Cyano-methylene-2h-pyrane derivatives, process for their synthesis and use thereof

Abstract

This invention belongs to the field of synthetic chemistry, specifically relating to a cyanomethylene-2- H 2-pyran derivatives, their synthesis methods, and applications. The synthesis method comprises the following steps: under inert gas conditions, alkenylformylacetonitrile, alkyne, catalyst, oxidant, and additives are dissolved in an organic solvent and subjected to a heating reaction to obtain the cyanomylidene-2-pyran derivative. H -Pyran derivatives. This invention uses inexpensive and readily available alkenylformylacetonitrile and alkyne as reactants to synthesize cyanomylidene-2-pyran derivatives via rhodium-catalyzed C-H bond activation. H -Pyran derivatives, the synthetic method described herein has advantages such as high atom economy, simple operation, high synthetic efficiency and regioselectivity, and good substrate applicability; the cyanomethylene-2 H The cyano substituents of pyran derivatives can also be readily converted into functional groups such as aldehydes and amides, thereby constructing a variety of functionalized pyran derivatives; the cyanomylidene-2 H -Pyran derivatives can be used in the field of fluorescence detection.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of synthetic chemistry, and particularly relates to a cyanomethylene-2H-pyrane derivative and a synthesis method and application thereof. BACKGROUND

[0002] The cyanomethylene-2H-pyrane derivative is an important oxygen-containing heterocyclic compound, and existing researches show that the compound has wide pharmacological and biological properties. The synthesis of the cyanomethylene-2H-pyrane derivative is rarely researched. The first similar report is a ring conversion reaction of 2H-pyrane and ketone under the action of KOH, which usually needs a long reaction time and obtains Z and E two configuration mixed products (literature: Org. Biomol. Chem. 2013, 11, 5239-5253). So far, there is no transition metal catalyzed C-H activation method for precisely constructing the cyanomethylene-2H-pyrane derivative. SUMMARY

[0003] In view of the deficiencies in the prior art, a first object of the application is to provide a cyanomethylene-2H-pyrane derivative, which has wide pharmacological and biological properties.

[0004] A second object of the application is to provide a synthesis method of the cyanomethylene-2H-pyrane derivative.

[0005] A third object of the application is to provide an application of the cyanomethylene-2H-pyrane derivative, which can be used as an organic probe for ion detection.

[0006] To achieve the above objects, the technical solutions adopted by the application are as follows:

[0007] A cyanomethylene-2H-pyrane derivative, the structural formula of the cyanomethylene-2H-pyrane derivative is shown as formula (I):

[0008]

[0009] Formula (I), R 1 is methyl; R 2 is methyl or hydrogen; R 3 is aryl, heteroaryl, alkyl, ester group; R 4 is aryl, heteroaryl, alkyl.

[0010] The synthesis method of the cyanomethylidene-2H-pyrane derivative is carried out by dissolving an alkenyl formyl acetonitrile represented by formula (II), an alkyne represented by formula (III), a catalyst, an oxidizing agent, and an additive in an organic solvent under an inert gas condition, and then heating to obtain a cyanomethylidene-2H-pyrane derivative represented by formula (I), as shown in the following reaction scheme:

[0011]

[0012] Further, the heating reaction is carried out at a temperature of 60-120°C for 2-15 hours.

[0013] Further, the alkenyl formyl acetonitrile is (1-methyl)alkenyl benzoyl acetonitrile, (1,2-dimethyl)alkenyl benzoyl acetonitrile, cyclopentenyl benzoyl acetonitrile, or cyclohexenyl benzoyl acetonitrile, etc.

[0014] Further, the alkyne is diphenylacetylene, 4,4'-dimethyl diphenylacetylene, 4,4'-dimethoxy diphenylacetylene, 4,4'-difluoro diphenylacetylene, 4,4'-dichloro diphenylacetylene, 4,4'-dibromo diphenylacetylene, 4,4'-ditrifluoromethyl diphenylacetylene, 4,4'-dinitro diphenylacetylene, 2,2'-difluoro diphenylacetylene, 3,3'-dimethyl diphenylacetylene, di(2-naphthalene)acetylene, di(2-thiophene)acetylene, di(3-thiophene)acetylene, methyl phenyl acetylene, phenyl propargyl acetate, or 4-heptyne, etc.

[0015] Further, the oxidizing agent is copper acetate, copper chloride, copper bromide, copper oxide, or copper triflate, etc.

[0016] Further, the additive is sodium acetate, acetic acid, trifluoroacetic acid, zinc acetate, or manganese acetate, etc.

[0017] Further, the organic solvent is N,N-dimethylformamide, acetonitrile, methanol, 1,2-dichloroethane, dichloromethane, tetrahydrofuran, or hexafluoroisopropanol, etc.

[0018] Further, the catalyst is [Cp*RhCl2]2.

[0019] Further, the molar volume ratio of the alkenyl formyl acetonitrile, the alkyne, the catalyst, the oxidizing agent, the additive, and the organic solvent is (0.2-2.0) mmol:(0.2-2.0) mmol:(0.01-0.1) mmol:(0.4-4.0) mmol:(0.1-2.0) mmol:(1-10) mL.

[0020] Further, the inert gas is argon, nitrogen, etc.

[0021] Further, the reaction mixture needs to be vacuum concentrated after the reaction is completed, and the cyanomethylidene-2H-pyrane derivative is obtained by column chromatography separation.

[0022] The cyanomethylidene-2H-pyrane derivative is used for constructing other functionalized pyran derivatives; and the cyanomethylidene-2H-pyrane derivative is used in the field of fluorescence detection.

[0023] In order to realize efficient and convenient synthesis of the compound cyanomethylidene-2H-pyrane derivative, the application provides a synthesis method which is easy to obtain raw materials, simple to operate, wide in substrate application range, high in atom utilization rate and high in atom economy. The application constructs the cyanomethylidene-2H-pyrane derivative by one-pot method under rhodium catalysis, taking alkenyl formyl acetonitrile and alkyne as raw materials.

[0024] Beneficial effects: 1. The application provides a synthesis method of cyanomethylidene-2H-pyrane derivative. The synthesis method has the advantages of high atom economy, simple operation, high synthesis efficiency and region selectivity, and good substrate applicability, and the like. The synthesis method has passed laboratory scale-up experiment, and can meet large-scale application and development in the medical, material and other industries.

[0025] 2. The application only generates Z-type product, and has high selectivity. The cyan group substituent of the cyanomethylidene-2H-pyrane derivative constructed by the application can be conveniently converted into other functional groups, which is helpful for quickly constructing pyran active compounds. The fluorescence property test of the cyanomethylidene-2H-pyrane derivative constructed by the application shows that the cyanomethylidene-2H-pyrane derivative can be used as an organic probe for ion detection, and can be used in the field of fluorescence detection. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 The cyanomethylidene-2H-pyrane derivative is used for constructing other functionalized pyran derivatives; and the cyanomethylidene-2H-pyrane derivative is used in the field of fluorescence detection.

[0027] Figure 2 The cyanomethylidene-2H-pyrane compounds prepared in Example 1, Example 2, Example 3, Example 6 and Example 7 are shown in the ultraviolet spectrum and fluorescence spectrum, Figure 2 The cyanomethylidene-2H-pyrane compounds prepared in Example 1, Example 2, Example 3, Example 6 and Example 7 are shown in the ultraviolet spectrum, Figure 2 The cyanomethylidene-2H-pyrane compounds prepared in Example 1, Example 2, Example 3, Example 6 and Example 7 are shown in the fluorescence spectrum. DETAILED DESCRIPTION

[0028] The specific details of the present application are further described in the following description for sufficient understanding of the present application. The terms used in the specification of the present application are only used to illustrate the advantages and characteristics of the present application, and are not intended to limit the present application.

[0029] Unless otherwise defined, all technical and scientific terms used in the present application have the same meanings as understood by those skilled in the art to which this application belongs. Unless otherwise specified, the drugs or reagents used in the present application are used according to the product instructions or using the conventional methods in the art. The process of the present application is further described according to the specification and specific embodiments.

[0030] Example 1

[0031] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, and the mixture was stirred at 100°C for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1a with a separation yield of 82%, mp: 182-183°C.

[0032]

[0033] Product NMR data: 1 H NMR (CDCl3, 500 MHz): δ 7.38 (d, J = 8.0 Hz, 2H), 7.31-7.26 (m, 4H), 7.22 (t, J = 7.3 Hz, 2H), 7.19-7.16 (m, 2H), 6.58 (s, 1H), 4.27 (s, 1H), 1.97 (s, 3H). 13 CNMR (CDCl3, 125 MHz): δ 166.4, 152.0, 136.9, 134.2, 131.8, 129.5, 128.9, 128.8, 128.2, 127.8, 124.4, 118.1, 117.2, 63.8, 17.1.

[0034] Product high-resolution mass spectrometry data: HRMS (ESI): Calcd for C 20 H 15 NNaO[M+Na] + 308.1046, found: 308.1047.

[0035] Figure 1 Process flow chart for the synthesis of cyanomethylidene-2H-pyran derivatives.

[0036] Example 2

[0037] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1b with an isolated yield of 84%, mp: 154-155 °C.

[0038]

[0039] Product NMR data: 1 H NMR (CDC13, 500 MHz): δ 7.29 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 7.06-7.02 (m, 4H), 6.55 (s, 1H), 4.23 (s, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.95 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 166.5, 152.1, 139.7, 137.5, 134.6, 134.1, 129.6, 128.9, 128.8, 128.7, 123.9, 118.3, 116.6, 100.0, 63.2, 21.4, 21.2, 17.1.

[0040] Product high-resolution mass spectrometry data: HRMS (ESI): Calcd for C 22 H 19 NNaO[M+Na] + 336.1359, found: 336.1357.

[0041] Example 3

[0042] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1b with an isolated yield of 84%, mp: 154-155 °C.

[0043]

[0044] Product NMR data: 1 H NMR (CDC13, 500 MHz): δ 7.35 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 6.54 (s, 1H), 4.22 (s, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 1.94 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 166.6, 160.4, 159.1, 151.7, 134.8, 130.3, 130.1, 129.4, 124.4, 123.4, 118.5, 115.7, 114.4, 113.6, 63.0, 55.3, 55.2, 17.1.

[0045] Product high resolution mass spectrum data: HRMS (ESI): Calcd for C 22 H 19 NNaO3[M+Na] + 368.1257, found: 368.1259.

[0046] Example 4

[0047] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1d with a separation yield of 71%, mp: 155-156 °C.

[0048]

[0049] Product NMR data: 1 H NMR (CDC13, 500 MHz): δ 7.39–7.32 (m, 2H), 7.16–7.10 (m, 2H), 7.02 (t, J = 8.4 Hz, 2H), 6.93 (t, J = 8.4 Hz, 2H), 6.52 (s, 1H), 4.29 (s, 1H), 1.96 (s, 3H). 13CNMR (CDC13, 125 MHz): δ 166.1, 163.2 (d, J = 251.5 Hz), 162.3 (d, J = 248.4 Hz), 151.0, 133.7, 132.6, 132.6, 130.8 (d, J = 8.6 Hz), 130.6 (d, J = 8.1 Hz), 127.7 (d, J = 3.4 Hz), 124.6, 116.1 (d, J = 21.7 Hz), 116.0, 115.5 (d, J = 21.8 Hz), 64.4, 17.1. 19 F NMR (CDC13, 471 MHz): δ -109.7, -113.3.

[0050] Product high resolution mass spectral data: HRMS (ESI): Calcd for C 20 H 13 F2NNaO[M+Na] + 344.0857, found: 344.0858.

[0051] Example 5

[0052] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1e with a separation yield of 77%, mp: 178-179 °C.

[0053]

[0054] Product nuclear magnetic data: 1 H NMR (CDC13, 500 MHz): δ 7.30 (m, 4H), 7.22 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.51 (s, 1H), 4.30 (s, 1H), 1.96 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 165.9, 150.9, 135.8, 135.0, 134.1, 133.3, 130.2, 130.0, 129.9, 129.4, 128.7, 125.1, 116.3, 64.7, 17.1.

[0055] Product high resolution mass spectral data: HRMS (ESI): Calcd for C20 H 13 Cl2NNaO[M+Na] + 376.0266, found:376.0268.

[0056] Example 6

[0057] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese(III) acetate dihydrate were added. The reaction tube was slowly injected with 1.5 mL of 1,2-dichloroethane under a nitrogen atmosphere, and stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1f with a separation yield of 74%, mp: 165-166 °C.

[0058]

[0059] Product NMR data: 1 H NMR (CDC13, 500 MHz): δ 7.46 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.50 (s, 1H), 4.30 (s, 1H), 1.96 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 165.9, 150.9, 135.5, 133.2, 132.3, 131.7, 130.5, 130.4, 130.2, 125.2, 124.3, 122.2, 116.4, 64.8, 17.1.

[0060] Product high-resolution mass spectrometry data: HRMS (ESI): Calcd for C 20 H 13 Br2NNaO[M+Na] + 463.9256and465.9236, found:463.9258and465.9239.

[0061] Example 7

[0062] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese(III) acetate dihydrate were added. The reaction tube was slowly injected with 1.5 mL of 1,2-dichloroethane under a nitrogen atmosphere, stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1g with a separation yield of 72%, mp: 178-179 °C.

[0063]

[0064] Product NMR data: 1 H NMR (CDC13, 500 MHz): δ 7.60 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.54 (s, 1H), 4.37 (s, 1H), 2.00 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 165.6, 150.7, 140.0, 134.7, 132.6, 131.9 (q, J = 32.8 Hz), 130.4 (q, J = 32.8 Hz), 129.3, 129.1, 126.2 (q, J = 3.7 Hz), 126.1, 125.4 (q, J = 3.7 Hz), 117.4, 117.2, 65.7, 17.2. 19 F NMR (CDC13, 471 MHz): δ -62.7, -63.0.

[0065] Product high-resolution mass spectrometry data: HRMS (ESI): Calcd for C 22 H 13 F6NNaO[M+Na] + 444.0794, found: 444.0796.

[0066] Example 8

[0067] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1h with a separation yield of 68% and a melting point of 173-174 °C.

[0068]

[0069] Product NMR data: 1 H NMR (CDCI3, 500 MHz): δ 8.22 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 6.55 (s, 1H), 4.45 (s, 1H), 2.03 (s, 3H). 13 C NMR (CDCI3, 125 MHz): δ 165.1, 150.2, 148.3, 147.7, 142.6, 137.0, 131.5, 129.9, 129.8, 127.2, 124.6, 123.8, 117.6, 67.0, 17.3.

[0070] Product high-resolution mass spectrometry data: HRMS (ESI): Calcd for C 20 H 13 N3NaO5[M+Na] + 398.0747, found: 398.0750.

[0071] Example 9

[0072] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1i with a separation yield of 70% and a melting point of 146-147 °C.

[0073]

[0074] Product NMR data:1 H NMR (CDC13, 500 MHz): δ 7.43 (t, J = 7.4 Hz, 1H), 7.34-7.29 (m, 1H), 7.25-7.21 (m, 1H), 7.11 (t, J = 7.6 Hz, 1H), 7.04-6.99 (m, 1H), 6.99-6.94 (m, 2H), 6.92-6.90 (m, 1H), 6.58 (s, 1H), 4.31 (s, 1H), 1.97 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 166.2, 159.8 (d, J = 247.9 Hz), 159.4 (d, J = 253.4 Hz), 148.7, 132.6 (d, J = 1.6 Hz), 131.8 (d, J = 8.4 Hz), 130.9 (d, J = 1.6 Hz), 130.7 (d, J = 2.7 Hz), 129.9 (d, J = 8.2 Hz), 125.1, 124.2 (d, J = 3.6 Hz), 124.1 (d, J = 3.6 Hz), 123.6 (d, J = 1.7 Hz), 120.3 (d, J = 13.8 Hz), 117.6, 116.0 (d, J = 21.6 Hz), 115.9 (d, J = 21.4 Hz), 114.2, 64.9, 17.3. 19 F NMR (CDC13, 471 MHz): δ -111.1, -114.7.

[0075] Product high resolution mass spectrometry data: HRMS (ESI): Calcd for C 20 H 13 F2NNaO[M+Na] + 344.0857, found: 344.0855.

[0076] Example 10

[0077] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1j with a separation yield of 78%, mp: 153-154 °C.

[0078]

[0079] Product nuclear magnetic resonance data:1 H NMR (CDC13, 500 MHz): δ 7.25 (s, 1H), 7.19-7.08 (m, 5H), 7.01 (s, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.57 (s, 1H), 4.24 (s, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 1.95 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 166.4, 152.0, 138.6, 137.7, 136.8, 134.4, 131.6, 130.3, 129.4, 129.3, 128.7, 128.4, 127.9, 126.1, 126.0, 124.1, 117.2, 63.5, 21.4, 21.3, 17.1.

[0080] Product high resolution mass spectrum data: HRMS (ESI): Calcd for C 22 H 19 NNaO[M+Na] + 336.1359, found: 336.1357.

[0081] Example 11

[0082] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. The reaction tube was slowly injected with 1.5 mL of 1,2-dichloroethane under a nitrogen atmosphere, stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1k with a separation yield of 73%, mp: 108-109 °C.

[0083]

[0084] Product nuclear magnetic data: 1 H NMR (CDC13, 500 MHz): δ 8.11 (s, 1H), 7.83-7.80 (m, 1H), 7.79-7.76 (m, 2H), 7.72 (d, J = 8.2 Hz, 3H), 7.56 (d, J = 8.7 Hz, 1H), 7.51-7.45 (m, 3H), 7.43-7.40 (m, 1H), 7.30 (dd, J = 8.7, 1.6 Hz, 1H), 7.21 (dd, J = 8.5, 1.5 Hz, 1H), 6.74 (s, 1H), 4.34 (s, 1H), 2.03 (s, 3H). 13C NMR (CDC13, 125 MHz): δ 166.3, 152.2, 139.0, 134.4, 134.4, 133.6, 133.5, 132.8, 132.6, 129.2, 129.0, 128.6, 127.9, 127.8, 127.7, 127.6, 127.5, 127.3, 127.1, 126.5, 126.4, 126.4, 125.6, 124.6, 120.8, 117.4, 64.1, 17.2.

[0085] Product high resolution mass spectral data: HRMS (ESI): Calcd for C 28 H 19 NNaO[M+Na] + 408.1359, found: 408.1357.

[0086] Example 12

[0087] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. The reaction tube was slowly charged with 1.5 mL of 1,2-dichloroethane under nitrogen atmosphere and stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1l with a separation yield of 75%, mp: 162-163 °C.

[0088]

[0089] Product nuclear magnetic data: 1 H NMR (CDC13, 400 MHz): δ 7.47-7.46 (m, 2H), 7.30 (d, J = 5.0 Hz, 1H), 7.13-7.10 (m, 1H), 7.04 (d, J = 3.4 Hz, 1H), 6.98-6.95 (m, 1H), 6.47 (s, 1H), 4.30 (s, 1H), 1.93 (s, 3H). 13 C NMR (CDC13, 100 MHz): δ 165.6, 148.7, 136.5, 134.0, 133.5, 129.6, 129.5, 128.7, 127.8, 127.7, 127.2, 123.2, 117.8, 108.4, 64.8, 17.0.

[0090] Product high resolution mass spectral data: HRMS (ESI): Calcd for C 16 H11 NNaOS2[M+Na] + 320.0174, found: 320.0176.

[0091] Example 13

[0092] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese(III) acetate dihydrate were added. The reaction tube was slowly injected with 1.5 mL of 1,2-dichloroethane under a nitrogen atmosphere, and stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was separated by column chromatography to obtain the target product 1m with a separation yield of 76%, mp: 151-152 °C.

[0093]

[0094] Product NMR data: 1 H NMR (CDCI3, 400 MHz): δ 7.57 (s, 1H), 7.38 (dd, J = 4.4, 3.1 Hz, 1H), 7.21 (s, 1H), 7.15 (dd, J = 4.7, 3.2 Hz, 1H), 6.94 (d, J = 4.9 Hz, 1H), 6.84 (d, J = 5.2 Hz, 1H), 6.49 (s, 1H), 4.26 (s, 1H), 1.94 (s, 3H). 13 C NMR (CDCI3, 100 MHz): δ 166.1, 148.2, 136.7, 134.0, 133.1, 128.2, 127.1, 126.7, 126.6, 125.5, 123.9, 123.7, 111.2, 63.9, 17.0.

[0095] Product high-resolution mass spectrometry data: HRMS (ESI): Calcd for C 16 H 11 NNaOS2[M+Na] + 320.0174, found: 320.0175.

[0096] Example 14

[0097] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of vinyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese(III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1n with a separation yield of 70%, mp: 93-94 °C.

[0098]

[0099]

[0100] Product NMR data: 1 H NMR (CDC13, 500 MHz): δ 7.61 (d, J = 7.0 Hz, 2H), 7.46-7.39 (m, 3H), 6.40 (s, 1H), 4.17 (s, 1H), 2.07 (s, 3H), 1.91 (s, 3H). 13 C NMR (CDC13, 100 MHz): δ 166.7, 151.5, 135.0, 132.3, 129.4, 128.4, 128.3, 124.4, 118.4, 110.6, 62.8, 17.1, 17.1.

[0101] Product high-resolution mass spectrometry data: HRMS (ESI): Calcd for C 15 H 13 NNaO[M+Na] + 246.0889, found: 246.0886.

[0102] Example 15

[0103] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of vinyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese(III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1n with a separation yield of 70%, mp: 93-94 °C.

[0104]

[0105] Product NMR data: 1H NMR (CDC13, 500 MHz): δ 7.56 (d, J = 7.1 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 6.90 (s, 1H), 4.35 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 1.96 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H). 13 C NMR (CDC13, 125 MHz): δ 165.5, 165.1, 161.2, 131.8, 131.0, 129.2, 129.1, 128.1, 124.0, 116.9, 109.2, 66.7, 61.3, 17.1, 13.7.

[0106] Product high resolution mass spectrum data: HRMS (ESI): Calcd for C 17 H 15 NNaO3[M+Na] + 304.0944, found: 304.0943.

[0107] Example 16

[0108] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese(III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1p with a separation yield of 65%, mp: 41-42 °C.

[0109]

[0110] Product nuclear magnetic data: 1 H NMR (CDC13, 500 MHz): δ 6.27 (s, 1H), 4.03 (s, 1H), 2.40 (t, J = 7.5 Hz, 2H), 2.18–2.07 (m, 2H), 1.82 (s, 3H), 1.71–1.64 (m, 2H), 1.49–1.40 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (CDC13, 125 MHz): δ 167.2, 155.4, 133.4, 123.1, 118.7, 113.9, 61.7, 31.5, 31.3, 22.9, 20.8, 17.1, 13.7, 13.5.

[0111] Product high resolution mass spectral data: HRMS (ESI): Calcd for C 14 H 19 NNaO[M+Na] + 240.1359, found: 240.1358.

[0112] Example 17

[0113] In a dry 25 mL Schlenk tube equipped with a magnetic bar, 0.3 mmol of alkenyl formyl acetonitrile, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. The reaction tube was slowly charged with 1.5 mL of 1,2-dichloroethane under nitrogen atmosphere and stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature and the reaction mixture was concentrated in vacuo. The residue was separated by column chromatography to obtain the target product 1q with an isolation yield of 81%, mp: 199-200 °C.

[0114]

[0115] Product nuclear magnetic data: 1 H NMR (CDC13, 500 MHz): δ 7.37-7.32 (m, 3H), 7.27-7.25 (m, 2H), 7.20-7.10 (m, 5H), 4.24 (s, 1H), 1.93 (s, 3H), 1.80 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 166.8, 151.1, 139.8, 135.8, 132.3, 130.7, 129.0, 128.9, 128.7, 127.9, 127.9, 120.4, 119.6, 119.1, 62.0, 17.3, 13.7.

[0116] Product high resolution mass spectral data: HRMS (ESI): Calcd for C 21 H 17 NNaO[M+Na] + 322.1202, found: 322.1203.

[0117] Example 18

[0118] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of ethyl alkenyl formate, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1r with an isolation yield of 74%, mp: 180-181 °C.

[0119]

[0120] Product NMR data: 1 H NMR (CDCI3, 500 MHz): δ 7.33-7.32 (m, 5H), 7.23 (t, J = 7.1 Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.14-7.12 (m, 2H), 4.04 (s, 1H), 2.61 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 7.4 Hz, 2H), 2.09-2.03 (m, 2H), 1.57 (s, 3H). 13 C NMR (CDCI3, 125 MHz): δ 164.3, 152.8, 149.0, 135.3, 132.0, 129.7, 129.3, 128.9, 128.9, 128.2, 128.0, 127.8, 118.6, 117.2, 61.6, 33.8, 30.4, 22.6.

[0121] Product high-resolution mass spectrometry data: HRMS (ESI): Calcd for C 22 H 17 NNaO[M+Na] + 334.1202, found: 334.1205.

[0122] Comparative Example 1

[0123] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of ethyl alkenyl formate, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. Under a nitrogen atmosphere, 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube, which was stirred at 100 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography to obtain the target product 1r with an isolation yield of 74%, mp: 180-181 °C.

[0124]

[0125] Comparative Example 2

[0126] In a 25 mL Schlenk tube equipped with a magnetic bar and dried, 0.3 mmol of alkenyl formyl pyruvate, 0.2 mmol of alkyne, 0.01 mmol of [Cp*RhCl2]2, 0.4 mmol of copper acetate and 0.2 mmol of manganese (III) acetate dihydrate were added. 1.5 mL of 1,2-dichloroethane was slowly injected into the reaction tube under a nitrogen atmosphere, and the mixture was stirred at 100°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was separated by column chromatography, but no product 1t containing a pyran structure was obtained.

[0127]

[0128] Performance test

[0129] 1. The cyanomethylidene-2H-pyrane compound constructed in the present application can be conveniently converted into other functionalized pyran derivatives. For example, 1a prepared in Example 1 can be reduced by diisobutylaluminum hydride or treated with concentrated sulfuric acid to obtain pyran derivatives 4 or 5 substituted with aldehyde or amide groups. The specific implementation method is as follows:

[0130] (1) At 0°C under a nitrogen atmosphere, 1.0 M diisobutylaluminum hydride (DIBAL-H) in toluene (2 mL) was slowly added to a toluene (4 mL) solution of 1a (1 mmol). After stirring at 0°C for 30 min, the mixture was stirred at room temperature for 1 h. Then, acetone (3 mL) was added to the reaction mixture and stirred for 5 min. Subsequently, an aqueous solution of sodium potassium tartrate (10 mL) and ethyl acetate (3 mL) were added to the mixed solution and stirred for 10 h. After the reaction was completed, the mixed solution was extracted with ethyl acetate (100 mL each time) for 3 times. The combined organic layer was dried with Na2SO4, filtered, and the solvent was concentrated under reduced pressure. The residue was separated by column chromatography to obtain the product 4 substituted with an aldehyde group, with a separation yield of 71%, mp: 153-154 ℃.

[0131]

[0132] Product NMR data: 1 H NMR (CDCl3, 500 MHz): δ 10.18 (d, J = 8.3 Hz, 1H), 7.36-7.29 (m, 6H), 7.24 (t, J = 7.7 Hz, 2H), 7.18-7.16 (m, 2H), 6.74 (s, 1H), 5.31 (d, J = 8.3 Hz, 1H), 2.03 (s, 3H). 13C NMR (CDC13, 125 MHz): δ 187.8, 166.3, 152.7, 136.6, 136.1, 132.1, 129.7, 128.9, 128.9, 128.9, 128.2, 127.8, 125.7, 118.4, 100.2, 17.5.

[0133] Product high resolution mass spectral data: HRMS (ESI): Calcd for C 20 H 16 NaO2[M+Na]+311.1043, found: 311.1044.

[0134] (2) The solution of 1a prepared in Example 1 (1 mmol) in concentrated H2SO4(2 mL) was stirred at room temperature for 18 h, after the reaction was completed, the mixture was slowly basified to pH > 10 by dropwise addition of 30% NH4OH solution while keeping the temperature below 0°C, then the mixture was extracted with CH2Cl2(15 mL) and the organic layer was washed successively with 10 mL water and 10 mL brine, the organic layer was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure, the residue was separated by column chromatography to give the amide substituted product 5 with separation yield of 82%, mp: 161-162 °C.

[0135]

[0136] Product nuclear magnetic data: 1 H NMR (CDC13, 500 MHz): δ 7.32-7.25 (m, 8H), 7.13-7.11 (m, 2H), 6.83 (s, 1H), 6.55 (s, 1H), 5.41 (s, 1H), 5.02 (s, 1H), 2.00 (s, 3H). 13 C NMR (CDC13, 125 MHz): δ 158.3, 150.9, 136.6, 132.9, 132.1, 129.4, 128.9, 128.7, 128.6, 128.5, 127.6, 126.5, 117.0, 92.9, 18.1.

[0137] Product high resolution mass spectral data: HRMS (ESI): Calcd for C 20 H 17 NNaO2[M+Na] + 326.1151, found: 326.1155.

[0138] 2, The spectral properties of the cyanomethylidene-2H-pyrans compounds constructed by the application are tested, first, the screened compounds (1a, 1b, 1c, 1f and 1g) are dissolved in dichloromethane (5.0*10 -5 M), and ultraviolet spectrum and fluorescence spectrum tests are conducted. Figure 2 The ultraviolet spectrum and fluorescence spectrum of the cyanomethylidene-2H-pyrans compounds prepared for Example 1, Example 2, Example 3, Example 6 and Example 7 are shown in Figures (a) and (b) respectively. Figure 2 Figure (a) is the ultraviolet spectrum of the cyanomethylidene-2H-pyrans compounds prepared for Example 1, Example 2, Example 3, Example 6 and Example 7. Figure 2 Figure (b) is the fluorescence spectrum of the cyanomethylidene-2H-pyrans compounds prepared for Example 1, Example 2, Example 3, Example 6 and Example 7. The ultraviolet spectrum test results show that the above compounds have a maximum absorption peak at 390-400 nm, and the fluorescence spectrum test results show that the above compounds have a maximum absorption peak at 350-400 when the excitation wavelength is 360 nm, which indicates that the cyanomethylidene-2H-pyrans compounds constructed by the application can be used as organic probes for ion detection.

[0139] The cyanomethylidene-2H-pyrans compounds prepared by the application can be used for the preparation of anti-malaria, anti-cancer and sedative active molecules; the cyano substituent of the cyanomethylidene-2H-pyrans compounds can also be conveniently converted into aldehyde groups, amides and other functional groups, and then a variety of functionalized pyran derivatives can be constructed; the cyanomethylidene-2H-pyrans derivatives can be used as organic probes for ion detection, and have important application value.

[0140] In the description of the specification, the description of the terms "one embodiment", "example", "specific example" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the application. In the specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0141] The above is only an example and description of the application, and those skilled in the art can make various modifications or supplements to the described specific embodiments or use similar ways to replace, as long as they do not deviate from the application or exceed the scope defined by the claims.

Claims

1. A method for synthesizing a cyanomycyl-2H-pyran derivative, characterized in that, The synthesis method comprises the following steps: under inert gas conditions, alkenylformylacetonitrile of formula (II), alkyne of formula (III), catalyst, oxidant and additive are dissolved in an organic solvent and subjected to heating reaction to obtain cyanomylidene-2H-pyran derivative of formula (I), and the reaction route is shown in the following formula; ； The structural formula of the cyanomycyl-2H-pyran derivative shown in formula (I) is as follows: , , , , , , , , , , , , , , , , , One of them; The oxidant is copper acetate, the additive is manganese acetate, and the catalyst is [Cp*RhCl2]2.

2. The synthesis method according to claim 1, characterized in that, The organic solvent is N,N-dimethylformamide, acetonitrile, methanol, 1,2-dichloroethane, dichloromethane, or tetrahydrofuran.

3. The synthesis method according to claim 1, characterized in that, The molar volume ratio of the alkenylformylacetonitrile, alkyne, catalyst, oxidant, additive and organic solvent is 0.2-2.0 mmol: 0.2-2.0 mmol: 0.01-0.1 mmol: 0.4-4.0 mmol: 0.1-2.0 mmol: 1-10 mL.

4. The synthesis method according to claim 1, characterized in that, The heating reaction is carried out at a temperature of 60-120℃ for 2-15 hours.

5. The synthesis method according to claim 1, characterized in that, The inert gas is argon or nitrogen; After the reaction is completed, the reaction mixture needs to be concentrated under vacuum and separated by column chromatography to obtain the cyanomycyl-2H-pyran derivative.

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