CN103408433A - Method for synthesizing propargylamine compounds - Google Patents
Method for synthesizing propargylamine compounds Download PDFInfo
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Abstract
The invention provides a method for synthesizing propargylamine compounds through coupling terminal alkyne, methylene dihalide and tertiary amine under the catalysis of a metal catalyst. The method is characterized in that the method uses a cheap and easily available raw material as a substrate, breakthroughs the limitation that the propargylamine compounds are synthesized only through using primary amine and secondary amine, the substrate simultaneously sensitive to the primary amine and the secondary amine has a very good adaptability in the invention, and there is no need of other oxidants or additives. The propargylamine compounds are synthesized through the selective fracture of C-N bonds when the propargylamine compounds having different substituent groups are used as an amine substrate. The method has the advantages of breakthrough of the previous limitation of the only use of the primary amine and the secondary amine, no need of an extra additive, cheap and easily available raw materials, mild reaction condition, high selectivity and high yield of a target product, and good industrial application prospect.
Description
[technical field]
The present invention relates to the organic synthesis field, be specifically related to a kind of synthetic method of propargylamine compounds.
[background technology]
The propargylamine compounds has purposes widely in fields such as medicine, synthetic chemistries, is also very important organic synthesis intermediate, therefore, and its synthetic attention that more and more is subject to the chemist.The initial synthetic method of propargylamine compounds is to synthesize by nucleophilic addition with stoichiometric alkynyl metallic compound and other reagent.This kind method need to be used the alkynyl metallic compound of equivalent, and complicated operation, thereby has limited its application.The synthetic method of propargylamine compounds is mainly three component couplings recently, comprises (the A of alkynes, aldehyde, primary amine and secondary amine
3) coupling of coupling and alkynes, methylene dichloride, secondary amine (AHA).Although can synthesize multiple propargylamine compounds by these two kinds of synthetic methods, but primary amine and secondary amine are generally than tertiary amine costliness, if and in substrate molecule, contain primary amine and secondary amine than more sensitive functional group, the synthetic of its corresponding propargylamine compounds will be subject to certain limitation.Tertiary amine is the amine the most easily synthesized in organic compound, be also stable amine, and therefore, adopting tertiary amine to synthesize the propargylamine compounds as the amine substrate is to solve the circumscribed important channel of amine substrate in its synthetic method.[reference: Journal Medicinal Chemistry 21 (1978) 253; J Am Chem Soc 112 (1990) 371; Angew Chem Int Ed 46 (2007) 2295; Org Lett 2 (2000) 1855; J Org Chem 64 (1999) 488; J Am Chem Soc 126 (2004) 5968; J Am Chem Soc 126 (2004) 11810; Chem Commun 7 (2002) 268; Angew Chem Int Ed 41 (2002) 3054; Chem Eur J 16 (2010) 9287; Adv Synth Catal 353 (2011) 163]
For the deficiency of existing propargylamine compounds synthetic method, the high efficiency method of designing and developing the propargylamine compounds with stronger application prospect is that industry is explored.
[summary of the invention]
The objective of the invention is to develop a kind of use tertiary amine cheap and easy to get is the amine raw material, by the selectivity fracture of C-N key, the method for the synthetic propargylamine compounds of high conversion and high productivity.
Goal of the invention of the present invention is achieved by the following technical solution:
A kind of structural formula is
The synthetic method of propargylamine compounds, comprise following steps:
The reactor that catalyzer is housed is vacuumized, fill rare gas element, in inert atmosphere, add solvent, terminal alkyne, methylene halide and tertiary amine, tube sealing, be heated to 80 ~ 120
oC reaction 8 ~ 72 hours, reaction is cooled to room temperature after finishing, and with the saturated salt solution washing, then uses organic solvent extraction, drying, underpressure distillation is except desolventizing, and thick product separates through column chromatography, obtains target product.
In described structural formula, R
1On aryl or phenyl ring, to contain the substituted aryl to electronics or electron-withdrawing substituent; Or R
1Chain-like alkyl, the 2-hydroxycyclopent base or trimethyl silicon based with 5 or 6 carbon atoms; R
2, R
3Alkyl or the ethylenic unsaturation alkyl that contains 1,2,3,4,8 carbon atom, R
2, R
3Can be identical, also can be different; Or R
2Methyl, R
3Cyclohexyl or benzyl; Or R
2~ R
3Be and alicyclic radical or oxygen replace and alicyclic radical.
In above-mentioned synthetic method, described catalyzer is to be selected from AlCl
3, PdCl
2, Pd (OAc)
2, Cu, CuO, Cu
2O, CuCl, CuCl
2, CuBr, CuBr
2, Cu (OAc)
2, CuSO
4, Cu (NO
3)
2, AgOAc, AgCl, AgBF
4, AgNO
3, Ag
2CO
3, CoCl
2.6H
2O, NiCl
2, FeCl
2In at least a.
In above-mentioned synthetic method, described solvent is selected from least a in Isosorbide-5-Nitrae-dioxane, DMF, methyl-sulphoxide, tetrahydrofuran (THF), trichloromethane, acetonitrile, toluene, ethyl acetate.
In above-mentioned synthetic method, described end alkynes is selected from phenylacetylene, to methylbenzene acetylene, to tert.-butylbenzene acetylene, to n-amylbenzene acetylene, to fluorobenzene acetylene, to chlorobenzene acetylene, to bromobenzene acetylene, to trifluoromethyl phenylacetylene, p-nitrophenylacetylene, 4-alkynyl methyl phenyl ketone, Isosorbide-5-Nitrae-diacetylene-benzene, 2-ethynyl pyridine, 2-thiophene acetylene, 2-ethynyl cyclopentanol, trimethylsilyl acetylene, 1-heptyne or 1-octyne.
In above-mentioned synthetic method, described tertiary amine is to be selected from triethylamine, Tri-n-Propylamine, tri-n-butylamine, tri-n-octyl amine, triallylamine, N, N-dimethylcyclohexylamine, N-methyl piperidine, N-ethylpiperidine, N-methylmorpholine, N, N-dimethyl benzylamine, N, N-dimethyl n butylamine, N, N-dimethyl TERTIARY BUTYL AMINE or N, the N-dimethyl allylamine.
In above-mentioned synthetic method, described methylene halide is selected from least a in methylene dichloride, methylene bromide and methylene iodide.
In above-mentioned synthetic method, the mole dosage of described catalyzer in reaction system is that 1-10 mol%(is based on end alkynes).
In above-mentioned synthetic method, the mol ratio between described end alkynes, tertiary amine, methylene halide is 1:[3 ~ 5]: [10 ~ 30].
According to experimental result, method of synthesizing the propargylamine compounds by metal catalyst catalysis end alkynes, methylene halide and tertiary amine provided by the present invention, have simple to operate, do not need that extra additive, raw material are cheap and easy to get, selectivity of product and yield advantages of higher very all, and have good prospects for commercial application.
[accompanying drawing explanation]
Fig. 1 is the building-up reactions formula of propargylamine compounds provided by the invention.
[embodiment]
Below in conjunction with synthesis example of the present invention, synthetic method of the present invention is described further, it should be noted that, embodiment does not form the restriction to the claimed scope of the present invention.
As shown in Figure 1, the synthesis step of propargylamine compounds provided by the invention is (below operate under the anhydrous and oxygen-free condition carry out): at N
2Or, under other inert atmospheres, in reactor, add 1-10 mol%(based on end alkynes) catalyzer (as silver acetate), add 1ml organic solvent (as, Isosorbide-5-Nitrae dioxane), 1 mmol end alkynes, 10 ~ 30 mmol methylene halides, 3 ~ 5 mmol tertiary amines.Be heated to 80 ~ 120 ℃, continue to stir 8 ~ 72 h, stopped reaction, be cooled to room temperature, with the saturated sodium carbonate solution washing, uses organic solvent extraction, drying, and the underpressure distillation desolventizing, thick product separates through column chromatography, obtains target product.
Synthesis example 1
N, N-diethyl-3-phenyl-2-propargylamine synthetic
In reactor, add 5 mol% AgOAc, vacuumize, backfill N
2, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol phenylacetylene, 3 mmol triethylamines, 10 mmol methylene dichloride.Be heated to 80
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium bicarbonate solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates and obtains target product, productive rate 90% through column chromatography.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.41–7.44 (m, 2H; Ar-H), 7.28–7.30 (m, 3H; Ar-H), 3.65 (s, 2H; CH
2), 2.62 (q, J = 7.2 Hz, 4H; CH
2), 1.12 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 2
N, N-diη-propyl-3-phenyl-2-propargylamine synthetic
In reactor, add 10 mol% Cu
2O, vacuumize, backfill N
2, add 0.5 ml acetonitrile and 0.5 ml tetrahydrofuran (THF), 1 mmol phenylacetylene, 3 mmol Tri-n-Propylamines, 15 mmol methylene bromides.Be heated to 90
oUnder C, reaction is 30 hours.Question response liquid is cooled to room temperature, adopts the saturated nacl aqueous solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates and obtains target product, productive rate 88% through column chromatography.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.42–7.44 (m, 2H; Ar-H), 7.28–7.30 (m, 3H; Ar-H), 3.62 (s, 2H; CH
2), 2.51 (t, J = 6.0 Hz, 4H; CH
2), 1.48-1.57 (m, 4H; CH
2), 0.92 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 3
N, N-di-n-butyl-3-phenyl-2-propargylamine synthetic
In reactor, add 1 mol% CuSO
4, vacuumize backfill N
2, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol phenylacetylene, 4 mmol tri-n-butylamines, 15 mmol methylene iodides.Be heated to 80
oUnder C, reaction is 50 hours.Question response liquid is cooled to room temperature, adopts the saturated ammonium chloride solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates and obtains target product, productive rate 85% through column chromatography.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.41–7.43 (m, 2H; Ar-H), 7.28–7.30 (m, 3H; Ar-H), 3.61 (s, 2H; CH
2), 2.53 (q, J = 6.0Hz, 4H; CH
2), 1.45-1.50 (m, 4H; CH
2), 1.32-1.38 (m, 4H; CH
2), 0.93 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 4
N, N-di-n-octyl-3-phenyl-2-propargylamine synthetic
In reactor, add 0.5 mol% Cu
2O and 0.5 mol% CuSO
4, vacuumize backfill N
2, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol phenylacetylene, 3 mmol tri-n-octyl amines, 20 mmol methylene dichloride.Be heated to 100
oUnder C, reaction is 72 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium carbonate solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates and obtains target product, productive rate 80% through column chromatography.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.42–7.45 (m, 2H; Ar-H), 7.28–7.31 (m, 3H; Ar-H), 3.72 (s, 2H; CH
2), 2.61-2.68 (m, 4H; CH
2), 1.58 (s, 4H; CH
2), 1.26-1.32 (m, 2H; CH
2), 0.88 (t, J = 6.8Hz, 6H; CH
3)。
Synthesis example 5
N, N-diallyl-3-phenyl-2-propargylamine synthetic
In reactor, add 5 mol% AgBF
4, vacuumizing, backfilled with inert gas, add 0.5 ml DMF and 0.5 ml methyl-sulphoxide, 1 mmol phenylacetylene, 3 mmol triallylamines, 12 mmol methylene dichloride.Be heated to 100
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated nacl aqueous solution washing, then uses chloroform extraction, use desiccant dryness, and underpressure distillation is except desolventizing, and slightly product separates and obtains target product, productive rate 90% through column chromatography.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.43–7.46 (m, 2H; Ar-H), 7.28–7.31(m, 3H; Ar-H), 5.83-5.92 (m, 2H; CH), 5.29 (q, J = 1.2Hz, 1H; CH
2), 5.25 (q, J = 1.2Hz, 1H; CH
2), 5.19 (t, J = 1.0Hz, 1H; CH
2), 5.17 (t, J = 1.0Hz, 1H; CH
2), 3.60 (s, 2H; CH
2), 3.19 (d, J = 2.4Hz, 4H; CH
2)。
Synthesis example 6
1-(3-phenyl-2-propargyl) piperidines is synthetic
In reactor, add 1 mol% Cu (OAc)
2, vacuumizing, backfilled with inert gas, add 1 ml methyl-sulphoxide, 1 mmol phenylacetylene, 3.3 mmol N-methyl piperidines, 8 mmol methylene bromides and 12 mmol methylene dichloride.Be heated to 90
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium carbonate solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates and obtains target product, productive rate 85% through column chromatography.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.42–7.45 (m, 2H; Ar-H), 7.27–7.30 (m, 3H; Ar-H), 3.48 (s, 2H; CH
2), 2.57 (s, 2H; CH
2), 1.61-1.67 (m, 4H; CH
2), 1.44 (s, 2H; CH
2)。
Synthesis example 7
4-(3-phenyl-2-propargyl) morpholine is synthetic
In reactor, add 1 mol% CuCl
2, vacuumizing, backfilled with inert gas, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol phenylacetylene, the luxuriant and rich with fragrance quinoline of 3 mmol N-methyl, 28 mmol methylene dichloride.Be heated to 80
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium bicarbonate solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates by column chromatography and obtains target product, productive rate 88%.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.43–7.45 (m, 2H; Ar-H), 7.29–7.32 (m, 3H; Ar-H), 3.78 (t, J = 4.6 Hz, 4H; CH
2), 3.52 (s, 2H; CH
2), 2.66 (t, J = 4.6Hz, 4H; CH
2)。
Synthesis example 8
Synthesizing of N-methyl-N-cyclohexyl-3-phenyl-2-propargylamine
In reactor, add 1 mol % CuBr
2, vacuumize backfill N
2, add 1 ml acetonitrile, 1 mmol phenylacetylene, 4 mmol N, N-dimethylcyclohexylamine, 8 mmol methylene bromides and 9 mmol methylene dichloride.Be heated to 80
oUnder C, reaction is 8 hours.Question response liquid is cooled to room temperature, adopts the saturated ammonium chloride solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates and obtains target product, productive rate 91% through column chromatography.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.42–7.44 (m, 2H; Ar-H), 7.28–7.31 (m, 3H; Ar-H), 3.65 (s, 2H; CH
2), 2.45-2.48 (m, 1H; CH), 2.43 (s, 3H; CH
3), 1.96-1.98 (d, J = 10.4Hz, 2H; CH
2), 1.80 (d, J = 2.0Hz, 2H; CH
2), 1.78 (d, J = 2.4Hz, 1H; CH), 1.23 (d, J = 1.2Hz, 4H; CH
2), 1.17-1.20 (m, 1H; CH)。
Synthesis example 9
N-methyl-N-benzyl-3-phenyl-2-propargylamine and N, N-dimethyl-3-phenyl-2-propargylamine synthetic
In reactor, add 1 mol% CuSO
4, vacuumizing, backfilled with inert gas, add 0.5 ml DMF and 0.5 ml Isosorbide-5-Nitrae-dioxane, 1 mmol phenylacetylene, 3 mmol N, and N-dimethyl benzylamine, 10 mmol methylene dichloride, be heated to 100
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium carbonate solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain two kinds of target products through column chromatography, and productive rate is respectively 50% and 25%.Wherein N-methyl-N-benzyl-3-phenyl-2-propargylamine is the propargylamine compound that can not synthesize by end alkynes, methylene dichloride and secondary amine.
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.42–7.44 (m, 2H; Ar-H), 7.28–7.30 (m, 3H; Ar-H), 3.49 (s, 2H; CH
2), 2.38 (s, 6H; CH
3)。
1H NMR (CDCl
3, 400 MHz, TMS): δ 7.36–7.48 (m, 2H; Ar-H), 7.32–7.34 (m, 3H; Ar-H), 7.24-7.31 (m, 5H; Ar-H), 3.64 (s, 2H; CH
2), 3.52 (s, 2H; CH
2), 2.41 (s, 3H; CH
3)。
Synthesis example 10
N, N-diethyl-3-(p-methylphenyl)-2-propargylamine synthetic
In reactor, add 5 mol% AgOAc, vacuumize, backfill N
2, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol to methylbenzene acetylene, 4 mmol triethylamines, 13 mmol methylene dichloride.Be heated to 100
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium bicarbonate solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 88%.
1H NMR (400 MHz, CDCl
3, TMS ): δ 7.31–7.35 (d, J = 8.0 Hz ,2H; Ar-H), 7.09–7.11 (d, J=8.0 Hz, 2H; Ar-H), 3.63 (s, 2H; CH
2), 2.63 (q, J = 11.2 Hz, 4H; CH
2), 2.33 (s, 3H; CH
3), 1.11 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 11
N, N-diethyl-3-(4-tert-butyl-phenyl)-2-propargylamine synthetic
In reactor, add 0.5 mol% CuBr
2With 0.5 mol% CuSO
4, vacuumize backfill N
2, add 1 ml trichloromethane, 1 mmol to tert.-butylbenzene acetylene, 3 mmol triethylamines, 10 mmol methylene bromides.Be heated to 105
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated ammonium chloride solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 80%.
1H NMR (400 MHz, CDCl
3, TMS): δ 7.35–7.37 (m, 2H; Ar-H), 7.25–7.31(m, 2H; Ar-H), 3.62 (s, 2H; CH
2), 2.61 (q, J = 7.2 Hz, 4H; CH
2), 1.29 (s, 9H, CH
3), 1.11 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 12
N, N-diethyl-3-(4-amyl group phenyl)-2-propargylamine synthetic
In reactor, add 1 mol% Cu (NO
3)
2, vacuumize backfill N
2, add 1 ml tetrahydrofuran (THF), 1 mmol to amylbenzene acetylene, 4 mmol triethylamines, 16 mmol methylene bromides.Be heated to 85
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium carbonate solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 89%.
1H NMR (400 MHz, CDCl
3, TMS): δ 7.32–7.34 (d, J = 8.0 Hz, 2H; Ar-H), 7.09–7.11 (d, J = 8.0 Hz, 2H; Ar-H), 3.64 (s, 2H; CH
2), 2.63 (q, J = 7.2 Hz, 2H; CH
2), 2.57 ( d, J = 8.0 Hz, 4H; CH
2), 1.55-1.63 (m, 2H; CH
2), 1.27-1.32 (m, 4H; CH
2), 1.11 (t, J = 7.2 Hz, 6H; CH
3), 0.88 (t, J = 7.2 Hz, 3H; CH
3)。
Synthesis example 13
N, N-diethyl-3-(4-p-methoxy-phenyl)-2-propargylamine synthetic
In reactor, add 5 mol% AgOAc, vacuumize, backfill N
2, add 0.5 ml tetrahydrofuran (THF) and 0.5 m14-dioxane, 1 mmol to anisole acetylene, 4.6 mmol triethylamines, 20 mmol methylene dichloride.Be heated to 90
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium bicarbonate solution washing, with dichloromethane extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 90%.
1H NMR (400 MHz, CDCl
3, TMS ): δ 7.34–7.36 (m, 2H; Ar-H), 6.80–6.82 (m, 2H; Ar-H), 3.79 (s, 3H; CH
3), 3.62 (s, 2H; CH
2), 2.60 (q, J = 11.2 Hz, 4H; CH
2), 1.11 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 14
N, N-diethyl-3-(4-bromophenyl)-2-propargylamine synthetic
In reactor, add 1 mol% PdCl
2, vacuumize backfill N
2, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol to bromobenzene acetylene, 4 mmol triethylamines, 3 mmol methylene bromides and 13 mmol methylene dichloride.Be heated to 110
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated nacl aqueous solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 92%.
1H NMR (400 MHz, CDCl
3, TMS): δ 7.40–7.44 (m, 2H; Ar-H), 7.27–7.29(m, 2H; Ar-H), 3.62 (s, 2H; CH
2), 2.60 (q, J = 7.2 Hz, 4H; CH
2), 1.10 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 15
N, N-diethyl-3-(4-chloro-phenyl-)-2-propargylamine synthetic
In reactor, add 5 mol% AgOAc, vacuumize, backfilled with inert gas, add 1 ml DMF, 1 mmol to chlorobenzene acetylene, 3 mmol triethylamines, 10 mmol methylene dichloride.Be heated to 115
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated ammonium chloride solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates stone through column chromatography and obtains target product, productive rate 90%.
1H NMR (400 MHz, CDCl
3, TMS): δ 7.33–7.35 (m, 2H; Ar-H), 7.25–7.27 (m, 2H; Ar-H), 3.62 (s, 2H; CH
2), 2.60 (q, J = 7.2 Hz, 4H; CH
2), 1.10 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 16
N, N-diethyl-3-(4-fluorophenyl)-2-propargylamine synthetic
In reactor, add 10 mol% NiCl
2, vacuumizing, backfilled with inert gas, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol to fluorobenzene acetylene, 3 mmol triethylamines, 18 mmol methylene bromides.Be heated to 105
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium bicarbonate solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 92%.
1H NMR (400 MHz, CDCl
3, TMS): δ 7.38–7.41 (m, 2H; Ar-H), 6.96–7.00 (m, 2H; Ar-H), 3.62 (s, 2H; CH
2), 2.62 (q, J = 7.2 Hz, 4H; CH
2), 1.11 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 17
N, N-diethyl-3-(4-trifluoromethyl)-2-propargylamine synthetic
In reactor, add 10 mol% CoCl
26H
2O, vacuumize, and backfilled with inert gas adds 1 ml tetrahydrofuran (THF), 1 mmol to trifluoromethyl phenylacetylene, 5 mmol triethylamines, 20 mmol methylene dichloride.Be heated to 110
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium carbonate solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 91%.
1H NMR (400 MHz, CDCl
3, TMS ): δ 7.54 (d, 2H; Ar-H), 7.50 (d, 2H; Ar-H), 3.66 (s, 2H; CH
2), 2.62 (q, J = 11.2 Hz, 4H; CH
2), 1.12 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 18
N, N-diethyl-3-(4-nitrophenyl)-2-propargylamine synthetic
In reactor, add 5 mol% AgNO
3, vacuumizing, backfilled with inert gas, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol p-nitrophenylacetylene, 3 mmol triethylamines, 25 mmol methylene dichloride.Be heated to 115
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated nacl aqueous solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 87%.
1H NMR (400 MHz, CDCl
3, TMS): δ 7.38–7.41 (m, 2H, Ar-H), 6.96–7.00 (m, 2H, Ar-H), 3.62 (s, 2H, CH
2), 2.62 (q, J = 7.2 Hz, 4H,CH
2), 1.11 (t, J = 7.2 Hz, 6H, CH
3)。
Synthesis example 19
N, N-diethyl-3-(4-acetyl phenyl)-the 2-propargylamine
In reactor, add 5 mol% AgOAc, vacuumize, backfilled with inert gas, add 1 ml methyl-sulphoxide, 1 mmol 4-acetylenylbenzene ethyl ketone, 3 mmol triethylamines, 15 mmol methylene dichloride.Be heated to 85
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium carbonate solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 89%.
1H NMR (400 MHz, CDCl
3, TMS ): δ 7.86 (d, J = 8.0 Hz ,2H; Ar-H), 7.47 (d, J = 8.0 Hz, 2H; Ar-H), 3.65 (s, 2H; CH
2), 2.60 (q, J = 11.2 Hz, 4H; CH
2), 2.57 (s, 3H; CH
3), 1.11 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 20
N, N-diethyl-3-(4-ethynyl phenyl)-2-propargylamine synthetic
In reactor, add 10 mol% AgOAc, vacuumize, backfill N
2, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol Isosorbide-5-Nitrae-diacetylene-benzene, 3 mmol triethylamines, 15 mmol methylene dichloride.Be heated to 90
oUnder C, reaction is 20 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium bicarbonate solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 88%.
1H NMR (400 MHz, CDCl
3, TMS): δ 7.35 (s, 4H; Ar-H), 3.66 (s, 4H; CH
2), 2.62 (q, J = 7.2 Hz, 8H; CH
2), 1.12 (t, J = 7.2 Hz, 12H; CH
3)。
Synthesis example 21
N, N-diethyl-3-(2-pyridyl)-2-propargylamine synthetic
In reactor, add 1 mol% Cu powder, vacuumize backfill N
2, add 1 ml DMF, 1 mmol 2-ethynyl pyridine, 5 mmol triethylamines, 20 mmol methylene iodides.Be heated to 85
oUnder C, reaction is 10 hours.Question response liquid is cooled to room temperature, adopts the saturated ammonium chloride solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 88%.
1H NMR (400 MHz, CDCl
3, TMS): δ 8.56 (d, J = 7.2 Hz, 1H; Ar-H), 7.61-7.65 (m, 1H; Ar-H), 7.22-7.42 (m, 1H; Ar-H), 7.20-7.22 (m, 1H; Ar-H), 3.70 (s, 2H; CH
2), 2.65 (q, J = 7.2 Hz, 8H; CH
2), 1.12 (t, J = 7.2 Hz, 12H; CH
3)。
Synthesis example 22
N, N-diethyl-3-(2-thienyl)-2-propargylamine synthetic
In reactor, add 1 mol% CuSO
4, vacuumize backfill N
2, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol 2-thiophene acetylene, 4 mmol triethylamines, 18 mmol methylene bromides.Be heated to 100
oUnder C, reaction is 12 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium bicarbonate solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 87%.
1H NMR (400 MHz, CDCl
3, TMS): δ 7.19-7.21 (m, 1H; Ar-H), 7.16-7.17 (m, 1H; Ar-H), 6.94-6.96 (m, 1H; Ar-H), 3.66 (s, 2H; CH
2), 2.62 (q, J = 7.2 Hz, 4H; CH
2), 1.11 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 23
N, N-diethyl-3-(2-hydroxycyclopent base)-the 2-propargylamine
In reactor, add 1 mol% Cu
2O, vacuumize, backfill N
2, add 0.5 ml DMF and 0.5 ml methyl-sulphoxide, 1 mmol 1-ethynyl cyclopentanol, 4 mmol triethylamines, 15 mmol methylene dichloride.Be heated to 85
oUnder C, reaction is 20 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium carbonate solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 92%.
1H NMR (400 MHz, CDCl
3, TMS): δ 3.44 (s, 2H; CH
2), 2.57 (s, 1H; OH), 2.54 (q, J = 7.2 Hz, 4H; CH
2), 1.91-1.95 (m, 4H; CH
2), 1.81-1.83 (m, 2H; CH
2), 1.72-1.81 (m, 2H; CH
2), 1.07 (t, J = 7.2 Hz, 6H; CH
3)。
Synthesis example 24
N, N-diethyl-3-(is trimethyl silicon based)-2-propargylamine synthetic
In reactor, add 1 mol% Cu
2O, vacuumize, backfill N
2, add 1 ml Isosorbide-5-Nitrae-dioxane, 1 mmol trimethylsilyl acetylene, 4 mmol triethylamines, 12 mmol methylene dichloride.Be heated to 90
oUnder C, reaction is 20 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium carbonate solution washing, with ethyl acetate extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 75%.
1H NMR (400 MHz, CDCl
3, TMS): δ 3.42 (s, 2H; CH
2), 2.55 (q, J = 7.2 Hz, 4H; CH
2), 1.07 (t, J = 7.2 Hz , 6H; CH
3), 0.16 (s, 9H; CH
3)。
Synthesis example 25
N, N-diethyl-2-alkynes nonyl amine synthetic
In reactor, add 1 mol% Cu
2O, vacuumize, backfill N
2, add 1 ml DMF, 1 mmol 1-octyne, 4 mmol triethylamines, 22 mmol methylene bromides.Be heated to 120
oUnder C, reaction is 20 hours.Question response liquid is cooled to room temperature, adopts the saturated sodium bicarbonate solution washing, with chloroform extraction, and drying, underpressure distillation is except desolventizing, and thick product separates to obtain target product through column chromatography, productive rate 83%.
1H NMR (400 MHz, CDCl
3, TMS): δ 3.47 (s, 2H; CH
2), 2.64 (q, J = 6.8 Hz, 4H; CH
2), 2.18-2.21 (m, 2H; CH
2), 1.25-1.50 (m, 12H; CH
2), 1.13 (t, J = 7.2 Hz, 6H; CH
3), 0.88 (t, J = 6.8 Hz, 3H; CH
3)。
Claims (9)
1. synthetic method with propargylamine compounds of structural formula (I), comprise following reactions steps: the reactor that catalyzer will be housed vacuumizes, and fills rare gas element, in inert atmosphere, adds solvent, terminal alkyne, methylene halide and tertiary amine, tube sealing, be heated to 80 ~ 120
oC reaction 8 ~ 72 hours, reaction is cooled to room temperature after finishing, and with the saturated salt solution washing, then uses organic solvent extraction, drying, underpressure distillation is concentrated except desolventizing, and thick product separates through column chromatography, obtains target product.
In described general formula (I),
R
1On aryl or phenyl ring, to contain the substituted aryl to electronics or electron-withdrawing substituent; Or
R
1Chain-like alkyl, the 2-hydroxycyclopent base or trimethyl silicon based with 5 or 6 carbon atoms;
R
2, R
3Alkyl or the ethylenic unsaturation alkyl that contains 1,2,3,4,8 carbon atom, R
2, R
3Can be identical, also can be different; Or
R
2Methyl, R
3Cyclohexyl or benzyl; Or
R
2~ R
3Be and alicyclic radical or oxygen replace and alicyclic radical.
2. the synthetic method of propargylamine compounds according to claim 1, is characterized in that, described catalyzer is selected from AlCl
3, PdCl
2, Pd (OAc)
2, Cu, CuO, Cu
2O, CuCl, CuCl
2, CuBr, CuBr
2, Cu (OAc)
2, CuSO
4, Cu (NO
3)
2, AgOAc, AgCl, AgBF
4, AgNO
3, Ag
2CO
3, CoCl
2.6H
2O, NiCl
2, FeCl
2In at least a.
3. the synthetic method of propargylamine compounds according to claim 1, it is characterized in that, described solvent is selected from least a in Isosorbide-5-Nitrae-dioxane, DMF, methyl-sulphoxide, tetrahydrofuran (THF), trichloromethane, acetonitrile, toluene, ethyl acetate.
4. the synthetic method of propargylamine compounds according to claim 1, it is characterized in that, described end is selected from phenylacetylene, to methylbenzene acetylene, to tert.-butylbenzene acetylene, to n-amylbenzene acetylene, to fluorobenzene acetylene, to chlorobenzene acetylene, to bromobenzene acetylene, to trifluoromethyl phenylacetylene, p-nitrophenylacetylene, to carbonyl phenylacetylene, Isosorbide-5-Nitrae-diacetylene-benzene, 2-ethynyl pyridine, 2-thiophene acetylene, 2-ethynyl cyclopentanol, trimethylsilyl acetylene, 1-heptyne or 1-octyne.
5. the synthetic method of propargylamine compounds according to claim 1, it is characterized in that, described tertiary amine is selected from triethylamine, Tri-n-Propylamine, tri-n-butylamine, tri-n-octyl amine, triallylamine, N, N-dimethylcyclohexylamine, N-methyl piperidine, N-ethylpiperidine, N-methylmorpholine, N, N-dimethyl benzylamine, N, N-dimethyl n butylamine, N, N-dimethyl TERTIARY BUTYL AMINE or N, N-dimethyl allylamine.
6. the synthetic method of propargylamine compounds according to claim 1, is characterized in that, described methylene halide is selected from least a in methylene dichloride, methylene bromide or methylene iodide.
7. the synthetic method of propargylamine compounds according to claim 1, is characterized in that, the mole dosage of described catalyzer in reaction system is that 1 ~ 10 mol%(is based on end alkynes).
8. according to the synthetic method of the described propargylamine compounds of claim any one, it is characterized in that, the mol ratio between described end alkynes, tertiary amine, methylene halide is 1:[3 ~ 5]: [10 ~ 30].
9. the synthetic method of propargylamine compounds according to claim 1, is characterized in that described saturated salt solution is mainly the solution of sodium carbonate, sodium bicarbonate, ammonium chloride or sodium-chlor; Organic solvent extract used is mainly to be selected from ethyl acetate, ether, trichloromethane or methylene dichloride.
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| CN103819424A (en) * | 2014-02-25 | 2014-05-28 | 苏州大学 | Method for preparing propargylamine |
| CN105481699A (en) * | 2016-01-14 | 2016-04-13 | 复旦大学 | Method for synthesizing propargylamine derivative with different substituent groups at alkyne terminal |
| CN107935860A (en) * | 2017-12-08 | 2018-04-20 | 苏州大学 | A kind of method for preparing allylic amines compound |
| CN108929286A (en) * | 2018-07-02 | 2018-12-04 | 河南师范大学 | The method that functionalized ion liquid promotes multi-component reaction synthesis propargylamine class compound |
| CN109320441A (en) * | 2017-07-31 | 2019-02-12 | 江西师范大学 | A method of efficiently preparing alkynyl amide class compound |
| WO2020087233A1 (en) * | 2018-10-29 | 2020-05-07 | 南通纺织丝绸产业技术研究院 | Application of ionic iron (iii) complex as catalyst in preparation of benzylamine compound |
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| CN103819424A (en) * | 2014-02-25 | 2014-05-28 | 苏州大学 | Method for preparing propargylamine |
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| CN109320441A (en) * | 2017-07-31 | 2019-02-12 | 江西师范大学 | A method of efficiently preparing alkynyl amide class compound |
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| CN107935860B (en) * | 2017-12-08 | 2019-09-10 | 苏州大学 | A method of preparing allylic amines compound |
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| CN110449183B (en) * | 2017-12-08 | 2021-12-28 | 苏州大学 | Application of ionic iron (III) complex in preparation of allylamine compound |
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| US11890602B2 (en) | 2018-10-29 | 2024-02-06 | Soochow University | Application of the ionic iron (III) complex as catalyst in preparation of benzylamine compound |
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