Carbonyl-substituted tetrahydronaphthalene imine compound and preparation method thereof

Abstract

The invention provides a carbonyl substituted tetrahydronaphthalene imine compound and a preparation method thereof. The tetrahydronaphthalene imine compound structurally contains imine and a carbonyl substituent, can be subjected to multidirectional derivative conversion, and has structural novelty. The preparation method comprises the following steps: reacting a 1, 6-eneyne compound with amine under the catalysis of transition metal to generate a tetrahydronaphthalene imine compound. The synthesis method is simple and rapid in preparation process, and the catalyst is low in price, so that the method is expected to be used for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a carbonyl-substituted tetrahydronaphthalene imine compound and a preparation method thereof. Background Art

[0002] Tetrahydronaphthalene imine is an important biopharmaceutical intermediate, and its preparation technology has received extensive research and attention. However, in terms of current technology, the preparation of tetrahydronaphthalene imine molecules requires the synthesis of the corresponding tetralone molecules in advance, and the resulting tetrahydronaphthalene imine is not compatible with carbonyl substituents, as shown below:

[0003] Method 1 (Angew. Chem. Int. Ed. 2021, 60, 24456–24460)

[0004]

[0005] Method 2 (J.Org.Chem.1990,55,4971-4973)

[0006]

[0007] Method 1 requires three steps to synthesize naphthalene ketone, while method 2 requires two steps. Too many steps make the production process complicated, which leads to inconvenience in operation and increases industrial production costs. Furthermore, in the above method, since imine is converted from carbonyl, if it is substituted with carbonyl, two imine substitution products will be obtained, and it is impossible to selectively synthesize tetrahydronaphthalene imine substituted with carbonyl. Summary of the invention

[0008] One of the purposes of the present invention is to disclose a new tetrahydronaphthalene imine compound with carbonyl substitution, which has both imine and carbonyl substituent in its structure, can be multi-directionally derived and transformed, and has a novel structure.

[0009] Another object of the present invention is to disclose a method for preparing carbonyl-substituted tetrahydronaphthalene imine. The preparation method does not require the construction of a tetralone skeleton in advance, and the raw material 1,6-enyne is cheap and readily available, and the carbonyl-substituted tetrahydronaphthalene imine can be constructed in one step. On this basis, the synthesized tetrahydronaphthalene imine molecule is compatible with the carbonyl substituent.

[0010] The present invention is an original method for synthesizing tetrahydronaphthalene imine, which has not been reported in the literature before the application date.

[0011] A carbonyl-substituted tetrahydronaphthalene imine compound is characterized by the following:

[0012] In the formula: R is aryl, heteroaryl, p-toluenesulfonyl or C1-C12 alkylsulfonyl;

[0013] Where: R1 For hydrogen atoms, C1~C 12 alkyl, aryl or heteroaryl; wherein R 1 Any one or more hydrogen atoms of the aromatic ring may be replaced by a substituent;

[0014] R 2 C1~C 12 alkyl, aryl or heteroaryl; wherein R 2 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent;

[0015] R 3 A hydrogen atom, a halogen, or a C1~C 12 alkyl;

[0016] R 3 The aromatic ring may be a heteroaromatic ring.

[0017] The present invention is achieved through the following technical solutions:

[0018] Under nitrogen protection, a 1,6-enyne compound is dissolved in a solvent, a catalyst and an amine are added, and after the reaction, the tetrahydronaphthalene imine compound is separated and purified to obtain the tetrahydronaphthalene imine compound.

[0019] Wherein: R is aryl, heteroaryl, p-toluenesulfonyl or C1~C 12 Alkylsulfonyl;

[0020] In the formula: R1 is a hydrogen atom, C1~C 12 Alkyl, aryl or heteroaryl; wherein any one or more hydrogen atoms of the aromatic ring on R1 may be substituted by a substituent;

[0021] R2 is C1~C 12 Alkyl, aryl or heteroaryl; wherein any one or more hydrogen atoms of the aromatic ring on R2 may be substituted by a substituent;

[0022] R3 is a hydrogen atom, a halogen or a C1~C 12 alkyl;

[0023] The aromatic ring where R3 is located can be a benzene ring or a heteroaromatic ring; preferably a benzene ring;

[0024] The catalyst is one of Cu(OAc)2, CuSO4·5H2O, AgOTf, CuSO4, CuCl2, CuO, CuCl, CuBr, and CuI. The preferred catalyst is Cu(OAc)2;

[0025] The molar ratio of the metal catalyst to the 1,6-enyne compound is preferably 0.01 to 1:1. The preferred ratio is 0.2:1.

[0026] The molar ratio of the amine to the 1,6-enyne compound is 0.1 to 10:1, preferably 1.5:1.

[0027] The solvent is selected from 1,1-dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, trifluorotoluene, 1,4-dioxane, acetonitrile, toluene, chlorobenzene, and xylene. The preferred solvent is 1,1-dichloromethane.

[0028] The ratio of the solvent to the 1,6-enyne compound is 1-20 mL:1 mmol, preferably 10 mL:1 mmol.

[0029] The conditions are preferably 25°C to 120°C for 0.5h to 48h, preferably 60°C for 3h.

[0030] The 1,6-enyne compound can be prepared by referring to known literature (eg Angew. Chem. Int. Ed. 2011, 50, 8968).

[0031]

[0032] Tetrahydronaphthylamine is an important biologically active molecular skeleton, such as the marketed antidepressant sertraline. Tetrahydronaphthyl imine is an important intermediate for the synthesis of tetrahydronaphthylamine, so the synthesis method of tetrahydronaphthyl imine or its derivatives has important potential application value. The present invention provides a simple and efficient method for constructing tetrahydronaphthyl imine.

[0033]

[0034] The tetrahydronaphthalene imine compounds that can be prepared by the present invention are exemplified as follows:

[0035]

[0036] Compared with the prior art, the present invention has the following advantages and effects:

[0037] The preparation process of the invention is simple and quick, and the corresponding tetralone does not need to be constructed in advance. The tetralamine compound can be efficiently synthesized in a simple step, and the operation is simple. The raw materials used are easy to prepare, the amount of the catalyst used is small, and it is cheap and easy to obtain, and the purification is simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The accompanying drawings have the same meaning as the reaction formula in row

[0017] of the specification, and the same technical scheme. In the figure, 1,6-enyne is equivalent to compound 1, amine is equivalent to compound 2, and tetrahydronaphthalene imine is equivalent to compound 3. DETAILED DESCRIPTION

[0039] The present invention is further described below in conjunction with specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art and can be directly purchased or synthesized by known literature methods.

[0040] Example 1

[0041]

[0042] Take a dry Schlenk tube with a stirring bar, add Cu(OAc)2 (7.3 mg, 20% mmol), replace with nitrogen three times, add 1a (61.6 mg, 0.2 mmol), 2a (27.9 mg, 0.3 mmol) and 1,2-dichloromethane (4 mL) and stir at 60 ° C for 3 h. After the reaction is complete, the solvent is removed by rotation and purified by flash column chromatography (eluent: petroleum ether: ethyl acetate volume ratio 10:1) to obtain product 3a (77%, unstable, partially decomposed during separation), brown oily liquid, 1 H NMR(400MHz, CDCl3)δ8.46(dd,J=7.9,1.6Hz,1H),7.60–7.49(m,2H),7.46–7.33(m,3H),7.33–7.19(m,5H),7.16–7.00(m,6H ),6.89–6.79(m,2H),5.25(d,J=4.6Hz,1H),3.70–3.62(m,1H),3.55(dd,J=16.4,14.2Hz,1H),2.73(dd,J=16.4,3.8Hz,1H); 13 C NMR (101MHz, CDCl3) δ200.7,166.0,150.1,140.7,139.1,137.9,134.1,133.1,131.1,129.2,128.7, 128.6,128.4,128.3,128.0,127.6,127.49,127.46,120.9,116.3,51.6,44.0,30.5; HRMS(ESI)Calcd forC 29 H 24 NO(M+H)+402.1852,found 402.1861.

[0043] Example 2

[0044]

[0045] Take a dry Schlenk tube with a stirring bar, add Cu(OAc)2 (7.3 mg, 20% mmol), replace the atmosphere with nitrogen three times, add 1a (61.6 mg, 0.2 mmol), 2b (40.5 mg, 0.3 mmol) and 1,2-dichloromethane (4 mL), stir at 60°C for 3 h, react completely, remove the solvent, and purify by flash column chromatography (eluent: petroleum ether: ethyl acetate volume ratio 5:1) to obtain product 3b (72 mg, 81%) as a white solid with a melting point of 133-134°C. 1 H NMR (400MHz, CDCl3) δ8.46(d,J=7.8Hz,1H),7.96(d,J=8.4Hz,2H),7.55(d, J=7.6Hz,2H),7.45–7.41(m,1H),7.41–7.32(m,2H),7.27–7.24(m,2H),7.12 –7.02(m,6H),6.96(d,J=8.3Hz,2H),5.26(d,J=4.5Hz,1H),3.69(dt,J=14. 2,4.2Hz,1H),3.63–3.51(m,1H),2.69(dd,J=16.2,3.6Hz,1H),2.56(s,3H); 13 CNMR(101MHz, CDCl3)δ200.5,197.2,165.4,156.4,140.5,139.2,137.9,133.8,133.0,132.5,131.2,1 29.9,128.6,128.5,128.4,128.3,127.9,127.5,127.4,119.2,51.5,43.9,30.7,26.4; HRMS(ESI)Calcd for C 31 H 26 NO2(M+H) + 444.1958, found 444.1962.

[0046] Example 3

[0047]

[0048] Take a dry Schlenk tube with a stirrer, add Cu(OAc)2 (7.3 mg, 20% mmol), replace the atmosphere with nitrogen three times, add 1a (61.6 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL), stir at 80°C for 3 h, react completely, remove the solvent, and purify by flash column chromatography (eluent: petroleum ether: ethyl acetate volume ratio 2:1) to obtain product 3c (60 mg, 63%) as a white solid with a melting point of 190-191°C. 1 H NMR (400MHz, CDCl3) δ8.24 (dd, J=8.0, 1.5Hz, 1H), 8.04–7.95 (m, 2H), 7.56–7 .50(m,2H),7.44–7.35(m,4H),7.34–7.26(m,2H),7.25–7.18(m,4H),7.17–7. 11(m,2H),7.07(dd,J=7.6,1.3Hz,1H),5.25(d,J=4.6Hz,1H),4.14(dd,J=18. 6,14.1Hz,1H),3.89(dd,J=18.6,4.6Hz,1H),3.84–3.76(m,1H),2.47(s,3H); 13 CNMR(101MHz, CDCl3)δ199.2,179.1,143.4,141.5,139.7,139.0,137.5,133.6,133.1,132.7,129.4 ,128.71,128.65,128.5,128.4,128.0,127.7,127.6,127.2,51.3,43.6,33.1,21.6; HRMS(ESI)Calcd for C 30 H 25 NO3NaS(M+Na) + 502.1447, found 502.1450.

[0049] Example 4

[0050]

[0051] Take a dry Schlenk tube with a stirring bar, add Cu(OAc)2 (7.3 mg, 20% mmol), replace the atmosphere with nitrogen three times, add 1b (65.2 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL), stir at 80°C for 3 h, react completely, remove the solvent, and purify by flash column chromatography (eluent: petroleum ether: ethyl acetate volume ratio 2:1) to obtain product 3d (60 mg, 61%) as a white solid with a melting point of 106-107°C. 1 H NMR(400MHz, CDCl3)δ8.23(dd,J=8.0,1.5Hz,1H),7.99(d,J=8.3Hz,2H),7.59–7.53(m,2 H),7.49–7.40(m,2H),7.37(d,J=8.1Hz,2H),7.30(dt,J=12.5,7.7Hz,3H),7.22–7.15(m ,2H),7.07(d,J=7.6Hz,1H),6.86(t,J=8.6Hz,2H),5.23(d,J=4.6Hz,1H),4.11(dd,J=18 .5,14.1Hz,1H),3.87(dd,J=18.5,4.6Hz,1H),3.79(dt,J=14.1,4.6Hz,1H),2.47(s,3H); 13 C NMR (101MHz, CDCl3) δ199.0,178.7,162.0(d, 1 J C-F =247.5Hz),143.5,141.2,138.9,137.3,135.6(d, 4 J C-F =4.0Hz),133.7,133.3,132.6,129.5,129.33,129.25,128.53(d, 3 J C-F =24.2Hz),128.51,128.1,127.2,115.6(d, 2 J C-F =21.2Hz),51.1,42.8,33.3,21.6; 19 F NMR(376MHz, CDCl3)δ-114.58; HRMS(ESI)Calcd for C 30 H 24 NO3NaSF(M+Na) + 520.1353, found 520.1355.

[0052] Example 5

[0053]

[0054] Take a dry Schlenk tube with a stirring bar, add Cu(OAc)2 (7.3 mg, 20% mmol), replace the atmosphere with nitrogen three times, add 1c (65.2 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL), stir at 80°C for 3 h, and the reaction is complete. Remove the solvent and purify by flash column chromatography (eluent: petroleum ether: ethyl acetate volume ratio 2:1) to obtain product 3e (57 mg, 58%) as a reddish brown solid with a melting point of 170-171°C. 1 H NMR (400MHz, CDCl3) δ8.24 (dd, J=8.1, 1.5Hz, 1H), 7.99 (d, J=8.2Hz, 2H), 7.59–7. 50(m,2H),7.42(td,J=7.4,1.5Hz,1H),7.39–7.29(m,3H),7.24–7.11(m,5H),7.05 (d,J=7.8Hz,1H),6.95–6.85(m,2H),5.18(d,J=4.6Hz,1H),4.09(dd,J=18.6,14. 1Hz, 1H), 3.89 (dd, J=18.6, 4.6Hz, 1H), 3.80 (dt, J=14.1, 4.5Hz, 1H), 2.47 (s, 3H); 13 C NMR)δ197.5,178.9,165.7(d, 1 J C-F =256.5Hz),143.4,141.3,139.6,138.9,133.9(d, 4 J C-F =3.0Hz),132.7,131.2(d, 3 J C-F =9.1Hz),129.5,128.8,128.7,128.3,128.1,127.8,127.6,127.2,115.5(d, 2 J C-F =22.2Hz),51.4,43.6,33.0,21.6; 19 F NMR(376MHz, CDCl3)δ-104.64; HRMS(ESI)Calcd for C 30 H 24 NO3NaSF(M+Na) + 520.1353, found 520.1355.

[0055] Example 6

[0056]

[0057] Take a dry Schlenk tube with a stirring bar, add Cu(OAc)2 (7.3 mg, 20% mmol), replace the atmosphere with nitrogen three times, add 1d (62.8 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL), stir at 80°C for 3 h, and the reaction is complete. Remove the solvent and purify by flash column chromatography (eluent: petroleum ether: ethyl acetate volume ratio 2:1) to obtain the product 3f (65 mg, 67%) as a white solid with a melting point of 162-163°C. 1 H NMR (400MHz, CDCl3) δ8.23 (dd, J=8.0, 1.4Hz, 1H), 7.99 (d, J=8.3Hz, 2H), 7.56 (dd, J= 2.9,1.3Hz,1H),7.43(td,J=7.5,1.5Hz,1H),7.38–7.30(m,3H),7.24(dd,J=5.1,1.3H z,1H),7.22–7.14(m,5H),7.14–7.09(m,2H),4.96(d,J=4.5Hz,1H),4.09(dd,J=18.6, 14.1Hz, 1H), 3.89 (dd, J=18.6, 4.5Hz, 1H), 3.78 (dt, J=14.1, 4.5Hz, 1H), 2.47 (s, 3H); 13 C NMR (101MHz, CDCl3) δ192.6,179.1,143.4,142.9,141.3,139.8,139.0,133.7,133.3,132.6,129.5,12 8.7,128.5,128.4,128.1,127.7,127.6,127.2,127.0,126.2,53.9,43.7,33.1,21.6; HRMS(ESI)Calcd forC 28 H 23 NO3NaS2(M+Na) + 508.1012, found 508.1008.

[0058] Example 7

[0059]

[0060] Take a dry Schlenk tube with a stirring bar, add Cu(OAc)2 (7.3 mg, 20% mmol), replace with nitrogen three times, add 1e (65.2 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL) and stir at 80 ° C for 3 h. The reaction is complete, the solvent is removed by rotation, and the product is purified by flash column chromatography (eluent is petroleum ether: ethyl acetate volume ratio 2: 1) to obtain the product 3g (67 mg, 68%), brown solid, melting point: 170-171 ° C, 1 H NMR (400MHz, CDCl3) δ8.27(dd,J=9.0,5.9Hz,1H),7.98(d,J=8.0Hz,2H),7.55–7.48(m,2H ),7.43(t,J=7.4Hz,1H),7.37(d,J=7.9Hz,2H),7.33–7.27(m,1H),7.24–7.07(m,6H),7.0 1(td,J=8.5,2.5Hz,1H),6.76(dd,J=8.6,2.6Hz,1H),5.21(d,J=4.6Hz,1H),4.09(dd,J=1 8.6,14.1Hz,1H),3.89(dd,J=18.6,4.5Hz,1H),3.80(dt,J=14.2,4.6Hz,1H),2.47(s,3H); 13 C NMR (101MHz, CDCl3) δ198.5,177.8,144.1,143.5,139.3,138.9,137.2,133.3,131.6(d, 3 J C-F =10.1Hz),129.5,129.1,128.8,128.5,128.4,127.8,127.7,127.2,115.7(d, 2 J C-F =21.2Hz),114.9(d, 2 J C-F =22.2Hz),51.3,43.6,32.9,21.6; 19 F NMR(376MHz, CDCl3)δ-103.98; HRMS(ESI)Calcd forC 30 H 24 NO3NaSF(M+Na) + 520.1353, found 520.1355.

[0061] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A carbonyl-substituted tetrahydronaphthalene imine compound, characterized in that: Wherein: R is aryl, heteroaryl, p-toluenesulfonyl or C1~C 12 Alkylsulfonyl; Where: R 1 For hydrogen atoms, C1~C 12 Alkyl, aryl or heteroaryl; wherein, R 1 Any one or more hydrogen atoms of the aromatic ring may be replaced by a substituent; R 2 C1~C 12 alkyl, aryl or heteroaryl; wherein R 2 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 3 A hydrogen atom, a halogen, or a C1~C 12 alkyl; R 3 The aromatic ring may be a heteroaromatic ring.

2. A method for preparing a carbonyl-substituted tetrahydronaphthalene imine compound, characterized in that: Wherein: R is aryl, heteroaryl, p-toluenesulfonyl or C1~C 12 Alkylsulfonyl; Where: R 1 For hydrogen atoms, C1~C 12 Alkyl, aryl or heteroaryl; wherein, R 1 Any one or more hydrogen atoms of the aromatic ring may be replaced by a substituent; R 2 C1~C 12 alkyl, aryl or heteroaryl; wherein R 2 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 3 A hydrogen atom, a halogen, or a C1~C 12 alkyl; R 3 The aromatic ring may be a heteroaromatic ring.

3. The method for preparing the tetrahydronaphthalene imine compound according to claim 2, characterized in that: The steps include: Under nitrogen protection, a 1,6-enyne compound is dissolved in a solvent, a catalyst and an amine are added, and after the reaction, the tetrahydronaphthalene imine compound is separated and purified to obtain the tetrahydronaphthalene imine compound.

4. The preparation method according to claim 3, characterized in that: The catalyst is one of Cu(OAc)2·H2O, Cu(OAc)2, CuSO4·5H2O, AgOTf, CuSO4, CuCl2, CuO, CuCl, CuBr and CuI.

5. The preparation method according to claim 3, characterized in that: The amine is aromatic amine, substituted aromatic amine, p-toluenesulfonamide or C1-C 12 Any of the alkylsulfonamides.

6. The preparation method according to claim 3, characterized in that: The solvent is selected from one of 1,1-dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, trifluorotoluene, 1,4-dioxane, acetonitrile, toluene, chlorobenzene and xylene.

7. The preparation method according to claim 3, characterized in that: The reaction is carried out at 25°C-120°C for 0.5h-48h.

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