Bicyclo [2.1. 1] hexane spiro-2-oxindole derivative and preparation method thereof

Abstract

The invention discloses a bicyclo [2.1. 1] hexane spiro-2-oxindole derivative, the structural formula of which is # imgabs0, in which R1 is selected from hydrogen, methyl, ethyl, benzyl, phenyl, allyl, acetyl or t-butyloxycarbonyl; r2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxyl or ethoxyl; r3 is selected from an ethyoxyl group, a methoxy group, a phenyl group, a 4-fluorophenyl group, a 4-chlorphenyl group, a 4-bromophenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenyl group, a 4-cyclohexyl phenyl group, a 2-thienyl group or a 2-naphthyl group; and R4 is selected from a methoxy group, an ethyoxyl group, a trifluoroethyoxyl group or a phenyl group. The invention also provides a preparation method of the bicyclo [2.1. 1] hexane spiro-2-oxindole. The method is simple, the reaction condition is mild, the reaction time is short, the yield is high, and the diastereoselectivity is high.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative and a preparation method thereof. Background Art

[0002] The oxidized indole spirocyclopentane skeleton is a common core skeleton of natural products. For example, Citrinadine B, Marcfortine A and Notoamide A are all natural products with certain biological activities containing oxidized indole spirocyclopentane. Therefore, the development of new strategies for the synthesis and modification of oxidized indole spirocyclopentane has certain application prospects in the fields of medicinal chemistry and new drug research and development. The bioisostere replacement strategy is a strategy to replace fragments with similar skeletons and substituent groups to improve the lipid solubility and pharmacokinetic properties of candidate drugs. Introducing a bridge ring into the oxidized indole spirocyclopentane skeleton to form a bicyclo[2.1.1]hexane spiro-2-oxidized indole skeleton is an effective isostere replacement strategy. After the bridge ring modification, this type of compound often has good lipid solubility, so it has great application prospects in the field of medicinal chemistry research.

[0003] At present, the synthesis strategy of bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives has not been reported. And there are very few reports on bicyclo[2.1.1]hexane spiro skeletons. In 2024, Wei-Ping Deng et al. reported a class of boron trifluoride ether-catalyzed benzofuran-derived oxadiene strain-releasing ring-opening [2σ+2π] cycloaddition reactions with aromatic bicyclo[1.1.0]butanes, and synthesized a series of bicyclo[2.1.1]hexane spiro compounds with high yields and excellent substrate adaptability (Wei-Ping Deng et al. Access to spiro-bicyclo[2.1.1]hexanes via BF3·Et2O-catalyzed formal[2π+2σ]cycloaddition of bicyclo[1.1.0]butanes with benzofuran-derived oxa(aza)dienes). In the same year, Jian-Jun Feng et al. reported a Lewis acid-catalyzed strain-release ring-opening [2σ+2π] cycloaddition reaction of thioenone and aromatic bicyclo[1.1.0]butane, and synthesized a series of bicyclo[2.1.1]hexane spiro compounds with relatively good yields (Jian-Jun Feng et al. Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles). Although bicyclo[2.1.1]hexane spiro compounds have been reported in the literature, the synthesis of the highly valuable bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives has not yet been reported. Developing new synthetic strategies for bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives to meet the huge demand for oxidoindole spirocyclopentane skeleton electronic isosteres in synthetic chemistry and medicinal chemistry will have important academic significance and industrial application value. Summary of the invention

[0004] In view of the above shortcomings, the present invention provides a bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative and a preparation method thereof, which has mild synthesis reaction conditions, safe and simple operation, short synthesis route and high synthesis yield. The specific technical scheme is as follows:

[0005] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is:

[0006]

[0007] Among them, R 1 is selected from hydrogen, methyl, ethyl, benzyl, phenyl, allyl, acetyl or tert-butyloxycarbonyl; R 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy; R 3 is selected from ethoxy, methoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-cyclohexylphenyl, 2-thienyl or 2-naphthyl; R 4 Selected from methoxy, ethoxy, trifluoroethoxy or phenyl.

[0008] A method for preparing the above-mentioned bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative comprises the following steps:

[0009] (1) A nitrogen-protected α,β-unsaturated 2-oxidoindole derivative 1 and a vinyl bicyclo[1.1.0]butane derivative 2 are stirred and mixed in an organic solvent, a palladium catalyst system is added, and the mixture is stirred and reacted under argon protection; after the reaction is completed, extraction is performed and the organic phase is collected;

[0010] (2) drying the organic phase obtained in step (1), concentrating under reduced pressure, and separating by silica gel column chromatography to obtain a bicyclo[2.1.1]hexanespiro-2-oxidoindole derivative 3;

[0011] The synthesis route of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative is:

[0012]

[0013] Preferably, in the above-mentioned method for preparing bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives, in the step (1), the reaction temperature is 70 to 85° C. and the reaction time is 10 to 15 hours.

[0014] Preferably, in the above-mentioned method for preparing bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives, in the step (1), the reaction temperature is 80° C. and the reaction time is 12 h.

[0015] Preferably, in the above-mentioned method for preparing bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives, the organic solvent is dichloromethane, chloroform, trifluorotoluene or toluene.

[0016] Preferably, in the above-mentioned method for preparing bicyclo[2.1.1]hexanespiro-2-oxidoindole derivatives, the organic solvent is toluene.

[0017] Preferably, in the above-mentioned method for preparing bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives, the palladium catalytic system is Pd(PPh3)4, Pd(OAc)2 / dppf or Pd(OAc)2 / DPPP.

[0018] Preferably, in the above-mentioned method for preparing bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives, the palladium catalytic system is Pd(PPh3)4.

[0019] Preferably, in the above-mentioned method for preparing bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives, the molar ratio of the nitrogen-protected α,β-unsaturated 2-oxidoindole derivative, the vinyl bicyclo[1.1.0]butane derivative, and the palladium catalyst system is 1:1-2.5:0.01-0.06.

[0020] Preferably, in the above-mentioned method for preparing bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives, the molar ratio of nitrogen-protected α,β-unsaturated 2-oxidoindole derivatives, vinyl bicyclo[1.1.0]butane derivatives, and palladium catalyst system is 1:2:0.05.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative of the present invention has a bicyclo[2.1.1]hexane spiro-2-oxidoindole skeleton, can meet the huge demand of synthetic chemistry and medicinal chemistry for the electronic isostere of the oxidoindole spirocyclopentane skeleton, and has high application value. The synthesis method is simple, the reaction conditions are mild, the operation is safe and simple, and the synthesis yield is high, and the derivative can be applied to the synthesis of different substituted bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives. DETAILED DESCRIPTION

[0023] 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.

[0024] The vinyl bicyclo[1.1.0]butane derivatives used in the following examples were prepared according to the literature (Ma, X.; Pinto, W.; Pham, LN; Sloman, DL; Han, Y., Synthetic Studies of 2,2-Difluorobicyclo[1.1.1]pentanes(BCP-F2):The Scope and Limitation of Useful Building Blocks for Medicinal Chemists. Eur. J. Org. Chem. 2020, 2020, (29), 4581-4605).

[0025] The synthetic route of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative of the present invention is:

[0026]

[0027] Example 1

[0028] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is as follows:

[0029]

[0030] The synthesis route of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives of this embodiment is:

[0031]

[0032] This embodiment also provides a method for preparing a bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, comprising the following steps:

[0033] (1) The reactant nitrogen-protected α,β-unsaturated 2-oxidoindole derivative 1a (0.1 mmol, 1 equivalent) and the reactant divinylcyclobutane derivative 2a (0.2 mmol, 2 equivalents) were dissolved in toluene (1 mL), and palladium catalyst Pd[PPh)3]4 (0.005 mmol, 0.05 equivalents) was added. The mixture was stirred at 80°C for 12 h under argon atmosphere. After the reaction was completed, the organic phase was extracted and collected;

[0034] (3) After drying, filtering, concentrating under reduced pressure, and separating by silica gel column chromatography, the bicyclo[2.1.1]hexanespiro-2-oxidoindole derivative 3a was obtained.

[0035] (4) The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3a in this example is 76%, and the nuclear magnetic resonance data are:

[0036] 1 H NMR (400MHz, CDCl3) δ7.3–7.2(m,6H),7.16(t,J=7.2Hz,1H),6.94(t,J=6.8Hz,1H),6.67(d, J=8.0Hz,1H),5.40(dd,J=17.2,10.4Hz,1H),5.01–4.92(m,4H),4.3–4.2(m,2H),3.96(d,J=2 .0Hz,1H),3.82–3.71(m,2H),3.31(dd,J=10.0,7.2Hz,1H),2.88(dd,J=10.0,8.4Hz,1H),2.2 4(dd,J=8.0,2.0Hz,1H),1.97(d,J=6.8Hz,1H),1.28(t,J=7.2Hz,3H),0.69(t,J=7.2Hz,3H).

[0037] 13 C NMR (100MHz, CDCl3) δ177.9,170.8,170.5,143.3,135.6,133.6,128.61,128.6,128.1,127.5,127 .0,124.5,122.3,118.0,109.0,60.7,60.6,60.3,57.7,56.6,48.6,43.8,43.1,42.6,14.2,13.6.

[0038] HRMS(TOF-ESI+)m / z:calcd for C 28 H 29 NO5[M+Na]+482.1938found 482.1929.

[0039] Example 2

[0040] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is as follows:

[0041]

[0042] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative in this example is the same as that in Example 1, except that the second reactant is a vinyl cyclobutane derivative 2b (0.2 mmol, 2 equivalents), and the structural formula of the vinyl cyclobutane derivative 2b is shown below.

[0043]

[0044] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3b in this example is 68%, and the nuclear magnetic resonance data are:

[0045] 1 H NMR (400MHz, CDCl3) δ7.22–7.16(m,6H),7.10–7.06(m,1H),6.89–6.84(m,1H),6. 60(d,J=7.6Hz,1H),5.33(dd,J=25.2,10.4Hz,1H),4.95–4.85(m,4H),3.89(d,J= 2.0Hz,1H),3.72–3.65(m,5H),3.25(dd,J=10.0,6.8Hz,1H),2.81(dd,J=9.6,8.0 Hz,1H),2.17(dd,J=8.0,2.0Hz,1H),1.90(d,J=7.2Hz,1H),0.60(t,J=6.8Hz,3H).

[0046] 13 C NMR (100MHz, CDCl3) δ176.8,170.2,169.5,142.3,134.5,132.5,127.6,127.0,126.5,126. 0,123.4,121.3,117.0,108.0,59.6,59.4,56.6,55.5,51.0,47.4,42.8,42.1,41.6,12.5.

[0047] HRMS(TOF-ESI+)m / z:calcd for C 27 H 27 NO5[M+Na] + 468.1781 found 468.1773.

[0048] Example 3

[0049] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is as follows:

[0050]

[0051] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative in this example is the same as that in Example 1, except that the second reactant is a vinyl cyclobutane derivative 2c (0.2 mmol, 2 equivalents), and the structural formula of the vinyl cyclobutane derivative 2c is shown below.

[0052]

[0053] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3c in this example is 65%, and the nuclear magnetic resonance data are:

[0054] 1 H NMR(400MHz, CDCl3)δ7.25–7.19(m,6H)7.13(t,J=7.2Hz,1H),6.92(t,J=7.6H z,1H),6.65(d,J=8.0Hz,1H),5.40–5.33(m,1H),4.99–4.91(m,4H),3.96(d,J= 2.0Hz,1H),3.80–3.68(m,2H),3.34(dd,J=10.0,7.2Hz,1H),2.90(t,J=8.0Hz, 1H), 2.25 (dd, J=8.0, 2.0Hz, 1H), 1.99 (d, J=7.2Hz, 1H), 0.68 (t, J=7.2Hz, 3H).

[0055] 13 C NMR (100MHz, CDCl3) δ176.6,169.2,168.1,142.3,134.4,132.1,127.8,127.7,126.7,126.5,126.0,123.4,121.4,117.3,108.1,60.1,59.63(d,J C-F =13.8Hz),59.3,59.0,56.5,55.4,46.9,42.8,42.2,41.7,12.5.

[0056] 19 F NMR(376MHz, CDCl3)δ-73.8(s).

[0057] HRMS(TOF-ESI+)m / z:calcd for C 28 H 26 F3NO5[M+Na] + 536.1655 found 536.1658.

[0058] Example 4

[0059] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is as follows:

[0060]

[0061] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative in this example is the same as that in Example 1, except that the second reactant is a vinyl cyclobutane derivative 2d (0.2 mmol, 2 equivalents), and the structural formula of the vinyl cyclobutane derivative 2d is shown below.

[0062]

[0063] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3d in this example is 50%, and the nuclear magnetic resonance data are:

[0064] 1 H NMR (400MHz, CDCl3) δ7.89(d,J=7.2Hz,2H),7.47(t,J=7.2Hz,1H),7.41(t,J=7.6Hz,2H),7 .23–7.19(m,6H),7.10(t,J=7.6Hz,1H),6.89(t,J=7.6Hz,1H),6.63(d,J=8.0Hz,1H),5.36 (dd,J=17.2,10.8Hz,1H),4.96–4.86(m,4H),4.17(d,J=2.0Hz,1H),3.63–3.56(m,3H),2.9 8(t,J=8.4Hz,1H)2.28(dd,J=8.4,2.0Hz,1H),2.01(d,J=7.2Hz,1H),0.53(t,J=7.2Hz,3H).

[0065] 13 C NMR (100MHz, CDCl3) δ198.7,177.0,169.3,142.3,136.3,134.5,132.4,131.5,127.7,127.5,127.4,127. 1,126.5,126.0,123.4,121.4,117.1,108.1,59.5,59.2,57.7,57.4,53.6,43.8,42.8,42.2,28.7,12.4.

[0066] HRMS(TOF-ESI+)m / z:calcd for C 32 H 29 NO4[M+Na] + 514.1989 found 514.1982

[0067] Example 5

[0068] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is as follows:

[0069]

[0070] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1b (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1b is shown below.

[0071]

[0072] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3e in this example is 65%, and the nuclear magnetic resonance data are:

[0073] 1 H NMR(400MHz, CDCl3)δ7.92(s,1H),7.19–7.13(m,2H),6.90–6.86(m,1H),6.80(d,J=7.6Hz ,1H),5.36(dd,J=17.2,10.4Hz,1H),4.92–4.85(m,2H),4.17–4.11(m,2H),3.81(d,J=2.4H z,1H),3.78–3.70(m,2H),3.11(dd,J=10.0,6.8Hz,1H),2.76(dd,J=10.0,8.4Hz,1H),2.15 (dd,J=8.0,2.0Hz,1H),1.85(d,J=7.2Hz,1H),1.21(t,J=4.8Hz3H),0.70(t,J=7.2Hz,3H).

[0074] 13 C NMR (100MHz, CDCl3) δ178.4,169.8,169.5,140.1,132.2,127.7,127.4,123.9,1 21.2,117.0,108.5,59.7,59.5,59.4,57.2,54.9,47.6,41.8,41.3,13.2,12.7.

[0075] HRMS(TOF-ESI+)m / z:calcd for C 21 H 23 NO5[M+Na] + 392.1468 found 392.1473

[0076] Example 6

[0077] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is:

[0078]

[0079] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1c (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1c is shown below.

[0080]

[0081] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3f in this example is 90%, and the nuclear magnetic resonance data are:

[0082] 1 H NMR(400MHz, CDCl3)δ7.24–7.15(m,2H)6.90(t,J=7.6Hz,1H),6.76(d,J=7.6Hz,1H), 5.25(dd,J=17.2,10.4Hz,1H),4.85(t,J=16.4Hz,2H),4.18–4.08(m,2H),3.79(d,J= 2.0Hz,1H),3.78–3.68(m,2H),3.19–3.15(m,4H),2.76,(t,J=8.4Hz,1H)2.14(dd,J= 8.0, 2.0Hz, 1H), 1.84 (d, J = 4.8Hz, 1H), 1.21 (t, J = 7.2Hz, 3H), 0.69 (t, J = 7.2Hz, 3H).

[0083] 13 C NMR (100MHz, CDCl3) δ176.6,169.8,169.6,143.2,132.3,127.7,127.0,123.4,121 .2,116.8,106.8,59.7,59.5,59.3,56.8,54.8,47.7,42.0,41.3,25.4,13.2,12.7.

[0084] HRMS(TOF-ESI+)m / z:calcd for C 22 H 25 NO5[M+H] + 384.1805 found 384.1812

[0085] Example 7

[0086] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is:

[0087]

[0088] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that: the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1d (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1d is shown below.

[0089]

[0090] The yield of 3 g of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative in this example is 81%, and the nuclear magnetic resonance data are:

[0091] 1 H NMR (400MHz, CDCl3) δ7.20–7.16(m,2H),6.91-6.87(m,1H),6.73–6.71(m,1H),5.78–5.69(m,1H),5. 31(dd,J=17.2,10.4Hz,1H),5.12–5.06(m,2H),4.91–4.83(m,2H),4.37–4.23(m,2H),4.17–4.08(m,2 H),3.82(d,J=2.0Hz,1H),3.76–3.66(m,2H),3.19(dd,J=10.0,7.2Hz,1H),2.78(dd,J=10.0,8.0Hz, 1H), 2.15 (dd, J=8.0, 2.0Hz, 1H), 1.86 (d, J=6.8Hz, 1H), 1.20 (t, J=7.2Hz, 3H), 0.66 (t, J=7.2Hz, 3H).

[0092] 13 C NMR (100MHz, CDCl3) δ176.5,169.8,169.5,142.3,132.4,129.9,127.6,127.0,123.5,121 .2,116.9,115.8,107.8,59.7,59.5,59.3,56.7,55.2,47.6,42.0,41.4,41.2,13.2,12.6.

[0093] HRMS(TOF-ESI+)m / z:calcd for C 24 H 27 NO5[M+Na]+ 432.1787 found 432.1792

[0094] Example 8

[0095] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is:

[0096]

[0097] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1e (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1e is shown below.

[0098]

[0099] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3h in this example is 50%, and the nuclear magnetic resonance data are:

[0100] 1 H NMR(400MHz, CDCl3)δ8.22(d,J=8.0Hz,1H),7.29–7.20(m,2H)7.06(t,J=7.2Hz,1H),5.24(dd,J=17.6,10.4Hz,1H),4.90 –4.87(m,2H),4.19–4.11(m,2H),3.86(d,J=2.0Hz,1H),3.83–3.71(m,2H),2.99(dd,J=10.4,7.6Hz,1H),2.77(t,J=8.0Hz 1H), 2.60 (s, 3H), 2.13 (dd, J = 8.0, 2.0Hz, 1H), 1.87 (d, J = 7.2Hz, 1H), 1.22 (t, J = 7.2Hz, 3H), 0.73 (t, J = 7.2Hz, 3H).

[0101] 13 C NMR (100MHz, CDCl3) δ177.8,169.7,169.5,169.1,139.4,131.8,128.1,125.9,123.8, 122.8,117.4,115.2,60.9,59.8,59.7,57.5,55.2,47.7,41.6,41.2,25.9,13.2,12.7.

[0102] HRMS(TOF-ESI+)m / z:calcd for C23 H 25 NO6[M+H] + 412.1755 found 412.1755

[0103] Example 9

[0104] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, the structural formula of which is:

[0105]

[0106] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1f (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1f is shown below.

[0107]

[0108] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3i in this example is 43%, and the nuclear magnetic resonance data are:

[0109] 1 H NMR(400MHz, CDCl3)δ7.80(d,J=8.0Hz,1H),7.24–7.17(m,2H),7.02–6.98(m,1H),5.33 –5.26(m,1H),4.90–4.85(m,2H),4.17–4.09(m,2H),3.87(d,J=2.0Hz,1H),3.82–3.70(m ,2H),3.06(dd,J=10.4,7.2Hz,1H),2.74(dd,J=10.0,8.4Hz,1H),2.12(dd,J=8.4,2.4H z,1H),1.83(d,J=7.2Hz,1H),1.57(s,9H),1.20(d,J=6.8Hz,3H),0.74(t,J=7.2Hz,3H).

[0110] 13 C NMR (100MHz, CDCl3) δ175.37,169.58,169.37,147.97,139.05,131.76,127.84,125.83,123.03,123.00 ,117.38,113.60,83.50,60.75,59.74,59.57,57.39,55.19,47.69,41.60,41.20,27.09,13.13,12.72.

[0111] HRMS(TOF-ESI+)m / z:calcd for C 26 H 31 NO7[M+Na] + 492.1993found 492.2002

[0112] Example 10

[0113] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, having the structural formula:

[0114]

[0115] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that: the first reactant is 1 g (0.1 mmol, 1 equivalent) of a nitrogen-protected α, β-unsaturated 2-oxidized indole derivative, and the structural formula of 1 g of the nitrogen-protected α, β-unsaturated 2-oxidized indole derivative is shown below.

[0116]

[0117] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3j in this example is 72%, and the nuclear magnetic resonance data are:

[0118] 1 H NMR(400MHz, CDCl3)δ7.23–7.10(m,6H),6.57–6.52(m,1H),6.34(dd,J=8.8,2.4Hz,1H), 5.32(dd,J=17.2,10.4Hz,1H),4.94–4.86(m,4H),4.18–4.10(m,2H),3.85(d,J=2.0Hz,1 H),3.79–3.67(m,2H),3.20(dd,J=10.0,7.2Hz,1H),2.75(dd,J=9.6,8.4Hz,1H),2.17(d d,J=8.4,2.0Hz,1H)1.90(d,J=7.2Hz,1H),1.19(t,J=7.2Hz,3H),0.69(t,J=7.2Hz,3H).

[0119] 13C NMR (100MHz, CDCl3) δ177.2,169.5(d,JC-F=19.1Hz),163.3,160.9,143.9(d,JC-F=11.4Hz),134.0,132.3,127.8,126.7,126.0,124.6(d,JC-F =9.6Hz),122.6(d,JC-F=3.0Hz),117.2,107.4,107.2,96.9,96.6,59.8 ,59.5(d,JC-F=13.0Hz),56.4,55.5,47.6,42.9,42.0,41.5,13.2,12.7.

[0120] 19 F NMR(376MHz, CDCl3)δ-111.25(s).

[0121] HRMS(TOF-ESI+)m / z:calcd for C 28 H 28 FNO5[M+Na]+500.1844found 500.1852

[0122] Embodiment 11

[0123] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, having the structural formula:

[0124]

[0125] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1h (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1h is shown below.

[0126]

[0127] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3j in this example is 55%, and the nuclear magnetic resonance data are:

[0128] 1H NMR (400MHz, CDCl3) δ7.26–7.16(m,5H),7.09(d,J=8.4Hz,1H),6.85(dd,J=8.0,1.6Hz,1H),6 .60(d,J=1.6Hz,1H),5.31(dd,J=17.2,10.8Hz,1H),4.94–4.86(m,4H),4.18–4.09(m,2H),3.8 6(d,J=2.0Hz,1H),3.80–3.67(m,2H),3.19(dd,J=10.0,7.2Hz,1H),2.73(t,J=8.4Hz,1H),2. 17(dd,J=8.0,1.6Hz,1H), 1.90(d,J=6.8Hz,1H), 1.19(t,J=7.2Hz,3H), 0.70(t,J=7.2Hz,3H).

[0129] 13 C NMR (100MHz, CDCl3) δ176.8,169.5,169.3,143.6,133.9,133.5,132.2,127.8,126.8,125.9,125 .5,124.4,121.1,117.3,108.5,59.8,59.6,59.5,56.5,55.5,47.7,42.9,42.0,41.5,13.2,12.7.

[0130] HRMS(TOF-ESI+)m / z:calcd for C 28 H 28 ClNO5[M+Na]+516.1548found 516.1555

[0131] Example 12

[0132] A bicyclo[2.1.1]hexane spiro-2-oxidoindole, the structural formula is:

[0133]

[0134] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1i (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1i is shown below.

[0135]

[0136] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3j in this example is 83%, and the nuclear magnetic resonance data are:

[0137] 1 H NMR (400MHz, CDCl3) δ7.24–7.15(m,5H),7.05–6.99(m,2H),6.75(s,1H),5.3 1(dd,J=17.2,10.8Hz,1H),4.94–4.85(m,4H),4.17–4.10(m,2H),3.86(d,J= 2.0Hz,1H),3.80–3.67(m,2H),3.19(dd,J=9.6,6.8Hz,1H),2.72(t,J=8.4Hz ,1H),2.17(dd,J=8.0Hz,1.6Hz,1H),1.89(d,J=7.2Hz,1H),1.20(t,J=7.2Hz 3H), 0.70 (t, J = 7.2 Hz, 3H).

[0138] 13 C NMR (100MHz, CDCl3) δ176.7,169.5,169.3,143.7,133.9,132.1,127.8,126.7,126.0,125.9,124 .7,124.0,121.4,117.3,111.3,59.8,59.6,59.5,56.6,55.4,47.7,42.9,42.0,41.5,13.2,12.7.

[0139] HRMS(TOF-ESI+)m / z:calcd for C 28 H 28 BrNO5[M+Na]+560.1043found 560.1050

[0140] Embodiment 13

[0141] A bicyclo[2.1.1]hexane spiro-2-oxidoindole, the structural formula is:

[0142]

[0143] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1j (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1j is shown below.

[0144]

[0145] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3m in this example is 62%, and the nuclear magnetic resonance data are:

[0146] 1 H NMR (400MHz, CDCl3) δ7.21–7.16(m,5H),6.99(s,1H),6.87(d,J=8.0Hz,1H),6.48(d,J=7.6Hz ,1H),5.34(dd,J=17.2,10.8Hz,1H),4.95–4.85(m,4H)4.18–4.09(m,2H),3.88(d,J=2.0Hz,1 H),3.74–3.68(m,2H),3.23(dd,J=10.0,6.8Hz,1H),2.80(dd,J=10.0,8.4Hz,1H),2.17(s,3H ), 2.14 (d, J = 2.0Hz, 1H), 1.89 (d, J = 6.8Hz, 1H), 1.20 (t, J = 7.2Hz, 3H), 0.62 (t, J = 7.2Hz, 3H).

[0147] 13 C NMR (100MHz, CDCl3) δ176.8,169.9,169.6,139.9,134.7,132.7,130.6,127.8,127.6,127.1,126.4, 126.0,124.4,116.9,107.7,59.7,59.5,59.3,56.8,55.5,47.5,42.8,42.0,41.6,20.2,13.2,12.6.

[0148] HRMS(TOF-ESI+)m / z:calcd for C 29 H 31 NO5[M+Na]+496.2094found 496.2102

[0149] Embodiment 14

[0150] A bicyclo[2.1.1]hexane spiro-2-oxidoindole, the structural formula is:

[0151]

[0152] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that: the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1k (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1k is shown below.

[0153]

[0154] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3n in this example is 84%, and the nuclear magnetic resonance data are:

[0155] 1 H NMR (400MHz, CDCl3) δ7.21–7.16(m,5H),6.81(d,J=2.4Hz,1H),6.60(dd,J=8.4,2.4Hz,1H) ,6.48(d,J=8.4Hz,1H),5.34(dd,J=17.2,10.8Hz,1H),4.95–4.86(m,4H),4.16–4.09(m,2H) ,3.89(d,J=2.0Hz,1H),3.77–3.72(m,2H),3.62(s,3H),3.24(dd,J=10.0,6.8Hz,1H),2.77 (dd,J=9.6,8.4Hz,1H),2.16(dd,J=8.0,2.0Hz,1H),1.89(d,J=6.8Hz,1H),1.20(t,J=7.2Hz 3H),0.67(t,J=7.2Hz,3H).

[0156] 13 C NMR (100MHz, CDCl3) δ176.6,169.7,169.5,154.5,135.8,134.6,132.5,128.3,127.6,126.5,126.0, 117.0,111.8,111.4,108.1,59.7,59.6,59.4,57.1,55.5,54.8,47.6,42.8,42.1,41.5,13.2,12.6.

[0157] HRMS(TOF-ESI+)m / z:calcd for C 29 H 31 NO6[M+Na]+512.2049found 512.2044

[0158] Embodiment 15

[0159] A bicyclo[2.1.1]hexane spiro-2-oxindole having the structural formula:

[0160]

[0161] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that: the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 11 (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 11 is shown below.

[0162]

[0163] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3o in this example is 50%, and the nuclear magnetic resonance data are:

[0164] 1 H NMR (400MHz, CDCl3) δ7.41–7.37(m,2H),7.25–7.19(m,5H),6.96(d,J=7.6Hz,1H),6.97–6.88(m,1H) ,6.70–6.66(m,1H),6.60–6.50(m,2H),6.50(d,J=8.0Hz,1H),5.23(dd,J=17.2,10.4Hz,1H),4.94–4 .84(m,4H),4.69(d,J=2.0Hz,1H),4.15–4.09(m,2H),3.30(dd,J=10.0,7.2Hz,1H),2.80(dd,J=10.0 ,8.4Hz,1H),2.20(dd,J=8.0,2.0Hz,1H),1.94(d,J=7.2Hz,1H),1.54(s,2H),1.15(t,J=7.2Hz,3H).

[0165] 13 C NMR (100MHz, CDCl3) δ195.5,176.9,170.1,163.0,141.7,134.7,132.3,132.0,129.1(d,JC-F=9.4Hz),127.8,127.5,126. 8(d,JC-F=6.0Hz),125.9,124.1,121.3,117.1,114.4,114.2,107.7,60.2,59.7,57.4,57.0,47.8,43.0,41.7,41.4,13.1.

[0166] 19 F NMR(376MHz, CDCl3)δ-104.98(s).

[0167] HRMS(TOF-ESI+)m / z:calcd for C 32 H 28FNO4[M+Na]+532.1895found 532.1895

[0168] Example 16

[0169] A bicyclo[2.1.1]hexane spiro-2-oxidoindole, the structural formula is:

[0170]

[0171] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that: the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1m (0.1mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1m is shown below.

[0172]

[0173] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3p in this example is 53%, and the nuclear magnetic resonance data are:

[0174] 1 H NMR (400MHz, CDCl3) δ7.32–7.19(m,7H),7.22(dd,J=10.4,5.5Hz,3H),6.97–6.87(m,4H) ,6.69(t,J=7.6Hz,1H),6.51(d,J=8.0Hz,1H),5.24(dd,J=17.2,10.8Hz,1H),4.94–4.84 (m,4H),4.68(d,J=1.6Hz,1H),4.15–4.08(m,2H),3.29(dd,J=10.0,7.2Hz,1H),2.80(t, J=8.4Hz,1H),2.20(dd,J=8.4,1.6Hz,1H),1.94(d,J=6.8Hz,1H),1.16(t,J=7.2Hz,3H).

[0175] 13 C NMR (100MHz, CDCl3) δ196.0,176.9,167.0,141.7,138.2,134.6,133.9,132.2,127.9,127.8,127.6,1 26.8,126.7,125.8,124.1,121.4,117.1,107.7,60.3,59.7,57.3,57.0,47.8,43.0,41.7,41.4,13.1.

[0176] HRMS(TOF-ESI+)m / z:calcd for C 32 H 28 ClNO4[M+Na]+548.1599found 5481603

[0177] Embodiment 17

[0178] A bicyclo[2.1.1]hexane spiro-2-oxidoindole, the structural formula is:

[0179]

[0180] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1n (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1n is shown below.

[0181]

[0182] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3q in this example is 44%, and the nuclear magnetic resonance data are:

[0183] 1 H NMR (400MHz, CDCl3) δ7.28–7.19(m,7H),7.06–7.04(m,2H),6.94(dd,J=18.8,8.0Hz ,2H),6.69(t,J=7.6Hz,1H),6.52(d,J=8.0Hz,1H),5.24(dd,J=17.6,10.8Hz,1H),4. 94–4.84(m,4H),4.68(s,1H),4.14–4.08(m,2H),3.28(dd,J=9.6,7.6Hz,1H),2.80( t,J=9.2Hz,1H),2.20(d,J=8.4Hz,1H),1.94(d,J=6.8Hz,1H),1.15(t,J=7.2Hz,3H).

[0184] 13C NMR (100MHz, CDCl3) δ196.2,176.8,170.0(s),141.7,134.6,134.3,132.2,130.5,128.0,127.8 127.6,127.0,126.8,126.7,125.7,124.1,121.4,117.1,107.8,60.3,59.7,57.3,57.0,47.8,43.0,41.7,41.4,13.1.

[0185] HRMS(TOF-ESI+)m / z:calcd for C 32 H 28 BrNO4[M+Na]+506.2326found 506.2329

[0186] Embodiment 18

[0187] A bicyclo[2.1.1]hexane spiro-2-oxidoindole, the structural formula is:

[0188]

[0189] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1o (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1o is shown below.

[0190]

[0191] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3r in this example is 56%, and the nuclear magnetic resonance data are:

[0192] 1H NMR(400MHz, CDCl3) δ7.31(d,J=8.4Hz,2H),7.24–7.21(m,5H),6.99(d,J=7.6Hz,1H),6.90–6.86(m,1H) ,6.76(d,J=8.0Hz,2H),6.69–6.65(m,1H),6.45(d,J=7.6Hz,1H),5.23(dd,J=17.2,10.4Hz,1H),4.94–4 .90(m,1H),4.86–4.80(m,3H),4.73(d,J=2.0Hz,1H),4.14–4.08(m,2H),3.29(dd,J=9.6,6.8Hz,1H),2. 83(dd,J=9.6,8.0Hz,1H),2.20–2.18(m,1H),2.14(s,3H),1.92(d,J=6.0Hz,1H),1.14(t,J=7.2Hz,3H).

[0193] 13 C NMR (100MHz, CDCl3) δ196.6,177.1,170.2,142.5,141.7,134.7,133.1,132.4,127.9,127.7,12 7.3,126.6,126.1,124.2,121.3,116.9,107.6,60.2,59.6,57.2,47.8,43.0,41.5,20.5,13.1.

[0194] HRMS(TOF-ESI+)m / z:calcd for C 33 H 31 NO4[M+Na]+506.2326found 506.2329

[0195] Embodiment 19

[0196] A bicyclo[2.1.1]hexane spiro-2-oxidoindole, the structural formula is:

[0197]

[0198] The preparation method of the bicyclo[2.1.1]hexane spiro-2-oxidized indole derivative in this example is the same as that in Example 1, except that the first reactant is a nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1p (0.1 mmol, 1 equivalent), and the structural formula of the nitrogen-protected α,β-unsaturated 2-oxidized indole derivative 1p is shown below.

[0199]

[0200] The yield of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3s in this example is 35%, and the nuclear magnetic resonance data are:

[0201] 1 H NMR(400MHz, CDCl3)δ7.43(d,J=8.0Hz,2H),7.26–7.10(m,7H),6.96–6.89(m,2H),6 .70–6.66(m,1H),6.52(d,J=8.0Hz,1H),5.25(dd,J=17.2,10.4Hz,1H),4.95–4.85( m,4H),4.80–4.72(m,2H),4.14–4.09(m,2H),3.32(dd,J=9.6,6.8Hz,1H),2.82–2.7 7(m,1H),2.22(dd,J=8.0,1.6Hz,1H),1.96(d,J=7.2Hz,1H),1.15(t,J=7.2Hz,3H).

[0202] 13 C NMR (100MHz, CDCl3) δ196.3,176.8,169.9,141.7,138.0,134.6,133.0,132.7,132.1,127.7(d,JC-F=17.5Hz),126.9(d,JC -F=15.4Hz),125.6,124.3,124.2,124.1,121.4,121.0,117.2,107.7,60.3,59.8,57.7,56.8,47.8,43.1,41.8,41.4,13.1.

[0203] 19 F NMR(377MHz, CDCl3)δ-63.22(s).

[0204] HRMS(TOF-ESI+)m / z:calcd for C 33 H 28 F3NO4[M+Na]+582.1863found 582.1871

[0205] Comparative Examples 1 to 12

[0206] Comparative Examples 1 to 11 differ from Example 1 in that the catalytic system or the organic solvent is different. The specific information of the catalytic system and the organic solvent is shown in Table 1. The amount of Xantphos, dppf, DPEphos and DPPP used in Comparative Examples 1 to 4 is 12% of the molar amount of the nitrogen-protected α,β-unsaturated 2-oxidoindole derivative 1a. The difference between the comparative examples and Example 1 is that the amount of the reactant divinylcyclobutane derivative 2a is 0.15 mmol (1.5 times equivalent). The yield of the obtained bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative is shown in Table 1.

[0207] Table 1 Reaction conditions and yield data of Example 1 and Comparative Examples 1 to 12

[0208] Serial number Reaction temperature Catalytic system solvent yield(%) Example 1 80℃ <![CDATA[Pd(PPh3)4]]> Toluene 76 Comparative Example 1 80℃ <![CDATA[Pd(OAc)2 / Xantphos]]> Toluene nd Comparative Example 2 80℃ <![CDATA[Pd(OAc)2 / dppf]]> Toluene 50 Comparative Example 3 80℃ <![CDATA[Pd(OAc)2 / DPEphos]]> Toluene 33 Comparative Example 4 80℃ <![CDATA[Pd(OAc)2 / DPPP]]> Toluene 53 Comparative Example 5 80℃ <![CDATA[Pd(PPh3)4]]> <![CDATA[CH2Cl2]]> 42 Comparative Example 6 80℃ <![CDATA[Pd(PPh3)4]]> <![CDATA[CH2ClCH2Cl]]> 36 Comparative Example 7 80℃ <![CDATA[Pd(PPh3)4]]> <![CDATA[CH3CN]]> 30 Comparative Example 8 80℃ <![CDATA[Pd(PPh3)4]]> THF 34 Comparative Example 9 80℃ <![CDATA[Pd(PPh3)4]]> <![CDATA[C6H5CF3]]> 54 Comparative Example 10 60℃ <![CDATA[Pd(PPh3)4]]> Toluene 23 Comparative Example 11 Room temperature <![CDATA[Pd(PPh3)4]]> Toluene 14 Comparative Example 12 80℃ <![CDATA[Pd(PPh3)4]]> Toluene 56

[0209] Synthesis and transformation of bicyclo[2.1.1]hexane spiro-2-oxidoindole derivatives

[0210] Application Example 1

[0211] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative has the structural formula:

[0212]

[0213] The synthetic route of the derivatives of this application example is:

[0214]

[0215] The synthesis method of the derivative of this application example comprises the following steps:

[0216] (1) The bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3a (0.1 mmol, 1.0 equivalent) obtained in Example 1 was dissolved in methanol (1.0 mL), palladium / carbon (4.6 mg, 10% m) was added, and argon was introduced for protection. The reactants were stirred at room temperature for 12 hours. The reaction was completed after TLC monitoring. The palladium / carbon was filtered and extracted with ethyl acetate (2.0 mL×2). The organic phase was collected;

[0217] (2) The combined organic layers were dried, concentrated and purified by flash silica gel chromatography using (petroleum ether:ethyl acetate 9:1) to afford the bicyclo[2.1.1]hexanespiro-2-oxoindole derivative 6 in 80% yield.

[0218] The NMR data are:

[0219] 1H NMR (400MHz, CDCl3) δ7.22–7.18(m,5H),7.14–7.06(m,2H),6.86(t,J=7.2Hz,1H),6.62(d,J=7.6Hz,1H ),5.06(d,J=15.6Hz,1H),4.78(d,J=15.6Hz,1H),4.15–4.10(m,2H),3.84(d,J=2.0Hz,1H),3.71–3.60 (m,2H),3.0–2.95(m,1H),2.51(d,J=8.4Hz,1H),2.12(dd,J=8.4,2.0Hz,1H),1.81(d,J=7.2Hz,1H),1. 20(t,J=7.2Hz,3H),1.15–1.11(m,1H),1.01–0.95(m,1H),0.68(t,J=7.6Hz,3H),0.58(t,J=6.8Hz,3H).

[0220] 13 C NMR (101MHz, CDCl3) δ177.7,170.1,169.7,142.5,134.6,127.9,127.6,127.4,126.5,125.9,12 3.6,121.3,107.9,59.8,59.6,59.2,56.8,56.2,47.5,42.7,40.3,38.2,20.2,13.2,12.5,9.7.

[0221] HRMS (TOF-ESI + )m / z:calcd for C 28 H 31 NO5[M+Na] + 484.2094 found 484.2086.

[0222] Application Example 2

[0223] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, having the structural formula:

[0224]

[0225] The synthesis route of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative of this application example is:

[0226]

[0227] The synthesis method of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative of this application example comprises the following steps:

[0228] (1) The bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3a (0.1 mmol, 1.0 equivalent) of Example 1 was dissolved in dichloromethane and acetic acid (volume ratio 3:1), pyridinium tribromide (0.11, 1.1 equivalent) was added, and the reactants were stirred at 25° C. for 2 hours. The reaction was completed by TLC monitoring, and the mixture was extracted with ethyl acetate (5 mL×2), and the organic phase was collected;

[0229] (2) The combined organic layers were dried, concentrated and purified by flash silica gel chromatography using (petroleum ether:ethyl acetate 3:1) to afford the bicyclo[2.1.1]hexanespiro-2-oxoindole derivative 7 in 36% yield.

[0230] The NMR data are:

[0231] 1 H NMR (400MHz, CDCl3) δ7.25–7.16(m,7H),6.91–6.87(m,1H),6.67(d,J=8.0Hz ,1H),5.13(d,J=15.6Hz,1H),4.76–4.69(m,1H),4.17–4.13(m,2H),3.89–3.8 6(m,1H),3.73–3.61(m,3H),3.46–3.42(m,2H),3.25–3.20(m,1H),2.87–2.8 2(m,1H),2.43(dd,J=8.4,2.0Hz,1H),2.03(d,J=7.2Hz,1H),1.21(t,J=7.2Hz 3H), 0.55 (t, J = 7.2 Hz, 3H).

[0232] 13 C NMR (101MHz, CDCl3) δ176.8,169.2,169.1,142.8,134.3,128.4,128.3,127.8,127.7,126.7,126.6,126.1,126.0,125.7,124.5,124.0 ,121.6,108.5,108.4,60.1,60.0,59.7,59.5,59.4,57.0,56.0,54.8,51.0,47.2,46.3,45.9,43.1,41.8,41.1,40.8,33.4,13.2,12.5.

[0233] HRMS (TOF-ESI + )m / z:calcd for C 28 H 29 Br2NO5[M+Na] +642.0284 found 642.0279.

[0234] Application Example 3

[0235] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, having the structural formula:

[0236]

[0237] The synthesis route of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative of this application example is:

[0238]

[0239] The synthesis method of bicyclo[2.1.1]hexane spiro-2-oxidoindole in this application example comprises the following steps:

[0240] (1) The bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3a (0.1 mmol, 1.0 equivalent) of Example 1 was added to dichloromethane (1.0 mL), and m-chloroperbenzoic acid (0.15 mmol, 1.5 equivalent, 85%) was added. The mixture was stirred at room temperature for 2 hours. The reaction was complete after TLC monitoring. The mixture was extracted with ethyl acetate (5 mL×2), washed with saturated sodium bicarbonate, and the organic phase was collected.

[0241] (2) The combined organic layers were dried, concentrated and purified by flash silica gel chromatography using (petroleum ether:ethyl acetate 1:1) to afford the bicyclo[2.1.1]hexanespiro-2-oxoindole derivative 8 in 79% yield.

[0242] The NMR data are:

[0243] 1H NMR (400MHz, CDCl3, major diastereomer)δ7.19(t,J=4.9Hz,6H),7.08(dt,J=7.7,3.9Hz,1H),6.88–6.84(m,1H),6 .60(d,J=7.7Hz,1H),5.37–5.30(m,1H),4.89(dd,J=6.6,2.7Hz,4H),4.13(dt,J=9.6,4. 8Hz,2H),3.89(d,J=2.2Hz,1H),3.74–3.65(m,2H),3.26–3.22(m,1H),2.83–2.78(m,1H) ,2.17(dd,J=8.1,2.1Hz,1H),1.90(d,J=6.9Hz,1H),1.21(s,3H),0.62(t,J=7.1Hz,3H).

[0244] 13C NMR (100MHz, CDCl3, major diastereomer)δ176.8,169.2,169.1,142.3,134.5,128.4,127.7,126.6,126.1,125.7,124.5,124.0 ,121.6,117.0,108.5,108.4,60.1,60.0,59.4,56.0,47.2,45.9,43.1,41.1,40.8,33.4,13.2,12.5.

[0245] HRMS(TOF-ESI+)m / z:calcd for C28H29NO6[M+Na]+498.1887found 498.1992.

[0246] Application Example 4

[0247] A bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, having the structural formula:

[0248]

[0249] The synthesis route of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative of this application example is:

[0250]

[0251] The synthesis method of bicyclo[2.1.1]hexane spiro-2-oxidoindole in this application example comprises the following steps:

[0252] (1) The bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative 3a (0.1 mmol, 1.0 equivalent) of Example 1 was added to dichloromethane (1.0 mL), cooled to -78°C, and ozone was introduced until a blue color appeared; oxygen and nitrogen were then blown into the solution, dimethyl sulfide (0.5 mmol, 5 equiv) was added, and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with dichloromethane (5.0 mL×2), and washed with brine (5.0 mL×2) to obtain an organic phase;

[0253] (2) The organic phase was dried and concentrated, and purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the bicyclo[2.1.1]hexanespiro-2-oxidoindole derivative 8 in a yield of 78%.

[0254] The NMR data are:

[0255] 1H NMR (400MHz, CDCl3) δ9.29(s,1H),7.25–7.19(m,5H),7.09(t,J=7.6Hz,2H),6.85(t,J=7.6Hz,1H),6.64(d,J=7.6Hz,1H),5.08(d,J=15.6H z,1H),4.85(d,J=16.0Hz,1H),4.19–4.13(m,2H),3.87(d,J=2.0Hz,1H),3.70–3.58(m,2H),3.38(dd,J=10.0,7.2Hz,1H),2.88(t,J=8.4Hz 1H), 2.65 (dd, J=8.0, 2.0Hz, 1H), 2.27 (d, J=7.2Hz, 1H), 1.22 (t, J=7.2Hz 3H), 0.57 (t, J=6.8Hz, 3H).

[0256] 13C NMR (100MHz, CDCl3) δ195.4,176.4,168.8,168.7,142.4,134.4,128.1,127.7,126.6,126.3,125 .9,123.2,121.5,108.4,64.1,60.1,59.6,55.9,52.7,48.3,42.9,41.6,39.2,28.7,13.1,12.5.

[0257] HRMS(TOF-ESI+)m / z:calcd for C27H27NO6[M+Na]+484.1731found 484.1821.

[0258] 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 bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative, characterized in that Its structural formula is: Among them, R 1 is selected from hydrogen, methyl, ethyl, benzyl, phenyl, allyl, acetyl or tert-butyloxycarbonyl; R 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy; R 3 is selected from ethoxy, methoxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-cyclohexylphenyl, 2-thienyl or 2-naphthyl; R 4 Selected from methoxy, ethoxy, trifluoroethoxy or phenyl.

2. A method for preparing the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative according to claim 1, characterized in that: The following steps are involved: (1) A nitrogen-protected α,β-unsaturated 2-oxidoindole derivative and a vinyl bicyclo[1.1.0]butane derivative are stirred and mixed in an organic solvent, a palladium catalyst system is added, and the mixture is stirred and reacted under argon protection; after the reaction is completed, extraction is performed and the organic phase is collected; (2) drying the organic phase obtained in step (1), concentrating under reduced pressure, and separating by silica gel column chromatography to obtain a bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative; The synthesis route of the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative is:

3. The method for preparing the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative according to claim 2, characterized in that: In the step (1), the reaction temperature is 70-85° C. and the reaction time is 10-15 h.

4. The method for preparing the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative according to claim 2, characterized in that: The organic solvent is dichloromethane, chloroform, trifluorotoluene or toluene.

5. The method for preparing the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative according to claim 4, characterized in that: The organic solvent is toluene.

6. The method for preparing the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative according to claim 2, characterized in that: The catalytic system is Pd(PPh3)4.

7. The method for preparing the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative according to claim 2, characterized in that: The molar ratio of the nitrogen-protected α,β-unsaturated 2-oxidoindole derivative, the vinyl bicyclo[1.1.0]butane derivative and the palladium catalyst system is 1:1-2.5:0.01-0.

06.

8. The method for preparing the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative according to claim 7, characterized in that: The molar ratio of the nitrogen-protected α,β-unsaturated 2-oxidoindole derivative, the vinyl bicyclo[1.1.0]butane derivative and the palladium catalyst system is 1:2:0.

05.

9. The method for preparing the bicyclo[2.1.1]hexane spiro-2-oxidoindole derivative according to claim 3, characterized in that: In the step (1), the reaction temperature is 80° C. and the reaction time is 12 h.

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