CN106831542A - A kind of synthetic method of the formic ether compounds of ring-type enamine 3 - Google Patents
A kind of synthetic method of the formic ether compounds of ring-type enamine 3 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of synthetic method of the formic ether compounds of ring-type enamine 3, belong to technical field of organic synthesis.Technical scheme main points are：；
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of conjunction of ring-type enamine -3- formic ether compounds
Into method.
Background technology
Ring-type enamine -3- formic ether compounds not only have significant bioactivity, and as intermediate in many
It is widely used in the synthesis of fine chemicals.Based on its importance, the new synthetic method research one of such compound
It is straight to be paid close attention to by chemists.At present, such compound is mainly obtained by following approach：1）N- benzyl-γ-chloro propylamine
With the condensation reaction of conjugation acetylenic acid ester；2）Triphenyl phosphine catalyst aziridine and [3+3] cyclization for joining olefin(e) acid ester；3）Primary
One pot of four component reaction of aminated compounds, beta-dicarbonyl compound, alpha, beta-unsaturated aldehyde and alcohol etc..Although these methods can be with
Effective synthesis of cyclic enamine -3- formic ether compounds, but still suffer from some urgent problems, such as：The original of reaction
Subeconomy is low, severe reaction conditions and raw material are difficult to obtain, and these weak points also cause the practicality of the above method
It is very limited.In view of this, further study and develop from the raw material being easy to get, the synthesis under gentle reaction condition
Simple and direct, the efficient new method of ring-type enamine -3- formic ether compounds has important theory significance and application value.
The content of the invention
Present invention solves the technical problem that a kind of synthetic method of ring-type enamine -3- formic ether compounds is there is provided,
The method be with azacycloalkyl hydro carbons compound, carbon monoxide and alcohol compound as raw material, it is direct by one pot of cascade reaction
Ring-type enamine -3- formic ether compounds are obtained, easy to operate, mild condition, wide application range of substrates is suitable for industrial metaplasia
Produce.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of ring-type enamine -3- formate ester chemical combination
The synthetic method of thing, it is characterised in that：Azacycloalkyl hydro carbons compound 1 and alcohol compound 2 are dissolved in solvent, are subsequently adding
Catalyst, oxidant and additive, in CO atmosphere or CO and O2Mixed atmosphere in, ring-type alkene is obtained in 60-100 DEG C of reaction
Amine -3- formic ether compounds 3, the reaction equation in the synthetic method is：
Wherein R1It is benzyl, substituted benzyl, phenethyl, C1-10Straight or branched alkyl, cyclopenta, phenyl or substituted-phenyl, should
Substitution base on substituted benzyl phenyl ring is cyano group, fluorine, chlorine, bromine, methyl or methoxy, and the substitution base on substituted-phenyl phenyl ring is one
Individual or multiple fluorine, chlorine, bromine, methyl or methoxy, R2It is hydrogen or methyl, R3It is benzyl or C1-5Straight or branched alkyl, n be 1 or
2, catalyst be palladium, palladium bichloride or three (dibenzalacetone) two palladium, oxidant be copper acetate, bromination ketone or copper chloride,
Additive is KI, KBr, potassium chloride or elemental iodine, and solvent is toluene, dichloroethanes, Isosorbide-5-Nitrae-dioxane or acetonitrile.
Further limit, described azacycloalkyl hydro carbons compound 1, alcohol compound 2, catalyst, oxidant and addition
The ratio between amount for the material that feeds intake of agent is 1:5-10:0.05-0.1:0.2-1:1.
A kind of synthetic method of ring-type enamine -3- formic ether compounds of the present invention, it is characterised in that：By azepine
Naphthene-based compounds 1 and alcohol compound 2 are dissolved in solvent, are subsequently adding catalyst and oxidant, CO atmosphere or CO with
O2Mixed atmosphere in, ring-type enamine -3- formic ether compounds 3 are obtained in 60-100 DEG C of reaction, it is anti-in the synthetic method
The equation is answered to be：
Wherein R1It is benzyl, substituted benzyl, phenethyl, C1-10Straight or branched alkyl, cyclopenta, phenyl or substituted-phenyl, should
Substitution base on substituted benzyl phenyl ring is cyano group, fluorine, chlorine, bromine, methyl or methoxy, and the substitution base on substituted-phenyl phenyl ring is one
Individual or multiple fluorine, chlorine, bromine, methyl or methoxy, R2It is hydrogen or methyl, R3It is benzyl or C1-5Straight or branched alkyl, n be 1 or
2, catalyst be palladium, palladium bichloride or three (dibenzalacetone) two palladium, oxidant be copper acetate, bromination ketone or copper chloride,
Solvent is toluene, dichloroethanes, 1,4- dioxane or acetonitrile.
Further limit, described azacycloalkyl hydro carbons compound 1, alcohol compound 2, catalyst and oxidant feed intake
The ratio between amount of material is 1:5-10:0.05-0.1:0.2-1.
The present invention has advantages below compared with prior art：（1）Using one pot of cascade reaction, it is to avoid cumbersome centre
Body isolates and purifies process, reduces waste discharge, reduces environmental pressure；（2）Raw material is readily available；（3）Reaction 100 DEG C with
Under carry out, mild condition is easy to operate；（4）Substrate it is applied widely；（5）The Atom economy of reaction is high.Therefore, this hair
The bright synthesis for ring-type enamine -3- formic ether compounds provides a kind of economical and practical and environmental protection new method.
Specific embodiment
The above of the invention is described in further details by the following examples, but this should not be interpreted as this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
1a (0.5 mmol, 88 mg) and acetonitrile are added in the reaction bulb of 25 mL（CH3CN, 5 mL）, it is subsequently adding 2a
（5 mmol, 292 µL）, palladium bichloride (PdCl2, 0.05 mmol, 9 mg), copper acetate (Cu (OAc)2, 0.1 mmol, 18
) and KI (KI, 0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours,
It is subsequently adding 10 mL saturated nacl aqueous solutions and reaction is quenched, is extracted with ethyl acetate（10 mL × 3）, merge organic phase, use
Anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a
（92 mg, 75%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.28 (t, J = 7.2
Hz, 3H), 1.79-1.82 (m, 2H), 2.31 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 6.0 Hz,
2H), 4.16 (q, J = 7.2 Hz, 2H), 4.30 (s, 2H), 7.23 (d, J = 6.8 Hz, 2H), 7.31-
7.36 (m, 3H), 7.56 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.7, 20.0, 21.3, 45.4,
58.9, 59.7, 94.9, 127.4, 127.7, 128.7, 137.1, 146.2, 168.8. HRMS calcd for
C15H20NO2: 246.14889 [M+H]+, found: 246.1492。
Embodiment 2
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium (0.05 mmol, 11 mg) and copper acetate (0.5 mmol, 91
mg).In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, it is subsequently adding 10 mL saturated nacl aqueous solutions and is quenched instead
Should, it is extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silicagel column
Separate（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（59 mg, 48%）.
Embodiment 3
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, three (dibenzalacetone) two palladium (0.05 mmol, 46 mg) and copper acetate
(0.5 mmol, 91 mg).In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, 10 mL saturation chlorine are subsequently adding
Change sodium solution and reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous sodium sulfate drying.Filtering,
It is spin-dried for, crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（43 mg, 35%）.
Embodiment 4
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg) and copper bromide (0.5 mmol, 111
mg).In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, it is subsequently adding 10 mL saturated nacl aqueous solutions and is quenched instead
Should, it is extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silicagel column
Separate（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（15 mg, 12%）.
Embodiment 5
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg) and copper chloride (0.5 mmol, 67
mg).In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, it is subsequently adding 10 mL saturated nacl aqueous solutions and is quenched instead
Should, it is extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silicagel column
Separate（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（12 mg, 10%）.
Embodiment 6
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and dichloroethanes in the reaction bulb of 25 mL
（5 mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（71
mg, 58%）.
Embodiment 7
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and Isosorbide-5-Nitrae-dioxy in the reaction bulb of 25 mL
Six rings（5 mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1
Mmol, 18 mg) and KI (0.5 mmol, 83 mg).In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12
Hour, it is subsequently adding 10 mL saturated nacl aqueous solutions and reaction is quenched, it is extracted with ethyl acetate（10 mL × 3）, merge organic
Phase, uses anhydrous sodium sulfate drying.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Yellow liquid is obtained to produce
Thing 3a（80 mg, 65%）.
Embodiment 8
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and toluene in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（49
mg, 40%）.
Embodiment 9
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.5 mmol, 91
) and KBr (0.5 mmol, 59 mg) mg.In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, it is subsequently adding
10 mL saturated nacl aqueous solutions are quenched reaction, are extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous slufuric acid
Sodium is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（76 mg,
62%）.
Embodiment 10
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.5 mmol, 91
) and elemental iodine (0.5 mmol, 127 mg) mg.In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, Ran Houjia
Enter 10 mL saturated nacl aqueous solutions and reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous sulphur
Sour sodium is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（86 mg,
70%）.
Embodiment 11
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.5 mmol, 91
) and potassium chloride (0.5 mmol, 37 mg) mg.In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, it is subsequently adding
10 mL saturated nacl aqueous solutions are quenched reaction, are extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous slufuric acid
Sodium is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（65 mg,
53%）.
Embodiment 12
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.025 mmol, 5 mg), copper acetate (0.5 mmol, 91
) and KI (0.5 mmol, 83 mg) mg.In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, it is subsequently adding
10 mL saturated nacl aqueous solutions are quenched reaction, are extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous slufuric acid
Sodium is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（49 mg,
40%）.
Embodiment 13
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.25 mmol, 46
) and KI (0.5 mmol, 83 mg) mg.In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, it is subsequently adding
10 mL saturated nacl aqueous solutions are quenched reaction, are extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous slufuric acid
Sodium is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（43 mg,
35%）.
Embodiment 14
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（2.5 mmol, 146 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.5 mmol, 91
) and KI (0.5 mmol, 83 mg) mg.In CO (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, it is subsequently adding
10 mL saturated nacl aqueous solutions are quenched reaction, are extracted with ethyl acetate（10 mL × 3）, merge organic phase, use anhydrous slufuric acid
Sodium is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（51 mg,
42%）.
Embodiment 15
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 100 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（86
mg, 70%）.
Embodiment 16
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 60 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3a（（76
mg, 62%）.
Embodiment 17
Method as described in embodiment 1, adds 1b (0.5 mmol, 95 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3b（97
mg, 75%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.25-1.29 (m, 3H),
1.83 (t, J = 5.6 Hz, 2H), 2.30-2.34 (m, 5H), 2.97-3.02 (m, 2H), 4.12-4.18 (m,
2H), 4.30 (s, 2H), 7.15-7.23 (m, 4H), 7.50 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
14.7, 19.2, 20.1, 21.3, 45.6, 57.5, 58.9, 94.7, 126.2, 127.8, 128.0, 130.7,
134.8, 136.4, 146.2, 168.8. HRMS calcd for C16H21NO2Na: 282.1465 [M+Na]+,
found: 282.1462。
Embodiment 18
Method as described in embodiment 1, adds 1c (0.5 mmol, 97 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3c（101
mg, 77%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.27-1.30 (m, 3H),
1.82 (t, J = 5.6 Hz, 2H), 2.31 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 6.4 Hz, 2H),
4.17 (q, J = 7.2 Hz, 2H), 4.29 (s, 2H), 6.92-7.02 (m, 3H), 7.32-7.34 (m, 1H),
7.52 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.7, 19.9, 21.2, 45.5, 59.1, 59.2,
95.4, 114.2 (d, 2 J C-F = 21.0 Hz), 114.7 (d, 2 J C-F = 20.8 Hz), 122.9, 130.3 (d,3 J C-F = 9.1 Hz), 139.9 (d, 4 J C-F = 6.2 Hz), 146.0, 163.1 (d, 1 J C-F = 245.5 Hz),
168.7. HRMS calcd for C15H19FNO2: 264.1394 [M+H]+, found: 264.1395。
Embodiment 19
Method as described in embodiment 1, adds 1d (0.5 mmol, 103 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3d（117
mg, 85%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz,
3H), 1.77-1.80 (m, 2H), 2.29 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H),
3.82 (s, 3H), 4.16 (q, J = 6.8 Hz, 2H), 4.23 (s, 2H), 6.88 (d, J = 8.8 Hz,
2H), 7.15 (d, J = 8.8 Hz, 2H), 7.55 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.7,
20.0, 21.3, 45.2, 55.3, 58.9, 59.2, 94.5, 114.1, 128.8, 129.0, 146.1, 159.2,
168.8. HRMS calcd for C16H22NO3: 276.1594 [M+H]+, found: 276.1595。
Embodiment 20
Method as described in embodiment 1, adds 1e (0.5 mmol, 105 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3e（110
mg, 79%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.26-1.30 (m, 3H),
1.79-1.82 (m, 2H), 2.30 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 4.16
(q, J = 7.2 Hz, 2H), 4.26 (s, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0
Hz, 2H), 7.52 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.7, 20.0, 21.2, 45.4,
59.0, 95.4, 117.2, 119.4, 126.3, 128.8, 128.9, 133.6, 135.6, 145.9, 168.7.
HRMS calcd for C15H18ClNO2Na: 302.0918 [M+Na]+, found: 302.0921。
Embodiment 21
Method as described in embodiment 1, adds 1f (0.5 mmol, 100 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3f（95
mg, 70%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.26-1.30 (m, 3H),
1.82 (s, 2H), 2.31 (s, 2H), 2.99 (s, 2H), 4.16 (q, J = 6.8 Hz, 2H), 4.35 (s,
2H), 7.34 (d, J = 7.6 Hz, 2H), 7.49 (s, 1H), 7.66 (d, J = 7.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 14.7, 19.9, 21.2, 30.9, 45.8, 59.2, 96.3, 111.7, 118.6,
127.9, 132.6, 142.8, 145.6, 168.6. HRMS calcd for C16H19N2O2: 271.1441 [M+H]+,
found: 271.1443。
Embodiment 22
Method as described in embodiment 1, adds 1g (0.5 mmol, 95 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3g（101
mg, 78%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz,
3H), 1.75-1.81 (m, 2H), 2.25 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H),
3.07 (t, J = 5.6 Hz, 2H), 3.34 (t, J = 7.2 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H),
7.17 (d, J = 8.4 Hz, 2H), 7.21-7.32 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 14.7,
20.0, 21.4, 35.6, 46.3, 57.6, 58.8, 94.3, 126.6, 128.6, 128.8, 138.6, 145.5,
168.7. HRMS calcd for C16H21NO2Na: 282.1465 [M+ Na]+, found: 282.1479。
Embodiment 23
Method as described in embodiment 1, adds 1h (0.5 mmol, 57 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3h（75
mg, 82%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.14-1.18 (m, 3H),
1.24-1.29 (m, 3H), 1.79-1.85 (m, 2H), 2.26-2.29 (m, 2H), 3.09 (t, J = 6.0 Hz,
2H), 3.15-3.21 (m, 2H), 4.11-4.17 (m, 2H), 7.38 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ 13.9, 14.7, 20.1, 21.4, 29.7, 45.2, 50.4, 58.8, 93.8, 145.5, 168.8.
HRMS calcd for C10H18NO2: 184.1332 [M+H]+, found: 184.1343。
Embodiment 24
Method as described in embodiment 1, adds 1i (0.5 mmol, 99 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3i（112
mg, 84%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.2 Hz,
3H), 1.24-1.32 (m, 13H), 1.53 (t, J = 6.8 Hz, 2H), 1.76-1.84 (m, 2H), 2.27
(t, J = 6.0 Hz, 2H), 3.08 (q, J = 6.8 Hz, 4H), 4.13 (q, J = 6.8 Hz, 2H), 7.35
(s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.1, 14.7, 20.1, 21.4, 22.6, 26.6, 28.5,
29.2, 29.3, 31.8, 45.7, 56.0, 58.8, 93.3, 146.0, 168.8. HRMS calcd for
C16H29NO2Na: 290.2091 [M+Na]+, found: 290.2112。
Embodiment 25
Method as described in embodiment 1, adds 1j (0.5 mmol, 77 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3j（61
mg, 55%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.20-1.27 (m, 3H),
1.56-1.87 (m, 10H), 2.28 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 5.6 Hz, 2H), 3.59
(t, J = 8.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 7.47 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ 14.8, 20.6, 21.6, 23.9, 29.9, 43.4, 58.8, 65.8, 93.6, 144.8, 168.9.
HRMS calcd for C13H21NO2Na: 246.1465 [M+Na]+, found: 246.1484。
Embodiment 26
Method as described in embodiment 1, adds 1k (0.5 mmol, 81 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3k（75
mg, 65%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 7.2 Hz,
3H), 1.97-2.00 (m, 2H), 2.39 (t, J = 6.4 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H),
4.19 (q, J = 7.2 Hz, 2H), 7.06 (t, J = 7.6 Hz, 3H), 7.32-7.36 (m, 2H), 7.89
(s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.6, 20.6, 21.5, 46.1, 53.4, 59.4, 101.2,
117.4, 122.6, 129.4, 140.5, 145.9, 168.6. HRMS calcd for C14H18NO2: 232.1332 [M
+H]+, found: 232.1342。
Embodiment 27
Method as described in embodiment 1, adds 1l (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3l（69
mg, 56%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.23-1.28 (m, 3H),
1.94-2.01 (m, 2H), 2.28 (s, 3H), 2.41 (t, J = 6.4 Hz, 2H), 3.43 (t, J = 5.6
Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 7.07 (dd, J 1 = 7.2 Hz, J 2 = 1.2 Hz, 1H),
7.14-7.24 (m, 3H), 7.47 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.6, 18.2, 20.5,
21.7, 48.8, 59.1, 97.9, 125.7, 126.4, 127.0, 131.5, 133.5, 144.6, 146.2,
168.7. HRMS calcd for C15H20NO2: 246.1489 [M+H]+, found: 246.1488。
Embodiment 28
Method as described in embodiment 1, adds 1m (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3m（86
mg, 70%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.25-1.30 (m, 3H),
1.95-1.98 (m, 2H), 2.31 (s, 3H), 2.38 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 5.6
Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 6.97 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 2H),
7.14 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 14.7, 20.5,
20.6, 21.5, 46.3, 53.4, 59.3, 100.3, 117.6, 129.9, 132.3, 140.9, 143.7,
168.6. HRMS calcd for C15H20NO2: 246.1489 [M+H]+, found: 246.1493。
Embodiment 29
Method as described in embodiment 1, adds 1n (0.5 mmol, 96 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3n（104
mg, 80%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.25-1.30 (m, 3H),
1.95-1.98 (m, 2H), 2.38 (t, J = 6.4 Hz, 2H), 3.55 (t, J = 5.6 Hz, 2H), 3.80
(s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 6.88 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 2H),
7.01 (dd, J 1 = 6.8 Hz, J 2 = 2.4 Hz, 2H), 7.78 (s, 1H). 13C NMR (100 MHz, CDCl3)
δ 14.7, 20.4, 21.5, 46.8, 55.6, 59.3, 99.6, 114.6, 119.5, 140.0, 141.4,
155.7, 168.7. HRMS calcd for C15H20NO3: 262.1438 [M+H]+, found: 262.1439。
Embodiment 30
Method as described in embodiment 1, adds 1o (0.5 mmol, 90 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3o（62
mg, 50%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.25-1.30 (m, 3H),
1.96-1.99 (m, 2H), 2.38 (t, J = 6.4 Hz, 2H), 3.56 (t, J = 5.6 Hz, 2H), 4.18
(q, J = 7.2 Hz, 2H), 7.00-7.03 (m, 4H), 7.78 (s, 1H). 13C NMR (100 MHz, CDCl3)
δ 14.6, 20.4, 21.4, 46.6, 59.4, 101.0, 115.9, 116.0 (d, 2 J C-F = 21.8 Hz),
119.2 (d, 3 J C-F = 8.0 Hz), 140.7, 142.4 (d, 4 J C-F = 2.9 Hz), 158.7 (d, 1 J C-F =
241.5 Hz), 168.5. HRMS calcd for C14H17FNO2: 250.1238 [M+H]+, found: 250.1243。
Embodiment 31
Method as described in embodiment 1, adds 1p (0.5 mmol, 102 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3p（104
mg, 76%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.23 (t, J = 7.2 Hz,
3H), 1.98-2.01 (m, 2H), 2.19 (s, 6H), 2.28 (s, 1H), 2.41 (t, J = 6.0 Hz, 2H),
3.29 (t, J = 5.6 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 6.90 (s, 2H), 7.30 (s,
1H). 13C NMR (100 MHz, CDCl3) δ 14.7, 17.9, 20.3, 20.9, 21.5, 47.6, 58.9,
95.3, 129.3, 136.0, 137.2, 141.9, 145.4, 168.8. HRMS calcd for C17H24NO2:
274.1802 [M+H]+, found: 274.1805。
Embodiment 32
Method as described in embodiment 1, adds 1q (0.5 mmol, 95 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3q（91
mg, 70%）.The characterize data of the compound is as follows：1H NMR (600 MHz, CDCl3) δ 1.06 (d, J = 6.0 Hz,
3H), 1.27 (t, J = 7.2 Hz, 3H), 1.61-1.66 (m, 2H), 2.17-2.25 (m, 1H), 2.42-
2.45 (m, 1H), 3.28 (s, 1H), 4.13-4.18 (m, 2H), 4.32-4.38 (m, 2H), 7.21-7.36
(m, 5H), 7.50 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 14.7, 16.5, 17.3, 27.1,
48.9, 57.4, 59.0, 94.1, 127.3, 127.7, 128.7, 137.6, 145.5, 168.8. HRMS calcd
for C16H22NO2: 260.1645 [M+H]+, found: 260.1652。
Embodiment 33
Method as described in embodiment 1, adds 1r (0.5 mmol, 95 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3r（95
mg, 73%）.The characterize data of the compound is as follows：1H NMR (600 MHz, CDCl3) δ 1.04 (d, J = 6.6 Hz,
3H), 1.27 (t, J = 7.2 Hz, 3H), 1.56-1.59 (m, 1H), 1.70-1.75 (m, 1H), 2.76-
2.78 (m, 1H), 2.91-2.93 (m, 1H), 3.03-3.07 (m, 1H), 4.12-4.19 (m, 2H) 4.29-
4.35 (m, 2H), 7.21 (d, J = 7.8 Hz, 2H), 7.28-7.36 (m, 3H), 7.53 (s, 1H). 13C
NMR (150 MHz, CDCl3) δ 14.7, 22.0, 24.1, 27.9, 41.1, 58.8, 59.8, 100.4,
127.3, 127.7, 128.8, 137.2, 145.6, 168.6. HRMS calcd for C16H22NO2: 260.1645 [M
+H]+, found: 260.1652。
Embodiment 34
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2b（5 mmol, 202 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3s（83
mg, 72%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.79-1.82 (m, 2H),
2.30 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 5.6 Hz, 2H), 3.70 (s, 3H), 4.30 (s,
2H), 7.22-7.37 (m, 5H), 7.56 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 20.0, 21.3,
45.4, 50.6, 59.8, 94.5, 127.4, 127.8, 128.8, 137.0, 146.3, 169.2. HRMS calcd
for C14H18NO2: 232.1332 [M+H]+, found: 232.1332。
Embodiment 35
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2c（5 mmol, 382 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3t（78
mg, 60%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.2 Hz,
3H) 1.65-1.71 (m, 2H), 1.81 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 6.0 Hz, 2H),
3.00 (t, J = 5.6 Hz, 2H), 4.07 (t, J = 6.4 Hz, 2H), 4.31 (s, 2H), 7.22-7.38
(m, 5H), 7.56 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 10.6, 20.0, 21.3, 22.4,
45.4, 59.8, 64.7, 94.8, 127.4, 127.7, 128.8, 137.1, 146.1, 169.0. HRMS calcd
for C16H22NO2Na: 282.1465 [M+Na]+, found: 282.1462。
Embodiment 36
Method as described in embodiment 1, adds 1a (0.5 mmol, 88 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2d（5 mmol, 519 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3u（83
mg, 54%）.The characterize data of the compound is as follows：1H NMR (600 MHz, CDCl3) δ 1.80 (t, J = 6.0 Hz,
2H), 2.33 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H), 4.28 (s, 2H), 5.16
(s, 2H), 7.20-7.39 (m, 5H), 7.59 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 20.0,
21.2, 30.9, 45.5, 59.8, 64.8, 94.4, 127.4, 127.6, 127.8, 127.9, 128.4, 128.8,
136.9, 137.7, 146.6, 168.4. HRMS calcd for C20H21NO2Na: 330.1465 [M+Na]+,
found: 330.1460。
Embodiment 37
Method as described in embodiment 1, adds 1s (0.5 mmol, 110 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3v（118
mg, 82%）.The characterize data of the compound is as follows：1H NMR (600 MHz, CDCl3) δ 1.02 (d, J = 6.6 Hz,
3H), 1.27 (t, J = 7.2 Hz, 3H), 1.55-1.57 (m, 1H), 1.68-1.73 (m, 1H), 2.74-
2.76 (m, 1H), 2.90-2.92 (m, 1H), 2.99-3.04 (m, 1H), 3.80 (s, 3H), 4.11-4.28
(m, 4H), 6.87 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.53 (s, 1H). 13C
NMR (150 MHz, CDCl3) δ 14.7, 22.0, 24.1, 27.9, 40.9, 55.3, 58.8, 59.3, 100.2,
114.1, 128.7, 129.0, 145.5, 159.2, 168.7. HRMS calcd for C17H23NO3Na: 312.1570
[M+Na]+, found: 312.1564。
Embodiment 38
Method as described in embodiment 1, adds 1t (0.5 mmol, 95 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3w（78
mg, 60%）.The characterize data of the compound is as follows：1H NMR (400 MHz, CDCl3) δ 1.15 (t, J = 7.2 Hz,
3H), 1.84-1.85 (m, 4H), 2.21 (d, J = 3.2 Hz, 3H), 2.59 (t, J = 6.0 Hz, 2H),
3.57 (t, J = 6.0 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 7.05-7.14 (m, 4H), 7.33
(s, 1H). 13C NMR (150 MHz, CDCl3) δ 14.6, 18.2, 25.4, 26.7, 28.9, 54.2, 59.6,
102.4, 126.1, 126.4, 127.0, 131.4, 134.1, 148.5, 149.3, 170.2. HRMS calcd for
C16H22NO2: 260.1645 [M+H]+, found: 260.1642。
Embodiment 39
Method as described in embodiment 1, adds 1u (0.5 mmol, 127 mg) and acetonitrile in the reaction bulb of 25 mL（5
mL）, it is subsequently adding 2a（5 mmol, 292 µL）, palladium bichloride (0.05 mmol, 9 mg), copper acetate (0.1 mmol, 18
) and KI (0.5 mmol, 83 mg) mg.In CO/O2In (1 atm) atmosphere, in 80 DEG C of stirring reactions 12 hours, then
Add 10 mL saturated nacl aqueous solutions that reaction is quenched, be extracted with ethyl acetate（10 mL × 3）, merge organic phase, with anhydrous
Sodium sulphate is dried.Filtering, is spin-dried for, and crosses silica gel post separation（Petrol ether/ethyl acetate=20:1）Obtain yellow liquid product 3x（82
mg, 51%）.The characterize data of the compound is as follows：1H NMR (600 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz,
3H), 1.82-1.89 (m, 4H), 2.62 (t, J = 6.0 Hz, 2H), 3.86 (t, J = 6.0 Hz, 2H),
4.18 (q, J = 7.2 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 9.0 Hz, 2H),
7.62 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 14.5, 24.9, 25.2, 27.4, 50.1, 60.0,
109.7, 115.0, 119.7, 132.2, 145.0, 145.6, 169.5. HRMS calcd for C15H19BrNO2:
324.0594 [M+H]+, found: 324.0596。
Embodiment above describes general principle of the invention, principal character and advantage.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, simply original of the invention is illustrated described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements each fall within
In the scope of protection of the invention.
Claims (4)
1. a kind of synthetic method of ring-type enamine -3- formic ether compounds, it is characterised in that：By azacycloalkyl hydro carbons compound
1 and alcohol compound 2 be dissolved in solvent, catalyst, oxidant and additive are subsequently adding, in CO atmosphere or CO and O2Mixing
In atmosphere, ring-type enamine -3- formic ether compounds 3, the reaction equation in the synthetic method are obtained in 60-100 DEG C of reaction
For：
Wherein R1It is benzyl, substituted benzyl, phenethyl, C1-10Straight or branched alkyl, cyclopenta, phenyl or substituted-phenyl, this takes
It is cyano group, fluorine, chlorine, bromine, methyl or methoxy for the substitution base on benzyl phenyl ring, the substitution base on substituted-phenyl phenyl ring is one
Or multiple fluorine, chlorine, bromine, methyl or methoxy, R2It is hydrogen or methyl, R3It is benzyl or C1-5Straight or branched alkyl, n is 1 or 2,
Catalyst is palladium, palladium bichloride or three (dibenzalacetone) two palladium, and oxidant is copper acetate, bromination ketone or copper chloride, is added
Plus agent is KI, KBr, potassium chloride or elemental iodine, solvent is toluene, dichloroethanes, Isosorbide-5-Nitrae-dioxane or acetonitrile.
2. the synthetic method of ring-type enamine -3- formic ether compounds according to claim 1, it is characterised in that：It is described
The ratio between the amount of the material that feeds intake of azacycloalkyl hydro carbons compound 1, alcohol compound 2, catalyst, oxidant and additive be 1:
5-10:0.05-0.1:0.2-1:1。
3. a kind of synthetic method of ring-type enamine -3- formic ether compounds, it is characterised in that：By azacycloalkyl hydro carbons compound
1 and alcohol compound 2 be dissolved in solvent, catalyst and oxidant are subsequently adding, in CO atmosphere or CO and O2Mixed atmosphere in,
Ring-type enamine -3- formic ether compounds 3 are obtained in 60-100 DEG C of reaction, the reaction equation in the synthetic method is：
Wherein R1It is benzyl, substituted benzyl, phenethyl, C1-10Straight or branched alkyl, cyclopenta, phenyl or substituted-phenyl, this takes
It is cyano group, fluorine, chlorine, bromine, methyl or methoxy for the substitution base on benzyl phenyl ring, the substitution base on substituted-phenyl phenyl ring is one
Or multiple fluorine, chlorine, bromine, methyl or methoxy, R2It is hydrogen or methyl, R3It is benzyl or C1-5Straight or branched alkyl, n is 1 or 2,
Catalyst be palladium, palladium bichloride or three (dibenzalacetone) two palladium, oxidant be copper acetate, bromination ketone or copper chloride, it is molten
Agent is toluene, dichloroethanes, 1,4- dioxane or acetonitrile.
4. the synthetic method of ring-type enamine -3- formic ether compounds according to claim 3, it is characterised in that：It is described
Azacycloalkyl hydro carbons compound 1, alcohol compound 2, catalyst and the ratio between the amount of the material that feeds intake of oxidant be 1:5-10:
0.05-0.1:0.2-1。
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| CN107474008A (en) * | 2017-09-29 | 2017-12-15 | 河南师范大学 | A kind of synthetic method of α formoxyls tetrahydropyridines |
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| CN109180406A (en) * | 2018-09-10 | 2019-01-11 | 河南师范大学 | The synthetic method of (4R*, 5R*) -5- benzyl -4- hydroxyl -2- cyclopentene-1-one class compound |
| CN109761845A (en) * | 2019-02-21 | 2019-05-17 | 河南师范大学 | A kind of synthetic method of N- nitroso -4-Aminobutanoicacid ester type compound |
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| CN107474008A (en) * | 2017-09-29 | 2017-12-15 | 河南师范大学 | A kind of synthetic method of α formoxyls tetrahydropyridines |
| CN107474001A (en) * | 2017-09-29 | 2017-12-15 | 河南师范大学 | A kind of synthetic method of α diethyls acyloxymethyl substituted nitrogen heterocycle compounds |
| CN107474001B (en) * | 2017-09-29 | 2020-01-31 | 河南师范大学 | synthetic method of α -diacetoxymethyl substituted nitrogen heterocyclic compounds |
| CN109180406A (en) * | 2018-09-10 | 2019-01-11 | 河南师范大学 | The synthetic method of (4R*, 5R*) -5- benzyl -4- hydroxyl -2- cyclopentene-1-one class compound |
| CN109180406B (en) * | 2018-09-10 | 2021-03-16 | 河南师范大学 | Synthesis method of (4R, 5R) -5-benzyl-4-hydroxy-2-cyclopentene-1-ketone compound |
| CN109761845A (en) * | 2019-02-21 | 2019-05-17 | 河南师范大学 | A kind of synthetic method of N- nitroso -4-Aminobutanoicacid ester type compound |
| CN109761845B (en) * | 2019-02-21 | 2021-08-20 | 河南师范大学 | Synthesis method of N-nitroso-4-aminobutyric acid ester compound |
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