1-vinyl cyclobutene derivative as well as synthesis method and application thereof

Abstract

The invention relates to the technical field of organic synthesis, in particular to a 1-vinyl cyclobutene derivative, the structural formula of the 1-vinyl cyclobutene derivative is # imgabs0 #, in the formula, R1 is methoxy, ethyoxyl, trifluoroethyoxyl or phenyl; r2 is a methoxy group, an ethyoxyl group, a benzyloxy group, a tert-butoxy group, a trifluoromethoxy group, a menthol group, a perilla alcohol group or a cholesteryl group; and R3 is hydrogen atom, fluorine, chlorine, bromine, methyl, methoxyl, ethyl, ethoxyl, nitryl, methyl ester group, trifluoromethyl, cyclohexyl or morpholinyl. The 1-vinyl cyclobutene derivative is novel in structure, can be easily converted into other cyclobutene derivatives, modifies the structures of natural products such as cholesterol, menthol and perillyl alcohol, and has certain application value in the field of modification of natural products and drugs.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a vinylcyclobutene derivative and a synthesis method and application thereof. Background Art

[0002] Cyclobutene is a very common core skeleton in natural products and drug molecules, and is also an important pharmaceutical intermediate. The development of new strategies for the construction of cyclobutene skeletons not only enriches the foundation and content of synthetic methodology, but also has very important significance for the field of medicinal chemistry. The cyclobutene skeleton can be constructed by the ring-opening isomerization reaction of bicyclo[1.1.0]butane, or by the Alder-ene reaction of bicyclo[1.1.0]butane with a pro-site reagent. For example, in 2023. Tan Bin et al. reported the chiral phosphoric acid-catalyzed ring-opening isomerization reaction of aromatic bicyclo[1.1.0]butane, realizing the asymmetric construction of cyclobutene derivatives (Journal of the American Chemical Society 2023,145,39,21152-21158). In 2022, David C.Leitch et al. reported the gallium trifluoromethanesulfonate-catalyzed Alder-ene reaction of aromatic bicyclo[1.1.0]butane with imine for the construction of cyclobutene derivatives. In 2024, Edward A. Anderson, Akkattu T. Bij and others reported the Alder-ene reaction of aromatic bicyclo[1.1.0]butane with phenylacetylene precursors or alkenyldiazo compounds, achieving the efficient construction of a series of cyclobutene derivatives containing all-carbon quaternary carbon centers.

[0003] Although there are many methods for synthesizing cyclobutene compounds, most of the methods reported in the literature can only synthesize 1-aryl-substituted cyclobutene derivatives, and the scope of substrate application is limited. More importantly, there is currently no effective way to synthesize 1-vinylcyclobutene derivatives. Therefore, developing an efficient, highly selective, and substrate-adaptable method for synthesizing 1-vinylcyclobutene compounds is of great significance for the promotion and application of cyclobutene derivatives. Summary of the invention

[0004] In view of the above shortcomings, the present invention provides a 1-vinylcyclobutene derivative and a synthesis method thereof, which has the advantages of mild synthesis reaction conditions, safe and simple operation, high synthesis yield, good substrate adaptability, etc. The specific technical scheme is as follows:

[0005] A 1-vinylcyclobutene derivative, wherein the structural formula of the 1-vinylcyclobutene derivative is:

[0006]

[0007] Among them, R1 is methoxy, ethoxy, trifluoroethoxy or phenyl; R2 is methoxy, ethoxy, benzyloxy, tert-butoxy, trifluoromethoxy, menthol, perillyl alcohol or cholesterol; R3 is hydrogen atom, fluorine, chlorine, bromine, methyl, methoxy, ethyl, ethoxy, nitro, methyl ester, trifluoromethyl, cyclohexyl or morpholinyl.

[0008] A method for synthesizing the above-mentioned 1-vinylcyclobutene derivative comprises the following steps:

[0009] (1) Vinyl bicyclo[1.1.0]butane 1 and α-keto ester 2 are mixed in an organic solvent, palladium salt and phosphine ligand are added, stirred for reaction, extracted after the reaction is completed, and the organic phase is collected;

[0010] (2) drying and concentrating the organic phase obtained in step (1) under reduced pressure to separate and obtain a 1-vinylcyclobutene derivative;

[0011] The synthetic route of the 1-vinylcyclobutene derivative is as follows:

[0012]

[0013] Preferably, in the above-mentioned method for synthesizing 1-vinylcyclobutene derivatives, the reaction temperature is 15 to 30° C., and the reaction time is 10 to 15 hours.

[0014] Preferably, in the above-mentioned method for synthesizing vinylcyclobutene derivatives, the organic solvent is dichloromethane, 1,2-dichloroethane, chloroform, acetone, acetonitrile or toluene.

[0015] Preferably, in the above-mentioned method for synthesizing vinylcyclobutene derivatives, the organic solvent is dichloromethane or 1,2-dichloroethane.

[0016] Preferably, in the above-mentioned method for synthesizing vinylcyclobutene derivatives, the metal catalyst / ligand system is that the palladium salt is Pd(OAc)2, Pd2(dba)3 or PdCl2.

[0017] Preferably, in the above-mentioned method for synthesizing vinylcyclobutene derivatives, the ligand is Xantphos or DPEphos.

[0018] Preferably, in the above-mentioned method for synthesizing vinylcyclobutene derivatives, the palladium salt is Pd(OAc)2, and the phosphine ligand is Xantphos.

[0019] Preferably, in the above-mentioned synthesis method of vinylcyclobutene derivatives, the molar ratio of the vinyl bicyclo[1.1.0]butane to the α-ketoester is 1.5-2.0:1, the molar amount of the palladium salt is 3-8% of the molar amount of the vinyl bicyclo[1.1.0]butane, and the molar amount of the phosphine ligand is 5-10% of the molar amount of the vinyl bicyclo[1.1.0]butane.

[0020] Preferably, in the above-mentioned synthesis method of vinylcyclobutene derivatives, the extraction is extraction with ethyl acetate; the separation is performed by silica gel column chromatography, the eluent in the silica gel column chromatography is petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 19:1 to 9:1.

[0021] On the other hand, the present application also provides the use of the above-mentioned 1-vinylcyclobutene derivatives in the structural modification of natural products such as cholesterol, menthol and perillyl alcohol.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The 1-vinylcyclobutene derivative of the present invention has a novel structure and can be easily converted into other cyclobutene derivatives, and can modify the structures of natural products such as cholesterol, menthol and perillyl alcohol, and has certain application value in the field of natural product and drug modification.

[0024] 2. The method for synthesizing 1-vinylcyclobutene derivatives of the present invention realizes the Alder-Ene reaction of vinyl bicyclo[1.1.0]butane and α-keto ester through a palladium salt / phosphine ligand system to synthesize 1-vinylcyclobutene derivatives containing two adjacent quaternary carbon centers. The synthetic reaction conditions are mild, the operation is safe and simple, the synthetic route is short, the synthetic yield is high, and the substrate adaptability is good, and it can be applied to the synthesis of 1-vinylcyclobutene derivatives with different substitutions. DETAILED DESCRIPTION

[0025] The specific embodiments of the present invention are described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments. Unless otherwise defined, all professional terms used hereinafter have the same meaning as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the protection scope of the present invention. Unless otherwise specifically stated, various raw materials, reagents, instruments and equipment used in the present invention, etc. can be purchased from the market or can be prepared by existing methods.

[0026] Example 1

[0027] A 1-vinylcyclobutene derivative, having the structural formula:

[0028]

[0029] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0030]

[0031] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment specifically comprises the following steps:

[0032] (1) The scope and Limitation of Useful Building Blocks for Medicinal will be determined in accordance with the literature (Ma, Chemists. Eur. J. Org. Chem. 2020, 2020, (29), 4581-4605) prepared vinyl bicyclo [1.1.0] butane 1a (0.2 mmol, 2.0 equivalents) and methyl benzoylformate 2a (0.1 mmol, 1.0 equivalents) were added to a reaction flask, dissolved with dichloromethane (1.0 mL), and Pd (OAc) 2 (0.01 mmol) and Xantphos (0.012 mmol) were added respectively. Argon was filled for protection, and the reactants were stirred at room temperature for 12 hours; the mixture was diluted with brine (2.0 mL), extracted with ethyl acetate (2.0 mL × 2), and the organic phase was collected;

[0033] (2) The organic phase was dried, concentrated under reduced pressure, and purified and separated using silica gel chromatography (petroleum ether: ethyl acetate 9:1) to obtain 1-vinylcyclobutene derivative 3a with a yield of 95% (0.095 mmol).

[0034] The nuclear magnetic resonance data of the 1-vinylcyclobutene derivative 3a in this example are:

[0035] 1 H NMR (400MHz, CDCl3) δ7.48–7.46(m,2H),7.22–7.19(m,3H),6.07(dd,J=17.6,10.8Hz,1H),5.92(s,1H),4.99–4.90(m,2 H),4.39(s,1H),4.13–4.07(m,2H),3.79(s,3H),2.82(d,J=13.6Hz,1H),2.56(d,J=13.6Hz,1H),1.16(t,J=7.2Hz,3H).

[0036] 13 C NMR (100MHz, CDCl3) δ173.9,173.1,146.8,136.4,129.1,127.5,127.1,126.4,125.8,116.6,80.3,60.4,56.8,51.8,34.2,13.0.

[0037] HRMS (TOF-ESI + )m / z:calcd for C 18 H 20 O5Na[M+Na] + 339.1203, found 339.1221.

[0038] Example 2

[0039] A 1-vinylcyclobutene derivative, having the structural formula:

[0040]

[0041] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0042]

[0043] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), vinyl bicyclo[1.1.0]butane 1b (0.1 mmol, 1.0 equivalent) is used to replace vinyl bicyclo[1.1.0]butane 1a to obtain vinyl cyclobutene derivative 3b with a yield of 65% (0.065 mmol).

[0044] The NMR data of the vinylcyclobutene derivative 3b in this example are:

[0045] 1 H NMR (400MHz, CDCl3) δ7.48–7.45(m,2H),7.22–7.18(m,3H),6.06(dd,J=17.6,10.8Hz,1H),5.92(s,1H),5 .00–4.90(m,2H),4.33(s,1H),3.80(s,3H),3.64(s,3H),2.82(d,J=13.6Hz,1H),2.57(d,J=13.6Hz,1H).

[0046] 13C NMR (100MHz, CDCl3) δ174.5,173.1,146.9,136.2,129.1,127.4,127.2,126.4,125.8,116.8,80.3,56.8,51.8,51.5,34.3.

[0047] HRMS (TOF-ESI + )m / z:calcd for C 17 H 18 O5Na[M+Na] + 325.1046, found 325.1054.

[0048] Example 3

[0049] A 1-vinylcyclobutene derivative, having the structural formula:

[0050]

[0051] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0052]

[0053] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that: in step (1), vinyl bicyclo[1.1.0]butane 1c (0.1 mmol, 1.0 equivalent) is used to replace vinyl bicyclo[1.1.0]butane 1a to obtain vinyl cyclobutene derivative 3c with a yield of 55% (0.055 mmol).

[0054] The nuclear magnetic resonance data of the 1-vinylcyclobutene derivative 3c in this example are:

[0055] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=7.6Hz,2H),7.55–7.53(m,2H),7.39(t,J=7.2Hz,1H),7.28(t,J=8.0Hz,2H),7.22–7.19(m,3H ),6.10–6.01(m,2H),4.97(d,J=10.4Hz,1H),4.86(d,J=16.8Hz,1H),4.44(s,1H),3.84(s,3H),2.76(dd,J=23.2,14.4Hz,2H).

[0056] 13C NMR (100MHz, CDCl3) δ205.9,173.3,147.4,137.8,136.6,130.6,128.9,128 .8,127.1,127.0,126.9,126.4,126.0,117.2,81.1,62.7,51.9,35.6,28.7.

[0057] HRMS (TOF-ESI + )m / z:calcd for C 22 H 20 O4Na[M+Na] + 371.1254, found 371.1263.

[0058] Example 4

[0059] A 1-vinylcyclobutene derivative, having the structural formula:

[0060]

[0061] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0062]

[0063] The synthesis method of the 1-vinylcyclobutene derivative of this example is the same as that of Example 1, except that in step (1), vinyl bicyclo[1.1.0]butane 1d (0.1 mmol, 1.0 equivalent) is used to replace vinyl bicyclo[1.1.0]butane 1a to obtain vinyl cyclobutene derivative 3d with a yield of 51% (0.051 mmol).

[0064] The 3d NMR data of the 1-vinylcyclobutene derivative of this example are:

[0065] 1 H NMR(400MHz, CDCl3) δ7.48(dd,J=6.8,3.6Hz,2H),7.23–7.19(m,3H),6.07(dd,J=17.2,10.4Hz,1H),5.90(s,1H) ,5.03–4.92(m,2H),4.47–4.37(m,2H),4.01(s,1H),3.83(s,3H),2.81(d,J=14.0Hz,1H),2.67(d,J=13.6Hz,1H).

[0066] 13C NMR (100MHz, CDCl3) δ172.8,171.9,146.9,136.2,128.9,127.4,126.7,126.6,125.6,117.2,79.8,59.9,59.6,56.6,52.0,34.5,28.7.

[0067] 19 F NMR(376MHz, CDCl3)δ-73.7(s).

[0068] HRMS (TOF-ESI + )m / z:calcd for C 18 H 17 F3O5Na[M+Na] + 393.0920, found 393.0929.

[0069] Example 5

[0070] A 1-vinylcyclobutene derivative, having the structural formula:

[0071]

[0072] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0073]

[0074] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), 4-chlorobenzoylformic acid methyl ester 2b (0.1 mmol, 1.0 equivalent) is used to replace benzoylformic acid methyl ester 2a to obtain 4-chlorovinylcyclobutene derivative 3e with a yield of 81% (0.081 mmol).

[0075] The nuclear magnetic resonance data of the 1-vinylcyclobutene derivative 3e in this example are:

[0076] 1 H NMR (400MHz, CDCl3) δ7.44–7.40(m,2H),7.19–7.16(m,2H),6.08(dd,J=17.6,10.8Hz,1H),5.89(s,1H),5.04–4.93(m,2 H),4.40(s,1H),4.13–4.07(m,2H),3.79(s,3H),2.83(d,J=14.0Hz,1H),2.51(d,J=13.6Hz,1H),1.16(t,J=7.2Hz,3H).

[0077] 13C NMR (100MHz, CDCl3) δ173.7,172.8,147.1,135.0,133.2,129.0,127.3,127.1,126.6,117.0,79.8,60.5,56.7,51.9,34.2,13.0.

[0078] HRMS (TOF-ESI + )m / z:calcd for C 18 H 19 ClO5Na[M+Na] + 373.0813, found 373.0820.

[0079] Example 6

[0080] A 1-vinylcyclobutene derivative, having the structural formula:

[0081]

[0082] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0083]

[0084] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), 4-bromobenzoylformate methyl ester 2c (0.1 mmol, 1.0 equivalent) is used to replace benzoylformate methyl ester 2a to obtain 4-bromovinylcyclobutene derivative 3f with a yield of 86% (0.086 mmol).

[0085] The 3f NMR data of the 1-vinylcyclobutene derivative of this example are:

[0086] 1 H NMR (400MHz, CDCl3) δ7.37–7.32(m,4H),6.09(dd,J=17.2,10.4Hz,1H),5.89(s,1H),5.04–4.93(m,2H),4.39( s,1H),4.12–4.09(m,2H),3.79(s,3H),2.83(d,J=13.6Hz,1H),2.51(d,J=14.0Hz,1H),1.16(t,J=7.2Hz,3H).

[0087] 13C NMR (100MHz, CDCl3) δ173.6,172.7,147.1,135.5,129.5,129.0,127.6,127.1,121.4,117.1,79.9,60.5,56.7,52.0,34.2,13.0.

[0088] HRMS (TOF-ESI + )m / z:calcd for C 18 H 19 BrO5Na[M+Na] + 417.0308, found 417.0317.

[0089] Example 7

[0090] A 1-vinylcyclobutene derivative, having the structural formula:

[0091]

[0092] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0093]

[0094] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), 4-methylbenzoylformate 2d (0.1 mmol, 1.0 equivalent) is used to replace methyl benzoylformate 2a to obtain 4-methylvinylcyclobutene derivative 3g with a yield of 76% (0.076 mmol).

[0095] The nuclear magnetic resonance data of 3g of the 1-vinylcyclobutene derivative of this example are:

[0096] 1 H NMR (400MHz, CDCl3) δ7.34(d,J=8.0Hz,2H),7.00(d,J=8.0Hz,2H),6.09(dd,J=17.6,10.4Hz,1H),5.92(s,1H),5.01–4.91(m,2H) ,4.32(s,1H),4.12–4.07(m,2H),3.78(s,3H),2.81(d,J=13.6Hz,1H),2.57(d,J=13.6Hz,1H),2.23(s,3H),1.16(t,J=7.2Hz,3H).

[0097] 13C NMR (100MHz, CDCl3) δ173.9,173.2,146.8,136.8,133.5,129.2,127.6,127.1,125.6,116.5,80.2,60.4,56.8,51.7,34.2,20.0,13.0.

[0098] HRMS (TOF-ESI + )m / z:calcd for C 19 H 22 O5Na[M+Na] + 353.1359, found 353.1367.

[0099] Example 8

[0100] A 1-vinylcyclobutene derivative, having the structural formula:

[0101]

[0102] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0103]

[0104] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), 4-nitrobenzoylformic acid methyl ester 2e (0.1 mmol, 1.0 equivalent) is used to replace benzoylformic acid methyl ester 2a to obtain 4-nitrovinylcyclobutene derivative 3h with a yield of 75% (0.075 mmol).

[0105] The 3h NMR data of the 1-vinylcyclobutene derivative of this example are:

[0106] 1 H NMR (400MHz, CDCl3) δ8.08–8.06(m,2H),7.71–7.69(m,2H),6.06(dd,J=17.2,10.4Hz,1H),5.90(s,1H),5.05–4.93(m,2 H),4.52(s,1H),4.15–4.09(m,2H),3.83(s,3H),2.87(d,J=13.6Hz,1H),2.51(d,J=13.6Hz,1H),1.17(t,J=7.2Hz,3H).

[0107] 13C NMR (100MHz, CDCl3) δ173.3,172.2,147.5,146.7,143.5,128.8,127.0,126.8,121.5,117.5,79.9,60.8,56.7,52.3,34.2,13.0.

[0108] HRMS (TOF-ESI + )m / z:calcd for C 18 H 19 NO7Na[M+Na] + 384.1054, found 384.1062.

[0109] Example 9

[0110] A 1-vinylcyclobutene derivative, having the structural formula:

[0111]

[0112] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0113]

[0114] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), 4-methylbenzoylmethyl benzoate 2f (0.1 mmol, 1.0 equivalent) is used to replace methyl benzoylformate 2a to obtain 4-methylbenzoyl vinylcyclobutene derivative 3i with a yield of 80% (0.080 mmol).

[0115] The nuclear magnetic resonance data of the 1-vinylcyclobutene derivative 3i in this example are:

[0116] 1 H NMR (400MHz, CDCl3) δ7.89–7.86(m,2H),7.58–7.55(m,2H),6.05(dd,J=17.2,10.4Hz,1H),5.90(s,1H),5.01–4.90(m,2H),4 .47(s,1H),4.14–4.08(m,2H),3.82(d,J=7.6Hz,6H),2.84(d,J=13.6Hz,1H),2.53(d,J=13.6Hz,1H),1.16(t,J=7.2Hz,3H).

[0117] 13C NMR (100MHz, CDCl3) δ173.6,172.6,165.8,147.1,141.4,128.9,128.8,127.6,127.1,125.9,117.1,80.2,60.6,56.7,52.0,51.1,34.2,13.0.

[0118] HRMS (TOF-ESI + )m / z:calcd for C 20 H 22 O7Na[M+Na] + 397.1258, found 397.1267.

[0119] Example 10

[0120] A 1-vinylcyclobutene derivative, having the structural formula:

[0121]

[0122] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0123]

[0124] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), 2 g (0.1 mmol, 1.0 equivalent) of 4-cyclohexylbenzoylformate is used to replace methyl benzoylformate 2a to obtain 4-cyclohexylvinylcyclobutene derivative 3j with a yield of 86% (0.086 mmol).

[0125] The nuclear magnetic resonance data of the 1-vinylcyclobutene derivative 3j in this example are:

[0126] 1 H NMR (400MHz, CDCl3) δ7.36(d,J=8.4Hz,2H),7.03(d,J=8.0Hz,2H),6.08(dd,J =17.6,10.4Hz,1H),5.92(s,1H),4.99–4.89(m,2H),4.31(s,1H),4.08(dd,J=1 3.2,6.8Hz,2H),3.77(s,3H),2.80(d,J=13.6Hz,1H),2.57(d,J=13.6Hz,1H), 2.38(s,1H),1.76–1.57(m,6H),1.29(t,J=10.8Hz,4H),1.14(t,J=7.2Hz,3H).

[0127] 13C NMR (100MHz, CDCl3) δ173.9,173.2,146.9,146.8,133.8,129.2,127.6,125. 7,124.8,116.4,80.2,60.3,56.9,51.7,43.1,34.3,33.3,25.8,25.1,13.0.

[0128] HRMS (TOF-ESI + )m / z:calcd for C 24 H 30 O5Na[M+Na] + 421.1985, found 421.1991.

[0129] Embodiment 11

[0130] A 1-vinylcyclobutene derivative, having the structural formula:

[0131]

[0132] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0133]

[0134] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that: in step (1), 4-morpholinylbenzoylformic acid methyl ester 2h (0.1 mmol, 1.0 equivalent) is used to replace benzoylformic acid methyl ester 2a to obtain 4-morpholinylvinylcyclobutene derivative 3k with a yield of 55% (0.055 mmol).

[0135] The 3k nuclear magnetic resonance data of the 1-vinylcyclobutene derivative of this example are:

[0136] 1 H NMR (400MHz, CDCl3) δ7.70 (d, J=2.0Hz, 1H), 7.38 (dd, J=8.4, 2.4Hz, 1H), 7.19 ( s,1H),6.87(d,J=8.4Hz,1H),6.11(dd,J=17.2,10.4Hz,1H),5.91(s,1H),5.05 –4.95(m,2H),4.34(s,1H),4.10(q,J=6.8Hz,2H),3.80–3.78(m,7H),2.98–2.9 2(m,4H),2.82(d,J=13.6Hz,1H),2.55(d,J=13.6Hz,1H),1.16(t,J=7.2Hz,3H).

[0137] 13 C NMR (100MHz, CDCl3) δ173.6,172.7,149.0,147.2,132.8,131.5,129.1,127.2,1 25.8,118.4,117.7,116.9,79.4,66.1,60.5,56.9,52.0,50.9,34.2,28.7,13.0.

[0138] HRMS (TOF-ESI + )m / z:calcd for C 22 H 27 NO6Na[M+Na] + 424.1731, found 424.1732.

[0139] Example 12

[0140] A 1-vinylcyclobutene derivative, having the structural formula:

[0141]

[0142] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0143]

[0144] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that: in step (1), 3-trifluoromethylbenzoylformate methyl ester 2i (0.1 mmol, 1.0 equivalent) is used to replace benzoylformate methyl ester 2a to obtain 3-trifluoromethylvinylcyclobutene derivative 3l with a yield of 53% (0.053 mmol).

[0145] The nuclear magnetic resonance data of the 1-vinylcyclobutene derivative 31 in this example are:

[0146] 1 H NMR (400MHz, CDCl3) δ7.79(s,1H),7.67(d,J=7.6Hz,1H),7.48(d,J=8.0Hz,1H),7.34(t,J=8.0Hz,1H),6.06(dd,J=17.6,10.8Hz,1H),5.90(s ,1H),5.03–4.91(m,2H),4.46(s,1H),4.13–4.08(m,2H),3.82(s,3H),2.85(d,J=13.3Hz,1H),2.49(d,J=13.6Hz,1H),1.16(t,J=7.2Hz,3H).

[0147] 13 C NMR (100MHz, CDCl3) δ173.4,172.5,147.3,137.5,129.0(d,J c-f =17.4Hz),126.9(d,J c-f =17.6Hz),124.0(d,J c-f =3.7Hz),122.9(d,J c-f =3.8Hz),117.1,79.9,60.6,56.7,52.1,34.2,13.0.

[0148] 19 F NMR(376MHz, CDCl3)δ-62.7(s).

[0149] HRMS (TOF-ESI + )m / z:calcd for C 19 H 19 F3O5Na[M+Na] + 407.1077, found 407.1085.

[0150] Embodiment 13

[0151] A 1-vinylcyclobutene derivative, having the structural formula:

[0152]

[0153] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0154]

[0155] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that: in step (1), 3-methoxybenzoylformic acid methyl ester 2j (0.1 mmol, 1.0 equivalent) is used to replace benzoylformic acid methyl ester 2a to obtain 3-methoxyvinylcyclobutene derivative 3m with a yield of 72% (0.072 mmol).

[0156] The 3m NMR data of the 1-vinylcyclobutene derivative of this example are:

[0157] 1H NMR (400MHz, CDCl3) δ7.19–7.02(m,4H),6.76–6.74(m,1H),6.10(dd,J=17.2,10.4Hz,1H),5.91(s,1H),5.02–4.93(m,2H),4. 38(s,1H),4.13–4.07(m,2H),3.79(s,3H),3.72(s,3H),2.81(d,J=13.6Hz,1H),2.65(d,J=13.6Hz,1H),1.16(t,J=7.2Hz,3H).

[0158] 13 C NMR (100MHz, CDCl3) δ173.8,173.0,157.8,146.8,138.1,129.2,127.6,12 7.3,118.2,116.7,112.5,112.1,80.1,60.4,56.8,54.3,51.8,34.3,13.0.

[0159] HRMS (TOF-ESI + )m / z:calcd for C 19 H 22 O6Na[M+Na] + 369.1309, found 353.1318.

[0160] Embodiment 14

[0161] A 1-vinylcyclobutene derivative, having the structural formula:

[0162]

[0163] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0164]

[0165] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that: in step (1), 3,5-difluorobenzoylformic acid methyl ester 2k (0.1 mmol, 1.0 equivalent) is used to replace benzoylformic acid methyl ester 2a to obtain 3,5-difluorovinylcyclobutene derivative 3n with a yield of 79% (0.079 mmol).

[0166] The 3n nuclear magnetic resonance data of the 1-vinylcyclobutene derivative of this example are:

[0167] 1H NMR (400MHz, CDCl3) δ7.08–7.03(m,2H),6.69–6.64(m,1H),6.11(dd,J=17.2,10.4Hz,1H),5.87(s,1H),5.07–4.98(m,2H ), 4.40 (s, 1H), 4.10 (q, J = 7.2Hz, 2H), 3.81 (s, 3H), 2.83 (d, J = 13.6Hz, 1H), 2.61 (d, J = 13.6Hz, 1H), 1.16 (t, J = 7.2Hz, 3H).

[0168] 13 C NMR(100MHz,CDCl3)δ173.2,172.2,162.4(d,J c-f =12.7Hz),159.9(d,J c-f =12.5Hz),147.2,140.6(t,J c-f =9.0Hz),129.0,127.0,117.2,109.3(dd,J=19.3,7.3Hz),102.9,102.7,102.4,79.5(d,J c-f =2.1Hz),60.6,56.7,52.2,34.2,13.0.

[0169] 19 F NMR(376MHz, CDCl3)δ-110.0(s).

[0170] HRMS (TOF-ESI + )m / z:calcd for C 18 H 18 F2O5Na[M+Na] + 375.1015, found 375.1025.

[0171] Embodiment 15

[0172] A 1-vinylcyclobutene derivative, having the structural formula:

[0173]

[0174] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0175]

[0176] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that: in step (1), benzyl benzoylformate 21 (0.1 mmol, 1.0 equivalent) is used to replace methyl benzoylformate 2a to obtain benzyl vinylcyclobutene derivative 3o with a yield of 87% (0.087 mmol).

[0177] The 3o NMR data of the 1-vinylcyclobutene derivative of this example are:

[0178] 1 H NMR (400MHz, CDCl3) δ7.44–7.42(m,2H),7.31–7.25(m,5H),7.18–7.14(m,3H),6.04(dd,J=17.2,10.4Hz,1H),5.91(s,1H),5.22( s,2H),4.97–4.86(m,2H),4.41(s,1H),4.07–3.99(m,2H),2.79(d,J=13.6Hz,1H),2.52(d,J=13.6Hz,1H),1.10(t,J=7.2Hz,3H).

[0179] 13 C NMR (100MHz, CDCl3) δ173.7,172.5,146.8,136.4,134.2,129.1,127.5,127.4,127.1,126.3,125.8,116.6,80.2,66.8,60.4,56.8,34.3,12.9.

[0180] HRMS (TOF-ESI + )m / z:calcd for C 24 H 24 O5Na[M+Na] + 415.1516, found 415.1524.

[0181] Example 16

[0182] A 1-vinylcyclobutene derivative, having the structural formula:

[0183]

[0184] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0185]

[0186] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), tert-butyl benzoylformate 2m (0.1 mmol, 1.0 equivalent) is used to replace methyl benzoylformate 2a to obtain the benzyl ester vinylcyclobutene derivative 3p with a yield of 86% (0.086 mmol).

[0187] The 3p nuclear magnetic resonance data of the 1-vinylcyclobutene derivative of this example are:

[0188] 1 H NMR (400MHz, CDCl3) δ7.54–7.52(m,2H),7.22–7.19(m,3H),6.08(dd,J=17.6,10.8Hz,1H),5.93(s,1H),5.00–4.90(m,2 H),4.30(s,1H),4.12–4.03(m,2H),2.80(d,J=13.6Hz,1H),2.56(d,J=13.6Hz,1H),1.48(s,9H),1.13(t,J=6.8Hz,3H).

[0189] 13 C NMR (100MHz, CDCl3) δ173.3,171.5,146.4,137.3,129.3,128.2,126.8,126.3,125.8,116.3,82.2,79.7,60.1,56.9,34.4,26.9,13.0.

[0190] HRMS (TOF-ESI + )m / z:calcd for C 21 H 26 O5Na[M+Na] + 381.1672, found 381.1679.

[0191] Embodiment 17

[0192] A 1-vinylcyclobutene derivative, having the structural formula:

[0193]

[0194] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0195]

[0196] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), trifluoroethyl benzoylformate 2n (0.1 mmol, 1.0 equivalent) is used to replace methyl benzoylformate 2a to obtain trifluoroethanol ester vinylcyclobutene derivative 3q with a yield of 89% (0.089 mmol).

[0197] The 3q NMR data of the 1-vinylcyclobutene derivative of this example are:

[0198] 1 H NMR (400MHz, CDCl3) δ7.53–7.51(m,2H),7.30–7.28(m,3H),6.15(dd,J=17.6,10.8Hz,1H),5.99(s,1H),5.10–5.00(m,2H) ,4.68–4.58(m,2H),4.38(s,1H),4.22–4.13(m,2H),2.88(d,J=13.6Hz,1H),2.62(d,J=14.0Hz,1H),1.23(t,J=7.2Hz,3H).

[0199] 13 C NMR (100MHz, CDCl3) δ173.9,171.3,147.1,135.6,129.0,127.5,127.0,126.5,125.6,117.0,80.4,60.7,60.6,60.2,56.7,34.1,12.9.

[0200] 19 F NMR(377MHz, CDCl3)δ-73.3(s).

[0201] HRMS (TOF-ESI + )m / z:calcd for C 19 H 19 F3O5Na[M+Na] + 407.1077, found 407.1086.

[0202] Embodiment 18

[0203] A 1-vinylcyclobutene derivative, having the structural formula:

[0204]

[0205] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0206]

[0207] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), L-menthol benzoylformate 2o (0.1 mmol, 1.0 equivalent) is used to replace methyl benzoylformate 2a to obtain L-menthol ester vinylcyclobutene derivative 3r with a yield of 86% (0.086 mmol).

[0208] The 3r nuclear magnetic resonance data of the 1-vinylcyclobutene derivative of this example are:

[0209] 1 H NMR (400MHz, CDCl3) δ7.51–7.43(m,2H),7.19–7.18(m,3H),6.10–6.03(m ,1H),5.94(d,J=20.0Hz,1H),5.02–4.90(m,2H),4.80–4.72(m,1H),4.12– 4.04(m,2H),2.90–2.82(m,1H),2.60–2.52(m,1H),2.01–1.94(m,1H),1.6 3–1.60(m,2H),1.43–1.37(m,2H),1.22–1.10(m,5H),0.85–0.64(m,12H).

[0210] 13 C NMR (100MHz, CDCl3) δ174.0,172.1,146.9,136.9,136.6,129.2,127.9(d,J=12.4Hz),127.0,126.2(d,J=11.5Hz),125.8(d,J=2.5Hz),116.6( d,J=18.8Hz),80.6,80.1,75.5,60.3,56.8,45.9,39.5,34.2,33.2,30 .5(d,J=6.9Hz),24.7,24.4,21.9,21.0,19.8,14.7,13.0(d,J=3.0Hz).

[0211] HRMS (TOF-ESI + )m / z:calcd for C 27 H 36 O5Na[M+Na] + 463.2455, found 463.2465.

[0212] Embodiment 19

[0213] A 1-vinylcyclobutene derivative, having the structural formula:

[0214]

[0215] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0216]

[0217] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), benzoylformic acid perillyl alcohol ester 2p (0.1 mmol, 1.0 equivalent) is used to replace benzoylformic acid methyl ester 2a to obtain perillyl alcohol ester vinylcyclobutene derivative 3s with a yield of 71% (0.071 mmol).

[0218] The 3s NMR data of the vinylcyclobutene derivative of this example are:

[0219] 1 H NMR (400MHz, CDCl3) δ7.49–7.46(m,2H),7.21–7.19(m,3H),6.08(dd,J=17.6,10.8Hz,1 H),5.94(s,1H),5.75(s,1H),5.00–4.90(m,2H),4.67–4.58(m,4H),4.39(d,J=6.8Hz,1 H),4.13–4.05(m,2H),2.82(dd,J=14.0,2.4Hz,1H),2.55(dd,J=13.6,1.6Hz,1H),2.12 –1.90(m,5H),1.79–1.75(m,1H),1.67(s,3H),1.45–1.38(m,1H),1.15(t,J=7.2Hz,3H).

[0220] 13 C NMR (100MHz, CDCl3) δ173.8,172.6,148.5,148.4,146.8,146.7,136.7,136.6,131.0,129.2,127.7, 127.1,126.3,125.8,116.6,107.8,80.2,69.2,60.4,56.8,39.7,34.3,29.5,26.3,25.5,19.8,13.0.

[0221] HRMS (TOF-ESI + )m / z:calcd for C 27 H 32 O5Na[M+Na] + 459.2142, found 459.2152.

[0222] Embodiment 20

[0223] A 1-vinylcyclobutene derivative, having the structural formula:

[0224]

[0225] The synthesis route of the 1-vinylcyclobutene derivative of this embodiment is:

[0226]

[0227] The synthesis method of the 1-vinylcyclobutene derivative of this embodiment is the same as that of Example 1, except that in step (1), cholesterol benzoylformate 2q (0.1 mmol, 1.0 equivalent) is used to replace methyl benzoylformate 2a to obtain cholesterol ester vinylcyclobutene derivative 3t with a yield of 79% (0.079 mmol).

[0228] The 3t nuclear magnetic resonance data of the 1-vinylcyclobutene derivative of this example are:

[0229] 1 H NMR(400MHz, CDCl3)δ7.52–7.48(m,2H),7.21–7.18(m,3H),6.07(dd,J=17.2,10.4Hz,1H),5.93 (s,1H),5.33(d,J=2.4Hz,1H),4.99–4.90(m,2H),4.76–4.71(m,1H),4.37(s,1H),4.12–4.06(m ,2H),2.82(d,J=13.6Hz,1H),2.56(dd,J=13.6,2.0Hz,1H),2.41–2.28(m,2H),1.97–1.72(m,6H ),1.55–1.23(m,11H),1.20–1.05(m,11H),0.99–0.94(m,5H),0.86–0.78(m,10H),0.61(s,3H).

[0230] 13C NMR (100MHz, CDCl3) δ173.6(d,J=2.9Hz), 172.0(d,J=1.5Hz), 146.7(d,J=2.9Hz), 138.3(d,J=2.8Hz), 136.8(d,J=1.3Hz),129.2,127.8,127.0,126.3,125.8,122.0(d,J=2.1Hz),116.5,79.9(d,J=1.3Hz), 75.1,60.3,56.9,55.7,55.1,49.0,41.3,38.7,38.5,37.0,36.8,35.9(d,J=2.8Hz),35.6,35.2,34.8, 34.4,30.9(d,J=5.5Hz),27.2,27.0,26.8,26.5,23.3,22.8,21.8,21.6,20.0,18.3,17.7,13.0,10.9.

[0231] HRMS (TOF-ESI + )m / z:calcd for C 44 H 64 O5Na[M+Na] + 695.4946, found 695.4955.

[0232] The synthetic routes of Examples 21 to 27 and Comparative Examples 1 to 7 are:

[0233]

[0234] The difference between Examples 21 to 25 and Comparative Examples 1 to 5 and Example 1 is that the catalyst and the ligand are different or the organic solvent is different. The specific information of the catalyst, the ligand and the organic solvent is shown in Table 1. The yield of the obtained vinylcyclobutene derivative is shown in Table 1. It can be seen from Table 1 that the catalyst, the ligand and the organic solvent will affect the progress of the synthesis reaction and the yield of the vinylcyclobutene derivative.

[0235] Table 1 Catalysts, ligands, organic solvents and yield data of Examples 21 to 25 and Comparative Examples 1 to 5

[0236]

[0237]

[0238] Application Example 1

[0239] A dibromocyclobutene derivative, the structural formula is:

[0240]

[0241] The synthesis route of the dibromocyclobutene derivative of this application example is:

[0242]

[0243] The synthesis method of the dibromocyclobutene derivative of this application example specifically comprises the following steps:

[0244] S1. Add vinylcyclobutene derivative 3a (0.1 mmol, 1.0 equivalent) and tribromopyridinium salt (0.11 mmol, 1.1 equivalent) into a reaction flask, dissolve with dichloroethane (1.0 mL), and stir the reactants at room temperature for 12 hours; dilute the mixture with brine (2.0 mL), and extract with ethyl acetate (2.0 mL×2), and collect the organic phase;

[0245] S2. The organic phase was dried, concentrated under reduced pressure, and purified and separated using silica gel chromatography (petroleum ether: ethyl acetate 19: 1) to obtain a dibromocyclobutene derivative 4 with a yield of 66% (0.066 mmol).

[0246] The nuclear magnetic resonance data of the dibromocyclobutene derivative 4 of this embodiment are:

[0247] 1 H NMR (400MHz, CDCl3) δ7.48–7.45(m,2H),7.24–7.19(m,3H),6.15(s,1H),7.41–7.30(m,2H),4.16–4.06(m,2H),3.82(s,3H) ),3.50–7.38(m,1H),3.31–3.18(m,1H),2.83(dd,J=14.0,4.0Hz,1H),2.61(d,J=13.6Hz,1H),1.19(td,J=7.2,1.2Hz,3H).

[0248] 13 C NMR (100MHz, CDCl3) δ173.2,172.9,146.0,145.9,135.9,138.8,131.7,131.3,127.4,126 .7,126.6,125.8,80.0,79.9,60.6,56.2,56.0,51.9,43.3,42.8,35.1,34.9,30.5,13.0.

[0249] HRMS (TOF-ESI + )m / z:calcd for C 18 H 20 Br2O5SNa[M+Na] +496.9570 found 496.9577.

[0250] Application Example 2

[0251] An alkenyl cyclobutene derivative, having the structural formula:

[0252]

[0253] The synthesis route of the alkenyl cyclobutene derivatives of this application example is:

[0254]

[0255] The synthesis method of the alkenylcyclobutene derivative of this application example specifically comprises the following steps:

[0256] S1. Alkenylcyclobutene derivative 3a (0.1 mmol, 1.0 equivalent), methyl acrylate (1.0 mmol, 10 equivalents) and Grubbs 2 nd Gen catalyst (0.005 mmol, 5 mol%) was added to the reaction flask, dissolved with dichloromethane (1.0 mL), and the reactants were stirred at room temperature for 12 hours; the mixture was diluted with brine (2.0 mL), and extracted with ethyl acetate (2.0 mL×2), and the organic phase was collected;

[0257] S2. The organic phase was dried, concentrated under reduced pressure, and purified and separated using silica gel chromatography (petroleum ether: ethyl acetate 5:1) to obtain an alkenylcyclobutene derivative 5 with a yield of 45% (0.045 mmol).

[0258] The nuclear magnetic resonance data of the alkenylcyclobutene derivative 5 of this example are:

[0259] 1 H NMR (400MHz, CDCl3) δ7.46–7.44(m,2H),7.20(dd,J=6.4,3.2Hz,4H),6.93(d,J=16.0Hz,1H),6.32(s,1H),5.54(d,J=16.0Hz,1H) ,4.35(s,1H),4.41–4.09(m,2H),3.82(s,3H),3.63(s,3H),2.85(d,J=13.6Hz,1H),2.63(d,J=13.6Hz,1H),1.18(d,J=7.2Hz,3H).

[0260] 13C NMR (100MHz, CDCl3) δ172.9,165.9,144.3,136.1,135.9,135.2,127.4,126.6,125.6,120.1,80.1,60.7,57.5,51.9,50.7,34.6,28.7,13.0.

[0261] HRMS (TOF-ESI + )m / z:calcd for C 20 H 22 O7SNa[M+Na] + 397.1258 found 397.1268.

[0262] In summary, the method for synthesizing vinylcyclobutene derivatives of the present invention has simple process, short synthesis route and high synthesis yield, and can be applied to the synthesis of vinylcyclobutene derivatives with different substitutions.

[0263] The foregoing description of specific exemplary embodiments of the present invention is for the purpose of illustration and demonstration. These descriptions are not intended to limit the present invention to the precise form disclosed, and it is clear that many changes and variations can be made based on the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical application, so that those skilled in the art can realize and utilize various different exemplary embodiments of the present invention and various different selections and changes. The scope of the present invention is intended to be limited by the claims and their equivalents.

Claims

1. A 1-vinylcyclobutene derivative, characterized in that The structural formula of the 1-vinylcyclobutene derivative is: Among them, R1 is methoxy, ethoxy, trifluoroethoxy or phenyl; R2 is methoxy, ethoxy, benzyloxy, tert-butoxy, trifluoromethoxy, menthol, perillyl alcohol or cholesterol; R3 is hydrogen atom, fluorine, chlorine, bromine, methyl, methoxy, ethyl, ethoxy, nitro, methyl ester, trifluoromethyl, cyclohexyl or morpholinyl.

2. A method for synthesizing a 1-vinylcyclobutene derivative as claimed in claim 1, characterized in that: The following steps are involved: (1) mixing vinyl bicyclo[1.1.0]butane and α-keto ester in an organic solvent, adding palladium salt and phosphine ligand, stirring for reaction, extracting after the reaction, and collecting the organic phase; (2) drying the organic phase obtained in step (1), concentrating under reduced pressure, and separating by silica gel column chromatography to obtain a 1-vinylcyclobutene derivative; The synthetic route of the 1-vinylcyclobutene derivative is as follows:

3. The method for synthesizing a 1-vinylcyclobutene derivative according to claim 2, characterized in that: The reaction temperature is 15-30° C., and the reaction time is 10-15 hours.

4. The method for synthesizing a 1-vinylcyclobutene derivative according to claim 2, characterized in that: The organic solvent is dichloromethane, 1,2-dichloroethane, chloroform, acetone, acetonitrile or toluene.

5. The method for synthesizing a 1-vinylcyclobutene derivative according to claim 4, characterized in that: The organic solvent is dichloromethane or 1,2-dichloroethane.

6. The method for synthesizing a 1-vinylcyclobutene derivative according to claim 2, characterized in that: The palladium salt is Pd(OAc)2, Pd2(dba)3 or PdCl2.

7. The method for synthesizing a 1-vinylcyclobutene derivative according to claim 2, characterized in that: The ligand is Xantphos or DPEphos.

8. The method for synthesizing a 1-vinylcyclobutene derivative according to claim 6 or 7, characterized in that: The palladium salt is Pd(OAc)2, and the phosphine ligand is Xantphos.

9. The method for synthesizing a 1-vinylcyclobutene derivative according to claim 2, characterized in that: The molar ratio of the vinyl bicyclo[1.1.0]butane to the α-keto ester is 1.5-2.0:1, the molar amount of the palladium salt is 3-8% of the molar amount of the vinyl bicyclo[1.1.0]butane, and the molar amount of the phosphine ligand is 5-10% of the molar amount of the vinyl bicyclo[1.1.0]butane.

10. Use of the 1-vinylcyclobutene derivative according to claim 1 in the structural modification of natural products such as cholesterol, menthol and perillyl alcohol.

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