Iodine-catalyzed primary alcohol dehydroxylation amination method and application thereof

Abstract

The invention relates to an iodine-catalyzed primary alcohol dehydroxylation amination method and application thereof, and particularly provides a primary alcohol dehydroxylation amination method which is characterized in that amine and various primary alcohols are subjected to efficient alkylation reaction under a neutral redox condition. According to the method, a simple inorganic iodide is used as an efficient catalyst, and an acidic additive (such as NaHSO4) plays an important role in promoting alkylation reaction. The method provides a practical scheme for synthesis of various nitrogen heterocyclic compounds, and can be successfully applied to later synthesis of drugs. The method provides a new green and efficient reaction platform for activation of primary alcohol, can be expected to be applied to the fields of amination, alcohol activation and drug synthesis, and has a wide prospect.

Description

Technical Field

[0001] The present invention relates to the fields of organic synthesis and biomedicine, and in particular to an iodine-catalyzed dehydroxylation method for primary alcohols and an application thereof. Background Art

[0002] Alkylation of amines has applications in numerous fields, including pharmaceutical synthesis, photosensitive materials, fuels, polymers, and latex additives. The synthesis of substituted amines often utilizes synthetic strategies such as coupling reactions, olefin difunctionalization, and reduction of unsaturated carbon-nitrogen bonds. In recent years, several new synthetic strategies have been developed, including the use of alkylating agents such as nitriles, olefins, and carboxylic acids. In contrast, alcohols are ubiquitous, inexpensive, and readily available natural products, making them ideal alkylating agents. Alkylation with alcohols offers one of the simplest methods for synthesizing substituted amines. Highly reactive benzyl alcohol, allyl alcohol, and propargyl alcohol have been widely used in synthetic research due to the stability and high reactivity of the carbocations they form. Primary alcohols are challenging to directly use as substrates for nucleophilic substitution due to the poor leaving ability of the hydroxyl group and the instability of the corresponding primary carbocation. This synthetic strategy for direct leaving of activated primary alcohols, which produces water as the sole byproduct, holds significant research significance and promises promising applications.

[0003] Primary alcohols are difficult to activate directly. One of the traditional strategies is to convert primary alcohols into corresponding organic halides, formate or sulfonates using stoichiometric activating reagents, overcoming the inherent kinetic and thermodynamic barriers to direct substitution with amines. Another commonly used method is to oxidize primary alcohols to aldehydes and then reductively aminize them. The disadvantages of these two strategies are low step economy and atom economy, the use of environmentally unfriendly reagents, and the production of stoichiometric by-products. The classic Mitsunobu reaction has been successfully applied to the substitution of alcohols with various nucleophiles, but cannot alkylate common basic amines. Bronsted acid or Lewis acid catalysts can activate highly active alcohols, but cannot catalyze the alkylation of amines with primary alcohols. In the past few decades, metal-catalyzed "borrowing hydrogen" strategies have been successfully used for the alkylation of amines with primary alcohols, but special metals and complex ligands are essential. Summary of the Invention

[0004] The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

[0005] To address the above-mentioned problems in the prior art, the inventors, through experimental exploration, have developed a method for the iodine-catalyzed dehydroxylation of primary alcohols. This method, for the first time, proposes a strategy for primary alcohol activation using an inorganic iodide as a catalyst and an acidic additive. This overcomes the primary alcohol activation barrier under metal-free conditions, providing a new, green and efficient reaction platform for amine alkylation reactions. This method can activate methanol, ethanol, and is also compatible with benzyl alcohol, allyl alcohol, and others. This method can achieve gram-scale synthesis and has successfully achieved the modification of various drug molecules and natural products, the cascade reaction construction of nitrogen heterocycles, and the later direct synthesis of drug molecules, showing promising application prospects in the pharmaceutical field.

[0006] To this end, the present invention provides a method for dehydroxylation of a primary alcohol, comprising:

[0007] (1) reacting the compound represented by Formula I with the compound represented by Formula II in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula III;

[0008] or,

[0009] (2) reacting the compound represented by Formula IV with the compound represented by Formula II in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula V;

[0010] or,

[0011] (3) reacting the compound represented by Formula IV with the compound represented by Formula VI in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula VII;

[0012] or,

[0013] (4) reacting the compound represented by Formula VIII with the compound represented by Formula II in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula IX;

[0014] or,

[0015] (5) reacting the compound represented by Formula X with the compound represented by Formula XI in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula XII;

[0016] (1)

[0017] (2)

[0018] (3)

[0019] (4)

[0020] (5)

[0021] in:

[0022] The catalyst is selected from HI, KI, NaI, LiI, CsI, and NH4I, preferably selected from HI and KI, and more preferably HI;

[0023] The acidic additive is selected from NaHSO4, H2SO4, TFA, HOTf, preferably selected from NaHSO4, H2SO4, more preferably NaHSO4;

[0024] R a 、R b are each independently selected from hydrogen and deuterium;

[0025] R 1 Selected from C1-C6 alkyl, C6-C10 aryl, 5-13 membered heteroaryl, 5-10 membered heterocyclic group, the C1-C6 alkyl, C6-C10 aryl, 5-13 membered heteroaryl, 5-10 membered heterocyclic group are each independently optionally substituted by 1-3 members selected from R c substituted by a group;

[0026] Preferably, R 1 Selected from C1-C6 alkyl, phenyl, naphthyl, 13-membered heteroaryl, 9-10-membered heterocyclic group, the C1-C6 alkyl, phenyl, naphthyl, 13-membered heteroaryl and 9-10-membered heterocyclic group are each independently optionally substituted by 1-3 groups selected from R c substituted by a group;

[0027] More preferably, R 1 Selected from ethyl, phenyl, naphthyl, The ethyl, phenyl, naphthyl, Each independently optionally selected from 1-3 R c substituted by a group;

[0028] R c Selected from oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, benzyl, phenyl, naphthyl, C3-C6 cycloalkyl, C1-C6 alkyl-(C=O)-, 5-6 membered heteroaryl, C1-C6 alkyl-(C=O)-NH-, C1-C6 haloalkyl, C1-C6 haloalkoxy,

[0029] Preferably, R cSelected from oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, benzyl, phenyl, naphthyl, C3-C6 cycloalkyl, C1-C6 alkyl-(C=O)-, pyrrolyl, C1-C6 alkyl-(C=O)-NH-, C1-C6 haloalkyl, C1-C6 haloalkoxy,

[0030] R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R d 、R e 、R f Each independently selected from hydrogen, methyl, ethyl;

[0031] More preferably, R c Selected from oxo, methyl, ethyl, isopropyl, tert-butyl, methoxy, fluorine, chlorine, nitro, benzyl, phenyl, naphthyl, cyclohexyl, trifluoromethyl, trifluoromethoxy,

[0032] More preferably, R 1 Selected from:

[0033] (1) in:

[0034] R 11 、R 12 、R 13 、R 14 、R 15 In, any one or any two or any three are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, benzyl, phenyl, C3-C6 cycloalkyl, C1-C6 alkyl-(C=O)-, pyrrolyl, C1-C6 alkyl-(C=O)-NH-, C1-C6 haloalkyl, C1-C6 haloalkoxy, The rest is hydrogen;

[0035] Preferably, R 11 、R 12 、R 13 、R 14 、R 15 Any one of them is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, benzyl, phenyl, C3-C6 cycloalkyl, C1-C6 alkyl-(C=O)-, pyrrolyl, C1-C6 alkyl-(C=O)-NH-, C1-C6 haloalkyl, C1-C6 haloalkoxy, The rest are hydrogen; or, any two are selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, and the rest are hydrogen; or, any three are selected from C1-C6 alkyl, halogen, nitro, and the rest are hydrogen;

[0036] R d Selected from C1-C6 alkyl; preferably, R d Ethyl;

[0037] More preferably, R 11 、R 12 、R 13 、R 14 、R 15 Among them, any one is selected from hydrogen, methyl, tert-butyl, methoxy, fluorine, chlorine, nitro, benzyl, phenyl, cyclohexyl, trifluoromethyl, trifluoromethoxy, The rest are hydrogen; or, any two are selected from isopropyl, methoxy, trifluoromethyl, chlorine, and the rest are hydrogen; or, any three are selected from methyl, fluorine, nitro, and the rest are hydrogen;

[0038] Most preferably, As a whole, selected

[0039] (2) in:

[0040] R 16 Selected from C1-C6 alkyl;

[0041] Preferably, R 16 Ethyl;

[0042] (3) in:

[0043] R 17 Selected from C1-C6 alkyl;

[0044] Preferably, R 17 is methyl;

[0045] (4) in:

[0046] R 18 、R 19 Each independently selected from hydrogen, phenyl, naphthyl,

[0047] Preferably, R 18 、R 19 Among them, any one is selected from phenyl, naphthyl, the other is hydrogen;

[0048] More preferably, R 18 、R 19 In, R 18 Selected from phenyl, R 19 is hydrogen; or, R 19 Selected from phenyl, naphthyl, R 18 is hydrogen;

[0049] R e 、R f Each is independently selected from C1-C6 alkyl; preferably, R e 、R f is methyl;

[0050] Most preferably, As a whole, selected

[0051] (5)

[0052] Most preferably, R 1 Selected from

[0053] R 2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl are each independently optionally substituted by 1-3 (preferably 1) selected from R g substituted by a group;

[0054] Preferably, R 2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, the phenyl group is optionally substituted by 1-3 (preferably 1) selected from R g substituted by a group;

[0055] R g Selected from C1-C6 alkoxy; preferably, R g is methoxy;

[0056] More preferably, R 2 Selected from hydrogen, methyl,

[0057] Or, R 1 、R 2 Together with the nitrogen atom to which they are commonly connected, they form a 6-12 membered heterocyclic group,

[0058] The 6-12 membered heterocyclic group is optionally substituted by 1-3 members selected from R h substituted by a group;

[0059] Or preferably, R 1 、R 2 Together with the nitrogen atoms they are connected to, they form

[0060] described Each independently optionally selected from 1-3 R h substituted by a group;

[0061] Or more preferably, R 1 、R 2 Together with the nitrogen atoms they are connected to, they form

[0062]

[0063] described Each independently optionally selected from 1-3 R h substituted by a group;

[0064] R h Selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl-C(=O)-, benzyl;

[0065] Preferably, R h Selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, pyrimidinyl, benzothienyl, furanyl-C(=O)-, benzyl;

[0066] More preferably, R h Selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, pyrimidinyl, benzothienyl, furanyl-C(=O)-, benzyl;

[0067] Each R iIndependently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro;

[0068] Preferably, each R i independently selected from hydrogen, methyl, methoxy, chlorine, cyano, nitro;

[0069] R j 、R k are each independently selected from hydrogen, halogen;

[0070] Preferably, R j 、R k are each independently selected from hydrogen, fluorine, and chlorine;

[0071] Each R l Independently selected from C1-C6 alkyl;

[0072] Preferably, R l is methyl;

[0073] Most preferably, R h Selected from methyl, fluorine, chlorine, methoxy, trifluoromethyl,

[0074] benzyl;

[0075] Or more preferably, R 1 、R 2 Together with the nitrogen atoms to which they are attached, they form:

[0076] (1) in:

[0077] R 21 、R 22 Each is independently selected from hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl;

[0078] Preferably, R 21 、R 22 Each independently selected from hydrogen, fluorine, chlorine, methoxy, methyl, trifluoromethyl;

[0079] More preferably, R 21 、R 22 Among them, any one is selected from hydrogen, fluorine, chlorine, methoxy, methyl, trifluoromethyl, and the other is hydrogen;

[0080] Most preferably, As a whole, selected

[0081] (2) in:

[0082] Each R 23 Independently selected from C1-C6 alkyl;

[0083] Preferably, R 23 is methyl;

[0084] (3) in:

[0085] R 24 、R 25 Each is independently selected from hydrogen, C1-C6 alkyl, halogen;

[0086] Preferably, R 24 、R 25 Each independently selected from hydrogen, methyl, chlorine;

[0087] More preferably, R 24 、R 25 Among them, any one is hydrogen or methyl, and the other is hydrogen or chlorine;

[0088] Most preferably, As a whole, selected

[0089] (4) in:

[0090] R 26 Selected from pyrimidinyl, benzothienyl, furanyl-C(=O)-,

[0091]

[0092] Preferably, R 26 Selected from pyrimidinyl, benzothienyl, furanyl-C(=O)-,

[0093]

[0094] Each R i Independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro;

[0095] Preferably, each R i independently selected from hydrogen, methyl, methoxy, chlorine, cyano, nitro;

[0096] R j 、R k are each independently selected from hydrogen, halogen;

[0097] Preferably, R j 、R k are each independently selected from hydrogen, fluorine, and chlorine;

[0098] More preferably, R 26 Selected from

[0099]

[0100] (5)

[0101] R 27 、R 28 Each independently selected from Preferably, R 27 、R 28 Any one of the other is hydrogen;

[0102] Each R l Independently selected from C1-C6 alkyl;

[0103] Preferably, R l is methyl;

[0104] More preferably, R 27 、R 28 Any one of the other is hydrogen;

[0105] Most preferably, As a whole, selected

[0106] (6)

[0107] R 29 、R 30 Each independently selected from phenyl, benzyl;

[0108] Preferably, R 29 、R 30 Among them, any one is selected from phenyl and benzyl, and the other is hydrogen;

[0109] More preferably, As a whole, selected

[0110] (7)

[0111]

[0112]

[0113] Or most preferably, R 1 、R 2 Together with the nitrogen atoms they are connected to, they form

[0114]

[0115] R 3 is selected from hydrogen, deuterium, C1-C12 alkyl, C2-C6 alkenyl, C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, wherein the C1-C12 alkyl, C2-C6 alkenyl, C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl are each independently optionally substituted by 1-3 (preferably 1) selected from R m substituted by a group;

[0116] Preferably, R 3 Selected from hydrogen, deuterium, C1-C12 alkyl, C2-C6 alkenyl, phenyl, 6-membered heteroaryl, The C1-C12 alkyl, C2-C6 alkenyl, phenyl, 6-membered heteroaryl, Each independently optionally selected from 1-3 (preferably 1) R m substituted by a group;

[0117] More preferably, R 3 Selected from hydrogen, deuterium, C1-C12 alkyl, C2-C6 alkenyl, phenyl, pyridyl, The C1-C12 alkyl, C2-C6 alkenyl, and phenyl groups are each independently optionally substituted by 1-3 (preferably 1) selected from R m substituted by a group;

[0118] More preferably, R 3 Selected from hydrogen, deuterium, C1-C12 alkyl, Pyridyl, The C1-C12 alkyl group is optionally replaced by 1-3 (preferably 1) selected from R m substituted by a group;

[0119] R 31 、R 32 Each is independently selected from hydrogen, halogen, C1-C6 alkyl;

[0120] Preferably, R 31 、R 32 Each is independently selected from hydrogen, chlorine, methyl, tert-butyl;

[0121] More preferably, R 31 、R 32 Among them, any one is selected from hydrogen, chlorine, methyl, tert-butyl, and the other is hydrogen;

[0122] R mSelected from C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, Indolyl,

[0123]

[0124] R n 、R o Each is independently selected from hydrogen, halogen, C1-C6 haloalkyl;

[0125] Preferably, R n 、R o Each independently selected from hydrogen, chlorine, trifluoromethyl;

[0126] More preferably, R n 、R o Among them, any one is selected from hydrogen, chlorine, trifluoromethyl, and the other is hydrogen;

[0127] Preferably, R m Selected from methyl, tert-butyl, chlorine,

[0128]

[0129] More preferably, R m Selected from

[0130]

[0131] Most preferably, R 3 Selected from hydrogen, deuterium, methyl, ethyl,

[0132]

[0133] R 4 Selected from hydrogen, C1-C6 alkyl, halogen;

[0134] Preferably, R 4 Selected from hydrogen, C1-C6 alkyl;

[0135] More preferably, R 4 is hydrogen;

[0136] R 5 、R 6 、R 7 Each is independently selected from hydrogen, C1-C6 alkyl, halogen;

[0137] Preferably, R 5 、R 6 、R 7 Among them, any one is selected from hydrogen, C1-C6 alkyl, halogen, and the rest are hydrogen;

[0138] More preferably, R 5 、R 6 、R 7 In, R 6 is selected from hydrogen, halogen, and the rest are hydrogen;

[0139] Most preferably, R 5 、R 6 、R 7 In, R 6 is selected from hydrogen and fluorine, the remainder being hydrogen;

[0140] L 1 Selected from C1-C6 alkylene, C1-C3 alkylene-O-C1-C3 alkylene, C1-C3 alkylene-S-C1-C3 alkylene, C1-C3 alkylene-NH-C1-C3 alkylene;

[0141] Preferably, L 1 Selected from C1-C6 alkylene, C1-C3 alkylene-O-C1-C3 alkylene;

[0142] More preferably, L 1 Selected from methylene,

[0143] L 2 Selected from a direct bond, a C1-C6 alkylene group;

[0144] Preferably, L 2 is a direct key;

[0145] L 3 Selected from C1-C6 alkylene;

[0146] Preferably, L 3 is a methylene group;

[0147] X is a halogen;

[0148] Preferably, X is bromine.

[0149] In some embodiments, As a whole, selected

[0150] In some embodiments, the solvent of the reaction is selected from NMP, DMF, and Cyrene.

[0151] In some embodiments, the solvent for the reaction is NMP.

[0152] In some embodiments, the reaction is carried out at a temperature of 100°C to 200°C (e.g., 100°C, 110°C, 120°C, 130°C, 140°C, 145°C, 150°C, 155°C, 160°C, 170°C, 180°C, 190°C, or 200°C).

[0153] In some embodiments, the reaction is carried out at a temperature of 120°C to 160°C.

[0154] In some embodiments, the reaction is carried out at a temperature of 150°C.

[0155] In some embodiments, the reaction time is 10h to 100h (such as 12h, 14h, 16h, 18h, 20h, 22h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 38h, 40h, 42h, 44h, 46h, 48h, 50h, 52h, 54h, 56h, 58h, 60h, 62h, 64h, 66h, 68h, 70h, 72h, 74h, 76h, 78h, 80h, 82h, 84h, 86h, 88h, 90h, 92h, 94h, 96h, 98h or 100h).

[0156] In some embodiments, the reaction time is 12 hours to 72 hours.

[0157] In some embodiments, the reaction time is 24 hours.

[0158] In some embodiments, the method has one or more technical features selected from the following (i)-(v):

[0159] (i) In reaction (1), the molar ratio of the compound represented by Formula II to the compound represented by Formula I is 1:1 to 20:1 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1), preferably 2:1 to 4:1;

[0160] (ii) In reaction (2), the molar ratio of the compound represented by formula II to the compound represented by formula IV is 1:1 to 20:1 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1), preferably 2:1 to 4:1;

[0161] (iii) In reaction (3), the molar ratio of the compound represented by Formula VI to the compound represented by Formula IV is 1:1 to 20:1 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1), preferably 2:1 to 4:1;

[0162] (iv) In reaction (4), the molar ratio of the compound represented by Formula II to the compound represented by Formula VIII is 1:1 to 20:1 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1), preferably 2:1 to 4:1;

[0163] (v) In reaction (5), the molar ratio of the compound represented by formula XI to the compound represented by formula X is 1:1 to 20:1 (e.g., 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1), preferably 2:1 to 4:1.

[0164] In some embodiments, the method has one or more technical features selected from the following (i)-(v):

[0165] (i) In reaction (1), the molar ratio of the catalyst to the compound represented by formula I is 0.1:1 to 1:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1 or 1:1), preferably 0.1:1 to 0.4:1;

[0166] (ii) In reaction (2), the molar ratio of the catalyst to the compound represented by formula IV is 0.1:1 to 1:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1 or 1:1), preferably 0.1:1 to 0.4:1;

[0167] (iii) In reaction (3), the molar ratio of the catalyst to the compound represented by formula IV is 0.1:1 to 1:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1 or 1:1), preferably 0.1:1 to 0.4:1;

[0168] (iv) In reaction (4), the molar ratio of the catalyst to the compound represented by formula VIII is 0.1:1 to 1:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1 or 1:1), preferably 0.1:1 to 0.4:1;

[0169] (v) In reaction (5), the molar ratio of the catalyst to the compound represented by formula X is 0.1:1 to 1:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1 or 1:1), preferably 0.1:1 to 0.4:1.

[0170] In some embodiments, the method has one or more technical features selected from the following (i)-(v):

[0171] (i) In reaction (1), the molar ratio of the acidic additive to the compound represented by formula I is 0.1:1 to 5:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1). 1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1 or 5:1), preferably 0.2:1 to 1.6:1;

[0172] (ii) In reaction (2), the molar ratio of the acidic additive to the compound represented by formula IV is 0.1:1 to 5:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5 :1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1 or 5:1), preferably 0.2:1 to 1.6:1;

[0173] (iii) In reaction (3), the molar ratio of the acidic additive to the compound represented by formula IV is 0.1:1 to 5:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1. 1, 2:1, 3:1, 3:1, 3:2:1, 3:4:1, 3:6:1, 3:8:1, 4:1, 4:2:1, 4:4:1, 4:6:1, 4:8:1 or 5:1), preferably 0.2:1 to 1.6:1;

[0174] (iv) In reaction (4), the molar ratio of the acidic additive to the compound represented by formula VIII is 0.1:1 to 5:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1. 1, 2:1, 3:1, 3:1, 3:2:1, 3:4:1, 3:6:1, 3:8:1, 4:1, 4:2:1, 4:4:1, 4:6:1, 4:8:1 or 5:1), preferably 0.2:1 to 1.6:1;

[0175] (v) In reaction (5), the molar ratio of the acidic additive to the compound represented by formula X is 0.1:1 to 5:1 (e.g., 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1). 1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1, 3.2:1, 3.4:1, 3.6:1, 3.8:1, 4:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1 or 5:1), preferably 0.2:1 to 1.6:1.

[0176] In some embodiments, the reaction is carried out in the presence of an inert gas.

[0177] In some embodiments, the inert gas is nitrogen, argon, or helium, preferably nitrogen.

[0178] In some embodiments, the HI is in the form of an aqueous solution.

[0179] In some embodiments, the mass fraction of HI in the HI aqueous solution is 45-58% (e.g., 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57% or 58%), preferably 55%.

[0180] In some embodiments, in reaction (1), the compound represented by formula I exists in the form of a salt; preferably, the compound represented by formula I exists in the form of a hydrochloride.

[0181] In some embodiments, in reaction (2), the compound represented by formula IV exists in the form of a salt; preferably, the compound represented by formula IV exists in the form of a hydrochloride.

[0182] In some embodiments, in reaction (3), the compound represented by formula IV exists in the form of a salt; preferably, the compound represented by formula IV exists in the form of a hydrochloride.

[0183] In some embodiments, in reaction (4), the compound represented by formula VIII exists in the form of a salt; preferably, the compound represented by formula VIII exists in the form of a hydrochloride.

[0184] In some embodiments, in reaction (5), the compound represented by formula X exists in the form of a salt; preferably, the compound represented by formula X exists in the form of a hydrochloride.

[0185] Definition of terms

[0186] In the present invention, unless otherwise explicitly stated, the description method "... are independently selected from" used throughout this document can mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0187] The substituents of the compounds of the present invention are disclosed by group class or range. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0188] The term "alkyl" refers to a branched and straight-chain saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "C1-C12 alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 or C12, that is, an alkyl group having 1 to 12 carbon atoms, preferably "C1-C11 alkyl" or "C1-C10 alkyl" or "C1-C9 alkyl", more preferably "C1-C8 alkyl", and further preferably "C1-C6 alkyl". "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably "C1-C4 alkyl", and more preferably "C1-C3 alkyl". Examples of "C1-C6 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl), and the like.

[0189] The term "alkoxy" refers to any of the above alkyl groups (e.g., C1-C12 alkyl, C1-C11 alkyl, C1-C10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) attached to the rest of the molecule through an oxygen atom (-O-).

[0190] The term "alkylene" refers to a divalent group formed by removing a hydrogen atom from any of the above alkyl groups (e.g., C1-C12 alkyl, C1-C11 alkyl, C1-C10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.), such as methylene, ethylene, propylene, etc.

[0191] The term "direct bond" refers to a bond where the groups or structures on both sides are directly connected. For example, the compound represented by formula X In, if L 2 is a direct bond, then the structural formula of the compound shown in formula X becomes

[0192] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0193] The term "C1-C6 haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in any of the above C1-C6 alkyl groups with halogen atoms, such as trifluoromethyl.

[0194] The term "C1-C6 haloalkoxy" refers to a group in which one or more hydrogen atoms in any of the above C1-C6 alkoxy groups are replaced by halogen atoms, such as trifluoromethoxy.

[0195] The term "C2-C6 alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms and containing one or more (preferably one) carbon-carbon double bonds, such as vinyl, allyl, and the like.

[0196] The term "C3-C6 cycloalkyl" refers to a saturated monocyclic hydrocarbon containing 3 to 6 carbon atoms, for example

[0197] The term "heterocyclyl" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered (preferably 3-7 membered or 3-6 membered or 5-10 membered) carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur, and the entire ring does not constitute an aromatic system. Non-limiting examples of heterocyclyls include, for example, pyrans, pyrrolidines, pyrroline, imidazoline, imidazolidines, pyrazolidines, pyrazoline, thiazoline, thiazolidines, dihydrofurans, tetrahydrofurans, 1,3-dioxolanes, piperidines, piperazines, morpholine, morpholinyls, tetrahydropyrrolyls, thiomorpholinyls, etc. For example, a "6-membered heterocyclyl" refers to a 6-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of 6-membered heterocyclyls include, for example, pyrans, piperidines, piperazines, morpholine, morpholinyls, thiomorpholinyls, etc. For another example, "5-membered heterocyclyl" refers to a 5-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-limiting examples of 5-membered heterocyclyls are, for example, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 1,3-dioxolane, and the like.

[0198] The term "aryl" refers to a group of a carbocyclic aromatic system. For example, "C6-C10 aryl" refers to a group of a carbocyclic aromatic system having 6 to 10 carbon atoms, non-limiting examples of which include but are not limited to phenyl, naphthyl, and the like.

[0199] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 8-, 9- or 10-membered bicyclic groups and 11- to 14-membered tricyclic groups having at least one heteroatom (N, O or S) in at least one ring, the heteroatom-containing ring optionally further having 1, 2 or 3 heteroatoms selected from N, O or S. Among them, substituted and unsubstituted aromatic 8-, 9- or 10-membered bicyclic groups and 11- to 14-membered tricyclic groups having at least one heteroatom (N, O or S) in at least one ring are "fused heteroaryl". For heteroaryl groups that are bicyclic or tricyclic, a bicyclic or tricyclic overall structure is required to form an aromatic system. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. It will be appreciated by those skilled in the art that two adjacent atoms (preferably carbon atoms) are shared between every two rings in the fused ring.

[0200] Exemplary monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and the like.

[0201] Exemplary bicyclic heteroaryl groups include, but are not limited to, indolyl, 5-azaindolyl, pyrrolo[2,3-d]pyrimidinyl, 5,6-diazaindolyl, 6-azaindolyl, 7-azaindolyl, pyrazolo[3,4-b]pyridinyl, pyrrolo[2,3-c]pyridazinyl, thieno[2,3-d]imidazolyl, thieno[2,3-d]imidazolyl, pyrazolo[3,4-c]pyridinyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzofuranyl, indolizinyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furopyridinyl, isoindolyl, and the like.

[0202] The term "substituted" means that any one or more hydrogens on the designated atom or group are replaced with the selection of the designated group, provided that the normal valence of the designated atom is not exceeded.

[0203] Beneficial effects

[0204] Under redox-neutral conditions, the inventors of the present application have provided a novel, highly efficient alkylation reaction of amines with various primary alcohols. This reaction utilizes a simple inorganic iodide as an efficient catalyst, while an acidic additive (such as NaHSO4) plays an important role in promoting the alkylation reaction. This reaction provides a practical approach for the synthesis of various nitrogen heterocyclic compounds and can be successfully applied to the later-stage synthesis of pharmaceuticals. This method provides a new, green, and efficient reaction platform for the activation of primary alcohols, and is expected to find applications in amination, alcohol activation, and pharmaceutical synthesis, with broad prospects.

[0205] Other features and advantages of the present invention will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present invention. The purpose and other advantages of the present invention can be achieved and obtained by the structures particularly pointed out in the description and claims. DETAILED DESCRIPTION

[0206] In order to make the purpose, technical solutions and advantages of the present application clearer, embodiments of the present invention will be described in detail below. It should be noted that, in the case of no conflict, the features in the embodiments in the present application and the embodiments can be combined arbitrarily with each other. In addition, unless otherwise specified, the reaction raw materials in the following examples can all be commercially available.

[0207] The following embodiments will help to further understand the present invention, but they do not limit the content of the present invention.

[0208] Example

[0209] 1. Exploration of reaction conditions

[0210] The inventors used tetrahydroquinoline (1) as an amine nucleophile and n-hexanol (2) as a primary alcohol alkylating agent to explore the reaction conditions.

[0211]

[0212] The standard steps are:

[0213] Under N2 atmosphere, tetrahydroquinoline 1 (0.5 mmol), n-hexanol 2 (1.0 mmol) and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1.0 mL), and HI (55% aqueous solution, 11.6 mg, 0.05 mmol) was added dropwise with stirring. The mixture was reacted at 150°C for 24 hours. After cooling to room temperature, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution (10 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated aqueous NaCl solution (20 mL × 3). The organic extracts were collected, dried over anhydrous MgSO4, filtered, and rotary evaporated to remove excess solvent. The alkylated product 3 was separated and purified by silica gel column chromatography to obtain the alkylated product 3 in a yield of 85%.

[0214] The inventors simultaneously carried out multiple sets of parallel experiments, and the conditions of each set and the yield of the alkylated product are shown in Table 1 below.

[0215] Table 1. Parallel experimental reaction conditions and results

[0216]

[0217]

[0218] Note: trace means trace amount

[0219] First, analyzing Group 1 and Groups 2-13, we can find that:

[0220] (1) Comparing the results of Group 1 and Group 2, it can be seen that in the primary alcohol dehydroxylation method of the present invention, if HI is not added, the reaction cannot proceed and the target product can basically not be obtained.

[0221] (2) Comparing the results of Group 1 with those of Group 3 and Group 4, it can be seen that in the primary alcohol dehydroxylation method of the present invention, if HI is replaced by HCl or HBr with similar properties, either the target product can basically not be obtained or the yield is greatly reduced.

[0222] (3) Comparing the results of Group 5 with those of Group 6 and Group 7, it can be seen that in the primary alcohol dehydroxylation method of the present invention, if KI is replaced with KCl or KBr with similar properties, either the target product can basically not be obtained or the yield is greatly reduced.

[0223] (4) Comparing the results of Group 8 with those of Group 9 and Group 10, it can be seen that in the primary alcohol dehydroxylation method of the present invention, if NaI is replaced with NaCl or NaBr with similar properties, either the target product can basically not be obtained or the yield is greatly reduced.

[0224] (4) From groups 5, 8, and 11-13, it can be seen that in the primary alcohol dehydroxylation method of the present invention, replacing HI with KI, NaI, LiI, CsI, or NH4I can still achieve good yields.

[0225] In summary, it can be seen that in the method for dehydroxylation of primary alcohols of the present invention, the inorganic iodide catalyst must be added.

[0226] Secondly, analyzing Group 1 and Groups 14-22, we can find that:

[0227] (1) Comparing the results of Group 1 with those of Group 14, it can be seen that in the primary alcohol dehydroxylation method of the present invention, if NaHSO4 is not added, the yield will be greatly reduced.

[0228] (2) By comparing the results of Group 1 with those of Groups 15-19, it can be seen that in the primary alcohol dehydroxylation method of the present invention, if NaHSO4 is replaced by HNTf2, m-NBSA, HAc, 4-NPBA, or (C6F5)B(OH)2, the yield will be greatly reduced.

[0229] (3) Comparing the results of Group 1, Group 5 and Group 20, it can be seen that if there is no proton (H + ), the reaction cannot proceed and the target product cannot be obtained.

[0230] (4) From Groups 21-22, it can be seen that in the primary alcohol dehydroxylation method of the present invention, replacing NaHSO4 with TFA or HOTf can still achieve a good yield.

[0231] In summary, in the primary alcohol dehydroxylation method of the present invention, an acidic additive is necessary, and several specific types need to be selected.

[0232] 2. Substrate expansion

[0233] 2.1 Alkylation of secondary amines:

[0234] Under standard conditions, the alkylation of various aromatic and alkylamines with hexanol was investigated. Tetrahydroquinolines with various substituents were obtained in good yields (3-8). Benzomorpholine, thiomorpholine, indoline, aza-polycyclic rings, and alkyl-substituted aromatic amines were well tolerated (10-16), and diaryl compounds were obtained in moderate yields (17-20).

[0235] The alkylation of aliphatic secondary amines is also compatible with a variety of functional groups, with high yields for N-aryl, acyl, and sulfonyl piperazines, and tolerance to functional groups such as halogen, cyano, nitro, pyrimidine, benzothiophene, and furan (21-32). Morpholine, nitrogen heterocycles, and nitrogen spirocycles all gave moderate to excellent yields (33-42). Conventional linear dialkylamines gave moderate yields of alkylated products (43). This method was applied to the late-stage alkylation of the natural product cytisine (46) and the drugs 44-49 (atomoxetine, lorcaserin, vortioxetine, palbociclib, and ceritinib), demonstrating tolerance to functional groups such as amides, sulfides, pyridines, and sulfones.

[0236] In addition, many primary alcohols can be activated for alkylation. For methanol or ethanol, which have lower reactivity, the target products can also be obtained in high yields (50-51). Long-chain fatty alcohols and cyclohexylethanol also have good alkylation yields (52-53). Natural products containing alkenyl groups (lecithin and citronellol) and trifluoromethyl groups are also compatible with the reaction system (54-56). Many nitrogen heterocyclic compounds such as indole (57), imidazolidinone (58), pyrrolidone (59) and pyridine (60) can also provide amination products in moderate yields. Benzyl alcohol can also be activated for amination at 120°C (61-62).

[0237] See Table 2 for details.

[0238] Table 2. Alkylation reaction of secondary amines with primary alcohols

[0239]

[0240] Condition A: Dissolve the amine (0.5 mmol), alcohol (1.0 mmol), HI (0.05 mmol), and NaHSO4 (0.1 mmol) in NMP (1.0 mL) and stir at 150°C under N2 for 24 h to obtain the isolated yield. Condition B: Dissolve the amine (0.5 mmol), alcohol (2.0 mmol), HI (0.2 mmol), and NaHSO4 (0.75 mmol) in NMP (1.0 mL) and stir at 150°C under N2 for 60 h to obtain the isolated yield. [a] Ethanol (2.0 mmol), HI (0.2 mmol), and NaHSO4 (0.5 mmol) were stirred at 150°C under N2 for 48 h. [b] H2SO4 (0.25 mmol) was used instead of NaHSO4. [c] The reaction was carried out at 160°C. [d] The amine was the hydrochloride substrate. [e] The amount of alcohol used was 10.0 mmol. [f] The reaction was carried out at 120°C.

[0241] 2.2 Alkylation of aniline derivatives:

[0242] This protocol is also applicable to the dialkylation of anilines. Various anilines with various substituents on aromatic hydrocarbons were alkylated in good yields (63-85, 93-98), and heterocycles such as pyrrole (73), carbazole (86), and coumarin (87) rings were also compatible. Furthermore, dialkylated lenalidomide and aminoglutethimide (88-89) can be readily prepared under these conditions, providing an effective route for the later modification of drugs. For example, aminoglutethimide can be easily converted into dimethylated (90), ethylated (91), and phenylated (92) products.

[0243] See Table 3 for details.

[0244] Table 3. Alkylation of aniline derivatives

[0245]

[0246] Condition C: Amine (0.5 mmol), alcohol (4.0 mmol), HI (0.1 mmol), and NaHSO₄ (0.25 mol) were dissolved in NMP (1.0 mL) and stirred at 150°C under N₂ for 24 h to obtain the isolated yield. [a] H₂SO₄ (0.2 mmol) was used instead of NaHSO₄; [b] H₂SO₄ (0.2 mmol) was used instead of NaHSO₄ and the reaction was continued for 36 h; [c] The amount of alcohol used was 10.0 mmol.

[0247] 2.3 Cascade reaction to construct heterocycles:

[0248] Compared with HI, KI salts are more practical. Tetrahydroquinoline (1) and hexanol (2) can be reacted on a gram scale under HI or KI catalysis to obtain alkylated products in high yields (Table 4A). This method can be applied to the cascade construction of N-heterocycles in one step by reacting diols with anilines (Table 4B). N-phenylpiperidine (99) can be obtained. In addition, different anilines can also synthesize a variety of piperidine derivatives (100-106). In addition to piperidine, polycyclic nitrogen heterocycles (107) and nitrogen phenylmorpholine (108) were also efficiently constructed. Unlike the classic "borrowing hydrogen" strategy, this method provides a simple, practical, and metal-free method for the efficient construction of N-heterocycles. This catalytic system can simultaneously achieve intramolecular and intermolecular amination of alcohols. For example, hydroxyl-bearing aniline (109) reacts with hexanol to obtain alkylated indoline 110 (eq b) in high yield. When aniline and 1-bromopropanol are reacted under standard conditions, a cascade of nitrogen alkylation and Friedel-Crafts alkylation can afford the polyvalent nitrogen heterocycle (111) (eq c).

[0249] See Table 4 for details.

[0250] Table 4. Application of alkylation reaction of amines with primary alcohols

[0251]

[0252] Condition D: Dissolve the amine (0.5 mmol), alcohol (2.0 mmol), HI (0.1 mmol), and NaHSO4 (0.25 mmol) in NMP (2.0 mL) and stir at 150°C under N2 for 36 h to obtain the isolated yield. eq b: Use alcohol (1.0 mmol) and NMP (1.0 mL) for 24 h; eq c: Use Condition D for 24 h. [a] HI (0.2 mmol) and NaHSO4 (0.5 mmol) for 48 h. [b] Use H2SO4 (0.25 mmol).

[0253] 2.4 Drug molecule synthesis:

[0254] This method has simple reaction conditions and readily available reagents, and has great application prospects in the later synthesis of drugs containing secondary or tertiary amines. By alkylation of amines with methanol, d4-methanol, propanol, and butanol, mepivacaine (112), d3-mepivacaine (113), ropivacaine (114), and butylpivacaine (115) were synthesized, respectively. After alkylation of primary amine derivatives, fendiline (116), cinacalcet (117), and tecalcet (118) were obtained. In addition to inert primary fatty alcohols, this catalytic system is also suitable for the alkylation reaction of allyl alcohol and benzyl alcohol to obtain the corresponding drug molecules cinnarizine (119), flunarizine (120), piribedil (121), meclizine (122), and buclizine (123). In addition, the drug buclizine (123) can also be synthesized on a gram scale, and the product can be obtained in a high yield. Compared with known amine alkylation preparation methods, the method of the present invention provides a highly atom-economical, practical and simple solution for these drugs.

[0255] See Table 5 for details.

[0256] Table 5. Application in drug synthesis

[0257]

[0258] Condition E: Amine (0.25 mmol), alcohol (1.0 mmol), HI (0.1 mmol), and NaHSO4 (0.38 mmol) were dissolved in NMP (0.5 mL) and stirred at 150°C under N2 for 48-60 h to obtain the isolated yield. [a] Alcohol (5.0 mmol) and H2SO4 (0.13 mmol). [b] Alcohol (5.0 mmol). [c] Reaction at 160°C for 72 h. [d] Reaction under Condition E for 48 h. [e] Amine (0.5 mmol), alcohol (1.0 mmol), HI (0.2 mmol), and NaHSO4 (0.5 mmol) were dissolved in NMP (1 mL) and stirred at 150°C under N2 for 48 h. [f] Amine (1.43 g, 5.0 mmol), alcohol (1.64 g, 10.0 mmol), HI (0.47 g, 2.0 mmol) and NaHSO4 (0.60 g, 5.0 mmol) were dissolved in NMP (10 mL) and reacted at 150 °C under N2 for 48 h.

[0259] 2.5. Methylation reaction:

[0260] This reaction system is also suitable for activating methanol to achieve nitrogen methylation reactions. Compared to other methylation reagents, methanol is environmentally friendly, inexpensive, readily available, and produces no toxicity or organic byproducts. It can achieve the dimethylation of anilines (124-125) and the methylation of secondary amines (126-133), and is compatible with halogens, ether bonds, heterocycles, and double bonds.

[0261] See Table 6 for details.

[0262] Table 6. Methylation reaction

[0263]

[0264] Condition F: Amine (0.5 mmol), methanol (10.0 mmol), HI (0.05 mmol), and NaHSO4 (0.10 mmol) were dissolved in NMP (1.0 mL) and stirred at 150°C under N2 for 24 h to obtain the isolated yield.

[0265] 3. Specific experimental operations for different types of substrates

[0266] 3.1 Experimental operation details

[0267] Condition A:

[0268] Under a nitrogen atmosphere, an amine (0.5 mmol), an alcohol (1.0 mmol), and NaHSO₄ (12.0 mg, 0.10 mmol) were dissolved in NMP (1.0 mL). HI (55% aqueous solution, 11.6 mg, 0.05 mmol) was added dropwise with stirring. The mixture was stirred at 150°C for the prescribed reaction time. After cooling to room temperature, the reaction mixture was neutralized with a saturated aqueous NaHCO₃ solution (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with a saturated aqueous NaCl solution (20 mL x 3). The organic extract was collected, dried over anhydrous MgSO₄, filtered, and rotary evaporated to remove excess solvent. The alkylated product was isolated and purified by silica gel column chromatography.

[0269] Condition B:

[0270] Under a nitrogen atmosphere, an amine (0.5 mmol), an alcohol (2.0 mmol), and NaHSO₄ (90.0 mg, 0.75 mmol) were dissolved in NMP (1.0 mL). HI (55% aqueous solution, 46.5 mg, 0.20 mmol) was added dropwise with stirring. The mixture was stirred at 150°C for the prescribed reaction time. After cooling to room temperature, the reaction mixture was neutralized with a saturated aqueous NaHCO₃ solution (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with a saturated aqueous NaCl solution (20 mL x 3). The organic extract was collected, dried over anhydrous MgSO₄, filtered, and rotary evaporated to remove excess solvent. The alkylated product was isolated and purified by silica gel column chromatography.

[0271] Condition C:

[0272] Under a nitrogen atmosphere, an amine (0.5 mmol), an alcohol (4.0 mmol), and NaHSO₄ (30.0 mg, 0.25 mmol) were dissolved in NMP (1.0 mL). HI (55% aqueous solution, 23.3 mg, 0.10 mmol) was added dropwise with stirring. The mixture was stirred at 150°C for the prescribed reaction time. After cooling to room temperature, the reaction mixture was neutralized with a saturated aqueous NaHCO₃ solution (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with a saturated aqueous NaCl solution (20 mL x 3). The organic extract was collected, dried over anhydrous MgSO₄, filtered, and rotary evaporated to remove excess solvent. The alkylated product was isolated and purified by silica gel column chromatography.

[0273] Condition D:

[0274] Under a nitrogen atmosphere, an amine (0.5 mmol), a diol (2.0 mmol), and NaHSO₄ (30.0 mg, 0.25 mmol) were dissolved in NMP (2.0 mL). HI (55% aqueous solution, 23.3 mg, 0.10 mmol) was added dropwise with stirring. The mixture was stirred at 150°C for the prescribed reaction time. After cooling to room temperature, the reaction mixture was neutralized with a saturated aqueous NaHCO₃ solution (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with a saturated aqueous NaCl solution (20 mL x 3). The organic extract was collected, dried over anhydrous MgSO₄, filtered, and rotary evaporated to remove excess solvent. The alkylated product was isolated and purified by silica gel column chromatography.

[0275] Condition E:

[0276] Under N2 atmosphere, the amine, alcohol, and NaHSO4 were dissolved in NMP, and HI (55% aqueous solution) was added dropwise with stirring. The mixture was stirred at 150°C for the prescribed reaction time. After cooling to room temperature, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution (10 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated aqueous NaCl solution (20 mL × 3). The organic extracts were collected, dried over anhydrous MgSO4, filtered, and rotary evaporated to remove excess solvent. The corresponding drug molecule product was separated and purified by silica gel column chromatography.

[0277] Condition F:

[0278] Under a nitrogen atmosphere, an amine (0.5 mmol), methanol (320.4 mg, 10.0 mmol), and NaHSO₄ (12.0 mg, 0.10 mmol) were dissolved in NMP (1.0 mL). HI (55% aqueous solution, 11.6 mg, 0.05 mmol) was added dropwise with stirring. The mixture was stirred at 150°C for the prescribed reaction time. After cooling to room temperature, the reaction mixture was neutralized with saturated aqueous NaHCO₃ (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated aqueous NaCl (20 mL x 3). The organic extract was collected, dried over anhydrous MgSO₄, filtered, and rotary evaporated to remove excess solvent. The alkylated product was isolated and purified by silica gel column chromatography.

[0279] Special Note:

[0280] a. When sulfuric acid is used as an additive, the reaction operation is adjusted to:

[0281] Under a nitrogen atmosphere, the amine and alcohol were dissolved in NMP. HSO (55% aqueous solution) was added dropwise with stirring, followed by HI (55% aqueous solution) with stirring. The mixture was stirred at 150°C for the prescribed reaction time. After cooling to room temperature, the reaction mixture was neutralized with saturated aqueous NaHCO (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated aqueous NaCl (20 mL x 3). The organic extracts were collected and dried over anhydrous MgSO, filtered, and then rotary evaporated to remove excess solvent. The alkylated product was isolated and purified by silica gel column chromatography.

[0282] b. When using low-boiling-point alcohols such as methanol or ethanol, in order to avoid volatilization of high-temperature raw materials, the inventors used a pressure-resistant tube to seal the reaction.

[0283] 3.2. Synthesis of Compounds and Related Spectral Data Experimental Procedure and Spectral Data for Aromatic Amines (Condition A)

[0284] 1-Hexyl-1,2,3,4-tetrahydroquinoline (3)

[0285] 1,2,3,4-Tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 92.6 mg (85%) of orange oil 3. 1 H NMR (400MHz, CDCl3): δ7.10–7.06(m,1H),6.97(dd,J=7.2,1.5Hz,1H),6.61–6.56(m,2H),3.31(t,J=5.6Hz,2H),3.27 (t,J=7.6Hz,2H),2.79(t,J=6.4Hz,2H),2.01–1.95(m,2H),1.65–1.60(m,2H),1.39–1.25(m,6H),0.97–0.93(m,3H). 13 C NMR (101MHz, CDCl3): δ145.32,129.06,126.99,122.09,115.12,110.40,51.50 ,49.40,31.76,28.20,26.93,26.14,22.67,22.24,14.03.HRMSm / z(ESI)calcd for C 15 H 23 N[M+H] +:218.1909,found:218.1911.

[0286] 6-Chloro-1-hexyl-1,2,3,4-tetrahydroquinoline (4)

[0287] 6-Chloro-1,2,3,4-tetrahydroquinoline (83.8 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 85.0 mg (68%) of brown oil 4. 1 H NMR (400MHz, CDCl3): δ6.97(dd,J=8.8,2.6Hz,1H),6.89(d,J=2.5Hz,1H),6.46(d,J=8.8Hz,1H),3.26(t,J=6.4Hz,2H),3 .20(t,J=7.6Hz,2H),2.71(t,J=6.4Hz,2H),1.95–1.89(m,2H),1.60–1.52(m,2H),1.34–1.31(m,6H),0.92–0.89(m,3H). 13 C NMR (101MHz, CDCl3): δ143.80,128.60,126.60,123.78,119.55,111.49,51.60 ,49.25,31.72,28.05,26.87,25.91,22.66,21.94,14.03.HRMSm / z(ESI)calcd for C 15 H 22 ClN[M+H] + :252.1519,found:252.1518.

[0288] 1-Hexyl-6-methoxy-1,2,3,4-tetrahydroquinoline (5)

[0289] 6-Methoxy-1,2,3,4-tetrahydroquinoline (81.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 h to obtain 89.2 mg (72%) of 5 as an orange oil. 1H NMR (400MHz, CDCl3): δ6.66(dd,J=8.8,3.0Hz,1H),6.59–6.58(m,1H),6.54(d,J=8.9Hz,1H),3.74(s,3H),3.23– 3.17(m,4H),2.75(t,J=6.4Hz,2H),1.96–1.93(m,2H),1.60–1.55(m,2H),1.34–1.31(m,6H),0.93–0.90(m,3H). 13 CNMR (101MHz, CDCl3): δ150.48,140.01,123.76,115.25,112.42,111.89,55.80,5 2.15,49.32,31.77,28.35,26.99,25.97,22.68,22.42,14.04.HRMSm / z(ESI)calcd for C 16 H 25 NO[M+H] + :248.2014,found:248.2012.

[0290] 1-Hexyl-6-methyl-1,2,3,4-tetrahydroquinoline (6)

[0291] 6-Methyl-1,2,3,4-tetrahydroquinoline (73.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 88.1 mg (76%) of orange oil 6. 1 HNMR (400MHz, CDCl3): δ6.90–6.87(m,1H),6.80(d,J=2.2Hz,1H),6.53(d,J=8.3Hz,1H),3.28–3.21(m,4H),2. 75(t,J=6.4Hz,2H),2.23(s,3H),2.00–1.93(m,2H),1.62–1.56(m,2H),1.35–1.34(m,6H),0.95–0.91(m,3H). 13C NMR (101MHz, CDCl3): δ143.09,129.86,127.38,124.33,122.29,110.75,51.71,49 .39,31.77,28.10,26.96,25.98,22.69,22.38,20.15,14.06.HRMSm / z(ESI)calcd for C 16 H 25 N[M+H] + :232.2065,found:232.2068.

[0292] 1-Hexyl-7-trifluoromethyl-1,2,3,4-tetrahydroquinoline (7)

[0293] 7-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline (100.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 100.4 mg (70%) of orange oil 7. 1 H NMR (400MHz, CDCl3): δ7.00(d,J=7.7Hz,1H),6.79–6.74(m,2H),3.32(t,J=5.7Hz,2H),3.27(t,J=7.5Hz ,2H),2.78(t,J=6.4Hz,2H),1.99–1.93(m,2H),1.63–1.59(m,2H),1.39–1.35(m,6H),0.95–0.92(m,3H). 13 C NMR (101MHz, CDCl3): δ145.36, 129.34 (q, J = 31.4Hz), 129.09, 125.62, 124.70 (d, J = 272.9Hz), 111.3 9(q,J=4.0Hz),106.39(q,J=3.9Hz),51.31,49.25,31.65,28.14,26.81,25.98,22.62,21.71,13.98. 19 F NMR(376MHz,CDCl3):δ-62.55.HRMSm / z(ESI)calcd for C 16 H 22 F3N[M+H] + :286.1783,found:286.1789.

[0294] 6-Fluoro-1-hexyl-2-methyl-1,2,3,4-tetrahydroquinoline (8)

[0295] 6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (82.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 84.7 mg (68%) of yellow oil 8. 1 HNMR (400MHz, CDCl3): δ6.81–6.73(m,2H),6.46(dd,J=9.2,4.7Hz,1H),3.51–3.46(m,1H),3.35–3.27(m,1H),3.17–3.11(m,1H),2.85–2.80(m ,1H),2.71–2.65(m,1H),1.94–1.88(m,1H),1.79–1.74(m,1H),1.62–1. 59(m,2H),1.37–1.31(m,6H),1.15(d,J=6.5Hz,3H),0.97–0.93(m,3H). 13 C NMR (100MHz, CDCl3): δ154.09 (d, J = 233.3Hz), 140.79, 122.91 (d, J = 6.5Hz), 115.23 (d, J = 21.5Hz), 112.95 ( d, J=21.5Hz), 110.93 (d, J=7.2Hz), 52.28, 50.05, 31.74, 27.90, 27.31, 26.90, 24.14, 22.70, 18.72, 14.02. 19 F NMR(376MHz,CDCl3):δ-131.61.HRMSm / z(ESI)calcd for C 16 H 24 FN[M+H] + :250.1971,found:250.1974.

[0296] 1-Hexyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (9)

[0297] 2,2,4-Trimethyl-1,2,3,4-tetrahydroquinoline (87.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 44.5 mg (34%) of green oil 9. 1 HNMR (400MHz, CDCl3): δ7.14(d,J=7.5,1H),7.08(t,J=7.2Hz,1H),6.62(t,J=7.2,Hz,1H),6.52(d,J=8.3,1H),3.35–3.27(m,1H) ,3.06–2.98(m,1H),2.94–2.85(m,1H),1.75–1.70(m,1H),1.59–1.52(m,3H),1.35–1.31(m,12H),1.18(s,3H),0.94–0.90(m,3H). 13 C NMR (101MHz, CDCl3): δ144.91,127.62,126.84,125.72,114.91,111.09,54.14,47.00,45 .21,31.69,29.63,29.25,27.30,26.91,25.07,22.76,19.96,14.07.HRMSm / z(ESI)calcd forC 18 H 29 N[M+H] + :260.2378,found:260.2382.

[0298] N-Hexylbenzomorpholine (10)

[0299] Benzomorpholine (67.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 88.4 mg (81%) of green oil 10. 1H NMR (400MHz, CDCl3): δ6.86–6.81(m,1H),6.79(dd,J=7.9,1.6Hz,1H),6.67(dd,J=8.2,1.5Hz,1H),6.62–6.58(m,1H),4 .25–4.23(m,2H),3.34(t,J=4.4Hz,2H),3.24(t,J=7.6Hz,2H),1.64–1.57(m,2H),1.35–1.33(m,6H),0.93–0.90(m,3H). 13 C NMR (101MHz, CDCl3): δ143.92,135.33,121.53,116.98,116.23,111.95,64.48,51.07,46.97,31.69,26.89,25.99,22.64,14.02.HRMS m / z(ESI)calcd for C 14 H 21 NO[M+H] + :220.1701,found:220.1706.

[0300] N-Hexylbenzothiomorpholine (11)

[0301] Benzothiomorpholine (75.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 83.5 mg (71%) of brown oil 11. 1 H NMR (400MHz, CDCl3): δ7.03 (dd, J=7.6, 1.6Hz, 1H), 7.00–6.96 (m, 1H), 6.65 (dd, J=8.4, 1.1Hz, 1H), 6.60–6.56 (m, 1H), 3.63–3.61(m,2H),3.27(t,J=7.6Hz,2H),3.04–3.02(m,2H),1.63–1.55(m,2H),1.35–1.31(m,6H),0.93–0.89(m,3H). 13C NMR (101MHz, CDCl3): δ143.36,127.86,125.86,117.30,116.73,112.46,52.66,49.93,31.70,26.86,26.30,25.74,22.66,14.02.HRMS m / z(ESI)calcd for C 14 H 21 NS[M+H] + :236.1473,found:236.1474.

[0302] 1-Hexylindoline (12)

[0303] Indoline (59.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 76.8 mg (76%) of brown oil 12. 1 H NMR (400MHz, CDCl3): δ7.07(t,J=7.4Hz,2H),6.64(t,J=7.3Hz,1H),6.47(d,J=7.9Hz,1H),3.35(t,J=8.3Hz ,2H),3.05(t,J=7.4Hz,2H),2.97(t,J=8.3Hz,2H),1.65–1.58(m,2H),1.42–1.28(m,6H),0.95–0.91(m,3H). 13 CNMR (101MHz, CDCl3): δ152.76,129.96,127.23,124.29,117.15,106.79,53.03,49.31,31.73,28.56,27.32,26.95,22.66,14.06.HRMSm / z(ESI)calcd for C 14 H 21 N[M+H] + :204.1752,found:204.1752.

[0304] 1-Hexyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (13)

[0305] 2,3,4,5-Tetrahydro-1H-benzo[b]azepine (73.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 99.5 mg (86%) of brown oil 13. 1 H NMR (400MHz, CDCl3): δ7.17–7.11(m,2H),6.93(dd,J=8.0,1.2Hz,1H),6.88–6.84(m,1H),3.12(t,J=7.1Hz,2H),2 .94–2.91(m,2H),2.81–2.78(m,2H),1.74–1.70(m,2H),1.63–1.55(m,4H),1.40–1.29(m,6H),0.93–0.89(m,3H). 13 C NMR (101MHz, CDCl3): δ152.66,136.27,129.85,126.42,120.70,117.64,54.19,54 .01,34.88,31.73,30.26,28.68,26.88,25.86,22.70,14.07.HRMSm / z(ESI)calcd for C 16 H 25 N[M+H] + :232.2065,found:232.2065.

[0306] 4-Hexyl-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole (14)

[0307] 1,2,3,3a,4,8b-Hexahydrocyclopenta[b]indole (79.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 h to obtain 88.4 mg (73%) of green oil 14. 1H NMR (400MHz, CDCl3): δ7.07–7.01(m,2H),6.58(t,J=7.3Hz,1H),6.32(d,J=7.8Hz,1H),4.22–4.17(m,1H),3.77–3.71(m ,1H),3.19–3.12(m,2H),2.02–1.98(m,1H),1.90–1.77(m,2H),1.72–1.56(m,5H),1.38–1.36(m,6H),0.97–0.93(m,3H). 13 C NMR (101MHz, CDCl3): δ152.17,133.48,127.37,123.97,115.89,104.90,69.03,46.83 ,45.75,35.03,33.47,31.74,27.26,27.00,24.51,22.66,14.05.HRMSm / z(ESI)calcd for C 17 H 25 N[M+H] + :224.2065,found:224.2064.

[0308] N-Butyl-N-hexylaniline (15)

[0309] N-Butylaniline (74.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 96.5 mg (83%) of yellow oil 15. 1 H NMR (400MHz, CDCl3): δ7.21–7.17(m,2H),6.64–6.59(m,3H),3.27–3.22(m,4H),1.59–1.52(m,4H),1.37–1.30(m,8H),0.96–0.88(m,6H). 13 C NMR (101MHz, CDCl3): δ148.16,129.14,115.03,111.66,51.05,50.74,31.75,29.41,27.20,26.87,22.70,20.36,14.04,14.01.HRMSm / z(ESI)calcd forC 16 H 27 N[M+H] +:234.2222,found:224.2224.

[0310] N-Cyclohexyl-N-hexylaniline (16)

[0311] N-Cyclohexylaniline (87.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 65.8 mg (51%) of a yellow oil 16. 1 H NMR (400MHz, CDCl3): δ7.24–7.22(m,2H),6.74(d,J=8.3Hz,2H),6.68(t,J=7.2Hz,1H),3.60–3.54(m,1H),3.19–3.15(m,2 H),1.88(d,J=10Hz,4H),1.71–1.70(m,1H),1.61–1.56(m,2H),1.46–1.30(m,10H),1.23–1.17(m,1H),0.96–0.93(m,3H). 13 C NMR (101MHz, CDCl3): δ148.67,129.10,115.54,112.69,57.37,45.05,31.69,30.71,29.48,26.92,26.27,25.96,22.74,14.05.HRMSm / z(ESI)calcd for C 18 H 29 N[M+H] + :260.2378,found:260.2377.

[0312] 5-Hexyl-5H-dibenzo[b,f]azepine (17)

[0313] 5H-Dibenzo[b,f]azepine (96.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 87.1 mg (63%) of 17 as a brown oil. 1H NMR (400MHz, CDCl3): δ7.29–7.25(m,2H),7.08(dd,J=7.6,1.7Hz,2H),7.04–6.97(m,4H),6.75(s,2H), 3.72(t,J=7.1Hz,2H),1.69–1.54(m,2H),1.43–1.36(m,2H),1.30–1.23(m,4H),0.86(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3): δ151.18,133.90,132.13,129.07,128.67,123.05,120.32,50.58,31.46,27.54,26.59,22.57,13.97.

[0314] HRMS m / z(ESI)calcd for C 20 H 23 N[M+H] + :278.1909,found:278.1908.

[0315] N-Hexyl-4-methoxy-N-(4-methoxyphenyl)aniline (18)

[0316] 4-Methoxy-N-(4-methoxyphenyl)aniline (114.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 93.7 mg (60%) of brown oil 18. 1 H NMR (400MHz, CDCl3): δ6.90–6.87(m,4H),6.85–6.82(m,4H),3.79(s,6H),3 .57(t,7.6Hz,2H),1.66–1.59(m,2H),1.37–1.28(m,6H),0.91–0.88(m,3H). 13 C NMR (101MHz, CDCl3): δ154.10,142.58,122.02,114.56,55.55,52.85,31.66,27.48,26.79,22.65,14.01.HRMS m / z(ESI)calcd for C 20 H 27 NO2[M+H] +:314.2111,found:314.2115.

[0317] 10-Hexyl-10H-phenoxazine (19)

[0318] 10H-phenoxazine (91.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (60.0 mg, 0.50 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 48 hours to obtain 68.8 mg (51%) of 19 as a brown oil. 1 H NMR (400MHz, CDCl3): δ6.81–6.77(m,2H),6.63(d,J=3.5Hz,4H),6.47(d,J=7.9Hz,2 H),3.48(t,J=9.2Hz,2H),1.71–1.63(m,2H),1.44–1.35(m,6H),0.95–0.91(m,3H). 13 C NMR (101MHz, CDCl3): δ145.00,133.41,123.56,120.61,115.27,111.23,44.11,31.57,26.60,24.86,22.66,14.00.HRMSm / z(ESI)calcd for C 18 H 21 NO[M+H] + :268.1701,found:268.1702.

[0319] 10-Hexyl-10H-phenothiazine (20)

[0320] 10H-phenothiazine (99.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (60.0 mg, 0.50 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 48 hours to obtain 58.8 mg (42%) of green oil 20. 1 H NMR (400MHz, CDCl3): δ7.18–7.14(m,J=7.5,4H),6.94–6.87(m,4H),3.85(brs,2 H),1.86–1.78(m,2H),1.47–1.41(m,2H),1.34–1.32(m,4H),0.92–0.88(m,3H).13 C NMR (101MHz, CDCl3): δ145.23,127.36,127.11,124.84,122.27,115.37,47.43,31.44,26.86,26.64,22.56,13.97.HRMSm / z(ESI)calcd for C 18 H 21 NS[M+H] + :284.1473,found:284.1479.

[0321] Experimental Procedure and Spectral Data for Alkylamines (Condition B)

[0322] 1-Hexyl-4-phenylpiperazine (21)

[0323] 1-Phenylpiperazine (81.1 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and H2SO4 (24.5 mg, 0.25 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 48 hours to obtain 92.5 mg (75%) of yellow oil 21. 1 H NMR (400MHz, CDCl3): δ7.28–7.24(m,2H),6.93(d,J=8.2Hz,2H),6.85(t,J=7.3Hz,1H),3.22(t,J=5.2Hz ,4H),2.61(t,J=5.2Hz,4H),2.41–2.37(m,2H),1.55–1.49(m,2H),1.33–1.30(m,6H),0.91–0.88(m,3H). 13 C NMR (101MHz, CDCl3): δ151.33,129.06,119.61,116.00,58.84,53.28,49.09,31.78,27.28,26.81,22.59,14.03.

[0324] HRMS m / z(ESI)calcd for C 16 H 26 N2[M+H] + :247.2174,found:247.2178.

[0325] 1-Hexyl-4-(p-tolyl)piperazine (22)

[0326] 1-(p-Tolyl)piperidine (88.1 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and H2SO4 (24.5 mg, 0.25 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 48 hours to obtain 99.2 mg (76%) of yellow oil 22. 1 H NMR (400MHz, CDCl3): δ7.08(d,J=8.4Hz,2H),6.87–6.85(m,2H),3.17(t,J=5.2Hz,4H),2.61(t,J=5 .2Hz,4H),2.41–2.37(m,2H),2.27(s,3H),1.56–1.50(m,2H),1.33–1.31(m,6H),0.92–0.89(m,3H). 13 C NMR (101MHz, CDCl3): δ149.27,129.56,129.05,116.32,58.87,53.33,49.69,31.79,27.30,26.87,22.59,20.38,14.03.HRMSm / z(ESI)calcd for C 17 H 28 N2[M+H] + :261.2331,found:261.2334.

[0327] 1-(4-Chlorophenyl)-4-hexylpiperazine(23)

[0328] 1-(4-Chlorophenyl)piperazine (98.2 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and H2SO4 (24.5 mg, 0.25 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 48 hours to obtain 113.2 mg (81%) of white solid 23. 1 H NMR (400MHz, CDCl3): δ7.20–7.16(m,2H),6.83–6.79(m,2H),3.15(t,J=5.2Hz,4H),2.57(t ,J=5.2Hz,4H),2.38–2.34(m,2H),1.53–1.47(m,2H),1.32–1.29(m,6H),0.91–0.87(m,3H).

[0329] 13C NMR (101MHz, CDCl3): δ149.89,128.80,124.24,117.01,58.71,53.06,49.03,31.73,27.20,26.80,22.54,14.00.HRMSm / z(ESI)calcd for C 16 H 25 ClN2[M+H] + :281.1785,found:281.1790.4-(4-Hexylpiperazin-1-yl)benzonitrile (24)

[0330] 4-(Piperazin-1-yl)benzonitrile (93.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and H2SO4 (24.5 mg, 0.25 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 48 hours to obtain 96.5 mg (71%) of yellow oil 24. 1 H NMR (400MHz, CDCl3): δ7.47–7.43(m,2H),6.83–6.80(m,2H),3.30(t,J=5.2Hz,4H),2.54(t ,J=5.2Hz,4H),2.36–2.33(m,2H),1.51–1.45(m,2H),1.31–1.25(m,6H),0.88–0.85(m,3H). 13 C NMR (101MHz, CDCl3): δ153.28,133.30,119.96,113.94,99.88,58.57,52.68,47.00,31.65,27.09,26.70,22.48,13.95.HRMSm / z(ESI)calcd for C 17 H 25 N3[M+H] + :272.2127,found:272.2131.

[0331] 1-Hexyl-4-(4-nitrophenyl)piperazine (25)

[0332] 1-(4-Nitrophenyl)piperazine (103.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 120.3 mg (83%) of yellow solid 25. 1 HNMR (400MHz, CDCl3): δ8.10–8.07(m,2H),6.80–6.78(m,2H),3.41(t,J=5.2Hz,4H),2.56(t, J=5.2Hz,4H),2.36(t,J=7.6Hz,2H),1.52–1.46(m,2H),1.31–1.29(m,6H),0.89–0.86(m,3H). 13 C NMR (101MHz, CDCl3): δ154.81,138.21,125.84,112.43,58.56,52.65,46.94,31.69,27.12,26.74,22.53,13.99.HRMSm / z(ESI)calcd for C 16 H 25 N3O2[M+H] + :292.2025,found:292.2025.

[0333] 1-Hexyl-4-(4-methoxyphenyl)piperazine (26)

[0334] 1-(4-Methoxyphenyl)piperazine (96.1 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and H2SO4 (24.5 mg, 0.25 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 48 hours to obtain 102.5 mg (74%) of colorless solid 26. 1 H NMR (400MHz, CDCl3): δ6.92–6.89(m,2H),6.84–6.82(m,2H),3.76(s,3H),3.11(t,J=4.8Hz,4H),2. 61(t,J=4.8Hz,4H),2.38(t,J=7.6Hz,2H),1.54–1.49(m,2H),1.33–1.30(m,6H),0.91–0.88(m,3H). 13C NMR (101MHz, CDCl3): δ153.71,145.79,118.10,114.39,58.86,55.54,53.41,50.61,31.80,27.31,26.89,22.60,14.04.HRMSm / z(ESI)calcd forC 17 H 28 N2O[M+H] + :277.2280,found:277.2286.

[0335] 2-(4-Hexylpiperazin-1-yl)pyrimidine (27)

[0336] 2-(Piperazin-1-yl)pyrimidine (82.1 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 114.0 mg (92%) of white solid 27. 1 H NMR (400MHz, CDCl3): δ8.30 (d, J = 4.7Hz, 2H), 6.47 (t, J = 4.7Hz, 1H), 3.83 (t, J = 5.1Hz, 4H), 2.4 9(t,J=5.1Hz,4H),2.38–2.34(m,2H),1.54–1.49(m,2H),1.33–1.30(m,6H),0.90–0.87(m,3H). 13 C NMR (101MHz, CDCl3): δ161.68,157.67,109.74,58.96,53.17,43.68,31.79,27.29,26.85,22.61,14.05.HRMSm / z(ESI)calcd for C 14 H 24 N4[M+H] + :249.2079,found:249.2082.1-(Benzo[b]thiophen-4-yl)-4-hexylpiperazine (28)

[0337] 1-(Benzo[b]thiophene-4-yl)piperazine (109.2 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 97.0 mg (64%) of brown solid 28. 1 H NMR (400MHz, CDCl3): δ7.55(d,J=8.1Hz,1H),7.43–7.38(m,2H),7.30–7.25(m,1H),6.91(d,J=7.6Hz,1H),3.21( t,J=4.8Hz,4H),2.73–2.71(m,4H),2.48–2.44(m,2H),1.59–1.53(m,2H),1.36–1.31(m,6H),0.93–0.90(m,3H). 13 C NMR (101MHz, CDCl3): δ148.47,141.08,134.06,124.98,124.85,121.87,116.93,11 2.16,58.88,53.61,52.06,31.80,27.29,26.83,22.60,14.05.HRMSm / z(ESI)calcd for C 18 H 26 N2S[M+H] + :303.1895,found:303.1895.

[0338] 1-Benzhydryl-4-hexylpiperazine (29)

[0339] 1-Benzhydrylpiperazine (126.2 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 94.5 mg (56%) of brown oil 29. 1 HNMR (400MHz, CDCl3): δ7.42–7.39(m,4H),7.27–7.23(m,4H),7.17–7.13(m,2H),4.21(s,1H) ,2.45(brs,8H),2.33–2.29(m,2H),1.49–1.42(m,2H),1.29–1.26(m,6H),0.88–0.85(m,3H).13 C NMR (101MHz, CDCl3): δ142.79,128.36,127.89,126.79,76.26,58.83,53.51,51.91,31.76,27.31,26.83,22.56,14.01.HRMSm / z(ESI)calcd for C 23 H 32 N2[M+H] + :249.2079,found:249.2082.

[0340] Furan-2-yl(4-hexylpiperazin-1-yl)methanone(30)

[0341] Furan-2-yl(piperazine-1-yl)methanone (90.1 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 110.4 mg (84%) of a yellow oil 30. 1 H NMR (400MHz, CDCl3): δ7.46–7.45(m,1H),6.96(d,J=3.4Hz,1H),6.45(dd,J=3.5,1.8Hz,1H),3.79(br s,4H),2.48–2.45(m,4H),2.36–2.32(m,2H),1.50–1.46(m,2H),1.31–1.27(m,6H),0.89–0.85(m,3H). 13 C NMR (101MHz, CDCl3): δ158.97,147.95,143.51,116.13,111.14,58.60,53.56 ,53.28,53.26,52.99,31.70,27.13,26.70,22.54,13.99.HRMSm / z(ESI)calcd for C 15 H 24 N2O2[M+H] + :265.1916,found:265.1920.

[0342] (4-Hexylpiperazin-1-yl)(phenyl)methanone (31)

[0343] Phenyl(piperazine-1-yl)methanone (95.1 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 101.2 mg (74%) of yellow oil 31. 1 H NMR(400MHz,DMSO-d6)δ7.44–7.42(m,3H),7.37–7.35(m,2H),3.60(brs,2H),3.31(brs,2H),2.37(b rs,2H),2.31(brs,2H),2.29–2.25(m,2H),1.43–1.37(m,2H),1.28–1.24(m,6H),0.87–0.84(m,3H). 13 C NMR(101MHz,DMSO-d6)δ168.76,135.93,129.35,128.31,126.79,57.68,52.87 ,52.53,47.08,41.50,31.17,26.54,26.11,22.05,13.87.HRMSm / z(ESI)calcd for C 17 H 26 N2O[M+H] + :275.2123,found:275.2124.

[0344] 1-Hexyl-4-(phenylsulfonyl)piperazine (32)

[0345] 4-(Phenylsulfonyl)piperazine (113.2 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 125.8 mg (81%) of white solid 32. 1 HNMR (400MHz, CDCl3): δ7.74–7.72(m,2H),7.59–7.55(m,1H),7.52–7.48(m,2H),3.02(t,J=4.8Hz,4H ),2.49(t,J=4.9Hz,4H),2.31–2.27(m,2H),1.40–1.35(m,2H),1.25–1.21(m,6H),0.85–0.82(m,3H). 13C NMR (101MHz, CDCl3): δ135.17,132.73,128.93,127.77,58.23,52.16,45.99,31.62,27.02,26.68,22.47,13.95.HRMSm / z(ESI)calcd for C 16 H 26 N2O2S[M+H] + :311.1793,found:311.1794.

[0346] 4-Hexyl-2-phenylmorpholine (33)

[0347] 2-Phenylmorpholine (81.5 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 84.5 mg (68%) of orange oil 33. 1 H NMR (400MHz, CDCl3): δ7.38–7.31(m,4H),7.29–7.26(m,1H),4.57(dd,J=10. 4,2.4Hz,1H),4.05–4.01(m,1H),3.87–3.84(m,1H),2.94(d,J=11.5Hz,1H),2 .80(dd,J=11.4,2.0Hz,1H),2.38–2.34(m,2H),2.22–2.21(m,1H),2.04(dd,J =11.5,10.3Hz,1H),1.53–1.48(m,2H),1.30–1.28(m,6H),0.90–0.87(m,3H). 13 C NMR (101MHz, CDCl3): δ140.52,128.25,127.68,126.14,78.21,67.11,60.68,59.02,53.03,31.75,27.17,26.52,22.56,14.01.HRMSm / z(ESI)calcdfor C 16 H 25 NO[M+H] + :248.2014,found:248.2018.

[0348] 2-Benzyl-4-hexylmorpholine (34)

[0349] 2-Benzylmorpholine (88.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 106.9 mg (81%) of colorless oil 34. 1 H NMR (400MHz, CDCl3): δ7.30–7.26(m,2H),7.22–7.19(m,3H),3.90–3.85(m,1H),3.77–3.74(m,1H),3.68–3.61(m,1H),2.89–2.84(m,1H),2.7 5–2.64(m,3H),2.30–2.26(m,2H),2.12–2.06(m,1H),1.85(dd,J=11.3 ,10.0Hz,1H),1.45–1.42(m,2H),1.29–1.25(m,6H),0.89–0.85(m,3H). 13 C NMR (101MHz, CDCl3): δ138.01,129.22,128.27,126.23,76.51,66.92,59.08, 58.59,53.04,40.38,31.73,27.17,26.51,22.57,14.02.HRMSm / z(ESI)calcd for C 17 H 27 NO[M+H] + :262.2171,found:262.2174.

[0350] (S)-3-Benzyl-4-hexylmorpholine (35)

[0351] 3-Benzylmorpholine (88.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 61.0 mg (47%) of yellow oil 35. 1H NMR (400MHz, CDCl3): δ7.29–7.26(m,2H),7.20–7.15(m,3H),3.75–3.71(m,2H),3.53–3.50(m,1H),3.41–3.37(m,1H),2.99(dd,J=1 2.8,3.1Hz,1H),2.82–2.72(m,2H),2.68–2.60(m,2H),2.50–2.41(m,2H),1.54–1.49(m,2H),1.34–1.30(m,6H),0.92–0.89(m,3H). 13 C NMR (101MHz, CDCl3): δ139.27,129.19,128.38,126.02,69.71,67.25,60.41, 54.25,50.02,32.17,31.78,27.21,26.17,22.62,14.04.HRMSm / z(ESI)calcd for C 17 H 27 NO[M+H] + :262.2171,found:262.2172.

[0352] 2-Hexyl-1,2,3,4-tetrahydroisoquinoline (36)

[0353] 1,2,3,4-Tetrahydroisoquinoline (66.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 76.4 mg (70%) of orange oil 36. 1 H NMR (400MHz, CDCl3): δ7.14–7.08(m,3H),7.04–7.02(m,1H),3.63(s,2H),2.92(t,J=6.0Hz,2H),2 .74(t,J=5.9Hz,2H),2.53–2.49(m,2H),1.63–1.58(m,2H),1.39–1.32(m,6H),0.93–0.90(m,3H). 13CNMR (101MHz, CDCl3): δ134.94,134.35,128.56,126.53,125.96,125.46,58.6 1,56.25,50.98,31.82,29.12,27.30,27.20,22.61,14.05.HRMSm / z(ESI)calcd forC 15 H 23 N[M+H] + :218.1909,found:218.1912.

[0354] 3-Hexyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (37)

[0355] 2,3,4,5-Tetrahydro-1H-benzo[d]azepine (73.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 61.1 mg (53%) of brown solid 37. 1 HNMR (400MHz, CDCl3): δ7.14–7.08(m,4H),3.03–3.01(m,4H),2.79(d,J=7.7Hz, 4H),2.62–2.58(m,2H),1.61–1.57(m,2H),1.32–1.29(m,6H),0.90–0.87(m,3H). 13 C NMR (101MHz, CDCl3): δ141.30,128.83,126.44,59.12,55.08,35.38,31.60,27.11,26.03,22.51,13.97.HRMSm / z(ESI)calcd for C 16 H 25 N[M+H] + :232.2065,found:232.2069.

[0356] 1-Hexyl-4-phenylpiperidine (38)

[0357] 4-Phenylpiperidine (80.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 56.4 mg (46%) of yellow solid 38. 1 H NMR (400MHz, CDCl3): δ7.32–7.17(m,5H),3.11(d,J=10.4Hz,2H),2.55–2.47(m,1H),2.42–2.38(m, 2H),2.12–2.05(m,2H),1.90–1.84(m,4H),1.58–1.54(m,2H),1.32–1.30(m,6H),0.91–0.88(m,3H). 13 C NMR (101MHz, CDCl3): δ146.18,128.39,126.84,126.13,59.15,54.34,42.65,33.20,31.76,27.37,26.79,22.59,14.04.HRMSm / z(ESI)calcd for C 17 H 27 N[M+H] + :246.2222,found:246.2228.

[0358] 5-Hexyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (39)

[0359] 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride (87.5 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 51.8 mg (46%) of brown solid 39. 1 H NMR (400MHz, CDCl3): δ7.07(d,J=4.5Hz,1H),6.72(d,J=4.5Hz,1H),3.57(s,2H),2.92–2.89(m,2H) ,2.82–2.79(m,2H),2.54(t,J=7.3Hz,2H),1.61–1.57(m,2H),1.36–1.32(m,6H),0.91–0.88(m,3H). 13C NMR (101MHz, CDCl3): δ133.78,133.35,125.20,122.59,57.97,53.11,50.92,31.80,27.32,27.24,25.40,22.60,14.05.HRMSm / z(ESI)calcd forC 13 H 21 NS[M+H] + :224.1473,found:224.1475.

[0360] 1'-Hexyl-2,3-dihydrospiro[indene-1,4'-piperidine](40)

[0361] 2,3-Dihydrospiro[indene-1,4'-piperidine] (93.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 60 hours to obtain 61.0 mg (45%) of white solid 40. 1 HNMR (400MHz, CDCl3): δ7.31–7.28(m,1H),7.21–7.19(m,3H),3.43–3.40(m,2H),2.94(t,J=7.3Hz,2H),2.86(t,J=8.3Hz,2H),2.74( brs,2H),2.45(brs,2H),2.04(t,J=7.3Hz,2H),1.81(t,J=8.1Hz,2H),1.69(d,J=14.1Hz,2H),1.35–1.30(m,6H),0.90–0.87(m,3H). 13 CNMR (101MHz, CDCl3): δ148.68,142.33,127.39,126.90,124.61,122.86,57.95,50.69, 45.21,34.65,34.11,31.26,29.79,26.68,24.45,22.41,13.89.HRMSm / z(ESI)calcdfor C 19 H 29 N[M+H] + :272.2378,found:272.2379.

[0362] 8-Hexyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (41)

[0363] 1-Phenyl-1,3,8-triazaspiro[4.5]decane-4-one (115.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 60.1 mg (38%) of white solid 41. 1 H NMR (400MHz, CDCl3): δ7.90(brs,1H),7.29(dd,J=8.6,7.2Hz,2H),6.93(d,J=8.2Hz,2H),6.86(t,J=7.3Hz,1H),4.75(s,2H),2 .97(brs,4H),2.80(brs,2H),2.54(brs,2H),1.76(d,J=13.8Hz,2H),1.60–1.56(m,2H),1.34–1.31(m,6H),0.91–0.88(m,3H). 13 C NMR (101MHz, CDCl3): δ178.25,143.11,129.21,118.96,115.55,59.51,59.36 ,58.66,49.65,31.77,29.12,27.36,27.04,22.62,14.05.HRMSm / z(ESI)calcd for C 19 H 29 N3O[M+H] + :316.2389,found:316.2386.

[0364] 5-Chloro-1-(4-hexylpiperidinyl)-2-benzimidazolidinone (42)

[0365] 5-Chloro-1-(4-piperidinyl)-2-benzimidazolidinone (125.9 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 116.4 mg (69%) of white solid 42. 1H NMR (400MHz, CDCl3): δ10.94(brs,1H),7.21(d,J=8.5Hz,1H),7.14(s,1H),7.00(d,J=8.2Hz,1H),4.39(t,J=12.6Hz,1H),3.17–3. 15(m,2H),2.49–2.42(m,4H),2.21–2.18(m,2H),1.84(d,J=10.9Hz,2H),1.57–1.53(m,2H),1.33–1.32(m,6H),0.92–0.88(m,3H). 13 C NMR (101MHz, CDCl3): δ155.42,129.11,127.52,126.81,120.93,110.53,110.11,5 8.58,53.11,50.84,31.73,29.07,27.25,26.90,22.58,14.03.HRMSm / z(ESI)calcd for C 18 H 26 ClN3O[M+H] + :336.1843,found:336.1843.

[0366] N-Methyl-N-phenethyl-1-hexylamine (43)

[0367] N-Methyl-2-phenylethylamine (67.6 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted at 160°C under N2 for 60 hours to obtain 66.2 mg (61%) of orange oil 43. 1 H NMR (400MHz, CDCl3): δ7.31–7.27(m,2H),7.22–7.18(m,3H),2.88–2.84(m,2H),2.75–2.70(m,2 H),2.52(t,J=7.6Hz,2H),2.41(s,3H),1.57–1.53(m,2H),1.32–1.29(m,6H),0.90–0.87(m,3H). 13C NMR (101MHz, CDCl3): δ139.65,128.65,128.44,126.17,59.13,57.40,41.77,33.13,31.67,27.05,26.52,22.56,14.00.HRMSm / z(ESI)calcd for C 15 H 25 N[M+H] + :220.2065,found:220.2068.

[0368] Hexyl-atomoxetine (44)

[0369] Atomoxetine hydrochloride (145.9 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 86.7 mg (51%) of brown solid 44. 1 H NMR (400MHz, CDCl3): δ7.37–7.30(m,4H),7.25–7.23(m,1H),7.13–7.10(m,1H),6. 98–6.93(m,1H),6.80–6.76(m,1H),6.61(dd,J=8.2,1.0Hz,1H),5.27(dd,J=8.3,4. 4Hz,1H),2.71(brs,2H),2.49–2.47(m,2H),2.36(s,3H),2.32(s,3H),2.27–2.20( m,1H),2.16–2.13(m,1H),1.54–1.50(m,2H),1.30–1.27(m,6H),0.89–0.86(m,3H). 13 C NMR (101MHz, CDCl3): δ155.86,141.64,130.57,128.60,127.55,126.84,126.57,125.74,120.29,112. 74,77.63,57.41,53.58,41.75,35.57,31.62,26.98,26.31,22.53,16.52,13.99.HRMSm / z(ESI)calcd forC 23 H 33 NO[M+H] + :340.2640,found:340.2637.

[0370] Hexyl-lorcaserin (45)

[0371] Lorcaserin (97.8 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 60 hours to obtain 101.2 mg (72%) of 45 as a brown oil. 1 H NMR (400MHz, CDCl3): δ7.12(d,J=2.2Hz,1H),7.08–7.06(m,1H),6.99(d,J=8.0Hz,1H),3.18(t,J=7.5Hz,1H),3.06(dd,J=14.6,10.0Hz,1H),2.94–2 ,89(m,1H),2.86–2.75(m,2H),2.50–2.46(m,2H),2.38–2.28(m,2H),1.52 –1.49(m,2H),1.34(d,J=7.2Hz,3H),1.30–1.27(m,6H),0.90–0.87(m,3H). 13 C NMR (101MHz, CDCl3): δ147.26,139.72,131.92,130.37,125.80,125.69,61.93,59.32 ,54.87,37.71,35.38,31.70,27.16,26.54,22.57,18.35,14.00.HRMSm / z(ESI)calcd for C 17 H 26 ClN[M+H] + :280.1832,found:280.1835.

[0372] Hexyl-cytisine (46)

[0373] Cytisine (95.1 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 125.9 mg (92%) of 46 as a brown oil. 1H NMR (400MHz, CDCl3): δ7.24 (dd, J=9.2, 7.0Hz, 1H), 6.40 (dd, J=9.0, 1.4Hz, 1H), 5 .94(dd,J=6.9,1.4Hz,1H),4.00(d,J=15.3Hz,1H),3.88–3.86(m,1H),2.92–2.84 (m,3H),2.40–2.37(m,1H),2.23(d,J=10.4,2H),2.19–2.15(m,2H),1.84–1.83(m ,1H),1.76–1.72(m,1H),1.26–1.23(m,2H),1.17–1.03(m,6H),0.80–0.77(m,3H). 13 C NMR (101MHz, CDCl3): δ163.56,151.67,138.46,116.39,104.37,60.30,60.19,57.50 ,50.02,35.54,31.45,28.04,26.49,26.33,26.00,22.51,13.97.HRMSm / z(ESI)calcd for C 17 H 26 N2O[M+H] + :275.2123,found:275.2126.

[0374] Hexyl-vortioxetine (47)

[0375] Vortioxetine (149.2 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 145.1 mg (76%) of yellow oil 47. 1 H NMR (400MHz, CDCl3): δ7.40(d,J=7.8Hz,1H),7.15(s,1H),7.10–7.07(m,2H),7.03(d,J=8.3Hz,1H),6.88–6.84(m,1H),6.51(d,J=7.9Hz,1H ),3.13(brs,4H),2.68(brs,4H),2.43(t,J=8.0Hz,2H),2.36(s,3H),2.33(s,3H),1.58–1.52(m,2H),1.35–1.33(m,6H),0.93–0.90(m,3H). 13C NMR (101MHz, CDCl3): δ149.18,142.42,139.07,136.22,134.51,131.56,127.94,127.70,125.90,125.32,1 24.16,119.70,58.88,53.61,51.57,31.78,27.30,26.87,22.57,21.13,20.54,14.04.HRMSm / z(ESI)calcd for C 24 H 34 N2S[M+H] + :383.2521,found:383.2521.

[0376] Hexyl-palbociclib (48)

[0377] Palbociclib (223.8 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 82.4 mg (31%) of yellow solid 48. 1 H NMR (400MHz, CDCl3): δ9.19(brs,1H),8.90(s,1H),8.15(d,J=9.1Hz,1H),8.11(d,J=2.9Hz ,1H),7.32(dd,J=9.1,3.0Hz,1H),5.92–5.83(m,1H),3.25(t,J=4.9Hz,4H),2.70(brs,4H), 2.54(s,3H),2.46(t,J=8.0Hz,2H),2.37(s,3H),2.36–2.31(m,2H),2.07–2.03(m,2H),1.8 8–1.86(m,2H),1.70–1.67(m,2H),1.59–1.55(m,2H),1.33–1.29(m,6H),0.90–0.87(m,3H). 13C NMR (101MHz, CDCl3): δ202.68,161.39,158.11,157.29,155.50,145.09,143.41,141.85,136.66,130.53,125.83,113.53,1 07.47,58.64,54.06,52.88,49.16,31.69,31.52,28.00,27.14,26.47,25.70,22.56,14.02,13.94.HRMSm / z(ESI)calcdfor C 30 H 41 N7O2[M+H] + :532.3400,found:532.3402.

[0378] Hexyl-ceritinib (49)

[0379] Ceritinib (279.1 mg, 0.50 mmol), 1-hexanol (2) (204.3 mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), and NaHSO4 (90.0 mg, 0.75 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 60 hours to obtain 144.4 mg (45%) of brown solid 49. 1 H NMR (400MHz, CDCl3): δ9.50(s,1H),8.59(d,J=8.4Hz,1H),8.15(s,1H),8.00(s,1H),7.92(dd,J=8.0,1.6Hz,1 H),7.65–7.60(m,1H),7.55(s,1H),7.25(t,J=7.7Hz,1H),6.84(s,1H),4.57–4.51(m,1H),3.30–3.23(m,1H), 3.16(d,J=11.2Hz,2H),2.73–2.66(m,1H),2.45(t,J=8.0Hz,2H),2.16(s,3H),2.15–2.11(m,2H),1.88–1.76( m,4H),1.61–1.56(m,2H),1.36(d,J=6.1Hz,6H),1.32(d,J=6.8Hz,6H),1.32–1.27(m,6H),0.91–0.88(m,3H). 13C NMR (101MHz, CDCl3): δ157.36,155.23,155.15,144.58,138.35,137.43,134.55,131.10,127.23,126.57,124.68,123.56,122.96,120.42 ,110.61,105.53,71.18,59.08,55.30,54.41,37.78,32.44,31.65,27.25,26.61,22.49,22.15,18.85,15.25,13.96.HRMSm / z(ESI)calcd for C 34 H 48 ClN5O3S[M+H] + :642.3253,found:642.3253.

[0380] Alcohol substrate expansion process and spectral data (condition A)

[0381] 1-Methyl-1,2,3,4-tetrahydroquinoline (50)

[0382] 1,2,3,4-Tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 58.3 mg (79%) of brown oil 50. 1 H NMR (400MHz, CDCl3): δ7.12–7.08(m,1H),6.99–6.97(m,1H),6.65–6.61(m,2H) ,3.24(t,J=5.6Hz,2H),2.91(s,3H),2.79(t,J=6.5Hz,2H),2.04–1.98(m,2H). 13 C NMR (101MHz, CDCl3): δ146.41,128.82,127.04,123.05,116.56,111.30,51.26,39.30,27.68,22.26.HRMSm / z(ESI)calcdfor C 10 H 13 N[M+H] + :148.1126,found:148.1127.

[0383] 1-Ethyl-1,2,3,4-tetrahydroquinoline (51)

[0384] 1,2,3,4-Tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), ethanol (460.7 mg, 10.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 65.1 mg (81%) of brown oil 51. 1 H NMR (400MHz, CDCl3): δ7.10–7.06(m,1H),6.97(dd,J=7.3,1.6Hz,1H),6.63(d,J=8.3Hz,1H),6.61–6.57(m,1H) ,3.38(q,J=7.1Hz,2H),3.29(t,J=6.4Hz,2H),2.79(t,J=6.4Hz,2H),2.02–1.96(m,2H),1.17(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ144.96,129.10,127.01,122.38,115.30,110.48,48.35,45.27,28.16,22.27,10.78.HRMSm / z(ESI)calcd for C 11 H 15 N[M+H] + :162.1283,found:162.1282.

[0385] 1-Dodecyl-1,2,3,4-tetrahydroquinoline (52)

[0386] 1,2,3,4-tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), 1-

[0387] Dodecanol (186.3 mg, 1.0 mmol), HI (55% aqueous solution,

[0388] 11.6mg, 0.05mmol), NaHSO4 (12.0mg, 0.10mmol)

[0389] The product was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 115.5 mg (77%) of 52 as an orange oil. 1H NMR (400MHz, CDCl3): δ7.16(t,J=7.9Hz,1H),7.05(d,J=7.3Hz,1H),6.70–6.65(m,2H),3.39(t,J=6.5Hz,2H),3.37 –3.33(m,2H),2.88(t,J=6.4Hz,2H),2.08–2.05(m,2H),1.74–1.70(m,2H),1.46–1.42(m,18H),1.05–1.02(m,3H). 13 C NMR (101MHz, CDCl3): δ145.20,129.01,126.95,121.94,115.10,110.34,51.45,49.36,31.91,29.66 ,29.66,29.62,29.62,29.57,29.35,28.17,27.25,26.13,22.67,22.22,14.09.HRMSm / z(ESI)calcd for C 21 H 35 N[M+H] + :302.2848,found:302.2842.

[0390] 1-(2-Cyclohexylethyl)-1,2,3,4-tetrahydroquinoline(53)

[0391] 1,2,3,4-Tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), 2-cyclohexylethanol (128.2

[0392] mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), NaHSO4

[0393] (12.0 mg, 0.10 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to give 91.0 mg (75%) of 53 as an orange oil. 1 H NMR (400MHz, CDCl3): δ7.08–7.03(m,1H),6.95(dd,J=7.3,1.6Hz,1H),6.59–6.54(m,2H),3.30–3.26(m,4H),2.76 (t,J=6.4Hz,2H),1.99–1.93(m,2H),1.80–1.70(m,4H),1.52–1.46(m,2H),1.29–1.23(m,4H),1.04–0.95(m,2H). 13C NMR (101MHz, CDCl3): δ145.20,129.07,127.01,122.19,115.12,110.37,49.21 ,49.17,35.89,33.38,33.11,28.18,26.59,26.30,22.24.HRMSm / z(ESI)calcd for C 17 H 25 N[M+H] + :244.2065,found:244.2068.

[0394] 1-(3-Alkenyl-hexyl)-1,2,3,4-tetrahydroquinoline (54)

[0395] 1,2,3,4-tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), leaf alcohol (100.2 mg,

[0396] 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), NaHSO4 (12.0

[0397] mg, 0.10 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 73.5 mg (68%) of 54 as a brown solid. 1 H NMR (400MHz, CDCl3): δ7.06(t,J=7.8Hz,1H),6.94(d,J=7.3Hz,1H),6.61–6.54(m,2H),5.50–5.46(m,1H),5.40–5.34(m,1H) ),3.32–3.25(m,4H),2.76(t,J=6.4Hz,2H),2.37–2.33(m,2H),2.09–2.05(m,2H),1.97–1.94(m,2H),0.98(t,J=7.5Hz,3H). 13 CNMR (101MHz, CDCl3): δ145.00,133.57,129.14,127.05,125.73,122.22,115.3 3,110.41,51.26,49.41,28.18,24.04,22.20,20.62,14.37.HRMSm / z(ESI)calcd for C 15 H 21 N[M+H] + :216.1752,found:216.1754.

[0398] 1-(3,7-Dimethyloctyl-6-enyl-1-yl)-1,2,3,4-tetrahydroquinoline(55)

[0399] 1,2,3,4-Tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), citronellol (156.3

[0400] mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol),

[0401] NaHSO 4 (12.0 mg, 0.10 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 112.1 mg (83%) of 55 as an orange solid. 1 H NMR (400MHz, CDCl3): δ7.09–7.05(m,1H),6.96(dd,J=7.3,1.6Hz,1H),6.60–6.55(m,2H),5.17–5.13(m,1H),3.33–3.26(m,4H),2.78(t, J=6.4Hz,2H),2.06–1.96(m,4H),1.73(s,3H),1.65(s,3H),1.62–1.46(m,2H),1.45–1.40(m,2H),1.28–1.24(m,1H),1.00(d,J=6.5,3H). 13 C NMR (101MHz, CDCl3): δ145.24,131.20,129.08,127.03,124.71,122.17,115.16,110. 36,49.48,49.20,37.10,32.65,30.70,28.19,25.71,25.48,22.27,19.67,17.64.HRMS m / z(ESI)calcd for C 19 H 29 N[M+H] + :272.2378,found:272.2381.

[0402] 1-(3-(3-(Trifluoromethyl)phenyl)propyl)-1,2,3,4-tetrahydroquinoline(56)

[0403] 1,2,3,4-tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), 3-(3-(trifluoromethyl)phenyl)propan-1-ol (204.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.

[0404] 6 mg, 0.05 mmol), NaHSO4 (12.0 mg, 0.10 mmol) was dissolved in NMP

[0405] The reaction mixture was added to 5% paraformaldehyde (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 124.9 mg (78%) of 56 as a red oil. 1 H NMR (400MHz, CDCl3): δ7.52–7.50(m,2H),7.45–7.43(m,2H),7.10–7.06(m,1H),6.99(dd,J=7.3,1.6Hz, 1H),6.64–6,60(m,1H),6.54(d,J=8.2Hz,1H),3.35–3.30(m,4H),2.82–2.76(m,4H),2.02–1.98(m,4H). 13 C NMR (101MHz, CDCl3): δ145.10, 142.72, 131.72, 130.62 (q, J = 31.9Hz), 129.19, 128.74, 127.03, 125.57, 124 .93(q,J=3.8Hz),122.74(q,J=3.7Hz),122.31,115.53,110.38,50.78,49.46,33.17,28.11,27.54,22.20. 19 F NMR(376MHz,CDCl3)δ-62.56.HRMSm / z(ESI)calcd for C 19 H 20 F3N[M+H] + :320.1633,found:320.1632.

[0406] 1-(2-(1H-indol-3-yl)ethyl)-1,2,3,4-tetrahydroquinoline (57)

[0407] 1,2,3,4-Tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), tryptophan (161.2 mg,

[0408] 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), NaHSO4 (12.0

[0409] mg, 0.10 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 81.0 mg (58%) of yellow solid 57. 1H NMR (400MHz, CDCl3): δ7.85(brs,1H),7.63(d,J=7.9,1H),7.32(d,J=8.0Hz,1H),7.21–7.18(m,1H),7.15–7.06(m,2H),6.96(s,1H),6.71(d ,J=8.0Hz,1H),6.58(t,J=7.4Hz,1H),3.57(t,J=7.2Hz,2H),3.27–3.25(m,2H),3.02(t,J=7.2Hz,2H),2.75–2.73(m,2H),1.91–1.88(m,2H). 13 CNMR (101MHz, CDCl3): δ144.96,136.18,129.20,127.45,127.15,122.27,121.97,121.61,119.28 ,118.73,115.35,113.92,111.12,110.41,52.05,49.46,28.17,22.14,21.74.HRMSm / z(ESI)calcd for C 19 H 20 N2[M+H] + :277.1705,found:277.1701.

[0410] 1-(2-(3,4-Dihydroquinolin-1(2H)-yl)ethyl)imidazolidin-2-one (58)

[0411] 1,2,3,4-tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), 1-(2-hydroxyethyl)imidazoline

[0412] -2-ketone (130.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol),

[0413] NaHSO4 (12.0 mg, 0.10 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to give 79.5 mg (65%) of 58 as a colorless solid. 1H NMR (400MHz, CDCl3): δ7.07–7.03(m,1H),6.94(dd,J=7.3,1.6Hz,1H),6.66(d,J=8.2Hz,1H),6.57(t,J=7.3Hz,1H) ,5.46(brs,1H),3.51–3.43(m,4H),3.39–3.36(m,4H),3.34–3.14(m,2H),2.75(t,J=6.3Hz,2H),1.97–1.91(m,2H). 13 CNMR (101MHz, CDCl3): δ162.99,144.96,129.10,127.06,122.21,115.71,110.24,49.70,49.50,46.11,40.75,38.30,27.99,22.10.HRMS m / z(ESI)calcd for C 14 H 19 N3O[M+H] + :246.1606,found:246.1610.

[0414] 1-(2-(3,4-Dihydroquinolin-1(2H)-yl)ethyl)pyrrolidin-2-one (59)

[0415] 1,2,3,4-tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), 1-(2-hydroxyethyl)pyrrolidine

[0416] -2-ketone (129.2 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol),

[0417] NaHSO 4 (12.0 mg, 0.10 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 77.0 mg (63%) of 59 as a red oil. 1 H NMR (400MHz, CDCl3): δ7.06–7.02(m,1H),6.93(dd,J=7.4,1.6Hz,1H),6.64(dd,J=8.3,1.0Hz,1H),6.56(t,J=7.3 Hz,1H),3.46–3.40(m,6H),3.02(t,J=6.4Hz,2H),2.74(t,J=6.3Hz,2H),2.33(t,J=8.1Hz,2H),1.98–1.90(m,4H). 13CNMR (101MHz, CDCl3): δ175.07,144.82,129.11,127.03,122.19,115.76,110.1 5,49.32,48.72,48.32,39.82,30.70,27.94,22.04,18.07.HRMSm / z(ESI)calcd for C 15 H 20 N2O[M+H] + :245.1654,found:245.1657.

[0418] 1-Benzyl-1,2,3,4-tetrahydroquinoline (60)

[0419] 1,2,3,4-tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), benzyl alcohol (108.1 mg, 1.0 mmol),

[0420] HI (55% aqueous solution, 11.6 mg, 0.05 mmol) and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 120°C under N2 for 24 hours to obtain 78.4 mg

[0421] (70%) brown oil 60. 1 H NMR (400MHz, CDCl3): δ7.32–7.17(m,5H),6.98–6.94(m,2H),6.58–6.54(m,1H),6.50–6. 48(m,1H),4.46(s,2H),3.34(t,J=6.0Hz,2H),2.80(t,J=6.3Hz,2H),2.03–1.97(m,2H). 13 C NMR (101MHz, CDCl3): δ145.53,138.87,128.95,128.52,127.13,126.70,126. 54,122.19,115.82,110.95,55.15,49.83,28.18,22.33.HRMSm / z(ESI)calcd for C 16 H 17 N[M+H] + :224.1439,found:224.1437.

[0422] 1-(4-Chlorobenzyl)-1,2,3,4-tetrahydroquinoline (61)

[0423] 1,2,3,4-Tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), 4-chlorobenzyl alcohol (142.3

[0424] mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), NaHSO4

[0425] (12.0 mg, 0.10 mmol) was dissolved in NMP (1 mL) and reacted at 120° C. under N 2 for 24 h to afford 93.8 mg (73%) of 61 as a brown oil. 1 H NMR (400MHz, CDCl3): δ7.26(d,J=8.4Hz,2H),7.21–7.17(m,2H),6.98–6.94(m,2H),6.60–6.56(m,1 H),6.43(d,J=8.2Hz,1H),4.41(s,2H),3.34–3.31(m,2H),2.80(t,J=6.3Hz,2H),2.03–1.97(m,2H). 13 C NMR (101MHz, CDCl3): δ145.31,137.45,132.35,129.05,128.66,127.91,127. 14,122.31,116.10,110.88,54.67,49.92,28.11,22.35.HRMSm / z(ESI)calcd for C 16 H 17 N[M+H] + :258.1050,found:258.1051.

[0426] 1-(Pyridin-3-ylmethyl)-1,2,3,4-tetrahydroquinoline (62)

[0427] 1,2,3,4-Tetrahydroquinoline (1) (66.6 mg, 0.50 mmol), 3-pyridinemethanol (109.1 mg, 1.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted under N2 at 150°C for 24 hours to obtain 65.5 mg (58%) of brown oil 62. 1H NMR (400MHz, CDCl3): δ8.56(d,J=1.5Hz,1H),8.50(dd,J=4.9,1.5Hz,1H),7.59(d,J=7.9Hz,1H),7.26–7.22(m,1H),7.00–6.97 (m,2H),6.63–6.59(m,1H),6.49(d,J=8.0Hz,1H),4.49(s,2H),3.36(t,J=5.6Hz,2H),2.82(t,J=6.3Hz,2H),2.06–2.00(m,2H). 13 C NMR (101MHz, CDCl3): δ148.56,148.22,145.14,134.53,134.46,129.17,127.18, 123.53,122.55,116.42,110.90,52.96,49.99,28.05,22.31.HRMSm / z(ESI)calcd for C 15 H 16 N2[M+H] + :225.1392,found:225.1388.

[0428] Experimental process and related spectra of aniline dialkylation (condition C)

[0429] N,N-Dihexylaniline (63)

[0430] Aniline (46.6 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg, 4.0 mmol),

[0431] HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg,

[0432] 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 111.7 mg (85%) of 63 as a colorless oil. 1 H NMR (400MHz, CDCl3): δ7.22 (dd, J=8.6, 7.0Hz, 2H), 6.67–6.62 (m, 3H), 3.27 (t,J=7.6Hz,4H),1.61–1.58(m,4H),1.36–1.34(m,12H),0.94–0.91(m,6H). 13C NMR (101MHz, CDCl3): δ148.17,129.15,115.02,111.65,51.05,31.76,27.21,26.87,22.70,14.04.HRMSm / z(ESI)calcd for C 18 H 31 N[M+H] + :262.2535,found:262.2530.

[0433] N,N-Dihexyl-4-methylaniline (64)

[0434] p-Toluidine (53.6 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg,

[0435] 4.0mmol), HI (55% aqueous solution, 23.3mg, 0.10mmol), NaHSO4

[0436] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to obtain 122.9 mg (89%) of 64 as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.06–7.03(m,2H),6.62–6.59(m,2H),3.27–3.23(m, 4H),2.27(s,3H),1.61–1.56(m,4H),1.36–1.34(m,12H),0.95–0.91(m,6H). 13 C NMR (101MHz, CDCl3): δ146.18,129.67,124.27,112.12,51.27,31.77,27.23,26.90,22.70,20.12,14.05.HRMSm / z(ESI)calcd for C 19 H 33 N[M+H] + :276.2691,found:276.2686.

[0437] 4-(tert-Butyl)-N,N-dihexylaniline (65)

[0438] 4-tert-Butylaniline (74.6 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0439] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0440] NaHSO4 (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 h to obtain 155.2 mg (98%) of 65 as a red oil. 1 H NMR (400MHz, CDCl3): δ7.31 (d, J = 8.4Hz, 2H), 6.68 (d, J = 8.4Hz, 2H), 3.31 (t, J = 7. 7Hz,4H),1.69–1.62(m,4H),1.42–1.40(m,12H),1.37(s,9H),1.00–0.97(m,6H). 13 C NMR (101MHz, CDCl3): δ146.00,137.58,125.92,111.31,51.15,33.61,31.78,31.56,27.34,26.91,22.72,14.06.HRMSm / z(ESI)calcd for C 22 H 39 N[M+H] + :318.3161,found:318.3154.

[0441] N,N-Dihexyl-4-methoxyaniline (66)

[0442] p-Anisidine (61.6 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0443] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0444] H2SO4 (19.6 mg, 0.20 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 h to afford 142.75 mg (98%) of 66 as an orange oil. 1 H NMR (400MHz, CDCl3): δ6.87(d,J=9.1Hz,2H),6.70(d,J=9.1Hz,2H),3.80(s,3H ),3.25–3.21(m,4H),1.61–1.57(m,4H),1.39–1.35(m,12H),0.97–0.94(m,6H). 13C NMR (101MHz, CDCl3): δ150.98,143.26,114.73,114.32,55.68,51.93,31.73,27.24,26.89,22.66,13.99.HRMSm / z(ESI)calcd for C 19 H 33 NO[M+H] + :292.2640,found:292.2635.4-Benzyl-N,N-dihexylaniline (67)

[0445] 4-Benzylaniline (91.6 mg, 0.50 mmol), 1-hexanol (2

[0446] (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg,

[0447] 0.10mmol), NaHSO4 (30.0mg, 0.25mmol) was dissolved in NMP

[0448] The reaction mixture was added to 1 mL of 4% paraformaldehyde (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 156.6 mg (89%) of 67 as a yellow oil. 1 H NMR (400MHz, CDCl3): δ7.28–7.23(m,2H),7.20–7.14(m,3H),7.00(d,J=8.4Hz,2H),6.56(d,J=8.6 Hz,2H),3.86(s,2H),3.22–3.18(m,4H),1.56–1.52(m,4H),1.31–1.28(m,12H),0.90–0.87(m,6H). 13 C NMR (101MHz, CDCl3): δ146.61,142.19,129.58,128.83,128.28,127.57,125.70 ,111.84,51.17,40.86,31.75,27.24,26.87,22.70,14.05.HRMSm / z(ESI)calcd forC 25 H 37 N[M+H] + :352.3004,found:352.2996.N,N-Dihexyl-[1,1'-biphenyl]-4-amine (68)

[0449] 4-aminobiphenyl (84.6 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0450] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0451] NaHSO4 (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL).

[0452] The reaction was carried out at 150° C. under N 2 for 24 hours to obtain 157.5 mg (93%) of 68 as a brown oil. 1 H NMR (400MHz, CDCl3): δ7.65(d,J=7.5Hz,2H),7.58(d,J=8.8Hz,2H),7.47(t,J=7.7Hz,2H),7.32(t,J=7.4H z,1H),6.80(d,J=8.9Hz,2H),3.40–3.37(m,4H),1.74–1,67(m,4H),1.45–1.43(m,12H),1.03–1.00(m,6H). 13 C NMR (101MHz, CDCl3): δ147.49,141.29,128.55,127.77,127.73,126.05,125.65,111.78,51.08,31.75,27.26,26.86,22.70,14.05.HRMSm / z(ESI)calcd for C 24 H 35 N[M+H] + :338.2848,found:338.2843.

[0453] 4-Fluoro-N,N-dihexylaniline (69)

[0454] 4-Fluoroaniline (55.6 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg,

[0455] 4.0mmol), HI (55% aqueous solution, 23.3mg, 0.10mmol), NaHSO4

[0456] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to obtain 132.2 mg (95%) of 69 as a brown oil. 1H NMR (400MHz, CDCl3): δ6.94–6.89(m,2H),6.59–6.56(m,2H),3.21(t,J=7.6Hz,4H),1.59–1.51(m,4H),1.34–1.31(m,12H),0.93–0.90(m,6H). 13 C NMR (101MHz, CDCl3): δ154.69 (d, J = 233.8Hz), 145.03, 115.42 (d, J = 21.8Hz), 113.06 (d, J = 7.0Hz), 51.66, 31.74, 27.15, 26.87, 22.69, 14.03. 19 F NMR(376MHz,CDCl3)δ-130.77.HRMSm / z(ESI)calcd for C 18 H 30 FN[M+H] + :280.2441,found:280.2436.

[0457] 4-Chloro-N,N-dihexylaniline (70)

[0458] 4-Chloroaniline (63.8 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg,

[0459] 4.0mmol), HI (55% aqueous solution, 23.3mg, 0.10mmol), NaHSO4

[0460] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 136.6 mg (92%) of 70 as a brown oil. 1 H NMR (400MHz, CDCl3): δ7.14–7.12(m,2H),6.55–6.53(m,2H),3.22(t,J=7.6Hz,4H),1.57–1.53(m,4H),1.34–1.30(m,12H),0,92–0.89(m,6H). 13 C NMR (101MHz, CDCl3): δ146.75,128.87,119.73,112.79,51.19,31.71,27.07,26.81,22.67,14.03.HRMSm / z(ESI)calcd for C 18 H 30 ClN[M+H] +:296.2145,found:296.2141.

[0461] 4-Cyclohexyl-N,N-dihexylaniline (71)

[0462] 4-Cyclohexylaniline (87.6 mg, 0.50 mmol), 1-hexanol (2

[0463] (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10

[0464] mmol), NaHSO4 (30.0 mg, 0.25 mmol) were dissolved in NMP (1

[0465] The mixture was added to 4% paraformaldehyde (5% paraformaldehyde) and reacted at 150° C. under N 2 for 24 hours to obtain 143.9 mg (84%) of orange oil 71. 1 H NMR (400MHz, CDCl3): δ7.17(d,J=8.4Hz,2H),6.71(d,J=8.5Hz,2H),3.34(t,J=7.7Hz,4H),2.53–2.48(m, 1H),2.00–1.93(m,4H),1.85(d,J=12.6Hz,1H),1.71–1.67(m,4H),1.53–1.44(m,17H),1.05–1.01(m,6H). 13 C NMR (101MHz, CDCl3): δ146.58,134.95,127.49,111.83,51.34,43.54,34.93,31.93,27.48,27.22,27.06,26.43,22.87,14.19.HRMSm / z(ESI)calcd for C 24 H 41 N[M+H] + :344.3317,found:344.3309.1-(4-(Dihexylamino)phenyl)-1-ethanone (72)

[0466] 1-(4-aminophenyl)ethan-1-one (67.6 mg, 0.50 mmol), 1-hexanol

[0467] (2) (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg,

[0468] 0.10mmol), NaHSO4 (30.0mg, 0.25mmol) was dissolved in NMP

[0469] (1 mL) was reacted at 150 ° C under N2 for 24 hours to obtain

[0470] 73.1 mg (48%) of 72 as a green oil. 1 H NMR(400MHz, CDCl3): δ7.84–7.82(m,2H),

[0471] 6.58–6.56(m,2H),3.33–3.28(m,4H),2.47(s,3H),1.61–1.57(m,4H),1.35–1.31(m,

[0472] 12H), 0.91–0.88 (m, 6H). 13 C NMR (101MHz, CDCl3): δ195.87,151.43,130.66,124.45,

[0473] 110.09,50.92,31.57,27.06,26.64,25.76,22.56,13.93.HRMSm / z(ESI)calcdfor C 20 H 33 NO

[0474] [M+H] + :304.2640,found:304.2633.

[0475] N,N-Dihexyl-4-(1H-pyrrol-1-yl)aniline (73)

[0476] 4-(1H-pyrrol-1-yl)aniline (79.1 mg, 0.50 mmol), 1-hexanol

[0477] (2) (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg,

[0478] 0.10mmol), NaHSO4 (30.0mg, 0.25mmol) was dissolved in NMP

[0479] The reaction was continued in 1 mL of 4% paraformaldehyde at 150° C. under N 2 for 24 h to afford 141.1 mg (86%) of 73 as a brown oil. 1H NMR (400MHz, CDCl3): δ7.21(d,J=8.8Hz,2H),6.95(s,2H),6.64(d,J=8.7Hz,2H),6.28( s,2H),3.25(t,J=7.7Hz,4H),1.60–1.56(m,4H),1.33–1.32(m,12H),0.92–0.89(m,6H). 13 CNMR (101MHz, CDCl3): δ146.57,130.02,122.53,119.79,112.03,109.05,51.26,31.73,27.19,26.85,22.68,14.03.HRMSm / z(ESI)calcd for C 22 H 34 N2[M+H] + :327.2800,found:327.2798.

[0480] N-(3-(Dihexylamino)phenyl)acetamide (74)

[0481] N-(3-aminophenyl)acetamide (75.1 mg, 0.50 mmol),

[0482] 1-Hexanol (2) (408.7 mg, 4.0 mmol), HI (55% aqueous solution,

[0483] 23.3mg, 0.10mmol), NaHSO4 (30.0mg, 0.25mmol)

[0484] The product was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to obtain 126.2 mg (79%) of green solid 74. 1 HNMR (400MHz, CDCl3): δ7.13–7.09(m,2H),6.98(s,1H),6.61(d,J=7.8Hz,1H),6.38(d,J=8.4Hz,1 H),3.24(t,J=7.6Hz,4H),2.15(s,3H),1.59–1.55(m,4H),1.32–1.31(m,12H),0.91–0.88(m,6H). 13 C NMR (101MHz, CDCl3): δ168.09,148.83,138.96,129.45,107.87,106.59,103.24,51.12,31.73,27.20,26.85,24.79,22.68,14.04.HRMSm / z(ESI)calcd forC20 H 34 N2O[M+H] + :319.2749,found:319.2742.3-Fluoro-N,N-dihexylaniline (75)

[0485] 3-Fluoroaniline (55.6 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg,

[0486] 4.0mmol), HI (55% aqueous solution, 23.3mg, 0.10mmol), NaHSO4

[0487] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 135.4 mg (97%) of 75 as a yellow oil. 1 HNMR(400MHz, CDCl3): δ7.15–7.09(m,1H),6.39(dd,J=8.5,2.2Hz,1H),6.33–6.29(m, 2H), 3.24 (t, J = 7.6Hz, 4H), 1.62–1.55 (m, 4H), 1.35–1.32 (m, 12H), 0.94–0.91 (m, 6H). 13 CNMR (101MHz, CDCl3): δ164.37 (d, J = 240.8Hz), 149.92 (d, J = 10.7Hz), 130.04 (d, J = 10.5Hz), 107.17 (d,J=2.0Hz),101.37(d,J=21.8Hz),98.38(d,J=26.1Hz),51.12,31.71,27.12,26.80,22.68,14.02. 19 F NMR(376MHz,CDCl3)δ-112.82.HRMSm / z(ESI)calcd for C 18 H 30 FN[M+H] + :280.2441,found:280.2443.

[0488] 3-Chloro-N,N-dihexylaniline (76)

[0489] 3-Chloroaniline (63.8 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg,

[0490] 4.0mmol), HI (55% aqueous solution, 23.3mg, 0.10mmol), NaHSO4

[0491] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 130.9 mg (88%) of 76 as a yellow oil. 1 HNMR (400MHz, CDCl3): δ7.11–7.07(m,1H),6.59–6.58(m,2H),6.50(dd,J=8.5,2.4Hz, 1H), 3.24 (t, J = 7.6Hz, 4H), 1.61–1.54 (m, 4H), 1.34–1.32 (m, 12H), 0.94–0.91 (m, 6H). 13 CNMR (101MHz, CDCl3): δ149.22,135.10,130.00,114.80,111.35,109.72,51.01,31.69,27.06,26.78,22.67,14.02.HRMSm / z(ESI)calcd for C 18 H 30 ClN[M+H] + :296.2145,found:296.2145.2-Fluoro-N,N-dihexylaniline (77)

[0492] 2-Fluoroaniline (55.6 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg,

[0493] 4.0mmol), HI (55% aqueous solution, 23.3mg, 0.10mmol), NaHSO4

[0494] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 122.5 mg (88%) of 77 as a colorless oil. 1 HNMR (400MHz, CDCl3): δ7.03–6.90(m,3H),6.86–6.82(m,1H),3.14(t,J=7.6Hz,4H),1.52–1.49(m,4H),1.31–1,30(m,12H),0.90–0.89(m,6H). 13C NMR (101MHz, CDCl3): δ155.92 (d, J = 244.7Hz), 138.69 (d, J = 8.6Hz), 123.92 (d, J = 3.3Hz), 120.80 (d, J = 3. 9Hz), 120.68 (d, J = 7.9Hz), 116.25 (d, J = 21.5Hz), 52.78 (d, J = 3.4Hz), 31.72, 27.40, 26.85, 22.65, 14.01. 19 F NMR(376MHz,CDCl3)δ-122.47.HRMSm / z(ESI)calcdfor C 18 H 30 FN[M+H] + :280.2441,found:280.2445.

[0495] N,N-Dihexyl-3,5-dimethoxyaniline (78)

[0496] 3,5-Dimethoxyaniline (76.6 mg, 0.50 mmol), 1-hexanol (2

[0497] (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10

[0498] mmol), H2SO4 (19.6 mg, 0.20 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 118.9 mg (74%) of 78 as a brown oil. 1 H NMR (400MHz, CDCl3): δ5.84 (s, 3H), 3.78 (s, 6H), 3.22 (t, J = 7.4Hz, 4H), 1.62–1.55 (m, 4H), 1.34–1.30 (m, 12H), 0.92–0.89 (m, 6H). 13 C NMR (101MHz, CDCl3): δ161.67,149.97,91.10,87.14,55.05,51.19,31.71,27.29,26.84,22.66,14.01.HRMSm / z(ESI)calcd for C 20 H 35 NO2[M+H] + :322.2746,found:322.2743.

[0499] N,N-Dihexyl-3,4-dimethoxyaniline (79)

[0500] 3,4-dimethoxyaniline (76.6 mg, 0.50 mmol), 1-hexanol (2

[0501] (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10

[0502] mmol), H2SO4 (19.6 mg, 0.20 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 131.9 mg (82%) of red oil 79. 1 H NMR (400MHz, CDCl3): δ6.79(d,J=8.8Hz,1H),6.33(d,J=2.8Hz,1H),6.21(dd,J=8.8,2.8Hz,1H),3.86 (s,3H),3.81(s,3H),3.19(t,J=7.6Hz,4H),1.58–1.53(m,4H),1.33–1.31(m,12H),0.92–0.89(m,6H). 13 C NMR (101MHz, CDCl3): δ149.80,143.90,140.41,113.42,104.42,99.02,56.66,55.62,51.78,31.64,27.19,26.82,22.56,13.91.HRMSm / z(ESI)calcd for C 20 H 35 NO2[M+H] + :322.2746,found:322.2739.

[0503] N,N-Dihexyl-2,6-diisopropylaniline (80)

[0504] 2,6-diisopropylaniline (88.6 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0505] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0506] H2SO4 (19.6 mg, 0.20 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 36 hours to obtain 121.0 mg (70%) of 80 as an orange oil. 1H NMR (400MHz, CDCl3): δ7.20(dd,J=8.5,6.6Hz,1H),7.13(d,J=7.5Hz,2H),3.60–3.53(m,2H),3.03( t,J=8.0Hz,4H),1.52–1.48(m,4H),1.31–1.29(m,12H),1.24(d,J=6.9Hz,12H),0.93–0.90(m,6H). 13 C NMR (101MHz, CDCl3): δ149.33,146.37,125.95,123.94,56.58,31.90,30.34,27.77,27.14,24.58,22.73,14.06.HRMSm / z(ESI)calcd for C 24 H 43 N[M+H] + :346.3474,found:346.3468.

[0507] N,N-Dihexyl-2,4,6-trimethylaniline (81)

[0508] 2,4,6-trimethylaniline (67.6 mg, 0.50 mmol), 1-hexanol (2

[0509] (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10

[0510] mmol), NaHSO4 (30.0 mg, 0.25 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 146.5 mg (97%) of brown oil 81. 1 H NMR (400MHz, CDCl3): δ6.84(s,2H),3.01–2.97(m,4H),2.28(s,6H),2.27(s,3H),1.46–1.40(m,4H),1.31–1.25(m,12H),0.91–0.88(m,6H). 13 CNMR (101MHz, CDCl3): δ146.06,137.66,133.96,129.39,54.54,31.88,29.75,27.15,22.74,20.71,19.49,14.06.HRMSm / z(ESI)calcd for C 21 H 37 N[M+H] +:304.3004,found:304.2998.2,4,6-Trifluoro-N,N-dihexylaniline (82)

[0511] 2,4,6-trifluoroaniline (73.6 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0512] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0513] H2SO4 (19.6 mg, 0.20 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 h to afford 113.1 mg (72%) of 82 as a colorless oil. 1 H NMR (400MHz, CDCl3): δ6.61(t,J=8.7Hz,2H), 3.00(t,J=7.3Hz,4H), 1.36–1.34(m,4H), 1.29–1.22(m,12H), 0.87–0.84(m,6H). 13 C NMR (101MHz, CDCl3): δ162.59–162.35(m), 160.11–159.86(m), 157.71–157.41(m), 123. 58–123,29(m),100.62–100.07(m),54.29–54.25(m),31.72,28.23,26.68,22.62,14.00. 19 F NMR(376MHz, CDCl3)δ-113.89(t,J=4.3Hz),-114.64(d,J=4.1Hz).HRMSm / z(ESI)calcd for C 18 H 28 F3N[M+H] + :316.2252,found:316.2249.

[0514] N,N-Dihexyl-3,4-dimethyl-5-nitroaniline (83)

[0515] 3,4-dimethyl-5-nitroaniline (83.1 mg, 0.50 mmol), 1-hexanol

[0516] (2) (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg,

[0517] 0.10mmol), NaHSO4 (30.0mg, 0.25mmol) were dissolved in NMP (1

[0518] The reaction was carried out in 4% paraformaldehyde (5% paraformaldehyde) in 4% paraformaldehyde (mL) at 150° C. under N 2 for 24 h to afford 113.8 mg (68%) of 83 as an orange oil. 1 H NMR (400MHz, CDCl3): δ6.83(d,J=2.8Hz,1H),6.64(d,J=2.8Hz,1H),3.24(t,J=7.6Hz,4 H),2.30(s,3H),2.23(s,3H),1.59–1.52(m,4H),1.33–1.31(m,12H),0.92–0.89(m,6H). 13 C NMR (101MHz, CDCl3): δ151.97,145.99,139.50,117.03,116.20,104.32,50.87,31.61,26.99,26.70,22.60,21.16,14.01,13.96.HRMSm / z(ESI)calcd for C 20 H 34 N2O2[M+H] + :335.2699,found:335.2692.

[0519] N,N-Dihexylnaphthalene-2-amine (84)

[0520] 2-naphthylamine (71.6 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg,

[0521] 4.0mmol), HI (55% aqueous solution, 23.3mg, 0.10mmol), NaHSO4

[0522] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 141.1 mg (91%) of 84 as a brown oil. 1H NMR (400MHz, CDCl3): δ7.62(dd,J=8.7,4.0Hz,2H),7.58(d,J=8.3Hz,1H),7.30(t,J=7.5Hz,1H),7.12(dd,J=8.2,6.7Hz,1H),7.0 3(dd,J=9.1,2.6Hz,1H),6.80(d,J=2.5Hz,1H),3.32(t,J=7.4Hz,4H),1.62–1.58(m,4H),1.35–1.29(m,12H),0.91–0.88(m,6H). 13 C NMR (101MHz, CDCl3): δ146.29,135.43,128.86,127.49,126.28,126.18,125.99,121 .48,116.01,105.39,51.35,31.91,27.47,27.04,22.86,14.21.HRMSm / z(ESI)calcd for C 22 H 33 N[M+H] + :312.2691,found:312.2683.

[0523] N,N-Dihexyl-5,6,7,8-tetrahydronaphthalene-1-amine (85)

[0524] 5,6,7,8-tetrahydronaphthalene-1-amine (73.6 mg, 0.50 mmol), 1-hexanol (2

[0525] (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0526] H2SO4 (19.6 mg, 0.20 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 36 hours to afford 126.5 mg (80%) of 85 as a colorless oil. 1 H NMR (400MHz, CDCl3): δ7.08(t,J=7.7Hz,1H),6.95(d,J=7.8Hz,1H),6.84(d,J=7.5Hz,1H),2.89(t,J=7.4 Hz,4H),2.83–2.74(m,4H),1.81–1.77(m,4H),1.46–1.42(m,4H),1.31–1.25(m,12H),0.91–0.87(m,6H). 13C NMR (101MHz, CDCl3): δ150.43,138.04,134.64,125.06,124.25,119.29,54.03,31 .76,29.85,27.28,27.06,25.39,23.32,23.10,22.70,14.05.HRMSm / z(ESI)calcd for C 22 H 37 N[M+H] + :316.3004,found:316.2996.

[0527] 9-Ethyl-N,N-dihexyl-9H-carbazol-3-amine (86)

[0528] 9-Ethyl-9H-carbazole-3-amine (105.1 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3

[0529] mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25 mmol) was dissolved in

[0530] The reaction mixture was added to NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 179.5 mg (95%) of 86 as a brown oil. 1 HNMR (400MHz, CDCl3): δ8.03(d,J=7.7Hz,1H),7.46(s,1H),7.38(t,J=7.7Hz,1H),7.29(d,J=8.2Hz,1H),7.24(d,J=8.8Hz,1H),7.16–7. 12(m,1H),7.02(d,J=8.8Hz,1H),4.24(q,J=7.2Hz,2H),3.26(t,J=6.8Hz,4H),1.60–1.56(m,4H),1.37–1.30(m,15H),0.90–0.87(m,6H). 13 C NMR (101MHz, CDCl3): δ142.95,140.29,133.67,125.11,123.49,122.80,120.15,117.78,115.89,10 8.75,108.19,106.13,53.05,37.39,31.75,27.30,27.01,22.66,14.02,13.81.HRMSm / z(ESI)calcd for C 26 H 38 N2[M+H] +:379.3113,found:379.3105.

[0531] 7-(Dihexylamino)-4-methyl-2H-benzopyran-2-one (87)

[0532] 7-amino-4-methyl-2H-benzopyran-2-one (87.6 mg, 0.50

[0533] mmol), 1-hexanol (2) (408.7 mg, 4.0 mmol), HI (55%

[0534] Aqueous solution, 23.3mg, 0.10mmol), H2SO4 (19.6mg, 0.20

[0535] mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 36 h to afford 120.5 mg (70%) of 87 as a brown oil. 1 H NMR (400MHz, CDCl3): δ7.35 (d, J=8.9Hz, 1H), 6.53 (dd, J=9.0, 2.5Hz, 1H), 6.44 (d, J=2.5Hz, 1H), 5.91 (s,1H),3.29(t,J=7.6Hz,4H),2.31(s,3H),1.60–1.57(m,4H),1.32–1.31(m,12H),0.91–0.88(m,6H). 13 C NMR (101MHz, CDCl3): δ162.17,155.92,152.81,150.87,125.33,108.90,108.53,10 8.41,97.63,51.17,31.60,27.07,26.66,22.59,18.34,13.96.HRMSm / z(ESI)calcd for C 22 H 33 NO2[M+H] + :344.2590,found:344.2586.

[0536] 2-Hexyl-Lenalidomide (88)

[0537] Lenalidomide (129.6mg, 0.50mmol), 1-hexanol (2) (408.7

[0538] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10

[0539] mmol), H2SO4 (19.6 mg, 0.20 mmol) were dissolved in NMP (1

[0540] mL) was reacted at 150 ° C for 36 hours to obtain 109.3 mg

[0541] (51%) brown solid 88. 1 H NMR (400MHz, CDCl3): δ8.73 (s, 1H), 7.42 (d, J = 7.4Hz, 1H), 7.35 (t, J = 7.7Hz, 1H) ,7.05(d,J=7.9Hz,1H),5.23(dd,J=13.2,5.1Hz,1H),4.43(d,J=15.9Hz,1H),4. 25(d,J=15.9Hz,1H),3.10(t,J=7.4Hz,4H),2.88–2.83(m,2H),2.38–2.33(m,1H ),2.21–2.17(m,1H),1.46–1.43(m,4H),1.26–1.23(m,12H),0.86–0.83(m,6H). 13 CNMR (101MHz, CDCl3): δ171.60,169.79,169.60,146.32,132.79,132.76,129.00,121.92,116. 10,52.46,51.67,47.03,31.56,31.49,27.35,26.71,23.38,22.54,13.95.HRMSm / z(ESI)calcd for C 25 H 37 N3O3[M+H] + :428.2913,found:428.2909.

[0542] 2-Hexyl-aminoglutethimide (89)

[0543] Aminoglutethimide (116.1 mg, 0.50 mmol), 1-hexanol (2

[0544] (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg,

[0545] 0.10mmol), NaHSO4 (30.0mg, 0.25mmol) were dissolved in

[0546] The reaction mixture was added to NMP (1 mL) and reacted at 150° C. under N 2 for 24 hours to obtain 189.7 mg (95%) of 89 as a yellow solid. 1H NMR (400MHz, CDCl3): δ7.89(s,1H),7.06(d,J=8.6Hz,2H),6.58(d,J=8.6Hz,2H),3.22(t,J=7.4Hz,4H),2.56–2.50(m,2H),2.31– 2.30(m,1H),2.16–2.15(m,1H),2.02–1.98(m,1H),1.90–1.86(m,1H),1.57–1.53(m,4H),1.32–1.31(m,12H),0.91–0.84(m,9H). 13 C NMR (101MHz, CDCl3): δ175.79,172.87,147.22,126.94,124.12,111.58,50.92,49.93,32.91,31.66,29.38,27.12,26.77,22.63,13.99,8.98.HRMS m / z(ESI)calcd for C 25 H 40 N2O2[M+H] + :401.3168,found:401.3162.

[0547] 2-Methyl-aminoglutethimide (90)

[0548] Aminoglutethimide (116.1 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol),

[0549] HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25

[0550] mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to obtain 91.4 mg (70%) of yellow solid 90. 1 H NMR (400MHz, CDCl3): δ7.97(brs,1H),7.13–7.10(m,2H),6.71–6.69(m,2H),2.94(s,6H),2.60–2.54(m,1H),2.51 –2.42(m,1H),2.36–2.31(m,1H),2.21–2.13(m,1H),2.04–1.98(m,1H),1.92–1.86(m,1H),0.86(t,J=7.4Hz,3H). 13C NMR (101MHz, CDCl3): δ175.77,172.85,149.52,126.81,125.84,112.61,49.97,40.32,32.85,29.28,26.84,8.92.HRMSm / z(ESI)calcd for C 15 H 20 N2O2[M+H] + :261.1614,found:261.1608.

[0551] 2-Ethyl-aminoglutethimide (91)

[0552] Aminoglutethimide (116.1 mg, 0.50 mmol), ethanol (460.7 mg, 10.0 mmol),

[0553] HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25

[0554] mmol) was dissolved in NMP (1 mL) and reacted at 150 ° C under N2 for 24 hours.

[0555] This gave 117.2 mg (81%) of 91 as a white solid. 1 H NMR (400MHz, CDCl3): δ8.51(brs,1H),7.08(d,J=8.9Hz,2H),6.62(d,J=8.9Hz,2H),3.32(q,J=7.1Hz,4H),2.56–2.49(m,2H ),2.33–2.29(m,1H),2.19–2.14(m,1H),2.02–1.98(m,1H),1.90–1.85(m,1H),1.14(t,J=7.0Hz,6H),0.85(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3): δ175.85,172.97,146.78,126.98,124.43,111.66,49.86,44.08,32.85,29.30,26.74,12.45,8.91.HRMSm / z(ESI)calcd forC 17 H 24 N2O2[M+H] + :289.1916,found:289.1920.

[0556] 2-Benzyl-aminoglutethimide (92)

[0557] Aminoglutethimide (116.1 mg, 0.50 mmol), benzyl alcohol (432.6 mg, 4.0 mmol),

[0558] HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25

[0559] mmol) was dissolved in NMP (1 mL) and reacted at 150 ° C under N2 for 24 hours.

[0560] This gave 168.5 mg (82%) of 92 as a colorless solid. 1 H NMR (400 MHz, CDCl3): δ

[0561] 8.25(s,1H),7.33–7.30(m,4H),7.26–7.21(m,6H),7.02(d,J=8.9Hz,2H),6.68(d,J=8.9Hz,2H),4.62(s,4H),2.5 3–2.45(m,2H),2.28–2.23(m,1H),2.16–2.11(m,1H),2.03–1.97(m,1H),1.87–1.81(m,1H),0.83(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3): δ175.59,172.82,148.26,138.24,128.61,126.95,126.90,12 6.53,126.04,112.50,54.12,50.00,32.85,29.33,26.73,8.98.HRMSm / z(ESI)calcd for C 27 H 28 N2O2[M+H] + :413.2229,found:413.2233.

[0562] N-Hexyl-2-trifluoromethylaniline (93)

[0563] 2-(Trifluoromethyl)aniline (80.6 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0564] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4

[0565] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 79.5 mg (65%) of 93 as a green oil. 1 HNMR (400MHz, CDCl3): δ7.45(d,J=7.8Hz,1H),7.37(t,J=7.8Hz,1H),6.75–6.69(m,2H),4 .32(brs,1H),3.20–3.15(m,2H),1.70–1.66(m,2H),1.46–1.34(m,6H),0.95–0.92(m,3H). 13 C NMR (101MHz, CDCl3): δ145.85, 133.02, 126.54 (q, J = 5.6Hz), 125.30 (d, J = 273Hz), 115.47,113.09(d,J=29.0Hz),111.69,43.57,31.54,29.10,26.69,22.58,13.96. 19 F NMR(376MHz,CDCl3)δ-62.57.HRMSm / z(ESI)calcd forC 13 H 18 F3N[M+H] + :246.1470,found:246.1467.

[0566] N-Hexyl-2-trifluoromethoxyaniline (94)

[0567] 2-(Trifluoromethoxy)aniline (88.6 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0568] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4

[0569] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 106.2 mg (81%) of 94 as an orange oil. 1 H NMR (400MHz, CDCl3): δ7.17–7.12(m,2H),6.73(dd,J=8.1,1.4Hz,1H),6.67–6.62(m,1H),4 .06(brs,1H),3.18–3.13(m,2H),1.70–1.62(m,2H),1.43–1.33(m,6H),0.94–0.81(m,3H). 13C NMR (101MHz, CDCl3): δ140.92, 136.10, 127.67, 120.96 (q, J=258.6Hz), 120.84, 115.89, 111.87, 43.45, 31.58, 29.29, 26.70, 22.59, 13.96. 19 FNMR(376MHz,CDCl3)δ-57.69.HRMSm / z(ESI)calcd for C 13 H 18 F3NO[M+H] + :262.1419,found:262.1420.

[0570] N-Hexyl-4-nitroaniline (95)

[0571] 4-Nitroaniline (69.1 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0572] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0573] NaHSO4 (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 87.3 mg (79%) of 95 as a yellow solid. 1 H NMR (400MHz, CDCl3): δ8.05(d,J=9.2Hz,2H),6.50(d,J=9.2Hz,2H),4.66(brs,1 H),3.21–3.16(m,2H),1.67–1.60(m,2H),1.41–1.29(m,6H),0.90–0.87(m,3H). 13 C NMR (101MHz, CDCl3): δ153.54,137.47,126.37,110.80,43.34,31.41,28.96,26.58,22.48,13.91.HRMSm / z(ESI)calcd for C 12 H 18 N2O2[M+H] + :223.1447,found:223.1443.

[0574] N-Hexyl-3,5-bis(trifluoromethyl)aniline (96)

[0575] 3,5-bis(trifluoromethyl)aniline (114.6 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg,

[0576] 0.10mmol), NaHSO4 (30.0mg, 0.25mmol) were dissolved in NMP (1

[0577] The reaction was carried out in 5% paraformaldehyde (5% paraformaldehyde) in 4% paraformaldehyde (mL) and the reaction was carried out at 150° C. under N 2 for 24 h to afford 105.6 mg (67%) of 96 as a blue oil. 1 HNMR (400MHz, CDCl3): δ7.13(s,1H),6.92(s,2H),4.05(brs,1H),3.15(q,J=6.8Hz,2H),1.68–1.61(m,2H),1.45–1.32(m,6H),0.93–0.90(m,3H). 13 C NMR (101MHz, CDCl3): δ148.97, 132.36 (q, J = 32.6Hz), 123.64 (q, J = 272.5Hz), 111 .61(d,J=4.0Hz),109.84–109.68(m),43.64,31.52,29.10,26.70,22.58,13.95. 19 F NMR(376MHz,CDCl3)δ-63.27.HRMSm / z(ESI)calcd for C 14 H 17 F6N[M+H] + :314.1343,found:314.1343.

[0578] 2,4-Dichloro-N-hexylaniline (97)

[0579] 2,4-dichloroaniline (81.0 mg, 0.50 mmol), 1-hexanol (2) (408.7

[0580] mg, 4.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0581] NaHSO4 (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 100.5 mg (82%) of 97 as a brown solid. 1H NMR (400MHz, CDCl3): δ7.26–7.23(m,1H),709(dd,J=8.8,2.3Hz,1H),6.55(d,J=8.7Hz,1H),4 .22(brs,1H),3.12(t,J=7.2Hz,2H),1.68–1.61(m,2H),1.43–1.31(m,6H),0.92–0.89(m,3H). 13 C NMR (101MHz, CDCl3): δ142.95,128.60,127.69,120.65,119.11,111.56,43.77,31.56,29.16,26.74,22.58,14.01.HRMSm / z(ESI)calcd for C 12 H 17 Cl2N[M+H] + :246.0816,found:246.0812.

[0582] 2,3-Dichloro-N-hexylaniline (98)

[0583] 2,3-Dichloroaniline (81.0 mg, 0.50 mmol), 1-hexanol (2) (408.7 mg,

[0584] 4.0mmol), HI (55% aqueous solution, 23.3mg, 0.10mmol), NaHSO4

[0585] (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 93.9 mg (76%) of 98 as a brown oil. 1 HNMR (400MHz, CDCl3): δ7.05 (t, J=8.1Hz, 1H), 6.77 (dd, J=8.0, 1.3Hz, 1H), 6.54 (dd, J=8.3, 1.3Hz, 1H), 4.42 (brs, 1H), 3.15 (t, J = 7.2Hz, 2H), 1.70–1.63 (m, 2H), 1.44–1.32 (m, 6H), 0.93–0.90 (m, 3H). 13 C NMR (101MHz, CDCl3): δ145.65,132.77,127.66,117.44,116.85,108.85,43.85,31.55,29.17,26.74,22.58,14.00.HRMSm / z(ESI)calcd for C 12 H 17Cl2N[M+H] + :246.0816,found:246.0820.

[0586] Synthetic Applications

[0587] Gram-scale synthesis experimental process

[0588]

[0589] HI: 1,2,3,4-Tetrahydroquinoline (1) (1.33 g, 10.0 mmol), 1-hexanol (2) (2.04 g, 20.0 mmol), HI (55% aqueous solution, 0.47 g, 2.0 mmol), and NaHSO4 (0.24 g, 2.0 mmol) were dissolved in NMP (15 mL) and reacted at 150°C under N2 for 36 h to obtain 1.69 g (78%) of 3 as an orange oil. KI: 1,2,3,4-Tetrahydroquinoline (1) (1.33 g, 10.0 mmol), 1-hexanol (2) (2.04 g, 20.0 mmol), KI (0.33 g, 2.0 mmol), and NaHSO4 (0.48 g, 4.0 mmol) were dissolved in NMP (15 mL) and reacted at 150°C under N2 for 36 hours to obtain 1.65 g (76%) of orange oil 3.

[0590] Cascade reaction to construct nitrogen heterocycles:

[0591] Diol cyclization (condition D)

[0592] 1-Phenylpiperidine(99)

[0593] Aniline (46.6 mg, 0.50 mmol), 1,5-pentanediol (208.3 mg, 2.0 mmol), HI (55%

[0594] aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25 mmol) dissolved in NMP

[0595] The reaction was carried out at 150°C for 36 hours to obtain 58.3 mg (72%) of brown solid 99.

[0596] 1 H NMR (400MHz, CDCl3): δ7.26–7.22(m,2H),6.93(d,J=8.1Hz,2H),6.81(t,J=7.3Hz,1H),3.14(t,J=5.2Hz,4H),1.73–1.68(m,4H),1.59–1.55(m,2H).13 CNMR(101MHz, CDCl3): δ152.29,129.02,119.20,116.56,50.72,25.91,24.36.HRMSm / z(ESI)calcd forC 11 H 15 N[M+H] + :162.1283,found:162.1285.

[0597] 1-(4-Chlorophenyl)piperidine(100)

[0598] 4-Chloroaniline (63.8 mg, 0.50 mmol), 1,5-pentanediol (208.3 mg, 2.0 mmol),

[0599] HI (55% aqueous solution, 23.3 mg, 0.10 mmol) and NaHSO4 (30.0 mg, 0.25 mmol) were dissolved in NMP (2 mL) and reacted at 150°C under N2 for 36 hours to obtain 57.4 mg (59%) of brown solid 100. 1 H NMR (400MHz, CDCl3): δ7.19–7.17(m,2H),6.86–6.83(m,2H),3.12(t,J=5.6Hz,4H),1.73–1.67(m,4H),1.60–1.56(m,2H). 13 C NMR (101MHz, CDCl3): δ150.78,128.79,123.83,117.60,50.62,25.69,24.15.HRMSm / z(ESI)calcd for C 11 H 14 ClN[M+H] + :196.0893,found:196.0897.

[0600] 1-(4-(tert-Butyl)phenyl)piperidine(101)

[0601] 4-tert-Butylaniline (74.6 mg, 0.50 mmol), 1,5-pentanediol (208.3 mg, 2.0

[0602] mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg,

[0603] 0.25 mmol) was dissolved in NMP (2 mL) and reacted at 150° C. under N 2 for 36 h to obtain 63.3 mg (58%) of brown solid 101. 1 H NMR (400MHz, CDCl3): δ7.28–7.25(m,2H),6.90–6.87(m,2H),3.12–3.10(m,4H),1.71–1.69(m,4H),1.57–1.55(m,2H),1.29(s,9H). 13 C NMR (101MHz, CDCl3): δ149.94,141.85,125.72,116.21,50.87,33.88,31.45,25.97,24.29.HRMSm / z(ESI)calcd forC 15 H 23 N[M+H] + :218.1909,found:218.1912.

[0604] 1-(4-(1H-pyrrol-1-yl)phenyl)piperidine(102)

[0605] 4-(1H-pyrrol-1-yl)aniline (79.1 mg, 0.50 mmol), 1,5-pentanediol (208.3

[0606] mg, 2.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4

[0607] (30.0 mg, 0.25 mmol) was dissolved in NMP (2 mL) and reacted at 150° C. under N 2 for 36 h to obtain 73.9 mg (65%) of 102 as a brown solid. 1 H NMR (400MHz, CDCl3): δ7.25(d,J=8.7Hz,2H),7.00–6.98(m,2H),6.95(d,J=8.6Hz,2 H),6.30–6.29(m,2H),3.14(t,J=5.6Hz,4H),1.74–1.70(m,4H),1.60–1.56(m,2H). 13 C NMR (101MHz, CDCl3): δ150.33,133.07,121.69,119.52,117.12,109.51,50.79,25.77,24.17.HRMSm / z(ESI)calcd for C 15 H 18 N2[M+H] +:227.1548,found:227.1549.

[0608] N-(3-(Piperidin-1-yl)phenyl)acetamide (103)

[0609] N-(3-aminophenyl)acetamide (75.1 mg, 0.50 mmol), 1,5-pentanediol (208.3

[0610] mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), NaHSO4

[0611] (60.0 mg, 0.50 mmol) was dissolved in NMP (2 mL) and reacted at 150° C. under N 2 for 48 h to obtain 49.2 mg (45%) of 103 as a gray solid. 1 H NMR (400MHz, CDCl3): δ7.35(brs,1H),7.24(s,1H),7.15(t,J=8.1Hz,1H),6.85–6.82(m,1H), 6.69–6.63(m,1H),3.15(t,J=5.4Hz,4H),2.14(s,3H),1.69–1.66(m,4H),1.59–1.54(m,2H). 13 C NMR (101MHz, CDCl3): δ168.29,152.75,138.72,129.28,112.38,110.42,107.87,50.38,25.70,24.67,24.27.HRMSm / z(ESI)calcd forC 13 H 18 N2O[M+H] + :219.1497,found:219.1501.

[0612] 1-(Naphthyl-2-yl)piperidine(104)

[0613] 2-naphthylamine (71.6 mg, 0.50 mmol), 1,5-pentanediol (208.3 mg, 2.0 mmol),

[0614] HI (55% aqueous solution, 23.3 mg, 0.10 mmol) and NaHSO4 (30.0 mg, 0.25 mmol) were dissolved in NMP (2 mL) and reacted at 150°C for 36 hours to obtain 65.4 mg (62%) of brown solid 104. 1H NMR (400MHz, CDCl3): δ7.77–7.73(m,3H),7.46–7.42(m,1H),7.33–7.26(m,2H),7 .18(d,J=2.4Hz,1H),3.30(t,J=5.6Hz,4H),1.84–1.79(m,4H),1.69–1.64(m,2H). 13 C NMR (101MHz, CDCl3): δ150.03,134.65,128.42,128.25,127.32,126.60,126.03,123.03,120.14,110.29,50.95,25.84,24.31.HRMSm / z(ESI)calcd for C 15 H 17 N[M+H] + :212.1439,found:212.1442.

[0615] 9-Ethyl-2-(piperidin-1-yl)-9H-carbazole (105)

[0616] 9-ethyl-9H-carbazole-2-amine (105.1 mg, 0.50 mmol), 1,5-pentanediol (208.3

[0617] mg, 2.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol), NaHSO4

[0618] (60.0 mg, 0.50 mmol) was dissolved in NMP (2 mL) and reacted at 150° C. under N 2 for 48 h to afford 100.5 mg (72%) of 105 as an orange solid. 1 H NMR (400MHz, CDCl3): δ8.04(d,J=7.7Hz,1H),7.70(d,J=2.2Hz,1H),7.40(t,J=7.6Hz,1H),7.31(d,J=8.1Hz,1H),7.27–7.21(m,2H ),7.16(t,J=7.4Hz,1H),4.25(q,J=7.2Hz,2H),3.15(t,J=5.4Hz,4H),1.82–1.77(m,4H),1.59–1.56(m,2H),1.35(t,J=7.2Hz,3H). 13C NMR (101MHz, CDCl3): δ146.02,140.25,135.36,125.26,123.06,122.84,120.17,118.92, 118.15,108.95,108.67,108.32,53.63,37.41,26.26,24.15,13.80.HRMSm / z(ESI)calcd for C 19 H 22 N2[M+H] + :279.1861,found:279.1861.

[0619] 3-Ethyl-3-(4-(piperidin-1-yl)phenyl)piperidine-2,6-dione (106)

[0620] Aminoglutethimide (116.1 mg, 0.50 mmol), 1,5-pentanediol (208.3 mg,

[0621] 2.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4

[0622] (30.0 mg, 0.25 mmol) was dissolved in NMP (2 mL) and reacted at 150°C for 36 h to afford 101.6 mg (68%) of 106 as a colorless solid. 1 HNMR (400MHz, CDCl3): δ8.44(s,1H),7.12–7.10(m,2H),6.89–6.87(m,2H),3.14(t,J=5.4Hz,4H),2.59–2.53(m,1H),2.47–2.38(m,1H), 2.34–2.29(m,1H),2.19–2.11(m,1H),2.02-1.97(m,1H),1.90–1.85(m,1H),1.71–1.65(m,4H),1.59–1.54(m,2H),0.84(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3): δ175.64,172.79,151.03,128.28,126.75,116.20,50.12,50.01,32.79,29.27,26.86,25.64,24.14,8.94.HRMSm / z(ESI)calcd forC 18 H 24 N2O2[M+H] + :301.1916,found:301.1920.

[0623] 1-Phenylazepane(107)

[0624] Aniline (46.6 mg, 0.50 mmol), 1,6-hexanediol (236.3 mg, 2.0 mmol), HI (55%)

[0625] aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25 mmol) dissolved in NMP

[0626] The reaction was carried out at 150°C for 36 hours to obtain 41.5 mg (47%) of 107 as a blue solid. 1 H NMR (400MHz, CDCl3): δ7.21–7.17(m,2H),6.68(d,J=7.9Hz,2H),6.63–6.60(m,1H),3.44(t,J=6.0Hz,4H),1.79–1.75(m,4H),1.55–1.52(m,4H). 13 CNMR (101MHz, CDCl3): δ148.84,129.20,115.07,111.10,49.02,27.77,27.14.HRMSm / z(ESI)calcd for C 12 H 17 N[M+H] + :176.1439,found:176.1441.

[0627] 4-Phenylmorpholine(108)

[0628] Aniline (46.6 mg, 0.50 mmol), diethylene glycol (212.2 mg, 2.0 mmol), HI (55%)

[0629] aqueous solution, 46.5 mg, 0.20 mmol), H2SO4 (24.5 mg, 0.25 mmol) dissolved in NMP

[0630] The reaction mixture was added to 4% paraformaldehyde (2 mL) and reacted at 150° C. under N 2 for 36 hours to obtain 28.9 mg (35%) of 108 as a brown oil. 1 H NMR (400MHz, CDCl3): δ7.30–7.25(m,2H), 6.93–6.86(m,3H), 3.86(t,J=4.8Hz,4H), 3.15(t,J=4.8Hz,4H). 13C NMR (101MHz, CDCl3): δ151.25,129.15,120.02,115.68,66.92,49.35.HRMSm / z(ESI)calcd for C 10 H 13 NO[M+H] + :164.1075,found:164.1079.

[0631] Synthesis of N-alkylindoline from aniline

[0632] Under N2 atmosphere, 2-aminophenylethanol (109) (68.6 mg, 0.50 mmol), 1-hexanol (2) (102.2 mg, 1.0 mmol), and NaHSO4 (30.0 mg, 0.25 mmol) were dissolved in NMP (1 mL) and dissolved in HI (55% aqueous solution, 23.3 mg, 0.10 mmol) with stirring. After cooling to room temperature, the reaction mixture was neutralized with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL x 3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and rotary evaporated. The residue was purified by silica gel column chromatography to yield 83.7 mg (82%) of 110 as a brown oil.

[0633] 1-Hexylindoline(110)

[0634] 1 H NMR (400MHz, CDCl3): δ7.07 (t, J = 7.4Hz, 2H), 6.64 (t, J = 7.3

[0635] Hz,1H),6.47(d,J=7.9Hz,1H),3.35(t,J=8.3Hz,2H),3.05(t,J=

[0636] 7.4Hz,2H),2.97(t,J=8.3Hz,2H),1.65–1.58(m,2H),1.42–1.28(m,6H),0.95–0.91(m,3H). 13 C NMR (101MHz, CDCl3): δ152.76,129.96,127.23,124.29,117.15,106.79,53.03,49.31,31.73,28.56,27.32,26.95,22.66,14.06.HRMSm / z(ESI)calcd for C 14 H 21 N[M+H]+ :204.1752,found:204.1752.

[0637] Polycyclic synthesis

[0638] Under N2 atmosphere, 4-fluoroaniline (55.6 mg, 0.50 mmol), 3-bromo-1-propanol (278.0 mg, 2.0 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (2 mL) and dissolved in HI (55% aqueous solution, 11.6 mg, 0.05 mmol) with stirring. After cooling to room temperature, the reaction mixture was neutralized with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (20 mL x 3). The combined organic extracts were dried over anhydrous MgSO4, filtered, and rotary evaporated. The residue was purified by silica gel column chromatography to yield 47.9 mg (50%) of 111 as an orange solid.

[0639] 9-Fluoro-julolidine (111)

[0640] 1 H NMR (400MHz, CDCl3): δ6.51 (d, J = 9.1Hz, 2H), 3.97 (t, J = 5.6Hz, 4H), 2.74 (t, J = 6.6Hz, 4H), 2.00–1.94 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ

[0641] 154.65 (d, J = 235.0Hz), 139.42, 123.19 (d, J = 6.7Hz), 113.01 (d, J = 21.3Hz), 50.12, 27.67 (d, J = 1.4Hz), 22.10. 19 F NMR(376MHz,CDCl3)δ-129.46.HRMSm / z(ESI)calcdfor C 12 H 14 FN[M+H] + :192.1189,found:192.1190.

[0642] Drug synthesis operation process and spectral data (condition E)

[0643] Mepivacaine (112)

[0644] N-(2,6-dimethylphenyl)piperidine-2-carboxamide (58.1 mg, 0.25 mmol), methanol (160.2

[0645] mg, 5.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol), H2SO4 (12.3

[0646] mg, 0.13 mmol) was dissolved in NMP (0.5 mL) and reacted at 150° C. under N 2 for 60 h to afford 27.9 mg (45%) of 112 as a white solid. 1 H NMR (400MHz, CDCl3): δ8.06(brs,1H),7.08–7.06(m,3H),3.01(d,J=11.6Hz,1H),2.68(d,J=11.3Hz,1H) ,2.43(s,3H),2.25(s,6H),2.17–2.13(m,2H),1.83–1.68(m,2H),1.65–1.58(m,2H),1.34–1.26(m,1H). 13 C NMR (101MHz, CDCl3): δ172.48,135.20,133.48,128.31,127.01,70.19,55.61,45.37,31.44,25.39,23.34,18.83.MSm / z(ESI)calcd for C 15 H 22 N2O[M+H] + :247.18,found:247.19.d3-Mepivacaine (113)

[0647] N-(2,6-dimethylphenyl)piperidine-2-carboxamide (58.1 mg, 0.25 mmol), methanol-d4

[0648] (180.4 mg, 5.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0649] H2SO4 (12.3 mg, 0.13 mmol) was dissolved in NMP (0.5 mL) and reacted at 150°C under N2 for 60 hours to obtain 40.1 mg (64%) of 113 as a yellow solid. 1 H NMR (400MHz, CDCl3): δ8.05(brs,1H),7.10–7.04(m,3H),2.99(d,J=11.9Hz,1H),2.66(d,J=11.2 Hz,1H),2.24(s,6H),2.15–2.08(m,2H),1.82–1.69(m,2H),1.67–1.53(m,2H),1.33–1.25(m,1H).13 C NMR (101MHz, CDCl3): δ172.50,135.13,133.42,128.23,126.93,69.99,55.43,44.48–44.03(m),31.41,25.34,23.30,18.77.HRMSm / z(ESI)calcd for C 15 H 19 D3N2O[M+H] + :250.1999,found:250.1995.

[0650] Ropivacaine (114)

[0651] N-(2,6-dimethylphenyl)piperidine-2-carboxamide (58.1 mg, 0.25 mmol), 1-propanol (300.5 mg, 5.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0652] NaHSO4 (45.0 mg, 0.38 mmol) was dissolved in NMP (0.5 mL) and reacted at 150°C under N2 for 60 hours to obtain 42.3 mg (62%) of 114 as a brown solid. 1 HNMR (400MHz, CDCl3): δ8.15(brs,1H),7.09–7.07(m,3H),3.22–3.19(m,1H),2.87(dd,J=10.5,3.6Hz,1H),2.82–2.75(m,1H),2.25(s,6H) ,2.21–2.19(m,1H),2.13–2.09(m,1H),2.06–2.00(m,1H),1.75–1.69(m,4H),1.54–1.49(m,2H),1.36–1.32(m,1H),0.91(t,J=7.4Hz,3H). 13 C NMR (101MHz, CDCl3): δ173.02,135.32,133.64,128.31,127.05,68.64,59.47,51.64,30.82,24.94,23.53,20.69,18.72,11.61.MSm / z(ESI)calcd for C 17 H 26 N2O[M+H] + :275.21,found:275.22.

[0653] Bupivacaine (115)

[0654] N-(2,6-dimethylphenyl)piperidine-2-carboxamide (58.1 mg, 0.25 mmol),

[0655] 1-Butanol (370.6 mg, 5.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10

[0656] mmol), NaHSO4 (45.0 mg, 0.38 mmol) were dissolved in NMP (0.5 mL) and reacted at 150°C under N2 for 60 hours to obtain 41.9 mg (58%) of brown solid 115. 1 H NMR (400MHz, CDCl3): δ8.16(brs,1H),7.09–7.07(m,3H),3.22–3.19(m,1H),2.89–2.79(m,2H),2.25(s,6H),2.12 –2.09(m,1H),2.06–2.01(m,1H),1.79–1.62(m,4H),1.52–1.46(m,2H),1.38–1.26(m,4H),0.92(t,J=7.3Hz,3H). 13 CNMR (101MHz, CDCl3): δ173.01,135.29,133.65,128.30,127.03,68.60,57.5 9,51.65,30.78,29.78,24.92,23.52,20.66,18.74,14.15.MSm / z(ESI)calcd for C 18 H 28 N2O[M+H] + :289.23,found:289.24.

[0657] Fentilin (116)

[0658] 1-phenylethan-1-amine (30.3 mg, 0.25 mmol), 3,3-diphenylpropan-1-ol

[0659] (212.3 mg, 1.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0660] NaHSO 4 (45.0 mg, 0.38 mmol) was dissolved in NMP (0.5 mL) and reacted at 160° C. under N 2 for 72 h to afford 57.0 mg (72%) of 116 as a yellow solid. 1H NMR (400MHz, CDCl3): δ7.27–7.20 (m, 10H), δ7.18–7.12 (m, 5H), 3.96 (t, J = 7.8Hz, 1H) ,3.72(q,J=6.7Hz,1H),2.49–2.44(m,2H),2.26–2.22(m,2H),1.32(d,J=6.6Hz,3H). 13 C NMR (101MHz, CDCl3): δ144.71,144.40,128.45,128.41,127.80,127.69,127.08 ,126.63,126.15,126.12,58.21,48.90,45.77,35.39,23.76.MSm / z(ESI)calcd for C 23 H 26 N[M+H] + :316.21,found:316.21.

[0661] Cinacalcet (117)

[0662] (R)-1-(naphthalen-1-yl)ethan-1-amine (42.8 mg, 0.25 mmol), 3-(3-(trifluoromethyl)phenyl)propan-1-ol (204.2 mg, 1.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (45.0 mg, 0.38 mmol) were added.

[0663] It was dissolved in NMP (0.5 mL) and the reaction mixture was heated at 160° C. under N 2 for 72 h to afford 67.6 mg (76%) of 117 as a yellow oil. 1 H NMR (400MHz, CDCl3): δ8.17(d,J=8.2Hz,1H),7.87(d,J=8.4Hz,1H),7.74(d,J=8.2Hz,1H),7.66(d,J=7.1Hz,1H),7.52–7.45(m,3 H),7.41(d,J=7.7Hz,2H),7.34–7.27(m,2H),4.64(q,J=6.6Hz,1H),2.70–2.60(m,4H),1.88–1.80(m,2H),1.50(d,J=6.6Hz,3H). 13CNMR (101MHz, CDCl3): δ142.96, 133.97, 131.73, 131.26, 130.57 (q, J = 32.0Hz), 128.99, 128.64, 127.29, 125.81, 125.68 ,125.59,125.34,125.01(q,J=3.8Hz),122.88,122.82,122.77,122.63(q,J=3.9Hz),53.76,47.17,33.35,31.64,23.47. 19 F NMR(376MHz,CDCl3):δ-62.53.MSm / z(ESI)calcd for C 22 H 23 F3N[M+H] + :358.18,found:358.18.

[0664] Tecalcet(118)

[0665] 1-(3-methoxyphenyl)ethan-1-amine (37.8 mg, 0.25 mmol), 3-(2-chlorophenyl)propan-1-ol (170.6 mg, 1.0 mmol), HI (55% aqueous solution, 23.3 mg,

[0666] 0.10mmol), NaHSO4 (45.0mg, 0.38mmol) were dissolved in NMP (0.5

[0667] The reaction mixture was added to 4% paraformaldehyde (5% paraformaldehyde) in 4% paraformaldehyde (mL) and reacted at 160° C. under N 2 for 72 hours to obtain 50.3 mg (66%) of yellow oil 118. 1 H NMR (400MHz, CDCl3): δ7.31–7.29(m,1H),7.26–7.22(m,1H),7.15–7.11(m,3H),6.93–6.90(m,2H),6.81–6.78(m,1 H),3.82(s,3H),3.81–3.78(m,1H),2.74–2.70(m,2H),2.58–2.55(m,2H),1.84–1.82(m,2H),1.40(d,J=6.6Hz,3H). 13C NMR (101MHz, CDCl3): δ159.84,146.22,139.43,133.83,130.25,129.49,129.39,127.26,12 6.69,119.10,112.64,112.05,58.36,55.21,46.96,31.16,29.50,23.74.MSm / z(ESI)calcd for C 18 H 22 ClNO[M+H] + :304.15,found:304.15.

[0668] Cinnarizine(119)

[0669] 1-Benzhydrylpiperazine (126.2 mg, 0.5 mmol), cinnamyl alcohol (134.2

[0670] mg, 1.0 mmol), HI (55% aqueous solution, 23.3 mg, 0.10 mmol),

[0671] NaHSO4 (30.0 mg, 0.25 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 48 hours to obtain 126.0 mg (68%) of 119 as a yellow solid. 1 H NMR (400MHz, CDCl3): δ7.41(d,J=7.1Hz,4H),7.35(d,J=7.6Hz,2H),7.31–7.21(m,7H),7.18–7.14(m,2H),6 .51(d,J=15.9Hz,1H),6.30–6.23(m,1H),4.24(s,1H),3.19(d,J=6.8Hz,2H),2.57(brs,4H),2.46(brs,4H). 13 CNMR (101MHz, CDCl3): δ142.65,136.87,133.01,128.47,128.38,127.87,12 7.39,126.82,126.43,126.24,76.10,60.95,53.39,51.77.MSm / z(ESI)calcd for C 26 H 29 N2[M+H] + :369.23,found:369.25.

[0672] Flunarizine (120)

[0673] 1-(Bis(4-fluorophenyl)methyl)piperazine (144.2 mg, 0.5 mmol),

[0674] Cinnamyl alcohol (134.2 mg, 1.0 mmol), HI (55% aqueous solution, 23.3

[0675] mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25 mmol) was dissolved in

[0676] NMP (1 mL) was reacted at 150°C under N2 for 48 hours.

[0677] This afforded 156.9 mg (78%) of 120 as a yellow solid. 1 H NMR (400 MHz,

[0678] CDCl3): δ7.37–7.27(m,8H),7.23–7.19(m,1H),6.95(t,J=8.5Hz,4H),6.51(d,J=15.8Hz, 1H),6.30–6.22(m,1H),4.23(s,1H),3.18(d,J=6.8Hz,2H),2.55(brs,4H),2.42(brs,4H). 13 C NMR (101MHz, CDCl3): δ161.76 (d, J = 245.5Hz), 138.11 (d, J = 2.9Hz), 136.79, 133.32, 129 .21(d,J=7.8Hz),128.52,127.50,126.28,115.43,115.22,74.36,60.85,53.27,51.54. 19 F NMR(376MHz,CDCl3):δ-115.66.MSm / z(ESI)calcd for C 26 H 27 F2N2[M+H] + :405.21,found:405.23.

[0679] Piribedil (121)

[0680] 2-(Piperazin-1-yl)pyrimidine (82.1 mg, 0.5 mmol), propanol (152.15

[0681] mg, 1.0 mmol), HI (55% aqueous solution, 46.5 mg, 0.20 mmol),

[0682] NaHSO4 (60.0 mg, 0.50 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 48 hours to obtain 131.8 mg (88%) of 121 as a yellow solid. 1 H NMR (400MHz, CDCl3): δ8.29(d,J=4.7Hz,2H),6.89(s,1H),6.76(d,J=1.0Hz,2H),6.47( t,J=4.7Hz,1H),5.95(s,2H),3.82(t,J=4.8Hz,4H),3.45(s,2H),2.49(t,J=5.1Hz,4H). 13 C NMR (101MHz, CDCl3): δ161.61,157.64,147.64,146.64,131.79,122.21,109.68,109.46,107.85,100.87,62.82,52.79,43.63.MSm / z(ESI)calcdfor C 16 H 19 N4O2[M+H] + :299.15,found:299.16.

[0683] Meclizine (122)

[0684] 1-((4-chlorophenyl)(phenyl)methyl)piperazine (143.4 mg, 0.5 mmol),

[0685] 3-Methylbenzyl alcohol (122.2 mg, 1.0 mmol), HI (55% aqueous solution, 46.5

[0686] mg, 0.20 mmol), NaHSO4 (60.0 mg, 0.50 mmol) was dissolved in NMP

[0687] (1 mL) was reacted at 150 ° C under N2 for 48 hours to obtain 172.9

[0688] mg (88%) of 122 as a yellow solid. 1 H NMR (400MHz, CDCl3): δ7.35–7.32(m,4H),7.22(t,J=8.5Hz,4H),7.18–7.15(m,2 H),7.10–7.03(m,3H),4.20(s,1H),3.47(s,2H),2.47–2.34(m,8H),2.31(s,3H). 13C NMR (101MHz, CDCl3): δ142.15,141.36,137.71,132.42,129.97,129.17,128.54,128.48,12 7.99,127.82,127.74,127.04,126.35,75.38,62.99,53.25,51.69,21.34.MSm / z(ESI)calcd for C 25 H 28 ClN2[M+H] + :391.19,found:391.21.

[0689] Buclizine (123)

[0690] Standard conditions: 1-((4-chlorophenyl)(phenyl)methyl)piperazine (143.4 mg, 0.5

[0691] mmol), (4-(tert-butyl)phenyl)methanol (164.2 mg, 1.0 mmol), HI

[0692] (55% aqueous solution, 46.5mg, 0.20mmol), NaHSO4 (60.0mg,

[0693] 0.50 mmol) was dissolved in NMP (1 mL) and reacted at 150° C. under N 2 for 48 h to afford 197.5 mg (91%) of 123 as a yellow solid.

[0694] Gram-scale synthesis conditions: 1-((4-chlorophenyl)(phenyl)methyl)piperazine (1.43 g, 5.0 mmol), (4-(tert-butyl)phenyl)methanol (1.64 g, 10.0 mmol), HI (55% aqueous solution, 0.47 g, 2.0 mmol), and NaHSO4 (0.60 g, 5.0 mmol) were dissolved in NMP (10 mL) and reacted at 150°C under N2 for 48 h to obtain 1.91 g (88%) of yellow solid 123.

[0695] 1 H NMR (400MHz, CDCl3): δ7.34–7.29(m,6H),7.23–7.19(m,6H),7.17–7.13(m, 1H),4.20(s,1H),3.47(s,2H),2.47(brs,4H),2.39(brs,4H),1.29(s,9H). 13C NMR (101MHz, CDCl3): δ149.80,142.14,141.35,134.84,132.40,129.18,128.92,128.53,12 8.47,127.84,127.03,124.99,75.39,62.62,53.24,51.77,34.39,31.36.MSm / z(ESI)calcd forC 28 H 34 ClN2[M+H] + :433.24,found:433.26.

[0696] Methylation synthesis experimental process and spectrum (condition F)

[0697] N,N-Dimethyl-[1,1'-biphenyl]-4-amine(124)

[0698] 4-aminobiphenyl (84.6 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol),

[0699] HI (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25 mmol)

[0700] Dissolved in NMP (1 mL), reacted at 150 ° C under N2 for 24 hours, and obtained 83.5

[0701] mg (85%) of 124 as a yellow solid. 1 H NMR (400MHz, CDCl3): δ7.56–7.53(m,2H),7.49(d,J=8.6Hz,2H),7.37(t,J=7.6Hz,2H),7.23(t,J=7.4Hz,1H),6.78(d,J=8.6Hz,2H),2.96(s,6H). 13 C NMR (101MHz, CDCl3): δ149.91,141.17,129.20,128.60,127.65,126.23,125.94,112.74,40.52.MSm / z(ESI)calcd for C 14 H 15 N[M+H] + :198.13,found:198.13.

[0702] 4-Chloro-N,N-dimethylaniline (125)

[0703] 4-Chloroaniline (63.8 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol), HI

[0704] (55% aqueous solution, 23.3 mg, 0.10 mmol), NaHSO4 (30.0 mg, 0.25 mmol)

[0705] Dissolved in NMP (1 mL), reacted at 150 ° C under N2 for 24 hours, and obtained 63.1

[0706] mg (81%) blue solid 125. 1 H NMR (400MHz, CDCl3): δ7.17–7.15(m,2H),6.63–6.61(m,2H),2.91(s,6H). 13 C NMR (101MHz, CDCl3): δ149.11,128.74,121.34,113.58,40.61.MSm / z(ESI)calcd for C8H 10 ClN[M+H] + :156.06,found:156.06.

[0707] 4-Chloro-N,N-dimethylaniline (126)

[0708] 4-Chloro-N-methylaniline (70.8 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol),

[0709] HI (55% aqueous solution, 11.6 mg, 0.05 mmol), NaHSO4 (12.0 mg, 0.10 mmol)

[0710] Dissolved in NMP (1 mL), reacted at 150 ° C under N2 for 24 hours, and obtained 70.9

[0711] mg (91%) of 126 as a blue solid. 1 H NMR (400MHz, CDCl3): δ7.17–7.15(m,2H),6.63–6.61(m,2H),2.91(s,6H). 13 C NMR (101MHz, CDCl3): δ149.11,128.74,121.34,113.58,40.61.MSm / z(ESI)calcd for C8H 10 ClN[M+H] + :156.06,found:156.06.

[0712] 1-Methylindoline(127)

[0713] Indoline (59.6 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol), HI (55%)

[0714] aqueous solution, 11.6 mg, 0.05 mmol), NaHSO4 (12.0 mg, 0.10 mmol) dissolved in NMP

[0715] The reaction mixture was added to 1 mL of 4% paraformaldehyde (1 mL) and reacted at 150° C. under N 2 for 24 h to afford 44.2 mg (66%) of 127 as a brown solid. 1 H NMR (400MHz, CDCl3): δ7.10–7.07(m,2H),6.67(t,J=7.4Hz,1H),6.49(d,J=8.0Hz,1H),3.29(t,J=8.1Hz,2H),2.94(t,J=8.1Hz,2H),2.76(s,3H). 13 C NMR (101MHz, CDCl3): δ153.36,130.29,127.28,124.24,117.76,107.23,56.14,36.28,28.71.MSm / z(ESI)calcd forC9H 11 N[M+H] + :134.10,found:134.10.

[0716] 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (128)

[0717] 2,3,4,5-tetrahydro-1H-benzo[b]azepine (73.6 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150 ° C for 24 hours to obtain 76.4 mg of

[0718] (95%) yellow oil 128. 1H NMR (400MHz, CDCl3): δ7.17–7.12(m,1H),7.09(d,J=8.0Hz,1H),6.91(d,J=8.0Hz,1H),6.87–6.83 (m,1H),2.91–2.88(m,2H),2.87(s,3H),2.79–2.77(m,2H),1.77–1.75(m,2H),1.60–1.57(m,2H). 13 C NMR (101MHz, CDCl3): δ152.68,135.50,129.97,126.54,120.84,116.11,57.02,43.09,35.23,30.10,25.58.HRMSm / z(ESI)calcd for C 11 H 15 N[M+H] + :162.1283,found:162.1281.

[0719] N-Cyclohexyl-N-methylaniline (129)

[0720] N-cyclohexylaniline (87.6 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol),

[0721] HI (55% aqueous solution, 11.6 mg, 0.05 mmol) and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 139.0

[0722] mg (68%) 129 as brown oil. 1 H NMR (400MHz, CDCl3): δ7.22(t,J=7.6Hz,2H),6.77(d,J=8.2Hz,2H),6.67(t,J=7.3Hz,1H),3.60–3.52 (m,1H),2.76(s,3H),1.88–1.76(m,4H),1.68(d,J=13.4Hz,1H),1.47–1.33(m,4H),1.17–1.11(m,1H). 13 C NMR (101MHz, CDCl3): δ150.14,129.06,116.19,113.12,58.10,31.13,30.01,26.18,25.92.HRMS m / z(ESI)calcd for C 13 H 19 N[M+H] +:190.1596,found:190.1597.

[0723] 4-Methyl-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole (130)

[0724] 1,2,3,3a,4,8b-Hexahydrocyclopenta[b]indole (79.6 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 68.4 mg (79%) of green oil 130. 1 H NMR (400MHz, CDCl3): δ7.04–6.98 (m, 2H), 6.59–6.55 (m, 1H), 6.28 (d, J = 7.6Hz, 1H), 4. 00–3.97(m,1H),3.68–3.65(m,1H),2.74(s,3H),1.95–1.84(m,2H),1.74–1.53(m,4H). 13 C NMR (101MHz, CDCl3): δ152.82,133.66,127.45,123.97,116.51,105.17,71.60,45.74,34.76,33.29,32.38,24.69.HRMS m / z(ESI)calcd for C 12 H 15 N[M+H] + :174.1283,found:174.1279.

[0725] 4-Methoxy-N-(4-methoxyphenyl)-N-methylaniline (131)

[0726] Bis(4-methoxyphenyl)amine (114.6 mg, 0.50 mmol), methanol (320.4

[0727] mg, 10.0 mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol),

[0728] NaHSO4 (12.0 mg, 0.10 mmol) was dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 110.3 mg (91%) of 131 as a white solid. 1H NMR (400MHz, CDCl3): δ7.05 (d, J = 8.5Hz, 4H), 6.86–6.84 (m, 4H), 3.79 (s, 6H), 3.26 (s, 3H). 13 C NMR (101MHz, CDCl3): δ154.32,143.68,121.52,114.54,55.56,40.98.HRMS m / z(ESI)calcd for C 15 H 17 NO2[M+H] + :244.1338,found:244.1334.

[0729] N-Methyl-benzomorpholine (132)

[0730] Benzomorpholine (67.6 mg, 0.50 mmol), methanol (320.4 mg, 10.0 mmol), HI (55%)

[0731] aqueous solution, 11.6 mg, 0.05 mmol), NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1

[0732] The mixture was added to 4% paraformaldehyde (5% paraformaldehyde) and reacted at 150° C. under N 2 for 24 hours to obtain 53.7 mg (72%) of yellow oil 132. 1 H NMR (400MHz, CDCl3): δ6.83(t,J=7.6Hz,1H),6.76(d,J=7.9Hz,1H),6.68–6.62(m,2H),4.29–4.28(m,2H),3.25–3.28(m,2H),2.87(s,3H). 13 C NMR (101MHz, CDCl3): δ144.25,136.54,121.37,118.18,115.85,112.51,64.81,49.17,38.74.HRMSm / z(ESI)calcd for C9H 11 NO[M+H] + :150.0919,found:150.0918.

[0733] 5-Methyl-5H-dibenzo[b,f]azepine (133)

[0734] 5H-dibenzo[b,f]azepine (96.6 mg, 0.50 mmol), methanol (320.4 mg, 10.0

[0735] mmol), HI (55% aqueous solution, 11.6 mg, 0.05 mmol), and NaHSO4 (12.0 mg, 0.10 mmol) were dissolved in NMP (1 mL) and reacted at 150°C under N2 for 24 hours to obtain 93.7 mg (90%) of yellow solid 133. 1 H NMR (400MHz, CDCl3): δ7.25–7.20(m,2H),7.02–6.93(m,6H),6.67(s,2H),3.31(s,3H). 13 C NMR (101MHz, CDCl3): δ152.29,132.83,132.41,129.20,128.88,123.13,118.82,39.29.HRMSm / z(ESI)calcd for C 15 H 13 N[M+H] + :208.1126,found:208.1130.

[0736] Although the embodiments disclosed in this application are as described above, the contents described are merely embodiments adopted to facilitate understanding of this application and are not intended to limit this application. Any person skilled in the art to which this application belongs may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application. However, the scope of patent protection of this application shall still be based on the scope defined by the attached claims.

Claims

1. A method for dehydroxylation of a primary alcohol, comprising: (1) reacting the compound represented by Formula I with the compound represented by Formula II in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula III; or, (2) reacting the compound represented by Formula IV with the compound represented by Formula II in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula V; or, (3) reacting the compound represented by Formula IV with the compound represented by Formula VI in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula VII; or, (4) reacting the compound represented by Formula VIII with the compound represented by Formula II in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula IX; or, (5) reacting the compound represented by Formula X with the compound represented by Formula XI in the presence of a catalyst and an acidic additive to obtain the compound represented by Formula XII; in: The catalyst is selected from HI, KI, NaI, LiI, CsI, and NH4I, preferably selected from HI and KI, and more preferably HI; The acidic additive is selected from NaHSO4, H2SO4, TFA, HOTf, preferably selected from NaHSO4, H2SO4, more preferably NaHSO4; R a 、R b are each independently selected from hydrogen and deuterium; R 1 Selected from C1-C6 alkyl, C6-C10 aryl, 5-13 membered heteroaryl, 5-10 membered heterocyclic group, the C1-C6 alkyl, C6-C10 aryl, 5-13 membered heteroaryl, 5-10 membered heterocyclic group are each independently optionally substituted by 1-3 members selected from R c substituted by a group; Preferably, R 1 Selected from C1-C6 alkyl, phenyl, naphthyl, 13-membered heteroaryl, 9-10-membered heterocyclic group, the C1-C6 alkyl, phenyl, naphthyl, 13-membered heteroaryl and 9-10-membered heterocyclic group are each independently optionally substituted by 1-3 groups selected from R c substituted by a group; More preferably, R 1 Selected from ethyl, phenyl, naphthyl, The ethyl, phenyl, naphthyl, Each independently optionally selected from 1-3 R c substituted by a group; R c Selected from oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, benzyl, phenyl, naphthyl, C3-C6 cycloalkyl, C1-C6 alkyl-(C=O)-, 5-6 membered heteroaryl, C1-C6 alkyl-(C=O)-NH-, C1-C6 haloalkyl, C1-C6 haloalkoxy, Preferably, R c Selected from oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, benzyl, phenyl, naphthyl, C3-C6 cycloalkyl, C1-C6 alkyl-(C=O)-, pyrrolyl, C1-C6 alkyl-(C=O)-NH-, C1-C6 haloalkyl, C1-C6 haloalkoxy, R d 、R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R d 、R e 、R f Each independently selected from hydrogen, methyl, ethyl; More preferably, R c Selected from oxo, methyl, ethyl, isopropyl, tert-butyl, methoxy, fluorine, chlorine, nitro, benzyl, phenyl, naphthyl, cyclohexyl, trifluoromethyl, trifluoromethoxy, More preferably, R 1 Selected from: (1) in: R 11 、R 12 、R 13 、R 14 、R 15 In, any one or any two or any three are independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, benzyl, phenyl, C3-C6 cycloalkyl, C1-C6 alkyl-(C=O)-, pyrrolyl, C1-C6 alkyl-(C=O)-NH-, C1-C6 haloalkyl, C1-C6 haloalkoxy, The rest is hydrogen; Preferably, R 11 、R 12 、R 13 、R 14 、R 15 Any one of them is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, benzyl, phenyl, C3-C6 cycloalkyl, C1-C6 alkyl-(C=O)-, pyrrolyl, C1-C6 alkyl-(C=O)-NH-, C1-C6 haloalkyl, C1-C6 haloalkoxy, The rest are hydrogen; or, any two are selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen, and the rest are hydrogen; or, any three are selected from C1-C6 alkyl, halogen, nitro, and the rest are hydrogen; R d Selected from C1-C6 alkyl; preferably, R d Ethyl; More preferably, R 11 、R 12 、R 13 、R 14 、R 15 Among them, any one is selected from hydrogen, methyl, tert-butyl, methoxy, fluorine, chlorine, nitro, benzyl, phenyl, cyclohexyl, trifluoromethyl, trifluoromethoxy, The rest are hydrogen; or, any two are selected from isopropyl, methoxy, trifluoromethyl, chlorine, and the rest are hydrogen; or, any three are selected from methyl, fluorine, nitro, and the rest are hydrogen; Most preferably, As a whole, selected (2) in: R 16 Selected from C1-C6 alkyl; Preferably, R 16 Ethyl; (3) in: R 17 Selected from C1-C6 alkyl; Preferably, R 17 is methyl; (4) in: R 18 、R 19 Each independently selected from hydrogen, phenyl, naphthyl, Preferably, R 18 、R 19 Among them, any one is selected from phenyl, naphthyl, the other is hydrogen; More preferably, R 18 、R 19 In, R 18 Selected from phenyl, R 19 is hydrogen; or, R 19 Selected from phenyl, naphthyl, R 18 is hydrogen; R e 、R f Each is independently selected from C1-C6 alkyl; preferably, R e 、R f is methyl; Most preferably, As a whole, selected (5) Most preferably, R 1 Selected from R 2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl are each independently optionally substituted by 1-3 (preferably 1) selected from R g substituted by a group; Preferably, R 2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, the phenyl group is optionally substituted by 1-3 (preferably 1) selected from R g substituted by a group; R g Selected from C1-C6 alkoxy; preferably, R g is methoxy; More preferably, R 2 Selected from hydrogen, methyl, Or, R 1 、R 2 Together with the nitrogen atom to which they are commonly connected, they form a 6-12 membered heterocyclic group, The 6-12 membered heterocyclic group is optionally substituted by 1-3 members selected from R h substituted by a group; Or preferably, R 1 、R 2 Together with the nitrogen atoms they are connected to, they form described Each independently optionally selected from 1-3 R h substituted by a group; Or more preferably, R 1 、R 2 Together with the nitrogen atoms they are connected to, they form described Each independently optionally selected from 1-3 R h substituted by a group; R h Selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl-C(=O)-, benzyl; Preferably, R h Selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, pyrimidinyl, benzothienyl, furanyl-C(=O)-, benzyl; More preferably, R h Selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, pyrimidinyl, benzothienyl, furanyl-C(=O)-, benzyl; Each R i Independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro; Preferably, each R i independently selected from hydrogen, methyl, methoxy, chlorine, cyano, nitro; R j 、R k are each independently selected from hydrogen, halogen; Preferably, R j 、R k are each independently selected from hydrogen, fluorine, and chlorine; Each R l Independently selected from C1-C6 alkyl; Preferably, R l is methyl; Most preferably, R h Selected from methyl, fluorine, chlorine, methoxy, trifluoromethyl, benzyl; Or more preferably, R 1 、R 2 Together with the nitrogen atoms to which they are attached, they form: (1) in: R 21 、R 22 Each is independently selected from hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl; Preferably, R 21 、R 22 Each independently selected from hydrogen, fluorine, chlorine, methoxy, methyl, trifluoromethyl; More preferably, R 21 、R 22 Among them, any one is selected from hydrogen, fluorine, chlorine, methoxy, methyl, trifluoromethyl, and the other is hydrogen; Most preferably, As a whole, selected (2) in: Each R 23 Independently selected from C1-C6 alkyl; Preferably, R 23 is methyl; (3) in: R 24 、R 25 Each is independently selected from hydrogen, C1-C6 alkyl, halogen; Preferably, R 24 、R 25 Each independently selected from hydrogen, methyl, chlorine; More preferably, R 24 、R 25 Among them, any one is hydrogen or methyl, and the other is hydrogen or chlorine; Most preferably, As a whole, selected (4) in: R 26 Selected from pyrimidinyl, benzothienyl, furanyl-C(=O)-, Preferably, R 26 Selected from pyrimidinyl, benzothienyl, furanyl-C(=O)-, Each R i Independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, nitro; Preferably, each R i independently selected from hydrogen, methyl, methoxy, chlorine, cyano, nitro; R j 、R k are each independently selected from hydrogen, halogen; Preferably, R j 、R k are each independently selected from hydrogen, fluorine, and chlorine; More preferably, R 26 Selected from (5) R 27 、R 28 Each independently selected from Preferably, R 27 、R 28 Any one of the other is hydrogen; Each R l Independently selected from C1-C6 alkyl; Preferably, R l is methyl; More preferably, R 27 、R 28 Any one of the other is hydrogen; Most preferably, As a whole, selected (6) R 29 、R 30 Each independently selected from phenyl, benzyl; Preferably, R 29 、R 30 Among them, any one is selected from phenyl and benzyl, and the other is hydrogen; More preferably, As a whole, selected (7) Or most preferably, R 1 、R 2 Together with the nitrogen atoms they are connected to, they form R 3 is selected from hydrogen, deuterium, C1-C12 alkyl, C2-C6 alkenyl, C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, wherein the C1-C12 alkyl, C2-C6 alkenyl, C6-C10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl are each independently optionally substituted by 1-3 (preferably 1) selected from R m substituted by a group; Preferably, R 3 Selected from hydrogen, deuterium, C1-C12 alkyl, C2-C6 alkenyl, phenyl, 6-membered heteroaryl, The C1-C12 alkyl, C2-C6 alkenyl, phenyl, 6-membered heteroaryl, Each independently optionally selected from 1-3 (preferably 1) R m substituted by a group; More preferably, R 3 Selected from hydrogen, deuterium, C1-C12 alkyl, C2-C6 alkenyl, phenyl, pyridyl, The C1-C12 alkyl, C2-C6 alkenyl, and phenyl groups are each independently optionally substituted by 1-3 (preferably 1) selected from R m substituted by a group; More preferably, R 3 Selected from hydrogen, deuterium, C1-C12 alkyl, Pyridyl, The C1-C12 alkyl group is optionally replaced by 1-3 (preferably 1) selected from R m substituted by a group; R 31 、R 32 Each is independently selected from hydrogen, halogen, C1-C6 alkyl; Preferably, R 31 、R 32 Each is independently selected from hydrogen, chlorine, methyl, tert-butyl; More preferably, R 31 、R 32 Among them, any one is selected from hydrogen, chlorine, methyl, tert-butyl, and the other is hydrogen; R m Selected from C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, Indolyl, R n 、R o Each is independently selected from hydrogen, halogen, C1-C6 haloalkyl; Preferably, R n 、R o Each independently selected from hydrogen, chlorine, trifluoromethyl; More preferably, R n 、R o Among them, any one is selected from hydrogen, chlorine, trifluoromethyl, and the other is hydrogen; Preferably, R m Selected from methyl, tert-butyl, chlorine, More preferably, R m Selected from Most preferably, R 3 Selected from hydrogen, deuterium, methyl, ethyl, R 4 Selected from hydrogen, C1-C6 alkyl, halogen; Preferably, R 4 Selected from hydrogen, C1-C6 alkyl; More preferably, R 4 is hydrogen; R 5 、R 6 、R 7 Each is independently selected from hydrogen, C1-C6 alkyl, halogen; Preferably, R 5 、R 6 、R 7 Among them, any one is selected from hydrogen, C1-C6 alkyl, halogen, and the rest are hydrogen; More preferably, R 5 、R 6 、R 7 In, R 6 is selected from hydrogen, halogen, and the rest are hydrogen; Most preferably, R 5 、R 6 、R 7 In, R 6 is selected from hydrogen and fluorine, the remainder being hydrogen; L 1 Selected from C1-C6 alkylene, C1-C3 alkylene-O-C1-C3 alkylene, C1-C3 alkylene-S-C1-C3 alkylene, C1-C3 alkylene-NH-C1-C3 alkylene; Preferably, L 1 Selected from C1-C6 alkylene, C1-C3 alkylene-O-C1-C3 alkylene; More preferably, L 1 Selected from methylene, L 2 Selected from a direct bond, a C1-C6 alkylene group; Preferably, L 2 is a direct key; L 3 Selected from C1-C6 alkylene; Preferably, L 3 is a methylene group; X is a halogen; Preferably, X is bromine.

2. The method according to claim 1, wherein The solvent of the reaction is selected from NMP, DMF, and Cyrene; Preferably, the solvent for the reaction is NMP.

3. The method according to any one of claims 1 to 2, wherein: The reaction is carried out at a temperature of 100°C to 200°C; Preferably, the reaction is carried out at a temperature of 120°C to 160°C; More preferably, the reaction is carried out at a temperature of 150°C.

4. The method according to any one of claims 1 to 3, wherein: The reaction time of the reaction is 10h to 100h; Preferably, the reaction time is 12h to 72h; More preferably, the reaction time is 24 hours.

5. The method according to any one of claims 1 to 4, wherein: The method has one or more technical features selected from the following (i)-(v): (i) In reaction (1), the molar ratio of the compound represented by formula II to the compound represented by formula I is 1:1 to 20:1, preferably 2:1 to 4:1; (ii) In reaction (2), the molar ratio of the compound represented by formula II to the compound represented by formula IV is 1:1 to 20:1, preferably 2:1 to 4:1; (iii) In reaction (3), the molar ratio of the compound represented by formula VI to the compound represented by formula IV is 1:1 to 20:1, preferably 2:1 to 4:1; (iv) In reaction (4), the molar ratio of the compound represented by formula II to the compound represented by formula VIII is 1:1 to 20:1, preferably 2:1 to 4:1; (v) In reaction (5), the molar ratio of the compound represented by formula XI to the compound represented by formula X is 1:1 to 20:1, preferably 2:1 to 4:

1.

6. The method according to any one of claims 1 to 5, wherein: The method has one or more technical features selected from the following (i)-(v): (i) In reaction (1), the molar ratio of the catalyst to the compound represented by formula I is 0.1:1 to 1:1, preferably 0.1:1 to 0.4:1; (ii) In reaction (2), the molar ratio of the catalyst to the compound represented by formula IV is 0.1:1 to 1:1, preferably 0.1:1 to 0.4:1; (iii) In reaction (3), the molar ratio of the catalyst to the compound represented by formula IV is 0.1:1 to 1:1, preferably 0.1:1 to 0.4:1; (iv) In reaction (4), the molar ratio of the catalyst to the compound represented by formula VIII is 0.1:1 to 1:1, preferably 0.1:1 to 0.4:1; (v) In reaction (5), the molar ratio of the catalyst to the compound represented by formula X is 0.1:1 to 1:1, preferably 0.1:1 to 0.4:

1.

7. The method according to any one of claims 1 to 6, wherein: The method has one or more technical features selected from the following (i)-(v): (i) In reaction (1), the molar ratio of the acidic additive to the compound represented by formula I is 0.1:1 to 5:1, preferably 0.2:1 to 1.6:1; (ii) In reaction (2), the molar ratio of the acidic additive to the compound represented by formula IV is 0.1:1 to 5:1, preferably 0.2:1 to 1.6:1; (iii) In reaction (3), the molar ratio of the acidic additive to the compound represented by formula IV is 0.1:1 to 5:1, preferably 0.2:1 to 1.6:1; (iv) In reaction (4), the molar ratio of the acidic additive to the compound represented by formula VIII is 0.1:1 to 5:1, preferably 0.2:1 to 1.6:1; (v) In reaction (5), the molar ratio of the acidic additive to the compound represented by formula X is 0.1:1 to 5:1, preferably 0.2:1 to 1.6:

1.

8. The method according to any one of claims 1 to 7, wherein: The reaction is carried out in the presence of an inert gas; Preferably, the inert gas is nitrogen, argon, or helium, preferably nitrogen.

9. The method according to any one of claims 1 to 8, wherein: The HI is in the form of an aqueous solution; Preferably, the mass fraction of HI in the HI aqueous solution is 45-58%, preferably 55%.

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