A tetrahydronaphthalene imine compound substituted with a carbonyl group and a preparation method thereof

Abstract

The application provides a tetrahydronaphthalene imine compound with a carbonyl substituent and a preparation method thereof. The tetrahydronaphthalene imine compound has both imine and carbonyl substituents in the structure, can be converted in multiple directions, and has structural novelty. The preparation method is as follows: a 1,6-alkynyl compound is reacted with an amine under the catalysis of a transition metal to generate a tetrahydronaphthalene imine compound. The preparation process of the above synthesis method is simple and fast, and the catalyst is low in price, so the synthesis method is expected to be used for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemical synthesis, and particularly relates to a tetrahydronaphthalene imine compound with a carbonyl substituent and a preparation method thereof. BACKGROUND

[0002] Tetrahydronaphthalene imine is an important biological and pharmaceutical intermediate, and its preparation technology has been widely studied and concerned. However, according to the current technology, the preparation of tetrahydronaphthalene imine molecules requires the prior synthesis of the corresponding tetrahydronaphthalene ketone molecules, and the formed naphthalene imine cannot be compatible with the carbonyl substituent, for example:

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

[0004]

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

[0006]

[0007] Method one requires three steps to synthesize naphthalene ketone, and method two requires two steps, which leads to a complex production process, inconvenient operation and increased industrial production cost. Further, since the imine is converted from the carbonyl group, if the carbonyl group is substituted, two imine substitution products will be obtained, and it is impossible to selectively synthesize tetrahydronaphthalene imine with a carbonyl substituent. SUMMARY

[0008] One of the purposes of the present application is to disclose a new tetrahydronaphthalene imine compound with a carbonyl substituent. The compound has both imine and carbonyl substituent in its structure, can be derived and converted in multiple directions, and has novel structure.

[0009] Another purpose of the present application is to disclose a preparation method of tetrahydronaphthalene imine with a carbonyl substituent. The preparation method does not need to construct a tetrahydronaphthalene ketone skeleton in advance, the raw material 1,6-alkyne is cheap and easy to obtain, and tetrahydronaphthalene imine with a carbonyl substituent can be constructed in one step. On this basis, the synthesized tetrahydronaphthalene imine molecule is compatible with the carbonyl substituent.

[0010] The present application is an original synthesis method of tetrahydronaphthalene imine, and no document has been reported before the application date.

[0011] A tetrahydronaphthalene imine compound with a carbonyl substituent is characterized as follows:

[0012]

[0013] In the formula, R is aryl, heteroaryl, p-toluenesulfonyl or C1-C12 alkylsulfonyl.

[0014] Where: R 1 For hydrogen atoms, C1~C 12 alkyl, aryl or heteroaryl; wherein R 1 Any one or more hydrogen atoms of the upper aromatic ring may be replaced by a substituent;

[0015] 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;

[0016] R 3 A hydrogen atom, a halogen, or a C1-C 12 alkyl;

[0017] R 3 The aromatic ring may be a heteroaromatic ring.

[0018] The present invention is achieved through the following technical solutions:

[0019]

[0020] Under nitrogen protection, a 1,6-enyne compound is dissolved in a solvent, a catalyst and an amine are added, and after reaction, the tetrahydronaphthalene imine compound is separated and purified to obtain the tetrahydronaphthalene imine compound.

[0021] Wherein: R is aryl, heteroaryl, p-toluenesulfonyl or C1~C 12 alkylsulfonyl;

[0022] Wherein: 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;

[0023] 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;

[0024] R3 is a hydrogen atom, a halogen or a C1-C 12 alkyl;

[0025] The aromatic ring where R3 is located can be a benzene ring or a heteroaromatic ring; preferably a benzene ring;

[0026] 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;

[0027] The molar ratio of the metal catalyst to the 1,6-alkynyl compound is preferably 0.01-1:1. The preferred ratio is 0.2:1.

[0028] The molar ratio of the amine to the 1,6-alkynyl compound is 0.1-10:1, and the preferred ratio is 1.5:1.

[0029] The solvent is selected from one of 1,1-dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, trifluorotoluene, 1,4-dioxane, acetonitrile, toluene, chlorobenzene, xylene. The preferred solvent is 1,1-dichloromethane.

[0030] The solvent to the 1,6-alkynyl compound is 1-20 mL:1 mmol, and the preferred ratio is 10 mL:1 mmol.

[0031] The conditions are preferably 25-120°C for 0.5-48 h. The preferred temperature is 60°C, and the reaction time is 3 h.

[0032] The 1,6-alkynyl compound can be prepared according to known literature (for example, Angew. Chem. Int. Ed. 2011, 50, 8968).

[0033]

[0034] Tetrahydronaphthylamine is an important bioactive molecule skeleton, such as the marketed antidepressant sertraline. Tetrahydronaphthylimine is an important intermediate for synthesizing tetrahydronaphthylamine, and thus the synthesis method of tetrahydronaphthylimine or its derivative has important potential application value. The present application provides a simple and efficient method for constructing tetrahydronaphthylimine.

[0035]

[0036] The tetrahydronaphthylimine compound prepared by the present application is exemplified as follows:

[0037]

[0038] Compared with the prior art, the present application has the following advantages and effects:

[0039] The preparation process of the present application is simple and fast, and does not need to construct the corresponding tetrahydronaphthalenone in advance. The tetrahydronaphthylimine compound can be efficiently synthesized through a simple one-step process. The operation is simple, the raw materials are easy to prepare, the catalyst used is small in amount, cheap and easy to obtain, and the purification is simple. BRIEF DESCRIPTION OF DRAWINGS

[0040] The meanings in the reaction formula and the technical solutions in the specification

[0017] are the same. In the figure, 1,6-alkynyl is equivalent to compound 1, amine is equivalent to compound 2, and tetrahydronaphthylimine is equivalent to compound 3. DETAILED DESCRIPTION

[0041] The application will be further described in conjunction with specific examples, which in no way intend to limit the scope of the application. Unless otherwise specified, the reagents, methods, and instruments employed in the present application are of routine use in the art and are commercially available or synthesized by known literature methods.

[0042] Example 1

[0043]

[0044] A dry Schlenk tube with a stir bar was charged with Cu(OAc)2(7.3 mg, 20% mmol), after three times of nitrogen replacement, 1a (61.6 mg, 0.2 mmol), 2a (27.9 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL) were added. The mixture was stirred at 60 °C for 3 h. The reaction was complete. The solvent was removed by rotary evaporation. The product 3a (77%, unstable, partially decomposed during isolation) was obtained as a brown oil after purification by flash column chromatography (eluent: petroleum ether: ethyl acetate, 10:1, v / v), 1 H NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 7.9, 1.6 Hz, 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 = 4.6 Hz, 1H), 3.70 - 3.62 (m, 1H), 3.55 (dd, J = 16.4, 14.2 Hz, 1H), 2.73 (dd, J = 16.4, 3.8 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 200.7, 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 for C 29 H 24 NO (M+H)+402.1852, found 402.1861.

[0045] Example 2

[0046]

[0047] A dry Schlenk tube with a stir bar was charged with Cu(OAc)2(7.3 mg, 20% mmol), after three times of nitrogen replacement, 1a (61.6 mg, 0.2 mmol), 2b (40.5 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL) were added. The mixture was stirred at 60 °C for 3 h. The reaction was complete. The solvent was removed by rotary evaporation. The product 3b (72 mg, 81%) was obtained as a white solid after purification by flash column chromatography (eluent: petroleum ether: ethyl acetate, 5:1, by volume). 1 H NMR (400 MHz, CDC13) δ 8.46 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 7.6 Hz, 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 = 8.3 Hz, 2H), 5.26 (d, J = 4.5 Hz, 1H), 3.69 (dt, J = 14.2, 4.2 Hz, 1H), 3.63 - 3.51 (m, 1H), 2.69 (dd, J = 16.2, 3.6 Hz, 1H), 2.56 (s, 3H); 13 CNMR (101 MHz, CDC13) δ 200.5, 197.2, 165.4, 156.4, 140.5, 139.2, 137.9, 133.8, 133.0, 132.5, 131.2, 129.9, 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.

[0048] Example 3

[0049]

[0050] A dry Schlenk tube with a stir bar was charged with Cu(OAc)2(7.3 mg, 20% mmol), after three times of nitrogen replacement, 1a (61.6 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL) were added. The mixture was stirred at 80 °C for 3 h. The reaction was complete. The solvent was removed by rotary evaporation. The product 3c (60 mg, 63%) was obtained as a white solid after purification by flash column chromatography (eluent: petroleum ether: ethyl acetate, 2:1, by volume), m.p. 190-191 °C, 1 H NMR (400 MHz, CDC13) δ 8.24 (dd, J = 8.0, 1.5 Hz, 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, 1.3 Hz, 1H), 5.25 (d, J = 4.6 Hz, 1H), 4.14 (dd, J = 18.6, 14.1 Hz, 1H), 3.89 (dd, J = 18.6, 4.6 Hz, 1H), 3.84 - 3.76 (m, 1H), 2.47 (s, 3H); 13 CNMR (101 MHz, CDC13) δ 199.2, 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.

[0051] Example 4

[0052]

[0053] A dry Schlenk tube with a stir bar was charged with Cu(OAc)2(7.3 mg, 20% mmol), after three times of nitrogen replacement, 1b (65.2 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL) were added. The reaction mixture was stirred at 80 °C for 3 h. The solvent was removed, and the product 3d (60 mg, 61%) was obtained as a white solid after purification by flash column chromatography (eluent: petroleum ether: ethyl acetate, 2:1, v / v), m.p. 106-107 °C, 1 H NMR (400 MHz, CDC13) δ 8.23 (dd, J = 8.0, 1.5 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.59 - 7.53 (m, 2H), 7.49 - 7.40 (m, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.30 (dt, J = 12.5, 7.7 Hz, 3H), 7.22 - 7.15 (m, 2H), 7.07 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 8.6 Hz, 2H), 5.23 (d, J = 4.6 Hz, 1H), 4.11 (dd, J = 18.5, 14.1 Hz, 1H), 3.87 (dd, J = 18.5, 4.6 Hz, 1H), 3.79 (dt, J = 14.1, 4.6 Hz, 1H), 2.47 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 199.0, 178.7, 162.0 (d, 1 J C-F = 247.5 Hz), 143.5, 141.2, 138.9, 137.3, 135.6 (d, 4 J C-F = 4.0 Hz), 133.7, 133.3, 132.6, 129.5, 129.33, 129.25, 128.53 (d, 3 J C-F = 24.2 Hz), 128.51, 128.1, 127.2, 115.6 (d, 2 J C-F = 21.2 Hz), 51.1, 42.8, 33.3, 21.6; 19 F NMR (376 MHz, CDC13) δ -114.58; HRMS (ESI) Calcd for C 30 H 24 NO3NaSF (M + Na) + 520.1353, found 520.1355.

[0054] Example 5

[0055]

[0056] A dry Schlenk tube with a stir bar was charged with Cu(OAc)2(7.3 mg, 20% mmol), after three times of nitrogen replacement, 1c (65.2 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL) was added. The mixture was stirred at 80 °C for 3 h. The reaction was complete. The solvent was removed. The product 3e (57 mg, 58%) was obtained as a red-brown solid, m.p. 170-171 °C,1H NMR (400 MHz, CDCl3) δ 8.24 (dd, J = 8.1, 1.5 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.59 - 7.50 (m, 2H), 7.42 (td, J = 7.4, 1.5 Hz, 1H), 7.39 - 7.29 (m, 3H), 7.24 - 7.11 (m, 5H), 7.05 (d, J = 7.8 Hz, 1H), 6.95 - 6.85 (m, 2H), 5.18 (d, J = 4.6 Hz, 1H), 4.09 (dd, J = 18.6, 14.1 Hz, 1H), 3.89 (dd, J = 18.6, 4.6 Hz, 1H), 3.80 (dt, J = 14.1, 4.5 Hz, 1H), 2.47 (s, 3H); 1 H NMR (400 MHz, CDCl3) δ 8.24 (dd, J = 8.1, 1.5 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.59 - 7.50 (m, 2H), 7.42 (td, J = 7.4, 1.5 Hz, 1H), 7.39 - 7.29 (m, 3H), 7.24 - 7.11 (m, 5H), 7.05 (d, J = 7.8 Hz, 1H), 6.95 - 6.85 (m, 2H), 5.18 (d, J = 4.6 Hz, 1H), 4.09 (dd, J = 18.6, 14.1 Hz, 1H), 3.89 (dd, J = 18.6, 4.6 Hz, 1H), 3.80 (dt, J = 14.1, 4.5 Hz, 1H), 2.47 (s, 3H); 13 C NMR) δ 197.5, 178.9, 165.7 (d, 1 J C-F = 256.5 Hz), 143.4, 141.3, 139.6, 138.9, 133.9 (d, 4 J C-F = 3.0 Hz), 132.7, 131.2 (d, 3 J C-F = 9.1 Hz), 129.5, 128.8, 128.7, 128.3, 128.1, 127.8, 127.6, 127.2, 115.5 (d, 2 J C-F = 22.2 Hz), 51.4, 43.6, 33.0, 21.6; 19 F NMR (376 MHz, CDCl3) δ -104.64; HRMS (ESI) Calcd for C 30 H 24 NO3NaSF (M + Na) + 520.1353, found 520.1355.

[0057] Example 6

[0058]

[0059] A dry Schlenk tube with a stir bar was charged with Cu(OAc)2(7.3 mg, 20% mmol), after three times of nitrogen replacement, 1d (62.8 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL) was added. The reaction mixture was stirred at 80 °C for 3 h. The solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate, 2:1, v / v) to give the product 3f (65 mg, 67%) as a white solid, m.p. 162-163 °C, 1 H NMR (400 MHz, CDC13) δ 8.23 (dd, J = 8.0, 1.4 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 2.9, 1.3 Hz, 1H), 7.43 (td, J = 7.5, 1.5 Hz, 1H), 7.38 - 7.30 (m, 3H), 7.24 (dd, J = 5.1, 1.3 Hz, 1H), 7.22 - 7.14 (m, 5H), 7.14 - 7.09 (m, 2H), 4.96 (d, J = 4.5 Hz, 1H), 4.09 (dd, J = 18.6, 14.1 Hz, 1H), 3.89 (dd, J = 18.6, 4.5 Hz, 1H), 3.78 (dt, J = 14.1, 4.5 Hz, 1H), 2.47 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 192.6, 179.1, 143.4, 142.9, 141.3, 139.8, 139.0, 133.7, 133.3, 132.6, 129.5, 128.7, 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 for C 28 H 23 NO3NaS2(M+Na) + 508.1012, found 508.1008.

[0060] Example 7

[0061]

[0062] A dry Schlenk tube with a stir bar was charged with Cu(OAc)2(7.3 mg, 20% mmol), after three times of nitrogen replacement, 1e (65.2 mg, 0.2 mmol), 2c (51.3 mg, 0.3 mmol) and 1,2-dichloroethane (4 mL) was added. The mixture was stirred at 80 °C for 3 h. The solvent was removed, and the residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 2:1) to give the product 3g (67 mg, 68%) as a brown solid, mp: 170-171 °C, 1 H NMR (400 MHz, CDC13) δ 8.27 (dd, J = 9.0, 5.9 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.55 - 7.48 (m, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.33 - 7.27 (m, 1H), 7.24 - 7.07 (m, 6H), 7.01 (td, J = 8.5, 2.5 Hz, 1H), 6.76 (dd, J = 8.6, 2.6 Hz, 1H), 5.21 (d, J = 4.6 Hz, 1H), 4.09 (dd, J = 18.6, 14.1 Hz, 1H), 3.89 (dd, J = 18.6, 4.5 Hz, 1H), 3.80 (dt, J = 14.2, 4.6 Hz, 1H), 2.47 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 198.5, 177.8, 144.1, 143.5, 139.3, 138.9, 137.2, 133.3, 131.6 (d, 3 J C-F = 10.1 Hz), 129.5, 129.1, 128.8, 128.5, 128.4, 127.8, 127.7, 127.2, 115.7 (d, 2 J C-F = 21.2 Hz), 114.9 (d, 2 J C-F = 22.2 Hz), 51.3, 43.6, 32.9, 21.6; 19 F NMR (376 MHz, CDC13) δ -103.98; HRMS (ESI) Calcd for C 30 H 24 NO3NaSF (M + Na) + 520.1353, found 520.1355.

[0063] The above embodiments are the preferred embodiments of the present application, but the embodiments of the present application are not limited to the above embodiments, and any changes, modifications, substitutions, combinations, simplifications, etc. made without departing from the spirit and principles of the present application should be equivalent replacement manners and should be included in the protection scope of the present application.

Claims

1. A preparation method of a tetrahydronaphthalene imine compound with carbonyl substitution, characterized by the following reaction formula of the preparation method: characterized in that comprising the following steps: dissolving a 1,6-alkynyl compound in a solvent under nitrogen protection, adding a catalyst and an amine, and separating and purifying after reaction to obtain a tetrahydronaphthalene imine compound; wherein R is aryl, heteroaryl, p-toluenesulfonyl or C1-C 12 alkylsulfonyl; Where: R 1 C1~C 12 alkyl, aryl or heteroaryl; R 2 is C1-C 12 alkyl, aryl or heteroaryl; R 3 is a hydrogen atom, halogen or Ci-C4alkyl; and 12 alkyl; the catalyst is one of Cu(OAc)2·H2O, Cu(OAc)2, CuSO4·5H2O, CuSO4 and CuCl2.

2. The method of claim 1, wherein: the solvent is one of 1,1-dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, trifluorotoluene, 1,4-dioxane, acetonitrile, toluene, chlorobenzene and xylene.

3. The method of claim 1, wherein: the reaction is carried out at 25-120°C for 0.5-48h.

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