CN109734705A - A method of preparation N- heterocyclic arene derivative is alkylated through dehalogenation - Google Patents
A method of preparation N- heterocyclic arene derivative is alkylated through dehalogenation Download PDFInfo
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Abstract
The invention discloses a kind of are alkylated through dehalogenation to prepareN‑The method of heterocyclic arene derivative, halogenated N- heterocyclic arene class compound, ether compound, mantoquita, N-F reagent and Bronsted acid are dissolved in organic solvent by it, it is stirred under oil bath, 3-20 h is reacted at a temperature of 20-60 DEG C, after reaction, reaction solution is post-treated obtains N- heterocyclic arene derivative.The present invention realizes halogenated under mantoquita catalysisN‑The alkylation of heterocyclic arene class compound dehalogenation, reaction has high regioselectivity, the substrate scope of application for having expanded reaction can make the haloheteroaromatics compounds such as halogenated quinoline derivatives, halogenated isoquinilone derivatives, halogenated benzoxazoles derivative, halogenated benzothiazole derivant realize selective dehalogenation alkylation.
Description
Technical field
The method for preparing N- heterocyclic arene derivative is alkylated through dehalogenation the present invention relates to a kind of.
Background technique
N- heterocyclic arene derivative compound is a kind of important native compound, is widely present in plant kingdom.Research
Show that N- heterocyclic arene derivative compound has good bioactivity, in terms of antibacterial, anti-inflammatory, anticancer, anti HIV-1 virus
There is remarkable result, has a wide range of applications in field of medicaments.In recent years, alkyl replaces the synthesis of N- heterocyclic arene compound to obtain
Extensive concern, and made some progress, but the dehalogenation alkylated reaction of halogen-containing N- heterocyclic arene compound
It reports at present less, there is huge researching value.
Before the present invention, N- heterocycle virtue is mainly prepared by the intersection dehydrogenation coupling reaction of N- heterocyclic arene and ethers
Hydrocarbon derivative: K2S2O8、(NH4)2S2O8, TBHP be common oxidant, but reaction temperature is higher, conversion zone poor selectivity,
The defects of substrate restricted application.Such as document: Synlett., 2016,27,1282；Chem Sci.,2017,8,4044；
Eur.J.Org.Chem.,2015,2015,4973。
The method of the N- Heterocyclylalkyl of above-mentioned report is usually the intersection dehydrogenation coupling reaction for using free radical to participate in
(CDC reaction), is widely used in C (sp2)-H and C (sp3) coupling building C-C key between-H.This method has had both Atom economy
And the features such as high efficiency, it has also become one of the research hotspot of organic synthesis field in recent years.But what existing CDC reacted
Product is often multidigit point substitution product, is difficult to realize high regioselectivity.It is de- by the selectivity of halogenated N- heterocyclic arene
Haloalkylation, it is available " fixed point substitution product ", however the synthetic method of this respect is seldom, there is huge researching value.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of easy, efficient, safe, mild halogenated N- heterocycle virtues
The highly selective alkylated method of hydrocarbon.
A kind of method that copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that tried in mantoquita, N-F
Agent, Bronsted acid and organic solvent exist under effect, halogenated N- heterocyclic arene class compound shown in formula (I) and ethers shown in formula (II)
Alkylated reaction occurs for ether compound shown in compound or formula (III), and reaction temperature is 20-60 DEG C, reaction time 3-
20h, after reaction, reaction solution is post-treated, and to obtain N- shown in N- heterocyclic arene derivative shown in formula (IV) or formula (V) miscellaneous
Cyclophane hydrocarbon derivative；Reaction equation is as follows:
In formula (I), substituent X indicates chlorine or bromine；
In formula (II) and formula (IV), n=1 or 2；
In formula (III) and formula (V), substituent R2And R3It is each independently selected from hydrogen or C1-C3 alkyl；
In formula (I), shown in the chemical structural formula of Ar-X such as formula (W1), formula (W2) or formula (W3):
In formula (W1), formula (W2) and formula (W3), substituent R1For H, C1-C3 alkyl, C1-C3 alkoxy, nitro, cyano,
Aldehyde radical, carboxyl, trifluoromethyl, fluorine, chlorine or bromine；Substituent group Y indicates oxygen or sulphur.
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that the mantoquita
For CuBr, Cu (OAc)2、CuCl、CuCl2、CuI、Cu(OTf)2Or CuBr2。
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that the N-F
Reagent is such as formula (A), formula (B), formula (C) or formula (D) compound represented；
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that the proton
Acid is trifluoroacetic acid, trifluoromethanesulfonic acid, sulfuric acid, acetic acid or p-methyl benzenesulfonic acid.
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that formula (I) institute
The halogenated N- heterocyclic arene class compound shown rubs with ether compound shown in ether compound shown in formula (II) or formula (III)
You are than being 1:1~30, preferably 1:1~20；The molar ratio of halogenated N- heterocyclic arene class compound and mantoquita shown in formula (I) is
1:0.01~0.3, preferably 1:0.01~0.15.
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that formula (I) institute
The molar ratio of the halogenated N- heterocyclic arene class compound and N-F reagent that show is 1:1~3, preferably 1:1~2；The Bronsted acid with
The molar ratio of halogenated N- heterocyclic arene class compound shown in formula (I) is 0.5~2:1, preferably 1~2:1.
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that described organic
Solvent is acetonitrile or nitromethane, preferably acetonitrile；Reaction temperature is 30~50 DEG C.
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that reaction solution warp
The step of post-processing are as follows: water is added into reaction solution and organic extractant is extracted, liquid separation is organic layer and water layer, organic layer
After being dried over anhydrous sodium sulfate, solvent is removed by being concentrated under reduced pressure, condensate residue is by pillar layer separation, with petroleum ether and second
Acetoacetic ester mixed solvent collects the eluent containing target product, solvent is evaporated off and obtains target product to get formula as eluant, eluent
(IV) N- heterocyclic arene derivative shown in the derivative of N- heterocyclic arene shown in or formula (V).
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that described organic
Extractant is methylene chloride or ethyl acetate.
The method that a kind of copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that the elution
In agent, the volume ratio of petroleum ether and ethyl acetate is 10~50:1.
Compared with prior art, the advantage of this method has the present invention:
1) at low cost using mantoquita as catalyst, reaction condition is mild.
2) the method for the present invention good reaction selectivity, and easy to operate, product yield high.
3) wide application range of substrates by means of the present invention, it is halogenated quinoline derivatives, halogenated isoquinilone derivatives, halogenated
It is de- that the haloheteroaromatics compounds such as benzoxazoles derivative, halogenated benzothiazole derivant can use this method to carry out selectivity
Haloalkylation.
In conclusion the present invention provides the halogenated alkylated methods of N- heterocyclic arene under a kind of catalysis of copper.This method
Have many advantages, such as raw material be easy to get, be easy to operate, good substrate applicability and economic and environment-friendly, be a kind of dehalogenation with higher novelty
Alkylation.The present invention realizes that halogenated N- heterocyclic arene dehalogenation alkylation, reaction have high region under mantoquita catalysis
Selectivity has expanded the substrate scope of application of reaction, can make halogenated quinoline derivatives, halogenated isoquinilone derivatives, halogeno-benzene
And the haloheteroaromatics compound such as oxazole derivatives, halogenated benzothiazole derivant realizes selective dehalogenation alkylation.This method
Mild condition, the cheap and traditional CDC reaction of reagent have complementary well.
Specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This:
Embodiment 1
By 4,7- dichloroquinoline (0.5mmol, 99mg), tetrahydrofuran (10mmol, 720mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol, 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain the chloro- 4- (four of 87.5mg light yellow oil 7-
Hydrogen furans -2- base) quinoline, yield 75%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3) δ 8.91 (d, J=4.5Hz, 1H), 8.16 (d,
J=1.8Hz, 1H), 7.90 (d, J=9.0Hz, 1H), 7.58-7.52 (m, 2H), 5.59 (t, J=7.1Hz, 1H), 4.25 (dd,
J=13.6,7.5Hz, 1H), 4.08 (dd, J=15.1,7.3Hz, 1H), 2.63 (td, J=14.2,7.6Hz, 1H), 2.18-
2.01(m,2H),1.91–1.83(m,1H)；13C NMR(101MHz,CDCl3)δ151.5,149.6,148.6,134.8,
129.1,127.3,124.6,124.0,116.7,76.6,69.0,33.9,25.9.HRMS(ESI+):C13H13ClNO([M+
H]+)；calculated:234.0680,found:234.0674.
Embodiment 2
Change the Bronsted acid in system into trifluoroacetic acid (0.5mmol, 57mg), other operating conditions are with embodiment 1, finally
Obtain the chloro- 4- of 70.3mg light yellow oil 7- (tetrahydrofuran -2- base) quinoline, yield 60%.
Embodiment 3
Tetrahydrofuran inventory is changed to 2.5mmol, it is yellowish to finally obtain 60.6mg with embodiment 1 for other operating conditions
The chloro- 4- of color grease 7- (tetrahydrofuran -2- base) quinoline, yield 52%.
Embodiment 4
Cuprous bromide inventory is changed to 0.01mmol, it is yellowish to finally obtain 58.4mg with embodiment 1 for other operating conditions
The chloro- 4- of color grease 7- (tetrahydrofuran -2- base) quinoline, yield 50%.
Embodiment 5
The selective fluorine reagent inventory of system is changed to 0.5mmol, other operating conditions are finally obtained with embodiment 1
The chloro- 4- of 64.3mg light yellow oil 7- (tetrahydrofuran -2- base) quinoline, yield 55%.
Embodiment 6
The inventory of trifluoromethanesulfonic acid is increased into 1mmol (150mg), other operating conditions are finally obtained with embodiment 1
The chloro- 4- of 85.3mg light yellow oil 7- (tetrahydrofuran -2- base) quinoline, yield 73%.
Embodiment 7
Solvent in reaction system is substituted for the nitromethane of peer accumulated amount, other operating conditions are with embodiment 1, most
The chloro- 4- of 49mg light yellow oil 7- (tetrahydrofuran -2- base) quinoline, yield 42% are obtained eventually.
Embodiment 8
Reaction time it will be shorten to 2h, other operating conditions finally obtain 76mg light yellow oil 7- with embodiment 1
Chloro- 4- (tetrahydrofuran -2- base) quinoline, yield 65%.
Embodiment 9
By 4- chloroquinoline (0.5mmol, 81.8mg), tetrahydrofuran (10mmol, 720mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 69.7mg light yellow oil 4- (tetrahydro furan
Mutter -2- base) quinoline, yield 70%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3) δ 8.90 (d, J=4.5Hz, 1H), 8.16 (d,
J=8.4Hz, 1H), 7.93 (d, J=8.4Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.58-7.55 (m, 2H), 5.63 (t, J
=7.1Hz, 1H), 4.26-4.23 (m, 1H), 4.09-4.03 (m, 1H), 2.63 (td, J=14.3,7.6Hz, 1H), 2.14-
1.96(m,2H),1.91–1.82(m,1H)；13C NMR(101MHz,CDCl3)δ150.4,149.6,148.0,130.1,
129.0,126.3,125.5,123.2,116.4,76.7,69.0,33.9,26.0.MS(ESI+):C13H14NO([M+H]+)；
calculated:200.1,found:200.1。
Embodiment 10
By 2- chloroquinoline (0.5mmol, 81.8mg), tetrahydrofuran (10mmol, 720mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 51.8mg light yellow oil 2- (tetrahydro furan
Mutter -2- base) quinoline, yield 52%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3) δ 8.15 (d, J=8.5Hz, 1H), 8.09 (d,
J=8.5Hz, 1H), 7.79 (d, J=8.1Hz, 1H), 7.70 (t, J=7.6Hz, 1H), 7.61 (d, J=8.5Hz, 1H), 7.50
(t, J=7.5Hz, 1H), 5.21 (t, J=7.0Hz, 1H), 4.18 (dd, J=14.4,7.0Hz, 1H), 4.05 (dd, J=
14.5,7.3Hz,1H),2.57–2.49(m,1H),2.14–1.98(m,3H)；13C NMR(101MHz,CDCl3)δ163.5,
147.5,136.7,129.4,129.0,127.6,127.4,126.0,118.0,82.0,69.2,33.4,25.9；MS(ESI+):
C13H14NO([M+H]+)；calculated:200.1,found:200.1.
Embodiment 11
By 4- methyl -2- chlorine-quinoline (0.5mmol, 88.8mg), tetrahydrofuran (10mmol, 720mg), CuBr
(0.025mmol, 3.6mg), selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg) are added
Into 5mL stand up reaction bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, instead
Answer liquid after washing, ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, decompression is steamed
It evaporates and is concentrated to get yellow oil.Yellow oil is by pillar layer separation, with petroleum ether and ethyl acetate volume ratio 10:1
Mixed liquor collects the eluent containing target compound, solvent is evaporated off and is dried to obtain the faint yellow oily of 60.8mg as eluant, eluent
Object 4- methyl -2- (tetrahydrofuran -2- base) quinoline, yield 57%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3) δ 8.10 (d, J=8.4Hz, 1H), 8.01 (d,
J=8.2Hz, 1H), 7.72 (t, J=7.6Hz, 1H), 7.56 (t, J=7.6Hz, 1H), 7.48 (s, 1H), 5.18 (t, J=
6.9Hz, 1H), 4.22 (dd, J=13.9,5.8Hz, 1H), 4.08 (dd, J=14.6,7.0Hz, 1H), 2.75 (s, 3H),
2.59–2.52(m,1H),2.16–2.03(m,3H)；13C NMR(101MHz,CDCl3)δ163.0,147.3,145.0,129.5,
129.1,127.4,125.8,123.7,118.6,82.0,69.2,33.3,26.0,18.9；MS(ESI+):C14H16NO([M+
H]+)；calculated:214.1,found:214.1.
Embodiment 12
By 4- methyl -2- chlorine-quinoline (0.5mmol, 88.8mg), ether (10mmol, 740mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 43mg light yellow oil 2- (1- ethyoxyl second
Base) -4- methylquinoline, yield 40%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3) δ 8.11 (d, J=8.4Hz, 1H), 8.03 (d,
J=8.3Hz, 1H), 7.74 (t, J=7.5Hz, 1H), 7.58 (t, J=7.5Hz, 1H), 7.49 (s, 1H), 4.72 (q, J=
6.6Hz, 1H), 3.59-3.43 (m, 2H), 2.77 (s, 3H), 1.58 (d, J=6.6Hz, 3H), 1.27 (t, J=7.0Hz, 3H)
；13C NMR(101MHz,CDCl3)δ164.0,147.1,145.3,129.5,129.2,127.6,125.0,123.7,118.3,
79.7,64.6,22.6,19.0,15.5；MS(ESI+):C14H18NO([M+H]+)；calculated:216.1,found:
216.1。
Embodiment 13
By 4- methyl -2- chlorine-quinoline (0.5mmol, 88.8mg), oxinane (10mmol, 860mg), CuBr
(0.025mmol, 3.6mg), selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg) are added
Into 5mL stand up reaction bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, instead
Answer liquid after washing, ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, decompression is steamed
It evaporates and is concentrated to get yellow oil.Yellow oil is by pillar layer separation, with petroleum ether and ethyl acetate volume ratio 10:1
Mixed liquor collects the eluent containing target compound, solvent is evaporated off and is dried to obtain the faint yellow oily of 51.1mg as eluant, eluent
Object 4- methyl -2- (tetrahydro -2H- pyrans -2- base) quinoline, yield 45%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3) δ 8.11 (d, J=8.4Hz, 1H), 8.01 (d,
J=8.3Hz, 1H), 7.72 (t, J=7.5Hz, 1H), 7.56 (t, J=7.5Hz, 1H), 7.51 (s, 1H), 4.66 (dd, J=
11.1,1.9Hz, 1H), 4.26 (dd, J=11.2,3.4Hz, 1H), 3.74 (td, J=11.4,2.2Hz, 1H), 2.75 (s,
3H), 2.15 (d, J=13.0Hz, 1H), 2.03-2.02 (m, 1H), 1.87-1.63 (m, 4H)；13C NMR(101MHz,CDCl3)
δ162.1,147.1,145.1,129.6,129.1,127.5,125.8,123.6,118.8,81.6,68.9,32.8,25.9,
23.7,18.8；MS(ESI+):C15H18NO([M+H]+)；calculated:228.1,found:228.1.
Embodiment 14
By 2- chloro benzothiazole (0.5mmol, 84.8mg), tetrahydrofuran (10mmol, 720mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 87.2mg light yellow oil 2- (tetrahydro furan
Mutter -2- base) benzothiazole, yield 85%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3) δ 8.06 (d, J=8.1Hz, 1H), 7.96 (d,
J=7.9Hz, 1H), 7.54 (t, J=7.3Hz, 1H), 7.44 (t, J=7.5Hz, 1H), 5.43 (dd, J=7.7,5.5Hz,
1H), 4.24 (dd, J=14.7,6.7Hz, 1H), 4.08 (dd, J=15.1,7.2Hz, 1H), 2.64-2.56 (m, 1H), 2.40-
2.32 (m, 1H), 2.11 (p, J=7.0Hz, 2H)；13C NMR(101MHz,CDCl3)δ176.3,153.6,134.7,125.9,
124.8,122.8,121.8,78.8,69.4,33.4,25.7；MS(ESI+):C11H12NOS([M+H]+)；calculated:
206.1,found:206.1。
Embodiment 15
By 2- chloro benzothiazole (0.5mmol, 84.8mg), oxinane (10mmol, 860mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 80mg light yellow oil 2- (tetrahydro -2H- pyrrole
Mutter -2- base) benzothiazole, yield 73%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3) δ 8.03 (d, J=8.1Hz, 1H), 7.91 (d,
J=8.0Hz, 1H), 7.48 (t, J=7.6Hz, 1H), 7.38 (t, J=7.5Hz, 1H), 4.82-4.79 (m, 1H), 4.24-
4.20(m,1H),3.74–3.68(m,1H),2.31–2.29(m,1H),2.05–1.99(m,1H),1.83–1.63(m,4H)；13C
NMR(101MHz,CDCl3)δ173.8,153.0,134.7,125.8,124.8,123.0,121.7,77.9,68.9,32.4,
25.6,23.0；MS(ESI+):C12H14NOS([M+H]+)；calculated:220.1,found:220.1.
Embodiment 16
By 2- chlorobenzene diozaiole (0.5mmol, 76.8mg), tetrahydrofuran (10mmol, 720mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 71mg light yellow oil 2- (tetrahydrofuran-
2- yl) benzoxazoles, yield 75%, chemical structural formula are as follows:
Characterize data: light yellow oil,1H NMR(400MHz,CDCl3)δ7.75–7.72(m,1H),7.56–7.54
(m, 1H), 7.37-7.32 (m, 2H), 5.23 (t, J=6.7Hz, 1H), 4.15 (dd, J=14.7,7.3Hz, 1H), 4.04 (dd,
J=14.1,7.6Hz, 1H), 2.43 (q, J=7.2Hz, 2H), 2.20 (tt, J=14.0,7.1Hz, 1H), 2.09 (tt, J=
14.2,7.3Hz,1H)；13C NMR(101MHz,CDCl3)δ166.2,150.9,140.8,125.1,124.3,120.2,
110.7,73.9,69.3,30.7,25.8；MS(ESI+):C11H12NO2([M+H]+)；calculated:190.1,found:
190.1。
Embodiment 17
By 1- chlorine isoquinolin (0.5mmol, 81.8mg), tetrahydrofuran (10mmol, 720mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 80.7mg light yellow oil 1- (tetrahydro furan
Mutter -2- base) isoquinolin, yield 81%, chemical structural formula are as follows:
Characterize data: light yellow oil；1H NMR(400MHz,CDCl3) δ 8.54 (d, J=5.7Hz, 1H), 8.38 (d,
J=8.4Hz, 1H), 7.86 (d, J=8.1Hz, 1H), 7.71 (t, J=7.2Hz, 1H), 7.63 (dd, J=15.3,7.0Hz,
2H), 5.76 (t, J=7.1Hz, 1H), 4.23 (dd, J=14.5,7.4Hz, 1H), 4.08 (dd, J=14.2,7.8Hz, 1H),
2.61–2.52(m,1H),2.49–2.40(m,1H),2.27–2.12(m,2H)；13C NMR(101MHz,CDCl3)δ159.6,
141.5,136.5,129.8,127.3,127.1,126.6,125.3,120.5,79.1,69.0,30.8,26.1；MS(ESI+):
C13H14NO([M+H]+)；calculated:200.1,found:200.1.
Embodiment 18
By 1- chlorine isoquinolin (0.5mmol, 81.8mg), oxinane (10mmol, 860mg), CuBr (0.025mmol,
3.6mg), it is anti-to be added to 5mL single port for selective fluorine reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg)
It answers in bottle, acetonitrile (5.0mL) is added and is used as solvent, oil bath heating to 50 DEG C of reaction 5h.After reaction, reaction solution through washing,
After ethyl acetate extraction, liquid separation is organic layer and water layer, and after organic layer is dried over anhydrous sodium sulfate, vacuum distillation is concentrated to get Huang
Color grease.Yellow oil is by pillar layer separation, using the mixed liquor of petroleum ether and ethyl acetate volume ratio 10:1 as washing
De- agent, collects the eluent containing target compound, solvent is evaporated off and is dried to obtain 71.4mg light yellow oil 1- (tetrahydro -2H-
Pyrans -2- base) isoquinolin, yield 67%, chemical structural formula are as follows:
Characterize data: light yellow oil；1H NMR(400MHz,CDCl3) δ 8.51 (d, J=5.6Hz, 1H), 8.34 (d,
J=8.3Hz, 1H), 7.78 (d, J=7.9Hz, 1H), 7.64-7.53 (m, 3H), 5.17 (dd, J=11.0,2.2Hz, 1H),
4.28-4.24 (m, 1H), 3.77 (td, J=11.6,2.1Hz, 1H), 2.16-1.96 (m, 3H), 1.92-1.72 (m, 2H),
1.66–1.63(m,1H)；13C NMR(101MHz,CDCl3)δ159.6,141.7,136.6,129.7,127.3,127.0,
126.0,125.2,120.5,79.2,69.4,31.1,25.9,23.9；MS(ESI+):C14H16NO([M+H]+)；
calculated:214.1,found:214.1。
Claims (10)
1. a kind of method that copper is catalyzed halogenated N- heterocyclic arene class alkylation, it is characterised in that mantoquita, N-F reagent,
Bronsted acid and organic solvent exist under effect, halogenated N- heterocyclic arene class compound shown in formula (I) and ethers shown in formula (II)
It closes ether compound shown in object or formula (III) and alkylated reaction occurs, reaction temperature is 20-60 DEG C, reaction time 3-20h,
After reaction, reaction solution is post-treated obtains the virtue of N- heterocycle shown in N- heterocyclic arene derivative shown in formula (IV) or formula (V)
Hydrocarbon derivative；Reaction equation is as follows:
In formula (I), substituent X indicates chlorine or bromine；
In formula (II) and formula (IV), n=1 or 2；
In formula (III) and formula (V), substituent R2And R3It is each independently selected from hydrogen or C1-C3 alkyl；
In formula (I), shown in the chemical structural formula of Ar-X such as formula (W1), formula (W2) or formula (W3):
In formula (W1), formula (W2) and formula (W3), substituent R1For H, C1-C3 alkyl, C1-C3 alkoxy, nitro, cyano, aldehyde radical,
Carboxyl, trifluoromethyl, fluorine, chlorine or bromine；Substituent group Y indicates oxygen or sulphur.
2. the method that a kind of copper according to claim 1 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
It is that the mantoquita is CuBr, Cu (OAc)2、CuCl、CuCl2、CuI、Cu(OTf)2Or CuBr2。
3. the method that a kind of copper according to claim 1 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
It is that the N-F reagent is such as formula (A), formula (B), formula (C) or formula (D) compound represented；
4. the method that a kind of copper according to claim 1 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
It is that the Bronsted acid is trifluoroacetic acid, trifluoromethanesulfonic acid, sulfuric acid, acetic acid or p-methyl benzenesulfonic acid.
5. the method that a kind of copper according to claim 1 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
It is ether shown in ether compound shown in halogenated N- heterocyclic arene class compound shown in formula (I) and formula (II) or formula (III)
The molar ratio of class compound is 1:1~30, preferably 1:1~20；Halogenated N- heterocyclic arene class compound and copper shown in formula (I)
The molar ratio of salt is 1:0.01~0.3, preferably 1:0.01~0.15.
6. the method that a kind of copper according to claim 1 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
The molar ratio for being halogenated N- heterocyclic arene class compound shown in formula (I) and N-F reagent is 1:1~3, preferably 1:1~2；
The molar ratio of the Bronsted acid and halogenated N- heterocyclic arene class compound shown in formula (I) is 0.5~2:1, preferably 1~2:1.
7. the method that a kind of copper according to claim 1 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
It is that the organic solvent is acetonitrile or nitromethane, preferably acetonitrile；Reaction temperature is 30~50 DEG C.
8. the method that a kind of copper according to claim 1 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
It is the post-treated step of reaction solution are as follows: water is added into reaction solution and organic extractant is extracted, liquid separation is organic layer
And water layer, after organic layer is dried over anhydrous sodium sulfate, solvent is removed by being concentrated under reduced pressure, condensate residue passes through column chromatography point
From using petroleum ether and ethyl acetate mixed solvent as eluant, eluent, eluent of the collection containing target product is evaporated off solvent and obtains mesh
Product is marked to get N- heterocyclic arene derivative shown in N- heterocyclic arene derivative shown in formula (IV) or formula (V).
9. the method that a kind of copper according to claim 8 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
It is that the organic extractant is methylene chloride or ethyl acetate.
10. the method that a kind of copper according to claim 8 is catalyzed halogenated N- heterocyclic arene class alkylation, feature
It is in the eluant, eluent, the volume ratio of petroleum ether and ethyl acetate is 10~50:1.
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| CN111606895A (en) * | 2020-06-01 | 2020-09-01 | 湖北工业大学 | Synthesis method of 1-alkyl-isoquinoline compound |
| CN115246798A (en) * | 2022-08-02 | 2022-10-28 | 浙江工业大学 | Method for synthesizing photocatalytic beta-C heteroaryl substituted alcohol |
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Cited By (2)
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| CN111606895A (en) * | 2020-06-01 | 2020-09-01 | 湖北工业大学 | Synthesis method of 1-alkyl-isoquinoline compound |
| CN115246798A (en) * | 2022-08-02 | 2022-10-28 | 浙江工业大学 | Method for synthesizing photocatalytic beta-C heteroaryl substituted alcohol |
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