CN103408433B - Method for synthesizing propargylamine compounds - Google Patents
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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 organic synthesis field, be specifically related to a kind of synthetic method of propargylamine compounds.
[background technology]
Propargylamine compounds has purposes widely in fields such as medicine, synthetic chemistries, and be also very important organic synthesis intermediate, therefore, its synthesis is more and more subject to the attention of chemist.The initial synthetic method of propargylamine compounds is synthesized by nucleophilic addition with stoichiometric alkynyl metallic compound and other reagent.This kind of method needs the alkynyl metallic compound using equivalent, and complicated operation, thus limit its application.The synthetic method mainly three components coupling of nearest propargylamine compounds, comprises (the A of alkynes, aldehyde, primary amine and secondary amine
3) coupling and alkynes, methylene dichloride, secondary amine (AHA) coupling.Although multiple propargylamine compounds can be synthesized by these two kinds of synthetic methods, but primary amine and secondary amine are generally expensive than tertiary amine, if and in substrate molecule containing to primary amine and secondary amine than more sensitive functional group, the synthesis of its corresponding propargylamine compounds will be subject to a definite limitation.Tertiary amine is the amine the most easily synthesized in organic compound, is also stable amine, and therefore, adopting tertiary amine to synthesize propargylamine compounds as amine substrate is 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 designing and developing the propargylamine compounds with stronger application prospect is that industry is explored.
[summary of the invention]
The object of the invention is a kind of tertiary amine cheap and easy to get of development is amine raw material, is ruptured by the selectivity of C-N key, the method for high conversion and high productivity synthesis propargylamine compounds.
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, fills 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, is cooled to room temperature after reaction terminates, and with saturated salt solution washing, then uses organic solvent extraction, and dry, underpressure distillation is except desolventizing, and thick product, through pillar layer separation, obtains target product.
In described structural formula, R
1containing to the substituted aryl of electronics or electron-withdrawing substituent on aryl or phenyl ring; Or R
1chain-like alkyl, the 2-hydroxycyclopent base or trimethyl silicon based with 5 or 6 carbon atoms; R
2, R
3the alkyl containing 1,2,3,4,8 carbon atom or ethylenic unsaturation alkyl, 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 replacement also alicyclic radical.
In above-mentioned synthetic method, 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 one.
In above-mentioned synthetic method, described solvent is selected from least one 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 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.
In above-mentioned synthetic method, described methylene halide is selected from least one 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].
Experimentally result, method of being synthesized 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 extra additive, cheaper starting materials is easy to get, selectivity of product and yield all very advantages of higher, and has good prospects for commercial application.
[accompanying drawing explanation]
Fig. 1 is the building-up reactions formula of propargylamine compounds provided by the invention.
[embodiment]
Be described further synthetic method of the present invention below in conjunction with synthesis example of the present invention, it should be noted that, embodiment does not form the restriction to application claims protection domain.
As shown in Figure 1, the synthesis step of propargylamine compounds provided by the invention is (carrying out under operating in anhydrous and oxygen-free condition below): at N
2or under other inert atmospheres, add 1-10 mol%(in the reactor based on end alkynes) catalyzer (as silver acetate), add 1ml organic solvent (e.g., Isosorbide-5-Nitrae dioxane), 1 mmol end alkynes, 10 ~ 30 mmol methylene halides, 3 ~ 5 mmol tertiary amines.Be heated to 80 ~ 120 DEG C, Keep agitation 8 ~ 72 h, stopped reaction, is cooled to room temperature, and with saturated sodium carbonate solution washing, with organic solvent extraction, dry, underpressure distillation desolventizing, thick product, through pillar layer separation, obtains target product.
Synthesis example 1
The synthesis of N, N-diethyl-3-phenyl-2-propargylamine
Add 5 mol% AgOAc in the reactor, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium bicarbonate solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and namely thick product obtains target product through pillar layer separation, productive rate 90%.
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
The synthesis of N, N-diη-propyl-3-phenyl-2-propargylamine
Add 10 mol% Cu in the reactor
2o, vacuumizes, 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
oreact 30 hours under C.Question response liquid is cooled to room temperature, adopts saturated nacl aqueous solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and namely thick product obtains target product through pillar layer separation, productive rate 88%.
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
The synthesis of N, N-di-n-butyl-3-phenyl-2-propargylamine
Add 1 mol% CuSO in the reactor
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
oreact 50 hours under C.Question response liquid is cooled to room temperature, adopts saturated ammonium chloride solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and namely thick product obtains target product through pillar layer separation, productive rate 85%.
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
The synthesis of N, N-di-n-octyl-3-phenyl-2-propargylamine
Add 0.5 mol% Cu in the reactor
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
oreact 72 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium carbonate solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and namely thick product obtains target product through pillar layer separation, productive rate 80%.
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
The synthesis of N, N-diallyl-3-phenyl-2-propargylamine
Add 5 mol% AgBF in the reactor
4, vacuumize, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated nacl aqueous solution washing, then uses chloroform extraction, and with desiccant dryness, underpressure distillation is except desolventizing, and namely thick product obtains target product through pillar layer separation, productive rate 90%.
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) synthesis of piperidines
Add 1 mol% Cu (OAc) in the reactor
2, vacuumize, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium carbonate solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and namely thick product obtains target product through pillar layer separation, productive rate 85%.
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) synthesis of morpholine
Add 1 mol% CuCl in the reactor
2, vacuumize, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium bicarbonate solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and namely thick product pillar layer separation 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
The synthesis of N-methyl-N-cyclohexyl-3-phenyl-2-propargylamine
Add 1 mol % CuBr in the reactor
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
oreact 8 hours under C.Question response liquid is cooled to room temperature, adopts saturated ammonium chloride solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and namely thick product obtains target product through pillar layer separation, productive rate 91%.
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
The synthesis of N-methyl-N-benzyl-3-phenyl-2-propargylamine and N, N-dimethyl-3-phenyl-2-propargylamine
Add 1 mol% CuSO in the reactor
4, vacuumize, backfilled with inert gas, add 0.5 ml DMF and 0.5 ml Isosorbide-5-Nitrae-dioxane, 1 mmol phenylacetylene, 3 mmol N, N-dimethyl benzylamine, 10 mmol methylene dichloride, be heated to 100
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium carbonate solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and thick product obtains two kinds of target products through pillar layer separation, 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) synthesis of-2-propargylamine
Add 5 mol% AgOAc in the reactor, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium bicarbonate solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 0.5 mol% CuBr in the reactor
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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated ammonium chloride solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 1 mol% Cu (NO in the reactor
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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium carbonate solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 5 mol% AgOAc in the reactor, vacuumize, backfill N
2, add 0.5 ml tetrahydrofuran (THF) and 0.5 m14-dioxane, 1 mmol to Methoxy-phenylacetylene, 4.6 mmol triethylamines, 20 mmol methylene dichloride.Be heated to 90
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium bicarbonate solution washing, and with dichloromethane extraction, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 1 mol% PdCl in the reactor
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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated nacl aqueous solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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-) synthesis of-2-propargylamine
Add 5 mol% AgOAc in the reactor, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated ammonium chloride solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation stone, 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) synthesis of-2-propargylamine
Add 10 mol% NiCl in the reactor
2, vacuumize, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium bicarbonate solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 10 mol% CoCl in the reactor
26H
2o, vacuumizes, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium carbonate solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 5 mol% AgNO in the reactor
3, vacuumize, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated nacl aqueous solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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)-2-propargylamine
Add 5 mol% AgOAc in the reactor, 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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium carbonate solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 10 mol% AgOAc in the reactor, 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
oreact 20 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium bicarbonate solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 1 mol% Cu powder in the reactor, vacuumize, backfill N
2, add 1 ml DMF, 1 mmol 2-ethynyl pyridine, 5 mmol triethylamines, 20 mmol methylene iodides.Be heated to 85
oreact 10 hours under C.Question response liquid is cooled to room temperature, adopts saturated ammonium chloride solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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) synthesis of-2-propargylamine
Add 1 mol% CuSO in the reactor
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
oreact 12 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium bicarbonate solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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)-2-propargylamine
Add 1 mol% Cu in the reactor
2o, vacuumizes, 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
oreact 20 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium carbonate solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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
-3-(is trimethyl silicon based for N, N-diethyl) synthesis of-2-propargylamine
Add 1 mol% Cu in the reactor
2o, vacuumizes, 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
oreact 20 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium carbonate solution washing, and with extraction into ethyl acetate, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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
The synthesis of N, N-diethyl-2-alkynes nonyl amine
Add 1 mol% Cu in the reactor
2o, vacuumizes, backfill N
2, add 1 ml DMF, 1 mmol 1-octyne, 4 mmol triethylamines, 22 mmol methylene bromides.Be heated to 120
oreact 20 hours under C.Question response liquid is cooled to room temperature, adopts saturated sodium bicarbonate solution washing, and with chloroform extraction, dry, underpressure distillation is except desolventizing, and thick product obtains target product through pillar layer separation, 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 (7)
1. one kind has the synthetic method of the propargylamine compounds of structural formula (I), comprise following reactions steps: vacuumized by the reactor that catalyzer is housed, fill rare gas element, solvent, terminal alkyne, methylene halide and tertiary amine is added in inert atmosphere, tube sealing, be heated to 80 ~ 120 DEG C of reactions 8 ~ 72 hours, room temperature is cooled to after reaction terminates, wash with saturated salt solution, then use organic solvent extraction, dry, underpressure distillation is concentrated except desolventizing, thick product, through pillar layer separation, obtains target product;
In described general formula (I),
R
1containing to the substituted aryl of electronics or electron-withdrawing substituent on aryl or phenyl ring; Or
R
1chain-like alkyl, the 2-hydroxycyclopent base or trimethyl silicon based with 5 or 6 carbon atoms;
R
2, R
3the alkyl containing 1,2,3,4,8 carbon atom or ethylenic unsaturation alkyl, 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 replacement also alicyclic radical;
Described terminal alkyne be 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; Mol ratio between described terminal alkyne, tertiary amine, methylene halide is 1:[3 ~ 5]: [10 ~ 30].
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
26H
2o, NiCl
2, FeCl
2in at least one.
3. the synthetic method of propargylamine compounds according to claim 1, it is characterized in that, described solvent is selected from least one 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 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.
5. the synthetic method of propargylamine compounds according to claim 1, is characterized in that, described methylene halide is selected from least one in methylene dichloride, methylene bromide or methylene iodide.
6. the synthetic method of propargylamine compounds according to claim 1, is characterized in that, the mole dosage of described catalyzer in reaction system is 1 ~ 10mol% of terminal alkyne.
7. the synthetic method of propargylamine compounds according to claim 1, is characterized in that, the solution of described saturated salt solution mainly sodium carbonate, sodium bicarbonate, ammonium chloride or sodium-chlor; Organic solvent extract used is mainly selected from ethyl acetate, ether, trichloromethane or methylene dichloride.
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