Synthesis method of benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone

Abstract

The invention provides a synthesis method of benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone, and relates to the technical field of organic chemical synthesis. In an inert atmosphere, a benzyloxy-18-labeled aromatic aldehyde or aromatic ketone is obtained by dissolving a benzyloxy-18 substrate, an electrolyte, an alkaline additive and oxy-18 water in an organic solvent, carrying out an electrochemical oxidation reaction and then carrying out separation and purification. According to the method, a green electrochemical strategy is adopted, no transition metal participates, the reaction conditions are mild (normal temperature and normal pressure), the oxygen isotope labeled aromatic aldehyde or aromatic ketone compound is directly synthesized in one step without pre-synthesizing an aldehyde / ketone precursor, the substrate application range is wide, various substituent groups such as halogen, alkyl and aryl can be compatible, and the method is suitable for industrial production. And electron-deficient aldehyde ketone which is difficult to mark by a traditional method can be synthesized. The synthesized product can be used in the fields of drug metabolism research, environment tracking and the like, and has the advantages of step economy, green synthesis and industrialization potential.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemical synthesis, in particular to a synthesis method of benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone. BACKGROUND

[0002] In the field of organic chemical synthesis, aromatic aldehyde and aromatic ketone compounds are important intermediates of fine chemicals, which are widely used in the synthesis of high value-added products such as drugs, pesticides, fragrances and dyes. At the same time, with the in-depth research, isotope labeling technology has become an important tool in the fields of chemistry, biology and medicine, among which, oxygen isotope labeling plays an important role in identifying and understanding chemical and biological processes, especially in drug metabolism identification in complex samples. Therefore, the synthesis of oxygen isotope labeled aromatic aldehyde or aromatic ketone is of great importance to meet the precise needs of scientific research, industrial application and medical field. As key tool molecules for mechanism research, metabolic analysis and drug development, these compounds have irreplaceable role.

[0003] However, there are still many limitations in the synthesis of oxygen isotope containing aromatic aldehyde or aromatic ketone in the prior art: (1) oxygen exchange method depending on pre-synthesized aldehyde or ketone: the aromatic aldehyde or aromatic ketone needs to be prepared in advance, and then oxygen-18 labeling is realized through photocatalysis or high temperature oxidation, which is long in steps and cannot realize oxygen-18 labeling at the same time of benzyl oxidation, involves the use of metal reagents or relatively complex catalysts, which is not environmentally friendly, does not meet the requirements of green chemistry and step economy, the oxygen exchange efficiency is low, and it is limited by the structure of the substrate (such as electron-deficient aldehyde) ; (2) metal-catalyzed oxidation method: palladium / copper catalyst needs high temperature and high pressure conditions, the energy consumption is high in the synthesis process, it is easy to be over-oxidized to carboxylic acid, and it cannot realize oxygen isotope labeling at the same time of benzyl oxidation, which needs to be carried out in steps.

[0004] Therefore, it is urgent to provide a solution to improve the above problems. SUMMARY

[0005] The purpose of the present application is to provide a synthesis method of benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone.

[0006] The present application provides a synthesis method of benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone, comprising: dissolving a benzyl substrate represented by formula (I), an electrolyte, a basic additive and oxygen-18 water in an organic solvent under an inert atmosphere, and separating and purifying the benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone represented by formula (II) after electrochemical oxidation reaction.

[0007]

[0008] wherein, R1 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C6-C10 aryl, hydroxyl, cyano, aldehyde, sulfonyl, nitro, C6-C 10 aromatic ring ester group, C6-C 10 aromatic ring carbonyl, C1-C6 alkyl sulfide group, trifluoromethyl, trifluoromethyl sulfonyloxy, p-nitrobenzenesulfonyloxy or pentachlorothio carbonate group; the R2 is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl or C6-C 10 aryl group.

[0009] Optionally, the electrolyte includes one of sodium difluorochloroacetate, sodium trifluoroacetate, lithium acetate, sodium acetate and sodium trifluoromethanesulfonate.

[0010] Optionally, the basic additive includes one of sodium hydroxide, potassium hydroxide and sodium carbonate.

[0011] Optionally, the organic solvent includes acetonitrile treated by super dry treatment.

[0012] Optionally, the molar ratio of the oxygen-18 water to the benzyl substrate compound is (5:1)-(20:1).

[0013] Optionally, the inert atmosphere includes one of nitrogen or argon.

[0014] Optionally, the condition of the electrochemical oxidation is constant current reaction, and the current intensity is 2mA-10mA.

[0015] Optionally, the reaction is carried out at room temperature for 5h-15h.

[0016] Optionally, the separation and purification includes column chromatography; the eluent used in the separation and purification by column chromatography includes mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (20:1)-(40:1). BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 The synthesis method of the benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone in the application;

[0018] Figure 2 The nuclear magnetic hydrogen spectrum of the compound 2a in deuterated CDCl3 in the application;

[0019] Figure 3 The nuclear magnetic carbon spectrum of the compound 2a in deuterated CDCl3 in the application;

[0020] Figure 4 The nuclear magnetic hydrogen spectrum of the compound 2b in deuterated CDCl3 in the application;

[0021] Figure 5The nuclear magnetic hydrogen spectrum of compound 2b in deuterated CDCl3 in the present application;

[0022] Figure 6 The nuclear magnetic hydrogen spectrum of compound 2c in deuterated CDCl3 in the present application;

[0023] Figure 7 The nuclear magnetic carbon spectrum of compound 2c in deuterated CDCl3 in the present application;

[0024] Figure 8 The nuclear magnetic hydrogen spectrum of compound 2d in deuterated CDCl3 in the present application;

[0025] Figure 9 The nuclear magnetic carbon spectrum of compound 2d in deuterated CDCl3 in the present application;

[0026] Figure 10 The nuclear magnetic hydrogen spectrum of compound 2e in deuterated CDCl3 in the present application;

[0027] Figure 11 The nuclear magnetic carbon spectrum of compound 2e in deuterated CDCl3 in the present application;

[0028] Figure 12 The nuclear magnetic hydrogen spectrum of compound 2f in deuterated CDCl3 in the present application;

[0029] Figure 13 The nuclear magnetic carbon spectrum of compound 2f in deuterated CDCl3 in the present application;

[0030] Figure 14 The nuclear magnetic hydrogen spectrum of compound 2g in deuterated CDCl3 in the present application;

[0031] Figure 15 The nuclear magnetic carbon spectrum of compound 2g in deuterated CDCl3 in the present application;

[0032] Figure 16 The nuclear magnetic hydrogen spectrum of compound 2h in deuterated CDCl3 in the present application;

[0033] Figure 17 The nuclear magnetic carbon spectrum of compound 2h in deuterated CDCl3 in the present application;

[0034] Figure 18 The nuclear magnetic hydrogen spectrum of compound 2i in deuterated CDCl3 in the present application;

[0035] Figure 19 The nuclear magnetic carbon spectrum of compound 2i in deuterated CDCl3 in the present application;

[0036] Figure 20 The nuclear magnetic hydrogen spectrum of compound 2j in deuterated CDCl3 in the present application;

[0037] Figure 21 NMR of compound 2j in deuterated CDCl3in the present application;

[0038] Figure 22 NMR of compound 2k in deuterated CDCl3in the present application;

[0039] Figure 23 NMR of compound 2k in deuterated CDCl3in the present application;

[0040] Figure 24 NMR of compound 2l in deuterated CDCl3in the present application;

[0041] Figure 25 NMR of compound 2l in deuterated CDCl3in the present application;

[0042] Figure 26 NMR of compound 2m in deuterated CDCl3in the present application;

[0043] Figure 27 NMR of compound 2m in deuterated CDCl3in the present application;

[0044] Figure 28 NMR of compound 2n in deuterated CDCl3in the present application;

[0045] Figure 29 NMR of compound 2n in deuterated CDCl3in the present application;

[0046] Figure 30 NMR of compound 2n in deuterated CDCl3in the present application. DETAILED DESCRIPTION

[0047] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of the present application. Unless otherwise defined, the technical terms or scientific terms used herein should be understood as their common meanings to those of ordinary skill in the art to which the present application belongs.

[0048] The application provides a synthesis method of benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone, comprising the following steps: dissolving a benzyl substrate shown in formula (I), an electrolyte, a basic additive and oxygen-18 water in an organic solvent under an inert atmosphere, and separating and purifying the benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone shown in formula (II) through an electrochemical oxidation reaction.

[0049]

[0050] R1 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, C6-C 10 aryl, hydroxyl, cyano, aldehyde, sulfonyl, nitro, C6-C 10 aromatic ring ester, C6-C 10 aromatic ring carbonyl, C1-C6 alkyl sulfide, trifluoromethyl, trifluoromethyl sulfonyloxy, p-nitrobenzenesulfonyloxy or pentachlorothiocarbonate; R2 is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl or C6-C 10 aryl.

[0051] In fact, the application adopts a green electrochemical strategy, does not involve transition metals, has mild reaction conditions (room temperature, normal pressure), does not need to pre-synthesize aldehyde / ketone precursors, and directly synthesizes oxygen isotope labeled aromatic aldehyde or aromatic ketone compounds in one step, and the substrate has a wide range of applications and can be compatible with halogen, alkyl, aryl and various substituents, and can synthesize electron-deficient aldehyde / ketone which is difficult to be labeled by traditional methods. The synthesis product can be used in the fields of drug metabolism research, environmental tracking and the like, has the advantages of economical steps and green synthesis, and has industrialization potential.

[0052] In some embodiments, the electrolyte used in the synthesis of oxygen-18 labeled aromatic aldehyde or aromatic ketone compounds comprises C1-C6 alkyl carboxylate, C1-C6 fluorinated carboxylate or C1-C6 alkyl sulfonate. Specifically, the C1-C6 alkyl carboxylate is one of lithium acetate and sodium acetate; the C1-C6 fluorinated carboxylate is one of sodium difluoro chloroacetate and sodium trifluoroacetate; and the C1-C6 alkyl sulfonate is sodium trifluoromethanesulfonate. In fact, the electrolyte (such as carboxylate, sulfonate) is dissociated into cations and anions in the organic solvent (acetonitrile) to form an ion conductive network, which can ensure stable current through the reaction system; in addition, the electrolyte anion (such as CF3COO-) can stabilize the electrochemically generated benzyl radical or positive ion through electrostatic interaction or coordination, preventing it from dimerization or over-oxidation; and the weakly nucleophilic anion (such as CF3SO3 - ) can reduce the competition with H2 18 O, and ensure the labeling efficiency of 18 O.

[0053] In some embodiments, the basic additive used in the synthesis of oxygen-18 labeled aromatic aldehyde or aromatic ketone compounds includes an alkali hydroxide, an alkali carbonate, or an alkali carbonate. Specifically, the basic additive is preferably one of sodium hydroxide, potassium hydroxide, or sodium carbonate. In fact, when the C-H bond of the benzyl group is electrochemically oxidized, protons are generated, and the basic additive, such as sodium hydroxide, can neutralize the generated protons in time, avoiding the decomposition of the substrate or product caused by the acidic environment; the basic additive can maintain the reaction system as weakly alkaline, creating an optimal environment for the nucleophilic addition of the benzyl carbocation and H2 18 O; in addition, in the final step of the oxidation of the benzyl group into an aldehyde, the alkaline condition can catalyze the dehydration of the alcohol to generate an aldehyde, ensuring the efficient oxidation of the C-H bond of the benzyl group and the specific introduction of O. 18 O label.

[0054] In some embodiments, the organic solvent used in the synthesis of oxygen-18 labeled aromatic aldehyde or aromatic ketone compounds includes acetonitrile treated by super-dry. In fact, the selection of the organic solvent is to dissolve the electrolyte, the basic additive, and the substrate of the benzyl group at the same time, forming a homogeneous system, ensuring the necessary contact of the reactants; in addition, as a polar aprotic solvent, acetonitrile can effectively dissociate the electrolyte, improve the conductivity of the system, and ensure the current efficiency of the electrochemical reaction; the weak coordination of acetonitrile can stabilize the benzyl carbocation generated by electrochemistry, inhibit side reactions such as dimerization or over-oxidation; super-dry treatment can avoid the competition of H2O and H2 18 O, ensuring the selective insertion of O 18 O into the carbonyl group, and ensuring the labeling efficiency of O 18 O in the product through a water-free environment. Therefore, the acetonitrile treated by super-dry is not only a solvent and a reaction medium, but also a key factor to achieve efficient electrochemical oxidation and precise O 18 O labeling.

[0055] In some embodiments, the molar ratio of oxygen-18 water to the substrate compound of the benzyl group is (5:1)-(20:1). In fact, the selection of the appropriate molar ratio of oxygen-18 water to the substrate compound of the benzyl group can ensure the completion of the reaction and the high labeling efficiency of O 18 O. The reaction of the benzyl carbocation and H2 18 O is a nucleophilic substitution, and increasing the concentration of H2 18 O can accelerate this step, and a high proportion of H2 18 O can promote the reaction to proceed in the direction of the product, avoiding the accumulation of intermediates; it can also reduce the influence of residual H2 16 O in the system, ensuring the labeling efficiency of O 18 O in the product. Too low a molar ratio of oxygen-18 water to the substrate compound of the benzyl group may lead to incomplete labeling, and too high a ratio increases the cost.

[0056] In some embodiments, the inert atmosphere comprises one of nitrogen or argon. In practice, the inert atmosphere can block air contact in the synthesis reaction, prevent the electrochemically generated benzyl radical and benzyl cation from being quenched by oxygen, prevent the benzyl substrate and the aldehyde or ketone product synthesized from being oxidized by oxygen, and avoid interference by water vapor in the air, preventing H2 16 O and H2 18 O from competing reactions, and reducing 18 the labeling efficiency of O.

[0057] In some embodiments, the conditions for electrochemical oxidation are constant current reactions, and the current intensity is 2 mA-10 mA. In practice, the current intensity directly determines the efficiency of electron transfer and affects the efficiency of activation of the C-H bond at the benzyl position. The synthesis of aldehydes or ketones can be adjusted by the current intensity, low current intensity is conducive to the synthesis of aldehydes, and high current intensity promotes the synthesis of ketones, but too low current intensity can cause incomplete reaction, and too high current intensity can easily lead to hydrogen evolution on the electrode or decomposition of the substrate.

[0058] In some embodiments, the synthesis of oxygen-18-labeled aromatic aldehyde or aromatic ketone compounds is carried out at room temperature for 5 h-15 h. In practice, the oxidation of the benzyl position needs to go through a multi-step conversion of radical, cation, alcohol, aldehyde / ketone, and sufficient time is needed to complete the reaction. If the reaction time is insufficient, it cannot be ensured that the reaction is complete, and if the reaction time is too long, the aldehyde can be oxidized to an acid. The selection of appropriate current intensity and reaction time can ensure complete reaction and improve the labeling efficiency of O 18 in the product.

[0059] In some embodiments, the separation and purification comprises column chromatography. The eluent used in the column chromatography comprises a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (20:1)-(40:1). In practice, mild elution conditions can avoid hydrolysis or exchange of the labeled C=O bond during purification, and in addition, the mixed solution of petroleum ether (non-polar) and ethyl acetate (moderately polar) can achieve gradient elution separation of the target product (aromatic aldehyde / ketone) and by-products (such as benzyl alcohol, carboxylic acid) by adjusting the ratio. If the volume ratio of petroleum ether to ethyl acetate is too high, the product can be retained in the column, reducing the recovery rate, and if the ratio is too low, impurities can be co-eluted with the product, reducing the purity. 18

[0060] Embodiment 1

[0061] This embodiment provides the synthesis of 4-methoxybenzaldehyde (2a):

[0062] ​Electrolyte sodium difluorochloroacetate (1.0 eq), additive base sodium hydroxide (1.5 eq) were added into a slant three-necked flask, an electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 4-tert-butyltoluene (1b) (61 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 4 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 40:1) gave 4-methoxybenzaldehyde (2a). The product was a yellowish liquid with a yield of 74%. Its synthetic route is as follows:

[0063]

[0064] The nuclear magnetic hydrogen spectrum (400 MHz, CDC13) of 4-methoxybenzaldehyde (2a) synthesized in Example 1 was characterized as shown in Figure 2 The nuclear magnetic carbon spectrum (101 MHz, CDC13) of 4-methoxybenzaldehyde (2a) synthesized in Example 1 was characterized as shown in Figure 3 The specific data are as follows: 1 H NMR (400 MHz, CDC13) δ 9.86 (s, 1H), 7.82 (dd, J = 9.0, 2.4 Hz, 2H), 6.98 (dd, J = 8.9, 2.5 Hz, 2H), 3.87 (s, 3H). 13 CNMR (101 MHz, CDC13) δ 190.69, 164.52, 131.87, 129.87, 114.22, 55.48.

[0065] Example 2

[0066] This example provides the synthesis of p-tert-butylbenzaldehyde (2b):

[0067] Electrolyte sodium difluorochloroacetate (1.0 eq), additive base sodium hydroxide (1.5 eq) were added into a slant three-necked flask, an electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 4-tert-butyltoluene (1b) (61 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 4 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 40:1) gave 4-methoxybenzaldehyde (2a). The product was a yellowish liquid with a yield of 74%. Its synthetic route is as follows:

[0068]

[0069] The nuclear magnetic hydrogen spectrum (400 MHz, CDC13) of 4-methoxybenzaldehyde (2a) synthesized in Example 1 was characterized as shown in Figure 4The 1H NMR (400 MHz, CDC13) was used to characterize the product as shown below: Figure 5 The specific data are as follows: 1 H NMR (400 MHz, CDC13) δ 9.95 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 1.32 (s, 9H). 13 C NMR (101 MHz, CDC13) δ 191.76, 158.19, 133.92, 129.50, 125.80, 35.14, 30.88.

[0070] Example 3

[0071] This example provides the synthesis of 4-phenylbenzaldehyde (2c):

[0072] The electrolyte sodium difluorochloroacetate (1.0 eq), the additive base sodium hydroxide (1.5 eq) were added into a slant three-port flask, an electrode was inserted and the reaction flask was kept in a nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 4-phenyltoluene (1c) (67 mg, 0.4 mmol) were added, and H2 18 O (54.0 μL, 3 mmol) was added at room temperature and reacted for 10 h at 4 mA. Column chromatography separation (using a silica gel column; eluent: petroleum ether and ethyl acetate in a volume ratio of 35:1) gave 4-phenylbenzaldehyde (2c). The product was a white solid with a yield of 55%. The synthetic route is as follows:

[0073]

[0074] The 1H NMR (400 MHz, CDC13) was used to characterize the product as shown below: Figure 6 The 13C NMR (101 MHz, CDC13) was used to characterize the product as shown below: Figure 7 The specific data are as follows: 1 H NMR (400 MHz, CDC13) δ 10.04 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 7.1 Hz, 2H), 7.48 (t, J = 7.3 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H). 13 C NMR (101 MHz, CDC13) δ 191.69, 146.88, 139.44, 134.99, 130.06, 128.84, 128.30, 127.44, 127.15.

[0075] Example 4

[0076] This example provides the synthesis of 4-cyanobenzaldehyde (2d):

[0077] The electrolyte sodium triflate (1.0 eq), the additive base sodium hydroxide (1.5 eq) were added into a conical flask, the electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 4-methylphenylacetone (1e) (62 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 6 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 30:1) gave 4-cyanobenzaldehyde (2d). The product was a yellow solid with a yield of 35%. The synthetic route is as follows:

[0078]

[0079] The 4-cyanobenzaldehyde (2d) synthesized in Example 4 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 8 , by nuclear magnetic carbon spectrum (101 MHz, CDC13) as shown in Figure 9 , and the specific data are as follows: 1 H NMR (400 MHz, CDC13) δ 10.08 (s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.1 Hz, 2H). 13 C NMR (101 MHz, CDC13) δ 190.54, 132.88, 132.36, 129.86, 128.29, 117.61.

[0080] Example 5

[0081] This example provides the synthesis of 4-cyanobenzaldehyde (2d):

[0082] The electrolyte sodium triflate (1.0 eq), the additive base sodium hydroxide (1.5 eq) were added into a conical flask, the electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 4-methylphenylacetone (1e) (62 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 6 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 30:1) gave 4-cyanobenzaldehyde (2d). The product was a yellow solid with a yield of 35%. The synthetic route is as follows:

[0083]

[0084] The 4-propionylbenzaldehyde (2e) synthesized in Example 5 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 10 The 4-propionylbenzaldehyde (2e) synthesized in Example 5 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 11 The 4-propionylbenzaldehyde (2e) synthesized in Example 5 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in 1 H NMR (400 MHz, CDC13) δ 10.08 (s, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H), 3.03 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 200.01, 191.51, 141.07, 138.85, 129.72, 128.40, 32.26, 7.96.

[0085] Example 6

[0086] This example provides the synthesis of 3-bromo-4-methoxybenzaldehyde (2f):

[0087] The electrolyte sodium triflate (1.0 eq), the additive base sodium hydroxide (1.5 eq) were added into a slant three-port flask, the electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 3-bromo-4-methoxytoluene (1f) (58 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) was added at room temperature and reacted for 10 h under 6 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 35:1) gave 3-bromo-4-methoxybenzaldehyde (2f). The product was a white solid with a yield of 70%. The synthetic route is as follows:

[0088]

[0089] The 3-bromo-4-methoxybenzaldehyde (2f) synthesized in Example 6 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 12 The 3-bromo-4-methoxybenzaldehyde (2f) synthesized in Example 6 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 13 The 3-bromo-4-methoxybenzaldehyde (2f) synthesized in Example 6 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in 1 H NMR (400 MHz, CDC13) δ 9.76 (s, 1H), 7.98 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 3.91 (s, 3H). 13C NMR (101 MHz, CDC13) δ 189.39, 160.42, 134.22, 131.11, 130.52, 112.42, 111.41, 56.47.

[0090] Example 7

[0091] This example provides the synthesis of p-bromobenzaldehyde (2g):

[0092] The electrolyte sodium triflate (1.0 eq), the additive base sodium hydroxide (1.5 eq) were added into a slant three-port flask, the electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and p-bromotoluene (1g) (49 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) was added and reacted at room temperature for 10 h under 6 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 35:1) gave p-bromobenzaldehyde (2g). The product was a yellow solid with a yield of 51%. The synthetic route is as follows:

[0093]

[0094] The p-bromobenzaldehyde (2g) synthesized in Example 7 was characterized by nuclear magnetic hydrogen spectrum (600 MHz, CDC13) as shown in Figure 14 The nuclear magnetic carbon spectrum (151 MHz, CDC13) characterization is as shown in Figure 15 The specific data are as follows: 1 H NMR (600 MHz, CDC13) δ 9.96 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H) 7.66 (d, J = 8.4 Hz, 2H). 13 C NMR (151 MHz, CDC13) δ 191.04, 134.94, 132.35, 130.91, 129.70.

[0095] Example 8

[0096] This example provides the synthesis of xanthone (2h):

[0097] The electrolyte sodium difluoro chloroacetate (1.0 eq), the additive base sodium hydroxide (1.5 eq) were added into a slant three-port flask, the electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and xanthene (1h) (73 mg, 0.4 mmol) were added, H2 18O (54.0 μL, 3 mmol) at room temperature for 10 h at 4 mA. Column chromatography (silica gel column; eluent: petroleum ether / ethyl acetate, 40:1 by volume) gave xanthone (2h). The product was a white solid with a yield of 85%. The synthetic route is as follows:

[0098]

[0099] The xanthone (2h) synthesized in Example 8 was characterized by1H NMR (400 MHz, CDC13) as shown in Figure 16 The xanthone (2h) synthesized in Example 8 was characterized by1H NMR (400 MHz, CDC13) as shown in Figure 17 The xanthone (2h) synthesized in Example 8 was characterized by1H NMR (400 MHz, CDC13) as shown in 1 H NMR (400 MHz, CDC13) δ 8.31 (dd, J = 8.0, 1.7 Hz, 2H) 7.68 (ddd, J = 8.7, 7.1, 1.7 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.36 - 7.32 (m, 2H). 13 CNMR (101 MHz, CDC13) δ 177.01, 156.02, 134.66, 126.57, 123.77, 121.71, 117.84.

[0100] Example 9

[0101] This example provides the synthesis of 3,4-dihydro-lH-2-benzopyran-l-one (2i):

[0102] The electrolyte sodium difluorochloroacetate (1.0 eq), the additive base sodium hydroxide (1.5 eq) were added into a slant three-necked flask, an electrode was inserted and the reaction flask was kept in a nitrogen atmosphere, 7.0 mL of super dry acetonitrile and isochroman (li) (49 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 4 mA. Column chromatography (silica gel column; eluent: petroleum ether / ethyl acetate, 40:1 by volume) gave xanthone (2h). The product was a white solid with a yield of 85%. The synthetic route is as follows:

[0103]

[0104] The xanthone (2h) synthesized in Example 8 was characterized by1H NMR (400 MHz, CDC13) as shown in Figure 18 The xanthone (2h) synthesized in Example 8 was characterized by1H NMR (400 MHz, CDC13) as shown in Figure 19 The xanthone (2h) synthesized in Example 8 was characterized by1H NMR (400 MHz, CDC13) as shown in 1H NMR (400 MHz, CDC13) δ 8.07 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 4.51 (t, J = 6.1 Hz, 2H), 3.04 (t, J = 6.1 Hz, 2H). 13 C NMR (101 MHz, CDC13) δ 165.05, 139.51, 133.62, 130.39, 127.66, 127.19, 125.32, 67.27, 27.82.

[0105] Example 10

[0106] This example provides the synthesis of benzophenone (2j):

[0107] Electrolyte sodium difluorochloroacetate (1.0 eq), additive base sodium hydroxide (1.5 eq) were added into a slant three-necked flask, an electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 1,2-diphenylmethane (1j) (67 mg, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) was added at room temperature and reacted for 10 h at 4 mA. Column chromatography separation (using a silica gel column; eluent: petroleum ether and ethyl acetate in a volume ratio of 45:1) gave benzophenone (2j). The product was a white solid with a yield of 69%. The synthetic route is as follows:

[0108]

[0109] The benzophenone (2j) synthesized in Example 10 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 20 The nuclear magnetic carbon spectrum (101 MHz, CDC13) characterization is as shown in Figure 21 The specific data are as follows: 1 H NMR (400 MHz, CDC13) δ 8.07 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 4.51 (t, J = 6.1 Hz, 2H), 3.04 (t, J = 6.1 Hz, 2H). 13 C NMR (101 MHz, CDC13) δ 165.05, 139.51, 133.62, 130.39, 127.66, 127.19, 125.32, 67.27, 27.82.

[0110] Example 11

[0111] This example provides the synthesis of p-bromoacetophenone (2k):

[0112] Electrolyte sodium triflate (1.0 eq), base additive sodium hydroxide (1.5 eq) were added into a slant three-necked flask, an electrode was inserted and the reaction flask was kept under nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 4-tert-butylphenethyl alcohol (3b) (49 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 6 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 35:1) gave p-bromophenacyl bromide (2k). The product was a white solid with a yield of 59%. The synthetic route is as follows:

[0113]

[0114] The p-bromophenacyl bromide (2k) synthesized in Example 11 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 22 , by nuclear magnetic carbon spectrum (101 MHz, CDC13) as shown in Figure 23 , and the specific data are as follows: 1 H NMR (400 MHz, CDC13) δ 7.80 (d, J = 8.4 Hz, 2H) 7.59 (d, J = 8.0 Hz, 2H), 2.57 (s, 3H). 13 C NMR (101 MHz, CDC13) δ 196.91, 135.72, 131.80, 129.76, 128.21, 26.48.

[0115] Example 12

[0116] This example provides the synthesis of p-tert-butylbenzaldehyde (2b):

[0117] Electrolyte sodium triflate (1.0 eq), base additive sodium hydroxide (1.5 eq) were added into a slant three-necked flask, an electrode was inserted and the reaction flask was kept under nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 4-tert-butylphenethyl alcohol (3b) (49 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 6 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 35:1) gave p-bromophenacyl bromide (2k). The product was a white solid with a yield of 59%. The synthetic route is as follows:

[0118]

[0119] The p-tert-butylbenzaldehyde (2b) synthesized in Example 2 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 24 , by nuclear magnetic carbon spectrum (101 MHz, CDC13) as shown inFigure 25 The synthesis route is shown below: 1 H NMR (400 MHz, CDC13) δ 9.95 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 1.32 (s, 9H). 13 C NMR (101 MHz, CDC13) δ 191.76, 158.19, 133.92, 129.50, 125.80, 35.14, 30.88.

[0120] Example 13

[0121] This example provides the synthesis of o-nitrobenzaldehyde (21):

[0122] Electrolyte sodium triflate (1.0 eq), additive sodium hydroxide (1.5 eq) were added into a slant three-necked flask, the electrode was inserted and the reaction flask was kept in nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 2-nitrophenethyl alcohol (11) (62 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) was added at room temperature under 6 mA for 10 h. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 35:1) gave o-nitrobenzaldehyde (21). The product was a yellow solid with a yield of 26%. The synthesis route is shown below:

[0123]

[0124] The o-nitrobenzaldehyde (21) synthesized in Example 13 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 26 The o-nitrobenzaldehyde (21) synthesized in Example 13 was characterized by nuclear magnetic hydrogen spectrum (400 MHz, CDC13) as shown in Figure 27 The synthesis route is shown below: 1 H NMR (400 MHz, CDC13) δ 10.40 (s, 1H), 8.10 (dd, J = 7.6, 1.7 Hz, 1H), 7.93 (dd, J = 7.4, 1.9 Hz, 1H), 7.78 (td, J = 8.0, 7.5, 1.7 Hz, 2H). 13 C NMR (101 MHz, CDC13) δ 188.07, 134.01, 133.65, 131.27, 129.55, 124.42.

[0125] Example 14

[0126] This example provides the synthesis of benzaldehyde (2m):

[0127] Electrolyte sodium difluorochloroacetate (1.0 eq), additive base sodium hydroxide (1.5 eq) were added into a flask, an electrode was inserted and the flask was kept under nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 5-(butoxymethyl)-2-methoxyphenyl trifluoromethanesulfonate (1n) (132 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 4 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 45:1) gave benzaldehyde (2m). The product was a colorless liquid with a yield of 74%. The synthetic route is as follows:

[0128]

[0129] Benzaldehyde (2m) synthesized in Example 14 was characterized by nuclear magnetic hydrogen spectrum (600 MHz, CDC13) as shown in Figure 28 , by nuclear magnetic carbon spectrum (151 MHz, CDC13) as shown in Figure 29 , and the specific data are as follows: 1 H NMR (600 MHz, CDC13) δ 9.99 (s, 1H), 7.85 (d, J = 7.0 Hz, 2H), 7.60 (t, J = 7.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H). 13 C NMR (151 MHz, CDC13) δ 192.24, 136.25, 134.32, 129.58, 128.85.

[0130] Example 15

[0131] This example provides the synthesis of 5-formyl-2-methoxyphenyl trifluoromethanesulfonate (2n):

[0132] Electrolyte sodium difluorochloroacetate (1.0 eq), additive base sodium hydroxide (1.5 eq) were added into a flask, an electrode was inserted and the flask was kept under nitrogen atmosphere, 7.0 mL of super dry acetonitrile and 5-(butoxymethyl)-2-methoxyphenyl trifluoromethanesulfonate (1n) (132 μL, 0.4 mmol) were added, H2 18 O (54.0 μL, 3 mmol) at room temperature for 10 h at 4 mA. Column chromatography separation (using silica gel column; eluent: petroleum ether and ethyl acetate in the volume ratio of 45:1) gave 5-formyl-2-methoxyphenyl trifluoromethanesulfonate (2n). The product was a colorless liquid with a yield of 40%. The synthetic route is as follows:

[0133]

[0134] The 5-formyl-2-methoxyphenyl triflate (2n) synthesized in Example 15 was characterized by1H NMR (600 MHz, CDC13) as shown in Figure 28 The 5-formyl-2-methoxyphenyl triflate (2n) synthesized in Example 15 was characterized by1H NMR (600 MHz, CDC13) as shown in Figure 29 The 5-formyl-2-methoxyphenyl triflate (2n) synthesized in Example 15 was characterized by1H NMR (600 MHz, CDC13) as shown in Figure 30 The 5-formyl-2-methoxyphenyl triflate (2n) synthesized in Example 15 was characterized by1H NMR (600 MHz, CDC13) as shown in 1 H NMR (600 MHz, CDC13) δ 10.03 (s, 1H), 8.05 (d, J = 13.4 Hz, 2H), 7.81 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 9.6 Hz, 1H). 13 C NMR (101 MHz, CDC13) δ 190.30, 152.12, 142.60, 136.73, 123.94, 123.10, 120.18, 117.00, 111.74, 56.39. 19 F NMR (565 MHz, Chloroform-d) δ -73.90.

[0135] While the embodiments of the application have been illustrated and described in detail, it will be readily apparent to those skilled in the art that various modifications and changes can be made therein without departing from the scope of the present application as defined by the appended claims. It is therefore intended that the present application cover all such modifications and changes as fall within the scope of the appended claims. Moreover, the application illustratively described herein suitably can take forms other than those explicitly described and fall within the scope of the appended claims.

Claims

1. A method for the synthesis of benzyl position oxygen-18 labeled aromatic aldehydes or aromatic ketones, characterized in that, The benzyl substrate of formula (I), electrolyte, alkaline additive and oxygen-18 water are dissolved in an organic solvent under inert atmosphere, and a benzyl oxygen-18 labeled aromatic aldehyde or aromatic ketone of formula (II) is obtained by electrochemical oxidation reaction and separation and purification. wherein said R1is hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, C6-C 10 aryl, hydroxyl, cyano, aldehydo, sulfonyl, nitro, C6-C 10 aryl, hydroxyl, cyano, aldehydo, sulfonyl, nitro, C6-C 10 aryl, hydroxyl, cyano, aldehydo, sulfonyl, nitro, C6-C 10 aryl, hydroxyl, cyano, aldehydo, sulfonyl, nitro, C6-C 2. The method of claim 1, wherein, The electrolyte comprises one of sodium difluorochloroacetate, sodium trifluoroacetate, lithium acetate, sodium acetate and sodium triflate.

3. The method of claim 1, wherein, The alkaline additive comprises one of sodium hydroxide, potassium hydroxide and sodium carbonate.

4. The method of claim 1, wherein, The organic solvent comprises acetonitrile treated by super dry treatment.

5. The method of claim 1, wherein, The molar ratio of the oxygen-18 water to the benzyl substrate is (5:1)-(20:1).

6. The method of claim 1, wherein, The inert atmosphere comprises one of nitrogen and argon.

7. The method of claim 1, wherein, The electrochemical oxidation is carried out under constant current reaction, and the current intensity is 2mA-10mA.

8. The method of claim 1, wherein, The reaction is carried out at room temperature for 5h-15h.

9. The method of claim 1, wherein, The separation and purification comprises column chromatography.

10. The method of claim 9, wherein, The eluent used in the column chromatography comprises a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (20:1)-(40:1).

Images