According to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 10:1) gave a yellow oily product 2d (298.5 mg, 68% yield). The product was characterized as follows: 1 HNMR (400MHz, CDCl 3 )δ9.91(s,1H),7.94(d,J=8.4Hz,2H),7.49(d,J=8.8Hz,2H),3.32(t,J=6.4Hz,2H),2.93(t,J=6.4Hz,2H),1.35(s,9H). 13 C NMR (100 MHz, CDCl 3 )δ200.7,197.3,156.9,133.7,127.9,125.5,37.5,35.0,31.0,30.8.IR(KBr):ν=3055,2970,2898,2868,1710,1680,1606,1405,1243,826cm -1 .HRMS:m / z(ESI)calculated for(C 14 H 19 O 2 )[M+H] + :219.1380,found:219.1388.

[0082] The product is 4-oxo-4-(o-tolyl)butyraldehyde (2e), with the structural formula: The preparation method is as follows: according to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 5:1) gave a yellow oily product 2e (194.4 mg, 55% yield). The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 )δ9.90(s,1H),7.74(d,J=8.0Hz 1H),7.41-7.37(m,1H),7.29-7.24(m,2H),3.23(t,J=6.4Hz,2H),2.91(t,J=6.8Hz,2H),2.49(s,3H).13 C NMR (100 MHz, CDCl 3 )δ201.4,200.5,138.0,137.0,131.8,131.3,128.4,125.5,37.6,33.5,21 .1.IR(KBr):ν=3023,2904,2834,2717,1720,1682,1602,1240,973,761cm -1 .HRMS:m / z(ESI)calculated for(C 11 H 13 O 2 )[M+H] + :177.0910,found:177.0917.

[0083] 4-(3-methoxyphenyl)-4-oxobutyraldehyde (2f), the structural formula is:

[0084] According to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 5:1) gave the yellow oily product 2f (258.6 mg, 67% yield). Product characterization: 1 HNMR (400MHz, CDCl 3 )δ9.90(s,1H),7.59-7.57(m,1H),7.50-7.49(m,1H),7.38(t,J=8.0Hz,1H), 7.14-7.11(m,1H),3.85(s,3H),3.32(t,J=6.4Hz,2H),2.93(t,J=6.4Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ200.5,197.5,159.6,137.5,129.5,120.5,119.5,112.1,55.2,37.4,31.0 .IR(KBr):ν=3068,2943,2839,2721,1723,1683,1592,1262,1049,785,685cm -1 .HRMS:m / z(ESI)calculated for(C 11 H 13 O 3 )[M+H] + :193.0859,found:193.0866.

[0085] 4-(3,5-difluorophenyl)-4-oxobutyraldehyde (2g), structural formula: The preparation method is as follows:

[0086] According to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 10:1) gave 2 g (246.3 mg, 62% yield) of a yellow oily product. The product was characterized as follows: 1 HNMR (400MHz, CDCl 3 )δ9.90(s,1H),7.52-7.47(m,2H),7.07-7.02(m,1H),3.26(t,J=6.0Hz,2H),2.97(t,J=6.8Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ200.0,195.3(t,J=3.0Hz),163.0(d,J=250.0Hz),162.9(d,J=249.3Hz),139.2(t,J =8.0Hz), 110.7 (d, J = 11.6Hz), 110.0 (d, J = 26.0Hz), 108.5 (t, J = 25.2Hz), 37.3, 31.0. 19 F NMR (376 MHz, CDCl 3 )δ-107.91.IR(KBr):ν=3088,2915,2841,2721,1724,1693,1598,1440,1125,986,865,668cm -1 .HRMS:m / z(ESI)calculated for(C 10 H 9 F 2 O 2 )[M+H] + :199.0565,found:199.0562.

[0087] 4-(3,5-dichloro-2-methoxyphenyl)-4-oxobutyraldehyde (2h), the structural formula is: The preparation method is as follows:

[0088] According to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 10:1) gave a yellow solid product 2h (242.5 mg, 47% yield), melting point = 58-59° C. The product was characterized as follows: 1H NMR (400 MHz, CDCl 3 )δ9.87(s,1H),7.53-7.52(m,1H),7.503-7.498(m,1H),3.91(s,3H),3.27(t,J=6.8Hz,2H),2.92(t,J=6.4Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ200.0,198.1,153.5,134.9,133.2,129.7,129.6,127.9,62.2,37.6,35.0 .IR(KBr):ν=3070,2914,2837,2733,1712,1685,1460,1245,985,674,575cm -1 .HRMS:m / z(ESI)calculated for(C 11 H 11 O 3 Cl 2 )[M+H] + :261.0080,found:261.0091.

[0089] 4-(Furan-2-yl)-4-oxobutyraldehyde (2i), the structure is: The preparation method is:

[0090] According to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 5:1) gave a yellow solid product 2i (137.6 mg, 45% yield), melting point = 58-59°C. Product characterization: 1 H NMR (400 MHz, CDCl 3 )δ9.88(s,1H),7.602-7.597(m,1H),7.24-7.23(m,1H),6.56-6.55(m,1H),3.19(t,J=6.8Hz,2H),2.92(t,J=6.4Hz,2H). 13 C NMR (100MHz, CDCl3) δ200.3,186.9,152.1,146.4,117.1,112.2,37.0,30.4 .IR(KBr):ν=3120,2908,2846,2738,1712,1670,1469,1270,991,795,595cm -1 .HRMS:m / z(ESI)calculated for(C 8 H9 O 3 )[M+H] + :153.0546,found:153.0551.

[0091] 4-(2-Methoxyphenyl)-4-oxobutyraldehyde (2j), the structural formula is: The preparation method is:

[0092] According to the experimental steps of Example 1, the raw materials The reaction was carried out on a 2.0 mmol scale and column chromatography (eluent = PE / EA, 100:0 to 5:1) afforded the product 2j (176.8 mg, 46% yield) as a yellow oil.

[0093] 1 H NMR (400 MHz, CDCl 3 )δ9.88(s,1H),7.76(dd,J=8.0Hz,1.6Hz,1H),7.50-7.46(m,1H),7.03-6.97(m,2H),3.92(s,3H),3.35(t,J=6.8Hz,2H),2.86(t,J=6.4Hz,2H). 13 CNMR (100MHz, CDCl 3 )δ201.2,199.6,158.8,133.8,130.4,127.1,120.6,111.5,55.4,38.0,36 .5.IR(KBr):ν=3074,2944,2835,2715,1714,1680,1596,1248,1023,759cm -1 .HRMS:m / z(ESI)calculated for(C 11 H 13 O 3 )[M+H] + :193.0859,found:193.0867.

[0094] Example 2

[0095] The present invention provides a method for preparing an α,β unsubstituted 1,4-ketoaldehyde compound prepared by a metal-free photocatalytic aqueous solution acetaldehyde α-position selective single alkylation reaction, using α-chloroacetophenone as a raw material, and the preparation method is as follows:

[0096] A magnetic particle was added to a clean 10 mL reaction tube, and photosensitizer 4CzIPN (8.0 mg, 0.5 mol%) and α-chloroacetophenone (2.0 mmol, 1.0 equiv.) were weighed and dissolved in 9 mL of chloroform. TEEDA (310.2 mg, 1.8 mmol), nBu 4 NI (517.1 mg, 1.4 mmol) and acetaldehyde aqueous solution (2.20 g, 20.0 mmol, 40 wt%) were stirred at room temperature. The reaction was monitored by TLC plate under white LED irradiation (2 x 3 W). After about 1 hour, the reaction was completed. The two phases of the reaction mixture were separated by a separatory funnel, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The mixture was purified by silica gel column chromatography (eluent: ethyl acetate and petroleum ether) to give product 2a (224.3 mg, 62% yield) and 2c (188.3 mg, 58% yield).

[0097] The preparation process is as follows:

[0098]

[0099] According to the experimental steps of Example 2 above, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 5:1) gave a yellow oily product 2a (62% yield). The product was 4-(4-fluorophenyl)-4-oxobutyraldehyde (2a), with the structural formula

[0100]

[0101] According to the experimental steps of Example 2 above, the raw materials The reaction was carried out on a 2.0 mmol scale, and column chromatography (eluent = PE / EA, 100:0 to 5:1) gave a yellow oily product 2c (58% yield). The product was 4-oxo-4-phenylbutyraldehyde (2c), with the structural formula

[0102]

[0103] The preparation mechanism of the α,β-unsubstituted 1,4-ketoaldehyde product 2a of the present invention is as follows: Figure 5As shown, first, under the irradiation of white LED, the organic photosensitizer 4CzIPN is excited to the excited state, and TEEDA or the intermediate int-II donates an electron to the excited state 4CzIPN* to obtain the reduced photocatalyst 4CzIPN·ˉ, which can reduce α-bromoacetophenone 1a through a single electron transfer (SET) process to form the key intermediate int-I; subsequently, the intermediate int-I undergoes free radical addition with the enol tautomer of acetaldehyde to produce the intermediate int-II, which is quenched by the excited state 4Cz IPN* or α-bromoacetophenone 1a under the action of TEEDA to obtain the target α, β-unsubstituted 1,4-ketoaldehyde product 2a.

[0104] Example 3

[0105] The application of the α,β unsubstituted 1,4-ketoaldehyde compound prepared by the present invention is used for the synthesis of biologically active γ-aminoketone haloperidol, specifically:

[0106] 1. Gram-scale scale-up experiment:

[0107] A magnetic particle was added to a clean 1L beaker, and the photosensitizer 4CzIPN (118.3 mg, 0.5 mol%) and 2-bromo-1-(4-fluorophenyl)ethan-1-one 1a (6.50 g, 30.0 mmol) were weighed and dissolved in 135 mL of chloroform. TEEDA (4.65 g, 27.0 mmol) and acetaldehyde aqueous solution (33.10 g, 300 mmol, 40 wt%) were added to the system in sequence, and stirred at -5°C and irradiated with a 30W white LED for 1.5 hours. After the reaction was completed (monitored by TLC plate), the two phases of the reaction mixture were separated by a separatory funnel, and the aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The mixture was purified by silica gel column chromatography (eluent = PE / EA, 30:1 to 5:1) to give a yellow solid product 2a (3.20 g, 59% yield). Reaction equation:

[0108]

[0109] 2. In an ice-water bath, acetic acid (30.6 mg, 0.5 mmol) and NaBH(OAc) were added. 3 (211.9 mg, 1.0 mmol) was added to a 5 mL dichloromethane mixed solution of 4-(4-fluorophenyl)-4-oxobutyraldehyde 2a (90.3 mg, 0.5 mmol) and 4-(3-chlorophenyl)piperidin-4-ol (139.8 mg, 0.5 mmol), and the reaction solution was returned to room temperature and stirred for 24 hours. After the reaction was completed, saturated Na 2 CO3 The reaction was quenched with aqueous solution and the resulting mixture was extracted with ether (10 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue is purified by silica gel column chromatography (eluent = DCM / CH 3 OH, 100:0-20:1), and a 69% yield of the biologically active γ-aminoketone haloperidol was obtained.

[0110] Reaction equation:

[0111] The product characterization is as follows:

[0112] 1 H NMR (400 MHz, CDCl 3 )δ8.03-8.00(m,2H),7.40-7.38(m,2H),7.32-7.30(m,2H),7.16-7.12(m,2H),3.01(t,J=7 .2Hz,2H),2.86(d,J=10.4Hz,2H),2.56-2.47(m,4H),2.10-1.99(m,4H),1.72-1.64(m,3H). 13 C NMR (100 MHz, CDCl 3 )δ198.3,165.6(d,J=253.6Hz),146.8,133.6(d,J=2.8Hz),132.7,130.7(d,J= 8.9Hz), 128.4, 126.1, 115.6 (d, J = 21.7Hz), 71.0, 57.8, 49.3, 38.2, 36.2, 21.7. 19 F NMR (376 MHz, CDCl 3 )δ-105.57.IR(KBr):ν=3325,3107,2953,2820,1682,1595,1409,1222,828,544cm -1 .HRMS:m / z(ESI)calculated for(C 21 H 24 35 ClFNO 2 )[M+H] + :376.1474,found:376.1479; m / z(ESI)calculatedfor(C 21 H 24 37 ClFNO 2 )[M+H]+ :378.1453,found:378.1453.

[0113] Example 4

[0114] The application of the α,β unsubstituted 1,4-ketoaldehyde compound prepared by the present invention is used for the synthesis of biologically active γ-aminoketone ebastine, specifically:

[0115] Under ice water bath, acetic acid (30.6 mg, 0.5 mmol) and NaBH(OAc) were added. 3 (211.9 mg, 1.0 mmol) was added to a 5 mL dichloromethane mixed solution of 4-(4-(tert-butyl)phenyl)-4-oxobutyraldehyde 2d (109.1 mg, 0.5 mmol) and 4-(diphenylmethoxy)piperidine 5b (133.7 mg, 0.5 mmol), and the reaction solution was returned to room temperature and stirred for 24 hours. After the reaction was completed, saturated Na 2 CO 3 The reaction was quenched with aqueous solution and the resulting mixture was extracted with ether (10 mL x 3). The combined organic phases were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by silica gel column chromatography (eluent = DCM / MeOH, 100:0 to 40:1) to give the bioactive γ-amino ketone ebastine in 71% yield.

[0116] The reaction equation is as follows:

[0117]

[0118] The product characterization is as follows: 1 H NMR (400 MHz, CDCl 3 )δ7.90(d,J=8.4Hz,2H),7.46(d,J=8.4Hz,2H),7.34-7.28(m,8H),7.25-7.21(m,2H),5.51(s,1H),3.42-3.40(m,1H),2.96 (t,J=7.2Hz,2H),2.76-2.73(m,2H),2.37(t,J=7.2Hz,2H),2.10(s,2H),1.94-1.85(m,4H),1.72-1.67(m,2H),1.33(s,9H). 13 C NMR (100 MHz, CDCl 3)δ199.8,156.4,142.8,134.5,128.2,128.0,127.2,127.0,125.4,79.9,72.6,57.6,51.0,36.2,3 5.0,31.3,31.0,21.9.IR(KBr):ν=3057,2938,2789,1729,1688,1446,1368,1112,1000,735,687cm -1 .HRMS:m / z(ESI)calculated for(C 32 H 40 NO 2 )[M+H] + :470.3054,found:470.3068.

[0119] Example 5

[0120] The application of the α,β unsubstituted 1,4-ketoaldehyde compound prepared by the present invention is specifically used for the gram-scale synthesis of the natural product pentabromopseudilin pentabromopseudilin, and the method is as follows:

[0121] 1. To a solution of 4-(2-methoxyphenyl)-4-oxobutyraldehyde 2j (1.92 g, 10.0 mmol) in methanol (150 mL) were added 4A molecular sieves (0.40 g, 20 wt% based on 2j), NH 4 OAc (1.16 g, 15.0 mmol) and a drop of acetic acid were added, and the reaction mixture was stirred at room temperature for 2 hours. 2 CO 3 The reaction was quenched, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent = PE / EA, 40:1) to give a yellow solid product 6 (1.52 g, 88% yield), melting point = 59-60°C.

[0122] The product compound 6 is characterized as follows: 1 H NMR (400 MHz, CDCl 3 )δ9.82(s,1H),7.66(dd,J=7.6Hz,1.6Hz,1H),7.17-7.13(m,1H),7.00-6.94(m,2H),6.85 (dd,J=4.0Hz,2.8Hz,1H),6.63-6.61(m,1H),6.28(dd,J=6.0Hz,2.8Hz,1H),3.94(s,3H). 13 C NMR (100 MHz, CDCl 3)δ154.5,129.6,126.5,126.3,121.2,120.8,117.6,111.4,108.6,105.9,55. 3.IR(KBr):ν=3407,3101,2933,1583,1470,1446,1231,1040,974,842,737cm -1 .HRMS:m / z(ESI)calculated for(C 11 H 12 NO)[M+H] + :174.0913,found:174.0920. The reaction equation is as follows:

[0123]

[0124] 2. At room temperature, sodium sulfide (3.75 g, 48.0 mmol) was added to a solution of compound 6 (1.39 g, 8.0 mmol) in NMP (32.0 mL), and the mixture was heated to 160°C (oil bath) for 3 hours. After the reaction was completed, the reaction was quenched with dilute hydrochloric acid aqueous solution, the organic phase was extracted three times with ethyl acetate, and the combined organic layer was washed with Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by silica gel column chromatography (eluent = PE / EA, 5:1) to give dark blue-grey crystal product compound 7 (841.1 mg, 66% yield), melting point = 94-95°C.

[0125] The reaction equation is as follows:

[0126]

[0127] The characterization data are as follows: 1 H NMR (400 MHz, CDCl 3 )δ9.41(s,1H),7.53(dd,J=7.6Hz,1.6Hz,1H),7.10-7.06(m,1H),6.98-6.94(m,1H),6.90-6. 88(m,1H),6.81(dd,J=8.0Hz,1.2Hz,1H),6.58-6.57(m,1H),6.33-6.31(m,1H),5.43(s,1H). 13 C NMR (100 MHz, CDCl 3)δ150.8,128.8,127.1,126.9,121.3,119.4,118.5,116.2,109.0,106.0. IR(KBr):ν=3441,3003,2941,1596,1492,1234,1112,1023,754,725,588cm -1 .HRMS:m / z(ESI)calculated for(C 10 H 10 NO)[M+H] + :160.0757,found:160.0763.

[0128] 3. Pyridinium tribromide (9.59 g, 30.0 mmol) was added to a dry ethanol solution (130 mL) of compound 7 (795.4 mg, 5.0 mmol) and the reaction was stirred at room temperature for 72 hours. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (eluent = PE / Et 2 O, 9:1) to give pentabromopseudilin (1.96 g, 71% yield) in purple crystals with a melting point of 169-171°C.

[0129] The reaction equation is as follows:

[0130]

[0131] The characterization data are as follows: 1 H NMR (400 MHz, DMSO-d 6 )δ12.60(s,1H),9.81(s,1H),7.80-7.79(m,1H),7.41-7.39(m,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ151.6,135.0,133.1,126.5,122.1,112.9,110.5,101.0,100.4,98.5.I R(KBr):ν=3457,3413,3063,1722,1468,1319,1229,1162,862,697,477cm -1 .HRMS:m / z(ESI)calculated for(C 10 H 3 Br 5 NO)[MH] - :547.6137,found:547.6143.

[0132] The present invention converts two types of cheap compounds, acetaldehyde in aqueous solution and α-bromo / chloroaryl ethyl ketone, into high value-added α, β-unsubstituted 1,4-ketoaldehyde products through metal-free photocatalytic free radical stratification, and realizes the conversion of acetaldehyde in aqueous solution from bulk commodity to high-value active drug molecules through some simple synthetic reactions.

[0133] The description of the above embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the protection scope of the present invention.

Claims

1. A method for preparing acetaldehyde α-position selective single alkylation reaction in aqueous solution by metal-free photocatalysis, characterized in that: The preparation method is: The photosensitizer and α-bromo / chloro aryl ethyl ketone are mixed in an organic solvent, and TEEDA, nBu4NI and acetaldehyde aqueous solution are added in sequence. The reaction is stirred under white light irradiation, and the α,β-unsubstituted 1,4-ketoaldehyde compound is obtained by separation and purification.

2. The preparation method according to claim 1, characterized in that: The molar ratio of the photosensitizer, α-bromo / chloroaryl ethyl ketone, TEEDA, nBu4NI and acetaldehyde in the acetaldehyde aqueous solution is: 0.01:2：1.8：0-1.4：20。 3. The preparation method according to claim 1 or 2, characterized in that: The α-bromo / chloroaryl acetone is α-bromoacetophenone, and the amount of nBu4NI is 0.

4. The preparation method according to claim 1 or 2, characterized in that: The α-bromo / chloroaryl acetophenone is α-chloroacetophenone, and the molar ratio of the photosensitizer, α-chloroacetophenone, TEEDA, nBu4NI and acetaldehyde in the acetaldehyde aqueous solution is: 0.01:2：1.8：1.4：20。 5. The preparation method according to claim 1 or 2, characterized in that: The structural formula of the α-bromo / chloroaryl acetone is: R 1 for or X=Br or Cl; R is any one or more of halogen, H, alkyl, alkoxy or aryl; preferably, R is one or more of H, F, Br, -CH3, -C(CH3)3, -OCH3.

6. The preparation method according to claim 1 or 2, characterized in that: The usage ratio of the α-bromo / chloroaryl ethyl ketone and the organic solvent is 0.20-0.25 mol / L.

7. The preparation method according to claim 1 or 2, characterized in that: The white light irradiation stirring reaction refers to the white LED irradiation of 2×3W under room temperature stirring conditions and the irradiation reaction time of 28-35 minutes.

8. The α,β-unsubstituted 1,4-ketoaldehyde compound prepared by the preparation method according to any one of claims 1 to 7, characterized in that: The structural formula of the α,β unsubstituted 1,4-ketoaldehyde compound is R 1 for or R is any one or more of halogen, H, alkyl, alkoxy or aryl; preferably, R is one or more of H, F, Br, -CH3, -C(CH3)3, -OCH3.

9. Use of the α,β-unsubstituted 1,4-ketoaldehyde compound according to claim 8, characterized in that: Used in organic synthesis.

10. The use according to claim 9, characterized in that: The α,β unsubstituted 1,4-ketoaldehyde compound is used for synthesizing haloperidol, ebastine or pentabromopseudilin.

Images