A process for the preparation of isoquinoline derivatives

Abstract

The application relates to the field of organic synthesis, in particular to a preparation method of an isoquinoline derivative. The application develops a method for directly obtaining an isoquinoline product by reacting o-diiodobenzene as a precursor with an aminoalkenone, the method avoids the use of transition metal catalysis, raw materials are cheap and easy to obtain, the substrate range is wide, and the method provides a new idea for the synthesis research of isoquinoline and has important significance.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically to a method for preparing an isoquinoline derivative. Background Technology

[0002] Isoquinolines are a common class of pharmacologically active structures, found in various types of drugs. Commonly used drugs containing isoquinoline core structures have various medicinal activities, including antitumor, antifungal, antiviral, anesthetic, and enzyme inhibitor activities. Naturally occurring isoquinoline alkaloids are extremely common in the pharmaceutical field, such as berberine, papaverine, and magnoflorine. Apart from some alkaloids found in natural plants, most isoquinolines and their derivatives require chemical synthesis.

[0003] Currently, commonly used synthetic methods include: 1. Cycling of 2-halobenzaldehyde imines with alkynes under the catalysis of transition metals such as cobalt, copper, nickel, palladium, rhodium, and ruthenium, intramolecular cyclization of o-alkynyl oximes or benzyl azides, and multi-component reactions of aldehydes or ketones with amines and isocyanates to obtain the corresponding isoquinoline derivatives. However, this method suffers from problems such as high metal prices and environmental pollution. 2. Without transition metal catalysis, using o-acetylbenzaldehyde with various aryl methylamines or heteroaryl methylamines as raw materials, reacting under alkaline conditions to obtain isoquinolines in various yields. In addition, there are some free radical reactions and the application of new technologies, such as the tandem cyclization of o-alkynylphenylacetaldehyde with ammonia to synthesize isoquinolines under microwave conditions. However, these methods have limitations such as harsh reaction conditions and poor functional group tolerance. Therefore, it is necessary to develop new methods for preparing isoquinolines that avoid the use of some transition metals, as well as harsh reaction conditions and highly toxic reagents, in line with the concept of modern green chemistry, and have significant application value. Summary of the Invention

[0004] This invention discloses a novel method for generating isoquinoline products from o-dihalobenzenes and aminoenones under the action of alkali metal hydrides. The method of this invention is simpler, uses inexpensive and readily available raw materials, operates under mild conditions, and achieves high-yield synthesis of isoquinolines without the need for transition metal catalysis.

[0005] The technical solution adopted in this invention is as follows:

[0006] A method for preparing an isoquinoline derivative includes the following steps: using o-dihalobenzene and aminoenone as raw materials, reacting them in the presence of an alkali metal hydride to obtain an isoquinoline structure product; specifically, adding the alkali metal hydride to a solvent, then adding the aminoenone and stirring, followed by adding the o-dihalobenzene, and then reacting at 20℃~80℃ for 12~18 h to obtain the isoquinoline derivative.

[0007] In this invention, the alkali metal hydride is one or more of NaH, KH, CaH2, and LiH, preferably NaH and KH, and more preferably NaH.

[0008] In this invention, the reaction is carried out in a solvent, which is one or more of THF, DMA, DMF, 1,4-dioxane, and toluene, preferably THF and DMF, and more preferably THF.

[0009] In this invention, the reaction temperature is 20 ℃~80 ℃, preferably 30 ℃~50 ℃, and most preferably 40 ℃.

[0010] In this invention, the molar ratio of aminoenone, o-dihalobenzene and alkali metal hydride is 1:(1.5-3):(3-10), preferably 1:(2-3):(5-8), and more preferably 1:2.5:6.

[0011] In this invention, the chemical structural formula of the aminoketone is as follows: ;

[0012] R 1 It is an alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group; R 2 It is selected from alkyl and aryl groups. The alkyl group is a straight-chain, branched, or cycloalkyl group having 1 to 10 carbon atoms; the aryl group contains 1 to 6 benzene rings; the aromatic heterocyclic group contains 1 to 3 benzene rings, and the heteroatoms are oxygen, sulfur, nitrogen, etc.; preferably, the alkyl group is methyl, ethyl, tert-butyl, etc., or heteroatom-substituted alkyl group; the aryl group is phenyl, naphthyl, pyridine, thiophene, etc.

[0013] In the aforementioned substituted aryl and substituted aromatic heterocyclic groups, the substituents are independently selected from one of alkyl, halogen, alkoxy, and aryl; wherein the alkyl group is methyl, ethyl, tert-butyl, heteroatom-substituted alkyl, etc.; the halogen is fluorine, chlorine, bromine, iodine, etc.; the alkoxy group is methoxy, ethoxy, etc.; and the aryl group is phenyl, etc.

[0014] In this invention, the chemical structural formula of the ortho-dihalobenzene is as follows: ;

[0015] R 3 X is selected from alkyl or alkoxy groups; X is selected from chlorine, bromine, iodine, or OTf, preferably iodine.

[0016] In this invention, the chemical structural formula of the product isoquinoline compound is as follows: ;

[0017] The substituents in the product are the same as those in the raw materials.

[0018] As one embodiment of the invention, the reaction can be represented as follows:

[0019] ;

[0020] Preferably, the added alkali metal compound is NaH, the solvent is THF, the reaction temperature is 40 °C, and the reaction time is 15 h.

[0021] The beneficial effects of the method for preparing isoquinoline structural products provided by this invention are as follows:

[0022] It is a transition metal-free catalyst, low in cost, simple to operate, less polluting, and environmentally friendly; the preparation is simpler and the atom economy is better; the reaction conditions are mild and the safety factor is high; it has strong functional group compatibility and a wide substrate range. Detailed Implementation

[0023] To better understand the technical content of this invention, the following embodiments are provided for detailed explanation.

[0024] The method for synthesizing isoquinoline structural products provided by this invention uses o-dihalobenzene and aminoenone as raw materials, and undergoes addition and rearrangement reactions in the presence of alkali metal hydrides to obtain isoquinoline structural products. Specifically, the alkali metal hydride is added to a solvent, then the aminoenone compound is added, and the mixture is stirred for 1 to 10 minutes. Subsequently, o-dihalobenzene is added dropwise, and the mixture is stirred at 20 ℃ to 80 ℃ for 12 to 18 hours to obtain isoquinoline structural products.

[0025] The preparation method provided by this invention, using aminoenones and o-dihalobenzenes as substrates, successfully constructs structurally diverse isoquinoline products in excellent yields through a series of addition and rearrangement reactions. The reactants are inexpensive and readily available, the conditions are mild, and high-yield synthesis of isoquinolines is achieved without transition metal catalysis. Compared with the classic method using Kobayashi precursors, this method is simpler and more atom-economical. Therefore, this type of method has great potential for application in other organic synthesis reactions.

[0026] The raw materials involved in the various embodiments of this invention are either commercially available products or can be prepared using existing methods. The specific preparation operations and characterization tests of this invention are conventional techniques.

[0027] Example 1: Preparation of isoquinoline structural products

[0028] At room temperature, NaH (60% in oil, 3.6 mmol, 6.0 equiv) was weighed into a round-bottom flask, and 2 mL of anhydrous THF was added and stirred to suspend it in the solvent. Aminoenone 1 (0.6 mmol, 1.0 equiv) was dissolved in anhydrous THF (2.0 mL) and added dropwise to the suspension under N2 protection. The mixture was stirred for 5 min, and then o-diiodobenzene 2a (1.5 mmol, 2.5 equiv) was added dropwise over 1 minute. The mixture was then stirred in an oil bath at 40 °C. After the reaction was complete, the reaction solution was allowed to cool naturally to room temperature, and then added dropwise to water (10 mL). The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The isoquinoline product 3 was purified by rapid column chromatography.

[0029] The different reaction substrates, aminoenone 1 and o-diiodobenzene 2, and the corresponding isoquinoline structural product 3, are shown in Tables 1 to 4. The reaction time is 12–18 h under stirring in an oil bath at 40 °C; the yield is the isolated yield. It can be observed that halogenated or polyhalogenated substrates exhibit moderate to high yields. For substrates with electron-withdrawing groups (e.g., OCF3, CF3, CN) and electron-donating groups (e.g., Me, OMe) on the benzene ring, the yield remains good. Furthermore, through the expansion of some substrates, it was found that the steric effect on the benzene ring has little impact on the reaction. Most aliphatic hydrocarbon substrates show moderate to high yields; in addition to the benzene ring (3al), long-chain alkanes (3am), sterically hindered alkanes (3ao, 3bb), and alkenes (3ap) can all be converted into structurally diverse isoquinoline products using this method. Moreover, commonly used protecting groups TBS and Boc (3aq, 3bc) are also compatible with this system. A series of isoquinoline products with (hetero)cycloalkanes (3ar-3az, 3bd) were synthesized in moderate to high yields, further demonstrating the versatility of this method. Substituted diiodobenzenes can all be readily used to synthesize polysubstituted isoquinoline products. Of particular note is the structural similarity of 3be to the drug mosavelin, providing a concise route for the synthesis of such drugs.

[0030]

[0031]

[0032]

[0033]

[0034] The above product data are characterized as follows:

[0035] The above product data are characterized as follows:

[0036] 3-Methyl-1-phenylisoquinoline (3a). Yellow solid, yield 75%, melting point 77-88 °C. 1 H NMR (400MHz, CDCl3) δ 8.01 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.68 (dd, J = 8.0, 1.4 Hz, 2H), 7.63 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.51 (dt, J = 11.8,6.0 Hz, 4H), 7.46 – 7.41 (m, 1H), 2.76 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ160.38, 150.90, 139.77, 137.64, 129.97, 128.50, 128.41, 127.59, 126.42,126.20, 124.98, 118.04, 24.50. LR-MS (ESI): m / z 220.1 [M+H] + .

[0037] 1-(4-fluorophenyl)-3-methylisoquinoline (3b). Yellow solid, yield 69%, melting point 55-64 °C. 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.69 –7.61 (m, 3H), 7.49 (s, 1H), 7.47 – 7.42 (m, 1H), 7.22 (t, J = 8.7 Hz (2H), 2.75 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 163.12 (d, J= 248.4 Hz), 159.24,150.91, 137.69, 135.82, 131.78 (d, J = 8.0 Hz), 130.06, 127.26, 126.52,126.36, 124.93, 118.18, 115.39 (d, J = 21.2 Hz), 24.44. 19 F NMR (377 MHz, CDCl3) δ -113.46. LR-MS (ESI): m / z 238.0 [M+H] + .

[0038] 1-(4-Chlorophenyl)-3-methylisoquinoline (3c). Yellow solid, yield 79%, melting point 111-116 °C. 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.66 –7.60 (m, 3H), 7.50 (d, J = 8.5 Hz, 3H), 7.48 – 7.42 (m, 1H), 2.74 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ 159.01, 150.98, 138.21, 137.66, 134.67, 131.34,130.09, 128.63, 127.10, 126.54, 126.42, 124.81, 118.31, 24.43. LR-MS (ESI): m / z 254.0 [M+H] + .

[0039] 1-(2-Chlorophenyl)-3-methylisoquinoline (3d). Yellow solid, yield 76%, melting point 63-74 °C. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 1H), 7.61 (ddd, J = 8.2, 6.8, 1.1 Hz,1H), 7.57 (dd, J = 8.4, 0.7 Hz, 1H), 7.53 (dd,J = 6.2, 3.0 Hz, 2H), 7.47 –7.44 (m, 1H), 7.43 – 7.38 (m, 3H), 2.76 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ158.27, 150.85, 138.51, 137.03, 133.38, 131.34, 130.17, 129.76, 129.69,127.14, 126.89, 126.40, 126.35, 125.38, 118.73, 24.37. LR-MS (ESI): m / z 254.0[M+H] + .

[0040] 1-(3-bromophenyl)-3-methylisoquinoline (3e). Yellow solid, yield 74%, melting point 67-72 °C. 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 1H), 7.84 (t, J = 1.6 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.67 – 7.56 (m, 3H), 7.50 (s, 1H), 7.48 – 7.42 (m, 1H),7.38 (t, J = 7.8 Hz, 1H), 2.75 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.58,150.93, 141.76, 137.60, 132.87, 131.52, 130.12, 129.85, 128.60, 127.02,126.51, 124.77, 122.61, 118.51, 24.40. LR-MS (ESI): m / z 299.1 [M+H] + .

[0041] 1-(3-Iodophenyl)-3-methylisoquinoline (3f). Yellow solid, yield 67%, melting point 72-83 °C. 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.94 (d, J= 8.5 Hz, 1H), 7.79 (dd, J =16.2, 8.1 Hz, 2H), 7.66 – 7.59 (m, 2H), 7.49 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 2.74 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ158.49, 150.92, 141.80, 138.65, 137.59, 137.46, 130.13, 129.95, 129.19,127.05, 126.51, 124.78, 118.49, 94.42, 24.41. LR-MS (ESI): m / z 346.0 [M+H] + .

[0042] 3-Methyl-1-(p-Tolyl)isoquinoline (3g). Yellow solid, yield 73%, melting point 72-78 °C. 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.61(t, J = 8.1 Hz, 3H), 7.46 (s, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.9Hz, 2H), 2.76 (s, 3H), 2.46 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.37,150.82, 138.25, 137.59, 136.86, 129.86, 129.82, 129.02, 127.60, 126.33,126.02, 124.95, 117.76, 24.44, 21.35. LR-MS (ESI): m / z 234.1 [M+H] + .

[0043] 3-Methyl-1-(o-tolyl)isoquinoline (3h). Yellow oily liquid, yield 76%. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 1H), 7.64 – 7.56 (m, 2H), 7.50 (s, 1H), 7.36(dtd, J = 12.0, 6.8, 1.3 Hz, 5H), 2.75 (s, 3H), 2.08 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 160.91, 150.78, 139.12, 137.10, 136.38, 130.27, 129.99, 129.54,128.32, 127.37, 126.26, 126.15, 125.63, 125.57, 117.86, 24.41, 19.78. LR-MS(ESI): m / z 234.1 [M+H] + .

[0044] 3-Methyl-1-(m-Tolyl)isoquinoline (3i). Yellow oily liquid, yield 69%. 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.65 – 7.59 (m,1H), 7.44 (ddd, J = 19.9, 16.8, 7.7 Hz, 5H), 7.29 (d, J = 7.4 Hz, 1H), 2.75(s, 3H), 2.46 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.60, 150.84, 139.68,138.14, 137.58, 130.53, 129.92, 129.22, 128.14, 127.68, 127.07, 126.35,126.10, 125.01, 117.93, 24.51, 21.57. LR-MS (ESI): m / z 234.1 [M+H] + .

[0045] 4-(3-methylisoquinoline-1-yl)benzyl nitrile (3j). Yellow solid, yield 73%, melting point 155-159 °C.1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 1H), 7.85 – 7.78 (m, 5H), 7.72 – 7.63(m, 1H), 7.55 (s, 1H), 7.52 – 7.45 (m, 1H), 2.75 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.03, 151.17, 144.30, 137.69, 132.25, 130.78, 130.35, 126.84,126.76, 126.54, 124.60, 119.01, 118.83, 112.31, 24.37. LR-MS (ESI): m / z 245.1[M+H] + .

[0046] 3-Methyl-1-(4-(methylthio)phenyl)isoquinoline (3k). Yellow solid, yield 47%, melting point 76-82 °C. 1 HNMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.66 – 7.59 (m, 3H), 7.49 – 7.39 (m, 4H), 2.74 (s, 3H), 2.55 (s, 3H). 13 C NMR(101 MHz, CDCl3) δ 159.72, 150.97, 139.22, 137.70, 136.56, 130.44, 129.98,127.42, 126.47, 126.45, 126.23, 124.91, 117.98, 24.48, 15.91. LR-MS (ESI): m / z 265.9 [M+H] + .

[0047] 1-(4-methoxyphenyl)-3-methylisoquinoline (3l). Yellow solid, yield 75%, melting point 80-85 °C. 1 HNMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 1H), 7.76 (d, J= 8.2 Hz, 1H), 7.63 (dd, J = 16.5, 8.4 Hz, 3H), 7.48 – 7.39 (m, 2H), 7.10 – 7.03 (m, 2H), 3.89 (s, 3H), 2.74 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.97, 150.83, 137.68,132.31, 131.31, 129.84, 127.60, 126.38, 126.05, 124.96, 117.63, 113.85,55.43, 24.48. LR-MS (ESI): m / z 250.1 [M+H] + .

[0048] 1-(3-(benzyloxy)phenyl)-3-methylisoquinoline (3m). Yellow oily liquid, yield 54%. 1 H NMR (400MHz, CDCl3) δ 8.03 – 7.97 (m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.5Hz, 1H), 7.47 (dd, J = 14.3, 6.6 Hz, 4H), 7.41 (dd, J = 13.0, 5.7 Hz, 3H), 7.35 (dd, J = 10.3, 3.6 Hz, 2H), 7.31 – 7.26 (m, 1H), 7.12 (dd, J = 8.2, 0.7Hz, 1H), 5.15 (s, 2H), 2.77 (d, J = 1.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ160.06, 158.77, 150.82, 141.07, 137.60, 137.02, 129.97, 129.47, 128.62,127.98, 127.57, 127.53, 126.37, 126.22, 124.91, 122.74, 118.13, 116.25,115.40, 70.09, 24.45. LR-MS (ESI): m / z 325.9 [M+H]+ .

[0049] 3-Methyl-1-(4-phenoxyphenyl)isoquinoline (3n). Yellow solid, yield 54%, melting point 116-125 °C. 1 HNMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.39(t, J = 8.0 Hz, 2H), 7.21 – 7.10 (m, 5H), 2.77 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.57, 157.72, 156.98, 150.78, 137.61, 134.63, 131.48, 129.89,129.79, 127.36, 126.38, 126.16, 124.86, 123.49, 119.16, 118.55, 117.89,24.40. LR-MS (ESI): m / z 311.1 [M+H] + .

[0050] 1-(2-Methoxyphenyl)-3-methylisoquinoline (3o). Yellow solid, yield 71%, melting point 84-99 °C. 1 HNMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 8.4, 0.6 Hz, 1H), 7.59 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.38 (td, J =7.8, 1.4 Hz, 2H), 7.12 (td, J = 7.4, 0.9 Hz, 1H), 7.04 (d, J= 8.3 Hz, 1H), 3.68 (s, 3H), 2.76 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.60, 157.15, 150.86,136.85, 131.21, 129.88, 129.80, 128.89, 127.80, 126.10, 125.90, 125.84,120.86, 118.17, 111.10, 55.49, 24.45. LR-MS (ESI): m / z 250.1 [M+H] + .

[0051] 1-(4-(tert-butyl)phenyl)-3-methylisoquinoline (3p). Yellow oily liquid, yield 60%. 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.68 –7.59 (m, 3H), 7.56 (d, J = 8.0 Hz, 2H), 7.46 (s, 1H), 7.43 (ddd, J = 8.2,6.9, 1.1 Hz, 1H), 2.77 (s, 3H), 1.42 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ160.36, 151.40, 150.81, 137.58, 136.83, 129.82, 129.61, 127.67, 126.30,125.99, 125.31, 124.92, 117.72, 34.69, 31.38, 24.41. LR-MS (ESI): m / z 276.1[M+H] + .

[0052] 1-(4-Isopropylphenyl)-3-methylisoquinoline (3q). Yellow oily liquid, yield 79%. 1 H NMR (400MHz, CDCl3) δ 8.09 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.62 (dd, J= 14.2, 7.7 Hz, 3H), 7.48 – 7.38 (m, 4H), 3.02 (dt, J = 13.8, 6.9 Hz, 1H), 2.76 (s, 3H), 1.34 (d, J = 7.0 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 160.40,150.80, 149.19, 137.58, 137.21, 129.89, 129.82, 127.66, 126.45, 126.30,126.00, 124.92, 117.73, 34.06, 24.41, 24.03. LR-MS (ESI): m / z 262.0 [M+H] + .

[0053] 1-(4-Ethylphenyl)-3-methylisoquinoline (3r). Yellow solid, 78% yield, melting point 60-64 °C. 1 HNMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 12.3, 4.4 Hz, 3H), 7.48 – 7.40 (m, 2H), 7.37 (d, J = 8.0 Hz,2H), 2.80 – 2.73 (m, 5H), 1.32 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ160.40, 150.82, 144.62, 137.59, 137.10, 129.91, 129.81, 127.88, 127.63,126.31, 126.01, 124.94, 117.73, 28.78, 24.44, 15.70. LR-MS (ESI): m / z 248.1[M+H] + .

[0054] 3-Methyl-1-(4-(trifluoromethyl)phenyl)isoquinoline (3s). Yellow solid, yield 62%, melting point 65-69 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 1H), 7.84 – 7.76 (m, 5H), 7.65 (t, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 2.76 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.68, 151.02, 143.27, 137.62, 130.55 (d, J =33.3 Hz), 130.33, 130.20, 126.84, 126.60, 125.61, 125.35 (q, J = 4.0 Hz),124.73, 122.90, 118.68, 24.31. 19 F NMR (377 MHz, CDCl3) δ -113.46. LR-MS(ESI): m / z 287.9 ​​[M+H] + .

[0055] 3-Methyl-1-(4-(trifluoromethoxy)phenyl)isoquinoline (3t). Yellow solid, 73% yield, melting point 61-67°C. 1 H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.5, 0.6 Hz, 1H), 7.79 (d, J = 8.2Hz, 1H), 7.75 – 7.69 (m, 2H), 7.67 – 7.61 (m, 1H), 7.50 (s, 1H), 7.48 – 7.43(m, 1H), 7.38 (d, J = 7.9 Hz, 2H), 2.75 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ158.76, 150.94, 149.47 (d, J = 2.0 Hz), 138.46, 137.64, 131.46, 130.11,127.01, 126.54, 126.47, 124.78, 120.93, 120.59 (q, J= 258.5 Hz), 118.39, 24.35. 19 F NMR (377 MHz, CDCl3) δ -57.69. LR-MS (ESI): m / z 304.0 [M+H] + .

[0056] 1-([1,1'-biphenyl]-4-yl)-3-methylisoquinoline (3u). Yellow solid, yield 51%, melting point 176-181 °C. 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.5 Hz, 1H), 7.83 – 7.75 (m,5H), 7.71 – 7.68 (m, 2H), 7.67 – 7.62 (m, 1H), 7.50 (dd, J = 9.9, 5.4 Hz, 4H), 7.40 (t, J = 7.4 Hz, 1H), 2.78 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ160.00, 151.00, 141.41, 140.92, 138.73, 137.70, 130.45, 130.00, 128.90,127.54, 127.28, 127.21, 126.47, 126.26, 124.99, 118.06, 24.49. LR-MS (ESI): m / z 296.1 [M+H] + .

[0057] 1-(2,5-Dimethylphenyl)-3-methylisoquinoline (3v). Yellow oily liquid, yield 66%. 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 7.64 – 7.57 (m, 2H), 7.49 (s,1H), 7.42 – 7.35 (m, 1H), 7.24 – 7.14 (m, 3H), 2.76 (s, 3H), 2.37 (s, 3H), 2.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.15, 150.78, 138.94, 137.04,135.04, 133.17, 130.11, 130.10, 129.97, 129.05, 127.49, 126.23, 126.12,125.55, 117.80, 24.41, 20.95, 19.29. LR-MS (ESI): m / z 247.9 [M+H] + .

[0058] 1-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-methylisoquinoline (3w). Yellow solid, yield 67%, melting point 85-93 °C. 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.21 –7.13 (m, 2H), 6.95 (d, J = 7.9 Hz, 1H), 6.06 – 5.99 (m, 2H), 2.73 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ 159.63, 150.72, 147.94, 147.70, 137.65, 133.70,129.88, 127.42, 126.36, 126.11, 124.86, 123.98, 117.83, 110.54, 108.19,101.20, 24.38. LR-MS (ESI): m / z 264.0 [M+H] + .

[0059] 1-(2,3-Dihydrobenzo[b][1,4]dioxane-6-yl)-3-methylisoquinoline (3x). Yellow oily liquid, yield 64%. 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.5 Hz, 1H), 7.74 (d, J =8.2 Hz, 1H), 7.59 (t, J= 7.5 Hz, 1H), 7.47 – 7.39 (m, 2H), 7.25 (s, 1H), 7.18 (dd, J = 8.3, 2.0 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 4.30 (s, 4H), 2.73 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.53, 150.69, 144.05, 143.41, 137.58,133.12, 129.79, 127.51, 126.28, 126.01, 124.78, 123.25, 119.02, 117.68,117.09, 64.49, 64.33, 24.37. LR-MS (ESI): m / z 278.1 [M+H] + .

[0060] 1-(3,4-Dimethoxyphenyl)-3-methylisoquinoline (3y). Yellow solid, yield 72%, melting point 87-101 °C. 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.46 – 7.39 (m, 2H), 7.23 (dd, J = 10.3, 1.8Hz, 2H), 7.00 (d, J = 7.9 Hz, 1H), 3.94 (d, J = 8.5 Hz, 6H), 2.73 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ 159.96, 150.73, 149.45, 148.96, 137.65, 132.46,129.84, 127.53, 126.35, 126.06, 124.95, 122.70, 117.72, 113.20, 110.93,56.04, 55.96, 24.37. LR-MS (ESI): m / z 279.9 [M+H] + .

[0061] 3-Methyl-1-(naphth-2-yl)isoquinoline (3z). Yellow oily liquid, yield 77%. 1 H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H),7.98 – 7.92 (m, 2H), 7.90 – 7.84 (m, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.59 – 7.53 (m, 2H), 7.52 (s, 1H), 7.44 (t, J = 7.6 Hz, 1H), 2.83 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.13, 150.86, 137.58, 137.10,133.21, 133.15, 129.88, 129.33, 128.41, 127.96, 127.69, 127.64, 127.47,126.41, 126.37, 126.25, 126.19, 125.04, 118.01, 24.43. LR-MS (ESI): m / z 269.9[M+H] + .

[0062] 1-(3,5-Difluorophenyl)-3-methylisoquinoline (3aa). Yellow solid, 73% yield, melting point 117-181 °C. 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (dd, J = 15.0, 7.1 Hz, 2H), 7.22 (d, J = 5.9Hz, 2H), 6.93 (t, J = 8.9 Hz, 1H), 2.74 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ164.14 (d,J = 12.1 Hz), 161.66 (d, J = 13.1 Hz), 157.55, 150.95, 142.90 (t, J = 9.0 Hz), 137.65, 130.25, 126.72, 126.63, 124.50, 118.88, 113.11 (dd, J =18.2, 7.0 Hz), 103.91 (t, J = 25.2 Hz), 24.32. 19 F NMR (377 MHz, CDCl3) δ -109.56. LR-MS (ESI): m / z 256.0 [M+H] + .

[0063] 1-(furan-2-yl)-3-methylisoquinoline (3ab). Brown oily liquid, yield 68%. 1 H NMR (400MHz, CDCl3) δ 8.66 (d, J = 8.6 Hz, 1H), 7.76 – 7.68 (m, 2H), 7.61 (ddd, J =8.2, 6.8, 1.2 Hz, 1H), 7.52 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.41 (s, 1H), 7.15 (d, J = 3.4 Hz, 1H), 6.61 (dd, J = 3.3, 1.7 Hz, 1H), 2.73 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ 153.64, 150.93, 148.64, 143.79, 137.92, 129.94,126.68, 126.64, 126.58, 123.89, 118.50, 112.60, 111.67, 24.38. LR-MS (ESI): m / z 210.0 [M+H] + .

[0064] 3-Methyl-1-(thien-2-yl)isoquinoline (3ac). Yellow oily liquid, yield 59%. 1 H NMR (400MHz, CDCl3) δ 8.43 (d,J = 8.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 3.5 Hz, 1H), 7.51 (t, J = 6.7 Hz, 2H), 7.43 (s,1H), 7.20 (t, J = 3.9 Hz, 1H), 2.73 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ153.05, 150.96, 142.77, 137.90, 130.02, 128.65, 127.79, 127.40, 126.83,126.63, 126.61, 124.56, 118.15, 24.32. LR-MS (ESI): m / z 226.0 [M+H] + .

[0065] 3-Methyl-1-(pyridin-4-yl)isoquinoline (3ad). Yellow solid, yield 37%, melting point 113-118 °C. 1 HNMR (400 MHz, CDCl3) δ 8.78 (d, J = 5.9 Hz, 2H), 7.93 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.60 (d, J = 5.9 Hz, 2H),7.55 (s, 1H), 7.48 (t, J = 7.7 Hz, 1H), 2.75 (s, 3H). 13 C NMR (101 MHz, CDCl3)δ 157.48, 151.21, 149.97, 147.39, 137.63, 130.38, 126.85, 126.73, 126.53,124.68, 124.52, 119.15, 24.37. LR-MS (ESI): m / z 221.1 [M+H] + .

[0066] 1,3-Dimethylisoquinoline (3ae). Yellow oily liquid, yield 84%. 1 H NMR (400 MHz, CDCl3) δ8.04 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.30 (s, 1H), 2.92 (s, 3H), 2.64 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.00, 150.21, 136.66, 129.85, 126.58, 126.00, 125.52,117.17, 24.22, 22.29. LR-MS (ESI): m / z 158.0 [M+H] + .

[0067] 1-(tert-butyl)-3-methylisoquinoline (3af). Yellow oily liquid, yield 52%. 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.5Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.32 (s, 1H), 2.66 (s, 3H), 1.67 (d, J =1.0 Hz, 9H). 13 C NMR (101 MHz, CDCl3) δ 166.55, 149.17, 138.34, 128.57,127.71, 127.26, 124.62, 124.20, 117.41, 39.79, 31.31, 24.41. LR-MS (ESI): m / z200.1 [M+H] + .

[0068] 1-Cyclopropyl-3-methylisoquinoline (3ag). Yellow solid, yield 55%, melting point 52-55 °C. 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.57(t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.23 (s, 1H), 2.72 – 2.63 (m,1H), 2.57 (s, 3H), 1.22 (dt, J = 4.8, 3.0 Hz, 2H), 1.06 (dq, J = 6.7, 3.7 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.03, 150.54, 136.84, 129.58, 126.68,125.93, 125.83, 125.07, 116.33, 24.46, 13.61, 9.00. LR-MS (ESI): m / z 184.1 [M+H] + .

[0069] 1-Cyclopentyl-3-methylisoquinoline (3ah). Yellow oily liquid, yield 85%. 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.64 – 7.56 (m,1H), 7.49 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.31 (s, 1H), 4.00 (p, J = 8.3 Hz,1H), 2.68 (s, 3H), 2.15 (td, J = 7.9, 2.9 Hz, 4H), 1.95 (dd, J = 9.0, 5.8 Hz, 2H), 1.80 (dd, J = 7.2, 4.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 163.87,150.37, 137.09, 129.30, 126.78, 125.62, 125.23, 125.15, 116.66, 43.20, 32.74,26.03, 24.55. LR-MS (ESI): m / z 212.0 [M+H] + .

[0070] 1-((3r,5r,7r)-adamantane-1-yl)-3-methylisoquinoline (3ai). White solid, yield 61%, melting point 176-178 °C. 1 H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 8.7 Hz, 1H), 7.72 (d, J =7.3 Hz, 1H), 7.58 – 7.51 (m, 1H), 7.44 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.31(s, 1H), 2.66 (s, 3H), 2.42 (d, J = 2.5 Hz, 6H), 2.21 (s, 3H), 1.95 – 1.86 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 165.99, 149.34, 138.41, 128.45, 127.88, 126.97, 124.34, 117.35, 42.47, 42.22, 37.29, 29.35, 24.43. LR-MS (ESI): m / z278.1 [M+H] + .

[0071] 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)isoquinoline (3aj). Yellow solid, 82% yield, melting point 102-106°C. 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.54 – 7.47 (m, 1H), 7.32 (s, 1H), 4.16 (dd, J= 11.4, 3.8 Hz, 2H), 3.78 (dd, J = 15.5, 7.6 Hz, 1H), 3.69 (t, J = 11.8 Hz,2H), 2.67 (s, 3H), 2.28 (ddd, J = 16.4, 12.6, 4.3 Hz, 2H), 1.86 (t, J = 13.1Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 162.67, 150.69, 137.25, 129.43, 127.13,125.91, 124.19, 117.02, 68.32, 38.83, 32.16, 24.45. LR-MS (ESI): m / z 228.0 [M+H] + .

[0072] 1-Cyclohexyl-3-methylisoquinoline (3ak). Yellow oily liquid, yield 71%. 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.58 (ddd, J =8.1, 6.8, 1.1 Hz, 1H), 7.48 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.30 (s, 1H), 3.61 – 3.49 (m, 1H), 2.68 (s, 3H), 2.02 – 1.80 (m, 7H), 1.62 – 1.37 (m, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.02, 150.51, 137.16, 129.29, 126.94, 125.67,124.65, 124.35, 116.67, 41.64, 32.53, 26.94, 26.25, 24.54. LR-MS (ESI): m / z225.9 [M+H] + .

[0073] 1,3-Diphenylisoquinoline (3al). Yellow solid, yield 71%, melting point 64-69 °C.1 H NMR (400MHz, CDCl3) δ 8.26 (d, J = 7.7 Hz, 2H), 8.16 (d, J = 8.5 Hz, 1H), 8.09 (s,1H), 7.94 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.72 – 7.65 (m, 1H), 7.55 (ddd, J = 15.2, 8.2, 5.0 Hz, 6H), 7.48 – 7.40 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 160.40, 150.20, 139.92, 139.65, 137.86, 130.27, 130.08, 128.75,128.63, 128.51, 128.32, 127.58, 127.49, 127.13, 126.94, 125.83, 115.73. LR-MS(ESI): m / z 282.0 [M+H] + .

[0074] 3-Propyl-1-(p-Tolyl)isoquinoline (3am). Yellow oily liquid, yield 63%. 1 H NMR (400MHz, CDCl3) δ 8.08 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.62 (ddd, J = 8.0, 6.4, 1.6 Hz, 3H), 7.48 – 7.40 (m, 2H), 7.36 (d, J = 7.8 Hz, 2H),3.06 – 2.95 (m, 2H), 2.48 (s, 3H), 2.00 – 1.85 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 160.31, 154.84, 138.22, 137.54, 137.02,129.92, 129.71, 129.02, 127.57, 126.53, 126.02, 125.18, 117.21, 40.26, 23.20,21.36, 13.99. LR-MS (ESI): m / z 262.1 [M+H] + .

[0075] 3-Isopropyl-1-(p-Tolyl)isoquinoline (3an). Yellow solid, yield 67%, melting point 45-48 °C. 1 HNMR (400 MHz, CDCl3) δ 8.13 (dd, J = 8.5, 0.6 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.64 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.53 (s,1H), 7.46 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 3.38(dt, J = 13.8, 6.9 Hz, 1H), 2.51 (s, 3H), 1.51 (d, J = 6.9 Hz, 6H). 13 C NMR(101 MHz, CDCl3) δ 160.13, 159.90, 138.18, 137.69, 137.16, 130.00, 129.58,128.97, 127.48, 126.75, 126.00, 125.27, 114.57, 36.01, 22.78, 21.35. LR-MS(ESI): m / z 262.0 [M+H] + .

[0076] 3-(tert-butyl)-1-(p-tolyl)isoquinoline (3ao). Yellow solid, yield 63%, melting point 120-132 °C. 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J= 8.5 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 6.9 Hz, 2H), 7.67 – 7.60 (m, 2H), 7.51 – 7.44 (m, 1H), 7.39 (d, J = 7.7 Hz, 2H), 2.51 (s, 3H), 1.55 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ162.15, 159.03, 138.17, 137.69, 137.55, 130.25, 129.40, 128.93, 127.30,127.15, 126.07, 124.79, 113.27, 37.28, 30.29, 21.42. LR-MS (ESI): m / z 275.9[M+H] + .

[0077] 3-(but-3-en-1-yl)-1-(p-tolyl)isoquinoline (3ap). Yellow oily liquid, yield 64%. 1 HNMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H),7.66 – 7.59 (m, 3H), 7.49 – 7.42 (m, 2H), 7.36 (d, J = 7.5 Hz, 2H), 6.09 –5.86 (m, 1H), 5.08 (dd, J = 42.8, 13.7 Hz, 2H), 3.12 (t, J = 7.7 Hz, 2H), 2.66 (dd, J = 14.2, 6.7 Hz, 2H), 2.48 (s, 3H). 13C NMR (101 MHz, CDCl3) δ160.39, 153.98, 138.28, 138.22, 137.52, 136.95, 129.92, 129.77, 129.03,127.57, 126.57, 126.15, 125.23, 117.35, 114.92, 37.50, 33.92, 21.36. LR-MS(ESI): m / z 274.1 [M+H] + .

[0078] 3-(3-((tert-butyldimethylsilyl)oxy)propyl)-1-(p-tolyl)isoquinoline (3aq). Yellow oily liquid, yield 63%. 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.66 – 7.58 (m, 3H), 7.49 (s, 1H), 7.44 (ddd, J = 8.2, 6.9,1.1 Hz, 1H), 7.35 (d, J = 7.8 Hz, 2H), 3.76 (t, J = 6.4 Hz, 2H), 3.08 (t, J =7.6 Hz, 2H), 2.47 (s, 3H), 2.19 – 2.06 (m, 2H), 0.95 (s, 9H), 0.10 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 160.35, 154.46, 138.25, 137.57, 136.98, 129.94,129.76, 129.01, 127.57, 126.54, 126.08, 125.19, 117.32, 62.75, 34.49, 32.93,26.04, 21.36, 18.40, -5.20. LR-MS (ESI): m / z 392.0 [M+H] + .

[0079] 3-Cyclopropyl-1-(p-Tolyl)isoquinoline (3ar). Yellow oily liquid, yield 83%. 1H NMR (400MHz, CDCl3) δ 8.09 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.67 – 7.57(m, 3H), 7.45 – 7.38 (m, 2H), 7.36 (d, J = 7.8 Hz, 2H), 2.49 (s, 3H), 2.32 –2.21 (m, 1H), 1.23 – 1.16 (m, 2H), 1.09 – 1.01 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.02, 155.27, 138.23, 137.56, 137.19, 130.05, 129.68, 128.91,127.53, 126.26, 125.61, 125.09, 115.18, 21.37, 17.21, 9.31. LR-MS (ESI): m / z260.1 [M+H] + .

[0080] 3-Cyclobutyl-1-(p-Tolyl)isoquinoline (3as). Yellow oily liquid, yield 75%. 1 H NMR (400MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.67 – 7.61 (m, 1H), 7.53 (s, 1H), 7.46 (ddd, J = 8.2, 6.9,1.1 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 3.96 (p, J = 8.7 Hz, 1H), 2.55 – 2.52(m, 2H), 2.51 (s, 3H), 2.49 (d, J = 6.2 Hz, 2H), 2.15 (dq, J = 17.7, 8.9 Hz,1H), 2.06 – 1.96 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 160.09, 157.42, 138.17,137.50, 137.13, 130.02, 129.61, 128.93, 127.48, 126.66, 125.99, 125.16,115.20, 42.19, 28.72, 21.31, 18.41. LR-MS (ESI): m / z 274.0 [M+H] + .

[0081] 3-Cyclopentyl-1-(p-Tolyl)isoquinoline (3at). Yellow oily liquid, yield 71%. 1 H NMR (400MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.52 (s, 1H), 7.49 – 7.42 (m, 1H), 7.37 (d, J = 7.7 Hz, 2H), 3.53 – 3.39 (m, 1H), 2.50 (s, 3H), 2.23 (d, J = 8.8Hz, 2H), 1.96 (dd, J = 23.1, 5.9 Hz, 4H), 1.85 – 1.71 (m, 2H). 13 C NMR (101MHz, CDCl3) δ 159.94, 158.28, 138.18, 137.60, 137.23, 130.06, 129.58, 128.96,127.48, 126.66, 125.93, 125.23, 115.59, 47.89, 33.65, 25.75, 21.36. LR-MS(ESI): m / z 288.1 [M+H] + .

[0082] 3-Cyclohexyl-1-(p-Tolyl)isoquinoline (3au). Yellow oily liquid, yield 79%. 1 H NMR (400MHz, CDCl3) δ 8.08 (d, J= 8.5 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.66 – 7.59(m, 3H), 7.47 (s, 1H), 7.44 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.36 (d, J = 8.2Hz, 2H), 2.98 (t, J = 11.7 Hz, 1H), 2.48 (s, 3H), 2.19 (d, J = 12.2 Hz, 2H), 1.93 (d, J = 12.8 Hz, 2H), 1.65 (ddd, J = 24.3, 12.3, 2.5 Hz, 2H), 1.52 (dd, J = 25.3, 12.6 Hz, 2H), 1.35 (dd, J = 25.8, 11.1 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.90, 159.43, 138.18, 137.70, 137.19, 130.00, 129.58, 129.01,127.51, 126.79, 125.98, 125.33, 115.00, 46.05, 33.23, 26.75, 26.32, 21.37.LR-MS (ESI): m / z 302.0 [M+H] + .

[0083] 3-(3,3-dimethoxycyclobutyl)-1-(p-tolyl)isoquinoline (3av). Yellow oily liquid, yield 47%. 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 6.9 Hz, 3H), 7.52 (s, 1H), 7.45 (ddd, J = 8.2, 6.9, 1.1 Hz,1H), 7.34 (d, J = 7.9 Hz, 2H), 3.64 (p, J= 8.7 Hz, 1H), 3.28 (s, 3H), 3.22(s, 3H), 2.81 – 2.69 (m, 2H), 2.56 (dd, J = 11.6, 9.6 Hz, 2H), 2.47 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.29, 156.16, 138.39, 137.55, 137.01, 130.11,129.84, 129.00, 127.60, 126.76, 126.30, 125.34, 115.94, 100.38, 48.90, 48.57,38.36, 32.08, 21.40. LR-MS (ESI): m / z 334.1 [M+H] + .

[0084] 3-(3,3-difluorocyclobutyl)-1-(p-tolyl)isoquinoline (3aw). Yellow oily liquid, yield 74%. 1 HNMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.67 (t, J = 7.0 Hz, 3H), 7.54 – 7.46 (m, 2H), 7.37 (d, J = 7.7 Hz, 2H), 3.66(p, J = 8.6 Hz, 1H), 3.20 – 2.93 (m, 4H), 2.49 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.73, 153.56, 138.66, 137.46, 136.87, 130.12, 129.08, 127.68,126.81, 126.73, 125.61, 120.06 (dd, J = 286.8, 269.6 Hz), 116.63, 41.56 (t, J = 22.2 Hz), 30.00 (d, J = 3.0 Hz), 29.84 (d, J = 3.0 Hz), 21.43.19 F NMR (377MHz, CDCl3) δ -81.72 (d, J = 191.5 Hz), -99.32 (d, J = 191.5 Hz). LR-MS(ESI): m / z 310.0 [M+H] + .

[0085] 3-(tetrahydrofuran-3-yl)-1-(p-tolyl)isoquinoline (3ax). Yellow oily liquid, yield 54%. 1 HNMR (400 MHz, CDCl3) δ 8.10 (dd, J = 8.5, 0.6 Hz, 1H), 7.81 (d, J = 8.2 Hz,1H), 7.67 – 7.59 (m, 3H), 7.53 (s, 1H), 7.47 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H),7.35 (d, J = 7.8 Hz, 2H), 4.28 (t, J = 8.0 Hz, 1H), 4.13 (td, J = 8.1, 5.5Hz, 1H), 4.09 – 3.97 (m, 2H), 3.80 (p, J = 7.6 Hz, 1H), 2.48 (d, J = 5.3 Hz, 3H), 2.46 – 2.34 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.38, 154.52, 138.49,137.58, 136.92, 130.04, 129.93, 129.05, 127.58, 126.77, 126.49, 125.51,116.58, 73.88, 68.75, 46.92, 33.51, 21.40. LR-MS (ESI): m / z 290.1 ​​[M+H] + .

[0086] 3-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl)isoquinoline (3ay). Yellow solid, yield 77%, melting point 88-97 °C. 1 H NMR (400 MHz, CDCl3) δ 8.10 (d,J = 8.5 Hz, 1H), 7.82 (d, J = 8.2Hz, 1H), 7.62 (dd, J = 11.4, 4.5 Hz, 3H), 7.50 – 7.42 (m, 2H), 7.35 (d, J =7.8 Hz, 2H), 4.16 (dd, J = 11.4, 2.6 Hz, 2H), 3.63 (td, J = 11.5, 2.5 Hz,2H), 3.27 – 3.13 (m, 1H), 2.47 (s, 3H), 2.02 (tt, J = 13.2, 9.2 Hz, 4H). 13 CNMR (101 MHz, CDCl3) δ 160.09, 157.11, 138.25, 137.56, 136.89, 129.88,129.70, 128.94, 127.44, 126.77, 126.25, 125.38, 115.01, 68.20, 42.87, 32.61,21.28. LR-MS (ESI): m / z 304.0 [M+H] + .

[0087] 3-(1,4-dioxospiro[4.5]decane-8-yl)-1-(p-tolyl)isoquinoline (3az). Yellow oily liquid, yield 60%. 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.2Hz, 1H), 7.61 (dd, J = 12.8, 4.5 Hz, 3H), 7.50 (s, 1H), 7.43 (ddd, J = 8.2,6.8, 1.2 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H), 4.00 (s, 4H), 3.02 (t, J = 11.7Hz, 1H), 2.46 (s, 3H), 2.19 (dd, J = 12.6, 2.2 Hz, 2H), 1.96 (dd,J = 24.3,12.8 Hz, 4H), 1.79 (td, J = 13.6, 4.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ160.03, 158.04, 138.27, 137.65, 137.02, 129.96, 129.72, 129.02, 127.54,126.83, 126.18, 125.45, 115.04, 108.83, 64.36, 64.32, 44.67, 34.97, 30.38,21.37. LR-MS (ESI): m / z 360.0 [M+H] + .

[0088] 3-(phenoxymethyl)-1-(p-tolyl)isoquinoline (3ba). Yellow solid, yield 69%, melting point 87-91 °C. 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.66 (ddd, J = 9.3, 8.1, 1.1 Hz, 3H), 7.51 (t, J = 7.7 Hz, 1H), 7.36 (dd, J =19.7, 7.4 Hz, 4H), 7.12 (d, J = 7.4 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 5.46(s, 2H), 2.49 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.65, 158.65, 149.78,138.59, 137.46, 136.55, 130.14, 129.89, 129.58, 129.15, 127.70, 127.18,126.90, 126.09, 121.05, 116.41, 114.94, 70.68, 21.40. LR-MS (ESI): m / z 325.9[M+H] + .

[0089] 3-((3r,5r,7r)-adamantane-1-yl)-1-(p-tolyl)isoquinoline (3bb). Yellow solid, 50% yield, melting point 147-153 °C. 1 H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 8.7 Hz, 1H), 8.18(d, J = 8.1 Hz, 2H), 7.92 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.59 (t, J = 7.2Hz, 1H), 7.53 – 7.46 (m, 1H), 7.32 (d, J = 8.0 Hz, 2H), 2.51 (d, J = 2.2 Hz, 6H), 2.44 (s, 3H), 2.25 (s, 3H), 1.98 – 1.89 (m, 6H). 13 C NMR (101 MHz, CDCl3)δ 166.08, 148.10, 138.67, 138.19, 137.25, 129.45, 128.91, 128.69, 127.01,126.71, 125.28, 125.06, 114.34, 43.18, 42.21, 37.31, 29.37, 21.38. LR-MS(ESI): m / z 354.0 [M+H] + .

[0090] 4-(1-(p-Tolyl)isoquinoline-3-yl)piperidine-1-carboxylic acid tert-butyl ester (3bc). Yellow solid, yield 64%, melting point 125-130 °C. 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.62 (dd, J = 15.0, 7.7 Hz, 3H), 7.49 – 7.41 (m, 2H), 7.34 (d, J = 7.8 Hz, 2H), 4.30 (s, 2H), 3.07 (t, J= 12.0 Hz, 1H), 2.90 (s, 2H), 2.46(s, 3H), 2.11 (d, J = 13.1 Hz, 2H), 1.83 (dt, J = 12.3, 8.7 Hz, 2H), 1.50 (s,9H). 13 C NMR (101 MHz, CDCl3) δ 160.19, 157.16, 154.89, 138.35, 137.58,136.92, 129.91, 129.80, 129.02, 127.52, 126.80, 126.34, 125.48, 115.25,79.31, 44.08, 31.91, 28.52, 21.34. LR-MS (ESI): m / z 403.0 [M+H] + .

[0091] 3-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-yl)-1-(p-tolyl)isoquinoline (3bd). Yellow oily liquid, yield 59%. 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 1H), 7.76(d, J = 8.2 Hz, 1H), 7.60 (ddd, J = 9.5, 6.3, 2.2 Hz, 3H), 7.42 (ddd, J =8.2, 6.8, 1.2 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.28 (s, 1H), 6.29 (dd, J =5.6, 3.0 Hz, 1H), 5.82 (dd, J = 5.6, 2.8 Hz, 1H), 3.85 (dt, J = 8.5, 4.1 Hz,1H), 3.44 (s, 1H), 3.02 (s, 1H), 2.47 (s, 3H), 2.33 (ddd, J = 13.1, 9.4, 3.8Hz, 1H), 1.57 (d, J = 9.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.46, 157.19,138.27, 137.31, 137.28, 137.13, 133.23, 130.07, 129.61, 129.05, 127.49,126.90, 126.03, 125.19, 116.14, 50.21, 47.93, 45.97, 43.34, 32.40, 21.42. LR-MS (ESI): m / z 312.1 [M+H] + .

[0092] 6,7-Dimethoxy-3-methyl-1-phenylisoquinoline (3be). Yellow solid, 77% yield, melting point 118-127°C. 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.3 Hz,2H), 7.48 – 7.41 (m, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.01 (s, 1H), 4.00 (s,3H), 3.82 (s, 3H), 2.68 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 157.89, 152.66,149.76, 149.30, 140.16, 134.48, 129.61, 128.43, 128.28, 120.53, 117.05,105.52, 104.41, 55.98, 55.80, 24.27. LR-MS (ESI): m / z 279.9 [M+H] + .

[0093] 3,6,7-Trimethyl-1-phenylisoquinoline (3bf). Yellow solid, 82% yield, melting point 114-118 °C. 1 HNMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.68 (dd, J = 8.0, 1.3 Hz, 2H), 7.51(tt, J = 14.4, 7.1 Hz, 4H), 7.37 (s, 1H), 2.73 (s, 3H), 2.44 (s, 3H), 2.36(s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.25, 149.98, 140.28, 140.09, 136.65,136.02, 129.89, 128.32, 128.25, 126.65, 125.87, 123.95, 117.22, 24.40, 20.38.LR-MS (ESI): m / z 248.1 [M+H] + .

[0094] 3,5,6,7,8-Pentamethyl-1-phenylisoquinoline (3bg). Yellow solid, yield 12%, melting point 80-94 °C. 1 HNMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.49 (dd, J = 8.1, 1.6 Hz, 2H), 7.40(dd, J = 12.5, 7.2 Hz, 3H), 2.72 (s, 3H), 2.62 (s, 3H), 2.45 (s, 3H), 2.32(s, 3H), 1.94 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.33, 148.37, 145.13,137.40, 136.81, 135.52, 130.61, 129.14, 128.37, 127.74, 127.36, 124.57,113.89, 24.35, 21.78, 17.66, 17.30, 15.30. LR-MS (ESI): m / z 276.0 [M+H] + .

[0095] 7-Methyl-5-phenyl-[1,3]dioxacyclopenteno[4,5-g]isoquinoline (3bh). Yellow solid, yield 51%, melting point 122-128 °C. 1 H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 8.1, 1.3 Hz, 2H), 7.48 (dt, J = 13.7, 7.0 Hz, 3H), 7.31 (s, 1H), 7.24 (s, 1H), 7.02 (s, 1H), 6.03 (s, 2H), 2.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.51, 150.51, 150.11,147.69, 140.15, 136.09, 129.69, 128.43, 128.30, 121.92, 117.94, 103.39,102.22, 101.47, 24.24. LR-MS (ESI): m / z 264.0 [M+H] + .

[0096] 8-Methyl-6-phenyl-2,3-dihydro-[1,4]dioxo[2,3-g]isoquinoline (3bi). Yellow solid, yield 63%, melting point 141-148 °C. 1 H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 8.0, 1.4 Hz, 2H),7.54 – 7.40 (m, 4H), 7.29 (s, 1H), 7.17 (s, 1H), 4.36 (dd, J = 5.9, 2.3 Hz, 2H), 4.30 (dd, J = 5.4, 2.9 Hz, 2H), 2.67 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ158.79, 149.25, 147.43, 143.82, 140.02, 134.22, 129.72, 128.40, 128.33,121.23, 116.63, 112.86, 110.82, 64.69, 64.30, 24.36. LR-MS (ESI): m / z 278.1[M+H] + .

[0097] 3,6-Dimethyl-1-phenylisoquinoline and 3,7-dimethyl-1-phenylisoquinoline (1:1) (3bj). Yellow oily liquid, yield 57%. 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.72 – 7.64 (m, 5H), 7.50 (ddd, J = 15.0, 9.5, 3.9 Hz, 8H), 7.45 (s, 1H), 7.39 (s, 1H), 7.27 (d, J= 1.5 Hz, 0.5H), 7.25 (d, J = 1.5 Hz, 0.5H), 2.73(s, 6H), 2.52 (s, 3H), 2.45 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.05,159.68, 150.97, 150.06, 140.22, 140.03, 139.95, 138.00, 136.01, 135.93,132.24, 129.95, 128.48, 128.41, 128.38, 127.41, 126.28, 126.19, 125.32,125.14, 123.41, 117.88, 117.57, 24.54, 24.43, 21.97, 21.94. LR-MS (ESI): m / z234.1 [M+H] + .

[0098] In Example 1 of this invention, each reaction substrate can be commercially available or prepared using conventional methods, such as:

[0099] Synthesis of compound 1a-1ak

[0100] ;

[0101] NaH (40 mmol, 4.0 equiv) was suspended in 20 mL of ethyl acetate, and ketone a (10 mmol, 1.0 equiv) was dissolved in 20 mL of ethyl acetate. The ethyl acetate solution of ketone a was slowly added dropwise to the NaH suspension at 0 °C. The mixture was then stirred at room temperature for 12 h. After the reaction was complete, the reaction was quenched by slowly adding 10% NH4Cl aqueous solution in an ice bath, and the pH was adjusted to 5 by adding dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the filtrate was distilled under reduced pressure. The solvent was evaporated, and the product b was purified by rapid column chromatography in yields of 76%–98%.

[0102] The product b (1.0 equiv) obtained in the previous step was dissolved in 40 mL MeOH, and CH3COONH4 (5.0 equiv) was added. The mixture was refluxed and stirred at 70 °C for 6–7 h. After the reaction solution cooled to room temperature, it was distilled under reduced pressure, the solvent was evaporated to dryness, and appropriate amounts of water and ethyl acetate were added. The mixture was extracted three times with ethyl acetate, and the organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the filtrate was distilled under reduced pressure, the solvent was evaporated to dryness, and the product was purified by rapid column chromatography to obtain products 1a–1ak. Yield: 48%–80%.

[0103] Synthesis of compound 1am-1bd

[0104] ;

[0105] The general procedure for synthesizing substrate 1am-1bd is as follows: NaH (30 mmol, 3.0 equiv) was suspended in 20 mL THF, and p-toluene ketone c (10 mmol, 1.0 equiv) was dissolved in 20 mL THF. At 0 °C, the THF solution of p-toluene ketone c was slowly added dropwise to the NaH suspension, and the mixture was stirred for approximately 1 h. Then, the ester (20 mmol, 2.0 equiv) was added dropwise at the same temperature, followed by stirring at room temperature for approximately 10 h. After the reaction was complete, the reaction was quenched by slowly adding 10% NH4Cl aqueous solution in an ice bath, and the pH was adjusted to 5 by adding dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the filtrate was distilled under reduced pressure. The solvent was evaporated to obtain the crude product d.

[0106] The crude product d (1.0 equiv) obtained in the previous step was dissolved in 40 mL MeOH, and CH3COONH4 (5.0 equiv) was added. The mixture was refluxed and stirred at 70 °C for 6–7 h. After the reaction solution cooled to room temperature, it was distilled under reduced pressure, the solvent was evaporated to dryness, and appropriate amounts of water and ethyl acetate were added. The mixture was extracted three times with ethyl acetate, and the organic phase was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the filtrate was distilled under reduced pressure, the solvent was evaporated to dryness, and the product 1am-1bd was purified by rapid column chromatography.

[0107] Example 2

[0108] ;

[0109] Standard reaction: At room temperature, NaH (60% in oil, 3.6 mmol, 6.0 equiv) was weighed into a round-bottom flask, and 2 mL of anhydrous THF was added and stirred to suspend it in the solvent. Aminoenone 1a (0.6 mmol, 1.0 equiv) was dissolved in anhydrous THF (2.0 mL) and added dropwise to the suspension under N2 protection. The mixture was stirred for 5 min, and then o-diiodobenzene 2a (1.5 mmol, 2.5 equiv) was added dropwise over 1 minute. The mixture was then stirred in an oil bath at 40 °C for 15 h. After the reaction was complete, the reaction solution was allowed to cool naturally to room temperature, and then added dropwise to water (10 mL). The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The isoquinoline product 3a was purified by rapid column chromatography with a yield of 75%.

[0110] The factors were varied based on the standard reaction, and the results are shown in Table 5.

[0111] Table 5. Changes and Results of Standard Response Factors

[0112] Group Factors of change 5a Yield (%) 1 none 75 2 3.0 equiv NaH 57 3 4.0 equiv NaH 59 4 5.0 equiv NaH 62 5 7.0 equiv NaH 72 6 8.0 equiv NaH 70 7 3.0 equiv 2a 71 8 DMA replaces THF 0 9 DMF replaces THF 32 10 1,4-dioxane replaces THF 0 11 Toluene replaces THF 0 12 0 °C reaction 0 13 25 °C reaction 48 14 60 °C reaction 53 15 KH replaces NaH 49 16 <![CDATA[Replace NaH with CaH2]]> 0 17 LiH replaces NaH 0 18 BuLi replaces NaH 0

[0113] This invention utilizes o-dihalobenzene and aminoenone to undergo a series of addition and rearrangement reactions at 40 °C under alkali metal hydride catalysis, successfully constructing structurally diverse isoquinoline products in moderate to high yields. The method exhibits good functional group tolerance and yields satisfactory results.

[0114] This invention involves the reaction of an aminoenone with o-diiodobenzene in the presence of NaH, yielding isoquinoline products through a novel process involving a series of addition and rearrangement reactions. This method eliminates the need for transition metal catalysis, offering a shorter preparation cycle, higher atom utilization, simpler preparation, milder reaction conditions, and readily available and inexpensive raw materials compared to existing methods. Furthermore, the substrates possess multiple reaction extension sites, allowing for the construction of structurally diverse isoquinolines with minimal yield fluctuations, demonstrating the system's versatility and stability. Isoquinolines exhibit broad pharmacological activities, and this invention provides a new pathway for synthesizing structurally diverse isoquinolines, holding significant importance and value for future drug synthesis development.

[0115] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing an isoquinoline derivative, comprising the following steps: using o-dihalobenzene and aminoenone as raw materials, reacting them in the presence of an alkali metal hydride to obtain the isoquinoline derivative; the alkali metal hydride is NaH; the reaction is carried out in a solvent, the solvent being THF; the chemical structural formula of the aminoenone is as follows: ； R1 is an alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group; R2 is selected from alkyl and aryl groups; the alkyl group is methyl, ethyl, or tert-butyl; in the substituted aryl and substituted aromatic heterocyclic groups, the substituent is independently selected from alkyl, halogen, alkoxy, and aryl groups; the aryl group contains 1 to 6 benzene rings; the aromatic heterocyclic group contains 1 to 3 benzene rings, and the heteroatom is oxygen, sulfur, or nitrogen; The chemical structural formula of the ortho-dihalobenzene is as follows: ； R 3 Selected from alkyl and alkoxy groups; X is iodine; The chemical structural formula of the product, isoquinoline, is as follows: ； The substituents in the product are the same as those in the raw materials.

2. The method for preparing the isoquinoline derivative according to claim 1, characterized in that, An alkali metal hydride is added to a solvent, followed by the addition of an amino ketone and an o-dihalobenzene. The mixture is then reacted at 20°C to 80°C for 12 to 18 h to obtain an isoquinoline derivative.

3. The method for preparing the isoquinoline derivative according to claim 1, characterized in that, The molar ratio of aminoenone, o-dihalobenzene and alkali metal hydride is 1:(1.5-3):(3-10).

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