A method for the synthesis of a cycloheptatriene derivative catalyzed by dmap

Abstract

The application discloses a method for synthesizing a cycloheptatriene derivative by using DMAP as a catalyst, and the method comprises the following steps: using methyl coumarin and a gamma-substituted allene acid ester as raw materials, and performing a reaction in a solvent under the action of an organic base catalyst to synthesize the cycloheptatriene derivative in one step, wherein R 1 is any one of alkyl and a phenyl substituted by F, Cl, Br, Me and OMe. 2 R is any one of Et, Me, Bn and tBu. The synthesis method is simple to operate, raw materials and catalysts are simple and easy to obtain, reaction time is short, the scope of reaction substrates is wide, the yield of the target product is high, and the method has a wide industrial production prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and relates to a synthesis method of a cycloheptatriene derivative. BACKGROUND

[0002] Cycloheptatriene structure widely exists in organic compounds, some in the form of cycloheptatrienone, and some in the form of bicyclo[5,3,0]decane structure, such as azulene, which is a cycloheptatriene and five-membered ring structure, and has special aromaticity. Cycloheptatriene structure also widely exists in natural products, and many drugs or drug intermediates contain cycloheptatriene derivative structural units. Cycloheptatriene derivatives mostly have biological activities such as anti-tumor, antibacterial, anti-viral, anti-inflammatory, etc. For example, natural product harringtonolid is a polycyclic compound based on cycloheptatrienone structure, which has anti-tumor and anti-viral activities, and reiswigin B and Cyanthiwigins show excellent anti-tumor activity. Due to the unique biological activities and potential application values of these compounds, it is of great significance to develop a new method for practically and effectively synthesizing cycloheptatriene derivatives.

[0003]

[0004] At present, the main synthesis methods of cycloheptatriene derivatives include ring expansion reaction of six-membered ring, cycloaddition reaction and ring-closing metathesis reaction, etc. The ring expansion of six-membered ring mainly includes the ring expansion reaction of simple six-membered ring and benzene ring, which has been widely applied to the synthesis of cycloheptatriene derivatives. The [4+3] cycloaddition reaction, [5+2] cycloaddition (see: Ma Z., Cheng B., Zhai H. Asian Journal of Organic Chemistry, 2014, 3(10): 1097-1101.; Hirsch D.R., Schiavone D.V., Berkowitz A.J., et al. Organic & Biomolecular Chemistry, 2018, 16(1): 62-69.; Chang Y., Shi L., Huang J., et al. Organic Letters, 2018, 20(10): 2876-2879.; Hegde V., Campitelli M., Quinn R.J., et al. Organic & Biomolecular Chemistry, 2011, 9(12): 4570-4579.) have been reported, but there is no report on the synthesis of cycloheptatriene derivatives catalyzed by DMAP. SUMMARY

[0005] In order to solve the problem that DMAP is not used to catalyze synthesis of cycloheptatriene derivatives at present, the application provides a method for synthesizing cycloheptatriene derivatives by using DMAP as a catalyst.

[0006] The technical scheme of the application is as follows:

[0007] The application provides a method for synthesizing cycloheptatriene derivatives, which uses methyl coumarate and γ-substituted allene acid ester as raw materials, and carries out a reaction in a solvent under the action of an organic base catalyst to synthesize the cycloheptatriene derivatives in one step.

[0008] Among them:

[0009] R 1 is alkyl, alkyl substituted at any position of a benzene ring, halogen, alkoxy and the like;

[0010] R 2 is alkyl; further, R 1 is C1-C6 alkyl, chloroethyl, phenethyl, thienyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is selected from halogen, C1-C4 alkyl or C1-C4 alkoxy; R 2 is any one of Bn and C1-C4 alkyl; further, R 1 is methyl, isopropyl, chloroethyl, n-hexyl, phenethyl, ethyl, phenyl, p-tolyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl or thienyl; R 2 is benzyl, t-butyl, ethyl or methyl.

[0011] As a preferred, the organic base catalyst is DMAP.

[0012] As a preferred, the loading of the organic base catalyst is 15-25 mol% relative to the amount of methyl coumarate.

[0013] As a preferred, the solvent is dichloromethane.

[0014] As a preferred, the reaction temperature is 20-40℃.

[0015] As a preferred, the molar ratio of methyl coumarate to γ-substituted allene acid ester is 1:1.4-1.6.

[0016] Further, the optimal reaction condition is that the feeding ratio of methyl coumarate to γ-substituted allene acid ester is 1:1.5, the catalyst loading is 20 mol%, the temperature is 30℃, and the reaction solvent is dichloromethane.

[0017] Advantages

[0018] Compared with the existing synthesis method of cycloheptatriene derivatives, the synthesis method has the advantages that the operation is simple, special reaction equipment is not needed, the reaction time is short, the reaction condition can be carried out at 30 DEG C and in an atmospheric environment, the production cost is reduced, the raw materials and catalysts needed are simple and easy to obtain, the reaction cost is low, the yield of the target product is high, the substrate application range is wide, the environment is friendly, and the industrial production prospect is wide. DETAILED DESCRIPTION

[0019] The technical solutions of the present application will be described in detail below with examples

[0020]

[0021] The aryl phenylacetylene (6.0 mmol, 1.0 equiv.) and CuI (0.3 mmol, 0.050 equiv.) were dissolved in acetonitrile, then ethyl diazoacetate (6.0 mmol, 1.0 equiv.) was slowly added under nitrogen protection, and the reaction liquid was reacted at room temperature for 13 hours. After monitoring by TLC plate, the acetonitrile was removed after the reaction was completed, and the target product γ-aryl-3-butynoate was obtained by column chromatography (Suárez, A.; Fu, G.C. Angew. Chem., Int. Ed. 2004, 43, 3580.).

[0022]

[0023] Phosphorus ylide (6.6 mmol, 1.1 equiv.) was weighed and dissolved in DCM, TEA (6.6 mmol, 1.1 equiv.) was added at 0 DEG C, the mixture was stirred for 10 minutes, then the acyl chloride (6.0 mmol, 1.0 equiv.) was slowly added, and the reaction was transferred to room temperature. After monitoring by TLC plate, the mixture was filtered, dried, and the target product γ-alkyl allenoate was obtained by column chromatography (Rout L.; Harned, A.M. Chem. Eur. J. 2009, 15, 12926-12928.).

[0024] Case 1:

[0025]

[0026] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-alkyl allenoate 1a (141.2 mg, 0.75 mmol, 1.5 equiv.) were weighed in a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% of DMAP catalyst was added. The reaction was stirred at 30 DEG C for 12 hours, and then column chromatography separation and purification (petroleum ether / ethyl acetate = 25 / 1) were carried out to obtain the product 2a, a colorless oily liquid, the separation yield was 123.7 mg, and the yield was 83%.

[0027] 1 H NMR (400 MHz, CDC13) δ 8.26 (s, 1H), 7.42 - 7.31 (m, 5H), 6.72 (d, J = 9.4 Hz, 1H), 6.48 (d, J = 6.1 Hz, 1H), 5.30 - 5.24 (m, 2H), 5.23 - 5.20 (m, 1H), 3.85 (s, 3H), 1.70 (q, J = 6.4 Hz, 1H), 1.42 (d, J = 6.9 Hz, 3H).

[0028] 13 C NMR (101 MHz, CDC13) δ 167.48, 165.80, 140.50, 135.90, 134.33, 133.72, 128.65, 128.36, 127.79, 127.44, 124.49, 66.90, 52.35, 33.38, 18.39.

[0029] MS (ESI): m / z calcd for C 18 H 18 O4[M+H] + = 299.1278, found = 299.1283.

[0030] Example 2:

[0031]

[0032] Methyl coumaric acid (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-alkyl allenic ester 1b (161.2 mg, 0.75 mmol, 1.5 equiv.) were weighed in a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30°C for 12 h, and then column chromatography was performed for separation and purification (petroleum ether / ethyl acetate = 25 / 1) to obtain the product 2b as a colorless oily liquid, separation yield 130.6 mg, yield: 80%.

[0033] 1 H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 7.43 - 7.30 (m, 5H), 6.80 (d, J = 9.3 Hz, 1H), 6.53 (d, J = 6.5 Hz, 1H), 5.32 - 5.26 (m, 2H), 5.23 (d, J = 12.4 Hz, 1H), 3.85 (s, 3H), 1.97 (d, J = 13.2, 6.6 Hz, 1H), 1.24 - 1.18 (m, 1H), 1.04 (d, J = 6.7 Hz, 6H).

[0034] 13 C NMR (101 MHz, CDC13) δ 167.50, 165.85, 135.99, 135.12, 133.96, 133.36, 128.63, 128.30, 128.25, 128.11, 125.29, 122.28, 66.83, 52.30, 45.80, 29.90, 20.55, 20.25.

[0035] MS (ESI): m / z calcd for C 20 H 22 O4[M+H] + = 327.1591, found = 327.1598.

[0036] Example 3:

[0037]

[0038] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-alkyl allenoate 1c (177.5 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography was performed for separation and purification (petroleum ether / ethyl acetate = 20 / 1) to obtain the product 2c as a colorless oily liquid, separation yield 112.5 mg, yield: 65%.

[0039] 1 H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 7.41 - 7.32 (m, 5H), 6.81 (d, J = 9.6 Hz, 1H), 6.44 (d, J = 6.3 Hz, 1H), 5.31 - 5.22 (m, 2H), 5.22 - 5.18 (m, 1H), 3.85 (s, 3H), 3.64 (t, J = 6.6 Hz, 2H), 2.23 (q, J = 8.3, 7.5 Hz, 2H), 1.90 (p, J = 6.5, 5.8 Hz, 1H).

[0040] 13 C NMR (101 MHz, CDC13) δ 167.50, 165.85, 135.99, 135.12, 133.96, 133.36, 128.63, 128.30, 128.25, 128.11, 125.29, 122.28, 66.83, 52.30, 45.80, 29.90, 20.55, 20.25.

[0041] MS (ESI): m / z calcd for C 19 H 19 ClO4[M+H] + = 347.1045, found = 347.1051

[0042] Example 4:

[0043]

[0044] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-alkyl allenoate 1d (193.8 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography (petroleum ether / ethyl acetate = 20 / 1) was performed to purify the product 2d, a colorless oily liquid, separation yield 134.0 mg, yield: 73%.

[0045] 1 H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 7.42 - 7.30 (m, 5H), 6.75 (d, J = 9.4 Hz, 1H), 6.49 (d, J = 6.2 Hz, 1H), 5.31 - 5.24 (m, 2H), 5.22 (d, J = 6.9 Hz, 1H), 3.85 (s, 3H), 1.82 - 1.74 (m, 2H), 1.56 (p, J = 5.8 Hz, 1H), 1.42 (p, J = 7.5, 7.0 Hz, 2H), 1.30 (dd, J = 9.8, 5.4 Hz, 6H), 0.91 - 0.86 (m, 3H).

[0046] 13 C NMR (101 MHz, CDC13) δ 167.48, 165.80, 138.25, 135.96, 134.17, 133.55, 128.63, 128.31, 128.29, 128.05, 125.18, 124.97, 66.85, 52.30, 38.87, 32.92, 31.76, 29.18, 27.24, 22.62, 14.11.

[0047] MS (ESI): m / z calcd for C 23 H 28 O4[M+H] + = 369.2060, found = 369.2068.

[0048] Example 5:

[0049]

[0050] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-alkyl allenoate 1e (208.8 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography (petroleum ether / ethyl acetate = 20 / 1) was performed to purify the product 2e, a colorless oily liquid, separation yield 147.5 mg, yield: 76%.

[0051] 1 H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 7.40 - 7.30 (m, 5H), 7.24 (d, J = 14.8 Hz, 2H), 7.15 (m, J = 12.5, 6.9 Hz, 3H), 6.77 (d, J = 9.3 Hz, 1H), 6.48 (d, J = 6.2 Hz, 1H), 5.29 - 5.23 (m, 2H), 5.21 (d, J = 12.3 Hz, 1H), 3.82 (s, 3H), 2.77 - 2.69 (m, 2H), 2.08 (m, J = 7.9, 2.8 Hz, 2H), 1.62 (q, J = 7.1 Hz, 1H).

[0052] 13 C NMR (101 MHz, CDC13) δ 167.41, 165.76, 141.32, 137.08, 135.96, 134.23, 133.58, 128.69, 128.57, 128.44, 128.40, 128.36, 128.27, 126.15, 125.38, 124.22, 66.95, 52.38, 38.31, 34.57, 33.57.

[0053] MS (ESI): m / z calcd for C 25 H 24 O4[M+H] + = 389.1747, found = 389.1759.

[0054] Example 6:

[0055]

[0056] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-alkyl allenoate 1f (126.2 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography separation and purification (petroleum ether / ethyl acetate = 25 / 1) was performed to obtain the product 2f, colorless oily liquid, separation yield 84.8 mg, yield: 61%.

[0057] 1 H NMR (400 MHz, CDC13) δ 8.17 (s, 1H), 6.71 (d, J = 9.4 Hz, 1H), 6.39 (d, J = 6.1 Hz, 1H), 5.25 (dd, J = 9.5, 5.2 Hz, 1H), 3.83 (s, 3H), 1.85 - 1.76 (m, 2H), 1.51 (s, 9H), 1.49 - 1.42 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H).

[0058] 13 C NMR (101 MHz, CDC13) δ 167.62, 165.10, 137.91, 134.64, 133.12, 129.76, 125.70, 124.69, 81.39, 52.20, 40.30, 28.14, 25.87, 11.64.

[0059] MS (ESI): m / z calcd for C 16 H 22 O4[M+H] + = 279.1591, found = 279.1598.

[0060] Example 7:

[0061]

[0062] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-aryl-3-butynoate 1g (141.2 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography separation and purification (petroleum ether / ethyl acetate = 20 / 1) was performed to obtain the product 2g, colorless oily liquid, separation yield 79.0 mg, yield: 53%.

[0063] 1H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 7.42 - 7.37 (m, 2H), 7.32 (d, J = 8.3 Hz, 3H), 6.94 (d, J = 8.9 Hz, 1H), 6.35 (d, J = 6.2 Hz, 1H), 5.20 (m, J = 9.1, 3.5 Hz, 1H), 4.28 (q, J = 7.1, 3.6 Hz, 2H), 3.88 (s, 3H), 2.58 - 2.53 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H).

[0064] 13 C NMR (101 MHz, CDC13) δ 167.23, 165.92, 141.45, 133.51, 132.59, 129.01, 128.31, 127.37, 127.26, 126.66, 126.22, 115.84, 61.31, 52.39, 43.16, 14.34;

[0065] MS (ESI): m / z calcd for C 18 H 18 O4[M+H] + = 299.1278, found = 299.1283.

[0066] Example 8:

[0067]

[0068] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-aryl-3-butynoate 1h (151.7 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography (petroleum ether / ethyl acetate = 20 / 1) was performed to purify the product 2h, a yellow oily liquid, separation yield 90.5 mg, yield: 58%.

[0069] 1 H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 7.21 (d, J = 1.8 Hz, 4H), 6.92 (d, J = 8.9 Hz, 1H), 6.38 (d, J = 6.2 Hz, 1H), 5.22 (dd, J = 9.9, 6.1 Hz, 1H), 4.27 (m, J = 7.1, 2.9 Hz, 2H), 3.88 (s, 3H), 2.56 - 2.52 (m, 1H), 2.37 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0070] 13 C NMR (101 MHz, CDC13) δ 167.25, 165.92, 138.45, 136.89, 133.59, 132.64, 129.67, 128.20, 127.68, 127.26, 126.36, 117.07, 61.27, 52.36, 43.02, 21.09, 14.34.

[0071] MS (ESI): m / z calcd for C 19 H 20 O4[M+H] + = 313.1434, found = 313.1440.

[0072] Example 9:

[0073]

[0074] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-aryl-3-butynoate 1i (163.7 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography was performed for separation and purification (petroleum ether / ethyl acetate = 20 / 1) to obtain the product 2i, a yellow oily liquid, separation yield 72.2 mg, yield: 44%.

[0075] 1 H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.96 - 6.88 (m, 3H), 6.39 (d, J = 6.3 Hz, 1H), 5.23 (d, J = 9.1, 5.2 Hz, 1H), 4.27 (q, J = 6.8, 3.7 Hz, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 2.54 (t, J = 5.8 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H).

[0076] 13 C NMR (101 MHz, CDC13) δ 167.28, 165.93, 158.83, 133.65, 133.47, 132.72, 128.74, 128.40, 128.10, 126.11, 118.04, 114.39, 61.28, 55.37, 52.37, 42.77, 14.33;

[0077] MS (ESI): m / z calcd for C 19 H 20 O5[M+H] + = 329.1384, found = 329.1390.

[0078] Example 10:

[0079]

[0080] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-aryl acetylene ester 1j (84.2 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography (petroleum ether / ethyl acetate = 20 / 1) was performed to purify and separate the product 2j, a colorless oily liquid, separation yield 85.5 mg, yield: 77%.

[0081] 1 H NMR (400 MHz, CDC13) δ 8.17 (s, 1H), 6.68 (d, J = 9.4 Hz, 1H), 6.42 (d, J = 6.1 Hz, 1H), 5.20 (dd, J = 9.4, 5.1 Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 1.67 (q, J = 6.8 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H).

[0082] 13 C NMR (101 MHz, CDC13) (101 MHz, CDC13) δ 167.42, 166.35, 140.32, 134.26, 133.60, 127.73, 127.43, 124.41, 52.28, 52.17, 33.28, 18.34.

[0083] MS (ESI): m / z calcd for C 12 H 14 O4[M+H] + = 223.0965, found = 223.0969.

[0084] Example 11:

[0085]

[0086] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-aryl-3-butynoate 1k (154.7 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography (petroleum ether / ethyl acetate = 20 / 1) was performed to purify the product 2j, a yellow oily liquid, isolated yield 80.6 mg, yield: 51%.

[0087] 1 H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 7.30 (dd, J = 8.5, 5.4 Hz, 2H), 7.08 (t, J = 8.6 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 6.33 (d, J = 6.3 Hz, 1H), 5.19 (dd, J = 9.9, 6.0 Hz, 1H), 4.28 (q, J = 7.1, 3.9 Hz, 2H), 3.88 (s, 3H), 2.57 (t, J = 5.8 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H).

[0088] 13 C NMR (101 MHz, CDC13) δ 167.13, 165.82, 163.24, 160.80, 137.13, 137.10, 133.58, 132.72, 128.93, 128.85, 128.34, 126.80, 126.55, 116.40, 115.93, 115.72, 61.36, 52.40, 42.51, 14.31.

[0089] MS (ESI): m / z calcd for C 18 H 17 04 [M+H] + = 317.1184, found = 317.1189.

[0090] Example 12:

[0091]

[0092] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-aryl-3-butynoate 1l (167.0 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography separation and purification (petroleum ether / ethyl acetate = 20 / 1) gave the product 2l, yellow oily liquid, separation yield 79.9 mg, yield: 48%.

[0093] 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.38 - 7.34 (m, 2H), 7.27 - 7.24 (m, 2H), 6.95 (d, J = 8.9 Hz, 1H), 6.26 (d, J = 6.2 Hz, 1H), 5.13 (dd, J = 8.1, 4.4 Hz, 1H), 4.28 (q, J = 7.1, 3.7 Hz, 2H), 3.88 (s, 3H), 2.54 (t, J = 5.5 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H).

[0094] 13 C NMR (101 MHz, CDCl3) δ 167.07, 165.79, 139.84, 133.47, 133.09, 132.60, 129.12, 128.70, 128.48, 126.99, 124.67, 114.54, 61.39, 52.43, 42.29, 14.33.

[0095] MS (ESI): m / z calcd for C 18 H 17 ClO4[M+H] + = 333.0888, found = 333.0891

[0096] Example 13:

[0097]

[0098] Methyl coumarate (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-aryl-3-butynoate 1m (200.3 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography separation and purification (petroleum ether / ethyl acetate = 30 / 1) gave the product 2m, yellow oily liquid, separation yield 91.2 mg, yield: 49%.

[0099] 1 H NMR (400 MHz, CDC13) δ 8.21 (s, 1H), 7.52 - 7.49 (m, 2H), 7.21 - 7.18 (m, 2H), 6.94 (d, J = 8.9 Hz, 1H), 6.24 (d, J = 6.2 Hz, 1H), 5.11 (dd, J = 9.1, 5.2 Hz, 1H), 4.27 (q, J = 7.1, 3.6 Hz, 2H), 3.87 (s, 3H), 2.51 (t, J = 5.5 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H).

[0100] 13 C NMR (101 MHz, CDC13) δ 167.06, 165.78, 140.37, 133.46, 132.59, 132.08, 129.07, 128.51, 127.06, 124.31, 121.12, 114.21, 61.40, 52.44, 42.31, 14.33.

[0101] MS (ESI): m / z calcd for C 18 H 17 BrO4[M+H] + = 377.0383, found = 377.0382.

[0102] Example 14:

[0103]

[0104] Methyl coumaric acid (77.1 mg, 0.5 mmol, 1.0 equiv.) and γ-aryl acetylene ester 1n (145.7 mg, 0.75 mmol, 1.5 equiv.) were weighed into a sealed tube, 5 mL of dichloromethane was added, and finally 20 mol% DMAP catalyst was added. The reaction was stirred at 30 °C for 12 h, and then column chromatography was performed for separation and purification (petroleum ether / ethyl acetate = 20 / 1) to obtain the product 2n, a yellow oily liquid, separation yield 100.3 mg, yield: 66%.

[0105] 1H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 7.37 (dd, J = 5.0, 3.0 Hz, 1H), 7.19 (d, J = 3.0 Hz, 1H), 7.10 (dd, J = 5.0, 1.4 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 6.50 (d, J = 6.3 Hz, 1H), 5.35 (dd, J = 8.7, 5.8 Hz, 1H), 4.27 (qd, J = 7.1, 3.8 Hz, 2H), 3.87 (s, 3H), 2.74 (t, J = 5.9 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H).

[0106] 13 C NMR (101 MHz, CDC13) δ 167.21, 165.82, 141.81, 133.97, 133.09, 130.25, 128.26, 126.81, 126.74, 125.82, 120.98, 119.26, 61.35, 52.41, 39.39, 14.34.

[0107] MS (ESI): m / z calcd for C 19 H 20 O5[M+H] + = 305.0842, found = 305.0843.

[0108] The above description is merely preferred embodiments of the present application, but the protection scope of the present application is not limited thereto, and simple changes or equivalent replacements of technical schemes that can be obviously obtained by any person skilled in the art within the technical scope disclosed by the present application all fall into the protection scope of the present application.

Claims

1. A method of synthesizing a cycloheptatriene derivative, characterized by, A cycloheptatriene derivative is synthesized by using methyl coumarate and γ-substituted allenoate as raw materials, and by carrying out a reaction in a solvent under the action of an organic base catalyst: The cycloheptatriene derivative has the following structural formula: wherein R1 1 is C1-C6 alkyl, chloroethyl or phenethyl; R 2 is any one of Bn, C1-C4 alkyl; The organic base catalyst is DMAP.

2. The method of synthesizing a cycloheptatriene derivative according to claim 1, characterized in that, R 1 is methyl, isopropyl, chloroethyl, n-hexyl, phenethyl or ethyl; R 2 is benzyl, t-butyl, ethyl or methyl.

3. The method of synthesizing a cycloheptatriene derivative according to claim 1, wherein, The loading of the organic base catalyst is 15-25 mol% relative to the amount of methyl coumarate.

4. The method of synthesizing a cycloheptatriene derivative according to claim 1, wherein The solvent is dichloromethane.

5. The method of synthesizing a cycloheptatriene derivative according to claim 1, wherein The reaction temperature is 20-40 ℃.

6. The method of synthesizing a cycloheptatriene derivative according to claim 1, wherein The molar ratio of methyl coumarate to γ-substituted allenoate is 1:1.4-1.6.

Images