A method of synthesizing a benzazepine derivative

Abstract

The application discloses a method for synthesizing a benzazepine derivative, which uses MBH carbonate and cycloheptatriene imine as raw materials, toluene as a solvent, heating to 80 DEG C, and one-step synthesis of a target product under the action of a commercial phosphine catalyst. 1 R is any one of Et, Me, tBu and Bn; R 2 is a phenyl or heteroaryl group substituted by any one of H, F, Cl, Me, OMe and NO2, 2-furyl, 2-quinolinyl and styryl; R 3 is any one of Me, 4-MeC6H5, 4-NO2C6H5 and 4-MeOC6H5. The synthesis method is simple in operation, simple in raw materials and catalyst, short in reaction time, wide in applicable range of reaction substrates, high in yield of the target product and wide in industrial production prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a benzo[a]azapyridine. Methods for synthesizing derivatives. Background Technology

[0002] Nitrogen heterocycles are crucial structural motifs in pharmaceuticals, alkaloids, and agrochemicals. Nearly 75% of FDA-approved drugs are nitrogen heterocycles. While four-, five-, and six-membered non-heterocyclic compounds dominate the pharmaceutical field, seven-membered nitrogen heterocycles have seen increasing popularity in recent years. and benzo[a]aza The structural motif of 1-benzodiazepines has also found its place in many drugs. For example, benazepril (an antihypertensive drug), epinastine (an antihistamine), tolvaptan (a drug for treating hyponatremia), and mianserin (an antidepressant) all contain 1-benzodiazepines. Commonly used drugs and natural alkaloids for stents. Similarly, 2-phenylazine... The skeleton is found in capsaicin and the alkaloid galantamine (used to treat Alzheimer's disease). The antihypertensive drug fenoldopam, the anti-obesity drug lorcaserin, and alkaloids such as lenoxamine and cephalotaxine are biologically active 3-benzodiazepines. Examples. This shows that benzo[a]aza The importance of scaffolds in medicinal chemistry and drug development necessitates the investigation of the synthesis of benzo[a]azapyridines. The skeleton will be of great significance.

[0003] Currently, constructing aza-seven-membered rings via simple cyclization reactions remains challenging due to unfavorable transcyclic interactions and entropy effects. Given the importance of aza-seven-membered ring compounds and the synthetic challenges, researchers have so far developed a series of cyclization reactions to construct aza-seven-membered ring derivatives, including the synthesis of benzo[a]azapyrrolizidine derivatives. However, these synthetic methods suffer from the following drawbacks:

[0004] (1) Expensive metal catalysts are required (see Zhao, Y.; Chen J.-R.; Xiao, WJ. Org. Lett., 2018, 20, 224-227.; Li, Y.; Hu, M.; Li, J.-H. ACS Catal., 2017, 7, 6757.; Perez, A.; Gonzalez-Rodriguez, C.; Garcia-Yebra, C.; Esteruelas, M. A.; Sa a, C. Angew. Chem. Int. Ed., 2015, 54, 13357-13361.; Guo, C.; Fleige, M.; Janssen-Muller, D.; Daniliuc, C. G.; Glorius, F. J. Am. Chem. Soc., 2016, 138, 25, 7840-7843);

[0005] (2) The substrates require multistep synthesis and final intramolecular cyclization (see Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem., 1976, 43, 1684. Dumoulin, D.; Lebrun, S.; Deniau, E.; Couture, A.; Grandclaudon, P. Eur. J. Org. Chem., 2009, 2009, 3741-3752.; Ouchakour, L.; Nonn, M.; D’hooghe, M.; Kiss, L. Journal of Fluorine Chemistry, 2020, 232, 109466.; Marepu, N.; Yeturu, S.; Pal, M. Asian J. Org. Chem., 2018, 7, 1806-1809.);

[0006] (3) The reaction conditions are harsh and hazardous (see Meyers, A. I.; Hutchings, R. H. Tetrahedron, 1993, 49, 1807-1820.; Kaldas, S. J.; Kran, E.; Muck-Lichtenfeld, C.; Yudin, A. K.; Studer, A. Chem. Eur. J., 2020, 26, 1501-1505.).

[0007] Therefore, it is still challenging to rapidly construct benzazepine derivatives from simple and readily available starting materials. SUMMARY

[0008] To solve the disadvantages of the current synthesis of benzazepine derivatives, the present application provides a method for synthesizing benzazepine derivatives, which directly obtains benzazepine derivatives from simple and readily available Morita-Baylis-Hillman carbonate and cycloheptimine under the action of a commercial phosphine catalyst.

[0009] The technical scheme of the present application is as follows:

[0010] A method for synthesizing a benzazepine derivative derivative is synthesized by heating MBH carbonate and cycloheptatriene imine in a solvent under the action of a phosphine catalyst derivative:

[0011] The structural formula of the cycloheptatriene imine is as follows:

[0012]

[0013] The structural formula of the MBH carbonate is as follows:

[0014]

[0015] The structural formula of the benzazepine derivative is as follows:

[0016]

[0017] R 1 is any one of C1-C4 alkyl, benzyl;

[0018] R 2 is substituted or unsubstituted phenyl or heteroaryl, the heteroaryl being 2-furyl or 2-quinolyl, and the substituent on the phenyl being halogen, C1-C4 alkyl, C1-C4 alkoxy or nitro;

[0019] R 3 is methyl, substituted or unsubstituted phenyl, and the substituent on the phenyl being C1-C4 alkyl, C1-C4 alkoxy or nitro.

[0020] The reaction formula is as follows:

[0021]

[0022] As a preference, R 1 is any one of Et, Me, tBu, Bn; R 2 is substituted or unsubstituted phenyl, 2-furyl, 2-quinolyl or styryl, and the substituent on the phenyl being any one of F, Cl, Me, OMe, NO2; R 3 is any one of Me, 4-MeC6H5, 4-NO2C6H5, 4-MeOC6H5.

[0023] The optimal reaction conditions are a cycloheptatriene imine to MBH carbonate feed ratio of 1:1, a catalyst loading of 30 mol%, a temperature of 80°C, and a reaction solvent of toluene.

[0024] Compared to existing benzodiazepines The synthetic method of this application is simple to operate, does not require special reaction equipment, has a short reaction time, requires simple and readily available raw materials and catalysts, and has low reaction cost. The target product has a high yield and a wide range of substrate applications. It is environmentally friendly and has broad prospects for industrial production. Attached Figure Description

[0025] Figure 1 The product obtained in Example 1 of this invention 1 HNMR spectrum;

[0026] Figure 2 The product obtained in Example 1 of this invention 13 CNMR spectrum;

[0027] Figure 3 The product obtained in Example 2 of this invention 1 HNMR spectrum;

[0028] Figure 4 The product obtained in Example 2 of this invention 13 CNMR spectrum;

[0029] Figure 5 The product obtained in Example 3 of this invention 1 HNMR spectrum;

[0030] Figure 6 The product obtained in Example 3 of this invention 13 CNMR spectrum;

[0031] Figure 7 The product obtained in Example 4 of this invention 1 HNMR spectrum;

[0032] Figure 8 The product obtained in Example 4 of this invention 13 CNMR spectrum;

[0033] Figure 9 The product obtained in Example 5 of this invention 1 HNMR spectrum;

[0034] Figure 10 The product obtained in Example 5 of this invention 13 CNMR spectrum;

[0035] Figure 11 The product obtained in Example 6 of this invention 1 HNMR spectrum;

[0036] Figure 12 The product obtained in Example 6 of this invention13 CNMR spectrum;

[0037] Figure 13 HNMR spectrum of the product obtained in Example 7 of the present invention 1 HNMR spectrum;

[0038] Figure 14 CNMR spectrum of the product obtained in Example 7 of the present invention 13 CNMR spectrum;

[0039] Figure 15 HNMR spectrum of the product obtained in Example 8 of the present invention 1 HNMR spectrum;

[0040] Figure 16 CNMR spectrum of the product obtained in Example 8 of the present invention 13 CNMR spectrum;

[0041] Figure 17 HNMR spectrum of the product obtained in Example 9 of the present invention 1 HNMR spectrum;

[0042] Figure 18 CNMR spectrum of the product obtained in Example 9 of the present invention 13 CNMR spectrum;

[0043] Figure 19 HNMR spectrum of the product obtained in Example 10 of the present invention 1 HNMR spectrum;

[0044] Figure 20 CNMR spectrum of the product obtained in Example 10 of the present invention 13 CNMR spectrum;

[0045] Figure 21 HNMR spectrum of the product obtained in Example 11 of the present invention 1 HNMR spectrum;

[0046] Figure 22 CNMR spectrum of the product obtained in Example 11 of the present invention 13 CNMR spectrum;

[0047] Figure 23 HNMR spectrum of the product obtained in Example 12 of the present invention 1 HNMR spectrum;

[0048] Figure 24 CNMR spectrum of the product obtained in Example 12 of the present invention 13 CNMR spectrum;

[0049] Figure 25 HNMR spectrum of the product obtained in Example 13 of the present invention 1 HNMR spectrum;

[0050] Figure 26 HNMR spectrum of the product obtained in Example 13 of the present invention 13 CNMR spectrum;

[0051] Figure 27 HNMR spectrum of the product obtained in Example 14 of the present invention 1 HNMR spectrum of the product obtained in Example 14 of the present invention

[0052] Figure 28 HNMR spectrum of the product obtained in Example 14 of the present invention 13 CNMR spectrum;

[0053] Figure 29 HNMR spectrum of the product obtained in Example 15 of the present invention 1 HNMR spectrum of the product obtained in Example 15 of the present invention

[0054] Figure 30 HNMR spectrum of the product obtained in Example 15 of the present invention 13 CNMR spectrum. DETAILED DESCRIPTION

[0055] The technical solutions of the present application will be described in detail below in combination with examples.

[0056] The raw material preparation method is as follows:

[0057]

[0058] Under nitrogen protection, cycloheptatrienone (15 mmol, 1.0 equiv.) was added to a suspension of the corresponding sulfonamide (16 mmol, 1.0 equiv.) in 1,2-dichloroethane (0.25 M) and the mixture was cooled to 0°C in a cold bath. Keeping the temperature, titanium tetrachloride (16.5 mmol, 1.8 mL, 1.1 equiv.) was slowly dropped into the reaction solution using a syringe for about 5 minutes, and then triethylamine (33 mmol, 4.6 mL, 2.2 equiv.) was also slowly dropped into the reaction system for about 10 minutes, to obtain a brown reaction mixture. Subsequently, under nitrogen protection, heating was continued to reflux overnight. After the reaction was completed, the reaction was cooled to room temperature, the reaction mixture was diluted with dichloromethane and water, and the insoluble matter was removed by filtration through diatomite. After the filtrate was separated by a separatory funnel, the aqueous phase was extracted with dichloromethane three times (3 x 60 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a cycloheptatriene imine (Manzano, R.; Romaniega, A.; Prieto, L. Org. Lett., 2020, 22, 4721-4725.)

[0059] Example 1:

[0060]

[0061] Cycloheptatrienylamine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2a (30.6 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added to the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15:1) was performed to obtain the product 3aa as a white solid with an isolated yield of 41.6 mg and a yield of 93%.

[0062] 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.57 (m, 1H), 7.56 - 7.50 (m, 2H), 7.31 - 7.18 (m, 6H), 7.13 (d, J = 8.0 Hz, 2H), 7.10 - 7.05 (m, 2H), 6.33 (d, J = 1.4 Hz, 1H), 4.60 (dd, J = 14.4, 5.6 Hz, 1H), 4.16 (ddd, J = 9.7, 5.6, 1.5 Hz, 1H), 3.94 (dd, J = 14.4, 9.7 Hz, 1H), 3.84 (q, J = 7.1 Hz, 2H), 2.31 (s, 3H), 0.89 (t, J = 7.1 Hz, 3H).

[0063] 13 C NMR (101 MHz, CDCl3) δ 170.4, 143.4, 142.1, 139.8, 138.6, 137.9, 133.3, 132.2, 129.8, 129.4, 128.9, 128.1, 127.9, 127.6, 127.5, 127.1, 126.5, 61.0, 52.1, 49.6, 21.4, 13.7.

[0064] HRMS (ESI): m / z calcd for C 26 H 25 NO4S[M+H] + = 448.1577, found = 448.1582.

[0065] Example 2

[0066]

[0067] Cycloheptatrienimine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2b (29.2 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added to the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15:1) was performed to obtain the product 3ab, white solid, with an isolated yield of 36.7 mg, a yield of 87%.

[0068] 1 H NMR (400 MHz, CDC13) δ 7.66 - 7.57 (m, 1H), 7.57 - 7.50 (m, 2H), 7.31 - 7.24 (m, 5H), 7.23 - 7.18 (m, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.10 - 7.04 (m, 2H), 6.35 (d, J = 1.3 Hz, 1H), 4.58 (dd, J = 14.4, 5.5 Hz, 1H), 4.17 (ddd, J = 9.4, 5.5, 1.4 Hz, 1H), 3.97 (dd, J = 14.4, 9.4 Hz, 1H), 3.39 (s, 3H), 2.32 (s, 3H).

[0069] 13 C NMR (101 MHz, CDC13) δ 170.9, 143.5, 142.1, 139.6, 138.6, 137.9, 133.2, 132.2, 130.0, 129.5, 128.8, 128.2, 128.0, 127.6, 127.5, 127.1, 126.4, 52.2, 52.1, 49.6, 21.4.

[0070] HRMS (ESI): m / z calcd for C 25 H 23 NO4S[M + H] + = 434.1421, found = 434.1421.

[0071] Example 3

[0072]

[0073] Cycloheptatrienimine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2c (33.4 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added into the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15:1) was performed to obtain the product 3ac, white solid, separation yield 34.6 mg, yield 73%.

[0074] 1 H NMR (400 MHz, CDC13) δ 7.65 - 7.58 (m, 1H), 7.56 - 7.48 (m, 2H), 7.36 - 7.17 (m, 6H), 7.15 - 7.05 (m, 4H), 6.29 (d, J = 1.4 Hz, 1H), 4.62 (dd, J = 14.4, 5.6 Hz, 1H), 4.05 (ddd, J = 9.9, 5.6, 1.5 Hz, 1H), 3.87 (dd, J = 13.0, 8.6 Hz, 1H), 2.29 (s, 3H), 1.06 (s, 9H).

[0075] 13 C NMR (101 MHz, CDC13) δ 169.4, 143.3, 142.3, 140.4, 138.5, 137.9, 133.5, 132.1, 129.4, 129.4, 129.2, 128.0, 127.8, 127.5, 127.4, 127.0, 126.7, 81.4, 52.2, 50.4, 27.3, 21.4.

[0076] HRMS (ESI): m / z calcd for C 28 H 29 NO4S[M+H] + = 476.1890, found = 476.1896.

[0077] Example 4

[0078]

[0079] Cycloheptatrienylamine la (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2d (33.4 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added into the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15: 1) was performed to obtain the product 3ad as a yellow viscous oil, with an isolated yield of 35.6 mg, a yield of 70%.

[0080] 1 H NMR (400 MHz, CDC13) δ 7.65 - 7.56 (m, 1H), 7.55 - 7.49 (m, 2H), 7.31 - 7.18 (m, 8H), 7.21 - 7.13 (m, 1H), 7.11 (d, J = 8.1 Hz, 2H), 7.08 - 7.02 (m, 2H), 7.01 - 6.96 (m, 2H), 6.34 (d, J = 1.4 Hz, 1H), 4.81 (s, 2H), 4.59 (dd, J = 14.5, 5.6 Hz, 1H), 4.23 (ddd, J = 9.5, 5.6, 1.5 Hz, 1H), 3.98 (dd, J = 14.5, 9.5 Hz, 1H), 2.30 (s, 3H).

[0081] 13 C NMR (101 MHz, CDC13) δ 170.3, 143.4, 142.0, 139.5, 138.6, 137.8, 135.1, 133.1, 132.2, 130.0, 129.4, 128.7, 128.4, 128.2, 128.2, 128.1, 127.9, 127.6, 127.5, 127.1, 126.5, 66.9, 52.1, 49.7, 21.4.

[0082] HRMS (ESI): m / z calcd for C 31 H 27 NO4S[M+H] + = 510.1734, found = 510.1731.

[0083] Example 5

[0084]

[0085] Cycloheptatrienylamine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2e (32.0 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added to the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15: 1) was performed to obtain the product 3ae, a light yellow solid, with an isolated yield of 37.0 mg, a yield of 80%.

[0086] 1 H NMR (400 MHz, CDC13) δ 7.65 - 7.58 (m, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.28 - 7.23 (m, 2H), 7.22 - 7.16 (m, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.97 (d, J = 7.8 Hz, 2H), 6.31 (s, 1H), 4.59 (dd, J = 14.4, 5.5 Hz, 1H), 4.17 - 4.09 (m, 2H), 3.93 (dd, J = 14.4, 9.6 Hz, 1H), 3.85 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.31 (s, 3H), 0.92 (t, J = 7.1 Hz, 3H).

[0087] 13 C NMR (101 MHz, CDC13) δ 170.5, 143.4, 139.7, 139.3, 138.5, 137.9, 137.3, 133.4, 132.1, 129.4, 129.2, 128.9, 128.8, 127.8, 127.5, 127.1, 126.4, 61.0, 52.2, 49.6, 21.4, 21.0, 13.7.

[0088] HRMS (ESI): m / z calcd for C 27 H 27 NO4S[M+H] + = 462.1734, found = 462.1740.

[0089] Example 6

[0090]

[0091] Cycloheptatrienylamine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2f (33.6 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added into the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15: 1) was performed to obtain the product 3af, white solid, separation yield 26.2 mg, yield 55%.

[0092] 1 H NMR (400 MHz, CDCl3) δ 7.64 - 7.56 (m, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.28 - 7.23 (m, 2H), 7.22 - 7.16 (m, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.04 - 6.99 (m, 2H), 6.83 - 6.76 (m, 2H), 6.28 (s, 1H), 4.58 (dd, J = 14.4, 5.5 Hz, 1H), 4.12 (ddd, J = 9.8, 5.5, 1.3 Hz, 2H), 3.89 (dd, J = 14.4, 5.5 Hz, 1H), 3.86 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 2.32 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H).

[0093] 13 C NMR (101 MHz, CDCl3) δ 170.5, 159.1, 143.4, 139.3, 138.4, 137.9, 134.6, 133.4, 132.1, 129.4, 128.9, 128.8, 127.7, 127.6, 127.5, 127.1, 113.4, 61.0, 55.3, 52.0, 49.7, 21.4, 13.8.

[0094] HRMS (ESI): m / z calcd for C 27 H 27 NO5S[M+H] + = 478.1683, found = 468.1684.

[0095] Example 7

[0096]

[0097] Cycloheptatrienimine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2g (32.4 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added to the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15:1) was performed to obtain the product 3ag as a white solid, with an isolated yield of 38.4 mg, a yield of 83%.

[0098] 1 H NMR (400 MHz, CDCl3) δ 7.64 - 7.56 (m, 1H), 7.56 - 7.50 (m, 2H), 7.30 - 7.24 (m, 2H), 7.23 - 7.17 (m, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.08 - 6.90 (m, 4H), 6.30 (d, J = 1.5 Hz, 1H), 4.58 (dd, J = 14.5, 5.6 Hz, 1H), 4.13 (ddd, J = 9.9, 5.6, 1.5 Hz, 1H), 3.94 - 3.89 (m, 1H), 3.86 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 0.92 (t, J = 7.1 Hz, 3H).

[0099] 13 C NMR (101 MHz, CDCl3) δ 170.2, 162.2 (d, 1 J C-F = 247.1 Hz), 143.5, 138.7, 138.2 (d, 4 J C-F = 3.3 Hz), 137.9, 133.0, 132.2, 130.0, 129.4, 128.8, 128.2 (d, 3 J C-F = 8.0 Hz), 128.1, 127.7, 127.2, 114.9 (d, 2 J C-F = 21.4 Hz), 61.1, 51.9, 49.9, 21.4, 13.7.

[0100] 19 F NMR (376 MHz, CDCl3) δ -114.44.

[0101] HRMS (ESI): m / z calcd for C26 H 24 NO4S[M+H] + = 466.1483, found = 466.1487.

[0102] Example 8

[0103]

[0104] Cycloheptatrienylamine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2h (34.0 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added to the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15:1) was performed to obtain the product 3ah, white solid, with an isolated yield of 43.4 mg, a yield of 90%.

[0105] 1 H NMR (400 MHz, CDCl3) δ 7.62 - 7.58 (m, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.30 - 7.27 (m, 2H), 7.26 - 7.18 (m, 3H), 7.14 (d, J = 8.1 Hz, 2H), 7.05 - 6.99 (m, 2H), 6.32 (d, J = 1.4 Hz, 1H), 4.58 (dd, J = 14.5, 5.6 Hz, 1H), 4.13 (ddd, J = 9.8, 5.7, 1.5 Hz, 1H), 3.94 - 3.81 (m, 3H), 2.32 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H).

[0106] 13 C NMR (101 MHz, CDCl3) δ 170.2, 143.5, 140.7, 138.7, 138.5, 137.9, 133.4, 132.9, 132.3, 130.3, 129.5, 128.8, 128.3, 128.2, 127.9, 127.6, 127.1, 61.2, 51.9, 49.7, 21.4, 13.8.

[0107] HRMS (ESI): m / z calcd for C 26 H 24 ClNO4S[M+H] += 482.1188, 484.1158, found = 482.1194, 484.1175.

[0108] Example 9

[0109]

[0110] Cycloheptatrienylamine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2i (35.1 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added to the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 10:1) was performed to obtain the product 3ai, yellow solid, with an isolated yield of 47.6 mg, a yield of 97%.

[0111] 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.7 Hz, 2H), 7.62 - 7.57 (m, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.33 - 7.27 (m, 3H), 7.25 - 7.24 (m, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.46 (s, 1H), 4.60 (dd, J = 14.6, 5.6 Hz, 1H), 4.23 (dd, J = 9.5, 6.0 Hz, 1H), 3.97 - 3.83 (m, 3H), 2.32 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H).

[0112] 13 C NMR (101 MHz, CDCl3) δ 169.8, 148.9, 146.9, 143.7, 139.0, 137.9, 137.6, 132.7, 132.4, 132.2, 129.5, 128.8, 128.6, 127.7, 127.3, 127.1, 123.5, 61.4, 51.9, 49.6, 21.4, 13.8.

[0113] HRMS (ESI): m / z calcd for C 26 H 24 N2O6S[M+H] + = 493.1428, found = 493.1430.

[0114] Example 10

[0115]

[0116] Cycloheptatrienylamine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2j (29.6 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added to the sealed tube, sealed and heated to 80 °C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 15:1) was performed to obtain the product 3aj, yellow solid, with an isolated yield of 43.3 mg, a yield of 98%.

[0117] 1 H NMR (400 MHz, CDCl3) δ 7.59 - 7.52 (m, 1H), 7.45 - 7.38 (m, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.26 - 7.20 (m, 3H), 6.98 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 6.36 (dd, J = 3.4, 1.8 Hz, 1H), 6.24 (d, J = 3.4 Hz, 1H), 4.55 (dd, J = 14.6, 6.1 Hz, 1H), 4.15 - 3.99 (m, 3H), 3.93 (dd, J = 14.6, 9.8 Hz, 1H), 2.25 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H).

[0118] 13 C NMR (101 MHz, CDCl3) δ 171.0, 153.8, 143.4, 141.9, 139.0, 137.1, 132.9, 132.5, 129.1, 128.4, 128.0, 127.6, 126.9, 125.1, 111.5, 106.6, 61.5, 52.6, 47.8, 21.4, 14.0.

[0119] HRMS (ESI): m / z calcd for C 26 H 23 NO5S[M+H] + = 438.1370, found = 438.1374.

[0120] Example 11

[0121]

[0122] Cycloheptatrienimine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2k (35.7 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added into the sealed tube, sealed and heated to 80 °C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 2:1) was performed to obtain the product 3ak, yellow solid, with an isolated yield of 45.0 mg, a yield of 90%.

[0123] 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.71 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.65 (dt, J = 7.1, 3.6 Hz, 1H), 7.62 - 7.53 (m, 3H), 7.34 - 7.27 (m, 3H), 7.16 (d, J = 8.0 Hz, 2H), 6.50 (d, J = 1.6 Hz, 1H), 4.67 (dd, J = 14.6, 5.7 Hz, 1H), 4.34 (ddd, J = 10.1, 5.8, 1.6 Hz, 1H), 3.96 (dd, J = 14.6, 10.0 Hz, 1H), 3.84 (q, J = 7.1 Hz, 2H), 2.27 (s, 3H), 0.85 (t, J = 7.1 Hz, 3H).

[0124] 13 C NMR (101 MHz, CDCl3) δ 170.0, 149.1, 147.2, 143.7, 138.9, 138.0, 136.4, 134.9, 132.7, 132.6, 132.6, 131.9, 129.6, 129.5, 129.1, 128.9, 128.5, 127.8, 127.7, 127.2, 127.1, 61.3, 51.8, 49.7, 21.4, 13.7.

[0125] HRMS (ESI): m / z calcd for C 29 H 26 N2O4S[M+H] + = 499.1686, found = 499.1685.

[0126] Example 12

[0127]

[0128] Cycloheptatrienylamine 1a (26.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2l (33.2 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added to the sealed tube, sealed and heated to 80 °C for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 5:1) was performed to obtain the product 3al, yellow solid, with an isolated yield of 24.8 mg, a yield of 55%.

[0129] 1 H NMR (400 MHz, CDCl3) d 7.61 - 7.53 (m, 1H), 7.52 - 7.45 (m, 2H), 7.39 - 7.30 (m, 4H), 7.26 - 7.16 (m, 4H), 7.08 (d, J = 8.1 Hz, 2H), 6.59 (d, J = 16.4 Hz, 1H), 6.45 (d, J = 16.4 Hz, 1H), 6.36 (s, 1H), 4.55 (dd, J = 14.6, 6.0 Hz, 1H), 4.24 - 4.02 (m, 3H), 3.88 (dd, J = 14.6, 10.1 Hz, 1H), 2.24 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0130] 13 C NMR (101 MHz, CDCl3) d 171.1, 143.4, 139.4, 137.3, 137.0, 136.9, 132.8, 132.6, 132.2, 129.3, 128.7, 128.5, 128.1, 128.0, 127.7, 127.4, 127.1, 126.4, 61.5, 52.1, 47.6, 21.4, 14.1.

[0131] HRMS (ESI): m / z calcd for C 28 H 27 NO4S[M+H] + = 474.1734, found = 474.1743.

[0132] Example 13

[0133]

[0134] Cycloheptatrienylamine 1b (18.3 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2a (30.6 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Subsequently, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added into the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 6:1) was performed to obtain the product 3ba as a white solid with an isolated yield of 30.5 mg and a yield of 81%.

[0135] 1 H NMR (400 MHz, CDC13) δ 7.68 - 7.61 (m, 1H), 7.47 - 7.41 (m, 2H), 7.40 - 7.27 (m, 6H), 6.79 (s, 1H), 4.39 - 4.27 (m, 2H), 4.13 (td, J = 10.6, 4.4 Hz, 1H), 3.93 (q, J = 7.2 Hz, 2H), 2.89 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H).

[0136] 13 C NMR (101 MHz, CDC13) δ 170.6, 142.4, 140.1, 138.4, 132.9, 132.5, 130.2, 128.5, 128.3, 127.9, 127.9, 127.7, 126.5, 61.2, 51.2, 50.5, 40.2, 13.7.

[0137] HRMS (ESI): m / z calcd for C 20 H 21 NO4S [M + H] + = 372.1264, found = 372.1266.

[0138] Example 14

[0139]

[0140] Cycloheptatrienylamine 1c (29.0 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2a (30.6 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added into the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 12:1) was performed to obtain the product 3ca, yellow solid, with an isolated yield of 32.7 mg, a yield of 68%.

[0141] 1 H NMR (400 MHz, CDC13) δ 8.16 - 8.09 (m, 2H), 7.78 - 7.71 (m, 2H), 7.67 - 7.59 (m, 1H), 7.42 - 7.31 (m, 2H), 7.30 - 7.23 (m, 3H), 7.23 - 7.17 (m, 1H), 7.09 - 7.02 (m, 2H), 6.25 (s, 1H), 4.65 (dd, J = 14.2, 5.7 Hz, 1H), 4.20 (dd, J = 14.2, 8.8 Hz, 1H), 4.09 (ddd, J = 8.8, 5.7, 1.0 Hz, 1H), 3.84 (q, J = 7.1, 2H), 0.89 (t, J = 7.1 Hz, 3H).

[0142] 13 C NMR (101 MHz, CDC13) δ 170.1, 149.8, 145.8, 141.1, 140.0, 137.1, 134.1, 131.9, 129.7, 129.3, 128.6, 128.5, 128.4, 128.3, 128.1, 126.0, 123.9, 61.3, 53.8, 48.8, 13.7.

[0143] HRMS (ESI): m / z calcd for C 25 H 22 N2O6S[M+H] + = 479.1271, found = 479.1276.

[0144] Example 15

[0145]

[0146] Cycloheptatrienylamine 1d (27.5 mg, 0.1 mmol, 1.0 equiv.) and MBH carbonate 2a (30.6 mg, 0.1 mmol, 1.0 equiv.) were added into a sealed tube, 1 mL of toluene (0.1 M) was added, and stirred at room temperature until it was completely dissolved. Then, tricyclohexylphosphine (8.4 mg, 0.03 mmol, 0.3 equiv.) was added into the sealed tube, sealed and heated to 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then column chromatography (petroleum ether: ethyl acetate = 5:1) was performed to obtain the product 3da as a white solid, with an isolated yield of 37.6 mg, a yield of 81%.

[0147] 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.60 (m, 1H), 7.59 - 7.53 (m, 2H), 7.31 - 7.23 (m, 5H), 7.23 - 7.17 (m, 1H), 7.16 - 7.11 (m, 2H), 6.82 - 6.75 (m, 2H), 6.35 (d, J = 1.5 Hz, 1H), 4.59 (dd, J = 14.5, 5.5 Hz, 1H), 4.20 (ddd, J = 9.8, 5.6, 1.5 Hz, 1H), 3.94 (dd, J = 14.5, 9.7 Hz, 1H), 3.85 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 0.89 (t, J = 7.1 Hz, 3H).

[0148] 13 C NMR (101 MHz, CDCl3) δ 170.4, 162.8, 142.1, 139.7, 138.6, 133.2, 132.3, 132.2, 129.8, 129.2, 128.9, 128.1, 127.9, 127.6, 127.5, 126.5, 113.9, 61.0, 55.5, 52.0, 49.6, 13.7.

[0149] HRMS (ESI): m / z calcd for C 26 H 25 NO5S[M+H] + = 479.1271, found = 479.1276.

[0150] The above description is only the preferred specific embodiments of the present application, the protection scope of the present application is not limited to this, any person skilled in the art can obviously obtain the simple changes or equivalent replacements of the technical solutions within the technical range disclosed by the present application, which all fall into the protection scope of the present application.

Claims

1. A method for synthesizing benzo[a]aza derivatives, characterized in that, Benzo[a]za derivatives were synthesized in one step by heating MBH carbonate and cycloheptatriene imine in a solvent under the action of a phosphine catalyst. The structural formula of the cycloheptatriene imine is as follows: ； The structural formula of the MBH carbonate is as follows: ； The structural formula of the benzo[a]aza derivative is as follows: ； Among them, R 1 It is any one of C1-C4 alkyl or benzyl; R 2 The phenyl group is substituted or unsubstituted, and the heteroaryl group is 2-furanyl or 2-quinolinyl, wherein the substituent on the phenyl group is halogen, C1-C4 alkyl, C1-C4 alkoxy or nitro; R 3 It is a methyl, substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is a C1~C4 alkyl, C1~C4 alkoxy or nitro group; The phosphine catalyst is tricyclohexylphosphine; The solvent is toluene; The reaction temperature is 70~90°C. o C.

2. The method for synthesizing benzo[a]aza derivatives according to claim 1, characterized in that, R 1 For Et, Me, t Bu, any one of Bn; R 2 The substituted or unsubstituted phenyl, 2-furanyl, 2-quinolinyl, or styryl group is used, wherein the substituent on the phenyl group is any one of F, Cl, Me, OMe, or NO2; R 3 It is any one of Me, 4-MeC6H5, 4-NO2C6H5, and 4-MeOC6H5.

3. The method for synthesizing benzo[a]aza derivatives according to claim 1, characterized in that, The phosphine catalyst loading is 20-40 mol based on cycloheptatrienimine.

4. The method for synthesizing benzo[a]aza derivatives according to claim 1, characterized in that, The molar ratio of MBH carbonate to cycloheptatrienimine is 1:1.0~1.1.

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