CN106518752B - A kind of synthetic method of 5- phenyl -1,2,3,6- 5,6-tetrahydropyridine derivative - Google Patents
A kind of synthetic method of 5- phenyl -1,2,3,6- 5,6-tetrahydropyridine derivative Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of 5- phenyl -1,2, the synthetic methods of 3,6- 5,6-tetrahydropyridine derivatives, it is in reaction dissolvent, using inactive halogenated alkyl hydrocarbon derivative as reaction raw materials, under metal palladium catalyst effect, reaction obtains polysubstituted 5- phenyl -1,2,3,6- 5,6-tetrahydropyridine derivatives.Reaction condition of the present invention is mild, and initial raw material is easy to get inexpensive, and the route for synthesizing substrate is mature, there is no particular/special requirement, method is simple, strong operability, crucial skeleton structure is provided for multiclass drug molecule and efficiently synthesizing for natural products, and industrial-scale production can be widely used in.
Description
Technical field
5- phenyl -1,2 is prepared present invention relates particularly to a kind of, the synthetic method of 3,6- 5,6-tetrahydropyridine derivatives, belonging to has
Machine compound technique applied technical field.
Background technique
5- phenyl -1,2,3,6- tetrahydropyridine skeletons are universally present in natural products and drug, such as (+) -
Ipalbidine, ergotic acid, P75NTR acceptor inhibitor etc. (as shown below) are a kind of extremely important chemical intermediate, tool
There is very high application value.Develop the method for efficiently synthesizing these bioactive molecules and the like, to pharmaceutical synthesis and drug
The development of research and development has very important practical significance.
Fig. 1 contains the natural products and drug molecule of 5- phenyl -1,2,3,6- tetrahydropyridine skeleton
Summary of the invention
The present invention innovatively proposes a kind of inexpensive efficient new side for preparing 5- phenyl -1,2,3,6- 5,6-tetrahydropyridine derivative
Method can efficiently realize the conversion of reaction by using metal palladium catalyst.
Fig. 2 formula (I)
As shown in the above formula (I), the present invention is using inactive halogenated alkyl hydrocarbon (substrate 1) as raw material, in Metal Palladium
It under the action of catalyst, is reacted in reaction dissolvent, synthesizes 5- phenyl -1,2,3,6- 5,6-tetrahydropyridine derivatives.
In the present invention, R1, R2It is hydrogen, alkyl；R3It is hydrogen, alkyl, halogen, hetero atom；PG is Ts.
Preferably, R1, R2It is hydrogen, alkane；R3It is hydrogen, Cl；PG is Ts.
In the present invention, R1, R2,R3Above-mentioned group is included but are not limited to, for example, R3It can also be multi-substituent.
In the present invention, the palladium catalyst is PdCl2(dppf)、Pd (PPh3)4、PdCl2(PPh3)2。
Preferably, the palladium catalyst is PdCl2(dppf)。
The dosage of the catalyst is the 1-10 mol% of raw material 1.
Preferably, the dosage of the catalyst is 10 mol%.
In the present invention, the ligand is dppf(1,1 '-bis- (diphenylphosphine) ferrocene).
The dosage of the ligand is the 20-30 mol% of raw material 1.
Preferably, the ligand dosage is 20 mol%.
In the present invention, the alkali is Cy2NMe(N- methyldicyclohexylamine), Et3N(triethylamine), DIPEA(N, N- diisopropyl
Base ethamine).
Preferably, the alkali is Cy2NMe。
Preferably, the dosage of the alkali is 2.0 equivalents
In the present invention, the reaction dissolvent is toluene, benzotrifluoride, dimethylbenzene or dioxane.
It preferably, is reacted in toluene.
The reaction dissolvent can also be dimethylbenzene, Isosorbide-5-Nitrae-dioxane, DMF, DMSO more than including but is not limited to.
In the present invention, the synthetic reaction is in 100-130oIt is carried out at a temperature of C.
It preferably, is 110oIt is reacted at a temperature of C.
In the present invention, the synthesising reacting time is 10-20 hours.
It preferably, is reaction 16 hours.
Specifically, synthetic reaction of the present invention is to be dissolved in alkyl iodide (substrate 1, X mmol) in reaction flask A
In Z mL reaction dissolvent, at room temperature, catalyst PdCl is sequentially added2(dppf) (W mol%), ligand dppf (V mol%),
Alkali Cy2NMe (2.0 equiv).Reaction is in 100-130o10-20 hour is reacted under C inert gas shielding.It is anti-with TLC detection
Answer process.After completion of the reaction, directly plus silica gel, dry chromatography, isolated target product 2 are revolved.
The advantages of synthetic reaction of the present invention includes: that reaction substrate used in synthetic method of the present invention is all simple and easy to get, institute
The raw material needed is commercialized product, from a wealth of sources, and performance is stablized, in addition, synthetic route is also all mature classics
Synthetic reaction.Various metallic catalysts used in the present invention are also all common commercial reagents, highly stable, and have and produce
The few characteristic of rate height, simple process, pollution, is applicable to industrialized production completely.
5- phenyl -1,2,3,6- the 5,6-tetrahydropyridine derivative that the present invention synthesizes is a kind of very important natural products and existing
For the core skeleton of drug, the reaction route of innovative design of the present invention for synthesize this kind of compound provide one it is generally applicable
Preparation method.5- phenyl -1,2 is synthesized, the general difficult operation of traditional method of 3,6- 5,6-tetrahydropyridine derivatives, yield are very low, right
Industrial applications cause very big limitation.
The invention patent, based on commercialization, cheap simple raw material, through mature classical synthetic reaction system
All kinds of alkyl iodide are obtained as reaction substrate, under metal palladium catalyst effect, reaction obtains polysubstituted 5- phenyl -1,2,
3,6- 5,6-tetrahydropyridine derivative.Operation is fairly simple, and reaction condition is mild, and yield is higher, is suitble to large-scale industrialization
Production.
Detailed description of the invention
Fig. 1 show 6 kinds of representative natural products containing 5- phenyl -1,2,3,6- tetrahydropyridine skeleton and modern medicine
Object schematic arrangement.
Fig. 2 show the overall reaction equation for preparing 5- phenyl -1,2,3,6- tetrahydropyridines.
Fig. 3 show the chemical equation schematic diagram of embodiment 1.
Fig. 4 show the chemical equation schematic diagram of embodiment 2.
Fig. 5 show the chemical equation schematic diagram of embodiment 3.
Fig. 6 show the chemical equation schematic diagram of embodiment 4.
Fig. 7 show the chemical equation schematic diagram of embodiment 5.
Fig. 8 show the chemical equation schematic diagram of embodiment 6.
Fig. 9 show the chemical equation schematic diagram of embodiment 7.
Figure 10 show the chemical equation schematic diagram of embodiment 8.
Figure 11 show the chemical equation schematic diagram of embodiment 9.
Figure 12 show the chemical equation schematic diagram of embodiment 10.
Figure 13 show the chemical equation schematic diagram of embodiment 11.
Figure 14 show the chemical equation schematic diagram of embodiment 12.
Figure 15 show the chemical equation schematic diagram of embodiment 13.
Figure 16 show the chemical equation schematic diagram of embodiment 14.
Figure 17 show the chemical equation schematic diagram of embodiment 15.
Figure 18 show the chemical equation schematic diagram of embodiment 16.
Figure 19 show the chemical equation schematic diagram of embodiment 17.
Figure 20 show the chemical equation schematic diagram of embodiment 18.
Figure 21 show the chemical equation schematic diagram of embodiment 19.
Figure 22 show the chemical equation schematic diagram of embodiment 20.
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail, and of the invention protects content not limit to
In following embodiment.Without departing from the spirit and scope of the invention, those skilled in the art it is conceivable that variation and excellent
Point is all included in the present invention, and using appended claims as protection scope.Implement process of the invention, condition,
Reagent, experimental method etc. are among the general principles and common general knowledge in the art, this hair in addition to what is specifically mentioned below
It is bright that there are no special restrictions to content.Data given by following embodiment include concrete operations and reaction condition and product.Product is pure
Degree is identified by nuclear-magnetism.
Embodiment 1
5- phenyl -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
1 reaction equation of Fig. 3 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1a (0.1 mmol, 44.1 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 33.1 μ L n,N-diisopropylethylamine (0.2 mmol,
25.9 mg).Reaction system is heated to 110oC reacts 20 hours.TLC is detected after reaction, and system is cooled to room
Temperature.Directly plus silica gel is spin-dried for, and column chromatography for separation obtains white solid 2a (43%).1H NMR (400 MHz, CDCl3): δ
7.72 (d, J = 8.0 Hz, 2H), 7.33-7.27 (m, 7H), 6.08-6.06 (m, 1H), 3.94 (d, J =
2.0 Hz, 2H), 3.24 (t, J = 5.6 Hz, 2H), 2.43 (s, 3H), 2.43-2.37 (m, 2H). 13C-
NMR (100 MHz, CDCl3): δ 143.6, 138.7, 133.3, 129.7, 128.5, 127.7, 125.2,
122.1, 46.4, 42.3, 25.6, 21.5. MS (EI) m/z 313 (M+);HRMS calculated value is C18H19NO2S
313.1136 actual value 313.1137.
Embodiment 2
5- phenyl -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
2 reaction equation of Fig. 4 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1a (0.1 mmol, 44.1 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
The triethylamine (0.2 mmol, 20.2 mg) of 27.7 μ L is then added in toluene (2 mL) with liquid-transfering gun into reaction tube.It will
Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly add silica gel
It is spin-dried for, column chromatography for separation obtains white solid 2a (50%).Analyze data consistent with Example 1.
Embodiment 3
5- phenyl -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
3 reaction equation of Fig. 5 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1a (0.1 mmol, 44.1 mg),
Pd(PPh3)4(0.01 mmol, 11.6 mg), dppf (0.02 mmol, 11.1 mg), are successively weighed into reaction tube, vacuumize
Nitrogen is changed, and toluene (2 mL) is added under nitrogen atmosphere, the N- first of 42.9 μ L is then added into reaction tube with liquid-transfering gun
Base dicyclohexyl amine (0.2 mmol, 39.1 mg).Reaction system is heated to 110oC reacts 20 hours.TLC detection reaction
After, system is cooled to room temperature.Directly plus silica gel is spin-dried for, and column chromatography for separation obtains white solid 2a (68%).Analyze number
According to same embodiment 1.
Embodiment 4
5- phenyl -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
4 reaction equation of Fig. 6 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1a (0.1 mmol, 44.1 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2a (80%).
Embodiment 5
5- phenyl -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
5 reaction equation of Fig. 7 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1a (0.1 mmol, 44.1 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Benzotrifluoride (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol,
39.1 mg).Reaction system is heated to 100oC reacts 20 hours.TLC is detected after reaction, and system is cooled to room
Temperature.Directly plus silica gel is spin-dried for, and column chromatography for separation obtains white solid 2a (55%).Analyze data consistent with Example 1.
Embodiment 6
5- phenyl -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
6 reaction equation of Fig. 8 embodiment.
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1a (0.1 mmol, 44.1 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Dimethylbenzene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol,
39.1 mg).Reaction system is heated to 100oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room
Temperature.Directly plus silica gel is spin-dried for, and column chromatography for separation obtains white solid 2a (63%).Analyze data consistent with Example 1.
Embodiment 7
5- phenyl -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
7 reaction equation of Fig. 9 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1a (0.1 mmol, 44.1 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Dioxane (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol,
39.1 mg).Reaction system is heated to 100oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room
Temperature.Directly plus silica gel is spin-dried for, and column chromatography for separation obtains white solid 2a (55%).Analyze data consistent with Example 1.
Embodiment 8
3- methyl -5- phenyl -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
8 reaction equation of Figure 10 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1b (0.1 mmol, 45.5 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2b (58%).1H NMR (400 MHz, CDCl3): δ 7.72 (d,J = 5.2 Hz, 2H), 7.63 (d, J = 4.4 Hz, 1H), 7.32-7.28 (m, 6H), 5.96-5.92 (m,
1H), 4.08 (d, J = 10.4 Hz, 1H), 3.71 (d, J = 10.8 Hz, 1H), 3.52 (dd, J = 7.2,
2.8 Hz, 1H), 2.66-2.59 (m, 1H), 2.59-2.54 (m, 1H), 2.43 (s, 3H), 1.09 (d, J =
4.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 143.6, 140.9, 138.5, 132.6, 129.7,
128.5, 127.7, 125.3, 49.1, 46.4, 30.7, 21.5, 18.4. MS (EI) m/z 327 (M+); HRMS
Calculated value is C19H21NO2S 327.1293, actual value 327.1291.
Embodiment 9
The chloro- phenyl of 5-(4-) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
9 reaction equation of Figure 11 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1c (0.1 mmol, 47.6 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2c (68%).1H NMR (400 MHz, CDCl3): δ 7.71 (d,J = 5.6 Hz, 2H), 7.33 (d, J = 5.6 Hz, 2H), 7.28 (d, J = 5.6 Hz, 2H), 7.21 (d,J = 5.6 Hz, 2H), 6.07-6.06 (m, 1H), 3.90 (d, J = 1.2 Hz, 2H), 3.23 (t, J =
4.0 Hz, 2H), 2.43 (s, 3H), 2.40-2.36 (m, 2H). 13C-NMR (100 MHz, CDCl3): δ
143.7, 137.1, 133.5, 133.3, 132.4, 129.8, 128.7, 127.7, 126.5, 122.8, 46.2,
42.3, 25.7, 21.6. MS (EI) m/z 347 (M+);HRMS calculated value is C18H18ClNO2S 347.0747, it is real
Actual value is 347.0748.
Embodiment 10
The chloro- phenyl of 2- methyl -5-(4-) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
10 reaction equation of Figure 12 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1d (0.1 mmol, 49.0 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2d (78%).1H NMR (400 MHz, CDCl3): δ 7.71 (d,J = 8.4 Hz, 2H), 7.31-7.27 (m, 4H),7.25-7.22 (m, 2H), 5.99-5.97 (m, 1H), 4.49
(d, J = 17.2 Hz, 1H), 4.37-4.30 (m, 1H), 3.86-3.80 (m, 1H), 2.45-2.42 (m,
2H), 2.41 (s, 3H), 1.02 (d, J = 6.8 Hz). 13C-NMR (100 MHz, CDCl3): δ 143.3,
137.1, 137.0, 133.4, 131.4, 129.7, 128.7, 127.1, 126.2, 121.2, 45.8, 41.3,
31.1, 21.6, 16.7. MS (EI) m/z 361 (M+);HRMS calculated value is C19H20ClNO2S 361.0903, it is real
Actual value is 361.0905.
Embodiment 11
The chloro- phenyl of 2- phenyl -5-(4-) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
11 reaction equation of Figure 13 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1e (0.1 mmol, 55.2 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2e (81%).1H NMR (400 MHz, CDCl3): δ 7.68 (d,J = 8.0 Hz, 2H), 7.34-7.28 (m, 4H), 7.24-7.14 (m, 7H), 6.12-6.06 (m, 1H),
5.34 (d, J = 6.4 Hz, 1H), 4.47 (d, J = 17.6 Hz, 1H), 3.68-3.60 (m, 1H), 2.63-
2.46 (m, 2H), 2.40 (s, 3H). 13C-NMR (100 MHz, CDCl3): δ 159.7, 143.6, 133.4,
129.7, 129.5, 127.7, 122.5, 117.8, 112.8, 111.4, 46.4, 42.4, 25.6, 21.6. MS
(EI) m/z 423 (M+);HRMS calculated value is C24H22ClNO2S 423.1060, actual value 423.1061.
Embodiment 12
The chloro- phenyl of 2- isopropyl -5-(4-) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
12 reaction equation of Figure 14 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1f (0.1 mmol, 51.8 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2f (70%).1H NMR (400 MHz, CDCl3): δ 7.66 (d,J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 8.0 Hz, 4H), 5.91-
5.86 (m, 1H), 4.58-4.50 (m, 1H), 3.95-3.86 (m, 1H), 3.65 (dd, J = 10.4, 6.4
Hz, 1H), 2.39 (s, 3H), 1.85-1.74 (m, 2H), 1.62-1.55 (m, 1H), 1.02 (d, J = 6.8
Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 143.1, 138.1,
136.9, 133.4, 131.6, 129.6, 128.7, 126.8, 126.0, 121.5, 56.5, 41.9, 28.3,
25.3, 21.6, 20.3, 20.1. MS (EI) m/z 389 (M+);HRMS calculated value is C21H24ClNO2S
389.1216 actual value 389.1213.
Embodiment 13
The chloro- phenyl of 2- benzyl -5-(4-) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
13 reaction equation of Figure 15 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1g (0.1 mmol, 56.6 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2g (79%).1H NMR (400 MHz, CDCl3): δ 7.58 (d,J = 8.0 Hz, 2H), 7.27-7.22 (m, 5H), 7.17-7.06 (m, 6H), 5.99-5.94 (m, 1H),
4.46 (d, J = 17.6 Hz, 1H), 4.37-4.31 (m, 1H), 3.92-3.87 (m, 1H), 2.69-2.58
(m, 2H), 2.32 (s, 3H), 2.22-2.16 (m, 1H), 2.00-1.94 (m, 1H). 13C-NMR (100 MHz,
CDCl3): δ 143.4, 138.0, 137.2, 136.9, 133.6, 131.8, 129.7, 129.2, 128.8,
128.6, 127.1, 126.6, 126.2, 121.1, 51.6, 41.9, 37.1, 27.1, 21.6. MS (EI) m/z
437 (M+);HRMS calculated value is C25H24ClNO2S 437.1216, actual value 437.1215.
Embodiment 14
5-(3,4- methylenedioxyphenyl) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
14 reaction equation of Figure 16 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1h (0.1 mmol, 48.5 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2h (89%).1H NMR (400 MHz, CDCl3): δ 7.74 (d,J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.81-6.72 (m, 3H), 5.95 (s, 2H),
5.47-5.41 (m, 1H), 4.45-4.01 (m, 2H), 3.08-3.03 (m, 2H), 2.42 (s, 3H), 2.38-
2.33 (m, 2H). 13C-NMR (100 MHz, CDCl3): δ 147.6, 146.7, 143.5, 137.9, 137.5,
136.9, 127.1, 119.1, 107.9, 106.2, 101.0, 42.9, 29.0, 21.6, 16.3. MS (EI) m/z
357 (M+);HRMS calculated value is C19H19NO4S 357.1035, actual value 357.1036.
Embodiment 15
The bromo- phenyl of 5-(4-) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
15 reaction equation of Figure 17 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1i (0.1 mmol, 52.0 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2i (61%).1H NMR (400 MHz, CDCl3): δ 7.72 (d,J = 8.0 Hz, 2H), 7.33-7.29 (m, 6H), 6.09-6.06 (m, 1H), 3.96-3.90 (m, 2H),
3.23 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H), 2.41-2.37 (m, 2H). 13C-NMR (100 MHz,
CDCl3): δ 143.7, 138.7, 133.4, 133.2, 129.7, 128.6, 127.7, 125.2, 122.2,
46.4, 42.4, 25.7, 21.6. MS (EI) m/z 391 (M+);HRMS calculated value is C18H18BrNO2S
391.0242 actual value 391.0243.
Embodiment 16
The bromo- phenyl of 5-(3-) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
16 reaction equation of Figure 18 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1j (0.1 mmol, 52.0 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2j (63%).1H NMR (400 MHz, CDCl3): δ 7.72 (d,J = 8.4 Hz, 2H), 7.33-7.29 (m, 6H), 6.10-6.04 (m, 1H), 3.94 (dd, J = 4.8, 2.4
Hz, 2H), 3.24 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H), 2.41-2.37 (m, 2H). 13C-NMR
(100 MHz, CDCl3): δ 143.6, 138.7, 133.5, 133.4, 129.7, 128.5, 127.7, 125.2,
122.2, 46.4, 42.4, 25.7, 21.5. MS (EI) m/z 391 (M+);HRMS calculated value is C18H18BrNO2S
391.0242 actual value 391.0243.
Embodiment 17
5-(2- ethyoxyl-phenyl) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
17 reaction equation of Figure 19 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1k (0.1 mmol, 48.5 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2k (73%).1H NMR (400 MHz, CDCl3): δ 7.71 (d,J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.22 (td, J = 8.4, 2.0 Hz, 1H),
7.07 (dd, J = 7.2, 1.6 Hz, 1H), 6.90-6.82 (m, 2H), 5.77-5.74 (m, 1H), 4.02-
3.98 (m, 4H), 3.26 (t, J = 5.6 Hz, 2H), 2.42 (s, 3H), 2.35-2.30 (m, 2H),
1.38-1.34 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 156.1, 143.3,
134.4, 133.9, 130.0, 129.5, 129.4, 128.9, 127.8, 123.5, 120.7, 111.6, 63.7,
47.2, 42.5, 25.5, 21.5, 14.8. MS (EI) m/z 357 (M+);HRMS calculated value is C20H23NO3S
357.1399 actual value 357.1401.
Embodiment 18
5-(3- methoxyl group-phenyl) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
18 reaction equation of Figure 20 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1l (0.1 mmol, 47.1 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2l (74%).1H NMR (400 MHz, CDCl3): δ 7.71 (d,J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.24-7.20 (m, 1H), 6.88-6.81 (m,
3H), 6.09-6.05 (m, 1H), 3.81 (s, 3H), 3.80-3.77 (m, 2H), 3.23 (t, J = 5.6 Hz,
2H), 2.43 (s, 3H), 2.40-2.36 (m, 2H). 13C-NMR (100 MHz, CDCl3): δ 159.7,
133.4, 129.7, 129.5, 127.7, 122.5, 117.8, 112.8, 111.4, 55.3, 46.4, 42.4,
25.6, 21.6. MS (EI) m/z 343 (M+);HRMS calculated value is C19H21NO3S 343.1242, actual value are
343.1240。
Embodiment 19
5-(4- methoxyl group-phenyl) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
19 reaction equation of Figure 21 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1m (0.1 mmol, 47.1 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg), are successively weighed into reaction tube, vacuum and exchange nitrogen, and be added under nitrogen atmosphere
Toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol, 39.1
mg).Reaction system is heated to 110oC reacts 16 hours.TLC is detected after reaction, and system is cooled to room temperature.Directly
Silica gel is added to be spin-dried for, column chromatography for separation obtains white solid 2m (65%).1H NMR (400 MHz, CDCl3): δ 7.69 (d,J = 8.0 Hz, 2H), 7.34-7.29 (m, 4H), 6.88 (d, J = 8.8 Hz, 2H), 5.54-5.55 (m,
1H), 3.82 (s, 3H), 3.61 (t, J =6.8 Hz, 2H), 3.45 (t, J = 6.8 Hz, 2H), 2.44
(s, 3H), 2.15 (d, J = 1.2 Hz, 2H). 13C-NMR (100 MHz, CDCl3): δ 159.8, 144.2,
143.9, 134.9, 132.0, 129.8, 127.5, 127.3, 121.1, 113.8, 55.3, 52.4, 41.3,
21.6, 16.7. MS (EI) m/z 343 (M+);HRMS calculated value is C19H21NO3S 343.1242, actual value are
343.1241。
Embodiment 20
5-(4- fluoro-phenyl) -1- p-toluenesulfonyl -1,2,3,6- tetrahydropyridine:
20 reaction equation of Figure 22 embodiment
In the test tube reactor of 25 mL, with nitrogen exchange of air 3 times.By substrate 1n (0.1 mmol, 45.9 mg),
PdCl2(dppf) (0.01 mmol, 7.3 mg) are successively weighed into reaction tube, vacuum and exchange nitrogen, and add under nitrogen atmosphere
Enter toluene (2 mL), be then added with liquid-transfering gun into reaction tube 42.9 μ L N- methyldicyclohexylamine (0.2 mmol,
39.1 mg).Reaction system is heated to 110oC reacts 20 hours.TLC is detected after reaction, and system is cooled to room
Temperature.Directly plus silica gel is spin-dried for, and column chromatography for separation obtains white solid 2n (87%).1H NMR (400 MHz, CDCl3): δ
7.71 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.25-7.22 (m, 2H), 7.00
(t, J = 8.8 Hz, 2H), 6.02-6.00 (m, 1H), 3.89 (dd, J = 4.4, 2.4 Hz, 2H), 3.22
(t, J = 6.0 Hz, 2H), 2.43 (s, 3H), 2.41-2.36 (m, 2H). 13C-NMR (100 MHz,
CDCl3): δ 143.7, 133.3, 132.6, 129.8, 127.7, 126.9, 126.9, 122.2, 115.5,
115.3, 46.5, 42.3, 25.6, 21.6. MS (EI) m/z 331 (M+);HRMS calculated value is C18H18FNO2S
331.1042 actual value 331.1043.
Claims (4)
1. a kind of 5- phenyl -1,2, the synthetic method of 3,6- tetrahydropyridines, which is characterized in that with disactivation alkyl iodide
Compound is as reaction raw materials, under the conditions of existing for the palladium catalyst and alkali, reacts time enough in a solvent under certain temperature,
5- phenyl -1,2,3,6- tetrahydropyridines can be obtained；Reaction equation is as shown in the formula (I):
Formula (I)；
Wherein, R1, R2It is hydrogen, alkyl；R3It is hydrogen, chlorine, bromine, fluorine, methoxyl group, ethyoxyl；PG is Ts；Catalyst is PdCl2
(dppf)、Pd(PPh3)4；Ligand is dppf；Alkali is Et3N、DIPEA、Cy2NMe；Solvent be toluene, benzotrifluoride, dimethylbenzene,
Dioxane；Reaction temperature is 100-130 DEG C；Reaction time is 10-20 hours.
2. 5- phenyl -1,2 as described in claim 1, the synthetic method of 3,6- tetrahydropyridines, which is characterized in that
On the basis of the dosage of compound 1, the palladium catalyst PdCl2(dppf)、Pd(PPh3)4Dosage be compound 1 mole
10 mol%。
3. 5- phenyl -1,2 as described in claim 1, the synthetic method of 3,6- tetrahydropyridines, which is characterized in that
On the basis of the dosage of compound 1, the dosage of the ligand dppf is 20 mol% of 1 mole of compound.
4. 5- phenyl -1,2 as described in claim 1, the synthetic method of 3,6- tetrahydropyridines, which is characterized in that
On the basis of the dosage of compound 1, the alkali Et3N、DIPEA、Cy2The dosage of NMe is 2.0 equivalents of 1 mole of compound.
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| Title |
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| Palladium(0)-Catalyzed Alkylative Cyclization of Alkynals and Alkynones:Remarkabletrans-Addition of Organoboronic Reagents;Hirokazu Tsukamoto，et al.;《J. AM. CHEM. SOC.》;20061231;第128卷;第1406-1407页 |
| Palladium-Catalyzed Intramolecular Reductive Cross-Coupling of Csp2-Csp3 Bond Formation;Hui Liu，et al.;《Chem. Eur. J.》;20141231;第20卷;第8308-8313页 |
| Pd-mediated synthesis of 2-arylquinolines and tetrahydropyridines from modified Baylis–Hillman adducts;Saravanan Gowrisankar，et al.;《Tetrahedron Letters》;20081231;第49卷;第1670-1673页 |
| Tuning the Reaction Paths in Palladium(0)-Catalyzed Coupling-Cyclization Reaction of β-Amino Allenes with Organic Halides: A Substituent Switch;Shengming Ma，et al.;《Organic Letters》;20021231;第4卷(第17期);第2989-2992页 |
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