CN109503405A - A kind of synthetic method of N- n-propyl amide - Google Patents

A kind of synthetic method of N- n-propyl amide Download PDF

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CN109503405A
CN109503405A CN201811572572.1A CN201811572572A CN109503405A CN 109503405 A CN109503405 A CN 109503405A CN 201811572572 A CN201811572572 A CN 201811572572A CN 109503405 A CN109503405 A CN 109503405A
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amide
ether
crown
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CN109503405B (en
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聂海瑜
阿迪拉·阿地江
李恒朝
赖泽敏
安杰
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China Agricultural University
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China Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/72—Ethanonaphthalenes; Hydrogenated ethanonaphthalenes

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Abstract

The invention belongs to organic synthesis fields, are related to a kind of alternative C-N σ key disconnected in azetidine amide, are translated into the novel reaction method to N- n-propyl amide.This method is electron donor using alkali metal/crown ether electronics salt system using azetidine amide class compound as starting material.

Description

A kind of synthetic method of N- n-propyl amide
Technical field
The invention belongs to organic synthesis fields, are related to a kind of alternative C-N σ key disconnected in azetidine amide, It is translated into the reaction method of corresponding N- n-propyl amide.
Background technique
Amide is most generally existing one of functional group.Although the reduction functionalization of amide is widely studied, Most of correlative study is reacted both for reduction of amide, converts corresponding amine or alcohol for amide.Only only a few example The function dough of amide can be realized by the non-carbonyl C-N σ key of Selective activation amide under conditions of reduction.2005 Year, Aube and its team report a kind of special bridging lactam compound extremely uncommon C-N σ under catalytic hydrogenation conditions Cleavage reaction (J.Am.Chem.Soc.2005,127,4552-4553).Recently, Szostak research group develops one kind more General single electron transfer (SET) method, uses TmI2- ROH reagent is used as but electron donor reagent is real under conditions of reduction The selectivity fracture (Int.Ed.2013,52,7237~7241 Angew.Chemie) of amide C-N σ key is showed.But the valence of thulium Lattice are very high, and reserves are relatively limited, and this item patent the method will replace TmI using more cheap single electron donating agent2, To realize the purpose for reducing cost.
Summary of the invention
In view of this, the purpose of the present invention is to provide a kind of using substituted azetidine amide as raw material, passes through The efficient green synthetic method of the selectivity fracture synthesis N- n-propyl amide of C-N σ key.To achieve the above object, of the invention Technical solution is as follows:
A method of the C-N σ in azetidine amide is disconnected by selectivity and is bonded to corresponding N- n-propyl amide, It is characterized by: this method is using the azetidine amide replaced as initial reactant, by with alkali metal/crown ether electronics salt body System's reaction, it is selective to be broken C-N σ key, generate corresponding N- n-propyl amide；The substituted azetidine amide The position of substitution is carbonyl.
This method synthesizes N- n-propyl amide using following methods:
Under 0 DEG C, argon gas protective condition, reaction vessel and violent is added in single electron donating agent, solvent and crown ether Stirring 5 minutes.Then reactant is added at 0 DEG C, the reaction was continued.
The reaction formula of this method is as follows:
Wherein, R is aliphatic or aromatic substituents；The single electron donating agent is sodium dispersion, sodium block, sodium Alkali metal reagent or the alloy such as sand, potassium dispersion, potassium block, Na-K alloy；The partial size of alkali metal in the alkali metal dispersion It is 5-100 μm；The dispersing agent is mineral oil, paraffin or toluene；The ethers is 18- crown- 6,15- crown- 5,12- hat 4, hexichol And the arbitrary proportion mixing of one or more of -18- crown- 6 and the cave [2.2.2] ether；The solvent be tetrahydrofuran, ether, The arbitrary proportion of one or more of n-hexane mixes.This method comprises the following steps:
Step S1: under conditions of argon gas protection, solvent and crown ether is added simultaneously into the dispersion of Na dispersion in the oil It is vigorously stirred 5 minutes.；
Step S2: after solution becomes navy blue, substituted azetidine amide is added；
Step S3: using saturated sodium bicarbonate aqueous solution quenching reaction,；
Step S4: being added anhydrous ether and saturated salt solution dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether It takes, and merges organic phase.With the dry organic phase of anhydrous sodium sulfate, filters and be concentrated using Rotary Evaporators.Obtain product；
The reaction temperature of the step S1 and S2 is 0-60 DEG C, and the step S2 reaction time is 10-120 minutes.
Alkali metal is used to react the electronics salt to be formed with crown ether as single electron donor.Solution becomes deep in the step S2 Blue shows the generation of electronics salt.
The beneficial effects of the present invention are:
1) present invention selects to use alkali metal/crown ether electronics using substituted or unsubstituted azetidine amide as raw material Salt system is single electron donating agent, realizes the reaction that C-N σ key is selectively broken in amide, converts N- positive third for reactant Base amide.The substrate scope of application of this method is wider, can obtain in aliphatic and aromatic series azetidinyl amide Higher yield.
2) reagent that this synthetic method is applied widely, yield is high, safe operation is simple, used is cheap and easy to get.
3) 15- crown- 5 can be recycled and be recycled.
4) in this synthetic method, range of reaction temperature is 0-60 DEG C, and pressure is normal pressure, and reaction condition is mild, reaction cost It is lower.
Specific embodiment
The present invention provides a kind of C-N σ by selectivity disconnection azetidine amide to be bonded to corresponding N- positive third The method of base amide, it is characterised in that: this method is using the azetidine amide replaced as initial reactant, by golden with alkali Category/crown ether electronics salt system reaction, it is selective to be broken C-N σ key, generate corresponding N- n-propyl amide；It is described substituted The position of substitution of azetidine amide is carbonyl.
This method synthesizes N- n-propyl amide using following methods:
Under 0 DEG C, argon gas protective condition, reaction vessel and violent is added in single electron donating agent, solvent and crown ether Stirring 5 minutes；Then reactant is added at 0 DEG C, the reaction was continued.
The reaction formula of this method is as follows:
Wherein, R is aliphatic or aromatic substituents；The single electron donating agent is sodium dispersion, sodium block, sodium Alkali metal reagent or the alloy such as sand, potassium dispersion, potassium block, Na-K alloy；The partial size of alkali metal in the alkali metal dispersion It is 5-100 μm；The dispersing agent is mineral oil, paraffin or toluene；The ethers is 18- crown- 6,15- crown- 5,12- hat 4, hexichol And the arbitrary proportion mixing of one or more of -18- crown- 6 and the cave [2.2.2] ether；The solvent be tetrahydrofuran, ether, The arbitrary proportion of one or more of n-hexane mixes.This method comprises the following steps:
Step S1: under conditions of argon gas protection, solvent and crown ether is added simultaneously into the dispersion of Na dispersion in the oil It is vigorously stirred 5 minutes.；
Step S2: after solution becomes navy blue, substituted azetidine amide is added；
Step S3: using saturated sodium bicarbonate aqueous solution quenching reaction,；
Step S4: being added anhydrous ether and saturated salt solution dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether It takes, and merges organic phase.With the dry organic phase of anhydrous sodium sulfate, filters and be concentrated using Rotary Evaporators.Obtain product；
The reaction temperature of the step S1 and S2 is 0-60 DEG C, and the step S2 reaction time is 10-120 minutes.
Alkali metal is used to react the electronics salt to be formed with crown ether as single electron donor.Solution becomes deep in the step S2 Blue shows the generation of electronics salt.
In order to further illustrate the present invention, below with reference to embodiment to a kind of conjunction of N- n-propyl amide provided by the invention It is described in detail at method, but they cannot be interpreted as limiting the scope of the present invention.
Embodiment 1
At 0 DEG C, under argon gas protective condition, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil Anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (2.0mL) solution of 1a (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 76.51mg targeted Object 2a is closed, product is faint yellow solid, yield 80%.
Structural identification data:1H NMR(300MHz,CDCl3)δ7.32–7.24(m,2H),7.24-7.15(m,3H),5.56 (s, 1H), 3.16 (dd, J=13.6,6.6Hz, 2H), 2.96 (t, J=7.7Hz, 2H), 2.46 (dd, J=8.5,6.9Hz, 2H), 1.44 (dd, J=14.6,7.3Hz, 2H), 0.84 (t, J=7.4Hz, 3H)；13C NMR(75MHz,CDCl3)δ172.2, 140.9,128.4,128.3,126.1,41.2,38.4,31.8,22.7,11.3。
Embodiment 2
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1b (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 97.52mg targeted Object 2b is closed, product is colorless oil, yield 95%.
Structural identification data:1H NMR(300MHz,CDCl3)δ7.33-7.23(m,2H),7.23–7.13(m,3H),5.49 (s, 1H), δ 3.20 (dd, J=13.3,6.8Hz, 2H), 2.65 (t, J=7.5Hz, 2H), 2.17 (t, J=7.5Hz, 2H), 2.03-1.91 (m, 2H), 1.51 (dd, J=14.6,7.3Hz, 2H), 0.91 (t, J=7.4Hz, 3H)；13C NMR(75MHz, CDCl3)δ172.7,141.6,128.6,128.4,126.0,41.3,36.0,35.3,27.2,23.0,11.4。
Embodiment 3
Under the conditions of at 0 DEG C, argon gas, anhydrous THF (0.5mL) and 12-crown-4 is added in sodium block (2.50mmol) In the solution of (2.50mmol) and it is vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1c (0.500mmol) is added at 0 DEG C.
After 1 hour, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 31.02mg targeted Object 2c is closed, product is light pink solid, yield 35%.
Structural identification data:1H NMR(300MHz,CDCl3)δ7.40–7.23(m,5H),5.41(s,1H),3.57(s, 2H), δ 3.17 (dd, J=13.4,6.7Hz, 2H), 1.44 (dd, J=14.5,7.4Hz, 2H), 0.83 (t, J=7.4Hz, 3H) ；13C NMR(75MHz,CDCl3)δ171.0,135.2,129.5,129.1,127.4,44.0,41.4,22.8,11.3。
Embodiment 4
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 4.00mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (4.00mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1d (0.500mmol) is added at 0 DEG C.
After 0.5 hour, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And be added anhydrous ether (10mL) and Saturated salt solution (20mL) dilution and liquid separation reservation organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 66.37mg target Compound 2d, product are colorless solid, yield 60%.
Structural identification data:1H NMR(300MHz,CDCl3) δ 7.11 (d, J=8.1Hz, 2H), 6.82 (d, J=8.1Hz, 2H), 5.53 (s, 1H), 3.77 (s, 3H), 3.16 (q, J=6.7Hz, 2H), 2.90 (t, J=7.5Hz, 2H), 2.42 (t, J= 7.6Hz, 2H), 1.45 (dd, J=14.6,7.3Hz, 2H), 0.85 (t, J=7.4Hz, 3H)；13C NMR(75MHz,CDCl3)δ 172.2,158.1,133.0,129.3,114.0,55.3,41.2,38.9,31.0,22.9,11.3。
Embodiment 5
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1e (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 100.60mg targeted Object 2e is closed, product is white solid, yield 98%.
Structural identification data:1H NMR(300MHz,CDCl3) δ 7.08 (s, 4H), 5.72 (s, 1H), 3.16 (dd, J= 13.0,6.2Hz, 2H), 2.91 (t, J=7.8Hz, 2H), 2.44 (t, J=7.8Hz, 2H), 2.30 (s, 3H), 1.45 (dd, J= 14.6,7.3Hz, 2H), 0.85 (t, J=7.4Hz, 3H)；13C NMR(75MHz,CDCl3)δ172.2,137.9,135.6, 129.1,128.2,41.2,38.6,31.4,22.8,21.0,11.3。
Embodiment 6
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 4.00mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (4.00mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1f (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 76.51mg targeted Object 2a is closed, product is weak yellow liquid, yield 80%.
Structural identification data:1H NMR(300MHz,CDCl3)δ7.32–7.24(m,2H),7.23–7.15(m,3H),5.50 (s, 1H), 3.16 (dd, J=13.3,6.8Hz, 2H), 2.96 (t, J=7.7Hz, 2H), 2.46 (dd, J=8.5,6.9Hz, 2H), 1.44 (dd, J=14.6,7.3Hz, 2H), 0.84 (t, J=7.4Hz, 3H)；13C NMR(75MHz,CDCl3)δ172.1, 141.0,128.6,128.4,126.3,41.3,38.6,31.9,22.9,11.3。
Embodiment 7
Under the conditions of at 0 DEG C, argon gas, anhydrous THF (0.5mL) and the cave [2.2.2] ether is added in potassium block (2.50mmol) In (2.50mmol) solution and it is vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1g (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 39.26mg targeted Object 2g is closed, product is white solid, yield 32%.
Structural identification data:1H NMR(300MHz,CDCl3)δ7.73–7.66(m,2H),7.26-7.21(m,2H), 6.32 (s, 1H), 3.39 (dd, J=13.3,6.8Hz, 2H), 2.53 (m, 1H), 1.94-1.73 (m, 5H), 1.61 (dd, J= 14.6,7.3Hz, 2H), 1.43-1.22 (m, 5H), 0.96 (t, J=7.4Hz, 3H)；13C NMR(75MHz,CDCl3)δ167.6, 151.6,132.4,127.0,44.5,41.7,34.3,26.8,26.1,23.0,11.5。
Embodiment 8
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1h (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 113.36mg targeted Object 2h is closed, product is colorless solid, yield 98%.
Structural identification data:1H NMR(300MHz,CDCl3)δ7.38-7.21(m,5H),5.22(s,1H),3.09(td, J=7.0,5.9Hz, 2H), 2.52-2.41 (m, 2H), 2.06-1.96 (m, 2H), 1.89-1.75 (m, 2H), 1.75-1.60 (m, 2H), 1.36 (dd, J=14.4,7.4Hz, 2H), 0.75 (t, J=7.4Hz, 3H)；13C NMR(75MHz,CDCl3)δ176.4, 144.4,128.6,126.8,126.8,59.3,41.4,36.9,24.0,22.7,11.1.
Embodiment 9
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1i (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 109.56mg targeted Object 2i is closed, product is weak yellow liquid, yield 99%.
Structural identification data:1H NMR(300MHz,CDCl3) δ 5.63 (s, 1H), 3.21 (dd, J=13.1,6.7Hz, 2H), 2.08-2.01 (m, 3H), 1.88-1.82 (m, 6H), 1.76-1.68 (m, 6H), 1.51 (dd, J=14.4,7.2Hz, 2H), 0.91 (t, J=7.4Hz, 3H)；13C NMR(75MHz,CDCl3)δ177.7,41.0,40.7,39.4,36.6,28.3, 23.0,11.4。
Embodiment 10
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1j (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 74.15mg targeted Object 2j is closed, product is yellow liquid, yield 60%.
Structural identification data:1H NMR(300MHz,CDCl3)δ7.22-7.16(m,2H),7.14-7.08(m,2H),5.41 (s, 1H), 3.53 (q, J=7.2Hz, 1H), 3.14 (td, J=7.1,5.9Hz, 2H), 2.45 (d, J=7.2Hz, 2H), 1.84 (dd, J=13.5,6.7Hz, 1H), 1.51 (d, J=7.2Hz, 3H), 1.41 (dd, J=14.5,7.3Hz, 2H), 0.90 (d, J =6.6Hz, 6H), 0.80 (t, J=7.4Hz, 3H)；13C NMR(75MHz,CDCl3)δ174.5,140.7,138.8,129.6, 127.4,46.8,45.1,41.3,30.2,22.8,22.4,18.5,11.2。
Embodiment 11
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1k (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 66.37mg targeted Object 2k is closed, product is colourless liquid, yield 94%.
Structural identification data:1H NMR(300MHz,CDCl3) δ 5.82 (t, J=8.7Hz, 1H), 5.69 (s, 1H), 5.04 (dd, J=18.9,13.6Hz, 2H), 3.22 (d, J=6.8Hz, 2H), 2.33 (dt, J=35.4,7.5Hz, 4H), 1.52 (dd, J=14.5,7.3Hz, 2H), 0.92 (t, J=7.2Hz, 3H)；13C NMR(75MHz,CDCl3)δ172.3,137.2,115.5, 41.3 36.0,29.8,22.9,11.4.
Embodiment 12
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1l (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 40.31mg targeted Object 2l is closed, product is colourless liquid, yield 70%.
Structural identification data:1H NMR(300MHz,CDCl3) δ 5.44 (s, 1H), 3.22 (dd, J=13.7,6.5Hz, 2H), 2.20 (q, J=7.6Hz, 2H), 1.52 (dd, J=14.6,7.3Hz, 2H), 1.16 (t, J=7.6Hz, 3H), 0.93 (t, J=7.6Hz, 3H)；13C NMR(75MHz,CDCl3)δ173.7,41.3,29.9,23.0,11.4,10.0。
Embodiment 13
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous Ether (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
Ether (anhydrous, the 2.0mL) solution of 1m (0.500mmol) is added at 25 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 32.24mg targeted Object 2m is closed, product is colourless liquid, yield 41%.
Structural identification data:1H NMR (300MHz, CDCl3) δ 5.64 (s, 1H), 3.21 (dd, J=13.7,6.5Hz, 2H), 2.16 (dd, J=8.5,6.7Hz, 2H), 1.69-1.58 (m, 2H), 1.52 (dd, J=14.6,7.3Hz, 2H), 1.36- 1.26(m,4H),0.96–0.85(m,6H)；13C NMR(75MHz,CDCl3)δ173.2,41.2,36.9,31.5,25.6, 23.0,22.5,14.0,11.4。
Embodiment 14
Under the conditions of at 0 DEG C, argon gas, it is added into the solution (33.9wt%, 2.50mmol) of Na dispersion in the oil anhydrous THF (0.5mL) and 15- crown- 5 (2.50mmol) are simultaneously vigorously stirred 5 minutes.
THF (anhydrous, the 2.0mL) solution of 1n (0.500mmol) is added at 0 DEG C.
After 2 hours, saturation NaHCO is used3Aqueous solution (2.0mL) quenching reaction.And anhydrous ether (10mL) is added and satisfies With saline solution (20mL) dilution and liquid separation retains organic phase.Water phase is extracted with anhydrous ether (2*10mL), and merges organic phase, is done Dry, concentration, after chromatography (silica, 0-100%EtOAc/ n-hexane) purification of crude product, obtains 135.12mg targeted Object 2n is closed, product is white solid, yield 83%.
Structural identification data:1H NMR (300MHz, CDCl3) δ 5.63 (s, 1H), 3.21 (dd, J=13.5,6.7Hz, 2H), 2.16 (t, J=7.6Hz, 2H), 1.69-1.58 (m, 2H), 1.52 (dd, J=14.6,7.3Hz, 2H), 1.37-1.20 (m,28H),0.96–0.82(m,6H)；13C NMR(75MHz,CDCl3)δ173.2,41.2,37.0,32.0,29.8,29.7, 29.7,29.6,29.4,29.4,25.9,23.0,22.7,14.2,11.4。
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered It is considered as protection scope of the present invention.

Claims (5)

1. a kind of disconnect the method that the C-N σ in azetidine amide is bonded to corresponding N- n-propyl amide by selectivity, Be characterized in that, this method using the azetidine amide replaced as initial reactant, by with alkali metal/crown ether electronics salt system Reaction, it is selective to be broken C-N σ key, generate corresponding N- n-propyl amide；The substituted azetidine amide takes Subrogate and is set to carbonyl.
2. synthetic method as described in claim 1, which is characterized in that this method synthesizes N- n-propyl acyl using following methods Amine:
Under 0 DEG C, argon gas protective condition, reaction vessel is added in single electron donating agent, solvent and crown ether and is vigorously stirred 5 Minute；Then reactant is added at 0 DEG C, the reaction was continued；
The reaction formula of this method is as follows:
Wherein, R is aliphatic or aromatic substituents；The single electron donating agent is sodium dispersion, sodium block, sodium sand, potassium Alkali metal reagent or the alloys such as dispersion, potassium block, Na-K alloy；The partial size of alkali metal in the alkali metal dispersion is 5- 100μm；The dispersing agent is mineral oil, paraffin or toluene；The ethers is 18- crown- 6,15- crown- 5,12- hat 4, dibenzo- The arbitrary proportion mixing of one or more of 18- crown- 6 and the cave [2.2.2] ether；The solvent be tetrahydrofuran, ether, just oneself The arbitrary proportion of one or more of alkane mixes.
3. the synthetic method of acyclic amide class compound as described in claim 1, which is characterized in that this method includes following step It is rapid:
Step S1: under conditions of argon gas protection, solvent and crown ether and violent are added into Na dispersion dispersion in the oil Stirring 5 minutes；
Step S2: after solution becomes navy blue, substituted azetidine amide is added；
Step S3: saturated sodium bicarbonate aqueous solution quenching reaction is used；
Step S4: being added anhydrous ether and saturated salt solution dilution and liquid separation retains organic phase；Water phase is extracted with anhydrous ether, and Merge organic phase；With the dry organic phase of anhydrous sodium sulfate, filters and be concentrated using Rotary Evaporators, obtain product.
4. the synthetic method of acyclic amide class compound as claimed in claim 3, which is characterized in that the step S1's and S2 Reaction temperature is 0-60 DEG C, and the step S2 reaction time is 10-120 minutes.
5. the synthetic method of acyclic amide class compound as claimed in claim 3, which is characterized in that use alkali metal and crown ether The electronics salt formed is reacted as single electron donor；Solution becomes navy blue in the step S2, shows the generation of electronics salt.
CN201811572572.1A 2018-12-21 2018-12-21 Synthesis method of N-N-propyl amide Expired - Fee Related CN109503405B (en)

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CN115052837A (en) * 2020-02-17 2022-09-13 国立研究开发法人科学技术振兴机构 Layered double hydroxide electronic compound and method for producing same
JP7296170B2 (en) 2020-02-17 2023-06-22 国立研究開発法人科学技術振興機構 Layered double hydroxide electride and method for producing the same

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