A gem-difluoroallyl compound and preparation method thereof

Abstract

The present invention discloses a gem-difluoroallyl compound and a preparation method thereof, and belongs to the technical field of pharmaceutical intermediates and organic synthesis. The present invention uses various natural or non-natural aldehydes and ketones to react with sulfonyl hydrazide to obtain the corresponding N ‑Sulfonylhydrazone, with 3,3‑difluoroallyl sulfide in NaOH, KOH, LiO t Bu、NaO t Bu、Cs 2 CO 3 Under alkaline conditions, Rh(OPiv) 2 ] 2 、[Rh(OAc) 2 ] 2 , [Rh(esp)] 2 、Ru(PPh 3 ) 2 Cl 2 、[Ru( p ‑cymene)Cl 2 ] 2 , Pd 2 (dba) 3 、Ag 2 CO 3 、AgSbF 6 、Cu(MeCN) 4 PF 6 The method of the present invention has a very wide substrate adaptability, the starting raw materials of the reaction, aldehydes and ketones, are cheap and easy to obtain, the reaction process is simple to operate, suitable for large-scale synthesis, and can also provide a new method and new target for the synthesis and modification of drugs.

Description

Technical Field

[0001] The invention relates to a gem-difluoroallyl compound and a preparation method thereof, belonging to the technical field of pharmaceutical intermediates and organic synthesis. Background Art

[0002] Due to the special physical and chemical properties of fluorine atoms, organic fluorine compounds have shown a significant effect in improving the properties of functional molecules. The introduction of fluorine atoms into organic molecules can often improve the fat solubility and electronegativity of the compounds. To date, 20% of organic drug molecules and 30% of agricultural organic matter contain fluorine atoms. Among the numerous fluorine-containing organic compounds, geminal-difluoromethylene ( gem -CF2) is a very useful fluorinated fragment, which is widely used in functional materials, pesticides and medicinal chemistry. Meanwhile, gem-difluoroallyl (CF2CH = CH2) is a more valuable fluorinated fragment due to its versatility of carbon-carbon double bond and potential application for further transformation. However, the synthetic methods to obtain this structure are very limited, mainly focusing on the development of halide-based cross-coupling methods and free radical strategies, that is, the construction of vinyl C (sp) through difluoroalkyl 2 )-CF2 bond of olefins. While efficient methods for the synthesis of direct geminal-difluoro compounds are rare, they are limited to the nucleophilic difluorination olefination of aldehydes, ketones or imides of 3,3-difluoroallyl borate esters, which are all obtained from trifluoromethyl-substituted olefins through metal-catalyzed coupling reactions. In addition, the inventors previously used diazo esters with 3,3-difluoroallyl sulfide through the photopromoted Doyle-Kirmse reaction to achieve the synthesis of a series of olefin compounds containing difluoromethylene (CF2) fragments. Despite all these achievements, the development of a method for the direct incorporation of geminal difluoroallyl groups to construct compounds that are easily transformed remains a highly desirable and challenging task.

[0003] Ketones and aldehydes are cheap and abundant building blocks in organic synthesis and can be used in a variety of transformations. N -Sulfonylhydrazones are easily derived from simple condensations of ketones or aldehydes and are also useful and versatile synthons in organic synthesis, especially as reaction partners in various transition metal-catalyzed carbene cross-coupling reactions, which provide a powerful synthetic strategy for the formation of carbon-carbon and carbon-heteroatom bonds. N -sulfonylhydrazones have been rapidly developed in transition metal-catalyzed cross-coupling reactions. These reactions are carried out via in situ generated diazo intermediates, but existing methods are unable to introduce fluorinated groups. N The present invention provides a method for directly incorporating gem-difluoroallyl into the carbonyl group of an aldehyde or ketone compound to construct a gem-difluoroallyl compound that is easy to convert. Summary of the invention

[0004] The object of the present invention is to provide a preparation of a geminal-difluoroallyl compound, the structural formula of which is:

[0005]

[0006] Among them, R 1 is one of an alkyl group, a cycloalkyl group, a phenyl group, a benzyl group, an alkylbenzene group, an alkoxybenzene group, a halogenated phenyl group, a polycyclic aromatic group, and a heterocyclic group; R 2 is selected from one of alkyl, alkoxy, cycloalkyl, phenyl, alkylbenzene, alkoxybenzene, halogenated phenyl, polycyclic aromatic group, heterocyclic group, halogen and other unsaturated hydrocarbon groups; R 3 , R 4 One selected from alkyl, alkoxy, cycloalkyl, phenyl, alkylbenzene, alkoxybenzene, halogenated phenyl, polycyclic aromatic group, ester group, heterocyclic group, ether group, halogen and other unsaturated hydrocarbon groups.

[0007] Another object of the present invention is to provide a method for preparing the geminal-difluoroallyl compound, wherein the aldehyde ketone reacts with sulfonyl hydrazide to obtain the corresponding N -sulfonylhydrazone, and 3,3-difluoroallyl sulfide in NaOH, KOH, LiO t Bu、NaO t Bu, Cs2CO3 and other alkaline conditions with Rh(OPiv)2]2, [Rh(OAc)2]2, [Rh(esp)]2, Ru(PPh3)2Cl2, [Ru( p -cymene)Cl2]2, Pd2(dba)3, Ag2CO3, AgSbF6, Cu(MeCN)4PF6 and other transition metal complexes are used as catalysts in tetrahydrofuran (THF), 1,2-dichloroethane (DCE), dimethyl sulfoxide (DMSO), toluene (PhMe), acetonitrile (MeCN) and other organic solvents and in an inert gas (Ar) atmosphere to obtain geminal-difluoroallyl compounds, which specifically includes the following steps:

[0008] (1) Add 1 part of aldehyde or ketone and 1 part of p-toluenesulfonyl hydrazide to a reaction vessel containing methanol (generally, 1 mL of methanol is added for every 1 mmol of the reaction raw materials) and heat at 55-65 °C. o C reacts for 10-20 minutes, then cools to room temperature, removes the solvent by filtration, and obtains the corresponding N -sulfonylhydrazone.

[0009] (2) In an inert gas atmosphere, 3,3-difluoroallyl sulfide, N -Sulfonylhydrazone, catalyst, base and solvent are added into the reactor in a molar ratio of 1:(1-3):(0.005-0.02):(0.5-2):(10-100), and reacted at 70-120° C. for 6-24 hours to generate a mixed product.

[0010] (3) The crude product is obtained by concentrating under reduced pressure, and then separated and purified by column chromatography (200-300 mesh silica gel) using a mixed solvent of ethyl acetate and petroleum ether as an eluent to obtain the gem-difluoroallyl compound product.

[0011] Preferably, the base of the present invention is NaOH, KOH, NaO t Bu、LiO t One of Bu and Cs2CO3.

[0012] Preferably, the catalyst of the present invention is [Rh(OPiv)2]2, [Rh(OAc)2]2, [Rh(esp)]2, Ru(PPh3)2Cl2, [Ru( p -cymene)Cl2]2, Pd2(dba)3, Ag2CO3, AgSbF6, Cu(MeCN)4PF6.

[0013] Preferably, the solvent of the present invention is one of tetrahydrofuran (THF), 1,2-dichloroethane (DCE), dimethyl sulfoxide (DMSO), toluene (PhMe), and acetonitrile (MeCN).

[0014] Preferably, the aldehydes and ketones described in the present invention are aromatic aldehydes and ketones, heterocyclic aldehydes and ketones, or alkyl aldehydes and ketones.

[0015] The substituents on the aromatic ring of the aromatic aldehyde or ketone are one or more substituents.

[0016] The heterocyclic ring in the heterocyclic aldehyde or ketone is one of thiophene, furan, pyridine, thiazole and oxazole.

[0017] The alkyl aldehyde or ketone is a straight chain alkyl, branched chain alkyl or cycloalkyl group having 1 to 10 carbon atoms, or a straight chain alkyl, branched chain alkyl or cycloalkyl group containing a substituent, and common substituents include phenyl, hydroxyl and halogen.

[0018] Principle of the invention: The method of the invention converts p-toluenesulfonylhydrazone and 3,3-difluoroallyl sulfide into gem-difluoroallyl compounds through the ylide / [2,3]-σ rearrangement reaction of metal carbene, has high reaction efficiency and low reaction cost, and can be widely used in the preparation of various gem-difluoroallyl compounds.

[0019] Compared with the prior art, the present invention has the following advantages:

[0020] (1) The substrate p-toluenesulfonylhydrazone involved in the present invention can be synthesized from various natural or non-natural aldehydes and ketones through a simple method with p-toluenesulfonylhydrazone, and 3,3-difluoroallyl sulfide is also easy to obtain, thereby accurately synthesizing various gem-difluoroallyl compounds.

[0021] (2) The reaction involved in the method of the present invention has good tolerance and universality to functional groups. Aldehydes and ketones can be aromatic aldehydes and ketones, heterocyclic aldehydes and ketones, and alkyl aldehydes and ketones. The catalytic system used is simple, cheap, and has little environmental pollution, which can meet the needs of large-scale industrial production.

[0022] (3) The compounds synthesized by the present invention contain allyl, thioether and difluoromethylene structural units at the same time, wherein the allyl and thioether structural units can undergo multi-step transformations. Fluorine atoms have important pharmacological significance and exist in many drugs, which also provides a new method and new target for the synthesis and modification of drugs. DETAILED DESCRIPTION

[0023] The present invention is further described in detail below in conjunction with embodiments, but the protection scope of the present invention is not limited to the described contents.

[0024] Example 1

[0025] The synthesis of 3-bromo-2,2-difluoro-1-phenylbut-3-en-1-ylphenyl sulfide (3a) specifically comprises the following steps:

[0026] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of benzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -benzylidene-4-toluenesulfonylhydrazone (2a).

[0027] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.5 mmol N -benzylidene-4-toluenesulfonylhydrazone (2a), 0.01 mmol [Rh(esp)]2, 2 mmol Cs2CO3, and 10 mmol DCE were added to the reactor at 100 o C for 12 hours to generate a mixed product.

[0028] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 340 mg of the product 3-bromo-2,2-difluoro-1-phenylbut-3-en-1-ylphenyl sulfide (3a) with a yield of 96%. The reaction equation is as follows.

[0029]

[0030] The NMR data of the compound are as follows:

[0031] 1 H NMR (500 MHz, CDCl3) δ 7.39 (dd, J = 9.3, 4.5 Hz, 4H), 7.32 (d, J =4.3 Hz, 3H), 7.26 (d, J = 5.4 Hz, 3H), 6.22 (d, J = 1.5 Hz, 1H), 5.81 (d, J =1.2 Hz, 1H), 4.81 (t, J = 15.2 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 135.16,133.75, 132.96, 129.51, 128.96, 128.35, 128.32, 127.97, 123.59 (d, J = 31.2Hz), 123.07 (t, J = 6.4 Hz), 118.70 (t, J = 250.8 Hz), 57.69 (t, J = 25.8Hz); 19 F NMR (471 MHz, CDCl3) δ -99.47 (dd, J = 242.8, 15.6 Hz, 1F), -100.24(dd, J = 242.7, 14.8 Hz, 1F).

[0032] Example 2

[0033] The synthesis of 3-bromo-1-(4-chlorophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3b) specifically comprises the following steps:

[0034] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of p-chlorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b).

[0035] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.2 mmol N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b), 0.005 mmol [Rh(OAc)2]2, 1.2 mmol Cs2CO3, and 15 mmol DMSO were added to the reactor and heated at 80 o C for 6 hours to generate a mixed product.

[0036] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 341 mg of the product 3-bromo-1-(4-chlorophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3b) with a yield of 88%. The reaction equation is as follows.

[0037]

[0038] The NMR data of the compound are as follows:

[0039] 1 H NMR (500 MHz, CDCl3) δ 7.35 – 7.28 (m, 4H), 7.24 (dd, J = 14.1, 7.2Hz, 5H), 6.21 (s, 1H), 5.81 (s, 1H), 4.74 (t, J = 15.1 Hz, 1H); 13 C NMR (126MHz, CDCl3) δ 134.44, 133.85, 133.31, 133.27, 131.01, 129.23, 128.71, 128.40,123.81, 123.63 – 123.23, 118.61 (t, J = 251.0 Hz), 57.31 (t, J = 25.9 Hz); 19 FNMR (471 MHz, CDCl3) δ -98.99 (dd, J= 243.4, 15.0 Hz, 1F), -100.93 (dd, J =243.4, 15.1 Hz, 1F).

[0040] Example 3

[0041] The synthesis of 3-bromo-1-(4-bromophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3c) specifically comprises the following steps:

[0042] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of p-bromobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Bromobenzylidene)-4-toluenesulfonylhydrazone (2c).

[0043] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.2 mmol N -(4-bromobenzylidene)-4-toluenesulfonylhydrazone (2c), 0.02 mmol [Ru( p -cymene)Cl2]2, 1.2 mmol NaOH, and 30 mmol MeCN were added to the reactor and heated at 120 o C for 2 hours to generate a mixed product.

[0044] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 354 mg of the product 3-bromo-1-(4-bromophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3c) with a yield of 82%. The reaction equation is as follows.

[0045]

[0046] The NMR data of the compound are as follows:

[0047] 1 H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 7.7Hz, 2H), 7.23 (d, J = 7.0 Hz, 5H), 6.21 (d, J = 2.5 Hz, 1H), 5.81 (d,J = 2.4Hz, 1H), 4.73 (t, J = 15.1 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 134.37 (d, J =2.5 Hz), 133.30, 133.24, 131.67, 131.31, 129.23, 128.41, 123.77, 123.47 (dd, J = 11.1, 4.7 Hz), 122.65, 118.54 (t, J = 251.0 Hz), 57.38 (t, J = 25.9 Hz); 19 F NMR (471 MHz, CDCl3) δ -98.92 (dd, J = 243.4, 14.9 Hz, 1F), -100.95 (dd, J = 243.4, 15.2 Hz, 1F).

[0048] Example 4

[0049] The synthesis of 3-bromo-1-(4-fluorophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3d) specifically comprises the following steps:

[0050] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of p-fluorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Fluorobenzylidene)-4-toluenesulfonylhydrazone (2d).

[0051] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.2 mmol N -(4-Fluorobenzylidene)-4-toluenesulfonylhydrazone (2d), 0.05 mmol Ag2CO3, 1.2 mmol KOH, and 30 mmol MeCN were added into the reactor and heated at 80 o C for 3 hours to generate a mixed product.

[0052] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 312 mg of the product 3-bromo-1-(4-fluorophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3d) with a yield of 84%. The reaction equation is as follows.

[0053]

[0054] The NMR data of the compound are as follows:

[0055] 1 H NMR (500 MHz, CDCl3) δ 7.36 – 7.30 (m, 4H), 7.23 (dt, J = 5.3, 2.5Hz, 3H), 6.97 (t, J = 8.7 Hz, 2H), 6.20 (d, J = 2.6 Hz, 1H), 5.80 (d, J = 2.5Hz, 1H), 4.77 (t, J = 15.1 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 162.75 (d, J =247.7 Hz), 133.30, 131.40 (d, J = 8.3 Hz), 131.07 (t, J = 3.0 Hz), 129.18,128.32, 123.69, 123.35 (dd, J = 14.0, 7.6 Hz), 118.69 (t, J = 250.7 Hz),115.55, 115.38, 57.15 (t, J = 25.9 Hz); 19 F NMR (471 MHz, CDCl3) δ -99.27 (dd, J = 243.1, 15.2 Hz, 1F), -100.91 (dd, J = 243.0, 15.0 Hz, 1F), -113.34 (s,1F).

[0056] Example 5

[0057] The synthesis of 3-bromo-1-(2-chlorophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3e) specifically comprises the following steps:

[0058] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 2-chlorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(2-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2e).

[0059] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.4 mmol N -(2-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2e), 0.01 mmol Pd2(dba)3, 2.0 mmol NaO t Bu and 15 mmol THF were added to the reactor and heated at 70 o C for 5 hours to generate a mixed product.

[0060] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 310 mg of the product 3-bromo-1-(2-chlorophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3e) with a yield of 80%. The reaction equation is as follows.

[0061]

[0062] The NMR data of the compound are as follows:

[0063] 1 H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 7.6 Hz, 1H), 7.37 (dd, J = 6.4,3.2 Hz, 2H), 7.33 (dd, J = 7.8, 1.5 Hz, 1H), 7.27 – 7.18 (m, 5H), 6.30 (dd, J = 2.5, 1.7 Hz, 1H), 5.86 (dd, J = 2.4, 1.9 Hz, 1H), 5.60 (dd, J = 18.9, 11.4Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 134.79, 133.27, 133.13, 131.11, 129.56,129.46, 129.10, 128.26, 127.18, 124.00 (t, J = 30.9 Hz), 123.45 (t, J = 6.3Hz), 118.90 (t, J = 251.0 Hz); 19 F NMR (471 MHz, CDCl3) δ -95.44 (dd, J =244.8, 11.4 Hz, 1F), -101.53 (dd, J = 244.9, 18.8 Hz, 1F).

[0064] Example 6

[0065] The synthesis of 3-bromo-1-(3-bromophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3f) specifically comprises the following steps:

[0066] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 3-bromobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(3-Bromobenzylidene)-4-toluenesulfonylhydrazone (2f).

[0067] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.4 mmol N -(3-bromobenzylidene)-4-toluenesulfonylhydrazone (2f), 0.05 mmol Cu(MeCN)4PF6, 1.8 mmol LiO t Bu and 15 mmol THF were added to the reactor and heated at 80 o C for 5 hours to generate a mixed product.

[0068] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 337 mg of the product 3-bromo-1-(3-bromophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3f) with a yield of 86%. The reaction equation is as follows.

[0069]

[0070] The NMR data of the compound are as follows:

[0071] 1 H NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 7.36 – 7.31 (m, 2H), 7.28 –7.19 (m, 6H), 6.24 (d, J = 2.6 Hz, 1H), 5.93 – 5.51 (m, 1H), 4.77 – 4.67 (m,1H); 13 C NMR (126 MHz, CDCl3) δ 137.28 (d, J = 2.5 Hz), 134.35, 133.34,133.21, 129.74, 129.68, 129.24, 128.70, 128.46, 127.93, 123.77, 123.50 (t, J = 6.4 Hz), 123.27, 118.58 (t, J = 251.1 Hz); 19 F NMR (471 MHz, CDCl3) δ -98.33(dd, J = 243.7, 14.4 Hz, 1F), -101.22 (dd, J = 243.7, 15.7 Hz, 1F).

[0072] Example 7

[0073] The synthesis of 3-bromo-1-(2-methylphenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3 g) specifically comprises the following steps:

[0074] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 2-methylbenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(2-Methylbenzylidene)-4-toluenesulfonylhydrazone (2 g).

[0075] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.4 mmol N-(2-Methylbenzylidene)-4-toluenesulfonylhydrazone (2 g), 0.005 mmol [Rh(OAc)2]2, 1.2 mmol LiO t Bu and 35 mmolPhMe were added to the reactor and heated at 80 o C for 2 hours to generate a mixed product.

[0076] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 313 mg of the product 3-bromo-1-(2-methylphenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3 g). The yield was 85%. The reaction equation is as follows.

[0077]

[0078] The NMR data of the compound are as follows:

[0079] 1 H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 5.6 Hz, 1H), 7.34 (dd, J = 7.7,1.6 Hz, 2H), 7.26 – 7.14 (m, 5H), 7.10 (d, J = 8.8 Hz, 1H), 6.29 (d, J = 1.7Hz, 1H), 5.83 (s, 1H), 5.12 (dd, J = 18.5, 12.2 Hz, 1H), 2.24 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 136.92, 133.67, 133.60, 130.30, 129.54, 129.03, 128.29,128.21, 126.43, 124.25 (t, J = 31.2 Hz), 123.23 (t, J = 6.3 Hz), 119.21 (t, J = 250.5 Hz), 52.55 (t, J = 26.1 Hz), 19.88; 19 F NMR (471 MHz, CDCl3) δ -96.11(dd, J = 244.6, 12.0 Hz, 1F), -100.89 (dd,J = 244.8, 17.7 Hz, 1F).

[0080] Example 8

[0081] The synthesis of 3-bromo-1-(4-isopropylphenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3h) specifically comprises the following steps:

[0082] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 4-isopropylbenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Isopropylbenzylidene)-4-toluenesulfonylhydrazone (2h).

[0083] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.4 mmol N -(4-isopropylbenzylidene)-4-toluenesulfonylhydrazone (2h), 0.05 mmol AgSbF6, 1.2 mmol LiO t Bu and 20 mmol DCE were added to the reactor and heated at 80 o C for 2 hours to generate a mixed product.

[0084] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 325 mg of the product 3-bromo-1-(4-isopropylphenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3h) with a yield of 82%. The reaction equation is as follows.

[0085]

[0086] The NMR data of the compound are as follows:

[0087] 1 H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 6.4, 3.1 Hz, 2H), 7.28 (d, J =8.0 Hz, 2H), 7.22 (dd, J = 7.8, 4.6 Hz, 3H), 7.14 (d, J = 8.2 Hz, 2H), 6.18(d, J= 2.5 Hz, 1H), 5.77 (d, J = 2.4 Hz, 1H), 4.76 (t, J = 15.3 Hz, 1H),3.00 – 2.64 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H); 13 C NMR (126 MHz, CDCl3) δ149.12, 134.27, 132.86, 132.48, 129.45, 129.05, 127.94, 126.58, 123.98 (t, J = 31.2 Hz), 123.15 (t, J = 6.4 Hz), 118.92 (t, J = 250.6 Hz), 57.41 (t, J =25.8 Hz), 33.88, 23.99; 19 F NMR (471 MHz, CDCl3) δ -99.27 (dd, J = 242.4, 15.5Hz, 1F), -100.28 (dd, J = 242.4, 14.9 Hz, 1F).

[0088] Example 9

[0089] The synthesis of 3-bromo-1-(4-cyanophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3i) specifically comprises the following steps:

[0090] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 4-cyanobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Cyanobenzylidene)-4-toluenesulfonylhydrazone (2i).

[0091] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylphenyl sulfide (1a), 1.4 mmol N -(4-cyanobenzylidene)-4-toluenesulfonylhydrazone (2i), 0.02 mmol Ag2CO3, 1.5 mmol LiO t Bu and 20 mmol DCE were added to the reactor at 100 oC for 3 hours to generate a mixed product.

[0092] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using ethyl acetate / petroleum ether (1:50, volume ratio) as the eluent to obtain 296 mg of the product 3-bromo-1-(4-cyanophenyl)-2,2-difluoro-3-en-1-ylphenyl sulfide (3i) with a yield of 78%. The reaction equation is as follows.

[0093]

[0094] The NMR data of the compound are as follows:

[0095] 1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.2Hz, 2H), 7.27 (ddd, J = 16.6, 10.9, 6.4 Hz, 5H), 6.27 (d, J = 2.1 Hz, 1H), 5.87 (s, 1H), 4.79 (dd, J = 16.4, 13.6 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ140.65 (d, J = 2.2 Hz), 133.59, 132.47, 132.21, 130.47, 129.36, 128.79,123.75 (t, J = 6.5 Hz), 123.17 (t, J = 30.7 Hz), 118.51, 118.41 (t, J = 251.4Hz), 112.40, 57.73 (t, J = 26.1 Hz); 19 F NMR (471 MHz, CDCl3) δ -97.40 (dd, J = 244.5, 13.4 Hz, 1F), -101.90 (dd, J = 244.6, 16.5 Hz, 1F).

[0096] Example 10

[0097] The synthesis of 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl 4-fluorophenyl sulfide (3j) specifically comprises the following steps:

[0098] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 4-chlorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b).

[0099] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallyl 4-fluorophenyl sulfide (1b), 1.4 mmol N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b), 0.002 mmol [Rh(OPiv)2]2, 1.5 mmol LiO t Bu and 20 mmol DCE were added to the reactor at 100 o C for 3 hours to generate a mixed product.

[0100] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 398 mg of the product 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl 4-fluorophenyl sulfide (3j) with a yield of 98%. The reaction equation is as follows.

[0101]

[0102] The NMR data of the compound are as follows:

[0103] 1 H NMR (500 MHz, CDCl3) δ 7.31 (dd, J = 8.8, 5.3 Hz, 2H), 7.26 (s,4H), 6.92 (t, J = 8.7 Hz, 2H), 6.21 (d, J = 2.7 Hz, 1H), 5.87 – 5.63 (m, 1H), 4.65 (t, J = 15.2 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 163.19 (d, J= 249.5Hz), 136.44, 136.38, 134.54, 133.57 (d, J = 2.5 Hz), 130.98, 128.76, 128.10(d, J = 3.4 Hz), 123.50 (d, J = 61.8 Hz), 123.44 (t, J = 6.5 Hz), 118.59 (t, J = 251.1 Hz), 116.38 (d, J = 21.9 Hz), 57.97 (t, J = 25.9 Hz); 19 F NMR (471MHz, CDCl3) δ -99.36 (dd, J = 243.5, 15.3 Hz, 1F), -100.62 (dd, J = 243.5, 14.9 Hz, 1F), -111.63 – -112.42 (m, 1F).

[0104] Embodiment 11

[0105] The synthesis of 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl 4-bromophenyl sulfide (3h) specifically comprises the following steps:

[0106] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 4-chlorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b).

[0107] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallyl 4-bromophenyl sulfide (1c), 1.4 mmol N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b), 0.002 mmol [Rh(OPiv)2]2, 2.0 mmol KOH, and 50 mmol DCE were added to the reactor at 100 o C for 3 hours to generate a mixed product.

[0108] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 442 mg of the product 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl 4-bromophenyl sulfide (3h) with a yield of 95%. The reaction equation is as follows.

[0109]

[0110] The NMR data of the compound are as follows:

[0111] 1 H NMR (500 MHz, CDCl3) δ 7.39 – 7.33 (m, 2H), 7.28 (s, 4H), 7.21 –7.16 (m, 2H), 6.20 (d, J = 2.7 Hz, 1H), 5.81 (d, J = 2.7 Hz, 1H), 4.70 (t, J = 15.0 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 134.95, 134.67, 133.40, 132.38,132.33, 130.94, 128.84, 123.53 (t, J = 6.4 Hz), 123.24 (d, J = 30.9 Hz),122.95, 118.51 (t, J = 251.2 Hz), 57.37 (t, J = 26.0 Hz); 19 F NMR (471 MHz, CDCl3) δ -99.58 (dd, J = 243.5, 15.4 Hz, 1F), -100.48 (dd, J = 243.5, 14.5Hz, 1F).

[0112] Example 12

[0113] The synthesis of 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl 4-tert-butylphenyl sulfide (3i) specifically comprises the following steps:

[0114] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 4-chlorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence.o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b).

[0115] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallyl 4-tert-butylphenyl sulfide (1d), 1.4 mmol N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b), 0.002 mmol [Rh(OPiv)2]2, 2.0 mmol NaOH and 30 mmol MeCN were added to the reactor and heated at 80 o C for 5 hours to generate a mixed product.

[0116] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 355 mg of the product 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl 4-tert-butylphenyl sulfide (3i) with a yield of 80%. The reaction equation is as follows.

[0117]

[0118] The NMR data of the compound are as follows:

[0119] 1 H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.6 Hz, 2H), 7.28 – 7.23 (m,6H), 6.20 (d, J = 2.6 Hz, 1H), 5.80 (d, J = 2.6 Hz, 1H), 4.70 (t, J = 15.3Hz, 1H), 1.27 (s, 9H); 13 C NMR (126 MHz, CDCl3) δ 151.78, 134.34, 134.13 (d, J = 2.6 Hz), 133.20, 131.04, 129.78, 128.66, 126.28, 123.80 (d, J = 31.0 Hz),123.37 (dd, J = 11.6, 5.2 Hz), 118.66 (t, J = 250.8 Hz), 57.43 (t, J= 25.9Hz), 34.73, 31.33; 19 F NMR (471 MHz, CDCl3) δ -98.93 (dd, J = 243.5, 15.0 Hz,1F), -100.80 (dd, J = 243.5, 15.3 Hz, 1F).

[0120] Example 13

[0121] The synthesis of 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl 4-methylphenyl sulfide (3j) specifically comprises the following steps:

[0122] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 4-chlorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b).

[0123] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallyl 4-methylphenyl sulfide (1e), 1.4 mmol N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b), 0.002 mmol [Rh(OAc)2]2, 1.5 mmol Cs2CO3, and 30 mmol THF were added to the reactor at 100 o C for 3 hours to generate a mixed product.

[0124] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 326 mg of the product 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl 4-methylphenyl sulfide (3j) with a yield of 81%. The reaction equation is as follows.

[0125]

[0126] The NMR data of the compound are as follows:

[0127] 1 H NMR (500 MHz, CDCl3) δ 7.27 (q, J = 8.8 Hz, 4H), 7.21 (d, J = 8.1Hz, 2H), 7.03 (d,J = 7.9 Hz, 2H), 6.21 (d, J = 2.6 Hz, 1H), 5.81 (d, J = 2.6Hz, 1H), 4.67 (t, J = 15.3 Hz, 1H), 2.29 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ138.75, 134.34, 134.01 (d, J = 2.6 Hz), 133.84, 131.03, 130.00, 129.54,128.66, 123.67, 123.35 (dd, J = 12.4, 6.0 Hz), 118.65 (t, J = 250.9 Hz),57.70 (t, J = 25.8 Hz), 21.28; 19 F NMR (471 MHz, CDCl3) δ -98.81 (dd, J =243.4, 14.9 Hz, 1F), -101.08 (dd, J = 243.4, 15.5 Hz, 1F).

[0128] Embodiment 14

[0129] The synthesis of 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl cyclohexyl sulfide (3k) specifically comprises the following steps:

[0130] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 4-chlorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b).

[0131] (2) Under Ar atmosphere, 1 mmol of 2-bromo-3,3-difluoroallylcyclohexyl sulfide (1f), 1.4 mmol N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b), 0.01 mmol Ru(PPh3)2Cl2, 2.0 mmol Cs2CO3, and 10 mmol PhMe were added to the reactor at 100 oC for 2 hours to generate a mixed product.

[0132] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 370 mg of the product 3-bromo-1-(4-chlorophenyl)-2,2-difluorobut-3-en-1-yl cyclohexyl sulfide (3k) with a yield of 94%. The reaction equation is as follows.

[0133]

[0134] The NMR data of the compound are as follows:

[0135] 1 H NMR (500 MHz, CDCl3) δ 7.38 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.6Hz, 2H), 6.16 (d, J = 2.3 Hz, 1H), 5.79 (d, J = 1.3 Hz, 1H), 4.53 (dd, J =15.7, 14.3 Hz, 1H), 2.69 – 2.50 (m, 1H), 1.94 (d, J = 11.5 Hz, 1H), 1.84 (d, J = 11.8 Hz, 1H), 1.77 – 1.64 (m, 2H), 1.55 (s, 1H), 1.27 (ddd, J = 27.2,21.7, 9.9 Hz, 5H); 13 C NMR (126 MHz, CDCl3) δ 134.60 (d, J = 2.7 Hz), 134.24,131.01, 128.70, 123.81 (t, J = 31.3 Hz), 123.10 (t, J = 6.4 Hz), 118.82 (t, J = 250.3 Hz), 50.76 (t, J = 26.2 Hz), 44.30, 33.43, 33.30, 25.94, 25.82,25.80; 19 F NMR (471 MHz, CDCl3) δ -98.26 (dd,J = 241.9, 13.8 Hz, 1F), -102.34(dd, J = 241.9, 15.8 Hz, 1F).

[0136] Embodiment 15

[0137] The synthesis of 2-3-bromo-1-(4-chlorophenyl)-2,2-difluoro-3-en-1-ylthiophene (3l) specifically comprises the following steps:

[0138] (1) In a beaker filled with methanol (1 mL of methanol is added for every 1 mmol of the reaction raw materials), add 1 part of 4-chlorobenzaldehyde and 1 part of p-toluenesulfonyl hydrazide in sequence. o C reacted for 15 minutes and then cooled to room temperature, and the solvent was removed by filtration to obtain the corresponding N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b).

[0139] (2) 1 mmol of 2-(2-bromo-3,3-difluoroallyl)thiophene (1j), 1.4 mmol N -(4-Chlorobenzylidene)-4-toluenesulfonylhydrazone (2b), 0.01 mmol Ru(PPh3)2Cl2, 2.0 mmol NaO t Bu and 10 mmol PhMe were added to the reactor at 90 o C for 3 hours to generate a mixed product.

[0140] (3) The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (200-300 mesh silica gel) using petroleum ether as the eluent to obtain 295 mg of the product 2-3-bromo-1-(4-chlorophenyl)-2,2-difluoro-3-en-1-ylthiothiophene (3l) with a yield of 75%. The reaction equation is as follows.

[0141]

[0142] The NMR data of the compound are as follows:

[0143] 1 H NMR (500 MHz, CDCl3) δ 7.34 (dd, J = 5.4, 1.2 Hz, 1H), 7.30 – 7.21(m, 4H), 7.00 (dd, J = 3.6, 1.2 Hz, 1H), 6.90 (dd, J= 5.4, 3.6 Hz, 1H), 6.22(d, J = 2.7 Hz, 1H), 5.82 (d, J = 2.6 Hz, 1H), 4.63 (t, J = 15.3 Hz, 1H); 13 CNMR (126 MHz, CDCl3) δ 136.65, 134.61, 133.29, 131.57, 131.02, 130.56,128.75, 127.71, 123.48 (t, J = 6.1 Hz), 123.44 (d, J = 61.7 Hz), 118.49 (t, J = 251.1 Hz), 59.60 (t, J = 25.7 Hz); 19 F NMR (471 MHz, CDCl3) δ -99.04 – -102.16 (m, 2F)。

Claims

1. A method for preparing a gem-difluoroallyl compound, characterized in that: The preparation method of the compound is selected from the following: ； ； ； ； ； ； ； ； ； ； ； ； 。

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